Evaluation of Anti-nociceptive and Anti-inflammatory Activities of the Crude Root Extract and Solvent Fractions of Cucumis ficifolius

Evaluation of Anti-nociceptive and Anti-inflammatory Activities of the Crude Root Extract and Solvent Fractions of Cucumis ficifolius (Cucurbitaceace) A. Rich in Mice Model
By:
Desalegn Getnet (B. Pharm)
A Thesis Submitted to the Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, Mekelle University in Partial Fulfillment of the Requirements for the Degree of Master of Science in Pharmacology
Advisor:Dr. Derbew Fikadu (PhD)
Co-advisors:Ebrahim Mohammed (MSc)
Birhanetensay Masresha (MSc, Asst. prof)
Abera Hadgu (MSc)

Mekelle, Ethiopia
June, 2018
Evaluation of Anti-nociceptive and Anti-inflammatory Activities of the Crude Root Extract and Solvent Fractions of Cucumis ficifolius A. Rich in Mice
By:
Desalegn Getnet (B. Pharm)
A Thesis Submitted to the Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, Mekelle University in Partial Fulfillment of the Requirements for the Degree of Master of Science in Pharmacology
Mekelle, Ethiopia
June, 2018
Supervisors
Dr. Derbew Fikadu (PhD)
Department of Pharmacology and Toxicology
College of Health Sciences
Mekelle University
Ebrahim Mohammed (MSc)
Department of Pharmacology and Toxicology
College of Health Sciences
Mekelle University
Birhanetensay Masresha (MSc, Ass’t prof.)
College of Health Sciences
Debrebrhan University
Abera Hadgu (MSc)
Department of Pharmacology and Toxicology
College of Health Sciences
Mekelle University
Mekelle University
This is to certify that the thesis prepared by Desalegn Getnet, titled “Evaluation of Anti-nociceptive and Anti-inflammatory Activities of Crude Methanolic Extract and Solvent Fractions of Cucumis Ficifolius (Cucurbitaceae) in Mice Model” submitted in partial fulfillment for the requirement of Master of Science in Pharmacology complies with the regulations of the university and meets the accepted standards with respect to originality and quality.

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Signed by the Examining committee
SignatureDate
Internal Examiner:_____________ ____________
External Examiner:_____________ ____________
Advisor: Derbew Fikadu (PhD) Signature _______________ ____________
Advisor: Ebrahim Mohammed (MSc)____________ ______________
Advisor: Birhanetensay Masresha (MSc, Ass’t prof.) ____________ ________
Advisor: Abera Hadgu (MSc) _________________ ______________________
AbstractBackground: The plant Cucumis ficifolius (C. ficifolius) has been used in the Ethiopian folklore medicine to treat inflammation and pain.
Objective: To evaluate the anti-nociceptive and anti-inflammatory activities of the crude root extract and solvent fractions of Cucumis ficifolius.
Methods: The analgesic activity of crude extract and solvent fractions of C. ficifolius was evaluated using acetic acid induced writhing test, hot plate and formalin induced paw licking tests. The anti-inflammatory activity of the crude methanolic root extract and solvent fractions of C. ficifolius was evaluated using carrageenan-induced paw edema. The negative control groups were treated with distilled water (10 ml/kg). Aspirin 150 mg/kg (in acetic acid test) and 200 mg/kg in formalin test, was used as a reference drug while morphine (20 mg/kg) was used in hot plate test. The crude extract was administered at 200mg/kg, 400mg/kg and 800mg/kg dose levels. The aqueous and butanol fractions were given at 100 and 200 mg/kg dose levels. All treatments were administered orally.

Result: In acetic acid test 200mg/kg, 400mg/kg and, 800mg/kg doses produced 24.5% (p<0.05), 48.7% (p<0.001), and 72.5% (p<0.001) of analgesic activity, respectively. In hot plate test, maximum dose (800mg/kg) showed maximal protection at 90 minute (82%, p<0.001). With regard to the formalin test, maximum reduction in lick time was observed at the dose of 800mg/kg with 64% (early phase) and 83% (late phase). Butanol fraction (200mg/kg) showed significantly higher activity as compared to the corresponding dose of aqueous fraction in all models, 68% in acetic acid; 89% in hot plate test at 60 minutes and 62% (early phase) and 69% (late phase) in formalin test. Inflammation was decreased by 69 % with butanol (200 mg/kg); 71 % (800 mg/kg of crude extract) and by 41 and 56 % with the use of aqueous fraction at 100 and 200 mg/kg, respectively (p<0.001).
Conclusion: The present study indicated that C. ficifolius crude methanolic extract and solvent fractions possess significant anti-inflammatory and analgesic actions, which support the traditionally claimed uses. However, further work is needed to identify the bioactive compounds responsible for the plant’s anti-inflammatory and analgesic activities as well as to come up with the possible mechanism of action of the isolated compound.
Keywords: Cucumis ficifolius, crude extract, anti-nociceptive, anti-inflammatory, solvent fractions
AcknowledgementsMy first gratitude goes to my advisor Dr. Derbew Fikadu (PhD) and co-advisors: Mr. Birhanetensay Masresha (MSc, Ass’t prof.); Mr. Abera Hadgu (MSc) and Mr. Ebrahim Mohammed (MSc for their invaluable advice and encouragement.

All staffs under department of Pharmacology and Toxicology, it is my pleasure admiring your enthusiastic contribution for the betterment of my work.

Special thanks to Mr. Kald Beshir (MSc) for his kind provision of carrageenan. I sincerely thank my friend Mr. Yohans Kelifa (MSc) for his intimate experience sharing and motivation.
I would also like to extend my gratitude for Messele Gebresilassie (Technical assistant) and Abadi Aynalem (B. Pharm) for their technical assistance in the lab.
My classmates, you were my impetus to look forward to the final end point of my work.

Last but not least I am grateful for Adigrat University and Mekelle University for the financial support to this project.
Table of Contents
TOC o “1-3” h z u Abstract PAGEREF _Toc515202365 h IAcknowledgements PAGEREF _Toc515202366 h IIList of Figures PAGEREF _Toc515202367 h VList of Tables PAGEREF _Toc515202368 h VIAbbreviations and Acronyms PAGEREF _Toc515202369 h VII1. Introduction PAGEREF _Toc515202370 h 81.1 Inflammation PAGEREF _Toc515202371 h 81.2 Pain PAGEREF _Toc515202372 h 101.3 Management of Pain and Inflammation PAGEREF _Toc515202373 h 131.4 Traditional Medicine PAGEREF _Toc515202374 h 141.5 Cucumis ficifolius PAGEREF _Toc515202375 h 151.6 Rational of the Study PAGEREF _Toc515202376 h 172. Objectives PAGEREF _Toc515202377 h 192.1. General Objective PAGEREF _Toc515202378 h 192.2. Specific Objectives PAGEREF _Toc515202379 h 193. Materials and Methods PAGEREF _Toc515202380 h 203.1. Materials PAGEREF _Toc515202381 h 203.1.1 Chemicals and Drugs PAGEREF _Toc515202382 h 203.1.2. Collection, Identification and Preparation of Plant Materials PAGEREF _Toc515202383 h 203.1.3. Experimental Animals PAGEREF _Toc515202384 h 203.2. Methods PAGEREF _Toc515202385 h 213.2.1. Extraction of Plant Material PAGEREF _Toc515202386 h 213.2.2. Solvent-Solvent Extraction PAGEREF _Toc515202387 h 213.2.3 Acute Oral Toxicity Test PAGEREF _Toc515202388 h 223.2.4 Anti-nociceptive Activity Test PAGEREF _Toc515202389 h 22i. Acetic Acid Induced Writhing Test PAGEREF _Toc515202390 h 22ii. Hot Plate Test PAGEREF _Toc515202391 h 23iii. Formalin Test PAGEREF _Toc515202392 h 243.2.5 Evaluation of Anti-inflammatory Activity PAGEREF _Toc515202393 h 253.2.6 Statistical Analysis PAGEREF _Toc515202394 h 264. Results PAGEREF _Toc515202395 h 274.1 Percent Yield PAGEREF _Toc515202396 h 274.2 Oral Acute Toxicity Test PAGEREF _Toc515202397 h 274.3. Analgesic and Anti-inflammatory Assays PAGEREF _Toc515202398 h 274.3.1 Analgesic Activity PAGEREF _Toc515202399 h 27i. Writhing Test PAGEREF _Toc515202400 h 27ii. Hot Plate PAGEREF _Toc515202401 h 29iii. Formalin Test PAGEREF _Toc515202402 h 314.3.2 Anti-inflammatory Activity Test PAGEREF _Toc515202403 h 335. Discussion PAGEREF _Toc515202404 h 356. Conclusion and Recommendation PAGEREF _Toc515202405 h 39References PAGEREF _Toc515202406 h 40
List of Figures TOC h z c “Figure” Figure 1: Tumor necrosis factor (TNF) dependent cytokine cascade PAGEREF _Toc515200846 h 9Figure 2:The molecular complexity of the primary afferent nociceptors in response to inflammatory mediators released at the site of tissue injury. PAGEREF _Toc515200847 h 12Figure 3:Photograph of Cucumis ficifolius A. Rich. PAGEREF _Toc515200848 h 16Figure 4: The extraction process of Cucumis ficifolius roots using 80% methanol. PAGEREF _Toc515200849 h 21Figure 5: Anti-nociceptive effect of the crude methanolic extract of Cucumis ficifolius on acetic acid induced writhing test. PAGEREF _Toc515200850 h 28Figure 6: Anti-nociceptive effect of oral aqueous and butanol fractions of Cucumis ficifolius on acetic acid writhing test. PAGEREF _Toc515200851 h 29Figure 7: Anti-nociceptive activity of aqueous and butanol fractions of Cucumis ficifolius on early phase of formalin induced lick test. PAGEREF _Toc515200852 h 33Figure 8: Anti-nociceptive activity of aqueous and butanol fractions of Cucumis ficifolius on late phase of formalin induced lick test. PAGEREF _Toc515200853 h 33
List of Tables TOC h z c “Table” Table 1: Grouping and dosing of mice used on formalin test PAGEREF _Toc515200912 h 25Table 2: Grouping and dosing of mice used anti-inflammatory activities of crude extract and solvent fractions of Cucumis ficifolius. PAGEREF _Toc515200913 h 26Table 3: Percentage yield of crude extract and different solvent fractions of Cucumis ficifolius PAGEREF _Toc515200914 h 27Table 4: Effect of oral Cucumis ficifolius methanolic crude root extract in hot plate test PAGEREF _Toc515200915 h 30Table 5: Anti-nociceptive effect of aqueous and butanol fractions of Cucumis ficifolius on hot plate test. PAGEREF _Toc515200916 h 30Table 6: Anti-nociceptive activity of 80% methanolic crude root extract of Cucumis ficifolius in formalin induced lick test. PAGEREF _Toc515200917 h 32Table 7: Anti-inflammatory activity of 80% methanolic extract and solvent fractions of Cucumis ficifolius on carrageenan induced paw edema. PAGEREF _Toc515200918 h 34
Abbreviations and Acronyms5-HT5-Hydroxy Tryptamine
ABPAcute Back Pain
BKBradykinin
CBPChronic Back Pain
CGRPCalcitonin Gene Related Peptide
CNSCentral Nervous System
COXCyclooxygenase
COX-1Cyclooxygenase-1
COX-2Cyclooxygenase-2
CPChronic Pain
DWDistilled Water
IASPInternational Association for the Study of Pain
IL-1Interlikeun-1
IL-6Interlikeun-6
IL-8Interlikeun-8
LTsLeukotrienes
NSNormal Saline
NSAIDsNon-Steroidal Anti-inflammatory Drugs
PAFPlatelet Activated Factor
PGsProstaglandins
TCMTraditional and Complementary Medicine
TNF?Tumor Necrosis Factor alpha
WHOWorld Health Organization
1. Introduction
1.1 InflammationInflammation is the immune system response to infection and injury and has been implicated in the pathogeneses of rheumatoid arthritis (RA), stroke, as well as in neurodegenerative and cardiovascular diseases. Tissue injury is usually caused by physical trauma, noxious chemicals, microbial agents, autoimmunity and recruitment of phagocytes, complement system and secretion of cytokines like IL-1?, IL-6 and TNF-? by activated cells, which are essential for the host defense system ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/j.jep.2010.08.043”, “ISBN” : “1872-7573 (Electronic)\r0378-8741 (Linking)”, “ISSN” : “03788741”, “PMID” : “20800670”, “abstract” : “Aim of study: The aim of this study was to establish the anti-inflammatory activity of the methanolic extract of Dregea volubilis leaves (MEDV) with its fractions and to delineate the possible mechanism of action for MEDV. Materials and methods: The anti-inflammatory activities of MEDV along with its petroleum ether and chloroform fractions were evaluated in a carrageenan induced model of acute inflammation. The effect of MEDV on lipopolysaccharide induced production of nitric oxide (NO) in macrophages was also studied. Results: MEDV (100, 200 and 400 mg/kg body weight) significantly reduced carrageenan induced paw edema; chloroform fraction was most potent (66%, p< 0.001). MEDV was non-toxic up to 125 u03bcg/ml in mouse peritoneal macrophages wherein it (0-100 u03bcg/ml) reduced lipopolysaccharide induced NO production. Conclusion: MEDV possesses significant anti-inflammatory activity. Chloroform fraction of MEDV showed best anti-inflammatory activity. u00a9 2010 Elsevier Ireland Ltd.”, “author” : { “dropping-particle” : “”, “family” : “Hossain”, “given” : “Emdad”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Sarkar”, “given” : “Debjani”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Maiti”, “given” : “Anup”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Chatterjee Mitali”, “given” : “M.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Mandal”, “given” : “Subhash C.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Gupta”, “given” : “Jayanta Kumar”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Ethnopharmacology”, “id” : “ITEM-1”, “issue” : “2”, “issued” : { “date-parts” : “2010” }, “page” : “525-528”, “publisher” : “Elsevier Ireland Ltd”, “title” : “Anti-inflammatory effect of a methanolic extract of leaves of Dregea volubilis”, “type” : “article-journal”, “volume” : “132” }, “uris” : “http://www.mendeley.com/documents/?uuid=d1b310af-2024-4b1b-8acd-88701fd8ca88” }, { “id” : “ITEM-2”, “itemData” : { “DOI” : “10.1016/j.fct.2013.06.038”, “ISBN” : “0278-6915”, “ISSN” : “02786915”, “PMID” : “23831308”, “abstract” : “Leea macrophylla (Leeaceae) is a wild edible plant with ethomedicinal importance as anti-inflammatory agent. However, no systematic studies on its anti-inflammatory activity and mechanisms have been reported. Present study was undertaken to evaluate anti-inflammatory activity of methanol extract of L. macrophylla leaves. Phytochemical investigation revealed presence of sterols, triterpenoids and ascorbic acid in extract. Methanol extract inhibited lipopolysaccharide stimulated production of inflammatory mediators viz. prostaglandin E2, tumor necrotic factor-u03b1, interleukin-6 and interleukin-1u03b2 in vitro in mouse peritoneal macrophages. Additionally, the in vivo anti-inflammatory activity of this extract was evaluated by using carrageenan induced paw edema and cotton pellet granuloma assays in experimental rats. Oral administration of extract (100 and 200. mg/kg) exhibited dose dependant inhibition of carrageenan induced inflammation (p<. 0.05) and the reduction of the granuloma tissue formation (p<. 0.05-0.01). The extract (100 and 200. mg/kg, orally) exhibited significant central and peripheral analgesic activity in hot-plate test (p<. 0.01) and acetic acid induced writhing test (p<. 0.05-0.01) respectively in experimental mice. Treatment with extract (100 and 200. mg/kg, orally) significantly reduced the yeast provoked elevated body temperature (p<. 0.05-0.01) in experimental rats. These results confirmed the traditional anti-inflammatory indication of L. macrophylla leaves. u00a9 2013 Elsevier Ltd.”, “author” : { “dropping-particle” : “”, “family” : “Dewanjee”, “given” : “Saikat”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Dua”, “given” : “Tarun K.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Sahu”, “given” : “Ranabir”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Food and Chemical Toxicology”, “id” : “ITEM-2”, “issued” : { “date-parts” : “2013” }, “page” : “514-520”, “publisher” : “Elsevier Ltd”, “title” : “Potential anti-inflammatory effect of Leea macrophylla Roxb. leaves: A wild edible plant”, “type” : “article-journal”, “volume” : “59” }, “uris” : “http://www.mendeley.com/documents/?uuid=f446f97e-fa00-43a8-8f4f-cd65f59b42d2” } , “mendeley” : { “formattedCitation” : “(Hossain et al., 2010; Dewanjee et al., 2013)”, “plainTextFormattedCitation” : “(Hossain et al., 2010; Dewanjee et al., 2013)”, “previouslyFormattedCitation” : “(Hossain et al., 2010; Dewanjee et al., 2013)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Hossain et al., 2010; Dewanjee et al., 2013). Hence, inflammation provides an intrinsically beneficial role in the removal of offending factors and restoration of tissue structure and physiological function ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1161/ATVBAHA.110.207449.Prostaglandins”, “author” : { “dropping-particle” : “”, “family” : “Emanuela Ricciotti”, “given” : “PhD”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Garret A. FitzGerald”, “given” : “MD.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Arteriosclerosis, Thrombosis, and Vascular Biology”, “id” : “ITEM-1”, “issue” : “5”, “issued” : { “date-parts” : “2011” }, “page” : “986-1000”, “title” : “NIH Public Access”, “type” : “article-journal”, “volume” : “31” }, “uris” : “http://www.mendeley.com/documents/?uuid=badc6a58-1da8-4459-ab41-bf448d52370e” } , “mendeley” : { “formattedCitation” : “(Emanuela Ricciotti and Garret A. FitzGerald, 2011)”, “plainTextFormattedCitation” : “(Emanuela Ricciotti and Garret A. FitzGerald, 2011)”, “previouslyFormattedCitation” : “(Emanuela Ricciotti and Garret A. FitzGerald, 2011)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Ricciotti and FitzGerald, 2011).
Inflammatory response could be immunological or non-immunological. Immunological response occurs when immunologically competent cells are activated in response to foreign organisms or antigenic substances liberated during the acute or chronic inflammatory response. Non- immunological response is triggered by inflammatory reactions capable of activating both humoral and cellular systems, normally present in the body in an inactive state and regulated by systemic inhibitors. ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “abstract” : “Analysis of cytokine mRNA and protein in rheumatoid arthritis tissue revealed that many proinflammatory cytokines such as TNFu00e0, IL-1, IL-6, GM-CSF, and chemokines such as IL-8 are abundant in all patients regardless of therapy.This is compensated to some degree by the increased production of anti-inflammatory cytokines such as IL-10 and TFGu00e1 and cytokine inhibitors such as IL-1ra and soluble TNF-R. However, this upregulation in homeostatic regulatory mechanisms is not sufficient as these are unable to neutralize all the TNFu00e0 and IL-1 produced. In rheumatoid joint cell cultures that spontaneously produce IL-1, TNFu00e0 was the major dominant regulator of IL-1. Subsequently, other proinflammatory cytokines were also inhibited if TNFu00e0 was neutralized, leading to the new concept that the proinflammatory cytokines were linked in a network with TNFu00e0 at its apex. This led to the hypothesis that TNFu00e0 was of major importance in rheumatoid arthritis and was a therapeutic target. This hypothesis has been successfully tested in animal models, of, for example, collagen-induced arthritis, and these studies have provided the rationale for clinical trials of anti-TNFu00e0 therapy in patients with long-standing rheumatoid arthritis. Several clinical trials using a chimeric anti-TNFu00e0 antibody have shown marked clinical benefit, verifying the hypothesis that TNFu00e0 is of major importance in rheumatoid arthritis. Retreatment studies have also shown benefit in repeated relapses, indicating that the disease remains TNFa dependent. Overall these studies demonstrate that analysis of cytokine expression and regulation may yield effective therapeutic targets in inflammatory disease.”, “author” : { “dropping-particle” : “”, “family” : “Feldman”, “given” : “M”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Brennan”, “given” : “F M”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Maini”, “given” : “R N”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issued” : { “date-parts” : “1996” }, “page” : “397-440”, “title” : “Role of cytokines in Rheumatoid Arthritis”, “type” : “article-journal”, “volume” : “14” }, “uris” : “http://www.mendeley.com/documents/?uuid=4d2c915d-b4f5-4f07-ac9a-9fcf3379183b” } , “mendeley” : { “formattedCitation” : “(Feldman et al., 1996)”, “manualFormatting” : “(Camussi et al., 1981)”, “plainTextFormattedCitation” : “(Feldman et al., 1996)”, “previouslyFormattedCitation” : “(Feldman et al., 1996)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Camussi et al., 1981).
When the outer barriers of the skin and other epithelial layers are damaged, the resulting innate responses to infection or tissue injury can induce a complex cascade of events known as the inflammatory response ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “ISBN” : “9781429219198”, “author” : { “dropping-particle” : “”, “family” : “Owen”, “given” : “”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issued” : { “date-parts” : “2007” }, “title” : “Kuby Immunology”, “type” : “article” }, “uris” : “http://www.mendeley.com/documents/?uuid=c4b60fe1-28ca-42e3-a519-d30b7178c0f2” } , “mendeley” : { “formattedCitation” : “(Owen, 2007)”, “plainTextFormattedCitation” : “(Owen, 2007)”, “previouslyFormattedCitation” : “(Owen, 2007)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Owen et al., 2007). Following an injury or sensitization by antigen antibody interactions, inflammatory mediators such as histamine, bradykinin (BK), tryptase, prostaglandins (PGs), leukotrienes (LTs), and platelet activating factor (PAF) produced and released from tissues and mast cells. Analysis of cytokine mRNA and protein in rheumatoid arthritis tissue revealed many pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF?), interleukin-1 (IL-1), IL-6, and chemokines such as IL-8 are abundant in all patients regardless of therapy ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “doi:10.1146/annurev.immunol.14.1.397”, “ISSN” : “0732-0582”, “PMID” : “8717520”, “author” : { “dropping-particle” : “”, “family” : “Feldmann”, “given” : “Marc”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Brennan”, “given” : “Fionula M”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Maini”, “given” : “Ravinder N”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issued” : { “date-parts” : “2008” }, “page” : “397-440”, “title” : “Role of Cytokines in Rheumatoid Arthritis”, “type” : “article-journal” }, “uris” : “http://www.mendeley.com/documents/?uuid=072f29a2-2542-491e-96c8-8163fcf9ac3e” } , “mendeley” : { “formattedCitation” : “(Feldmann et al., 2008)”, “plainTextFormattedCitation” : “(Feldmann et al., 2008)”, “previouslyFormattedCitation” : “(Feldmann et al., 2008)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Feldmann et al., 2008). Although unchecked inflammatory response leads to painful disorders, the role of biological cytokines should not be under estimated. Potential therapeutic role of TNF? was ascertained in the results obtained from human rheumatoid synovial cultures (Fig.1).

Figure SEQ Figure * ARABIC 1: Tumor necrosis factor (TNF) dependent cytokine cascade ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “abstract” : “Analysis of cytokine mRNA and protein in rheumatoid arthritis tissue revealed that many proinflammatory cytokines such as TNFu00e0, IL-1, IL-6, GM-CSF, and chemokines such as IL-8 are abundant in all patients regardless of therapy.This is compensated to some degree by the increased production of anti-inflammatory cytokines such as IL-10 and TFGu00e1 and cytokine inhibitors such as IL-1ra and soluble TNF-R. However, this upregulation in homeostatic regulatory mechanisms is not sufficient as these are unable to neutralize all the TNFu00e0 and IL-1 produced. In rheumatoid joint cell cultures that spontaneously produce IL-1, TNFu00e0 was the major dominant regulator of IL-1. Subsequently, other proinflammatory cytokines were also inhibited if TNFu00e0 was neutralized, leading to the new concept that the proinflammatory cytokines were linked in a network with TNFu00e0 at its apex. This led to the hypothesis that TNFu00e0 was of major importance in rheumatoid arthritis and was a therapeutic target. This hypothesis has been successfully tested in animal models, of, for example, collagen-induced arthritis, and these studies have provided the rationale for clinical trials of anti-TNFu00e0 therapy in patients with long-standing rheumatoid arthritis. Several clinical trials using a chimeric anti-TNFu00e0 antibody have shown marked clinical benefit, verifying the hypothesis that TNFu00e0 is of major importance in rheumatoid arthritis. Retreatment studies have also shown benefit in repeated relapses, indicating that the disease remains TNFa dependent. Overall these studies demonstrate that analysis of cytokine expression and regulation may yield effective therapeutic targets in inflammatory disease.”, “author” : { “dropping-particle” : “”, “family” : “Feldman”, “given” : “M”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Brennan”, “given” : “F M”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Maini”, “given” : “R N”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issued” : { “date-parts” : “1996” }, “page” : “397-440”, “title” : “Role of cytokines in Rheumatoid Arthritis”, “type” : “article-journal”, “volume” : “14” }, “uris” : “http://www.mendeley.com/documents/?uuid=4d2c915d-b4f5-4f07-ac9a-9fcf3379183b” } , “mendeley” : { “formattedCitation” : “(Feldman et al., 1996)”, “plainTextFormattedCitation” : “(Feldman et al., 1996)”, “previouslyFormattedCitation” : “(Feldman et al., 1996)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Feldman et al., 1996).Synthesis and release of inflammatory mediators and activation of macrophages, mast cells and dendritic following inflammatory response lead to acute or chronic signs of inflammation. The acute phase of inflammation is characterized by the rapid influx of blood granulocytes, typically neutrophils, followed swiftly by monocytes that mature into inflammatory macrophages that subsequently proliferate and thereby affect the functions of resident tissue macrophages. This process causes the cardinal signs of acute inflammation: redness), heat, swelling) and pain ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1161/ATVBAHA.110.207449.Prostaglandins”, “author” : { “dropping-particle” : “”, “family” : “Emanuela Ricciotti”, “given” : “PhD”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Garret A. FitzGerald”, “given” : “MD.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Arteriosclerosis, Thrombosis, and Vascular Biology”, “id” : “ITEM-1”, “issue” : “5”, “issued” : { “date-parts” : “2011” }, “page” : “986-1000”, “title” : “NIH Public Access”, “type” : “article-journal”, “volume” : “31” }, “uris” : “http://www.mendeley.com/documents/?uuid=badc6a58-1da8-4459-ab41-bf448d52370e” } , “mendeley” : { “formattedCitation” : “(Emanuela Ricciotti and Garret A. FitzGerald, 2011)”, “plainTextFormattedCitation” : “(Emanuela Ricciotti and Garret A. FitzGerald, 2011)”, “previouslyFormattedCitation” : “(Emanuela Ricciotti and Garret A. FitzGerald, 2011)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Ricciotti and FitzGerald, 2011). In the vascular system, acute inflammatory response causes vasodilation and consequent increased vascular flow; increased vascular permeability and leucocytes migration. Histamine and 5-hydroxy tryptamine are usually responsible for eliciting the immediate response of inflammation whereas kinins and prostaglandins mediate the more prolonged delayed onset responses ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “P Shikha, PG Latha, S R Suja, G I Anuja, S Shyamal, VJ Shine, S Sini”, “given” : “N M Krishnakumar and S Rajasekharan”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Indian Journal of Natural Products and Resources”, “id” : “ITEM-1”, “issue” : “3”, “issued” : { “date-parts” : “2010” }, “page” : “356-361”, “title” : “Anti-inflammatory and analgesic activity of Barringtonia racemosa Roxb . Fruits”, “type” : “article-journal”, “volume” : “1” }, “uris” : “http://www.mendeley.com/documents/?uuid=52c29a67-8668-43e6-bcc3-6a0cd85fcea1” } , “mendeley” : { “formattedCitation” : “(P Shikha, PG Latha, S R Suja, G I Anuja, S Shyamal, VJ Shine, S Sini, 2010)”, “manualFormatting” : “(Shikha et al., 2010)”, “plainTextFormattedCitation” : “(P Shikha, PG Latha, S R Suja, G I Anuja, S Shyamal, VJ Shine, S Sini, 2010)”, “previouslyFormattedCitation” : “(P Shikha, PG Latha, S R Suja, G I Anuja, S Shyamal, VJ Shine, S Sini, 2010)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Shikha et al., 2010).

Through the action of regulatory cytokines such as IL-10, the initiating noxious stimulus is removed via phagocytosis after which the inflammatory reaction is decreased and resolved ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/j.imbio.2012.04.005”, “ISSN” : “01712985”, “abstract” : “Analysis of the mechanisms underlying the inflammatory response in amoebiasis is important to understand the immunopathology of the disease. Mucosal associated effector and regulatory T cells may play a role in regulating the inflammatory immune response associated to Entamoeba histolytica infection in the colon. A subpopulation of regulatory T cells has recently been identified and is characterized by the expression of the chemokine receptor CCR9. In this report, we used CCR9 deficient (CCR9-/-) mice to investigate the role of the CCR9+T cells in a murine model of E. histolytica intestinal infection. Intracecal infection of CCR9+/+, CCR9+/-and CCR9-/-mice with E. histolytica trophozoites, revealed striking differences in the development and nature of the intestinal inflammatory response observed between these strains. While CCR9+/+and CCR9+/-mice were resistant to the infection and resolved the pathogen-induced inflammatory response, CCR9-/-mice developed a chronic inflammatory response, which was associated with over-expression of the cytokines IFN-u03b3, TNF-u03b1, IL-4, IL-6 and IL-17, while IL-10 was not present. In addition, increased levels of CCL11, CCL20 and CCL28 chemokines were detected by qRT-PCR in CCR9-/-mice. E. histolytica trophozoites were identified in the lumen of the cecum of CCR9-/-mice at seven days post infection (pi), whereas in CCR9+/+mice trophozoites disappeared by day 1 pi. Interestingly, the inflammation observed in CCR9-/-mice, was associated with a delayed recruitment of CD4+CD25+FoxP3+T cells to the cecal epithelium and lamina propria, suggesting that this population may play a role in the early regulation of the inflammatory response against E. histolytica, likely through IL-10 production. In support of these data, CCR9+T cells were also identified in colon tissue sections obtained from patients with amoebic colitis. Our data suggest that a population of CCR9+CD4+CD25+FoxP3+T cells may participate in the control and resolution of the inflammatory immune response to E. histolytica infection. u00a9 2012 Elsevier GmbH.”, “author” : { “dropping-particle” : “”, “family” : “Rojas-Lu00f3pez”, “given” : “A. E.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Soldevila”, “given” : “G.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Meza-Pu00e9rez”, “given” : “S.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “DuPont”, “given” : “G.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Ostoa-Saloma”, “given” : “P.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Wurbel”, “given” : “M. A.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Ventura-Juu00e1rez”, “given” : “J.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Flores-Romo”, “given” : “L.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Garcu00eda-Zepeda”, “given” : “E. A.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Immunobiology”, “id” : “ITEM-1”, “issue” : “8”, “issued” : { “date-parts” : “2012” }, “page” : “795-807”, “publisher” : “Elsevier GmbH.”, “title” : “CCR9+T cells contribute to the resolution of the inflammatory response in a mouse model of intestinal amoebiasis”, “type” : “article-journal”, “volume” : “217” }, “uris” : “http://www.mendeley.com/documents/?uuid=a1dfbc82-0f19-4355-87b2-32fd01494789” }, { “id” : “ITEM-2”, “itemData” : { “DOI” : “10.1016/j.jclinane.2016.08.041”, “ISBN” : “0952-8180”, “ISSN” : “18734529”, “PMID” : “27871587”, “abstract” : “Peripheral nerve blocks (PNBs) are increasingly used as a component of multimodal analgesia and may be administered as a single injection (sPNB) or continuous infusion via a perineural catheter (cPNB). We undertook a qualitative review focusing on sPNB and cPNB with regard to benefits, risks, and opportunities for optimizing patient care. Meta-analyses of randomized controlled trials have shown superior pain control and reductions in opioid consumption in patients receiving PNB compared with those receiving intravenous opioids in a variety of upper and lower extremity surgical procedures. cPNB has also been associated with a reduction in time to discharge readiness compared with sPNB. Risks of PNB, regardless of technique or block location, include vascular puncture and bleeding, nerve damage, and local anesthetic systemic toxicity. Site-specific complications include quadriceps weakness in patients receiving femoral nerve block, and pleural puncture or neuraxial blockade in patients receiving interscalene block. The major limitation of sPNB is the short (12-24 hours) duration of action. cPNB may be complicated by catheter obstruction, migration, and leakage of local anesthetic as well as accidental removal of catheters. Potential infectious complications of catheters, although rare, include local inflammation and infection. Other considerations for ambulatory cPNB include appropriate patient selection, education, and need for 24/7 availability of a health care provider to address any complications. The ideal PNB technique would have a duration of action that is sufficiently long to address the most intense period of postsurgical pain; should be associated with minimal risk of infection, neurologic complications, bleeding, and local anesthetic systemic toxicity; and should be easy to perform, convenient for patients, and easy to manage in the postoperative period.”, “author” : { “dropping-particle” : “”, “family” : “Joshi”, “given” : “Girish”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Gandhi”, “given” : “Kishor”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Shah”, “given” : “Nishant”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Gadsden”, “given” : “Jeff”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Corman”, “given” : “Shelby L.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Clinical Anesthesia”, “id” : “ITEM-2”, “issued” : { “date-parts” : “2016” }, “page” : “524-529”, “publisher” : “The Authors”, “title” : “Peripheral nerve blocks in the management of postoperative pain: challenges and opportunities”, “type” : “article-journal”, “volume” : “35” }, “uris” : “http://www.mendeley.com/documents/?uuid=0e41aac4-8ce3-4a07-9648-595cff344dc9” } , “mendeley” : { “formattedCitation” : “(Rojas-Lu00f3pez et al., 2012; Joshi et al., 2016)”, “plainTextFormattedCitation” : “(Rojas-Lu00f3pez et al., 2012; Joshi et al., 2016)”, “previouslyFormattedCitation” : “(Rojas-Lu00f3pez et al., 2012; Joshi et al., 2016)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Rojas-López et al., 2012; Joshi et al., 2016). Rather than persistence dysfunction which can lead to scarring and loss of organ function, the usual outcome of the acute inflammatory program is successful resolution and repair of tissue damage. It may be anticipated, therefore, that failure of acute inflammation to resolve may predispose to chronic inflammatory disorders such as, rheumatoid arthritis, osteoarthritis, psoriasis, and inflammatory bowel disease ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “doi:10.1146/annurev.immunol.14.1.397”, “ISSN” : “0732-0582”, “PMID” : “8717520”, “author” : { “dropping-particle” : “”, “family” : “Feldmann”, “given” : “Marc”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Brennan”, “given” : “Fionula M”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Maini”, “given” : “Ravinder N”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issued” : { “date-parts” : “2008” }, “page” : “397-440”, “title” : “Role of Cytokines in Rheumatoid Arthritis”, “type” : “article-journal” }, “uris” : “http://www.mendeley.com/documents/?uuid=072f29a2-2542-491e-96c8-8163fcf9ac3e” } , “mendeley” : { “formattedCitation” : “(Feldmann et al., 2008)”, “manualFormatting” : “(Feldmann et al., 1996; Neogi, 2016)”, “plainTextFormattedCitation” : “(Feldmann et al., 2008)”, “previouslyFormattedCitation” : “(Feldmann et al., 2008)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Feldmann et al., 1996; Neogi, 2016).
These inflammatory disorders are identified as a major cause of morbidity worldwide ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/j.fct.2013.06.038”, “ISBN” : “0278-6915”, “ISSN” : “02786915”, “PMID” : “23831308”, “abstract” : “Leea macrophylla (Leeaceae) is a wild edible plant with ethomedicinal importance as anti-inflammatory agent. However, no systematic studies on its anti-inflammatory activity and mechanisms have been reported. Present study was undertaken to evaluate anti-inflammatory activity of methanol extract of L. macrophylla leaves. Phytochemical investigation revealed presence of sterols, triterpenoids and ascorbic acid in extract. Methanol extract inhibited lipopolysaccharide stimulated production of inflammatory mediators viz. prostaglandin E2, tumor necrotic factor-u03b1, interleukin-6 and interleukin-1u03b2 in vitro in mouse peritoneal macrophages. Additionally, the in vivo anti-inflammatory activity of this extract was evaluated by using carrageenan induced paw edema and cotton pellet granuloma assays in experimental rats. Oral administration of extract (100 and 200. mg/kg) exhibited dose dependant inhibition of carrageenan induced inflammation (p<. 0.05) and the reduction of the granuloma tissue formation (p<. 0.05-0.01). The extract (100 and 200. mg/kg, orally) exhibited significant central and peripheral analgesic activity in hot-plate test (p<. 0.01) and acetic acid induced writhing test (p<. 0.05-0.01) respectively in experimental mice. Treatment with extract (100 and 200. mg/kg, orally) significantly reduced the yeast provoked elevated body temperature (p<. 0.05-0.01) in experimental rats. These results confirmed the traditional anti-inflammatory indication of L. macrophylla leaves. u00a9 2013 Elsevier Ltd.”, “author” : { “dropping-particle” : “”, “family” : “Dewanjee”, “given” : “Saikat”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Dua”, “given” : “Tarun K.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Sahu”, “given” : “Ranabir”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Food and Chemical Toxicology”, “id” : “ITEM-1”, “issued” : { “date-parts” : “2013” }, “page” : “514-520”, “publisher” : “Elsevier Ltd”, “title” : “Potential anti-inflammatory effect of Leea macrophylla Roxb. leaves: A wild edible plant”, “type” : “article-journal”, “volume” : “59” }, “uris” : “http://www.mendeley.com/documents/?uuid=f446f97e-fa00-43a8-8f4f-cd65f59b42d2” } , “mendeley” : { “formattedCitation” : “(Dewanjee et al., 2013)”, “plainTextFormattedCitation” : “(Dewanjee et al., 2013)”, “previouslyFormattedCitation” : “(Dewanjee et al., 2013)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Dewanjee et al., 2013). Inflammation is usually managed with non-steroidal anti-inflammatory drugs (NSAIDs). However these agents are usually associated with serious adverse effects and their affordability is a concern ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Croff”, “given” : “Leslie J”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issue” : “Suppl 3”, “issued” : { “date-parts” : “2013” }, “title” : “Use of NSAIDs in treating patients with arthritis”, “type” : “article-journal”, “volume” : “15” }, “uris” : “http://www.mendeley.com/documents/?uuid=820afa7e-331e-42ff-bd5c-e54e11d5dc73” } , “mendeley” : { “formattedCitation” : “(Croff, 2013)”, “plainTextFormattedCitation” : “(Croff, 2013)”, “previouslyFormattedCitation” : “(Croff, 2013)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Croff, 2013). In chronic pain conditions, for example, the utilization of NSAIDs accompanies severe toxicities including gastric and renal adverse effects ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/j.bpg.2009.11.005”, “ISBN” : “1521-6918”, “ISSN” : “15216918”, “PMID” : “20227026”, “abstract” : “Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most widely prescribed medication in the world. Their main benefit derives from their anti-inflammatory and analgesic effect, but the use of these agents is not innocuous since they mainly increase the risk of gastrointestinal (GI) and cardiovascular complications compared with non-NSAID users. NSAIDs injures the upper and lower gut by depleting COX-1 derived prostaglandins and causing topical injury to the mucosa. The risk of upper GI complications varies, depending on the presence of one or more risk factors. Among them, the three main risk factors are prior history of peptic ulcer, the single most important risk factor, age, the most common, and concomitant aspirin use, due to their GI and cardiovascular implications. Those individuals at-risk should be considered for alternatives to NSAID therapy and modifications of risk factors. If NSAID therapy is required, patients at risk will need prevention strategies including co-therapy of NSAID with gastroprotectants (PPI or misoprostol) or the prescription of COX-2 selective inhibitors. The probable introduction of NO-NSAIDs in the market in the near future may open a new therapeutic option for patients with hypertension who need NSAIDs.”, “author” : { “dropping-particle” : “”, “family” : “Sostres”, “given” : “Carlos”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Gargallo”, “given” : “Carla J.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Arroyo”, “given” : “Maria T.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Lanas”, “given” : “Angel”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Best Practice & Research Clinical Gastroenterology”, “id” : “ITEM-1”, “issue” : “2”, “issued” : { “date-parts” : “2010” }, “page” : “121-132”, “publisher” : “Elsevier Ltd”, “title” : “Adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs, aspirin and coxibs) on upper gastrointestinal tract”, “type” : “article-journal”, “volume” : “24” }, “uris” : “http://www.mendeley.com/documents/?uuid=4f100761-5961-445e-802e-10030cc3712b” } , “mendeley” : { “formattedCitation” : “(Sostres et al., 2010)”, “plainTextFormattedCitation” : “(Sostres et al., 2010)”, “previouslyFormattedCitation” : “(Sostres et al., 2010)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Sostres et al., 2010). Thus the current health care system needs inclusion of newer anti-inflammatory drugs with minimal adverse effect, improved efficacy and at affordable cost
Worldwide, many natural products are used as part of the traditional medical system to control symptoms of inflammatory disorders. Therefore, investigation of natural remedies is required to efficiently control the pain and inflammation with least side effects ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Riedel”, “given” : “R”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Marrassini”, “given” : “C”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Anesini”, “given” : “C”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Gorzalczany”, “given” : “S”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issue” : “September 2014”, “issued” : { “date-parts” : “2015” }, “page” : “59-66”, “title” : “Anti-Inflammatory and Antinociceptive Activity of Urera aurantiaca”, “type” : “article-journal”, “volume” : “66” }, “uris” : “http://www.mendeley.com/documents/?uuid=d433fe3a-911a-43c3-bddf-c93a117fc918” } , “mendeley” : { “formattedCitation” : “(Riedel et al., 2015)”, “plainTextFormattedCitation” : “(Riedel et al., 2015)”, “previouslyFormattedCitation” : “(Riedel et al., 2015)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Riedel et al., 2015). One way of drug discovery is screening natural products through different animal models ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/j.jep.2010.08.043”, “ISBN” : “1872-7573 (Electronic)\r0378-8741 (Linking)”, “ISSN” : “03788741”, “PMID” : “20800670”, “abstract” : “Aim of study: The aim of this study was to establish the anti-inflammatory activity of the methanolic extract of Dregea volubilis leaves (MEDV) with its fractions and to delineate the possible mechanism of action for MEDV. Materials and methods: The anti-inflammatory activities of MEDV along with its petroleum ether and chloroform fractions were evaluated in a carrageenan induced model of acute inflammation. The effect of MEDV on lipopolysaccharide induced production of nitric oxide (NO) in macrophages was also studied. Results: MEDV (100, 200 and 400 mg/kg body weight) significantly reduced carrageenan induced paw edema; chloroform fraction was most potent (66%, p< 0.001). MEDV was non-toxic up to 125 u03bcg/ml in mouse peritoneal macrophages wherein it (0-100 u03bcg/ml) reduced lipopolysaccharide induced NO production. Conclusion: MEDV possesses significant anti-inflammatory activity. Chloroform fraction of MEDV showed best anti-inflammatory activity. u00a9 2010 Elsevier Ireland Ltd.”, “author” : { “dropping-particle” : “”, “family” : “Hossain”, “given” : “Emdad”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Sarkar”, “given” : “Debjani”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Maiti”, “given” : “Anup”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Chatterjee Mitali”, “given” : “M.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Mandal”, “given” : “Subhash C.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Gupta”, “given” : “Jayanta Kumar”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Ethnopharmacology”, “id” : “ITEM-1”, “issue” : “2”, “issued” : { “date-parts” : “2010” }, “page” : “525-528”, “publisher” : “Elsevier Ireland Ltd”, “title” : “Anti-inflammatory effect of a methanolic extract of leaves of Dregea volubilis”, “type” : “article-journal”, “volume” : “132” }, “uris” : “http://www.mendeley.com/documents/?uuid=d1b310af-2024-4b1b-8acd-88701fd8ca88” } , “mendeley” : { “formattedCitation” : “(Hossain et al., 2010)”, “plainTextFormattedCitation” : “(Hossain et al., 2010)”, “previouslyFormattedCitation” : “(Hossain et al., 2010)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Hossain et al., 2010). Among the different inflammation models, carrageenan induced paw edema model is well-known to investigate the anti-inflammatory activities of various synthetic or natural compounds (Di Rosa et al., 1971; ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/j.ejphar.2007.03.046”, “ISSN” : “00142999”, “PMID” : “17475238”, “abstract” : “Amiodarone is a widely used anti-arrhythmic agent. We have investigated alterations in the glutathione (GSH) level and the activities of anti-oxidative enzymes (superoxide dismutase, catalase, glutathione s-transferase and glutathione reductase) and myeloperoxidase, as marker of acute inflammation, following oral administration of amiodarone and diclofenac in rats with carrageenan-induced paw edema. In the present study, we found that 1) Amiodarone reduced the development of carrageenan-induced paw edema, to a greater degree than diclofenac; 2) Amiodarone and diclofenac alleviated increases in the activities of catalase and glutathione s-transferase enzymes resulting from edema; 3) Amiodarone and diclofenac ameliorated depressions in the GSH level and the activities of superoxide dismutase and glutathione reductase enzymes caused by carrageenan injection; and 4) All doses of amiodarone and diclofenac caused an amplification in myeloperoxidase activity resulting from induced paw edema. These results suggest that the anti-inflammatory effect of amiodarone on carrageenan-induced acute inflammation can be attributed to its ameliorating effect on the oxidative damage. u00a9 2007 Elsevier B.V. All rights reserved.”, “author” : { “dropping-particle” : “”, “family” : “Halici”, “given” : “Zekai”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Dengiz”, “given” : “Gunnur Ozbakis”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Odabasoglu”, “given” : “Fehmi”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Suleyman”, “given” : “Halis”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Cadirci”, “given” : “Elif”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Halici”, “given” : “Mesut”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “European Journal of Pharmacology”, “id” : “ITEM-1”, “issue” : “1-3”, “issued” : { “date-parts” : “2007” }, “page” : “215-221”, “title” : “Amiodarone has anti-inflammatory and anti-oxidative properties: An experimental study in rats with carrageenan-induced paw edema”, “type” : “article-journal”, “volume” : “566” }, “uris” : “http://www.mendeley.com/documents/?uuid=b5d8f99f-4d8c-4242-af38-1b1fec46eec5” } , “mendeley” : { “formattedCitation” : “(Halici et al., 2007)”, “plainTextFormattedCitation” : “(Halici et al., 2007)”, “previouslyFormattedCitation” : “(Halici et al., 2007)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Halici et al., 2007).
1.2 Pain
International association for the study of pain (IASP) defines pain as unpleasant sensory and emotional experience associated with actual or potential tissue damage, or describe in terms of such damage ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Bonica”, “given” : “J.J.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Pain”, “id” : “ITEM-1”, “issue” : “3”, “issued” : { “date-parts” : “1979” }, “page” : “247-248”, “title” : “International for the Study of Pain: Pain Definition.”, “type” : “article-journal”, “volume” : “6” }, “uris” : “http://www.mendeley.com/documents/?uuid=462d8549-95ff-4f30-ba6d-3977e25a7b73” } , “mendeley” : { “formattedCitation” : “(Bonica, 1979)”, “manualFormatting” : “(IASP, 1979)”, “plainTextFormattedCitation” : “(Bonica, 1979)”, “previouslyFormattedCitation” : “(Bonica, 1979)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(IASP, 1979). Pain serves as a warning of impending injury, triggering appropriate protective response that threatens the integrity of cells or tissues ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Bonica”, “given” : “J.J.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Pain”, “id” : “ITEM-1”, “issue” : “3”, “issued” : { “date-parts” : “1979” }, “page” : “247-248”, “title” : “International for the Study of Pain: Pain Definition.”, “type” : “article-journal”, “volume” : “6” }, “uris” : “http://www.mendeley.com/documents/?uuid=462d8549-95ff-4f30-ba6d-3977e25a7b73” }, { “id” : “ITEM-2”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Treede”, “given” : “Rolf-detlef”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “R”, “given” : “Richard A M E Y”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Raja”, “given” : “Srinivasa N”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Campbell”, “given” : “James N”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-2”, “issued” : { “date-parts” : “2000” }, “title” : “I1 ~ F”, “type” : “article-journal”, “volume” : “38” }, “uris” : “http://www.mendeley.com/documents/?uuid=97b713ee-d76a-49c7-8caa-fa24728321a2” } , “mendeley” : { “formattedCitation” : “(Bonica, 1979; Treede et al., 2000)”, “plainTextFormattedCitation” : “(Bonica, 1979; Treede et al., 2000)”, “previouslyFormattedCitation” : “(Bonica, 1979; Treede et al., 2000)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Bonica, 1979). Chronic pain, however, is a pathological condition that does not serve any useful purpose, but results in a rather substantial loss of quality of life. Indeed, chronic pain is one of the most common and costly health problems ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “ISBN” : “3527310312”, “author” : { “dropping-particle” : “”, “family” : “Dubuison”, “given” : “Dennis”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issued” : { “date-parts” : “2006” }, “page” : “221-235”, “title” : “Animal Models of Nociception”, “type” : “article-journal” }, “uris” : “http://www.mendeley.com/documents/?uuid=f70833c1-ceb4-483c-82ff-8264f5a9d2a9” } , “mendeley” : { “formattedCitation” : “(Dubuison, 2006)”, “plainTextFormattedCitation” : “(Dubuison, 2006)”, “previouslyFormattedCitation” : “(Dubuison, 2006)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Dubuison, 2006).
On the basis of pathophysiology, pain can be classified as nociceptive and neuropathic. Nociceptive pain is caused by the ongoing activation of A? and C-nociceptors in response to a noxious stimulus and serves a function of indicating real or potential tissue damage (Demerol, 2000).
Activation of the free nerve endings with chemical, physical or noxious thermal stimuli results in release of inflammatory mediators like histamine, calcitonin gene-related peptide (CGRP), BK, serotonin (5-HT), LTs, PGs and, substance P from injured tissues (Fig.2). Then inflammatory mediators will lead to activation or sensitization of nociceptors ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Basbun”, “given” : “Julius and”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issued” : { “date-parts” : “2001” }, “title” : “Molecular mechanisms of nociception _ Nature”, “type” : “article” }, “uris” : “http://www.mendeley.com/documents/?uuid=0efe19f6-7c20-4304-a6e3-bbdb00918514” } , “mendeley” : { “formattedCitation” : “(Basbun, 2001)”, “plainTextFormattedCitation” : “(Basbun, 2001)”, “previouslyFormattedCitation” : “(Basbun, 2001)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Basbun, 2001).
Once sensitization of nociceptors occurs, the action potential generated is propagated through the primary afferent nerve fibers to the spinal cord where they synapse with second order neurons in the grey matter of the dorsal horn. Thereafter, second order neurons from spinal cord project their axons to brain stem or to the thalamocortical system that produces the conscious pain in response to noxious stimuli ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Fields”, “given” : “Howard L”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Basbaum”, “given” : “Allan I”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Ann. Rev. Physiol”, “id” : “ITEM-1”, “issue” : “253”, “issued” : { “date-parts” : “1978” }, “page” : “217-48”, “title” : “Brainstem Control of Spinal P Ain -Transmission Neurons”, “type” : “article-journal”, “volume” : “40” }, “uris” : “http://www.mendeley.com/documents/?uuid=60bdc799-b245-4c06-8e66-4d1d58da82be” } , “mendeley” : { “formattedCitation” : “(Fields and Basbaum, 1978)”, “plainTextFormattedCitation” : “(Fields and Basbaum, 1978)”, “previouslyFormattedCitation” : “(Fields and Basbaum, 1978)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Fields and Basbaum, 1978).

Neuropathic pain is caused by aberrant signal processing in the peripheral or central nervous system. After peripheral nerve injury, damaged and non-damaged A and C-fibers begin to generate spontaneous action potentials. Lesions alter the structure and function of the somatosensory nervous system so that pain occurs spontaneously and responses to noxious and innocuous stimuli are pathologically amplified ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/j.jpain.2009.06.012”, “ISSN” : “1526-5900”, “author” : { “dropping-particle” : “”, “family” : “Latremoliere”, “given” : “Alban”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Woolf”, “given” : “Clifford J”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “The Journal of Pain”, “id” : “ITEM-1”, “issue” : “9”, “issued” : { “date-parts” : “2009” }, “page” : “895-926”, “publisher” : “Elsevier Ltd”, “title” : “Central Sensitization: A Generator of Pain Hypersensitivity by Central Neural Plasticity”, “type” : “article-journal”, “volume” : “10” }, “uris” : “http://www.mendeley.com/documents/?uuid=c562124a-fa10-491f-9f38-c853af0eef82” } , “mendeley” : { “formattedCitation” : “(Latremoliere and Woolf, 2009)”, “plainTextFormattedCitation” : “(Latremoliere and Woolf, 2009)”, “previouslyFormattedCitation” : “(Latremoliere and Woolf, 2009)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Latremoliere and Woolf, 2009). Any process that causes damage to the nerves, such as metabolic, traumatic, infectious, ischemic, toxic or immune-mediated pathological conditions, can result in neuropathic pain. In addition, neuropathic pain can be caused by nerve compression or the abnormal processing of pain signals by the brain and spinal cord. Neuropathic pain can be either peripheral (arising as a direct consequence of a lesion or disease affecting the peripheral nerve, the dorsal root ganglion or dorsal root) or central (arising as a direct consequence of a lesion or disease affecting the CNS). However, a clear distinction is not always possible ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1007/s00415-017-8641-6”, “ISBN” : “0123456789”, “ISSN” : “1432-1459”, “author” : { “dropping-particle” : “”, “family” : “St”, “given” : “Ewan”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Smith”, “given” : “John”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Neurology”, “id” : “ITEM-1”, “issue” : “0123456789”, “issued” : { “date-parts” : “2017” }, “publisher” : “Springer Berlin Heidelberg”, “title” : “Advances in understanding nociception and neuropathic pain”, “type” : “article-journal” }, “uris” : “http://www.mendeley.com/documents/?uuid=8d0c07b7-c8a1-4ce5-80de-400286973085” } , “mendeley” : { “formattedCitation” : “(St and Smith, 2017)”, “manualFormatting” : “(Ewan and Smith, 2017)”, “plainTextFormattedCitation” : “(St and Smith, 2017)”, “previouslyFormattedCitation” : “(St and Smith, 2017)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Ewan and Smith, 2017)

Figure SEQ Figure * ARABIC 2:The molecular complexity of the primary afferent nociceptors in response to inflammatory mediators released at the site of tissue injury.Pain is associated with a number of problems such as, inability to carry out daily activities, feeling of anxiety, depression, anger, or cognitive dysfunction that interfere with the normal physiology and patients’ quality of life and risk of all-cause mortality ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/j.jbspin.2015.05.001”, “ISBN” : “1297-319X”, “ISSN” : “17787254”, “PMID” : “26231097”, “abstract” : “OBJECTIVES: To evaluate the impact of rheumatoid arthritis (RA) on career, productivity, and employability.
METHODS: A retrospective cross-sectional survey was conducted in 2012-2013 in France among patients with RA who were younger than 60 years of age and employed or unemployed. Patients were either recruited during a rheumatologist visit or among members of a nationwide patient-support organization (ANDAR). They completed a questionnaire on the functional impact of RA evaluated by the Health Assessment Questionnaire (HAQ) and on the impact of their disease on work ability.
RESULTS: Of 488 surveyed patients, 364 (74.6%) were actively employed, 31 (6.4%) were job seekers, and 93 (19.1%) had left the workforce. In the employed group, mean age was 48.9 years; 82.1% of patients were women; mean RA duration was 11.6 years; and the HAQ score correlated strongly with various markers for decreased productivity including sick leaves, temporary or permanent work discontinuation, and having unwillingly downgraded from a full-time to a part-time work schedule or changed to a different job. Among job seekers, 54% had lost their previous job because of their RA.
CONCLUSION: RA is associated with various forms of work disability, which are directly related to the severity of disease-related functional impairments.”, “author” : { “dropping-particle” : “”, “family” : “Bertin”, “given” : “Philippe”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Fagnani”, “given” : “Francis”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Duburcq”, “given” : “Anne”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Woronoff”, “given” : “Anne Sophie”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Chauvin”, “given” : “Pierre”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Cukierman”, “given” : “Gabrielle”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Tropu00e9-Chirol”, “given” : “Sonia”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Joubert”, “given” : “Jean Michel”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Kobelt”, “given” : “Gisela”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Joint, bone, spine : revue du rhumatisme”, “id” : “ITEM-1”, “issue” : “1”, “issued” : { “date-parts” : “2016” }, “page” : “47-52”, “publisher” : “Elsevier Masson SAS”, “title” : “Impact of rheumatoid arthritis on career progression, productivity, and employability: The PRET Study”, “type” : “article-journal”, “volume” : “83” }, “uris” : “http://www.mendeley.com/documents/?uuid=54b54348-2a9e-4208-afe2-2cc6b2a8e245” } , “mendeley” : { “formattedCitation” : “(Bertin et al., 2016)”, “manualFormatting” : “(Bertin et al., 2016; Da Costa et al., 2016)”, “plainTextFormattedCitation” : “(Bertin et al., 2016)”, “previouslyFormattedCitation” : “(Bertin et al., 2016)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Bertin et al., 2016; Da Costa et al., 2016). Left unchecked or inadequate control of these symptoms can contribute to more serious consequences ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1093/fampra/cmx034”, “ISSN” : “0263-2136”, “PMID” : “28444208”, “abstract” : “Background. Chronic pain has major clinical and social consequences. Few studies have examined any variation in the extent of impairment on quality of life and work productivity by site and type of chronic pain. Objective. The objective of our study is to examine adverse impacts of chronic pain on physical and psychological health and work productivity. Methods. Our community-population study was based on a phone-interview of adults with chronic pain, residing in Olmsted County, MN. Chronic pain groups were categorized into abdominal pain, back pain, joint pain, multisite pain, neuropathic pain or no chronic pain. We used standardized instruments, including the Brief Pain Inventory, the Patients Health Questionnair-9, and Work Productivity and Activity Impairment Questionnaire. Results. We evaluated 591 patients suffering from chronic pain and 150 participants with no chronic pain. Almost one third of patients with multisite pain (33%) and neuropathic pain (32%) reported mild/major depressive symptoms. Patients suffering from chronic pain, particularly from multisite pain and neuropathic pain, reported significant pain interferences with daily activities and impairments in physical function. Chronic pain was significantly associated with reduced performance at work but not with missed work hours. The average reported reduction in work productivity ranged from 2.4 hours (u00b15.6) per week for adults with joint chronic pain to 9.8 hours (u00b111.1) per week for adults with multisite chronic pain. Conclusions. Chronic pain, particularly multisite pain and neuropathic pain, significantly affected physical and psychological health. Chronic pain is a multifaceted health condition that requires a multidisciplinary treatment approach.”, “author” : { “dropping-particle” : “”, “family” : “Kawai”, “given” : “Kosuke”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Kawai”, “given” : “Alison Tse”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Wollan”, “given” : “Peter”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Yawn”, “given” : “Barbara P”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Family Practice”, “id” : “ITEM-1”, “issue” : “6”, “issued” : { “date-parts” : “2017” }, “page” : “656-661”, “title” : “Adverse impacts of chronic pain on health-related quality of life, work productivity, depression and anxiety in a community-based study”, “type” : “article-journal”, “volume” : “34” }, “uris” : “http://www.mendeley.com/documents/?uuid=afb865ad-551b-48cc-becf-8c166460c123” } , “mendeley” : { “formattedCitation” : “(Kawai et al., 2017)”, “plainTextFormattedCitation” : “(Kawai et al., 2017)”, “previouslyFormattedCitation” : “(Kawai et al., 2017)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Kawai et al., 2017).

Prevalence study estimated that 20% of adults suffer from pain globally and 10% are newly diagnosed with chronic pain each year ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1186/1471-2458-11-770”, “ISBN” : “14712458”, “ISSN” : “1471-2458; 1471-2458”, “PMID” : “21978149”, “abstract” : “Background: Pain is an enormous problem globally. Estimates suggest that 20% of adults suffer from pain globally and 10% are newly diagnosed with chronic pain each year. Nevertheless, the problem of pain has primarily been regarded as a medical problem, and has been little addressed by the field of public health. Discussion. Despite the ubiquity of pain, whether acute, chronic or intermittent, public health scholars and practitioners have not addressed this issue as a public health problem. The importance of viewing pain through a public health lens allows one to understand pain as a multifaceted, interdisciplinary problem for which many of the causes are the social determinants of health. Addressing pain as a global public health issue will also aid in priority setting and formulating public health policy to address this problem, which, like most other chronic non-communicable diseases, is growing both in absolute numbers and in its inequitable distribution across the globe. Summary. The prevalence, incidence, and vast social and health consequences of global pain requires that the public health community give due attention to this issue. Doing so will mean that health care providers and public health professionals will have a more comprehensive understanding of pain and the appropriate public health and social policy responses to this problem. u00a9 2011 Goldberg and McGee; licensee BioMed Central Ltd.”, “author” : { “dropping-particle” : “”, “family” : “Goldberg”, “given” : “D S”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “McGee”, “given” : “S J”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “BMC Public Health”, “id” : “ITEM-1”, “issued” : { “date-parts” : “2011” }, “page” : “770”, “title” : “Pain as a global public health priority”, “type” : “article-journal”, “volume” : “11” }, “uris” : “http://www.mendeley.com/documents/?uuid=c408fcd8-eda2-40c0-b6c4-14c84570718d” } , “mendeley” : { “formattedCitation” : “(Goldberg and McGee, 2011)”, “plainTextFormattedCitation” : “(Goldberg and McGee, 2011)”, “previouslyFormattedCitation” : “(Goldberg and McGee, 2011)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Goldberg and McGee, 2011). Worldwide, 10 to 15 percent of population is affected by symptomatic osteoarthritis, with 27 and 8.5 million people affected in the United States and United Kingdom, respectively ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “abstract” : “IASP brings together scientists, clinicians, health-care providers, and policymakers to stimulate and support the study of pain and translate that knowledge into improved pain relief worldwide. Musculoskeletal pain, especially joint and back pain, is the most common type of chronic pain. The most common cause of joint pain is related to arthritis, of which there are numerous types. Patients routinely seek medical attention for joint pain, and it is one of the leading causes of disability. In the United States, based on data from the National Health Interview Survey, an estimated 52.5 million (22.7 percent) of adults have self-reported doctor-diagnosed arthritis, and 22.7 million (9.8 percent) have arthritis and arthritis-attributable activity limitation. It is estimated that by the year 2030, 67 millionu2014one in every four American adultsu2014will have doctor-diagnosed arthritis. About 30 percent of adults report some form of joint pain within the prior 30 days, with the knee joint being the most common site. A 2007 European Commission Eurobarometer survey found that 22 percent of respondents reported musculoskeletal issuesu2014 higher than any other health condition.”, “author” : { “dropping-particle” : “”, “family” : “Neogi”, “given” : “Tuhina”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Fact Sheet”, “id” : “ITEM-1”, “issue” : “11”, “issued” : { “date-parts” : “2016” }, “page” : “18-20”, “title” : “Joint Pain Epidemiology”, “type” : “article-journal” }, “uris” : “http://www.mendeley.com/documents/?uuid=882c5559-6012-4917-bed8-777122aa6cdf” } , “mendeley” : { “formattedCitation” : “(Neogi, 2016)”, “plainTextFormattedCitation” : “(Neogi, 2016)”, “previouslyFormattedCitation” : “(Neogi, 2016)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Neogi, 2016)). Lower back pain (LBP) is also a leading cause of global disability with a global point prevalence of 9.4% (95% CI = 9.0 to 9.8%) (Hoy et al., 2014). A cross-sectional survey conducted in Ethiopia indicated that the mean intensity of migraine in the adult population was 2.6 from which tension type head 2.4%; medication over use headache 2.95; and other headaches 2.6% (Zebenigus, 2017). Another cross-sectional on adult HIV-infected patients in Gonder indicated that the prevalence of pain was 51.2%. Headache (17.9%), abdominal pain (15.6%), and backache (13.3%) were the most common symptoms of study participants ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Azagew”, “given” : “Abere Woretaw”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Woreta”, “given” : “Hiwot Kassa”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Tilahun”, “given” : “Ambaye Dejen”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Anlay”, “given” : “Degefaye Zelalem”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issued” : { “date-parts” : “2017” }, “page” : “2461-2469”, “title” : “High prevalence of pain among adult HIV-infected patients at University of Gondar Hospital , Northwest Ethiopia”, “type” : “article-journal” }, “uris” : “http://www.mendeley.com/documents/?uuid=97366b43-c286-4937-a20f-da764a37946e” } , “mendeley” : { “formattedCitation” : “(Azagew et al., 2017)”, “plainTextFormattedCitation” : “(Azagew et al., 2017)”, “previouslyFormattedCitation” : “(Azagew et al., 2017)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Azagew et al., 2017).

1.3 Management of Pain and Inflammation
Pain conditions, acute or chronic and are treated pharmacologically with a number of drug classes via several routes of administration as drug delivery systems have progressed. These drug classes include, anti-inflammatory drugs, muscle relaxants, antiepileptic medicines, antidepressants, opioids, and local anesthetics ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/j.spen.2016.10.004”, “ISBN” : “1071-9091
1558-0776”, “ISSN” : “15580776”, “PMID” : “27989328”, “abstract” : “Adolescents and children are frequently affected by chronic pain conditions that can lead to disability and distress. The best approach to evaluation and treatment of these conditions involves use of the biopsychosocial model, which includes use of medication management. Chronic pain conditions are treated pharmacologically with a number of different medication classes via several routes of administration as drug delivery systems have progressed. These include anti-inflammatory drugs, muscle relaxants, antiepileptic medicines, antidepressants, opioids, and local anesthetics. Most are prescribed without regulatory body approval to treat specific pain syndromes as data to support their use are sparse. Medical decision making is guided by experience, empiric evidence, extrapolation from adult studies, and matching medication classes with the theorized mechanism of the pain condition. It is not recommended that nonpain practitioners prescribe opioid medications for treatment of chronic pain conditions, and pain management practitioners should seek to minimize their use. The appropriate and commonly used medications for pain conditions are presented in this narrative review.”, “author” : { “dropping-particle” : “”, “family” : “Mathew”, “given” : “Eapen”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Kim”, “given” : “Eugene”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Zempsky”, “given” : “William”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Seminars in Pediatric Neurology”, “id” : “ITEM-1”, “issue” : “3”, “issued” : { “date-parts” : “2016” }, “page” : “209-219”, “publisher” : “Elsevier”, “title” : “Pharmacologic Treatment of Pain”, “type” : “article-journal”, “volume” : “23” }, “uris” : “http://www.mendeley.com/documents/?uuid=51f8526b-e3ce-439b-b02f-3155678af0ed” } , “mendeley” : { “formattedCitation” : “(Mathew et al., 2016)”, “plainTextFormattedCitation” : “(Mathew et al., 2016)”, “previouslyFormattedCitation” : “(Mathew et al., 2016)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Mathew et al., 2016).
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs in the world. Non-steroidal anti-inflammatory drugs (NSAIDs) belong to a class of drugs; their main benefit derives from their anti-inflammatory and analgesic effect. They act mainly by inhibiting cyclooxygenase (COX) enzymes including COX-1 and COX-2, which are involved in prostaglandin synthesis. This class of medications includes the traditional, non-selective NSAIDs that inhibit both COX-1 and COX-2, and the newer selective COX-2 inhibitors ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/S0140-6736(13)60900-9”, “ISBN” : “1474-547X”, “ISSN” : “1474547X”, “PMID” : “23726390”, “abstract” : “Background The vascular and gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (tNSAIDs), are not well characterised, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomised trials. Methods We undertook meta-analyses of 280 trials of NSAIDs versus placebo (124 513 participants, 68 342 personyears) and 474 trials of one NSAID versus another NSAID (229 296 participants, 165 456 person-years). The main outcomes were major vascular events (non-fatal myocardial in farction, non-fatal stroke, or vascular death); major coronary events (non-fatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, ob struction, or bleed). Findings Major vascular events were increased by about a third by a coxib (rate ratio RR 1u00b737, 95% CI 1u00b714-1u00b766; p=0u00b70009) or diclofenac (1u00b741, 1u00b712-1u00b778; p=0u00b70036), chiefl y due to an increase in major coronary events (coxibs 1u00b776, 1u00b731-2u00b737; p=0u00b70001; diclofenac 1u00b770, 1u00b719-2u00b741; p=0u00b70032). Ibuprofen also significantly increased major coronary events (2u00b722, 1u00b710-4u00b748; p=0u00b70253), but not major vascular events (1u00b744, 0u00b789-2u00b733). Compared with placebo, of 1000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (0u00b793, 0u00b769-1u00b727). Vascular death was increased significantly by coxibs (1u00b758, 99% CI 1u00b700-2u00b749; p=0u00b70103) and diclofenac (1u00b765, 0u00b795-2u00b785, p=0u00b70187), nonsignificantly by ibuprofen (1u00b790, 0u00b756-6u00b741; p=0u00b717), but not by naproxen (1u00b708, 0u00b748-2u00b747, p=0u00b780). The proportional eff ects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (coxibs 1u00b781, 1u00b717-2u00b781, p=0u00b70070; diclofenac 1u00b789, 1u00b716-3u00b709, p=0u00b70106; ibuprofen 3u00b797, 2u00b722-7u00b710, p<0u00b70001; and naproxen 4u00b722, 2u00b771-6u00b756, p<0u00b70001). Interpretation The vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. 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A.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Philipson”, “given” : “R.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Curtis”, “given” : “S.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Reicin”, “given” : “A.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Bond”, “given” : “J.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Moore”, “given” : “A.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Essex”, “given” : “M.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Fabule”, “given” : “J.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Morrison”, “given” : “B.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Tive”, “given” : “L.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Bhala”, “given” : “N.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Davies”, “given” : “K.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Emberson”, “given” : “J.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Halls”, “given” : “H.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Holland”, “given” : “L. E.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Kearney”, “given” : “P. M.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Merhi”, “given” : “A.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Patrono”, “given” : “C.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Wilson”, “given” : “K.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Yau”, “given” : “F.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “The Lancet”, “id” : “ITEM-1”, “issue” : “9894”, “issued” : { “date-parts” : “2013” }, “page” : “769-779”, “publisher” : “Elsevier Ltd”, “title” : “Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: Meta-analyses of individual participant data from randomised trials”, “type” : “article-journal”, “volume” : “382” }, “uris” : “http://www.mendeley.com/documents/?uuid=be045063-825c-491f-94a8-affa14255230” } , “mendeley” : { “formattedCitation” : “(Baigent et al., 2013)”, “plainTextFormattedCitation” : “(Baigent et al., 2013)”, “previouslyFormattedCitation” : “(Baigent et al., 2013)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Baigent et al., 2013). They are highly effective in treating various painful conditions such as osteoarthritis and dysmenorrhea ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/j.jval.2017.08.1150”, “ISSN” : “10983015”, “author” : { “dropping-particle” : “”, “family” : “Asghar”, “given” : “W”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Jamali”, “given” : “F”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Value in Health”, “id” : “ITEM-1”, “issue” : “9”, “issued” : { “date-parts” : “2017” }, “page” : “A601”, “title” : “The Effect Of Nsaids On Myocardial, Vascular And Renal Risk Categories:Systematic Review Of Randomized Controlled Trial And Observational Studies”, “type” : “article-journal”, “volume” : “20” }, “uris” : “http://www.mendeley.com/documents/?uuid=56173af0-cb61-45e3-92a1-4ad66f256038” } , “mendeley” : { “formattedCitation” : “(Asghar and Jamali, 2017)”, “plainTextFormattedCitation” : “(Asghar and Jamali, 2017)”, “previouslyFormattedCitation” : “(Asghar and Jamali, 2017)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Asghar and Jamali, 2017). Despite their paramount use in pain management NSAIDs are associated with a number of adverse effects like increased the risk of gastrointestinal (GI) and cardiovascular complications compared with non-NSAID users ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/j.bpg.2009.11.005”, “ISBN” : “1521-6918”, “ISSN” : “15216918”, “PMID” : “20227026”, “abstract” : “Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most widely prescribed medication in the world. Their main benefit derives from their anti-inflammatory and analgesic effect, but the use of these agents is not innocuous since they mainly increase the risk of gastrointestinal (GI) and cardiovascular complications compared with non-NSAID users. NSAIDs injures the upper and lower gut by depleting COX-1 derived prostaglandins and causing topical injury to the mucosa. The risk of upper GI complications varies, depending on the presence of one or more risk factors. Among them, the three main risk factors are prior history of peptic ulcer, the single most important risk factor, age, the most common, and concomitant aspirin use, due to their GI and cardiovascular implications. Those individuals at-risk should be considered for alternatives to NSAID therapy and modifications of risk factors. If NSAID therapy is required, patients at risk will need prevention strategies including co-therapy of NSAID with gastroprotectants (PPI or misoprostol) or the prescription of COX-2 selective inhibitors. The probable introduction of NO-NSAIDs in the market in the near future may open a new therapeutic option for patients with hypertension who need NSAIDs.”, “author” : { “dropping-particle” : “”, “family” : “Sostres”, “given” : “Carlos”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Gargallo”, “given” : “Carla J.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Arroyo”, “given” : “Maria T.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Lanas”, “given” : “Angel”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Best Practice & Research Clinical Gastroenterology”, “id” : “ITEM-1”, “issue” : “2”, “issued” : { “date-parts” : “2010” }, “page” : “121-132”, “publisher” : “Elsevier Ltd”, “title” : “Adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs, aspirin and coxibs) on upper gastrointestinal tract”, “type” : “article-journal”, “volume” : “24” }, “uris” : “http://www.mendeley.com/documents/?uuid=4f100761-5961-445e-802e-10030cc3712b” } , “mendeley” : { “formattedCitation” : “(Sostres et al., 2010)”, “plainTextFormattedCitation” : “(Sostres et al., 2010)”, “previouslyFormattedCitation” : “(Sostres et al., 2010)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Sostres et al., 2010).
Corticosteroids are the most effective anti-inflammatory therapy for many chronic inflammatory diseases, such as asthma. It works by decreasing inflammation and reducing the activity of the immune system ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1038/sj.bjp.0706736”, “ISBN” : “0007-1188 (Print)\n0007-1188 (Linking)”, “ISSN” : “00071188”, “PMID” : “16604091”, “abstract” : “Corticosteroids are the most effective anti-inflammatory therapy for many chronic inflammatory diseases, such as asthma but are relatively ineffective in other diseases such as chronic obstructive pulmonary disease (COPD). Chronic inflammation is characterised by the increased expression of multiple inflammatory genes that are regulated by proinflammatory transcription factors, such as nuclear factor-kappaB and activator protein-1, that bind to and activate coactivator molecules, which then acetylate core histones to switch on gene transcription. Corticosteroids suppress the multiple inflammatory genes that are activated in chronic inflammatory diseases, such as asthma, mainly by reversing histone acetylation of activated inflammatory genes through binding of liganded glucocorticoid receptors (GR) to coactivators and recruitment of histone deacetylase-2 (HDAC2) to the activated transcription complex. At higher concentrations of corticosteroids GR homodimers also interact with DNA recognition sites to active transcription of anti-inflammatory genes and to inhibit transcription of several genes linked to corticosteroid side effects. In patients with COPD and severe asthma and in asthmatic patients who smoke HDAC2 is markedly reduced in activity and expres-sion as a result of oxidative/nitrative stress so that inflammation becomes resistant to the anti-inflammatory actions of corticosteroids. Theophylline, by activating HDAC, may reverse this corticosteroid resistance. This research may lead to the development of novel anti-inflammatory approaches to manage severe inflammatory diseases.”, “author” : { “dropping-particle” : “”, “family” : “Barnes”, “given” : “Peter J.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “British Journal of Pharmacology”, “id” : “ITEM-1”, “issue” : “3”, “issued” : { “date-parts” : “2006” }, “page” : “245-254”, “title” : “How corticosteroids control inflammation: Quintiles Prize Lecture 2005”, “type” : “article-journal”, “volume” : “148” }, “uris” : “http://www.mendeley.com/documents/?uuid=56a8dd18-ba74-4197-8b36-77942cac9e2c” }, { “id” : “ITEM-2”, “itemData” : { “DOI” : “10.1016/S0140-6736(09)60326-3”, “ISBN” : “0140-6736”, “ISSN” : “01406736”, “PMID” : “19482216”, “abstract” : “Glucocorticoid resistance or insensitivity is a major barrier to the treatment of several common inflammatory diseases-including chronic obstructive pulmonary disease and acute respiratory distress syndrome; it is also an issue for some patients with asthma, rheumatoid arthritis, and inflammatory bowel disease. Several molecular mechanisms of glucocorticoid resistance have now been identified, including activation of mitogen-activated protein (MAP) kinase pathways by certain cytokines, excessive activation of the transcription factor activator protein 1, reduced histone deacetylase-2 (HDAC2) expression, raised macrophage migration inhibitory factor, and increased P-glycoprotein-mediated drug efflux. Patients with glucocorticoid resistance can be treated with alternative broad-spectrum anti-inflammatory treatments, such as calcineurin inhibitors and other immunomodulators, or novel anti-inflammatory treatments, such as inhibitors of phosphodiesterase 4 or nuclear factor u03baB, although these drugs are all likely to have major side-effects. An alternative treatment strategy is to reverse glucocorticoid resistance by blocking its underlying mechanisms. Some examples of this approach are inhibition of p38 MAP kinase, use of vitamin D to restore interleukin-10 response, activation of HDAC2 expression by use of theophylline, antioxidants, or phosphoinositide-3-kinase-u03b4 inhibitors, and inhibition of macrophage migration inhibitory factor and P-glycoprotein. u00a9 2009 Elsevier Ltd. All rights reserved.”, “author” : { “dropping-particle” : “”, “family” : “Barnes”, “given” : “Peter J.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Adcock”, “given” : “Ian M.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “The Lancet”, “id” : “ITEM-2”, “issue” : “9678”, “issued” : { “date-parts” : “2009” }, “page” : “1905-1917”, “title” : “Glucocorticoid resistance in inflammatory diseases”, “type” : “article-journal”, “volume” : “373” }, “uris” : “http://www.mendeley.com/documents/?uuid=c14f7e7b-437b-4779-80d9-2d194e099b3d” } , “mendeley” : { “formattedCitation” : “(Barnes, 2006; Barnes and Adcock, 2009)”, “plainTextFormattedCitation” : “(Barnes, 2006; Barnes and Adcock, 2009)”, “previouslyFormattedCitation” : “(Barnes, 2006; Barnes and Adcock, 2009)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Barnes, 2006; Barnes and Adcock, 2009)). Despite their use as a powerful therapeutic option to treat inflammatory diseases, serious adverse effects were reported including, physiologic and psychiatric adverse drug reactions (ADRs). The most common adverse reactions were upper respiratory tract infections, headache, hypertension, and elevated liver enzymes. Serious infections including tuberculosis, fungal, viral, and other opportunistic infections. Neutropenia and reduction in platelet counts occur occasionally, and demands regular monitoring. GI perforation has been reported when using tocilizumabin patients with diverticulitis or who are using corticosteroids ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.4065/81.10.1361”, “ISBN” : “0025-6196 (Print)\r0025-6196”, “ISSN” : “00256196”, “PMID” : “17036562”, “abstract” : “Psychiatric adverse effects during systemic corticosteroid therapy are common. Two large meta-analyses found that severe reactions occurred in nearly 6% of patients, and mild to moderate reactions occurred in about 23%. Although disturbances of mood, cognition, sleep, and behavior as well as frank delirium or even psychosis are possible, the most common adverse effects of short-term corticosteroid therapy are euphoria and hypomania. Conversely, long-term therapy tends to induce depressive symptoms. Dosage is directly related to the incidence of adverse effects but is not related to the timing, severity, or duration of these effects. Neither the presence nor the absence of previous reactions predicts adverse responses to subsequent courses of corticosteroids. Corticosteroid-induced symptoms frequently present early in a treatment cycle and typically resolve with dosage reduction or discontinuation of corticosteroids. In severe cases or situations in which the dose cannot be reduced, antipsychotics or mood stabilizers may be required. This review offers an approach to identifying and managing corticosteroid-induced psychiatric syndromes based on the type of symptoms and anticipated duration of corticosteroid treatment. u00a9 2006 Mayo Foundation for Medical Education and Research.”, “author” : { “dropping-particle” : “”, “family” : “Warrington”, “given” : “Thomas P.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Bostwick”, “given” : “J. Michael”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Mayo Clinic Proceedings”, “id” : “ITEM-1”, “issue” : “10”, “issued” : { “date-parts” : “2006” }, “page” : “1361-1367”, “title” : “Psychiatric adverse effects of corticosteroids”, “type” : “article-journal”, “volume” : “81” }, “uris” : “http://www.mendeley.com/documents/?uuid=1914db09-b901-49d8-8ec9-1e5708970dff” } , “mendeley” : { “formattedCitation” : “(Warrington and Bostwick, 2006)”, “plainTextFormattedCitation” : “(Warrington and Bostwick, 2006)”, “previouslyFormattedCitation” : “(Warrington and Bostwick, 2006)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Warrington and Bostwick, 2006).
Another classes of drugs used in the management of pain are opioids. Opioid analgesics act at cellular level by activating opioid receptors that are found widely distributed in the central nervous system. High levels of opioid receptors are found in the nuclei of tractus solitarius, periaqueductal grey area (PAG), cerebral cortex, thalamus and the substantia gelatinosa (SG) of the spinal cord. Peripheral afferent nerve terminals also contain opioid receptors. Central administration of these analgesic agents produce pronounced effect, but their action is less reliable when applied peripherally like in case of post-traumatic and inflammatory states. Opioid receptor coupling to G-proteins results in closure of voltage sensitive calcium channels and stimulation of potassium efflux. Following receptor stimulation, reduced cyclic adenosine monophosphate production and hyperpolarization occur which could help in the suppression of pain. Overall, the effect is a reduction in neuronal cell excitability that in turn results in reduced transmission of nociceptive impulse ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Trivedi”, “given” : “Mahesh”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Shaikh”, “given” : “Shafee”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Registrars”, “given” : “Specialist”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “AAGBI Tutorials”, “id” : “ITEM-1”, “issue” : “August”, “issued” : { “date-parts” : “2007” }, “page” : “1-7”, “title” : “Pharmacology of Opioids u2013 Part 1 Anaesthesia Tutorial of the Week 64 12Th August 2007”, “type” : “article-journal” }, “uris” : “http://www.mendeley.com/documents/?uuid=2b99c2ef-6cc3-4cc0-b30e-170aa8a48157” } , “mendeley” : { “formattedCitation” : “(Trivedi et al., 2007)”, “plainTextFormattedCitation” : “(Trivedi et al., 2007)”, “previouslyFormattedCitation” : “(Trivedi et al., 2007)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Trivedi et al., 2007).
Despite their use as analgesics from moderate to severe pain, opioids action is limited by the development of dependence and tolerance especially when employed in chronic pain conditions ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/j.conb.2007.10.004”, “author” : { “dropping-particle” : “”, “family” : “Martini”, “given” : “Lene”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Whistler”, “given” : “Jennifer L”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issued” : { “date-parts” : “2007” }, “page” : “556-564”, “title” : “The role of mu opioid receptor desensitization and endocytosis in morphine tolerance and dependence”, “type” : “article-journal” }, “uris” : “http://www.mendeley.com/documents/?uuid=d1e53613-2437-4123-b9ea-e554bd35212f” } , “mendeley” : { “formattedCitation” : “(Martini and Whistler, 2007)”, “plainTextFormattedCitation” : “(Martini and Whistler, 2007)”, “previouslyFormattedCitation” : “(Martini and Whistler, 2007)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Martini and Whistler, 2007).
1.4 Traditional Medicine
Pharmaceutical development has led to a great deal of medicines, however many of them are not effective as expected; patients encountered escalating health care costs; and adverse drug reactions are reported in some of the patients. As a result, people showed increased tendency to the use of traditional medicine with an extent not less than 80 % worldwide ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1017/CBO9781107415324.004”, “ISBN” : “9788578110796”, “ISSN” : “1098-6596”, “PMID” : “25246403”, “abstract” : “Predicting the binding mode of flexible polypeptides to proteins is an important task that falls outside the domain of applicability of most small molecule and proteinu2212protein docking tools. Here, we test the small molecule flexible ligand docking program Glide on a set of 19 non-u03b1-helical peptides and systematically improve pose prediction accuracy by enhancing Glide sampling for flexible polypeptides. In addition, scoring of the poses was improved by post-processing with physics-based implicit solvent MM- GBSA calculations. Using the best RMSD among the top 10 scoring poses as a metric, the success rate (RMSD u2264 2.0 u00c5 for the interface backbone atoms) increased from 21% with default Glide SP settings to 58% with the enhanced peptide sampling and scoring protocol in the case of redocking to the native protein structure. This approaches the accuracy of the recently developed Rosetta FlexPepDock method (63% success for these 19 peptides) while being over 100 times faster. Cross-docking was performed for a subset of cases where an unbound receptor structure was available, and in that case, 40% of peptides were docked successfully. We analyze the results and find that the optimized polypeptide protocol is most accurate for extended peptides of limited size and number of formal charges, defining a domain of applicability for this approach.”, “author” : { “dropping-particle” : “”, “family” : “Fallis”, “given” : “A.G”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Chemical Information and Modeling”, “id” : “ITEM-1”, “issue” : “9”, “issued” : { “date-parts” : “2013” }, “page” : “1689-1699”, “title” : “The Contribution of Complementary and Alternative Medicine to Sustainable Healthcare in Europe”, “type” : “article-journal”, “volume” : “53” }, “uris” : “http://www.mendeley.com/documents/?uuid=8de7f4d5-7489-45a5-975b-3a3654e82055” } , “mendeley” : { “formattedCitation” : “(Fallis, 2013)”, “plainTextFormattedCitation” : “(Fallis, 2013)”, “previouslyFormattedCitation” : “(Fallis, 2013)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Fallis, 2013).
Medicinal plants have been used since ancient times in Africa and viewed as a fundamental component of the traditional healthcare system. In many parts of rural Africa, traditional healers prescribing medicinal plants are the most easily accessible and affordable health resource available to the local community ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Tabuti”, “given” : “John R. S.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issued” : { “date-parts” : “2013” }, “title” : “Evidence u00ad Based Complementary and Alternative Medicine Traditional Medicines in Africa : An Appraisal of Ten Potent African Medicinal Plants”, “type” : “article-journal”, “volume” : “2013” }, “uris” : “http://www.mendeley.com/documents/?uuid=7f7dced1-8d0e-4e27-9146-a0e04f03698d” } , “mendeley” : { “formattedCitation” : “(Tabuti, 2013)”, “manualFormatting” : “(Tabuti, 2013; WHO, 2013)”, “plainTextFormattedCitation” : “(Tabuti, 2013)”, “previouslyFormattedCitation” : “(Tabuti, 2013)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Tabuti, 2013; WHO, 2015). Besides traditional use, scientific study on medicinal plants provides herbal medicines as a medicinal resource for drug discovery in the future ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/S1995-7645(14)60259-5”, “ISSN” : “19957645”, “PMID” : “25312151”, “abstract” : “Objective: To identify, present and review the respiratoty medicinal plants which used by Urmian herbalists. Methods: The list of traditional healers of West Azarbaijan Province was prepared and data were obtained by direct observation, interviews and the questionnaires After that, herbarium samples were collected from the desired area and deposited in herbarium unit of the Faculty of Agriculture, Urmia University, Urmia, Iran. Results: Our results demonstrated that 20 medicinal plants from 10 plant families are used to treat respiratory disorders. Also, the most plant part that used for treating of respiratory disorders was seed (27%) and the most traditional form prescribed by herbalists was boiled (54%). Forty three percentage of Urmia herbalists have used herbs for the treatment of cough. Conclusions: People in this area have a strong belief that plants have a positive impact in the treatment of respiratory disorders and they have used medicinal plants since ancient times to treat these disorders. Our study revealed the importance of herbal medicines and traditional medicine in this area as medicinal resource for drug discovery in future.”, “author” : { “dropping-particle” : “”, “family” : “Asadbeigi”, “given” : “Mohsen”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Mohammadi”, “given” : “Tahereh”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Rafieian-Kopaei”, “given” : “Mahmoud”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Saki”, “given” : “Kourosh”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Bahmani”, “given” : “Mahmoud”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Delfan”, “given” : “Mohammad”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Asian Pacific Journal of Tropical Medicine”, “id” : “ITEM-1”, “issue” : “S1”, “issued” : { “date-parts” : “2014” }, “page” : “S364-S368”, “title” : “Traditional effects of medicinal plants in the treatment of respiratory diseases and disorders: An ethnobotanical study in the Urmia”, “type” : “article-journal”, “volume” : “7” }, “uris” : “http://www.mendeley.com/documents/?uuid=8c4cb8a7-f875-4895-b803-b299ef2bdf01” } , “mendeley” : { “formattedCitation” : “(Asadbeigi et al., 2014)”, “plainTextFormattedCitation” : “(Asadbeigi et al., 2014)”, “previouslyFormattedCitation” : “(Asadbeigi et al., 2014)” }, “properties” : { “noteIndex” : 27 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Asadbeigi et al., 2014).

In Ethiopian traditional medicine a variety of medicinal plants have been used to treat pain and inflammation. These plants include Malva verticillata, Otostegia integrifolia ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.18782/2320-7051.2240”, “author” : { “dropping-particle” : “”, “family” : “Getnet”, “given” : “Zelalem”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Chandrodyam”, “given” : “Subramanian”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Masresha”, “given” : “Getinet”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Int. J. Pure App. Biosci.”, “id” : “ITEM-1”, “issue” : “2”, “issued” : { “date-parts” : “2016” }, “page” : “38-45”, “title” : “Studies on Traditional Medicinal Plants in Ambagiorgis Area of Wogera District, Amhara Regional State, Ethiopia”, “type” : “article-journal”, “volume” : “4” }, “uris” : “http://www.mendeley.com/documents/?uuid=8949f410-b532-4a73-8fd2-f94118e1ba49” } , “mendeley” : { “formattedCitation” : “(Getnet et al., 2016)”, “plainTextFormattedCitation” : “(Getnet et al., 2016)”, “previouslyFormattedCitation” : “(Getnet et al., 2016)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Getnet et al., 2016), croton macrostchyus ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.2202/1553-3840.1255”, “ISSN” : “1553-3840”, “abstract” : “The present study evaluates the anti-nociceptive and anti-inflammatory properties of the aqueous and methylene chloride/methanol (CH2Cl2 / CH3OH) extracts of the stem bark of Croton macrostachyus. The extracts administered orally at the doses of 150, 300 and 600 mg/kg were examined against pain induced by acetic acid, formalin and pressure and against inflammation induced by carragenan, histamine and formalin. Both extracts induced a significant dose-dependent (P < 0.001) reduction in the number of abdominal constrictions induced by acetic acid. The three doses of the two extracts also significantly reduced (P < 0.001) the two phases of pain induced by formalin. At the dose of 600 mg/kg, the aqueous and the CH2Cl2 / CH3OH extracts exhibited a significant analgesic activity against pressure-induced pain. The two extracts also exhibited anti-inflammatory activity, the CH2Cl2 / CH3OH extract being the most active, inhibited acute inflammation induced by carrageenan, histamine and formalin. Both extracts also significantly reduced the chronic inflammation induced by formalin. These results show that the aqueous and CH2Cl2 / CH3OH extracts of the stem bark of Croton macrostachyus possess analgesic and anti-inflammatory properties. These findings are in accordance with the traditional use of the plant and indicate that Croton macrostachyus is a potent source of analgesic and anti-inflammatory principles. Copyright u00a92009 The Berkeley Electronic Press. All rights reserved.”, “author” : { “dropping-particle” : “”, “family” : “Kamanyi”, “given” : “Albert”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Mbiantcha”, “given” : “Marius”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Nguelefack”, “given” : “Telesphore Benoit”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Ateufack”, “given” : “Gilbert”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Watcho”, “given” : “Pierre”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Ndontsa”, “given” : “Blanche Laure”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Tane”, “given” : “Pierre”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Complementary and Integrative Medicine”, “id” : “ITEM-1”, “issue” : “1”, “issued” : { “date-parts” : “2009” }, “title” : “Anti-Nociceptive and Anti-Inflammatory Activities of Extracts from the Stem Bark of Croton macrostachyus (Euphorbiaceae) in Mice and Rats”, “type” : “article-journal”, “volume” : “6” }, “uris” : “http://www.mendeley.com/documents/?uuid=ef14312c-a102-46d6-8b01-1d413a9237e0” } , “mendeley” : { “formattedCitation” : “(Kamanyi et al., 2009)”, “plainTextFormattedCitation” : “(Kamanyi et al., 2009)”, “previouslyFormattedCitation” : “(Kamanyi et al., 2009)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Kamanyi et al., 2009), Ocimum suave ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/j.jep.2012.04.041”, “ISSN” : “03788741”, “PMID” : “22561892”, “abstract” : “Ethnopharmacological relevance: Ocimum suave has been used in the Ethiopian traditional medicine to relieve pain, fever, inflammation and other disease conditions. Aim of the study: The aim of the present study was to investigate the anti-inflammatory activities of the aqueous and ethanol leaf extracts and some fractions of Ocimum suave in mice. Materials and methods: The crude extracts were screened for their anti-inflammatory activities on carrageenan-induced mouse paw edema at three dose levels. The butanol and aqueous fractions of the aqueous extract were also evaluated for their anti-inflammatory activities using carrageenan, histamine and serotonin-induced mouse paw edema at three dose levels. Normal saline and aspirin were employed as negative and positive control groups, respectively. Results: Both ethanol and aqueous extracts significantly decreased carrageenan-induced inflammation at all the three doses used. However, greater paw edema inhibition was observed with the aqueous extract. The two fractions also showed significant reduction of inflammation against inflammatory models in which the aqueous residue exhibited the highest inhibition. Conclusions: From the present findings, it can be concluded that the ethanol and aqueous leaf extracts as well as butanol and aqueous fractions of Ocimum suave have shown anti-inflammatory properties. u00a9 2012 Elsevier Ireland Ltd. All rights reserved.”, “author” : { “dropping-particle” : “”, “family” : “Masresha”, “given” : “Birhanetensay”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Makonnen”, “given” : “Eyasu”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Debella”, “given” : “Asfaw”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Ethnopharmacology”, “id” : “ITEM-1”, “issue” : “1”, “issued” : { “date-parts” : “2012” }, “page” : “201-205”, “publisher” : “Elsevier”, “title” : “In vivo anti-inflammatory activities of Ocimum suave in mice”, “type” : “article-journal”, “volume” : “142” }, “uris” : “http://www.mendeley.com/documents/?uuid=ebf854d5-6a6a-4e82-83bd-8101e4c48cb4” } , “mendeley” : { “formattedCitation” : “(Masresha et al., 2012)”, “plainTextFormattedCitation” : “(Masresha et al., 2012)”, “previouslyFormattedCitation” : “(Masresha et al., 2012)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Masresha et al., 2012), Cucumis ficifolius ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1186/1746-4269-9-65”, “ISBN” : “10.1186/1746-4269-9-65”, “ISSN” : “1746-4269”, “PMID” : “24011232”, “abstract” : “BACKGROUND: The Ethiopian people have been dependent on traditional medicine, mainly medicinal plants, from time immemorial for control of human and animal health problems, and they still remain to be largely dependent on the practice. The purpose of the current study was to conduct ethnobotanical study to document medicinal plants used to treat diseases of human and domestic animals in Kilte Awulaelo District in the Tigray Region of Ethiopia.\n\nMETHODS: Ethnobotanical data were collected between July and September 2011 through semi-structured interviews, ranking exercises and field observations. For the interviews, 72 knowledgeable informants were sampled using purposive sampling method. For the different ranking exercises, key informants were identified with the help of elders and local administrators from informants that were already involved in the interviews.\n\nRESULTS: The study revealed 114 medicinal plant species belonging to 100 genera and 53 families. The plants were used to treat 47 human and 19 livestock diseases. Of the species, the majority (74%) were obtained from the wild. Herbs were the most utilized plants, accounting for 44% of the species, followed by shrubs (29%). Leaf was the most commonly used plant part accounting for 42.98% of the plants, followed by roots (25.73%). Preference ranking exercise on selected plants used against abdominal pain indicated the highest preference of people for Solanum marginatum. Direct matrix ranking showed Cordia africana as the most preferred multipurpose plant in the community. Preference ranking of selected scarce medicinal plants indicated Myrica salicifolia as the most scarce species, followed by Boscia salicifolia and Acokanthera schimperi. According to priority ranking, drought was identified as the most destructive factor of medicinal plants, followed by overgrazing and firewood collection.\n\nCONCLUSION: Medicinal plants are still playing significant role in the management of various human and livestock diseases in the study area with herbs taking the lead in the number of plants used in the preparation of remedies, which may be an indication of their relatively better abundance as compared to other life forms. Recurrent drought was reported to have seriously threatened medicinal plant resources in the District. Awareness is thus needed be raised among local people on sustainable utilization and management of plant resources. Ex situ and in situ conservation measures should be taken to protu2026”, “author” : { “dropping-particle” : “”, “family” : “Teklay”, “given” : “Abraha”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Abera”, “given” : “Balcha”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Giday”, “given” : “Mirutse”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Ethnobiology and Ethnomedicine”, “id” : “ITEM-1”, “issue” : “1”, “issued” : { “date-parts” : “2013” }, “page” : “65”, “publisher” : “Journal of Ethnobiology and Ethnomedicine”, “title” : “An ethnobotanical study of medicinal plants used in Kilte Awulaelo District, Tigray Region of Ethiopia”, “type” : “article-journal”, “volume” : “9” }, “uris” : “http://www.mendeley.com/documents/?uuid=fbac5dd9-383f-4a59-8c00-1f84b51b5a88” } , “mendeley” : { “formattedCitation” : “(Teklay et al., 2013)”, “plainTextFormattedCitation” : “(Teklay et al., 2013)”, “previouslyFormattedCitation” : “(Teklay et al., 2013)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Teklay et al., 2013), Arisaema schimperianum, Euclea racemose, Malva verticillata ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Enyew”, “given” : “Abiyu”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Asfaw”, “given” : “Zemede”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Kelbessa”, “given” : “Ensermu”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Nagappan”, “given” : “Raja”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issue” : “4”, “issued” : { “date-parts” : “2014” }, “page” : “154-167”, “title” : “Ethnobotanical Study of Traditional Medicinal Plants in and Around Fiche District , Central Ethiopia”, “type” : “article-journal”, “volume” : “6” }, “uris” : “http://www.mendeley.com/documents/?uuid=edc7ba09-a477-47e2-98b3-7a87905b5e23” } , “mendeley” : { “formattedCitation” : “(Enyew et al., 2014)”, “plainTextFormattedCitation” : “(Enyew et al., 2014)”, “previouslyFormattedCitation” : “(Enyew et al., 2014)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Enyew et al., 2014), Impatients tinctoria ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “abstract” : “ABSTRACT Introduction: Ethnobotany involves an interdisciplinary approach encompassing the fields of botany, chemistry, pharmacology and anthropology. The usage of traditional and complementary medicine is on the increase in many developed and developing countries. Objective: The study was done to identify major medicinal plants, and also to document the traditional medicinal plants and their medicinal uses in Dega Damot Woreda, Amhara Region, Ethiopia. Methodology and Materials: A community based cross-sectional descriptive study is conducted on a total of 70 informants, among which 20 were traditional healers and the rest were heterogeneous groups of study participants to survey the usage customs of traditional medicinal plants. Results and discussion: In this study, 50 participants were included of which 62% of them were illiterates. 20 well recognized traditional healers were also included, among which 18 were males and 2 females. Most of the traditional healers indicated that their sources of knowledge was from their fathers. In the study area Croton macrostachyus and Ranunculus multifidus were ranked first which were most effective for the treatment of malaria and the treatment of visceral leishimaniasis (Chinkur) respectively. Also, 54 plant species were reported for their medicinal values. Euphorbiaceae are the dominant family, followed by Solanaceae. The 54 plant species were used for 38 types of ailments. Roots and leaves were the most frequently used plant parts. Chopping, pounding and crushing are the most frequently used ways of preparing drugs in the study area and the drugs were administered orally. Conclusion: The people in the study area are knowledgeable about the plants, their distribution, parts of the plants and its use. Different medicinal plants are used to treat various illnesses and herbal medicine remains the most important component of public health care. It is important to create awareness about the conservation of medicinal plant and the importance of maintaining the knowledge about herbal medicine. Keywords:”, “author” : { “dropping-particle” : “”, “family” : “Wolde-mariam”, “given” : “Messay”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Limenih”, “given” : “Yayesh”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Umer”, “given” : “Shemsu”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “International Journal of Research in Pharmacy and Chemistry”, “id” : “ITEM-1”, “issue” : “2”, “issued” : { “date-parts” : “2015” }, “page” : “258-273”, “title” : “Ethnobotanical study on traditional medicinal plants in Dega Damot woreda, Amhara region, North Ethiopia”, “type” : “article-journal”, “volume” : “5” }, “uris” : “http://www.mendeley.com/documents/?uuid=3044599e-67c0-4a9c-b6af-208cf784d91f” } , “mendeley” : { “formattedCitation” : “(Wolde-mariam et al., 2015)”, “plainTextFormattedCitation” : “(Wolde-mariam et al., 2015)”, “previouslyFormattedCitation” : “(Wolde-mariam et al., 2015)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Wolde-mariam et al., 2015), Balanites, Ehretia cymosa ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Legese”, “given” : “Getu Alemayehu”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Kelbessa”, “given” : “Ensermu”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Asfaw”, “given” : “Zemede”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Medicinal Plants Studies”, “id” : “ITEM-1”, “issue” : “6”, “issued” : { “date-parts” : “2015” }, “page” : “1-11”, “title” : “Ethnobotanical Study of Medicinal Plants Used by Local Communities of Minjar-Shenkora District, North Shewa Zone of Amhara Region, Ethiopia”, “type” : “article-journal”, “volume” : “3” }, “uris” : “http://www.mendeley.com/documents/?uuid=afe88165-067a-4c35-9c6e-231ad122c473” } , “mendeley” : { “formattedCitation” : “(Legese et al., 2015)”, “plainTextFormattedCitation” : “(Legese et al., 2015)”, “previouslyFormattedCitation” : “(Legese et al., 2015)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Legese et al., 2015).

1.5 Cucumis ficifoliusCucumis ficifolius (Cucrbitaceace) is found widely distributed in the East Africa especially in Ethiopia and Kenya. The plant is known locally in Amharic as, ‘yemdir enbuay’, in Tigrigna as, ‘Rambo-ambo’. It is perennial usually with prostrate herb that stems up to 1 m long (Fig. 3). It has finer intermixed spreading hairs; basal stems thickened with light-colored bark, arising from a thickened rootstock (ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1007/s00535-013-0753-x”, “ISBN” : “0944-1174”, “ISSN” : “09441174”, “PMID” : “23397116”, “abstract” : “Opioid receptors are widely distributed in the human body and are crucially involved in numerous physiological processes. These include pain signaling in the central and the peripheral nervous system, reproduction, growth, respiration, and immunological response. Opioid receptors additionally play a major role in the gastrointestinal (GI) tract in physiological and pathophysiological conditions. This review discusses the physiology and pharmacology of the opioid system in the GI tract. We additionally focus on GI disorders and malfunctions, where pathophysiology involves the endogenous opioid system, such as opioid-induced bowel dysfunction, opioid-induced constipation or abdominal pain. Based on recent reports in the field of pharmacology and medicinal chemistry, we will also discuss the opportunities of targeting the opioid system, suggesting future treatment options for functional disorders and inflammatory states of the GI tract.”, “author” : { “dropping-particle” : “”, “family” : “Sobczak”, “given” : “Marta”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Sau0142aga”, “given” : “Maciej”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Storr”, “given” : “Martin A.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Fichna”, “given” : “Jakub”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Gastroenterology”, “id” : “ITEM-1”, “issue” : “1”, “issued” : { “date-parts” : “2014” }, “page” : “24-45”, “title” : “Physiology, signaling, and pharmacology of opioid receptors and their ligands in the gastrointestinal tract: Current concepts and future perspectives”, “type” : “article-journal”, “volume” : “49” }, “uris” : “http://www.mendeley.com/documents/?uuid=93c9d18d-17a0-461f-83c0-aa73d23f1940” } , “mendeley” : { “formattedCitation” : “(Sobczak et al., 2014)”, “manualFormatting” : “Jeffrey, 1980)”, “plainTextFormattedCitation” : “(Sobczak et al., 2014)”, “previouslyFormattedCitation” : “(Sobczak et al., 2014)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }Jeffrey, 1980).

In the Ethiopian folklore medicine, C. ficifolius has traditionally been utilized to treat a number of ailments. In Kilteawlaelo district, Tigray region, Ethiopia, the root of C. ficifolius is chewed with the diseased teeth to treat tooth ache; crushed, filtered and fluid is drunk to treat joint pain; mixed with bark of Croton macrostachyus, the dried paste is mixed with butter and drunk or the product is chewed and then the fluid is drunk to treat stomach ache ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1186/1746-4269-9-65”, “ISBN” : “10.1186/1746-4269-9-65”, “ISSN” : “1746-4269”, “PMID” : “24011232”, “abstract” : “BACKGROUND: The Ethiopian people have been dependent on traditional medicine, mainly medicinal plants, from time immemorial for control of human and animal health problems, and they still remain to be largely dependent on the practice. The purpose of the current study was to conduct ethnobotanical study to document medicinal plants used to treat diseases of human and domestic animals in Kilte Awulaelo District in the Tigray Region of Ethiopia.\n\nMETHODS: Ethnobotanical data were collected between July and September 2011 through semi-structured interviews, ranking exercises and field observations. For the interviews, 72 knowledgeable informants were sampled using purposive sampling method. For the different ranking exercises, key informants were identified with the help of elders and local administrators from informants that were already involved in the interviews.\n\nRESULTS: The study revealed 114 medicinal plant species belonging to 100 genera and 53 families. The plants were used to treat 47 human and 19 livestock diseases. Of the species, the majority (74%) were obtained from the wild. Herbs were the most utilized plants, accounting for 44% of the species, followed by shrubs (29%). Leaf was the most commonly used plant part accounting for 42.98% of the plants, followed by roots (25.73%). Preference ranking exercise on selected plants used against abdominal pain indicated the highest preference of people for Solanum marginatum. Direct matrix ranking showed Cordia africana as the most preferred multipurpose plant in the community. Preference ranking of selected scarce medicinal plants indicated Myrica salicifolia as the most scarce species, followed by Boscia salicifolia and Acokanthera schimperi. According to priority ranking, drought was identified as the most destructive factor of medicinal plants, followed by overgrazing and firewood collection.\n\nCONCLUSION: Medicinal plants are still playing significant role in the management of various human and livestock diseases in the study area with herbs taking the lead in the number of plants used in the preparation of remedies, which may be an indication of their relatively better abundance as compared to other life forms. Recurrent drought was reported to have seriously threatened medicinal plant resources in the District. Awareness is thus needed be raised among local people on sustainable utilization and management of plant resources. Ex situ and in situ conservation measures should be taken to protu2026”, “author” : { “dropping-particle” : “”, “family” : “Teklay”, “given” : “Abraha”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Abera”, “given” : “Balcha”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Giday”, “given” : “Mirutse”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Ethnobiology and Ethnomedicine”, “id” : “ITEM-1”, “issue” : “1”, “issued” : { “date-parts” : “2013” }, “page” : “65”, “publisher” : “Journal of Ethnobiology and Ethnomedicine”, “title” : “An ethnobotanical study of medicinal plants used in Kilte Awulaelo District, Tigray Region of Ethiopia”, “type” : “article-journal”, “volume” : “9” }, “uris” : “http://www.mendeley.com/documents/?uuid=fbac5dd9-383f-4a59-8c00-1f84b51b5a88” } , “mendeley” : { “formattedCitation” : “(Teklay et al., 2013)”, “plainTextFormattedCitation” : “(Teklay et al., 2013)”, “previouslyFormattedCitation” : “(Teklay et al., 2013)” }, “properties” : { “noteIndex” : 1 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Teklay et al., 2013). An ethnobotany study South Gonder, Amhara region showed that the crushed root of C. ficifolius is given to humans, cattles, goat and sheep mixed with milk to treat bloody diarrhea; crushed and powdered then sniffed, drink with coffee cup and fumigated to treat Evil eye; the pilled is chewed and the juice is swallowed/Crushed and drunk with water to treat stomach ache; the affected nail is inserted into the fruits stay until recovery to treat “Lifie” (wound); the shoot is crushed, squeezed and inserted through ear tube to expel ear-mites ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1186/1746-4269-11-4”, “ISBN” : “1746-4269”, “ISSN” : “1746-4269”, “PMID” : “25572933”, “abstract” : “Background: Remnant forests found in areas that have long been converted to agricultural landscapes are refuges of wild useful plants; and societies inhabiting them are custodians of rich indigenous botanical knowledge. This study was undertaken to document the medicinal plants used by the people living in and around Tara-gedam and Amba remnant forests, northwestern Ethiopia, together with the associated ethnomedicinal knowledge. Methods: Data were collected from 105 informants through semi-structured interviews, guided field walk, market survey; and analyzed using standard ethnobotanical analytical tools including ranking and comparison. Results: A total of 163 medicinal plant species in 145 genera and 67 families were recorded among which Zehneria scabra drew the highest community consensus. Seventy-one percent of the medicinal plants were those used for treating human ailments only, 21% for both human and livestock and 8% for livestock only. Asteraceae, with 14 species, had the highest number of medicinal plant species. The medicinal plants mainly (79.1%) belong to the shrub and herb categories and most of them were sourced from the wild habitats. Leaves and fresh plant materials were more frequently used for medicine preparation than other parts. Protected government and church forests as well as tree propagation in nurseries followed by planting them and local practices constitute the major forest conservation efforts that indirectly protect the medicinal plants in the area. Elders and healers knew more about the medicinal plants, their distribution, the local ethnomedicinal practices and knowledge transfer patterns. Though important for the local healthcare system and with potentials for modern drug discovery, both the plants and the knowledge pool are under threat. Conclusion: The diversity of medicinal plants and the associated indigenous knowledge of Tara-gedam and its environs are of a considerable value to the local community and beyond. There is, therefore, a need for conservation of the vegetation and the medicinal plants along with preservation of the wealth of the indigenous knowledge.”, “author” : { “dropping-particle” : “”, “family” : “Chekole”, “given” : “Getnet”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Asfaw”, “given” : “Zemede”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Kelbessa”, “given” : “Ensermu”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Ethnobiology and Ethnomedicine”, “id” : “ITEM-1”, “issue” : “1”, “issued” : { “date-parts” : “2015” }, “page” : “4”, “title” : “Ethnobotanical study of medicinal plants in the environs of Tara-gedam and Amba remnant forests of Libo Kemkem District, northwest Ethiopia”, “type” : “article-journal”, “volume” : “11” }, “uris” : “http://www.mendeley.com/documents/?uuid=00da5f51-74dc-4451-b41e-5caff86e4a5a” } , “mendeley” : { “formattedCitation” : “(Chekole et al., 2015)”, “plainTextFormattedCitation” : “(Chekole et al., 2015)”, “previouslyFormattedCitation” : “(Chekole et al., 2015)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Chekole et al., 2015). In the Harla and Dengego valleys, eastern Ethiop, Cucumis dipsaceus is used to treat Gonorrhea, urinary retention and ischuria skin fungus; Cucumis prophetarum is also utilized to treat wound and swollen body partADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.18782/2320-7051.2240”, “author” : { “dropping-particle” : “”, “family” : “Getnet”, “given” : “Zelalem”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Chandrodyam”, “given” : “Subramanian”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Masresha”, “given” : “Getinet”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Int. J. 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Other medicinal plants under the cucurbitaceace has also been used actively as traditional herbal remedies for various diseases. A number of compounds of this group have been investigated for their demonstrated anti-inflammatory, antitumor, hepatoprotective, cardiovascular, immunoregulatory, anti-fungal, anti-bacterial, anti-viral, anti-diabetic, anti-tumor and anti-AIDS activities ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “ISSN” : “09754873”, “abstract” : “The family cucurbitaceae includes a large group of crops like cucumbers, and melon which are medicinally essential. The plants of the family are collectively known as cucurbits. It is a distinct family without any close relatives. Plants of this family have many medicinal and nutritional benefits. So it is important to find out the active agents possessing pharmacological activity in plants coming under the family. The major elements present are the phytochemicals like Glycosides, Terpenoids, Saponins, Tannins, Steroids, Carotenoids, and Resins etc. and most commonly the terpenoid substance called Cucurbitacins”, “author” : { “dropping-particle” : “”, “family” : “Rajasree”, “given” : “R. S.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Sibi”, “given” : “P. I.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Francis”, “given” : “Femi”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “William”, “given” : “Helen”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “International Journal of Pharmacognosy and Phytochemical Research”, “id” : “ITEM-1”, “issue” : “1”, “issued” : { “date-parts” : “2016” }, “page” : “113-123”, “title” : “Phytochemicals of cucurbitaceae family u2013 A review”, “type” : “article-journal”, “volume” : “8” }, “uris” : “http://www.mendeley.com/documents/?uuid=62b4315e-87d4-4a99-9fb8-35a84cdcf1ab” } , “mendeley” : { “formattedCitation” : “(Rajasree et al., 2016)”, “plainTextFormattedCitation” : “(Rajasree et al., 2016)”, “previouslyFormattedCitation” : “(Rajasree et al., 2016)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Rajasree et al., 2016).

According to a recent report 80% methanol extract of C. ficifolius showed anti-oxidant and hepato-protective activities (Efrem et al., 2017). Some species of the family also exhibited a pharmacologically validated activity. For instance, Cucumis melo extract demonstrated antioxidant and anti-inflammatory properties ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/j.jep.2004.04.023”, “author” : { “dropping-particle” : “”, “family” : “Vouldoukis”, “given” : “Ioannis”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Lacan”, “given” : “Dominique”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Kamate”, “given” : “Caroline”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Coste”, “given” : “Philippe”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Calenda”, “given” : “Alphonse”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Mazier”, “given” : “Dominique”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Conti”, “given” : “Marc”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Dugas”, “given” : “Bernard”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issued” : { “date-parts” : “2004” }, “page” : “67-75”, “title” : “Antioxidant and anti-inflammatory properties of a Cucumis melo LC . extract rich in superoxide dismutase activity”, “type” : “article-journal”, “volume” : “94” }, “uris” : “http://www.mendeley.com/documents/?uuid=e8b2be21-cddd-40a3-a5f9-d5dc1932b0d9” } , “mendeley” : { “formattedCitation” : “(Vouldoukis et al., 2004)”, “plainTextFormattedCitation” : “(Vouldoukis et al., 2004)”, “previouslyFormattedCitation” : “(Vouldoukis et al., 2004)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Vouldoukis et al., 2004). Previous reports also pointed that the methanolic extract of Cucumis colossus exhibited significant analgesic activity in acetic acid induced writhing test, tail flick and hot plate pain models; it was also indicated in carrageenan acute model that the plant exhibited significant anti-inflammatory activity ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.5567/pharmacologia.2016.283.289”, “author” : { “dropping-particle” : “”, “family” : “Panda”, “given” : “Siva Prasad”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Sarkar”, “given” : “Nilanjan”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Das”, “given” : “Sudipta”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Bala”, “given” : “Asis”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Haldar”, “given” : “Pallab Kanti”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issued” : { “date-parts” : “2016” }, “title” : “Short Communication Evaluation of Analgesic and Anti-inflammatory Activity of Methanol Extract of Cucumis callosus Roots in Animal Models”, “type” : “article-journal” }, “uris” : “http://www.mendeley.com/documents/?uuid=abe3fd93-f4d0-4734-a09e-c331757c5638” } , “mendeley” : { “formattedCitation” : “(Panda et al., 2016)”, “plainTextFormattedCitation” : “(Panda et al., 2016)”, “previouslyFormattedCitation” : “(Panda et al., 2016)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Panda et al., 2016).
The phytochemical screening demonstrated C. ficifolius constituted secondary metabolites such as, phenols, flavonoids, terpenoids, steroids and saponins (Efrem et al., 2017) which might confer the plant anti-oxidant and hepatoprotective effects. The diverse biological actions of the Cucurbitaceae family is believed to be due to the presence of different bioactive constituents such as cucurbitacins, triterpenes, sterols, alkaloid, saponins, tannins, flavonoids and phenolic compounds ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “K. Dhiman, A. Gupta, D. K. Sharma”, “given” : “N. S. Gill and A. Goyal.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issued” : { “date-parts” : “2012” }, “page” : “16-26”, “title” : “Review of the medicinally plants of the cucurbitaceae family”, “type” : “article-journal” }, “uris” : “http://www.mendeley.com/documents/?uuid=c8cd8261-b659-4388-b90d-d7af1db0ac1e” }, { “id” : “ITEM-2”, “itemData” : { “ISSN” : “09754873”, “abstract” : “The family cucurbitaceae includes a large group of crops like cucumbers, and melon which are medicinally essential. The plants of the family are collectively known as cucurbits. It is a distinct family without any close relatives. Plants of this family have many medicinal and nutritional benefits. So it is important to find out the active agents possessing pharmacological activity in plants coming under the family. The major elements present are the phytochemicals like Glycosides, Terpenoids, Saponins, Tannins, Steroids, Carotenoids, and Resins etc. and most commonly the terpenoid substance called Cucurbitacins”, “author” : { “dropping-particle” : “”, “family” : “Rajasree”, “given” : “R. S.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Sibi”, “given” : “P. I.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Francis”, “given” : “Femi”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “William”, “given” : “Helen”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “International Journal of Pharmacognosy and Phytochemical Research”, “id” : “ITEM-2”, “issue” : “1”, “issued” : { “date-parts” : “2016” }, “page” : “113-123”, “title” : “Phytochemicals of cucurbitaceae family u2013 A review”, “type” : “article-journal”, “volume” : “8” }, “uris” : “http://www.mendeley.com/documents/?uuid=62b4315e-87d4-4a99-9fb8-35a84cdcf1ab” } , “mendeley” : { “formattedCitation” : “(K. Dhiman, A. Gupta, D. K. Sharma, 2012; Rajasree et al., 2016)”, “plainTextFormattedCitation” : “(K. Dhiman, A. Gupta, D. K. Sharma, 2012; Rajasree et al., 2016)”, “previouslyFormattedCitation” : “(K. Dhiman, A. Gupta, D. K. Sharma, 2012; Rajasree et al., 2016)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(K. Dhiman, A. Gupta, D. K. Sharma, 2012; Rajasree et al., 2016).

Although C. ficifolius has been used in Ethiopian traditional medicine to treat different ailments, scientific investigation pharmacological actions related to the inflammatory process and pain has not been carried out.

Therefore, the aim of the study was to investigate the anti-inflammatory and anti-nociceptive activities of Cucumis ficifolius

Figure SEQ Figure * ARABIC 3:Photograph of Cucumis ficifolius A. Rich.1.6 Rational of the Study
Pain and inflammation imposes an enormous problem globally. The global prevalence of pain indicated that 20% of adults suffer from pain. The World Health Organization has estimated that 22% of the world’s primary care patients have chronic debilitating pain. Nevertheless, the problem of pain has primarily been regarded as a medical problem, and has been little addressed by the field of public health (Goldberg and McGee, 2011). It is considered a major clinical, social, and economic problem in communities around the world ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/j.mayocp.2014.09.010”, “ISBN” : “0025-6196”, “ISSN” : “19425546”, “PMID” : “25572198”, “abstract” : “Pain is considered a major clinical, social, and economic problem in communities around the world. In this review, we describe the incidence, prevalence, and economic burden of pain conditions in children, adolescents, and adults based on an electronic search of the MEDLINE and EMBASE databases for articles published from January 1, 2000, through August 1, 2014, using the keywords pain, epidemiology, burden, prevalence, and incidence. The impact of pain on individuals and potential risk factors are also discussed. Differences in the methodology and conduct of epidemiological studies make it difficult to provide precise estimates of prevalence and incidence; however, the burden of pain is unquestionably large. Improved concepts and methods are needed in order to study pain from a population perspective and further the development of pain prevention and management strategies.”, “author” : { “dropping-particle” : “”, “family” : “Henschke”, “given” : “Nicholas”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Kamper”, “given” : “Steven J.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Maher”, “given” : “Chris G.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Mayo Clinic Proceedings”, “id” : “ITEM-1”, “issue” : “1”, “issued” : { “date-parts” : “2015” }, “page” : “139-147”, “publisher” : “Elsevier Inc”, “title” : “The epidemiology and economic consequences of pain”, “type” : “article-journal”, “volume” : “90” }, “uris” : “http://www.mendeley.com/documents/?uuid=a61a32ca-e7d6-47f5-a104-724328983e1e” } , “mendeley” : { “formattedCitation” : “(Henschke et al., 2015)”, “manualFormatting” : “(Henschke et al., 2015; Azevedo et al., 2016)”, “plainTextFormattedCitation” : “(Henschke et al., 2015)”, “previouslyFormattedCitation” : “(Henschke et al., 2015)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Henschke et al., 2015; Azevedo et al., 2016).
Pain and inflammatory disorders are associated with a range of deleterious consequences such as, disability, temporary or permanent work discontinuation, reduced quality of life, heightened risk of other physical and mental health comorbidities and greatly increased health care costs, and death ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.2147/NDT.S71768”, “ISSN” : “11782021”, “PMID” : “25792837”, “abstract” : “BACKGROUND: Depression is often associated with painful physical symptoms. Previous research has seldom assessed the relationship between the severity of physical symptoms and the severity of mental and emotional symptoms of depression or other health outcomes, and no such studies have been conducted previously among individuals with depression in Japan. The aim of this study was to assess the relationship between the severity of physical pain and depression and other outcomes among individuals in Japan diagnosed with depression. METHODS: Data for individuals aged 18 and older in Japan who reported being diagnosed with depression and also reported physical pain were obtained from the Japan National Health and Wellness Survey. These respondents were characterized on sociodemographics and health characteristics, and the relationship between ratings of severity on pain in the last week and health outcomes were assessed using bivariate correlations and generalized linear models. Measures included the Patient Health Questionnaire for depression severity, Medical Outcomes Study 12-Item Short Form Survey Instrument for health-related quality of life, the Work Productivity and Activity Impairment for work and activity impairment, and 6-month report of health care use. RESULTS: More severe physical pain in the past week was correlated with more severe depression, worse health-related quality of life, lower health utility, greater impairment at work, and more health care provider visits. These relationships remained significant after incorporating sociodemographics and health characteristics in the statistical models. CONCLUSION: Individuals whose depression is accompanied by more severe physical pain have a higher burden of illness than those whose depression includes less severe pain, suggesting that even partially ameliorating painful physical symptoms may significantly benefit patients with depression. Clinicians should take the presence and severity of physical pain into account and consider treating both the physical and emotional symptoms of these patients.”, “author” : { “dropping-particle” : “”, “family” : “Vietri”, “given” : “Jeffrey”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Otsubo”, “given” : “Tempei”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Montgomery”, “given” : “William”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Tsuji”, “given” : “Toshinaga”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Harada”, “given” : “Eiji”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Neuropsychiatric Disease and Treatment”, “id” : “ITEM-1”, “issued” : { “date-parts” : “2015” }, “page” : “675-683”, “title” : “Association between pain severity, depression severity, and use of health care services in Japan: Results of a nationwide survey”, “type” : “article-journal”, “volume” : “11” }, “uris” : “http://www.mendeley.com/documents/?uuid=145bd371-50df-42d6-be20-17cf8fdde5b2” }, { “id” : “ITEM-2”, “itemData” : { “DOI” : “10.1016/j.jbspin.2015.05.001”, “ISBN” : “1297-319X”, “ISSN” : “17787254”, “PMID” : “26231097”, “abstract” : “OBJECTIVES: To evaluate the impact of rheumatoid arthritis (RA) on career, productivity, and employability.
METHODS: A retrospective cross-sectional survey was conducted in 2012-2013 in France among patients with RA who were younger than 60 years of age and employed or unemployed. Patients were either recruited during a rheumatologist visit or among members of a nationwide patient-support organization (ANDAR). They completed a questionnaire on the functional impact of RA evaluated by the Health Assessment Questionnaire (HAQ) and on the impact of their disease on work ability.
RESULTS: Of 488 surveyed patients, 364 (74.6%) were actively employed, 31 (6.4%) were job seekers, and 93 (19.1%) had left the workforce. In the employed group, mean age was 48.9 years; 82.1% of patients were women; mean RA duration was 11.6 years; and the HAQ score correlated strongly with various markers for decreased productivity including sick leaves, temporary or permanent work discontinuation, and having unwillingly downgraded from a full-time to a part-time work schedule or changed to a different job. Among job seekers, 54% had lost their previous job because of their RA.
CONCLUSION: RA is associated with various forms of work disability, which are directly related to the severity of disease-related functional impairments.”, “author” : { “dropping-particle” : “”, “family” : “Bertin”, “given” : “Philippe”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Fagnani”, “given” : “Francis”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Duburcq”, “given” : “Anne”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Woronoff”, “given” : “Anne Sophie”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Chauvin”, “given” : “Pierre”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Cukierman”, “given” : “Gabrielle”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Tropu00e9-Chirol”, “given” : “Sonia”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Joubert”, “given” : “Jean Michel”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Kobelt”, “given” : “Gisela”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Joint, bone, spine : revue du rhumatisme”, “id” : “ITEM-2”, “issue” : “1”, “issued” : { “date-parts” : “2016” }, “page” : “47-52”, “publisher” : “Elsevier Masson SAS”, “title” : “Impact of rheumatoid arthritis on career progression, productivity, and employability: The PRET Study”, “type” : “article-journal”, “volume” : “83” }, “uris” : “http://www.mendeley.com/documents/?uuid=54b54348-2a9e-4208-afe2-2cc6b2a8e245” }, { “id” : “ITEM-3”, “itemData” : { “DOI” : “10.1093/fampra/cmx034”, “ISSN” : “0263-2136”, “PMID” : “28444208”, “abstract” : “Background. Chronic pain has major clinical and social consequences. Few studies have examined any variation in the extent of impairment on quality of life and work productivity by site and type of chronic pain. Objective. The objective of our study is to examine adverse impacts of chronic pain on physical and psychological health and work productivity. Methods. Our community-population study was based on a phone-interview of adults with chronic pain, residing in Olmsted County, MN. Chronic pain groups were categorized into abdominal pain, back pain, joint pain, multisite pain, neuropathic pain or no chronic pain. We used standardized instruments, including the Brief Pain Inventory, the Patients Health Questionnair-9, and Work Productivity and Activity Impairment Questionnaire. Results. We evaluated 591 patients suffering from chronic pain and 150 participants with no chronic pain. Almost one third of patients with multisite pain (33%) and neuropathic pain (32%) reported mild/major depressive symptoms. Patients suffering from chronic pain, particularly from multisite pain and neuropathic pain, reported significant pain interferences with daily activities and impairments in physical function. Chronic pain was significantly associated with reduced performance at work but not with missed work hours. The average reported reduction in work productivity ranged from 2.4 hours (u00b15.6) per week for adults with joint chronic pain to 9.8 hours (u00b111.1) per week for adults with multisite chronic pain. Conclusions. Chronic pain, particularly multisite pain and neuropathic pain, significantly affected physical and psychological health. Chronic pain is a multifaceted health condition that requires a multidisciplinary treatment approach.”, “author” : { “dropping-particle” : “”, “family” : “Kawai”, “given” : “Kosuke”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Kawai”, “given” : “Alison Tse”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Wollan”, “given” : “Peter”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Yawn”, “given” : “Barbara P”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Family Practice”, “id” : “ITEM-3”, “issue” : “6”, “issued” : { “date-parts” : “2017” }, “page” : “656-661”, “title” : “Adverse impacts of chronic pain on health-related quality of life, work productivity, depression and anxiety in a community-based study”, “type” : “article-journal”, “volume” : “34” }, “uris” : “http://www.mendeley.com/documents/?uuid=afb865ad-551b-48cc-becf-8c166460c123” } , “mendeley” : { “formattedCitation” : “(Vietri et al., 2015; Bertin et al., 2016; Kawai et al., 2017)”, “plainTextFormattedCitation” : “(Vietri et al., 2015; Bertin et al., 2016; Kawai et al., 2017)”, “previouslyFormattedCitation” : “(Vietri et al., 2015; Bertin et al., 2016; Kawai et al., 2017)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Vietri et al., 2015; Bertin et al., 2016; Kawai et al., 2017)
Thus, any type of pain should be managed with optimal pain relief approaches for optimizing post-operative recovery and reducing morbidity and convalescence. In line with managing pain and inflammation as a target of priority, proposed recommendations such as, weighing the analgesic efficacy and potential risks and provide optimal analgesia with minimal adverse events should be considered ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/j.jclinane.2016.08.041”, “ISBN” : “0952-8180”, “ISSN” : “18734529”, “PMID” : “27871587”, “abstract” : “Peripheral nerve blocks (PNBs) are increasingly used as a component of multimodal analgesia and may be administered as a single injection (sPNB) or continuous infusion via a perineural catheter (cPNB). We undertook a qualitative review focusing on sPNB and cPNB with regard to benefits, risks, and opportunities for optimizing patient care. Meta-analyses of randomized controlled trials have shown superior pain control and reductions in opioid consumption in patients receiving PNB compared with those receiving intravenous opioids in a variety of upper and lower extremity surgical procedures. cPNB has also been associated with a reduction in time to discharge readiness compared with sPNB. Risks of PNB, regardless of technique or block location, include vascular puncture and bleeding, nerve damage, and local anesthetic systemic toxicity. Site-specific complications include quadriceps weakness in patients receiving femoral nerve block, and pleural puncture or neuraxial blockade in patients receiving interscalene block. The major limitation of sPNB is the short (12-24 hours) duration of action. cPNB may be complicated by catheter obstruction, migration, and leakage of local anesthetic as well as accidental removal of catheters. Potential infectious complications of catheters, although rare, include local inflammation and infection. Other considerations for ambulatory cPNB include appropriate patient selection, education, and need for 24/7 availability of a health care provider to address any complications. The ideal PNB technique would have a duration of action that is sufficiently long to address the most intense period of postsurgical pain; should be associated with minimal risk of infection, neurologic complications, bleeding, and local anesthetic systemic toxicity; and should be easy to perform, convenient for patients, and easy to manage in the postoperative period.”, “author” : { “dropping-particle” : “”, “family” : “Joshi”, “given” : “Girish”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Gandhi”, “given” : “Kishor”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Shah”, “given” : “Nishant”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Gadsden”, “given” : “Jeff”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Corman”, “given” : “Shelby L.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Clinical Anesthesia”, “id” : “ITEM-1”, “issued” : { “date-parts” : “2016” }, “page” : “524-529”, “publisher” : “The Authors”, “title” : “Peripheral nerve blocks in the management of postoperative pain: challenges and opportunities”, “type” : “article-journal”, “volume” : “35” }, “uris” : “http://www.mendeley.com/documents/?uuid=0e41aac4-8ce3-4a07-9648-595cff344dc9” } , “mendeley” : { “formattedCitation” : “(Joshi et al., 2016)”, “plainTextFormattedCitation” : “(Joshi et al., 2016)”, “previouslyFormattedCitation” : “(Joshi et al., 2016)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Joshi et al., 2016).
Presently, a number of drug classes are available to manage inflammation and pain. Anti-inflammatory drugs, muscle relaxants, antiepileptic medicines, antidepressants, opioids, and local anesthetics are used through different routes of administration ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “WHO”, “given” : “”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issued” : { “date-parts” : “2012” }, “title” : “WHO, guidelines on the pharmacological treatment of persisting pain in children with medical illnesses”, “type” : “article-journal” }, “uris” : “http://www.mendeley.com/documents/?uuid=10a4947d-20c2-49bf-88c8-3d6f1a7ce05a” }, { “id” : “ITEM-2”, “itemData” : { “DOI” : “10.1016/j.spen.2016.10.004”, “ISBN” : “1071-9091
1558-0776”, “ISSN” : “15580776”, “PMID” : “27989328”, “abstract” : “Adolescents and children are frequently affected by chronic pain conditions that can lead to disability and distress. The best approach to evaluation and treatment of these conditions involves use of the biopsychosocial model, which includes use of medication management. Chronic pain conditions are treated pharmacologically with a number of different medication classes via several routes of administration as drug delivery systems have progressed. These include anti-inflammatory drugs, muscle relaxants, antiepileptic medicines, antidepressants, opioids, and local anesthetics. Most are prescribed without regulatory body approval to treat specific pain syndromes as data to support their use are sparse. Medical decision making is guided by experience, empiric evidence, extrapolation from adult studies, and matching medication classes with the theorized mechanism of the pain condition. It is not recommended that nonpain practitioners prescribe opioid medications for treatment of chronic pain conditions, and pain management practitioners should seek to minimize their use. The appropriate and commonly used medications for pain conditions are presented in this narrative review.”, “author” : { “dropping-particle” : “”, “family” : “Mathew”, “given” : “Eapen”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Kim”, “given” : “Eugene”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Zempsky”, “given” : “William”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Seminars in Pediatric Neurology”, “id” : “ITEM-2”, “issue” : “3”, “issued” : { “date-parts” : “2016” }, “page” : “209-219”, “publisher” : “Elsevier”, “title” : “Pharmacologic Treatment of Pain”, “type” : “article-journal”, “volume” : “23” }, “uris” : “http://www.mendeley.com/documents/?uuid=51f8526b-e3ce-439b-b02f-3155678af0ed” } , “mendeley” : { “formattedCitation” : “(WHO, 2012; Mathew et al., 2016)”, “plainTextFormattedCitation” : “(WHO, 2012; Mathew et al., 2016)”, “previouslyFormattedCitation” : “(WHO, 2012; Mathew et al., 2016)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(WHO, 2012; Mathew et al., 2016)
However, the clinical use of anti-inflammatory and analgesic agents is limited by their affordability, accessibility, adverse drug reactions and many medicines are not effective as expected in all patients ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Croff”, “given” : “Leslie J”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issue” : “Suppl 3”, “issued” : { “date-parts” : “2013” }, “title” : “Use of NSAIDs in treating patients with arthritis”, “type” : “article-journal”, “volume” : “15” }, “uris” : “http://www.mendeley.com/documents/?uuid=820afa7e-331e-42ff-bd5c-e54e11d5dc73” } , “mendeley” : { “formattedCitation” : “(Croff, 2013)”, “plainTextFormattedCitation” : “(Croff, 2013)”, “previouslyFormattedCitation” : “(Croff, 2013)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Croff, 2013). Another major challenge is development of tolerance and dependence particularly with the chronic use of opioids ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/j.conb.2007.10.004”, “author” : { “dropping-particle” : “”, “family” : “Martini”, “given” : “Lene”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Whistler”, “given” : “Jennifer L”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issued” : { “date-parts” : “2007” }, “page” : “556-564”, “title” : “The role of mu opioid receptor desensitization and endocytosis in morphine tolerance and dependence”, “type” : “article-journal” }, “uris” : “http://www.mendeley.com/documents/?uuid=d1e53613-2437-4123-b9ea-e554bd35212f” } , “mendeley” : { “formattedCitation” : “(Martini and Whistler, 2007)”, “plainTextFormattedCitation” : “(Martini and Whistler, 2007)”, “previouslyFormattedCitation” : “(Martini and Whistler, 2007)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Martini and Whistler, 2007).
A meta-analysis comparing the effectiveness of different NSAIDS showed that despite their clinical utility against pain associated with osteoarthritis, their benefit has to be weighed against their potential harmful effects and not all NSAIDS were effective in the pain resolution ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/S0140-6736(13)60900-9”, “ISBN” : “1474-547X”, “ISSN” : “1474547X”, “PMID” : “23726390”, “abstract” : “Background The vascular and gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (tNSAIDs), are not well characterised, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomised trials. Methods We undertook meta-analyses of 280 trials of NSAIDs versus placebo (124 513 participants, 68 342 personyears) and 474 trials of one NSAID versus another NSAID (229 296 participants, 165 456 person-years). The main outcomes were major vascular events (non-fatal myocardial in farction, non-fatal stroke, or vascular death); major coronary events (non-fatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, ob struction, or bleed). Findings Major vascular events were increased by about a third by a coxib (rate ratio RR 1u00b737, 95% CI 1u00b714-1u00b766; p=0u00b70009) or diclofenac (1u00b741, 1u00b712-1u00b778; p=0u00b70036), chiefl y due to an increase in major coronary events (coxibs 1u00b776, 1u00b731-2u00b737; p=0u00b70001; diclofenac 1u00b770, 1u00b719-2u00b741; p=0u00b70032). Ibuprofen also significantly increased major coronary events (2u00b722, 1u00b710-4u00b748; p=0u00b70253), but not major vascular events (1u00b744, 0u00b789-2u00b733). Compared with placebo, of 1000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (0u00b793, 0u00b769-1u00b727). Vascular death was increased significantly by coxibs (1u00b758, 99% CI 1u00b700-2u00b749; p=0u00b70103) and diclofenac (1u00b765, 0u00b795-2u00b785, p=0u00b70187), nonsignificantly by ibuprofen (1u00b790, 0u00b756-6u00b741; p=0u00b717), but not by naproxen (1u00b708, 0u00b748-2u00b747, p=0u00b780). The proportional eff ects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (coxibs 1u00b781, 1u00b717-2u00b781, p=0u00b70070; diclofenac 1u00b789, 1u00b716-3u00b709, p=0u00b70106; ibuprofen 3u00b797, 2u00b722-7u00b710, p<0u00b70001; and naproxen 4u00b722, 2u00b771-6u00b756, p<0u00b70001). Interpretation The vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. Although NSAIDs increase vascular and gastrointestinal risks, the size of these risks can be predicted, u2026”, “author” : { “dropping-particle” : “”, “family” : “Baigent”, “given” : “Colin”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Bhala”, “given” : “N.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Emberson”, “given” : “J.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Merhi”, “given” : “A.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Abramson”, “given” : “S.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Arber”, “given” : “N.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Baron”, “given” : “J. 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E.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Kearney”, “given” : “P. M.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Merhi”, “given” : “A.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Patrono”, “given” : “C.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Wilson”, “given” : “K.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Yau”, “given” : “F.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “The Lancet”, “id” : “ITEM-1”, “issue” : “9894”, “issued” : { “date-parts” : “2013” }, “page” : “769-779”, “publisher” : “Elsevier Ltd”, “title” : “Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: Meta-analyses of individual participant data from randomised trials”, “type” : “article-journal”, “volume” : “382” }, “uris” : “http://www.mendeley.com/documents/?uuid=be045063-825c-491f-94a8-affa14255230” } , “mendeley” : { “formattedCitation” : “(Baigent et al., 2013)”, “plainTextFormattedCitation” : “(Baigent et al., 2013)”, “previouslyFormattedCitation” : “(Baigent et al., 2013)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Baigent et al., 2013). Diclofenac was superior in efficacy but highly associated with cardiovascular risks ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/S1995-7645(14)60259-5”, “ISSN” : “19957645”, “PMID” : “25312151”, “abstract” : “Objective: To identify, present and review the respiratoty medicinal plants which used by Urmian herbalists. Methods: The list of traditional healers of West Azarbaijan Province was prepared and data were obtained by direct observation, interviews and the questionnaires After that, herbarium samples were collected from the desired area and deposited in herbarium unit of the Faculty of Agriculture, Urmia University, Urmia, Iran. Results: Our results demonstrated that 20 medicinal plants from 10 plant families are used to treat respiratory disorders. Also, the most plant part that used for treating of respiratory disorders was seed (27%) and the most traditional form prescribed by herbalists was boiled (54%). Forty three percentage of Urmia herbalists have used herbs for the treatment of cough. Conclusions: People in this area have a strong belief that plants have a positive impact in the treatment of respiratory disorders and they have used medicinal plants since ancient times to treat these disorders. Our study revealed the importance of herbal medicines and traditional medicine in this area as medicinal resource for drug discovery in future.”, “author” : { “dropping-particle” : “”, “family” : “Asadbeigi”, “given” : “Mohsen”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Mohammadi”, “given” : “Tahereh”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Rafieian-Kopaei”, “given” : “Mahmoud”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Saki”, “given” : “Kourosh”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Bahmani”, “given” : “Mahmoud”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Delfan”, “given” : “Mohammad”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Asian Pacific Journal of Tropical Medicine”, “id” : “ITEM-1”, “issue” : “S1”, “issued” : { “date-parts” : “2014” }, “page” : “S364-S368”, “title” : “Traditional effects of medicinal plants in the treatment of respiratory diseases and disorders: An ethnobotanical study in the Urmia”, “type” : “article-journal”, “volume” : “7” }, “uris” : “http://www.mendeley.com/documents/?uuid=8c4cb8a7-f875-4895-b803-b299ef2bdf01” } , “mendeley” : { “formattedCitation” : “(Asadbeigi et al., 2014)”, “plainTextFormattedCitation” : “(Asadbeigi et al., 2014)”, “previouslyFormattedCitation” : “(Asadbeigi et al., 2014)” }, “properties” : { “noteIndex” : 27 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Asadbeigi et al., 2014). Naproxen substantially increased the likelihood of upper gastrointestinal complications ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “ISSN” : “1011601X”, “PMID” : “24577913”, “abstract” : “Anchomanes difformis is a tropical plant that has been used in folklore to treat diverse complications. The leaf extract of A. difformis was investigated for possible anti-nociceptive and anti-inflammatory effects in albino wistar rats. In these independent studies, two sets of twenty five rats were divided into five groups of five rats per group. Formalin induced pain in rats was used to investigate the anti-nociceptive effect of the extract. The extract was administered orally in the treated groups at doses 200, 400, 800 and 1600 mg/kg with aspirin serving as the positive drug control while the normal control group was not given any extract but water. Studies were also carried out on the egg albumin induced anti-inflammatory activity in rats by inducing oedema on the left hind paw. The result showed a significant inhibition (p<0.05) on the later phase (800mg/kg) of formalin pain induction in rats; similarly, a significant (p<0.05) anti-inflammatory activity was observed at 60, 90 and 120 minutes. The study thus validates the ethnomedicinal usage of A. difformis in the treatment of pain and inflammation.”, “author” : { “dropping-particle” : “”, “family” : “Adebayo”, “given” : “Abiodun Humphrey”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “John-Africa”, “given” : “Lucy Binda”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Agbafor”, “given” : “Amarachi Grace”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Omotosho”, “given” : “Omolola Elizabeth”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Mosaku”, “given” : “Timothy Olusoji”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Pakistan Journal of Pharmaceutical Sciences”, “id” : “ITEM-1”, “issue” : “2”, “issued” : { “date-parts” : “2014” }, “page” : “265-270”, “title” : “Anti-nociceptive and anti-inflammatory activities of extract of Anchomanes difformis in rats”, “type” : “article-journal”, “volume” : “27” }, “uris” : “http://www.mendeley.com/documents/?uuid=031b9cfe-1c09-412a-980f-a2a781d0e502” } , “mendeley” : { “formattedCitation” : “(Adebayo et al., 2014)”, “plainTextFormattedCitation” : “(Adebayo et al., 2014)”, “previouslyFormattedCitation” : “(Adebayo et al., 2014)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Adebayo et al., 2014). Occurrence of serious adverse effects impedes dose increment according to the extent of pain ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/S1995-7645(14)60259-5”, “ISSN” : “19957645”, “PMID” : “25312151”, “abstract” : “Objective: To identify, present and review the respiratoty medicinal plants which used by Urmian herbalists. Methods: The list of traditional healers of West Azarbaijan Province was prepared and data were obtained by direct observation, interviews and the questionnaires After that, herbarium samples were collected from the desired area and deposited in herbarium unit of the Faculty of Agriculture, Urmia University, Urmia, Iran. Results: Our results demonstrated that 20 medicinal plants from 10 plant families are used to treat respiratory disorders. Also, the most plant part that used for treating of respiratory disorders was seed (27%) and the most traditional form prescribed by herbalists was boiled (54%). Forty three percentage of Urmia herbalists have used herbs for the treatment of cough. Conclusions: People in this area have a strong belief that plants have a positive impact in the treatment of respiratory disorders and they have used medicinal plants since ancient times to treat these disorders. Our study revealed the importance of herbal medicines and traditional medicine in this area as medicinal resource for drug discovery in future.”, “author” : { “dropping-particle” : “”, “family” : “Asadbeigi”, “given” : “Mohsen”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Mohammadi”, “given” : “Tahereh”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Rafieian-Kopaei”, “given” : “Mahmoud”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Saki”, “given” : “Kourosh”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Bahmani”, “given” : “Mahmoud”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Delfan”, “given” : “Mohammad”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Asian Pacific Journal of Tropical Medicine”, “id” : “ITEM-1”, “issue” : “S1”, “issued” : { “date-parts” : “2014” }, “page” : “S364-S368”, “title” : “Traditional effects of medicinal plants in the treatment of respiratory diseases and disorders: An ethnobotanical study in the Urmia”, “type” : “article-journal”, “volume” : “7” }, “uris” : “http://www.mendeley.com/documents/?uuid=8c4cb8a7-f875-4895-b803-b299ef2bdf01” } , “mendeley” : { “formattedCitation” : “(Asadbeigi et al., 2014)”, “plainTextFormattedCitation” : “(Asadbeigi et al., 2014)”, “previouslyFormattedCitation” : “(Asadbeigi et al., 2014)” }, “properties” : { “noteIndex” : 27 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Asadbeigi et al., 2014)
Therefore, patients are increasingly interested to explore other options for the disease management using natural products with good effectiveness and fewer side effects. Despite it is inconclusive, herbal medicines are believed and considered to be safe and effective agents as compared to synthetic medicine. Hence people every year turn to use herbal medicine because they believe plant remedies are free from undesirable side effects ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “abstract” : “Implication for health policy/practice/research/medical education: Although medicinal plants are widely used and assumed to be safe, however, they can potentially be toxic especially in pregnancy. Where poisoning from medicinal plants has been reported, it usually has been due to misidentification of the plants in the form in which they are sold, or incorrectly preparation and administration by inadequately trained personnel. Therefore, preferably should be administered by trained personnel.”, “author” : { “dropping-particle” : “”, “family” : “Nasri”, “given” : “Hamid”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Shirzad”, “given” : “Hedayatollah”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “J HerbMed Pharmacol.”, “id” : “ITEM-1”, “issue” : “2”, “issued” : { “date-parts” : “2013” }, “page” : “21-22”, “title” : “Toxicity and safety of medicinal plants”, “type” : “article-journal”, “volume” : “2” }, “uris” : “http://www.mendeley.com/documents/?uuid=687ceb86-a6bd-4e87-b20d-e6111970a02a” } , “mendeley” : { “formattedCitation” : “(Nasri and Shirzad, 2013)”, “plainTextFormattedCitation” : “(Nasri and Shirzad, 2013)”, “previouslyFormattedCitation” : “(Nasri and Shirzad, 2013)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Nasri and Shirzad, 2013).

One of the medicinal plants believed to have anti-inflammatory and analgesic activity is Cucumis ficifolius (Cucurbitaceae). In Ethiopia, the plant has been used in the treatment of different ailments including, stomachache, wound, ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1186/1746-4269-11-4”, “ISBN” : “1746-4269”, “ISSN” : “1746-4269”, “PMID” : “25572933”, “abstract” : “Background: Remnant forests found in areas that have long been converted to agricultural landscapes are refuges of wild useful plants; and societies inhabiting them are custodians of rich indigenous botanical knowledge. This study was undertaken to document the medicinal plants used by the people living in and around Tara-gedam and Amba remnant forests, northwestern Ethiopia, together with the associated ethnomedicinal knowledge. Methods: Data were collected from 105 informants through semi-structured interviews, guided field walk, market survey; and analyzed using standard ethnobotanical analytical tools including ranking and comparison. Results: A total of 163 medicinal plant species in 145 genera and 67 families were recorded among which Zehneria scabra drew the highest community consensus. Seventy-one percent of the medicinal plants were those used for treating human ailments only, 21% for both human and livestock and 8% for livestock only. Asteraceae, with 14 species, had the highest number of medicinal plant species. The medicinal plants mainly (79.1%) belong to the shrub and herb categories and most of them were sourced from the wild habitats. Leaves and fresh plant materials were more frequently used for medicine preparation than other parts. Protected government and church forests as well as tree propagation in nurseries followed by planting them and local practices constitute the major forest conservation efforts that indirectly protect the medicinal plants in the area. Elders and healers knew more about the medicinal plants, their distribution, the local ethnomedicinal practices and knowledge transfer patterns. Though important for the local healthcare system and with potentials for modern drug discovery, both the plants and the knowledge pool are under threat. Conclusion: The diversity of medicinal plants and the associated indigenous knowledge of Tara-gedam and its environs are of a considerable value to the local community and beyond. There is, therefore, a need for conservation of the vegetation and the medicinal plants along with preservation of the wealth of the indigenous knowledge.”, “author” : { “dropping-particle” : “”, “family” : “Chekole”, “given” : “Getnet”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Asfaw”, “given” : “Zemede”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Kelbessa”, “given” : “Ensermu”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Ethnobiology and Ethnomedicine”, “id” : “ITEM-1”, “issue” : “1”, “issued” : { “date-parts” : “2015” }, “page” : “4”, “title” : “Ethnobotanical study of medicinal plants in the environs of Tara-gedam and Amba remnant forests of Libo Kemkem District, northwest Ethiopia”, “type” : “article-journal”, “volume” : “11” }, “uris” : “http://www.mendeley.com/documents/?uuid=00da5f51-74dc-4451-b41e-5caff86e4a5a” } , “mendeley” : { “formattedCitation” : “(Chekole et al., 2015)”, “plainTextFormattedCitation” : “(Chekole et al., 2015)”, “previouslyFormattedCitation” : “(Chekole et al., 2015)” }, “properties” : { “noteIndex” : 1 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Chekole et al., 2015); joint pain and tooth ache ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1186/1746-4269-9-65”, “ISBN” : “10.1186/1746-4269-9-65”, “ISSN” : “1746-4269”, “PMID” : “24011232”, “abstract” : “BACKGROUND: The Ethiopian people have been dependent on traditional medicine, mainly medicinal plants, from time immemorial for control of human and animal health problems, and they still remain to be largely dependent on the practice. The purpose of the current study was to conduct ethnobotanical study to document medicinal plants used to treat diseases of human and domestic animals in Kilte Awulaelo District in the Tigray Region of Ethiopia.\n\nMETHODS: Ethnobotanical data were collected between July and September 2011 through semi-structured interviews, ranking exercises and field observations. For the interviews, 72 knowledgeable informants were sampled using purposive sampling method. For the different ranking exercises, key informants were identified with the help of elders and local administrators from informants that were already involved in the interviews.\n\nRESULTS: The study revealed 114 medicinal plant species belonging to 100 genera and 53 families. The plants were used to treat 47 human and 19 livestock diseases. Of the species, the majority (74%) were obtained from the wild. Herbs were the most utilized plants, accounting for 44% of the species, followed by shrubs (29%). Leaf was the most commonly used plant part accounting for 42.98% of the plants, followed by roots (25.73%). Preference ranking exercise on selected plants used against abdominal pain indicated the highest preference of people for Solanum marginatum. Direct matrix ranking showed Cordia africana as the most preferred multipurpose plant in the community. Preference ranking of selected scarce medicinal plants indicated Myrica salicifolia as the most scarce species, followed by Boscia salicifolia and Acokanthera schimperi. According to priority ranking, drought was identified as the most destructive factor of medicinal plants, followed by overgrazing and firewood collection.\n\nCONCLUSION: Medicinal plants are still playing significant role in the management of various human and livestock diseases in the study area with herbs taking the lead in the number of plants used in the preparation of remedies, which may be an indication of their relatively better abundance as compared to other life forms. Recurrent drought was reported to have seriously threatened medicinal plant resources in the District. Awareness is thus needed be raised among local people on sustainable utilization and management of plant resources. Ex situ and in situ conservation measures should be taken to protu2026”, “author” : { “dropping-particle” : “”, “family” : “Teklay”, “given” : “Abraha”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Abera”, “given” : “Balcha”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Giday”, “given” : “Mirutse”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Ethnobiology and Ethnomedicine”, “id” : “ITEM-1”, “issue” : “1”, “issued” : { “date-parts” : “2013” }, “page” : “65”, “publisher” : “Journal of Ethnobiology and Ethnomedicine”, “title” : “An ethnobotanical study of medicinal plants used in Kilte Awulaelo District, Tigray Region of Ethiopia”, “type” : “article-journal”, “volume” : “9” }, “uris” : “http://www.mendeley.com/documents/?uuid=fbac5dd9-383f-4a59-8c00-1f84b51b5a88” } , “mendeley” : { “formattedCitation” : “(Teklay et al., 2013)”, “plainTextFormattedCitation” : “(Teklay et al., 2013)”, “previouslyFormattedCitation” : “(Teklay et al., 2013)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Teklay et al., 2013).

Investigation of the plant might contribute for the search of novel bioactive compounds which might serve as a lead compound in the discovery of new analgesic and anti-inflammatory agents.
2. Objectives2.1. General ObjectiveTo evaluate the anti-nociceptive and anti-inflammatory properties of crude the 80% methanolic crude root extract and solvent fractions of C. ficifolius A. Rich
2.2. Specific ObjectivesTo determine oral acute toxicity of crude root extract of C. ficifolius
To evaluate the anti-nociceptive activity of crude root extract and solvent fractions on acetic acid writhing, formalin and hot plate tests
To investigate the anti-inflammatory properties of methanolic crude root extract and solvent fractions of C. ficifolius.

3. Materials and Methods3.1. Materials3.1.1 Chemicals and DrugsChemicals and solvents of laboratory and analytical grade were used throughout this work: Carrageenan (Tokyo chemical industries, Japan), methanol, n-butanol, chloroform, acetylsalicylic acid (Addis Pharmaceutical Factory/APF), acetic acid, morphine (AMINO Ltd. Neuenhof, Switzerland), formalin, distilled water and normal saline were used.
3.1.2. Collection, Identification and Preparation of Plant Materials
The roots of C. ficifolius were collected from Kilte Awlaelo district of Tigray Regional State, 829 kilometers from Addis Ababa. The plant was then identified and authenticated by a botanist and the sample specimen deposited in Herbarium unit of Department of Biology, College of Computational and Natural Science, University of Gondar with voucher number of DG0024/210.
3.1.3. Experimental AnimalsSwiss albino mice of either sex 6-8 weeks (25–35 g) from Pharmacology and Toxicology laboratory, School of Pharmacy, College of Health Sciences, Mekelle University were used in the present study. Experimental animals were housed in polypropylene cage and maintained under standard animal house condition (at ambient temperature, and with a 12 h light-dark cycle) and allowed free access to the standard pellet diet and water ad libitum. Before initiation of the experiment the animals were acclimatized to laboratory condition for a period of seven days. All procedures have been undertaken as per the Guide for the Care and Use of Laboratory Animals ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “OECD”, “given” : “”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Oecd Guidelines for the Testing of Chemicals”, “id” : “ITEM-1”, “issue” : “October”, “issued” : { “date-parts” : “2008” }, “page” : “1-27”, “title” : “Acute Oral Toxicity u2013 Up-and-Down-Procedure (UDP)”, “type” : “article-journal”, “volume” : “425” }, “uris” : “http://www.mendeley.com/documents/?uuid=5407a2f6-80e9-48a1-bc11-cd7e166b8406” } , “mendeley” : { “formattedCitation” : “(OECD, 2008)”, “plainTextFormattedCitation” : “(OECD, 2008)”, “previouslyFormattedCitation” : “(OECD, 2008)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(OECD, 2008). The study protocol was approved by Health Research Ethics Review Committee (HRERC), College of Health Sciences, Mekelle University with protocol number (ERC1206/2018). Animals were scarified under halothane anesthesia after completion of the experiments.
3.2. Methods3.2.1. Extraction of Plant MaterialThe roots were cleaned from the dust and debris and washed gently with water; reduced to appropriate size and air dried under shade for two weeks. The dried root material was then pulverized with grinder.

Figure SEQ Figure * ARABIC 4: The extraction process of Cucumis ficifolius roots using 80% methanol.Then a total amount 1.335 kg of dried root powder was macerated in methanol (80%) for 72 hours ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1186/1472-6882-14-79”, “ISBN” : “1996-0875”, “ISSN” : “1472-6882”, “PMID” : “24580778”, “abstract” : “BACKGROUND: The issue of resistance in malarial infection makes development of novel drugs a necessity. An alternative source for discovering such drugs is natural products. Croton macrostachyus H. (Euphorbiaceae) is used in Ethiopian folklore medicine for the treatment of malaria and found to possess antimalarial activity in vitro. However, no further scientific investigations have been carried out to substantiate the claim. This study therefore aimed at investigating the in vivo antiplasmodial activity of 80% methanol extract and solvent fractions of the leaves of Croton macrostachyus H. in rodent model of malaria.\n\nMETHODS: A rodent malaria parasite, Plasmodium berghei, was used to inoculate healthy male Swiss Albino mice of age 6-8u00a0weeks and weight 23-27u00a0g. A hydro-alcoholic crude extract and the solvent fractions (chloroform, methanol and aqueous) were administered at different doses 200, 400 and 600u00a0mg/kg. Parameters, including parasitemia, survival time, body weight, temperature, and packed cell volume were then determined using standard tests such as Peter’s and Rane’s test.\n\nRESULTS: Chemoprotective effect exerted by the crude extract and fractions ranged between 44-91% and 12-76%, respectvely. The chemotherapeutic effect of the crude extract and chloroform fraction was in the range of 39-83% and 66-82%, respectively. Maximum effect in both tests was observed with the larger dose of the crude extract and chloroform fraction. The crude extract prevented loss of weight and reduction in temperature but did not affect packed cell volume. However, the chloroform fraction did also reverse reduction in packed cell volume due to the absence of saponins in the fraction.\n\nCONCLUSIONS: The results collectively indicate that the plant has a promising antiplasmodial activity against Plasmodium berghei, which upholds the earlier in vitro findings as well as its folkloric use. Thus, it could be considred as a potential source to develop new antimalarial agents.”, “author” : { “dropping-particle” : “”, “family” : “Bantie”, “given” : “Laychiluh”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Assefa”, “given” : “Solomon”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Teklehaimanot”, “given” : “Tilahun”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Engidawork”, “given” : “Ephrem”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “BMC Complementary and Alternative Medicine”, “id” : “ITEM-1”, “issue” : “1”, “issued” : { “date-parts” : “2014” }, “page” : “79”, “title” : “In vivo antimalarial activity of the crude leaf extract and solvent fractions of Croton macrostachyus Hocsht. (Euphorbiaceae) against Plasmodium berghei in mice”, “type” : “article-journal”, “volume” : “14” }, “uris” : “http://www.mendeley.com/documents/?uuid=7fabe206-c007-4032-9072-aa54e08e23a3” } , “mendeley” : { “formattedCitation” : “(Bantie et al., 2014)”, “plainTextFormattedCitation” : “(Bantie et al., 2014)”, “previouslyFormattedCitation” : “(Bantie et al., 2014)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Bantie et al., 2014). The extraction process was facilitated by using an orbital shaker at 120 rpm. The mixture was first filtered using muslin cloth and then with Whatman filter paper no.1. Re-maceration of the remaining residue was done for another 72 hours twice to obtain maximal yield. The filtrates were concentrated in oven dryer set at 40 oC. The dried powder of the extract was kept in a refrigerator at 4 oC in air-tight containers until use.3.2.2. Solvent-Solvent ExtractionThe procedure of solvent-solvent fraction was carried out using a separatory funnel. A total of 45 g of the crude extract was dissolved in 270 ml of distilled water. The dissolved crude extract was transferred into separating funnel of 500 ml capacity. Then extraction was performed successively using solvents of increasing polarity, starting from chloroform (200 ml X 3) then n-butanol (200 ml X 3). After collecting the chloroform and n-butanol fractions the remaining residue was considered as aqueous fraction. The fractions were concentrated using oven dryer at 40°C. The dried powders were kept in air-tight containers wrapped with the aluminum foil and stored in a refrigerator at 4 oC until further use.
3.2.3 Acute Oral Toxicity Test
The acute oral toxicity test was carried out according to limit test recommendations of Organization for Economic Co-operation and Development (OECD) 425 Guideline ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “OECD”, “given” : “”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Oecd Guidelines for the Testing of Chemicals”, “id” : “ITEM-1”, “issue” : “October”, “issued” : { “date-parts” : “2008” }, “page” : “1-27”, “title” : “Acute Oral Toxicity u2013 Up-and-Down-Procedure (UDP)”, “type” : “article-journal”, “volume” : “425” }, “uris” : “http://www.mendeley.com/documents/?uuid=5407a2f6-80e9-48a1-bc11-cd7e166b8406” } , “mendeley” : { “formattedCitation” : “(OECD, 2008)”, “plainTextFormattedCitation” : “(OECD, 2008)”, “previouslyFormattedCitation” : “(OECD, 2008)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(OECD, 2008). Nulliparous, non-pregnant and healthy female Swiss albino mice (age of 8-12 weeks) weighing from 20-30gm were employed for this test. A total of five female animals were used. The extract to be tested was calculated based on fasting body weight and volume administered was determined based on OECD guideline that states 1 mL/100 g of body weight of the animal. On day one, a mouse fasted for four hours was orally given 2000 mg/kg of the extract dissolved in distilled water by oral gavage. The mouse was then observed for physical or behavioral changes at least once during the first 30 min, periodically for 24 h, with special attention during the first 4 h. After 24 h other four mice were selected and fasted for 4 h and administered a single dose of 2000 mg/kg. The mouse was then observed for at least once during the first 30 min, periodically for 24 h, with special attention during the first 4 h, and daily thereafter for a total of 14 days Animals were observed for any manifestations including tremors, convulsions, salivation, diarrhea, lethargy, sleep and coma.

3.2.4 Anti-nociceptive Activity Testi. Acetic Acid Induced Writhing TestThe test was carried out as per the method described by Birhane et al., (2015) with slight modification. Mice of either sex (26-35 gm) were used. Animals fasted for 12 hours were randomly divided into five and six groups of six mice each for evaluation of the crude extract and fractions, respectively.
The negative control group was administered with distilled water (DW) 10 ml/kg, whereas the positive control group received 150 mg/kg aspirin. The remaining 3 groups were treated with the crude extract at doses of 200, 400, and 800 mg/kg. The 200, 400 and 800 mg/kg doses were selected based on the acute toxicity study. In fractions, six groups of animals were used: Group I received DW (10ml/kg); Group II and III were treated with 100 mg/kg and 200 mg/kg aqueous fraction, respectively; Group IV was administered with 100 mg/kg butanol fraction and Group V (200 mg/kg, butanol fraction) while Group VI was treated with aspirin 150 mg/kg. Thirty minutes following administration of vehicle, standard drug and test substance; the animals were subjected to intraperitoneal (i.p) injection of acetic acid solution (0.6%, 10 ml/kg) (Debebe et al., 2007).
The writhing response which consists of a contraction of the abdominal muscle together with a stretching of the hind limbs and arching of the back were used as a writhing response and measured for 20 min after a latency period of 5 min. Percent protection was calculated by applying the formula ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/j.jep.2017.02.036”, “ISSN” : “18727573”, “abstract” : “Background Pain and inflammation are associated with the pathophysiology of various clinical conditions. Most analgesic and anti-inflammatory drugs available in the market present a wide range of problems. The current study was aimed at investigating the analgesic and anti-inflammatory activity of 80% methanol extract of J. abyssinicum root. Methods The analgesic activity was determined using tail-flick test and acetic acid induced writhing, whereas anti-inflammatory activity was determined by carrageenan induced paw edema and formalin induced pedal edema, carried out in vivo. The test group received three different doses of the extract (50u00a0mg/kg, 100u00a0mg/kg and 200u00a0mg/kg) orally. The positive control group received diclofenac (10u00a0mg/kg), aspirin (100u00a0mg/kg or 150u00a0mg/kg) or morphine (20u00a0mg/kg) orally. The negative control group received vehicle (2% Tween 80, 10u00a0ml/kg) orally. Furthermore, preliminary phytochemical screening was carried out. Results Oral administration of J. abbysinicum 80% methanol extract (at all doses) significantly (p<0.001) inhibit pain sensation in the pain models. Similarly, the extract demonstrated anti-inflammatory effect in the inflammation models in mice. Preliminary phytochemical screening showed the presence of saponins, flavonoids, terpenoids, triterpenens and glycosides. Conclusion The data obtained from the present study indicates that the extract possessed a significant analgesic and anti-inflammatory activity, upholding the folkloric use of the plant.”, “author” : { “dropping-particle” : “”, “family” : “Tadiwos”, “given” : “Yohannes”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Nedi”, “given” : “Teshome”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Engidawork”, “given” : “Ephrem”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Ethnopharmacology”, “id” : “ITEM-1”, “issue” : “November 2016”, “issued” : { “date-parts” : “2017” }, “page” : “281-289”, “publisher” : “Elsevier Ireland Ltd”, “title” : “Analgesic and anti-inflammatory activities of 80% methanol root extract of Jasminum abyssinicum Hochst. ex. Dc. (Oleaceae) in mice”, “type” : “article-journal”, “volume” : “202” }, “uris” : “http://www.mendeley.com/documents/?uuid=eb4f1592-635e-4678-9916-ee2773999703” } , “mendeley” : { “formattedCitation” : “(Tadiwos et al., 2017)”, “plainTextFormattedCitation” : “(Tadiwos et al., 2017)”, “previouslyFormattedCitation” : “(Tadiwos et al., 2017)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Tadiwos et al., 2017).

% Analgesic activity=Mean no. writhes (control) -Mean no. of writhes (treated)Mean no. of writhes (control) ×100ii. Hot Plate TestThe hot plate test was performed according to the method described by Debebe et al. (2007) with a slight modification using hot-plate apparatus (ORCHID Scientific, India) which was maintained at 55 ± 0.1 °C. Overnight fasted animals were randomized and assigned into different groups. The positive control group received morphine 20 mg/kg orally. Details of grouping and dosing of this experiment is presented in Table 1.

The baseline latencies were determined twice at 15minute intervals and the first readings were discarded. Latencies were then determined at 30, 60, 90 and 120 minutes after test substance, vehicle or standard drug administration. A cut off time of 20 secs was considered by taking three times the mean pre-drug latency was imposed to minimize tissue damage ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Debebe”, “given” : “Eyob”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Makonnen”, “given” : “Eyasu”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Health”, “given” : “Ethiopian”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Ababa”, “given” : “Addis”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issued” : { “date-parts” : “2007” }, “page” : “41-48”, “title” : “Pharmacologyonline 1: 41-48 (2007)”, “type” : “article-journal”, “volume” : “48” }, “uris” : “http://www.mendeley.com/documents/?uuid=31245730-c6f5-4457-80ea-1f4e7ba55710” } , “mendeley” : { “formattedCitation” : “(Debebe et al., 2007)”, “plainTextFormattedCitation” : “(Debebe et al., 2007)”, “previouslyFormattedCitation” : “(Debebe et al., 2007)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Debebe et al., 2007). The nociceptive latency in seconds was quantified by considering the interval between the instant the animal reached the hot plate and licked its paw or jumping off the hot plate.
The post-drug latency: T1 was estimated according to the reaction time of each mouse at 30, 60, 90 and 120 minutes after treatment. T0 represented the mean pre-drug latencies. For each group, the percentage of protection against thermal stimulus was determined by using the formula described by Yonathan et al.(2006) ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/j.jep.2006.06.006”, “ISBN” : “0378-8741 (Print)”, “ISSN” : “03788741”, “PMID” : “16876348”, “abstract” : “In Ethiopia inflammatory skin diseases are among the most common health problems treated with traditional remedies which mainly comprise medicinal plants. In the present work, the anti-inflammatory and anti-nociceptive activities of Cheilanthes farinosa (Forsk.) Kaulf (Adianthaceae), a fern used in many parts of Ethiopia to treat inflammatory skin disorders, were studied using in vivo models of inflammation and pain. The results of the study showed that the fronds Cheilanthes farinosa possess strong anti-inflammatory and anti-nociceptive properties. It was further demonstrated that the active ingredients of the fern reside mainly in the methanol fraction from which three compounds viz. the flavonol glycoside rutin, and the natural cinnamic acids, caffeic acid and its quinic acid derivative chlorogenic acid have been isolated. The methanol extract was also shown to potentiate the anti-inflammatory activity of acetyl salicylic acid. At the tested concentrations, the methanol extract displayed a better anti-nociceptive activity than that of ASA in both the early and late phases of formalin induced nociception in mice. However, the activity of the extract was more pronounced in the late phase, which is commonly associated with inflammatory pain. Evaluation of the pharmacological properties of the compounds isolated from the active fractions pointed out that chlorogenic acid possesses strong anti-inflammatory and anti-nociceptive activities while caffeic acid and rutin were inactive. Moreover, on molar basis chlorogenic acid was proved to be superior in its anti-inflammatory action to acetyl salicylic acid. It was therefore concluded that chlorogenic acid contributes, in full or in part, to the anti-inflammatory and anti-nociceptive activities of Cheilanthes farinosa. Both the methanolic extract and pure chlorogenic acid failed to display anti-nociceptive activity when tested by the tail-flick test indicating that the plant is not a centrally acting analgesic but instead exerts its analgesic activity by way of its antinflammtory action. ?? 2006 Elsevier Ireland Ltd. All rights reserved.”, “author” : { “dropping-particle” : “”, “family” : “Yonathan”, “given” : “Mariamawit”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Asres”, “given” : “Kaleab”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Assefa”, “given” : “Ashenafi”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Bucar”, “given” : “Franz”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Ethnopharmacology”, “id” : “ITEM-1”, “issue” : “3”, “issued” : { “date-parts” : “2006” }, “note” : “https://l.facebook.com/l.php?u=http%3A%2F%2Fonlinelibrary.wiley.com%2Fdoi%2F10.1002%2Fprp2.383%2Fabstract&amp;h=ATMBex2-_u4SiTBPhn6A8iaT9SQ-3luPKnJn42TWzKDN91b5is8Mu-NyYdVswQMKSViK85cd1ZiCD1fdnXVI0MHT5JFkQ9-36r6mKCu8–1dQzqp065w7APpQRutgoa0Qj6D4QpIrCagpm4f”, “page” : “462-470”, “title” : “In vivo anti-inflammatory and anti-nociceptive activities of Cheilanthes farinosa”, “type” : “article-journal”, “volume” : “108” }, “uris” : “http://www.mendeley.com/documents/?uuid=b4e80a79-fa11-4948-9cd9-dadff8a1d9b8” } , “mendeley” : { “formattedCitation” : “(Yonathan et al., 2006)”, “plainTextFormattedCitation” : “(Yonathan et al., 2006)”, “previouslyFormattedCitation” : “(Yonathan et al., 2006)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Yonathan et al., 2006).

% Protection against thermal stimulus=T0-T1T0 ×100iii. Formalin Test
Formalin test was performed using the method developed by and Hunskar et al, 1986. Mice of either sexes fasted overnight with the provision of water were used. Mice of either sex were fasted overnight and randomly selected and assigned into groups of five each with six mice. Group I received DW (10 ml/kg) was served as the negative control while group II received aspirin at dose of 200 mg/kg served as positive control. The remaining groups (III to V) were given the test extract at a dose of 200, 400 and 800 mg/kg. Grouping dosing used in solvent fractions is also indicated in (Table 3).

Mice in each group was allowed for at least 20 minutes acclimatization in transparent observation cage before starting the experiment ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1054/npep.2000.0805”, “author” : { “dropping-particle” : “”, “family” : “Chung”, “given” : “K M”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Song”, “given” : “D K”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Huh”, “given” : “S O”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Kim”, “given” : “Y H”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Choi”, “given” : “M R”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Suh”, “given” : “H W”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issued” : { “date-parts” : “2000” }, “page” : “158-166”, “title” : “Supraspinal NMDA and non-NMDA receptors are differentially involved in the production of antinociception by morphine and u03b2 -endorphin administered intracerebroventricularly in the formalin pain model”, “type” : “article-journal”, “volume” : “34” }, “uris” : “http://www.mendeley.com/documents/?uuid=8a6a8892-f218-4e97-abd5-ddda47d1eae1” } , “mendeley” : { “formattedCitation” : “(Chung et al., 2000)”, “plainTextFormattedCitation” : “(Chung et al., 2000)”, “previouslyFormattedCitation” : “(Chung et al., 2000)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Chung et al., 2000). Then 0.02 ml of 5 % formalin solution was administered by intraplantar injection in to the mice dorsal surface of the right hind paw.
Two phases of nociception namely, the early and late phase were observed during the course of the experiment. The first phase was recorded by taking the time of the animal spent licking the paw for 0-5 minutes after injection of formalin ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/0165-0270(85)90116-5”, “ISBN” : “0165-0270”, “ISSN” : “01650270”, “PMID” : “4033190”, “abstract” : “A modification of the formalin test appropriate for testing of mice is described. Formalin 1 or 5% was injected into the dorsal surface of a hindpaw, and the time the animal spent licking the paw was recorded. On the basis of the response pattern, two distinct periods of intensive licking activity were identified; an early (0-5 min after injection) and a late response (20-30 min after injection). The following analgesics were investigated (dose range): acetylsalicylic acid (100-400 mg/kg), paracetamol (100-400 mg/kg) and morphine (0.6-10 mg/kg). Acetylsalicylic acid (200-400 mg/kg early response, 300-400 mg/kg late response), paracetamol (200-400 mg/kg early response, 300-400 mg/kg late response) and morphine (2.5-10 mg/kg) inhibited the responses in a dose-dependent manner. The results indicate that the test is useful for evaluating mild analgesics. It may have advantages over some of the tests that are commonly used for testing analgesics. u00a9 1985.”, “author” : { “dropping-particle” : “”, “family” : “Hunskaar”, “given” : “Steinar”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Fasmer”, “given” : “Ole Bernt”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Hole”, “given” : “Kjell”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Neuroscience Methods”, “id” : “ITEM-1”, “issue” : “1”, “issued” : { “date-parts” : “1985” }, “page” : “69-76”, “title” : “Formalin test in mice, a useful technique for evaluating mild analgesics”, “type” : “article-journal”, “volume” : “14” }, “uris” : “http://www.mendeley.com/documents/?uuid=8c1cb1a0-04da-49a3-a8b9-6f2ced086b52” } , “mendeley” : { “formattedCitation” : “(Hunskaar et al., 1985)”, “plainTextFormattedCitation” : “(Hunskaar et al., 1985)”, “previouslyFormattedCitation” : “(Hunskaar et al., 1985)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Hunskaar et al., 1985) while the second phase was recorded by taking the time of the animal spent licking the paw for 15-30 min after formalin injection ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.5681/apb.2014.087”, “author” : { “dropping-particle” : “”, “family” : “Adedapo”, “given” : “Adeolu Alex”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Aremu”, “given” : “Olujoke Janet”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Oyagbemi”, “given” : “Ademola Adetokunbo”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issue” : “Suppl 2”, “issued” : { “date-parts” : “2014” }, “page” : “591-598”, “title” : “Anti-Oxidant , Anti-Inflammatory and Antinociceptive Properties of the Acetone Leaf Extract of Vernonia Amygdalina in Some Laboratory Animals”, “type” : “article-journal”, “volume” : “4” }, “uris” : “http://www.mendeley.com/documents/?uuid=f3df182b-2a0a-4559-924c-38c52687f5ea” }, { “id” : “ITEM-2”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Santos”, “given” : “A R S”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Vedana”, “given” : “E M A”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “De”, “family” : “Freitas”, “given” : “G A G”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-2”, “issued” : { “date-parts” : “1998” }, “page” : “302-307”, “title” : “Original Research Papers Antinociceptive effect of meloxicam , in neurogenic and inflammatory nociceptive models in mice”, “type” : “article-journal”, “volume” : “47” }, “uris” : “http://www.mendeley.com/documents/?uuid=276053ae-3681-4c06-bf8e-8330ac50cd11” } , “mendeley” : { “formattedCitation” : “(Santos et al., 1998; Adedapo et al., 2014)”, “plainTextFormattedCitation” : “(Santos et al., 1998; Adedapo et al., 2014)”, “previouslyFormattedCitation” : “(Santos et al., 1998; Adedapo et al., 2014)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Santos et al., 1998; Adedapo et al., 2014). The percentage of inhibition nociception for the two phases was calculated using the following formula ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1054/npep.2000.0805”, “author” : { “dropping-particle” : “”, “family” : “Chung”, “given” : “K M”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Song”, “given” : “D K”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Huh”, “given” : “S O”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Kim”, “given” : “Y H”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Choi”, “given” : “M R”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Suh”, “given” : “H W”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issued” : { “date-parts” : “2000” }, “page” : “158-166”, “title” : “Supraspinal NMDA and non-NMDA receptors are differentially involved in the production of antinociception by morphine and u03b2 -endorphin administered intracerebroventricularly in the formalin pain model”, “type” : “article-journal”, “volume” : “34” }, “uris” : “http://www.mendeley.com/documents/?uuid=8a6a8892-f218-4e97-abd5-ddda47d1eae1” } , “mendeley” : { “formattedCitation” : “(Chung et al., 2000)”, “plainTextFormattedCitation” : “(Chung et al., 2000)”, “previouslyFormattedCitation” : “(Chung et al., 2000)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Chung et al., 2000)
% Inhibition=Control mean-Test meanControl mean ×100
Table SEQ Table * ARABIC 1: Grouping and dosing of mice used on formalin testGroup Dose (ml/kg or mg/kg) Group Dose (ml/kg or mg/kg)
DW 10ml DW 10ml
Crude methanolic extract 200 Aqueous fraction 100
400 200
800 Butanol fraction 100
Aspirin 200 200
Aspirin 200

3.2.5 Evaluation of Anti-inflammatory Activity
Anti-inflammatory activity of the 80% methanolic crude root extract and solvent fractions of C. ficifolius was performed using the method described by Winter et al. (1962) with slight modification. Swiss albino mice of either sex weighting from 20-37gm were used. Animals fasted overnight were randomly assigned into nine groups each with six mice Swiss albino mice of either sex (27-37gm) were used (Table 2).
Thirty minutes before injection of carrageenan, distilled water (DW, 10ml/kg), the test substances and aspirin (200mg/kg) were administered orally. Just before induction of inflammation the leg of each mouse was marked on the skin over the lateral maleous ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.3181/00379727-111-27849”, “ISBN” : “0037-9727 (Print)\r0037-9727 (Linking)”, “ISSN” : “1535-3702”, “PMID” : “14001233”, “abstract” : “A method is presented for measuring the edema induced by injection of 0.05 ml of 1% solution of carrageenin, an extract of Chondrus, into the plantar tissues of the hind paw of the rat. Peak edema develops within the first 3 to 4 hours, and is inhibited by pretreatment of the animals by single oral doses of antiinflammatory agents, steroid or non-steroid. Log dose responses to drugs are linear and parallel, and yield potency ratios with relatively narrow confidence limits. The potency ratios obtained for aspirin, phenylbutazone and hydrocortisone are fairly close to the ratios of their respective daily doses in the treatment of rheumatic disease. A potent antihistaminic-antiserotonin compound, cyproheptadine, is without effect on carrageenin-induced edema.”, “author” : { “dropping-particle” : “”, “family” : “Winter”, “given” : “C. A.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Risley”, “given” : “E. A.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Nuss”, “given” : “G. W.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Experimental Biology and Medicine”, “id” : “ITEM-1”, “issue” : “3”, “issued” : { “date-parts” : “1962” }, “page” : “544-547”, “title” : “Carrageenin-Induced Edema in Hind Paw of the Rat as an Assay for Antiinflammatory Drugs”, “type” : “article-journal”, “volume” : “111” }, “uris” : “http://www.mendeley.com/documents/?uuid=c1135a61-d60d-4a5b-ac9a-8fa7de341730” } , “mendeley” : { “formattedCitation” : “(Winter et al., 1962)”, “plainTextFormattedCitation” : “(Winter et al., 1962)”, “previouslyFormattedCitation” : “(Winter et al., 1962)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Winter et al., 1962). The basal volume of the right hind paw of individual mouse was measured with digital plethysmometer (PLM 02). Then 0.05 ml of 1% carrageenan in normal saline was injected in to the dorsal surface of the right hind paw. The volume of injected paw was measured at 1, 2, 3 and 4 hours after carrageenan injection.

Paw diameter before carrageenan injection was compared with the same paw diameter after administration of carrageenan by calculating the percentage inhibition applying the following formula ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/j.jep.2012.04.041”, “ISSN” : “03788741”, “PMID” : “22561892”, “abstract” : “Ethnopharmacological relevance: Ocimum suave has been used in the Ethiopian traditional medicine to relieve pain, fever, inflammation and other disease conditions. Aim of the study: The aim of the present study was to investigate the anti-inflammatory activities of the aqueous and ethanol leaf extracts and some fractions of Ocimum suave in mice. Materials and methods: The crude extracts were screened for their anti-inflammatory activities on carrageenan-induced mouse paw edema at three dose levels. The butanol and aqueous fractions of the aqueous extract were also evaluated for their anti-inflammatory activities using carrageenan, histamine and serotonin-induced mouse paw edema at three dose levels. Normal saline and aspirin were employed as negative and positive control groups, respectively. Results: Both ethanol and aqueous extracts significantly decreased carrageenan-induced inflammation at all the three doses used. However, greater paw edema inhibition was observed with the aqueous extract. The two fractions also showed significant reduction of inflammation against inflammatory models in which the aqueous residue exhibited the highest inhibition. Conclusions: From the present findings, it can be concluded that the ethanol and aqueous leaf extracts as well as butanol and aqueous fractions of Ocimum suave have shown anti-inflammatory properties. u00a9 2012 Elsevier Ireland Ltd. All rights reserved.”, “author” : { “dropping-particle” : “”, “family” : “Masresha”, “given” : “Birhanetensay”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Makonnen”, “given” : “Eyasu”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Debella”, “given” : “Asfaw”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Ethnopharmacology”, “id” : “ITEM-1”, “issue” : “1”, “issued” : { “date-parts” : “2012” }, “page” : “201-205”, “publisher” : “Elsevier”, “title” : “In vivo anti-inflammatory activities of Ocimum suave in mice”, “type” : “article-journal”, “volume” : “142” }, “uris” : “http://www.mendeley.com/documents/?uuid=ebf854d5-6a6a-4e82-83bd-8101e4c48cb4” } , “mendeley” : { “formattedCitation” : “(Masresha et al., 2012)”, “plainTextFormattedCitation” : “(Masresha et al., 2012)”, “previouslyFormattedCitation” : “(Masresha et al., 2012)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Masresha et al., 2012).

% inflammation inhibition =(Vt-Vo) control-(Vt-Vo) treated (Vt-Vo) control ×100Where, Vt =the mean paw volume in control and drug treated group at time t
Vo =the mean paw volume in control and treated group at time 0
In addition the increase in paw volume, i.e., inflammation expressed in percentage was calculated according to the formula given by ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/j.jep.2012.04.041”, “ISSN” : “03788741”, “PMID” : “22561892”, “abstract” : “Ethnopharmacological relevance: Ocimum suave has been used in the Ethiopian traditional medicine to relieve pain, fever, inflammation and other disease conditions. Aim of the study: The aim of the present study was to investigate the anti-inflammatory activities of the aqueous and ethanol leaf extracts and some fractions of Ocimum suave in mice. Materials and methods: The crude extracts were screened for their anti-inflammatory activities on carrageenan-induced mouse paw edema at three dose levels. The butanol and aqueous fractions of the aqueous extract were also evaluated for their anti-inflammatory activities using carrageenan, histamine and serotonin-induced mouse paw edema at three dose levels. Normal saline and aspirin were employed as negative and positive control groups, respectively. Results: Both ethanol and aqueous extracts significantly decreased carrageenan-induced inflammation at all the three doses used. However, greater paw edema inhibition was observed with the aqueous extract. The two fractions also showed significant reduction of inflammation against inflammatory models in which the aqueous residue exhibited the highest inhibition. Conclusions: From the present findings, it can be concluded that the ethanol and aqueous leaf extracts as well as butanol and aqueous fractions of Ocimum suave have shown anti-inflammatory properties. u00a9 2012 Elsevier Ireland Ltd. All rights reserved.”, “author” : { “dropping-particle” : “”, “family” : “Masresha”, “given” : “Birhanetensay”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Makonnen”, “given” : “Eyasu”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Debella”, “given” : “Asfaw”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Ethnopharmacology”, “id” : “ITEM-1”, “issue” : “1”, “issued” : { “date-parts” : “2012” }, “page” : “201-205”, “publisher” : “Elsevier”, “title” : “In vivo anti-inflammatory activities of Ocimum suave in mice”, “type” : “article-journal”, “volume” : “142” }, “uris” : “http://www.mendeley.com/documents/?uuid=ebf854d5-6a6a-4e82-83bd-8101e4c48cb4” } , “mendeley” : { “formattedCitation” : “(Masresha et al., 2012)”, “plainTextFormattedCitation” : “(Masresha et al., 2012)”, “previouslyFormattedCitation” : “(Masresha et al., 2012)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Masresha et al., 2012).

%inflammation (%I)=Vf-Vi Vi ×100
Where, Vi is the mean volume of the paw before carrageenan injection and Vf, the volume of the paw after carrageenan injection.

Table SEQ Table * ARABIC 2: Grouping and dosing of mice used anti-inflammatory activities of crude extract and solvent fractions of Cucumis ficifolius.Groups Treatments Dose (mg/kg or ml/kg)
GI Distilled water 10
GII Methanol extract 200
GIII Methanol extract 400
GIV Methanol extract 800
GV Aqueous fraction 100
GVI Aqueous fraction 200
GVII Butanol fraction 100
GVIII Butanol fraction 200
GIX Aspirin 200
3.2.6 Statistical AnalysisData was entered and analyzed with the IBM statistical package for social sciences (SPSS) version 20. The data obtained in the study was tabulated and expressed as mean ± standard errors of the mean (SEM). Then statistical analysis was carried out using one-way analysis of variance (ANOVA) followed by Tukey post-hoc test to compare variations among groups. The result was considered significant when p < 0.05.
4. Results
4.1 Percent YieldAs shown in Table 3, the 80% methanolic crude extract of C. ficifolius was gummy and yellowish in color with 5.69% (w/w). Among the fractions the highest yield was found from the aqueous fraction.

Table SEQ Table * ARABIC 3: Percentage yield of crude extract and different solvent fractions of Cucumis ficifolius
Extract/fraction Color Actual mass (g) Percentage yield (w/w)
Crude extract Yellow 75.9 5.69
Aqueous Yellow 33.5 74.44
n-butanol Yellow 6.3 14
Chloroform Blue black 5.2 11.56
4.2 Oral Acute Toxicity TestAcute toxicity studies revealed that administration of the crude extract of C. ficifolius (at a dose of 2000 mg/kg) did not cause significant changes in behaviors such as alertness, motor activity, breathing, restlessness, diarrhea, convulsions, coma, and appearance of the animals during the two weeks follow up period. Therefore, the LD50 of the extract is greater than 2000 mg/kg.

4.3. Analgesic and Anti-inflammatory Assays4.3.1 Analgesic Activity
i. Writhing TestAs depicted in, the reduction in the number of contractions produced by all dose levels of methanolic extract, aqueous and butanol fractions of C. ficifolius were significant compared to negative control. The standard drug, aspirin at 150 mg/kg also prevented frequency of writhing significantly. The percentage pain protection produced by the use of the crude at three doses (200, 400 and 800 mg/kg), and 200 mg/kg of ASA was 24.9% (p < 0.05), 48.7% (p < 0.001),72.5% (p < 0.001) and 80.4% (p < 0.001), respectively as compared to the vehicle group. As illustrated in Fig. 5, 800 mg dose of 80% methanolic extract of C. ficifolius revealed nearly comparable reduction in the mean number of writhes to aspirin.

The butanol fraction resulted in greater reduction of the frequency of writhing response with protection 35% (p < 0.01) and 68% (p < 0.001) in the lower and higher dose levels, respectively. And also, a significant reduction in the mean number of writhing observed at dose of 100 mg/kg (33%, p < 0.01) and 200 mg/kg (62%, p < 0.001) of aqueous fraction (Fig.6).
4465320388620a?b?c?
a?b?c?
3543300445770a?b?c?
a?b?c?
2680335695325a?b*d*e?
a?b*d*e?
1781175962025a*c*d?e?
a*c*d?e?

Figure SEQ Figure * ARABIC 5: Anti-nociceptive effect of the crude methanolic extract of Cucumis ficifolius on acetic acid induced writhing test.
The results are expressed in mean ± SEM, n = 6, a compared with vehicle group, DW10: distilled water 10 ml/kg, b compared with CM200: Cucumis ficifolius extract 200 mg/kg, c compared with CM400: Cucumis ficifolius extract 400 mg/kg: d compared with CM800: Cucumis ficifolius extract 800 mg/kg, e compared with ASA150: Aspirin 150 mg/kg. Statistical analysis of data was carried out using One-way ANOVA followed by post hoc Tukey’s test: *P;0.05, ?P;0.01, ?P;0.001.1676400916305a?c?e?f?
a?c?e?f?
2428240553720a?b?d?
a?b?d?
3181350935355a?c*e?f?
0a?c*e?f?
3885565649605a?b?d?
a?b?d?
4596130421005a?b?d?
a?b?d?

Figure SEQ Figure * ARABIC 6: Anti-nociceptive effect of oral aqueous and butanol fractions of Cucumis ficifolius on acetic acid writhing test.
The results are expressed in mean ± SEM, n = 6, a compared with vehicle group, b compared with AQ100: aqueous fraction 100 mg/kg, c compared with AQ200: aqueous fraction 200 mg/kg, d compared with B100: butanol fraction 100 mg/kg, e compared with B200: butanol fraction 200 mg/kg, f compared with ASA150: acetylsalicylic acid 150mg/kg. Statistical analysis of data was carried out using One-way ANOVA followed by post hoc Tukey’s test: *P<0.05, ?P<0.01, ?P<0.001.ii. Hot PlateThe crude root extract and solvent fractions of C. ficifolius increased the latency of pain response at all dose levels in all-time series. Treatment of mice with 200 and 400 mg/kg crude extract significantly increased the latency to maximum record of 10.12 (46.62%) and 11.16 (52.88%) secs at 120 min of observation compared to control, respectively. The highest dose level (800mg/kg) showed greater protection at all times of observation in relation to the vehicle group with maximum pain protection (82%, P<0.001) at 90 min (Table 4).
The mean difference between the middle dose and lowest dose levels was not significant throughout the observation. However, 800 mg/kg of the crude root extract showed a significance mean difference compared to post drug values of the lowest dose while a significant difference was obtained at 90 minutes (p < 0.01) in relation to the middle dose.
With regard to the aqueous and butanol fractions, the delay in nociception reaction was significant with the exception of 100 mg/kg of aqueous fraction at 30 minutes, compared to the negative control. Nevertheless, effects attributed to the use were within a considered level of significance in time intervals beyond 30 min (Table 5). The remaining dosses of the two fractions significantly prolong the nociception latency in a dose dependent manner. The aqueous fraction, 100 mg/kg (60%, p<0.01), 200 mg/kg (86.8%, p<0.001) and butanol 100 mg/kg (76%, p<0.001) resulted in greater protection at 90 minutes, whereas 200 mg/kg butanol fraction provided greater protection at 60 minute (89.8%, p<0.001).

Table SEQ Table * ARABIC 4: Effect of oral Cucumis ficifolius methanolic crude root extract in hot plate testGroup Mean latency (sec) ± S.E.M (%protection)
30 60 90 120
DW10 6.78+0.40 (1.24) 6.80+0.27(1.49) 7.12+0.31(6.22) 7.22+0.19(7.71)
CM200 9.35+0.73(35.51)
a*d*e? 9.42+0.51(36.47)
a*d*e? 9.95+0.49(44.2)
a?d?e? 10.12+0.43(46.62) a?d*e?
CM400 10.04+0.54(37.53)
A*e* 10.86+0.60(48.77)
a?e? 10.92+0.34(49.59)
a?d?e? 11.16+0.52(52.88)
a?e?
CM800 11.98+0.74(59.78)
a?b* 12.35+0.63(64.67)
a?b* 13.67+0.65(82.22)
a?b?c? 12.53+0.73(67.11)
a?b*
MO20 13.17+0.56(77.93)
a?b?c* 14.12+0.76(90.77) a?b?c? 14.35+0.58 (93.92)
a?b?c? 14.00+0.52 (89.19)
a?b?c?
The results are expressed in mean ± SEM, n = 6, DW10: distilled water 10 ml/kg, CM200: Cucumis ficifolius 200 mg/kg, CM400: Cucumis ficifolius 400 mg/kg, CM800: Cucumis ficifolius 800 mg/kg, MO20: Morphine 20 mg/kg, a compared with DW10, b compared with CM200, c compared with CM400, d compared with CM800, e compared with MO20. Statistical analysis of data was carried out using One-way ANOVA followed by post hoc Tukey’s test: *p;0.05, ?p;0.01, ?p;0.001.

Table SEQ Table * ARABIC 5: Anti-nociceptive effect of aqueous and butanol fractions of Cucumis ficifolius on hot plate test.Group Dose (mg/kg)
Mean latency (sec) ± S.E.M (percent protection)
30min 60min 90min 120min
DW 10 ml/kg 6.8±0.82 7.1±0.73609 7.2±0.86 7.9±0.54
Aqueous residue 100 9.9±0.61(23.8)
acdef? 10.3±.7(28.1)
acde*f* 12.8±.96(60)
a?cdef* 12.4±1(55)
A*cdef
200 10.9±1.19(42.8) a*bdef* 12±1.38(58)
a*bdef 14.2±.77(86.8)
a?bdef 12.8±.74(68.6)
a?bdef
Butanol fraction 100 10.3±0.68(24.5)
a*cdef? 13.3±.62(60)
a?cdef 14.6±.53(76)
a?cdef 13.6±.48(63)
a?cdef
200 12.3±0.49(53.5)
a?bcdf 15.2±1.15(89.8)
a?bcdf 14.4±.52(80)
a?bcdf 14.7±1(84)
a?bcdf
Morphine 20 14.6±0.75(74)
a?bde 14.7±.94(75)
a?bde 16.5±1.22(96)
a?bde 15.8±1.2(88)
a?bde
The results are expressed in mean ± SEM, n = 6, a compared with vehicle group, b compared with AQ100: aqueous fraction 100 mg/kg, c compared with AQ200: aqueous fraction 200 mg/kg, d compared with B100: butanol fraction 100 mg/kg, e compared with B200: butanol fraction 200 mg/kg, f compared with MO20: morphine 20 mg/kg. Statistical analysis of data was carried out using One-way ANOVA followed by post hoc Tukey’s test: *P<0.05, ?P<0.01, ?P<0.001.

iii. Formalin TestThe crude methanolic root extract of C. ficifolius significantly diminished the mean time of animals spend licking the injected paw in the two phases. In the early phase, the 200, 400 and 800 mg/kg doses of the test extract shortened time of licking by 26%, 53% and 64%, respectively. In the late phase, a percentage protection of 45.76, 67 and 83% were recorded from the lower to the higher dose levels. The 400 (53 %) and 800 (64 %) mg/kg crude extract better activity in the early phase of the test as compared to the standard drug, aspirin (31%). Although statistically not significant, 800 mg/kg methanolic extract of C. ficifolius exhibited greater pain protection (83%) compared to ASA (72%) in the late phase (Table 6). The analgesic gap between aspirin and test different dose of the test extract was wider especially in the initial phase.

The aqueous fraction at 100 mg/kg and 200 mg/kg decreased time of licking by 28% and 56%, respectively in the early phase while butanol fraction showed higher protection action as compared to the aqueous fraction. For instance, in the early phase, 37% and 62% of pain protection was attained with the lower and higher doses of butanol fraction (Fig.7). In the late phase, the aqueous fraction decreased the time by 29% and 57% while butanol fraction reduced by 41% and 69% at the respective lower and higher dose levels (Fig. 8).
Table SEQ Table * ARABIC 6: Anti-nociceptive activity of 80% methanolic crude root extract of Cucumis ficifolius in formalin induced lick test. Group Dose (mg/kg) Mean lick time (sec) ± S.E.M (%protection)
Early phase Late phase
DW 10ml 109.8 ± 7.16029 254.9 ± 8.6
CM200 200 80.7 ± 6.4 (26) a*c*d? 138± 11.5 (45.76) a?c?d?e?
CM400 400 51.4±4.7 (53) a?b*e* 83.9± 7.4 (67) a?b?d*
CM800 800 39.3±4.7 (64) a?b?e? 42.6±(2.5 (83) a?b?d*
ASA200 200 75±6.97 (31) a*c*d? 70±14.7 (72) a?b?
The results are expressed in mean ± SEM, n = 6, DW10: distilled water 10 ml/kg, CM200: Cucumis ficifolius 200 mg/kg, CM400: Cucumis ficifolius 400 mg/kg, CM800: Cucumis ficifolius 800 mg/kg, ASA200: Acetylsalicylic acid 200 mg/kg, a compared with DW10, b compared with CM200, c compared with CM400, d compared with CM800, e compared with ASA200. Statistical analysis of data was carried out using One-way ANOVA followed by post hoc Tukey’s test: *p;0.05, ?p;0.01, ?P;0.001.

14839951142365*c*e*
*c*e*
2238375513715a?b*
a?b*
2958465894715a?e*
a?e*
3672840332740a?b*d*
a?b*d*
4435475885190a?
a?

Figure SEQ Figure * ARABIC 7: Anti-nociceptive activity of aqueous and butanol fractions of Cucumis ficifolius on early phase of formalin induced lick test.
Values are expressed as mean ± S.E.M (n=6). aas compared to negative control, bas compared to AQ100: 100 mg/kg aqueous fraction, cas compared to AQ200: 200 mg/kg aqueous fraction, das compared to B100: butanol fraction (100 mg/kg), eas compared to B200: butanol fraction (200 mg/kg) and fas compared to ASA200: aspirin (200 mg/kg). Statistical analysis of data was carried out using One-way ANOVA followed by post hoc Tukey’s test: *p<0.05, ?p<0.01, ?P<0.001.

14071601276350a*c*e?f?
a*c*e?f?
2340610790575a?b*(57)
a?b*(57)
31032451087755a?e*f?
a?e*f?
3848100504190a?b?d*
a?b?d*
4572000351790a?b?d?
a?b?d?
Figure SEQ Figure * ARABIC 8: Anti-nociceptive activity of aqueous and butanol fractions of Cucumis ficifolius on late phase of formalin induced lick test. Values are expressed as mean ± S.E.M (n=6). *p<0.05, ?p<0.01, ?p<0.001. aas compared to negative control, bas compared to AQ100: 100 mg/kg aqueous fraction, cas compared to AQ200: 200 mg/kg aqueous fraction, das compared to B100: butanol fraction (100 mg/kg), eas compared to B200: butanol fraction (200 mg/kg) and fas compared to ASA200: aspirin (200 mg/kg). Statistical analysis of data was carried out using One-way ANOVA followed by post hoc Tukey’s test: *p;0.05, ?p;0.01, ?P;0.001.

4.3.2 Anti-inflammatory Activity Test As indicated in Table 7, all the tested doses of the crude extract significantly decreased the volume compared to negative control. The lower dose of methanolic extract achieved a minimum (22%) anti-inflammatory activity at the first hour and maximum value (40%) at the fourth hour while the middle and higher doses inhibit inflammation by 56% (p ; 0.001) and 71% (p ; 0.001), respectively, at the fourth hour.
The aqueous and butanol fractions revealed an inhibitory action in all times of observations. At the first hour, the 100 mg/kg of aqueous and butanol fractions inhibited inflammation by 24% and 34%, respectively. On the other hand, maximum activity was recorded with the same doses at the fourth hour with aqueous fraction (41%, p ; 0.001) and butanol fraction (53%, p ; 0.001). The 200 mg/kg of the two fractions attained greater anti-inflammatory action as compared to the lower dose levels and were statistically significant as compared to the negative control group. The aqueous fraction produced 56% (p;0.001) and butanol fraction resulted in 69% (p;0.001) anti-inflammatory activity at the fourth hour. Table SEQ Table * ARABIC 7: Anti-inflammatory activity of 80% methanolic extract and solvent fractions of Cucumis ficifolius on carrageenan induced paw edema.Group Percent inflammation (%I) ± S.E.M (%A)
1 hour 2 hours 3 hours 4 hours
NC 54±.043 67±.04 73±.04956 65±.02
CM200 48±.06(22) 57±.061(24)* 58±.06(30)** 44±.04(40)***
CM400 43±.08(34)** 46±.08(44)*** 47±.086(48)*** 35±.034(56)***
CM800 36±.035(44)** 30±.032(51)*** 35±.031(60)*** 23±.039(71)***
AQ100 49±.089(24)** 54±.08(33)*** 56±.08(37)*** 46±.064(41)***
AQ200 45±.045(37)*** 46±.056(50)*** 49±.037(51)*** 39±.03(56)***
B100 48±.059(34)*** 50±.052(44)*** 52±.050(48)*** 39±.04(53)***
B200 44±.063(42)*** 48±.0476(48)*** 46±.0589(56)*** 28±.033(69)***
ASA200 50±.06(29)*** 57±.061(35)*** 58±.055(40)*** 33±.063(62)***
Values expressed as percent inflammation ± S.E.M. *P;0.05, as compared to negative control, **p;0.01, as compared to negative control, ***p;0.001, as compared to negative control. NC: negative control, CM200: crude extract, 200 mg/kg, CM 400: crude extract, 400 mg/kg, CM800: crude extract, 800 mg/kg, AQ100: aqueous fraction, 100 mg/kg, AQ200: aqueous fraction, 200 mg/kg, B100: butanol fraction, 100 mg/kg, ASA200: Acetylsalicylic acid, 200 mg/kg. Statistical analysis of data was carried out using One-way ANOVA followed by post hoc Tukey’s test
5. DiscussionIn this study, the potential anti-nociceptive and anti-inflammatory effects of crude methanolic extract and solvent fractions of Cucumis ficifolius was investigated using different animal models. In the acetic acid, hot plate and formalin nociception models the test substance significantly provided pain protection. In addition, the anti-inflammatory activity was investigated using carrageenan induced paw edema model.
The 80 % methanolic extract exhibited greater analgesic and anti-inflammatory activities than aqueous and butanol fractions; active principle(s) responsible for the anti-inflammatory activity might be available in this extract. In addition, higher reduction of paw edema and pain protection was observed in butanol than aqueous fraction. The superior efficacy of crude extract and butanol fraction suggests there is possibly a higher presence of phyotoconstituents with anti-inflammatory and analgesic activity in medium polar (butanol) and high polar (80 % methanol) solvents.
The abdominal constrictions response induced by acetic acid is a sensitive procedure to evaluate peripherally acting analgesics and primary tool for screening analgesic potential of test compounds ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Mallam”, “given” : “Danjuma”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Joseph”, “given” : “A”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Abdulkadir”, “given” : “U”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Ben”, “given” : “A”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Mohammed”, “given” : “B”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issue” : “8”, “issued” : { “date-parts” : “2016” }, “page” : “1-7”, “title” : “Analgesic and Anti-Inflammatory activities of Rothmannia Longiflora Salisb In Mice And Rats”, “type” : “article-journal”, “volume” : “6” }, “uris” : “http://www.mendeley.com/documents/?uuid=c788e811-5d6a-411d-be14-f9a166e7cb78” } , “mendeley” : { “formattedCitation” : “(Mallam et al., 2016)”, “plainTextFormattedCitation” : “(Mallam et al., 2016)”, “previouslyFormattedCitation” : “(Mallam et al., 2016)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Mallam et al., 2016). Intraperitoneal injection of acetic acid causes irritation in the peritoneal cavity where various endogenous inflammatory mediators such as histamine, serotonin, bradykinin substance P, and prostaglandins are released. These inflammatory mediatory sensitize C fibers in acetic acid induced visceral pain ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.3389/fneur.2017.00069”, “author” : { “dropping-particle” : “”, “family” : “Afify”, “given” : “Elham A”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Alkreathy”, “given” : “Huda M”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Ali”, “given” : “Ahmed S”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Alfaifi”, “given” : “Hassan A”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Khan”, “given” : “Lateef M”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Alonso-castro”, “given” : “Angel Josabad”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issue” : “March”, “issued” : { “date-parts” : “2017” }, “page” : “1-12”, “title” : “Characterization of the Antinociceptive Mechanisms of Khat Extract ( Catha edulis ) in Mice”, “type” : “article-journal”, “volume” : “8” }, “uris” : “http://www.mendeley.com/documents/?uuid=55678633-d8ff-4ff7-93d6-2a6cc886d64b” }, { “id” : “ITEM-2”, “itemData” : { “DOI” : “10.1211/0022357001773580”, “ISBN” : “0022-3573”, “ISSN” : “0022-3573”, “PMID” : “10716611”, “abstract” : “We have compared the analgesic properties of khat (Catha edulis Forsk) extract, amphetamine and ibuprofen in mice. After intragastric administration of the drugs analgesia was measured relative to water-injected controls using the hot-plate, the tail-flick, and abdominal-constriction tests. At the highest doses examined (amphetamine 1.8 mg kg(-1), ibuprofen 90 mg kg(-1), khat extract 1800 mg kg(-1)), all three substances produced analgesia, but the order of efficacy varied with the test. Khat and ibuprofen were significantly different from the control in the hot-plate assay at three or more time points post-injection. In the tail-flick test, khat and amphetamine were efficacious; ibuprofen means were somewhat lower but still significantly different from control. Higher doses of the drugs decreased the number of responses in the acetic acid-induced abdominal-constriction assay. We conclude that khat, like amphetamine and ibuprofen, can relieve pain. Differences in assay results may reflect differences in modes and sites of action, as well as in the type of pain generated by the chemical and thermal stimuli for nociception.”, “author” : { “dropping-particle” : “”, “family” : “Connor”, “given” : “J”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Makonnen”, “given” : “E”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Rostom”, “given” : “a”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “The Journal of pharmacy and pharmacology”, “id” : “ITEM-2”, “issue” : “1”, “issued” : { “date-parts” : “2000” }, “page” : “107-10”, “title” : “Comparison of analgesic effects of khat (Catha edulis Forsk) extract, D-amphetamine and ibuprofen in mice.”, “type” : “article-journal”, “volume” : “52” }, “uris” : “http://www.mendeley.com/documents/?uuid=c38f1139-8e2d-4261-b259-4abc2f861395” } , “mendeley” : { “formattedCitation” : “(Connor et al., 2000; Afify et al., 2017)”, “plainTextFormattedCitation” : “(Connor et al., 2000; Afify et al., 2017)”, “previouslyFormattedCitation” : “(Connor et al., 2000; Afify et al., 2017)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Connor et al., 2000; Afify et al., 2017). The Stimulation of the nerve endings of the primary afferent nerves produces pain characterized by constriction of abdominal muscle with extension of the fore limbs and elongation of the body ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Mallam”, “given” : “Danjuma”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Joseph”, “given” : “A”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Abdulkadir”, “given” : “U”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Ben”, “given” : “A”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Mohammed”, “given” : “B”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issue” : “8”, “issued” : { “date-parts” : “2016” }, “page” : “1-7”, “title” : “Analgesic and Anti-Inflammatory activities of Rothmannia Longiflora Salisb In Mice And Rats”, “type” : “article-journal”, “volume” : “6” }, “uris” : “http://www.mendeley.com/documents/?uuid=c788e811-5d6a-411d-be14-f9a166e7cb78” }, { “id” : “ITEM-2”, “itemData” : { “DOI” : “10.1211/0022357001773580”, “ISBN” : “0022-3573”, “ISSN” : “0022-3573”, “PMID” : “10716611”, “abstract” : “We have compared the analgesic properties of khat (Catha edulis Forsk) extract, amphetamine and ibuprofen in mice. After intragastric administration of the drugs analgesia was measured relative to water-injected controls using the hot-plate, the tail-flick, and abdominal-constriction tests. At the highest doses examined (amphetamine 1.8 mg kg(-1), ibuprofen 90 mg kg(-1), khat extract 1800 mg kg(-1)), all three substances produced analgesia, but the order of efficacy varied with the test. Khat and ibuprofen were significantly different from the control in the hot-plate assay at three or more time points post-injection. In the tail-flick test, khat and amphetamine were efficacious; ibuprofen means were somewhat lower but still significantly different from control. Higher doses of the drugs decreased the number of responses in the acetic acid-induced abdominal-constriction assay. We conclude that khat, like amphetamine and ibuprofen, can relieve pain. Differences in assay results may reflect differences in modes and sites of action, as well as in the type of pain generated by the chemical and thermal stimuli for nociception.”, “author” : { “dropping-particle” : “”, “family” : “Connor”, “given” : “J”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Makonnen”, “given” : “E”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Rostom”, “given” : “a”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “The Journal of pharmacy and pharmacology”, “id” : “ITEM-2”, “issue” : “1”, “issued” : { “date-parts” : “2000” }, “page” : “107-10”, “title” : “Comparison of analgesic effects of khat (Catha edulis Forsk) extract, D-amphetamine and ibuprofen in mice.”, “type” : “article-journal”, “volume” : “52” }, “uris” : “http://www.mendeley.com/documents/?uuid=c38f1139-8e2d-4261-b259-4abc2f861395” } , “mendeley” : { “formattedCitation” : “(Connor et al., 2000; Mallam et al., 2016)”, “plainTextFormattedCitation” : “(Connor et al., 2000; Mallam et al., 2016)”, “previouslyFormattedCitation” : “(Connor et al., 2000; Mallam et al., 2016)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Connor et al., 2000; Mallam et al., 2016). Analgesic effect of the crude extract and solvent fractions in this study may be linked to C fibers mediated via inhibition of prostaglandins histamine, serotonin bradykinin and substance P.
The second pain model used was the hot plate test which is thermic stimuli involving stimulation of A? fibers. In this test two behavioral responses namely, paw licking and jumping are produced. The two response are supraspinally integrated and sensitive to opioid analgesics ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “ISSN” : “1011601X”, “PMID” : “24577913”, “abstract” : “Anchomanes difformis is a tropical plant that has been used in folklore to treat diverse complications. The leaf extract of A. difformis was investigated for possible anti-nociceptive and anti-inflammatory effects in albino wistar rats. In these independent studies, two sets of twenty five rats were divided into five groups of five rats per group. Formalin induced pain in rats was used to investigate the anti-nociceptive effect of the extract. The extract was administered orally in the treated groups at doses 200, 400, 800 and 1600 mg/kg with aspirin serving as the positive drug control while the normal control group was not given any extract but water. Studies were also carried out on the egg albumin induced anti-inflammatory activity in rats by inducing oedema on the left hind paw. The result showed a significant inhibition (p<0.05) on the later phase (800mg/kg) of formalin pain induction in rats; similarly, a significant (p<0.05) anti-inflammatory activity was observed at 60, 90 and 120 minutes. The study thus validates the ethnomedicinal usage of A. difformis in the treatment of pain and inflammation.”, “author” : { “dropping-particle” : “”, “family” : “Adebayo”, “given” : “Abiodun Humphrey”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “John-Africa”, “given” : “Lucy Binda”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Agbafor”, “given” : “Amarachi Grace”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Omotosho”, “given” : “Omolola Elizabeth”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Mosaku”, “given” : “Timothy Olusoji”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Pakistan Journal of Pharmaceutical Sciences”, “id” : “ITEM-1”, “issue” : “2”, “issued” : { “date-parts” : “2014” }, “page” : “265-270”, “title” : “Anti-nociceptive and anti-inflammatory activities of extract of Anchomanes difformis in rats”, “type” : “article-journal”, “volume” : “27” }, “uris” : “http://www.mendeley.com/documents/?uuid=031b9cfe-1c09-412a-980f-a2a781d0e502” }, { “id” : “ITEM-2”, “itemData” : { “DOI” : “10.3389/fneur.2017.00069”, “author” : { “dropping-particle” : “”, “family” : “Afify”, “given” : “Elham A”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Alkreathy”, “given” : “Huda M”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Ali”, “given” : “Ahmed S”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Alfaifi”, “given” : “Hassan A”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Khan”, “given” : “Lateef M”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Alonso-castro”, “given” : “Angel Josabad”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-2”, “issue” : “March”, “issued” : { “date-parts” : “2017” }, “page” : “1-12”, “title” : “Characterization of the Antinociceptive Mechanisms of Khat Extract ( Catha edulis ) in Mice”, “type” : “article-journal”, “volume” : “8” }, “uris” : “http://www.mendeley.com/documents/?uuid=55678633-d8ff-4ff7-93d6-2a6cc886d64b” }, { “id” : “ITEM-3”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Mallam”, “given” : “Danjuma”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Joseph”, “given” : “A”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Abdulkadir”, “given” : “U”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Ben”, “given” : “A”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Mohammed”, “given” : “B”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-3”, “issue” : “8”, “issued” : { “date-parts” : “2016” }, “page” : “1-7”, “title” : “Analgesic and Anti-Inflammatory activities of Rothmannia Longiflora Salisb In Mice And Rats”, “type” : “article-journal”, “volume” : “6” }, “uris” : “http://www.mendeley.com/documents/?uuid=c788e811-5d6a-411d-be14-f9a166e7cb78” }, { “id” : “ITEM-4”, “itemData” : { “DOI” : “10.1211/0022357001773580”, “ISBN” : “0022-3573”, “ISSN” : “0022-3573”, “PMID” : “10716611”, “abstract” : “We have compared the analgesic properties of khat (Catha edulis Forsk) extract, amphetamine and ibuprofen in mice. After intragastric administration of the drugs analgesia was measured relative to water-injected controls using the hot-plate, the tail-flick, and abdominal-constriction tests. At the highest doses examined (amphetamine 1.8 mg kg(-1), ibuprofen 90 mg kg(-1), khat extract 1800 mg kg(-1)), all three substances produced analgesia, but the order of efficacy varied with the test. Khat and ibuprofen were significantly different from the control in the hot-plate assay at three or more time points post-injection. In the tail-flick test, khat and amphetamine were efficacious; ibuprofen means were somewhat lower but still significantly different from control. Higher doses of the drugs decreased the number of responses in the acetic acid-induced abdominal-constriction assay. We conclude that khat, like amphetamine and ibuprofen, can relieve pain. Differences in assay results may reflect differences in modes and sites of action, as well as in the type of pain generated by the chemical and thermal stimuli for nociception.”, “author” : { “dropping-particle” : “”, “family” : “Connor”, “given” : “J”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Makonnen”, “given” : “E”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Rostom”, “given” : “a”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “The Journal of pharmacy and pharmacology”, “id” : “ITEM-4”, “issue” : “1”, “issued” : { “date-parts” : “2000” }, “page” : “107-10”, “title” : “Comparison of analgesic effects of khat (Catha edulis Forsk) extract, D-amphetamine and ibuprofen in mice.”, “type” : “article-journal”, “volume” : “52” }, “uris” : “http://www.mendeley.com/documents/?uuid=c38f1139-8e2d-4261-b259-4abc2f861395” } , “mendeley” : { “formattedCitation” : “(Connor et al., 2000; Adebayo et al., 2014; Mallam et al., 2016; Afify et al., 2017)”, “plainTextFormattedCitation” : “(Connor et al., 2000; Adebayo et al., 2014; Mallam et al., 2016; Afify et al., 2017)”, “previouslyFormattedCitation” : “(Connor et al., 2000; Adebayo et al., 2014; Mallam et al., 2016; Afify et al., 2017)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Connor et al., 2000; Adebayo et al., 2014; Mallam et al., 2016; Afify et al., 2017). The plate was maintained at 55 OC, and at this temperature only opioid like agents are active ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Debebe”, “given” : “Eyob”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Makonnen”, “given” : “Eyasu”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Health”, “given” : “Ethiopian”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Ababa”, “given” : “Addis”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issued” : { “date-parts” : “2007” }, “page” : “41-48”, “title” : “Pharmacologyonline 1: 41-48 (2007)”, “type” : “article-journal”, “volume” : “48” }, “uris” : “http://www.mendeley.com/documents/?uuid=31245730-c6f5-4457-80ea-1f4e7ba55710” } , “mendeley” : { “formattedCitation” : “(Debebe et al., 2007)”, “plainTextFormattedCitation” : “(Debebe et al., 2007)”, “previouslyFormattedCitation” : “(Debebe et al., 2007)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Debebe et al., 2007). In agreement with this, morphine produced a significant analgesia at all times of observation. It was selected as a reference drug by considering its advantages like provision of longer analgesia and lesser variability of response among animals ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “ISBN” : “3527310312”, “author” : { “dropping-particle” : “”, “family” : “Dubuison”, “given” : “Dennis”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issued” : { “date-parts” : “2006” }, “page” : “221-235”, “title” : “Animal Models of Nociception”, “type” : “article-journal” }, “uris” : “http://www.mendeley.com/documents/?uuid=f70833c1-ceb4-483c-82ff-8264f5a9d2a9” } , “mendeley” : { “formattedCitation” : “(Dubuison, 2006)”, “manualFormatting” : “(Dubuison and Dennis, 2006)”, “plainTextFormattedCitation” : “(Dubuison, 2006)”, “previouslyFormattedCitation” : “(Dubuison, 2006)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Dubuison and Dennis, 2006)
The maximum dose (800mg/kg) of methanol extract achieved maximum prolongation of reaction time at the point of time like morphine. However, the lowest and middle doses (200mg/kg and 400 mg/kg) produced maximum protection later on the course of observation (120 min) (Table 4). The 200 mg/kg butanol fraction exhibited more protection at 60 min. Variation in effect may be attributed to the plasma concentration of the test substances ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/S0952-8180(99)00030-6”, “ISBN” : “0952-8180 (Print)\n0952-8180 (Linking)”, “ISSN” : “09528180”, “PMID” : “10434218”, “abstract” : “Study Objective: To determine the onset and clinical duration of cisatracurium and rocuronium in equipotent doses in balanced opioid/isoflurane anesthesia. Design: Randomized, controlled study. Setting: University hospital. Patients: 40 healthy patients scheduled for elective surgery. Interventions: Patients underwent anesthesia induction with thiopental or propofol with a cisatracurium intubating dose of either 0.15 or 0.2 mg/kg or a rocuronium dose of either 0.9 or 1.2 mg/kg. These doses correspond to three and four times the ED95dose. Measurements and Main Results: The onset time and time to 25% recovery of baseline first twitch in a train-of-four were determined using an accelerometric sensor. Rocuronium had a faster onset time that cisatracurium at equipotent doses (3 x ED95:134 vs. 220 sec respectively, and at 4 x ED95: 95 vs. 162 sec). Recovery tended to be faster but not statistically different for cisatracurium compared to rocuronium. Conclusions: With equipotent intubating doses of rocuronium and cisatracurium, rocuronium produces a more rapid onset of muscle relaxation. The data suggest a tendency toward more rapid clinical recovery of cisatracurium compared to equipotent doses of rocuronium, although these differences were not statistically significant.”, “author” : { “dropping-particle” : “”, “family” : “Lighthall”, “given” : “Geoffrey K.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Jamieson”, “given” : “Mark A.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Katolik”, “given” : “Jadwiga”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Brock-Utne”, “given” : “John G.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Clinical Anesthesia”, “id” : “ITEM-1”, “issue” : “3”, “issued” : { “date-parts” : “1999” }, “page” : “220-225”, “title” : “A comparison of the onset and clinical duration of high doses of cisatracurium and rocuronium”, “type” : “article-journal”, “volume” : “11” }, “uris” : “http://www.mendeley.com/documents/?uuid=102cdec2-e02b-4144-949d-454e367d9115” } , “mendeley” : { “formattedCitation” : “(Lighthall et al., 1999)”, “plainTextFormattedCitation” : “(Lighthall et al., 1999)”, “previouslyFormattedCitation” : “(Lighthall et al., 1999)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Lighthall et al., 1999). Over all, methanol extract and solvent fractions elicited a considerable nociception latency comparing to the reaction time values to thermal stimulus in the negative control group. Presumably, the effectiveness of the methanolic extract and solvent fractions of the root of C. ficifolius observed in the present study could be due to an opioid action via A? fibers.
The third model used to measure analgesic activity of the experimental plant was formalin test. The formalin test in mice is a valid and reliable model of nociception and is sensitive for various classes of analgesic drugs. Injection of diluted formalin with the sub-plantar rout in to the dorsal surface of the hind paw produces unambiguous nociception reaction: paw licking ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/0304-3959(87)90088-1”, “ISBN” : “0304-3959 (Print)\n0304-3959 (Linking)”, “ISSN” : “03043959”, “PMID” : “3614974”, “abstract” : “The formalin test in mice is a valid and reliable model of nociception and is sensitive for various classes of analgesic drugs. The noxious stimulus is an injection of dilute formalin (1% in saline) under the skin of the dorsal surface of the right hindpaw. The response is the amount of time the animals spend licking the injected paw. Two distinct periods of high licking activity can be identified, an early phase lasting the first 5 min and a late phase lasting from 20 to 30 min after the injection of formalin. In order to elucidate the involvement of inflammatory processes in the two phases, we tested different classes of drugs in the two phases independently. Morphine, codeine, nefopam and orphenadrine, as examples of centrally acting analgesics, were antinociceptive in both phases. In contrast, the non-steroid anti-inflammatory drugs indomethacin and naproxen and the steroids dexamethasone and hydrocortisone inhibited only the late phase, while acetylsalicylic acid (ASA) and paracetamol were antinociceptive in both phases. The results demonstrate that the two phases in the formalin test may have different nociceptive mechanisms. It is suggested that the early phase is due to a direct effect on nociceptors and that prostaglandins do not play an important role during this phase. The late phase seems to be an inflammatory response with inflammatory pain that can be inhibited by anti-inflammatory drugs. ASA and paracetamol seem to have actions independent of their inhibition of prostaglandin synthesis and they also have effects on non-inflammatory pain. u00a9 1987.”, “author” : { “dropping-particle” : “”, “family” : “Hunskaar”, “given” : “Steinar”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Hole”, “given” : “Kjell”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Pain”, “id” : “ITEM-1”, “issue” : “1”, “issued” : { “date-parts” : “1987” }, “page” : “103-114”, “title” : “The formalin test in mice: dissociation between inflammatory and non-inflammatory pain”, “type” : “article-journal”, “volume” : “30” }, “uris” : “http://www.mendeley.com/documents/?uuid=c5b6b46e-96e7-491b-9007-7c2e3c9c0899” } , “mendeley” : { “formattedCitation” : “(Hunskaar and Hole, 1987)”, “plainTextFormattedCitation” : “(Hunskaar and Hole, 1987)”, “previouslyFormattedCitation” : “(Hunskaar and Hole, 1987)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Hunskaar and Hole, 1987). Unlike other pain models, formalin test provides a number of advantages such as, little or no restraint, unhindered observation of the complete range of behavioral responses, and greater resemblance to clinical pain ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “D.DUBUISSON; SG.”, “given” : “DENNIS”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Pain”, “id” : “ITEM-1”, “issued” : { “date-parts” : “1977” }, “page” : “161-174”, “title” : “The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats”, “type” : “article-journal”, “volume” : “4” }, “uris” : “http://www.mendeley.com/documents/?uuid=f24c6ed2-6b06-478a-9167-c7924013a99a” }, { “id” : “ITEM-2”, “itemData” : { “DOI” : “10.1016/0304-3959(86)90014-X”, “ISBN” : “0304-3959 (Print)\r0304-3959 (Linking)”, “ISSN” : “03043959”, “PMID” : “3714284”, “abstract” : “It is assumed that the mild analgesia produced by acetylsalicylic acid (ASA) and indomethacin is due to a common mode of action, namely inhibition of the cyclo-oxygenase reaction in the synthesis of prostaglandins. It has, however, been difficult to separate the influence of the anti-inflammatory activity from pure analgesia in standard animal tests using a fully developed inflammatory state. In the present experiments a modification of the formalin test in mice is used. Licking of the injected paw is recorded after the injection of a small nociceptive amount of formalin (20 u03bcl, 1%). The results show that the response to formalin is biphasic with an early (0-5 min) and a late (20-30 min) phase of high licking activity. ASA had a dose-dependent antinociceptive effect during both the early and the late phases. In contrast, antinociceptive effect of indomethacin was found only during the late phase. On the basis of these results it may be suggested that inhibition of the cyclo-oxygenase reaction has no major effect on the early phase in the formalin test. This also suggests that ASA and indomethacin are antinociceptive through partially different modes of action. In addition to an anti-inflammatory effect common to both drugs, ASA may have a direct antinociceptive action. u00a9 1986.”, “author” : { “dropping-particle” : “”, “family” : “Hunskaar”, “given” : “Steinar”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Berge”, “given” : “Odd Geir”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Hole”, “given” : “Kjell”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Pain”, “id” : “ITEM-2”, “issue” : “1”, “issued” : { “date-parts” : “1986” }, “page” : “125-132”, “title” : “Dissociation between antinociceptive and anti-inflammatory effects of acetylsalicylic acid and indomethacin in the formalin test”, “type” : “article-journal”, “volume” : “25” }, “uris” : “http://www.mendeley.com/documents/?uuid=c3dacbeb-2311-43ed-9f27-0bf38d5b4b02” }, { “id” : “ITEM-3”, “itemData” : { “DOI” : “10.1111/j.1440-1681.2007.04592.x”, “author” : { “dropping-particle” : “”, “family” : “Hasanein”, “given” : “Parisa”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Parviz”, “given” : “Mohsen”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Keshavarz”, “given” : “Mansoor”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Javanmardi”, “given” : “Kazem”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-3”, “issue” : “April 2006”, “issued” : { “date-parts” : “2007” }, “page” : “439-449”, “title” : “CB1 RECEPTOR ACTIVATION IN THE BASOLATERAL AMYGDALA PRODUCES ANTINOCICEPTION IN ANIMAL MODELS OF ACUTE AND TONIC NOCICEPTION”, “type” : “article-journal” }, “uris” : “http://www.mendeley.com/documents/?uuid=3fc13269-d7f3-4865-af98-82b0fda9487c” } , “mendeley” : { “formattedCitation” : “(D.DUBUISSON; SG., 1977; Hunskaar et al., 1986; Hasanein et al., 2007)”, “manualFormatting” : “(Dubuisson, 1977; Hunskaar et al., 1986; Hasanein et al., 2007)”, “plainTextFormattedCitation” : “(D.DUBUISSON; SG., 1977; Hunskaar et al., 1986; Hasanein et al., 2007)”, “previouslyFormattedCitation” : “(D.DUBUISSON; SG., 1977; Hunskaar et al., 1986; Hasanein et al., 2007)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Dubuisson, 1977; Hunskaar et al., 1986; Hasanein et al., 2007).
Following injection of formalin two phases of behavioral responses were observed. This is an indication that the nociception response has biphasic nature with different pain pathways. The early phase (neurogenic that involves stimulation of nociceptors directly by a chemical and detected by central nociceptive afferent terminals stimulating the A? fibers. The second phase is an inflammatory response due to direct stimulation of chemical nociceptors resulting in an increased input from C fibers ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Meunier”, “given” : “Christine J”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Burton”, “given” : “Josiane”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Cumps”, “given” : “Jean”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Verbeeck”, “given” : “Roger K”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issued” : { “date-parts” : “1998” }, “page” : “307-312”, “title” : “Evaluation of the formalin test to assess the analgesic activity of diflunisal in the rat”, “type” : “article-journal”, “volume” : “6” }, “uris” : “http://www.mendeley.com/documents/?uuid=15ac0977-afd8-4c49-8d56-34e5308b60b9” }, { “id” : “ITEM-2”, “itemData” : { “DOI” : “10.1111/j.1440-1681.2007.04592.x”, “author” : { “dropping-particle” : “”, “family” : “Hasanein”, “given” : “Parisa”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Parviz”, “given” : “Mohsen”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Keshavarz”, “given” : “Mansoor”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Javanmardi”, “given” : “Kazem”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-2”, “issue” : “April 2006”, “issued” : { “date-parts” : “2007” }, “page” : “439-449”, “title” : “CB1 RECEPTOR ACTIVATION IN THE BASOLATERAL AMYGDALA PRODUCES ANTINOCICEPTION IN ANIMAL MODELS OF ACUTE AND TONIC NOCICEPTION”, “type” : “article-journal” }, “uris” : “http://www.mendeley.com/documents/?uuid=3fc13269-d7f3-4865-af98-82b0fda9487c” }, { “id” : “ITEM-3”, “itemData” : { “DOI” : “10.1016/0165-0270(85)90116-5”, “ISBN” : “0165-0270”, “ISSN” : “01650270”, “PMID” : “4033190”, “abstract” : “A modification of the formalin test appropriate for testing of mice is described. Formalin 1 or 5% was injected into the dorsal surface of a hindpaw, and the time the animal spent licking the paw was recorded. On the basis of the response pattern, two distinct periods of intensive licking activity were identified; an early (0-5 min after injection) and a late response (20-30 min after injection). The following analgesics were investigated (dose range): acetylsalicylic acid (100-400 mg/kg), paracetamol (100-400 mg/kg) and morphine (0.6-10 mg/kg). Acetylsalicylic acid (200-400 mg/kg early response, 300-400 mg/kg late response), paracetamol (200-400 mg/kg early response, 300-400 mg/kg late response) and morphine (2.5-10 mg/kg) inhibited the responses in a dose-dependent manner. The results indicate that the test is useful for evaluating mild analgesics. It may have advantages over some of the tests that are commonly used for testing analgesics. u00a9 1985.”, “author” : { “dropping-particle” : “”, “family” : “Hunskaar”, “given” : “Steinar”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Fasmer”, “given” : “Ole Bernt”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Hole”, “given” : “Kjell”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Neuroscience Methods”, “id” : “ITEM-3”, “issue” : “1”, “issued” : { “date-parts” : “1985” }, “page” : “69-76”, “title” : “Formalin test in mice, a useful technique for evaluating mild analgesics”, “type” : “article-journal”, “volume” : “14” }, “uris” : “http://www.mendeley.com/documents/?uuid=8c1cb1a0-04da-49a3-a8b9-6f2ced086b52” }, { “id” : “ITEM-4”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Kamei”, “given” : “Junzo”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-4”, “issued” : { “date-parts” : “1997” }, “page” : “31-36”, “title” : “The role of spinal d 1 -opioid receptors in inhibiting the formalin-induced nociceptive response in diabetic mice”, “type” : “article-journal” }, “uris” : “http://www.mendeley.com/documents/?uuid=11bef7b6-0bf0-47d6-8226-7651b17833f7” }, { “id” : “ITEM-5”, “itemData” : { “DOI” : “10.3389/fneur.2017.00069”, “author” : { “dropping-particle” : “”, “family” : “Afify”, “given” : “Elham A”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Alkreathy”, “given” : “Huda M”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Ali”, “given” : “Ahmed S”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Alfaifi”, “given” : “Hassan A”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Khan”, “given” : “Lateef M”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Alonso-castro”, “given” : “Angel Josabad”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-5”, “issue” : “March”, “issued” : { “date-parts” : “2017” }, “page” : “1-12”, “title” : “Characterization of the Antinociceptive Mechanisms of Khat Extract ( Catha edulis ) in Mice”, “type” : “article-journal”, “volume” : “8” }, “uris” : “http://www.mendeley.com/documents/?uuid=55678633-d8ff-4ff7-93d6-2a6cc886d64b” } , “mendeley” : { “formattedCitation” : “(Hunskaar et al., 1985; Kamei, 1997; Meunier et al., 1998; Hasanein et al., 2007; Afify et al., 2017)”, “plainTextFormattedCitation” : “(Hunskaar et al., 1985; Kamei, 1997; Meunier et al., 1998; Hasanein et al., 2007; Afify et al., 2017)”, “previouslyFormattedCitation” : “(Hunskaar et al., 1985; Kamei, 1997; Meunier et al., 1998; Hasanein et al., 2007; Afify et al., 2017)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Hunskaar et al., 1985; Kamei, 1997; Meunier et al., 1998; Hasanein et al., 2007; Afify et al., 2017). The nociception response in the initial phase was recorded from 0-5 minutes while the late phase was recorded from 15-30 minutes ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.5681/apb.2014.087”, “author” : { “dropping-particle” : “”, “family” : “Adedapo”, “given” : “Adeolu Alex”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Aremu”, “given” : “Olujoke Janet”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Oyagbemi”, “given” : “Ademola Adetokunbo”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issue” : “Suppl 2”, “issued” : { “date-parts” : “2014” }, “page” : “591-598”, “title” : “Anti-Oxidant , Anti-Inflammatory and Antinociceptive Properties of the Acetone Leaf Extract of Vernonia Amygdalina in Some Laboratory Animals”, “type” : “article-journal”, “volume” : “4” }, “uris” : “http://www.mendeley.com/documents/?uuid=f3df182b-2a0a-4559-924c-38c52687f5ea” }, { “id” : “ITEM-2”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Santos”, “given” : “A R S”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Vedana”, “given” : “E M A”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “De”, “family” : “Freitas”, “given” : “G A G”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-2”, “issued” : { “date-parts” : “1998” }, “page” : “302-307”, “title” : “Original Research Papers Antinociceptive effect of meloxicam , in neurogenic and inflammatory nociceptive models in mice”, “type” : “article-journal”, “volume” : “47” }, “uris” : “http://www.mendeley.com/documents/?uuid=276053ae-3681-4c06-bf8e-8330ac50cd11” }, { “id” : “ITEM-3”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Kamei”, “given” : “Junzo”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-3”, “issued” : { “date-parts” : “1997” }, “page” : “31-36”, “title” : “The role of spinal d 1 -opioid receptors in inhibiting the formalin-induced nociceptive response in diabetic mice”, “type” : “article-journal” }, “uris” : “http://www.mendeley.com/documents/?uuid=11bef7b6-0bf0-47d6-8226-7651b17833f7” } , “mendeley” : { “formattedCitation” : “(Kamei, 1997; Santos et al., 1998; Adedapo et al., 2014)”, “plainTextFormattedCitation” : “(Kamei, 1997; Santos et al., 1998; Adedapo et al., 2014)”, “previouslyFormattedCitation” : “(Kamei, 1997; Santos et al., 1998; Adedapo et al., 2014)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Kamei, 1997; Santos et al., 1998; Adedapo et al., 2014)
The late phase of formalin induced licking behavior is partly mediated by prostaglandins and can be inhibited by NSAIDs and steroids, as well as the centrally acting drugs ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/0304-3959(87)90088-1”, “ISBN” : “0304-3959 (Print)\n0304-3959 (Linking)”, “ISSN” : “03043959”, “PMID” : “3614974”, “abstract” : “The formalin test in mice is a valid and reliable model of nociception and is sensitive for various classes of analgesic drugs. The noxious stimulus is an injection of dilute formalin (1% in saline) under the skin of the dorsal surface of the right hindpaw. The response is the amount of time the animals spend licking the injected paw. Two distinct periods of high licking activity can be identified, an early phase lasting the first 5 min and a late phase lasting from 20 to 30 min after the injection of formalin. In order to elucidate the involvement of inflammatory processes in the two phases, we tested different classes of drugs in the two phases independently. Morphine, codeine, nefopam and orphenadrine, as examples of centrally acting analgesics, were antinociceptive in both phases. In contrast, the non-steroid anti-inflammatory drugs indomethacin and naproxen and the steroids dexamethasone and hydrocortisone inhibited only the late phase, while acetylsalicylic acid (ASA) and paracetamol were antinociceptive in both phases. The results demonstrate that the two phases in the formalin test may have different nociceptive mechanisms. It is suggested that the early phase is due to a direct effect on nociceptors and that prostaglandins do not play an important role during this phase. The late phase seems to be an inflammatory response with inflammatory pain that can be inhibited by anti-inflammatory drugs. ASA and paracetamol seem to have actions independent of their inhibition of prostaglandin synthesis and they also have effects on non-inflammatory pain. u00a9 1987.”, “author” : { “dropping-particle” : “”, “family” : “Hunskaar”, “given” : “Steinar”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Hole”, “given” : “Kjell”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Pain”, “id” : “ITEM-1”, “issue” : “1”, “issued” : { “date-parts” : “1987” }, “page” : “103-114”, “title” : “The formalin test in mice: dissociation between inflammatory and non-inflammatory pain”, “type” : “article-journal”, “volume” : “30” }, “uris” : “http://www.mendeley.com/documents/?uuid=c5b6b46e-96e7-491b-9007-7c2e3c9c0899” } , “mendeley” : { “formattedCitation” : “(Hunskaar and Hole, 1987)”, “plainTextFormattedCitation” : “(Hunskaar and Hole, 1987)”, “previouslyFormattedCitation” : “(Hunskaar and Hole, 1987)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Hunskaar and Hole, 1987). Substance P and bradykinin participate in the manifestation of the first phase response, whereas histamine, serotonin, prostaglandin and bradykinin are involved in the second phase ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1054/npep.2000.0805”, “author” : { “dropping-particle” : “”, “family” : “Chung”, “given” : “K M”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Song”, “given” : “D K”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Huh”, “given” : “S O”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Kim”, “given” : “Y H”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Choi”, “given” : “M R”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Suh”, “given” : “H W”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issued” : { “date-parts” : “2000” }, “page” : “158-166”, “title” : “Supraspinal NMDA and non-NMDA receptors are differentially involved in the production of antinociception by morphine and u03b2 -endorphin administered intracerebroventricularly in the formalin pain model”, “type” : “article-journal”, “volume” : “34” }, “uris” : “http://www.mendeley.com/documents/?uuid=8a6a8892-f218-4e97-abd5-ddda47d1eae1” } , “mendeley” : { “formattedCitation” : “(Chung et al., 2000)”, “plainTextFormattedCitation” : “(Chung et al., 2000)”, “previouslyFormattedCitation” : “(Chung et al., 2000)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Chung et al., 2000).
The presence of edema is one of the prime signs of inflammation. Carrageenan-induced paw edema is a well-defined model of acute inflammation that a variety of inflammatory mediators participates in its development ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/j.ejphar.2011.05.053”, “ISBN” : “0014-2999”, “ISSN” : “00142999”, “PMID” : “21243294”, “abstract” : “Anti-inflammatory effects of antidepressants have been reported in some studies, but the mechanisms underlying these effects remain unknown. Amitriptyline, a tricyclic antidepressant, is widely used in the management of psychological disorders and various types of pain, including neuropathic pain or fibromyalgia. In our previous work, we found the role of supraspinal mechanisms in the anti-inflammatory effect of amitriptyline. In the line of the indicated study, we sought to evaluate the effects of intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) application of amitriptyline in the carrageenan-induced paw edema in rats in more details. Our findings confirmed that i.p. (40 and 80 mg/kg) and i.c.v. (100 u03bcg/rat) injection of amitriptyline inhibited carrageenan-induced inflammation at different times. We also found that both i.p. and i.c.v. amitriptyline significantly decreased migration of polymorphonuclear (PMN) leucocytes into the site of inflammation, according to pathological evidence and the activity of myeloperoxidase (MPO). Furthermore, i.p. amitriptyline at the applied doses markedly reduced interleukin (IL)-1u03b2 and tumor necrosis factor (TNF)-u03b1 levels in the paw treated with carrageenan. Our results also showed that i.c.v. amitriptyline noticeably decreased the concentration of IL-1u03b2 in the inflamed paws. The TNF-u03b1 levels reduced in the i.c.v. group, even though these reductions were not statistically significant. These results confirmed the anti-inflammatory effects of systemic and central amitriptyline in the carrageenan-induced paw edema in rats, and demonstrated that these effects mediated mostly through the inhibition of PMN cells migration and release of IL-1u03b2 and TNF-u03b1 into the site of inflammation. u00a9 2011 Elsevier B.V. All rights reserved.”, “author” : { “dropping-particle” : “”, “family” : “Sadeghi”, “given” : “Hossein”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Hajhashemi”, “given” : “Valiolla”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Minaiyan”, “given” : “Mohsen”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Movahedian”, “given” : “Ahmad”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Talebi”, “given” : “Ardeshir”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “European Journal of Pharmacology”, “id” : “ITEM-1”, “issue” : “1-3”, “issued” : { “date-parts” : “2011” }, “page” : “396-401”, “title” : “A study on the mechanisms involving the anti-inflammatory effect of amitriptyline in carrageenan-induced paw edema in rats”, “type” : “article-journal”, “volume” : “667” }, “uris” : “http://www.mendeley.com/documents/?uuid=0bfac3d8-9063-4eee-af05-df733351bf3a” } , “mendeley” : { “formattedCitation” : “(Sadeghi et al., 2011)”, “plainTextFormattedCitation” : “(Sadeghi et al., 2011)”, “previouslyFormattedCitation” : “(Sadeghi et al., 2011)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Sadeghi et al., 2011). The evolution of carrageenan induced acute inflammation is characterized by two phases, namely initial and late phases ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.7860/JCDR/2015/12543.5928”, “author” : { “dropping-particle” : “”, “family” : “Sangeetha”, “given” : “S.Umamaheswari and K.S.Sridevi”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Clinical and Diagnostic Research”, “id” : “ITEM-1”, “issue” : “5”, “issued” : { “date-parts” : “2015” }, “page” : “5-7”, “title” : “Anti-Inflammatory Effect of Selected Dihydroxyflavones”, “type” : “article-journal”, “volume” : “9” }, “uris” : “http://www.mendeley.com/documents/?uuid=f2562215-8e0c-4b8d-b3e4-bc615c22c71a” } , “mendeley” : { “formattedCitation” : “(Sangeetha, 2015)”, “plainTextFormattedCitation” : “(Sangeetha, 2015)”, “previouslyFormattedCitation” : “(Sangeetha, 2015)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Sangeetha, 2015).
Following injection of carrageenan, inflammatory mediators such as bradykinin, serotonin and histamine are released and contribute the initial phase that occurs between 0 and 2.5 h ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.7860/JCDR/2015/12543.5928”, “author” : { “dropping-particle” : “”, “family” : “Sangeetha”, “given” : “S.Umamaheswari and K.S.Sridevi”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Clinical and Diagnostic Research”, “id” : “ITEM-1”, “issue” : “5”, “issued” : { “date-parts” : “2015” }, “page” : “5-7”, “title” : “Anti-Inflammatory Effect of Selected Dihydroxyflavones”, “type” : “article-journal”, “volume” : “9” }, “uris” : “http://www.mendeley.com/documents/?uuid=f2562215-8e0c-4b8d-b3e4-bc615c22c71a” }, { “id” : “ITEM-2”, “itemData” : { “DOI” : “10.1016/j.jep.2012.04.041”, “ISSN” : “03788741”, “PMID” : “22561892”, “abstract” : “Ethnopharmacological relevance: Ocimum suave has been used in the Ethiopian traditional medicine to relieve pain, fever, inflammation and other disease conditions. Aim of the study: The aim of the present study was to investigate the anti-inflammatory activities of the aqueous and ethanol leaf extracts and some fractions of Ocimum suave in mice. Materials and methods: The crude extracts were screened for their anti-inflammatory activities on carrageenan-induced mouse paw edema at three dose levels. The butanol and aqueous fractions of the aqueous extract were also evaluated for their anti-inflammatory activities using carrageenan, histamine and serotonin-induced mouse paw edema at three dose levels. Normal saline and aspirin were employed as negative and positive control groups, respectively. Results: Both ethanol and aqueous extracts significantly decreased carrageenan-induced inflammation at all the three doses used. However, greater paw edema inhibition was observed with the aqueous extract. The two fractions also showed significant reduction of inflammation against inflammatory models in which the aqueous residue exhibited the highest inhibition. Conclusions: From the present findings, it can be concluded that the ethanol and aqueous leaf extracts as well as butanol and aqueous fractions of Ocimum suave have shown anti-inflammatory properties. u00a9 2012 Elsevier Ireland Ltd. All rights reserved.”, “author” : { “dropping-particle” : “”, “family” : “Masresha”, “given” : “Birhanetensay”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Makonnen”, “given” : “Eyasu”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Debella”, “given” : “Asfaw”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Ethnopharmacology”, “id” : “ITEM-2”, “issue” : “1”, “issued” : { “date-parts” : “2012” }, “page” : “201-205”, “publisher” : “Elsevier”, “title” : “In vivo anti-inflammatory activities of Ocimum suave in mice”, “type” : “article-journal”, “volume” : “142” }, “uris” : “http://www.mendeley.com/documents/?uuid=ebf854d5-6a6a-4e82-83bd-8101e4c48cb4” }, { “id” : “ITEM-3”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Samad”, “given” : “T A”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Nature”, “id” : “ITEM-3”, “issued” : { “date-parts” : “2001” }, “page” : “471-475”, “publisher” : ” “, “title” : “Interleukin-1u03b2-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity”, “type” : “article-journal”, “volume” : “410” }, “uris” : “http://www.mendeley.com/documents/?uuid=1a38830c-12d2-4f3f-b089-7c3fd68ecc42” }, { “id” : “ITEM-4”, “itemData” : { “DOI” : “10.1016/j.phymed.2014.07.015”, “ISSN” : “1618095X”, “PMID” : “25442259”, “abstract” : “The current study was designed to explore the antinociceptive, antiinflammatory and antipyretic activity of pistagremic acid (PA), isolated from Pistacia integerima bark in various animal paradigms. The results illustrated significant inhibition of noxious stimulation in acetic acid induced writhing test with maximum effect of 68% at 10 mg/kg i.p. In tail immersion test, pretreatment with PA demonstrated marked activity during various assessment times in a dose dependent manner. The maximum pain inhibition was 59.46% at 10 mg/kg i.p. after 90 min of PA treatment. However, the injection of naloxone did not antagonize this induced effect. PA significantly ameliorated post carrageenan induced edema dose dependently during various stages of inflammation. The effect was most dominant (60.02%) after 3rdh of drug administration when examined for 5 h. Similarly, it provoked dose dependent antipyretic effect in febrile mice with maximum of 60.04% activity at 10 mg/kg i.p. after 3rd hour of PA post treatment. Furthermore, molecular docking was carried out to understand the binding mode of PA. From the docking study it was observed that PA fits well in the active site of COX-2 enzyme due to hydrogen and hydrophobic moiety interactions to the important active site of molecule. In conclusion, PA possesses strong peripheral and central antinociceptive activity independent of opioidergic effect which was augmented by its anti-inflammatory and antipyretic activities.”, “author” : { “dropping-particle” : “”, “family” : “Rauf”, “given” : “Abdur”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Uddin”, “given” : “Ghias”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Siddiqui”, “given” : “Bina S.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Khan”, “given” : “Ajmal”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Khan”, “given” : “Haroon”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Arfan”, “given” : “Mohammad”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Muhammad”, “given” : “Naveed”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Wadood”, “given” : “Abdul”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Phytomedicine”, “id” : “ITEM-4”, “issue” : “12”, “issued” : { “date-parts” : “2014” }, “page” : “1509-1515”, “publisher” : “Elsevier GmbH.”, “title” : “In-vivo antinociceptive, anti-inflammatory and antipyretic activity of pistagremic acid isolated from Pistacia integerrima”, “type” : “article-journal”, “volume” : “21” }, “uris” : “http://www.mendeley.com/documents/?uuid=09676004-c880-4dd2-a9f6-a1674fa46909” } , “mendeley” : { “formattedCitation” : “(Samad, 2001; Masresha et al., 2012; Rauf et al., 2014; Sangeetha, 2015)”, “plainTextFormattedCitation” : “(Samad, 2001; Masresha et al., 2012; Rauf et al., 2014; Sangeetha, 2015)”, “previouslyFormattedCitation” : “(Samad, 2001; Masresha et al., 2012; Rauf et al., 2014; Sangeetha, 2015)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Samad, 2001; Masresha et al., 2012; Rauf et al., 2014; Sangeetha, 2015). As indicated in Table 7 maximum peak of edema was observed at (180 min) which is thought to be due to the release of kinin-like substances, especially of bradykinin ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.7860/JCDR/2015/12543.5928”, “author” : { “dropping-particle” : “”, “family” : “Sangeetha”, “given” : “S.Umamaheswari and K.S.Sridevi”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Clinical and Diagnostic Research”, “id” : “ITEM-1”, “issue” : “5”, “issued” : { “date-parts” : “2015” }, “page” : “5-7”, “title” : “Anti-Inflammatory Effect of Selected Dihydroxyflavones”, “type” : “article-journal”, “volume” : “9” }, “uris” : “http://www.mendeley.com/documents/?uuid=f2562215-8e0c-4b8d-b3e4-bc615c22c71a” } , “mendeley” : { “formattedCitation” : “(Sangeetha, 2015)”, “plainTextFormattedCitation” : “(Sangeetha, 2015)”, “previouslyFormattedCitation” : “(Sangeetha, 2015)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Sangeetha, 2015). The second phase of edema is a result of overproduction of prostaglandins in tissues and may occur from 2.5 to 6 h post-carrageenan injection ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/j.jep.2012.04.041”, “ISSN” : “03788741”, “PMID” : “22561892”, “abstract” : “Ethnopharmacological relevance: Ocimum suave has been used in the Ethiopian traditional medicine to relieve pain, fever, inflammation and other disease conditions. Aim of the study: The aim of the present study was to investigate the anti-inflammatory activities of the aqueous and ethanol leaf extracts and some fractions of Ocimum suave in mice. Materials and methods: The crude extracts were screened for their anti-inflammatory activities on carrageenan-induced mouse paw edema at three dose levels. The butanol and aqueous fractions of the aqueous extract were also evaluated for their anti-inflammatory activities using carrageenan, histamine and serotonin-induced mouse paw edema at three dose levels. Normal saline and aspirin were employed as negative and positive control groups, respectively. Results: Both ethanol and aqueous extracts significantly decreased carrageenan-induced inflammation at all the three doses used. However, greater paw edema inhibition was observed with the aqueous extract. The two fractions also showed significant reduction of inflammation against inflammatory models in which the aqueous residue exhibited the highest inhibition. Conclusions: From the present findings, it can be concluded that the ethanol and aqueous leaf extracts as well as butanol and aqueous fractions of Ocimum suave have shown anti-inflammatory properties. u00a9 2012 Elsevier Ireland Ltd. All rights reserved.”, “author” : { “dropping-particle” : “”, “family” : “Masresha”, “given” : “Birhanetensay”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Makonnen”, “given” : “Eyasu”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Debella”, “given” : “Asfaw”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Ethnopharmacology”, “id” : “ITEM-1”, “issue” : “1”, “issued” : { “date-parts” : “2012” }, “page” : “201-205”, “publisher” : “Elsevier”, “title” : “In vivo anti-inflammatory activities of Ocimum suave in mice”, “type” : “article-journal”, “volume” : “142” }, “uris” : “http://www.mendeley.com/documents/?uuid=ebf854d5-6a6a-4e82-83bd-8101e4c48cb4” } , “mendeley” : { “formattedCitation” : “(Masresha et al., 2012)”, “plainTextFormattedCitation” : “(Masresha et al., 2012)”, “previouslyFormattedCitation” : “(Masresha et al., 2012)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Masresha et al., 2012).
The treatments achieved maximum anti-inflammatory activity at the four hour. This is supported by reports that the second phase is known to be sensitive to most clinically effective anti-inflammatory drugs ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.7860/JCDR/2015/12543.5928”, “author” : { “dropping-particle” : “”, “family” : “Sangeetha”, “given” : “S.Umamaheswari and K.S.Sridevi”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Clinical and Diagnostic Research”, “id” : “ITEM-1”, “issue” : “5”, “issued” : { “date-parts” : “2015” }, “page” : “5-7”, “title” : “Anti-Inflammatory Effect of Selected Dihydroxyflavones”, “type” : “article-journal”, “volume” : “9” }, “uris” : “http://www.mendeley.com/documents/?uuid=f2562215-8e0c-4b8d-b3e4-bc615c22c71a” } , “mendeley” : { “formattedCitation” : “(Sangeetha, 2015)”, “plainTextFormattedCitation” : “(Sangeetha, 2015)”, “previouslyFormattedCitation” : “(Sangeetha, 2015)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Sangeetha, 2015). Production of arachidonic metabolites via the COX-2 enzyme is the main factor responsible for the late phase of carrageenan induced inflammation ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/j.jep.2006.06.006”, “ISBN” : “0378-8741 (Print)”, “ISSN” : “03788741”, “PMID” : “16876348”, “abstract” : “In Ethiopia inflammatory skin diseases are among the most common health problems treated with traditional remedies which mainly comprise medicinal plants. In the present work, the anti-inflammatory and anti-nociceptive activities of Cheilanthes farinosa (Forsk.) Kaulf (Adianthaceae), a fern used in many parts of Ethiopia to treat inflammatory skin disorders, were studied using in vivo models of inflammation and pain. The results of the study showed that the fronds Cheilanthes farinosa possess strong anti-inflammatory and anti-nociceptive properties. It was further demonstrated that the active ingredients of the fern reside mainly in the methanol fraction from which three compounds viz. the flavonol glycoside rutin, and the natural cinnamic acids, caffeic acid and its quinic acid derivative chlorogenic acid have been isolated. The methanol extract was also shown to potentiate the anti-inflammatory activity of acetyl salicylic acid. At the tested concentrations, the methanol extract displayed a better anti-nociceptive activity than that of ASA in both the early and late phases of formalin induced nociception in mice. However, the activity of the extract was more pronounced in the late phase, which is commonly associated with inflammatory pain. Evaluation of the pharmacological properties of the compounds isolated from the active fractions pointed out that chlorogenic acid possesses strong anti-inflammatory and anti-nociceptive activities while caffeic acid and rutin were inactive. Moreover, on molar basis chlorogenic acid was proved to be superior in its anti-inflammatory action to acetyl salicylic acid. It was therefore concluded that chlorogenic acid contributes, in full or in part, to the anti-inflammatory and anti-nociceptive activities of Cheilanthes farinosa. Both the methanolic extract and pure chlorogenic acid failed to display anti-nociceptive activity when tested by the tail-flick test indicating that the plant is not a centrally acting analgesic but instead exerts its analgesic activity by way of its antinflammtory action. ?? 2006 Elsevier Ireland Ltd. All rights reserved.”, “author” : { “dropping-particle” : “”, “family” : “Yonathan”, “given” : “Mariamawit”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Asres”, “given” : “Kaleab”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Assefa”, “given” : “Ashenafi”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Bucar”, “given” : “Franz”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Ethnopharmacology”, “id” : “ITEM-1”, “issue” : “3”, “issued” : { “date-parts” : “2006” }, “note” : “https://l.facebook.com/l.php?u=http%3A%2F%2Fonlinelibrary.wiley.com%2Fdoi%2F10.1002%2Fprp2.383%2Fabstract&amp;h=ATMBex2-_u4SiTBPhn6A8iaT9SQ-3luPKnJn42TWzKDN91b5is8Mu-NyYdVswQMKSViK85cd1ZiCD1fdnXVI0MHT5JFkQ9-36r6mKCu8–1dQzqp065w7APpQRutgoa0Qj6D4QpIrCagpm4f”, “page” : “462-470”, “title” : “In vivo anti-inflammatory and anti-nociceptive activities of Cheilanthes farinosa”, “type” : “article-journal”, “volume” : “108” }, “uris” : “http://www.mendeley.com/documents/?uuid=b4e80a79-fa11-4948-9cd9-dadff8a1d9b8” } , “mendeley” : { “formattedCitation” : “(Yonathan et al., 2006)”, “plainTextFormattedCitation” : “(Yonathan et al., 2006)”, “previouslyFormattedCitation” : “(Yonathan et al., 2006)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Yonathan et al., 2006), but not to lipoxygenase inhibitors ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/j.jep.2012.04.041”, “ISSN” : “03788741”, “PMID” : “22561892”, “abstract” : “Ethnopharmacological relevance: Ocimum suave has been used in the Ethiopian traditional medicine to relieve pain, fever, inflammation and other disease conditions. Aim of the study: The aim of the present study was to investigate the anti-inflammatory activities of the aqueous and ethanol leaf extracts and some fractions of Ocimum suave in mice. Materials and methods: The crude extracts were screened for their anti-inflammatory activities on carrageenan-induced mouse paw edema at three dose levels. The butanol and aqueous fractions of the aqueous extract were also evaluated for their anti-inflammatory activities using carrageenan, histamine and serotonin-induced mouse paw edema at three dose levels. Normal saline and aspirin were employed as negative and positive control groups, respectively. Results: Both ethanol and aqueous extracts significantly decreased carrageenan-induced inflammation at all the three doses used. However, greater paw edema inhibition was observed with the aqueous extract. The two fractions also showed significant reduction of inflammation against inflammatory models in which the aqueous residue exhibited the highest inhibition. Conclusions: From the present findings, it can be concluded that the ethanol and aqueous leaf extracts as well as butanol and aqueous fractions of Ocimum suave have shown anti-inflammatory properties. u00a9 2012 Elsevier Ireland Ltd. All rights reserved.”, “author” : { “dropping-particle” : “”, “family” : “Masresha”, “given” : “Birhanetensay”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Makonnen”, “given” : “Eyasu”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Debella”, “given” : “Asfaw”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Ethnopharmacology”, “id” : “ITEM-1”, “issue” : “1”, “issued” : { “date-parts” : “2012” }, “page” : “201-205”, “publisher” : “Elsevier”, “title” : “In vivo anti-inflammatory activities of Ocimum suave in mice”, “type” : “article-journal”, “volume” : “142” }, “uris” : “http://www.mendeley.com/documents/?uuid=ebf854d5-6a6a-4e82-83bd-8101e4c48cb4” } , “mendeley” : { “formattedCitation” : “(Masresha et al., 2012)”, “plainTextFormattedCitation” : “(Masresha et al., 2012)”, “previouslyFormattedCitation” : “(Masresha et al., 2012)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Masresha et al., 2012).
Based on the result of the present study, methanolic crude extract, aqueous and butanol fractions of C. ficifolius significantly decreased paw edema in both phases of carrageenan induced acute inflammation. This suggests bioactive constituents in the crude extract and solvent fractions may suppress both phases of acute inflammation by inhibiting the release and/or activity of the inflammatory mediators such as, bradykinin, histamine, and serotonin in the initial phase. In the late phase, a reduction in edema may be attributed to COX inhibitory action of 80% methanol extract and solvent fractions.

Preliminary phytochemical screening demonstrated the presence of phenols, flavonoids, terpinoids, steroids and saponins (Efrem et al., 2017) in hydro-alcoholic extract of C. ficifolius. The anti-nociceptive and anti-inflammatory effect of many plants has been attributed to their flavonoid, terpenoid, tannin, phenol, steroid, alkaloid and saponin constituents ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.4314/epj.v30i2.1”, “author” : { “dropping-particle” : “”, “family” : “Rahel Birhane”, “given” : “Workineh Shibeshi and Kaleab Asres”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “ETHIOPIAN PHARMACEUTICAL JOURNA”, “id” : “ITEM-1”, “issued” : { “date-parts” : “2014” }, “page” : “65-76”, “title” : “Evaluation of Analgesic and Antiinflammatory Activities of the Root Extracts of Indigofera spicata F . in Mice”, “type” : “article-journal”, “volume” : “30” }, “uris” : “http://www.mendeley.com/documents/?uuid=189e0a5a-36e6-44d1-ab45-b7d4693a050a” } , “mendeley” : { “formattedCitation” : “(Rahel Birhane, 2014)”, “manualFormatting” : “(Rahel et al., 2014)”, “plainTextFormattedCitation” : “(Rahel Birhane, 2014)”, “previouslyFormattedCitation” : “(Rahel Birhane, 2014)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Birhane et al., 2014). Flavonoids exert anti-inflammatory via scavenging reactive oxygen species (ROS) and reducing pro-inflammatory cytokines (e.g., nuclear factor-kappa B (NF-?B), TNF-?, IL-1?, and interleukin -6 (IL-6) ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/j.jep.2017.02.036”, “ISSN” : “18727573”, “abstract” : “Background Pain and inflammation are associated with the pathophysiology of various clinical conditions. Most analgesic and anti-inflammatory drugs available in the market present a wide range of problems. The current study was aimed at investigating the analgesic and anti-inflammatory activity of 80% methanol extract of J. abyssinicum root. Methods The analgesic activity was determined using tail-flick test and acetic acid induced writhing, whereas anti-inflammatory activity was determined by carrageenan induced paw edema and formalin induced pedal edema, carried out in vivo. The test group received three different doses of the extract (50u00a0mg/kg, 100u00a0mg/kg and 200u00a0mg/kg) orally. The positive control group received diclofenac (10u00a0mg/kg), aspirin (100u00a0mg/kg or 150u00a0mg/kg) or morphine (20u00a0mg/kg) orally. The negative control group received vehicle (2% Tween 80, 10u00a0ml/kg) orally. Furthermore, preliminary phytochemical screening was carried out. Results Oral administration of J. abbysinicum 80% methanol extract (at all doses) significantly (p<0.001) inhibit pain sensation in the pain models. Similarly, the extract demonstrated anti-inflammatory effect in the inflammation models in mice. Preliminary phytochemical screening showed the presence of saponins, flavonoids, terpenoids, triterpenens and glycosides. Conclusion The data obtained from the present study indicates that the extract possessed a significant analgesic and anti-inflammatory activity, upholding the folkloric use of the plant.”, “author” : { “dropping-particle” : “”, “family” : “Tadiwos”, “given” : “Yohannes”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Nedi”, “given” : “Teshome”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Engidawork”, “given” : “Ephrem”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Ethnopharmacology”, “id” : “ITEM-1”, “issue” : “November 2016”, “issued” : { “date-parts” : “2017” }, “page” : “281-289”, “publisher” : “Elsevier Ireland Ltd”, “title” : “Analgesic and anti-inflammatory activities of 80% methanol root extract of Jasminum abyssinicum Hochst. ex. Dc. (Oleaceae) in mice”, “type” : “article-journal”, “volume” : “202” }, “uris” : “http://www.mendeley.com/documents/?uuid=eb4f1592-635e-4678-9916-ee2773999703” }, { “id” : “ITEM-2”, “itemData” : { “DOI” : “10.7860/JCDR/2015/12543.5928”, “author” : { “dropping-particle” : “”, “family” : “Sangeetha”, “given” : “S.Umamaheswari and K.S.Sridevi”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Clinical and Diagnostic Research”, “id” : “ITEM-2”, “issue” : “5”, “issued” : { “date-parts” : “2015” }, “page” : “5-7”, “title” : “Anti-Inflammatory Effect of Selected Dihydroxyflavones”, “type” : “article-journal”, “volume” : “9” }, “uris” : “http://www.mendeley.com/documents/?uuid=f2562215-8e0c-4b8d-b3e4-bc615c22c71a” } , “mendeley” : { “formattedCitation” : “(Sangeetha, 2015; Tadiwos et al., 2017)”, “manualFormatting” : “(Singh et al., 2013; Amelo et al., 2014; Sangeetha, 2015; Tadiwos et al., 2017)”, “plainTextFormattedCitation” : “(Sangeetha, 2015; Tadiwos et al., 2017)”, “previouslyFormattedCitation” : “(Sangeetha, 2015; Tadiwos et al., 2017)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(Singh et al., 2013; Sangeetha, 2015; Tadiwos et al., 2017).

The analgesic and anti-inflammatory activities of 80% methanol root extract and fractions might be due to the presence of phenols, tannins, saponins, terpenoids and flavonoids.

,
6. Conclusion and RecommendationCrude methanolic extract, aqueous and butanol fractions of C. ficifolius proved to have analgesic properties against thermal, chemical noxious stimuli pain models; and anti-inflammatory in carrageenan induced paw edema. The crude extract and solvent fractions possess peripheral and central analgesic activity. The mechanism of anti-inflammatory actions may involve a multitude of inflammatory mediators.

Further constituent isolation, binding studies and electrophysiological procedures may be useful to fully elucidate the anti-nociceptive effects and mechanism of C. ficifolius butanol fraction.

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