title: Pharmacological basis for the medicinal use of Carissa carandas in constipation and diarrhea.
abstract: BACKGROUND
  Carissa carandas Linn. commonly known as "Karaunda" (Apocynaceae) is a popular medicinal herb widely distributed in different parts of Pakistan. In addition to other medicinal uses, Carissa carandas is popular in indigenous system of medicine for its medicinal use in gut motility disorders like, constipation and diarrhea.
  
  
  OBJECTIVE
  This study was planned to provide pharmacological basis to the medicinal use of Carissa carandas in constipation and diarrhea.
  
  
  METHODS
  The crude extract of the leaves of Carissa carandas (Cc.Cr) was prepared in methanol and its fractionation was carried out with ethylacetate, petroleum ether and n-butanol. In-vivo studies were conducted on mice, while isolated rabbit jejunum and guinea-pig ileum preparations were used for the in-vitro experiments. The spasmogenic and spasmolytic responses of gut tissues were recorded using isotonic transducers coupled with PowerLab data acquisition system.
  
  
  RESULTS
  The HPLC fingerprints of Cc.Cr, its petroleum (Cc.Pef), ethylacetate (Cc.Eaf) and n-butanol (Cc.Baf) fractions showed the presence of oleanolic acid, ursolic acid, stigmasterol and β-sitosterol. Oral administration of Cc.Cr to mice increased fecal output at lower doses (30 and 50 mg/kg), while it showed protection against castor oil-induced diarrhea at higher doses (300 and 600 mg/kg). In isolated guinea-pig ileum and rabbit jejunum, Cc.Cr and Cc.Baf exhibited stimulatory effect at 0.003-3 mg/ml, which was partially sensitive to atropine or pyrillamine or partially/fully sensitive to atropine+pyrillamine, followed by relaxation at higher tested concentrations, being more potent in rabbit tissues. The ethylacetate fraction (0.1-5 mg/ml) exhibited fully atropine-sensitive contractions in both guinea-pig and rabbit tissues, being more potent in guinea-pig while more efficacious in rabbit tissues. However, the petroleum fraction (0.003-1.0 mg/ml) showed only spasmolytic activity in spontaneously contracting rabbit tissues, similar to nifedipine. In guinea-tissue, Cc.Pef did not cause any stimulant effect. When studied against high K(+) (80 mM)-induced contraction, the crude extract and its fractions caused a dose-dependent inhibition, with the following order of potency: Cc.Pef>Cc.Eaf>Cc.Cr≥Cc.Baf, similar to nifedipine indicating Ca(++) channel antagonist like activity, which was further confirmed when the plant extract displaced Ca(++) curves to the right with suppression of maximum effect similar to that of nifedipine.
  
  
  CONCLUSIONS
  This study demonstrates that the crude extract of Carissa carandas possesses a gut-stimulatory effect mediated primarily through the activation of muscarinic and histaminergic receptors while its spasmolytic effect was mediated possibly through Ca(++) antagonist pathway. Thus, this study provides a clear evidence for the dual effectiveness of Carissa carandas in constipation and diarrhea, thus validating its medicinal use.
authors.affiliation: Natural Product Research Division, Department of Biological and Biomedical Sciences, The Aga Khan University Medical College, Karachi 74800, Pakistan.
authors.forename: Malik Hassan
authors.initials: MH
authors.lastname: Mehmood
authors.affiliation: Natural Product Research Division, Department of Biological and Biomedical Sciences, The Aga Khan University Medical College, Karachi 74800, Pakistan; Department of Pediatrics, Winthrop University Hospital, 120 Mineola Boulevard, NewYork.
authors.forename: Nfn
authors.initials: N
authors.lastname: Anila
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Sabira
authors.initials: S
authors.lastname: Begum
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Saqib A
authors.initials: SA
authors.lastname: Syed
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Bina S
authors.initials: BS
authors.lastname: Siddiqui
authors.affiliation: Natural Product Research Division, Department of Biological and Biomedical Sciences, The Aga Khan University Medical College, Karachi 74800, Pakistan; Department of Pharmacy, College of Health Sciences, Mekelle University, P.O. Box 1871, Mekelle, Ethiopia. Electronic address: anwar.gilani@aku.edu.
authors.forename: Anwarul-Hassan
authors.initials: AH
authors.lastname: Gilani
mesh_terms: D000818:Animals; D029062:Apocynaceae; D003248:Constipation / Q000188:drug therapy* / Q000503:physiopathology; D003967:Diarrhea / Q000188:drug therapy* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D007583:Jejunum / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009924:Organ Culture Techniques; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D011817:Rabbits; D016896:Treatment Outcome
chemical_list: D010936:Plant Extracts
keywords: Antidiarrheal; Ca(++) antagonist; Carissa carandas; Cholinergic; Histaminergic; Laxative