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Dept. a/Pharmacology, Faculty a/Medicine & Health Sciences, Sana 'a University. *Dept. 0/ Pharmacology, Faculty a/Pharmacy, Khartoum University ,Sudan. Summary: "" Al-Adhal, A. A. Yemen The aim of this study is to investigate the effect of Medical (Catha Journal, edu/is on some Vol. 4, NO.1, October 2001 39~49 biochemical parameters on short and long-term basis. YMJ Fresh Khat in Sub-Acute a dose of 20 grams/kilogram, wasof given to three groups of rabbits toxicity studies Catha edulis (Khat) AL-ADHAL, A. and A., aMOHAMMED, O.Y.' (nine each), for one, two, and three weeks, fourth group was left as a control, "SAEED, N.S.*, GANEM, N.S and in another trial fresh Khat was given in three doses 20, 30 and 40 gram/kilogram to three groups of rabbits (six each), for six months, and a fourth group was left as a control. The results were as follows: fasting blood sugar (FBS), triglyceride (TG), GOT, and GPT were increased in both trials. The CBC which was measured only in the second trial showed that Khat lowered hemoglobin, WBCs, and lymphocytes while it increased neutrophils. The Khat treated groups showed lowered body weights in the second (six months) tria1. The heart weight relative to the body weight was increased in the first trial, while this result was not seen in the second trial. . INTRODUCTION middle and lower sections are also Khat is a natural stimulant from the used. Other names by which Khat is Catha EduIi.l' For.l'k plant, family; known include: Qat, Kat, Chat, Kut-es Celastraceae, found in the flowering Salihin, Mirra, Tohai, Tschat, Catha, I evergreen tree or large shrub which Qaut, Abssynian Tea, African Tea, and grows in East Africa and Southern African Salad. Kutes-Salihin (Arabic) Arabia (1). It grows wild at altitudes of means a diet to help pious people to ] 500-2000 meters above sea level (2). stay awake at night for praying. That I j i It reaches height from 10 feet to 20 feet made some western authors to name and its - scrawny leaves resemble Khat (incorrectly) as an addictive drug withered basil. Fresh Khat leaves are of Islam (3). Khat leaves contain r I crimson-brown and glossy but become psychoactIve ingredients known as I Jyellow-green Corresponding Author. as they age. They also cathinone, which is structurally and AI-Adhal A.A. Faculty of Medicine & Health Sciences Sana'a emit University a strong smel1. The most favored chemically similar to d-amphetamine; part of the leaves are the young and cathine, milder form Yemen Medicalshoots Journal, Vol. 4, No. I,a October 200] of S~.thil)one. near the top of the plant. However, leaves and stems at the t Fresh leaves contain both ingredients; those left unrefrigerated beyond 48 hours would contain only cathine, which explains user's preference for fresh leaves (4).There appear to be a number of different varieties of the plant differing in khatamine content between 0.1 % (Yemen, Madagascar) and 0.5% (Kenya). On a dry basis the leaves contain about 1.0% of (+)norpseudoephedrine (cathine), and for many years this was thought to be the principle responsible for the stimulant effect of the drug. In 1975 another phenylpropane, (- )-a aminopropiophenone (cathinone), was isolated at UN laboratories and is considered to be the principal CNS stimulant of the fresh plant (5). The Sisomer is more active than the other enamiomer (6). (-)-cathinone has phannacological properties analogous to those of (+)amphetamine, possessing a similar potency and the same mechanism of action. Many other components (alkaloids. sesquiterpenes, triterpenes, flavonoids, numerous acids as esters), including an essential oil containing about 40 components, have been characterized (7). Khat is also very rich in Ascorbic acid which is an excellent antidote to amphetaminetype compounds (8). Among the isolated alkaloids are the cathadulins, with molecular weights range from 600 to 1200 (9). Protocol for the first trial 1- Rabbits were grouped into 4 groups: group 1 (control), 2, 3, and 4. 2- Nine rabbits were allocated for each gn;>up, and their weights were recorded. 3- Fresh Khat of the Saoti type was given in a dose of 20 gram/kilogram of animal weight Yemen Medical Jouma], Vol. 4, No. I, October J 39 200] '--r~' for one, two and three weeks to groups 2, 3 and 4 respectively. The control group was kept without Khat. 4- This dose was given at 8 am, and before handing food)o make sure that Khat was consurrfed. 5- Green fodder was.: given as a standard food during the trial. 6- All groups were kept in the same environment, under the same conditions and were fed the same food. 7- At the end of the study the animals were weighed and killed and their blood samples were examined. 8- The hearts, livers, and kidneys were separated and weighed. 9- Blood sugar, cholesterol, GOT, GPT, alkaline phosphatase, urea and creatinine were also measured. Protocol for the second trial 1- Rabbits were grouped into 4 groups; group I; control 2, 3, and 4, 2- Six rabbits were allocated for each/' group, and their weights were recorded. 3- Fresh Khat of the Saoti type was given in doses of 20, 30 and 40 gram/kilogram of animal weight for six months to groups 2, 3 and 4 respectively. The control group was kept without Khat. 4- This dose was given at 8 am, and before handing food to make sure that Khat was consumed. 5- Green fodder was given as a standard food during the trial. 6- All groups were kept in the same environment, under the same conditions and were fed the same food. 7- At the end of the study the animals were weighed and killed and their blood samples were examined. ~. Ai-Adhal, A. A. Sub-Acute toxicity studies of Catha edu/is Figure (3) Mean values ofHb in rabbits in the control group, and after 20, 30 and 40mg/kg Khat respectively Figure (5) Mean values of fasting blood sugar (FBS) in rabbits in the control group, and after 20, 30 and 40mg/kg Khat for 6 m~nths respectively .,. I 'I L~-Iobi"1 A. . ~I " Group 1 ICFBS I Group 2 Group 3 Group 4 ,1 . ., if L P value < 0.05 Figure (4) Mean values ofWBCs in rabbits in the control group, and after 20, 30 and 40mg/kg Khat for 6 months Group 1 Group 2 Group 3 Group 4 P value < 0.05 Figure (6) Mean values of triglyceride (TG) in rabbits in the control group, and after 20, 30 and 40mg/kg Khat for 6 months. 8000 7000 6000 5000 4000 lawsc I 3000 2000 ICTG 1000 I 0 Group 1 . Group 2 Group 3 Group 4 P value = 0.056 .", Group 1 Group 2 Group 3 Group 4 P value < 0.05 Yemen Medical Joumal, Vol. 4, No. I, October 2001 43 Yemen Medical Journal, Vol. 4, No.1, October 2001 -. AI-Adhal, A. A. Sub-Acute toxicity studies of Catha edu/is Figure (7) Mean values of sGOT & sGPT in rabbits in the control group, and after 20, 30 and 40mg/kg Khat for 6 months Figure (9) increase in body wt in rabbits in the control group, and after 20, 30 and 40mg/kg Khat for 6 months respectively 60 50 D.OOT ..OPT Group 1 Group 2 Group 3 Group 4 Group 1 P value < 0.05 Figure (8) Mean values of alkaline phosphatase (Alk. P.) in rabbits in the control group, and after 20, 30 and 40mg/kg Khat for 6 months respectively. 195'm 190.pb 185 180 175t:Jf. 170 165 Group 2 P value < 0.05 Figure (10) The effect of20mg/kg/day Khat in 3 groups ofrabbits (9 each) on the heart weight relative to the body weight after 1,2 and 3 weeks, group 2,3 and 4 respectively, group 1 is control . 60 50 40 IDAIk. p.1 ID"'~"'"bod'_I'" I 20r.. 10 Group 2 Group 3 Group 4 0 Group 1 Group 2 Group 3 Group 4 P value < 0.05 '. " <. P value < 0.05 'L Sub-Acute toxicity studies of Catha edulis AI-Adhal, A. A. r ,. ri i I i I I I I ' i from the 'vascular bed to lymphoid tissue (20, 29). The explanation of the significant d<::crease in hemoglobin caused by Khat may be due to the inhibition of de novo RNA synthesis (3'0), where RNA is required for the synthesis of globin the component of hemoglobin. In both the 3 weeks- and the six months trials, results showed increase in the body weight in all groups the Khat treated and non- Khat treated animals. However, the increase in body weight showed a dose-dependent reduction with Khat in the second trial, the means increase in body weight after six months were 58.6 :f: 0.32%, 51.3 :r. 0.6%,48.8::1:0.37% and 40:f: 0.4]% in the control group, group 2, group 3 and group 4 respectively. The last three groups are given 20, 30, and 40 gram fresh Khat per kg body weight respectively. This may be due to the anorectic effect of Khat. The anorectic effect of cathinone starts at 16 mg/kg (3]), this is found in ] 6 grams of fresh Khat (Trease and Evans, 1996). The anorectic effect is thought to be mediated through opiate mechanism (32), which is not antagonized by pizotifen as seen in our study. Indeed, I recommend another study to be done using an opioid antagonist to investigate its effect on the anorectic effect of Khat. some authors that Khat chewing may be associated with hepatitis (23, 24, 25). The high contents of Tannins in Khat may be responsible for this detrimental effect on the liver (26). On the other hand" alkaline phosphatase, which reflects bone disease and obstructive jaundice (I 8) was not increased byKhat. . The decrease in triglycerides produced by Khat can be explained by its sympathomimetic acti~n which favors lipolysis and this action is mediated through stimulation of 83receptors (27). The stimulation of 83receptors, as other B3 receptors results in activation of adenyl cyclase, and increase conversion of A TP to c-AMP (20). The adrenocortical action of Khat also contributes to the dosedependent decrease in the blood triglyceride level seen in our study (28), Blood urea in the animal study was insignificantly increased this may be due to the decrease in the urinary flow rate seen in the clinical study. In the complete blood count (CBC), the most important results were significant decrease in WBCs and hemoglobin by ] 8% and] 1.5% respectively. The decrease in the WBCs lies in the lymphocytes, while neutrophils were significantly increased by 39.1 %. These result can be explained by knowing that Khat may have stimulating effects on the adrenocortical function in animals (28). Glucocorticoids increase the concentration of neutrophils, and decrease the concentration of lymphocytes, monocytes, eosinophils . and basophils. The increase in ~ neutrophils is due both to the increase influx into the blood from the bone marrow and decreased migration from the blood vessels. The. reduction in circulating lymphocytes and other cells is the result of their movements Many studies, in animals showed a dose-dependent decrease in body weight, with chronic administration of Khat, but these occurred in doses range from 50-200' ~ mg Khatamines/Kg (33, 34). The heart weight relative to the body'weight is significautly decreased 'by Khat in the first trial (the three-weeks trial), while this effect is not seen in the ; Yemen Medical Journal, Vol. 4, No. I, October 2001 47 six-month trial. The decrease in the heart weight relative to the body weight in the three-weeks trial may be explained by the ..increased contractility of the myocardium caused by the sympathetic effect of Khat mediated by B-receptors. Finany, the disappearance of this increase can be interpreted by the tolerance developed to the sympathetic effects of Khat (35). References 1. Ahmed, M.B. and E1-Qirbi. A.B., Biochemial effects of catha edulis, cathine and cathinone on adrenocortical functions,Journa]of Ethnopharmacology, ] 993 39: 3. 213-216. 2. AI-Ahdal, M.N., McGarrv. TJ., and -Honnan, MA., Cytotoxicity of Khat (Catha edulis) extract on culture mammalian cells: effects on macromolecule biosynthesis,. Mutat Res.,1988 204(2): 317322. 3. Ba-Jubair, M.A., 1998. The effect of Khat on the liver and Kidney functions, Obadi center for publications, First Edition. 4. Barnes, J. and Rossiter, R., Toxicity of tannic acid, Lancet,1943 21 :218. 5- Bergmeyer, H.U., New values for the molar extinction coefficient of NADH and NADPH for the use in routine laboratories, Zeitschriji fur Klinchie Chern. Klin Biochem., ]975 13: 507. 6. Crombie, L., The cathedulin alkaloids, Bulletin' on Narcotics, 198032(3): 37-50. 7. Elmi, .S.,The chewing of Khat in Somalia, J.Ethnopharmacology, ]9838(2): 163-176. 8. EImi, A.S., Khat and blood glucose levels in man,. J, Ethnopharmacology, 1983 8(3): 331-334. 9. Emile, F., Abbatte, E., Said, S., Niel, T., Habiba, H., and James, N,. Transaction of the Royal Society of Tropical Medicine and I-Hygiene, 1998 82: 750 752 10. Fawcett, J.K. and Scott, J .E., The use of urease in the detetmination of urea. Journal of Clinical Pathology, 1960 13: ]56. 11. Feichtmer, T.V. and Wrenn, H. T., The enzymati~ method for the assay of uric acid. American Journal of Clinical Pathology, 1955 25: 833. 12. Fox, E., Abbatte, E.A., Said, S., Constantine, N.T., Wassef, H.B., and Woody, IN., Viral hepatitis markers in Djibouti: an epidemiological survey, Transactions of the Royal Society of Tropical Medicine & Hygiene,1988 82(5): 750.752 13. Foltin, R.W. and Schuster, C. R., The effects of dl-cathinone in a gustatory avoidance paradigm,. Pharmacology Biochemistry Behavior,198] 14 (6):907-909, 14. Ganong, W. F,.]987 Review of Medical Physiology, 13th Edition. 15. Glennon, R.A., Young, R., Hauck, A.E., and McKenney, JD., Structure-activity studies on amphetamine analogs using drug discrimination methodology,. Pharmacology Biochemistry & Behavior, 1984 2] (6): 895-901. ] 6.Kalix, P., Khat: a plant with amphetamine effects,. l Substance Abuse Treatment, 1988 5(3): 163-169. ] 7.Katzung, B. G. ] 998. Basic & Clinical pharmacology, seventh edition. 18. Kind. P.R.N. and Kind E 1.. The two point colorimetric assay of Yemen Medical Journa], :Vol. 4, No. I, October 2001 48 r it " iI .,,-"'Yilt", ft. ft. alkaline phosphatase, . Journal of Clinical Pathology. 1954 7: 322. 19. Lewin, L., Narcotic and stimulating drugs, ] 93 ], Phantastica. 20. Luqman, W. and Danowski T.S., The use of Khat in Yemen, social and medical obseryations, . Annals of Internal medicif)e, ] 976 85(2): 246-9. . 21.MaIIoy, H.T. and Evelyn ,K.A., The diazo reaction method for the determination of bilirubin, Journal of Biological Chemistry. ] 937 ]19:48] 22.Michaelsson, M., Nosslin B.. and Sjolin. S.. The modified diazo reaction method for the determination of bilirubin. Pediatrics,] 965 35: 925. 23.Nencini, P., The role of opiate mechanisms in the development of tolerance to the anorectic effects of amphetamines,. Pharmacology, Biochemistry & Behavior, 1988 30(3): 755-764. 24.0wen, I.A., Iggo, B., Scandrett, F.J., and Stewart, c.P., The determination of creatinine in plasma or serum and urine, a critical examination.. Biochemical Joumal.1954 58: 426. 25.Receptor NomenClature Supplement, ] 994, Trends Pharmacological science. 26.Schorno, H.X., Khat, an addictive drug of Islam,. Pharmazie in Unserer Zeit,] 982 ] 1 (3) : 65-73. 27. Scott, D.A., Burans, J.P., AIOuzeib, H.D.. Arunkumar. B.K., AI-Fadeel, M., Nigad, YR.. A]Hadad, A., Alyazeed, R.R., Hyams, KC., and Woody, IN., A . seroepidemiological survey of viral hepatitis in the Yemen Arab Republic,. Transaction of the Royal Society of Tropical Medicine & Hygiene.1990 84(2): 288-291. 28.Szendrei, K., The chemistry of Khat,.' Bulletin on Narcotics, ] 980 32(3): 5-35. 29. Trease and Evanse, ] 996. Pharmacognosy, ] 4th Edition. 30.Trinder, P., Determination of the blood glucose using 4aminophenazone as oxygen acceptor,. Annals of Clinical Biochemistry, ] 969 6: 24. 31.Wootton, J.D. and Freeman. H., ] 982. Microanalysis in Medical Biochemistry, 6th Edition. " -. ,. Yemen Medical Journal, Vol. 4, No, I, October 2001 49