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Title of the Topic: INTERACTION OF CARROT (DAUCUS CAROTA) WITH PANTOPRAZOLE AND RANITIDINE FOR ANTIULCER ACTIVITY IN ANIMALS A) BRIEF RESUME OF THE INT ENDED WORK: Need of study: Peptic ulcer diseases (PUD) are the disorder of the gastrointestinal system and millions of people suffer from this disease globally. The main causes of peptic ulcers are hyperacidity, excessive intake of alcohol, overeating, high intake of spicy foods, food poisoning, high intake of coffee, smoking, NSAIDs, stress, presence of helicobacter pylori or secondary due to pathological conditions such as Zollinger-Ellison syndrome1. Several gastric antisecretory and cytoprotective drugs are available in the market for the treatment of PUD and none of them are free from side effects. It is well established that diet rich in vegetables and fruits can reduce disturbances in gastrointestinal system. Moreover, large number of populations today uses herbal therapies and home remedies along with conventional medications. However, concurrent use of these remedies with modern medications may cause either potentially dangerous side effects or enhanced therapeutic efficacy2. Currently, there is very little information available on possible interaction between herb and drug whilst the use of combined management is progressively escalating across the world. Hence it is widely accepted that in-depth and appropriate studies should be carried out to confirm the possible role of combined herb- drug treatments. The carrot (Daucus carota) belongs to the family Apiaceae. The edible part of a carrot is a taproot. The carrot gets its characteristic and bright orange colour from β-carotene, which is metabolised into vitamin A in humans when bile salts are present in the intestines. Carrots are credited with many medicinal properties; they are said to cleanse the intestines and to be diuretic. They nourish the entire system and help in the maintenance of acid-alkaline balance in the body3. The carrot also has a reputation as a vegetable that helps to maintain good eyesight. The carrot and its constituent, β-carotene, has a particularly beneficial effect on the liver4. Further, carrot is known to provide relief from diarrhea, constipation, intestinal inflammation, weakness, illness and in treating rickets. Their protective actions are attributed to active constituents mainly A-retinol, beta carotene, A-carotenoid, thiamin, riboflavin, niacin, pantothenic acid, folate, vitamins A, B6, B12, C, E, K. Eventhough, carrot is employed in traditional Indian system of medicine for variety of ailments in gastrointestinal system, so far there is no scientific report available confirming its ethnopharmacological claim. We also felt necessary to determine the biological role of carrot in presence of conventional antiulcer drugs such as proton pump inhibitor and H2 antagonist as most patients uses traditional healer ‘carrot’ with these drugs. Thus the present study will be undertaken to substantiate the traditional belief by evaluating the carrot and to determine its interaction with pantoprazole (PZL) and ranitidine (RTN) for antiulcer activity using different experimental models. Review of Literature: The carrot (Daucus carota subsp. Sativus) is a root vegetable, usually orange or purple, red, white, and yellow in colour, with a crisp texture when fresh. The edible part of a carrot is a taproot. It is a domesticated form of the wild carrot Daucus carota, native to Europe and southwestern Asia. It has been bred for its greatly enlarged and more palatable, less woody-textured edible taproot, but is still the same species3. It is a biennial plant which grows a rosette of leaves in the spring and summer, while building up the stout taproot, which stores large amounts of sugars for the plant to flower in the second year. The flowering stem grows to about 1 metre (3 ft) tall, with an umbel of white flowers that produce a fruit called a mericarp by botanists, which is a type of schizocarp 5. Carrots can be eaten in a variety of ways. The simplest way is raw as carrots are perfectly digestible without requiring cooking. Alternatively they may be chopped and boiled, fried or steamed, and cooked in soups and stews, as well as baby and pet foods. A well-known dish is carrots julienne. Grated carrots are used in carrot cakes, as well as carrot puddings, an old English dish thought to have originated in the early 1800s. The greens are edible as a leaf vegetable, but are rarely eaten by humans, as they are mildly toxic6. Together with onion and celery, carrots are one of the primary vegetables used in a mirepoix to make various broths. Ethnomedically, the roots are used to treat digestive problems, intestinal parasites, and tonsillitis or constipation. Massive overconsumption of carrots can cause hypercarotenemia, a condition in which the skin turns orange (although hypercarotenemia is not itself dangerous unlike overdose of vitamin A, which can cause liver damage). Carrots are also rich in dietary fibre, antioxidants, and minerals. B) MATERIALS AND METHODS: Source of Data: Data will be obtained from laboratory based studies by using albino rats of either sex weighing between 150-200 gms, maintained at room temperature, having free access to food (std pellet diet), tap water ad libitum. These studies will be carried out using different experimental models such as pylorus ligation, NSAIDs, ethanol and stress induced gastric ulcer, cysteamine inducesd duodenal ulcer as well acetic acid induced chronic gastric ulcer. Method of Collection of Data: The data collected will be based on animal experimentation using rats as per the parameters studied under each animal model, which are mentioned under the objectives of the study. Methods: The rats will be grouped as follows Group I: Control Group II: Low dose of carrot extract (LCE) Group III: High dose of carrot extract (HCE) Group IV : Ranitidine (50 mg/kg p.o)7 (RTN) Group V : Pantoprazole (20 mg/kg p.o) (PZL) 8 Group VI: Low dose of carrot extract (LCE) plus RTN Group VII: High dose of carrot extract (HCE) plus RTN Group VIII: Low dose of carrot extract (LCE) plus PZL Group IX: High dose of carrot extract (HCE) plus PZL The doses of carrot extract will be selected based on acute toxicity study carried out as per OPPTS limit test procedure9. Preparation of extract and preliminary phytochemical investigation: The extract will be prepared by suitable method. Qualitative tests for chemical constituents present in the extract will be carried out. Antiulcer evaluations will be done by following models in experimental animals: 1. Acetic acid induced chronic gastric ulcers The method described by Asad et al7 will be followed. Briefly, the rats will be anaesthetized using ether followed by laporatomy, glacial acetic acid 0.05 ml will be added onto the serosal surface of the stomach through a cylindrical mould of 6.0 mm diameter. The acid solution will be removed after 1 min and the mould will be rinsed with normal saline to avoid damage to surrounding tissues. The abdomen will be closed and the animals will be treated with the drug for 10 days. On the 11th day, the animals will be sacrificed and ulcer index and ulcer score will be determined. The tissues will also be subjected to histopathological studies 2. Pylorus ligated rats The Shay rat10 model with modification described by Kulkarni11 will be followed. The pyloric end of the stomach will be ligated under light ether anaesthesia. Drug will be administered by intraduodenal route. After 6 hr, animals will be sacrificed. The contents of the stomach will be used for free acidity and total acidity estimations. The ulcer index and gastric mucus content will be determined12. 3. Healing of indomethacin induced gastric ulcers, a model to study free radical scavenging activity12 The gastric ulcers will be induced by administering indomethacin (5mg/kg. p.o.) for 5 days to the normally fed rats. The animals were then treated with the drug for 5 days after induction of ulcer while the control group will receive only vehicle. The last dose of indomethacin will be considered as 0th day. Rats will be sacrificed on the 0th day and 5th day. The stomach will be removed; ulcer score and ulcer index will be determined. The glandular portion of the stomach will be used for estimation of mucin content13, total proteins14, antioxidant factors like super oxide dismutase activity15, total tissue sulfhydryl groups16 and catalase activity17. 4. Ethanol induced gastric ulcers18 Albino rats will be fasted for 36 hr before administration of 90 % ethanol (1 ml/200gm). The drug will be administered 1 hr before ethanol administration. One hour after ethanol administration, the animals will be sacrificed, stomach will be isolated and ulcer index will be determined. 5. Stress induced gastric ulcers19 The rats will be placed in a restraint cage and the cage will be placed at a temperature of 2° C for 3 hr. The drug will be administered 30 min prior to subjection of stress. The animals will be sacrificed, stomach will be isolated and ulcer index was determined. 6. Cysteamine induced duodenal ulcers20 Duodenal ulcers will be induced by administering cysteamine hydrochloride (400 mg/kg p.o) twice at an interval of 4 hr. Drug will be administered 30 min prior to each dose of cysteamine hydrochloride. After 24 hr of the first dose of cysteamine, animals will be sacrificed and the duodenum will be excised carefully and cut open along the antimesentric side. The duodenal ulcer area, ulcer score and ulcer index will be determined. C) List of References: 1. Crawford JW. The gastrointestinal tract. In: Robbins pathologic Basis of Disease. Cotran RS, Kumar V, Collins T (Eds), 6th Edn, Saunders, Noida India, 2000, pp 793-796. 2. Fugh-Berman A. Herb-drug interaction. The Lancet. 2000; 355:134-138. 3. http://en.wikipedia.org/wiki/Carrot.Retrieved on 29/05/09 at 9.50 am. 4. Joram Wardi, Ram Reifen, Hussein Aeed, Liliana Zadel, Yona Avni and Rafael Bruck. Beta-Carotene Attenuates Experimentally Induced Liver Cirrhosis in Rats. IMAJ 2001; 3:151-154. 5. http://www.northernontarioflora.ca/fruits_term_types.cfm 6. http://www.ohsu.edu/poison/documents/mildlyToxicPlants.pdf 7. Asad M, Shewade DG, Koumaravelou K, Abraham BK, Vasu S, Ramaswamy S. Gastric anti-secretary and ant-ulcer activity of oxytocin in rats and guinea pigs. Life Sci 2001; 70:17-24. 8. Shah PJ, Gandhi MS, Shah MB, Goswami SS, Santani D. Study of Mimusops elengi bark in experimental gastric ulcers. : J Ethnopharmacol. 2003 ;89(2-3):30511 9. Health Effect Test Guidelines. Acute Oral Toxicity (Computer programme OPPTS 870.1100 United State Office of Prevention. Pesticides and Toxic Substances Environmental Protection Agency (7101). Available from URL: http://www.epa.gov/oppts/home/guideline.htm. 10. Shay H, Komarov SA, Fele SS, Meranze D, Gruenstein H, Siplet H. A simple method for uniform production of gastric ulceration in rat. Gastroenterology 1945; 5: 43-61. 11. Kulkarni SK. Handbook of experimental pharmacology. 3rd ed. Vallabh Prakashan, New Delhi, India: 1999, pp148-50. 12. PrabhaT, Babu MD, Priyambada S, Agrawal VK, Goel RK. Evaluation of Pongamia pinnata root extract on gastric ulcers and mucosal offensive and defensive factors in rats. Indian J Exp.Biol 2003; 41(4):304 -310. 13. Majumdar B, Chaudhri SGR, Ray A, Bandyopadhyay SK. Effect of ethanol extract of piper betle linn leaf on healing of NSAID-induced experimental ulcer– A novel role of free radical scavenging action. Indian J Exp Biol 2003; 41(4):311315. 14. Lowry CH, Roseborough NI, Farr AL, Randall RJ. Protein measurement with folin phenol reagent J Biol Chem 1951; 193:265-75. 15. Erich F, Elastner. Inhibition of nitrite formation from hydroxyl ammonium chloride. A simple assay for super oxide dismutase. Anal Chem 1976; 70:616-20. 16. Ellman GL. Tissue sulfhydryl groups. Arch Biochem Biophyi 1959;82:70-77. 17. Eva ML. Mechanism of pH dependent hydrogen per oxide cytotoxicity invitro. Arch Biochem Biophy 1988; 365(2):362-72. 18. Brzozowski T, Konturek P Ch, Konturek SJ, Kwiecien S, Pajdo R, Brzozowski I, Hahn EG. Involvement of endogenous cholecystokinin and somatostatin in gastroprotection induced by intra duodenal fat. J Clin Gastroenterol 1998; 27:125137. 19. Parmar NS, Jagruthi KD, A review of the current methodology for the evaluation of gastric and duodenal anti ulcer agents. Indian J Pharmacol 1993; 25:120-135. 20. Szabo S. Animal model for human disease: Duodenal ulcer disease. Am J Pathol 1978; 73:273- 276.