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Comparison of Antiulcer Effects of Tricyclic Antidepressants with Cimetidine and Omeprazole in Rats

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Comparison of Antiulcer Effects of Tricyclic Antidepressants with Cimetidine and Omeprazole in Rats Volume 11 Medical Journal of the Number 2 Islamic Republic ofIran Summer 1376 August 1997 COMPARISON OF ANTIULCER EFFECTS OF TRICYCLIC ANTIDEPRESSANTS WITH CIMETIDINE AND OMEPRAZOLE IN RATS HAMID REZAJAMSIDDI, Ph.D., AND TAGID GHAFGHAZI, Ph.D. From the Department of Pharmacology, Isfahan Universityof Medical Sciences, Isfahan, Islamic Republic of Iran. ABSTRACT The antiulcer effects of different tricyclic antidepressants (trimipramine, doxepin, imipramine, and amitriptyline) in comparison with those of cimetidine, pirenzepine and omeprazole were investigated in male rats with acute gastric ulcer. Acute gastriculcer was induced by oral administrationof O. 6N H Cl solution, 1 mL/rat. Pretreatmentof animals with doxepin, trimipramine,amitriptyline, imipramine (in doses of 10, 25, 40, 50, and 75 mg/kg, SC), cimetidine (in doses of 50,75, 100, 150 and 200 mg/kg, SC), omeprazole and pirenzepine (in doses of 10, 20, 30,40 and 50 mg/kg, SC) inhibited the formation of erosions dose-dependently. The ED 50 of these agents revealed that the most active agents were omeprazole, doxepin and pirenzepine, followed by trimipramine and cimetidine. Imipramine and amitriptyline had slight antiulcer activity. MJIRI, Vol. I I, No.2, 123-125, 1997. Downloaded from mjiri.iums.ac.ir at 9:24 IRST on Thursday November 12th 2020 INTRODUCTION MATERIALS AND METHODS Tricyclic antidepressantsare widely used for the treatment Male Wistar rats,weighing 220±25g were used. They of major depression. Recently these agents have been used were kept in a 12 hr light/dark cycle. The animals were in treating peptic ulcer.! placed in wire-bottomed cages and were starved for 24 h According to the findings of Mangla et al.4 doxepin before the experiments. The following drugs were given to accelerated the healing of duodenal ulcers in man. The acute different groups of rats (5 animals per group): doxepin development of duodenal ulcer in rats has been inhibited by hydrochloride, trimipramine maleate, amitriptyline doxepin.2 hydrochloride (Sigma, USA) with doses of 10,25, 40, 50 There are several reports about the clinical effects of and 75 mg/kg(SC); cimetidine hydrochloride (Sigma,USA) tricyclican tidepressants on duodenal ulcer. Therefore,this with doses of 50, 75, 100, 150 and 200 mg/kg (SC); investigation has focused on the experimental effects of pirenzepine (Thomae, Germany) and omeprazole (MSD, these agents on gastric lesions in rats. Germany) with doses of 10,20, 30, 40 and 50 mg/kg (SC). The other purposeof the present study is to demonstrate All of these drugs were injected 60 minutes before the the antiulcer effectof graded doses of tricyclicantidepressants administration of the ulcerogenic agent. The controls were in comparison with those of cimetidine,pirenzepine and given similar volumes of saline subcutaneously. omeprazole. Gastriclesions were induced by 0.6 N hydrochloricacid 123 Antiulcer Effects of TeAs (Merck, Gennany) given orally in a volume of ImL/rat; 1h 100 later,all of the ratswere killed,their stomachs were removed, ! cut open along the greater curvature, rinsed with saline 80 solution and pinned flat onto a plastic board. After removal x a> of hemorrhagic matter, the erosions could be seen. The "0 E a> 60 gastric mucosa of each animal was examined, and the > largest diameter of each ulcer was measured; ulcers E a> > measuring less than 1 mm were not scored. The value in 40 a..� centimeters of these detenninations was considered as an *- ulcer index for each stomach.3 20 The results were shown in tenns of a "preventive index" which is expressed as follows: 0 10 100 " ill (ulcer index)roo rol-ill ... PI (preventIve lOdeX) xl 00 (%) Log Dose (mg/Kg) illroorol Fig. 1. The effects of different doses of amitriptyline (-----) and trirnipramine (-) on gastric lesions induced by H(:1. Values are For detennination of the EDso values, however, the mean (±S.E.M.) of animals per group. percentage change from control values was calculated and' 5 the effective doseso (the dose that reduced the ulcer to 50% of control value) was estimatedgraphically after plotting the data. The data were anal yzed statistically by Student's t -test. RESULTS Pretreatment of animals with doxepin, trimipramine, amitriptyline and imipramine in doses of 10, 25, 40,50 and 75 mg/kg (SC) dose-dependentlyinhibited the fonnation of erosions by 0.6N HCI solution in therat. Figs. 1 and 2 show the percent of inhibition of doxepin, trimipramine, imipramine and amitriptylineon gastriclesions. TheEDso of doxepin and trimipraminewas 15.9 mg/kgand 32.5 mg/kg, respectively. The strongest effect was shown by doxepin, followed by trimipramine, imipramine and amitriptyline. Fig. 2. The effects of different doses of imipramine (-----) and Fig. 3 shows that cimetidine, in doses of 50,75, 100,150 doxepin (-) on gastric lesions induced by HeI. Values are mean (±S.E.M.) of 5 animals per group. Downloaded from mjiri.iums.ac.ir at 9:24 IRST on Thursday November 12th 2020 and 200 mg/kg (SC), produced a dose-dependentreduction in gastric lesions. Maximum reductionwas producedby 200 mg/kg of the drug with a preventive index of 79.4%. The Cimetidine: y= 115.4x - 187.7 EDso of cimetidine was 114.7 mg/kg. Omeprazole: y= lUx + 44.9 Fig. 4 shows that omeprazole and pirenzepine, in doses Pirenzepine: y= 83x - 69.3 of 10,20, 30,40 and 50 mg/kg(SC), inhibited the fonnation of erosions in adose-dependent manner. Maximumreduction was achieved by the 50 mg/kg dose of omeprazole and DISCUSSION pirenzepine with preventive indices of 65% and 81.7%, respectively. The EDso was 2.9 mg/kg for omeprazole and There are several controversial reports concerning the 27.4 mg/kg for pirenzepine. antiulcer effect of tricyclic antidepressants. These drugs Plotting the preventive index against log doses of each have been shown to produce healing of duodenalulcers in drug gave the regression with the following equations: cases where cimetidinehad failed,4 and differences in healing rate between cimetidine and trimipramine were not Doxepin: y= 58.2x - 20 significant.5 On the other hand,it has been demonstrated Trimipramine: y= 84.2x - 77.7 that trimipramine was less effective than cimetidine and no Imipramine: y= 38.9x - 35.6 better than placebo.6 Amitriptyline: y= 69x - 78.7 In light of the aboveconflicting results aboutthe effects 124 H.R. Jamshidi, Ph.D., and T. Ghafugazi, Ph.D. centrally.13 Based on the aboveresults, bothantihista minergic 100 and anticholinergic effects of doxepin, peripherally and centrally, may contribute to its antiulcer action. 80 We demonstrated that doxepin had the strongest effect x CI> "U compared with the other tricyclicanti depressants. This is in c CI> 60 agreement with the results of other investigators who showed > E that doxepin had the most potent antihistaminic property in CI> > comparison with other available tricyclic compounds.4 It CI> 40 0: was also shown that doxepin was as effectiveas cimetidine '#. H pig bra 12 in inhibitionof histamine 2 receptors in guinea in. 20 The antidepressant and sedative effects of tricyclic antidepressants may also contribute to their ability to heal 0 ulcers. It was suggested that trimipramine may have a 10 100 1 beneficial effect on masked depression, a condition often Log Dose (mg/Kg) found in patientswith duodenal ulcers. 1 Additionalresearch Fig.3. The effect of different doses of cimetidine on gastriclesions is needed to establish the place of tricyclic agents in the induced by HCI. Values are mean (±S.E.M.) of 5 animals per overall treatment of peptic ulcer disease. group. REFERENCES 100 lit I 1. Guldahi M: The effect of trimipramine on masked depression in patients with duodenal ulcer. Scand J Gastroenterol 12 80 x (suppI. 43): 27-31, 1977. II> "U 2: Leitold M, Fleissig Antiulcer and secretion-inhibitory c W: II> 60 uJ1 properties of the tricyclic derivative doxepin in rats and dogs. > "" / Arzneim-Forsch 34(1): 468-73, 1984. C / II> / >I< > 3. Ferri S, Speroni E, Cavicchini E, Romualdi P, Govoni P, II> 40 '" / �I Marchini M: Protection by opioids against gastric lesions 0: / '#. / '* caused by necrotizing agents. Pharmacology36: 140-44, 1988. � / / 4. 20 , Mangla JC, Pereira M: Tricyclic antidepressants in the ;It treatment of peptic ulcer disease. Arch Intern Med142: 273- 75,1982. 0 5. Daneshmend TK, Homeida MMA, et al: Clinical trial value of 10 100 trimipramine versus placebo in duodenal ulcer healing. Gut Log Dose (mg/Kg) 22:1045- 1047,198 1. Becker Comparative study of cimetidine and trimipramine Fig. 4. The effects of different doses of orneprazole (-) and 6. U: pirenzepine (-----) on gastric lesions induced by HCI. Values are in treatment of duodenal ulcer . Scand J Gastroenterol19: 405, 1984. mean (±S.E.M.) of 5 animals per group. Downloaded from mjiri.iums.ac.ir at 9:24 IRST on Thursday November 12th 2020 7. Valnes K, Myren J, Quigstal T: Trimipramine in the treatment of gastric ulcer. Scand J Gastroenterol13: 497-500,1978 . of tricyclic antidepressants on peptic ulcers, we studied the 8. Anderson OK, Betrgasker J, Halvorsen L, Giercksky KE: antiulcer properties of the tricyclic compounds doxepin, Doxepin in the treatment of duodenal ulcer. Scand J trimipramine, imipramine and amitriptyline. The strongest Gastroenterol19: 923-25, 1984 . effectwas shown by doxepin and trimipramine,followed by 9. Mackay HP, Mitchell KG, Pickard WR,Hearns J, Crean GP: imipramine and amitriptyline. The effect of trimipramine on the gastric secretion of acid and 2 Our results confmned those of previous studies •7•lo pepsin in patients with duodenal ulceration. J Int Med Res12: indicating the antiulcer effect of tricyclic antidepressants. 303-6,1984. Thisstudy alsocompared the antiulcereffect of tricyclic 10. Becker U, Fawrschou PR, et al: Efficacy of trimipramine and antidepressants with pirenzepine, omeprazole and cimetidine in the treatment of duodenal ulcer.
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