Comparitive activities and mechanisms of action of three novel antiulcer agents
Antiulcer agents, notably inhibitors of gastric acid secretion, have been the most successful category of drugs to be discovered in recent years; and moreover, there are currently four such agents in the world list of top 25 best selling drugs. Histamine H2 antagonists have been the number one selling pharmaceutical product for more than a decade and inhibitors of the parietal cell HIC-ATPase, so called "proton pump inhibitors" (PPI), look set to continue this success. The proposed study was designed to establish the relative efficacy and mechanisms of action of three novel agents using both in vitro and in vivo models. The three compounds namely AG-1749 (Lansoprazole), PD-136450 and transforming growth factor alpha (TGF(x) were studied to evaluate their antisecretory and antiulccr activities. Lansoprazole, the second PPI to be developed for clinical use, is a non-competitive inhibitor of the H1C-ATPase and has recently been launched in a number of countries. PD-136450 is a competitive antagonist of central and peripheral cholecystokinin-B (CCK-B) receptors (gastrin receptor) and it under clinical development as an anxiolytic but which has actions on the stomach and pancreas. Anxiolytic drug is otherwise known as anti-anxiety drugs, which are used to treat anxiety disorders, like depression, panic disorders, phobias and many personality disorders. TOFu is a polypeptide growth factor, which acts at the EGF receptor and displays potent mitogenic and antisecretory activity. The initial study deals with the comparison of the three compounds with omeprazole and ranitidine in terms of their ability to inhibit acid secretion and their activity in a range of experimental ulcer models. Potency, duration of action and activity against a range of stimulants of acid secretion (histamine, pentagastrin and basal) was determined in anaesthetized rat models by establishing dose-response relationships. The compounds represent a spectrum of activities in as much as lansoprazole is a potent, long acting inhibitor, PD-136450 is an orally active but selective inhibitor, while TOFu has a very short duration and is only active after parenteral administration. In a view to find out the mechanism of action of these drugs on gastric acid secretion, isolated gastric glands from rabbits were employed as an in vitro technique using radiolabeled 14C-aminopyrine as a marker. The results show that lansoprazole was the most potent antisecretory agent compared to other two drugs. The second phase of the study deals with the activity of the three compounds against gastric ulcers induced by acid hypersecretion, indomethacin and stress. This study enabled us to assess the extent to which antisecretory activity per se compared with other actions such as wound healing (TGFa) or anxiolytic activity (PD-136450) contribute to ulcer healing. As other workers already established that prostaglandins and nitric oxide are involved in the cytoprotective activity, the present study investigated the influence of prostaglandin and nitric oxide by using indomethacin and L-NAME pretreatment on the cytoprotective activity of lansoprazole, PD-136450 and TGFcz. Moreover, the three drugs were tested for their activities on the mucus and bicarbonate production in the stomach. It was found that lansoprazole and TGFc increased the gastric mucus secretion while PD-136450 did not show any change. Moreover it was evidenced from this study that the protective activity of PD-136450 is associated with the influence of bicarbonate secretion from the pancreas. In conclusion, the results of this study have indicated that lansoprazole, PD- 136450 and TGFct are potent antisecretory and antiulcer agents which have great therapeutic importance.
C990 - Biological sciences not elsewhere classified
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