BY 1023/SK&F 96022 INN pantoprazole, a novel gastric proton pump inhibitor, potently inhibits acid secretion but lacks relevant cytochrome P450 interactions.

The novel H+/K(+)-adenosine triphosphatase inhibitor (gastric proton pump inhibitor), BY 1023/SK&F 96022, was found to be more potent than omeprazole in some rat models and slightly less potent in a dog model. Overall, both compounds are of a similar potency and efficacy. BY 1023/SK&F 96022 exhibited a somewhat longer duration of the antisecretory action than omeprazole in the Ghosh-Schild rat. In the modified Shay rat, on the basis of equieffective doses in terms of the initial effect, both compounds had a comparable duration of action. However, the p.o./i.v. dose ratio upon acute administration was larger for omeprazole, possibly reflecting its lower stability in the acidic environment of the secreting stomach, compared to BY 1023/SK&F 96022. As in vivo, both compounds were equipotent to inhibit acid production in rabbit isolated fundic glands. However, omeprazole interacted with the 7-ethoxycoumarin dealkylase in vitro with high affinity (Ki = 38.5 mumol/l), in contrast to BY 1023/SK&F 96022 (Ki = 135 mumol/l). Compared to omeprazole, BY 1023/SK&F 96022 also showed less interaction with the cytochrome P450 enzyme hydroxylating ionazolac. Moreover, this difference between the two compounds was also found in the rat in vivo with respect to their interaction with diazepam. Thus, both compounds displayed a comparable antisecretory potency in vivo and in vitro but showed a different interference with cytochrome P450 in favor of less interaction by BY 1023/SK&F 96022.

Direct comparison between the ulcer-healing effects of two H(+)-K(+)-ATPase inhibitors, one M1-selective antimuscarinic and one H2 receptor antagonist in the rat.

A direct comparison of the ulcer-healing effects of two H(+)-K(+)-ATPase inhibitors (pantoprazole and omeprazole), one M1 antimuscarinic (telenzepine) and one H2 receptor antagonist (cimetidine) was performed in the rat. Gastric and duodenal ulcers were induced by local application of acetic acid and thereafter treated over 10 days by the test drugs. Overall and on a molar basis, ulcer healing was comparably accelerated by pantoprazole, omeprazole and telenzepine and less so by cimetidine. The same rank order was found with respect to the inhibition of gastric acid secretion in the modified Shay rat.

An acid-independent antiulcer effect of M1 antimuscarinics in the rat.

In the rat, the antiulcer potencies of the M1 antimuscarinics telenzepine and pirenzepine, the H2 receptor blocker cimetidine, and the H+/K+-ATPase inhibitor omeprazole were compared with their antisecretory potencies. On a molar basis and with regard to inhibition of cysteamine-induced acid secretion, telenzepine ranked first, followed by omeprazole, cimetidine, and pirenzepine; cysteamine-induced duodenal ulcers were best inhibited by telenzepine, with pirenzepine, omeprazole and cimetidine ranking 2nd, 3rd and 4th. Up to the highest dose tested, cimetidine and omeprazole caused inhibition by 26 and 37%, respectively. While, with the antimuscarinics, lesion inhibition runs parallel with inhibition of acid secretion, the H2 receptor blocker and the H+/K+-ATPase inhibitor markedly impair acid secretion, but do not or merely negligibly inhibit cysteamine-induced formation of duodenal ulcers. This suggests that in this animal model the antiulcer effect cannot be attributed exclusively to the antisecretory action.

Pharmacological evidence for selective inhibition of gastric acid secretion by telenzepine, a new antimuscarinic drug.

The new antisecretory drug, telenzepine (4,9-dihydro-3-methyl-4-[(4-methyl-1-piperazinyl)acetyl]-10H-thieno-[3,4 - b][1,5]benzodiazepin-10-one), was investigated for its inhibition of functionally intact muscarinic receptors involved in gastric acid secretion in rabbit fundic glands, perfused mouse stomach in vitro, perfused rat stomach in situ, gastric fistula in rats and dogs with a Heidenhain pouch. The effects on these receptors were contrasted with effects on receptors located on smooth muscle and heart, i.e. isolated rat urinary bladder, stomach and atrium. The results were compared to those values obtained with nonselective antimuscarinic drugs (N-methylscopolamine, atropine) and the selective M-1 antagonist pirenzepine. Telenzepine was found to be 4-10 times more potent than pirenzepine with respect to depressing both gastric acid secretion and smooth muscle or myocardial responses. Based on -log EC50 and pA2 values, both drugs exhibited a similar selectivity profile differing from the pattern of effects observed with atropine or a second reference compound, zolenzepine. As compared with atropine, telenzepine exhibited a 5 fold higher relative affinity to muscarinic receptors involved in gastric acid secretion. It was concluded that telenzepine is selective to discriminate between muscarinic receptors mediating gastric acid secretion and affecting muscle contractility and that this finding supports the concept of muscarinic receptor heterogeneity.

[Studies on the effect of urapidil on the central nervous system and various organ functions in animal experiments (author's transl)]. / Tierexperimentelle Untersuchungen über Wirkungen von Urapidil auf das Zentralnervensystem und verschiedene Organfunktionen.

Compared to the changes in spontaneous behaviour of mice and rats, 6-(3-[4-(o-methoxyphenyl)-1-piperazinyl]-propyl-amino)-1,3-dimethyluracil (urapidil, Ebrantil) in doses from 10 mg/kg p.o. has a central sedative action, for which it is typical that it can be interrupted by external stimuli after doses of up to approx. 100 mg/kg. By this action urapidil differs from other central-acting drugs, e.g. chlor-promazine, diazepam and clonidine. It can be assumed that urapidil has no central dopamine blocking qualities because it does neither influence the conditioned avoidance response nor the amphetamine-induced gnawing of the rat. Urapidil is also different from diazepam bacause it does not hinder spinal polysynaptic motor reflexes of the decerebrated cat. Up to 80 mg/kg p.o. of urapidil, there was no hypotensive effect in the rat to be seen and, therefore, it can be concluded that changes in spontaneous and reactive behaviour are not due to acute changes in cardiovascular functions. The antihistamine effect of urapidil in the isolated ileum of the guinea pig is approx. 15 times weaker than that of chlorpromazine, furthermore urapidil has no anticholinergic quality.