Gastric antisecretory 9H-xanthen-9-amines.

A series of 9H-xanthen-9-amines possessing a wide variety of nitrogen substituents at C-9 was prepared for evaluation of gastric antisecretory activity. These substituents included the acetamidine, imidate, pyrimidine, thiazoline, quinuclidine, 2-hydrazinopyridine, aminopiperidine, aminoalkylimidazole, and aminoalkylpyridine moieties. The majority of compounds in this series inhibited gastric acid secretion when tested orally in the pylorus-ligated rat. Potency was increased by intraduodenal administration and diminished by incubation with gastric juice, suggesting partial degradation of the compounds in the gastric environment. A representative example, 3-(9H-xanthen-9-ylamino)-1-ethylpiperidine, exhibited similar activity in dogs, although no free compound could be detected in the blood. It is therefore hypothesized that this compound is either rapidly bound to tissue and/or metabolized to an active species.

Regulation of the synthesis and release of slow-reacting substance of anaphylaxis from sensitized monkey lung.

Immunological challenge of sensitized fragmented cynomolgus monkey lung with anti-human IgE (immunoglobulin E) induced the appearance of slow reacting substance of anaphylaxis (SRS-A) in the tissue and evoked the release of SRS-A into the Tyrode's supernatant. The elevation of tissue or residual SRS-A levels was maximal 2 min after anti-IgE challenge and remained at that plateau for at least 60 min. The released SRS-A, first detectable 3 to 5 min after challenge, achieved a plateau by 10 min. Both the released and residual SRS-A were similarly inactivated by soybean lipoxidase and were antagonized by FPL 55712 on the guinea-pig ileum. Isoproterenol, 5, 8, 11, 14-eicosatraynoic acid and SK & F 64398 all inhibited the anti-IgE induced elevation in residual SRS-A and blocked SRS-A release. Indomethacin stimulated both the elevation of residual SRS-A and the amount released. Removal of the Tyrode's supernatant containing 209 +/- 73 U of released SRS-A/g of tissue 20 min after anti-IgE resulted in the release of an additional 239 +/- 69 U/g; residual SRS-A levels remained at the plateau level. Incubation of the Tyrode's supernatant from challenged, but not control, tissue with fresh lung tissue caused a 90 +/- 7% inhibition of SRS-A release from the fresh tissue. Leukotriene D4 at 5 to 50 ng/ml (concentrations relevant to SRS-A release) showed a concentration-dependent inhibition of SRS-A release, but no effect on histamine release. Leukotriene C4 at 5 to 50 ng/mg failed to significantly alter the amount of SRS-A release. However, at 150 ng/ml, significant inhibition was observed which, in part, may have been produced by metabolism to leukotriene D4. These results demonstrate a potential role for LTD in regulating the amount of SRS-A released from monkey lung.

Immunologic histamine release in vitro from the heart and lung of the cynomolgus monkey.

Immunologic histamine release was evoked from the sensitized fragmented cardiac and pulmonary tissue of the cynomolgus monkey by a reverse anaphylactic reaction. Ventricular and pulmonary tissue released a similar fraction (approximately 6%) of the total tissue histamine when challenged with antihuman IgE, presumably reflecting the 'active' sensitization of the monkey in vivo. Passive sensitization of these tissues in vitro resulted in significantly greater immunologic histamine release in 6 of the 14 ventricles and d a similar fraction (approximately 6%) of the total tissue histamine when challenged with antihuman IgE, presumably reflecting the 'active' sensitization of the monkey in vivo. Passive sensitization of these tissues in vitro resulted in significantly greater immunologic histamine release in 6 of the 14 ventricles and d a similar fraction (approximately 6%) of the total tissue histamine when challenged with antihuman IgE, presumably reflecting the 'active' sensitization of the monkey in vivo. Passive sensitization of these tissues in vitro resulted in significantly greater immunologic histamine release in 6 of the 14 ventricles and in the lungs. The antiallergic compounds, disodium cromoglycate and SK&F 64398, inhibited immunologic histamine release from passively sensitized monkey ventricular tissue. These results demonstrate that ventricular histamine may be immunologically released and that this release process can be pharmacologically inhibited in a manner similar to that of pulmonary tissue.