piperidines and sufotidine

In a double blind study, 24 hour intragastric acidity and 24 hour plasma gastrin concentrations were measured simultaneously in seven duodenal ulcer subjects on the fifth day of receiving either sufotidine 600 mg bd or placebo. Compared with placebo, during treatment with sufotidine 600 mg bd the median integrated 24 hour intragastric acidity was decreased by 95% (range 74% to 99%) from 1000 to 51 mmol/h/l, whilst the median integrated 24 hour plasma gastrin concentration increased from 416 to 927 pmol/h/l.

Topics: Adult; Circadian Rhythm; Double-Blind Method; Duodenal Ulcer; Gastric Acid; Gastrins; Histamine H2 Antagonists; Humans; Male; Middle Aged; Piperidines; Triazoles

The suppression of intragastric acidity with H2-receptor antagonists may diminish with repeated administration. To assess the degree and dose-dependence of this tolerance after short-term dosing, two doses of the H2-receptor antagonists, ranitidine (300 mg nocte or q.d.s.) and sufotidine (300 mg or 600 mg b.d.), were given to healthy volunteers for 1 and 2 weeks, respectively. After 1 and 7 days of dosing with ranitidine 300 mg q.d.s. the median 24-h and night-time pH, measured by continuous 24-h pH-metry, dropped from 3.7 to 2.2 and 5.8 to 3.2, respectively (P less than 0.0001 for both). The decline in median pH with ranitidine 300 mg nocte was only significant during the night (from 4.1 to 2.9) (P less than 0.04). There was little change in plasma gastrin concentrations between days 1 and 7 with either dosage. With sufotidine 300 mg b.d. and 600 mg b.d. for 1 and 14 days, the median 24-h pH fell from 3.7 to 2.1 and from 4.6 to 2.6, respectively (P less than 0.0001). The equivalent medians for the night decreased from 6.3 to 2.3 and from 6.6 to 3.1 (P less than 0.0001). Gastrin concentrations did not change after 14 days of dosing with sufotidine 300 mg b.d., but increased significantly during dosing with sufotidine 600 mg b.d. (P less than 0.001). Significant tolerance developed in 7-14 days and it seemed to show some dose relationship. The mechanisms behind tolerance and the role of gastrin are discussed, but remain unclear.

Topics: Adolescent; Adult; Dose-Response Relationship, Drug; Double-Blind Method; Drug Tolerance; Electrodes; Gastric Acid; Gastrins; Histamine H2 Antagonists; Humans; Hydrogen-Ion Concentration; Male; Middle Aged; Piperidines; Ranitidine; Triazoles

Simultaneous 24-h intragastric and plasma gastrin concentrations were measured in 36 healthy subjects, when receiving placebo (day 0) and on days 1 and 8 of dosing with either placebo (n = 8), or high-dose H2-blockade with either ranitidine 300 mg q.d.s. (n = 8), ranitidine 1200 mg o.m. (n = 8), or sufotidine 600 mg b.d. (n = 12). Triplicate placebo studies demonstrated good reproducibility for this technique, with no significant differences of acidity or plasma gastrin concentration between the studies. There was a decrease in the anti-secretory activity of all three high-dose H2-antagonist regimens on day 8, when compared with that observed on day 1. This occurred in the presence of sustained or increasing hypergastrinaemia. It is concluded that a degree of tolerance develops during continued H2-blockade, and that this could be due to increasing gastrin drive to the parietal cells.

Topics: Adult; Drug Tolerance; Gastric Acid; Gastrins; Histamine H2 Antagonists; Humans; Hydrogen-Ion Concentration; Male; Piperidines; Placebos; Ranitidine; Triazoles

The acid inhibitory effect of sufotidine, a potent, long-lasting, competitive H2-receptor antagonist, was studied in 12 healthy males in a double-blind, randomized, three-way cross-over study of the effect of placebo, sufotidine 600 mg nocte and sufotidine 600 mg b.d. given over 15 days. On day 1 and 15 of dosing with each regimen, each subject's 24-h ambulatory intragastric acidity was measured by radiotelemetry and 24-h plasma gastrin profiles were derived from hourly venous blood samples. Acid suppression was calculated as the decrease in the area under the curve of hydrogen ion activity vs time from that observed on placebo, and 24-h plasma gastrin calculated as the area under the curve of plasma gastrin concentration vs time. Twenty-four hour intragastric acidity during the fifteenth day of dosing with sufotidine 600 mg nocte and sufotidine 600 mg b.d. did not differ significantly, but on the first and fifteenth day of dosing nocturnal acidity was decreased to a greater extent by sufotidine 600 mg nocte than sufotidine 600 mg b.d. (P less than 0.005). After 15 days, the acid suppression afforded by sufotidine 600 mg b.d. was significantly attenuated (P less than 0.0005); this was associated with a rise in 24-h plasma gastrin (P less than 0.001). Thus, tolerance to the acid inhibitory effect of H2-receptor antagonists exists and is of rapid onset. We suggest that tolerance is mediated by the temporally associated rise in 24-h plasma gastrin, but we cannot exclude the possibility that other mechanisms, such as up-regulation of H2-receptors, also play a part.

Topics: Adult; Double-Blind Method; Gastric Acid; Gastrins; Histamine H2 Antagonists; Humans; Hydrogen-Ion Concentration; Male; Piperidines; Triazoles

1. The inhibitory effect of sufotidine, a new histamine H2-receptor antagonist, on gastric secretion of acid and pepsin was studied in six healthy male volunteers. This was a three-way, cross-over, randomized, double-blind study. On each of 3 study days, the drug in a dose of 600 mg, or placebo, was administered either once or twice daily at 08.00 and 20.00 h. 2. The morning dose of sufotidine maintained intragastric pH above 3 until 18.00 h. Twice daily sufotidine maintained the pH above 3 throughout the 24 h. The median 24 h concentration of acid was significantly reduced from 86.9 mmol l-1 after placebo to 22.8 mmol l-1 and 4.9 mmol l-1 following the morning only or twice daily dose of sufotidine, respectively. Mean night-time output of acid was reduced by 81% after the morning dose of sufotidine and by 97% following treatment with sufotidine twice daily. 3. We conclude that sufotidine, in the doses studied, markedly inhibits gastric secretion and may therefore prove useful in the treatment of peptic ulceration and oesophagitis.

Topics: Administration, Oral; Adult; Double-Blind Method; Esophagitis; Gastric Acid; Gastric Juice; Histamine H2 Antagonists; Humans; Hydrogen-Ion Concentration; Male; Pepsin A; Piperidines; Triazoles

IT-066 (3-amino-4-[4-[4-(1-piperidinomethyl)-2-pyridyloxy]-cis-2- butenylamino]-3-cyclobutene-1,2-dione hydrochloride), an H2-receptor antagonist, shows highly potent, time-dependent, and irreversible antagonism at H2-receptors. We identified the structurally important parts of IT-066 involved in its interaction with the H2-receptor, and explored its unique mode of action by investigating the H2-receptor blocking action of IT-066 and related compounds in guinea pig isolated atria. IT-066 is structurally divided into three different parts: a tertiary amine and hydrophobic group, a connecting carbon chain, and a polar group. Though the replacement of its pyridine ring with a benzene ring maintained the mode of the H2-receptor blocking action of IT-066, the oxidation of the piperidine ring completely attenuated this blocking action. By replacing the connecting carbon chain of IT-066, cis-2-butene, with butane, trans-2-butene, or 2-butyne, the irreversible antagonism disappeared and the potency was reduced. On the other hand, BMY25368, whose connecting carbon chain is trimethylene, showed irreversible antagonism comparable to that of IT-066. Hydrolysis of the polar group of IT-066 completely attenuated the H2-receptor blocking activity. Among the compounds tested, only the compound that had 3,4-diamino-3-cyclobutene-1,2-dione as a polar group showed time-dependent and insurmountable H2-receptor blocking action. These data suggest the importance of the following structural features of IT-066: the piperidine ring of IT-066 and -NH2 in its polar group are essential for the interaction with the H2-receptor; and the 3,4-diamino-3-cyclobutene-1,2-dione group and the connecting carbon chain of IT-066 are crucial for determining the irreversibility of H2-receptor blocking action, though the connecting carbon chain is replaceable with another chain with appropriate length and configuration.

Topics: Animals; Guinea Pigs; Heart Atria; Heart Rate; Histamine; Histamine H2 Antagonists; In Vitro Techniques; Male; Molecular Structure; Piperidines; Pyridines; Structure-Activity Relationship; Triazoles

Topics: Gastric Acid; Gastrins; Histamine H2 Antagonists; Humans; Piperidines; Triazoles

Gastric secretory responses to histamine were investigated in anaesthetized dogs following treatment with oral ranitidine at 5 mg/kg twice daily for 358 weeks, and in isolated gastric mucosae from mice receiving sufotidine 240-280 mg.kg/day for 15 months. In neither study were there any significant differences between the acid secretory dose-response curves to histamine in control and test animals. The antisecretory activity of oral sufotidine (1 mg/kg) against histamine-induced acid secretion in the Heidenhain pouch dog was unaltered by twice daily dosing with sufotidine for 14 days. These studies on the effects of H2-antagonists on histamine-stimulated acid secretion found no evidence for development of direct tolerance at the parietal H2-receptor level.

Topics: Animals; Dogs; Dose-Response Relationship, Drug; Gastric Acid; Gastric Mucosa; Histamine; Histamine H2 Antagonists; Male; Mice; Mice, Inbred C57BL; Piperidines; Triazoles