Antisecretory effects of two new histamine H2-receptor antagonists

N-(3-[3-(1-Piperidinylmethyl)phenoxy]propyl)acetoxyaceta mide hydrochloride (Hoe 760) and N-(3-[3-(1-piperidinylmethyl)phenoxy]propyl)glycolamine hydrochloride (Hoe 062) are highly specific H2-receptor antagonists. The compounds are equipotent after intragastrical or intravenous administration. The antagonists inhibited gastric acid secretion in the rat induced by all stimuli tested, carbachol, desglugastrin and histamine. In the Heidenhain pouch dog whose gastric acid secretion was stimulated by food or histamine the two receptor blockers proved to be 4-6 times more potent inhibitors than cimetidine.     

Antisecretory and antiulcer effect of the H2-receptor antagonist famotidine in the rat: comparison with ranitidine.

1 The effects of the new H2-receptor antagonist famotidine, administered orally, on gastric secretion and emptying as well as on experimentally-induced gastric and duodenal ulcers were studied in the rat. Ranitidine was used as a reference compound. 2 Both compounds inhibited acid secretion in a dose-dependent manner. Calculated ED50 values were 0.80 and 6.84 mg kg-1 for famotidine and ranitidine, respectively. However, the duration of the antisecretory action was the same for both drugs. 3 The effect of the two drugs, administered at equiactive antisecretory doses, on gastric emptying was different. Ranitidine significantly accelerated the emptying rate whereas famotidine had no effect. 4 Famotidine reduced, in a dose-dependent manner, ulcer incidence in stomachs of dimaprit-treated rats and in duodena of cysteamine-treated animals with a potency respectively 2 and 7 times higher than that of ranitidine. 5 Famotidine is therefore an effective antisecretory and untiulcer compound. Its potency, but not its efficacy, is higher than that of ranitidine. Moreover, the duration of the antisecretory action is virtually the same for both drugs.     

JB-9322, a new selective histamine H2-receptor antagonist with potent gastric mucosal protective properties.

1. The opioid activity of the amphibian peptide, [Lys7]dermorphin, was studied in rats and mice. When administered intracerebroventricularly (i.c.v.), intravenously (i.v.) or subcutaneously (s.c.) it produced a long lasting analgesia. Its antinociceptive potency exceeded that of morphine 290 times by i.c.v. injection, and 25-30 times by peripheral administration. 2. The dose-response curves of [Lys7]dermorphin antinociception were shifted to the right by the pretreatment with naloxone (0.1 mg kg-1, s.c.) or with the mu 1-selective antagonist, naloxonazine (10 mg kg-1, i.v. 24 h before peptide injection). 3. The peptide also displayed potent antinociceptive effects in a chronic inflammatory pain model (rat Freund's adjuvant arthritis). In this pain model, systemic administration of the peptide raised the nociceptive threshold more in inflamed than in healthy paw. 4. High central and peripheral doses of [Lys7]dermorphin in rats produced catalepsy. The cataleptic response was antagonized by naloxone but left unchanged by naloxonazine pretreatment. 5. In rats and mice, central or peripheral administration of [Lys7]dermorphin induced a significantly slower development of tolerance to the antinociceptive effect than did morphine. 6. Upon naloxone precipitation of the withdrawal syndrome, [Lys7]dermorphin-dependent mice made fewer jumps and lost less weight than the morphine-dependent animals. Withdrawal hyperalgesia did not develop in [Lys7]dermorphin-dependent mice. 7. In conclusion, [Lys7]dermorphin seems to be a unique opioid peptide having a high penetration into the blood-brain barrier despite its low lipid solubility. This peptide causes fewer side-effects than other opioids and appears less likely than morphine to cause physical dependence in rats and mice.     

Cholinergic-like effects of the new histamine H2-receptor antagonist ranitidine

The new H2-receptor blocker ranitidine, together with the effect on histamine H2-receptors, possesses a series of cholinergic-like actions: it provokes atropine-sensitive contractions of several isolated smooth muscle preparations from different animal species and it potentiates the stimulant effect of acetylcholine. Moreover it contracts human lower esophageal sphincter in vivo, an effect which is completely prevented by small doses of atropine. Finally, ranitidine potentiates the stimulant effect of bethanechol and of carbachol on salivary glands of the rat while leaving unaffected the secretagogue effect of physalaemin which is known to be completely independent of the cholinergic system. In the in vivo experiments the doses of ranitidine capable of eliciting cholinergic-like effects were of the same order of magnitude as those necessary to cause the H2-receptor blockade.     

Interaction of the new histamine H2-receptor antagonist pibutidine hydrochloride with canine cloned H2-receptor expressed cells

The effect of a new histamine H2-receptor antagonist, pibutidine hydrochloride ((Z)-3-amino-4-{4-{4-[(piperidinomethyl)pyrid-2-yl]oxy} but-2-enylamino}cyclobut-3-ene-1,2-dione monohydrochloride, CAS 126463-66-9, IT-066 displaced the binding of [3H]tiotidine to cells transfected with the wild-type H2-receptor in a concentration-dependent manner. Compared with the 50% inhibitory concentration values (IC50) among five H2-receptor antagonists tested, the value of IT-066 was lowest. The inhibitory effect of IT-066 was enhanced by preincubation of IT-066 with the cells, and preincubation for 60 min increased potency about 2-fold. Famotidine also has such effects. When H2-receptor transfected cells were treated with IT-066 for 30 min, the inhibitory effect of IT-066 on the [3H]tiotidine binding still remained even after the cells were extensively washed. Scatchard plot analysis supported the non-competitive and irreversible action of IT-066. When the canine mutated H2-receptor-expressed cells were used, which have substituted amino acid of 190Alanine (Ala; position: 190th amino acid) for 190Threonine (Thr) in the fifth transmembrane domain, IT-066 also inhibited [3H]tiotidine binding to the cells concentration-dependently. However, in the case of the 190Ala mutated cells, the inhibitory effect of IT-066 attenuated with a decrease in maximal response after washing of the cells. These results show that IT-066 could tightly bind H2-receptor in a time-dependent manner and suggest the possibility that the irreversible inhibition of IT-066 is important in the interaction with 190Thr in the fifth transmembrane domain of H2-receptor.     

Pharmacology of JB-9315, a new selective histamine H2-receptor antagonist

• 1.1. The histamine H₂-receptor antagonistic activity and antisecretory and antiulcer effects of JB-9315 were studied in comparison with the standard H₂ blocker ranitidine.
• 2.2. In vitro, JB-9315 is a competitive antagonist of histamine H₂ receptors in the isolated, spontaneously beating guinea-pig right atrium, with a pA₂ value of 7.30 relative to a value of 7.36 for ranitidine. JB-9315 was specific for the histamine H₂ receptor because, at high concentration, it did not affect histamine- or acetylcholine-induced contractions in guinea-pig isolated ileum or rat isolated duodenum, respectively.
• 3.3. JB-9315 dose dependently inhibited histamine-, pentagastrin- or carbachol-stimulated acid secretion and basal secretion in the perfused stomach preparation of the anesthetized rat. In the pylorusligated rat after intraperitoneal administration, total acid output over 4 h was inhibited by JB-9315 with an ID₅₀ of 32.8 mg/kg, confirming its H₂-receptor antagonist properties.
• 4.4. JB-9315 showed antiulcer activity against cold stress plus indomethacin-induced lesions with an ID₅₀ of 6.8 mg/kg.
• 5.5. JB-9315, 50 and 100 mg/kg, inhibited macroscopic gastric hemorrhagic lesions induced by ethanol. In contrast, ranitidine (50 mg/kg) failed to reduce these lesions.
• 6.6. These results indicate that JB-9315 is a new antiulcer drug that exerts a cytoprotective effect in addition to its gastric antisecretory activity.

     

Ranitidine: a new H2-receptor antagonist

The pharmacology, pharmacokinetics, clinical efficacy, adverse reactions, drug interactions, and dosage of ranitidine are reviewed; specific comparisons are made of this new H2-receptor antagonist with the older agent, cimetidine. Ranitidine is a potent inhibitor of gastric acid secretion whose chemical structure lacks the imidazole group previously believed to be essential for H2-receptor blocking activity. The new agent does not bind substantially to the cytochrome P-450 mixed-function oxidase system and does not penetrate the cerebrospinal fluid appreciably. Peak serum ranitidine concentrations occur within one to two hours after oral administration; approximately 50% of an oral dose reaches systemic circulation. There are at least three metabolites of ranitidine, but substantial fractions of both i.v. and oral doses are recovered unchanged in the urine. Ranitidine's duration of action is 8-12 hours. Controlled clinical trials have shown ranitidine to be effective in the treatment of duodenal and gastric ulcers, Zollinger-Ellison syndrome, and prophylaxis against aspiration during anesthesia. Ranitidine has been effective in patients unresponsive to or intolerant of cimetidine. In clinical trials, the incidence of adverse effects from ranitidine has been low; certain rare but serious side effects that have been noted with cimetidine have not been associated with ranitidine therapy. There is no evidence thus far that certain drug-drug interactions observed with cimetidine therapy will occur with ranitidine. Oral adult daily doses of ranitidine are likely to be 300 mg given as the hydrochloride salt in two divided doses. Ranitidine is similar to cimetidine in efficacy but has an apparently safer adverse-effects profile. Ranitidine is likely to be the preferred agent in certain clinical situations.     

Antisecretory effect of imidazole and its derivatives in an isolated gastric mucosa preparation and an anesthetized young chicken preparation; comparison with a histamine H2-receptor antagonist.

We invesigated the influences of imidazole on the basal and the secretagogue-stimulated gastric acid secretion in isolated bullfrog gastric mucosa preparations and in anesthetized young chickens. Imidazoles (1 x 10(-4) g/ml) readily depressed the basal acid secretion in gastric mucosa in vitro. The inhibitory effect of imidazole was diminished considerably after washing out of the drug. The maximum acid secretion elicited by tetragastrin or bethanechol was completely antagonized by imidazole (1 x 10(-4) g/ml). The stimulatory action of histamine or dibutyryl cyclic AMP was also remarkably depressed in the presence of imidazole (3 x 10(-4) g/ml). after dibenamine pretreatment (5 x 10(-5) g/ml) for 60 min, the isolated gastric mucosa preparation became refractory to tetragastrin, bethanechol and histamine, but responded to dibutyryl cyclic AMP. Imidazole protected the histamine sensitivity against dibenamine blockade in the concentration of 5 x 10(-4) g/ml. In anesthetized young chickens, imidazole (200 mg/kg, s.c.) depressed tetragastrin- and histamine-stimulated gastric acid secretion. The effects of the imidazole derivatives and several antagonists (metiamide, atropine, diphenhydramine, acetazolamide and 2,4-dinitrophenol) on acid production were compared with that of imidazole. From these results, it is concluded that imidazole has a potent antisecretory effect on the basal and the secretagogue-stimulated acid secretion.     

The metabolism in animals and man of oxmetidine--a new histamine H2-receptor antagonist

The absorption, distribution, metabolism and excretion of [14C]oxmetidine in rat, dog and man has been studied following both i.v. and oral administration. Excretion is rapid and essentially complete in all three species. The biliary route is predominant. Distribution of radioactivity is widespread although none is seen in the brain. Metabolite patterns in urine from rat, dog and man have been compared by thin-layer chromatography. Metabolite patterns in urine and bile from rat and dog have been compared by high pressure liquid chromatography. Six major metabolites have been isolated and identified including two O-glucuronides and one N-glucuronide.     

Pharmacokinetics of a new histamine H2-receptor antagonist,Z-300, in rat and dog

1. The plasma level of Z-300 reached a maximum (C_max) at 30?min after the oral administration of Z-300 to dog, and disappeared from the systemic circulation with a halflife of 8-9 h. The bioavailability of Z-300 was 52% after the oral administration of Z-300, 3?mg/kg. At doses ranging from 3 to 30?mg/kg, C_max and AUC (area under the plasma concentration-time curve) were proportional to the dose. 2. The plasma level of Z-300 reached C_max at 10?min after the oral administration of Z-300 to rat, and disappeared from the systemic circulation with a half-life of 0.8-1.6 h. The bioavailability of Z-300 was 39% after the oral administration of Z-300, 10?mg/kg, and there was a non-linear relationship between the plasma level-time profile of Z-300 and the administered dose (3-50?mg/kg). 3. The binding of Z-300 to plasma protein was 92% in man, 65% in dog and 25% in rat. It is suggested that these species differences were due to the content of α₁-acid glycoprotein (α₁-AG), because Z-300 bound more strongly to α₁-AG than to albumin.     

Cardiovascular studies with impromidine (SK&F 92676), a new very potent and specific histamine H2-receptor agonist

Impromidine (SK & F 92676) has recently been identified as a potent and specific histamine H₂-receptor agonist. The present paper describes some cardiovascular studies with the drug. Impromidine lowers blood pressure in cats and rats by interaction with H₂-receptors. During continuous intravenous infusions of impromidine, the fall in blood pressure is due to a reduction in total peripheral resistance; cardiac output increases during hypotension. The responses to impromidine are similar to responses to histamine in mepyramine-treated cats. Impromidine administered intra-arterially also causes vasodilatation in the femoral and mesenteric vasculature by interaction with H₂-receptors. Impromidine stimulates all measured parameters including coronary flow in the isolated working heart of the guinea-pig. Dose-response curves to impromidine were displaced to the right in the presence of cimetidine.     

L-643.441: an H2-receptor antagonist with potent and long-lasting effects in man.

Submaximal dose pentagastrin tests conducted in normal male volunteers with L-643.441, a novel histamine H2-receptor antagonist, indicate that it is a potent and long-acting inhibitor of gastric acid secretion. The effect appears dose-dependent and single doses of 50 mg are sufficient to reduce secretory potential by at least 50% when examined 24 h after drug administration. No adverse effects attributable to treatment were observed.     

SK&F 93574, a histamine H2-receptor antagonist, releases histamine in the dog

This study was designed to establish whether SK&F 93574 releases histamine in dogs. Three female beagle dogs each received single infusions (on separate days) of each of SK&F 93574 (2.5 mg kg-1), polyvinylpyrrolidone (PVP, 20 mg kg-1) and sterile saline. The treatments were given at 14 day intervals by rapid intravenous infusion at 0.5 mL kg-1 min-1 for 2 minutes. Dogs showed clinical signs of histamine release such as vasodilation, licking lips, head drooping and increased gut movement after treatment with the known histamine releaser PVP or the test compound SK&F 93574. These signs were of similar severity and duration for the two compounds. No such changes were observed when the dogs received vehicle alone. Treatment with PVP or SK&F 93574 also resulted in markedly elevated plasma histamine concentrations (greater than 10-fold increase over control). It is concluded that intravenous administration of SK&F 93574 to dogs is associated with histamine release.     

Zolantidine (SK&F 95282) is a potent selective brain-penetrating histamine H2-receptor antagonist.

1. The novel benzthiazole derivative zolantidine (SK&F 95282) is a potent antagonist of histamine at H2-receptors in guinea-pig atrium and rat uterus. Only apparent pA2 values of 7.46 and 7.26 respectively could be calculated since the slopes of the Schild plots were significantly less than unity. 2. Zolantidine is equally potent as an antagonist at histamine H2-receptors in guinea-pig brain. The compound inhibited histamine stimulated adenylate cyclase (pKi 7.3) and dimaprit stimulated adenosine 3':5'-cyclic monophosphate (cyclic AMP) accumulation (approx pA2 7.63), and competed with [3H]-tiotidine binding (pKi 7.17). 3. Zolantidine is at least 30 fold more potent at H2-receptors than at other peripheral and central receptors investigated. 4. Infusion of zolantidine into rats produces a brain concentration greater than the plateau blood concentration (brain/blood ratio 1.45). 5. Zolantidine is thus characterized as a potent selective brain-penetrating H2-receptor antagonist, and will be a valuable pharmacological tool for investigating possible physiological and pathological roles for histamine in the central nervous system.     

Pharmacokinetics of a new histamine H2-receptor antagonist, Z-300, in rat and dog.

1. The plasma level of Z-300 reached a maximum (Cmax) at 30 min after the oral administration of Z-300 to dog, and disappeared from the systemic circulation with a half-life of 8-9 h. The bioavailability of Z-300 was 52% after the oral administration of Z-300, 3 mg/kg. At doses ranging from 3 to 30 mg/kg, Cmax and AUC (area under the plasma concentration-time curve) were proportional to the dose. 2. The plasma level of Z-300 reached Cmax at 10 min after the oral administration of Z-300 to rat, and disappeared from the systemic circulation with a half-life of 0.8-1.6 h. The bioavailability of Z-300 was 39% after the oral administration of Z-300, 10 mg/kg, and there was a non-linear relationship between the plasma level-time profile of Z-300 and the administered dose (3-50 mg/kg). 3. The binding of Z-300 to plasma protein was 92% in man, 65% in dog and 25% in rat. It is suggested that these species differences were due to the content of alpha1-acid glycoprotein (alpha1-AG), because Z-300 bound more strongly to alpha1-AG than to albumin.