Movement of gastric acid secretion and influence of proton pump inhibitors on histamine H2 receptor antagonist resistant ulcer]

Treatment of peptic ulcers has become easier with the advent of H2 blockers. However, H2 resistant ulcer still remain. These cases were screened by 24 hr-intragastric pH monitoring, which well reflects the status of gastric acid secretion. On the one hand, there were cases in which no nocturnal elevation in gastric pH was seen even after administration of H2 blocker (H2 blocker resistant ulcer). On the other hand, there were cases which were resistant to treatment with H2 blocker, although the gastric pH elevated. It is considered that omeprazole is effective for the former cases.     

Proton pump inhibitor H2 receptor antagonist

Recently, Japanese guidelines for the treatment and prevention of peptic ulcers were established by the Japanese Society of Gastroenterology. Herein, we focus on proton pump inhibitor(PPI) and H2 receptor antagonist (H2RA) for prophylaxis and treatment of peptic ulcer associated with NSAIDs including low dose of aspirin. Double dose of H2RAs are effective at preventing chronic NSAID related ulcers, however, the effect is not superior to PPI. Full-dose misoprostol and PPI are clinically equivalent, although the potential adverse effects of misoprostol are a major cause of poor compliance. Overall, PPIs have the best profile of efficacy and side-effects for the healing and prevention of NSAID-associated ulcers, especially in the patients with high risk, such as history of peptic ulcer.     

Combination H1 and H2 receptor antagonist therapy in diabetic autonomic neuropathy

Autonomic neuropathy occurs frequently in diabetic patients but is seldom effectively treated. In our patient, a 34-year-old man with poorly controlled type 1 diabetes and autonomic neuropathy manifested by postural hypotension and diarrhea, treatment with diphenhydramine and cimetidine (H1 and H2 histamine antagonists, respectively) markedly improved the hypotension and diarrhea and led to better blood glucose control.     

A potent and selective histamine H4 receptor antagonist with anti-inflammatory properties

Histamine mediates its physiological function through binding to four known histamine receptors. Here, we describe the first selective antagonist of the histamine H4 receptor, the newest member of the histamine receptor family, and provide evidence that such antagonists have anti-inflammatory activity in vivo. 1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine (JNJ 7777120) has a K(i) of 4.5 nM versus the human receptor and a pA(2) of 8.1. It is equipotent against the human, mouse, and rat receptors. It exhibits at least 1000-fold selectivity over H1, H2, or H3 receptors and has no cross-reactivity against 50 other targets. This compound has an oral bioavailability of approximately 30% in rats and 100% in dogs, with a half-life of approximately 3 h in both species. JNJ 7777120 blocks histamine-induced chemotaxis and calcium influx in mouse bone marrow-derived mast cells. In addition, it can block the histamine-induced migration of tracheal mast cells from the connective tissue toward the epithelium in mice. JNJ 7777120 significantly blocks neutrophil infiltration in a mouse zymosan-induced peritonitis model. This model is reported to be mast cell-dependent, which suggests that the compound effect may be mediated by mast cells. These results indicate that the histamine H4 receptor plays a role in the inflammatory process. Selective H4 receptor antagonists like JNJ 7777120 may have the potential to be useful in treating inflammation in humans.     

Treatment and prevention of histamine-2 receptor antagonist for elderly gastric ulcer

H. pylori infection and non-steroidal anti-inflammatory drugs(NSAIDs) are considered the two major causes of gastric mucosal lesions. Chronic administration of NSAIDs is associated with an increased incidence of significant adverse events such as upper gastrointestinal hemorrhage or perforation. The inhibition of prostaglandin synthesis, the decrease of gastric mucosal blood flow and the involvement of gastric acid are believed to be the mechanisms of NSAIDs-associated gastric mucosal lesions. In future, the significance of NSAIDs-associated gastric mucosal lesions may increase in Japan. Many studies have reported that proton pump inhibitor, high dosages of histamine-2 receptor antagonist (H2RA), and prostaglandin analogs provide excellent prevention and therapeutic actions for NSAIDs-associated gastric ulcer. Additionally, recent studies have shown that regular dosages of H2RA provide excellent prevention and therapeutic actions for NSAIDs-associated gastric mucosal lesions in Japan.     

Pharmacological control of the human gastric histamine H2 receptor by famotidine:comparison with H1, H2 and H3 receptor agonists and antagonists

Abstract. Histamine 0–1 µM-0.1 mM increased adenylate cyclase activity five- to ten-fold in human fundic membranes, with a potency Ka = 3 µM. The histamine dose-response curve was mimicked by the H₃ receptor agonist (R) α-MeHA, but at 100 times lower potency, Ka = 0.3 mM. Histamine-induced adenylate cyclase activation was abolished by H₂, H₁ and H₃ receptor antagonists, according to the following order of potency IC₅₀:famotidine (0.3 µM) > triprolidine (0.1 mM) thioperamide (2 mM), respectively. Famotidine has no action on membrane components activating the adenylate cyclase system, including the Gs subunit of the enzyme stimulated by forskolin and cell surface receptors sensitive to isoproterenol (β₂-type), PGE₂ and VIP. The Schild plot was linear for famotidine (P < 0.01), with a regression coefficient r= 0.678. The slope of the regression line was 0.64 and differs from unity. Accordingly, famotidine showed a slow onset of inhibition and dissociation from the H₂ receptor in human cancerous HGT-1 cells. The results demonstrate that famotidine is a potent and selective H₂ receptor antagonist with uncompetitive actions in human gastric mucosa. Consequently, famotidine might be a suitable drug with long-lasting actions in the treatment of Zollinger-Ellison syndrome. The results also confirm and extend the previous observations that (R) α-MeHA and thioperamide are two selective ligands at histamine H₃ receptor sites. In the human gastric mucosa, these drugs are respectively 330 and 6700 times less potent than histamine and famotidine on the adenylate cyclase system. The possible involvement of histamine H₃ receptors in the regulation of gastric secretion is proposed.     

Histamine-2 receptor antagonist

H. pylori infection and non-steroidal anti-inflammatory drugs (NSAIDs) are considered the two major causes of gastric mucosal lesions. Chronic administration of NSAIDs is associated with an increased incidence of significant adverse events such as upper gastrointestinal hemorrhage or perforation. The inhibition of prostaglandin synthesis, the decrease of gastric mucosal blood flow and the involvement of gastric acid are believed to be the mechanisms of NSAIDs-associated gastric mucosal lesions. In future, the significance of NSAIDs-associated gastric mucosal lesions may increase in Japan. Many studies have reported that proton pump inhibitor, high dosages of H2-RA, and prostaglandin analogs provide excellent prevention and therapeutic actions for NSAIDs-associated gastric ulcer. Additionally, recent studies have shown that regular dosages of H2-RA provide excellent prevention and therapeutic actions for NSAIDs-associated gastric mucosal lesions in Japan.     

应用H2—受体拮抗剂及胃动力药治疗胃性哮喘的护理

目的：研究胃性哮喘的护理。方法：观察胃性哮喘25例应用H2-受体拮抗及胃动力药后的反应并采取积极有效的护理措施。结果：25例哮喘症状均得到了明显的缓解与改善。结论：对哮喘患应严密察病情变化,在应用糖皮质激素及支气管扩张药无效时,应考虑为胃性哮喘并对症治疗。     

Inhibition of canine gastric acid secretion by an H-1 receptor antagonist to histamine.

Histamine H-2 receptors are thought to mediate gastric acid secretory responses, whereas H-1 receptors supposedly regulate mucosal vascular responses to histamine. In an in vivo chambered canine stomach flap preparation, the H-1 receptor antagonist, tripelennamine, injected intraarterially (22.1 mumol/kg) into the stomach flap reduced histamine-stimulated (1.25 micron/kg/min intravenously) acid secretion by approximately two thirds with a secondary reduction in gastric mucosal blood flow. This antisecretory action does not appear to be due to nonspecific mucosal damage. The H-2 receptor antagonist, metiamide, injected intraarterially (2.5 mumol/kg) also inhibited gastric acid secretion by about two thirds as did intravenously injected metiamide (4.5 mumol/kg), whereas intravenously administered tripelennamine (40.8 mumol/kg) was ineffective as an acid secretory inhibitor. Intraarterial tripelennamine reduced the secretory actions of the H-2 agonist, 4-methylhistamine (2.2 micron/kg/min intravenously), while intravenous metiamide depressed the gastric mucosal dilator responses to the H-1 agonist, 2-methylhistamine (5 micron/kg/min intravenously). Both histamine-receptor antagonists also reversed the systemic circulatory depressor effects of histamine and its analogs. These results suggest the need for reevaluation of inferences based upon the assumed specificity of H-2 and H-1 agonists and antagonists.     

Actions of nizatidine, a selective histamine H2-receptor antagonist, on gastric acid secretion in dogs, rats and frogs

Nizatidine (LY139037), a selective histamine H2-receptor antagonist, is a potent inhibitor of gastric acid secretion. It was 17.8 times as active as cimetidine on histamine (10(-5) M)-induced secretion from the isolated gastric mucosa of the bullfrog. Nizatidine was 8.9 times as active as cimetidine on basal acid secretion of the chronic gastric fistula rats after s.c. administration. Against acid secretion from the vagally innervated gastric fistula and Heidenhain pouch of dogs stimulated with submaximal doses of histamine, methacholine and gastrin, nizatidine was, respectively, 6.5, 5 and 4.7 times as active as cimetidine by i.v. administration. Nizatidine was very well absorbed from the gut and was 5 to 10 times as active as cimetidine on gastric acid secretion of dogs induced by submaximal and maximal doses of histamine when given p.o. Equal molar doses of nizatidine showed equal peak effects when given i.v., s.c. or i.m. Pharmacological data indicate that nizatidine is safe and effective as an agent for the control of excessive gastric acid secretion.     

The outcome of bleeding duodenal ulcer in the era of H2 receptor antagonist therapy

We studied 2119 patients presenting with duodenal ulcer as sole lesion, in the period 1976-1993, the era of H2 receptor antagonist (H2RA) therapy, prior to the introduction of Helicobacter pylori eradication. We used clinical assessment and serial check endoscopy to investigate the incidence of bleeding at presentation (group I, n = 286, 13.5%), the long-term outcome in this group and in that presenting with pain alone (group II, n = 1833, 87%) with respect to ulcer recurrence and bleeding, and the effect of H2RA maintenance therapy. Most patients were treated with H2RA, principally cimetidine. In group I, seven patients died early on; 38 had urgent surgery, of whom six died post- operatively. The remainder were treated; five immediately re-bled, of whom three were operated on. On follow-up, 98/227 group I patients relapsed, 21 (21%) of whom rebled. Relapse in group II was 1017/1668, with only 42 (4%) bleeding (p < 0.001). In patients without maintenance treatment, relapse was markedly higher (50/78 group I, 529/742 group II), but group II still bled significantly less (20% group I vs. 3% group II). Relapse on maintenance was: 48/149 with five (10%) rebleeding in group I, and 488/926 with five (1%) bleeding in group II (p < 0.001). Despite the introduction of H2RA therapy, patients presenting with haemorrhage still have a risk of bleeding at ulcer relapse about 7-fold higher than that for those presenting with pain alone.      

Effect of an antiandrogenic H2 receptor antagonist on hepatic regeneration in rats

Because biochemical "feminization" of the liver in males is observed with hepatic regeneration and because the hepatic regenerative response in females is greater than that in males, the possibility that antiandrogens might potentiate liver regeneration was investigated. Before 70% hepatectomy, adult male Wistar rats were treated with cimetidine, an antiandrogenic H2 antagonist, at doses up to 10 times greater than those used clinically. Control animals received either the saline vehicle or ranitidine, an H2 antagonist without antiandrogenic properties. Treatment with cimetidine reduced the hepatic cytosolic androgen receptor content compared with ranitidine treatment. Hepatectomy caused a further reduction in androgen receptor activity in all groups. Hepatic cytosolic estrogen receptor activity was comparable in all groups throughout the study. Moreover, the rate of liver growth and the levels of ornithine decarboxylase and thymidine kinase activity induced as part of the regenerative response were similar in all groups. Thus, cimetidine, despite its ability to bind to androgen receptors, and ranitidine, an H2 receptor antagonist without antiandrogen action, do not modulate the hepatic regenerative response to a 70% partial hepatectomy.     

Treatment of acute pancreatitis with protease inhibitor, H2 receptor antagonist and somatostatin analogue

Acute pancreatitis sometimes develops to severe condition with a variety of clinical manifestations and high mortality. Autodigestion of the pancreas, secondary to the activation of digestive enzymes, plays a major role in the pathogenetic mechanism of acute pancreatitis. To improve the mortality and complication rates, appropriate treatments based on the precise prediction of disease severity are required. To this end, the early administration of protease inhibitors has commonly been employed for the therapy of acute pancreatitis in Japan. However, a number of clinical trials have failed to show the clinical effects of protease inhibitors, H2 receptor antagonist and somatostatin analogue on the treatment of acute pancreatitis. To evidence the therapeutic value of these agents for acute pancreatitis, well-organized clinical studies will be required.     

Characterization of a sphingosine 1-phosphate receptor antagonist prodrug

Sphingosine 1-phosphate (S1P) is a phospholipid that binds to a set of G protein-coupled receptors (S1P(1)-S1P(5)) to initiate an array of signaling cascades that affect cell survival, differentiation, proliferation, and migration. On a larger physiological scale, the effects of S1P on immune cell trafficking, vascular barrier integrity, angiogenesis, and heart rate have also been observed. An impetus for the characterization of S1P-initiated signaling effects came with the discovery that FTY720 [fingolimod; 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol] modulates the immune system by acting as an agonist at S1P(1). In the course of structure-activity relationship studies to better understand the functional chemical space around FTY720, we discovered conformationally constrained FTY720 analogs that behave as S1P receptor type-selective antagonists. Here, we present a pharmacological profile of a lead S1P(1/3) antagonist prodrug, 1-(hydroxymethyl)-3-(3-octylphenyl)cyclobutane (VPC03090). VPC03090 is phosphorylated by sphingosine kinase 2 to form the competitive antagonist species 3-(3-octylphenyl)-1-(phosphonooxymethyl)cyclobutane (VPC03090-P) as observed in guanosine 5'-O-(3-[(35)S]thio)triphosphate binding assays, with effects on downstream S1P receptor signaling confirmed by Western blot and calcium mobilization assays. Oral dosing of VPC03090 results in an approximate 1:1 phosphorylated/alcohol species ratio with a half-life of 30 h in mice. Because aberrant S1P signaling has been implicated in carcinogenesis, we applied VPC03090 in an immunocompetent mouse mammary cancer model to assess its antineoplastic potential. Treatment with VPC03090 significantly inhibited the growth of 4T1 primary tumors in mice. This result calls to attention the value of S1P receptor antagonists as not only research tools but also potential therapeutic agents.     

Binding of a thromboxane A2/prostaglandin H2 receptor antagonist to washed human platelets

A binding site for the thromboxane A2/prostaglandin H2 (TXA2/PGH2) antagonist [125I]9,11-dimethylmethano-11, 12-methano-16-(3-iodo-4-hydroxyphenyl)-13,14-dihydro-13-aza-15 alpha beta-omega-tetranor-TXA2 to washed human platelets was studied. 9,11-Dimethylmethano-11, 12-methano-16-(3-iodo-4-hydroxyphenyl)-13,14-dihydro-13-aza-15 alpha beta-omega-tetranor-TXA2 competitively antagonized aggregation of washed human platelets induced by the TXA2/PGH2 mimetic U46619. A Schild analysis of the pharmacologic study revealed a pA2 of 8.08 and a slope of -1.12. The pA2 value yielded a Kd of 8 nM. The association rate constant (k1) for [125I]PTA-OH was 6.6 X 10(6)M-1 min-1 and the dissociation rate constant (k-1) was 1.82 X 10(-1), yielding a kinetically determined Kd (k-1/k1) of 27 nM. Scatchard analysis of [125I]PTA-OH binding to washed human platelets revealed one class of binding sites with a Kd of 21 +/- 5 nM and maximum binding of 42 +/- 6.4 fmol/10(7) platelets (N = 5) (2530 +/- 380 binding sites/platelet). Several TXA2/PGH2 receptor agonists and antagonists competed with [125I]PTA-OH for binding. For the four antagonists used in this study, the rank order of potency for displacing the ligand from its binding site correlated (r = 0.93) with the rank order of potency for their ability to inhibit U46619-induced aggregation in human platelet-rich plasma. The antiaggregatory prostaglandins prostaglandin F2 alpha, prostaglandin D2, and Iloprost also displaced the ligand, but only at concentrations considerably higher than that required to produce their pharmacologic effects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of cefpodoxime proxetil and interactions with an antacid and an H2 receptor antagonist.

Cefpodoxime proxetil is a new oral esterified cephem antibiotic with a broad antibacterial spectrum. The dissolution of cefpodoxime proxetil is pH dependent. The objectives of this study were to characterize the pharmacokinetics of cefpodoxime proxetil in two different oral doses and to examine possible interactions with an antacid, aluminum magnesium hydroxide (Maalox 70), and an H2 receptor antagonist, famotidine. Two studies involving the same 10 healthy volunteers were performed. In the first study, cefpodoxime proxetil was administered in two doses, 0.1 and 0.2 g. In the second study, two interventions were performed in a randomized crossover design. For one intervention, the volunteers were pretreated with 40 mg of famotidine 1 h before 0.2 g of cefpodoxime proxetil was administered. In the second trial, participants were given 10 ml of Maalox 70 2 h and 10 ml of Maalox 70 15 min before they received 0.2 g of cefpodoxime proxetil. Serum and urine concentrations were determined by high-performance liquid chromatography. For the statistical evaluation, these data were tested by using the pharmacokinetics of 0.2 g of cefpodoxime proxetil from the first study. The maximum concentrations were 1.19 +/- 0.32 mg/liter after 0.1 g of cefpodoxime proxetil and 2.54 +/- 0.64 mg/liter after 0.2 g of cefpodoxime proxetil. The elimination half-lives were 149 min for 0.1 g and 172 min for 0.2 g of cefpodoxime proxetil. The total increase in the area under the concentration-time curve (AUC) was dose dependent. Combination with Maalox 70 caused a reduction in the AUC from 14.0 +/- 3.9 to 8.44 +/- 1.85 mg.h/liter. After famotidine, the AUC decreased to 8.36 +/- 2.0 mg . h/liter. Corresponding changes were registered for the maximum concentration of drug in serum, 24-h urine recovery, and the time to maximum concentration of drug serum. Cefpodoxime proxetil was well tolerated without any seriously adverse drug reactions.     

Effect of histamine H1- and H2-receptor blockade on canine gastric acid secretion

In dogs with gastric fistulae and Heidenhain pouches, inhibition of histamine-stimulated gastric acid secretion by the histamine H2-receptor antagonist metiamide is not increased by the addition of a histamine H1-receptor antagonist (mepyramine maleate). Under the conditions of this study there is no evidence for the presence of histamine H1-receptor sites on the gastric parietal cell.     

Pentagalloylglucose, an antisecretory component of Paeoniae radix, inhibits gastric H+, K(+)-ATPase

We purified a compound with strong inhibitory effect on H+, K(+)-ATPase from Paeoniae radix, which has been used in Japan for the treatment of gastritis and peptic ulcers. The compound was identified as 1,2,3,4,6,-penta-o-galloyl-beta-D-glucose by proton nuclear magnetic resonance, carbon-13 nuclear magnetic resonance, and fast atomic bombardment mass spectrometry. The IC50 of the compound for H+, K(+)-ATPase was 166 nmol/l. Kinetic analyses indicated that the inhibition of the enzyme by pentagalloylglucose was noncompetitive with respect to K+. Pentagalloylglucose had relatively weak inhibitory effects for Mg(+)-ATPase (IC50: > 10 mumol/l) and Na+, K(+)-ATPase (IC50: 2.7 mumol/l). Pentagalloylglucose also inhibited the accumulation of [14C]aminopyrine in parietal cells that had been isolated from guinea pig stomach and stimulated by 10 mumol/l histamine (IC50: 7.8 mumol/l) and 1 mmol/l dbc-AMP (IC50: 10 mumol/l). These results suggest that pentagalloylglucose is a potent inhibitor of H+, K(+)-ATPase and may be responsible for inhibition of acid secretion by Paeoniae radix.