Effects of nicorandil on experimentally induced gastric ulcers in rats: a possible role of K(ATP) channels. (1/872)

The anti-ulcer effects of nicorandil [N-(2-hydroxyethyl)nicotinamide nitrate ester] were examined on water-immersion plus restraint stress-induced and aspirin-induced gastric ulcers in rats, compared with those of cimetidine. Nicorandil (3 and 10 mg/kg) given orally to rats dose-dependently inhibited the development of acid-related damage (water-immersion- and aspirin-induced gastric lesions) in the models. Cimetidine (50 mg/kg, p.o.) also had anti-ulcer effects in the same models. However, in the presence of glibenclamide (20 mg/kg, i.v.), an antagonist of K(ATP) channels, nicorandil did not inhibit the formation of gastric lesions. Nicorandil (10 mg/kg) given intraduodenally (i.d.), like cimetidine (50 mg/kg), significantly reduced the volume of the gastric content, total acidity and total acid output in the pylorus ligation model. Glibenclamide reversed the changes caused by i.d. nicorandil. I.v. infusion of nicorandil (20 microg/kg per min) significantly increased gastric mucosal blood flow, without affecting blood pressure and heart rate, but the increase in the blood flow was not observed after i.v. treatment with glibenclamide (20 mg/kg). These results indicate that nicorandil administered orally to rats produces the anti-ulcer effect by reducing the aggressive factors and by enhancing the defensive process in the mucosa through its K(ATP)-channel-opening property.  (+info)

Cimetidine transport in brush-border membrane vesicles from rat small intestine. (2/872)

In previous studies, sulfoxide metabolite was observed in animal and human intestinal perfusions of cimetidine and other H2-antagonists. A sequence of follow-up studies is ongoing to assess the intestinal contributions of drug metabolism and drug and metabolite transport to variable drug absorption. An evaluation of these contributions to absorption variability is carried out in isolated fractions of the absorptive cells to uncouple the processes involved. In this report, data is presented on the drug entry step from a study on [3H]cimetidine uptake into isolated brush-border membrane vesicles from rat small intestine. A saturable component for cimetidine uptake was characterized with a Vmax and Km (mean +/- S.E.M.) of 6.1 +/- 1.5 nmol/30s/mg protein and 8.4 +/- 2.0 mM, respectively. Initial binding, and possibly intravesicular uptake, was inhibited by other cationic compounds including ranitidine, procainamide, imipramine, erythromycin, and cysteamine but not by TEA or by the organic anion, probenecid. Initial uptake was not inhibited by amino acids methionine, cysteine, or histidine, by the metabolite cimetidine sulfoxide, or by inhibitors of cimetidine sulfoxidation, methimazole, and diisothiocyanostilbene-2,2'-disulfonic acid. Equilibrium uptake was inhibited by ranitidine, procainamide, and cysteamine but not by erythromycin or imipramine. Initial cimetidine uptake was stimulated by an outwardly directed H+ gradient, and efflux was enhanced by an inwardly directed H+ gradient. Collapse of the H+ gradient as well as voltage-clamping potential difference to zero significantly reduced initial cimetidine uptake. The data is supportive of both a cimetidine/H+ exchange mechanism and a driving-force contribution from an inside negative proton or cation diffusion potential.  (+info)

Glomerular filtration rate estimation from plasma creatinine after inhibition of tubular secretion: relevance of the creatinine assay. (3/872)

BACKGROUND: Estimation of glomerular filtration rate (GFR) from plasma creatinine concentration after inhibition of tubular creatinine secretion with cimetidine provides a good assessment in patients with various nephropathies and with non-insulin-dependent diabetes mellitus (NIDDM). The aim of this study was to compare cimetidine-aided GFR estimations using various creatinine assays. METHODS: In 30 outpatients with NIDDM GFR was measured as the urinary clearance of continuously infused [125I]iothalamate. Plasma creatinine concentration was analysed after oral cimetidine with an alkaline picrate (AP) method, with an enzymatic (PAP) assay and with HPLC. GFR estimations were calculated with the Cockcroft Gault formula (CG). RESULTS: AP creatinine concentrations were significantly higher than PAP or HPLC values. GFR estimations by AP (CG(AP) 66 +/- 19 ml/min/1.73 m2, mean SD) were significantly lower than GFR (89 +/- 30), whereas CG(PAP) (85 +/- 30) and CG(HPLC) (84 +/- 34 ml/min/1.73 m2) were not. Bland and Altman analysis showed a difference between CG(AP) and GFR of -22.4 +/- 17.7 ml/min/1.73 m2; this difference becomes larger when the GFR increases. The difference between CG and GFR was only -3.8 +/- 14.8 ml/min/1.73 m2 for PAP and -4.4 +/- 17.5 ml/min/1.73 m2 for HPLC, without any systematic difference. CONCLUSION: A good assessment of the GFR from plasma creatinine after cimetidine administration is possible when creatinine is measured with an enzymatic assay or with the less convenient HPLC method. The more widespread and cheaper alkaline picrate assay is not suitable for GFR-estimation.  (+info)

Drug interactions of H2-receptor antagonists involving cytochrome P450 (CYPs) enzymes: from the laboratory to the clinic. (4/872)

This paper reviews the main steps in the research of the interactions of H2-receptor antagonist drugs with cytochrome P450 (CYP) enzymes. Cimetidine, ranitidine, and related compounds are used as examples. The results from in vitro studies are related to the observed clinically significant in vivo drug-drug and drug-chemical interactions. Uses of the in vitro results are discussed for the interpretation and possible prediction of drug-drug interactions, which may be important in developing new drugs. Other approach in the use of the in vitro data is to prevent undesirable and toxic actions of drugs related to the catalytic activity of CYP enzymes. In the case of H2-receptor antagonists, the inhibition of the metabolic reactions due to the binding of the drugs with the enzymes was used to avoid side effects of co-administered drugs. The in vitro metabolic studies using recombinant human as well as animal CYP enzymes are now widely used as model syste ms for designing new drugs with improved therapeutic properties.  (+info)

Histamine response and local cooling in the human skin: involvement of H1- and H2-receptors. (5/872)

AIMS: Histamine may contribute locally to cutaneous blood flow control under normal and pathologic conditions. The objective of this study was to observe the influence of skin temperature on histamine vasodilation, and the roles of H1-and H2-receptors using novel noninvasive methods. METHODS: Eleven healthy subjects received, double-blind, single doses of the H1-receptor antagonist cetirizine (10 mg), cetirizine (10 mg) plus the H2-receptor antagonist cimetidine (400 mg), or placebo on separate occasions. Histamine was dosed cumulatively by iontophoresis to the forearm skin at 34 degrees C and 14 degrees C. Laser-Doppler flux (LDF) was measured at the same sites using customised probeholder/iontophoretic chambers with Peltier cooling elements. Finger mean arterial pressure (MAP) was measured and cutaneous vascular conductance calculated as LDF/MAP. RESULTS: Histamine vasodilation was reduced in cold skin. Cetirizine shifted the histamine dose-response at both temperatures: statistically significantly at 14 degrees C only. Combined H1- and H2-receptor antagonism shifted the response significantly at both temperatures. CONCLUSIONS: H1- and H2-receptors mediate histamine-induced skin vasodilation. The sensitivity of these receptors, particularly the H1- receptor, is attenuated at low skin temperature. Whether the reduced effect in cold skin represents specific receptor or postreceptor desensitization, or nonspecific attenuation of cutaneous vasodilation remains to be elucidated.  (+info)

Antiulcer effect of lafutidine on indomethacin-induced gastric antral ulcers in refed rats. (6/872)

Lafutidine is a new type antiulcer agent with antisecretory and gastroprotective activities. We investigated the effect of lafutidine on indomethacin-induced antral ulcer in refed rats. Subcutaneous indomethacin injection resulted in the formation of gastric antral ulcer. Lafutidine (1-10 mg/kg, p.o.) reduced the area of ulcer in a dose-dependent manner when administered immediately after the indomethacin injection. Capsaicin at 3 mg/kg, p.o. and 16,16-dimethyl prostaglandin E2 at 3 microg/kg, p.o. also reduced the ulcer area. Chemical deafferentation of capsaicin-sensitive neurons or N(G)-nitro-L-arginine treatment aggravated the ulcer formation and abolished the preventive effect of lafutidine and capsaicin. After the induction of gastric ulcer, lafutidine given twice daily for 2.5 days reduced the area of ulcer in a dose-dependent manner with a significant effect at 10 mg/kg, p.o., as compared with that of the control group. In chemically-deafferentated rats, lafutidine did not show any healing effect. Cimetidine (30 mg/kg, p.o.) and famotidine (1 mg/kg, p.o.) had no significant effect on indomethacin-induced antral ulcer. These results may suggest that lafutidine, unlike cimetidine and famotidine, can prevent the indomethacin-induced antral ulcer formation and accelerate the healing of the ulcer in refed rats through mechanisms involving the capsaicin-sensitive afferent neurons and nitric oxide.  (+info)

Use of cimetidine, omeprazole, and ranitidine in pregnant women and pregnancy outcomes. (7/872)

Evidence documenting the safety of acid-suppressing drugs in pregnancy is very limited. The authors assessed the prevalence of congenital malformations in first trimester-exposed pregnancies to cimetidine, omeprazole, and ranitidine and compared it with nonexposed pregnancies between 1991 and 1996. Two different sources were used, the United Kingdom General Practice Research Database and the Italian Friuli-Venezia Giulia Health Database. The final study cohort included 1,179 pregnancies from the United Kingdom and 1,057 from Italy. Abortions or ectopic pregnancies were not included. There were 20 stillbirths and 2,261 live-born babies in both cohorts combined, with 100 offspring identified with a malformation. The overall malformation rate was 4.4%. The relative risks for nongenetic congenital malformations associated with the use of cimetidine, omeprazole, and ranitidine were 1.2 (95% confidence interval (CI): 0.6, 2.3), 0.9 (95% CI: 0.3, 2.2), and 1.4 (95% CI: 0.8, 2.4), respectively, compared with the nonexposed. No specific grouping in the distribution of malformations was observed in any of the three exposed groups. Moreover, no relation was found between drug exposure and preterm delivery or growth retardation. These findings suggest that the use of acid-suppressing drugs during the first trimester of pregnancy is not associated with a major teratogenic risk.  (+info)

Does cimetidine improve prospects for cancer patients?. A reappraisal of the evidence to date. (8/872)

BACKGROUND: Evidence first appeared in 1988 that cimetidine as an adjuvant may improve the survival of severely ill gastro-intestinal cancer patients when given peri- or postoperatively. Since then, several studies have appeared which suggest an anticancer activity for cimetidine, although few attempts have been made to corroborate their findings in large, placebo-controlled, double-blind studies. METHOD: We reviewed the literature concerning cimetidine's potential anticancer activity, particularly with regard to gastro-intestinal cancers. RESULTS: Most studies suggest that cimetidine may improve the outcome in cancer patients by a three-pronged mechanism involving (1) inhibition of cancer cell proliferation; (2) stimulation of the lymphocyte activity by inhibition of T cell suppressor function, and (3) inhibition of histamine's activity as a growth factor in tumours. CONCLUSION: Bearing in mind the experimental evidence, as well as the potential and excellent safety profile of cimetidine, more studies are required and justified to clarify cimetidine's protherapeutic activity.  (+info)

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