Inhibition of tolbutamide elimination by cimetidine but not ranitidine

This study was designed to compare the effects of equivalent therapeutic doses of two H2 antagonists, cimetidine and ranitidine, on tolbutamide pharmacokinetics. Twelve healthy men were given a 1-g oral dose of tolbutamide on three occasions. Subjects were randomly assigned to three treatments in a crossover fashion: cimetidine 1,200 mg/d, ranitidine 300 mg/d, and placebo. Cimetidine significantly increased the tolbutamide area under the plasma concentration-time curve by 20% (range, -5% to 42%), increased the elimination half-life by 17%, and decreased the carboxytolbutamide:tolbutamide plasma ratio from 0.042 to 0.036. Ranitidine did not significantly alter tolbutamide pharmacokinetics.     

Cimetidine decreases aspirin-induced gastric mucosal damage in humans

Aspirin induces gastric mucosal damage in animals and humans. The purpose of this study was to examine whether cimetidine protects the human gastric mucosa from acute aspirin-induced damage. Eight healthy subjects were studied on 4 separate days. Cimetidine, 400 mg, or placebo was given orally 1 hour before initial endoscopy. The stomach was isolated and atropine given to suppress basal acid secretion. Each study consisted of four 15 min periods during which an acidic test solution was instilled into the stomach. During the second period only, either aspirin (1300 mg, 36 mmol) or control for aspirin (36 mmol HCl) was added to the test solution. Ion fluxes and gastric mucosal potential difference were measured, and endoscopy performed following each test. After placebo, aspirin significantly altered hydrogen ion flux and potential difference versus basal and control. Cimetidine decreased the damaging effect of aspirin. Endoscopic scores increased after aspirin plus placebo, whereas they remained unchanged after aspirin plus cimetidine. Therefore, cimetidine decreased aspirin-induced gastric mucosal damage in humans. As gastric acidity was identical during all studies, the effect of cimetidine was independent of gastric acid secretion.     

Ranitidine and cimetidine; drug interactions with single dose and steady-state nifedipine administration.

The effect of ranitidine 300 mg once daily and cimetidine 800 mg once daily on the disposition of nifedipine was studied in two groups of 12 volunteers. Both investigations were placebo-controlled cross-over studies. The first group received ranitidine, cimetidine or placebo for 5 days with 20 mg nifedipine given on the 5th day. Each period was separated by 1 week. The second group received nifedipine 10 mg three times daily for 5 days together with the H2-receptor antagonist or placebo. Cimetidine produced a significant increase in the AUC of both single and steady state dosing of nifedipine. Peak nifedipine levels were significantly increased only in the chronic dose study compared to placebo. Ranitidine did not produce any significant changes in either study.     

The effects of chronic oral diltiazem and cimetidine dosing on the pharmacokinetics and negative dromotropic action of intravenous and oral diltiazem in the dog.

The kinetics and negative dromotropic action of intravenous (1 mg kg-1) and oral (5 mg kg-1) diltiazem were studied in dogs after acute doses, after treatment for 3 days with oral diltiazem (5 mg kg-1, t.i.d.), and after 3 days' treatment with oral diltiazem (5 mg kg-1 t.i.d.) and cimetidine (200 mg t.i.d.). Plasma concentrations of diltiazem and two of its metabolites, desacetyldiltiazem and desmethyldiltiazem were measured by HPLC. Chronic oral dosing significantly lowered both the systemic and oral clearance of diltiazem, with no changes in either the volume of distribution or blood binding of diltiazem. Cimetidine treatment resulted in a significant reduction in diltiazem oral clearance from chronic control with no effect on its systemic clearance. The AUCs of both metabolites increased by greater than threefold from acute to chronic oral dosing; however, the ratio of each metabolite's AUC to that of diltiazem AUC was not significantly altered. Cimetidine treatment significantly lowered these ratios. The negative dromotropic potency of diltiazem after the acute oral dose was three times greater than that after intravenous or chronic control dosing. Cimetidine treatment resulted in further lowering chronic oral diltiazem potency. These data indicate that the disposition and negative dromotropic action of diltiazem is dependent both on the route of administration and the duration of treatment, and can be altered by co-administration with cimetidine.     

The effects of ranitidine and cimetidine on the pharmacokinetics and pharmacodynamics of metoprolol

The impact of cimetidine, ranitidine and placebo on the pharmacokinetics of metoprolol, given either as a single dose (100 mg) or for 7 days (100 mg b.d.), has been evaluated in two separate studies. The doses used were 800 mg cimetidine daily and 300 mg ranitidine daily. The subjects were all young, healthy volunteers. In the single dose study, cimetidine produced a marked increase in the peak plasma concentration of metoprolol and in the area under the plasma concentration-time curve; ranitidine had less effect, though the area under the curve was significantly greater than placebo. In the chronic dosing study, the area under the curve for metoprolol was also significantly higher on cimetidine (1796 ng h/ml; P less than 0.001) whereas the area under the curve on ranitidine (1258 ng h/ml) was comparable to that on placebo (1183 ng h/ml). Despite these drug-induced changes in plasma metoprolol concentration, neither cimetidine nor ranitidine altered the change in exercise-induced heart rate during dosing with metoprolol.     

Effect of a short-term oral administration of cimetidine and ranitidine on the basal and thyrotropin-releasing hormone-stimulated serum concentrations of prolactin, thyrotropin and thyroid hormones in healthy volunteers. A double-blind cross-over study

Cimetidine (400 mg b.d.), ranitidine (150 mg b.d.) and placebo were administered for 1 week to 6 healthy male volunteers in a randomized double-blind cross-over fashion. Hormonal concentrations before and after a TRH test were assessed before and after each treatment. A spontaneous decrease in the hormonal response to TRH was observed after placebo treatment. Both cimetidine and ranitidine induced a significant increase in basal prolactin (PRL) values. Neither TSH nor T3 were modified by cimetidine or by ranitidine. The basal concentration of reverse T3 was increased during cimetidine treatment. There was a significant rise in post-TRH T4 after cimetidine and ranitidine administration. These results suggest a role for histamine H2 receptors in the secretion of PRL and T4. Moreover, cimetidine affects the hepatic metabolism of thyroid hormones.     

The influence of diltiazem versus cimetidine on propranolol metabolism.

The present study was undertaken to examine whether the inhibitory effect of diltiazem on the metabolism of propranolol differs from that of cimetidine. Six healthy male volunteers received a single oral dose of 20 mg propranolol with pretreatment with placebo, 60 mg diltiazem, or 400 mg cimetidine three times daily for 4 days. Diltiazem and cimetidine increased the area under the concentration (AUC) of propranolol and its glucuronide. Cimetidine also increased the urinary excretion of propranolol glucuronide. There were no significant differences in the AUC of 4-hydroxypropranolol (4OHPPL) and its conjugates or the urinary excretion of conjugated 4OHPPL. Diltiazem increased the AUC of naphthoxylactic acid (NLA) and the urinary excretion to NLA. After cimetidine pretreatment, there was the trend toward a decrease in the partial metabolic clearance to 4OHPPL and a significant decrease in that of NLA. These results suggest that diltiazem and cimetidine inhibit the oxidation pathways of propranolol in different manners. Cimetidine might inhibit both oxidative pathways to 4OHPPL and NLA, whereas diltiazem might not inhibit the pathway to NLA.     

A pharmacokinetic and pharmacodynamic interaction study between nebivolol and the H2-receptor antagonists cimetidine and ranitidine

Aims The study was designed to investigate the effects of the H₂-receptor antagonists, cimetidine and ranitidine on the pharmacokinetics and pharmacodynamics of nebivolol in healthy volunteers. Methods Twelve healthy volunteers took part in a randomized placebo-controlled cross-over study. Each subject received on three separate occasions placebo, cimetidine (400 mg twice daily) or ranitidine (150 mg twice daily) for 24 h before and 48 h after a single oral dose of nebivolol (5 mg). Nebivolol and its individual (+) and (−) enantiomers were determined tby h.p.l.c. Results Ranitidine had no significant effect on nebivolol pharmacokinetics. Cimetidine, however, resulted in a 21–23% increase in C_max of unchanged nebivolol and of each enantiomer plus its hydroxylated metabolites. Cimetidine significantly (P<0.05) increased the AUC [mean±s.d. (95% C.I. of differences in mean)] for unchanged (±)-nebivolol [7.76±3.07 ng ml⁻¹h with placebo; 11.50±5.40 (1.75, 8.76) ng ml⁻¹h with cimetidine], (+)-nebivolol plus its hydroxylated metabolites [73.0±18.0 ng ml⁻¹h with placebo; 91.5±25.7 (1.0, 23.1) ng ml⁻¹h with cimetidine] and (−)-nebivolol plus its hydroxylated metabolites [101±32 ng ml⁻¹h with placebo; 123±38 (3.3, 27.0) ng ml⁻¹h with cimetidine]. Statistical analysis of the resting blood pressure and heart rate and exercise data did not suggest any consistent effects of ranitidine or cimetidine upon the pharmacodynamic effects of nebivolol. Conclusions There was no interaction between ranitidine and nebivolol. Although cimetidine inhibited nebivolol metabolism, it did not have a significant influence on the pharmacodynamics of the drug.     

Effect of omeprazole and cimetidine on plasma diazepam levels

Summary The effects of steady state dosing with omeprazole and cimetidine on plasma diazepam levels have been studied in 12 healthy males. Single doses of diazepam (0.1 mg · kg⁻¹ i.v.) were administered after one week of treatment with omeprazole 20 mg once daily, cimetidine 400 mg b. d. or placebo, and the treatment was continued for a further 5 days. Blood was collected for 120 h after the dose of diazepam for the measurement of diazepam and its major metabolite desmethyl diazepam. The mean clearance of diazepam was decreased by 27% and 38% and its half-life was increased by 36% and 39% after omeprazole and cimetidine, respectively. Neither drug had any apparent effect on the volume of distribution of diazepam. Desmethyldiazepam appeared more slowly after both omeprazole and cimetidine. It is concluded that the decrease in diazepam clearance was associated with inhibition of hepatic metabolism both by omeprazole and cimetidine. However, since diazepam has a wide therapeutic range, it is unlikely that concomitant treatment with therapeutically recommended doses of either omeprazole or cimetidine will result in a clinically significant interaction with diazepam.     

Gastrointestinal microbleeding associated with the use of etodolac, ibuprofen, indomethacin, and naproxen in normal males

Etodolac, a nonsteroidal antiinflammatory and analgesic drug, was used in a randomized, parallel group, open-label design study, with stool analysis conducted in a blind fashion, to compare its effect in normal men in doses of 400 mg (N = 11) and 600 mg (N = 12) b.i.d. on gastrointestinal microbleeding with that of 600 mg ibuprofen, q.i.d. (N = 12), 50 mg indomethacin in the morning, 50 mg at noon, and 100 mg h.s. (N = 9), and 375 mg naproxen b.i.d. (N = 9). Etodolac was given at about 2 1/2 and 3 1/2 times the mean effective dose used for treating patients with rheumatoid arthritis. The other drugs were given at their manufacturers' maximum recommended doses. Lead-in placebo was given for one week, active drug for one week, and washout placebo for one week. Fecal blood loss was measured by the 51Cr-tagged red cell method, and was averaged over days 4-7 (baseline), 11-14 (treatment period), and 17-20 (washout). The mean increase in blood loss for the treatment period for the 400 mg etodolac b.i.d. group (0.13 ml) and 600 mg etodolac b.i.d. group (0.10 ml) was significantly less (P = 0.001) than the corresponding values for ibuprofen (1.14 ml), indomethacin (1.20 ml), and naproxen (0.87 ml). There was no tendency for greater blood loss at higher doses of etodolac. Etodolac at doses in excess of the mean effective dose in osteoarthritis and rheumatoid arthritis caused significantly less microbleeding in normal male volunteers during the seven-day treatment period than the other drugs tested, and not clinically more than that occurring during baseline placebo.     

Multiple-Dose Pharmacokinetics and Pharmacodynamics of Adinazolam in Elderly Subjects

The pharmacokinetics and pharmacodynamics of adinazolam (AD) were evaluated in 21 elderly subjects (mean age, 69 ± 4 years) at four dose levels during a placebo-controlled, double-blind, dose escalation regimen in which the oral dose was varied from 10 to 60 mg daily, in divided doses. Fifteen subjects received adinazolam mesylate; six received placebo. Plasma samples collected during a single dosing interval in each dosing period (3 days) were assayed for adinazolam and monodesmethyl adinazolam (NDMAD) by high-performance liquid chromatography (HPLC). Urine samples were collected during a single interval during the 20- and 40-mg daily dose periods and assayed for NDMAD by HPLC. Pharmacologic effects of adinazolam were assessed using psychomotor performance tests and sedation ratings. Adinazolam pharmacokinetics were linear over the dosage range studied. Daily dose had no significant effect on dose-normalized AUC and C _max for AD. Dose-normalized NDMAD AUC values as well as values were not significantly affected by the daily dose of adinazolam. The ratio NDMAD/AD was not substantially affected by the dose. Renal clearance of NDMAD for the 20-and 40-mg daily doses were 5.6 ± 2.1 and 5.5 ± 2.2 liters/hr, respectively, and did not correlate with creatinine clearance. Adinazolam and NDMAD did not substantially accumulate in elderly subjects, even upon multiple dosing at 8-hr intervals. The dosing regimens in this experiment appeared to be well tolerated in the elderly, as performance tests and sedation scores indicated no substantial dose-related effects of adinazolam on psychomotor performance.     

Effect of cimetidine on hepatic biochemical changes, liver toxicity and major urinary metabolite excretion of trichloroethylene in rats

The effects of cimetidine (CIM) (an inhibitor of the hepatic microsomal monooxygenase system) on the metabolism and hepatotoxicity of trichloroethylene (TRI) were studied in male Sprague-Dawley rats. Rats were given three doses of 120 mg/kg i.p. (low-dose regimen) of CIM at 0, 6 and 11 h for 1 day, or ten doses of 200 mg/kg (high-dose regimen) at 8, 11, 14 and 17 h for 2 days and 8 and 11 h on 3rd day. Trichloroethylene (0.5 or 0.65 ml/kg) was administered i.p. 1 h after 2nd dose (low-dose regimen) or 9th dose (high-dose regimen) of CIM. In the low-dose regimen study, the activity of hepatic microsomal aminopyrine N-demethylase was decreased 1 and 5 h after the second dose and 7 h after the third dose of CIM, but became normal 20 h after the last dose. The cytochrome P-450 content and the activities of aniline hydroxylase and epoxide hydratase remained unchanged. Trichloroethylene at both dose levels produced liver toxicity, as verified by increase in activities of SDH and SGPT as well as by liver histology. Cimetidine alone had no such effect. An apparent reduction in TRI toxicity by CIM (at both dose regimens) could be observed histologically. The biochemical tests (SDH and SGPT) corroborated the histological changes only when TRI was given at a dose of 0.5 ml/kg combined with a high-dose regimen of CIM. Cimetidine at both dose regimens had a tendency to decrease the in vivo metabolism of TRI.(ABSTRACT TRUNCATED AT 250 WORDS)     

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

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.     

The effect of liver microsomal enzyme inducing and inhibiting drugs on insulin mediated glucose metabolism in man.

The effects of hepatic microsomal enzyme inducing (phenobarbitone and flumecinol), and inhibiting (cimetidine) drugs, and placebo treatment on insulin mediated glucose metabolism (M) were investigated in 29 healthy volunteers. Phenobarbitone (50 mg for 10 days) increased M (30%), metabolic clearance rate of glucose (MCRg), and antipyrine clearance rate (33%). Fasting immunoreactive insulin (IRI) decreased while fasting blood glucose (BG) remained unaltered. Flumecinol, another inducer, tested in two doses (200 mg and 600 mg for 6 days), did not alter glucose or antipyrine metabolism. Fasting IRI reduced on treatment with 600 mg of flumecinol, but not with the smaller dose. Cimetidine (600 mg for 6 days) decreased M (19.5%), MCRg (26%), and antipyrine clearance rate (20%). The placebo did not alter glucose or antipyrine metabolism. The results indicate that the insulin mediated glucose disposal rate can be altered by drugs influencing hepatic microsomal enzyme activity.     

The effects of cimetidine and ranitidine on psychomotor function in healthy volunteers

Single oral doses of cimetidine (400 mg), ranitidine (150 mg), promethazine (25 mg) or placebo were administered to 8 healthy volunteers in a double-blind study. Cimetidine and ranitidine did not cause any significant change in critical flicker frequency (c.f.f.), reaction time, pursuit rotor of the visual analogue scale scores for sedation. Promethazine significantly lowered c.f.f., prolonged reaction time and increased sedation when compared with placebo. It is concluded that in this study cimetidine and ranitidine had little, if any, effect on psychomotor function.     

Pharmacokinetic and pharmacodynamic interactions of propafenone and cimetidine

The pharmacokinetics and pharmacodynamics of the extensively metabolized antiarrhythmic agent propafenone were assessed alone and during concomitant administration of cimetidine. Twelve healthy subjects were given successively the following treatments: propafenone 225 mg q8h plus cimetidine placebo; cimetidine 400 mg q8h plus propafenone placebo; and propafenone 225 mg plus cimetidine 400 mg q8h. After a minimum of 5 days on each regimen, plasma drug concentrations and electrocardiogram conduction intervals were measured during a drug washout period. The maximum concentration of propafenone in plasma was 993 +/- 532 ng/mL when propafenone was given alone compared with 1230 +/- 591 ng/mL when propafenone was given with cimetidine (P = .0622). Differences in tmax, t1/2, and Cp ss did not approach statistical significance when propafenone alone was compared with propafenone plus cimetidine. When compared with cimetidine, propafenone significantly increased the PR interval from 161 +/- 5 msec to 192 +/- 6 msec (P less than .01) and the QRS duration from 89 +/- 3 msec to 98 +/- 4 msec (P less than .01). Combination therapy caused a modest additional increase in QRS duration to 103 +/- 3 msec (P less than .01). In conclusion, cimetidine caused small changes in propafenone pharmacokinetics and pharmacodynamics; but these changes are unlikely to be clinically important.     

H2-receptor blockade and exercise-induced asthma.

While in vitro studies suggest that H2-receptor blockade enhances mediator release from bronchial mast cells and leads to bronchoconstriction, in vivo studies have given conflicting results. Eight asthmatic subjects were given cimetidine 800 mg and placebo double-blind on different days. Baseline values of forced expiratory volume in one second (FEV1) were obtained before an 8 min standardized exercise test using a bicycle ergometer. Subjects inhaled cold, dry air and exercise on cimetidine and placebo days was matched for ventilation and thermal load. FEV1 was measured immediately, 5, 10, 15, and 20 min after exercise. No significant differences were observed between mean baseline FEV1, immediate post exercise FEV1, or maximum percentage fall from baseline after exercise on cimetidine or placebo days. Cimetidine does not appear to effect lung function or bronchial responses to cold air exercise challenge.     

Interaction of steady-state procainamide with H2-receptor antagonists cimetidine and ranitidine

This study was designed to compare the effects of equivalent therapeutic doses of two H2 antagonists, cimetidine and ranitidine, on steady-state procainamide pharmacokinetics. Six healthy men were given 500 mg sustained-release procainamide every 6 h, for a total of 13 doses, on three occasions. Subjects were randomly assigned to three treatments by a Latin-square design: cimetidine 1,200 mg/day, ranitidine 300 mg/day, and no H2-receptor antagonist (control) for 4 days. Cimetidine significantly increased the procainamide area under the serum concentration-time curve by 43%, decreased renal clearance by 36%, and decreased the ratio of systemic clearance of procainamide to bioavailability by 28%. Ranitidine did not significantly alter procainamide steady-state pharmacokinetics.     

A cortisol suppression dose-response comparison of budesonide in controlled ileal release capsules with prednisolone

AIM: To assess the systemic effect of oral budesonide, given as Entocort controlled ileal release capsules, over a dose range of 3-15 mg/day, compared with that of a moderate dose (20 mg/day) of prednisolone. METHODS: Twenty four healthy subjects were given 3, 9 or 15 mg budesonide or 20 mg prednisolone once daily, or 4.5 mg budesonide b.d., or placebo for 5 days in a randomized, double-blind crossover study. The area under the curve (AUC) of plasma cortisol concentration and the amount of cortisol excreted in the urine were monitored. RESULTS: Both plasma and urine cortisol suppression showed a dose-response for the daily doses of budesonide. Prednisolone, 20 mg, suppressed plasma cortisol (AUC) statistically significantly more than 15 mg budesonide (P = 0.014), and 3 mg budesonide statistically significantly more than placebo (P = 0.010). No difference in AUC was detected between 9 mg and 4.5 mg budesonide b.d. Similar results for budesonide vs. placebo were obtained from urine cortisol excretion data. However, prednisolone affected urine cortisol less than it affected plasma cortisol. CONCLUSION: After 5 days of administration, budesonide controlled ileal release capsules, in both clinical (9 mg/day) and high doses (15 mg/day), affected plasma cortisol less than a moderate (20 mg/day) dose of prednisolone.