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H2-receptor antagonists are among the most widely-used drugs in the world and, since many patients receive a variety of other drugs concomitantly, it is important to investigate the interaction potential of new H2-receptor antagonists such as nizatidine. It is well documented that cimetidine can inhibit the hepatic elimination of many drugs by binding to the cytochrome P-450 system. Therefore we investigated in vitro and in vivo the effects of nizatidine on drug metabolism. With rat liver microsomes the effects of nizatidine and four other H2-blockers (cimetidine, oxmetidine, ranitidine, famotidine) on the activity of three marker enzymes (aryl-hydrocarbon-hydroxylase, 7-ethoxycoumarin-O-deethylase, 7-ethoxy-resorufin-O-deethylase) were tested. While cimetidine and oxmetidine exhibited marked and dose-dependent inhibition of all three metabolic reactions, nizatidine showed some weak inhibition only at very high concentrations. Similarly, binding to cytochrome P-450 of human liver microsomes could be seen only with cimetidine and oxmetidine, whereas nizatidine did not affect the binding spectra. In nine healthy mal volunteers the pharmacokinetics of diazepam (10 mg po) was studied under the influence of nizatidine (300 mg day nocte). Nizatidine had no significant effect on the hepatic elimination of diazepam, as characterized by its elimination half-life (mean +/- SD) of 35.3 +/- 24.2 h (control) and 37.3 +/- 18.3 h (+ nizatidine) or its total plasma clearance of 28.2 +/-12.0 ml/min (control) and 26.7 +/- 10.4 ml/min (+ nizatidine). The formation of the major metabolite-desmethyldiazepam-was also unaffected by nizatidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Nizatidine, a new H2-receptor antagonist, was compared with ranitidine in a double-blind, randomized, multicentre trial for the prevention of duodenal ulcer relapse. This is the interim analysis of 197 patients admitted to the study by 1 September 1985, having finished a 6-month treatment period by 1 March 1986. At night, 96 and 101 patients received 150 mg nizatidine and 150 mg ranitidine, respectively. Both groups were well matched for demographic data, duration and severity of ulcer disease. Calculating cumulative relapse rates by the life-table method of Cutler and Ederer, 18% on nizatidine and 13% on ranitidine had experienced a symptomatic or asymptomatic recurrence. The difference is not statistically significant. The symptomatic response was identical in both groups, 3/4 of the patients in both groups being free of any symptom over all 6 months. During maintenance treatment, 24% of the patients on nizatidine and 32% of those on ranitidine reported new symptoms, listed as 'adverse events'. However, none of these events was likely to be drug related. There was no difference between the two groups concerning the percentage change of laboratory variables from baseline to endpoint.

In this report, the pharmacokinetic, pharmacodynamic, and hormonal effects of nizatidine are reviewed in healthy volunteers and in patients with renal or hepatic impairment. The absolute oral bioavailability of nizatidine exceeded 90%; the half-life (t1/2), plasma clearance (Clp), and volume of distribution (Vd) of iv nizatidine were 1.3 h, 461/h, and 1.21/kg, respectively. Within 16 h of dosing volunteers with nizatidine, more than 90% of the administered dose was recovered in urine as parent drug and metabolites; unchanged nizatidine accounted for 65 and 75% of the recovered substances, after oral and intravenous administration, respectively. Renal impairment decreased the elimination of nizatidine and dosage reductions are recommended for patients with creatinine clearance (Clcr) less than 50 ml/min/m2. Nizatidine suppressed gastric acid secretion produced by sham meals, protein meals, or pentagastrin; its antisecretory activity was dose and concentration dependent. Nizatidine was three times more potent than cimetidine. Nizatidine, after oral or iv administration, did not alter hormone concentrations in plasma.

To determine the antisecretory potency of bedtime doses of the new thiazole H2-receptor antagonist nizatidine in the suppression of nocturnal acid secretion, this randomized, cross-over, single-blind study was performed in 10 healthy male subjects. The actions of a single bedtime (2100 h) dose of the H2-receptor antagonist nizatidine (150 mg and 300 mg), ranitidine (300 mg), cimetidine (800 mg), and famotidine (40 mg), as well as placebo on nocturnal gastric acid and volume secretion (2400 to 0600 h) and on overall 24 h H+-ion concentration were studied. Compared with placebo, night-time (2300 to 0700 h) H+ ion concentration was reduced by 70, 79, 95, 75, and 89% (p less than 0.05 to p less than 0.01). Nocturnal acid secretion, too, was significantly lower for the H2-blockers than for placebo (p less than 0.01). A significant reduction in total night-time gastric volume secretion was observed (p less than 0.01). Nizatidine 300 mg nocte, ranitidine, cimetidine and famotidine had no significant carry-over effects on daytime acidity (0800 to 1800 h). No significant pharmacodynamic differences between nizatidine 300 mg nocte, ranitidine 300 mg nocte, cimetidine 800 mg nocte and famotidine 40 mg nocte were observed. Thus, it may be concluded that these four H2-blockers will be equally effective in accelerating peptic ulcer healing and pain relief.

The safety of nizatidine as treatment for active duodenal or gastric ulcer disease or as maintenance therapy following ulcer healing was assessed in 3800 nizatidine-treated individuals in clinical trials conducted in the USA and Europe. Safety parameters included physical examinations, electrocardiograms, eye examinations, serum chemistries and testosterone, hematology, and urinalyses. Adverse events were recorded without judgment of causality. Early discontinuations and adverse events, including complications of active duodenal ulcer disease, occurred more frequently in placebo-treated patients than in those given nizatidine. No differences were observed between the nizatidine and ranitidine treatment groups in regard to adverse event incidence or severity. Minimal changes in uric acid values were observed during ranitidine and nizatidine therapy. Abnormal liver function tests occurred infrequently and to an equal extent in nizatidine and placebo treatment groups. No clinically relevant differences in laboratory test results were observed between treatment groups in studies conducted in Europe.

Patients (859) from six countries were randomized into an endoscopically controlled double-blind trial. The objective of this study was to compare the efficacy and safety of nizatidine 300 mg nocte with ranitidine 300 mg nocte in the therapy of duodenal ulceration. Patients fulfilling the entry criteria and completing the protocol numbered 777 (388 nizatidine, 389 ranitidine). Endoscopy was performed on entry and at 4-week intervals (up to 8 weeks) until the ulcer healed, except in Germany where endoscopy was also performed after 14 days. Both groups appeared well matched for population demographics, duodenal ulcer history, previous therapy and pre-study symptomatology. Overall healing rates in the nizatidine group compared favourably with the ranitidine group at 4 weeks (nizatidine 81%, ranitidine 80%) and 8 weeks (nizatidine 92%, ranitidine 93%). Data from Germany alone showed similar ulcer healing rates after 2 weeks therapy (nizatidine 60%, ranitidine 64%). Although there were no differences between or within the treatment groups, overall ulcer healing was significantly impaired (p less than 0.05 or less) in patients with a large ulcer (greater than 15 mm), a family history of peptic ulcer disease, verified disease or greater than 5 years duration, or heavy smokers (greater than 20 cigarettes/day). Age did not influence healing. Overall healing rates were significantly influenced by country of patient origin, being higher in Germany, and lower in Belgium (p less than 0.001). After 2 weeks therapy, about 60% of the nizatidine and ranitidine treated patients were pain free, while 4 weeks therapy was associated with relief of all symptoms in 72% of patients and relief of night pain in more than 90%. Antacid consumption reduced at a similar rapid rate during the study. Events were reported equally in both treatment groups, events compatible with peptic ulcer disease predominating. Events associated with study termination appeared related to documented disease or protocol violations. Monitoring of laboratory data suggested no significant haematological or biochemical abnormalities in the nizatidine group. Nizatidine 300 mg nocte appears to be as effective as ranitidine 300 mg nocte in both ulcer healing and symptomatic response.

In well-established animal models, nizatidine is a potent, specific, and competitive orally active H2-receptor antagonist. In rat and dog models, species in which the absorption, plasma half-life and routes of metabolism are similar to that of humans, nizatidine was three- to four-fold more active than cimetidine and was of similar potency to ranitidine. On repeated daily dosing in dogs for two weeks, no tolerance was developed to the pharmacological action. Following oral dosing to dogs, nizatidine reduced gastric acid secretion for up to 8 h suggesting that this compound could be used in humans with a once or twice daily dosage regime. Apart from its H2-antagonist activity on the gastric mucosa, nizatidine produced few effects on the cardiovascular, respiratory, or central nervous system of animals. Nizatidine was rapidly and well-absorbed orally in mice, rats, and dogs, was widely distributed in tissues and the majority of the dose was excreted in the urine within 24 h. A similar absorption and excretion profile has been seen in humans. The plasma half-life in each of the animal species was between 1 and 2 h and no accumulation of nizatidine or its metabolites was seen in rats or dogs after daily oral administration for long periods. Similarities in the pharmacokinetic profile of nizatidine in the laboratory animals and humans supported the selection of the mouse, rat, and dog for acute and chronic toxicity studies. Nizatidine was well-tolerated in animals after both intravenous and oral administration and following single or repeated administration.(ABSTRACT TRUNCATED AT 250 WORDS)

A new H2-receptor antagonist, nizatidine (150 mg h.s.), was compared with placebo as maintenance therapy in a randomized, parallel, double-blind, one-year study of 513 patients with recently healed duodenal ulcer. Endoscopies were performed at 0, 3, 6, and 12 months and at unscheduled times if symptoms of active peptic ulcer disease were present. Cumulative ulcer recurrence rates for nizatidine and placebo were 13 versus 40% at 3 months, 24 versus 57% at 6 months, and 34 versus 64% at 12 months. The differences were significant (p less than 0.001) at each treatment period. Smokers in both treatment groups had significantly greater recurrence rates than non-smokers. Symptoms of peptic ulcer disease were significantly less in nizatidine-treated patients in the first 3 months of treatment. Adverse events, including those related to peptic ulcer disease, occurred more frequently in placebo-treated patients. Nizatidine proved to be safe and effective in preventing recurrences of duodenal ulcer.

Nizatidine, a new H2-receptor antagonist for the treatment of duodenal ulcer disease, was compared with placebo in a dose-response, double-blind, parallel, multicenter clinical trial. Patients were randomly allocated to receive either nizatidine (25 mg b.i.d., 150 mg b.i.d., or 300 mg at bedtime) or placebo. At the end of 4 weeks, patients whose ulcer had not healed were randomly reallocated to receive either the nizatidine 150 mg b.i.d. dosage regime or placebo for an additional 4 weeks. Nizatidine doses of 300 mg at bedtime and 150 mg b.i.d. demonstrated similar healing frequencies. Both of these doses were statistically significantly superior in ulcer healing to the nizatidine 25 mg b.i.d. dose and to placebo at the end of 4 weeks. Patients randomly reallocated to receive nizatidine had significantly greater healing rates than patients randomly reallocated to receive placebo. In summary, nizatidine given as a single evening dose of 300 mg or as 150 mg b.i.d. proved to be equally safe and effective in the healing of active duodenal ulcers.

The effect of two different H2-receptor antagonists, nizatidine and cimetidine, on sperm counts and hypothalamic-pituitary-gonadal function as determined by responses to provocative gonadotropin releasing factor, GnRH, thyrotropin releasing factor, TRH, and clomiphene were compared to those of men receiving placebo medication. All subjects studied gave informed written consent and were greater than 18 but less than 55 years of age. Sperm concentrations in collected semen specimens, and GnRH and TRH responses before and after 6 weeks of drug exposure were assessed as were the gonadotropin responses to clomiphene while on the drug for an additional 3 weeks. All had normal sperm concentrations and hormone levels before drug exposure and normal responses to both GnRH and TRH. Following drug exposure, the LH response to GnRH and the growth hormone, prolactin, TSH and T4 responses to TRH were similar to those obtained prior to drug use. Sperm concentrations were unchanged in both placebo and nizatidine exposed men, but were significantly reduced (p less than 0.05) in the cimetidine exposed men. Based on these data, nizatidine does not appear to influence hormone function or fertility.

Two hundred and seventy five patients from six countries were randomized into an endoscopically controlled, eight-week, double-blind, study. The objective of this investigation was to compare the efficacy and safety of nizatidine, administered as either a single (300 mg nocte) or twice daily (150 mg B.D.) dose, with ranitidine 150 mg twice daily, in the therapy of benign gastric ulceration. Two hundred and fifty-two patients fulfilled entry criteria and completed the protocol (80 nizatidine 150 mg B.D.; 89 nizatidine 300 mg nocte; 83 ranitidine 150 mg B.D.). Endoscopy was performed on entry and at four-week intervals until the ulcer healed. The diagnosis of benign ulceration was always supported by endoscopic histology and/or cytology. On entry into the study, both groups appeared well matched (i.e. for population demographics, duodenal ulcer history, previous therapy and pre-study symptomatology), except for epigastric day pain which was significantly less in the ranitidine group (p = 0.020). Overall gastric ulcer healing rates were similar in the three groups at four weeks (nizatidine B.D. 66.2%: nizatidine nocte 65.2%: ranitidine B.D. 63%) and at eight weeks (nizatidine B.D. 90%: nizatidine nocte 86.5%: ranitidine B.D. 86.7%). Healing was not consistently influenced by country of origin or smoking. After four weeks of therapy, 66% (nocte dose) to 68% (B.D. dose) of nizatidine treated patients were symptom free, while 93% (nocte dose) to 95% (B.D. dose) were free of night pain. Events were similar in the three treatment groups, and the majority were gastro-intestinal.(ABSTRACT TRUNCATED AT 250 WORDS)

An evening oral dose of nizatidine, a new H2-receptor antagonist, was tested for its ability to suppress nocturnal gastric acid secretion and to inhibit food stimulated acid secretion the following day. Using a double-blind, randomized, cross-over design, nizatidine 30, 100, and 300 mg and placebo were compared in 8 male subjects with basal acid secretion greater than or equal to 3 mmol/h. Continuous nasogastric suction was started 2 h after oral dosing, and acid secretion was measured hourly overnight. Phenol red was used to determine the completeness of gastric aspiration. The following day, food stimulated acid secretion in response to 8% peptone meals was measured by intragastric titration to determine the carry-over effect of nizatidine. Serum gastrin levels were measured by RIA. Nizatidine inhibited overnight acid secretion in a dose-related manner with 30, 100, and 300 mg producing 57, 73, and 90% suppression. The effect was long-lasting, with nizatidine 300 mg decreasing acid secretion by 52% 10 h after administration. Peptone stimulated acid secretion on the following day was not inhibited by nizatidine. Gastrin levels did not differ significantly among the treatment groups. Nizatidine's effects on nocturnal acid secretion therefore resemble other H2-receptor antagonists.