Alosetron relieves pain and improves bowel function compared with mebeverine in female nonconstipated irritable bowel syndrome patients.

BACKGROUND: Irritable bowel syndrome is one of the most common gastrointestinal disorders, yet no therapy convincingly controls the multiple symptoms of this syndrome. AIM: To compare the efficacy and tolerability of the new 5-HT3-receptor antagonist alosetron and the smooth muscle relaxant mebeverine in a double-blind, multicentre, randomized trial. METHODS: Six hundred and twenty-three nonconstipated females with irritable bowel syndrome were randomized to receive alosetron 1 mg twice daily (n=319) or mebeverine 135 mg three times daily (n=304) for 12 weeks, followed by a 4-week post-treatment period. The primary efficacy end-point was monthly responders for adequate relief of irritable bowel syndrome related abdominal pain and discomfort (defined as patients reporting adequate relief on at least 2 out of 4 weeks). Secondary end-points included assessments of bowel function, including urgency, stool frequency and stool consistency. RESULTS: There were significantly more responders in the alosetron group compared with mebeverine at months 2 and 3 (P < 0.01). Compared with mebeverine, the alosetron group experienced significant decreases in proportion of days with urgency and mean stool frequency, and had firmer stools within 1 week of starting treatment. A similar proportion of patients reported adverse events in the two treatment groups. CONCLUSIONS: In nonconstipated female irritable bowel syndrome patients, alosetron is significantly more effective than mebeverine in improving symptoms.

A prospective randomised controlled study of the use of ranitidine in patients with gastric cancer. Yorkshire GI Tumour Group.

BACKGROUND: Does the use of the histamine H2 receptor antagonist ranitidine improve the outcome of patients with gastric cancer? PATIENTS: A total of 222 patients with gastric cancer who had received radical or palliative resection or who were deemed inoperable at presentation. SETTING: Hospitals within Yorkshire, the participating clinicians being members of the Yorkshire GI Tumour Group. METHODS: A multicentre prospective randomised double blind trial comparing ranitidine 150 mg twice daily with placebo twice daily was undertaken. The principal outcome measures were survival and survival excluding those who died within 30 days of operation. RESULTS: The median survival (95% confidence intervals) was 331 (232 to 393) days for patients in the ranitidine group compared with 187 (143 to 269) for those in the placebo group. The difference in survival was not statistically significant (p = 0.225). When patients who died within 30 days of operation were excluded (21 in the placebo group, 15 in the ranitidine group), the difference in survival remained not significant (p = 0.358). No subgroup could be identified who significantly benefited from treatment, but for patients with stage VIa cancer the median survival was 134 days with placebo compared with 313 days with ranitidine (p = 0.073). CONCLUSION: This study does not show significant benefit from the use of ranitidine for gastric cancer but further larger studies may be indicated.

Use of a novel electronic data collection system in multicenter studies of irritable bowel syndrome.

BACKGROUND: The reliability of symptom data collected during efficacy studies in irritable bowel syndrome (IBS) is paramount to the proper assessment of potential therapeutic agents. Historically, data have been collected on paper diary cards, which patients were requested to fill out at a specified interval. However, with paper diary cards it is not possible to determine whether the cards are filled out as required, or at random times. To circumvent this problem, a novel electronic data collection system that ensures the reliability and security of data entry was used. METHODS: Data were collected from 640 patients during the 2-week screening and 12-week treatment phases of two multicentre trials of IBS. The electronic data collection system used was based upon a touchtone telephone system. RESULTS: The electronic data collection system had a potential 8135 up-time hours during the study. An up-time of 8040 h and down-time of 95 h was observed. This corresponds to an up-time of approximately 99%. Patient compliance for data entry in the two studies was 81% and 83%, respectively. On a single random day during their daily telephone call, patients were asked questions to assess satisfaction with the system. On aggregate, 79% of patients were satisfied or very satisfied with the system, only 10% were dissatisfied or very dissatisfied. CONCLUSION: A unique electronic data collection system was tested for use in clinical studies in IBS. This system provided 100% reliability as to the date of data entry, and data were not subject to modification once entered. This methodology represents a marked advancement in clinical studies of IBS.

Association of age with the efficacy and safety of ranitidine and cimetidine in acute duodenal ulcer disease.

This multinational double-blind trial compared the efficacy and safety of ranitidine 300 mg nocte, 300 mg post-evening meal (pem) and cimetidine 800 mg nocte in patients with endoscopically verified duodenal ulcer disease aged < 60 years (n = 1318) and > or = 60 years (n = 354). The relative efficacy of the treatments was not dependent upon age after either 2 or 4 weeks of therapy. However, ulcer healing after 2 weeks of therapy was significantly higher in patients receiving ranitidine 300 mg pem than in those receiving cimetidine (p = 0.003) in the < 60-year group, but the difference was not significant in the > or = 60-year group. Fewer patients aged > or = 60 years on cimetidine (62%) became pain free compared with those on ranitidine (72% in both groups). Relief of epigastric pain and heartburn was related to pre-trial severity in both age groups. The incidence and type of adverse events were similar in the two age groups. It is concluded that ranitidine and cimetidine are as effective at healing duodenal ulcer and relieving ulcer symptoms in elderly as in younger patients.

Early evening dosing of ranitidine. Comparison with nighttime dosing of ranitidine or cimetidine in duodenal ulceration.

A double-blind multinational comparison of ranitidine 300 mg post evening meal (pem), ranitidine 300 mg nocte and cimetidine 800 mg nocte has been carried out in 1677 patients with endoscopically verified duodenal ulcer disease. Fifty-three percent of ulers healed by two weeks during treatment with ranitidine 300 mg pem and 88% by four weeks, while the results for ranitidine 300 mg nocte were 50% and 86%, respectively, and 44% and 84% for cimetidine. The difference between ranitidine 300 mg pem and cimetidine was significant at two weeks (P = 0.002, Mantel-Haenszel chi-squared test). The relative efficacy of the treatments was not dependent upon gender, smoking habit, alcohol intake, or ulcer frequency. However, the overall differences in healing between patients with small and large ulcers and patients with single and multiple ulcers were significantly different at weeks 2 and 4 (P < 0.001). Significantly more patients treated with ranitidine (60%) had complete relief of epigastric pain than those treated with cimetidine (54%) (P < 0.05). A meta-analysis of the four double-blind comparisons of ranitidine 300 mg pem (N = 841) and 300 mg nocte (N = 849), including the present study, failed to show the benefits of pem dosing, predicted from pharmacological studies.

Ranitidine in the treatment of gastric and duodenal ulcers associated with non-steroidal anti-inflammatory drugs.

To assess the effect of 4 weeks' therapy with ranitidine 150 mg twice daily on the healing of symptomatic NSAID-associated gastric and duodenal ulcers, 149 arthritic patients were randomly allocated to one of three treatment groups: ranitidine with NSAID continued, ranitidine with NSAID discontinued, and placebo with NSAID discontinued. The healing frequency in patients with gastric ulceration was 67, 68 and 47%, and in those with duodenal ulceration 61, 81 and 42%, respectively. Only the difference between the duodenal ulcer healing rates for ranitidine with NSAID discontinued and placebo was statistically significant (P = 0.02). Healing rates were uninfluenced by gender, age, smoking habits, alcohol consumption, ulcer frequency or size, arthritic disease, or participating country.

Prevention of gastroduodenal damage induced by non-steroidal anti-inflammatory drugs: controlled trial of ranitidine.

OBJECTIVE: To evaluate the prophylactic effect of ranitidine 150 mg twice daily in patients requiring one of the following non-steroidal anti-inflammatory drugs: naproxen, piroxicam, diclofenac, and indomethacin. In addition, risk factors were studied in order to help in targeting of such treatment to specific groups of patients. DESIGN: Double blind, placebo controlled, randomised, parallel group with endoscopic assessments at 0, 4, and 8 weeks. SETTING: Multicentre outpatient study at secondary referral centres in five European countries. PATIENTS--297 patients with rheumatoid arthritis or osteoarthritis over the age of 18 without lesions in the stomach and duodenum at baseline endoscopy (after one week without taking non-steroidal anti-inflammatory drugs). Those taking other antirheumatic agents, concomitant ulcerogenic drugs, or treatment for peptic ulcers within the previous 30 days were excluded. Age, sex, arthritic disease, and type of non-steroidal anti-inflammatory drug used were comparable in the two treatment groups. In all, 263 patients completed the trial. INTERVENTIONS: Ranitidine 150 mg twice daily or placebo (plus the selected non-steroidal anti-inflammatory drug) was prescribed within five days after the baseline endoscopy for two consecutive periods of four weeks. Paracetamol was permitted during the study, but not antacids. Patients were withdrawn if the most severe grade of damage (including ulceration) was found at the four week endoscopy or when indicated, or with lesser damage at the investigator's discretion. END POINT: Frequency of gastric and duodenal ulceration or lesions, or both. MEASUREMENTS AND MAIN RESULTS: The cumulative incidence of peptic ulceration by eight weeks was 10.3% (27/263); 2 out of 135 (1.5%) developed duodenal ulceration in the ranitidine group, compared with 10 out of 126 (8%) taking placebo. The frequency of gastric ulceration was the same (6%) for the two groups at eight weeks. Though significantly fewer gastric lesions developed in the ranitidine group by eight weeks. The frequency of non-ulcerative lesions in the duodenum did not differ greatly for the two groups at either time point. Twelve out of 75 (16%) patients taking piroxicam developed peptic ulceration, of whom two thirds had duodenal ulceration. Patients with a history of peptic ulcer were particularly susceptible to recurrent ulceration, against which ranitidine offered some protection. CONCLUSIONS: Ranitidine 150 mg twice daily significantly reduced the incidence of duodenal ulceration but not gastric ulceration when prescribed concomitantly with one of four commonly used non-steroidal anti-inflammatory drugs.

A single night time dose of ranitidine in the acute treatment of gastric ulcer: a European multicentre trial.

Four hundred and twenty eight patients with endoscopically diagnosed gastric ulcers, randomly allocated to treatment with ranitidine 300 mg at night or ranitidine 150 mg twice daily, were evaluated in a double blind multicentre trial conducted in 10 European countries. After four weeks, complete ulcer healing was observed in 138 of 211 patients (65%) treated with ranitidine 300 mg nocte and in 155 of 217 patients (71%) receiving 150 mg bd. Cumulative healing rates at eight weeks were 90% and 93%, respectively. There was no statistically significant difference between the healing rates at either four or eight weeks. The treatment regimens were equally effective at rapidly reducing the incidence of ulcer related symptoms. Adverse events reported were minor and equally distributed between the two groups. The results of this trial show that 300 mg of ranitidine administered at night is an effective and safe alternative to the current twice daily regimen for the short term treatment of gastric ulcer.

The effect of bromazepam (Lexotan) administration on antipyrine pharmacokinetics in humans.

Six healthy volunteers were given a standard regimen of bromazepam (Lexotan) (6 mg t.d.s.) for five days. Compliance with the study protocol was demonstrated by measuring drug concentrations at steady state. Steady-state levels of 3-hydroxybromazepam were also determined. These were found to be much lower than the concentrations of bromazepam. Since the metabolite is known to be less active than the parent drug, it is likely that the metabolic will contribute little to the pharmacological effects of the drug in humans. Antipyrine pharmacokinetics were studied immediately before bromazepam administration was started, after the dosing schedule had been completed and one week after dosing had been discontinued. There were no significant changes in the disposition of antipyrine on any occasion. Therefore, although previous studies have demonstrated enzyme induction in laboratory animals given high doses of bromazepam, similar effects are unlikely to occur in humans being treated with therapeutic doses of the compound.

A comparison of diclofensine and desmethylimipramine using tyramine pressor tests in normal subjects.

Eight male volunteers received placebo, diclofensine 25 mg, diclofensine 50 mg and desmethylimipramine (DMI) 50 mg at least a week apart. Using tyramine pressor tests, no statistically significant differences between the noradrenaline reuptake blocking effects of the three active treatments could be demonstrated. Visual analogue rating scales showed an increase in dryness of the mouth at 3 h after DMI but no similar effect after either dose of diclofensine.

A clinical pharmacological comparison of diclofensine (Ro 8-4650) with nomifensine and amitriptyline in normal human volunteers.

1 Ten healthy male volunteers participated in a double-blind placebo-controlled crossover comparison of the pharmacodynamic profiles of single oral doses of diclofensine 25 mg and 50 mg, nomifensine 75 mg and amitriptyline 50 mg. 2 Diclofensine did not influence salivary flow or consistently affect pupil diameter and had no significant effect on subjective measurements of sedation and mood. It had no effect on reaction time, or on critical flicker frequency. 3 By contrast, amitriptyline significantly reduced salivary flow, produced significant sedation and impairment of mood, prolonged reaction time, and appeared to decrease (but not significantly) critical flicker frequency. 4 Nomifensine significantly reduced (i.e. improved) reaction time, and inhibited salivary flow. 5 Diclofensine did not significantly influence heart rate, blood pressure, systolic time intervals or high speed electrocardiogram. 6 No significant treatment-related differences were observed in serum prolactin, cortisol or growth hormone levels.

A double-blind crossover study of diazepam rectal suppositories, 5 mg and 10 mg, for sedation in patients with advanced malignant disease.

The efficacy of diazepam suppositories as sedatives was investigated in anxious patients with defined advanced malignant disease. Twenty-four patients, age range 54 to 89 years (mean 72 years) with a mean weight of 52 kg, were randomly allocated 5 mg or 10 mg diazepam suppositories for 5 nights each in a crossover fashion, with a 2-day drug-free washout period in between. Sleep was rated daily as 'well', 'same' or 'badly' by the night nurse and by the patient. The majority of patients slept well while taking diazepam, with no apparent difference between the two doses. The most common side-effects reported were day-time drowsiness (58% of patients), dry mouth (29%) and amnesia (21%). No adverse reaction necessitated premature withdrawal from the study. Results indicated that diazepam suppositories were well tolerated and appeared to provide effective night-time sedation in anxious patients with terminal cancer.

Platelet monoamine uptake in relatives of patients with Huntington's chorea.

Uptake of dopamine and 5-hydroxytryptamine (5-HT) by the platelets of 25 symptom-free relatives of patients with established Huntington's chorea (HC) was not significantly different from that of control subjects. Platelet uptake of 5-HT in 3 subjects with early signs of the disease showed increased Km and Vmax values. Increased platelet uptake of 5-HT in patients with established HC was confirmed in a further 3 patients. It seems that this phenomenon appears with the clinical evidence of the disease. Further investigation of the nature of the platelet uptake abnormality may cast light on pathogenic factors in HC.

A comparison of the pharmacodynamic profiles of nomifensine and amitriptyline in normal subjects.

1 Six healthy male volunteers participated in a double-blind placebo crossover comparison of the pharmacodynamic profiles of single oral doses of 75 mg nomifensine and 50 mg amitriptyline. 2 Nomifensine treatment did not influence salivary flow and did not significantly affect psychomotor performance (critical flicker fusion, pursuit rotor and reaction time): in addition nomifensine had no significant effect on subjective measurements of sedation and concentration. 3 By contrast, amitriptyline treatment significantly reduced salivary flow and was associated with significant sedation and reduced concentration: significant changes in psychomotor performance were also noted. 4 Plasma concentrations of amitriptyline and nomifensine were measured at 2 h. The respective median concentration values were 55.0 ng/ml and 52.0 ng/ml. 5 Ex vivo platelet amine uptake of dopamine (DA) and 5-hydroxytryptamine (5HT) was measured 2 h after each treatment. Both nomifensine and amitriptyline treatment significantly inhibited DA uptake to a similar extent. Amitriptyline treatment additionally inhibited 5-HT uptake.

Uptake of 5-hydroxytryptamine and dopamine into platelets from depressed patients and normal subjects--influence of clomipramine, desmethylclomipramine and maprotiline.

Platelet uptake of 5-hydroxytryptamine (5-HT) and dopamine (DA) in normal subjects in vitro has already been shown to be significantly inhibited by clomipramine and less markedly by maprotiline (Turner and Ehsanullah, 1977). This effect has now been studied in greater detail, in patients categorized as having endogenous or neurotic/reactive depression, treated or untreated, and in normal volunteers, in whom the inhibitory activity of the metabolite desmethylclomipramine was also studied. Platelet uptake of 5-HT and DA in both types of depression is lower than in healthy, which supports the hypothesis that central monamine function is reduced or impaired in depressives. Clomipramine potently inhibits platelet uptake of DA as well as 5-HT, its antidepressant action cannot be attributed to 5-HT alone, while the observation that maprotiline has no effect on 5-HT uptake shows that its antidepressant action is not based on a serotonergic mechanism. Desmethylclomipramine has a marked inhibitory effect on platelet 5-HT uptake and its effect on DA uptake is greater than that of the parent compound.

Platelet uptake of 5-hydroxytryptamine and dopamine and its relationship to mood in normal subjects.

Platelet uptake of the amines 5-hydroxytryptamine (5-HT) and dopamine has been found to be lower in depressed than in normal subjects. In the latter the values were more scattered. To discover whether this scatter was due to mild depression or predisposition to depression, 50 normal subjects whose amine uptake had been studied were asked to complete a questionnaire on symptoms and history of depression. No significant correlation between decreased amine uptake and answers to the questionnaire was found, but a correlation of minor significance (r=0.33; P less than 0.025) was found between increased number of potentially depressing life events and increased 5-HT uptake, contrary to what might have been expected. The scatter of values for amine uptake does not appear to be related to mood, or to personal or family history of depression.

Influence of ciclazindol on monoamine uptake and CNS function in normal subjects.

The potential antidepressant drug ciclazindol inhibited dopamine uptake into human platelets without affecting 5-hydroxytryptamine uptake as compared with a control. It inhibited the tyramine pressor response less than desipramine after single 50-mg oral doses in 6 healthy volunteers under double-blind conditions. Compared with tandamine in a double-blind placebo-controlled study in nine healthy subjects, ciclazindol 50 mg orally caused no significant anticholinergic effects but reduced appetite according to an analysis of variance. Nonparametric analysis did not confirm the anorectic effect. Previous studies had shown that ciclazindol increased glucose uptake into isolated human skeletal muscle independently of insulin. Overall, ciclazindol resembles the antiobesity drug mazindol in molecular structure and pharmacological effects in man. Interactions with sympathomimetic amines and adrenergic neurone-blocking drugs cannot be excluded on the basis of these studies.

Uptake of dopamine and 5-hydroxytryptamine by platelets of patients with Parkinsonism.

The uptake of tritiated dopamine and 5-hydroxytryptamine by platelets from 11 patients with Parkinsonism who were not receiving any medication, and from 11 control subjects matched for sex and for age within a decade was compared. No significant differences were found in the uptake of either amine. Our findings, therefore, provide no support for the belief that there is a generalised defect of dopamine systems in Parkinson's disease.