Dose-effect relationship of disulfiram in human volunteers. I: Clinical studies.

The aim of this study was to investigate the relation between Antabus dosage and the disulfiram-alcohol reaction (DAR) after ethanol challenge. Fifty-two healthy volunteers, 29 men and 23 women, aged 20-61 years, were treated with increasing doses of Antabuse (1, 100, 200, 300 mg) for 14 days each. At the end of each 14 days the volunteers were challenged with 0.15 g ethanol/kg body weight. Blood pressure, pulse rate, respiration rate, and symptoms such as flushing, heat sensation, nausea, vomiting, palpitations, breathlessness, and headache were monitored for the next 50 min. The volunteers left the study when they had experienced a valid DAR. A valid DAR, which was principally defined on the basis of the patients' feeling of discomfort, but for safety reasons also on the basis of unacceptable circulatory changes, was reached in 21 out of 52 volunteers after 100 mg Antabuse, in 27 after 200 mg, and in 4 after 300 mg. Most of them left the study after flushing and circulatory changes, but did not feel ill enough to be convinced that they should abstain from drinking. Ten volunteers with weak subjective symptoms, but with a valid DAR, were therefore rechallenged after the next increased dose and experienced a somewhat stronger reaction. We conclude that a daily dose of 200 mg Antabuse brings about a substantial reaction in volunteers in the presence of alcohol. The possible need for a 300 mg dose of Antabuse to prevent a patient from drinking was discussed.

Dose-effect relationship of disulfiram in human volunteers. II: A study of the relation between the disulfiram-alcohol reaction and plasma concentrations of acetaldehyde, diethyldithiocarbamic acid methyl ester, and erythrocyte aldehyde dehydrogenase activity.

The study was designed to elucidate the basic pharmacological and biochemical effects of the disulfiram dose (Antabus) provoking disulfiram-alcohol reaction (DAR) in 52 human volunteers after ethanol challenge. Disulfiram was given daily in increasing doses (1, 100, 200, and 300 mg) in successive 14 day periods, with ethanol challenge at the end of each period, until a DAR was achieved. Irrespective of dose (except the 1 mg dose), the DAR was always accompanied by almost complete inactivation (about 97%) of aldehyde dehydrogenase (ALDH) activity in erythrocytes, plasma concentrations of diethyldithiocarbamic acid methyl ester (Me-DDC) in the range of 8-472 nmol/l and accumulated plasma concentrations of acetaldehyde in the range of 7-197 mumol/l. In four of the volunteers, the cardiovascular effects of the DAR were recorded as a decrease in diastolic blood pressure (14-47 mmHg) and an increase in pulse rate (9-40 beats/min.), accompanied by a two- to fourfold increase in the plasma concentrations of adrenaline and noradrenaline. The enzyme kinetics of ALDH in erythrocytes were regularly analysed in eight volunteers during DSF intake. In addition to the expected decrease in oxidizing capacity, the Km values were also impaired, which suggests that the inhibitor is implicated in an active site directed reaction.

Side effects after disulfiram. Comparison of disulfiram and placebo in a double-blind multicentre study.

A double-blind, randomized study was carried out on the side effects of disulfiram in 241 men and women with alcohol abuse. Of the 158 patients completing the study, 83 received disulfiram and 75 placebo. Each patient was questioned on side effects after a 2-week wash-out period and thereafter once a week during the 6-week treatment period.. There was no statistically significant difference between the two groups, apart from over-representation of complaints of sexual problems in the placebo group. The patients who dropped out of the study were equally distributed between the two groups with regard to the number, diagnosis, and reasons for dropping out.

Treatment of benign essential hypertension with frusemide in different doses.

A double-blind, randomized, crossover trial was carried out in 26 hypertensive patients to investigate the hypotensive effects of three different dosages of frusemide (40 mg, 60 mg, and 80 mg twice daily) and the effects on serum potassium and urinary output. The study included a 4-week treatment period with placebo, three periods of 6 weeks with frusemide, and an intervening placebo period of 4 weeks. The mean arterial blood pressure fell about 10 mmHg within the first 2 weeks and was independent of the frusemide dosage. During the following weeks of treatment, there was a constant, slow fall in blood pressure. The period on placebo was too brief for values to return to the initial level. In contrast, the increase in urinary output, which was dose-dependent, ceased when medication was withdrawn. The diuretic effect was maintained throughout the treatment periods. There was a correlation between the fall in serum potassium and the diuretic effect whereas no correlation with the fall in blood pressure could be shown. Except for a significant increase in serum zinc, no changes were observed in other electrolyte parameters. Body weight, pulse, haemoglobin and erythrocyte sedimentation rate remained unchanged. Side-effects were few and mild, but tended to increase with higher doses.

Barbital and diazepam plasma levels during treatment of delirium tremens.

Plasma concentrations of barbital and diazepam were measured daily during a double-blind study of the efficacy of the two drugs in the treatment of delirium tremens and less severe clinical states. Treatment was estimated as satisfactory in the majority of cases; the present study deals with the satisfactory groups only. Both in the barbital group and in the diazepam group the same plasma level was seen in different clinical states. This result is discussed in relation to the theories about the aetiology of delirium tremens, and it is concluded that the data fits best with the assumption that delirium tremens is released from a withdrawal state, but once established, the delirious state is not interrupted by the drugs. The barbital concentrations were rather high, many at a level where non-alcoholics would show pronounced intoxication symptoms not seen in the present material. The diazepam concentrations on the other hand were low, often below a level where a cerebral effect is measurable in normal subjects. On this basis it is concluded, that the two drugs have different modes of action. Barbital may act by its cross-dependence properties with alcohol and thus diminish the withdrawal reaction, whereas diazepam may act by its anti-anxiety effect, but not in the doses here applied, by cross-dependence properties with alcohol. Finally, this hypothesis is discussed in relation to clinical experience in the treatment of delirium tremens.

Disposable plastic tray for large plate assays of antibiotics.

A new disposable plastic tray for large plate assays of antibiotics was compared with conventional trays with plate-glass bottoms, and was found to be entirely satisfactory.