Alcohol sensitivity and smoking history in men and women.

Many studies have found genetic effects to contribute to alcoholism risk in both men and women. Based on preliminary evidence for shared genetic risk between smoking and drinking problems, a reanalysis of alcohol challenge data on 412 Australian twins was performed to explore the possibility that smoking may diminish or moderate the intoxicating effects of alcohol. We found history of smoking to be strongly associated with self-reported intoxication after alcohol challenge in women (women: r = -0.44 +/- 0.08; men: r = -0.21 +/- 0.08), comparable with self-reported average weekly consumption of alcohol, which was more strongly associated in men (women: r = -0.37 +/- 0.07; men: r = -0.54 +/- 0.06). Structural equation model-fitting indicated a strong association between heavy drinking and smoking, but the association between smoking and postalcohol intoxication remained even when the effects of heavy drinking were controlled for. These results prompt the question of whether smoking cigarettes directly influences the transition from moderate to excessive use of alcohol by diminishing feelings of alcohol intoxication.

A review of the hepatotoxicity of paracetamol at therapeutic or near-therapeutic dose levels, with particular reference to alcohol abusers.

The number of published reports associating hepatotoxicity with paracetamol ingestion at therapeutic or near-therapeutic dose levels is small but is, nevertheless, suggestive of a relationship. There is however, mounting evidence that certain groups of patients, such as alcohol-dependent people, patients receiving enzyme-inducing drugs (particularly anti-convulsant and anti-tuberculosis medications) as well as those with certain infectious diseases, are rendered more susceptible to paracetamol-induced hepatotoxicity. Seventy-four case reports where therapeutic or near-therapeutic doses of paracetamol resulted in hepatic injury are reviewed and factors and mechanisms which might explain this apparently increased vulnerability to damage are discussed.

Studies on the chronopharmacology of ethanol.

Male subjects (n = 10) were given ethanol (0.75 g/kg) at four equally spaced times in the 24 hr cycle (9 am, 3 pm, 9 pm 3 am) in random order. Blood ethanol concentrations were monitored by breath analysis and measurements were made of the blood or plasma levels of ethanol, acetaldehyde, acetate, pyruvate, lactate and cortisol. Blood pressure, heart rate and body temperature were measured before and at 60 and 120 min after ethanol administration and the effects of ethanol on a number of behavioural parameters and mood were studied. After ethanol ingestion, there was a significant decrease in body temperature, systolic blood pressure, plasma cortisol and pyruvate levels, whilst acetate levels and the lactate:pyruvate ratio were significantly increased. Standing steadiness, critical flicker fusion threshold and divided attention tracking control were significantly impaired under ethanol and self-report data indicated a significant decrease in alertness, co-ordination, concentration and attentiveness. Although a significantly higher peak blood ethanol concentration was attained at the 9 am session, other time-of-day differences did not reach significance and the pharmacokinetics of ethanol were essentially unchanged. Since the only significant diurnal variations in the response to ethanol identified in this study (apart from the subjective results) were for plasma cortisol concentrations and body temperature (both of which are well known to exhibit diurnal rhythmicity), it appears that major circadian variability in the metabolic and/or behavioural effects of ethanol is unlikely to occur.

Effects of increasing the rate of alcohol metabolism on plasma acetate concentration.

Plasma acetate concentration is increased during alcohol metabolism. However, measures which increase the rate of alcohol metabolism do not always increase plasma acetate concentration. Plasma samples from normal male subjects who had been given alcohol and then either fructose or glucose were analysed for acetate. Although each of these carbohydrates increased the mean rate of alcohol metabolism, only fructose increased the plasma acetate concentration. It was concluded that the further metabolism of acetate produced from alcohol may be increased by glucose.

The effect of fructose on alcohol metabolism and on the [lactate]/[pyruvate] ratio in man.

Ten male subjects were given alcohol by intravenous infusion and maintained at a constant blood alcohol level. The rate of alcohol metabolism was measured before and after an oral dose of fructose (100 g), as the amount of alcohol required to maintain the steady state. The mean rate of alcohol metabolism increased by 80% after fructose but there was considerable variation among the subjects, which was related to their plasma fructose concentrations. Blood lactate increased after fructose to a greater degree than blood pyruvate, resulting in a significant increase in [lactate]/[pyruvate] ratio. Since fructose increased the [lactate]/[pyruvate] ratio when it increased alcohol metabolism, the action of fructose cannot be explained by a decrease in the liver cytoplasmic [NADH]/[NAD] ratio and some other mechanism must be sought.

The effects of orally administered delta 9-tetrahydrocannabinol in man on mood and performance measures: a dose-response study.

A dose-response study of the effect of orally administered delta 9-tetrahydrocannabinol (THC) on human mood and skills performance was conducted. Using five dose levels of THC (0, 5, 10, 15, 20 mg) with 16 volunteers per dosage group, mood and performance measures were recorded at five testing occasions, one before and four after drug administration. The slope of the linear regression of performance on the test battery was significant for up to 200 minutes after dosage. That is to say, oral THC, at the doses used, produced significant dose-dependent impairment of performance for a period in excess of three hours. A similar time course for the effect of THC on the subjective assessment of intoxication ('stone') suggested a correlation between drug-induced impairment skills and the effects on mood.

Effect of diet on [lactate]/[pyruvate] ratios during alcohol metabolism in man.

Ten subjects received alcohol by intravenous infusion on two occasions, after five-day periods on high- or low-carbohydrate diets. Blood [lactate]/[pyruvate] ratios were significantly higher during fasting alcohol metabolism after the low-carbohydrate, high-fat diet. The carbohydrate/fat balance in the diet may affect cytoplasmic-mitochondrial NADH transfer. Dietary composition may modify the metabolic changes caused by alcohol.

Effect of oral glucose on the rate of metabolism of ethanol in humans.

We have tested whether the effect of carbohydrate on the rate of alcohol metabolism can be reproduced by glucose alone. Ten male subjects were given ethanol by intravenous infusion until a steady state was established and 100 g glucose in solution was then taken orally. The rate of alcohol metabolism, measured as the rate of infusion required to maintain a constant breath alcohol reading, increased significantly after glucose but there were differences between the subjects. The presence or absence of a change in the rate of alcohol metabolism after glucose was associated with the subject's fasting rate and with their glucose tolerance.

Differing effects of carbohydrate, fat and protein on the rate of ethanol metabolism.

The rate of metabolism of ethanol in humans has been assessed by intravenous infusion of ethanol/saline under feedback control to maintain a constant blood alcohol concentration. After equilibration, meals consisting predominantly of carbohydrate, fat or protein were eaten and changes in ethanol metabolic rate were found. Carbohydrate caused a significant increase in this rate and fat or protein caused small but non-significant decreases. Infusion of ethanol/saline resulted in a temporary fall in plasma free fatty acid levels and a steady rise in plasma triglycerides. The changes in alcohol metabolism following carbohydrate cannot be accounted for by changes in insulin, free fatty acid or lactate/pyruvate levels.

Studies on o-methylflavinantine.

The antinociceptive effects of O-methylflavinantine (OMF), a morphinandienone alkaloid, were investigated in the mouse hot plate and abdominal constriction tests (nociceptive agents: 5-Hydroxytryptamine, acetylcholine, bradykinin, prostaglandin, E (1) (PGE (1), formic acid and phenylquinone). The potency of OMF in the hot plate test was approximately 10 times less than that of morphine and the effect was naloxone reversible. In the abdominal constriction test, morphine was 78-650 times more potent than OMF, depending on the nociceptive agent used, but a higher dose of naloxone was necessary to reverse the response to formic acid. Pretreatment of mice with reserpine (1 mg/kg, s.c., 24 h) reduced and alpha-methyl-p-tyrosine (200 mg/kg, i.p., 3 h) potentiated the antinociceptive effects of both morphine and OMF in the hot plate test. The results are considered to indicate that OMF possesses centrally mediated antinociceptive activity which is similar to that of morphine.

Investigating drug--ethanol interactions.

Methodology developed in our laboratories for testing the interactive effects of ethanol and drugs on human psychomotor performance is discussed. An attempt has been made to relate the findings of our studies to the results of real-life impairment, particularly in traffic crashes. Proposals for more comprehensive testing of drug--ethanol interactions have been put forward which may increase the predictive value of such tests.

Involvement of catecholamines in acute tolerance to ethanol in mice.

The percentage of mice able to remain on a rolling drum for 45 s was recorded at 1.25 min and 30 min after administration of ethanol (2.4 g/kg). Though there was no significant difference in brain ethanol levels at the two test times, performance was markedly different with significantly fewer mice able to remain on the drum at 1.25 min than at 30 min. This phenomenon, known as acute tolerance, was antagonised by pretreating mice with haloperidol (0.4 mg/kg), FLA-63 (25 mg/kg), diethyldithiocarbamate (400 mg/kg), phenoxybenzamine (40 mg/kg), phentolamine (20 mg/kg), yohimbine (3 mg/kg) and clozapine (1 mg/kg), but not by spiperone (0.16 mg/kg), alpha-methyl-p-tyrosine (300 mg/kg) or phenobarbitone (10 mg/kg). The relative potencies of the effective blocking agents suggest that alpha 2-receptors may play an important role in mediating acute ethanol tolerance.