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  • 1
    Electronic Resource
    Electronic Resource
    Diazepam actions and plasma concentrations following ethanol ingestion (1977)
    Springer
    European journal of clinical pharmacology 11 (1977), S. 345-349 
    Details
    ISSN: 1432-1041
    Keywords: Diazepam ; ethanol ; plasma levels ; interaction ; motor performance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In eight normal volunteers, the combination of ethanol (0.5 g/kg) and diazepam (10 mg) administered orally produced a greater decrease in motor performance on a pursuit rotor than diazepam alone. The pharmacologic effect of diazepam was enhanced by 73% and this potentiation was associated with significantly greater diazepam concentrations (p〈0.01) than after diazepam alone. The failure to observe any increase in the concentrations of the principal metabolite, N-desmethyl diazepam, during the period of enhanced pharmacologic effect precludes any change in the demethylating metabolic process as being responsible. The data suggest (0.10〉p〉0.05) a trend to a smaller volume of distribution of diazepam when ethanol is administered prior to diazepam ingestion. The subjects showed acute tolerance to the effects of diazepam. Lower plasma concentrations on the ascending side of the plasma diazepam concentration versus time profile were linked with the same pharmacologic responses associated with a greater drug concentration on the descending portion, of the same curve.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00566531
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  • 2
    Electronic Resource
    Electronic Resource
    Absorption of oral and intramuscular chlordiazepoxide (1978)
    Springer
    European journal of clinical pharmacology 13 (1978), S. 267-274 
    Details
    ISSN: 1432-1041
    Keywords: Chlordiazepoxide ; benzodiazepines ; pharmacokinetics ; bioavailability ; intramuscular injection ; alcohol withdrawal
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absorption of oral and intramuscular (i. m.) chlordiazepoxide hydrochloride (CDX · HCl) was compared in two pharmacokinetic studies. In Study One, single 50-mg doses of CDX · HCl were administered orally and by i. m. injection to 14 healthy volunteers using a crossover design. Whole-blood concentrations of chlordiazepoxide (CDX) and its first active metabolite, desmethylchlordiazepoxide (DMCDX), were determined in multiple samples drawn after the dose. Mean pharmacokinetic variables for CDX following oral and i. m. administration, respectively, were: highest measured blood concentration, 1.65 vs 0.87 µg/ml (p〈0.001); time of highest concentration, 2.3 vs 7.6 h after dosing (p〈0.001); apparent absorption half-life, 0.71 vs 3.39 h (p〈0.001). Biphasic absorption after i. m. injection, consistent with precipitation at the injection site, was observed in 9 of 14 subjects. Based upon comparison with previous intravenous data, the completeness of absorption was 100% for oral vs 86% for i. m. CDX · HCl (p〈0.1). In Study Two, 28 male chronic alcoholics with clinical manifestations of the acute alcohol withdrawal syndrome were randomly assigned to one of four treatment conditions: 50 or 100 mg doses of CDX · HCl, by mouth or by i. m. injection. Concentrations of CDX and DMCDX, determined in plasma samples drawn every 20 min for 5 h following the dose, were significantly higher after oral administration of a given dose than at corresponding points in time after i.m. injection after the same dose. Thus absorption of oral CDX is reasonably rapid and complete, whereas the absorption rate of i. m. CDX is slow.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00716362
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  • 3
    Electronic Resource
    Electronic Resource
    Ethanol-induced inhibition of hepatic uptake of propranolol in perfused rat liver and in man (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 209-215 
    Details
    ISSN: 1432-1041
    Keywords: propranolol ; hepatic drug disposition ; rat liver perfusion ; pharmacokinetics in man ; heart rate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Studies were conducted to determine the mechanism whereby ethanol alters the hepatic disposition of propranolol. In eight isolated perfused rat livers, ethanol ( $$\bar x$$ =40.1 mmol/l diminished the clearance of dl-propranolol (1.93±0.43 to 1.24±0.22 ml/min/g liver, p〈0.05); increased its t1/2 (12.8±1.5 to 20.7±3.25 min, p〈0.01); and decreased the proportion metabolized (68.7±4.7% to 34.3±10.3%, p〈0.01). These results suggest that ethanol could substantially increase the oral bioavailability of propranolol in humans. However, in normal human volunteers administered 80 mg of propranolol orally, alone, or preceded and followed by ethanol to maintain breath ethanol concentrations of 800–1000 mg/l, increases in propranolol AUC were smaller than anticipated. Seven subjects had increases in free propranolol AUC0–8h (32%, range: 12–61%) (p〈0.05), while total propranolol AUC0–8h increased by a mean 22% (range: −4–+49%). Propranolol free fraction varied with time and was higher after ethanol ( $$\bar x$$ =0.090 vs 0.084) (p〈0.077). The extent of the propranolol-induced slowing of heart rate was not influenced by ethanol (mean decrease from baseline of 13 bpm at peak propranolol effect vs 9 bpm without ethanol); mean heart rates following propranolol with ethanol were higher at all times (mean of 7.5 bpm) (p〈0.001) than after propranolol alone. Ethanol inhibits the hepatic oxidative metabolism of propranolol in vitro; however, any effect on heart rate of higher concentrations of propranolol induced by ethanol in humans is off-set by the cardio-acceleratory effect of ethanol.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00544047
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  • 4
    Electronic Resource
    Electronic Resource
    The ambiguity of adverse drug reactions (1977)
    Springer
    European journal of clinical pharmacology 11 (1977), S. 75-78 
    Details
    ISSN: 1432-1041
    Keywords: Adverse drug effects ; evaluation untoward clinical events ; divergent clinical judgement
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Three clinical pharmacologists independently evaluated 500 untoward clinical events reported by physicians as adverse drug reactions (ADRs). They often disagreed with the reporting physicians and with each other. They judged 14.4–28.2% of the events to be definite, 26.4–38.0% probable, 21.4–31.0% possible and 15.8–28.2% unlikely ADRs. In their opinion 19.1–32.4% of the drugs blamed were definitely, 29.8–34.4% probably, 24.9–36.7% possibly and 8.4–14.5% not responsible for the adverse reactions. Evaluators disagreed among themselves about the drug most likely to have been responsible in 36.4% of the events, about ADRs causing hospital admission in 56.8%, about severe ADR morbidity in 55.8%, about ADR prolongation of hospitalization in 67.3% and about ADR contribution to death in 71.0%. The divergence of judgements suggests that suspected ADRs are usually ambiguous clinical events, and that incidence, severity, medical consequences and cost of ADRs can only be estimated.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00562895
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  • 5
    Electronic Resource
    Electronic Resource
    Amitriptyline and ethanol: Pharmacokinetic and pharmacodynamic interaction (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 325-331 
    Details
    ISSN: 1432-1041
    Keywords: amitriptyline ; ethanol ; pharmacokinetic interaction ; plasma concentrations ; psychomotor skills ; nortriptyline
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Amitriptyline has clinically important interactions with ethanol. Five healthy volunteers received 25 mg of amitriptyline orally, preceded by one hour and followed for eight hours by oral ethanol (or juice), dosed to achieve and maintain blood ethanol concentrations of 800 mg/l. In the presence of ethanol, amitriptyline free plasma concentrations were increased by a logarithmic mean of 204%, 186% and 127% at 1.5, 2, and 2.5 h, respectively, and amitriptyline free AUC0–8h was increased by 48%±13% ( $$\bar x$$ ± SEM) (t=5.21,p〈0.01). Nortriptyline total AUC0–8h was increased by 26.6%±12% ( $$\bar x$$ ± SEM) (t=2.21,p〈0.09). At the time of peak amitriptyline plasma concentrations, mean postural sway was increased over baseline by 92% with, and 2% without ethanol; likewise, mean short term memory (word recall) was decreased over baseline by 71% with, and 37% without ethanol. Ethanol increases free amitriptyline plasma concentrations most dramatically during the period of drug absorption; this is due to a decrease in amitriptyline hepatic clearance, resulting in decreased first-pass extraction. Together with the pharmacodynamic interaction, the kinetic changes provide a rationale for the toxicity of this combination and its deleterious effects on psychomotor skills.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01037943
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  • 6
    Electronic Resource
    Electronic Resource
    Kinetic and dynamic interactions of oral viqualine and ethanol in man (1989)
    Springer
    European journal of clinical pharmacology 36 (1989), S. 93-96 
    Details
    ISSN: 1432-1041
    Keywords: viqualine ; ethanol ; 5-hydroxytryptamine uptake inhibitors ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the interaction of viqualine, a 5-hydroxytryptamine (5-HT) uptake inhibitor, with ethanol in 16 healthy men aged 20 to 34 years. The subjects were randomly assigned to receive ethanol dosed to maintain blood alcohol concentrations of 17–22 mmol · l−1 (n=8) or orange juice (n=8) on each of two test days one week apart and preceded, in random order, by 3 days of viqualine 75 mg bd or placebo. Ethanol had no effect on steady-state viqualine concentrations or the inhibition of 5-HT uptake. Viqualine did not affect acetaldehyde concentrations or cause an aversive alcohol-sensitizing reaction. The deleterious effects of ethanol on word recall, manual tracking, body sway, and self-ratings of intoxication, sedation, and performance were not modified by the presence of viqualine. Within each beverage group performances and self-ratings on viqualine and placebo days were not different. The first dose of viqualine was associated with transient nausea. Viqualine and ethanol do not interact kinetically or dynamically on the variables examined in this study.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00561033
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  • 7
    Electronic Resource
    Electronic Resource
    Effect of cimetidine and ranitidine on the hepatic and renal elimination of nicotine in humans (1990)
    Springer
    European journal of clinical pharmacology 38 (1990), S. 165-169 
    Details
    ISSN: 1432-1041
    Keywords: nicotine ; cimetidine ; ranitidine ; pharmacokinetics ; H2-receptor antagonists ; hepatic oxidation ; renal secretion ; tobacco smoking ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a randomized, double-blind, cross-over experiment, 6 healthy consenting male subjects were administered cimetidine 600 mg or ranitidine 300 mg or placebo p.o. q12h×2 days. Nicotine bitartrate was administered i.v. on day 2 (1 ug/kg/min)×30 min. After cimetidine mean nicotine total and metabolic clearances were decreased by 30% and 27% while after ranitidine the clearances were decreased by 10% and 7% respectively. Since smokers regulate their smoke intake based in large part on their nicotine blood levels these results suggest that the diminished nicotine total clearance in the presence of cimetidine could be important in assisting smoking reduction or cessation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00265978
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  • 8
    Electronic Resource
    Electronic Resource
    Disposition of intravenous diazepam in young men and women (1981)
    Springer
    European journal of clinical pharmacology 20 (1981), S. 207-213 
    Details
    ISSN: 1432-1041
    Keywords: diazepam ; benzodiazepines ; N-desmethyldiazepam ; plasma ; saliva ; pharmacokinetics ; pharmacodynamics ; psychomotor ; impairment ; oral contraceptives
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of a single intravenous dose of diazepam (10 mg) was studied in 11 young, healthy subjects (6 males and 5 females on oral contraceptives). Plasma samples were obtained over 28 days and diazepam and N-desmethyldiazepam plasma concentrations and diazepam free fractions were determined. The salivary excretion of diazepam and N-desmethyldiazepam was studied over 72 h. A series of psychomotor performance tests were administered over the first 8 h. Interindividual variation in mean diazepam disposition over time is not principally related to variation in plasma protein binding; 93% of the variation in clearance is accounted for by variation in intrinsic clearance. Interindividual variation in diazepam disposition is modest but the plasma clearance of diazepam in women on oral contraceptives (median 14.0 ml/min) is significantly (p=0.004) less than in men (median 23.4 ml/min) and the area under the curve (AUC) of diazepam is highly correlated with the AUC of the principal active metabolite (r=0.90, p〈0.001). The AUC of N-desmethyldiazepam (median 9.2 µg·h/ml) in women is greater (p=0.06) than in men (median 7.5 µg·h/ml). On chronic administration of diazepam, therefore, women taking oral contraceptives will have greater plasma concentrations per unit dose of both diazepam and N-desmethyldiazepam than men. The clearance of diazepam in control groups of 11 young men (median 23.8 ml/min) and 10 young women not taking oral contraceptives (median 26.8 ml/min) is not significantly different. Plasma and salivary concentratrions of diazepam are correlated (p〈0.001) but the predictive value of this correlation is limited (r=0.70) since the ratio of salivary to plasma concentrations varies significantly over the day. The use of calculated free diazepam plasma concentrations does not improve the correlation (r=0.68) but the slope of this regression (1.00) is that predicted by theory.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00544599
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  • 9
    Electronic Resource
    Electronic Resource
    Lack of effect of cimetidine on cigarette smoking (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 51-55 
    Details
    ISSN: 1432-1041
    Keywords: Cigarette smoking ; Cimetidine ; nicotine regulation ; nicotine elimination ; nicotine kinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The efficacy of cimetidine as a treatment that could reduce smoking in heavily dependent smokers has been determined. In a randomised, double-blind, double-crossover experiment, 43 heavy smokers were divided into two groups, one receiving cimetidine 400 mg orally three times a day, and the other receiving placebo for two weeks followed by the alternative treatment (placebo or cimetidine). No significant difference in the mean alveolar carbon monoxide, nicotine or cotinine levels was found between the two treatment groups compared to baseline. Since the alveolar carbon monoxide level reflects the intensity of smoking behaviour, the results suggest that no change in smoking behaviour occurred in the subjects. Contrary to our previous findings that cimetidine decreased the total body clearance of nicotine by 30% in a population of non-smokers, in the heavily dependent smokers, cimetidine did not appear to alter nicotine elimination. One possible explanation for the discrepancy is that tobacco smoking is known to induce nicotine metabolism and the induction might have offset any effect of cimetidine on nicotine elimination. Cimetidine does not appear to be a useful treatment leading to a reduction or cessation of cigarette smoking.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315280
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  • 10
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    Absorption of oral and intramuscular chlordiazepoxide (1978)
    Springer
    Details
    Publication Date: 1978-01-01
    Print ISSN: 0031-6970
    Electronic ISSN: 1432-1041
    Topics: Chemistry and Pharmacology , Medicine
    Published by Springer
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