K. Aranko

A potentially hazardous interaction between erythromycin and midazolam

Interaction between erythromycin and midazolam was investigated in two double‐blind, randomized, crossover studies. In the first study, 12 healthy volunteers were given 500 mg erythromycin three times a day or placebo for 1 week. On the sixth day, the subjects ingested 15 mg midazolam. In the second study, midazolam (0.05 mg/kg) was given intravenously to six of the same subjects, after similar pre‐treatments. Plasma samples were collected, and psychomotor performance was measured. Erythromycin increased the area under the midazolam concentration–time curve after oral intake more than four times (p <0.001) and reduced clearance of intravenously administered midazolam by 54% (p <0.05). In psychomotor tests (e.g., saccadic eye movements), the interaction between erythromycin and orally administered midazolam was statistically significant (p <0.05) from 15 minutes to 6 hours. Metabolism of both erythromycin and midazolam by the same cytochrome P450IIIA isozyme may explain the observed pharmacokinetic interaction. Prescription of midazolam for patients receiving erythromycin should be avoided or the dose of midazolam should be reduced by 50% to 75%.

Effects of alcohol on buspirone and lorazepam actions

Psychomotor and psychologic effects of single doses of buspirone (10 and 20 mg) and lorazepam (2.5 mg) alone or combined with alcohol (1 gm/kg) were investigated in 12 healthy young men. crossover study in 12 healthy young men. Lorazepam alone impaired psychomotor skills (tracking, body balance, extraocular muscle balance, and flicker recognition), the effects being maximal at 180 min. This impairment was not subjectively perceived by the subjects. Neither dose of buspirone alone impaired objective measurements, although buspirone, especially in the 20‐mg dose, was felt to cause drowsiness, weakness, and faintness. Lorazepam, but not buspirone, interacted with alcohol.

Anxiogenic effects in benzodiazepine withdrawal are linked to the development of tolerance

Rats were tested in the elevated plus-maze test of anxiety after a probe injection of chlordiazepoxide (CDP 5 mg/kg) following short-term (5 days) or long-term (20 days) pretreatment with 5 or 20 mg/kg/day. After short-term pretreatment with either dose, the probe dose had anxiolytic effects (it increased the % number of entries, and % of time spent, on the open arms). After long-term pretreatment with either dose of CDP there was tolerance to these effects. When the rats were tested 24 hours after their last dose of CDP, there was no indication of spontaneous withdrawal responses in the rats from the short-term pretreatment groups, but the rats in the long-term pretreatment groups showed increased anxiety (decreases in the % number of entries, and the % of time spent, on the open arms, compared with controls). These results support suggestions that the development of tolerance and the incidence of withdrawal anxiety may both be manifestations of the underlying changes occurring during drug dependence.

A pharmacokinetic interaction between roxithromycin and midazolam.

The interaction between roxithromycin and midazolam was investigated in a double-blind, randomised crossover study of two phases. Ten healthy volunteers were given roxithromycin (300 mg) or placebo once daily for 6 days. On the sixth day they ingested 15 mg midazolam. Plasma samples were collected and psychomotor performance measured for 17 h.Roxithromycin administration significantly increased the area under the plasma midazolam concentration-time curve from 8.3 to 12.2 ώg·ml−1·min and the elimination half-lives from 1.7 to 2.2 h. In psychomotor performance only minor differences were seen between the treatments in one of the measured psychomotor parameters.Thus, in contrast to the strong interaction between erythromycin and midazolam, the interaction between roxithromycin and midazolam appears less likely to be clinically significant.

Interaction of diazepam or lorazepam with alcohol

SummaryNine healthy volunteers in a double-blind, cross-over trial received diazepam (DZ) 10 mg, lorazepam (LZ) 2.5 mg, or placebo (P). Serum benzodiazepine (BZ) was bioassayed (radioreceptor method) and psychomotor tests were carried out on Day 1 (before and 1 h after the first dose) and on Day 4 (before and after the fifth dose). In each session alcohol 1 g/kg was administered 1.5 h after drug intake and the measurements were repeated twice. Serum BZ concentrations, expressed as DZ equivalents (µg/l), ranged from 390 to 440 and from 990 to 1240 measured 2 h 45 min after the first doses of DZ and LZ, respectively. On Day 1 BZ alone impaired psychomotor skills. LZ affected performance more in objective tests, but DZ was subjectively rated as causing more drowsiness. After the intake of alcohol, all groups showed impairment in various tests. The rank order was LZ+alcohol>DZ+alcohol>P+alcohol. Residual BZ activity on Day 4, measured 18 h after the fourth dose, averaged 290 and 450 µg/l after DZ and LZ, respectively. At the same time slight residual exophoria was found after both BZs. Tolerance to BZs on Day 4 was unambiguous only when drug effects were related to the bioassayed serum levels. The combined action of BZs and alcohol was similar on Days 1 and 4. However, a tendency to an increased drug-alcohol interaction during advanced treatment with DZ was seen in the body sway test. An attempt to clarify the very different serum BZ level after DZ and LZ was made in vitro by evaluating the displacement curves for DZ and LZ standards. The potencies of these BZs differed more in the presence than in the absence of serum. Thus, the psychomotor effects of DZ and LZ, as well as their BZ receptor occupation activity in serum, were not equipotent at doses 10 mg DZ and 2.5 mg LZ. The BZ-alcohol interaction was consistent at least over the first 5 doses.

Sodium Valproate and Chlordiazepoxide in the Elevated Plus-Maze Test of Anxiety in the Rat

The effects of sodium valproate (25-200 mg/kg i.p.) were investigated in the elevated plus-maze test of anxiety in the rat. No single dose significantly increased the percentage of entries made onto the open arms. Chlordiazepoxide (5 mg/kg) both acutely and after 5 days of administration significantly increased the percentage of entries onto open arms and this anxiolytic effect was neither potentiated, nor antagonised, by sodium valproate (25-200 mg/kg). Chlordiazepoxide also increased the total number of arm entries (indicating a stimulant effect). When valproate (25-100 mg/kg) was given together with acute chlordiazepoxide it produced a dose-related antagonism of this stimulant effect. The group receiving valproate (200 mg/kg) plus acute chlordiazepoxide (5 mg/kg) had a total number of entries significantly lower than the controls. Thus, the combination of 2 non-sedative doses resulted in a significant sedative effect.

Effect of food on the bioavailability of oxybutynin from a controlled release tablet.

Objective: The effect of food on the bioavailability of oxybutynin was assessed in a randomised cross-over study in 23 healthy volunteers. A single oral 10 mg dose of a controlled release oxybutynin tablet was administered after a high fat breakfast and to fasting subjects. The AUC, Cmax, tmax, t1/2 and MRT of oxybutynin and its active metabolite N-desethyloxybutynin were determined.Results: Breakfast did not change the AUC of oxybutynin but increased the AUC of N-desethyloxybutynin by about 20% . The Cmax of oxybutynin and N-desethyl oxybutynin were two-fold higher when the drug was administered after breakfast compared to the fasting state.Conclusion: Breakfast significantly reduced the MRT of oxybutynin and N-desethyloxybutynin.

Itraconazole moderately increases serum concentrations of oxybutynin but does not affect those of the active metabolite

AbstractObjective: Oxybutynin has low oral bioavailability due to an extensive presystemic metabolism. It has been suggested that the biotransformation of oxybutynin is dependent on CYP3A. Because itraconazole, a widely used mycotic, is a potent inhibitor of CYP3A4, we wanted to study a possible interaction between oxybutynin and itraconazole. Methods: In this double-blind, randomized, two-phase cross-over study, ten healthy volunteers received either 200 mg itraconazole or placebo for 4 days. On day 4, each volunteer ingested a single dose of 5 mg oxybutynin. Serum concentrations of oxybutynin, its active metabolite N-desethyloxybutynin, and itraconazole were monitored over 24 h. Results: Itraconazole significantly increased both the area under the serum drug concentration-time curve (AUC0–t) and the peak concentration of oxybutynin twofold. The AUC0–t and the peak concentration of N-desethyloxybutynin were not significantly affected by itraconazole. Itraconazole did not change the peak time or the elimination half-life of either oxybutynin or N-desethyloxybutynin. The occurrence of adverse events after oxybutynin administration was not increased by itraconazole. Conclusions: Itraconazole moderately increases serum concentrations of oxybutynin, probably by inhibiting the CYP3A-mediated metabolism. However, the concentrations of N-desethyloxybutynin were practically unchanged. Since about 90% of the antimuscarinic activity of oxybutynin is attributable to N-desethyloxybutynin, any interaction of oxybutynin with CYP3A4 inhibiting drugs has only minor clinical significance.

Objective and subjective assessments of the effects of flupentixol and benzodiazepines on human psychomotor performance.

The aim of this double-blind crossover trial was to compare the objective and subjective effects of flupentixol and lorazepam on human performance, and to reveal possible interactions between flupentixol and diazepam. Twelve healthy students received at 1-week intervals oral single doses of flupentixol 1 mg, flupentixol 2 mg, lorazepam 2.5 mg, placebo, and diazepam 15 mg alone and with flupentixol 1 mg. After the baseline measurements, the drugs were given in capsule form, and the tests were repeated 1.5, 3 and 4.5 h later. Diazepam was given at 1.5 h, to time its peak effect to coincide with that of lorazepam. Drug effects were measured objectively (two tracking tests, digit substitution, letter cancellation, flicker fusion, Maddox wing, tapping, memory) and subjectively (visual analogue scales, questionnaire). Blood samples were taken after each test time. Flupentixol 1 mg did not differ from placebo objectively or subjectively. Flupentixol 2 mg proved nearly inert objectively and on visual analogue scales. Lorazepam impaired objectively measured test performance, the clearest effects occurring at 3 and 4.5 h. It also impaired subjectively assessed performance. Diazepam impaired objective performance less than lorazepam, its effects peaking at 1.5 h after intake. Diazepam caused subjective drowsiness, clumsiness, mental slowness etc. as much as or more than lorazepam. The combination of 1 mg flupentixol and diazepam modified performance as much as diazepam alone. After the administration of 1 mg flupentixol, plasma concentrations were undetectable and levels after 2 mg were hardly detectable. Concentrations of lorazepam exceeded those of diazepam in direct bioassay, but they were much lower when bioassayed after solvent extraction. Flupentixol 1 mg did not modify plasma diazepam levels. The clinical anxiolytic effects of lorazepam and flupentixol have not been compared directly, but we conclude that recommended anxiolytic doses of flupentixol have no or negligible influence on psychomotor performance while lorazepam does impair performance. No relevant interaction between 1 mg flupentixol and diazepam was detected.

Sodium valproate decreases exploratory behaviour in mice: development of tolerance and cross-tolerance with chlordiazepoxide

Sodium valproate (400 mg/kg) significantly reduced exploratory head-dipping in mice, without significant reductions in locomotor activity or rearing. After 5 daily injections of sodium valproate (50 or 400 mg/kg) there was tolerance to the effects of a test dose of 400 mg/kg. Pretreatment for 5 days with chlordiazepoxide (5 mg/kg) did not change the effects of sodium valproate (400 mg/kg), but 5 days pretreatment with chlordiazepoxide (20 mg/kg) did produce cross-tolerance. Sodium valproate (50 mg/kg) was without significant effect acutely, or after 5 days of pretreatment with sodium valproate (50 or 400 mg/kg) or chlordiazepoxide (5 or 20 mg/kg). Daily injections of the benzodiazepine antagonist, flumazenil (10 mg/kg), immediately after the daily injection of sodium valproate (400 mg/kg) or chlordiazepoxide (20 mg/kg) did not prevent the development of tolerance or cross-tolerance. This suggests that benzodiazepine receptors may not mediate these phenomena; possible roles of GABA and 5-HT are also discussed.