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Biomedical subjects

K Aranko

Publications and source records attributed to K Aranko.

At least 19 recordsLinked to original sources
PubMed1997

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

OBJECTIVE: 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.

Adolescent↗
PubMed1997

Effect of time interval between food and drug ingestion on the absorption of oxybutynin from a controlled-release tablet.

The effect of time interval between food and drug ingestion on the bioavailability of oxybutynin was investigated in a randomized, three-phase cross-over study in 31 healthy volunteers. The serum concentrations of oxybutynin and the metabolite, N-desethyloxybutynin were measured up to 48 hr after ingestion of a controlled-release 10 mg oxybutynin tablet either in fasting state, 2 hr after breakfast or 1 hr before. The Cmax of both oxybutynin (P < 0.0001) and N-desethyloxybutynin (P < 0.0001) and the AUC0-1 of N-desethyloxybutynin (P < 0.05) were significantly larger when oxybutynin was ingested 2 hr after breakfast, than during the fasting, but the AUC0-1 of oxybutynin remained unchanged. Breakfast ingested 1 hr after oxybutynin did not affect the pharmacokinetic parameters of oxybutynin or N-desethyloxybutynin. The saliva secretion rate decreased slightly more (P < 0.05), when oxybutynin was administered 2 hr after breakfast than during fasting. The effect of food ingestion on the serum concentrations of oxybutynin and N-desethyloxybutynin is expected to have minor clinical significance only. However, ingestion of the controlled-release tablet 1 hr before meal increases the likelihood of obtaining constant drug levels with lower peak concentrations during the dosage interval, and thus ingestion of the controlled-release tablet 0.5-1 hr before food may well improve tolerability and compliance in patients who suffer from adverse reactions.

Adult↗
PubMed1996

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-desethyloxybutynin 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.

Adult↗
PubMed1994

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 micrograms.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.

Adult↗
PubMed1994

Dose of midazolam should be reduced during diltiazem and verapamil treatments.

1. The effects of diltiazem and verapamil on the pharmacokinetics and pharmacodynamics of midazolam were investigated in a double-blind randomized cross-over study of three phases. 2. Nine healthy volunteers were given orally diltiazem (60 mg), verapamil (80 mg) or placebo three times daily for 2 days. On the second day they received a 15 mg oral dose of midazolam, after which plasma samples were collected and performance tests carried out for 17 h. 3. The area under the midazolam concentration-time curve was increased from 12 +/- 1 microgram ml-1 min to 45 +/- 5 micrograms ml-1 min by diltiazem (P < 0.001) and to 35 +/- 5 micrograms ml-1 min by verapamil (P < 0.001). The peak midazolam concentration was doubled (P < 0.01) and the elimination half-life of midazolam prolonged (P < 0.05) by both diltiazem and verapamil treatments. 4. These changes in the pharmacokinetics of midazolam were also associated with profound and prolonged sedative effects. 5. If the administration of midazolam cannot be avoided, the dose of midazolam should be reduced during concomitant treatment with diltiazem and verapamil.

Administration, Oral↗
PubMed1994

The effect of erythromycin on the pharmacokinetics and pharmacodynamics of zopiclone.

1. The effect of erythromycin on the pharmacokinetics and pharmacodynamics of oral zopiclone, a non-benzodiazepine hypnotic, was investigated in a double-blind, cross-over study. 2. Ten healthy volunteers were given placebo or 500 mg erythromycin orally three times a day for 6 days followed by an oral dose of 7.5 mg zopiclone. 3. Erythromycin increased plasma zopiclone concentration by 4-fold at 0.5 h (P < 0.05) and by 2-fold at 1 h (P < 0.05). There were increases of 3- and 2-fold in the AUC(0,1 h) and AUC(0,2 h) values (P < 0.05). The total AUC of zopiclone increased by 80% (P < 0.05) but the peak concentration by only 40% (P < 0.05). The peak time of zopiclone concentration was reduced from 2 to 1 h (P < 0.001). 4. Significant pharmacodynamic differences between the treatments were observed from 0.5 h to 2 h with respect to saccadic latency and digit symbol substitution tests. 5. The interaction between erythromycin and zopiclone resulted mainly in accelerated absorption which may lead to a faster hypnotic effect in patients.

Administration, Oral↗
PubMed1993

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 pretreatments. 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%.

Administration, Oral↗
PubMed1993

Diazepam effects on the performance of healthy subjects are not enhanced by treatment with the antihistamine ebastine.

1. We have given 12 healthy subjects the H1-antihistamine ebastine (20 mg) or placebo in a randomized double-blind and crossover study for 1 week each. The subjects were tested for drug effects on day 6 of each period, and for interactions of ebastine with oral 15 mg diazepam (DZ) on day 7. On both days, the testing runs were at baseline and 1.5, 3, 4.5 and 6 h after intake. 2. The performance was evaluated both objectively (digit symbol substitution, flicker fusion, Maddox wing, simulated driving, body balance) and subjectively (visual analogue scales, questionnaires). Venous blood was sampled daily during the maintenance and during each testing round for the assay of plasma carebastine (the active metabolite of ebastine) by high pressure liquid chromatography and plasma diazepam by radioreceptor assay. Three-way ANOVA, paired t-test, Wilcoxon rank sign test and Fisher's fourfold table test were used for data analysis. 3. Plasma carebastine reached steady levels from day 3 onwards. The mean concentrations in the morning were 82 micrograms l-1 on day 6 and 85 micrograms l-1 on day 7. The rise (+ 150%) in plasma carebastine after an extra 20 mg ebastine was not modified by DZ. Ebastine did not affect performance objectively or subjectively, yet borderline drowsiness was recorded during the first 3 h. On day 7, plasma DZ concentrations peaked (mean 480 micrograms l-1) at 1.5 h after the intake. DZ produced impaired performance in various objective tests, and drowsiness, weakness, clumsiness, mental slowness and poor performance were reported on visual analogue scales.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1993

Ethanol inhibits melatonin secretion in healthy volunteers in a dose-dependent randomized double blind cross-over study.

To elucidate the effects of alcohol on pineal rhythmicity, ethanol was administered in the evening in amounts usually consumed during social ingestion to nine healthy volunteers in a double blind, cross-over study. Plasma concentrations of melatonin, catecholamines (norepinephrine and epinephrine), and ethanol were measured by RIA, high pressure liquid chromatography, and gas chromatography before and for 12 h after the administration of 0, 0.5, and 1 g ethanol/kg wt. Plasma melatonin and catecholamines displayed expected diurnal rhythms, with peak values at 0300-0400 h for melatonin and trough values at 0100-0400 h for catecholamines. Intake of ethanol between 1900-1945 h inhibited the nocturnal melatonin secretion dose-dependently during the first half of the night, with no changes in urinary excretion of melatonin. The inhibition was 41% (P < 0.05) from the control at midnight for both ethanol doses, 33% (P < 0.05) at 0100 h, and 18% (P < 0.05) at 0200 h for the higher dose. In addition, the higher dose of ethanol increased plasma norepinephrine levels at 2000 and 2200 h (P < 0.01) until 0400 h (P < 0.05). Taking into account the involvement of melatonin in the regulation of sleep and diurnal rhythms, we suggest that ethanol-induced suppression of nocturnal melatonin secretion and an increase in noradrenergic activity may be closely associated with disturbances in sleep and performance.

Adult↗
PubMed1991

Misuse of zopiclone and convulsions during withdrawal.

It has been documented that benzodiazepines have the potential to cause dependence and withdrawal reactions, including convulsions. However, the available data concerning zopiclone, a nonbenzodiazepine hypnotic, are insufficient. The present study describes the case of a 36-year-old man who repeatedly misused zopiclone, in daily doses of 60-90 mg. Furthermore, the patient suffered from convulsion on two occasions following abrupt withdrawal of zopiclone. The concomitant use of alcohol, trimipramine, and promazine may have contributed to the development of convulsions. It is concluded that zopiclone may cause problems associated with misuse and withdrawal reactions similar to those of benzodiazepines.

Adult↗
PubMed1991

A survey of sudden death associated with the use of antipsychotic or antidepressant drugs: 49 cases in Finland.

Phenothiazines have repeatedly been found to be associated with cases of sudden death, but the issue of causality has remained controversial. A survey of medicolegal autopsies performed in Finland over a 3-year period revealed that sudden unexpected deaths of 31 women (mean age 44 years, range 25-69) and 18 men (mean age 40 years, range 26-62) were associated with either the use of antipsychotic or antidepressant drugs. Therapeutic use of phenothiazines was documented in all but 3 of these 49 cases and thioridazine was involved in over half of them. Thus, whereas thioridazine was the only antipsychotic drug associated with 15 cases, only 5 cases were associated with any of the other antipsychotic or antidepressant drugs. The differences between the subgroups of psychotropic drugs remained clear after adjustment according to the respective data on drug use in the population. Although there are several uncontrolled confounding factors, the overrepresentation of phenothiazines, especially thioridazine, among psychiatric patients who died suddenly is striking and, taken together with their well-established arrhythmogenic effects, warrants further attention.

Adult↗
PubMed1990

Actions of zopiclone and carbamazepine, alone and in combination, on human skilled performance in laboratory and clinical tests.

1. Possible interactions of zopiclone and carbamazepine on human skilled performance were studied in a randomized, double-blind, crossover trial with 12 healthy young subjects. 2. Psychomotor performance (coordination, reactions, attention, cognition) and subjective effects (VAS) were measured and venous blood sampled before and 1.5, 3, 4.5 and 6 h after single oral doses of placebo, 7.5 mg of zopiclone and 600 mg of carbamazepine, which were given alone or combined. Clinical test for drunkenness (CTD) was done 2 and 5 h after drug intake. 3. Both zopiclone and carbamazepine, when administered alone, impaired performance on laboratory tests, the decrements being recorded 1.5 to 6 h after intake. In line with the plasma concentrations, the zopiclone effects peaked earlier (at 1.5 h) and lasted for a shorter time than those of carbamazepine. Zopiclone had a more pronounced effect on perceptual and cognitive functions (digit substitution) and it affected extraocular muscle tone (Maddox wing), whereas carbamazepine had stronger effects on attention. Additive pharmacodynamic actions were found in most tests after the combined treatment with zopiclone and carbamazepine. 4. CTD proved to be less sensitive than the laboratory tests in revealing drug-induced decrement of performance after administration of one agent alone. However, it revealed the combined decremental effects of zopiclone and carbamazepine. 5. When the drugs were given together, the absorption of drugs was retarded. Carbamazepine-10,11-epoxide levels were lower after intake of the drug combination than those measured after intake of carbamazepine alone. 6. The results suggest that the clinical tests developed to detect alcohol effects do not necessarily reveal drug-induced impairment of performance.

Adult↗
PubMed1989

Diazepam reverses the effects of pentylenetetrazole in rat pups by acting at type 2 benzodiazepine receptors.

Pentylenetetrazole (75 mg/kg) induced a characteristic coarse body tremor (accompanied by limb extension) and hyperactivity in 4-day-old rat pups. These effects were reversed by diazepam (0.5 and 2 mg/kg) but not by CL 218,872 (10 and 20 mg/kg) which is selective for type 1 benzodiazepine receptors. Diazepam did not affect the brain concentrations of pentylenetrazole, indicating that the reversal was not based on a pharmacokinetic interaction. Neither diazepam nor CL 218,872 had significant effects on the behavior of the rat pups, although diazepam (2 mg/kg) tended to increase locomotor activity. The results suggest that diazepam displays an anticonvulsant effect in the neonatal rat which is mediated by type 2 receptors.

Animals↗
PubMed1988

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.

Animals↗
PubMed1988

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.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

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.

Animals↗