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Biomedical subjects

P J Neuvonen

Publications and source records attributed to P J Neuvonen.

At least 19 recordsLinked to original sources
PubMed1996

Rifampin drastically reduces plasma concentrations and effects of oral midazolam.

BACKGROUND: Midazolam is a short-acting benzodiazepine that is metabolized by CYP3A enzymes. Rifampin is a potent enzyme inducer that may seriously interact with some substrates of CYP3A4. METHODS: The possible interaction between rifampin and midazolam was investigated in a double-blind, randomized crossover study of two phases. Rifampin (600 mg once daily) or placebo was administered to 10 healthy subjects for 5 days. On the sixth day, the subjects were given 15 mg oral midazolam. Plasma samples were collected for determination of midazolam, and pharmacodynamic effects were measured for 10 hours. RESULTS: Rifampin pretreatment decreased the area under the plasma midazolam concentration-time curve by 96% (i.e., from 10.2 +/- 0.8 to 0.42 +/- 0.05 micrograms.min/ml [mean +/- SEM; p < 0.001]) and the maximum concentration by 94% (i.e., from 55 +/- 4 to 3.5 +/- 0.7 ng/ml [p < 0.001]). The elimination half-life of midazolam was decreased from 3.1 +/- 0.2 to 1.3 +/- 0.2 hours by rifampin (p < 0.001). During the rifampin phase, the pharmacodynamic effects of midazolam were markedly smaller than the effects during the placebo phase in all the tests (e.g., the Digit Symbol Substitution Test; p < 0.001). CONCLUSIONS: The observed substantial decrease in plasma concentrations and effects of midazolam most likely results from induction of CYP3A4 by rifampin in both the gut wall and the liver. Orally administered midazolam is ineffective during rifampin treatment.

Administration, Oral↗
PubMed1996

Diltiazem enhances the effects of triazolam by inhibiting its metabolism.

BACKGROUND: Triazolam is metabolized by CYP3A4. Diltiazem is an inhibitor of this isozyme and interacts with midazolam, another substrate of this enzyme. Therefore the possible interaction between triazolam and diltiazem is worth investigation. METHODS: A balanced, randomized, double-blind crossover study design was used, with an interval of 2 weeks between phases. Ten healthy volunteers were given 60 mg diltiazem orally or placebo three times a day for 2 days. On the second day they received a single 0.25 mg oral dose of triazolam, after which plasma samples were collected and effects of triazolam measured for up to 17 hours. RESULTS: Diltiazem increased the mean area under the triazolam concentration-time curve threefold (p < 0.001) and the elimination half-life (p < 0.001) and the peak plasma concentration of triazolam twofold (p < 0.005). The increased concentrations of triazolam during the diltiazem phase were associated with increased and prolonged pharmacodynamic effects. CONCLUSIONS: Diltiazem has a clinically significant interaction with oral triazolam. The data is highly suggestive that diltiazem inhibits the metabolism of triazolam during the first-pass and elimination phases. Prescription of triazolam should be avoided if a patient is using diltiazem or other potent inhibitors of CYP3A.

Administration, Oral↗
PubMed1996

Itraconazole drastically increases plasma concentrations of lovastatin and lovastatin acid.

BACKGROUND: Lovastatin is a cholesterol-lowering drug that can cause myopathy as a rare side effect. Concomitant use of certain drugs (e.g., cyclosporine) increases the risk of skeletal muscle toxicity. Lovastatin is metabolized by CYP3A4. Because itraconazole is a potent inhibitor of CYP3A4, we wanted to study a possible interaction between these drugs. METHODS: In this double-blind, randomized, two-phase crossover study, 12 healthy volunteers received either 200 mg itraconazole or placebo orally once a day for 4 days. On day 4, each subject ingested a single 40 mg dose of lovastatin. Plasma concentrations of lovastatin, lovastatin acid, itraconazole, hydroxyitraconazole, and creatine kinase were measured up to 24 hours. RESULTS: On average, itraconazole increased the peak concentration (Cmax) of lovastatin and the area under the lovastatin concentration-time curve (AUC) more than twentyfold (p < 0.001). The mean Cmax of the active metabolite, lovastatin acid, was increased 13-fold (range, tenfold to 23-fold; p < 0.001) and the AUC(0-24) twentyfold (p < 0.001). In one subject plasma creatine kinase was increased tenfold within 24 hours of lovastatin administration during the itraconazole phase but not during the placebo phase. No increase in creatine kinase was observed in the other subjects. CONCLUSIONS: Itraconazole greatly increases plasma concentrations of lovastatin and lovastatin acid. Inhibition of CYP3A4-mediated metabolism probably explains the increased toxicity of lovastatin caused not only by itraconazole but also by cyclosporine, erythromycin, and other inhibitors of CYP3A4. Their concomitant use with lovastatin and simvastatin should be avoided, or the dose of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors should be reduced accordingly.

Adult↗
PubMed1996

Fluconazole, but not terbinafine, enhances the effects of triazolam by inhibiting its metabolism.

1. The interaction between triazolam and two antifungal agents, fluconazole and terbinafine, was investigated in a double-blind, randomized crossover study of three phases. 2. Twelve healthy young volunteers received 100 mg fluconazole, 250 mg terbinafine or placebo orally once a day for 4 days. On day 4 they took a single 0.25 mg dose of triazolam. Plasma samples were collected and pharmacodynamic effects were measured up to 17 h after the intake of triazolam. 3. Fluconazole increased the area under the triazolam concentration time-curve more than twofold (P < 0.001) and prolonged the elimination half-life of triazolam nearly twofold (P < 0.001). The peak concentration of triazolam was also increased significantly (P < 0.05) by fluconazole. 4. During the fluconazole phase pharmacodynamic effects of triazolam (e.g. digit symbol substitution test, body sway and drowsiness) were enhanced significantly (P < 0.05) when compared with the placebo phase. 5. Terbinafine did not change significantly the pharmacokinetics or pharmacodynamics of triazolam. 6. Care should be taken when triazolam is prescribed to patients using fluconazole. Although the interaction is not as strong as that of triazolam with ketoconazole or itraconazole, it is clinically significant. Triazolam and probably other drugs metabolized by CYP3A4 can be used in normal doses with terbinafine.

Administration, Oral↗
PubMed1996

The effects of the systemic antimycotics, itraconazole and fluconazole, on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam.

We studied the interaction of azole antimycotics with intravenous (IV) and oral midazolam using a cross-over design in 12 volunteers, who ingested placebo, itraconazole, or fluconazole for 6 days. A 7.5-mg dose of midazolam was ingested on the first day, 0.05 mg/kg was administered IV on the fourth day, and 7.5 mg orally on the sixth day. Itraconazole reduced the clearance of IV midazolam by 69% and fluconazole reduced the clearance of IV midazolam by 51% (P < 0.001). A single dose of itraconazole and fluconazole increased the area under the oral midazolam concentration-time curve [AUC(0-infinity)] 3.5-fold (P < 0.001) and the peak concentration two-fold (P < 0.05) compared to placebo. On the sixth day the AUC(0-infinity) of oral midazolam was almost seven times greater with itraconazole (P < 0.001) and 3.6 times greater with fluconazole (P < 0.001) than without the antimycotics. The psychomotor effects of midazolam were also profoundly increased (P < 0.001). The psychomotor tests demonstrated only a weak interaction between the antimycotics and IV midazolam. When bolus doses of midazolam are given for short- time sedation, the effect of midazolam is not increased to a clinically significant degree by itraconazole and fluconazole, and it can be used in normal doses. However, the use of large doses of IV midazolam increases the risk of clinically significant interactions also after IV midazolam. Use of oral midazolam with itraconazole and fluconazole should be avoided.

Administration, Oral↗
PubMed1996

Lack of effect of antimycotic itraconazole on the pharmacokinetics or pharmacodynamics of temazepam.

The azole antimycotics itraconazole and ketoconazole are potent and relatively nonspecific inhibitors of cytochrome P450 enzymes and have a potentially dangerous interaction with midazolam and triazolam. The possible interaction between itraconazole and a short-acting benzodiazepine, temazepam, was investigated in a double-blind, randomized crossover study. Ten healthy volunteers were given placebo or 200 mg itraconazole a day orally for 4 days. The challenge dose of 20 mg of temazepam was ingested on the fourth day, after which plasma samples were collected, and psychomotor performance tests were carried out for 24 h. Despite a statistically significant small increase of the area under the temazepam concentration-time curve, there was no clinically significant interaction, as determined by the psychomotor performance tests. The different metabolic pathways and the lack of significant firstpass metabolism of temazepam explain the great difference in the interaction potential of temazepam compared with midazolam and triazolam. Temazepam, unlike midazolam and triazolam, can be prescribed in usual doses for patients receiving itraconazole and other inhibitors of P450 3A4.

Adolescent↗
PubMed1996

Concentrations and effects of oral midazolam are greatly reduced in patients treated with carbamazepine or phenytoin.

Midazolam is a short-acting benzodiazepine which is used as an oral hypnotic agent in several countries. We studied the pharmacokinetic and pharmacodynamic aspects of an oral 15-mg dose of midazolam in 6 patients with epilepsy who are also taking carbamazepine (CBZ) or phenytoin (PHT). We compared results with those obtained in 7 noninduced control subjects. Plasma concentrations and effects of midazolam were measured for 10 h. In patients with epilepsy, the area under the plasma concentration-time curve (AUC) of midazolam (mean +/- SEM) was only 5.7% (0.60 +/- 0.16 vs. 10.5 +/- 0.6 microgram x min/ml), and the peak midazolam concentration was 7.4% (5.2 +/- 1.2 vs. 70.4 +/- 9.0 ng/ml) of its value in control subjects (p < 0.001). The elimination half-life (t l/2) of midazolam was 1.3 +/- 0.2 h in patients and 3.1 +/- 0.1 h in controls (p < 0.001). The low plasma midazolam concentrations in the patient group were associated with reduced pharmacodynamic effects as compared with control subjects [e.g., the Critical Flicker Fusion Test (CFFT), p < 0.05]. Induction of CYP3A (cytochrome P-450IIIA) enzymes by CBZ and PHT is the most likely explanation of the great difference in the pharmacokinetic and pharmacodynamic profiles of oral midazolam in the two groups.

Administration, Oral↗
PubMed1995

Plasma concentrations of triazolam are increased by concomitant ingestion of grapefruit juice.

BACKGROUND: Grapefruit juice increases the bioavailability of several drugs known to be metabolized by CYP3A enzymes. Ketoconazole and itraconazole can increase the area under the concentration-time curve [AUC(0-infinity)] of triazolam, a substrate of CYP3A, by more than twenty times. METHODS: In this randomized crossover study the effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of triazolam was investigated. Ten healthy young subjects received a single 0.25 mg dose of triazolam with either 250 ml grapefruit juice or water. Plasma concentrations and effects of triazolam were measured up to 17 hours. RESULTS: Grapefruit juice increased the AUC(0-infinity) of triazolam in each subject and the peak concentration in nine of the 10 subjects. The mean AUC(0-infinity) of triazolam was increased 1.5-fold (p < 0.001) and the peak concentration was increased 1.3-fold (p < 0.05) by grapefruit juice. Grapefruit juice postponed the peak time of triazolam from 1.6 hours to 2.5 hours (p < 0.05). Grapefruit juice increased the effects of triazolam slightly; drowsiness was significantly (p < 0.05) enhanced. CONCLUSIONS: Grapefruit juice can increase the plasma concentrations and effects of oral triazolam.

Administration, Oral↗
PubMed1995

Interaction between erythromycin and nitrazepam in healthy volunteers.

Interaction between erythromycin, a strong inhibitor of CYP3A4, and nitrazepam, a long-acting benzodiazepine, was investigated in a double-blind and randomized cross-over study of two phases. Ten healthy volunteers received erythromycin (500 mg x 3) orally or placebo for 6 days. On the fourth day they were given a challenge dose of 5 mg nitrazepam. Plasma samples were collected and psychomotor effects were measured during 42 hr after intake of nitrazepam. There was a statistically significant pharmacokinetic interaction between erythromycin and nitrazepam. Erythromycin increased the area under the nitrazepam concentration-time curve by 25% (P < 0.05) and the peak concentration by 30% (P < 0.05). The concentration peak time of nitrazepam was shortened by over 50% (P < 0.05). The elimination half-lives did not change. Accordingly, as far as the metabolism of nitrazepam is concerned, erythromycin does not cause any major changes in the metabolism of nitrazepam. In psychomotor performance only minor differences were seen. It is concluded that the interaction between erythromycin and nitrazepam is of little clinical significance.

Absorption↗
PubMed1995

Azithromycin does not increase plasma concentrations of oral midazolam.

Interaction between azithromycin and midazolam was investigated in a double-blind, randomized crossover study of 2 phases. Ten healthy volunteers were given azithromycin (500 mg on day 1 and 250 mg on days 2-5) or placebo pretreatments. On day 5 they ingested 15 mg midazolam. Plasma samples were collected and psychomotor performance measured for 17 h. Azithromycin treatment increased the median (range) concentration peak time of midazolam from 1.0 (0.5-2) h to 1.25 (0.5-5) h and decreased plasma concentrations of midazolam during initial 3 hours after the intake of midazolam (p < 0.05). Mean +/- SE mean peak concentration of midazolam was decreased from 86 +/- 17 ng ml-1 to 57 +/- 9 ng ml-1 (p < 0.05). Azithromycin did neither increase the total area under concentration-time curve nor change the elimination half-life of midazolam. In Maddox wing test the maximum effects of midazolam were reached later during azithromycin phase, but no other changes were observed in pharmacodynamics of midazolam. Azithromycin may delay the absorption of midazolam, which can postpone the onset of action of midazolam.

Administration, Oral↗
PubMed1995

Effect of itraconazole and terbinafine on the pharmacokinetics and pharmacodynamics of midazolam in healthy volunteers.

Twelve healthy volunteers were given orally placebo, itraconazole 100 mg or terbinafine 250 mg for 4 days. Midazolam 7.5 mg was ingested on the fourth day, after which plasma samples were collected and psychomotor performance tests carried out for 17 h. Itraconazole increased the area under the midazolam concentration-time curve six-fold (P < 0.001), the peak concentration 2.5-fold (P < 0.001) and the elimination half-life two-fold (P < 0.001) compared with placebo and terbinafine pretreatments. The pharmacokinetic parameters did not differ between placebo and terbinafine phases. The higher concentrations of midazolam during the itraconazole phase were associated with increased effects. In contrast to itraconazole, terbinafine had no effect on midazolam pharmacokinetics and psychomotor performance tests were unchanged from placebo.

Administration, Oral↗
PubMed1994

Receptor binding assays in analysing the bioavailability and pharmacodynamic bioequivalence of active drug moieties. A study of metoprolol.

The bioavailability and pharmacodynamic bioequivalence of a conventional and an experimental sustained-release formulation of 100 mg metoprolol tartrate were studied in a randomised cross-over study in seven healthy volunteers by assessing over 24 h the plasma kinetics of R,S-metoprolol, its beta 1-adrenoceptor binding component, and by determining the extent to which the active drug moiety in plasma occupied rabbit lung beta 1- and rat reticulocyte beta 2-adrenoceptors. The formulations differed markedly in their kinetic characteristics: the peak plasma concentration (Cmax) of R,S-metoprolol after administration of the conventional formulation was 140 ng.ml-1, (n = 7) and it was approximately one-third of that after the sustained-release formulation, 49 ng.ml-1, (n = 6); the AUC0-24 h-values for the formulations were 700 and 310 ng.h.ml-1, respectively. The Cmax for the beta 1-adrenoceptor binding component of metoprolol was 180 ng.ml-1 (n = 7) after administration of the conventional, and 74 ng.ml-1 after administration of the sustained-release formulation. The corresponding AUC0-24 h-values for the receptor binding component were 920 and 470 ng.h.ml-1 (n = 7). Thus, the kinetic differences between R,S-metoprolol and the beta 1-receptor binding component were considerable and they were affected by the type of formulation. In general, after administration of the sustained-release formulation, the percentage beta 1- and beta 2-adrenoceptor occupancy of metoprolol in plasma was 5-15% less than after administration of the conventional formulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-1 Receptor Antagonists↗
PubMed1994

Pharmacokinetics and pharmacodynamics of transdermal dexmedetomidine.

Dexmedetomidine is a novel alpha 2-adrenoceptor agonist that may provide beneficial effects as premedication for anesthesia. The pharmacokinetics and pharmacodynamics of transdermal (TD) and intravenous (i.v.) dexmedetomidine were studied in nine healthy male subjects in a crossover trial. The TD preparation, containing 625 micrograms of dexmedetomidine base, was applied on the forehead and left in place for 12 h. The i.v. dose (2.0 micrograms.kg-1 as dexmedetomidine hydrochloride) was administered as an infusion over 5 min. Dose-normalized total AUC values were used to calculate dexmedetomidine bioavailability. The bioavailability of dexmedetomidine from the TD preparation was 51%. However, the bioavailability of dexmedetomidine released from the preparation was 88%. The mean terminal half-life was 3.1 h after i.v. and 5.6 h after TD administration. After TD administration, the mean maximal reductions in blood pressure (systolic/diastolic) and heart rate were 28/20 mmHg, and 19 beats.min-1. A sedative effect was obvious within 5 min and 1-2 h after i.v. and TD administration, respectively.

Administration, Cutaneous↗
PubMed1994

Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole.

BACKGROUND: Triazolam is metabolized by CYP3A4 isozyme. Ketoconazole and itraconazole may seriously interact with some of the substrates of CYP3A4 (e.g., terfenadine); hence their possible interaction with triazolam in humans is important to uncover. METHODS: In this double-blind, randomized, three-phase crossover study, the interaction between ketoconazole, itraconazole, and triazolam was investigated. Nine healthy young volunteers received either 400 mg ketoconazole, 200 mg itraconazole, or matched placebo (control phase) orally once a day for 4 days. On day 4, each ingested a single 0.25 mg dose of triazolam. Plasma concentrations of triazolam and antimycotics were determined, and pharmacodynamic effects were measured up to 17 hours. RESULTS: On average, ketoconazole and itraconazole increased the area under the triazolam concentration-time curve [AUC(0-infinity)] 22-fold and 27-fold (p < 0.001), the peak concentrations threefold (p < 0.001), and the elimination half-life sixfold and sevenfold (p < 0.001), respectively. In seven of the nine subjects, even the maximum concentration of triazolam in plasma was lower without the antimycotics than were the 17-hour concentrations during the ketoconazole and itraconazole phases. All pharmacodynamic effects (e.g., the Digit Symbol Substitution Test) revealed a significant difference between the antimycotic and placebo phases. CONCLUSIONS: Both ketoconazole and itraconazole seriously affect the pharmacokinetics of triazolam and increase the intensity and duration of its effects. Inhibition of CYP3A4 during the absorption and elimination phases of triazolam seems to explain the interaction observed. Because of the potentially hazardous consequences of this interaction, triazolam should be avoided if patients are using ketoconazole or itraconazole.

Administration, Oral↗
PubMed1994

Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole.

Interaction between ketoconazole, itraconazole, and midazolam was investigated in a double-blind, randomized crossover study of three phases at intervals of 4 weeks. Nine volunteers were given either 400 mg ketoconazole, 200 mg itraconazole, or matched placebo orally once daily for 4 days. On day 4, the subjects ingested 7.5 mg midazolam. Plasma samples were collected and psychomotor performance was measured. Both ketoconazole and itraconazole increased the area under the midazolam concentration-time curve from 10 to 15 times (p < 0.001) and mean peak concentrations three to four times (p < 0.001) compared with the placebo phase. In psychomotor tests (e.g., the Digit Symbol Substitution Test), the interaction was statistically significant (p < 0.05) until at least 6 hours after drug administration. Inhibition of the cytochrome P450IIIA by ketoconazole and itraconazole may explain the observed pharmacokinetic interaction. Prescription of midazolam for patients receiving ketoconazole and itraconazole should be avoided.

Adult↗
PubMed1994

Plasma concentration and protein binding of alfentanil during high-dose infusion for cardiac surgery.

We have studied plasma protein binding of alfentanil in 10 patients given a mean total dose of 949 micrograms kg-1 as the principal anaesthetic agent for coronary artery bypass grafting. The mean unbound fraction of plasma alfentanil increased from 0.09 to 0.16 after administration of heparin and to 0.26 after beginning cardiopulmonary bypass (CPB). After CPB until the end of surgery, the unbound fraction decreased to 0.12. These changes in the unbound fraction were associated with significant changes in plasma total and unbound concentrations of alfentanil also. Within the first 1 min of CPB, total alfentanil concentration had decreased by more than the unbound concentration and the decrease observed in the latter disappeared rapidly. From induction of anaesthesia until awakening of the patient, plasma protein binding of alfentanil was related significantly (P = 0.0166) to the serum concentration of orosomucoid (alpha 1-acid glyco-protein).

Aged↗
PubMed1994

Lack of interaction of erythromycin with temazepam.

Erythromycin is a strong inhibitor of cytochrome P450 [CYP3A4] and has a potentially dangerous interaction with midazolam and triazolam. The possible interaction between erythromycin and a short-acting benzodiazepine, temazepam, was investigated in a double-blind, randomized crossover study. Ten healthy volunteers received 500 mg erythromycin or placebo orally three times a day for 6 days followed by a challenge dose of 20 mg temazepam. Plasma samples were collected for the determination of temazepam, oxazepam, and erythromycin, and psychomotor effects were measured during the 24 h after intake of temazepam. Erythromycin did not change the pharmacokinetics or pharmacodynamics of temazepam to a statistically significant degree. The metabolic fate of temazepam and its almost complete bioavailability explain the lack of interaction. Temazepam, unlike midazolam or triazolam, can thus be prescribed in the usual doses for patients receiving erythromycin.

Administration, Oral↗