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Biomedical subjects

P J Neuvonen

Publications and source records attributed to P J Neuvonen.

At least 145 records · Page 8Linked to original sources
PubMed1996

Effect of diltiazem on midazolam and alfentanil disposition in patients undergoing coronary artery bypass grafting.

BACKGROUND: Midazolam and alfentanil are desirable anesthetic adjuncts for cardiac anesthesia. They are metabolized by cytochrome P450 3A (CYP3A) enzymes. These isozymes are inhibited by concurrent medications, including the calcium channel antagonist diltiazem, which may have an effect on recovery from anesthesia. METHODS: Thirty patients having coronary artery bypass grafting were randomly assigned to receive either diltiazem (60 mg orally 2 h before induction of anesthesia and an infusion of 0.1 mg.kg-1.h-1 started at induction and continued for 23 h) or placebo in a double-blind study. Anesthesia was induced with 0.1 mg/kg midazolam, 50 micrograms/kg alfentanil, and 20 to 80 mg propofol and maintained with infusions of 1 microgram.kg-1.min-1 of both midazolam and alfentanil supplemented with isoflurane. Plasma midazolam and alfentanil concentrations and areas under the plasma concentration-time curves were determined. The terminal half-life and the time for the drug plasma level to decrease 50% after cessation of the infusion (t50) were calculated for midazolam and alfentanil. Separation from mechanical ventilation and tracheal extubation were performed according to the study protocol. RESULTS: Diltiazem increased the mean concentration-time curves (from end of anesthesia until 23 h) of midazolam by 24% (P < 0.05) and that of alfentanil by 40% (P < 0.05). The mean half-life of midazolam was 43% (P < 0.05) and that of alfentanil was 50% (P < 0.05) longer in patients receiving diltiazem. The mean t50 of alfentanil was 40% longer (P < 0.05) in patients receiving diltiazem, but the change in the mean t50 of midazolam (25%) was not statistically significant. In patients receiving diltiazem, tracheal extubation was performed on average 2.5 h later (P = 0.054) than in those receiving placebo. CONCLUSIONS: Diltiazem slows elimination of midazolam and alfentanil and may delay tracheal extubation after large doses of these anesthetic adjuncts. CYP3A-mediated drug interactions should be considered as confounders when recovery from anesthesia with midazolam and alfentanil infusions is assessed.

Adjuvants, Anesthesia↗
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

The effect of the antimycotic itraconazole on the pharmacokinetics and pharmacodynamics of diazepam.

The azole antimycotic itraconazole is a potent and relatively unspecific inhibitor of cytochrome P450 enzymes and has a potentially dangerous interaction with midazolam and triazolam. The possible interaction between itraconazole and diazepam was investigated in a double-blind, randomized, cross-over study. Ten healthy volunteers were given orally placebo or itraconazole 200 mg a day for 4 days. The challenge dose of 5 mg of diazepam was ingested on the fourth day, after which plasma samples were collected and psychomotor performance tests were carried out for 42 h. Despite a statistically significant small increase in the area under the plasma diazepam concentration-time curve and the elimination half-life of diazepam, there was no clinically significant interaction as determined by the psychomotor performance tests. The lack of significant first-pass metabolism and the different metabolic pathways of diazepam explain the smaller interaction potential of diazepam compared with midazolam and triazolam. Diazepam, unlike midazolam and triazolam, can be prescribed in usual doses for patients receiving itraconazole and probably other inhibitors of P4503A4, at least when diazepam is used as single doses.

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↗
PubMed1996

Interaction between erythromycin and the benzodiazepines diazepam and flunitrazepam.

The effect of erythromycin on the pharmacokinetics and pharmacodynamics of diazepam and flunitrazepam was investigated in two randomized, double-blind, cross-over studies. Healthy volunteers ingested erythromycin for one week 500 mg t.i.d. On the 4th day they ingested a single 5 mg dose of diazepam (6 subject, Study 1) or 1 mg dose of flunitrazepam (5 subjects, Study 2), respectively. Plasma drug concentrations and psychomotor effects were measured during 42 hr after the ingestion of diazepam or flunitrazepam. In Study 1 erythromycin increased the area under the diazepam plasma concentration-time curve [AUC (0-42 hr)] by 15% (P < 0.05) and the concentration of diazepam in plasma at 42 hr by 63% (P < 0.05). The median peak concentration (Cmax) and the half-life (t1/2) of diazepam were increased but they did not change significantly (P = 0.17 and 0.12, respectively). Plasma N-desmethyldiazepam concentrations were slightly reduced during erythromycin treatment up to 8 hr (P < 0.05). In Study 2 the AUC (0-42 hr) of flunitrazepam was increased by 25% (P < 0.05) during the erythromycin treatment. The t1/2 of flunitrazepam increased significantly (P < 0.05), but the Cmax remained unchanged. The psychomotor effects of diazepam or flunitrazepam were not changed significantly by erythromycin. These pharmacokinetic interactions can be explained by the reduced metabolic elimination of diazepam and flunitrazepam. The interactions of erythromycin with diazepam and flunitrazepam seem to be slight and of limited clinical significance only.

Adult↗
PubMed1996

The effect of activated charcoal on the absorption of fluoxetine, with special reference to delayed charcoal administration.

The effect of activated charcoal on fluoxetine (40 mg) absorption, with special reference to delayed charcoal administration, was investigated in a randomized study with four parallel groups of eight Healthy volunteers. The first group ingested fluoxetine on an empty stomach with water only (control). The second group received 25 g of activated charcoal as a suspension immediately after fluoxetine. The third and fourth groups took fluoxetine with water and received 25 g of charcoal 2 or 4 hr after fluoxetine. Timed blood samples were taken and plasma fluoxetine and norfluoxetine concentrations were measured by GC for 96 hr. When charcoal was administered immediately after fluoxetine, the AUC (0-96 hr) of fluoxetine was reduced by more than 96% (P < 0.0005) and the Cmax by more than 98% (P < 0.0005). The reduction in the AUC (0-96 hr) and Cmax of norfluoxetine was similar to that of fluoxetine. When the administration of charcoal was delayed 2 or 4 hr, there was a non-significant mean reduction of 16% and 23% in the AUC (0-96 hr) of fluoxetine. Similarly, the Cmax was not significantly reduced by charcoal given 2 or 4 hr later. Also, the half-life of fluoxetine was not significantly reduced (by 25%) by the late administration of charcoal. We conclude that activated charcoal, ingested immediately after fluoxetine, practically completely prevents the gastrointestinal absorption of fluoxetine. However, regardless of the relatively slow absorption of fluoxetine, delaying charcoal administration 2-4 hr greatly reduces its antidotal efficacy.

Adult↗
PubMed1996

Itraconazole increases serum digoxin concentration.

Itraconazole can interact with several drugs by inhibiting their metabolism. Many drugs known to increase serum digoxin concentration are inhibitors of CYP enzymes (e.g. verapamil, diltiazem, amiodarone, cyclosporine). Case reports suggest that itraconazole, added to digoxin therapy, may induce digoxin intoxications; hence we wanted to study their possible interaction. In this two-phase study ten healthy young volunteers ingested 0.25 mg of digoxin daily for 20 days. Concomitantly, they received either 200 mg itraconazole or placebo orally once daily for 10 days in a double-blind, randomized, cross-over study design. Serum concentrations of digoxin and itraconazole were measured (12 hr after administration) on days 1, 2, 4, 6, 8, 10, 11, 12, 14, 16, 18 and 20. Digoxin concentrations were measured by fluorescence polarization immunoassay and confirmed (days 10 and 20) by affinity column-mediated immunoassay. Itraconazole increased serum digoxin concentration in each of the subjects. On the 10th day of the placebo phase serum digoxin concentration was 1.0 +/- 0.1 nmol/l, and on the 10th day of the itraconazole phase 1.8 +/- 0.1 nmol/l (P < 0.001). Care should be taken if itraconazole is prescribed to patients using digoxin. The mechanism of the itraconazole-digoxin interaction is unclear but may be related to CYP3A4-mediated changes in the pharmacokinetics of digoxin.

Adult↗
PubMed1996

The effect of pH on the in-vitro dissolution of three second-generation sulphonylurea preparations: mechanism of antacid-sulphonylurea interaction.

Simultaneously administered magnesium hydroxide or sodium bicarbonate can increase the rate and extent of absorption of non-micronized glibenclamide and glipizide. To clarify the mechanism of this interaction we have studied the effect of pH on the dissolution of two different formulations of glibenclamide (micronized and non-micronized) and one formulation of glipizide. One tablet of each sulphonylurea preparation was placed in a dissolution chamber containing continuously mixed dissolution medium at pH 2, pH 6 or pH 9; 5 mL of the medium was replaced every 2 min. The amount of glibenclamide dissolved from the non-micronized formulation within 2 h, was 1.2, 4.5 and 76% at pH 2, pH 6 and pH 9, respectively (P < 0.01), whereas 21, 29 and 100% was dissolved from the micronized formulation (P < 0.01). The amount of glipizide dissolved within 2 h at pH 2, pH 6 and pH 9 was 3.9, 24 and 92%, respectively (P < 0.01). We conclude that the elevated pH of the gastric contents is the most likely explanation for the interactions previously demonstrated between antacids and sulphonylureas after their concomitant ingestion.

Antacids↗
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↗