Biomedical subjects

P J Neuvonen

Publications and source records attributed to P J Neuvonen.

At least 127 records · Page 7Linked to original sources

PubMed1997

Effect of continuous venovenous haemofiltration and haemodiafiltration on the elimination of fluconazole in patients with acute renal failure.

The elimination of fluconazole was studied in six patients with acute renal failure undergoing continuous venovenous haemofiltration (CVVH) for 24 h, continuous venovenous haemodiafiltration (CVVHD) 1 L/h for 24 h and CVVHD 2 L/h for 24 h. Fluconazole 200 mg once daily was given intravenously on three successive days and the concentrations of fluconazole in serum, ultrafiltrate/dialysate and urine were determined for 24 h after each dose. The half-life of fluconazole in patients during CVVH (83.5 +/- 30.1 h; mean +/- S.D.) was significantly (P < 0.05) longer than that during CVVHD 1 L/h (30.4 +/- 5.0 h) or CVVHD 2 L/h (21.8 +/- 3.5 h). The total fluconazole clearance was 0.57 +/- 0.16 L/h, 1.50 +/- 0.24 L/h and 1.85 +/- 0.17 L/h in CVVH, CVVHD 1 L/h and CVVHD 2 L/h, respectively, and there was a significant difference (P < 0.05) between all these treatments. Daily renal excretion of fluconazole was minimal, ranging from 0.002 mg to 11.2 mg in different patients with different treatment modes. The methods tested increased the elimination of the unchanged drug 20- to 400-fold in patients with acute renal failure. Patients undergoing CVVHD therapy with a dialysis flow rates of 1 or 2 L/h should be treated with a daily dose of at least 200 mg of fluconazole to maintain therapeutic drug concentrations. However, in patients on CVVH therapy smaller doses of fluconazole may be enough.

Acute Kidney Injury↗

PubMed1997

Effect of activated charcoal on the pharmacokinetics of pholcodine, with special reference to delayed charcoal ingestion.

We conducted a randomized study with four parallel groups to investigate the effect of single and multiple doses of activated charcoal on the absorption and elimination of pholcodine administered in a cough syrup. The first group received 100 mg of pholcodine on an empty stomach with water only (control); the second group took 25 g of activated charcoal immediately after pholcodine; the third group received 25 g of activated charcoal 2 h and the fourth group 5 h after ingestion of the 100-mg dose of pholcodine. In addition, the fourth group received multiple doses (10 g each) of charcoal every 12 h for 84 h. Blood samples were collected for 96 h and urine for 72 h. Pholcodine concentrations were measured by high-performance liquid chromatography. A significant reduction in absorption was found when charcoal was administered immediately after pholcodine; the AUC0-96h was reduced by 91% (p < 0.0005), the Cmax by 77% (p < 0.0005), and the amount of pholcodine excreted into urine by 85% (p < 0.0005). When charcoal was administered 2 h after pholcodine, the AUC0-96h was reduced by 26% (p = 0.002), the Cmax by 23% (p = NS), and the urinary excretion by 28% (p = 0.004). When administered 5 h after pholcodine, charcoal produced only a 17% reduction in the AUC0-96h (p = 0.06), but reduced the further absorption of pholcodine still present in the gastrointestinal tract at the time of charcoal administration, as measured by AUC5-96h (p = 0.006). Repeated administration of charcoal failed to accelerate the elimination of pholcodine. We conclude that activated charcoal is effective in preventing the absorption of pholcodine, and its administration can be beneficial even several hours after pholcodine ingestion.

Adult↗

PubMed1997

Pharmacokinetics of diltiazem in massive overdose.

Several cases of poisoning with diltiazem have been described in the literature, but information about the pharmacokinetics of diltiazem in overdose is sparse. The authors report pharmacokinetic and clinical observations in a patient who ingested 7.2 g of slow-release dilitiazem. Grave, persistent hypotension was the overriding clinical manifestation, but the patient eventually survived with aggressive cardiovascular support. No serious conduction abnormalities were seen. Blood samples were taken repeatedly for 2-3 days for analysis of serum diltiazem and desacetyldiltiazem and desacetyldiltiazem concentrations. The serum diltiazem concentration measured in the first sample taken (16.5 h postingestion), 3,171 ng/ml, is one of the highest concentrations reported in a patient who survived. The half-life was 13.3 h for diltiazem and 10.5 h for desacetyldiltiazem. Charcoal hemoperfusion had no apparent effect on the elimination of either compound. The relatively long half-life of diltiazem may have resulted from rate-limiting absorption and probably does not indicate saturation of diltiazem metabolism. The patient was discharged with no apparent neurological or cardiological deficits.

Adult↗

PubMed1997

Itraconazole decreases renal clearance of digoxin.

Itraconazole strongly interacts with some drugs metabolized by cytochrome P450 3A4, for example, felodipine and lovastatin, by inhibiting their metabolism. A concomitant use of itraconazole increases the serum concentrations of digoxin, although digoxin is excreted mainly unchanged in urine. To reveal the mechanism of the itraconazole-digoxin interaction, the effect of itraconazole on the serum concentrations and urinary excretion of digoxin was studied. Ten healthy volunteers in a double-blind, randomized, two-phase crossover study received either 200 mg itraconazole or placebo orally once a day for 5 days. On day 3, each volunteer ingested a single 0.5-mg oral dose of digoxin. The serum concentrations of digoxin and its excretion into urine as well as plasma concentrations of itraconazole were determined up to 72 hours after dosing. The mean area under the serum digoxin concentration-time curve, AUC(0-72), was approximately 50% higher (P < 0.001) during the itraconazole phase than during the placebo phase. In addition, the renal clearance of digoxin decreased about 20% (P < 0.01) by itraconazole. The increases in digoxin Cmax and T(1/2) by itraconazole were not statistically significant. The decreased renal clearance of digoxin during the itraconazole phase partially explains increased concentrations of digoxin during their concomitant use and may be caused by the inhibition of P-glycoprotein-mediated digoxin secretion in the renal tubular cells.

Administration, Oral↗

PubMed1997

Prevention of amlodipine absorption by activated charcoal: effect of delay in charcoal administration.

AIMS: The purpose of this study was to investigate the effect of activated charcoal on the absorption of amlodipine, with special reference to delayed charcoal administration. METHODS: Thirty-two healthy volunteers, eight subjects in four parallel groups, ingested 10 mg of amlodipine on an empty stomach. Activated charcoal (25 g in 300 ml of water) was ingested either immediately afterwards or 2 h or 6 h after amlodipine, or amlodipine was ingested with 300 ml of water only (control). Plasma concentrations and the cumulative excretion of amlodipine into urine were measured by GC-MS for 96 h and 72 h, respectively. In addition, adsorption of amlodipine to charcoal was studied in vitro. RESULTS: Activated charcoal administered immediately after amlodipine reduced the amlodipine AUC(0.96 h) and the 72-h urinary excretion by 99% (P < 0.0005). After a delay of 2 h in charcoal administration the AUC(0.96 h) was reduced by 49% (P = 0.001), but after a delay of 6 h the reduction was 15% only (P = NS). At a charcoal:drug ratio of 5:1, about 90% of amlodipine was adsorbed by charcoal in vitro; at ratios of 10:1 and 20:1, adsorption was practically complete. CONCLUSIONS: Activated charcoal almost completely prevented amlodipine absorption when administered immediately after amlodipine ingestion. Charcoal also markedly reduced amlodipine absorption when given 2 h after amlodipine; in amlodipine overdose, administration of charcoal may be beneficial even later. We conclude that administration of activated charcoal is the method of choice to prevent absorption of amlodipine in amlodipine overdose.

Adsorption↗

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↗

PubMed1997

Pharmacokinetics of verapamil in overdose.

The information on the pharmacokinetics of verapamil in overdose is scanty. We report two adults who ingested 3.2 g and 4 g of verapamil, respectively. Both patients had hypotension and a severe bradycardia. The highest plasma verapamil concentration in these patients was about 2200 ng/ml and 2700 ng/ml, respectively. The decline in plasma verapamil and norverapamil concentrations followed first-order kinetics, and the half-life of verapamil was 7.8 h and 15.1 h, respectively. The free fraction of verapamil (non-protein bound) was higher at total concentrations exceeding 2000 ng/ml (12-15%) than at lower concentrations (2-6%). There seems to be no marked saturation of the metabolism of verapamil in acute poisoning. The apparent concentration-dependent changes in the free fraction may be due to therapeutic measures.

Adult↗

PubMed1997

Methylprednisolone exposure, rather than dose, predicts adrenal suppression and growth inhibition in children with liver and renal transplants.

Some patients receiving glucocorticoids develop adverse effects even with very low doses, whereas others fail to achieve the desired effects with the usual therapeutic doses. We hypothesized that glucocorticoid exposure, rather than the dose, would predict the development of adverse effects in children receiving long-term glucocorticoid treatment. Sixteen liver and 10 renal transplant recipients on triple immunosuppression were studied. Serum total methylprednisolone (MP) and cortisol were determined before and up to 10 h after peroral MP administration. Heights were recorded 6 months before and after the study day. The MP dose (in milligrams per kilogram) was not correlated with the serum cortisol concentration or with the change in height SD score. The area under the serum MP time vs. concentration curve was inversely related to the serum cortisol concentration and to the height SD score, and was the best predictor of both adrenal function and growth. Dosing according to area under the serum MP time vs. concentration curve in children receiving long-term glucocorticoid treatment may substantially reduce the incidence of adverse effects without affecting therapeutic efficacy.

Adolescent↗

PubMed1997

Effect of delayed administration of activated charcoal on the absorption of conventional and slow-release verapamil.

OBJECTIVE: To investigate the effect of simultaneous and delayed administration of activated charcoal on the absorption of two verapamil formulations. METHODS: In the first study, 9 healthy volunteers received the following treatments: 1) verapamil 80 mg (conventional formulation) with 50 mL water only, 2) verapamil 80 mg and 25 g activated charcoal immediately afterwards, and 3) verapamil 80 mg with 50 mL water, followed by 25 g charcoal 2 h after verapamil ingestion. In the second study, 8 healthy volunteers received the following treatments: 1) verapamil 240 mg (slow-release formulation) with 50 mL water only, 2) verapamil slow-release 240 mg and 25 g activated charcoal immediately afterwards, 3) verapamil slow-release 240 mg with 50 mL water, followed by 25 g charcoal 2 h after verapamil ingestion, and 4) verapamil slow-release 240 mg with 50 mL water, followed by 25 g charcoal 4 h later. Plasma verapamil concentrations over 24 h were measured by high performance liquid chromatography. RESULTS: Activated charcoal given immediately after the conventional formulation of verapamil reduced the AUC0-24 h by 99% (p < 0.0005) and the Cmax by 98% (p < 0.0005). When the administration of charcoal was delayed 2 h, no significant change in verapamil absorption was observed. With the slow-release formulation of verapamil, charcoal given immediately after verapamil ingestion reduced the verapamil AUC0-24 h by 86% (p = 0.001) and the Cmax by 82% (p = 0.002). When the administration of charcoal was delayed 2 or 4 h, the AUC0-24 h was reduced by 35% (p = 0.04) and 32% (p = 0.001), respectively, but the Cmax was decreased by 13% (p = NS) and 9% (p = NS) only. CONCLUSIONS: Activated charcoal was effective in preventing absorption of verapamil when it was administered immediately after verapamil ingestion. In the case of slow-release formulation, charcoal reduced verapamil absorption by over 30% even when given 4 h after verapamil.

Administration, Oral↗

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↗

PubMed1996

Effect of itraconazole on the pharmacokinetics and pharmacodynamics of zopiclone.

OBJECTIVE: We studied the possible interaction between itraconazole, a potent inhibitor of CYP3A, and zopiclone, a short-acting hypnotic. METHODS: A double-blind, randomized, two-phase crossover design was used. Ten healthy young subjects received daily either 200 mg itraconazole or placebo for 4 days. On day 4 they ingested a single 7.5-mg oral dose of zopiclone. Plasma concentrations of zopiclone and itraconazole were determined and pharmacodynamic responses were measured up to 17 h. RESULTS: Itraconazole significantly increased the Cmax of zopiclone from 49 to 63 ng.ml-1. The t 1/2 of zopiclone was prolonged from 5.0 to 7.0 h. The AUC(0-inifinity) of zopiclone was increased from 415 to 719 ng.ml-1 h by itraconazole. No statistically significant differences were observed in the pharmacodynamic responses between the groups. CONCLUSIONS: Itraconazole has a statistically significant pharmacokinetic interaction with zopiclone but this is only of limited clinical importance, at least in young adults.

Adult↗

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

The effect of ingestion time interval on the interaction between itraconazole and triazolam.

BACKGROUND: The plasma concentrations and effects of triazolam are markedly increased when it is ingested with itraconazole. The dependence of this interaction on the time interval of their ingestion and the possibility of avoiding the interaction by a correct daily dosing was studied. METHODS: Ten healthy volunteers took part in this randomized crossover study of five phases, each separated by 4 weeks. The subjects received a single 0.25 mg oral dose of triazolam either without itraconazole or with a single 200 mg dose of itraconazole that was ingested either simultaneously with triazolam or 3, 12, or 24 hours before triazolam. Plasma concentrations of triazolam and itraconazole were determined and pharmacodynamic effects were measured up to 17 hours. RESULTS: Itraconazole ingested simultaneously or 3, 12, or 24 hours before triazolam increased the mean area under the triazolam concentration-time curve 3.1-, 4.8-, 4.6-, and 3.8-fold (p < 0.001), respectively. The mean increase in the peak concentration of triazolam ranged from 1.4-fold (taken simultaneously, p < 0.05) to 1.8-fold (3 or 12 hours after itraconazole, p < 0.001). The elimination half-life of triazolam was increased about threefold (p < 0.001) during all itraconazole phases. Pharmacodynamic effects of triazolam were increased along with increased plasma concentrations of triazolam. CONCLUSIONS: Even a single 200 mg dose of itraconazole interacts considerably with triazolam when this hypnotic agent is ingested within 24 hours after itraconazole. Thus during the daily itraconazole use this interaction cannot be avoided by increasing the time interval between their intake. Furthermore, the risk of interaction is obvious for several days after the cessation of itraconazole therapy.

Adult↗

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

Effect of fluconazole dose on the extent of fluconazole-triazolam interaction.

1. Azole antimycotics interact with the short acting hypnotic triazolam. The effect of fluconazole dose on the extent of fluconazole-triazolam interaction was investigated in a double-blind, randomized cross-over study of four phases. 2. Eight healthy volunteers received either 50 mg, 100 mg or 200 mg (400 mg on day 1) of fluconazole or placebo orally once a day for 4 days. On day 4, they took a 0.25 mg oral dose of triazolam, after which plasma samples were collected and pharmacodynamic effects measured for 18 h. 3. The mean area under the triazolam concentration-time curve (AUC) was increased 1.6-, 2.1- and 4.4-fold (P < 0.001) by fluconazole 50 mg, 100 mg and 200 mg, respectively. The increase in the elimination half-life of triazolam (t1/2,z) varied from 1.3-fold (fluconazole 50 mg, P < 0.05) to 2.3-fold (fluconazole 200 mg, P < 0.001). The peak concentration of triazolam was also increased significantly during all fluconazole phases; more than twofold by fluconazole 200 mg (P < 0.001). 4. The pharmacodynamic effects of triazolam were increased significantly (P < 0.05) by fluconazole 100 mg and 200 mg. 5. Even a small 50 mg daily dose of fluconazole can interact with triazolam and the extent of the interaction increases with increasing fluconazole dose. When triazolam is used concomitantly with fluconazole 50-200 mg, the dose of triazolam should be reduced, accordingly. Simultaneous use of triazolam with higher fluconazole doses should be avoided.

Adult↗

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↗