Biomedical subjects

K M Jalava

Publications and source records attributed to K M Jalava.

6 recordsLinked to original sources

PubMed1997

Itraconazole greatly increases plasma concentrations and effects of felodipine.

BACKGROUND: Felodipine, a dihydropyridine calcium antagonist, is extensively metabolized by CYP3A4. Itraconazole strongly interacts with some of the substrates of CYP3A4 (e.g., terfenadine, triazolam and lovastatin); hence it is important to uncover the possible interaction of itraconazole with felodipine. METHODS: A double-blind, randomized, two-phase crossover design was used to investigate the interaction between felodipine and itraconazole. Nine healthy volunteers received either 200 mg itraconazole or placebo orally once a day for 4 days. On day 4, each ingested a single 5 mg oral dose of felodipine. Plasma concentrations of felodipine and itraconazole were determined and systolic and diastolic blood pressures and heart rate were measured up to 32 hours. RESULTS: On average, itraconazole increased the peak plasma concentration (Cmax) of felodipine nearly eightfold (p < 0.001), the areas under the felodipine concentration-time curve [AUC(0-32) and AUC(0-infinity)] about sixfold (p < 0.001), and the elimination half-life twofold (p < 0.05). In seven of the nine subjects, even the Cmax of felodipine was lower without itraconazole than the 32-hour concentrations during the itraconazole phase. The decreases in blood pressure and the increases in heart rate were significantly greater during the itraconazole phase than during the placebo phase. CONCLUSIONS: Itraconazole greatly increases plasma concentrations and effects of oral felodipine. The inhibition of CYP3A4 during the first-pass and elimination phases of felodipine seems to be the mechanism of the observed interaction. The concomitant use of itraconazole and some other azole antifungals with felodipine and other dihydropyridine calcium antagonists should be avoided or their doses should be reduced accordingly.

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↗

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

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

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↗

PubMedDate not supplied

Lorazepam and diazepam differently impair divided attention.

Effects of ethanol (EtOH, 0.65 + 0.35 g.kg-1), diazepam (DZ, 15 and 30 mg), lorazepam (LZ, 2 mg) on divided attention were measured in two placebo-controlled crossover studies with healthy young subjects. The test comprised four parallel computer screens with a ball moving along a circular obstacle course on each screen at different rates. When the ball entered an obstacle on any screen, the subject had to press the respective button. The obstacles varied in numbers and shapes, and randomly changed their location every 10 s. Concomitant aural stimuli were responded to by pushing the foot pedals. The primary visual variables were the absolute and percent numbers of correct responses on each screen. Concentrated attention was measured with a symbol digit substitution (SDST) and digit copying (DDCT) tests, for 3 min each. In Study I, with 12 subjects, the tests (4 min) were made before the treatment (placebo, EtOH, DZ) and 1, 3, and 6 h after intake. EtOH impaired attention on the lateral but not on medial screens, with and without aural stimuli, the "special" obstacles of deviating shape being the most sensitive targets to EtOH effects. DZ 15 mg did not modify divided attention whereas it impaired SDST performance and was subjectively slightly more potent than EtOH on visual analog scales. DZ 30 mg impaired attention on the lateral screens, with and without aural stimuli, but without preference to "special" obstacles. It also reduced responses to aural stimuli, strongly impaired SDST and DDCT, and caused subjective sedation. In Study II, with 9 subjects, the test run without aural stimuli was easier but lasted for 15 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Acoustic Stimulation↗