Nizoral
Terfenadine-ketoconazole interaction. Pharmacokinetic and electrocardiographic consequences.

Honig PK, Wortham DC, Zamani K, Conner DP, Mullin JC, Cantilena LR.

Division of Clinical Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Md. 20814-4799.

OBJECTIVE--To examine prospectively the effects of ketoconazole on the pharmacokinetics and electrocardiographic repolarization pharmacodynamics (corrected QT intervals) of terfenadine in men and women. DESIGN--Prospective cohort study with each subject serving as his or her own control. SETTING--Outpatient cardiology clinic and inpatient telemetry unit for monitoring period. PARTICIPANTS--Six healthy volunteers (four men and two women, aged 24 to 35 years) not taking any prescription or over-the-counter medications. INTERVENTION--After achieving a steady state while taking terfenadine (60 mg every 12 hours for 7 days), daily concomitant oral ketoconazole (200 mg every 12 hours) was added to the subjects' regimen. Pharmacokinetic profiles were obtained while subjects were taking terfenadine alone and after the addition of ketoconazole. Electrocardiograms were obtained at baseline, after 1 week of taking terfenadine alone, and at the time of the second pharmacokinetic profile after the addition of ketoconazole to the regimen. MAIN OUTCOME MEASURES--Terfenadine and its acid metabolite serum concentrations and corrected QT intervals. RESULTS--All subjects had detectable levels of unmetabolized terfenadine after the addition of ketoconazole, which was associated with QT prolongation. Only two of the six subjects could complete the entire course of ketoconazole coadministration. Four subjects received a shortened duration of ketoconazole therapy because of significant electrocardiographic repolarization abnormalities. There was a significant change in the area under the curve of the acid metabolite of terfenadine after the addition of ketoconazole administration. CONCLUSIONS--Ketoconazole alters the metabolism of terfenadine in normal men and women and results in the accumulation of unmetabolized parent drug, which is associated with significant prolongation of the corrected QT interval. This drug combination should be avoided.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8445813&dopt=Abstract ketoconazole Nizoral



Nizoral
Invitro drug sensitivity of Trichophyton species against griseofulvin and ketoconazole.

Dodia S, Bajpai R, Singh BG.

Department of Botany, St. John's College, Agra 282 002, India.

The in vitro activity of griseofulvin and ketoconazole was investigated against Trichophyton mentagrophytes (Robin) Blanchard and T. Simii (Pinoy) Stockdale, Mackenzie and Austwick. A gradual decrease in growth was observed with increase in concentration of both antibiotics. Ketoconazole was the more effective antibiotic than griseofulvin as it observed to inhibit > 50% mycelial weight even at a lower concentration of 100 ppm. While griseofulvin was effective to cause > 50% growth inhibition only at higher dosage of 400 ppm.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15061594&dopt=Abstract ketoconazole Nizoral



Nizoral
Mevinolin (lovastatin) potentiates the antiproliferative effects of ketoconazole and terbinafine against Trypanosoma (Schizotrypanum) cruzi: in vitro and in vivo studies.

Urbina JA, Lazardi K, Marchan E, Visbal G, Aguirre T, Piras MM, Piras R, Maldonado RA, Payares G, de Souza W.

Laboratorio de Quimica Biologica, Instituto Venezolano de Investigaciones Cientificas, Caracas.

We have studied the antiproliferative effects of mevinolin (lovastatin), an inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, on the protozoan parasite Trypanosoma (Schizotrypanum) cruzi and its ability to potentiate the action of specific ergosterol biosynthesis inhibitors, such as ketoconazole and terbinafine, both in vitro and in vivo. Against the epimastigote form in vitro, mevinolin produced a dose-dependent reduction of the growth rate up to 25 microM, but at 50 and 75 microM, complete growth arrest and cell lysis took place after 144 and 96 h, respectively. A systematic study of the effects of mevinolin combined with ketoconazole and terbinafine, which act at different points in the ergosterol biosynthesis pathway, on the proliferation of epimastigotes indicated a synergic action, as shown by concave isobolograms and fractional inhibitory concentration indexes ranging from 0.17 to 0.54. Analysis of the sterol composition and de novo sterol synthesis in control and treated cells by thin-layer and gas-liquid chromatographies showed that the antiproliferative effects of the drug alone and in combination were correlated with the depletion of the endogenous ergosterol pool and particularly with a critical (exogenous) cholesterol/endogenous 4-desmethyl sterol ratio in the cells. When we studied the effects of mevinolin on the amastigote form proliferating inside Vero cells in vitro, only very modest effects on the parasites were observed up to 0.75 microM; above this concentration, significant deleterious effects on the host cells were found. However, when the same concentration of the drug was combined with ketoconazole, it was able to reduce by a factor of 10 the concentration of the azole required to eradicate the parasite (from 10 to 1 nM), again indicating a synergic action. On the other hand, a combination of mevinolin and terbinafine had only additive effects on amastigotes, but a ternary combination of mevinolin, ketoconazole, and terbinafine was again clearly synergistic. In vivo studies with a murine model of Chagas' disease showed that mevinolin can also potentiate the therapeutic effects of ketoconazole in this system; combined treatment with the two drugs at doses that alone offered only limited protection against the parasite was able to essentially eliminate circulating parasites and produce complete protection against death. These results confirm the synergic action against the proliferative stages of T. cruzi both in vitro and in vivo and in vivo of combined ergosterol biosynthesis inhibitors that act at different points in the pathway and suggest that mevinolin combined with azoles, such as ketoconazole, can be used in the treatment of human Chagas' disease.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8460926&dopt=Abstract ketoconazole Nizoral



Nizoral
Disposition of azole antifungal agents. I. Nonlinearities in ketoconazole clearance and binding in rat liver.

Matthew D, Brennan B, Zomorodi K, Houston JB.

Department of Pharmacy, University of Manchester, UK.

The disposition of ketoconazole was characterized in the rat over a wide dose/concentration range. Bolus dose (0.03-10 mg/kg) studies indicate that plasma concentration-time profiles for ketoconazole are not superimposable when dose normalized because of nonlinearities occurring in both volume of distribution and clearance. The volume of distribution decreases from 3 to less than 1 L/kg, while the plasma clearance decreases 10-fold from 25 mL/min/kg as the dose is escalated. From these results, infusion rates were calculated to maintain the plasma concentrations achieved with particular bolus doses. The curvilinear relationship between steady-state plasma concentration (0.015-8.3 mg/L) and ketoconazole infusion rate (0.021-2.45 mg/hr/kg) was analyzed in terms of Michaelis-Menten kinetics. A Vmax of 3.2 mg/hr/kg and Km of 2.1 mg/L were obtained by nonlinear regression analysis. At the end of the ketoconazole infusion, liver, adrenals and kidneys were removed and assayed for ketoconazole. Tissue-to-plasma partition coefficients for the liver and adrenals showed a marked dependence upon steady-state plasma concentration. Both parameters (liver, 22; and adrenals, 53) showed a decrease of approximately 10-fold as the plasma concentrations were increased. In contrast, the kidney:plasma partition coefficient (1.8), blood:plasma concentration ratio (0.6), and plasma binding (96%) of ketoconazole did not show a concentration dependence over the range studied. It is concluded that the liver is an important determinant of ketoconazole's volume of distribution and that saturation of this process accounts largely for the reduction in volume of distribution with increasing dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8464816&dopt=Abstract ketoconazole Nizoral



Nizoral
Ketoconazole administration in hypercortisolemic depression.

Wolkowitz OM, Reus VI, Manfredi F, Ingbar J, Brizendine L, Weingartner H.

Department of Psychiatry, University of California, San Francisco.

Ketoconazole, an antiglucocorticoid drug, was administered to 10 hypercortisolemic depressed patients for up to 6 weeks. Three patients dropped out because of side effects or intercurrent illness. The remaining seven had significant ketoconazole-associated decreases in serum cortisol levels and in depression ratings. Antiglucocorticoid agents may be useful probes for investigating the sequelae of hypercortisolemia in patients with major depression.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8480829&dopt=Abstract ketoconazole Nizoral



Nizoral
Azoles, allylamines and drug metabolism.

Back DJ, Tjia JF, Abel SM.

Department of Pharmacology and Therapeutics, University of Liverpool, UK.

Four antifungal drugs, the azoles ketoconazole, itraconazole and fluconazole, and the allylamine terbinafine, were studied for their effects on the metabolism of cyclosporin A (CyA) and cortisol by human liver microsomes in vitro (n = 3). Ketoconazole produced marked inhibition of CyA hydroxylase (to metabolites M17 and M1) with IC50 and Ki values of 0.24 +/- 0.01 and 0.022 +/- 0.004 microM, respectively. On the basis of the IC50, itraconazole was 10 times less potent (IC50 of 2.2 +/- 0.2 microM), and fluconazole and terbinafine were each above 100 microM. No kinetic parameters were calculated for terbinafine because of the lack of inhibitory effects. Ketoconazole was the most potent inhibitor of cortisol metabolism (to 6 beta-hydroxycortisol, IC50 = 0.6 microM). Itraconazole produced marked inhibition of cortisol metabolism (IC50 = 2.4 microM), but fluconazole and terbinafine had little effect. These data confirm that ketoconazole is a potent inhibitor of cytochrome P-450-IIIA4, and this has clinical relevance. Although the inhibition with fluconazole was much less than with itraconazole at equimolar concentrations, it should be noted that in-vivo plasma concentrations of fluconazole are much greater than that of itraconazole. Clinical interactions of CyA with both fluconazole and itraconazole have been reported; in contrast to these azoles, terbinafine does not have the same interaction potential.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1311943&dopt=Abstract ketoconazole Nizoral



Nizoral
Comparison of azoles against aspergilli in vitro and in an experimental model of pulmonary aspergillosis.

Schmitt HJ, Edwards F, Andrade J, Niki Y, Armstrong D.

Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, N.Y.

Current treatment modalities for bronchopulmonary aspergillosis are not very satisfying. We determined the in vitro activity of recently available azoles against Aspergillus fumigatus, Aspergillus flavus and Aspergillus niger. Subsequently, these agents were evaluated in an animal model of bronchopulmonary aspergillosis using A. fumigatus as test organism. In vitro, detectable activity was only found for itraconazole (all minimal inhibitory concentrations, MICs, less than or equal to 3.2 micrograms/ml). The MICs for SCH39304 were greater than or equal to 12.8 micrograms/ml and greater than or equal to 25.6 micrograms/ml for ketoconazole and fluconazole. In vivo, amphotericin B was the most active agent tested, and SCH39304 was the most active azole in terms of survival and reduction in lung weight, followed by itraconazole. Ketoconazole and fluconazole did not improve survival nor reduce the lung weight of infected animals. We conclude, (1) that in vitro activity of azoles against aspergilli does not always correlate with in vivo activity; (2) that in vivo, SCH39304 was the most active azole tested, followed by itraconazole; (3) that for those agents for which data about effectiveness in human pulmonary aspergillosis are available (amphotericin B, ketoconazole, itraconazole) antifungal activity in our model corresponds to activity as seen in human beings, and (4) that SCH39304 and itraconazole are rational choices for clinical trials in human pulmonary aspergillosis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1317280&dopt=Abstract ketoconazole Nizoral