Nizoral
Comparative effects of two antimycotic agents, ketoconazole and terbinafine on the metabolism of tolbutamide, ethinyloestradiol, cyclosporin and ethoxycoumarin by human liver microsomes in vitro.

Back DJ, Stevenson P, Tjia JF.

Department of Pharmacology and Therapeutics, University of Liverpool.

Two antimycotic agents, the azole ketoconazole and the allylamine terbinafine, have been examined for their effects on the metabolism of tolbutamide, ethinyloestradiol, cyclosporin and ethoxycoumarin by human liver microsomes (n = 4) in vitro. Ketoconazole caused marked inhibition of all enzyme activities with mean IC50 values (concentration producing 50% inhibition) of 17.9 microM (tolbutamide hydroxylase), 1.9 microM (ethinyloestradiol 2-hydroxylase), 2.0 microM (cyclosporin N-demethylase), 2.1 microM (cyclosporin hydroxylase) and 25 microM (ethoxycoumarin O-deethylase). At 50 microM terbinafine concentration, inhibition was less than 5% for tolbutamide and ethoxycoumarin, approximately 12% for both cyclosporin pathways and 35% for ethinyloestradiol. Terbinafine does not have the same inhibitory potential for cytochrome P-450 isozymes as ketoconazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2775622&dopt=Abstract ketoconazole Nizoral



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Comparison of ketoconazole suspension and nystatin in the treatment of newborns and infants with oral candidosis.

Boon JM, Lafeber HN, Mannetje AH, van Olphen AH, Smeets HL, Toorman J, van der Vlist GJ.

Ketoconazole suspension (20 mg per ml) was compared with nystatin (100,000 units per ml) in the treatment of oral candidosis in newborns and infants. In all patients Candida infection was proven by culture. Twenty patients were treated with ketoconazole and 15 patients with nystatin. Treatment was discontinued 2 days after clinical cure, or after 3 weeks. The investigator assessed the severity of the thrush and accompanying symptoms at the start of the study and at weekly controls. After one week all 20 patients on ketoconazole (100%) and 8 (53%) patients on nystatin were cured clinically. At the end of the treatment 12 patients on nystatin (80%) were cured. Clinical cure was confirmed by negative culture in 94% of the patients on ketoconazole and in 73% of the patients on nystatin. No side-effects were observed in the patients on ketoconazole. Only in the case of one patient on nystatin, was vomiting observed. This study shows that ketoconazole cures thrush faster and more effectively than nystatin.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2779612&dopt=Abstract ketoconazole Nizoral



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Pharmacokinetics of the cyclosporine-ketoconazole interaction in dogs.

D'mello A, Venkataramanan R, Satake M, Todo S, Takaya S, Ptachcinski RJ, Burckart GJ, Starzl TE.

School of Pharmacy, University of Pittsburgh, Pa 15261.

Numerous clinical reports have documented an increase in trough blood concentrations of cyclosporine in transplant recipients treated concomitantly with ketoconazole. The objective of this study was to elucidate the mechanism(s) underlying the cyclosporine-ketoconazole interaction using a choledochoureterostomy dog model. Five male beagle dogs received a 4 mg/kg, i.v. bolus dose of cyclosporine either alone or on day seven of a 10-day, 13 mg/kg/day, oral dosing regimen of ketoconazole. Blood samples were collected prior to and at predetermined times for 60 hrs after the cyclosporine dose, while the bile/urine mixture was collected quantitatively for 96 hours after the cyclosporine dose. Ketoconazole decreased the systemic clearance of cyclosporine from 7.0 ml/min/kg to 2.5 ml/min/kg. The terminal disposition rate constant was also decreased significantly from 0.0794 to 0.0354 hrs-1. Ketoconazole caused no significant changes in cyclosporine steady state volume of distribution, or plasma unbound fraction. Ketoconazole did not significantly alter the excretion of cyclosporine and various cyclosporine metabolites in the bile/urine mixture. Inhibition of hepatic drug metabolizing enzymes appears to be the primary reason for the ketoconazole induced elevation in cyclosporine concentration.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2781141&dopt=Abstract ketoconazole Nizoral



Nizoral
Incidence, severity, and prevention of infections in chronic granulomatous disease.

Mouy R, Fischer A, Vilmer E, Seger R, Griscelli C.

Department of Pediatrics, Hopital des Enfants-Malades, Paris, France.

We retrospectively analyzed the frequency and nature of infections occurring in 48 patients with chronic granulomatous disease. The long-term use of trimethoprim-sulfamethoxazole and ketoconazole as a preventive therapy for infections has also been evaluated. Lymphadenitis, lung infections, dermatitis, enteral infections, and hepatic abscesses were the most frequent infections. Staphylococcus aureus, Salmonella, and Aspergillus were the main microorganisms encountered. Twelve patients died: five from lung aspergillosis, three from hepatic abscesses, two from pneumonopathy of unknown origin, one from salmonellosis, and one from another probable infection that could not be proved. The actuarial survival rate was 50% at 10 years of age, with a prolonged plateau thereafter. There was no difference in survival rates between patients with X-linked and those with autosomal recessive chronic granulomatous disease. The 8-year actuarial survival rate was significantly higher for patients born in 1978 or afterward than for patients born before 1978 (92.9% vs 70.5%). A retrospective analysis of the occurrence of bacterial and fungal infections in patients who received trimethoprim-sulfamethoxazole and ketoconazole as infection prophylaxis indicated that the former was effective against bacterial infections but that ketoconazole provided no protection against Aspergillus infections.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2784499&dopt=Abstract ketoconazole Nizoral



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Coinduction of multiple hepatic cytochrome P-450 proteins and their mRNAs in rats treated with imidazole antimycotic agents.

Hostetler KA, Wrighton SA, Molowa DT, Thomas PE, Levin W, Guzelian PS.

Life Science Research, Hershey Foods Corporation, Hershey, Pennsylvania 17033.

To characterize the molecular basis by which imidazole antimycotic drugs increase cytochrome P-450, we examined the effects of treating female rats with clotrimazole, miconazole, or ketoconazole on expression of the major inducible forms of hepatic cytochromes P-450 (P-450p, P-450b/e, P-450c/d, and P-450j). From measurements of the content of immunoreactive cytochromes P-450 in liver microsomes and of the amounts of liver RNA hybridizing to cloned P-450 cDNAs, we established that the glucocorticoid-responsive P-450p is the form predominantly induced by clotrimazole, miconazole, and ketoconazole, to as much as 382 times above control values. The phenobarbital-responsive cytochromes P-450b/e were also induced strongly by clotrimazole and miconazole, but not by ketoconazole. Aromatic hydrocarbon-inducible cytochromes P-450c/d were modestly elevated by each of these three antifungal drugs whereas ethanol-responsive P-450j was marginally induced by ketoconazole, but not by clotrimazole or miconazole. In some, but not all cases, treatment of rats with antifungal drugs resulted in accumulation of P-450 protein that significantly exceeded the increase in the corresponding P-450 mRNA. In conclusion, imidazole antifungal drugs differentially modulate the expression of at least four distinct gene subfamilies of rat hepatic cytochrome P-450 by separate mechanisms involving accumulation of P-450 mRNA and protein.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2784534&dopt=Abstract ketoconazole Nizoral



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Antifungal effects of selenocystine and its derivatives on dermatophytes.

Kunert J.

Antifungal effects of DL-selenocystine and its derivatives (DL-selenolanthionine, DL-Se-sulfoselenocysteine) and of sodium selenite were tested in 14 dermatophytes and 7 species of keratinolytic and non-keratinolytic soil fungi. Minimal inhibitory concentrations of the compounds were measured and compared to those of ketoconazole. Organic selenocompounds behaved similarly. They were on average less inhibitory than ketoconazole but, in some cases, MICs were equal or even lower. The effects of selenite were but small. The action of selenocystine and ketoconazole in concentrations up to 50 micrograms/ml was found to be mostly fungistatic. Free L-cystine (100 micrograms/ml) antagonized the antifungal effect of its selenoanalog.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2797051&dopt=Abstract ketoconazole Nizoral



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Oxidative metabolism of cholesterol precursors: sensitivity to ketoconazole, an inhibitor of cytochrome P-450.

Iglesias J, Gibbons GF.

Metabolic Research Laboratory, Nuffield Department of Clinical Medicine, Radcliffe Infirmary, Oxford, UK.

The effects of ketoconazole, an inhibitor of cytochrome P-450, on the metabolism of the cholesterol precursors lanosterol, dihydrolanosterol, lanost-8-en-3 beta,32-diol, and 3 beta-hydroxylanost-8-en-32-al were investigated in subcellular fractions of rat liver and in rat hepatocytes in culture. At low (1-2 microM) concentrations of the drug, the oxidative demethylation of lanosterol was inhibited by about 70% in the subcellular fractions but there was no effect on the metabolism of the 3 beta, 32-diol or the 32-aldehyde. Higher drug concentrations (10-20 microM) were required to inhibit the oxidative metabolism of these cholesterol precursors. Similar results were obtained during longer-term incubations using hepatocytes in culture medium, but higher concentrations of ketoconazole were required to effect the same degree of inhibition of each precursor. In the subcellular fractions, dihydrolanosterol, the 3 beta,32-diol and the 32-aldehyde were each metabolized to more polar sterols, in addition to cholesterol. Ketoconazole also inhibited the formation of these polar substances.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2799848&dopt=Abstract ketoconazole Nizoral