Nizoral
Ketoconazole inhibits self-induced metabolism of 1,25-dihydroxyvitamin D3 and amplifies 1,25-dihydroxyvitamin D3 receptor up-regulation in rat osteosarcoma cells.

Reinhardt TA, Horst RL.

National Animal Disease Center, U.S. Department of Agriculture, Ames, Iowa 50010.

Ketoconazole (an inhibitor of vitamin D-24 hydroxylase) was used to study the role of self-induced 1,25-dihydroxyvitamin D3 (1,25-D3) metabolism on cellular responsiveness to 1,25-D3. Eighteen hours of treatment with 1,25-dihydroxy-[26,27-methyl-3H]vitamin D3 (1,25-[3H]D3) increased total 1,25-D3 receptors (VDR) from 60 to 170 fmol mg/protein. In cells treated with both 1,25-[3H]D3 and ketoconazole, up-regulation of VDR was increased by 40% over that observed with cells receiving 1,25-[3H]D3 alone. Ketoconazole alone had no agonistic activity. Treatment of cells with 1 nM 1,25-[3H]D3 plus increasing doses of ketoconazole (0-30 microM) resulted in a dose-dependent increase in occupied VDR and total VDR. This up-regulation was associated with reduced 1,25-[3H]D3 catabolism. 1,25-[3H]D3-induced up-regulation of VDR typically peaked at 14 h and declined thereafter. Ketoconazole lengthened the time to reach peak VDR up-regulation to 20 h. The ability of ketoconazole to increase cell responsiveness (VDR up-regulation) was the result of both increased and prolonged occupancy of VDR by 1,25-[3H]D3. The t1/2 of occupied VDR was 2 h in the absence of ketoconazole and greater than 7 h when ketoconazole was present. Collectively, these results suggested that self-induced catabolism of 1,25-D3 is an important regulator of VDR occupancy and therefore cellular responsiveness to hormone. These data also demonstrate the usefulness of ketoconazole as an inhibitor of vitamin D hydroxylases in intact cells.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2546501&dopt=Abstract ketoconazole Nizoral



Nizoral
[Long-term treatment of Cushing's disease using ketoconazole. Possibility of therapeutic escape]

[Article in French]

Diop SN, Warnet A, Duet M, Firmin C, Mosse A, Lubetzki J.

Service de Medecine interne et Nutrition-Endocrinologie, Universite Paris-VII.

Five women suffering from Cushing's disease were treated with ketoconazole 800 mg per day for 2 to 28 months (mean 12.4 months). Four of them had full clinical and biochemical regression. However, after 8 months of therapy the disease failed to respond in three of these four women. Increasing the ketoconazole dosage up to 1,200 mg per day was ineffective in two patients. Such an escape phenomenon, not described until now, will restrict the use of ketoconazole in the treatment of Cushing's disease, although the drug is easy to administer and well tolerated globally and by the liver in most cases.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2552430&dopt=Abstract ketoconazole Nizoral



Nizoral
[Comparison of the susceptibility of Candida strains to ketoconazole and itraconazole in in vitro experiments]

[Article in Polish]

Gwiezdzinski Z, Nierebinska E, Urbanowski S.

The activity of ketoconazole and itraconazole against 102 strains of Candida sp. was compared in the investigation "in vitro". The investigational material was taken from patients with different types of mycosis. The values of MICs of ketoconazole and itraconazole were 0.04-100.0 micrograms/ml and 0.02-35.0 micrograms/ml, respectively. From the data obtained it is evident that the average efficacy of itraconazole is 3 to 10 times higher in comparison with ketoconazole though 8 strains (7, 8 percent) of investigated strains have shown greater sensitivity to ketoconazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2561924&dopt=Abstract ketoconazole Nizoral



Nizoral
[Antifungal activity of itraconazole and ketoconazole investigated in vitro, determined with minimal inhibitory concentrations and mycelial cell transformation in Candida albicans]

[Article in Polish]

Urbanowski S, Nierebinska E, Gwiezdzinski Z.

Results of studies "in vitro" of the susceptibility of 82 strains of Candida albicans for itraconazole and ketoconazole have been report. The strains were isolated from lesions of the mucous membranes and skin. The susceptibility of Candida albicans was tested to Minimal Inhibitory Concentration (MIC) and Total Inhibition Germination Tubes (TI100). The values of MICs and TI100 of itraconazole were 0.02-35.0 micrograms/ml and 0.02-18.0 micrograms/ml, respectively. The similar values of MICs and TI100 of ketoconazole were 0.04-80.0 micrograms/ml and 0.04-20.0 micrograms/ml. It has been showed that TI100 can be used as preliminary and rapid test of Candida albicans susceptibility for these drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2561925&dopt=Abstract ketoconazole Nizoral



Nizoral
Fluconazole is a potent inhibitor of antipyrine metabolism in vivo in mice.

La Delfa I, Zhu QM, Mo Z, Blaschke TF.

Department of Medicine, Stanford University School of Medicine, CA 94305.

Fluconazole, a bis-triazole antifungal, is distinguished from imidazole antifungals (e.g. ketoconazole) by its potency and pharmacokinetic characteristics. Imidazole-containing compounds are well documented to inhibit the hepatic cytochrome P-450-dependent enzyme system; whether this effect occurs with a bis-triazole agent is unknown. The [14C]antipyrine breath test was employed to investigate the effects of fluconazole on this enzyme system in CD-1 male mice. Control, ketoconazole (100 mg/kg), and fluconazole (1 and 10 mg/kg) were studied in single- and multiple-dose experiments. Fluconazole had potent inhibitory effects on the total (mean = -73% +/- 2%), demethylase (mean = -90% +/- 2%), and nondemethylase (mean = -60% +/- 4%) elimination rate constants (all p less than 0.001). The fraction of the administered radioactivity excreted as 14CO2 was decreased by 50-80% in the fluconazole groups (p less than 0.001). These effects were seen after single- and multiple-dose studies; however, return to baseline occurred more quickly in the multiple-dose group. These effects were significantly more pronounced than those observed with equipotent doses of ketoconazole. These results provide evidence that fluconazole is a potent, partially selective, and reversible inhibitor of the cytochrome P-450-dependent enzyme system in mice. Future studies will be required to assess this property and possible interactions with drugs metabolized by this enzyme system in humans.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2566469&dopt=Abstract ketoconazole Nizoral



Nizoral
Concomitant administration of cyclosporin and ketoconazole in renal transplant recipients.

First MR, Schroeder TJ, Weiskittel P, Myre SA, Alexander JW, Pesce AJ.

Department of Internal Medicine, College of Medicine, University of Cincinnati Medical Center, Ohio.

18 renal transplant recipients receiving cyclosporin, prednisone, and azathioprine were given ketoconazole, a potent inhibitor of the cytochrome P-450 enzyme system. Within a month ketoconazole-induced blockade of cyclosporin metabolism allowed a significant reduction (451 vs 106 mg/day; 77%) of the mean dose of cyclosporin without altering cyclosporin whole blood trough levels, although maximum blood levels were almost halved. This dose reduction was maintained in patients followed up for up to 13 months. Renal and hepatic function were unchanged after the addition of ketoconazole. This drug interaction has the potential to reduce dramatically expenditure on cyclosporin in transplant recipients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2572912&dopt=Abstract ketoconazole Nizoral



Nizoral
Influence of human nail etching for the assessment of topical onychomycosis therapies.

Repka MA, Mididoddi PK, Stodghill SP.

Department of Pharmaceutics, School of Pharmacy, The University of Mississippi, University, MS 38677-1848, USA. marepka olemiss.edu

The purpose of this investigation was to study the physico-chemical properties of hot-melt extruded films containing ketoconazole and to determine the influence of 'nail etching' on film bioadhesion and drug permeability for the assessment of topical onychomycosis therapies. Hot-melt extrusion (HME) was used to prepare films containing 20% w/w ketoconazole. Ketoconazole 0.125% gel was also prepared using Carbopol 974P NF. Films were processed at a temperature range of 115-120 degrees C utilizing a Killion extruder (KLB-100), and were evaluated for post-extrusion drug content, content uniformity, bioadhesion, thermal behavior and nail drug permeation. The extruded films demonstrated excellent content uniformity and post-processing drug content. Tensile and peel tests were recorded to determine the bioadhesive profiles. In this study, work of adhesion and peak adhesive force determinations using the peel tests provided more sensitive results for evaluating the bioadhesivity of the HME films than the tensile tests. The in vitro permeability profiles have demonstrated, that nail samples treated with an 'etchant' demonstrated a significant increase in drug permeability compared to control. Differential scanning calorimetry (DSC) thermograms indicated that ketoconazole was in solid solution within the HME films. These findings are encouraging for the future design and formulation of novel drug delivery systems for the topical treatment of onychomycosis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15336385&dopt=Abstract ketoconazole Nizoral