Nizoral
Pharmacology of novel steroidal inhibitors of cytochrome P450(17) alpha (17 alpha-hydroxylase/C17-20 lyase).

Barrie SE, Potter GA, Goddard PM, Haynes BP, Dowsett M, Jarman M.

Drug Development Section, Institute of Cancer Research, Sutton, Surrey, England.

Medical or surgical castration for the treatment of prostatic cancers prevents androgen production by the testes, but not by the adrenals. Inhibition of the key enzyme for androgen biosynthesis, cytochrome P450(17) alpha, could prevent androgen production from both sources. The in vivo effects of 17-(3-pyridyl)androsta-5,16-dien-3 beta-ol (CB7598) and 17-(3-pyridyl)androsta-5,16-dien-3-one (CB7627), novel potent steroidal inhibitors of this enzyme, on WHT mice were compared with those of castration and two clinically active compounds, ketoconazole and flutamide. Flutamide and surgical castration caused significant reductions in the weights of the ventral prostate and seminal vesicles. CB7598, in its 3 beta-O-acetate form (CB7630), and CB7627 caused significant reductions in the weights of the ventral prostate, seminal vesicles, kidneys and testes when administered once daily for 2 weeks. Ketoconazole, given on the same schedule, caused no reductions. Plasma testosterone was reduced to < or = 0.1 nM by CB7630, despite a 3- to 4-fold increase in the plasma level of luteinizing hormone. Adrenal weights were unchanged following treatment with CB7630 or CB7627 but were markedly increased following ketoconazole, indicating no inhibition of corticosterone production by these steroidal compounds. These results indicate that CB7598, CB7630 or CB7627 may be useful in the treatment of hormone-dependent prostatic cancers.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7918112&dopt=Abstract ketoconazole Nizoral



Nizoral
Disposition of azole antifungal agents. II. Hepatic binding and clearance of dichlorophenyl-bis-triazolylpropanol (DTP) in the rat.

Bomont HL, Tarbit MH, Humphrey MJ, Houston JB.

Department of Pharmacy, University of Manchester, UK.

DTP (dichlorophenyl-bis-triazolylpropanol) was evaluated as a probe of drug-cytochromes P450 interactions in vitro and in vivo. Studies with rat liver microsomes demonstrate that DTP shows similar P450 binding affinity to its analog, ketoconazole, as determined by P450 difference spectra and inhibition of the metabolism of methoxycoumarin. As a more polar azole, DTP shows less affinity for rat plasma albumin (fraction unbound 0.56) than ketoconazole (fraction unbound 0.037). DTP metabolism is simpler than that of ketoconazole, with only one pathway, N-dealkylation which removes a triazole ring to yield DTP glycol. This primary metabolite is further metabolised to a carboxylic acid, a glycol glucuronide and a third unknown secondary metabolite (probably an acid glucuronide). Over a dose range of 0.1-24mg/kg there is complete mass balance recovery in urine via the five metabolites and unchanged drug. However DTP metabolism is dose dependent and while the affinity of DTP for the cytochromes P450 carrying out the initial dealkylation is high (1.5 microM based on unbound blood concentration), the capacity of the reaction is low (1 nmole/min). Under linear conditions, metabolic clearance is low (19ml/h), but ten-fold higher than renal clearance. The liver is the major distribution site for both DTP and ketoconazole. At low DTP concentrations, a specific high affinity process dominates the hepatic binding of DTP resulting in a liver:blood partition coefficient of approximately 30. Hepatic binding is concentration dependent and the progressive decrease in partition coefficient observed as the dose of DTP is escalated is coincident with a decrease in volume of distribution. The two saturable processes involved in the disposition of DTP result in an unusual concentration dependency in the blood concentration-time profile of this azole. Following administration of a high dose (10mg/kg) of DTP the log concentration-time profile is sigmoidal. At high concentrations (above 1mg/L) both the N-dealkylation and the hepatic binding of DTP are saturated, but as concentrations fall to approximately 0.05mg/L the former process becomes linear and the time profile is convex over this concentration range. At later times as DTP concentrations decline further, the tissue binding also reaches the linear region and the time profile becomes concave. Only at low concentrations (below 0.05mg/L) do both processes become first order and the true half life is evident.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7937554&dopt=Abstract ketoconazole Nizoral



Nizoral
Effect of antifungal drugs on pathogenic Naegleria spp isolated from natural water sources.

Tiewcharoen S, Junnu V, Suvoutho S.

Department of Parasitology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.

Five of 16 strains of pathogenic Naegleria spp isolated from 350 natural water sources in Taling Chan District, Bangkok had similar molecular weights and zymogram patterns to those of Naegleria fowleri CDCVO 3081 and Thai strain. The in vitro effects of antifungal drugs (amphotericin B, ketoconazole, fluconazole and itraconazole) were tested at the following concentrations: amphotericin B 0.01-0.55 microg/ml, ketoconazole 0.01-0.3 microg/ml, fluconazole 0.75-3.5 mg/ml and itraconazole 4-12 mg/ml respectively. Aliquots (15,000 cells/ml) of the amoebae were placed in the cells of the microtiter plate and incubated at 37 degrees C. Amoebae from each treatment sample were exposed to one of the four antifungal drugs. Statistical analysis was done by dependent t-test. The sensitivity of the antifungal drugs (MIC50) was as follows: amphotericin B 0.03-0.035 microg/ml ketoconazole 0.05-0.15 microg/ml fluconazole 1.75 mg/ml and itraconazole 8-9 mg/ml respectively (p < 0.005). CONCLUSION: Amphotericin B and ketoconazole are more active against Naegleria fowleri in vitro. The results of the present study should be used as an in vitro screening test for drugs that have potential amebicidal activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14649973&dopt=Abstract ketoconazole Nizoral



Nizoral
[Oral treatment of onychomycosis of the toe nails; comparison of cost-effectiveness of griseofulvin, itraconazole, ketoconazole and terbinafine]

[Article in Dutch]

Bergman W, Rutten FF.

Academisch Ziekenhuis, afd. Dermatologie, Leiden.

OBJECTIVE. Determination of the most cost-effective oral drug treatment of onychomycosis of the toenails in the Dutch situation, by comparing griseofulvin, itraconazole, ketoconazole and terbinafine. DESIGN. Calculation of cost prices using a published meta-analysis. SETTING. The Netherlands. METHOD. Published efficacy and adverse reactions of treatment with griseofulvin, itraconazole, ketoconazole or terbinafine were related to 1993 Dutch cost prices of treatment. RESULTS. Itraconazole and terbinafine offered similar chances of success, but itroconazole treatment had to be repeated more often. On average, the costs of the treatment with itraconazole were 1.5 times as high as those of treatment with terbinafine. Griseofulvin treatment was cheapest but required the longest treatment course. CONCLUSION. A treatment with terbinafine is the most cost-effective, provided that onychomycosis has actually been established mycologically and all possible measures have been taken to prevent recurrence. It remains to be seen whether this drug treatment should be offered to all people affected by this essentially cosmetic problem.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7969635&dopt=Abstract ketoconazole Nizoral



Nizoral
Potentializing effect of ketoconazole on cyclosporin A-induced inhibition of keratinocyte DNA synthesis.

Amsellem C, Haftek M, Thivolet J, De Doncker P, Schmitt D.

INSERM U 346 affiliee CNRS, Department of Dermatology, E. Herriot Hospital, Lyon, France.

Keratinocyte growth in vitro and DNA synthesis by epidermal cells in vivo are inhibited by therapeutic doses of cyclosporin A (CsA). This effect may be potentialized by topical treatment with ketoconazole, since this drug has been shown to inhibit CsA metabolism. Normal human skin grafts on nude mice receiving intraperitoneal injections of CsA were treated with ketoconazole cream or its placebo for 3 weeks. The keratinocyte DNA synthesis rate was evaluated through the rates of bromodeoxyuridine (BrdU) incorporation, and the trough blood levels of CsA were checked at the end of the experiment. Counting of the BrdU-labelled nuclei in human tissue sections confirmed a dose-dependent inhibition of BrdU incorporation by keratinocytes exposed to CsA. This CsA-induced inhibition was further increased in the animals treated with ketoconazole cream. This effect was best seen in the groups treated with the low-to-medium doses of CsA (12.5 and 25 mg/kg/day). However, the simultaneous increase in the circulating CsA levels was also observed in these animals. Based on our results, we speculate that the potentializing effect of ketoconazole on CsA-induced inhibition of keratinocyte DNA synthesis is systemic rather than local.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7976080&dopt=Abstract ketoconazole Nizoral



Nizoral
In vitro evaluation of griseofulvin, ketoconazole, and itraconazole against various dermatophytes in Singapore.

Goh CL, Tay YK, Ali KB, Koh MT, Seow CS.

National Skin Centre, Singapore.

BACKGROUND. Superficial cutaneous fungal infection, principally dermatophytosis, is an extremely common skin disease. Various in vitro test systems have been developed in recent years to determine the antifungal activity of various drugs. The minimum inhibitory concentration (MIC) obtained may give an indication of the in vivo potency of the drugs. METHODS. One hundred patients (69 men and 31 women) with a clinical diagnosis of dermatophytosis were entered into the study. Direct microscopy and culture were done on all patients. The MICS were determined using the broth dilution method. RESULTS. The age range was 1-76 years. The most common diagnosis was tinea corporis (36%), followed by tinea cruris (22%), and tinea pedis (19%). The most common fungus isolated was T. rubrum (58%), followed by E. floccosum (14%), and T. mentagrophytes (10%). The majority of the isolates was sensitive to the three drugs tested (griseofulvin, ketoconazole, and itraconazole). Of the isolates, 82% were sensitive to griseofulvin, 78% to ketoconazole, and 81% to itraconazole, all at a concentration of < 0.25 micrograms/mL. For T. rubrum, there were four isolates that had an MIC of > or = 64 micrograms/mL to griseofulvin, seven isolates and nine isolates with an MIC > or = 64 micrograms/mL to ketoconazole and itraconazole, respectively. T. interdigitale was relatively resistant to the three drugs in vitro with four of seven isolates having an MIC > or = 4 micrograms/mL with griseofulvin, one of seven isolate with an MIC > or = 64 micrograms/mL with ketoconazole, and three of seven isolates with an MIC > or = 32 micrograms/mL with itraconazole. CONCLUSIONS. The in vitro antifungal activity of griseofulvin, ketoconazole, and itraconazole are similar against dermatophytes in Singapore. Griseofulvin may be given as the first-line drug for treating such infections in Singapore.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8002147&dopt=Abstract ketoconazole Nizoral



Nizoral
Esophageal candidiasis after renal transplantation: comparative study in patients on different immunosuppressive protocols.

Gupta KL, Ghosh AK, Kochhar R, Jha V, Chakrabarti A, Sakhuja V.

Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

OBJECTIVES: The incidence of esophageal candidiasis (EC) in renal allograft recipients has not been well documented. The present study was done to determine the incidence of EC in renal allograft recipients receiving different forms of immunosuppressive therapy and to identify patients at a high risk of developing Candida esophagitis. METHODS: We conducted a retrospective study of 265 live related renal allograft recipients and compared three groups: patients given azathioprine and prednisolone (group I), those given cyclosporine, azathioprine, and prednisolone (group II), and those given cyclosporine and prednisolone (group III). EC was diagnosed by esophagogastroduodenoscopy. RESULTS: The overall incidence of EC was 10.5%. Group II patients had a significantly higher incidence (28.6%) than those in group I (10.4%) and group III (3.8%). EC was noted earlier in patients in groups II and III, who were on higher doses of steroids than group I patients. Dysphagia (57.1%) was the most common presenting symptom of EC, but 21.4% of patients were asymptomatic. Oral thrush was present in 42.9%. The entire esophageal mucosa was affected in six (46.1%) patients in group II and one (20%) in group III. No correlation was found between fungal serology or daily dose of steroids and extent of esophageal involvement. Treatment included nystatin in seven, nystatin and ketoconazole in 10, ketoconazole alone in eight, amphotericin B in one, and ketoconazole and amphotericin B in two episodes. Treatment failure occurred in seven (25%). Three patients died of disseminated candidiasis. Serology and biopsy were poor predictors of dissemination. CONCLUSIONS: In this retrospective study of renal allograft recipients, patients on triple drug immunosuppression, diabetics, and those with myelosuppression had an increased risk of developing EC. This high incidence calls for prophylactic use of antifungal agents in selected renal transplant recipients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8017366&dopt=Abstract ketoconazole Nizoral