Nizoral
Synergy of itraconazole with macrophages in killing Blastomyces dermatitidis.

Brummer E, Bhagavathula PR, Hanson LH, Stevens DA.

Department of Medicine, Santa Clara Valley Medical Center, San Jose, California.

We examined in vitro interaction between the azole antifungal agents itraconazole and ketoconazole and macrophages and their activities against Blastomyces dermatitidis. Fungistatic and fungicidal concentrations for B. dermatitidis in vitro were assessed in a microculture system in which fungistasis was measured as inhibition of multiplication and fungicidal activity was measured as reduction of inoculum CFU. Resident peritoneal murine macrophages, which surround but do not phagocytize the fungus, were not fungicidal for B. dermatitidis isolates but were fungistatic for some isolates studied. Synergy was demonstrated when fungistatic concentrations (e.g., 0.01 micrograms/ml) of itraconazole, which limited growth 55% compared with that of controls, were cocultured with macrophages; this resulted in fungicidal activity (85% killing) against B. dermatitidis (ATCC 26199) in 72-h assays. This synergy could occur even if itraconazole was added after the macrophages had surrounded the fungus. Ketoconazole at fungistatic concentrations did not act synergistically with macrophages to kill B. dermatitidis. Lymph node lymphocytes could not substitute for macrophages in synergy with itraconazole to kill B. dermatitidis. When B. dermatitidis was separated by a filter from macrophages in Transwell cultures, fungicidal synergy with itraconazole was less efficient. Pretreatment of B. dermatitidis with itraconazole for 24 h did not render the fungus susceptible to killing by macrophages in the absence of itraconazole, whereas pretreatment of nonfungistatic macrophages with itraconazole rendered them fungistatic in a dose-dependent manner. Three other isolates were killed by otherwise fungistatic concentrations of itraconazole when the isolates were cocultured with macrophages. These findings indicate that one basis for the efficacy of itraconazole versus ketoconazole in treating blastomycosis could be synergy of a fungistatic concentration of itraconazole with macrophages in killing of B. dermatitidis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1336949&dopt=Abstract ketoconazole Nizoral



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Topical ketoconazole does not potentiate oral cyclosporin A in allergic contact dermatitis.

McLelland J, Shuster S.

University Department of Dermatology, Royal Victoria Infirmary, Newcastle, UK.

Cyclosporin A is an effective drug but its use is limited by its side effects. Since oral ketoconazole inhibits the metabolism of oral cyclosporin, we set out to find out whether topical ketoconazole would enhance the effect in the skin of oral cyclosporin. Five patients with contact allergic dermatitis (CAD) were given a 6-day course of cyclosporin (1 mg/kg/day) and applied 2% ketoconazole cream to an area on one arm and the inert base to the other. Serial dilutions of the relevant allergen were applied to the arms at 3 days for 48 hours, and the responses were measured objectively a day later. There was no significant difference between responses at the two sites, indicating that topical ketoconazole does not enable the dose of oral cyclosporin to be reduced in CAD.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1357888&dopt=Abstract ketoconazole Nizoral



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In vitro sensitivity of Penicillium marneffei and Pythium insidiosum to various antifungal agents.

Sekhon AS, Padhye AA, Garg AK.

National Reference Center for Human Mycotic Diseases, University of Alberta, Edmonton, Canada.

Ten isolates of Penicillium marneffei and eight of Pythium insidiosum were tested for their in vitro sensitivity to amphotericin B, hamycin (a polyene heptaene), two water-soluble analogs of amphotericin B and hamycin, namely, JAI-Amb, and JAI-hamycin,5-fluorocytosine, fluconazole, itraconazole,ketoconazole and miconazole. Itraconazole manifested the strongest activity against all of the 10 isolates of P. marneffei and would be the drug of choice in the treatment of penicilliosis due to P. marneffei. The polyene antibiotics amphotericin B and hamycin and their water-soluble analogs showed no appreciable activity against P. insidiosum. Pytium insidiosum isolates were sensitive to fluconazole, ketoconazole, and miconazole. Miconazole exhibited the strongest in vitro activity against all of the 8 isolates of P. insidiosum, followed by ketoconazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1397206&dopt=Abstract ketoconazole Nizoral



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Reduced azole susceptibility of oral isolates of Candida albicans from HIV-positive patients and a derivative exhibiting colony morphology variation.

Gallagher PJ, Bennett DE, Henman MC, Russell RJ, Flint SR, Shanley DB, Coleman DC.

Trinity College, Department of Pharmacology, School of Pharmacy, University of Dublin, Republic of Ireland.

Approximately 50% (15/28) of a selection of oral isolates of Candida albicans from separate individuals infected with the human immunodeficiency virus (HIV) exhibited low susceptibility to ketoconazole as determined by hyphal elongation assessment. Nine of these isolates exhibited colony morphology variation or switching at 37 degrees C, of which six expressed low ketoconazole susceptibility. To determine whether colony morphology variation could give rise to derivatives with reduced azole susceptibility, several high-frequency switching variants of three HIV-patient isolates were recovered and assessed. All but one of the variants expressed similar azole susceptibility profiles to their respective parental strains. However, the C. albicans derivative 132ACR expressed significantly reduced susceptibility to ketoconazole in comparison to its parental strain 132A. In whole cells, on the basis of total growth the switched derivative 132ACR was markedly less susceptible than its parental isolate 132A to ketoconazole at 10 microM. A much smaller difference was observed with fluconazole at 10 microM, with the switched derivative 132ACR exhibiting a threefold lower susceptibility compared with the parental isolate 132A. The incorporation of [14C]acetate in control and azole-treated cells of both organisms was higher for the parental strain. When cell lysates of strain 132A and its derivative 132ACR were incubated with [14C]mevalonic acid and ketoconazole, the IC50 for 14C-label incorporation into C-4 demethyl sterols was fivefold higher for lysates of the switched derivative 132ACR compared with those of the parental strain 132A. With fluconazole the IC50 value for the derivative 132ACR was 25-fold higher than for strain 132A. The 14-sterol demethylase of the switched derivative 132ACR was possibly less sensitive to azole inhibition than that of the enzyme of strain 132A. These studies indicated that colony morphology variation in vitro can generate derivatives with stable, reduced azole susceptibility without prior exposure to azoles.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1402791&dopt=Abstract ketoconazole Nizoral



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[The effect of ketoconazole on the cholesterol content of the blood serum lipoproteins and bile in experimental hypercholesterolemia]

[Article in Russian]

Dushkin MI, Ivanova MV.

Inclusion of ketonazole (in a daily dose of 400 mg/kg for 8 days) into the diet of intact and cholesterol-fed (5% dietary cholesterol) rats produced a respective 20- and 30-percent lowering of cholesterol content in blood serum. In all the animals, the hypocholesterolemic effect of ketoconazole was realized via a decrease of the concentration of very low and low density lipoproteins. Ketoconazole also gave rise to a reduction of the concentration of cholesterol and bile acids in bile of the intact rats and of cholesterol in bile of the cholesterol-fed animals.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1422455&dopt=Abstract ketoconazole Nizoral



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Intraocular penetration of ketoconazole in rabbits.

Hemady RK, Chu W, Foster CS.

Cornea and Immunology Services, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston 02114.

We studied penetration of the antifungal agent ketoconazole into the cornea, aqueous humor, and vitreous of rabbits after topical, subconjunctival, and oral administration. The effect of debridement of corneal epithelium on penetration was also investigated. Ketoconazole levels in the cornea and aqueous humor were high after topical or subconjunctival administration, and increased markedly (especially in the cornea) if the corneal epithelium had been debrided before administration of the drug. For example, concentration of ketoconazole in the cornea 1 h after topical drug administration with or without complete corneal epithelial debridement was 44.0 +/- 10.1 and 1,391.5 +/- 130.0 micrograms/g, respectively. Drug levels in the vitreous were not detectable after topical or subconjunctival drug administration, but were improved slightly by prior epithelial debridement (8.3 and 0.12 micrograms/mL after 1 h, respectively). Orally administered ketoconazole resulted in high corneal concentrations (45.0 +/- 7.6 micrograms/g after 1 h) that were still substantial 24 h later (55.0 +/- 7.0 micrograms/g); levels in the aqueous were low.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1424654&dopt=Abstract ketoconazole Nizoral



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Pharmacokinetic and pharmacodynamic studies of the effect of ketoconazole on reproductive function in male rats.

Wang JM, Wu XL, You W, Ling LX, Wu J, Zhang GY.

Department of Pharmacology, Nanjing Institute of Materia Medica, People's Republic of China.

A single oral dose (300 mg kg-1) of ketoconazole induced reversible immobilization of rat epididymal spermatozoa at 8-24 h after dosing. This occurred when the drug concentrations in cauda epididymal fluid and seminal plasma were at their peak (18.0 +/- 7.3 and 13.5 +/- 3.0 micrograms ml-1, respectively), and which was preceded by a peak plasma concentration (Cmax) of 64.82 +/- 2.47 micrograms ml-1 at 5.15 +/- 0.68 h (Tmax). In contrast, rete testis fluid collected from the same animals contained only minute amounts of ketoconazole (0.47 +/- 0.34 micrograms ml-1). Plasma testosterone concentration showed a sharp decline within 4 h of dosing, followed by a recovery from suppression, even after administration of a low dose (100 mg kg-1) which did not affect sperm motility. These findings suggest that ketoconazole gains access to the post-testicular sex organs and affects the mature spermatozoa therein much more readily than it affects testicular spermatogenesis. Synthesis and screening of compounds with a related molecular structure but which exhibit more pronounced spermicidal and less pronounced anti-androgenic effects are thus suggested in the hope that rapidly acting and reversible male contraceptives might be identified and developed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1428196&dopt=Abstract ketoconazole Nizoral