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Antithyroid action of ketoconazole: in-vitro studies and rat in-vivo studies.

Comby F, Lagorce JF, Buxeraud J, Raby C.

Laboratoire de Chimie Therapeutique et Chimie Organique, Faculte de Pharmacie, Limoges, France.

Inspection of the chemical structure of ketoconazole indicates that it may have antithyroid activity. The antithyroid action of this drug was demonstrated in-vitro and in-vivo. In-vitro, it was found to form a complex with iodine (formation constant Kc 141 L mol-1), and to inhibit lactoperoxidase (IC50 2 x 10(-4) M). Its effects in-vivo in the rat were assessed by assay of circulating-thyroxine, and from the histological appearance of the thyroid gland. Thyroid gland weight was increased in rats treated with ketoconazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7515419&dopt=Abstract ketoconazole Nizoral



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Ketoconazole activates Cl- conductance and blocks Cl- and fluid absorption by cultured cystic fibrosis (CFPAC-1) cells.

Kersting U, Kersting D, Spring KR.

National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.

The role of arachidonic acid metabolites in the regulation of apical cell membrane Cl- conductance and transepithelial transport of fluid and Cl- by cultured pancreatic cells from cystic fibrosis (CFPAC-1) and corrected (PAC-1) cell lines was evaluated by the use of inhibitors. CFPAC-1 cells did not exhibit an apical membrane Cl- conductance, absorbed Cl- and fluid, and did not respond to stimulation or inhibition of cAMP action. PAC-1 cells exhibited a cAMP-responsive apical Cl- conductance, which was blocked by indomethacin, a cyclooxygenase inhibitor. Ketoconazole, an epoxygenase inhibitor, had virtually no effects on PAC-1 cell Cl- conductance but caused CFPAC-1 cells to develop a cAMP-insensitive Cl- conductance, blocked Cl- and fluid absorption, and reduced transepithelial electrical resistance. Ketoconazole treatment effectively reversed the cystic fibrosis defect in these cultured cells.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7683418&dopt=Abstract ketoconazole Nizoral



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The dual mode of inhibition of calmodulin-dependent nitric-oxide synthase by antifungal imidazole agents.

Wolff DJ, Datto GA, Samatovicz RA.

Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway 08854.

The antifungal imidazoles miconazole, ketoconazole, and clotrimazole inhibit citrulline formation by nitric-oxide synthase. These agents both increase the concentration of calmodulin required to activate the enzyme half-maximally and reduce the maximal velocity of citrulline formation. This inhibition was not reversed by increased concentrations of either the arginine substrate or (6R)-5,6,7,8-tetrahydro-L-biopterin. Miconazole, ketoconazole, and clotrimazole also inhibited the cytochrome-c reductase activity of nitric-oxide synthase competitively versus calmodulin concentration, with apparent Ki (IC50) values of 8, 20, and 0.8 microM, respectively. Miconazole, ketoconazole, and clotrimazole inhibited the activity of calmodulin-dependent cyclic nucleotide phosphodiesterase competitively versus calmodulin concentration, with apparent Ki values of 6, 18, and 25 microM, respectively. These observations are consistent with the proposal that the antifungal imidazoles inhibit citrulline formation by interaction with the nitric-oxide synthase at two sites. Interaction at site 1 reduces the responsiveness of the enzyme to activation by calmodulin, whereas interaction at site 2 (involving putative binding of the imidazole to the heme iron) reduces the maximal velocity of citrulline formation. The interactions of calmodulin antagonists at site 1 occur at substantially lower concentrations of drug than those at site 2 and are the principal determinant of enzyme inhibition.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7683652&dopt=Abstract ketoconazole Nizoral



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Perilla ketone increases endothelial cell monolayer permeability in vitro.

Waters CM, Alexander JS, Harris TR, Haselton FR.

Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee 37235.

Perilla ketone (PK) is a potent lung toxin that causes increased microvascular permeability pulmonary edema in grazing animals. Because the mechanism of action of PK is not know, we investigated whether PK directly affects endothelial cells. Bovine aortic endothelial cells were grown to confluence on Cytodex-3 microcarrier beads and placed in a chromatographic cell column. Monolayer permeability was evaluated from the elution profiles of three optical tracers: blue dextran (2 x 10(6) mol wt), sodium fluorescein (NaF, 342 mol wt), and cyanocobalamin (B12, 1,355 mol wt). Perfusion with 1.2 mM PK increased permeability within 15 min to NaF and B12 by 51 +/- 6 and 54 +/- 11%, respectively. Permeability returned to baseline after PK removal. These in vitro results suggest that PK produces a rapid and reversible increase in endothelial permeability directly. Staining of fixed cells with rhodamine-phalloidin revealed a major disruption of actin microfilaments after PK treatment. Because previous reports suggested that PK may be activated via cytochrome P-450, we attempted to block this using the cytochrome P-450 inhibitor ketoconazole. Ketoconazole alone did not significantly affect permeability, and the combination of PK and ketoconazole resulted in permeability increases similar to those measured for PK alone. This suggests that PK may not require cytochrome P-450 to increase vascular permeability.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7687599&dopt=Abstract ketoconazole Nizoral



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Effects of ketoconazole (an imidazole antifugal agent) on the fertility and reproductive function of male mice.

Joshi SC, Jain GC, Lata M.

Department of Zoology University of Fajasthan, Jaipur, India.

Administration of ketoconazole, an imidazole antifungal agent (400 mg/kg b.wt. orally for a period of 60 days) resulted in a significant decline in sperm motility and density in cauda epididymis. A sharp decline in fertility (50% negative) in Ketoconazole treated mice was observed. A significant reduction in the total protein and sialic acid contents of testes, epididymis, seminal vesicle and ventral prostate were noticed. The cholesterol contents of testes were raised while fructose contents of seminal vesicle were reduced significantly. The ketoconazole treatment altered the biochemical milieu of the reproductive tract. The mechanism of action is discussed.

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Ketoconazole effectively reverses multidrug resistance in highly resistant KB cells.

Siegsmund MJ, Cardarelli C, Aksentijevich I, Sugimoto Y, Pastan I, Gottesman MM.

Laboratory of Molecular Biology, DCBDC, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.

The antifungal agent ketoconazole was found to overcome resistance to vinblastine and doxorubicin in multidrug resistant KB-V1 cells in vitro. These cells are several hundred-fold more resistant than the parental cell line KB-3-1. Ketoconazole had little or no effect on the parental KB-3-1 cells. The concentrations used to overcome drug resistance in vitro have already been safely used in vivo for treatment of fungal infections and in the monotherapy of hormone independent prostate carcinomas to block adrenal androgen production. Because of a possible beneficial effect of a combination of ketoconazole and a chemotherapeutic drug in multidrug resistant cancers, we examined a panel of 11 prostate carcinoma tissues for the expression of the MDR1 gene by an RNA-PCR assay. MDR1 expression was detectable, albeit at low levels, in 8 of the 11 tumors, suggesting a possible role of this gene in the drug resistance of prostate carcinomas. Our data suggest that ketoconazole might be useful in overcoming multidrug resistance in concentrations that are achievable in humans.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7904313&dopt=Abstract ketoconazole Nizoral



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In vitro analysis of the interaction between sucralfate and ketoconazole.

Hoeschele JD, Roy AK, Pecoraro VL, Carver PL.

Department of Chemistry, University of Michigan, Ann Arbor 48109-1065, USA.

In healthy volunteers, the bioavailability of ketoconazole is significantly decreased during simultaneous administration with sucralfate. In an effort to address this problem, we examined the interaction between sucralfate and ketoconazole in aqueous solutions and in simulated gastric fluid (SGF) at various initial pHs (1, 2, 3, and 6) in the presence or absence of glutamic acid hydrochloride (GA). Samples from each solution were taken 30 min and 2 h after the addition of ketoconazole to evaluate the solubility of ketoconazole over the usual time period of maximal absorption of ketoconazole in humans. The addition of GA to SGF leads to an increase in solution acidity, while the pHs of SGF at a pH of 1, 2, or 3 are markedly increased by the addition of sucralfate. There is a net decrease in acidity from initial pHs for the pH 1, 2, and 3 solutions when GA and sucralfate are combined. The concentration of ketoconazole in SGF at pHs of 1, 2, 3, 4, and 6 was evaluated in order to assess the pH-dependent solubility properties of the drug in the absence of other interacting species. Regardless of the initial pH, combinations of GA plus ketoconazole showed high concentrations of ketoconazole (approximately 100%) in solution. In contrast, significant decreases in the concentration of soluble ketoconazole were observed when sucralfate was mixed with ketoconazole, and, in some cases, soluble ketoconazole was not detectable. The addition of GA to a mixture of sucralfate and ketoconazole leads to a significant increase in the concentration of solubilized ketoconazole. Nonetheless, important sucralfate-ketoconazole interactions are still observed. After 2 h, approximately 35% of the maximal ketoconazole concentration remained in solution. Comparison of the ketoconazole concentrations at different pHs with the predicted concentrations of the three protonation species of ketoconazole [H2(ketoconazole)(2+), H(ketoconazole)(+), or ketoconazole] showed no correlation. Therefore, the decrease in ketoconazole solubility is not simply a reflection of pH perturbation associated with the dissolution of sucralfate. The observed data are most consistent with a model that has H2(ketoconazole)(2+) or H(ketoconazole)(+) forming an electrostatic interaction with the sucralfate polyanion. The findings of this study suggest that the coadministration of sucralfate with other azole antifungal agents should be investigated.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7910723&dopt=Abstract ketoconazole Nizoral