Nizoral
Suppression of circulating calcitriol and duodenal active Ca transport by ketoconazole in pregnant rats.

Boass A, Toverud SU.

Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill 27599, USA.

Active Ca transport in the duodenum and the circulating level of calcitriol are elevated during pregnancy and lactation in the rat. Because calcitriol stimulates Ca transport in nonmated rats, we investigated its contribution to the increased transport during pregnancy and lactation. Rapid suppression of calcitriol from 28 +/- 3 to 8 +/- 0.4 pg/ml with the steroid hydroxylase inhibitor ketoconazole resulted in a 34% suppression of Ca transport in nonmated rats. At the end of pregnancy, when calcitriol concentration was suppressed from 64 +/- 7 to 12 +/- 2 pg/ml, the transport ratio decreased by 44%. Ca transport did not correlate with calcitriol levels between 40 and 80 pg/ml, suggesting a threshold level for maximal Ca transport stimulation. During lactation at even higher calcitriol levels, ketoconazole treatment again resulted in marked reduction in calcitriol from 124 +/- 1 to 71 +/- 12 pg/ml, but without any concurrent reduction in Ca transport in the duodenum. We conclude that in the vitamin D-replete rat the pregnancy-mediated, and probably also the lactation-mediated, increase in active Ca transport capacity is dependent on an increase in circulating calcitriol up to a certain threshold level.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7491946&dopt=Abstract ketoconazole Nizoral



Nizoral
Ketoconazole inhibits acetaminophen-induced hepatotoxicity in mice.

Culo F, Renic M, Sabolovic D, Rados M, Bilic A, Jagic V.

Department of Physiology and Immunology, School of Medicine, Zagreb, Croatia.

OBJECTIVE: To investigate the effect of ketoconazole on acetaminophen (AAP)-induced hepatotoxicity in mice. MATERIALS AND METHODS: Mice were given AAP intragastrically (300 mg/kg) and treated with ketoconazole (100 mg/kg intraperitoneally) or saline either 30 min before or 2-3 h after AAP administration. Mortality was recorded for 48 h, during which all mice given saline either died or recovered fully. Serum alanine and aspartate transaminase levels were determined 24 h after administration of AAP. Prostaglandin E2, thromboxane A2 and leukotriene C4 production was determined 6 h after AAP administration in the supernatants from the short-term culture of liver fragments by radioimmunoassay. RESULTS: Ketoconazole significantly decreased mortality and transaminase levels when given to mice either 30 min before or 2 h after AAP. Liver fragments from mice with AAP hepatitis produced greater quantities of prostaglandin E2, thromboxane A2 and leukotriene C4 than fragments from normal liver. Pretreatment of mice with ketoconazole or its addition to liver fragments ex vivo further increased the production of prostaglandin E2 and reduced the production of thromboxane A2. The effect of ketoconazole on leukotriene C4 synthesis was different in vivo (synthesis stimulation) from in vitro (synthesis inhibition). CONCLUSION: The protective effect of ketoconazole in AAP hepatitis is most probably mediated by modulation of eicosanoid synthesis by liver cells.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7496865&dopt=Abstract ketoconazole Nizoral



Nizoral
Superficial fungal infections. Getting rid of lesions that don't want to go away.

Kovacs SO, Hruza LL.

Division of Dermatology, Washington University School of Medicine, St Louis, USA.

Systematic analysis of possible dermatophyte and candidal skin infections leads to an accurate diagnosis and prompt treatment with a specific regimen. The first steps are thorough skin examination and evaluation with a potassium hydroxide preparation. Tinea corporis, tinea cruris, tinea pedis, cutaneous candidiasis, and tinea versicolor can be treated with many topical antifungal agents, whereas tinea capitis requires oral griseofulvin therapy. Frequently used topical medications for tinea and candidal infections include clotrimazole (Lotrimin, Mycelex), econazole nitrate (Spectazole), ketoconazole (Nizoral), miconazole nitrate (Monistat-Derm, Micatin), oxiconazole nitrate (Oxistat), and ciclopirox olamine (Loprox). Topical selenium sulfide lotion can also be used for tinea versicolor, which is often a recalcitrant problem.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7501581&dopt=Abstract ketoconazole Nizoral



Nizoral
Ketoconazole blocks organic osmolyte efflux independently of its effect on arachidonic acid conversion.

McManus M, Serhan C, Jackson P, Strange K.

Department of Medicine, Children's Hospital, Boston, Massachusetts.

Ketoconazole, cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate, and gossypol are reported inhibitors of the lipoxygenase (LO) and cytochrome P-450 enzyme systems and are potent blockers of swelling-activated efflux of organic osmolytes and volume-sensitive anion channels in C6 glioma cells. To directly test the hypothesis that LO- or cytochrome P-450-derived products of arachidonic acid (AA) participate in the regulation of these volume-sensitive transport pathways, we incubated C6 cells with [1-14C]AA and observed the extent and profile of its conversion under basal conditions and after acute swelling. High-performance liquid chromatographic analysis revealed that most (70-80%) of the labeled AA remained unchanged with only 6-8% and 10-20% of label converted to LO- [12(S)- and 15(S)-hydroxyeicosatetraenoic acid (12- and 15-HETE)] and cyclooxygenase- [prostaglandin (PG) E2 and PGF2a] derived products, respectively. Leukotrienes and epoxyeicosatrienoic acid compounds were not produced. The conversion profile of [1-14C]AA was not altered substantially by cell swelling. Treatment of cells with the LO-derived products 5-, 12-, and 15-HETE or their immediate metabolic precursors, 5(S)-, 12(S)-, and 15(S)-hydroxyperoxyeicosatetraenoic acid, at 5 microM concentrations did not stimulate efflux of [3H]inositol. In addition, treatment with HETEs did not override the inhibition of efflux observed with the LO-cytochrome P-450 blocker ketoconazole. Whole cell patch-clamp experiments demonstrated that volume-sensitive anion channels, the postulated pathway for organic osmolyte efflux in C6 cells, are rapidly and reversibly blocked by ketoconazole in a fashion suggestive of direct inhibition rather than via interruption of a second messenger pathway.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7519397&dopt=Abstract ketoconazole Nizoral



Nizoral
Differential expression of rat microsomal epoxide hydrolase gene by imidazole and triazole antimycotic agents.

Kim SG, Cho JY, Jung KH.

College of Pharmacy, Duksung Women's University, Seoul, South Korea.

Previous studies from this laboratory revealed that imidazole antimycotic agents, including ketoconazole and clotrimazole, induce microsomal epoxide hydrolase (mEH) and that the mEH induction involves large increases in mRNA with transcriptional activation. To establish whether these compounds elevate mEH mRNA levels in a dose-related manner and whether triazole antimycotic agents, fluconazole and itraconazole, affect mEH gene expression to similar extents, hepatic mEH mRNA levels were quantified in rats by RNA blot analyses using an mEH cDNA probe. Treatment of rats (males) with ketoconazole caused approximately 4-, 10-, and 11-fold increases in mEH mRNA levels at 24-hr posttreatment at the doses of 50, 100, and 200 mg/kg body weight, respectively, whereas mEH mRNA levels were increased approximately 18-fold at 24 hr after a single administration of clotrimazole at 50 mg/kg body weight or at greater doses, with EC50 value being noted as 20 mg/kg body weight. Fluconazole elevated mEH mRNA levels by 2-, 3-, and 6-fold at the doses of 50, 100, and 200 mg/kg body weight, respectively. However, hepatic microsomes isolated from rats treated with fluconazole for 3 days failed to exhibit significant elevation in mEH protein levels, as assessed by immunoblot analyses. No significant increase in mEH mRNA nor protein levels was observed at 1 or 3 days after treatment of rats with itraconazole (200 mg/kg body weight/day). To characterize gender-related differences in hepatic mEH gene expression in response to azole antimycotic agents, the effects of ketoconazole and clotrimazole were examined in females.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7600912&dopt=Abstract ketoconazole Nizoral



Nizoral
Ketoconazole inhibits oxidative modification of low density lipoprotein.

Dushkin MI, Zenkov NK, Menshikova EB, Pivovarova EN, Lyubimov GYu, Volsky NN.

Department of Atherogenesis, Institute of General Pathology and Human Ecology, Novosibirsk, Russia.

Known cytochrome P450-dependent oxygenase inhibitor ketoconazole (5-50 microM) blocked the murine macrophage-mediated modification of human low density lipoprotein (LDL) as measured by production of thiobarbituric acid-reactive substance, stimulation of [125I]LDL degradation in a fresh set of macrophages and LDL electrophoretic mobility, in a dose-dependent manner with complete inhibition at 30-40 microM. When resident macrophages were incubated with LDL in the presence of metyrapone, methoxsalen and alpha-naphthaflavone at concentrations that have been shown to inhibit the cytochrome P450-dependent oxygenases, there was no change in LDL modification. Induction of benzo[alpha]pyrene hydroxylase activity in macrophages by 24 h incubation with benzo[alpha]pyrene was accompanied by a 1.5-fold increase of LDL modification which has been leveled down by ketoconazole as well as methoxsalen and alpha-naphthaflavone. Furthermore, ketoconazole effectively diminished cell-free LDL oxidation induced by iron, but not copper ions, and reduced the spontaneous and zymosan-stimulated lucigenin-amplified chemiluminescence of macrophages. The data allow us to suggest that ketoconazole inhibits LDL oxidation by acting as an iron chelator and/or inhibitor of prooxidant forms of iron-containing enzymes.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7605380&dopt=Abstract ketoconazole Nizoral



Nizoral
Ketoconazole and sulphaphenazole as the respective selective inhibitors of P4503A and 2C9.

Baldwin SJ, Bloomer JC, Smith GJ, Ayrton AD, Clarke SE, Chenery RJ.

Department of Drug Metabolism and Pharmacokinetics, SmithKline Beecham Pharmaceuticals, The Frythe, Welwyn, UK.

1. The potential of ketoconazole and sulphaphenazole to inhibit specific P450 enzyme activities (1A2, 2A6, 2B6, 2C9/8, 2C19, 2D6, 2E1, 3A and 4A) was investigated using human liver microsomes. 2. Ketoconazole demonstrated an inhibitory effect on cyclosporine oxidase and testosterone 6 beta-hydroxylase activities, with mean IC50's of 0.19 and 0.22 microM respectively. Ketoconazole inhibition of the other P450 activities investigated was significantly less, as illustrated by IC50's of at least a magnitude higher. 3. Sulphaphenazole was shown to have an inhibitory effect on tolbutamide hydroxylase activity, with a mean IC50 of 0.8 microM in incubations containing 100 microM tolbutamide. Sulphaphenazole (at concentrations of up to 100 microM) did not exhibit any significant inhibition of the other enzyme activities investigated. 4. Ketoconazole and sulphaphenazole are the respective selective inhibitors of P4503A and 2C9. Ketoconazole at 1 microM and sulphaphenazole at 10 microM can be used to establish the involvement of P4503A and 2C9 respectively in oxidative reactions in human liver microsomes.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7618352&dopt=Abstract ketoconazole Nizoral