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Evaluation of ketoconazole and itraconazole for treatment of disseminated cryptococcosis in cats.

Medleau L, Greene CE, Rakich PM.

Department of Small Animal Medicine, College of Veterinary Medicine, University of Georgia, Athens 30602.

During the first part of a study, cats were inoculated with Cryptococcus neoformans via the following routes: intradermal, intranasal, IV, and intracisternal. Only use of the IV route of inoculation consistently induced disseminated cryptococcosis. In the second part of the study, disseminated cryptococcosis was experimentally induced in cats via IV inoculation of C neoformans. One month after inoculation, 3 cats were treated with ketoconazole (10 mg/kg of body weight/d) and 3 cats were treated with itraconazole (10 mg/kg/d) for 3 months. One of the ketoconazole-treated and 2 of the itraconazole-treated cats also had cryptococcosis of the CNS when treatment was begun. During treatment, serum cryptococcal antigen titer progressively decreased in all cats. Abnormalities in CBC values or the serum biochemical profile were not found in any cat during treatment. However, all ketoconazole-treated cats became anorectic and lost weight. Side effects were not seen in itraconazole-treated cats. During the 3-month posttreatment observation period, all cats remained healthy. At necropsy, histologic evidence of cryptococcosis was not found in the 3 ketoconazole-treated cats or in 2 of the itraconazole-treated cats. In the third itraconazole-treated cat, cryptococcal organisms were found in the kidneys.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2168688&dopt=Abstract ketoconazole Nizoral



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Ketoconazole use in the treatment of ovarian hyperandrogenism.

Pepper G, Brenner SH, Gabrilove JL.

Department of Medicine, Long Island Jewish Medical Center, New Hyde Park, New York.

Ovarian hyperandrogenism is a common disorder of women of reproductive age. The therapies that are presently available to treat this disorder are not uniformly effective or free of adverse effects. We conducted a prospective study of eight women receiving ketoconazole for a mean duration of 44 +/- 15 (SEM) weeks, as therapy of ovarian hyperandrogenism. Serum testosterone and hair growth rate declined in patients while on 600 to 1,000 mg ketoconazole daily. Menses normalized in seven of eight subjects during treatment. Ketoconazole therapy was not associated with a change in basal or postgonadotropin-releasing hormone stimulation gonadotropin levels. Basal cortisol levels were also unchanged on ketoconazole though responsiveness of cortisol to adrenocorticotropic hormone stimulation tended to be reduced. We conclude that ketoconazole can effectively reverse the biochemical and clinical abnormalities of ovarian hyperandrogenism. Until the issue of its safety is resolved, ketoconazole therapy is best limited to select individuals who agree to careful monitoring and the use of reliable birth control methods during treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2168844&dopt=Abstract ketoconazole Nizoral



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In vitro inhibition by ketoconazole of human testicular steroid oxidoreductases.

Higashi Y, Yoshida K, Oshima H.

Department of Urology, Tokyo Medical and Dental University School of Medicine, Japan.

An oral antimycotic agent, ketoconazole has been demonstrated to be an inhibitor of cytochrome P-450-dependent monooxygenases. To investigate its effect on steroid oxidoreductases, in vitro studies were carried out using subcellular fractions of human testes. Ketoconazole competitively inhibited activities of 3 beta-hydroxy-5-ene-steroid oxidoreductase/isomerase and NADH-linked 20 alpha-hydroxysteroid oxidoreductase for steroid substrate and the Ki values were 2.9 and 0.9 microM, respectively. In contrast, ketoconazole inhibited neither 17 beta-hydroxysteroid oxidoreductase nor NADPH-linked 20 alpha-hydroxysteroid oxidoreductase, indicating that the two 20 alpha-hydroxysteroid oxidoreductases are distinct. Further, ketoconazole inhibited non-competitively the above enzyme activities for the corresponding cofactors of NAD and NADH. From the binding mode of ketoconazole to cytochrome P-450 and the present findings, it appears likely that the agent binds to a site which is different from that of steroids or pyridine nucleotides.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2214784&dopt=Abstract ketoconazole Nizoral



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The inhibition of human prostatic aromatase activity by imidazole drugs including ketoconazole and 4-hydroxyandrostenedione.

Ayub M, Levell MJ.

Department of Chemical Pathology, University of Leeds, U.K.

Ketoconazole, an orally active imidazole drug and bifonazole, clotrimazole, econazole, isoconazole, miconazole and tioconazole are known as inhibitors of cytochrome P450 dependent steroidogenic enzymes including human placental aromatase. The aim of the present study was to investigate the effectiveness of these imidazole drugs to inhibit human prostatic aromatase activity compared with the known inhibitor of aromatase 4-hydroxyandrostenedione (4-OHA). The imidazole drugs and 4-OHA inhibited prostatic aromatase activity in a dose-dependent manner. The order of decreasing inhibitory potency determined from IC50 values (mumol/L) was: 4-OHA (1.57) greater than bifonazole (1.6) greater than tioconazole (1.69) greater than clotrimazole (1.73) greater than econazole (1.87) greater than miconazole (2.0) greater than isoconazole (2.2) greater than ketoconazole (4.7). The IC50 values for the inhibition of prostatic homogenate aromatase activity are 3-9-fold higher than that for the inhibition of human placental aromatase activity, previously reported, except that of ketoconazole which was 1.5-fold lower than that for the inhibition of placental microsomal aromatase.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2222512&dopt=Abstract ketoconazole Nizoral



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Acetylated low-density lipoprotein as a vehicle for antiinfectious drugs: preparation and antileishmanial activity of Ac-LDL containing ketoconazole-oleate.

Nicolas JM, Pirson P, Leclef B, Trouet A.

Medgenix Group, C/O Ire B3, Fleurus, Belgium.

Previous studies have demonstrated that mouse peritoneal macrophages take up low-density lipoproteins (LDL) which have been chemically modified by the acetylation of lysine residues (Ac-LDL). This uptake is mediated through a specific receptor known as the scavenger receptor. Ac-LDL therefore appear to have excellent potential for antiinfectious drug targeting. We have developed a new method to incorporate ketoconazole-oleate, a lipophilic derivative of ketoconazole, into Ac-LDL. The method involves solubilization of LDL in the presence of Na deoxycholate, the addition of a micellar solution of the drug to be incorporated, and the subsequent removal of the detergent leading to the formation of reconstituted LDL (referred to as LDL-KOL). The LDL-KOL contain 200 drug molecules per LDL particle and compete for the binding of native 125I-LDL on human skin fibroblast monolayers. Furthermore, reconstituted LDL-KOL are indistinguishable from native LDL with regard to lipid composition and electrophoretic mobility. LDL-KOL, when acetylated, are recognized by the scavenger receptor. Acetylated LDL-KOL show antileishmanial activity when tested on infected macrophages. The activity appears to be mediated through the scavenger-cell pathway, as LDL-KOL are inactive under the same conditions. Moreover, acetylated LDL-KOL are selectively accumulated within infected macrophages rather than in normal cells. This may be of value in the treatment of intracellular infections.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2260896&dopt=Abstract ketoconazole Nizoral



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Ketoconazole in the treatment of Cushing's disease.

Dash RJ, Khandekar S, Lata V, Bhansali A.

Department of Endocrinology, Postgraduate Institute of Medical Education and Research, Chandigarh.

Six patients with Cushing's disease received ketoconazole for 7-10 weeks following ketoconazole challenge test. Clinical and hormonal alterations in circulating cortisol, 17 OH progesterone, androstenedione and testosterone were assessed during the therapy. There was significant clinical improvement which corresponded to a fall in cortisol, androstenedione and testosterone. The rise in 17 OH progesterone and the fall in cortisol suggest a blockade at 17,20 desmolase and 11 B-hydroxylase in the cortisol bio-synthetic pathway.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2292555&dopt=Abstract ketoconazole Nizoral



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Potentiation of interleukin 1 alpha mediated antitumor effects by ketoconazole.

Braunschweiger PG, Kumar N, Constantinidis I, Wehrle JP, Glickson JD, Johnson CS, Furmanski P.

Laboratory of Experimental Therapeutics, AMC Cancer Research Center, Denver, Colorado.

In the present studies, the regulatory role of adrenal hormones on the antitumor activity of recombinant human interleukin 1 alpha (IL-1 alpha) was investigated. Ketoconazole, a potent but transient inhibitor of adrenal steroid hormone biosynthesis, inhibited IL-1 alpha induced increases in plasma corticosterone. In s.c. RIF-1 tumors (C3H/HeJ mice) ketoconazole potentiated IL-1 alpha induced hemorrhagic necrosis (59Fe labeled RBC uptake) and prolonged intervals of low tumor perfusion (86Rb+ uptake) and attendant depletion of tumor high energy phosphate reserves as determined by in vivo 31P nuclear magnetic resonance spectroscopy. In normal muscle and skin the ketoconazole-IL-1 alpha combination had no effect on RBC content and little or no effect on tissue perfusion. Ketoconazole potentiation of IL-1 alpha induced tumor pathophysiologies was accompanied by time and ketoconazole dose dependent potentiation of RIF-1 tumor clonogenic cell killing. Although ketoconazole at 40 mg/kg and IL-1 alpha at 25 micrograms/kg alone each produced approximately 50% clonogenic cell kill, a combined treatment (IL-1 alpha 1 h after ketoconazole) resulted in surviving fractions of approximately 1.5%. In vitro, ketoconazole and IL-1 alpha induced only additive clonogenic cell kill in primary RIF-1 explant cultures. The effect of elevated plasma corticosterone levels, induced by ketamine-acepromazine anesthesia, on IL-1 alpha responsiveness was also studied in the RIF-1 tumor model. In C3H/HeJ mice, anesthesia increased plasma corticosterone levels within 30 min, abrogated the IL-1 alpha effect on tumor perfusion, and prevented depletion of tumor high energy phosphate metabolite reserves. Our results are consistent with the hypothesis that IL-1 alpha mediated adrenal hormone responses exert a profound negative feedback on IL-1 alpha antitumor activities. Our data also indicate that adrenal steroid hormone biosynthetic pathways could provide a focus for modulation strategies to increase the efficacy of cytokine based therapeutic interventions.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2369744&dopt=Abstract ketoconazole Nizoral