Nizoral
Plasma cortisol response to ketoconazole administration in dogs with hyperadrenocorticism.

Feldman EC, Bruyette DS, Nelson RW, Farver TB.

Department of Veterinary Reproduction, University of California, Davis 95616.

The effect of orally administered ketoconazole on plasma cortisol concentration in dogs with hyperadrenocorticism was evaluated. Every 30 minutes from 0800 hours through 1600 hours and again at 1800 hours, 2000 hours, and 0800 hours the following morning, 15 clinically normal dogs and 49 dogs with hyperadrenocorticism had plasma samples obtained and analyzed for cortisol concentration. The mean (+/- SD) plasma cortisol concentration for the initial 8-hour testing period was highest in 18 dogs with adrenocortical tumor (5.3 +/- 1.6 micrograms/dl), lowest in 15 control dogs (1.3 +/- 0.5 micrograms/dl), and intermediate in 31 dogs with pituitary-dependent hyperadrenocorticism (PDH; 3.4 +/- 1.2 micrograms/dl). Results in each of the 2 groups of dogs with hyperadrenocorticism were significantly (P less than 0.05) different from results in control dogs, but not from each other. The same cortisol secretory experiment was performed, using 8 dogs with hyperadrenocorticism (5 with PDH; 3 with adrenocortical tumor) before and after administration at 0800 hours of 15 mg of ketoconazole/kg of body weight. Significant (P less than 0.05) decrease in the 8-hour mean plasma cortisol concentration (0.9 +/- 0.2 microgram/dl) was observed, with return to baseline plasma cortisol concentration 24 hours later. Twenty dogs with hyperadrenocorticism (11 with PDH, 9 with adrenocortical tumor) were treated with ketoconazole at a dosage of 15 mg/kg given every 12 hours for a half month to 12 months. The disease in 2 dogs with PDH failed to respond to treatment, but 18 dogs had complete resolution of clinical signs of hyperadrenocorticism and significant (P less than 0.05) reduction in plasma cortisol responsiveness to exogenous adrenocorticotropin (ACTH).(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2370223&dopt=Abstract ketoconazole Nizoral



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Sclerosing mediastinitis: improved management with histoplasmosis titer and ketoconazole.

Urschel HC Jr, Razzuk MA, Netto GJ, Disiere J, Chung SY.

Department of Thoracic/Cardiovascular Surgery, University of Texas Health Science Center, Baylor University Medical Center, Dallas.

Recognition that many patients with benign sclerosing mediastinitis have smoldering disease responsible for failure of surgical procedures or for development of collateral circulation in patients with superior vena caval obstruction has markedly improved management of these difficult patients. Histoplasmosis complement fixation titers have been used to detect unsuspected subacute disease and to follow the therapeutic adjunctive management with ketoconazole, an oral antifungal agent. Twenty-two patients with benign sclerosing mediastinitis demonstrated a variety of symptoms relating to the area of compression: superior vena cava, 13; esophagus, 3; pulmonary artery and pericardium, 3; and trachea, 3. Histoplasmosis was documented in 12 patients. Operation is used initially for diagnosis, to rule out carcinoma, and to treat the complications: superior vena caval reconstruction, 6; tracheal decompression, 2; right middle lobectomy, 1; esophageal decompression, 2; division of tracheoesophageal fistula, 1; and release of pericardial effusion and cardiac tamponade, 1. Postcardiotomy syndrome occurred in 1 patient and wound infection in another. No deaths resulted. In 6 cases of histoplasmosis, symptoms recurred in 100% of patients and were successfully managed with ketoconazole treatment, and then clinical progress was monitored with serial histoplasmosis complement fixation studies. One patient had four superior vena caval reconstructions at an outside hospital, each 1 year apart, with symptoms recurring each time. With ketoconazole therapy alone, she has been asymptomatic for more than 2 years. Vigorous search for a fungal cause may even obviate the necessity for surgical intervention. If an operation is necessary, preoperative and postoperative use of ketoconazole has assured success.

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Hepatic effects of ketoconazole in the male Swiss Webster mouse: temporal changes in drug metabolic parameters.

Whitehouse LW, Pakuts AP, Paul CJ, Mueller RW, Thomas BH.

Drug Identification Division, Health and Welfare Canada, Tunney's Pasture, Ottawa, Ont.

There have been conflicting observations regarding the effects of ketoconazole on hepatic metabolism. The objectives of these studies were to determine whether ketoconazole was an enzyme inducer or inhibitor in the mouse and then to establish the time frame of these ketoconazole-induced enzyme changes. Ketoconazole was administered (150 mg/kg p.o. X 4 days) to male Swiss Webster mice. Biochemical observations over a period of 6 days following treatment indicated that ketoconazole had a temporal biphasic effect on the liver. Although liver weight and microsomal protein were elevated, all other parameters monitored were lower at 2 h following ketoconazole treatment. At 24 h after the last dose of ketoconazole, hepatic biochemical parameters (liver wt., % liver wt./body wt., microsomal protein, and cytochrome P-450) were statistically elevated, while enzyme activities (benzphetamine N-demethylation, 6 beta- and 7 alpha-hydroxylation of testosterone, formation of androstenedione and UDP-glucuronyltransferase) were inhibited. At 72 h the ketoconazole-induced changes in the hepatic biochemical parameters were comparable to those observed at 24 h, and enzymatic parameters generally appeared to be induced by ketoconazole, with the exception of benzphetamine N-demethylase and UDP-glucuronyltransferase, which exhibited lower enzyme activities. Ethoxyresorufin O-deethylase, 7 alpha-hydroxylation of testosterone and glutathione S-transferase, on the other hand, were unaltered by ketoconazole treatment. The opposing effects of ketoconazole on benzphetamine N-demethylase and ethylmorphine N-demethylase at 72 h were further examined. Enzyme kinetics studies indicated that ketoconazole did not effect the Michaelis constants (Km) of the two substrates, but the maximum velocity (Vmax) of the reactions was altered.(ABSTRACT TRUNCATED AT 250 WORDS)

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Therapeutic effect of the triazole Bay R 3783 in mouse models of coccidioidomycosis, blastomycosis, and histoplasmosis.

Pappagianis D, Zimmer BL, Theodoropoulos G, Plempel M, Hector RF.

Department of Medical Microbiology, School of Medicine, University of California, Davis 95616.

A new triazole, Bay R 3783, was compared with ketoconazole, itraconazole, and fluconazole, which were given via the alimentary tract at three dosages, and amphotericin B, which was given at 1 mg/kg intraperitoneally, in murine models of the systemic mycoses coccidioidomycosis, histoplasmosis, and blastomycosis. In a pulmonary coccidioidomycosis model, Bay R 3783, fluconazole, and itraconazole were essentially equally efficacious and more active than ketoconazole in protecting mice against death; but they were inferior to amphotericin B. In a short-term organ load experiment, Bay R 3783 and amphotericin B were equally effective and were more effective than the other drugs in reducing the amount of Coccidioides immitis in the lungs. Against meningocerebral coccidioidomycosis, Bay R 3783, itraconazole, and fluconazole at 25 mg/kg and amphotericin B prevented death only during therapy, with mortalities ensuing shortly thereafter. In mice with systemic histoplasmosis, Bay R 3783 and itraconazole at 25 mg/kg and amphotericin B prevented death in all mice through a 44-day observation period. Clearance of Histoplasma capsulatum from organs was similar in mice treated with Bay R 3783 and itraconazole; this clearance was greater than that in mice treated with ketoconazole and fluconazole but less than that in mice treated with amphotericin B. In mice with systemic blastomycosis, Bay R 3783 at 25 mg/kg yielded 90% survivors at 60 days, which was greater than that achieved with amphotericin B (60%) or itraconazole (30%). Clearance of Blastomyces dermatitidis from the lungs was greatest with Bay R 3783, followed by that with amphotericin B, itraconazole, fluconazole, and ketoconazole, in that order. Therefore, Bay R 3783 showed effectiveness comparable to or exceeding those of itraconazole and fluconazole and exceeding that of ketoconazole against these systemic mycoses in mice.

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[Polarographic examination of drugs derived from imidazol. I. Clotrimazole and ketoconazole]

[Article in Polish]

Fijalek Z, Chodkowski J, Warowna M.

Zaklad Chemii Nieorganicznej i Analitycznej, Instytut Nauki o Leku, Akademia Medyczna, Warszawa.

By means of linear sweep voltammetry the electrode processes of imidazole, clotrimazole and ketoconazole was studied. The methods of determination of clotrimazole and ketoconazole in substance and ketoconazole in tablets was elaborated.

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Secretion of alpha-subunit and intact gonadotropins after surgical and chemical castration.

Ceda GP, Denti L, Ceresini G, Cortellini P, Banchini A, Frattini A, Hoffman AR, Valenti G.

Chair of Geriatrics, University of Parma, Italy.

In order to investigate the regulatory mechanisms involved in the secretion of glycoprotein hormones, we studied the secretory patterns of LH, FSH and alpha-subunit in hypogonadal men. Three groups of patients with carcinoma of the prostate were studied both before and 15 days after orchiectomy, or the initiation of ketoconazole or LHRH analog therapy. There were significant increases (P less than 0.01) in LH and alpha-subunit levels in the patients treated with orchiectomy and ketoconazole, but FSH levels increased only in the orchiectomized patients. After LHRH analog treatment, LH levels were significantly decreased when assayed with an immunoradiometric assay method which does not cross-react with alpha-subunit. FSH values were significantly lower than pretreatment levels, while alpha-subunit levels remained significantly elevated throughout the study period. These results demonstrate that after both chemical (ketoconazole) and surgical castration, the secretion of alpha subunit follows a pattern which is tightly correlated with that of LH but not of FSH. However, after LHRH analog treatment, alpha-subunit appears to be the sole secretory product of the gonadotroph.

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The use of rat Leydig tumor (R2C) and human hepatoma (HEPG2) cells to evaluate potential inhibitors of rat and human steroid aromatase.

Doody KM, Murry BA, Mason JI.

Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas 75235.

The efficacies of 10-propargylestr-4-ene-3,17-dione (PED), 4-hydroxyandrostenedione (4-OHA) and the imidazole broad spectrum antimycotic drugs, econazole, imazalil, miconazole and ketoconazole, to inhibit the steroid aromatase activities of rat Leydig tumor (R2C) cells and human hepatoma (HEPG2) cells have been determined. The analysis of inhibition of steroid aromatase activity of intact cells provided further insight into the potential use of such drugs to block cellular estrogen synthesis. The IC50 values for the inhibition of aromatase activity of R2C cells by econazole, imazalil, miconazole, ketoconazole, 4-OHA and PED were 4, 9, 40, 1100, 11 and 10 nM, respectively. These drugs also inhibited the steroid aromatase activity of HEPG2 cells with corresponding IC50 values of 13, 27, 20, 15000, 2 and 2 nM, respectively; these findings were suggestive that the steroid aromatase of rat has many similarities to the human enzyme in its interaction with putative inhibitory compounds. Importantly, however, ketoconazole inhibited the rat aromatase more effectively than it did the human enzyme, while PED and 4-OHA were less effective inhibitors of the rat enzyme compared to that of human. These findings indicate differences in the potencies of various drugs to inhibit estrogen biosynthesis in human and rat cells. These may relate to differences in the two aromatase systems and/or differences in the stability of the drugs in the human hepatoma and rat Leydig tumor cells.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1965908&dopt=Abstract ketoconazole Nizoral