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Prostate specific antigen for assessing response to ketoconazole and prednisone in patients with hormone refractory metastatic prostate cancer.

Gerber GS, Chodak GW.

Department of Surgery, University of Chicago, Illinois 60614.

Serial prostate specific antigen levels were assessed in 15 patients with hormone refractory metastatic prostate cancer treated with ketoconazole and prednisone. Of the men 12 (80%) with continually increasing prostate specific antigen levels before treatment had a decrease in prostate specific antigen with a median duration of response of 3 months. Three patients (20%) had a prolonged response (greater than or equal to 8 months) as seen by a persistently decreasing prostate specific antigen and improvement in bone pain. There appears to be a small subgroup of patients with progressive prostate cancer despite androgen ablation who will benefit from ketoconazole and glucocorticoid treatment. The use of serial prostate specific antigen levels appears to help define this subgroup and avoid the need for multiple radiological procedures to assess response.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1700145&dopt=Abstract ketoconazole Nizoral



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Comparison of capillary zone electrophoresis and high performance liquid chromatography methods for quantitative determination of ketoconazole in drug formulations.

Velikinac I, Cudina O, Jankovic I, Agbaba D, Vladimirov S.

Department of Pharmaceutical Chemistry and Drug Analysis, Faculty of Pharmacy, Vojvode Stepe 450, P.O. Box 146, 11000 Belgrade, Serbia and Montenegro.

A capillary zone electrophoresis (CZE) and a high-performance liquid chromatography (HPLC) method have been developed for identification and determination of ketoconazole, an imidazole antifungal, in pharmaceutical preparations. The suitabilities of both methods for quantitative determination of ketoconazole were approved through validation specification such as linearity, precision, accuracy, limit of detection and quantification. The proposed methods were used for determination of ketoconazole in commercial pharmaceutical dosage forms (tablets and creams). Under described conditions, CZE method is more selective, while the HPLC method is more sensitive. Both methods are rapid (tR(CZE)=5.14 min and tR(HPLC)=2.66 min), which is important for routine application. However, the HPLC method provides a repeatability of the quantitative analysis of ketoconazole in drug formulations below 1.5% relative standard deviation (R.S.D), while the repeatability of the CZE method is in the order of 2-3% R.S.D. Copyright 2004 Elsevier SAS

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15120322&dopt=Abstract ketoconazole Nizoral



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Ketoconazole treatment in Cushing's syndrome: experience in 34 patients.

Sonino N, Boscaro M, Paoletta A, Mantero F, Ziliotto D.

Institute of Semeiotica Medica, University of Padova, Italy.

OBJECTIVE: Ketoconazole treatment of Cushing's syndrome has been reported in single cases and a few small groups of 5-8 patients. We report our experience in 34 patients. DESIGN: Clinical study, with pretreatment and post-treatment evaluations. PATIENTS: Out of 67 patients with Cushing's syndrome admitted during the last 6 years, 34 (28 females/six males; age range 14-67 years) received ketoconazole as a palliative treatment due to severe clinical conditions or management of the disease while awaiting results of definitive therapy. MEASUREMENTS: Urinary cortisol, plasma cortisol and ACTH, and routine chemistry were measured every week for 4 weeks, and then once a month. RESULTS: Comparing the last values (mean +/- SEM) during treatment with baseline, urinary cortisol decreased from 1296 +/- 176 to 270 +/- 69 nmol/d (n = 34; P less than 0.001); plasma cortisol decreased from 672 +/- 31 to 549 +/- 35 nmol/l (n = 34; P less than 0.001). For patients with pituitary-dependent Cushing's syndrome, urinary cortisol decreased from 1073 +/- 126 to 200 +/- 21 nmol/d (n = 28; P less than 0.001) while plasma ACTH changed from 12.5 +/- 1.3 to 11.3 +/- 0.8 pmol/l (n = 26; not significant). Twelve patients were treated for more than 6 months, and those with pituitary-dependent disease all received pituitary radiation therapy, except the two who eventually escaped pharmacological control. One additional patient with adrenal carcinoma and one with ectopic ACTH syndrome showed lack of control of urinary cortisol levels. Ketoconazole was withdrawn within the first week in two patients for allergic reaction and acute liver toxicity. Other side-effects included: asymptomatic liver function abnormalities in three patients; gastrointestinal symptoms in four; worsening of gynaecomastia in one. Rapid clinical improvement was observed together with the normalization of urinary cortisol levels, with regression of symptoms such as diabetes mellitus, hypertension, hypokalaemia, and restoration of well being. CONCLUSIONS: These data confirm that ketoconazole is valuable in the management of hypercortisolism, provided that patients are closely watched to exclude those who may develop liver toxicity and to prevent the occurrence of adrenal insufficiency.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1752063&dopt=Abstract ketoconazole Nizoral



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Evidence against the involvement of a cytochrome P-450 mechanism in pulmonary hemodynamics in the newborn pig.

Perreault T, De Marte J, Coceani F.

Montreal Children's Hospital, Newborn Medicine, Que., Canada.

Control mechanisms operating through a cytochrome P-450 system have emerged lately as a possible important determinant of pulmonary hemodynamics. Their action may be expressed in the adjustment of vascular tone under both physiologic and pathophysiologic conditions. One such condition is the pulmonary constrictor response to hypoxia. The identity of the effector agent, or agents, is not known, though there are data implicating monooxygenase products of arachidonic acid. From this premise, we wanted to evaluate the effect of cytochrome P-450 inhibitors on basal pulmonary vascular tone during normoxia, and their effect upon hypoxic pulmonary vasoconstriction response. Experiments were performed in an isolated, perfused lung preparation from 1- and 7-day-old piglets, and the effects of two cytochrome P-450 inhibitors (metyrapone and ketoconazole) were tested on the perfusion pressure. At 10(-5) and 10(-4) M, metyrapone caused a modest, but significant, increase in pulmonary pressure (p less than 0.05) in 7-day-old preparations, while it was without effect in the 1-day-old preparation. Similarly, ketoconazole at concentrations from 10(-6) M upwards increased the perfusion pressure in the older animal (p less than 0.01). Responses to the inhibitors were not seen in preparations that had been pretreated with a cyclooxygenase inhibitor (indomethacin, 2.8 x 10(-6) M) or a dual cyclooxygenase-lipoxygenase inhibitor (BW755C, 10(-5) M). Hypoxic vasoconstriction was marginally enhanced by 10(-4) M metyrapone, while it was affected inconsistently by 10(-5) M ketoconazole. We conclude that vasoactive agents formed through cytochrome P-450 reactions have a minor role, or no role at all, in the control of pulmonary hemodynamics in the newborn pig.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1777839&dopt=Abstract ketoconazole Nizoral



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Comparative studies of steroidogenesis inhibitors (econazole, ketoconazole) on human breast cancer MCF-7 cell proliferation by growth experiments, thymidine incorporation and flow cytometric DNA analysis.

Najid A, Ratinaud MH.

Laboratoire de Biochimie, Faculte de Pharmacie, Universite de Limoges, France.

The effects of aminoglutethimide, econazole and ketoconazole on human breast cancer cells in culture were compared with those of tamoxifen using four methods (growth experiments, thymidine incorporation, monoparameter and bivariate DNA content flow cytometry analysis). Aminoglutethimide (1 nM-10 microM) had no effect on cell proliferation after 8 days of treatment and did not decrease thymidine tritiated incorporation during logarithmic phase. Even at 20 microM, similar results were obtained with flow cytometry. Econazole and ketoconazole (1 nM-1 microM) decreased MCF-7 cell proliferation in a time- and dose-dependent fashion. They also decreased tritiated thymidine incorporation. By using flow cytometry and a monoclonal antibody against bromodeoxyuridine, we showed an accumulation of MCF-7 cells treated by imidazoles derivatives in G0-G1 phase of the cell cycle.

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Development of resistance in candida isolates from patients receiving prolonged antifungal therapy.

Fan-Havard P, Capano D, Smith SM, Mangia A, Eng RH.

Rutgers College of Pharmacy, Piscataway, New Jersey 08854.

The impact of prolonged antifungal therapy on the development of resistance was examined in 61 patients with oropharyngeal thrush. Fifty-nine patients had symptomatic human immunodeficiency virus infection, one had lung cancer, and one had metastatic prostate cancer. Cultures of pharyngeal samples from all patients were positive for yeasts and included 57 (93.4%) Candida albicans, 3 (4.9%) Candida glabrata, and 1 (1.6%) Candida krusii. Of 61 patients, 32 (52.5%) were receiving or had recently received antifungal therapy. Clotrimazole was the most commonly prescribed azole, followed by ketoconazole and fluconazole. Two patients had received amphotericin B therapy and one had received flucytosine. The duration of therapy with clotrimazole, ketoconazole, and fluconazole ranged from 3 to 240, 14 to 44, and 7 to 138 days, respectively. There was no overall difference in the susceptibilities of the clinical isolates from treated and untreated patients to amphotericin B, nystatin, flucytosine, clotrimazole, ketoconazole, and fluconazole. A.C. albicans isolate from one patient who had clinically failed on ketoconazole, fluconazole, and amphotericin B was resistant to these drugs. The lack of difference in the susceptibility pattern indicates that clinically significant emergence of resistance does not occur in those patients who receive prolonged antifungal therapy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1804002&dopt=Abstract ketoconazole Nizoral



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Oral ketoconazole and miconazole vaginal pessary treatment for vaginal candidosis.

Sharma JB, Buckshee K, Gulati N.

Department of Obstetrics & Gynaecology, All India Institute of Medical Sciences, New Delhi.

This prospective study was carried out on 250 patients having clinical and mycological evidence of vaginal candidosis. One hundred patients received ketoconazole orally (400 mg/day for 5 days), another 100 patients received miconazole vaginal pessary treatment (one 100 mg tablet locally for 14 days), while the other 50 patients received combination therapy of oral ketoconazole and miconazole vaginal tablets. Although all 3 regimens were significantly effective in relieving patients symptoms and physical signs, the combination therapy gave the best results. There was 98% symptomatic relief with the combination therapy in contrast to 82% and 78% in the oral ketocanozole and vaginal micronazole groups respectively (p less than 0.001). Mycological cure rates were also significantly higher in the combination therapy group (94% versus 80% and 76%). The relapse rate was least in the combination group 2% versus 8% and 12%. The combination therapy is recommended for the best results in vaginal candidosis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1804095&dopt=Abstract ketoconazole Nizoral