Nizoral
Fluconazole and ketoconazole in the treatment of oral and esophageal candidiasis in AIDS patients.

Barchiesi F, Giacometti A, Arzeni D, Branchesi P, Crescenzi G, Ancarani F, Scalise G.

Institute of Infectious Diseases, University of Ancona, Italy.

In our study 77 AIDS patients suffering from oral and/or esophageal candidiasis were evaluated: 38 received fluconazole, 39 ketoconazole. We analyzed the rates of clinical and mycological responses, relapses and toxicities. In vitro susceptibility tests for both antifungal drugs were performed by evaluating their Minimal Inhibitory Concentrations (MICs). The azole drugs investigated show a good activity in the treatment of oropharyngeal and esophageal candidiasis also in advanced stages of HIV infection. Clinical cure or improvement were achieved in 29 (76.3%) and 31 (79.4%) of the patients treated with fluconazole or ketoconazole respectively. Clinical or laboratory adverse experiences related to fluconazole were seen in 7 (21.2%) patients while ketoconazole provoked adverse experiences in 9 (26.4%) patients. In vitro susceptibility tests, if repeated more than once, both in primary infection and relapses, could be important to demonstrate a probable sensitivity change or resistance of the tested strains.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1287140&dopt=Abstract ketoconazole Nizoral



Nizoral
Quantitative assessment of the efficacy of oral ketoconazole for oral candidosis in HIV-infected patients.

Korting HC, Blecher P, Froschl M, Braun-Falco O.

Department of Dermatology, Ludwig-Maximilians University, Munich, Germany.

Fifteen male patients with manifest oral candidosis due to Candida albicans, suffering from AIDS-related complex (ARC) or full-blown AIDS, were investigated both clinically and microbiologically before and about 1 and 4 weeks after 7 to 10 days of treatment with 200 mg ketoconazole p.o. per day. Candida albicans was quantitated in mouthwash fluid. The antimicrobial susceptibility of the Candida albicans isolates was assessed using the IC30 test. In the short term, clinical cure was obtained in 87%, mycological cure in 53%. In the long term, the corresponding figures were 56 and 9%, respectively. Eradication of Candida albicans was not possible if IC30 values exceeded 256 micrograms ml-1. While pretreatment counts of Candida albicans in those patients also taking zidovudine did not differ from those in the rest of the study population, both the clinical and the mycological efficacy of ketoconazole seem to be higher both in the short and the long term when administered together with zidovudine. In consideration of the high relapse rate after about 4 weeks, an interval treatment protocol with oral ketoconazole is proposed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1287481&dopt=Abstract ketoconazole Nizoral



Nizoral
Oral treatment of candida vaginitis: experience at the Special Treatment Clinic University College Hospital, Ibadan, Nigeria.

Ojengbede OA, Ochei J.

Department of Obstetrics and Gynaecology, College of Medicine, University College Hospital, Ibadan, Nigeria.

Seventy-four patients with clinical and laboratory diagnosis of candida vaginitis at Special Treatment Clinic, U.C.H., Ibadan were treated with daily dose of 400mg Ketoconazole (Nizoral) for 5 days. Forty had primary infection and 34 (46.0%) had recurrent infection. Vaginal skin infection, discharge, vulva pruritus and dyspareunia were the key symptoms and signs. Follow-up showed disappearance of findings a week following treatment except vaginal infection which was still present in 2 (2.9%) patients. Four weeks after treatment, 4--7% of the cases had one symptom or the other but more experienced dyspareunia. Mycological tests showed positive results in wet smear examination in 6.7%. Nevertheless, 80% of the 34 with recurrent infection preferred oral treatment to topical vaginal applications which they had had in the past. The implication of this result in treatment of acute and chronic vaginal candidosis in our community is discussed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1304794&dopt=Abstract ketoconazole Nizoral



Nizoral
Ketoconazole inhibits alveolar macrophage production of inflammatory mediators involved in acute lung injury (adult respiratory distress syndrome).

Williams JG, Maier RV.

Department of Surgery, University of Washington School of Medicine, Seattle, Wash.

BACKGROUND. Acute inflammatory lung injury (adult respiratory distress syndrome [ARDS]) causes significant morbidity and death in surgical patients. The alveolar macrophage elaborates proinflammatory mediators implicated in acute pulmonary injury. The macrophage products, leukotriene B4 (LTB4), thromboxane A2 (TXA2), and procoagulant activity (PCA), initiate inflammatory cascades that lead to microvascular thrombosis and neutrophil infiltration, two common features of ARDS. One potential method of preventing or attenuating lung injury is to inhibit the production of inflammatory mediators. Preliminary studies indicate that ketoconazole, known primarily for its antifungal properties, may prevent ARDS. METHODS. LTB4, TXB2, and PCA production by rabbit alveolar macrophages was measured after treatment with endotoxin or Ca ionophore and ketoconazole or selective 5-lipoxygenase (MK 886) and thromboxane synthetase (imidazole) inhibitors. RESULTS. Ketoconazole significantly inhibits alveolar macrophage production of LTB4, TXB2, and PCA. Ketoconazole inhibition of PCA is independent of effects on 5-lipoxygenase and thromboxane synthetase. CONCLUSIONS. Ketoconazole inhibition of alveolar macrophage proinflammatory mediators may be of benefit in preventing ARDS by minimizing neutrophil infiltration and microvascular thrombosis. Inhibition of 5-lipoxygenase and thromboxane synthetase, without affecting cyclooxygenase, may offer a selective advantage by allowing production of other homeostatic eicosanoids.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1322565&dopt=Abstract ketoconazole Nizoral



Nizoral
Development of an in vivo preclinical screen model to estimate absorption and first-pass hepatic extraction of xenobiotics. II. Use of ketoconazole to identify P-glycoprotein/CYP3A-limited bioavailability in the monkey.

Ward KW, Stelman GJ, Morgan JA, Zeigler KS, Azzarano LM, Kehler JR, McSurdy-Freed JE, Proksch JW, Smith BR.

Preclinical Drug Discovery, Cardiovascular & Urogenital CEDD, GlaxoSmithKline, King of Prussia, PA 19406, USA. Keith_W_Ward GSK.com

The effect of P-glycoprotein (Pgp) and/or CYP3A on the disposition of xenobiotics has been extensively investigated and is often of interest during drug discovery lead optimization. We have previously described a monkey pharmacokinetic screen to rapidly estimate absorption and first-pass extraction. In the present work, this monkey screen has been expanded to include an assessment of Pgp/CYP3A effects on absorption and first-pass extraction, using ketoconazole as a prototypic dual Pgp/CYP3A inhibitor. To generate a ketoconazole dosing regimen, the pharmacokinetics of ketoconazole were first determined in the monkey and were found to be consistent with that previously described in the rat, dog, and human. Dose-ranging experiments demonstrated that a single 10-mg/kg intraduodenal ketoconazole dose would provide an appropriate exposure; this dose was used throughout subsequent interaction experiments. Next, erythromycin and propranolol were explored as positive and negative control substrates for Pgp/CYP3A interactions, respectively. As anticipated, ketoconazole produced no change in the absorption or first-pass extraction of propranolol but resulted in a substantial increase in absorption and decrease in first-pass extraction of erythromycin. Finally, this ketoconazole-based monkey screen was deployed in a drug discovery setting, and examples of such use are presented. These experiments have allowed a more complete characterization of ketoconazole as a prototypic dual Pgp/CYP3A inhibitor and its use as a tool in a preclinical setting and further demonstrate the use of the monkey to investigate the role of Pgp/CYP3A in limiting the oral bioavailability of new drug candidates.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14744938&dopt=Abstract ketoconazole Nizoral



Nizoral
Lack of immunosuppression by ketoconazole and itraconazole.

Cools M, Aerts F, Van Wauwe J.

Janssen Research Foundation, Beerse, Belgium.

The antifungal drugs ketoconazole and itraconazole were evaluated for their effects in the following test systems: in vitro, phytohaemagglutinin (PHA)-induced proliferation of human peripheral blood mononuclear cells and IL-2-driven proliferation of CTLL-2 cells; in vivo, antibody response to sheep red blood cells (SRBC) and delayed-type hypersensitivity (DTH) reaction to oxazolone. At a concentration of 10 microM, ketoconazole moderately and itraconazole strongly inhibited thymidine (Thd) incorporation in human peripheral blood mononuclear cells cultured in medium supplemented with 5% human serum. Increasing the serum concentration from 5 to 20% almost completely reversed these inhibitory effects. Also, cell viability, found to be less than 15% in cultures containing 10 microM itraconazole was restored by increasing the serum concentrations in the culture medium. Similar observations were made in experiments using IL-2-stimulated CTLL-2 cells: the growth inhibition in the presence of 10 microM ketoconazole or 1 microM itraconazole could be counteracted by increased serum supplementation. In vivo, subchronic intraperitoneal dosing with 40 mg/kg ketoconazole or itraconazole to mice had no effect on the antibody response to SRBC as measured by the number of splenic IgM and IgG plaque-forming cells and did not significantly affect the DTH response to oxazolone. These data indicate that neither ketoconazole nor itraconazole exert immunosuppressive properties in vivo. Their in vitro inhibitory effects on PHA-induced lymphocyte proliferation and IL-2-dependent CTLL-2 growth are reversed by the serum supplementation to the culture medium and these activities should therefore be considered as in vitro artefacts.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1330944&dopt=Abstract ketoconazole Nizoral



Nizoral
Effects of ketoconazole on the iodide uptake by FRTL-5 cells.

Kohan SL, Guillen CE, Pardes EM, Junco M, Soto RJ, Sartorio GC.

Division Endocrinologia, Hospital Ramos Mejia, Buenos Aires, Argentina.

Ketoconazole is an imidazole derivative used as an antimycotic agent with reported effects on the endocrine system, but very little is known about its possible actions on thyroid function. Our purpose was to study the influence of this substance on the basal and TSH-stimulated iodide uptake in the rat thyroid cell strain FRTL-5. Ketoconazole (1-50 mumol/l) was shown to slightly increase the basal iodide uptake but, at higher concentrations (75-100 mumol/l), it sharply decreased iodide uptake below the basal levels. When the cells were cultured under bTSH stimulation (30 UI/l), the inhibitory effect of ketoconazole was exerted at concentrations as low as 25 mumol/l. This inhibition was observed even if it was added to the culture medium immediately before the Na125I addition. Forskolin, a stimulator of adenylate cyclase activity, was unable to prevent the iodide uptake inhibition. Low doses of ketoconazole increased cAMP concentrations. In the presence of TSH this effect was more evident in an inverse dose-dependent way. Because of its dual action, it can be assumed that ketoconazole could influence the iodide uptake in the FRTL-5 cells through more than one mechanism.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1335201&dopt=Abstract ketoconazole Nizoral