Nizoral
Antiproliferative effects of delta 24(25) sterol methyl transferase inhibitors on Trypanosoma (Schizotrypanum) cruzi: in vitro and in vivo studies.

Urbina JA, Vivas J, Lazardi K, Molina J, Payares G, Piras MM, Piras R.

Instituto Venezolano de Investigaciones Cientificas, Facultad de Ciencias, Universidad Central de Venezuela, Caracas.

We have studied the antiproliferative effects of two sterol analogs previously reported as potent inhibitors of delta 24(25) sterol methyl transferase (E.C. 2.1.1.43) of yeasts and fungi on epimastigotes and amastigotes on Trypanosoma (Schizotrypanum) cruzi, the causative agents of Chagas disease, as well as its chemotherapeutic effects in a murine model of the disease. On the epimastigote form proliferating in liver infusion tryptose medium at 28 degrees C 22,26-azasterol (AZA), a cholestanol analog with a 6-membered aza ring as a side chain produced a dose-dependent reduction of the growth rate up to 3 microM, but at 10 microM complete growth arest and cell lysis took place after 120-144 h. For 24(R,S),25-epiminolanosterol (EIL), complete growth arrest and lysis took place with 6 microM. In both cases the antiproliferative effects were potentiated by the simultaneous incubation of the epimastigotes with inhibitors of sterol C-14 alpha-demethylase such as ketoconazole or SDZ 89,485, as indicated by concave isobolograms and fractional inhibitory concentrations ranging from 0.11 to 0.46. Analysis of the sterol composition in control and treated cells by thin-layer and capillary gas-liquid chromatography coupled to mass spectrometry showed that growth inhibition correlated with the complete disappearance of the native endogenous sterols of the parasite (ergosterol and 24-ethyl analogs) and the accumulation of 24-desalkyl sterols. Against the clinically relevant amastigote form proliferating inside cultured Vero cells at 37 degrees C, AZA eradicated the parasite of 100 nM, while the corresponding concentration for EIL was 300 nM. Synergic effects of both inhibitors when combined with ketoconazole against this form of the parasite was demonstrated using a three-dimensional analytic method which allowed the identification of optimal drug concentrations. Finally, it was found that daily oral administration of AZA at 50 mg/kg/day for a total of 43 doses to mice infected with a lethal inoculum of T. cruzi allowed survival of all treated animals 25 days after infection, while all control (untreated) animals were dead at this point of time. Increased survival correlated with a 90% reduction in parasitemia in the treated animals. The antiparasitic effects of the azasterol were potentiated in combined treatments with ketoconazole. This is the first report of a successful application of a sterol methyl transferase inhibitor as a chemotherapeutic agent in a protozoal infection.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8804798&dopt=Abstract ketoconazole Nizoral



Nizoral
Antifungal susceptibility pattern of non-albicans Candida species & distribution of species isolated from Candidaemia cases over a 5 year period.

Chakrabarti A, Ghosh A, Batra R, Kaushal A, Roy P, Singh H.

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

A marked increase in the incidence of patients of candidaemia is reported from a tertiary care hospital in north India over the last five years (15 patients in 1991 and 275 in 1995). The distribution of Candida species isolated from January 1991 through December 1995 was investigated. Antifungal susceptibility against amphotericin B, 5-fluorocytosine, ketoconazole and fluconazole of 100 randomly selected non-albicans Candida species isolated during 1995 was determined by an in-house standardized disc diffusion method and the standard broth dilution procedure recommended by the National Committee for Clinical Laboratory Standards (NCCLS, USA). The disc diffusion method correlated well with NCCLS method except for ketoconazole. Resistance against any antifungal was confirmed only by results of NCCLS method. A shift to higher isolation of non-albicans Candida species was observed during this period (52.6% in 1992 to 89.5% in 1995). Resistance was observed against 5-fluorocytosine in 3 per cent strains of C. krusei; and against fluconazole in 24.2 per cent of C. krusei, 15.4 per cent of C. guilliermondii and 5.7 per cent strains of C. tropicalis. No resistance was detected against amphotericin B and ketoconazole. Thus Candida species with fluconazole resistance have become more prominent in recent years.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8840655&dopt=Abstract ketoconazole Nizoral



Nizoral
A comparative study of the broth micro- and macro-dilution techniques for the determination of the in vitro susceptibility of Aspergillus fumigatus.

Manavathu EK, Alangaden GJ, Lerner SA.

Department of Internal Medicine (Division of Infectious Diseases), Wayne State University, Detroit, MI 48201, USA, manavath netcore.ca

The effects of inoculum size, medium, temperature, and duration of growth on the in vitro susceptibility testing of Aspergillus fumigatus were investigated using broth micro- and macro-dilution techniques. The minimum inhibitory concentrations (MICs) of ketoconazole, miconazole, itraconazole, fluconazole, and amphotericin B were significantly influenced by the inoculum size, regardless of the techniques used. Two- to four-fold higher MIC values were obtained when the inoculum size was increased 100-fold. The use of peptone yeast extract glucose and RPMI 1640 media provided essentially identical MIC values at 30 and 35 degrees C after incubation for 48 h or longer. A comparison of broth micro- and macro-dilution techniques revealed that, under equivalent conditions, the latter with an inoculum size between 1 x 10(3) and 1 x 10(4) conidia (strain W73355)/mL consistently provided the lowest MICs of fluconazole (256 micrograms/mL), ketoconazole (8 micrograms/mL), miconazole (2 micrograms/mL), itraconazole (0.25 micrograms/mL), and amphotericin B (0.25 micrograms/mL). Using the broth macrodilution technique we screened 24 clinical isolates of A. fumigatus obtained from the Detroit Medical Center in 1994. The MIC values of fluconazole, ketoconazole, miconazole, itraconazole and amphotericin B for all the isolates were 128-256, 8-16, 1-2, 0.25-0.5, and 0.25-1.0 micrograms/mL, respectively, indicating that none of the clinical isolates that we tested shows acquired resistance to the antifungals used.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8864219&dopt=Abstract ketoconazole Nizoral



Nizoral
Ketoconazole and phorbol myristate acetate regulate osteoclast precursor fusion in primary murine marrow culture.

Fan X, Biskobing DM, Bain S, Rubin J.

Department of Medicine, Veterans Affairs Medical Center, Atlanta, Georgia, USA.

Osteoclast formation requires both precursor proliferation and then fusion into a multinuclear cell. These processes can be separated in primary murine marrow culture where osteoclastogenesis is stimulated by 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Here we investigate the regulation of precursor fusion. Ketoconazole, an agent known to inhibit cell fusion, added during the fusion period (days 5-6), dose-dependently inhibited formation of tartrate-resistant acid phosphatase+ (TRAP+) multinucleated cells (TRAP+MNCs), maximally at 62 +/- 4% (n = 10). TRAP+MNCs in cultures exposed to 48 h of ketoconazole (1 microM) during fusion had fewer nuclei compared with control (11.7 +/- 0.6 vs. 15.1 +/- 0.9). This inhibitory effect was completely reversed 24 h after removal of ketoconazole from culture. Phorbol myristate acetate (PMA) stimulated TRAP+MNC formation when given during the last 12 h of culture (2.3 +/- 0.2 fold compared with control). This increased formation was unaffected by the addition of hydroxyurea and accompanied by an increase in nuclei per TRAP+MNC (15.5 +/- 0.9 vs. 13.1 +/- 0.6). Finally, staurosporine decreased TRAP+MNC formation in the presence or absence of PMA, implying that protein kinase C is involved in fusogenic processes. Regulation of fusion appears to be another mechanism by which bone remodeling can be modulated in vivo.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8864902&dopt=Abstract ketoconazole Nizoral



Nizoral
Stability of ketoconazole, metolazone, metronidazole, procainamide hydrochloride, and spironolactone in extemporaneously compounded oral liquids.

Allen LV Jr, Erickson MA 3rd.

College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City 73117, USA. loyd-allen uokhsc.edu

The stability of drugs commonly prescribed for use in oral liquid dosage forms but not commercially available as such was studied. Ketoconazole 20 mg/mL, metolazone 1 mg/mL, metronidazole 50 mg/mL, procainamide hydrochloride 50 mg/ mL, and spironolactone 25 mg/mL were prepared in a 1:1 mixture of Ora-Sweet and Ora-Plus (Paddock Laboratories), a 1:1 mixture of Ora-Sweet SF and Ora-Plus (Paddock Laboratories), and cherry syrup and placed in 120-mL polyethylene terephthalate bottles. The sources of the drugs were powder, capsules, and tablets. Six bottles were prepared per liquid; three were stored at 5 degrees C and three at 25 degrees C, all in the dark. A sample was removed from each bottle immediately after preparation and at intervals up to 60 days and analyzed for drug concentration by stability-indicating high-performance liquid chromatography. At least 93% of the initial drug concentration was retained in all the oral liquids for up to 60 days. There were no substantial changes in the appearance or odor of the liquids, or in the pH. Ketoconazole 20 mg/mL, metolazone 1 mg/mL, metronidazole 50 mg/mL, procainamide hydrochloride 50 mg/ mL, and spironolactone 25 mg/mL were stable for up to 60 days at 5 and 25 degrees C in three extemporaneously compounded oral liquids. INDEX TERMS: Anti-infective agents; Antifungals; Capsules; Cardiac drugs; Cherry syrup; Compounding; Containers; Diuretics; Incompatibilities; Ketoconazole; Liquids; Metolazone; Metronidazole; Polyethylene terephthalate; Powders; Procainamide hydrochloride; Spironolactone; Stability; Storage; Suspending agents; Tablets; Temperature; Vehicles.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8870895&dopt=Abstract ketoconazole Nizoral



Nizoral
The role of ketoconazole in the QTc interval prolonging effects of H1-antihistamines in a guinea-pig model of arrhythmogenicity.

Gras J, Llenas J, Palacios JM, Roberts DJ.

Research Centre Almirall Laboratories, Cardener, Barcelona, Spain.

We have carried out experiments to re-evaluate the influence of ketoconazole (400 mg kg-1,p.o.) on the effects of ebastine, terfenadine and loratadine on the QTc interval in conscious guinea-pigs. Following a previously described protocol of oral drug administration, but using telemetric recording of the ECG, we have found that the prolongation of the QTc interval attributed to ebastine and terfenadine is in fact entirely due to ketoconazole, and that neither terfenadine, ebastine nor loratadine produce any additional effects on subsequent administration.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8886395&dopt=Abstract ketoconazole Nizoral



Nizoral
Clinical characteristics and management responses in 85 HIV-infected patients with oral candidiasis.

Silverman S Jr, Gallo JW, McKnight ML, Mayer P, deSanz S, Tan MM.

Division of Oral Medicine, School of Dentistry, University of California, San Francisco, USA.

Eighty-five consecutively seen HIV-positive persons with oral candidiasis were evaluated for clinical characteristics, staging of HIV disease, quantitation of candidal colony formation, and response to systemic antifungal treatment with Nizoral (ketoconazole). Fifty-five had CD4 counts less than 200. There was an inconsistent association between clinical signs, patient symptoms, CD4 counts, and candidal colony-forming units. However, there was a trend toward higher colony-forming unit counts (> 500) in patients with lower CD4 cells (< 200). Sixty-five patients had a complete clinical response to the ketoconazole treatment (200 mg daily for 7 days), even though 81% of posttreatment cultures remained positive. Nonsmokers were more likely to respond to antifungal treatment when compared with smokers, and there was a slight tendency for complete responses when colony-forming unit counts were low. The most common lesion presentation was a combination of the white (pseudomembranous) and red (erythematous) forms. Forty-nine percent had complaints of pain. The variable responses indicated the importance of flexible dose-time and drug considerations in antifungal management. Candida albicans was the predominant species.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8899777&dopt=Abstract ketoconazole Nizoral