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The effect of ketoconazole on pulmonary pathology associated with dead Dirofilaria immitis.

Tarish J, Atwell R.

Department of Companion Animal Medicine and Surgery, School of Veterinary Science, University of Queensland, Australia.

The involvement of thromboxane and lipoxygenase in the regulation of pulmonary lesions and immune responses was investigated in dogs given ketoconazole and exposed to dead adult Dirofiliara immitis. Immunopathological reactions to the dead filariae were monitored by light and transmission electron microscopy and serology. When compared with control tissues, ketoconazole administration enhanced the level of pulmonary haemorrhage and early parenchymal fibrosis associated with dead adult filariae. Ultrastructurally, alveolar capillaries were filled with erythrocyte aggregations and proteinaceous material. These results suggested that an intact thromboxane and lipoxygenase pathway within the arachidonic acid system is necessary to minimize the effect of dead D. immitis in this pulmonary artery model.

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Experimental chemotherapy with combinations of ergosterol biosynthesis inhibitors in murine models of Chagas' disease.

Maldonado RA, Molina J, Payares G, Urbina JA.

Departamento de Parasitologia, Facultad de Ciencias, Universidad Central de Venezuela, Caracas.

We report the effects of ketoconazole and the bistriazole ICI 195,739 acting alone or in combination with the allylamine terbinafine (Lamisil) on murine models of Chagas' disease. Mice infected with 10(5) Trypanosoma (Schizotrypanum) cruzi blood trypomastigotes and treated orally with 30 mg of ketoconazole per kg of body weight per day for 7 days, starting at 24 h postinoculation, had 100% survival after 35 days, while controls (untreated) or animals that received 15 mg of ketoconazole or 100 mg of terbinafine per kg/day by the same route had 0% survival after the same period of time. However, all mice receiving the combination of 15 mg of ketoconazole plus 100 mg of terbinafine per kg/day survived for 35 days after infection; it was shown that the survival of the animals treated with this combination was statistically greater than that obtained with either drug acting alone and was indistinguishable from that observed with the high doses of ketoconazole, indicating a synergistic action of the drugs in vivo. However, most animals that survived after the 7-day treatments were not cured, as indicated by a delayed but persistent parasitemia. When the treatment was extended to 14 days, 100% survival was obtained 10 weeks after inoculation for mice treated with 30 mg of ketoconazole per kg/day and the combination of 15 mg of ketoconazole per kg/day plus 100 mg of terbinafine per kg/day, while two-thirds of the mice treated with 15 mg of ketoconazole per kg/day alone were alive after the 14-day treatment; controls or animals that received 100 mg of terbinafine per kg/day did not survive after 25 days. Parasitemia in all surviving mice was negative after 55 days but parasitological cure, as assessed by subinoculation of organs in naive animals, was predominant only in animals that received the combined drug treatment. We also investigated the bistriazole ICI 195,739 and found, as reported previously, that just 1 mg of the compound per kg/day administered orally for 5 days was enough to protect most mice from death 30 days after inoculation, but no parasitological cures were observed. However, in the protocol used in the present study, the protective activity of ICI 195,739 at suboptimal doses (0.5 mg/kg/day) could be enhanced when it was used in combination with terbinafine at doses of the allylamine that by themselves induced no significant protection. Survival of the mice was inversely correlated with the levels of parasitemia in all cases. Extension of the treatment period with the triazole to 15 days at 1 mg/kg/day afforded definitive protection against death, with parasitological cure being achieved in 50% of mice at 10 weeks postinoculation, but no enhancement of its activity at suboptimal doses was observed when it was used in combination with terbinafine during this extended observation period. Taken together, these results supports the proposition that ketoconazole used in combination with terbinafine could be useful in the treatment of humans with Chagas' disease because it can promote parasitological cure without the need to resort to the use of high levels of the azole, which is known to interfere with hepatic function and steroid synthesis in the host. They also support the conclusions of previous in vitro studies which suggested that the triazole ICI 195,739 blocks the proliferation of T. cruzi by a mechanism which differs from those of classical ergosterol biosynthesis inhibitors.

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Coccidioidomycosis and heart transplantation.

Hall KA, Sethi GK, Rosado LJ, Martinez JD, Huston CL, Copeland JG.

Section of Cardiovascular and Thoracic Surgery, University of Arizona, Tucson 85724.

Eleven episodes of Coccidioides immits infection (cocci) were documented in nine of 199 heart transplant recipients. Cocci was confirmed by fungal cultures and treated with 1 gram of intravenous amphotericin B, after which all patients were put on ketoconazole 200 mg orally twice a day. Two recurrent cocci episodes were noted, both occurring when ketoconazole maintenance therapy was discontinued. When compared with the group of patients without cocci, actuarial survival at 1 and 5 years was identical. We conclude that cocci does not seem to affect the early and late clinical outcome and that prophylactic use of ketoconazole (or other oral antifungal agents) after successful treatment of the initial infection is recommended.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8329432&dopt=Abstract ketoconazole Nizoral



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Effects of the combination of ketoconazole and calcium channel antagonists against Candida albicans in vitro.

Krajewska-Kulak E, Niczyporuk W.

Department of Dermatology, Medical Academy, Bialystok, Poland.

Susceptibility of 66 strains of Candida albicans from patients were tested against ketoconazole (Ktz, CAS 65277-42-1), cinnarizine (Cin), verapamil (Ver), nifedipine (Nif), nimodipine (Nim) and the combination of Ktz with these calcium channel antagonists, using Sabouraud's broth. Minimal inhibitory concentrations (MICs) determined on diagnostic plates gave values of Ktz: 34.5 +/- 3.9 micrograms/ml, Cin 413 +/- 11.3 micrograms/ml, Ver 334 +/- 11.4 micrograms/ml, Nif 374 +/- 19.3 micrograms/ml and Nim 486 +/- 20 micrograms/ml. The combination of Ktz and calcium channel antagonists in various ratios (1 : 1, 1 : 2, 2 : 1) was found to exert synergistic effect and the mean values of the combinations were: Ktz+Cin 6.52 +/- 1.67, 6.4 +/- 1.71, 6.06 +/- 1.7 micrograms/ml: Ktz+Ver 11.13 +/- 2.13, 11.63 +/- 2.22, 10.6 +/- 2.1 micrograms/ml: Ktz+Nif 7.37 +/- 1.6, 7.7 +/- 1.57, 7.4 +/- 1.75 micrograms/ml: Ktz+Nim 10.1 +/- 2.28, 10.6 +/- 2.31, 9.91 +/- 2.21 micrograms/ml. These results were significantly different (p < 0.001) compared with ketoconazole. Our findings indicate that some calcium channel antagonists increase the antifungal activity of Ktz against C. albicans in vitro.

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Potential use of ketoconazole in a dynamic endocrine test to differentiate between biological outliers and testosterone use by athletes.

Kicman AT, Oftebro H, Walker C, Norman N, Cowan DA.

Drug Control and Teaching Centre, King's College London, UK.

Determination of the ratio of testosterone to epitestosterone (T/E) in urine is used to detect testosterone administration in athletes, with a ratio > 6 considered as evidence of an offense. We show that administration of ketoconazole, which inhibits testosterone biosynthesis, may be useful for differentiating between an athlete who is using testosterone and one who naturally gives a ratio > 6. In a control subject pretreated with testosterone, ketoconazole caused the ratio to increase; conversely, it caused a decrease in the ratio in an athlete under investigation. Repeated administration of ketoconazole to two normal men caused a decrease in the ratio due to a large decrease in the urinary excretion rate of testosterone relative to epitestosterone. Stimulation with human chorionic gonadotropin exacerbated the differences in excretion rates. A single administration of ketoconazole to six normal men caused the T/E ratios to decrease significantly within 8 h, a suitable time scale for use in a dynamic test.

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Necturus gallbladder epithelial cell volume regulation and inhibitors of arachidonic acid metabolism.

Kersting U, Napathorn S, Spring KR.

Laboratory of Kidney and Electrolyte Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892.

Inhibition of the metabolism of arachidonic acid by the epoxygenase (cytochrome P-450) pathway with the inhibitor ketoconazole results in excessive cell swelling upon exposure to hyposmolality instead of the rapid and complete regulatory volume decrease (RVD) normally observed. NaCl entry from bathing solutions to cell interior was shown to cause this swelling, with Na influx occurring across the basolateral membrane and electrically silent Cl influx across the apical membrane. Ion substitution experiments show that the KCl efflux mediating RVD was unimpaired by ketoconazole, but was overwhelmed by the NaCl influx. Measurements of transepithelial fluid flux, Cl concentration, osmolality and pH showed that gallbladders treated with ketoconazole transiently secreted fluid rather than the normal absorption. We conclude that inhibition of arachidonic acid metabolism does not directly affect RVD by Necturus gallbladder, but that blockade of the epoxygenase pathway can have a profound influence on NaCl entry into gallbladder epithelial cells.

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Effects of ketoconazole on cholesterol precursors and low density lipoprotein kinetics in hypercholesterolemia.

Gylling H, Vanhanen H, Miettinen TA.

Second Department of Medicine, University of Helsinki, Finland.

Ketoconazole, an inhibitor of cholesterol synthesis at 14 alpha-demethylation of lanosterol, effectively reduces serum total and low density lipoprotein (LDL) cholesterol levels. We studied the effects of ketoconazole (400 mg/day for 5 weeks) on serum lipids, free and esterified noncholesterol sterols, and kinetics of LDL apolipoprotein B (apoB) in seven patients with heterozygous familial hypercholesterolemia (FH) and in three patients with primary hypercholesterolemia (nonFH). The total, intermediate density, and LDL cholesterol levels were significantly reduced by 24, 27, and 29%, respectively, and LDL apoB by 23%. Serum total and lipoprotein triglycerides were unchanged. The LDL cholesterol/apoB ratio decreased significantly. Serum ratios of lanosterols to cholesterol were increased over 50 times, almost the same in all lipoproteins and mainly as the unesterified form; free delta 8-precursor sterols, 2-5 times; cholestanol, slightly; while ratios of lanosterol of desmosterol, lathosterol, and plant sterols were virtually unchanged. Inconsistent esterification of methyl sterols might indicate unaltered acyl CoA:cholesterol acyltransferase activity. LDL apoB transport was decreased in all nonFH subjects but inconsistently in FH. The fractional catabolism rate (FCR) for LDL apoB was increased significantly in FH by 13% and inconsistently by 4% in nonFH. In a subgroup of three FH patients, more dense LDL (d 1.037-1.055 g/ml) was transported and catabolized faster on than off ketoconazole so that the serum level of this more dense LDL subfraction was unchanged, the decrease of LDL being due to a reduction of the less dense LDL subfraction.(ABSTRACT TRUNCATED AT 250 WORDS)

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