Comparison of the in vitro and in vivo activity of the bis-triazole derivative UK 49,858 with that of amphotericin B against Histoplasma capsulatum

Kobayashi, George S.; Travis, S J; Medoff, Gerald

doi:10.1128/aac.29.4.660

Cited by 39 publications

(23 citation statements)

References 5 publications

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“…injection in treating normal AKR and C57BL/6 mice infected with Histoplasma capsulatum (7). Others have reported that fluconazole was more effective than the imidazole ketoconazole in treating normal mice (12,14) and rats (12,13) infected systemically with Candida albicans.…”

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Comparison of fluconazole and amphotericin B in treating histoplasmosis in immunosuppressed mice

Kobayashi

Travis

Medoff

1987

Antimicrob Agents Chemother

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Fluconazole (UK-49,858) was compared with amphotericin B in treating histoplasmosis in female AKR mice immunosuppressed with either cyclophosphamide or cortisone. Both drugs protected animals from a lethal challenge with Histoplasma capsulatum, but neither regimen resulted in cures since viable organisms were cultured from spleens of survivors.We have previously shown that the triazole fluconazole 858) given orally was as effective as amphotericin B given by intraperitoneal (i.p.) injection in treating normal AKR and C57BL/6 mice infected with Histoplasma capsulatum (7). Others have reported that fluconazole was more effective than the imidazole ketoconazole in treating normal mice (12,14) and rats (12,13) (14) reported that fluconazole was more than 20 times as effective as ketoconazole in C. albicans-infected mice that were immunocompromised by daily administration of dexamethasone. Fluconazole is an attractive antifungal agent in that (i) it is less toxic than amphotericin B, (ii) it is renally excreted, (iii) it readily penetrates cerebral spinal fluid, and (iv) it has a high serum half-life that can be maintained by daily oral administration (5). In the present study, we evaluated the efficacy of fluconazole and amphotericin B in the treatment of histoplasmosis in mice immunosuppressed with either cyclophosphamide or cortisone.For these studies, 6-to 8-week-old female AKR mice (average weight before beginning the experiment was 22 g) were purchased from Charles River Mouse Farms, Wilmington, Mass. All mice were housed and held for 1 week before experimentation. organisms per mouse in normal mice (7). The drug dosages for fluconazole were tested in twofold increments between 1.42 and 90.91 mg/kg per mouse, given twice a day in 0.5-ml volumes orally for a total of 6 consecutive days. For amphotericin B, the range of dosages tested was in twofold increments between 0.85 and 2.73 mg/kg per mouse, given every other day for a total of six injections by the i.p. route. Each dosage of drug was tested in groups of 10 animals, and the experiments were repeated at least three times with essentially the same results. The doses were calculated on the basis of milligrams per kilogram of average body weight of the animals at the start of therapy. According to procedures previously described (7), both fluconazole, given by gavage twice daily in 0.5-ml volumes for a total of 6 consecutive days, and amphotericin B, administered by i.p. injections on alternate days for a total of six injections begun 24 h after infection, protected the cyclophosphamide-induced leukopenic mice from fatal histoplasmosis (LD,00 dose of 5 x 105 organisms per mouse). The dosage of drugs that protected 50% of the infected mice (PD50) was 9.6 ± 2.9 mg/kg per day of fluconazole and 0.54 ± 0.1 mg/kg per day of amphotericin B (Table 1). With this drug regimen, the PD90 for fluconazole was 14.4 mg/kg per day and the PD,0 was 6.4 mg/kg per day; for amphotericin B, the PD%0 was 0.78 mg/kg per day and the PD20 was 0.31 mg/kg per day.We also studied the ef...

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“…However, despite the immunosuppression, the PD50 of fluconazole was unchanged and the PD50 of amphotericin B actually decreased compared with the levels previously found in the treatment of murine histoplasmosis of nonimmunosuppressed mice (7). In the latter study (7) …”

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Comparison of fluconazole and amphotericin B in treating histoplasmosis in immunosuppressed mice

Kobayashi

Travis

Medoff

1987

Antimicrob Agents Chemother

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“…It has been shown that when complex media are used for in vitro testing of fluconazole, the MIC results may be falsely high and may not correlate with clinical efficacy (16). Complex media appear to contain substances which may inhibit fluconazole in vitro (7). Furthermore, in vitro susceptibility testing of fluconazole is troublesome and difficult to reproduce among different laboratories even when the same growth medium is used (17).…”

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“…In normal rats, oral fluconazole at 10 mg/kg per day for 7 days reduced Candida colony counts in the kidneys and livers as well as amphotericin B did and was nearly as effective as amphotericin B in a 21-day treatment trial. There was no further reduction in Candida colony counts when normal rats were treated with fluconazole at 40 mg/kg twice a day for 7 days. In streptozotocin-induced diabetic rats, fluconazole at 20 mg/kg per day for either 7 or 21 days compared favorably with amphotericin B in efficacy.…”

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“…Fluconazole (UK-49,858) is an investigational bistriazole antifungal agent (Pfizer Inc., Groton, Conn.) which has demonstrated activity against C. albicans as well as other fungi that are pathogenic in humans (7,11,17,19). Oral fluconazole is well absorbed and nontoxic and is eliminated by the kidneys in a biologically active form, a feature which may be an advantage in treating renal candidiasis (6).…”

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Fluconazole (UK-49,858) treatment of candidiasis in normal and diabetic rats

Fisher

Lee

Tarry

1989

Antimicrob Agents Chemother

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Fluconazole (UK-49,858), a new oral bistriazole antifungal agent, was compared with amphotericin B in the treatment of established systemic infection with Candida albicans in normal and diabetic rats. In normal rats, oral fluconazole at 10 mg/kg per day for 7 days reduced Candida colony counts in the kidneys and livers as well as amphotericin B did and was nearly as effective as amphotericin B in a 21-day treatment trial. There was no further reduction in Candida colony counts when normal rats were treated with fluconazole at 40 mg/kg twice a day for 7 days. In streptozotocin-induced diabetic rats, fluconazole at 20 mg/kg per day for either 7 or 21 days compared favorably with amphotericin B in efficacy. Results of our study suggest that oral fluconazole may be useful in the treatment of established disseminated candidiasis in normal as well as diabetic hosts.

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Fluconazole Penetration into Cerebrospinal Fluid in Humans

Foulds

Brennan

Wajszczuk

et al. 1988

The Journal of Clinical Pharma

114

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One hour after intravenous doses of 50 mg/d fluconazole for 6 days or 100 mg/d for seven days to healthy subjects, the cerebrospinal fluid concentrations of fluconazole were 1.26 mg/L and 2.74 mg/L, respectively. These values were approximately 52% and 62% those of serum. Four patients with an initial clinical diagnosis of meningitis also had significant concentrations of fluconazole in the cerebrospinal fluid.

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Comparison of the in vitro and in vivo activity of the bis-triazole derivative UK 49,858 with that of amphotericin B against Histoplasma capsulatum

Cited by 39 publications

References 5 publications

Comparison of fluconazole and amphotericin B in treating histoplasmosis in immunosuppressed mice

Comparison of fluconazole and amphotericin B in treating histoplasmosis in immunosuppressed mice

Fluconazole (UK-49,858) treatment of candidiasis in normal and diabetic rats

Fluconazole Penetration into Cerebrospinal Fluid in Humans

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