In vitro and in vivo anti-Candida activity and toxicology of LY121019.

LY121019 (N-p-octyloxybenzoylechinocandin B nucleus) is a semisynthetic antifungal antibiotic that possesses potent anti-Candida activity. The MIC50 and the MIC90 for both LY121019 and amphotericin B were 0.625 and 1.25 micrograms/ml, respectively. Only an 8-fold increase in the MIC against C. albicans occurred during 34-day exposure to subinhibitory concentrations indicating that LY121019 has a low potential for causing resistance development. Scanning electron microscopic studies revealed that LY121019 caused severe damage to the C. albicans cell. The ED50's for LY121019 and amphotericin B administered parenterally to mice were 7.4 and 2.5 mg/kg, respectively. Parenterally administered LY121019 at doses of 6.25 mg/kg significantly reduced the recovery of C. albicans from infected mouse kidneys. Orally administered 50 and 100 mg/kg doses of LY121019 were effective in eliminating C. albicans from the gastrointestinal tract of infected mice. Topical application of 5% LY121019 was as effective as 3% nystatin in the treatment of superficial C. albicans infections. Local administration of LY121019, nystatin, or miconazole was effective against rat vaginal candidiasis. LY121019 was administered intravenously to dogs at doses up to 100 mg/kg/day, 5 days a week for 3 months; all dogs survived. Compound related effects included a histamine-like reaction, increased serum alkaline phosphatase and SGPT, fatty vacuolization of the liver, and some tissue damage at the injection site. The no effect dose in dog was 10 mg/kg. LY121019 had no more than 1/20 the toxicity of amphotericin B in the dog.

A32390A, a new biologically active metabolite. III. In vitro and in vivo antifungal activity.

A32390A, an isonitrile-containing derivative of mannitol, represents a new class of antifungal antibiotics. In vitro antifungal activity of A32390A was found against Candida albicans, Cryptococcus neoformans and Histoplasma capsulatum. In vivo antifungal activity of A32390A was demonstrated in mice infected with C. albicans. Accumulative doses of 37.5 approximately 600 mg/kg, administered subcutaneously over a 24-hour period, showed significant activity without demonstrating toxicity. A32390A was effective, but not as effective as amphotericin B, in reducing the number of Candida cells isolated from the kidney of infected mice. Urinary excretion of A32390A accounted for only 10% of the administered dose. Improved bioavailability of A32390A was accomplished when the antibiotic was combined with polyvinyl pyrrolidone (PVP) in a solid dispersion. Administration of A32390A as a 10% dispersion in PVP resulted in increased urinary excretion of the drug and reduced the amount of drug required for in vivo activity.