Rapamycin (AY-22,989), a new antifungal antibiotic. III. In vitro and in vivo evaluation.

Abstract

The activity of rapamycin, a new anti-Candida antibiotic, was not affected by pH values between 6 and 8; at pH 4, however, activity was abolished. The MIC of rapamycin did not vary drastically with the size of inoculum: a ten-fold dilution of the inoculum reduced the MIC only two-fold. Serum binding was extensive. Serum levels obtained in mice were higher on subcutaneous injection than with oral administration. Dogs absorbed rapamycin after oral administration.Rapamycin cured systemic candidosis in mice: PD50 s. c. was 9.5 mg/kg; PDso p. o. was 11 mg/kg. In the same experimental infections amphotericin B and nystatin exhibited PDso values of <0.25 mg and >4,000 units/kg respectively. Rapamycin and amphotericin B, administered at 1, 4 and 24 hours after infection, gave approximately the same percent survival after 30 days of observation. When the above treatment was extended by an additional daily treatment for 6 days, rapamycin by the subcutaneous route yielded a higher percentage of survival than either rapamycin or amphotericin B, administered orally, after a 30-day observation period. Vaginal candidosis in female rats was treated efficiently (91 % cure) by rapamycin administered orally. No increase of resistance of C. albicans was observed during treatment.

Systemic inhibition of mTOR kinase via rapamycin disrupts consolidation and reconsolidation of auditory fear memory

“…As a result, the two-trial, conditioning procedure was employed for all subsequent experiments, since this procedure was sufficient at achieving maximal freezing to the conditioned tone. T he half-life of RAP in circulation of mice is between 4 and 6 hours (Baker, Sidorowicz, Sehgal, & Vezina, 1978), thus, the drug has been fully excreted when the fear-memory is challenged during recall 48 hours after training and drug injection (See Figs. 2a & b).…”

Direct effects of non-antifungal agents used in cancer chemotherapy and organ transplantation on the development and virulence ofCandidaandAspergillusspecies

“…69 In another study, oral administration of 10 and 12.5 mg/kg rapamycin protected 50% and 90%, respectively, of mice against death from C. albicans infection. 70 Despite having high MICs (>10-100 μg/ml) in Candida spp., 66 both tacrolimus and CsA (which complex with FKBP12 and cyclophilin, respectively) may influence the efficacy of antifungal drugs and reduce C. albicans virulence ( Table 2). 62,71,72 These in vitro results are supported by gene deletion studies showing that calcineurin-defective C. albicans mutants were more sensitive to stress conditions than isogenic wild-type controls, were markedly hypersensitive to azoles, and had attenuated virulence in mice with systemic candidiasis.…”

The rapamycin-sensitive signal transduction pathway as a target for cancer therapy

“…Ras, Raf), and cyclin-dependent kinases, are being developed as anti-cancer agents (Rowinsky et al, 1999, Senderowicz andSausville 2000). One such agent, rapamycin (sirolimus; Rapamune 1 ; Wyeth-Ayerst, PA, USA), a macrolide fungicide isolated from the bacteria Streptomyces hygroscopicus, possesses potent antimicrobial, immunosuppressant, and antitumor properties (Baker et al, 1978;Sehgal et al, 1975;Vezina et al, 1975). Because of its profound immunosuppressive actions, rapamycin was initially developed and received regulatory approval for the indication of prevention of allograft rejection following organ transplantation (Sehgal, 1995).…”