In acute and subacute toxicological studies, amphotericin B methyl ester was shown to be much less toxic than the parent antibiotic. As a single intravenous dose in mice, the methyl ester was approximately 20 times less toxic than amphotericin B. Also, the acute toxicity of the methyl ester in mice was not enhanced by the presence of chemically induced hepatic or renal damage or by the concurrent administration of amphotericin B or flucytosine. In a 1-month intraperitoneal study in rats, the methyl ester was about one-fourth as nephrotoxic as amphotericin B. In a 1-month intravenous study in dogs, the methyl ester was about one-eighth as nephrotoxic and one-fourth to one-half as hepatotoxic as the parent compound. In addition, the methyl ester, unlike amphotericin B, produced minimal renal effects, which did not increase in severity with increasing dosage. Based on the results of these studies, it is concluded that amphotericin B methyl ester has the potential for an improved therapeutic ratio in the treatment of systemic mycoses.Intravenously administered amphotericin B is the most effective agent currently available for the treatment of many systemic fungal infections. This drug is therapeutically active in a number of mycoses that, prior to its availability, were invariably fatal. The use of amphotericin B for the treatment of systemic disease, however, is associated with toxic side effects; the most common of these is nephrotoxicity. Over 80% of patients given intravenous amphotericin B develop decreased renal function and abnormal urine sediment, and it is often the degree of kidney malfunction, and not the patient's therapeutic response, that determines the duration of drug administration (1, 11).Amphotericin B methyl ester (AME) is a water-soluble derivative of amphotericin B that was developed by Mechlinski and Schaffner (8,10). Both in vitro and in vivo studies have demonstrated that AME possesses significant antifungal activity (2, 4, 5, 7). Also, based on single-dose parenteral experiments in mice and dogs, AME was shown to be much less toxic than amphotericin B (6). The initial studies were conducted with the hydrochloride salt of AME, which proved to be unstable. Subsequently, the free base of AME was found to be stable (3). This report presents toxicological data from repeat-dose studies in which AME free base was compared to amphotericin B. Results from additional single-dose tests are also summarized.MATERIALS AND METHODS Drugs. AME (batch NNO09NB) with a bioassay potency of 1,210 gg/mg was stored at -20°C. A 1% solution of the antibiotic in 0.2% ascorbic acid was prepared immediately prior to use. This procedure resulted in the formation of AME ascorbate in situ. Amphotericin B for injection, USP (Fungizone Intravenous, lots 5B530 and 5D573, E. R. Squibb and Sons, Inc., Princeton, N.J.) was reconstituted according to the manufacturer's instructions. Another antifungal compound, flucytosine (Ancobon, 250-mg capsules, lot 0005-05163, Roche Laboratories, Nutley, N.J.), was tested in a single acute ...

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Cephradine, a semisynthetic cephalosporin antibiotic, has a low order of oral and parenteral toxicity in animals. The oral LD,0 in mice and rats ranged from 5 to >8 g/kg, and the intraperitoneal LD50 values in mice and rats were 0.7 to 1.5 g/kg and 4.0 g/kg, respectively. The intravenous LD50 in mice ranged from 3.0 to 3.8 g/kg. In anesthetized dogs, intravenous doses of cephradine (40 and 120 mg/kg, given 45 min apart) had no effect on either the renal or cardiovascular systems. Single intramuscular injections (0.25 ml or 0.5 ml of a solution containing 125 to 235 mg of cephradine/ml) elicited no signs of either pain or local irritation in dogs, and only transient signs of slight-to-moderate irritation were observed in rabbits. In subacute toxicity studies, cephradine was administered for 4 weeks to rats (daily intraperitoneal doses of 160, 480, or 1,600 mg/kg) and dogs (daily intravenous doses of 80, 240, or 800 mg/kg); in addition, over a 2-week period, monkeys were given daily intravenous doses of 60, 180, or 600 mg/kg. No clinical, biochemical, gross, or micropathological changes due to cephradine were observed in these animals; especially notable was the absence of any signs of nephrotoxicity. In chronic toxicity studies, daily doses of cephradine were administered orally to rats (100 to 1,000 mg/kg), dogs (50 to 500 mg/kg), and monkeys (50 to 500 mg/kg) for 26, 26, and 13 weeks, respectively. Significant responses were observed only in rats, in which grossly enlarged, but histologically normal, ceca developed, a common finding in rodents dosed with antibiotics; in addition, there were increases in the relative and absolute weights of the adrenal glands. None of these effects was observed in rats that were necropsied 3 weeks after termination of dosage. In reproduction studies in mice and rats given either daily oral doses (100 or 300 mg/lkg) or daily intraperitoneal doses (rats only; 80 or 320 mg/kg) of cephradine, no drug-related teratogenic changes in the offspring were observed.

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