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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The Bulletin of the Society of Pharmacological and Environmental Pathologists encephalitozoonosis is entirely speculative and cannot be proved. Alimentary helminthic infection was absent, and protozoal infection of the alimentary systems was almost entirely eliminated. It is of interest that in Colony No. 1, there was a total absence of conditions seen at birth or shortly after which could be attributed to a genetic background while several were seen in Colony No. 2. These included: imperforate vagina with inguinal hernia (20 cases), imperforate vagina with distended uterus (5 cases), hypotrichosis (4 cases), bilateral cataracts (3 cases). unilateral cataracts (2 cases), and bent tail (1 case). Thirty-nine deaths occurred in the adult breeding stock due to: birth trouble (10). thymoma (31, leukemia with lymphadenopathy and splenomegaly (5). accidents f3), no cause determined (11). In addition to the above, we drew attention to the occurrence of a "new" disease, which occurred exclusively in adult males and almost certainly had some genetic background. Death occurred suddenly. The characteristic, unmistakable pathologic features included massive bleeding (mostly without clotting) in the pleural cavity with atelectasis of the lungs, or as pericardial tamponade, and also testicular changes. In addition to these macroscopic features, histologically there was an acute myocarditis. The unusual syndrome is comparable to that described by Angevine and Furth (1943) with no causation determined. Alternatively, it might be related to a disease described by Allen, Meier, and Hoag (1962). at Bar Harbor. The latter established that their condition had a multifactorial causation and occurred mostly in males. The bleeding was proved to be due to specific clotting abnormalities which, in turn, were precipitated in some way by toxic effects of ethylene glycol produced during ethylene oxide sterilization of bedding.

distribution), intracellular fluid volume, water intake, urine output, insensible water loss, and serum and urinary sodium potassium, and osmolality. Glomerular filtration rate (51Cr-EDTA clearance), hemoglobin, hematocrit, erythrocyte count, serum glucose, cholesterol, urea nitrogen, and ketones were also determined. . The great majority of studies concerning the physiologyof human starvation have been reported within the last 15years. The cause of this recent interest is the popular use of fasts of varying duration as a technique in the correction and control of intractable obesity. Presently, opinion on the safety of therapeutic fasting falls into three main categories: 1) prolonged fasting is an extremely useful and relatively safe method of treatment for the massively obese; 2) prolonged fasts are an unnecessary risk since substantial weight losses can be achieved by repeated fasts of shorter duration; and 3) fasts of any duration expose the patient to unjustifiable hazards. The question of benefit to be achieved versus risk involved in therapeutic fasting has not been answered conclusively. Moreover, studies of body fluids in man during starvation have yielded somewhat contradictory results. Although rapid decreases in total body water (TBW) during the initial days are well documented, it is not clear which fluid compartments are diminished, or whether these decreases result from urinary or insensible water loss.An ideal weight-reduction program should yield 2 loss of fat while sparing lean body mass. In addition to the loss of water, decreases in body weight must be composed largely of fat or protein becausecarbohydratestores in the body of man represent only about 840 calories. Unfortunately, losses of lean tissue during fasting are of such magnitude as to be of concern for a number of authors. Benoit, Martin, and Watten (2) estimated that 65% of an average 9.6-kg loss during 10-day fasts in seven obese men was lean tissue, with only a 3.4-kg decrease in body fat. Ball et al(1) reported that five obese patients, fasted for 16 days, lost 563 g of lean tissue and only 202 g of fat daily. The lean tissue loss represented almost 75% of the total weight decrease.Employing lean and obese rats as a model, investigations were made to elucidate the tissue components of weight loss and the influence of excess adipose tissueon body fluidsand renal function during fasting. The results of some of these studies will be summarized briefly.MATERIALS AND METHODS Three hundred male Charles River CD outbred albino rats were offered ground Purina Laboratory Chow (PLC) and water ad libitum. At approximately 6 weeks of age, the anima!s were separated randomly into two groups. One group was offered a diet containing 42.5% fat, and the other group cqntinued to receive PLC. The fasting (no chow; water ad libitum) periQd began when the.,rats were 22 weeks old.The following' parameters were evaluated prior to and throughout prolonged fasts: body weight, body fat (extraction with chloroform/methanol), lean dry mass, total body water...