Robert E. Bagdon

Experimental and clinical toxicology of chlordiazepoxide (Librium

Abstract The effects of excessive doses of chlordiazepoxide in animals and in 22 patients who had attempted suicide are described. In most subjects, single doses up to 2250 mg caused sedation, often ataxia and dysarthria, and in rare instances sleep and coma. No organs or blood changes were noted, and recovery was uneventful in all cases. In animals, similar symptoms were observed with doses of 20–40 mg/kg and higher. The depressant effects in animals could be counteracted by analeptics and intensified by high doses of sedatives and hypnotics. Only slight changes of blood pressure and respiration occurred when large doses were given. Prolonged administration of chlordiazepoxide to animals in amounts severalfold higher than the clinical dosage schedule over a period of many months failed to produce toxic alterations of blood cells and tissues. An experiment is described in which a human volunteer took a total of 9700 mg of chlordiazepoxide over a period of 12 days; the only symptoms detected were irritability, ataxia, and dysarthria, and these were completely reversible.

Toxicologic and metabolic studies on 2,4-dimethoxy-6-sulfanilamido-1,3-diazine (Madribon)

Abstract Sulfadimethoxine (2,4-dimethoxy-6-sulfanilamido-1,3-diazine) is a new sulfonamide having low toxicity after single oral administration to rats and dogs. Chronic toxicity studies of sulfadimethoxine [Madribon (Ro-4-0517)] were conducted in rats at dose levels of 25, 50, 100, and 200 mg/kg and in dogs at 20, 40, 80, and 160 mg/kg. As the results of these studies do not indicate a direct toxic effect of sulfadimethoxine upon the tissues studied, the question of whether or not this new sulfonamide will produce hypersensitivity reactions awaits further evaluation in man. After oral administration to rats the tissue concentrations of sulfadimethoxine are, in decreasing order: blood, kidney, liver, muscle and brain. Repeated daily doses increase the concentration on the second or third day, but there is no further cumulative action. After single doses, the sulfonamide is present in tissues for at least 4 days. The half-life in blood is 48 hours. After a single dose, 59% was excreted in the urine in 48 hours. After multiple doses, 48–53% was excreted daily. A large proportion is excreted in the bound form in rats.

The Effects of Tranquilizers On Myocardial Metabolism

e Hoffmann-La Roche, Inc. f Wallace Laboratories, Half Acre Rd., Cranbury, New Jersey. In his discussions on the function of myocardial tissue, Bing1 has classified metabolic dysfunction in two major groups. In our experience we found that the myocardial effects of tranquilizers also are two-fold; that is, changes in myocardial function which are dependent on the modulant effect of drug-induced changes in the autonomic and central nervous systems, and changes in myocardial function which reflect the direct actions of the drug on the cardiac tissue

Toxicity studies of some derivatives of pantothenic acid.

Abstract Evidence of hepatotoxicity was not found in Sprague-Dawley rats given sodium pantothenate, d -panthenol, or d -pantethine intramuscularly in doses ranging from 0.2 g/kg to 2.0 g/kg. A slight increase in the amount of liver lipid deposition was observed in the rats weighing 110–120 g which were given 0.2 g/kg and 2.0 g/kg of d -panthenol, but not in rats weighing 220–275 g.

Studies on the toxicity and metabolism of β-apo-8′-carotenal in dogs

Abstract Dogs tolerated daily administration of 1000 mg and 100mg of β-apo-8′-carotenal for 14 weeks without the occurrence of toxic manifestations; general health, blood counts, liver and kidney function tests remained within normal limits. In terms of vitamin A activity, these doses are equivalent to 1,166,900 IU and 116,690 IU. Gross and microscopic findings were not unusual except for some deposition of yellow pigment in mesenteric and perirenal adipose tissue of dogs treated with 1000 mg of apocarotenal; on occasion, some pigment was also found in the renal cortex, adrenals, and liver of these animals. Plasma vitamin A levels were not elevated despite the prolonged treatment interval; levels of apocarotenal in plasma were significantly increased in dogs given 1000 mg of this carotenoid. Assays of the tissues showed the kidneys of treated animals to contain three- to fivefold higher amounts of vitamin A than controls; apocarotenal concentrations also tended to be elevated in dogs administered this carotenoid orally. Metabolites found in the urine of dogs repeatedly administered this carotenoid include, in addition to β-apo-8′-carotenal, free and esterified vitamin A and β-8′-apocarotenoic acid.

Toxicity and tissue distribution of the schistosomicide TWSb (RO 41544/6) in rats

Abstract Toxicity measurements of the schistosomicide TWSb indicate this trivalent antimonial to be well tolerated by rats given daily intramuscular injections of 100 mg/kg, 10 mg/kg, and 1 mg/kg for 15 weeks; these doses are equivalent to daily administration of 25 mg/kg, 2.5 mg/kg, and 0.25 mg/kg of antimony. The parameters measured include observation of general health, blood counts, and gross and microscopic examination of the tissues. Single intramuscular doses of 100 mg/kg or 1 mg/kg of TWSb produced high levels of antimony in serum and tissues after 1 hour, and significant amounts were still present after 144 hours. The peak concentrations of antimony in intestines occurred at a later time interval than observed in serum, liver, or kidneys, suggesting that the drug is excreted via the biliary route at a relatively slow rate.

Drug toxicity and its impact on drug evaluation in man

A necessary concomitant of the rapid expansion of therapeutics witnessed over the past decade has been the introduction of large numbers of new drugs into clinical trial. New expressions of drug toxicity have been the “biologic price” of this progress. In an attempt to meet this challenge, animal toxicologic procedures have been greatly expanded and the current methods are briefly outlined. It is clear, however, that, although these animal studies may eliminate frankly pOisonous material from human trial, “safety” in animals does not eliminate idiosyncrasy, allergy, and other more subtle reactions in humans. Thus, the adverse effects of new drugs must be actively sought as an integral part of clinical studies. A classification of drug toxicity organized to indicate the stages of clinical trials in which the specific types of reactions might be expected to appear is presented. On the other hand, tOXicity in animals is not conclusive evidence that a given drug will be toxic for man. Indeed, many important currently used medications are highly toxic in one or more species of animals. Thus, rigid interpretation of animal data could seriously hamper the progress which holds so much promise for the future.