Paul N. Harris

Short-term toxicity of propoxyphene salts in rats and dogs

Abstract Two salts of d -propoxyphene, the hydrochloride and the 2-naphthalene sulfonate (napsylate), were compared in short-term toxicity studies. In rats and dogs the effects produced by daily administration of equimolar doses of these salts were indistinguishable. Large daily doses of propoxyphene, representing between 40 and 110 times the maximum human clinical dose, resulted in liver enlargement, slight fatty change in the liver, and reduced growth rate in rats. Signs of developing toxicity in dogs were observed during 90 days of treatment with oral doses of 30–40 mg/kg of propoxyphene HCl or equivalent doses of propoxyphene napsylate. The following effects were dose-related in incidence or degree: loss of body weight, increased serum alkaline phosphatase values, increased liver weight, and slight fatty change in the liver. Lower doses were tolerated by dogs without significant toxicity.

THE TOXICITY OF CAPREOMYCIN IN LABORATORY ANIMALS

The chemical and biological properties of capreomycin have been described by Herr”’ and Stark et a l s Because of its antibiotic activity against Mycobacterium tuberculosis and because this compound was a polypeptide, differing in structure from other currently used antituberculous agents, it was of clinical interest. Studies were undertaken to determine its toxic effects in laboratory animals. Capreomycin was administered as the disulfate salt unless otherwise indicated. Dose values reported were expressed in terms of milligrams of antibiotic activity. The average lot of antibiotic assayed 620 mg. of activity per gram.

Toxicity of 3,3-Methylenebis (4-hydroxycoumarin)

Summary (1) The median lethal doses of Dicumarol have been determined intravenously or by mouth in mice, rats, and guinea pigs. (2) Death uniformly occurs in rabbits with intravenous injection of daily doses of 1-2 mg per kg; in dogs with oral administration of daily doses of 5-50 mg per kg; and in mice and rats with the feeding of 0.01-1% Dicumarol in food. The majority of rabbits can tolerate daily doses of 0.1-0.5 mg per kg by vein for 6 weeks, and a few mice and rats can survive 30 days on a diet containing 0.005% Dicumarol. (3) Most animals dying from Dicumarol develop hemorrhage into various tissues and organs, and pulmonary edema. Central necrosis of the liver has been observed in about one-half of the rats examined, and occasionally in rabbits, mice, and dogs.

Toxicological studies on tylosin: its safety as a food additive.

Abstract Tylosin has been shown to be relatively non-toxic following oral administration of large single doses to mice, rats and dogs. Intravenous injection of solutions of various salts showed the acute lethal dose in mice and rats to be 580–695 mg/kg. The toxicity in guinea-pigs was of the same order as erythromycin and penicillin. Diets containing tylosin base up to 1% were well tolerated by rats for 2 yr. Growth was normal and no visceral or haematopoietic damage was produced. Reproduction and lactation studies through three generations showed no alterations in growth or viability at a concentration of 1% in the diet. In an attempt to produce toxic effects, diets containing levels of 2 and 5% tylosin were well tolerated for 2 yr. Lack of palatability of higher concentrations caused retardation of growth and death from malnutrition. Studies designed to demonstrate the possible toxicity of transformation products of tylosin formed during food processing revealed no effect on growth nor any visceral damage. 2-Yr studies in dogs showed that doses up to 100 mg/kg/day, equivalent to 4000 ppm of the diet, produced no visceral or haematopoietic damage. Two dogs had slight sulphobromophthalein retention that returned to normal within 2 wk after withdrawal of treatment. No alteration in the faecal flora was found. Higher daily doses of 200 mg/kg were well tolerated for 2 yr with one of four dogs showing mild pyelonephritis. Of the four dogs that received 400 mg/kg/day for over 2 yr, one revealed bilateral nephrosis, mild chronic pyelonephritis and mild chronic cystitis. Serum levels of tylosin in dogs were detectable at a dietary level of 10 mg/kg/day and were quite high after larger doses. There was no evidence of accumulation in the serum after 2 yr. The no-effect level in rats was 10,000 ppm or higher and in dogs, 4000 ppm. These studies have demonstrated the safety of tylosin and should justify a tolerance for the use of tylosin as a direct food additive.

Toxicological Studies on Carbutamide

In 1942, Janbon first observed the hypoglycemic action of certain sulfonamides when he was investigating the antibacterial action of sulfanilamido-isopropylthiadiazoles. Loubatieres showed that the compound was inactive in depancreatized dogs and postulated that it brought about hypoglycemia in normal animals by stimulating insulin secretion. In 1955, Achelis and Hardebeck and others 5 reported on the hypoglycemic action of /r-aminophenylsulfonyl butyl carbamide, carbutamide or BZ-55, in normal rabbits, in normal man and in some diabetic patients. Inasmuch as carbutamide has continued to lower the blood sugar of certain diabetics, long-term toxicity studies have been pursued.

Oncogenicity of 1-(4-chlorophenyl)-1-phenyl-2-propynyl carbamate for rats

Abstract 1-(4-Chlorophenyl)-1-phenyl-2-propynyl carbamate was given throughout life to groups of 10 male and 10 female Harlan rats by incorporation in the food at levels of 0, 0.025, 0.05 and 0.1%. One female and 3 males had intracranial tumors after 218, 260, 294 and 540 days. There was a high incidence of other tumor types. These occurred earlier in females than in males, and many rats had multiple tumors, of the same and of different organs. Mammary adenocarcinoma was the most common tumor in females, whereas in males adenocarcinoma of the duodenum and upper jejunum predominated. The development of tumors in 56 of the 60 treated rats reveals the compound to be a potent oncogen.

Effect of Cyanide Poisoning on the Central Nervous System of Rats and Dogs.

Summary 1. Prolonged cyanide poisoning in rats may cause cerebral changes in 10% of the animals. 2. Daily injection of potassium thiocyanate similarly results in brain injury in 10% of rats. 3. In the rat continuous administration of sodium nitrite does not produce lesions in the central nervous system. 4. In dogs cyanide poisoning with or without the nitrite-thiosulfate therapy does not induce abnormal behavior. When they die from the poisoning, their brains usually show a normal appearance.

Are Foamy Cells in Atheromata of Reticulo-endothelial Origin?

Summary Atherosclerosis was induced in rabbits by administration of cholesterol while the reticulo-endothelial cells were being laden with carbon. Carbon-laden phagocytes were not found in the atheromata. I am indebted to Messrs. John Owen and Henry West for technical assistance.

Liver Injury Following Administration of α-and β-Longilobine.

Summary Four closely related alkaloids-longilobine, retrorsine, α- and β-longilobine -have been compared in mice by intravenous injection. There is no significant difference in their toxicity as measured by the median lethal doses. All 4 substances produce liver damage with central necrosis as the predominating lesion.