The renal oncogenic activity of streptozotocin in male Holtzman rats was significantly decreased by nicotinamide. Adenomas of the kidney were noted in 77% (21/28) of the animals treated with single iv dose of the streptozotocin, 50 mg/kg, while only 18% (5/28) of animals given nicotinamide ip, 350 mg/kg, 10 min before and 180 min after the same dose of streptozotocin had demonstrable renal tumors. Moreover, the renal adenomas induced by streptozotocin alone occurred sooner and were generally larger when compared with those in the animals treated with the nicotinamide-streptozotocin combination. The 50 mg/kg dose of streptozotocin was diabetogenic in all rats, but the diabetic state was not permanent. Spontaneous recovery from the diabetes was first noted after 8 and 10 months of followup, and after 16 months none of the surviving rats were diabetic.

Hypoglycemic rats bearing insulin-secreting islet-cell adenomas produced by the combined action of streptozotocin and nicotinamide were treated with streptozotocin. Antitumor response was demonstrated by elevation of blood glucose, reduction in plasma and tumor IRI, and histopathologic changes in the beta-cell neoplasm. The rodent tumor model may serve as a predictive system for selection and investigation of mechanisms of action of future antitumor agents to be used in the treatment of malignant insulinoma in man.

SummaryStreptozotocin produces a permanent diabetic state in monkeys and dogs which can be prevented by the use of oral or intravenous nicotinamide. A total dose that is diabetogenic in the monkey when administered by a single injection is ineffective in producing a diabetic state when administered over a 4–14 day period. This observation may have relevance in regard to the schedule employed in the treatment of malignant insulinoma in man.Rhesus monkeys observed in a persistent diabetic state for up to two years failed to demonstrate any of the known extra pancreatic complications of human diabetes mellitus. There was no evidence of renal tumor induction in these animals, as had previously been reported in rats.

1. Saramycetin, a polypeptide antifungal antibiotic has been found to retard the clearance of sulphobromophthalein (BSP) in man. An explanation for this observation was sought in several lower species.2. Doses of Saramycetin without effect on the other standard tests of hepatic function or on hepatic morphology profoundly altered the disposition of BSP and several other dyes in mice and dogs.3. Saramycetin strongly inhibited the hepatic enzyme which conjugates BSP to reduced glutathione, provoked a regurgitation of BSP from the liver into the bloodstream, and was anticholeretic in the dog.4. These diverse actions of Saramycetin may, in concert, explain the altered clearance of BSP. It is suggested that low doses of Saramycetin exert a pharmacological effect on certain hepatic excretory processes, whereas high doses are toxic.

Summary Pancreatic islet cell tumors (nesidioblastomas) were produced in 64% (18/28) of the male Holtzman rats treated with both streptozotocin and nicotinamide, while only one tumor was noted in 26 male Holtzman rats treated with streptozotocin alone, and none in rats treated with nicotinamide alone or with the streptozotocin vehicle. The majority of these neoplasms occurred in animals sacrificed 14-18 months after treatment. Hypoglycemia, intensely basophilic cytoplasmic granulation in the islet tumors, and the presence of immunoreactive insulin in tumor extracts indicate that the adenomas secreted insulin.

Phleomycin (NSC 61586) is nephrotoxic in beagles and rhesus monkeys after iv daily doses of 0.16 mg/kg and above. Nephrotoxicity is dose related and irreversible. In dogs it was delayed (up to 28 days) following 0.16 mg/kg/day × 28 and in monkeys after 0.31 or 0.16 mg/kg/day × 28. At 0.08 mg/kg/day × 28, it was not nephrotoxic to either species. Azotemia was the most sensitive index of toxicity. Urea, creatinine, and PSP clearances, UGOT or urinalysis were no more definitive. The LD50 in mice was, po 371 mg/kg, iv 20.6 mg/kg; rat, po 649 mg/kg, iv 3.9 mg/kg; and beagle iv <2.5 mg/kg. Deaths were both acute and delayed. Acute deaths were due to respiratory failure preceded by prostration and convulsions, and delayed deaths were associated with general debilitation and intestinal hemorrhage. In dogs convulsions, cholinergic symptoms, hepatotoxicity, bone marrow depression and gastrointestinal tract pathology followed single doses of 5–25 mg/kg, and repeated doses of 1.25 mg/kg/day × 4, 6, or 7. These doses were lethal to the dogs as was 0.31 × 18 and repeated doses of 1.25 and 0.62 mg/kg/day to the monkeys. In dogs 5 mg/kg iv caused a rapid fall in systolic blood pressure (BP) with a slow recovery period: 0.16, 0.31, or 0.62 mg/kg had no effect on the systolic BP. No hypotension was noted 24 hours after 1.25 mg/kg/day × 6 or 7, nor were any changes in the EKG 24 hours after 0.31 mg/kg/day × 12, or 1–10 min after 13 doses. Phleomycin is a local irritant when administered iv, im, or sc.

Summary l-Asparaginase-containing extracts from Escherichia coli have undergone toxicologic evaluation in mice, guinea pigs, rabbits, beagle dogs, and Rhesus monkeys. The preparation elicited acute anaphylaxis in sensitized guinea pigs and produced precipitating antibodies in one of six rabbits. In five of nine batches, temperature elevations of one degree Fahrenheit or more, associated with leukocytosis, were observed in the monkey. With continued treatment the monkey demonstrated varying degrees of weight loss, colitis, leukopenia, and abnormal liver function and histology, which could not be directly correlated with dose or specific activity of the enzyme preparation. The dog was resistant to all toxic effects other than a reversible anemia. Measurement of plasma enzyme concentration after dosing revealed that the monkey maintained significantly higher peak levels than the dog one hour after injection. Both the monkey and dog maintained high plasma activity for the eight hours after the first injection of a twice-daily schedule, and in the monkey the enzyme remained at detectable levels for at least 18 hours. The role that contaminating bacterial endotoxin may be contributing to the overall toxicity is discussed.

l -Menthol in Propylene glycol produces a fall in blood pressure of cats and rabbits when administered i.v. in dosages of 0.25 mg./Kg. and above. When mixtures of l -menthol in propylene glycol and nicotine are administered i. v. to cats and rabbits the vasoconstriction produced by nicotine is blocked completely when the ratio of menthol to nicotine is 40 to 80. The degree of vasoconstriction is decreased 10 to 60 per cent when the ratio of menthol to nicotine is 6 to 20.

Rats were exposed to menthol vapor of various concentrations for a period from seventy-one to seventy-nine days and a study was made of the over-all effects. It was found that there were no gross toxic effects, but a histopathological examination of organ tissues revealed that changes indicative of irritation had occurred in the lungs of animals exposed to the highest concentration of menthol.

1. DL-alpha, alpha-diphenyl, gamma-dimethylaminovaleramide, Centrine (previously referred to as BL-139), shows approximately one-half the activity of atropine and one-fifth the activity of papaverine on isolated guinea pig and rabbit ileum strips. 2. Centrine causes a decrease in tone and a reduction in activity of most portions of the gastro-intestinal tract. It effectively counteracts the spasmogenic responses to acetylcholine and arecoline. 3. Oral administration requires very little increase in dosage to obtain responses comparable to those following intramuscular or intravenous administration. 4. Centrine is more effective in decreasing the activity of the intact colon than either atropine or Banthine and also has a greater duration of action. 5. Centrine is slightly less active than atropine in blocking the vasodepressor responses to acetylcholine and arecoline. Atropine is at least four times more active in blocking the effects of vagal stimulation on the heart. 6. Centrine has less mydriatic and salivary effects than atropine. 7. Dogs tolerate prolonged daily oral feedings of 25 mgm./kgm. of Centrine. Higher doses produce drying of the mucous surfaces. Prolonged daily oral administration of doses up to 50 mgm./kgm. does not produce any gross or microscopic abnormalities.

THE PRESENT study was undertaken to determine the effects of menthol, nicotine, and the smoke of mentholated and nonmentholated cigarettes on excised mammalian respiratory epithelium from humans, rabbits, and rats. Previous studies on the effects of menthol on ciliated epithelium and on the respiratory tract have given equivocal findings. Proetz1reported that a 1% solution of menthol in liquid petrolatum had no effect on the ciliary activity of excised tissue immersed in it for 84 minutes. Similarly, Haggard and Greenberg2could find no toxic or irritant action of menthol in concentrations contained in the smoke of mentholated cigarettes on the respiratory tract of rats. Mendenhall and Shreeve,8however, reported that smoke solutions from cigarettes produced a depression in the ciliary rate of sections of calf's trachea and that smoke solutions from mentholated cigarettes caused a greater decrease in rate than did those from nonmentholated cigarettes. Further, Fox

1. The administration by stomach tube of equivalent amounts of three antihistamine drugs (Phenoxadrine, Benadryl, Pyribenzamine) does not cause a significant change in adrenal ascorbic acid concentration in the rat. 2. The intraperitoneal injection of histamine phosphate (10 mgm./kgm. of body weight) lowers the adrenal ascorbic acid concentration from 400 mgm./100 gm. of tissue to 277 mgm./100 gm. of tissue. 3. Histamine injection one hour after pretreatment with Phenoxadrine or Pyribenzamine results in a smaller fall in adrenal ascorbic acid than that in control animals. Pretreatment with Benadryl, however, does not prevent or modify the adrenal ascorbic acid response to histamine. 4. Under the conditions of these experiments Benadryl administration was followed consistently by a small but significant hyperglycemia while Phenoxadrine and Pyribenzamine did not elicit this response. 5. Pretreatment with an antihistamine drug did not prevent or modify the adrenal ascorbic acid response to the stress of intraperitoneal carbon tetrachloride administration. 6. A description is given of the hypotensive effect of intraperitoneally administered histamine and the modification of this effect by antihistamine drugs in the rat.

Biological safety tests are proposed for parenteral water-soluble drugs and for drugs in oil suspensions. The test dosages are base on the intravenous or intramuscular administration of the drugs in doses which approach or surpass symptomatic doses in the species of animal used. The tests thus aid in detecting serious departure from proper compounding procedures and are suggested as routine control measures in the manufacture of the enumerated drugs.