Glen C. Todd

Toxicology of vindesine (desacetyl vinblastine amide) in mice, rats, and dogs

Comparative acute intravenous toxicity studies of vinblastine sulfate (VLB), vincristine sulfate (VCR), and vindesine in mice and rats indicated that vindesine was more toxic than VLB and less toxic than VCR. Rats were able to tolerate larger repeated doses of vindesine than dogs. Rats given intravenous doses totaling 0.15 mg/kg-wk vindesine for 3 months developed no remarkable signs of toxicity. Doses of 0.3 mg/kg-wk or greater produced anorexia, depressed blood cell counts, atrophic intestinal mucosa, inhibition of spermatogenesis, extramedullary hematopoiesis, and infections. Dogs were given total weekly intravenous doses of 0.04, 0.08, 0.1, or 0.16 mg/kg vindesine for 3 months. The only observed effect in the two lower dose groups was inhibition of spermatogenesis. Groups receiving 0.1 or 0.16 mg/kg developed leukopenia, slight erythropenia, inhibition of spermatogenesis, focal skeletal muscle degeneration, elevated lactic dehydrogenase, and an increase in bone marrow myeloid: erythroid ratio. No evidence of functional or structural changes in neural tissues was found. The above effects are common to animals given VCR at lower doses and for a shorter test period. It is therefore concluded that vindesine is less toxic in animals than VCR.

Comparative Cardiovascular Toxicity in Dogs Given Inotropic Agents by Continuous Intravenous Infusion

A comparative study of the toxicity of the inotropic amines isoproterenol hydrochloride (IP), 1-norepi-nephrine bitartrate (NE), dopamine hydrochloride (DP), and dobutamine hydrochloride (DB) was conducted in beagle dogs (2/sex/dose group). All drugs were administered at doses that produced maximal contractile tension in dog myocardium. Doses, continuously infused for 96 hr, were 0.625, 1.25, and 2.5 μg/kg/min IP, 2.5 and 5 μg/kg/min NE, and 25, 50, and 100 μg/kg/min DP and DB. Three of 4 dogs that received 5 μg/kg/min NE and one of 4 given 100 μg/kg/min DP died. Pronounced tachycardia (mean peak rate increases from baseline of 88-104 beats/min) was observed at all doses of IP. DB produced a transient moderate tachycardia (mean peak rate increases from baseline of 25-27 beats/min) at 25 and 50 μg/kg/min and pronounced tachycardia (mean peak rate increases from baseline of 74 beats/min) at 100 μg/kg/min. Moderate bradycardia occurred at both doses of NE and at 25 and 50 μg/kg/min DP (mean peak rate decreases from baseline of 42-46 and 22-38 beats/min, respectively). At high doses the 4 inotropes produced focal to multifocal myocardial necrosis located mainly in left ventricle and segmental medial necrosis of the coronary arteries, mainly in small intramural muscular branches. Segmental medial hemorrhage was also seen following administration of high doses of NE and DP. An additional intramural coronary arterial lesion produced by all of the inotropes consisted of a mild periadventitial cellular infiltrate and fibroplasia. The results indicated that NE and DP produced the most severe cardiovascular lesions, followed by IP which produced lesions of more moderate severity. DB produced only slight lesions in comparison to the other 3 inotropic amines.

An Immunocytochemical Study of Pituitary Adenomas and Focal Hyperplasia in Old Sprague-Dawley and Fischer 344 Rats

Spontaneous pituitary tumors occurring in groups of 100 Sprague-Dawley (SD) and 100 Fischer 344 (F344) rats of each sex on a 2-year aging study were characterized by immunocytochemistry. The SD strain had a total of 75 tumors with 10% in males and 65% in females. Tumors immunoreactive for prolactin (PRL) alone were the most common tumor (64%) with the immunonegative tumor being the second most common (17.3%). F344 rats had a total of 62 tumors with 26% in males and 36% in females. The majority of the tumors were reactive for prolactin alone (56.5%) and tumors reactive for both growth hormone (GH) and PRL were the second most common (21%). Most tumors were immunoreactive for only 1 hormone; however, both strains had tumors that expressed multiple hormones in unusual combinations.

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.

Ganglioneuroma of the adrenal medulla in rats. A report of 3 cases.

Three cases of ganglioneuroma of the adrenal medulla from Wistar-derived rata were described. These tumor were similar histologically, composed of large ganglion cells and nerve fibers. Associated with one of the ganglioneuromas was a well-differentiated pheochromocytoma.

Long-term toxicity study of mycophenolic acid in rabbits

Abstract Rabbits were chosen for a long-term toxicity study of mycophenolic acid (MPA) because the rate of formation of the MPA-glucuronide metabolite was rapid and similar to that for man and because they were able to tolerate larger daily doses than other laboratory species such as rats, dogs, and monkeys. Dutch Belted rabbits were given daily (5 days/week) oral doses of 0, 80, or 320 mg of MPA/kg for 1 yr. Survival of the animals was similar for each test group. There were no apparent signs of toxicity. The hematologic and blood chemistry values were unaffected with the exception of a dose-related decrease in lactic dehydrogenase (LDH). It was concluded that the rabbit was an appropriate animal model and tolerated large daily doses of MPA for 1 yr without important treatment-related changes.

Fibrosarcoma with Metastasis in a Rhesus Monkey

Malignant neoplasms that metastasize are uncommon in nonhuman primates. A naturally occurring fibrosarcoma of the forearm with metastasis to the axillary lymph nodes was found in an adult male Rhesus monkey. The primary neoplasm grew rapidly to a size of 8 x 10 x 18 cm. Diagnosis was based on characteristic morphologic findings by light and electron microscopy.

Target Organ Toxicity and Leukopenia in Fischer 344 Rats Given Intravenous Doses of Vinblastine and Desacetyl Vinblastine

The toxicity and leukopenia produced by vinblastine or desacetyl vinblastine were established in 1-month studies in rats. Groups of male Fischer 344 rats were given weekly intravenous doses of vinblastine or desacetyl vinblastine at doses of 0.08, 0.16, 0.32, 0.64, or 1.28 mg/kg. The target organ toxicity was similar for both compounds. Decreased cell production in the thymus, testes, and bone marrow was produced in the animals of the two highest dose groups for both compounds with the degree of severity greater in the highest dose group. All high dose rats (1.28 mg/kg) given desacetyl vinblastine and three rats given vinblastine died prior to study termination. Body weight loss was more pronounced in high dose rats given desacetyl vinblastine, but at lower doses there were no significant differences in body weight reduction for rats receiving either compound. Leukopenia occurred at all dose levels of 0.32 mg/kg and higher. During the first 2 weeks of the study, rats given 1.28 mg/kg of desacetyl vinblastine had a greater leukopenic response than rats given 1.28 mg/kg of vinblastine. It is concluded that both compounds produced similar target organ toxicity and leukopenia without deaths at doses of 0.32 and 0.64 mg/kg given once a week for 4 weeks. At the high dose (1.28 mg/kg) desacetyl vinblastine was more toxic than vinblastine resulting in greater mortality and body weight reduction.

Lymphocytic Thyroiditis, Rat

The gross appearance varies with the stage of the disease. The thyroid glands may not appear abnormal when only minimally involved. However, if there is considerable lymphocytic infiltration, the glands are symmetrically enlarged and the cut surfaces are pale. The thyroids may weigh up to ten times their normal weight. The capsule is intact and usually smooth, but can be lobulated.