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PubMedDate not supplied

Toxicological evaluation of 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(methylaminocarbonyl)hydrazine (VNP40101M), a novel alkylating agent with potential antitumor activity, with intravenous administration in rats and dogs.

These studies investigated the toxicological effects of 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(methylaminocarbonyl) hydrazine, VNP40101M, a novel alkylating antitumor agent, in animals. Sprague-Dawley rats (2-10/sex/time point at each dose) and Beagle dogs (1-3/sex/time point at each dose) were treated with VNP40101M (0 [vehicle], 1, 3, 10, and 20 mg/kg in rats and 0, 0.3, 1, and 3 mg/kg in dogs), given intravenously (IV, bolus via the tail or slow push via the cephalic or saphenous vein, respectively) once daily for 5 consecutive days. Clinical signs, mortality, body weight, clinical pathology, gross necropsy, organ weights, and histopathology were evaluated for as long as 43 days in rats and 50 days in dogs. In rats, the toxic doses were found to be at 10 and 20 mg/kg, which induced mainly pulmonary toxicity and mortality. The pulmonary toxicity was reflected by an increase in lung weight; clear, pink or red fluid within the thoracic cavity observed at necropsy; and histopathological evidence of alveolar edema, vascular congestion, alveolar histiocytosis, and vascular thrombi. Although some of these effects were observed in rats treated with 3 mg/kg, the incidence was low (approximately 7%-30%) and may be reversible (based on the time-dependent reduction in the magnitude of lung weight increases). Therefore, the maximum tolerated dose (MTD, or the maximum dose that did not induce significant toxicity or induced reversible toxicity) was > or = 3 mg/kg. VNP40101M at 1 mg/kg did not induce any toxicity, other than low incidence of alveolar edema (2/30 rats), and increased incidences of capillary ectasis/congestion and alveolar histocytosis (2-6/30 rats vs. 1/30-36 in control rats). Therefore, the low effect level (LOEL) is considered to be 1 mg/kg in rats when given IV for 5 days. In dogs, LOEL, MTD, and toxic dose levels were comparable (based on a body weight/surface area conversion) to those in rats, except for some gastrointestinal (GI) effects (i.e., red lesion in the ileum) observed at 0.3 mg/kg (equivalent to 1 mg/kg, or similar to the LOEL in rats) and the associated effects (slight body weight loss and inappetence). For dogs treated with 1 mg/kg (equivalent to approximately 3 mg/kg, or MTD, in rats), VNP40101M induced the same GI effects seen in dogs treated with 0.3 mg/kg of VNP40101M. Additionally, a transient reduction in white blood cell counts was also observed. Three mg/kg (equivalent to approximately 10 mg/kg, or toxic dose level, in rats) was toxic to dogs, as reflected by the poor clinical condition of these dogs, which subsequently required euthanasia. In conclusion, VNP40101M, when given IV once daily for 5 consecutive days, has a LOEL of 1 mg/kg, a MTD of 3 mg/kg, and toxic doses at > or = 10 mg/kg in rats. The primary toxicity of VNP40101M was pulmonary toxicity and mortality. Based on an interspecies body weight/surface area conversion, VNP40101M had comparable LOEL (0.3 mg/kg), MTD (1 mg/kg), and toxic doses (> or = 3 mg/kg) in dogs, except that dogs appeared to be more sensitive to the GI effects of VNP40101M.

Animals↗
PubMed1989

Toxicological evaluations of the benzodiazepine doxefazepam.

1-(2-Hydroxyethyl)-3-hydroxyl-7-chloro-1,3-dihydro-5-(O-fluorophenyl)-2H - 1,4-benzodiazepin-2-one (doxefazepam, SAS 643, Doxans) was investigated in a series of toxicological studies. Oral LD50 values were greater than 2000 mg/kg in mice, rats and dogs, while endoperitoneal LD50 values were 746 and 544 mg/kg in the mice and rats, respectively, and greater than 1000 mg/kg in the dogs. Subacute and chronic studies in rats and dogs evidenced a transient ataxia after administration of the test compound, which was dose-dependent in the subacute experiment, and occurred only at the highest dose in the chronic studies. No pathological findings were registered at necropsy or in microscopic observations, except an increase of liver weight at the highest dosage in the chronic study in the rat. Doxefazepam did not exert any teratogenic effects in rats and rabbits. Moreover in rats it did not alter the reproductive performance. The mutagenic studies did not reveal any mutagenic potential. In the cancerogenicity study in rats doxefazepam did not show positive carcinogenic potential.

Animals↗
PubMed2005

Pharmacologic and toxicologic evaluation of C. novyi-NT spores.

Clostridium novyi-NT (C. novyi-NT) spores have been shown to be potent therapeutic agents in experimental tumors of mice and rabbits. In the present study, pharmacologic and toxicologic studies were performed to better understand the factors influencing the efficacy and toxicity of this form of therapy. We found that spores were rapidly cleared from the circulation by the reticuloendothelial system. Even after large doses were administered, no clinical toxicity was observed in healthy mice or rabbits. The spores were also not toxic in mice harboring poorly vascularized non-neoplastic lesions, including myocardial infarcts. In tumor-bearing mice, toxicity appeared related to tumor size and spore dose, as expected with any bacterial infection. However, there was no laboratory or histopathologic evidence of sepsis, and the toxicity could be effectively controlled by simple hydration.

Animals↗
PubMed1981

The toxicological evaluation of carminomycin - an antineoplastic anthracycline antibiotic.

Carminomycin, an anthracycline antibiotic discovered in the Soviet Union, possesses antitumor activity and is chemically related to adriamycin and daunorubicin. The toxic effects of carminomycin observed in single-dose toxicologic studies in mice iv (4.5-13.5 mg2) and po (18.9-52.2 mg/m2), rats iv (6.0-21.0 mg/m2), dogs iv (1.0-16.0 mg/m2) and po (16.0-80.0 mg/m2), Rhesus monkeys po (24.0-144.0 mg/m2); and in multiple-dose studies in dogs iv (18 doses 0..6-5.0 mg/m2, 2X/week) and rats sc (9 doses 3.0-12.0 mg/m2, 3X/week), were dose-related and primarily manifested as suppression of hematopoiesis. Other toxicities observed included nephrotoxicity, gastrointestinal toxicity, decreased spermatogenesis, decrease in size and activity of the prostate and seminal vesicles, and ovarian alterations. In general, these toxicities were reversible in surviving animals during recovery periods. Cardiotoxicity, similar to that seen with adriamycin sc (13 doses 12.0 mg/m2, 1X/week) was not observed with carminomycin sc (13 doses 6.0 mg/m2, 1X/week).

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