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[Toxicological studies on a new cephamycin, MT-141. VI. Its chronic toxicity in beagle dogs]
Abstract:
MT-141 was dosed to male and female Beagle dogs through intravenous (i.v.) route at 100, 200, 400 and 800 mg/kg/day for 182 days. The toxic effects of MT-141 were as follows. The male and female Beagle dogs exhibited no particular behavior and symptom except vomiting and soft stool after treatments with 800 mg/kg/day i.v. of MT-141. MT-141 even at the high doses of 400 to 800 mg/kg/day i.v. did not significantly change toxicological parameters such as consumption of food and water, volume of excreted urine, electrocardiogram, eyeground and analysis of blood, serum and urine. Only one of 4 male Beagle dogs died of severe intestinal invagination, which is not related to the drug effect, at 120th day after the start of treatments with the highest dose of 800 mg/kg/day i.v. of MT-141. The fatality of Beagle dogs for 800 mg/kg/day of MT-141 was 25% (1/4) in males and 0% (0/4) in females. MT-141 caused the hemorrhage accompanied with fibrosis and round cells at the site of injections but the change induced by MT-141 was not so much different from that by saline. MT-141 at the highest dose induced histopathological changes in only 2 females, such as atrophy and degeneration of cardiac muscle, necrosis and fibrosis of hepatic cells and hyperplasia of spleen and bone marrow cells. Electron-microscopic examinations revealed no ultrastructural change related to the toxicity of MT-141 in the livers and kidneys. It is considered from the above-mentioned results that the maximal "no effective" dose is 400 mg/kg/day i.v. in male and female Beagle dogs.
Insights
MT-141, administered intravenously to dogs, showed minimal toxicity. The maximal no-observed-adverse-effect level (NOAEL) was determined to be 400 mg/kg/day, with only mild gastrointestinal signs at higher doses.
Area of Science:
- Pharmacology
- Toxicology
- Veterinary Medicine
Context:
- Subchronic toxicity studies are crucial for assessing drug safety.
- Beagle dogs are a standard model for preclinical drug evaluation.
- Intravenous administration bypasses first-pass metabolism, providing direct systemic exposure.
Purpose:
- To evaluate the toxicological profile of MT-141 following repeated intravenous administration in Beagle dogs.
- To determine the maximal no-observed-adverse-effect level (NOAEL) of MT-141.
- To identify potential target organs and dose-dependent adverse effects.
Summary:
- Male and female Beagle dogs received MT-141 intravenously at doses of 100, 200, 400, and 800 mg/kg/day for 182 days.
- Adverse effects were limited to vomiting and soft stools at 800 mg/kg/day. One male fatality occurred due to intestinal invagination, unrelated to MT-141.
- No significant changes in clinical parameters, hematology, or urinalysis were observed. Mild injection site hemorrhage and, in two females at the highest dose, minor cardiac, hepatic, spleen, and bone marrow changes were noted. Electron microscopy showed no ultrastructural changes.
Impact:
- Establishes a NOAEL of 400 mg/kg/day for MT-141 in this species and model.
- Provides essential safety data for the further development of MT-141.
- Highlights the generally good tolerability of MT-141 via the intravenous route.