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[Toxicological studies on a new cephamycin, MT-141. V. Its subacute toxicity in beagle dogs]
Abstract:
The 30-day subacute toxicity of MT-141 was studied in adult Beagle dogs with intravenous (i.v.) administrations of 100 to 1,200 mg/kg/day. The obtained results were as follows. MT-141 at the doses lower than 800 mg/kg/day i.v. had no toxicity in male and female Beagle dogs. An increase in water intake was closely related to that in urine excretion after i.v. treatments with 1,200 mg/kg/day of MT-141 in the males and females. MT-141 at the doses higher than 1,000 mg/kg/day i.v. of MT-141 caused slight local irritation at the site of injection in the males and females. In the females, the dose-dependent changes induced by treatments with the doses above 1,000 mg/kg/day i.v. of MT-141 were a significant decrease in the level of serum K and a significant increase in the activity of serum LAP. In the males, this compound produced significant dose-dependent changes in toxicological parameters such as a decrease in the activity of GOT at the doses higher than 1,000 mg/kg/day i.v., a descent in the levels of U-K, U-Cl and OP at the dose of 1,200 mg/kg/day i.v., an elevation in the level of serum alpha 1- and alpha 2-G, and an increase in the volume of excreted urine at the dose of 1,200 mg/kg/day i.v. It is concluded from the above-mentioned results that the maximal "no effective" dose of MT-141 is 800 mg/kg/day i.v. and the toxic dose of MT-141 is above 1,000 mg/kg/day i.v. in male and female Beagle dogs.
Insights
MT-141 demonstrated no toxicity in Beagle dogs below 800 mg/kg/day. Doses exceeding 1,000 mg/kg/day intravenously (i.v.) caused local irritation and dose-dependent toxicological changes in male and female dogs.
Area of Science:
- Pharmacology
- Toxicology
- Veterinary Medicine
Context:
- Subacute toxicity studies are crucial for assessing drug safety.
- Beagle dogs are a standard model for preclinical toxicity testing.
- Intravenous administration allows for direct systemic exposure assessment.
Purpose:
- To determine the 30-day subacute toxicity profile of MT-141 in adult Beagle dogs.
- To identify the maximal no-observed-adverse-effect level (NOAEL) and the lowest-observed-adverse-effect level (LOAEL) for MT-141.
- To evaluate dose-dependent toxicological effects following intravenous administration.
Summary:
- MT-141 showed no toxicity at doses below 800 mg/kg/day i.v.
- Doses above 1,000 mg/kg/day i.v. induced slight local irritation.
- Significant changes in serum electrolytes (K), enzyme activities (LAP, GOT), and urine parameters were observed at higher doses in a dose-dependent manner.
- The maximal non-effective dose was determined to be 800 mg/kg/day i.v., with toxicity observed above 1,000 mg/kg/day i.v.
Impact:
- Establishes a clear threshold for MT-141 toxicity in a relevant animal model.
- Provides critical data for risk assessment and safe dosage determination in potential therapeutic applications.
- Informs future research on the specific mechanisms underlying MT-141's observed toxicological effects.