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Toxicological studies on bestatin. I. Acute toxicity test in mice, rats and dogs
Abstract:
Studies on acute toxicities of bestatin (NK421) were carried out in both sexes of mice and rats, and male dogs. NK421 was administered subcutaneously, intraperitoneally and orally in mice and rats, and orally in dogs respectively. Mice and rats were observed for 14 days after treatment and LD50 values were calculated by the probit method. NK421 showed very low toxicity and no death occurred in any species following the oral administration of the maximum dose capable of dosing such as 4 g/kg for mice, 2 g/kg for rats and 1.2 g/kg for dog. General toxic signs seen in mice and rats following subcutaneous and intraperitonial injections were as follows; depression, suppressed movement, piloerection, inhibition of spontaneous movement, anorexia and emaciation. Death occurred within 5 days after administration. The toxic target organs of NK421 were found to be kidney, lymphoid tissue and liver based on histopathological examination of dead animals.
Insights
Bestatin (NK421) demonstrated very low acute toxicity via oral administration in mice, rats, and dogs. However, subcutaneous and intraperitoneal injections revealed target organ toxicity in kidneys, lymphoid tissues, and liver.
Area of Science:
- Pharmacology
- Toxicology
Background:
- Bestatin is an aminopeptidase inhibitor with potential therapeutic applications.
- Understanding the acute toxicity profile of bestatin (NK421) is crucial for its safe development.
Purpose of the Study:
- To evaluate the acute toxicity of bestatin (NK421) in preclinical models.
- To determine lethal dose 50 (LD50) values and identify potential target organs.
Main Methods:
- Acute toxicity studies were conducted in male and female mice and rats, and male dogs.
- NK421 was administered via oral, subcutaneous, and intraperitoneal routes.
- Animals were observed for 14 days post-administration, with LD50 calculated using the probit method. Histopathological examinations were performed on dead animals.
Main Results:
- Oral administration showed very low toxicity, with no deaths at maximum doses (4 g/kg in mice, 2 g/kg in rats, 1.2 g/kg in dogs).
- Subcutaneous and intraperitoneal injections in rodents resulted in toxic signs including depression, suppressed movement, anorexia, and emaciation, with deaths occurring within 5 days.
- Histopathology identified kidney, lymphoid tissue, and liver as primary target organs for toxicity.
Conclusions:
- Bestatin (NK421) exhibits a favorable safety profile when administered orally.
- Non-oral routes of administration present potential toxicity concerns, targeting the kidney, lymphoid tissue, and liver.