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Safety evaluations of a synthetic antimicrobial peptide administered intravenously in rats and dogs
Laura Cresti1,2, Chiara Falciani3, Giovanni Cappello3,2
1Azienda Ospedaliera Universitaria Senese, via M. Bracci, 53100, Siena, Italy.
Abstract:
The antimicrobial peptide SET-M33 is under study for the development of a new antibiotic against major Gram-negative pathogens. Here we report the toxicological evaluation of SET-M33 administered intravenously to rats and dogs. Dose range finding experiments determined the doses to use in toxicokinetic evaluation, clinical biochemistry analysis, necroscopy and in neurological and respiratory measurements. Clinical laboratory investigations in dogs and rats showed a dose-related increase in creatinine and urea levels, indicating that the kidneys are the target organ. This was also confirmed by necroscopy studies of animal tissues, where signs of degeneration and regeneration were found in kidney when SET-M33 was administered at the highest doses in the two animal species. Neurological toxicity measurements by the Irwin method and respiratory function evaluation in rats did not reveal any toxic effect even at the highest dose. Finally, repeated administration of SET-M33 by short infusion in dogs revealed a no-observed-adverse-effect-level of 0.5 mg/kg/day.
Insights
The antimicrobial peptide SET-M33 shows kidney toxicity in rats and dogs, but no neurological or respiratory effects. The no-observed-adverse-effect level in dogs was 0.5 mg/kg/day.
Area of Science:
- Pharmacology
- Toxicology
- Infectious Diseases
Background:
- Antimicrobial peptides are promising candidates for new antibiotics.
- SET-M33 is being developed to combat Gram-negative pathogens.
Purpose of the Study:
- To evaluate the toxicological profile of the antimicrobial peptide SET-M33.
- To determine the target organs and potential adverse effects of SET-M33 in preclinical models.
Main Methods:
- Intravenous administration of SET-M33 to rats and dogs.
- Dose range finding, toxicokinetic evaluation, clinical biochemistry, necroscopy, neurological, and respiratory assessments.
- Irwin method for neurological toxicity and respiratory function evaluation.
Main Results:
- Kidney toxicity, evidenced by increased creatinine and urea levels, was observed in rats and dogs.
- Histopathological examination revealed kidney degeneration and regeneration at high doses.
- No neurological or respiratory toxicity was detected in rats, even at the highest dose.
Conclusions:
- The kidneys are the primary target organ for SET-M33 toxicity.
- SET-M33 demonstrated a no-observed-adverse-effect level (NOAEL) of 0.5 mg/kg/day in dogs upon repeated administration.
- Further studies are needed to establish the safety profile for potential clinical use.
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