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Caspofungin Effects on Electrocardiogram of Mice: An Evaluation of Cardiac Safety

Abstract

Caspofungin is an echinocandin, exhibiting efficacy against most Candida species invasive infection. Its cardiotoxicity was reported in isolated rat heart and ventricular myocytes, but in vivo and clinical studies are insufficient. Our objective was to evaluate caspofungin in vivo cardiac effects using an efficacious dose against Candida albicans. Female Swiss mice were infected with C. albicans, and treated with caspofungin, 5 or 10 mg/kg, intraperitoneal along 5 days. Survival rate and colony-forming units (CFU) into vital organs were determined. For cardiac effects study, mice were treated with caspofungin 10 mg/kg, and electrocardiogram (ECG) signal was obtained on C. albicans-infected mice, single dose-treated, and uninfected mice treated along 5 days, both groups to measure ECG intervals. Besides, ECG was also obtained by telemetry on uninfected mice to evaluate heart rate variability (HRV) parameters. The MIC for caspofungin on the wild-type C. albicans SC5314 strain was 0.3 μg/ml, indicating the susceptible. Survival rate increased significantly in infected mice treated with caspofungin compared to mice treated with vehicle. None of the survived infected mice presented positive CFU after treatment with 10 mg/kg. C. albicans infection induced prolongation of QRS, QT, and QTc intervals; caspofungin did not alter this effect. Caspofungin induced increase of PR and an additional increase of QRS after 24 h of a single dose in infected mice. No significant alterations occurred in ECG intervals and HRV parameters of uninfected mice, after caspofungin treatment. Caspofungin showed in vivo cardiac relative safety maintaining its antifungal efficacy against C. albicans.

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Acknowledgements

We would like to thank Maria Elisabete S. Barros, Rejane M. Souza, Jéssica E. S. Silva, and Mariella A. D. Soares for suggestions and collaboration on experiments, School of Pharmacy, UFOP.

Funding

This work was supported by Fundação de Amparo a Pesquisa de Minas Gerais—FAPEMIG, Minas Gerais, Brazil (NANOBIOMG-Network #0007-14; CDS-PPM-00481-13; APQ02346-11); Pharmaceutical Science Program (CiPharma), UFOP.

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De Paula, D.C.C., Leite, E.A., Araujo, C.M. et al. Caspofungin Effects on Electrocardiogram of Mice: An Evaluation of Cardiac Safety. Cardiovasc Toxicol 21, 93–105 (2021). https://doi.org/10.1007/s12012-020-09599-x

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Keywords

  • Caspofungin
  • Candida albicans
  • Electrocardiogram
  • QT interval
  • Telemetry
  • Heart rate variability