Evaluation of the cardiotoxicity of the fungicide Fluconazole

• Grant number: 23/14219-6
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: May 01, 2024
• End date: April 30, 2028
• Field of knowledge: Biological Sciences - Pharmacology - Toxicology
• Principal Investigator: Danilo Roman Campos
• Grantee: Fabiana da Silva Alcântara
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 21/05584-7 - Assessment of acute and chronic toxicity of the heart and brain exposed to pesticides found in potable water in Brazil, AP.JP2

Abstract

Invasive or disseminated fungal infections represent a global health problem, affecting millions of patients worldwide. Currently, there are several drugs available to treat these infections, with Fluconazole being one of the most commonly used in clinical practice. It is known for its ability to inhibit ergosterol biosynthesis, leading to the death of fungi or inhibiting their growth. However, the use of Fluconazole is not without adverse effects, such as nausea, vomiting, diarrhea, hepatotoxicity, and cardiovascular alterations. Among these alterations, the prolongation of the QT interval is particularly concerning and may or may not be associated with torsade de pointes. The attributed mechanism is the inhibition of the rectifying potassium channel current. However, there is evidence of Fluconazole's interaction with other ion channels. Still, the detailed mechanism of Fluconazole cardiotoxicity is unknown. Understanding Fluconazole's cardiotoxicity could enable proposing concurrent therapy to mitigate its cardiac side effects. In this context, the project aims to investigate the cardiotoxic effects of Fluconazole. To achieve this goal, a 28-day in vivo model of Fluconazole exposure will be used, employing clinically relevant dosages. Possible alterations in heart electrical activity will be assessed through in vivo and ex vivo electrocardiograms, patch-clamp technique, as well as changes in cardiac injury markers, morphometric and histological parameters, oxidative state, susceptibility to arrhythmias under stressors, and cellular contractility. Ultimately, it will be determined whether the fungicide induces cardiac alterations and the associated mechanisms.