Dr Abdala obtained a first-class honours BSc in Biomedical Sciences, a PhD in Pharmacology and Physiology at the Federal University of Sao Paulo, Brazil, and a Diploma in Advanced Pharmacology from the British Pharmacological Society. Currently, she is a Senior Lecturer in Pharmacology at the University of Bristol, and scientific advisor to Rett UK. Dr Abdala is a systems neuroscientist, and her research focuses on autonomic dysfunction, in particular central apnoeas (with a focus on rare diseases), obstructive sleep apnoea, respiratory depression induced by drugs, treatment-resistant hypertension, and heart failure. Dr Abdala also works closely with mathematicians providing experimental input for the development of computational models of the mammalian respiratory central pattern generator. She has successfully applied the insight offered by the models to identify mechanisms of central apnoeas in Rett syndrome and potential treatment targets. This led to several target validation projects for treatment of respiratory dysfunction in Rett syndrome.
Ana Introduces Herself
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Potent hERG channel inhibition by sarizotan, an investigative treatment for Rett Syndrome
Hongwei Chenga,Chunyun Dua,Yihong Zhanga, Andrew F. Jamesa, Christopher E. Dempseyb, Ana P. Abdalaa, Jules C. Hancoxa
Some people with Rett syndrome have an abnormality in their heart rhythm, called QT prolongation. The QT interval corresponds approximately to the time interval from the start of contraction of the heart ventricles to their full relaxation. A prolonged QT interval can be caused by genetic mutations or by certain medications. Prolonged QT interval has been associated with increased risk of sudden cardiac death. Therefore, it is important that drugs used to treat symptoms of Rett syndrome do not worsen existing heart rhythm abnormalities. In this study, we evaluated Sarizotan’s ability to block an ion channel called hERG, as nearly all drugs that prolong the QT interval do so via this mechanism. At the time, Sarizotan was being tested for treatment of breathing abnormalities in Rett syndrome, in a double-blind, placebo controlled clinical trial. In our study, we used in vitro heart cells and computational methods to investigate Sarizotan’s ability to bind to and block hERG channels. We found that Sarizotan was more potent at blocking hERG channels than quinidine, another drug that is well known for causing QT prolongation in humans. Further, we estimated that peak blood concentrations reached after a therapeutic dose of Sarizotan could feasibly be high enough to block hERG channels in the heart. We concluded that Sarizotan would be contraindicated for people with Rett syndrome who already had a long QT interval. While Sarizotan could be safe for those who did not have prologued QT intervals, those who were borderline could be at risk. This study highlighted the importance of understanding cardiac drug safety in the context of Rett syndrome, as safety margins determined in the general neurotypical population may not be applicable. Many drugs that have acceptable safety margins in the general population are hERG blockers. In the absence of alternatives, these drugs can be prescribed to people with Rett syndrome but under close monitoring of the heart rhythm and blood electrolytes. Combinations of drugs with potential to block hERG channels should be avoided, and other risk factors for long QT should be considered (like low blood oxygen levels).