The Cardiovascular Toxicity of Antimalarial Drugs

点击翻译按钮获取中文摘要

Malaria is an ancient mosquito-borne parasitic disease from which over a thousand - mostly children in sub-Saharan Africa - still die of needlessly every day. For half a millennium, quinine and quinine-like antimalarial drugs have been the mainstay of malaria treatment and prevention. In the 18th century, the chance observation of their ability to quell palpitations led to their becoming the first anti-arrhythmic agents. Some of these anti-arrhythmic antimalarials later came to define the adverse drug reaction of repolarisation-related cardiotoxicity as sudden deaths, ventricular tachyarrhythmias, and electrocardiographic QT interval prolongation were in turn causally associated with their use. With increasing population-level use of antimalarials for malaria elimination, there has been renewed global interest in defining the cardiovascular toxicity of key members of this drug class to guide antimalarial choice and dosage for development and deployment. I investigate the repolarisation-related cardiotoxicity of the quinoline and structurally-related oral antimalarials mostly widely used in malaria treatment, prevention, and drug development through systematic reviews and meta-analyses of global data.In particular, I assess the risk of:1) Sudden unexplained death after dihydroartemisinin-piperaquine, a leading candidate for mass drug administration and intermittent preventive therapy for malaria2) Torsade de pointes and other clinically significant arrhythmias after front-line antimalarials at standard malaria doses I also evaluate the effects on the QT interval, the most commonly used surrogate marker for repolarisation-related cardiotoxicity risk, of:3) Malaria disease, including severity and fever, which may account for differences in QT interval changes seen between healthy individuals and malaria patients4) Amodiaquine, the quinoline antimalarial recommended by the WHO for seasonal malaria chemoprevention of millions of young children aged 3-59 months in the Sahel subregion of Africa as well as the treatment of uncomplicated malaria