The Cardiovascular Toxicity of Antimalarial Drugs

疟疾是一种古老的蚊子传播的寄生虫病，每天仍有1000多人死于疟疾，其中大多数是撒哈拉以南非洲的儿童。500年来，奎宁和类似奎宁的抗疟药物一直是疟疾治疗和预防的主要药物。在18世纪，人们偶然发现了它们有镇静心悸的能力，从而使它们成为第一种抗心律失常药物。其中一些抗疟疾药物后来被定义为复极相关心脏毒性的药物不良反应，因为猝死、室性快速性心律失常和心电图QT间期延长反过来与其使用有因果关系。随着越来越多的人口使用抗疟药物消灭疟疾，全球重新关注确定这类药物的主要成员的心血管毒性，以指导抗疟药物的选择和剂量的开发和部署。我通过对全球数据的系统综述和荟萃分析，研究了喹啉和结构相关口服抗疟药的复极相关心脏毒性，这些药物大多广泛用于疟疾治疗、预防和药物开发。特别是，我评估了以下风险：1）使用双氢青蒿素-哌喹后不明原因的猝死，大规模药物管理和疟疾间歇性预防治疗的主要候选者2）尖端扭转型室性心动过速和其他临床显著的心律失常，标准疟疾剂量的一线抗疟药我还评估了以下药物对QT间期的影响，QT间期是复极相关心脏毒性风险的最常用替代标志物：3）疟疾疾病，包括严重程度和发热，这可能是健康个体和疟疾患者之间QT间期变化差异的原因4）阿莫地喹，世卫组织推荐的喹啉抗疟药，用于非洲萨赫勒次区域数百万3-59个月幼儿的季节性疟疾化学预防以及无并发症疟疾的治疗

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