Assessing the safety of low dose primaquine in Plasmodium falciparum infected African children with glucose 6 phosphate dehydrogenase deficiency.

疟疾仍然是热带国家，特别是非洲的一个主要问题。经过杀虫剂处理的蚊帐和新型强效抗疟药物已导致疟疾死亡人数减少。然而，疟疾控制在许多地区仍然很差，如果我们要在世界上消除并最终根除这一疾病，我们将需要使用我们掌握的所有工具，一个目前未充分使用的潜在的非常有价值的工具是抗疟药物伯氨喹，它具有独特的能力杀死成熟的雄性和雌性疟疾寄生虫。研究表明，伯氨喹大大减少了蚊子体内的疟疾后代，从而有效地减少了疾病的传播。因此，伯氨喹似乎是一种很好的“传播阻断剂”，如果广泛用于患者，可能会减少疟疾传播，并有助于在社区消除疟疾。它可以破坏红细胞，并导致贫血的个人谁携带一个非常常见的遗传异常缺乏酶称为葡萄糖-6-磷酸脱氢酶，G6 PD的简称。这种缺陷在男性中更为常见，因为它是遗传的。这就是所谓的溶血。这是伯氨喹的一个真实的缺点，尽管这个问题主要出现在连续多日高剂量服用伯氨喹时。然而，对于其对疟疾寄生虫的“传播阻断”作用，认为仅需要单次低剂量的伯氨喹。大多数专家认为这是伯氨喹太少，不会引起溶血的主要问题。尽管如此，许多疟疾控制方案不愿意使用伯氨喹，因为他们认为它太危险了。您可以测试G6 PD缺乏症，但这需要测试试剂盒和工作人员来管理它们。许多国家无法负担在给予伯氨喹之前对数百万疟疾患者进行检测的费用。2012年，世界卫生组织（世卫组织）根据现有证据和专家意见得出结论，即使在G6 PD缺乏症的疟疾患者中，单次低剂量伯氨喹也是安全的。然而，世界卫生组织也呼吁进行更多的研究。四年后，几乎没有人使用低剂量的伯氨喹，因为这项研究还没有完成。如果我们能毫无疑问地证明低剂量伯氨喹对患有G6 PD缺陷的疟疾儿童是安全的，疟疾项目会更高兴地给予它，然后我们可以去制药公司，要求他们生产适合儿童的伯氨喹。为了看看单次低剂量伯氨喹是否像专家认为的那样安全，我们计划研究超过1，在乌干达的两家医院和刚果的一家医院接受门诊治疗的500名疟疾儿童。使用G6 PD缺乏症的简单测试，我们将发现750名患有G6 PD缺乏症的疟疾儿童，以及750名G6 PD水平正常的儿童。在这两组中，我们将随机给予一半患者常规抗疟治疗，另一半患者常规抗疟治疗加单次低剂量伯氨喹。然后，我们将非常仔细地观察儿童，看看是否给予伯氨喹比不给予伯氨喹引起更多的贫血，以及这种情况是否特别发生在G6 PD缺乏组中。我们需要将没有接受伯氨喹治疗的儿童和一些没有G6 PD缺乏症的儿童进行比较，因为疟疾本身会引起溶血，在某些情况下，即使没有伯氨喹治疗，G6 PD缺乏症也会引起溶血。和伯氨喹的给药，以真正确定是否在所有情况下给予低剂量伯氨喹是安全的。如果这项研究表明，给予单次低剂量伯氨喹是安全的，这将使世卫组织和各国政府能够推荐安全的治疗方案，既治愈病人，又防止疟疾传播给其他儿童。

Malaria remains a major problem in tropical countries, especially in Africa. Insecticide treated bednets and new powerful antimalarial drugs have led to a reduction in the number of malaria deaths. However malaria control remains poor in many areas, and if we are to eliminate and eventually eradicate the disease from the world we will require the use of all the tools at our disposal.One potentially very valuable tool, currently underused, is the antimalarial drug primaquine, which is uniquely able to kill the mature male and female sexual forms of the malaria parasite. Research has shown that primaquine greatly reduces the malaria offspring in the mosquito and thus effectively reduces transmission of the disease. So, primaquine looks to be a good 'transmission blocker' and, if used widely in patients, may reduce malaria transmission and contribute to the elimination of malaria in a community.Unfortunately primaquine has one major disadvantage. It can damage the red blood cells and cause anaemia in individuals who carry a very common genetic abnormality deficiency of an enzyme called glucose-6-phosphate dehydrogenase, G6PD for short. This deficiency is much more common in men because of the way it is inherited. This is called haemolysis. This is a real downside of primaquine, though this problem has mainly been seen when primaquine is given in high doses for many days. However, for its 'transmission blocking' effects on the malaria parasite only a single, low dose of primaquine is thought to be required. This is considered by most experts to be too little primaquine to cause a major problem with haemolysis. Despite this many malaria control programmes are unwilling to use primaquine because they consider it too dangerous. You can test for G6PD deficiency but this requires test kits and staff to administer them. Many countries cannot afford to test millions of malaria patients before giving primaquine. In 2012 the World Health Organization (WHO) concluded on the basis of the available evidence and expert opinion that single low dose primaquine was safe to use even in malaria patients with G6PD deficiency. However the WHO also called for more research.Four years later virtually no one is using low dose primaquine because that research has not been done. If we can show beyond doubt that low dose primaquine is safe in G6PD deficient children with malaria, malaria programmes would feel much happier giving it and we could then go to the drug companies and ask them to make primaquine that is suitable for children.To see if single low dose primaquine is as safe as experts think we plan to study over 1,500 children with malaria attending outpatients in two hospitals in Uganda and one in the Democratic Republic of the Congo. Using a simple test for G6PD deficiency we will find 750 children with malaria who have G6PD deficiency, and 750 who have normal G6PD levels. Within these two groups we will, on a random basis, give half of the patients normal antimalarial treatment and the other half normal antimalarial treatment PLUS single low dose primaquine. We will then watch the children very carefully to see whether giving primaquine causes more anaemia than not giving primaquine, and whether this occurs particularly in the G6PD deficient group. We need to have comparison groups of children who do not receive primaquine and some children who do not have G6PD deficiency as malaria itself causes haemolysis, as can G6PD deficiency in some circumstances even without primaquine treat. Our aim is to unpick the effects of G6PD deficiency, malaria, and primaquine administration to really be sure whether in all circumstances giving low dose primaquine is safe.If this research shows that giving single low dose primaquine is safe, this will enable WHO and national governments to recommend safe treatment regimens that will both cure the patient and also prevent transmission of malaria to other children.