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

评估低剂量伯氨喹对感染恶性疟原虫且患有葡萄糖 6 磷酸脱氢酶缺乏症的非洲儿童的安全性。

• 批准号: MR/P006973/1
• 负责人: Nicholas Day
• 金额: $ 251.63万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP006973%2F1
• 关键词: Assessing; safety; low; dose; primaquine

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.

疟疾仍然是热带国家的一个主要问题，特别是在非洲。经杀虫剂处理的蚊帐和新的强力抗疟疾药物减少了疟疾死亡人数。然而，疟疾在许多地区的控制仍然很差，如果我们要从世界上消灭并最终根除这种疾病，我们将需要使用我们可以使用的所有工具。一个潜在的非常有价值的工具，目前没有得到充分利用，就是抗疟疾药物伯氨喹，它是唯一能够杀死成熟的男性和女性疟疾寄生虫的药物。研究表明，伯喹极大地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，伯氨喹看起来是一种很好的“传播阻滞剂”，如果在患者中广泛使用，可能会减少疟疾的传播，并有助于在社区消除疟疾。不幸的是，伯氨喹有一个主要缺点。它会损害红细胞，并导致携带一种名为葡萄糖-6-磷酸脱氢酶(简称G6PD)的酶的非常常见的遗传异常缺陷的个人贫血。这一缺陷在男性中更为常见，因为它是遗传的。这叫做溶血。这是伯喹的一个真正的缺点，尽管这个问题主要出现在伯喹大剂量服用很多天的时候。然而，对于它对疟疾寄生虫的“传播阻断”作用，人们认为只需要一剂低剂量的伯喹。大多数专家认为，伯喹含量太低，不会造成严重的溶血问题。尽管如此，许多疟疾控制方案不愿使用伯喹，因为他们认为它太危险了。你可以检测G6PD缺乏症，但这需要检测试剂盒和工作人员来管理。许多国家负担不起在给予伯氨喹之前对数百万疟疾患者进行测试。2012年，世界卫生组织(WHO)根据现有证据和专家意见得出结论，即使在G6PD缺乏的疟疾患者中，单用小剂量伯喹也是安全的。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喹，因为这项研究还没有完成。如果我们能够毫无疑问地证明低剂量伯喹对患有G6PD缺陷的疟疾儿童是安全的，疟疾项目会更乐意给予它，然后我们可以去找制药公司，要求他们制造适合儿童的伯喹。为了了解单一的低剂量伯喹是否像专家认为的那样安全，我们计划对乌干达和刚果民主共和国的两家医院和一家医院的1500多名疟疾儿童进行门诊研究。使用G6PD缺乏的简单测试，我们将发现750名疟疾儿童G6PD缺乏，750名G6PD水平正常。在这两组患者中，我们将随机给予一半患者常规抗疟疾治疗，另一半患者常规抗疟疾治疗加单一小剂量伯氨喹。然后，我们将非常仔细地观察孩子们，看看服用伯喹是否会比不服用伯喹导致更多的贫血，以及这种情况是否尤其发生在G6PD缺陷组。我们需要有未接受伯喹治疗的儿童和一些没有G6PD缺乏症的儿童的对比组，因为疟疾本身会导致溶血，G6PD缺乏症在某些情况下甚至在没有伯氨喹治疗的情况下也会。我们的目标是消除G6PD缺乏、疟疾和伯喹的影响，以真正确定在所有情况下给予低剂量伯喹是否安全。如果这项研究表明单一给予低剂量伯喹是安全的，这将使世卫组织和各国政府能够推荐安全的治疗方案，既能治愈患者，又能防止疟疾传播给其他儿童。

项目成果

Single low-dose primaquine for blocking transmission of Plasmodium falciparum malaria - a proposed model-derived age-based regimen for sub-Saharan Africa.

用于阻断恶性疟原虫疟疾的传播的单剂量primaquine - 拟建了撒哈拉以南非洲的基于模型的基于年龄的疗法。

• DOI: 10.1186/s12916-017-0990-6
• 发表时间: 2018-01-18
• 期刊: BMC medicine
• 影响因子: 9.3
• 作者: Taylor WR;Naw HK;Maitland K;Williams TN;Kapulu M;D'Alessandro U;Berkley JA;Bejon P;Okebe J;Achan J;Amambua AN;Affara M;Nwakanma D;van Geertruyden JP;Mavoko M;Lutumba P;Matangila J;Brasseur P;Piola P;Randremanana R;Lasry E;Fanello C;Onyamboko M;Schramm B;Yah Z;Jones J;Fairhurst RM;Diakite M;Malenga G;Molyneux M;Rwagacondo C;Obonyo C;Gadisa E;Aseffa A;Loolpapit M;Henry MC;Dorsey G;John C;Sirima SB;Barnes KI;Kremsner P;Day NP;White NJ;Mukaka M
• 通讯作者: Mukaka M

Pharmacokinetics of single low dose primaquine in Ugandan and Congolese children with falciparum malaria.

• DOI: 10.1016/j.ebiom.2023.104805
• 发表时间: 2023-10
• 期刊: EBioMedicine
• 影响因子: 11.1