Assessing the tolerability of a potentially safer radical curative regimen of primaquine in healthy volunteers with glucose 6 phosphate dehydrogenase

疟疾是人类最重要的寄生虫病，由蚊子传播，有两种类型：恶性疟原虫（Pf）和间日疟原虫（Pv）。在非洲以外，Pf占主导地位，Pv是最常见的疟疾物种，估计造成600 - 1200万病例和1800-4900例死亡。疟疾发生时，寄生虫进入红细胞，在那里繁殖并产生雄性和雌性形式，需要被蚊子吸收以完成其生命周期。Pv已经找到了一种避免蚊子传播的方法，通过在肝脏中形成一种睡眠形式，称为催眠虫，它周期性地醒来，引起新的疾病，称为复发。在某些地区，特别是东南亚，催眠虫经常复发，占所有Pv疾病的80%左右。反复Pv导致儿童贫血，生长迟缓，发育迟缓，学习成绩差，失业和经济损失。因此，催眠虫储层是我们研究的一个重要方向。唯一可用的药物杀死催眠虫是伯氨喹，七十年前开发的药物。不幸的是，它会导致红细胞缺乏葡萄糖-6-磷酸脱氢酶（G6 PD）的人红细胞破坏（溶血）。G6 PD缺乏症（G6 PDd）是常见的，通过缺陷的X染色体遗传。因此，在某些地区，高达30%的男性患有重度G6 PDd，约75%的女性患有轻度G6 PDd。G6 PDd红细胞不能产生足够的抗氧化剂;红细胞越缺乏，它们产生的抗氧化剂就越少。伯氨喹被代谢后，会产生氧化剂，破坏红细胞，导致溶血。伯氨喹剂量越高，溶血越多。如果病情严重，患者会很快贫血，这可能危及生命。我们可以在实验室里检测G6 PDd，这很麻烦。有一些容易使用的快速检测方法，但它们很昂贵，政府负担不起在整个卫生服务中部署它们。因此，伯氨喹被认为是危险的，不使用，这阻碍了消除PV。大约60年前，医生发现每周给患有轻度非洲G6 PDd的非洲裔美国人服用伯氨喹8周是安全有效的，可以阻止复发。然而，当这个剂量在柬埔寨（一个G6 PDd中度严重的国家）进行测试时，一些Pv患者的血红蛋白（红细胞中的红色素）显著下降福尔斯，其中一人需要输血。因此，应监测接受治疗的患者，这是另一种昂贵的预防措施。这也适用于中东、巴基斯坦和阿富汗，那里存在最严重的G6 PDd。我们问自己这样一个问题：“伯氨喹是否可以更安全地用于G6 PD患者，而无需进行G6 PD检测？伯氨喹破坏的是较老的而不是较年轻的红细胞。结合红细胞如何产生的知识，以及给予伯氨喹的健康个体和Pv患者的溶血数据，我们使用数学建模来找到导致“缓慢燃烧”溶血的伯氨喹剂量。我们发现，每5天增加伯氨喹的剂量，持续20天，会导致缓慢的烧伤溶血，与柬埔寨患者每周剂量相比，血红蛋白的下降会更少。下一步是在泰国的G6 PD d男性中测试该剂量，其中G6 PD Mahidol很常见，与柬埔寨G6 PD维昂占相似。这项研究的设计是为了让我们可以根据血红蛋白的下降来改变伯氨喹的剂量，这被称为适应性设计。将有一个严密的安全网，所有研究参与者将在医院接受密切监测，每天检查血红蛋白。如果这项研究成功，我们将在Pv患者中测试剂量，并将调整伯氨喹剂量用于G6 PD地中海国家的研究。最终，如果我们能证明伯氨喹分阶段给药是安全有效的，这将是一个巨大的飞跃，各国政府可以迅速采用这种新剂量。

Malaria, the most important parasite disease of Man, is transmitted by mosquitoes and has two types: Plasmodium falciparum (Pf) and P. vivax (Pv). Outside Africa, where Pf predominates, Pv is the most common malaria species causing an estimated 6-12 million cases and 1800-4900 deaths. Malaria occurs when the parasites enter the red blood cells where they multiply and produce male and female forms that need to be taken up by mosquitoes to complete their life cycle. Pv has found a way to avoid mosquito transmission by developing a sleeping form in the liver, called a hypnozoite which wake up periodically to cause new illnesses, called relapses. In some areas, notably SE Asia, hypnozoites frequently relapse and account for about 80% of all Pv illness.Repeated Pv leads to childhood anaemia, growth retardation, developmental delay, poor school performance, time off work and economic loss. So the hypnozoite reservoir is an important focus of our research. The only available drug to kill hypnozoites is primaquine, a drug developed seventy years ago. Unfortunately, it causes red cell destruction (haemolysis) in people whose red cells are deficient in the enzyme, glucose -6-phosphate dehydrogenase (G6PD). G6PD deficiency (G6PDd) is common and inherited through defective X chromosomes. Thus, in some regions, up to 30% of men have severe G6PDd and some 75% of women have milder G6PDd. G6PDd red cells cannot produce enough antioxidants; the more the red cells are deficient, the fewer antioxidants they produce. When primaquine is metabolised, it produces oxidants that damage red cells resulting in haemolysis. The higher the primaquine dose, the more haemolysis. If severe, patients can become anaemic very quickly which can be life threatening. We can test for G6PDd in the laboratory, which is cumbersome. There are easy to use rapid tests but they are expensive and governments cannot afford to deploy them throughout the health service. So, primaquine is considered dangerous and is not used and this hinders the elimination of Pv. About 60 years ago, doctors found that giving primaquine every week for 8 weeks to African Americans with the mild African form of G6PDd was safe and effective at stopping relapses. However, when this dose was tested in Cambodia, a country with moderately severe G6PDd, some Pv patients had significant falls in haemoglobin (the red pigment in red cells) and one needed to be transfused. Therefore, treated patients should be monitored, another costly precaution. This would apply also in the Middle East, Pakistan and Afghanistan where the most severe G6PDd is present. We asked ourselves this question: "Could primaquine be given more safely to G6PDd patients without requiring G6PD testing ? Primaquine destroys older rather than younger red blood cells. Combining this with knowledge of how red cells are produced, and haemolysis data in healthy individuals and Pv patients given primaquine, we used mathematical modelling to find a primaquine dose that led to a 'slow burn' haemolysis. We found that increasing the dose of primaquine every 5 days for 20 days gave that slow burn haemolysis and the fall in haemoglobin would be less compared to the weekly dose given to the Cambodian patients. The next step is to test this dose in G6PDd males in Thailand where G6PD Mahidol is common and similar to Cambodian G6PD Viangchan. The study is designed so that we can alter the primaquine dose according to the fall in the haemoglobin, called an adaptive design. There will be a tight safety net and all study participants will be monitored closely in hospital and have their haemoglobin checked every day. If this study is successful, we will test the dose in Pv patients and will also adapt the primaquine dose for studies in G6PD Mediterranean countries. Ultimately, if we show that dosing primaquine in steps is safe and effective, it will be a giant leap forward and governments could adopt this new dose quickly.