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，有恶性疟原虫(PF)和间日疟原虫(PV)两种类型。在PF占主导地位的非洲以外，光伏是最常见的疟疾物种，估计造成600万至1200万病例和1800至4900人死亡。当寄生虫进入红细胞并在那里繁殖并产生雄性和雌性形态时，疟疾就会发生，蚊子需要这些形态来完成它们的生命周期。光伏已经找到了一种避免蚊子传播的方法，方法是在肝脏中形成一种名为催眠虫的睡眠形式，它会定期醒来，导致新的疾病，称为复发。在一些地区，特别是东南亚，催眠者经常复发，约占所有PV疾病的80%。反复PV会导致儿童贫血、生长迟缓、发育迟缓、学习成绩差、休假和经济损失。因此，催眠岩储集层是我们研究的一个重要重点。唯一可用的杀死催眠药的药物是伯氨喹，这是一种70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(G6PD)的人的红细胞破坏(溶血)。G6PD缺乏症(G6PDd)是一种常见的X染色体缺陷遗传病。因此，在一些地区，高达30%的男性患有重度G6PDD，约75%的女性患有轻度G6PDD。G6PDd红细胞不能产生足够的抗氧化剂；红细胞越缺乏，产生的抗氧化剂就越少。伯喹在代谢时会产生氧化剂，破坏红细胞，导致溶血。伯喹剂量越大，溶血作用越强。如果病情严重，患者可能很快就会贫血，这可能会危及生命。我们可以在实验室里检测G6PDd，这很麻烦。快速检测很容易使用，但它们很昂贵，政府负担不起在整个医疗服务中部署这些检测。因此，伯喹被认为是危险的，不能使用，这阻碍了PV的消除。大约60年前，医生们发现，每周给患有轻度非洲型G6PDd的非裔美国人连续8周服用伯氨喹在防止复发方面是安全有效的。然而，当这种剂量在柬埔寨进行测试时，一些PV患者的血红蛋白(红细胞中的红色素)显著下降，其中一人需要输血。柬埔寨是G6PDD中度严重的国家。因此，应该对接受治疗的患者进行监测，这是另一种代价高昂的预防措施。这也适用于中东、巴基斯坦和阿富汗，这些地区出现了最严重的G6PDD。我们问自己这个问题：“伯氨喹能否在不需要G6PD检测的情况下更安全地用于G6PDD患者？伯喹破坏的是较老的红细胞，而不是较年轻的红细胞。结合红细胞是如何产生的知识，以及健康人和服用伯喹的PV患者的溶血数据，我们使用数学模型找到了导致缓慢烧伤的溶血的伯喹剂量。我们发现，连续20天，每隔5天增加一次伯氨喹的剂量，与柬埔寨患者每周服用的剂量相比，可以获得缓慢的烧伤溶血和血红蛋白下降。下一步是在泰国的G6PD男性身上测试这种剂量，在那里G6PD Mahidol很常见，与柬埔寨的G6PD Viangchan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，所有研究参与者都将在医院受到密切监测，并每天检查他们的血红蛋白。如果这项研究成功，我们将在PV患者身上测试剂量，并将调整伯氨喹剂量用于G6PD地中海国家的研究。最终，如果我们证明按部就班地服用伯喹是安全有效的，这将是一个巨大的飞跃，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.