Paracetamol Effect on Oxidative Stress and Renal Function in Severe Falciparum Malaria With Intravascular Haemolysis: A Randomised Controlled Clinical Trial
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 62
- 试验地点
- 2
- 主要终点
- Effect of paracetamol concentrations
研究概览
简要总结
Blackwater fever, characterized by intravascular haemolysis and hemoglobinuria, is an important cause of renal impairment and mortality in severe malaria caused by Plasmodium falciparum. The largest malaria clinical trials report blackwater incidences of 5-7% in Asian adults and 4% in African children with severe malaria treated with artesunate or quinine. The prevalence of blackwater fever in Chittagong, Bangladesh is 15% with associated rates of renal failure and mortality of 42.9% and 14.2% respectively.
The fundamental characteristic of blackwater fever is the presence of intravascular hemolysis of both infected and uninfected erythrocytes and release of free haemoglobin. The cytotoxic free haemoglobin present can cause severe oxidative damage as a result of haem redox cycling yielding ferric and ferryl heme, which generate radical species that induce lipid peroxidation and subsequent production of F2-isoprostanes (F2-IsoPs). Evidence suggests that F2-IsoPs generated by the hemoprotein-catalyzed oxidation of lipids are responsible for the oxidative damage and vasoconstriction associated with renal injury in haemolytic disorders and rhabdomyolysis.
A novel mechanism of paracetamol was recently demonstrated, showing that paracetamol is a potent inhibitor of hemoprotein-catalyzed lipid peroxidation by reducing ferryl heme to its less toxic ferric state and quenching globin radicals. In a recent proof of concept trial, paracetamol at therapeutic levels was shown to significantly decrease oxidant kidney injury, improve renal function and reduce renal damage by inhibiting the hemoprotein-catalyzed lipid peroxidation in a rat model of rhabdomyolysis-induced renal injury. Since adults with severe malaria demonstrate increased concentrations of cell-free haemoglobin, and urinary F2-IsoPs, the investigators hypothesize that this novel inhibitory mechanism of paracetamol may provide renal protection in this population by reducing the hemoprotein-induced lipid peroxidation. As there is currently no consensus that exists concerning adequate medical treatment for blackwater fever, the potential application of this safe and extensively used drug would be of great benefit.
详细描述
Mortality in severe malaria remains ~15% despite the best available parasiticidal antimalarial therapy, intravenous artesunate. Adjunctive therapies in combination with anti-parasitic drugs have the potential to improve outcomes. However, currently there are no proven adjunctive therapies for the treatment of severe malaria, which can improve case-fatality when used in combination with anti-parasitic drugs. This research proposal focuses on exploring if paracetamol prevents renal dysfunction caused by free haemoglobin induced oxidative damage in severe malaria.
Blackwater fever epidemiology As early as the 1800s, blackwater fever complicating severe malaria caused by Plasmodium falciparum was recognized as an important cause of morbidity and mortality, with a 25-30% mean mortality rate. The etiology and pathogenesis is poorly understood but it is characterized by massive intravascular haemolysis and passage of black or red urine, which can lead to renal impairment and death. This manifestation was linked to quinine therapy as its occurrence nearly disappeared during the chloroquine era from 1950 to 1980. Since 1990, the resurgence in the number of cases noted in both malaria-free and malarious areas in non-immune and immune individuals has generated renewed interest into this manifestation of severe malaria. The largest malaria clinical trials report blackwater fever incidences of 7% and 4% in Asian adult patients with severe malaria treated with artesunate and quinine, respectively and 4% in African children treated with either drug. The prevalence of blackwater fever in Chittagong, Bangladesh was recently determined in a pilot study to be 15% with associated renal failure and mortality rates of 42.9% and 14.2% respectively.
Blackwater fever pathogenesis Although the exact mechanism linking falciparum malaria and blackwater fever is uncertain, numerous explanations have been suggested. It has been proposed to occur in 4 specific circumstances: (1) in case patients with G6PD deficiency with or without malaria who take oxidant drugs (primaquine) (2) in case patients with G6PD deficiency and malaria untreated and treated with quinine (3) when patients (normal G6PD) with severe malaria are treated with quinine (4) when people exposed to malaria self-medicate with quinine or related amino-alcohol drugs. However, new circumstances of blackwater fever have emerged, occurring in patients with normal G6PD levels with severe malaria who have received artesunate rather than quinine.
Role of oxidative stress and free haem The fundamental characteristic of blackwater fever is the presence of massive haemolysis of both infected and uninfected erythrocytes and release of free haemoglobin. The free haem is highly cytotoxic, and an important scavenger of nitric oxide, promoting endothelial damage and is proposed to be involved in the pathogenesis of renal injury and cerebral malaria. When the degree of intravascular haemolysis exceeds the capacity of plasma haptoglobin to bind the haemoglobin released from red blood cells, free haemoglobin is then filtered by the glomeruli and enters the renal tubules. In a series of renal biopsies, fine and coarse haemoglobin granules are present in the proximal tubules, while haemoglobin casts and granular casts predominate in the distal and collecting tubules in patients with blackwater fever and intravascular haemolysis. This classic theory of renal damage by tubular precipitation is challenged by recent findings of reversing oxidative properties of free haem can prevent renal damage. The free haemoglobin present is pathogenic as the ferrous haem can be oxidized to the ferric state (FeIII) subsequently conferring peroxidase activity to the haemoglobin. Consequently, the haemoglobin can reduce hydroperoxides, such as hydrogen peroxide (H2O2) and lipid hydroperoxides, which generate the ferryl state (FeIV=O) of haemoglobin and a globin protein radical.
Haem Fe(III) protein + H2O2 --> haem [Fe(IV)=O] protein• + H+ + H2O The ferryl haem and protein radical can then generate lipid radicals by oxidation of free and phospholipid-esterified unsaturated fatty acids. The arachidonic side chains of membrane phospholipids are particularly vulnerable to this free radical-mediated damage in the complex cascade of lipid oxidation leading to the generation of F2-isoprostanes (F2-IsoPs) and isofurans (IsoFs). Evidence suggests that F2-isoPs generated by the haemoprotein-catalyzed oxidation of lipids are responsible for the oxidative damage and vasoconstriction associated with renal injury in the setting of hemolytic disorders and rhabdomyolysis.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 12 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patient age >12 years
- •Presence of severe or moderately severe P. falciparum malaria, with and without blackwater fever, confirmed by positive blood smear with asexual forms of P. falciparum
- •Temperature >38 degrees Celsius on admission or fever during the preceding 24hours
- •Written informed consent from patient or attending relative able to and willing to give informed consent. Consent form and information sheets will be translated into Bangla and copies provided to the patient.
排除标准
- •Patient or relatives unable or unwilling to give informed consent
- •History of chronic liver disease
- •History of alcohol use (>3drinks per day)
- •Contraindication or allergy to paracetamol or artesunate therapy
- •Contraindication to nasogastric tube insertion i.e. facial fracture, bleeding diathesis
研究组 & 干预措施
Paracetamol
>50kg: Paracetamol 1gm PO/NG q6hourly for 72 hours and febrile for 24 hours (maximum total dose 4g/24 hours) plus intravenous Artesunate
<50kg: Paracetamol 12.5-15mg/kg/dose q6hourly for 72 hours and febrile for 24 hours (maximum total dose 5 doses/24hours;75mg/kg) plus intravenous Artesunate
干预措施: Paracetamol (Drug)
No Paracetamol
No paracetamol + Intravenous Artesunate
- If temperature > 40°C, ibuprofen PO/PR will be administered in the absence of renal impairment and dehydration; 500mg paracetamol PO/PR will be administered in the presence of renal impairment or dehydration. Dengue testing will be done prior to the administration of ibuprofen.
干预措施: No Paracetamol (Drug)
结局指标
主要结局
Effect of paracetamol concentrations
时间窗: 72 hours
Compare the effect of therapeutic paracetamol concentrations compared with absent or low paracetamol concentration on renal function, peak creatinine levels or trough creatinine clearance, defined as the change at 72 hours compared to baseline, in patients with severe and moderately severe falciparum malaria stratified by the level of intravascular haemolysis (cell-free haemoglobin).
次要结局
- Assessment of Acute Kidney Injury(7 days)
- Mortality and hemodialysis trends(4 weeks)
- Urine scoring of dehydration and haemolysis(72 hours)
- Paracetamol pharmacodynamics(72 hours)
- Area under the plasma concentration versus time curve (AUC)(72 hours)
- The maximum concentration (Cmax)(72 hours)
- Compare treatment arm with control arm with respect to duration of Acute Kidney Injury (AKI) and development of AKI.(14 days)
- Compare between groups correlations between oxidative stress, cell-free hemoglobin and renal function(3 days)
- Assessment of Blackwater fever and association with renal function(7 days)
- Host factors of Intravascular Haemolysis(4 weeks)
- Fever clearance time(7 days)
- Parasite clearance time(7 days)
- Parasite sequestration(7 days)
- Safety assessment(6 weeks)
- Assess the antimalarial drug sensitivity of patients treated with paracetamol(72 hours)
- Paracetamol pharmacokinetics(72 hours)