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Acetaminophen as a Renoprotective Adjunctive Treatment in Patients With Severe and Moderately Severe Falciparum Malaria: A Randomized, Controlled, Open-Label Trial.


ABSTRACT: Background:Acute kidney injury independently predicts mortality in falciparum malaria. It is unknown whether acetaminophen's capacity to inhibit plasma hemoglobin-mediated oxidation is renoprotective in severe malaria. Methods:This phase 2, open-label, randomized controlled trial conducted at two hospitals in Bangladesh assessed effects on renal function, safety, pharmacokinetic (PK) properties and pharmacodynamic (PD) effects of acetaminophen. Febrile patients (>12 years) with severe falciparum malaria were randomly assigned to receive acetaminophen (1 g 6-hourly for 72 hours) or no acetaminophen, in addition to intravenous artesunate. Primary outcome was the proportional change in creatinine after 72 hours stratified by median plasma hemoglobin. Results:Between 2012 and 2014, 62 patients were randomly assigned to receive acetaminophen (n = 31) or no acetaminophen (n = 31). Median (interquartile range) reduction in creatinine after 72 hours was 23% (37% to 18%) in patients assigned to acetaminophen, versus 14% (29% to 0%) in patients assigned to no acetaminophen (P = .043). This difference in reduction was 37% (48% to 22%) versus 14% (30% to -71%) in patients with hemoglobin ?45000 ng/mL (P = .010). The proportion with progressing kidney injury was higher among controls (subdistribution hazard ratio, 3.0; 95% confidence interval, 1.1 to 8.5; P = .034). PK-PD analyses showed that higher exposure to acetaminophen increased the probability of creatinine improvement. No patient fulfilled Hy's law for hepatotoxicity. Conclusions:In this proof-of-principle study, acetaminophen showed renoprotection without evidence of safety concerns in patients with severe falciparum malaria, particularly in those with prominent intravascular hemolysis. Clinical Trials Registration:NCT01641289.

SUBMITTER: Plewes K 

PROVIDER: S-EPMC6137116 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Acetaminophen as a Renoprotective Adjunctive Treatment in Patients With Severe and Moderately Severe Falciparum Malaria: A Randomized, Controlled, Open-Label Trial.

Plewes Katherine K   Kingston Hugh W F HWF   Ghose Aniruddha A   Wattanakul Thanaporn T   Hassan Md Mahtab Uddin MMU   Haider Md Shafiul MS   Dutta Prodip K PK   Islam Md Akhterul MA   Alam Shamsul S   Jahangir Selim Md SM   Zahed A S M ASM   Sattar Md Abdus MA   Chowdhury M A Hassan MAH   Herdman M Trent MT   Leopold Stije J SJ   Ishioka Haruhiko H   Piera Kim A KA   Charunwatthana Prakaykaew P   Silamut Kamolrat K   Yeo Tsin W TW   Lee Sue J SJ   Mukaka Mavuto M   Maude Richard J RJ   Turner Gareth D H GDH   Faiz Md Abul MA   Tarning Joel J   Oates John A JA   Anstey Nicholas M NM   White Nicholas J NJ   Day Nicholas P J NPJ   Hossain Md Amir MA   Roberts Ii L Jackson LJ   Dondorp Arjen M AM  

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20180901 7


<h4>Background</h4>Acute kidney injury independently predicts mortality in falciparum malaria. It is unknown whether acetaminophen's capacity to inhibit plasma hemoglobin-mediated oxidation is renoprotective in severe malaria.<h4>Methods</h4>This phase 2, open-label, randomized controlled trial conducted at two hospitals in Bangladesh assessed effects on renal function, safety, pharmacokinetic (PK) properties and pharmacodynamic (PD) effects of acetaminophen. Febrile patients (>12 years) with se  ...[more]

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