Acetaminophen as a Renoprotective Adjunctive Treatment in Patients with Severe and Moderately Severe Falciparum Malaria: A Randomized, Controlled, Open-Label Trial
© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. Background Acute kidney injury independently predicts mortality in falciparum malaria. It is unknown whether acetaminophen's capacity to inhibit plasma hemoglobin-mediated oxidation is ren...
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th-mahidol.463252019-08-23T18:43:50Z Acetaminophen as a Renoprotective Adjunctive Treatment in Patients with Severe and Moderately Severe Falciparum Malaria: A Randomized, Controlled, Open-Label Trial Katherine Plewes Hugh W.F. Kingston Aniruddha Ghose Thanaporn Wattanakul Md Mahtab Uddin Hassan Md Shafiul Haider Prodip K. Dutta Md Akhterul Islam Shamsul Alam Selim Md Jahangir A. S.M. Zahed Md Abdus Sattar M. A.Hassan Chowdhury M. Trent Herdman Stije J. Leopold Haruhiko Ishioka Kim A. Piera Prakaykaew Charunwatthana Kamolrat Silamut Tsin W. Yeo Sue J. Lee Mavuto Mukaka Richard J. Maude Gareth D.H. Turner Md Abul Faiz Joel Tarning John A. Oates Nicholas M. Anstey Nicholas J. White Nicholas P.J. Day Md Amir Hossain L. Jackson Roberts Arjen M. Dondorp Harvard School of Public Health Menzies School of Health Research Mahidol University Chittagong Medical College Hospital The University of British Columbia Nuffield Department of Clinical Medicine Vanderbilt University School of Medicine Nanyang Technological University Ramu Upazilla Health Complex Dev Care Foundation Medicine © The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. 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. 2019-08-23T11:43:50Z 2019-08-23T11:43:50Z 2018-09-14 Article Clinical Infectious Diseases. Vol.67, No.7 (2018), 991-999 10.1093/cid/ciy213 15376591 10584838 2-s2.0-85045900185 https://repository.li.mahidol.ac.th/handle/123456789/46325 Mahidol University SCOPUS https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85045900185&origin=inward |
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Medicine Katherine Plewes Hugh W.F. Kingston Aniruddha Ghose Thanaporn Wattanakul Md Mahtab Uddin Hassan Md Shafiul Haider Prodip K. Dutta Md Akhterul Islam Shamsul Alam Selim Md Jahangir A. S.M. Zahed Md Abdus Sattar M. A.Hassan Chowdhury M. Trent Herdman Stije J. Leopold Haruhiko Ishioka Kim A. Piera Prakaykaew Charunwatthana Kamolrat Silamut Tsin W. Yeo Sue J. Lee Mavuto Mukaka Richard J. Maude Gareth D.H. Turner Md Abul Faiz Joel Tarning John A. Oates Nicholas M. Anstey Nicholas J. White Nicholas P.J. Day Md Amir Hossain L. Jackson Roberts Arjen M. Dondorp Acetaminophen as a Renoprotective Adjunctive Treatment in Patients with Severe and Moderately Severe Falciparum Malaria: A Randomized, Controlled, Open-Label Trial |
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© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. 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. |
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Harvard School of Public Health |
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Harvard School of Public Health Katherine Plewes Hugh W.F. Kingston Aniruddha Ghose Thanaporn Wattanakul Md Mahtab Uddin Hassan Md Shafiul Haider Prodip K. Dutta Md Akhterul Islam Shamsul Alam Selim Md Jahangir A. S.M. Zahed Md Abdus Sattar M. A.Hassan Chowdhury M. Trent Herdman Stije J. Leopold Haruhiko Ishioka Kim A. Piera Prakaykaew Charunwatthana Kamolrat Silamut Tsin W. Yeo Sue J. Lee Mavuto Mukaka Richard J. Maude Gareth D.H. Turner Md Abul Faiz Joel Tarning John A. Oates Nicholas M. Anstey Nicholas J. White Nicholas P.J. Day Md Amir Hossain L. Jackson Roberts Arjen M. Dondorp |
format |
Article |
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Katherine Plewes Hugh W.F. Kingston Aniruddha Ghose Thanaporn Wattanakul Md Mahtab Uddin Hassan Md Shafiul Haider Prodip K. Dutta Md Akhterul Islam Shamsul Alam Selim Md Jahangir A. S.M. Zahed Md Abdus Sattar M. A.Hassan Chowdhury M. Trent Herdman Stije J. Leopold Haruhiko Ishioka Kim A. Piera Prakaykaew Charunwatthana Kamolrat Silamut Tsin W. Yeo Sue J. Lee Mavuto Mukaka Richard J. Maude Gareth D.H. Turner Md Abul Faiz Joel Tarning John A. Oates Nicholas M. Anstey Nicholas J. White Nicholas P.J. Day Md Amir Hossain L. Jackson Roberts Arjen M. Dondorp |
author_sort |
Katherine Plewes |
title |
Acetaminophen as a Renoprotective Adjunctive Treatment in Patients with Severe and Moderately Severe Falciparum Malaria: A Randomized, Controlled, Open-Label Trial |
title_short |
Acetaminophen as a Renoprotective Adjunctive Treatment in Patients with Severe and Moderately Severe Falciparum Malaria: A Randomized, Controlled, Open-Label Trial |
title_full |
Acetaminophen as a Renoprotective Adjunctive Treatment in Patients with Severe and Moderately Severe Falciparum Malaria: A Randomized, Controlled, Open-Label Trial |
title_fullStr |
Acetaminophen as a Renoprotective Adjunctive Treatment in Patients with Severe and Moderately Severe Falciparum Malaria: A Randomized, Controlled, Open-Label Trial |
title_full_unstemmed |
Acetaminophen as a Renoprotective Adjunctive Treatment in Patients with Severe and Moderately Severe Falciparum Malaria: A Randomized, Controlled, Open-Label Trial |
title_sort |
acetaminophen as a renoprotective adjunctive treatment in patients with severe and moderately severe falciparum malaria: a randomized, controlled, open-label trial |
publishDate |
2019 |
url |
https://repository.li.mahidol.ac.th/handle/123456789/46325 |
_version_ |
1763494183313604608 |