Fever in uncomplicated Plasmodium falciparum malaria: randomized double-[] blind\'comparison of ibuprofen and paracetamol treatment

TXANSACTI~NS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HVGIENE (1995) 89, 507-509

507

Fever in uncompticated Piasmodium falciparum malaria: randomized double-‘blind’ comparison of ibuprofen and paracetamol treatment S. Krishna1>2*, S. Pukrittayakameel, W. Supanaranond’, F. ter Kuilel, M. Ruprah3, T. Sura4 and N. J. Whitely2 ‘Faculty of Tropical Medicine, Mahidol Universiry, 42016 Rttjvithi Road, Bangkok 10400, Thailand; 2Centre for Tropical Diseases,Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, OX3 9DU, UK; 3Poisons Unit, Avonley Road, London, SE14 5ER, UK; 4Department ofMedicine, Ramathipodi Hospital, Rama 6 Road, Bangkok 10400, Thailand

Abstract Fever almost invariably accompanies uncomplicated falciparum malaria. In a randomized, double-‘blind’ study, we compared a sin le dose of ibuprofen (10 mg/kg, n=X) with racetamol(l5 mg/kg, 7a=8)for the treatment of fever >38*5 4 due to uncomplicated falciparum malaria. rbuprofen was sigmficantly more effective than paracetamol in lowering temperatures throughout the fust 4.5 h after dosing (P=O.O16) and should be considered as an antipyretic agent in the management of uncomplicated falciparum infections, providing there is no contraindication to its use. Keywords: malaria,Plasmodiumfalcipawn, anupyreti, ibuprofen,paracetamol Introduction We have recently shown that quinine alone was ineffective as an antipyretic agent in uncomplicated falciparum malaria, whereas paracetamol rapidly lowered temperatures and improved symptoms associatedwith fever in malaria (KRISHNA et aZ., 1995). Ibuprofen, the safest of the non-steroidal anti-inflammatory drugs (NSAIDS) (LANCMAN et al., 1994; RODRIGUEZ & JICK, 1!294), has

been shown in somecomparative trials to produce a more rapid, larger, and more sustained fall in fever than paracetamol (reviewed by MACKOWIAK, 1991). However, any antipyretic advantage of ibuprofen must be weighed against an increased potential for adverse effects, The purpose of this trial was to compare the antipyretic efficacy and tolerance of ibuprofen and paracetamol in adult febrile patients with uncomplicated falciparum malaria. Methods Patients

This was a randomized, double ‘blind’ comparison of a single dose of ibuprofen or paracetamol in the treatment of malarial fever in non-pregnant adults. Patients were enrolled into the study providing they had uncomplicated falciparum malaria (WHO, 1990), an oral temperature >38*5”C, and gave informed consent. Patients were excluded if they had contraindications to the use of paracetamol or ibuprofen (specifically a history of asthma, dyspeptic symptoms, gastro-intestinal bleeding, or allergy to ibuprofen), or gave a history of antipyretic or antimalarial drug use within 6 h of presentation. The study was approved by the Ethical Clearance Committee of the Faculty of Medicine, Ramathipodi Hospital, Bangkok, Thailand. Procedures

Randomization and administration of antipyretic medication was carried out by an individual otherwise unconnected with the study. The physicians responsible for patient care and for monitoring antipyretic responses ren&ned unaware of the patients’antipytetic treatments until the studv had been comuleted. After a full historv and examination the patient was weighed and blood wa’s sampled for biochemical and haematological indices, parasitaemia and drug assay (paracetamol and ibuprofen). Thereafter plasma was sampled at 2 and 5 h after admission for determination of antipyretic drug _. levels. On admission, all patients received oral quinine sulphate (1Omgsalt/kg; Government Pharmaceutical Organ*Current addressfor correspondence:Division of Infectious Diseases, Departmentof Cellular and Molecular Sciences,St George’sHospital Medical School,CranmerTerrace,London, SW17ORB,UK.

ization, Bangkok, Thailand). Patients were then allocated at random to receive either paracetamol elixir (15 mg/kg in a 50 mgimL suspension; Calpol@, Wellcome Foundation, UK) or ibuprofen suspension (10 mg/kg in a 20 mg/mL suspension; Jutien@, kindly supplied by Boots Pharmaceuticals, UK). Symptoms of headache,myalgia, nausea, vomiting and sweating were recorded on a standard form every half hour during the 8 h study period. Oral temperatures, measured with a standard mercury thermometer, were recorded twice at each half hour and remeasured if the 2 readings differed >O*I”C. Patients were monitored for parasitological responses to treatment in the standard way (WHITE & KRISHNA, 1989). Tetracycline (250 mg every 6 h) was added to quinine to complete a 7 d course of both drugs. Drug assay The paracetamol assay has been described previously (KRISHNAer al., 1995). Ibuprofen levels were measured in dunlicate on nlasma satnnles for standards of 5.10.20. 30, 4b mg/L in’ porcine pias&)after mixing w>thace: to&rile (100 uL, 1:1 v/v) containing benoxaprofen (5 mgiL) asan internal standard, The mixture was vortexed and centrifuged (995Og,2 min) and 13OuL were injected on to a high performance liquid chromatography (HPLC; Hypersil 5 ODS) system. The detection wavelength was 220 nm. The inter- and intra-assay coefticients of variation between O-7 and 45.8 mg/L were