547 Am. J. Trop. Med. Hyg., 60(4), 1999, pp. 547–555 Copyright  1999 by The American Society of Tropical Medicine and Hygiene ADVERSE EFFECTS IN PATIENTS WITH ACUTE FALCIPARUM MALARIA TREATED WITH ARTEMISININ DERIVATIVES RIC PRICE, MICHELE VAN VUGT, LUCY PHAIPUN, CHRISTINE LUXEMBURGER, JULIE SIMPSON, ROSE McGREADY, FEIKO TER KUILE, AM KHAM, TAN CHONGSUPHAJAISIDDHI, NICHOLAS J. WHITE, AND FRANC ¸ OIS NOSTEN Shoklo Malaria Research Unit, Mae Sod, Tak Province, Thailand; Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Department of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Headington, Oxford, United Kingdom Abstract. In prospective studies of acute uncomplicated, multidrug-resistant falciparum malaria on the western border of Thailand, the oral artemisinin derivatives were used alone in the treatment of 836 patients (artesunate 630, artemether 206), were combined with mefloquine (15–25 mg base/kg) in 2,826 patients, and mefloquine alone was used in 1,303 patients. The combined regimens of mefloquine plus an artemisinin derivative were associated with more side effects than those with an artemisinin derivative alone; acute nausea (31% versus 16%), vomiting (24% versus 11%), anorexia (51% versus 34%), and dizziness (47% versus 15%) (P  0.001). Oral artesunate and arte- mether alone were very well tolerated. There was no difference in the incidence of possible adverse effects between the two drugs, and no evidence that either derivative caused allergic reactions, neurologic or psychiatric reactions, or cardiovascular or dermatologic toxicity. Blackwater fever occurred in three patients treated with mefloquine plus artesunate regimens. Oral artesunate and artemether are safe and well tolerated antimalarial drugs. The antimalarial artemisinin (qinghaosu) is the active principle extract of the plant qinghao (Artemisia annua L). This plant has been used for centuries in traditional Chinese medicine although its specific antimalarial properties were only discovered in China in 1972. In the last two decades, more than two million patients have been treated with artem- isinin or one of its derivatives (artesunate or artemether), predominantly in China and southeast Asia. Although these antimalarials have proved highly efficacious in clinical trials with very few reported adverse effects, 1–3 there are few sys- tematic large detailed clinical studies of the toxicity of ar- temisinin derivatives in clinical practice. The general toxicity profile in experimental animals has been good, but in all mammal species tested to date, these compounds have pro- duced an unusual selective pattern of damage to certain brain stem nuclei, particularly those involved in auditory process- ing. Although there have been no reported neurotoxic reac- tions to artemisinin or its derivatives in humans, the rele- vance of these observations in animals to toxicity in humans is unresolved. Plasmodium falciparum has developed resistance to chlo- roquine, sulfadoxine-pyrimethamine, and mefloquine on the borders of Thailand. 4 Sensitivity to quinine has also de- creased. The rapid decrease in mefloquine efficacy in this region, and the lack of effective alternatives, has necessitated the introduction of treatment regimens containing artemisi- nin derivatives. A series of comparative drug studies have been conducted on the western border of Thailand with ar- tesunate and artemether that have established their safety and efficacy. 5 Since 1994, these drugs have become an integral part of the treatment of uncomplicated falciparum malaria in this area. 6 The combination of mefloquine plus three days of artesunate is currently the standard first-line treatment for uncomplicated falciparum malaria. The extensive use of the artemisinin derivatives in this area provided us with the op- portunity to review the human toxicity of these compounds in a cumulative experience of more than 3,500 prospectively studied treatment courses. METHODS Study site. This review is based on a series of large pro- spective chemotherapeutic trials aimed at optimizing anti- malarial treatment regimens in an area of multidrug-resistant falciparum malaria. The studies took place between 1991 and 1995 in a Karen community living in an area of malar- ious hill forest along the Thai-Burmese border. Studies in- volving 2,593 of the patients described here have been re- ported previously. 6–13 The epidemiology of malaria at this site has also been described in detail recently. 14 Transmission of malaria is low (approximately one vivax, and one falci- parum malaria infection per person every two years) and seasonal. Nearly all falciparum malaria infections are symp- tomatic. Patients. All patients treated at the Shoklo Malaria Re- search Unit (SMRU) with an artemisinin derivative during the study period were included in the analysis. To determine whether the coadministration of an artemisinin derivative al- tered the toxicity profile of mefloquine therapy, adverse ef- fects in all patients receiving mefloquine monotherapy were also studied for comparison. Patients of all ages were eligi- ble to enroll in these prospective chemotherapeutic studies if they presented with slide-confirmed falciparum malaria to the SMRU or the outpatient clinics of Me ´decins Sans Fron- tie `res (MSF). They were recruited into these prospective studies provided that they or their accompanying relatives gave fully informed consent. Pregnant women, children weighing  5 kg, and patients with signs of severity 15 or concomitant disease requiring hospital admission were all excluded. Therapeutic studies in Shoklo were carried out in three prospectively defined patient groups: 1) primary epi- sodes of falciparum malaria, 2) recrudescent cases of malaria (recurrence of malaria within 63 days of a previous episode), and 3) hyperparasitemic falciparum malaria ( 4% parasit- ized red blood cells) as each of these required a different treatment approach. Apart from this categorization, the in- clusion and exclusion criteria were identical between studies. All studies were approved by the Ethics Committee of the