gastrointestinal upset, headache, dizziness, fatigue, sleep disturbance, palpitations, maylgia, arthralgia, and rash (Bakshi et al., 2000). Detailed prospective studies have not demonstrated any cardiotoxicity (van Vugt et al., 1999; Bindschedler et al., 2000). Twenty severe adverse effects in 1,869 patients include 19 that could be explained on the basis of the malarial episode or a concurrent illness; artemether-lumefantrine may have contributed to the development of hemolytic anemia in one 35-year-old patient 13 days following discontinuation of the drug (Bakshi et al., 2000).

Neurotoxicity: Animal Studies

Dogs receiving high doses of intramuscular artemether or arteether have developed a peculiar selective pattern of brain stem damage, in particular involving the reticular formation, the vestibular system nuclei, and nuclei related to the auditory system. Clinical features included gait disturbances; loss of spinal and pain response reflexes; prominent loss of brain stem and eye reflexes; cardiorespiratory depression; and death. ECG changes included prolongation of QTc interval and bizarre ST-T segment changes (Brewer et al., 1994). A similar selective pattern of brain stem pathology also was found in mice, rats, and Rhesus monkeys given arteether or arthemether (Genovese et al., 1998; Petras et al., 2000). In mice, parenteral artemether was more neurotoxic than artesunate, resulting in escalating, irreversible neurological deficits involving balance, and death with increasing doses (Nontprasert et al., 1998). Recent studies have shown that neurotoxicity is determined by the pharmacokinetic properties of the drugs. Sustained CNS exposure from slowly absorbed or eliminated artemisinins is considerably more neurotoxic than intermittent brief exposure. Thus intramuscular artemether and arteether are more neurotoxic in experimental animals than the same drugs given orally, or artesunate given by any route.

Neurotoxicity in Humans

One case report to date has described acute cerebellar dysfunction including slurred speech, ataxia, impaired heel to shin movement, and dysdiadochokinesis after treatment of falciparum malaria with oral artesunate (Miller and Panosian, 1997). Detailed neurologic data from Price and colleagues (1999a) include neurological examinations conducted in nearly 2,000 children older than 5 at baseline, and on days 2, 7, and 28 posttreatment, with artemether alone, artesunate alone, or artesunate plus mefloquine. Short-course therapy with the artemisinins either alone or in combination with mefloquine was associated with self-limited, minor neurological deficits in a minority (<1 percent) of patients during the first few days of falciparum malaria.



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