Info

a Abbreviations: o = oral, i.m. = intramuscular injection, i.v. = intravenous injection, s = suppository b Survival rate.

treatment of recrudescence after treatment with mefloquine), artemisinin and its derivatives should be given for seven days (White 1996a). Apart from mefloquine, doxycycline has been combined with artesunate (Looareesuwan et al., 1994c), however the cure rate of this combination (80%), is not high.

Although there are many reports of clinical trials on artesunate, artemether and their combinations, there are few clinical reports on arteether (Looareesuwan et al., 1996f), dihydroartemisinin (Looareesuwan et al., 1996e; Wilairatana et al., 1998), and co-artemether (artemether plus lumefantrine (benflumetol)) (Looareesuwan et al., 1996a; van Vugt et al., 1998a; 1998b). However, preliminary studies showed that the latter three drugs rapidly clear the parasites and gave high cure rates (Table 2).

Severe and Complicated Malaria

The goal of treating patients with severe or complicated malaria is survival, not parasitological cure (White 1994). In severe and complicated falciparum malaria (WHO 1990), parenteral antimalarial therapy should be given to the patients. WHO recommended that the use of parenteral artemether or artesunate should be confined to areas where quinine resistance is demonstrable since the limited data available did not show a marked advantage of these drugs over quinine (WHO, 1994). Artesunate may be given by intravenous or intramuscular injection. Artemether is formulated in peanut oil and is given by intramuscular injection. Arteether is a very similar compound to artemether. It is the oil-soluble ethyl ether and is given by intramuscular injection. Artelinic acid is a water-soluble second-generation compound under development (White 1996b). Both arteether and artelinic acid have been developed in the West, but only arteether has undergone clinical trials for severe malaria treatment. In recent studies, rectal suppositories of artemisinin and artesunate have proved as effective as the parenteral drugs (Hien et al., 1991, 1992; Looareesuwan et al., 1995, 1996d). Therefore, effective drug treatment for severe malaria can be given in rural areas where parenteral administration by injection is no possible. These drugs are the most rapidly acting antimalarials known (ter Kuile et al., 1993). They also have a broad window of antimalarial activity during the 48 hour asexual life cycle of the parasite from the ring forms to the mature trophozoites and prevent parasitized erythrocytes from adhering to uninfected cells (rosetting) or to vascular endothelium (cytoadherance) (Udomsangpetch et al., 1996). These drugs produce rapid parasite clearance and appear to be very safe in clinical practice.

Of the currently available artemisinin derivatives, artesunate is the most rapidly acting drug, possibly because it is immediately bioavailable (as dihydroartemisinin) after intravenous injection, and is absorbed rapidly after oral or intramuscular administration. In recent large comparative studies, treatment with intramuscular artemether accelerated parasite clearance but slightly prolonged recovery from coma, and it did not reduce mortality significantly in comparison with quinine (Boel van Hensbrock et al., 1996; Hien et al., 1996). These trials confirm that artemether is an alternative to quinine in severe malaria. Parenteral artemisinin derivatives are, however, easier to use than quinine and do not induce hypoglycaemia.

Mortality associated with cerebral malaria treated with the parenteral artemisinin and its derivatives has been around 13% in countries in both Africa and Asia (Danis et al., 1996; Hien et al., 1996; Wilairatana and Looareesuwan 1995). However, the mortality in quinine-treated groups has consistently been around 20% in countries of Southeast Asia, compared with 15% in others, such as countries in Africa, indicating the decreased efficacy of quinine against some Southeast Asian strains of P. falciparum (Looareesuwan et al., 1992a).

Children

Most of the reported information on artemisinin and its derivatives concerns adults, but there are sufficient data to conclude that children also tolerate the drugs very well, that no serious adverse effects have been observed, and that the therapeutic response resembles that of adults with similar levels of immunity (Hien et al., 1991; Taylor et al., 1993; White et al., 1992).

Pregnancy

Non-clinical studies showed no mutagenicity or teratogenicity but the drug caused foetal resorption in rodents even at relatively low doses of 1/200-1/1400 of the LD50 (i.e. above 10 mg) when administered after the sixth day of gestation (Qinghaosu Antimalarial Coordinating Research Group, 1979). There are few reports of the use of artemisinin and its derivatives in pregnancy, and they show no abnormalities in children whose mothers were treated with artemisinin or artemether during the second and third trimesters (Li et al., 1990; Shen 1989; Wang 1989). For the management of uncomplicated malaria in pregnancy, artemisinin and its derivatives can be used in the second and third trimester, but their use in the first trimester is not recommended. In severe malaria, artemisinin derivatives are the drug of choice in the second and third trimester. For the treatment of severe malaria in the first trimester, the advantages of artemisisnin-like drugs over quinine, especially the lower risk of hypoglycaemia, must be weighed against the fact that there is still limited documentation on pregnancy outcomes following their use (WHO, 1998).

Resistance

Cross-resistance with mefloquine, quinine, and amodiaquine has been observed following in vivo induction of resistance to artemisinin in chloroquine-resistant strains of P. yoelii in rodents (Ding 1988; Chawira et al., 1986, 1987). The resistance to artemisinin is thought to be due to a change in the membrane structure which could in part explain resistance to other antimalarials. Multidrug resistant isolates of P. falciparum from Southeast Asia appear to be less sensitive in vitro to artemisinin and its derivatives than isolates from other geographical areas (WHO 1994). However, there is no good evidence of true resistance to these drugs. Infections recurring after treatment have been attributed to inadequate primary treatment resulting in recrudescence. At present, artemisinin and its derivatives are the only group of antimalarial drugs to which resistance of P. falciparum has not yet developed in the field (WHO, 1998).

Overdosage

No reports on overdosage in human have become available. Adverse Effects

Over two million patients are estimated to have been treated with artemisinin and its derivatives, and no adverse effects have been noted (Hien et al., 1993; WHO 1994). Cardiac and gut toxicity has also occurred in animals, usually with higher doses (White 1996b). Although transient dose-related reductions in reticulocyte counts were noted in some early preclinical toxicology studies, they have not been observed in human clinical trials. Foetal resorption was observed in some animal toxicology studies (China Cooperative Research Group on Qinghaosu and its Derivatives as Antimalarials, 1982). The principal toxicity in animals is a dose-related selective pattern of neurotoxicity affecting brain stem nuclei involved in auditory relays (Brewer et al., 1994). Although there has been one report (Miller et al., 1997), of a patient with ataxia and slurred speech after artesunate treatment, there is no definite proof of a causal relationship in man; ataxia and slurred speech may be due to other causes such as malaria itself.

In some countries, artemisinin and its derivatives can be obtained easily because of wide-spread availability of over-the-counter antimalarial chemotherapy in shops and the market places. Self-treatment, presumptive treatment, and repeated treatment of uncomplicated infections are most frequently performed with oral-dosage forms because these are most convenient for outpatients. Once a drug is released and available, drug toxicity particularly with chronic or repeated administration may become a very important issue (Meshnick et al., 1996).

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