Premature and unregulated use of artemisinin and its derivatives, especially oral forms, could accelerate the development of drug resistance, thus compromising the efficacy of these drugs when multidrug resistance develops in Africa. Also, over-prescription of artemisinin and its derivatives particularly in areas without multi-drug-resistance is a matter of concern. Therefore, WHO (1994; 1998) have proposed guidelines for using these drugs. Following are the present guidelines for using the artemisinin group of antimalarials.
Situations Where Multi-Drug Resistant Malaria is Prevalent
Artemisinin and its derivatives should be used in areas where quinine and mefloquine resistant P. falciparum has been reported (WHO 1994, 1998). Oral artemisinin and its derivatives have been extensively studied in Thailand (Table 2). These drugs should be administered in combination with another effective blood schizontocide to reduce recrudescence and to slow the development of resistance. There are many reports on the efficacy of the use of artemsinin derivatives with mefloquine (15-25 mg base/kg). Tolerance to 25 mg base/kg doses of mefloquine may be further improved by administering 15 mg base/kg on the second or third day with the rest 6-24 hours later. If compliance is a concern, mefloquine can be given on the first day. The dose of mefloquine depends on the local sensitivity of the parasite to mefloquine (WHO, 1998). Recently, a fixed combination of artemether with lumefantrine (benflumatol) has been developed and this appears to have a promising future (Looareesuwan, 1999; van Vugt et al., 1998a,b). Under exceptional circumstances, such as when there is a history of an adverse reaction to the combination agent, artemisinin monotherapy may be indicated, but a 7-day course of treatment is recommended and effort should be made to ensure compliance. In areas where mefloquine is already the first-line drug or a change to mefloquine is being considered, a 3-day course of an artemisinin-like drug should be given in combination with mefloquine (White, 1997; WHO, 1998). Artemisinin derivatives are not indicated for the treatment of malaria due to P. malariae, P. ovale, or chloroquine-sensitive P. vivax. Possible treatment of chloroquine-resistant P. vivax with these drugs requires further study. The use of parenteral preparations of these drugs in patients who can take oral medications is not indicated.
Severe falciparum malaria is a serious disease with high mortality that requires intensive care. There is the same urgency to treat this condition with adequate doses of parenteral antimalarials as there is to treat septicaemia with antibacterials. Parenteral artesunate or artemether are effective alternatives to parenteral quinine for the treatment of severe falciparum malaria. Use of these drugs should be confined to areas where there is quinine-resistance. If parenteral formulations are not available, artemisinin or artesunate suppositories may be an effective alternative (Looareesuwan et al., 1996d). Following parenteral treatment, radical cure should be effected by completing treatment with a fully curative dose of an effective antimalarial (e.g., a single 15-25 mg/kg oral dose of mefloquine).
The recommended schedules are shown in Table 3. Although adverse effects with the recommended regimens have rarely been reported, prolonged or higher doses in animals have demonstrated neurotoxic and cardiotoxic effects. Therefore, it is important not to exceed the recommended doses, or to repeat courses of treatment at short intervals until such time as the acute and cumulative risk can be quantitatively evaluated clinically.
CLINICAL USE OF ARTEMISININ DERIVATIVES Table 3 Treatment of falciparum malaria with artemisinin and its derivatives.
(i) Oral artesunate (50 mg/tablet): In combination with a total of 25 mg/kg mefloquine, give a total of 10-12 mg/kg in divided doses over 3-5 days (e.g., 4 mg/kg daily for 3 days or 4 mg/kg followed by 1.5 mg/kg/day for 4 days). If used alone, the same total dose is given over 7 days (usually 4 mg/kg initially, followed by 2 mg/kg on days 2 and 3 and 1 mg/kg on days 4-7). Recently, Mepha Company (Switzerland) has produced oral artesunate (200 mg/tablet). It has been used effectively for falciparum malaria treatment.
(ii) Oral artemether (40 mg/capsule): Same regimens as for artesunate.
(iii) Oral dihydroartemisin (20 mg/tablet): 3 mg/kg immediately, then 1.5 mg/kg once daily for 7 days.
Oral co-artemether (CGP 56697, a combination of artemether 20 mg and lumefantrine
(benflumetol) 120 mg/tablet): 4 doses of 4 tablets at 0, 8, 24 and 48 h in 2 days or 6 doses of
4 tablets at 0, 8, 24, 36, 48 and 60 h or at 0, 8, 24, 48, 72 and 96 h.
(i) Artesunate (60 mg/vial); 2.4 mg/kg intravenously or intramuscularly, followed by 1.2 mg/kg at 12 and 24 h, then 1.2 mg/kg daily. Artesunate is dissolved in 0.6 ml of 5% sodium bicarbonate, diluted to 3-5 ml with 5% dextrose, and given by bolus intravenous or intramuscular injection.
(ii) Artemether (80 mg/ampoule); 3.2 mg/kg intramuscularly, followed by 1.6 mg/kg daily. Not to be given intravenously
(iii) Artesunate suppository (200 mg/rectocap, Mepha Company, Switzerland); 4 mg/kg given twice daily at 0, 4, 8, 12, 24, 36, 48, and 60 h
(iv) Artemisinin suppository: 10 mg/kg at 0 and 4 h followed by 7 mg/kg at 24, 36, 48, and 60 h.
1. For monotherapy using an artemisinin derivative as a single antimalarial drug, treatment given for 5-7 days will give a cure rate of over 85%. If the duration of treatment is shorter than 5 days, artemisinin derivatives should be combined with a long acting antimalarial drug, preferably mefloquine 25 mg/kg given orally in two divided doses of 15 mg/kg and 10 mg/kg given 12 hours apart. The two drugs may be given simultaneously on the first day of treatment (e.g. artesunate plus mefloquine) or in sequence, the mefloquine being given immediately following the completion of treatment with the artemisinin derivative.
2. At present it is recommended that none of the artemisinin derivatives should be used as a single agent (monotherapy). An artemisinin derivative should always be used in combination with a long acting antimalarial in order to reduce recrudescence and slow the development of resistance.
Situations Where Multidrug-Resistant Malaria is Rare or Absent
The use of artemisinin and its derivatives was previously not recommended in areas where multidrug-resistant malaria is rare or absent, e.g. Africa (WHO 1994). The reasons for this were as follows; first, available drugs such as chloroquine, sulfa-pyrimethamine combinations, and mefloquine are still effective for the treatment of uncomplicated malaria. Secondly, quinine is still effective for the treatment of severe and complicated malaria. Thirdly, premature and unregulated use of the artemisinin and its derivatives, particularly oral preparations, might result in the development of resistance and could thereby compromise their efficacy in the future when they may be needed for the treatment of severe and complicated malaria because of decreased efficacy of quinine. Recently, however experts have taken the view that as artemisinin derivatives are potent antimalarials without significant adverse effects they may be used more widely; however, they should be used in combination with another effective blood schizontocide for the treatment of both multidrug-resistant and non-drug-resistant falciparum malaria to reduce recrudescence and to slow the development of resistance (Looareesuwan et al., 1998).
Although, information concerning the risk of artemisinin and its derivatives in pregnancy is incomplete, these drugs should not be withheld from pregnant women in areas where these drugs are indicated (White 1996a; WHO 1994). For pregnant women with uncomplicated malaria, it is preferable to avoid the use of these drugs in the first trimester but for those suffering from severe malaria in areas with low quinine efficacy the risk-benefit ratio may favour their use even in the first trimester.
P. vivax, P. malariae, and P. ovale still respond well to chloroquine and other antimalarials, therefore the use of artemisinin or its derivatives against these malaria species is not recommended. Hypnozoites of P. vivax and P. ovale (i.e. liver stages) are not eliminated by artemisinin and its derivatives.
At the present time, there is a strong consensus that artemisinin and its derivatives should not be used as prophylaxis (WHO 1994). This is based on concerns of current uncertainities on the effect of higher doses and frequently repeated doses, and about continuous drug pressure leading to the emergence of resistance.
In the rodent malaria P. berghei, artemisinin potentiated the antimalarial effects of mefloquine, primaquine and tetracycline, is additive with chloroquine, and antagonises pyrimethamine, cycloguanil and sulphonamides (Chawira et al., 1987). When mefloquine was given at 6 h after oral artesunate, the mefloquine concentrations were below those observed with mefloquine alone. Later mefloquine administrations had no such effect.
Co-administration of artemisinin derivatives and desferrioxamine B to cerebral-malaria patients was thought to be useful, combining the rapid parasite clearance of the artemisinin and the potential central-nervous system protection of the iron chelator. Although data from in vitro studies indicate that artesunate and desferrioxamine B are antagonistic in terms of antiparasitic efficacy (Meshnick et al., 1993), subsequent studies in mice have found no evidence of such antagonism (Meshnick, unpubl. obs). In humans there was no evidence of adverse effects or toxicity resulting from this combination (Looareesuwan et al., 1996c).
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