Further studies are needed especially in the following areas:
Studies on the mode of action and mechanism of resistance. Identification of genetic markers of resistance. Studies on the mechanism of selective toxicity.
Clinical evaluation of combinations of artemisinin derivatives with other antimalarial drugs, such as sulfadoxine/pyrimethamine, amodiaquine, chloroquine, pyronari-dine, doxycycline and tetracycline to determine pharmacokinetic interactions, efficacy and tolerability and their impact on the development of resistance to the components. These studies, particularly with sulfadoxine/pyrimethamine, should be given the highest priority.
Determination of the optimum regimens for the oral administration of dihy-droartemisinin and artemether.
Studies on the potential role of artemisinin derivatives in the treatment of chloro-quine-resistant vivax malaria.
Studies to determine whether the regimens of artemisinin derivatives can be shortened, without loss of efficacy, when used in combination with other drugs.
Studies on presentation and packaging of artemisinin-based drugs to improve compliance.
4 Treatment of Severe Malaria
Determination of optimal regimens for parenteral and rectal administration of artemisinin derivatives.
Determination of the speed and reliability of absorption of intramuscular and rectal administration of artemisinin derivatives.
Determination of the clinical significance of delayed recovery from coma following administration of artemisinin derivatives.
Determination of the safety of artemisinin drugs in the first trimester of pregnancy by follow up of patients inadvertently given drugs during the early stages of undisclosed pregnancies.
Determination of the importance of the activity of artemisinin drugs on gametocyto-genesis in different epidemiological situations, with particular reference to malaria incidence and transmission.
Expansion of post marketing surveillance, currently only carried out in Thailand, to other countries where artemisinin and its derivatives are widely used.
Continued surveillance of pregnant women given artemisinin drugs and all patients receiving repeated treatments, with special attention to the temporary suppression of reticulocyte response and neurotoxicity (see Price et al., 1999).
8 Monitoring of Drug Resistance and Therapeutic Efficacy
Evaluation of recently developed protocols for monitoring therapeutic efficacy of antimalarial drugs for their applicability to artemisinin drugs.
Further evaluation of in vitro tests for susceptibility of P. falciparum to artemisinin and its derivatives.
Establishment of sentinel site monitoring of therapeutic efficacy testing.
9 Antimalarial Drug Policy
Determination of the cost implications of the use of artemisinin derivatives in combination with other appropriate drugs.
Evaluation of the impact of global recommendations on the use of artemisinin and its derivatives on drug policies and their use in the public and private sector.
Development of improved formulations and new derivatives of artemisinin. Development of paediatric formulations for oral administration. Technology transfer to improve standards of manufacture of all formulations to GMP.
Improvement of shelf life of formulations.
Strengthening of national and regional regulations and capacities for quality assurance of artemisinin and its derivatives.
ANNEX: TREATMENT GUIDELINES
The role of artemisinin and its derivatives are best defined within the context of the national drug policy and should take into account drug recommendations, and the concerns of, neighboring countries within a region. The information below has been published in Model Prescribing Information, through WHO (WHO, 1995, 1998). Care must be taken not to exceed recommended dosages, or to repeat courses of treatment at short intervals, to reduce the risk of adverse drug effects.
1 Treatment of Uncomplicated Malaria
Combination therapy (Oral)
Artemisinin and its derivatives should be administered in combination with another effective blood schizontocide to reduce recrudescences and to slow the development of resistance. At present data only support the operational use of the combination with mefloquine (15-25 mg base/kg) but a fixed combination of artemether with lumefrantrine is at an advanced state of development and research on other combinations is also being carried out. Administration of mefloquine on the second or third day considerably reduces the risk of vomiting once the clinical condition has been improved. Tolerance to the 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 hrs 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.
The following regimens are recommended:
• Artemisinin: 20 mg/kg as a divided loading dose on the first day, followed by 10 mg/kg once a day for a further 2 days, plus mefloquine (15-25 mg base/kg) as a single or split dose on the second or third day.
• Artesunate: 4 mg/kg once a day for 3 days, plus mefloquine (15-25 mg base/kg) as a single or split dose on the second or third day.
• Artemether: 4 mg/kg once a day for 3 days, plus mefloquine (15-25 mg base/kg) as a single or split dose on the second or third day.
The combination of dihydroartemisinin with mefloquine and other drugs is still being evaluated in clinical trials.
In those situations where the use of artemisinin combinations is impossible, for example because of patient intolerance to mefloquine, monotherapy with artemisinin drugs may be used in regimens of 7 days with every effort being made to ensure compliance. Administration of shorter regimens to non-immune patients leads to unacceptably high levels of recrudescences.
The following regimens are recommended:
• Artemisinin: 20 mg/kg in a divided loading dose on the first day, followed by 10 mg/kg once a day for 6 days.
• Artesunate: 4 mg/kg in a divided loading dose on the first day, followed by 2 mg/kg once a day for 6 days.
• Artemether: 4 mg/kg in a divided loading dose on the first day, followed by 2 mg/kg once a day for 6 days.
There are limited data on dihydroartemisinin and further research is required to determine optimal dosage regimens.
2 Treatment of Severe and Complicated Malaria
The following schedules are recommended for adults and children over 6 months. Intramuscular artemether
3.2 mg/kg as a loading dose on the first day, followed by 1.6 mg/kg daily for a minimum of 3 days until the patient can take oral therapy of an effective antimalarial. The daily dose of artemether can be given as one single injection. In children, the use of a 1 ml tuberculin syringe is advisable since the injection volumes will be small. A formulation (40 mg/lml) that is more easily used in children is available from one manufacturer.
2.4 mg/kg as a loading dose on the first day, followed by 1.2 mg/kg daily for a minimum of 3 days until the patient can take oral therapy of an effective antimalarial.
The anhydrous acid contents are dissolved in 0.6ml 5% (w/v) sodium hydrogen carbonate. The solution should be prepared just before use, because of the instability of the acid, and be diluted with 5.4 ml of 5% (w/v) dextrose solution or dextrose in normal saline.
In view of the serious health implications of malaria in pregnancy, artemisinin and related compounds should not be withheld from pregnant women in areas where these drugs are indicated. 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. For the treatment of severe malaria in the first trimester, the advantages of artemisinin 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. The inade quacy of current knowledge on the use of these drugs during pregnancy should be understood by care providers, and if possible, all pregnancies exposed to these drugs should be monitored. Reports of all clinical outcomes, both successful and adverse events should be made to regulatory authorities.
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