Artemisinin (qinghaosu) is the antimalarial principle isolated by Chinese scientists from Artemisia annua L. It is a sesquiterpene lactone with a peroxide bridge linkage. Artemisinin is poorly soluble in oils or water but the parent compound has yielded dihydroartemisinin, the oil-soluble derivatives artemether and arteether, and the more water-soluble derivatives sodium artesunate and artelinic acid. These derivatives have more potent blood schizonticidal activity than the parent compound and are the most rapidly effective antimalarial drugs known. They are used for the treatment of severe and uncomplicated malaria (222). They are not hypnozoiticidal but gametocytocidal activity has been observed (13).

Formulations

A wide variety of formulations for oral or parenteral use or as suppositories are available (see below). China and Viet Nam continue to be the main producers of artemisinin and its derivatives.

Efficacy

The antimalarial activity of artemisinin and its derivatives is extremely rapid and most patients show clinical improvement within 1-3 days after treatment. However, the recrudescence rate is high when the drugs are used in monotherapy, depending on the drug dose administered, the duration of treatment and the severity of disease, but not at present on parasite resistance (34-38). Treatment for < 7 days gave unacceptably high recrudescence rates (39). So far there is no confirmed in vivo evidence of resistance of P. falciparum to artemisinin and its derivatives. The susceptibility of P. falciparum strains from the China-Lao People’s Democratic Republic and China-Myanmar border areas to various antimalarial drugs have been tested in vitro. The results have indicated declining susceptibility of P. falciparum to artemisinin derivatives (223).

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 therapy is recommended and efforts should be made to improve adherence to the treatment. Preliminary results from Africa indicate that combinations of artesunate plus amodiaquine or sulfadoxine-pyrimetha-mine are highly efficacious, although efficacy may be compromised in areas with moderate to high levels of resistance to sulfadoxine-pyrimethamine (224, 225;
P. Olliaro, personal communication)

These compounds are not recommended for use in the treatment of malaria due to P. vivax, P. malariae or P. ovale since other effective antimalarial drugs are available for this purpose. However, they may be used in the absence of micro-scopic diagnosis if they are the recommended first-line treatment.

Use in pregnancy

Preclinical studies have consistently shown that artemisinin and its derivatives do not exhibit mutagenic or teratogenic activity, but all of these drugs caused fetal resorption in rodents at relatively low doses of 1/200-1/400 of the LD50,
i.e. > 10 mg/kg, when given after the sixth day of gestation (226). Reports on the use of these drugs during pregnancy are limited (227, 228). However, malaria can be particularly hazardous during pregnancy. Artemisinin and its derivatives are therefore the drugs of choice for severe malaria and can be used for treatment of uncomplicated malaria during the second and third trimester of pregnancy in areas of multiple drug resistance (229). Owing to lack of data, their use in the first trimester is not recommended. The inadequacy of current knowledge on the use of these drugs during pregnancy should be understood by prescribers and all such use should, in principle, be monitored. Clinical outcomes of both a successful and adverse nature should be reported to regulatory authorities.

Drug disposition

High-performance liquid chromatography-electron capture detection (HPLCECD) and bioassay methods for studying the pharmacokinetics of artemisinin and its derivatives have now been validated. HPLC-ECD detects separately the parent compound and the major metabolite, dihydroartemisinin, whereas bioassays measure total activity, i.e. parent compound plus metabolite(s). Both methods are cumbersome and only a limited number of laboratories have the capability of conducting assays, especially using HPLC-ECD, which requires a reductive-mode electrochemical analysis and must be performed under oxygen-free conditions. An alternative HPLC method that uses ultraviolet detection is somewhat easier and quicker to use. So far, all methods are for plasma only; no method is available to measure levels in whole blood. With few exceptions, the lower limit of detection of HPLC-based methods is = or <5mg/ml.

Oral bioavailability varies with the derivative and is influenced by disease status. All derivatives, but not artemisinin itself are metabolized to a common bioactive metabolite, dihydroartemisinin, at variable rates (230, 231).

Adverse effects

Extensive clinical trials in China, Myanmar, Thailand and Viet Nam demonstrated no acute cardiovascular or other vital organ toxicity. However, animal studies have demonstrated severe neurotoxicity following parenteral administration of very high doses of artemether or arteether. Both drugs produced a unique pattern of selective neuropathy with chromatolysis and necrosis of scattered neurons in vestibular, motor and auditory brain stem nuclei in rats, dogs and rhesus monkeys (232, 233). Such effects have not been observed with oral administration of any artemisinin derivative or with intravenous artesunate. This has led to the suggestion that the effect is related to specific molecules and their route of administration. The cause, however, appears to be due to sustainable high levels of the drugs and their metabolites, which may occur following intramuscular injection, rather than to the route of administration itself (T.G. Brewer, personal communication, 1996).

There is no clinical evidence to date of serious neurotoxicity resulting from the use of any artemisinin drug in humans in prospective studies of more than 10 000 patients or in the more than 2 million persons who have received these drugs (234, 235). In Thailand, full neurological examinations in more than 1 100 patients who had received an artemisinin drug showed no specific pattern of neurological abnormalities. Studies in Thailand and Viet Nam provided no evidence of any brain stem toxicity attributable to artemisinin and artesunate (236, 237). There is some concern about cerebellar dysfunction (238, 239), and prolonged or repetitive treatment with artemisinin and its derivatives, which may occur in areas of high transmission, must be viewed with caution. Additional studies to monitor subtle neurological changes and hearing loss are required, especially in patients undergoing repetitive treatment. Post-marketing surveillance in countries where these drugs are marketed and used is recommended.

A. ARTEMISININ

Formulations

• Tablets and capsules containing 250 mg of artemisinin (Viet Nam).
• Suppositories containing 100 mg, 200 mg, 300 mg, 400 mg or 500 mg of artemisinin (Viet Nam).

Efficacy

Artemisinin is a sesquiterpene lactone with a peroxide bridge linkage that appears to be responsible for its antimalarial activity. Artemisinin is a potent and rapidly acting blood schizonticide, eliciting shorter parasite clearance times than chloroquine or quinine and rapid symptomatic responses (240).

Artemisinin is poorly soluble in oils or water. Preclinical and clinical studies show that artemisinin is effective against parasites resistant to all other operationally used antimalarial drugs (240). It is not hypnozoiticidal. It reduces gametocyte carriage (13).

Use

To reduce the recrudesence rate and the risk of development of resistance, as well as to improve compliance, artemisinin should preferably be administered in combination with another effective blood schizonticide. The use of artemisinin as monotherapy should be limited to specific indications, such as in patients with a history of adverse reactions to the combination drug. When mono-therapy is used, a 7-day course of therapy is recommended and adherence to the treatment should be ensured.

When given as monotherapy to patients with uncomplicated falciparum malaria who have some degree of immunity, a 5-day oral regimen of artemisinin has generally proven to be curative.

Rectal formulations of artemisinin have a potentially important role to play in the treatment of uncomplicated falciparum infections in children who vomit oral medication, and as emergency treatment prior to referral in situations when parenteral antimalarial drugs are not available or cannot be administered. Studies in Viet Nam have shown the latter to be highly efficacious (241, 242).

Recommended treatment

Although oral artemisinin has been widely employed in the treatment of uncomplicated multidrug-resistant falciparum infections (243, 244), very few well-designed dose-finding studies of artemisinin and its derivatives have been published. The dosage schedules indicated below are based on available clinical data, as pharmacokinetic data are still insufficient for formulating treatment regimens. When used as monotherapy, a minimum 7-day course is required owing to the problem of recrudescent infections. If regimens of < 7 days are employed, combination with mefloquine is indicated to prevent such recrudescence. Pharmacokinetic modelling suggests that a mefloquine dose of 25 mg/kg provides better protection against development of resistance in combination therapy regimens than one of 15 mg/kg (N. White, personal communication, 2000).

Monotherapy 20 mg/kg in a divided loading dose on the first day, followed by 10 mg/kg once a day for 6 days.

Combination therapy

20 mg/kg in a divided loading dose on the first day, followed by 10 mg/kg once a day for two more days plus mefloquine (15-25 mg of base per kg) as a single or split dose on the second and/or third day.

In outpatient settings where adherence is questionable, combination with mefloquine (15 mg or 25 mg of base per kg) is indicated. Several clinical trials have shown that this is the most effective treatment of multidrug-resistant P. falciparum malaria (245-247). Mefloquine is administered on the second or third day because there is less risk of vomiting once the clinical condition has improved.

Rectal administration

In emergency pre-referral treatment of severe malaria or for patients who cannot take oral medication, artemisinin can be given by rectal administration before referral to hospital or before medication becomes possible (241, 242). This is intended as emergency management of malaria in life-treatening circumstances and may be provided on a presumptive diagnosis of malaria.

A single dose of 40 mg/kg should be given intarectally, then 20 mg/kg 24, 48 and 72 hours later, followed by oral treatment with an effective antimalarial drug.

Chemoprophylaxis

There is no rationale at present for using artemisinin for chemoprophylaxis.

Use in pregnancy

Artemisinin can be used for treatment of uncomplicated malaria during the second and third trimester of pregnancy in areas of multidrug resistance (229). Owing to lack of data, use in the first trimester of pregnancy is not recommended (see above).

Drug disposition

Oral artemisinin is rapidly but incompletely absorbed with peak concentrations 1-2 h after administration (248-250). Artemisinin is rapidly metabolized in vivo to dihydroartemisinin. The elimination half-life is 2-5 hours (249, 250). Bioavailability with rectal suppository formulations is 30% less than with oral administration, although there is large inter-individual variation. Studies comparing parasite clearance times following oral and rectal administration have led to the conclusion that therapeutic concentrations should be achieved with suppositories (251, 252). Suppositories have been shown to be as effective as parenteral anti-malarial drugs in clinical trials for the treatment of severe malaria (241, 242, 253).

Adverse effects

Adverse effects may include headache, nausea, vomiting, abdominal pain, itching, drug fever (254), abnormal bleeding and dark urine. Minor cardiac changes (mainly non-specific ST changes and first degree atrioventricular block) have been noted during clinical trials. These returned to normal after improvement of malaria symptoms. Experience indicates that artemisinin and its derivatives are less toxic than the quinoline antimalarial drugs, few adverse effects being associated with their use.

Prolonged or repetitive treatment with artemisinin and its derivatives must be treated with caution. Additional studies, which monitor subtle neurological changes and hearing loss, are required especially in patients undergoing repetitive treatment. Post-marketing surveillance is recommended in countries where these drugs are marketed and used .

Contraindications

Artemisinin is not recommended in the first trimester of pregnancy because of limited data.

Overdosage

There is no experience with overdosage with artemisinin.

B. ARTEMETHER

Formulations

• Capsules containing 40 mg of artemether (China).
• Composite tablets containing 50 mg of artemether (China).
• Ampoules of injectable solution for intramuscular injection containing 80 mg in

1 ml (China and France), or 40 mg in 1 ml for paediatric use (France).

Efficacy

Artemether is an oil-soluble methyl ether derivative of dihydroartemisinin. As with artemisinin, it is effective against P. falciparum resistant to all other operationally used antimalarial drugs (240). It is not hypnozoiticidal but it reduces gametocyte carriage (13).

Use

As with artemisinin, when artemether is used for the treatment of uncomplicated P. falciparum malaria, it should always be administered in combination with another effective blood schizonticide to prevent recrudescence and delay the selection of resistant strains. Monotherapy with oral or intramuscular artemether with a dose of 1-4 mg/kg per day for 3-5 days results in an unacceptable rate of recrudescence (255). The use of artemether as monotherapy should be limited to specific indications, such as in patients with a history of adverse reactions to the combination drug. When monotherapy is used, a 7-day course is recommended and efforts should be made to ensure adherence.

Artemether is not recommended for the treatment of malaria caused by P. vivax, P. ovale and P. malariae since other effective antimalarial drugs are available for this purpose. However, it may be used in the absence of microscopic diagnosis if the compound is the recommended first-line treatment.

Recommended treatment

Because well-designed dose-finding studies of artemether are limited, the dosage schedules outlined below for uncomplicated and severe malaria are based on available clinical data. When used as monotherapy, a minimum 7-day course is required to prevent recrudescence. If regimens of less than 7 days are employed, combination with mefloquine or another effective blood schizonticide is indicated.

Uncomplicated malaria

Monotherapy: 4 mg/kg loading dose on the first day, followed by 2 mg/kg once a day for 6 days.

Combination therapy

4 mg/kg once a day for 3 days, plus mefloquine (15 mg or 25 mg of base per kg) as a single dose or split dose on the second and/or third day.

Where adherence to the treatment is questionable, especially in outpatients, combination with mefloquine is indicated (256, 257). Cure rates of 95-98% have been demonstrated with this combination in multidrug-resistant areas (258). Mefloquine is administered on the second or third day because there is less risk of vomiting once the clinical condition has improved.

Severe malaria

3.2 mg/kg by the intramuscular route as a loading dose on the first day, followed by 1.6 mg/kg daily for a minimum of 3 days or until the patient can take oral therapy to complete a 7-day course. The daily dose can be given as a single injection. In children, the use of a tuberculin syringe is advisable since the injection volume will be small.

Chemoprophylaxis

Similar to artemisinin.

Use in pregnancy

Similar to artemisinin.

Drug disposition

The pharmacokinetics of artemether following oral administration appear to be similar to those for artemisinin with mean peak plasma concentrations and mean plasma half lives of 1-2 h and 2-3 h, respectively (259). The plasma concentrations of artemether are similar in healthy subjects and those with acute uncomplicated malaria. Plasma antimalarial activity is significantly greater with intramuscular administration than with oral use because the first-pass biotransformation is bypassed (260). Bioavailability of artemether following intramuscular administration was increased and clearance reduced in patients with acute renal failure (261).

Adverse effects

Toxicity studies in dogs and rats indicate that dose-dependent and potentially fatal neurotoxic effects may occur after intramuscular injection of artemether at doses higher than those used for malaria treatment (262). These changes can be widespread but mainly affect areas associated with vestibular, motor and auditory functions (232, 233). No similar findings have been reported in humans treated with normal therapeutic doses of artemether.

Contraindications

Similar to artemisinin.

Overdosage

Similar to artemisinin.

C. ARTESUNATE

Formulations

• Tablets containing 50 mg of sodium artesunate (China, France and Viet Nam) or 200 mg of sodium artesunate (Switzerland).
• Ampoules for intramuscular or intravenous injection containing 60 mg of sodium artesunate in 1 ml of injectable solution (China and Viet Nam).
• Suppositories of sodium artesunate (China).
• Rectal capsules containing 100 mg or 400 mg of sodium artesunate (Switzerland).

Efficacy

Artesunate, a water-soluble hemisuccinate derivative of dihydroartemisinin, is the most widely used member of this family of drugs. It is unstable in neutral solutions and is therefore only available for injections as artesunic acid. It is effective against P. falciparum resistant to all other operationally used anti-malarial drugs (240). It does not have hypnozoiticidal activity. It reduces gametocyte carriage rate (13).

Use

As with artemisinin, when artesunate is used for the treatment of uncomplicated

P. falciparum malaria, it should always be administered in combination with another effective blood schizonticide to prevent recrudescence and delay the selection of resistant strains. The use of artesunate as monotherapy should be limited to specific indications, such as in patients with a history of adverse reactions to the combination drug. When monotherapy is used, a 7-day course of therapy is recommended and efforts should be made to ensure adherence.

Artesunate is not recommended for the treatment of malaria caused by P. vivax,
P. ovale and P. malariae since other effective antimalarial drugs are available for this purpose. However, it may be used in the absence of microscopic diagnosis if the compound is the recommended first-line treatment.

Recommended treatment

Giving a dose twice daily offered no advantage over once daily dosing (34). While 7-day regimens have a therapeutic advantage over 5-day regimens, this might be offset by decreased patient adherence to the treatment; recrudescence rates of 50% are reported following 3-day regimens regardless of the dosage used (263, 264). The shorter courses provided higher cure rates when a double dose was given on the first day of treatment or if the drugs were combined with a longer-acting single-dose antimalarial such as mefloquine (254, 263, 265-267). A regimen of 3-5 days of artesunate in combination with mefloquine given either concomitantly or sequentially provides cure rates of nearly 100% (258, 268, 269).

Because well-designed dose-finding studies of artesunate are limited, dosage schedules are based on available clinical data. When used as monotherapy, a minimum 7-day course is required to prevent recrudescence. If regimens of less than 7 days are employed, combination with mefloquine or another effective blood schizonticide is indicated. A once-daily regimen has been shown to have similar parasite and fever clearance times as a twice-daily regimen (270).

Uncomplicated malaria

Monotherapy: 4 mg/kg loading dose on the first day, followed by 2 mg/kg once a day for 6 days.

Combination therapy

4 mg/kg once a day for 3 days, plus mefloquine (15 mg or 25 mg of base per kg) as a single dose or split dose on the second and/or third day (256).

Where adherence to the treatment is questionable, especially in an outpatient situation, combination with mefloquine (15 or 25 mg of base per kg) is indicated (253, 256-258, 270, 271).

Recent studies in Africa have demonstrated that combinations of artesunate (oral administration of 4 mg/kg daily for 3 days) plus a single dose of sulfadoxine-pyrimethamine on the first day are highly efficacious, although efficacy appears to be reduced in areas with pre-existing moderate levels of sulfadoxine-pyrimethamine resistance (225). Other studies have demonstrated the efficacy of combinations of amodiaquine, 25 mg/kg over 3 days, plus artesunate, 4 mg/kg daily for 3 days (P. Olliaro, personal communication, 2000). The impact of the combination of sulfadoxine-pyrimethamine and artesunate on the development of resistance and the level of malaria transmission is being evaluated in a large-scale trial in the United Republic of Tanzania and in southern Africa (South Africa, Swaziland and Mozambique).

Severe malaria

2.4 mg/kg by the intramuscular route followed by 1.2 mg/kg at 12 and 24 h, then 1.2 mg/kg daily for 6 days. If the patient can swallow, the daily dose can be given orally.

2.4 mg/kg intravenously on the first day followed by 1.2 mg/kg daily until the patient can take orally artesunate or another effective antimalarial drug.

Drug disposition

The pharmacokinetics of artesunate following oral administration appear to be similar to those for artemisinin, with mean peak plasma concentrations and mean plasma half-lives of 1-2 h and 2-3 h, respectively. The plasma concentrations of artesunate are more erratic following administration by suppository compared to the intravenous route, but inadequate absorption is unusual (235).

Adverse effects

Prospective clinical studies of more than 10 000 patients, and post-marketing surveillance of over 4 600 patients in Thailand has not shown any serious drug-related adverse reactions.

Rectal administration

In emergency pre-referral treatment of severe malaria or for patients who cannot take oral medication, artesunate can be given by rectal administration before referral to hospital or before oral medication becomes possible (238, 246). This is intended as emergency pre-referral management of malaria in life-threatening circumstances and may be provided to patients on a presumptive diagnosis of malaria.

A single dose should be given rectally (rectal capsules/suppositories, 10 mg/kg) as soon as possible once a diagnosis of malaria is made. If the rectal capsule is expelled within the first hour, another rectal capsule should be inserted immediately. A second dose might be required 24 h after the first dose if the patient is still unable to take oral medication at that time, and has not been able to access recommended parenteral treatment.

Table 15 indicates the number of rectal capsules to be inserted for each weight category and probable age category by weight. A new 50-mg suppository is being developed by WHO for infants but is not yet available for use.

There is no information on efficacy in patients with severe and complicated malaria who have organ and systems failure, including renal failure and liver disease. No studies have been undertaken with this formulation in pregnant or lactating women or in patients with diarrhoea.

Rectal artesunate should not be given for the prevention of malaria.

D. DIHYDROARTEMISININ

Formulations

• Tablets containing 20 mg, 60 mg or 80 mg of dihydroartemisinin (China).
• Suppositories containing 80 mg of dihydroartemisinin (China).

Efficacy

Dihydroartemisinin is the active metabolite of artemisinin and its derivatives.

These derivatives have more potent blood schizonticidal activity than the parent compound. Dihydroartemisinin is the most potent antimalarial of this group of compounds but it is also the least stable.

Oral dihydroartemisinin has been shown to be effective in the treatment of multidrug-resistant uncomplicated P. falciparum malaria in China, but experience outside that country is limited (227). Recent studies in Thailand demonstrated a cure rate of 90% in 52 patients given 120 mg of dihydroartemisinin followed by 60 mg once daily for 7 days, i.e. a total adult dose of 480 mg (S. Looareesuwan, personal communication, 1995).

Dihydroartemisinin does not have activity against hypnozoites. It reduces gametocyte carriage rate (13).

Use

Dihydroartemisinin appears to offer no advantage over artesunate or artemether for the treatment of uncomplicated or severe malaria.

Dihydroartemisinin is not recommended for the treatment of malaria caused by
P. vivax, P ovale and P. malariae since other effective antimalarial drugs are available for this purpose. However, it may be used in the absence of micro-scopic diagnosis if the compound is the recommended first-line treatment.

Recommended treatment

4 mg/kg in a divided loading dose on the first day followed by 2 mg/kg daily for 6 days.

Data on dihydroartemisinin are very limited, but the currently recommended dosage is as shown above. Dihydroartemisinin has been used in combination with mefloquine (153, 272, 273). Short courses of treatment of less than 5 days have higher recrudescence rates (272, 274).

Drug disposition

Oral dihydroartemisinin is rapidly absorbed and has a short elimination half-life although little is known of its metabolism. Peak plasma concentrations are achieved in 1-2 h and the drug disappears from the circulation within 8-10 h.

E. ARTEETHER

Formulations

Ampoules containing 150 mg of arteether in 2 ml of injectable solution (India, Netherlands).

Efficacy

Arteether is the oil-soluble ethyl derivative of dihydroartemisinin. Clinical trials in India have indicated that it is an effective and rapidly-acting drug for the treatment of uncomplicated (275) and severe falciparum malaria (276, 277).

Use

When arteether is used for the treatment of uncomplicated P. falciparum malaria, it should always be administered in combination with another effective blood schizonticide to improve its efficacy and delay the selection of resistant strains. A recrudescence rate of 6-14% has been observed with the use of alpha, beta-arteether (275). The use of arteether as monotherapy should therefore be limited to specific indications, such as in patients with a history of adverse reactions to the combination drug. When given as monotherapy, a 7-day course is recommended and efforts should be made to ensure adherence.

Arteether is not recommended for the treatment of malaria caused by P. vivax, P. ovale and P. malariae since other effective antimalarial drugs are available for this purpose.

Recommended treatment

The recommended regimen according to the Manufacturer is:

For adults, 150 mg/day administrated once daily by the intramuscular route for 3 days.

For children, 3 mg/kg per day by the intramuscular route for 3 days.

Drug disposition

Intramuscular arteether has the lowest bioavailability (34%) of all the artemisinin derivatives tested in the rat, with approximately 14% converted to dihydroartemisinin. It has a long elimination half-life (> 20 h) and is more stable and more lipophilic than the other artemisinin compounds.

Adverse effects

Animal studies have demonstrated limited symptomatic and pathological evidence of neurotoxicity following parenteral administration of high doses (8-24 mg/kg per day for 14 days) of either arteether or artemether (232, 264). Both drugs produced a unique pattern of selective neuronopathy with chromatolysis and necrosis of scattered neurons in vestibular, motor and auditory brain stem nuclei in rats, dogs and rhesus monkeys (232, 233).

F. ARTELINIC ACID

Efficacy

Artelinic acid is a water-soluble derivative of artemisinin and is thought to be more stable than artesunate in solution (278) thus offering the potential for oral administration. The compound is still under investigation. It is the only preparation undergoing transdermal studies (279).