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Artemisinin derivatives
General information
The herb Qinghaosu ( Artemisia annua ) has been known to Chinese medicine for centuries and was used in the treatment of fevers, in particular malaria fever; it is not clear why it did not become more widely used elsewhere. The plant can be grown in locations other than China, and field studies in propagating and growing the plant are being carried out in many parts of the world. In 1979 the Qinghaosu Antimalarial Coordinating Research Group reported their experience with four formulations of qinghaosu in both Plasmodium vivax and Plasmodium falciparum malaria [ , ].
Artemisinin is an antimalarial constituent isolated from Qinghao. It is a sesquiterpene lactone with an endoperoxide bridge, structurally distinct from other classes of antimalarial agents. Several derivatives of the original compound have proved effective in the treatment of Plasmodium falciparum malaria and are currently available in a variety of formulations: artesunate (intravenous, rectal, oral), artelinate (oral), artemisinin (intravenous, rectal, oral), dihydroartemisinin (oral), artemether (intravenous, oral, rectal), and artemotil (intravenous). Artemisinic acid (qinghao acid), the precursor of artemisin, is present in the plant in a concentration up to 10 times that of artemisinin. Several semisynthetic derivatives have been developed from dihydroartemisinin [ ].
Artemether
Artemether is a methyl ether derivative of dihydroartemisinin. It is dispensed in ampoules for intramuscular injection suspended in groundnut oil and in capsules for oral use. Like artesunate and artemisinin it has been used for both severe and uncomplicated malaria. Artesunate is probably faster-acting than the other two.
Artemotil (arteether)
Artemotil is the ethyl ether derivative of dihydroartemisinin. It was the choice of the WHO for development and was considered less toxic, because one would expect it to be metabolized to ethanol rather than methanol. It is also more lipophilic than artemether, a possible advantage for accumulation in brain tissues. The beta anomer was chosen since it is a crystalline solid and relatively easy to separate from the alpha anomer, which is liquid; it was necessary to choose a single anomer because of the more complex rules for the development of a drug with two anomers in the USA.
Artesunate
Artesunate is a water-soluble hemisuccinate derivative, available in parenteral and oral formulations. The parenteral drug is dispensed as powdered artesunic acid. Neutral aqueous solutions are unstable. Artesunate is effective by the intravenous, intramuscular, and oral routes in a dose of 10 mg/kg given for 5–7 days. The combination with mefloquine is very effective even against highly multiresistant strains of Plasmodium falciparum ; the combination must be given for at least 3 days.
None of these medications has yet been registered for use in Europe or North America. In recent years there has been a substantial increase in our knowledge of their safety, efficacy, and pharmacokinetics. Higher cure rates are achieved when they are combined with longer-acting antimalarial drugs, such as mefloquine. After years of continued use, the sequential use of artesunate and mefloquine remains an effective treatment in areas of multidrug resistance in South-East Asia and provides an impetus for the evaluation of other artesunate-containing combination regimens for the treatment of uncomplicated malaria, such as artemether + benflumetol [ ].
Mechanism of action
All three Artemisia derivatives are quickly hydrolysed to the active substance dihydroartemisinin. They produce a more rapid clinical and parasitological response than other antimalarial drugs. There are no reports of significant toxicity, and as late as 1994 there was no convincing evidence of specific resistance, but chloroquine-resistant Plasmodium berghei is resistant to artemisinin as well. The recrudescence rate is fairly high [ ].
The mode of action is not fully known. There is strong evidence that the antimalarial activity of these drugs depends on the generation of free radical intermediates; free radical scavengers, such as ascorbic acid and vitamin E, therefore antagonize the antimalarial activity.
Drug activation by iron and heme may explain why endoperoxides are selectively toxic to malaria parasites. The malaria parasites live in a milieu of heme iron, which the parasite converts into insoluble hemozoin. Chloroquine, which binds heme, antagonizes the antimalarial activity of artemisinin.
Drug studies
Observational studies
Some impression of possible adverse reactions in humans can be gained from a primarily pharmacokinetic study, in which artemotil solution in sesame oil was given intramuscularly. The half-life was 25–72 hours. Adverse reactions in 23 subjects after the single dose included local pain in two, bitter taste and dryness of the mouth in one, and a mild but slightly itching papular rash that persisted for 14 days in another. There were no biochemical or electrocardiographic changes. Similar adverse reactions were seen after 5 days of therapy in 14 of the 27 subjects; there was local pain in three, metallic taste in two, flu-like symptoms in three, and in two a maculopapular rash, which receded within 24 hours. One subject developed shivering, clammy hands and feet, dizziness, headache, nausea, and a metallic taste in the mouth, all lasting for about an hour, but the same reaction occurred after an injection of sesame oil only. Apart from some increase in eosinophil count in all groups, there were no significant hematological changes [ ].
In 25 patients with acute uncomplicated Plasmodium falciparum malaria treated with artemotil (3.2 mg/kg followed by either 1.6 mg/kg or 0.8 mg/kg), the most frequent adverse events were headache, dizziness, nausea, vomiting, and abdominal pain; two patients complained of mild pain at the site of injection [ ].
In a postmarketing surveillance study of artemotil in 300 patients, 294 (98%) were cured, five improved, and one did not show any change [ ]. The adverse reactions were mild headache, nausea, vomiting, and giddiness.
Combination therapy
The artemisinin derivatives are limited by an unacceptable incidence of recrudescence with monotherapy, and they therefore need to be used in combination. A summary of prospective trials that looked specifically for adverse reactions showed that artemisinins alone are very well tolerated [ ]. The same study showed no evidence of adverse interactions of artesunate with mefloquine, with an incidence of adverse reactions similar to that expected from malaria and mefloquine (25 mg/kg) together. Reducing doses of mefloquine increases recrudescence rates to unacceptable levels [ ]. Combinations of artemisinins with quinine, co-trimoxazole, and doxycycline are well tolerated.
Artesunate + amodiaquine
Of 1017 patients aged 6 months to 10 years with uncomplicated malaria, 400 were randomized to chloroquine (25 mg/kg over 3 days) + a single dose of sulfadoxine–pyrimethamine (sulfadoxine 25 mg/kg, pyrimethamine 1.25 mg/kg); amodiaquine 25 mg/kg over 3 days + sulfadoxine–pyrimethamine; or amodiaquine + artesunate (4 mg/kg/day for 3 days); 396 were assessed for safety [ ]. There were no major adverse events.
Amodiaquine and artesunate have been compared alone and in combination for the treatment of uncomplicated malaria in 87 children aged 1–15 years, who were randomly assigned to amodiaquine 10 mg/kg (n = 27), artesunate 4 mg/kg (n = 27), or amodiaquine + artesunate (n = 33) [ ]. All the regimens were well tolerated and there were no major adverse events. Hematological profiles and serum transaminases were normal in all the groups. Only one child treated with artesunate developed a transient rise in alanine transaminase, which normalized after a few days.
Artemether + benflumetol
A large trial of the first fixed-dose combination of an artemisinin derivative likely to be licensed (artemether + benflumetol) had disappointing relapse rates compared with mefloquine monotherapy [ ]. In the 126 patients who took artemether + benflumetol there were no adverse reactions attributed to drug treatment. However, less than 70% of patients were cured at 28 days. Benflumetol may be more effective at higher concentrations [ ] but toxicity studies are lacking.
Artesunate + clindamycin
The combination of artesunate + clindamycin (2 mg/kg + 7 mg/kg 12 hourly for 3 days) has been compared with quinine + clindamycin (15 mg/kg + 7 mg/kg 12 hourly for 3 days) in 100 patients in a randomized comparison [ ]. Asexual parasite clearance time was faster with artesunate + clindamycin (29 versus 46 hours), and patients who took artesunate + clindamycin also experienced a shorter time to fever clearance (21 versus 30 hours). Both regimens were well tolerated and no severe adverse events were recorded. However, one patient who took artesunate + clindamycin had diarrhea and two who took quinine + clindamycin developed diarrhea and tinnitus.
Artesunate + lumefantrine
There has been a meta-analysis of 15 trials from Africa, Europe, and Asia of the use of varying doses of artesunate plus lumefantrine compared with several alternative antimalarial drugs in 1869 patients conducted by the manufacturers Novartis into its clinical safety and tolerability in the treatment of uncomplicated malaria [ ]. The most common adverse events were gastrointestinal—nausea (6.3%), abdominal pain (12%), vomiting (2.4%), anorexia (13%)—or central nervous—headache (21%) or dizziness (16%). There were 20 serious adverse events with artesunate plus lumefantrine, but only one (hemolytic anemia) was possibly due to artesunate plus lumefantrine. There was no QT prolongation associated with artesunate plus lumefantrine.
Artesunate + mefloquine
Artesunate has been combined with mefloquine in areas with a high prevalence of multiresistant Plasmodium falciparum in Thailand and the Thai-Burmese border. In a study reported in 1992 in 127 patients who were followed for 28 days, group A took artesunate 100 mg immediately and then 50 mg every 12 hours for 5 days (total 600 mg), group M took mefloquine 750 mg and another 500 mg 6 hours later, and group AM took first artesunate and then the two doses of mefloquine [ ]. Fever and parasite clearance time were significantly shorter in the two groups treated with artesunate. Table 1 gives the results and adverse reactions. The combination of artesunate with mefloquine was more effective than either drug alone. However, the trial design was such that the patients who took both drugs were in fact treated twice, so the findings did not prove synergism between the two drugs.
Table 1
Adverse effects of artesunate with or without mefloquine in acute uncomplicated malaria tropica
| Artesunate | Mefloquine | Artesunate + mefloquine | |
|---|---|---|---|
| Total number of patients (M/F) | 38/4 | 39/4 | 39/3 |
| Number of patients with 18-day follow-up | 40 | 37 | 39 |
| Number (%) cured at 28 days | 35 (88) | 30 (81) | 39 (100) |
| Fever clearance time (hours) | 35 | 70 | 38 |
| Parasite clearance time (hours) | 36 | 64 | 38 |
| Headache (%) | 14 (33) | 17 (39) | 12 (28) |
| Vomiting (%) | 8 (19) | 7 (16) | 11 (26) |
| Nausea (%) | 6 (14) | 9 (20) | 9 (21) |
| Dizziness (%) | 6 (14) | 8 (18) | 5 (11) |
| Diarrhea (%) | 3 (7) | 1 (2) | 1 (2) |
| Itching and rash (%) | 3 (7) | 0 | 1 (2) |
| Abdominal pain (%) | 2 (4) | 1 (2) | 1 (2) |
In a second Thai study, 652 adults and children were treated with artesunate plus mefloquine [ ]. A single dose of artesunate 4 mg/kg plus mefloquine 25 mg/kg gave a rapid response but did not improve cure rate. Artesunate given for 3 days in a total dose of 10 mg/kg plus mefloquine was 98% effective. The incidence of vomiting was significantly reduced by giving the mefloquine on day 2 of the treatment. There were no adverse reactions attributed to artesunate.
Adults and children with uncomplicated malaria were randomized to either a combined formulation of artesunate + mefloquine (n = 251) or artesunate and mefloquine as separate tablets (n = 249) [ ]. The PCR cure rates after 63 days were 92% (95% CI = 88, 96) with the combined formulation and 89% (85, 93) with the separate tablets. Patients who took the separate tablets had more vomiting.
Artesunate + pyrimethamine + sulfadoxine
In Irian Jaya, a randomized, controlled trial (n = 105; 88 children) of oral artesunate (4 mg/kg od for 3 days) with pyrimethamine (1.25 mg/kg) + sulfadoxine or pyrimethamine + sulfadoxine alone (same dose) showed reduced gametocyte carriage and reduced treatment failure rates (RR = 0.3; 95% CI = 0.1, 1.3) in the combination group [ ]. Self-limiting adverse events of combination treatment were mild diarrhea (2.1%), rashes (4.3%), and itching (2.1%).
In a double-blind, randomized, placebo-controlled trial in Gambian children with uncomplicated falciparum malaria treated with pyrimethamine + sulfadoxine (25/500 mg; n = 600) or pyrimethamine + sulfadoxine combined with two regimens of oral artesunate (4 mg/kg, n = 200 or 4 mg/kg od for 3 days, n = 200), there were mild adverse events, such as headache, anorexia, nausea, vomiting, abdominal pain, and diarrhea, in a high proportion of children (56%) [ ]. Combination treatment with artesunate was associated with more rapid parasite clearance and less gametocytemia. Three-dose artesunate conferred no additional benefit over the one-dose regimen.
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