Artemisinin Derivatives: First-Line Antimalarial Agents?

ABSTRACTS & COMMENTARY

Synopsis: Two recent articles provide some good news regarding the safety and promise of artemisinin and its compounds as first-line agents in the treatment of drug-resistant malaria, but other studies suggest caution.

Sources: Kamchonwongpaisan S., et al. Artemisinin neurotoxicity: Neuropathology in rats and mechanistic studies in vitro. Am J Trop Med Hyg 1997;56:7-12; Benakis A, et al. Pharmacokinetics of artemisinin and artesunate after oral administration in healthy volunteers. Am J Trop Med Hyg 1997;56:17-23.

Artemisinin and its derivatives comprise a promising new class of antimalarial agents, structurally unrelated to any other antimalarials. Artemisinin derivatives are highly effective drugs in the treatment of P. falciparum malaria.1,2 They lead to faster parasite and fever clearance times than other agents with particularly good activity against multidrug resistant strains, and are in widespread use in southeast Asia, where resistance to antimalarials is common.3 Few adverse effects have been observed in humans, but, presently, the preclinical and toxicity data are insufficient for licensing of these drugs, and neurotoxicity reported in only animals, including primates11 and possibly humans,10 remains concerning.4 A series of articles appeared in the January 1997 issue of the American Journal of Tropical Medicine and Hygiene. One provides further insight into neurotoxicity, which appeared to occur only at extremely high doses, at least in rats. Another elaborates on the pharmacokinetics of oral artemisinin compounds in human volunteers.

Kamchonwongpaisan et al described neuropathology in rats and in vitro mechanisms of neurotoxicity. The artemisinin derivative, arteether, is an oil soluble intramuscular preparation that is known to be neurotoxic when administered to rats at doses of 50 mg/kg/d for five or six days. Manifestations of toxicity included shaking and loss of balance. Neuropathologic evaluation revealed acute neuronal necrosis in the vestibular nuclei, most evident in the lateral and superior vestibular nuclei, as well as the red nuclei in the midbrain. Other nearby structures were spared. In this study, when animals received 25 or 30 mg/kg/d, no neurologic symptoms occurred, and there was no demonstrable neuropathology.

Selective uptake of artemisinin by P. falciparum generates free radicals that lead to the alkylation of several specific malarial proteins.5 Studies done on mouse neuroblastoma cells (Neu 2a), using P. falciparum infected RBCs as controls, compared mechanisms of neurotoxicity and antimalarial activity, drug intake, drug distribution, and protein alkylation. Under identical conditions in vitro, Neu 2a cells took up far less radiolabeled artemisinin derivative (1%) than did malarial parasites (30%). Furthermore, protein alkylation, a permanent alteration, could be observed in Neu 2a cells but occurred at a much slower rate than in P. falciparum-infected erythrocytes. In summary, neurotoxicity is observed only at doses many times higher than those that have potent antimalarial activity in mice, and drug uptake is far less in neuronal cells than in malaria-infected RBCs.

Benakis et al reported on the pharmacokinetics of oral preparations of artemisinin and artesunate determined by HPLC analysis and a new electrochemical detection method. In a previous study, this group established the pharmacokinetics of artesunate in malaria patients after IM and IV administration, which showed that artemisinin disappears quickly from plasma yielding dihydroartemisinin, the metabolite associated with parasite clearance. Here, seven healthy physician volunteers ages 30-65 were studied before and after receiving a single dose of artemisinin 500 mg po (2 LACTAB 250 mg coated tablets). Artesunate 200 mg po (Plasmotrim 200 mg LACTAB coated tablets) was administered six months later, and patients were studied similarly. The above doses represent those effectively used in the treatment of malaria, although repeat dosing is necessary for complete treatment. Vital signs and blood tests were performed before and after dose administration (time 0, 15, 30 min and 1, 1.5, 2, 3, 4, 8, and 24 hours after.) An EKG was recorded at time 0, 30 minutes, and 24 hours. Both artemisinin and artesunate were well tolerated. One subject reported a metallic taste after administration of artemisinin. No complaints or neurologic symptoms were reported, and vital signs remained within normal limits, as did routine laboratory and EKGs.

A new extraction method was employed for recovery and purity of plasma artemisinin, artesunate, and dihydroartemisinin extracts by HPLC separation and electrochemical detection. The analytical method used was validated with an extraction efficiency of 100%. Low concentrations of artemisinin appeared after 15 minutes with maximal values observed 1-3 hours after administration. Plasma levels decreased slowly and were undetectable (< 10 ng/mL) 24 hours after administration. Artesunate levels remained very low, detected only 15 and 30 minutes after administration in five of six volunteers. Dihydroartemisinin was detected in all subjects 15 minutes after administration of artesunate, with a maximum concentration between 30 and 60 minutes. Dihydroartemisinin decreased more slowly than artesunate and was undetectable three hours after administration. The mean elimination half-life after oral administration of 500 mg of artemisinin was 4.34 hours (± 3.46). The mean elimination half-life of artesunate after oral administration of 200 mg was 0.65 hours (± 0.21 hours). This study confirms that both orally administered artemisinin compounds are rapidly and adequately absorbed, then rapidly eliminated from the blood. The data strongly suggest that the pharmacodynamic action of artesunate is due to dihydroartemisinin and that doses should be given every three hours.

COMMENT BY MARIA D. MILENO, MD

The increasing need for therapy of drug-resistant malaria has led to the development of artemisinin compounds, which have come a long way from their initial use in 340 A.D. by traditional Chinese practitioners as herbal remedies for fever.1 The mechanisms of action of these endoperoxide-containing compounds is such that in the presence of intraparasitic iron the drugs are converted into free radicals and other intermediates which then alkylate specific malaria target proteins.5 Thousands of patients have been treated with artesunate or artemisinin in clinical trials conducted in Thailand,6,7 Vietnam,3 and Tanzania.8 These drugs have repeatedly proven to be rapidly effective and safe. They are licensed for use in southeast Asia. Oral, intravenous, intramuscular, and rectal suppository formulations are available. Reports of toxicity in animals and lack of pharmacokinetic data have kept these products from meeting U.S. licensing standards.

Recrudescent infections are associated with high gametocyte carriage rates in an area of malarious hill forest on the western boarder Thailand.6 One study in western Thailand suggests that artemisinin derivatives may actually prevent the spread of malaria, as retreatment of recrudescent infections reduced subsequent gametocyte carriage.6 The pharmacokinetic data presented above suggest that dosing is indicated every three hours; however, optimal duration of therapy was not confirmed. Recrudescence rates are high when artemisinin derivatives were used alone for less than five days.7-9 Combinations with other antimalarials may also prove useful.

Together, the two reviewed articles provide some good news regarding the safety and promise of these compounds as first-line agents in the treatment of drug-resistant malaria and warrant a close look. While I was reviewing this material for TMA Update, Miller and Panosian published a letter and case report in the May 1st issue of the New England Journal of Medicine regarding a patient who developed acute cerebellar dysfunction, temporally associated with the use of oral artesunate.10 The case involved an American geologist in Ghana who had been treated for falciparum malaria. Gait became unsteady two days after completing a five-day course of oral artesunate. Over the next week, worsening ataxia and slurred speech occurred. Neurologic sequelae of his illness, possibly related to artesunate toxicity, continued over a four-month period; the authors indicated this to be an unlikely consequence of falciparum malaria.

In addition, Petras et al reported their rhesus monkey studies in the April issue of the American Journal of Tropical Medicine and Hygiene, showing dose-dependent brainstem neurotoxicity in the primate model associated with arteether administration for 14 days.11 Toxicity was demonstrated at the histopathological level, but it was not clinically evident in these experimental animals. Injury was greatest at the 24 mg/kg/d dose level, with damage to the reticular, vestibular, and auditory systems. Although the data reviewed prior to these reports do not seem to indicate that neurotoxicity will be a major issue in human usage of the artemisinin derivatives, given the current dosing regimens, any information on potential clinical neurological side effects of these agents in treated patients should be reported.

References

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2. Skinner TS, et al. In vitro stage-specific sensitivity of Plasmodium falciparum to quinine and artemisinin drugs. Int J Parasitol 1996;26:519-525.

3. Tran TH, et al. A controlled trial of artemether or quinine in Vietnamese adults with severe falciparum malaria. N Engl J Med 1996;335:76-83.

4. Phillips-Howard PA, ter-Kuile FO. CNS adverse events associated with antimalarial agents. Fact or fiction? Drug-Saf 1995;12:370-383.

5. Meshnick SR, et al. Artemisinin and the antimalarial endoperoxides: From herbal remedy to targeted chemotherapy. Microbiol-Rev 1996;60:301-315.

6. Price RN, et al. Effects of artemisinin derivatives on malaria transmissibility. Lancet 1996;347:1654-1658.

7. Looareesuwan S. Overview of clinical studies on artemisinin derivatives in Thailand. Trans R Soc Trop Med Hyg 1994;88 (Suppl 1):9-11.

8. Hassan-Alin M, et al. Multiple dose pharmacokinetics of oral artemisinin and comparison of its efficacy with that of oral artesunate in falciparum malaria patients. Trans R Soc Trop Med Hyg 1996;90:61-65.

9. Augustijns P, et al. Transport of artemisinin and sodium artesunate in Caco-2 intestinal epithelial cells. J Pharm Sci 1996;85:577-579.

10. Miller LG, Panosian CB. Ataxia and slurred speech after artesunate treatment for falciparum malaria. N Engl J Med 1997;336:1328.

11. Petras JM, et al. Arteether: Risks of two-week administration in Macca Mulatta. Am J Trop Med Hyg 1997;56:390-396.