The mechanism of neurotoxicity of artemisinin and its derivatives is still unclear. A relationship to the potential of the peroxide bridge, which is present in all artemisinin derivatives, to generate toxic carbon-centered free radicals (oxidative stress) and metabolic stress (hypoxia, hypoglycemia) can cause mitochondrial changes resulting in the formation of pores in the mitochondrial membrane (permeability transition pores) with subsequent cellular degeneration (SMITH et al., 1997). The fact that depletion of glutathione seems to be a prerequisite for artemisinin neurotoxicity in mice represents additional evidence for the pathogenetic role of free radical mediated damage (SMITH et al., 2001).
In almost all studies with toxic effects of artemisinin compounds in animals, oil-based intramuscular injections were used as the route of administration. Most of these studies presented these compounds as toxic, not considering the underlying pharmacokinetic properties of oil-based formulations. It is also noteworthy that the volumes of injected oil in most animal studies were significantly larger. Such a relatively large volume would undoubtedly act as a reservoir for the administered drugs, ensuring a sustained release from the site of injection (TITULAER et al., 1990). In another study, plasma concentrations of artemether and its metabolite dihydroartemisinin declined much faster after oral administration compared to a formulation based on arachis oil after intramuscular application (TEJA-ISAVADHARM et al., 1996). The duration of intramuscular administrations, however, is generally limited to less than 4 days in humans. Such a short duration is not expected to result in any accumulation of the compounds and therefore does not possess an increased risk of toxicity. In a recent investigation (HIEN et al., 2003) on malaria patients who died of malaria despite treatment with high doses of i. m. artemether (4 mg/kg followed by 2 mg/kg every 8 h) or quinine (20 mg salt/kg followed by 10 mg/kg every 8 h), the median time to death was 76.5 hours in the artemether group and 31.1
hours in the quinine group. This observation supports a longer standing effect of arthemether compared to quinine salt. Morphological changes associated with the toxic effects of artemether observed in animal studies were thought to be specific comprising damage to neurons, neuroparenchyma, and axons. However, in human patients with malaria there was no evidence of neurotoxic effects of artemether (HORTOBAGYI and AL-SARRAJ 2008).
Whatever the mechanism of the neurotoxicity of artemisinins is, it is evident that the observed toxicity in laboratory animals is related more to the presence of these compounds in a high concentration for a long period of time. Obviously, if eliminated rapidly from the body, artemisinin drugs possess a low toxic potential. Oral intake is the most frequently used route of administration. In patients with intramuscular administration a conversion to oral dosing is normal practice once signs of recovery occurred and the number of parasites decreased, normally within 2-3 days.
Obviously, oil injections can act as a depot and result in sustained release of the drugs from the site of injection. The combination of short treatment time, small injection volume, and lower doses compared to animal studies make the development of neurotoxic side effects in humans very unlikely. New formulations of artemisinin have recently been synthesized showing improved bioavailability as well as stability (GABRIELS and PLAIZIER-VERCAMMEN, 2003; JUNG et al., 2002;
MAGUEUR et al., 2003; WONG and YUEN, 2001). It is generally argued that short artemisinins half-lives necessitate more frequent applications. Increasing the half-life of these compounds by chemical manipulation or pharmaceutical formulation would improve the therapeutic outcome. The anti-parasitic action of these compounds is much more complex than a linear drug-effect relationship and constant drug levels are not necessary for a satisfactory effect. Moreover, animal data suggest that persistent drug plasma levels seemed to be associated with an increased risk for toxicity, which might be manifested at clinically relevant doses. The most common use of artemisinin drugs is as once- or twice-daily oral doses for treatment of uncomplicated malaria. Due to their short elimination half-lives, no accumulation is expected in these patients. Moreover, these compounds exhibit the fastest known parasite clearance, with relief of the clinical symptoms within the first day and low or no detectable parasites within 2-3 days after treatment initiation. This fast action is likely to result in poor compliance and aborted intake, which might increase the risk
of resistance. However, shorter administration times would also result in lower risk of drug toxicity effects.
The pharmacological activity of a drug is related to the degree and rate of exposure, even if the effect manifests itself long after the compound has been eliminated from the body, or is present in minute amounts. The limited available data on the pharmacokinetics of these compounds are demanding for caution of taken up by high doses and for long periods. In conclusion, the signs of toxicity of the artemether in laboratory animals, and the lack of similar findings in humans, can be explained by persistent drug concentrations after repeated intramuscular administrations using oil-based vehicles in animals. Oral intake, the most commonly used route of administration in humans, results in fast absorption and elimination of these compounds. Comparing the animal and human toxicity of artemisinins, the pharmacokinetic properties of these drugs after various administration routes should be considered (GORDI and LEPIST, 2004).
6 SUMMARY
Investigations on the neurotoxic effects of the anti-malaria components artemether and artemether-lumefantrine in dogs
Mohamed A. E. Elhensheri
Artemisinin compounds are now used as first-line antimalarial drugs but converse information is available regarding animal and human toxicity. The aim of this study was a morphological evaluation of brains and ears of dogs after administration of multiple-doses of artemether or artemether-lumefantrine for three and eight-days in two various modes of application (i. m. or orally).
Dogs treated with high-doses (40 mg/kg b. w.) of artemether for eight days intramuscularly displayed significantly more neuropathological changes in the brain stem with various degrees of severity compared to all other experimental groups of animals. The alterations in the brain occurred in a dose- and time-related and non-specific manner. The lesions included neuronal degeneration characterized by central chromatolysis, total chromatolysis, swelling and rounding of neurons, increased granular eosinophilic cytoplasm, vacuolization of cytoplasm and neuronal necrosis characterized by karyopyknosis, karyorrhexis and karyolysis. In addition, axonal damage in form of spheroid formation, and mild inflammatory changes were present. Reactive lesions were characterized by gliosis located in areas with neuronal damage. Occasionally mild inflammatory infiltrations were observed.
The pathogenesis of neurotoxicity is not well understood, but appears to be closely related to a sustained level of the circulating drug (prolonged exposure time) or a metabolite. Laboratory research on this topic has decreased in recent years, even as major questions regarding to neurotoxicity remained to be addressed. If effective pharmacovigilance is to be maintained with the continued increase in the use of artemisinins, it is particularly important that progress is made in these areas.
Although neurotoxicity in animal studies has been documented fairly well, the artemisinins have been increasingly deployed in the global fight against falciparum
malaria in humans, even though it cannot be completely ruled out that the artemisinin derivatives have a potential neurotoxic effect in humans.
7 ZUSAMMENFASSUNG
Untersuchungen über die neurotoxischen Wirkungen der Anti-Malaria-Substanzen Artemether und Artemether-Lumefantrin bei Hunden
Mohamed A. E. Elhensheri
Artemisinin-Verbindungen wurden zur Bekämpfung der Malaria entwickelt und werden derzeit als „First-Line“-Medikamente eingesetzt. Über ihre Toxizität bei Tieren und Menschen gibt es allerdings gegenteilige Informationen. Diese Studie diente der neuropathologischen Untersuchung von Hunden, die mit Artemether oder Artemether-Lumefantrin über drei oder acht Tage auf zwei verschiedenen Applikationsarten (i. m. oder per os) behandelt wurden.
Hunde, denen eine hohe Dosis Artemether (40 mg/kg Körpergewicht) intramuskulär über acht Tage appliziert wurde, zeigten signifikant mehr und schwerere Läsionen als die Kontrolltiere und alle anderen Behandlungsgruppen. Topographisch waren die Veränderungen insbesondere im Hirnstamm lokalisiert. Sie waren durch neuronale Degenerationen in Form von zentraler Chromatolyse, totaler Chromatolyse mit Zellschwellung, Granulierung oder Vakuolisierung des Zytoplasmas sowie neuronale Nekrosen gekennzeichnet. Darüber hinaus wurden axonale Schäden in Form von Sphäroidbildungen beobachtet. In Gebieten mit neuronalen Läsionen wurden auch reaktive Veränderungen festgestellt, die durch Gliosen charakterisiert waren. Gelegentlich wurden geringfügige entzündliche Veränderungen nachgewiesen.
Die genauen Mechanismen der Neurotoxizität der Substanzen sind nicht bekannt, aber wahrscheinlich stehen diese Wirkungen mit einer länger bestehenden, hohen Konzentration der zirkulierenden Substanz oder einer ihrer Metaboliten in einem engen Zusammenhang. Bemerkenswerterweise wurde die Forschung in diesem Bereich in den letzten Jahren eingeschränkt, obwohl noch viele wichtige Fragen hinsichtlich zur Neurotoxizität ungelöst sind. Wenn in den kommenden Jahren die
permanente Pharmakovigilanz im Hinblick auf dieses Fertigarzneimittel erfolgreich ist, wird mit der weiteren Zunahme der Nutzung von Artemisininen zu rechnen sein.
Trotz der Neurotoxizität in Tierstudien können die Artemisinine zunehmend im globalen Kampf gegen die falciparum Malaria bei Menschen zum Einsatz kommen, auch wenn nicht absolut ausgeschlossen werden kann, dass neurotoxische Wirkungen beim Menschen auftreten.
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