2.2.1 Overview
The artemisinin compounds are new, highly-effective anti-malaria drugs, discovered in China. Their chemical structure is depicted in Fig. 2.3. A crude extract of the wormwood plant Artemisia annua (qinghao) was first used as an antipyretic substance 2000 years ago. Its specific effect on the fever of malaria was already reported in the 16th century (KLAYMAN, 1985; DAVIS et al., 2005a). The active constituent of the extract was identified and purified in the 1970s, and named qinghaosu or artemisinin (C15H22O5). Artemisinin has been developed pharmacologically into different derivatives with various properties and antimalarial potency (KLAYMAN, 1985; DAVIS et al., 2005a; HIEN and WHITE, 1993). Several million patients have been treated successfully with these compounds during the past three decades (HIEN and WHITE, 1993). Each artemisinin derivative is highly active against asexual forms of the four species of Plasmodium that infect humans. The initial reduction of parasitemia by these compounds is the most rapid of all available antimalarial drugs (HIEN and WHITE, 1993; VRIES and DIEN, 1996). Their half-lives are short (Fig. 2.3) relative to the duration of their effect on parasite clearance, suggesting an equivalent to a “post-antibiotic effect”, characterized by persistent suppression of bacterial growth following limited exposure to an antimicrobial agent (DAVIS et al., 2005a).
The artemisinin derivatives are also active against the sexual form of the parasites (gametocytes) taken up by the mosquito and can therefore reduce transmission rates (CHEN et al., 1994). Their exact mechanism of action is unknown. An endoperoxide moiety, which is essential for the antimalarial activity, may generate destructive free radicals within the parasite and form covalent bonds impairing the function of key parasite proteins, including membrane transport ways (ECKSTEIN-LUDWIG et al., 2003). The artemisinin derived free radicals appear to damage specific intracellular
Fig. 2.3 Chemical structure and pharmacology of artemisinin derivatives
*Arteether is a closely related compound with an ethylether instead of a methylether group that has been developed for intramuscular use “elimination half-life, 12–30 hours”
(DAVIS et al., 2005a)
targets, possibly via alkylation. This observation suggested that free radicals might be involved in the mechanism of action (MESHNICK, 2002). Short treatment periods (3 - 5 days) with low doses (about 50 mg/kg) are associated with high recrudescence rates (HIEN and WHITE, 1993; VRIES and DIEN, 1996). Although such recrudescence can be re-treated successfully with an artemisinin drug, this phenomenon highlights the limitations of a monotherapy. There are no documented cases of parasite resistance to artemisinin derivatives in humans (WHITE, 2004).
Artemisinin
Route of administration: oral, rectal;
Elimination half-life: 2–3 hours
Artesunate (artesunic acid) Route of administration: oral, rectal, intravenous, intramuscular;
Elimination half-life: 2–5 minutes (converted to dihydroartemisinin)
Dihydroartemisinin
Route of administration: oral, rectal;
Elimination half-life: 40–60 minutes Artemether*
Route of administration: oral, intramuscular;
Elimination half-life: 3–7 hours (converted to dihydroartemisinin)
The therapeutic index, i. e. the relation of the therapeutic to the toxic dose of artemisinin derivatives is wide. The most common reported adverse effects include nausea, vomiting, bowel disturbance, abdominal pain, headache and dizziness.
However, these signs may also result from the malaria infection itself. Mild and reversible hematological and electrocardiographic abnormalities, such as thrombocytopenia and first-degree heart block, are observed infrequently (PRICE et al., 1999). Neurotoxicity, principally in the form of brain stem lesions, were first identified in animals (dog, rat, mouse, and monkey) receiving high doses over long periods (BREWER et al., 1994a; 1994b; GENOVESE and NEWMAN, 2007;
NONTPRASERT et al., 2002). Neurological side-effects such as ataxia, slurred speech and hearing loss have also been reported in few adult humans (MILLER and PANOSIAN, 1997; TOOVEY and JAMIESON, 2004), but are unlikely to be of clinical importance (JOHANN-LIANG and ALBRECHT, 2003; KISSINGER et al., 2000), especially as there is limited penetration of artemisinin derivatives into the cerebrospinal fluid (DAVIS et al., 2003; VRIES and DIEN, 1996). The pharmacokinetics of artemisinin derivatives such as artesunate is not influenced significantly by the severity of the infection (DAVIS et al., 2003).
Among the available derivatives, artesunate has the most favourable pharmacological profile for use in ACT treatment of uncomplicated malaria. The presence of a hemisuccinate group in the molecule confers water solubility and relatively high oral bioavailability. It is rapidly and quantitatively converted in vivo to the potent active metabolite (DAVIS et al., 2003). Dihydroartemisinin, artemisinin and artemether are all poorly water-soluble, resulting in slow and incomplete absorption.
Furthermore, the Role Back Malaria (RBM) strategy parallels multidrug treatment used successfully in patients with HIV and cancer, and combines the rapid schizontocidal effect of an artemisinin compound with a longer half-life of the drug.
The World Health Organization (WHO) has recently endorsed ACT as the “policy standard” for all malaria infections in areas where P. falciparum is the predominant infecting species (ANONYMUS “RBM”, 2004-2008).
2.2.2 Candidate partner drugs in artemisinin-based-combination therapy (ACT) In South-East Asian countries, artesunate-mefloquine has been used widely for many years and remained highly effective for uncomplicated cases of P. falciparum
malaria. Under the WHO system of efficacy assessment, more than 95% of patients will remain free of malaria 28 days after such a treatment (HIEN et al., 2004).
However, the neuropsychiatric effects of mefloquine as well as its relative cost are problematic. No coformulation is available, but in Cambodia there is a blister pack available containing tablets of each constituent drug grouped by the doses to be administered over 3 days. It is therefore possible for patients to identify and take the artesunate and avoiding the less tolerated mefloquine (SHWE et al., 1998), which results in a reduction of therapeutic efficacy.
Artemether-lumefantrine has been given priority as the first-line ACT combination for uncomplicated malaria (ANONYMUS “RBM”, 2004-2008). In comparison to halofantrine and quinine as partner drugs of ACT lumefantrine exhibits no significant cardiotoxicity (TYLOR and WHITE, 2004; KARUNAJEEWA et al., 2003), but initial studies with a four doses artemether–lumefantrine regimen showed a relatively high rate of late treatment failure (OMARI et al., 2004).
The most promising form of ACT seems to be dihydroartemisinin-piperaquine.
Piperaquine is a bisaminoquinoline frequently used in China in the 1970s and 1980s, when chloroquine resistance increased in the south of the country (DAVIS et al., 2005b). It was rediscovered in the 1990s as a candidate for ACT, and is currently combined with dihydroartemisinin. There have been two recent Indo-Chinese studies that have demonstrated its effectiveness, with 28-day cure rates greater than 95%
(DENIS et al., 2002; HUNG et al., 2003). The 2-day, 4-dose recommended treatment regimen is well tolerated and there are no significant side-effects (KARUNAJEEWA et al., 2003). Although the long half-life of piperaquine may theoretically allow resistant parasites to be selected by the subtherapeutic concentrations present after treatment (HUNG et al., 2003), this has not been of concern in areas of Thailand where the transmission rate is low and where mefloquine (a drug with a similarly long elimination phase) has been used extensively with artesunate (NOSTEN et al., 2000).
2.2.3 Use of artemisinin-based-combination therapy
Malaria can be particularly severe in pregnancy causing low birth weight, anemia and an increased risk of a fatal outcome. Because of the potential benefits of the artemisinin derivatives in pregnancy, a WHO review of available safety data states
(ANONYMUS, 2002; 2007a) that use of artemisinin derivatives in 731 pregnancies was not associated with human fetal toxicity. In contrast, animal studies have shown significant adverse effects. Due to these data, the WHO currently advises against the use of artemisinin drugs in the first trimester, unless in a life threatening situation where no other drugs are suitable, while, in later pregnancy, alternative therapies should be used if available.
Antimalarial treatment per se was not associated with an increased risk of abortion.
Recent studies show, that the risks of abortion due to malaria infection far outweighed any risks of abortion due to the use of antimalarial medicines including artemisinin derivatives. The evidence regarding first trimester exposures to artemisinins was reassuring but still inadequate and warrants a change in the current WHO recommendations for the treatment of malaria in the first trimester of pregnancy (ANONYMUS, 2007a; DUFFY and DESOWITZ, 2001). ACT has been used safely in children up to 5 years of age in Africa, south-east Asia and Europe and shows a high cure rate and tolerability. The combination should be taken as a 6-dose regimen. The safety of ACT has not yet been established in children of less than 5 kg body weight, and its use in this group is not recommended until further safety data are available (ANONYMUS, 2005).
2.2.4 Neurotoxicity of artemisinin and its derivatives
The use of artemisinins has risen substantially in the last 5 years and large increases in their deployment are impending as countries systematically introduce and adopt ACT to replace existing therapies, which have fading effectiveness as a result of drug resistance (ANONYMUS, 2007b; LALLOO et al., 2007). While generally believed to be well tolerated, the safety of artemisinins has been the subject of some debate (GORDI and LEPIST, 2004; TOOVEY, 2006).
Numerous studies with artemisinins have demonstrated that, under certain conditions, their administration can result in a relatively specific brain stem lesion in laboratory animals. Furthermore, the relationship between neuropathology and the application form, treatment duration, dose and type of artemisinin is not completely understood. The mode of action in neurotoxicity and the mode of action in antimalarial efficacy of artemisinins are also not yet defined (GOLENSER et al., 2006). Despite the documented occurrence of artemisinin induced brain stem
neurotoxicity in laboratory animals 14 years ago (BREWER et al., 1994a; 1994b), there is a distinct paucity of recent information on the subject, even as the number and amount of artemisinins in use grows at an accelerating pace as does the situations in which their use is recommended.
Neurotoxicity of artemisinins has been observed in mice (NONTPRASERT et al., 2002), rats (GENOVESE et al., 1998; 1999; 2000; 2001), and rhesus monkeys (PETRAS et al., 1997). The occurrence and severity of lesions are dose dependent and ranged from minimal neuronal abnormalities (BREWER et al., 1994a; 1994b;
CLASSEN et al., 1999; GENOVESE et al., 1999) to extensive necrosis associated with morbidity (BREWER et al., 1994a; KAMCHONWONGPAISAN et al., 1997). The lesions occur in a specific pattern affecting predominantly selected brain stem nuclei of the medulla oblongata, pons, and mesencephalon. Affected areas in the telencephalon and diencephalon are conspicuously spared (KAMCHONWONGPAISAN et al., 1997). Within the pons and medulla oblongata, nuclei associated with auditory and vestibular functions are particularly vulnerable.
The auditory pathway includes Corti’s organ, ganglion spirale, cochlear nerve, nucleus cochlearis, corpus trapezoideum, nucleus olivaris anterior (nucleus trapezoidium dorsalis), leminiscus lateralis and its nuclei, colliculus superior, corpus geniculatum medialis, capsula interna and auditory cortex at the sulcus ectosylvius (Fig. 2.4). In addition, precerebellar nuclei including lateral reticular and reticulotegmental nuclei and nuclei in the large medial reticular core (e. g., nucleus pontis caudalis and nucleus gigantocellularis) were also affected. Alterations in the mesencephalon including the red nucleus were notably observed. Deep cerebellar nuclei, such as the fastigial nucleus, are also damaged. The cause of the topographical selectivity of the lesions is not known. The neuronal damage is characterized by swollen cell bodies, dissolution of Nissl’s substance (chromatolysis), cytoplasmic vacuolization, nuclear eccentricity, nuclear shrinkage, nucleolar swelling, karyopyknosis, satellitosis, axonal degeneration, necrosis and neuronophagia.
Sulcus ectosylvius Auditory
cortex
Corpus geniculatum
medialis Colliculus superior
Leminiscus lateralis Nuclei
cochleares
Nucleiolivares anterior
Nervus cochlearis
Corpus trapezoieum