Artesunate
Artesunate is the firstline treatment for severe malaria according to WHO recomendation. Its administration is followed by other antimalarials like quinine tablets or artemether Lumefantrine
Moa
Artesunate is a hemisuccinate derivative of dihydroartemisinin, which is
itself formed by the reduction of artemisinin .artemisinin is a sesquiterpene
lactone endoperoxide extracted from qinghao (sweet wormwood, Artemisia annua) ,
a plant which has been used for centauries in traditional Chinese medicine. The
mechanism of action of artemisinins likely
involves cleavage of the internal endoperoxide bride through reaction with the
heme within the infected erythrocyte, thereby generating free radicals which
alkylate vital parasite proteins. However, artemisinins have also been reported
to inhibit an essential parasite calcium adenosine triphosphate.
The artemisinins are distinguished by their ability to kill
erythrocytic stages of the malaria parasite, including the relatively inactive
ring stage and late schizonts, as well as gametocytes responsible for malaria
transmission. Artesunate and artemisisnins are the most rapid acting of the
antimalarials, and they have also been shown to enhance splenic clearance of
infected erythrocytes by reducing cytoadhearance.
Invitro dihydroartemisinin(DHA), the active ingredient of
artesunate ,exhibits similar potency against chloroquine-resistant and
chloroquine sensitive clones of P. falciparum.
Artesunate and other artemisinins are essentially inactive against extra
erythrocyte forms, sporozoites, liver schizonts or merozoites.
Pharmacokinetics
Intravenous
After intravenous infusion, artesunate is rapidly biotransformes
to its active metabolite , dihydroartemisinin (DHA) , consequently artesunates
half life (t1/2) is estimated to be less than 5 minutes. Following a single
dose of 2.4/kg, the maximum artesunate plasma concentration (Cmax) were estimated to be 77µmol/l in a study in
Gabonese children with severe malaria , and 42 and 367µmol/l in two studies in
Vietnamese adults with uncomplicated malaria. High concentration of DHA are
observed within 5 minutes of artesunate administration. In the above studies ,
(adult and pediatric), the ranges of value for the estimated time to maximum
concentration (tmax) and t1/2 for DHA were
0.5-15 minutes and 21-6 minutes , respectively ,while DHA Cmax values ranged
from 5.3-10.6 µmol/l
Intramuscular
Artesunate is rapidly absorbed following intramuscular
injection, and peak plasma levels are generally achieved within 30 minutes of
administration. Thus , after
intramuscular injection, 2.4 mg/kg of artesunate , absorption was rapid
in Gabonese children and Vietnamese adults, with Tmax values of 8-12 minutes,
respectively. The corresponding t1/2 values were estimated to be 48 minutes in
children and 41 minutes in adults, and the Cmax values were 1.7 and 2.3 µmol/l
for children and adults respectively
Distribution
DHA has been shown to
substantially accumulate in P.falciparum infected erythrocytes . Plasma protein
binding was estimated to be 93% in patients and 88% in healthy volunteers.
Metabolism and elimination
Artesunate is extensively and rapidly hydrolyzed by plasma
esterases, with possible minimal contribution by CYP2A6. The main metabolite,
dihydroartemisinin accounts for most of the in-vivo anti-malarial activity of
oral artesunate, however following iv administration, artesunate may contribute
more significantly. DHA is further metabolized in the liver via glucuronidation
and is excreted in urine ; α-dihydroartemisinin-β-glucuronide has been identified as the major urinary
product in patients with falciparum malaria
Special populations
No pharmacokinetic data are available for patients with
impaired renal or hepatic functions. However, based on the known mechanism of
metabolism and elimination of artesunate, combined with clinical data from
patients with severe malaria and accompanying renal and/or hepatic compromise
of various degrees, no dose modifications are considered necessary in renal or
hepatic impairment
Preclinical safety data
General toxicity
Artesunate poses low acute toxicity . After repeated
administration of 50mg/kg/day in rats, and 82.5mg/kg/day in dogs, i.e
approximately 10 and 17 times the proposed maximal therapeutic dose in man, no evidence
of toxicity were observed in the hematopoietic
organs, the immune system and
response , the liver and kidneys.
Genotoxicity
Artesunate did not show any mutagenic or clastrogenic
potential in invitro and in invivo tests (Ames, mouse, micronucleus)
Carcinogenesis
No studies of carcinogen
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