Perkembangan Kaedah Pra-Klinlkal Asid Artesunik, Satu Terbitan Artemisinin Yang Baru
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Date
2002-04
Authors
V.SATHASIVAM, KATHIRESAN
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Abstract
Artesunic acid, a derivative of artemisinin has proven to be rapidly effective and safe in the
treatment of malaria. Artesunic acid has been formulated for parenteral and oral use and
has recently become available as suppositories for rectal administration. Artesunic acid and
it's active metabolite, dihydroartemisinin used in all these studies was characterized using
infrared and nuclear magnetic resonance. The purity was determined by high performance
liquid chromatography coupled with an electrochemical detector. To date, there is no
dissolution method available to determine the dissolution profile of artesunic acid from
suppositories. This study describes a newly developed dissolution procedure for analysis of
artesunic acid suppositories. In vitro dissolution profiles of artesunic acid from the
suppositories were examined by means of basket (Apparatus I, USP XXII) and paddle
(Apparatus II, USP XXII) methods. The dissolution profiles were also studied using a
modified paddle method as the capsule floated after 2 hours in this method. The paddle
method was then modified by using a stainless steel helix and mesh that were placed at the
bottom of the vessel. In conclusion, the modified paddle method with 0.05% of sodium
doedecyl sulphate as surfactant was adopted for artesunic acid suppository developmental
studies. Next, a pre-clinical study was initiated to investigate the stability of artesunic acid
in buffer solutions at pH 1.2 -10.0 and in biological fluids. Pre-clinical studies 'in buffers
and biological fluids indicated that ARS was biotransformed to its active metabolite,
dihydroartemisinin. The rate for the biotransformation of· artesunic acid to
dihydroartemisinin in biological media at 37°C was more rapid when compared to the rates
in buffer solutions with pH values similar to biological fluids. This result tends to suggest
that acetocolinesterase enzyme increases the biotransformation rate of artesunic acid to
dihydroartemisinin. Pre-clinical studies in buffer solutions ranging from pH 8.5 - pH 10.0
indicated that aJiesunic acid is degraded into a new product (s) which absorps at Amax =
289nm and 236nm. Following an oral administration in rats, rapid absorption and extensive
biotransformation artesunic acid to dihydroartemisinin was observed. The mean AUCo_t
and Tmax values of artesunic acid were 713.1 ± 233.3 nghr/ml and 5.0 ± 0.0 minutes
respectively. The corresponding values of dihydroartemisinin were 2040.3 ± 650.0 nghr/ml
and 37.5 ± 8.7 minutes. The calculated absorption tl/2 mean was 2.73 ± 0.85 minutes for
artesunic acid and 12.49 ± 2.49 minutes for dihydroartemisinin. The data from this study
indicates that rapid conversion of artesunic acid to dihydroartemisinin occurs in the
stomach.
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Keywords
Perkembangan Kaedah Pra-Klinlkal Asid Artesunik , Satu Terbitan Artemisinin Yang Baru