تطوير دواء اولي مبتكر للاتوفاكوون? الدواء المضاد للملاريا: تصنيع كيميائي, تشخيص و تقييم القوى المحركه المخبريه
Date
2016-01-05
Authors
بيسان وضاح امين الفتاش
Beesan Waddah Amin Alfattash
Journal Title
Journal ISSN
Volume Title
Publisher
AL-Quds University
جامعة القدس
جامعة القدس
Abstract
Malaria is a global public health problem, resulting in tow million deaths per year .The
majority of death cases are due to the most severe form of malaria caused by Plasmodium
falciparum. As a result, efforts were directed toward the development of new effective
medications intended for the treatment of this endemic disease. Atovaqoune is a new
treatment option, showed an improvement in malaria treatment. Although Atovaqoune is
an effective medication, it has its own limitations.
Atovaqoune is highly lipophilic compound (water solubility < 0.2 µg/ mL), has low water
solubility and low absorption, hence low bioavailability (< 10% in the fasted state).
Accordingly, increasing atovaqoune aqueous solubility will improve its pharmacokinetic
profile in particular bioavailability, thus improving its effectiveness and ability to
administer the drug through different routs of administration.
So that, our goal was to develop atovaqoune prod rug that possesses increased aqueous
solubility by linking water soluble moiety to the 3- hydroxyl group, via chemical synthesis.
Purification techniques including extraction, re-crystallization and column chromatography
were used. Identity confirmation was done using, IR, NMR and LC/MS. Based on purity
and identity results; in vitro kinetic studies using the HPLC instrument were performed at
pH 2.2, 5.5 and 7.4.
ATQ succinate (ProD1) has been successfully synthesized, purified and evaluated. T1/2 of
ProD1 at pH 2.2, 5.5 and 7.4 is 28.8 days, 2.2 days, 3.2 days, respectively.
It can be concluded from these data, that ProD1 is converted into ATQ in pH dependentmanner, and the hydrolysis of the prodrug follows first order kinetics, as the data plotted
gives a straight line, and the Kobs is nearly constant. Concisely, modifying atovaqoune
structure may result in enhancing its pharmacokinetic profile mainly absorption into body
tissues, consequently increasing efficacy and ability to formulate atovaqoune in different
dosage forms.
Keywords: Malaria, drug resistance, atovaquone, bioavailability, prodrugs .
Description
Keywords
العلوم الصيدلانية , Pharmaceutical Sciences