تصنيع ودراسة المواصفات والقوى المحركة المخبرية للأدوية المساعدة للدوبامين
Date
2016-12-21
Authors
يحيى فؤاد رشيد خواجا
yahya fuad rasheed khawaja
Journal Title
Journal ISSN
Volume Title
Publisher
AL-Quds University
جامعة القدس
جامعة القدس
Abstract
Parkinson patients have insufficient dopamine in specific regions of the brain, so attempts have
been made to replenish the deficiency in the dopamine. Dopamine itself doesn't cross blood brain
barrier, but its precursor, levodopa (LD) is actively transported into the CNS and is converted to
dopamine in the brain. The bioavailability of LD is less than 10% with only 1% of administered
oral levodopa penetrates the brain. Large doses of levodopa are required because much of the
drug is decarboxylated to dopamine in the periphery, resulting in side effects that include nausea,
vomiting, cardiac arrhythmias, and hypotension. To minimize the conversion to dopamine (DA)
outside the central nervous system (CNS), LD is usually co- administered with peripheral
inhibitors of amino acid decarboxylase (carbidopa and benserazide). In spite of that, other
central nervous side effects such as dyskinesia, on-off phenomenon and end-of-dose
deterioration still remain.Based on DFT calculations a novel dopamine prodrugs for the treatment of Parkinson’s disease
that can improve the overall biopharmaceutical profile of the current medications to enhance
effectiveness and to ease the use of the medications were synthesized, characterized, in vitro
intra-conversion to their parent drugs and in silico pharmacokinetics and toxicity prediction were
also studied. The synthesized dopamine prodrugs have a carboxylic group as a hydrophilic
moiety and a hydrocarbon skeleton as a lipophilic moiety, where the combination of both groups
ensures a moderate hydrophilic lipophilc balance value. The potential prodrugs are expected to
give better bioavailability than the parental drug owing to improved absorption. Furthermore,
these prodrugs are believed to be more effective than L-dopa because the latter undergoes
decarboxylation in the periphery before reaching the blood– brain barrier. Additionally, the
synthesized prodrugs can be used in different dosage forms (I.V., S.C., tablets, and others)
because of their potential solubility in organic and aqueous media. For dopamine ProD 1 the
experimental t½ values in 0.1N HCl, buffer pH 2.2, buffer pH 5.5 and buffer pH 7.4 were 60.3
hours, 54.66 hours, 99.93 hours and 138.13 hours, respectively. Dopamine ProD 2 was readily
converted in 0.1N HCl, buffer pH 2.2, pH 5.5 and pH 7.4 with half -life time (t½) of 48.34 hours,
54.22 hours, 131.98 hours and 193.42 hours, respectively. Finally, in silico predicting of
physiochemical parameters, ADMET (Absorption, Distribution, Metabolism, Excretion and
Toxicity) properties, oral bioavailability and BBB permeability for the synthesized prodrugs
were studied. The results revealed that no prodrug had a high risk of toxicity, and all the
prodrugs showed good pharmacokinetic properties. Moreover, all synthesized dopamine
prodrugs were found to obey Lipinski’s rule of five.
Description
Keywords
العلوم الصيدلانية , Pharmaceutical Sciences