اسم المؤلف:
نوري محمد عزيز فياض الجبوري
اسم المشرف:
فراس شوقي عبد الرزاق
اياد سعدي حميد
المستخلص:
يعد الاسبرين والايبوبروفين من الحوامض الاريلية المستخدمة كادوية مضادة للالتهابات غير استيرويدية (NSAID) ولغرض التقليل من التاثيرات الجانبية السلبية للاسبرين والايبوبروفين من خلال ازالة التاثير السام لمجاميع الكاربوكسيل الحرة المرتبطة بهما، هدفت الدراسة ا | Aspirin and ibuprofen are aryl acids of (NSAID) with good analgesic , anti - inflammatory. For reducing the gastrointestinal toxicity accociated with Aspirin and Ibuprofen therefor the present work is aimed to synthesized a novel ester prodrugs of these two drugs, 1,2 : 5,6 - Di - O - isopropylidine - ? - D - glucofuranose is used a carrier alcohol for attachment of non - steroidal anti - inflammatory Drugs (Aspirin and Ibuprofen ).This work was accomplished according to the following steps.1 - Aspirin and Ibuprofen acid chlorides(1,2) were prepared through the reaction of the corresponding acid with thionyl chloride.2 - 1,2 : 5,6 - Di - O - isopropylidine - ? - D - glucofuranose is afforded by reaction D - Glucose with acetone and Lewis acid catalyst.3 - Esterification reaction of 3 - OH group in compound [AA] with compounds (1) and (2) yielded the corresponding Aspirin ester and Ibuprofen ester prodrugs [AB] and [AC].4 - Deacetonation of Compound [AB]. Using 70% acetic acid afforded Compound [AD].5 - The purity of the compounds synthesized was established by (TLC) and column chromatography.While the structures of their mutual prodrug was confirmed by (FTIR, H1NMR,C13NMR) and the result obtained given good evidence for structures proposed to their compounds.6 - Using through the study 36 rabbit, proximate in the weight and divided in to six groups. First group (six rabbit) control group did not have any dose, second group have (DMSO) dose ,third group have the Aspirin dose, fourth group have the Ibuprofen dose , Fifth group have the compound (AD) and sixth group have the compound (AC), After two hours withdrawal sample of blood from each rabbit, separated the serum to use in the biochemical study to the parameter at the following : The measured parameters include : enzymes activity (Lactate dehydrogenase(LDH) , Acid phosphatase, creatinkinase (MB) , Alkaline phosphatase(ALP) , Gloutamate - pyrovate transaminase (GPT) , Glutamate - oxaloacetate transaminase (GOT) , cholinesterase , peroxidase) , and measured concentration of (Glutathione , malonldialdehdy ,creatinine , albumin , total protein , globulin , uric acid ) and some element’s (Mg ,Fe ,Cu ,Zn). Statistical data analysis revealed signification increase in the levels of creatinkinase activity (147.130±16.176) U/I،(157.785 ±21.590)U/I)، 146.995 ±29.314) U/I by effect Ibuprofen (D), compound (AD), compound (AC) a succession. and alkaline phosphatase (121.933±13.061) U/I، (129.158±17.052)U/I by effect compound (AD), compound (AC) a succession.And Gloutamate - pyrovate transaminase (30.521 ± 6.365)U/I، (31.387 ± 3.005)U/I،(26.863±7.470)U/I، (22.973±6.052)U/I by effect Aspirin (C) ,Ibuprofen (D), compound (AD), compound (AC) a succession. And Glutamate - oxaloacetate transaminase (72.731 ± 5.533) U/I، (75.366 ± 5.032)U/I، (77.560 ± 6.681)U/I by effect Ibuprofen (D), compound (AD), compound (AC) a succession. and peroxidase enzyme(26.433±7.722) U/I، (29.500±3.555)U/I، 31.150 ±4.932)U/I by effect Ibuprofen (D), compound (AD), compound (AC) a succession. And signification increase in the concentration of glutathione (4.897 ±0.448) µmol/L، (4.957 ± 0.501)µmol/L، (4.771 ± 0.366)µmol/L by effect Ibuprofen (D) , compound (AD), compound (AC) a succession. And signification increase in the concentration of malonldialdehyde(11.507±1.841) µmol/L،(12.744±2.275)µmol/L، (14.240±2.861)µmol/L، (14.409 ±1.712)µmol/L by effect Aspirin (C) ,Ibuprofen (D), compound (AD), compound (AC) a succession. And signification increase in the concentration of creatinine (138.847 ± 16.116)µmol/L، (153.021 ± 14.307) µmol/L، (162.466 ± 19.269) µmol/L and (156.074±19.99) µmol/L by effect Aspirin (C) ,Ibuprofen (D), compound (AD), compound (AC) a succession. And signification increase in the concentration of uric acid (108.994 ± 17.347) µmol/L، (90.972 ± 17.567) µmol/L، (101.322±18.090) µmol/L، (101.990±22.918)µmol/L by effect Aspirin (C) ,Ibuprofen (D), compound (AD), compound (AC) a succession (All compared with the serum levels of the control group.The study also showed a signification decrease in level of cholinesterase activity (3140.43±295.54) U/I، (2964.57±351.77)U/I، (2708.40 ±348.29)U/I، (2748.90±464.21)U/I by effect Aspirin (C) ,Ibuprofen (D), compound (AD), compound (AC) a succession.The study also showed a signification increase in level of Total protein by effect compound (AD) ,(AC) (64.821±3.116)g/Land (64.228±5.733)g/La succession.Results had also confirmed a presence of signification increase in the concentration of Mg (0.953±0.147) mmol/L by effect compound (AC). and signification increase in the concentration of Cu (23.964±2.043) µmol/L، (24.740±1.449)µmol/L، (25.367±1.656) µmol/L، 25.003±2.008) µmol/L by effect Aspirin (C) ,Ibuprofen (D), compound (AD), compound (AC) a succession, compared with the serum levels of the control group. The study also showed a signification decrease in concentration of Zn (13.810±0.904) µmol/L،(16.112 ± 1.565) µmol/L،(12.025 ± 1.306) µmol/L، 11.654 ± 2.194) µmol/L by effect Aspirin (C) ,Ibuprofen (D), compound (AD), compound (AC) a succession, compared with the serum levels of the control group.The study also showed non - signification decrease in the activity of Lactate dehydrogenase, acid phosphatase. and non - signification increase in the levels Albumin , Globulin and Iron. And no effect on the level Mg. compared with the serum levels of the control group.7 - To ensure the release of parent drugs (Aspirin, Ibuprofen) a hydrolytic studies of the ester prodrugs [AD],[AC] were done at different pH [ 2 , 4 , 10 ,12 ] and at constant temperature (25 C0) ,The results should that the hydrolysis at basic pH were faster than acidic pH then it mean that the most hydrolysis will obtain at intestine not at stomach.
