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Pharmacological Evaluation of Synthetic New Fenamic Acid Amide Pro-Drugs

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Pharmacological Evaluation of Synthetic New Fenamic Acid Amide Pro-Drugs بسم ه الرحمن الرحيم International University of Africa Postgraduate college Pharmacological Evaluation of Synthetic New Fenamic Acid Amide Pro-drugs A thesis submitted to the department of pharmacology and Toxicology, faculty of pharmacy, International University of Africa, for the full fulfillment of requirement for the degree of Master of pharmacology By Samrin Khalil Nogd Alla Ahmed (B. Pharm., 2013) Supervisor Dr. Aimun Abdelgaffar Elhassan Ahmed (B. Pharm., M. Pharm., Ph.D.) Co-supervisor Dr. Talal Elsaman Elemam Elbashir (B. Pharm., M. Pharm., Ph.D.) October, 2016 ~@DEDICATION@~ I dedicate this work To my parents To my brothers and sisters To my teachers To my families To my friends To all whom I love With my deepest love and respect ~@Samrin @~ ACKNOWLEDGEMENT I thank the almighty God for giving us the courage and the determination as well as guidance in conducting this research. Many people should be thanked for their contribution in this study. This research is made possible through the help and support from everyone, including: parents, teachers, family, friends, and in essence, all sentient beings. Especially, please allow me to dedicate my acknowledgment of gratitude toward the following significant advisors and contributors: First and foremost, I would like to thank Dr. AIMUN AE.AHMED for the continuous support of my master study and research, for his patience, motivation, enthusiasm, and immense knowledge. His guidance helped me in all the time of research and writing of this thesis. I could not have imagined having a better advisor and mentor. Second, I would like to thank Dr. TALAL EE.ELBASHIR for his support by ready synthetic compounds and encouragement. He kindly read my paper and offered invaluable detailed advices on grammar, organization, and the theme of the dissertation. I would like to thank my colleagues Dr. MAWAHIB ELMUTASIM and Dr. MAZIN YOUSIF for support and co-operation to complete this thesis. I Our thanks also go to the Lecturers and Technical staff at the Department of Pharmacology, Faculty of Pharmacy, IUA. Finally, I sincerely thank to my parents, family, and friends, who provide the advice and support. The product of this research paper would not be possible without all of them. II CONTENTS ACKNOWLEDGEMENT ............................................................................... I CONTENTS .................................................................................................. III LIST OF TABLES ....................................................................................... VII LIST OF FIGURES ...................................................................................... IX LIST OF ABBREVIATIONS ................................................................... XIV ENGLISH ABSTRACT .............................................................................. XV XVII .............................................................................................. لص لعبي 1.INTRODUCTION AND LITRETURE REVIEW ....................................... 1 1.1. Introduction ............................................................................................... 1 1.1.1. The pain ................................................................................................. 1 1.1.2. The inflammation process ..................................................................... 2 1.1.3. The available analgesics agents ............................................................. 7 1.1.4. Non steroidal anti-inflammatory drugs (NSAIDs) ................................ 8 1.1.5. Need for new Drugs, Why? ................................................................. 11 1.1.6. Drug sources ........................................................................................ 11 III 1.1.7. The pre-clinical Studies in Drug discovery ......................................... 12 1.1.8. Animal models in drug discovery ........................................................ 13 1.1.9. The models for anti-inflammatory and analgesic studies .................... 13 1.1.10. Drug safety and toxicological studies for new drug entity ................ 14 1.1.11. Methods for LD50 determination ...................................................... 15 1.1.12. Protocol 425 as a best available one for LD50 determination .......... 15 1.2.Literature Review .................................................................................... 17 1.2.1. Drug Discovery and Development for synthetic compounds ............. 17 1.2.2. The selected compounds for the study ................................................ 17 1.2.3. Fenamate derivatives ........................................................................... 18 1.3. The rationale of the Study ...................................................................... 26 1.4. Study Objectives ..................................................................................... 26 2. MATERIALS AND METHODS .............................................................. 28 2.1. Materials ................................................................................................. 28 2.1.1. The standard drugs ............................................................................... 28 2.1.2. The synthetic compounds .................................................................... 28 2.1.3. Chemicals ............................................................................................ 29 IV 2.1.4. Experimental Animals ......................................................................... 30 2.1.5. Equipments .......................................................................................... 30 2.1.6. Study schematic diagram……………………………………………31 2.2. Methods .................................................................................................. 32 2.2.1. Pharmacological investigations ........................................................... 32 2.2.2. In vivo anti-inflammatory activity method .......................................... 33 2.2.3. In vitro anti-inflammatory activity using albumin denaturation ......... 33 2.2.4. In vitro isolated preparations studies ................................................... 34 2.2.5. The LD50 determination from acute oral toxicity, in vivo on rats ..... 38 2.2.6. Statistical analysis methods ................................................................. 39 3. RESULTS .................................................................................................. 41 3.1. Effect of tested compounds on tail flick latency .................................... 41 3.2. Anti-inflammatory activity of TFAD-01 ............................................... 44 3.3. In vitro effects on isolated Rabbit intestine ............................................ 50 3.4. Acute oral toxicity of the most active compound using Protocol 425 ... 65 4- DISCUSSION ........................................................................................... 68 4.1. Effect of analgesic activity of Synthetic new Fenamic Acids Amide Pro- drugs in vivo ................................................................................................... 69 V 4.2. Anti-inflammatory activity of the selected most active Compound (TFAD-01) ..................................................................................................... 70 4.3. Effect of TFAD-01 synthetic compound on isolated rabbit intestine .... 72 4.4. Investigation of mechanism of action ..................................................... 72 4.5. Possible Pharmacodynamic Interactions ................................................ 73 4.6. Acute oral toxicity of TFAD-01 ............................................................. 74 5. CONCLUSION AND RECOMMENDATIONS ...................................... 75 5.1. Conclusion .............................................................................................. 75 5.2. Recommendations .................................................................................. 77 REFERENCES ............................................................................................. 78 VI LIST OF TABLES Table 2.1: Chemicals used in the experiment ...............................................29 Table 3.1: Summary of the main pharmacological parameters EC50 and Emax of TFAD-01 synthetic compound and vehicle control presented as Mean ± S.E.M in both conditions. .................................................................51 Table 3.2: Summary of the main pharmacological parameters EC50 and Emax of TFAD-01 synthetic compound and standard acetylcholine presented as Mean±S.E.M in both conditions. ..............................................53 Table 3.3: Summary of the main pharmacological parameters EC50 and Emax of TFAD-01 synthetic compound and standard 5-hydroxy tryptamine presented as Mean±S.E.M in both conditions. ..............................................54 Table 3.4: Summary of the main pharmacological parameters EC50 and Emax of TFAD-01 synthetic compound and standard Barium chloride presented as Mean±S.E.M in both conditions. ..............................................56 -8 - Table 3.5: pA2 values of the action of Atropine in a dose of [10 M and 10 10M] on contraction activity of TFAD-01synthetic compound and standard Acetylcholine on isolated rabbit intestine. ....................................................58 VII -8 Table 3.6: pA2 values of the action of cyprohepatadine in a dose of [10 M and 10-10M] on contraction activity of TFAD-01 synthetic
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