Download (4Mb) - Etheses - Saurashtra University

2. Aim of the Present WorkPart-IAim of Present WorkA careful study and scrutiny of the review of literature on the currently used Proton PumpInhibitors (PPI’s) especially of the pyridylmethylsulfinyl benzimidazoles (PMSB) typesindicate some important drawbacks 1,2 associated with their usage, such as;1. They have irreversible inhibitory effects on gastric acid secretion and can causeextreme irreversible gastric acid suppression2. They cause achlorhydria at recommended doses & may lead to enteric infectionslike typhoid, cholera & dysentery etc.3. They may affect digestion & nutrition4. They have significant drug interactions5. They are not recommended for maintenance6. They have un-predictable action and variation in individual responsiveness ofduodenal ulcer patients7. Hypergastrinemia causes rebound phenomena8. They can cause cause gastric polyps and carcinoma9. Their affinity for various cytochrome P-450’s can lead to their self inhibition.Therefore, there is need for the discovery and development of milder, reversible PPI’s.This fact has been realized by the medicinal chemists’ worldover.An investigation into the mechanism of action of these PPI’s can throw some light on theprobable reasons for these drawbacks. These molecules rearrange in the strongly acidicenvironment of the parietal cells. 3 Covalent binding of the rearranged inhibitor to theH + /K + -ATPase results in inactivation of proton pump. 4 In the covalent binding, adisulfide linkage of the drug is formed with the active site of the cystine-rich H + /K + -ATPase (Proton Pump). One of these sites has been identified as cystine-813 (andprobably cystine-822) of H + /K + -ATPase as shown in Fig. 1.56