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Dhawan Subhash; Puri Raj K.; Kumar Ashok; Duplan Helen; Masson Jean-Michel; Aggarwal Bharat B. 《Blood》1997,90(4):1535-1544
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Inhibition kinetics of human kidney aldose and aldehyde reductases by aldose reductase inhibitors 总被引:1,自引:0,他引:1
Kinetic patterns of inhibition of homogenous human kidney aldose reductase (AR, EC 1.1.1.21) and aldehyde reductase II (AR II, EC 1.1.1.19) by statil, ICI 105552 [1-(3,4-dichlorobenzyl)-3-methyl-1,2-dihydro-2-oxoquinol-4-yl acetic acid], tolrestat, alrestatin, chromone carboxylic acid (CCA), quercetin, phenobarbital and sorbinil were studied. On the basis of the kinetic nature of inhibition, the inhibitors were classified into four distinct categories. For aldose reductase, sorbinil and phenobarbital were noncompetitive (NC; category I) and CCA and alrestatin were uncompetitive (UC; category II) to both the aldehyde substrate and NADPH. Quercetin and ICI 105552 were NC to the aldehyde and UC to NADPH (category III) and tolrestat and statil were UC to the aldehyde and NC to NADPH (category IV). For AR II, sorbinil and alrestatin were category I inhibitors, ICI 105552 and statil belong to category II, phenobarbital, tolrestat and CCA to category III, and quercetin to category IV. To determine the specificity of inhibition, the ratios of the inhibition constants (Kii) for AR and AR II were calculated. A lower ratio indicates greater specificity. With aldehyde as the varied substrate the specificity ratios were: statil less than ICI 105552 less than alrestatin less than tolrestat less than quercetin less than CCA less than sorbinil less than phenobarbital, and with NADPH as the varied substrate, ICI 105552 less than statil less than alrestatin less than tolrestat less than quercetin less than CCA less than sorbinil less than phenobarbital. For AR, double-inhibition plots generated for one inhibitor from each kinetic category versus sorbinil showed that AR inhibitors of categories I-III bind to the same site on the protein molecule as sorbinil. However, tolrestat seemed to bind to a site different from the sorbinil binding site. For AR II, inhibitors from all the four categories appeared to bind to the same inhibitor binding site. 相似文献
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5-(2-Acylethynyl)-2,4-dimethoxypyrimidines (3-6) were synthesized in excellent yields from 2,4-dimethoxy-5-[2-(trimethylsilyl)ethynyl]pyrimidine (2) by treatment with acid chlorides in the presence of anhydrous aluminum chloride. Compounds 3-6 were deblocked with chlorotrimethylsilane and sodium iodide in acetonitrile to the corresponding 5-[(2-acyl-1-iodo)vinyl]uracils (7-10), which on treatment with potassium hydroxide in dioxane yielded the corresponding 5-(2-acylethynyl)uracils (11-14). The 5-(2-acylethynyl)uracils were found to be active against Ehrlich ascites carcinoma (EAC) cells in vivo, the most active compounds being 5-(2-benzoylethynyl)uracil (11) and 5-(2-p-toluoylethynyl)uracil (12). The T/C values of 281 and 300 were obtained for compounds 11 and 12, respectively, in the case of mice bearing EAC cells. The 5-(2-acylethynyl)uracils have also shown in vitro activity against CCRF-CEM and L1210/0 tumor cell lines. The lead compound 5-(2-p-toluoylethynyl)uracil effectively inhibited thymidylate synthetase. 相似文献
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Objective: To determine if drip infusion should be discontinued after full recovery of the patient from anaesthesia after minilaparotomy cholecystectomy in uncomplicated cases.Design: A randomised controlled clinical trial on 60 patients, from the waiting list, of cholelithiasis/cholecystitis operated by minilaparotomy cholecystectomy between November 1995 to March 1996. 30 patients did not receive postoperative IV drip infusion and in 30 patients 12–24 hours of standard drip transfusion was continued according to the current practice.Setting: Single Surgical Unit, SS Hospital, Banaras Hindu University, Varanasi, India.Main outcome measure: Recognition of clinical indication for continuation of. IV drip infusion after full recovery from anaesthesia.Results: In the cohorts of 30 patients each who were or were not given IV drip infusion after full recovery from anaesthesia following minilaparotomy cholecystectomy the observations on pulse rate, blood pressure, time to first voiding of urine and time to start first oral intake of fluids were identical. However postoperative urinary retention occured in 6 (20%) patients in whom the IV drip infusion was given.Conclusion: There is no clinical indication to continue IV drip infusion after full recovery from anaesthesia in patients operated for minilaparotomy cholecystectomy. 相似文献