| Budget Amount *help |
¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1986: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1985: ¥600,000 (Direct Cost: ¥600,000)
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| Research Abstract |
1. MANY LINES OF EVIDENCE HAVE ACCUMULATED THAT ALDOSE REDUCTASE INHIBITORS ARE USEFUL FOR THE TREATMENT OF DIABETIC COMPLICATIONS. SEVEN 1-(ARYLSULFONYL)HYDANTOINS, WHICH WERE SYNTHESIZED BY US AND FOUND TO BE POTENT ALDOSE REDUCTASE INHIBITORS IN VITRO, WERE ORALLY ADMINISTERED TO STREPTOZOTOCIN-DIABETIC RATS AT A DOSE OF 50 MG/KG/DAY FOR 12 DAY. THEIR INHIBITORY EFFECTS ON SORBITOL ACCUMULATION IN THE LENS AND THE SCIATIC NERVE WERE ESTIMATED. 1-[(2,4,5-TRICHLOROPHENYL)SULFONYL] HYDANTOIN (TRI-CL-PSH), 1-[(2,5-DICHLOROPHENYL)SULFONYL]HYDANTOIN (DI-CL-PSH), AND 1-[( <beta> -NAPHTHYL)SULFONYL]HYDANTOIN ( <beta> -NSH) WERE THE THREE MOST POTENT INHIBITORS. TRI-CL-PSH, HOWEVER, SEEMS TO HAVE SOME UNFAVORABLE ACTIVITY, SINCE THE BODY WEIGHT OF RATS GIVEN THIS COMPOUND WAS SIGNIFICANTLY LESS THAN THAT OF CONTROL RATS. ORAL ADMINISTRATION OF <beta> -NSH AT 25 MG/KG TO NORMAL RABBITS INDUCED A SIGNIFICANT DECREASE OF THE BLOOD GLUCOSE CONCENTRATION, WHILE DI-CL-PSH WAS INEFFECTIVE. BOTH <beta> -NSH AND DI-CL-PSH, GIVEN ORALLY AT 50 MG/KG/DAY, WERE EFFECTIVE IN AMELIORATING THE MOTOR NERVE CONDUCTION VELOCITY OF THE TAIL NERVE OF DIABETIC RATS WITH A LITTLE HIGHER ACTIVITY IN <beta> -NSH THAN IN DI-CL-PSH. THESE RESULTS INDICATE THAT <beta> -NSH IS HIGHLY PROMISING AS A NEW DRUG FOR TREATING DIABETIC COMPLICATIONS.
2. HYPERGLYCEMIA PROMOTES THE NONENZYMATIC GLYCOSYLATION OF BOTH CIRCULATING AND TISSUE PROTEINS, PROVIDING INSIGHT INTO THE PATHOGENETIC MECHANISMS ASSOCIATED WITH THE CHRONIC COMPLICATIONS OF DIABETES. IN THIS STUDY, I ATTEMPTED TO DEVELOP SOME COMPOUNDS WHICH INHIBIT NONENZYMATIC GLYCOSYLATION BY GLUCOSE OF HUMAN SERUM ALBUMIN AS A MODEL PROTEIN. FIFTEEN COMPOUNDS POSSESSING EITHER AMINO GROUP(S) OR CARBONYL GROUP(S) OR BOTH WERE TESTED FOR THEIR INHIBITORY ACTIVITIES. OTHER COMPOUNDS THAN DL-GLYCERALDEHYDE AND PYRIDOXAL-5-PHOSPHATE SHOWED AS SMALL INHIBITION PERCENTAGES AS LESS THAN 20 %. I WILL CONTINUE TO SEARCH MORE POTENT COMPOUNDS.
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