Sorbinil clinical trials

The aldose reductase inhibitors inhibit or reduce secondary complications induced by diabetes, specifically in tissues in which glucose uptake is not insulin-dependent (probably neural tissue, the lens, and glomeruli). Many of them (including alrestatin, imirestat, ponalrestat, and sorbinil) have been used in clinical trials, but have been withdrawn because of adverse effects or lack of effect (2). Their main adverse effects include fever, nausea, diarrhea, increases in liver enzymes, skin rashes, including toxic epidermal necrolysis and Stevens-Johnson syndrome, marked thrombocytopenia, lymphadenopathy, splenomegaly, and adult respiratory distress syndrome. 

Tolrestat was withdrawn because of deaths from fatal hepatic necrosis (3) and poor efficacy in clinical trials. Sorbinil was withdrawn because of hypersensitivity reactions in more than 10% of patients. 

The absence of side effects in a 1-year clinical trial with ponalrestat was reported by Ziegler et al. (1991), but in this study no therapeutic efficacy was seen A 6-month study with ponalrestat to elucidate the effects on kidney function was also free from side effects (Pedersen et al., 1991). Dizziness, possibly based on a blood pressure-lowering effect, was reported for tolrestat. In addition, hepatocyte lesion accompanied by changes in hepatic parameters within the first 3-6 months of treatment was seen (Ryder et al., 1987). For sorbinil, significant hypersensitivity reactions have been reported (Sarges, 1989). 

Combining the chroman ring with hydantoin afforded a series of potent spirohydan-toins.11 Sorbinil (Fig. 11-9) is now in advanced phases of clinical trials. One study has already demonstrated the drug s ability to relieve symptoms of chronic diabetes neuropathy. 

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