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| |  ADA: LY333531 Shows Promise in Diabetic Peripheral Neuropathy By Jill Stein Special to DG News SAN FRANCISCO, CA -- June 18, 2002 -- New data released at the 62nd Scientific Sessions of the American Diabetes Association (ADA) suggest that treatment with LY333531 may improve diabetic peripheral neuropathy (DPN) diagnosed by abnormal vibration detection threshold. The investigators say that LY333531 treatment may also address the underlying pathogenesis of diabetic microvascular complications. Dr. William Litchy, with Health Partners Medical Group in Minneapolis, Minnesota, headed a study that evaluated the effect of LY333531 -- a protein kinase C beta inhibitor -- on neurological examinations, composite scores, and physician assessments in patients with DPN. "There is increasing evidence for the role of protein kinase C beta hyperactivity in the biochemical pathway leading to microvascular damage and eventual neuronal degeneration in diabetes," Dr. Litchy noted. An increase in protein kinase C activity has been demonstrated in preclinical animal models of DPN. LY333531 prevents and reverses the diabetes-induced alterations in endoneural blood flow and prevents and reverses the decrease in nerve conduction velocity in animal models, he continued. Given the possible importance of ischemic injury in the pathogenesis of DPN, normalization of blood flow may improve the electrophysiologic function of the peripheral nerve and sensory ability in persons with DPN. In the one-year, double-blind, placebo-controlled, parallel trial, 205 type 1 or 2 diabetic patients with DPN were randomized to placebo or to 32 mg or 64 mg of LY333531. The treatment groups were well matched with respect to baseline scores, subscores and baseline composite scores on the Neuropathic Impairment Score (NIS), with reduction in score being indicative of clinical improvement. Compared with placebo, 32 mg LY333531 resulted in significant improvements in change from baseline to end point in NIS of the lower limbs and NIS of the reflexes subscores. Improvement relative to placebo was also observed in NIS scores but this difference did not reach statistical significance. Compared with placebo, 32 mg LY333531 resulted in significant improvements in change from baseline to endpoint in NIS of the lower limbs + 4. The 64 mg LY333531 dose did not result in significant improvements in NIS score or subscores compared with placebo. Improvement relative to placebo was also observed in the NIS of the lower limbs +4 + vibration detection threshold score but this difference did not reach statistical significance. The 64 mg LY333531 dose did not result in significant differences in composite scores compared with placebo. Compared with the placebo group, the 32 mg LY333531 group had significantly improved clinical global impression (GCI) ratings at end point. The 64 mg LY333531 dose did not result in significant differences in GCI ratings at end point compared with placebo (p=0.044). In patients with DPN diagnosed by abnormal vibration detection threshold, treatment with 32 mg LY333531 for one year resulted in improvements in neurological examination, composite scores of nerve function, and patient well being as evidenced by CGI, Dr. Litchy concluded. No significant improvement was demonstrated relative to placebo in patients receiving LY333531, 64 mg. LY333531 is being developed by Eli Lilly.
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