Inhibitory Effect of α1 Receptor Antagonists on Paclitaxel-Induced Peripheral Neuropathy in a Rodent Model and Clinical Database.

Abstract

The anticancer drug, paclitaxel, is widely used for ovarian, breast, non-small cell lung, and gastric cancers; however, it induces peripheral neuropathy as a side effect. There is insufficient evidence-based prophylaxis, and new prophylaxis and treatment methods are required. We examined the effect of α1-receptor antagonists on paclitaxel-induced peripheral neuropathy using Sprague-Dawley rats and a large adverse event database. The repeated administration of doxazosin or tamsulosin significantly reduced the response threshold to paclitaxel administration in animal models. In the sciatic nerve tissue, axonal degeneration and myelopathy were significantly suppressed. Furthermore, an analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) database suggested that the group using α1 inhibitors showed a lower reporting rate for paclitaxel-related peripheral neuropathy than the group that did not use these inhibitors (odds ratio (95% confidence interval): tamsulosin 0.21 (0.08-0.56), p < 0.01, doxazosin 0.41 (0.10-1.65), p = 0.195; any α1 receptor antagonist 0.54 (0.38-0.76), p < 0.01). Thus, doxazosin and tamsulosin may inhibit the development of paclitaxel-induced peripheral neuropathy by suppressing neurodegeneration, particularly axonal degeneration and myelopathy.