Effects Of Dimiracetam On Oxaliplatin-Induced Hyperalgesia And Allodynia In The Rat

e20650 Background: Painful neuropathy is a common adverse event associated with oxaliplatin treatment. It can occur within the first days and may persist from months to years beyond chemotherapy completion, negatively impacting the quality of life of cancer survivors. It is a frequent cause of chemotherapy dose reduction or early treatment discontinuation. The 2014 ASCO clinical practical guideline states there are no agents recommended for the treatment of chemotherapy-induced peripheral neuropathy. Dimiracetam, a compound originally developed as a cognition enhancer, is effective in the treatment of neuropathic pain in several rat models. Here we report that dimiracetam is also effective for prevention of oxaliplatin-induced neuropathy when administered orally, concomitantly with the chemotherapeutic agent. We have used duloxetine and vehicle as comparators. Methods: Oxaliplatin (2.4 mg/kg ip) was administered qd; concomitant dimiracetam (75 and 150 mg/kg po) or duloxetine (5 and 15 mg/kg po) or vehicle, were administered bid. Results: Repeated administration of dimiracetam from day 1 to day 21 of oxaliplatin treatment prevented the development of mechanical hyperalgesia, as assessed by the Randall-Selitto analgesymeter. Mechanical and thermal allodynia were also prevented, as assessed by Von Frey and Cold Plate tests, respectively. The effect of dimiracetam was dose-dependent and persisted throughout the 21-day treatment period. In a second experimental protocoloxaliplatin was co-administered from day 1 to day 11 with twice-daily dimiracetam or duloxetine or vehicle. Dimiracetam and duloxetine completely prevented the development of both mechanical hyperalgesia and allodynia. Both doses of dimiracetam were similarly effective to the higher dose of duloxetine. The effect of both compounds persisted up to day 16, five days after treatment discontinuation. Conclusions: In a rat model of oxaliplatin-induced peripheral neuropathy, dimiracetam prevented oxaliplatin-induced peripheral neuropathy, exhibiting efficacy also in the post-treatment period. Dimiracetam is a promising drug candidate for prevention of oxaliplatin-induced neuropathy and warrants further investigation in clinical trials.