MK-0431 epothilone D, and sagopilone are the furthest along in clinical development. Ixabepilone, the first in a new class of antimicrotubule agents, was approved in the USA and eight other countries both as a monotherapy in metastatic or locally advanced breast cancer after failure of an anthracycline (A), a taxane (T), and capecitabine (C), and as a combination with capecitabine for treatment of metastatic or locally advanced breast cancer resistant to an anthracycline and a taxane. Peripheral neuropathy (PN), caused by morphologic or functional abnormalities in peripheral nerves, is a nonhematological adverse event associated with all MTSA-based chemotherapies; it may be dose limiting and associated with functional impairment.

The nature of PN may vary depending on the type of nerve fibers involved: sensory Silibinin (manifested by paresthesia, numbness and pain in the feet and hands), motor (usually preceded by sensory neuropathy and usually mild with muscle weakness such as foot drop or difficulty in climbing stairs), or autonomic. The mechanism of MTSA-induced PN is unclear. Preclinical models have demonstrated that both ixabepilone and taxanes produce a very similar neurotoxicity profile. Analysis of accumulation of paclitaxel and ixabepilone in the dorsal root ganglia of mice following intravenous (i.v.) compound administrations showed that at equineurotoxic doses, there was ~10-fold more paclitaxel bound to neuronal microtubule than ixabepilone in peripheral neurons (unpublished data). The pathophysiological consequence of the higher deposit of tubulin-bound drug in peripheral neurons by paclitaxel is currently uncertain, but could be responsible for affecting the duration of neuropathic symptoms and time to resolution following treatment cessation. In this report, we present data on the incidence and characteristics of PN induced by purchase Voriconazole ixabepilone treatment and evaluate potential risk factors for its development.

PN is the predominant side effect of ixabepilone similar to other tubulin-targeting agents, as well as other anticancer agents with different mechanisms of action. PN associated with ixabepilone is primarily sensory and cumulative. The median time from onset to order Voriconazole resolution is 5 to 6 weeks in patients who develop severe neuropathy. Data from the phase II studies indicated that the incidence of PN is correlated with the dose of ixabepilone administered per treatment cycle, the duration of infusion, and the cumulative dose. A regression analysis evaluating the association of several prognostic factors with PN found preexisting neuropathy to be significantly associated with onset of grade 3/4 PN. None of the other factors tested in the analyses appeared to be associated with an increased risk of severe neuropathy from ixabepilone. In an earlier analysis that included 945 patients, diabetes mellitus was found to be a significant risk factor, which was not observed in this analysis.

In all trials of patients with heavily pretreated MBC and other advanced solid tumors such as refractory prostate cancer, neuropathy has been managed with dose reduction and vasculature treatment delay. No study with a neuroprotectant has been conducted. Many patients have been able to continue therapy after the ixabepilone dose was reduced.