Xaliproden lessens oxaliplatin-mediated neuropathy

Susman, Ed

doi:10.1016/s1470-2045(06)70639-8

Cited by 18 publications

(15 citation statements)

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“…Certain authors tested unsuccessfully glutathione, amifostine, or alipoic acid, increasing the pathway of heavy metal detoxication (33 -35). The last attempt with xaliproden did not provide convincing results (36). The other approach was to block the action of oxaliplatin on sodium channels with carbamazepine or gabapentin or to chelate oxalate by i.v.…”

Section: Discussionmentioning

confidence: 99%

Predictive Factors of Oxaliplatin Neurotoxicity: The Involvement of the Oxalate Outcome Pathway

Gamelin¹,

Capitain

Morel³

et al. 2007

Clinical Cancer Research

112

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Purpose: Oxaliplatin displays a frequent dose-limiting neurotoxicity due to its interference with neuron voltage-gated sodium channels through one of its metabolites, oxalate, a calcium chelator. Different clinical approaches failed in neurotoxicity prevention, except calcium-magnesium infusions. We characterized oxalate outcome following oxaliplatin administration and its interference with cations and amino acids. We then looked for genetic predictive factors of oxaliplatininduced neurotoxicity.Experimental Design: We first tested patients for cations and oxalate levels and did amino acid chromatograms in urine following oxaliplatin infusion. In the second stage, before treatment with FOLFOX regimen, we prospectively looked for variants in genes coding for the enzymes involved (a) in the oxalate metabolism, especially glyoxylate aminotransferase (AGXT), and (b) in the detoxification glutathione cycle, glutathione S-transferase k, and for genes coding for membrane efflux proteins (ABCC2). Results: In the first 10 patients, urinary excretions of oxalate and cations increased significantly within hours following oxaliplatin infusion, accompanied by increased excretions of four amino acids (glycine, alanine, serine, and taurine) linked to oxalate metabolism. In a further 135 patients, a minor haplotype of AGXT was found significantly predictive of both acute and chronic neurotoxicity. Neither glutathione S-transferase k nor ABCC2 single nucleotide polymorphisms we looked for were linked to neurotoxicity. Conclusion: These data confirm the involvement of oxalate in oxaliplatin neurotoxicity and support the future use of AGXTgenotyping as a pretherapeutic screening test to predict individual susceptibility to neurotoxicity.Oxaliplatin, a platinum-based chemotherapeutic agent with a 1,2-diaminocyclohexane (DACH) carrier ligand, displays a characteristic pattern of neurotoxicity, which is the most frequent dose-limiting toxicity, with an acute onset of distal dysesthesia and/or paresthesia, induced or exacerbated by cold and prolonged muscular contraction after a voluntary contraction. Although these symptoms that occur during or short after infusion are transient and generally mild, when treatment is continued, a persistent sensory peripheral neuropathy can develop, eventually causing superficial and deep sensory loss, sensory ataxia, and functional impairment (1). The mechanism of chronic neurotoxicity evoked by some authors is close to that of cisplatin-being the progressive accumulation of a heavy metal, the DACH platin, in neurons and the implication of the detoxication system of glutathione (2).However, clinical neurophysiologic examinations and nerve biopsy studies have shown that patients displaying sensory symptoms have no signs or very mild signs of axonal degeneration (1). Oxaliplatin has a direct ''pharmacologic'' effect on the excitability of sensory neurons and muscle cells that has not previously been described with other platinum agents (3). Furthermore, the acute symptoms induced by oxaliplati...

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Section: Discussionmentioning

confidence: 99%

Predictive Factors of Oxaliplatin Neurotoxicity: The Involvement of the Oxalate Outcome Pathway

Gamelin¹,

Capitain

Morel³

et al. 2007

Clinical Cancer Research

112

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“…On the other hand, attempts to prevent oxaliplatin-induced neuropathy have not been sufficiently successful. There are previous randomized controlled studies [9][10][11][12][13]21] regarding prevention of oxaliplatin-induced neuropathy, including this present report. Five of the seven studies showed the efficacy of the agent in preventing oxaliplatin-induced peripheral neuropathy.…”

Section: Discussionmentioning

confidence: 58%

“…Gamelin et al [7,8] reported that administration of calcium gluconate and magnesium sulfate (Ca/Mg) before and after oxaliplatin therapy could alleviate peripheral neurotoxicity. Other similar treatments have been described, including glutathione [9], N-acetylcysteine [10], xaliproden [11], carbamazepine [12], or glutamine [13], but a preventive agent for oxaliplatin-induced neuropathy has not yet been established. The Kampo medicine, Goshajinkigan (GJG), is composed of 10 natural ingredients and is classified as a drug that affects sensory nerves [14,15].…”

Section: Introductionmentioning

confidence: 99%

The Kampo medicine, Goshajinkigan, prevents neuropathy in patients treated by FOLFOX regimen

et al. 2011

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“…[135][136][137] Notably, xaliproden was reported to lessen oxaliplatin-mediated neuropathy in a large, randomized, double-blind, placebo-controlled phase III study (n ϭ 649). 138,139 Although the use of xaliproden in this trial was not associated with a higher cumulative oxaliplatin dose or with a longer time on therapy, patients in the xaliproden arm had a significant (39%) risk reduction of developing grade 3/4 neuropathy. A phase III trial in approximately 900 patients is ongoing to confirm these results (NCT00305188), as well as a trial in ϳ250 subjects to assess the effect of xaliproden to treat the peripheral sensory neuropathy resulting from oxaliplatin-based chemotherapy (NCT00603577).…”

Section: Nonpeptide Neurotrophic Factor Modulatorsmentioning

confidence: 85%

Targeting Neuroprotection as an Alternative Approach to Preventing and Treating Neuropathic Pain

Bordet

Pruss

2009

Neurotherapeutics

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Summary:Neuropathic pain syndromes arise from dysfunction of the nerve itself, through traumatic or nontraumatic injury. Unlike acute pain syndromes, the pain is long-lasting and does not respond to common analgesic therapies. Drugs that disrupt nerve conduction and transmission or central sensitization, currently the only effective treatments, are only modestly effective for a portion of the patients suffering from neuropathic pain and come with the cost of serious adverse effects. Neurodegeneration, as a reaction to nerve trauma or chronic metabolic or chemical intoxication, appears to be an underlying cause of neuropathic pain. Identifying mechanisms of neurodegeneration and designing neuroprotective therapies is an ambitious goal toward treating or even preventing the development of these disabling disorders.

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Xaliproden lessens oxaliplatin-mediated neuropathy

Cited by 18 publications

References 0 publications

Predictive Factors of Oxaliplatin Neurotoxicity: The Involvement of the Oxalate Outcome Pathway

Predictive Factors of Oxaliplatin Neurotoxicity: The Involvement of the Oxalate Outcome Pathway

The Kampo medicine, Goshajinkigan, prevents neuropathy in patients treated by FOLFOX regimen

Targeting Neuroprotection as an Alternative Approach to Preventing and Treating Neuropathic Pain

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