Oxaliplatin-induced Neuropathy Research Articles

Goshajinkigan reduces oxaliplatin-induced peripheral neuropathy without affecting anti-tumour efficacy in rodents

Oxaliplatin is a key drug in the treatment of colorectal cancer, but it causes acute and chronic neuropathies in patients. Goshajinkigan (GJG) is a Kampo medicine that is used for the treatments of several neurological symptoms including pain and numbness. More recently, GJG has been reported to prevent the oxaliplatin-induced peripheral neuropathy in clinical studies. No experimental study, however, has been conducted to date to determine the effect of GJG on pain behaviour in a rat model of oxaliplatin-induced neuropathy. Moreover, the impact on the anti-tumour effect of oxaliplatin remains unknown. In the present study, we examined the effects of GJG on the peripheral neuropathy and anti-tumour activity of oxaliplatin in rodents. Repeated administration of oxaliplatin caused cold hyperalgesia from days 3 to 37 and mechanical allodynia from days 21 to 28. Repeated administration of GJG prevented the oxaliplatin-induced cold hyperalgesia but not mechanical allodynia and axonal degeneration in rat sciatic nerve. Single administration of GJG reduced both cold hyperalgesia and mechanical allodynia after the development of neuropathy. In addition, GJG did not affect the anti-tumour effect of oxaliplatin in the tumour cells or tumour cells-implanted mice. These results suggest that GJG relieves the oxaliplatin-induced cold hyperalgesia and mechanical allodynia without affecting anti-tumour activity of oxaliplatin, and, therefore, may be useful for the oxaliplatin-induced neuropathy in clinical practice.

Longitudinal assessment of oxaliplatin-induced neuropathy

To characterize the natural history of oxaliplatin-associated neuropathy (ON) and determine whether intraepidermal nerve fiber density (IENFD) is a sensitive measure of neuropathy progression. In addition, we sought to assess the potential of ON as a neuroprotection model and gain insight into the relationship between axon loss and neuropathic symptoms. Eight subjects receiving oxaliplatin for advanced colorectal cancer were prospectively followed prior to starting chemotherapy and at 30, 90, 180, and 360 days (180 days after completing treatment). Electrophysiology, punch biopsies, symptom assessment, and examinations with calculation of a reduced total neuropathy score (rTNS) were performed at each time point. Changes over time were assessed through Poisson regression for IENFD and a mixed effects model for rTNS and electrophysiology measures. The distal leg IENFD, rTNS, peroneal, and sural amplitudes were all significantly reduced over time, while conduction velocity (peroneal and sural) and distal thigh IENFD were not. Measures of axon loss continued to worsen following discontinuation of oxaliplatin. Five of 8 subjects reported prominent symptoms associated with oxaliplatin administration. This study demonstrates that oxaliplatin is associated with mild, sensory, and motor axon loss that may not be reversible. Axonal loss was detected by electrophysiology, rTNS, and distal leg IENFD. Several subjects reported prominent sensory symptoms that were not associated with axon loss, and that may or may not represent neuropathy. ON is an attractive paradigm for neuroprotection studies and the distal leg IENFD is an objective measure that requires minimal subject participation or study site expertise.

Human mu‐opioid receptor gene A118G polymorphism predicts the efficacy of tramadol/acetaminophen combination tablets (ultracet) in oxaliplatin‐induced painful neuropathy

The A118G polymorphism of the mu-opioid receptor gene (OPRM1), resulting in the substitution of an amino acid, has been found to be associated with functional effects and response to opioid treatment. The purpose of this study was to assess whether this polymorphism contributes to the variability in response to tramadol/acetaminophen combination tablets (Ultracet) for treating oxaliplatin-induced painful neuropathy. A total of 96 patients with adenocarcinoma of the colon or rectum (n = 84), or stomach (n = 12) who had developed oxaliplatin-induced painful neuropathy were enrolled. Ultracet was administered at 1 tablet every 6 hours, and pain was assessed and scored using a visual analog scale (VAS). The OPRM1 A118G polymorphism was examined with a polymerase chain reaction-direct sequencing method. The allelic frequency of variant (118G) allele was 39.6%, and the prevalence of OPRM1-118 AA, AG, and GG genotypes was 31.3% (n = 30), 58.3% (n = 56), and 10.4% (n = 10), respectively. For all patients, the mean pre-treatment and post-treatment VAS scores were 3.1 and 2.1, respectively (P < .001). Patients with AA genotype had a better analgesic effect than those with G allele variants (AG or GG genotypes). Pre-treatment and post-treatment VAS scores for patients with G allele variants were 3.1 and 2.6, respectively; however, for patients with AA genotype, pre-treatment and post-treatment VAS scores were 3.0 and 0.9, respectively (P < .001). The requirement for rescue analgesia was also higher for patients with G allele variants (P = .01). These data suggest that Ultracet is effective in the management of oxaliplatin-induced painful neuropathy. A118G polymorphism of OPRM1, by altered function of the mu-opioid receptor and consequential analgesic effect on opioid agents, could be a key determinant for decreased response to Ultracet.

Duloxetine improves oxaliplatin-induced neuropathy in patients with colorectal cancer: an open-label pilot study

This open-label pilot study is aimed to evaluate the efficacy and tolerability of the antidepressant duloxetine, which is effective for diabetic neuropathic pain, in the treatment of chronic oxaliplatin-induced peripheral neuropathy (OIPN). We enrolled a total of 39 patients with stage III or IV colorectal cancer with chronic OIPN. They were treated with duloxetine by increasing the dose from 30 mg/day to 60 mg/day. Patients' pain intensity was rated at baseline and 12 weeks after duloxetine administration. The severity of neuropathic pain was evaluated using the visual analog scale (VAS) score and the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 3 (NCI-CTCAE v3.0). Nine patients (23.1%) discontinued duloxetine before the end of treatment because of adverse events. Of the remaining 30 patients, 19 patients (63.3%) had a VAS score improvement. Among them, nine (47.4%) showed a simultaneous grade improvement, and the other 10 patients (52.6%) had a stable grade according to NCI-CTCAE v3.0. Treatment with duloxetine did not impair renal or liver function and did not interfere with chemotherapy. Duloxetine is feasible in treating chronic OIPN with tolerable toxicity at a daily dose of 60 mg/day.

Neurotoxicity Caused by the Treatment with Platinum Analogues

Platinum agents (cisplatin, carboplatin, and oxaliplatin) are a class of chemotherapy agents that have a broad spectrum of activity against several solid tumors. Toxicity to the peripheral nervous system is the major dose-limiting toxicity of at least some of the platinum drugs of clinical interest. Among the platinum compounds in clinical use, cisplatin is the most neurotoxic, inducing mainly sensory neuropathy of the upper and lower extremities. Carboplatin is generally considered to be less neurotoxic than cisplatin, but it is associated with a higher risk of neurological dysfunction if administered at high dose or in combination with agents considered to be neurotoxic. Oxaliplatin induces two types of peripheral neuropathy, acute and chronic. The incidence of oxaliplatin-induced neuropathy is related to various risk factors such as treatment schedule, cumulative dose, and time of infusion. To date, several neuroprotective agents including thiol compounds, vitamin E, various anticonvulsants, calcium-magnesium infusions, and other nonpharmacological strategies have been tested for their ability to prevent platinum-induced neurotoxicity with controversial results. Further studies on the prevention and treatment of neurotoxicity of platinum analogues are warranted.

Prolonged Oxaliplatin Exposure Alters Intracellular Calcium Signaling: A New Mechanism to Explain Oxaliplatin-Associated Peripheral Neuropathy

Oxaliplatin is a platinum-based cytotoxic agent commonly used to treat colorectal cancers. Despite its effectiveness, oxaliplatin administration is associated with the development of cold-induced peripheral neuropathy. This potentially permanent side effect is provoked by cold exposure and can range from mild and self limited to severe and debilitating. Even with tumor shrinkage, these painful side effects can force dose reduction or discontinuation of treatment. Neither the mechanism of action of oxaliplatin nor that of cold-induced neuropathy is understood. Paclitaxel, an entirely different chemotherapeutic agent used to treat a variety of malignancies, also is associated with the development of peripheral neuropathy. Unlike oxaliplatin, neurotoxicity arising from paclitaxel treatment was previously found to have profound effects on intracellular calcium signaling. In this study we examined the effects of oxaliplatin on calcium signaling pathways and found that acute exposure of either a neuroblastoma cell line or primary neurons with therapeutic concentrations of oxaliplatin had no effect on intracellular calcium signaling. We also found that cellular temperature sensors (transient receptor potential [TRP] channels) were also not activated by oxaliplatin. Interestingly, prolonged exposure of oxaliplatin sensitized cells to subsequent stimuli and enhanced the magnitude of intracellular calcium responses. Taken together, our results suggest that acute oxaliplatin exposure will not induce abnormal calcium signaling but oxaliplatin-primed cells do exhibit enhanced sensitivity. These findings provide new insight to the mechanism behind oxaliplatin-induced neuropathy.

Long-Term Neuropathy After Oxaliplatin Treatment: Challenging the Dictum of Reversibility

Oxaliplatin-induced neuropathy is a significant and dose-limiting toxicity that adversely affects quality of life. However, the long-term neurological sequelae have not been adequately described. The present study aimed to describe the natural history of oxaliplatin-induced neuropathy, using subjective and objective assessments. From a population of 108 oxaliplatin-treated patients referred for neurological assessment in 2002-2008, 52.2% of the surviving patient cohort (n = 24) was available for follow-up at a median of 25 months post-oxaliplatin. Patients underwent a protocol that incorporated clinical assessment scales, patient questionnaires, standard electrodiagnostic assessments, and novel nerve excitability studies to precisely assess nerve function. At follow-up, 79.2% of patients reported residual neuropathic symptoms, with distal loss of pin-prick sensibility in 58.3% of patients and loss of vibration sensibility in 83.3% of patients. Symptom severity scores were significantly correlated with cumulative dose. There was no recovery of sensory action potential amplitudes in upper and lower limbs, consistent with persistent axonal sensory neuropathy. Sensory excitability parameters had not returned to baseline levels, suggesting persisting abnormalities in nerve function. The extent of excitability abnormalities during treatment was significantly correlated with clinical outcomes at follow-up. These findings establish the persistence of subjective and objective deficits in oxaliplatin-treated patients post-oxaliplatin, suggesting that sensory neuropathy is a long-term outcome, thereby challenging the literature on the reversibility of oxaliplatin-induced neuropathy.

Dose Effects of Oxaliplatin on Persistent and Transient Na+ Conductances and the Development of Neurotoxicity

BackgroundOxaliplatin, a platinum-based chemotherapy utilised in the treatment of colorectal cancer, produces two forms of neurotoxicity- acute sensorimotor neuropathic symptoms and a dose-limiting chronic sensory neuropathy. Given that a Na+ channelopathy has been proposed as the mechanism underlying acute oxaliplatin-induced neuropathy, the present study aimed to determine specific mechanisms of Na+ channel dysfunction.Methodology/Principal FindingsSpecifically the function of transient and persistent Na+ currents were followed during treatment and were investigated in relation to oxaliplatin dose level. Eighteen patients were assessed before and after a single oxaliplatin infusion with motor and sensory axonal excitability studies performed on the median nerve at the wrist. While refractoriness (associated with Na+ channel inactivation) was significantly altered post-oxaliplatin infusion in both motor (Pre: 31.7±6.4%; Post: 68.8±14.5%; P≤.001) and sensory axons (Pre: 31.4±5.4%; Post: 21.4±5.5%; P<.05), strength-duration time constant (marker of persistent Na+ conductances) was not significantly altered post-infusion (Motor Pre: 0.395±0.01 ms; Post: 0.394±0.02 ms; NS; Sensory Pre:0.544±0.03 ms; Post: 0.535±0.05 ms; NS). However, changes in strength-duration time constant were significantly correlated with changes in refractoriness in motor and sensory axons (Motor correlation coefficient = −.65; P<.05; Sensory correlation coefficient = .67; P<.05).Conclusions/SignificanceIt is concluded that the predominant effect of acute oxaliplatin exposure in human motor and sensory axons is mediated through changes in transient rather than persistent Na+ conductances. These findings are likely to have implications for the design and trial of neuroprotective strategies.

Oxaliplatin‐induced cold hypersensitivity is due to remodelling of ion channel expression in nociceptors

Cold hypersensitivity is the hallmark of oxaliplatin-induced neuropathy, which develops in nearly all patients under this chemotherapy. To date, pain management strategies have failed to alleviate these symptoms, hence development of adapted analgesics is needed. Here, we report that oxaliplatin exaggerates cold perception in mice as well as in patients. These symptoms are mediated by primary afferent sensory neurons expressing the thermoreceptor TRPM8. Mechanistically, oxaliplatin promotes over-excitability by drastically lowering the expression of distinct potassium channels (TREK1, TRAAK) and by increasing the expression of pro-excitatory channels such as the hyperpolarization-activated channels (HCNs). These findings are corroborated by the analysis of TREK1-TRAAK null mice and use of the specific HCN inhibitor ivabradine, which abolishes the oxaliplatin-induced cold hypersensibility. These results suggest that oxaliplatin exacerbates cold perception by modulating the transcription of distinct ionic conductances that together shape sensory neuron responses to cold. The translational and clinical implication of these findings would be that ivabradine may represent a tailored treatment for oxaliplatin-induced neuropathy.

A randomized, double-blind, placebo-controlled trial for prevention of oxaliplatin-induced neuropathy symptoms with pregabalin.

553 Background: Sensorial peripheral neuropathy (PNP) is a major limitation for pts receiving oxaliplatin-based ctx for CRC. Pregabalin is widely used for treatment of oxaliplatin-induced PNP. We evaluated the efficacy of pregabalin vs. placebo for the prevention of paresthesia from the onset of oxaliplatin-based ctx over each cycle. Methods: Rd, db, placebo-controlled study in adult CRC pts with ECOG 0-2 to undergo a new oxaliplatin/5-FU/FA-based ctx. Pts were excluded if they had neuropathic pain or other of painful paresthesia prior to baseline. Paresthesia, dysesthesia, and pain were rated on a numerical scale (NRS 0-10) every day. Primary endpoint was the time of onset of persistent symptoms (NRS &gt;4). Results: Of the 69 screened pts, 64 were randomized and 61 received study medication (32 pregabalin vs. 29 placebo). Pts were balanced in both arms regarding age, sex, stage, and ctx. There were no differences between both treatment groups for all PNP parameters at any cycle. One pt in both arms developed paresthesia (5.3%) after 9 cycles of ctx, 1 pt had persistent pain (placebo arm). During the follow-up period persistent paresthesic, dysesthesic, and persistent pain developed in 2 vs. 1, 2 vs. 2, and 0 vs. 2 pts, respectively. The study was terminated after a blinded data review found that there were very few events of persistent symptoms, which was then confirmed an interim analysis. Nausea and anorexia were the most frequently reported AE in both groups. Conclusions: The results of this study, which was terminated early at interim analysis, is that too few patients developed persistent symptoms to allow any meaningful treatment difference for prevention of neuropathic pain related to oxaliplatin by pregabalin. There remains an unmet need for oxaliplatin-induced PNP with new trial design issues in this field urgently needed. No significant financial relationships to disclose.

A randomized phase II study of modified OPTIMOX1 or FOLFOX in advanced colorectal cancer.

519 Background: A combination of leucovorin (LV) and fluorouracil (FU) with oxaliplatin (FOLFOX) is a standard first-line regimen for advanced or unresectable colorectal cancer. Sensory neurotoxicity is its dose-limiting toxicity, but the OPTIMOX1 (stop and go) approach offers a reasonable strategy. This study evaluates a new strategy of intermittent oxaliplatin treatment that is based on FOLFOX4 or modified FOLFOX6 (+/− bevacizumab), a simplified leucovorin and fluorouracil regimen with normal-dose oxaliplatin. Methods: Previously untreated patients were randomly assigned to either FOLFOX administered every 2 weeks until progression (arm FOL) or FOLFOX for six cycles, maintenance without oxaliplatin for six cycles, and continued every six cycles until progression (arm OPT). Results: Sixty patients (arm FOL [n=35], arm OPT [n=33]) were enrolled. The median number of treatment cycles was 10 (range, 3-28) in arm FOL and 12.5 (range, 1-32) in arm OPT. Cumulative dose of oxaliplatin was 850 mg/m2 in arm FOL and 552.5 mg/m2 in arm OPT. Median progression-free survival was 8.5 months in patients allocated to arm FOL compared with 15 months in patients allocated to arm OPT. Response rates evaluated by RECIST criteria were 50% with arm FOL and 64% with arm OPT. National Cancer Institute Common Toxicity Criteria grade 3 toxicity was observed in 37.1% of the patients in arm FOL and 24.0% of patients in arm OPT. Grade 3 sensory neuropathy was observed in 22.8% of the patients in arm FOL and 6% of patients in arm OPT. Conclusions: Our modified OPTIMOX1 regimen may be effective and safe treatment to prevent oxaliplatin-induced neuropathy in advanced or unresectable colorectal cancer patients. No significant financial relationships to disclose.

Oxaliplatin-Induced Neuropathy in Colorectal Cancer

Oxaliplatin use in palliative and adjuvant treatment of colon cancer is frequently limited by cumulative neurotoxicity, leading to reduced quality of life and decreased dose. The mechanism of this neurotoxicity is unclear, but may relate to neuronal voltage-gated sodium channels involving calcium chelation by a metabolite of the drug. Various preventative measures have been tested to reduce the incidence of neurotoxicity, including calcium and magnesium infusions, dose interruption of the drug, and prophylactic neuromodulatory agents. Despite the promising efficacy of these measures, they are not universally accepted. Less is known about the best way to treat established neurotoxicity, which is permanent in some patients, although venlafaxine has shown promise in small clinical trials. This paper analyzes the extent, cause and risk factors for neuropathy, and the potential preventative and therapeutic treatments for oxaliplatin-induced neuropathy.

Gene polymorphisms and oxaliplatin-induced neuropathy

Gene polymorphisms and oxaliplatin-induced neuropathy

Associations between oxaliplatin-induced peripheral neuropathy and polymorphisms of the ERCC1 and GSTP1 genes

Oxaliplatin-induced chronic neuropathy is cumulative and dose-limiting; reliable predictors and determination of the mechanism of this toxic effect are needed. We retrospectively studied 51 Japanese adults with colorectal cancer who had received oxaliplatin-based chemotherapy to explore the pharmacogenetic association between oxaliplatin-induced neuropathy and polymorphisms of the excision repair cross-complementation Group 1 (ERCC1) and glutathione-S-transferases pi 1 (GSTP1) genes. For the ERCC1 C118T polymorphism, Grade 1 chronic neuropathy developed earlier in patients with C/T and T/T genotypes (median number of treatment cycles at onset = 6) than in those with the reference C/C genotype (7 cycles; p = 0.0162 by the generalized Wilcoxon test). For the GSTP1 Ile105Val polymorphism, chronic neuropathy developed earlier in patients with the reference Ile/Ile genotype (6 cycles) than in those with Ile/Val and Val/Val genotypes (9 cycles; p = 0.0321). ERCC1 C118T and GSTP1 Ile105Val polymorphisms were not significantly associated with an increased risk of developing Grade 2 or more severe chronic neuropathy. Our results suggest that ERCC1, C118T and GSTP1 Ile105Val polymorphisms are more strongly related to the time until onset of neuropathy than to the grade of neuropathy. Most likely these polymorphisms influence patients' sensitivity to neuropathy.

Utilizing natural activity to dissect the pathophysiology of acute oxaliplatin-induced neuropathy

Oxaliplatin is first-line chemotherapy for colorectal cancer, but produces dose-limiting neurotoxicity. Acute neurotoxicity following infusion produces symptoms including cold-triggered fasciculations and cramps, with subsequent chronic neuropathy developing at higher cumulative doses. Axonal excitability studies were undertaken in 15 oxaliplatin-treated patients before and immediately after oxaliplatin infusion to determine whether the mechanisms underlying acute neurotoxicity altered resting membrane potential or Na+/K+ pump function. Excitability properties were assessed before and after maximal voluntary contraction (MVC) of the abductor pollicis brevis. Following oxaliplatin infusion, abnormalities developed in the recovery cycle with refractoriness markedly increased. Following activity, changes developed consistent with axonal hyperpolarization, with proportional changes pre- and post-oxaliplatin in normalized threshold. However, recovery cycle parameters following activity were significantly and disproportionally enhanced post-oxaliplatin, with partial normalization of the recovery cycle curve post-activity. Patients with the most abnormal change in the recovery cycle after infusion demonstrated the greatest changes post-contraction. Prominent abnormalities developed in Na+ channel-associated parameters in response to natural activity, without significant alteration in axonal membrane potential or Na+/K+ pump function. Findings from the present series suggest that oxaliplatin affects nerve excitability through voltage-dependent mechanisms, with specific effects mediated through axonal Na+ channel inactivation.

Prevention of oxaliplatin-induced mechanical allodynia and neurodegeneration by neurotropin in the rat model

Oxaliplatin is a key drug for colorectal cancer, but it causes acute peripheral neuropathy (triggered by cold) and chronic neuropathy (sensory and motor neuropathy) in patients. Neurotropin, a non-protein extract from the inflamed rabbit skin inoculated with vaccinia virus, has been used to treat various chronic pains. In the present study, we investigated the effect of neurotropin on the oxaliplatin-induced neuropathy in rats. Repeated administration of oxaliplatin caused cold hyperalgesia from Day 5 to Day 29 and mechanical allodynia from Day 15 to Day 47. Repeated administration of neurotropin relieved the oxaliplatin-induced mechanical allodynia but not cold hyperalgesia, and inhibited the oxaliplatin-induced axonal degeneration in rat sciatic nerve. Neurotropin also inhibited the oxaliplatin-induced neurite degeneration in cultured pheochromocytoma 12 (PC12) and rat dorsal root ganglion (DRG) cells. On the other hand, neurotropin did not affect the oxaliplatin-induced cell injury in rat DRG cells. These results suggest that repeated administration of neurotropin relieves the oxaliplatin-induced mechanical allodynia by inhibiting the axonal degeneration and it is useful for the treatment of oxaliplatin-induced neuropathy clinically.

Étude prospective de la qualité de vie après une CHIP par oxaliplatine pour carcinose péritonéale

BackgroundCytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC) is now the reference technique for limited peritoneal carcinomatosis (PC). Operative mortality is actually at 3 or 4%, and decrease as morbidity. Together, they did not limit acceptation of HIPEC. However, one of the major limitation of this aggressive treatment is that patient can be afraid to impair overall quality of life (QoL). The aim of this article was to assess QoL in patients at least 12 months after HIPEC using Oxaliplatin. MethodPatients completed a questionnaire before and after surgery at 1, 3, 6 and 12 months. QoL was assessed with the EORTC QLQ-C30 questionnaire. ResultatsBetween September 2006 and October 2008, 32 of 35 patients who had undergone HIPEC were interviewed. PC originated in primary lesions of the colon/rectum (N = 17), ovary (N = 3), stomach (N = 3), appendix (N = 2), mesothelium (N = 2), pseudomyxoma peritonei (N = 3) and primary carcinoma of peritoneum (N = 2). The percentage of patients completing the questionnaire at each time point was: baseline = 87% (N = 28); 1 and 3 months = 46% (N = 15); 6 months = 62% (N = 20); and 12 months = 59% (N = 19). Morbidity and mortality were respectively 35 and 5%. Median hospital stay was 19 days. QoL score had decreased considerably in 60% of patients in the early postoperative assessment period after HIPEC (1 month), as compared with baseline score. Forty five per cent had reported significant pain and limitations on physical functioning. QoL score had returned to baseline at 3 months in 53,3% of patients: 20% reported lack of energy and fatigue. Fifty-five and 73% of patients had recovered their overall QoL at 6 and 12 months, respectively. Also, psychosocial problems, diarrhea and constipation, and peripheral neuropathy of oxaliplatin were reported in 20% of survivors over the course of the first year after HIPEC. ConclusionShort-term QoL with physical and functional well-being are impaired in the first few months after surgery plus HIPEC using oxaliplatin. Long-term QoL returns to baseline at 3 months; however 20% of patients still report psychosocial problems, gastrointestinal symptoms and oxaliplatin-induced neuropathy. It is useful and important for patients to see this HIPEC QoL data at the time of consultation before treatment.

Enhancement of axonal potassium conductance reduces nerve hyperexcitability in an in vitro model of oxaliplatin-induced acute neuropathy

Oxaliplatin is used in the chemotherapeutic treatment of malignant tumours. A common side effect of oxaliplatin is an acute peripheral neuropathy characterized by axonal hyperexcitability, which can be painful and is aggravated by exposure to cold. Electrophysiological studies on isolated segments of peripheral rodent nerve have been able to replicate oxaliplatin's effect on axonal hyperexcitability in vitro. In the present study we have used this in vitro model to examine whether flupirtine, a clinically available analgesic, which activates slow axonal potassium (Kv7) channels, can suppress axonal hyperexcitability resulting from exposure of peripheral nerve to oxaliplatin. In the presence of oxaliplatin (30 μM), the A-fibre compound action potential response of isolated rat nerve segments to a brief electrical stimulus (0.1 ms) changed considerably with the emergence of after-activity that persisted for a period of tens of milliseconds after the electrical stimulus. Lowering the bath temperature by 4 °C enhanced the magnitude and prolonged the time course of this axonal after-activity. Application of flupirtine (10 μM) reduced both the magnitude and duration of oxaliplatin-induced axonal after-activity in myelinated axons. These findings were also confirmed in isolated human sural nerve segments. The data indicate that activation of slow potassium channels in the A-fibres of peripheral nerve may attenuate the acute neuropathy associated with oxaliplatin in humans.

Associations between glutathione S-transferase π Ile 105Val and glyoxylate aminotransferase Pro 11Leu and Ile 340Met polymorphisms and early-onset oxaliplatin-induced neuropathy

Purpose: Although the risk of oxaliplatin-induced neuropathy depends on cumulative oxaliplatin dose, susceptibility to this adverse event differs greatly among patients. In this study, we investigated the associations between oxaliplatin-induced neuropathy and the following polymorphisms: glutathione S-transferase π ( GSTP1) Ile 105Val, and glyoxylate aminotransferase ( AGXT) Pro 11Leu and AGXT Ile 340Met. Experimental design: Eighty-two Japanese patients with histologically confirmed colorectal cancer who received at least six cycles of the modified FOLFOX6 (m-FOLFOX6) regimen were enrolled. To minimize differences in cumulative oxaliplatin dose between patients, oxaliplatin-induced neuropathy was evaluated using an oxaliplatin-specific scale during the 2-week period after completion of the sixth cycle of treatment. Results: Forty-four patients developed grade 2/3 oxaliplatin-induced neuropathy. There were more patients carrying at least one GSTP1 105Val allele among the group with grade 2/3 neuropathy (18/44, 41%) than among the group with grade 1 neuropathy (9/38, 24%), although the difference was not statistically significant ( P = 0.098). There were similar numbers of patients carrying at least one AGXT 105Met allele in the grade 2/3 neuropathy (7/44, 16%) and grade 1 neuropathy groups (5/38, 13%; P = 0.725). The AGXT 11Leu allele was not found in any of our patients or controls. Conclusions: We found no significant association between oxaliplatin-induced neuropathy and the GSTP1 Ile 105Val and AGXT Ile 340Met polymorphisms. Given that no AGXT 11Leu allele was found among our study population ( n = 177), evaluating this polymorphism in Japanese patients in future studies is likely to be uninformative.

Oxaliplatin-induced neuropathy: glial activation in spinal cord and brain

Oxaliplatin-induced neuropathy: glial activation in spinal cord and brain