Acute Peripheral Motor Neuropathy Induced by Oxaliplatin-Correlated Hypokalaemia.
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ABSTRACT:
SUBMITTER: Giampieri R
PROVIDER: S-EPMC7360012 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Oxaliplatin is a commonly used drug to treat cancer, extending the rate of disease-free survival by 20% in colorectal cancer. However, oxaliplatin induces a disabling form of neuropathy resulting in more than 60% of patients having to reduce or discontinue oxaliplatin, negatively impacting their chance of survival. Oxaliplatin-induced neuropathies are accompanied by degeneration of sensory fibers in the epidermis and hyperexcitability of sensory neurons. These morphological and functional changes have been associated with sensory symptoms such as dysesthesia, paresthesia and mechanical and cold allodynia. Various strategies have been proposed to prevent or treat oxaliplatin-induced neuropathies without success. The anti-diabetic drug metformin has been recently shown to exert neuroprotection in other chemotherapy-induced neuropathies, so here we aimed to test if metformin can prevent the development of oxaliplatin-induced neuropathy in a rat model of this condition. Animals treated with oxaliplatin developed significant intraepidermal fiber degeneration, a mild gliosis in the spinal cord, and mechanical and cold hyperalgesia. The concomitant use of metformin prevented degeneration of intraepidermal fibers, gliosis, and the altered sensitivity. Our evidence further supports metformin as a new approach to prevent oxaliplatin-induced neuropathy with a potential important clinical impact.
| S-EPMC7260677 | biostudies-literature
Project description:BackgroundThe majority of patients receiving the platinum-based chemotherapy drug oxaliplatin develop peripheral neurotoxicity. Because this neurotoxicity involves ROS production, we investigated the efficacy of mangafodipir, a molecule that has antioxidant properties and is approved for use as an MRI contrast enhancer.MethodsThe effects of mangafodipir were examined in mice following treatment with oxaliplatin. Neurotoxicity, axon myelination, and advanced oxidized protein products (AOPPs) were monitored. In addition, we enrolled 23 cancer patients with grade ≥ 2 oxaliplatin-induced neuropathy in a phase II study, with 22 patients receiving i.v. mangafodipir following oxaliplatin. Neuropathic effects were monitored for up to 8 cycles of oxaliplatin and mangafodipir.ResultsMangafodipir prevented motor and sensory dysfunction and demyelinating lesion formation. In mice, serum AOPPs decreased after 4 weeks of mangafodipir treatment. In 77% of patients treated with oxaliplatin and mangafodipir, neuropathy improved or stabilized after 4 cycles. After 8 cycles, neurotoxicity was downgraded to grade ≥ 2 in 6 of 7 patients. Prior to enrollment, patients received an average of 880 ± 239 mg/m2 oxaliplatin. Patients treated with mangafodipir tolerated an additional dose of 458 ± 207 mg/m2 oxaliplatin despite preexisting neuropathy. Mangafodipir responders managed a cumulative dose of 1,426 ± 204 mg/m2 oxaliplatin. Serum AOPPs were lower in responders compared with those in nonresponders.ConclusionOur study suggests that mangafodipir can prevent and/or relieve oxaliplatin-induced neuropathy in cancer patients. Trial registration. Clinicaltrials.gov NCT00727922. Funding. Université Paris Descartes, Ministère de la Recherche et de l'Enseignement Supérieur, and Assistance Publique-Hôpitaux de Paris.
| S-EPMC3871222 | biostudies-literature
Project description:Purpose:Oxaliplatin is a platinum compound widely used in gastrointestinal cancer treatment but produces dose-limiting peripheral neuropathy. New insights into oxaliplatin-induced peripheral neuropathy (OIPN) assessment are needed to detect more effectively this condition. In this context, we conducted Canaloxa study, a prospective preliminary clinical trial that aimed to investigate how Electrochemical Skin Conductance (ESC), a parameter used in small fiber neuropathy assessment, could be helpful in OIPN diagnosis. Methods:Cancer patients treated for at least three months with oxaliplatin and suffering from clinically OIPN were included. Electrochemical Skin Conductance, thermal thresholds, and neuropathic pain were assessed in all included patients. Results:During one year, 36 patients were included. The main result was the correlation between ESC and Neuropathic Pain Symptom Inventory score for hands (rho value = -0.69, p < 0.0001) and feet (rho value = -0.79, p < 0.0001). ESC values were lower in neuropathic patients with painful symptoms than in ones without painful symptoms (p = 0.0003 and p < 0.0001 for hands and feet, respectively). No correlation was observed between ESC and thermal thresholds. Conclusion:These preliminary data suggest that ESC could be a useful objective marker of painful oxaliplatin-induced neuropathy and could complement the use of subjective clinical scales. This study was prospectively registered on clinicaltrials.gov (NCT02827916) before patient recruitment has begun.
| S-EPMC6186322 | biostudies-literature
Project description:Management of oxaliplatin-induced peripheral neuropathy (OIPN) has proven challenging owing to the concern that any OIPN-preventing agents may also decrease the efficacy of the chemotherapeutic agent and fail to reverse established neuronal damage. Nevertheless, targeting redox signaling pathways constitutes a promising therapy in OIPN and we have previously demonstrated the protective role of nuclear factor erythroid-2 related factor 2 (NRF2) in this disorder. Here, we investigated the protective properties of formononetin (FN), a clinical preparation extract, in OIPN. RNA interference experiments revealed that FN protects against OIPN directly through activation of the NRF2 pathway. Further expression profile sequencing showed that FN exerts its protective effect via the NRF2 downstream-oxaliplatin metabolism enzyme, GSTP1. We also demonstrated that FN does not influence the chemotherapeutic function of oxaliplatin, as NRF2 exhibits a different drug metabolic enzyme activation state downstream in colorectal cell lines than that in neurons. Following synthesis of Bio-FN to screen the target binding proteins, we found that FN selectively binds to His129 and Lys131 in the BTB domain of KEAP1. In vivo experiments revealed that FN-induced activation of the NRF2 signaling pathway alleviated the nociceptive sensations in mice. Our findings highlight a new binding mechanism between KEAP1 and isoflavones for activation of the NRF2 system and suggest that pharmacological or therapeutic activation of the NRF2-GSTP1 axis may serve as an effective strategy to prevent or attenuate the progression of OIPN.
| S-EPMC7451796 | biostudies-literature
Project description:BackgroundOxaliplatin-induced peripheral neurotoxicity (OIPN) limits the dose of chemotherapy and seriously affects the quality of life. Huangqi Guizhi Wuwu Decoction (HGWD) is a classical Traditional Chinese Medicine (TCM) formula for the prevention of OIPN. However, its specific pharmacological mechanism of action remains unknown. Our study found that HGWD can effectively alleviate chronic OIPN and regulate intestinal flora. Therefore, we explored the mechanism of action of HGWD in alleviating chronic OIPN from the perspective of intestinal flora.MethodsIn this study, we established an OIPN model in C57BL/6 mice treated with different concentrations of HGWD. Mechanical pain and cold pain were assessed at certain time points, and samples of mice colon, dorsal root ganglion (DRG), serum, and feces were collected. Associated inflammation levels in the colon and DRG were detected using immunohistochemical techniques; the serum lipopolysaccharide (LPS) levels and associated inflammation were assessed using the appropriate kits; and 16S rRNA sequencing was used to examine the dynamic changes in gut microorganisms. Finally, established fecal microbiota transplantation (FMT) and antibiotic (ABX) pretreatment models were used to validate flora's role in HGWD for chronic OIPN by pain scoring and related pathological analysis.ResultsHGWD treatment significantly alleviated pain sensitivity in chronic OIPN mice. Pathological results showed that HGWD treatment improved intestinal ZO-1 expression and reduced serum LPS levels and associated inflammatory factors in the colon, serum, and DRG. The 16S rRNA results showed that HGWD restored the composition of the intestinal flora in a time-dependent manner to alleviate OIPN. FMT and ABX experiments demonstrated that HGWD can alleviate chronic OIPN by regulating intestinal flora homeostasis.ConclusionsHGWD prevents chronic OIPN by dynamically regulating intestinal flora homeostasis, thereby ameliorating intestinal barrier damage and reducing serum LPS and relevant inflammatory factor levels in the colon, serum, and DRG.
| S-EPMC10485938 | biostudies-literature
Project description:BackgroundChemotherapy-induced peripheral neuropathy (CIPN) is regarded as one of the most common dose-limiting adverse effects of several chemotherapeutic agents, such as platinum derivatives (oxaliplatin and cisplatin), taxanes, vinca alkaloids and bortezomib. CIPN affects more than 60% of patients receiving anticancer therapy and although it is a nonfatal condition, it significantly worsens patients' quality of life. The number of analgesic drugs used to relieve pain symptoms in CIPN is very limited and their efficacy in CIPN is significantly lower than that observed in other neuropathic pain types. Importantly, there are currently no recommended options for effective prevention of CIPN, and strong evidence for the utility and clinical efficacy of some previously tested preventive therapies is still limited.MethodsThe present article is the second one in the two-part series of review articles focused on CIPN. It summarizes the most recent advances in the field of studies on CIPN caused by oxaliplatin, the third-generation platinum-based antitumor drug used to treat colorectal cancer. Pharmacological properties of oxaliplatin, genetic, molecular and clinical features of oxaliplatin-induced neuropathy are discussed.ResultsAvailable therapies, as well as results from clinical trials assessing drug candidates for the prevention of oxaliplatin-induced neuropathy are summarized.ConclusionEmerging novel chemical structures-potential future preventative pharmacotherapies for CIPN caused by oxaliplatin are reported.
| S-EPMC7329798 | biostudies-literature
Project description: Not available
| S-EPMC5794697 | biostudies-literature
Project description:ContextOxaliplatin-induced peripheral neuropathy (OIPN) is a dose-limiting toxicity of oxaliplatin and affects most colorectal cancer patients. OIPN is commonly evaluated by patient symptom report, using scales to reflect impairment. They do not discriminate between unique grouping of symptoms and signs, which impedes prompt identification of OIPN.ObjectiveThe objective of this study was to identify clusters of symptoms and signs that differentiated underlying clinical severity and segregated patients within our population into OIPN subgroups.MethodsChemotherapy-naive colorectal cancer patients (N = 148) receiving oxaliplatin were administered the Total Neuropathy Score clinical (TNSc©), which includes symptom report (sensory, motor, autonomic) and sensory examination (pin sense, vibration, reflexes). The TNSc was administered before chemotherapy initiation (T0) and after cumulative doses of oxaliplatin 510-520 mg/m2 (T1) and 1020-1040 mg/m2 of oxaliplatin (T2). Using mean T2 TNSc scores, latent class analysis grouped patients into OIPN severity cohorts.ResultsLatent class analysis categorized patients into four distinct OIPN groups: low symptoms and low signs (n = 54); low symptoms and intermediate signs (n = 44); low symptoms and high signs (n = 21); and high symptoms and high signs (n = 29). No differences were noted among OIPN groups on age, sex, chemotherapy regimen, or cumulative oxaliplatin dose.ConclusionWe identified OIPN patient groups with distinct symptoms/signs, demonstrating variability of OIPN presentation regardless of cumulative oxaliplatin dose. Over half of the sample had positive findings on OIPN examination despite little or no symptoms. Sensory examination of all patients receiving oxaliplatin is indicated for timely identification of OIPN, which will allow earlier symptom management.
| S-EPMC5659746 | biostudies-literature
Project description:Chemotherapy-induced peripheral neuropathy (CIPN) is a common, dose limiting, and long-lasting side effect of chemotherapy treatment. Unfortunately, no treatment has proven efficacious for this side effect. Rodent models play a crucial role in the discovery of new mechanisms underlying the initiation, progression, and recovery of CIPN and the potential discovery of new therapeutics. However, there is limited consistency in the dose, the sex, age, and genetic background of the animal used in these studies and the outcome measures used in evaluation of CIPN rely primarily on noxious and reflexive measures. The main objective of this study was to provide a comprehensive and systematic characterization of oxaliplatin-induced peripheral neuropathy in mice by using a battery of behavioral, sensory, electrophysiological, and morphometric measures in both sexes of the two widely used strains of mice, C57BL/6J and BALB/cJ. Mice received intraperitoneal injections of 3 or 30 mg/kg cumulative doses of oxaliplatin over the course of 2 weeks. Both doses induced long-term and time-dependent mechanical and cold hypersensitivity. Our results show that 30 mg/kg oxaliplatin reduced the locomotor activity in C57BL/6J mice, and C57BL/6J females showed anxiety-like behavior one-week post completion of treatment. In the same dose group, BALB/cJ males and females sustained a larger decrease in sucrose preference than either male or female C57BL/6J mice. Both strains failed to show significant changes in burrowing and nesting behaviors. Two clinically relevant assessments of changes to the peripheral nerve fibers, nerve conduction and intraepidermal nerve fiber density (IENFD) were evaluated. Only BALB/cJ females showed significant reduction in the nerve conduction amplitude 1 week after 30 mg/kg oxaliplatin regimen. Moreover, this dose of the chemo agent reduced the IENF density in both sexes and strains. Our findings suggest that mouse strain, sex, and assay type should be carefully considered when assessing the effects of oxaliplatin and potential therapeutic interventions.
| S-EPMC8915759 | biostudies-literature
Project description:Oxaliplatin, a pivotal drug in the management of colorectal cancer, causes chemotherapy-induced peripheral neuropathy (CIPN) in a third of cancer survivors. Based on a previous cross-sectional study assessing oxaliplatin-related sensory CIPN in colorectal cancer survivors, a secondary analysis was designed to explore the possibility that different clusters of patients may co-exist among a cohort of patients with oxaliplatin-related CIPN. Other objectives were to characterize these clusters considering CIPN severity, anxiety, depression, health-related quality of life (HRQOL), patients' characteristics and oxaliplatin treatments. Among the 96 patients analyzed, three clusters were identified (cluster 1: 52, cluster 2: 34, and cluster 3: 10 patients). Clusters were significantly different according to CIPN severity and the proportion of neuropathic pain (cluster 1: low, cluster 2: intermediate, and cluster 3: high). Anxiety, depressive disorders and HRQOL alteration were lower in cluster 1 in comparison to clusters 2 and 3, but not different between clusters 2 and 3. This study underlines that patients with CIPN are not a homogenous group, and that CIPN severity is associated with psychological distress and a decline of HRQOL. Further studies are needed to explore the relation between clusters and CIPN management.
| S-EPMC8599933 | biostudies-literature