Oxaliplatin-induced Peripheral Neurotoxicity Research Articles

Efficacy and safety of traditional plant-based medicines for preventing chronic oxaliplatin-induced peripheral neurotoxicity in patients with colorectal cancer: A systematic review and meta-analysis with core herb contribution

Ethnopharmacological relevanceTraditional plant-based medicines (TMs) have been widely used to prevent chronic oxaliplatin-induced peripheral neurotoxicity (OIPN). However, the prevention and safety of TMs for chronic OIPN remain ambiguous. Furthermore, diverse TM prescriptions and complicated components limit in-depth research on the mechanisms of TMs. Aim of this studyTo determine core TMs and potential pharmacological pathways on the basis of a thorough investigation into the preventive benefits and safety of oral TMs for chronic OIPN in colorectal cancer (CRC). MethodsA search of the PubMed, Cochrane, Embase, CNKI, VIP, and Wanfang databases for RCTs reporting on TMs for chronic OIPN was conducted through December 1, 2022. Subgroup analysis, sensitivity analysis and meta-regression were applied to assess the impacts of influencing variables. The assessment of Risk of Bias was relied on Cochrane Risk of Bias tool. The funnel plot, Egger's test, and the Trim and Fill method were applied to identify potential publication bias. Trial sequential analyses (TSA) were carried out by the TSA tool to increase the robustness. The assessment of the quality of evidence was according to the GRADE system. System pharmacology analysis was employed to screen core herbal combinations to elucidate possible mechanisms for preventing chronic OIPN in CRC. ResultsThe pooled effect estimate with robustness increased by TSA analysis demonstrated that oral TMs appeared to significantly decrease the incidence of chronic OIPN (RR = 0.66, 95% CI (0.56, 0.78); P＜0.00001), leukocytopenia (RR = 0.65, 95% CI (0.54,0.79); P＜0.00001), and nausea and vomiting (RR = 0.72, 95% CI (0.61,0.84); P＜0.0001) as well as improve the Objective Response Rate (ORR) (RR = 1.31, 95% CI (1.09,1.56); P = 0.003). The incidence of severe chronic OIPN was revealed a significant reduction, particularly when chemotherapy was administered for periods of time shorter than six months (RR = 0.33, 95% CI (0.15,0.71); P = 0.005; actuation duration＜3 months; RR = 0.33, 95% CI (0.17,0.62); P = 0.0007; actuation duration≥3 months, ＜6 months). The considerable heterogeneity among studies may be attributable to the severity of dysfunction categorized by grade and accumulated dosage. Using core TMs consisting of Astragalus membranaceus (Fisch.) Bunge, Atractylodes Macrocephala Koidz., Poria cocos (Schw.) Wolf, and Codonopsis pilosula (Franch.) Nannf. To regulate nuclear factor-kappa B against inflammation caused by activation of microglia might be an approach to preventing chronic OIPN. ConclusionsTMs appear to be effective and safe in the prevention of chronic OIPN, especially severe chronic OIPN. Additionally, core TMs consisting of Astragalus membranaceus (Fisch.) Bunge, Atractylodes Macrocephala Koidz., Poria cocos (Schw.) Wolf, and Codonopsis pilosula (Franch.) Nannf were presumably responsible for reducing the incidence of chronic OIPN, and the mechanism may be related to relieving inflammation. However, quality-assured trials with long-term follow-up for exploring inflammatory factors and preliminary research on core TMs and pharmacological pathways are needed.

Oxaliplatin-induced peripheral neurotoxicity in colorectal cancer patients: mechanisms, pharmacokinetics and strategies.

Oxaliplatin-based chemotherapy is a standard treatment approach for colorectal cancer (CRC). However, oxaliplatin-induced peripheral neurotoxicity (OIPN) is a severe dose-limiting clinical problem that might lead to treatment interruption. This neuropathy may be reversible after treatment discontinuation. Its complicated mechanisms are related to DNA damage, dysfunction of voltage-gated ion channels, neuroinflammation, transporters, oxidative stress, and mitochondrial dysfunction, etc. Several strategies have been proposed to diminish OIPN without compromising the efficacy of adjuvant therapy, namely, combination with chemoprotectants (such as glutathione, Ca/Mg, ibudilast, duloxetine, etc.), chronomodulated infusion, dose reduction, reintroduction of oxaliplatin and topical administration [hepatic arterial infusion chemotherapy (HAIC), pressurized intraperitoneal aerosol chemotherapy (PIPAC), and hyperthermic intraperitoneal chemotherapy (HIPEC)]. This article provides recent updates related to the potential mechanisms, therapeutic strategies in treatment of OIPN, and pharmacokinetics of several methods of oxaliplatin administration in clinical trials.

RETRACTION NOTICE: Molecular mechanism of electroacupuncture treatment on oxaliplatin-induced peripheral neurotoxicity in rats

RETRACTION NOTICE: Molecular mechanism of electroacupuncture treatment on oxaliplatin-induced peripheral neurotoxicity in rats

Inhibition of NHE1 transport activity and gene transcription in DRG neurons in oxaliplatin-induced painful peripheral neurotoxicity

Oxaliplatin (OHP)-induced peripheral neurotoxicity (OIPN), one of the major dose-limiting side effects of colorectal cancer treatment, is characterized by both acute and chronic syndromes. Acute exposure to low dose OHP on dorsal root ganglion (DRG) neurons is able to induce an increase in intracellular calcium and proton concentration, thus influencing ion channels activity and neuronal excitability. The Na+/H+ exchanger isoform-1 (NHE1) is a plasma membrane protein that plays a pivotal role in intracellular pH (pHi) homeostasis in many cell types, including nociceptors. Here we show that OHP has early effects on NHE1 activity in cultured mouse DRG neurons: the mean rate of pHi recovery was strongly reduced compared to vehicle-treated controls, reaching levels similar to those obtained in the presence of cariporide (Car), a specific NHE1 antagonist. The effect of OHP on NHE1 activity was sensitive to FK506, a specific calcineurin (CaN) inhibitor. Lastly, molecular analyses revealed transcriptional downregulation of NHE1 both in vitro, in mouse primary DRG neurons, and in vivo, in an OIPN rat model. Altogether, these data suggest that OHP-induced intracellular acidification of DRG neurons largely depends on CaN-mediated NHE1 inhibition, revealing new mechanisms that OHP could exert to alter neuronal excitability, and providing novel druggable targets.

Targeting OCT2 with Duloxetine to Prevent Oxaliplatin-Induced Peripheral Neurotoxicity.

We found that duloxetine has potent OCT2-inhibitory properties and can diminish excessive accumulation of oxaliplatin into DRG neurons. In addition, pre-treatment of mice with duloxetine prevented OIPN without significantly altering the plasma pharmacokinetics and antitumor properties of oxaliplatin. These results suggest that intentional inhibition of OCT2-mediated transport by duloxetine can be employed as a prevention strategy to ameliorate OIPN without compromising the effectiveness of oxaliplatin-based treatment.

Efficacy of Traditional Chinese Medicine Injection in Preventing Oxaliplatin-Induced Peripheral Neurotoxicity: An Analysis of Evidence from 3598 Patients.

Background Oxaliplatin is an effective chemotherapeutic agent for the treatment of malignant tumors. However, severe oxaliplatin-induced peripheral neurotoxicity (OIPN) has been well documented. Traditional Chinese medicine injections (TCMIs) have shown significant efficacy in preventing OIPN. However, it is difficult for clinicians to determine the differences in the efficacy of various TCMIs in preventing OIPN. The aim of this study was to compare the efficacy of various TCMIs in preventing OIPN through a network meta-analysis (NMA) to further inform clinical decision-making. Methods The Chinese Journal Full Text Database, Chinese Biomedical Literature Database, Wanfang Data Knowledge Service Platform, Chinese Science and Technology Journal Full Text Database, the Cochrane Library, Web of Science, PubMed, and Embase databases were searched for randomized controlled trials (RCTs) of TCMIs for OIPN prevention. The retrieval time was from the establishment of the database to April 12, 2021. NMA was performed using Stata 14.0 software after 2 evaluators independently screened the literature, extracted information, and evaluated the risk of bias of the included studies. Results A total of 45 eligible RCTs involving 3598 cancer patients and 13 TCMIs were included. The 13 TCMIs included Xiaoaiping injection (XAPI), compound kushen injection (CKSI), Aidi injection (ADI), Brucea javanica oil emulsion injection (BJOEI), Shenmai injection (SMI), Kangai injection (KAI), Astragalus injection (AI), elemene emulsion injection (EEI), Shenfu injection (SFI), Shenqi Fuzheng injection (SIFZI), Kanglaite injection (KLEI), Huachansu injection (HCSI), and lentinan injection (LI). NMA results showed that AI was superior to AD and SIFZI was superior to ADI in reducing the incidence of grade I neurotoxicity. SIFZI was superior to EEI and ADI, and BJOEI was superior to chemotherapy alone in reducing the incidence of grade II neurotoxicity. SMI was superior to LI and CKSI in reducing the incidence of grade III neurotoxicity. SIFZI was superior to LI, BJOEI, XAPI, EEI, SMI, chemotherapy alone, HCSI, KLEI, and ADI in reducing the total incidence of grade I–IV neurotoxicity. SFI was superior to ADI. Based on the SUCRA values, AI was the most likely intervention to reduce the incidence of grade I neurotoxicity, SIFZI was the most likely intervention to reduce the total incidence of grade II and I–IV neurotoxicity, and SMI was the most likely intervention to reduce the incidence of grade III and IV neurotoxicity. Conclusion TCMIs can prevent OIPN to some extent, among which SIFZI, SMI, and AI may be the most promising TCMIs. However, given the limitations of current studies, more well-designed, high-quality clinical trials will be needed in the future to validate the benefits of TCMIs.

Quantitative proteomic analysis of oxaliplatin induced peripheral neurotoxicity

Oxaliplatin (OXA)-induced peripheral neurotoxicity (OIPN) is a high-incidence and dose-dependent adverse reaction during OXA treatment. Its underlying mechanisms remain unclear, and no effective treatment or prevention therapies are currently available. Here, we employed a data independent acquisition (DIA)-based quantitative proteomic strategy to investigate the global proteome alterations in the dorsal root ganglion (DRG) tissues from mice injected with OXA for different periods. We identified 1128 differentially regulated proteins that were divided into six subclusters according to their alteration trends. Interestingly, these proteins were involved in cellular processes such as cell cycle, ribosomal stress, metabolism, and ion transport. In addition, OXA administration induced abundance changes of ion channels and proteins associated with mitochondrial function and reactive oxygen species production. Furthermore, we investigated the effects of diroximel fumarate (DRF), an FDA-approved oral fumarate drug for the treatment of relapsing forms of multiple sclerosis. Our findings showed that DRF could effectively ameliorate symptoms of OIPN and reduce the level of oxidative stress in mice. Taken together, our study systematically mapped the proteome alteration associated with the neural toxicity of OXA, and the findings could be leveraged to better understand the mechanisms of OIPN and to develop more effect treatment therapies. SignificanceOxaliplatin (OXA)-induced peripheral neurotoxicity (OIPN) is a high-incidence and dose-dependent adverse reaction with unclear mechanism. Here we employed a data independent acquisition (DIA)-based quantitative proteomic strategy to explore the proteome changes in dorsal root ganglion (DRG) tissues from mice treated by OXA. The findings provided novel insights regarding the mechanisms of OIPN. For example, our data showed that OXA induced a broad disturbance in metabolism, particularly in glycolysis and amino acid metabolism. Additionally, we observed abundance changes of many ion channels and proteins associated with mitochondrial function and reactive oxygen species production. Furthermore, this study provided the first evidence for the possibility of repositioning diroximel fumarate (DRF) for treating OIPN.

Preliminary study of astragaloside IV on oxaliplatin-induced peripheral neurotoxicity in rats

Objective: As an effective component of Astragalus membranaceus, astragaloside IV (AS-IV) has a history of thousands of years in China. Many evidences have indicated that AS-IV has a potential neuroprotective effect. In this study, we aimed to preliminarily study the effects of AS-IV on oxaliplatin-induced peripheral neurotoxicity (OIPN) in rats. Methods: Intraperitoneal injection of oxaliplatin for 4 weeks (4 mg/kg, twice a week) was used to establish peripheral neurotoxicity in rats. 40 Sprague Dawley rats were randomly divided into five groups, eight rats in each group, including control group, model group, and three AS-IV treated groups. Different doses of AS-IV (5 mg/kg, 10 mg/kg, and 20 mg/kg, daily) were orally administrated to OIPN rats once a day for 4 weeks at beginning of oxaliplatin administration. Behaviors and histologic evaluation of sciatic nerve and dorsal root ganglia (DRG) were performed to assess the changes of peripheral neurotoxicity through mechanical allodynia and cold allodynia, immunofluorescence, H&E staining, myelin staining, and Nissl staining. Results: AS-IV treatments were able to significantly reduce oxaliplatin induced mechanical and cold allodynia. Moreover, AS-IV administration could increase the levels of NGF, but decrease the levels of TNF-α and IL-6 in oxaliplatin induced rats. AS-IV suppressed the activation of Iba-1 in anterior horn of spinal cord of OIPN rats. The myelin sheath degenerations in the sciatic nerve of OIPN rats were repaired after AS-IV administration. Through observation of sciatic nerves and DRG, AS-IV treatments improved the oxaliplatin induced pathologic injuries in a dose-dependent. Conclusion: AS-IV administration was able to attenuate the oxaliplatin-induced peripheral neurotoxicity in rats.

Monosialotetrahexosylganglioside in the treatment of chronic oxaliplatin-induced peripheral neurotoxicity: TJMUCH-GI-001, a randomised controlled trial.

BackgroundChronic oxaliplatin-induced peripheral neurotoxicity (OIPN) is the most troublesome and dose-limiting side effect of oxaliplatin. There is no effective treatment for chronic OIPN. We conducted a randomised controlled trial to investigate the efficacy of monosialotetrahexosylganglioside (GM1) in treating chronic OIPN.MethodsIn this single-centre, double-blind, phase Ⅲ trial, gastrointestinal cancer patients with persistent chronic OIPN were randomised in 1:1 ratio to receive either GM1 or placebo at Tianjin Medical University Cancer Institute and Hospital, China. GM1 was dosed at 60 mg daily for every 3 weeks or 40 mg daily for every 2 weeks. Seven- and fourteen- day infusions were administered to concurrent oxaliplatin users and oxaliplatin discontinuation patients, respectively. The primary endpoint was the relief of neurotoxicity (≥30% improvement), measured by a newly developed patient reported outcome measure (MCIPN) based on prior questionnaires including the European Organization for Research and Treatment of Cancer Quality of Life Chemotherapy Induced Peripheral Neuropathy Questionnaire twenty-item scale. Visual analogue score (VAS) was used as another instrument for patients to evaluate the total Chronic OIPN treatment effect. VAS responders (≥30% improvement), double responders (≥30% improvement in both MCIPN and VAS), and high responders (≥50% improvement in the MCIPN total score) were also calculated. The secondary endpoints were safety and quality of life. The additional endpoints are progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), and tumour response. (Trial registration number: NCT02486198 at ClinicalTrials.gov).FindingsBetween May 2015 to December 2017, 145 patients were randomly assigned to receive either GM1 (n=73) and placebo (n=72). Majority of the patients in both arms (90% in GM1 and 83% in placebo) continued receiving oxaliplatin on the trial. More patients responded in the GM1 group than in the placebo group (MCIPN responders: 53% vs 14%, VAS responders: 49% vs 22%, double responders: 41% vs 7%, and high responders: 32% vs 13%, all P < ·01). Analyses were also performed in concurrent oxaliplatin users. The results were consistent with those of the whole group. No deleterious effects of GM1 on survival or tumour response were found. There were no ≥G3 GM1-related adverse events.InterpretationIn patients with chronic OIPN, the use of GM1 reduces the severity of chronic OIPN compared with placebo.FundingThis work was supported by clinical trial development fund of Tianjin Medical University Cancer Institute and Hospital (No.C1706).

Predictive Biomarkers of Oxaliplatin-Induced Peripheral Neurotoxicity.

Oxaliplatin (OXA) is a platinum compound primarily used in the treatment of gastrointestinal cancer. OXA-induced peripheral neurotoxicity (OXAIPN) is the major non-hematological dose-limiting toxicity of OXA-based chemotherapy and includes acute transient neurotoxic effects that appear soon after OXA infusion, and chronic non-length dependent sensory neuronopathy symmetrically affecting both upper and lower limbs in a stocking-and-glove distribution. No effective strategy has been established to reverse or treat OXAIPN. Thus, it is necessary to early predict the occurrence of OXAIPN during treatment and possibly modify the OXA-based regimen in patients at high risk as an early diagnosis and intervention may slow down neuropathy progression. However, identifying which patients are more likely to develop OXAIPN is clinically challenging. Several objective and measurable early biomarkers for OXAIPN prediction have been described in recent years, becoming useful for informing clinical decisions about treatment. The purpose of this review is to critically review data on currently available or promising predictors of OXAIPN. Neurological monitoring, according to predictive factors for increased risk of OXAIPN, would allow clinicians to personalize treatment, by monitoring at-risk patients more closely and guide clinicians towards better counseling of patients about neurotoxicity effects of OXA.

Oxaliplatin rechallenge in metastatic colorectal cancer patients with clinically significant oxaliplatin-induced peripheral neurotoxicity.

We investigated whether rechallenge with oxaliplatin (OXA) can worsen the pre-existing oxaliplatin-induced peripheral neurotoxicity (OXAIPN) in metastatic colorectal cancer (mCRC) patients. Patients previously treated with OXA, having clinically significant grade 1 or 2 OXAIPN were assessed, after receiving rechallenge with OXA, using the clinical version of the Total Neuropathy Score (TNSc). Peripheral neuropathy was assessed at the end of first OXA exposure and at completion of OXA rechallenge. The first line OXA-based chemotherapy was completed at least 9 months earlier (OXA-free interval). We studied 25 mCRC patients, 14 males and 11 females, with a median age of 63 (35-77) years. After their first exposure to OXA-based chemotherapy, 9 (36%) patients developed grade 1 OXAIPN and 16 patients grade 2 (64%) neurotoxicity. OXA reintroduction with a median of 10 (8-14) cycles led to grade 1 OXAIPN in two patients (8%), grade 2 in 19 patients (76%), and grade 3 neuropathy in 4 (16%) patients Worsening of pre-existing OXAIPN was documented in seven (28%) patients and was significantly associated with higher OXA delivered cumulative dose (P < .001). Median TNSc scores following treatment (10; range 4-18) were significantly increased (P < .001), when compared to the scores recorded at the end of first line treatment (8; range 2-12). Rechallenging OXA appears to relatively worsen the severity of existing OXAIPN. However, the majority of rechallenged patients developed a clinically significant (grade 2) OXAIPN, rather than treatment-emergent grade 3. As such, OXA rechallenge might be a feasible option in patients previously having OXAIPN.

The relevance of multimodal assessment in experimental oxaliplatin-induced peripheral neurotoxicity

Chemotherapy-induced peripheral neurotoxicity represents one of the most relevant dose-limiting side effects that can affect cancer patients treated with the common antineoplastic agents. Since the severity of neurotoxicity often leads to dose reduction or early cessation of chemotherapy, the investigation of molecular mechanisms underlying chemotherapy-induced peripheral neurotoxicity is an urgent clinical need in order to better understand its physiopathology and find effective strategies for neuroprotection. Several in vivo preclinical models of chemotherapy-induced peripheral neurotoxicity have been developed but a great variability in mouse strain, dose, route of administration of the drug, treatment schedule and assessment of neurotoxicity is observed between the different published studies making difficult the comparison and interpretation of their results. In many of these studies only behavioural tests are used as outcome measures, while possible neurophysiological and neuropathological changes are not evaluated.In this study, focused on experimental oxaliplatin-induced peripheral neurotoxicity, we reproduced and compared four mouse models with very different drug dose (low or high dose-intensity) and treatment schedules (short or long-term treatment), selected from the literature. Using a multimodal assessment based on behavioural, neurophysiological and neuropathological methods, we evidenced remarkable differences in the results obtained in the selected animal models. This work suggests the importance of a multimodal approach including extensive pathological investigation to confirm the behavioural results.

Reply to a Comment Paper on the Published Paper by Canta, A. et al: "Calmangafodipir Reduces Sensory Alterations and Prevents Intraepidermal Nerve Fibers Loss in a Mouse Model of Oxaliplatin Induced Peripheral Neurotoxicity"-Antioxidants 2020, 9, 594.

The comments sent by Stehr, Lundstom and Karlsson with reference to our article "Calmangafodipir reduces sensory alterations and prevents intraepidermal nerve fiber loss in a mouse model of oxaliplatin-induced peripheral neurotoxicity" are very interesting, since they suggest possible mechanisms of action of the compound, which might contribute to its protective action [...].

Neuronal uptake transporters contribute to oxaliplatin neurotoxicity in mice.

Peripheral neurotoxicity is a debilitating condition that afflicts up to 90% of patients with colorectal cancer receiving oxaliplatin-containing therapy. Although emerging evidence has highlighted the importance of various solute carriers to the toxicity of anticancer drugs, the contribution of these proteins to oxaliplatin-induced peripheral neurotoxicity remains controversial. Among candidate transporters investigated in genetically engineered mouse models, we provide evidence for a critical role of the organic cation transporter 2 (OCT2) in satellite glial cells in oxaliplatin-induced neurotoxicity, and demonstrate that targeting OCT2 using genetic and pharmacological approaches ameliorates acute and chronic forms of neurotoxicity. The relevance of this transport system was verified in transporter-deficient rats as a secondary model organism, and translational significance of preventive strategies was demonstrated in preclinical models of colorectal cancer. These studies suggest that pharmacological targeting of OCT2 could be exploited to afford neuroprotection in cancer patients requiring treatment with oxaliplatin.

The Incidence of Oxaliplatin-Induced Peripheral Neurotoxicity at Khartoum Oncology Hospital: A Cross-Sectional Survey

Objective:Using oxaliplatin-based chemotherapy in the treatment of cancer patients can cause a unique form of acute and chronic peripheral neurotoxicities. This study mainly aims to assess the incidence of oxaliplatin-induced peripheral neuropathy (OXAIPN).Methods:A cross-sectional study among 121 patients treated with oxaliplatin-based chemotherapy was conducted during the period of January to April 2019 at Khartoum Oncology Hospital. The incidence of acute neurotoxicity was assessed using a descriptive questionnaire for most common hyperexcitability and transient symptoms, while the incidence of chronic neurotoxicity was measured by the 20-item European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for patients with chemotherapy-induced peripheral neuropathy and graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.03.Results:Acute and chronic OXAIPN were found in 49.6% and 41.3% of patients, respectively. Most of the patients who developed acute OXAIPN symptoms manifested cold-induced pharyngolaryngeal dysesthesias (73.3%) or perioral paresthesias (71.7%). No significant association exists between the severity of chronic neurotoxicity and basic demographics. Most (79.1%) of the patients did not inform the doctors about their complaints, and 43.5% of those who informed doctors did not take any medication to manage OXAIPN.Conclusions:This study exhibits that oxaliplatin-based chemotherapy can cause symptoms of peripheral neurotoxicity in most of the patients with colorectal or gastric cancer in the form of acute neurotoxicity or chronic neurotoxicity.

Acute changes in nerve excitability following oxaliplatin treatment in mice.

Oxaliplatin chemotherapy produces acute changes in peripheral nerve excitability in humans by modulating voltage-gated Na+ channel activity. However, there are few animal studies of oxaliplatin-induced neuropathy that demonstrate similar changes in excitability. In the present study, we measured the excitability of motor and sensory caudal nerve in C57BL/6 mice after oxaliplatin injections either systemically (intraperitoneal) or locally (intramuscular at the base of the tail). As opposed to intraperitoneal administration of oxaliplatin, a single intramuscular injection of oxaliplatin produced changes in both motor and sensory axons. In motor axons, oxaliplatin caused a greater change in response to long-lasting depolarization and an upward shift in the recovery cycle, particularly at 24 h [depolarizing threshold electrotonus (TEd) 10-20 ms, P = 0.0095; TEd 90-100 ms, P = 0.0056) and 48 h (TEd 10-20 ms, P = 0.02; TEd 90-100 ms, P = 0.04) posttreatment. Oxaliplatin treatment also stimulated the production of afterdischarges in motor axons. These changes were transient and showed dose dependence. Mathematical modeling demonstrated that these changes could be accounted for by slowing inactivation of voltage-gated Na+ channels by 73.3% and reducing fast K+ conductance by 47% in motor axons. In sensory axons, oxaliplatin caused an increase in threshold, a reduction in peak amplitude, and greater threshold changes to strong hyperpolarizing currents on days 4 and 8. Thus, local administration of oxaliplatin produced clinically relevant changes in nerve excitability in mice and may provide an alternative approach for the study of acute oxaliplatin-induced neurotoxicity.NEW & NOTEWORTHY We present a novel mouse model of acute oxaliplatin-induced peripheral neurotoxicity that is comparable to clinical observations. Intramuscular injection of oxaliplatin produced acute changes in motor nerve excitability that were attributable to alterations in Na+ and K+ channel activity. Conversely, we were unable to show any significant changes in nerve excitability with systemic intraperitoneal injections of oxaliplatin. This study suggests that local intramuscular injection is a valid approach for modelling oxaliplatin-induced peripheral neuropathy in animals.

Management of Oxaliplatin-Induced Peripheral Sensory Neuropathy.

Oxaliplatin-induced peripheral neurotoxicity (OIPN) is a severe and potentially permanent side effect of cancer treatment affecting the majority of oxaliplatin-treated patients, mostly with the onset of acute symptoms, but also with the establishment of a chronic sensory loss that is supposed to be due to dorsal root ganglia neuron damage. The pathogenesis of acute as well as chronic OIPN is still not completely known, and this is a limitation in the identification of effective strategies to prevent or limit their occurrence. Despite intense investigation at the preclinical and clinical levels, no treatment can be suggested for the prevention of OIPN, and only limited evidence for the efficacy of duloxetine in the treatment setting has been provided. In this review, ongoing neuroprotection clinical trials in oxaliplatin-treated patients will be analyzed with particular attention paid to the hypothesis leading to the study, to the trial strengths and weaknesses, and to the outcome measures proposed to test the efficacy of the therapeutic approach. It can be concluded that (1) prevention and treatment of OIPN still remains an important and unmet clinical need, (2) further, high-quality research is mandatory in order to achieve reliable and effective results, and (3) dose and schedule modification of OHP-based chemotherapy is currently the most effective approach to limit the severity of OIPN.

Real world, open label experience with lacosamide against acute painful oxaliplatin-induced peripheral neurotoxicity.

We report the outcome of a pilot, open-label study that tested the potential of lacosamide (200 mg/bi.d) as an effective and safe symptomatic treatment against acute painful oxaliplatin-induced peripheral neurotoxicity (OXAIPN). Lacosamide was introduced in 18 colorectal cancer patients with evidence of clinically significant acute, painful OXAIPN after infusion of the third course (T1) of oxaliplatin-based chemotherapy (FOLFOX4) and was maintained until completion of all 12 courses (T4). The OXA-Neuropathy Questionnaire (OXA-NQ) was used to record the severity of acute OXAIPN; the PI-NRS estimated the severity of neuropathic pain, while the chronic OXAIPN was graded with TNSc. The EuroQOL (EQ-5D) instrument was also applied. The Patient Global Impression of Change (PGIC) scale measured the lacosamide-attributed perception of change. LCM-responders were considered those with ≥50% reduction in PI-NRS and OXA-NQ scores at T4, compared to T1. Patients experienced on T1 a median number of acute OXAIPN symptoms of 4 and had a median neuropathic pain severity score of 6, which was strongly related to lower quality of life, according to EQ-VAS (P < .001). At T4, 12 patients (66.7%) were classified as responders. A significant clinical improvement was documented in the severity of acute OXAIPN and neuropathic pain in relation to lacosamide (P < .001) at T4 compared to T1, which was associated with improved EQ-VAS scores (P < .001). Twelve patients scored PGIC ≥5 (lacosamide-attributed) at T4. There were no incidences of early drop-outs for safety reasons. Lacosamide appears to be an effective and well-tolerated symptomatic treatment against acute, painful OXAIPN.

The clinical effect of Kampo medicine in multimodal treatment for Gastrointestinal Cancer in Japan.

Kampo medicine or Japanese/Chinese traditional herbal medicine has long been used for the treatment of various diseases, mainly in Asian countries. In recent years, Asian investigators have attempted to clarify the mechanism and clinical efficacy of Kampo medicine. This review summarizes the background, current status, and future perspectives of Kampo medicine in the multimodal treatment of gastrointestinal cancer. Regarding the clinical effect of Kampo medicine on postoperative dysfunction after gastrointestinal surgery, several investigators have reported that Daikenchuto (TJ-100) had clinical efficacy after abdominal digestive surgery. The administration of TJ-100 during the immediate postoperative period after esophageal cancer surgery, gastric cancer surgery, and liver cancer surgery appeared to promote early recovery of the postoperative bowel function. Regarding Kampo medicine for chemotherapy-induced adverse effects in gastrointestinal cancer, promising results have been obtained for Hangeshashinto (TJ-14) and Goshajinkigan (TJ-107). The addition of TJ-14 might be associated with an improvement in the duration of chemotherapy-induced oral mucositis, and the addition of TJ-107 might be associated with an improvement in oxaliplatin-induced peripheral neurotoxicity. However, while several clinical trials have shown the positive results of Kampo medication for gastrointestinal cancer treatment, the clinical effects of such medicines have been limited. Further trials to investigate the clinical benefits of Kampo medicine are needed.

RETRACTED: Molecular mechanism of electroacupuncture treatment on oxaliplatin-induced peripheral neurotoxicity in rats

Oxaliplatin (L-OHP) has been widely used in the treatment of various tumors, especially in colorectal cancer. The mechanism of peripheral neurotoxicity induced by L-OHP (OIPN) is unclear and current therapeutic options only serve to alleviate the symptoms rather than prevent OIPN. To observe the effects of electroacupuncture (EA) stimulation on OIPN in rats, rats were randomly divided into the control group, OIPN model group, and OIPN + EA group. To establish OIPN rat models, a single intraperitoneal injection with 10 mg/kg L-OHP in the OIPN model rats. Rats in the control group received a single intraperitoneal injection with 0.9% lactose. From the third day after establishing OIPN models, the rats were treated with EA. Cold allodynia and heat sensitivity were assessed using the acetone drop and the Hargreaves method, respectively. Pathological changes in nerves were detected using hematoxylin and eosin (H&amp;E) staining and transmission electron microscopy. Related mRNA and protein expression levels were measured by real-time polymerase chain reaction (PCR) and western blotting from 14 days after establishing OIPN models. Our results showed that L-OHP significantly increased the sensitivity to cold allodynia and nervous injury, which were ameliorated after EA treatment. The expression of glucocorticoid receptor alpha (GR-α) and B-cell lymphoma 2 (Bcl-2) was significantly decreased and that of Bax was significantly increased in sciatic nerve of OIPN model rats compared with control rats. However, EA treatment significantly inhibited L-OHP-induced protein expressions in rats. Moreover, compared with the control rats, the nucleus NF-κBp65 levels were significantly increased, while the cytoplasm NF-κBp65 levels were significantly decreased, which were reversed by EA treatment. In conclusion, EA treatment may reduce peripheral neurotoxicity induced by L-OHP through regulating related protein expression.