Duloxetine to prevent neuropathy in breast cancer patients under paclitaxel chemotherapy (a double-blind randomized trial).

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is one of the major side effects and main reasons for affecting quality of life and dose reduction or even discontinuation of treatment in breast cancer patients. One of the most widely prescribed chemotherapies is the "taxanes." Considering that duloxetine has been used in treating neuropathies in recent years, this study aimed to investigate its effectiveness in preventing taxane-related neuropathy. MATERIAL AND METHODS: This is a randomized controlled trial on 47 patients: 24 received a placebo and 23 received duloxetine at 30 mg daily in the first week following the injection of paclitaxel and 60 mg during the second week in each chemotherapy cycle. Patients objective (nerve conduction velocity (NCV) values) and subjective symptoms (visual analog scale including; neuropathy, paresthesia, pain, cold sensitivity, and numbness), the grades of the patients' neuropathy (calculated according to Common Terminology Criteria for Adverse Events (CTCAE) v.5), and the presence of complications, before and after each chemotherapy cycle, were recorded. RESULTS: The placebo group experienced significantly higher occurrences of new neuropathy (8/23 in duloxetine vs 16/24 in placebo, P = 0.029) in NCV by tibial nerve latency (- 0.28% vs 19.87%, P = 0.006), tibial amplitude (4.40% vs - 10.88%, P = 0.049), and median nerve latency (8.72% vs 31.16%, P = 0.039); administration of duloxetine significantly reduced the scores of neuropathies (P < 0.001), pain (P = 0.027), during chemotherapy, and 6 weeks later; however, no significant effect was observed on paresthesia, numbness, cold sensitivity, and other NCV measurements. CONCLUSIONS: Paclitaxel can cause neuropathy, lasting for a long time. Our study showed duloxetine is potentially an effective medication that can prevent subjective and objective neuropathy.

Efficacy of cryotherapy in the prevention of chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis.

PURPOSE: The study investigates cryotherapy's efficacy in mitigating Chemotherapy-induced peripheral neuropathy (CIPN), an adverse effect of chemotherapy that often leads to dosage reduction or treatment discontinuation. METHOD: The study was registered with PROSPERO (CRD42023428936). A literature search was conducted using the PubMed, Embase, and Cochrane Library databases. Randomized and nonrandomized controlled trials that investigated the effects of cryotherapy on CIPN were included for systematic review and meta-analysis. The primary outcome for prevention was the incidence of CIPN. RESULTS: We identified 17 trials involving 2,851 patients. In total, 11 trials compared the incidence of CIPN between cryotherapy and control groups. Significant differences in the incidence of CIPN at the midpoint and end of chemotherapy were observed, with risk ratios (RRs) of 0.23 (95% confidence interval [CI] = 0.13 to 0.43) and 0.54 (95% CI = 0.33 to 0.88), respectively. Cryotherapy also significantly reduced the incidence of sensory CIPN, with an RR of 0.67 (95% CI = 0.49 to 0.92). Additionally, cryotherapy demonstrated a significant reduction in the incidence of CIPN in patients with gynecological cancers (RR = 0.24, 95% CI = 0.14 to 0.41). Significantly favorable global quality of life scores following chemotherapy (standardized mean difference = 1.43; 95% CI = 0.50 to 2.36) and relieved neuropathic symptoms were found with cryotherapy. CONCLUSIONS: Cryotherapy demonstrates a pronounced preventive effect against the development of CIPN, providing substantial symptomatic relief and quality of life improvements for patients undergoing chemotherapy. The administration of cryotherapy through the use of frozen gloves and socks, or continuous-flow cooling systems, optimally initiated 15 min prior to and concluded 15 min following chemotherapy, is recommended for achieving maximum therapeutic efficacy.

Cropsi study: Efficacy and safety of cryotherapy and cryocompression in the prevention of chemotherapy-induced peripheral neuropathy in patients with breast and gynecological cancer-A prospective, randomized trial.

OBJECTIVE: This study aimed to demonstrate the superiority of cryocompression over cryotherapy alone in the prevention of chemotherapy-induced peripheral neuropathy (CIPN) grade 2 or above. METHODS: This prospective randomized study was conducted between May 2020 and January 2023 in Innsbruck. Eligible patients had a diagnosis of gynecological cancer and received a minimum of 3 cycles of taxane-based CT (neoadjuvant, adjuvant or palliative therapy). Patients were randomized 1:1 to receive either cryotherapy or cryocompression on their upper extremities during chemotherapy (CT). We performed temperature measurements, two QoL questionnaires and neurological tests during CT and at follow-up 3 and 6-9 months after the completion of CT. CIPN was assessed using the CTCAE score. RESULTS: Of 200 patients recruited, both groups showed a lower prevalence of CIPN in this study compared to recent literature. In the group receiving cryotherapy, the prevalence of grade 1 CIPN was 30.1 %, and that of grade 2 CIPN or above was 13.7 %; in the group treated with cryocompression, the prevalence of grade 1 CIPN was 32.8 %, and that of grade 2 or above CIPN was 17.2 %. We found a significant reduction in temperature in the cryotherapy and cryocompression groups. Regarding the two QOL questionnaires as well as the neurological tests no significant differences were found between the two groups. CONCLUSION: Our study suggests that cryotherapy as well as cryocompression is a safe and effective way to cool patients' extremities to lower the prevalence of CIPN. Cryocompression was not more effective than cryotherapy alone in the prevention of CIPN.

Effect of gradient pressure therapy on the prevention of chemotherapy-induced peripheral neuropathy in patients with breast cancer.

PURPOSE: To investigate the effect of gradient pressure therapy on the prevention of chemotherapy-induced peripheral neuropathy (CIPN) and improvement in activities of daily living (ADL) in patients with breast cancer. METHODS: Eighty female patients with breast cancer treated at Tangshan People's Hospital between October 2022 and July 2023 were selected as research participants and divided into control and intervention, with 40 patients in each group. The control group received routine treatment and care, whereas the intervention group received gradient pressure therapy based on routine treatment and care. Incidence of peripheral neuropathy and the degree of impact on ADL between the two groups were compared after the intervention for cycles 2, 4, and 6. RESULTS: There was no significant difference in the general information between the two groups (P > 0.05). After two intervention cycles, there was no significant difference in the incidence of CIPN, various dimensions of Chemotherapy-Induced Peripheral Neuropathy Assessment Tool (CIPNAT), and total scores between the two groups (P > 0.05). After four intervention cycles, the two groups had a statistically significant difference in the incidence of CIPN, sensory dimension, general activity dimension, and total CIPNAT score (P < 0.05). After six intervention cycles, there was a significant difference in the incidence of CIPN, sensory dimension, fine activity dimension, general activity dimension, and total CIPNAT score between the two groups (P < 0.05), while there was no significant difference in the other dimensions (P > 0.05). CONCLUSIONS: Gradient pressure therapy can effectively prevent or alleviate peripheral neuropathy in patients with breast cancer undergoing chemotherapy and improve their ability to perform ADL. Thus, it is safe, effective, and worthy of clinical application. TRIAL REGISTRATION: RMYY-LLKS-2022-054.

Efficacy of the traditional Chinese medicine, Buyang Huanwu Decoction, at preventing taxane-induced peripheral neuropathy in breast cancer patients: A prospective, randomized, controlled study.

BACKGROUND: Buyang Huanwu Decoction (BYHWD) is a traditional Chinese prescription, originally derived from Yi Lin Gai Cuo during the Qing Dynasty. This study aimed to evaluate the efficacy and safety of BYHWD in the prevention of taxane-induced peripheral neuropathy (TIPN) in patients with breast cancer. METHODS: This single-center, statistician-blinded, parallel-group, simple randomized, no-treatment controlled study was conducted at the China-Japan Friendship Hospital in Beijing. Sixty breast cancer patients scheduled to receive nab-paclitaxel-based chemotherapy were randomly assigned to either the BYHWD group (N = 30) or the control group (N = 30) using simple randomization procedures. The data analysts were unaware of the treatment allocation. The primary efficacy endpoints were the incidence and severity of TIPN in the 2 groups, assessed using the Common Terminology Criteria for Adverse Events (CTCAE) and Patients' Neurotoxicity Questionnaire (PNQ). The secondary efficacy endpoint was the score of Functional Assessment of Cancer Therapy-Breast for both groups. The primary safety endpoints were routine blood test results and liver and renal functions. Both groups were subjected to 4 chemotherapy cycles. Efficacy and safety analyses were conducted on an intention-to-treat basis. RESULTS: The incidence of TIPN in the BYHWD group was 50.0%, which was lower than the 80.0% incidence in the control group (ß = -1.881 [95%CI -3.274, -.488]; P = .008, adjusted). The probability of TIPN in the BYHWD group was 15.2% of that in the control group, representing a significant reduction in incidence (odds ratio = .152, [95%CI .038, 0.614]; P = .008, adjusted). The CTCAE and PNQ grades of the BYHWD group were 1.527 and 1.495 points lower than those of the control group at the same cycle, respectively (CTCAE: ß = -1.527 [95%CI -2.522, -.533]; P = .003, adjusted; PNQ: ß = -1.495 [95%CI -2.501, -.489]; P = .004, adjusted, respectively). After treatment, the Functional Assessment of Cancer Therapy-Breast scores in the BYHWD group were significantly better than those in the control group (P = .003), especially in the physiological, functional, and additional concerns domains. CONCLUSION: Buyang Huanwu decoction (BYHWD) can effectively prevent TIPN and improve the quality of life in patients with breast cancer.

Study protocol: fish oil supplement in prevention of oxaliplatin-induced peripheral neuropathy in adjuvant colorectal cancer patients - a randomized controlled trial. (OxaNeuro).

BACKGROUND: Oxaliplatin-induced peripheral neuropathy (OIPN) in general and painful OIPN in particular is a debilitating late effect that severely affects cancer survivors' quality of life and causes premature cessation of potentially lifesaving treatment. No preventive treatments and no effective treatment for chronic OIPN exist despite many attempts. One of several suggested mechanisms includes neuroinflammation as a contributing factor to OIPN. Fish oil containing long-chain n-3 polyunsaturated fatty acids (n-3 LCPUFAs) are precursors to specialized proresolving mediators that mediate the resolution of inflammation. Our primary hypothesis is that a high supplementation of n-3 LCPUFAs will lower the prevalence and severity of OIPN. METHODS: The OxaNeuro project is an investigator-initiated, multicenter, double-blinded, randomized, placebo-controlled clinical study. We will include 120 patients eligible to receive adjuvant oxaliplatin after colorectal cancer surgery. Patients will receive fish oil capsules containing n-3 LCPUFAs or corn oil daily for 8 months. The primary endpoint is the prevalence of OIPN at 8 months defined as relevant symptoms, including one of the following: abnormal nerve conduction screening, abnormal vibration threshold test, abnormal skin biopsy, or abnormal pinprick test. Additional endpoints include the intensity and severity of OIPN-related neuropathic pain, patient-reported OIPN symptoms, quality of life, mental health symptoms, body composition, and cognitive evaluation. Furthermore, we will evaluate inflammatory biomarkers in blood samples and skin biopsies, including the potential OIPN biomarker neurofilament light protein (NfL) which will be measured before each cycle of chemotherapy. DISCUSSION: If readily available fish oil supplementation alleviates OIPN prevalence and severity, it will significantly improve the lives of both cancer survivors and palliative cancer patients receiving oxaliplatin; it will improve their quality of life, optimize chemotherapeutic treatment plans by lowering the need for dose reduction or premature cessation, and potentially increase survival. TRIAL REGISTRATION: ClinicalTrial.gov identifier: NCT05404230 Protocol version: 1.2, April 25th. 2023.

Compression therapy using surgical gloves is ineffective for the prevention of vincristine-induced neuropathy in patients with malignant lymphoma.

PURPOSE: Vincristine (VCR) often induces peripheral neuropathy (PN) as an adverse event. Currently, there is no consensus on the prevention of vincristine-induced PN (VIPN). In this study, we aimed to investigate the efficacy of compression therapy using surgical gloves for preventing VIPN. METHODS: Patients with malignant lymphoma (vincristine-naïve) who were receiving chemotherapy with cyclophosphamide, doxorubicin, VCR, and prednisolone, with or without rituximab, every 3 weeks for six cycles were eligible. For every VCR infusion, each patient wore two one-size-smaller gloves on one hand (study hand) for 90 min. The other hand was left bare (control hand). PN was assessed at each treatment using the Common Terminology Criteria for Adverse Events ver. 4.0. RESULTS: Fifty-one patients with malignant lymphoma were enrolled and 44 were evaluated. At 1 month after treatment, the occurrence rates of grade ≥ 2 sensory PN were 13.6 and 13.6% in the study and control hands, respectively (p = 1.0), and those of grade ≥ 2 motor PN were 15.9 and 15.9% in the study and control hands, respectively (p = 1.0). CONCLUSION: Compression therapy using surgical gloves showed no significant effect for the prevention of VIPN. TRIAL REGISTRATION: November 1, 2018, National University Hospital Council of Japan (UMIN 000034145).

Contributions of neuroimmune interactions to chemotherapy-induced peripheral neuropathy development and its prevention/therapy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating sequela that is difficult for both clinicians and cancer patients to manage. Precise mechanisms of CIPN remain elusive and current clinically prescribed therapies for CIPN have limited efficacy. Recent studies have begun investigating the interactions between the peripheral and central nervous systems and the immune system. Understanding these neuroimmune interactions may shift the paradigm of elucidating CIPN mechanisms. Although the contribution of immune cells to CIPN pathogenesis represents a promising area of research, its fully defined mechanisms have not yet been established. Therefore, in this review, we will discuss (i) current shortcoming of CIPN treatments, (ii) the roles of neuroimmune interactions in CIPN development and (iii) potential neuroimmune interaction-targeting treatment strategies for CIPN. Interestingly, monocytes/macrophages in dorsal root ganglia; microglia and astrocytes in spinal cord; mast cells in skin; and Schwann cell near peripheral nerves have been identified as inducers of CIPN behaviors, whereas T cells have been found to contribute to CIPN resolution. Additionally, nerve-resident immune cells have been targeted as prevention and/or therapy for CIPN using traditional herbal medicines, small molecule inhibitors, and intravenous immunoglobulins in a preclinical setting. Overall, unveiling neuroimmune interactions associated with CIPN may ultimately reduce cancer mortality and improve cancer patients' quality of life.

Diabetes-induced peripheral neuropathy: Is prescribing physical exercise the answer?

Diabetes mellitus, a chronic metabolic disorder characterized by hyperglycemia, has become a global health concern with an increasing prevalence worldwide. The International Diabetes Federation (IDF) estimates that over 537 million adults currently have diabetes, and they project that this figure will likely exceed 780 million by 2045. In addition, a further 541 million adults are thought to exhibit impaired glucose tolerance/prediabetes. Among its many complications, diabetic peripheral neuropathy (DPN) affects up to 50% of sufferers, with some studies showing that its prevalence, even in prediabetes, may be as high as 77%. Read more in the PDF.

Discovery and Preclinical Evaluation of a Novel Inhibitor of FABP5, ART26.12, Effective in Oxaliplatin-Induced Peripheral Neuropathy.

Oxaliplatin-induced peripheral neuropathy (OIPN) is a dose-limiting toxicity characterised by mechanical allodynia and thermal hyperalgesia, without any licensed medications. ART26.12 is a fatty acid-binding protein (FABP) 5 inhibitor with antinociceptive properties, characterised here for the prevention and treatment of OIPN. ART26.12 binds selectively to FABP5 compared to FABP3, FABP4, and FABP7, with minimal off-target liabilities, high oral bioavailability, and a NOAEL of 1,000 mg/kg/day in rats and dogs. In an established preclinical OIPN model, acute oral dosing (25-100 mg/kg) showed a cannabinoid receptor type 1 (CB1)-dependent anti-allodynic effect lasting up to 8 hours (persisting longer than plasma exposure to ART26.12). Antagonists of cannabinoid receptor type 2 (CB2), peroxisome proliferator-activated receptor alpha, and transient receptor potential cation channel subfamily V member 1 (TRPV1) may have also been implicated. Twice daily oral dosing (25 mg/kg bis in die (BID) for 7 days) showed anti-allodynic effects in an established OIPN model without the development of tolerance. In a prevention paradigm, coadministration of ART26.12 (10 and 25 mg/kg BID for 15 days) with oxaliplatin prevented thermal hyperalgesia, mitigated mechanical allodynia, and attenuated OXA-induced weight loss. Multi-scale analyses revealed widespread lipid modulation, particularly among N-acyl amino acids in the spinal cord, including potential analgesic mediators. Additionally, ART26.12 administration led to upregulation of ion channels in the periaqueductal grey, and broad translational upregulation within the plasma proteome. These results show promise that ART26.12 is a safe and well-tolerated candidate for the treatment and prevention of OIPN through lipid modulation. PERSPECTIVE: Inhibition of fatty acid-binding protein 5 (FABP5) is a novel target for reducing pain associated with chemotherapy. ART26.12 is a safe and well-tolerated small molecule FABP5 inhibitor effective at preventing and reducing pain induced with oxaliplatin through lipid modulation and activation of cannabinoid receptors.

Protective Effects of Glatiramer Acetate Against Paclitaxel-Induced Peripheral Neuropathy in Rats: A Role for Inflammatory Cytokines and Oxidative Stress.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major challenge for cancer patients who undergo chemotherapy with paclitaxel. Therefore, finding effective therapies for CIPN is crucial. Glatiramer acetate is used to treat multiple sclerosis that exerts neuroprotective properties in various studies. We hypothesized that glatiramer acetate could also improve the paclitaxel-induced peripheral neuropathy. We used a rat model of paclitaxel (2 mg/kg/every other day for 7 doses)-induced peripheral neuropathy. Rats were treated with either different doses of glatiramer acetate (1, 2, 4 mg/kg/day) or its vehicle for 14 days in separate groups. The mechanical and thermal sensitivity of the rats by using the Von Frey test and the Hot Plate test, respectively, were assessed during the study. The levels of oxidative stress (malondialdehyde and superoxide dismutase), inflammatory markers (TNF-α, IL-10, NF-kB), and nerve damage (H&E and S100B staining) in the sciatic nerves of the rats were also measured at the end of study. Glatiramer acetate (2 and 4 mg/kg) exerted beneficial effects on thermal and mechanical allodynia tests. It also modulated the inflammatory response by reducing TNF-α and NF-κB levels, enhancing IL-10 production, and improving the oxidative stress status by lowering malondialdehyde and increasing superoxide dismutase activity in the sciatic nerve of the rats. Furthermore, glatiramer acetate enhanced nerve conduction velocity in all treatment groups. Histological analysis revealed that glatiramer acetate (2 and 4 mg/kg) prevented paclitaxel-induced damage to the nerve structure. These results suggest that glatiramer acetate can alleviate the peripheral neuropathy induced by paclitaxel.

Protective effect of alpha-lipoic acid and epalrestat on oxaliplatin-induced peripheral neuropathy in zebrafish.

INTRODUCTION/AIMS: Oxaliplatin is a platinum-based anti-cancer drug widely used in colorectal cancer patients, but it may cause peripheral neuropathy. As one of the main causes of oxaliplatin-induced peripheral neuropathy (OPN) is oxidative stress, which is also a key factor causing diabetic peripheral neuropathy (DPN), the aim of this study was to evaluate the preventive effects of alpha-lipoic acid (ALA) and epalrestat (EP), which are used for the treatment of DPN, in an OPN zebrafish model. METHODS: Tg(nbt:dsred) transgenic zebrafish, with sensory nerves in the peripheral lateral line, were treated with oxaliplatin, oxaliplatin/EP, and oxaliplatin/ALA for 4 days. A confocal microscope was used to visualize and quantify the number of axon bifurcations in the distal nerve ending. To analyze the formation of synapses on sensory nerve terminals, quantification of membrane-associated guanylate kinase (MAGUK) puncta was performed using immunohistochemistry. RESULTS: The number of axon bifurcations and intensity of MAGUK puncta were significantly reduced in the oxaliplatin-treated group compared with those in the embryo medium-treated group. In both the oxaliplatin/EP and oxaliplatin/ALA-treated groups, the number of axon bifurcations and intensity of MAGUK puncta were greater than those in the oxaliplatin-treated group (p < .0001), and no significant difference was observed between larvae treated with oxaliplatin/ALA 1 µM and oxaliplatin/EP 1 µM (p = .4292). DISCUSSION: ALA and EP have protective effects against OPN in zebrafish. Our findings show that ALA and EP can facilitate more beneficial treatment for OPN.

Spinal Neuronal miR-124 Inhibits Microglial Activation and Contributes to Preventive Effect of Electroacupuncture on Chemotherapy-Induced Peripheral Neuropathy in Mice.

Chemotherapy-induced peripheral neuropathy (CIPN) is a persistent and irreversible side effect of antineoplastic agents. Patients with CIPN usually show chronic pain and sensory deficits with glove-and-stocking distribution. However, whether spinal neuronal microRNA (miR)-124 is involved in cisplatin-induced peripheral neuropathy remains to be studied. In this study, miR-124 was significantly reduced in the spinal dorsal horn in CIPN mice. Overexpression of neuronal miR-124 induced by injecting adeno-associated virus with neuron-specific promoter into the spinal cord of mice prevented the development of mechanical allodynia, sensory deficits, and the loss of intraepidermal nerve fibers induced by cisplatin. Meanwhile, cisplatin-induced M1 microglia activation and the release of proinflammatory cytokines were significantly inhibited by overexpression of neuronal miR-124. Furthermore, electroacupuncture (EA) treatment upregulated miR-124 expression in the spinal dorsal horn of CIPN mice. Interestingly, downregulation of spinal neuronal miR-124 significantly inhibited the regulatory effect of EA on CIPN and microglia activity as well as spinal neuroinflammation induced by cisplatin. These results demonstrate that spinal neuronal miR-124 is involved in the prevention and treatment of EA on cisplatin-induced peripheral neuropathy in mice. Our findings suggest that spinal neuronal miR-124 might be a potential target for EA effect, and we provide, to our knowledge, a new experimental basis for EA prevention of CIPN.

Randomized adaptive selection trial of cryotherapy, compression therapy, and placebo to prevent taxane-induced peripheral neuropathy in patients with breast cancer.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating adverse effect of taxane therapy. Small non-randomized studies in patients with early-stage breast cancer (ESBC) suggest both cryotherapy and compression therapy may prevent CIPN. It is unknown which is more effective. METHODS: We conducted a randomized phase IIB adaptive sequential selection trial of cryotherapy vs. compression therapy vs. placebo ("loose" gloves/socks) during taxane chemotherapy. Participants were randomized in triplets. Garments were worn for 90-120 min, beginning 15 min prior and continuing for 15 min following the infusion. The primary goal was to select the best intervention based on a Levin-Robbins-Leu sequential selection procedure. The primary endpoint was a < 5-point decrease in the Functional Assessment of Cancer Therapy Neurotoxicity (FACT-NTX) at 12 weeks. An arm was eliminated if it had four or more fewer successes than the currently leading arm. Secondary endpoints included intervention adherence and patient-reported comfort/satisfaction. RESULTS: Between April 2019 and April 2021, 63 patients were randomized (cryotherapy (20); compression (22); placebo (21)). Most patients (60.3%) were treated with docetaxel. The stopping criterion was met after the 17th triplet (n = 51) was evaluated; success at 12 weeks occurred in 11 (64.7%) on compression therapy, 7 (41.1%) on cryotherapy, and 7 (41.1%) on placebo. Adherence to the intervention was lowest with cryotherapy (35.0%) compared to compression (72.7%) and placebo (76.2%). CONCLUSION: Compression therapy was the most effective intervention in this phase IIB selection trial to prevent CIPN and was well tolerated. Compression therapy for the prevention of CIPN should be evaluated in a phase III study. CLINICAL TRIAL REGISTRATION: ClinicaTrials.gov Identifier: NCT03873272.

Prevention of vincristine-induced peripheral neuropathy by protecting the endothelial glycocalyx shedding.

Vincristine-induced peripheral neuropathy (VIPN) adversely affects the quality of life and treatment continuity of patients. The endothelial glycocalyx (eGCX) protects nerves from harmful substances released from the capillary vessels, but its role in peripheral neuropathy remains unclear. We investigated the impact of eGCX protection on VIPN. Using a murine model of VIPN, we administered nafamostat mesylate to protect the eGCX shedding, and analyzed the eGCX integrity and manifestation of peripheral neuropathy. Nafamostat treatment suppressed allodynia associated with neuropathy. Additionally, nafamostat administration resulted in the suppression of increased vascular permeability in capillaries of peripheral nerves, further indicating its positive influence on eGCX in VIPN model mice. This study provided the importance of eGCX in VIPN. With the potential for rapid clinical translation through drug repositioning, nafamostat may be a new promising treatment for the prevention of VIPN.

A partial agonist of PPARγ prevents paclitaxel-induced peripheral neuropathy in mice, by inhibiting neuroinflammation.

BACKGROUND AND PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of paclitaxel, affecting 30-50% of patients. Increased survival and concern with patients' quality of life have encouraged the search for new tools to prevent paclitaxel-induced neuropathy. This study presents the glitazone 4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-N-phenylbenzene-sulfonamide (TZD-A1) as a partial agonist of peroxisome proliferator-activated receptor γ (PPARγ), its toxicological profile and effects on paclitaxel-induced CIPN in mice. EXPERIMENTAL APPROACH: Interactions of TZD-A1 with PPARγ were analysed using in silico docking and in vitro reporter gene assays. Pharmacokinetics and toxicity were evaluated using in silico, in vitro and in vivo (C57Bl/6 mice) analyses. Effects of TZD-A1 on CIPN were investigated in paclitaxel-injected mice. Axonal and dorsal root ganglion damage, mitochondrial complex activity and cytokine levels, brain-derived neurotrophic factor (BDNF), nuclear factor erythroid 2-related factor 2 (Nrf2) and PPARγ, were also measured. KEY RESULTS: Docking analysis predicted TZD-A1 interactions with PPARγ compatible with partial agonism, which were corroborated by in vitro reporter gene assays. Good oral bioavailability and safety profile of TZD-A1 were shown in silico, in vitro and in vivo. Paclitaxel-injected mice, concomitantly treated with TZD-A1 by i.p. or oral administration, exhibited decreased mechanical and thermal hypersensitivity, effects apparently mediated by inhibition of neuroinflammation and mitochondrial damage, through increasing Nrf2 and PPARγ levels, and up-regulating BDNF. CONCLUSION AND IMPLICATIONS: TZD-A1, a partial agonist of PPARγ, provided neuroprotection and reduced hypersensitivity induced by paclitaxel. Allied to its safety profile and good bioavailability, TZD-A1 is a promising drug candidate to prevent and treat CIPN in cancer patients.

Mitotherapy prevents peripheral neuropathy induced by oxaliplatin in mice.

Oxaliplatin (OXA) is an antineoplastic agent used for the treatment of cisplatin-resistant tumours, presenting lower incidence of nephrotoxicity and myelotoxicity than other platinum-based drugs. However, OXA treatment is highly associated with painful peripheral neuropathy, a well-known and relevant side effect caused by mitochondrial dysfunction. The transfer of functional exogenous mitochondria (mitotherapy) is a promising therapeutic strategy for mitochondrial diseases. We investigated the effect of mitotherapy on oxaliplatin-induced painful peripheral neuropathy (OIPN) in male mice. OIPN was induced by i.p. injections of oxaliplatin (3 mg/kg) over 5 consecutive days. Mechanical (von Frey test) and cold (acetone drop test) allodynia were evaluated between 7 and 17 days after the first OXA treatment. Mitochondria was isolated from donor mouse livers and mitochondrial oxidative phosphorylation was assessed with high resolution respirometry. After confirming that the isolated mitochondria were functional, the organelles were administered at the dose of 0.5 mg/kg of mitochondrial protein on days 1, 3 and 5. Treatment with OXA caused both mechanical and cold allodynia in mice that were significant 7 days after the initial injection of OXA and persisted for up to 17 days. Mitotherapy significantly prevented the development of both sensory alterations, and attenuated body weight loss induced by OXA. Mitotherapy also prevented spinal cord ERK1/2 activation, microgliosis and the increase in TLR4 mRNA levels. Mitotherapy prevented OIPN by inhibiting neuroinflammation and the consequent cellular overactivity in the spinal cord, presenting a potential therapeutic strategy for pain management in oncologic patients undergoing OXA treatment.

Cryotherapy for prevention of chemotherapy induced peripheral neuropathy in breast cancer.

Peripheral neuropathy is a well-described complication of chemotherapy. There are no known treatments to reverse peripheral neuropathy. Chemotherapy-induced peripheral neuropathy is a dose-limiting toxicity in cancer treatment and is debilitating. Cryotherapy, or the use of cold garments/ice bags applied to extremities during chemotherapy, is a method to prevent or minimize treatment related neuropathy. There is no standard method of providing cryotherapy currently. A review of the literature was performed revealing that a variety of cryotherapy methods exist. While small studies suggest potential preventive effect of some forms of cryotherapy, consistent results from well-designed randomized studies are lacking. A small benefit from the use of cryotherapy to prevent peripheral neuropathy might exist, but conflicting studies exist. In light of the low cost to implement ice bags during chemotherapy and the low risk of toxicity, the use of ice bags may be reasonable during taxane chemotherapy for the treatment of breast cancer.

Renin-angiotensin-aldosterone system inhibitors are associated with improved paclitaxel-induced peripheral neuropathy in lung cancer: a study using administrative claims data.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) has been reported to reduce patients' quality of life and impair cancer treatment by causing anticancer drug withdrawal or interruption. However, there are currently no effective methods for the prevention of CIPN. Renin-angiotensin-aldosterone system (RAAS) inhibitors may be associated with a reduced risk of developing oxaliplatin-induced peripheral neuropathy, and it would be valuable to examine whether they have the same effect on CIPN caused by other anticancer drugs. Our study explored the potential preventive effects of RAAS inhibitors on preventing paclitaxel-induced peripheral neuropathy (PIPN). METHODS: An exploratory cohort study was conducted using commercially available administrative claims data on lung cancer patients treated with paclitaxel-based chemotherapy. Cumulative paclitaxel doses, RAAS inhibitor prescriptions, and incidences of PIPN were identified using patient medical records. Fine-Gray analyses with death as a competing risk were performed. A propensity score approach was applied to address the problem of confounding. RESULTS: Patients with lung cancer who received paclitaxel-based chemotherapy were classified into users of RAAS inhibitor (n = 1320) and non-users of RAAS inhibitor (n = 4566). The doses of RAAS inhibitors in our study were similar to those commonly used to treat hypertension. The PIPN incidence was significantly lower in users of RAAS inhibitor than in the non-users of RAAS inhibitor (sub-distribution hazard ratio, 0.842; 95% confidence interval, 0.762-0.929). The result was consistent in various sensitivity analyses and important subgroup analyses. CONCLUSIONS: RAAS inhibitors at doses commonly used for hypertension were associated with a reduced incidence of PIPN in patients with lung cancer.