ArticleLiterature Review

Wolf S, Barton D, Kottschade L, Grothey A, Loprinzi CChemotherapy-induced peripheral neuropathy: prevention and treatment strategies. Eur J Cancer 44: 1507-1515

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  • West Cancer Center
Article

Wolf S, Barton D, Kottschade L, Grothey A, Loprinzi CChemotherapy-induced peripheral neuropathy: prevention and treatment strategies. Eur J Cancer 44: 1507-1515

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Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose limiting side effect of many commonly used chemotherapeutic agents, including platinum drugs, taxanes, epothilones and vinca alkaloids, and also newer agents such as bortezomib and lenolidamide. Symptom control studies have been conducted looking at ways to prevent or alleviate established CIPN. This manuscript provides a review of studies directed at both of these areas. New evidence strongly suggests that intravenous calcium and magnesium therapy can attenuate the development of oxaliplatin-induced CIPN, without reducing treatment response. Accumulating data suggest that vitamin E may also attenuate the development of CIPN, but more data regarding its efficacy and safety should be obtained prior to its general use in patients. Other agents that look promising in preliminary studies, but need substantiation, include glutamine, glutathione, N-acetylcysteine, oxcarbazepine, and xaliproden. Effective treatment of established CIPN, however, has yet to be found. Lastly, paclitaxel causes a unique acute pain syndrome which has been hypothesised to be caused by neurologic injury. No drugs, to date, have been proven to prevent this toxicity.

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... In addition, the solvent used to formulate paclitaxel, Cremophor ® EL (now renamed as Kolliphor ® EL), has been associated with neurotoxic effects in animal studies (Authier, Gillet, Fialip, Eschalier, & Coudore, 2000;Windebank, Blexrud, & de Groen, 1994). Unfortunately, effective therapies for treating all patients with TIPN are not yet available (Wolf, Barton, Kottschade, Grothey, & Loprinzi, 2008). Several medications are used in the treatment of neuropathic symptoms; however, the effectiveness of those therapies is questionable (Pachman, Barton, Watson, & Loprinzi, 2011). ...
... Other causes of peripheral neuropathy, such as tumor compression or blood clots, do not normally display this pattern. On the other hand, neuropathy caused by diabetes may present similarly to that caused by chemotherapy; therefore, an awareness of a patient's comorbid conditions is important in assessing TIPN (Wolf et al., 2008). ...
Article
As with many other types of chemotherapy, taxanes are associated with side effects that can affect patients' quality of life. One of the major side effects of taxane therapy is taxane-induced peripheral neuropathy (TIPN). The development of TIPN is accompanied by troublesome burning, tingling, and numbness; TIPN also can affect patient safety because of the decreased ability to perceive sensations (e.g., pain, heat). Pain and fatigue are common side effects of taxane therapy. These particular symptoms may hinder patients from working or performing daily activities, thus affecting quality of life. This case vignette provides an example of the symptoms that can accompany taxane therapy, including TIPN. The case vignette also demonstrates the long-lasting effects that TIPN can have on patients receiving taxane-based therapy, as well as the hindrance to the ability to work and perform daily activities because of numbness, pain, and fatigue. In addition, identification and management of taxane-related side effects are explored from the nursing perspective, and important aspects of patient education are discussed.
... Chemotherapy-induced peripheral neuropathy (CIPN) is another symptom experienced by patients with cancer who are undergoing chemotherapy [46]. It is a progressive, prolonged, and often irreversible side effect of many chemotherapeutic agents and affects 30-40% of patients undergoing treatment [47]. CIPN affects the peripheral sensory and/or motor systems and causes numbness, pain, burning, tingling, heat and hyperalgesia, and mechanical allodynia, as well as reduced motor function [47]. ...
... It is a progressive, prolonged, and often irreversible side effect of many chemotherapeutic agents and affects 30-40% of patients undergoing treatment [47]. CIPN affects the peripheral sensory and/or motor systems and causes numbness, pain, burning, tingling, heat and hyperalgesia, and mechanical allodynia, as well as reduced motor function [47]. It has been reported that CIPN may continue to worsen after chemotherapy as 68% of patients with cancer still experience the problems in the first month and 30% in the sixth month after chemotherapy [48,49]. ...
Chapter
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There are growing interests in promoting health of patients with cancer targeting on prevention and control as there are several modifiable risk factors that can be controlled to prevent cancer such as smoking, sedentary lifestyle, and unhealthy behaviors. Once diagnosis of cancer has been determined, health promotion interventions can be targeted on helping patients overcome the physiological and psychological effects of the diagnosis. Health promotion interventions should continue during treatment, survivorship, and for those receiving palliative care. More specifically is the promotion of psychological health of patients with cancer. Introduction of the incidence of cancer, cancer risk protection interventions and innovative health promotion interventions along these different periods in the life of patients with cancer are presented. Some theoretical frameworks used in health promotion research with examples of studies are discussed.
... Chemotherapy induced peripheral neuropathy (CIPN) is mostly related with an axonal degeneration and the "dying back" axon degeneration of distal nerve endings (5,6). Although some of the neuropathy processes induced by chemotherapy is reversible, in up to 40% of cancer survivors, the damage is irreversible which makes it crucial to diagnose and control CIPN in the early stage (7). However, precise methods for early diagnosis of CIPN are not established, and the diagnosis is mostly based on clinical symptoms. ...
... Therefore, the application of standard NCS diagnostic criteria may have limited utility in such patients. Patients with risk factors for CIPN including prior therapy with a neurotoxic agent, diabetes mellitus, folate/vitamin B12 deficiencies, African race, and older age (7,24) needs to be informed about CIPN and monitored carefully with baseline NCS and serial FU studies. This will not only enhance the sensitivity of NCS test but also provide prognostic outcome as well as evidence of early treatment. ...
Article
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Introduction Taxanes are associated with a distal sensory neuropathy, significantly affecting cancer survivor quality of life. However, chemotherapy-induced peripheral neuropathy (CIPN) assessments are primarily based on clinical symptoms rather than objective neurophysiologic findings. Therefore, we investigated neurophysiologic changes in symptomatic subjects, comparing them with symptom severity. Materials and Methods Medical charts of 111 subjects who were referred for CIPN diagnosis after chemotherapy for breast or ovarian cancer between May 1, 2016, and December 31, 2019, were retrospectively reviewed. Demographics, anthropometric parameters, and Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) pain scale data were collected. The nerve conduction study (NCS) results, including sensory nerve action potentials recorded from sural nerves, were analyzed relative to clinical symptoms. To optimize follow-up (FU) NCS diagnostic sensitivity, relative references of FU sural amplitude reductions to >30% and an absolute reference <10 μV were used. Results Eighty-eight female patients met the criteria, and 20 underwent FU NCS. Baseline and FU sural amplitudes showed significant positive correlation with respective LANSS scores ( p < 0.01). FU sural amplitude was significantly lower than the initial result ( p < 0.05). The FU LANSS score was not different from the initial score. Initial NCS sensitivity and specificity for clinically suspected CIPN diagnoses with LANSS were 69.7 and 47.3%, respectively. All 20 subjects with FU evaluation were clinically compatible with CIPN (LANSS >12) at initial and FU assessments. Among them, only six (30.0%) had abnormal sural amplitudes (<10μV for ≤50 s, <3 μV for 60 s, <1 μV for 70 s) in the initial NCS. In the FU NCS, sural amplitude became abnormal in five additional subjects. Between the initial and FU NCS, sural amplitude was reduced by > 30% in eight subjects (40.0%). NCS sensitivity increased to 65.0% when including either abnormal sural amplitudes or a > 30% reduction in sural amplitude in FU studies. Conclusions Although clinical symptoms and NCS results were positively correlated, a single NCS point had limited value for suspected CIPN electrophysiological diagnoses. Serial NCS during chemotherapy might help assess the degree of chemotherapy-induced nerve damage, attain evidence of CIPN prior to symptom aggravation, and monitor the progression of CIPN. Further study is needed to find specific relative references for variable patient factors to increase the sensitivity of electrophysiological studies of clinically suspected CIPN.
... Pregabalin and Chiral Amino Acid-based Peptides acid analogue, pregabalin (brand name: Lyrica), is used to treat neuropathic pain, epilepsy, restless leg syndrome, fibromyalgia, and generalized anxiety disorder. Case reports and studies have indicated that pregabalin is effective against neuropathic pain [9,10]. Moreover, cancer-related neuropathic pain negatively affects patients' life quality and is associated with delays in the ongoing cancer treatment and dose reduction [11]. ...
... Intermediate 7 was dissolved in DCM followed by acidified with cold HCl and then stirred for 3-4 h at room temperature to obtain compound 8. The diverse targeted motif, i.e. tripeptide (9), was formed by coupling of 4 and 8 (HCl salt) in the presence of C2H4Cl2 and DMAP at room temperature, stirred overnight. This intermediate (Int. ...
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Because of the medicinal application of peptides in the current drug discovery process, we report the synthesis and in vitro anticancer activity of various pregabalin containing peptides using chiral amino acids. The structures of newly synthesized compounds were assigned based on IR, 1H NMR, 13C NMR and mass spectral analysis. Synthesized peptides were screened for their anticancer activity on human breast cancer MCF-7 cells line by MMT assays method. Evaluation of anticancer activity shown that compound 13a (16.65% cell proliferation) was found to be most active against selected MCF-7 cell line.
... Peripheral neuropathy occurs in 30-40% of patients treated with adjuvant chemotherapy for breast cancer, is usually chronic, and recovery from symptoms is often incomplete 3,4 . Therefore, identi cation of risk factors, early detection and treatment of chemotherapy-induced peripheral neuropathy (CIPN) is essential for long-term management of breast cancer patients. ...
... Among the risk factors for CIPN, clinical factors including chemotherapeutic regimen, cumulative dose and pre-existing neuropathy are known, and demographic factors include age and obesity 3 . However, the role of psychiatric factors associated with CIPN is unknown, except one report that suggested an association between anxiety and persistent CIPN 5 . ...
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The purpose of this longitudinal prospective cohort study was to investigate the role of chronotype in the incidence of chemotherapy-induced peripheral neuropathy (CIPN) among women with breast cancer. A total of 128 subjects with breast cancer awaiting adjuvant chemotherapy without peripheral neuropathy participated in this study. The presence of CIPN was defined as a response of 3 or higher on a peripheral neuropathy subscale in the MD Anderson Symptom Inventory. Candidate psychiatric factors associated with CIPN were assessed, using the Composite Scale of Morningness, the Pittsburgh Sleep Quality Index, and the Hospital Anxiety and Depression Scale. To examine the association between chronotype and CIPN, we built logistic regression models, adjusting for demographic, clinical, and other psychiatric variables. Forty-nine participants received a chemotherapy regimen containing docetaxel, of which 29 (59%) developed CIPN. We performed subgroup analyses of docetaxel-treated participants. The morning chronotype was inversely associated with CIPN (odds ratio, 0.07; confidence interval, 0.01–0.48; p = 0.016) after adjusting for age, BMI, education, alcohol use, smoking, disease stage, sleep quality, depression, and anxiety. Our results suggest that the morning chronotype is a protective factor against the development of CIPN in patients with breast cancer who were treated with docetaxel.
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Article
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Abstract: Neuropathic pain caused by antitumor chemotherapeutics is a common and serious problem. Increased survival is achieved in more patients, but in the same time many of them suffer from long-term damage to the peripheral nerves – chemotherapy-induced peripheral neuropathy (CIPN). Evidence suggests that CIPN occurs in about 30% of patients a year or more after completion of chemotherapy. CIPN is characterized by sensory abnormalities such as an unpleasant abnormal touch sensation (dysesthesia), an increased response to pain stimuli (hyperalgesia), and pain as a result of a stimulus that does not normally provoke pain (allodynia). Unlike nociceptive pain, neuropathic pain is not affected by the use of conventional analgesics such as nonsteroidal anti-inflammatory drugs or opioids. Tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors, and some antiepileptic drugs have demonstrated efficacy in the treatment of neuropathic pain. The numerous side effects of these pharmacological groups, as well as the slow onset of action of the antiepileptic drugs, have forced the search for more appropriate treatments of CIPN.
... More than half of patients on chemotherapy develop peripheral neuropathy, and they often suffer from chemotherapy-induced pain and other sensory abnormalities. These agents affect the neurons through different mechanisms by causing microtubular damage/instability, mitochondrial dysfunction, neuronal apoptosis, impaired axonal transmission, and/or Ca 2+ deregulation (96)(97)(98). ...
... Chemotherapy induced peripheral neuropathy (CIPN) is an unpleasant and debilitating side-effect of numerous neurotoxic chemotherapeutics, including epothilones, proteasome inhibitors, taxanes, vinca alkaloids and platinum-based agents (Starobova & Vetter, 2017). Characteristically, CIPN presents itself in a 'glove and stocking' fashion, initially affecting the extremities before progressing proximally (Wolf et al., 2008). It typically induces a range of sensory abnormalities including paresthesias and dysesthesias, which can be exacerbated by warm or cool temperatures, impaired vibration and even sensory loss (Staff et al., 2017;Zajączkowska et al., 2019). ...
Article
Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling side effect of various chemotherapeutic agents, including oxaliplatin. It is highly prevalent amongst cancer patients, causing sensory abnormalities and pain. Unfortunately, as the underlying mechanisms remain poorly understood, effective therapeutics are lacking. Neuro-immune interactions have been highlighted as potential contributors to the development and maintenance of CIPN, however, whether this is the case in oxaliplatin-induced peripheral neuropathy (OIPN) is yet to be fully established. Methods: In this study we used flow cytometry to examine the peripheral immune response of male C57BL/6 mice following both single and repeated oxaliplatin administration. In animals exposed to repeated dosing, we also undertook mechanical and thermal behavioural assays to investigate how oxaliplatin alters phenotype, and conducted RT-qPCR experiments on bone marrow derived macrophages in order to further inspect the effects of oxaliplatin on immune cells. Results: In contrast to other reports, we failed to observe substantial changes in overall leukocyte, lymphocyte or myeloid cell numbers in dorsal root ganglia, sciatic nerves or inguinal lymph nodes. We did however note subtle, tissue-dependant alterations in several myeloid subpopulations following repeated dosing. These included a significant reduction in MHCII antigen presenting cells in the sciatic nerve and an increase in infiltrating cell types into the inguinal lymph nodes. Though repeated oxaliplatin administration had a systemic effect, we were unable to detect a pain-like behavioural phenotype in response to either cold or mechanical stimuli. Consequently, we cannot comment on whether the observed myeloid changes are associated with OIPN. Conclusions: Our discussion puts these results into the wider context of the field, advocating for greater transparency in reporting, alignment in experimental design and the introduction of more clinically relevant models. Only through joint concerted effort can we hope to increase our understanding of the underlying mechanisms of CIPN, including any immune contributions.
... Chemotherapy-induced peripheral neuropathy (CIPN) can become a major drug-induced adverse reaction that becomes a dose-limiting toxicity of chemotherapy [1][2][3][4][5]. In recent years, the e cacy of cryotherapy using frozen gloves (FGs) and compression therapy using surgical gloves (SGs) to prevent taxaneinduced peripheral neuropathy has been reported [6-8]. ...
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Purpose In a previous study, we showed that cryotherapy and compression therapy have comparable efficacy in preventing nab-paclitaxel-induced peripheral neuropathy. However, even with cryotherapy or compression therapy, there were patients with National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grade ≥ 2 and/or Patient Neurotoxicity Questionnaire (PNQ) grade ≥ D peripheral neuropathies. Therefore, a sub-analysis was performed to identify predictors of nab-paclitaxel-induced peripheral neuropathy. Methods The clinical data in this sub-analysis were the data of 38 breast cancer patients receiving chemotherapy with nanoparticle albumin-bound paclitaxel (nab-PTX) at our outpatient chemotherapy center from August 2017 to March 2019. The number of patients was analyzed assuming that there were data for 76 hands. Variables related to the development of nab-PTX-induced peripheral neuropathy were used for regression analysis. Multivariate ordered logistic regression analysis was performed to identify predictors for the development of nab-PTX-induced peripheral neuropathy. Results Significant factors included smoking history [odds ratio (OR) = 4.64, 95% confidence interval (CI) = 1.60–13.5; P = 0.0048] with neuropathy evaluated by CTCAE, body mass index (BMI) (OR = 1.13, 95% CI = 1.01–1.26; P = 0.039) with neuropathy evaluated by PNQ (sensory), and smoking history (OR = 3.80, 95% CI = 1.40–10.30; P = 0.0087) and age (OR = 1.06, 95% CI = 1.01–1.11; P = 0.012) with neuropathy evaluated by PNQ (motor). Conclusions Smoking history, BMI and age were identified as significant predictors of the development of nab-PTX-induced-peripheral neuropathy.
... These studies tend to focus primarily on left ventricular dysfunction and cardiomyopathy as clinical endpoints for cardiotoxicity. Additionally, many cancer-directed treatments are known to cause peripheral neuropathy and generalized autonomic dysfunction (AD) such as gastrointestinal and genitourinary dysfunction [7][8][9][10]. More recently, cardiovascular AD among cancer survivors is increasingly being recognized as its own distinct entity [11][12][13][14][15]. ...
Article
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Purpose of Review Cardiovascular autonomic dysfunction (AD) among cancer survivors is increasingly being recognized. However, the mechanisms and incidence are poorly understood. In this review, the clinical features, diagnostic modalities, proposed mechanisms, and currently available treatments of cardiovascular AD in cancer survivors are described. Recent Findings Much of our current understanding of cardiovascular AD is based on disease states such as diabetes, multisystem atrophy, and Parkinson’s disease. Several non-invasive tests, measurements, and scoring systems have been developed as surrogates for autonomic function, with some even demonstrating associations with all-cause mortality. The mechanism of cardiovascular AD specifically in the cancer population, however, has not been directly studied. The etiology of cardiovascular AD in cancer survivors is likely multifactorial, and proposed mechanisms include direct nerve damage by chemoradiation, the pro-inflammatory state associated with malignancy, and paraneoplastic syndromes. It may also be that cardiovascular AD is an early marker of global cardiomyopathy rather than its own condition. Current pharmacologic options for cardiovascular AD are extrapolated from how it has been treated in other disease processes, and these agents have not been studied in the cancer population or compared head-to-head. Summary Cardiovascular AD in cancer survivors can cause significant debilitation and may be associated with all-cause mortality. Current diagnostic modalities have several limitations, such as standardization and validity. However, given the nonspecific nature of cardiovascular AD, these tools provide an objective marker for diagnosis and tracking treatment response. While the mechanism of cardiovascular AD in cancer survivors has not been directly studied, it may be useful to evoke mechanisms of cardiovascular AD in other disease states such as diabetes, Parkinson’s disease, and multisystem atrophy in addition to identifying unique conditions associated with malignancy like a pro-inflammatory state. Until further studies are performed, management of cardiovascular AD as seen in other disease states may serve as a guide for symptom management in cancer survivors.
... In addition, neuropathy causes a significant loss of functional abilities and decreases the quality of life of patients. Among chemotherapeutic agents, platinum drugs (oxaliplatin and cisplatin), vinca alkaloids (vincristine and vinblastine), taxanes (paclitaxel and docetaxel), and bortezomib induce the most severe effects on the peripheral nervous system [4][5][6][7]. Since little is known about the mechanisms involved in the development of CIPN, no drugs are currently available to prevent or treat CIPN. ...
Article
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Chemotherapy-induced peripheral neuropathy is a common factor in limiting therapy which can result in therapy cessation or dose reduction. Gabapentin, a calcium channel inhibitor, and duloxetine, a serotonin noradrenaline reuptake inhibitor, are used to treat a variety of pain conditions such as chronic low back pain, postherpetic neuralgia, and diabetic neuropathy. It has been reported that administration of gabapentin suppressed oxaliplatin- and paclitaxel-induced mechanical hyperalgesia in rats. Moreover, duloxetine has been shown to suppress oxaliplatin-induced cold allodynia in rats. However, the mechanisms by which these drugs prevent oxaliplatin- and paclitaxel-induced neuropathy remain unknown. Behavioral assays were performed using cold plate and the von Frey test. The expression levels of proteins were examined using western blot analysis. In this study, we investigated the mechanisms by which gabapentin and duloxetine prevent oxaliplatin- and paclitaxel-induced neuropathy in mice. We found that gabapentin and duloxetine prevented the development of oxaliplatin- and paclitaxel-induced cold and mechanical allodynia. In addition, our results revealed that gabapentin and duloxetine suppressed extracellular signal-regulated protein kinase 1/2 (ERK1/2) phosphorylation in the spinal cord of mice. Moreover, PD0325901 prevented the development of oxaliplatin- and paclitaxel-induced neuropathic-like pain behavior by inhibiting ERK1/2 activation in the spinal cord of mice. In summary, our findings suggest that gabapentin, duloxetine, and PD0325901 prevent the development of oxaliplatin- and paclitaxel-induced neuropathic-like pain behavior by inhibiting ERK1/2 phosphorylation in mice. Therefore, inhibiting ERK1/2 phosphorylation could be an effective preventive strategy against oxaliplatin- and paclitaxel-induced neuropathy.
... Physiatrists will also address pain from CIPN with the same oral and topical medications utilized for pain emanating from any other neuropathic causes, while simultaneously addressing the functional impact from the neuropathy. Topical agents can help temporarily treat the focal pain, including anesthetic based topical agents in cream or patch form, as well as compounding agents such as baclofen/ amitriptyline/ketamine gel [12][13][14]. Capsaicin topical cream may have benefit for neuropathic pain but has not been tested in CIPN [15]. Oral medications have shown limited efficacy in relieving CIPN compared to their ability to treat other causes of neuropathic pain such as diabetic neuropathy. ...
Chapter
Cancer patients have unique symptoms from tumor burden and cancer treatments, which affect functional status and quality of life. Reports have shown approximately 65% of cancer patients have at least one functional/rehabilitation need, yet fewer than 10% of these needs get addressed during their cancer journey.
... Disorders of the nervous system are the second most common side-effect [1]. Chemotherapy-induced peripheral neuropathy (CIPN) is a disorder associated with exercise, sensation, and autonomic nerves, caused by damage to the peripheral nerve after anti-cancer drug treatment, which eventually leads to various symptoms such as muscle weakness, decreased sensation, and pain, disrupting daily life [2][3][4]. The pain associated with CIPN is distinguished from cancer pain caused by direct invasion of nerve tissues and pressure on the nerves or passage through the bone. ...
Article
Background: Pharmacological and non-pharmacological therapies have been used to treat patients with chemotherapy-induced peripheral neuropathy (CIPN). However, the effect of therapies in cancer patients has yet to be investigated comprehensively. We hypothesized that cyclic thermal therapy would improve blood flow and microcirculation and improve the symptoms driven by CIPN. Methods: The criteria of assessment were blood volume in region of interest (ROI) in the images, and European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20 questionnaire scores. The blood volume was quantified by using red blood cell (RBC) scintigraphy. All patients were treated 10 times during 10 days. The thermal stimulations, between 15° and 41°, were repeatedly delivered to the patient's hands. Results: The total score of the questionnaires, the score of questions related to the upper limbs, the score of questions closely related to the upper limbs, and the score excluding the upper limbs questions was decreased. The blood volume was decreased, and the variance of blood volume was decreased. During cooling stimulation, the blood volume was decreased, and its variance was decreased. During warming stimulation, the blood volume was decreased, and its variance was decreased. Conclusions: We suggest that cyclic thermal therapy is useful to alleviate CIPN symptoms by blood circulation improvement. RBC scintigraphy can provide the quantitative information on blood volume under certain conditions such as stress, as well as rest, in peripheral tissue.
... GLOSSARY AAV = adeno-associated virus; ANOVA = analysis of variance; BCA = bicinchoninic acid; cAMP = cyclic adenosine monophosphate; CCL3 = C-C motif chemokine ligand 3; CD = cluster of differentiation; CFA = complete Freund's adjuvant; CIPN = chemotherapy-induced peripheral neuropathy; CNS = central nervous system; CRE = cyclization recombinase; Cre-ERT2 = CRE-estrogen receptor, tamoxifen 2; DAP12 = DNAX-activating protein of 12 kDa; DAPI = 4',6-diamidino-2-phenylindole; DCs = dendritic cells; DRG = dorsal root ganglion; EA = electroacupuncture; eGFP = enhanced green fluorescent protein; EPI = epinephrine; ERK = extracellular regulated protein kinase; GAPDH = glyceraldehyde-3-phosphate dehydrogenase; GPCR = G protein-coupled receptor; GRK2 = G proteincoupled receptor kinase 2; hSyn = human synapsin; i.p. = intraperitoneally; IENFs = intraepidermal nerve fibers; IL = interleukin; iNOS = inducible nitric oxide synthase; mRNA = messenger RNA; NeuN = neuronal nuclei; ns = nonsignificant; PBS = phosphate-buffered saline; PBST = phosphate-buffered saline Tween-20; PCR = polymerase chain reaction; PGE2 = prostaglandin E2; PGP = protein gene product; PKA = protein kinase A; PKCε = protein kinase C ε; PWT = paw withdrawal threshold; qPCR = quantitative polymerase chain reaction; SEM = standard error of the mean; shEA = sham electroacupuncture; shRNA = short hairpin RNA; SYN = synapsin; TNF = tumor necrosis factor; TGF = tumor growth factor; TREM2 = triggering receptor expressed on myeloid cells 2; WB = Western blot C hemotherapy-induced peripheral neuropathy (CIPN) is one of the common dose-limiting adverse effect of chemotherapy. 1 Symptoms of CIPN include numbness and hyperalgesia of the feet or hands in the distribution of stockings and gloves, accompanied with the loss of intraepidermal nerve fibers (IENFs). This seriously affects the quality of life of patients. ...
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Background: The main symptoms of chemotherapy-induced peripheral neuropathy (CIPN) include pain and numbness. Neuronal G protein-coupled receptor kinase 2 (GRK2) plays an important role in various pain models. Cisplatin treatment can induce the activation of proinflammatory microglia in spinal cord. The purpose of this study was to investigate the role of spinal neuronal GRK2 in cisplatin-induced CIPN and in the prevention of CIPN by electroacupuncture (EA). Methods: The pain and sensory deficit behaviors of mice were examined by von Frey test and adhesive removal test. The expression of neuronal GRK2 in the spinal cord is regulated by intraspinal injection of adeno-associated virus (AAV) containing neuron-specific promoters. The protein levels of GRK2, triggering receptor expressed on myeloid cells 2 (TREM2), and DNAX-activating protein of 12 kDa (DAP12) in spinal dorsal horn were detected by Western blot, the density of intraepidermal nerve fibers (IENFs) was detected by immunofluorescence, and microglia activation were evaluated by real-time polymerase chain reaction (PCR). Results: In this study, cisplatin treatment led to the decrease of GRK2 expression in the dorsal horn of spinal cord. Overexpression of neuronal GRK2 in spinal cord by intraspinal injection of an AAV vector expressing GRK2 with human synapsin (hSyn) promotor significantly inhibited the loss of IENFs and alleviated the mechanical pain and sensory deficits induced by cisplatin. Real-time PCR analysis showed that the overexpression of neuronal GRK2 significantly inhibited the messenger RNA (mRNA) upregulation of proinflammatory cytokine interleukin (IL)-1β, IL-6, inducible nitric oxide synthase (iNOS), and M1 microglia marker cluster of differentiation (CD)16 induced by cisplatin. Furthermore, the TREM2 and DAP12, which has been demonstrated to play a role in microglia activation and in the development of CIPN, were also downregulated by overexpression of neuronal GRK2 in this study. Interestingly, preventive treatment with EA completely mimics the effect of overexpression of neuronal GRK2 in the spinal cord in this mouse model of cisplatin-induced CIPN. EA increased GRK2 level in spinal dorsal horn after cisplatin treatment. Intraspinal injection of AAV vector specifically downregulated neuronal GRK2, completely reversed the regulatory effect of EA on CIPN and microglia activation. All these indicated that the neuronal GRK2 mediated microglial activation contributed to the process of CIPN. Conclusions: Neuronal GRK2 in the spinal cord contributed to the preventive effect of EA on CIPN. The neuronal GRK2 may be a potential target for CIPN intervention.
... A recent meta-analysis of clinical trial data suggested TCAs and the gabapentinoids pregabalin and gabapentin or duloxetine (a serotonin and norepinephrine reuptake inhibitor) as first-line treatments (7). The TCAs are associated with significant side effects, including sedation and cardiovascular complications, as well as only marginal efficacy (8). The AEDs, despite their efficacy in animal models of CIPN, are only partially effective in the majority of patients suffering from CIPN (9). ...
Article
The use of cannabis is not unfamiliar to many cancer patients, as there is a long history of its use for cancer pain and/or pain, nausea, and cachexia induced by cancer treatment. To date, the US Food and Drug Administration has approved 2 cannabis-based pharmacotherapies for the treatment of cancer chemotherapy-associated adverse effects: dronabinol and nabilone. Over the proceeding decades, both research investigating and societal attitudes toward the potential utility of cannabinoids for a range of indications have progressed dramatically. The following monograph highlights recent preclinical research focusing on promising cannabinoid-based approaches for the treatment of the 2 most common adverse effects of cancer chemotherapy: chemotherapy-induced peripheral neuropathy and chemotherapy-induced nausea and vomiting. Both plant-derived and synthetic approaches are discussed, as is the potential relative safety and effectiveness of these approaches in relation to current treatment options, including opioid analgesics.
... Among the risk factors for CIPN, clinical factors including chemotherapeutic regimen, cumulative dose and pre-existing neuropathy are known, and demographic factors include age and obesity. 6 However, the role of psychiatric factors associated with CIPN is unknown, except one report that suggested an association between anxiety and persistent CIPN. 7 Psychiatric symptoms are known to affect not only QoL but are also related to developing treatment complications. ...
Article
Background: The purpose of this longitudinal prospective cohort study was to investigate the role of chronotype in the incidence of chemotherapy-induced peripheral neuropathy (CIPN) among women with breast cancer. Methods: We recruited women with breast cancer awaiting adjuvant chemotherapy, including four cycles of docetaxel. Participants reported peripheral neuropathy symptoms of numbness/tingling at the baseline, and at 4weeks after completion of chemotherapy. Candidate psychiatric factors associated with CIPN were assessed at the baseline, using the Composite Scale of Morningness, the Pittsburgh Sleep Quality Index, and the Hospital Anxiety and Depression Scale. To examine the association between chronotype and CIPN, we built logistic regression models, adjusting for demographic, clinical, and other psychiatric variables. Results: Among 48 participants, 29 participants developed CIPN. The morning chronotype was inversely associated with CIPN (odds ratio, 0.06; confidence interval, 0.01-0.74; P = 0.028) after adjusting for age, BMI, education, type of operation, alcohol use, smoking, sleep quality, depression, and anxiety. Conclusion: Our results suggest that the morning chronotype is a protective factor against the development of CIPN in patients with breast cancer who were treated with docetaxel. Trial registration: ClinicalTrials.gov Identifier: NCT01887925.
... Sensory abnormalities may persist for months, or even years after the cessation of chemotherapy and recovery is usually incomplete (23). Effective treatment of established chemotherapy-induced peripheral neuropathy (CIPN), however, has yet to be determined (23,24). Krishnan (9) showed that cumulative dose is clearly critical in determining the development of oxaliplatin-induced neurotoxicity, and the possibility that chronic effects may be minimized by using a lower single-infusion dosage requires further study. ...
Article
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Background: Dose-limiting neurotoxicity is the major side effect caused by oxaliplatin treatment. Optimization of oxaliplatin-containing chemotherapeutic regimens may potentially benefit advanced gastric cancer (AGC) patients. We tried to reduce the dose of oxaliplatin and add a drug to compensate for the efficacy. This cohort study evaluated the efficacy and side effects of low-dose oxaliplatin combined with pegylated liposomal doxorubicin and S-1 (D-SOX) as first-line treatment for AGC. Methods: 64 AGC patients treated in our hospital between January 2015 and December 2018 were included in this study. Among them, 29 cases received standard S-1 and oxaliplatin (SOX) regimen, and 35 cases received D-SOX. Progression-free survival (PFS), overall survival (OS), response rate (RR), and safety were analyzed. Discussion: The median PFS was 7.0 months [95% confidence interval (CI): 5.77 to 8.23 months] in the SOX group and 9.3 months (95% CI: 8.145 to 10.45 months) in the D-SOX group (P=0.021). The median OS was 12.5 months (95% CI: 7.00 to 17.97 months) in the SOX group and 18.7 months (95% CI: 14.485 to 22.9 months) in the D-SOX group (P=0.027). The incidence of treatment-related grade III-IV adverse events (AEs) was less than 10%. The RRs to these 2 regimens were similar (P=0.609). The incidence of neurotoxicity was significantly reduced in the D-SOX group (62.8% vs. 82.7%). Conclusions: Low-dose oxaliplatin combined with S-1 and pegylated liposomal doxorubicin (PLD) regimen improved OS and PFS, while exhibiting better toxicity profile as compared with standard SOX regimen for AGC.
... The administration of drugs such as acetyl-L-carnitine, alpha-lipoid acid, and olesoxime (cholest-4-en-3-one, oxime), which are known to have mitotoprotective effects, has been effective in vincristine-and paclitaxel-induced painful neuropathy in animals (Xia and Bennett, 2008;Bordet and Pruss, 2009;Xiao et al., 2009). The long-term treatment effects of mitoprotective agents have been related to the prevention of axonal degeneration, which in this context is confined to the region of the sensory fiber's receptor terminals in the skin and associated with activation of cutaneous Langerhans cells (LC) (Siau et al., 2006;Wolf et al., 2008). However, the effect of JM-20 on the loss of intra-epidermal nerve fibers and LCs in this model should be elucidated. ...
Article
Full-text available
Context: JM-20 is a hybrid synthetic molecule, which is based on a multimodal drug design paradigm for cerebrovascular disease. In addition to its neuroprotective effects, JM-20 also decreased sciatic nerve chronic constriction injury (CCI)-induced mechanical hypersensitivity in rats. JM-20 has a strong mitoprotective ability, and its effects could be in correspondence with the mitotoxicity hypothesis for paclitaxel-induced painful peripheral neuropathy. Aims: To evaluate the efficacy of the JM-20 to reduce neuropathic pain manifestations induced by the administration of paclitaxel in rats. Methods: In this study was implemented a rat model of painful peripheral neuropathy, produced by the chemotherapeutic agent paclitaxel, to determine whether JM-20 (10 mg/kg, p.o) could prevent the development of neuropathic pain during the exposure to paclitaxel. As well as to determine whether JM-20 (20 mg/kg, p.o) could reverse the established neuropathic pain. Mechanical behavioral assessment using von Frey filaments applied to the hind paws was applied before, during, and after treatments for 35 days. Results: Giving JM-20 during the exposure to paclitaxel significantly reduced the severity of mechanical allodynia and mechanical hyperalgesia. Moreover, JM-20 significantly reduced both established neuropathic pain manifestations. There was no evidence of tolerance to the effect during three days of dosing, and a long-term effect was observed after JM-20 discontinuation. Conclusions: JM-20 may be clinically relevant for both the prevention and treatment of paclitaxel-induced painful peripheral neuropathy.
... The incidence of chemotherapyinduced peripheral neurotoxicity (CIPN) is currently unknown but has been reported to be about 40% (13). In one report, vincristine-induced peripheral neurotoxicity was as high as 80% in some small retrospective studies (9). ...
Article
Small fiber neuropathy (SFN) is a disorder of small afferent nerve fibers that can result in debilitating pain and functional limitations. There are many etiologies including, but not limited to, diabetes, vitamin deficiencies, infections, and exposure to neurotoxic drugs such as chemotherapeutics. The constellation of signs and symptoms overlap with other disease states leading to potential misdiagnosis. New tests including histologic studies of skin biopsies and autonomic nerve tests have emerged in the last 20 years improving differentiation between these disease processes and SFN. Multiple chemotherapeutic medications have been implicated in causing SFN, including vincristine which was the causative agent in this case report. The exact incidence of chemotherapy-induced peripheral neurotoxicity (CIPN) is currently unknown, but according to some publications it has been reported to be as high as 40% in patients that have been treated with chemotherapy. As the number of cancer survivors continues to grow, the number of patients with painful SFN will potentially increase. Devising an effective analgesic regimen for patients with painful SFN can be difficult, and often requires the pain physician to employ multiple pharmacologic and non-pharmacologic therapies. Treatments include analgesics from several drug classes: antidepressants, opioids, and anticonvulsants. Often times however, more advanced interventional techniques must be employed as effective pain control may be limited by medication side effects or inadequate return of function. While dorsal column stimulation was approved for a limited number of applications, a number of new applications are reported in the literature. In this paper, we present a case of vincristineinduced SFN successfully treated with neuromodulation via spinal cord stimulator. Key words: Vincristine, vinblastine, chemotherapy- induced neuropathy, chronic pain, spinal cord stimulation, dorsal column stimulation, neuromodulation, small fiber neuropathy, neuropathic pain
... The onset and course of symptoms are variable, as it starts within weeks or months of therapy initiation and, in most cases, is partially reversible or possibly permanent [28]. The degree and severity of neuronal damage and its relative clinical symptoms depend on several risk factors, including the chemotherapeutic agent and associated drug combination, the dose and duration of therapy, in addition to individual predisposing factors that include age and preexisting neuropathic conditions, e.g., diabetes [29]. Symptoms can sometimes persist after discontinuation of chemotherapy. ...
Article
Full-text available
Chemotherapy-induced peripheral neuropathy (CIPN) is a significant dose-limiting long-term sequela in cancer patients undergoing treatment, often leading to discontinuation of treatment. No established therapy exists to prevent and/or ameliorate CIPN. Reactive oxygen species (ROS) and mitochondrial dysregulation have been proposed to underlie the pathobiology of CIPN. However, interventions to prevent and treat CIPN are largely ineffective. Additional factors and mechanism-based targets need to be identified to develop novel strategies to target CIPN. The role of oxidative stress appears to be central, but the contribution of endoplasmic reticulum (ER) stress remains under-examined in the pathobiology of CIPN. This review describes the significance of ER stress and its contribution to CIPN, the protective role of herbal agents in countering ER stress in nervous system-associated disorders, and their possible repurposing for preventing CIPN.
... CIPN can induce severe pain and impairment leading to significant loss of functional ability and reduced quality of life. Neurotoxic chemotherapy can cause peripheral nerve structural damage resulting in aberrant somatosensory processing of the peripheral and central nervous system [14]. It is rare to reach the firing threshold in normal primary afferent neurons without the input of a stimulus. ...
Article
Full-text available
Chemotherapy-induced peripheral neuropathy (CIPN) is the most prevalent neurological complication of cancer treatment which involves sensory and motor nerve dysfunction. Severe CIPN has been reported in around 5% of patients treated with single and up to 38% of patients treated with multiple chemotherapeutic agents. Present medications available for CIPN are the use of opioids, nonsteroidal anti-inflammatory agents, and tricyclic antidepressants, which are only marginally effective in treating neuropathic symptoms. In reality, symptom reappears after these drugs are discontinued. The pathogenesis of CIPN has not been sufficiently recognized and methods for the prevention and treatment of CIPN remain vulnerable to therapeutic problems. It has witnessed that the present medicines available for the disease offer only symptomatic relief for the short term and have severe adverse side effects. There is no standard treatment protocol for preventing, reducing, and treating CIPN. Therefore, there is a need to develop curative therapy that can be used to treat this complication. Melittin is the main pharmacological active constituent of honeybee venom and has therapeutic values including in chemotherapeutic-induced peripheral neuropathy. It has been shown that melittin and whole honey bee venom are effective in treating paclitaxel and oxaliplatin-induced peripheral neuropathy. The use of melittin against peripheral neuropathy caused by chemotherapy has been limited despite having strong therapeutic efficacy against the disease. Melittin mediated haemolysis is the key reason to restrict its use. In our study, it is found that α-Crystallin (an eye lens protein) is capable of inhibiting melittin-induced haemolysis which gives hope of using an appropriate combination of melittin and α-Crystallin in the treatment of CIPN. The review summarizes the efforts made by different research groups to address the concern with melittin in the treatment of chemotherapeutic-induced neuropathy. It also focuses on the possible approaches to overcome melittin-induced haemolysis. Graphic Abstract
... These effects of MT modulation on cognitive flexibility could be due to the impairments induced by MT stabilizers and destabilizers on brain connectivity [126]. MT stabilizers-induced neuropathic pain [122,123] could also reduce cognitive flexibility as observed in some pain models [369]. ...
Article
Full-text available
Neuronal microtubules (MTs) are complex cytoskeletal protein arrays that undergo activity-dependent changes in their structure and function as a response to physiological demands throughout the lifespan of neurons. Many factors shape the allostatic dynamics of MTs and tubulin dimers in the cytosolic microenvironment, such as protein–protein interactions and activity-dependent shifts in these interactions that are responsible for their plastic capabilities. Recently, several findings have reinforced the role of MTs in behavioral and cognitive processes in normal and pathological conditions. In this review, we summarize the bidirectional relationships between MTs dynamics, neuronal processes, and brain and behavioral states. The outcomes of manipulating the dynamicity of MTs by genetic or pharmacological approaches on neuronal morphology, intrinsic and synaptic excitability, the state of the network, and behaviors are heterogeneous. We discuss the critical position of MTs as responders and adaptative elements of basic neuronal function whose impact on brain function is not fully understood, and we highlight the dilemma of artificially modulating MT dynamics for therapeutic purposes.
... The administration of drugs such as acetyl-L-carnitine, alpha-lipoid acid, and olesoxime (cholest-4-en-3-one, oxime), which are known to have mitotoprotective effects, has been effective in vincristine-and paclitaxel-induced painful neuropathy in animals (Xia and Bennett, 2008;Bordet and Pruss, 2009;Xiao et al., 2009). The long-term treatment effects of mitoprotective agents have been related to the prevention of axonal degeneration, which in this context is confined to the region of the sensory fiber's receptor terminals in the skin and associated with activation of cutaneous Langerhans cells (LC) (Siau et al., 2006;Wolf et al., 2008). However, the effect of JM-20 on the loss of intra-epidermal nerve fibers and LCs in this model should be elucidated. ...
Article
Full-text available
Context: JM-20 is a hybrid synthetic molecule, which is based on a multimodal drug design paradigm for cerebrovascular disease. In addition to its neuroprotective effects, JM-20 also decreased sciatic nerve chronic constriction injury (CCI)-induced mechanical hypersensitivity in rats. JM-20 has a strong mitoprotective ability, and its effects could be in correspondence with the mitotoxicity hypothesis for paclitaxel-induced painful peripheral neuropathy. Aims: To evaluate the efficacy of the JM-20 to reduce neuropathic pain manifestations induced by the administration of paclitaxel in rats. Methods: In this study was implemented a rat model of painful peripheral neuropathy, produced by the chemotherapeutic agent paclitaxel, to determine whether JM-20 (10 mg/kg, p.o) could prevent the development of neuropathic pain during the exposure to paclitaxel. As well as to determine whether JM-20 (20 mg/kg, p.o) could reverse the established neuropathic pain. Mechanical behavioral assessment using von Frey filaments applied to the hind paws was applied before, during, and after treatments for 35 days. Results: Giving JM-20 during the exposure to paclitaxel significantly reduced the severity of mechanical allodynia and mechanical hyperalgesia. Moreover, JM-20 significantly reduced both established neuropathic pain manifestations. There was no evidence of tolerance to the effect during three days of dosing, and a long-term effect was observed after JM-20 discontinuation. Conclusions: JM-20 may be clinically relevant for both the prevention and treatment of paclitaxel-induced painful peripheral neuropathy.
... Chemotherapy-induced peripheral neuropathy (CIPN) can become a major drug-induced adverse reaction that becomes a dose-limiting toxicity of chemotherapy [1][2][3][4][5]. In recent years, the efficacy of cryotherapy using frozen gloves (FGs) and compression therapy using surgical gloves (SGs) to prevent taxane-induced peripheral neuropathy has been reported [6][7][8]. ...
Article
Full-text available
In a previous study, we showed that cryotherapy and compression therapy have comparable efficacy in preventing nab-paclitaxel-induced peripheral neuropathy. However, even with cryotherapy or compression therapy, there were patients with National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grade ≥ 2 and/or Patient Neurotoxicity Questionnaire (PNQ) grade ≥ D peripheral neuropathies. Therefore, this post hoc analysis was performed to identify predictors of nab-paclitaxel-induced peripheral neuropathy. The clinical data in this post hoc analysis were the data of 38 breast cancer patients receiving chemotherapy with nanoparticle albumin-bound paclitaxel (nab-PTX) at our outpatient chemotherapy center from August 2017 to March 2019. The number of patients was analyzed assuming that there were data for 76 hands. Variables related to the development of nab-PTX-induced peripheral neuropathy were used for regression analysis. Multivariate-ordered logistic regression analysis was performed to identify predictors for the development of nab-PTX-induced peripheral neuropathy. Significant factors included smoking history [odds ratio (OR) 4.64, 95% confidence interval (CI) 1.60–13.5; P = 0.0048] with neuropathy evaluated by CTCAE, body mass index (BMI) (OR 1.13, 95% CI 1.01–1.26; P = 0.039) with neuropathy evaluated by PNQ (sensory), and smoking history (OR 3.80, 95% CI 1.40–10.30; P = 0.0087) and age (OR 1.06, 95% CI 1.01–1.11; P = 0.012) with neuropathy evaluated by PNQ (motor). In conclusion, smoking history, BMI and age were identified as significant predictors of the development of nab-PTX-induced-peripheral neuropathy.
... CIPN is a progressive neurodegenerative condition in which the peripheral nervous system is damaged by chemotherapeutic drugs, such as cisplatin, used in cancer therapy. This condition can induce significant axon degeneration, leading to numerous neurological deficits, which are dose limiting factors for chemotherapy in cancer patients [52][53][54][55] . The increased vulnerability of peripheral axons to systemic chemotherapy is likely because of the large surface area of peripheral axons and their close association with the vasculature 56 . ...
Article
Full-text available
While the consequences of nuclear DNA damage have been well studied, the exact consequences of acute and selective mitochondrial DNA (mtDNA) damage are less understood. DNA damaging chemotherapeutic drugs are known to activate p53-dependent apoptosis in response to sustained nuclear DNA damage. While it is recognized that whole-cell exposure to these drugs also damages mtDNA, the specific contribution of mtDNA damage to cellular degeneration is less clear. To examine this, we induced selective mtDNA damage in neuronal axons using microfluidic chambers that allow for the spatial and fluidic isolation of neuronal cell bodies (containing nucleus and mitochondria) from the axons (containing mitochondria). Exposure of the DNA damaging drug cisplatin selectively to only the axons induced mtDNA damage in axonal mitochondria, without nuclear damage. We found that this resulted in the selective degeneration of only the targeted axons that were exposed to DNA damage, where ROS was induced but mitochondria were not permeabilized. mtDNA damage-induced axon degeneration was not mediated by any of the three known axon degeneration pathways: apoptosis, axon pruning, and Wallerian degeneration, as Bax-deficiency, or Casp3-deficiency, or Sarm1-deficiency failed to protect the degenerating axons. Strikingly, p53, which is essential for degeneration after nuclear DNA damage, was also not required for degeneration induced with mtDNA damage. This was most evident when the p53-deficient neurons were globally exposed to cisplatin. While the cell bodies of p53-deficient neurons were protected from degeneration in this context, the axons farthest from the cell bodies still underwent degeneration. These results highlight how whole cell exposure to DNA damage activates two pathways of degeneration; a faster, p53-dependent apoptotic degeneration that is triggered in the cell bodies with nuclear DNA damage, and a slower, p53-independent degeneration that is induced with mtDNA damage.
... It is mainly located in the presynaptic zone of the synaptic cleft of glutamatergic synapses and acts as an auto-receptor which inhibits the glutamate release from the presynaptic terminal, producing a negative feedback loop (Cartmell and Schoepp 2000). An excessive amount of extracellular glutamate has been considered as a candidate key element in elucidation of chemotherapy-induced neuropathic pathogenesis (Wolf et al. 2008). Pharmacological inhibition of enzyme glutamate carboxy peptidase leading to decreased glutamate was associated with neuroprotective effects in animal models of cisplatin, paclitaxel, and bortezomib chemo-neuropathy (Carozzi et al. 2010). ...
Article
Full-text available
Rationale Paclitaxel-induced acute pain syndrome (P-APS), characterized by deep muscle aches and arthralgia, occurs in more than 70% of patients who receive paclitaxel. P-APS can be debilitating for patients and lead to reductions and discontinuation of potentially curable therapy. Despite being relatively common in clinical practice, no clear treatment exists for P-APS and the underlying mechanisms remain poorly defined. Regulation of glutamatergic transmission by metabotropic glutamate receptors (mGluRs) has received growing attention with respect to its role in neuropathic pain. To our knowledge, no study has been conducted on alterations and functions of group III mGluR7 signaling in P-APS. Objectives In the present study, we determined whether a single administration of paclitaxel induces glutamatergic alterations and whether mGluR7 activation blocks paclitaxel-induced neuropathic pain by suppressing glial reactivity in the spinal cord. Results A single paclitaxel injection dose-dependently induced acute mechanical and thermal hypersensitivity, and was associated with increased glutamate level accompanied by reduction in mGluR7 expression in the spinal cord. Selective activation of mGluR7 by its positive allosteric modulator, AMN082, blocked the development of paclitaxel-induced acute mechanical and thermal hypersensitivity, without affecting the normal pain behavior of control rats. Moreover, activation of mGluR7 by AMN082 inhibited glial reactivity and decreased pro-inflammatory cytokine release during P-APS. Abortion of spinal glial reaction to paclitaxel alleviated paclitaxel-induced acute mechanical and thermal hypersensitivity. Conclusions There results support the hypothesis that spinal mGluR7 signaling plays an important role in P-APS; Selective activation of mGluR7 by its positive allosteric modulator, AMN082, blocks P-APS in part by reducing spinal glial reactivity and neuroinflammatory process.
... We addressed this contradictory issue with animal model of chemotherapy-induced neuropathy, which exhibits both persistent pain 325 and memory/emotional deficits. 326,327 We found that NR2B expression was downregulated in hippocampus but upregulated in spinal dorsal horn in vincristine-treated animals, and the opposite changes were prevented by oral L-TAMS. ...
Article
Full-text available
Xian-Guo Liu Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, Guangzhou, People’s Republic of ChinaCorrespondence: Xian-Guo Liu, Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, 74 Zhongshan Road2, Hemulou 806, Guangzhou, 510080, People’s Republic of China, Tel/Fax +86 87331956, Email liuxg@mail.sysu.edu.cnAbstract: Chronic pain, which affects around 1/3 of the world population and is often comorbid with memory deficit and mood depression, is a leading source of suffering and disability. Studies in past decades have shown that hyperexcitability of primary sensory neurons resulting from abnormal expression of ion channels and central sensitization mediated pathological synaptic plasticity, such as long-term potentiation in spinal dorsal horn, underlie the persistent pain. The memory/emotional deficits are associated with impaired synaptic connectivity in hippocampus. Dysregulation of numerous endogenous proteins including receptors and intracellular signaling molecules is involved in the pathological processes. However, increasing knowledge contributes little to clinical treatment. Emerging evidence has demonstrated that the neuroinflammation, characterized by overproduction of pro-inflammatory cytokines and glial activation, is reliably detected in humans and animals with chronic pain, and is sufficient to induce persistent pain and memory/emotional deficits. The abnormal expression of ion channels and pathological synaptic plasticity in spinal dorsal horn and in hippocampus are resulting from neuroinflammation. The neuroinflammation is initiated and maintained by the interactions of circulating monocytes, glial cells and neurons. Obviously, unlike infectious diseases and cancer, which are caused by pathogens or malignant cells, chronic pain is resulting from alterations of cells and molecules which have numerous physiological functions. Therefore, normalization (counterbalance) but not simple inhibition of the neuroinflammation is the right strategy for treating neuronal disorders. Currently, no such agent is available in clinic. While experimental studies have demonstrated that intracellular Mg2+ deficiency is a common feature of chronic pain in animal models and supplement Mg2+ are capable of normalizing the neuroinflammation, activation of upregulated proteins that promote recovery, such as translocator protein (18k Da) or liver X receptors, has a similar effect. In this article, relevant experimental and clinical evidence is reviewed and discussed.Keywords: ion channels, synaptic plasticity, cytokine, glial cell, monocytes
... With the gradual prolongation of the survival time of cancer patients, attention should increasingly focus on the longterm toxicity associated with cancer treatment because of its potential to affect the quality of life of cancer patients [1]. Chemotherapy-induced peripheral neuropathy (CIPN), which can lead to permanent symptoms and disability in cancer survivors, is a prominent complication associated with this long-term toxicity [2]. CIPN is a frequent side effect of several commonly used antineoplastic agents, including platinum-based drugs (cisplatin, carboplatin, and Jialin Gu and Hong Lu contributed equally to this work. ...
Article
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Background To identify the association between diabetes mellitus (DM) and the risk of chemotherapy-induced peripheral neuropathy (CIPN) through a systematic review and meta-analysis. Methods An electronic literature search was conducted in PubMed, Embase, Web of Science, the Wanfang database, the VIP Journals database (CQVIP), the China National Knowledge Infrastructure (CNKI) database, and the China Biology Medicine database (Sinomed) between January 2010 and January 2021. Articles were included if they investigated CIPN and DM. Stata 15.1 was used to analyze the data. Results We examined 8923 cancer patients from 25 studies comprising 9 cohort studies and 16 case–control studies. Meta-analysis showed that there was a statistically significant positive correlation between DM and CIPN (odds ratio [OR] = 1.60, 95% confidence interval [CI] = 1.38–1.85, P < 0.001). Egger’s test ( P = 0.824) showed no evidence of publication bias. The positive associations did not significant differ by study type, study quality, evaluation instrument, and type of antineoplastic drug. Omission of any single study had little effect on the combined risk estimate. Little evidence of heterogeneity was observed. Conclusion This meta-analysis provides evidence of a significant positive association between DM and risk of CIPN. Furthermore, a more detailed evaluation is warranted for cancer patients with diabetes when they are treated with antineoplastic drugs that have the potential to cause peripheral neuropathy.
Chapter
Cancer is one of the devastating diseases worldwide, causing desperate outcomes and high mortality rates. Despite undeniable improvements in cancer treatment, many patients with malignancies still suffer from adverse drug reactions, among which peripheral neurotoxicity holds great importance. Peripheral neuropathy as a representation of peripheral neurotoxicity is a usual complication of chemotherapy, reducing the life quality of individuals since it can adversely induce sensory and motor dysfunctions influencing patients’ life. Mitosis inhibitors are substantially administered drugs during chemotherapy. However, these drugs may induce the occurrence of chemotherapy-induced peripheral neuropathy (CIPN). Efficient therapy with fewer side effects specifically focusing on the eradication of malignant cells without affecting healthy cells adversely constitutes today’s approach for chemotherapy. Therefore, to target the discovery of functional chemotherapeutics with minimized adverse effects is a rational approach. In this context, medicinal plants and phytochemicals may come into the focus to avoid or treat the complications of peripheral neurotoxicity, if combined with standard chemotherapy regimens, or as complementary and alternative therapy interventions. In the present chapter, we review the factors involved in the pathogenesis of CIPN, neurotoxic mitosis inhibitors, and natural products as neuroprotective and/or neuropreventive agents. Future perspectives will be further manifested for the prevention or treatment of CIPN occurrence.
Article
Chemotherapy for cancer patients induces peripheral neuropathic pain as a refractory side effect. We reported that the prophylactic repeated oral administration of a traditional herbal medicine, shakuyakukanzoto (SKT), peripherally inhibited paclitaxel‐induced mechanical allodynia in mice. In the present study, we therefore developed external gel forms of SKT and the major constituent paeoniflorin (PF), and evaluated their effects on paclitaxel‐induced mechanical allodynia in mice. A single intraperitoneal injection of paclitaxel was given to mice. SKT or PF external gel (SKT‐Gel or PF‐Gel) was topically applied to the right planar surface twice daily for 13 days. Mechanical allodynia was evaluated by the von Frey filament test. The prophylactic repeated topical application of SKT‐Gel or PF‐Gel on the right planar surface inhibited the exacerbation of paclitaxel‐induced mechanical allodynia. However, the prophylactic repeated topical application of external base gel (BS‐Gel) on the left planar surface in the same mice treated with paclitaxel did not affect the allodynia. Prophylactic repeated topical applications of SKT‐Gel and PF‐Gel locally inhibited the exacerbation of paclitaxel‐induced mechanical allodynia. These gels were useful for the control of paclitaxel‐induced peripheral neuropathic pain.
Article
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Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect caused by chemotherapy drugs, and its existence seriously affects the quality of life of patients. We first established an oxaliplatin-induced peripheral neuropathy (OIPN) model and then measured and evaluated mechanical hyperalgesia, thermal nociception, cold allodynia, and intraepidermal nerve fiber (IENF) density to determine Siwei Jianbu Decoction's role in preventing OIPN. Then, we conducted a systematic pharmacological study that revealed important roles for the MAPK signaling pathway and proinflammatory immune pathway and confirmed these roles by western blot, immunofluorescence, and qPCR. The data show that Siwei Jianbu Decoction can effectively prevent oxaliplatin-induced neuroinflammation by inhibiting an increase in NF-κB expression via downregulation of p-ERK1/2 and p-p38. The present study showed that SWJB may be beneficial in preventing oxaliplatin-induced peripheral neuropathy.
Preprint
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Spinal astrocyte activation contributes to the pathogenesis of paclitaxel-induced neuropathic pain (PINP) in animal models. We examined gene expression of glial fibrillary acidic protein (GFAP; an astrocyte marker), glutamate transporters and receptor subunits in the anterior cingulate cortex (ACC) by real time PCR at 7 days post first administration of paclitaxel, a time point when mice had developed thermal hyperalgesia. Changes in the ACC, an area in the brain involved in pain perception and modulation, might contribute to the pathophysiology of PINP. GFAP transcripts levels were elevated by more than fivefold in the ACC of paclitaxel-treated mice. The 6 glutamate transporters (GLAST, GLT-1 EAAC1, EAAT4, VGLUT-1 and VGLUT-2) quantified were not significantly altered by paclitaxel treatment. Of the 12 ionotropic glutamate receptor subunits transcripts analysed 6 (GLuA1, GLuA3, GLuK2, GLuK3, GLuK5 and GLuN1) were significantly up-regulated, whereas GLuA2, GLuK1, GLuK4, GLuN2A and GLuN2B were not significantly altered and GLuA4 was lowly expressed. Amongst the 8 metabotropic receptor subunits analysed only mGLuR 8 was significantly elevated. In conclusion, during PINP there is astrocyte activation, no change in glutamate transporter expression and differential up-regulation of glutamate receptor subunits in the ACC. Thus, targeting astrocyte activation and the glutamatergic system might be another therapeutic avenue for management of PINP.
Preprint
Full-text available
Spinal astrocyte activation contributes to the pathogenesis of paclitaxel-induced neuropathic pain (PINP) in animal models. We examined glial fibrillary acidic protein (GFAP; an astrocyte marker) immunoreactivity and gene expression of GFAP, glutamate transporters and receptor subunits by real time PCR in the anterior cingulate cortex (ACC) at 7 days post first administration of paclitaxel, a time point when mice had developed thermal hyperalgesia. The ACC, an area in the brain involved in pain perception and modulation, was chosen because changes in this area might contribute to the pathophysiology of PINP. GFAP transcripts levels were elevated by more than fivefold and GFAP immunoreactivity increased in the ACC of paclitaxel-treated mice. The 6 glutamate transporters (GLAST, GLT-1 EAAC1, EAAT4, VGLUT-1 and VGLUT-2) quantified were not significantly altered by paclitaxel treatment. Of the 12 ionotropic glutamate receptor subunits transcripts analysed 6 (GLuA1, GLuA3, GLuK2, GLuK3, GLuK5 and GLuN1) were significantly up-regulated, whereas GLuA2, GLuK1, GLuK4, GLuN2A and GLuN2B were not significantly altered and GLuA4 was lowly expressed. Amongst the 8 metabotropic receptor subunits analysed only mGLuR8 was significantly elevated. In conclusion, during PINP there is astrocyte activation, no change in glutamate transporter expression and differential up-regulation of glutamate receptor subunits in the ACC. Thus, targeting astrocyte activation and the glutamatergic system might be another therapeutic avenue for management of PINP.
Book
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This Open Access textbook represents a vital contribution to global health education, offering insights into health promotion as part of patient care for bachelor’s and master’s students in health care (nurses, occupational therapists, physiotherapists, radiotherapists, social care workers etc.) as well as health care professionals, and providing an overview of the field of health science and health promotion for PhD students and researchers. Written by leading experts from seven countries in Europe, America, Africa and Asia, it first discusses the theory of health promotion and vital concepts. It then presents updated evidence-based health promotion approaches in different populations (people with chronic diseases, cancer, heart failure, dementia, mental disorders, long-term ICU patients, elderly individuals, families with newborn babies, palliative care patients) and examines different health promotion approaches integrated into primary care services. This edited scientific anthology provides much-needed knowledge, translating research into guidelines for practice. Today’s medical approaches are highly developed; however, patients are human beings with a wholeness of body-mind-spirit. As such, providing high-quality and effective health care requires a holistic physical-psychological-social-spiritual model of health care is required. A great number of patients, both in hospitals and in primary health care, suffer from the lack of a holistic oriented health approach: Their condition is treated, but they feel scared, helpless and lonely. Health promotion focuses on improving people’s health in spite of illnesses. Accordingly, health care that supports/promotes patients’ health by identifying their health resources will result in better patient outcomes: shorter hospital stays, less re-hospitalization, being better able to cope at home and improved well-being, which in turn lead to lower health-care costs. This scientific anthology is the first of its kind, in that it connects health promotion with the salutogenic theory of health throughout the chapters. We here expand the understanding of health promotion beyond health protection and disease prevention. The book focuses on describing and explaining salutogenesis as an umbrella concept, not only as the key concept of sense of coherence.
Article
Objective Chemotherapy-related peripheral neuropathies are observed frequently in lung cancer treatment in clinical practice. The present study aimed to evaluate the electrophysiologic findings and clinical symptoms in patients treated for lung cancer with different chemotherapy regimens who had the findings of peripheral neuropathy. Methods Patients who had electromyography (EMG) examinations with the prediagnosis of peripheral neuropathy at two different centers between January 2011 and December 2019 were included. The demographic data, neurologic examination findings, symptoms, EMG findings, and chemotherapeutic agents used in the treatment were evaluated retrospectively. Results A total of 742 patients were included in the study, with 630 (84.90%) male and 112 (15.10%) female patients. Of the patients included in the study, 406 (54.71%) had positive sensorial symptoms, 494 (66.57%) had negative sensorial symptoms, 162 (21.83%) had motor symptoms, and 254 (34.23%) had pain symptoms. The patients were classified into two groups on the basis of the presence of polyneuropathy detected via EMG as group I (n = 500, 67.38%) including the patients with polyneuropathy and group II (n = 242, 32.61%) including the patients without polyneuropathy. Negative sensorial symptoms and motor symptoms in group I along with dysesthesia and paresthesia symptoms in group II were observed at ratios that were higher at a statistically significant level ( p = 0.001, p = 0.001, p = 0.001, p = 0.001). Conclusion Sensorial symptoms are observed most frequently in chemotherapy-related peripheral neuropathies in lung cancer treatment and motor symptoms may also increase according to the chemotherapy regimen.
Chapter
Chemotherapy-Induced Peripheral Neurotoxicity (CIPN) is a side effect frequently caused by common antitumor drugs, which may induce a severe and persistent limitation of the quality of life of cancer patients. Today, nerve conduction studies are considered the most objective indicators for CIPN diagnosis. Unfortunately, they are not easily available at most oncology centers. Therefore, a noninvasive and highly sensitive method is required to confirm nerve damage. Increased evidence supports the potential utility of fluid-based biomarkers to predict tissue damage and to monitor neurotoxicity due to drug administration or the efficacy of disease-modifying treatments. Neurofilaments, the major intermediate filaments in neurons that are specifically expressed in axons, have been investigated as potential biomarker candidates that might be used for this purpose. Neurofilament light chain (NfL) protein is increasingly proposed as a blood biomarker in several neurological diseases mainly affecting the central nervous system. In addition, analysis of serum NfL was evaluated also in peripheral neuropathies including Guillain–Barré syndrome, chronic inflammatory demyelinating and vasculitic neuropathies, and Charcot–Marie–Tooth. This chapter aims to provide an overview of the methods that allow NfL quantification in serum, focusing on the most recent ultrasensitive single molecule array (Simoa) assay. This technique is likely to be the best method for NfL dosage in CIPN models to predict the onset of large caliber neuronal dysfunction. Since blood sampling is an easily accessible technique, serum NfL may provide important help to monitor neuroaxonal damage after chemotherapy treatment, and might represent promising tools to follow CIPN progress.
Article
Introduction: Therapy with anticancer drugs like paclitaxel, platinum complexes and vincristine result in severe peripheral neuropathy. Very few treatment options are available to overcome this debilitating side effect. Flavone and its monohydroxy derivatives have been proved to possess anti-nociceptive and anti-inflammatory effects in animal models. Aim: To investigate flavone, 5-hydroxy flavone, 6-hydroxy flavone and 7-hydroxy flavone for their effect on neuropathy induced by vincristine and oxaliplatin in mice. Materials and Methods: In this experimental animal study, neuropathy was induced in mice by multiple doses of vincristine or a single dose of oxaliplatin. The manifestations of mechanical allodynia, cold allodynia and thermal hyperalgesia were measured by von Frey’s hair aesthesiometer, acetone spray test and hot water tail immersion test. The data was subjected to ANOVA followed by Dunnett’s test for multiple comparison and paired t-test at appropriate places.Results: Flavone and monohydroxy flavones significantly reduced the paw withdrawal response scores due to mechanical allodynia and cold allodynia resulting from vincristine or oxaliplatin administration (pmechanical allodynia. Opioid mediated antinociceptive effect, interaction with cation channels and anti-inflammatory effect of the investigated flavones may be suggested as possible mechanisms for their beneficial effects in neuropathy due to chemotherapeutic agents. Conclusion: Various neuropathic manifestations induced by vincristine and oxaliplatin were effectively attenuated by flavone and monohydroxy flavones.
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Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling side effect of various chemotherapeutic agents, including oxaliplatin. It is highly prevalent amongst cancer patients, causing sensory abnormalities and pain. Unfortunately, as the underlying mechanisms remain poorly understood, effective therapeutics are lacking. Neuro-immune interactions have been highlighted as potential contributors to the development and maintenance of CIPN, however, whether this is the case in oxaliplatin-induced peripheral neuropathy (OIPN) is yet to be fully established. Methods: In this study we used flow cytometry to examine the peripheral immune response of male C57BL/6 mice following both single and repeated oxaliplatin administration. In animals exposed to repeated dosing, we also undertook mechanical and thermal behavioural assays to investigate how oxaliplatin alters phenotype, and conducted RT-qPCR experiments on bone marrow derived macrophages in order to further inspect the effects of oxaliplatin on immune cells. Results: In contrast to other reports, we failed to observe substantial changes in overall leukocyte, lymphocyte or myeloid cell numbers in dorsal root ganglia, sciatic nerves or inguinal lymph nodes. We did however note subtle, tissue-dependant alterations in several myeloid subpopulations following repeated dosing. These included a significant reduction in MHCII antigen presenting cells in the sciatic nerve and an increase in infiltrating cell types into the inguinal lymph nodes. Though repeated oxaliplatin administration had a systemic effect, we were unable to detect a pain-like behavioural phenotype in response to either cold or mechanical stimuli. Consequently, we cannot comment on whether the observed myeloid changes are associated with OIPN. Conclusions: Our discussion puts these results into the wider context of the field, advocating for greater transparency in reporting, alignment in experimental design and the introduction of more clinically relevant models. Only through joint concerted effort can we hope to increase our understanding of the underlying mechanisms of CIPN, including any immune contributions.
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Background: Chemotherapy-induced peripheral neuropathy is a common adverse effect of chemotherapeutic treatment and is associated with decreased quality of life. The aim of this study was to evaluate the validity and reliability of the neurotoxicity subscale of the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) for the Chilean population. Methods: A cross-sectional study in which 101 participants with haematologic, colorectal, breast, gastric, gynaecological, and other types of cancer completed the FACT/GOG-Ntx. Content validity (n = 14 health professionals evaluated the subscale in four categories: test-retest reliability (n = 20 patients), dimensionality, internal consistency, and concurrent validity and discriminant validity. In all analyses, p < 0.05 was considered significant. Results: There was an agreement among the evaluators for all categories of the subscale (Kendall's coefficient, W = 0.4, p < 0.01) and moderate to high intrarater reliability (intraclass correlation coefficient = 0.7-0.9). Of the 11 original items that make up the subscale, none was eliminated. The factor analysis generated four factors that represented 72.2% of the total variance. Cronbach's α was 0.8 for the 11 items. Women showed greater compromise in emotional well-being and neurotoxicity symptoms compared with men, and age was directly correlated with the questions 'I have difficulty hearing' (r = 0.2, p = 0.019) and 'I feel a noise or buzzing in my ears' (r = 0.2, p = 0.03). Conclusion: The Chilean version of the FACT/GOG-Ntx neurotoxicity subscale is a valid and reliable scale for evaluating neurotoxicity symptoms in adult cancer survivors in Latin America. The scales also adequately distinguish between sex-based well-being among the afflicted population.
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Docetaxel-based therapy has been applied to kill cancers including lung and breast cancers but frequently causes peripheral neuropathy such as mechanical allodynia. Lack of effective drugs for chemotherapy-induced peripheral neuropathy (CIPN) treatment leads us to find novel drugs. Here, we investigated whether and how novel anticancer herbal prescription SH003 alleviates mechanical allodynia in mouse model of docetaxel-induced neuropathic pain. Docetaxel-induced mechanical allodynia was evaluated using von Frey filaments. Nerve damage and degeneration in paw skin of mice were investigated by immunofluorescence staining. Neuroinflammation markers in bloodstream, lumbar (L4-L6) spinal cord, and sciatic nerves were examined by ELISA or western blot analysis. Docetaxel (15.277 mg/kg) was intravenously injected into the tail vein of C57BL/6 mice, and mechanical allodynia was followed up. SH003 (557.569 mg/kg) was orally administered at least 60 min before the mechanical allodynia test, and von Frey test was performed twice. Docetaxel injection induced mechanical allodynia, and SH003 administration restored withdrawal threshold. Meanwhile, degeneration of intraepidermal nerve fibers (IENF) was observed in docetaxel-treated mice, but SH003 treatment suppressed it. Moreover, docetaxel injection increased levels of TNF-α and IL-6 in plasma and expressions of phospho-NF-κB and phospho-STAT3 in both of lumbar spinal cord and sciatic nerves, while SH003 treatment inhibited those changes. Taken together, it is worth noting that TNF-α and IL-6 in plasma and phospho-NF-κB and phospho-STAT3 in spinal cord and sciatic nerves are putative biomarkers of docetaxel-induced peripheral neuropathy (DIPN) in mouse models. In addition, we suggest that SH003 would be beneficial for alleviation of docetaxel-induced neuropathic pain.
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Pharmacological strategies for chemotherapy-induced peripheral neurotoxicity (CIPN) are very limited. We systematically reviewed data on rehabilitation, exercise, physical therapy, and other physical non-pharmacological interventions and offered evidence-based recommendations for the prevention and treatment of CIPN. A literature search using PubMed, Web of Science and CINAHL was conducted from database inception until May 31st, 2021. 2791 records were title-abstract screened, 71 papers were full-text screened, 41 studies were included, 21 on prevention and 20 on treatment of CIPN. Treatment type, cancer type, chemotherapy compounds were heterogeneous, sample size was small (median: N = 34) and intention-to-treat analysis was lacking in 26/41 reports. Because of the methodological issues of included studies, the reviewed evidence should be considered as preliminary. Exercise, endurance, strength, balance, and sensorimotor training have been studied in low-to-moderate quality studies, while the evidence for other treatments is preliminary/inconclusive. We offer recommendation for the design of future trials on CIPN.
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Chemotherapy-induced peripheral neurotoxicity is a common dose-limiting side effect of several cancer chemotherapeutic agents, and no effective therapies exist. Here we constructed a systems pharmacology model of intracellular signaling in peripheral neurons to identify novel drug targets for preventing peripheral neuropathy associated with proteasome inhibitors. Model predictions suggested the combinatorial inhibition of TNFα, NMDA receptors, and reactive oxygen species should prevent proteasome inhibitor-induced neuronal apoptosis. Dexanabinol, an inhibitor of all three targets, partially restored bortezomib-induced reduction of proximal action potential amplitude and distal nerve conduction velocity in vitro and prevented bortezomib-induced mechanical allodynia and thermal hyperalgesia in rats, including a partial recovery of intraepidermal nerve fiber density. Dexanabinol failed to restore bortezomib-induced decreases in electrophysiological endpoints in rats, and it did not compromise bortezomib anti-cancer effects in U266 multiple myeloma cells and a murine xenograft model. Owing to its favorable safety profile in humans and preclinical efficacy, dexanabinol might represent a treatment option for bortezomib-induced neuropathic pain.
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Chemotherapy-induced peripheral neuropathy (CIPN) is one of the main and most prevalent side effects of chemotherapy, significantly affecting the quality of life of patients and the course of chemotherapeutic treatment. Nevertheless, despite its prevalence, the management of the CIPN is considered particularly challenging, with this condition often being perceived as very difficult or even impossible to prevent with currently available agents. Therefore, it is imperative to find better options for patients diagnosed with this condition. While the search for the new agents must continue, another opportunity should be taken into consideration—repurposing of the already known medications. As proposed, acetyl-L-carnitine, vitamins (group B and E), extracts of medical plants, including goshajinkigan, curcumin and others, unsaturated fatty acids, as well as the diet composed of so-called “sirtuin-activating foods”, could change the typical way of treatment of CIPN, improve the quality of life of patients and maintain the continuity of chemotherapy. This review summarizes currently available data regarding mentioned above agents and evaluates the rationale behind future research focused on their efficacy in CIPN. View Full-Text
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Since the first clinical trials conducted after World War II, chemotherapeutic drugs have been extensively used in the clinic as the main cancer treatment either alone or as an adjuvant therapy before and after surgery. Although the use of chemotherapeutic drugs improved the survival of cancer patients, these drugs are notorious for causing many severe side effects that significantly reduce the efficacy of anti-cancer treatment and patients' quality of life. Many widely used chemotherapy drugs including platinum-based agents, taxanes, vinca alkaloids, proteasome inhibitors, and thalidomide analogs may cause direct and indirect neurotoxicity. In this review we discuss the main effects of chemotherapy on the peripheral and central nervous systems, including neuropathic pain, chemobrain, enteric neuropathy, as well as nausea and emesis. Understanding mechanisms involved in chemotherapy-induced neurotoxicity is crucial for the development of drugs that can protect the nervous system, reduce symptoms experienced by millions of patients, and improve the outcome of the treatment and patients' quality of life.
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Background: Triterpenes such as euphol and pristimerin, which are plant secondary metabolites, were the first to be characterized as monoacylglycerol lipase (MAGL) inhibitors. MAGL inhibitors alleviate chemotherapy-induced neuropathic pain (CINP) in rodent models. Pristimerin has been shown to have additive anticancer activity with paclitaxel, a chemotherapeutic drug. However, the activity of pristimerin on CINP has not been evaluated. Objectives: The aims of this study were to evaluate whether various triterpenes had activity against recombinant human MAGL and MAGL activity in mouse tissues, and whether pristimerin could prevent development of paclitaxel-induced mechanical allodynia. Methods: The effects of four triterpenes betulinic acid, cucurbitacin B, euphol, and pristimerin on the activity human recombinant MAGL and MAGL activity of mice brain and paw skin tissues were evaluated using MAGL inhibitor screening and MAGL activity assay kits. The effects of treatment of female BALB/c mice with pristimerin intraperitoneally on the development of paclitaxel-induced mechanical allodynia were assessed using the dynamic plantar aesthesiometer and on nuclear factor-2 erythroid related factor-2 ( Nrf2 ) gene expression in the paw skin were evaluated by real time polymerase chain reaction. Results: Pristimerin inhibited the human recombinant MAGL activity in a concentration-dependent manner like JZL-195, a MAGL inhibitor. Betulinic acid, cucurbitacin B and euphol inhibited human recombinant MAGL activity but their effects were not concentration dependent and were less to that of pristimerin. Pristimerin inhibited both mouse brain and paw skin MAGL activity in a concentration-dependent manner. Paclitaxel induced mechanical allodynia and increase in MAGL activity in the paw skin. Treatment with pristimerin prevented the development of paclitaxel-induced mechanical allodynia and the paclitaxel-induced increase in MAGL activity. Pristimerin significantly upregulated mRNA expression of Nrf2, a regulator of endogenous antioxidant defense. Conclusion: These results indicate that triterpenes inhibit human recombinant MAGL activity with varying degrees. Pristimerin inhibits both mouse brain and paw skin MAGL activity in a concentration-dependent manner, prevents both the development of paclitaxel-induced mechanical allodynia and the associated increase in MAGL activity in the paw skin, and might protect against paclitaxel-induced oxidative stress. Co-treatment with pristimerin and paclitaxel could be useful in the treatment of cancer and prevention of CINP.
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Breast cancer is one of the most commonly diagnosed cancers in American women. Triple negative breast cancer is among the most advanced and aggressive forms of breast cancer. Treatment options are limited for such cancers, making chemotherapy a convenient and effective treatment. Although these therapies can reduce morbidity and mortality, it is often followed by systemic side effects or relapse. Nanoparticles (NPs) have been considered for drug delivery approaches due to their ability to target various disease sites. Herein, we aim to develop a biomimetic NP construct (cell membrane-cloaked NPs) that exhibits specific affinity with triple negative breast cancer cells. In this regard, we designed biomimetic supramolecular nanoconstructs composed of a poly(vinyl pyrrolidone)-tannic acid (PVP-TA NPs/ PVT NPs) core and biofunctionalized with neutrophil cell membranes (PVT-NEU NPs). In this study, we have synthesized a PVT-NEU NP construct, characterized it, and evaluated it for improved targeting and therapeutic benefits in in vitro and in vivo models. Analysis of PVT-NEU NPs confirms the presence of the core of PVP-TA NPs coated with activated human neutrophil membranes. The study results confirmed that PVT-NEU NPs demonstrated an enhanced interaction and targeting with the tumor cells, thus improving the therapeutic activity of a model therapeutic agent (paclitaxel). Altogether, this study suggests the potential of biomimetic NPs as a promising therapeutic option for targeted drug delivery for advanced-stage breast cancer and other similar diseased conditions.
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Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) is one of the common reasons that colorectal cancer patients cannot maintain their routine chemotherapy schedules. Some medications are used for pain relief; however, the effect of medication is disappointing. We carried out this study to confirm that a rehabilitation program using minor muscles might provide a valuable aid in symptom relief of CIPN.Methods: Eleven colorectal cancer patients participated in the basic craftwork program which encouraged the use of the minor muscles of the hands to make and decorate the handicrafts and it was held for 2 hours once a week, for a total of four times. There were no limitations in the stage of cancer or types of chemotherapy to participate the program. Questionnaires were obtained from participants before and after the basic handicrafts program.Results: Of the 11 patients (3 men, 8 women; mean age, 53.0±11.2 years), six received 5-fluorouracil (5-FU) chemotherapy, four received FOLFOX4 (combination of 5-FU, leucovorin, and oxaliplatin) chemotherapy, and one received 5-FU, FOLFOX4, and FOLFIRI (combination of 5-FU, leucovorin, and irinotecan) chemotherapy sequentially. Patients attended the program a mean of 3.8±0.4 times. Common symptoms of CIPN were “throbbing pain,” “aching pain,” and “numbness.” The mean score of the questionnaires between pre- and post-program was 34.1±31.7 points and 24.4±21.5 points each, and it was significantly decreased (P=0.040).Conclusion: Patients often suffered from CIPN symptoms like throbbing or aching pain and numbness during their adjuvant chemotherapy. A rehabilitation program using minor muscles for CIPN is expected to be effective.
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Vincristine, a widely used chemotherapeutic agent, produces painful peripheral neuropathy. The underlying mechanisms are not well understood. In this study, we investigated whether voltage-gated sodium channels are involved in the development of vincristine-induced neuropathy. We established a mouse model in which repeated systemic vincristine treatment results in the development of significant mechanical allodynia. Histological examinations did not reveal major structural changes at proximal sciatic nerve branches or distal toe nerve fascicles at the vincristine dose used in this study. Immunohistochemical studies and in vivo two-photon imaging confirmed that there is no significant change in density or morphology of intra-epidermal nerve terminals throughout the course of vincristine treatment. These observations suggest that nerve degeneration is not a prerequisite of vincristine-induced mechanical allodynia in this model. We also provided the first detailed characterization of tetrodotoxin-sensitive (TTX-S) and resistant (TTX-R) sodium currents in dorsal root ganglion neurons following vincristine treatment. Accompanying the behavioural hyperalgesia phenotype, voltage-clamp recordings of small and medium dorsal root ganglion neurons from vincristine-treated animals revealed a significant upregulation of TTX-S Na+ current in medium but not small neurons. The increase in TTX-S Na+ current density is likely mediated by Nav1.6, because in the absence of Nav1.6 channels, vincristine failed to alter TTX-S Na+ current density in medium dorsal root ganglion neurons and, importantly, mechanical allodynia was significantly attenuated in conditional Nav1.6 knockout mice. Our data show that TTX-S sodium channel Nav1.6 is involved in the functional changes of dorsal root ganglion neurons following vincristine treatment and it contributes to the maintenance of vincristine-induced mechanical allodynia.
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Amitriptyline reduces the pain caused by peripheral-nerve disease, but treatment is often limited by side effects related to the drug's many pharmacologic actions. Selective agents might be safer and more effective. We carried out two randomized, double-blind, crossover studies in patients with painful diabetic neuropathy, comparing amitriptyline with the relatively selective blocker of norepinephrine reuptake desipramine in 38 patients, and comparing the selective blocker of serotonin reuptake fluoxetine with placebo in 46 patients. Fifty-seven patients were randomly assigned to a study as well as to the order of treatment, permitting comparison among all three drugs and placebo as the first treatment. The patients rated the degree of pain present each day using verbal descriptors, and they also assessed the extent of pain relief globally at the end of each treatment period. After individual dose titration, the mean daily doses of the drugs were as follows: amitriptyline, 105 mg; desipramine, 111 mg; and fluoxetine, 40 mg. There was moderate or greater relief of pain in 28 of the 38 patients (74 percent) who received amitriptyline, 23 of the 38 patients (61 percent) who received desipramine, 22 of the 46 patients (48 percent) who received fluoxetine, and 19 of the 46 patients (41 percent) who received placebo. The differences in responses between amitriptyline and desipramine and between fluoxetine and placebo were not statistically significant, but both amitriptyline and desipramine were superior to placebo. Amitriptyline and desipramine were as effective in patients who were not depressed as in depressed patients, but fluoxetine was effective only in depressed patients. Desipramine relieves pain caused by diabetic neuropathy with efficacy similar to that of amitriptyline, offering an alternative for patients unable to tolerate the latter. Blockade of norepinephrine reuptake is likely to mediate the analgesic effect of these antidepressant drugs in diabetic neuropathy. Fluoxetine, which blocks serotonin uptake, is no more effective than placebo for the relief of pain.
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Taxol, a novel antimicrotubule agent that enhances tubulin polymerization and microtubule stability, was administered to adults with refractory leukemias as a 24-h i.v. infusion in a Phase I study. The primary objectives were to determine the maximum tolerated dose of taxol administered on this schedule to patients with acute leukemias and describe the nonhematological toxicities which became dose limiting. The starting dose, 200 mg/m2, was based on the maximum tolerated dose in solid tumor trials, in which myelosuppression precluded dose escalation. Seventeen patients received 28 evaluable courses at 200, 250, 315, and 390 mg/m2. Severe mucositis limited further dose escalation. Other nonhematological effects included peripheral neuropathy, alopecia, myalgias, arthralgias, nausea, vomiting, diarrhea, and an acute pulmonary reaction that was presumptively due to taxol's Cremophor vehicle. Mean peak taxol plasma concentrations at all dose levels were in the range of concentrations that were previously demonstrated to induce microtubule bundles, a morphological effect associated with cytotoxicity, in leukemia cells in vitro. Pretreatment blasts from 12 patients were incubated with taxol ex vivo. Taxol-induced microtubule bundles were apparent in the blasts of eight patients who also had cytoreduction of tumor, and sensitivity to bundle formation was related to the magnitude of antitumor activity. In contrast, taxol did not induce microtubule bundles ex vivo in the blasts of the other four total nonresponders. Based on this study, the maximum tolerated doses and recommended Phase II doses for taxol, limited by nonhematological toxicity and administered as a 24-h i.v. infusion to patients with refractory leukemias, are 390 and 315 mg/m2. Phase II trials at these myelosuppressive doses are required to determine taxol's activity in the treatment of leukemias. In addition, further evaluation of microtubule bundle formation ex vivo in Phase II studies is necessary to determine the ultimate utility of this assay in assessing tumor sensitivity to taxol.
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Early clinical trials have suggested that glutathione (GSH) offers protection from the toxic effects of cisplatin. One hundred fifty-one patients with ovarian cancer (stage I-IV) were evaluated in a clinical trial of cisplatin (CDDP) +/- glutathione (GSH). The objective was to determine whether GSH would enhance the feasibility of giving six cycles of CDDP at 100 mg/m2 without dose reduction due to toxicity. When considering the proportion of patients receiving six courses of CDDP at any dose, GSH produced a significant advantage over control--58% versus 39%, (P = 0.04). For these patients there was a significant difference between the reduction in creatinine clearance for GSH treated patients compared with control--74% versus 62% (P = 0.006). Quality of life scores demonstrated that for patients receiving GSH there was a statistically significant improvement in depression, emesis, peripheral neurotoxicity, hair loss, shortness of breath and difficulty concentrating. As an indication of overall activity, these patients were statistically significantly more able to undertake housekeeping and shopping. Clinically assessed response to treatment demonstrated a trend towards a better outcome in the GSH group (73% versus 62%) but this was not statistically significant (P = 0.25). The results demonstrate that adding GSH to CDDP allows more cycles of CDDP treatment to be administered because less toxicity is observed and the patient's quality of life is improved.
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Our aim was 2-fold: to investigate the role of alpha-tocopherol supplementation on the antitumor activity of DDP and to evaluate the effect of alpha-tocopherol on the survival and neurotoxicity of DDP-treated mice. Experiments performed on the M14 human melanoma line demonstrated that alpha-tocopherol supplementation did not influence the efficacy of DDP; the inhibition of cell survival and of the in vivo tumor growth after treatment with alpha-tocopherol and DDP combination was similar to that observed after DDP alone. Conversely, alpha-tocopherol was also able to increase survival of mice treated with a high dose of DDP. While DDP alone produced death in about 70% of mice, the combination reduced deaths to about 30%. Analysis of oxidative stress markers and peroxidative damage in organs indicated that the protective effect of alpha-tocopherol was mainly related to its antioxidant activity. A significant increase in the concentration of TBARS and decreased PUFAs and catalase activity were observed after DDP treatment, while with alpha-tocopherol the levels of these markers were comparable to those observed in untreated mice. Histologic analysis performed on peripheral nerve revealed that alpha-tocopherol also protected mice from severe neurologic damage induced by DDP treatment. In conclusion, our results demonstrate that alpha-tocopherol protects against the systemic toxicity and neurotoxicity induced by DDP without interfering with its antitumor activity and suggest that this combination is a promising strategy to improve the therapeutic index of DDP-based chemotherapy.
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The involvement of ongoing peripheral activity in the generation of nociceptive input in neuropathic pain suggests that topical drug delivery may be useful as a treatment strategy. This is a pilot study providing initial information regarding the use of novel topical preparations containing amitriptyline (AMI), ketamine (KET), and a combination of both in the treatment of neuropathic pain. The study design included a 2 day randomized, double blind, placebo controlled, 4 way cross-over trial of all treatments, followed by an open label treatment phase using the combination cream for 7 days. Twenty volunteers with chronic neuropathic pain were randomly assigned to treatment order and applied 5 mls of each topical treatment (1% AMI, 0.5% KET, combination AMI 1%/KET 0.5%, and placebo) for 2 days. Measures of pain at the end of each block included the short form McGill Pain Questionnaire (MPQ) and visual analog scales (VAS) for present pain intensity and pain relief. Eleven subjects who judged subjective improvement from any treatment in the initial trial entered the open-label trial and used the combination cream for 7 days. Pain levels were recorded daily using the same measures. Blood levels for amitriptyline and ketamine were performed at 7 days to determine whether systemic absorption had occurred. There was no statistically significant difference from placebo after 2 days for any treatment during the double blind component of the trial. In the 11 subjects who used the combination cream, there was a statistically significant effect, with subjects reporting significantly greater analgesia by days 3 to 7 according to measures of pain and pain relief. Blood levels revealed that there was no significant systemic absorption of amitriptyline or ketamine. Only 2 subjects experienced side effects; these were minor and did not lead to discontinuation of the cream. This pilot study demonstrated a lack of effect for all treatments in the 2 day double blind placebo controlled trial, followed by analgesia in an open label trial in a subgroup of subjects who chose to use the combination cream for 7 days. Blood analysis revealed no significant systemic absorption of either agent after 7 days of treatment, and creams were well tolerated. A larger scale randomized trial over a longer interval is warranted to examine further effects observed in the open label trial.
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Many patients with cancer take antioxidant nutritional supplements during cancer treatment to alleviate treatment toxicities and to improve long-term outcomes, but little is known about the efficacy and safety of antioxidant use during cancer treatment. We reviewed English-language manuscripts published in the biomedical literature, reporting the results of observational studies of antioxidant status and cancer outcomes and of intervention trials of antioxidants among patients receiving chemotherapy with or without radiation for various malignancies. We searched the Medline database and the bibliographies of the retrieved manuscripts, reviews, and books on antioxidants and cancer. The retrieved studies are grouped by study design, malignancy, and end points. More than 100 citations were retrieved; 52 met our criteria, 31 were observational studies, and 21 were intervention trials. The studies varied in study design, timing of observation/intervention, intervention protocol, malignancy, and anticancer regimen. These inconsistencies preclude a definitive conclusion as to the effect of chemotherapy on antioxidant status in patients undergoing anticancer therapy. However, our review suggests that total antioxidant status (measured by total radical antioxidant parameter) declines during cancer treatment. Adequately powered trials or observational studies among patients with a specific cancer diagnosis receiving a specific treatment regimen are needed to address patients' and physicians' concerns regarding these associations.
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Neuropathic pain is often resistant to opioids, so other medication classes, such as tricyclic antidepressants, anticonvulsants, and local anesthetics, are often used. Central sensitization, or pain 'wind-up', may perpetuate chronic neuropathic pain even when ongoing peripheral sensory input is absent. Wind-up is thought to cause allodynia, hyperalgesia, and hyperpathia. Receptors such as NMDA, AMPA, and M-glu have recently been identified for their role in central sensitization or pain 'wind-up'. Ketamine has been proposed recently for neuropathic pain secondary to its NMDA receptor activity. The current application as a topical gel stems from the theory that ketamine has peripheral action at both opioid and Na+-K+ channels. This case study involved 5 patients from 25 to 70 years old (3 RSD, 1 lumbar radiculopathy, 1 post-herpetic neuralgia). Dose used was determined by site and surface area of involvement and ranged from 0.093 mg/kg to 9.33 mg/kg. All five patients reported significant pain relief at initial application and wished to continue treatment. The average numerical analogue scale (NAS) score preapplication was 8.8. The average 15 minutes post application NAS was 1.6. Patients reported alterations in temperature sensation, feelings of relaxation and decreased tension in the area of application, and pain relief. Reduction in numerical pain scores postapplication of ketamine gel ranged from 53-100% using a 1-10 numerical pain intensity scale. No significant side effects were reported. Ketamine Gel may provide clinicians with a new option in the battle against chronic neuropathic pain. Until further information is available and larger trials can be conducted, we can only recommend this type of therapy for refractory cases in which all primary and secondary options have been exhausted.
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In vitro and animal studies suggest that antitumor effect of chemotherapeutic agents may be enhanced by antioxidants. Therefore, we initiated a clinical study to test the efficacy of high-dose multiple antioxidants (vitamins C, E and beta carotene) as an adjunct to chemotherapy (paclitaxel and carboplatin) in non-small-cell lung cancer. 136 patients of stage IIIb and stage IV NSCLC were randomized to receive chemotherapy (paclitaxel and carboplatin) alone (chemotherapy arm, n = 72) or chemotherapy in combination with ascorbic acid 6100 mg/day, dl-alpha-tocopherol (vitamin E) 1050 mg/day and beta-carotene 60 mg/day (combination arm, n = 64). Survival were calculated by the Kaplan-Meier method and compared using the log-rank test. An overall response rate (RR) of 33% was observed in chemotherapy arm with 24 patients showing a partial response (PR) and none showing a complete response (CR). In combination arm the overall RR was 37% with 24 patients showing PR and two showing CR. The median survival times in chemotherapy arm and combination arm were nine and 11 months respectively. The overall survival (OS) rates in chemotherapy arm and combination arm at one year were 32.9% and 39.1%, and at two years, 11.1% and 15.6% respectively. None of these differences were statistically significant (p = 0.20). Toxicity profiles were similar in both arms. These results do not support the concern that antioxidants might protect cancer cells from the free radical damage induced by chemotherapy. Larger trials are needed to demonstrate whether high-dose multiple antioxidants in conjunction with chemotherapy increase the response rates and/or survival time in advanced lung cancer.
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To determine whether recombinant human leukemia inhibitory factor (rhuLIF, AM424, emfilermin) can prevent or ameliorate the development of chemotherapy-induced peripheral neuropathy (CIPN) after treatment with carboplatin (AUC 6) and paclitaxel (175 mg/m(2) over 3 hours). Randomized double-blind placebo-controlled phase II clinical trial. Eligible patients had solid tumors for which treatment with carboplatin/paclitaxel was appropriate. The primary end point was a standardized composite peripheral nerve electrophysiology (CPNE) score, based on nerve velocities and amplitudes, measured at baseline and after four cycles of chemotherapy. Secondary efficacy end points included CPNE score at last cycle and at exit evaluation, vibration perception threshold, H-reflex latency, symptom scores, and quantitative assessment of neurologic signs. Study drug was given s.c. daily for 7 days starting the day before chemotherapy. Patients were randomized to receive low-dose rhuLIF (2 microg/kg), high-dose rhuLIF (4 microg/kg), or placebo. Patients (n = 117) were randomized across seven neurology test centers. Thirty-six patients received low dose rhuLIF (2 microg/kg), 39 received high dose rhuLIF (4 microg/kg) and 42 received placebo. rhuLIF was well tolerated with 95% compliance and no adverse effects on quality of life. No differences between groups in CPNE or any of the individual neurologic testing variables were observed between baseline and cycle 4 or by the secondary efficacy variables. rhuLIF is not effective in preventing CIPN caused by carboplatin and paclitaxel. CPNE is a reliable and valid tool that was sensitive to the onset and progression of CIPN.
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A double-blind, randomized, placebo-controlled 3-week study evaluated the efficacy of topical 2% amitriptyline, 1% ketamine, and a combination of both in treating patients with neuropathic pain. Ninety-two patients with diabetic neuropathy, postherpetic neuralgia, or postsurgical/posttraumatic neuropathic pain with allodynia, hyperalgesia, or pinprick hypesthesia were randomly assigned to receive one of four creams (placebo, 2% amitriptyline, 1% ketamine, or 2% amitriptyline-1% ketamine combined). The primary outcome measure was change in average daily pain intensity (baseline week vs. final week) using an 11-point numerical pain rating scale. Secondary outcomes included the McGill Pain Questionnaire, measures of allodynia and hyperalgesia, and patient satisfaction. A reduction in pain scores of 1.1-1.5 units was observed in all groups, and there was no difference between groups. Blood concentrations revealed no significant systemic absorption. Minimal side effects were encountered. This randomized, placebo-controlled trial examining topical 2% amitriptyline, 1% ketamine, and a combination in the treatment of neuropathic pain revealed no difference between groups. Optimization of doses may be required, because another study has revealed that higher concentrations of these agents combined do produce significant analgesia.
Article
9114 Background: Peripheral neurotoxicity is a well recognized effect of cisplatin chemotherapy that can result in severe disability and represents a major dose-limiting factor. Several phase II studies have recently investigated the role of vitamin E as neuroprotectant in the prevention of cisplatin induced peripheral neurotoxicity and ototoxicity. Methods: An Italian randomized, placebo controlled, double blind multicentric study is ongoing to confirm the role of vitamin E supplementation in the prevention of neurotoxicity and ototoxicity induced by cisplatin Patients candidates to cisplatin chemotherapy were randomised to either vitamin E supplementation (a-tocopherol 400 mg/day) or to placebo. Patients were evaluated with neurological and neurophysiological examination before and after treatment. Neurotoxicity was measured using the comprehensive clinical and neurophysiological Total Neuropathy Score (TNS). Ototoxicity was evaluated with audiometric test and acoustic evoked potential before and after treatment. Results: 81 patients have been enrolled in 3 italian oncologic centers. An interim analysis on the first 50 patients was carried out. 25 patients (11 in the vit E group and 14 in the placebo group) received a cumulative dose higher than 300 mg/mq and were evaluable for neurotoxicity. Statistical analysis showed a significant difference (p < 0.05) in median neurotoxicity score observed in vit E group (TNS=1) respect to the placebo group (TNS=5). Conclusions: This is the first randomised, placebo controlled, double blind trial exploring the efficacy of vitamin E in the neuroprotection of cisplatin neurotoxicity. The results of this study confirm the neuroprotective effect of vitamin E supplementation against cisplatin-induced neurotoxicity. No significant financial relationships to disclose.
Article
PURPOSE: Oxaliplatin is a novel platinum compound with clinical activity in several malignancies. Neurotoxicity is dose-limiting and occurs in two distinct forms, an acute neurologic symptom complex that occurs within hours or days of therapy and a chronic, cumulative sensory neuropathy. PATIENTS AND METHODS: Patients were treated in a phase I study designed to establish the maximum-tolerated dose of capecitabine given with oxaliplatin. Because of the unusual neurosensory toxicity of oxaliplatin, detailed neurologic examination, needle electromyography (EMG), and nerve conduction studies (NCS) were performed before and the day after oxaliplatin in a subset of 13 patients. Carbamazepine therapy was tried in 12 additional patients to determine whether the neurologic effects might be relieved. RESULTS: All patients experienced acute, reversible neurotoxicities with oxaliplatin. Symptoms included paresthesias, dysesthesias, cold hypersensitivity, jaw pain, eye pain, pain in the arm used for drug infusion, ptosis, leg cramps, and visual and voice changes. Serial EMG and NCS revealed striking signs of hyperexcitability in motor nerves after oxaliplatin. In patients who achieved therapeutic levels, carbamazepine did not alter the clinical or electromyographic abnormalities. CONCLUSION: The acute neurotoxicity seen with oxaliplatin is characterized by peripheral-nerve hyperexcitability, and the findings are similar to the clinical manifestations of neuromyotonia. Carbamezepine, which provides symptomatic relief in acquired neuromytonia, did not seem to be beneficial. Efforts to identify a successful neuroprotectant strategy would have a major impact on improving patient quality of life and the ability to deliver full doses of oxaliplatin.
Article
3507 Background: X, an orally administered non-peptide neurotrophic agent developed by sanofi-aventis, was shown in vitro to minimize neuritic damage induced by Ox (co-culture of Schwann cells and dorsal roots ganglia explant). The probability of occurrence of Grade (Gr) 3–4 PSN at a cumulative dose of Ox of 1000 mg/m ² , was consistently reported to be of 18–20%. Methods: First line MCRC pts were randomized to receive, in a DB fashion, FOLFOX4 and either Plcb or X 1mg daily. X was administered from the 1 st day of chemotherapy till 15 days post last Ox cycle. Co-primary objectives were reduction in the risk of occurrence of Gr 3–4 PSN relative to cumulative dose of Ox (Kaplan-Meier method) and non-inferiority in response rate (RR). Secondary endpoints included evaluation of sensory action potential (SAP) and safety. Results: From July 2002 to May 2004, 649 pts were randomized (324 Plcb, 325 X). Pts characteristics were well balanced across arms, median number of Ox cycles was 12 in both arms, median relative dose intensity (%) was 83.8 (Plcb) and 85.2 (X). A significant risk reduction of 39% in the probability of Grade 3–4 PSN in favor of X was reported (hazard ratio [95% CI] = 0.61 [0.40; 0.93], p= 0.0203). Overall RR [95 % CI] was: Plcb 42.6% [37.1; 48.2] and X 44.9% [39.4; 50.6]. As prospectively defined in the protocol, the lower bound of the CI of the RR ratio above 0.8 confirms noninferiority in RR (1.055 [0.88; 1.26]). In both arms the mean % of change in SAP worsens as a function of PSN severity. 17.3 (Plcb) and 13.5% (X) of the pts discontinued Ox because of PSN. Severe toxicities (% Gr 3–4), reported with a ≥2% difference between arms, were (plcb vs X): diarrhea 10.9 vs 13.0, pulmonary embolism 0.9 vs 3.1, fatigue 3.7 vs 1.5, neutropenia 43.0 vs 37.8. Conclusion: X was shown to be efficient in reducing the risk of Grade 3–4 oxaliplatin-induced PSN without impacting FOLFOX4 antitumor activity. No significant financial relationships to disclose.
Article
Sixteen patients treated with cisplatin (CDDP) 40 mg/m2 on days 1-5 every 4 weeks for three courses (cumulative dose 600 mg/m2) were clinically and neurophysiologically tested before, during and 1, 3, 6, 9 and 12 months after CDDP administration. The first symptoms of polyneuropathy occurred in 4 of 9 patients after the second course (cumulative dose 400 mg/m2). One month after treatment 1 of 9 patients was asymptomatic, 5 complained of symptoms and 3 showed clinical and neurophysiological signs of polyneuropathy. Three months after CDDP all patients were affected. Clinical and neurophysiological signs of severity progression were noted up to 6 months after treatment with CDDP.
Article
The taxanes represent the first class of antimicrotubule agents with a new mechanism of cytotoxic action since the introduction of the vinca alkaloids several decades ago. These compounds may prove to be the "anticancer drugs of the 1990s," just as the anthracyclines and the platinum compounds were the "anticancer drugs" of the 1970s and 1980s. Like the platinums, taxol, the prototypic taxane, has shown significant antineoplastic activity in patients with advanced ovarian cancer, with response rates ranging from 20% to 50%. Moreover, taxol has been shown to be useful in patients with platinum-resistant ovarian cancer. Although phase II screening is not yet complete, the results of phase II studies of taxol in advanced cancers of the ovary, breast (response rates, 56% to 62%), and lung (response rates, 21% to 24%) have rekindled interest in the microtubule as a prime strategic target for cancer therapy. After briefly reviewing the mechanisms of antineoplastic action and resistance and the results of preliminary clinical and pharmacological studies, this review will discuss several critical issues that will be addressed in future clinical trials, developmental directions, and drug supply. Although this review will focus primarily on taxol, the results of preliminary investigations with the semisynthetic taxane analog taxotere will also be discussed.
Article
In a randomized, double-blind, placebo-controlled study, we assessed the efficacy of an ACTH(4-9) analogue, Org 2766, in the prevention of cisplatin neuropathy in 55 women with ovarian cancer. The analogue was given subcutaneously in a dose of 0.25 mg (low dose) or 1 mg (high dose) per square meter of body-surface area before and after treatment with cisplatin and cyclophosphamide (75 and 750 mg per square meter every three weeks). The threshold of vibration perception was used as the principal measure of neurotoxicity. After four cycles of chemotherapy, the mean (+/- SEM) threshold value for vibration perception in the placebo group increased from 0.67 +/- 0.12 to 1.61 +/- 0.43 microns of skin displacement (P less than 0.0001). In the high-dose treatment group, there was no increase in the threshold value after four cycles (from 0.54 +/- 0.12 to 0.50 +/- 0.06 micron). After six cycles of chemotherapy, the threshold value was 5.87 +/- 1.97 microns in the placebo group (more than an eight-fold increase from base line), as compared with 0.88 +/- 0.17 micron (less than a twofold increase) in the high-dose treatment group (P less than 0.005). In the high-dose group, fewer neurologic signs and symptoms were recorded than in the placebo group. With the lower dose of the analogue, these protective effects were less prominent. No side effects were seen after treatment with Org 2766. The rates of clinical response to chemotherapy were similar in all groups. These results suggest that Org 2766 can prevent or attenuate cisplatin neuropathy without adversely affecting the cytotoxic effect of the drug.
Article
We performed a randomized double-blind placebo-controlled trial to assess the efficacy of glutathione (GSH) in the prevention of cisplatin (CDDP)-induced neurotoxicity. Fifty patients with advanced gastric cancer treated with a weekly CDDP-based regimen were included in this study. In patients randomized to receive GSH, GSH was given at a dose of 1.5 g/m2 in 100 mL of normal saline solution over a 15-minute period immediately before CDDP administration, and at a dose of 600 mg by intramuscular injection on days 2 to 5. Normal saline solution was administered to placebo-randomized patients. Clinical neurologic evaluation and electrophysiologic investigations have been performed at baseline and after 9 (CDDP dose, 360 mg/m2) and 15 (CDDP dose, 600 mg/m2) weeks of treatment. At the 9th week, no patients showed clinically evident neuropathy in the GSH arm, whereas 16 patients in the placebo arm did. After the 15th week, four of 24 assessable patients in the GSH arm suffered from neurotoxicity versus 16 of 18 in the placebo arm (P = .0001). In confirmation of this neuroprotective effect, the neurophisiologic investigations, based on the evaluation of the median, ulnar, and sural sensory nerve conduction, showed a statistically significant reduction of these values in the placebo arm but not in the GSH arm, above all considering potential amplitude. In this trial, GSH also reduced hemotransfusion requirements (32 v 62 hemotransfusions) and treatment delay (55 v 94 weeks). The response rate was 76% (20% complete response) in the GSH group and 52% (12% complete response) in the placebo arm, confirming preliminary reports about the lack of reduction in activity of cytotoxic drugs induced by GSH. This study provides evidence that GSH is a promising and effective new drug for the prevention of CDDP-induced neuropathy, and that it does not reduce the clinical activity of chemotherapeutic drugs.
Article
The safety profile of Taxol administered intravenously as a single agent has been established based on the experience of 655 patients. Of these patients, 253 were treated in nine phase I studies, and 402 were treated in eight disease-oriented phase II studies. Myelosuppression, specifically neutropenia, was the dose-limiting toxicity in all studies conducted in patients with solid tumors. Neutropenia was schedule dependent and was less severe when Taxol was administered via a 3-hour infusion. Severe hypersensitivity reactions were controlled in the phase II program with a premedication regimen consisting of dexamethasone, an antihistamine, and an H2 blocker. Cardiovascular toxicities were minimal and do not indicate constant electrocardiographic monitoring during Taxol infusions. Peripheral neuropathy was usually mild to moderate and dose related; however, it rarely caused treatment discontinuation. Additional adverse events associated with Taxol include arthralgia/myalgia, mucositis, nausea and vomiting, and alopecia.
Article
Cyclosporin A has been shown to reverse paclitaxel resistance in vitro by inhibiting P-gp function. Therefore, we determined whether addition of cyclosporine to paclitaxel reversed clinical paclitaxel resistance in patients with non-Hodgkin's lymphoma (NHL). Patients with relapsed NHL were eligible if they had no intervening treatment after failure to respond to paclitaxel (200 mg/m2 over 3 hours), and if they had adequate marrow, renal, and hepatic function, no serious cardiac disease, no CNS involvement, and no antibodies to human immunodeficiency virus-1. A cyclosporin A bolus dose (5 mg/kg over 3 hours) was followed by intravenous infusion (15 mg/kg) over 24 hours. Six hours after the beginning of cyclosporin A, the immediately preceding paclitaxel dose was administered over 3 hours. All patients were premedicated with dexamethasone, diphenhydramine, and cimetidine. Response was assessed after two cycles, and those patients who achieved at least a partial response received a maximum of six courses. All 26 patients entered were assessable for toxicity and 25 were assessable for response. One patient whose disease had progressed during paclitaxel treatment had a partial remission after the addition of cyclosporin A (response rate, 4%; 95% confidence interval, 1% to 20%). Disease progressed in 17 patients (71%) and did not respond in seven (25%). Serum cyclosporin A A levels measured at the time of initiation of paclitaxel infusion were greater than 2,000 ng/mL during 81% of cycles. Treatment toxicity included peripheral neuropathy in 57%, myalgia or arthralgia in 30%, neutropenia in 53%, neutropenic fever in 8%, and thrombocytopenia in 42% of patients. One patient with preexisting asthma had an acute bronchospasm during the first cycle and was removed from the study. There were no renal or hepatic toxicity and no infectious or hemorrhagic deaths. Cyclosporin A administered on this schedule did not reverse established clinical resistance to paclitaxel, which suggests that P-gp-mediated drug efflux is unlikely to be the only cause of paclitaxel resistance in this patient population.
Article
The levels of nerve growth factor (NGF) mRNA can be regulated in vitro and in vivo in the hippocampal formation by events associated with pharmacological activation of glutamate receptors. In the present study, the level of NGF mRNA in the hippocampal formation was examined following an intrahippocampal injection of 1 nmole fluorocitrate, which temporarily inhibits the astrocyte metabolic activity in vivo. Consistent with previous findings, fluorocitrate treatment significantly increased glutamate levels and decreased glutamine levels in the dentate gyrus as determined by in vivo microdialysis. The increased ratio of glutamate to glutamine was followed by a significant increase in NGF mRNA expression selectively in dentate gyrus granule cells. The effects of increasing glutamate levels were blocked by pretreatment with 50 nmole 2-amino-5-phosphonovalerate (AP5), a competitive antagonist that acts at the N-methyl-D-aspartate (NMDA) glutamate receptor subtype. These findings suggest that NGF mRNA expression is regulated, in part, by changes in endogenous glutamate levels, partially through enhanced excitatory neurotransmission through NMDA receptors.
Article
The objective was to evaluate the efficacy of Org 2766 (a hexapeptide analogue of ACTH) in the prevention or delay of cisplatin-induced neuropathy during chemotherapy in women with ovarian cancer as measured by vibration perception threshold (VPT). In this randomized, multicenter, double-blind, placebo-controlled study, 196 women with ovarian cancer were treated with cisplatin 75-100 mg/m2, cyclophosphamide 600-1000 mg/m2 plus placebo or two dose levels of Org 2766. The cisplatin-induced neuropathies were monitored by determining the VPT with the Vibratron II. VPT was determined for both the most sensitive great toe and the index finger on a monthly basis during treatment and months 1, 2, and 3 postchemotherapy. Once the blind was broken, it was found that 174 women (59 in placebo, 58 in 2 mg, and 57 in 4 mg) had enough data to allow evaluation. Over the course of follow-up, the VPT was found to increase. This is consistent with the development of cisplatin-induced peripheral neuropathies. The baseline VPT for the index finger was less than that of the great toe (0.65 vs 2.13), but the percentage change in VPT was the same for both (percentage increase in VPT of about 350%). When the VPTs are compared according to the dose of Org 2766 given, there appears to be no difference in the rate of change or degree of neuropathies that developed in these women receiving cisplatin and cyclophosphamide. The development of cisplatin-induced neuropathies is confirmed by measurement of the VPT. The rate of development of neuropathies seems to accelerate after the sixth course of cisplatin. When the development of neuropathies is evaluated on the basis of Org 2766 dosage, it is found that there is no difference in the rate or degree of neuropathies seen. Instead of providing protection from and delay of onset of peripheral neuropathies caused by cisplatin, these results suggest that the administration of Org 2766 appears to cause an increase in the rate of change and degree of neuropathies (P > 0.05).
Article
Our previous randomised trial in patients with advanced ovarian cancer indicated a significant response and survival advantage for those receiving high-dose (100 mg/m2) as compared with low-dose (50 mg/m2) cisplatin in combination with cyclophosphamide (750 mg/m2). However, this was accompanied by more toxicity; peripheral neuropathy was troublesome, with 32% of patients experiencing > or = WHO grade 2 at the cisplatin dose of 100 mg/m2. Nimodipine is a calcium-channel antagonist that has provided protection from cisplatin-induced neurotoxicity in a rat model system. We performed a pilot study in 50 patients that demonstrated the feasibility of co-administration of nimodipine in a chronic oral dosing schedule with cisplatin-based chemotherapy in an open-label non-randomised trial. This led us to initiate a double-blind, placebo-controlled, randomised trial in patients with ovarian cancer, which was prematurely discontinued because of problems with nausea and vomiting, leading to poor patient compliance, that were not predicted by the pilot study. These studies did not demonstrate a neuroprotective effect for nimodipine. The primary efficacy variable, i.e, the neurotoxicity score at the end of treatment, gave a significantly lower mean for placebo patients than for nimodipine patients. This report details our experience and discusses the reasons for premature termination of the randomised trial.
Article
We retrospectively analysed neuromuscular toxicity associated with paclitaxel 210 mg m(-2) given by 3-h infusion in 247 patients. The severity correlated significantly with total cumulative dose, but could not be predicted by the pretreatment clinical variables or by pharmacokinetic parameters. The toxicity tended to occur in early treatment cycles.
Article
The aim of this study was to examine the clinical utility of low-dose oral prednisone in preventing severe paclitaxel-associated arthralgias and myalgias. Patients treated with paclitaxel in the gynecologic oncology program of the Cleveland Clinic Foundation who developed arthralgias/myalgias which were uncontrolled through the use of nonsteroidal anti-inflammatory medications received low-dose oral prednisone (10 mg B.I.D. starting 24 h after the completion of chemotherapy and continuing for a total of 5 days) with their next paclitaxel course. Of 46 patients meeting the criteria for treatment with the oral prednisone regimen (i.e., subjective feeling of unacceptable discomfort despite the use of nonsteroidal anti-inflammatory agents), 39 (85%) experienced substantial relief of symptoms. All but one of the responding patients requested continuation of the oral prednisone regimen with subsequent paclitaxel treatment cycles. There were no significant toxicities noted in any patient receiving prednisone. This low-dose oral prednisone regimen results in substantial improvement in the majority of patients experiencing significant paclitaxel-associated arthralgias/myalgias.
Article
Calcium ion transiently blocks Na+ channels, and it shortens the time course for closing of their activation gates. We examined the relation between block and closing kinetics by using the Na+ channels natively expressed in GH3 cells, a clonal line of rat pituitary cells. To simplify analysis, inactivation of the Na+ channels was destroyed by including papain in the internal medium. All divalent cations tested, and trivalent La3+, blocked a progressively larger fraction of the channels as their concentration increased, and they accelerated the closing of the Na+ channel activation gate. For calcium, the most extensively studied cation, there is an approximately linear relation between the fraction of the channels that are calcium-blocked and the closing rate. Extrapolation of the data to very low calcium suggests that closing rate is near zero when there is no block. Analysis shows that, almost with certainty, the channels can close when occupied by calcium. The analysis further suggests that the channels close preferentially or exclusively from the calcium-blocked state.
Article
To determine whether the neurotoxicity of paclitaxel 250 mg/m(2) given over 3 hours every 3 weeks could be reduced by pretreatment with amifostine 910 mg/m(2). Secondary objectives included comparing myelosuppression, myalgias, and response rates of the two groups. Forty women with metastatic breast cancer were randomized to receive either paclitaxel alone (arm 1) or paclitaxel preceded by amifostine (arm 2). All were assessable for toxicity, and 37 were assessable for response. At baseline and after each cycle, all patients completed questionnaires for neurologic symptoms and had standardized neurologic examinations, including objective assessments of power and vibration sense. In addition, standard follow-up assessments for other toxicities and tumor response were undertaken. Changes from baseline after courses 1, 2, and 3 were assessed. The sample size was sufficient to detect a 50% improvement in the expected determination in sensory change. There were no differences observed in any of the measures of neurotoxicity. Other toxicity was similar in arms 1 and 2, including hair loss (95% v 90%), neurosensory changes (100% v 100%), fatigue/lethargy (85% v 90%), myalgia (95% v 90%), and grade 4 neutropenia (47% v 60%). Nausea, vomiting, dizziness, hypotension, and sneezing were more common in the amifostine arm. Response rates (22.2% v 36.8%) and paclitaxel pharmacokinetics were not significantly different. There was no protection from paclitaxel-related neurotoxicity or hematologic toxicity in this study. These results suggest that the mechanism of action of paclitaxel-related toxic effects is not amenable to the cytoprotective action of amifostine.
Article
Peripheral neurotoxicity is a dose-limiting side-effect for a number of effective chemotherapeutic agents, including platinum compounds, taxanes, and vinca alkaloids. New experimental chemotherapy drugs that cause neuropathy include suramin and Dolostatin-10. A better understanding of cellular mechanisms will lead to novel treatment strategies that will protect neurons without decreasing therapeutic efficacy.