Drug-induced Peripheral Neuropathy Research Articles

Tubulin interaction at tubulin-binding sequence 1 (TBS1) is required for proper surface expression and TRPV1 channel activity

TRPV1, a polymodal and nonselective cation channel has unique gating mechanisms which is regulated by supramolecular complexes at the plasma membrane formed with membrane proteins, lipids and kinase pathways. Crosstalk between microtubule cytoskeleton with TRPV1 at various level has been established. Previously we demonstrated that the positively-charged residues present at specific tubulin-binding stretch sequences (i.e. TBS1 and TBS2, AA 710–730 and 770–797 respectively) located at the C-terminus of TRPV1 are crucial for tubulin interaction and such sequences have evolutionary origin. The nature of TRPV1-tubulin complex and its functional importance remain poorly understood. Here, we made several mutations in the TBS1 and TBS2 regions and characterized such mutants. Though these mutations reduce tubulin interaction drastically, a low and basal-level of tubulin interaction remains with these mutants. Substitution of positively-charged residues (Lys and Arg) to Ala in the TBS1, but not in TBS2 region results in reduced ligand-sensitivity. Such ligand-sensitivity is altered in response to Taxol or Nocodazole. We suggest that tubulin interaction at the TBS1 region favours channel opening while interaction in TBS2 favours channel closure. We demonstrate for the first time the functional significance of TRPV1-tubulin complex and endorse microtubule dynamics as a parameter that can alter TRPV1 channel functions. These findings can be relevant for several physiological functions and also in the context of chemotherapy-induced neuropathic pain caused by various microtubule stabilizing chemotherapeutic drugs. Thus, this characterization may indicate TRPV1 as a potential therapeutic target relevant for chemotherapeutic drug-induced peripheral neuropathies, neurodegeneration and other neurological disorders.

Mitochondrial trafficking as a protective mechanism against chemotherapy drug-induced peripheral neuropathy: Identifying the key site of action

AimsChemotherapy induced peripheral neuropathy (CIPN) is a common side effect seen in patients who have undergone most chemotherapy treatments to which there are currently no treatment methods. CIPN has been shown to cause axonal degeneration leading to Peripheral Neuropathy (PN), which can lead to major dosage reduction and may prevent further chemotherapy treatment due to oftentimes debilitating pain. Previously, we have determined the site-specific action of Paclitaxel (PTX), a microtubule targeting agent, as well as the neuroprotective effect of Fluocinolone Acetonide (FA) against Paclitaxel Induced Peripheral Neuropathy (PIPN). Main methodsMitochondrial trafficking analysis was determined for all sample sets, wherein FA showed enhanced anterograde (axonal) mitochondrial trafficking leading to neuroprotective effects for all samples. Key findingsUsing this system, we demonstrate that PTX, Monomethyl auristatin E (MMAE), and Vincristine (VCR), are toxic at clinically prescribed levels when treated focally to axons. However, Cisplatin (CDDP) was determined to have a higher toxicity when treated to cell bodies. Although having different targeting mechanisms, the administration of FA was determined to have a significant neuroprotective effect for against all chemotherapy drugs tested. SignificanceThis study identifies key insights regarding site of action and neuroprotective strategies to further development as potential therapeutics against CIPN. FA was treated alongside each chemotherapy drug to identify the neuroprotective effect against CIPN, where FA was found to be neuroprotective for all drugs tested. This study found that treatment with FA led to an enhancement in the anterograde movement of mitochondria based on fluorescent imaging.

DRUG INDUCED NEUROPATHY

Neuropathy is a painful condition and originates from a variety of etiologies. Many drugs can cause neuropathy, which is known as Drug-Induced Neuropathy (DIN), which is included in iatrogenic cases. These drugs are chemotherapy agents, antimicrobials, cardiovascular drugs, psychotropics, anticonvulsants, etc. Not all neuropathies require pharmacological therapy, but simply stop therapy, and the complaints will improve (reversible). However, there are quite a few DINs with a “coasting" response neuropathy when DIN is stopped. This review synthesizes current clinical concepts regarding mechanisms, drug-induced neuropathy, and treatment options for drug-induced peripheral neuropathy.

Sensory-motor polyneuropathy due to the use of antiparasitic drugs: A case report

Introduction: The term polyneuropathy refers to a generalized involvement of peripheral nerves, usually involving mainly the distal nerves and, more often, presenting with sensory, motor, and autonomic symptoms and clinical findings. Drug-induced peripheral neuropathy (DIPN) is a persistent condition, most often associated with anticonvulsants, chemotherapy, cardiovascular, psychotropic, and antimicrobial drugs, such as Metronidazole. In this article, we report the case of a patient who developed polyneuropathy secondary to the use of Metronidazole. Case Report: D.D.S.L., a 45-year-old female, previously healthy, presented with abdominal discomfort. Entamoeba histolytica was detected after investigation, and she started a 7-day cycle of 500 mg of Metronidazole three times a day for seven days, without clinical response. A new therapeutic approach was attempted, with three cycles of 2 grams of Secnidazole single dose and Tinidazole for four weeks. However, the patient presented dysesthesia in the distal third of the thighs, followed by allodynia in the four limbs and trunk. After new abdominal discomfort, three months after the first medication cycle, another pharmacological cycle was started. Neurological examination and electroneuromyography (ENM) examination suggested axonal sensorimotor polyneuropathy in all four limbs. Conclusion: Polyneuropathy can be caused by many factors, including some frequently prescribed drugs such as Metronidazole and other medications in the 5-nitroimidazole group. Therefore, although the relationship between these drugs and polyneuropathy is not fully elucidated, their neurotoxicity is indisputable, even in rare cases, but with significant variability in terms of the dose-dependent potential for this disease.

Effectiveness of Foot reflexology on level of fatigue among peripheral neuropathy, patient with Tuberculosis

Background: In India, Tuberculosis has been mentioned in the Vedas and the old Ayurvedic scriptures. Historically speaking, fight against Tuberculosis in India can be broadly classified into three periods: early period, before the discoveries of x-ray and chemotherapy; post-independence period, during which nationwide Tuberculosis control programs were initiated and implemented; and the current period, during which the ongoing WHO-assisted Tuberculosis control program is in place. Tuberculosis incidence is seasonal, with peaks occurring every spring and summer. The reasons for this are unclear, but may be related to vitamin D deficiency during the winter. There are also studies linking tuberculosis to different weather conditions like low temperature, low humidity and low rainfall. It has been suggested that tuberculosis incidence rates may be connected to climate change Tuberculosis is closely linked to both overcrowding and malnutrition, making it one of the principal diseases of poverty. Those at high risk thus include: people who inject illicit drugs, inhabitants and employees of locales where vulnerable people gather (e.g., prisons and homeless shelters), medically underprivileged and resource-poor communities, high-risk ethnic minorities, children in close contact with high-risk category patients, and health-care providers serving these patients. Factors contributing to this include higher prevalence of predisposing health conditions and behaviours, and overcrowding and poverty. In some Canadian aboriginal groups, genetic susceptibility may play a role. Methods: Quasi-experimental design (one group pre-test post-test design) was recruited by non-probability purposive sampling technique used for the present study. Necessary administrative permission was obtained from the concerned authority. The Structured interview schedule was used to elicit the baseline data. Result: The study revealed that among 180 Tuberculosis patients, the Chalder Fatigue scale pre-median was 27.0, Post-test I median was 14.0, and whereas post-test II median was 7.0. In Michigan Neuropathy scale pre-median was 15.0, the post-test I median was 14.0, and post-test II median was 7.0. Conclusion:-The study concluded that the foot reflexology of anti-tuberculosis drug-induced peripheral neuropathy among Tuberculosis patients from selected community area, Ramanagara Taluk & District, Karnataka carried out the study was found to be effective in decreasing the fatigue levels among peripheral neuropathy in person with Tuberculosis patients as evidenced by the significant change between pre-test and post-test scores.

Drug-Induced Peripheral Neuropathy: Diagnosis and Management.

Peripheral neuropathy comes in all shapes and forms and is a disorder which is found in the peripheral nervous system. It can have an acute or chronic onset depending on the multitude of pathophysiologic mechanisms involving different parts of nerve fibers. A systematic approach is highly beneficial when it comes to cost-effective diagnosis. More than 30 causes of peripheral neuropathy exist ranging from systemic and auto-immune diseases, vitamin deficiencies, viral infections, diabetes, etc. One of the major causes of peripheral neuropathy is drug-induced disease, which can be split into peripheral neuropathy caused by chemotherapy or by other medications. This review deals with the latest causes of drug-induced peripheral neuropathy, the population involved, the findings on physical examination and various workups needed and how to manage each case.

The Potential Role of Proinflammatory Cytokines and Complement Components in the Development of Drug-Induced Neuropathy in Patients with Multiple Myeloma.

The launch of novel chemotherapeutic agents—in particular, proteasome inhibitors and immunomodulatory drugs—dramatically changed multiple myeloma (MM) therapy, improving the response rate and prolonging progression-free survival. However, none of the anti-MM drugs are deprived of side effects. Peripheral neuropathy (PN) seems to be one of the most pressing problems. Despite extensive research in this area, the pathogenesis of drug-induced peripheral neuropathy (DiPN) has not yet been fully elucidated. In the present study, we aimed to assess the potential relationship between proinflammatory factors and the development of PN in MM patients with particular emphasis on the application of VTD (bortezomib, thalidomide, dexamethasone) regimen. Our analysis identified increased concentrations of CCL2, IL-1β, and IFN-γ in plasma of MM patients during treatment, both with and without symptoms of PN, compared with untreated neuropathy-free MM patients. At the same time, the plasma concentration of IL-1β in patients with neuropathy was significantly increased compared with patients without PN before and during treatment. Moreover, the results were enhanced at the transcript level by performing global mRNA expression analysis using microarray technology. The most significant changes were observed in the expression of genes responsible for regulating immunological and apoptotic processes. An in-depth understanding of the mechanisms responsible for the development of DiPN might in the future reduce the incidence of PN and accelerate diagnosis, allowing the choice of neuropathy-free treatment strategies for MM.

MicroRNAs as the biomarkers of chemotherapy-induced peripheral neuropathy in patients with multiple myeloma

Multiple myeloma (MM) is a malignant, incurable neoplastic disease. The currently used treatment significantly improves the prognosis and extends the survival time of patients. Unfortunately, a common side effect of the therapy is peripheral neuropathy, which may lead to dose reduction or complete treatment discontinuation/modification. In this study, we examined the changes in plasma levels of circulating miRNAs in myeloma patients to define potential factors characteristic for drug-induced peripheral neuropathy (DiPN). Global miRNA expression profile in the plasma of patients with MM during treatment was determined using miRNA microarray technology. Receiver operating characteristic (ROC) analysis allowed the identification of three miRNAs (miR-22-3p; miR-23a-3p; miR-24-3p) that could be a potential biomarker of PN. The most promising results were obtained for miR-22-3p, which was characterized by ROC area under curve (AUC) = 0.807. Our results suggest a relationship between the DiPN in patients with MM and the level of selected miRNAs in the plasma.

Comparative Analysis of Lenalidomide versus Thalidomide in Multiple Myeloma; Drug-Induced Peripheral Neuropathy

Comparative Analysis of Lenalidomide versus Thalidomide in Multiple Myeloma; Drug-Induced Peripheral Neuropathy

Drug-Induced Peripheral Neuropathy: A Narrative Review.

BackgroundPeripheral neuropathy is a painful condition deriving from many and varied etiologies. Certain medications have been implicated in the iatrogenic development of Drug Induced Peripheral Neuropathy (DIPN) and include chemotherapeutic agents, antimicrobials, cardiovascular drugs, psychotropic, anticonvulsants, among others. This review synthesizes current clinical concepts regarding the mechanism, common inciting medications, and treatment options for drug-induced peripheral neuropathy.MethodsThe authors undertook a structured search of bibliographic databases for peer-reviewed research literature using a focused review question and inclusion/exclusion criteria. The most relevant and up to date research was included.ResultsDrug-induced peripheral neuropathy is a common and painful condition caused by many different and frequently prescribed medications. Most often, DIPN is seen in chemotherapeutic agents, antimicrobials, cardiovascular drugs, psychotropic, and anticonvulsant drugs. Certain drugs exhibit more consistent neuropathic side effects, such as the chemotherapeutic compounds, but others are more commonly prescribed by a larger proportion of providers, such as the statins. DIPN is more likely to occur in patients with concomitant risk factors such as preexisting neuropathy, diabetes, and associated genetically predisposing diseases. DIPN is often difficult to treat, however medications including duloxetine, and gabapentin are shown to reduce neuropathic pain. Advanced techniques of neuromodulation offer promise though further randomized and controlled studies are needed to confirm efficacy.ConclusionAwareness of the drugs covered in this review and their potential for adverse neuropathic effect is important for providers caring for patients who report new onset symptoms of pain, paresthesia, or weakness. Prevention of DIPN is especially important because treatment often proves challenging. While many pharmacologic therapies have demonstrated analgesic potential in the pain caused by DIPN, many patients remain refractive to treatment. More studies are needed to elucidate the effectiveness of interventional, neuromodulating therapies.

Drug-Induced Peripheral Neuropathy: A Narrative Review

Drug-Induced Peripheral Neuropathy: A Narrative Review

Chronic Pain in HIV.

The evolution of therapeutics for and management of human immunodeficiency virus-1 (HIV-1) infection has shifted it from predominately manifesting as a severe, acute disease with high mortality to a chronic, controlled infection with a near typical life expectancy. However, despite extensive use of highly active antiretroviral therapy, the prevalence of chronic widespread pain in people with HIV remains high even in those with a low viral load and high CD4 count. Chronic widespread pain is a common comorbidity of HIV infection and is associated with decreased quality of life and a high rate of disability. Chronic pain in people with HIV is multifactorial and influenced by HIV-induced peripheral neuropathy, drug-induced peripheral neuropathy, and chronic inflammation. The specific mechanisms underlying these three broad categories that contribute to chronic widespread pain are not well understood, hindering the development and application of pharmacological and nonpharmacological approaches to mitigate chronic widespread pain. The consequent insufficiencies in clinical approaches to alleviation of chronic pain in people with HIV contribute to an overreliance on opioids and alarming rise in active addiction and overdose. This article reviews the current understanding of the pathogenesis of chronic widespread pain in people with HIV and identifies potential biomarkers and therapeutic targets to mitigate it.

Use of Nerve Conduction Assessments to Evaluate Drug-Induced Peripheral Neuropathy in Nonclinical Species—A Brief Review

The peripheral nervous system (PNS) is subject to a wide range of structural and functional insults including direct damage to axons, loss of myelin, and progressive deficits in saltatory conduction. Drugs that damage the PNS often result in neuropathies that impact the structure and function of targeted nerves. In most cases, both sensory and motor neurons are affected with damage initially evident in the distal extremities. Drug-induced neuropathies are potentially reversible following cessation of treatment, but early stages of neuropathy can be subclinical and asymptomatic making diagnosis difficult. Nerve biopsy is highly validated and provides definitive evidence of nerve injury and corresponding severity; however, it is limited in some respects and electrophysiological measures can complement histopathological assessments and provide a functional measure of potential toxicity. In a drug development setting, nerve conduction assessments are valuable to monitor nerve function longitudinally if nerve damage is suspected or confirmed, and importantly, can be used to monitor progression and/or recovery of a drug-induced neuropathy. This review will summarize the methodology used in nerve conduction assessments as well as discuss data interpretation and considerations for use in nonclinical species. Finally, the use of nerve conduction assessments in nonclinical drug development is discussed.

A Network Pharmacology Approach for the Identification of Common Mechanisms of Drug-Induced Peripheral Neuropathy.

Drug‐induced peripheral neuropathy is a side effect of a variety of therapeutic agents that can affect therapeutic adherence and lead to regimen modifications, impacting patient quality of life. The molecular mechanisms involved in the development of this condition have yet to be completely described in the literature. We used a computational network pharmacology approach to explore the Connectivity Map, a large collection of transcriptional profiles from drug perturbation experiments to identify common genes affected by peripheral neuropathy‐inducing drugs. Consensus profiles for 98 of these drugs were used to construct a drug–gene perturbation network. We identified 27 genes significantly associated with neuropathy‐inducing drugs. These genes may have a potential role in the action of neuropathy‐inducing drugs. Our results suggest that molecular mechanisms, including alterations in mitochondrial function, microtubule and cytoskeleton function, ion channels, transcriptional regulation including epigenetic mechanisms, signal transduction, and wound healing, may play a critical role in drug‐induced peripheral neuropathy.

Pathophysiology of drug-induce peripheral neuropathy in patients with multiple myeloma.

Multiple myeloma (MM) is a disease of unknown, complex etiology that affects primarily older adults. The course of the disease and the patients' survival time are very heterogeneous, but over the last decade, clear progress in the treatment of this incurable disease has been observed. Therapeutics that have proven to be highly effective include the immunomodulatory drug thalidomide and its newer analogs, lenalidomide and pomalidomide, as well as the proteasome inhibitors bortezomib and carfilzomib. However, the administration of some of the treatments, e.g., thalidomide or bortezomib, has also been associated with the occurrence of a serious and common adverse effect, drug-induced peripheral neuropathy. The mechanism of the development of the peripheral neuropathy is poorly understood. Nevertheless, one of its potential causes could be inadequate concentrations of crucial trophic factors, including neurotrophic and/or angiogenic factors, which are responsible for the proliferation, differentiation, survival and death of neuronal and nonneuronal cells.

Ontology-based literature mining and class effect analysis of adverse drug reactions associated with neuropathy-inducing drugs

BackgroundAdverse drug reactions (ADRs), also called as drug adverse events (AEs), are reported in the FDA drug labels; however, it is a big challenge to properly retrieve and analyze the ADRs and their potential relationships from textual data. Previously, we identified and ontologically modeled over 240 drugs that can induce peripheral neuropathy through mining public drug-related databases and drug labels. However, the ADR mechanisms of these drugs are still unclear. In this study, we aimed to develop an ontology-based literature mining system to identify ADRs from drug labels and to elucidate potential mechanisms of the neuropathy-inducing drugs (NIDs).ResultsWe developed and applied an ontology-based SciMiner literature mining strategy to mine ADRs from the drug labels provided in the Text Analysis Conference (TAC) 2017, which included drug labels for 53 neuropathy-inducing drugs (NIDs). We identified an average of 243 ADRs per NID and constructed an ADR-ADR network, which consists of 29 ADR nodes and 149 edges, including only those ADR-ADR pairs found in at least 50% of NIDs. Comparison to the ADR-ADR network of non-NIDs revealed that the ADRs such as pruritus, pyrexia, thrombocytopenia, nervousness, asthenia, acute lymphocytic leukaemia were highly enriched in the NID network. Our ChEBI-based ontology analysis identified three benzimidazole NIDs (i.e., lansoprazole, omeprazole, and pantoprazole), which were associated with 43 ADRs. Based on ontology-based drug class effect definition, the benzimidazole drug group has a drug class effect on all of these 43 ADRs. Many of these 43 ADRs also exist in the enriched NID ADR network. Our Ontology of Adverse Events (OAE) classification further found that these 43 benzimidazole-related ADRs were distributed in many systems, primarily in behavioral and neurological, digestive, skin, and immune systems.ConclusionsOur study demonstrates that ontology-based literature mining and network analysis can efficiently identify and study specific group of drugs and their associated ADRs. Furthermore, our analysis of drug class effects identified 3 benzimidazole drugs sharing 43 ADRs, leading to new hypothesis generation and possible mechanism understanding of drug-induced peripheral neuropathy.

Utilization of iPSC-derived human neurons for high-throughput drug-induced peripheral neuropathy screening

As the number of cancer survivors continues to grow, awareness of long-term toxicities and impact on quality of life after chemotherapy treatment in cancer survivors has intensified. Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common side effects of modern chemotherapy. Animal models are used to study peripheral neuropathy and predict human risk; however, such models are labor-intensive and limited translatability between species has become a major challenge. Moreover, the mechanisms underlying CIPN have not been precisely determined and few human neuronal models to study CIPN exist. Here, we have developed a high-throughput drug-induced neurotoxicity screening model using human iPSC-derived peripheral-like neurons to study the effect of chemotherapy agents on neuronal health and morphology using high content imaging measurements (neurite length and neuronal cell viability). We utilized this model to test various classes of chemotherapeutic agents with known clinical liability to cause peripheral neuropathy such as platinum agents, taxanes, vinca alkaloids, proteasome inhibitors, and anti-angiogenic compounds. The model was sensitive to compounds that cause interference in microtubule dynamics, especially the taxane, epothilone, and vinca alkaloids. Conversely, the model was not sensitive to platinum and anti-angiogenic chemotherapeutics; compounds that are not reported to act directly on neuronal processes. In summary, we believe this model has utility for high-throughput screening and prediction of human risk for CIPN for novel chemotherapeutics.

Drug-induced peripheral neuropathy

Summary Drug-induced peripheral neuropathy is an important clinical problem. It can cause irreversible symptoms such as pain and numbness that have an enormous impact on ability to function normally and perceived quality of life. This can lead to dose reductions or a requirement to cease treatment with a particular drug. The mechanisms of damage are not always fully understood, but particular drugs such as the cancer chemotherapy agents are well known as identified causes of peripheral neuropathy. Investigative methods are not always satisfactory and the diagnosis is frequently clinical. It is important for clinicians to be aware of the problem so that patients at risk are asked the relevant questions.

Role of Transient Receptor Potential Channels in Paclitaxel- and Oxaliplatin-induced Peripheral Neuropathy

Peripheral neuropathy is a common adverse effect of paclitaxel and oxaliplatin treatment. The major dose-limiting side effect of these drugs is peripheral sensory neuropathy. The symptoms of paclitaxel-induced neuropathy are mostly sensory and peripheral in nature, consisting of mechanical allodynia/hyperalgesia, tingling, and numbness. Oxaliplatin-induced neurotoxicity manifests as rapid-onset neuropathic symptoms that are exacerbated by cold exposure and as chronic neuropathy that develops after several treatment cycles. Although many basic and clinical researchers have studied anticancer drug-induced peripheral neuropathy, the mechanism is not well understood. In this review, we focus on (1) analysis of transient receptor potential vanilloid 1 (TRPV1) channel expression in the rat dorsal root ganglion (DRG) after paclitaxel treatment and (2) analysis of transient receptor potential ankyrin 1 (TRPA1) channel in the DRG after oxaliplatin treatment. This review describes that (1) paclitaxel-induced neuropathic pain may be the result of up-regulation of TRPV1 in small- and medium-diameter DRG neurons. In addition, paclitaxel treatment increases the release of substance P, but not calcitonin gene-related peptide, in the superficial layers of the spinal dorsal horn. (2) TRPA1 expression via activation of p38 mitogen-activated protein kinase in small-diameter DRG neurons, at least in part, contributes to the development of oxaliplatin-induced acute cold hyperalgesia. We suggest that TRPV1 or TRPA1 antagonists may be potential therapeutic lead compounds for treating anticancer drug-induced peripheral neuropathy.

Drug-induced peripheral neuropathy.

Peripheral neuropathy can be caused by medication, and various descriptions have been applied for this condition. In this MiniReview, the term 'drug-induced peripheral neuropathy' (DIPN) is used with the suggested definition: Damage to nerves of the peripheral nervous system caused by a chemical substance used in the treatment, cure, prevention or diagnosis of a disease. Optic neuropathy is included in this definition. A distinction between DIPN and other aetiologies of peripheral neuropathy is often quite difficult and thus, the aim of this MiniReview is to discuss the major agents associated with DIPN.