Pharmacological augmentation of nicotinamide phosphoribosyltransferase (NAMPT) protects against paclitaxel-induced peripheral neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) arises from collateral damage to peripheral afferent sensory neurons by anticancer pharmacotherapy, leading to debilitating neuropathic pain. No effective treatment for CIPN exists, short of dose-reduction which worsens cancer prognosis. Here, we report that stimulation of nicotinamide phosphoribosyltransferase (NAMPT) produced robust neuroprotection in an aggressive CIPN model utilizing the frontline anticancer drug, paclitaxel (PTX). Daily treatment of rats with the first-in-class NAMPT stimulator, P7C3-A20, prevented behavioral and histologic indicators of peripheral neuropathy, stimulated tissue NAD recovery, improved general health, and abolished attrition produced by a near maximum-tolerated dose of PTX. Inhibition of NAMPT blocked P7C3-A20-mediated neuroprotection, whereas supplementation with the NAMPT substrate, nicotinamide, potentiated a subthreshold dose of P7C3-A20 to full efficacy. Importantly, P7C3-A20 blocked PTX-induced allodynia in tumored mice without reducing antitumoral efficacy. These findings identify enhancement of NAMPT activity as a promising new therapeutic strategy to protect against anticancer drug-induced peripheral neurotoxicity.

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Effect of goshajinkigan on peripheral neuropathy in breast cancer patients treated with docetaxel.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e11564 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e11564-e11564

Author(s):

Hajime Abe ◽

Tsuyoshi Mori ◽

Yuki Kawai ◽

Hirotomi Cho ◽

Yoshihiro Kubota ◽

...

Keyword(s):

Breast Cancer ◽

Peripheral Neuropathy ◽

Oral Administration ◽

Cancer Patients ◽

Concomitant Administration ◽

Breast Cancer Patients ◽

Peripheral Neurotoxicity ◽

Drug Induced ◽

Traditional Japanese Medicine ◽

Grade 3

e11564 Background: Although taxanes have become a key chemotherapeutic drug in breast cancer treatment, one of the side effects is peripheral neuropathy. Goshajinkigan (GJG) is a traditional Japanese medicine that is used for the treatment of several neurological symptoms including pain and numbness. Recently, GJG has been reported to prevent anticancer drug-induced peripheral neuropathy in colorectal cancer in the gynecology field. We investigated the efficacy of GJG and mecobalamin (B12) on peripheral neurotoxicity associated with docetaxel (DOC) in breast cancer patients. Methods: Between 2007 and 2011, 60 breast cancer patients were treated with DOC. Thirty-three patients (GJG group) received oral administration of 7.5 g/day GJG every day during DOC therapy and 27 patients (B12 group) received oral administration of 1500 μg/day B12. Peripheral neuropathy was evaluated during every course according to DEB-NTC (Neurotoxicity Criteria of Debiopharm), Common Terminology Criteria for Adverse Events (CTCAE) ver. 3.0, and a visual analogue scale (VAS). Results: The median age of the GJG group was 58 years old (35 to 70 years old), the B12 group was 55 years old (33 to 69 years old), and they were all females. For the regimens, in the GJG group, TC (DOC and cyclophosphamide), DOC only, and XT (capecitabine and DOC) were administered in 19 cases, 13 cases and 1 case, respectively. In the B12 group, they were 15 cases, 11 cases and 12 cases, respectively. The cumulative dose of DOC was 338.5 mg/m2 in the GJG group, and 340 mg/m2 in the B12 group. The completion rate was 100% in both groups. The incidence of peripheral neuropathy was 39.3% in the GJG group, and 88.9% in the B12 group (p < 0.01). In the GJG group, grade 1 DEB-NTC was observed in 2 cases, grade 2 in 5 cases and grade 3 in 5 cases. Grade 1 CTCAE was observed in 7 cases, grade 2 in 6 cases, and VAS was 2.7 ± 2.2. In the B12 group, grades 1, 2 and 3 DEB-NTC were observed in one case, 12 cases and 12 cases, respectively; and grades 1 and 2 CTCAE were observed in 12 cases each, and VAS was 4.9 ± 2.4. Peripheral neuropathy was significantly controlled in the GJG group. Conclusions: Concomitant administration of GJG is useful in preventing peripheral neuropathy in breast cancer patients treated with DOC regimen.

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POS0291 THE IMPACT OF DRUG INDUCED AND OTHER RHEUMATIC MUSCULOSKELETAL DISORDERS (MD) ON THE QUALITY OF LIFE (QOL) OF CANCER PATIENTS RECEIVED ANTICANCER DRUG TREATMENT

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.2286 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 371.1-371

Author(s):

A. Koltakova ◽

A. Lila ◽

L. P. Ananyeva ◽

A. Fedenko

Keyword(s):

Drug Treatment ◽

Cancer Patients ◽

Anticancer Drug ◽

Physical Functioning ◽

Role Functioning ◽

Drug Induced ◽

Significant Difference ◽

Eortc Qlq C30 ◽

Eortc Qlq ◽

The Impact

Background:Pts with cancer may have MD that can be caused by neoplastic/paraneoplastic disease, rheumatic diseases or be induced by anticancer drug treatment. There is no data about MD influence on the QoL of cancer patients. The EORTC QoL questionnaire (QLQ)-C30 is a valid questionnaire designed to assess different aspects (Global health (GH), Functional (FS) and symptoms (SS) scales) that define the QoL of cancer patients [1].Objectives:The objective of the study was to assess the impact of drug induced and other types of MD on the QoL of cancer patients that received anticancer drug treatment by using of EORTC QLQ-C30 v3.0.Methods:The sampling of 123 pts (M/F – 40/83; mean age 54.4±12.8) with breast (32,5%), gastrointestinal (17%), ovary (8%), lung (7%) and other cancer was observed by rheumatologist in the oncology outpatient clinic. All pts received anticancer drug treatment: chemotherapy (104 pts), target therapy (16 pts) checkpoint-inhibitors (14 pts), hormone therapy (13 pts) in different combinations. 102(82.9%) of 123pts had MD include arthritis (12 pts), synovitis (5 pts), arthralgia (66 pts), periarthritis (34 pts), osteodynia (13 pts). There were 58 pts (group 1; M/F – 14/44; mean age 52.5±12.2) with anticancer drug treatment induced MD and 44 pts (group 2; M/F – 16/27; mean age 57.6±13.5) with other type of MD include 26 pts with skeletal metastasis. The were 21 pts (group 3; M/F – 10/11; mean age 52.9±11.1) without MD. All pts fulfilled EORTC QLQ-C30 v3.0 (tab.1).Table 1.The median [Q1;Q3] of results of GH, SS and SS of EORTC QLQ-C30ScaleSubscaleGroup1Group2Group3GH58.3[50;58]58.3[41.7;83.3]50[50;66.7]FS*Physical functioning73.3[60;86.7]73.3[66.7;86.7]86.7[80;93]Role functioning66.7[66.7;100]83.3[50;100]100[83;100]Emotional functioning83.3[66.7;100]75[66.7;91.7]91.6[83.3;100]Social functioning83.3[66.7;100]83.3[50;100]100[83.3;100]SS*Pain33.3[0;50]16.7[0;33.3]0[0;16.7]*There are only the scores that had got a statistical difference between the groups.Kruskal-Wallis H and post-hoc (Dwass-Steel-Critchlow-Fligner (DSCF) pairwise comparisons) tests for data analysis were performed.Results:A Kruskal-Wallis H test has shown a statistically significant difference in physical (χ2(2)=7.54; p=0.023), role (χ2(2)=9.87; p=0.007), emotion (χ2(2)=7.69; p=0.021) functioning and pain (χ2(2)=8.44; p=0.015) scores between the different groups. A post-hoc test with DSCF pairwise comparisons of median has shown a statistically significant difference between 1 and 3 groups (W=3.904; p=0.016) for physical functioning, between 2 and 3 groups (W=3.35; p=0.004) for role functioning, between 2 and 3 groups (W=4.03; p=0.012) for emotional functioning, between 1 and 3 groups (W=-3.97; p=0.014) for pain scale.Conclusion:The study has shown that MD associated with anticancer drug treatment adversely affected the QoL of cancer patients received anticancer drug treatment by reducing a physical functioning and by increasing pain scores. Presence of other types of MD adversely affect the QoL by reducing emotional and role functioning.References:[1]Aaronson NK,et al.The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst.1993;85(5):365-376. doi:10.1093/jnci/85.5.365Disclosure of Interests:None declared

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Electrophilic and Drug-Induced Stimulation of NOTCH3 N-terminal Fragment Oligomerization in Cerebrovascular Pathology

Translational Stroke Research ◽

10.1007/s12975-021-00908-2 ◽

2021 ◽

Author(s):

K. Z. Young ◽

N. M. P. Cartee ◽

S. J. Lee ◽

S. G. Keep ◽

M. I. Ivanova ◽

...

Keyword(s):

Drug Induced ◽

Cerebrovascular Pathology ◽

Terminal Fragment ◽

Stimulation Of

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Drug-induced QTc interval prolongation: A proposal towards an efficient and safe anticancer drug development

European Journal of Cancer ◽

10.1016/j.ejca.2007.10.001 ◽

2008 ◽

Vol 44 (4) ◽

pp. 494-500 ◽

Cited By ~ 30

Author(s):

Giuseppe Curigliano ◽

Gianluca Spitaleri ◽

Howard J. Fingert ◽

Filippo de Braud ◽

Cristiana Sessa ◽

...

Keyword(s):

Drug Development ◽

Anticancer Drug ◽

Qtc Interval ◽

Interval Prolongation ◽

Drug Induced ◽

Qtc Interval Prolongation ◽

Anticancer Drug Development

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Drug-Induced Peripheral Neuropathy: Diagnosis and Management

Current Cancer Drug Targets ◽

10.2174/1568009621666210720142542 ◽

2021 ◽

Vol 21 ◽

Author(s):

Diala Merheb ◽

Georgette Dib ◽

Maroun Bou Zerdan ◽

Clara El Nakib ◽

Saada Alame ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Systematic Approach ◽

Viral Infections ◽

Cost Effective ◽

Nerve Fibers ◽

Drug Induced ◽

Vitamin Deficiencies ◽

Effective Diagnosis ◽

Different Parts ◽

Pathophysiologic Mechanisms

: 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.

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