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Table 7 Emerging drug candidates tested in clinical trials for the prevention and treatment of OIPN

From: Targeting strategies for oxaliplatin-induced peripheral neuropathy: clinical syndrome, molecular basis, and drug development

Agent Mechanism of action/targets Clinical trial number/ PubMed Unique Identifier: Status/Findings
Ion channel-targeted therapies
 Riluzole Prevents the excessive accumulation of glutamate [94]
Interaction with potassium channels of the K2P family (TREK, TRAAK) [141]
NCT03722680: Recruiting
NCT04761614: Not yet recruiting
 Lidocaine Blocks sodium channels [142] NCT03254394: Active, not recruiting
PMID 28458593: Intravenous lidocaine has a direct analgesic effect in CIPN with a moderate long-term effect and seems to influence the area of cold and pinprick perception. Additional research is needed, using a control group and larger sample sizes to confirm these results [143].
 Pregabalin Blockade of voltage-gated calcium channels [144] NCT01450163: Completed:The preemptive use of pregabalin during OHP infusions was safe, but did not decrease the incidence of chronic pain related to OIPN.
NCT02394951: Completed
 Calcium and Magnesium Infusion Intravenous delivery of calcium and magnesium facilitates the action of sodium channels, thereby blocking them [145] PMID 21067912: Ca/Mg infusions significantly reduced all grade oxaliplatin-related neurotoxicity [146].
PMID 21189381: Intravenous Ca/Mg as an effective neuroprotectant against oxaliplatin-induced cumulative sNT in adjuvant colon cancer [147].
NCT01099449: This study does not support using calcium/magnesium to protect against oxaliplatin-induced neurotoxicity (Completed) [148].
PMID 24156389: Ca/Mg infusions do not alter the clinical pharmacokinetics of oxaliplatin and do not seem to reduce its acute neurotoxicity [149].
Neurotransmitter-based therapy
 Duloxetine Serotonin-noradrenaline reuptake inhibitor [150] NCT04137107: Recruiting
NCT03812523: Not yet recruiting
NCT00489411: Duloxetine-treated patients with high emotional functioning are more likely to experience pain reduction (p = 0.026) (Completed).
NCT00489411: Among patients with painful chemotherapy-induced peripheral neuropathy, the use of duloxetine compared with a placebo for 5 weeks resulted in a greater reduction in pain (Completed).
PMID 30105459: Duloxetine seems to be more effective than venlafaxine in decreasing the symptoms of chemotherapy-induced peripheral neuropathy. Duloxetine was more effective than venlafaxine in decreasing motor neuropathy and neuropathic pain grade [141].
 Venlafaxine Serotonin-noradrenaline reuptake inhibitor [144, 151] NCT01611155: The present study neither supports the use of venlafaxine for preventing oxaliplatin-induced neuropathy in clinical practice nor the initiation of a phase III trial to investigate venlafaxine in this setting (Completed).
PMID 21427067: Venlafaxine has clinical activity against oxaliplatin-induced acute neurosensory toxicity [152].
Antioxidants
 Amifostine Prodrug that is dephosphorylated by alkaline phosphatase in tissues to a pharmacologically active free thiol metabolite [55] NCT00601198: Terminated
PMID 12960114: Amifostine, at a dose of 1000 mg, is better tolerated when administered s.c. Switching to the s.c. route in patients with poor tolerance and using i.v. administration allows the continuation of cytoprotection with minor side effects. Although preliminary, 1000 mg of amifostine effectively protected against the lower, still more frequently administered doses of chemotherapy given once every 2 weeks [153, 154].
 Calmangafodipir Mitochondrial MnSOD mimetic that reduces ROS tissue levels [155, 156] NCT00727922: Mangafodipir can prevent and/or relieve oxaliplatin-induced neuropathy in cancer patients (Completed).
NCT04034355: Completed
NCT03654729: Completed
NCT01619423: Calmangafodipir at a dose of 5 μmol/kg appears to prevent the development of oxaliplatin-induced acute and delayed CIPN without apparent influence on tumor outcomes (Completed).
Anti-Inflammatory Therapy
 Minocycline A microglia inhibitor and a MMP9 blocker, inhibits the release of proinflammatory cytokines and alleviates the development and symptoms of OIPN [157, 158] PMID 28551844: Results of this pilot study do not support the use of minocycline to prevent CIPN, but suggest that it may reduce P-APS and decrease fatigue; further study of the impact of this agent on those endpoints may be warranted [159].
Targeting Chemotherapeutic Drug Uptake Transporters
 Dasatinib Targeting chemotherapeutic drug uptake transporters: OCTN2 inhibitor [150] NCT04164069: Recruiting
Targeting apurinic/apyrimidinic endonuclease function
 APX3330
APX2009
Targeting apurinic/apyrimidinic endonuclease function: Enhance APE1 expressio n[160] PMID 27608656: APX3330 and APX2009 might be effective in preventing or reversing platinum-induced CIPN without reducing the anticancer activity of platinum-based chemotherapeutics [160].
NCT03375086: Completed
Targeting the Inhibition of Neuronal Apoptosis and Astrocyte Activation
 Fingolimod Targeting the inhibition of neuronal apoptosis and astrocyte activation: S1PR1 antagonism [161] PMID 31882542: The development of a specific S1P2 agonist may represent a promising therapeutic approach for the management of chemotherapy-induced neuropathy [162].
NCT03943498: Recruiting
Sigma 1 Receptor Antagonism
 MR309 Sigma 1 receptor antagonism [163] PMID 28924870: A Randomized, Double-Blind, Placebo-Controlled Phase IIa Clinical Trial: Intermittent treatment with MR309 was associated with reduced acute OIPN and higher oxaliplatin exposure, and showed a potential neuroprotective role for chronic cumulative oxaipn. Furthermore, MR309 showed an acceptable safety profile [164].
Angiotensin II Type 2 Receptor Antagonism
 EMA401 (Olodanrigan) Angiotensin II type 2 receptor antagonism [165] EudraCT Number: 2011–004033-13
Carbonic Anhydrase Inhibitor
 Topiramate
Acetazolamide
Carbonic anhydrase inhibitor PMID 31634341: topiramate and acetazolamide; revert oxaliplatin-induced acute cold allodynia in mice while not affecting OHP-induced cytotoxicity in cancer cells [166].
Lipid Peroxidation Inhibitors
 L-Carnosine Scavenge the reactive oxygen species (ROS) formed by excessive oxidation of fatty acids and α-β unsaturated aldehydes [167] PMID: 30592963: L-Carnosine exerted a neuroprotective effect against oxaliplatin-induced peripheral neuropathy in colorectal cancer patients by targeting Nrf-2 and NF-κB pathways [168].
 GM1 Neuroprotective, neurotrophic-factor-like activity by activating the Trk neurotrophin receptors, prevent seizures and oxidative stress [169, 170] NCT02251977: Patients receiving GM1 were less troubled by the symptoms of acute neuropathy. However, we do not support the use of GM1 to prevent cumulative neurotoxicity (Completed).
5-HT2C Receptor Agonists
 Lorcaserin 5-HT2C receptor agonist [171] NCT04205071: Withdrawn
NCT03812523: Not yet recruiting
 TRK-750   NCT04282590: Not yet recruiting
Non-Pharmacological Studies
 General management Dose reductions in patients
Delay the cycle of therapy
PMID 25417732: Cumulative dose of oxaliplatin is associated with long-term CIPN. The risk of developing long-term CIPN could only be reduced by decreasing the cumulative dose, whereas probable delay is not beneficial. Patients receiving a dose reduction because of acute neuropathy are still at risk of developing long-term CIPN. Future studies should focus on identifying patients who are at risk of developing CIPN [172].
 rTMS A noninvasive form of brain stimulation in which a changing magnetic field is used to provide electric current at a specific area of the brain through electromagnetic induction [173]. NCT03219502: Recruiting
 Strength and Balance Training Program Lifestyle-related factors can aid in preventing or reducing the neurological side effects of chemotherapy NCT01422993: Completed
 Diet Polyamine-deprived diet NCT01775449: Completed
 Henna Application Herbal extracts used in the treatment of diabetic cutaneous ulcers [174] NCT04201587: Completed
  1. APE1 Apyrimidinic endonuclease/redox effector factor, CIPN Chemotherapy-induced peripheral neuropathy, GM1 Monosialotetrahexosylganglioside, MMP9 Matrix Metallo-peptidase 9, MnSOD Manganese superoxide dismutase, OCTN2 Organic cation transporter-2, OHP Oxaliplatin, OIPN Oxaliplatin-induced peripheral neuropathy, ROS Reactive oxygen species, rTMS Repetitive Transcranial Magnetic Stimulation, S1P2 Sphingosine-1-phosphate receptor2, S1PR1 Sphingosine-1-Phosphate Receptor 1, TRAAK TWIK-related arachidonic acid-stimulated K+ channel, TREK TWIK-Related K+Channel