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Toxins
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Tetrodotoxin (TTX) as a Therapeutic Agent
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Tetrodotoxin (TTX) as a Therapeutic Agent

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Marine and Freshwater Toxins".

Deadline for manuscript submissions: closed (31 May 2021) | Viewed by 35748

Special Issue Editors

Dr. Francisco Rafael Nieto

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Guest Editor
Department of Pharmacology, Biomedical Research Center and Institute of Neuroscience, Faculty of Medicine, University of Granada, Granada, Spain.
Interests: analgesics; pain behavior; inflammation; neuropathic pain; visceral pain; neuroimmune interactions; microglia; rheumatoid arthritis.
Dr. Rafael González-Cano

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Guest Editor
Department of Pharmacology, Biomedical Research Center and Institute of Neuroscience, Faculty of Medicine, University of Granada, Granada, Spain.
Interests: analgesics; pain; animal behavior; inflammation; neuropathy; visceral pain; programming; data science; machine learning.

Special Issue Information

Dear Colleagues,

Tetrodotoxin (TTX) is a neurotoxin found in puffer fish and other marine and terrestrial animals. It has been used since ancient times for therapeutic purposes, and extensively used to elucidate the role of specific voltage-gated sodium channel (VGSC) subtypes in a wide range of physiological and pathophysiological processes in the nervous system. TTX use regards their mechanisms of action, mainly VGSC blockade and, hence, the alteration of neuronal function. TTX is in clinical development as an analgesic drug, and it is currently undergoing Phase III clinical trials for the treatment of cancer-related pain.

The purpose of this Special Issue is to collect original research and review articles that provide recent advances and/or a comprehensive view of the therapeutic potential of TTX, such as its use as anesthetic, analgesic in different pain conditions, or any other therapeutic use. Submissions of preclinical or clinical manuscripts are welcome.

Dr. Francisco Rafael Nieto
Dr. Rafael González-Cano
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a double-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxins is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • tetrodotoxin
  • anesthetic
  • analgesic
  • pain
  • neuropathy
  • cancer

Published Papers (5 papers)

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Research

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16 pages, 4479 KiB  
Article
Tetrodotoxin for Chemotherapy-Induced Neuropathic Pain: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Dose Finding Trial
by Samuel A. Goldlust, Mojgan Kavoosi, Jennifer Nezzer, Mehran Kavoosi, Walter Korz and Kenneth Deck
Toxins 2021, 13(4), 235; https://doi.org/10.3390/toxins13040235 - 25 Mar 2021
Cited by 15 | Viewed by 3385
Abstract
Tetrodotoxin (TTX) has emerged as a potentially efficacious agent for chemotherapy-induced neuropathic pain (CINP), a prevalent, debilitating condition often resistant to analgesics. This randomized, double-blind, dose-finding study was undertaken to explore safety and trends in efficacy of four TTX doses and to identify [...] Read more.
Tetrodotoxin (TTX) has emerged as a potentially efficacious agent for chemotherapy-induced neuropathic pain (CINP), a prevalent, debilitating condition often resistant to analgesics. This randomized, double-blind, dose-finding study was undertaken to explore safety and trends in efficacy of four TTX doses and to identify a dose for further study. One hundred and twenty-five patients with taxane- or platinum-related CINP received subcutaneous placebo or TTX (7.5 µg twice daily (BID), 15 µg BID, 30 µg once daily (QD), 30 µg BID) for four consecutive days. Primary outcome measure was average patient-reported Numeric Pain Rating Scale (NPRS) score during Days 21–28 post-treatment. Changes in mean NPRS score were not statistically different between cohorts, due to small trial size and influence of a few robust placebo responders. Cumulative responder analysis showed significant difference from placebo with 30 µg BID cohort using the maximum response at any timepoint (p = 0.072), 5-day (p = 0.059), 10-day (p = 0.027), and 20-day (p = 0.071) rolling averages. In secondary quality of life (QOL) outcomes, 30 µg BID cohort also differed significantly from placebo in a number of SF-36 and CIPN20 subscales. Most adverse events (AE) were mild or moderate with oral paresthesia (29.6%) and oral hypoesthesia (24.8%) as most common. Full article
(This article belongs to the Special Issue Tetrodotoxin (TTX) as a Therapeutic Agent)
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20 pages, 1388 KiB  
Article
Safety, Tolerability, Pharmacokinetics, and Concentration-QTc Analysis of Tetrodotoxin: A Randomized, Dose Escalation Study in Healthy Adults
by Mojgan Kavoosi, Terry E. O’Reilly, Mehran Kavoosi, Peng Chai, Caroline Engel, Walter Korz, Christopher C. Gallen and Robert M. Lester
Toxins 2020, 12(8), 511; https://doi.org/10.3390/toxins12080511 - 9 Aug 2020
Cited by 9 | Viewed by 5497
Abstract
Tetrodotoxin (TTX) is a highly specific voltage-gated sodium channel (VGSC) blocker in clinical evaluation as a peripheral-acting analgesic for chronic pain. This study presents the first published results of the safety including cardiac liability of TTX at therapeutic-relevant concentrations in twenty-five healthy adults. [...] Read more.
Tetrodotoxin (TTX) is a highly specific voltage-gated sodium channel (VGSC) blocker in clinical evaluation as a peripheral-acting analgesic for chronic pain. This study presents the first published results of the safety including cardiac liability of TTX at therapeutic-relevant concentrations in twenty-five healthy adults. Randomized, double-blind, placebo-, and positive- (moxifloxacin) controlled study evaluated single ascending doses of 15 µg, 30 µg, and 45 µg TTX over 3 periods with a 7-day washout between each period. Subcutaneous injections of TTX were readily absorbed, reaching maximum plasma concentration (Cmax) within 1.5 h. Both extent of exposure (AUC) and Cmax increased in proportion to dose. No QT prolongation was identified by concentration-QTc analysis and the upper bounds of the two-sided 90% confidence interval of predicted maximum baseline and placebo corrected QTcF (ΔΔQTcF) value did not exceed 10 ms for all tetrodotoxin doses, thereby meeting the criteria of a negative QT study. Safety assessments showed no clinically relevant changes with values similar between all groups and no subject withdrawing due to adverse events. Paresthesia, oral-paresthesia, headache, dizziness, nausea, and myalgia were the most common TEAEs (overall occurrence ≥5%) in the TTX treatment groups. TTX doses investigated in this study are safe, well-tolerated, and lack proarrhythmic proclivity. Full article
(This article belongs to the Special Issue Tetrodotoxin (TTX) as a Therapeutic Agent)
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Review

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24 pages, 7051 KiB  
Review
From Poison to Promise: The Evolution of Tetrodotoxin and Its Potential as a Therapeutic
by Gary M. Bucciarelli, Maren Lechner, Audrey Fontes, Lee B. Kats, Heather L. Eisthen and H. Bradley Shaffer
Toxins 2021, 13(8), 517; https://doi.org/10.3390/toxins13080517 - 24 Jul 2021
Cited by 18 | Viewed by 12541
Abstract
Tetrodotoxin (TTX) is a potent neurotoxin that was first identified in pufferfish but has since been isolated from an array of taxa that host TTX-producing bacteria. However, determining its origin, ecosystem roles, and biomedical applications has challenged researchers for decades. Recognized as a [...] Read more.
Tetrodotoxin (TTX) is a potent neurotoxin that was first identified in pufferfish but has since been isolated from an array of taxa that host TTX-producing bacteria. However, determining its origin, ecosystem roles, and biomedical applications has challenged researchers for decades. Recognized as a poison and for its lethal effects on humans when ingested, TTX is primarily a powerful sodium channel inhibitor that targets voltage-gated sodium channels, including six of the nine mammalian isoforms. Although lethal doses for humans range from 1.5–2.0 mg TTX (blood level 9 ng/mL), when it is administered at levels far below LD50, TTX exhibits therapeutic properties, especially to treat cancer-related pain, neuropathic pain, and visceral pain. Furthermore, TTX can potentially treat a variety of medical ailments, including heroin and cocaine withdrawal symptoms, spinal cord injuries, brain trauma, and some kinds of tumors. Here, we (i) describe the perplexing evolution and ecology of tetrodotoxin, (ii) review its mechanisms and modes of action, and (iii) offer an overview of the numerous ways it may be applied as a therapeutic. There is much to be explored in these three areas, and we offer ideas for future research that combine evolutionary biology with therapeutics. The TTX system holds great promise as a therapeutic and understanding the origin and chemical ecology of TTX as a poison will only improve its general benefit to humanity. Full article
(This article belongs to the Special Issue Tetrodotoxin (TTX) as a Therapeutic Agent)
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15 pages, 6570 KiB  
Review
Tetrodotoxin: A New Strategy to Treat Visceral Pain?
by Ana Campos-Ríos, Lola Rueda-Ruzafa, Salvador Herrera-Pérez, Paula Rivas-Ramírez and José Antonio Lamas
Toxins 2021, 13(7), 496; https://doi.org/10.3390/toxins13070496 - 16 Jul 2021
Cited by 4 | Viewed by 4597
Abstract
Visceral pain is one of the most common symptoms associated with functional gastrointestinal (GI) disorders. Although the origin of these symptoms has not been clearly defined, the implication of both the central and peripheral nervous systems in visceral hypersensitivity is well established. The [...] Read more.
Visceral pain is one of the most common symptoms associated with functional gastrointestinal (GI) disorders. Although the origin of these symptoms has not been clearly defined, the implication of both the central and peripheral nervous systems in visceral hypersensitivity is well established. The role of several pathways in visceral nociception has been explored, as well as the influence of specific receptors on afferent neurons, such as voltage-gated sodium channels (VGSCs). VGSCs initiate action potentials and dysfunction of these channels has recently been associated with painful GI conditions. Current treatments for visceral pain generally involve opioid based drugs, which are associated with important side-effects and a loss of effectiveness or tolerance. Hence, efforts have been intensified to find new, more effective and longer-lasting therapies. The implication of VGSCs in visceral hypersensitivity has drawn attention to tetrodotoxin (TTX), a relatively selective sodium channel blocker, as a possible and promising molecule to treat visceral pain and related diseases. As such, here we will review the latest information regarding this toxin that is relevant to the treatment of visceral pain and the possible advantages that it may offer relative to other treatments, alone or in combination. Full article
(This article belongs to the Special Issue Tetrodotoxin (TTX) as a Therapeutic Agent)
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16 pages, 594 KiB  
Review
Tetrodotoxin, a Potential Drug for Neuropathic and Cancer Pain Relief?
by Rafael González-Cano, M. Carmen Ruiz-Cantero, Miriam Santos-Caballero, Carlos Gómez-Navas, Miguel Á. Tejada and Francisco R. Nieto
Toxins 2021, 13(7), 483; https://doi.org/10.3390/toxins13070483 - 12 Jul 2021
Cited by 21 | Viewed by 8236
Abstract
Tetrodotoxin (TTX) is a potent neurotoxin found mainly in puffer fish and other marine and terrestrial animals. TTX blocks voltage-gated sodium channels (VGSCs) which are typically classified as TTX-sensitive or TTX-resistant channels. VGSCs play a key role in pain signaling and some TTX-sensitive [...] Read more.
Tetrodotoxin (TTX) is a potent neurotoxin found mainly in puffer fish and other marine and terrestrial animals. TTX blocks voltage-gated sodium channels (VGSCs) which are typically classified as TTX-sensitive or TTX-resistant channels. VGSCs play a key role in pain signaling and some TTX-sensitive VGSCs are highly expressed by adult primary sensory neurons. During pathological pain conditions, such as neuropathic pain, upregulation of some TTX-sensitive VGSCs, including the massive re-expression of the embryonic VGSC subtype NaV1.3 in adult primary sensory neurons, contribute to painful hypersensitization. In addition, people with loss-of-function mutations in the VGSC subtype NaV1.7 present congenital insensitive to pain. TTX displays a prominent analgesic effect in several models of neuropathic pain in rodents. According to this promising preclinical evidence, TTX is currently under clinical development for chemo-therapy-induced neuropathic pain and cancer-related pain. This review focuses primarily on the preclinical and clinical evidence that support a potential analgesic role for TTX in these pain states. In addition, we also analyze the main toxic effects that this neurotoxin produces when it is administered at therapeutic doses, and the therapeutic potential to alleviate neuropathic pain of other natural toxins that selectively block TTX-sensitive VGSCs. Full article
(This article belongs to the Special Issue Tetrodotoxin (TTX) as a Therapeutic Agent)
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