Addressing the Issue of Tetrodotoxin Targeting

Melnikova, Daria I.; Magarlamov, Timur Yu.

doi:10.3390/md16100352

Cited by 23 publications

(28 citation statements)

References 93 publications

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“…The inflammation induced by the allergy, thermal stimulation and mechanical pain could be inhibited by TTX [21]. The inflammatory pain of rats could be reduced with the systemic administration [22].…”

Section: Discussionmentioning

confidence: 99%

Analgesia Effect of Enteric Sustained-Release Tetrodotoxin Pellets in the Rat

Hong

Sun

et al. 2020

Pharmaceutics

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Tetrodotoxin (TTX) was identified as a latent neurotoxin that has a significant analgesia effect. It was rapidly absorbed and excreted in rat after intramuscular (i.m.) injection. To maintain the effect, frequent injections were required. The enteric sustained-release TTX pellets with sucrose pellets as a drug carrier was prepared by fluidized bed spray irrigation, coated in sequence with Eudragit NE30D as a sustained-release layer, hydroxypropyl methylcellulose (HPMC) as a barrier layer and Eudragit L30D-55 as an enteric coating. TTX in the pellets could be sustained released for 12 h in dissolution test. In vivo, TTX pellets reached Cmax at 5 h, and t1/2 was 14.52 ± 2.37 h after intragastrically (i.g.) administration in rat. In acetic acid induced writhing test in rat, the pellets at the dosages of 20, 40, 60 and 80 μg·kg−1 produced analgesic effect at about 1.5 h to 9 h and the strongest effect was at about 3 h to 6 h. Simultaneously, the LD50 of the enteric sustained-release TTX pellets was 840.13 μg·kg−1, and the ED50 was about 30 μg·kg−1. Thus, the therapeutic index was about 25. The enteric sustained-release TTX pellets with absolute analgesia effect and greatly enhanced safety was prepared.

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Section: Discussionmentioning

confidence: 99%

Analgesia Effect of Enteric Sustained-Release Tetrodotoxin Pellets in the Rat

Hong

Sun

et al. 2020

Pharmaceutics

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“…Despite these promissory effects, there are some limitations for the use of TTX in patients, one of them is its toxicity. This may appear as a consequence of its systemic distribution and it can involve the blocking of diaphragmatic nerves ending in respiratory tract paralysis [17]. Even with previous findings, current studies are needed to improve its use in SCI.…”

Section: Tetrodotoxinmentioning

confidence: 97%

“…Tetrodotoxin (TTX) is a low-molecular-weight guanidine neurotoxin that acts as a specific blocker of voltage-gated sodium (NaV) channel [17]. TTX has neuroprotective properties by blocking NaV channels, preventing neuronal death by diminishing depolarization, cellular Na + /Ca +2 exchange, and neuronal glutamate release [18].…”

Section: Tetrodotoxinmentioning

confidence: 99%

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Trends in Neuroprotective Strategies after Spinal Cord Injury: State of the Art

Rodríguez-Barrera¹,

Garibay-López²,

Ibarra³

2020

Neuroprotection - New Approaches and Prospects

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Spinal cord injury (SCI) is an important pathology leading to possibly fatal consequences. The most common repercussions are those affecting motor and sensitivity skills. SCI-damage occurs in its first phase-as a result of the lesion mechanism (contusion, compression, transection, and primary lesion). After this primary damage, there is a second phase with further deleterious effects on neural degeneration and tissue restoration. At the moment, several investigation groups are working on developing therapeutic strategies to induce neuroprotection. This chapter pretends to introduce the reader to a wide range of these therapies, particularly those with promising results and tested in preclinical and clinical studies. In the first section, physiopathology of SCI will be addressed. Afterwards, the chapter will review neuroprotective strategies such as cyclooxygenase, calpain, and apoptosis inhibitors. Finally, the effect of immunophilin ligands, neural-derived peptides, antioxidants, hypoglycemic agent, gonadal hormones, Na channel blockers, and transplant of cultured cells will also be reviewed.

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“…If successful, TTX will be one of a select few peripherally acting analgesics. To date, preclinical studies have shown TTX to be effective at inhibiting neuropathic [13,14] and inflammatory pain [15][16][17]. In patients with moderate to severe pain due to either cancer or chemotherapy-induced neuropathy who failed other treatments, TTX was seen to reduce pain by 30% below baseline levels in some patients [18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Safety, Tolerability, Pharmacokinetics, and Concentration-QTc Analysis of Tetrodotoxin: A Randomized, Dose Escalation Study in Healthy Adults

Kavoosi

O’Reilly

Kavoosi

et al. 2020

Toxins

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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.

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Addressing the Issue of Tetrodotoxin Targeting

Cited by 23 publications

References 93 publications

Analgesia Effect of Enteric Sustained-Release Tetrodotoxin Pellets in the Rat

Analgesia Effect of Enteric Sustained-Release Tetrodotoxin Pellets in the Rat

Trends in Neuroprotective Strategies after Spinal Cord Injury: State of the Art

Safety, Tolerability, Pharmacokinetics, and Concentration-QTc Analysis of Tetrodotoxin: A Randomized, Dose Escalation Study in Healthy Adults

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