A Multicentre Open-Label Safety and Efficacy Study of Tetrodotoxin for Cancer Pain

Hagen, Neil A.; Lapointe, Bernard; Ong-Lam, May; Dubuc, Benoit; Walde, David; Gagnon, Bruno; Love, Robin; Goel, Ravi Kumar; Hawley, Pippa; Ngoc, Anh Ho; Souich, Patrick du

doi:10.3747/co.v18i3.732

Cited by 53 publications

(63 citation statements)

References 23 publications

(28 reference statements)

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“…Clinical studies suggest that low doses of TTX can safely relieve severe cancer-related pain [9,10,11] and reduce cue-induced drug craving and anxiety in abstinent heroin addicts [12]. TTX is a powerful sodium channel blocker [13] and the median lethal dose (LD 50 ) is about 10 μg/kg for adult Sprague-Dawley (SD) rats with intramuscular injection.…”

Section: Introductionmentioning

confidence: 99%

A Study of 11-[3H]-Tetrodotoxin Absorption, Distribution, Metabolism and Excretion (ADME) in Adult Sprague-Dawley Rats

et al. 2017

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Tetrodotoxin (TTX) is a powerful sodium channel blocker that in low doses can safely relieve severe pain. Studying the absorption, distribution, metabolism and excretion (ADME) of TTX is challenging given the extremely low lethal dose. We conducted radiolabeled ADME studies in Sprague-Dawley rats. After a single dose of 6 µg/(16 µCi/kg) 11-[ 3 H]TTX, pharmacokinetics of plasma total radioactivity were similar in male and female rats. Maximum radioactivity (5.56 ng Eq./mL) was reached in 10 min. [ 3 H]TTX was below detection in plasma after 24 h. The area under the curve from 0 to 8 h was 5.89 h·ng Eq./mL; mean residence time was 1.62 h and t 1 2 was 2.31 h. Bile secretion accounted for 0.43% and approximately 51% of the dose was recovered in the urine, the predominant route of elimination. Approximately 69% was recovered, suggesting that hydrogen tritium exchange in rats produced tritiated water excreted in breath and saliva. Average total radioactivity in the stomach, lungs, kidney and intestines was higher than plasma concentrations. Metabolite analysis of plasma, urine and feces samples demonstrated oxidized TTX, the only identified metabolite. In conclusion, TTX was rapidly absorbed and excreted in rats, a standard preclinical model used to guide the design of clinical trials.

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Section: Introductionmentioning

confidence: 99%

A Study of 11-[3H]-Tetrodotoxin Absorption, Distribution, Metabolism and Excretion (ADME) in Adult Sprague-Dawley Rats

et al. 2017

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“…In this study, they noted that the side effects of tetrodotoxin were tolerable to the test subjects; however, fewer than half of the subjects reported significant pain relief [84]. Also noteworthy is the observation that those that benefitted from tetrodotoxin received only transitory relief [84]. Other studies support potential clinical use for tetrodotoxin.…”

Section: Voltage-gated Sodium Channel Pharmacologymentioning

confidence: 95%

“…Unfortunately, Nav 1.8 and 1.9 are largely present in the peripheral nervous system, a fact that could explain limitations in the clinical efficacy of tetrodotoxin as an analgesic [56, 58]. For example, Hagen et al [84] tested tetrodotoxin in the setting of cancer-related pain. In this study, they noted that the side effects of tetrodotoxin were tolerable to the test subjects; however, fewer than half of the subjects reported significant pain relief [84].…”

Section: Voltage-gated Sodium Channel Pharmacologymentioning

confidence: 99%

“…For example, Hagen et al [84] tested tetrodotoxin in the setting of cancer-related pain. In this study, they noted that the side effects of tetrodotoxin were tolerable to the test subjects; however, fewer than half of the subjects reported significant pain relief [84]. Also noteworthy is the observation that those that benefitted from tetrodotoxin received only transitory relief [84].…”

Section: Voltage-gated Sodium Channel Pharmacologymentioning

confidence: 99%

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Pain transduction: a pharmacologic perspective

McEntire

Kirkpatrick

Dueck

et al. 2016

Expert Review of Clinical Pharmacology

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Pain represents a necessary physiological function yet remains a significant pathological process in humans across the world. The transduction of a nociceptive stimulus refers to the processes that turn a noxious stimulus into a transmissible neurological signal. This involves a number of ion channels that facilitate the conversion of nociceptive stimulus into an electrical signal. Because an understanding of nociceptive physiology complements a discussion of analgesic pharmacology, the relationships between the two are presented together. In this review article, a critical evaluation is provided on the findings relating to both the physiology and pharmacology of relevant acid-sensing ion channels (ASIC), and transient receptor potential (TRP) cation channels, and voltage-gated sodium (Nav) channels.

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“…It is, therefore, perhaps surprising that tetrodotoxin, which blocks most subtypes of sodium ion channels, is also in clinical trials. Most of the clinical work has been in Canada with patients suffering from severe cancer-related pain (Hagen et al, 2007(Hagen et al, , 2008(Hagen et al, , 2011. Results show some promise, with some patients noting improvements in symptoms, but more extensive testing may prove to be more demanding.…”

Section: Trials and Tribulationsmentioning

confidence: 99%

Toxins and Drug Discovery

Cruz¹,

Luo²

2017

Toxinology

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Components from venoms have stimulated many drug discovery projects, with some notable successes. These are briefly reviewed, from captopril to ziconotide. However, there have been many more disappointments on the road from toxin discovery to approval of a new medicine. Drug discovery and development is an inherently risky business, and the main causes of failure during development programmes are outlined in order to highlight steps that might be taken to increase the chances of success with toxin-based drug discovery. These include having a clear focus on unmet therapeutic needs, concentrating on targets that are well-validated in terms of their relevance to the disease in question, making use of phenotypic screening rather than molecular-based assays, and working with development partners with the resources required for the long and expensive development process.

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A Multicentre Open-Label Safety and Efficacy Study of Tetrodotoxin for Cancer Pain

Cited by 53 publications

References 23 publications

A Study of 11-[3H]-Tetrodotoxin Absorption, Distribution, Metabolism and Excretion (ADME) in Adult Sprague-Dawley Rats

A Study of 11-[3H]-Tetrodotoxin Absorption, Distribution, Metabolism and Excretion (ADME) in Adult Sprague-Dawley Rats

Pain transduction: a pharmacologic perspective

Toxins and Drug Discovery

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