Tetrodotoxin for prolonged local anesthesia with minimal myotoxicity

Abstract

Conventional local anesthetics such as bupivacaine cause considerable myotoxicity and neurotoxicity, whereas tetrodotoxin (TTX) does not. Tetrodotoxin combined with bupivacaine or vasoconstrictors produces long-duration nerve blockade. To assess whether these prolonged blocks can be produced without increased myotoxicity, Sprague-Dawley rats were injected with bupivacaine, TTX, and both, or TTX plus epinephrine. Median durations of thermal nociceptive blockade were, respectively, 188, 401, 882, and 972 min. On dissection 4 days later, all tissues appeared macroscopically pristine. Muscle injury was at most mild to moderate in all animals, and the muscle injury scores for the combination formulations were not higher than for bupivacaine alone. Similarly, in differentiated cells from a myoblast cell line (C2C12), TTX caused either no or minimal worsening of cell viability from bupivacaine at 2 or 7 days. Epinephrine did not worsen TTX's relatively minimal cytotoxicity. Tetrodotoxin may thus be useful in producing prolonged nerve block with minimal myotoxicity and perhaps neurotoxicity.

Local Toxicity from Local Anesthetic Polymeric Microparticles

“…By way of comparison, 0.5% (w/v) bupivacaine reliably yields a nerve block lasting approximately 150 min, 19,47 with minimal tissue toxicity. 42,48 These observations are not consistent with the lack of difference in toxicity being simply due to excessive levels of local anesthetic.…”

“…We have previously noted that the mere presence of a sustained release vehicle can exacerbate local tissue toxicity 19,42 in vivo, even though the vehicle might have no effect on local anesthetic cytotoxicity in cell culture. 6 The mechanism for this effect is unknown.…”

“…21 The samples were scored for inflammation (0-4) and myotoxicity (0-6). 42 The inflammation score was a subjective assessment of severity. The myotoxicity score reflected two characteristic features of local anesthetic myotoxicity: nuclear internalization and regeneration.…”

“…Most do not describe myotoxicity [2][3][4][5][7][8][9][11][12][13][14][15]18,[22][23][24] (including the liposomal formulation undergoing human trials 16,17 ), while some others document mild muscle injury comparable to single injections of unencapsulated drug. 10,25,26 In our own work, we have found muscle injury to be a ubiquitous finding in a wide range of extended-release bupivacaine formulations independent of the delivery vehicle 6,19,21,41 or co-encapsulated agent, 32,37,42,43 and it is sometimes severe. That tissue injury can be a crucial issue with sustained release formulations is seen in the example of a sustained-release bupivacaine-dexamethasone formulation; 3 nerve and muscle injury in preclinical animal studies and clinical human trials led to withdrawal of its Investigational New Drug application (IND#53,441).…”

Microtúbulos y terapia neural: propuesta de una investigación promisoria

“…La estructura de los MT y los mecanismos involucrados en su ensamblaje y desensamble están bien establecidos (4,(43)(44)(45)(46)(47) (39,41,47). En un MT típico hay trece protofilamentos.…”