## 6 Medical Applications of Tetrodotoxin
The response of different organs or tissues to TTX will vary depending on the VGSC isoforms present in their cells, since the response of the different nine existing isoforms varies in kinetics and sensitivity to TTX [113, 119, 124]. For instance, TTX sensitivity of the cardiac Na\({}^{+}\) current is different among distinct groups of vertebrates, being more TTX resistant in mammals and reptiles (and some fish like lamprey) than in teleost fish, frog and bird [125]. VGSCs play a key role in nociception, since they are implicated in driving the information to the central nervous system. Dysfunctional VGSCs have been related to several pain states, and data from human genetic studies and transgenic mouse models suggest that specific VGSC are associated with specific types of pain [119, 126]. This situation would allow the development of drugs that selectively block a single channel or selected channels and theoretically, the use of specific blockers could help to avoid some adverse effects associated with non-selective sodium channel blockers. Distribution of the diverse isoforms along the body tissues and their implication in different types of pain has been reviewed by [PERSON] _et al._[119]. The effects of TTX on acute and on inflammatory pain have not been broadly studied, but it seems that TTX exerts little effect on acute pain. On the other hand, promising results have been achieved against inflammatory pain and even on the neurogenic inflammatory response to an injury [119]. The role of TTX in neuropathic pain has been investigated more intensely than acute or inflammatory pain. TTX has been studied in several animal models, mainly in rodents, but also in rabbits, cats and dogs [40, 119, 126]. Pain models include cold pain, mechanical pressure, inflammatory pain, heat, visceral pain, pain induced as side effect by therapeutic drugs, formalin test or neuropathic pain Writhing test. Studies of TTX in animal pain models have been recently reviewed [119]. The use of TTX has been investigated for medical purposes other than pain mitigation in animal models. These investigations include several urinary bladder dysfunction studies in pigs [127], treatment of drug addiction in rats [128], corneal injury induced photophobia in rats [129] or schizophrenia in rats [130]. Some researchers are trying to make use of the analgesic activity of TTX to treat various types of pains such as in severe cancer [29, 34, 119]. In a clinic trial performed in Canada, TTX was administered subcutaneously to cancer patients. The time course of the apparent analgesic response to TTX was an additive analgesic effect until Day 4 or 5, the effect peaked around Day 10, and then became less after that time, wearing off two weeks or longer after TTX was first administered. During the study, physical examination, vital signs, oxygen saturation, corrected QT interval (QTc) and other electrocardiographic parameters, neurological examination, clinical chemistry, and haematology measures were not affected by TTX, although three TTX-treated patients were withdrawn from the study due to adverse effects occurrence (moderately severe but transient ataxia, malignant epidural spinal cord compression and transient moderate dysphagia, respectively). Overall, treatment-emergent adverse events in TTX-treated patients were mild and related to tingling, numbness, or other transient sensory symptoms [29]. In a later clinic trial, the patients participating in the former enrolled a study designed to evaluate long-term TTX safety and efficacy. In this study, 30 \(\upmu\)g TTX was administered subcutaneously twice daily for four days. One patient was withdrawn because of adverse effects. Toxicity was usually mild or moderate, and remained so through subsequent treatment cycles, with no evidence of cumulative toxicity or tolerance with long-term administration. Surprisingly, only about 50% of patients responded to TTX, with no explanation for this achievement.