Neosaxitoxin
Neosaxitoxin (NSTX) is included, as other saxitoxin-analogs, in a broad group of natural neurotoxic alkaloids, commonly known as the paralytic shellfish toxins (PSTs). The parent compound of PSTs, saxitoxin (STX), is a tricyclic perhydropurine alkaloid, which can be substituted at various positions, leading to more than 30 naturally occurring STX analogues. All of them are related imidazoline guanidinium derivatives. Sources. NSTX, and other PSTs, are produced by several species of marine dinoflagellates (eukaryotes) and freshwater cyanobacteria, blue-green algae (prokaryotes), which can form extensive blooms around the world. Under special conditions, during harmful algal blooms (HAB) or red  tide, all these toxins may build up in filter-feeding shellfish, such as mussels, clams and oysters, and can produce an outbreak of Paralytic Shellfish Poisoning (PSP). Saxitoxin analogues associated to PSP can be divided into three categories: Structure and properties. NSTX is quite similar to saxitoxin, like all the neurotoxins associated to PSP, the only difference is that NSTX shows one hydroxyl group bonded to nitrogen "1", where saxitoxyn contains one hydrogen. This purine is highly hydrophilic and thermostable, it is not destroyed by cooking. Moreover, is very stable in usual storage, specially in acidic condition. Mechanism of action . NSTX blocks the extracellular portion, the outer vestibule, of some voltage gated sodium channels in a very powerful and reversible manner, without affection of other ion channels. "Voltage-gated", also called "voltage-sensitive" and "voltage-dependent" sodium channel also known as "VGSCs" or "Nav channel" are crucial elements of normal physiology in a variety of animals, including flies, leeches, squid and jellyfish, as well as mammalian and non-mammalian vertebrates. This large integral membrane protein plays an essential role in the initiation and propagation of action potentials in neurons, myocytes and other excitable cells. Nav channels form the basis for  electrical excitability in animals. Nav channels evolved from Ca channels and were present in the common ancestor of choanoflagellates and animals, although this channel was likely permeable to both Na and Ca. Thus, like many other neuronal channels and receptors, Nav channels predated neurons. Invertebrates possess two Nav channels (Nav1 and Nav2), whereas vertebrate Nav channels are of the Nav1 family. Sodium-channel proteins in the mammalian brain are composed of an association that include one alpha subunit and one or more auxiliary beta subunits. Nine types of alpha subunits have been described (Na1.1 to Na1.9), and a tenth related  isoform (Na) may also play some role as a Nav channel. Based in this information, ten Nav classes can be described: Na1.1 to Na1.9, and Na. Former five, but more recently, six neurotoxin receptor sites have been recognized between the seven receptor site located in the vertebrate sodium channel receptor alpha subunit: NSTX and other site 1 blockers have high affinity (very low dissociation constant) and high specificity for Nav channels. The action of NSTX produces minimal effect on cardiac Nav, where it exhibits about 20–60 fold lesser affinity than in Nav channels from rat skeletal muscle and rat brain . Most data emphasize the role of "STX resistant" Na channel 1.5 in human heart. Toxins such as neosaxitoxin and tetrodotoxin have less affinity for most cardiac Nav channels than for most Nav channels in nerve tissue. Moreover, NSTX is so active on nerve Nav channel than is roughly a million-fold more potent than lidocaine. Effects on humans. This mechanism of action can produce two well known kinds of effects in humans: Toxic effect, associated to plasmatic levels of NSTX. It can be approximately described using one of the classical model of neurotoxic disease, known from ancient times as red  tide, the most harmful algal bloom (HAB). This well known clinical model is the "paralytic shellfish poisoning". Of course, there are great differences between different algal blooms, because of the mix of species included in each HAB, usually related to environmental conditions; because of the levels and quality of PSTs produced in each HAB, that may be modulated by concurrent microorganism; and, last but not least, because of the specific properties of each kind of PST, for example: In spite of its heterogeneous and poorly understood epidemiology, the clinical picture of PSP could be useful to anticipate clinical effects of  systemic NSTX. Usually, the victims of mild and severe acute intoxications eliminate the toxin in urine during the first 24 hours after ingestion, and improve to full recovery in the first day of intrahospital care (when vital support is provided in a timely manner). When outbreaks of PSP occur in remote locations, where medical assistance is limited, reported lethality is under 10% in adults, but can reach 50% in children younger than six years old. This difference could be secondary to dissimilar doses and composition of involved mixes of PSTs; delay in medical support; or some kind of susceptibility of  children. More recent information suggest that lethality could be around 1% of symptomatic patients, including cases where air transportation was required from remote locations of Alaska. Electrophysiologic observations demonstrated sub clinical abnormalities lasting for some days or weeks after clinical recovery . Some evidence suggest the presence of metabolic pathways for the sequential oxidation and glucuronidation of PST in vitro, both being the initial detoxication reactions for the excretion of these toxins in humans. Forensic analysis of fatalities after severe cases, conclude that PSP toxins are metabolically transformed by humans and that they are removed from the body by excretion in  the urine and feces like any other xenobiotic compound. Considering the heterogeneous nature of toxins mixes contained in contaminated bivalve molluscs, the safe limit of toxin content in shellfish adequate for human ingestion is expressed in "saxitoxin equivalents". According to the Food and Agriculture Organization of the United Nations (FAO) and European Parliament, this limit is 80 microgram of saxitoxin equivalent per 100 gram of mussel meat (each mussel weights around 23 g). The U.S. Food and Drug Administration extends the same definition to "fish" quality, but the term "fish" refers to fresh or saltwater fin fish, crustaceans, other forms  of aquatic animal life other than birds or mammals, and all mollusks; and incorporate the use of "ppm" as another measure for saxitoxin equivalent concentration in mentioned foods. Paradoxically, the chronic and/or repeated exposure to marine seafood toxins, which is a much more realistic phenomenon, has not been fully examined. One study in rats exposed to chronic (12 weeks) NSTX administration demonstrated some reduction in water and food intake, and a mild degree of transient cholestasis, probably associated to fasting, without other abnormalities. Anesthetic effect, produced by local infiltration of NSTX. This action has been demonstrated in animals and humans . The medical use of the NSTX anesthetic effect is supported by three reasons: In conclusion, NSTX is a well defined molecule with a long-lasting and sometimes dangerous relationship with human subjects. Recent investigations suggest a clinical application as a new local anesthetic that sounds "too good to be true", but more investigation is required.