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- 1. Unit - 2 Marine Toxins
- 2. Unit 2 - Venomous Bites This golf ball-sized octopus is small, about 7 cm long, shy and hides in coral crevices or under rocks. It may look cute, harmless and attractive but is amongst the most dangerous creatures on the planet. Its venomous bite has claimed a number of human lives as its saliva contains TTX. Blue ringed Octopus
- 3. Sea Snakes Sea snakes are reptiles, have scales and flattened, paddle- like tails with heads that resemble land snakes whereas eels are fishes, have a fish-like face and mouth as well as one long continuous dorsal fin. All sea snakes are highly venomous and should not be handled even though they are shy, gentle and do not normally pose a threat unless provoked.
- 4. Venomous spines The family of fishes known as Scorpaenidae include lionfish, scorpion fish and stonefish. They have venomous spines on their dorsal fins as a defence against rays and sharks. Scorpion fish
- 5. Stone fish The stonefish, the most venomous fish in the world, looks like encrusted rock or dead coral. Most human victims injure themselves when they accidentally step on it or place their hands on it. 13 hard spines on its back, sharp enough to puncture rubber soled shoes, carry neurotoxic venom into the wound when the spines are pressed, causing excruciating pain, temporary paralysis and shock, and in rare cases, even death (only 3 fatalities from stonefish envenomation has ever been recorded).
- 6. Star fish Crown of thorns The Crown of Thorns starfish Acanthaster planci is the only venomous starfish. It can grow up to a metre in diameter and can have as many as 21 arms. It is covered with sharp spines all over its body except on its underside. Spines can grow up to 6 cm in length and can easily penetrate a wetsuit. On contact, the spines release a variety of toxins which although not fatal, are painful, causes redness and local swelling.
- 7. Sea Urchin Venomous urchins like fire urchins (Asthenosoma species) and long-spined urchins (Diadema species) deliver their venom through their spines while flower urchins (Toxopneustes pileolus) deliver venom through jaw-like organs called Pedicellaria supported on stalks and surrounded by non-venomous spines.
- 8. Venomous stings Cone shells are highly sought after by shell collectors due to their attractive and intricate markings. The venom is contained in the tongue-like proboscis (radula) equipped with harpoon-shaped teeth. About 30 recorded fatalities from cone shell stings, most of them from the Conus geographus species. Cone shells
- 9. Sting rays Stingrays are shy and frequently hide in shallow waters under rocks or buried under the sand with only their eyes slightly exposed. The front half of the tail may have up to 7 barbs or spines located on the top side which the ray can use to inflict a painful, venomous sting to any aggressor by whipping its tail upwards in an arc, much like the way a scorpion stings.
- 10. Box Jelly fish The box jelly Chironex fleckeri is the world's most venomous jellyfish and possibly the world's most venomous creature, causing about 70 fatalities just in Australia, and between 20- 40 deaths annually in the Philippines. It is found mainly in the northern coastal waters of Australia and in some parts of the Indo-Pacific.
- 11. Puffer fish The pufferfish is so poisonous that contains TTX in the body. There are over 120 species of puffer fish in the world and unfortunately most are dangerous so its best to avoid them. Consumption
- 15. Potent neurotoxin Named after fish Tetraodontiformes = four toothed or Tetrodon Pufferfish Family Tetraodontidae and Diodontidae In Japan Fugu poison Non protein and colourless crystals Chemical name Amino Perhydroquinazoline Formula C11 H17 N3 O8 Identified from California Newt, Salamander, Parrotfish, Starfish, Frogs of the genus Atelopus, Blue-ringed Octopus, Xanthid Crabs, Boxfish, Horseshoe crabs, Marine Snails.
- 16. Binds to site of voltage gated Na+ channels; where it binds and blocking the passage of Na+ ions into the nerve cell. It blocks the Na+ current in human hearts and prevents contraction. Virtually insoluble in all organic solvents but soluble in acidic media. 3 nitrogen atoms of tetrodotoxin are present in the molecule as a guanidine moiety. 10,000 times more lethal than cyanide. LD50 5.0 8.0 g/kg.
- 17. Controversies on production of TTX 1. TTX is produced by the associated bacteria lives inside the pufferfish. 2. It is secreted by the fish itself. Bacteria like Vibrionaceae family, Pseudomonas tetraodonis, Photobacterium phosphoreum. TTX found in liver, ovary, muscle and skin.
- 18. Intoxication Intoxication of TTX is characterised by rapid onset of weakness, dizziness; paresthesia in the lips, tongue and throat. In extremities, nausea and occasionally vomiting occur. In more severe cases, include sweating, salivation, muscular weakness, respiratory distress. In very severe cases, muscular paralysis and death due to apparent respiratory paralysis occur 6-24 hrs following ingestion of the toxic fish. Cysteine is reported to react with TTX (by binding) in in vitro at pH 7.0 and produce a non-toxic substance.
- 19. Pharmacological potency of TTX The initial action of TTX is blocking the Na+ channel of muscle and nerve block. Direct blocking action in the muscle fibers is usually longer than the nerve block. Toxin found in highest conc. in kidney & heart and lowest in brain & blood after 20 min. s.c. administration of toxin in rat. TTX has proved to be a useful tool of the analysis of events, which occurs in the nerve, result in impulse propagation.
- 20. A good hypertensive agent & produces fall of blood pressure of the cat in the doses of 2-3 g/kg in i.v. Also a potent respiratory inhibitor at very low doses (0.5-3 g/kg ) to arrest the respiration. TTX inhibit the stimulation of respiration & metabolism in preparations of in vitro guinea pig brain. Clinically used as a pain relieving compound, in the cases of patients suffering from the neurogenic form of Hansens disease (Leprosy).
- 21. Natural defense Puffer fishes swims very slow, therefore comparatively easy targets for predators. As a defense mechanism, puffers have the ability to inflate rapidly, filling their extremely elastic stomachs with water.
- 22. Sensitivity TTX-R and TTX-S on VG sodium channels (out of 9 VGNC, 6 are TTX-S and 3 for TTX-R) Binds at site-1 of (VGSC) Na+ channel Very less effect on cardiac sodium channels than nerve and muscle Na+ channels
- 23. Clinical trials Pain relief for Cancer Patients 15-90g of TTX administered intramuscularly for four days; 17 out of 31 cancer patients reported pain reduction. Significant analgesic effect also observed in another study. 30 g of TTX administered subcutaneously twice daily for 4 days; 21 out of 41 cancer patients reported pain relief.
- 25. Conotoxin - Conus species
- 26. Conotoxin Conotoxin - a group of Neurotoxic peptide from the venom of marine snail Genus Conus. Tropical seas in worldwide including California and South Africa. Peptide contains 10-40 amino acids. Rich in Cysteine amino acid residues (1 or above) disulphide bridges. Blocking the neuromuscular system of the prey, which may be fish, mollusc or marine worm. LD50 of conotoxin varies species to species.
- 27. Piscivores, Molluscivores and Vermivores. Most dangerous animal to humans are the fish hunting Conus sp., particularly Conus geographus. Reportedly 20 human fatalities were identified, due to careless handling of divers and shell collectors. Sting by radula. Sting includes, numbness at the site of stinging which spreads to upper parts of the limb and to rest of the body. Blurring of vision, impaired speech and muscle paralysis precede to death.
- 28. Conus geographus C. catus C. textile
- 29. Venom Gland and Radula
- 30. In rats & guinea pigs showed marked respiratory depression and resp.failure accompanied by blood pressure fluctuations upon i.v. injection of venom of C. geographus. LD50 of freeze dried C. geographus venom in mice was 0.82 mg/kg on i.v. injection & 1.3 mg/kg upon i.p. injection. Approximately 700 sp. of cone snails recorded and all are Carnivores.
- 31. They are nocturnal hunters. C. geographus, C. catus, C. aulicus, C.gloriamaris, C. omaria, C. magus, C.striatus, C. tulipa, C. textile. C. geographus is most dangerous to humans. Piscivores are having stronger toxin than molluscivores and vermivores; it shows that due to highly movable fish to be hunted by stronger toxin. No specific antidote available for conotoxin sting. Molluscivores like C.textile, C.regius are mollusc eater and hazardous to humans.
- 32. Types of Conotoxin Type of Conotoxin Site of action Details Species Alpha Nicotinic Ach receptors Inhibits nicotinic acetylcholine receptors at nerves and muscles. The result is paralysis. Conus magus C. geographus Gamm a Ion channel inhibitor Gamma-conotoxins may act on voltage-gated non- specific cation pacemaker channels (HCN). Triggers depolarization and firing of action potential bursts in the caudodorsal neurons of lymnaea. C. geographus C. textile C. consors C. magus Delta Na channel Inhibits the inactivation of voltage dependent sodium channels (delta slows the inactivation of the sodium channel, mu inhibits the sodium channel) C. striatus C. purpurascens C. textile Epsilon Ca channel Epsilon-conotoxins act at presynaptic membranes, blocking the calcium channels or G protein-coupled receptors. C. textile Iota Na channel Iota-conotoxins bind to voltage-gated sodium channels (Nav) and act as agonists by shifting the voltage- dependence of activation to more hyperpolarized levels. C. litteratus C. striatus C. radiatus Kappa K channel Inhibits voltage-graded potassium channels, resulting in tremors. C. betulinus C. striatus C. radiatus
- 33. Type of Conotoxin Site of action Details Species Mu Na channel Inhibits voltage-graded sodium channels in muscles. The mechanism is similar to that of saxitoxin produced from red tide algae. C. geographus C. tulipa C. striatus Rho Alpha adrenal receptors Allosteric inhibitor of alpha-1B adrenergic receptors (ADRA1B). Binds to an allosteric modulatory site on transmembrane helix 6 and 7 at the base of extracellular loop 3 of ADRA1B. C. tulipa Sigma Affects serotonin activity Sigma-conotoxins bind and inhibit serotonin-gated ion channels. C. geographus Chi Neuronal adrenergic transporter Chi-conotoxins inhibit the neuronal noradrenaline transporter. C. marmoreus Omega Ca channel Affects the calcium channels associated with nerve impulse transmission at the neuromuscular junction. Calcium channels are related to sensitivity to pain. C. geographus C. textile C. striatus Conantokins NMDA receptors Blocks nerve impulses that use glutamic acid rather than acetylcholine as the neurotransmitter. C. geographus Conopressin s Modulate Vasopressin / Oxytocin receptors (Increases blood pressure) Targets vasopressin-oxytocin related receptors. C. textile
- 35. Clinical symptoms Non Fatal Case (full recovery) Fatal Cases Burning pain Numbness without pain (some species produce severe pain and spreading numbness) Swollen arm and pain Lips become stiff Local numbness spreading rapidly to involve the entire body, with some cardiac and respiratory distress Blurred vision Progressive weakness, loss of coordination, drooping eyelids, shallow breathing Paralysis Headache, nausea, stomach cramps, shortness of breath Coma These symptoms occur almost immediately upon injection Death occurs as the result of respiratory and/or cardiovascular collapse.
- 36. Pharmacology of Conotoxins Estimated 50,000 1,00,000 conotoxins, approximately 0.1% have been characterised pharmacologically. Important tool for defining ion channels function (Neurobiologists). Studies found that C.geographus cause convulsions and resp. suppression in mice. Conotoxins target and block potently a wide range of ion channels, such as voltage-gated sodium channels (Nav), voltage-gated calcium channels (Cav), voltage-gated potassium channels (Kv), nicotinic acetylcholine receptor (nAchRs) and NMDA (N-methyl D-aspartate) receptor.
- 37. Ionic channels and Receptor
- 38. LD50 of 留 conotoxin is 10-100g/kg in mice but hydrogen cyanide is 1-3 mg/kg. Acetylcholine (Ach) is released by a motor neuron and it attaches to the nicotinic receptors on the muscle and then the muscle starts to contract. Physically blocking the nicotinic receptor with a drug or toxin would stop the contraction and cause paralysis. The first isolated -conotoxin were named as GI, GIA and GII found in C.geographus, it does not affect the CNS.
- 39. Inhalation of 留 conotoxin is similar to the inhalation of botulism toxin. Muscle paralysis by blocking ion channels in muscle found from C.purpurascens, is piscivore; causes both flacid paralysis & Sudden tetanus on its prey named as PIVA & -conotoxin PIIIA to paralyse its fish prey. conotoxin of piscivores inactivate Na channel in mammals. Nav channel is necessary for normal electrical functioning.
- 40. Activation and block of ion channels
- 41. Classes Alpha-competitive nicotinic acetylcholine receptor antagonists Developmental site nicotine and alcohol suppressant www.mpg.de/bilderBerichteDokumente
- 42. Classes Delta -inhibits the inactivation of voltage-dependent Na channels. -Hyperactivity, epilepsy -keeping sodium channels open and interfering with action potential propagation
- 43. Classes Kappa -inhibits K channels -Preventing potassium efflux , disrupting resting potentials -Treatment of Neurodegenerative disorders
- 44. Classes Mu -inhibits voltage-dependent Na channels in muscle. -hyperactivity Treatments for epilepsy and cardiovascular disorders www.mpg.de/bilderBerichteDokumente
- 45. Classes Omega -inhibits N-type Ca channels on primary nociceptive nerves -Hypertension Analgesic properties
- 46. Classes Conantonkins -similar to alpha but in cases when glutamic acid is NT.
- 47. Ziconotide 1st drug of marine origin which obtained approval by the USFDA on December 31st 2004. Isolated from C.magus of -conotoxin MVIIA for under the brand name of Prialt, commercial drug in USA and E.U. Treating Parkinsons Alzheimers diseases. Blocks the N-Type calcium channels on the primary nociceptive nerves in the spinal cord.
- 48. Used only for management of severe chronic pain Approved for the treatment of chronic pain as a morphine replacement therapy. It is the most powerful painkiller known to date. Must be administered intrathecally. Common side effects: dizziness, nausea, confusion & headache. Rare side effects: hallucinations, suicidal thoughts, new or worsening depression, meningitis and seizures.
- 51. Ciguateratoxin Most commonly reported fish poisoning or Seafood poisoning. Caused by bioaccumulation of toxins produced by Gambierdiscus toxicus (Dinoflagellate) in large reef fish e.g. barracuda, grouper, snapper, sea bass. Toxins accumulate in greater quantities in the flesh of bigger fishes and enter human organism after consumption of these fishes. 20,000-50,000 cases worldwide annually Estd 1600/yr in USA In some countries as high as 1200 per 1,00,000. Symptoms of Ciguateratoxin are the reversal of thermal sensation called Dry Ice Sensation.
- 52. Outbreaks associated with wholesale of imported fish. Hawaii and Florida report 90% of all cases. Ciguatera fish poisoning (CFP) is most frequent in Caribbean, Indian Ocean, Maldives, Seychelles, Solomon islands, Guam islands, Fortuna islands, Williams islands etc. CFP reported for the first time in 1601 in Indian Ocean. The fishes that are connected to this poisoning are more than 420 kinds. They are so called vector fishes genus Herbivores and Carnivores.
- 53. Route cause of Ciguateratoxin Structure
- 54. Ciguatoxins (CTXs) are neurotoxins. They are lipid soluble polyether compounds made up of 13 or 14 rings fused into rigid ladder-like structures. The Pacific ciguatoxin-1 (P-CTX-1) is the most potent and its structure is slightly different from that of the Caribbean ciguatoxin-1 (C-CTX-1). LD50 of C-CTX-1 for guinea pigs intraperitoneally is 0.45 ng/kg. A dose of 0.1 ng causes intoxication in humans. The toxin is lipid soluble - accumulated and stored in the flesh of fishes.
- 55. Symptoms The initial symptoms appear between the 4th and the 12th hour (on the average 12 hours) after the consumption of fish with preserved taste qualities. Three main clinical syndromes develop: gastrointestinal, neurologic and cardiocirculatory. The first complaints are from abdominal pain, nausea and vomiting. Cardiotoxicity include: cardiac bradycardia, arrhythmias or cardiac block appear. The intensity and duration of symptoms are different in different individuals and regions, where the poisoning had taken place.
- 56. Lethal cases were reported with frequency from 0.1% to 12%. The lethal exit is associated to consumption of the most toxic parts of the fish liver, other internal organs. Cases of ciguatera poisoning have been described in a newborn baby and a breast fed baby, because the lipid soluble ciguatoxin can pass through placental barrier and mothers milk.
- 58. Nerve Cell Ciguatoxic Effects on the Sodium Channel
- 59. Mechanism of Ciguateratoxin The mechanism of action of ciguatoxins is related to its direct effect on excitable membranes. Ciguatoxins are characterized by their affinity binding to voltage sensitive sodium channels, causing them to open at normal cell resting membrane potentials. This results in an influx of Na+ ions, cell depolarization and the appearance of spontaneous action potentials in excitable cells. As a consequence of the increased Na+ permeability, the plasma membrane is unable to maintain the internal environment of cells and volume control. This results in alteration of bioenergetic mechanisms, cell and mitochondrial swelling and bleb formation on cell surfaces.
- 60. In myocardium, when ciguatoxin affects voltage-dependent Na+ channels, causing Na+ to move intracellularly, normal cellular mechanisms begin to extrude sodium and take up calcium. Calcium is the intracellular trigger for muscle contraction. Although much of the increased calcium is buffered by the sarcoplasmic reticulum, it is likely that locally increased calcium concentrations increase the force of cardiac muscle contraction.
- 61. Pharmacokinetics Ciguatoxins are fat soluble and absorption from the gut is rapid and substantial, although an early onset of vomiting and diarrhoea may exist in expelling some of the toxins before they are absorbed. Since cleaning ciguateric fish can cause tingling of the hands and eating them can cause altered sensation in the oral cavity and dysphagia, it would appear that ciguateratoxins can penetrate the skin and mucous membranes.
- 62. Symptoms
- 63. CIGUATERA (3009 Cases) Frequency of Signs and Symptoms Sign or Symptom Percentage Paresthesias (extremities) 89.2 Paresthesias (circumoral) 89.1 Temperature reversal 87.6+ Arthalgia 87.5 Myalgia 81.5 Diarrhea 70.6 Headache 59.2 Chills 59 Abdominal Pain 46.5 Pruritus 44.9 Nausea 42.9 Vertigo 42.3 Ataxia 37.7
- 64. Many species and many families of reef fishes are involved in ciguatera globally. These include the herbivorous Acanthuridae and corallivorous Scaridae (parrot fish), which are considered key vectors in the transfer of ciguatoxins to carnivorous fish. Species of carnivorous fish cause ciguatera, includes Muraenidae (moray eels) and Lutjanidae (snappers such as red bass) which are notorious in the Pacific, Serranidae (groupers) including coral trout from the Great Barrier Reef, Epinephelidae, Lethrinidae, Scombridae (mackerel), Carrangidae (jacks) and Sphyraenidae (barracudas). The latter two families are a particular problem in the Caribbean.
- 65. Sources of ciguatera toxin
- 66. Jacks
- 67. Surgeon Fish
- 68. Grouper
- 69. Snappers
- 70. Wrasses
- 71. Muscle Tissue 0.2 Brain 0.6 Liver 1.5 Gonads 1.4 CTX Concentration (ng/g) in ten samples of Cephalopholis argus Deposition of Toxin
- 72. Treatment There is no specific antidote. The most important is Mannitol therapy for two primary goals: reduction of acute symptoms (especially neurologic) and possible prevention of chronic neurologic symptoms. It is a diuretic may increase the urine output. I.V. Mannitol administered at 0.5 to 1.0 g/kg body weight over a 30-45 minute period. It is suggested that to be given within 48-72 hours of ingestion of toxic fish, although beneficial effects have been observed even up to several weeks after intoxication.
- 73. Prevention Prevention requires educating people to the risk of eating coral reef fish such as barracuda, grouper, snapper, amberjack, and surgeonfish that are caught in areas known to be contaminated, such as the waters off Pacific, south Florida and the Caribbean. Because the toxins are colorless, odorless, and tasteless and are not destroyed by cooking, they are difficult to detect.