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Prialt By: Nick Giron Angela Shaw Victor Salayandia Agustin Salcido Why Prialt • Interest in naturally occurring drugs • Huge potential for other drugs to come from the genus, conus • Very effective drug non-opioid pain reliever, that is none addictive. Introduction • Why research Conus magus and ω-conotoxin peptide? – Fascinating creature that produces therapeutically beneficial pain-relieving toxin Intro (cont.) Genus • Genus: Conus – Large genus comprising over 600 species – Reside in warm, tropical marine environments throughout the world • Common in small pacific islands especially in the Philippines • Habitat is coral reefs – Predatory marine gastropod mollusks (sea snails) • Its predators are crabs and other crustaceans • cone snail hunting Intro (cont.) Genus • Genus: Conus (cont.) – Hunt and consume small fish, marine worms, mollusks, and other cone snails • Use a hook-and-line method • Engulfs prey after it has been paralyzed by its venom. – Shell Pattern • Extremely variable and will look different depending on which island they are found. – All cone snails are venomous • Move at a "snail's pace," half a millimeter per second, evolved the ability to produce and deliver paralytic venom to capture prey • Siphon: sensory organ used to detect prey • Venom delivery: Hypodermic-like radula made of chitin and coated in venom at the end of a proboscis that can be extended from the mouth • No anti-venom available at this time. • There are 15 reported death contributed to cone snail envenomation’s. stings most commonly occur when the cone snail are picked up. What is a toxin • A toxin is a substance produced by an organism with adverse affects on another organism – Can be deffensive – Can be offensive • A Small molecule, peptide, or protein that can cause disease Conotoxins • Characteristics: disulfide rich peptides 10-30 amino acids in length with high specificity to ion channel receptors and transporters in nervous system http://grimwade.biochem.unimelb.edu.au/cone/3d-ctx.html Conotoxin (cont.) http://physrev.physiology.org/content/84/1/41/F2.expansion.html Conotoxicity signs and symptoms • Non-fatal cases include: – Burning pain – Swollen arm and pain – Local numbness spreading rapidly to involve the entire body with some cardiac and respiratory distress – Progressive weakness, loss of coordination, drooping eyelids, shallow breathing – Headache, nausea, stomach cramps, shortness of breath Conotoxicity signs and symptoms (cont.) • Fatal Cases include: – These symptoms occur almost immediately upon injection • Numbness without pain (some species produce severe pain and spreading numbness) • Lips become stiff • Blurred vision • Paralysis • Coma • Death occurs as the result of respiratory and/or cardiovascular collapse. (http://www.aristatek.com/Newsletter/MAY08/TechSpeak.pdf) Pharmacological families Family α (alpha) Nicotinic acetylcholine receptors (nAChR) γ (gamma) Neuronal pacemaker cation currents (inward cation current) δ (delta) Voltage-gated Na channels (agonist, delay inactivation) ε (epsilon) Presynaptic Ca channels or G protein-coupled presynaptic receptors ι (iota) Voltage-gated Na channels (agonist, no delayed inactivation) κ (kappa) Voltage-gated K channels (blocker) μ (mu) Voltage-gated Na channels (antagonist, blocker) ρ (rho) Alpha1-adrenoceptors (GPCR) σ (sigma) Serotonin-gated ion channels (GPCR) χ (chi) Neuronal noradrenaline transporter ω (omega) Voltage-gated Ca channels (blocker) ω-conotoxin peptide from Conus magus • Discovered in late 1960s by Baldomero Olivera during his postdoc work at Stanford University • Peptide that consist of 10 to 30 amino acids Mechanism • blocks N-type voltagegated calcium channels which are involved in analgesia (pain sensitivity) Administration • administration through oral and intravenous routes often have severe adverse effects • Intrathecal pump system is the safest way for delivery – This carries additional risk such as infection. • Used in chronic pain suffering patients Uses for Prialt • Bioterrorism • Chronic pain – Failed back surgery – Multiple sclerosis – Neuropathy – Cancer – AIDS Side effects • “Abnormal walking; back pain; bad taste in mouth; burning, aching, tingling sensation on the skin; constipation; diarrhea; dizziness; dry skin; feeling of a whirling motion; incoordination; increased cough; loss of appetite; muscle tension; pain; pain at insertion site; rapid, jerky eye movements; ringing in the ears; runny nose; skin irritation; sleepiness; sore throat; stomach pain; sweating; vision changes.” (http://www.drugs.com/sfx/prialt-side-effects.html) Side effects (cont.) • • • • • • • 33% reported confusion 22% reported memory impairment 14% reported Speech disorder 12% reported aphasia 8% reported abnormal thinking 1% reported amnesia Cognitive impairment may appear after several weeks (toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+107452-89-1) Severe side effects • If the following reaction occur, doctors advise immediate medical help: – “ Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); abnormal thinking; anxiety; change in mental state (eg, lack of energy, confusion, disorientation); change in mood or perception (eg, hallucinations; unusual sensations in the mouth; paranoia; hostility; delirium; manic reactions; psychosis); chest pain; dark urine; depression; fainting; fever; flu-like symptoms; headache; inability to empty the bladder; memory problems or memory loss; muscle cramps; muscle or joint pain; nausea; nervousness; pounding in the chest; seizures; speech problems; stiff neck; stupor; suicidal thoughts or behaviors; unresponsiveness; urination problems; vomiting; weakness.” (http://www.drugs.com/sfx/prialt-side-effects.html) Metabolism • Following intrathecal administration, Prialt is rapidly distributed and metabolized in the spinal cerebrospinal fluid • Followed by rapid mass transport from the CSF to the plasma Drug-drug interaction • Can interact with: – anti-seizure medication – Antihistamine – Sleep or anxiety medication – Narcotic pain relievers – Muscle relaxants – Psychiatric Further research on Conus • With over 600 species of conus snail, there is huge promise for many other new medications. – ACV1 is one example and is entering phase 2 testing • Potentially 10000 times more potent than morphine. • Potentially can repair injured nerves which is unique for an analgesic Literature cited • • • • • • • • http://www.webmd.com/drugs/drug-92576Prialt+IT.aspx?drugid=92576&drugname=Prialt+IT&source=1 http://grimwade.biochem.unimelb.edu.au/cone/3d-ctx.htm http://physrev.physiology.org/content/84/1/41/F2.expansion.html http://www.aristatek.com/Newsletter/MAY08/TechSpeak.pdf http://www.drugs.com/sfx/prialt-side-effects.html toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+107452-89-1 http://www.drugs.com/sfx/prialt-side-effects.html grimwade.biochem.unimelb.edu.au/cone/