Prialt

By: Nick Giron

Angela Shaw Victor SalayandiaAgustin 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 voltage-gated 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-92576-Prialt+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/