Transcript Conus Magus revised

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.)
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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
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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/