"What will limit the use of Prialt, and other potential drugs derived from tree frogs and other creatures with natural venoms, is that it cannot be taken in pill form. It has to be delivered directly into the fluid that surrounds the spinal cord, which carries it to the brain without affecting other organs. Because it is so potent, tiny amounts of the drug could be dangerous to the heart and possibly other organs.

"This drug is for patients in chronic and severe pain who are not getting substantial and meaningful relief with oral opiates, or are having unacceptable side effects with them," said Robert Meyer, director of the FDA's Office of Drug Evaluation II. "At this point we don't see this class of drug expanding to general use."

bullet Sea snail venom paves way for potent new painkiller
bullet New Drug Is Approved To Treat Chronic Pain       This is an archive from 2004 but very informative. 
bullet Cone snail venom Attacking Pain
bulletJournal Neurology  Back Pain Brain  
bullet Venomous snails aid medical science

For more information on this cone snail, Google "Cone snail"




Sea snail venom paves way for potent new painkiller

From our ANI Correspondent

Washington, July 3 2007 : Boffins have used the magical properties of the deadly sea snail venom to create a drug that can kill pain in humans.

The snail uses venom to paralyze passing fish, but scientists found that chemicals in the poison could also obstruct pain signals in the human brain.

About 25 years ago, scientists at the University of Utah, in the US, were able to detach a molecule from the venom that also had painkilling properties in humans. ow researchers have produced a synthetic version of the compound with parallel pain-killing effects, and it forms the foundation of the new drug, Prialt.

Prialt is designed to ease persistent pains in people who suffer from various types of cancer and other very serious diseases. It is a very powerful drug, as it was created to lessen chronic pains in individuals that no longer responded to morphine therapy.

The treatment is expected to block the calcium channels of the nerves that transmit pain signals in the body. It targets a particular subgroup known as N-type calcium channels , which play a role in some kinds of pain.

Prialt is 1,000 times more potent than morphine but, unlike that drug, is not addictive.

The treatment based on synthetic venom will not be administered orally, but directly into the fluid around the spinal cord through a little push. However, it may have side effects such as nausea, dizziness or blurred vision due to the fact that it is a very strong drug.

Prialt, or ziconotide, is the result of more than 20 years' research by a scientist born in the Philippines, Baldomera Olivera, who is a professor at the University of Utah.

Copyright Dailyindia.com/ANI
Sea snail venom paves way for potent new painkiller


New Drug Is Approved To Treat Chronic Pain

Synthetic Snail Venom Is Considered a Last Resort

By Marc Kaufman
Washington Post Staff Writer
Wednesday, December 29, 2004; Page A03

A synthetic form of a sea-snail venom was approved yesterday by the Food and Drug Administration as a novel approach to treating severe, chronic pain.

The drug, called Prialt, was approved for hard-to-treat pain associated with cancer, AIDS and neuropathies. Based on a compound found in the poison of the South Pacific cone snail, it controls pain in a new way -- by blocking the calcium channels in nerve cells that transmit pain signals -- and may have broad implications for the future of pain management.

Because it is as much as 1,000 times more powerful than morphine, it is considered a last resort for long-suffering patients, rather than a first-line pain medication. But the manufacturer, Elan Corp. of Ireland, hopes that will change.

Researchers believe the snail venom, and products like it, can become an alternative to opioid drugs such as OxyContin and morphine. Ultimately, it may also provide an alternative for severely affected patients dependent on medications such as Celebrex, Aleve and now-withdrawn Vioxx -- which have come under fire because of indications that they may cause heart problems.

"This drug is very exciting because it's a very potent analgesic but isn't a narcotic," said Richard L. Rauck of Wake Forest University medical center and the Carolinas Pain Institute. Rauck, an investigator for one of the Elan-funded clinical trials that led to yesterday's FDA approval, said he found the drug to be "effective in almost all types of chronic pain it's been studied in."

What will limit the use of Prialt, and other potential drugs derived from tree frogs and other creatures with natural venoms, is that it cannot be taken in pill form. It has to be delivered directly into the fluid that surrounds the spinal cord, which carries it to the brain without affecting other organs. Because it is so potent, tiny amounts of the drug could be dangerous to the heart and possibly other organs.

"This drug is for patients in chronic and severe pain who are not getting substantial and meaningful relief with oral opiates, or are having unacceptable side effects with them," said Robert Meyer, director of the FDA's Office of Drug Evaluation II. "At this point we don't see this class of drug expanding to general use."

Nonetheless, Elan's president for global research and development, Lars Ekman, said as many as 100,000 people in the United States might be helped by the drug.

He said about 50,000 patients have implanted or external devices that pump morphine directly into the spinal column, and many of them may want to try Prialt because opioids can gradually lose their effectiveness. In addition, he said, many patients in severe pain who take pain pills may want to try the spinal cord route if the drug involved is not an opioid.

"There are thousands of people out there who have pain like a bad toothache all day and night, week after week," Ekman said. "Many of these people have tried morphine and it either didn't work or made them unable to function."

Elan, a relatively small company, has won FDA approval for two novel drugs in two months. In November, the FDA approved its multiple sclerosis drug Tysabri.

Prialt is a synthetic form of the venom that the Conus magus cone snail, which lives in tropical saltwater shallows, uses to stun passing prey.

Efforts to turn the substance into a pill faltered because of its potency, but researchers found that small drips of the drug into the spinal cord fluid went safely to the brain.

In 2000, the FDA required an additional clinical trial to better determine the best dosages, and Ekman said patients will initially receive smaller amounts as a result.

Chris McNeil, a California small-business man who has taken the drug for almost a year as part of a clinical trial, said it has changed his life. He said sharp, unexplained pain in his legs -- and the fog that enveloped him when he took opioid painkillers -- had kept him virtually homebound for six years.

"Once I started taking the new drug, I could walk again and laugh again and start having a life," said McNeil, 48. "I lift heavy boxes in my shop and even play a little soft tennis."

Prialt, which is expected to reach the market next month, will come with a "black box" warning regarding its risks, which include hallucinations and even psychosis in vulnerable people. McNeil said he experienced hallucinations in the first two weeks he was taking the drug, but they stopped.

Despite the limitations of Prialt, Mary Pat Aardrup, executive director of the National Pain Foundation, a nonprofit education group, called yesterday a "red-letter day" for pain patients. "To have another pain drug in an entirely new class is very exciting and very hopeful."


2004 The Washington Post Company
Source: New Drug Is Approved To Treat Chronic Pain


From The Times
July 10, 2006


The deadly sea snail venom that will take away your pain

By Nigel Hawkes, Health Editor
A NEW painkiller based on the venom of a sea snail will be available in Britain from today.

Prialt, or ziconotide, is the result of more than 20 years? research by a scientist born in the Philippines, Baldomera Olivera, who is a professor at the University of Utah.

It is 1,000 times more potent than morphine but, unlike that drug, is not addictive. It is aimed at people suffering from severe, chronic pain who would normally require morphine.

Given by injection into the fluid around the spine, it is the first non-opioid painkiller using this method of administration to be approved in Europe.

Chronic pain is a common problem, surveys indicating that it is suffered by as many as one in seven people. Back pain and arthritis are the commonest causes, with headache and injury also affecting many people.

Painkillers given by mouth, such as paracetamol or ibuprofen, are the first resort. But those whose pain persists may be treated with painkillers injected into the spinal fluid, using a pump worn by the patient.

Prialt, made by Eisai, is designed for these extreme cases. It is a synthetic version of the venom used by Conus magus, the Magician?s Cone Snail, to hunt prey.

The two-inch snail, native to coral reefs in the Pacific, hunts by shooting out a thin wormlike tube into fish swimming by. The venom is injected into the fish, which are paralysed and can be swallowed whole. Professor Olivera used to collect the shells of the snails as a boy, then went on to study them.

The venom was discovered by a teenager, Michael McIntosh, who started to help with the research soon after leaving school. Now, 25 years later, he is a research psychiatrist at the University of Utah and still works with Professor Olivera.

Together they analysed the venom and identified one peptide (a short chain of amino acids) that stopped nerve cells sending signals to the brain. It acts by blocking the calcium channels on the nerves that transmit pain signals. Once the channels are blocked, calcium cannot enter the cells, and pain signals are blocked from travelling between nerve cells.

Prialt was licensed in Europe by Elan, which sold it to Eisai, a Japanese pharmaceutical company best known in Britain for the Alzheimer drug Aricept. There may be more to come from the cone snail, Professor Olivera believes. There are 500 different types, and each produces as many as 100 toxins in its venom. He hopes that they will provide compounds to treat a wide range of conditions, from Parkinson?s disease to depression.

Source The deadly sea snail venom that will take away your pain




bulletCone snail venom Attacking Pain

For millions of chronic pain sufferers, big relief could come from a small sea snail. **This ScienCentral News video has more. ** 

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bulletAttacking Aches and Pains

It strikes without warning, harpooning its prey and injecting a toxic cocktail that paralyzes its victim. Despite its small size—only a few inches in length—predatory cone snails wield a venom weapon deadly enough to kill a human. Together, the chemicals in a cone snail's venom do serious damage, but each one on its own can actually do some good.

bulletCone snail venom is just one example of toxic tinctures researchers are turning into therapeutic treatments for chronic pain. One such drug, called Prialt, is poised for approval by the US Food and Drug Administration this fall.

Roughly 50 million people in the United States suffer from pain lasting more than three to six months. "There's been a big venom movement in the chronic pain field," says Michel Dubois, director of NYU Medical Center's Pain Program. "That's some kind of reflection on the fact that our patients are quite desperate for treatment." According to the National Institute of Neurological Disorders and Stroke, chronic pain is usually caused by nerve signals misfiring in the central nervous system that continuously send pain messages to the brain.

Many chronic patients have tried a host of treatments, ranging from physical therapy to electrostimulation to heavy-duty drugs like morphine. "Morphine is the gold stallion for any analgesics," says Dubois. "It is very effective on pain and any new drug will likely be tested against morphine." The problem with morphine—in addition to side effects like constipation and nausea, for example—is its addictive nature. People build up a tolerance to the drug and need more and more of it to kill any pain. Venom-based medications can have their own side effects like dizziness, but patients don't build up a tolerance to the drug.

"Prialt is as effective the first day as the thirtieth day," says Toto Olivera, who pioneered research on cone snail venom some 20 years ago. A 19-year-old undergraduate first isolated the chemical, called ziconotide, on which this drug is based, back in the early 1980s. "We were just trying to figure out why cone snails were able to use their venom to paralyze their prey and why certain snail killed people. So it was really a basic science investigation and we never dreamt when we started that it would lead to a therapeutic application."

bulletNo Pain on the Brain

"We feel pain because pain fibers carry an electrical signal to the spinal cord, and then that signal is transmitted across a gap, a synapse, to a nerve cell that then sends a signal to the brain," explains Olivera. "In order to communicate across that gap, the key thing is the electrical signal has to be converted into a chemical signal. What is important is that calcium enters the end of the pain fiber to allow the chemical signal to be released."

Administered in the right dose, ziconotide blocks the calcium gateways, so the chemical pain signal never crosses the synapse. "It blocks the transmission of the chemical across the gap, the synapse," continues Olivera. "As a result, you don't perceive any pain because your brain isn't receiving the signal."

Prialt was tested in human clinical trials over the past few years. One volunteer, Brian Braun, started using the drug in 1999, after suffering 10 years of excruciating pain that left him in a wheelchair. "I couldn't walk," says Braun. "The pain just got overwhelming." Braun's chronic pain resulted as a delayed complication to back surgery he had in 1974. "The pain began about 1989," he says. "They treated me with heavy steroids, all types of drugs, and that didn't do any good. Then I had an implanted stimulator for three years, then they started me on morphine for a good many years, but morphine just wasn't doing it." On Prialt, Braun slowly regained mobility, and no longer needs his wheelchair. He says he cooks and cleans and even cuts the grass.

Not everyone has enjoyed Braun's success with ziconotide, but his doctor, Michel Dubois, is happy to see such a good response. "If this drug has changed his life," says Dubois, "this is a major step forward in the modalities available to our patients. This drug is not for everyone, but it is definitely useful for a few selected patients who are desperately in need of help."

Meanwhile, Toto Olivera will continue to sift through the more than 50,000 individual chemicals found in the venom of the 500 different species of cone snails. His recent review of cone snail venoms was published in the January 2004 issue of Physiological Reviews, and the study was funded by the National Institute of General Medical Sciences and the Biofuture Prize for the German Ministry of Education and Research.

bulletSource http://www.sciencentral.com/articles/view.php3?language=english&type=&article_id=218392338


~~Journal Neurology  Back Pain Brain  

Brain Pain (07.22.04) - The pain of severe burns may be the most excruciating pain a person can experience. But the August issue of Scientific American describes how the ultimate in pain may be eased by the ultimate in high-tech distractions. (After visiting Brain Pain  and other hyperlinks in this article, please use your back button to return to CHN )

Brain Mechanisms of Pain 



bullet Journal Neurology  Back Pain Brain

That pain in your back could be more than uncomfortable. As this ScienCentral News video reports, for the first time researchers have found evidence that it could be shrinking your brain.

Achy Breaky Back

Here's what Mary Jo O'Kelley avoids thanks to a warehouse accident that left her with chronic back pain: bending, squatting, exercising and lifting anything of almost any kind. But that might not be all the damage her injury caused. For the first time, researchers have found evidence that chronic back pain may be at least partially responsible for shrinking the brain.

Neuroscientist Vania Apkarian of Northwestern University used magnetic resonance imaging (MRI) scans to collect 26 brain images from people who reported suffering back pain that lasted for a year or more and 26 images from pain-free subjects matched for age and sex. After looking at average brain size across each group, he compared the pain subjects with subjects free of pain and found significant differences in brain density in gray matter­the tissue in the brain that houses neurons, or nerve cells, that communicate with each other to help us process information. With age, we naturally lose some gray matter but Apkarian notes a difference when pain comes into play.

"The amount of gray matter decrease per year that we see for normal aging is about 2.5 ccs in volume; that's about a teaspoon," he explains. "The chronic back pain condition has an additional half a teaspoon, about 1.5 cc of additional of gray matter brain atrophy on top of the normal aging effect."

Loss of gray matter that results from chronic pain­he's found it's generally in the pre-frontal cortex and the thalamus­can bring cognition problems, as Apkarian explains: "Neurons are probably not functioning as well as they should be functioning, all of which will decrease that ability of that area of the brain to process the kinds of things that are involved in processing in everyday behavior."

With the American Chiropractic Association reporting 50 percent of all working Americans with back symptoms each year, a third over age 18 reporting a back problem in the past five years severe enough to require professional help and as many as 80 percent of Americans expected to experience back pain during their lives at a cost of $50 billion yearly, neutralizing that pain in our backs could change millions of lives.

Pain specialist Carmen Green of the University of Michigan treats O'Kelley and suspects Apkarian's research might prove something she says she's long believed: "It really supports the fact that pain is not a symptom, it is a disease because now you have MRI evidence that pain is in the brain."

O'Kelley tells Green with some bitterness that getting a diagnosis was difficult and not until she went to "doctor after doctor after doctor" did someone finally find that she had bulging discs and hip problems probably caused by her accident. But even with diagnosis she can no longer do the work she once enjoyed.

Green's own research on pain investigates how it might manifest differently based on age and race. She reported in the journal Pain Medicine that of the 5,834 African-American and Caucasian adult pain patients who filled out questionnaires about their symptoms, those over age 50 reported being better able to cope with pain than younger people. She says she'd like to see Apkarian's next study include minority pain patients to gauge whether there are brain density differences in pain patients based on race. "That is important in the context of the fact [that studies] are showing that African-Americans have more disability, have increased problems," she says. "And then you talk about access to pain care, inadequate treatment."

Whatever fresh evidence Apkarian's study ultimately provides could change the way chronic back pain is treated. Woefully lacking are most drug therapies used to treat such pain, he says, adding that chronic back pain sufferers have an additional burden in that they don't generally respond to painkillers and even when they do, they can't stay on the strongest, opiate-based pain relievers because of their addictive properties. Instead, Apkarian believes he'll be able to use his research findings to develop "drugs that will… either reverse or control this shrinkage and inhibit the emotional component of the pain perception itself."

Should that day come, Mary Jo O'Kelley may finally be able to live with her achy back without it compromising her lifestyle.

This research appeared in the November 23, 2004 issue of the Journal of Neuroscience and was funded by the National Institutes of Health.

Source http://www.sciencentral.com/articles/view.php3?language=english&type=&article_id=218392338

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bullet Venomous snails aid medical science


By Louise Yeoman
BBC producer

Dr Jon-Paul Bingham, of Clarkson University, has an unusual note on his file at the local hospital in New York State.

If he is admitted unconscious, they are to check to see whether he has been harpooned by a deadly snail.

Every week, he milks lethal marine molluscs called cone shells for their venom, using a condom, barbecue tongs and a fish. If anything goes wrong, though, it is no laughing matter.

Cone shells look like a seaside souvenir from the tropics. You find them in places like the Great Barrier Reef or Hawaii. The shells themselves are sometimes two to three inches long, often with striking patterns which make them collectable. 


Photographs on original web page

  These snails will produce millions of changes in their toxins that they use to kill their prey
Dr Jon-Paul Bingham, Clarkson University
The snails inside are not all poisonous but the fish-eating ones are right up there with snakes and scorpions in the danger stakes. If you get stung by one of them, there will be enough venom in your system to kill up to 15 people; but it is not entirely hopeless.

"Get on a life support system. There have been cases where people have survived," Jon-Paul says helpfully.

Biological 'kit bag'

It is quite an overkill for a little marine animal whose usual dinner is no bigger than a goldfish, but what grips scientists is not the potency of its venom but the complexity.


"These snails will produce millions of changes in their toxins that they use to kill their prey," Jon-Paul tells the BBC Radio 4 programme Danger! Venomous Snails.

"If they don't make these changes, they can be at an evolutionary disadvantage, so the snails have become good pharmaceutical chemists. It is these compounds that we are trying to harness to use as specific medicines."

One of these compounds is already at work. Just over a year ago, the US Federal Drug Agency approved the first of a new type of painkiller - Prialt® - which can work in cases where ordinary drugs fail. The drug has also been approved for use in Europe.

It blocks a particular channel in nerves which communicates pain signals to the brain. The original toxin behind the drug was discovered in the lab of Professor Baldomero Olivera, at the University of Utah, and he's excited about the future.


"There's an explosion of data about neuroscience and what can go wrong," he says.

"We'd like to understand and affect many different molecules in the normal brain. Using very specific toxins that wipe out the function of just one thing in the nervous system, lets us do that.

"We see applications in epilepsy, stroke and cardiovascular conditions. Some are in development and one has reached clinical trials."

Just the beginning

Another way of stopping strokes and heart attacks is to cut down on smoking. Snail toxins might help here, too.

Professor Bruce Livett, of the University of Melbourne, Australia, is looking at how they affect the nicotinic receptor - the very thing that gets a hit when you puff on a cigarette.

A drug to inhibit that might help you stop smoking, but this research is already tackling severe pain in diabetic patients.


There could even be applications in Alzheimer's or Parkinson's disease, says Bruce, but one thing bothers him: we should take time to get to know the snail, not just its venom.

"There's a whole world of invertebrate biology out there far more advanced than our own mammalian biology," he says.

That is where Jon-Paul Bingham's work has been important. By developing his way of milking the snails, Jon-Paul keeps the animals alive in his lab and learns more about them.

He does not need to dissect the "goose that lays the golden egg" to study its venom. He analyses their venoms and then synthesises the compounds he finds for further work.

His hope is to set up a library of venoms to help other researchers get access to this field. He sees potential for snail toxins to be used in everything from agriculture to anti-fouling paints against marine worms.

Cone shells research appears to be advancing much more quickly than your average snail.

Danger! Venomous Snails was broadcast on BBC Radio 4 on Monday 27 March. It can still be heard at the Listen again page.


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