The hormone exendin-4 occurs naturally in the saliva of the Gila monster, a large venomous lizard native to the southwestern United States and northwestern Mexico. (Credit: iStockphoto/Rusty Dodson) 

Drug Derived From Gila Monster Saliva Helps Diabetics Control Glucose, Lose Weight


Exenatide, a drug that is a synthetic form of a substance found in Gila monster saliva, led to healthy sustained glucose levels and progressive weight loss among people with type 2 diabetes who took part in a three-year study.

“The weight loss factor is important because being overweight and weight gain is an almost universal problem for people with diabetes,” said John Buse, M.D., Ph.D., lead researcher in the study and chief of endocrinology in the University of North Carolina at Chapel Hill School of Medicine.

“In that context, it is exciting that patients that continue exenatide injections continue to lose a bit of weight while maintaining blood sugar control, even in their third year of therapy,” Buse said.

“While this weight loss is encouraging, it’s important for people to understand that exenatide is not intended as a weight-loss drug and it is not approved for that purpose,” Buse said. “Only people with type 2 diabetes should take exenatide.”

Exenatide, marketed as Byetta, was approved by the Food and Drug Administration in April 2005 to treat type 2 diabetes in patients who were not able to get their high blood sugar under control in a combination with one or more of three other medications, metformin or sulfonylurea thiazolidinedione.

Weight loss was not the only significant finding. After three years of including exenatide in the drug regimen, 46 percent of participants achieved sustained glucose – or blood-sugar – levels of 7 percent, and 30 percent had levels of 6.5 percent. The ADA considers levels of 7 percent or lower to be healthy.

Exenatide, which is manufactured by Amylin Pharmaceuticals Inc. in collaboration with Eli Lilly and Company, comes in a prefilled pen that type 2 diabetics use to give themselves twice-daily injections within an hour before their morning and evening meals. It is typically given in addition to sulfonylurea, or with a combination of metformin and sulfonylurea.

Exenatide is a synthetic form of a hormone called exendin-4 that occurs naturally in the saliva of the Gila monster, a large venomous lizard native to the southwestern United States and northwestern Mexico. The lizard hormone is about 50 percent identical to a similar hormone in the human digestive tract, called glucagon-like peptide-1 analog, or GLP-1, that increases the production of insulin when blood sugar levels are high. Insulin helps move sugar from the blood into other body tissues where it is used for energy. The lizard hormone remains effective much longer than the human hormone, and thus its synthetic form helps diabetics keep their blood sugar levels from getting too high. Exenatide also slows the emptying of the stomach and causes a decrease in appetite, which is how it leads to weight loss.

The results being reported now come from following patients who took exenatide for three years. In the study, Buse and colleagues analyzed data from 217 diabetes patients. After three years of treatment, most patients showed sustained reductions in blood sugar levels, in blood biomarkers that indicate liver injury and sustained, progressive weight loss averaging 11 pounds.

The study’s co-authors are Leigh MacConell, Ph.D., Anthony H. Stonehouse, Ph.D., Xuesong Guan, James K. Malone, M.D., Ted E. Okerson, M.D., David G. Maggs, M.D. and Dennis D. Kim, M.D. All of the co-authors work for Amylin Pharmaceuticals except for Malone, who works for Eli Lilly and Company. Amylin has a global agreement with Eli Lilly and Company to collaborate on the development and commercialization of exenatide. Funding for this study was provided by Amylin and Eli Lilly and Company.

Source: University of North Carolina at Chapel Hill.

Read more about the scientist who discovered that the saliva of the Gila Monster, contains a hormone that treats diabetes better then any other medicine………Dr. John Eng………………and the story behind the patent…………..

LIZARD LIPS Amylin has created a synthetic version of a peptide hormone, exendin-4, first

 found in the saliva of the Gila monster.

A gila monster at Spur Cross Ranch Conservation Area.              Suzanne Starr/The Arizona Republic

Did you hear the one about the researcher who went to Arizona and discovered Byetta? There are so many stories about how exenatide was discovered and made it to the market that I thought you would like the real story. I have had a couple of opportunities to talk with Dr. John Eng, the discoverer of exenatide, and have the real story.

“This (discovery) has taken on a life of its own,” Eng said.

Lizard spit makes Dr. John Eng feel like a proud parent.

For more than 25 years Eng has unceremoniously reported to work at the Bronx Veterans Administration Medical Center in New York, where he treated thousands of people for diabetes and other hormone related diseases.

But now he shows up as a multimillionaire – thanks to his discovery that the poisonous venom of a Gila monster lizard had the potential to treat diabetes.

The endangered lizard’s poison stimulates the body’s production of insulin, a hormone that helps cells process blood sugar. It can prevent blood sugar levels from dipping perilously low, or stop it from spiking and causing damage to the liver, kidneys, eyes and limbs.

Eleven years ago, Eng licensed his discovery to Amylin Pharmaceuticals of San Diego so the tiny biotechnology company could develop it into a drug for people with Type 2 diabetes.

Diabetes, the inability of the body to produce proper amounts of insulin, is the fifth deadliest disease in the United States. And the number of people with type 2, or adult on-set diabetes, is growing at alarming speeds.

Exenatide,  which was approved in the US in 2005 and is made to help diabetics avoid or postpone the use of insulin injection therapies when other treatments have failed. It is , according to analysts, a billion dollar a year drug.

“This (discovery) has taken on a life of its own – it’s as though it has become my fifth child,” Eng said recently. “The FDA review is a lot like one of the children taking a final exam that will determine whether they graduate from college and go off into the world to do good, and maybe help a lot of people.”

The tale of Eng’s discovering the magic that lizard venom can stimulate inside the gut is the essence of basic research that feeds a burgeoning biotechnology industry.

Besides treating patients as an endocrinologist Eng is a scientific researcher. As a young research fellow just starting out at the VA hospital, Eng worked in the laboratory of Dr. Rosalyn Yalow, a 1978 Nobel Prize winner for inventing a method to find novel hormones in different animal species.

Amylin Chairman Joseph Cook described Eng as “someone who is unusually capable to see things, particularly patterns, that others don’t see when looking at an object, or data set, or event.”

Yalow encouraged the gentle and soft-spoken Eng to work hard and think big. She stoked the Harvard College-educated man’s desire to search for something that might benefit society in a sweeping way.

Eng’s special area of research, like his mentor’s, is peptide hormones. In the late 1980s, he began trying to advance Yalow’s research by creating a new and more sensitive test that would help identify hormones with potentially untested benefits.
He did studies on the hormones of guinea pigs, and later, chinchillas. Then he looked for animal subjects that might be more difficult to analyze.

Eng came across what he thought were very interesting studies done in the early 1980s by gastroenterologists at the National Institutes of Health, who noted that the venom in certain snakes and lizards caused inflammation of the pancreas, where insulin is made. Of particular interest was the hormone in the venom of the Gila monster.

Eng thought he had developed a test that would allow him to further investigate the lizard’s venom. So he ordered some dried and preserved samples out of a catalog from a serpentarium in Utah.

Two compounds in venom

In 1992, Eng’s studies revealed that the venom contained two compounds, including one that had never been documented. He named it exendin-4.

The compound seemed to have properties similar to a human gut hormone, GLP-1, that was being researched around that time by scientists at Massachusetts General Hospital.

GLP-1 was exciting to researchers because it stimulates insulin secretion from the pancreas only when blood sugar is high, Eng said. When blood sugar levels are normal, GLP-1 seems to know not to stimulate insulin, the hormone that helps cells process blood sugar.

“That’s ideal for treating diabetic patients,” Eng said. “As a clinician working with diabetics, the struggle is to try and achieve as much glucose (blood sugar) control as you can to prevent bad complications like kidney failure, retinal disease that can cause blindness and nerve damage that causes loss of sensation in the feet.”

While insulin injections are an effective treatment, timing the dose and amount is a constant balancing act. Too much insulin causes hypoglycemia, a dangerous and sometimes fatal drop in blood sugar.

But GLP-1 seems to help the body keep the blood sugar from dropping too low, Eng said.

The problem with GLP-1, however, is that enzymes in the blood cause it to degrade quickly, Eng said. If it were to be used as a treatment for diabetics, it would have to be injected into the body almost hourly, something most people would not be willing to do.

But studies Eng performed showed that the Gila monster’s hormone, exendin-4, doesn’t degrade for hours, making it a much better candidate for a drug.

Eng took his findings to administrators at the VA, which had funded his years of research.

Typically hospitals, research institutions and universities give these discoveries to a designated office charged with determining the marketability of the science. If it is thought to have commercial value, that office then deals with the expensive and complicated process of patenting the discovery and then trying to find someone willing to pay to use it.

The VA, however, said it wasn’t interested in patenting Eng’s discovery because it did not address a veteran-specific ailment, such as spinal cord damage or some other combat injury, he said.

Path to a patent

Eng was convinced his discovery had the potential to offer relief to diabetics like the ones he treated every day. He also knew it would wither and die if it wasn’t patented.

Pharmaceutical and biotechnology companies typically invest hundreds of millions of dollars and a dozen years or more developing a drug. They are not willing to make such a risky investment without the assurance they get from a patent – knowing they are the only company with access to the crucial science behind the drug
By the time his discovery was two years old, Eng had convinced his wife that they should hire attorneys themselves to patent the drug.

“Psychologically, the process was pretty tough,” Eng recalled. “Every month you get a bill from patent lawyers. And there’s no end to it. It’s a scary venture because there are no guarantees and no landmarks where you can say, ‘OK, I’m halfway across the river.’ ”

At the end of the second year, the patent was approved. But that posed yet another problem: What to do with it.
“I had problems paying the patent bills,” he said. “Developing a drug candidate requires hundreds of millions of dollars. I don’t have the resources, or the expertise, or the access to people who do.”
So Eng went on a road show.

“I called up every pharmaceutical company with a name that was familiar and said I had a patent that could be useful in developing a treatment for diabetes.”

But big pharmaceutical companies move slowly. And they are adverse to risk.

By September 1996, Eng was frustrated with his failure to find a home for exendin-4. He decided to present his findings at the American Diabetes Association annual meeting in San Francisco. He stood with other presenters in a conference hall next to a poster describing his research and hawked it to anyone who would listen.

Andrew Young, the head of physiology at Amylin Pharmaceuticals, read Eng’s poster and was immediately interested. Amylin, which had also been researching peptide hormones with the interest of treating diabetes, had experience with GLP-1. But the company’s researchers were frustrated, like many others, with the rapidity with which it degraded, Young recalled.
“What was notable about Eng’s work with the Gila monster was that it didn’t degrade for four to 24 hours,” Young said.

Lilly shows interest

As he read Eng’s poster, a researcher from the pharmaceutical giant Eli Lilly & Company leaned over Young’s right shoulder to read. Young knew that Lilly, which manufactures synthetic insulin, had been working on its own peptide hormone. It would be a race to secure Eng’s work.

Young immediately called together Amylin’s vice presidents of research, marketing and business development, who were also attending the conference, and explained the significance of Eng’s discovery. Before they left San Francisco, the group had initiated talks with Eng about getting access to his science.

Meanwhile, Young called his Amylin colleagues in San Diego and instructed them to buy as much exendin-4 as they could and begin running animal tests as quickly as possible.

The ability for small biotech companies to move quickly, and their ability to take on risks, can sometimes give them an advantage over the deep pockets of big pharmaceutical companies.

By the time Amylin hosted Eng at a meeting in San Diego four weeks later, its scientists had discovered several other properties about exendin-4 that even Eng had not known, Young said. And the company had filed for patents on its work, which would complement Eng’s intellectual property, he said.

“I think that was part of our leverage with him and part of his attraction to working with Amylin – he knew it would enhance the value of his science,” Amylin chief operating officer Dan Bradbury recalls. “I think he also saw that we are passionate about what we want to do. And that, I think, is why he chose to work with the little company in San Diego, rather than Lilly.”
Eng described his negotiations with both Amylin and Lilly as being worlds apart.

“At Amylin, I walked into a conference room filled with people and they said ‘this is everyone who counts, so start talking,’ ” Eng recalled.

“The Lilly experience was very different. They had a full day of me meeting with people every half hour, in every department. I felt like it was a job interview for my compound.”

In October 1996, Eng licensed his discovery to Amylin.

Three years later, despite research showing promise for the drug, Amylin executives considered cutting the exenatide program to conserve cash and stay alive. Instead, Amylin reduced its staff from 300 to 37.
Exenatide survived, executives said, because it was a pipeline to the future for the company should it survive the hard financial times.

A shot in the arm

Then in 2002, Lilly gave Amylin a $325 million shot in the arm by agreeing to work with the biotech company on exenatide. Lilly beat out several other enthusiastic pharmaceutical companies seeking to a cut on the potential of exenatide.
Eng said the ironic twist comforted him.

“I thought Lilly’s interest, money and expertise increased the chances of the compound becoming a drug and helping diabetics,” Eng said.

Much of the licensing deal between Eng and Amylin is confidential. Eng said Amylin reimbursed him for the money he spent patenting exendin-4. He also received stock options when Amylin was trading around $10.50. Yesterday shares traded at $18.18 at the close of market.

Neither party would say what percentage of the drug’s eventual profits were promised to Eng, but Bradbury said it is commensurate with typical licensing deals made by research institutions. It is not unusual for such deals to pay the research institution around 1 percent.

But the doctor, who is still treating patients and who is also responsible for introducing the electronic records keeping system at the hospital, says he hasn’t stopped to think about the money.

“Really, how many fancy meals can you eat?” he said when asked about the potential windfall. “And I’m pretty sure I’m still going to have to take out the garbage, although my wife might give me a one-day reprieve.
“I have four wonderful children and a wonderful wife and everyone is in good health . . . so I already consider myself rich.”
He said he’s spent more time thinking about lizards and prescriptions than money.

He’s had other firsts, thanks to his drug. He had his first face-to-face encounter with a Gila monster last summer, when a British television production company flew him to the Arizona desert, where they taped a story on his discovery.

“It really is a beautiful lizard,” Eng said. “Like many other animal species it is under pressure from development and other environmental concerns. “The question is, what other animal has something to teach us that can be of future value? And plants, too? We will never know their value if they are gone.”

Princeton Longevity Center, June/July 2010, by David A Fein MD  –  Cardiovascular disease remains the leading cause of death.  According to the American Heart Association, for about 65% of men and 47% of women who are developing coronary artery disease the first symptom of their disease is a heart attack or sudden death.  Most physicians still rely on a Cardiac Stress Test to find evidence of this silent killer before it strikes.  For the patient, a “normal” stress test is usually taken as a reassuring sign that all is well.  Yet the evidence is clear that in the vast majority of those with coronary disease a stress test is very likely to be normal right up until suddent death or a heart attack strikes.

A cardiac stress test can be a very useful tool when performed properly and in the right circumstances.  But, as a screening test for detecting developing plaque in a coronary artery its usefulness is severely limited.  To understand why this is so it is important to understand what a stress test is designed to find versus how heart attacks usually happen.

The major limitation of all cardiac stress tests is that it requires a high level of blockage in one or more coronary arteries to produce an abnormal result.  The underlying principle of a stress test is very simple: increase the heart rate, either with exercise or drugs, and look for evidence that a portion of the left ventricle muscle does not get enough additional blood flow to match the increase in demand as the heart rate rises. This will usually require at least a 65% narrowing in one of the arteries on the surface of the heart before the amount of blood flow through that artery can not increase enough to meet the demand and a portion of the muscle begins to starve.

At that point the treatment options are to re-open the artery with a stent or bypass surgery.  Either way, the treatment is invasive and the patient has already been at very high risk for a heart attack for many years. 

This limitation in stress testing does not depend on what type of stress test is done.  An Exercise Treadmill Test looks for changes in the ECG as the heart rate rises.  A Stress-Echo Test uses ultrasound to image the heart after exercise to detect portions of the left ventricle that do not move as well as expected because of lack of blood flow.  A Nuclear Stress Test uses an injection of Thallium or Technetium radio-isotopes and a gamma-ray camera to image the distribution of blood flow in the heart muscle before and after exercise.  All of these techniques still depend upon there being a limitation of blood flow to a portion of the left ventricle.  This simply does not occur unless there is a high-grade blockage in the artery.

The nuclear stress test is generally considered to be the most accurate type of stress test.   It has a sensitivity of about 81%, meaning that it will miss about 19% of high-grade blockages.  (As noted above, it will miss almost all of the blockages that narrow an artery less than about 65%)  It has a specificity of about 90%, meaning that 10% of the abnormal nuclear stress tests will turn out not have a significant blockage.

A nuclear stress test also involves substantial radiation exposure.  Many physicians remain unaware that a nuclear stress test is likely to expose their patients to more radiation than any other cardiac test, including CT scans.  A nuclear stress test done with thallium will average 25 mSv of radiation.  A test done with technetium-sestamibi will be around 12 mSv.  For comparison, the average person receives about 3 mSv / yr of radiation from natural sources.  The lifetime risk of cancer is about 0.004% per mSv or about 0.1% per thallium scan. While this risk is low for any single nuclear stress test, many patients undergo numerous stress tests over a period of years.  Frequent use of nuclear stress tests has to balance the benefits against the risks of radiation.

A stress test is a useful tool in certain circumstances such as deciding whether an episode of chest pain is from blocked artery.  Some patients, particularly diabetics, may not experience chest pain even when an artery is blocked and a stress test can be helpful in those patients when a blockage is suspected in the absence of symptoms.  However, by the time your stress test turns positive, the opportunity for preventing severe coronary disease is long past.  A stress test is not suitable for early detection and treatment or screening.

The stress test’s poor ability to detect impending problems stems from the fact that most heart attacks happen in arteries that are less than 40% narrowed.  This is too little of a blockage to cause the reduction in maximal coronary blood flow that is required for detection by stress testing.  Research in the 1990’s showed that the primary event in a heart attack is rupture of a plaque in the artery wall.  This causes a blood clot to form at the site where the surface of the plaque has split open.  It is the sudden formation of a clot, not the plaque itself, which stops blood flow through the artery. The typical heart attack occurs in an artery where there is extensive plaque within the wall of the artery but a narrowing of the lumen of only 20%.

More effective tools have been developed to detect the presence of plaque many years before a stress test is likely to be abnormal.  High definition CT scanners can painlessly and non-invasively look directly at the arteries to see the presence of calcium deposits in the artery wall that are associated with developing plaque.  The amount of calcium is an excellent indicator of the severity of heart attack risk.  CT Angiography, a scan that uses an intravenous dye injection and even higher resolution scanning, can measure the degree of narrowing in an artery.  CT Angiography can be very helpful in deciding whether an abnormal stress test result is a false-positive or truly indicates a narrowing that needs further treatment.

A CT coronary calcium scan will generally expose a patient to only 0.5-2.0 mSv and a CT Angiography is typically 1-8 mSv.  These doses are significantly lower than those associated with nuclear stress tests.

It is clear that stress testing detects only late stage coronary artery disease when the opportunity for prevention has already been lost.  While there is a role for stress tests in deciding on the significance of symptoms or assessing the status of a patient with known coronary disease, it is not a screening test for detecting early plaque.  Unfortunately, a normal stress test often causes patients with substantial cardiac risk to forgo treatment and have a false sense of security.  Utilizing newer techniques to directly image the arteries in patients at intermediate or high risk can detect early stage disease, when treatment is easier and more effective, at lower cost and less risk than stress testing.

David A Fein, MD is the Medical Director at Princeton Longevity Center, June/July 2010

What Is a Stroke?

Stroke is a medical emergency and the third leading cause of death in the U.S. It occurs when a blood vessel in the brain bursts or, more commonly, when a blockage develops. Without treatment, cells in the brain quickly begin to die. The result can be serious disability or death. If a loved one is having stroke symptoms, seek emergency medical attention without delay.

Stroke Symptoms

Signs of a stroke may include:

  • Sudden numbness or weakness of the body, especially on one side.
  • Sudden vision changes in one or both eyes.
  • Sudden, severe headache with unknown cause.
  • Sudden problems with dizziness, walking, or balance.
  • Sudden confusion, difficulty speaking or understanding others.

Call 911 immediately if you notice any of these symptoms.

Stroke Test: Talk, Wave, Smile

The F.A.S.T. test helps spot symptoms. It stands for:

Face. Ask for a smile. Does one side droop?

Arms. When raised, does one side drift down?

Speech. Can the person repeat a simple sentence? Does he or she have trouble or slur words?

Time. Time is critical. Call 911 immediately if any symptoms are present.

Stroke: Time = Brain Damage

Every second counts when seeking treatment for a stroke. When deprived of oxygen, brain cells begin dying within minutes. There are clot-busting drugs that can curb brain damage, but they have to be used within three hours of the initial stroke symptoms. Once brain tissue has died, the body parts controlled by that area won’t work properly. This is why stroke is a top cause of long-term disability.

Diagnosing a Stroke

When someone with stroke symptoms arrives in the ER, the first step is to determine which type of stroke is occurring. There are two main types, and they are not treated the same way. A CT scan can help doctors determine whether the symptoms are coming from a blocked blood vessel or a bleeding one. Additional tests may also be used to find the location of a blood clot or bleeding within the brain.

Ischemic Stroke

The most common type of stroke is known as an ischemic stroke. Nearly nine out of 10 strokes fall into this category. The culprit is a blood clot that obstructs a blood vessel inside the brain. The clot may develop on the spot or travel through the blood from elsewhere in the body.

Hemorrhagic Stroke

Hemorrhagic strokes are less common but far more likely to be fatal. They occur when a weakened blood vessel in the brain bursts. The result is bleeding inside the brain that can be difficult to stop.

“Mini-Stroke” (TIA)

A transient ischemic attack, often called a “mini-stroke,” is more like a close call. Blood flow is temporarily impaired to part of the brain, causing symptoms similar to an actual stroke. When the blood flows again, the symptoms disappear. A TIA is a warning sign that a stroke may happen soon. It’s critical to see your doctor if you think you’ve had a TIA. There are therapies to reduce the risk of stroke.

What Causes a Stroke

A common cause of stroke is atherosclerosis — hardening of the arteries. Plaque made of fat, cholesterol, calcium, and other substances builds up in the arteries, leaving less space for blood to flow. A blood clot may lodge in this narrow space and cause an ischemic stroke. Atherosclerosis also makes it easier for a clot to form. Hemorrhagic strokes often result from uncontrolled high blood pressure that causes a weakened artery to burst.

Risk Factors: Chronic Conditions

Certain chronic conditions increase your risk of stroke. These include:

  • High blood pressure
  • High cholesterol
  • Diabetes
  • Obesity

Taking steps to control these conditions may reduce your risk.

Stroke: Emergency Treatment

For an ischemic stroke, emergency treatment focuses on medicine to restore blood flow. A clot-busting medication is highly effective at dissolving clots and minimizing long-term damage, but it must be given within three hours of the onset of symptoms. Hemorrhagic strokes are more difficult to manage. Treatment usually involves attempting to control high blood pressure, bleeding, and brain swelling.

Stroke Prevention: Medications

For people with a high risk of stroke, doctors often recommend medications to lower this risk. Anti-platelet medicines, including aspirin, keep platelets in the blood from sticking together and forming clots. Anti-clotting drugs, such as warfarin, may be needed to help ward off stroke in some patients.  Finally, if you have high blood pressure, your doctor will prescribe medication to lower it.

Stroke Prevention: Surgery

In some cases, a stroke results from a narrowed carotid artery — the blood vessels that travel up each side of the neck to bring blood to the brain. People who have had a mild stroke or TIA due to this problem may benefit from surgery known as carotid endarterectomy. This procedure removes plaque from the lining of the carotid arteries and can prevent additional strokes.

Stroke Prevention: Balloon and Stent

Doctors can also treat a clogged carotid artery without major surgery in some cases. The procedure, called angioplasty, involves temporarily inserting a catheter into the artery and inflating a tiny balloon to widen the area that is narrowed by plaque. A metal tube, called a stent, can be inserted and left in place to keep the artery open.