, March 16, 2010 — Scientists from the Helmholtz Zentrum München and the Technische Universität München (TUM) under the direction of Prof. Michael Sattler have developed a new strategy allowing them to determine the spatial structure of biomolecules in solution. The method is flexible and generally applicable to obtaining structural information for signal forwarding pathways in the cell or in the regulation of gene expression.

The current online issue of the scientific journal Angewandte Chemie reports on their results.

Most larger proteins have complex spatial structures in which various compact subunits are connected by flexible linkers. There is sufficient space between these subunits for solution molecules and reactants. However, in protein crystals used for the classical structure elucidation with X-rays, the subunits are much more tightly packed. A number of questions on the interaction of these subunits — questions relevant to understanding the mechanisms of diseases — can thus not be answered.

The team headed by Prof. Michael Sattler, director of the Institute of Structural Biology at the Helmholtz Zentrum München and head of the Bavarian NMR Center at the TU München, combined a number of existing approaches into an efficient strategy, allowing the scientists to determine the spatial structure of biomolecules in solution. The basis for this technique is biomolecular NMR spectroscopy (nuclear magnetic resonance). “NMR spectroscopy is the only method that allows us to determine atomic details in the spatial structure of biomolecules in solutions,” explaines Prof. Sattler.

Because of their size, when proteins or protein complexes are analyzed using NMR one initially obtains a number of overlapping signals that are hardly suitable for processing. Thanks to a four-step strategy that the scientists integrated into an existing software program for the evaluation of NMR measurements, Michael Sattler and his team can now separate the signals and thus obtain a structure that closely resembles reality.

In the first step of the new procedure the scientists collect existing structural information for the subunits. This information is obtained from X-ray structure analysis, for instance, or from conventional NMR-based structure determinations. The next steps determine how these subunits are spatially oriented with respect to each other. Two different types of information are used for this purpose, both of which are obtained through NMR experiments. So-called dipolar residual couplings provide information on the relative orientation of the individual subunits of the complex.

In the next step the scientists introduce nitroxyl groups (molecules containing an unpaired electron) at various positions in the protein. These set off so-called paramagnetic relaxation enhancements, enabling the scientists to measure larger distances between the subunits and thereby deduce the three-dimensional structure of the protein complex.

The team conducted the procedure on two structural subunits of the human splicing factor U2AF65. Splicing factors are decisive in regulating gene expression and enable the formation of different proteins from a single gene, among other things. The structure of the complex can then be calculated by skillfully combing the various NMR data. The results confirmed that the structure in solution differs significantly from the structure determined using X-ray crystallography.

“Our method is generally applicable to a wide variety of protein complexes, even when they are very large or comprise numerous subunits,” says Prof. Sattler. “This allows us to examine biological regulation mechanisms in which weak and transient interactions play an important role.” Proteins are not rigid structures — they are flexible, allowing them to bind and release reactants. These dynamic effects are essential for the molecular identification of countless biological processes.

As such, the new procedure is particularly useful in research: The characterization of the structure and interaction of proteins and reactants provides information on the ways in which metabolic processes evolve and how diseases develop, and thus provides a scientific basis for the development of new medication.

The research was funded though EU grants (3D Repertoire, Functional and Structural Genomics of Viral RNA) and the Deutsche Forschungsgemeinschaft (DFG). Prof. Michael Sattler is member of the Excellence Cluster Center for Integrated Protein Science Munich (CIPSM).

Story Source:

Adapted from materials provided by Helmholtz Zentrum Muenchen – German Research Centre for Environmental Health.

Journal Reference:

  1. 1.                       Bernd Simon, Tobias Madl, Cameron D. Mackereth, Michael Nilges, Michael Sattler DOI: 10.1002/anie.200906147. An Efficient Protocol for NMR-Spectroscopy-Based Structure Determination of Protein Complexes in Solution. Angewandte Chemie International Edition, Published Online: Feb 10 2010 DOI: 10.1002/anie.200906147

Dupuytren’s contracture is a condition that keeps bent fingers from straightening. To treat it, Xiaflex is injected into the hand to dissolve problematic collagen. A day later, the doctor tries to straighten the finger. Several shots might be needed.


The New York Times, March 16, 2010, by Andrew Pollack  –  As her fingers began curling toward her palm, Karen Mercaldo lost the ability to play the piano, knit and paint. She would poke herself in the eye when washing her face. She could not even wear her wedding ring.

But Ms. Mercaldo, 61, who lives in Huntington Station, N.Y., is now enjoying her hobbies and wearing her ring again after being treated with the drug Xiaflex in a clinical trial.

Xiaflex is the first drug approved as an alternative to surgery to treat Dupuytren’s contracture, in which ropelike cords of collagen form under the skin of the hand, stretching from the palm to the fingers. The cords shorten and keep bent fingers from straightening.

The ring finger is most often affected, followed by the pinkie. The disease is most common in men over 50 of Northern European descent.

Xiaflex, an enzyme that dissolves collagen, is injected directly into the cord. A day later, after the enzyme has had time to work, the doctor tries to straighten the finger. Several injections, spaced over months, might be needed, especially if more than one finger is affected.

In the drug’s main clinical trial, involving 306 patients, 64 percent of joints treated with Xiaflex straightened out, compared with only 7 percent injected with a placebo.

An advisory committee to the Food and Drug Administration recommended unanimously last September that Xiaflex be approved. Ms. Mercaldo and four other participants in the clinical trials were flown to the committee’s meeting by the drug’s manufacturer, Auxilium Pharmaceuticals, to testify.

“Most people never think about the blessing it is to have the use of their hands, but I think about it every single day, and every day I’m thankful,” Ms. Mercaldo told the committee.

In the trials, Xiaflex was not compared with surgery, the standard treatment, so it is not clear which is better. It is also uncertain how long the benefits of Xiaflex will last, since the condition can come back.

“Surgery still works better,” said Dr. Vincent R. Hentz, a professor at Stanford and an adviser to Auxilium. But most patients would prefer to avoid it, he said.

The risks of surgery, in which the hand is sliced open and the collagen cord removed, include infections and damage to nerves and arteries. It can take months to recover, and physical therapy is often required.

Xiaflex has side effects, though. In rare circumstances it can rupture tendons, rendering a finger nearly immobile. The injections often cause temporary pain, bruising, swelling and sometimes allergic reactions. Xiaflex worked on three of William Lanahan’s fingers, but a fourth finger needed surgery. Having experienced both, he vastly preferred the drug.

“I don’t know how you can say there’s any comparison at all,” said Mr. Lanahan, 79, of Los Altos Hills, Calif.

Xiaflex will be priced around $3,250 per injection, and Auxilium estimates the average cost per patient will be about $5,400.

The company says that cost is usually less than that of surgery. But Xiaflex will be more expensive than a procedure that is catching on among some doctors, which is to break apart the cords by poking them repeatedly with a needle through the skin. That procedure, which takes about half an hour, generally costs less than $1,000.

Dr. Prosper Benhaim, chief of hand surgery at the University of California, Los Angeles, said some doctors and patients were “very excited” about Xiaflex. Others, he said, “are a little put off by the cost.”

Thomas L. Wegman is the president of BioSpecifics, which is collecting royalties on sales of Xiaflex. “We will be a cash machine going forward,” he said.
The New York Times, March 16, 2010, by Andrew Pollack  –  It took half a century. But a tiny drug maker on Long Island has finally found a potentially lucrative use for its only medicine: straightening clenched fingers. And, if research proves successful, treating a condition that causes bent penises.

The Food and Drug Administration approved the drug, known as Xiaflex, last month as a nonsurgical treatment for Dupuytren’s contracture, a condition in which one or more fingers cannot be straightened.

Hundreds of thousands of Americans have Dupuytren’s, which can make it difficult to type, shake hands, wear gloves, reach into a pocket or perform numerous other tasks. The afflicted have included Ronald Reagan, Margaret Thatcher, the playwright Samuel Beckett and the classical pianist Misha Dichter.

Xiaflex, an injectable drug that goes on sale later this month, will not be cheap, at an estimated average cost per course of treatment of $5,400. But analysts expect sales to reach hundreds of millions of dollars a year.

And that total could go higher, if Xiaflex eventually wins approval for a related condition known as Peyronie’s disease, in which a bent penis makes intercourse painful or even impossible.

About one in 20 men is estimated to have Peyronie’s, but figures are not precise because people with the condition tend not to discuss it publicly.

Although the company selling Xiaflex will be Auxilium Pharmaceuticals of Malvern, Pa., the F.D.A. approval was a belated triumph for the drug’s original developer, BioSpecifics Technologies of Lynbrook, N.Y., on Long Island. Founded in 1957, it struggled for decades to find uses for the product, almost going out of business before licensing the drug to Auxilium in 2004.

“It sort of proves to people that if you really believe in a drug you should never give up,” said Matthew Geller, a biotechnology investment banker who is a member of the BioSpecifics board.

Shares of BioSpecifics closed Monday at $27.61, up from $1 as recently as late 2006.

Some people treated with Xiaflex in clinical trials for the Dupuytren’s hand condition said it had made a big difference in their lives, and had allowed them to avoid painful surgery.

“When I looked down and saw my finger straightened out, I cried,” said Kenneth Nelson, 65, of Indianapolis. “It was to me just like a miracle.”

Xiaflex is an enzyme produced by a gangrene-causing bacterium, Clostridium histolyticum, which uses it to eat away the tissues of its victims. The enzyme, called collagenase, breaks down collagen, a major component of the body’s connective tissue that is found in skin, tendons, cartilage and other organs.

But collagenase by itself does not cause gangrene. And there are times doctors need to break down collagen, such as when an excess builds up in the hand or penis, causing Dupuytren’s and Peyronie’s. The ailments are named for French surgeons who described the conditions in the 18th and 19th centuries.

The enzyme was first extracted from the bacteria around 1950 by Ines Mandl, a young biochemist at Columbia University. Edwin H. Wegman, a Long Island entrepreneur, learned about Dr. Mandl’s work and set up a company called Advance Biofactures, which later became BioSpecifics, to turn collagenase into a drug.

In 1965, the company won approval of an ointment containing collagenase for use in removing dead tissue from skin ulcers and burns. The ointment, sold by licensees under the name Santyl, was a modest success, but the company never truly prospered.

So in the 1970s the company began developing what it thought would be a bigger money-maker, an injectable collagenase. It tested that drug for numerous uses, including herniated disks. Finally, in the early 1990s, two professors of orthopedics at the nearby State University of New York at Stony Brook suggested using the drug for Dupuytren’s.

The professors, Dr. Lawrence C. Hurst and Marie A. Badalamente, injected the drug into the tails of rats, as a stand-in for human fingers. They found they could dissolve the collagen in tendons, making the tails floppy, without harming nearby nerves and arteries. Then they organized clinical trials in patients and got federal grants to help pay for the work. The professors and Stony Brook will share a royalty of one half of 1 percent of sales of Xiaflex for use in treating Dupuytren’s.

But work was slowed by lack of money, and by 2004, BioSpecifics was about out of cash. In desperation, Ed Wegman’s son Mark, a top computer scientist at I.B.M., called a childhood friend, Laurence Korn, who had been the chief executive of a successful biotechnology company now known as PDL BioPharma.

With Dr. Korn’s help, BioSpecifics licensed the drug to Auxilium in a matter of weeks, receiving $5 million initially.

Auxilium was interested because of Peyronie’s disease. It already was selling a gel for men with low testosterone and had learned from urologists about the need for better treatments for bent penises.

“From talking with surgeons and patients who have Peyronie’s, neither of them wants to do the surgery,” said Will Sargent, a spokesman for Auxilium.

Two years ago, the drug giant Pfizer, which sells the erectile dysfunction drug Viagra, licensed the European rights to Xiaflex from Auxilium for an initial payment of $75 million. BioSpecifics got $6.4 million of that amount and will receive 8.5 percent of additional payments of up to $410 million that Pfizer might make.

Auxilium sought approval for treating Dupuytren’s first because it was easier to measure success in straightening fingers. But the company hopes to begin late-stage trials of Xiaflex for Peyronie’s disease later this year. In a midstage trial, injections of Xiaflex into the collagen plaque in the penis reduced the curvature. But the drug did not reduce pain or discomfort during intercourse by a statistically significant amount.

While collagenase itself is not patented, the companies do have patents on the use of the enzyme to treat Dupuytren’s and Peyronie’s. They are also shielded from competition for seven years under a federal law aimed at spurring development of drugs for rare, or “orphan,” diseases — even though newer estimates suggest these two diseases are not as rare as thought when the drugs were given orphan status.

Auxilium and BioSpecifics hope that the half-century-old collagenase might eventually become as versatile as Botox, another bacterial product. They are looking at uses that range from loosening up immobile “frozen shoulders” to eliminating fat bulges and cellulite.

With its belated success, BioSpecifics has sold off its ointment business. It now has only five employees and a business of collecting a roughly 11 to 12 percent royalty on sales of Xiaflex.

“We will be a cash machine going forward,” said Thomas L. Wegman, the president and the other son of the company founder. “We don’t have to pay for marketing. We don’t have to pay for manufacturing.”

The Wegman family — the two sons and the founder’s 75-year-old wife, Toby — controls about 25 percent of the company’s stock.

Ed Wegman, the company’s founder, did not live to see the F.D.A. approval, dying at age 87 in 2007. On Feb. 2, the day the drug was approved, one BioSpecifics director sent an e-mail message to the others saying, “Well done. Hope Ed is looking on.”

Meanwhile, Dr. Mandl, the biochemist who first isolated collagenase from the bacteria, is nearing 93. Last year, when BioSpecifics stock rose above $30, she sold the last 1,000 shares she had been given for serving as a consultant to the company over the years.

Unfortunately, she had sold most of her holdings years earlier for a relative pittance. “If I still had what I originally had,” she said. “I’d be very rich.”

Princeton Longevity Center, March 16, 2010, by David A. Fein MD  –  The blood thinner Plavix (clopidogrel) is often prescribed for people who are considered at high risk for heart attacks or strokes or have a stent in their coronary arteries.  On March 12, 2010, the Food and Drug Administration (FDA) issued a Safety Announcement concerning Plavix. The warning comes because as many as 14% of those given Plavix may not be get the expected level of protection from the drug.

Plavix helps to prevent heart attacks and strokes by inhibiting the activity of platelets, a component of blood responsible for forming clots.  Most heart attacks occur because of the formation of a blood clot inside an artery.  This is usually a result of a phenomenon doctors refer to as plaque rupture.

Over a period of years cholesterol and other substances are gradually deposited in the walls of the arteries.  This process, called atherosclerosis, creates a thickened area in the artery wall often simply called plaque.  Most plaque does not cause any significant narrowing of the inside, or lumen, of the artery where the blood flows.  The artery actually expands to accommodate the thickening of the wall without impeding blood flow.

The contents of the plaque are separated from the blood flow within the lumen by a thin membrane.  As the plaque enlarges, or if inflammation within the plaque causes that membrane to become too thin, that thin barrier between the inside of the plaque and the lumen can split open.  That is plaque rupture.  When the plaque ruptures it exposes the contents of the plaque to the bloodstream. Some of those substances inside the plaque activate the platelets that are passing by and start the process of clot formation.  Once this happens, an artery that had an asymptomatic, non-obstructive plaque for many years can become completely blocked by a blood clot within just minutes. 

If the blood clot completely obstructs the artery, the portion of the heart muscle down the length of that artery starts to die and a heart attack occurs.

If a clot forms from plaque rupture in one of the arteries to the brain the result can be a stroke. 

In some cases, the plaque has progressed to the point where the artery can no longer continue to expand enough to accommodate the plaque and maintain an adequate lumen.  If the lumen becomes narrowed by more than about 70% a stent, which is basically a spring-like metal cage, may be placed in the artery to help hold it open.  However, the stent itself can cause blood clots to form, blocking the stent and stopping blood flow.  This can occur months, or even years, after the stent is placed.

Medications such as aspirin and plavix help to prevent heart attacks and strokes by interfering with the ability of the platelets to form blood clots.  When plaque rupture occurs the medication helps to limit the size of the clot, hopefully allowing just a big enough clot to seal the rupture but not a big enough clot to completely block the artery. Overall, these medications can reduce the risk of heart attacks and strokes by 35% or more.

Nearly one quarter of people who take aspirin for heart attack prevention turn out to be resistant to its blood thinning effects.  (See our newsletter on Aspirin Resistance) Fortunately, this can be detected with a simple urine test.  Those who are resistant to aspirin are usually advised to try a higher dose or switch to Plavix.

The FDA’s warnings stem from the way that Plavix works in the body.  Plavix is actually a “pro-drug”.  That means that the medication in the tablet is not the active form of the drug.  It must first be converted, or “metabolized”, in the liver into the form of the drug that actually affects platelet function.  This is done by an enzyme in the liver known as CYP2C19.  The problem is that some people have a variation of this enzyme that is much less effective, or not effective at all, in metabolizing Plavix into its active form.  Which type of the CYP2C19 enzyme you have is genetically determined.  Estimates range from 2% to 14% of the population having a form of the enzyme that is so ineffective at converting Plavix into the active metabolite that they get little or no protection from the medication.

A simple test is available to determine whether you have a form of the enzyme that will not adequately process Plavix into its active form.  With either a small blood sample or a swab from the inside of the cheek a DNA analysis determines which genetic type you have and, therefore, which form of the enzyme you make.  If you have a variation of the enzyme that does not metabolize Plavix effectively your doctor may need to increase your dose or consider using other medications to help protect you against blood clots in your arteries or stent. We recommend that every patient who is currently taking Plavix to help reduce their cardiovascular risk should have this test done.

Other medications that you may be taking can also interfere with the ability of the enzyme to convert Plavix to its active form.  In November, 2009, the FDA issued a warning that Prilosec (omeprazole) commonly taken to reduce stomach acidity, could block the CYP2C19 enzyme and render Plavix ineffective.  Many other medications may have the same effect.  If you are taking any other medications with Plavix you should check with your doctor or pharmacist about potential drug interactions.

Also from Princeton Longevity Center……………………..

By: David A Fein, MD
Medical Director

Taking a daily aspirin tablet can dramatically lower your heart attack risk.  But that does not mean that everyone should be taking a daily aspirin.  For those who are at low risk for a heart attack daily aspirin use may actually increase their risk of serious illness.  At the same time, in as many as one-quarter of those who are at high risk for heart attacks and have been told to take a daily aspirin, it may not be working at all.

Aspirin’s ability to prevent heart attacks and strokes is directly tied to its “blood thinning” effects.  Actually, aspirin does not make the blood “thinner”.  Instead, it inhibits the ability of platelets to form a clot.  People who are taking aspirin, for any reason, may notice that when they cut themselves it takes longer for the bleeding to stop because the aspirin has interfered with platelet function.

Most heart attacks are caused by clots.  Modern medicine tends to focus on narrowing of the arteries as the main problem in need of treatment.  Narrowed arteries can cause chest pain with exertion and other symptoms but most heart attacks do not occur at those spots.  Rather than a gradual narrowing of the artery, most heart attacks occur when the surface of a relatively mild plaque in the artery wall splits open.  This exposes the inside of the plaque to the bloodstream and some of the substances inside the plaque cause a blood clot to form at that spot.  If a very small clot forms and seals the rupture it may not interefere with bloodflow through the artery.  When a larger clot occurs it can completely occlude the flow of blood through the artery and a heart attack ensues. 

The idea behind taking a daily aspirin is that inhibiting clot formation makes it more likely you will form a small clot rather than a large one when plaque rupture occurs.  In general it appears that this effect can reduce the risk of heart attacks by about 30%.

On the other hand, aspirin can have potentially dangerous side effects.  It can irritate the lining of the intestinal tract and cause ulcers.  If those ulcers start to bleed, the anti-platelet effect can make that bleeding much more dangerous.  This is estimated to happen in as many as 1% per year of the people who take daily aspirin.  Aspirin can also increase the risk of a hemorrhagic stroke due to bleeding into the brain.  This may happen to about 1 person per year out of every 1000 who take aspirin daily and can be a devastating event.

While these events are not common, they are potentially very dangerous.  So aspirin really makes sense only for those where the reduction in heart attack risk is greater than the risk of side effects.  Unless your heart attack risk is at least 2-3 % per year, taking a daily aspirin may actually increase your risk of stroke or intestinal bleeding more than it lowers your heart attack risk. 
For those who are at high risk for heart attacks, aspirin can be a life-saver.  But, in about 25% of the people who take a daily aspirin they do not get the protection they are expecting.  This phenomenon is known as “aspirin resistance”.  In “aspirin resistant” patients, the usual recommended dose of one baby aspirin (81 mg,) per day does not adequately block the ability of the platelets to clot.  Without this anti-platelet effect, they get little or no reduction in their heart attack risk.

Aspirin blocks production of a chemical called Thromboxane.  A simple and inexpensive urine test, from AspirinWorks and available at Princeton Longevity Center, can measure the level of one of the metabolites of Thromboxane.  This test can determine whether your daily aspirin dose is effective at protecting you against blood clots and lowering your heart attack risk.  If the urine test shows the aspirin is not having the desired effect your doctor can opt to increase the daily dosage.  In some patients even higher doses of aspirin do not offer adequate protection.  In these patients prescription medications, such as Plavix, are available to block clot formation by a different mechanism.

Taking a daily aspirin can be one of the most effective tools available to prevent heart attacks.  But taking a daily aspirin without knowing whether or not you have plaque in your arteries may actually increase your health risks if you don’t have plaque in the first place.  If you are at high risk and could benefit from aspirin therapy then it is very important to determine if you need a higher dose or don’t respond to aspirin at all. 

We recommend that men over 40 and women over 50 check their arteries with a Coronary Calcium Heart Scan.  If your score is over 100 you are at elevated risk and should consider anti-clotting therapy with aspirin.  If you need to be on daily aspirin, you should have the AspirinWorks urine test done to determine your optimum dosage or the need for other medication.

Safety Announcement

[03-12-2010] The U.S. Food and Drug Administration (FDA) has added a Boxed Warning to the label for Plavix, the anti-blood clotting medication. The Boxed Warning is about patients who do not effectively metabolize the drug (i.e. “poor metabolizers”) and therefore may not receive the full benefits of the drug.

The Boxed Warning in the drug label will include information to:

  • Warn about reduced effectiveness in patients who are poor metabolizers of Plavix. Poor metabolizers do not effectively convert Plavix to its active form in the body.
  • Inform healthcare professionals that tests are available to identify genetic differences in CYP2C19 function.
  • Advise healthcare professionals to consider use of other anti-platelet medications or alternative dosing strategies for Plavix in patients identified as poor metabolizers.

Plavix is given to reduce the risk of heart attack, unstable angina, stroke, and cardiovascular death in patients with cardiovascular disease. Plavix works by decreasing the activity of blood cells called platelets, making platelets less likely to form blood clots.

For Plavix to work, enzymes in the liver (particularly CYP2C19) must convert (metabolize) the drug to its active form. Patients who are poor metabolizers of the drug, do not effectively convert Plavix to its active form. In these patients, Plavix has less effect on platelets, and therefore less ability to prevent heart attack, stroke, and cardiovascular death. It is estimated that 2 to 14% of the population are poor metabolizers; the rate varies based on racial background.

Healthcare professionals should be aware that a subgroup of patients are poor metabolizers and do not metabolize Plavix effectively; this can result in reduced effectiveness of Plavix. Healthcare professionals should consider use of other anti-platelet medications or alternative dosing strategies for Plavix in these patients.

Patients should not stop taking Plavix unless told to do so by their healthcare professional. They should talk with their healthcare professional if they have any concerns about Plavix, or to find out if they should be tested for being a poor metabolizer.

In May 2009, FDA added information about poor metabolizers of Plavix to the drug label. However, based on additional data reviewed by the agency (see Data Summary below) the Boxed Warning is now being added to highlight the reduced effectiveness of Plavix in these patients and to recommend that healthcare professionals consider use of other anti-platelet medications or alternative dosing strategies for Plavix in patients identified as poor metabolizers.

Additional Information for Patients

Patients currently taking Plavix should:

  • Be aware that some patients do not convert Plavix to its active form as well as other patients. These patients may not get the same benefit from Plavix and are known as poor metabolizers.
  • Not stop taking Plavix unless told to do so by their healthcare professional.
  • Talk with their healthcare professional if they have any concerns about Plavix.
  • Talk with their healthcare professional to see if testing to determine their metabolizer status is appropriate.

Additional Information for Healthcare Professionals

FDA recommends that healthcare professionals should:

  • Be aware that some patients may be poor metabolizers of Plavix. They do not effectively convert Plavix to its active form because of low CYP 2C19 activity.The effectiveness of Plavix as a preventive therapy is reduced in these patients.
  • Be aware that tests are available to determine patients’ CYP2C19 status.
  • Consider use of other anti-platelet medications or alternative dosing strategies for Plavix in patients who have been identified as poor metabolizers.
  • Be aware that although a higher dose regimen (600 mg loading dose followed by 150 mg once daily) in poor metabolizers increases antiplatelet response, an appropriate dose regimen for poor metabolizers has not been established in a clinical outcome trial.
  • Review the newly approved Plavix drug label for complete information on the use of Plavix

Data Summary

The liver enzyme CYP2C19 is primarily responsible for the formation of the active metabolite of Plavix. Pharmacokinetic and antiplatelet tests of the active metabolite of Plavix show that the drug levels and antiplatelet effects differ depending on the genotype of the CYP2C19 enzyme. The following represent the different alleles of CYP2C19 that make up a patient’s genotype:

  • The CYP2C19*1 allele has fully functional metabolism of Plavix.
  • The CYP2C19*2 and *3 alleles have no functional metabolism of Plavix. These two alleles account for most of the reduced function alleles in patients of Caucasian (85%) and Asian (99%) descent classified as poor metabolizers.
  • The CYP2C19*4, *5, *6, *7, and *8 and other alleles may be associated with absent or reduced metabolism of Plavix, but are less frequent than the CYP2C19*2 and *3 alleles.
  • A patient with two loss-of-function alleles (as defined above) will have poor metabolizer status.

The pharmacokinetic and antiplatelet responses to Plavix were evaluated in a crossover trial in 40 healthy subjects. Ten subjects in each of the four CYP2C19 metabolizer groups (ultrarapid, extensive, intermediate and poor) were randomized to two treatment regimens: a 300 mg loading dose followed by 75 mg per day, or a 600 mg loading dose followed by 150 mg per day, each for a total of 5 days. After a washout period, subjects were crossed over to the alternate treatment. Decreased active metabolite exposure and increased platelet aggregation were observed in the poor metabolizers compared to the other groups. When poor metabolizers received the 600 mg loading dose followed by 150 mg daily, active metabolite exposure and antiplatelet response were greater than with the 300 mg/75 mg regimen. Healthcare professionals should note that an appropriate dose regimen for patients who are poor metabolizers has not been established in clinical outcome trials.

also from………………………………2009 Warning…………….


For Immediate Release:

Patients should avoid using the stomach acid reducer Prilosec/Prilosec OTC (omeprazole) with the anti-clotting drug Plavix (clopidogrel), the U.S. Food and Drug Administration warned on Nov. 17.

New data suggest that when patients take both Prilosec and Plavix, Plavix’s ability to block platelet aggregation (anti-clotting effect) may be reduced by about half.

“Both of these drugs, when used properly, provide significant benefits to patients.” said Mary Ross Southworth, Pharm.D., of the Division of Cardiovascular and Renal Products in the FDA’s Center for Drug Evaluation and Research. “However, patients at risk for heart attacks or strokes who use Plavix to prevent platelet aggregation will not get the full effect of this medicine if they are also taking Prilosec.”

Plavix is used to prevent blood clots that could lead to heart attacks or strokes in at-risk patients. Omeprazole, the active ingredient of Prilosec and Prilosec OTC, is a proton pump inhibitor (PPI) used to reduce the production of stomach acid and prevent stomach irritation.

Plavix does not have anti-clotting effects until it is converted or metabolized into its active form with the help of the liver enzyme, CYP2C19. Prilosec blocks this enzyme, thereby reducing the effectiveness of Plavix.

After issuing an Early Communication in January about possible drug interactions involving Plavix, the FDA requested new studies from the drug’s manufacturers, sanofi-aventis and Bristol-Myers-Squibb. These new studies support the existence of a significant interaction that could negatively impact a person’s health. Based on the current scientific information, the Plavix label has been updated with new warnings about the use of Prilosec and other drugs that inhibit the CYP2C19 enzyme and that could interact with Plavix in the same way.

The new studies compared people who took Plavix and Prilosec together with people who took Plavix alone. A reduction in Plavix’s anti-clotting effect was found in those individuals who took the combination. Similar results were seen irrespective of whether the two drugs were taken at the same or different times of day.

It is unknown how other PPIs may interfere with Plavix. Other drugs that should not be used with Plavix because they may have a similar interaction with CYP2C19 include Nexium (esomeprazole), Tagamet and Tagamet HB (cimetidine), Diflucan (fluconazole), Nizoral (ketoconazole), VFEND (voriconazole), Intelence (etravirine), Felbatol (felbamate), Prozac, Serafem, Symbyax (fluoxetine), Luvox (fluvoxamine) and Ticlid (ticlopidine).

Patients who take Plavix and need to take a drug to reduce stomach acid should discuss their therapy with a health care professional. Zantac (ranitidine), Pepcid (famotidine), Axid (nizatidine), and antacids do not inhibit the CYP2C19 enzyme and aren’t expected to interfere with the anti-clotting activity of Plavix.

Plavix’s manufacturers have agreed to continue conducting studies to explore this and other drug interactions. When the FDA has reviewed additional data, the agency will communicate any new recommendations or conclusions.

FDA Public Health Advisory:

Follow-Up to the Jan. 26, 2009 Early Communication about an Ongoing Safety Review of Clopidogrel Bisulfate and Omeprazole:

Harvard Medical School, March 16, 2010  –  If you are having a heart attack, chewing a full-strength aspirin tablet can be a lifesaving move. If you have heart disease, have had a heart attack or stroke, or are at very high risk for having one, taking a low-dose aspirin every day is part of a proven strategy for preventing one of these life-changers. Aspirin makes blood platelets less “sticky.” This limits the formation of clots in the bloodstream, which can trigger heart attacks and strokes. But what if you are relatively healthy? Will taking aspirin help you keep heart attack, stroke, and other forms of cardiovascular disease at bay?

If taking aspirin were without side-effects and completely risk free,  it might make sense for everyone with heart disease, or just worried about it, to take it. But aspirin does have risks. Reducing blood’s clotting potential can lead to hemorrhagic stroke (bleeding inside the brain). In the stomach, aspirin can cause everything from a feeling of mild heartburn to bleeding ulcers. Severe gastrointestinal bleeding can be deadly.

The benefit-risk balance

It’s the balance of benefits and risks that guides who should take aspirin for primary prevention — preventing heart attack, stroke, or another manifestation of cardiovascular disease in seemingly healthy people.

Researchers from six large primary prevention trials of aspirin pooled their data and analyzed them as if they were from a single large trial. It’s a legitimate technique called meta-analysis. In this relatively healthy group of 95,000 volunteers, the reduction in heart attacks and strokes in people taking aspirin was almost counterbalanced by major bleeding in the gastrointestinal system and the brain. The researchers concluded that for individuals without previously diagnosed cardiovascular disease, “aspirin is of uncertain net value.”

Another meta-analysis showed only a modest overall benefit, if any, for aspirin among people with diabetes but no cardiovascular disease, and it had little impact on heart attack or stroke. When the researchers analyzed the data by sex, aspirin reduced the risk of heart attack in men but not women.

The British journal Drug and Therapeutic Bulletin also weighed in on the topic in November 2009. After reviewing and analyzing information from relevant primary prevention studies, the journal’s editors concluded that the benefits and harms “may be more finely balanced than previously thought,” and aspirin should not be recommended as an across-the-board option to help healthy people prevent heart attack and stroke.


Finding the tipping point


Don’t take aspirin just because you’ve heard it can help prevent a heart attack or stroke. It can , but it can also do some damage. There’s no exact tipping point at which it makes sense to start taking an aspirin a day. If you are healthy, haven’t been diagnosed with heart disease or other cardiovascular disease, and don’t have risk factors for them, aspirin probably isn’t for you. You’ll reap little benefit while exposing yourself to side effects you’d rather stay away from. The less healthy your heart and arteries, the more likely the advantages of taking aspirin will outweigh any risks.

It isn’t the easiest decision to make. If you are in the gray zone, talking with your doctor could make it more black and white.

Read more from Harvard Medical School………………..

Does heart rate affect blood pressure?

Q. When doctors interpret a blood pressure reading, should they also consider the heart rate? I am a 78-year-old man and have had high blood pressure (under control) for more than 40 years. I frequently monitor my blood pressure at home, resting for five minutes before I take the reading. My blood pressure is often higher when my heart rate is close to its usual resting rate (about 50 beats per minute) and lower when my heart is beating faster than that. Can the body’s demands that cause higher blood pressure be partially satisfied by a faster heart rate?

A. First, let me congratulate you on monitoring your blood pressure at home. This is a great way for you to take control of your high blood pressure, and a good step toward preventing a stroke. Knowing that your blood pressure at home is under consistent control is more important than getting isolated readings at the doctor’s office. You are also resting before taking the reading, and this is important to avoid spuriously high readings that happen when someone rushes around, and then sits down quickly to take a blood pressure reading.

Heart rate and blood pressure are intimately related. Nerves and hormones constantly monitor and balance the heart rate and blood pressure. It is true that an isolated increase in blood pressure can drop the heart rate a little. But the reflexes that control blood pressure and heart rate are not simple. Sometimes, both heart rate and blood pressure can fall simultaneously, as happens with a typical fainting episode. Often, both heart rate and blood pressure rise together, such as when you exercise, get angry, or have an overactive thyroid.

I suggest that you write down your heart rate along with your blood pressure, and bring that information to your doctor every time you see him or her. Heart rate trends can provide useful data on your cardiovascular health. A consistently low heart rate, like yours, can indicate that some medicines might not be good for you. A consistently high heart rate can suggest that the thyroid be checked.

— Richard Lee, M.D.

Associate Editor, Harvard Heart Letter

Studies Suggest That Correcting Vitamin D Deficiency Improves Heart Health

By Charlene Laino
WebMD Health News,


Reviewed by Laura J. Martin, MD

March 15, 2010 (Atlanta) — Extra sunshine and vitamin D supplements may help ward off heart disease in people with low vitamin D levels, two new studies suggest.

The studies build on the researchers’ previous work linking low levels of vitamin D to an increased risk for heart disease.

The researchers, from the Intermountain Medical Center Heart Institute in Murray, Utah, presented the new studies at the American College of Cardiology’s 59th annual scientific session.

Vitamin D vs. Heart Disease: Study Details

The first study involved more than 9,400 patients whose blood tests revealed low vitamin D levels during a routine trip to the doctor.  Their average vitamin D level was 19.3 nanograms per milliliter; levels of 30 are generally considered “normal,” according to J. Brent Muhlestein, MD, the Institute’s director of cardiovascular research.

At their next follow-up visit, about half had raised their vitamin D levels to above 30 nanograms per milliliter.

Compared with patients whose vitamin D levels were still low, patients who raised their vitamin D levels were 33% less likely to have a heart attack, 20% less likely to develop heart failure, and 30% less likely to die between the two visits.

In the second study, the researchers placed more than 41,000 patients into three categories based on their levels of vitamin D — normal, moderate deficiency, and severe deficiency. Then they combed their medical records to see who had been diagnosed with heart disease or stroke.

As expected, patients with severe deficiency were most likely to have been diagnosed with heart disease or stroke, Muhlestein tells WebMD.

Then the researchers put all the information into a computer algorithm to see if there is an optimal level of vitamin D when it comes to heart disease prevention.

“While normal has generally been considered to be 30, some people have suggested 40 or 50 is better.

“What we found is that people who increased their vitamin D blood level to 43 nanograms per milliliter had the lowest rates of heart disease and stroke. But increasing it beyond that, say to 60 or 70, offered no greater benefit,” he says.

Vitamin D Findings May Change Some Doctors’ Practices

Although doctors say better-designed studies showing that vitamin D supplements help are needed, Muhlestein says the results of this research will already change the way he treats his patients.

“There is enough information here for me to start treatment based on these findings,” he says.

Treatment options in this case are simple, starting with a blood test to determine a patient’s vitamin D level. If low levels are detected, Muhlestein recommends that men and women boost their vitamin D levels by taking vitamin supplements and briefly exposing skin to the sun’s vitamin D-producing ultraviolet light.

The Institute of Medicine suggests that an adequate daily intake of vitamin D is between 200 and 400 international units (IU) for children and adults up to age 70. But increasing vitamin D intake by 1,000 to 5,000 IU a day may be appropriate, depending on a patient’s health and genetic risk, Muhlestein says.
Gina Lundberg, MD, medical director of St. Joseph’s Heart Center for Women in Atlanta, says more and more patients are reading about the link between vitamin D and heart disease and asking to be tested.

Vitamin D Findings May Change Some Doctors’ Practices continued…

“Sometimes if a 28 or 29-year-old turns out to have slightly low levels, we just recommend a little more time in the sun. These new results may make us think about supplementation to bring levels higher,” Lundberg tells WebMD.

American Heart Association spokeswoman Alice Lichtenstein, DSc, a nutritionist at Tufts University, says the research “is interesting,” adding to growing evidence suggesting a link between vitamin D insufficiency and cardiovascular disease.

But people should refrain from taking supplements on their own, Lichtenstein says. “This should always be done under a doctor’s supervision.”

Michelle V. Agins/The New York Times

“The real danger is the skewed public perception of the danger of honeybees,” said Andrew Coté, of the New York City Beekeepers Association.

The New York Times, March 16, 2010, by Mireya Navarro  –  Kathleen Boyer suspects the mailman. She said she could not think of anyone else in her neighborhood who would have complained about the two beehives she kept under a pine tree in her front yard in Flatbush, Brooklyn, leading the city’s health department to fine her $2,000 last fall.

“I was kind of surprised,” said Mrs. Boyer, an art director with a media company. “People see us in our bee suit and they’d bring their kids to watch us and ask us questions.”

New York City is among the few jurisdictions in the country that deem beekeeping illegal, lumping the honeybee together with hyenas, tarantulas, cobras, dingoes and other animals considered too dangerous or venomous for city life. But the honeybee’s bad rap — and the days of urban beekeepers being outlaws — may soon be over.

On Tuesday, the Department of Health and Mental Hygiene’s board will take up the issue of amending the health code to allow residents to keep hives of Apis mellifera, the common, nonaggressive honeybee. Health department officials said the change was being considered after research showed that the reports of bee stings in the city were minimal and that honeybees did not pose a public health threat.

The officials were also prodded by beekeepers who, in a petition and at a public hearing last month, argued that their hives promoted sustainable agriculture in the city.

A ban, of course, has not deterred many New Yorkers from setting up hives on rooftops and in yards and community gardens, doing it as a hobby, to pollinate their plants or to earn extra income from honey. Although the exact number of beekeepers in the city is unknown, many openly flout the law. They have their own association, hold beekeeping workshops, sell their honey at farmers’ markets and tend to their hives as unapologetically as others might jaywalk, blaming their legal predicament on people’s ignorance of bees.

“People fear that if there’s a beehive on their rooftop, they’ll be stung,” said Andrew Coté, president of the New York City Beekeepers Association, which was formed two years ago and has 220 members.

“Honeybees are interested in water, pollen and nectar,” he said. “The real danger is the skewed public perception of the danger of honeybees.”

Still, some beekeepers say their renegade status causes headaches.

Sam Elchert, 22, a Columbia University student who is majoring in writing and philosophy, said it took him months to find a suitable home for his hives, which resemble short wood filing cabinets with movable frames inside. His building’s management turned him down, fearing legal problems because of the hives, he said. A community garden in Brooklyn welcomed the hives, but wanted them tucked away in the bushes where they would not get the sunlight they needed.

A friend of Mr. Elchert’s, who owned a brownstone in Manhattan complete with a backyard, declined to house the hives because his father was a lawyer, Mr. Elchert said. So did Columbia, where officials in charge of dining services and some green roofs said no, though they were supportive.

A teacher hosted the bees on her farm in Connecticut for a couple of months while Mr. Elchert kept up his search for a home for his hives. Finally, in June, a community garden in Harlem agreed, and Mr. Elchert goes there every other week to tend to the hives. He said that an article he read last year about beekeeping introduced him to the hobby, which he finds “oddly relaxing,” he said. He said he had also read about declines in the bee population and wanted to do his part to nurture the insects.

“It is a good cause, and there’s some sense of morality, even if we’re not on the right side of the law,” he said.

But Mr. Elchert admits that so far he has found his hobby more “nerve-racking” than relaxing, and inspects the garden only on weekdays to avoid weekend crowds.

“What if somebody, some cop, sees me?” he said. “It’d cost me $2,000. It’d really ruin my day.”

Busted beekeepers, as it turns out, are not exactly common. In 2009, 53 inspections were conducted in response to calls related to the harboring of bees and wasps, health officials said, and 13 resulted in notices of violation and fines of $200 to $2,000. In 2008, 48 inspections were made and 7 citations were issued.

Beekeepers say that beekeeping is a relatively low-maintenance and inexpensive endeavor — Mr. Elchert said he spent $500 on hives, equipment and about 20,000 bees to start.

Recently, 70 people filled a room in Lower Manhattan for an “Urban Beekeeping 101” workshop held by the New York City Beekeepers Association.

The class seemed more concerned about the challenges of keeping hives in tight, tall spaces than with the legality of beekeeping, asking questions like: “How high should the hives be?” (About five stories.) And “How much space is needed around the hives so that the bees can fly out to pollinate?” (At least 10 feet.)

But some students were worried about their liability should someone be stung, a hazard that leads most beekeepers to wear protective gear when they tend their hives.

“I’m not even allowed on the roof of my building,” said Matt Griffin, 33, a cook from Queens who said he would probably wait for the law to change and figure out “a few issues” before setting up his hives.

Katrinka Moore, 56, a poet and book editor in the financial district, said that if the law changed, she would ask neighboring churches to host her bees.

That would mean an end to life on the run for Mrs. Boyer’s two hives. They are now lodged with a friend — Mrs. Boyer would not say where — but she plans to retrieve them once they are legal.

Mrs. Boyer said that she and her husband, Chico, took up beekeeping last year so that they could teach workshops in Haiti, where Mr. Boyer was born.

The earthquake has delayed the couple’s plans, but their hives are thriving with 80,000 bees that have yielded more than 100 pounds of honey.

“We gave it to friends for Christmas,” Mrs. Boyer said. “They love it. Everybody is asking for more.”

Ms. Moore said that after working in advocacy against gas drilling in upstate New York, she looked to beekeeping for some relief.

She said: “You get honey. You’re also pollinating gardens. It’s such a positive, happy thing to do.”

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