Cholesterol-Regulating Genes Identified By Scientists

Scientists at the European Molecular Biology Laboratory (EMBL) and the University of Heidelberg, Germany, have come a step closer to understanding how cholesterol levels are regulated. In a study published in the journal Cell Metabolism, the researchers identified 20 genes that are involved in this process. Besides giving scientists a better idea of where to look to uncover the mechanisms that ensure cholesterol balance is maintained, the discovery could lead to new treatments for cholesterol-related diseases.



"This finding may open new avenues for designing targeted therapies, for example by looking for small molecules that could impact these genes," says Heiko Runz, whose group at the University Clinic Heidelberg carried out the research together with Rainer Pepperkok's lab at EMBL.



High levels of cholesterol in the bloodstream are a major risk factor for atherosclerosis and coronary heart disease, one of the leading causes of death in developed countries today. Nevertheless, cholesterol is an important cellular component: 90% of the cholesterol in our bodies is inside our cells, where it does not cause any harm. Blood cholesterol levels are partly regulated by cells taking up cholesterol from the bloodstream, a process Runz and his colleagues are helping to unveil.



The researchers deprived isolated human cells of cholesterol and then looked at the whole genome to find the genes that react to changes in cholesterol levels by altering their expression. This large-scale approach pointed to hundreds of genes which might be involved in cholesterol regulation. To check which genes really were involved, the scientists used a technique called RNA interference to systematically turn each of the candidate genes off. With a microscope they then observed what effect switching off different genes had, both on cholesterol uptake and on the total amount of cholesterol inside cells.



Of the 20 genes the scientists identified as involved in regulating cholesterol levels and uptake, 12 were previously unknown. The remainder were known to have some link to lipid metabolism - how the body breaks down fat - including two genes that when mutated may cause heart disease, but which were only now shown to also play a part in bringing cholesterol into cells in the first place.



The scientists are now trying to discover exactly how the novel genes regulate cholesterol levels inside cells, as well as looking at patients to determine whether these genes (or alterations in them) do constitute risk factors, and investigating if and how they could be useful drug targets.



This discovery could help fight not only heart disease, but also other conditions, as one of the genes identified appears to influence the behaviour of NPC1, a protein involved in the neuro-degenerative Niemann-Pick disease.



The research was conducted under the Molecular Medicine Partnership Unit (MMPU), a collaboration between EMBL and Heidelberg University. "It is very convenient to have such a close partnership here in Heidelberg", says Rainer Pepperkok from EMBL, adding, "it allowed us to use the sophisticated techniques and technology from EMBL to answer questions that first arose at the University clinic, whose clinical aspects will now help in the follow-up."

Cleveland Clinic To Lead First Head-to-Head Comparison Of The Two Most Potent Statins

Cleveland Clinic researchers will
coordinate the first head-to-head comparison of the two most powerful
statin medications. The trial intends to begin enrollment as early as next
week. Statins are the world's most commonly prescribed drugs and widely
used to treat patients with elevated cholesterol levels.


The two drugs, atorvastatin (Lipitor) and rosuvastatin (Crestor), lower
LDL ("bad") cholesterol and raise HDL ("good") cholesterol. But which drug
is best for patients with heart disease? This study will seek to answer
this important scientific question by measuring the rate of regression of
coronary disease using intravascular ultrasound (IVUS), a technique that
directly measures the amount of plaque in the coronary arteries.



The SATURN study (Study of Coronary Atheroma by InTravascular
Ultrasound: Effect of Rosuvastatin Versus AtorvastatiN) will compare the
ability of these two statins to stop the progression of atherosclerosis,
the main cause of cardiovascular disease, over a two year treatment period.



SATURN, a multicenter, double-blind Phase IIIb trial, will use IVUS
imaging to study approximately 1,300 patients at 150 hospitals in 20
countries worldwide. The trial is expected to be completed in 2011.
Cleveland Clinic cardiologist Stephen J. Nicholls, M.D., PhD., will lead
the trial.



Cleveland Clinic researchers have conducted two previous studies with
IVUS looking at statins and the rate of atherosclerosis regression.
Researchers have found a significant benefit with statins by intensively
lowering LDL- cholesterol and the inflammatory marker C-reactive protein
(CRP) and by raising levels of HDL cholesterol. SATURN aims to determine if
differences in the ability of the different statins to lower LDL and raise
HDL can promote regression (reduction in the amount of plaque in the
coronary arteries).



About Cleveland Clinic



Cleveland Clinic, located in Cleveland, Ohio, is a not-for-profit
multispecialty academic medical center that integrates clinical and
hospital care with research and education. Cleveland Clinic was founded in
1921 by four renowned physicians with a vision of providing outstanding
patient care based upon the principles of cooperation, compassion and
innovation. U.S. News & World Report consistently names Cleveland Clinic as
one of the nation's best hospitals in its annual "America's Best Hospitals"
survey. Approximately 1,800 full-time salaried physicians and researchers
at Cleveland Clinic and Cleveland Clinic Florida represent more than 100
medical specialties and subspecialties. In 2006, there were 3.1 million
outpatient visits to Cleveland Clinic. Patients came for treatment from
every state and from more than 80 countries. There were more than 53,000
hospital admissions to Cleveland Clinic in 2006. Cleveland Clinic's Web
site address is clevelandclinic.


Cleveland Clinic

clevelandclinic



View drug information on Crestor.

Joint effects of cardiac risk factors mean more then just double trouble

High blood pressure and high LDL-cholesterol add up to more than just double trouble for heart health, a Penn State College of Medicine study reports.


"The whole is larger than the sum of the parts when it comes to the combined risk of heart attack from high blood pressure and high LDL-cholesterol," said Duanping Liao, M.D., Ph.D., associate professor of health evaluation sciences, Penn State College of Medicine, Penn State Milton S. Hershey Medical Center, and lead investigator of the study. "Our study showed that about 21 percent of middle-aged Americans might have both risk factors, implying that these findings could have significant public health implications with regard to controlling both hypertension and high cholesterol in reducing cardiovascular disease."


Liao's study is one of the few to identify people with these joint risk factors and evaluate on a long-term basis the relationship between the clustering of the risk factors and the incidence of myocardial infarction, or heart attack. The study was presented today (Aug. 30, 2004) at the European Society of Cardiology Congress in Munich, Germany.


Cardiovascular disease remains the No. 1 killer in the United States with about 1 million Americans dying of the disease each year. High blood pressure, or hypertension, and high LDL (low-density lipoprotein) cholesterol are highly prevalent and well-established risk factors for cardiovascular disease.



The study team used data from 14,500 people in the Atherosclerosis Risk in Communities (ARIC) study who were free of coronary disease at initial examination and were followed for an average of nine years. Started in 1987, the ARIC is an ongoing, long-term, observational study of cardiovascular and pulmonary diseases sponsored by the National Heart, Lung, and Blood Institute of the National Institutes of Health.

The ARIC study initially included about 16,000 men and women between the ages of 45 and 64 from four U.S. communities (Washington County, Md., Forsyth County, N.C., selected suburbs of Minneapolis, Minn., and Jackson, Miss.). Participants were given questionnaires and were examined every three years. Follow-up occurs yearly by telephone to maintain contact with participants and to assess participants' health status.


The study showed that those without high blood pressure or high cholesterol showed an incidence for heart attack of 23 per 10,000 person-years, which is roughly 23 cases per 10,000 persons per year. Because these people lacked any risk factors, the incidence of 23 is considered background risk and is subtracted from the total number of heart attacks for those with risk factors present. After deducting background risk, those with high blood pressure had an incidence of 16 and those with elevated LDL-cholesterol had an incidence of 12. The expected incidence for those with both high blood pressure and elevated LDL-cholesterol would be the sum of those two risks, or 28. In fact, the actual incidence of heart attack for those with both risk factors was 51.


"The observed disease rate due to the combination of these two risk factors was significantly higher than what was expected," Liao said. "In terms of excess risk, 31 percent of the risk of developing heart attack among people with both high blood pressure and elevated LDL-cholesterol was attributable to the synergistic interaction of these two risk factors."


In terms of relative risk, the findings showed that those with high blood pressure, elevated LDL-cholesterol or both have a 1.95, 1.70 and 3.31 times higher risk of having a heart attack than those without either of the two conditions.


"This study highlighted the need for physicians to consider treating both high blood pressure and high cholesterol in persons with both risk factors," Liao said, "because the patient's risk of developing a heart attack is beyond simple addition of each risk factor acting alone."


In addition to Liao, the study team included: Jingping Mo, M.D., Ph.D., Global Epidemiology, Pfizer Inc.; and Yinkang Duan, M.D., M.S., Megan Darnell, M.S., Hung-Mo Lin, Ph.D., Zhengmin Qian, M.D., Ph.D., Department of Health Evaluation Sciences, Penn State College of Medicine, Penn State Hershey Medical Center.


The study was partially supported by a research grant from Pfizer Inc., New York.


CONTACT: Valerie Gliem

vgliempsu

814-865-9481

717-531-8604

Penn State

Think Treatments For Cancer, Diabetes Don't Grow On Trees? Think Again

Supported by thousands of years of use, a new wave of polymolecular botanical drugs (PBDs), backed by strong biomedical research and clinical trials, are growing in acceptance as a viable new drug category for the treatment and prevention of a wide spectrum of diseases from cancer to obesity.



Leading researchers in drug development from the National Cancer Institute, Wake Forest University, the University of California, the Scripps Centre for Integrative Medicine, King's College in London UK, and many Canadian Universities will be among the twenty panellists at a Toronto forum on November 15th. Speakers will highlight recent discoveries, discuss current and future research, and chart regulatory landscapes for the promising field of polymolecular drug development. Treatment areas include diabetes, cholesterol management, and cancer.



Research findings will be presented illustrating the advances in the development of polymolecular drugs and their growing recognition as potential mainstream therapies to not only treat illness, but to prevent it. Since polymolecular drugs are composed of multiple components, they often produce biological and/or clinical efficacy through multiple mechanisms of action rather than through a single pathway, as conventional drugs do. An added advantage of this new class of drugs is the synergy between their components, which allows for lower concentrations of each individual ingredient with no reduction in efficacy. As a result they are, as a category, safer and more tolerable than conventional drugs.



Discussion will also focus on recent successes in standardization, which overcome the greatest challenge of botanical medicine and allow for assurances of consistency, safety, and efficacy.



The list of speakers at the forum will include:
Dr. Erminia Guarneri, founder and medical director of the Scripps Center for Integrative Medicine, who will deliver the keynote address, titled Personalized, Predictive, Pro-Active Health: Treating the Whole Person, Body, Mind & Spirit
Dr. Pierre Haddad, Professor at the University of Montreal presenting on novel anti-obesity and anti-diabetic properties of plants originating from the Boreal forest of Canada.
Dr. Peter Hyland: Professor, King's College, UK, presenting on novel standardization methods for polymolecular drugs.
Dr. Auro del Giallo, ABC Foundation School of Medicine, San Paulo Brazil presenting on polymolecular drugs and their role in treating cancer related fatigue
Dr. Jeffrey White, MD, Director, Office of Cancer Complementary and Alternative Medicine, National Cancer Institute, NIH, DHHS presenting on the US National Cancer Institute and its botanical research

Academic and clinical researchers, business development professionals and government agencies involved in the drug development field have been invited to attend and learn about this emerging field of health and therapeutics, and to network with other professionals in the field.



Learn more about the November 15th meeting in Toronto by visiting the MaRS Discovery District website. A webinar of the event will be posted after the event.

Explaining An Important Genetic Cardiovascular Risk Factor

New findings reported in the September issue of Cell Metabolism, a Cell Press publication, appear to explain why people who carry specific and common versions of a single gene are more likely to have high cholesterol and to suffer a heart attack. Studies in mice show that the gene, known as sortilin (SORT1), controls the release of LDL (a.k.a. "bad") cholesterol from the liver into the bloodstream.



The findings suggest that SORT1 may be a good target for new cholesterol-lowering drugs, according to the researchers.



"The vast majority - some 95 percent - of cardiovascular disease is the result of environmental factors modified by genes," said Anders Nykjaer of Aarhus University in Denmark. "Some people can eat a diet enriched in fat, be overweight, and not develop cardiovascular disease. Others can't." SORT1 appears to be one of those important genetic variables, and now the researchers have a pretty good idea why that might be.



The researchers had earlier studied SORT1 in a completely different context. The gene also plays a role in the nervous system. So they were intrigued by the results of genome-wide association studies, which look for associations between common variation in the human genome and diseases or traits, showing that a particular stretch of sequence on chromosome 1 was linked to cardiovascular risk. That sequence covered three genes, including SORT1. (It was not immediately clear which of those three genes was responsible for the rise in cardiovascular risk.)



To investigate SORT1's role further, the researchers created a mouse that lacked SORT1 altogether. That mouse showed 20 percent lower blood cholesterol levels when fed a high-fat Western diet than did normal mice. Importantly, this reduction in cholesterol translated into an approximately 50 to 60 percent reduction in the buildup of plaque in the animals' artery walls. Mice with higher-than-normal levels of SORT1, on the other hand, had higher cholesterol.



If the mice fared better without SORT1 at all, what is it good for? "Everybody says that LDL cholesterol is a bad guy, but you can't do without cholesterol," Nykjaer explains. Cholesterol is a key ingredient in cell membranes and in steroid hormones, for instance. SORT1 facilitates the release of cholesterol into the bloodstream, making that fat available to body tissues that need a certain amount of it.



The problem comes in when you start eating a diet loaded with fat and cholesterol. "Overall, it's good to have sortilin if you don't eat that much," Nykjaer said. "Now, it might be better not to have it all."



Based on the findings, Nykjaer said it might be helpful for people to know what version of SORT1 they carry. Almost a quarter of all people carry the "bad" version of the gene. But he would sooner suggest that everyone live a healthier lifestyle, given that cardiovascular disease is influenced by many factors.



Perhaps the most important implication of the study, he says, is that SORT1 might be a good target for drugs that could block excess cholesterol in the liver, keeping it out of the bloodstream and protecting the heart.



"Lowering LDL cholesterol is considered one of the most efficient strategies to reduce the risk of coronary artery disease," the researchers wrote in conclusion. "Identification of regulators in lipoprotein metabolism such as sortilin will help to develop therapeutic strategies aimed at reducing plasma LDL cholesterol, the single most predictive cardiovascular risk factor."



Notably, loss of SORT1 doesn't result in a buildup of bad cholesterol in the liver, as one might expect, Nykjaer said. That's because the blocked path to the bloodstream engages other molecular players that dump cholesterol from the liver into bile. In other words, he says, the liver appears to protect itself by ridding the body of that cholesterol.



The researchers include Mads Kjolby, Aarhus University, Aarhus, Denmark; Olav M. Andersen, Aarhus University, Aarhus, Denmark; Tilman Breiderhoff, Max-Delbruck-Center for Molecular Medicine, Berlin, Germany; Anja W. Fjorback, Aarhus University, Aarhus, Denmark; Karen Marie Pedersen, Aarhus University, Aarhus, Denmark; Peder Madsen, Aarhus University, Aarhus, Denmark; Pernille Jansen, Aarhus University, Aarhus, Denmark; Joerg Heeren, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Thomas E. Willnow, Max-Delbruck-Center for Molecular Medicine, Berlin, Germany; and Anders Nykjaer, Aarhus University, Aarhus, Denmark.

RNA Treatment Lowers Cholesterol in Mice

Alnylam Pharmaceuticals, Inc, a leading therapeutic RNA interference (RNAi) company, today announced the first in vivo demonstration ever published of RNAi-mediated gene silencing in mammals by a method that potentially can be applied to systemic RNAi therapeutics for human disease. The research, published in Nature, represents a significant advance in the development of systemic RNAi therapeutics. Systemic delivery through the bloodstream potentially enables RNAi therapeutics to target virtually any gene involved in the cause of human disease, opening up the prospect for broad application of RNAi therapeutics to treat a wide range of diseases.


In the published research, Alnylam scientists demonstrated in vivo silencing of the gene for apolipoprotein B (apoB), a protein involved in cholesterol metabolism, and a consequent reduction in blood cholesterol levels. This was achieved using a specially engineered short interfering RNA (siRNA) that was given intravenously by a clinically relevant route of administration. siRNAs are the molecules within cells that trigger RNAi.


To enable the synthetic siRNA used in the study to reach and enter appropriate cells, this siRNA incorporated proprietary chemical modifications designed to provide it with "drug-like" properties. Intravenous injection of the modified siRNA into mice resulted in silencing of apoB messenger RNA (mRNA) in liver and intestine, and reduced blood levels of both apoB protein and total cholesterol. In parallel experiments, the ability of siRNAs to silence the human apoB gene in a transgenic mouse model was also demonstrated. The apoB gene is highly relevant clinically and to date has not been amenable to targeting with traditional small molecule, protein, or antibody therapies.


"We have meaningfully advanced the field of RNAi in this first ever demonstration of RNAi mediated by systemically delivered siRNAs, providing tangible evidence of the broad potential for RNAi therapeutics," said Hans- Peter Vornlocher, Ph.D., Vice President of Research at Alnylam Europe AG. "We are excited that our research progress has been recognized by the prestigious journal Nature, as Alnylam continues our leading-edge therapeutic research to harness RNAi for a whole new class of medicines."


In this robust and well controlled study, Alnylam scientists generated the first in vivo evidence that a siRNA triggers RNAi-mediated degradation of its target mRNA in mice. Specific cleavage of the apoB mRNA at the predicted site was demonstrated, using sophisticated analytical methods. This confirmation of the specific mechanism of action of siRNAs reinforces their therapeutic potential to harness the natural catalytic process of RNAi for the treatment of disease.


"This significant research is a major step forward as we seek to develop systemic RNAi therapeutics for the broad-based application of RNAi to important diseases such as cardiovascular disease, diabetes, obesity, hepatitis, cancer, and many infectious diseases," said John Maraganore, Ph.D., Chief Executive Officer of Alnylam Pharmaceuticals. "Alnylam remains committed to applying our scientific expertise and proprietary technologies to advance both direct and systemic applications of RNAi, including the continued improvement of systemic RNAi technology for human therapeutics."















Conference Call Information


Alnylam will discuss these results during its regularly scheduled earnings conference call, which will take place today, November 10, 2004, at 4:30 pm EST. The call may be accessed by dialing 800-260-8140 (domestic) or 617-614- 3672 (international) five minutes prior to the start time, and providing the passcode 34345993.


A replay of the call will be available from 6:30 pm EST on November 10, 2004 until November 17, 2004. To access the replay, please dial 888-286-8010 (domestic) or 617-801-6888 (international), and provide the access code 61185381. A live audio webcast of the call will also be available on the "Investors" section of the Company's website, alnylam. An archived webcast will be available on the Alnylam website approximately two hours after the event, and will be archived for 14 days thereafter.


About RNAi


RNA interference, or RNAi, is a naturally occurring mechanism within cells for selectively silencing and regulating specific genes that is potentially the basis for a new class of therapeutic products. Since many diseases are caused by the inappropriate activity of specific genes, the ability to silence and regulate such genes selectively through RNAi could provide a means to treat a wide range of human diseases. The discovery of RNAi has been heralded by many as a major breakthrough, and the journal Science named RNAi the top scientific achievement of 2002, as well as one of the top ten scientific advances of 2003.


About Alnylam


Alnylam is a biopharmaceutical company seeking to develop and commercialize novel therapeutics based on RNA interference, or RNAi. Growing from its foundation as the world's first company focused on RNAi therapeutics, the company's leadership in the field of RNAi is supported by its preeminent founders and advisors and its strengths in fundamental patents, technology, and know-how that underlie the commercialization of RNAi therapeutics. Alnylam is developing a pipeline of RNAi products using Direct RNAi(TM) to treat ocular, central nervous system, and respiratory diseases and Systemic RNAi(TM) to treat a broad range of diseases, including oncologic, metabolic, and autoimmune diseases. The company's global headquarters are in Cambridge, Massachusetts. For additional information, please visit alnylam.


Forward-Looking Statements


Various statements in this release concerning our future expectations, plans, prospects and future operating results constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including risks related to: our approach to discover and develop novel drugs, which is unproven and may never lead to marketable products; our ability to obtain additional funding to support our business activities; our dependence on third parties for development, manufacture, marketing, sales and distribution of our products; the successful development of products, all of which are in early stages of development; obtaining regulatory approval for products; competition from others using technology similar to ours and others developing products for similar uses; obtaining, maintaining and protecting intellectual property utilized by our products; our dependence on collaborators; and our short operating history; as well as those risks more fully discussed in the "Certain Factors That May Affect Future Results" section of our Form 10-Q filed with the Securities and Exchange Commission. In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. We do not assume any obligation to update any forward-looking statements.


Contact


Lilian Stern, Stern Investor Relations, Inc., Telephone: 1-212-362-1200


Media Contacts:


In USA, Kathryn Morris, KMorrisPR, Telephone: 1-845-635-9828


In Europe, Michael Sinclair, Halsin Partners, Telephone: 44-(0)870-747- 0800


alnylam

New Research Claims Cholesterol Drug Could Reduce Risk Of Amputations In People With Diabetes

People with diabetes who were prescribed the cholesterol-lowering drug fenofibrate reduced their risk of minor amputations by 36 per cent, according to new research.


Researchers in Australia, Finland and New Zealand looked at almost 10,000 people aged between 50 and 75 with Type 2 diabetes. About half of them were given fenofibrate while the other half were given placebos.


New discovery


The study, first published in 2005, aimed to see if fenofibrate prevented heart disease, which it did not. But in this new analysis, experts found patients on fenofibrate had a 36 per cent lower risk of a first amputation than those on the placebo.


The risk of minor amputations in people without large vessel arterial disease was nearly 50 per cent lower in the group taking fenofibrates, but the risk of a major amputation was not substantially different between the two groups. Taller people were also more likely to have amputations.


Fenofibrates can cause side effects including abdominal pain, nausea, pancreas and lung problems.


Leading research forward


"This large trial suggests that the drug fenofibrate could play a role in the reduction of below-the-ankle amputations in people with Type 2 diabetes," said Dr Victoria King, Research Manager at Diabetes UK.


"We know that approximately 100 people a week in the UK lose a toe, foot or lower limb due to diabetes.


"Managing blood glucose levels by keeping them within acceptable limits can cut the risk of diabetes-related amputations, and trials like this one guide us towards further ways of reducing the risk of diabetes associated amputations."

Source
Diabetes UK


View drug information on Fenofibrate.

Potential Health Benefits Study Of Natural Chemicals In Muscadine Grape Seeds

Could some of the natural chemicals found in plants be powerful enough to improve cardiovascular health? Researchers at Wake Forest University Baptist Medical Center are conducting the first-ever clinical study to evaluate the potential cardiovascular health effects of Nature's Pearl Muscadine Grape Seed Supplement.



The scientists are evaluating the influence of this supplement on blood vessel function in 50 participants who have cardiovascular disease or are at high risk for developing it. They'll also determine whether there are effects on cholesterol and other fats in the blood, blood sugar levels and vessel inflammation, which are all associated with increased risk of cardiovascular disease.



Nature's Pearl is prepared in a way that generates a high concentration of plant chemicals, including gallic acid, ellagic acid, oligomeric proanthocyanidins (OPCs) and resveratrol. These are known to be antioxidants, or nutrients that can prevent or slow the oxidative damage to the body. The role of oxidative stress in blood vessel disease has generated interest in dietary sources of antioxidants, including black and green tea, grape seeds, olive oil and cocoa.



Muscadine grapes have been shown to be more potent in antioxidants than any other variety of grapes, and laboratory studies have suggested that grape seeds have higher antioxidant capacity than grape skins. Studies in humans have shown improved antioxidant capacity when grape seed supplement is added to the diet, as well as improvements in blood vessel function. However, the studies did not specifically include muscadine grapes, which have extremely high levels of antioxidant and anti-inflammatory compounds when compared to other fruits.



"The goal of the current study is to determine if daily doses of the Nature's Pearl supplement, which is specially prepared to maximize its natural antioxidant and anti-inflammatory concentrations, will have a favorable effect on cardiovascular risk factors," said David Herrington, M.D., M.P.H., lead investigator and a professor of cardiology.



Study participants are patients at Wake Forest Baptist's Family Medicine and Internal Medicine practices and are between 18 years and 65 years old. For the first four weeks of the study, participants are randomly assigned to take either 1,300 mg. (two capsules) of the Nature's Pearl Muscadine Grape Seed Supplement (grape seeds) daily or a placebo (inactive capsule).



For the next four weeks, participants do not take capsules to allow the product to "wash out" of their systems. Then, the groups will switch so that those who took placebo originally will take the supplement for four weeks.



Ultrasound technology is used to determine blood vessel function or "reactivity." Blood flow in the brachial artery, the major vessel in the arm, is measured both before and after the arteries are constricted with a blood pressure cuff. In a healthy subject, the artery dilates after the constriction. Decreased reactivity is a sign of reduced artery function and is thought to be a precursor to atherosclerosis, the buildup of fatty deposits in the vessels that can lead to heart attack or stroke.



The test is used in the brachial arteries because the heart's arteries cannot be directly imaged with ultrasound. However, atherosclerosis is a disease that affects vessels throughout the body, and the test is considered a good indicator of overall vessel function.



The study will also measure any effects on total cholesterol, low-density lipoprotein or "bad" cholesterol, triglycerides, high-density lipoprotein or "good" cholesterol, blood sugar levels and markers for inflammation, such as C-reactive protein and interleukin-6.



Patients have been recruited and the results are expected to be analyzed in early 2008.



"Cardiovascular disease is a significant problem in this country so it is worthwhile to examine foods that may have medicinal benefits," said Herrington. "In this case, our goal is to determine whether the Nature's Pearl supplement, which looks promising because of its extremely high antioxidant and anti-inflammatory content, will positively affect artery health."







The study is sponsored by Nature's Pearl Corporation.



Wake Forest University Baptist Medical Center is an academic health system comprised of North Carolina Baptist Hospital and Wake Forest University Health Sciences, which operates the university's School of Medicine. The system comprises 1,154 acute care, psychiatric, rehabilitation and long-term care beds and is consistently ranked as one of "America's Best Hospitals" by U.S. News & World Report.

Simplified Clinical Tool Affects Treatment Decisions For Heart Health

Millions of Americans potentially reclassified into high-risk or low-risk groups with different treatment as a result.


The widespread use of a simplified clinical tool to estimate future coronary risk could lead to the classification of millions of Americans into different risk groups than when using the original, "gold-standard" tool. Millions of patients may have been misclassified into higher-risk groups and therefore potentially over-treated, while others may have ended up in lower-risk groups and therefore potentially under-treated for heart disease. The study, led by William Gordon from Weill Cornell Medical College in the US and colleagues, is published in the Journal of General Internal Medicine, published by Springer.


American national cholesterol guidelines use the well-known Framingham model (a mathematical equation) to calculate a person's 10-year risk of heart attack and coronary death. Based on this risk, patients are categorized into different risk groups, which are used to guide treatment decisions.


Because the original Framingham model is very complex, the formula has been simplified into a point-based clinical tool to make it available without calculators or computers. However, the rapid take-up and widespread use of computers and PDAs in clinical medicine has made it possible to implement the original, mathematically complex model at the point of care. Yet, the point-based system continues to be used widely in clinical practice.


"While the point-based system is a substantial improvement over having no standardized method for predicting risk, just about any computer or PDA in use today can calculate the original Framingham model," says principal investigator Michael Steinman, MD. "This means that your doctor can calculate your risk just as easily using the complex equation, which is likely to be more accurate than the point-based system. So there's not much reason to use the point-based system anymore in most instances."


The authors looked at whether the simplified version might lead to different risk estimates and potentially different treatment recommendations as a consequence. The researchers used data for 2,543 people (representing 39 million adults) aged 20-79 years. For each individual, the authors calculated the 10-year risk of major coronary events using both the original and simplified point-based Framingham models. They looked at the differences in these risk estimates and whether these differences would place subjects into different risk categories.


Gordon and team found that the two estimates of coronary risk differed significantly. The simplified version reclassified 15 percent of adults into different risk groups, corresponding to 5.7 million people. Of those, 10 percent (3.9 million) were reclassified into higher-risk groups and 5 percent (1.8 million) into lower-risk groups. As a consequence, 25-45 percent of reclassified adults could have been treated differently i.e. either received more or less intensive therapy than would otherwise be recommended according to drug treatment guidelines.


The authors conclude: "Current guidelines should strongly consider endorsing the original model as the preferred method of risk calculation and as the sole appropriate option for computer or PDA-based risk calculators. Patients and clinicians who made treatment decisions based on the point-based system should also consider recalculating risk based on the original Framingham model and, where appropriate, adjust treatment plans accordingly."


The original Framingham model estimates risk based on the patient's age, total and HDL cholesterol, systolic blood pressure, treatment for hypertension, and smoking status. The point-based system assigns each risk factor level a number. These risk factor values are then added up into a score; the risk for that score is then determined from a table.


Sources: Springer Science+Business Media, AlphaGalileo Foundation.

New study provides support for Atkins type diet

Was Atkins Right? New Study Provides Support For Those Who Advocate A High Protein Diet For Weight Loss And Better Health.


Bethesda, MD - "Shape Up America," a new coalition of various health groups recently announced their collective opinion that "booming low-carb diets were unlikely to lead to long-term weight loss and may be dangerous for health." At the same time, high protein diets are attracting their share of critics, among them the American Heart Association, which has stated that the focus on animal proteins cholesterol raises harmful LDL cholesterol levels.


The scientific community knows that high protein diets induce early marked metabolic changes in human and animal models, especially when the diet contains at least 50 percent of energy as protein, but the physiological and functional consequences of a long-term high protein (HP) diet have not been fully explored. Now, a long-term study involving male rats has found that a protein intake of three times the requirements did not produce any adverse effects in key systems.


A New Study


Researchers are aware that no long-term interventional human studies on the issue exist nor are there any complete toxicological studies on high protein diet effects. This has led to a new investigation of the wide range of biochemical, anatomical and histological parameters to determine whether long-term ingestion of a high protein diet could have adverse and/or beneficial effects in an obesity prone strain of rats.


The authors of "A long-term high-protein diet markedly reduces adipose tissue without major side-effects in Wistar male rats," are Magali Lacroix, Claire Gaudichon, Celine Morens, Veronique Mathe, Daniel Tome, and Jean-Francois Huneau, all from the Physiologie de la Nutrition et du Comportement alimentaire, Institut National Agronomique Paris-Grignon, Paris; and Antoine Martin, at the Service d'Anatomie pathologique, H?pital Avicenne, Bobigny, both in France.


Their findings appear in the Articles in Press section of the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. The journal is one of 14 scientific publications issued each month by the American Physiological Society (APS) (the-aps).


Methodology


This study used male Wistar rats that were administered either a no protein diet or a high protein diet for six months. Detailed body composition, biomarkers of oxidative stress [reduced and oxidized glutathione, thiobarbituric acid reactive substances, expression of glutamy-cysteine-ligase, and detoxification function (Glutathione-S-Transferase), plasma hormones (insulin, cortisol and leptine)] and liver and kidney histopathology were investigated. Calcium balance was also assessed over four months after this protocol.















Results


This study sought to estimate the consequences of a long-term intake of high levels of protein in an obesity-prone rat strain. The results showed that the long-term effect of eating protein at will led to a markedly reduced food intake and lowered white adipose tissue. At the same time, basal blood insulin, leptin and triglyceride levels, and glucose tolerance were improved. Calcium balance was not affected by a high intake of milk proteins.


Moreover, in contrast to what has generally been admitted, no adverse effects of the high protein diet were reported, particularly regarding kidney and liver health. After six months of the experiment, the body weight of rats fed the high protein diet was 18 percent lower than that of rats fed the non-protein diet.

Body composition measurements revealed remarkable differences between the two groups, especially concerning the subcutaneous fat pad.


This study also revealed that the weight reduction in rats fed the high protein diet was strongly associated with lower basal blood sugar and insulin levels, as previously described, and improved glucose tolerance. As the isocaloric exchange between high and low protein diets was performed on carbohydrate, the flattening effect of the high protein diet on insulin and glucose basal levels could be attributed to its reduced carbohydrate content. This contrasts with the results of many studies that have acknowledged the fact that high protein intakes induce an increase in glucose and insulin concentrations.


Conclusions


This unique long-term study found that in male rats, a protein intake of three times the requirements did not produce any adverse effects on the renal and hepatic functions, on oxidative stress or on the calcium balance. On the contrary, exchanging carbohydrates for proteins was beneficial regarding body composition, basal triglycerides, glucose, leptin, and insulin plasma concentrations. The results of the present study agree with the idea that long-term dietary management is of major importance to preventing obesity.


This study will not settle the long-standing debate regarding the merits of a high protein diet. However, these findings will provide support to those who advocate such a regimen for weight loss and better health.


-end-

In Pediatric Genetic Neurological Disease Niemann-Pick Type C, Researchers Report Breakthrough

A paper announcing a breakthrough discovery in the fight against Niemann-Pick Type C, coauthored by Olaf Wiest and Paul Helquist of the University of Notre Dame's Department Chemistry & Biochemistry and Frederick Maxfield, Chair of Biochemistry at Cornell University Weill College of Medicine, appears in the Proceedings of the National Academy of Sciences this week. The paper shows how use of a histone deacetylase inhibitor correct the damage done by the genetic disorder and allowed once-diseased cells to function normally.



Niemann-PickType C (NPC) involves a genetic flaw that keeps cells from using lipids appropriately and leaves the lipids trapped in the cell. Brain cells are especially impacted, and destruction of brain cells typically kills victims by their teen years and there is currently no treatment available in the U.S. NPC is an inherited cholesterol metabolism disorder that strikes one in every 150,000 children. It has been referred to by the National Institutes of Health as "childhood Alzheimer's" because of similarities in the brains of NPC and Alzheimer's disease patients.



Three of the four grandchildren of former Notre Dame head football coach Ara Parseghian died of NPC, and the University has been involved in research on the disorder for years. Last year, it formally united with the Parseghian Foundation, which sponsored this work.



Last summer, Notre Dame College of Science Dean Gregory Crawford and his wife Renate bicycled 2,300 miles from Tucson to Notre Dame to raise awareness of the newly strengthened partnership with the Parseghian Foundation. Notre Dame's Center for Rare and Neglected Diseases works to develop therapies and outreach efforts for people suffering from conditions, like NPC, that have bee3n largely ignored by pharmaceutical companies.



A team of led by Wiest and Helquist at Notre Dame and Maxfield at Cornell, uncovered evidence that histone deacetylase inhibitors correct NPC's genetic flaw. Detailed images obtained at Cornell by Maxfield's group gave vivid evidence of the drug's effectiveness, showing how NPC cells became indistinguishable from normal human cells after treatment with the drug. The histine deacetylase inhibitors have a wide range of potential uses, from rare diseases, the focus at Notre Dame, to several forms of cancer, including leukemia, where they can increase the number of bone marrow cells.



Several of the compounds studied are shown to be safe in advanced clinical studies of cancer and one compound is currently approved by the FDA.



"Our biggest single emphasis the last few years has been Niemann-Pick among these rare diseases," Helquist said. "We developed several processes for the efficient preparation of these types of drugs. There's a stream of publications and also a stream of patents starting in June 2007 and continuing this year."



"If the results in human cells can be confirmed in clinical trials, the fact that the histone deacetylase inhibitors are already in advanced clinical trials or even approved drugs could greatly accelerate the development of a treatment for this devastating disease."

Cholesterol and genes

Why does it seem like some people can eat all the ice cream they want without increasing their cholesterol or gaining much weight, while others with high cholesterol have to watch their diets like a hawk? Because no matter what their lifestyle, people's genes play an overriding role in their cholesterol response.


So says a new study by researchers at the Department of Energy's Lawrence Berkeley National Laboratory and the Children's Hospital Oakland Research Institute (CHORI), conducted by Paul Williams of Berkeley Lab's Life Sciences Division in collaboration with Robin Rawlings and Patricia Blanche of CHORI and Ronald M. Krauss of CHORI and Berkeley Lab's Genomics Division. They report their findings in the July 8, 2005, issue of the American Journal of Clinical Nutrition.


The investigators analyzed how "bad" cholesterol (low-density lipoprotein, or LDL, cholesterol) responded to diets that were either high or low in fat in 28 pairs of identical male twins - one twin a vigorous exerciser, the other a comparative couch potato.


"Although identical twins share exactly the same genes, we chose these twins because they had very different lifestyles," says Williams. "One member of each pair was a regular long-distance runner, someone we contacted through Runner's World magazine or at races around the country. His brother clocked 40 kilometers a week less, at least, if he exercised at all."


For six weeks the twins ate either a high-fat diet (40 percent of its calories from fat) or a low-fat diet (only 20 percent of its calories from fat); then the pairs switched diets for another six weeks. After each six-week period the twins' blood cholesterol levels were tested.


The researchers were interested in learning if blood cholesterol changes due to the different diets would be the same or different in each pair of genetically identical twins, even though their lifestyles were very different. A correlation of zero between the two would mean that their responses to the diets had no relation to each other, while a correlation of 1.0 would mean that their responses were identical.


The researchers found an astounding 0.7 correlation in responses to the change in diet, an incredibly strong similarity in the way each pair of twins responded - even though the responses themselves among different pairs of twins differed considerably.


"If one of the twins could eat a high-fat diet without increasing his bad cholesterol, then so could his brother," says Williams. "But if one of the twins' LDL cholesterol shot up when they went on the high-fat diet, his brother's did too."


The correlations showed that the twins had very similar changes in LDL cholesterol because they had the same genes. Some twins had one or more genes that made them very sensitive to the amount of fat in their diets. Other twins had genes that made them insensitive to dietary fat, no matter how much they exercised.


"Our experiment shows how important our genes are," says Williams. "Some people have to be careful about their diets, while others have much more freedom in their dietary choices."


He adds, "This type of experiment allows us to test whether genes are important without having to identify the specific genes involved." Although several specific genes have been associated with cholesterol changes in response to changes in diet, these cannot account for the large correlations seen in this study. Williams hopes his findings will inspire additional research to identify the specific genes involved.


"Concordant lipoprotein and weight responses to dietary fat change in identical twins with divergent exercise levels," by Paul T. Williams, Patricia J. Blanche, Robin Rawlings, and Ronald M. Krauss, appears in the July 8, 2005, issue of the American Journal of Clinical Nutrition. The work was supported by Dairy Management Incorporated, with additional support from the National Institutes of Health.


Berkeley Lab is a U.S. Department of Energy national laboratory located in Berkeley, California. It conducts unclassified scientific research and is managed by the University of California. Visit our website at

lbl.


Berkeley Lab News Release

QuatRx Pharmaceuticals Initiates Phase I Trial For Treatment To Reduce Both LDL Cholesterol And Lipoprotein (A)

QuatRx Pharmaceuticals, a privately held biopharmaceutical company focused on research and development of therapeutic compounds for the treatment of major endocrine,
metabolic and cardiovascular diseases, today announced that it has
initiated a Phase I clinical study of QRX-431, a novel compound in
development for the treatment of elevated cholesterol levels and obesity.


In pre-clinical primate studies, QRX-431, a selective thyroid beta agonist,
lowered LDL, lipoprotein (a) and weight without significantly increasing
heart rate. High levels of low-density lipoproteins (LDL) have been shown
to be a major cause of coronary heart disease, a condition affecting more
than 13 million Americans. Elevated lipoprotein (a) [Lp(a)] has been linked
to an increased risk of stroke and coronary heart disease.



"We are extremely encouraged by the preclinical results for QRX-431. We
feel this new drug candidate offers great promise as a therapy to help the
millions of people with elevated lipid levels and obesity who may be at
risk for stroke and coronary heart disease," said Robert L. Zerbe, M.D.,
chief executive officer and president of QuatRx.



Preclinical Study Results



In preclinical primate studies, QRX-431 significantly reduced LDL
cholesterol and Lp(a). To date, there are no approved therapies for the
treatment of elevated Lp(a) levels. Study results also suggest that QRX-431
activates reverse cholesterol transport, a protective mechanism involving
transport of cholesterol from the arteries to the liver. QRX-431 may also
act to induce weight loss. QRX-431 demonstrated a weight reduction in seven
days in a primate study and did not significantly affect heart rate.



LDL Cholesterol, Cardiovascular Disease and Current Treatments



Collectively, more than 71 million Americans have some form of
cardiovascular disease, according to the American Heart Association.
Cardiovascular disease is the number one killer in the United States,
claiming more lives than cancer, chronic lower respiratory diseases,
accidents, and diabetes combined. Statins are commonly used to lower LDL
cholesterol and reduce the risk of cardiovascular disease. Though effective
for many people with high LDL cholesterol, statins have no effect on Lp(a),
can cause many side effects and many people cannot tolerate the higher
doses needed to achieve target LDL levels. Thyroid hormone has been shown
to lower LDL levels and Lp(a), but unlike QRX-431, thyroid hormone also
stimulates the thyroid alpha receptor, which produces increases in heart
rate. For this reason, thyroid hormone has not been considered a viable
therapy for lowering cholesterol or weight.



About QuatRx



QuatRx Pharmaceuticals Company is focused on discovering, licensing,
developing and commercializing compounds in the endocrine, metabolic and
cardiovascular therapeutic areas. In addition to QRX-431, QuatRx currently
has three product candidates in clinical development. QuatRx's two lead
compounds target hormone deficiencies that result from aging in women and
men. Ophena(TM) is in Phase III development initially for the treatment of
vaginal atrophy, a common problem associated with estrogen deficiency in
post- menopausal women. Fispemifene, a treatment for testosterone
deficiency, is in Phase II clinical testing. QuatRx is also developing
Asord(TM), a topical product candidate for the treatment of psoriasis,
which has completed a Phase IIb clinical trial.


QuatRx Pharmaceuticals Company

quatrx

Link Between Apolipoprotein E Genotypes With Lipid Levels And Coronary Risk

There are linear links between apolipoprotein E (apoE) genotypes with lipid levels and coronary risk, according to an analysis of previous studies published in the Journal of the American Medical Association (JAMA).


apoE, a multifunctional protein, plays a vital part in cholesterol and triglycerides metabolism, explain the writers. A number of studies have identified a link between some apoE genotypes and lipid levels and coronary risk. However, the majority of those studies were small and perhaps biased.


Anna M. Bennet, Ph.D., University of Cambridge, England, and team looked at a number of studies in order to see whether there was really a link between apoE with circulating lipid levels and coronary risk. There were 82 studies of lipid levels, involving 86,067 healthy subjects, and 121 studies of coronary outcomes - 37,850 cases and 82,727 controls - with a focus on studies with 1,000 healthy subjects or more for lipids and those with 500 or more coronary outcomes.


In the most extreme comparison, the scientists explained, individuals with the E2/E2 genotype had 31% lower average LDL-C (low-density lipoprotein cholesterol) values compared to people with the E4/E4 genotype. The authors wrote "??¦a difference comparable with that produced by 'statin' medication. The relationship of apoE genotypes with high-density lipoprotein cholesterol (HDL-C) was shallow and inverse and that with triglycerides was nonlinear and largely confined to the E2/E2 genotype, with the latter about 2 times weaker than previously reported."


The researchers added "We found that, in comparison with the commonest E3/E3 genotype, E2 carriers had a 20 percent reduced coronary risk, in contrast with previous estimates that E2 carriage is neutral for coronary risk. We noted strong evidence of selective publication in previous estimates based on smaller studies. This is a serious concern given that apoE genotypes and coronary risk had hitherto been considered among the few quantitatively secure associations in cardiovascular disease genetics."


E4 carriers have a slightly higher risk of coronary disease compared with E3/E3 individuals, the authors wrote.


JAMA. 2007;298(11):1300-1311

jama.ama-assn

Most Americans do not know that high cholesterol comes from two sources

Results from a recent nationwide survey showed that most respondents did not know that high cholesterol comes from two sources, even though the respondents reported having high cholesterol. When asked about the sources of cholesterol, more than three-quarters of respondents (77 percent) stated incorrectly that the food they eat contributes the most to high cholesterol. In fact, the cholesterol in the bloodstream is not just absorbed from the food people eat, but the majority is produced naturally in the body.


Other findings from the survey showed that 45 percent of high cholesterol patients said they were more concerned about cholesterol compared to other personal health issues and 75 percent felt that their cholesterol should be lower.


"Patients with high cholesterol should make an extra effort to be as informed about their cholesterol levels as possible. Knowing about the sources of cholesterol is a key step in this process," says David Cohen, M.D., director of hepatology, Brigham and Women's Hospital. "The fact is that both diet and heredity play a critical role in your cholesterol levels. While diet can contribute significantly to elevated cholesterol, the body's natural chemistry can often produce dangerously high levels of LDL ("bad") cholesterol based on heredity alone. When working with a physician to manage your condition, it is important for patients to understand that there are two sources of cholesterol and in many cases both need to be addressed."


The survey results also showed:


Respondents did have a general sense that the lower their cholesterol the better; with 75 percent agreeing that their cholesterol should be lower than it currently is now.


Most respondents (85 percent) said they were aware there are national guidelines for where their overall cholesterol number should be. However, only 27 percent of those people actually knew that the optimal level for LDL cholesterol is less than 100mg/dL.


"The cholesterol awareness gap that is seen in this survey can and should be remedied," says Bonna Kol, executive director of Mended Hearts, a volunteer organization affiliated with the American Heart Association that provides supportive services to heart disease patients and their families nationwide. "High cholesterol is a serious condition, but it can be treated. Following a heart healthy diet, managing weight and staying physically active are essential lifestyle components we've encouraged for years. We've also emphasized the importance of informed patients talking with their doctor to ensure cholesterol goals are met. These findings reinforce that importance. Patients should work with their doctors on developing an approach to lowering cholesterol that is best for them."



The survey was sponsored by Merck/ Schering-Plough Pharmaceuticals in conjunction with Mended Hearts. The two organizations are developing educational materials and local awareness campaigns based on the findings to educate heart patients on the importance of reaching their cholesterol treatment goals.















About Cholesterol


Cholesterol is a form of fat or "lipid" found in the blood and all cells of the body. It is critically important in helping to form cell membranes, steroid hormones and bile acids. There are two sources of cholesterol: cholesterol comes from the food you eat and is produced naturally in the body. However, over time, excess LDL (or bad) cholesterol in the blood can build up on the inner walls of the arteries that supply blood to the heart. These deposits form plaque, which can cause the arteries to narrow, making them less efficient at transporting blood. This condition, called atherosclerosis, restricts blood flow, which can result in heart attack.


About the Survey


Merck/ Schering-Plough Pharmaceuticals, in partnership with Mended Hearts, sponsored the survey, which was conducted among 1,118 patients who reported having high cholesterol and who were members in a sub-panel of the Harris Interactive Chronic Illness Panel. This survey was composed of 566 respondents currently being treated with cholesterol lowering medicines and 552 currently untreated. The Harris Interactive Chronic Illness Panel(CIP) consists of over 1 million households where members have been screened for more than 50 separate medical conditions. The panel members are recruited from among Harris Interactive's general online consumer panel. The CIP allows targeted and effective sampling on specific populations of interest. Participants receive incentives for each survey they complete. Incentives are in the form of HI Points, which are ultimately redeemable for rewards (like pens, radios, and watches) at various point levels.


About Mended Hearts


Mended Hearts, a national nonprofit organization affiliated with the American Heart Association, has been offering the gift of hope to heart disease patients, their families and caregivers for more than 50 years. Recognized for its role in facilitating a positive patient-care experience, Mended Hearts partners with 460 hospitals and rehabilitation clinics and offers services to heart patients through visiting programs, support group meetings and educational forums. Its mission is to "inspire hope in heart disease patients and their families."


About Merck/Schering-Plough Pharmaceuticals


Merck/Schering-Plough Pharmaceuticals is a joint venture between Merck & Co., Inc. and Schering-Plough Corporation formed in May 2000 to develop and market in the United States new prescription medicines in cholesterol management. The collaboration was expanded in December 2001 to include worldwide markets (excluding Japan).


About Harris Interactive®


Harris Interactive (harrisinteractive) is a worldwide market research and consulting firm best known for The Harris Poll®, and for pioneering the Internet method to conduct scientifically accurate market research. Headquartered in Rochester, New York, Harris Interactive combines proprietary methodologies and technology with expertise in predictive, custom and strategic research. The Company conducts international research from its U.S. offices and through wholly owned subsidiaries--London-based HI Europe (hieurope), Paris-based Novatris and Tokyo-based Harris Interactive Japan--as well as through the Harris Interactive Global Network of independent market- and opinion-research firms.


For more information on cholesterol and its sources, please go to 2cholesterolsources.


Media Contacts:

Tim Elsner

214-706-1406

Mended Hearts


Kristin Francini

202-352-4806

Porter Novelli


Daphne Hoytt

212-601-8162

Porter Novelli

Metabolex Begins Phase 2 Trial Of MBX-8025 For Treatment Of Dyslipidemia

Metabolex, Inc., a
biotechnology company dedicated to the discovery and development of novel
therapeutics for diabetes and related metabolic disorders, announced
that it has begun a 180 patient Phase 2 trial of MBX-8025 in overweight or
obese patients with high cholesterol and triglycerides to assess the drug's
effect on dyslipidemia, insulin-resistance and obesity.


Preclinical and clinical testing of MBX-8025 indicates that the drug
has the potential to improve a number of lipid parameters that are abnormal
in different types of dyslipidemia, including high LDL (or "bad")
cholesterol, high Apo B-100 (the atherogenic lipoprotein), low HDL (or
"good") cholesterol and high triglycerides (fats). In addition, MBX-8025
has been shown to exhibit positive effects on insulin sensitization and
body weight. The randomized, double blind Phase 2 trial will assess the
potential of the drug alone and in combination with Lipitor(R)
(atorvastatin).



"Although high LDL levels are widely treated as a risk factor for heart
disease, many patients are unable to reach increasingly low LDL targets on
a statin alone. Additionally, existing drugs do a poor job of targeting the
entire range of different lipid disorders that contribute to cardiac risk.
We believe this trial will provide us crucial evidence in assessing the
ability of MBX-8025 to lower Apo B-100, LDL and triglyceride levels, as
well as raise HDL levels, improve insulin sensitivity and reduce body
weight," said David B. Karpf, M.D., the chief medical officer of Metabolex.
"In addition, we are testing the drug in conjunction with Lipitor, the
best-selling lipid-lowering drug in the world, to determine whether
combination therapy with a statin will be well tolerated and lead to even
better results."



The study will enroll 180 overweight or obese non diabetic patients and
assess two different doses of MBX-8025, given over an 8-week treatment
period, both alone and in combination with Lipitor(R). The primary endpoint
is the reduction in Apo B-100 compared with placebo. Secondary endpoints
include measurements of the effect of treatment on LDL, HDL, triglycerides
and body weight and composition. Metabolic parameters, including glucose
and insulin levels, will also be assessed.



MBX-8025 regulates fatty acid degradation, lipid storage/transport and
insulin sensitivity. Metabolex has in-licensed the patents and the
exclusive development and commercialization rights to MBX-8025 from Janssen
Pharmaceutica NV, a Johnson & Johnson company.



About Metabolex



Metabolex is a privately held biotechnology company dedicated to the
discovery and development of novel therapeutics to transform the treatment
of diabetes and related metabolic disorders. Metabolex has drawn on its
deep understanding of diabetes to create the largest database of genes
involved in diabetes and to build a rich pipeline of product candidates and
drug discovery targets. The company has three clinical-stage compounds:
MBX-102/JNJ 39659100, in Phase 2/3 testing; MBX-2044, in Phase 2a; and
MBX-8025, being studied in dyslipidemia, now in Phase 2. Ortho-McNeil, Inc.
has the exclusive right to develop and commercialize MBX-102/JNJ 39659100
and MBX-2044. For additional information about Metabolex and its
development pipeline, visit metabolex.


Metabolex, Inc.

metabolex

Treat The Risk, Not The Cholesterol: Study Challenges Current Cholesterol Recommendations

A new study by the University of Michigan Medical School and VA Ann Arbor Health System challenges the medical thinking that the lower the cholesterol, the better.


Tailoring treatment to a patient's overall heart attack risk, by considering all their risk factors, such as age, family history, and smoking status, was more effective, and used fewer high-dose statins, than current strategies to drive down cholesterol to a certain target, according to the U-M study.


While study authors support the use of cholesterol-lowering statins, they conclude that patients and their doctors should consider all the factors that put them at risk for heart attack and strokes.


The findings will be released online Monday ahead of print in the Annals of Internal Medicine.


"We've been worrying too much about people's cholesterol level and not enough about their overall risk of heart disease," says Rodney A. Hayward, M.D., director of the Veterans Affairs Center for Health Services Research and Development and a professor of internal medicine at the University of Michigan Medical School.


The National Cholesterol Education Program recommends harmful LDL cholesterol levels should be less than 130 for most people. High risk patients should be pushed even lower -- to less than 70.


The U-M study took a different approach, called tailored treatment, which uses a person's risk factors and mathematical models to calculate the expected benefit of treatment, by considering:


???A person's risk of a heart attack or stroke without treatment;

???How much a statin decreases the risk; and

???Potential harms from the treatment


"These are the three factors that determine the net benefit of a treatment. Our fixation on just one factor, LDL cholesterol, is leading us to often treat the wrong people," Hayward says.


In the recent study, U-M physicians who worked with Yale University School of Medicine used data from statin trials that included Americans ages 30-75 with no history of heart attack.


Study authors evaluated the benefit of five years of treatment that was tailored, on coronary artery disease risk factors such as age, family history, diabetes, high blood pressure, smoking status, and recently CRP, C-reactive protein.


The tailored approach was more efficient (more benefit per person treated) and prevented substantially more heart attacks, strokes and cardiovascular deaths than the currently recommended treat-to-target approaches.


The tailored strategy treated fewer individuals with high-dose statins and saved 500,000 more quality-adjusted life years.


"The bottom line message - knowing your overall heart attack risk is more important than knowing your cholesterol level," Hayward says. "If your overall risk is elevated, you should probably be on a statin regardless of what your cholesterol is and if your risk is very high, should probably be on a high dose of statin," the U-M physician says.


"However, if your LDL cholesterol is high, but your overall cardiac risk is low, taking a statin does not make sense for you," Hayward says. "If your cholesterol is your only risk factor and you're younger, you should work on diet and exercise."


Research has increasingly emerged questioning the value of cholesterol targets and which of statins mechanisms is most important to preventing cardiac events. Cholesterol-lowering drugs work by blocking a key enzyme linked with LDL cholesterol production, but they initiate other changes in the body.


"Statins also affect inflammation on the inside of our blood vessels which is often what causes heart attacks and strokes - it's not just a matter of cholesterol alone," he says.


Additional authors: Harlan M. Krumholz, M.D., Yale University School of Medicine, and Donna M. Zulman, M.D., Justin W. Timbie, Ph.D., and Sandeep Vijan, M.D, all of the VA Center for Health Services Research and Development, VA Ann Arbor Health Care System.


Funding: VA Health Services Research and Development Service's Quality Enhancement Research Initiative and the Measurement Core of the Michigan Diabetes Research & Training Center of the National Institutes of Health.


Source
University of Michigan Health System

ISIS 301012 Reduces Atherosclerotic Plaques In Animal Models

Isis
Pharmaceuticals, Inc. (Nasdaq: ISIS) today announced results of a study
showing that ISIS 301012 reduced atherosclerotic plaques, apoB-100, and
circulating inflammatory cytokines in an animal model of atherosclerosis.
These data support a growing body of evidence demonstrating that ISIS
301012 has the potential to treat patients with coronary artery disease.
Isis recently reported in a Phase 2 trial that ISIS 301012 produced rapid,
dose-dependent and prolonged reductions of its target, apoB-100, with
concomitant reductions in low density lipoprotein (LDL or "bad"
cholesterol), very low density lipoprotein (VLDL), total cholesterol and
triglyceride levels in patients with high cholesterol. ISIS 301012 is a
second-generation antisense drug that inhibits the expression of apoB-100,
a protein critical to the formation and transport of the "bad" cholesterol
particles involved in heart disease -- LDL and VLDL. Rosanne Crooke, Ph.D.,
Director of Cardiovascular Research of Isis Pharmaceuticals, presented
these data at the Arteriosclerosis, Thrombosis and Vascular Biology (ATVB)
meeting in Denver, Colorado.


ISIS 301012 was administered to mice that were bred to contain no LDL
receptor. These transgenic mice also expressed human apoB-100. In this
transgenic model, mice develop extensive atherosclerotic plaques. A 14-week
treatment with ISIS 301012 produced a dose-dependent reduction in apoB-100
levels, with concomitant decreases in aortic plaque volume. At 50 mg/kg/wk,
ISIS 301012 treatment reduced the levels of apoB-100 by 69% (p







ABOUT ISIS 301012


ISIS 301012 is a second-generation antisense drug that inhibits
apoB-100, a protein critical to the synthesis and transport of the "bad"
cholesterol involved in heart disease -- low density lipoprotein
cholesterol (LDL) and very low density lipoprotein (VLDL). Lowering
cholesterol and triglyceride levels is a key component in the prevention
and management of cardiovascular disease.


Development plans for ISIS 301012 include the rapid development of the
drug for patients with familial hypercholesterolemia (FH), a genetic
disorder that causes extremely high cholesterol levels and results in the
early onset of heart disease. ISIS 301012 has the potential for an
accelerated pathway to commercialization because of the unmet medical need
in this desperate patient population. Additional trials have been designed
to address the larger commercial market represented by the traditional
population of patients with high cholesterol who are still not reaching
their targeted cholesterol levels.


In September 2005, Isis initiated the Phase 2 development program of
ISIS 301012. Phase 2 trials of ISIS 301012 are being conducted in patients
with high cholesterol. Isis is continuing its Phase 2 single-agent trial
using higher dosing (300 and 400 mg/wk) of ISIS 301012 in patients with
high cholesterol. Isis is also conducting a Phase 2 trial of ISIS 301012 in
combination with statin therapy in patients with high cholesterol. Isis is
also conducting Phase 2 studies of ISIS 301012 in FH.


Isis recently reported initial data from the low-dose cohorts of a
Phase 2 clinical trial of ISIS 301012 as a single-agent in patients with
high cholesterol. ISIS 301012 produced rapid, dose-dependent and prolonged
reductions of its target, apoB-100, with concomitant reductions in LDL,
VLDL, total cholesterol and triglyceride levels in patients with high
cholesterol. In Phase 1 trials, ISIS 301012 produced rapid, dose-dependent
and prolonged reductions of its target, apoB-100, with concomitant
reductions in LDL, VLDL, total cholesterol and triglycerides in normal
subjects with elevated cholesterol. In a drug-drug interaction study, ISIS
301012 did not interact with simvastatin or ezetimibe, currently available
lipid lowering drugs with which ISIS 301012 may be dosed in combination.
Additionally, the drug has been well tolerated.


ABOUT CHOLESTEROL AND CARDIOVASCULAR DISEASE


According to the American Heart Association, an estimated 107 million
American adults have total blood cholesterol values of 200 mg/dL and
higher, and of these about 38 million American adults have levels of 240 or
above. In adults, total cholesterol levels of 240 mg/dL or higher are
considered "high risk". Levels from 200 to 239 mg/dL are considered
"borderline-high risk". Low-density lipoprotein, or LDL, known as the "bad"
cholesterol, can clog arteries, increasing the risk of heart attack and
stroke.


According to the World Health Organization (WHO), heart disease and
stroke kill 17 million people a year, which is almost one-third of all
deaths globally. By 2020, the WHO projects that heart disease and stroke
will become the leading cause of both death and disability worldwide, with
the number of fatalities projected to increase to over 20 million a year
and by 2030 to over 24 million a year.


Familial hypercholesterolemia is a dominantly inherited genetic
condition that results in markedly elevated LDL (low-density lipoprotein)
cholesterol levels beginning at birth, and resulting in heart attacks at an
early age. Affected people have consistently high levels of low-density
lipoprotein, which leads to premature atherosclerosis of the coronary
arteries.


ABOUT ISIS' SYMPHONY GENISIS COLLABORATION


In April 2006, Isis entered into a collaboration with Symphony Capital
Partners, L.P. and a group of co-investors to form Symphony GenIsis, Inc.,
capitalized with $75 million, to fund the development of Isis'
cholesterol-lowering drug, ISIS 301012, and two novel drugs from Isis'
metabolic disease program. Isis licensed to Symphony GenIsis the
intellectual property for its apoB-100, glucagon receptor and
glucocorticoid receptor programs. The financing will support Isis'
development of ISIS 301012 through the completion of
registration-supporting clinical studies in patients with familial
hypercholesterolemia and the completion of Phase 2b clinical trials in
patients with high cholesterol. The financing will also support Isis'
development of two novel diabetes drugs through initial proof of concept in
human clinical trials. In addition to providing the financial support to
move these drugs forward aggressively, the transaction allows Isis to
continue to control and manage the development of ISIS 301012 and two other
potentially valuable drugs through key development milestones.


ABOUT ISIS PHARMACEUTICALS, INC.


Isis is exploiting its expertise in RNA to discover and develop novel
drugs for its product pipeline and for its partners. The Company has
successfully commercialized the world's first antisense drug and has 15
drugs in development. Isis' drug development programs are aimed at treating
cardiovascular, metabolic and inflammatory diseases. Isis' partners are
focused in disease areas such as inflammatory, ocular, viral and
neurodegenerative diseases, and cancer. In its Ibis division, Isis is
developing and commercializing the IBIS biosensor system, a revolutionary
system to identify infectious organisms. As an innovator in RNA-based drug
discovery and development, Isis is the owner or exclusive licensee of
approximately 1,500 issued patents worldwide. Additional information about
Isis is available at isispharm


.
This press release includes forward-looking statements regarding the
development, therapeutic potential and safety profile of ISIS 301012 for
the treatment of high cholesterol and cardiovascular disease. Any statement
describing Isis' goals, expectations, intentions or beliefs is a
forward-looking statement and should be considered an at-risk statement,
including those statements that are described as Isis' goals. Such
statements are subject to certain risks and uncertainties, particularly
those inherent in the process of discovering, developing and
commercializing drugs that are safe and effective for use as human
therapeutics, and in the endeavor of building a business around such
products. Isis' forward-looking statements also involve assumptions that,
if they never materialize or prove correct, could cause its results to
differ materially from those expressed or implied by such forward-looking
statements. Although Isis' forward-looking statements reflect the good
faith judgment of its management, these statements are based only on facts
and factors currently known by Isis. As a result, you are cautioned not to
rely on these forward-looking statements. These and other risks concerning
Isis' programs are described in additional detail in Isis' annual report on
Form 10-K for the year ended December 31, 2005, which is on file with the
U.S. Securities and Exchange Commission (SEC) and available from the
Company.


Isis Pharmaceuticals, Inc.

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View drug information on Glucagon.

The Facts About Soy Protein And Heart Health

Recent controversy has surfaced regarding the efficacy of soy protein consumption in reducing serum cholesterol. Of primary concern is whether a 1995 meta-analysis (which generated considerable excitement in the medical community) accurately estimated the impact of soy consumption on cholesterol lowering. Following are the facts you should know about soy and heart health.


FACT: Experts agree soy protein lowers cholesterol


A 2006 American Heart Association (AHA) research review found that soy protein lowers blood cholesterol above and beyond that realized from a low fat, low cholesterol diet. This finding is consistent with the U.S. Food and Drug Administration (FDA) recognizing that soy protein lowers cholesterol by between 3 and 8 percent.


FACT: Experts agree soy has additional heart health benefits


The AHA report noted that soy foods are heart healthy because of their high content of polyunsaturated fats, fiber, vitamins, minerals and low content of saturated fat, making them an ideal substitute for less healthy foods that are high in saturated fat and cholesterol. The FDA and, similarly, the AHA have agreed that soy foods appear to modestly lower triglycerides and raise HDL ("Good") blood cholesterol levels.


FACT: Eight governments recognize the heart health benefits of soy


Authorities around the world have approved health claims supporting the consumption of soy protein and a lowering of blood cholesterol, including the USA, Korea, Japan, Brazil, Philippines, Indonesia, Malaysia and the United Kingdom. These claims were approved based on an extensive review of scientific literature to determine that the relationship between soy protein and lowered cholesterol was well established. It's the weight of this scientific evidence that led so many government health authorities to approve soy/heart health claims.


FACT: Soy protein is a food, not a prescription drug


Soy foods have the unique ability to both lower LDL ("Bad") cholesterol and lower triglycerides, but not to the degree expected from cholesterol-lowering medications. That soy products have been found to lower blood cholesterol even a small amount, however, has the potential to dramatically impact public health. One may argue whether a 3 8 percent reduction in cholesterol is "clinically significant," but the bottom line is that heart disease prevention depends on small life changes. Neither pharmaceuticals nor soy foods are by themselves panaceas for a healthy heart.


Solae Company

PO Box 88940

St. Louis, MO 63188

United States

solae

Trans Fat Ban: Watch Saturated Fats And Calories Too

In December, New York City passed a law to phase out the use of trans fat in restaurants. Other cities, including Boston and Chicago, might follow suit. According to Alice H. Lichtenstein, DSc, Gershoff professor of nutrition science and policy at the Friedman School of Nutrition Science and Policy at Tufts University, the ban is a step in the right direction, but restaurateurs need to replace partially hydrogenated fat with unsaturated fat. If they choose saturated fat it would diminish the health benefits of this new initiative. Another new regulation that requires some restaurants to provide calorie information as prominently as price might be even more important, notes Lichtenstein.


"There is no biological need for trans fat and intake is associated with adverse health outcomes. However, the media attention on the trans fat announcement to the exclusion of the calorie labeling is unfortunate. Two-thirds of Americans are overweight or obese. The New York City Department of Health and Mental Hygiene has proposed that the calorie content of food items be displayed as prominently as the price, at the point of purchase," says Lichtenstein, also director of the Cardiovascular Nutrition Laboratory at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts.


"That means," Lichtenstein continues, "that if you are wavering between placing an order for a small versus a medium order of French fries, both the price and the number of calories per serving will be displayed. People will become more aware of the caloric cost of the foods they order, and the next step on a public health level would be to educate the consumer on the amount of calories their body needs per day. This way, they will be able to put the numbers they see on the board or menu into perspective. Because the amount of food and beverages we eat that is prepared outside the home is so large, even if this regulation just covers a fraction of food service establishments, it can have a tremendous impact on caloric intake."


"Trans fat," says Lichtenstein, "is a double whammy, because like saturated fat, it raises levels of LDL or ???bad cholesterol,??™ but it also lowers levels of HDL or ???good??™ cholesterol." Most of the trans fats we eat are formed during the partial hydrogenation of oils used in fried foods and commercial baked goods. Partially hydrogenated oils provide processed foods with longer shelf lives and therefore greater economic profitability.


"But, trans fat is just one part of the diet. In general, people are still eating far more saturated fat than trans fat, and both need to be reduced in order to maintain optimal cholesterol levels and promote heart health," says Lichtenstein. "And the big giant ???" total calories ???" is always looming in the background."















In one study to assess the effects of consuming different types of oils on cholesterol levels, led by Lichtenstein and published earlier this year, fifteen adult volunteers with moderately high LDL cholesterol were fed each of four diets with a different source of primary fat, including partially hydrogenated soybean oil (trans fat), palm oil (50 percent saturated fat), non-hydrogenated soybean oil (only 16 percent saturated fat), and canola oil (only 7 percent saturated fat).


The results, published in the American Journal of Clinical Nutrition (AJCN), reported that after a trial of 35 days on each diet, participants consuming the partially hydrogenated soybean oil and palm oil diets had levels of LDL cholesterol that were 12 and 14 percent higher, respectively, than when consuming the non-hydrogenated soybean oil diet. An even greater difference was observed when the partially hydrogenated soybean oil and palm oil diets were compared to the canola oil diet. While participants were on the partially hydrogenated soybean oil and palm oil diets their LDL levels were 16 and 18 percent higher, respectively, than when on the canola oil diet.


"On the basis of this and other work, it??™s clear that phasing out partially hydrogenated oils (trans fats) will improve diet in some ways", says Lichtenstein, corresponding author on the AJCN study. "However, just decreasing trans fat intake without changing other dietary habits, such as minimizing saturated fat intake and controlling total calorie intake, will result in some real disappointments with respect to both heart health and obesity."


Lichtenstein recommends that other cities monitor the successes and challenges of the trans fat ban in New York City before implementing their own regulations, and also advises that the focus on the new regulations shift to the mandate to display calorie labeling in food service establishments, and educating people about their total daily caloric requirements.


Vega-Lopez S, Ausman LM, Jalbert SM, Erkkila AT, Lichtenstein AH. ???Palm and partially hydrogenated soybean oils adversely alter lipoprotein profiles compared with soybean and canola oils in moderately hyperlipidemic subjects.??? American Journal of Clinical Nutrition. 2006 (July);84(1):54-62.


The Gerald J. and Dorothy R. Friedman School of Nutrition Science and Policy at Tufts University is the only independent school of nutrition in the United States. The school??™s eight centers, which focus on questions relating to famine, hunger, poverty, and communications, are renowned for the application of scientific research to national and international policy. For two decades, the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University has studied the relationship between good nutrition and good health in aging populations. Tufts research scientists work with federal agencies to establish the USDA Dietary Guidelines, the Dietary Reference Intakes, and other significant public policies.


Tufts University

Medford Somerville, MA

United States

Tufts University

Risk For High-Grade Prostate Cancer May Be Reduced By Low Cholesterol

Men with lower cholesterol are less likely than those with higher levels to develop high-grade prostate cancer - an aggressive form of the disease with a poorer prognosis, according to results of a Johns Hopkins collaborative study.



In a prospective study of more than 5,000 U.S. men, epidemiologists say they now have evidence that having lower levels of heart-clogging fat may cut a man's risk of this form of cancer by nearly 60 percent.



"For many reasons, we know that it's good to have a cholesterol level within the normal range," says Elizabeth Platz, Sc.D., M.P.H., associate professor at the Johns Hopkins Bloomberg School of Public Health and co-director of the cancer prevention and control program at the Johns Hopkins Kimmel Cancer Center. "Now, we have more evidence that among the benefits of low cholesterol may be a lower risk for potentially deadly prostate cancers."



Normal range is defined as less than 200 mg/dL (milligrams per deciliter of blood) of total cholesterol.



Platz and her colleagues found similar results in a study first published in 2008, and in 2006, she linked use of cholesterol-lowering statin drugs to lower risk of advanced prostate cancer.



For the current study, Platz, members of the Southwest Oncology Group, and other collaborators analyzed data from 5,586 men aged 55 and older enrolled in the Prostate Cancer Prevention Trial from 1993 to 1996. Some 1,251 men were diagnosed with prostate cancer during the study period.



Men with cholesterol levels lower than 200 mg/dL had a 59 percent lower risk of developing high-grade prostate cancers, which tend to grow and spread rapidly. High-grade cancers are identified by a pathological ranking called the Gleason score. Scores at the highest end of the scale, between eight and 10, indicate cancers considered the most worrisome to pathologists who examine samples of the diseased prostate under the microscope.



In Platz's study, cholesterol levels had no significant effect on the entire spectrum of prostate cancer incidence, only those that were high-grade, she says.



Platz cautions that, while the group took into account factors that could bias the results, such as smoking history, weight, family history of prostate cancer, and dietary cholesterol, other things could have affected their results. One example is whether men in the study were taking cholesterol-lowering drugs at the time of the blood collections, a data point the researchers expect to analyze soon.



Results of the current study are expected to be published online Nov. 3 in the journal Cancer Epidemiology, Biomarkers & Prevention. Also in the journal is an accompanying paper from the National Cancer Institute showing that lower cholesterol in men conferred a 15 percent decrease in overall cancer cases.



"Cholesterol may affect cancer cells at a level where it influences key signaling pathways controlling cell survival," says Platz. "Cancer cells use these survival pathways to evade the normal cycle of cell life and death."



She says that targeting cholesterol metabolism may be one route to treating and preventing the disease, but this remains to be tested.



Funding for the study was provided by the National Cancer Institute.



Authors of the study include Cathee Till, Phyllis J. Goodman, Marian L. Neuhouser and Alan R. Kristal from the Fred Hutchinson Cancer Research Center; Howard L. Parnes, William D. Figg, and Demetrius Albanes from the National Cancer Institute; Eric A. Klein from the Cleveland Clinic; and Ian M. Thompson Jr., from the University of Texas Health Sciences Center.

About 63% Of U.S. Women Concerned About High Cholesterol; Only 32% Know Their Number, Survey Finds

About 63% of U.S. women are concerned about high cholesterol, but only 32% know their cholesterol number, according to a nationwide survey released Tuesday by the Society for Women's Health Research, United Press International reports (United Press International, 8/21).

According to a SWHR release, the firm GfK Custom Research North America conducted the telephone survey of 524 women from June 29 to July 1. The survey found that nearly 88% of the women know that high cholesterol is linked to hardening of the arteries and heart disease, and almost 85% know high cholesterol can lead to stroke. However, only 50% of the women reported receiving a cholesterol test in the past year (SWHR release, 8/21). About 60% of women surveyed said they actively were trying to manage their cholesterol (Soltis, New York Post, 8/22).

According to the survey, only 35% of the women knew any of the four numbers for monitoring cholesterol: total cholesterol level, low density lipoprotein, high density lipoprotein and triglyceride level. Nearly all women know that exercise can help fight high cholesterol, and about 95% know that eating more fruits and vegetables and less high-fat foods can help heart health, the survey found (United Press International, 8/21).

"Clearly, strides have been made in educating women on the risks of high cholesterol, but the disconnect between awareness and action needs to be addressed," Phyllis Greenberger, president and CEO of SWHR, said, adding, "Knowing your cholesterol number is the first step in controlling cholesterol" (SWHR release, 8/21).

"Reprinted with permission from kaisernetwork. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at kaisernetwork/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork, a free service of The Henry J. Kaiser Family Foundation . © 2005 Advisory Board Company and Kaiser Family Foundation. All rights reserved.

Protein controls metabolism and circadian rhythms - U of T research

University of Toronto researchers have gained new insight into how a specific protein may control circadian rhythms and metabolic processes, which has implications for treating cholesterol-related diseases.


U of T professor Henry Krause and his colleagues have identified heme, an iron compound, best known for its oxygen carrying capabilities in hemoglobin, as the molecule that allows the protein E75 to regulate a number of key developmental processes. In a paper published in the July 29 issue of Cell, the researchers use fruit flies to show that heme attaches itself to E75, allowing the protein to respond to a variety of cellular signals necessary for controlling systemic processes such as metabolism and circadian rhythms, the human body's clock.


Since the human body contains a nuclear hormone receptor comparable to E75, the research is an important first step to understanding how people metabolize fat, how their circadian rhythms are regulated and how their bodies age. The researchers studied fruit flies, because they have many genes similar to those found in humans and they reproduce rapidly.


"The important role heme plays in the body's smooth operation has been previously identified, but it was quite unexpected to find it binding to a member of the nuclear hormone receptor family of proteins," says Krause, a professor in the Banting and Best Department of Medical Research and the Department of Medical Genetics and Microbiology."


There are practical reasons for exploring the relationship between heme and E75, says Krause, whose lab purified the protein, then used mass spectrometry to analyze it. About 15 per cent of successful drugs on the market target nuclear hormone receptors like E75.


"In addition to finding out how E75 and its human counterpart control metabolic processes, and learning how to control these functions, it should also help us to discover the other hormones that control the rest of this nuclear hormone receptor family," says Krause. As they are identified, new drugs can be designed to control the many metabolic diseases, such as high cholesterol, associated with the malfunction of these proteins.


Other researchers involved in this study include U of T professor Aled Edwards, head of the Structural Genomics Consortium; U of T post-doctoral student Jeff Reinking, master's degree holder Mandy Lam, doctoral students Keith Pardee and Heidi Sampson and post-doctoral fellow Ping Yang; researchers Shawn Williams and Wendy White from GlaxoSmithKline; and technician Suya Liu and Professor Gilles Lajoie from the University of Western Ontario.


The study was funded by the Canadian Institutes of Health Research and GlaxoSmithKline.


CONTACT:


Elaine Smith

U of T Public Affairs

416-978-5948

elaine.smithutoronto.ca


Henry Krause

h.krauseutoronto.ca

416-978-8602

University of Toronto

utoronto.ca

Nearly Half Of Statin-Treated Patients Not Currently Reaching LDL-C Target

Almost half (48%) of statin-treated patients are not meeting target levels of low-density lipoprotein cholesterol (LDL-C), according to the results of a new international study, conducted by Merck Sharp & Dohme Limited and presented today at the European Society of Cardiology (ESC) congress in Barcelona, Spain.1 Additionally, nearly three-quarters (73%) of the same patients had at least one lipid abnormality across LDL-C, HDL-C and triglyceride levels.1 In a separate UK survey, results have also shown a need for improving education of the public around how to proactively manage their lipid levels.2



The DYSlipidemia International Study (DYSIS) was a large study involving 22,000 statin-treated patients, extending across 12 countries in Europe and Canada. 28 centres were involved from the UK.1 Patients were aged 45 and older, had been on statin-treatment for three months or more, and had other cardiovascular conditions, including high blood pressure, diabetes, family history of premature CV disease or had coronary heart disease, among others.1 The study assessed the prevalence of LDL-C, HDL-C and triglyceride levels according to lipid goals in ESC guidelines.1



The DYSIS results showed that even in those patients reaching their LDL-C target, 25% still had abnormal levels of triglycerides and/or HDL-C.1 Additionally, 38% of the study population had elevated triglyceride levels, and 26% had HDL-C levels below target.1



"Although statins have represented a considerable advancement in cardiovascular disease prevention, the DYSIS results indicate that clinicians must continue to monitor their patients' lipid levels closely, including LDL-C, HDL-C and triglyceride levels," said Professor David Wood Lead UK investigator and Professor of Cardiovascular Medicine at Imperial College London, and Honorary Consultant Cardiologist at Imperial College Healthcare NHS Trust. He continued: "Many patients could benefit from additional management in order to further reduce their risk of cardiovascular disease, achieved through improved adherence, lifestyle changes, or further drug intervention."



In conjunction with the release of the DYSIS data, MSD UK announced findings from a UK-wide survey of over 2000 people. According to the survey:2


- the majority of people (85%) in the UK now know that cardiovascular disease is the leading cause of death in the UK and many are aware of LDL-C ('bad' cholesterol) and HDL-C ('good' cholesterol) (71% and 59% respectively).


- Despite this wide awareness, many did not know 'how to change' their LDL-C (57%) or HDL-C (74%).


- Furthermore, only around one third (36%) had heard of 'triglycerides', with most (77%) thinking triglycerides should be raised rather than reduced and 90% not knowing how to change them.



Dr Marc Evans, Consultant Diabetologist at Llandough Hospital in Wales commented: "DYSIS highlights that a significant CVD risk can remain for some patients." He continued: "A comprehensive approach that addresses HDL-C and triglycerides as well as LDL-C levels may be beneficial in these cases. This can be particularly important for patients who are at high risk of CVD such as secondary prevention patients, people with diabetes and South Asian populations. The UK survey of the general public also highlighted the need for educating people about the three lipids - this is essential if we want the public to become engaged in their own health."



About DYSIS1


DYSIS is an epidemiological study designed to examine the lipid profile of statin-treated patients (n=22,000) in an out-patient setting. Patients were enrolled from treatment centres across Austria, Canada, Denmark, France, Germany, Ireland, the Netherlands, Norway, Portugal, Spain, Sweden and the United Kingdom.



Patients were eligible for inclusion if they had been on statin therapy for at least three months prior to the time of assessment, aged ?‰?45 years, and had at least one lipid parameter available in their chart while receiving statin therapy. Patients were recruited by primary and secondary care physicians. All patients had a clinical examination and their latest lipid values were recorded.



About the UK-wide public survey2


This survey was conducted by Opinion Matters on behalf of Merck, Sharp & Dohme Ltd. The fieldwork was conducted via an online questionnaire between 27th July and 10th August 2009. The sample consisted of 2140 UK adults.



Source
Merck Sharp & Dohme Limited