Production Of Key Alzheimer's Protein Monitored For First Time In Humans

Science is now poised to answer an important and longstanding question about the origins of Alzheimer's disease: Do Alzheimer's patients have high levels of a brain protein because they make too much of it or because they can't clear it from their brains quickly enough?

Researchers from the Alzheimer's Disease Research Center (ADRC) at Washington University School of Medicine in St. Louis have developed the first safe and sensitive way to monitor the production and clearance rates of amyloid beta peptide (Abeta) in the human central nervous system. According to the authors, the New testing process opens a valuable window into the genesis of Alzheimer's disease that, in addition to helping scientists better understand the origins of the condition, will likely help them improve its diagnosis and treatment.

The scientists' results was published online on June 25 by Nature Medicine.

High levels of Abeta in the brain are a hallmark of Alzheimer's disease and believed to be a pivotal cause of the condition.. Tests that measure Abeta levels in the cerebrospinal fluid have been available for some time. However, those fixed assessments of Abeta gave no indication of whether the flood of Abeta in patient's brains came from an increase in the mechanisms that make the protein or a reduction in the processes that regularly clear it from the brain.

Because Alzheimer's symptoms take many years to develop, some researchers had assumed that the creation and clearance rates for Abeta were very slow. But the initial test of the New technique, applied to six healthy volunteers, suggests the opposite.

"Abeta has the second-fastest production rate of any protein whose production rate has been measured so far," says lead author Randall Bateman, M.D., assistant professor of neurology. "In a time span of about six or seven hours, you make half the amyloid beta found in your central nervous system."

Ideally, the production and clearance rates stay balanced, causing the overall amount of Abeta in the central nervous system to remain constant. In the healthy volunteers who were the first test subjects, Bateman found the production and clearance rates were the same. He is now applying the technique to individuals with Alzheimer's disease.

Researchers are developing Alzheimer's drugs that either decrease Abeta production or increase its clearance, Bateman notes, and the New test could be very important in determining which approach is most effective.

Prior to the New test, the only way to assess the effectiveness of a New Alzheimer's drug was to follow the mental performance of patients receiving the treatment over many months or years.

"This New test could let us directly monitor patients in clinical trials to see if the drug is really doing what we want it to do in terms of Abeta metabolism," Bateman says. "If further study confirms the validity of our test, it could be very valuable for determining which drugs go forward in clinical trials and at what doses."

The test also may be useful in diagnosis of Alzheimer's prior to the onset of clinical symptoms, which occurs after Alzheimer's has inflicted widespread and largely irreversible damage to the brain.

"We hope to study whether we can develop ways to identify potential Alzheimer's patients on the basis of a metabolic imbalance between Abeta synthesis and clearance rates," Bateman says.

The test combines technologies that have been available for some time but only through recent technical and procedural advances has become sufficiently sensitive. Via an intravenous drip, scientists give test subjects a form of the amino acid leucine that has been very slightly altered to label it. Inside the leucine are carbon atoms with 13 neutrons and protons in their nucleus instead of the more common 12 neutrons and protons--in scientific parlance, carbon 13 instead of carbon 12.

"Normally only about 1.1 percent of the carbon atoms in our bodies are carbon 13--the vast majority is carbon 12," Bateman notes. "Physiologically and biochemically, carbon 13 acts just like carbon 12, meaning it won't alter the normal Abeta production and clearance processes and is very safe to use."

Over the course of hours, cells in the brain pick up the labeled leucine and incorporate it into the New copies they make of Abeta and other proteins. Scientists take periodic samples of the subjects' cerebrospinal fluid through a lumbar catheter, purify the Abeta from the samples and then use a device known as a mass spectrometer to determine how much of the Abeta includes carbon-13-labeled leucine.

Tracking the rise of the percentage of Abeta with labeled leucine over time gives scientists the subject's Abeta production rate. When the percentage of Abeta containing labeled leucine plateaus, scientists remove the IV drip supplying the labeled leucine. Periodic sampling of the patients' CSF continues, allowing scientists to get a measurement of how quickly the nervous system clears out the labeled Abeta. In the first test subjects, the test procedure lasted for 36 hours.

Other research groups have expressed an interest in applying the New test to Alzheimer's research and to other neurological disorders such as Huntington's disease.

###

This study was performed in the laboratories of David M. Holtzman, M.D., the Andrew and Gretchen Jones Professor and chair of Neurology, and Kevin E. Yarasheski, Ph.D., associate professor of medicine and assistant director of the Washington University Biomedical Mass Spectrometry Resource. It was also supported by the ADRC, directed by John C. Morris, M.D., the Friedman Distinguished Professor of Neurology.

Bateman RJ, Munsell LY, Morris JC, Swarm R, Yarasheski KE, Holtzman DM. Human amyloid-b synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nature Medicine, June 25, 2006.

Funding from the American Academy of Neurology and the National Institutes of Health supported this research.

View online: http://mednews.wustl.edu/news/page/normal/7348.html?emailID=9821 By Michael Purdy

Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

Contact: Michael C. Purdy

Washington University School of Medicine


Saludos Cordiales
Dr. José Manuel Ferrer Guerra

New Data Demonstrate Sustained Efficacy Of Single Tablet Combination Migraine Therapy Compared To Monotherapy

New Data Demonstrate Sustained Efficacy Of Single Tablet Combination Migraine Therapy Compared To Monotherapy

NYSE: GSK; Nasdaq: POZN) A single tablet combination therapy containing sumatriptan 85 mg, as the succinate salt, formulated with RT Technology(TM), and naproxen sodium 500 mg showed superior sustained pain-free results in treating acute migraine pain compared to use of sumatriptan alone, naproxen sodium alone or placebo, according to New data presented at the Annual Meeting of the American Headache Society (AHS) in Los Angeles. Sustained pain-free was defined as no pain at two hours maintained through 24 hours without use of additional, or rescue, medication. In addition, results showed that patients taking sumatriptan/naproxen sodium needed a rescue medication less often than patients taking sumatriptan alone, naproxen sodium alone or placebo. Findings from two identical studies of migraine sufferers also showed more patients in the sumatriptan/naproxen sodium arm reported pain relief at two hours and four hours compared to sumatriptan alone or placebo.

Recent data suggest that the pathophysiology of migraine is complex and that migraine is not merely a vascular problem, but a result of a chain of events that are both vascular and neurological. These events develop early in the migraine process, often long before a patient actually feels the sensation of headache pain.

"These data suggest that a therapy designed to target multiple mechanisms of migraine may be an effective treatment option and good news for both physicians and migraine patients, many of whom still have not found a treatment that provides both early and sustained relief," said Jan Lewis Brandes, MD, director of the Nashville Neurosciences Institute and lead study investigator.

About the Studies

The studies evaluated the clinical efficacy and tolerability of an acute migraine treatment currently under review by the United States Food and Drug Administration (FDA) under the proposed trade name Trexima(TM) (sumatriptan succinate/naproxen sodium). The data were derived from two identical randomized, double-blind, placebo controlled parallel group, single attack multicenter studies of adult migraineurs in the U.S. Study results indicated:

-- The compound was more effective than sumatriptan 85 mg formulated with RT Technology alone, naproxen sodium 500 mg alone or placebo for pain relief at two hours in study 1 (57, 50, 43, 29 percent respectively) and also in study 2 (65, 55, 44, 28 percent respectively). The compound was more effective than sumatriptan 85 mg formulated with RT Technology alone, naproxen 500 mg alone or placebo for pain relief at four hours in study 1 (72, 61, 54, 37 percent respectively) and in study 2 (78, 66, 55, 37 percent respectively).

-- The compound was more effective than sumatriptan 85 mg formulated with RT Technology alone, naproxen sodium 500 mg alone or placebo for sustained pain free response (from two to 24 hours) in study 1 (23, 14, 10, 7 percent respectively) and in study 2 (25, 16, 10, 8 percent respectively).

-- In comparison to sumatriptan 85 mg formulated with RT Technology alone, naproxen sodium 500 mg alone or placebo, patients in the compound arm were less likely to use as a rescue medication in study 1 (23, 38, 39, 58 percent respectively) and in study 2 (22, 32, 38, 53 percent respectively).

-- In comparisons with placebo, the compound resulted in lower rates of associated symptoms of migraine - photophobia, phonophobia and nausea - at two hours after dosing. Data for nausea show a significant reduction with the compound compared to placebo from two to 24 hours. These results were statistically significant with the exception of nausea incidence in study 1 where a baseline imbalance in the incidence of nausea was present.

-- All treatments were well-tolerated. The adverse event profile of the compound was similar to those of the individual components.


Multiple Mechanisms of Migraine

Migraine pain is believed to be induced not only by the widening of blood vessels, or vasodilation, but also by inflammation, leading to nociception (perception of pain) and central and peripheral sensitization. Understanding the multiple mechanisms of migraine may also explain why migraine sufferers often experience different types of symptoms. For example, during a migraine, stimulation of the trigeminal nerve (fifth cranial nerve, carrying sensory information from the face) may cause referral of pain to any of the nerve's three branches, resulting in facial pain. It can also cause referral of pain to the sensory nerves of the posterior head and neck, resulting in neck pain.

About Imitrex(R) (sumatriptan succinate) Tablets

Imitrex is a prescription medication indicated for the acute treatment of migraine in adults. Imitrex should only be used when a clear diagnosis of migraine has been established. Patients should not take Imitrex if they have certain types of heart disease, history of stroke or TIAs, peripheral vascular disease, Raynaud syndrome, or blood pressure that is uncontrolled. Patients with risk factors for heart disease, such as high blood pressure, high cholesterol, diabetes or are a smoker, should be evaluated by a doctor before taking Imitrex. Very rarely, certain people, even some without heart disease, have had serious heart related problems. Patients who are pregnant, nursing, or taking medications should talk to their doctor.

About Naproxen Sodium

Naproxen sodium is a non-steroidal anti-inflammatory drug (NSAID) and is contained in Anaprox(R), Anaprox DS(R), Naprelan(R), Aleve(R) and in a number of over-the-counter medications. Naproxen sodium is indicated for the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and juvenile arthritis. It is also indicated for the treatment of tendinitis, bursitis, acute gout and for the management of pain and primary dysmenorrhea. Naproxen-containing products should not be used by patients who have had allergic reactions to any product containing naproxen, nor in patients in whom aspirin or other NSAIDs induce the syndrome of asthma, rhinitis, and nasal polyps. Patients who have a history of peptic ulcer or gastrointestinal bleeding, kidney problems, uncontrolled hypertension or heart failure should consult a physician before using naproxen-containing medications. NSAIDs may cause increased risk of serious cardiovascular thrombotic events, myocardial infarction and stroke. This risk may increase with duration of use and in patients with cardiovascular disease or risk factors for cardiovascular disease. Serious gastrointestinal toxicity such as bleeding, ulceration and perforation can occur at any time in patients treated chronically with NSAID therapy and physicians should remain alert for such effects even in the absence of previous GI tract symptoms. Patients who are pregnant or are nursing should consult a physician before use of a naproxen-containing medication.

About GlaxoSmithKline

GlaxoSmithKline (NYSE: GSK) -- one of the world's leading research-based pharmaceutical and healthcare companies -- is committed to improving the quality of human life by enabling people to do more, feel better and live longer. For detailed company information, see GlaxoSmithKline's website: http://www.gsk.com.

About POZEN

POZEN (Nasdaq: POZN) is a pharmaceutical company committed to developing therapeutic advancements for diseases with unmet medical needs where it can improve efficacy, safety, and/or patient convenience. Since its inception, POZEN has focused its efforts primarily on the development of pharmaceutical products for the treatment of acute and chronic pain and other pain related conditions. The company's common stock is traded on The Nasdaq Stock Market under the symbol "POZN".

For detailed company information, including copies of this and other press releases, see POZEN's website: http://www.pozen.com .

Statements included in this press release that are not historical in nature are "forward-looking statements" within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. You should be aware that our actual results could differ materially from those contained in the forward-looking statements, which are based on management's current expectations and are subject to a number of risks and uncertainties, including, but not limited to, our failure to successfully commercialize our product candidates; costs and delays in the development and/or FDA approval of our product candidates, including as a result of the need to conduct additional studies, or the failure to obtain such approval of our product candidates, including as a result of changes in regulatory standards or the regulatory environment during the development period of any of our product candidates; uncertainties in clinical trial results or the timing of such trials, resulting in, among other things, an extension in the period over which we recognize deferred revenue or our failure to achieve milestones that would have provided us with revenue; our inability to maintain or enter into, and the risks resulting from our dependence upon, collaboration or contractual arrangements necessary for the development, manufacture, commercialization, marketing, sales and distribution of any products; competitive factors; our inability to protect our patents or proprietary rights and obtain necessary rights to third party patents and intellectual property to operate our business; our inability to operate our business without infringing the patents and proprietary rights of others; general economic conditions; the failure of any products to gain market acceptance; our inability to obtain any additional required financing; technological changes; government regulation; changes in industry practice; and one-time events, including those discussed herein and in our Quarterly Report on Form 10-Q for the period ended March 31, 2006. We do not intend to update any of these factors or to publicly announce the results of any revisions to these forward-looking statements.

POZEN Inc. sponsored and GlaxoSmithKline supported these studies.
POZEN Inc.; GlaxoSmithKline
http://www.gsk.com



Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Kiss1 Neurons And Neuroendocrine Regulation

Mammalian ovulation is the culmination of a complex neurohormonal signaling pathway. Gonadotropin-releasing hormone (GnRH) is normally under tonic negative feedback control, but estrogen triggers a GnRH/luteinizing hormone (LH) surge that leads to ovulation. This week, Smith et al. Investigated the kisspeptins as potential mediators of this signaling cascade. This family of neuropeptides, encoded by the Kiss1 gene, is expressed in neurons of the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus. The authors hypothesized that activation of Kiss1 neurons is linked to the GnRH/LH surge. In rats, estradiol acted at the two nuclei with opposite effects. Kiss1 mRNA expression was inhibited in the arcuate nucleus but upregulated in the AVPV. The latter coincided with expression of the immediate early gene Fos, consistent with their activation during the GnRH/LH surge. As necessary for their hypothesis, Kiss1 neurons also expressed the estradiol receptor ERa.

####

News tips from the Journal of Neuroscience
Jeremy T. Smith, Simina M. Popa, Donald K. Clifton, Gloria E. Hoffman, and Robert A. Steiner

Contact: Sara Harris

Society for Neuroscience


Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Parkinson's Disease Mechanism Discovered

Howard Hughes Medical Institute researchers have pinpointed defects in a critical cellular pathway that can lead to the death of dopamine-producing nerve cells and ultimately Parkinson's symptoms. Their studies have also identified a New way to rescue dying neurons in several animal models of Parkinson's disease.

According to the researchers, the findings offer a promising opportunity for developing New drugs to treat the underlying causes of Parkinson's disease and related neurodegenerative disorders.

The research team, which included Howard Hughes Medical Institute investigators Susan L. Lindquist and Nancy M. Bonini, published their findings in June 2006, in Science Express, which provides electronic publication of selected Science papers in advance of print. Lindquist is at the Whitehead Institute for Biomedical Research and Bonini is at the University of Pennsylvania. Antony Cooper of the University of Missouri-Kansas City and Aaron Gitler, who is in Lindquist's laboratory, were co-lead authors on the paper. Other co-authors were from Purdue University, the University of Alabama, Medical College of Georgia and New York University.

The researchers' began their experiments seeking to clarify the role of the protein alpha-synuclein in Parkinson's disease. It had long been known that abnormalities in alpha-synuclein could cause a lethal buildup of the protein in neurons. Researchers also knew that accumulation of alpha-synuclein caused neurodegeneration in animal models of Parkinson's disease, but little was known about alpha-synuclein's normal cellular function or how it contributed to disease. One major problem facing researchers, Lindquist said, was that alpha-synuclein accumulation causes a range of abnormalities, and it was not possible to sort out which were causes and which were effects in Parkinson's disease pathology.

However, Lindquist's team developed a technique to switch on overproduction of alpha-synuclein in yeast, so they could determine which abnormalities arose earliest in the pathological process. Those experiments by Cooper revealed that an important early defect affected the machinery that transports proteins between two major cellular organelles -- the endoplasmic reticulum (ER) and the Golgi apparatus. The endoplasmic reticulum is the site of protein production, and the Golgi apparatus is the cell's "post office," which modifies, sorts and adds the molecular addresses that designate the specific destinations in the cell where proteins are needed.

Lindquist and her colleagues had conducted a genetic screen in yeast to discover genes whose activity affected the toxicity of alpha-synuclein. That study showed that genes enhancing ER-to-Golgi trafficking prevented alpha-synuclein toxicity. In particular, they found that one protein, called Ypt1p, which is involved in regulating trafficking could also be switched on to suppress alpha-synuclein toxicity in yeast cells.

"Our findings indicated that this ER-to-Golgi trafficking pathway is intimately coupled to the pathology, although in humans there are likely others involved as well, given how many genes we found that modified alpha-synuclein toxicity," said Lindquist. "But these findings were so persuasive that we decided we needed to test whether enhancing Ypt1p activity would suppress alpha-synuclein toxicity in animal models of the disease. Fortunately, we had an excellent team of collaborators with expertise in these models, who could conduct these studies."

The researchers next studied whether enhancing activity of the mammalian Ytp1p counterpart, called Rab1, suppressed alpha-synuclein toxicity in the fruitfly Drosophila, the roundworm C. Elegans and in cultures of rat neurons. Bonini and her colleagues tested the effect in fruitflies; co-author Guy Caldwell and his colleagues at the University of Alabama performed the tests in roundworms; and co-author Jean-Christophe Roche and his colleagues at Purdue performed the tests in rat neurons. Caldwell is also coordinator of HHMI's Undergraduate Research Intern Program at the University of Alabama.

"They all came back with the same answer," said Lindquist. "All saw significant suppression of toxicity; although none saw complete suppression, which confirms our yeast studies showing that other pathways are affected by alpha-synuclein accumulation. However, importantly, the results of our genetic screen have given us a way to ask important questions about these other aspects of alpha-synuclein toxicity," she said.

Lindquist also said the findings give important clues to why dopamine-producing neurons in the brain are the most vulnerable neurons to toxic alpha-synuclein accumulation. The death of such neurons reduces brain dopamine levels, causing the tremors and other symptoms of Parkinson's disease. Dopamine is one of many types of neurotransmitter -- chemical signals that one neuron launches at its neighbor to trigger a nerve impulse.

"Of all the neurotransmitters, dopamine has a higher potential for being toxic," she said. "Its toxicity is normally prevented in the neuron by sequestration within vesicles for transport from the ER. But a defect in ER trafficking caused by alpha-synuclein accumulation could cause the toxic buildup of dopamine to occur in these neurons."

Lindquist and her colleagues believe their findings will guide the search for New drugs that suppress alpha-synuclein toxicity by enhancing the machinery of ER-to-Golgi transport. Thus, she said, they have already conducted a screen of 150,000 compounds for those with therapeutic potential.

"We have found compounds that reverse alpha-synuclein toxicity, and we plan to publish those results soon," she said. "These findings are exciting because they tell us we have a platform for discovering new therapeutic strategies and for speeding the process of discovering treatments for these disorders."

Current treatments for Parkinson's disease do not aim at protecting the dopamine-producing neurons themselves. Rather, the treatments seek to restore dopamine levels in the brain or to treat symptoms of the disease.

Lindquist cautioned that the findings "have not by any means proven that this mechanism of pathology or the compounds that affect it are relevant to humans. However, given the fact that we've found the same results in yeast, flies, worms and rat neurons, I would be very surprised if we didn't find that they were relevant in humans," she said.

Bonini added that the research team's findings illustrate the power of animal models in revealing insight into Parkinson's disease. "These results highlight the value and importance of very simple model organisms in studying these disorders," she said. "For example, yeast is only a single cell, not even a neuron, and yet it can reveal proteins that modify the toxicity of alpha-synuclein. And in flies, it is possible to study the effects of these proteins on alpha-synuclein toxicity in dopaminergic neurons. Clearly, these kinds of basic research collaborations, in which you can progress up the evolutionary tree using multiple model organisms, will open the door to new therapeutic opportunities for Parkinson's," said Bonini.

###

Contact: Jim Keeley
Howard Hughes Medical Institute



Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Nexium removed from Medicaid list

MONTPELIER — The acid reflux-fighting drug Nexium has been taken off the state's preferred drug list for Medicaid patients as officials seek to slow the rapid rise in costs for prescription drugs.

The heavily advertised "purple pill," made by AstraZeneca, will not be available to patients under the publicly funded health care system unless their doctors certify that no other drug is effective with the individual patient.

The move comes as the state tries to save money in a health program that is projected to have a $42 million deficit as of July 1, 2007, and as drug costs have moved to the forefront of the trend toward higher health care expenditures.

"It's not unique to Vermont. It's not unique to Medicaid," said Ann Rugg, deputy director of the Office of Vermont Health Access, which administers the Medicaid program. Drug costs "are number one for any insurance program."

Prescription drugs cost the state $191.4 million in the 12 months ending last June 30. That was up 24 percent from the previous year and was three times more than the cost for Medicaid patients' inpatient hospitalizations.

"Using chemicals for treatment is a tool for saving costs in other areas and it has a huge impact on quality of life," Rugg said.

But brand-name drugs often are significantly more expensive than generic versions. And in the case of Nexium, the Drug Utilization Review Board, a group of 12 doctors and pharmacists that studies the use of medicines, determined that "there are adequate clinically appropriate alternatives available at lesser cost," Rugg said.

Medicaid patients can have pharmacists automatically fill prescriptions for medications on the preferred drug list. For a drug not on the list, the pharmacist has to ask the doctor to get approval from the state's prescription drug manager.


Saludos Cordiales
Dr. José Manuel Ferrer Guerra

New Data Shows Crestor Helped African American, Hispanic American and South Asian American Patients Significantly Lower LDL-C and Achieve Cholesterol

New Data Shows Crestor Helped African American, Hispanic American and South Asian American Patients Significantly Lower LDL-C and Achieve Cholesterol Goals

WILMINGTON, Del., June 22, 2006 /PRNewswire-FirstCall/ -- Data from an analysis of three first-ever large-scale, prospective studies presented today at the International Symposium on Atherosclerosis (ISA) demonstrate that AstraZeneca's CRESTOR(R) (rosuvastatin calcium) effectively reduced cholesterol levels in several distinct ethnic populations that have generally been underrepresented in clinical trials -- African American, Hispanic American and South Asian American. The three studies, ARIES (African American Rosuvastatin Investigation of Efficacy and Safety), STARSHIP (STudy Assessing RoSuvastatin in HIspanic Population) and IRIS (Investigation of Rosuvastatin In South Asian Subjects) are all part of AstraZeneca's US GALAXY program which is designed to address important unanswered questions in statin research and to investigate the impact of CRESTOR on cardiovascular risk reduction and patient outcomes.


"These ethnic groups represent a significant -- and growing -- sector of the U.S. Population and have specific health-related concerns based on genetics, demographic structure and other cultural factors(1)," said Prakash C.. Deedwania, M.D., Chief of Cardiology at the Veterans Affairs Central California Health Care System and Professor of Medicine at the University of California, San Francisco, School of Medicine. "The results of ARIES, STARSHIP and IRIS have, for the first time, shown us that we can effectively lower LDL-C or 'bad' cholesterol levels and bring a majority of patients to goal with the 10-mg start dose of CRESTOR in these populations."

ARIES (774 patients), STARSHIP (696) and IRIS (740) were each six-week, randomized, controlled, open-label, multi-Center trials designed to evaluate the efficacy of CRESTOR and atorvastatin in various ethnic populations with elevated cholesterol -- African Americans, Hispanic Americans and South Asian Americans, respectively. After a six-week dietary lead-in, patients with hypercholesterolemia were randomized to one of four open-label treatments for six weeks: CRESTOR 10 or 20 mg or atorvastatin 10 or 20 mg.

Specific results from the studies include:

In ARIES, CRESTOR 10 and 20 mg reduced LDL-C by 37 and 46 percent, compared to 32 and 39 percent at similar doses of atorvastatin (p<0.017). CRESTOR 10 and 20 mg brought 66 and 79 percent of patients to their individual NCEP ATP III cholesterol goals.

The STARSHIP study showed that CRESTOR 10 and 20 mg reduced LDL-C by 45 and 50 percent compared to 36 and 42 percent with atorvastatin 10 and 20 mg (p<0.017). CRESTOR 10 and 20 mg brought 78 and 88 percent of patients to their individual NCEP ATP III cholesterol goals.

Results of the IRIS study demonstrate that CRESTOR 10 mg reduced LDL-C by 45 percent compared to 40 percent with atorvastatin 10 mg (p<0.017). The 50 percent LDL-C reduction seen with CRESTOR 20 mg compared to the 47 percent reduction seen with atorvastatin 20 mg was not statistically significant. CRESTOR 10 and 20 mg brought 79 and 89 percent of patients to their individual NCEP ATP III cholesterol goals.

Both treatments were well-tolerated and had similar safety profiles in the studies.

Cholesterol in Diverse Populations
African Americans
* Approximately 42 percent of African American men and 47 percent of
African American women have total blood cholesterol levels of 200
mg/dL or higher.(2)
* Over 12 percent of African American men and 17.4 percent of African
American women have total blood cholesterol levels of 240mg/dL or
Higher.(2)
* An estimated 24..9 percent of this population have never had their
Cholesterol levels checked.(3)

Hispanic Americans
* Among Mexican Americans age 20 and older, 52 percent of men and 45
Percent of women have total blood cholesterol levels of 200 mg/dL or
Higher.(4)
* Of these, nearly 17 percent of men and nearly 14 percent of women
Have total cholesterol over 240 mg/dl.(4)
* Hispanics are 36 percent less likely than Caucasians to have
Properly controlled cholesterol.(5)

South Asian Americans
* Heart disease is the leading cause of death for South-Asian
Americans, a population that has more than doubled (106%) in the
Past ten years in the United States.(6)
* The prevalence of heart disease is higher in this population as
Compared to Asians and non-Hispanic Whites.(6)

About the GALAXY Program

The ARIES, STARSHIP and IRIS studies are all trials in AstraZeneca's GALAXY Program, which is a large, comprehensive, long-term and evolving global research initiative designed to address important unanswered questions in statin research and to investigate the impact of CRESTOR on cardiovascular risk reduction and patient outcomes. The GALAXY Program has recruited over 50,000 subjects in more than 50 countries around the world.

About CRESTOR

CRESTOR (rosuvastatin calcium) is a once-daily prescription medication for use as an adjunct to diet in the treatment of various lipid disorders including primary hypercholesterolemia, mixed dyslipidemia and isolated hypertriglyceridemia. It is a member of the statin (HMG-CoA reductase inhibitors) class of drug therapy. CRESTOR has not been determined to prevent heart disease, heart attacks, or strokes. For patients with hypercholesterolemia and mixed dyslipidemia, the usual recommended starting dose of CRESTOR is 10 mg. However, initiation of therapy with 5 mg once daily should be considered for patients requiring less aggressive LDL-C reductions or who have predisposing factors for myopathy, and for special populations such as patients taking cyclosporine, Asian patients, and patients with severe renal insufficiency. For patients with marked hypercholesterolemia (LDL-C >190 mg/dL) and aggressive lipid targets, a 20-mg starting dose may be considered. AstraZeneca licensed worldwide rights to CRESTOR from the Japanese pharmaceutical company Shionogi & Co., Ltd.

Important Safety Information

CRESTOR is contraindicated in patients with active liver disease or unexplained persistent elevations of serum transaminases, in women who are pregnant or may become pregnant, and in nursing mothers. It is recommended that liver function tests be performed before and at 12 weeks following both the initiation of therapy and any elevation of dose, and periodically (e.g., semiannually) thereafter. Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with CRESTOR and with other drugs in this class. The 40-mg dose of CRESTOR is reserved only for those patients who have not achieved their LDL-C goal utilizing the 20 mg dose of CRESTOR once daily. When initiating statin therapy or switching from another statin therapy, the appropriate CRESTOR starting dose should first be utilized, and only then titrated according to the patient's individualized goal of therapy. Initiation of therapy with 5mg once daily should be considered for Asian patients (having either Filipino, Chinese, Japanese, Korean, Vietnamese or Asian-Indian origin). The benefit of further alterations in lipid levels by the combined use of rosuvastatin with fibrates or niacin should be carefully weighed against the potential risks of this combination. Combination therapy with rosuvastatin and gemfibrozil should generally be avoided. CRESTOR should be prescribed with caution in patients with predisposing factors for myopathy, such as renal impairment, advanced age, and inadequately treated hypothyroidism. Patients should be advised to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. CRESTOR is generally well-tolerated. Adverse reactions have usually been mild and transient. The most frequent adverse events thought to be related to CRESTOR were myalgia (3.3%), constipation (1.4%), asthenia (1.3%), abdominal pain (1.3%) and nausea (1.3%).

About AstraZeneca

AstraZeneca is a major international healthcare business engaged in the research, development, manufacture and marketing of prescription pharmaceuticals and the supply of healthcare services. It is one of the world's leading pharmaceutical companies with healthcare sales of over $21.4 billion and leading positions in sales of gastrointestinal, cardiovascular, respiratory, oncology and neuroscience products. In the United States, AstraZeneca is a $9.6 billion healthcare business with more than 12,000 employees. AstraZeneca is listed in the Dow Jones Sustainability Index (Global) as well as the FTSE4Good Index. For more information about AstraZeneca, please visit: http://www.astrazeneca-us.com.

(1) Results of 3 North American Trials (ARIES, IRIS, STARSHIP) Comparing Rosuvastatin and Atorvastatin in African Americans, South Asians, and Hispanics. P. Deedwania, K. Ferdinand, R. Lloret, J. Ycas, M. Stein VACCHCS/UCSF, Fresno, CA; Heartbeats Life Center, New Orleans, LA; CV Center of South Florida, Miami, FL; AstraZeneca, Wilmington, DE, USA

(2) American Heart Association. African Americans and Cardiovascular Diseases - Statistics. Dallas, TX.; 2006.

(3) Behavioral Risk Factor Surveillance System prevalence data page. National Center for Chronic Disease Prevention and Health Promotion Web site. Available at: http://apps.nccd.cdc.gov/brfss/race.asp?yr=2005&state=UB&qkey=1488&grp=0. Accessed May 22, 2006.

(4) American Heart Association. Hispanics/Latinos and Cardiovascular - Statistics - 2006 Update. Dallas, TX.; 2006.

(5) American Heart Association. "American Ethnic Groups less likely to have cholesterol controlled." Online. Internet. Available at http://www.americanheart.org/presenter.jhtml?identifier=3026059.. Accessed February 15, 2006.

(6) South Asian Public Health Association. A Brown Paper: The Health of South Asians in the United States: Executive Summary. N. Gupta, K. Bhandarkar, A. Gandhi, M. Shah, S. Rao, S. Akram, S. Ivey, B. Bhattacharya, A. Ghosh, R. Gupta, H. P. Mangto, M. Carvalho, N. Islam, N. Zojwalla, M. Khatta, R.. Vedanthan, S. Rajpathak, P. Mukherji, L. Groetzinger, J. Gupta, U. D. Upadhyay, M. Rastogi, V. Suthakaran, S. S. Jonnalagadda, S. Diwan, S. Patel. July 2003.

CONTACT: Christopher Sampson, +1-302-885-8908,, or Michele Pelkowski, +1-302-885-4055,, both of AstraZeneca LP Christopher.Sampson@astrazeneca.com Michele.Pelkowski@astrazeneca.com

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Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Cognitive Behaviour Therapy Can Help Some Women Become Fertile Again

Some women can become fertile again after cognitive behaviour therapy alone, said researchers at a European Fertility Conference, Prague, Czech Republic. They found some perfectionist women who had stopped menstruating and ovulating benefited enormously as a result of having counselling. Several of them had not had periods or ovulated for twenty years.

Up to 10% of pre-menopausal women at any one time are infertile. The number of women who have fertility difficulties is much higher.

Cognitive behaviour therapy is commonly used to treat patients with depression.

The researchers, from Emory University in Atlanta, Georgia, USA, said that by helping women ‘make molehills out of mountains', their fertility can be regained. Many of the women who benefited were perfectionists. Perfectionist people tend to live life in a more stressful way than people who are not. The stresses and demands life places on them can sometimes become overwhelming.

None of the women in this study had been diagnosed with depression or anxiety.

The researchers found a link between stress hormones and reproductive hormone levels.

Initially, 16 women were studied. None of them had had a period for at least six months. Some of then were mothers. All the women had functional hypothalamic amennhorea (FHA), a condition in which hormones that signal the release of hormones that simulate ovulation have been at a very low level for a long time. The researchers also found that all the women had high levels of cortisol in their bloodstream. Cortisol levels are linked to stress.

Eight of the women received 20 weeks of cognitive behavioural therapy (CBT) while the other half were observed, but received no treatment.

Six of the eight women receiving CBT became fully fertile during that time. A seventh woman was beginning to get her fertility back. Two of them became pregnant. All of them experienced much lower cortisol levels by the end of the twenty weeks.

Of the eight women who were just observed but received no CBT, one regained her fertility while another one showed signs of starting to regain it.

Telling a woman who wants to get pregnant to relax is not enough, said Prof. Sarah Berga, lead researcher. People need to be taught how to relax.

The researchers now plan to carry out a study on 4,000 nurses. Their aim will be to see what the link is between stress and reproductive hormonal changes.

CBT is much cheaper than traditional fertility treatments.

Written by: Christian Nordqvist
Editor: Medical News Today




Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Study Contradicts USA Warning That An Antidepressant Can Cause Congenital Abnormalities

A study carried out by German researchers has failed to show that a popular antidepressant, paroxetine®, causes congenital abnormalities if taken by pregnant women, the 22nd annual conference of the European Society of Human Reproduction and Embryology heard.

Dr Wolfgang Paulus said the results were important because they contradicted a warning issued by the US Food and Drug Administration in October 2005 that the use of paroxetine (brand names: Seroxat®, Paxil®, Aropax®, Deroxat® or Pondera®) could increase the risk of major congenital abnormalities. The warning may have caused women to terminate their pregnancies unnecessarily.

Dr Paulus, director of the Institute of Reproductive Toxicology at the University of Ulm, Germany, told a news briefing: "Our results show the importance of a reliable pharmaco-vigilance system documenting foetal outcome after medication in pregnancy. We need international networks of registries to do this, but financial support for this purpose is lacking. We hope for more serious efforts from the pharmaceutical industry and governmental authorities in Europe. We think that this is also an ethical challenge because many patients opt for termination of pregnancy due to fear of congenital malformations.

The FDA warning about the drug, which is a selective serotonin reuptake inhibitor (SSRI), was issued on the basis of unpublished research. "It showed that the absolute rate of major congenital malformations seen in the first trimester for paroxetine® users was 4%, and 2% for cardiovascular malformations. Yet the retrospective study of 5,956 women by the producer, GlaxoSmithKline, had only 591 cases of medication with paroxetine® during the first trimester and did not include controls of women not taking an antidepressant," he said.*

In contrast, the research carried out by Dr Paulus and his colleagues was a prospective follow-up study that collected data on pregnancy outcomes after medication with paroxetine® in 119 women between 1990 and 2005. "Our national Teratology Information Service (TIS) was contacted by physicians and patients after exposure to paroxetine® in the first trimester of pregnancy. We compared the results with a control group of 645 women over the same period of time, who had not been exposed, or not severely exposed, to the drug.

"We found that the rate of congenital abnormalities was not increased after using paroxetine® in early pregnancy. Three abnormalities were reported after exposure to paroxetine®: club feet after exposure throughout pregnancy, a large port wine mark after exposure up to the seventh week, and spastic torticollis (painful spasms of the neck muscles) after exposure in the first twelve weeks. However, in the non-paroxetine® group there was a similar rate of abnormalities, with 25 out of 557 babies affected."

However, the researchers did find that the number of women deciding to terminate their pregnancies was much higher amongst the paroxetine group. "Eighteen out of 119 paroxetine users (just over 15%) preferred termination of pregnancy compared to 17 out of 645 women in the control group (2.6%). In most cases the patients opted for termination of pregnancy because of a combination of reasons: partly because of their depression, but also because of confusion caused by information on possible damage to the foetus from the package labelling.

"Our prospective controlled follow-up study does not support the assumption that paroxetine® can cause congenital abnormalities. Although our study of 119 paroxetine users was relatively small, there are three other, peer-reviewed, published studies that show no increased rates of cardiovascular malformations with paroxetine®, whereas there has been no published research that shows that paroxetine can cause abnormalities. We continue collecting data as a member of the European Network of Teratology Services (ENTIS) in order to reassure patients who need a long-term antidepressant medication."

Dr Paulus highlighted the damage that incomplete research can have not only on the unborn babies, through decisions to terminate pregnancies, but also on the mental and physical well-being of mothers, through not treating their depression or stopping their medication abruptly.

"Depression, anxiety, obsessive-compulsive disorder and premenstrual stress are common disorders during child-bearing years and can be treated with antidepressants such as paroxetine®. Failure to treat depression during pregnancy can have significant negative ramifications for both mother and child. Women and their physicians should discuss this information and make an informed decision, whether or not to continue with paroxetine® during pregnancy. Concerned patients can be offered ultrasound and echocardiogram, which can rule out foetal cardiac problems in early pregnancy. Antidepressants should never be stopped abruptly as this can have serious ramifications for the mother. If a woman does decide, following a discussion with her physician, that she wants to discontinue paroxetine®, the drug should be slowly tapered off."

###

Notes
The rate of major congenital malformations in the normal population in the USA is 3% and 1% for cardiovascular malformations.

Abstract no: O-030, Monday 10.45-11.00 hrs CET (Small Hall, Level 0)

Contact: Emma Mason
European Society for Human Reproduction and Embryology



Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Significantly More Effective Than Crestor(R) (rosuvastatin) At Lowering LDL 'Bad' Cholesterol At

Results from a New clinical study which included 2,855 patients with high cholesterol showed that VYTORIN(R) (ezetimibe/simvastatin) was significantly more effective than Crestor(R) (rosuvastatin) in reducing LDL "bad" cholesterol across all study dose comparisons, 52-61 percent for VYTORIN 10/20 mg to 10/80 mg and 46-57 percent for Crestor 10 mg to 40 mg. In addition, both VYTORIN and Crestor raised HDL "good" cholesterol by 8 percent, averaged across all doses studied. The primary endpoint of the study was LDL cholesterol reduction from baseline averaged across all doses. Key secondary endpoints included LDL cholesterol reductions from baseline at each dose comparison. With the results of this study, VYTORIN now has been shown in clinical studies to provide greater LDL cholesterol lowering efficacy versus Zocor (simvastatin), Lipitor (atorvastatin) and Crestor (rosuvastatin) at all study dose comparisons.

In a post-hoc subgroup analysis of 715 high risk patients included in the study, the results revealed that VYTORIN, as a result of greater LDL cholesterol reduction, helped significantly more high-risk patients achieve an LDL cholesterol of less than 70 mg/dL and less than 100 mg/dL compared to patients taking Crestor (50 percent vs. 29 percent; p <0.001 and 90 percent vs. 82 percent, p<0.05 respectively) averaged across the doses studied.

"In this study, VYTORIN was significantly more effective than Crestor in reducing LDL cholesterol and averaged across the doses in attaining an LDL cholesterol goal of less than 100 mg/dL and LDL cholesterol of less than 70 mg/dL in high-risk patients," said Michael Davidson, M.D., professor of medicine, director of Preventive Cardiology, Rush University Medical Center, Chicago. "These data provide further evidence that VYTORIN is an excellent option to help lower the LDL, or bad, cholesterol levels of patients with high cholesterol."

The results were presented today at the International Symposium on Atherosclerosis (ISA 2006) meeting in Rome.

VYTORIN, which contains ezetimibe and simvastatin, is the first and only product approved to treat the two sources of cholesterol by inhibiting the production of cholesterol in the liver and blocking the absorption of cholesterol in the intestine, including cholesterol from food. VYTORIN is marketed as INEGY outside the U.S.

"Recent data shows that many patients do not reach recommended LDL cholesterol treatment goals," added Dr. Davidson, who was the principal investigator of the study. "Now with the New recommendations from the American Heart Association and the American College of Cardiology calling for more aggressive treatment of high cholesterol in certain high risk patients, physicians should consider providing more patients with greater LDL cholesterol lowering right from the start to help more patients reach recommended LDL cholesterol treatment goals."

About the study

This double-blind, six-week, parallel-group study included 2,855 patients. Patients were randomized equally to one of six treatment groups.

VYTORIN provided significantly greater LDL cholesterol reduction, compared to Crestor, when averaged across all dose comparisons (56 percent vs. 52 percent; p<0.001), and at all individual dose comparisons. The LDL cholesterol reductions for VYTORIN compared to Crestor were 52 percent, VYTORIN 10/20 mg vs. 46 percent, Crestor 10 mg, 55 percent, VYTORIN 10/40 mg vs. 52 percent, Crestor 20 mg and 61 percent, VYTORIN 10/80 mg vs. 57 percent for Crestor 40 mg. In addition, VYTORIN provided greater reductions compared to Crestor in total cholesterol, apolipoprotein B, and non-HDL cholesterol when averaged across all doses studied and at each dose comparison. VYTORIN also lowered triglycerides by similar levels compared to Crestor when averaged across all doses studied. Effects on HDL cholesterol were similar between VYTORIN and Crestor, each raising HDL cholesterol by 8 percent averaged across the doses studied. High triglycerides and low HDL cholesterol are both risk factors for cardiovascular disease (CVD). The relationship between treatment-induced changes in triglycerides, HDL, and apolipoprotein B and reduction of CVD risk has not been established. Also, the clinical significance of the above comparisons has not been established.

Both medicines were generally well tolerated in this study. As previously noted, the primary endpoint of the overall study was LDL cholesterol reduction from baseline averaged across all doses. Key secondary endpoints included changes from baseline in LDL cholesterol at each dose comparison and changes in total cholesterol, apolipoprotein B, non-HDL cholesterol, triglycerides and HDL cholesterol.

Important information about VYTORIN

VYTORIN contains simvastatin and ezetimibe. VYTORIN is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol, LDL cholesterol, Apo B(1), triglycerides and non-HDL cholesterol and to increase HDL cholesterol in patients with primary (heterozygous familial and non-familial) hypercholesterolemia or mixed hyperlipidemia.

VYTORIN is also indicated for the reduction of elevated total cholesterol and LDL cholesterol in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are unavailable.

VYTORIN is a prescription medicine and should not be taken by people who are hypersensitive to any of its components. VYTORIN should not be taken by anyone with active liver disease or unexplained persistent elevations of serum transaminases. Women who are of childbearing age (unless highly unlikely to conceive), are nursing or who are pregnant should not take VYTORIN.

Selected cautionary information for VYTORIN

Muscle pain, tenderness or weakness in people taking VYTORIN should be reported to a doctor promptly because these could be signs of a serious side effect. VYTORIN should be discontinued if myopathy is diagnosed or suspected. To help avoid serious side effects, patients should talk to their doctor about medicine or food they should avoid while taking VYTORIN. In three placebo-controlled, 12-week trials, the incidence of consecutive elevations (greater than or equal to 3 X ULN) in serum transaminases were 1.7 percent overall for patients treated with VYTORIN and 2.6 percent for patients treated with VYTORIN 10/80 mg. In controlled long-term (48-week) extensions, which included both newly-treated and previously-treated patients, the incidence of consecutive elevations (greater than or equal to 3 X ULN) in serum transaminases was 1.8 percent overall and 3.6 percent for patients treated with VYTORIN 10/80 mg. These elevations in transaminases were generally asymptomatic, not associated with cholestasis and returned to baseline after discontinuation of therapy or with continued treatment. Doctors should perform blood tests before, and periodically during treatment with VYTORIN when clinically indicated to check for liver problems. People taking VYTORIN 10/80 mg should receive an additional liver function test prior to and three months after titration and periodically during the first year.

Due to the unknown effects of increased exposure to ezetimibe (an ingredient in VYTORIN) in patients with moderate or severe hepatic insufficiency, VYTORIN is not recommended in these patients. The safety and effectiveness of VYTORIN with fibrates have not been established; therefore, co-administration with fibrates is not recommended. Caution should be exercised when initiating VYTORIN in patients treated with cyclosporine and in patients with severe renal insufficiency. VYTORIN has been evaluated for safety in more than 3,800 patients in clinical trials and was generally well tolerated at all doses (10/10 mg, 10/20 mg, 10/40 mg, 10/80 mg). In clinical trials, the most commonly reported side effects, regardless of cause, included headache (6.8 percent), upper respiratory tract infection (3.9 percent), myalgia (3.5 percent), influenza (2.6 percent) and extremity pain (2.3 percent).

About Merck/Schering-Plough Pharmaceuticals

Merck/Schering-Plough Pharmaceuticals is a joint venture between Merck & Co., Inc. and Schering-Plough Corporation formed to develop and market in the United States new prescription medicines in cholesterol management. The collaboration includes worldwide markets (excluding Japan). VYTORIN is marketed as INEGY outside the U.S.

Merck Forward-Looking Statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the cautionary statements in Item 1 of Merck's Form 10-K for the year ended Dec. 31, 2005, and in its periodic reports on Form 10-Q and Form 8-K, which the Company incorporates by reference.

Schering-Plough Disclosure Notice

The information in this press release includes certain "forward-looking statements" within the meaning of the Securities Litigation Reform Act of 1995, including statements relating to VYTORIN and the potential market for VYTORIN. Forward-looking statements relate to expectations or forecasts of future events. Schering-Plough does not assume the obligation to update any forward- looking statement. Many factors could cause actual results to differ materially from Schering-Plough's forward-looking statements, including market forces, economic factors, product availability, patent and other intellectual property protection, current and future branded, generic or over-the-counter competition, the regulatory process, and any developments following regulatory approval, among other uncertainties. For further details about these and other factors that may impact the forward-looking statements, see Schering-Plough's Securities and Exchange Commission filings, including Item 1A. Risk Factors in the Company's 2005 10-K.

Schering-Plough Corporation
http://www..schering-plough.com




Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Mild Cognitive Impairment Heralds Dementia

ROCHESTER, Minn., May 12 — Mild cognitive impairment appears to be a signpost at the crossroads leading to Alzheimer's disease or other forms of dementia.

In a study comparing autopsy findings from the brains of patients with amnestic mild cognitive impairment with those of healthy controls and those diagnosed with probable Alzheimer's, Mayo Clinic investigators found that most patients with amnestic mild cognitive impairment did not have full-blown Alzheimer's. However, there was evidence that their brains were developing some of the hallmarks of the disease.


"All the patients with amnestic mild cognitive impairment had pathologic findings involving medial temporal lobe structures, likely accounting for their memory impairment," wrote Ronald C. Petersen, Ph.D., M.D., of the Mayo Clinic here and in Jacksonville, Fla., and colleagues.


In addition, the majority of patients had other pathologic abnormalities, including argyrophilic grain disease, hippocampal sclerosis, and vascular lesions, the investigators noted in one of several studies examining the link between mild cognitive impairment and dementia published in the March Archives of Neurology.


The investigators conducted a community based cohort study of the neuropathologic features of those who died during the time that they had a clinical classification of amnestic mild cognitive impairment. They identified 15 who had memory impairment considered abnormal for their age, but who were not diagnosed as demented, and compared them with 28 healthy controls, and 23 patients with a diagnosis of probable Alzheimer's.


They used standard neuropathologic techniques and classification according to Khachaturian, Consortium to Establish a Registry for Alzheimer Disease, and National Institute on Aging-Reagan criteria to analyze autopsy tissue from the patients with amnestic mild cognitive impairment and compared the results with data from the autopsies of controls.


They found that three to seven of the patients with amnestic mild cognitive impairment had possible or probable Alzheimer's, depending on the criteria used.


But although only a minority met the criteria for full-fledged Alzheimer's, many had concomitant neuropathologic features that may have contributed to their clinical presentations. For example, seven patients with mild cognitive impairment had argyrophilic grain disease, ranging in severity from "occasional grains in the medial temporal lobe to argyrophilic grains constituting the major pathologic abnormality," the authors wrote.


Three patients had argyrophilic grains in conjunction with neurofibrillary tangles, one in conjunction with diffuse plaques, and two in conjunction with hippocampal sclerosis. In addition, five patients had concomitant vascular disease; the vascular disease was definitely linked to cognitive decline in one patient, and possibly linked to decline in the four others.


Four patients were classified as having probable neuropathologic Alzheimer's, three with intermediate probability, and one with high probability.


"We found that the regional involvement by neurofibrillary tangles correlated best with the degree of clinical impairment across the spectrum of healthy to amnestic mild cognitive impairment to AD," the investigators wrote..


"In contrast, the amyloid plaque burden was less discriminating. In general, patients with Alzheimer's disease had more cored plaques without dystrophic neurites and neuritic plaques, whereas the amyloid burden of patients with amnestic mild cognitive impairment was more similar to that of the healthy individuals," they wrote. "Thus, it may be that the transition to dementia occurs when neurofibrillary abnormalities spread beyond the medial temporal lobe."


The study "should serve as a model for individuals striving to establish and describe meaningful clinicopathologic correlations in a lucid fashion," wrote Harry V. Vinters, M.D., a neurologist at UCLA, in an accompanying editorial. "The observation that amnestic mild cognitive impairment patients show 'early Alzheimer's disease' pathologic change within the central nervous system may not come as a great surprise, but it has now been firmly established by this important study."


In a separate study in the same issue of the Archives of Neurology, the authors examined post-mortem the brains of 34 patients who were diagnosed with amnestic mild cognitive impairment and went on to develop dementia. Of this group, 24 were found to have Alzheimer's, and 10 developed other forms of dementia, such as Lewy body disease and hippocampal sclerosis.


The investigators found that regardless of the cause, all of the patients had a sufficient degree of abnormalities in medial temporal lobe structures to explain their amnestic symptoms, and most had secondary contributing pathologies, such as vascular disease, Lewy body disease, or argyrophilic grain disease.


There were no significant differences between patients with proven Alzheimer's and other forms of dementia in terms of demographics or apolipoprotein E genotype, nor were the detectable differences in cognitive test measures at the time of onset of mild cognitive impairment or dementia, or at the last clinical exam, the authors found.


"Our study highlights the heterogeneous pathologic outcomes of amnestic mild cognitive impairment following progression to dementia in a community-based cohort," they wrote.


"The presence of cognitive impairments in addition to memory problems did not seem to predict who would have Alzheimer's disease pathologically," they added. "These data raise the question of potential pathologic heterogeneity of subjects recruited into diagnostic and therapeutic trials in mild cognitive impairment."


In an accompanying editorial, Lawrence A. Hansen, M.D., of the University of California at San Diego, commented that "such results are a sobering reminder that even with a thoroughly documented clinical course progressing from mild cognitive impairment to dementia, a final clinical diagnosis of Alzheimer's may be wrong in a significant minority of patients."

Primary source: Archives of Neurology
Source reference:
Petersen RC et al. "Neuropathologic Features of Amnestic Mild Cognitive Impairment." Arch Neurol. 2006;63:665-672.

Additional source: Archives of Neurology
Source reference:
Jicha GA et al. "Neuropathologic Outcome of Mild Cognitive Impairment Following Progression to Clinical Dementia." Arch Neurol. 2006;63:674-681.

Additional source: Archives of Neurology
Source reference:
Vinters HV. "Neuropathology of Amnestic Mild Cognitive Impairment." Arch Neurol. 2006;63:645-6.




Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Emergency Medical System In Crisis, USA

The Institute of Medicine (IOM) says the American emergency Medical system is in crisis - it is seriously short of resources, fragmented and splitting at the seams. Ambulances are commonly turned away from emergency departments, it is not unusual for patients to have to wait for hours and/or days for a bed. The whole system would fall apart if it had to deal with disasters or outbreaks.

According to Dr. Rick Blum, President, American College of Emergency Physicians, the IOM report stresses issues which have been around for a long time. The main problem facing emergency medicine in the USA is reimbursement, overcrowding, ambulance diversion and lack of on-call specialists.

For 40 years there has not been an in-depth study of America's emergency Medical system, said Gail Warden, head of the Hospital Based Emergency Care Committee, IOM.

Among the list of problems in the report, are:

-- Emegency rooms are seriously overcrowded
-- Patients have to wait for a long time to be admitted
-- Ambulances are often turned away from emergency departments
-- A chronic shortage of specialists to provide care many emergency rooms
-- Ambulance transport to emergency Medical services is generally fragmented, chaotic and inconsistent
-- Emergency rooms are badly prepared for children

The report stresses that money has to be allocated for emergency departments so that the number of specialists can be boosted and overcrowding reduced. It also says emergency Medical services need to cooperate more so that the whole system operates more like a team.

As the number of cases attended rises, the number of hospitals with emergency departments has been falling. In 2003 emergency departments received 114 million patients, 26% more than in 1993. However, in 1993 there were 703 hospitals and 425 emergency departments which were closed down by 2003.

Emergency departments have become the safety net for the growing number of America's uninsured. Emergency departments are often not paid for treatment carried out on uninsured people.

Although emergency departments do and are expected to play a major role in dealing with disasters, they only received 4% of the £3.3 billion the Dept of Homeland Security awarded in 2002.

As the number of uninsured people in the USA approaches the 50 million mark, emergency departments are having to care for a disproportionate number of uninsured cases. About 50% of emergency care is uncompensated. No other developed country has such a large percentage of its population without any Medical cover at all. In the UK, for example, the number of people without Medical cover is zero - the same in most of the European Union and Canada.

The situation in emergency departments has become so dire that health professionals and administrators are no longer concerned about long term issues and planning - all the focus is on coping with the day-at-hand as resources dwindle and patient number rise.

It is not uncommon in America today for hospitals to simply close down their emergency department - not to have one at all.

Written by: Christian Nordqvist
Editor: Medical News Today



Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Scientists Find Gene in Obese Mice That Increases Type 2 Diabetes

In a painstaking set of experiments in overweight mice, scientists from the University of Wisconsin-Madison have discovered a gene that appears to play an important role in the onset of type 2 diabetes.
The finding is important because it provides evidence that the same gene in humans could provide clinicians with a powerful tool to determine the likelihood that some individuals will acquire the condition. Moreover, the finding that the gene works through a pathway not generally studied in the context of diabetes, suggests New avenues to explore in the search for New drugs to treat or prevent the disease, says Alan Attie, a UW-Madison professor of biochemistry and the senior author of the study published this week (May 7) in the Journal Nature Genetics.

Type 2 diabetes is the most common form of the condition in the United States, with an estimated 16 million Americans afflicted with the disease. It is caused by an inability of the pancreas to produce enough insulin, or by the body's reduced ability to respond to insulin, or both. Insulin is necessary for the body to properly utilize sugar.

Often, the development of type 2 diabetes is caused by obesity. Obese individuals tend to have insulin resistance; that is, it takes more insulin for the body to respond normally. Type 2 diabetes occurs when the pancreas is unable to manufacture enough insulin to compensate for the body's increased demand for the hormone, which it does by growing more insulin-producing beta cells or by ramping up insulin secretion.

The Wisconsin study, comparing two strains of obese mice differing in susceptibility to diabetes, helps explain why this is so.

"Most people who are obese don't have diabetes, but people who are obese are insulin resistant," says Attie. "If there is a fall-off in insulin production, that's when you go from prediabetes to diabetes."

The gene found by Attie's group likely influences the ability of the pancreas to recruit a type of cell essential for constructing the walls of blood vessels.
The beta cells of the pancreas, which are the critical insulin producing cells of the organ, are found clustered together in structures called islets and are nourished by a complex network of small blood vessels. If there are changes in this gene, the Wisconsin scientists believe, the blood vessels within islets may not form properly.
The consequences of this, says Attie, may be that not all beta cells receive the proper nutrition critical for their survival, that they may not receive the proper signals to secrete insulin, or that the blood vessels are insufficient to receive all the insulin they secrete.

The findings, says Attie, provide New insight into a process that might be impaired in individuals who fail to increase or maintain beta cell mass in the pancreas and sufficient insulin secretion to compensate for resistance.

What's more, because the Wisconsin group believes the gene plays a role in regulating the tiny blood vessels that nourish the insulin-producing islet cells of the pancreas, it implicates features beyond defective beta cells in the onset of the disease.

"The hope is this will open up scientists' thinking to realize that there are other cells of importance (in diabetes) beyond beta cells," says Susanne Clee, the lead author of the New Nature Genetics study.

Genetic factors are believed to account for roughly half of an individual's risk of developing type 2 diabetes. Knowing which genes might contribute to the onset of the disease can help clinicians develop profiles of obese individuals at the greatest risk.

Importantly, the New Wisconsin study looks beyond genetic influences exerted directly on insulin resistance and secretion to genes that govern structures of the pancreas that may help the organ compensate for diminished insulin production and insulin resistance. In humans, the search for such genes has yielded little success so far.

The New findings, according to Attie, will give scientists searching for those genes in people a roadmap to help locate a New "genetic bottleneck" that contributes to the onset of type 2 diabetes in humans.

"We hope this is replicating what happens in humans," Attie says. "Our work covered a lot of genetic real estate, and it should help others drill down to something similar in people. Time will tell, but I think we'll have answers to the question about how general this is pretty quickly."

In addition to Attie and Clee, authors of the New study include Brian S. Yandell, Kathryn M. Schueler, Mary E. Rabaglia, Oliver C. Richards, Summer M. Raines, Edward A. Kabara, Daniel M. Klass, Eric T.-K. Mui, Donald S. Stapleton, Mark P. Gray-Keller, Matthew B. Young, Jonathan P. Stoehr, Hong Lan, Igor Boronenkov, Phillip W. Raess, and Matthew T. Flowers.




Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Aspirin-Persantine Duo Best After Ischemic Stroke

UTRECHT, The Netherlands, May 19 — Aspirin teamed with the antiplatelet drug Persantine (dipyridamole) provided superior antithrombotic therapy after an ischemic stroke, researchers here reported.

Compared with aspirin therapy alone, results of the Dutch study and a meta-analysis of previous trials found the combined treatment reduced the relative risk of vascular death, stroke, or heart attack by 18%, according to results of a study in the May 20 issue of The Lancet.


Results of the two medications versus aspirin alone for the prevention of vascular events after ischemic stroke have been conflicting and inconsistent, said Ale Algra, M.D., Ph.D., at University Medical Center Utrecht and colleagues. The purpose of this study was to resolve that uncertainty.


The 79-hospital, 14-country study, known as the European/Australasian Stroke Prevention in Reversible Ischemia Trial (ESPIRIT), was coordinated by researchers at the University Medical Center Utrecht.


In a randomized controlled trial, 1,363 patients were assigned to 30 mg to 325 mg of aspirin daily and Persantine at 200 mg twice daily, while 1,376 patients were given aspirin alone within six months of a transient ischemic attack or minor stroke. The mean length of follow-up was 3.5 years.


Median aspirin dose was 75 mg in both treatment groups (30 mg to 325 mg); extended-release Persantine was used by 83% (1,131) of the patients receiving the combination regimen.


The primary outcome events included the composite of death from all vascular causes, non-fatal stroke, non-fatal myocardial infarction, or major bleeding complication, whichever happened first, the researchers said.


The combo patients had fewer circulatory events than those taking aspirin alone. A primary event occurred in 173 (13%) of the patients on combined treatment, versus 216 (16%) on aspirin alone (hazard ratio 0.80, 95% CI 0.66-0.98). The absolute risk reduction was 1.0% per year (95% CI 0.1-1.8) for combined treatment.


The ESPRIT findings are consistent with those of the earlier ESP 2 (Second European Stroke Prevention Study) and show robust evidence for the efficacy of combination therapy, Dr. Algra said.


ESPIRIT findings combined with a meta-analysis of previous trials resulted in an 18% reduction in the risk of vascular death, stroke, or myocardial infarction (overall risk ratio, 0.82, 95% CI 0.74-0.91).


Patients given combined treatment discontinued the trial medication more often than those taking aspirin alone (470 vs. 184), the researchers noted.


Of patients taking the combo, 34 % discontinued the treatment mainly because of adverse effects, including 26% (123) who reported headache as one of the reasons. The headache effect, the researchers said, was an important concern needing further study.


Of patients allocated to aspirin alone, 184 (13%) discontinued their medication mainly because of Medical reasons, such as a New TIA, stroke, or an indication for oral anticoagulant therapy.


One surprising finding, the researchers said, was that patients given combined treatment had fewer major bleeding complications than the aspirin-alone patients, although the finding did not reach significance. The prescribed dose of aspirin was similar in both group, however, and an equal rate of minor bleeding complications was reported in both groups, the researchers said.


"With the simple, pragmatic study design that had few exclusion criteria, we feel that a large proportion of patients with transient ischemic attack or non-disabling stroke were probably eligible," Dr. Algra said. "On the basis of this reasoning, we believe that the generalizability of our findings is equally broad."


The results of ESPIRT, combined with the earlier ESP 2 trial, provide sufficient evidence to prefer combination treatment over aspirin monotherapy, the researchers concluded.


Writing an accompanying commentary, Bo Norrving, M.D., of University Hospital in Lund, Sweden, praised the ESPRIT trial for its researchers, and said a major strength is the meta-analysis showing a robust treatment effect.


The fact that the endpoint interpretation was not blinded, could be a possible source of bias, he said.


One problem with the therapy, Dr. Norrving noted, is that the dual therapy is difficult to maintain, mainly because of the headache side-effect, well known with Persantine.


Importantly, he added, the study raised no concern about adverse effects on coronary heart disease, such as angina or MI.


"With today's report," he wrote, "dual dipyridamole and aspirin therapy joins the podium of well-established interventions to be applied in routine clinical practice in secondary stroke prevention."


He added: "Antiplatelet therapy, even if dual, is far from being the sole panacea for stroke prevention: risk factor and lifestyle modification should not be forgotten."

Primary source: The Lancet
Source reference:
Ale Algra, et al, "Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomized controlled trial," The Lancet, 2006; 367: 1665-1672.

Additional source: The Lancet
Source reference:
Bo Norrving, "Dipyridamole with aspirin for secondary stroke prevention,"Lancet, 2006; 367:1638-1639.




Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Delayed Cord Clamping at Birth May Reduce Neonatal Anemia

News Author: Laurie Barclay, MD
CME Author: Penny Murata, MD

April 20, 2006 — Delayed cord clamping at birth reduces neonatal anemia, according to the results of a randomized trial reported in the April issue of Pediatrics.

"The umbilical cord is usually clamped immediately after birth," write José M. Ceriani Cernadas, MD, from the Hospital Italiano de Buenos Aires in Argentina, and colleagues. "There is no sound evidence to support this approach, which might deprive the newborn of some benefits such as an increase in iron storage.... Iron deficiency early in life may have pronounced central nervous system effects such as cognitive impairment; iron deficiency is also the main cause of anemia, one of the most serious conditions in childhood, especially in developing countries."

In 2 obstetrical units in Argentina, 276 neonates born at term without complications to mothers with uneventful pregnancies were randomized to cord clamping within the first 15 seconds (group 1), at 1 minute (group 2), or at 3 minutes (group 3) after birth.

At 6 hours after birth, mean venous hematocrit values were 53.5% in group 1, 57.0% in group 2, and 59.4% in group 3. Statistical analyses showed equivalent results among groups because the hematocrit increase in neonates with late clamping was within the prespecified physiologic range.

The prevalence of anemia, defined as hematocrit less than 45%, was significantly lower in groups 2 and 3 than in group 1. The prevalence of hematocrit greater than 65% was similar in group 1 (4.4%) and in group 2 (5.9%) but significantly higher in group 3 (14.1%) than in group 1. Other neonatal outcomes and maternal postpartum hemorrhage were not significantly different in the 3 groups.

"Delayed cord clamping at birth increases neonatal mean venous hematocrit within a physiologic range," the authors write. "Furthermore, this intervention seems to reduce the rate of neonatal anemia. This practice has been shown to be safe and should be implemented to increase neonatal iron storage at birth."

The authors recommend controlled follow-up studies of the relationship between delayed cord clamping and the presence of anemia and iron status in infants.

"Another benefit of delayed clamping would be the increase of hematopoietic stem cells transfused to the newborn, which might play a role on different blood disorders and immune conditions," the authors conclude. "The advantages of umbilical cord clamping at least at 1 minute after birth could decrease the prevalence of iron-deficiency anemia in the first year of life, especially in populations with limited access to health care."

United Nations Children's Fund (UNICEF) Argentina supported this study. The authors have disclosed no financial relationships.

Pediatrics. 2006;117:e779-e786

Learning Objectives for This Educational Activity

Upon completion of this activity, participants will be able to:

• Compare the effect of early vs late umbilical cord clamping on neonatal venous hematocrit.
• Describe the effect of timing of umbilical cord clamping on clinical outcomes in term newborns and maternal postpartum hemorrhage.
  

Clinical Context

It is common practice to clamp the umbilical cord immediately, within 15 seconds, after birth. According to an observational study by Saigal and Usher in the 1977 issue of Biology of the Neonate, delayed umbilical cord clamping could increase the risk for polycythemia, respiratory problems, and hyperbilirubinemia. However, in a systematic review by Van Rheenen and Brabin in the March 2004 issue of the Annals of Tropical Paediatrics, they reported that late umbilical cord clamping helps to reduce iron deficiency anemia in infants.

The current study is a prospective, randomized, controlled trial to determine the effect of early vs delayed umbilical cord clamping on venous hematocrit and clinical outcomes in the term neonate as well as maternal postpartum blood loss.

Study Highlights

• 267 neonates who met enrollment criteria (uneventful cephalic vaginal or cesarean delivery; term singleton; no maternal clinical disease or complications; no evidence of congenital malformations or intrauterine growth restriction) were randomized to 1 of 3 different cord-clamping time intervals.
  
• 93 neonates had early cord clamping within first 15 seconds; 91 neonates had delayed cord clamping at 1 minute; 92 neonates had delayed cord clamping at 3 minutes.
  
• Baseline characteristics were similar: maternal age, parity, gestational age, antenatal visits, maternal anemia, cesarean delivery rates, third-stage active management, maternal hematocrit before birth, and newborn weight..
  
• At clinician's discretion, newborns assigned to delayed clamping group instead underwent early clamping if there was no spontaneous breathing in the first 10 seconds, major congenital malformation, birth weight less than the tenth percentile, or tight nuchal cord.
  
• Primary outcome measure of newborn venous hematocrit at 6 hours of age was not significantly different for the groups: 53.5% for early clamping group; 57.0% for 1-minute group; 59.4% for 3-minute group.
  
• At 6 hours, anemia prevalence (venous hematocrit less than 45%) was higher in early clamping group (8.9%) vs 1-minute group (1%; P = .034) and 3-minute group (0%; P = .003)
  
• At 6 hours, polycythemia prevalence (hematocrit greater than 65%) was higher in 3-minute group vs early group (14.1% vs 4.4%; P =.039), but similar for 1-minute group (5.5%) and early group. None were symptomatic..
  
• At 24 to 48 hours, venous hematocrit values were similar for the 3 groups. Anemia prevalence was higher in the early group (16.8%) vs 1-minute group (2.2%; P = .0014) and 3-minute group (3.3%; P = .0027).. Polycythemia prevalence was similar for the 3 groups.
• There were no significant differences for other secondary outcome measures: plasma bilirubin levels at 24 to 48 hours, neonatal morbidity (respiratory distress, tachypnea, grunting, jaundice, seizures, sepsis, necrotizing enterocolitis), mortality (none), neonatal intensive care unit admission, length of hospital stay, disease up to 1 month of age, weight or rate of breast-feeding at 1 month, maternal postpartum blood-loss volume, and maternal hematocrit level at 24 hours postpartum.
  

Pearls for Practice

• In term newborn infants, delayed umbilical cord clamping at 1 or 3 minutes after birth results in decreased prevalence of anemia at 6 hours and at 24 to 48 hours of age vs early cord clamping; the difference in hematocrit levels was not significant.
  
• In term newborn infants, delayed vs early umbilical cord clamping has no effect on newborn clinical outcomes or maternal postpartum hemorrhage.
  
  
  
  
  
  Saludos Cordiales
  Dr. José Manuel Ferrer