For patients with primary biliary cirrhosis, obeticholic acid produces meaningful biochemical and clinical improvements

Results from an international Phase III study presented at the International Liver Congress^TM 2014 have shown obeticholic acid (OCA) given to patients suffering from Primary Biliary Cirrhosis (PBC) who previously had an inadequate response to, or have been unable to tolerate ursodeoxycholic acid (UDCA), produced meaningful biochemical and clinical improvements. UDCA is the only therapy currently approved to treat PBC.

Obeticholic acid at both a 10 mg dose and a 5 mg dose titrated to 10 mg, met the trial's primary composite endpoint of achieving a serum alkaline phosphatase (ALP) activity of less than 1.67 times the upper limit of normal (ULN), a total bilirubin within normal limits, and at least a 15% decrease in ALP.

The proportion of patients meeting the primary endpoint was: 47% in the 10 mg OCA group and 46% in the 5-10 mg OCA group vs. only 10% in the placebo group (both dose groups p<0.0001). In addition, both OCA dose groups met secondary endpoints of improvements in other liver function parameters, including gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT) and total bilirubin.

Presenting these results, EASL's Scientific Committee Member Dr. Frank Lammert, Professor of Internal Medicine at the Saarland University Medical Center, Homburg, Germany pointed out: "These trial results indicate that a statistically greater number of OCA-treated patients achieved the response criteria as defined by Global Primary Biliary Cirrhosis Study Group. We know that these endpoints have, in turn, been shown in previous studies to strongly correlate with clinical benefits and an improved long-term prognosis, with a reduced risk of liver transplantation and death."

"While UDCA has been the standard PBC therapy for the past 20 years, a significant percentage of patients fail to get an adequate response with this treatment, or are unable to tolerate it. We therefore need new therapies to prevent PBC from progressing to cirrhosis and liver failure, and this study suggests that OCA has the potential to be a much needed advance for these patients," Dr. Frank Lammert added.

PBC is a chronic disease that primarily occurs in women. It is characterised by the destruction of bile ducts in the liver, which in turn leads to liver scarring. Long-term damage from PBC over the years can result in cirrhosis and liver failure. PBC affects around 30 people per million, with an estimated prevalence of 12,000 - 15,000 in the UK. It has been reported that PBC is more prevalent in some geographic areas, such as Northern Europe and Northern America.

OCA is a new bile acid analogue (6alpha-ethyl-chenodeoxycholic acid) and first-in-class agonist of the nuclear receptor (FXR), which represents the central bile acid sensor in humans. It is being studied in PBC, as well as non-alcoholic steatohepatitis (NASH) and other liver and intestinal diseases.

Study methodology and adverse event data

This Phase III study enrolled 217 patients with primary biliary cirrhosis who had either failed to get an adequate response with UDCA, or had been unable to tolerate it. Patients were randomised to placebo or one of two doses of OCA, with the lower dose titrated to the higher strength after six months based on clinical response. Patients who were able to tolerate UDCA were allowed to continue on it; the median UDCA dose was 15.3mg/kg; 7% of patients were UDCA-intolerant. All three treatment groups were well matched. Mean age: 55.8yrs, female: 91%, Caucasian: 94%.

Pruritus, generally mild to moderate, was the most frequently reported adverse event associated with OCA treatment (placebo: 38%, OCA 10 mg: 68%, OCA 5-10 mg titration: 56%).

However, only a few patients withdrew due to pruritus: none in the placebo group, seven (10%) of the patients in the 10 mg OCA group, and only one (1%) of the patients in the OCA 5-10 mg titration group.

Apart from pruritus, the incidence of adverse events was generally similar across both OCA and placebo groups (placebo: 90%, OCA 10 mg: 86%, OCA 5-10 mg titration group: 89%). Overall, serious adverse events (SAEs) occurred in (10%) of the patients and, although there were more SAEs in the OCA treatment groups, none were considered drug-related and there were no apparent patterns in the SAEs.

PBC patients typically have significantly elevated HDL cholesterol levels; modest decreases in HDL were observed in both OCA dose groups, similar to those seen in the prior PBC clinical trials. In addition, slight decreases in triglycerides, but no changes in LDL cholesterol were observed in the OCA dose groups.

Other new data further support role of obeticholic acid in PBC

In addition to these new Phase III data, there are three other presentations on OCA at this year's International Liver CongressTM, which further support the potential role of this new drug in treating PBC.

• Two 12-week, double-blind, placebo-controlled Phase 2 trials of OCA in PBC patients with persistently high ALP (≥1.5-10x ULN) and bilirubin <2x ULN, showed OCA resulted in a highly significant improvement in the biochemical response criteria which are associated with improved transplant-free survival versus placebo, in both the OCA monotherapy and UDCA-combination therapy studies.
• Having previously demonstrated the efficacy of 10mg and 50mg doses of OCA, given as monotherapy, in achieving highly significant reductions in ALP and other biochemical markers, compared with placebo, an open label, long-term study extension has shown that OCA treatment resulted in a durable improvement in ALP and other liver chemistry. UDCA was added in 11 of the patients. Pruritus, while prevalent appeared to diminish in incidence and severity with continued therapy.
• In an experimental rat model of cholestasis, FXR-agonism was shown to restore ileal permeability and decrease bacterial translocation (which is known to drive infectious complications of cirrhosis), potentially showing a crucial protective role for FXR in the gut-liver axis.

Read More: http://www.medicalnewstoday.com/releases/275475.php

After stroke care initiative can significantly improve blood pressure, cholesterol

Stoke patients managed by a pharmacist had a 12.5% improvement in blood pressureand low-density lipoprotein (LDL), or "bad"cholesterol levels compared with a control group, according to a clinical trial published in CMAJ (Canadian Medical Association Journal).

Patients who have a stroke or "mini stroke" (transient ischemic attack) are at high risk of adverse cardiovascular events. Management of high blood pressure and cholesterol after a stroke is important because it can substantially reduce the risk of a negative event; however, many patients receive suboptimal care.

Some evidence indicates designated "case managers" could better manage patients to reduce the risk.

Researchers undertook a randomized controlled trial to determine if a pharmacist case manager could improve blood pressure and cholesterol levels in people who had had strokes or mini strokes. The trial included 279 adult participants in Edmonton, Alberta, who either received care from a pharmacist or a nurse (control group) who managed the case over a 6-month period. About 60% of participants were 65 years of age or older and 58% were men.

Both nurses and pharmacists counselled participants on diet, smoking, exercise and other lifestyle factors; checked blood pressure and LDL levels and provided summaries to patients' physicians after each visit. In addition, pharmacists prescribed medications based on the current Canadian guidelines and adjusted doses to achieve the best result for each patient.

At the start of the study, none of the participants had blood pressure or cholesterol levels that met targets recommended in the Canadian Stroke Guidelines. By 6 months, both groups had significant improvements, with a 30% improvement in the control group managed by nurses and a 43% improvement in patients managed by pharmacists.

"Calling our control arm "usual care" would be a misnomer, and patients in the active control group (nurse-led group) showed a 30% absolute improvement in risk factor control over a 6-month period," writes Dr. Finlay McAlister, Division of General Internal Medicine, and the Epidemiology Coordinating and Research (EPICORE) Centre, University of Alberta, with coauthors. "The 43% absolute improvement at 6 months seen in our pharmacist case manager group was achieved despite the fact that over three-quarters of patients were already taking an antihypertensive or lipid-lowering medication at baseline."

The pharmacists did not receive additional training, but all were at similar stages of their careers and received the same patient educational materials and treatment guidelines.

Although patients in both groups had similar reductions in blood pressure, patients in the pharmacist-led group had greater improvements in LDL cholesterol targets (51%) compared with 34% in the nurse-led group. The researchers point out that the pharmacist case managers actively adjusted medication to achieve desired results (medication titration) and suggest this contributed to the beneficial effect. Several other studies involving case managers who did not have prescribing authority found minimal benefit.

"We believe that both approaches hold great promise, not only for patients with stroke or transient ischemic attack but also for all patients with, or at high risk of, vascular disease, and our study provides much-needed information on their comparative effectiveness," the authors conclude.

Read More: http://www.medicalnewstoday.com/releases/275525.php

Report outlines dietary fat intake among 266 countries

Harvard School of Public Health researchers and colleagues have compiled the first global data on dietary intakes of specific fats worldwide. The report compares the intake of saturated fat, cholesterol, trans fats, omega 3s, and other fats and oils among 266 countries.

The report, written on behalf of the Global Burden of Diseases Nutrition and Chronic Diseases Expert Group, was published online April 15, 2014 in the British Medical Journal (BMJ).

Poor diet is believed to be the single leading modifiable cause of poor health in the world. By 2020, it likely will contribute to about 75% of all deaths from such chronic diseases as heart disease, type 2 diabetes, obesity, and cancer.

The analysis of dietary assessments across the world provides estimates of the global consumption of major dietary fats and oils by region, country, age, and sex. The study was led by Renata Micha, research associate in the Department of Epidemiology at HSPH and research director, Department of Food Science and Human Nutrition, Agricultural University of Athens, Greece, and senior author Dariush Mozaffarian, associate professor in the Department of Epidemiology at HSPH.

Among the findings:

• Between 1990 and 2010, global saturated fat, dietary cholesterol, and trans fat intakes remained stable, while omega 6, seafood omega 3, and plant omega 3 fat intakes each increased.
• In 2010, global saturated fat consumption averaged 9.4%; country-specific intakes varied dramatically from 2.3 to 27.5%. The world's highest consumption of saturated fat in adults in 2010 was in Samoa, Kiribati, and similar palm oil producing island nations, as well as Sri Lanka, Romania, and Malaysia. The lowest intake was in Bangladesh, Nepal, Bolivia, Bhutan, and Pakistan.
• Country-specific consumption of trans fat ranged from 0.2 to 6.5% (global mean: 1.4%) for trans fat; and for dietary cholesterol, from 97 to 440 mg/day (global mean: 228 mg/day).
• Globally, the average intake of seafood omega-3's was 163 mg/d, but with tremendous national variation from 5 to 3,886 mg/d. Highest intakes were identified in island nations including Maldives, Barbados, the Seychelles, and Iceland; as well as in Malaysia, Thailand, Denmark, South Korea, and Japan. 100 nations had very low consumption (<100 mg/d), generally in Sub-Saharan African and Asian regions as well as North Africa and the Middle East, representing 3 billion adults and 66.8% of the world's adult population.
• Within regions and countries, consumption of fats and oils were generally similar for men and women. For instance, women generally consumed only slightly more saturated fat and plant omega-3s than men. Trans fat intakes were generally higher at younger ages; and dietary cholesterol and seafood omega-3 fats generally higher at older ages.

Read More: http://www.medicalnewstoday.com/releases/275682.php

Narrowing of the carotid arteries may lead to memory and thinking problems

Problems with learning, memory, thinking and decision-making could be linked to narrowing of the neck's carotid artery, according to new research presented at the American Academy of Neurology's 66th Annual Meeting in Philadelphia, PA.

The American Academy of Neurology have previously published research in their journalNeurology that explored using individuals' stroke risk profile - which includes high blood pressure, smoking and diabetes - to predict whether people would develop memory and thinking problems later in life.

However, this is the first research to specifically link narrowing of the carotid arteries - the two major blood vessels that deliver blood to the brain - to memory and thinking problems.

Most clinical investigation of the carotid arteries relates to when the arteries become blocked by fatty, waxy deposits or "plaque" - which is known to cause stroke or transient ischemic attack.

When these arteries become narrowed, as well as restricting the flow of blood to the brain, little pieces of plaque can also be showered into the brain.

"To date, the focus of diagnosis and management of carotid artery blockages has been prevention of stroke since that was the only harm that these blockages were thought to cause to patients," says Dr. Brajesh K. Lal, from VA Maryland Health Care System's Baltimore VA Medical Center and the University of Maryland School of Medicine in Baltimore.

"These results underscore the importance of assessing the status of memory and thinking in people with carotid artery narrowing," Dr. Lal adds.

Patients with asymptomatic carotid stenosis 'at risk of memory and thinking problems'

This is the first research to link narrowing of the carotid arteries - the two major blood vessels that deliver blood to the brain - to memory and thinking problems.

Dr. Lal and his team of researchers assessed 67 patients with asymptomatic carotid stenosis (ACS), and 60 people with risk factors for ACS - such as diabetes, high blood pressure, highcholesterol and coronary artery disease - but without the condition. The ACS patients had a reduction of 50% in the diameter of their carotid artery.

Both groups were tested for processing speed, learning, memory, decision-making, language and overall thinking abilities.

The patients who had ACS performed "significantly worse" on the memory and thinking tests - particularly on the tests for processing speed and language.

The study found no difference, however, in the language abilities of the two groups.

Though this was a small observational study, Dr. Lal considers his team's findings to be significant:

"If these findings are confirmed in larger studies, they hold significant implications for new treatment targets and open the door for more questions, such as: should these patients be treated more aggressively with medications, cognitive rehabilitation or even surgery to open up the artery.

"I anticipate a large number of follow-up studies searching for causes and the best treatment option for this newly identified morbidity associated with carotid narrowing," Dr. Lal says.

Read More: http://www.medicalnewstoday.com/articles/275774.php

Scientists alter fat metabolism in animals to prevent most common type of heart disease

Working with mice and rabbits, Johns Hopkins scientists have found a way to block abnormal cholesterol production, transport and breakdown, successfully preventing the development of atherosclerosis, the main cause of heart attacks and strokes and the number-one cause of death among humans. The condition develops when fat builds inside blood vessels over time and renders them stiff, narrowed and hardened, greatly reducing their ability to feed oxygen-rich blood to the heart muscle and the brain.

In a series of experiments, described April 7 in the journal Circulation, the Johns Hopkins team says it identified and halted the action of a single molecular culprit responsible for a range of biological glitches that affect the body's ability to properly use, transport and purge itself of cholesterol - the fatty substance that accumulates inside vessels and fuels heart disease.

The offender, the researchers say, is a fat-and-sugar molecule called glycosphingolipid, or GSL, which resides in the membranes of all cells, and is mostly known for regulating cell growth. Results of the experiments, the scientists say, reveal that this very same molecule also regulates the way the body handles cholesterol.

The Johns Hopkins team used an existing man-made compound called D-PDMP to block the synthesis of the GSL molecule, and by doing so, prevented the development of heart disease in mice and rabbits fed a high-fat, cholesterol-laden diet. The findings reveal that D-PDMP appears to work by interfering with a constellation of genetic pathways that regulate fat metabolism on multiple fronts - from the way cells derive and absorb cholesterol from food, to the way cholesterol is transported to tissues and organs and is then broken down by the liver and excreted from the body.

"Current cholesterol-lowering medications tackle the problem on a single front - either by blocking cholesterol synthesis or by preventing the body from absorbing too much of it," says lead investigator Subroto Chatterjee, Ph.D., a cardio-metabolic expert at the Johns Hopkins Children's Center. "But atherosclerosis is a multi-factorial problem that requires hitting the abnormal cholesterol cycle at many points. By inhibiting the synthesis of GSL, we believe we have achieved exactly that."

Specifically, the experiments showed that treatment with D-PDMP led to:

• a drop in the animals' levels of so-called bad cholesterol or low-density lipoprotein, LDL;
• a drop in oxidized LDL, a particularly virulent form of fat that forms when LDL encounters free radicals. Oxidized LDL easily sticks to the walls of blood vessels, where it ignitesinflammation, damaging the vessel walls and promoting the growth of fatty plaque;
• a surge in good cholesterol or high-density lipoprotein, HDL, known to counteract the effects of LDL by mopping it up; and
• a significant drop in triglycerides, another type of plaque-building fat.

The treatment also prevented fatty plaque and calcium deposits from building up inside the animals' vessels. These effects were observed in animals on a daily D-PDMP treatment even though they ate a diet made up of 20 percent triglycerides - the human equivalent of eating a greasy burger for breakfast, lunch and dinner. In addition, the researchers say, D-PDMP appears to precision-target the worst byproducts of aberrant cell growth signaling, such as oxidized LDL and the activity of certain chemicals that fuel vessel inflammation, without altering cell growth itself.

Read More: http://www.medicalnewstoday.com/releases/275836.php

HIV progression slowed by low cholesterol in immune cells

Scientists at the University of Pittsburgh have identified why some HIV-infected people experience much slower disease progression, even without medication, and it has to do with cholesterol levels in specific immune cells. They report their findings in mBio®, the online open-access journal of the American Society for Microbiology.

"A fascinating aspect of the AIDS epidemic is that a small percentage of HIV-1-infected persons, termed nonprogressors or controllers, maintain a relatively normal number of CD4 T cells (Th cells) and low viral load for many years without receiving antiviral therapy," says lead author Giovanna Rappocciolo. "Knowing how these individuals naturally control their HIV-1 infection and prevent the virus from progressively destroying their Th cells could be critically important to developing effective therapeutic and prevention strategies for HIV-1/AIDS."

When HIV enters the body, it is typically picked up by immune system cells, called antigen-presenting cells (APCs), including dendritic cells and B lymphocytes. Those cells then transport the virus to lymph nodes where the APCs pass it to other immune system cells, including Th cells, via a process known as trans infection. HIV then uses Th cells as its main site of replication. It is through replication in the Th cells that levels of HIV increase and overwhelm the immune system.

Even without antiretroviral drugs, approximately one in 20 people infected with HIV do not have the persistent increase in levels of HIV after initial infection and can sometimes go many years, even more than a decade, without the virus seriously compromising the immune system or leading to AIDS.

In the study Rappocciolo and her colleagues compared the ability of APCs from nonprogessors, progressors and uninfected control subjects to trans infect T cells. They found that while the cells from progressors and control subjects were highly effective at mediating trans infection, those from nonprogressors lacked the ability.

The researchers took a closer look and discovered that the APCs from nonprogressors had low levels of cholesterol, even though the patients had regular levels of cholesterol in their blood. Moreover, they found that trans infection could be restored by reconstituting cholesterol levels in the APCs of nonprogressors and could also be inhibited by reducing the cholesterol levels in the APCs of progressors.

Additionally, analysis of APCs from two nonprogressors obtained one to four years before primary HIV infection shows similar results, suggesting this is a genetically acquired trait.

"This defect in cholesterol metabolism is not a direct consequence of virus infection, but rather is likely present as an inherited trait in a low percentage of individuals. Understanding how this works could be an important clue in developing new approaches to prevent progression of HIV infection," says Rappocciolo.

Read More: http://www.medicalnewstoday.com/releases/276130.php

Blood pressure control, lifestyle changes key to preventing subsequent strokes

Controlling blood pressure, cholesterol and irregular heart rhythms are key to strokesurvivors avoiding another stroke.

Updated guidelines emphasize lifestyle management, including diet, exercise and weight management.

Other important updates affect management of narrowed neck arteries and irregular heartbeat.

Stroke survivors should control their blood pressure, cholesterol and weight and do moderate physical activity regularly to avoid having another stroke, according to an American Heart Association/American Stroke Association scientific statement.

They should also receive other evidence-based therapy specific to their individual health, which may include aspirin therapy or a surgical procedure to keep neck arteries open.

The statement, "Guidelines for the Prevention of Stroke in Patients with Stroke and Transient Ischemic Attack (TIA)," is published in the American Heart Association journal Stroke.

"A vast amount of new research is revealing new and improved ways to protect patients with an ischemic stroke or transient ischemic attack from having recurrent events and further brain damage," said Walter Kernan, M.D., lead author and chair of the guideline writing group and professor of medicine at Yale University School of Medicine in New Haven, Conn.

Treating high blood pressure is possibly most important for secondary prevention of ischemic stroke, according to the statement. About 70 percent of people who have had a recent ischemic also have high blood pressure.

The statement notes that intensive cholesterol-lowering therapy is also important for survivors whose stroke was caused by hardened arteries. However, the association no longer recommends niacin or fibrate drugs to raise good cholesterol, due to sparse data establishing their effectiveness at reducing secondary stroke risk.

It's also good for stroke/TIA survivors capable of engaging in physical activity to have three to four sessions per week of moderate-vigorous intensity aerobic physical exercise such as walking briskly or riding a bike, according to the statement.

Since the last update in 2011, the association added sections on nutrition, sleep apnea, aortic arch atherosclerosis and pre-diabetes.

New recommendations include:

• Screening stroke and TIA survivors for diabetes and obesity
• Possible screening for sleep apnea
• Possible nutritional assessment
• 30-day monitoring for irregular heart beat (atrial fibrillation) for those who had a stroke of unknown cause
• Anticoagulants in specific situations
• Following a Mediterranean-type diet that emphasizes vegetables, fruits, whole grains and includes low-fat dairy, poultry, fish, legumes and nuts and limits sweets and red meat
• Clinical trials haven't proven the benefits of a Mediterranean diet after ischemic stroke or TIA, so statement recommendations are based on compelling but lower levels of research.

Each year in the United States, more than 690,000 adults have an ischemic stroke, which originate from blood clots that block blood flow in the brain or in a vessel leading to the brain.

Another 240,000 Americans will experience a TIA. Although TIA leaves no immediate impairment, survivors are at high risk for a future stroke.

On average, the annual risk for a future ischemic stroke after an initial ischemic stroke or TIA is about 3 percent to 4 percent.

"The key to staying healthy after an ischemic stroke or TIA is careful and rapid assessment of the cause of the event and identification of stroke risk factors so that appropriate preventive interventions can be quickly provided," Kernan said. "Then, patients must work with their doctors regularly to stay on their prevention program. With this approach, every patient can look forward to a healthier future."

Read More: http://www.medicalnewstoday.com/releases/276106.php