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Denufosol improves Cystic Fibrosis in clinical trials

Cystic fibrosis is a genetic disease that causes a thick, sticky mucus to build up in the lungs and digestive tract. A clinical trial of a new drug called denufosol found that those given the medication for six months prevented some of the accumulation and improved performance on lung tests.

The Cystic Fibrosis Foundation estimates that about 30,000 children and adults in the United States have the condition that clogs the lungs and leads to life-threatening lung infections. The mucus also obstructs the pancreas and stops natural enzymes from helping the body break down and absorb food.

Cystic fibrosis is caused by a genetic mutation that disrupts the cystic fibrosis transmembrane regulator (CFTR) protein, an ion channel. Denufosol tetrasodium inhalation solution works by correcting ion transport in patients to enhance airway hydration and mucus clearance by increasing chloride secretion, inhibiting sodium absorption and increasing ciliary beat frequency.

Frank J. Accurso MD of the University of Colorado and colleagues included about 350 children with cystic fibrosis aged five and older in the study called TIGER-1, The Transport of Ions to Generate Epithelial Rehydration. All had a forced expiratory volume (FEV1) at least 75% of normal, indicating normal to mildly impaired lung function characteristic of early cystic fibrosis.

The patients were randomized to receive either 60 milligrams of inhaled denufosol three times daily or a matching placebo for 24 weeks. This was followed by another 24-week open-label safety extension phase.

The patients on the new medication had increase in FEV1 of 0.048 L, approximately 2% over baseline. In addition, the researchers found further lung improvement by 0.115L by the end of the open-label phase. The placebo group, when switched over to denofusol in the open-label phase, also improved by a mean 0.078 L in FEV1.

Big improvements weren't expected, says Accurso, because the drug is primarily designed to prevent or delay loss of lung function rather than act as a rescue therapy.

Denufosol appeared to be safe without serious adverse events or impaired growth of the young patients, suggesting it could be suitable as an early intervention. Intervention for cystic fibrosis early in its course has the potential to delay or prevent progressive changes that lead to irreversible airflow obstructions, the researchers say in their study published in the American Journal of Respiratory and Critical Care Medicine.

A second phase III trial, which is called TIGER-2, is ongoing which will incorporate a longer placebo-controlled treatment phase. Inspire Pharmaceuticals is targeting a potential US commercial launch of the drug for 2012, pending FDA approval.

Source reference:
Accurso FJ, et al “Denufosol Tetrasodium in Patients with Cystic Fibrosis and Normal to Mildly Impaired Lung Function” Am J Respir Crit Care Med 2011.

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Curry protects against fatty liver disease

Curcumin, a natural phytochemical from turmeric that is used as a spice in curry, holds promise in treating or preventing liver damage from an advanced form of a condition known as fatty liver disease, new Saint Louis University research suggests. Curcumin is contained in turmeric, a plant used by the Chinese to make traditional medicines for thousands of years. SLU's recent study highlights its potential in countering an increasingly common kind of fatty liver disease called non-alcoholic steatohepatitis (NASH). Linked to obesity and weight gain, NASH affects 3 to 4 percent of U.S. adults and can lead to a type of liver damage called liver fibrosis and possibly cirrhosis, liver cancer and death.

“My laboratory studies the molecular mechanism of liver fibrosis and is searching for natural ways to prevent and treat this liver damage,” said Anping Chen, Ph.D., corresponding author and director of research in the pathology department of Saint Louis University. The findings were published in the September 2010 issue of Endocrinology. “While research in an animal model and human clinical trials are needed, our study suggests that curcumin may be an effective therapy to treat and prevent liver fibrosis, which is associated with non-alcoholic steatohepatitis (NASH).”

High levels of blood leptin, glucose and insulin are commonly found in human patients with obesity and type 2 diabetes, which might contribute to NASH-associated liver fibrosis. Chen's most recent work tested the effect of curcumin on the role of high levels of leptin in causing liver fibrosis in vitro, or in a controlled lab setting. “Leptin plays a critical role in the development of liver fibrosis,” he said.

High levels of leptin activate hepatic stellate cells, which are the cells that cause overproduction of the collagen protein, a major feature of liver fibrosis. The researchers found that among other activities, curcumin eliminated the effects of leptin on activating hepatic stellate cells, which short-circuited the development of liver damage (Courtesy of EurekAlert!, a service of AAAS).

Reference: Youcai Tang, Anping Chen. Curcumin Protects Hepatic Stellate Cells against Leptin-Induced Activation in Vitro by Accumulating Intracellular Lipids. Endocrinology Vol. 151, No. 9 4168-4177 begin_of_the_skype_highlighting 9 4168-4177 end_of_the_skype_highlighting. doi:10.1210/en.2010-0191

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New approach for diabetes therapy

Nutrition experts at Oregon State University have essentially “cured” laboratory mice of mild, diet-induced diabetes by stimulating the production of a particular enzyme. The findings could offer a new approach to diabetes therapy, experts say, especially if a drug could be identified that would do the same thing, which in this case was accomplished with genetic manipulation.

Increased levels of this enzyme, called fatty acid elongase-5, restored normal function to diseased livers in mice, restored normal levels of blood glucose and insulin, and effectively corrected the risk factors incurred with diet-induced diabetes. “This effect was fairly remarkable and not anticipated,” said Donald Jump, a professor of nutrition and exercise sciences at Oregon State, where he is an expert on lipid metabolism and principal investigator with OSU’s Linus Pauling Institute. “It doesn’t provide a therapy yet, but could be fairly important if we can find a drug to raise levels of this enzyme,” Jump said. “There are already some drugs on the market that do this to a point, and further research in the field would be merited.”

The studies were done on a family of enzymes called “fatty acid elongases,” which have been known of for decades. Humans get essential fatty acids that they cannot naturally make from certain foods in their diet. These essential fatty acids are converted to longer and more unsaturated fatty acids. The fatty acid end products of these reactions are important for managing metabolism, inflammation, cognitive function, cardiovascular health, reproduction, vision and other metabolic roles.

The enzymes that do this are called fatty acid elongases, and much has been learned in recent years about them. In research on diet-induced obesity and diabetes, OSU studied enzyme conversion pathways, and found that elongase-5 was often impaired in mice with elevated insulin levels and diet-induced obesity.

The scientists used an established system, based on a recombinant adenovirus, to import the gene responsible for production of elongase-5 into the livers of obese, diabetic mice. When this “delivery system” began to function and the mice produced higher levels of the enzyme, their diet-induced liver defects and elevated blood sugar disappeared.

“The use of a genetic delivery system such as this was functional, but it may not be a permanent solution,” Jump said. “For human therapy, it would be better to find a drug that could accomplish the same thing, and that may be possible. There are already drugs on the market, such as some fibrate drugs, that induce higher levels of elongase-5 to some extent.”

There are also drugs used with diabetic patients that can lower blood sugar levels, Jump said, but some have side effects and undesired complications. The potential for raising levels of elongase-5 would be a new, specific and targeted approach to diabetes therapy, he said. While lowering blood sugar, the elevated levels of elongase-5 also reduced triglycerides in the liver, another desirable goal. Elevated triglycerides are associated with “fatty liver,” also known as non-alcoholic fatty liver disease. This can progress to more severe liver diseases such as fibrosis, cirrhosis and cancer.

Further research is needed to define the exact biological mechanisms at work in this process, and determine what the fatty acids do that affects carbohydrate and triglyceride metabolism, he said. It appears that high fat diets suppress elongase-5 activity.

“These studies establish a link between fatty acid elongation and hepatic glucose and triglyceride metabolism,” the researchers wrote in their report, “and suggest a role for regulators of elongase-5 activity in the treatment of diet-induced hyperglycemia and fatty liver.”

The study was published in the Journal of Lipid Research. The research was supported by the National Institutes of Health and the National Institute for Food and Agriculture of the U.S. Department of Agriculture.

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Watercress may help fight cancer

The pilot study used four women, all of whom were breast cancer survivors, and monitored changes in their blood of key molecules involved in the growth of cancer cells. The participants were asked to fast on the day of the tests and had blood samples taken before and after eating a portion of watercress. The scientists found that six hours after they had eaten the leaves, the women experienced a drop in the activity of a molecule called 4E binding protein, which is thought to be involved in helping cancer cells survive.

Laboratory studies also showed that extracts taken from watercress leaves inhibited the growth of breast cancer cells. The findings build on epidemiological studies that have shown people who eat watercress and other vegetables rich in isothiocyanates, such as broccoli and cabbage, are at lower risk of developing cancer.

Hazel Nunn, Cancer Research UK's health information manager, said the current study was too small to draw any firm conclusions.

She added: “Watercress may well have benefits but there's no reason to believe that it should be superior to a generally healthy, balanced diet that is high in fibre, vegetables and fruit and low in red and processed meat, salt, saturated fat and alcohol.”

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Folate Helps Repair Damage Due to Ageing

Since the 1960s, researchers have been studying how the water-soluble vitamin supports the healthy functioning of cells. They discovered that it's essential for cell division and replication, making it especially important for expectant mothers.

It's also important to proper replication of DNA and RNA — a lack of folate has been linked to genetic mutations that can lead to cancer.

Folate is commonly found in leafy green vegetables like spinach and turnip greens. Since 1998, the U.S. Food and Drug Administration has mandated that many foods, such as rice, flour and cornmeal, be enriched with a synthetic folate known as folic acid.

While folate deficiency is no longer a problem in the U.S., it remains widespread in developing nations and much of Europe, where enriching grain products is not widely practiced.

This new research, funded by the National Science Foundation and originally sparked by funding from the U.S. Department of Energy, links folate to the production or repair of compounds called iron-sulfur clusters through a recently discovered intermediary protein called COG0354.

These clusters are part of the mechanism cells use to produce energy and carry out other vital reactions. But they are also sensitive to a byproduct of the energy-producing process: highly reactive oxygen-based molecules, some of which are called free radicals.

The oxidative stress caused when these molecules pollute a cell has been linked to cell death and aging, as well as to conditions such as atherosclerosis, Parkinson's disease, heart disease, Alzheimer's, fragile X syndrome and many more.

Examining the folate-iron-sulfur cluster link required the team to pull experience from not only UF's microbiology and cell science and food science and human nutrition departments, but also the McKnight Brain Institute and the National High Magnetic Field Laboratory.

Expertise from the latter two institutions was needed because the researchers used nuclear magnetic resonance analysis to observe folate interacting with COG0354 protein — molecular-scale activity that could otherwise only have been shown indirectly, said Arthur Edison, the NHMFL's director of chemistry and biology and an associate professor with UF's biochemistry and molecular biology department.

The researchers have found that COG0354 is present in creatures from each of the six kingdoms of life, from mice and plants to one-cell organisms that may predate bacteria.

The findings will open new avenues of study into the overall mechanism of oxidative stress repair, and may someday lead to new medicines. For now, the researchers emphasize that this is another example of the vitamin's importance in one's diet.

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