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Wednesday, September 23, 2009

Euope approves Aztreonam

Gilead Sciences Inc. said Wednesday that European regulators gave conditional marketing approval to Cayston, a treatment for a type of chronic lung infection in patients with cystic fibrosis.

Cayston is intended to treat chronic lung infections caused by the bacterium Pseudomonas aeruginosa. ( news - people ) said those lung infections are the biggest killer of people with cystic fibrosis.

The drug will be available in some EU countries in early 2010, Gilead said.

The company said Cayston, or aztreonam lysine, is intended to be given three times per day for 28 days to treat the infection. Cayston was approved conditionally because it addresses an unmet medical need, Gilead said, and could receive full approval after a current late-stage clinical trial is complete.

Gilead said the drug has been approved in Canada. The Food and Drug Administration has asked Gilead to run another study before requesting approval.

Nutrition proactivity in CF

When was the last time you got your Oral Glucose Tolerance Test and your DEXA (bone density) scan?!

Click here to read
Nutrition in cystic fibrosis.

Matel JL, Milla CE.

The Stanford Cystic Fibrosis Center, Center for Excellence in Pulmonary Biology, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, California 94304, USA.

Cystic fibrosis (CF) is mostly recognized for its pulmonary morbidity, but the earliest manifestations of the disease are related to its gastrointestinal and nutritional derangements. Destruction of acinar pancreatic tissue, pancreatic ductular obstruction, and lack of enzymatic activity lead to malabsorption (particularly of fats), diarrhea, and failure to thrive. A minority of CF patients carrying milder CF transmembrane conductance regulator (CFTR) mutations have preserved pancreatic secretory activity and are free from significant malabsorption early in life. However, these patients are at risk for losing pancreatic function over time. Nutritional status plays an important role in the progression of the pulmonary disease in CF. Further, CF patients with better nutritional status have a survival advantage. Several factors contribute to impaired nutritional status in CF (e.g., pancreatic insufficiency, chronic malabsorption, recurrent sinopulmonary infections, chronic inflammation, increased energy expenditure, suboptimal intake). Progressive lung disease further increases calorie requirements by increasing the work of breathing. Treatment programs that place an emphasis on higher caloric intake and more aggressive nutritional management in CF patients report better outcomes. Basic tenets of nutritional repletion in CF include the use of pancreatic enzyme replacement therapy and following a high calorie, high protein, unrestricted diet. At the Stanford Cystic Fibrosis Center, nutritional status is assessed on an ongoing basis through anthropometric parameters and annual assessment of body composition, bone density, glucose tolerance, and various biochemical and micronutrient levels. Based on the anthropometric data obtained on routine clinical encounters, patients are categorized as to their nutritional risk. This proactive approach for the early identification of nutritional risk has become a major theme within the network of US CF centers. Aggressive nutritional support with adequate pancreatic replacement management should lead to both normal growth and lung function preservation. In addition, nutritional status has to be monitored closely during routine encounters to allow for early intervention once derangements are noted. This will include increasing calories in the early stages of lung disease and being vigilant of gastrointestinal symptomatology and complications. Copyright Thieme Medical Publishers.

PMID: 19760545 [PubMed - in process]

Diabetes and bone disease in CF

Diabetes mellitus and bone disease in cystic fibrosis.

Curran DR, McArdle JR, Talwalkar JS.

Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8057, USA.

Patients with cystic fibrosis are frequently affected with pancreatic insufficiency and are predisposed to the development of diabetes mellitus (DM) and bone demineralization. Cystic fibrosis-related diabetes mellitus is a clinical entity distinct from type 1 and type 2 diabetes, with important implications for the nutritional and pulmonary health of cystic fibrosis patients. This form of diabetes owes largely to insulin deficiency, but alterations in insulin sensitivity and hepatic glucose production have also been described. Therapy for cystic fibrosis-related diabetes differs substantially from type 2 DM, with careful attention to prandial glycemic excursions crucial to controlling its metabolic effects. Bone disease, including osteopenia and osteoporosis, also occurs with increased frequency in cystic fibrosis, owing to defects in intestinal absorption, chronic inflammation, lung disease, low body weight, and gonadal dysfunction. The pathogenesis, implications, diagnosis, and therapy of cystic fibrosis-related bone demineralization are discussed, with attention to recommended approaches to prevention of and treatment of established bone disease. Copyright Thieme Medical Publishers.

Saturday, September 19, 2009


18 Sep 2009

Pharmaxis announced that its second pivotal Phase 3 clinical trial of Bronchitol for the treatment of cystic fibrosis has now passed its recruitment target of 300 subjects

SYDNEY, AUSTRALIA | SEPTEMBER 18, 2009 | Pharmaxis (ASX:PXS) today announced that its second pivotal Phase 3 clinical trial of Bronchitol for the treatment of cystic fibrosis has now passed its recruitment target of 300 subjects.

The first efficacy data from the trial is expected to be available during the first half of 2010. This trial is the second of two trials in cystic fibrosis, required by the U.S. FDA, before a marketing application can be submitted in the U.S. When complete, more than 600 cystic fibrosis patients will have been recruited into the two Bronchitol Phase 3 clinical trials.

The trial is taking place across 58 sites in 7 countries and is a double blind, placebo controlled, randomised study comparing 400 mg of Bronchitol twice a day to placebo. The trial includes a 26-week efficacy and safety component, with an optional 26 week openlabel Bronchitol safety extension.

Pharmaxis Chief Executive Officer, Alan Robertson said: “I am excited about this trial: the recruitment has gone well and the compliance rate is good and the support from the patients and clinical centres has been excellent. My expectation is that this trial, and the one that has gone before, will show that Bronchitol has the opportunity to fundamentally impact the way people with cystic fibrosis manage the disease.”

The primary efficacy end-point is change in lung function from baseline as determined by FEV1 (forced expiratory volume in one second) over 26 weeks.

Approximately two thirds of the subjects entering the study were being treated with rhDNase. This trial is being conducted under the FDA’s Special Protocol Assessment (SPA) scheme. Pharmaxis has received Orphan Drug Designation and fast track status from the FDA for Bronchitol.

More than 75,000 people in the major pharmaceutical markets are affected by cystic fibrosis and no products have been approved to improve lung hydration. Pharmaxis will file a marketing authorization application with the European Medicines Agency shortly based on the first pivotal trial reported in May of 2009.

About Pharmaxis

Pharmaxis (ACN 082 811 630) is a specialist pharmaceutical company involved in the research, development and commercialization of therapeutic products for chronic respiratory and immune disorders. Its development pipeline of products includes Aridol for the management of asthma, Bronchitol for cystic fibrosis, bronchiectasis and chronic obstructive pulmonary disease (COPD), PXS25 for the treatment of lung fibrosis and PXS4159 for asthma.

Founded in 1998, Pharmaxis is listed on the Australian Securities Exchange (symbol PXS). The company is headquartered in Sydney at its TGA-approved manufacturing facilities. For more information about Pharmaxis, go to www.pharmaxis.com.au or contact Investor Relations on phone +61 2 9454 7200.

About Bronchitol

Pharmaxis Ltd is developing Bronchitol for the management of chronic obstructive lung diseases including bronchiectasis, cystic fibrosis and chronic bronchitis. Bronchitol is a proprietary formulation of mannitol administered as a dry powder in a convenient hand-held inhaler. It is designed to hydrate the lungs, restore normal lung clearance mechanisms, and help patients clear mucus more effectively. Clinical studies have shown Bronchitol to be well tolerated, to improve lung function and quality of life, and to stimulate mucus hydration and clearance in people with bronchiectasis and cystic fibrosis.

SOURCE: Pharmaxis

Thursday, September 17, 2009

Showerheads may harbor bacteria dangerous to some

Showerheads may harbor bacteria dangerous to some

WASHINGTON — In what may be the scariest shower news since Alfred Hitchcock's "Psycho," a study says showerheads can harbor tiny bacteria that come spraying into your face when you wash. People with normal immune systems have little to fear, but these microbes could be a concern for folks with cystic fibrosis or AIDS, people who are undergoing cancer treatment or those who have had a recent organ transplant.

Researchers at the University of Colorado tested 45 showers in five states as part of a larger study of the microbiology of air and water in homes, schools and public buildings. They report their shower findings in Tuesday's edition of Proceedings of the National Academy of Sciences.

In general, is it dangerous to take showers? "Probably not, if your immune system is not compromised in some way," lead author Norman R. Pace says. "But it's like anything else — there is a risk associated with it."

The researchers offer suggestions for the wary, such as getting all-metal showerheads, which microbes have a harder time clinging to.

Still, showerheads are full of nooks and crannies, making them hard to clean, the researchers note, and the microbes come back even after treatment with bleach.

People who have filtered showerheads could replace the filter weekly, added co-author Laura K. Baumgartner. And, she said, baths don't splash microbes into the air as much as showers, which blast them into easily inhaled aerosol form.

It doesn't seem as frightening as the famous murder-in-the-shower scene in Hitchcock's classic 1960 movie. But it's something to be reckoned with all the same.

The bugs in question are Mycobacterium avium, which have been linked to lung disease in some people.

Indeed, studies by the National Jewish Hospital in Denver suggest increases in pulmonary infections in the United States in recent decades from species like M. avium may be linked to people taking more showers and fewer baths, according to Pace.

Symptoms of infection can include tiredness, a persistent, dry cough, shortness of breath, weakness and "generally feeling bad," he said.

Showerheads were sampled at houses, apartment buildings and public places in New York, Illinois, Colorado, Tennessee and North Dakota.

The researchers sampled water flowing from the showerheads, then removed them, swabbed the interiors of the devices and separately sampled water flowing from the pipes without the showerheads.

By studying the DNA of the samples they were able to determine which bacteria were present.

They found that the bacteria tended to build up in the showerhead, where they were much more common than in the incoming feed water.

Most of the water samples came from municipal water systems in cities such as New York and Denver, but the team also looked at showerheads in four rural homes supplied by private wells. No M. avium were found in those showerheads, though some other bacteria were.

In previous work, the same research team has found M. avium in soap scum on vinyl shower curtains and above the water surface of warm therapy pools.

And stay tuned. Other studies under way by Pace's team include analyses of air in New York subways, hospital waiting rooms, office buildings and homeless shelters.

The research was funded by the Alfred P. Sloan Foundation and the National Institute of Occupational Safety and Health.

Virginia Tech microbiologist Joseph O. Falkinham welcomed the findings, saying M. avium can be a danger because in a shower "the organism is aerosolized where you can inhale it."

In addition to people with weakened immune systems, Falkinham also cited studies showing increased M. avium infections in slender, elderly people who have a single gene for cystic fibrosis, but not the disease itself.

Two copies of the gene are needed to get cystic fibrosis, but having just one copy may result in increased vulnerability to M. avium infection as people age, said Falkinham, who was not part of Pace's research team.

Scientists Identify Gene For Short-circuiting Excess Mucus In Lung Disease, Common Colds

Scientists Identify Gene For Short-circuiting Excess Mucus In Lung Disease, Common Colds

ScienceDaily (Sep. 15, 2009) — Scientists have identified the main genetic switch that causes excessive mucus in the lungs, a discovery that one day could ease suffering for people with chronic lung diseases like asthma and cystic fibrosis, or just those fighting the common cold.

The discovery was reported in a study posted online Sept. 14 by the Journal of Clinical Investigation. The new research sheds light on what has been a medical mystery - the precise biological reasons that the lungs in people with asthma, cystic fibrosis and other respiratory ailments clog with thick mucus.

Identifying the genetic circuits that cause mucous hyper-production gives researchers potential targets for new therapies to moderate or stop it, said Jeffrey Whitsett, M.D., the head of Neonatology, Perinatal and Pulmonary Biology at Cincinnati Children's Hospital Medical Center and the study's senior investigator.

"Everyone has had a stuffed up nose and cough after two or three weeks of a bad cold and most over-the-counter cold medications deal with mucus," Whitsett explained. "We still don't have effective therapies for removing excess mucous, whether it's someone with a cold or chronic lung disease. That's why we still tap on the chests of kids with cystic fibrosis to try and clear it."

The current study provides an entirely new understanding of how certain cells promote chronic lung infection and excess mucus production. Scientists previously thought that, after airways were attacked by an allergic response or inflammation, mucus cells (known as goblet cells) divided and proliferated at a very fast rate - a process known as hyperplasia. Instead, the Cincinnati Children's team discovered that beneficial lung cells, called Clara cells, instead change their cell type to become goblet/mucous cells in a process called metaplasia.

Dr. Whitsett and his colleagues also found the metaplasia process in this instance to be reversible. Goblet cells can change back to Clara cells if the detrimental genetic influence is blocked, highlighting a possible pathway for new treatments, according to Dr. Whitsett, who also is executive director of the Perinatal Institute at Cincinnati Children's.

The study identifies a transcription factor, SPDEF, as the master gene that regulates a chain of dozens of downstream genes involved in mucus production. SPDEF is an active player in other organ systems that need to produce mucus for normal function, such as the digestive system. In healthy lungs, however, the researchers report the gene is mostly quiet, as healthy lungs don't produce significant amounts of mucus.

Using an egg white protein called ovalbumin to induce an allergic reaction and inflammation in the lungs of mice, the researchers observed a dramatic elevation in the expression of SPDEF in the lung tissues of the affected animals. The animals also experienced hyper-production of thick mucus in their lungs. In mice where the SPDEF gene was switched off, inflammation and excessive mucus production did not occur, demonstrating the gene's potential as therapeutic or diagnostic target. Mice lacking SPDEF were unable to increase mucus production or develop goblet cells.

In mice where respiratory inflammation and excessive mucus production were present, the researchers report that SPDEF turned off genes involved in biological processes that help protect lung tissues from infection and damage. Conversely, SPDEF activated genes that promote inflammation and excessive mucus - in particular FOXA3, AGR2 and mucins.

By composition, mucus is a sugar-coated collection of large proteins that, in healthy conditions, help the body defend itself by collecting and then clearing out contaminants. In the case of AGR2 for example, the gene helps assemble mucus proteins by folding together different molecules. When SPDEF is over-expressed, it results in increased production of AGR2, which in turn promotes an over-abundance of protein folding and mucus production.

Dr. Whitsett cautioned it will be several years before the research results in a specific therapeutic approach that can be tested in people. In the meantime, his team has received several significant grants to conduct more extensive studies into the various genetic and molecular influences that control, or are controlled by, SPDEF and involved in excess mucus production.

The first author on the current study was Gang Chen, a graduate student in Dr. Whitsett's laboratory. The laboratory's research is supported by funding from the National Institutes of Health and the Cystic Fibrosis Foundation. The study was done in collaboration with the Netherlands Institute of Developmental Biology, with the research there being led by Dr. Hans Clevers.

Positive news on Phase II of Inhaled Alpha-1 Antitrypsin

Kamada Presents Data on Inhaled Alpha-1 Antitrypsin in Cystic Fibrosis Patients at the European Respiratory Society Meeting 2009, Vienna

Mon Sep 14, 2009 9:00am EDT
NESS ZIONA, Israel--(Business Wire)--
Kamada, a bio-pharmaceutical company engaged in the development, manufacturing
and marketing of specialty life-saving therapeutics, announced that data on its
next-generation alpha-1 antitrypsin (Inhaled-AAT) in cystic fibrosis patients
was presented today, at the Annual Congress of the European Respiratory Society
(ERS) 2009, Vienna. As previously reported, the study showed that inhaled-AAT
was safe and biologically effective.

David Tsur, Chief Executive Officer of Kamada said, "We are delighted that
Kamada was invited to present the results of its Phase II clinical study with
inhaled-AAT at the European Respiratory Society meeting at a session focused on
novel therapies for cystic fibrosis". David Tsur continued, "We believe this
demonstrates the excitement around our inhaled version of AAT within the field
of respiratory medicine. Our product could have a significant impact on the
lives of patients with cystic fibrosis and we look forward to advancing it into
further clinical trials in the future".

About the Study

The Phase II trial was a randomized, double blind, study that examined efficacy
and safety of Kamada`s inhaled-AAT versus placebo. Twenty-one patients were
randomized 2:1 to receive 80mg Inhaled-AAT or placebo, once-daily, for up to 28
days. The data showed encouraging efficacy, as measured by a reduction in sputum
neutrophil elastase and neutrophil count in patients treated with Inhaled-AAT.
There were no serious adverse events reported in the study and the only adverse
event, possibly related to study drug, was dry mouth (n=1). The results from
this proof-of-concept study demonstrate that AAT administered via the inhaled
route appears safe and biologically effective.

About Inhaled AAT

Kamada`s Inhaled AAT is a high purity, liquid formulation of alpha-1
antitrypsin, manufactured using Kamada`s proprietary chromatographic
purification technology, that is delivered via an optimized Investigational
eFlow Nebulizer System (PARI Pharma GmbH). Kamada has successfully completed two
Phase II clinical trials in cystic fibrosis and bronchiectasis and further
studies in these patients, and in patients with alpha-1 deficiency, are planned.
The product has been designated Orphan Drug status for the treatment of, alpha-1
deficiency and cystic fibrosis, in Europe and for bronchiectasis, ha-1
deficiency and cystic fibrosis in the U.S.

About Kamada

Kamada is a public biopharmaceutical company (TASE:KMDA) developing, producing
and marketing a line of specialty, life-saving therapeutics using a
sophisticated chromatographic purification technology. Utilizing its proprietary
know-how, Kamada manufactures more than 10 high quality biopharmaceuticals which
are marketed in over 15 countries around the world. Kamada also has a number of
products in development and has recently completed six clinical trials for its
high-purity, liquid formulation of alpha-1 antitrypsin which is suitable for
inhalation and intravenous use. Additional information is available at

Senate Introduces Bill to Boost Participation in Clinical Trials for Rare Diseases

Senate Introduces Bill to Boost Participation in Clinical Trials for Rare

Bill would remove financial penalties for participating in research studies

BETHESDA, Md., Sept. 16 /PRNewswire-USNewswire/ -- Four members of the United
States Senate introduced legislation today to allow patients with rare
diseases to participate in clinical drug studies without losing their
eligibility for public healthcare coverage, echoing a move by the House of
Representatives last month.

The "Improving Access to Clinical Trials Act" is co-sponsored by Senators Ron
Wyden (D-OR), Chris Dodd (D-CT), James Inhofe (R-OK) and Richard Shelby

Researchers who develop drugs to treat rare diseases such as cystic fibrosis
often struggle to recruit participants for clinical trials because of limited
patient populations. To compound the problem, current law prevents many people
who receive Supplemental Security Income (SSI) from accepting research
compensation because it would make them ineligible to continue receiving
government medical benefits. This financial penalty prevents significant
numbers of people with rare diseases from participating in clinical studies.

"For many suffering from rare diseases, access to clinical trials is their
best hope for treatment," said Senator Wyden. "This legislation will make sure
the small financial incentives these people receive will not be counted
against them if they are on SSI or Medicaid. Patients suffering from rare
diseases should not have to choose between their best hope for treatment or
losing benefits, nor be denied the access more financially fortunate patients

"For those living with a rare disease, clinical drug studies can offer a ray
of hope: access to cutting-edge medical technologies that may help treat or
even cure a serious illness," Senator Dodd said. "Currently, individuals who
receive public assistance often do not participate in compensated clinical
trials for fear of losing their Medicaid or Supplemental Security Income. This
legislation will remedy this inequity by ensuring that more Americans,
including those who receive public assistance, have access to these
potentially life-saving clinical drug studies."

"This bill allows patients with a rare disease to disregard up to $2,000 of
compensation received for participation in a clinical trial in their SSI and
Medicaid income calculations," said Senator Inhofe. "Though it will have a
negligible impact on the federal budget, it will make a dramatic difference in
the lives of those who will gain access to potentially life-saving treatments
by enrolling in clinical trials as well as all those in the future whose lives
will be improved by the medical advances that arise from this research.

"Scientists and researchers across our nation continually produce new
therapies that have the potential to save the lives of countless Americans who
suffer from life-threatening rare illnesses," said Senator Shelby. "These
patients should not be forced to choose between the health benefits they
desperately need and the opportunity to participate in a clinical trial that
could improve their medical condition. I am confident that this legislation
will open a pathway for more patients to receive life-saving treatments."

Fifty years ago, there were no drugs for people with CF and those with the
disease rarely lived to attend elementary school. Today, because of the Cystic
Fibrosis Foundation's focus on innovative and aggressive research, there are
more than 30 potential therapies in development, and the median life
expectancy is higher than 37 years.

SOURCE Cystic Fibrosis Foundation

Laurie Fink of Cystic Fibrosis Foundation, +1-301-841-2602; lfink@cff.org

Saturday, September 12, 2009

Mpex Pharmaceuticals Announces Positive Phase 2b Clinical Trial Results With Aeroquin(R) (MP-376) Treatment In Cystic Fibrosis Patients

Mpex Pharmaceuticals Announces Positive Phase 2b Clinical Trial Results With Aeroquin(R) (MP-376) Treatment In Cystic Fibrosis Patients

11 Sep 2009

Mpex Pharmaceuticals, Inc. announced positive data from its Phase 2b clinical trial with Aeroquin((R)) (a novel aerosol formulation of levofloxacin, MP-376) in cystic fibrosis (CF). Trial results showed that nebulized Aeroquin met the primary endpoint of reducing bacterial counts of Pseudomonas aeruginosa (P. aeruginosa) in sputum after 28 days of dosing versus placebo. Clinically and statistically significant improvements versus placebo were also seen in a number of important clinical endpoints, including FEV1, percent predicted FEV1, FEF25-75 (all measures of respiratory function) and time to need for anti-pseudomonal antibiotics (a measure of exacerbations). Both once and twice-daily dosing of Aeroquin showed activity in this trial, with higher doses showing improved responses. Aeroquin was well tolerated and no significant change in antibiotic resistance was observed in this study. Detailed results will be presented at a major respiratory meeting in the near future.

The Phase 2b, multi-center randomized, double-blind, placebo-controlled trial (Mpex 204) studied 151 CF patients to evaluate the safety, tolerability and efficacy of inhaled Aeroquin administered for 28 days using an Investigational eFlow Nebulizer System (PARI Pharma GmbH). Patients were then followed for an additional 28 days after completion of dosing. The trial was conducted in the U.S., Germany and the Netherlands.

To ensure that results from this trial were as predictive as possible for a future Phase 3 program, Mpex 204 enrolled patients that have recently received multiple courses of inhaled antibiotics and in most cases were already receiving other medication shown to improve lung function and reduce exacerbations. To be eligible for the trial, CF patients had to have received at least three 28 day cycles of other inhaled antibiotic therapy over the previous 12 months. Patients were also allowed to remain on all other stable CF therapies during the study.

"The results of this study are very gratifying, particularly given the heavily treated nature of the patients included in this trial," stated Dr. Jeff Loutit, Chief Medical Officer of Mpex Pharmaceuticals. "It is difficult for new agents to show benefit on top of state-of-the-art care in CF, and generating statistically significant results across a broad range of key endpoints in this Phase 2b study bodes well for success in Phase 3."

"We thank the participating CF patients and physicians for helping make this trial a success," stated Daniel Burgess, President and CEO of Mpex Pharmaceuticals. "We are eager to meet with CF experts and regulatory authorities in the U.S. and Europe to discuss these results and determine the most expeditious path to move Aeroquin through Phase 3 development."

Patients with CF suffer from chronic infections of the lower respiratory tract that can be caused by multiple bacteria, including P. aeruginosa. Chronic pulmonary infection is associated with a decrease in lung function over time caused by inflammation arising from bacteria and their toxins. Periodic exacerbations in the lung result from bacterial overgrowth, and these exacerbations are implicated as a major cause of morbidity and mortality in CF patients.

About Aeroquin (MP-376)

MP-376 is a proprietary formulation of levofloxacin that has been optimized for aerosol delivery using a customized Investigational eFlow(R) Nebulizer System (PARI Pharma GmbH). Levofloxacin is a fluoroquinolone antibiotic that has been widely used in a variety of indications for over a decade and has established safety and efficacy when administered orally or intravenously against many bacterial pathogens, including P. aeruginosa. Administration of MP-376 with a high efficiency nebulizer to the lungs allows for the rapid delivery of high concentrations of active drug directly to the site of infection, while minimizing systemic exposure. In addition to the trial described above in CF, Mpex is also conducting a large Phase 2 study in COPD that is now fully enrolled, with results expected to be available in the first half of 2010.

About Mpex Pharmaceuticals

Mpex Pharmaceuticals is a clinical stage biopharmaceutical company whose mission is to develop important new therapies to combat the growing issue of antibiotic resistance. The company's internal development pipeline focuses on combining proprietary formulations, PK/PD strategies and novel potentiating agents with proven antibiotics to overcome or directly inhibit the molecular mechanisms in bacteria responsible for antibiotic resistance. Mpex's most advanced product candidate, Aeroquin((R)) (MP-376), is a proprietary aerosol formulation of levofloxacin that is being developed clinically as a maintenance therapy for patients with CF or COPD. The company has also built a separate discovery and development platform and intellectual property estate around inhibitors of multi-drug resistant (MDR) efflux pumps (EPIs) found in many gram-negative bacterial pathogens. Bacterial efflux of antibiotics is a leading source of multi-drug resistance, particularly in gram-negative organisms. Mpex compounds have been shown in both in vitro and in vivo studies to overcome efflux-based resistance to multiple classes of antibiotics. Mpex has established a collaboration with GlaxoSmithKline focused on developing multiple drug candidates utilizing Mpex's EPI technology.

About the Investigational eFlow Nebulizer System and PARI Pharma

Aeroquin (MP-376) is delivered via an Investigational eFlow Nebulizer System, an inhalation delivery device optimized specifically for Aeroquin. The Investigational eFlow Nebulizer System uses eFlow Technology to enable highly efficient aerosolization of medication via a vibrating, perforated membrane that includes thousands of small holes to produce the aerosol mist. Compared to other nebulization technologies, eFlow Technology produces aerosols with a very high density of active drug, a precisely defined droplet size, and a high proportion of respirable droplets delivered in the shortest possible period of time. Combined with its quiet mode of operation, small size (it fits in the palm of the patient's hand), light weight and battery use, eFlow Technology reduces the burden of taking daily, inhaled treatments. PARI Pharma focuses on the development of aerosol delivery devices and comprehensive inhalation drug development to advance aerosol therapies where drug and device can be optimized together.

Curcumin cross-links cystic fibrosis transmembrane conductance regulator (CFTR) polypeptides and potentiates CFTR channel activity by distinct mechani

Curcumin cross-links cystic fibrosis transmembrane conductance regulator (CFTR) polypeptides and potentiates CFTR channel activity by distinct mechanisms.

Bernard K, Wang W, Narlawar R, Schmidt B, Kirk KL.

University of Alabama at Birmingham, United States;

Cystic fibrosis (CF) is caused by loss-of-function mutations in the CFTR chloride channel. Wild type and mutant CFTR channels can be activated by curcumin, a well tolerated dietary compound with some appeal as a prospective CF therapeutic. However, we show here that curcumin has the unexpected effect of cross-linking CFTR polypeptides into SDS-resistant oligomers. This effect occurred for CFTR channels in microsomes as well as in intact cells and at the same concentrations that are effective for promoting CFTR channel activity (5-50 microM).

Both mature CFTR polypeptides at the cell surface and immature CFTR protein in the endoplasmic reticulum were cross-linked by curcumin, although the latter pool was more susceptible to this modification. Curcumin cross-linked two CF mutant channels (deltaF508 and G551D) as well as a variety of deletion constructs that lack the major cytoplasmic domains. In vitro cross-linking could be prevented by high concentrations of oxidant scavengers (i.e., reduced glutathione and sodium azide) indicating a possible oxidation reaction with the CFTR polypeptide. Importantly, cyclic derivatives of curcumin that lack the reactive beta- diketone moiety had no cross-linking activity. One of these cyclic derivatives stimulated the activities of wild type CFTR channels, 1198-CFTR channels and G551D-CFTR channels in excised membrane patches. Like the parent compound, the cyclic derivative irreversibly activated CFTR channels in excised patches during prolonged exposure (> 5 min).

Our results raise a note of caution about undesired biochemical effects of reactive compounds like curcumin in the treatment of CF. Cyclic curcumin derivatives may have better therapeutic potential in this regard.

PMID: 19740743 [PubMed - as supplied by publisher]

FULL ARTICLE http://www.jbc.org/cgi/reprint/M109.056010v1.pdf

Trends in pathogens colonising the respiratory tract of adult patients with cystic fibrosis, 1985-2005.

Trends in pathogens colonising the respiratory tract of adult patients with cystic fibrosis, 1985-2005.

Millar FA, Simmonds NJ, Hodson ME.

Adult Cystic Fibrosis Dept, NHLI/Imperial College and Royal Brompton Hospital, London, United Kingdom.

INTRODUCTION: The treatment of patients with CF has continued to evolve. We hypothesised that sputum microbiology may have changed as a result of this.

METHOD: Retrospective analysis of sputum microbiology from adult CF patients (1985 to 2005) using the Royal Brompton Hospital CF database.

RESULTS: Colonisation with Pseudomonas aeruginosa or Staphylococcus aureus between 1985 and 2005 remained stable (77 to 82%, p=0.159; 54 to 47%, p=0.108; respectively). Haemophilus influenzae (48 to 6%; p<0.001), Aspergillus species (18 to 9%; p=0.002) and Burkholderia cepacia complex (9 to 4%; p=0.041) prevalence decreased. Stenotrophomonas maltophilia and MRSA increased (1 to 4%, p=0.02; 1 to 6%, p=0.002, respectively).

CONCLUSION: P. aeruginosa colonisation has remained stable; there has been a decline in B. cepacia complex, H. influenzae and Aspergillus sp., and only a small increase in S. maltophilia and MRSA. Intensive antibiotic strategies have been employed, which, so far, have not resulted in clinically significant emergence of new pathogens.

CFRD incidence, mortality rates narrowed

Cystic fibrosis-related diabetes is present in 2% of children, 19% of adolescents and 45% to 50% of adults aged older than 30 years, according to a review of data from 1992 to 2008.

The review revealed that previously noted differences in cystic fibrosis-related diabetes between sexes and gaps in mortality have disappeared and considerably narrowed, with the exception of a higher prevalence in women aged 30 to 39 years.

“Diabetes is exceptionally common in cystic fibrosis, especially as cystic fibrosis patients get older,” Antoinette Moran, MD,told Endocrine Today.

“In the past, the added diagnosis of diabetes has meant a patient (especially a woman) with cystic fibrosis is at increased risk for early death — this is no longer the case,” she said. “We believe the difference is that we are now screening effectively so that we diagnose early and we are treating it aggressively.”

Moran and colleagues at the University of Minnesota examined current trends in the incidence, prevalence and mortality related to cystic fibrosis-related diabetes using a comprehensive clinical database. The review included 872 patients with cystic fibrosis followed at the University of Minnesota during 1992 to 1997, 1998 to 2002 and 2003 to 2008.

Current trends

During 15 years, cystic fibrosis-related diabetes mortality rates decreased by more than 50% in women, from 6.9 deaths per 100 patient-years in 1992 to 1997 to 3.2 deaths per 100 patient-years in 2003 to 2008. Rates also decreased in men — 6.5 deaths per 100 patient-years in 1992 to 1997 to 3.8 deaths per 100 patient-years in 2003 to 2008.

The overall incidence of cystic fibrosis-related diabetes was 2.7 cases per 100 patient-years, with the exception of women aged 30 to 39 years in whom the incidence more than doubled.

Previously, diabetes was diagnosed as a perimorbid event in nearly 20% of patients with cystic fibrosis. During 2003 to 2008, only two of 61 patients diagnosed with diabetes died.

Cystic fibrosis-related diabetes without fasting hyperglycemia predominated in younger patients; however, the presence of fasting hyperglycemia rose with age.

Still, lung function is worse in patients with cystic fibrosis-related diabetes compared with patients without diabetes. Nutritional and pulmonary statuses were similar between patients with and without fasting hyperglycemia.

The data are “encouraging” because “diabetes is an expected condition as individuals with cystic fibrosis grow older,” Moran said during the interview.

The researchers attributed several reasons to the improved incidence, prevalence and mortality rates related to cystic fibrosis-related diabetes, including more aggressive treatment and early diagnosis.

Better antibiotics, digestive enzymes and respiratory therapies may have also contributed to the changes. “However, these therapies affect all people with cystic fibrosis and it is those with diabetes who have shown the greatest improvement,” Moran said.

Moran A. Diabetes Care. 2009;32:1626-1631.

Detecting CFRLD

Non-invasive liver elastography (Fibroscan) for detection of cystic fibrosis-associated liver disease.

Witters P, De Boeck K, Dupont L, Proesmans M, Vermeulen F, Servaes R, Verslype C, Laleman W, Nevens F, Hoffman I, Cassiman D.

Department of Paediatrics, Katholieke Universiteit Leuven, Belgium; Liver Facility, Katholieke Universiteit Leuven, Belgium.

BACKGROUND: Cystic fibrosis-associated liver disease (CFLD) is the second cause of mortality in CF. The prevalence is estimated to be 26-45%, but sensitive diagnostic tools are lacking. We investigated whether non-invasive liver elastography (Fibroscan) could serve as a screening tool. METHODS: Fibroscan measurements were performed in 66 CF patients. Age-specific cutoff values were determined in a control population (n=59). The measurements were compared to clinical data, biyearly biochemistry and ultrasound. RESULTS: Fibroscan was easy to perform in this patient population. There were 14 patients (21%) with abnormal liver stiffness measurements. Liver stiffness was significantly increased in patients with clinical CFLD (11.2kPa versus 5.1kPa), biochemical CFLD (7.4kPa versus 5.4kPa) or ultrasonographical CFLD (8.2 versus 4.3kPa) (p<0.02 for all). CONCLUSIONS: Fibroscan is an objective measure and is easy to perform in CF patients, even in children and could provide a valuable tool to detect, and quantify CFLD.

PMID: 19733131 [PubMed - as supplied by publisher]

Clinical phenotype of cystic fibrosis patients with the G551D mutation.

I think that other things influence phenotype aside from just CF genes (modifier genes, etc), but this is still interesting:

Clinical phenotype of cystic fibrosis patients with the G551D mutation.

Comer DM, Ennis M, McDowell C, Beattie D, Rendall J, Hall V, Elborn JS.

From the Regional Adult Cystic Fibrosis Centre, Belfast City Hospital, Respiratory Medicine Research Group, Centre for Infection and Immunity, The Queen's University of Belfast, Biostatistician, The Northern Ireland Clinical Research Support Centre, The Royal Group of Hospitals and Regional Genetics Laboratories, Belfast City Hospital, Belfast, N Ireland, UK.

BACKGROUND: Data on whether the phenotype of cystic fibrosis (CF) patients with compound heterozygocity for G551D (Gly551Asp) differs from patients with F508del (Phe508del) homozygous mutations is divergent. AIM: We hypothesized that CF patients with the G551D mutation would have less severe disease than F508del homozygotes. DESIGN: We compared the clinical phenotype of adult patients with a G551D mutation with adult patients homozygous for F508del and those with the missense mutation R117H (Arg117His). Compound heterozygotes for the G551D and R117H were analysed separately. METHODS: Data were collected for 101 adult CF patients. Group 1-4 represents in order F508del homozygote patients (n = 61), those with the G551D mutation and a more severe mutation (n = 13), those with R117H mutation and a more severe mutation (n = 23) and also those compound for both the R117H and G551D mutations (n = 4). RESULTS: Our findings have shown that adult patients with the G551D mutation and a second severe mutation have a milder clinical phenotype than F508del homozygous adult patients. Higher FEV(1) and body mass index and less impaired glucose tolerance was demonstrated in the patients with G551D and R117H compared to F508del homozygotes. There was a reduced yearly rate of decline of FEV(1) (P <>

Wednesday, September 9, 2009

Gene Linked to Liver Disease in Cystic Fibrosis

Gene Linked to Liver Disease in Cystic Fibrosis

Screening for the variation could help identify risk factors early on, researchers say

Posted September 8, 2009

TUESDAY, Sept. 8 (HealthDay News) -- A variant of a particular gene in people with cystic fibrosis greatly increases their chances of developing severe liver disease, new research shows.

Cystic fibrosis is an inherited disorder that can lead to deadly lung infections and digestive problems.

About 3 percent to 5 percent of the 30,000 people in the United States with the condition will also develop a serious form of liver disease, including cirrhosis and portal hypertension, or high blood pressure caused by obstruction in the liver, according to the Cystic Fibrosis Foundation.

Researchers from University of North Carolina at Chapel Hill analyzed nine variants in five genes previously implicated in cystic fibrosis liver disease. The study included 124 patients with cystic fibrosis liver disease and 843 patients without liver disease. A second study looked at a different group of 136 patients with cystic fibrosis liver disease and 1,088 without liver disease.

The researchers found that people who had the "SERPINA1 Z allele," or gene variation, had a five times greater chance of developing liver disease. The other variants did not increase the risk of liver disease.

About 2.2 percent of people with cystic fibrosis carry the SERPINA1 Z allele, according to the study published in the Sept. 9 issue of the Journal of the American Medical Association


Screening for the gene variation could help identify those at risk of developing the liver disease, the researchers wrote.

"The identification of the SERPINA1 Z allele as the first marker for the development of severe liver disease in CF [cystic fibrosis] illustrates the possibility of identifying CF risk factors early in life, conceptually as a secondary component of neonatal screening after the diagnosis of CF is confirmed," researchers wrote.

Sunday, September 6, 2009

Bicarbonate Linked To Sticky Mucus In Cystic Fibrosis

ScienceDaily (Aug. 27, 2009) — A hallmark of cystic fibrosis, a disease caused by mutations in the CTFR gene, is the accumulation of abnormally thick and sticky mucus in the lung, intestine, and various other organs. Although the accumulation of this mucus is thought likely to play a central role in the development of disease, how mutations in the CTFR gene lead to mucus accumulation have not been determined.

However, Paul Quinton and colleagues, at the University of California at San Diego, La Jolla, have now provided insight into this issue by studying mouse small intestine segments ex vivo, according to a paper to be published in the August 24 issue of the Journal of Clinical Investigation. In an accompanying commentary, Robert DeLisle, at the University of Kansas School of Medicine, Kansas City, highlights the importance of the study and the potential new take on how mutations in the CTFR gene lead to mucus accumulation and disease.

One of the functions of the CTFR protein generated by the nonmutated CTFR gene is to transport bicarbonate (HCO3–) out of cells. In their study, Quinton and colleagues developed a new ex vivo system for monitoring mucus release from the mouse small intestine to investigate whether defects in this function of CFTR might affect mucus secretion. Although basal rates of mucus release were similar in the presence or absence of bicarbonate, mucus release stimulated by natural chemicals such as serotonin was markedly decreased in the absence of bicarbonate. Interestingly, in a mouse model of cystic fibrosis, mucus release stimulated by natural chemicals was minimal in the presence or absence of bicarbonate. The authors therefore suggest that normal mucus release requires concurrent bicarbonate secretion and that the abnormally thick and sticky mucus that characterizes cystic fibrosis might be caused by defective bicarbonate secretion.

Journal references:

  1. Garcia et al. Normal mouse intestinal mucus release requires cystic fibrosis transmembrane regulator-dependent bicarbonate secretion. Journal of Clinical Investigation, 2009; DOI: 10.1172/JCI38662
  2. Robert C. De Lisle. Pass the bicarb: the importance of HCO3– for mucin release. Journal of Clinical Investigation, 2009; DOI: 10.1172/JCI40598

new study to prevent CFRD

Cool study at Emory in prevention of CFRD:

If you or someone you know is in the Atlanta area, please contact them! :)

Acute systemic hyperglycemia causes oxidative stress and a pro-inflammatory response. The pro-inflammatory cytokines induced by hyperglycemia are toxic to islet cells, the insulin producing cells, and thus worsen glucose intolerance. Patients with cystic fibrosis (CF) have a high prevalence of CF related diabetes (CFRD) and up to 40% of CF adults develop CFRD. During the prediabetic phase in CF, there is progression from normal glucose homeostasis to impaired glucose tolerance (IGT) characterized by episodes of acute hyperglycemia after meals and during respiratory exacerbations. The mild hyperglycemia seen in CF patients with IGT following a meal would be expected to induce a degree of systemic inflammation and oxidant stress. These repetitive episodes of acute postprandial hyperglycemia in CF patients, if left unchecked, could lead to progression of glucose impairment, worsening severity of postprandial hyperglycemia, worsening severity of oxidant stress and inflammation, and ultimately the development of CFRD, all via hyperglycemia-induced toxicity to beta cells. Furthermore, this process may be accelerated in CF because CF lung disease and resultant respiratory exacerbations are associated with oxidative stress and inflammation and this will further contribute to beta cell damage.

Sitagliptin is a recently approved agent for type 2 diabetes and markedly enhances insulin secretion in the presence of hyperglycemia and has been shown to be effective in preventing postprandial hyperglycemia. The hypothesis to be tested in this project is that sitagliptin will prevent the development of CF diabetes in CF subjects with IGT by blocking postprandial hyperglycemia. The investigators propose a randomized, double-blind, placebo-controlled, multicenter, 24-month longitudinal study in 186 CF subjects with IGT to test this hypothesis.

Specifically, the investigators aim to show that chronic treatment with sitagliptin: prevents the conversion to diabetes; results in preservation of beta cell mass and function; reduces airway and systemic measures of oxidative stress and inflammation; and slows the rate of progression of lung disease. The investigators further hypothesize that treatment with sitagliptin of CFRD early in the course of the disease will result in normalization of glucose levels without requiring insulin treatment. Specifically, in those subjects that convert to diabetes, the investigators will show that sitagliptin improves glucose control, nutrition, and degree of lung dysfunction.


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