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Thursday, July 30, 2009

Mutation Responsible For Cystic Fibrosis Also Involved In Muscle Atrophy

ScienceDaily (July 30, 2009) — Patients with cystic fibrosis (CF) usually experience significant muscle loss, a symptom traditionally considered to be a secondary complication of the devastating genetic disease. However, a recent study by Dr. Basil Petrof reverses the equation: his results show that muscle atrophy and weakness may be a primary symptom caused by the effects of CFTR gene mutations on the muscle itself.

Dr. Petrof's findings will be published on July 31 in Public Library of Science – Genetics.

Cystic fibrosis is known to be caused by a specific mutation on the CFTR gene. Dr. Petrof's study demonstrates for the first time that the CFTR gene is also present in skeletal muscles, where it plays a role in calcium regulation.

"After analyzing our results, we believe that defects in the CFTR gene are directly involved in the skeletal muscle wasting and weakness seen in many CF patients," Dr. Petrof explained. "And in the specific case of the diaphragm, a muscle required for breathing, this can potentially lead to fatal respiratory failure when the lungs are infected."

The researchers' data also show that lung infection and increased inflammation in the body are major triggers which interact with the genetic mutation to cause muscle atrophy and weakness in CF mice. These results are also applicable to humans.

"Our study suggests that one way to fight CF-related muscle atrophy is to aggressively control inflammation and infection in our patients. In fact", continued Dr. Petrof, "this is what current treatments already try to do; we simply need to reinforce them. In addition, our study suggests that a new way to treat the problem in the future may be to use drugs which can prevent an excess calcium build-up in their muscle cells."

These new findings run contrary to the traditional belief that muscle atrophy in CF patients is simply the consequence of a lack of exercise or poor nutrient absorption. Although these explanations undoubtedly play a role in some patients, it now appears that a primary cause of the muscle loss could actually be genetic in origin. This new evidence that the CFTR gene plays a role in skeletal muscle could help researchers to develop novel therapies for improving the function of the diaphragm and other muscles in CF patients.

CF is a genetic disease caused by mutations in the CFTR gene. This gene is involved in the movement of chloride and other ions across cell membranes; its mutation causes a thickening of secretions in the lungs and other organs. In the lungs, these thicker secretions clog and block air passages which promote respiratory infections.

This study was funded by the Canadian Cystic Fibrosis Foundation, the Canadian Institutes of Health Research and BREATHE program, the Quebec Respiratory Health Network of the Fonds de la recherche en santé du Québec (FRSQ), and a Chercheur National Award from the FRSQ to Dr. Basil Petrof.

This article was co-authored by Dr. Maziar Divangahi, Dr. Haouaria Balghi (co-first authors), Dr. Gawiyou Danialou, Dr. Alain Comtois, Dr. Alexandre Demoule, Dr. Sheila Ernest, Dr. Christina Haston, Dr. Danuta Radzioch and Dr. Basil Petrof of the Research Institute of the MUHC, as well as by Dr. Renaud Robert and Dr. John W. Hanrahan of McGill University.


Sunday, July 26, 2009

eFLow / Trio Summary

Hi guys,

I know I have quite a bit of info under this category, so I wanted to sum it up for everyone here in case you don't have time at the moment to read my blabbing.

  1. The eFlow/ Trio was approved for use in the United States in 2004. The FDA says that the eFlow is approved "with patients for whom doctors have prescribed medication for nebulization. The Trio™ is intended for adult and pediatric patients."

2. Thousands of Cystic Fibrosis physicians from around the world have prescribed the eFLow to their patients. In Europe, the eFLow is given to Pulmozyme patients for free to use with this medication.

3. In the United States, the eFlow is distributed through SourceCF, a division of PARI. There are 3 pharmacies in the US who distribute under SourceCF, and the pharmacy you should use will depend on where you live. You can call Source CF and they'll tell you which pharmacy to contact. 1-888-335-6946 http://www.sourcecf.com/eflow.htm#get . Through this network, as long as you order your neb antibiotics through them, you get the eFlow FOR FREE. So if you order tobramycin, colistin, etc through them, the eFlow is free. Jackpot. And they will send you replacement "heads/membranes" for free every 3 months.

4. As you'll see from pictures below, the eFlow has plastic parts just like your traditional nebulizers. They can be washed & sterilized in the same way. The only difference with the eFlow is the metal "head" or "membrane."

5. After each medication treatment, rinse the "head" or "membrane" with distilled water (better than tap water because it doesn't have the minerals, etc. to clog the tiny, laser drilled holes). Soak the head in between treatments in alcohol to keep the laser drilled holes open (and to sanitize the head). Boil the head once a week for 10 minutes.

6. That's the only difference in care for the eFLow vs. the traditional compressors/nebulizers. People complain of the eFlow being a pain to clean - I have no idea why. Rinsing in distilled water for 1-2 minutes is pretty simple in my mind.

7. If your eFlow treatments start to slow down, invest in a ultrasonic jewelry cleaner (Foundation Care gave me one for free). http://www.walmart.com/catalog/product.do?product_id=2416364
Leave the head/membrane in the cleaner overnight with distilled water and you should notice improved performance.

8. The eFlow is great because you can use it internationally. I've brought mine to Europe and Asia and because it's battery operated, it always works. For those of you who have been to Europe and Asia with your PARI ProNeb Ultra or other compressor, you konw, you need to get a compressor for that specific continent in order to get the full benefit of your treaetments. What a pain!

9. I think I have posted studies below (look for them), but there have been several studies demonstrating why pulmozyme, tobi and albuterol work in the eFLow.

Saturday, July 25, 2009

Pulmozyme 2x a day

scroll down to find the red section


Pulmozyme® (dornase alfa) Inhalation Solution is a sterile, clear, colorless, highly purified solution of recombinant human deoxyribonuclease I (rhDNase), an enzyme which selectively cleaves DNA. The protein is produced by genetically engineered Chinese Hamster Ovary (CHO) cells containing DNA encoding for the native human protein, deoxyribonuclease I (DNase). Fermentation is carried out in a nutrient medium containing the antibiotic gentamicin, 100-200 mg/L. However, the presence of the antibiotic is not detectable in the final product. The product is purified by tangential flow filtration and column chromatography. The purified glycoprotein contains 260 amino acids with an approximate molecular weight of 37,000 daltons1. The primary amino acid sequence is identical to that of the native human enzyme.

Pulmozyme is administered by inhalation of an aerosol mist produced by a compressed air driven nebulizer system (see Clinical Experience, Dosage and Administration). Each Pulmozyme single-use ampule will deliver 2.5 mL of the solution to the nebulizer bowl. The aqueous solution contains 1.0 mg/mL dornase alfa, 0.15 mg/mL calcium chloride dihydrate and 8.77 mg/mL sodium chloride. The solution contains no preservative. The nominal pH of the solution is 6.3.

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Clinical Pharmacology


In cystic fibrosis (CF) patients, retention of viscous purulent secretions in the airways contributes both to reduced pulmonary function and to exacerbations of infection2,3.

Purulent pulmonary secretions contain very high concentrations of extracellular DNA released by degenerating leukocytes that accumulate in response to infection4. In vitro, Pulmozyme hydrolyzes the DNA in sputum of CF patients and reduces sputum viscoelasticity1.


When 2.5 mg Pulmozyme was administered by inhalation to eighteen CF patients, mean sputum concentrations of 3 µg/mL DNase were measurable within 15 minutes. Mean sputum concentrations declined to an average of 0.6 µg/mL two hours following inhalation. Inhalation of up to 10 mg TID of Pulmozyme by 4 CF patients for six consecutive days, did not result in a significant elevation of serum concentrations of DNase above normal endogenous levels5,6. After administration of up to 2.5 mg of Pulmozyme twice daily for six months to 321 CF patients, no accumulation of serum DNase was noted.

Pulmozyme, 2.5 mg by inhalation, was administered daily to 98 patients aged 3 months to ≤10 years, and bronchoalveolar lavage (BAL) fluid was obtained within 90 minutes of the first dose. BAL DNase concentrations were detectable in all patients but showed a broad range, from 0.007 to 1.8 µg/mL. Over an average of 14 days of exposure, serum DNase concentrations (mean ± s.d.) increased by 1.3 ± 1.3 ng/mL for the 3 months to <5>

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Clinical Experience

Pulmozyme has been evaluated in a randomized, placebo-controlled trial of clinically stable cystic fibrosis patients, 5 years of age and older, with baseline forced vital capacity (FVC) greater than or equal to 40% of predicted and receiving standard therapies for cystic fibrosis7. Patients were treated with placebo (325 patients), 2.5 mg of Pulmozyme once a day (322 patients), or 2.5 mg of Pulmozyme twice a day (321 patients) for six months administered via a Hudson T Up-draft II® nebulizer with a Pulmo-Aide® compressor.

Both doses of Pulmozyme resulted in significant reductions when compared with the placebo group in the number of patients experiencing respiratory tract infections requiring use of parenteral antibiotics. Administration of Pulmozyme reduced the relative risk of developing a respiratory tract infection by 27% and 29% for the 2.5 mg daily dose and the 2.5 mg twice daily dose, respectively (see Table 1). The data suggest that the effects of Pulmozyme on respiratory tract infections in older patients (>21 years) may be smaller than in younger patients, and that twice daily dosing may be required in the older patients. Patients with baseline FVC>85% may also benefit from twice a day dosing (see Table 1). The reduced risk of respiratory infection observed in Pulmozyme treated patients did not directly correlate with improvement in FEV1 during the initial two weeks of therapy.

Within 8 days of the start of treatment with Pulmozyme, mean FEV1 increased 7.9% in those treated once a day and 9.0% in those treated twice a day compared to the baseline values. The overall mean FEV1 during long-term therapy increased 5.8% from baseline at the 2.5 mg daily dose level and 5.6% from baseline at the 2.5 mg twice daily dose level. Placebo recipients did not show significant mean changes in pulmonary function testing (see Figure 1).

For patients 5 years of age or older, with baseline FVC greater than or equal to 40%, administration of Pulmozyme decreased the incidence of occurrence of first respiratory tract infection requiring parenteral antibiotics, and improved mean FEV1, regardless of age or baseline FVC.

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Table 1: Incidence of First Respiratory Tract Infection Requiring Parenteral Antibiotics in Patients with FVC ≥40% of Predicted

PlaceboN=325 2.5 mg QDN=322 2.5 mg BIDN=321
Percent of Patients Infected Relative Risk (vs placebo)
p-value (vs placebo)
43% 34%0.730.015 33%0.710.007
Subgroup by Age and Baseline FVC Placebo(N) 2.5 mg QD(N) 2.5 mg BID(N)
5-20 years
21 years and older
Baseline FVC
40-85% Predicted
>85% Predicted
42% (201)
44% (124)
54% (194)
27% (131)
25% (199)
48% (123)
41% (201)
21% (121)
28% (184)
39% (137)
44% (203)
14% (118)

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Figure 1: Mean Percent Change from Baseline FEV1 in Patients with FVC ≥40% of Predicted

Figure 1: Mean Percent Change

Pulmozyme has also been evaluated in a second randomized, placebo-controlled study in clinically stable patients with baseline FVC <40%>8. Patients were enrolled and treated with placebo (162 patients) or Pulmozyme 2.5 mg QD (158 patients) for 12 weeks. In patients who received Pulmozyme, there was an increase in mean change (as percent of baseline) compared to placebo in FEV1 (9.4% vs. 2.1%, p< risk =" .93," p="0.62).

Other Studies

Clinical trials have indicated that Pulmozyme therapy can be continued or initiated during an acute respiratory exacerbation.

Short-term dose ranging studies demonstrated that doses in excess of 2.5 mg BID did not provide further improvement in FEV1. Patients who have received drug on a cyclical regimen (i.e., administration of Pulmozyme 10 mg BID for 14 days, followed by a 14 day wash out period) showed rapid improvement in FEV1 with the initiation of each cycle and a return to baseline with each Pulmozyme withdrawal.

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Indications and Usage

Daily administration of Pulmozyme® (dornase alpha) Inhalation Solution in conjunction with standard therapies is indicated in the management of cystic fibrosis patients to improve pulmonary function. In patients with an FVC ≥40% of predicted, daily administration of Pulmozyme has also been shown to reduce the risk of respiratory tract infections requiring parenteral antibiotics.

Safety and efficacy of daily administration have not been demonstrated in patients for longer than 12 months.

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Pulmozyme is contraindicated in patients with known hypersensitivity to dornase alfa, Chinese Hamster Ovary cell products, or any component of the product.

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Pulmozyme should be used in conjunction with standard therapies for CF.

Information for Patients

Pulmozyme must be stored in the refrigerator at 2-8°C (36-46°F) and protected from strong light. It should be kept refrigerated during transport and should not be exposed to room temperatures for a total time of 24 hours. The solution should be discarded if it is cloudy or discolored. Pulmozyme contains no preservative and, once opened, the entire contents of the ampule must be used or discarded. Patients should be instructed in the proper use and maintenance of the nebulizer and compressor system used in its delivery.

Pulmozyme should not be diluted or mixed with other drugs in the nebulizer. Mixing of Pulmozyme with other drugs could lead to adverse physicochemical and/or functional changes in Pulmozyme or the admixed compound.

Drug Interactions

Clinical trials have indicated that Pulmozyme can be effectively and safely used in conjunction with standard cystic fibrosis therapies including oral, inhaled and/or parenteral antibiotics, bronchodilators, enzyme supplements, vitamins, oral or inhaled corticosteroids, and analgesics. No formal drug interaction studies have been performed.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: Lifetime studies in Sprague Dawley rats showed no carcinogenic effect when Pulmozyme was administered at doses up to 246 µg/kg body weight per day. Pulmozyme was administered to rats as an aerosol for up to 30 minutes per day, daily for two years, with resulting lower respiratory tract doses of up to 246 µg/kg per day, which represents up to a 28.8-fold multiple of the clinical dose. There was no increase in the development of benign or malignant neoplasms and no occurrence of unusual tumor types in rats after lifetime exposure.

Mutagenesis: Ames tests using six different tester strains of bacteria (4 of S. typhimurium and 2 of E. coli) at concentrations up to 5000 µg/plate, a cytogenetic assay using human peripheral blood lymphocytes at concentrations up to 2000 µg/plate, and a mouse lymphoma assay at concentrations up to 1000 mg/plate, with and without metabolic activation, revealed no evidence of mutagenesis potential. Pulmozyme was tested in a micronucleus (in vivo) assay for its potential to produce chromosome damage in bone marrow cells of mice following a bolus intravenous dose of 10 mg/kg on two consecutive days. No evidence of chromosomal damage was noted.

Impairment of Fertility: In studies with rats receiving up to 10 mg/kg/day, a dose representing systemic exposures greater than 600 times that expected following the recommended human dose, fertility and reproductive performance of both males and females was not affected.

Pregnancy (Category B)

Reproduction studies have been performed in rats and rabbits with intravenous doses up to 10 mg/kg/day, representing systemic exposures greater than 600 times that expected following the recommended human dose. These studies have revealed no evidence of impaired fertility, harm to the fetus, or effects on development due to Pulmozyme. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of the human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether Pulmozyme is excreted in human milk. Small amounts of dornase alfa were detected in maternal milk of cynomolgus monkeys when administered a bolus dose (100 µg/kg) of dornase alfa followed by a six hour intravenous infusion (80 µg/kg/hr). Little or no measurable dornase alfa would be expected in human milk after chronic aerosol administration of recommended doses. Because many drugs are excreted in human milk, caution should still be exercised when Pulmozyme is administered to a nursing woman.

Pediatric Use

Because of the limited experience with the administration of Pulmozyme to patients younger than 5 years of age, its use should be considered only for those patients in whom there is a potential for benefit in pulmonary function or in risk of respiratory tract infection.

Geriatric Use

Cystic fibrosis is primarily a disease of pediatrics and young adults. Clinical studies of Pulmozyme did not include sufficient numbers of subjects aged 65 or older to determine whether they respond differently from younger subjects.

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Adverse Reactions

Patients have been exposed to Pulmozyme for up to 12 months in clinical trials.

In a randomized, placebo-controlled clinical trial in patients with FVC ≥40% of predicted, over 600 patients received Pulmozyme once or twice daily for six months; most adverse events were not more common on Pulmozyme than on placebo and probably reflected the sequelae of the underlying lung disease. In most cases events that were increased were mild, transient in nature, and did not require alterations in dosing. Few patients experienced adverse events resulting in permanent discontinuation from Pulmozyme, and the discontinuation rate was similar for placebo (2%) and Pulmozyme (3%). Events that were more frequent (greater than 3%) in Pulmozyme treated patients than in placebo-treated patients are listed in Table 2.

In a randomized, placebo-controlled trial of patients with advanced disease (FVC <40%>

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Table 2: Adverse Events Increased 3% or More in PulmozymeTreated Patients Over Placebo in CF Clinical Trials

Trial in Mild to Moderate CF Patients (FVC ≥40% of predicted) treated for 24 weeks Trial in Advanced CF Patients (FVC <40%>
Adverse Event (of any severity or seriousness) Placebon=325 Pulmozyme QDn=322 Pulmozyme BIDn=321 Placebon=159 Pulmozyme QDn=161
Voice alteration 7% 12% 16% 6% 18%
Pharyngitis 33% 36% 40% 28% 32%
Rash 7% 10% 12% 1% 3%
Laryngitis 1% 3% 4% 1% 3%
Chest Pain 16% 18% 21% 23% 25%
Conjunctivitis 2% 4% 5% 0% 1%
Rhinitis Differences were less than 3% for these adverse events in the Trial in mild to moderate CF patients. 24% 30%
FVC decrease of ≥10% of predicted° 17% 22%
Fever 28% 32%
Dyspepsia 0% 3%
Dyspnea (when reported as serious) Difference was less than 3% for this adverse event in the Trial in mild to moderate CF patients. 12%† 17%†

° Single measurement only, does not reflect overall FVC changes.† Total reports of dyspnea (regardless of severity or seriousness) had a difference of less than 3% for the Trial in advanced CF patients.

Events Observed at Similar Rates in Pulmozyme® (dornase alfa) Inhalation Solution and Placebo Treated Patients with FVC ≥40% of predicted

Body as a Whole Abdominal pain, Asthenia, Fever, Flu syndrome, Malaise, Sepsis
Digestive System Intestinal Obstruction, Gall Bladder disease, Liver disease, Pancreatic disease
Metabolic Nutritional System Diabetes Mellitus, Hypoxia, Weight Loss
Respiratory System Apnea, Bronchiectasis, Bronchitis, Change in Sputum, Cough Increase, Dyspnea, Hemoptysis, Lung Function Decrease, Nasal Polyps, Pneumonia, Pneumothorax, Rhinitis, Sinusitis, Sputum Increase, Wheeze

Mortality rates observed in controlled trials were similar for the placebo and Pulmozyme treated patients. Causes of death were consistent with progression of cystic fibrosis and included apnea, cardiac arrest, cardiopulmonary arrest, cor pulmonale, heart failure, massive hemoptysis, pneumonia, pneumothorax, and respiratory failure.

The safety of Pulmozyme, 2.5 mg by inhalation, was studied with 2 weeks of daily administration in 98 patients with cystic fibrosis (65 aged 3 months to <5>™ reusable nebulizer (which uses a facemask instead of a mouthpiece) was utilized in patients unable to demonstrate the ability to inhale or exhale orally throughout the entire treatment period (54/65, 83% of the younger and 2/33, 6% of the older patients). The number of patients reporting cough was higher in the younger age group as compared to the older age group (29/65, 45% compared to 10/33, 30%) as was the number reporting moderate to severe cough (24/65, 37% as compared to 6/33, 18%). Other events tended to be of mild to moderate severity. The number of patients reporting rhinitis was higher in the younger age group as compared to the older age group (23/65, 35% compared to 9/33, 27%) as was the number reporting rash (4/65, 6% as compared to 0/33). The nature of adverse events was similar to that seen in the larger trials of Pulmozyme.

Allergic Reactions

There have been no reports of anaphylaxis attributed to the administration of Pulmozyme to date. Urticaria, mild to moderate, and mild skin rash have been observed and have been transient. Within all of the studies, a small percentage (average of 2-4%) of patients treated with Pulmozyme developed serum antibodies to Pulmozyme. None of these patients developed anaphylaxis, and the clinical significance of serum antibodies to Pulmozyme is unknown.

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Single-dose inhalation studies in rats and monkeys at doses up to 180-times higher than doses routinely used in clinical studies are well tolerated. Single dose oral administration of Pulmozyme in doses up to 200 mg/kg are also well tolerated by rats.

Cystic fibrosis patients have received up to 20 mg BID for up to 6 days and 10 mg BID intermittently (2 weeks on/2 weeks off drug) for 168 days. These doses were well tolerated.

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Dosage and Administration

The recommended dose for use in most cystic fibrosis patients is one 2.5 mg single-use ampule inhaled once daily using a recommended nebulizer. Some patients may benefit from twice daily administration (see Clinical Experience, Table 1). Clinical trial results and laboratory information are only available to support use of the following nebulizer/compressor systems (see Table 3).

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Table 3: Recommended Nebulizer/Compressor Systems

Jet Nebulizer Compressor
Hudson T Up-draft II® with Pulmo-Aide®
Marquest Acorn II® with Pulmo-Aide®
Durable Sidestream® with MOBILAIRE™
Durable Sidestream® with Porta-Neb®

* Patients who are unable to inhale or exhale orally throughout the entire nebulization period may use the PARI BABY™ nebulizer.

Patients who use the Sidestream® Nebulizer with the MOBILAIRE™ compressor should turn the compressor control knob fully to the right and then turn on the compressor. At this setting, the needle on the pressure gauge should vibrate between 35 and 45 pounds per square inch (highest pressure output).

No data are currently available that support the administration of Pulmozyme with other nebulizer systems. The patient should follow the manufacturer's instructions on the use and maintenance of the equipment.

Pulmozyme should not be diluted or mixed with other drugs in the nebulizer. Mixing of Pulmozyme with other drugs could lead to adverse physicochemical and/or functional changes in Pulmozyme or the admixed compound. Patients should be advised to squeeze each ampule prior to use in order to check for leaks.

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How Supplied

Pulmozyme is supplied in single-use ampules. Each ampule delivers 2.5 mL of a sterile, clear, colorless, aqueous solution containing 1.0 mg/mL dornase alfa, 0.15 mg/mL calcium chloride dihydrate and 8.77 mg/mL sodium chloride with no preservative. The nominal pH of the solution is 6.3.

Pulmozyme is supplied in:

  • 30 unit cartons containing 5 foil pouches of 6 single-use ampules: NDC 50242-100-40.


Pulmozyme should be stored under refrigeration (2-8°C/36-46°F). Ampules should be protected from strong light. Do not use beyond the expiration date stamped on the ampule. Unused ampules should be stored in their protective foil pouch under refrigeration.

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  1. Shak S, Capon DJ, Hellmiss R, Marsters SA, Baker CL. Recombinant human DNase I reduces the viscosity of cystic fibrosis sputum. Proc Natl Acad Sci USA 1990; 87: 9188-92.
  2. Boat TF. Cystic Fibrosis. In: Murray JF, Nadel JA, editors. Textbook of respiratory medicine. Philadelphia: Saunders WB, 1988; 1: 1126-52.
  3. Collins FS. Cystic Fibrosis: molecular biology and therapeutic implications. Science 1992; 256: 774-9.
  4. Potter JL, Spector S, Matthews LW, Lemm J. Studies of pulmonary secretions. Am Rev Respir Dis 1969; 99: 909-15.
  5. Hubbard RC, McElvaney NG, Birrer P, Shak S, Robinson WW, Jolley C, et al. A preliminary study of aerosolized recombinant human deoxyribonuclease I in the treatment of cystic fibrosis. N Eng J Med 1992; 326: 812-5.
  6. Aitken ML, Burke W, McDonald G, Shak S, Montgomery AB, Smith A. Recombinant human DNase inhalation in normal subjects and patients with cystic fibrosis. JAMA 1992; 267(14): 1947-51.
  7. Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, et al. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. N Engl J Med 1994; 331: 637-42.
  8. McCoy K, Hamilton S, Johnson C. Effects of 12-week administration of dornase alfa in patients with advanced cystic fibrosis lung disease. Chest 1996; 110: 889-95.


Thursday, July 23, 2009

Provision of contraception services and advice for women with cystic fibrosis.

Provision of contraception services and advice for women with cystic fibrosis.

J Fam Plann Reprod Health Care. 2009 Jul;35(3):157-60

Authors: Gatiss S, Mansour D, Doe S, Bourke S

BACKGROUND AND METHODOLOGY: As the prognosis of patients with cystic fibrosis (CF) improves, issues of sexual health, fertility, pregnancy and contraception are increasingly important. In order to plan the provision of a contraception and sexual health service for women with CF we studied their sexual and reproductive history, their current usage of contraception, the sources and quality of advice they had received, and their particular needs using a confidential questionnaire sent to all women over 16 years of age attending a regional CF centre.

RESULTS: Of 55 women (mean age 29.7 years) surveyed, 42 (76%) responded. Thirty-three women (79%) were sexually active and 13 (31%) had experienced 19 pregnancies, five (26%) of which were unplanned. Only half of the women who responded were using contraception. No woman used female sterilisation, the progestogen implant, intrauterine system (IUS) or copper-bearing intrauterine device (IUD) for contraception. Twenty-six (62%) women reported not having received contraceptive advice specific to CF and 24 (57%) said that they had not been warned about the potential interaction between broad-spectrum antibiotics and the combined pill.

DISCUSSION: Women with CF have a relatively high rate of unplanned pregnancy and do not receive optimal advice or use the full range of contraceptive methods. CF teams lack training in contraception and contraceptive services may not have a detailed knowledge of CF and its complications. New strategies are needed to focus the knowledge and skills of both teams in providing better services for women with CF.

Tuesday, July 21, 2009

Encouraging New Results For Miglustat

Web address:

Treatment Of Cystic Fibrosis: Encouraging New Results For Miglustat

ScienceDaily (July 21, 2009) — Miglustat is a drug currently under phase 2 clinical trials on patients suffering from cystic fibrosis (1). Its potential for treating the disease was discovered in 2006 thanks to the work of Frédéric Becq's team at the Institute of Cell Physiology and Biology (CNRS/Université de Poitiers), funded by the associations Vaincre la Mucoviscidose, MucoVie66, La Pierre Le Bigaut and ABCF2.

In new work to be published on 1 August 2009 in the American Journal of Respiratory Cell and Molecular Biology, the researchers show that daily, long-term treatment of human cystic fibrosis cells with low doses of miglustat corrects the main pathological abnormalities. They are therefore extremely hopeful that miglustat will prove effective with patients, and become the first drug able to treat the disease rather than the symptoms.

Cystic fibrosis is a genetic disease, transmitted jointly by both parents, and affects around 6000 people in France. It is caused by the dysfunction of a membrane protein (CFTR), present especially in the epithelial cells in the lungs, which controls exchange of water and mineral salts between the cell and the exterior. On the cell level, the disease manifests itself by the absence of chloride secretion, sodium hyperabsorption, deregulation of calcium homeostasis, and heightened inflammatory response. This results in thickening of the mucus that lines the bronchial tubes and the pancreatic ducts, leading to lung infections and digestive disorders. At the current time, there is no treatment that cures cystic fibrosis. In order to alleviate the symptoms, extremely strict daily treatment is necessary.

In 2006, Frédéric Becq's team at the Institute of Cell Physiology and Biology (CNRS/Université de Poitiers) showed that a drug called miglustat restored the activity of the CFTR protein and could thus temporarily correct the specific phenotype characteristic of cystic fibrosis. Used to treat two rare diseases (Gaucher's disease and Niemann-Pick type C disease), its safety and tolerance had already been assessed, and clinical trials could be rapidly begun in September 2007.

In the new study published in American Journal of Respiratory Cell and Molecular Biology, the researchers show that daily treatment of human respiratory cells that are homozygous for the F508del mutation with low concentrations of miglustat leads to progressive, sustained and reversible correction of the diseased phenotype. The researchers cultured diseased human respiratory cells in the presence of miglustat for two months. The correction observed in the cells takes place after 3-4 days, and then stabilizes. When the treatment is stopped, the cells revert to the diseased phenotype. The low doses used (3 micromolars) mean that they can be administered to patients and that their presence in the bloodstream causes no problems.

This study is the first that shows that a cystic fibrosis cell can acquire a sustained non-diseased phenotype when treated daily with a pharmacological agent. The researchers are therefore very optimistic about the results of the clinical trials under way.

(1) The clinical study is being carried out by the Actelion pharmaceutical laboratory on 15 patients suffering from cystic fibrosis and carrying the delta F508 mutation (F508del), which is the most common and the most serious of the mutations affecting children with cystic fibrosis. The results will be known in the coming weeks.

Journal reference:

  1. C. Norez, F. Antigny, S. Noel, C. Vandebrouck, F. Becq. A CF respiratory epithelial cell chronically treated by miglustat acquires a non-CF like phenotype. American Journal of Respiratory Cell and Molecular Biology, August 2009
Adapted from materials provided by CNRS (Délégation Paris Michel-Ange).

Saturday, July 18, 2009

Obesity and Underweight are Associated with an Increased Risk of Death after Lung Transplantation.

Obesity and Underweight are Associated with an Increased Risk of Death after Lung Transplantation.

Lederer DJ, Wilt JS, D'Ovidio F, Bacchetta MD, Shah L, Ravichandran S, Lenoir J, Klein B, Sonett JR, Arcasoy SM.

Department of Medicine and, the New York Presbyterian Lung Transplant Program, College of Physicians and Surgeons, Columbia University, New York, New York, United States.

RATIONALE: Obesity is considered a relative contraindication to lung transplantation based on studies that have not accounted for key confounders. Little is known about the risk of death after transplantation of underweight candidates.

OBJECTIVE: To examine the associations of pre-transplant obesity and underweight with the risk of death after lung transplantation.

METHODS: We examined 5,978 adults with cystic fibrosis, chronic obstructive pulmonary disease, and diffuse parenchymal lung disease who underwent lung transplantation in the United States between 1995 and 2003. We used Cox models and generalized additive models to examine the association between pre-transplant body mass index and the risk of death after lung transplantation with adjustment for donor and recipient factors.

RESULTS: The median follow-up time was 4.2 years. Compared to normal weight recipients, the multivariable-adjusted rates of death were 15% higher for underweight recipients (95% confidence interval 3 to 28%), 15% higher for overweight recipients (95% confidence interval 6 to 26%), and 22% higher for obese recipients (95% confidence interval 8 to 39%). These relationships persisted when stratified by diagnosis. The multivariable-adjusted population attributable fraction was 12% at 1 year and 8% at 5 years.

CONCLUSIONS: Both obesity and underweight are independent risk factors for death after lung transplantation, contributing to up to 12% of deaths in the first year after transplantation. Primary care providers and pulmonologists should promote a healthy weight for patients with lung disease long before transplantation is considered.

PMID: 19608717 [PubMed - as supplied by publisher]

Friday, July 17, 2009

Peds show increased likelihood of thrombosis issues

Increased Thrombophilic Tendency in Pediatric Cystic Fibrosis Patients.

Williams VK, Griffiths A, Yap Z, Martin J, Smith G, Couper R, Revesz T.

Thrombophilia has recently been reported to be increased in patients with cystic fibrosis (CF). We wanted to determine whether this was applicable to our population with CF and how our patients compared to the previously reported groups. Seventy one pediatric CF patients were assessed for a thrombophilic tendency, using a lupus anticoagulant screen, protein C, protein S, antithrombin assay, and activated protein C resistance (APCR) screen. The incidence of activate protein C resistance (4.2%) was within expected limits for the general population as was the incidence of antithrombin deficiency. However there was a marked increase in the incidence of lupus anticoagulants (18%) and 14% and 19.7% of the patients showed a reduced protein C and protein S, respectively, far in excess of the general population.

This increased incidence of thrombophilia was not related to any specific CF phenotype and while perturbed liver function cannot be entirely ruled out, it appeared unlikely to be responsible for all the abnormal coagulation findings. Despite the apparent thrombophilic tendency, no clinically evident thrombotic episodes were noted during the study period. Thrombophilia is of concern because of the increasingly frequent placement of indwelling catheters in CF patients. The precise cause for the thrombophilic tendency in CF patients is unknown at this stage.

PMID: 19605377 [PubMed - as supplied by publisher]

Thursday, July 16, 2009

Liposomal Tobramycin Receives Second Orphan Drug Designation Within Weeks

ZURICH, July 16 /PRNewswire/ -- An innovative treatment for infections of the respiratory tract in cystic fibrosis patients has received a second orphan drug designation in the US only weeks after a first designation was granted. The recent designation relates to Burkholderia cepacia pathogens that can cause lethal infections in cystic fibrosis patients. For Axentis Pharma AG of Zurich, Switzerland, both designations affirm the therapeutic potential of its product candidate Fluidosomes(TM)-tobramycin, whose unique microbiological profile sets it apart from other antibiotic formulations (including free tobramycin).

Axentis Pharma (Switzerland) announced today that the Office of Orphan Products Development of the US Food and Drug Administration (FDA) has granted a second orphan drug designation to its lead product candidate Fluidosomes(TM)-tobramycin. This drug is a liposomal formulation of tobramycin and an innovative treatment for infections of the respiratory tract in patients with cystic fibrosis. Only three months ago, the FDA granted Fluidosomes(TM)-tobramycin orphan drug designation for the treatment of pulmonary infections caused by Pseudomonas aeruginosa. The newly granted second designation relates to pulmonary infections caused by Burkholderia cepacia (B. cepacia) pathogens.

Despite stringent infection control practices, B. cepacia infections still occur in cystic fibrosis patients and can lead to fatal sepsis. The cell envelopes of these especially virulent bacteria are impermeable to most antibiotics, which makes them particularly difficult to treat. Due to its unique mode of action, which allows the antibiotics to penetrate into the bacteria, Fluidosomes(TM)-tobramycin could become a particularly effective treatment for B. cepacia infections.

Prof. Dr. Miguel A Valvano, MD, Medical Advisor to Axentis Pharma, comments on the development: "Burkholderia cepacia is almost always multi-resistant to antibiotics and this, in conjunction with the poor prognosis of patients with B. cepacia infection, makes the treatment of these patients exceedingly complex. Tobramycin is in principle an effective antibiotic. The drug is however rather ineffective due to the impermeability of B. cepacia's cell envelope. In addition, B. cepacia - just like many other pathogens - has developed mechanisms to eliminate antibiotics once they have entered the cell. Fluidosomes(TM)-tobramycin seems to overcome these limitations by packing tobramycin into liposomes, which, by allowing effective penetration of the antibiotic into the bacterial cell, completely changes the microbiological profile of this antibiotic. Hence, Fluidosomes(TM)-tobramycin could be a totally new antibiotic formulation that addresses microbiological needs that no other antibiotic can."

What exactly happens when Fluidosomes(TM)-tobramycin encounters the bacterium is still not entirely clear, but pre-clinical data indicate a novel mode of action. Dr. Helmut Brunar, CEO of Axentis Pharma explains: "Once at the site of infection, tobramycin-containing liposomes seem to fuse with the cell membrane of the pathogen. In this way, the entire load of tobramycin contained in the Fluidosomes(TM) is released into the bacterial cell. Additionally, our data indicate that bacterial rescue mechanisms that pump tobramycin out of the cell are inhibited by the fusion process. The efficient delivery and maximum release of tobramycin into the bacterial cell together with inhibition of the clearance mechanism indicate that Fluidosomes(TM)-tobramycin has a highly efficient therapeutic effect."

About Axentis Pharma AG (http://www.axentispharma.com)

Axentis Pharma is a respiratory specialty pharmaceutical company whose core competence is the combination of a fully patented, liposome-based drug delivery system with already established and well-characterized therapeutic agents. The company is using its platform delivery technology, named Fluidosomes(TM) technology, for the development of its lead product, an inhalable liposomal formulation of tobramycin. Axentis Pharma's lead product is designed to treat bacterial infections in the lungs.

About Fluidosomes(TM) technology

Axentis Pharma's Fluidosomes(TM) technology uses biocompatible lipids endogenous to the lung that are formulated into small liposomes. This nanocapsule platform offers wide-ranging potential for unmet medical needs, including chronic respiratory infections of the lung. In the case of Fluidosomes(TM)-tobramycin, the interaction between tobramycin and the microbial cell is triggered when the liposomes undergo a fusion process with the outer membrane of the bacterial cell wall. Tobramycin then penetrates into the inner cell compartment and triggers bacterial cell death.

For further information, please contact:
Dr. Helmut Brunar, Ph.D., CEO
Axentis Pharma AG
Limmatquai 138
8001 Zurich, Switzerland
T +41-44-202-7878
E board@axentispharma.com
W http://www.axentispharma.com

Copy Editing & Distribution:
PR&D - Public Relations for Research & Education
Campus Vienna Biocenter 2
1030 Vienna, Austria
T +43-1-505-70-44
E contact@prd.at
W http://www.prd.at

Wednesday, July 15, 2009

Tuesday, July 14, 2009

Insulin Therapy to Improve BMI in CFRD

Insulin Therapy to Improve BMI in Cystic Fibrosis Related Diabetes Without Fasting Hyperglycemia: Results of the CFRDT Trial.

Moran A, Pekow P, Grover P, Zorn M, Slovis B, Pilewski J, Tullis E, Liou TG, Allen H; the CFRDT Study Group.

From the University of Minnesota, Minneapolis (AM, TG); University of Massachusetts, Amherst (PP, MZ); Vanderbilt University, Nashville, Tennessee (BS); University of Pittsburgh, Philadelphia (JP); St. Michael's Hospital, Toronto, Canada (ET); University of Utah, Salt Lake City (TL); and Baystate Medical Center, Springfield, Massachusetts (HA).

Objective: Cystic fibrosis related diabetes (CFRD) without fasting hyperglycemia (FH-) is not associated with microvascular or macrovascular complications, leading to controversy about the need for treatment. The CFRD Therapy Trial (CFRDT) sought to determine whether diabetes therapy improves body mass index (BMI) in these patients. Research Design and

Methods: A 3-arm multi-center randomized trial compared 1 year of therapy with pre-meal insulin aspart, repaglinide, or oral placebo in CF subjects with abnormal glucose tolerance.

Results: One hundred adult patients were enrolled. Eighty-one completed the study including 61 with CFRD FH- and 20 with severely impaired glucose tolerance (IGT). During the year before therapy, BMI declined in all groups. Amongst CFRD FH-, insulin-treated patients lost 0.30+/-0.21 BMI units the year before therapy; after one year of insulin therapy, this pattern reversed and they gained 0.39+/-21 BMI units (p=0.02). No significant change in the rate of BMI decline was seen in placebo-treated patients (p=0.45).

Repaglinide-treated patients had an initial significant BMI gain (0.53+/-0.19 BMI units, p=0.01) but this effect was not sustained. After 6 months of therapy they lost weight so that by 12 months there was no difference in the rate of BMI change during the study year compared to the year before (p=0.33). Amongst IGT patients, neither insulin nor repaglinide affected the rate of BMI decline. No significant differences were seen in the rate of lung function decline or the number of hospitalizations in any group.

Conclusions: Insulin therapy safely reversed chronic weight loss in patients with CFRD FH-.

PMID: 19592632 [PubMed - as supplied by publisher]

Sunday, July 12, 2009

Recombinant activated factor VII for massive hemoptysis in patients with cystic fibrosis.

Recombinant activated factor VII for massive hemoptysis in patients with cystic fibrosis.

Lau EM, Yozghatlian V, Kosky C, Moriarty C, Dentice R, Waugh R, Torzillo PJ, Bye PT.

Departments of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Sydney, NSW, Australia.

Massive hemoptysis is a common complication in patients with cystic fibrosis (CF) and is associated with significant morbidity and mortality. Conventional treatment with antibiotic therapy and early bronchial artery embolization (BAE) is usually successful in achieving hemostasis in the majority of patients.

Recombinant activated factor VII (rFVIIa), originally developed for use in patients with hemophilia, has emerged as a general hemostatic agent that is potentially useful in the management of many life-threatening bleeding conditions. In this article, we present four patients with CF lung disease and massive hemoptysis who were treated successfully with rFVIIa.

We suggest that in patients with CF who present with massive hemoptysis, the use of rFVIIa can be considered in patients with refractory hemoptysis despite conventional therapy or as a temporizing therapy when BAE is not immediately available.

PMID: 19584209 [PubMed - in process]

Inhaled surfactants may improve mucus clearance

Effect of Lucinactant on Mucus Clearance in Cystic Fibrosis Lung Disease
This study is currently recruiting participants.
Verified by The University of North Carolina, Chapel Hill, July 2009
First Received: July 6, 2009 Last Updated: July 7, 2009 History of Changes
Sponsors and Collaborators: The University of North Carolina, Chapel Hill
Cystic Fibrosis Foundation
Discovery Laboratories
Information provided by: The University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT00934362

Mucus clearance is impaired in cystic fibrosis. Inhaled surfactants may reduce adhesive forces between mucus and airway surfaces and improve mucus clearance. This in turn my improve lung health. The investigators propose to measure mucus clearance before and after lucinactant or vehicle administration in patients with cystic fibrosis.

Condition Intervention Phase
Cystic Fibrosis
Drug: Lucinactant
Drug: Placebo
Phase II

Study Type: Interventional
Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Crossover Assignment, Safety/Efficacy Study
Official Title: A Double Blind, Cross-Over Study Comparing Aerosolized Lucinactant and Vehicle on Mucociliary Clearance for Cystic Fibrosis Lung Disease

Resource links provided by NLM:

Further study details as provided by The University of North Carolina, Chapel Hill:

Primary Outcome Measures:
  • Mucociliary clearance rate [ Time Frame: baseline and after 5 doses ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Spirometry [ Time Frame: acute and after 5 doses ] [ Designated as safety issue: Yes ]
  • Lung clearance index [ Time Frame: baseline and after 5 doses ] [ Designated as safety issue: No ]
  • Quality of Life (CFQ-R) [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]
  • Sputum rheology [ Time Frame: After 5 doses ] [ Designated as safety issue: No ]

Estimated Enrollment: 16
Study Start Date: October 2008
Estimated Study Completion Date: April 2010
Estimated Primary Completion Date: March 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Lucinactant: Experimental Drug: Lucinactant
lucinactant 120 mg (20 mg/ml) x 5 doses over 24 hours
Placebo: Placebo Comparator Drug: Placebo
6 mL normal saline x 5 doses over 24 hours

Detailed Description:

This single-center pilot study is designed as a double-blind, randomized, cross-over clinical trial to evaluate the effects of inhaled lucinactant, an investigational peptide-containing synthetic surfactant (6 ml of 20 mg total phospholipid (TPL)/mL solution x 5 doses) in patients with mild to moderate CF lung disease. Lucinactant and vehicle will be delivered via a 510k approved vibrating mesh nebulizer, the Pari eFlowTM. The study duration corresponds to a 2-10 day screening phase, followed by a 20 day post-randomization phase that consists of two treatment periods (3 days each) and a washout period (14 days). A total of 16 patients will be enrolled and randomly assigned to one of two treatment sequences (Lucinactant followed by vehicle or vehicle followed by lucinactant). The primary outcome will be the rate of MC, as assessed via gamma scintigraphy, post-lucinactant and post vehicle. Secondary outcomes will include the rate of cough clearance (CC), lung clearance index (LCI), absolute change from baseline in FEV1 after 5 doses of study medication, CF-specific quality of life score (via CFQ-R instrument), in vitro assessments of sputum rheology, and various safety parameters.


Ages Eligible for Study: 14 Years and older
Genders Eligible for Study: Both
Accepts Healthy Volunteers: No

Inclusion Criteria:

  • Cystic fibrosis
  • FEV1>40%

Exclusion Criteria:

  • Unstable lung disease
  • Unable or unwilling to stop hypertonic saline and dornase alfa for 3 days prior to each study period
  • Relevant drug allergy or intolerance
  • Recent investigational drug use (30 days)
Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00934362

United States, North Carolina
University of North Carolina Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Scott H Donaldson, MD 919-966-9198 scott_donaldson@med.unc.edu
Contact: Scott H Donaldson, MD 9199669198 scott_donaldson@med.unc.edu
Sponsors and Collaborators
The University of North Carolina, Chapel Hill
Cystic Fibrosis Foundation
Discovery Laboratories
Principal Investigator: Scott H Donaldson, MD The University of North Carolina, Chapel Hill
More Information
No publications provided

Responsible Party: University of North Carolina CF Research and Treatment Center ( Scott H. Donaldson, MD )
Study ID Numbers: 08-0795, KL4-CF-01, DONALD04A0
Study First Received: July 6, 2009
Last Updated: July 7, 2009
ClinicalTrials.gov Identifier: NCT00934362 History of Changes
Health Authority: United States: Food and Drug Administration

Study placed in the following topic categories:
Lung Diseases, Interstitial
Digestive System Diseases
Genetic Diseases, Inborn
Respiratory Tract Diseases
Cystic Fibrosis
Lung Diseases
Infant, Newborn, Diseases
Pancreatic Diseases
Pulmonary Fibrosis
Pulmonary Surfactants

Additional relevant MeSH terms:
Pulmonary Fibrosis
Cystic Fibrosis
Lung Diseases, Interstitial
Pathologic Processes
Digestive System Diseases
Genetic Diseases, Inborn
Respiratory Tract Diseases
Lung Diseases
Infant, Newborn, Diseases
Pancreatic Diseases

ClinicalTrials.gov processed this record on July 10, 2009


Saturday, July 11, 2009

Decision Aid for Cystic Fibrosis Patients Considering Lung Transplantation

Am J Respir Crit Care Med. 2009 Jul 9. [Epub ahead of print]

Randomized Trial of a Decision Aid for Cystic Fibrosis Patients Considering Lung Transplantation.

Vandemheen KL, O'Connor A, Bell SC, Freitag A, Bye P, Jeanneret A, Berthiaume Y, Brown N, Wilcox P, Ryan G, Brager N, Rabin H, Morrison N, Gibson P, Jackson M, Paterson N, Middleton P, Aaron SD.

The Ottawa Health Research Institute, University of Ottawa, Ottawa, ON, Canada.

RATIONALE: We developed an evidence based decision aid for cystic fibrosis patients with advanced lung disease considering referral for lung transplantation.

OBJECTIVE: To prospectively evaluate whether use of the decision aid increased knowledge about the options, improved realistic expectations, and decreased decisional conflict in adult patients.

METHODS: We performed a single-blind randomized controlled trial involving 149 adult cystic fibrosis patients with an FEV1

MEASUREMENTS AND MAIN RESULTS: The primary end points measured were participants' knowledge, realistic expectations, and decisional conflict evaluated three weeks after randomization. Patients randomized to the decision aid had greater knowledge about their options (P <0.0001) and had more realistic expectations about the benefits and risks of lung transplantation (P <0.0001) compared to those randomized to usual care. The total decisional conflict score was significantly lower in the decision aid group 3 weeks post randomization compared to the usual care group (11.6 vs 20.4; P = 0.0007). Decisions were durable; 88% of patients in the decision aid group and 75% in the usual care group maintained the same choice 12 months after randomization (P = 0.06).

CONCLUSIONS: Use of a decision aid for cystic fibrosis patients considering referral for lung transplantation, in addition to usual education and counseling, improves patient knowledge, realistic expectations, decisional conflict, and patient satisfaction.

Clinical Trial Registry Information: ID# NCT00345449 registered at www.clinicaltrials.gov.

Amitriptyline in patients with cystic fibrosis

Therapeutic efficacy and safety of amitriptyline in patients with cystic fibrosis.

Riethmüller J, Anthonysamy J, Serra E, Schwab M, Döring G, Gulbins E.

Department of Paediatrics, University Hospital Tuebingen, Tuebingen, Germany. joachim.riethmueller@med.uni-tuebingen.de

Amitriptyline, a blocker of acid sphingomyelinase and acid ceramidase, significantly reduces Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) mice with concurrent increase of survival. Our aim was to establish whether amitriptyline is safe and effective in the treatment of CF patients.

In a randomised, double-blinded, placebo-controlled, cross-over pilot study, 4 adult CF patients received 37.5 mg of amitriptyline or placebo twice daily for 14 days. Subsequently in a phase II study 19 adult CF patients were randomly allocated to three treatment groups receiving amitriptyline once daily for 28 days at doses of 25 mg (n=7), 50 mg (n=8), or 75 mg (n=8) or placebo (n=13).

The primary outcome was the difference of forced expiratory volume in 1 sec (FEV(1)) at day 14 between amitriptyline and placebo. Primary endpoint measures improved significantly in three of four patients in the pilot study after amitriptyline treatment vs placebo (relative FEV(1): 14.7+/-5%; p = 0.006) and in the 25 mg treatment group of the phase II study (relative FEV(1): 4.0+/-7%; p = 0.048). Amitriptyline was well tolerated in both studies and 96% of the patients completed the studies.

Amitriptyline as a novel therapeutic option in patients with CF is safe and seems to be efficacious. 2009 S. Karger AG, Basel.

Publication Types:
PMID: 19590194 [PubMed - in process]

Friday, July 10, 2009

Modifier genes influence CFRD (full text!)

A susceptibility gene for type 2 diabetes confers substantial risk for diabetes complicating cystic fibrosis.

Blackman SM, Hsu S, Ritter SE, Naughton KM, Wright FA, Drumm ML, Knowles MR, Cutting GR.

Division of Pediatric Endocrinology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

AIMS/HYPOTHESIS: Insulin-requiring diabetes affects 25-50% of young adults with cystic fibrosis (CF). Although the cause of diabetes in CF is unknown, recent heritability studies in CF twins and siblings indicate that genetic modifiers play a substantial role. We sought to assess whether genes conferring risk for diabetes in the general population may play a risk modifying role in CF.

METHODS: We tested whether a family history of type 2 diabetes affected diabetes risk in CF patients in 539 families in the CF Twin and Sibling family-based study. A type 2 diabetes susceptibility gene (transcription factor 7-like 2, or TCF7L2) was evaluated for association with diabetes in CF using 998 patients from the family-based study and 802 unrelated CF patients in an independent case-control study.

RESULTS: Family history of type 2 diabetes increased the risk of diabetes in CF (OR 3.1; p = 0.0009). A variant in TCF7L2 associated with type 2 diabetes (the T allele at rs7903146) was associated with diabetes in CF in the family study (p = 0.004) and in the case-control study (p = 0.02; combined p = 0.0002). In the family-based study, variation in TCF7L2 increased the risk of diabetes about three-fold (HR 1.75 per allele, 95% CI 1.3-2.4; p = 0.0006), and decreased the mean age at diabetes diagnosis by 7 years. In CF patients not treated with systemic glucocorticoids, the effect of TCF7L2 was even greater (HR 2.9 per allele, 95% CI 1.7-4.9, p = 0.00011).

CONCLUSIONS/INTERPRETATION: A genetic variant conferring risk for type 2 diabetes in the general population is a modifier of risk for diabetes in CF.

PMID: 19585101 [PubMed - as supplied by publisher]

Full Text:


Tuesday, July 7, 2009

Whey Protein and GSH

Thanks to @immuneprotect on Twitter for tweeting this article

: J Cyst Fibros. 2003 Dec;2(4):195-8.
Erratum in:
J Cyst Fibros. 2004 Mar;3(1):62.

Improved glutathione status in young adult patients with cystic fibrosis supplemented with whey protein.

The Department of Pathology and Molecular Medicine, McMaster Division, Hamilton Health Sciences, Hamilton, Ontario, Canada.

BACKGROUND: The lung disease of cystic fibrosis is associated with a chronic inflammatory reaction and an over abundance of oxidants relative to antioxidants. Glutathione functions as a major frontline defense against the build-up of oxidants in the lung. This increased demand for glutathione (GSH) in cystic fibrosis may be limiting if nutritional status is compromised. We sought to increase glutathione levels in stable patients with cystic fibrosis by supplementation with a whey-based protein.

METHODS: Twenty-one patients who were in stable condition were randomly assigned to take a whey protein isolate (Immunocal, 10 g twice a day) or casein placebo for 3 months. Peripheral lymphocyte GSH was used as a marker of lung GSH. Values were compared with nutritional status and lung parameters.

RESULTS: At baseline there were no significant differences in age, height, weight, percent ideal body weight or percent body fat. Lymphocyte GSH was similar in the two groups. After supplementation, we observed a 46.6% increase from baseline (P <>

ONCLUSION: The results show that dietary supplementation with a whey-based product can increase glutathione levels in cystic fibrosis. This nutritional approach may be useful in maintaining optimal levels of GSH and counteract the deleterious effects of oxidative stress in the lung in cystic fibrosis. Copyright 2003 European Cystic Fibrosis Society

PMID: 15463873 [PubMed - indexed for MEDLINE]