Eur Respir J. 2011 Apr 8. [Epub ahead of print]

Inhaled dry powder mannitol in cystic fibrosis: an efficacy and safety study.

Bilton D, Robinson P, Cooper P, Gallagher CG, Kolbe J, Fox H, Jaques A, Charlton B.

* Royal Brompton Hospital London United Kingdom.

Abstract

This international phase III study of inhaled dry powder mannitol was a randomised double blind 26 week study, followed by a further 26 week open-label extension. 324 subjects were randomised 3:2 to mannitol (400 mg bid) or control. The primary efficacy endpoint was to determine the change in FEV1 over the double-blind phase. Secondary endpoints included changes in FVC and pulmonary exacerbations. 

A significant improvement in FEV1 was seen over 26 weeks (p<0.001) and was apparent by 6 weeks irrespective of concomitant rhDNase use. At 26 weeks, there was a significant improvement of 92.9 mL in FEV1 for subjects receiving mannitol compared with control (change from baseline 118.9 mL [6.5%] vs. 26.0 mL [2.4%]; p<0.001). Improvements in FEV1 were maintained up to 52 weeks in the open-label part of the study. There was a 35.4% reduction in the incidence of having an exacerbation on mannitol (p=0.045). 

The incidence of adverse events (AE) was similar in both groups, though treatment related AEs were higher in the mannitol compared to the control group. The most common mannitol related AEs were cough, haemoptysis and pharyngolaryngeal pain. Mannitol shows sustained, clinically meaningful benefit in airway function in CF, irrespective of concomitant rhDNase use. Mannitol appears to have an acceptable safety profile for patients with CF.

Insulin Production and Resistance in CF: Effect of Age, Disease Activity and Genotype

J Endocrinol Invest. 2011 Apr 6. [Epub ahead of print]

INSULIN PRODUCTION AND RESISTANCE IN CYSTIC FIBROSIS: EFFECT OF AGE, DISEASE ACTIVITY, AND GENOTYPE.

Street ME, Spaggiari C, Ziveri MA, Rossi M, Volta C, Viani I, Grzincich GL, Sartori C, Zanzucchi M, Raia V, Terzi C, Pisi G, Zanetti E, Boguszewski MC, Kamoi TO, Bernasconi S.

Department of Paediatrics, University Hospital of Parma, Via Gramsci, 14, 43126 Parma, Italy.

Abstract

Aim: To assess the major determinants of glucose tolerance between age, genotype and clinical status in cystic fibrosis (CF) patients, and study if defects of insulin secretion and insulin sensitivity were associated with the onset of CF related diabetes (CFRD). Subjects and Methods: 119 patients, in stable clinical condition were studied. They were subdivided into 3 groups based on age, and 2 groups based on Schwachman-Kulczycki clinical score. All patients were genotyped, and subsequently divided into 3 groups. Ninety-four healthy normal-weight controls, comparable for sex and age also were also studied. All subjects had baseline blood samples taken for glucose and insulin, C-peptide, and glycated hemoglobin. HOMA-IR, fasting glucose/insulin ratio(FGIR) were calculated as indices of insulin resistance and insulinogenic index as a marker of pancreatic β cell function. All patients underwent an OGTT, and 57 underwent an IVGTT for the calculation of first phase(FPIR) and acute insulin responses(AIR).

 Results:The F508del homozygous patients had an increased chance of developing impaired glucose tolerance (IGT) and significantly lower FPIR, decreased HOMA-IR, and insulinogenic index. Heterozygote F508del patients had an increased chance of having normal glucose tolerance. HOMA-IR, FGIR, and insulinogenic index did not change with age or clinical score. HOMA-IR correlated with FPIR. FPIR correlated positively with insulinogenic index. AIR correlated negatively with FGIR, and positively with C-reactive protein. In multiple linear regression analyses glucose tolerance was related to the age-group, and to the HOMA-IR ans insulinogenic indexes. Conclusions: IGT and CFRD were related mainly to genotype, although as expected the prevalence increased with age. The data suggested a possible combined contribution of insulin deficiency, β-cell function and reduced insulin sensitivity to the onset of CFRD, however further studies are warranted to better elucidate this aspect.

Mannitol-Guided delivery of ciprofloxacin

Biotechnol Bioeng. 2011 Jun;108(6):1441-9. doi: 10.1002/bit.23046. Epub 2011 Jan 15.

Mannitol-Guided delivery of ciprofloxacin in artificial cystic fibrosis mucus model.

Yang Y, Tsifansky MD, Shin S, Lin Q, Yeo Y.

College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907; telephone: +1-765-496-9608; fax: +1-765-494-6545; Research Center for Drug Metabolism, College of Life Science, Jilin University, Changchun, PR China.

Abstract

Abnormal airway mucus presents a significant challenge for inhalational drug delivery. Recognizing the thick and tenacious airway mucus seen in the cystic fibrosis (CF) patients as a critical barrier to effective drug delivery, both into the mucus layer itself as well as across that layer to the underlying airway epithelium, we hypothesize that mannitol or NaCl can form inhalable drug carriers, improve drug penetration into the mucus, and ultimately enhance the drug's therapeutic effect. The objective of this study is to test whether mannitol and NaCl particles, as inhalable drug carriers, improve drug delivery into and enhance a drug's activity within a mucus-like material. 

Microparticles containing Ciprofloxacin (Cipro), an active ingredient, and either mannitol or NaCl were produced by spray-drying. Cipro encapsulated in mannitol particles (Cipro-mannitol) was significantly more effective at killing Pseudomonas aeruginosa (P. aeruginosa) grown in artificial mucus (AM) than Cipro encapsulated in either NaCl particles (Cipro-NaCl) or in hydrophobic particles consisting of dipalmitoylphosphatidylcholine (DPPC), albumin, and lactose (Cipro-DAL). The relatively high antibacterial effectiveness of Cipro-mannitol was not due to the effect of mannitol on bacteria or on Cipro. Rather, the unique performance of the mannitol-based particles in AM is attributable to its ability to increase local water content in the AM and enhance drug penetration into it. Mannitol is a promising excipient for inhalable microparticles that facilitate the drug delivery into the CF mucus.

TOBI® Podhaler® approved in Canada

Canadian cystic fibrosis patients can now lead more independent lives

New dry powder tobramycin formulation and the easy-to-use, pocket-sized, portable device will treat lung infections due to Pseudomonas aeruginosa (Pa) and reduce treatment burden

MONTRÉAL, April 5 /CNW/ - Novartis Canada announced today that it has received Health Canada Notice of Compliance (NOC) for TOBI^® Podhaler^®, a fast and convenient inhaled therapy¹ for cystic fibrosis (CF) patients aged six and over. Canadian CF patients will be the first in the world to have access to TOBI^® Podhaler^®. The TOBI^® Podhaler^® offers a new dry-powder formulation of tobramycin delivered in a convenient and portable breath-activated inhaler for treating Pseudomonas aeruginosa (Pa) infections in CF patients.

"It is anticipated that the introduction of portable therapy for Pa infections will be a tremendous advance for CF patients, and may have a significant, positive impact on quality of life and treatment success," says Dr. Felix Ratjen, Paediatric Respirologist. "By eliminating the need for a nebulizer and regular disinfection of the equipment, it is anticipated that the risk of bacterial contamination will be greatly reduced while patient compliance will likely improve. Ultimately, this will lead to more effective treatment and help CF patients live more active, normal lives."

Pseudomonas aeruginosa infection is one of the most common pulmonary pathogens for Canadians with CF.²  As a CF patient ages, they are more likely to develop a Painfection.³ By the age of 25 years, more than 70 per cent of CF patients will develop a lung infection due to Pa.⁴ This common respiratory pathogen is one of the main drivers of morbidity and mortality in CF.⁵

Due to the complexity of current anti-Pa treatment, most patients do not fully adhere to their therapy.^6,7,8 Although disinfection and cleaning are suggested every time a nebulizer is used, it is estimated that only 30 per cent of patients comply, and  some never clean their nebulizer.⁹ TOBI^® Podhaler^® is a dry formulation with a disposable inhaler device which can be replaced weekly and potentially reduce the risk of bacterial contamination.¹⁰

In addition, data shows that patients using TOBI^® Podhaler^® completed their tobramycin treatment in five to six minutes, a reduction of 72 per cent¹¹ in the time traditionally required to administer nebulized tobramycin. By improving the delivery of tobramycin and reducing treatment administration times, the TOBI^® Podhaler^® has the potential to help patients lead more independent lives.

Unique formulation and delivery system

TOBI^® Podhaler^® has a unique dry powder formulation, developed using novel PulmoSphere^® technology to produce particles that are light and porous for deep delivery into the lung. This means treatment can be given with a portable, patient-friendly device, in contrast to current treatment options which are administered with a nebulizer.

By eliminating the use of a nebulizer, TOBI^® Podhaler^® does not require additional time for assembly and disinfection of the delivery device. In addition, TOBI^® Podhaler^® removes the need for refrigeration and a power source for the delivery device. A study found that patients treated with TOBI^® Podhaler^® had significantly higher treatment satisfaction than those treated with TOBI^®.¹²

In addition, TOBI^® Podhaler^® was generally well tolerated during clinical trials. The most frequent reactions associated with TOBI^® Podhaler^® during the first treatment cycle were: cough, dysphonia, productive cough and oropharyngeal pain. The frequency of these adverse reactions decreased over the study duration.