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.

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.

Co-spray dried mannitol-ciprofloxacin dry powder inhaler for cystic fibrosis

Eur J Pharm Sci. 2010 Apr 2.

Co-spray dried mannitol-ciprofloxacin dry powder inhaler for cystic fibrosis and chronic obstructive pulmonary disease.

Adi H, Young PM, Chan HK, Agus H, Traini D.

Advanced Drug Delivery Group, Faculty of Pharmacy (A15), University of Sydney, Sydney, NSW 2006, Australia.

Abstract
The aim of this study was to assess the potential of delivering a combination therapy, containing mannitol (a sugar alcohol with osmotic characteristics), and ciprofloxacin hydrochloride, (an antibacterial fluoroquinolone), as a dry powder inhaler (DPI) formulation for inhalation.

Single and combination powders were produced by spray drying ciprofloxacin and mannitol, from aqueous solution, at different ratios and under controlled conditions, as to obtain similar particle size distributions. Each formulation was characterised using laser diffraction, scanning electron microscopy, differential scanning calorimetry, dynamic vapour sorption, X-ray powder diffraction, and colloidal force microscopy.

The in vitro aerosol performance of each formulation was studied using an Aerolizer(R) DPI device and a multistage liquid impinger (analysed using high performance liquid chromatography). In addition, a disk diffusion test was performed to assess the in vitro antimicrobial activity of each formulation and starting materials.

All formulations had similar particle size distributions, however, the morphology, thermal properties and moisture sorption was dependent on the relative percentages of each component. In general, the combination formulation containing 50% w/w mannitol appeared to have the best aerosol performance, good stability and lowest particle cohesion (as measured by colloid probe microscopy. Furthermore, of the formulations tested, mannitol did not appear to alter the effectiveness of the ciprofloxacin antimicrobial activity to Staphylococcus aureus, Pseudomonas aeruginosa and Streptococcus pyrogenes.

The combination of co-spray dried mannitol and ciprofloxacin from a DPI is an attractive approach to promote mucous clearance in the respiratory tract while simultaneously treating local chronic infection, such as chronic obstructive pulmonary disease and cystic fibrosis.

Comparison of inhaled mannitol, daily rhDNase, and a combination of both

Comparison of inhaled mannitol, daily rhDNase, and a combination of both in children with cystic fibrosis: a randomised trial.

Minasian CC, Wallis C, Metcalfe C, Bush A.Royal Brompton Hospital & Imperial College, London, United Kingdom;

BACKGROUND: Osmotic agents, such as inhaled dry powder mannitol may increase mucociliary clearance (MCC) by rehydrating the airway-surface liquid (ASL) and thus act as disease-modifying treatments in cystic fibrosis (CF). This is the first therapeutic trial of inhaled mannitol in children with CF. We have compared it to human recombinant deoxyribonuclease (rhDNase), the current best established mucolytic therapy.

METHODS: 38 children were recruited to an open crossover study. Subjects underwent an initial bronchial provocation challenge with dry powder mannitol. Those children with a negative challenge were randomly allocated to one of three consecutive twelve-week treatment blocks (inhaled mannitol alone, nebulised rhDNase alone and mannitol + rhDNase). The primary outcome was forced expiratory volume in 1 second (FEV(1)). A number of secondary outcome measures were also studied.

RESULTS: Twenty children completed the study. Bronchoconstriction and cough associated with mannitol administration contributed to the high attrition rate. The mean increase in FEV(1) following 12 weeks of treatment was 0.11 litres (6.7%) (p=0.055) for mannitol alone, 0.12 litres (7.2%) (p=0.03) for rhDNase alone & 0.03 litres (1.88%) (p=0.67) for rhDNase and mannitol. None of the secondary clinical outcomes were statistically significantly different between treatments.

CONCLUSIONS: Inhaled mannitol was at least as effective as rhDNase after 3 months treatment. There was a marked individual variation in tolerance to mannitol and in response to therapy however. Children who do not respond to rhDNase many benefit from a trial of inhaled mannitol. The combination of mannitol and rhDNase was not useful.

The trial was registered with ClinicalTrials.gov (Identifier NCT00117208).

Inhaled Mannitol Improves the Hydration and Surface properties of Sputum in patients with Cystic Fibrosis

Chest. 2009 Oct 31. [Epub ahead of print]
Inhaled Mannitol Improves the Hydration and Surface properties of Sputum in patients with Cystic Fibrosis.

Daviskas E, Anderson SD, Jaques A, Charlton B.

Royal Prince Alfred Hospital, Respiratory and Sleep Medicine, 11 West, Missended Rd, Camperdown, Sydney, New South Wales, Australia, 2050, 61 2 9515 7410, 61 2 95158196, daviskas@med.usyd.edu.au.

BACKGROUND: The airway mucus in patients with cystic fibrosis (CF) is dehydrated and adhesive, and accumulates in the airways resulting in chronic inflammation, infection and progressive loss of lung function. Inhaled mannitol improves mucus clearance and, when administered over 2-weeks, it improves lung function in CF (Jaques A et al. CHEST 2008;133:1388-1396). The changes in the physical properties of sputum after a 2-week treatment with mannitol were investigated in the same CF subjects. M

ETHODS: Sputum was collected before and at the end of the 2-week treatment period from 28 CF subjects who participated in the double blind crossover study. Mannitol or placebo 420 mg was inhaled twice daily over 2-weeks. The solids content, surface tension, contact angle and viscoelasticity was measured.

RESULTS: Two-week treatment with mannitol reduced the solids from 7.3+/-3.0 to 5.7+/-3.0% (p=0.012), surface tension from 83.1+/-7.2 to 78.6+/-8.0 mN/m (p<0.039) and contact angle from 52.4+/-7.7 to 47.9+/-7.3 degrees. There was no significant change in the viscoelastic properties of sputum (p>0.1). Placebo treatment had no significant effect on the sputum properties. The change in solids content correlated with the change in both FEV(1) (r(s)=-0.78, p=0.004) and FEF(25-75) (r(s)=-0.80, p=0.003) and the % change in surface tension and contact angle correlated with the % change in the FEV(1) (r(s)=-0.73, p=0.012 and r(s)=-0.63, p=0.03 respectively) in these subjects.

CONCLUSION: Treatment with inhaled mannitol over 2 weeks improved the hydration and surface properties of sputum in patients with CF. This effect was sustained and correlated with airway function changes.

Pharmaxis' Bronchitol inhaler has encouraging Phase 3 trial results for cystic fibrosis patients

Pharmaxis' Bronchitol inhaler has encouraging Phase 3 trial results for cystic fibrosis patients

Australian listed pharmaceutical company Pharmaxis (ASX:PXS, Nasdaq:PXSL) has received encourgaging results for its recently completed international Phase III trial of the company's Bronchitol portable inhaler in patients with cystic fibrosis.

Bronchitol has received Orphan Drug Designation and fast track status for cystic fibrosis from the U.S. Food and Drug Administration and Orphan Drug Designation from the European Medicines Agency.

The trial was a multi-centre, randomised, double blind, placebo controlled, 26 week study, with an optional further 6 month open label uncontrolled period. It was conducted in 40 centres in the United Kingdom, Ireland, Australia and New Zealand.

The primary endpoint of the trial was to assess whether Bronchitol improves lung function as measured by a change in FEV when administered twice per day for six months.

The key secondary endpoint of the trial was to assess whether Bronchitol further improves lung function in patients already being treated with the most commonly used CF therapeutic, rhDNase. Additional endpoints included changes in the Forced Vital Capacity of the lung, pulmonary exacerbations and antibiotic use.

Clinical Results showed there was a clinically meaningful change from baseline (119mL) and placebo (93mL) at week 26 with Bronchitol for FEV1 (p<0.001).>

For the subgroup of patients on concomitant rhDNase there was also a significant improvement in FEV1 from baseline (88mL) and from placebo (109mL) at week 26 with Bronchitol (p=0.001). Again, there was an immediate and sustained improvement in FEV1 over the 26 week period of the study (p=0.003).

While the study was not powered to show a reduction in the secondary endpoint of exacerbation, the rate of a protocol defined pulmonary exacerbation (PDPE) per subject for the 26 weeks was lower for Bronchitol versus control: overall reduction in rate of 25% (p=0.2).

In September 2008 Pharmaxis submitted a marketing application in Australia for Bronchitol as a treatment for bronchiectasis. This follows a long-term Phase 3 safety study of more than 360 subjects finding that Bronchitol is safe, with no serious adverse events attributable to the medicine. This supports results from an earlier stage of the trial showing that Bronchitol delivered a highly significant improvement in users' quality of life.

The medicine is expected to be approved for bronchiectasis first in Australia, and later in the U.S. and Europe following the completion of a further Phase 3 trial. Bronchitol will be the first targeted medication for sufferers in over 20 years.

Small cap fund manager Acorn Capital is one of the largest shareholders in Pharmaxis owning 7.8% of the company.

http://www.proactiveinvestors.com.au/companies/news/1739/pharmaxis-bronchitol-inhaler-has-encouraging-phase-3-trial-results-for-cystic-fibrosis-patients-1739.html

Sugar sweet and deadly? Cepacia and CF

Microbiology 155 (2009), 665-666; DOI 10.1099/mic.0.024752-0

Microbiology 155 (2009), 665-666; DOI 10.1099/mic.0.024752-0
© 2009 Society for General Microbiology

Comment

Sugar sweet and deadly?

D. W. Reid¹ and S. C. Bell²

¹ Menzies Research Institute, Hobart, Tasmania, Australia
² The Prince Charles Hospital, Chermside, Brisbane, Queensland, Australia

Correspondence
D. W. Reid
(d.e.c.reid@utas.edu.au)

The recent report by Bartholdson et al. (2008) demonstrating production of large amounts of exopolysaccharide (EPS) by organisms of the Burkholderia cepacia complex (Bcc), which changed the phenotype from non-mucoid to mucoid when the bacteria were exposed in vitro to a variety of sugar alcohols including mannitol, fructose and sucrose, raises a worrying scenario. Mannitol as an inhaled therapy appears to increase the hydration of airway secretions and thus promote airway clearance, with demonstrated improvements in lung function (Jaques et al., 2008; Minasian et al., 2007). As Bartholdson and colleagues highlight, cystic fibrosis (CF) patients infected with Bcc have been excluded from the clinical trials of mannitol in order not to confound results, given the potential adverse impact of some of these strains on lung function decline. In Australia, 4.1 % of all CF individuals are infected with Bcc, but the prevalence rises with increasing age (Australian CF Data Registry Report 2005). Similar or higher prevalence of Bcc infection has been reported from Europe, the USA and Canada (Lambiase et al., 2006). The obvious concern is that despite the findings of Bartholdson and colleagues, mannitol will be prescribed in Bcc-infected patients. The large multi-centre studies of hypertonic saline (Elkins et al., 2006) and azithromycin (Saiman et al., 2003) have also excluded patients with Bcc infection; however, these treatments are now frequently prescribed in this patient population (unpublished observations). Interestingly, strains of the more virulent ET12 strain of Burkholderia cenocepacia did not produce EPS following growth on mannitol, and the critical determinant here appears to be the bce gene cluster, with ET12 strains possessing an 11 bp deletion that prevented bce upregulation by mannitol and thus EPS production. Paradoxically therefore, mannitol may not be of great concern when administered to patients infected with the ET12 strain, but may have adverse consequences when used in the setting of what are generally considered less virulent strains.

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The other consideration from a microbiological perspective prompted by the study of Bartholdson and colleagues is the impact of increased sugar moiety availability to Bcc in the setting of CF-related diabetes (CFRD). To our knowledge, no comprehensive longitudinal study has been undertaken of the impact of CFRD on Bcc infection. Insulin therapy for CFRD has been shown to improve lung function and nutritional indices as well as reduce the prevalence of positive sputum cultures for Streptococcus pneumoniae and Haemophilus influenzae, suggesting that abnormal glucose homeostasis may promote infection in CF (Lanng et al., 1994). Assessment of sugar moieties has not been undertaken in CF sputum, but levels of fructose and other sugar alcohols are elevated in the serum of patients with diabetes and are likely to be similarly increased in airway secretions in patients with CFRD, providing a favourable substrate for bacterial growth (Kawasaki et al., 2002). The findings of Bartholdson and colleagues would also suggest that the lungs of patients with CFRD may promote bacterial virulence, i.e. EPS production by Bcc. Careful analysis of the impact of CFRD on CF patients with Bcc infection is required but will need international collaboration to ensure sufficient patient numbers to provide statistical power. New therapies such as mannitol will require close scrutiny in patients with Bcc infection, although the evidence indicates that this therapy will be of benefit in those infected with P. aeruginosa, who constitute the vast majority of the CF population.

REFERENCES

Bartholdson, S. J., Brown, A. R., Mewburn, B. R., Clarke, D. J., Fry, S. C., Campopiano, D. J. & Govan, J. R. (2008). Plant host and sugar alcohol induced exopolysaccharide biosynthesis in the Burkholderia cepacia complex. Microbiology 154, 2513–2521.[Abstract/Free Full Text]

Elkins, M. R., Robinson, M., Rose, B. R., Harbour, C., Moriarty, C. P., Marks, G. B., Belousova, E. G., Xuan, W. & Bye, P. T. (2006). A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N Engl J Med 354, 229–240.[Abstract/Free Full Text]

Jaques, A., Daviskas, E., Turton, J. A., McKay, K., Cooper, P., Stirling, R. G., Robertson, C. F., Bye, P. T., Lesouëf, P. N. & other authors (2008). Inhaled mannitol improves lung function in cystic fibrosis. Chest 133, 1388–1396.[CrossRef][Medline]

Kawasaki, T., Akanuma, H. & Yamanouchi, T. (2002). Increased fructose concentrations in blood and urine in patients with diabetes. Diabetes Care 25, 353–357.[Abstract/Free Full Text]

Lambiase, A., Raia, V., Del Pezzo, M., Sepe, A., Carnovale, V. & Rossano, F. (2006). Microbiology of airway disease in a cohort of patients with cystic fibrosis. BMC Infect Dis 6, 4[CrossRef][Medline]

Lanng, S., Thorsteinsson, B., Nerup, J. & Koch, C. (1994). Diabetes mellitus in cystic fibrosis: effect of insulin therapy on lung function and infections. Acta Paediatr 83, 849–853.[Medline]

Minasian, C. C., Wallis, C. & Bush, A. (2007). Mannitol as a mucolytic in cystic fibrosis. J R Soc Med 100 (Suppl. 47), 53–56.[Medline]

Saiman, L., Marshall, B. C., Mayer-Hamblett, N., Burns, J. L., Quittner, A. L., Cibene, D A., Coquillette, S., Fieberg, A. Y., Accurso, F. J. & other authors (2003). Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA 290, 1749–1756.[Abstract/Free Full Text]

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