Cystic fibrosis DNase

Recombinant DNase preparations have been used in the treatment of cystic fibrosis since the end of 1993. This genetic disorder is common, particularly in ethnic groups of northern European extraction, where the frequency of occurrence can be as high as 1 in 2500 live births. A higher than average incidence has also been recorded in southern Europe, as well as in some Jewish and African-American populations. 

Pulmozyme DNAse I cystic fibrosis CHO 1993 Sweden, USA, Switzerland... 

Retention of viscous purulent secretions, which contain high concentrations of extracellular DNA—released by degenerating leukocytes that accumulate in response to infection [24]—in the airways contributes both to reduced pulmonary function and to exacerbations of infection [24,25], Digestion of DNA polymers in purulent secretion with DNAse (dornase-a or Pulmozyme) has been shown to reduce sputum viscosity in cystic fibrosis patients. The availability of recombinant DNAse has allowed its use in an aerosol formulation to deliver the enzyme into the deep lung alveoli of CF patients. The purihed glycoprotein contains 260 amino acids with an approximate molecular weight of 37,000 daltons [26], The primary amino-acid sequence is identical to that of the... 

Shak, S., D.J. Capon, R. Hellmiss, S.A. Marsters, and C.L. Baker, Recombinant human DNase I reduces the viscosity of cystic fibrosis sputum. Proc Natl Acad Sci USA, 1990. 87(23) 9188-92. 

Fuchs, H.J., D.S. Borowitz, D.H. Christiansen, E.M. Morris, M.L. Nash, B.W. Ramsey, B.J. Rosenstein, A.L. Smith, and M.E. Wohl, Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group. N Engl J Med, 1994. 331(10) 637 2. 

Aerosolized DNase (dornase) is a therapeutic protein designed for alveoli delivery to achieve local effects in the deep lung. Aerosolized DNase is formulated as a pulmonary dosage form, targeted for deep-lung delivery to reduce opportunistic infections due to the increased viscosity of mucus in the lung that affects respiratory function in patients with cystic fibrosis. 

Enzymes Pulmozyme (Dnase I) Cystic fibrosis rCHO, suspension... 

Davoodian, K., B.W. Ritchings, R. Ramphal, and M.R. Bubb. 1997. Gelsolin activates DNase I in vitro and cystic fibrosis sputum. Biochemistry. 36 9637—41. 

A major respiratory disease for which treatment with DNase 1 can be considered is cystic fibrosis (CF) [45,46], The CF defective gene leads to a dysfunction of the exocrine secretory glands, often resulting in both severe gastrointestinal as well as resoiratorv clinical svmntoms. Patients suffer from the obstruction of the... 

P. L. Shah,. P. Scott, R. A. Knight, C. Marriott, C. Rnnasiidia, and M. E, Hodson. In vivo effects of recombinant human DNase I on sputum in patients with cystic fibrosis. Thorax JJ 119-125 (1996). 

M. L. Altken, W. Burke G. McDonald, S. Shak, A. B. Montgomery, and A. Smith. Recombinant human DNase inhalation in normal robjects and patients with cystic fibrosis a phase I study. JAMA 267 1947-1951 (1992). 

P. L. Shah, S. F. Scott, and M. E. Hod son. Report on a multicentre study using aerosolised recombinant human DNase I in the treatment of cystic fibrosis patients with severe pulmonary disease. Pediatr. FuimanoL tSuppi 9]r. 157-158 (1993). 

L A. Lester, K. McCoy, L P, McKean, R. Moss, M. L, Nash, C. P. Jue, W. Reelmaan, D, C. Stokes, and H. J. Fuchs. Aeraolized recombinant human DNase in hospitalized cystic fibrosis patients with acute pulmonary exacerbations. Am. J. Respir. Crit. Care Med. 753 1914-1917 (1996). 

Although routine oral delivery of proteins has not been realized, some protein formulations have been developed for pulmonary delivery. Pulmonary delivery can result in either parenteral or local administration of the drug and, like oral delivery, is considered non-invasive. As with other routes of delivery, the size of the protein may limit its ability to be delivered systemi-cally via the pulmonary route of administration. Pulmozyme , a DNase-based formulation approved for the treatment of cystic fibrosis (CF), is delivered to the lungs by a nebulizer to clear blockage of the airways in the CF patient.Formulations for insulin to be administered by inhalation for systemic delivery of... 

Indications Cystic fibrosis Category Recombinant DNase Half-life N/A... 

Zahm JM, Galabert C, Chaffin A, Chazalette JP, Grosskopf C, Puchelle E. Improvement of cystic fibrosis airway mucus transportability by recombinant human DNase is related to changes in phospholipid profile. AM J Respir Crit Care Med 1998, 157, 1779-1784. 

Fuchs HJ, Borwitz DS, Christainsen DH, 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 331 637-642. 

J. M. Zahm, S. Girod de Bentzmann, E. Deneuville, C. Perrot-Minot, A. Dabadie, F. Pennaforte, M. Roussey, S. Shak, and E. Puchelle. Dose-dependent in vitro effect of recombinant human DNase on rheological and transport properties of cystic fibrosis respiratory mucus. Eur. Respir. J. 8 381-386 (1995). 

P. L. Shah, S. Scott, A. Lansley, G. Martin, C. Marriott, and M. E. Hodson. Preliminary report on in vivo reduction of sputum viscosity in cystic fibrosis patients treated with aerosolised recombinant human DNase. Thorax 49 394 (1994). 

D. V. Sinicropi, M. Williams, W. S. Prince, J. A. Lofgren, M. Lucas, A. Devault, S. Baughman, S. Nash, H. Fuchs, and S. Shak. Sputum pharmacodynamics and pharmacokinetics of recombinant human DNase I in cystic fibrosis. Am. J. Respir. Crit. Care Med. 749 A671 (1994). 

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