In vivo effects of recombinant human DNase I on sputum in patients with cystic fibrosis

P L Shah, S F Scott, R A Knight, C Marriott, C Ranasinha, M E Hodson, P L Shah, S F Scott, R A Knight, C Marriott, C Ranasinha, M E Hodson

Abstract

Background: Viscoelastic secretions in cystic fibrosis cause impaired mucus clearance and persistence of bacteria within the lung. The abnormal rheology is partly due to the presence of high molecular weight deoxyribonucleic acid (DNA). Recombinant human DNase I (rhDNase) has been shown to depolymerise DNA and thereby reduce the in vitro viscoelasticity of sputum in patients with cystic fibrosis. A phase II double blind placebo controlled study showed that rhDNase improved pulmonary function in patients with cystic fibrosis. The object of the present study was to evaluate the in vivo effects of rhDNase on sputum rheology and to determine whether these were correlated with changes in pulmonary function.

Methods: Patients were randomised to receive either placebo or rhDNase 2.5 mg twice daily for 10 days. Sputum samples were collected in sterile containers during screening and during treatment with the study drug. Pulmonary function and rheological analysis were the primary outcomes evaluated. Other parameters assessed were quantitative sputum bacteriology, sputum DNA concentration, and change in molecular mass of DNA polymers.

Results: The viscoelasticity of the sputum in untreated patients with cystic fibrosis was high and treatment with rhDNase reduced all the rheological parameters measured: dynamic storage modulus (a measure of elasticity), dynamic loss modulus (a measure of viscosity), and log complex modulus (a measure of mucus rigidity). The calculated cough clearance index was also improved following treatment with rhDNase. These rheological parameters showed a correlation with forced expiratory volume in one second (FEV1) which was improved by a mean (SE) of 13.3 (5.6)% on day 10 of treatment with rhDNase compared with a change of 0.2 (3.1)% in the placebo group. There was no change in bacterial colony counts or sputum DNA concentrations following treatment with rhDNase, but a small decrease in high molecular weight DNA was observed.

Conclusions: Patients with cystic fibrosis treated with rhDNase show an improvement in rheological properties and pulmonary function, one of the mechanisms being a reduction in the proportion of high molecular weight DNA.

References

    1. Am Rev Respir Dis. 1974 Dec;110(6):740-5
    1. Pediatrics. 1959 Nov;24:739-45
    1. Am Rev Respir Dis. 1975 Sep;112(3):341-7
    1. Cell. 1976 Apr;7(4):531-42
    1. Eur J Respir Dis Suppl. 1980;110:195-208
    1. Am Rev Respir Dis. 1977 Jun;115(6):989-95
    1. Am Rev Respir Dis. 1983 Jun;127(6):725-34
    1. J Appl Physiol (1985). 1985 Jun;58(6):1776-82
    1. Eur J Pediatr. 1985 Nov;144(4):374-8
    1. Thorax. 1987 Jul;42(7):526-32
    1. Eur Respir J. 1988 Feb;1(2):161-7
    1. Biorheology. 1987;24(6):589-97
    1. Eur Respir J. 1989 Mar;2(3):234-7
    1. Eur Respir J. 1990 Jan;3(1):19-23
    1. Am Rev Respir Dis. 1990 Nov;142(5):1053-8
    1. Proc Natl Acad Sci U S A. 1990 Dec;87(23):9188-92
    1. N Engl J Med. 1992 Mar 19;326(12):812-5
    1. JAMA. 1992 Apr 8;267(14):1947-51
    1. Br Med Bull. 1992 Oct;48(4):931-48
    1. J Pediatr. 1993 Jan;122(1):1-9
    1. Am Rev Respir Dis. 1993 Jul;148(1):145-51
    1. Lancet. 1993 Jul 24;342(8865):199-202
    1. Science. 1994 Feb 18;263(5149):969-71
    1. N Engl J Med. 1994 Sep 8;331(10):637-42
    1. Pediatrics. 1959 Mar;23(3):545-9
    1. Proc Natl Acad Sci U S A. 1974 Dec;71(12):4742-6

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