Medium term treatment of stable stage cystic fibrosis with recombinant human DNase I.

Shah, Pallav L.; Scott, Sandra; Fuchs, Henry J.; Geddes, Duncan M.; Hodson, Margaret E.

doi:10.1136/thx.50.4.333

Cited by 51 publications

(28 citation statements)

References 17 publications

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“…Fifty nine CF patients with mildto-moderate pulmonary disease (forced vital capacity (FVC) >40% predicted) were treated with rhDNase 2.5 mg twice daily for 6 months [18]. Sputum samples were obtained from these patients on pretreatment (Day 0), and on treatment days 28, 84 and 168.…”

Section: In Vivo Studiesmentioning

confidence: 99%

The effects of recombinant human DNase on neutrophil elastase activity and interleukin-8 levels in the sputum of patients with cystic fibrosis

Shah

Scott²,

Knight³

et al. 1996

Eur Respir J

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In cystic fibrosis (CF), neutrophil-dominated airway inflammation results in high levels of neutrophil elastase (NE). Some of these proteases are sequestered by the large amounts of deoxyribonucleic acid (DNA) present in purulent sputum. Recombinant human deoxyribonuclease (rhDNase), a new treatment in CF, depolymerizes DNA. Our concerns were that this might release proteases bound to DNA, which could be potentially harmful. The in vitro and in vivo effects of rhDNase on NE and interleukin-8 (IL-8) were evaluated.The acute effects of rhDNase were evaluated in CF patients during the first 6 days of treatment. Medium-term effects were evaluated in stable CF patients observed on rhDNase over 6 months. Sputum samples were collected at regular intervals and NE activity was measured by a fluorimetric assay and IL-8 with a radioimmunoassay.In vitro addition of rhDNase resulted in a twofold increase in protease activity and this was reflected in an acute transient rise on initiation of treatment with rhDNase. Medium-term treatment was associated with a decline in NE activity and IL-8.These in vivo results are encouraging, since the increase in protease activity was transient and the trend over 6 months was a reduction in both inflammatory markers. Eur Respir J., 1996, 9, 531- Impaired clearance and stasis of abnormally viscoelastic airway secretions in cystic fibrosis (CF) contributes to bacterial colonization. This stimulates and perpetuates the detrimental inflammatory response, which is predominantly neutrophil-mediated. Neutrophil elastase (NE) released by the neutrophils degrades elastin, collagen and proteoglycans, and therefore causes damage to the lung [1][2][3]. The high levels of NE overwhelm the host antiprotease defence, damage epithelial cells by cleaving fibronectin [4], impair ciliary function [5,6], and contribute to enhanced Pseudomonas aeruginosa adhesion in vitro [7], and in vivo [8]. NE also impairs successful opsonophagocytosis. It cleaves immunoglobulins [9], complement [10], and receptors on cell surfaces [11]. The NE-induced immuno-incompetence allows further bacterial persistence.Following the process of "frustrated" phagocytosis, disintegrating neutrophils release large amounts of deoxyribonucleic acid (DNA) into the airway secretions [12]. The complexes formed between extracellular DNA and mucous glycoproteins further exacerbate the abnormal rheology of airway secretions in CF. NE is a potent secretagogue [13] and, therefore, further increases the quantity of viscous airway secretions. A further positive loop within the "vicious cycle" is due to induction of interleukin-8 (IL-8) expression by airway epithelial cells following exposure to NE [14]. IL-8 is a potent chemoattractant, which causes further neutrophil accumulation and promotes the inflammatory state [15].Large polyanionic DNA polymers present in the purulent secretions electrostatically bind and sequester cationic proteases, such as NE [16]. Depolymerization of extracellular DNA may result in a reduction in the electrostati...

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Section: In Vivo Studiesmentioning

confidence: 99%

The effects of recombinant human DNase on neutrophil elastase activity and interleukin-8 levels in the sputum of patients with cystic fibrosis

Shah

Scott²,

Knight³

et al. 1996

Eur Respir J

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“…It has been specifically designed for this disease, and appears to have a dramatic effect on the viscosity and stickiness of the purulent bronchial secretions that hamper the daily life of CF patients. Several, well-controlled studies have demonstrated the clinical benefit that can be expected from this treatment [3][4][5][6][7][8][9][10]. However, as recently noted in an editorial [23], there is so far no evidence that rhDNase may prevent the development of progressive lung damage.…”

Section: Discussionmentioning

confidence: 99%

“…In two of them, large cohorts of patients have been treated for 24 weeks and more [7,8]. The investigators found a sustained, statistically significant improvement of forced expiratory volume in one second (FEV1) by a mean of 6% over baseline values.…”

mentioning

confidence: 94%

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Aerosolized rhDNase in cystic fibrosis: effect on leucocyte proteases in sputum

Rochat¹,

Pastore²,

Schlegel-Haueter³

et al. 1996

Eur Respir J

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A Ae er ro os so ol li iz ze ed d r rh hD DN Na as se e i in n c cy ys st ti ic c f fi ib br ro os si is s: : e ef ff fe ec ct t o on n l le eu uc co oc cy yt te e p pr ro ot te ea as se es s i in n s sp pu ut tu um m Free human leucocyte elastase (HLE), human leucocyte cathepsin G (HCG), total chemotactic activity, and interleukin-8 (IL-8) were determined in sputum from eight patients before, during and after rhDNase treatment.After 15 days of treatment, HLE activity increased by 81±44% (NS), and HCG by 189±70% (p<0.05). One week after stopping a 4-6 months treatment, HLE activity decreased by 35±18% (p<0.05), and HCG by 43±11% (p<0.05). Sputum bacterial density, chemotactic activity, and IL-8 concentration did not change.Thus, treatment with rhDNase can indeed increase the activity of HLE and HCG in the bronchial secretions of CF patients, and this effect is still detectable after several months of treatment. If this can be shown to be clinically relevant, combination therapy of recombinant human deoxyribonuclease with protease inhibitors should be considered as an approach to the problem.

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“…Sixty-five out of 184 (35%) patients experienced 106 episodes of airway reactivity in response to nebulized rhDNase [45]. However, most studies did not demonstrate significantly more BHR, dyspnea, cough, wheeze and/or increased pulmonary obstruction in CF patients compared to controls (Supplementary Tables 1) [42,[46][47][48][49][50][51][52][53][54].…”

Section: Rhdnasementioning

confidence: 99%

Bronchial Hyperreactivity Related to Inhalation Therapy in Cystic Fibrosis Patients

Eyns¹

2014

J Pulm Respir Med

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It is presumed that bronchial hyperreactivity (BHR) can occur with any inhaled agent and may be a reason for discontinuation of inhalation therapy in cystic fibrosis (CF) patients. On the other hand, inhalation of antibiotics is being increasingly used to eradicate or treat infections.This review focuses on identifying the mechanisms of BHR for a better understanding of its impact on inhalation treatment. BHR in CF is suggested to be secondary to underlying airway disease (associated to poor pulmonary function, chronic inflammation and aerosol distribution) or to be a separate condition occurring more in CF. Furthermore, certain characteristics of the aerosol solution itself, such as the active molecule, chemical additives and particle size, can cause BHR.Recombinant human DNase (rhDNase), hypertonic saline (HS) and the antibiotics tobramycin, colistin and aztreonam lysine for inhalation (AZLI) are frequently used inhalation drugs in the treatment of CF. Prevalence of BHR related to both short and long-term inhalation of these drugs as reported in the literature was investigated. Acute BHR is documented in up to two thirds of CF patients. Despite the widespread use of rhDNase, HS, tobramycin, colistin and AZLI, only one long-term trial looked for, but did not demonstrate, BHR at the end of the trial period.

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Medium term treatment of stable stage cystic fibrosis with recombinant human DNase I.

Cited by 51 publications

References 17 publications

The effects of recombinant human DNase on neutrophil elastase activity and interleukin-8 levels in the sputum of patients with cystic fibrosis

The effects of recombinant human DNase on neutrophil elastase activity and interleukin-8 levels in the sputum of patients with cystic fibrosis

Aerosolized rhDNase in cystic fibrosis: effect on leucocyte proteases in sputum

Bronchial Hyperreactivity Related to Inhalation Therapy in Cystic Fibrosis Patients

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