Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:BIOD00001 (DNase I)
 8,324 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

rhDNase (Pulmozyme) is a new agent in the therapeutic strategy for patients with cystic fibrosis. It is one of the first specific treatments aimed at the respiratory tract. It affects the extracellular DNA which is present in abundant quantities in the bronchial secretions of these patients. rhDNase significantly reduces the incidence of infections and improves respiratory function. It should be used as a major treatment in combination with all other treatments in patients over 5 years of age with a vital capacity of at least 40% the theoretical value. It is important to schedule the respiratory exercises as a function of rhDNase intake. The long-term therapeutic benefit remains to be evaluated.
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PMID:[New pharmacological approaches: rhDNase]. 756 83

Respiratory symptoms, recurrent infectious exacerbations, and progressive lung destruction in cystic fibrosis can be attributed to bacterial persistence and the accumulation of viscous purulent secretions in the airways. Purulent secretions contain high concentrations of extracellular DNA, a viscous material released by leukocytes. To evaluate the potential clinical utility of recombinant human DNase I (rhDNase or Pulmozyme), the human enzyme was cloned, sequenced, and expressed. In in vitro studies, rhDNase has been shown to reduce the viscoelasticity, reduce the adhesiveness, and improve the mucociliary transportability of cystic fibrosis sputum. In short-term phase 1 and phase 2 clinical trials, rhDNase has been shown to be safely tolerated and to improve the FEV1, FVC, and symptoms of dyspnea. A long-term placebo-controlled phase 3 study was performed in 968 adults and children (> or = 5 years) with cystic fibrosis to determine the effect of rhDNase on the risk of respiratory exacerbations requiring parenteral antibiotics and on the FEV1. Compared with placebo-treated patients, patients treated with rhDNase once daily or twice daily experienced a reduced risk of respiratory exacerbations by 28% (p = 0.04) and 37% (p = 0.01), respectively, and had a mean improvement in FEV1 of 5.8% (p < 0.01) and 5.6% (p < 0.01), respectively. Compared with placebo-treated patients, patients treated with rhDNase spent 2.7 fewer days receiving parenteral antibiotics (p = 0.04) and spent 1.3 fewer days in the hospital (p = 0.06) over the 6-month treatment period. Inhalation of rhDNase did not cause anaphylaxis but was associated with upper airway symptoms (ie, voice alteration, hoarseness, pharyngitis) that were generally mild and transient. In conclusion, aerosol administration of rhDNase was safely tolerated, reduced the risk of infectious exacerbations requiring parenteral antibiotics, and improved pulmonary function and patient well-being.
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PMID:Aerosolized recombinant human DNase I for the treatment of cystic fibrosis. 784 16

A simple, high throughput, and precise assay was developed for quantification of deoxyribonuclease I (DNase; IUB 3.1.21.1) activity. The method was adapted from the procedure devised by Kurnick which employs a substrate comprised of highly polymerized native DNA complexed with methyl green. Hydrolysis of the DNA produced unbound methyl green and a decrease in the absorbance of the solution at 620 nm. By adjusting the time and temperature of the reaction, the assay permits quantification of DNase activity over a wide concentration range (0.4 to 8900 ng/ml). Samples and standards were added to the substrate in microtiter plates and were incubated for 1-24 h at 25-37 degrees C to achieve the desired assay range. The DNase activity of the samples was interpolated from a standard curve generated with Pulmozyme recombinant human deoxyribonuclease I (rhDNase). Interassay precision was less than 12% CV and recovery was within 100 +/- 11%. Activity determination by the DNA-methyl green method correlated well with that determined by the widely used "hyperchromicity" method originated by Kunitz, which is based on the increase in absorbance at 260 nm upon hydrolysis of DNA. The DNA-methyl green assay was simpler and more versatile than the hyperchromicity method and was used to characterize the activity of rhDNase and DNase isolated from human urine.
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PMID:Colorimetric determination of DNase I activity with a DNA-methyl green substrate. 786 58

The major causes of morbidity and mortality in cystic fibrosis (CF) are the obstruction and damaged airways that result from the accumulation of viscid and infected secretions. Dornase alfa, also called recombinant human DNase I (rhDNase), cleaves extracellular DNA, which is present in inordinately high concentrations in purulent CF airway secretions. Dornase alfa has been found to increase the pourability and reduce the viscoelasticity of CF sputum in vitro and, in an animal model, to increase its mucociliary transportability. Short-term (10-day) Phase I and II clinical trials showed dornase alfa to be safe and effective in improving pulmonary function in clinically stable CF patients with mild to moderate pulmonary disease (FVC > or = 40% of predicted value). A long-term (24-week) Phase IIB clinical trial demonstrated the importance of administering dornase alfa daily to maintain its efficacy. A large-scale, long-term, Phase III clinical trial, consisting of a 24-week double-blind period and a 24-week open-label extension, confirmed these findings and further demonstrated that dornase alfa reduces the incidence of respiratory tract infectious exacerbations requiring parenteral antibiotic therapy. Dornase alfa also decreased the rate of hospitalizations, the number of days missed from work or school, and the frequency of CF-related symptoms. Adverse events were limited to upper airway irritation (i.e., voice alteration, laryngitis, pharyngitis), rash, chest pain, and conjunctivitis. These manifestations generally were mild and transient, and they did not limit the use of dornase alfa. A small proportion (2 to 4%) of patients developed serum antibodies to dornase alfa, but no patient developed anaphylaxis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Aerosolized dornase alfa (rhDNase) for therapy of cystic fibrosis. 788 98

Dornase alfa is the first new drug released in 30 years for the treatment of patients with CF. Although it does not represent a replacement for current standard therapies, it is an effective agent in improving lung function. The development of this drug has helped to provide treatment to a medical problem that physicians have struggled with treating for years.
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PMID:Pulmozyme--Dornase alfa. 800 77

Advances in the treatment and management of respiratory and pancreatic disorders has increased the life expectancy of patients with cystic fibrosis to 28 years (1). Despite the use of potent antibiotics and chest physiotherapy, persistent bacterial infection of the lung is the major cause of morbidity and mortality in these patients (2). This occurs, in part, because of the production of copious amounts of pulmonary secretions. It has been found that these secretions contain high amounts of human DNA (3-8). This high DNA concentration causes two problems. First, it increases the viscosity of sputum. This, in conjunction with reduced mucociliary clearance, decreases the removal of sputum. Second, the DNA binds to aminoglycosides, which decreases their antimicrobial efficacy (9, 10). Until recently there was no effective drug to decrease the viscosity of sputum in patients with cystic fibrosis. Dornase alpha (Pulmozyme) is the first drug to offer a safe and effective method to treat excessive DNA in sputum. In vitro studies demonstrated that rhDNase greatly decreased the viscosity of sputum by decreasing the concentration of DNA in a concentration-dependent manner (11).
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PMID:Aerosolized dornase alpha (rhDNase) in cystic fibrosis. 884 68

The poor clearance of airway secretions in patients with cystic fibrosis perpetuates the chronic bronchopulmonary sepsis that is predominant. In recent years, novel drugs have been developed to alter the rheologic properties of the secretions in an attempt to improve airway clearance. Dornase alfa reduces the viscoelasticity of sputum from patients with cystic fibrosis and may enhance the clearance of secretions. Current clinical knowledge suggests that it is a safe treatment that improves pulmonary function and reduces respiratory exacerbations. The response, however, is heterogeneous and unpredictable. Scientific studies support the therapeutic rationale for the use of dornase alfa in that treatment reduces the viscoelasticity of airway secretions. Its effect on bacterial persistence and airway inflammation, however, is marginal. The key piece of information that would influence the long-term use of dornase alfa is how it affects disease progression, and at present this is unknown.
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PMID:The overuse or underuse of dornase alfa. 939 59

Aerosolized recombinant human DNase (dornase alfa) reduces mucus viscoelasticity in vitro and improves pulmonary function in patients with cystic fibrosis (CF). We postulated that if dornase alfa could be delivered more peripherally to small airways in the lung in the form of smaller aerosol droplets in patients with early airway obstruction, the increase in pulmonary function from baseline might be improved. CF patients (n = 749) with mild lung disease (baseline forced vital capacity > or = 70% predicted) were randomly assigned to receive dornase alfa 2.5 mg daily for 2 weeks by one of two nebulizer systems: 1) the Medic-Aid Durable SideStream nebulizer powered by the MobilAire Compressor (SS/MA) producing a droplet size with a mass median aerodynamic diameter (MMAD) of 2.1 microm; or 2) the Hudson T Up-draft nebulizer with a DeVilbiss Pulmo-Aide compressor (HT/PA) with an MMAD of 4.9 microm. Spirometry was performed at baseline and following 14 days of treatment. Dornase alfa delivered by both nebulizer systems produced small but statistically significant improvements in pulmonary function compared with baseline. There was a trend (P = 0.06) toward greater improvement in forced expiratory flow in 1 s in the SS/MA group (4.3%) compared with the HT/PA group (2.5%). These results indicate that the short-term spirometric response to dornase alfa is influenced in part by the physical characteristics of the aerosol in patients with mild lung disease. We speculate that this may be true for other therapeutic aerosols, and it appears that localization of disease in the lung plays a role in the response to inhaled agents.
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PMID:Effect of smaller droplet size of dornase alfa on lung function in mild cystic fibrosis. Dornase Alfa Nebulizer Group. 951 89

The purpose of this study was to assess the delivery to the lungs and the short-term safety of recombinant human deoxyribonuclease (rhDNase, Pulmozyme) in children with cystic fibrosis younger than 5 years of age compared with older children. Patients between the ages of 3 months and 10 years had bronchoscopic examination with bronchoalveolar lavage (BAL) after administration of an aerosol dose of 2.5 mg of rhDNase. After recovery from the procedure, patients were discharged home for an additional 13 days of rhDNase therapy. During this time adverse events were recorded to assess short-term safety. A total of 98 patients were enrolled, 65 (66%) aged 3 months to 5 years and 33 (34%) aged 5 years to 10 years. Deoxyribonuclease concentrations in BAL fluid were variable (interquartile range, 752 to 3943 micrograms/mL epithelial lining fluid [ELF]) and did not depend on patient age, weight, or height or differ when delivered through a mouthpiece or mask. The median value for the BAL DNA concentration in the younger group was 432 micrograms/mL ELF compared with 703 micrograms/mL ELF in the older patients. This study demonstrates the value of bronchoscopy and BAL for assessing nebulized medication delivery in young children and shows that aerosolized medications can be delivered to and are present in comparable amounts in the lower airways of younger and older children. Exposure to rhDNase appears to be safe over 2 weeks in infants and young children with cystic fibrosis.
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PMID:Aerosol delivery and safety of recombinant human deoxyribonuclease in young children with cystic fibrosis: a bronchoscopic study. Pulmozyme Pediatric Broncoscopy Study Group. 978 85

Mucolytic treatment with rhDNase is part of the current therapy for cystic fibrosis (CF) lung disease. The Flutter valve, a device for enhancing airway mucus clearance, has recently been approved for use in CF patients. Exhalation through the Flutter valve leads to oscillations of expiratory airflow, improving mucus viscoelasticity and stimulating clearance. The goal of our in vitro study was to evaluate the individual and combined effects of Flutter valve oscillations and rhDNase treatment on the viscoelastic (rheological) properties of CF sputum. Sputum specimens were collected from 19 CF patients and subjected to the following protocols: 1) baseline sample with no treatment applied; 2) application of oscillations generated by airflow through the Flutter valve; 3) incubation at 37 degrees C for 30 min with 10% vol/wt rhDNase (Pulmozyme) to achieve a final concentration of 2.5 microg/mL (approximately 100 nM); 4) combination of Flutter valve oscillations and 10% vol/wt normal saline (0.9% NaCl); 5) combination of Flutter valve oscillations and 10% vol/wt rhDNase at 2.5 microg/mL final concentration. For each protocol, the mucus rigidity index (log G* at 1 rad/s) was measured at baseline and at 30 min. Values are presented as mean+/-SEM. The cough clearability index (CCI) was computed from measurements of mucus viscoelasticity, based on relationships established in model studies. Flutter valve treatment alone did not result in a significant reduction in the rigidity of CF sputum (2.24+/-0.13 vs. 2.11+/-0.13, P=0.19), nor did rhDNase (2.5 microg/mL) alone, although we have previously shown (Pediatr. Pulmonol. 1995; 20:78) that both of these treatments reduce sputum spinnability, which is more sensitive to molecular weight reduction. In comparison to individual treatments, combined treatment with Flutter valve oscillations and rhDNase significantly reduced the mucus rigidity to 1.85+/-0.19 from 2.24+/-0.13 (P< 0.001), consequently increasing the predicted clearability of the sputum (from 1.09+/-0.26 to 1.83+/-0.48, P=0.012). These in vitro results suggest that a combination of biochemical treatment (e.g., DNase) and mechanical oscillation may have a better therapeutic potential for mucus clearance in CF lung disease.
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PMID:Effects of sputum oscillations and rhDNase in vitro: a combined approach to treat cystic fibrosis lung disease. 981 Oct 74


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