Dornase Research Articles

(649) - The Effect of Dornase Alfa (rhDNase) on Recurrent Gram Negative Infections in Adult Cystic Fibrosis Lung Transplant Recipients

The Effect of Dornase Alfa (rhDNase) on Recurrent Gram Negative Infections in Adult Cystic Fibrosis Lung Transplant Recipients L.J. Stuckey ,1 A.M. Clark,1 S. Chang,2 K.M. Chan,3 C.E. Bartos,4 T.C. Ojo.3 1Pharmacy Services, University of Michigan Hospital and Health Systems, Ann Arbor, MI; 2College of Pharmacy, University of Michigan, Ann Arbor, MI; 3Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Hospital and Health Systems, Ann Arbor, MI; 4Transplant Center, University of Michigan Hospital and Health Systems, Ann Arbor, MI.

Geographic variations in cystic fibrosis: An analysis of the U.S. CF Foundation Registry.

Emerging evidence suggests that the prevalence of pathogens common in cystic fibrosis (CF) may be unevenly distributed across the United States (U.S.). However, very little is known regarding the U.S. distribution of other CF modifiers such as medication usage and patient demographics. Therefore, we sought to determine if regional differences exist in the distribution of demographic variables and patient disease characteristics in the U.S. that may play a role in differential CF outcomes. Data were analyzed from the 30,896 subjects in the U.S. CF Foundation Patient Registry during the years 2007-2012, via geographical grouping of states based upon the Nationwide Inpatient Sample classification. Significant differences in racial distribution were seen, including half of the total U.S. African-American CF population residing in the South. Both African-Americans and Hispanics had increased Medicaid usage (52.2%, 41.8%, respectively). Culture-reported pathogens were markedly different across the U.S., with the highest percentage of patients with Methicillin-resistant Staphylococcus aureus (41.9%), Pseudomonas aeruginosa (71.2%), and non-tuberculous mycobacterium (10.0%) in the South. The South region also had the lowest mean body mass index and forced expiratory volume in one second. Chronic medication usage such as inhaled tobramycin or macrolides followed P. aeruginosa distribution, while inhaled dornase alfa was most used in the West (84.7%). Co-morbid conditions varied, with the highest percentage of depressed subjects in the Midwest (18.3%). Mean regional mortality rates were not statistically different among regions, although highest in each age grouping of the South. The U.S. has significant regional variations in CF demographics, insurance, pathogens, medication usage, and co-morbidities, without an overall impact on regional mortality. Regional variations in care practices should be studied further based on the findings.

Model of mucociliary clearance in cystic fibrosis lungs.

Mucus clearance is a primary innate defense mechanism in the human airways. Cystic fibrosis (CF) is a genetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CF is characterized by dehydration of airway surface liquid and impaired mucociliary clearance. As a result, microorganisms are not efficiently removed from the airways, and patients experience chronic pulmonary infections and inflammation. We propose a new physiologically based mathematical model of muco-ciliary transport consisting of the two major components of the mucociliary clearance system: (i) periciliary liquid layer (PCL) and (ii) mucus layer. We study mucus clearance under normal conditions and in CF patients. Restoring impaired clearance of airway secretions in one of the major goals of therapy in patients with CF. We consider the action of the aerosolized and inhaled medication dornase alfa, which reduces the viscosity of cystic fibrosis mucus, by selectively cleaving the long DNA strands it contains. The results of the model simulations stress the potential relevance of the location of the drug deposition in the central or peripheral airways. Mucus clearance was increased in case the drug was primarily deposited peripherally, i.e. in the small airways.

Enzymes approved for human therapy: indications, mechanisms and adverse effects.

Research and drug developments fostered under orphan drug product development programs have greatly assisted the introduction of efficient and safe enzyme-based therapies for a range of rare disorders. The introduction and regulatory approval of 20 different recombinant enzymes has enabled, often for the first time, effective enzyme-replacement therapy for some lysosomal storage disorders, including Gaucher (imiglucerase, taliglucerase, and velaglucerase), Fabry (agalsidase alfa and beta), and Pompe (alglucosidase alfa) diseases and mucopolysaccharidoses I (laronidase), II (idursulfase), IVA (elosulfase), and VI (galsulfase). Approved recombinant enzymes are also now used as therapy for myocardial infarction (alteplase, reteplase, and tenecteplase), cystic fibrosis (dornase alfa), chronic gout (pegloticase), tumor lysis syndrome (rasburicase), leukemia (L-asparaginase), some collagen-based disorders such as Dupuytren's contracture (collagenase), severe combined immunodeficiency disease (pegademase bovine), detoxification of methotrexate (glucarpidase), and vitreomacular adhesion (ocriplasmin). The development of these efficacious and safe enzyme-based therapies has occurred hand in hand with some remarkable advances in the preparation of the often specifically designed recombinant enzymes; the manufacturing expertise necessary for commercial production; our understanding of underlying mechanisms operative in the different diseases; and the mechanisms of action of the relevant recombinant enzymes. Together with information on these mechanisms, safety findings recorded so far on the various adverse events and problems of immunogenicity of the recombinant enzymes used for therapy are presented.

Alternative outcomes for the multiple breath washout in children with CF

BackgroundThe lung clearance index (LCI) measured by multiple-breath washout (MBW) has been proposed as an outcome for clinical trials; however, MBW is time consuming and LCI can be affected by breathing pattern. We aimed to evaluate moment ratios and abbreviated LCI in school-aged children with mild-to-moderate CF lung disease. MethodsUsing existing data from three studies we assessed the sensitivity of moment ratios and abbreviated LCIs to (i) detect mild-to-moderate CF lung disease and (ii) detect treatment effects after 4weeks of hypertonic saline or dornase alfa inhalation. MBW was measured by respiratory mass spectrometry using 4% ""sulphur hexafluoride as a tracer gas. ResultsCompared to the traditional LCI, moment ratios and abbreviated LCIs were similarly sensitive to detect CF lung disease. Moment ratios consistently demonstrated treatment effects, whereas abbreviated LCIs were less sensitive. ConclusionsBoth moment ratios and abbreviated LCI are suitable to differentiate health from disease. Sensitivity is decreased for abbreviated LCIs in interventional studies in mild CF lung disease.

Antimicrobial efficacy of tobramycin polymeric nanoparticles for Pseudomonas aeruginosa infections in cystic fibrosis: Formulation, characterisation and functionalisation with dornase alfa (DNase)

Inhaled antibiotics, such as tobramycin, for the treatment of Pseudomonas aeruginosa pulmonary infections are associated with the increase in life expectancy seen in cystic fibrosis (CF) patients over recent years. However, the effectiveness of this aminoglycoside is still limited by its inability to penetrate the thick DNA-rich mucus in the lungs of these patients, leading to low antibiotic exposure to resident bacteria. In this study, we created novel polymeric nanoparticle (NP) delivery vehicles for tobramycin. Using isothermal titration calorimetry, we showed that tobramycin binds with alginate polymer and, by exploiting this interaction, optimised the production of tobramycin alginate/chitosan NPs. It was established that NP antimicrobial activity against P. aeruginosa PA01 was equivalent to unencapsulated tobramycin (minimum inhibitory concentration 0.625mg/L). Galleria mellonella was employed as an in vivo model for P. aeruginosa infection. Survival rates of 90% were observed following injection of NPs, inferring low NP toxicity. After infection with P. aeruginosa, we showed that a lethal inoculum was effectively cleared by tobramycin NPs in a dose dependent manner. Crucially, a treatment with NPs prior to infection provided a longer window of antibiotic protection, doubling survival rates from 40% with free tobramycin to 80% with NP treatment. Tobramycin NPs were then functionalised with dornase alfa (recombinant human deoxyribonuclease I, DNase), demonstrating DNA degradation and improved NP penetration of CF sputum. Following incubation with CF sputum, tobramycin NPs both with and without DNase functionalisation, exhibited anti-pseudomonal effects. Overall, this work demonstrates the production of effective antimicrobial NPs, which may have clinical utility as mucus-penetrating tobramycin delivery vehicles, combining two widely used CF therapeutics into a single NP formulation. This nano-antibiotic represents a strategy to overcome the mucus barrier, increase local drug concentrations, avoid systemic adverse effects and improve outcomes for pulmonary infections in CF.

Immunoglobulin replacement therapy in antibody deficiency syndromes: are we really doing enough?

Immunoglobulin replacement therapy in antibody deficiency syndromes: are we really doing enough?

The expanding armamentarium of drugs to aid sputum clearance: how should they be used to optimize care?

This review examines the evidence for use of agents that improve sputum clearance in cystic fibrosis. The basic defect in cystic fibrosis causes abnormal airway surface liquid leading to mucus plugging and subsequent infection and inflammation in the airways. Agents that improve clearance of secretions should improve lung function, reduce infective exacerbations and may enhance survival. There are two main varieties of mucoactive therapy, namely mucolytic therapy, which reduces viscosity in order to improve clearance, and hyperosmolar therapy, which increases the airway surface liquid volume and increases mucociliary clearance. The development of mannitol as a hyperosmolar agent in dry powder form has heightened the debate regarding the optimal approach to sputum clearance. The evidence for use of individual agents is discussed, as well as a practical approach to combining therapies. Dornase alfa, a mucolytic agent, and hypertonic saline and mannitol, both hyperosmolar agents, have all been shown to benefit patients with cystic fibrosis. The optimal combination of therapies has not been identified, but a combination of a hyperosmolar agent combined with a mucolytic provides the most logical approach to improving lung function and reducing exacerbations.

Nebulized Therapy. SEPAR Year

Inhaled drugs are deposited directly in the respiratory tract. They therefore achieve higher concentrations with faster onset of action and fewer side effects than when used systemically. Nebulized drugs are mainly recommended for patients that require high doses of bronchodilators, when they need to inhale drugs that only exist in this form (antibiotics or dornase alfa) or when they are unable to use other inhalation devices. Technological development in recent years has led to new devices that optimize pulmonary deposits and reduce the time needed for treatment. In this review we focus solely on drugs currently used, or under investigation, for nebulization in adult patients, basically bronchodilators, inhaled steroids, antibiotics, antifungals, mucolytics and others such as anticoagulants, prostanoids, and lidocaine.

Cystic fibrosis -- disease burden and health-related quality of life of patients and their caregivers: results of the European BURQOL-RD survey in Hungary

Data on disease burden of cystic fibrosis in Hungary are scarce. To assess quality of life and resource utilisations of patients with cystic fibrosis. In a cross-sectional survey (BURQOL-RD project), the EQ-5D-5L questionnaire was applied and healthcare utilisations were retrospectively surveyed. 110 patients participated in the study (age-groups, year: 0-13, N = 48; 14-17, N = 12; ≥18, N = 50), median age at the diagnosis was 1 year. EQ-5D-5L score in age-groups 18-24 and 25-34 was significantly lower than in the general population (p<0.05). 75 patients (68%) attended pulmonology care, 55 patients (50%) were hospitalised in the past 6 and 12 months, respectively, and 57 patients (52%) were taking dornase alpha. Five adult patients (10%) received help from non-professional caregiver. Cystic fibrosis leads to significant deterioration of quality of life. This study is the first from the Central Eastern European region that provides basic inputs for further health economic evaluations of cystic fibrosis care.

Children and young adults with CF in the USA have better lung function compared with the UK

BackgroundPeople with cystic fibrosis (CF) are managed differently in the USA and UK providing an opportunity to learn from differences in practice patterns.ObjectivesTo compare cross-sectional demographics, practice patterns and clinical...

Terapia nebulizada. Año SEPAR

Inhaled drugs are deposited directly in the respiratory tract. They therefore achieve higher concentrations with faster onset of action and fewer side effects than when used systemically. Nebulized drugs are mainly recommended for patients that require high doses of bronchodilators, when they need to inhale drugs that only exist in this form (antibiotics or dornase alfa) or when they are unable to use other inhalation devices. Technological development in recent years has led to new devices that optimize pulmonary deposits and reduce the time needed for treatment. In this review we focus solely on drugs currently used, or under investigation, for nebulization in adult patients; basically bronchodilators, inhaled steroids, antibiotics, antifungals, mucolytics and others such as anticoagulants, prostanoids and lidocaine.

INFLUENCE OF THE AGE OF THE DIAGNOSIS AND THE BEGINNING OF SPECIFIC THERAPY ON MAIN CLINICAL AND LABORATORY MANIFESTATIONS OF A DISEASE IN PATIENTS WITH CYSTIC FIBROSIS

Background: To establish features of a clinical course of a disease at patients depending on age of firstly determine diagnosis of cystic fibrosis. Patients and methods : We examined 130 patients with cystic fibrosis aged under 25 years old. Depending on the age of diagnosis 3 groups of patients were formed: diagnosed at the age of 0–7, 8–18 and 18–25 years old. Results: There were no differences in the main anthropometric, functional, microbiological characteristics and frequency of complications at the age of 25 years between the patients of all three groups. However significant differences in «severity» of genotypes are defined: in group with the diagnosis established at preschool age, «severe» genotypes dominated, in group with the diagnosis established in 7–18 and 18–25 years, — «mild» genotypes. Importance of treatment with dornase alfa in all patients with cystic fibrosis regarding age of establishment of the diagnosis was shown. Conclusion: Early diagnostics determines appropriate beginning of the treatment, which can improve the further prognosis of the disease course. However late diagnostics in patients with «mild» genotype does not have significant influence on the clinical course at the age of 25 years old, which proves protective effects of «mild» mutations.

Maintaining Respiratory Health in Cystic Fibrosis Patients

Cystic fibrosis (CF) is an inherited disease that primarily affects the lungs and the digestive system, however, it also affects a number of other organs and systems. More than 90% of mortality of CF patients is due to lung complications. Healthy lungs are important for a long life for people with CF, We will discuss two important topics for maintaining respiratory health. Chronic use of drugs for maintaining respiratory health There are a number of drugs available to keep CF lungs healthy. We will discuss the science behind the recommendations for use of: Inhaled antibiotics Dornase alfa Azithromycin Hypertonic saline High-dose ibuprofen Ivacaftor CF Airway Clearance Therapies Airway Clearance therapy is very important to keeping CF lungs healthy. Our discussions cover the following topics such as the: Daily airway clearance Different techniques of airway clearance Effect of aerobic exercise on airway clearance

The evidence base for non‐CF bronchiectasis is finally evolving

See article, page 321

Sinonasal inhalation of dornase alfa administered by vibrating aerosol to cystic fibrosis patients: A double-blind placebo-controlled cross-over trial

BackgroundChronic rhinosinusitis significantly impairs CF patients' quality of life and overall health. The Pari-Sinus™ device delivers vibrating aerosol effectively to paranasal sinuses. After a small pilot study to assess sinonasal inhalation of dornase alfa and placebo (isotonic saline) on potential sinonasal outcome measures, we present the subsequent prospective double-blind placebo-controlled crossover-trial. Methods23 CF patients were randomised to inhale either dornase alfa or isotonic saline for 28days with the Pari-Sinus™ and after 28days (wash-out) crossed over to the alternative treatment. The primary outcome parameter was primary nasal symptom score in the disease-specific quality of life Sino-Nasal Outcome-Test-20 (SNOT-20: nasal obstruction/sneezing/runny nose/thick nasal discharge/reduced smelling). ResultsPrimary nasal symptoms improved significantly with dornase alfa compared with no treatment, while small improvements with isotonic saline did not reach significance. SNOT-20 overall scores improved significantly after dornase alfa compared with isotonic saline (p=0.017). Additionally, sinonasal dornase alfa but not isotonic saline significantly improved pulmonary function (FEF75–25: p=0.021). ConclusionVibrating sinonasal inhalation of dornase alfa reduces rhinosinusitis symptoms in CF.

Predictors and Outcome of Low Initial Forced Expiratory Volume in 1 Second Measurement in Children with Cystic Fibrosis

To identify the characteristics of children with cystic fibrosis with low initial forced expiratory volume in 1 second (FEV1) % predicted and to investigate their outcome. Patients were categorized into low or high initial FEV1 groups using cluster analysis. Comparisons of the demographic and clinical data were performed between the 2 groups. From 122 children, 21 clustered into the low and 101 into the high FEV1 group. The mean FEV1 was 69% ± 12% predicted for the low and 95% ± 12% predicted for the high FEV1 group (P < .001). The low FEV1 group had lower body mass index percentiles (P = .003), were hospitalized more frequently (P = .001), and had been on dornase alfa longer (P = .006). Low FEV1 group had more patients with positive cultures for Pseudomonas aeruginosa (P = .002) and Stenotrophomonas maltophilia (P < .001) and had more total number of cultures positive for mucoid P. aeruginosa (P = .009) and methicillin resistant Staphylococcus aureus + P. aeruginosa (P = .005). The low FEV1 group continued to have low FEV1 measurements, their FEV1 declined slower, required more hospitalizations per year (P = .01), and had more cultures for mucoid (P = .003) and nonmucoid P. aeruginosa (P = .02) ± methicillin resistant S. aureus (P = .002) in comparison with the high FEV1 group. Poor adherence was associated with lower initial FEV1 values in females, and early, rapid decline of FEV1 in males. Some children with cystic fibrosis may present with poor lung function early in life and continue to have subnormal lung function associated with reduced body mass index, more frequent hospitalization, and higher rates of infection. Such children may benefit from careful evaluation and close follow-up.

Successful treatment of atelectasis with Dornase alpha in a patient with congenital muscular dystrophy

Successful treatment of atelectasis with Dornase alpha in a patient with congenital muscular dystrophy

СРАВНИТЕЛЬНЫЕ ХАРАКТЕРИСТИКИ ИЗВЕСТНЫХ МУКОЛИТИКОВ В БАЗИСНОЙ ТЕРАПИИ МУКОВИСЦИДОЗА У ДЕТЕЙ

научный биометрический журнал, который знакомит читателя с клиническими рекомендациями и особенностями применения лекарственных и вакцинных средств у детей, предоставляет исчерпывающую информацию о воздействии лекарственных средств на плод, о проводимых в

Medical management of chronic rhinosinusitis in cystic fibrosis: A systematic review

To systematically review existing literature on the effectiveness of medical management of chronic rhinosinusitis (CRS) in cystic fibrosis (CF) patients. Systematic review. We performed a literature search of PubMed, Embase, and Cochrane CENTRAL from 1987 to 2012. Inclusion criteria included English language as containing original data, with five or more subjects, measurable clinical outcomes, and readily available interventions. Data were systematically collected on study design, patient demographics, clinical characteristics and outcomes, and level of evidence. Two investigators independently reviewed all manuscripts and performed a comprehensive quality assessment. Of 415 abstracts identified, 12 articles were included. These 12 studies reported on 701 adult and pediatric CF patients who underwent medical therapy. Medical treatment included antibiotics (4/12), topical steroids (4/12), dornase alfa (3/12), and ibuprofen (1/12). Outcome measures included symptom scores (7/12), endoscopic findings (7/12), radiographic findings (4/12), pulmonary function testing (4/12), and rhinomanometry (2/12). Most studies found improvement in at least one of the outcome measures. There was statistical significance in clinical outcomes with dornase alfa, beclomethasone, and betamethasone. Most studies were level 3 or 4 evidence (9/12), but three studies were level 1 or 2 evidence (two dornase alfa studies, one betamethasone study). Dornase alfa and, to a lesser extent, topical steroids demonstrated significant benefits in the medical treatment CRS in CF. There was a lack of evidence to support antibiotic therapy in the outcomes assessed. Further high-quality studies should be carried out to determine the efficacy of various medical therapies for CRS in CF. NA.