Dornase-alfa

UNSTRUCTURED Dornase alfa, the recombinant form of the human DNase I enzyme, breaks down neutrophil extracellular traps (NET) that include a vast amount of DNA fragments, histones, microbicidal proteins and oxidant enzymes released from necrotic neutrophils in the highly viscous mucus of cystic fibrosis patients. Dornase alfa has been used for decades in patients with cystic fibrosis to reduce the viscoelasticity of respiratory tract secretions, to decrease the severity of respiratory tract infections, and to improve lung function. Previous studies have linked abnormal NET formations to lung diseases, especially to acute respiratory distress syndrome (ARDS). Coronavirus disease 2019 (COVID-19) pandemic affected more than two million people over the world, resulting in unprecedented health, social and economic crises. The COVID-19, viral pneumonia that progresses to ARDS and even multiple organ failure, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). High blood neutrophil levels are an early indicator of SARS-CoV-2 infection and predict severe respiratory diseases. A similar mucus structure is detected in COVID-19 patients due to the accumulation of excessive NET in the lungs. Here, we show our preliminary results with dornase alfa that may have an in-vitro anti-viral effect against SARS-CoV-2 infection in a bovine kidney cell line, MDBK without drug toxicity on healthy adult peripheral blood mononuclear cells. In this preliminary study, we also showed that dornase alfa can promote clearance of NET formation in both an in-vitro and three COVID-19 cases who showed clinical improvement in radiological analysis (2-of-3 cases), oxygen saturation (SpO2), respiratory rate, disappearing of dyspnea and coughing.

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Inspiration and Exasperation: The Challenges of Inhaled Biologics

Toxicologic Pathology ◽

10.1177/0192623320984715 ◽

2021 ◽

pp. 019262332098471

Author(s):

Peter Hall ◽

John L. Vahle ◽

Karyn Colman

Keyword(s):

Nucleic Acids ◽

Scientific Knowledge ◽

Human Disease ◽

Regulatory Approval ◽

Special Edition ◽

Mechanisms Of Toxicity ◽

Dornase Alfa

The delivery of biotherapeutic molecules (antibodies, proteins, peptides) and nucleic acids via the respiratory route has presented challenges for regulatory approval, due in part to a lack of understanding of the expected pathology, mechanisms of toxicity, and immunogenicity induced by the inhalation route. Although the first inhaled biotherapeutic was approved some time ago (Dornase Alfa, Pulmozyme; Genetech, 1993), no other inhaled biotherapeutics have been marketed for the treatment of human disease other than the inhaled insulins (Exubera; Pfizer, 2006 and Afrezza; Mannkind Corporation, 2014). As a result, scientific knowledge within the toxicologic pathology community is fragmented with precious little publicly available data. Therefore, one of the aims of this special edition was to generate a collection of manuscripts that pathologists and toxicologists could refer in order to understand the pathology, mechanisms of toxicity, immunogenicity, and challenges associated with the development of inhaled biotherapeutics.

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Variation in treatment preferences of pulmonary exacerbations among Australian and New Zealand cystic fibrosis physicians

BMJ Open Respiratory Research ◽

10.1136/bmjresp-2021-000956 ◽

2021 ◽

Vol 8 (1) ◽

pp. e000956

Author(s):

Grace Currie ◽

Anna Tai ◽

Tom Snelling ◽

André Schultz

Keyword(s):

Cystic Fibrosis ◽

Clinical Trials ◽

New Zealand ◽

Treatment Options ◽

Early Response ◽

Treatment Preferences ◽

Dornase Alfa ◽

Clinical Scenarios ◽

Professional Opinion ◽

Pulmonary Exacerbations

BackgroundDespite advances in cystic fibrosis (CF) management and survival, the optimal treatment of pulmonary exacerbations remains unclear. Understanding the variability in treatment approaches among physicians might help prioritise clinical uncertainties to address through clinical trials.MethodsPhysicians from Australia and New Zealand who care for people with CF were invited to participate in a web survey of treatment preferences for CF pulmonary exacerbations. Six typical clinical scenarios were presented; three to paediatric and another three to adult physicians. For each scenario, physicians were asked to choose treatment options and provide reasons for their choices.ResultsForty-nine CF physicians (31 paediatric and 18 adult medicine) participated; more than half reported 10+ years of experience. There was considerable variation in primary antibiotic selection; none was preferred by more than half of respondents in any scenario. For secondary antibiotic therapy, respondents consistently preferred intravenous tobramycin and a third antibiotic was rarely prescribed, except in one scenario describing an adult patient. Hypertonic saline nebulisation and twice daily chest physiotherapy was preferred in most scenarios while dornase alfa use was more variable. Most CF physicians (>80%) preferred to change therapy if there was no early response. Professional opinion was the most common reason for antibiotic choice.ConclusionsVariation exists among CF physicians in their preferred choice of primary antibiotic and use of dornase alfa. These preferences are driven by professional opinion, possibly reflecting a lack of evidence to base policy recommendations. Evidence from high-quality clinical trials is needed to inform physician decision making.

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Dornase alfa for cystic fibrosis

Cochrane Database of Systematic Reviews ◽

10.1002/14651858.cd001127.pub5 ◽

2021 ◽

Author(s):

Connie Yang ◽

Mark Montgomery

Keyword(s):

Cystic Fibrosis ◽

Dornase Alfa

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Nebulized in-line endotracheal dornase alfa and albuterol administered to mechanically ventilated COVID-19 patients: a case series

Molecular Medicine ◽

10.1186/s10020-020-00215-w ◽

2020 ◽

Vol 26 (1) ◽

Cited By ~ 2

Author(s):

Andrew G. Weber ◽

Alice S. Chau ◽

Mikala Egeblad ◽

Betsy J. Barnes ◽

Tobias Janowitz

Keyword(s):

Case Series ◽

Mechanically Ventilated ◽

Mechanically Ventilated Patients ◽

Dornase Alfa ◽

Extracellular Traps ◽

Dnase 1 ◽

Fraction Of Inspired Oxygen ◽

Oxygen Requirements ◽

Inspired Oxygen ◽

Ventilated Patients

Abstract Background Mechanically ventilated patients with COVID-19 have a mortality of 24–53%, in part due to distal mucopurulent secretions interfering with ventilation. DNA from neutrophil extracellular traps (NETs) contribute to the viscosity of mucopurulent secretions and NETs are found in the serum of COVID-19 patients. Dornase alfa is recombinant human DNase 1 and is used to digest DNA in mucoid sputum. Here, we report a single-center case series where dornase alfa was co-administered with albuterol through an in-line nebulizer system. Methods Demographic and clinical data were collected from the electronic medical records of five mechanically ventilated patients with COVID-19—including three requiring veno-venous extracorporeal membrane oxygenation—treated with nebulized in-line endotracheal dornase alfa and albuterol, between March 31 and April 24, 2020. Data on tolerability and response were analyzed. Results The fraction of inspired oxygen requirements was reduced for all five patients after initiating dornase alfa administration. All patients were successfully extubated, discharged from hospital and remain alive. No drug-associated toxicities were identified. Conclusions Results suggest that dornase alfa will be well-tolerated by patients with severe COVID-19. Clinical trials are required to formally test the dosing, safety, and efficacy of dornase alfa in COVID-19, and several have been recently registered.

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Dornase alfa in young patients with cystic fibrosis

The Journal of Pediatrics ◽

10.1067/mpd.2002.128748 ◽

2002 ◽

Vol 141 (6) ◽

pp. 838

Author(s):

Edward R. Carter

Keyword(s):

Cystic Fibrosis ◽

Young Patients ◽

Dornase Alfa

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Dornase-alfa beneficial in advanced cystic fibrosis

Inpharma Weekly ◽

10.2165/00128413-199610620-00009 ◽

1996 ◽

Vol &NA; (1062) ◽

pp. 5

Author(s):

&NA;

Keyword(s):

Cystic Fibrosis ◽

Dornase Alfa

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A first-year dornase alfa treatment impact on clinical parameters of patients with cystic fibrosis: the Brazilian cystic fibrosis multicenter study

Revista Paulista de Pediatria ◽

10.1590/s0103-05822013000400002 ◽

2013 ◽

Vol 31 (4) ◽

pp. 420-430 ◽

Cited By ~ 2

Author(s):

Tatiana Rozov ◽

Fernando Antônio A. e Silva ◽

Maria Angélica Santana ◽

Fabíola Villac Adde ◽

Rita Heloisa Mendes

Keyword(s):

Cystic Fibrosis ◽

Emergency Room ◽

Age Groups ◽

Forced Expiratory Volume ◽

First Year ◽

Age Group ◽

Emergency Room Visits ◽

Dornase Alfa ◽

Pulmonary Exacerbations ◽

One Year

OBJECTIVE: To describe the clinical impact of the first year treatment with dornase alfa, according to age groups, in a cohort of Brazilian Cystic Fibrosis (CF) patients. METHODS: The data on 152 eligible patients, from 16 CF reference centers, that answered the medical questionnaires and performed laboratory tests at baseline (T0), and at six (T2) and 12 (T4) months after dornase alfa initiation, were analyzed. Three age groups were assessed: six to 11, 12 to 13, and >14 years. Pulmonary tests, airway microbiology, emergency room visits, hospitalizations, emergency and routine treatments were evaluated. Student's t-test, chi-square test and analysis of variance were used when appropriated. RESULTS: Routine treatments were based on respiratory physical therapy, regular exercises, pancreatic enzymes, vitamins, bronchodilators, corticosteroids, and antibiotics. In the six months prior the study (T0 phase), hospitalizations for pulmonary exacerbations occurred in 38.0, 10.0 and 61.4% in the three age groups, respectively. After one year of intervention, there was a significant reduction in the number of emergency room visits in the six to 11 years group. There were no significant changes in forced expiratory volume in one second (VEF1), in forced vital capacity (FVC), in oxygen saturation (SpO2), and in Tiffenau index for all age groups. A significant improvement in Shwachman-Kulczychi score was observed in the older group. In the last six months of therapy, chronic or intermittent colonization by P. aeruginosa was detected in 75.0, 71.4 and 62.5% of the studied groups, respectively, while S. aureus colonization was identified in 68.6, 66.6 and 41.9% of the cases. CONCLUSIONS: The treatment with dornase alfa promoted the maintenance of pulmonary function parameters and was associated with a significant reduction of emergency room visits due to pulmonary exacerbations in the six to 11 years age group, with better clinical scores in the >14 age group, one year after the intervention.

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