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#33686652   2021/03/09 To Up

Timing of dornase alfa inhalation for cystic fibrosis.

Inhalation of the enzyme dornase alfa reduces sputum viscosity and improves clinical outcomes of people with cystic fibrosis. This is an update of a previously published Cochrane Review.
Ruth Dentice, Mark Elkins

1042 related Products with: Timing of dornase alfa inhalation for cystic fibrosis.

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#33547099   2021/02/05 To Up

Successful drainage of complex haemoserous malignant pleural effusion with a single modified low-dose intrapleural alteplase and dornase alfa.

Patients with symptomatic complex malignant pleural effusion (MPE) are frequently unfit for decortication and have a poorer prognosis. Septations can develop in MPE, which may lead to failure of complete drainage and pleural infection. Intrapleural fibrinolytic therapy (IPFT) is an alternative treatment. The use of IPFT in patients with anaemia and high risk for intrapleural bleeding is not well established. We report a successful drainage of complex haemoserous MPE with a single modified low-dose of intrapleural 5 mg of alteplase and 5 mg of dornase alfa in a patient with pre-existing anaemia with no significant risk of intrapleural bleeding.
Boon Hau Ng, Nur Husna Mohd Aminudin, Mona Zaria Nasaruddin, Jamalul Azizi Abdul Rahaman

2255 related Products with: Successful drainage of complex haemoserous malignant pleural effusion with a single modified low-dose intrapleural alteplase and dornase alfa.

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#33435568   2021/01/08 To Up

Orchestration of Neutrophil Extracellular Traps (Nets), a Unique Innate Immune Function during Chronic Obstructive Pulmonary Disease (COPD) Development.

Morbidity, mortality and economic burden caused by chronic obstructive pulmonary disease (COPD) is a significant global concern. Surprisingly, COPD is already the third leading cause of death worldwide, something that WHO had not predicted to occur until 2030. It is characterized by persistent respiratory symptoms and airway limitation due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles of gases. Neutrophil is one of the key infiltrated innate immune cells in the lung during the pathogenesis of COPD. Neutrophils during pathogenic attack or injury decide to undergo for a suicidal death by releasing decondensed chromatin entangled with antimicrobial peptides to trap and ensnare pathogens. Casting neutrophil extracellular traps (NETs) has been widely demonstrated to be an effective mechanism against invading microorganisms thus controlling overwhelming infections. However, aberrant and massive NETs formation has been reported in several pulmonary diseases, including chronic obstructive pulmonary disease. Moreover, NETs can directly induce epithelial and endothelial cell death resulting in impairing pulmonary function and accelerating the progression of the disease. Therefore, understanding the regulatory mechanism of NET formation is the need of the hour in order to use NETs for beneficial purpose and controlling their involvement in disease exacerbation. For example, DNA neutralization of NET proteins using protease inhibitors and disintegration with recombinant human DNase would be helpful in controlling excess NETs. Targeting CXC chemokine receptor 2 () would also reduce neutrophilic inflammation, mucus production and neutrophil-proteinase mediated tissue destruction in lung. In this review, we discuss the interplay of NETs in the development and pathophysiology of COPD and how these NETs associated therapies could be leveraged to disrupt NETopathic inflammation as observed in COPD, for better management of the disease.
Anjali Trivedi, Meraj A Khan, Geetanjali Bade, Anjana Talwar

2143 related Products with: Orchestration of Neutrophil Extracellular Traps (Nets), a Unique Innate Immune Function during Chronic Obstructive Pulmonary Disease (COPD) Development.

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#33397211   2021/01/05 To Up

Inspiration and Exasperation: The Challenges of Inhaled Biologics.

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.
Peter Hall, John L Vahle, Karyn Colman

1371 related Products with: Inspiration and Exasperation: The Challenges of Inhaled Biologics.

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#33264072   // To Up

Polysulfated Hyaluronan GlycoMira-1111 Inhibits Elastase and Improves Rheology in Cystic Fibrosis Sputum.

Cystic fibrosis (CF) lung disease is marked by high concentrations of neutrophil elastase (NE) and DNA polymers; both factors contribute to airway disease. Although inhaled recombinant human dornase alfa reduces the frequency of CF pulmonary exacerbations, it also increases free NE activity in the sputum. There are no approved anti-NE therapies for patients with CF. We investigated whether synthetic, low-molecular weight polysulfated hyaluronan GlycoMira-1111 (GM-1111) would be effective as an anti-NE drug using CF sputum. Anti-NE activity of GM-1111 was tested in CF sputum in the presence or absence of dornase alfa and/or hypertonic saline using a spectrophotometric assay specific for human NE and was compared with unfractionated heparin. We tested whether GM-1111 disaggregated DNA from CF sputum (using gel electrophoresis analysis) or modified CF sputum viscoelastic properties (using a dynamic rheometer). GM-1111 and unfractionated heparin had near equivalent anti-NE activity in CF sputum in the presence of dornase alfa. Both GM-1111 and unfractionated heparin retained anti-NE activity in hypertonic saline but with decreased activity. GM-1111 increased the release of soluble DNA in CF sputum, resulting in improved depolymerization efficacy of dornase alfa. GM-1111 decreased CF sputum elasticity. GM-1111 inhibited NE activity, enhanced DNA depolymerization by deoxyribonuclease, and decreased viscoelastic properties of CF sputum, similar to effects reported previously for unfractionated heparin. Unlike heparins, GM-1111 is synthetic, with minimal anticoagulant activity, and is not derived from animal products. These key attributes provide advantages over unfractionated heparin as a potential therapeutic for CF.
Apparao B Kummarapurugu, Shuo Zheng, Abigail Pulsipher, Justin R Savage, Jonathan Ma, Bruce K Rubin, Thomas P Kennedy, Judith A Voynow

2814 related Products with: Polysulfated Hyaluronan GlycoMira-1111 Inhibits Elastase and Improves Rheology in Cystic Fibrosis Sputum.

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#33095650   // To Up

Neutrophil Extracellular Traps Increase Airway Mucus Viscoelasticity and Slow Mucus Particle Transit.

Mucus obstruction is a key feature of many inflammatory airway diseases. Neutrophil extracellular traps (NETs) are released upon neutrophil stimulation and consist of extracellular chromatin networks studded with cytotoxic proteins. When released in the airways, these NETs can become part of the airway mucus. We hypothesized that the extracellular DNA and/or oxidative stress (e.g., by the release of reactive oxygen species and myeloperoxidase during NETs formation in the airways) would increase mucus viscoelasticity. We collected human airway mucus from endotracheal tubes of healthy patients admitted for elective surgery and coincubated these samples with NETs from phorbol 12-myristate 13-acetate-stimulated neutrophils. Unstimulated neutrophils served as controls, and blocking experiments were performed with dornase alfa for extracellular DNA and the free radical scavenger dimethylthiourea for oxidation. Compared with controls, the coincubation of mucus with NETs resulted in ) significantly increased mucus viscoelasticity (macrorheology) and ) significantly decreased mesh pore size of the mucus and decreased movement of muco-inert nanoparticles through the mucus (microrheology), but ) NETs did not cause visible changes in the microstructure of the mucus by scanning EM. Incubation with either dornase alfa or dimethylthiourea attenuated the observed changes in macrorheology and microrheology. This suggests that the release of NETs may contribute to airway mucus obstruction by increasing mucus viscoelasticity and that this effect is not solely due to the release of DNA but may in part be due to oxidative stress.
Rosalie S Linssen, Guihong Chai, Jonathan Ma, Apparao B Kummarapurugu, Job B M van Woensel, Reinout A Bem, Logan Kaler, Gregg A Duncan, Lei Zhou, Bruce K Rubin, Qingguo Xu

1901 related Products with: Neutrophil Extracellular Traps Increase Airway Mucus Viscoelasticity and Slow Mucus Particle Transit.

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#32993479   2020/09/29 To Up

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

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.
Andrew G Weber, Alice S Chau, Mikala Egeblad, Betsy J Barnes, Tobias Janowitz

2084 related Products with: Nebulized in-line endotracheal dornase alfa and albuterol administered to mechanically ventilated COVID-19 patients: a case series.



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#32922804   2020/09/07 To Up

Preliminary report of and effectiveness of dornase alfa on SARS-CoV-2 infection.

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). It is well known that novel coronavirus disease 2019 (COVID-19) pneumonia progresses to ARDS and even multiple organ failure. High blood neutrophil levels are an early indicator of COVID-19 and predict severe respiratory diseases. Also it is reported that mucus structure in COVID-19 is very similar to that in cystic fibrosis due to the accumulation of excessive NET in the lungs. In this study, we showed the recovery of three individuals with COVID-19 after including dornase alfa in their treatment. We followed clinical improvement in the radiological analysis (two of three cases), oxygen saturation (Spo), respiratory rate, disappearance of dyspnoea, coughing and a decrease in NET formation and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load after the treatment. Also here, we share our preliminary results suggesting that dornase alfa has an anti-viral effect against SARS-CoV-2 infection in a green monkey kidney cell line, Vero, and a bovine kidney cell line, MDBK, without determined cytotoxicity on healthy peripheral blood mononuclear cells.
H K Okur, K Yalcin, C Tastan, S Demir, B Yurtsever, G S Karakus, D D Kancagi, S Abanuz, U Seyis, R Zengin, C Hemsinlioglu, M Kara, M E Yildiz, E Deliceo, N Birgen, N B Pelit, C Cuhadaroglu, A S Kocagoz, E Ovali

1490 related Products with: Preliminary report of and effectiveness of dornase alfa on SARS-CoV-2 infection.

250ul200ul250ul200ul200ug 5 G10 mg~2x10(6) cells200ul200ug

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