Inhaled nebulized glatiramer acetate against Gram-negative bacteria is not associated with adverse pulmonary reactions in healthy, young adult female pigs
The developmental speed of new antimicrobials does not meet the emergence of multidrug-resistant bacteria sufficiently. A potential shortcut is assessing the antimicrobial activity of already approved drugs. Intrudingly, the antibacterial action of glatiramer acetate (GA) has recently been discovere...
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| Veröffentlicht in: | PloS one 2019-10, Vol.14 (10), p.e0223647-e0223647 |
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| creator | Skovdal, Sandra M Christiansen, Stig Hill Johansen, Karen Singers Viborg, Ole Bruun, Niels Henrik Jensen-Fangel, Søren Holm, Ida Elisabeth Vorup-Jensen, Thomas Petersen, Eskild |
| description | The developmental speed of new antimicrobials does not meet the emergence of multidrug-resistant bacteria sufficiently. A potential shortcut is assessing the antimicrobial activity of already approved drugs. Intrudingly, the antibacterial action of glatiramer acetate (GA) has recently been discovered. GA is a well-known and safe immunomodulatory drug particular effective against Gram-negative bacteria, which disrupts biological membranes by resembling the activity of antimicrobial peptides. Thus, GA can potentially be included in treatment strategies used to combat infections caused by multidrug-resistant Gram-negatives. One potential application is chronic respiratory infections caused by Pseudomonas aeruginosa, however the safety of GA inhalation has never been assessed. Here, the safety of inhaling nebulized GA is evaluated in a preclinical pig model. The potential side effects, i.e., bronchoconstriction, respiratory tract symptoms and systemic- and local inflammation were assessed by ventilator monitoring, clinical observation, biochemistry, flowcytometry, and histopathology. No signs of bronchoconstriction assessed by increased airway peak pressure, Ppeak, or decreased oxygen pressure were observed. Also, there were no signs of local inflammation in the final histopathology examination of the pulmonary tissue. As we did not observe any potential pulmonary side effects of inhaled GA, our preliminary results suggest that GA inhalation is safe and potentially can be a part of the treatment strategy targeting chronic lung infections caused by multidrug-resistant Gram-negative bacteria. |
| doi_str_mv | 10.1371/journal.pone.0223647 |
| format | Article |
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A potential shortcut is assessing the antimicrobial activity of already approved drugs. Intrudingly, the antibacterial action of glatiramer acetate (GA) has recently been discovered. GA is a well-known and safe immunomodulatory drug particular effective against Gram-negative bacteria, which disrupts biological membranes by resembling the activity of antimicrobial peptides. Thus, GA can potentially be included in treatment strategies used to combat infections caused by multidrug-resistant Gram-negatives. One potential application is chronic respiratory infections caused by Pseudomonas aeruginosa, however the safety of GA inhalation has never been assessed. Here, the safety of inhaling nebulized GA is evaluated in a preclinical pig model. The potential side effects, i.e., bronchoconstriction, respiratory tract symptoms and systemic- and local inflammation were assessed by ventilator monitoring, clinical observation, biochemistry, flowcytometry, and histopathology. No signs of bronchoconstriction assessed by increased airway peak pressure, Ppeak, or decreased oxygen pressure were observed. Also, there were no signs of local inflammation in the final histopathology examination of the pulmonary tissue. As we did not observe any potential pulmonary side effects of inhaled GA, our preliminary results suggest that GA inhalation is safe and potentially can be a part of the treatment strategy targeting chronic lung infections caused by multidrug-resistant Gram-negative bacteria.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0223647</identifier><identifier>PMID: 31600340</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Administration, Inhalation ; Animal welfare ; Animals ; Anti-infective agents ; Antibacterial agents ; Antibiotics ; Antimicrobial activity ; Antimicrobial agents ; Antimicrobial peptides ; Bacteria ; Biochemistry ; Biofilms ; Biological membranes ; Biology and Life Sciences ; Bronchi - drug effects ; Bronchi - microbiology ; Bronchi - pathology ; Bronchoconstriction ; Bronchoconstriction - drug effects ; Bronchopulmonary infection ; Clinical medicine ; Copolymer 1 ; Cystic fibrosis ; Drug approval ; EDTA ; Engineering and Technology ; Female ; Food ; Glatiramer acetate ; Glatiramer Acetate - administration & dosage ; Glatiramer Acetate - pharmacology ; Gram-negative bacteria ; Gram-Negative Bacteria - drug effects ; Health aspects ; Histochemistry ; Histopathology ; Hospitals ; Immunology ; Immunomodulation ; Infection ; Infectious diseases ; Inflammation ; Inhalation ; Laboratories ; Leukocyte Count ; Lung - drug effects ; Lung - microbiology ; Lung - pathology ; Lung diseases ; Mannitol - administration & dosage ; Mannitol - pharmacology ; Medicine and Health Sciences ; Membranes ; Microbial drug resistance ; Mucous Membrane - drug effects ; Multidrug resistance ; Multidrug resistant organisms ; Multiple sclerosis ; Nebulizers and Vaporizers ; Oxygen ; Peak pressure ; Peptides ; Pharmaceuticals ; Physical Sciences ; Physiological aspects ; Pressure ; Pseudomonas aeruginosa ; Research and Analysis Methods ; Respiration ; Respiratory therapy ; Respiratory tract ; Respiratory tract diseases ; Safety ; Side effects ; Swine ; Women's health ; Young adults ; Youth</subject><ispartof>PloS one, 2019-10, Vol.14 (10), p.e0223647-e0223647</ispartof><rights>COPYRIGHT 2019 Public Library of Science</rights><rights>2019 Skovdal et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2019 Skovdal et al 2019 Skovdal et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-383fab4f8f760dbce84ff945581f526844ed5fe12e490d7c8425e61083fb76e3</citedby><cites>FETCH-LOGICAL-c692t-383fab4f8f760dbce84ff945581f526844ed5fe12e490d7c8425e61083fb76e3</cites><orcidid>0000-0003-2602-197X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786617/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786617/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2100,2926,23864,27922,27923,53789,53791,79370,79371</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31600340$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Cartelle Gestal, Monica</contributor><creatorcontrib>Skovdal, Sandra M</creatorcontrib><creatorcontrib>Christiansen, Stig Hill</creatorcontrib><creatorcontrib>Johansen, Karen Singers</creatorcontrib><creatorcontrib>Viborg, Ole</creatorcontrib><creatorcontrib>Bruun, Niels Henrik</creatorcontrib><creatorcontrib>Jensen-Fangel, Søren</creatorcontrib><creatorcontrib>Holm, Ida Elisabeth</creatorcontrib><creatorcontrib>Vorup-Jensen, Thomas</creatorcontrib><creatorcontrib>Petersen, Eskild</creatorcontrib><title>Inhaled nebulized glatiramer acetate against Gram-negative bacteria is not associated with adverse pulmonary reactions in healthy, young adult female pigs</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The developmental speed of new antimicrobials does not meet the emergence of multidrug-resistant bacteria sufficiently. A potential shortcut is assessing the antimicrobial activity of already approved drugs. Intrudingly, the antibacterial action of glatiramer acetate (GA) has recently been discovered. GA is a well-known and safe immunomodulatory drug particular effective against Gram-negative bacteria, which disrupts biological membranes by resembling the activity of antimicrobial peptides. Thus, GA can potentially be included in treatment strategies used to combat infections caused by multidrug-resistant Gram-negatives. One potential application is chronic respiratory infections caused by Pseudomonas aeruginosa, however the safety of GA inhalation has never been assessed. Here, the safety of inhaling nebulized GA is evaluated in a preclinical pig model. The potential side effects, i.e., bronchoconstriction, respiratory tract symptoms and systemic- and local inflammation were assessed by ventilator monitoring, clinical observation, biochemistry, flowcytometry, and histopathology. No signs of bronchoconstriction assessed by increased airway peak pressure, Ppeak, or decreased oxygen pressure were observed. Also, there were no signs of local inflammation in the final histopathology examination of the pulmonary tissue. As we did not observe any potential pulmonary side effects of inhaled GA, our preliminary results suggest that GA inhalation is safe and potentially can be a part of the treatment strategy targeting chronic lung infections caused by multidrug-resistant Gram-negative bacteria.</description><subject>Administration, Inhalation</subject><subject>Animal welfare</subject><subject>Animals</subject><subject>Anti-infective agents</subject><subject>Antibacterial agents</subject><subject>Antibiotics</subject><subject>Antimicrobial activity</subject><subject>Antimicrobial agents</subject><subject>Antimicrobial peptides</subject><subject>Bacteria</subject><subject>Biochemistry</subject><subject>Biofilms</subject><subject>Biological membranes</subject><subject>Biology and Life Sciences</subject><subject>Bronchi - drug effects</subject><subject>Bronchi - microbiology</subject><subject>Bronchi - pathology</subject><subject>Bronchoconstriction</subject><subject>Bronchoconstriction - drug 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microbiology</subject><subject>Lung - pathology</subject><subject>Lung diseases</subject><subject>Mannitol - administration & dosage</subject><subject>Mannitol - pharmacology</subject><subject>Medicine and Health Sciences</subject><subject>Membranes</subject><subject>Microbial drug resistance</subject><subject>Mucous Membrane - drug effects</subject><subject>Multidrug resistance</subject><subject>Multidrug resistant organisms</subject><subject>Multiple sclerosis</subject><subject>Nebulizers and Vaporizers</subject><subject>Oxygen</subject><subject>Peak pressure</subject><subject>Peptides</subject><subject>Pharmaceuticals</subject><subject>Physical Sciences</subject><subject>Physiological aspects</subject><subject>Pressure</subject><subject>Pseudomonas aeruginosa</subject><subject>Research and Analysis Methods</subject><subject>Respiration</subject><subject>Respiratory therapy</subject><subject>Respiratory tract</subject><subject>Respiratory tract 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peptides</topic><topic>Bacteria</topic><topic>Biochemistry</topic><topic>Biofilms</topic><topic>Biological membranes</topic><topic>Biology and Life Sciences</topic><topic>Bronchi - drug effects</topic><topic>Bronchi - microbiology</topic><topic>Bronchi - pathology</topic><topic>Bronchoconstriction</topic><topic>Bronchoconstriction - drug effects</topic><topic>Bronchopulmonary infection</topic><topic>Clinical medicine</topic><topic>Copolymer 1</topic><topic>Cystic fibrosis</topic><topic>Drug approval</topic><topic>EDTA</topic><topic>Engineering and Technology</topic><topic>Female</topic><topic>Food</topic><topic>Glatiramer acetate</topic><topic>Glatiramer Acetate - administration & dosage</topic><topic>Glatiramer Acetate - pharmacology</topic><topic>Gram-negative bacteria</topic><topic>Gram-Negative Bacteria - drug effects</topic><topic>Health 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Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Skovdal, Sandra M</au><au>Christiansen, Stig Hill</au><au>Johansen, Karen Singers</au><au>Viborg, Ole</au><au>Bruun, Niels Henrik</au><au>Jensen-Fangel, Søren</au><au>Holm, Ida Elisabeth</au><au>Vorup-Jensen, Thomas</au><au>Petersen, Eskild</au><au>Cartelle Gestal, Monica</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhaled nebulized glatiramer acetate against Gram-negative bacteria is not associated with adverse pulmonary reactions in healthy, young adult female pigs</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2019-10-10</date><risdate>2019</risdate><volume>14</volume><issue>10</issue><spage>e0223647</spage><epage>e0223647</epage><pages>e0223647-e0223647</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The developmental speed of new antimicrobials does not meet the emergence of multidrug-resistant bacteria sufficiently. A potential shortcut is assessing the antimicrobial activity of already approved drugs. Intrudingly, the antibacterial action of glatiramer acetate (GA) has recently been discovered. GA is a well-known and safe immunomodulatory drug particular effective against Gram-negative bacteria, which disrupts biological membranes by resembling the activity of antimicrobial peptides. Thus, GA can potentially be included in treatment strategies used to combat infections caused by multidrug-resistant Gram-negatives. One potential application is chronic respiratory infections caused by Pseudomonas aeruginosa, however the safety of GA inhalation has never been assessed. Here, the safety of inhaling nebulized GA is evaluated in a preclinical pig model. The potential side effects, i.e., bronchoconstriction, respiratory tract symptoms and systemic- and local inflammation were assessed by ventilator monitoring, clinical observation, biochemistry, flowcytometry, and histopathology. No signs of bronchoconstriction assessed by increased airway peak pressure, Ppeak, or decreased oxygen pressure were observed. Also, there were no signs of local inflammation in the final histopathology examination of the pulmonary tissue. As we did not observe any potential pulmonary side effects of inhaled GA, our preliminary results suggest that GA inhalation is safe and potentially can be a part of the treatment strategy targeting chronic lung infections caused by multidrug-resistant Gram-negative bacteria.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>31600340</pmid><doi>10.1371/journal.pone.0223647</doi><tpages>e0223647</tpages><orcidid>https://orcid.org/0000-0003-2602-197X</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2019-10, Vol.14 (10), p.e0223647-e0223647 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_2303979370 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Administration, Inhalation Animal welfare Animals Anti-infective agents Antibacterial agents Antibiotics Antimicrobial activity Antimicrobial agents Antimicrobial peptides Bacteria Biochemistry Biofilms Biological membranes Biology and Life Sciences Bronchi - drug effects Bronchi - microbiology Bronchi - pathology Bronchoconstriction Bronchoconstriction - drug effects Bronchopulmonary infection Clinical medicine Copolymer 1 Cystic fibrosis Drug approval EDTA Engineering and Technology Female Food Glatiramer acetate Glatiramer Acetate - administration & dosage Glatiramer Acetate - pharmacology Gram-negative bacteria Gram-Negative Bacteria - drug effects Health aspects Histochemistry Histopathology Hospitals Immunology Immunomodulation Infection Infectious diseases Inflammation Inhalation Laboratories Leukocyte Count Lung - drug effects Lung - microbiology Lung - pathology Lung diseases Mannitol - administration & dosage Mannitol - pharmacology Medicine and Health Sciences Membranes Microbial drug resistance Mucous Membrane - drug effects Multidrug resistance Multidrug resistant organisms Multiple sclerosis Nebulizers and Vaporizers Oxygen Peak pressure Peptides Pharmaceuticals Physical Sciences Physiological aspects Pressure Pseudomonas aeruginosa Research and Analysis Methods Respiration Respiratory therapy Respiratory tract Respiratory tract diseases Safety Side effects Swine Women's health Young adults Youth |
| title | Inhaled nebulized glatiramer acetate against Gram-negative bacteria is not associated with adverse pulmonary reactions in healthy, young adult female pigs |
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