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. 2019 Oct 10;14(10):e0223647.
doi: 10.1371/journal.pone.0223647. eCollection 2019.

Inhaled nebulized glatiramer acetate against Gram-negative bacteria is not associated with adverse pulmonary reactions in healthy, young adult female pigs

Sandra M Skovdal  1   2   3 , Stig Hill Christiansen  4 , Karen Singers Johansen  5 , Ole Viborg  6 , Niels Henrik Bruun  7 , Søren Jensen-Fangel  2 , Ida Elisabeth Holm  8 , Thomas Vorup-Jensen  4 , Eskild Petersen  1   2
Affiliations

Inhaled nebulized glatiramer acetate against Gram-negative bacteria is not associated with adverse pulmonary reactions in healthy, young adult female pigs

Sandra M Skovdal et al. PLoS One. .

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.

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Conflict of interest statement

I have read the journal's policy and the authors of this manuscript have the following competing interests: SHC, EP, and TVJ are the inventors on the US patent #10166253 “Positively charged co-polymers for use as antimicrobial agents” and an identically entitled application to the European Patent Office (EP3185882A1) describing the use of GA as an antimicrobial agent. The patent is owned by Aarhus University and Region Midtjylland, Aarhus, Denmark, and licensed to Cycle Pharmaceuticals Ltd, Cambridge, UK. Neither the patent nor the mentioned application alters our adherence to all PLOS ONE policies on sharing data and materials. The other authors declare no competing interests.

Figures

Fig 1
Fig 1. Comparing the effect on Ppeak of GA inhaled with GA s.c. and mannitol.
Although there is a statistically significant larger effect for GA inhaled with respect to the effect of mannitol (confidence interval above red line at 0), both confidence intervals lay within the bounds of the measurement error (-2 and 2 cmH2O), red vertical lines), i.e. they are equivalent and clinically insignificant.
Fig 2
Fig 2. WBC counts by flow cytometry (mean, 95% CI).
Change in effect (POST—PRE) in blood cell counts compared for mannitol and GA s.c. vs. GA inhaled. Effect (POST—PRE) is the increase in blood cell count for mannitol, GA s.c., and GA inhaled. The effects are compared as differences between mannitol and GA inhaled, as well as differences between GA s.c. and GA inhaled. The red line at zero should be within the shown confidence intervals if there are no difference between mannitol and GA inhaled (above); or GA s.c. and GA inhaled (below). * p < 0.05; ** p < 0.01.
See this image and copyright information in PMC

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