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Research ArticleToxicology

A Preclinical Safety Study of Thyroid Hormone Instilled into the Lungs of Healthy Rats—an Investigational Therapy for ARDS

Craig M. Flory, Beverly J. Norris, Nicole A. Larson, Lia G. Coicou, Brenda L. Koniar, Margaret A. Mysz, Timothy P. Rich, David H. Ingbar and Robert J. Schumacher
Journal of Pharmacology and Experimental Therapeutics January 2021, 376 (1) 74-83; DOI: https://doi.org/10.1124/jpet.120.000060
Craig M. Flory
Pulmonology, Allergy, Critical Care and Sleep Medicine Division (T.P.R., D.H.I.), Center for Translational Medicine (C.M.F., B.J.N., N.A.L., L.G.C., B.L.K., M.A.M., R.J.S.), University of Minnesota, Minneapolis, Minnesota and Department of Pulmonary, Critical Care, Sleep Medicine and Respiratory Care, Essentia Health, Duluth, Minnesota (T.P.R.)
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Beverly J. Norris
Pulmonology, Allergy, Critical Care and Sleep Medicine Division (T.P.R., D.H.I.), Center for Translational Medicine (C.M.F., B.J.N., N.A.L., L.G.C., B.L.K., M.A.M., R.J.S.), University of Minnesota, Minneapolis, Minnesota and Department of Pulmonary, Critical Care, Sleep Medicine and Respiratory Care, Essentia Health, Duluth, Minnesota (T.P.R.)
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Nicole A. Larson
Pulmonology, Allergy, Critical Care and Sleep Medicine Division (T.P.R., D.H.I.), Center for Translational Medicine (C.M.F., B.J.N., N.A.L., L.G.C., B.L.K., M.A.M., R.J.S.), University of Minnesota, Minneapolis, Minnesota and Department of Pulmonary, Critical Care, Sleep Medicine and Respiratory Care, Essentia Health, Duluth, Minnesota (T.P.R.)
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Lia G. Coicou
Pulmonology, Allergy, Critical Care and Sleep Medicine Division (T.P.R., D.H.I.), Center for Translational Medicine (C.M.F., B.J.N., N.A.L., L.G.C., B.L.K., M.A.M., R.J.S.), University of Minnesota, Minneapolis, Minnesota and Department of Pulmonary, Critical Care, Sleep Medicine and Respiratory Care, Essentia Health, Duluth, Minnesota (T.P.R.)
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Brenda L. Koniar
Pulmonology, Allergy, Critical Care and Sleep Medicine Division (T.P.R., D.H.I.), Center for Translational Medicine (C.M.F., B.J.N., N.A.L., L.G.C., B.L.K., M.A.M., R.J.S.), University of Minnesota, Minneapolis, Minnesota and Department of Pulmonary, Critical Care, Sleep Medicine and Respiratory Care, Essentia Health, Duluth, Minnesota (T.P.R.)
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Margaret A. Mysz
Pulmonology, Allergy, Critical Care and Sleep Medicine Division (T.P.R., D.H.I.), Center for Translational Medicine (C.M.F., B.J.N., N.A.L., L.G.C., B.L.K., M.A.M., R.J.S.), University of Minnesota, Minneapolis, Minnesota and Department of Pulmonary, Critical Care, Sleep Medicine and Respiratory Care, Essentia Health, Duluth, Minnesota (T.P.R.)
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Timothy P. Rich
Pulmonology, Allergy, Critical Care and Sleep Medicine Division (T.P.R., D.H.I.), Center for Translational Medicine (C.M.F., B.J.N., N.A.L., L.G.C., B.L.K., M.A.M., R.J.S.), University of Minnesota, Minneapolis, Minnesota and Department of Pulmonary, Critical Care, Sleep Medicine and Respiratory Care, Essentia Health, Duluth, Minnesota (T.P.R.)
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David H. Ingbar
Pulmonology, Allergy, Critical Care and Sleep Medicine Division (T.P.R., D.H.I.), Center for Translational Medicine (C.M.F., B.J.N., N.A.L., L.G.C., B.L.K., M.A.M., R.J.S.), University of Minnesota, Minneapolis, Minnesota and Department of Pulmonary, Critical Care, Sleep Medicine and Respiratory Care, Essentia Health, Duluth, Minnesota (T.P.R.)
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Robert J. Schumacher
Pulmonology, Allergy, Critical Care and Sleep Medicine Division (T.P.R., D.H.I.), Center for Translational Medicine (C.M.F., B.J.N., N.A.L., L.G.C., B.L.K., M.A.M., R.J.S.), University of Minnesota, Minneapolis, Minnesota and Department of Pulmonary, Critical Care, Sleep Medicine and Respiratory Care, Essentia Health, Duluth, Minnesota (T.P.R.)
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Abstract

Acute respiratory distress syndrome (ARDS) is a severe, life-threatening form of respiratory failure characterized by pulmonary edema, inflammation, and hypoxemia due to reduced alveolar fluid clearance (AFC). Alveolar fluid clearance is required for recovery and effective gas exchange, and higher rates of AFC are associated with reduced mortality. Thyroid hormones play multiple roles in lung function, and L-3,5,3′-triiodothyronine (T3) has multiple effects on lung alveolar type II cells. T3 enhances AFC in normal adult rat lungs when administered intramuscularly and in normal or hypoxia-injured lungs when given intratracheally. The safety of a commercially available formulation of liothyronine sodium (synthetic T3) administered intratracheally was assessed in an Investigational New Drug Application–enabling toxicology study in healthy rats. Instillation of the commercial formulation of T3 without modification rapidly caused tracheal injury and often mortality. Intratracheal instillation of T3 that was reformulated and brought to a neutral pH at the maximum feasible dose of 2.73 µg T3 in 300 µl for 5 consecutive days had no clinically relevant T3-related adverse clinical, histopathologic, or clinical pathology findings. There were no unscheduled deaths that could be attributed to the reformulated T3 or control articles, no differences in the lung weights, and no macroscopic or microscopic findings considered to be related to treatment with T3. This preclinical safety study has paved the way for a phase I/II study to determine the safety and tolerability of a T3 formulation delivered into the lungs of patients with ARDS, including coronavirus disease 2019–associated ARDS, and to measure the effect on extravascular lung water in these patients.

SIGNIFICANCE STATEMENT There is growing interest in treating lung disease with thyroid hormone [triiodothyronine (T3)] in pulmonary edema and acute respiratory distress syndrome (ARDS). However, there is not any published experience on the impact of direct administration of T3 into the lung. An essential step is to determine the safety of multiple doses of T3 administered in a relevant animal species. This study enabled Food and Drug Administration approval of a phase I/II clinical trial of T3 instillation in patients with ARDS, including coronavirus disease 2019–associated ARDS (T3-ARDS ClinicalTrials.gov Identifier NCT04115514).

Footnotes

    • Received April 20, 2020.
    • Accepted October 20, 2020.
  • This study was funded by the University of Minnesota Center for Translational Medicine.

  • Primary laboratory of origin: (Center for Translational Medicine, University of Minnesota, Minneapolis, MN).

  • Author Disclosure Statement: R.J.S., T.P.R. and D.H.I. are inventors on a pending patent related to this work. For C.M.F., B.J.N., N.A.L., L.G.C., B.L.K. and M.A.M., no competing financial interests exist.

  • https://doi.org/10.1124/jpet.120.000060.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 376 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 1
1 Jan 2021
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Research ArticleToxicology

Preclinical Safety of Lung Instillation of Thyroid Hormone

Craig M. Flory, Beverly J. Norris, Nicole A. Larson, Lia G. Coicou, Brenda L. Koniar, Margaret A. Mysz, Timothy P. Rich, David H. Ingbar and Robert J. Schumacher
Journal of Pharmacology and Experimental Therapeutics January 1, 2021, 376 (1) 74-83; DOI: https://doi.org/10.1124/jpet.120.000060

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Research ArticleToxicology

Preclinical Safety of Lung Instillation of Thyroid Hormone

Craig M. Flory, Beverly J. Norris, Nicole A. Larson, Lia G. Coicou, Brenda L. Koniar, Margaret A. Mysz, Timothy P. Rich, David H. Ingbar and Robert J. Schumacher
Journal of Pharmacology and Experimental Therapeutics January 1, 2021, 376 (1) 74-83; DOI: https://doi.org/10.1124/jpet.120.000060
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