Clinical Development of Sphingosine as Anti-Bacterial Drug: Inhalation of Sphingosine in Mini Pigs has no Adverse Side Effects
| Autor: | Burkhard Kleuser, Fabian Schumacher, Katrin Anne Becker, Simone Keitsch, Daniel Herrmann, Matthias Soddemann, Rabea Verhaegh, Claudine Kühn, Erich Gulbins, Ashraf Swaidan, Alexander Carpinteiro, Gero Hilken, Melanie Kramer, Barbara Wilker, Marko Dubicanac, A. Wissmann, Michael J. Edwards, Carolin Sehl, Henning Carstens, Markus Kamler |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Staphylococcus aureus Ceramide Swine Physiology Medizin Bronchi Inflammation Pharmacology Ceramides medicine.disease_cause Cystic fibrosis Mass Spectrometry lcsh:Physiology lcsh:Biochemistry 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Sphingosine In vivo Administration Inhalation medicine Animals Humans lcsh:QD415-436 Lung lcsh:QP1-981 Inhalation business.industry Pseudomonas aeruginosa medicine.disease Anti-Bacterial Agents Trachea 030104 developmental biology medicine.anatomical_structure chemistry 030220 oncology & carcinogenesis Swine Miniature Lysophospholipids medicine.symptom business |
| Zdroj: | Cellular Physiology and Biochemistry, Vol 53, Iss 6, Pp 1015-1028 (2019) |
| ISSN: | 1421-9778 1015-8987 |
| Popis: | BACKGROUND/AIMS: Pulmonary infections with Pseudomonas aeruginosa (P. aeruginosa) or Staphylococcus aureus (S. aureus) are of utmost clinical relevance in patients with cystic fibrosis, chronic obstructive pulmonary disease, after trauma and burn, upon ventilation or in immuno-compromised patients. Many P. aeruginosa and S. aureus strains are resistant to many known antibiotics and it is very difficult or often impossible to eradicate the pathogens in patient´s lungs. We have recently shown that the sphingoid base sphingosine very efficiently kills many pathogens, including for instance P. aeruginosa, S. aureus or Acinetobacter baumannii, in vitro. In vivo experiments of our group on cystic fibrosis mice indicated that inhalation of sphingosine prevents or eliminates existing acute or chronic pneumonia with P. aeruginosa or S. aureus in these mice. We also demonstrated that sphingosine is safe to use for inhalation up to high doses, at least in mice. To facilitate development of sphingosine to an anti-bactericidal drug that can be used in humans for inhalation, safety data on non-rodents, larger animals are absolutely required. METHODS: Here, we inhaled mini pigs with increasing doses of sphingosine for 10 days and analyzed the uptake of sphingosine into epithelial cells of bronchi as well as into the trachea and lung and the systemic circulation. Moreover, we measured the generation of ceramide and sphingosine 1-phosphate that potentially mediate inflammation, the influx of leukocytes, epithelial cell death and disruption of the epithelial cell barrier. RESULTS: We demonstrate that inhalation of sphingosine results in increased levels of sphingosine in the luminal membrane of bronchi and the trachea, but not in systemic accumulation. Inhaled sphingosine had no side effects up to very high doses. CONCLUSION: In summary, we demonstrate that inhalation of sphingosine results in an increase of sphingosine concentrations in the luminal plasma membrane of tracheal and bronchial epithelial cells. The inhalation has no systemic or local side effects. CA Gulbins |
| Databáze: | OpenAIRE |
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