Clinical Development of Sphingosine as Anti-Bacterial Drug: Inhalation of Sphingosine in Mini Pigs has no Adverse Side Effects

• Published in: Cellular physiology and biochemistry Vol. 53; no. 6; pp. 1015 - 1028
• Main Authors: Carstens, Henning, Schumacher, Fabian, Keitsch, Simone, Kramer, Melanie, Kühn, Claudine, Sehl, Carolin, Soddemann, Matthias, Wilker, Barbara, Herrmann, Daniel, Swaidan, Ashraf, Kleuser, Burkhard, Verhaegh, Rabea, Hilken, Gero, Edwards, Michael J, Dubicanac, Marko, Carpinteiro, Alexander, Wissmann, Andreas, Becker, Katrin Anne, Kamler, Markus, Gulbins, Erich
• Format: Journal Article
• Language: English
• Published: Germany Cell Physiol Biochem Press GmbH & Co KG 2019
• Subjects: Administration, Inhalation; Animals; Anti-Bacterial Agents - metabolism; Anti-Bacterial Agents - pharmacology; Bronchi - metabolism; Bronchi - pathology; Ceramides - analysis; Humans; Lung - pathology; Lysophospholipids - analysis; Mass Spectrometry; Pseudomonas aeruginosa - drug effects; Sphingosine - analogs & derivatives; Sphingosine - analysis; Sphingosine - metabolism; Sphingosine - pharmacology; Staphylococcus aureus - drug effects; Swine; Swine, Miniature; Trachea - metabolism; Trachea - pathology; Sphingosine; Inhalation; Lung; Side effects; Inflammation; Cell death
• ISSN: 1015-8987; 1421-9778
• DOI: 10.33594/000000194

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. 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. 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. 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.