Clinical Development of Sphingosine as Anti-Bacterial Drug: Inhalation of Sphingosine in Mini Pigs has no Adverse Side Effects.
Clinical Development of Sphingosine as Anti-Bacterial Drug: Inhalation of Sphingosine in Mini Pigs has no Adverse Side Effects.
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DOI：
10.33594/000000194
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发表时间：
2019-01-01
期刊：
影响因子：
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通讯作者：
Gulbins, Erich
中科院分区：
文献类型：
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作者：
Carstens, Henning;Schumacher, Fabian;Gulbins, Erich
背景/目的：铜绿假单胞菌或金黄色葡萄球菌肺部感染。金黄色葡萄球菌）在患有囊性纤维化、慢性阻塞性肺病的患者中、在创伤和烧伤后、在通气时或在免疫受损的患者中具有最大的临床相关性。铜绿假单胞菌和S.金黄色葡萄球菌菌株对许多已知的抗生素具有抗性，并且很难或常常不可能根除患者肺部的病原体。我们最近已经表明，鞘氨醇非常有效地杀死许多病原体，包括例如铜绿假单胞菌、S。金黄色葡萄球菌或鲍曼不动杆菌。我们小组对囊性纤维化小鼠进行的体内实验表明，吸入鞘氨醇可预防或消除现有的铜绿假单胞菌或链球菌急性或慢性肺炎。金黄色葡萄球菌。我们还证明了鞘氨醇吸入高剂量是安全的，至少在小鼠中是如此。为了促进鞘氨醇的发展，一种抗杀菌药物，可用于人类的吸入，非啮齿类动物的安全数据，较大的动物是绝对requirement.METHODS：在这里，我们吸入小型猪增加剂量的鞘氨醇10天，并分析了吸收鞘氨醇到支气管上皮细胞，以及进入气管和肺和体循环。此外，我们测量的神经酰胺和鞘氨醇1-磷酸，可能介导的炎症，白细胞的流入，上皮细胞死亡和破坏的上皮细胞barrier.RESULTS：我们表明，吸入鞘氨醇的结果增加鞘氨醇在支气管和气管的管腔膜的水平，但不是在全身积累。吸入鞘氨醇没有副作用，非常高的doses.CONCLUSION：总之，我们表明，吸入鞘氨醇的结果增加鞘氨醇浓度在气管和支气管上皮细胞的管腔质膜。吸入无全身或局部副作用。
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 patients 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.