Abstract
BackgroundN-chlorotaurine, a long-lived oxidant produced by human leukocytes, can be applied in human medicine as an endogenous antiseptic. Its antimicrobial activity can be enhanced by ammonium chloride. This study was designed to evaluate the tolerability of inhaled N-chlorotaurine (NCT) in the pig model.MethodsAnesthetized pigs inhaled test solutions of 1% (55 mM) NCT (n = 7), 5% NCT (n = 6), or 1% NCT plus 1% ammonium chloride (NH4Cl) (n = 6), and 0.9% saline solution as a control (n = 7), respectively. Applications with 5 ml each were performed hourly within four hours. Lung function, haemodynamics, and pharmacokinetics were monitored. Bronchial lavage samples for captive bubble surfactometry and lung samples for histology and electron microscopy were removed.ResultsArterial pressure of oxygen (PaO2) decreased significantly over the observation period of 4 hours in all animals. Compared to saline, 1% NCT + 1% NH4Cl led to significantly lower PaO2 values at the endpoint after 4 hours (62 ± 9.6 mmHg vs. 76 ± 9.2 mmHg, p = 0.014) with a corresponding increase in alveolo-arterial difference of oxygen partial pressure (AaDO2) (p = 0.004). Interestingly, AaDO2 was lowest with 1% NCT, even lower than with saline (p = 0.016). The increase of pulmonary artery pressure (PAP) over the observation period was smallest with 1% NCT without difference to controls (p = 0.91), and higher with 5% NCT (p = 0.02), and NCT + NH4Cl (p = 0.05).Histological and ultrastructural investigations revealed no differences between the test and control groups. The surfactant function remained intact. There was no systemic resorption of NCT detectable, and its local inactivation took place within 30 min. The concentration of NCT tolerated by A549 lung epithelial cells in vitro was similar to that known from other body cells (0.25–0.5 mM).ConclusionThe endogenous antiseptic NCT was well tolerated at a concentration of 1% upon inhalation in the pig model. Addition of ammonium chloride in high concentration provokes a statistically significant impact on blood oxygenation.
Highlights
N-chlorotaurine, a long-lived oxidant produced by human leukocytes, can be applied in human medicine as an endogenous antiseptic
Subcultures were grown in 96 well microtitre plates, washed two times with PBS and incubated in 100 μl PBS containing 0.1 – 55 mM (0.002 – 1.0%) NCT, 0.1 – 1 mM NCT plus 0.37 – 3.74 mM (0.02 – 0.002%) ammonium chloride for 30 min at 37°C and pH 7.4
Haemodynamics Pulmonary artery pressure as a further highly sensitive parameter for functional pulmonary disorders increased over the observation period in all animals. 1% NCT showed the smallest increase of pulmonary artery pressure (PAP) without difference to saline (p = 0.9), while it was higher after 4 hours with 5% NCT (p = 0.02) and NCT + NH4Cl (p = 0.05) (Figure 3)
Summary
N-chlorotaurine, a long-lived oxidant produced by human leukocytes, can be applied in human medicine as an endogenous antiseptic. N-chlorotaurine (Cl-HN-CH2-CH2-SO3-), the N-chloro derivative of the amino acid taurine, is a long-lived oxidant produced by activated human granulocytes and monocytes [1], and in low concentration probably in macrophages [2]. It is the main representative of chloramines, i.e. oxidizing R-NHCl compounds, created during the oxidative burst [3]. A 90% stability of both the pure product and the aqueous solution at 2–4°C per year makes it suitable for practical use [6] This facilitated a comprehensive investigation of its antimicrobial properties. Studies disclosed broad spectrum bactericidal (Gram-positive and Gram-negative bacteria), fungicidal (yeasts and moulds) and virucidal activity of NCT [7,8,9,10] without development of resistance [7]
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