Tolerability of inhaled N-chlorotaurine in the pig model

<p>Abstract</p> <p>Background</p> <p>N-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.</p> <p>Methods</p> <p>Anesthetized 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.</p> <p>Results</p> <p>Arterial 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 PaO₂values 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, AaDO₂was 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).</p> <p>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 <it>in vitro </it>was similar to that known from other body cells (0.25–0.5 mM).</p> <p>Conclusion</p> <p>The 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.</p

Tolerability of inhaled N-chlorotaurine in humans: a double-blind randomized phase I clinical study

Background: N-chlorotaurine (NCT), a long-lived oxidant produced by human leukocytes, can be synthesized chemically and used topically as a well-tolerated antiseptic to different body regions including sensitive ones. The aim of this study was to test the tolerability of inhaled 1% NCT in aqueous solution upon repeated application. Methods: The study was performed double-blind and randomized with a parallel test group (1% NCT) and control group (0.9% NaCl as placebo). There were two Austrian centres involved, the hospitals, Natters and Vöcklabruck. Healthy, full age volunteers were included, 12 in each centre. A total of 12 patients were treated with NCT, and 12 with placebo, exactly half of each group from each centre. The single dose was 1.2 ml inhaled over a period of 10 min using an AKITA JET nebulizer. One inhalation was done every day for five consecutive days. The primary criterion of evaluation was the forced expiratory volume in 1 second (FEV 1 ). Secondary criteria were subjective sensations, further lung function parameters such as airway resistance, physical examination, and blood analyses (gases, electrolytes, organ function values, pharmacokinetic parameters taurine and methionine, immune parameters). Results: All included 15 females and 9 males completed the treatment and the control examinations according to the study protocol. FEV 1 (100.83% ± 8.04% for NCT and 92.92% ± 11.35% for controls) remained unchanged and constant during the treatment and in control examinations 1 week and 3 months after the treatment (98.75% ± 7.37% for NCT and 91.17% ± 9.46% for controls, p > 0.082 between time points within each group). The same was true for all other objective parameters. Subjective mild sensations with a higher frequency in the test group were chlorine taste ( p < 0.01) and occasional tickle in the throat ( p = 0.057). Taurine and methionine plasma concentrations did not change within 60 min after inhalation or later on. Conclusions: Inhaled NCT is well tolerated as in other applications of different body regions. Side effects are mild, topical and transitory. The study was registered prospectively in the European Clinical Trials Database of the European Medicines Agency. The EudraCT number is 2012-003700-12