Tolerability of inhaled N-chlorotaurine in the pig model.
BACKGROUND
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.


METHODS
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.


RESULTS
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 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).


CONCLUSIONS
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.
Geiger
Ralf
R
Department of Hygiene, Microbiology and Social Medicine, Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Innsbruck, Austria. Ralf.Geiger@i-med.ac.at
Treml
Benedikt
B
Pinna
Anna
A
Barnickel
Linn
L
Prossliner
Harald
H
Reinstadler
Hannes
H
Pilch
Michael
M
Hauer
Maria
M
Walther
Christoph
C
Steiner
Hans-Jörg
HJ
Giese
Thomas
T
Wemhöner
Andreas
A
Scholl-Bürgi
Sabine
S
Gottardi
Waldemar
W
Arnitz
Roland
R
Sergi
Consolato
C
Nagl
Markus
M
Löckinger
Alexander
A
D000280:Administration, Inhalation; D000643:Ammonium Chloride / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000818:Animals; D000891:Anti-Infective Agents, Local / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D001794:Blood Pressure / Q000502:physiology; D045853:Exhalation / Q000502:physiology; D023421:Models, Animal; D015656:Respiratory Mechanics / Q000502:physiology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000502:physiology*; D013552:Swine; D013654:Taurine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D013990:Tidal Volume / Q000502:physiology
D000891:Anti-Infective Agents, Local; D000643:Ammonium Chloride; D013654:Taurine; C043410:N-chlorotaurine