Therapeutic preventative for pulmonary oxygen toxicity

Oral inhalation of tiotropium bromide within 24 hours before a dive or decompression therapy session prevents the onset and development of PO2T

Medical & Biotechnology

U.S. Navy scientists have recently tested tiotropium bromide for the prevention of pulmonary oxygen toxicity (PO2T). The patent-pending technology is available via license agreement to companies that would make, use, or sell it commercially.

Exposure to enriched levels of oxygen can be dangerous to divers, astronauts, and patients undergoing hyperbaric treatment after relatively short periods of time. The pulmonary toxic effect of oxygen can arise after exposure to oxygen greater than 0.5 atmospheres absolute (ATA), the clinical features of which include (a) tracheobronchitis (b) exudative phase (c) proliferative phase. Tracheobronchitis is characterized by a reduction in pulmonary vital capacity and the onset of symptoms such as fatigue, burning upon inspiration, and cough. The exudative phase is characterized by lung injury, pulmonary edema, and alveoli collapse. The proliferative phase is characterized by immune cell infiltration, pulmonary fibrosis, and hemorrhage.

Studies at the Navy Experimental Diving Unit have demonstrated that more than 40% of divers had a diminished pulmonary function after a six-hour in-water dive at 1.3 ATA. Further, 33% of subjects in that study complained of symptoms such as cough, tracheal burning and chest tightness. Not always in association with the overt symptoms, almost 60% of the divers showed adverse effects of the dives.

Navy researchers have now identified and studied a pharmacologic agent and protocol which can mitigate PO2T. Treatment comprises prophylactic administration of an anticholinergic including salts of tiotropium, oxitropium, flutropium, ipratropium, glycopyrronium, and trospium. The therapeutic is administered prior (preferably 24 hours prior) to exposure to an enriched oxygen environment via oral inhalation and prevents the onset of tracheobronchitis and decrements in pulmonary compliance due to PO2T.

As a method of action, anticholinergic agents, such as tiotropium bromide, can directly block parasympathetic afferent nerve fibers through selective muscarinic antagonism. Tiotropium bromide acts mainly on M3 muscarinic receptors located on smooth muscle cells and submucosal glands. This leads to a reduction in smooth muscle contraction, and mucus secretion, and thus produces a bronchodilatory effect. Interestingly, tiotropium bromide is also known to reduce airway reactivity and cough by inhibiting transient receptor potential (TRP) channels. As such, tiotropium bromide makes a unique and promising candidate for the prevention of PO2T owing to its ability to target both the TRP and anti-muscarinic receptors.

Tiotropium bromide is currently marketed as Spiriva®, by Boehringer Ingelheim Pharmaceuticals as a long-acting, 24-hour, anticholinergic bronchodilator used in the management of chronic obstructive pulmonary disease (COPD) and asthma.

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