Nitric oxide (NO, brand name Thiolanox) is a naturally occurring gas that, when inhaled, may reduce lung infections, leading to improved lung function in people with cystic fibrosis (CF). The gas possesses various biochemical characteristics, such as efficient broad spectrum anti-infective properties, as well as antimicrobial activity against gram-positive and gram-negative bacteria, yeast, fungi and viruses both in vitro and in vivo.

Thiolanox is an investigational drug product of Novoteris and is not approved for sale in the U.S.

How inhaled nitric oxide works to treat CF

Nitric oxide is one of the major signaling molecules in biological systems. It has been shown that it can promote the growth and activity of immune cells at low concentrations, while at higher concentrations it establishes connections with DNA, RNA, proteins, or lipids that contain iron or sulfur to inhibit or kill target pathogens. It also has lipophilic and hydrophilic properties that allow it to cross cell membranes and dissolve readily in water.

Inhaled NO has the ability to connect to hemoglobin, creating methemoglobin that has a very short half-life. Then it is converted to nitrites that are excreted in the urine within hours.

Nitric oxide is also a mucolytic and vasodilator. It is a muscle relaxant with an effective short-acting bronchodilator. This effect could contribute to the removal of secretions and maintain airway stillness.

Nitric oxide has also been seen to control ciliary beat frequency in the airways.

Administration of NO to the airways before or during lung infections may reduce viral load and, therefore, bacterial susceptibility. It can thin secretions, restore the mucociliary system, and increase removal of secretions.

During an infection, NO may improve oxygenation as well as local blood flow to the respiratory tract due to its vasodilatory effect. This increased blood flow could increase an influx of nutrients and white blood cells while also increasing local temperature, all of which are useful for the resolution of an infection.

Nitric oxide studies

A Phase 2 study (NCT02498535), not yet open for recruitment, will evaluate the effectiveness and safety of inhaled NO in people with CF. The trial will be a prospective, randomized, placebo-controlled study involving participants changing from an approved inhaled antibiotic to inhaled nitric oxide as compared to a placebo control arm. The primary objectives will be the comparison of the mean absolute change in FEV1 (a measure of lung function) from the beginning of the study until the 15th day between treatment groups.

The inhaled antimicrobial effect in people with CF during pilot studies has resulted in improved lung function. It may also have other benefits for people with CF including anti-inflammatory, muscle-relaxant, and secretion-thinning effects.

The pharmacology, toxicity, and safety data for inhaled NO in humans for other applications have been well defined in other approved drugs in Europe, Canada, the U.S., and in other studies.

The reduction of bacteria identified in people with CF infections has been shown to be safe and effective in a Phase 1 study in 10 healthy participants.

An open-label nonrandomized controlled study in eight adults with CF with a primary endpoint of establishing safety confirmed that nitric oxide therapy is safe and lacks serious adverse effects. It also showed changes to bacterial or fungal load and change in lung function (FEV1) at the end of the treatment.

Based on laboratory tests, in vivo models, and healthy human data, NO is administered in 30-minute sessions, three to five times a day for multiple days at a dose 160 ppm.

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