Chemistry: analytical and immunological testing – Nitrogen containing – Oxides of nitrogen
Patent
1996-01-05
1999-07-13
Le, Long V.
Chemistry: analytical and immunological testing
Nitrogen containing
Oxides of nitrogen
436181, 436106, 422 83, 422 84, 422 93, 600532, G01N 3300, G01N 33497
Patent
active
059226102
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
See the title. The invention is based on the fact, that for mammals, including humans, the level of nitric oxide (NO) in exhaled air of a mammal (including human) is indicative of certain disorders (diseases) including risks for acquiring them. This concept has now been shown useful at least for the diagnosis of inflammatory conditions of the airways, such as allergic asthma and rhinitis, and respiratory tract infections in humans, and Kartagener's syndrome. In particular infections in the lower respiratory tract may be diagnosed.
The measuring principle employed has indicated that NO production in normal human airways is restricted to the upper airways, specifically the nasal sinuses. It has also been shown that NO is produced in the stomach.
By airways is meant the conducting airways from the nostrils down to the respiratory bronchioles, containing mucosal tissue; and the nasal sinuses.
BACKGROUND
Over the last decade several approaches to the biological role of nitric oxide (NO) have been made. The synthesis of NO, which is catalysed by specialized NO synthases using L-arginine as a substrate, has now been shown to take place in many cell types (Nathan C., FASEB J. 6 (1992) 3051-64). The NO synthase exists in several isotypes that can be divided into two major classes: constitutive and inducible. The constitutive isotypes have been described in endothelial cells (Moncada S. et al., Pharmacol. Rev. 43 (1991) 109-42) and for instance in parasympathetic vasodilator nerves (Kummer W. et al., Neuroreport 3 (1992) 653-55). The inducible isotypes are found, after activation, in macrophages, neutrophils, endothelium, vascular smooth muscle (Moncada S. et al., Pharmacol. Rev. 43 (1991) 109-42) and even epithelium in the airways of asthmatic subjects (Springall et al., Am. Rev. Resp. Dis. 147 (1993) A515). The production of NO has so far been difficult to measure directly in vivo, although increases in the end-products nitrite and nitrate in plasma and urine can be used in some cases (Archer S., FASEB J. 7 (1992) 349-360). Recently, it was shown, however, that NO can be found in parts per billion (p.p.b.) levels in exhaled air of experimental animals and humans (Gustafsson L. E. et al., Biochem. Biophys. Res. Commun. 181 (1992) 852-7). Gustafsson et al have measured NO levels either by connecting a chemiluminescence detector to the exhaled air or by bubbling the exhaled air through a solution in which NO was chemically trapped. The human experiments appear to have been performed on one single individual who was allowed to inhale through the nose and exhale through the mouth. The relatively high NO level Gustafsson et al. have obtained compared to ours might be explained by passage of NO into the inhaled air when it passes through the nose. In a later publication Persson M. G. and Gustafsson L. E. have reported that ethanol intake will reduce NO formation as measured in exhaled air of rabbits (Eur. J. Pharmacol. 224 (1992) 99-100). Gustafsson L. E. himself has also suggested that measured NO levels in exhaled air may be used to check lung function (WO-A-9305709 and SE-91032433). The works of Gustafsson L. E. et al appears to be the closest prior art. During the priority year, data on increased levels of NO in exhaled air of asthmatic patients and decreased levels smokers have been published (Alving K. et al., Eur. Resp. J. 6 (October, 1993) 1368-70; Hamid Q. et al., Lancet 342 (December 1993) 1510-13; Karithonov S. A. et al., Lancet 343 (January 1994) 133-35; and Persson M. G et al., Lancet 343 (January 1994) 146-7.
THE OBJECTIVES OF THE INVENTION
A first and main objective of the invention is to provide utilities for earlier findings that endogenously produced nitric oxide (NO) can be detected in exhaled breathing air.
A second objective is to provide improved systems for the measurement of NO levels in exhaled air.
A third objective is improved and more reliable diagnostic methods for disorders (diseases) that are associated with an abnormal NO level in exhaled air. At the priority date, w
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Alving Kjell
Lundberg Jan
Weitzberg Edward
Aerocrine AB
Le Long V.
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