Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form
Patent
1998-08-10
2000-04-18
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
424422, 424423, A61K 900
Patent
active
060512415
DESCRIPTION:
BRIEF SUMMARY
This invention relates to the use of a stable gaseous compound on a base of nitrogen monoxide (NO) and carbon dioxide (CO.sub.2) to produce a gaseous medication intended for the treatment or prevention, by the intra-abdominal route, of hypoperfusion of the abdominal organs, in particular, in the case of a procedure involving laparoscopy or laparosurgery.
Nitrogen monoxide is produced naturally in mammals by an enzyme, called NO-synthase, which is expressed in terms of its makeup by the endothelial cells, by the platelets, and by the central and peripheral nervous systems. Another form of calcium-independent NO-synthase can be induced by different stimuli (especially liposaccharides) in numerous cells, such as macrophages, lymphocytes, myocardial cells, endothelial cells, and the smooth muscular cells.
Nitrogen monoxide is an important biological messenger in mammals, and this molecule plays a decisive role in the local control of hemodynamics.
It has been possible to make evident the release of NO by means of the endothelial cells in the case of variations in the blood flow. Nitrogen monoxide appears especially as a major component of the physiological adaptation of the vascular diameter to blood perfusion: reactive hyperemia is thus attenuated in a most noticeable fashion on the coronary level. Conversely, a chronic increase in the blood flow, produced by an arteriovenous fistula, increases the dependent relaxations of the endothelium.
The capacity of nitrogen monoxide, produced at the level of the vascular wall and in the neighboring tissues, to regulate precisely the vascular tonus by adaptation of the blood flow is remarkable. Likewise, it has been assumed that the NO that is released during neuronal activity could regulate the tonus of cerebral microcirculation, thus linking the activity and the cerebral blood flow. We also recall the role played by NO in the regulation of the proliferation of smooth vascular muscle which is a decisive factor in vascular compliance.
Nitrogen monoxide furthermore controls the post-capillar venular permeability.
Nitrogen monoxide also participates in hormonal regulation mechanisms at the level of the kidney by inhibiting the release of renin, and on the cardiovascular level by opposing the release of the natriuretic factor (ANF).
Finally, in vivo, platelet activation is under the permanent control of endothelial nitrogen monoxide and, to a lesser degree, it is under the control of platelet NO-synthase itself. During aggregation, the platelets release nucleotides (ATP, ADP), serotonin, PAF, thromboxane A2, and vasopressin; they can also initiate the gush of coagulation by releasing thrombin. In response to ATP, ADP, serotonin, PAF, and thrombin, the endothelial cells release NO and prostacyclin, both of which act together to prevent and counter the process of platelet aggregation.
The abnormal decline in the nitrogen monoxide rate, observed in the case of numerous diseases, seems to confirm the importance of its role in the organism. Such a decline is characteristic of hypertension, hypercholesterolemia, atherosclerosis, and diabetes.
Likewise, a very early reduction of the basal release of NO would be the cause of problems related to the re-perfusion of ischemic areas, such as coronary thrombosis and vasospasms.
Various vasodilator agents have been developed so far on the basis of these findings. These substances, known as nitrovasodilators, produce NO in vivo and thus make up for a deficiency in the endogenous NO. By way of example, one might mention molsidomine or sodium nitroprussiate, which make it possible to prevent the phenomena of platelet adhesion and aggregation.
To make up for insufficient production of NO, there has even been a proposal for the administration of L-arginine or analogues of L-arginine, since L-arginine intervenes directly in the biosynthesis of nitrogen monoxide as a substrate of NO-synthase.
In view of the significant contribution made by nitrogen monoxide to the maintenance of a low pulmonary circulation pressure and the importance of the re
REFERENCES:
patent: 5443826 (1995-08-01), Borody
Briend Robert
Renaudin Marie-Helene
Benston, Jr. William E.
L'Air Liquide, Societe Anonyme pour L'Etude et L'Exploitation de
Page Thurman K.
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