Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1997-02-18
1999-10-19
Kunz, Gary L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514 47, 514261, 514264, 514740, 514851, C07H 19167, C07H 1920, A01N 4390
Patent
active
059689110
DESCRIPTION:
BRIEF SUMMARY
Throughout this application, various references are referred to within parentheses or by arabic numberals. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains. Where not given in the text, full bibliographic citations for these references may be found at the end of each section, preceding the claims.
BACKGROUND OF THE INVENTION
Pulmonary hypertension is associated with significant morbidity and mortality, yet therapeutic options remain limited because agents which lower pulmonary vascular resistance (PVR) also lower systemic vascular resistance (SVR) (1). Nitric oxide (NO) gas has recently been shown to selectively lower PVR in pulmonary hypertension (2,3), but concerns remain involving its potential chromosomal effects (4), formation of toxic products from reaction with oxygen (4,5), logistic difficulties associated with delivery of a gas, and its short biological half-life, necessitating constant administration for continued effect (3,6).
Initial observations dealing with the use of cAMP and cGMP compounds go back to models of heart transplantation, where it was demonstrated that these systems were dysfunctional in the blood vessels of a transplanted heart. Supplementation of either the cGMP or the cAMP pathways could enhance the function of blood vessels within the graft, promoting successful transplantation. Stimulators of cAMP pathway used in these experiments included Sp-cAMPs, 8-Br-cAMP, db-cAMP, and phosphodiesterase inhibitors (indolidan, rolipram), all of which helped graft preservation. An antagonist of this pathway (RpcAMPS) blocked the beneficial effects of 8-Br-cAMP.
Nitric oxide is formed by cells lining blood vessels from the amino acid L-arginine, and leads to the formation of cGMP in the nearby cells. In the transplantation model, compounds which give off NO (nitroglycerin, nitroprusside), the NO precursor L-arginine, or 8-Br-cGMP (which acts like native cGMP but is capable of passing through cell membranes and therefore getting into cells) similarly benefitted heart preservation.
Both pathways (cAMP and cGMP) seemed to be dysfunctional in the setting of transplantation because of their roles in maintaining proper blood vessel function. Beneficial effects included improving blood flow, reducing damaging white blood cell infiltrations into blood vessels, preventing blood vessel leakiness, and preventing blood clot formation. The basis for these effects have been described in numerous basic science papers elsewhere, in which the roles of these compounds on these functions had been studied. Experiments performed in the context of lung transplantation indicated that these same beneficial effects were found in the blood vessels of the lungs.
SUMMARY OF THE INVENTION
This invention provides a method of decreasing pulmonary vascular resistance in a subject which comprises administering endotracheally or endobronchially an effective amount of a drug selected from the group consisting of cyclic nucleotides, phosphodiesterase inhibitors, nitric oxide precursors, nitric oxide donors, and nitric oxide analogs, thereby decreasing pulmonary vascular resistance.
This invention provides a method of selectively decreasing pulmonary vascular resistance in a subject which comprises administering endotracheally or endobronchially an effective amount of a drug selected from the group consisting of cyclic nucleotides, phosphodiesterase inhibitors, nitric oxide precursors, nitric oxide donors, and nitric oxide analogs, thereby decreasing pulmonary vascular resistance.
DESCRIPTION OF THE FIGURES
FIGS. 1A-1C: Establishment of pulmonary hypertension in three porcine models. (A) The thromboxane (Tx) A.sub.2 analog 9,11-dideoxy-11.alpha.,9.alpha.-epoxymethanoprostaglandin F.sub.2.alpha. was infused intravenously (n=9) initially at 0.1 .mu.g/kg/min, and titered until a stable mean PA pressure of 30 mmHg was reached, after which no dosage adjustments were made. Bar graphs r
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A.G. Gilman, et al., "Goodman and Gilman's The Pharmacological Basis of Therapeutics", Published 1980 by Macmillan Publishing Co., Inc. (N.Y.)592-607 Archer, et al. J. Appl. Physiol. (1990) 68(2):735-747.
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Lawson, et al., abstract presented at American Heart Association Meeting, Atlanta, Georgia, Nov. 8-11, 1993; and Rossaint, et al. The New England Journal of Medicine (Feb. 11, 1993) 328(6):399-405.
Lawson Charles A.
Pinsky David J.
Smerling Arthur
Stern David M.
Kunz Gary L.
The Trustees of Columbia University in the City of New York
White John P.
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