Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-23
2002-11-05
Reamer, James H (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S262100, C514S253030, C514S565000
Reexamination Certificate
active
06476037
ABSTRACT:
CROSS-REFERENCE TO RELATED APPLICATIONS
[Not Applicable]
FIELD OF THE INVENTION
This invention relates the regulation of vascular hemodynamics in various pathologies. In particular this invention pertains to the discovery that L-arginine and type V phosphodiesterases act synergistically to inhibit vasospasm and/or to induce vasodilation.
BACKGROUND OF THE INVENTION
Impotence (erectile dysfunction) is the consistent inability to achieve or sustain an erection of sufficient rigidity for sexual intercourse. It has recently been estimated that approximately 10 million American men are impotent (Shabsigh et al. (1988)
Urology
32: 83-90; Furlow (1985)
Med Aspects Hum. Sex
. 19:13-16). Impotence is recognized to be an age-dependent disorder, with an incidence of 1.9 percent at 40 years of age and 25 percent at 65 years of age (Kinsey et al. (1948) pages 218-262 in
Sexual Behavior in the Human Male
; A. C. Kinsey et al., eds., Philadelphia, Pa.: W. B. Saunders). In 1985 in the United States, impotence accounted for more than several hundred thousand outpatient visits to physicians Rational Center for Health Statistics (National Hospital Discharge Survey, 1985, Bethesda, Md., Department of Health and Human Services, 1989 D-ES publication no. 87-1751). Depending on the nature and cause of the problem, treatments include psychosexual therapy, hormonal therapy, administration of vasodilators such as nitroglycerin and &agr;-adrenergic blocking agents (“&agr;-blockers-”), oral administration of other pharmaceutical agents, vascular surgery, implanted penile prostheses, vacuum constriction devices and external aids such as penile splints to support the penis or penile constricting rings to alter the flow of blood through the penis.
Recent approaches to the treatment of impotence involve the use of type V phosphodiesterase inhibitors (e.g. Viagra™) increase vasodilation. Viagra™, has demonstrated significant side effects. In addition, interaction with other systemically administered medications has posed substantial risks.
Vasodilators been of interest and some use in the management of heart disease, in particular in the management of perioperative myocardial ischemia and, in certain cases, in the management of acute myocardial infarction. One of the possible etiologies of perioperative myocardial ischemia is impaired endothelium-dependent coronary flow (Hasdai (1997)
Circulation
, 96(10): 3390-3395). Endothelial cells contribute to the control of local vascular tone by formation of nitric oxide (NO) (Furchgott et al. (1987)
Blood Vessels
, 24(3): 145-149). In patients with atherosclerotic coronary arteries, basal secretion of NO is lower (Chester et al. (1990)
Lancet
, 336(8720): 897-900) and NO-mediated endothelium-dependent relaxations fail to occur. (Chester et al. supra.; Bossaller (1987)
Basic Res Cardiol
, 82(4): 396-404; Golino et al. (1991)
N Engl J Med
., 324(10): 641-648). As a consequence, NO-dependent factors which cause vasodilation in normal coronary arteries, paradoxically cause vasoconstriction in atherosclerotic vessels (Golino et al. supra.). Endothelial dysfunction may result in platelet adhesion, aggregation, and platelet-induced contractions of coronary smooth muscle, and thus facilitate events such a vasospasm, myocardial ischemia, and coronary thrombosis (Pearson (1991)
Ann Thorac Surg
, 51(5): 788-793).
SUMMARY OF THE INVENTION
In particular this invention pertains to the discovery that L-arginine and type V phosphodiesterases act synergistically to inhibit vasospasm and/or to induce vasodilation. The combination is particularly useful in the treatment of erectile dysfunction and/or various cardiac pathologies. Thus, in one embodiment, this invention provides methods for ameliorating erectile dysfunction in a male individual. The methods involve administering to the individual an effective amount of a pharmaceutical composition comprising a type V phosphodiesterase inhibitor and L-arginine. In preferred embodiments, the type V phosphodiesterase inhibitor zaprinast; dipyridamole; pyrazolopyrimidinones; griseolic acid derivatives; 2-phenylpurinones; phenylpyridone derivatives; pyrimidines; pyrimidopyrimidines; purines; quinazolines; phenylpyrimidinones; imidazoquinoxalinones or aza analogues thereof; phenylpyridones; 4-bromo-5-(pyridylmethylamino)-6-[3-(4-chlorophenyl)propoxy]-3(2H)pyridazinone; 1-[4-[(1,3-benzodioxol-5-ylmethyl)amiono]-6-chloro-2-quinazolinyl]-4-piperidine-carboxylic acid, monosodium salt; (+)-cis-5,6a,7,9,9,9a-hexahydro-2-[4-(trifluoromethyl)-phenylmethyl-5-methyl-cyclopent-4,5]imidazo[2,1-b]purin-4(3H)one; furazlocillin; cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5]imidazo[2,1- b]purin-4-one; 3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate; 4-bromo-5-(3-pyridylmethylamino)-6-(3-(4-chlorophenyl)propoxy)-3-(2H)pyridazinone; 1-methyl-5-(5-morpholinoacetyl-2-n-propoxyphenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one; and 1-[4[(1,3-benzodioxol-5-ylmethyl)amino]-6-chloro-2-quinazolinyl]4-piperidinecarboxylic acid, or combinations thereof. In particularly preferred embodiments, the phosphodiesterase inhibitor is zaprinast, or a pyrazolopyrimidinone, or sildenafil. The method may further involve administering to the individual a beta blocker to prevent an excessive heart rate leading to ischemia. In one embodiment, the individual is given a daily dose of phosphodiesterase inhibitor in the range of approximately 0.1 to 500 mg/day. The phosphodiesterase inhibitor is can be formulated as a unit dosage pharmaceutical formulation. In certain embodiments, this method is used to amelioriate vasculogenic impotence.
In another embodiment, this invention provides methods of inducing vasodilation or inhibiting vasospasm of a coronary artery or bypass graft. The methods involve contacting the coronary artery or bypass graft with L-arginine and a type V phosphodiesterase inhibitor, whereby L-arginine and the type V phosphodiesterase inhibitor act synergistically to induce or increase vasodilation or to inhibit vasospasm of the coronary artery or bypass graft. In one embodiment, the L-arginine is preferably administered at a concentration ranging from about 10
−5
M to about 10
−2
M and the type V phosphodiestersase inhibitor is administered at a concentration sufficient to inhibit vasospasm (in combination with the L-arginine). In certain embodiments, the phosphodiesterase inhibitor concentration ranges from about 1×10
−7
M to about 5×10
−4
M to inhibit vasospasm. In particularly preferred embodiments, the type V phosphodiesterase inhibitor is sildenafil administered at a concentration ranging from about 2×10
−7
M to about 2×10
−4
M, or zaprinast administered at a concentration ranging from about 5×10
−7
M to about 5×10
−4
M.
In another embodiment, the L-arginine is administered at a concentration ranging from about 10
−5
M to about 10
−2
M and the type V phosphodiestersase inhibitor is administered at a concentration ranging from about 10
−7
M to about 10
−4
M to induce vasodilation.
In certain embodiments, the L-arginine and the phosphodiestersase inhibitor are combined in a single formulation, and, optionally, combined with a pharmaceutically acceptable excipient. In particularly preferred embodiments, the L-arginine is formulated as L-arginine hydrochloride. Preferred type V phosphodiestersase inhibitors include zaprinast, sildenafilm, DMPPO, and 1-arylnaphthalene lignan series, in which 1-(3-bromo-4,5-dimethoxyphenyl)-5-chloro-3-[4-(2-hydroxyethyl)-1- piperazinylcarbonyl]-2-(methoxycarbonyl)naphthalene hydrochloride. The contacting can involve an intravenous injection of the L-arginine and/or the phosphodiesterase inhibitor or an oral administration of the L-arginine and/or the phosphodiesterase inhibitor.
In still another embodiment, this invention provides a pharmaceutical composition
Hunter Tom
Quine Intellectual Property Law Group P.C.
Reamer James H
The Regents of the University of California
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