Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-06-07
2003-04-08
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S565000
Reexamination Certificate
active
06544994
ABSTRACT:
The invention relates to the use of at least folic acid or a folate and tetrahydrobiopterin (BH
4
) or derivatives thereof for treating or preventing cardiovascular or neurological disorders by modulation of the activity of nitric oxide synthase (NOS). The present invention also relates to the use of at least folic acid or a folate and tetrahydrobiopterin (BH
4
) or derivatives thereof for the production of a pharmaceutical preparation suitable for influencing the nitric oxide (NO) level, particularly by modulation of the activity of nitric oxide synthase (NOS) by reducing superoxide (O
2
) production and enhancing nitric oxide (NO) synthesis. This effect occurs in the absence of any negative changes in other risk factors, e.g. lipids, blood pressure and homocysteine. Clinical areas of application include all anomalies of the nitric oxide level, particularly the prevention and treatment of cardiovascular and of neurological disorders. The present invention also relates to pharmaceutical preparations comprising at least one compound selected from the group consisting of 5-formyl-(6 S)-tetrahydrofolic acid, 5-methyl-(6 S)-tetrahydrofolic acid, 5,10-methylene-(6R)-tetrahydrofolic acid, 5,10-methanyl-(6R)-tetrahydrofolic acid, 10-formyl-(6R)-tetrahydrofolic acid, 5-formimino-(6 S)-tetrahydrofolic acid or (6 S)-tetrahydrofolic acid, together with tetrahydrobiopterin (BH
4
) or pharmaceutically compatible salts thereof and with pharmaceutically compatible active and adjuvant substances, such as arginine for influencing the nitric oxide (NO) level.
Within this text the term a folate or a derivative thereof, if not explicitly defined otherwise, always refers to the natural and unnatural stereoisomeric form of each substance, pharmaceutically compatible salts thereof and any mixtures of the isomers and the salts. As drugs, tetrahydrofolates have predominantly been used hitherto as the calcium salt of 5-formyl-5,6,7,8-tetrahydrofolic acid (leucovorin) or of 5-methyl-5,6,7,8-tetrahydrofolic acid (MTHF) for the treatment of megaloblastic folic acid deficiency anemia, as an antidote for increasing the compatibility of folio acid antagonists, particularly of aminopterin and methotrexate in cancer chemotherapy (“antifolate rescue”), for increasing the therapeutic effect of fluorinated pyrimidines and for the treatment of autoimmune diseases such as psoriasis and rheumatoid arthritis, for increasing the compatibility of certain antiparasitic agents, for instance trimethoprim-sulfamethoxazole, and for decreasing the toxicity of dideazatetra-hydrofolates in chemotherapy and for influencing the homocysteine level, particularly for assisting the remethylation of homocysteine.
The term tetrahydrobiopterin (BH
4
) or a derivative thereof, if not explicitly defined otherwise, always refers to all natural and unnatural stereoisomeric forms of tetrahydrobiopterin, pharmaceutically compatible salts thereof and any mixtures of the isomers and the salts. The term tetrahydrobiopterin also includes any precursors of tetrahydrobiopterin, especially 7,8-dihydrobiopterin. (6R)-tetrahydrobiopterin is a naturally occuring cofactor of the aromatic amino acid hydroxylases and is involved in the synthesis of the three common aromatic amino acids tyrosine, phenylalanine, tryptophan and the neurotransmitters dopamine and serotonin. It is also essential for nitric oxide synthase catalysed oxidation of L-arginine to L-citrullin and nitric oxide. Tetrahydrobiopterin is involved in many other biochemical functions, many of which have been just recently discovered.
The term arginine, if not explicitly defined otherwise, always refers to the natural and unnatural stereoisomeric form of arginine. L-arginine, a natural amino acid, is the precursor of endogenous nitric oxide (NO), which is a ubiquitous and potent vasodilator acting via the intracellular second-messenger cGMP. In healthy humans, L-arginine induces peripheral vasodilation and inhibits platelet aggregation due to an increased NO production. Both an excess and a lack of production of NO have been linked to pathological conditions, including cardiovascular disorders, septic shock, inflammation and infection, and brain damage in stroke and neurological disorders. The term nitric oxide synthase (NOS), if not explicitly defined otherwise, always refers to all isoforms endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS).
Nitric oxide (NO) has been identified as a mediator of atherosclerosis. Therefore it is a therapeutic target in cardiovascular prevention trials. It also plays an important role in neurological disorders. Biological effects of nitric oxide (NO) are not limited to vascular relaxation, but are also important in the respiratory, urogenital and gastrointestinal system, central and peripheral nervous system, neuroendocrine and endocrine systems, and nonspecific immunity.
Nitric oxide (NO) and superoxide (O
2
.) are cytotoxins on their own, yet it has been demonstrated that the two relatively unreactive radicals can rapidly combine (k=3.7×10
7
M
−1
s
−1
) under physiological conditions to the strong oxidizing agent peroxynitrite (ONOO
−
). This reaction is about 3 times faster than the detoxifying catabolism of superoxide by superoxide dismutase (SOD). It is believed that the formation of peroxynitrite is an important factor in the oxidative damage associated with ischemia/reperfusion. A variety of pathologies are associated with the formation of peroxynitrite. Peroxynitrite is invariably formed in larger amounts when more NO is produced, and/or when an elevated level of superoxide prevails. In this regard, pathologies such as diabetes, atherosclerosis, and ischemia-reperfusion injury, are associated with oxidative stress characterized by an elevated level of superoxide that can lead to increased peroxynitrite formation. Also when glutathione detoxification mechanism against peroxynitrite is impaired critical concentrations of peroxinitrite may occur. Recent evidence also suggests multiple sclerosis and Alzheimer's disease are associated with peroxynitrite formation. In addition, peroxynitrite has also been implicated during sepsis and adult respiratory distress syndrome. Ischemia and reperfusion are accompanied by an increase in superoxide due to the activation of xanthine oxidase and NAPDH oxidase, respectively. Thus, peroxynitrite is likely to be implicated in a number of pathologies in which an imbalance of NO and superoxide occurs.
Several factors can contribute to reduced bioavailability of NO, ranging from impaired production to increased degradation, depending on the risk factors involved. NO is synthesized by dimers of the 130 kD enzyme endothelial NO synthase in a reaction where arginine is oxidized to NO and citrulline. It has been shown that eNOS produces superoxide radicals as well as NO. Under physiological conditions, NOS predominantly produces NO, controlled by the regulatory co-enzyme calmodulin, the substrate arginine and the cofactor tetrahydrobiopterin (BH
4
). Under pathophysiological conditions, such as dyslipidemia, production shifts from NO to superoxide. Clinical studies have shown impaired NO bio-availability in patients with (risk factors for) atherosclerosis. Evidence has accumulated showing that increased production of superoxide and increased degradation of NO by superoxide, rather than impaired formation of NO is the predominant cause of impaired NO bioavailability in early atherosclerosis. These observations indicate that atherogenesis is linked to a pathological imbalance between NO and superoxide, rather than reduced NO production per se.
The level of superoxide can be lowered by substances showing a relevant scavenging capacity for superoxide radicals. Measurements revealed that arginine does not react with superoxide. However, both arginine and tetrahydrobiopterin (BH
4
) are required to minimize or abolish superoxide formation by NOS. Tetrahydrobiopterin (BH
4
) shows a reaction rate with superoxide which is rou
Moser Rudolf
Rabelink Ton J.
Eprov AG
Henley III Raymond
Millen White Zelano & Branigan P.C.
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