Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Conjugate or complex
Reexamination Certificate
2001-05-24
2003-05-20
Gitomer, Ralph (Department: 1651)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Conjugate or complex
C424S776000, C514S456000
Reexamination Certificate
active
06565851
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to the use of proanthocyanidins to stimulate the enzyme NO-synthase, which acts as a catalyst to release nitric oxide from L-arginine (or its salts). Such is advantageous in relieving symptoms of erectile dysfunction.
2. Discussion of Related Art
The normal penis reaction is based on a series of neurally mediated changes of bloodstream in the erectile tissue. The condition for an increased blood supply is the relaxation of smooth muscles in the erectile tissue. The relaxation takes place as follows:
As a result of sexual stimuli, the enzyme NO-synthase (NOS) gets activated in endothelial cells of the erectile tissue. This enzyme acts as a catalyst for the synthesis of nitric oxide (NO) from its substrate, amino acid L-arginine. The NO in turn activates the guanylyl cyclase which leads to an increased development of cyclic guanosine monophosphate (cGMP).
The cGMP causes relaxation of smooth muscles. Due to the reduction of cGMP by means of further enzymes, of which the phosphodiesterase type 5 (PDE type 5) is the most important one, the vasodilation can be rescinded.
The male impotence or erectile dysfunction is a widespread problem. It is the persistent inability of a man to get an erection and to maintain it long enough for satisfying sexual intercourse. The erectile dysfunction occurs mainly in older men; approximately 30% of men in their forties and 67% of men in their seventies are affected.
Present treatments comprise vacuum pumps, penis protheses, vascular surgery and the use of vasodilatory medicaments, such as Alprostadil, which can either be injected into the erectile tissue (Corpus cavernosum) or be brought into the urethra by means of an applicator. In March 1998, the American health authority FDA approved sildenafil (Viagra) as an oral treatment. In addition, there are other substances that are available that have the same, or substantially the same, mechanism of action as sildenafil. These other substances inhibit phosphodiesterase type 5 and/or prevent the decrease of cGMP.
Proanthocyanidins are homogeneous or heterogenous polymers consisting of the monomer units catechin or epicatechin, which are connected either by 4-8 or 4-6 linkages, to the effect that a great number of isomer proanthocyanidins exist. Typically, the procyanidin oligomers have a chain length of 2-12 monomer units.
Proanthocyanidins can be found in vegetable extracts, as well as in extracts of the bark of a maritime pine, the cones of cypresses, and the seeds and skin of grapes. A well-known product containing proanthocyanidins, which is available in trade as a preparation of a food supplement under the name Pycnogenol®, is an extract of the maritime pine bark (Pinus pinaster). The Pycnogenol® food supplement contains approximately 70-80% of proanthocyanidins and is a complex mixture of phenolic substances. It possesses a multitude of interesting and useful biochemical and pharmacological qualities. In particular, it is well known for its protecting effect against aging associated chronic diseases, such as atherosclerosis and its cardiovascular events such as stroke or heart infarction. Besides proanthocyanidins and its monomeric unit catechin, Pycnogenol® food supplement contains taxifolin and a wide range of phenolic acids, e.g. free acids like p-hydroxybenzoic acid, protoacatechic acid, vanillic acid, caffeic acid and ferulic acid as well as its glucosides and glucose esters. Most of the positive effects of Pycnogenol® are attributed to its antioxidant qualities.
Pycnogenol® food supplement deactivates superoxide radicals and hydroxyl radicals and inhibits the development of other oxygen radicals. In vitro, Pycnogenol® food supplement inhibits the peroxidization of LDL, the fat peroxidization in phospolipid liposomes and the fat peroxidization caused by t-butylhydroperoxide as well as the damage to cells induced by UV-B. As Pycnogenol® inhibits, in particular, the fat peroxidization of LDL, the risk of arteriosclerosis decreases. Moreover, Pycnogenol® food supplement contains procyanidins protecting collagen and elastin against enzymatical decomposition, which has a positive influence on the capillary resistance. The oral supply of this preparation to humans decreases the development of leg oedema.
It is known that some vegetable extracts containing proanthocyanidins show an endothelium-dependent relaxing activity (EDR). This has already been proven in red wine, grape juice and extracts of the peel of grapes ex vivo in aorta rings of rats (Fitzpatrick et al, Am., Physiol, 1993, 265 H774-8). Also, as concerns Pycnogenol® food supplement, such has also been found (Fitzpatrick et al: J Cardiovac, Pharmacol, Volume 32 Nr. 4, 1998) in that the fractions 3 preserved by sephadex LH-20 exclusion chromatography contained proanthocyanidins with a higher molecular weight showed the strongest EDR. Thus, it had been shown that proanthocyanidins increase the activity of the NO-synthase. The inhibition of the NO-synthase by well known inhibitors has been compensated by means of Pycnogenol® food supplement.
Sildenafil inhibits selectively the phosphodiesterase type 5 and thus prevents the decrease of cGMP. However, as Sildenafil does not promote the development of cGMP, but merely inhibits the decrease of existing cGMP, it is only effective, when there is already a quantity of cGMP sufficient enough for an erection, as for example in case of a strong sexual arousal. In case that there is an insufficient production of nitric oxide, which is necessary for stimulation of cGMP synthesis, the possibility exists that the quantity of cGMP is insufficient for an erection.
It is therefore desirable to develop a stimulation technique which does not interfere with the above mentioned chain reaction at the end, i.e., the prevention of the decrease of cGMP, but has a positive influence on the preceding reactions by stimulating NO-synthase and raising NO and cGMP concentrations.
SUMMARY OF THE INVENTION
One aspect of the invention resides in a stimulation technique that uses a combination of a source of nitric oxide, namely, amino acid L-arginine or its salts, and an active ingredient, namely, proanthocyanidins. Both the proanthocyanidins and the L-arginine or its salts are in therapeutically effective amounts to relieve symptons of erectile dysfunction and increase blood vessel diameter.
The proanthocyanidins are in an amount sufficient to stimulate the endothelial NO-synthase enzyme. Once stimulated, endothelial NO-synthase enzyme acts as a catalyst to synthesize nitric oxide from its substrate amino acid, L-arginine. Such a stimulator is necessary for the production of cGMP in larger amounts so that after neural activation, the development of nitric oxide may increase. The nitric oxide activates guanylyl cyclase, which increases cGMP and results in relaxation of smooth muscles.
The combination may also have sildenafil or an inhibitor that inhibits an enzyme phosphodiesterase type 5 from reducing an amount of the cGMP. In addition, both proanthocyanidins and L-arginine may be taken simultaneously. For instance, if both are in oral dosage form, both would be swallowed and be present within the stomach at the same time.
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Ferrari Victor
Rohdewald Peter
Gibbons Del Deo Dolan Griffinger & Vecchione
Gitomer Ralph
Horphag Research Limited
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