Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-07-12
2003-01-14
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S002600, C514S045000, C514S046000, C514S048000, C514S561000, C514S565000, C424S195110
Reexamination Certificate
active
06506736
ABSTRACT:
BACKGROUND OF THE INVENTION
Field of Invention
The invention relates to obtaining a drug intended to prevent or treat sexual dysfunction in men or women. The invention relates in particular to obtaining a drug able to combat disorders of physiological and/or anatomical response to sexual stimulation in human beings. Such a drug contains a purine and a nitric oxide donor in combination.
It is known that, in men, the erection process is as described schematically below. The erectile tissue of the penis, called corpus cavernosum, is a spongy tissue able to fill with blood. In the resting state, the arteries of the penis are controlled by the adrenergic tonus that keeps them in spasm so that no appreciable blood flow fills the corpus cavernosum. Upon an appropriate stimulation, the nervi erigentes inhibit the adrenergic tonus and release certain mediators favoring dilation of the arteries of the penis, causing blood to accumulate in the corpus cavernosum. The latter enlarges, while the increase in its internal pressure causes it to harden. As it enlarges, it crushes the cavernous veins against the envelope of the erectile body, preventing evacuation of the blood it contains, which maintains the rigidity. After ejaculation, adrenaline is once again released locally, the flow of blood into the arteries also decreases, the pressure in the corpus cavernosum drops, and the blood accumulated in the corpus cavernosum can be evacuated by the veins that are no longer compressed, causing loss of rigidity and return to the resting state.
In women, sexual arousal results in particular in vasodilation of the blood vessels irrigating the genital organs. This vasodilation brings about in particular swelling and erectile response of the clitoris, and congestion of the vaginal wall vessels with exudation of vaginal fluids.
It is known that a fairly high proportion of men (between 10 and 50% depending on the population studied and the age group) suffers from permanent or temporary erectile dysfunction. These difficulties may be organic, in which case they require specific treatments adapted to each cause. However, the majority of erectile dysfunctions are not organic, and are often of psychological origin.
In women as well, the physiological response to sexual arousal and its anatomical manifestations may be temporarily altered, sometimes permanently, even with no detectable organic cause. The difficulties most frequently observed include the absence of sexual desire even after stimulation, difficulty in achieving orgasm, low intensity of sexual pleasure, and decreased or even absent natural vaginal lubrication. They often lead to a lack of interest in sexual activity. These disorders of physiological and/or anatomical response to sexual stimulation are termed “female sexual dysfunction” in the present patent application. According to some estimates, the frequency of temporary or chronic sexual dysfunction in women is equivalent to that of erectile dysfunction in men.
Hence it is desirable to have treatments enabling the severity and/or duration of these disorders to be reduced, or prevent their appearance, and to restore the ability to achieve satisfactory sexual intercourse in subjects, men or women, who have such disorders or fear that they will occur.
For cases of male impotence, various treatments have been proposed. In severe forms, intracavernous injection of vasoactive substances may give good results. In the case of moderate or incipient erectile dysfunction, oral treatments are more appropriate and are generally better accepted. A number of products, often of plant origin, have been proposed for this purpose. The use of an oral vasodilator (WO 96/33705; WO 96/16644) and a transdermal, transmucosal, intranasal, or rectal vasodilator (WO 95/05172) has also been proposed.
Of the known vasodilators, a distinction is made between those with antagonist effects on &agr;-adrenergic receptors (phentolamine for example) which inhibit adrenergic tonus thus favoring dilation of the arteries, and those that play the role of nitric oxide (NO) donors, either directly or during their metabolism. It is known that the endothelial cells that coat the interior of blood vessels are able to secrete a substance that dilates the arteries, this substance being nitric oxide. It has been established that nitric oxide stimulates synthesis of cyclic guanosine monophosphate (or cGMP) which brings about relaxation of the muscles of the arteries. It is also known that nitric oxide is the main physiological neurotransmitter brought into play by the nonadrenergic and noncholinergic peripheral neurons innervating the corpus cavernosum and its arteries, and that its release at the effector synapse is an important factor in inducing erection; see in particular Burnett et al.,
Science
257:401-403(1992) and Fajfer et al.,
New Eng. J Med.
326:90-94(1992). International application WO 92/21346recommends administration of a nitric oxide donor, linsidomine, for treating erectile dysfunction.
Substances acting on dilation of the arteries by producing nitric oxide that may be cited as examples are arginine, sodium nitroprussiate, organic nitrates (glycerol trinitrate, isosorbide mononitrate or dinitrate), organic nitrites (amyl or butyl nitrites), thionitrites as described in document WO 96/16645(e.g. S-nitrosocysteine, S-nitrosoglutathion), molsidomine, and, where applicable, pharmaceutically acceptable salts of these compounds.
It is known that other agents are involved in the physiological phenomenon of turgidity of erectile bodies. Examples of these agents are prostaglandins, vasoactive peptides such as bradykinin, the neuropeptide known as vasoactive intestinal peptide (or VIP), neuropeptide Y, etc. Also, rabbit studies have shown that purines are able to induce relaxation of the corpus cavernosum; see Wu H—Y et al.,
Int. J. Impotence Res .
5, 161-167(1993). It has also been shown that intravenous injection of adenosine triphosphate induces erection in dogs; see Takahashi Y. et al.,
Int. J. Impotence Res .
4, 27-34(1992). Purines are reported to act as nonadrenergic noncholinergic neurotransmitters.
It has now been discovered that the combination of purine activity and nitric oxide donor activity gives favorable results in prevention and treatment of disorders of physiological and anatomical response to sexual stimulation in humans (men or women) allowing said disorders to be combatted by a synergistic effect.
In the present application, “nitric oxide donor” is understood to be any agent able to produce in vivo, directly or indirectly, nitric oxide (NO) or any metabolic precursor of such an agent, as well as any agent able to favor production of endogenous nitric oxide, for example phosphodiesterase inhibitors that have the indirect effect of increasing the level of nitric oxide. Nitric oxide donors are in particular the substances referred to hereinabove. Nitric oxide donor activity is obtained by the presence of such an agent.
In the present application, “purine” is understood to be purine bases, particularly adenine, purine-based nucleosides, particularly adenosine, as well as the corresponding phosphates, particularly AMP, ADP, and ATP, as well as their pharmaceutically acceptable salts (for example adenine or adenosine hydrochloride, or adenosine-phosphate sodium salts). More generally, “purine” is understood to be any substance able to act on the purine receptors. Such substances are known or can be detected by known methods. Purine activity is activity obtained by the presence of a purine as defined above.
If a compound has both purine activity and nitric oxide donor activity, it can be used as a single active ingredient in the drug obtained according to the invention.
To study the effects of agents intended to treat disorders of physiological and anatomical response to sexual stimulation in men and women, known methods such as the tests described by Boolell M. et al, Int.
J. of Impotence Res
., 8, 47-52 (1996) and PCT WO 95/05172, or the tests described hereinbelow, may be used.
The drug obtained according to
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