Surgery – Diagnostic testing – Cardiovascular
Reexamination Certificate
1999-12-29
2001-04-03
Krass, Frederick (Department: 1614)
Surgery
Diagnostic testing
Cardiovascular
C600S301000, C600S586000, C600S587000, C514S929000, C514S573000
Reexamination Certificate
active
06210343
ABSTRACT:
The invention relates to the use of an already known pharmaceutical substance, misoprostol as well as its first metabolite, misoprostol acid, for the preparation of a drug for external use which is destined to cure erectile dysfunction. Nowadays the pharmaceutical treatment of erectile dysfunction—except of the cases of hormonal insufficiency, which are generally rare and in which a suitable substitution therapy is followed—includes mainly the use of intracavernosous injections consisting in the direct injection of vasodilatory drugs (papaverine, phentolamine and alprostadil) into the corpora cavernosa of the penis (Campell's Urology, ed. W. B. Saunders Company, 6
th
edition, volume III, p.3055-3057). Although this method is the most efficient and perhaps the only scientifically acceptable, it has the serious disadvantage of the form (injection) as well as the manner of administration intracavernosal. Yohimbin, an a
2
-adrenergic inhibitor, is administrated per os, however the efficiency of this old method is doubtful (Campell's Urology, ed. W. B. Saunders Company,6
th
edition, volume III, p.3053).
In former times the topical application of a nitroglycerin paste had been proposed (Claes et al 1989), but the method was not therapeutically applied because of doubtful efficacy and serious side-effects (Campell's Urology, ed. W. B. Saunders Company,6
th
edition, volume III, p.3053). The topical application of prostaglandin E
1
(or alprostadil) in the form of an endourethral gel or stick as a means of limited efficacy in the therapy of male impotence of a vascular cause (International Journal of Impotence Research, Stocton ed., vol. 7, September 1995, supplement I, p.05-06) was recently proposed we must note that the discovery of vasodilatory drugs with sufficient transcutaneous absorption or the use of methods (e.g.ionophoresis) which can reinforce the penetration of such drugs through the skin of the mucosal membranes, inside the corpora cavernosa of the penis has for long attracted the interest of many research workers (Campell's Urology, ed. W. B. Saunders Company,
6
th
ed. vol. III, p.3057)
Up to day a common denominator of the methods destined for external application is mainly the low efficacy combined with increased therapy cost and the apparition of more or less serious side-effects.
But the most serious technical difficulty that can be especially confronted by the methods for external use, is that drugs must penetrate through the various barriers of the skin and the mucosals and reach—in a satisfactory gathering—into the corpora cavernosa in order to act. The present method aims at the removal of the drawbacks of the above methods using misoprostol in the symptom therapy of male impotency. Misoprostol is the general name of a synthetic prostaglandin belonging to the E
1
series (PGE
1
analogs). Synthesis: P. W. Collins, R Pappo, Belgian patent 827.127, U.S. Pat. No. 3,965,143 (The Merck Index, ed. Merck & Co. Inc, 11
th
edition, 1989, p. 6128).
Its chemical name is (11a, 13E)-(±)-11, 16-Dihydroxy-16-methyl-9-oxoprost-13-en-1-oic acid methyl ester or (±)-(methyl)-(1R, 2R, 3R)-3-hydroxy-2-[(E)-(4RS)-4-hydroxy-4-methyl-1-octenyl]-5-oxocyclopentaneheptanoate or (±)-15-deoxy-(16RS)-16-hydroxy-16-methyl-PGE
1
methyl ester.
It is consisted of 4 stereoisomers in about equal proportions [(+)&(−) enantiomers of 16R- and 16S-forms]. (The Merck Index, 11
th
edition, 1989, p. 6128). The empirical formula is C
22
H
38
O
5
. Its structural formula appears in FIG. I.
Compared with other prostaglandins of group E
1
and especially alprostadil, misoprostol bears a methyl group (—CH
3
) on the carbon atom of position 16.
According to a method which relates the biological action of various medicament molecules to its chemical structure (Method of Minimum Stereochemical Difference, “Planning of drugs”, P. Kourounakis-E. Rekka, ed. Graphical Arts, Thessaloniki, 1992, p. 152) it appears that due to this group we have a big penetration of misoprostol in the underlying tissues and a local vasodilation which cures erection dysfunctions. Misoprostol is used today orally as antiulcer drug (Physicians Desc Reference, PDR, ed. Medical Economics Data, Production Company at Montrale 48
th
edition, 1994, P. 2197-2199).
In particular it is administered for the prevention of gastric ulcer to patients who take non-steroid antiinflammatory drugs. It is available in the countries of Europe and U.S.A. by Searle Company under the commercial name Cytoteco®. In none country is the drug mentioned as suitable for male impotence nor are there any relevant reports on the international bibliography. On a contrary amongst the undesirable effects in oral therapy with misoprostol is male impotence (Physicians Desc Reference, ed. Medical Economics Data, Production Company at Montrale, 48
th
edition, 1994, p. 2197-2199).
Misorostol instead of the fact that creates slighter vasodilatory action, compared to alprostadil when provided intracavernosaly, it does cause larger vasodilation when applicated externaly. This is happening because the action mechanism on the erectile function among misoprostol and other vasodilatories (e.g. alprostadil) seriously differs. Misoprostol applicated topically penetrates through the corpora cavernosa and creates slight action-compared to other vasodilatories-onthesmooth muscle fibres of the vessels. But, its main action is revealed atthe gland vessels and in a smaller degree at the prepuce.
Because of the strong topical vasodilation, into the intense bleed of these vessels is caused. Consequently as natural, a negative pressure into the corpora cavernosa is created, and is getting balanced by the abundant blood entrance into these, finally resulting at the provocation of erection. In other words, the gland vessels act as “blood pumps” and by that mechanism the erectile function is getting operated at once.
On the other hand due to the fact that the degree of response to a small dose of misoprostol (durability and hardness of erection) depends on the physiological condition and function of the penile vessels, misoprostol can be used as accessory diagnostic means (instead of papaverine or alprostadil) in the “Doppler” method or the cavernosometry, for the determination of the extent and kind of vascular damage (about the use of vasodilatory drugs as accessory diagnostic means in the “Doppler” method or cavernosometry, see Erektile Impotenz, ed. Enke, p.68-77 & p. 88-110).
Equally strong topical vasodilatory action after external application is exerted by the hydrolysis product of misoprostol, (misoprostol acid) which anyway constitutes the first misoprostol metabolite after its introduction in the organism (see FIG.II).
Finally because of the topical vasodilatory action of misoprostol and the relative free acid, both pharmaceutical molecules facilitate the absorption of other drugs through the skin and the mucosals. In other words, they act as “penetration enhancers”. Especially regarding to vasodilatory substances (e.g. alprostadil) on the one hand it facilitates the passing through the skin and the mucosals, resulting to high gatherings of these drugs into the tissues and especially into the corpora cavernosa and on the other hand it expresses a synergic action with them. Misoprostol can be dissolved in water and its compatibility with excipients provides the opportunity of production of a variety of simple pharmacotechnical forms for external use, which are at the same time very well tolerated by the skin and the mucousa. From the above mentioned description it appears that the most serious advantage of the method is the manner of administration of the drug (external in combination with the lack of undesirable action in the suggested doses or/and the proposed pharmacotechnical forms) the relatively low cost and especially the most satisfactory result together with corresponding methods.
But mostly, with the application of the described method a serious technical difficulty is getting overcome. Actually the
Kanakaris Panagiotis
Karouzakis Petros
Bromberg & Sunstein LLP
Jagoe Donna
Krass Frederick
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