Use of misoprostol or/and misoprostol acid for diagnosis of vascular damage in a subject with erectile dysfunction

A method is provided for diagnosing vascular damage in a subject with erectile dysfunction that includes applying an effective dose of a therapeutic formulation having an excipient and at least one of misoprostol and misoprostolic acid topically to the glans penis of the subject and determining the vascular damage by the Doppler method or cavernosometry

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.sup.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.sub.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.sup.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.sup.th edition, volume III, p.3053).
 The topical application of prostaglandin E.sub.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,
 .sub.6.sup.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.sub.1 series
 (PGE.sub.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.sup.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-oxocyclopentane
 heptanoate or (.+-.)-15-deoxy-(16RS)-16-hydroxy-16-methyl-PGE.sub.1 methyl
 ester.
 It is consisted of 4 stereoisomers in about equal proportions [(+)&(-)
 enantiomers of 16R- and 16S-forms]. (The Merck Index, 11.sup.th edition,
 1989, p. 6128). The empirical formula is C.sub.22 H.sub.38 O.sub.5. Its
 structural formula appears in FIG. I.
 ##STR1##
 Compared with other prostaglandins of group E.sub.1 and especially
 alprostadil, misoprostol bears a methyl group (--CH.sub.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.sup.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.RTM.. 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.sup.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).
 ##STR2##
 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 difficulty for a
 drug to pass through various barriers of the skin and the mucosal and
 reach in a satisfactory gathering at the corpora cavernosa in order to
 actis overcome". Amongst the probable methods of application, most
 advantageous is a synthesis in the gel form of relatively low viscosity
 which contains 0, 9 % w/v misoprostol in the methylform of methylester
 and/or free acid, a complexforming means, as 1, 6% w/v a-cyclodextrine and
 substances suitable for the formation of a gel e.g. hydroxypropyl
 methylcellulose "3000" 2% w/v, propylene glycol 10% v/v and Water to 100
 ml. The gel contains 9 mg of active substance per ml.

Method of application: 0, 1-0, 25 ml (or more, depending on responce) are
 pasted or spread on the glans of penis. 9 examples related to the
 pharmacotechnical forms and the ways of application of misorostol:
 1) 0,05-0, 20 ml gel, relatively low viscosity containing 0, 9% w/v
 misoprostol to apply on the glans of the penis or on the prepuce.

Synthesis:
 1-1.Misoprostol 0,9 g
 Hydroxypropyl Methylcellulose "3000" 2 g
 Water purified to 100 ml
 1-2.Misoprostol 0,9 g
 Sodium Carboxymethylcellulose 2 g
 Propylene Glycol 25 ml
 Water purified to 100 ml
 2)0.05-0.20 ml gel of relatively high viscosity, containing 0.50% w/v in
 misoprostol for endourethral application at a depth 2-5 cm from the
 outside urethra opening.

Synthesis:
 2-1.Misoprostol 0,50 g
 Hydroxypropyl Methylcellulose "3000" 4 g
 Water purified to 100 ml
 2-2.Misoprostol 0,50 g
 Sodium Carboxymethylcellulose 4 g
 Propylene Glycol 25 ml
 Water purified to 100 ml
 3)0.05-0.20 ml of aqueous solution of misoprostol containing 0.9% w/v for
 spreading on the glans of the penis or of the prepuce. The solution can
 also contain propylene glycol or glycerol in the corresponding proportions
 (e.g. 10%) to increase the viscosity of the solution.
 4)0.05-0.20 ml of ointment or emulsion of containing 0.9% w/w misoprostol
 for apply on the glans of the penis or on the prepuce, where misoprostol
 is found spread in the continuous (aqueous) phase.

Synthesis:
 4-1.Misoprostol 0,9 g
 Vanishing Cream to 100 g
 (Although for the requirements of this example as Vanishing Cream we used
 bepanthene.RTM. Cream of Roche, we have various creams o/w which are
 available in commerce or are described in National Pharmacopoeies and can
 be used for the same purpose).
 5)Endourethral sticks of suitable dimensions, weight about 500 mg,
 containing 0, 04-0, 20% w/w misoprostol to apply on the urethral mucosa.

Synthesis:
 5-1.Misoprostol 0,04-0,20 g
 Glycerol 70 g
 Gelatine 20 g
 Water purified to 100 g
 6)0, 05-0,25 ml gel (or more depending of response) according to the
 examples (1-1) and (2-1) which contains moreover 1, 6% w/v
 a-cyclodextrine.
 7)0, 05-0,25 ml gel (or more depending of response) according to the
 example (6) which contains moreover 10 ml ethyl alcohol 96.degree. and 0,
 5 mg/ml alprostadil.
 Notes: 1) The incorporation of misoprostol in bases already mentioned took
 place in normal temperature (20-25.degree. C.) and at a temperature not
 exceeding 40.degree. C.
 2) No significant changes in misoprostol activity was observed as a
 function of pH, we observent however an important reduction or/and
 neutralization of misoprostol action in the presence of Polysorbate "80".
 3) The time of appearance of the result varies from 20-40 minutes. The
 timing of the appearance and the intensity of the result seems to be able
 been positively influenced by certain moisturising agents (e.g. Propylene
 Glycol, Glycerol) as well as by certain substances which reinforce by
 various mechanisms the transcutaneous absorption (e.g. Urea, Acid Citric).
 High once only doses of misoprostol (&gt;1800 mcg on the glans of the penis
 and &gt;1000 mcg in the urethra) cause certain systematic undesirable effects
 as shudder, feeling of hard ship, excitement and diarrhea. The presence of
 a-cycodextrine reduces the undesirable effects and allows the application
 once only of higher doses (&gt;2000 mcg) without notable effect on the timing
 of its action but with positive effect on the intensity result and with
 prolonging of its duration.
 5) The doses which are mentioned in the examples are only indicative since
 the intensity of the result depends, apart from the cause and the grade of
 the erectile dysfunction on other factors as e.g. the degree of
 moisturising of the underlying tissue, the physiological situation of the
 skin or the mucosa etc. As had already been mentioned, misoprostol is an
 extremely hydrophile molecule compared with other prostaglandins of
 E.sub.1 series (e.g. with alprostadil which can be dissolved in alcohol
 but her solubility in water is only 8000 mcg/100 ml at 35.degree. C.).
 This consists an important advantage:
 a) Because no use of organic factors is required (e.g. ethyl alcohol) which
 usually irritate tissues and are thus unsuitable for application on the
 skin and especially the mucus.
 b) Because it allows the incorporation of active substances on a very small
 amount of excipient, suitable for application on surfaces of limited
 extent, as e.g. the urethra or the glans of the penis.
 6) Because of the described irritation of the uterine fibers (Physicians
 Desc Reference, ed. Medical Economics Data, Production Company at
 Montrale, 48.sup.th edition, 1994, p. 2197-2199) misoprostol must not
 contact the female genital apparatus.