MXPA06000623A - Treatment of sexual dysfunction. - Google Patents

Abstract

This invention relates to the use of cyclic guanosine 3', 5'-monophosphate phosphodiesterase type five (PDE5) inhibitors, in combination with 5HT1a agonists for the treatment of sexual dysfunction, particularly female sexual arousal disorder (FSAD) with concomitant hypoactive sexual desire disorder (HSDD).

Description

TREATMENT OF SEXUAL DYSFUNCTION This invention relates to the use of cyclic type 5 (PDE5) guanosine-3 ', 5'-monophosphate phosphodiesterase inhibitors in combination with 5HT1a agonists, for the treatment of sexual dysfunction, in particular the arousal disorder female sexual arousal disorder (FSAD) with concomitant hypoactive sexual desire disorder (HSDD). Male sexual dysfunction includes erectile dysfunction in men, ejaculation disorders such as premature ejaculation (PE), anorgasmia (inability to achieve orgasm) and desire disorders such as hypoactive sexual desire disorder (lack of interest in the sex). The categories of female sexual dysfunction (FSD) are best defined by contrasting with the phases of a woman's normal sexual response: desire, arousal and orgasm (see the work of SR Lei-blum, (1998), Definition and Classification of Female Sexual Disorders, Int. J. Impotence Res. 10, S104-S106). Desire or libido is the impulse of sexual expression. Their manifestations often include sexual thoughts either when in the company of an interested partner or when exposed to other erotic stimuli. Excitement includes the vascular response to sexual stimulation, an important component of which is genital engorgement and increased vaginal lubrication, lengthening of the vagina and increased genital sensation / sensation, and a subjective arousal response. Orgasm is the release of sexual tension that has culminated during the excitement. Therefore, FSD occurs when a woman has an absent, inadequate or unsatisfactory response in any one or more of these phases, usually desire, arousal or orgasm. The American Psychiatric Association classifies female sexual dysfunction (FSD) into four classes: FSAD, hypoactive sexual desire disorder (HSDD), female orgasmic disorder (FOD), and sexual pain disorders (eg, dyspareunia and vaginismus) [see American Psy-chiatric Associa- tion's Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV)]. The DSM-IV defines the four classes as follows: HSDD - Sexual fantasies and desire for permanent or periodically deficient (or absent) sexual activity that causes anguish or accused interpersonal difficulties. The judgment of the deficiency or absence is made by the doctor taking into account all the factors that affect the function, such as the age and context of people's lives.

FSAD - Permanent or periodic inability to achieve or maintain until the termination of sexual activity, an adequate turgor-lubrication response of sexual arousal.

• Permanent or periodic delay in orgasm, or lack thereof, after a normal phase of sexual arousal. Women manifest a wide variability in the type or intensity of the stimulation that triggers the orgasm. The diagnosis of FOD should be based on the physician's judgment that the orgasmic capacity of the woman is less than what would be reasonable for her age, sexual experience, and the adequacy of the sexual stimulation she receives.

Sexual disorders due to pain such as dyspareunia and vaginismus. Dyspareunia is the periodic or permanent genital pain associated with sexual intercourse. Vaginismus is the involuntary, periodic or permanent spasm of the musculature of the external third of the vagina that interferes with the sexual relationship.

More recently, the American Foundation for Urologic Disease has developed definitions using the same four classes (see The Journal of Urology, 2000, Vol. 163, pages 888-893). The definitions follow, together, lines similar to those followed in the DSM-IV: HSDD is the periodic or permanent deficiency (or absence) of sexual fantasies / thoughts, and / or desire for receptivity to sexual activity, which causes personal distress.

• FSAD is the permanent or periodic inability to achieve or maintain sufficient sexual arousal, which causes personal anguish, which can be expressed as lack of subjective excitement, or genital responses (lubrication / swelling) or other somatic responses.

• FOD is the permanent or periodic difficulty, delay or absence of reaching orgasm after enough stimulation and sexual arousal, which causes personal anguish.

· Sexual pain disorders: Dyspareunia is the periodic or permanent genital pain associated with sexual intercourse. Vaginismus is the involuntary, periodic or permanent spasm of the musculature of the external third of the vagina that interferes with vaginal penetration, which causes personal anguish.

The HSDD is present if a woman does not have or has little desire to be sexual, and she does not have or has very few sexual thoughts or fantasies. This type of FSD can be caused by low levels of testosterone, due either to natural menopause or to surgical menopause. Other causes both in pre-menopausal women (that is, women who are pre-menopausal and who have suffered hysterectomies or not) as well as post-menopausal women, include illness, medications, fatigue, depression and / or anxiety. Factors that have a potential psychological impact (conscious or subconscious) such as relationship difficulties or religious factors, may be related to the presence / development of HSDD in women. FSAD is a very common sexual disorder that affects pre-, peri- and post-menopausal women. This disorder is associated with concomitant disorders such as depression, cardiovascular diseases, diabetes and UG disorders. FSAD is characterized by an inadequate genital response to sexual stimulation. The genitals do not suffer the swelling that characterizes normal sexual arousal. The walls of the vagina are poorly lubricated, so the sexual relationship is painful. Orgasms may be impeded. FSAD may be caused by a reduced estrogen level at menopause or after the birth of children and during the period of lactation, as well as by disease, with vascular components such as diabetes and atherosclerosis. Other causes result from treatment with diuretics, antihistamines, antidepressants, for example, selective inhibitors of serotonin reuptake, or antihypertensive agents. Sexual pain disorders (including dyspareunia and vaginismus) are characterized by pain resulting from penetration and sexual activity, and can be caused by medications that reduce lubrication, endometriosis, pelvic inflammatory disease, intestinal disease inflammatory or urinary tract problems.

It has been discovered that inhibitors of PDE5 in combination with 5HT1a agonists act well in the treatment of people suffering from sexual dysfunction. The combination can be considered synergistic. Adequate sexual dysfunctions include FSAD, HSDD and FOD in women and MED in men. It has been discovered that inhibitors of PDE5 in combination with 5HT1a agonists act especially well in people with FSAD who are suffering from important HSDD at the same time. The combination can be considered synergistic. According to a first aspect, the invention provides the use of a PDE5 inhibitor in combination with a 5HT1a agonist, for the manufacture of a medicament for the treatment of sexual dysfunction. According to a preferred aspect, the invention provides the use of a PDE5 inhibitor in combination with a 5HT1a agonist for the manufacture of a medicament for the treatment of FSAD and HSDD in a person suffering from FSAD and at the same time important HSDD . The term "significant HSDD", as defined herein, means a level of HSDD that causes some degree of personal distress to the female person. Preferably, significant HSDD means a level of HSDD that causes some degree of distress and that can be measured. Preferably, the HSDD can be measured by evaluation by a physician using a semi-structured questionnaire.

More preferably, significant HSDD means a level of HSDD that causes some degree of distress and that can be measured as a score less than or equal to 16 on the desired domain of the Sexual Function Questionnaire (SFQ) below. in this memory. A female person with significant FSAD and HSDD may occasionally experience a slight increase in desire, for example as a result of psychological factors. It will be appreciated that such a person has typical and generally important HSDD and, therefore, is included within the scope of the invention. The term "concurrent" as used herein means a person who experiences FSAD at the same time as experiencing significant HSDD. The term "concurrent" as defined herein, does not include female individuals with circumstantial HSDD, i.e., persons who normally experience satisfactory levels of desire and who are usually able to become aroused, but who are occasionally unable to experience satisfactory levels of desire and excitement, as a result of external factors, for example, specific HSDD of the couple. In one embodiment of the invention, the female person is replenished with estrogens and androgens. Levels full of estrogens and androgens can already exist in the person or can be obtained artificially. The estrogen-laden levels can be artificially achieved by the administration of estradiol, estrone, estriol, a synthetic estrogen (for example estrogen benzoate), an agent that causes the body to produce estrogen and / or a modulator / agonist of a receptor. estrogens (for example raloxifene or lasofoxifene). Full levels of androgens can be achieved by administration of an androgen (such as including androsterone, dehydroandrosterone, testosterone, androsta-nodione or a synthetic androgen), an agent that causes the body to produce androgens and / or a modulator / agonist of an androgen receptor (for example tibolone). As used herein, the term "full" means concentrations of estrogens and androgens equal to or greater than the minimum psychological concentrations found in a normal person. Estrogen: is the general term for any substance that possesses the psychological activity of estradiol. The term includes natural and synthetic estrogens. Natural estrogens include estradiol, estrone, estriol and their conjugates, predominantly bound to proteins. An example of a synthetic estrogen is the estradiol benzoate. In a preferred MODALITY the person has an estrogen concentration equal to or greater than 40 picograms per milliliter of blood. The concentration of estradiol provides a reliable measure of total estrogen levels in the body. The psychological concentration of estradiol varies depending on the phase of ovulation. The minimum concentration of estradiol (bound to proteins and free) of a normal woman is approximately 40 picograms per milliliter of blood. Therefore, in a preferred MODALITY, the person possesses a concentration of estradiol (bound to proteins and free) equal to or greater than 40 picograms per milliliter of blood. Methods and kits for determining the concentration of estradiol in blood are well known to the experts. For example, Coat-a-Count® Esradiol ([obtainable via DPC® (Diagnostic Products Corporation, 5700 West 96th Street, Los Angeles, CA900456-5597) provides a kit for measuring the concentration of estradiol bound to proteins and free estradiol Androgen is the collective term for a group of spheroids, both natural and artificial, and in women, androgens are produced by the ovaries and adrenocortex.The natural androgens include androsterone, dehydroandrosterone, testosterone and androstane -dione Testosterone is by far the most potent natural hormone Testosterone circulates through the body almost entirely bound to proteins, less than one percent is in free status. Free testosterone provides an accurate measure of the concentration of androgens. The concentration of free testosterone in the normal pre-menopausal woman is approximately 0.9 picograms per milliliter of blood. Therefore, in a preferred MODALITY the person possesses a free testosterone concentration equal to or greater than 0.9 picograms per milliliter of blood. Methods and kits for determining free blood testosterone concentrations are well known to those skilled in the art, for example Coat-a-Count® Esradiol [obtainable by means of DOC® (Diagnostic Products Corporation, 5700 West 96th Street, Los Angeles , CA900456-5597].

The female person can be pre-menopausal, peri-menopausal, post-menopausal or menopausal surgically, ie, post-isterectomy. In a preferred MODALITY the person is post-menopausal. Those skilled in the art will appreciate that the person, in addition to suffering from FSAD, may also suffer from FOD or sexual pain disorders as long as they are secondary to FSAD. In this specification, hereafter, the expression "PDE5 inhibitor" means the PDE5 inhibitors for use with the invention. The ex-pressure includes pharmaceutically acceptable salts, solvates and polymorphs of the PDE5 inhibitors, for use with the invention. The ability to adapt the PDE5 inhibitor can be easily determined by evaluating its potency and selectively using the methods described in the literature, which are followed for the evaluation of its toxicity, absorption, metabolism, pharmacokinetic characteristics, etc. in accordance with standard pharmaceutical practice. Preferably, PDE5 inhibitors possess an IC50 against PDE5 enzyme less than 100 nanomolar, more preferably, less than 50 nanomolar. The IC50 values for PDE5 inhibitors can be determined using the PDE5 assay set out in the Test Methods Section, below.

Preferably, the PDE5 inhibitors are selective for the PDE5 enzyme. Preferably they possess a selectivity of PDE5 on PDE3 greater than 100, more preferably greater than 300. More preferably, PDE5 has a selectivity on both PDE3 and PDE 4 greater than 100. more preferably greater than 300. The selectivity ratios can be easily determined by those skilled in the art, by the ratio corresponding to the IC 50 values for the particular enzymes to which it concerns. The IC 50 values for the enzyme PDE3 and PDE4 can be determined using the methodology established in the scientific literature (see the work of S.A. Ballard et al., Journal of Urology, 1998, vol.15 159, pages 2164-2171). Preferably the PDE5 inhibitors possess an IC50 against PDE5 of less than 100 nM and a selectivity over PDE3 of more than 100 times. Examples of PDE5 inhibitors for use with the invention are: The pyrazolo [4,3-d] pyrimidin-7-ones described in EP-A-0463756; the pyrazolo [4,3-d] pyrimidin-7-ones, described in the published international patent application WO 93/06104; isomeric p-arazoo [3,4-d] pyrimidin-4-ones, described in published international patent application WO 93/07149; the quinazolin-4-ones described in the published international patent application WO 93/12095; the pyrido [3,2-d] pyrimidin-4-ones described in the published international patent application WO 94/05661; the purin-6-ones described in the published international patent application WO 94/00453; the pyrazolo [4,3-d] pyrimidin-7-ones described in the published international patent application WO 98/49166; the pyrazolo [4,3-d] pyrimidin-7-ones described in the published international patent application WO 99/54333; the pyrazolo [4,3-d] pyrimidin-4-ones described in EP-A-0995751; the pyrazolo [4,3-d] pyrimidin-7-ones described in the published international patent application WO 00/24745; the pyrazolo [4,3-d] pyrimidin-4-ones described in EP-A-0995750; the compounds described in the published international patent application W095 / 19978; the compounds described in the published international patent application WO 99/24433 and the compounds described in the published international patent application WO 93/07124. The pyrazolo [4,3-d] pyrimidin-7-ones described in the published international patent application WO 01/27112; the pyrazolo [4,3-d] pyrimidin-7-ones described in the published international patent application WO 01/27113; the compounds described in EP-A-109278 and the compounds described in EP-A-1092719. Preferred PDE5 inhibitors for use with the invention: 5- [2-Ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro- 7H-pyrazolo [4,3-d] pyrimidin-7-one (sildenafil) also known as 1 - [[3- (6,7-dihydro-1-methyl-7-oxo-3-propyl-1 H-pyrazolo [4,3-d] pyrimidin-5-yl) -4-ethoxyphenyl] sulfo-nyl] -4-methylpiperazine (see EP-A-0463756); 5- (2-ethoxy-5-morpholinoacetylphenyl) -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (see EP document -A-0526004); 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2-n-propoxyphenyl] -2- (pyridin-2-yl) methyl-2,6-dydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (see WO 98/49166) 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridine -3-yl] -2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrrazolo [4,3-d] pyrimidin-7-one (see WO 99) / 54333). (+) - 3-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy-1 (R) -methyletoxy) pyridin-3-yl] -2-methyl-2, 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one, also known as 3-ethyl-5-. { 5- [4-ethylpiperazin-1-ylsulfonyl] -2 - ([(1 R) -2-methoxy-1-methylethyl] oxy) pyridin-3-yl} -2-methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (see WO 99/54333); 5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- [2-methoxyethyl] -2,6-dihydro-7H-pyrazolo [4 , 3-d] pyrimidin-7-one, also known as 1-. { 6-Ethoxy-5- [3-ethyl-6,7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-pyrazolo [4,3-d] pyrimidin-5-yl] -3-pyridylsulfon l} -4-ethylpiperazine (see WO 01/27113, Example 8); 5- [2- / so-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- (1-methylpperidin-4-yl) -2,6- dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (see WO 01/27113, Example 15); 5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-etl-2-phenyl-2,6-dlhydro-7H-pyrazolo [4.3 -d] pirimdin-7-one (see WO 01/27113, Example 66); 5- (5-acetyl-2-propoxy-3-pyridinyl) -3-ethyl-2- (1-isopropyl-3-azetidyl) -2,6-dihydro-7H-pyrazolo [4.3- d] pyrimidin-7-one (see WO 01/27112, Example 124); 5- (5-acetyl-2-butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-d] py! midin-7-one (see WO 01/27112, Example 132); (eR. ^ aR ^ .S.ej. ^. ^ a-hexahydro ^ -methyl-e-S S -methylendyl-xyphenyl) pyrazino- [2 ', 1': 6,1] pyrido [3,4-b ] indole-1,4-dione (IC-351), that is to say, the compound of examples 78 and 95 of published international patent application WO 95/19978, as well as the compound of examples 1, 3, 7 and 8. 2- [2-ethoxy-5- (4-ethylpiperazin-1-yl] -1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-ylamido [5,1-f ] [1, 2,4] triazin-4-one (vardenafil), also known as 1 - [[3- (3,4-dihydro-5-methyl-4-oxo-7-propylimidazo [5]] , 1-f] -as-triazin-2-yl) -4-ethoxyphenyl] -4-ethylpiperazine, ie the compound of examples 20, 19, 337 and 336 of the published international patent application WO 99/24433; and the compound of Example 11 of published international patent application WO 93/07124 (EISAI); and compounds 3 and 14 of Rotella D P, in J. Med. Chem., 2000, 43, 1257. Still other PDE5 inhibitors for use with the invention include: 4-bromo-5- (pyridylmethylamino) -6- [3- (4-chlorophenyl) propoxy] -3 (2H) pyridazinone; 1- [4 - [(1,3-benzodioxol-5-methylmethyl) amino] -6-chloro-2-quinozolinyl] -4-pyridine-carboxylic acid, monosodium salt; (+) - cis-5,6a, 7,9,9,9a-hexahydro-2- [4- (trifluoromethyl) phenylmethyl-5-methylcyclopent-4,5] imidazo [2, ^ b] purin-4 - (3H) ona; furazlocilli-na; c \ s-2- ex \\ - 5-met \\ - 3,4,5, Q3i, 8, Q, 9a ~ octahydrocyclopent [4,5] -imidazo [2,1-b] purin-4-one; 3-acetyl-1- (2-chlorobenzyl) -2-propylindole-6-carboxylate; 3-acetyl-1- (2-ciorobenzyl) -2-propyldole-6-carboxylate; 4-bromo-5- (3-pyridylmethylamino) -6- (3- (4-chlorophenyl) propoxy) -3- (2H) pyridazinone; 1-methyl-5- (5-morpholinoacetyl-2-n-propoxyphene-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one: acid 1 - [4 - [(1,3-benzodioxol-5-ylmethyl) amino] -6-chloro-2-quinazolinyl] -4-piperidine carboxylic acid, monosodium salt; Pharmaprojects No. 4516 (Glaxo Wellcome); Pharmaprojects No. 5051 (Bayer); Pharmaprojects No. 5064 (Kyowa Hakko, see WO 98/26940); Pharma-. projects No. 5069 (Schering Plow); GF-196960 (Glaxo Wellcome); E-8010 and E-4010 (Eisai); Bay-38-3045 and 38-9456 (Bayer) and Sch-51866. The contents of published patent applications and articles of journals and, in particular, the general formulas of the therapeutically active compounds of the claims and the exemplified compounds therein, are hereby incorporated by reference in their entirety. More preferred PDE5 inhibitors for use with the invention are selected from the group of: 5- [2-Ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1 , 6-D-Hydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (sildenafil); (6R, 12aR) -2,3,6,7, 2, 12a-hexahydro-2-methyl-6- (3,4-methylenedioxypheni pyrazino-P'.l'ie.ljpiridoIS ^ -bjíndole-l ^ -dione (IC-351); 2- [2-ethoxy-5- (4-ethylpiperazin-1-yl-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-n- [ 1, 2,4] triazin-4-one (vardenafil), and 5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-et L-2- [2-methoxyethyl] -2,6-dithy-7-pyrazolo [4,3-d] pyrimidin-7-one or 5- (5-acetyl-2-butoxy-3) -pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one, and its pharmaceutically acceptable salts. of the particularly preferred PDE5 is 5- [2-ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4, 3-d] -pyrimidin-7-one (sildenafil) (also known as 1 - [[3- (6,7-dihydro-1-methyl-7-oxo-3-propyl-1 H-pyrazolo [4,3] -d] pyrimidin-5-yl) -4-ethoxyphenyl] -sulfonyl] -4-methylpiperazine) and its pharmaceutically acceptable salts The sildenafil citrate is a preferred salt. this memory, the expression "the agonist of 5HT1 a "means the agonists of 5HT1a for use with the invention Expression includes pharmaceutically acceptable salts, solvates and polymorphs of the 5HT1a agonists for use with the invention The fitness of 5HT1a agonists can be easily determined by evaluation of its potency and selectivity using methods listed in the scientific literature, followed by evaluation of its toxicity, absorption, metabolism, pharmacokinetic characteristics, etc., in accordance with standard pharmaceutical practice.

Preferably, 5HT1a agonists possess affinity for the recombinant human 5HT1a receptor with a Ki less than or equal to 300 nM, preferably with a Ki less than or equal to 100 nM, more preferably with a Ki less than or equal to 30 nM, still more preferably with a Ki less than or equal to 10 nM and most preferably, with a Ki less than or equal to 1 nM. The EC50 values for the 5HT1a agonists can be determined using the 5HT1a assay of the Test Methods Section set forth hereinafter. Preferably, the agonists have an EC50 less than or equal to 300 nM, preferably an EC50 less than or equal to 100 nM, more preferably an EC50 less than or equal to 30 nM, still more preferably an EC50 less than or equal to 10 nM, and at most preferable, an EC50 less than or equal to 1 nM. Preferably, the 5HT1 a agonists are selective for the 5HT a receptor on alpha-adrenergic receptors and dopamine. Examples of 5HT1a agonists for use with the invention are: Zaprasidone, buspirone.HCl, Urapidil, Tandosporin, Sunepitron, Ebalzotan, Ipsapirone, Zalospirone, Genopirone, Repinotan, Alnespirone, MKC242, Eptapirone, SR57746A, AP-521, SUN-N4057, Lesopitron, DU-125530, VML-670, Flesinoxan, E6265, Flibanserin, Buspar, AP-521, SUN-N4057, LY293284, LY301317 and 8-OH-DPAT. Flibanserin is particularly preferred.

Particularly preferred combinations are those of Sildenafil or 2- (methoxyethyl) -5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2,6-dihydro-7H -pyrazolo [4,3-d] pyrimidin-7-one with Flibanserin. Oral bioavailability refers to the proportion of a drug administered orally that reaches the systemic circulation. The factors that determine the oral bioavailability of a drug are dissolution, permeability through membranes and metabolic stability. Typically, a cascade of techniques exploration is used to determine the oral bioavailability, first in vitro and then in vivo. The dissolution, the solubilization of the drug by the aqueous contents of the gastrointestinal tract (GIT) can be predicted starting from in vitro solubility experiments carried out at an appropriate pH that simulates that of the GIT. Preferably, the PDE5 inhibitors have a minimum solubility of 50 mcg / ml. Solubility can be determined by standard operating procedures known in the art, as described in Adv. Drug Deliv. Rev. 23, 3-25, 1997. Membrane permeability refers to the passage of a compound through the cells of the GIT. Lipophilicity is a key property to predict this and is defined by in vitro measurements of Log D7,4 using organic solvents and buffer solutions. Preferably, the PDE5 inhibitors possess a Log D7 | 4 of -2 to +4, more preferably of -1 to +3. Log D can be determined by standard procedures known in the art, as described in J. Pharm. Pharmacol. 1990, 42: 144. Assays in monolayers of cells such as CaCo2 are substantially added to the prediction of favorable membrane permeability in the presence of flow transporters such as p-glycoprotein, termed caco-2 flux. Preferably, the PDE5 inhibitors possess a caco-2 flux greater than 2x10"6 cm" 1 more preferably greater than 5 x 10"6 cm" 1. The value of the flux can be determined by standard procedures known in the art, as described in J. Pharm. Sci., 1990, 79, 595-600. Metabolic stability expresses the ability of the GIT or the liver to metabolize compounds during the absorption process: the first effect of the pass. Test systems such as microsomes, hepatocytes, etc. They are able to predict metabolic responsibility. Preferably, the PDE5 inhibitors demonstrate metabolic stability in the assay system, which is provided with a liver extraction less than 0.5. Examples of test and data handling systems are described in Curr. Opin. Drug Disc. Devel., 201, 4, 36-44, Drug Met. Disp., 2000, 28, 1518-1523. Due to the reciprocal action of the above processes, it is further supported that a drug can be bioavailable orally in humans by live experiments carried out on animals. Absolute bioavailability is determined in these studies by administering the compound separately or in mixtures, by oral route. For absolute determinations (% absorbed), the intravenous route is also used. Examples of the verification of oral bioavailability in animals can be found in Drug Met. Disp., 2001, 29, 82-87; J. Med. Chem., 1997, 40, 827-829, and Drug Met. Disp., 1999, 27, 221-226. PDE5 inhibitors and 5HT1a agonists can also be combined with one or more additional active agents to treat sexual dysfunction, particularly FSAD in people with concurrent major HSDD. Additional active agents may be selected from the following list: 1) one or more of the natural or synthetic prostaglandins or their esters (prostaglandins suitable for use in this invention include compounds such as alprostadil, prostaglandin Ei, prostaglandin glandin E0, 13,14-dihydroprostaglandin Ei, prostaglandin E2, eprostinol, natural, synthetic and semi-synthetic prostaglandins and their derivatives, including those described in WO-00033825 and / or US 6,037,346 issued on 14 March 2000, all incorporated herein by reference, PGE0, PGE ^ PGA ^ PGBL PGF! a, 19-hydroxy PGAi, 19-hydroxy-PGBi, PGE2, PGB2, 19-hydroxy-PGA2, 19-hydroxy-PGB2 , PGE3 a, carboprost tromethamine dino- prost, tromethamine, dinoprostone, lipoprost, germeprost, metenoprost, sulprostuna, tiaprost and moxislate); one or more a-adrenergic receptor antagonists (also known as a-adrenoreceptor blockers, a-blockers or a-blockers); Suitable α-adrenergic receptor antagonists include: phentolamine, prazosin, phentolamine mesylate, trazodone, alfusozin, indoramin, naftopidil, tamsulosin, phenoxybenzamine, rauwolfia alkaloids, Recordati 15/2739, SNAP 1069, SNAP 5089, RS17053, SL 89.0591 , doxazosin, terazosin and abanoquilo; Suitable a2-adrenergic receptor antagonists include dibenamine, tolazoline, trimazosin, efaroxan, yohimbine, ida-zoXan clonidine and dibenamine; suitable non-selective a-adrenergic receptor antagonists include dapiprazole; other a-adrenergic receptor antagonists are described in PCT patent application WO 99/30697 published June 14, 1998 and in U.S. Pat. 4,188,390; 4,026,894; 3,511,836; 4,315,007; 3,527,761; 3,997,666; 2,503,059; 4,703,063; 3,381,009; 4,252,721 and 2,599,000, each of which is incorporated herein by reference. one or more NO-donating compounds (NO agonists) (NO-donor compounds suitable for use in this invention include organic nitrates such as mono-, di- or trinitrates or organic nitrate esters including glyceryl trinitrate (also known as nitroglycerin) , 5-isosorbide mononitrate, isosorbide dinitrate, pentaerythritol tetra nitrate, erythrityl tetranitrate, sodium nitroprusside (SNP), 3-morpholinosidnonimine molsidomine, S-nitroso-N-acetyl penicilliamine (SNAP), Snirose N-glutathione (SON-GLU), N-hydroxy-L-arginine, amyl nitrate, linsidomine, linsidomine hydrochloride, (SIN-1) S-nitroso-N-cysteine, diazenium diolate, (NONOatos), 1, 5-pentanodinitrate, L-arginine, ginseng, zizfi fructus, molsidomine, Re-2047, nitrosylated maxisilyl derivatives such as NMI-.678-11 and MI-937 as described in published PCT patent application WO 0012075) , one or more potassium channel openers or modulators (openers / mo suitable potassium channel dulators for use in this invention include nicorandil, cromokalim, levcromakalim, lemakalim, pi-nacidyl, cliazoxide, minoxidil, charibdotoxin, glyburide, 4-aminopyridine, BaCl2); one or more dopaminergic agents, preferably apomorphine or a selective agonist D2, D3 or D2 / D3 such as, pramipexole and ropyrinol (as claimed in WO-0023056), PNU95666 (as claimed in WO-0040226); one or more vasodilating agents (vasodilating agents suitable for use herein include nimodepine, pinacidil, cycllandelate, isoxsuprine, chloroprumazine, alloperidol, Rec 15/2739, trazodone); one or more thromboxane A2 agonists; one or more ergot alkaloids (suitable ergot alkaloids are described in U.S. Patent 6,037,346 issued March 14, 2000 and include, acetergamine, brazergoline, bromerguride, cyanarginine, delorgotrila, dysulergine, maleate ergonovine, ergo- tamine tartrate, etisulergine, lergotryl, lysergide, mesulergine, met- rogoline, methylgotamine, nicergoline, pergolide, propysergide, proterguride, terguride); ) one or more compounds that modulate the action of natriuretic factors, in particular atrial natriuretic factor (also known as atrial natriuretic peptide), type B and type C natriuretic factors such as inhibitors or neutral endopeptidase (see below); 10) one or more angiotensin receptor antagonists such as lortartan; 11) one or more substrates for NO-synthase, such as L-arginine; 12) one or more calcium channel blockers, such as amiodipine; 13) one or more receptor antagonists and inhibitors of endothelin or endothelin conversion enzyme; 14) one or more cholesterol lowering agents such as statins (e.g., atorvastatin / Lipitor-registered trademark) and fibrates; 15) one or more antiplatelet and antithrombotic agents, for example tPA, uPA, warfarin, hirudin and other thrombin inhibitors, heparin, inhibitors of thromboplastin activation factor; 16) one or more insulin sensitizing agents, such as rezulin and hypoglycemic agents such as glipizide; ) one or more acetylcholinesterase inhibitors such as donezipyl; ) one or more modulators of estrogen receptors and / or estrogen agonists and / or estrogen antagonists, preferably raloxifene, tibolone or lasofoxifene, (-) - cis-6-phenyl-5- [4- (2-pyrrolidin-1) -yl-ethoxy) phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol and its pharmaceutically acceptable salts, the preparation of which is detailed in WO 96/21656; ) one or more other PDE inhibitors, in particular a PDE 2, 7 or 8 inhibitor, preferably a PDE2 inhibitor, said inhibitors preferably having an IC 50 against the respective enzyme of less than 100 nM; ) one or more of an NPY inhibitor (neuropeptide Y), more particularly an inhibitor of NPY1 or NPY5, preferably an inhibitor of NPY1, preferably having said NPY inhibitors (including NPY Y1 and NPY Y5) an IC50 of less than 100 nM, more preferably less than 50 nM (an assay for identifying inhibitors of NPY is presented in WO-A-98/52890 (see page 96, lines 1 to 18)); ) one or more of the vasoactive (VIP) intestinal protein, mimic (mimetic) of VIP, analog of VIP, more particularly mediated by one or more of the VIP receptor subtypes VPAC1, VPAC or PACAP (pituitary activation peptide) adenylate cyclase), one or more of a VIP receptor agonist or a VIP analogue (eg Ro-125-1553) or a VIP fragment, one or more of a c-adrenoceptor antagonist with VIP combination , for example, Invicorp, Aviptadilo); 22) one or more of an melanocortin receptor or melanocortin receptor agonist or modulator, such as melanotan II, PT-14, PT-141 or compounds claimed in WO-09964002, WO-00074679, WO-09955679, WO-00105401, WO-00058361, WO-00114879, WO-00113112, WO-09954358; 23) one or more of an agonist, antagonist or modulator of the serotonin receptor, more particularly agonists, antagonists or modulators, for example the 5HT2A, 5HT2C, 5HT3, 5HT6 and / or 5HT7 receptors, including those described in WO- 09902159, WO-00002550 and / or WO-00028993; 24) one or more of an androgen such as androsterone, dehydroandrosteran, testosterone, androstanedione and a synthetic androgen; 25) one or more of an androgen receptor modulator, for example tibolone; 26) one or more of an estrogen such as estradiol, estrone, estriol and a synthetic estrogen, such as estrogen benzoate: 27) one or more of a modulator of noradrenaline, dopamine and / or serotonin transporters, such as bupropion, GW-320659; 28) one or more of an agonist and / or a modulator of a purinergic receptor; 29) one or more of a neurokinin receptor (NK) antagonist, including those described in WO-09964008; 30) one or more of an opioid receptor agonist, antagonist or modulator, preferably ORL-1 receptor agonists; 31) one or more of an oxytocin / vasopressin receptor agonist or modulator, preferably a selective oxytocin agonist or modulator; 32) one or more of a cannabinoid receptor modulator; 33) one or more NEP inhibitors, preferably wherein said NEP is EC 3.4.24.11 and more preferably wherein said NEP inhibitor is a selective inhibitor for EC 3.4.24.11, more preferably a selective NEP inhibitor is a selective inhibitor for EC 3.4.24.11, which has an IC50 of less than 100 nM (for example, ompatrilat, sam-patrilat); Suitable NEP inhibitor compounds are described in EP-A-1097719; the IC50 values against NEP and ACE can be determined using the methods described in published patent application EP1097719-A1, paragraphs

[0368] to

[0376]; 34) one or more compounds that inhibit the angiotensin-converting enzyme such as enalapril, and one or more combined inhibitors of the angiotensin-converting enzyme, and neutral endopeptidase, such as omapatrilat; 35) one or more of L-DOPA and carbidopa; 36) One or more COX2 inhibitors; 37) pregabalene and gabapentene; 38) one or more non-steroidal anti-inflammatory agents; 39) one or more inhibitors of the angiotensin converting enzyme (ACE), for example, quinapril; 40) one or more of a bombesin receptor modulator, preferably selective for the BB1 receptor; 41) one or more antidepressants such as bupion; If a combination of active agents is administered, then these agents can be administered simultaneously, separately or successively. Preferably, the inhibitors of PDE5 (in particular the silde-naphyl) and the 5HT1a agonist can be combined with one or more active agents selected from the following list: i) one or more of an androgen such as androsterone, dehydroandrosterone , testosterone, androstanedione and a synthetic androgen; ii) one or more of an estrogen, such as estradiol, estrone, estriol and a synthetic estrogen, such as estrogen benzoate; iii) one or more NEP inhibitors, preferably wherein said NEP is EC 3.4.24.11 and more preferably wherein said NEP inhibitor is a selective inhibitor for EC 3.4.24.11, more preferably a selective NEP inhibitor is a selective inhibitor for EC 3.4.24.11, which has an IC50 less than 100 nM (e.g., ompatrilat, sampatrilat); Suitable NEP inhibitor compounds are described in EP-A-1097719; one or more than one NPY1 having an IC50 of less than 100 nM, more preferably less than 50 nM; for examples see published European patent application EP1 097 718 A1; one or more modulators of estrogen receptors and / or estrogen agonists and / or estrogen antagonists, preferably raloxifene, tibolone or lasofoxifene, (-) - cis-6-phenyl-5- [4- (2-pyrrolidin-1- il-ethoxy) phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol and their pharmaceutically acceptable salts, the preparation of which is detailed in WO 96/21656; one or more of an melanocortin receptor agonist or modulator or melanocortin enhancer, such as melanothane II, PT-14, PT-141 or compounds claimed in WO-09964002, WO-00074679, WO-09955679, WO-00105401 , WO-00058361, WO-00114879, WO-00113112, WO-09954358 (preferably PT-141); one or more dopaminergic agents, preferably apomorphine or a selective agonist D2, D3 or D2 / D3 such as pramipexole and ropinol (as claimed in WO-0023056), PNU95666 (as claimed in WO-0040226); one or more bombesin receptor modulators; one or more antidepressants such as bupion; and one or more modulators of 5HT a (for example VML 670).

Particularly preferred combinations are for treating FSAD in subjects with concurrent major HSDD: Sildenafil, Flibanserin and an androgen; sildenafil, Flibanserin and an estrogen; sildenafil, Flibanserin, an androgen and an estrogen; sildenafil, Flibanserin and lasofoxifene; sildenafil, Flibanserin, lasofoxifene and an androgen; sildenafil, Flibanserin, lasofoxifene and an estrogen; or sildenafil, Flibanserin, lasofoxifene, an androgen and an estrogen; sildenafil, Flibanserin and a NEP inhibitor; sildenafil, Flibanserin, an inhibitor of NEP and an androgen; sildenafil, Flibanserin, an inhibitor of NEP and an estrogen; or sildenafil, Flibanserin, an inhibitor of NEP, an androgen and an estrogen; sildenafil, Flibanserin and a dopaminergic agent (preferably apomorphine); sildenafil, Flibanserin, a dopaminergic agent (preferably apomorphine) and an androgen; sildenafil, Flibanserin, a dopaminergic agent (preferably apomorphine) and an estrogen; sildenafil, Flibanserin, a dopaminergic agent (preferably apomorphine), an androgen and an estrogen; sildenafil, Flibanserin and a melanocortin enhancer (preferably PT-141); sildenafil, Flibanserin, a melanocortin enhancer (preferably PT-141) and an androgen; sildenafil, Flibanserin, a melanocortin enhancer (preferably PT-141) and an estrogen; sildenafil, Flibanserin, a melanocortin enhancer (pre-ferred PT-141), an androgen and an estrogen; Sildenafil, Flibanserin and Buprion; sildenafil, Flibanserin, bupion and an androgen; Sildenafil, Flibanserin, Buprion and an Estrogen; Sildenafil, Flibanserin, Buprion, an androgen and an estrogen.

PDE5 inhibitors with 5HT1a agonists and their combinations can be administered alone, but are generally administered in admixture with a suitable excipient, diluent or pharmaceutical carrier, selected with respect to the intended route of administration and standard pharmaceutical practice. For example, inhibitors of PDE5 with 5HT1a agonists and their combinations can be administered orally, buccally or sublingually, in the form of tablets, capsules, multi-particulate preparations, gels, films, ovules, elixirs, solutions or suspensions, which may contain flavoring agents or coloring agents, for immediate, delayed, modified, sustained, pulsed or controlled release applications. PDE5 inhibitors with 5HT1a agonists and their combinations can also be administered as fast dispersing pharmaceutical forms or rapid dissolving dosage forms, or in the form of a high energy dispersion or as coated particles. Suitable formulations may be in coated or uncoated form, as desired. Such solid pharmaceutical compositions, for example, compounds, may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably corn starch, potato starch or tapioca starch), disintegrating agents such as sodium starch glycolate, cros-carmellose sodium and certain complex silicates, and binders for granulation such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC). sucrose, gelatin and gum arabic. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. The examples of formulations listed below are illustrative only and are not intended to limit the scope of the invention. Active ingredient means an inhibitor of PDE5 with 5HT1a agonists, or their combination.

FORMULATION 1 A tablet is prepared using the following ingredients: Active ingredient (50 mg) is mixed with cellulose (microcrystalline) silicon dioxide, stearic acid (smoked), and the mixture is compressed by taking tablets.

FORMULATION 2 An intravenous formulation can be prepared by mixing active ingredient (100 mg) with isotonic saline (1000 ml).

The tablets are manufactured by a standard procedure, for example, direct compression, or a wet or dry granulation process. The tablet cores can be coated with appropriate coatings. Solid compositions of a similar type can also be used as fillers in gelatin or HPMC capsules. Preferred excipients in this regard include lactose, starch, a cellulose, lactose or high molecular weight polyethylene glycols. For suspensions and / or aqueous elixirs, PDE5 inhibitors with 5HT1a agonists can be mixed with various sweetening or flavoring agents, coloring matters or colors, with emulsifying agents and / or suspending agents, and with diluents such as water, ethanol, propylene glycol and glycerin, and their combinations.

The pharmaceutical forms of modified release and pulsatile delivery may contain excipients such as those detailed for immediate release pharmaceutical forms together with additional excipients such as transfer rate modifiers, being coated and / or included in the body of the device. Transfer rate modifiers include, but are not limited to, hydroxypropylmethylcellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, ethylene polyoxide, xanthan gum, Carbomer, ammonium methacrylate copolymer, hydrogenated castor oil , carnauba wax, paraffin wax, cellulose acetalphthalate, hydroxypropylmethylcellulose phthalate, methacrylic acid copolymer and their mixtures The pharmaceutical forms of modified release and pulsatile cession may contain one or a combination of excipients to modify the transfer speed . The excipients for modifying the transfer rate can be present both within the pharmaceutical form, that is, within the matrix, and / or on the pharmaceutical form, that is, on the surface or coating. Pharmaceutical dispersion or rapid dissolution formulations (FDDFs) may contain the following ingredients: aspartame, acesul-famo potassium, citric acid, croscarmellose sodium, crospovidone, diascorbic acid, ethyl acrylate, ethylcellulose, gelatin, hydroxypropylmethylcellulose, stearate magnesium, mannitol, methyl methacrylate, mint-flavored flavorings, polyethylene glycol, fumed silica, silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, sorbitol, xylitol. The terms "dispersion" and "dissolution" as used herein to describe FDDFs depend on the solubility of the drug substance employed, ie, when the drug substance is insoluble, a pharmaceutical form of rapid dispersion can be prepared and when the substance medicament is soluble a quick dissolving pharmaceutical form can be prepared. PDE5 inhibitors with 5HT1a agonists and combinations thereof can also be administered parenterally, for example, intracavernously, intravenously, intraarterially, intraperitoneally, intrathecally, intra-ventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously, or be administered by infusion techniques or injection techniques without the need for a needle. For such parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the preparation isotonic with the blood. The aqueous solutions should be suitably buffered (preferably at a pH from 3 to 9) if necessary. The preparation of suitable parenteral formulations under sterile conditions is easily carried out by standard pharmaceutical techniques, well known to those skilled in the art. The following dose levels and other dose levels shown herein are for the average human being with a weight range of approximately 65 to 70 kg. Those skilled in the art will be able to easily determine the dose levels required for a person whose weight falls outside this range, such as children and adults.

The dosage of the PDE5 inhibitor with 5HT1a agonists in such formulations will depend on its potency, but it is expected to be in the range of from 1 to 500 mg for administration up to three times a day. In the case of sildenafil, the preferred dose is in the range of 10 to 100 mg (eg, 10, 25, 50 and 100 mg) which may be administered once, twice or three times a day (preferably at one time) . However, the precise dose will be determined by the doctor who prescribes the administration and will depend on the age and weight of the person and the severity of the symptoms. For oral and parenteral administration to human patients, the daily dose level of the PDE5 inhibitors is usually from 5 to 500 mg / kg (in a single dose or in divided doses). Thus, the tablets or capsules may contain from 5 mg to 250 mg (for example 10 to 100 mg) of the PDE5 inhibitor to be administered once or two or more at a time, as appropriate. In any case, the doctor will determine the most appropriate real dose for an individual patient and this dose will vary with the age, weight and response of the particular patient. The above doses are examples of the middle case. There may, of course, be individual cases in which it is necessary to apply higher or lower doses, and such cases are within the scope of the invention. Those skilled in the art will appreciate that PDE5 inhibitors can be taken as a single dose as needed or desired (ie, prn). It is to be appreciated that all references in this specification relating to treatment include acute treatment (taken as needed) and chronic treatment (continued longer term treatment). PDE5 inhibitors with 5HT1a agonists and combinations thereof can also be administered intranasally or by inhalation, and are conveniently provided in the form of a dry powder inhaler or in an aerosol spray presentation from a package placed under pressure, pump, spray, atomizer or nebulizer, with or without the use of a suitable propellant agent, for example, dichlorodifluoromethane, trichloro-fluoromethane, diclochlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1-tetrafluoroethane (HFA 134A [trademark] ) or 1, 1,1, 2,3,3,3-heptafluoropropane (HFA 227EA [trademark]), carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dose unit can be determined by supplying a valve to provide a measured quantity. The package placed under pressure, pump, spray, atomizer or nebulizer may contain a solution or suspension of the active compound, prepared, for example, using a mixture of ethanol and the propellant agent as a solvent, which may additionally contain a lubricant, for example, sorbitan trioleate. Capsules and cartridges (made, for example, of gelatin) for use in an inhaler or insufflator can be formulated so as to contain a powder mixture of the PDE5 inhibitor and a suitable powder base such as lactose or starch. The formulations in the form of an aerosol or of dry powder are preferably arranged in such a way that each metered dose or "impulse" contains from 1 μg to 50 mg of a PDE5 inhibitor, to be administered to the patient. The general daily dose with an aerosol will be in the range from 1 μg to 50 mg, which can be administered in a single dose or, more usually, in divided doses throughout the day. Alternatively, inhibitors of PDE5 with agonists of 5HT1a and its combinations can be administered in the form of suppositories or pessaries, or they can be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or powder to sprinkle. PDE5 inhibitors with 5HT1a agonists and their combinations can also be administered dermally or transdermally, for example, by using a patch to apply to the skin, or injection "depot" or a subcutaneous injection. They can also be administered through the pulmonary or rectal routes. To apply topically to the skin, inhibitors of PDE5 with 5HT1a agonists and combinations thereof can be formulated as a suitable ointment containing the active ingredient suspended or dissolved therein, eg, a mixture with one or more of the following compounds: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or cream, suspended or dissolved, for example, in a mixture of one or more of the following compounds: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, wax cetyl esters, ketostearyl alcohol, 2-octyldodecanol, benzyl alcohol and water PDE5 inhibitors with 5HT1 agonists and their combinations can also be used in admixture with a cyclodextrin. It is known that cyclodextrins form inclusion and non-inclusion complexes with drug molecules. The formation of a drug-cyclodextrin complex can modify the solubility, dissolution rate, bioavailability and / or stability property of a drug molecule. The drug-cyclodextrin complexes are useful, in general, for most pharmaceutical forms and routes of administration. As an alternative to the direct formation of complexes with the drug, the cyclodextrin can be used as an auxiliary additive, for example, as a carrier, a diluent or a solubilizer. Alpha, beta and gamma cyclodextrins are the most commonly used and suitable examples are described in WO-A-91/11172, WO-A-94/02518 and WO-A-98/55 48. Oral administration of the PDE5 inhibitors with 5HT1a agonists and their combinations is a preferred route because it is the most convenient. In cases where the recipient suffers from a swallowing disorder or from deterioration of the absorption of the drug after oral administration, the drug can be administered parenterally, sublingually or buccally. Transdermal administration of PDE5 inhibitors with 5HT1a agonists and combinations thereof is another preferred route, in particular local administration to the female genital tract, preferably intravaginally. A preferred method of transdermal administration of estrogen and testosterone is the use of a patch, "depot" or implants in the skin.

The preferred dose of an estrogen to combine with the PDE5 inhibitor and the 5HT1a agonist is in the range of 0 to 5 mg per day. The preferred dose of an androgen to combine with the PDE5 inhibitor and the 5HT1a agonist is in the range of 0 to 25 mg per day. Since the invention has a MODALITY that relates to the treatment of sexual dysfunction, with a combination of compounds that can be administered separately at the same time, the invention also relates to the combination of pharmaceutical compositions in the form of a kit. Accordingly, according to another aspect, the invention provides a kit comprising: a) a first pharmaceutical composition comprising a PDE5 inhibitor and a pharmaceutically acceptable excipient or diluent; b) a second pharmaceutical composition comprising a 5HT1a agonist and a pharmaceutically acceptable excipient or diluent; and a container for the two compositions. According to another aspect, since the invention has a MODALITY that relates to the treatment of FSAD with concomitant HSDD, with a combination of compounds that can be co-administered separately, the invention also relates to combining separate pharmaceutical compositions in the form of kit Accordingly, the invention provides a kit comprising: a) a first pharmaceutical composition comprising a PDE5 inhibitor and a pharmaceutically acceptable excipient or diluent; b) a second pharmaceutical composition comprising a 5HT1a agonist and a pharmaceutically acceptable excipient or diluent; c) a third pharmaceutical composition comprising an androgen and a pharmaceutically acceptable excipient or diluent; d) a fourth pharmaceutical composition comprising an estrogen and a pharmaceutically acceptable excipient or diluent and a container for the four compositions. The four compositions are separate components intended for joint administration to a female person suffering from FSAD, in which the patient has hormone concentrations lower than those of the physiological levels found in a normal pre-menopausal woman. By "joint administration" it is meant that the four components can be removed from the kit and combined to be administered together as a composition or as a part thereof, as a unit dosage form, such as a solution administered parenterally or orally. "Joint administration" also includes the administration of the components separately (for example, as pills or capsules), but as part of the same program or therapeutic treatment regimen. Administration "separately" is the preferred mode of administration. It is not necessary to administer all four components at essentially the same time, although this can be done if desired. Thus, "co-administration" includes, for example, administration of the four components as separate doses or dosage forms and essentially at the same time. "Joint administration" also includes separate administration at different times, in any order, and if preferred, by different administration routes. If administered separately, it is preferred that all four components be administered essentially at the same time. If they are administered separately and at different times, it is preferred that the four components be administered within 24 hours of each other. If administered separately, it is preferred that all four components are administered by the same route. An example of a kit is the so-called "blister pack" well known in the packaging industry, in particular for packaging pharmaceutical forms. It will be appreciated that the invention covers the following other aspects and that the embodiments specified hereinabove for the first aspect extend to these aspects. i) a PDE5 inhibitor with a 5HT1a agonist to treat sexual dysfunction; ii) a PDE5 inhibitor with a 5HT1a agonist to treat FSAD in a person having concurrent major HSDD; iii) a pharmaceutical combination (for simultaneous, separate or sequential administration) for the treatment of sexual dysfunction, comprising a PDE5 inhibitor and a 5HT1a agonist, an estrogen, an androgen and, optionally, an active agent additional as defined above in this specification; a pharmaceutical combination (for simultaneous, separate or sequential administration) to treat FSAD in a person having concurrent major HSDD, comprising a PDE5 inhibitor, a 5HT1a agonist, an estrogen, an androgen and, optionally, an agent additional asset as defined above in this specification; The use of a pharmaceutical combination for the manufacture of a medicament for treating FSAD in a person having major concurrent HSDD, comprising a PDE5 inhibitor, a 5HT1a agonist, an estrogen, an androgen and, optionally, an active agent. additional as defined above in this specification; a kit for treating FSAD in a subject that does not have important, concurrent HSDD, which kit contains a) a first pharmaceutical composition comprising a PDE5 inhibitor; b) a second pharmaceutical composition comprising a 5HT1a agonist; c) a third pharmaceutical composition comprising an androgen; d) a fourth pharmaceutical composition comprising an estrogen; e) optionally, a pharmaceutical composition comprising an additional active agent as defined hereinbefore; and f) a container for the compositions; vi) a method for treating FSAD in a patient having significant, concurrent HSDD, comprising treating said patient with an effective amount of a PDE5 inhibitor and a 5HT1a agonist; vil) a method for treating FSAD in a patient having significant, concurrent HSDD, comprising treating said patient with a pharmaceutical combination comprising a PDE5 inhibitor, a 5HT1a agonist, an estrogen, an androgen and, optionally, a additional active agent as defined above in this specification; Y viii) a method to treat FSAD in a person who has important, concurrent HSDD, which comprises the steps of: a) measuring the person's physiological levels of estrogens and androgens: b) if they are not full, administer to the person a estrogen and an androgen to get full levels; and then c) administering a PDE5 inhibitor and a 5HT1a agonist.

TEST The values of the action power of the PDEs referred to in this specification are determined by the following tests.

Preferred PDE compounds, suitable for use according to the present invention, are potent and selective PDE5 inhibitors. The inhibitory activities of PDE in vitro against the phosphodiesterases of guanosine-3 ', 5'-cyclic monophosphate (cGMP) and adenosine-3', 5'-cyclic monophosphate (cAMP), can be determined by measuring their IC50 values ( the concentration of compound required for a 50% inhibition of enzymatic activity). The required PDE enzymes can be isolated from a variety of sources including the human corpus cavernosum, human and rabbit platelets, human cardiac ventricle, human skeletal muscle and bovine retina, essentially by the WJ method. Thompson and M. Apple-man (Biochem., 1971, 10, 311). In particular, cGMP-specific PDE (PDE5) and cAMP PDE inhibited by cGMP (PDE3) can be obtained from human cavernous body tissue, human platelets or cone-platelets; PDE stimulated by cGMP (PDE2) was obtained from human cavernous body; calcium / calmodulin-dependent PDE (Ca / CAM) (PDE1) from human cardiac ventricle; cAMP-specific PDE (PDE4) was obtained from human skeletal muscle; and the photoreceptive PDE (PDE6) of bovine retina. Phosphodiesterases 7-11 can be generated from full length human recombinant clones transfected into SF9 cells. The assays can be carried out or using a modification of the "batch" method of W.J. Thompson et al., (Biochem., 1979, 18, 5528) or using a scintillation proximity assay, for the direct detection of AMP / GMP using a modification of the protocol described by Amers-ham foot under product code TRKQ7090 / 7100 In summary, the effect of PDE inhibitors was investigated by analyzing a fixed amount of enzyme in the presence of varying concentrations of inhibitor and low substrate, (cGMP or cAMP in the 3: 1 ratio unchecked to [3H] labeled in a conc . ~ 1/3 Km) such that IC50 = K¡. The final assay volume was completed to 00 μ? with assay buffer [Tris-HCl 20 mM, pH 7.4, 5 mM MgCb, 1 mg / ml bovine serum albumin]. Reactions were started with the enzyme, incubated for 30-60 minutes at 30 ° C obtaining a rotation of the substrate < 30% and it was finished with 50 μ? of trio-silicate SPA globules (containing 3 mM of the unlabeled cyclic nucleotide, respectively, for PDEs 9 and 11). The plates were hermetically sealed and shaken for 20 minutes, after which the pellets were allowed to settle for 30 minutes in the dark and then counted in a TopCount plate reader (Packard, Meriden, CT). ). The radioactivity units were converted to% activity of an uninhibited control (100%), plotted against the inhibitor concentration and IC50 values of the inhibitor were obtained using the Microsoft Excel extension 'Fit Curve'. Suitable assays for identifying agonists of 5HT1 a are described in J. Pharmacol. Exp. Ther. 1998, 284 (3), 1082-1094 and in J. Phar-macol. Toxicol Methods, 1998, 40 (1), 47-55. Other suitable assays are well known to those skilled in the art.

The diagnosis of FSAD with concomitant HSDD can be achieved through the use of the Sexual History Interview (SHI) administered by sexual health experts for the diagnosis of FSD of potential people. The SHI was developed by a team of internal clinical staff at Pfizer and external experts in sexual health. The SHI leads to two main aspects concerning the inclusion / exclusion of the person; identification of the FSD subcomponent and psychosexual eligibility. These two aspects are key aspects to ensure the proper identification of the "target" population and that the key inclusion and exclusion criteria important for psychosexual eligibility are met. The SHI is detailed later in this report as Appendix 2. An additional "tool" is the use of a female sexual function questionnaire (SFQ) developed by the applicants, published in "Development of a Sexual Function. Questionnaire for Clinical Triais of Sexual Function, "referred to by Heiman in the International Journal of Fertility and Women's Health; 2000, 45; 200 (incorporated herein by reference in its entirety) and as detailed below in Appendix 1.

Appendix 1 The Female Sexual Function Questionnaire (SFQ) RATIONALE AND SCORING The female sexual function questionnaire (SFQ) is the result of a self-report measuring female sexual function, which has been developed to be multidimensional and focused in the person. The SFQ applies to all aspects of the sexual response cycle (desire, arousal, orgasm), as well as pain, which is in accordance with the DSM-IV diagnostic criteria and recently defined AFUD definitions. The concepts content of the SFQ was generated based on the aggregate responses of 82 women in a semi-structured interview. The content of the interview directed, among other things, women's knowledge of the terms and expressions commonly used to describe the phases of the sexual response (for example, desire and excitement) and the language they themselves used to describe these changes. These interviews also uncovered some of the consequences of female sexual dysfunction (FSD) for women, their partners and their relationship, and some of these fundamental consequences are also represented within the content of SFQ concepts. Both aspects, the physical and the cognitive, of the sexual response are evaluated within the SFQ concepts, since these two elements were strongly defined as important, both in terms of the impact of FSD and changes in function. , both positive and negative, in the sample of the women's interview. The content of concepts contained in the SFQ has also been judged as clinically important by an external panel of physicians with experience in psychology, physiology, gynecology, physical medicine and the treatment of FSD. The subsequent use of SFQ in clinical trials in a large sample of women (approximately 900) has shown that it has excellent psychometric properties and has also demonstrated a dis criminative and constructive validity, reliability in retesting, internal consistency and sensitivity with respect to changes. This is the case both at the level of concepts and at the level of mastery (seven domains have been identified through the analysis of factors: Desire, excitement (sensation), excitation (lubrication), orgasm, pain, pleasure and partner) SFQ validity both at the level of concepts and at the domain level, supports the use of individual SFQ domains as primary endpoints (eg, excitement or orgasm), with the remaining domains or individual concepts being used as secondary endpoints . This approach also ensures that all aspects of sexual function are evaluated in a therapeutic area in which the effects of dysfunction and intervention are not currently fully understood. The SFQ has been developed and validated in several languages (18) as well as for use in the USA. and in Australia.

The development of the SFQ has been presented at the Washington Consensus Conference (Bethesda, 1998), the Cape Cod FSD conference (1998) and the International Conference for Medical Studies of Women's Health (San Francisco, 1999). A manuscript, which briefly describes the development of the SFQ, has been provided to the Journal of Women's Health and Gender-Based Medicine ("Development of a sexual function questionnaire for clinical trials of female sexual dysfunction", FH Quirk et al.) The summary has been published in the International Journal of Health and Women's Health2.

References: 1. "Report of the International Consensus Development Conference on Female Sexual Dysfunction: Definitions and Classifications", R. Bas-son et al, Journal of Urology, Vol. 163, pages 888-893, 2000). 2. "Development of a Sexual Function Questionnaire for Clinical Triais of Female Sexual Dysfunction ", J. Helman, International Journal of Fertility and Women's Medicine, vol 45, 2, p200, 2000.

SFQ scoring system (concepts, Total, Domains) INDIVIDUAL CONCEPTS The SFQ contains 34 concepts and each of the concepts has between 5 or 7 possible answer options.

Concepts 1-5, 27-28 and 33-34 are punctuated from 1 to 5 (in ascending order), for example:. In the last 4 weeks, how many times have you had pleasant thoughts and feelings about sexual activity? None at all (1) Rarely (2) Sometimes (3) Frequently (4) Many times (5) Concepts 6-14, 16, 20-21, 23-26 are scored from 1 to 5 (in ascending order) with the category "not applicable" (for example, "I did not take part in sexual activities", I did not have orgasms ") fixed for" lost ", for example: 6. In the last 4 weeks, in general, how was it nice to be touched and caressed sensually by your partner? I have not been touched or caressed (lost) No pleasant (1) Slightly pleasant (2) Moderately pleasant (3) Very pleasant 4) Extremely pleasant (5) Concepts 15 and 19 are scored from 0 to 6 (in ascending order) for example: 15. In 4 Last few weeks how many times do I take part in penetrative sexual activities (for example, vaginal penetration and sexual intercourse)? I did not take part in sexual activities (0) Once / twice (1) 3-4 times (2) 5-8 times (3) 9-12 times (4) 13-16 times (5) > 16 times (6) The concepts 17 * -18 *, 29 *, 30 and 31 are scored from 1 to 5 (in descending order) [* For concepts 17, 18 and 29, the category "I did not take part in sexual activities" is set at "lost"] for example: 30. Thinking about the last 4 weeks, how worried did you that your partner could look for another sexual relationship due to problems with your sex life? Nothing at all (5) Slightly (4) Moderately (3) A lot (2) Very much (1) The concept 22 is scored from 5 to 1 with the "I did not take part in sexual activities" qualified as "lost" and the "I did not take part in sexual activities due to being anguished or worried about the pain" was scored with 0. that is, 22. In the last 4 weeks, how many times have you been distressed or worried about the pain during sexual activity? I did not take part in sexual activities (lost) I did not take part in sexual activities because I was worried or distressed by the pain None at all (5) Sometimes (4) Often (3) Many times (2) All times (1) Note: The concept 32 is not included in the global score, but can be tabulated if desired. TOTAL SCORE The total score can be derived by adding the individual scores of the concepts for each of the concepts except the concept 32- The total score range is 30-167 A higher score indicates a better sexual function SCORE SCORES Seven domains have been identified by means of factor analysis * These scores indicating a high probability of normal function have been derived using discriminant analysis from the current database and should be used only as guidelines. There is a band of scores below these in which the functional status (excluding the "couple" domain) should be considered as limits, depending on other clinical indexes. See Table 1.

Table 1. SFQ scoring intervals indicative of the possibility of sexual dysfunction When used in association with an interview to conduct a clinical sexual history, the SFQ scores should support the information that comes from the person (that is, if the person indicates that the orgasm is their maximum sexual complaint, it would be expected a score within the range of 3-11, a score greater than 12 should suggest a review and subsequent discussion).

When there are discrepancies between the score of the SFQ and the problem or sexual problems that arise from the sexual history interview, the opportunity arises that this should be taken to discuss it with the person and determine the cause or causes of the discrepancies. The actual SFQ completed by the person is as follows: SEXUAL FUNCTION QUESTIONNAIRE These questions ask about your sexual activity during the last 4 weeks. Please answer each question by checking a box with a cross. If you are not sure about how to answer, please give the best answer you can. In answering these questions the following definitions apply: Sexual activity includes any activity that may result in sexual stimulation or sexual pleasure, for example, relationship, aca-riciamiento, preliminary excitement, masturbation (ie, self-masturbation) or masturbation of you by your partner) and oral sex (that is, your partner gives you oral sex). Sexual Life includes both the physical sexual activities and the emotional sexual relationships you have with your partner. 1. During the past 4 weeks, how many times have you had pleasurable thoughts and feelings about sexual activity? Selection of answers: None at all; Few times; Sometimes; Frequently; Very often During the last 4 weeks, how many times have you wanted to be touched and caressed sensually by your partner? Selection of answers: None at all; Few times; Sometimes; Frequently; Very often. During the last 4 weeks, ¡. How many times have you wanted to take part in a sexual activity? Selection of answers: None at all; Few times; Sometimes; Frequently; Very often. During the last 4 weeks, how many times have you started a sexual activity with your partner? Selection of answers: None at all; Few times; Sometimes; Frequently; Very often. During the last 4 weeks, how many times have you been touched and caressed sensually by your partner? Selection of answers: None at all; Few times; Sometimes; Frequently; Very often. During the last 4 weeks, in general, how pleasant has it been for you to be touched and caressed sensually by your partner? Selection of answers: I have not been touched or caressed; Not pleasant; Slightly pleasurable; Moderately pleasurable; Very pleasant; Extremely pleasant.

During the last 4 weeks, how many times have you had a "burning" feeling in your vaginal / genital area when you took part in a sexual activity? Selection of answers: I did not take part in sexual activities; None at all; Sometimes; Frequently; Very often; Every time During the last 4 weeks, in general, how much "burning" did you feel in your vaginal / genital area when you took part in a sexual activity? Selection of answers: I did not take part in sexual activities; Any; Slight "burning"; Moderate "burning"; A lot of "burning"; Very much "ardor". During the past 4 weeks, how many times did you experience a "throbbing" ("tingling") in your vaginal / genital area when you took part in a sexual activity? Selection of answers: I did not take part in sexual activities; None at all; Sometimes; Frequently; Very often; Every time During the last 4 weeks, in general, how much "pulsation" ("tingling") did you notice in your vaginal / genital area when you took part in a sexual activity? Selection of answers: I did not take part in sexual activities; No sensation; A soft feeling; A moderate sensation; A strong feeling; A very strong feeling. During the past 4 weeks, how many times did you notice vaginal wetting / lubrication when you took part in a sexual activity? Selection of answers: I did not take part in sexual activities; None at all; sometimes; Frequently; Very often; Every time 12. During the last 4 weeks, in general i. How much vaginal wetness / lubrication did you notice when you took part in a sexual activity? Selection of answers: I did not take part in sexual activities; Without wetting / lubrication; Slightly moistened / lubricated; Moderately dampened / lubricated; Very humid lubricated; Extremely moistened / lubricated 13. During the last 4 weeks, how many times did you have feelings of emotional sexual arousal when you took part in a sexual activity? (for example, feeling of excitement, feeling of "openness", desire to continue sexual activity). Selection of answers: I did not take part in sexual activities; None at all; Sometimes; Frequently; Very often; every time 14. During the last 4 weeks, how much sexual arousal did you notice when you took part in a sexual activity? (for example, feeling of excitement, feeling of "openness," desire to continue sexual activity). Selection of answers: I did not take part in sexual activities; Any; Slightly excited; Moderately excited; Very excited; Extremely excited. 15. During the last 4 weeks, how many times do I take part in a sexual activity with penetration (for example vaginal penetration and sexual intercourse)? Selection of responses: I did not take part in sexual activities; One time two times; 3.4 times; 5.8 times: 9-12 times; 13-16 times; > 16 times 6. During the last 4 weeks, in general, how much did you enjoy penetration and sexual intercourse? Selection of answers: I did not take part in sexual activities; Unpleasant sensation; Slightly pleasant: Moderately pleasurable; Very pleasant; Extremely pleasant. 17. During the past 4 weeks, how many times did you experience pain in your vaginal / genital area during or after sexual activity (eg, penetration, sexual intercourse?) Choice of responses: I did not take part in sexual activities; Absolute; Sometimes; Frequently; Very frequently; All times 18. During the past 4 weeks, in general, how much pain did you experience in your vaginal / genital area during or after a sexual activity (eg, penetration, relationships Sexual Selection of answers: I did not take part in sexual activities, there was no pain, slightly painful, moderately painful, very painful, extremely painful, 19. During the last 4 weeks, how many times did you take part in sexual activity without penetration (for example, masturbation and oral sex)? Selection of answers: I did not take part in sexual activities, once / twice, 3-4 times, 5-8 times, 9-12 times, 13-16 times;> 16 times During the last 4 weeks, in general, ¡. how much did you enjoy sexual activity without penetration (eg, masturbation, oral sex)? Selection of answers: I did not take part in sexual activities; There was no enjoyment; Lightweight enjoyment; Moderate enjoyment;, Much enjoyment; Very much enjoyment. During the past 4 weeks, how many times did you feel emotionally close to your partner when you took part in a sexual activity? Selection of answers: I did not take part in sexual activities; None at all; Sometimes; Frequently; Very often; Every time During the past 4 weeks, how many times have you been worried or distressed about the pain experienced during sexual activity? Selection of answers: I did not take part in sexual activities due to being worried or distressed by the pain; None at all; Sometimes; Frequently; Very often; Every time During the past 4 weeks, did you feel good about yourself when you had sexual activity? Selection of answers: I did not take part in sexual activities; Not at all; Slightly; Moderately Extremely. 24. During the last 4 weeks, how many times did you have an orgasm when you took part in a sexual activity (could it be with or without a partner)? Selection of answers: I did not take part in a sexual activity; None at all; Sometimes; Frequently; Very often; Every time 25. During the last 4 weeks, how pleasant were the orgasms you had? Selection of answers: I did not have orgasms; Not pleasant; Slightly pleasurable; Moderately pleasurable; Very pleasant; Extremely pleasant. 26. During the last 4 weeks, in general, how was it easy for you to reach orgasm? Selection of answers: I did not have orgasms; Very difficult, Fairly difficult; Neither easy nor difficult; Quite easy; Very easy. 27. During the past 4 weeks, how have you felt confident about yourself as a sexual partner? Selection of answers: No security; Slightly safe; Moderately safe; Very safe; Extremely safe 28. Thinking about your sex life during the last 4 weeks,? how many times were you excited about sexual activity? Selection of answers: None at all; Scarcely; Sometimes; Frequently; Very often. 29. Thinking about your sex life during the last 4 weeks, did you feel disenchanted with your sexual response (for example, ability to become aroused, lubrication)? Selection of answers: I did not take part in sexual activities; Not at all; Slightly; Moderately A lot; Extremely. Conring the last 4 weeks, > . How worried did your partner find another sexual relationship due to problems with their sex life? Selection of answers: Nothing at all; Slightly; Moderately A lot; Extremely. Conring the last 4 weeks, how worried were your negative feelings about your sexual life (for example, your partner's feeling of anger, pity, rejection)? Selection of responses: Nothing at all; Slightly; Moderately, Much; Extremely. Conring your sexual life during the last 4 weeks, how did you feel about the frequency of your sexual activity?: Selection of answers: Much less than desired; A little less than desired; Approximately correct; A little more than desired; Much more than desired. In general, how important is it for you to have a pleasant sexual life? Selection of answers: Not important at all; Slightly important; Moderately important; Very important; Very important. During the last 4 weeks, taking into account the totality of your sexual life, how have you felt satisfied? Selection of answers: Unsatisfied; Slightly satisfied; Moderately satisfied; Very satisfied; Extremely satisfied.

Appendix 2 Pfizer A Sexual Health Interview (SH1) A Semi-structured sexual history exploration interview GUIDELINES FOR ADMINISTRATION Time: Spend at least 90 minutes to complete this process: 60-90 minutes for the interview; 15-30 minutes to write the justification. Interviewer: Only an FSD expert approved by Pfizer is authorized to conduct the interview; the function can not be delegated. The FSD expert is invested with signature authority on the inclusion / exclusion criteria in the protocol related to the psychological and sexual history; The joint signature of both the FSD expert and the principal investigator is required for a person to enter the study. Take out in a private room, only with the candidate (without partners). The order of the questions can be altered, at your discretion, and the questions can be ignored if, in your opinion, sufficient information has been obtained and has been noted, coming from the previous questions to satisfy the inclusion / exclusion criteria that apply to such a concept.

Additional questions are allowed. Nevertheless, clearly state both the question and the answer. The annotations must be legible for re-interviewers from outside. The text must be understandable, even though it is not necessary for the structure and grammatical characteristics of the phrase to be perfect. A style of telegraphic writing is acceptable. Please read these instructions to the people before beginning the interview: "I am going to ask you a series of questions that I would like you to answer as honestly and frankly as you can, if you can, please consider a time frame of 6 months, at least; nevertheless, it is correct to influence in other times. If you are not sure or comfortable about answering a question, it is perfectly correct to say "In the answer to these questions, the following definitions apply: Sexual activity: Includes any activity that may result in sexual stimulation or sexual pleasure, for example, sexual intercourse, caressing, preliminary arousal, masturbation (ie, self-masturbation or having your partner masturbate to you) and oral sex (ie, your pa-reja gives you oral sex). Sexual intercommunication: Sexual activity that results in penetration of your vagina by your partner Sexual stimulation: Caressing, preliminary excitement.

Self-stimulation (for example masturbation): Caressing your own genitals, caressing your partner, or by using a device. " For the first question, you may want to review the range of typical physical and cognitive changes a woman might experience when she is sexually stimulated or sexually aroused, including accelerated heart rate and breathing, feelings of contiguity and intimacy with the partner, nipples that are made more sensitive and erect; increased sensitivity to contact; increased genital sensitivity; pleasant sensations in the clitoris (pulsation / tingling); sensations of heat and lubrication / genital wetting; "excited" sensitivity / excited desire to continue sexual stimulation.

The question 1 OR can be treated as open (without fixed limits), marking all the options, voluntary and suggested, for concepts not cited, OR the person interviewed can fill them out directly, and then you review the answers together. 1 What kind of sexual complaints do you have? Definitions: "Now" refers to during the past 6 months. "Before" refers to when you thought your sexual function was normal. Score scale: Never = 0; Rarely = 1; Occasionally Almost always = 4; Not applicable = NA Rating 0 to 4 Notes 1a Desire How many times do you think about sexual feelings or feelings of desire? Before How often do you first act on these sensations alone? Now, how often do you act on these feelings with your partner? Now 1b EXCITATION: How does your body become sexually aroused and how does it change? Physiological response Now The breathing accelerates Before The pulse accelerates Now Before Pleasurable sensations Now in your breasts Before Pleasurable sensations Now in your clitoris and lips Before Pleasurable sensations Now in your vagina Before Lubrication: Hume- Now decimiento in your vaaina Before How many times Is it now difficult or impossible to have sex because Before your vagina is dry? 1c PAIN How many times do you now experience pain during intercourse? Before 1d ORGASM: How often do you reach orgasm using the following: Manual stimulation (or with a device now) / alone Before Manual stimulation (or with a device now) / partner Before Oral stimulation Now Before Sexual relationship Now Before 1e What changes (if any) have you appreciated in your orgasm at the time of the time. Will I respond now with your response before you have a problem? Now the frequency, intensity, time to reach my orgasm is Much Something Equal Something minor Much smaller greater greater Frequency of orgasms Intensity of orgasms Time needed to reach orgasm Check the complaints about your sexual function that you have written down in these pages and put an asterisk (*) near your maximum complaint.

What do you think has caused these changes in your sexual response? Please list as many reasons as you can identify (eg surgery, menopause, consequence of sexual intercourse, age, pain, medications) Approximate date of initiation = Have there been any 1-2 week intervals during the last 6 months when you have not had problems with sexual response or orgasms? (for example, weekend without children, different couple, etc ...) Do you currently have a partner OR do you currently have a sexual relationship? Yes No If yes, how long? Sex of the couple: Male, Female How often do you and your partner have another sexual activity now? times in a month. How does the frequency of your sexual activity compare now with that of before (for example, when your sexual function was normal)? Surround with a circle: More Equal Less If you have not had sexual complaints, ideally, how often would you like to have sex or other sexual activity? times in a month Who usually initiates sexual intercourse or other sexual activity? I always do it Usually my partner does it Usually I do it I always do my partner My partner and I approximately equal Others < specify > Are you comfortable initiating the sexual relationship or activity? If not When your partner makes sexual advances, how do you usually respond? Check what is appropriate My partner never makes sexual advances. I usually accept it with pleasure. I often accept it with pleasure. I accept it reluctantly I accept his motives, but I do not get pleasure or get little pleasure with it. I often reject. I usually reject. I avoid situations in which sexual advances could be made. Others, < specific 9 a On a scale of 1 to 10, how would you rate your current global relationship with your partner? (1 = Totally unsatisfactory, 5 = Medium, 10 = Completely satisfactory) 9b Is this a change from before? Yes No If yes, how and when did it change? 10 a On a scale of 1 to 10, how would you rate your sexual relationship with your partner? (1 = Totally unsatisfactory, 5 = Medium, 10 = Completely satisfactory) b If your sexual relationship is somehow unsatisfactory, what factors of your partner do you think contribute to the problem? Question 10b OR can be treated as "without fixed limits", marking all the voluntary and suggested options for concepts that have not been mentioned OR the patient can fill them out directly, and then you review and explore the answers to establish the relationship with current sexual problems.

Scale: 1 = Not important; 5 = Important sometimes; 10 = Very important Interviewer review of the couple's contributions to dissatisfaction: Inquire if and how some of these factors have changed. You must concentrate on whether they are related to the person's current sexual complaint or complaints. 10c Interviewer review of the person's contributions to dissatisfaction: Inquire if and how many of these factors have changed. Concentrate on whether they are related to the person's current sexual complaint or complaint. Question 10c can be treated as OR without fixed limits, by marking all voluntary and suggested options for concepts not cited, OR the person can fill them out directly, then review the answers and explore the connection with current sexual problems.

How do you think your partner will feel about the details of their sexual activities that you record in a diary taken at home? (For example, "Did you feel physically sexually aroused? If you had a sexual relationship, was it satisfactory for you?) (Exclude the person if her reluctance to fill out a journal is related to an important outcome of a relationship) Do you think that some of the following factors contribute to your sexual difficulties? Scale: 1 = Not important; 5 = It is important sometimes; 10 = It is very important to CHECK ALL FACTOPut in a RES CONTRIBUTED scale from 1 to 10. Hav practical reasons why do not you take part in sexual activities as much as you would like? (for example, children, tiring, trip of the couple, travel of yours, insufficient reserve, overwhelming work, affection for relationships, etc.) Please list Personal dissatisfaction with your body Anger with your partner Personal depression Feelings of frustration or Anxiety Feelings of guilt Feelings of shame Religious prohibitions Attitudes of their father about sex Other Other Interviewers: For the following 4 questions, focus on being certain whether the result of abuse or emotional consequence is unresolved and / or is related to the patient's current sexual complaints. If it is Yes, exclude. No extensive historical details are necessary to ve the adequacy to enter the study.

Has it always happened that you consider having been physically abused (for example, pushed or beaten) by someone? If not Has it ever happened that you feel you have been emotionally abused (eg, depressed, intimidated?) Yes No Has it always happened that you have been touched in a way that you would not have liked to be touched, or have been forced or pressured to have sexual activity against your will IJContract yourself in the fitness of inclusion in the study] Yes No Age, Context Solved l (advice, follow-up, etc.) Related to current sexual complaints? Are there some important emotional episodes in your life, such as marital problem, depression, anxiety / panic, grief, eating disorders or some other difficulty? [Focus on the fitness of inclusion in the study and Yes No [Interviewer's brief]: At the beginning of this interview you said that your biggest complaint of sexual function was < call attention to the answer of n ° 1 > . Are you still satisfied with the answer or would you like to change something? [Interviewer's writing: "Is there something I still want to add or do you think is important for me to know before we finish? Thank you very much Duration of the interview: B Assessment and interviewer's justification for inclusion / exclusion of candi- dates Instruction: A fully annotated synopsis of appropriate length is needed for the following three questions. You are not limited to the space that is provided. All text should consistently refer to the respondent's responses to specific questions and to the interviewer's notes as appropriate. The text must be legible / inspectable by a Pfizer agent or by a regulatory agent in the country. If it is recommended that a person be included in the study, the text should justify why some potentially exclusionary information was considered less important. Please keep in mind that if you think that person's problem is mainly attributable to an emotional episode or relationship, to the partner in some way (for example, it is circumstantial), or is a matter of sexual enthusiasm, it is unlikely that she benefits from treatment with the study medication and should be excluded by protocol.

A justification for the diagnosis of FSAD: Circle the appropriate answers to the concepts listed below, supporting your conclusions in a diagnostic summary that integrates the interview information and that adequately justifies the inclusion or exclusion of the study from the people who are subject of the same Use of DSM-IV definitions (see below): • Is the person under study with FSAD the most salient aspect of her sexual dysfunction? Yes No • Has FSAD been present for at least 6 months? Yes No. • Is it dysfunctional? Yes No • Are some of the following disorders associated with FSAD? Support why you consider these secondary disorders regarding FSAD. • Orgasmic Disorder Yes No • Sexual Desire Disorder Hypoactive Yes No • Superficial / introital dyspareunia subordinated to lubrication disorder Yes No Definitions of DSM-IV: Hypoactive Sexual Desire Disorder Sexual fantasies and desire for permanent or periodically deficient (or absent) sexual activity - (Deficiency or absence judgment is made by the physician taking into account factors affecting sexual function such as age and context of the person's life). The disorder occasion anguish or interpersonal difficulty Sexual dysfunction is not better explained by another clinical state (other than sexual dysfunction and is not due exclusively to the direct physiological effects of a substance (eg, a drug addiction, a medication) or a state general practitioner Female sexual arousal disorder Permanent or periodic inability to achieve or maintain a proper lubrication-swelling response until the end of sexual activity, of sexual excitement The disorder causes an accused anguish or interpersonal difficulty. Sexual dysfunction is not better explained by another clinical state (except for other sexual dysfunction) and is not due exclusively to the direct physiological effects of a substance (for example, a drug addiction, a medication) or a general medical condition.

Female orgasmic disorder Permanent or periodic delay in orgasm (or absence of this) after a phase of normal sexual arousal. (The women show a variability in the type or intensity of the stimulation that triggers the orgasm). The diagnosis of Female Orgasmic Disorder should be based on the judgment of a physician that the orgasmic capacity of the woman is less than what would be reasonable for her age, sexual experience and the appropriateness of the sexual stimulation she receives. The disorder causes anguish or accused interpersonal difficulty. Orgasmic dysfunction is not better explained by another clinical state (except for another Sexual Dysfunction) and is not due exclusively to the direct physiological effects of a substance (for example a drug addiction, a medication) or a general medical condition Dyspareunia Periodic or permanent genital pain associated with sexual intercourse. The disorder causes anguish or accused interpersonal difficulty. The dysfunction is not best explained by vaginismus or other clinical condition (except for another Sexual Dysfunction) and is not due exclusively to the direct physiological effects of a substance (eg, a substance abuse, a medication) or a general medical condition. space any other impressions of the diagnosis If the person under study has been recommended for participation in it despite the potentially exclusive disclosure of information, please describe the information and justify why it has been considered minor.

Checklist by concepts: The FSD expert is vested with signature authority on the inclusion / exclusion criteria, of the protocol that follows: Inclusions: All these must be "Yes". A check mark in any "No" box excludes the person from the study 6.1.2 Specifically. has been present for six months, if not months, at least the FSAD. FSAD may or may not be associated with: Orgasmic disorder [excluding primary anorgasmia] Hypoactive Sexual Desire Disorder [excluding pre-eminent desire disorder] Superficial / introital dyspareunia 6. 1.5 Has the person had a stable sexual relationship? YES No for at least 6 months 1 6.1.6 Is the person motivated to seek treatment? Yes No Do not willingly try to have sexual activity once a week (on average) per at least during all phases of the study (including the interval between the Selection and the Baseline)? Exclusions: All of these must be "No". A check mark in any "Yes" box excludes the person from the study. 6.2.4 Is it true that the person has never had a sex life? Yes No satisfactory? 6.2.5 Is the sexual dysfunction of the Yes No person circumstantial, for example, limited to certain types of stimulation, situation or specific partners? 6.2.7 Has the person received treatment for any major non-psychiatric disorder? for example psychosis or major depression) within the past 12 months? 6.2.8 Does the person have any other significant psychological or non-sexual Yes disorder (not listed in the DSM-IV FSD selection, in inclusion 6.1.2) that is considered the primary diagnosis explaining sexual dysfunction? (a signature with that of the principal investigator) 6.2.10 If the person currently has a male sexual partner, does he or she have this experience (or has a recent history) of unresolved premature ejaculation, erectile dysfunction, or delayed ejaculation that does not Has it been treated satisfactorily? (Write "NA" if the partner is female) 6.2.23 Does the person have any medical or psychological condition? Yes No or social circumstances that could impair her ability to participate in the study in a reliable way, or that could increase to herself or others the risk of participation? (Attach your signature to that of the principal investigator) I ACCEPT The person meets all of the above criteria REFUSAL _ One or more criteria are not met Signature of the interviewer Date:

Claims (4)

1. CLAIMS 1. - The use of a PDE5 inhibitor in combination with a 5HT1a agonist to manufacture a drug for the treatment of sexual dysfunction. 2. The use according to claim 1, wherein the dysfunction is selected among FSD, FSAD, HSDD, FOD and MED. 3. The use of a PDE5 inhibitor in combination with a 5HT1a agonist to manufacture a medicament for the treatment of FSAD and HSDD in a person suffering from FSAD and concurrent major HSDD. 4. The use of a PDE5 inhibitor in combination with a 5HT1a agonist to prepare a medicament for the treatment of FSAD in a person who has concurrent major HSDD. 5. The use according to claims 1 to 4, wherein the PDE5 inhibitor is selected from the group of: 5- [2-Ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenol ] -1-methyl-3-n-propyl-, 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (sildenafil); (6R, 12aR) -2,3, ef7l12l12a-hexahydro-2-methyl-6- (3, -methylenedioxyphenyl) pyrazino- [2 ', 1': 6,1] pyrido [3,4-b] indole-1 , 4-dione (IC-351); 2- [2-ethoxy-5-4-ethylpiperazin-1-yl-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-fJ- [1, 2,4] triazin -4-one (vardenafil); and 5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-etiI-2- [2-methoxyethyl] -2,6-dihi-dro-7H-pyrazolo [ 4.3-d] pyrimidin-7-one or 5- (5-acetyl-2-butoxy-3-pyridinyl) -3-etii-2- (1-ethyl-3-azeM ona, and its pharmaceutically acceptable salts 6. The use according to claims 1 to 4, wherein the PDE5 inhibitor is 5- [2-ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl] -1-methyl-3-n. -propyl-1, 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (sildenafil) (also known as 1 - [[3- (6,7-dihydro-1-methyl-7- oxo-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl) -4-ethoxyphenyl] -4-methylpiperazine), and pharmaceutically acceptable salts thereof. claims 1 to 4, wherein the PDE5 inhibitor is Sildenafil Citrate 8. The use according to claims 1 to 4, wherein the 5HT1a agonist is selective for the 5HT1a receptor on alpha- adrenergic and dopamine 9. The use according to claims 1 to 4, wherein the 5H agonist T1a is selected from: Zaprasidone, Buspirone HCl, Urapidil, Tandosporin, Sunepitron, Ebalzotan, Ipsapirone, Zalospirone, Gepirone, Repinotan, Alnespirone, MKC242, Eptapirone, SR57746A, AP-521, SUN-N4057, Lesopitron, DU-125530, VML- 670, Flesinoxan, E6265, Flibanserin, buspar, AP-521, SUN-N4057, LY293284, LY301317 and 8-OH-DPAT. 10. The use according to claims 1 to 4, wherein the 5HT1a agonist is Flibanserin. 1 - A pharmaceutical composition that includes a PDE5 inhibitor, a 5HT1a agonist and a pharmaceutically acceptable excipient, diluent or vehicle. 12. A kit comprising: a) a first pharmaceutical composition comprising a PDE5 inhibitor and a pharmaceutically acceptable excipient or diluent; b) a second pharmaceutical composition comprising a 5HT1 a agonist and a pharmaceutically acceptable excipient or diluent; and a container for the two compositions.