US 2005OO65158A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0065158A1 Naylor et al. (43) Pub. Date: Mar. 24, 2005

(54) TREATMENT OF SEXUAL DYSFUNCTION (30) Foreign Application Priority Data (75) Inventors: Alasdair Mark Naylor, Kent (GB); Pieter Hadewijn Van Der Graaf, Kent Jul. 16, 2003 (GB)...... O316673.3 (GB); Christopher Peter Wayman, Aug. 1, 2003 (GB). ... O318095.7 Kent (GB) Sep. 11, 2003 (GB)...... O321308.9 Correspondence Address: PFIZER INC. Publication Classification PATENT DEPARTMENT, MS8260-1611 EASTERN POINT ROAD (51) Int. Cl." ...... A61K 31/519 GROTON, CT 06340 (US) (52) U.S. Cl...... 514/252.16; 514/262.1 (73) Assignee: Pfizer Inc. (21) Appl. No.: 10/883,622 (57) ABSTRACT (22) Filed: Jul. 1, 2004 This invention relates to the use of cyclic guanosine 3', Related U.S. Application Data 5'-monophosphate phosphodiesterase type five (PDE5) inhibitors, in combination with 5HT1a agonists for the (60) Provisional application No. 60/512,030, filed on Oct. treatment of Sexual dysfunction, particularly female Sexual 17, 2003. Provisional application No. 60/513,125, arousal disorder (FSAD) with concomitant hypoactive filed on Oct. 21, 2003. sexual desire disorder (HSDD). US 2005/0065158A1 Mar. 24, 2005

TREATMENT OF SEXUAL DYSFUNCTION 0009 FOD-Persistent or recurrent delay in, or absence of, orgasm following a normal Sexual CROSS-REFERENCE TO RELATED excitement phase. Women exhibit wide variability in APPLICATION the type or intensity of Stimulation that triggers orgasm. The diagnosis of FOD should be based on 0001. This application claims priority from United King the clinician's judgement that the woman's orgasmic dom Application Number 0316673.3, filed on Jul. 16, 2003, capacity is less than would be reasonable for her age, United Kingdom Application Number 0318095.7, filed on Sexual experience, and the adequacy of the Sexual Aug. 1, 2003, United Kingdom Application Number Stimulation she receives. 0321308.9, filed on Sep. 11, 2003 and the benefit from U.S. Provisional Application No. 60/512,030, filed on Oct. 17, 0010 Sexual Pain Disorders such as Dyspareunia 2003 and U.S. Provisional Application No. 60/513,125, filed and Vaginismus. Dyspareunia is the recurrent or on Oct. 21, 2003. persistent genital pain associated with Sexual inter course. Vaginismus is the recurrent or persistent 0002 This invention relates to the use of cyclic gua involuntary Spasm of the musculature of the outer nosine 3', 5'-monophosphate phosphodiesterase type five third of the vagina that interferes with sexual inter (PDE5) inhibitors, in combination with 5HT1a agonists for COSC. the treatment of Sexual dysfunction, particularly female 0011 More recently the American Foundation for Uro sexual arousal disorder (FSAD) with concomitant hypoac logic Disease has developed definitions using the same four tive sexual desire disorder (HSDD). classes (see The Journal of Urology, 2000, Vol 163, page 0.003 Male sexual dysfunction includes male erectile 888-893). The definitions are along similar lines as follows dysfunction, ejaculatory disorderS Such as premature ejacu to DSM-IV: lation (PE), anorgasmia (inability to achieve orgasm) and 0012 HSDD is the persistent or recurrent deficiency desire disorderS Such as hypoactive Sexual desire disorder (or absence) of Sexual fantasies/thoughts, and/or (lack of interest in sex). desire for or receptivity to Sexual activity, which 0004 The categories of female sexual dysfunction (FSD) causes personal distress. are best defined by contrasting them to the phases of normal female Sexual response: desire, arousal and orgasm (see S R 0013 FSAD is the persistent or recurrent inability to Leiblum, (1998), Definition and Classification of Female attain or maintain Sufficient Sexual eXcitement, caus Sexual Disorders, Int. J. Impotence Res., 10, S104-S106). ing personal distress, which may be expressed as a Desire or libido is the drive for sexual expression. Its lack of Subjective excitement, or genital (lubrication/ manifestations often include Sexual thoughts either when in Swelling) or other Somatic responses. the company of an interested partner or when exposed to 0014 FOD is the persistent or recurrent difficulty, other erotic Stimuli. Arousal includes the vascular response delay in or absence of attaining orgasm following to Sexual Stimulation, an important component of which is Sufficient Sexual Stimulation and arousal, which genital engorgement and increased vaginal lubrication, elon causes personal distress. gation of the vagina and increased genital Sensation/sensi tivity and a Subjective eXcitement response. Orgasm is the 0015 Sexual pain disorders: Dyspareunia is the release of Sexual tension that has culminated during arousal. recurrent or persistent genital pain associated with Hence, FSD occurs when a woman has an absent, inad Sexual intercourse. Vaginismus is the recurrent or equate or unsatisfactory response in any one or more of these persistent involuntary Spasm of the musculature of phases, usually desire, arousal or orgasm. the outer third of the vagina that interferes with vaginal penetration, which causes personal distreSS. 0005 The American Psychiatric Association classifies 0016 HSDD is present if a woman has no or little desire female sexual dysfunction (FSD) into four classes: FSAD, to be sexual, and has no or few Sexual thoughts or fantasies. hypoactive sexual desire disorder (HSDD), female orgasmic This type of FSD can be caused by low testosterone levels, disorder (FOD), and sexual pain disorders (e.g. dyspareunia due either to natural menopause or to Surgical menopause. and vaginismus) see the American Psychiatric ASSocia Other causes in both pre-menopausal woman (i.e. woman tion's Diagnostic and Statistical Manual of Mental Disor who are pre-menopausal and who have not have hysterec ders, 4th Edition (DSM-IV)). tomies) as well as post menopausal women include illness, 0006 DSM-IV defines the four classes as follows: medications, fatigue, depression and/or anxiety. Factors having a potential (conscious or Sub-conscious) psychologi 0007 HSDD-Persistently or recurrently deficient cal impact Such as relationship difficulties or religious (or absent) Sexual fantasies and desire for Sexual factors may be related to the presence of/development of activity which causes marked distreSS or interper HSDD in females. Sonal difficulties. The judgement of deficiency or absence is made by the clinician, taking into account 0017 FSAD is a highly prevalent sexual disorder affect factors that affect functioning, Such as age and the ing pre-, peri-, and post menopausal women. It is associated context of the perSons life. with concomitant disorderS Such as depression, cardiovas cular diseases, diabetes and UG disorders. FSAD is charac 0008 FSAD-Persistent or recurrent inability to terised by inadequate genital response to Sexual Stimulation. attain, or to maintain until completion of the Sexual The genitalia do not undergo the engorgement that charac activity, an adequate lubrication-Swelling response terises normal Sexual arousal. The Vaginal walls are poorly of Sexual excitement. lubricated, So that intercourse is painful. Orgasms may be US 2005/0065158A1 Mar. 24, 2005 impeded. FSAD can be caused by reduced oestrogen at 0029. In an embodiment of the invention, the female menopause or after childbirth and during lactation, as well Subject is oestrogen and androgen replete. Replete levels of as by illnesses, with vascular components Such as diabetes the oestrogen and androgen may already exist in the Subject and atherosclerosis. Other causes result from treatment with or they may be achieved artificially. Replete levels or diuretics, antihistamines, antidepressants e.g. Selective Sero Oestrogen may be achieved artificially by administration of tonin reuptake inhibitors or antihypertensive agents. estradiol, estrone, estriol, a synthetic oestrogen (for example 0018 Sexual pain disorders (includes dyspareunia and Oestrogen benzoate), an agent which causes the body to vaginismus) are characterised by pain resulting from pen produce oestrogen and/or an oestrogen receptor modulator/ etration and Sexual activity and may be caused by medica agonist (for example raloxifene or lasofoxifene). Replete tions which reduce lubrication, endometriosis, pelvic levels of androgen may be achieved by administration of an inflammatory disease, inflammatory bowel disease or uri androgen (Such as include androsterone, dehydro-androster nary tract problems. one, testosterone, androstanedione or a synthetic androgen), an agent which causes the body to produce androgen and/or 0019 We have now found that PDE5 inhibitors in com bination with 5HT1a agonists work well in treating subjects androgen receptor modulator/agonist (for example tibolone) who suffer from sexual dysfunction. The combination may 0030 AS used herein the term replete means having be deemed Synergistic. concentrations of Oestrogen and androgen equal to or greater 0020 Suitable sexual dysfunctions include FSAD, than minimum physiological concentrations found in a nor HSDD and FOD in women and MED in men. mal Subject. 0021 We have found that PDE5 inhibitors in combina 0031 Oestrogen is the general term for any substance tion with 5HT1a agonists work particularly well in FSAD having the physiological activity of oestradiol. It includes subjects who suffer from concurrent significant HSDD. The natural and Synthetic Oestrogens. Naturally occurring oestro combination may be deemed Synergistic. gens include oestradiol, Oestrone, Oestriol and their conju gates, predominantly protein-bound. An example of a Syn 0022. According to a first aspect, the invention provides thetic oestrogen is oestradiol benzoate. In a preferred the use of a PDE5 inhibitor in combination with a 5HT1a embodiment the Subject has a concentration of Oestrogen agonist in the manufacture of a medicament for the treat equal to or greater than 40 picogrammes per millilitre of ment of Sexual dysfunction blood. 0023. According to a preferred aspect, the invention 0032. Oestradiol concentration provides a reliable mea provides the use of a PDE5 inhibitor in combination with a Sure of total oestrogen levels in the body. The physiological 5HT1a agonist in the manufacture of a medicament for the concentration of Oestradiol varies depending on the Stage of treatment of FSAD and HSDD in a subject suffering from ovulation. The minimum concentration of oestradiol (pro FSAD and concurrent significant HSDD. tein-bound and free) in a normal women is approximately 40 0024. The term “significant HSDD” as defined herein picogrammes per millilitre of blood. Therefore in a preferred means a level of HSDD which causes some degree of embodiment the Subject has a concentration of Oestradiol personal distress to the female Subject. Preferably significant (protein-bound and free) equal to or greater than 40 pico HSDD means a level of HSDD which causes some degree grammes per millilitre of blood. Methods and kits for of distreSS and is measurable. determining oestradiol blood concentrations are well-known to the skilled person, for example Coat-a-Count(R) Esradiol 0025 Preferably the HSDD is measurable through evalu available through DPC(R(Diagnostic Products Corporation, ation by a clinician using a Semi-structured questionnaire. 5700 West 96th Street, Los Angeles, Calif. 900456-5597) 0026. More preferably significant HSDD means a level of provides a kit to measure the concentration of protein-bound HSDD which causes some degree of distress and is mea and free oestradiol. Surable as a Score of less than or equal to 16 on the desire 0033 Androgen is the collective term for a group of domain in the Sexual Function Questionaire (SFQ) herein Steroids, both natural and artificial. In females androgens are below. produced by the Ovaries and adrenocortex. The natural 0027) A female subject with FSAD and significant HSDD androgens include androsterone, dehydroandrosterone, tes may occasionally experience a slight increase in her desire, tosterone and androstanedione. Testosterone is by far the for example as a result of psychological factors. It will be most potent natural hormone. Testosterone circulates in the appreciated that Such a Subject typically and generally has body almost entirely bound to proteins. Normally less than significant HSDD and is therefore included within the scope one percent is free. Free testosterone provides an accurate of the invention. measure of androgen concentration. The free-testosterone concentration in a normal pre-menopausal women is 0028. The term “concurrent” as used herein means a approximately 0.9 picogrammes per millilitre of blood. Subject who experiences FSAD at the same time as experi Therefore in a preferred embodiment the subject has a encing significant HSDD. The term “concurrent” as defined concentration of free testosterone equal to or greater than 0.9 herein does not encompass female Subjects with situational picogrammes per millilitre of blood. Methods and kits for HSDD, i.e. Subjects who normally experience satisfactory determining free-testosterone blood concentrations are well levels of desire and who are normally able to become known to the skilled perSon, for example Coat-a-Count(R) aroused, but occasionally are unable to experience any Esradiol available through DPC(R(Diagnostic Products Satisfactory levels of desire and arousal as a result of Corporation, 5700 West 96th Street, Los Angeles, Calif. external factors, for example partner specific HSDD. 900456-5597). US 2005/0065158A1 Mar. 24, 2005

0034. The female subject can be pre-menopausal, peri midin-4-ones disclosed in EP-A-0995750; the compounds menopausal, post-menopausal or Surgically menopausal i.e. disclosed in published international application WO95/ post-hysterectomy. In a preferred embodiment the Subject is 19978; the compounds disclosed in published international post-menopausal. application WO 99/24433 and the compounds disclosed in 0035. The skilled person will appreciate that the subject published international application WO 93/07124. in addition to suffering from FSAD may also suffer from 004.5 The pyrazolo 4,3-dpyrimidin-7-ones disclosed in FOD or Sexual pain disorders provided these are Secondary published international application WO 01/27112; the pyra to FSAD. Zolo4,3-dipyrimidin-7-ones disclosed in published interna tional application WO 01/27113; the compounds disclosed 0036) Hereinafter the term “the PDE5 inhibitor” means the PDE5 inhibitors for use with the invention. The term in EP-A-1092718 and the compounds disclosed in EP-A- includes pharmaceutically acceptable Salts, Solvates and 1092719. polymorphs of the PDE5 inhibitors for use with the inven 0046 Preferred PDE5 inhibitors for use with the inven tion. tion: 0037. The suitability of the PDE5 inhibitor can be readily 0047 5-2-ethoxy-5-(4-methyl-1-piperazinylsul determined by evaluation of its potency and Selectivity using phonyl)phenyl-1-methyl-3-n-propyl-1,6-dihydro literature methods followed by evaluation of its toxicity, 7H-pyrazolo 4,3-dipyrimidin-7-one (sildenafil) also absorption, metabolism, pharmacokinetics, etc in accor known as 1-3-(6,7-dihydro-1-methyl-7-oxo-3-pro dance with Standard pharmaceutical practice. pyl-1H-pyrazolo 4,3-dipyrimidin-5-yl)-4-ethox yphenylsulphonyl-4-methylpiperazine (see EP-A- 0038 Preferably, the PDE5 inhibitors have an IC50 against the PDE5 enzyme of less than 100 nanomolar, more 0463756); preferably, at less than 50 nanomolar. 0048 5-(2-ethoxy-5-morpholinoacetylphenyl)-1- methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo 4,3-d 0039 IC50 values for the PDE5 inhibitors may be deter mined using the PDE5 assay in the Test Methods Section pyrimidin-7-one (see EP-A-0526004); hereinafter. 0049) 3-ethyl-5-5-(4-ethylpiperazin-1-ylsulpho 0040 Preferably the PDE5 inhibitors are selective for the nyl)-2-n-propoxyphenyl-2-(pyridin-2-yl)methyl-2, PDE5 enzyme. Preferably they have a selectivity of PDE5 6-dihydro-7H-pyrazolo 4,3-dipyrimidin-7-one (see over PDE3 of greater than 100 more preferably greater than WO98/49166); 300. More preferably the PDE5 has a selectivity over both 0050) 3-ethyl-5-5-(4-ethylpiperazin-1-ylsulpho PDE3 and PDE4 of greater than 100, more preferably nyl)-2-(2-methoxyethoxy)pyridin-3-yl)-2-(pyridin greater than 300. 2-yl)methyl-2,6-dihydro-7H-pyrazolo4,3-dipyrimi 0041) Selectivity ratios may readily be determined by the din-7-one (see WO99/54333); skilled person, by ratio of corresponding IC50 values for the 0051 (+)-3-ethyl-5-5-(4-ethylpiperazin-1-ylsul particular enzymes concerned. IC50 values for the PDE3 phonyl)-2-(2-methoxy-1(R)-methylethoxy)pyridin and PDE4 enzyme may be determined using established 3-yl)-2-methyl-2,6-dihydro-7H-pyrazolo 4,3-dipyri literature methodology, see S A Ballard et al., Journal of midin-7-one, also known as 3-ethyl-5-5-4- Urology, 1998, vol.159, pages 2164-2171. ethylpiperazin-1-ylsulphonyl-2-((1R)-2-methoxy 0042 Preferably the PDE5 inhibitors have an IC50 1-methylethylloxy)pyridin-3-yl)-2-methyl-2,6- against PDE5 of less than 100 nM and a selectivity over dihydro-7H-pyrazolo 4,3-dipyrimidin-7-one (see PDE3 of greater than 100 fold. WO99/54333); 0.052 5-2-ethoxy-5-(4-ethylpiperazin-1-ylsulpho 0043. Examples of PDE5 inhibitors for use with the nyl)pyridin-3-yl)-3-ethyl-2-2-methoxyethyl-2,6- invention are: dihydro-7H-pyrazolo 4,3-dipyrimidin-7-one, also 0044) The pyrazolo 4,3-dpyrimidin-7-ones disclosed in known as 1-6-ethoxy-5-3-ethyl-6,7-dihydro-2-(2- EP-A-0463756; the pyrazolo 4,3-dipyrimidin-7-ones dis methoxyethyl)-7-oxo-2H-pyrazolo 4,3-dipyrimidin closed in EP-A-0526004; the pyrazolo 4,3-dipyrimidin-7- 5-yl)-3-pyridylsulphonyl)-4-ethylpiperazine (see ones disclosed in published international patent application WO 01/27113, Example 8): WO 93/06104; the isomeric pyrazolo 3,4-dipyrimidin-4- ones disclosed in published international patent application 0053 5-2-iso-Butoxy-5-(4-ethylpiperazin-1-ylsul WO 93/07149; the quinazolin-4-ones disclosed in published phonyl)pyridin-3-yl)-3-ethyl-2-(1-methylpiperidin international patent application WO 93/12095; the pyrido 4-yl)-2,6-dihydro-7H-pyrazolo 4,3-dipyrimidin-7- 3,2-dpyrimidin-4-ones disclosed in published international one (see WO 01/27113, Example 15); patent application WO94/05661; the purin-6-ones disclosed 0054 5-2-Ethoxy-5-(4-ethylpiperazin-1-ylsulpho in published international patent application WO94/00453; nyl)pyridin-3-yl)-3-ethyl-2-phenyl-2,6-dihydro-7H the pyrazolo 4,3-dpyrimidin-7-ones disclosed in published pyrazolo 4,3-dipyrimidin-7-one (see WO 01/27113, international patent application WO 98/49166; the pyrazolo Example 66); 4,3-dpyrimidin-7-ones disclosed in published international patent application WO 99/54333; the pyrazolo 4,3-dpyri 0055 5-(5-Acetyl-2-propoxy-3-pyridinyl)-3-ethyl midin-4-ones disclosed in EP-A-0995751; the pyrazolo 4, 2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyra 3-dipyrimidin-7-ones disclosed in published international Zolo4,3-dipyrimidin-7-one (see WO 01/27112, patent application WO 00/24745; the pyrazolo 4,3-dpyri Example 124); US 2005/0065158A1 Mar. 24, 2005

0056 5-(5-Acetyl-2-b--AcetV-2-butoxV-3-OWrdnWI)-3-ethW-2- y-3-pyridinyl)-3-ethyl-2 0067 5-2-ethoxy-5-(4-ethylpiperazin-1-ylsulpho (1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo 4,3- nyl)pyridin-3-yl)-3-ethyl-2-2-methoxyethyl-2,6- dpyrimidin-7-one (see WO 01/27112, Example dihydro-7H-pyrazolo 4,3-dipyrimidin-7-one O 132); 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1- 0057 (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-me ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo 4,3-d thyl-6-(3,4-methylenedioxyphenyl)-pyrazino 2,1':6, pyrimidin-7-one and pharmaceutically acceptable 1pyrido 3,4-bindole-1,4-dione (IC-351), i.e. the salts thereof. compound of examples 78 and 95 of published 0068 A particularly preferred PDE5 inhibitor is 5-2- international application WO95/19978, as well as the ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl-1-me compound of examples 1, 3, 7 and 8; thyl-3-n-propyl-1,6-dihydro-7H-pyrazolo 4,3-dipyrimidin 0.058 2-2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sul 7-one (sildenafil) (also known as 1-3-(6,7-dihydro-1- phonyl)-phenyl-5-methyl-7-propyl-3H-imidazo[5, methyl-7-oxo-3-propyl-1H-pyrazolo 4,3-dipyrimidin-5-yl)- 1-f1,2,4-triazin-4-one (Vardenafil) also known as 4-ethoxyphenylsulphonyl-4-methylpiperazine) and 1-3-(3,4-dihydro-5-methyl-4-oxo-7-propylimidazo pharmaceutically acceptable Salts thereof. Sildenafil citrate 5,1-f-as-triazin-2-yl)-4-ethoxyphenylsulphonyl 4 is a preferred Salt. ethylpiperazine, i.e. the compound of examples 20, 0069. Hereinafter the term “the 5HT1a agonist” means 19, 337 and 336 of published international applica the 5HT1a agonists for use with the invention. The term tion WO99/24433; and includes pharmaceutically acceptable Salts, Solvates and 0059 the compound of example 11 of published polymorphs of the 5HT1a agonists for use with the inven international application WO93/07124 (EISAI); and tion. 0060 compounds 3 and 14 from Rotella DPJ. Med. 0070 The suitability of the 5HT1a agonists can be Chem., 2000, 43, 1257. readily determined by evaluation of its potency and Selec 0061 Still further PDE5 inhibitors for use with the inven tivity using literature methods followed by evaluation of its tion include: 4-bromo-5-(pyridylmethylamino)-6-3-(4- toxicity, absorption, metabolism, pharmacokinetics, etc in chlorophenyl)-propoxy-3(2H)pyridazinone; 1-4-(1,3- accordance with Standard pharmaceutical practice. benzodioxol-5-ylmethyl)amiono-6-chloro-2-quinozolinyl 0071 Preferably, the 5HT1a agonists have an affinity for 4-piperidine-carboxylic acid, monosodium salt; (+)-cis-5,6a, 7.9,9.9a-hexahydro-2-4-(trifluoromethyl)-phenylmethyl-5- the recombinant human 5HT1a receptor with a Ki of less methyl-cyclopent-4.5imidazo2,1-bpurin-4(3H)one; than or equal to 300 nM, preferably with a Ki of less than furazlocillin; cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-oc or equal to 100 nM, more preferably with a Ki of less than tahydrocyclopent4.5-imidazo2,1-bpurin-4-one, 3-acetyl or equal to 30 nM, yet more preferably with a Ki of less than 1-(2-chlorobenzyl)-2-propylindole-6-carboxylate, 3-acetyl or equal to 10 nM, most preferably with a Ki of less than or 1-(2-chlorobenzyl)-2-propylindole-6-carboxylate, 4-bromo equal to 1 nM. 5-(3-pyridylmethylamino)-6-(3-(4-chlorophenyl) propoxy)- 0072 EC50 values for the 5HT1a agonists may be deter 3-(2H)pyridazinone; 1-methyl-5(5-morpholinoacetyl-2-n- mined using the 5HT1a assay in the Test Methods Section propoxyphenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo(4,3- hereinafter. Preferably the agonists have an EC50 less than d)pyrimidin-7-one; 1-4-(1,3-benzodioxol-5- or equal to 300 nM, preferably with an EC50 of less than or ylmethyl)amino-6-chloro-2-quinazolinyl-4- equal to 100 nM, more preferably with an EC50 of less than piperidinecarboxylic acid, monosodium Salt, or equal to 30 nM, yet more preferably with an EC50 of less Pharmaprojects No. 4516 (Glaxo Wellcome); Phar than or equal to 10 nM, most preferably with a EC50 of less maprojects No. 5051 (Bayer); Pharmaprojects No. 5064 than or equal to 1 nM. (Kyowa Hakko; see WO 96/26940); Pharmaprojects No. 0073 Preferably the 5HT1a agonists are selective for the 5069 (Schering Plough); GF-196960 (Glaxo Wellcome); 5HT1a receptor over alphaadrenoceptors and dopamine. E-8010 and E4010 (Eisai); Bay-38-3045 & 38-9456 (Bayer) and Sch-51866. 0074 Examples of 5HT1a agonists for use with the invention are: 0062) The contents of the published patent applications and journal articles and in particular the general formulae of 0075 Zaprasidone, buspirone HCl, Urapidil, Tan the therapeutically active compounds of the claims and dosporine, Sunepitron, EbalZotan, Ipsapirone, exemplified compounds therein are incorporated herein in Zalospirone, Gepirone, Repinotan, Alnespirone, their entirety by reference thereto. MKC242, Eptapirone, SR57746A, AP-521, SUN N4057, Lesopitron, DU-125530, VML-670, Flesi 0063 More preferred PDE5 inhibitors for use with the noxan, E6265, Flibanserin, buspar, AP-521, SUN invention are Selected from the group: N4057, LY293284, LY301317 and 8-OH-DPAT. 0064 5-2-ethoxy-5-(4-methyl-1-piperazinylsul phonyl)phenyl-1-methyl-3-n-propyl-1,6-dihydro 0.076 Particularly preferred is Flibanserin 7H-pyrazolo 4,3-dipyrimidin-7-one (sildenafil); 0.077 Particularly preferred combinations are Sildenafil 0065 (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-me or 2-(Methoxyethyl)-5-2-ethoxy-5-(4-ethylpiperazin-1-yl thyl-6-(3,4-methylenedioxyphenyl)-pyrazino 2,1':6, sulfonyl)pyridin-3-yl)-3-ethyl-2,6-dihydro-7H-pyrazolo.4, 1pyrido 3,4-bindole-1,4-dione (IC-351); 3-dipyrimidin-7-one with Flibanserin. 0066 2-2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sul 0078 Oral bioavailablity refers to the proportion of an phonyl)-phenyl-5-methyl-7-propyl-3H-imidazo[5, orally administered drug that reaches the Systemic circula 1-f1,2,4-triazin-4-one (vardenafil); and tion. The factors that determine oral bioavailability of a drug US 2005/0065158A1 Mar. 24, 2005

are dissolution, membrane permeability and metabolic Sta 6,037,346 issued on 14 Mar. 2000 all incorporated bility. Typically, a Screening cascade of firstly in vitro and herein by reference, PGE, PGE, PGA, PGB, then in Vivo techniques is used to determine oral bioavail PGF.C., 19-hydroxy PGA, 19-hydroxy -PGB, ablity. PGE, PGB, 19-hydroxy-PGA, 19-hydroxy-PGB, 0079 Dissolution, the solubilisation of the drug by the PGEC, carboprost tromethamine dinoprost, aqueous contents of the gastro-intestinal tract (GIT), can be tromethamine, dinoprostone, lipo prost, gemeprost, predicted from in vitro Solubility experiments conducted at metenoprost, Sulprostune, tiaprost and moxisylate); appropriate pH to mimic the GIT Preferably the PDE5 0.086 2) one or more C-adrenergic receptor antago inhibitors have a minimum solubility of 50 mcg/ml. Solu nists (also known as C.-adrenoceptor blockers, C-re bility can be determined by Standard procedures known in ceptor blockers or C-blockers); Suitable O.-adrener the art such as described in Adv. Drug Deliv. Rev. 23, gic receptor antagonists include: phentolamine, 3-25, 1997. prazosin, phentolamine meSylate, traZOdone, alfu 0080 Membrane permeability refers to the passage of a Zosin, indoramin, naftopidil, tamsulosin, phenoxy compound through the cells of the GIT. Lipophilicity is a benzamine, rauwolfa alkaloids, Recordati 15/2739, key property in predicting this and is defined by in Vitro Log SNAP 1069, SNAP 5089, RS17053, SL 89.0591, D7 measurements using organic Solvents and buffer. Pref doxazosin, teraZoSin and abanoquil, Suitable C2-adr erably the PDE5 inhibitors have a Log D, of -2 to +4, more energic receptor antagonists include dibenarnine, preferably -1 to +3. The log D can be determined by tolaZoline, trimaZosin, efaroXan, yohimbine, ida ZOXanclonidine and dibenarnine, Suitable non-Selec Standard procedures known in the art Such as described in J. tive C.-adrenergic receptor antagonists include Pharm. Pharmacol. 1990, 42:144. dapiprazole; further C.-adrenergic receptor antago 0081 Cell monolayer assays such as CaCo add substan nists are described in PCT application WO99/30697 tially to prediction of favourable membrane permeability in published on 14 Jun. 1998 and U.S. Pat. Nos. 4,188, the presence of efflux transporterS Such as p-glycoprotein, 390; 4,026,894; 3,511,836; 4,315,007; 3,527,761; so-called caco-2 flux. Preferably, the PDE5 inhibitors have 3,997,666; 2,503,059; 4,703,063; 3,381,009; 4,252, a caco-2 flux of greater than 2x10 cms, more preferably 721 and 2,599,000 each of which is incorporated greater than 5x10 cms. The caco flux value can be herein by reference; determined by Standard procedures known in the art Such as described in J. Pharm. Sci, 1990, 79, 595-600 0087 3) one or more NO-donor (NO-agonist) com pounds (suitable NO-donor compounds for use 0082) Metabolic stability addresses the ability of the GIT herein include organic nitrates, Such as mono-di or or the liver to metabolise compounds during the absorption tri-nitrates or organic nitrate esters including glyc process: the first pass effect. ASSay Systems Such as eryl brinitrate (also known as nitroglycerin), isosor microSomes, hepatocytes etc are predictive of metabolic bide 5-mononitrate, isosorbide dinitrate, pentaeryth liability. Preferably the PDE5 inhibitors show metabolic ritol tetranitrate, erythrityl tetranitrate, Sodium Stability in the assay System that is commensurate with an nitroprusside (SNP), 3-morpholinosydnonimine hepatic extraction of less then 0.5. Examples of assay molsidomine, S-nitroso-N-acetyl penicilliamine Systems and data manipulation are described in Curr. Opin. (SNAP) S-nitroso-N-glutathione (SNO-GLU), Drug Disc. Devel., 201, 4, 36-44, Drug Met. Disp.,2000, 28, N-hydroxy-L-arginine, amylnitrate, linsidomine, lin 1518-1523 sidomine chlorohydrate, (SIN-1) S-nitroso-N-cys 0.083 Because of the interplay of the above processes teine, diazenium diolates, (NONOates), 1,5-pentane further support that a drug will be orally bioavailable in dinitrate, L-arginene, ginseng, Zizphi fructus, humans can be gained by in Vivo experiments in animals. molsidomine, Re-2047, nitrosylated maxisylyte Absolute bioavailability is determined in these studies by derivatives Such as NMI-678-11 and NMI-937 as administering the compound Separately or in mixtures by the described in published PCT application WO oral route. For absolute determinations (% absorbed) the 0012075); intravenous route is also employed. Examples of the assess 0088) 4) one or more potassium channel openers or ment of oral bioavailability in animals can be found in Drug modulators (Suitable potassium channel openerS/ Met. Disp.2001, 29, 82-87; J. Med Chem, 1997, 40, 827 modulators for use herein include nicorandil, 829, Drug Met. Disp., 1999, 27, 221-226. cromokalim, levcromakalim, lemakalim, pinacidil, 0084. The PDE5 inhibitors and 5HT1a agonists may also cliaZOxide, minoxidil, charybdotoxin, glyburide, be combined with one or more additional active agents for 4-aminopyridine, BaCl); treating Sexual dysfunction, particularly FSAD in Subjects 0089 5) one or more dopaminergic agents, prefer with concurrent significant HSDD. The additional active ably apomorphine or a selective D, D, or agents may be Selected from the following list: D/Dagonist Such as, pramipexole and ropirinol (as 0085 1) one or more naturally occurring or syn claimed in WO-0023056), PNU95666 (as claimed in thetic prostaglandins or esters thereof (Suitable pros WO-0040226); taglandins for use herein include compounds Such as 0090 6) one or more vasodilator agents (suitable alproStadil, prostaglandin E, prostaglandin Eo, vasodilator agents for use herein include nimode 13,14-dihydroprosta glandin E, prostaglandin E, pine, pinacidil, cyclandelate, isoxSuprine, chloropru eprostinol, natural Synthetic and Semi-synthetic pros taglandins and derivatives thereof including those mazine, halo peridol, Rec 15/2739, trazodone); described in WO-OOO33825 and/or U.S. Pat. No. 0091) 7) one or more thromboxane A2 agonists; US 2005/0065158A1 Mar. 24, 2005

0092) 8) one or more ergot alkoloids (suitable ergot a VIP receptor agonist or a VIP analogue (eg alkaloids are described in U.S. Pat. No. 6,037,346 Ro-125-1553) or a VIP fragment, one or more of a issued on 14 Mar. 2000 and include acetergamine, C.-adrenoceptor antagonist with VIP combination eg braZergoline, bromerguride, cianergoline, delorgot Invicorp, Aviptadil); rile, disulergine, ergonovine maleate, ergotamine tar trate, etisulergine, lergotrile, lysergide, meSulergine, 0106 22) one or more of a melanocortin receptor metergoline, metergotamine, nicergoline, pergolide, agonist or modulator or melanocortin enhancer, Such as melanotan II, PT-14, PT-141 or compounds propisergide, proterguride, terguride); claimed in WO-09964002, WO-00074679, 0093 9) one or more compounds which modulate WO-09955679, WO-00105401, WO-00058361, the action of natruretic factors in particular atrial WO-00114879, WO-00113112, WO-0995.4358; naturetic factor (also known as atrial naturetic pep 0107 23) one or more of a serotonin receptor ago tide), B type and C type naturetic factorS Such as nist, antagonist or modulator, more particularly ago inhibitors or neutral endopeptidase (see later); nists, antagonists or modulators for example 5HT2A, 0094) 10) one or more angiotensin receptor antago 5HT2C, 5HT3,5HT6 and/or 5HT7 receptors, includ nists Such as losartan; ing those described in WO-09902159, 0095) 11) one or more substrates for NO-synthase, WO-00002550 and/or WO-00028993; Such as L-arginine; 0108 24) one or more of an androgen such as 0096 12) one or more calcium channel blockers androsterone, dehydroandrosterone, testosterone, Such as amlodipine, androstanedione and a Synthetic androgen; 0097 13) one or more antagonists of endothelin 0109 25) one or more of an androgen receptor receptors and inhibitors or endothelin-converting modulator, for example tibolone, enzyme, 0110 26) one or more of an oestrogen, such as 0098. 14) one or more cholesterol lowering agents Oestradiol, Oestrone, oestriol and a Synthetic estro Such as Statins (e.g. atorvastatin/Lipitor-trade gen, Such as Oestrogen benzoate); mark) and fibrates; 0111 27) one or more of a modulator of transporters 0099. 15) one or more antiplatelet and antithrom for noradrenaline, dopamine and/or serotonin, Such botic agents, e.g. tRA, uPA, warfarin, hirudin and as bupropion, GW-320659; other thrombin inhibitors, heparin, thromboplastin 0112 28) one or more of a purinergic receptor activating factor inhibitors, agonist and/or modulator; 0100 16) one or more insulin sensitising agents 0113 29) one or more of a neurokinin (NK) receptor Such as reZulin and hypoglycaemic agents Such as antagonist, including those described in glipizide, WO-09964008; 0101 17) one or more acetylcholinesterase inhibi 0114 30) one or more of an opioid receptor agonist, torS Such as doneZipil,. antagonist or modulator, preferably agonists for the 0102 18) one or more estrogen receptor modulators ORL-1 receptor; and/or estrogen agonists and/or estrogen antagonists, preferably raloxifene, tibolone or lasofoxifene, (-)- 0115 31) one or more of an agonist or modulator for cis-6-phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)-phe Oxytocin/vasopressin receptors, preferably a Selec nyl-5,6,7,8-tetrahydronaphthalene-2-ol and phar tive oxytocin agonist or modulator; maceutically acceptable Salts thereof the preparation 0116 32) one or more of a modulator of cannabinoid of which is detailed in WO 96/21656; receptorS, 0103) 19) one or more further PDE inhibitors, par 0117 33) one or more NEP inhibitors, preferably ticularly a PDE 2, 7 or 8 inhibitor, preferably a PDE2 wherein said NEP is EC 3.4.24.11 and more prefer inhibitor, said inhibitors preferably having an IC50 ably wherein said NEP inhibitor is a selective inhibi against the respective enzyme of less than 100 nM; tor for EC 3.4.24.11, more preferably a selective 0.104) 20) one or more of an NPY (neuropeptide Y) NEP inhibitor is a selective inhibitor for EC inhibitor, more particularly NPY1 or NPY5 inhibitor, 3.4.24.11, which has an ICs of less than 100 nM preferably NPY1 inhibitor, preferably said NPY (e.g. ompatrilat, sampatrilat) suitable NEP inhibitor inhibitors (including NPYY1 and NPY Y5) having compounds are described in EP-A-1097719; IC50 an IC50 of less than 100 nM, more preferably less values against NEP and ACE may be determined than 50 nM (an assay for identifying NPY inhibitors using methods described in published patent appli is presented in WO-A-98/52890 (see page 96, lines cation EP1097719-A1, paragraphs 0368 to 0376): 2 to 28)); 0118 34) one or more compounds which inhibit angiotensin-converting enzyme Such as enalapril, 0105 21) one or more of vasoactive intestinal pro tein (VIP), VIP mimetic, VIP analogue, more par and one or more combined inhibitors of angiotensin ticularly mediated by one or More of the VIP recep converting enzyme and neutral endopeptidase Such tor subtypes VPAC1,VPAC or PACAP (pituitory as omapatrilat; adenylate cyclase activating peptide), one or more of 0119) 35) one or more of L-DOPA and carbidopa; US 2005/0065158A1 Mar. 24, 2005

0120 36) one or more COX2 inhibitors; 013.6 x) one or more antidepressants such as bup 0121 37) pregabalene or gabapentene; rion, and 0137 xi) one or more 5HT1a modulators (for 0122) 38) one or more non-steroidal anti-inflamma example VML 670). tory agents, 0.138 Particularly preferred combinations for treating 0123. 39) one or more angiotensin-converting FSAD in subjects with concurrent significant HSDD are: enzyme (ACE) inhibitors, e.g. quinapril; 0.139 Sildenal fil, Flibanserin and an androgen; 0124 40) one or more of a bombesin receptor modu lator, preferably selective for the BB1 receptor; 0140 sildenafil, Flibanserin and an oestrogen; 0141 Sildenafil, Flibanserin an androgen and an 0125 41) one or more antidepressants such as bup Oestrogen, rion; 0.142 sildenafil, Flibanserin and lasofoxifene; 0.126 If a combination of active agents are administered, then they may be administered Simultaneously, Separately or 0.143 sildenafil, Flibanserin, lasofoxifene and an Sequentially. androgen; 0127 Preferably, the PDE5 inhibitors (particularly 0144 sildenafil, Flibanserin, lasofoxifene and an sildenafil) and the 5HT1a agonist may be combined with one Oestrogen; Or or more active agents Selected from the following list: 0145 Sildenafil, Flibanserin, lasofoxifene, an andro 0128 i) one or more of an androgen such as andros gen and an Oestrogen; terone, dehydro-androsterone, testosterone, andros 0146 sildenafil, Flibanserin and a NEP inhibitor; tanedione and a Synthetic androgen; 0147 sildenafil, Flibanserin, a NEP inhibitor and an 0129 ii) one or more of an oestrogen, such as androgen; Oestradiol, Oestrone, oestriol and a Synthetic estro 0148 sildenafil, Flibanserin, a NEP inhibitor and an gen, Such as oestrogen benzoate); Oestrogen; Or 0.130) iii) one or more NEP inhibitors, preferably 0149 sildenafil, Flibanserin, a NEP inhibitor, an wherein said NEP is EC 3.4.24.11 and more prefer androgen and an Oestrogen; ably wherein said NEP inhibitor is a selective inhibi tor for EC 3.4.24.11, more preferably a selective 0150 sildenafil, Flibanserin and a dopaminergic NEP inhibitor is a selective inhibitor for EC agent (preferably apomorphine); 3.4.24.11, which has an ICs of less than 100 nM 0151 sildenafil, Flibanserin, a dopaminergic agent (e.g. ompatrilat, sampatrilat) suitable NEP inhibitor (preferably apomorphine) and an androgen; compounds are described in EP-A-1097719, 0152 sildenafil, Flibanserin, a dopaminergic agent 0131 v) one or more of an NPY1 having an IC50 of (preferably apomorphine) and an oestrogen; less than 100 nM, more preferably less than 50 nM, 0153 sildenafil, Flibanserin, a dopaminergic agent for examples See published European Patent Appli (preferably apomorphine), an androgen and an cation EP1097 718 A1; Oestrogen, 0132 vi) one or more estrogen receptor modulators and/or estrogen agonists and/or estrogen antagonists, 0154 sildenafil, Flibanserin and a melanocortin preferably raloxifene, tibolone or lasofoxifene, (-)- enhancer (preferably PT-141); cis-6-phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)-phe O155 sildenafil, Flibanserin, a melanocortin nyl-5,6,7,8-tetrahydronaphthalene-2-ol and phar enhancer (preferably PT-141) and an androgen; maceutically acceptable Salts thereof the preparation 0156 sildenafil, Flibanserin, a melanocortin of which is detailed in WO 96/21656; enhancer (preferably PT-141) and an oestrogen; 0133 vii) one or more of a melanocortin receptor agonist or modulator or melanocortin enhancer, Such O157 sildenafil, Flibanserin, a melanocortin as melanotan II, PT-14, PT-141 or compounds enhancer (preferably PT-141), an androgen and an claimed in WO-09964002, WO-00074679, Oestrogen, WO-09955679, WO-00105401, WO-00058361, 0158 sildenafil, Flibanserin and buprion; WO-00114879, WO-00113112, WO-09954358 (preferably PT-141); 0159 sildenafil, Flibanserin, buprion and an andro gen, 0.134 viii) one or more dopaminergic agents, pref erably apomorphine or a Selective D, D, or 0160 sildenafil, Flibanseri, buprion and an oestro D/Dagonist Such as, pramipexole and ropirinol (as gen, claimed in WO-0023056), PNU95666 (as claimed in 01.61 sildenafil, Flibanserin, buprion, an androgen WO-0040226); and an Oestrogen; 0135) ix) one or more of a bombesin receptor modu 0162 The PDE5 inhibitors with 5HT1a agonists and lators, combinations thereof can be administered alone but will US 2005/0065158A1 Mar. 24, 2005

generally be administered in admixture with a Suitable rate modifiers include, but are not exclusively limited to, pharmaceutical excipient, diluent or carrier Selected with hydroxypropylmethyl cellulose, methyl cellulose, Sodium regard to the intended route of administration and Standard carboxymethylcellulose, ethyl cellulose, cellulose acetate, pharmaceutical practice. polyethylene oxide, Xanthan gum, Carbomer, ammonio methacrylate copolymer, hydrogenated castor oil, carnauba 0163 For example, the PDE5 inhibitors with 5HT1a wax, paraffin wax, cellulose acetate phthalate, hydroxypro agonists and combinations thereof can be administered pylmethyl cellulose phthalate, methacrylic acid copolymer orally, buccally or sublingually in the form of tablets, and mixtures thereof. Modified release and pulsatile release capsules, multi-particulates, gels, films, ovules, elixirs, Solu dosage forms may contain one or a combination of release tions or Suspensions, which may contain flavouring or rate modifying excipients. Release rate modifying excipients colouring agents, for immediate-, delayed-, modified-, Sus may be present both within the dosage form i.e. within the tained-, pulsed- or controlled-release applications. The matrix, and/or on the dosage form, i.e. upon the Surface or PDE5 inhibitors with 5HT1a agonists and combinations coating. thereof may also be administered as fast-dispersing or fast-dissolving dosage forms or in the form of a high energy 0173 Fast dispersing or dissolving dosage formulations dispersion or as coated particles. Suitable formulations may (FDDFs) may contain the following ingredients: aspartame, be in coated or uncoated form, as desired. aceSulfame potassium, citric acid, croScarmelloSe Sodium, croSpoVidone, diascorbic acid, ethyl acrylate, ethyl cellu 0164. Such solid pharmaceutical compositions, for lose, gelatin, hydroxypropylmethyl cellulose, magnesium example, tablets, may contain excipients Such as microcryS Stearate, mannitol, methyl methacrylate, mint flavouring, talline cellulose, lactose, Sodium citrate, calcium carbonate, polyethylene glycol, fumed Silica, Silicon dioxide, Sodium dibasic calcium phosphate, glycine and Starch (preferably Starch glycolate, Sodium Stearyl fumarate, Sorbitol, Xylitol. corn, potato or tapioca Starch), disintegrants Such as Sodium The terms dispersing or dissolving as used herein to describe Starch glycolate, croScarmellose Sodium and certain com FDDFs are dependent upon the solubility of the drug Sub plex Silicates, and granulation binderS Such as polyvinylpyr stance used i.e. where the drug Substance is insoluble a fast rolidone, hydroxypropylmethylcellulose (HPMC), hydrox dispersing dosage form can be prepared and where the drug ypropylcellulose (HPC), Sucrose, gelatin and acacia. Substance is Soluble a fast dissolving dosage form can be Additionally, lubricating agents Such as magnesium Stearate, prepared. Stearic acid, glyceryl behenate and talc may be included. 0174) The PDE5 inhibitors with 5HT1a agonists and 0.165. The following formulation examples are illustra combinations thereof can also be administered parenterally, tive only and are not intended to limit the Scope of the for example, intracavernously, intravenously, intra-arteri invention. Active ingredient means a PDE5 inhibitor with ally, intraperitoneally, intrathecally, intraventricularly, 5HT1a agonists or combination thereof. intraurethrally, intrasternally, intracranially, intramuscularly or Subcutaneously, or they may be administered by infusion 0166 Formulation 1: or needleless injection techniques. For Such parenteral 0167 A tablet is prepared using the following ingredi administration they are best used in the form of a Sterile ents: Active ingredient (50 mg) is blended with cellulose aqueous Solution which may contain other Substances, for (microcrystalline), Silicon dioxide, Stearic acid (fumed) and example, enough Salts or glucose to make the Solution the mixture is compressed to form tablets. isotonic with blood. The aqueous solutions should be suit ably buffered (preferably to a pH of from 3 to 9), if 0168 Formulation 2: necessary. The preparation of Suitable parenteral formula 0169. An intravenous formulation may be prepared by tions under Sterile conditions is readily accomplished by combining active ingredient (100 mg) with isotonic Saline Standard pharmaceutical techniques well-known to those (1000 ml) skilled in the art. 0170 The tablets are manufactured by a standard pro 0.175. The following dosage levels and other dosage ceSS, for example, direct compression or a wet or dry levels herein are for the average human Subject having a granulation process. The tablet cores may be coated with weight range of about 65 to 70 kg. The skilled person will appropriate overcoats. readily be able to determine the dosage levels required for a Subject whose weight falls outside this range, Such as 0171 Solid compositions of a similar type may also be children and the elderly. employed as fillers in gelatin or HPMC capsules. Preferred 0176) The dosage of the PDE5 inhibitor with 5HT1a excipients in this regard include lactose, Starch, a cellulose, agonists in Such formulations will depend on its potency, but milk Sugar or high molecular weight polyethylene glycols. can be expected to be in the range of from 1 to 500 mg for For aqueous suspensions and/or elixirs, the PDE5 inhibitors administration up to three times a day. In the case of with 5HT1a agonists may be combined with various Sweet Sildenafil, a preferred dose is in the range 10 to 100 mg (e.g. ening or flavouring agents, colouring matter or dyes, with 10, 25, 50 and 100 mg) which can be administered once, emulsifying and/or Suspending agents and with diluents twice or three times a day (preferably once). However the Such as water, ethanol, propylene glycol and glycerin, and precise dose will be as determined by the prescribing combinations thereof. physician and will depend on the age and weight of the 0172 Modified release and pulsatile release dosage Subject and Severity of the Symptoms. forms may contain excipients Such as those detailed for 0177 For oral and parenteral administration to human immediate release dosage forms together with additional patients, the daily dosage level of the PDE5 inhibitors will excipients that act as release rate modifiers, these being usually be from to 5 to 500 mg/kg (in single or divided coated on and/or included in the body of the device. Release doses). US 2005/0065158A1 Mar. 24, 2005

0.178 Thus tablets or capsules may contain from 5 mg to polySorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyl 250 mg (for example 10 to 100 mg) of the PDE5 inhibitor dodecanol, benzyl alcohol and water. for administration Singly or two or more at a time, as 0183) The PDE5 inhibitors with 5HT1a agonists and appropriate. The physician in any event will determine the combinations thereof may also be used in combination with actual dosage which will be most suitable for any individual a cyclodextrin. Cyclodextrins are known to form inclusion patient and it will vary with the age, weight and response of and non-inclusion complexes with drug molecules. Forma the particular patient. The above dosages are exemplary of tion of a drug-cyclodextrin complex may modify the Solu the average case. There can, of course, be individual bility, dissolution rate, bioavailability and/or stability prop instances where higher or lower dosage ranges are merited erty of a drug molecule. Drug-cyclodextrin complexes are and such are within the scope of this invention. The skilled generally useful for most dosage forms and administration person will appreciate that the PDE5 inhibitors may be taken routes. As an alternative to direct complexation with the as a single dose as needed or desired (i.e. prin). It is to be drug the cyclodextrin may be used as an auxiliary additive, appreciated that all references herein to treatment include e.g. as a carrier, diluent or Solubiliser. Alpha-, beta- and acute treatment (taken as required) and chronic treatment gamma-cyclodextrins are most commonly used and Suitable (longer term continuous treatment). examples are described in WO-A-91/11172, WO-A-94/ 0179 The PDE5 inhibitors with 5HT1a agonists and O2518 and WO-A-98/55148. combinations thereof can also be administered intranasally 0184 Oral administration of the PDE5 inhibitors with or by inhalation and are conveniently delivered in the form 5HT1a agonists and combinations thereof is a preferred of a dry powder inhaler or an aeroSol Spray presentation route, being the most convenient. In circumstances where from a preSSurised container, pump, Spray, atomiser or the recipient Suffers from a Swallowing disorder or from nebuliser, with or without the use of a Suitable propellant, impairment of drug absorption after oral administration, the e.g. dichlorodifluoromethane, trichlorofluoromethane, drug may be administered parenterally, Sublingually or buc dichlorotetrafluoroethane, a hydrofluoroalkane Such as 1,1, cally. 1,2-tetrafluoroethane (HFA 134A trade mark) or 1,1,1,2,3, 3.3-heptafluoropropane (HFA227EA trade mark), carbon 0185. Transdermal administration of the PDE5 inhibitors dioxide or other Suitable gas. In the case of a pressurised with 5HT1a agonists and combinations thereof is a further aeroSol, the dosage unit may be determined by providing a preferred route, particularly local to the female genitalia, Valve to deliver a metered amount. The pressurised con preferably intravaginally. A preferred method of transdermal tainer, pump, spray, atomiser or nebuliser may contain a administration of Oestrogen and testosterone is using a skin Solution or Suspension of the active compound, e.g. using a patch, depot or implants. mixture of ethanol and the propellant as the Solvent, which 0186 A preferred dose of an estrogen for combination may additionally contain a lubricant, e.g. Sorbitan trioleate. with the PDE5 inhibitor and 5HT1a agonist is in the range Capsules and cartridges (made, for example, from gelatin) 0 to 5 mg per day. for use in an inhaler or insufflator may be formulated to contain a powder mix of the PDE5 inhibitor and a suitable 0187. A preferred dose of an androgen for combination powder base Such as lactose or Starch. with the PDE5 inhibitor and 5HT1a agonist is in the range 0 to 25 mg per day. 0180 Aerosol or dry powder formulations are preferably arranged So that each metered dose or "puff contains from 0188 Since the invention has an embodiment that relates 1 tug to 50 mg of a PDE5 inhibitor for delivery to the patient. to treatment of Sexual dysfunction, with a combination of The overall daily dose with an aerosol will be in the range compounds which may be co-administered Separately, the of from 1 lug to 50 mg which may be administered in a Single invention also relates to combining Separate pharmaceutical dose or, more usually, in divided doses throughout the day. compositions in kit form. Therefore according to a further aspect, the invention provides a kit comprising: a) a first 0181 Alternatively, the PDE5 inhibitors with 5HT1a pharmaceutical composition comprising a PDE5 inhibitor agonists and combinations thereof can be administered in and a pharmaceutically acceptable carrier or diluent; b) a the form of a Suppository or pessary, or they may be applied Second pharmaceutical composition comprising 5HT1a ago topically in the form of a gel, hydrogel, lotion, Solution, nist and a pharmaceutically acceptable carrier or diluent, and cream, ointment or dusting powder. The PDE5 inhibitors a container for the two compositions. with 5HT1a agonists and combinations thereof may also be dermally or transdermally administered, for example, by the 0189 According to a further aspect, since the invention use of a skin patch, depot or Subcutaneous injection. They has an embodiment that relates to treatment of FSAD with may also be administered by the pulmonary or rectal routes. concomitant HSDD, with a combination of compounds which may be co-administered Separately, the invention also 0182 For application topically to the skin, the PDE5 relates to combining Separate pharmaceutical compositions inhibitors with 5HT1a agonists and combinations thereof in kit form. Accordingly, the invention provides a kit com can be formulated as a Suitable ointment containing the prising: a) a first pharmaceutical composition comprising a active compound Suspended or dissolved in, for example, a PDE5 inhibitor and a pharmaceutically acceptable carrier or mixture with one or more of the following: mineral oil, diluent; b) a second pharmaceutical composition comprising liquid petrolatum, white petrolatum, propylene glycol, poly 5HT1a agonist and a pharmaceutically acceptable carrier or oxyethylene polyoxypropylene compound, emulsifying wax diluent; c) a third pharmaceutical composition comprising and water. Alternatively, they can be formulated as a Suitable an androgen and a pharmaceutically acceptable carrier or lotion or cream, Suspended or dissolved in, for example, a diluent; d) a fourth pharmaceutical composition comprising mixture of one or more of the following: mineral oil, an oestrogen and a pharmaceutically acceptable carrier or Sorbitan monoStearate, a polyethylene glycol, liquid paraffin, diluent and a container for the four compositions. The four US 2005/0065158A1 Mar. 24, 2005 compositions are separate components intended for co androgen; d) a fourth pharmaceutical composition administration to a female subject suffering from FSAD, comprising an oestrogen; e) optionally a pharmaceu wherein the patient has concentrations of hormone less than tical composition comprising an additional active the physiological levels found in a normal pre-menopausal agent as hereinabove defined; and f) a container for woman. By “co-administration”, it is meant that the four the compositions, components can be taken from the kit and combined for administration together as a composition or as part of the 0197) vi) a method of treating FSAD in a subject Same, unitary dosage form, Such as an parenterally or orally who has concurrent significant HSDD comprising administered Solution. “Co-administration” also includes treating Said patient with an effective amount of a administering the components separately (e.g. as tablets or PDE5 inhibitor and a 5HT1a agonist; capsules), but as part of the same therapeutic treatment 0198 vii) a method of treating FSAD in a subject program or regimen. “Separate’ administration is the pre who has concurrent significant HSDD comprising ferred mode of administration. The four components need treating Said patient with pharmaceutical combina not be administered at essentially the Same time, although tion comprising a PDE5 inhibitor, a 5HT1a agonist, they can be if so desired. Thus “co-administration” includes, an oestrogen, an androgen and optionally an addi for example administering all four components as Separate tional active agent as hereinabove defined; and dosages or dosage forms and at essentially the same time. "Co-administration” also includes Separate administration at 0199 viii) a method of treating FSAD in a subject different times, in any order, and if preferred by different who has concurrent significant HSDD comprising routes of administration. If administered Separately it is the Steps of: preferred that the four components be administered at essen 0200) a) measuring the subject's physiological tially the same time. If administered Separately and at levels of oestrogen and androgen; different times, it is preferred that the four components be administered within 24 hours of each other. If administered 0201 b) if not replete, administering to the Sub Separately, It is preferred that the four components be ject an oestrogen and/or an androgen until replete administered by the same route. An example of a kit is the levels are achieved; then So-called blister pack well known in the packaging industry 0202 c) administering a PDE5 inhibitor and a particularly for packaging pharmaceutical dosage forms. 5HT1a agonist. 0190. It will be appreciated that the invention covers the 0203 Assay following further aspects and that the embodiments Specified 0204 PDE action potency values referred to herein are hereinabove for the first aspect extend to these aspects: determined by the following assayS. 0191) i) a PDE5 inhibitor with a 5HT1a agonist for treating Sexual dysfunction; 0205 Preferred PDE compounds suitable for use in accordance with the present invention are potent and Selec 0.192 ii) a PDE5 inhibitor with a 5HT1a agonist for tive PDE5 inhibitors. In vitro PDE inhibitory activities treating FSAD in a subject who has concurrent against cyclic guanosine 3',5'-monophosphate (cGMP) and significant HSDD; cyclic adenosine 3',5'-monophosphate (cAMP) phosphodi 0193 iii) a pharmaceutical combination (for simul esterases can be determined by measurement of their ICso taneous, separate or sequential administration) for values (the concentration of compound required for 50% treating Sexual dysfunction comprising a PDE5 inhibition of enzyme activity). inhibitor and a 5HT1a agonist, an oestrogen, an 0206. The required PDE enzymes can be isolated from a androgen and optionally an additional active agent as variety of Sources, including human corpus cavernoSum, hereinabove defined; human and rabbit platelets, human cardiac ventricle, human 0194 iv) a pharmaceutical combination (for simul skeletal muscle and bovine retina, essentially by the method taneous, separate or sequential administration) for of W. J. Thompson and M. M. Appleman (Biochem., 1971, treating FSAD in a subject who has concurrent 10, 311). In particular, the cQMP-specific PDE (PDE5) and significant HSDD comprising a PDE5 inhibitor, a the coMP-inhibited cAMP PDE (PDE3) can be obtained 5HT1a agonist, an oestrogen, an androgen and from human corpus cavernoSum tissue, human platelets or rabbit platelets; the coMP-stimulated PDE (PDE2) was optionally an additional active agent as hereinabove obtained from human corpus cavernoSum; the calcium/ defined; calmodulin (Ca/CAM)-dependent PDE (PDE1) from human 0195 iv) the use of a pharmaceutical combination cardiac ventricle; the cAMP-specific PDE (PDE4) from for the manufacture of a medicament for treating human skeletal muscle; and the photoreceptor PDE (PDE6) FSAD in a Subject who has concurrent significant from bovine retina. Phosphodiesterases 7-11 can be gener HSDD comprising a PDE5 inhibitor, a 5HT1a ago ated from full length human recombinant clones transfected nist, an oestrogen, an androgen and optionally an into SF9 cells. additional active agent as hereinabove defined; 0207 Assays can be performed either using a modifica 0196) v) a kit for treating FSAD in a subject who tion of the “batch' method of W. J. Thompson et al. does not have concurrent significant HSDD, the kit (Biochem., 1979, 18, 5228) or using a scintillation proximity comprising: a) a first pharmaceutical composition assay for the direct detection of AMP/GMP using a modi comprising a PDE5 inhibitor; b) a second pharma fication of the protocol described by Amersham plc under ceutical composition comprising a 5HT1a agonist; c) product code TRKQ7090/7100. In summary, the effect of a third pharmaceutical composition comprising an PDE inhibitors was investigated by assaying a fixed amount US 2005/0065158A1 Mar. 24, 2005 of enzyme in the presence of varying inhibitor concentra 0215. The order of questions may be altered at your tions and low substrate, (cGMP or cAMP in a 3:1 ratio discretion & questions may be skipped if, in your opinion, unlabelled to 3H-labeled at a conc ~/3 Km) such that Sufficient information has been acquired and annotated from ICsos K. The final assay volume was made up to 100 ul with preceding questions to Satisfy the inclusion/exclusion crite assay buffer 20 mM Tris-HCl pH 7.4, 5 mM MgCl2, 1 ria which apply to that issue. Additional questions are mg/ml bovine Serum albumin. Reactions were initiated with permitted, however, please clearly annotate both the ques enzyme, incubated for 30-60 min at 30° C. to give <30% tion & the answer. substrate turnover and terminated with 50 ul yttrium silicate SPA beads (containing 3 mM of the respective unlabelled 0216) Annotations must be legible to outside reviewers. cyclic nucleotide for PDEs 9 and 11). Plates were re-sealed Text must be comprehensible, but Sentence Structure & and shaken for 20 min, after which the beads were allowed grammar need not be perfect. A telegraphic writing Style is to settle for 30 min in the dark and then counted on a acceptable. TopCount plate reader (Packard, Meriden, Conn.) Radioac 0217 Please read these instructions to the subjects prior tivity units were converted to % activity of an uninhibited to Starting the interview: control (100%), plotted against inhibitor concentration and inhibitor ICs values obtained using the Fit Curve 0218 "I am going to ask you a Series of questions, Microsoft Excel extension. which I would like you to answer as honestly and candidly as you can. If you can, please use a time 0208 Suitable assays to identify 5HT1a agonists are frame of the last 6 months, however it is okay to disclosed in J Pharmacol Exp Ther. 1998, 284(3), 1082-1094 bring in other times. If you are unsure, or are and in J Pharmacol Toxicol Methods 1998, 40(1), 47-55. uncomfortable, about answering any question, it is Other suitable assays are well known to the man skilled in perfectly OK to say so.” the art. 0219. In answering these questions, the following defi 0209 Diagnosis of FSAD with concomitant HSDD may nitions apply: be achieved through the use of the Sexual History Interview (“SHI”), administered by sexual health experts for the FSD 0220 Sexual Activity: Includes any activity which diagnosis of potential subjects. The SHI was developed by may result in Sexual Stimulation or Sexual pleasure, a team of internal clinical perSonnel at Pfizer and external e.g. intercourse, caressing, foreplay, masturbation Sexual health experts. The SHI addresses two main aspects (i.e. self-masturbation or your partner masturbating relevant to Subject inclusion/exclusion; identification of the you) and oral Sex (i.e. your partner giving you oral sub-component of FSD and psychosexual eligibility. These sex). two aspects are key to ensuring appropriate identification of the target population and that the main inclusion and exclu 0221 Sexual Intercourse: Sexual activity which Sion criteria relevant to psychoSexual eligibility are met. The results in penetration of your vagina by your partner. SHI is detailed hereinafter. 0222 Sexual Stimulation: Caressing, foreplay Pfizer Sexual Health Interview (SHI) 0223 Self-stimulation (e.g. masturbation): Caress 0210 AScreening Sexual History Semi-Structured Inter ing or fondling of genitals yourself, your partner view caressing them, or by using a device.” 0211 Administration Guidelines 0224 For the first question, you may wish to review the range of typical physical & cognitive changes a woman 0212 Time: Schedule at least 90 minutes to complete this might experience when Sexually Stimulated or Sexually process: 60-90 minutes for the Interview; 15-30 minutes to aroused, including: increased heart rate & breathing, feel write the justification. ings of closeneSS & intimacy with the partner; nipples 0213 Interviewer: Only a Pfizer-approved FSD expert is becoming more Sensitive & erect, increased Sensitivity to authorized to conduct the interview: the function cannot be touch, increased genital Sensitivity; pleasurable Sensations delegated. The FSD expert is invested with sign-off author in the clitoris (pulsating/tingling); Sensations of genital ity on psychological & Sexual history-related protocol inclu warmth & lubrication/wetness, feeling excited/aroused sion/exclusion criteria: co-signature of both the FSD expert wanting Sexual Stimulation to continue. and the principal investigator is required for any Subject to 0225 Question 1 can EITHER be treated as open-ended, enter the Study. with you checking all options Volunteered & prompting for 0214) Conduct in a private room alone with the candidate items not mentioned OR Subject can fill in directly, then you (no partners). review answers together. US 2005/0065158A1 Mar. 24, 2005 12

1 What kind of sexual complaints do you have? Definitions: "Now" refers to over the past 6 months; "Before" refers to when you thought your sexual function was normal. Rating Scale: Never = 0; Seldom = 1; Occasionally = 2; Usually = 3; Nearly always = 4; Not applicable FNA

1a DESIRE How often do you have Sexual thoughts or feelings of desire? US 2005/0065158A1 Mar. 24, 2005 13

Frequency you act on these feelings alone? Frequency you act on these feelings with partner?

Physiologic Now 3:. : TeSponse. Breathing Speeds Before Pulse Speeds up Now Before Pleasurable Now sensations in your breasts Pleasurable sensations in your clitoris & labia Pleasurable sensations in your Vadina Lubrication: Wetness in your HOW Often is interCourse difficult or impossible because your wadina is dry? 1c. PAIN How often do you experience pain

followings.1d ORGASM Manual (or device) stimulation/alone US 2005/0065158A1 Mar. 24, 2005 14

Manual (or device) Now stimulation/partner Before Oral Stimulation NOW Before interCourse NOW Before

NOW is... Much Some

Creater US 2005/0065158A1 Mar. 24, 2005 15

Have there been any 1-2 week intervals during the last 6 months when you have had no problems with Sexual response or orgasms? (e.g. weekend away from the kids, different partner, etc...). V Do you currently have a partner OR Are you currently in a sexual relationship? Yes No lf yes, for how long? Sex of partner: Male Female

5a How frequently do you & your partner have sexual intercourse or other sexual activity now? times in One month

5b. How does your frequency of sexual activity now compare to before (e.g. when your sexual function was normal)? Circle: More Same LeSS

If you had no sexual complaints, ideally how frequently would you like to have sexual intercourse or other sexual activity? times in One month

7a. Who usually initiates sexual intercourse or other sexual activity? I always do My partner usually does usually do My partner always does My partner and are Other about equal

Are you comfortable initiating sexual intercourse or activity? Yes No US 2005/0065158A1 Mar. 24, 2005 16

8 When your partner makes sexual advances, how do you usually respond? Check all that apply

My partner never makes sexual advances usually accept with pleasure sometimes accept with pleasure accept reluctantly accept for his/her sake, but I get little or no pleasure from it often refuse usually refuse avoid situations where sexual advances Could be made Other

9a On a scale of 1 to 10, how would you rate your current, overal relationship with your partner? (1=Totally unsatisfactory, 5-FAverage; 10 = Totally satisfactory)

9b is this a change from before? Yes No lf yes, how & when did it change?

10a On a Scale of 1 to 10, how would you rate your sexual relationship with your partner? (1=Totally unsatisfactory, 5=Average; 10 = Totally satisfactory) US 2005/0065158A1 Mar. 24, 2005 17

Check all partner facto bute: Partner's erectile dysfunction/impotence Partner's delayed ejaculation F Partner's premature ejaculation nadequate forepla

inadequate Communication Relationship difficult Pressure to have Sex Partner's ander with VOu Partner doesn't fully understand how to Satisfv VOu Partner isn't Willind to experiment Partner isn't interested in havind Sex Partner won't initiate activit Partner is depressed Nedative (annovind) habits of partner Partner's phVsical appearance

US 2005/0065158A1 Mar. 24, 2005 18 Scale: 1 = Not important; 5 = Sometimes important; 10 = Very important

Are there practical reasons why you do not take part in sexual activity as much as you would like? (e.g. children, tiredness, partner travel, your travel, insufficient privacy, stressful job, caring for relations, etc..) Please list:

Reliqious prohibitions Your parents attitudes about Sex US 2005/0065158A1 Mar. 24, 2005 19

other T. Other T Interviewers: For the following 4 questions, focus on ascertaining whether the abuse or emotional issue is unresolved and/or connected to the subject's current sexual complaints. If yes, exclude. Extensive historical detail is not necessary to assess suitability for study entry.

12 Have you ever been what you consider to be physically abused (e.g. pushed or hit) by anyone? Yes No

Age, Context ReSolved? (counseling, Orosecution, etc... Connected to Current sexual complaints?

13 Have you ever been what you consider to be emotionally abused (e.g. belittled, bullied)? Yes NO Age, Context Resolved? (counseling, Orosecution, etc... Connected to Current Sexual Complaints?

14 Have you ever been touched in a way you didn't want to be touched, or forced or pressured into having Sexual activity against your will? IFocus on study includability) Yes No

Age, Context Resolved? (counseling, Orosecution, etc... Connected to Current Sexual Complaints? US 2005/0065158A1 Mar. 24, 2005 20

Problem Resolved? Connected to current sexual complaints? US 2005/0065158A1 Mar. 24, 2005 21

Justification of FSAD Diagnosis: Circle the appropriate answers below, supporting your conclusions in a diagnostic summary which integrates interview information & adequately justifies the subjects inclusion or exclusion from the study.

Using DSM-IV definitions (see below): O Does the Subject have FSAD and is it the most prominent aspect of her Sexual dysfunction Yes No () Has the FSAD been present for at least 6 months Yes No () ls her dysfunction situational Yes No O Are any of the following associated with the FSAD? Defend why you consider these secondary to FSAD O Orgasmic Disorder Yes No O Hypoactive Sexual Desire Disorder Yes No O Superficial/introital dyspareunia secondary to lubrication disorder Yes No US 2005/0065158A1 Mar. 24, 2005 22

DSM-IV definitions:

Hypoactive Sexual Desire Disorder Persistently or recurrently deficient (or absent) sexual fantasies and desire for sexual activity. (Judgement of deficiency or absence is made by the clinician, taking into account factors that affect sexual functioning, such as age and the context of the person's life.) The disturbance causes marked distress or interpersonal difficulty The sexual dysfunction is not better accounted for by another clinical condition (other than another sexual dysfunction) and is not due exclusively to the direct physiological effects of a substance (e.g. a drug of abuse, a medication) or a general medical Condition

Female Sexual Arousal Disorder Persistent or recurrent inability to attain, or to maintain until completion of the sexual activity, an adequate lubrication-swelling response of sexual excitement. The disturbance causes marked distress or interpersonal difficulty The sexual dysfunction is not better accounted for by another clinical condition (except another sexual dysfunction) and is not due exclusively to the direct physiological effects of a substance (e.g. a drug of abuse, a medication) or a general medical condition Female Orgasmic Disorder Persistent or recurrent delay in, or absence of, orgasm following a normal sexual excitement phase. (Women exhibit wide variability in the type or intensity of stimulation that triggers orgasm.) The diagnosis of Female Orgasmic Disorder should be based on the clinician's judgement that the woman's orgasmic capacity is less that would be reasonable for her age, Sexual experience, and the adequacy of sexual stimulation she receives. The disturbance causes marked distress or interpersonal difficulty The orgasmic dysfunction is not better accounted for by another clinical Condition (except another Sexual Dysfunction) and is not due exclusively to the direct physiological effects of a substance (e.g. a drug of abuse, a medication) or a general medical condition US 2005/0065158A1 Mar. 24, 2005 23

Dyspareunia Recurrent or persistent genital pain associated with sexual interCourse The disturbance causes marked distress or interpersonal difficulty The dysfunction is not better accounted for by vaginismus or another clinical condition (except another Sexual Dysfunction) and is not due exclusively to the direct physiological effects of a substance (e.g. a drug of abuse, a medication) or a general medical condition.

Summmarize any other diagnostic impressions in this space:

If the subject is recommended for study participation despite the revelation of potentially exclusionary information, please describe the information and justify why it is considered less relevant.

Itemized Checklist: The FSD expert is invested with sign-off authority on the following protocol inclusion/exclusion criteria: inclusions:wim These should all be "yes'. A check in any 'no' box excludes the Subiect from the stud 6.1.2 Specifically, has FSAD been present for at least six Yes months? The FSAD may or may not be associated with: Orgasmic Disorder primary anorgasmia excluded) Hypoactive Sexual Desire Disorder pre-eminent desire disorder excluded) Superficial/introital dySpareunia 6.1.5. Has the subject been in a stable sexual relationship Yes N for at least 6 months? 6 .1.6. ls the subject motivated to seek treatment and willing to attempt sexual activity at least once per week (on average) during all phases of the study (including the interval between Screen and Baseline)? Exclusions: These should all be "no". A check in any 'yes' box excludes the Subiect from the stud ls it true that the subject has never had a satisfactory Sex life? 6.2.5 ls the subject's sexual dysfunction considered to be situational, i.e. limited to Certain types of stimulation, US 2005/0065158A1 Mar. 24, 2005 24

Does the subject have any other major psychological or sexual disorder (not listed in the DSM-IV FSD selection in inclusion 6.1.2) which is considered to be the primary diagnosis explaining the sexual dysfunction? (Joint Sign-Off With principal investidator if the subject currently has a male sexual partner, does he experience (or has he a recent history of) unresolved premature ejaculation, erectile dysfunction or delayed ejaculation which has not been Successfully treated? (Write "NA" if partner is female Does the subject have any medical or psychological condition or social circumstances which would impair her ability to participate reliably in the study, or who may increase the risk to herself or others by participatina? (Joint Sign-off with principal investiaator

ACCEPT Subject meets all of the above criteria DECLINE One or more Criteria are not met US 2005/0065158A1 Mar. 24, 2005 25

0226. An additional tool is the use of a female sexual Cape Cod FSD Conference (1998) and the International function questionnaire (SFQ) developed by the applicants as Conference for Medical Studies in Female Health (San published in “Development of a Sexual Function Question Francisco 1999). A manuscript, which briefly describes the naire for Clinical Trials of Sexual Function', as referred to SFQ development, has been submitted to the Journal of in Heiman, International Journal of Fertility and Women's Women's Health and Gender-Based Medicine (Develop Health; 2000, 45; 200 (incorporated herein by reference in ment of a Sexual Function Questionnaire for Clinical Trials its entirety) and as detailed hereinafter. of Female Sexual Dysfunction. F. H Quirk et al.) 0236 An abstract has been published in the International The Female Sexual Function Questionnaire (SFQ) Journal of Fertility and Women's Health. 0227 Background and Scoring 0237 References: 0228. The Female Sexual Function Questionnaire (SFQ) is a Self-report outcomes measure of female Sexual function 0238 1. Report of the International Consensus Devel that has been developed to be multi-dimensional and Sub opment Conference on Female Sexual Dysfunction: ject-centered. Definitions and Classifications, R. Basson et al, Jour nal of Urology, Vol163, p888-893, 2000. 0229. The SFQ addresses all aspects of the sexual response cycle (desire, arousal, orgasm) as well as pain, 0239 2. Development of a Sexual Function Question which is in keeping with the DSM-IV diagnostic criteria and naire for Clinical Trials of Female Sexual Dysfunc the newly generated AFUD definitions'. tion, J. Heiman, International Journal of Fertility and 0230. The item content of the SFQ was generated from Women's Medicine, vol 45, 2, p200, 2000. the aggregated responses of 82 women to a Semi-structured 0240 SFQ Scoring System (Items, Total, Domains) interview. The content of the interview addressed, amongst other things, women's understanding of the terms com 0241) Individual Items monly used to describe the phases of Sexual response (e.g. desire and arousal) and the language that they themselves 0242. The SFQ contains 34 items and each item has used to describe these changes. These interviews also between 5 or 7 possible response options. addressed Some of the consequences of female Sexual dyS 0243 Items 1-5, 27-28, and 33-34 are scored 1-5 (in function (FSD) for the woman, her partner and their rela ascending order) e.g. tionship and Some of these core issues are also represented within the SFO item content. 0244 1. Over the last 4 weeks, how often have you had pleasurable thoughts and feelings about Sexual activity? 0231. Both the physical and the cognitive aspects of Sexual response are evaluated within the SFQ items as these two elements were Strongly identified as being important, both in relation to the impact of FSD and to changes in Not at all (1) Rarely (2) function, both positive and negative, in the interview Sample Sometimes (3) of women. The item content of the SFQ has also been judged Often (4) to be clinically relevant by an external panel of clinicians Very often (5) with expertise in Psychology, Physiology, Gynaecology, Physical Medicine and the treatment of FSD. 0232 Subsequent use of the SFQ in clinical trials in a 0245) Items 6-14, 16, 20-21, 23-26 are scored 1-5 (in large sample of women (approx. 900) has demonstrated that ascending order) with the not applicable category (e.g. 'I it has excellent psychometric properties and has demon did not take part in Sexual activity, I did not have any Strated discriminative and construct validity, test-retest reli orgasms) set to missing. e.g. ablility, internal consistency and Sensitivity to change. This 0246 6. Over the last 4 weeks, in general, how enjoyable is the case at both the item level and the domain level (seven has it been to be sensually touched and caressed by your domains have been identified through factor analysis: partner? Desire, Arousal (Sensation), Arousal (lubrication), Orgasm, Pain, Enjoyment and Partner). 0247 I have not been touched or caressed (missing) 0233. The validity of the SFQ at both the item level and the domain level supports the use of individual SFQ domains as primary endpoints (e.g. Arousal or Orgasm) with Not enjoyable (1) the remaining domains or individual items being utilised as Slightly enjoyable (2) Moderately enjoyable (3) Secondary endpoints. This approach also ensures that all Very enjoyable (4) aspects of Sexual function are evaluated in a therapeutic area Extremely enjoyable (5) in which the effects of dysfunction and intervention are not currently wholly understood. 0234. The SFQ has been developed and validated in a 0248 Items 15 and 19 are scored 0-6 (in ascending order) number of languages (18) as well as for use in the USA and C.9. Australia. 0249. 15. Over the last 4 weeks, how often did you take 0235. The development of the SFQ has been presented at part in Sexual activity with penetration (e.g. vaginal pen the Washington Consensus Conference (Bethesda 1998), the etration and intercourse)? US 2005/0065158A1 Mar. 24, 2005 26

-continued

I did not take part in sexual activity (O) Scores Once?twice (1) Suggesting 3-4 times (2) normal 5-8 times (3) Domain # of items Items Score range function 9-12 times (4) 13-16 times (5) Orgasm 3 24-26 3-15 >12 >16 times (6) Pain 3 17, 18, 22 2-15 >12 Enjoyment 6 6, 16, 20, 21, 6-30 >23 23, 27 0250 Items 17*-18*, 29*, 30 and 31 are scored 1-5 (in Partner 2 30, 31 2-10 >8 descending order)* For items 17, 18 and 29, the “I did not *These scores indicating a high likelihood of normal function have been take part in Sexual activity category is set to missing.e.g. derived using discriminant analyses from the current database and should be used as guidelines only. There is a band of score below these where 0251 30. Thinking about the last 4 weeks, how much did functional status (excluding Partner domain) would be considered as bor you worry that your partner may look for another Sexual derline depending on other clinical indices. See Table 1. relationship because of problems with your sexual life? 0260 TABLE 1. Not at all (5) Slightly (4) SFQ Score ranges indicative of likelihood of Sexual dysfunction Moderately (3) Very (2) Score range Extremely (1) Score range indicating high Score range indicating probability of indicating high borderline sexual normal sexual 0252) Item 22 is scored from 5-1 with the “I did not take Domain probability of FSD function function part in Sexual activity Scored as missing and the “I did not Desire 5-17 18-22 23-31 take part in Sexual activity because of being worried or Arousal (S) 4-10 11-13 14-20 Arousal (L) 2-5 6-7 8-10 anxious about pain scored as 0 i.e. Orgasm 3-8 9-11 12-15 0253 22. Over the last 4 weeks, how often have you been Pain 2-8 9-11 12-15 worried or anxious about pain during Sexual activity? Enjoyment 6-16 17-22 23-30

0261) When used in conjunction with a clinical sexual I did not take part in sexual activity (missing) history interview the SFQ scores should be supportive of I did not take part in sexual activity because (O) of being worried or anxious about pain information derived from the subject (i.e. if the subject Not at all (5) proposes that orgasm is her greatest Sexual complaint a Score Sometimes (4) within the range of 3-11 would be expected. A Score greater Often (3) than 12 should prompt a review and further discussion). Very often (2) Every time (1) 0262. Where discrepancies between the SFQ score and the sexual problem (s) derived from the sexual history interview arise the opportunity should be taken to discuss 0254) Note: Item 32 is not included in the overall scoring this further with the subject and determine the cause(s) for but may be tabulated if desired. any discrepancy. 0255 Total Score 0263. The actual SFQ completed by the subject is as 0256 A total score may be derived from Summing the follows: individual item score for each item, except item 32. The total score range is 30-167. 0264. Sexual Function Questionnaire 0265. These questions ask about your sexual activity over 0257. A higher score indicates better sexual function. the last 4 weeks. Please answer every question by marking 0258 Domain Scores one box with a croSS. If you are unsure about how to answer, 0259. Seven domains have been identified through factor please give the best answer you can. In answering these analysis. questions the following definitions apply: 0266 Sexual Activity includes any activity which may Scores result in Sexual Stimulation or Sexual pleasure e.g. inter Suggesting course, caressing, foreplay, masturbation (i.e. Self mastur normal bation or your partner masturbating you) and oral Sex (i.e. Domain # of items Items Score range function your partner giving you oral Sex). Desire 6 1-4, 15, 28 5-31 >23 Arousal (S) 4 7-10 4-20 >14 0267 Sexual Life includes both the physical sexual Arousal (L) 2 11-12 2-10 >8 activities and the emotional Sexual relationship that you have with your partner. US 2005/0065158A1 Mar. 24, 2005 27

0268 1. Over the last 4 weeks, how often have you had 0280 13. Over the last 4 weeks, how often did you pleasurable thoughts and feelings about Sexual activ have feelings of emotional Sexual arousal when you ity'? Answer selection: Not at all, Rarely; Sometimes; took part in Sexual activity? (e.g. feeling excited, feel Often; Very often ing turned on, wanting sexual activity to continue). Answer Selection: I did not take part in Sexual activity; 0269 2. Over the last 4 weeks, how often have you Not at all; Sometimes; Often; Very often; Every time wanted to be sensually touched and caressed by your partner'? Answer selection: Not at all; Rarely; Some 0281. 14. Over the last 4 weeks, how much emotional times; Often; Very often Sexual arousal did you notice when you took part in Sexual activity? (e.g. feeling excited, feeling turned 0270. 3. Over the last 4 weeks, how often have you on, wanting Sexual activity to continue). Answer Selec wanted to take part in Sexual activity? Answer Selec tion: I did not take part in Sexual activity; None; tion: Not at all; Rarely; Sometimes; Often; Very often Slightly aroused; Moderately aroused; Very aroused; 0271 4. Over the last 4 weeks, how often have you Extremely aroused initiated Sexual activity with your partner? Answer 0282) 15. Over the last 4 weeks, how often did you take selection: Not at all; Rarely; Sometimes; Often; Very part in Sexual activity with penetration (e.g. vaginal often penetration and intercourse)? Answer Selection: I did 0272 5. Over the last 4 weeks, how often have you not take part in Sexual activity, Once/twice, 3-4 times, been Sensually touched and caressed by your partner? 5-8 times; 9-12 times; 13-16 times; >16 times Answer selection: Not at all; Rarely; Sometimes; 0283 16. Over the last 4 weeks, in general, how much Often; Very often did you enjoy penetration and intercourse? Answer 0273 6. Over the last 4 weeks, in general, how enjoy Selection: I did not take part in Sexual activity; Not able has it been to be sensually touched and caressed by enjoyable, Slightly enjoyable; Moderately enjoyable; your partner? Answer Selection: I have not been Very enjoyable; Extremely enjoyable touched or caressed; Not enjoyable; Slightly enjoyable; 0284 17. Over the last 4 weeks, how often did you Moderately enjoyable; Very enjoyable; Extremely experience pain in your Vagina/genital area during or enjoyable. after Sexual activity (e.g. penetration, intercourse)? 0274 7. Over the last 4 weeks, how often did you have Answer selection: I did not take part in sexual activity; a feeling of warmth in your vagina/genital area when Not at all; Sometimes; Often; Very often; Every time you took part in Sexual activity? Answer Selection: I did 0285) 18. Over the last 4 weeks, in general, how much not take part in Sexual activity; Not at all; Sometimes, pain did you experience in your vagina/genital area Often; Very often; Every time during or after Sexual activity (e.g. penetration, inter course)? Answer Selection: I did not take part in Sexual 0275 8. Over the last 4 weeks, in general, how much activity; No pain; Slightly painful; Moderately painful; warmth did you feel in your vagina/genital area when Very painful; Extremely painful you took part in Sexual activity? Answer Selection: I did not take part in Sexual activity; None; Slightly warm, 0286 19. Over the last 4 weeks, how often did you take Moderately warm; Very warm; Extremely warm part in Sexual activity without penetration (e.g. mas 0276 9. Over the last 4 weeks, how often did you have turbation and oral sex)? Answer selection: I did not take a Sensation of pulsating (tingling) in your vagina/ part in Sexual activity, Once/twice, 3-4 times; 5-8 genital area when you took part in Sexual activity? times; 9-12 times; 13-16 times; >16 times Answer Selection: I did not take part in Sexual activity, 0287. 20. Over the last 4 weeks, in general, how much Not at all; Sometimes; Often; Very often; Every time did you enjoy Sexual activity without penetration (e.g. masturbation, oral Sex)? Answer Selection: I did not 0277 10. Over the last 4 weeks, in general, how much take part in Sexual activity, No enjoyment, Slightly pulsating (tingling) in your vagina/genital area did enjoyable; Moderately enjoyable; Very enjoyable; you notice when you took part in Sexual activity? Extremely enjoyable Answer Selection: I did not take part in Sexual activity; No Sensation; A mild Sensation; A moderate Sensation; 0288 21. Over the last 4 weeks, how often did you feel A Strong Sensation; A very Strong Sensation emotionally close to your partner when you took part in Sexual activity? Answer Selection: I did not take part in 0278 11. Over the last 4 weeks, how often did you sexual activity; Not at all; Sometimes; Often; Very notice vaginal wetness/lubrication when you took part often; Every time in Sexual activity? Answer Selection: I did not take part in sexual activity; Not at all; Sometimes; Often; Very 0289 22. Over the last 4 weeks, how often have you often; Every time been worried or anxious about pain during Sexual activity? Answer Selection: I did not take part in Sexual 0279 12. Over the last 4 weeks, in general, how much activity because of being worried or anxious about vaginal wetneSS/lubrication did you notice when you pain; Not at all; Sometimes; Often; Very often; Every took part in Sexual activity? Answer Selection: I did not time take part in Sexual activity, No wetneSS/lubrication; Slightly wet/lubricated; Moderately wet/lubricated; 0290) 23. Over the last 4 weeks, did you feel good Very wet/lubricated; Extremely wet/lubricated about yourself when you were sexually active'? Answer US 2005/0065158A1 Mar. 24, 2005 28

Selection: I did not take part in Sexual activity; Not at 3. The use of a PDE5 inhibitor in combination with a all; Slightly; Moderately; Very; Extremely 5HT1a agonist in the manufacture of a medicament for the treatment of FSAD and HSDD in a subject suffering from 0291 24. Over the last 4 weeks, how often did you FSAD and concurrent significant HSDD. have an orgasm when you took part in Sexual activity 4. The use of a PDE5 inhibitor in combination with a (may be with or without a partner)? Answer selection: 5HT1a agonist in the preparation of a medicament for the I did not take part in Sexual activity; Not at all; treatment of FSAD in a subject who has concurrent signifi Sometimes; Often; Very often; Every time cant HSDD. 0292) 25. Over the last 4 weeks, in general, how 5. The use as claimed in claims 1 to 4 wherein the PDE5 pleasurable were the orgasms that you had'? Answer inhibitor is Selected from the group: Selection: I did not have any orgasms, Not pleasurable; 5-2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phe Slightly pleasurable; Moderately pleasurable; Very nyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo 4, pleasurable; Extremely pleasurable 3-dipyrimidin-7-one (sildenafil); 0293 26. Over the last 4 weeks, in general, how easy (6R, 12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4- was it for you to reach orgasm? Answer Selection: I did methylenedioxyphenyl)-pyrazino 2,1":6,1pyrido3,4- not have any orgasms; Very difficult, Quite difficult, bindole-1,4-dione (IC-351); Neither easy nor difficult, Quite easy, Very easy 2-2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-Sulphonyl)-phe 0294 27. Over the last 4 weeks, how confident have nyl-5-methyl-7-propyl-3H-imidazo[5,1-f1,2,4-tri you felt about yourself as a Sexual partner? Answer azin-4-one (vardenafil); and selection: Not at all; Slightly; Moderately; Very; 5-2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin Extremely 3-yl)-3-ethyl-2-2-methoxyethyl-2,6-dihydro-7H 0295 28. Thinking about your sexual life over the last pyrazolo 4,3-dipyrimidin-7-one or 5-(5-Acetyl-2-bu 4 weeks, how often did you look forward to sexual toxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6- activity'? Answer selection: Not at all; Rarely; Some dihydro-7H-pyrazolo 4,3-dpyrimidin-7-one and times; Often; Very often pharmaceutically acceptable Salts thereof. 6. The use as claimed in claims 1 to 4 wherein the PDE5 0296. 29. Thinking about your sexual life over the last inhibitor is 5-2-ethoxy-5-(4-methyl-1-piperazinylsulpho 4 weeks, did you feel disappointed with your Sexual nyl)phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo response (e.g. ability to become aroused, lubrication)? 4,3-dipyrimidin-7-one (sildenafil) (also known as 1-3-(6, Answer Selection: I did not take part in Sexual acvity; 7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo 4,3-d Not at all; Slightly; Moderately; Very; Extremely pyrimidin-5-yl)-4-ethoxyphenylsulphonyl-4- 0297 30. Thinking about the last 4 weeks, how much methylpiperazine) and pharmaceutically acceptable Salts did you worry that your partner may look for another thereof. Sexual relationship because of problems with your 7. The use as claimed in claims 1 to 4 wherein the PDE5 sexual life'? Answer selection: Not at all; Slightly; inhibitor is Sildenafil citrate. Moderately; Very, Extremely 8. The use as claimed in claims 1 to 4 wherein the 5HT1a 0298. 31. Thinking about the last 4 weeks, how much agonist is selective for the 5HT1a receptor over alpha did you worry about your partner's negative feelings adrenoceptors and dopamine. about your sexual life (e.g. partner feeling angry, hurt, 9. The use as claimed in claims 1 to 4 wherein the 5HT1a rejected)? Answer selection: Not at all; Slightly; Mod agonist is Selected from: erately; Very; Extremely Zaprasidone, buSpirone HCl, Urapidil, Tandosporine, Sunepitron, EbalZotan, Ipsapirone, Zalospirone, 0299 32. Thinking about your sexual life over the last Gepirone, Repinotan, Alnespirone, MKC242, Epta 4 weeks, how did you feel about the frequency of your pirone, SR57746A, AP-521, SUN-N4057, Lesopitron, Sexual activity? Answer Selection: A lot less than you DU-125530, VML-670, Flesinoxan, E6265, Fli desired; A little less than you desired; About right for banserin, buspar, AP-521, SUN-N4057, LY293284, you; Alittle more than you desired; Alot more than you LY301.317 and 8-OH-DPAT. desired 10. The use as claimed in claims 1 to 4 wherein the 5HT1a 0300 33. In general, how important is being able to agonist is Flibanserin have an enjoyable Sexual life to you? Answer Selection: 11. A pharmaceutical composition including a PDE5 Not at all; Slightly; Moderately; Very; Extremely inhibitor, a 5HT1a agonist and a pharmaceutically accept able excipient, diluent or carrier. 0301 34. Over the last 4 weeks, taking the whole of 12. A kit comprising: your Sexual life into account, how Satisfied have you been? Answer selection: Not satisfied; Slightly satis a) a first pharmaceutical composition comprising a PDE5 fied; Moderately satisfied; Very satisfied; Extremely inhibitor and a pharmaceutically acceptable carrier or Satisfied diluent; b) a second pharmaceutical composition comprising 1. The use of a PDE5 inhibitor in combination with a 5HT1a agonist and a pharmaceutically acceptable car 5HT1a agonist in the manufacture of a medicament for the rier or diluent; treatment of Sexual dysfunction and a container for the two compositions. 2. The use as claimed in claim 1 wherein the dysfunction is selected from FSD, FSAD, HSDD, FOD, and MED. k k k k k