Patent Abstract:
this invention concerns a method for the treatment of vaginal dryness or sexual dysfunction in women during or after the menopause , said method comprising administering to the woman an effective amount of the compound toremifene or a pharmaceutically acceptable salt or ester thereof , or a metabolite thereof .

Detailed Description:
this invention relates to the use of the estrogen receptor modulator fc - 1271 a , ( deaminohydroxy ) toremifene , in elderly women suffering from vaginal dryness or sexual dysfunction . fc - 1271 a , one of the main metabolites of toremifene , is known to be an estrogen agonist and antagonist ( kangas , 1990 ; international patent publications wo 96 / 07402 and wo 97 / 32574 ). the compound shall be understood to also include its geometric isomers and stereoisomers . the term “ metabolite ” shall be understood to cover any ( deaminohydroxy ) toremifene metabolite already discovered or to be discovered . as examples of such metabolites can be mentioned the oxidation metabolites mentioned in kangas ( 1990 ) on page 9 ( tore vi , tore vii , tore xviii , tore viii , tore xiii ), especially tore vi and tore xviii , and other metabolites of the compound . the new and surprising effect of this compound was found in a clinical study . in this study , raloxifene ( 60 mg / day ) or fc - 1271a at different doses were given to elderly female volunteers for a period of 3 months . at the dose levels of 30 , 60 and 90 mg daily , a significant decrease in vaginal dryness was observed . an improved sexual activity was also reported . these properties are new and unique among the known selective estrogen receptor modulators ( serms ) and indicate that fc - 1271a at the doses from 25 mg to slightly lower than 100 mg daily , particularly 30 to 90 mg daily , can be successfully used to alleviate vaginal dryness and sexual dysfunction of elderly women . furthermore , fc - 1271 a has a superior profile of estrogenic and antiestrogenic effects when compared to any known antiestrogen or serm compound . the compound fc - 1271 a has been found to alleviate sexual dysfunction and to increase the sexual activity . types and causes of female sexual dysfunction are 1 ) desire disorders , 2 ) arousal disorders , 3 ) orgasmic disorders and 4 ) painful intercourse ( dyspareunia ). most of these are due to hormonal reasons , especially to reduced estrogen and testosterone concentrations . vaginal dryness is one of the main causes of female sexual dysfunction and will typically develop after the menopause when the estrogen concentrations decrease . typically this leads to painful intercourse , which indirectly may influence on any type of sexual dysfunction , including psychological causes . in elderly women vaginal dryness is often the main reason for decreased sexual activity . ( spector i p , carey m p : incidence and prevalence of sexual dysfunctions : a critical review of the empirical literature . archives of sexual behaviour 19 : 389 - 408 , 1990 ). estrogens and testosterone are useful pharmaceutical treatments of vaginal dryness and it is not surprising that pure antiestrogens like raloxifene cause vaginal dryness . subsequently , the patients are not satisfied with the treatment which causes painful intercourse and will stop the therapy . the compound can be administered by various routes of which oral or transdermal administration routes are the most preferable . suitable preparation forms include for example tablets , capsules , granules , powders , suspensions , syrups and transdermal ointments or gels . a clinical phase i - ii study was carried out to study the effects of fc - 1271a on endometrial thickness , endometrial pathology , ( biopsy taken by curettage as described by vuopala et al , 1982 ) and cervical smear in healthy postmenopausal female volunteers in the age range 55 to 69 years . tolerability and pharmacokinetics were also assessed . raloxifene ( 60 mg daily ) was used as reference . fc - 1271 a was given perorally at the doses of 30 , 60 and 90 mg daily . there were 29 volunteers at each dose level , as well as in the raloxifene group . fc - 1271a was administered in gelatine capsules containing either 30 , 60 or 90 mg of fc - 1271 a . the thickness of the endometrium was evaluated by ultrasonography using a hitachi eub - 405 instrument . the vaginal epithelium was assessed by karyopyknosis index which is a well known assessment method among the skilled persons . in this method , the vaginal fraction of the cervical smears is estimated as the percentage of the number of cells from different layers : the parabasal cell layer ; the intermediate cell layer ; and the superficial cell layer . estrogenicity is seen by a shift towards superficial cell fraction . in postmenopausal women this fraction usually is close to zero and estradiol treatment increases the fraction close to 100 . samples were taken before and after the treatment ( at 3 months ). the vaginal dryness symptoms were also assessed by using a visual analogue scale where the volunteers themselves recorded their subjective estimates . the scale is based on a 100 - mm line on paper . the left end represents no symptom and the right end the worst possible symptom . the change from pretreatment to 3 months estimates was assessed and considered to be indicative of the treatment efficacy . there were no differences in the demographic data between the treatment groups in any of the pretreatment measurements . table 1 below shows the change in maturity index for parabasal cells ( mi 1 ) and maturity index for superficial cells ( mi 3 ), after 3 months &# 39 ; administration of varying doses of fc - 1271a or raloxifene . in fig1 a to 1 d there are shown changes ( from start to 12 weeks &# 39 ; treatment ) in the karyopyknosis index for superficial cells of the vaginal epithelium for the individuals treated daily with 30 mg fc - 1271a ( 1 a ), 60 mg fc - 1271a ( 1 b ), 90 mg fc - 1271a ( 1 c ), and 60 mg raloxifene ( 1 d ). cervical smear assessments indicate that no one in the raloxifene group ( fig1 d ) had a significant change from baseline to postreatment in the karyopyknosis index for superficial cells . most of the individuals in the fc - 1271a groups had slight increases in the index , but in other subjects the estrogenic effect was very weak , if measurable at all . in all cases the increase was small (& lt ; 40 except for one case which was 45 in the 90 mg group ) when compared to estradiol which is known to increase the index virtually by 100 . a weak but statistically significant estrogenic effect in the cervical smear was therefore documented . no pathological changes were seen in any sample . fig2 shows that raloxifene caused only a minor decrease on vaginal dryness , assessed by the individuals &# 39 ; subjective estimate , while all the fc - 1271a dosage levels indicated a clear decreasing effect . the dose level 60 mg fc - 1271a daily gave the best result . fc - 1271a had a weak estrogenic effect on endometrial histology . this effect is clearly weaker than that seen with estrogen replacement therapy . there were no malignant findings in the endometrium . the thickness of the endometrium as assessed by ultrasonography showed only a minor , statistically not significant , increase in the thickness ( average 0 . 2 mm , 0 . 5 mm and 0 . 5 mm ) at the dose levels of 30 , 60 and 90 mg , respectively . the measured values were always smaller than 8 mm , which is considered to be a thickness which is indicative for a physiologically significant estrogenicity of antiestrogenic drugs like tamoxifen ( hann et al , 1997 ; lahti et al , 1993 ). in the clinical study , where the effects of fc - 1271 a on quality of life and cardiovascular parameters were studied , the patients were asked for sexual activity . the questionnaire included “ worsening ” or “ no effect ” on sexual activity . improvement on sexual activity was not asked . when 70 patients had been followed up for 6 weeks , 27 of them had spontaneously reported to the investigators increased sexual activity . similar reports were independently obtained from different centers of the study . this strongly suggests that fc - 1271a has a positive effect on the sexual activity and quality of life . the results indicate that fc - 1271 a has a unique pharmacological profile with regard to estrogen - like effects on vaginal dryness and insignificant endometrial effects . in the clinical study , fc - 1271 a has a weak estrogen - like activity in the vagina and uterus . in these tissues the estrogenicity is markedly lower than that of the known antiestrogens tamoxifen and toremifene , but higher than that of raloxifene . in contrast to other antiestrogens , it does not cause menopausal symptoms . actually fc - 1271a at the doses of 25 mg or more , and especially 30 - 90 mg daily , alleviated such symptoms . fc - 1271a has an especially beneficial effect in that it decreases vaginal dryness and sexual dysfunction . based on the present data , the optimal clinical dose is expected to be higher than 25 mg daily and lower than 100 mg daily . a particularly preferable daily dose is found in the range 30 to 90 mg . at the higher doses ( 100 and 200 mg daily ), fc - 1271a shows more antiestrogen - like properties and behaves almost like tamoxifen and toremifene . fc - 1271a is an especially valuable drug because it has an excellent tolerability . in addition , fc - 1271a decreases total and ldl cholesterol , increases hdl cholesterol , and prevents osteoporosis and early stage breast cancer . the present invention suggests that fc - 1271a can be also used during menopause as hormone replacement therapy instead of estrogens , which are known to increase the risk of breast and endometrium cancers . it will be appreciated that the methods of the present invention can be incorporated in the form of a variety of embodiments , only a few of which are disclosed herein . it will be apparent for the specialist in the field that other embodiments exist and do not depart from the spirit of the invention . thus , the described embodiments are illustrative and should not be construed as restrictive . delmas p d , bjarnason n h , mitlak b h , ravoux a c , shah a s , huster w j , draper m , christiansen c : effects of raloxifene on bone mineral density , serum cholesterol concentrations , and uterine endometriun in postmenopausal women . n engl j med 337 : 1641 - 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