HK1056694B - Method for the treatment of climacteric disorders in women during or after the menopause - Google Patents

Description

Method for treating climacteric disorders in menopausal or postmenopausal women

Technical Field

The present invention relates to a method for the treatment of climacteric disorders, i.e. vaginal dryness or sexual dysfunction in menopausal or postmenopausal women.

Background

The publications and other materials used herein to illuminate the background of the invention, and in particular, examples to provide additional details respecting the practice, are incorporated by reference.

Women during and after menopause often develop symptoms due to estrogen deficiency. These symptoms include: hot flashes, sweating, insomnia, depression, vaginal dryness, urinary incontinence, nausea, pain, osteoporosis, coronary heart disease, breast tenderness, edema, fatigue, decreased sexual activity, and concomitant psychosocial problems (Payer, 1990; Rekers, 1990). In addition, estrogen is thought to have a neuroprotective effect. Thus, the decreasing estrogen concentrations in older women may have a negative effect on their mental activities (Schneider & Finch, 1997; Wickelgren, 1997). Estradiol is known to be excellent in the treatment of climacteric symptoms, and its use for the treatment of the above symptoms is rapidly increasing. However, estradiol leads to an increased risk of endometrial and breast cancer development. It is feasible to reduce the risk of endometrial cancer by the sequential administration of a progestogen, which does not reduce the risk of breast cancer. Although it is very useful to continue the long-term use of estrogen replacement therapy for the protection of the skeleton, cardiovascular system, central nervous system and relief of urological symptoms, the carcinogenic risk limits the long-term use of estrogen replacement therapy.

Antiestrogens, now commonly referred to as "Selective Estrogen Receptor Modulators (SERMs)" possess both estrogen-like and antiestrogenic properties (Kauffman & Bryant, 1995). The effects of tamoxifen and toremifene, which may be tissue specific, have estrogen-like effects in bone, partial estrogen-like effects in uterus and liver, and pure antiestrogenic effects in breast cancer. Raloxifene and droloxifene are similar to tamoxifen and toremifene, but their antiestrogenic properties are predominant. According to published information, all SERMs are more likely to cause climacteric symptoms than to prevent the onset of these symptoms. They have other important benefits for elderly women: they reduce the risk of cardiovascular disease in postmenopausal women by lowering total and LDL cholesterol, and prevent osteoporosis and inhibit breast cancer growth in postmenopausal women. Almost pure antiestrogens are also being studied. Their treatment is mainly directed to breast cancer (Wakeling & Bowler, 1988).

The compound (deaminohydroxy) tommifene, also known under the code FC-1271a, has relatively weak estrogenic and antiestrogenic effects in a classical hormonal test (Kangas, 1990). It has an anti-osteoporosis effect and it lowers total and LDL cholesterol levels in experimental models and human volunteers (International patent publications WO 96/07402 and WO 97/32574). It has antitumor activity in the early stages of breast cancer development in an animal breast cancer model. The effects of antiestrogens on climacteric symptoms have not been studied before. FC-1271a is the first SERM that has been shown to have beneficial effects on age-related symptoms in healthy women.

Summary of The Invention

The present invention relates to a method for the treatment of menopausal or postmenopausal vaginal dryness or sexual dysfunction, which comprises administering to a woman an effective amount of the compound (deaminohydroxy) tommifene or a pharmaceutically acceptable salt or ester thereof, or a metabolite thereof.

Brief Description of Drawings

FIGS. 1A-1D show the nuclear compaction index of vaginal epithelial surface cells from an individual treated daily with 30mg FC-1271A (1A), 60mg FC-1271A (1B), 90mg FC-1271A (1C), and 60mg raloxifene (1D).

FIG. 2 shows the effect of FC-1271a and raloxifene (60mg daily) at daily doses of 30mg, 60mg and 90mg on subjective evaluation of vaginal dryness in patients.

Detailed Description

The present invention relates to the use of the estrogen receptor modulator FC-1271a, i.e. (deaminated hydroxyl) tolmifene, in elderly women suffering from vaginal dryness or sexual dysfunction. FC-1271a is a major metabolite of toremifene, which is known to be an estrogen agonist and antagonist (Kangas, 1990; International patent applications WO 96/07402 and WO 97/32574).

The structural formula of FC-1271a (or (deamination hydroxyl) tolmifene) is

It is to be understood that the compounds also include geometric isomers and stereoisomers thereof.

It is to be understood that "metabolite" includes any metabolite of (deaminated hydroxyl) tommifene that has been found or will be found. Examples of such metabolites include those mentioned by Kangas (1990) on page 9 (TORE VI, TORE VII, TORE XVIII, TORE VIII, TORE XIII), in particular TORE VI and TORE XVIII, as well as other metabolites of the compound.

A new and surprising effect of this compound was found in a clinical study. In this study, different doses of raloxifene (60 mg/day) or FC-1271a were administered to elderly female volunteers for 3 months. At daily dosage levels of 30, 60 and 90mg, a significant reduction in vaginal dryness was observed. Improvement in sexual activity is also reported. These properties are new and unique among the known Selective Estrogen Receptor Modulators (SERMs) and indicate that FC-1271a at doses ranging from 25mg to slightly below 100mg daily, especially 30-90mg daily, can be successfully used to alleviate vaginal dryness and sexual dysfunction in elderly women. In addition, FC-1271a has stronger estrogenic and antiestrogenic effects than any known antiestrogenic drugs or SERMs.

Compound FC-1271a has been found to reduce sexual dysfunction and increase sexual activity. The types and causes of female sexual dysfunction are 1) need disorder, 2) impulse disorder, 3) orgasmic disorder and 4) dyspareunia. Most of these are due to hormonal reasons, especially because estrogen and testosterone concentrations are reduced. Vaginal dryness is the major cause of female sexual dysfunction and generally occurs when the concentration of estrogen is reduced post-menopausal. This generally results in pain during sexual intercourse, which indirectly affects any form of sexual dysfunction, including psychological causes. Vaginal dryness is often the major cause of decreased Sexual activity in older women (Spectror IP, Carey M P: identification and reliability of clinical dynamics: architectural review of clinical physiology 19: 389-.

It is not surprising that estrogens and testosterone can be used in the pharmacological treatment of vaginal dryness, with pure antiestrogens such as raloxifene causing vaginal dryness. Thus, the patient is not satisfied with the treatment that caused the dyspareunia and will stop the treatment.

The compounds may be administered by a variety of routes, with oral and transdermal routes being most preferred.

Suitable formulation forms include, for example, tablets, capsules, granules, powders, suspensions, slurries and transdermal patches or gels.

Experiment of

A phase I-II clinical study was conducted in postmenopausal healthy female volunteers 55-69 years old to investigate the effect of FC-1271a on endometrial thickness, endometrial pathology (biopsy by curettage as described by Vuopaleatal, 1982), and cervical smears. Tolerability and pharmacokinetics were also evaluated. Raloxifene (60mg daily) was used as a control. FC-1271a was administered orally at doses of 30, 60 and 90mg daily. There were 29 volunteers per dose level, as were the raloxifene groups. FC-1271a was administered as a gelatin capsule containing 30, 60 or 90mg FC-1271 a. Endometrial thickness was assessed by ultrasound using a Hitachi EUB-405 instrument. The vaginal epithelium is evaluated by the nuclear compaction index, which is one of the evaluation methods known to those skilled in the art. In this method, the vaginal proportion of cervical smears is estimated as a percentage of the number of cells from the different layers: a basolateral (parabasal) cell layer, an intermediate cell layer, and a surface cell layer. Estrogenicity can be observed by a shift in the proportion of cells to the surface. In postmenopausal women, this ratio is increased to nearly 100 by estradiol treatment, approaching 0. Samples were taken before and after treatment (3 months).

Vaginal dryness symptoms were also assessed by visual similar criteria, with volunteers recording their subjective assessments themselves. The standard is based on a 100mm line on paper. The left end represents no symptoms and the right end is the worst possible symptom. Estimates of changes from before treatment to 3 months were evaluated, which are considered indicative of efficacy.

There were no differences between the statistics of each treatment group in any pre-treatment measurements.

Evaluation of estrogenic Effect of FC-1271a on vagina

Table 1 below shows the change in the maturation index of basolateral cells (MI 1) and of surface cells (MI 3) after 3 months of administration of various doses of FC-1271a or raloxifene

TABLE 1 Change in the maturation index of basolateral cells (MI 1) and surface cells (MI 3) 3 months after administration of various doses of FC-1271a or raloxifene (MI 1: index 100, no estrogenicity; index 0, complete estrogen, MI 3: index 100, complete estrogen; index 0, no complete estrogenSex hormone of female

Compounds and dosages	Average value of MI 1	MI 1Sd	Average value of MI 3	MI 3 15sd
					FC-1271a，30mg，(n＝21)	-40	42	+12.4	13.6
FC-1271a，60mg，(n＝20)	-26	39	+5.5	13.4
					FC-1271a，90mg，(n＝22)	-48	44	+12.5	14.0
Raloxifene, 60mg, (n ═ 19)	-2	34	-0.3	4.1

In FIGS. 1A-1D, individuals treated daily with 30mg FC-1271A (1A), 60mg FC-1271A (1B), 90mg FC-1271A (1C), and 60mg raloxifene (1D) exhibited changes in the nuclear pycnotic index of cells on the surface of the vaginal epithelium (from the start to 12 weeks of treatment).

Cervical smear examination showed that none of the people in the raloxifene group showed a significant change in surface cell nuclear pyknosis index from baseline to post-treatment (fig. 1D). The index was slightly increased in most individuals in the FC-1271a group, but estrogenic effects were very weak, if not measurable, in other individuals. In all cases, the increase was very small compared to estradiol (< 40, one example except in the 90mg group was 45), and estradiol was known to increase this index almost 100-fold. Thus, a weak but statistically significant estrogenic effect was recorded in cervical smear examinations. There were no pathological changes in any of the samples.

Figure 2 shows that raloxifene only causes a weak change in vaginal dryness, as assessed by subjective evaluation of the individuals, while all FC-1271a dose levels showed clear reduction. FC-1271a at 60mg per day gives the best results.

Evaluation of endometrial Estrogen Effect of FC-1271a

FC-1271a has a weak estrogenic effect on endometrial histology. This effect is significantly weaker than that observed in estrogen replacement therapy. There was no evidence of malignancy in the endometrium. Endometrial thickness assessed by ultrasound showed only a slight, statistically insignificant increase in thickness (average 0.2mm, 0.5mm and 0.5mm) in the 30, 60 and 90mg groups, respectively. The measured values are always less than 8mm, 8mm being considered to represent a physiologically significant estrogenic thickness of antiestrogenic drugs such as tamoxifen (Hann et al, 1997; Lahti et al, 1993).

Effects on sexual activity

In clinical studies, the effect of FC-1271a on quality of life and cardiovascular parameters was studied, asking the patient for sexual activity. Questionnaires include "worsening" or "no effect" on sexual activity. No improvement in sexual activity was queried. 70 patients were followed up for 6 weeks, 27 of which actively reported to the investigator an increase in sexual activity. Similar reports were also obtained independently from different centers of the study. This strongly suggests that FC-1271a has a positive effect on sexual activity and quality of life.

These results indicate that FC-1271a has a unique pharmacological profile with respect to estrogen-like effects on vaginal dryness and insignificant endometrial effects. In this clinical study, FC-1271a had weak estrogen-like activity in the vagina and uterus. In these tissues, estrogenicity is significantly lower than the known antiestrogenic drugs tamoxifen and tolmifene, but higher than raloxifene. In contrast to other antiestrogens, it does not cause menopausal symptoms. In practice, FC-1271a at doses of 25mg or more per day, especially 30-90mg per day, alleviates these symptoms. FC-1271a has a particularly beneficial effect, it reduces vaginal dryness and sexual dysfunction. Based on current data, the optimal clinical dose is expected to be above 25mg daily and below 100mg daily. A particularly preferred daily dosage is 30-90 mg. At higher doses (100 and 200mg daily), FC-1271a showed more estrogenic characteristics, with effects nearly similar to those of tamoxifen and toremifene. FC-1271a is a particularly valuable drug due to its excellent tolerability. In addition, FC-1271a lowers total and LDL cholesterol, increases HDL cholesterol, and prevents osteoporosis and early breast cancer. The present invention shows that FC-1271a may also be used as an estrogen replacement therapy in the menopausal phase instead of estrogen, which is known to increase the risk of breast and endometrial cancer.

It is to be understood that the methods of the present invention are incorporated in the form of various embodiments, only a few of which are disclosed herein. It will be apparent to those skilled in the art that other embodiments exist and do not depart from the spirit of the invention. The described embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

Reference to the literature

Delmas PD，Bjarnason NH，Mitlak BH，Ravoux AC，Shah AS，Huster WJ，Draper M，Christiansen C：Effects of raloxifene on bone mineral density，serum cholesterol concentrations，and uterine endometrium inpostmenopausal women.N Engl J Med 337：1641-1647，1997

Ettinger B，Genant HK，Cann CE：Long-term estrogen replacement therapyprevents bone loss and fractures.Ann Intem Med 102：319-324，1985

Hann LE，Giess CS，Bach AM，Tao Y，Baum HJ，Barakat RR：Endometrialthickness in tamoxifen-treated patients：correlation with clinical andpathologic findings.Am J Roentgenol 168：657-661，1997

Gustafsson J-Å：Estrogen receptor β-getting in on the actionNatureMedicine 3：493-494，1997

Kangas L：Biochemical and pharmacological effects of toremifenemetabolites.Cancer Chemother Pharmacol 27：8-12，1990

Kauffman RF，Bryant HU：Selective estrogen receptor modulators.DrugNews Perspect 8：531-539，1995

Lahti E，Blanco G，Kauppila A，Apaja-Sarkkinen M，Taskinen PJ，Laatikainen T：Endometrial changes in postmenopausal breast cancer patientsreceiving tamoxifen.Obstet Gynecol 81：660-664，1993

Palkowitz AD，Glasebrook AL，Thraser KJ，Hauser KL，Short LL，PhillipsDL，Muchi BS，Sato M，Shetler PK，Cullinan GJ，Pell TR，BryantHU：Discovery and synthesis of[6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene：anovel，highly potent，selective estrogen receptor modulator.Med Chem 40：1407-1416，1997

Payer L：The menopause in various cultures.In：A portrait of the menopause.Expert reports on medical and therapeutic strategies for the 1990s.Ed.BurgerH & Boulet M，Parthenon Publishing，Park Ridge，NJ，USA，1991.pp 3-22Rekers H：Matering the menopause.In：A portrait of the menopause.Expertreports on medical and therapeutic strategies for the 1990s.Ed.Burger H &Boulet M，Parthenon Publishing，Park Ridge，NJ，USA，1991.pp 23-43Schneider LS，Finch CE：Can estrogens prevent neurodegeneration.Drugs &Aging 11：87-95，1997

Spector IP，Carey MP：Incidence and prevalence of sexual dysfunctions：acritical review of the empirical literature.Archives of Sexual Behaviour 19：389-408，1990.

Vuopala S，Kauppila A，Mikkonen M，Stenbck F：Screening ofasymptomatic postmenopausal women for gynecological malignancies，withspecial reference to endometrial sampling methods.Arch Gyncol 231：119-127，1982

Wakeling AE，Bowler J：Biology and mode of action of pure antiestrogens.JSteroid Biochem 30：1-6，1988

Wickelgren I：Esttogen stakes claim to cognition.Science 276：675-678，1997

Claims (2)

1. Use of a compound (deaminohydroxy) toremifene, or a pharmaceutically acceptable salt or ester thereof, or a metabolite thereof selected from 4-hydroxy (deaminohydroxy) toremifene, 4' -dihydroxy (deaminohydroxy) toremifene, (deaminocarboxy) toremifene, 4-hydroxy (deaminocarboxy) toremifene and toremifene monophenol, in the manufacture of a medicament for the treatment of vaginal dryness or sexual dysfunction in a menopausal or postmenopausal woman.

2. The use according to claim 1, wherein the medicament is in a form for oral or transdermal administration.