JP2005536490A - Treatment of infertility with exemestane - Google Patents
Treatment of infertility with exemestane Download PDFInfo
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- JP2005536490A JP2005536490A JP2004519563A JP2004519563A JP2005536490A JP 2005536490 A JP2005536490 A JP 2005536490A JP 2004519563 A JP2004519563 A JP 2004519563A JP 2004519563 A JP2004519563 A JP 2004519563A JP 2005536490 A JP2005536490 A JP 2005536490A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
- A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/566—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol having an oxo group in position 17, e.g. estrone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
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Abstract
エキセメスタンの卵胞刺激有効量を投与することからなる雌の宿主の不妊症を治療する治療法が提供される。There is provided a treatment for treating infertility in a female host comprising administering an effective follicle stimulating amount of exemestane.
Description
本発明は、雌の宿主にエキセメスタンの卵胞刺激に有効な量を投与することからなる不妊症の治療を必要とする雌の宿主での不妊症の治療方法に関する。 The present invention relates to a method for treating infertility in a female host in need of treatment of infertility comprising administering to the female host an effective amount of exemestane for follicle stimulation.
Ｈａｒｒｉｓｏｎ Ｄｉｃｔｉｏｎａｒｙによれば、ヒトの不妊症とは１２ヶ月の無防備での***後の姙娠不能と定義されている。不妊症には、受胎率の低下または医療介入の必要性から回復不能の不妊症原因までの不妊症の範囲が存在している。不妊症は、主に２５％が男性の要因、５８％が女性の要因に帰することができ、そしてカップルの約１７％では解明されていない。 According to the Harrison Dictionary, human infertility is defined as the inability to conceive after 12 months of unprotected sex. Infertility has a range of infertility ranging from reduced conception rates or the need for medical intervention to irreversible causes of infertility. Infertility can be attributed primarily to male factors in 25%, female factors in 58%, and is unresolved in about 17% of couples.
***は、卵巣から卵子が放出されるプロセスである。月経周期内での***の時期が姙娠にとって一番重要なことである。卵胞は、脳下垂体ゴナドトロピンで刺激される成長および成熟に続く***能力を獲得していることがよく知られている。***誘発は、不妊症の患者を管理するのに普通に使用されている治療手法である。***誘発は、特に次の二つの目的に使用される：１）低ゴナドトロピン性性機能低下、多嚢胞性卵巣症候群およびその他の月経周期障害に罹っている患者での無***の治療のため、そして２）介助生殖技法（assisted reproduction techniques）の希望者である患者（殆どが正常な月経周期を有している）での多重卵胞発生を刺激するため。これらの手法はまたコントロールされた卵巣刺激または過刺激とも呼ばれている。しかしながら、***誘発によって生じる合併症がいくつか認められ、例えば、多重姙娠および卵巣過刺激症候群がこれに包含される。合併症はその殆どが多重卵胞発生患者で起こり、そして／または総量ゴナドトロピン投与計画が使用されている。 Ovulation is the process by which eggs are released from the ovaries. The time of ovulation within the menstrual cycle is the most important for pregnancy. It is well known that follicles have acquired the ability to ovulate following growth and maturation stimulated by pituitary gonadotropins. Ovulation induction is a treatment technique commonly used to manage infertile patients. Ovulation induction is used specifically for the following two purposes: 1) for the treatment of anovulation in patients with hypogonadotropic hypogonadism, polycystic ovary syndrome and other menstrual cycle disorders; 2) To stimulate multiple follicle development in patients (mostly having a normal menstrual cycle) who wish to use assisted reproduction techniques. These techniques are also referred to as controlled ovarian stimulation or overstimulation. However, there are some complications arising from ovulation induction, including, for example, multiple pregnancy and ovarian hyperstimulation syndrome. Most of the complications occur in patients with multiple follicular development and / or a total gonadotropin regimen is used.
本発明者はエキセメスタンが、不妊症治療を必要とする宿主での不妊症治療のための卵胞刺激に安全に、即ち上記の副作用を生じることなく、使用し得ることを見いだした。 The inventor has found that exemestane can be used safely for follicular stimulation for infertility treatment in a host in need of infertility treatment, i.e. without causing the side effects described above.
エキセメスタンは米国特許第４,８０８,６１６号に初めて教示され、現在は閉経後の女性での乳がんの治療に当たり２５ｍｇ／日の投与量で経口投与されている。エキセメスタンには特異なアロマターゼ阻害メカニズムが賦与されている。アロマターゼ酵素（４５０arom）は、Ｐ４５０（ヘム）部分およびペプチド部分からなるチトクロームＰ４５０ヘムタンパク質の特殊な形態である。この酵素は、補助因子ＮＡＤＰＨの存在を必要とする、エストローゲンへのアンドロゲン基質（主にアンドロステンジオン）のＡ環の芳香化をなす多段階反応の触媒作用を果たしている。この酵素反応後に、酵素分子は再度利用可能であって新しい芳香化を達成する。エキセメスタンのアロマターゼ阻害メカニズムについては、広汎な研究がされていて、酵素の不活性化をきたす化合物が見いだされている。事実、エキセメスタンは天然基質アンドロステンジオンに構造上関連を有し、当初はアロマターゼ酵素により偽基質と認識されるので、エキセメスタンは酵素の活性部位でアンドロステンジオンと競合する。次いで、この化合物は（ＮＡＤＰＨ−依存メカニズムにより）中間体に変換され、この中間体は酵素と不可逆的に結合してその不活性化を齎す（自殺不活性化阻害としても知られている）。従って、この酵素は確実に不活性化され、そして新生酵素合成にはエストローゲン産生を必要とする。 Exemestane was first taught in US Pat. No. 4,808,616 and is currently administered orally at a dose of 25 mg / day for the treatment of breast cancer in postmenopausal women. Exemestane is endowed with a unique aromatase inhibition mechanism. The aromatase enzyme (450 arom ) is a special form of cytochrome P450 heme protein that consists of a P450 (heme) moiety and a peptide moiety. This enzyme catalyzes a multi-step reaction that aromatizes the A ring of an androgen substrate (mainly androstenedione) to estrogen that requires the presence of the cofactor NADPH. After this enzymatic reaction, the enzyme molecule can be reused to achieve a new aromatization. Extensive research on the mechanism of aromatase inhibition by exemestane has been conducted, and compounds that cause enzyme inactivation have been found. In fact, exemestane competes with androstenedione at the active site of the enzyme because exemestane is structurally related to the natural substrate androstenedione and is initially recognized as a pseudosubstrate by the aromatase enzyme. This compound is then converted (by a NADPH-dependent mechanism) into an intermediate that binds irreversibly with the enzyme, leading to its inactivation (also known as inhibition of suicide inactivation). Thus, this enzyme is reliably inactivated, and nascent enzyme synthesis requires estrogen production.
エキセメスタンの新に見いだされた治療上の効用は実際には意外なことである。薬理学的な観点からみて、エキセメスタンの卵胞刺激活性には、いくつかの併存する因子が見られ、これらにはその特異なアロマターゼ不活性化メカニズム、用量および治療計画が包含される。 The new therapeutic benefits of exemestane are actually surprising. From a pharmacological point of view, exemestane's follicle-stimulating activity has several coexisting factors, including its specific aromatase inactivation mechanism, dose and treatment regimen.
本発明の第一の目的は、不妊症の治療を必要とする雌の宿主に治療上有効な卵胞刺激量のエキセメスタンを投与することを特徴とする上記宿主の不妊症を治療する方法を提供することにある。 A first object of the present invention is to provide a method for treating infertility in a host, characterized by administering a therapeutically effective follicle stimulating amount of exemestane to a female host in need of treatment for infertility. There is.
本発明の好ましい実施態様によれば、卵胞刺激の誘発を必要とする雌の宿主に治療上有効な卵胞刺激量および／または阻害量のエキセメスタンを投与し、そして次に除去することを特徴とする上記宿主の卵胞刺激を誘発する方法が提供される。 According to a preferred embodiment of the invention, a therapeutically effective follicle stimulating and / or inhibitory amount of exemestane is administered to a female host in need of induction of follicular stimulation and then removed. Methods are provided for inducing follicular stimulation of the host.
本発明による雌の宿主は、例えば、哺乳動物の雌、特に女性である。このような宿主の好ましい例は、低ゴナドトロピン性性機能低下、多嚢胞卵巣症候群およびその他の月経周期障害を持つ患者、および他に介助生殖技法の希望者である患者である。 The female host according to the invention is, for example, a mammalian female, in particular a female. Preferred examples of such hosts are patients with hypogonadotropic hypogonadism, polycystic ovary syndrome and other menstrual cycle disorders, and patients who are also interested in assisted reproductive techniques.
本明細書で使用される臨床上の用語は、当該分野で周知のそれらの平易な意義を有している。いずれにせよ、無***とは言うまでもなく***の欠如を言うものである。卵胞刺激とは、エキセメスタンを使用して他に無***である雌の宿主に***を生じさせ、その結果として卵胞裂開および姙娠可能な卵母細胞の***をもたらすプロセスを言うものである。 The clinical terms used herein have their plain meaning well known in the art. In any case, it is a lack of ovulation, not to mention anovulation. Follicle stimulation refers to the process of using exemestane to cause ovulation in other non-ovulatory female hosts, resulting in ovulation of follicular cleaved and fertile oocytes.
本明細書で使用される「治療上有効な卵胞刺激量」なる用語は、患者に単回または多重用量での投与で、例えば、投与中かまたは卵巣のリバウンド過刺激をきたす投与中止後に、卵胞刺激を誘発することによって、不妊症を治療するのに有効な量を言うものである。 As used herein, the term “therapeutically effective follicle stimulating amount” refers to administration of a single or multiple doses to a patient, for example, during administration or after cessation of administration resulting in ovarian rebound hyperstimulation. It is an amount effective to treat infertility by inducing irritation.
本発明のさらに他の実施態様では、低ゴナドトロピン性性機能低下、多嚢胞性卵巣症候群およびその他の月経周期障害に罹っている雌の宿主または介助生殖技法の希望者である雌の宿主に、治療上有効な卵胞刺激量のエキセメスタンを投与することを特徴とする上記雌の宿主での卵胞刺激を誘発する方法が提供される。 In yet another embodiment of the invention, treatment is provided to a female host suffering from hypogonadotropic hypogonadism, polycystic ovary syndrome and other menstrual cycle disorders, or a female host who is a candidate for assisted reproductive techniques. There is provided a method of inducing follicular stimulation in the female host, characterized by administering an effective follicle stimulating amount of exemestane.
本発明のさらに他の目的は、雌の宿主での不妊症の治療に使用するための医薬の製造におけるエキセメスタンの使用にある。 Yet another object of the present invention is the use of exemestane in the manufacture of a medicament for use in the treatment of infertility in a female host.
本発明はまた雌の宿主での卵胞刺激の誘発に使用するための医薬の製造におけるエキセメスタンの使用を提供するものである。 The present invention also provides the use of exemestane in the manufacture of a medicament for use in inducing follicular stimulation in a female host.
卵胞刺激の誘発に対するエキセメスタンの効果は、例えば、一旦その投与を中止し卵胞発育および裂開の増大を生じた動物モデルで観察することができる。 The effect of exemestane on the induction of follicle stimulation can be observed, for example, in animal models that once stopped administration and resulted in increased follicular development and dehiscence.
本発明によって治療を実施するにあたり、エキセメスタンはいずれの形態または様式でも投与することができ、これによりこの化合物の治療上有効な量で生物学的利用が可能となる。例えば、投与経路は経口、舌下、鼻腔内、皮下、皮内、腹腔内、筋肉内、静脈内、動脈内、径皮、膣内、直腸内などが包含される。経口または筋肉内投与が一般に好ましい。製剤を調製する当業者は特別な状況に基いて適切な投与形態および様式を容易に選定することができる。例えば、適当な経口剤形の例は、錠剤、カプセル剤、糖衣およびフィルムコーティング錠剤である。 In practicing treatment according to the present invention, exemestane can be administered in any form or manner, which allows bioavailability of the compound in therapeutically effective amounts. For example, routes of administration include oral, sublingual, intranasal, subcutaneous, intradermal, intraperitoneal, intramuscular, intravenous, intraarterial, radial, intravaginal, intrarectal, and the like. Oral or intramuscular administration is generally preferred. Those skilled in the art of preparing formulations can readily select an appropriate dosage form and mode based on the particular circumstances. For example, examples of suitable oral dosage forms are tablets, capsules, dragees and film-coated tablets.
使用すべきエキセメスタンの投与量は言うまでもなく様々な要因、例えば治療する宿主（例えば、年齢、体重および一般的健康状態）そして治療スケジュールに左右される。 The dosage of exemestane to be used will of course depend on various factors such as the host being treated (eg, age, weight and general health) and the treatment schedule.
エキセメスタンは、約５ｍｇ／日乃至約２００ｍｇ／日に変化する投与量範囲で、例えば経口で、場合によっては分割した用量、例えば、２〜３または４回の分割用量で女性に投与することができる。 Exemestane can be administered to women in a dosage range that varies from about 5 mg / day to about 200 mg / day, eg, orally, optionally in divided doses, eg 2-3 or 4 divided doses. .
好ましい投与スケジュールによれば、所望の有効な血中卵胞刺激性ホルモンレベルを達成するために、エキセメスタンは月経周期の初期部分（５日目〜７日目）に投与し、次に中止するか、またはこのものは全周期を通して投与し、次いで中断する。 According to a preferred dosing schedule, exemestane is administered in the early part of the menstrual cycle (day 5-7) and then discontinued, in order to achieve the desired effective blood follicle stimulating hormone level Or it is administered throughout the entire cycle and then discontinued.
Claims (13)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US39332002P | 2002-07-02 | 2002-07-02 | |
| PCT/US2003/016252 WO2004004634A2 (en) | 2002-07-02 | 2003-07-02 | Infertility treatment with exemestane |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2005536490A true JP2005536490A (en) | 2005-12-02 |
| JP2005536490A5 JP2005536490A5 (en) | 2006-08-17 |
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ID=30115565
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2004519563A Pending JP2005536490A (en) | 2002-07-02 | 2003-07-02 | Treatment of infertility with exemestane |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP1531829A2 (en) |
| JP (1) | JP2005536490A (en) |
| KR (1) | KR20050077045A (en) |
| CN (1) | CN1665516A (en) |
| AU (1) | AU2003247404A1 (en) |
| BR (1) | BR0312393A (en) |
| CA (1) | CA2491372A1 (en) |
| IL (1) | IL165813A0 (en) |
| MX (1) | MXPA05000251A (en) |
| PL (1) | PL373219A1 (en) |
| WO (1) | WO2004004634A2 (en) |
| ZA (1) | ZA200410135B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR102432156B1 (en) * | 2020-05-18 | 2022-08-11 | 제주대학교 산학협력단 | Composition comprising chemical material for inhibiting gonadal maturation in fishes and method for inhibiting gonadal maturation in fishes using the same |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004526764A (en) * | 2001-04-17 | 2004-09-02 | アレス トレーディング ソシエテ アノニム | Aromatase inhibitors for enhancing assisted reproduction |
| JP2004529924A (en) * | 2001-04-17 | 2004-09-30 | アレス トレーディング ソシエテ アノニム | Single dose aromatase inhibitors for the treatment of infertility |
-
2003
- 2003-07-02 EP EP03762980A patent/EP1531829A2/en not_active Withdrawn
- 2003-07-02 CN CN038157306A patent/CN1665516A/en active Pending
- 2003-07-02 MX MXPA05000251A patent/MXPA05000251A/en unknown
- 2003-07-02 PL PL03373219A patent/PL373219A1/en not_active Application Discontinuation
- 2003-07-02 BR BR0312393-6A patent/BR0312393A/en not_active IP Right Cessation
- 2003-07-02 AU AU2003247404A patent/AU2003247404A1/en not_active Abandoned
- 2003-07-02 KR KR1020057000051A patent/KR20050077045A/en not_active Application Discontinuation
- 2003-07-02 JP JP2004519563A patent/JP2005536490A/en active Pending
- 2003-07-02 WO PCT/US2003/016252 patent/WO2004004634A2/en active Application Filing
- 2003-07-02 CA CA002491372A patent/CA2491372A1/en not_active Abandoned
-
2004
- 2004-12-16 IL IL16581304A patent/IL165813A0/en unknown
-
2005
- 2005-12-15 ZA ZA200410135A patent/ZA200410135B/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004526764A (en) * | 2001-04-17 | 2004-09-02 | アレス トレーディング ソシエテ アノニム | Aromatase inhibitors for enhancing assisted reproduction |
| JP2004529924A (en) * | 2001-04-17 | 2004-09-30 | アレス トレーディング ソシエテ アノニム | Single dose aromatase inhibitors for the treatment of infertility |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20050077045A (en) | 2005-07-29 |
| BR0312393A (en) | 2005-04-12 |
| CN1665516A (en) | 2005-09-07 |
| CA2491372A1 (en) | 2004-01-15 |
| EP1531829A2 (en) | 2005-05-25 |
| WO2004004634A2 (en) | 2004-01-15 |
| MXPA05000251A (en) | 2005-07-15 |
| PL373219A1 (en) | 2005-08-22 |
| WO2004004634A3 (en) | 2004-04-08 |
| IL165813A0 (en) | 2006-01-15 |
| ZA200410135B (en) | 2006-07-26 |
| AU2003247404A1 (en) | 2004-01-23 |
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