JP6534439B2 - 非糖尿病の雌性哺乳動物において生殖能力及び正常な妊孕力を刺激するための及び生殖補助医療の有効性を改善させるための、不妊症の治療に使用されるタングステン(vi)塩 - Google Patents
非糖尿病の雌性哺乳動物において生殖能力及び正常な妊孕力を刺激するための及び生殖補助医療の有効性を改善させるための、不妊症の治療に使用されるタングステン(vi)塩 Download PDFInfo
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Description
*低受胎状態では:定期的な、避妊を行わない性交を行った12カ月の間に妊娠する;及び、
*不妊症状態では:定期的な、避妊を行わない性交を行った12カ月を過ぎて妊娠する。本明細書において、排卵を回復及び/促進させ、卵母細胞及び胚の品質を改善させ、子宮壁への接合体の着床を増大させ、多嚢胞性卵巣症候群、メタボリックシンドローム、高プロラクチン血症、子宮内膜症、甲状腺機能低下症、多発性硬化症、関節リウマチ、全身性エリテマトーデス、肝硬変、関節リウマチ、セリアック病、慢性腎不全、特発性の原因及び摂食障害、例えば神経性無食欲症及び多食症を含む、視床下部−下垂体−卵巣軸の障害を調節する必要を含む。
正常な妊孕力及び生殖能力を促すためのタングステン(VI)塩の活性を求めるために使用されたマウスモデルは、Irs2遺伝子ノックアウトマウスであるIRS2−/−である[Burks et. al., "IRS-2 pathways integrate female reproduction and energy homeostasis", Nature, 2000, vol. 407, pp. 377-382]。Irs2遺伝子の欠失が、生殖能力及び糖質代謝に関連する明らかな性的二型性を示すと解釈されている。
A.動物
6週齢〜8週齢の10匹のIRS2−/−雌性マウス。
6週齢〜8週齢の6匹の「野生型」(IRS2wt)雄性マウス。
前処理段階
順応期間の後、IRS2−/−雌性マウスを1つのケージ当たり4匹〜6匹のマウス群で飼育した。前処理段階(2週間)の間、動物にタングステン酸塩不含飲用水を投与した。
前処理段階(治療0日目)後から動物を屠殺する4週間前まで、蒸留水中、タングステン酸ナトリウム二水和物(Carlo Erbaにより販売される)の2mg/ml溶液を用いた飲用水(任意)においてタングステン酸ナトリウムを投与した。マウスにより摂取されたタングステン酸ナトリウムの1日用量は体重1kg当たり約180mgであった。
治療の最初の3週間の後、IRS2−/−雌性マウスをIRS2wt雄性マウスと継続的につがいでケージにおいて飼育した。
この期間の後、雌性マウスを屠殺し、妊娠の兆候を求めて生検を行った。
排卵調査の結果
前処理期間中及び治療の最初の3週間の間、−8日目、−5日目、−2日目、−1日目、7日目、8日目、14日目、15日目及び22日目に無作為に選択した6匹の雌性マウスにおいて膣垢検査を行い、それらのマウスの発情周期の段階を求めた。
50体積%アルコール中に10回浸漬、
ハリスヘマトキシリン溶液中に3分間浸漬、
流水ですすぐ、
酸アルコール(1%塩酸)中に10回浸漬、
流水ですすぐ、
95体積%アルコール中に10回浸漬、
OG−6溶液中に30秒間浸漬、
96体積%アルコール中に10回浸漬、
エオシン溶液中に1分間浸漬、
96体積%アルコール中に10回浸漬、
86体積%アルコール中に10回浸漬、及び、
キシロール中に10回浸漬。
B欄の方法の交配期間の後、雌性マウスを屠殺し、妊娠の兆候を求めて生検を行った。
A.動物
6週齢〜8週齢の6匹のIRS2−/−雌性マウス。
治療段階
順応期間の後、前処理段階(治療0日目)後に、及び12日間に亘り、蒸留水中、タングステン酸ナトリウム二水和物(Carlo Erbaにより販売される)の2mg/ml溶液を用いた飲用水(任意)においてタングステン酸ナトリウムを投与した。
治療期間の0日目、2日目、5日目、7日目、9日目及び12日目に体重をモニターし、上述の日の各々において6時間の絶食の後、尾静脈からの採血及びグルコースセンサー(ドイツ国マンハイムのRocheのAccuTrendグルコースセンサー)により血中グルコースを求めた。
A.モデル
HEC1−A子宮内膜細胞株及びJEG−3栄養外胚葉細胞株から作製された「in vitro」のヒト−ヒト胚の接着モデルを使用し、子宮内膜の受容性に対するタングステン酸ナトリウムの影響を求めた。
細胞株は、子宮内膜の胚の接着実験を行うために市販のものが購入された(米国培養細胞系統保存機関(ATCC);米国メリーランド州ロックビル)。これらの細胞を解凍し、十分な細胞を得るため4回増殖させ、全てのアッセイを行った。
得られた結果を表5に挙げる。より高い割合の胚の接着は、HEC−1A株をタングステン酸ナトリウムで処理していないものに対してタングステン酸ナトリウムで処理した条件下において観察された。陰性対照(C−)である、WithaferinAで処理した細胞において接着は一切観察されなかった。
本発明による食品組成物を以下の説明のように調製する。組成物は、本発明の範囲を限定するものとして解釈されるものではない。
タングステン塩を多く含むサラダドレッシングを調製する。25mgのNa2WO4(100mg/kg)を、250グラムの市販のドレッシングに添加し、それを30分間機械により撹拌する。
タングステン塩を多く含むケチャップタイプサルサを調製する。そのため170mgのCa2WO4を、200グラムの市販のケチャップに添加し、それを1時間機械により撹拌する。
タングステン塩を多く含むミルクを調製する。そのため1kgの全牛乳を用意し、150mgのZnWO4を添加し、それを20分間機械により撹拌する。摂取直前にパッケージを振ることが推奨される。
タングステン塩を多く含むフルーツジュースを調製する。500mgのMgWO4を1kgの市販のジュースに添加し、それを10分間機械により撹拌する。摂取直前にパッケージを振ることが推奨される。
以下の組成物でコーティングした錠剤を調製する:
PH200微結晶セルロース(希釈剤/滑沢剤) 250.00mg
コロイド状無水シリカ(滑沢剤/吸着剤) 3.00mg
ステアリン酸マグネシウム(潤滑剤) 5.00mg
タルク(潤滑剤) 7.00mg
オパドライ(商標)ホワイト(オパドライ(商標)及び−1−7000ホワイト)(*)(コーティングフィルム) 8.00mg
タングステン酸ナトリウム二水和物 200.00mg
(*)ヒドロキシプロピルメチルセルロース、ポリエチレングリコール6000及び酸化チタン(E−171)の混合物
以下の組成物を含む発泡性錠剤を調製する:
ソルビトール、アスパルテーム、スクロース及びキシリトール(甘味剤) 10mg当たり0.025mg
炭酸カルシウム 10mg当たり0.350mg
クエン酸(酸味料) 10mg当たり0.650mg
酸性炭酸ナトリウム(pH調整剤) 10mg当たり0.350mg
オレンジ香味料 10mg当たり0.25mg
タングステン塩
以下の組成物を含むゼラチンカプセルを調製する:
ニフェジピン 6mg
キサンタンガム 5mg
オレンジ香味料 0.3mg
クエン酸 0.4mg
ゲルシア(Gelucire)44/14 90mg
PH10微結晶セルロース(希釈剤) 92.00mg/カプセル
タングステン酸ナトリウム二水和物 100.00mg/カプセル
Claims (22)
- 非糖尿病の雌性哺乳動物において正常な妊孕力及び生殖能力を促すために、又は哺乳動物において生殖補助医療の効果を改善するために使用され、
該生殖補助医療は、排卵の誘発、人工授精、体外受精及び胚移植から選択される、タングステン酸塩又はその溶媒和物を含む医薬。 - 前記哺乳動物がヒトである、請求項1に記載の医薬。
- 雌性哺乳動物の体重1kg当たり0.001mg〜1000mgのタングステン酸塩の1日用量にて投与する、請求項1又は2に記載の医薬。
- タングステン酸アニオン及び薬学的、獣医学的又は栄養学的に許容可能なカチオンを含む、請求項1〜3のいずれか一項に記載の医薬。
- 前記カチオンがアルカリ金属カチオン又はアルカリ土類金属カチオンである、請求項1〜4のいずれか一項に記載の医薬。
- 前記カチオンがナトリウム、カリウム、マグネシウム、カルシウム及び亜鉛からなる群から選択されることを特徴とする、請求項1〜5のいずれか一項に記載の医薬。
- 前記カチオンがナトリウムであることを特徴とする、請求項6に記載の医薬。
- 前記カチオンが亜鉛である、請求項6に記載の医薬。
- 前記タングステン酸アニオンがWO4 2−イオン、HWO4 −イオン、W2O7 2−イオン及びHW2O7 −イオンから選択されることを特徴とする、請求項1〜8のいずれか一項に記載の医薬。
- 前記アニオンがWO4 2−であることを特徴とする、請求項9に記載の医薬。
- 前記溶媒和物が二水和物である、請求項1〜10のいずれか一項に記載の医薬。
- 非糖尿病の雌性哺乳動物において正常な妊孕力及び生殖能力を促すための、又は哺乳動物に適用された生殖補助医療の効果を改善するための、100mg/kg以上の濃度の請求項1〜11のいずれか一項に記載のタングステン酸塩又はその溶媒和物と少なくとも1つの薬学的、獣医学的又は栄養学的に許容可能な賦形剤又はベヒクルとを含み、
該生殖補助医療は、排卵の誘発、人工授精、体外受精及び胚移植から選択される、組成物。 - 前記賦形剤又はベヒクルが薬学的に又は獣医学的に許容可能であり、前記組成物が非糖
尿病の雌性哺乳動物において不妊症を治療するための医薬組成物であることを特徴とする、請求項12に記載の組成物。 - 前記賦形剤又はベヒクルが薬学的又は獣医学的に許容可能であり、前記組成物が哺乳動物に適用した生殖補助医療の効果を増大させるための医薬組成物であることを特徴とする、請求項12に記載の組成物。
- ピル、錠剤、トローチ、カプセル、粉末、ウエハー、発泡性粉末若しくは錠剤、溶液、懸濁液、シロップ又は顆粒の形態であることを特徴とする、請求項13又は14に記載の組成物。
- 非糖尿病の雌性哺乳動物において正常な妊孕力及び生殖能力を促すための食品組成物であることを特徴とする、請求項12に記載の組成物。
- 液状組成物又は飲料であることを特徴とする、請求項16に記載の組成物。
- 固形組成物であることを特徴とする、請求項16に記載の組成物。
- 前記食品組成物が栄養補助剤又は補足物であることを特徴とする、請求項16に記載の組成物。
- スクロースを含むことを特徴とする、請求項12〜19のいずれか一項に記載の組成物。
- 非糖尿病の雌性哺乳動物において正常な妊孕力及び生殖能力を促すための、又は哺乳動物に適用した生殖補助医療の効果を増大させるための、医薬品の製造における請求項1〜11のいずれか一項に記載のタングステン酸塩又はその溶媒和物の使用であって、
該生殖補助医療は、排卵の誘発、人工授精、体外受精及び胚移植から選択される、使用。 - 非糖尿病の雌性哺乳動物(ただし、ヒトを除く)において正常な妊孕力及び生殖能力を促すための、又は哺乳動物(ただし、ヒトを除く)に適用した生殖補助医療の効果を増大させるための方法であって、治療有効量の請求項1〜11のいずれか一項に記載のタングステン酸塩又はその溶媒和物を投与することを含み、
該生殖補助医療は、排卵の誘発、人工授精、体外受精及び胚移植から選択される、方法。
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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PCT/ES2014/070586 WO2016012632A1 (es) | 2014-07-21 | 2014-07-21 | Sales de tungsteno (vi) para su uso en el tratamiento de la infertilidad, para favorecer la fertilidad y la reproducción normal en un mamífero hembra no diabético, así como para mejorar la eficacia de las técnicas de reproducción asistida |
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JP2017523170A JP2017523170A (ja) | 2017-08-17 |
JP6534439B2 true JP6534439B2 (ja) | 2019-06-26 |
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JP2017502966A Active JP6534439B2 (ja) | 2014-07-21 | 2014-07-21 | 非糖尿病の雌性哺乳動物において生殖能力及び正常な妊孕力を刺激するための及び生殖補助医療の有効性を改善させるための、不妊症の治療に使用されるタングステン(vi)塩 |
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CN (1) | CN106715332B (ja) |
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AU (1) | AU2014401750B2 (ja) |
BR (1) | BR112017001287A2 (ja) |
CA (1) | CA2955914C (ja) |
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SG (1) | SG11201700485VA (ja) |
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FR2245374B1 (ja) * | 1973-07-27 | 1977-02-25 | Anvar | |
US4328134A (en) * | 1980-05-06 | 1982-05-04 | Schally Andrew Victor | Anorexigenic peptides |
ES2108642B1 (es) | 1995-07-26 | 1998-08-16 | Quimica Farm Bayer Sa | Composiciones de tungsteno (vi) para el tratamiento oral de la diabetes mellitus. |
RU2202314C2 (ru) * | 2001-04-11 | 2003-04-20 | Алексей Иванович Ступко | Способ подготовки пациентки к искусственному оплодотворению |
ES2187276B1 (es) * | 2001-05-16 | 2004-08-01 | Quimica Farmaceutica Bayer,S.A. | Composiciones orales para el tratamiento de humanos obesos y no diabeticos. |
AU2002368261A1 (en) * | 2002-10-02 | 2004-04-23 | Yeda Research And Development Co. Ltd. | Long-acting gonadotropin-releasing hormone analogs and methods of use thereof |
EP1523985B1 (en) * | 2003-10-17 | 2010-03-10 | Oy Neurofood Ab | Non-radioactive strontium agent for treating cancer |
JP4682152B2 (ja) * | 2003-12-31 | 2011-05-11 | ザ・ペン・ステート・リサーチ・ファンデーション | 卵巣がんの化学療法に対する抵抗性を予測および克服するための方法ならびに結腸がんの発生を予測するための方法 |
EA200800260A1 (ru) * | 2005-07-05 | 2008-06-30 | ЭДИЛЕЙД ФЭТИЛИТИ СЭНТЭ ПиТиУай ЭлТиДи | Способы, композиция и комбинированный продукт для улучшения репродуктивного здоровья у особи мужского пола или улучшения исхода беременности у особи женского пола, сперма (варианты), способ ее получения и животный организм, не принадлежащий к человеческому роду, появившийся в результате оплодотворения указанной спермой |
KR20080046170A (ko) | 2005-07-29 | 2008-05-26 | 우니베르시닷 데 바르셀로나 | 신경 퇴행성 장애 처리용 약제학적 조성물 |
US20060100154A1 (en) * | 2005-10-13 | 2006-05-11 | Yeda Research And Development Co | Long-acting gonadotropin-releasing hormone analogs and methods of use thereof |
ES2524458T3 (es) * | 2006-10-18 | 2014-12-09 | Periness Ltd. | DNasa para el tratamiento de la subfertilidad masculina |
ES2478790B1 (es) | 2013-01-22 | 2015-05-06 | Oxolife, S. L. | Uso de sales de tungsteno (VI) para el tratamiento de la infertilidad femenina en mamíferos no diabéticos |
ES2551828B1 (es) * | 2014-05-21 | 2016-09-12 | Oxolife S.L. | Composiciones alimentarias que comprenden sales de tungsteno (VI) |
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