JP5108303B2 - インスリン様成長因子(igf−i)のレベル上昇による内臓脂肪の低下方法 - Google Patents
インスリン様成長因子(igf−i)のレベル上昇による内臓脂肪の低下方法 Download PDFInfo
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- JP5108303B2 JP5108303B2 JP2006524043A JP2006524043A JP5108303B2 JP 5108303 B2 JP5108303 B2 JP 5108303B2 JP 2006524043 A JP2006524043 A JP 2006524043A JP 2006524043 A JP2006524043 A JP 2006524043A JP 5108303 B2 JP5108303 B2 JP 5108303B2
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Description
本発明は、被検体において内臓脂肪を低下させるための方法および組成物に関する。
本出願は、参照として本明細書に組み入れられる2003年8月21日に出願された米国仮特許出願第60/497,008号に基づく恩典を主張するものである。
肥満には、寿命の短縮、ならびにインスリン抵抗性という代謝の問題、および真性糖尿病、および腎疾患、眼疾患、および循環器疾患を含むその多くの続発症を含む、多くの医学的な状態が伴う。Rissanen et al., 1990, Br Med J, 301:835-837を参照されたい。
本発明は、被検体において生物活性のあるインスリン様成長因子-I (IGF-I)の血清濃度を上昇させる化合物を治療上有効な量、被検体に投与することによって、内臓脂肪を低下させ、それにより内臓肥満の負の効果を軽減させるための方法および組成物を提供する。本発明は、例えば、循環器疾患およびメタボリックシンドロームを含む、内臓肥満またはIGF-I欠乏に関連する状態の1つまたは複数の症状の治療、予防、または軽減に有用である。
本発明を詳細に説明する前に、本発明を説明するために使用される用語の意味および範囲を説明および定義するために、以下に定義を示す。
本発明は、ヒトに投与されたIGF-Iは内臓脂肪を減少させ、被検体の体脂肪分布が改善される(例えば、治療後の被検体では、皮下脂肪に対する内臓脂肪の比が低下している)という驚くべき所見に基づいている。本発明の目的は、内臓脂肪減少のための方法および組成物を提供することである。1つの態様では、本方法に使用するために適した化合物は、それぞれ生物活性のあるIGF-Iレベルを上昇させる化合物を含む、内臓脂肪減少剤、内臓脂肪蓄積阻害剤、または体脂肪分布改善剤を含む。別の態様では、化合物はIGF-Iを含む。特定の態様では、IGF-Iは活性成分としての他の血糖低下剤と組み合わせて投与される。IGF-I欠乏被検体のような特定の態様では、治療の目標は同じ年齢および性別の正常な被検体に見られる範囲内にIGF-Iレベルを回復することである。
本発明は、生物活性のあるIGF-Iの血清濃度を上昇させる化合物を被検体に投与する段階を含む、被検体の内臓脂肪を減少させる方法および組成物を提供する。本発明の方法は、成長ホルモンが使用されないという条件で、生物活性のあるIGF-Iの血清濃度を上昇させる任意の化合物を投与することにより実施できる。
IGF-Iレベルを上昇させる化合物と、血中の総IGF-Iを上昇させるか、またはIGF-Iの効果を増強するような1つまたは複数の他の適当な試薬の組み合わせ療法もまた、本発明により意図される。1つの態様では、これらの更なる試薬は、一般的に血清中のIGFBPの量を上回る過剰の血清IGF-Iを可能にするか、またはIGFBPからのIGF-Iの放出を可能にし、成長促進剤はこれに含まれる。
内臓肥満の被検体における皮下脂肪に対する内臓脂肪の比を低下させる方法を用いて、内臓脂肪に伴う疾病および状態のリスクを低下させることができる。内臓脂肪は、冠動脈性心疾患、特定の癌、糖尿病、糖不耐性、および高インスリン血症のような疾病および状態の重要な予測因子である。Montague, CT et al., 2000, Diabetes 49:883-888を参照されたい。特定の理論に縛られることはないが、内臓脂肪は肝臓に対してより大きな脂肪酸負荷をかけ、上記の状態の多くを誘導すると考えられている。さらに、体脂肪分布は寿命に非常に重要な影響を与え、男性の内臓脂肪の程度が高いために、特に寿命の性差に非常に重要な影響を持つことが示されている。Kissebah AH et al., 1994, Physiol Rev 74:761-811を参照されたい。内臓脂肪の蓄積は、肥満男性において高血圧の予測因子であることも示されている。Watanabe et al., 2003, Clin Exp Hypertens 25:199-208を参照されたい。内臓脂肪は歯周病にも関連している。Wood N et al, 2003, J Clin Periodontol 30:321-327を参照されたい。
本発明の方法は、皮下脂肪に対する内臓脂肪の比、または総体脂肪のうち内臓脂肪に起因する割合%として表されてもよい、過剰の内臓脂肪を有する被検体を助けると考えられる。特定の態様では、被検体は、肥満、糖尿病、またはIGF-I欠乏を持つ。
治療または美容上有効な用量の選択は、当技術分野で公知のいくつかの要因を考慮して、臨床家または医師のような熟練した専門家によって決定され得る(例えば臨床試験)。そのような要因には、例えば、IGF-I血清濃度を上昇させる化合物の特定の型、バイオアベイラビリティ、代謝、半減期等のような化合物の薬物動態パラメータが含まれ、これらは、薬学的化合物の薬事承認において通常使用される開発過程において確立される。用量の検討における更なる要因には、治療する疾病または状態、被検体において達成される恩典、被検体の体重、被検体の免疫状態、投与経路、化合物または併用剤の投与が急性であるか慢性であるか、併用剤、および投与される薬剤の有効性に影響することが当業者で公知の他の要因が含まれる。
以下の実施例は、当業者に本発明をどのように作成し使用するかを完全に開示および記述するために提供され、発明者らが本発明と見なす発明の範囲を限定する意図はなく、以下の実験が実施されたすべてあるいは唯一の実験であるという意図はない。使用する数字(例えば、量、温度等)については正確さを保証する努力がなされたが、いくらかの実験誤差および逸脱は考慮される必要がある。特に記載がない限り、割合は重量により、分子量は平均分子量、温度は摂氏、および圧力は大気圧またはその付近である。
初めは食事療法および運動によって治療されたII型糖尿病(DM)の大部分の個体は、後に血糖コントロールのために経口血糖低下薬を必要とするようになる。10年後には、経口剤に初めは反応した個体の50%は血糖コントロールが不十分になり、最終的にはインスリン療法を必要とするようになる。Yki-Jarvinen H et al., 1992, N Engl J Med 327:1426-33を参照されたい。短期間のインスリン療法には、平均5〜6 kgの体重増加が伴い、その3分の2は長期にわたる脂肪量の増加に起因する。Koivisto VA., 1993, Diabetes Care 16 Suppl 3:29-39を参照されたい。
有効性のエンドポイントは、ヘモグロビンA1c (HbA1c)レベルのベースライン(1日目から12週目)からの変化により評価した血糖コントロール、および空腹時血糖(BG)、体重、ならびに内臓および大腿中央部の脂肪のベースライン(1日目から12週目)からの変化だった。
本試験に使用された範囲の用量のrhIGF-Iを用いた臨床試験に基づくと、最も一般的に予想される有害事象には、顎の疼痛、浮腫、関節痛、および筋肉痛が含まれた。これらの事象が起きたときには、通常は本試験で使用された用量ではrhIGF-Iの中止は必要ではなかった。浮腫は外見上の問題であることが多く、特に治療をしなくても通常は解消した。まれに、軽い利尿剤治療が必要だった。
本試験は現在経口血糖低下薬でのみ治療されているII型糖尿病の男女約200名(男女とも最低85名)を含めることを目的とした。
rhIGF-Iは、保存料としてベンジルアルコールを添加した7 mLの酢酸/NaCl,pH 5.4中の70 mgのrhIGF-I無菌溶液を含むバイアル中で、Genentech, Inc.より提供された。
表1に示されたように、被検体を12週間の治療期間の間の5つの投与計画(各群約40名)のうちの1つに無作為に割り付けた。無作為化は、性別、以前の血糖低下薬治療、および14日目のHbA1cレベルによって層別化された。
12週目における血糖コントロールに対する治療効果の評価のための主要有効性変数は、HbA1cレベルのベースライン(1日目)からの変化だった。12週目の血糖コントロールの副次的有効性変数は以下の各変数のベースライン(1日目)からの変化だった:空腹時血糖濃度、体重、ならびに内臓および大腿中央部脂肪。
すべてのCTスキャンはGE Sytec 4000 CTスキャナーまたは同等のスキャナーで行われた。
最初の大腿部スキャンを以下の手順で行った。
kV = 100
MA = 170
1秒
DFOV = 21
アルゴリズム=標準
最初の腹部スキャンを以下の手順で行った。
大腿部
・大腿部全体のトポグラム
・大腿部距離が測定されたトポグラム(距離全体および中点を示した距離)
・大腿部断面図全体
胴部
・L3の中点に印をつけた脊椎側面像
・L3レベルでの全体のスライス
ディスクは以下の情報を含んでいた:
・大腿部の断面
・L3における胴部の断面
スライスはスキャナーにダウンロードし、光ディスク(または可能ならばインターネット)を介して解析用のコンピュータに伝送した。解析時には下腹部および皮下の脂肪ならびに斜筋、腰筋、腰方形筋、および仙棘筋も測定された。画像はNIH IMAGEプログラムの改良版を用いて光学密度によってデジタル化し、骨、筋肉、および脂肪コンパートメントを分離した。ピクセル単位は、内部較正基準を用いて面積の測定に変換した。デジタル化画像は盲目で解析した。単一のスキャンの繰り返し解析の変動係数は、< 1.5%である。
血糖コントロールに対する治療効果
血糖コントロールに対する治療効果の評価のための主要有効性変数は、HbA1cレベルのベースライン(1日目)からの変化だった。結果は表2に示されている。基礎HbA1c値が高い場合には、ベースラインにおける患者のII型糖尿病のコントロールは良くないことを示す。表2を調べると、IGF-1治療はHbA1cに対して持続する進行性の有益な効果を示すことが分かる。
IGF-I治療の安全性
グリブリドと組み合わされたIGF-I治療の安全性は、表3および表4に示されている。表3に示されるように、使用されたIGF-Iの用量では、副作用の発生率は低かった。表4は5つの治療群の被検体の網膜のETDRSスコアを示す。IGF-I治療が網膜症の進行(ETDRSスコアの上昇)を引き起こさなかったことは明らかである。
治療に反応した体重およびBMIの変化
12週目の血糖コントロールを評価する副次的有効性変数は、以下の各々の項目についてのベースライン(1日目)からの変化だった:体重、ならびに内臓および大腿中央部の脂肪。表5は各治療群における体重の変化および平均の標準誤差(SE)を示す。
治療に反応した体脂肪のコンピュータ断層撮影(CT)スキャン測定の変化
別の独立した尺度は、腹部径および腹囲(例、ベルトサイズ)を測定したCTスキャンだった。グリブリド単独で治療された被検体の腹部径は変化しなかったが(-0.3±0.8 cm、平均±SEM)、20μg/kgのIGF-Iで治療された被検体では低下し(-1.4±0.8 cm)、40μg/kgで治療された被検体ではさらに低下した(-2.9±1.3 cm)。高用量IGF-Iにより引き起こされた胴回りのこの低下は、普通の言葉で言うと1インチを超える、またはベルト穴1つ分であるが、12週目でのみ明らかに有意な効果だった。
Claims (21)
- 過剰の内臓脂肪を有する被検体において内臓脂肪を低下させるために有効な量の、インスリン様成長因子I(IGF−I)を、該被検体に投与する段階を含む、過剰の内臓脂肪を有する被検体において内臓脂肪を低下させる方法において使用するための、IGF−Iを含む、薬学的組成物。
- 被検体における内臓脂肪の低下が、皮下脂肪に対する内臓脂肪の比を決定することによって評価される、請求項1記載の薬学的組成物。
- 被検体における内臓脂肪の低下が、被検体の尻囲の値に対する腰囲の値の比の減少によって評価される、請求項1記載の薬学的組成物。
- 被検体における内臓脂肪の低下が、コンピュータ断層撮影(CT)スキャンによって評価される、請求項1記載の薬学的組成物。
- IGF−Iがインスリン様成長因子結合蛋白質−3(IGFBP−3)と複合体を形成する、請求項1記載の薬学的組成物。
- IGF−Iの量が40μg/kg/日またはそれ以上である、請求項1記載の薬学的組成物。
- IGF−Iが皮下投与用に製剤化される、請求項1記載の薬学的組成物。
- 薬学的組成物が使用される方法が、有効量の血糖低下剤を被検体に投与する段階をさらに含む、請求項1記載の薬学的組成物。
- 血糖低下剤がインスリンである、請求項8記載の薬学的組成物。
- 血糖低下剤が、スルホニル尿素、ビグアニド、およびチアゾリジンジオンからなる群より選択される、請求項8記載の薬学的組成物。
- 血糖低下剤がグリブリドである、請求項8記載の薬学的組成物。
- 過剰の内臓脂肪を有する被検体における内臓脂肪沈着を低下させるために有効な量の、インスリン様成長因子−I(IGF−I)を、該被検体に投与する段階を含む、過剰の内臓脂肪を有する被検体において内臓脂肪沈着を低下させる方法において使用するための、IGF−Iを含む、薬学的組成物。
- 治療を必要とする被検体における薬剤に起因する内臓脂肪沈着の軽減に有効な量の、インスリン様成長因子−I(IGF−I)を、該被検体に投与する段階を含む、薬剤に起因する内臓脂肪沈着を軽減する方法において使用するための、IGF−Iを含む、薬学的組成物。
- 被検体が、薬学的組成物による治療の前には、被検体と同じ性別およびボディマス指数(BMI)を有する正常な成人の平均的な体組成を特徴付ける皮下脂肪に対する内臓脂肪の比よりも高い、皮下脂肪に対する内臓脂肪の比によって特徴付けられる体組成を示す成人である、請求項1記載の薬学的組成物。
- 被検体が、薬学的組成物による治療の前には、II型糖尿病を特徴とする状態、並びに、(1)被検体が男性の場合は40インチより大きい腰囲、および被検体が女性の場合は35インチより大きい腰囲、(2)110 mg/dLまたはそれ以上の空腹時血糖レベル、(3)150 mg/dLまたはそれ以上の空腹時トリグリセリドレベル、(4)被検体が男性の場合は40 mg/dL未満、および被検体が女性の場合は50 mg/dL未満の高比重リポ蛋白(HDL)レベル、および(5)130/85より高い血圧レベル、からなる群より選択される3つまたはそれ以上の症状を示す成人被検体である、請求項1記載の薬学的組成物。
- (i)被検体が、薬学的組成物による治療の前には、II型糖尿病、および少なくとも40インチの腰囲を有する成人男性である、または(ii)被検体が、薬学的組成物による治療の前にはII型糖尿病、および少なくとも35インチの腰囲を有する成人女性である、請求項1記載の薬学的組成物。
- 被検体が、薬学的組成物による治療の前には、尻囲の値に対する腰囲の値の比が1より大きいまたは約1のヒトである、請求項1記載の薬学的組成物。
- 被検体が、薬学的組成物による治療の前には、II型糖尿病を特徴とする状態、並びに、(1)被検体が男性の場合は40インチより大きい腰囲、および被検体が女性の場合は35インチより大きい腰囲、(2)110 mg/dLまたはそれ以上の空腹時血糖レベル、(3)150 mg/dLまたはそれ以上の空腹時トリグリセリドレベル、(4)被検体が男性の場合は40 mg/dL未満、および被検体が女性の場合は50 mg/dL未満の高比重リポ蛋白(HDL)レベル、および(5)130/85より高い血圧レベル、からなる群より選択される3つまたはそれ以上の症状を示す成人である、請求項12記載の薬学的組成物。
- (i)被検体が、薬学的組成物による治療の前には、II型糖尿病、および少なくとも40インチの腰囲を有する成人男性である、または(ii)被検体が、薬学的組成物による治療の前にはII型糖尿病、および少なくとも35インチの腰囲を有する成人女性である、請求項12記載の薬学的組成物。
- 薬学的組成物が使用される方法が、被検体に投与されるIGF−Iとの組み合わせで被検体における内臓脂肪沈着の低下に有効な量の成長ホルモンを被検体に投与する段階をさらに含む、請求項13記載の薬学的組成物。
- IGF−Iが、組換えヒトIGF−Iである、請求項1、12または13記載の薬学的組成物。
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MX2012000757A (es) | 2009-07-22 | 2012-08-03 | Ipsen Pharma Sas | Analogos de factor de crecimiento insulinoide tipo 1 (igf-1) que tienen sustitucion de aminoacidos en la posicion 59. |
US20140286966A1 (en) * | 2010-07-06 | 2014-09-25 | Youngman Oh | Methods and compositions for the treatment of metabolic syndrome, obstructive respiratory disorders, cancer and related diseases |
US20140178456A1 (en) * | 2012-08-30 | 2014-06-26 | Udaya Sankar Devanaboyina | Methods and compositions for treating type 2 diabetes and related conditions |
US20160011207A1 (en) * | 2012-12-07 | 2016-01-14 | Virginia Commonwealth University | Diagnosis and therapy of chronic inflammation-induced disorders |
US20170368149A1 (en) * | 2014-12-16 | 2017-12-28 | Puretein Bioscience Llc. | Methods for increasing serum igf-1 in an animal |
KR102245539B1 (ko) | 2018-02-12 | 2021-04-29 | 주식회사 지앤피바이오사이언스 | 코어-쉘 구조의 마이크로 입자를 유효성분으로 포함하는 성장인자 유전자 발현 증가용 조성물 |
KR102288366B1 (ko) * | 2018-03-09 | 2021-08-10 | 경북대학교 산학협력단 | 한속단 추출물을 유효성분으로 포함하는 비만 예방 또는 치료용 약학적 조성물 |
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US4988675A (en) * | 1988-02-05 | 1991-01-29 | Ciba-Geigy Corporation | Method for preventing secondary effects |
US5126324A (en) | 1990-06-07 | 1992-06-30 | Genentech, Inc. | Method of enhancing growth in patients using combination therapy |
JPH08502969A (ja) | 1992-10-29 | 1996-04-02 | ジェネンテク,インコーポレイテッド | 肥満の予防または治療方法 |
US5579782A (en) * | 1993-08-12 | 1996-12-03 | Omron Corporation | Device to provide data as a guide to health management |
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US7122515B2 (en) * | 1996-05-17 | 2006-10-17 | Pharmacia Ab | Methods for treating a patient having Metabolic Syndrome |
US6846800B1 (en) * | 1996-05-17 | 2005-01-25 | Pharmacia Ab | Method for treating a patient having metabolic syndrome |
TW529930B (en) * | 1999-08-27 | 2003-05-01 | Yamato Scale Co Ltd | Health condition judging/displaying device |
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WO2005020898A3 (en) | 2008-02-21 |
US7833964B2 (en) | 2010-11-16 |
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WO2005020898A8 (en) | 2005-05-19 |
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