JP5068253B2 - 心臓血管疾患の治療 - Google Patents
心臓血管疾患の治療 Download PDFInfo
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- JP5068253B2 JP5068253B2 JP2008510316A JP2008510316A JP5068253B2 JP 5068253 B2 JP5068253 B2 JP 5068253B2 JP 2008510316 A JP2008510316 A JP 2008510316A JP 2008510316 A JP2008510316 A JP 2008510316A JP 5068253 B2 JP5068253 B2 JP 5068253B2
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Description
血管機能障害(たとえば、血管機能不全)は、たとえば、血管系の構造および/または機能の障害もしくは欠陥を含めて、さまざまな異常に起因すると考えられる。血管機能障害は、血管系のさまざまな病変および損傷を伴い、その結果、たとえば、動脈壁硬化、血管透過性、および血管石灰化につながる有害な変化をもたらす。
心臓機能障害(たとえば、心臓機能不全)および心臓病は、たとえば、心臓および心筋の収縮および/または弛緩の障害もしくは損傷を含めた、さまざまな異常に起因すると考えられる。臨床上の観点から、心臓機能障害は、心臓機能の異常のために、代謝を行う組織の要求に見合う速度で心臓が血液を拍出することができない状態、および/または異常に増大した心室拡張期容積からのみ拍出することができる状態とみなすことができる。心臓機能障害(たとえば、心臓機能不全、心不全)は、収縮期心臓機能障害または拡張期心臓機能障害とすることができるが、それぞれ収縮期心不全および拡張期心不全として知られている。
上記のいずれの方法においても、抗CTGF薬はポリペプチド、ポリヌクレオチド、または小分子;たとえば、CTGFと結合する抗体、アンチセンス分子、siRNA、小分子化合物などであることが、特に想定される。具体的には、本発明は、CTGFの阻害が、CTGFの発現および活性を調節するための当技術分野で公知の任意の手段によって達成できることを想定している。抗CTGF薬、たとえば、CTGFに対するヒトモノクローナル抗体を使用することが好ましいが、ただし、CTGFをコードする遺伝子の発現を阻害する方法、CTGFの産生を阻害する方法、またはCTGFの活性を阻害する方法のいずれも、本発明によって意図される。
本発明の組成物は、そのままで、もしくは当業者によく知られているように添加剤を含有する医薬組成物として投与することができる。本発明の治療方法は、有効量の本発明の化合物を、血管機能不全(すなわち血管機能障害)もしくは心臓機能不全(すなわち心臓機能障害)を有する、またはそのリスクのある被験体に投与することを含んでなる。好ましい実施形態において、被験体は哺乳類被験体であり、もっとも好ましい実施形態では、被験体はヒト被験者である。
抗CTGF治療は血流力学パラメータおよび心機能を改善する
本発明の方法を用いて、糖尿病に伴う血管合併症のある特定の態様について、動物モデルで広範な効果を下記のように立証した。ストレプトゾトシン(STZ)(65 mg/kg)の単回i.v.投与によって、Sprague Dawleyラットに真性糖尿病を誘発した。STZ誘発糖尿病は、ラットにおいて血管透過性の増大をもたらし(Lawsonら、(2005) Regul Pept 124:221-224)、心機能の低下を招く(Machackovaら、(2004) Mol Cell Biochem 261:271-278)。実験用ラットは、第0日に、65 mg/kg (65mg/ml)の用量で0.1Mクエン酸緩衝ストレプトゾトシン(pH 4.1)の静脈注射を受けた。STZで処理した動物における糖尿病誘発の成功は、第2日に、空腹時血糖値の上昇(>250mg/dl)によって確認した。
抗CTGF治療が動脈壁硬化を低下させる
抗CTGF治療が動脈壁硬化(血管機能、および特に大血管機能の尺度)に及ぼす効果を、上記実施例1に記載の糖尿病の動物モデルを用いて評価した。頸動脈から得られた受動圧-および能動圧-体積データを含めて、動脈壁硬化のさまざまな測定値が得られた。こうした測定のために、左頸動脈の遠位部分に、三方活栓に連結されたPE-50チューブのカニューレを挿入した。改変Krebsバッファー溶液を、カニューレを通して頸動脈内に注入した。頸動脈の近位端を、血管閉塞器具を用いて閉塞した。バッファー溶液の注入時に発生した力を測定するために、圧力トランスデューサーを三方活栓に接続した。PEチューブの末端をアイソメトリック・フォース・トランスデューサー(力変換機)に接続し、加圧時の、等尺性の軸方向の力を測定した。デジタル画像解析システムを用いて、上記動脈セグメントの外側の半径の変化を測定した。受動的な動脈壁硬化度は、動脈セグメントにCa2+フリーのバッファーを潅流することによって測定した。能動的な動脈壁硬化度を測定するために、血管拡張薬および血管収縮薬、たとえばノルエピネフリンを潅流液に加えた。特定の実験では、動脈セグメントを動物から摘出し、同様の装置を用いて、in vivo伸び長さでex vivo評価した。
本発明の方法および薬剤を用いて、糖尿病に伴う血管合併症のある特定の態様について、動物モデルで広範な有効性を立証した。一連の実験で、抗CTGF治療が動脈壁硬化(血管機能、特に大血管機能の尺度)に及ぼす効果を、下記のように糖尿病の動物モデルを用いて評価した。0.1Mクエン酸緩衝(pH 4.1)ストレプトゾトシン(STZ)(65 mg/kg)の単回i.v.注射によってSprague Dawleyラットに糖尿病(1型糖尿病)を誘発した。STZで処理した動物の糖尿病誘発の成功は、第2日に、空腹時血糖値の上昇(>250mg/dl)によって確認した。
大動脈輪を、摘出した頸動脈セグメントの中央部分から切除し、Krebs溶液中に入れた。無負荷状態の大動脈輪の横断面のデジタル写真を撮影した。そのリングに半径方向に切れ目を入れて、扇形に開いた。粘弾性クリープが生じるままにして20分後にデジタル写真を撮影した。開放角は、扇形の内側表面の中心点を内側先端につなぐ線の間の角度として定義され、ゼロ応力状態を特徴付ける。実験糖尿病は、図10に示すように6週間までに、開放角を増大させた。抗CTGF抗体による治療は、増大した開放角を、第12週までに健康な対照と変わらないレベルにまで正常化したが、溶媒で処置した動物では開放角は増加し続けた。開放角は、動脈壁の残留応力の指標である。
抗CTGF治療は血管透過性を低下させる
抗CTGF治療が血管透過性(血管機能、特に大血管機能の尺度)に及ぼす効果を、上記実施例1に記載の糖尿病の動物モデルを用いて評価した。糖尿病誘発後のさまざまな時点で、ラットの血管透過性(VP)の増加を次のように検査した。無麻酔ラットにエバンスブルー(EB)色素を静脈注射で投与した(20mg/kg)。20分後に、麻酔薬の過量投薬によって動物を屠殺し、心臓を摘出した。肩より後ろの胴体から皮膚切片を切り取って秤量した。このアッセイにおいて、血管透過性の増加は、色素の皮膚への血管外遊出によって特徴付けられる。皮膚はホルムアミド(4ml/g湿重量)に24℃で24時間浸漬した。その後、ホルムアミド中に抽出されたEB色素の吸光度を、プレートリーダーを用いて620 nmで分光光度法によって測定した。このアッセイにおいて、EB色素の濃度は、血管透過性の程度と比例する。さらに、6 mmバイオプシーパンチを用いて皮膚切片を採取した。この切片を秤量した後、60℃にて一晩乾燥した。乾燥したサンプルを秤量し、乾重量に対する湿重量の比を測定した。湿重量/乾重量比の増加は組織浮腫を示す。
抗CTGF治療は血管石灰化を軽減する
抗CTGF抗体の血管石灰化への効果を次のように調べた。カルシウム鉱物沈着物についてのvon Kossa染色を、STZによる糖尿病誘発の6週間後の動物から得られた頸動脈切片に対して行った。総頸動脈の2 cmセグメントを10%亜鉛 ホルマリン(0.1 M)に24時間入れ、段階的な一連のエタノール溶液に入れて脱水した後、パラフィンに包埋した。厚さ3μmの頸動脈組織切片を切り取り、脱パラフィンして、蒸留水中で水和した後、5% AgNO3で60分間処理した。その後、頸動脈組織標本を蒸留水ですすぎ、5% Na2S2O3で2分間処理した。次に標本を順次、蒸留水および95%エタノールですすいだ。標本をその後エオシンで対比染色し、光学顕微鏡下で検査し、血管壁の内膜層に沿って暗黒/茶色の染色が存在することによって血管壁石灰化を評価した。血管石灰化は、光学顕微鏡で観察した血管壁内に存在する、または存在しないとして、評価される。
抗CTGF治療は、心臓血管合併症の糖尿病動物モデルにおいて、治療上の利点を有する
8週齢の雄db/dbマウス(C57BLKS/J-leprdb/leprdb)およびそれと週齢の一致した糖尿病でないdb/+同腹子(C57BLKS/J-leprdb/+)(Jackson Labs, Bar Harbor, ME)を使用した。db/dbマウスは、初期体重が約40 gであった。糖尿病でないdb/+マウスの初期体重は約20 gであった。特定の実験群においては、飲料水に、ロサルタン約2 mg/日の投与を保証する濃度であるロサルタン(200 mg/L)を添加した。
1. Roestenberg, P.ら、「結合組織成長因子は腎症を伴う1型糖尿病患者の血漿中で増加する」(Connective tissue growth factor is increased in plasma of type 1 diabetic patients with nephropathy.)、Diabetes Care 27:1164-1170 (2004)
2. Jaffa, A.A.ら、「結合組織成長因子(CTGF)Nフラグメント:進行性糖尿病性腎症のマーカー」(Connective Tissue Growth Factor (CTGF) N Fragment: a marker of progressive diabetic nephropathy.)、Amer. Soc. Neprol. (2002 Annual Meeting)
3. Gilbert, R.E.ら、「1型糖尿病および腎症に罹患した患者における尿中結合組織成長因子排泄」(Urinary connective tissue growth factor excretion in patients with type 1 diabetes and nephropathy.)、Diabetes Care 26:2632-36 (2003)
4. Lemley, K.V.ら、「IgA腎症ならびに2型糖尿病性腎症において、結合組織成長因子の尿中排泄は疾患の重症度にともなって増加する」(Urinary excretion of connective tissue growth factor increases with disease severity in IgA nephropathy and type 2 diabetic nephropathy.)、J. Am. Soc. Nephrol. (2001年、年次総会)
5. Ito, Y.ら、「慢性腎臓病の進行の予測指標としてのヒト尿中CTGF (CCN2)」、(Human urinary CTGF (CCN2) as a predictor of progression of chronic renal disease.)、Amer. Soc. Nephrol. (2003年、年次総会)
6. Murphy, M.ら、「Suppression subtractive hybridization法は、ヒト メサンギウム細胞における結合組織成長因子および他の遺伝子発現に対する刺激として、高グルコース濃度を特定する」(Suppression subtractive hybridization identifies high glucose levels as a stimulus for expression of connective tissue growth factor and other genes in human mesangial cells.)、J. Biol. Chem. 274(9):5830-4 (1999)
7. Lam, S.ら、「結合組織成長因子およびigf-Iはヒト腎線維芽細胞によって産生され、高グルコースによるコラーゲン産生の誘導に共同して作用する」(Connective tissue growth factor and igf-I are produced by human renal fibroblasts and cooperate in the induction of collagen production by high glucose.)、Diabetes 52:2975-2983 (2003)
8. Hishikawa, K.ら、「ヒト メサンギウム細胞において、静圧が結合組織成長因子の発現を制御する」(Static pressure regulates connective tissue growth factor expression in human mesangial cells.)、J. Biol. Chem. 276(20): 16797-16803 (2001)
9. Twigg, S.M.ら、「終末糖化産物がヒト線維芽細胞において結合組織成長因子(インスリン様成長因子-結合タンパク質-関連タンパク質2)をアップレギュレートする:糖尿病における細胞外マトリクス増大の考えられるメカニズム」(Advanced glycosylation end products up-regulate connective tissue growth factor (insulin-like growth factor-binding protein-related protein 2) in human fibroblasts: a potential mechanism for expansion of extracellular matrix in diabetes mellitus.)、Endocrinology 142(5):1760-9 (2001)
10. Suzuma, K.ら、「血管内皮成長因子は、網膜血管細胞においてKDR、Flt1、およびホスファチジルイノシトール3-キナーゼ-akt-依存性経路を介して、結合組織成長因子の発現を誘導する」(Vascular endothelial growth factor induces expression of connective tissue growth factor via KDR, Flt1, and phosphatidylinositol 3-kinase-akt-dependent pathways in retinal vascular cells.)、J. Biol. Chem. 275(52):40725-31 (2000)
11. Ruiz-Ortega, R.M.ら、「アンジオテンシンIIは腎臓の結合組織成長因子を増加させる」(Angiotensin II increases connective tissue growth factor in the kidney.)、Am. J. Pathol. 163(5):1937-47 (2003)
12. Abdel-Wahab, N.ら、「結合組織成長因子およびメサンギウム細胞サイクルの制御:細胞肥大における役割」(Connective tissue growth factor and regulation of the mesangial cell cycle: role in cellular hypertrophy.)、J. Am. Soc. Nephrol. 13:2437-2445 (2002)
13. Riser, B.L.ら、「培養ラットメサンギウム細胞における結合組織成長因子活性の制御、ならびに糖尿病性糸球体硬化におけるその発現」(Regulation of connective tissue growth factor activity in cultured rat mesangial cells and its expression in experimental diabetic glomerulosclerosis.)、J. Am. Soc. Nephrol. 11:25-38 (2000)
14. Liu, B.C.ら、「アンジオテンシンIIによって誘導されるヒト近位尿細管細胞の肥大を仲介する、結合組織成長因子の役割」(Role of connective tissue growth factor in mediating hypertrophy of human proximal tubular cells induced by angiotensin II.)、 Am. J. Nephrol. 23(6):429-437 (2003)
15. Igarashi, A.ら、「創傷修復時の結合組織成長因子遺伝子発現の制御」(Regulation of connective tissue growth factor gene expression in and during wound repair.)、 Mol. Biol. Cell. 4(6):637-645 (1993)
16. Gilbert, R.E.ら、「実験糖尿病の腎尿細管間質におけるトランスフォーミング増殖因子β1およびIV型コラーゲンの発現」(Expression of transforming growth factor-beta1 and type IV collagen in the renal tubulointerstitium in experimental diabetes: effects of ACE inhibition.)、Diabetes. 47(3):414-22 (1998)
17. He, S.ら、「脈絡膜血管新生の発症機序における結合組織成長因子の役割」(A role for connective tissue growth factor in the pathogenesis of choroidal neovascularization.)Arch. Ophthalmol. 121:1283-1288 (2003)
18. Kuiper, E.J.ら、「硝子体の結合組織成長因子はヒトの眼の硝子体網膜障害における線維化と関係がある」(Connective tissue growth factor in vitreous correlates with fibrosis in vitreoretinal disorders in the human eye.)、The Association for Research in Vision and Ophthalmology. 4145 (2004年、年次総会)
19. Oemar, B.S.およびLuscher, T.F.、「結合組織成長因子-敵か味方か?」(Connective tissue growth factor. Friend or foe?)、Arterioscler. Thromb. Vasc. Biol. 17(8):1483-9 (1997)
20. Finckenberg, P.ら、「アンジオテンシンIIは、カルシニューリン依存性経路を介して結合組織成長因子遺伝子発現を誘導する」(Angiotensin II induces connective tissue growth factor gene expression via calcineurin-dependent pathways.)、Am. J. Pathol. 163(1):355-366 (2003)
21. Liu, B.C.ら、「ストレプトゾシン誘発糖尿病ラットの腎臓障害の予防におけるイルベサルタンのメカニズム」(Mechanisms of irbesartan in prevention of renal lesion in streptozotocin-induced diabetic rats.)、Acta. Pharmacol. Sin. 24(1):67-73 (2003)。
23. Peng, H.ら、「Ac-SDKPは、腎血管性高血圧ラットの心臓線維化を回復させる」(Ac-SDKP reverses cardiac fibrosis in rats with renovascular hypertension.)、Hypertension. 42(6):1164-70 (2003)
24. Kapoun, A.M.ら、「B型ナトリウム利尿ペプチドは、初代ヒト心臓線維芽細胞のトランスフォーミング増殖因子βに対して広範に機能的に対抗する;線維化、筋線維芽細胞転換、増殖および炎症」(B-type natriuretic peptide exerts broad functional opposition to transforming growth factor-beta in primary human cardiac fibroblasts: fibrosis, myofibroblast conversion, proliferation, and inflammation.)Circ. Res. 5;94(4):453-61 (2004)
25. Candido, R.ら、「終末糖化産物を分解するものは糖尿病によって誘発される心筋構造の変化を減少させる」(A breaker of advanced glycation end products attenuates diabetes-induced myocardial structural changes.)、Circ. Res. 92(7):785-92 (2003)。
Claims (15)
- 有効量の抗CTGF抗体を含む、糖尿病に罹患した被験体における心臓機能を改善するための医薬組成物。
- 前記組成物が駆出率を改善するための組成物である、請求項1に記載の医薬組成物。
- 前記組成物が1回拍出量を改善するための組成物である、請求項1に記載の医薬組成物。
- 前記組成物が心拍出量を改善するための組成物である、請求項1に記載の医薬組成物。
- 前記組成物が心室弛緩を改善するための組成物である、請求項1に記載の医薬組成物。
- 前記組成物が心室収縮を改善するための組成物である、請求項1に記載の医薬組成物。
- 前記組成物が拡張末期圧を改善するための組成物である、請求項1に記載の医薬組成物。
- 前記組成物が拡張末期容積を改善するための組成物である、請求項1に記載の医薬組成物。
- 前記組成物が心臓合併症を治療または予防するための組成物である、請求項1〜8のいずれか1項に記載の医薬組成物。
- 心臓合併症が心臓肥大、鬱血性心不全および心筋症から選択される、請求項9に記載
の医薬組成物。 - 前記組成物が血中LDL濃度を下げることによって心臓合併症を治療または予防するための組成物である、請求項9または10に記載の医薬組成物。
- 被験体が哺乳類の被験体である、請求項1〜11のいずれか1項に記載の医薬組成物。
- 被験体がヒト被験者である、請求項1〜12のいずれか1項に記載の医薬組成物。
- 抗CTGF抗体が、CTGFに対するモノクローナル抗体、もしくはそのフラグメントである、請求項1に記載の医薬組成物。
- 抗CTGF抗体が、WO 2004/108764に記載のCLN-1、もしくはそのフラグメントである、請求項1に記載の医薬組成物。
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US60/734,433 | 2005-11-07 | ||
PCT/US2006/017760 WO2006122047A1 (en) | 2005-05-05 | 2006-05-05 | Cardiovascular disease therapies |
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JP2008510315A Pending JP2008540456A (ja) | 2005-05-05 | 2006-05-05 | 血管疾患の治療 |
JP2008510316A Active JP5068253B2 (ja) | 2005-05-05 | 2006-05-05 | 心臓血管疾患の治療 |
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EP (2) | EP1891109A1 (ja) |
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CA (2) | CA2606778A1 (ja) |
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WO2007098065A2 (en) * | 2006-02-17 | 2007-08-30 | The United States Of America As Represented By The Department Of Veterans Affairs | Human sodium channel isoforms |
US9114133B2 (en) | 2006-08-25 | 2015-08-25 | U.S. Dept. Of Veterans Affairs | Method of improving diastolic dysfunction |
US20080075666A1 (en) * | 2006-08-25 | 2008-03-27 | Dudley Samuel C Jr | Methods and compositions for treating diastolic dysfunction |
US9211301B2 (en) | 2007-10-18 | 2015-12-15 | U.S. Department Of Veterans Affairs | Method for ameliorating or preventing arrhythmic risk associated with cardiomyopathy by improving conduction velocity |
US9220720B2 (en) | 2007-10-18 | 2015-12-29 | U.S. Department Of Veterans Affairs | Method for ameliorating or preventing arrhythmic risk associated with cardiomyopathy |
US9050350B2 (en) | 2007-10-18 | 2015-06-09 | U.S. Department Of Veterans Affairs | Method for modulating or controlling connexin 43(Cx43) level of a cell and reducing arrhythmic risk |
US9114151B2 (en) * | 2007-10-18 | 2015-08-25 | The United States Of America Dept. Of Veterans Affairs | Method for modulating or controlling sodium channel current by reactive oxygen species (ROS) originating from mitochondria |
US8946172B2 (en) | 2008-08-25 | 2015-02-03 | Excaliard Pharmaceuticals, Inc. | Method for reducing scarring during wound healing using antisense compounds directed to CTGF |
CA2733262C (en) | 2008-08-25 | 2019-12-10 | Excaliard Pharmaceuticals Inc. | Antisense oligonucleotides directed against connective tissue growth factor and uses thereof |
EP2344181A1 (en) * | 2008-09-18 | 2011-07-20 | Universitetet I Oslo | Use of ctgf as a cardioprotectant |
US20110262398A1 (en) * | 2010-04-21 | 2011-10-27 | University Of Illinois | Cardiac treatment using anti-fibrotic agents |
KR101249041B1 (ko) * | 2010-04-28 | 2013-03-29 | 포항공과대학교 산학협력단 | 결합조직 성장인자를 이용한 약학적 조성물 |
ES2729956T3 (es) | 2011-02-02 | 2019-11-07 | Excaliard Pharmaceuticals Inc | Compuestos antisentido dirigidos al factor de crecimiento de tejido conectivo (ctgf) para su uso en un procedimiento de tratamiento de queloides o cicatrices hipertróficas |
DE102012103096A1 (de) * | 2012-04-11 | 2013-10-17 | Eberhard-Karls-Universität Tübingen Universitätsklinikum | Prophylaxe und Behandlung einer Gefäßkalzifizierung |
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US5408040A (en) * | 1991-08-30 | 1995-04-18 | University Of South Florida | Connective tissue growth factor(CTGF) |
US7384634B2 (en) * | 1991-08-30 | 2008-06-10 | University Of South Florida | Connective tissue growth factor |
US5770209A (en) | 1991-08-30 | 1998-06-23 | University Of South Florida | Acceleration of wound healing using connective tissue growth factor |
JPH11180895A (ja) | 1997-09-12 | 1999-07-06 | Masaharu Takigawa | 血管新生阻害剤 |
AU1682699A (en) * | 1997-12-25 | 1999-07-19 | Japan Tobacco Inc. | Monoclonal antibody against connective tissue growth factor and medicinal uses thereof |
US20010006979A1 (en) | 1998-07-08 | 2001-07-05 | Richard Stratton | Method for treatment of fibrosis related diseases by the administration of prostacyclin derivatives |
JP4634614B2 (ja) | 1998-12-14 | 2011-02-16 | ユニバーシティー オブ マイアミ | 結合組織成長因子(ctgf)断片とそれを用いた方法および使用 |
US7115390B1 (en) * | 1998-12-14 | 2006-10-03 | Fibrogen, Inc. | Connective tissue growth factor fragments and methods and uses thereof |
JP2004502644A (ja) * | 2000-03-09 | 2004-01-29 | ジェンザイム、コーポレーション | 腎機能の喪失を治療または予防するためのTGF−β拮抗薬の使用 |
US6965025B2 (en) * | 2001-12-10 | 2005-11-15 | Isis Pharmaceuticals, Inc. | Antisense modulation of connective tissue growth factor expression |
JP2005519881A (ja) | 2001-12-11 | 2005-07-07 | ファイブローゲン、インコーポレーテッド | 眼プロセスの抑制方法 |
US7405274B2 (en) * | 2003-06-04 | 2008-07-29 | Fibrogen, Inc. | Connective tissue growth factor antibodies |
PL1715890T3 (pl) | 2004-02-11 | 2009-01-30 | Fibrogen Inc | CTGF jako cel dla terapii mikroalbinurii u pacjentów z nefropatią cukrzycową |
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JP2008540456A (ja) | 2008-11-20 |
AU2006244148A1 (en) | 2006-11-16 |
AU2006244147A1 (en) | 2006-11-16 |
WO2006122046A2 (en) | 2006-11-16 |
IL187113A (en) | 2011-06-30 |
JP2008540457A (ja) | 2008-11-20 |
EP1891109A1 (en) | 2008-02-27 |
EP1885756A2 (en) | 2008-02-13 |
US20060281667A1 (en) | 2006-12-14 |
WO2006122046A3 (en) | 2007-05-31 |
MX2007013834A (es) | 2008-02-05 |
NO20076241L (no) | 2008-02-04 |
US8088381B2 (en) | 2012-01-03 |
IL187115A0 (en) | 2008-02-09 |
WO2006122047A1 (en) | 2006-11-16 |
NO20076121L (no) | 2008-02-04 |
MX2007013819A (es) | 2008-02-05 |
US20120039882A1 (en) | 2012-02-16 |
US20060281668A1 (en) | 2006-12-14 |
NZ563493A (en) | 2010-10-29 |
IL187113A0 (en) | 2008-02-09 |
CA2606778A1 (en) | 2006-11-16 |
CA2607044A1 (en) | 2006-11-16 |
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