TWI415599B - Pdeiii抑制劑用於降低罹患心臟衰竭之哺乳動物之心臟大小之用途 - Google Patents
Pdeiii抑制劑用於降低罹患心臟衰竭之哺乳動物之心臟大小之用途 Download PDFInfo
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Description
本發明係關於第III型磷酸二酯酶(PDE III)抑制劑或"Ca2 +
增敏劑"或其醫藥學上可接受之衍生物用於製備降低罹患心臟衰竭之患者之心臟大小的藥物之用途。
靜脈內正性心肌收縮劑在急性心臟衰竭之處理中起重要作用,並常可導致患有擴張型心肌症(DCM)之犬得到短期改善。許多患DCM之犬具有令人非常警惕之預後情況(Monnet等人,1995),尤其是通常經歷很短存活時間之德伯曼犬(Dobermanns)(Calvert等人,1982;Calvert等人,1997)。雖然患DCM之犬之生命研究的次分析(subanalysis)表明彼等接受依那普利(enalapril)治療失敗之犬與安慰劑組相比時間上有了改良(存活時間分別為142.8天對56.5天)(Ettinger等人,1998),但觀察治療作用對患DCM犬之生存時間之影響的研究仍很少。總的看來,在許多試驗揭示儘管口服正性心肌收縮劑對短期血液動力學有益處但是對生存時間具有副作用之後(Packer等人,1991;Cowley及Skene,1994),近年來其在治療慢性心臟衰竭人類患者方面已失去有利地位。近來已經提出鈣增敏劑可導致正性心肌收縮作用而不會產生一些與諸如多巴酚丁胺(dobutamine)、氨力農(amrinone)及米力農(milrinone)之更傳統正性心肌收縮劑相關的副作用(包括鈣超載)。
匹莫苯丹(Pimobendan)係一具有鈣增敏作用及一定第III型磷酸二酯酶抑制作用之強心擴張劑(inodilator)化合物。鈣增敏劑係藉由改變鈣與肌鈣蛋白-C(troponin-C)之結合使得收縮性蛋白對現存胞內鈣敏感達成其正性心肌收縮作用,而非藉由增加進入心肌細胞內之鈣達成該作用。因此藉由鈣增敏作用所產生之正性心肌收縮作用可以避免一些胞內鈣超載所產生之副作用。胞內鈣含量增加與心律不整及猝死趨勢的增加有關。臨床試驗表明,患心臟衰竭之人類患者長期以經口方式服用匹莫苯丹可改善運動耐受性及生活品質,而對存活時間無明顯副作用(Kubo等人,1992;Katz等人,1992)。
已知心臟衰竭之進程與心臟大小之增加有關。在擴張型心肌症(DCM)中,左心室壁厚度與心房直徑之比例是減少的,而二尖瓣及三尖瓣環帶圓周按照心房擴張程度之比例增加。DCM可能主要由諸如基因異常或其次由諸如瓣膜功能不足產生,此二者均導致心容積超載。然而,DCM通常包含心臟重塑作用,該作用可定義為基因表達、分子、細胞及間質的變化,該等變化在臨床上表現為心臟大小、形狀及功能變化。心臟重塑作用通常係不良徵召,且與心臟衰竭之進程相聯繫。逆轉心臟重塑作用係心臟衰竭治療之目的。
心臟衰竭治療傳統上主要集中於症狀緩解而非集中於處理根本之疾病問題。
本發明之根本問題在於提供一種藥物,該藥物可重塑心臟之大小以降低罹患冠心病之患者死亡之危險。詳言之,本發明之根本問題在於提供一種藥物,該藥物可減小心臟之大小以降低罹患心臟衰竭之患者死亡之危險。
已驚人地發現,第III型磷酸二酯酶(PDE III)抑制劑及/或Ca2 +
增敏劑或其醫藥學上可接受之衍生物可用於製備降低罹患心臟衰竭之患者之心臟大小之藥物。
而且,本發明係關於一種降低罹患心臟衰竭之患者之心臟大小的方法,該方法包括投予該患者有效量之PDE III抑制劑或其醫藥學上可接受之衍生物。
此外,本發明係關於一種包含包裝材料之製造物件,其中含有一有效減小罹患心臟衰竭之患者之心臟大小的組合物,且該包裝材料包含一標籤,其指示該組合物可用於降低罹患心臟衰竭之患者之心臟大小,其中該組合物包含至少一種PDE III抑制劑或Ca2 +
增敏劑或其醫藥學上可接受之衍生物。
本發明係關於第III型磷酸二酯酶(PDE III)抑制劑,較佳係PDE III抑制劑、Ca2 +
增敏劑,或額外表現鈣增敏作用(Ca2 +
增敏劑)之PDE III抑制劑,或其醫藥學上可接受之衍生物用於製備降低罹患心臟衰竭之患者之心臟大小的藥物上之用途。
用於上文及下文中之術語"PDE III抑制劑"係關於第III型磷酸二酯酶(PDE)抑制劑,其可避免cAMP分解為5'AMP並因此維持cAMP對蛋白激酶及其他第二訊息活化之作用。
PDE III抑制劑之作用係作為一常規正性心肌收縮劑及血管舒張劑,其可減輕心臟衰竭患者之後負載,使其感覺較好。
術語"Ca2 +
增敏劑"係關於一種能增加心臟收縮性蛋白之Ca2 +
敏感性的化合物,意即在特定Ca2 +
濃度下增加所發展之收縮力。
較佳之PDE III抑制劑或Ca2 +
增敏劑係西絡他唑(cilostazol)、匹莫苯丹(pimobendan)、米力農(milrinone)、左西孟旦(levosimendan)、氨力農(amrinone)、依諾昔酮(enoximone)及匹羅昔酮(piroximone)TZC-5665或其醫藥學上可接受之鹽類、衍生物類、代謝物類或前藥類。最佳為匹莫苯丹及左西孟旦,或其醫藥學上可接受之鹽類、衍生物類、代謝物類或前藥類。甚至更佳為匹莫苯丹及左西孟旦。甚至更佳為匹莫苯丹,其醫藥學上可接受之鹽類、衍生物類、代謝物類或前藥類。
匹莫苯丹即眾所周知之4,5-二氫-6-[2-(4-甲氧苯基)-1H-苯幷咪唑-5-基]-5-甲基-3(2H)-噠酮,例如揭示於歐洲專利第008 391 B1號中。左西孟旦為噠酮-二腈衍生物。詳言之,左西孟旦為眾所周知之(R)-[[4-(1,4,5,6-四氫-4-甲基-6-氧代-3-噠嗪基)苯基]亞肼醯基]丙二腈,並早在例如英國專利第2228004號、美國專利第5,151,420號及美國專利第5,569,657號中已有所表述。
用於上文及下文中之術語"患者"係關於一罹患心臟衰竭之動物或人。術語"患者"包括諸如靈長類之哺乳動物,包括人類。
除了靈長類外,多種其他哺乳動物亦可藉由本發明方法進行治療。例如,可治療下列哺乳動物,包含(但不限於)牛、綿羊、山羊、馬、犬、貓、天竺鼠、大老鼠或其他牛科、綿羊科、馬科、犬科、貓科,齧齒科或鼠科動物。然而,該方法亦可用於諸如鳥類之其他物種身上。
較佳係人類患者、犬、貓及馬。人類患者為罹患心臟衰竭之女性或男性。通常該等人係年齡在6至80歲之間,較佳係30至65歲之間的兒童、青年人、成年人或老年人。
用於上文及下文中之術語"心臟衰竭"係關於任何心臟收縮病症或心臟病。臨床表現通常是心臟細胞及分子成分變化及行使穩態控制之介質變化之結果。心臟衰竭通常伴有心臟大小之增加及心臟功能之退化。
患者所罹患之心臟衰竭主要係慢性充血性心臟衰竭、由於因心跳停止所致心肌梗塞或心肌缺血而產生之心臟衰竭。
用於上文及下文中之術語"降低心臟大小"係關於降低患者之心臟大小,其可藉由James W.Buchanan等人(Buchanan 1995)所建議之射線照片方法判定,並表示為椎骨心臟大小之相對變化。較佳地,在用PDE III抑制劑及/或Ca2 +
增敏劑治療時,該患者之相對平均脊柱心臟總數(vertebral heart sum(VHS))在10至100天內減少了0.05至0.25,詳言之,在約60天內減少了約0.15。
本文所用之術語"有效量"意謂當該PDE III抑制劑及/或Ca2 +
增敏劑以單劑型投予時足以降低心臟大小之量。
該PDE III抑制劑及/或Ca2 +
增敏劑較佳與一第二活性治療劑組合投予。該第二活性治療劑較佳係選自由以下各物組成之群:鈣離子通道阻斷劑、ACE抑制劑、利尿劑、血小板抑制劑、β阻斷劑及血管緊張素II拮抗劑、醛固酮(aldosterone)拮抗劑、洋地黃苷(digitalis glycosides)、抗心律不整劑或利尿劑。詳言之其中鈣離子通道阻斷劑係選自由以下各物組成之群:地而硫卓(diltiazem)、微拉帕米(verapamil)及非洛地平(felodipine)或其醫藥學上可接受之衍生物;及/或其中ACE抑制劑係選自由以下各物組成之群:奧馬曲拉(omapatrilat)、MDL100240、阿拉普利(alacepril)、貝那普利(benazepril)、卡托普利(captopril)、西拉普利(cilazapril)、地拉普利(delapril)、依那普利(enalapril)、依那普拉(enalaprilat)、福辛普利(fosinopril)、福辛普拉(fosinoprilat)、咪達普利(imidapril)、賴諾普利(lisinopril)、培哚普利(perindopril)、喹那普利(quinapril)、雷米普利(ramipril)、雷米普拉(ramiprilat)、醋酸沙拉辛(saralasin acetate)、替莫普利(temocapril)、群多普利(trandolapril)、群多普拉(trandolaprilat)、ceranapril、莫西普利(moexipril)、喹那普拉(quinaprilat)及螺普利(spirapril)或其醫藥學上可接受之衍生物;及/或其中β阻斷劑係選自由以下各物組成之群:比索洛爾(bisoprolol)、卡維地洛(carvediol)、美托洛爾(metoprolol)、普奈洛爾(propranolol)及滴目露(timolol)或其醫藥學上可接受之衍生物,及/或其中血管緊張素II拮抗劑係選自由以下各物組成之群:醋酸沙拉辛、坎地沙坦(candesartan cilexetil)、纈沙坦(valsartan)、坎地沙坦(candesartan)、洛沙坦鉀(losartan potassium)、依普沙坦(eprosartan)、依貝沙坦(irbesartan)、他索沙坦(tasosartan)、泊米沙坦(pomisartan)及替米沙坦(telmisartan)或其醫藥學上可接受之衍生物,及/或其中醛固酮拮抗劑係選自由以下各物組成之群:螺內酯(spironolactone)、依普利酮(eplerenone)、坎利酮(canrenone)、坎利酮鉀或其醫藥學上可接受之衍生物,及/或其中抗心律不整劑係選自由以下各物組成之群:胺碘酮(amiodarone)、betrylium、丙吡胺(disopyramide)、多非利特(dofetilide)、氟尼卡(flecainide)、伊布利特(ibutilide)、美西律(mexiletine)、妥尼卡(tocainide)、普卡因醯胺(procainamide)、普羅帕酮(propafenone)、奎尼丁(quinidine)、索他洛爾(sotalol)或其醫藥學上可接受之衍生物;及/或其中利尿劑係選自由以下各物組成之群:呋喃苯胺酸(furosemide)、托拉塞米(torasemide)、布美他尼(bumetanide)、依他尼酸(etacrynic acid)、阿佐塞米(azosemide)、莫唑胺(muzolimine)、吡咯他尼(piretanide)、曲帕胺(tripamide)、苄氟噻嗪(bendroflumethazide)、氯噻嗪(chlorothiazide)、氫氯噻嗪(hydrochlorothiazide)、氫氟噻嗪(hydroflumethiazide)、甲氯噻嗪(methychlothiazide)、多噻嗪(polythiazide)、三氯甲噻嗪(trichlormethiazide)、氯噻酮(chlorthialidone)、吲噠帕胺(indapamide)、美托拉宗(metolazone)、喹乙唑酮(quinethazone)、依託唑林(etozolin)、氨苯蝶啶(triamteren)、胺氯吡脒(amiloride)或其醫藥學上可接受之衍生物;及/或其中洋地黃苷係選自由以下各物組成之群:地高辛(digoxin)、洋地黃毒苷(digitoxin)、毒毛旋花子苷(g-strophantin)、β-甲基地高辛(β-methyldigoxin)、β-乙醯基地高辛(β-acetyldigoxin)或其醫藥學上可接受之衍生物。最佳將PDE III抑制劑或Ca2 +
增敏劑,尤其為匹莫苯丹或左西孟旦(更佳係匹莫苯丹)與一或多種選自由以下各物組成之群中之藥物一起投予:一或多種ACE抑制劑、一或多種利尿劑及一或多種洋地黃苷。
本發明之化合物可以諸如下列形式之經口劑型投予:錠劑、膠囊劑(各膠囊包含延緩釋放或延時釋放之調配物)、丸劑、散劑、顆粒、酒劑、酊劑、懸浮劑、糖漿及乳劑。該等化合物亦可以靜脈內(大丸劑或輸液)、腹膜內、皮下或肌肉內方式投予,所有方式都使用為一般醫藥學技術者所熟知之劑型。該等化合物可單獨投予,但通常根據投予路徑及標準醫藥學實踐之選擇而與醫藥學載劑一起投予。
本發明中化合物之給藥方式當然視已知因素而變化,諸如特定藥劑成分之藥效特徵及其投予模式及路徑;接受者之物種、年齡、性別、健康狀況、醫療狀況及體重;症狀之性質及程度;當前治療之種類;治療頻率;投予路徑、患者之肝腎功能狀態、欲達到之效果。醫師或獸醫可決定及規定欲預防、逆轉或停止病症進程之所需藥物之有效劑量。
就大體用藥指導而言,當各有效成分(較佳係匹莫苯丹或左西孟旦)用於達到指示的效果時,其日口服劑量範圍為約10μg/kg至10 mg/kg,較佳為0.05 mg/kg至5 mg/kg,尤其為0.1 mg/kg至2 mg/kg。
匹莫苯丹最佳係每天投予約0.1 mg/kg至1.5 mg/kg。
PDE III抑制劑及/或Ca2 +
增敏劑可以單一日劑量投予,或總日劑量每天可以兩次、三次或四次分劑量投予。
PDE III抑制劑及/或Ca2 +
增敏劑可經由局部使用適當鼻腔內媒劑以鼻腔內形式投予,或以經皮路徑使用經皮貼劑投予。當以經皮傳遞系統形式投予時,給藥方式中之劑量的投予當然是持續投予而非間隙投予。
PDE III抑制劑及/或Ca2 +
增敏劑通常與適當之醫藥學稀釋劑、賦型劑或載劑(本文共同稱作醫藥學載劑)混合投予,該等物質係相對於所要投予形式(即經口錠劑、膠囊、酒劑、糖漿及其類似物)而適當選擇,且PDE III抑制劑及/或Ca2 +
增敏劑與習知醫藥學實踐相一致。
例如,對以錠劑或膠囊形式經口投予而言,活性藥物組份可與經口的、無毒性的、醫藥學上可接受之惰性載劑組合,該載劑可為諸如乳糖、澱粉、蔗糖、葡萄糖、甲基纖維素、硬脂酸鎂、磷酸二鈣、硫酸鈣、甘露糖醇、山梨糖醇及其類似物;對以液體形式經口投予而言,經口藥物組份可與任何經口的、無毒性的,醫藥學上可接受之惰性載劑組合,該載劑可為諸如乙醇、甘油、水及其類似物。而且,必要時或必需時,亦可將適當之黏合劑、潤滑劑、崩解劑及著色劑一起加入該混合物中。適當之黏合劑包括澱粉、明膠、諸如葡萄糖或β-乳糖之天然糖類、玉米甜味劑、諸如阿拉伯樹膠、黃芪膠之天然及合成膠,或海藻酸鈉、羥甲基纖維素、聚乙二醇、石蠟及其類似物。該等劑型中所用之潤滑劑包括油酸鈉、硬脂酸鈉、硬脂酸鎂、苯甲酸鈉、醋酸鈉、氯化鈉及其類似物。崩解劑包括(但不限於)澱粉、甲基纖維素、瓊脂、膨潤土、黃原膠及其類似物。
PDE III抑制劑及/或Ca2 +
增敏劑亦可以脂質體傳遞系統形式投予,諸如單層小微脂粒、單層大微脂粒、多層微脂粒。亦可自諸如膽固醇、硬脂胺(stearylamine)或磷脂醯膽鹼之多種膦脂形成脂質體。
PDE III抑制劑及/或Ca2 +
增敏劑亦可與作為靶向藥物載劑之可溶性聚合物偶合。該等聚合物可包括聚乙烯基吡咯啶酮、哌喃共聚物、聚羥丙基甲基丙烯醯胺-苯酚、聚羥乙基門冬醯胺苯酚(polyhydroxyethylaspart-amidephenol)或經棕櫚醯殘基取代之聚氧化乙烯聚離胺酸。
此外,PDE III抑制劑及/或Ca2 +
增敏劑可與一類用於達成控制藥物釋放作用之可生物降解聚合體偶合,例如,聚乳酸、聚乙醇酸、聚乳酸與聚乙醇酸之共聚物、聚ε-己內酯、聚羥基丁酸、聚原酸酯、聚縮醛、聚二氫哌喃、聚氰基丙烯酸酯(polycyanoacylates)及水凝膠之交聯或兩性嵌段共聚物。
適於投予之劑型(醫藥組合物)每劑量單位可含有約1 mg至約100 mg之活性成分。
在該等醫藥組合物中,活性成分通常存在含量以組合物之總重量計約0.5-95%重量比。
明膠膠囊可含有活性成分及粉狀載劑,諸如乳糖、澱粉、纖維素衍生物、硬脂酸鎂、硬脂酸及其類似物。可使用類似稀釋劑以用於製備壓縮錠劑。錠劑與膠囊二者均作為延緩釋放產物製造以在數個小時期間內提供藥物之持續釋放。壓縮錠劑可塗覆糖衣或膜衣以掩蓋任何不愉快之氣味且保護錠劑不與大氣接觸,或塗覆腸衣以選擇性地在胃腸道中崩解。
經口投予之液體劑型可含有著色劑及調味劑以增加患者之接受性。
一般來講,水、適當之油、鹽水、水性右旋糖(葡萄糖)及相關糖溶液及乙二醇(諸如丙二醇或聚乙二醇)係用於非經腸溶液之適當載劑。非經腸投予之溶液較佳含有活性成分之水溶性鹽、適當穩定劑,及必要時之緩衝物質。諸如亞硫酸氫鈉、亞硫酸鈉或抗壞血酸之抗氧化劑係適當之穩定劑,其可單獨使用或組合使用。亦可用檸檬酸及其鹽及EDTA鈉。此外,非經腸溶液可含有防腐劑,諸如氯苄烷銨、對羥基苯甲酸甲酯或對羥基苯甲酸丙酯及氯丁醇。
適當之醫藥學載劑係如Reminqton's Pharmaceutical Sciences,Mack Publishing Company(此領域中之標準參考文章)中所述。
當兩種或兩種以上前述第二治療劑與PDE III抑制劑及/或Ca2 +
增敏劑一起投予時,鑒於治療劑組合投子時之累加效應或協同效應,典型日劑量及典型劑型中之各組份量通常相對於藥劑單獨投予時之常用劑量減少。
尤其是當作為單一劑量單位投子時,在經組合活性成分之間存在潛在的化學相互作用。因此,當式1之組合物與第二治療劑以單一劑量單位組合時,係如此調配,使得雖然活性成分以單一劑量單位組合,但該等活性成分之間的體接觸減至最小(即減少)。例如,可將一種活性成分塗覆腸衣。藉由腸衣塗覆活性成分中之一種,不僅可使得經組合活性成分之間的體接觸減至最小,亦可在胃腸道中控制該等組份中之一種的釋放,以使該等組份中之一種不在胃中釋放而是在腸中釋放。活性成分中之一種亦可塗覆有一材料,其作用為延緩在胃腸道內之釋放並且亦可使經組合活性成分之間的體接觸減至最小。
此外,延緩釋放之組合物可額外經腸衣塗覆,以使該組份之釋放僅發生在腸道。還有另一個方法涉及調配組合產物,其中一種組份塗覆有延緩釋放及/或腸衣釋放之聚合物,而另一種組份亦塗覆有諸如低黏度等級之羥丙基甲基纖維素(HPMC)的聚合物或此項技術中已知的其他適當材料,以更進一步分離開該等活性組份。聚合物塗層可形成一額外屏障以與其他組份相互作用。
以實例說明之製備根據本發明之組合物的程式在下文中將會更詳細表述。以下實例僅作為詳細說明,並非限制本發明之主題。
實例1
為評估長期功效及對匹莫苯丹之耐受性及其對患DCM之可卡犬(cocker spaniels)及德伯曼犬長期生存時間之影響,進行雙盲試驗。
材料及方法:經主人同意,招募因患DCM出現在R(D)SVS心肺科之可卡犬(n=10)及德伯曼犬(n=10)用於研究。在用地高辛、依那普利及呋喃苯胺酸習知治療穩定後,使用雙盲研究設計,該等犬另外接受匹莫苯丹(Vetmedin)或安慰劑中之一種。
結果:相對於安慰劑組可卡犬平均存活時間為589天(自51天至1127天範圍),匹莫苯丹組可卡犬平均存活時間為612天(自61天至1428天範圍)。差異無統計學上顯著性(Wilcoxon-Mann-Whitney-U檢定,p>0.05)。
相對於安慰劑組德伯曼犬平均存活時間為72天(自13天至196天範圍),匹莫苯丹組德伯曼犬平均存活時間為280天(自42天至369天範圍)。差異具有統計學上顯著性不同(司徒登特t-檢定,p<0.05)。該藥具有良好耐受性且在任一品種犬上未見與治療相關之副作用。
結論:
與安慰劑組相比,匹莫苯丹能顯著改良罹患DCM之德伯曼犬之生存時間,但對可卡犬生存時間無統計學上顯著影響。改良德伯曼犬之存活時間在疾病處理上是一個重大進展,因為該疾病在診斷後通常導致急速死亡。
在兩個品種犬中,在標準治療方式中加入匹莫苯丹可顯著改良患者NYHA分級狀況。因此匹莫苯丹療法之益處與呋喃苯胺酸、依那普利及地高辛之有益作用係累加的,且可在可卡犬上觀察到,與許多患DCM之犬相比,曾認為用習知療法可使該等可卡犬具有有益之臨床過程(Monnet等人,1995)。
在用匹莫苯丹治療之德伯曼犬(Doberman pinscher)上可發現存活時間具有顯著差異。雖然已知該品種犬在有充血症狀發展後有不良預後情況,但用匹莫苯丹治療之動物可見存活時間顯著延長。
實例2
為評價匹莫苯丹治療(日劑量為0.4-0.6毫克/公斤)與血管緊張素轉換酶(ACE)抑制劑治療(鹽酸貝那普利日劑量為約0.25-0.5毫克/公斤身體重量)相比之臨床功效,進行雙盲、隨機、正控制之多中心域試驗。兩種治療均可適當組合呋喃苯胺酸(多達每天8毫克/公斤)或抗心律不整藥物。該研究在藥品優良臨床試驗規範(Good Clinical Practice(GCP))之準則下,由經驗豐富之獸醫心臟病專家在歐洲十一個研究中心進行。對每一個患者治療之強制最短期限為56天。該等犬在首次治療前第0天及開始治療後第7天及第56天進行檢查。為獲取長期存活時間資料,研究者可選擇在56天後繼續進行治療。在可選研究期間,由於不允許在貝那普利組中加入匹莫苯丹,為了維持適當匹莫苯丹對照組,可解開動物治療編碼。可允許進行所有其他得到許可之伴隨療法。就存活時間分析而言,剔除之動物或因治療失敗而改變療法之動物亦列入死亡。然而,該等狀況在統計學上作為經審查資料來評價。
功效結論之主要參數為心臟衰竭症狀之臨床嚴重程度,根據國際小動物心臟健康協會(ISACHC)之規則進行分類。次要參數為運動耐受性、行為、呼吸及循環系統之研究結果、整體功效等級及心臟超音波資料。
總共包括76隻犬,匹莫苯丹組中41隻及貝那普利組35隻。所有犬臨床上表現出因瓣膜關閉不全而導致心臟衰竭之明顯症狀。在包括之前,匹莫苯丹組中症狀的平均持續時間為4.05個月,貝那普利組中則為2.77個月。在開始治療前,兩組之間無任何所研究之參數的臨床相關性差異。
依據ISACHC心臟衰竭分類標準,在56天治療週期後,匹莫苯丹治療組主要參數改良84%,貝那普利治療組僅改良56%。在此時間點,ISACHC分類之Ib(評分為2),即無臨床症狀者,在匹莫苯丹組中報導76%,而在貝那普利組僅報導48%。兩組關於主要參數之差異在統計學上顯著有利於匹莫苯丹組,表現在第7天(p=0.0280)及第56天(p=0.0201)。結果,在匹莫苯丹組中有85%整體功效評價列入"非常好"或"好",但在貝那普利組中僅41%(p<0.0001)。其他次要參數結果與心臟衰竭分類標準之臨床結果一致。
在56天研究期間,匹莫苯丹組中2隻犬及貝那普利組中7隻犬死亡或因心臟原因處安樂死。根據Kaplan-Meier法對存活時間分析揭示顯著差異有利於匹莫苯丹組(p=0.0386)。長期存活資料之分析證實了56天研究期間之結果。經匹莫苯丹治療之犬的中值存活時間為430天,而未接受匹莫苯丹治療之犬為228天。此外,根據Kaplan-Meier法對存活時間分析揭示顯著差異有利於匹莫苯丹組(p=0.0020)。
拍攝從左至右側視之射線照片。用椎骨衡量系統(vertebral scale system)測定心臟大小。
在側面射線照片中,心臟之長軸(L)用兩腳規量測,該兩腳規自左主幹支氣管(氣管分歧門,龍骨)之腹面延伸至左心室頂端之最遠端周線。兩腳規沿脊柱重新定位,開始於第四胸椎之顱邊緣處。將心臟長度記錄為彼點尾端之椎骨數目,且估計到椎骨之最近0.1。最大垂直短軸(S)可用同樣方式在第四胸椎處開始量測。
然後將椎骨(v)長軸及短軸之長度相加以獲得椎骨心臟總數(VHS),其可提供一單數目,其代表與犬大小成比例之心臟大小。對健康犬而言,VHS之正常範圍係自8.5 v至10.5 v(平均為9.7 v)。
在匹莫苯丹組犬中,第0天及第56天射線照片上所量測之平均椎骨心臟總數顯示出改良。關於自基線值之變化,平均值之差異指示經匹莫苯丹治療之犬平均心臟大小之降低。兩組犬之間關於整體臨床功效之平均差異在統計學上顯著有利於匹莫苯丹治療組(p<0.0001)。見表1。貝那普利對照組平均得分顯示相對於自基線值之變化的惡化(圖7)。此證明心臟大小之降低通常不能在因瓣膜關閉不全而致心臟衰竭之犬身上用標準療法達成。在標準療法(ACE抑制劑+/-利尿劑)(平均心臟大小惡化0.22 v)及匹莫苯丹治療(平均大小改良-0.15 v)之間的驚人差異是意想不到的,並因而具有創造性。
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圖1顯示罹患擴張型心肌症之英國可卡犬之側面胸部射線照片,顯示肺泡水腫及心臟增大。
圖2a及2b顯示圖1中之同一犬在用呋喃苯胺酸、依那普利、地高辛及匹莫苯丹治療四個月後之胸部射線照片。
圖3顯示用匹莫苯丹(每一左側黑色柱)或貝那普利(每一右側灰色柱)治療之犬在第0、7及56天之心功能不足評分(ISACHC)。
圖4顯示用匹莫苯丹(左側黑色柱)或貝那普利(右側灰色柱)治療之犬在第56天時之整體臨床效果。
圖5顯示用匹莫苯丹(上部-○-曲線)或貝那普利(下部-□-曲線)治療之犬之存活函數(56天治療期間)。
圖6顯示用匹莫苯丹(430天期間/上部-○-曲線)或貝那普利(228天期間/下部-□-曲線)治療之犬之存活函數。
圖7顯示相對於經貝那普利治療之犬(+0.22 v)經匹莫苯丹治療之犬平均心臟大小減少(-0.15 v)的曲線。
Claims (10)
- 一種匹莫苯丹(pimobendan)之用途,其係用於製備降低罹患心臟衰竭之患者之心臟大小的藥物。
- 如請求項1之用途,其中匹莫苯丹係以經口方式或非經腸方式應用。
- 如請求項1或2之用途,其中匹莫苯丹係投用10微克/公斤至10毫克/公斤之日劑量。
- 如請求項1或2之用途,其中匹莫苯丹係與一選自由以下各物組成之群之藥物一起投予:鈣離子通道阻斷劑、ACE抑制劑、利尿劑、阿司匹林、β-阻斷劑及血管緊張素II拮抗劑。
- 如請求項1或2之用途,其中該ACE抑制劑係選自由以下各物組成之群:奧馬曲拉(omapatrilat)、MDL100240、阿拉普利(alacepril)、貝那普利(benazepril)、卡托普利(captopril)、西拉普利(cilazapril)、地拉普利(delapril)、依那普利(enalapril)、依那普拉(enalaprilat)、福辛普利(fosinopril)、福辛普拉(fosinoprilat)、咪達普利(imidapril)、賴諾普利(lisinopril)、培哚普利(perindopril)、喹那普利(quinapril)、雷米普利(ramipril)、雷米普拉(ramiprilat)、醋酸沙拉辛(saralasin acetate)、替莫普利(temocapril)、群多普利(trandolapril)、群多普拉(trandolaprilat)、ceranapril、莫西普利(moexipril)、喹那普拉(quinaprilat)及螺普利(spirapril)。
- 如請求項1或2之用途,其中該血管緊張素II拮抗劑係選自由以下各物組成之群:醋酸沙拉辛(saralasin acetate)、坎 地沙坦(candesartan cilexetil)、纈沙坦(valsartan)、坎地沙坦(candesartan)、洛沙坦鉀(losartan potassium)、依普沙坦(eprosartan)、依貝沙坦(irbesartan)、他索沙坦(tasosartan)及替米沙坦(telmisartan)。
- 如請求項1或2之用途,其中匹莫苯丹係與一或多種選自由以下各物組成之群之藥物一起投予:一或多種ACE抑制劑、一或多種利尿劑及一或多種洋地黃苷(digitalis glycosides)。
- 如請求項1或2之用途,其中該患者之相對平均椎骨心臟總數(vertebral heart sum;VHS)經以匹莫苯丹治療10至100天內降低了0.05至0.25。
- 如請求項1或2之用途,其中該心臟衰竭係慢性充血性心臟衰竭、由於因絞痛惡化或心跳停止所致心肌梗塞或心肌缺血而產生之心臟衰竭。
- 如請求項1或2之用途,其中該患者係一選自由以下各物組成之群之哺乳動物:包括人類之靈長類、犬、貓及馬。
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2004
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- 2005-03-19 WO PCT/EP2005/002957 patent/WO2005092343A1/en active Application Filing
- 2005-03-19 BR BRPI0509086-5A patent/BRPI0509086A/pt not_active Application Discontinuation
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- 2005-03-23 AR ARP050101138A patent/AR048588A1/es active Pending
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