CN107334770A - 治疗脂质代谢紊乱的组合物及其方法 - Google Patents
治疗脂质代谢紊乱的组合物及其方法 Download PDFInfo
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- CN107334770A CN107334770A CN201710291105.0A CN201710291105A CN107334770A CN 107334770 A CN107334770 A CN 107334770A CN 201710291105 A CN201710291105 A CN 201710291105A CN 107334770 A CN107334770 A CN 107334770A
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Abstract
本发明提供一种用于抑制温血动物脂质代谢紊乱的方法。所述方法包括对罹患脂质代谢紊乱的温血动物给予包含磷酸二酯酶类型5抑制剂与他汀类(Statin)类似物的药物组合物。
Description
技术领域
本发明关于一种包含磷酸二酯酶类型5抑制剂与他汀类(Statin)类似物的药物组合物,以用于抑制温血动物脂质代谢紊乱。尤其,本发明关于包含第一类或第二类磷酸二酯酶类型5抑制剂与Statin类似物的搭配以及混合的药物组合物,以发挥疗效。
背景技术
KMUP-1化合物已被证实可经由增强内皮型一氧化氮合酶(endothelial nitricoxide synthase,eNOS)/环鸟嘌呤苷单磷酸盐(guanosine 3',5'-cyclic monophosphate,cGMP)途径,包括增加可溶性鸟苷酸环化酶α1(soluble guanylyl cyclaseα1,GCα1)和蛋白激酶G(protein kinase G,PKG)的表现,呈现放松血管和气道平滑肌肉收缩。
本发明发明人于《脂质代谢期刊(J.Lipid Res.)》2015年第56卷第11期第2070-2084页报导的KMUP-1和Das A等人于《药理学及治疗学(Pharmacol.Ther.)》2015年第147期第12-21页报导的西地那非(Sildenafil)均证实可增加cGMP/PKG脂质代谢,所述等化合物为磷酸二酯酶类型5(phosphodiesterase type 5,PDE-5)抑制剂,但其对于肥胖的影响情况未明确。增加cGMP可以扩大和降低白色脂肪组织,其与内脏附睾脂肪垫不同。事实上,eNOS和激素敏感性脂肪酶(hormone-sensitive lipase,HSL)在肥胖病症与减少皮下脂肪组织的脂肪分解有关;而抑制NOS导致白色组织内脂肪分解的增加,且增加一氧化氮(NO)可抑制脂肪的分解。
发明内容
发明人鉴于习知技术尚呈现所不完备处,经过悉心试验与研究,并一本锲而不舍的精神,终构思出本案「治疗脂质代谢紊乱的组合物及其方法」,能够克服先前技术的不足,以下为本案的简要说明。
根据本发明的一个构想,本发明揭示一种治疗脂质代谢紊乱的方法。所述方法包括步骤:投予足供疗效用量的活性剂药物组合物于脂质代谢紊乱的温血动物,其是选自磷酸二酯酶类型5抑制剂与Statin类似物所组成的药物组合物。上述疾病,包括非酒精性脂肪肝、过度肥胖(hyperadiposity)、血脂异常症(dyslipidemia)、肝脏脂肪变性(hepaticsteaotosis)、高脂肪食品诱发肝脏脂质蓄积、高脂肪食品诱发肥胖、胰岛素抗性、高脂肪食品诱发脂质蓄积(lipid accumulation)并发炎症和肝脏损伤的后续症候其组合。
根据本发明的另一个构想,本发明揭示一种药物组合物。所述药物组合物为磷酸二酯酶类型5抑制剂或与其药学上可接受载体,与Statin类似物或与其药学上可接受载体所组成的药物组合物。
根据本发明的其他构想,本发明揭示一种投予足供疗效用量的磷酸二酯酶类型5抑制剂及Statin类似物活性剂于温血动物,以治疗疾病的组合投药(combinedadministration)方法。
不同的磷酸二酯酶(phosphodiesterase,PDE)家族依据调控细胞内环-3',5'-磷酸腺苷(cyclic-3’,5’-adenosine monophosphate,cAMP)和环-3',5'-磷酸鸟嘌呤(cyclic-3’,5-guanosine monophosphate,cGMP)第二讯息含量的关键作用而呈现细胞功能。目前至少有11种或是12种次家族已被确认可水解cAMP、cGMP或两者。
一些研究指出,增加环-3',5'-磷酸鸟嘌呤(cGMP)的讯号可能是减少糖尿病恶化多个途径的重要方式。在血糖的控制上,即使以增加细胞内钙离子作为活化胰岛素胞吐作用(exocytosis)的主要讯号,cGMP也可经由显著的讯号和增效葡萄糖的刺激而有所参与。
一些体外研究同时显示,cGMP可经由刺激葡萄糖转运蛋白4(Glucosetransporter type 4,GLUT4)补充到细胞膜,以提高肌肉和脂肪细胞的目标器官的胰岛素敏感性。此外,因为NO/cGMP为基本的血管保护讯号,此途径的增量可为受人瞩目的方式来减低糖尿病慢性并发症的血管内皮功能的障碍,亦即减轻糖尿病患者造成残疾和死亡的主要成因。
增加cGMP讯号的药理方式可经由两条主要途径来达成:(1)直接藉由NO的增加而直接活化鸟苷酸环化酶;及/或(2)经由PDE5抑制剂而降低环磷酸鸟苷水解,此已被认为是治疗糖尿病患内皮功能障碍的一个重要工具。
磷酸二酯酶5(PDE5)可作用于心脏、肺脏、胰脏、阴茎等组织,且对环磷酸鸟苷(cGMP)呈现特定的水解作用。在脂肪细胞,环磷酸鸟苷经由活化cGMP依赖的蛋白激酶G(cGMP-dependent protein kinase G,PKG)调控关键性功能。因此,保持其生理健康至关重要,以避免局部及全身疾病。文献的实验结果显示,一氧化氮(NO)/环-3',5'-磷酸鸟嘌呤(cGMP)/蛋白激酶G(PKG)讯号转导途径在脂肪细胞生物学的重要性。磷酸二酯酶5(PDE5)担负着cGMP失活,而其抑制剂更可加强脂肪组织的平衡。
例如3-异丁基-1-甲基黄嘌呤、咖啡因、茶碱和可可豆碱等黄嘌呤衍生物为已知非选择性磷酸二酯酶(PDE)异构体。最近一些PDE5抑制剂被证实可影响脂肪的分化和芳香化酶的功能。作为本发明活性剂,具疗效表现力的PDE5抑制剂可根据其结构的相似性包括下列两种类型:第一类为哌嗪类似物和哌嗪基复合类似物,第二类为含杂环衍生物(例如,吡咯烷基、嘌呤、喹唑啉、吡啶基)及含氮杂环的稠合衍生物(例如,嘧啶并嘧啶(pyrimido-pyrimidin)、吡嗪并吡啶吲哚(pyrazino-pyrido-indole)、三唑嘧啶(triazolo-pyrimidin)和糖苷类衍生物)。
在具体的实施例中,本文用语「第二类PDE5抑制剂」包括但并非限于阿伐那非(Avanafil)、Benzamidenafil、Dasantafil、双嘧达莫(Dipyridamole)、E4021、淫羊藿苷(Icariin)、Rolipram、Piclamilast、他达拉非(Tadalafil)、苯氮嘌呤酮(Zaprinast)的组成。阿伐那非(Avanafil)化合物的化学名为4-[(3-氯基-4-甲氧基苯)氨基]-2-[(2S)-2-(羟甲基)-1-吡咯烷基]-N-(2-嘧啶基甲基)-5-嘧啶甲酰胺(4-[(3-chloro-4-methoxyphenyl)amino]-2-[(2S)-2-(hydroxymethyl)-1-pyrrolidinyl]-N-(2-pyrimidinyl-methyl)-5-pyrimidincarboxamide)。Benzamidenafil化合物的化学名为N-(3,4-二甲氧基苄基)-2-((2-羟基-1-甲基乙基)氨基)-5-硝基苯甲酰胺(N-(3,4-dimethoxybenzyl)-2-((2-hydroxy-1-methylethyl)amino)-5-nitrobenzamide)。Dasantafil化合物的化学名为7-[(3-溴基-4-甲氧基苯)甲基]-1-乙基-8-[(2-羟基环戊基)氨基]-3-(2-羟乙基)嘌呤-2,6-二酮(7-[(3-bromo-4-methoxyphenyl)methyl]-1-ethyl-8-[(2-hydroxycyclopentyl)amino]-3-(2-hydroxyethyl)purine-2,6-dione)。双嘧达莫(Dipyridamole)化合物的化学名为2-[[2-[双(2-羟基乙基)氨基]-4,8-二(哌啶-1-基)嘧啶并[5,4-d]嘧啶-6-基]-(2-羟基乙基)氨基]乙醇(2-[[2-[bis(2-hydroxyethyl)amino]-4,8-di(piperidin-1-yl)pyrimido[5,4-d]pyrimidin-6-yl]-(2-hydroxyethyl)amino]ethanol)。E4021化合物的化学名为1-[4-(1,3-苯并二氧戊环-5-甲基)氨基)-6-氯喹唑啉-2-基]哌啶-4-甲酸钠(sodium;1-[4-(1,3-benzodioxol-5-ylmethylamino)-6-chloroquinazolin-2-yl]piperidine-4-carboxylate)。淫羊藿苷(Icariin)化合物的化学名为3,5,7-三羟基-4'-甲氧基-8-异戊烯基黄酮-3-0-α-L-吡喃鼠李糖-7-0-β-D-吡喃葡萄糖苷(3,5,7-threehydroxy-4'-methoxy-8-prenyl flavonoids-3-0-α-L-topiramateNomrhamnose-7-0-D-gluco-pyranoside)。Rolipram化合物的化学名为4-[3-(环戊基氧基)-4-甲氧基苯基]-2-吡咯烷酮(4-[3-(Cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidinone)。Piclamilast化合物的化学名为3-(环戊基氧基)-N-(3,5-二氯吡啶-4-基)-4-甲氧基苯甲酰胺(3-(cyclopentyloxy)-N-(3,5-dichloro-pyridin-4-yl)-4-methoxybenzamide)。他达拉非(Tadalafil)化合物的化学名为(6R-反式)-6-(1,3-苯并二氧戊环-5-基)-2-甲基-2,3,6,7,12,12a-六氢吡嗪并[1',2'-1,6]-吡啶并[3,4-b]吲哚-1,4-二酮((6R-trans)-6-(1,3-benzo-dioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexa-hydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione)。苯氮嘌呤酮(zaprinast)化合物的化学名为5-(2-丙氧基苯)-2,3-二氢三唑[4,5-d]嘧啶-7-酮(5-(2-propoxyphenyl)-2,3-dihydrotriazolo[4,5-d]pyrimidin-7-one)。
根据本发明的一个构想,哌嗪基类似物和哌嗪基复合类似物为第一类PDE5抑制剂,哌嗪基类似物和哌嗪基复合类似物均可分别再区分为两次类,其中一次类为哌嗪基类似物(Piperazinyl Analogue),包括KMUPs衍生物和西地那非(Sildenafil)类似物,而另一次类为哌嗪基复合类似物(Piperazinyl Complex Analogue),包括KMUPs衍生物复合物和西地那非类似物复合物。KMUPs衍生物复合物如通式KMUPs-RX(I)或是KMUPs-RX-RX(II)所示,西地那非类似物复合物也如通式西地那非类似物-RX(IV,V)所示。而RX为羧酸基团提供者,与KMUPs衍生物(III)或是西地那非类似物(VI)的活性剂相结合,可形成KMUPs衍生物复合物或西地那非类似物复合物。
在优选的实施例,结构式I和结构式II皆可代表KMUPs衍生物复合物,其中结合一分子的RX基团形成的单量体KMUPs-RX复合物(式I),而双量体KMUPs-RX-RX结构(式II)为结合两分子的RX基团。KMUPs衍生物(式III)化学结构的R2和R4取代基为各自独立地选自C1-C5烷氧基、氢原子、硝基和卤素原子所组成的群组。上述卤素是指氟原子、氯原子、溴原子和碘原子。
用语「KMUPs衍生物」是指选自KMUP-1、KMUP-2、KMUP-3、KMUP-4及其药学可接受的盐类所组成的群组。在优选的实施例中,更包括至少一个药学上可接受的载体和辅料的药物组合物。
本发明所揭示优选的KMUPs衍生物,其中KMUP-1的R2为氯原子且R4为氢原子,其一般化学名为7-[2-[4-(2-氯苯)哌嗪基]乙基]-1,3-二甲基黄嘌呤(7-[2-[4-(2-chlorophenyl)piperazinyl]ethyl]-1,3-dimethyl xanthine)。KMUP-2的一般化学名为7-[2-[4-(2-甲氧基苯基)哌嗪基]乙基]-1,3-二甲基黄嘌呤(7-[2-[4-(2-methoxyphenyl)piperazinyl]ethyl]-1,3-dimethyl xanthine),其中R2为甲氧基且R4为氢原子基团。KMUP-3的一般化学名为7-[2-[4-(4-硝基苯基)哌嗪基]乙基]-1,3-二甲基黄嘌呤(7-[2-[4-(4-nitrophenyl)piperazinyl]ethyl]-1,3-dimethyl xanthine),其中R2为氢原子且R4为硝基基团。KMUP-4的R2为硝基且R4为氢原子基团,其一般化学名为7-[2-[4-(2-硝基苯基)哌嗪基]乙基]-1,3-二甲基黄嘌呤(7-[2-[4-(2-nitrophenyl)piperazinyl]ethyl]-1,3-dimethyl xanthine)。
于具体的实施例中,本文用语「RX基团」是指选自D-抗坏血酸(D-ascorbic acid)、L-抗坏血酸(L-ascorbic acid)、DL-抗坏血酸(DL-ascorbic acid)、油酸(oleic acid)、磷酸(phosphoric acid)、柠檬酸(citric acid)、烟碱酸(nicotinic acid)、羧甲基纤维素钠(sodium carboxyl methylcellulose,sodium CMC)、玻尿酸(hyaluronic acid)、聚丙烯酸(polyacrylic acid,PAA)、聚甲基丙烯酸甲酯(polymethylmethacrylates,PMMA)、丙烯酸树脂(Eudragit)、葡聚糖硫酸(dextran sulfate)、硫酸乙酰肝素(heparan sulfate)、聚乳酸或聚乳酸酯(polylactide,PLA)、聚乳酸钠、聚羟基磺酸钠(polyglycolic acid sodium,PGCA sodium)、聚-γ-聚麸胺酸钠(sodiumγ-polyglutamate,poly-γ-polyglutamicacid sodium,γ-PGA sodium)、γ-聚麸胺酸、海藻酸钠-聚-l-离胺酸-海藻酸钠(alginate-poly-l-lysine-alginate,APA)和聚γ-聚麸胺酸衍生物(poly-γ-polyglutamic acid derivative)的群组其中之一。
在具体的实施例中,KMUP-1、KMUP-2、KMUP-3和KMUP-4的药学上可接受的盐类包括但非限于柠檬酸酸、烟碱酸和盐酸。另一方面,除已发现的西地那非类似物化合物,所述类似物的盐类也不限于柠檬酸盐、二钠盐和盐酸盐。
根据本发明的一个构想,用语「西地那非类似物化合物」具有杂环化学结构。西地那非类似物的化学结构如通式VI所示,其RB取代基包括但非限于被取代的杂环基团,例如吡唑并嘧啶(pyrazolopyrimidinone)基团、吡嗪并吡啶吲哚(pyrazinopyridoindole)基团、咪唑三嗪酮(imidazotriazinone)基团、吡咯啶(pyrrolidin)基团。杂环主链上的六元环通常有一个氧原子或硫原子与环的碳形成双键连接、氧基-噻唑-N-甲基亚硝胺(oxyl-thiazol-N-methylnitrous amide)的氧原子与环的碳形成单键连接。RS取代基依据结构式分别结合磺酰苯基团或乙酰苯基团。R3取代基包括烷基,而R7取代基包括未取代与被取代的六氢吡啶(piperidine)基团、被取代吡咯烷(pyrrolidin)基团、氢原子、N-alkyl含氮烷基、烷氧基、醇基。
西地那非类似物化合物已获美国食品和药物管理局(美国FDA)、中国、欧洲、澳大利亚、英国、加拿大以及日本等制药、医疗和健康相关的政府机构所核准,可用于人类治疗药物。
许多西地那非类似物已被开发。因此,用语「西地那非类似物」包括但非限于下列化合物:Acetidenafil、Aildenafil、Avanafil、Benzyl-Sildenafil、Carbodenafil、Cinnamyldenafil、Cyclopenylnafil、Descarbon-Sildenafil、N-Desmethyl-Sildenafil、Desmethyl Carbodenafil、Dimethyl-Acetidenafil、Dioxy-Acetidenafil、Dithiodesmethyl Carbodenafil、Gendenafil、Gisadenafil、Hydroxy-Acetidenafil、Hydroxy Chlorodenafil、Hydroxyhomo-Sildenafil、Hydroxythiohomo-Sildenafil、Homo-Sildenafil、Isopiperazinonafil、Lodenafil Carbonate、Mirodenafil、Nitrodenafil、Nor-Acetidenafil、Normeo-Sildenafil、Piperildino-Acetidenafil、Piperazinonafil、Propoxyphentyl-Aildenafil、Propoxyphentyl-Sildenafil、SulfohomoSildenafil、Propoxyphentylthio-Aildenafil、ThioAildenafil、ThioSildenafil、Udenafil及Vardenafil。此处揭示西地那非类似物包括但非限于不含盐类的化合物、或含药学上可接受的盐类、化合物的溶剂、或化合物的前药。
在优选的实施例中,本文所叙述用语「西地那非类似物」包括但并非限于Acetidenafil、Avanafil、DesmethylSildenafil、Gisadenafil、HomoSildenafil、HydroxyhomoSildenafil、Mirodenafil、Lodenafil Carbonate、西地那非(Sildenafil)、Udenafil和伐地那非(Vardenafil)的组成化合物。Acetidenafil化合物的化学名为5-{2-乙氧基-5-[2-(4-乙基哌嗪-1-基)-乙酰基]苯基}-1-甲基-3-丙基-4氢-吡唑并[4,3-d]嘧啶-7-酮(5-{2-ethoxy-5-[2-(4-ethylpiperazin-1-yl)acetyl]phenyl}-1-methyl-3-propyl-4H-pyrazolo[4,3-d]pyrimidin-7-one)。Avanafil化合物的化学名为4-[(3-氯基-4-甲氧基苯基)甲基胺基]-2-[(2S)-2-(羟甲基)吡咯-1-基]-N-(2-嘧啶-2-基甲基)-5-嘧啶甲酰胺(4-[(3-Chloro-4-methoxyphenyl)methylamino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide)。Desmethylsildenafil化合物的化学名为5-[2-乙氧基-5-哌啶-1-基磺酰苯基]-1-甲基-3-丙基-4氢-吡唑并[4,3d]嘧啶-7-酮(5-[2-ethoxy-5-piperazin-1-ylsulfonylphenyl]-1-methyl-3-propyl-4H-pyrazolo[4,3-d]pyrimidin-7-one)。Gisadenafil化合物的化学名为5-[2-乙氧基-5-(4-乙基哌啶-1-基)磺酰吡啶-3-基]-3-乙基-2-(2-甲氧基乙基)-4氢-吡唑并[4,3-d]嘧啶-7-酮(5-[2-Ethoxy-5-(4-ethylpiperazin-1-yl)sulfonyl-pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-4H-pyrazolo[4,3-d]pyrimidin-7-one)。HomoSildenafil化合物的化学名为5-[2-乙氧基-5-(4-乙基哌嗪-1基)磺酰苯基]-3-丙基-4H-吡唑并[4,3-d]嘧啶-7-酮(5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylphenyl]-1-methyl-3-propyl-4H-pyrazolo[4,3-d]pyrimidin-7-one)。Hydroxyhomo-Sildenafil化合物的化学名为5-[2-乙氧基-5-[4-(2-羟基乙基)哌啶-1-基]磺酰苯基]-1-甲基-3-丙基-4氢-吡唑并[4,3d]嘧啶-7-酮(5-[2-ethoxy-5-[4-(2-hydroxyethyl)piperazin-1-yl]sulfonylphenyl]-1-methyl-3-propyl-4H-pyrazolo[4,3-d]pyrimidin-7-one)。Mirodenafil化合物的化学名为5-乙基-2-(5-{[4-(2-羟乙基)哌啶-1-基]磺酰)-2-丙氧基苯基]-7-丙基-1氢-吡唑并[3,2-d]嘧啶-4-酮(5-Ethyl-2-{5-[4-(2-hydroxyethyl)piperazin-1-yl]sulfonyl-2-propoxyphenyl}-7-propyl-1H-pyrrolo[3,2-d]pyrimidin-4-one)。Lodenafil Carbonate化合物的化学名为双[2-[4-[4-乙氧基-3-(1-甲基-7-氧基-3-丙基-4氢-吡唑并[4,3-d]嘧啶-5-基)苯基]磺酰]-1-基]乙基]碳酸酯(bis[2-[4-[4-ethoxy-3-(1-methyl-7-oxo-3-propyl-4H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl]sulfonyl-piperazin-1-yl]ethyl]Carbonate)。西地那非化合物的化学名为5-[2-乙氧基-5-(4-甲基哌啶-1-基-磺酰)苯基]-1-甲基-3-丙基-4氢-吡唑并[4,3-d]嘧啶-7-酮(5-[2-ethoxy-5-(4-methylpiperazin-1-yl)sulphonylphenyl]-1-methyl-3-propyl-4H-pyrazolo[4,3-d]pyrimidin-7-one)或是1-[3-(4,7-二氢-1-甲基-7-氧基-3-丙基-1氢-吡唑并[4,3-d]嘧啶-5-基)-4-乙氧基苯基]磺酰]-4-甲基哌啶(1-[3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine)。Udenafil化合物的化学名为3-(1-甲基-7-氧基-3-丙基-4氢-吡唑并[4,3-d]嘧啶-5-基)-N-[2-(1-甲基吡咯烷-2-基)乙基]-4-丙氧基-苯磺酰胺(3-(1-methyl-7-oxo-3-propyl-4H-pyrazolo[4,3-d]pyrimidine-5-yl)-N-[2-(1-methylpyrollidin-2-yl)ethyl]-4-propoxybenzene sulfonamide)。Vardenafil化合物的化学名为2-[2-乙氧基-5-(4-乙基哌啶-1-基)磺酰苯基]-5-甲基-7-丙基-1H-咪唑并[5,1-f][1,2,4]三唑-4-酮(2-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylphenyl]-5-methyl-7-propyl-1H-imidazo[5,1-f][1,2,4]triazin-4-one)。
本文用语「他汀类类似物(Statin Analogue)」是指市售的他汀类衍生药物。在优选的实施例中,他汀类类似物包括但并不仅限于阿伐他汀(Atorvastatin)、西立伐他汀(Cerivastatin)、氟伐他汀(Fluvastatin)、洛伐他汀(Lovastatin)、美伐他汀(Mevastatin)、普伐他汀(Pravastatin)、罗伐他汀(Rosuvastatin)、辛伐他汀(Simvastatin)和普玛他汀酸(Pravastatin acid)及其药学上可接受的盐类。
根据本发明的另一个构想,取决于临床应用及效果的需求,本发明揭示适于投予组合物方法的构成药物,包含磷酸二酯酶类型5抑制剂及他汀类类似物,其投予包括选自口服给药、静脉注射、皮下注射、腹腔注射、肌内注射和舌下给药其中之一。
根据本发明的另一个构想,揭示足以治疗如人类、山羊(goat)、羔羊(lamb)、猪(pig)、牛(cow)、鸡(chicken)、鸭(duck)等温血动物脂质代谢紊乱的方法,所述治疗必需投予上述动物足供疗效用量的活性剂,其选自磷酸二酯酶类型5抑制剂与Statin类似物所组成的药物组合物,或所述化合物的药学可接受的盐类、溶剂化物、溶剂、或盐类或前药。
本文用语「载体」是指赋形剂,其与活性剂配方制备成组合物。无菌注射组合物可溶解或悬浮于无毒性的静脉注射稀释剂或溶剂,例如1,3-丁二醇。其他可接受的载体如甘露醇或水。此外,固定油(fixing oil)、合成的甘油酯或双甘油酯(di-glycerol ester)均为常用溶剂。脂肪酸如油酸、橄榄油、或蓖麻油和丙三酯衍生物等,尤其是乙酰化类型(oxy-acetylatedtype),可制备为注射油和天然的药学上可接受油。此等油溶液或悬浮液可包含长链醇类稀释剂(alcohol diluent)或分散剂、羧甲基纤维素或类似的分散剂。其他载体如Tween、Spans或其他类似的乳液或药学上可接受的固体、液体或其他生物可用的促进剂均常见于药学工业的配方。
关于一般口服的制剂,载体颗粒用于改善药物颗粒的流动性以及剂量的精确度和减少剂量变异性,易于观察药物配方而更利于生产处理的安定性。口服投予组合物采用任何口服可接受的配方,包括胶囊、锭剂、丸剂、乳液、悬浮分散剂、溶剂。以锭剂为例,载体可为乳糖、玉米淀粉、润滑剂和镁硬脂酸盐等基本的添加剂。而胶囊使用的稀释剂包括乳糖、干燥的玉米淀粉。制备悬浮液或乳状液配方,其活性成分悬浮或溶解在与乳液或悬浮剂组合的油性界面,并根据需要添加适量的甜味剂、香料或色素。
本发明的化合物也可制备为皮下注射、肌肉注射、或关节内、颅内、关节腔内流体和脊髓内注射、动脉注射、胸骨注射、疤痕内注射(intra-lesion injection)或其他适当的注射投药。
在本发明的适当实施例中,采用组合治疗(combination therapy)以治疗及/或防止脂肪代谢紊乱的疾病。本发明内文将详述治疗及/或防止所需组合物的组合和投予的方式。取决于所欲的目标治疗,选自第一类及第二类磷酸二酯酶类型5抑制剂其中之一者为活性剂可与Statin类似物组合治疗方式投予以发挥疗效。于其他实施例中,组合治疗也包括投予不同剂型的组合物,所述组合物包含活性剂及其药学赋形剂,其选自磷酸二酯酶类型5抑制剂,和Statin类似物以及其药学赋形剂,本质上投予的时间相同,例如同时投予,或者不同时间的相继地依序投予。在某些实施例中,所述组合治疗的投予采取在疗程的不同时段以单一组合制剂但各自分开。或者,以同时、交错和交替地投予药物制剂治疗。
在适当的实施例中,选自第一类及第二类磷酸二酯酶类型5抑制剂其中之一与活性剂Statin类似物其中之一,于单一配方可采用如片剂或胶囊的口服剂型组合物投予病患,或各自分开的口服剂型组合物。将不同的活性剂制备成各自分开的口服剂型组合物则可于同一时间投予。在组合治疗的适当实施例中,可采用适宜的投予途径包括口服(包括颊、舌下含锭)、直肠、鼻腔、呼吸道吸入(例如,液雾、干粉或雾化吸入的配方)、阴道和注射(包括皮下、肌肉注射、静脉注射和皮下),局部给药包括但并不限于喷剂、雾、气溶胶、液剂、乳液、凝胶、面霜、药膏、糊剂、油膏、乳剂(emulsion)和悬浮液,以口服或注射为佳。优选的投予途径随着条件与年龄而变化。
也可采取单独投予活性剂原料,优选为药物制剂剂型的一部分所组成。在本发明的制剂中,如上所述,包括两种主成分以及一个或多个可接受的载体。载体必须是「药学上可接受的」,其意义是与其他成分的配方具备兼容性,且并无和不利于病患。
将药用活性剂以任何方式投予至少其中一部分,优选约1重量%至约100重量%,以到达有机体的血液。因此,活性剂可经由消化道或其他途径投予,例如,经由静脉滴注、皮下注射、肌内注射、吸入或经皮吸收等。
本发明揭示的药物组合物,其活性剂为磷酸二酯酶类型5抑制剂与Statin类似物,具有增加环磷酸鸟苷(guanosine 3',5'-cyclic monophosphate,cGMP)进行脂肪生成(adipogenesis)或是脂肪分解(lipoysis)作用,而参与磷酸化激素敏感性脂肪酶/脂肪三酸甘油酯脂肪酶(phosphorylated hormone-sensitive lipase/adipose triglyceridelipase,p-HSL/ATGL)呈现治疗脂质代谢紊乱的作用。
本发明所揭示的药物组合物包含选自第一类或第二类磷酸二酯酶类型5抑制剂至少其中之一,作为活性剂,采取组合治疗方式投予,以及Statin类似物的活性剂,能有效地抑制组织的油脂累积,减少脂肪性肝炎,所述药物组合物与抑制脂质代谢紊乱有关。
脂肪组织为一种内分泌器官,负责释放多种具有最多变化代谢功能的细胞激素。代谢是生物体将蛋白质、碳水化合物和脂肪等养分经由消化作用转换为能量的过程。生物体将此等能量累积在肝脏、肌肉和身体脂肪。生物体的细胞利用所述反应过程提供的能量于生理过程和合成新组织的材质。
白色脂肪细胞(white adipocytes)因应运动的高代谢需求或饮食限制造成的负能量平衡(negative energy balance)将球形细胞加以特化和分化,其存储三酸甘油酯的容量可获得增加以利后续脂肪酸的释出。与白色脂肪细胞的内分泌角色类似,棕色脂肪组织也合成及分泌多种因子。
胰岛素调节使脂肪分解的失活,与脂肪三酸甘油酯脂肪酶(adiposetriglyceride lipase,ATGL)转录下调和激素敏感脂肪酶(hormone-sensitive lipase,HSL)表现之间呈现着相关性。此外,蛋白激酶B(protein kinase B,PKB/Akt)磷酸化及各种磷酸二酯酶(PDE)异构体的活化,传递的胰岛素讯号致使腺苷-3',5'-环化单磷酸(cyclicadenosine monophosphate,cAMP)催化PDE水解,因而造成被活化的蛋白激酶A(PKA)的减量。
在脂肪组织、肝脏、骨骼肌、肠和胰脏的脂肪酸代谢干扰在胰岛素抗性、葡萄糖代谢异常以及第2型糖尿病(type 2diabetes mellitus,T2DM)的发展上扮演重要角色。在内分泌功能异常的过程中,改变血脂的存储和转化特性可在胰岛素抗性及代谢紊乱的发展呈现着极具大的影响作用。因而代谢性疾病包括所有扰乱正常性新陈代谢过程的疾病或障碍。具体而言,代谢紊乱包括第一型或第二型糖尿病,和例如肥胖、糖耐量受损、高胰岛素血症、血脂异常和胰岛素抗性等相关疾病。
近年来,以高脂饲料诱发肥胖小鼠的实验显示出脂肪细胞和肝脏内巨噬细胞可经由减少巨噬细胞炎性蛋白-1α、M1/M2巨噬细胞的极化与迁移同时诱导,减轻肥胖引起的炎症与胰岛素增敏作用。
另外从人类和动物的研究数据也显示,由巨噬细胞产生的细胞激素及趋化激素可生成局部与全身炎症反应,且此状况导致肝脏、脂肪和骨骼肌组织呈现出胰岛素抗性和胰岛β细胞功能障碍。巨噬细胞经由细胞与细胞间相互作用和释放的促炎性细胞激素、趋化激素和蛋白酶诱导炎症细胞、细胞凋亡、血管生成和基质蛋白重塑,促使第二型糖尿病患者罹患并发症。
该等研究足以说明,肥胖影响着白色脂肪组织的慢性和间歇性缺氧,以及基因表现和细胞新陈代谢,在脂肪组织的慢性炎症(特别对于肥胖相关胰岛素抗性)的发展担负重要的作用。
G蛋白偶联受体(G-protein-coupled receptors,GPCRs)为颇常见具有潜在的药理作用,然而尚无G蛋白偶联受体拮抗剂可抑制脂肪组织的脂肪形成(adipogenesis)的报告。主要激酶(包括丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)、细胞外讯号调节激酶(extracellular signal-regulated protein kinases,ERK)和丝裂原活化蛋白激酶激酶1(mitogen-activated protein kinase 1,MEK1))的G蛋白偶联受体调控的活化作用很可能对于确定G蛋白偶联受体拮抗剂(GPCRs antagonist)针对脂肪的分解与形成变得重要。
他汀类为降低血浆低密度脂蛋白胆固醇(LDL-C)和高敏度C-反应蛋白(high-sensitivityc-reactive protein)含量颇为理想的药物。烟碱酸作为降血脂(hypolipidemic)药物,其可经由G-蛋白偶联受体调控在脂肪组织的脂肪分解(lipolysis)。然而最近的预后试验结果显示在主要心血管高危险患者减少血脂,烟碱酸对于他汀类药物并未能增加治疗的效果。
拥有G蛋白偶联受体拮抗剂活性的KMUP-1于长期期间投予,其作用于肝细胞/脂肪细胞的脂解,可防止肥胖生物体进行慢性过度刺激儿茶酚胺的现象。相对于一般的G蛋白偶联受体激动剂,无法经由刺激中枢神经系统而降低食欲呈现抑制肥胖效果。KMUP-1可经由抑制磷酸二酯酶(PDE)增加PKA/PKG/HSL刺激脂肪细胞/肝细胞。
游离脂肪酸含量升高,部分与胰岛素减少抑制脂肪组织的脂肪分解有关,导致更多的游离脂肪酸传送到肝脏。在肝脏合成多余的三酸甘油酯是经由脂肪酸供应来驱动,且肝脂肪过量累积则加剧了肝脂肪酸因氧化而受损,继发胰岛素抗性。
在糖尿病前期或显性糖尿病时,当血糖含量升高更促使三酸甘油酯合成。此外,通常发生在胰岛素抗性的受损极低密度脂蛋白(VLDL)分泌更促使肝脂肪堆积。胰岛素抗性不仅是肥胖和糖尿病的因素,即使在正葡萄糖胰岛素钳夹试验(euglycemic insulin clampstudy)注意到的无糖尿病的非肥胖个体,胰岛素抗性也是非酒精性脂肪肝疾病的潜在机制。
经由高脂肪食品(high-fat diet,HFD)可造成过度肥胖(hyperadiposity)的肝脏脂肪变性(hepatic steaotosis),所述类肝脏组织的过度肥胖包括在肝脏因为炎症反应而并发脂质蓄积(lipid accumulation),以及导致更严重的肝脏损伤。经由长期食用高脂肪食品而诱发活性氧簇(reactive oxygen species,ROS),通常生物体也伴随着呈现氧化应激状态,而并发造成脂肪性肝炎(steatohepatitis)。HFD所造成的肥胖则由于活性氧簇而呈现氧化应激状态,间接地可增加肝细胞的促分裂素原活化蛋白激酶(MAPK)和细胞外讯号调节激酶(ERK)的表现。本发明发现被巨噬细胞包围的脂肪细胞能抑制活性氧簇、抑制炎症的肿瘤坏死因子(tumor necrosis factor alpha,TNF-α)和基质金属蛋白酶-9(matrixmetallopeptidase,MMP-9)。
代谢综合症表示群集相关的代谢异常,包括中心性肥胖、高血压、血脂异常、高血糖、胰岛素抗性,其中中心性肥胖和胰岛素抗性特别是公认的诱发因素。这些代谢紊乱对于心血管疾病、第二型糖尿病显示为明显的危险因素,被公认为主要的临床结局。
身体脂肪存储随热量过剩和逐步肥胖而扩大,脂质代谢的改变、脂肪组织的发炎反应以及异位性脂肪的沉积导致胰岛素抗性,显著地仅次于胰岛素讯号路径的后受体异常。
肥胖的脂肪组织发炎反应的特性受典型活化的巨噬细胞(classicallyactivated macrophages,CAM)、M1/M2开关(M1/M2 switching)所调控;大多数HFD诱导肝脏炎症可经由巨噬细胞的免疫染色(immunostaining)而呈现。
提高高密度脂蛋白(high density lipoprotein,HDL)和降低低密度脂蛋白(low-density of lipoprotein,LDL)含量的疗法被认为可运用于内皮型一氧化氮合酶(eNOS)的活化、增加过氧化物酶体增殖物活化受体γ(peroxisome proliferator activatedreceptorγ,PPARγ)以及抑制清道夫受体B族1型(scavenger receptor class B type 1,SR-B1)影响粥样含量。
肝细胞经由甲羟戊酸(mevalonate)生合成异戊二烯化合物的法尼酯焦磷酸(farnesyl pyrophosphate,FPP)和香叶基香叶基焦磷酸(geranylgeranylpyrophosphate,GGPP),而后形成胆固醇的过程,Statin类药物可竞争性地抑制3-羟基-3-甲基戊二酰辅酶A还原酶(3-hydroxy-3-methylglutaryl-CoA reductase,HMG CoAreductase,HMGR)而减少甲羟戊酸的生成进而影响胆固醇产量。香叶基香叶基焦磷酸的衍生活化RhoA/ROCK II,后续介入PPARγ参与高密度脂蛋白(HDL)的增加。人类转运体亚族成员之一的ATP结合盒转运体(ATP-binding cassette transporter,ABCA1)与载脂蛋白A-I(apolipoprotein A-I)参与着胆固醇流出的调控,此等物质影响着高密度脂蛋白的主要蛋白质成分。
细胞内胆固醇能否稳态存在,部分受PPARs和肝X受体(Liver X receptor,LXRα)所影响。他汀类药物导致RhoA/ROCK的失活有助于激发LXRα/PPARs以及呈现多效性作用。异戊二烯化合物中间体能影响PPARs和LXRα的活化。异戊二烯化合物的活化产生FPP和GGPP,其抑制着ABCA1直接经由LXRα的拮抗作用和四异戊二烯化(geranylgeranylation)的激活而间接经由RhoA。在脂肪存储方面其PPARγ的表现伴随着炎症的生成。
具体实施方式
食物摄取影响着体重增加量、血清内脂肪的状态
如表1所示,以标准饲料(standard diet,STD)或是高脂肪饲料(high-fat diet,HFD)喂饲8周的小鼠的体重增加量(weight gain)。为期8周投予高脂肪饲料,所述组小鼠体重的增加量与标准饲料相比较呈现显著地增加现象(p<0.05)。每天经口投予(p.o.)2.5、5毫克/公斤的KMUP-1或是5毫克/公斤的西地那非(Sildenafil),其体重的增加量与高脂肪饲料组相比较均呈现减少现象(p<0.05)。而西地那非降低所述体重的增加量以及三酸甘油酯残留含量与KMUP-1相比较分别呈现较少或是较多的现象。
表1KMUP-1与西地那非影响着体重增加量、血清内脂肪的状态
(注)KMUP-1=KMUP-1HCl
SIDAF=Sildenafil=Sildenafil citrate
如表2所示,喂饲高脂肪饲料组血清的三酸甘油酯(triglyceride,TG)、总胆固醇(totalcholesterol)、低密度脂蛋白胆固醇(low density lipoprotein cholesterol,LDL)、胰岛素,与标准饲料组相比较呈现显著增加现象。而高脂肪饲料诱发高胆固醇血症(hypercholesterolemia),经投予KMUP-1、KMUP-1-DL-ascorbic acid+Simva或是KMUP-1-CMC+Simva可显著地改善。尤其,胰岛素改善较显著。另外,高密度脂蛋白胆固醇(high-density lipoprotein cholesterol,HDL cholesterol)含量,经投予KMUP-1、KMUP-1-DL-ascorbic acid+Simva或是KMUP-1-CMC+Simva呈现显著增加。喂饲高脂肪饲料8周的小鼠,于期满到第14周,其饲料摄取量下降,或许尚有些未知因素影响饲料的摄取。
表2待测药物对于高脂肪食品诱发小鼠脂肪含量的影响
(注)Simva=Simvastatin,Simvastatinic Acid
KMUP-1-CMC=KMUP-1-sodium carboxyl methylcellulose
KMUP-1-VC=KMUP-1-DL-ascorbic acid
Sildenafil=Sildenafil citrate
Sildenafil-CMC=Sildenafil-sodium carboxyl methylcellulose
Sildenafil-VC=Sildenafil-DL-ascorbic acid
肝脏的重量与整体形态的改变
让高脂肪饲料小鼠组经由饮用方式投予200毫升含有2.5毫克KMUP-1盐酸盐的液态药物,不论于预防组或是治疗组,均可减少其因喂食高脂肪饲料而增加体重的现象。喂食高脂肪饲料小鼠,肝脏表面可发现大量的白色脂肪组织。于预防组可显著地减少脂肪组织,与治疗组的肝脏相比较呈现显著减少现象。
高脂肪饲料诱发肝脏内SR-B1的表现
喂饲高脂肪饲料(HFD)小鼠,饮用KMUP-1液态药物,如表3所示,可发现能抑制HFD诱发肝脏清道夫受体B族1型(scavenger receptor class B type 1,SR-B1)的表现。不论于预防组或是治疗组,均可促进蛋白激酶A/蛋白激酶G(PKA/PKG)的表现。
表3HFD诱发肝炎的肝脏清道夫受体B族1型表现
肝脏组织的苏木精-伊红染色(Hematoxylin and eosin(H&E)stain)
从喂食14周高脂肪饲料小鼠所分离的发炎肝脏整体组织与喂食高脂肪饲料以及KMUP-1预防组小鼠的红棕色肝脏组织相比较,呈现大量的白色脂肪组织。形态于预防组可显著地减少脂肪组织,与治疗组的肝脏相比较呈现显著减少现象。
苏木精-伊红(Hematoxylin and eosin,H&E)染色的肝脏切片细胞,不论是以高脂肪饲料喂饲的治疗组或预防组,其小鼠肝脏运用有机溶剂清洗可呈现大空泡的脂肪球(macrovesicular fat globules)。喂食高脂肪饲料的肥胖小鼠从第8周起投予2.5毫克浓度KMUP-1到第14周共6周治疗组,可发现大空泡的脂肪球及玻璃样透明体(Mallory'shyalinebodies)。而以2.5毫克/千克浓度投予KMUP-1预处理6周/14周,其脂肪球减少,玻璃样透明体几乎消失。
以IHC染色的脂肪性肝炎
喂食高脂肪饲料小鼠的肝脏组织切片,对照组的激素敏感性脂肪酶/磷酸化激素敏感性脂肪酶(HSL/p-HSL)呈现深棕色,显示包含大量的发炎性蛋白质或酶,如发炎性基质金属蛋白酶-9/肿瘤坏死因子-α,失活的激素敏感性脂肪酶/p-HSL/脂肪三酸甘油酯脂肪酶(ATGL),白色油滴的肥胖过度以及肥胖肝脏生成的活性氧簇(ROS)产物。
表4脂肪油滴数量及直径
肿瘤坏死因子-α的深棕色抗体反应,于预防组或治疗组呈现不一样的遮蔽现象,其中油滴几乎消失,然而反应的色泽并无大幅度地减少,显示抗发炎作用不彰。基质金属蛋白酶-9(Matrix metallopeptidase 9,MMP-9)的深棕色抗体反应,于治疗组也呈现遮蔽现象,油滴于治疗组也几乎消失。如表4所示,油滴直径变化和数目的分布于预防组或治疗组呈现大幅度地减少。于阴性对照组中,投予KMUP-1的预防组或治疗组,即使不再增加抗体,喂食高脂肪饲料小鼠的肝脏组织切片内油滴几乎消失。
在预防组及治疗组中,减少的白色油滴表示因为KMUP-1活化p-HSL产生脂肪分解,但是并非完全为HSL所造成脂解的结果。投予KMUP-1的治疗组或预防组,部分可增加HSL,也可经由活化ATGL同时改变一些p-HSL现象。如表5所示,HSL同时改变油滴数量和直径。抗体反应伴随着多数油滴数量的改变,经染色的p-HSL在预防组比治疗组更显著,表明KMUP-1抑制脂肪性肝炎的主要角色p-HSL比HSL还突出。
表5脂肪性肝炎的油滴数量及直径
同样地抗体反应和油滴数量数变化在经染色的ATGL,显示KMUP-1诱发脂解抑制脂肪性肝炎,在预防组与治疗组相比较,ATGL为重要角色。
免疫组织化学染色脂肪肝炎的2种巨噬细胞
以F4/80和CD11c染料进行典型活化的巨噬细胞(M1)的免疫组织化学染色,以及以CD206和CD209a染料进行另一种活化的巨噬细胞(M2)的免疫组织化学染色。其中CD209a染色是极敏感的抗体反应。在喂食高脂肪饲料小鼠的肝脏组织可发现大量的白色油滴,显示为导致脂肪性肝炎过度肥胖(hyperadiposity)。这些白色油滴受背景颜色的干扰而影响对比差异的区分程度。HFD的油滴数量及直径显现于KMUP-1的预防组。所有标本经免疫组织化学染色(IHC)的影像于相同的光照条件进行光学显微镜观察。对于M1或M2型巨噬细胞的所有抗体反应,经计算机计算颜色强度,平均区分为4种类型的饱和度。如表5所示,预防组的油滴直径变化和治疗组相比较呈现显著差异。
表6脂肪肝炎附睾脂肪垫的重量变化
附睾脂肪垫的苏木精-伊红染色
喂食高脂肪饲料诱发小鼠的肥厚/增生白细胞类型附睾脂肪垫(epididymal fatpad),经苏木精-伊红(H&E)染色的切片显示投予2.5毫克/千克浓度KMUP-1的预防组可呈现抑制效果。如表7所示,喂食高脂肪饲料的附睾脂肪垫重量呈现增加,投予KMUP-1进行14周的治疗组可减少其重量。KMUP-1每天投予2.5毫克/公斤浓度的预防组,其附睾脂肪垫重量以及脂肪细胞直径均呈现显著地减少现象。
表7投予KMUP-1于附睾脂肪垫的直径以及免疫反应百分率
经免疫组织化学染色附睾脂肪垫的eNOS/HSL以及IL-10/TNF-α
喂食高脂肪饲料进行为期14周诱发的脂肪组织,针对eNOS、HSL、白细胞介素-10(IL-10)及肿瘤坏死因子-α(TNF-α)进行免疫组织化学(IHC)染色。每天投予2.5毫克/千克浓度KMUP-1的预防组可抑制eNOS、TNF-α,而增加HSL、IL-10分别显示能改变附睾脂肪垫的免疫反应百分率。
表8投予KMUP-1于附睾脂肪垫的免疫反应百分率
(注)a2.5=2.5mg/200mL drink
HMGR=3-羟基-3-甲基戊二酰辅酶A还原酶
表9辛伐他汀的免疫反应百分率
(%) | HMGR | ROCK II | PPARγ | ABCA1 |
对照组 | 100 | 100 | 100 | 100 |
Simva 5mg/kg | 100 | 43 | 280 | 100 |
(注)HMGR=3-羟基-3-甲基戊二酰辅酶A还原酶(HMG CoA reductase)
Simva=Simvastatin,Simvastatinic Acid
高脂肪饲料诱发肝脏内SR-B1、HMG CoA reductase、ROCK II、PPARγ与ABCA1的表现
喂饲高脂肪饲料老鼠8周后,经口强饲KMUP-1能影响3-羟基-3-甲基戊二酰辅酶A还原酶(HMG CoA reductase)受高脂肪饲料减少的表现。喂饲高脂肪饲料老鼠与标准饲料组相比较,所述还原酶的表现呈现减少现象。经口投予2.5、5毫克/公斤浓度的KMUP-1和KMUP-1DL-ascorbic acid+simvastatin和5毫克/千克浓度的辛伐他汀(simvastatin),如表9所示,均可显著地可逆肝脏内受到高脂肪饲料而降低3-羟基-3-甲基戊二酰辅酶A还原酶的表现。此外KMUP-1也能活化喂饲高脂肪饲料小鼠肝脏内PPARγ、ABCA1的表现,使其ROCK II失活。
表10甲羟戊酸诱导3-羟基-3-甲基戊二酰辅酶A还原酶的表现的对照组百分率
HMGR(%) | 10-9 | 10-8 | 10-7 | 10-6 | 10-5 | 对照组 |
KMUP-1 | 120 | 125 | 210 | 220 | 270 | 100 |
Simva | 150 | 152 | 220 | 225 | 280 | 100 |
(μm) | 20 | 40 | 60 | 80 | 100 | |
mevalonate | 110 | 95 | 55 | 48 | 13 | 100 |
(注)Simva=Simvastatin,Simvastatinic Acid
HMGR=HMG CoA reductase
Simva溶液(vehicle)HMGR=120%
表11待测药物对于HepG2细胞内HMGR表现的对照组百分率
于HepG2细胞血清/生理食盐水培养基内甲羟戊酸诱导3-羟基-3-甲基戊二酰辅酶A还原酶的表现
以含血清/生理食盐水的培养基培养HepG2细胞24小时,投予10-9~10-5M KMUP-1或辛伐他汀,与生理食盐水或溶液的对照组相比较,如表11显示随着KMUP-1或辛伐他汀浓度的增加,3-羟基-3-甲基戊二酰辅酶A还原酶的表现也呈现依赖性的增加。于HepG2细胞培养基内添加60、80、100μM的甲羟戊酸(mevalonate),如表11所示随着浓度的增加,3-羟基-3-甲基戊二酰辅酶A还原酶的表现呈现依赖性下降现象。以100μM甲羟戊酸能大幅抑制3-羟基-3-甲基戊二酰辅酶A还原酶的表现,以甲羟戊酸与10-5M浓度的KMUP-1或辛伐他汀的组合能逆转所述抑制作用,显示是3-羟基-3-甲基戊二酰辅酶A还原酶最终产物回馈(end-product feedback)的调节现象。
当脂肪细胞呈现脂质代谢的表现,PPARγ可反应所述脂质代谢的讯号。抑制PDE-3B/PDE-5A导致激素敏感脂肪酶(hormone sensitive lipase,HSL)的活化,显示脂肪细胞承受反应而经cGMP/PKG诱导呈现脂肪分解。HSL调节各器官中甘油酯(acylglycerol或glyceride)和胆固醇酯(cholesteryl ester)的水解,且被PKG活化而增加脂肪油滴的脂肪分解(lipolysis)。表12显示eNOS、PDE-5A及ROCK II的表现。
表12 eNOS、PDE-5A及ROCK II的表现
eNOS | PDE-5A | ROCK II | |
对照组 | 100(%) | 100(%) | 100(%) |
KMUP-1HCl | 155.16±14.8 | 64.5±4.5 | 42.5±6.3 |
KMUP-1-CMC | 152.14±6.3 | 58.7±3.5 | 38.6±2.7 |
KMUP-1-VC | 147.21±8.6 | 68.8±5.3 | 40.8±3.7 |
(注)KMUP-1-CMC=KMUP-1-sodium carboxyl methylcellulose
KMUP-1-VC=KMUP-1-DL-ascorbic acid
肝细胞内PPARγ/ABCA1/ApoA-I/LXRα表现的增加
以10-9-10-5M浓度的KMUP-1或辛伐他汀可增加在HepG2肝细胞的过氧化物酶体增殖物活化受体(PPARγ)与三磷酸腺苷结合盒转运体A1(ABCA1)的表现。显示KMUP-1或辛伐他汀可影响脂质代谢过程内高密度脂蛋白胆固醇的形成。投予KMUP-1增加的PPARγ达2-3倍,符合增加体重幅度的减少,表明KMUP-1活化PPARγ可参与降低身体的重量。随着投予10-9-10-5M浓度的KMUP-1或辛伐他汀的浓度,在肝细胞内ApoA-I/LXRα的表现呈现依赖性增加。
表13 ROCK II、PPARγ与ABCA1的表现
cGMP途径与RhoA/ROCK II
如表13所示,5ng/ml的RhoA激酶拮抗剂C3胞外酶(C3exoenzyme)以及10-5M的ROCK拮抗剂Y27632均可使ROCK II的表现失活,而经由10μM的cGMP拮抗剂Rp-8-pCPT-cGMPS(8-(p-chlorophenylthio)guanosine-3,5-monophosphorothioate)可使其表现增加,若并用10μM的KMUP-1则呈现抑制作用,上述作用涉及肝细胞内cGMP信号传递途径的参与。此外KMUP-1、辛伐他汀、C3胞外酶以及Y27632均能增加PPARγ与ABCA1的表现。KMUP-1也增加PPARγ同时降低体重增加量,表示PPARγ在降低体重增加量扮演重要角色。
表14 GGPP与FPP的存在可导致RhoA/ROCK II的活化
表15 GGPP的存在下ROCK II与PPARγ的表现
(注)Simva=辛伐他汀(Simvastatin),Simvastatinic Acid
在HepG2肝细胞内,如表15所示,KMUP-1运用香叶基香叶基焦磷酸(geranylgeranyl pyrophosphat,GGPP)和焦磷酸法尼酯(Farnesyl pyrophosphate,FPP)可削弱其中的PRhoA与ROCK II的表现,受外源性GGPP或FPP的活化现象。而辛伐他汀则不能经由外源性GGPP或FPP使ROCK II失活。
外源性GGPP或FPP可减少PPARγ与ABCA1的表现
单独以10μM浓度的FPP或GGPP培养HepG2细胞可抑制PPARγ与ABCA1的表现。不论于FPP或GGPP的培养基内投予10-9-10-5M浓度的KMUP-1,均可反转此现象,恢复PPARγ与ABCA1的表现。但在10μM的GGPP培养基内添加内辛伐他汀无法使PPARγ的形成获得还原。
[14C]甲羟戊酸的生合成
10μM的KMUP-1并未减少[14C]甲羟戊酸的形成。相反地,辛伐他汀与溶媒对照组相比较,可抑制[14C]甲羟戊酸的形成达86.6±4.2%。以Sigma-Adrich公司90%以上纯度的[14C]3-羟基-3-甲基戊二酰辅酶A还原酶([14C]HMG CoA reductase)为例,以20units/mg的用量用于测定[14C]甲羟戊酸的形成。
肝脏LDLRs的免疫组织化学染色与PKG/PKA的表现
喂食高脂肪饲料诱发的肝脏,其低密度脂蛋白受体(Low density lipoproteinreceptor,LDLRs)的表现可经由免疫组织化学染色法(IHC staining methods)进行评估。不论喂食高脂肪饲料的预防组或是治疗组,KMUP-1HCl可增加其肝脏的低密度脂蛋白受体。于高脂肪饲料饲养小鼠肝脏,运用西方墨点法比较LDLRs与PKA/PKG的表现。肝脏内存在着低密度脂蛋白受体(500μg/mL),投予KMUP-1(10、20及40μM),无法呈现显著影响其PKA蛋白表现的现象。所述高脂血症的病理模型却可增加PKG的表现。然而200μg/mL氧化低密度脂蛋白(oxidized low density lipoprotein,oxidized LDL,oxLDL)诱发减少PKA蛋白的表现,投予KMUP-1(1、10及100μM)可呈现反转现象。
细胞内LDLRs/PKA/HSL的荧光染色
肝脏HepG2细胞的荧光(fluorencent)染色。其结果是随着KMUP-1浓度10-6、10-5至10-4M或是10-5M浓度辛伐他汀(simvastatin)的增加而呈现低密度脂蛋白受体(LDLR)的绿色荧光的增加现象。所述HepG2细胞绿色荧光增加量与未投予KMUP-1处理的对照组进行比较,随着KMUP-1超过10-4M浓度,绿色染色反而呈现不明原因的衰退,于HepG2细胞KMUP-1浓度接近可运用的范围。于HepG2细胞投予KMUP-1或是辛伐他汀处理则显示PKA与HSL的绿色荧光增加其免疫活性也增加。而KMUP-1无法显著地影响PKG蛋白的免疫活性。
综上所述,本发明中揭示以磷酸二酯酶类型5抑制剂与Statin类似物的药物组合物,可改善脂质代谢紊乱症。其是以高脂肪饲料喂食C57BL/6J雄性小鼠8周后,经口投予磷酸二酯酶类型5抑制剂,或是磷酸二酯酶类型5抑制剂与Statin类似物的药物组合物进行实验。待测药物可降低血清与肝脏的三酸甘油酯、总胆固醇、低密度脂蛋白,增加HDL/HMGR/ROCK II/PPAR/ABCA1的表现,增加量与清道夫受体B族1型(SR-B1)、PKA/PKG的表现,以及增加低密度脂蛋白受体(LDLRs)/PKA的免疫活性。
材料和方法(Materials and Methods)
实验动物与血清(Animals and serum)
于8周的高脂血症模式实验中是使用禁食的21~22克重C57BL/6J雄性小鼠,再喂饲高脂肪饲料(HFD)。于2个月的实验中,小鼠于实验前禁食一夜,以高脂肪饲料代替标准饲料(standard diet,STD),然后随机分为13组,包括1个预防组、2个对照组和10个治疗组,各组均为6只小鼠。对照组于14周内均喂饲一般标准饲料或高脂肪饲料,而治疗组喂饲高脂肪饲料,并于9~14周强饲投予2.5或5mg/kg/day的KMUP-1HCl、Sildenafil、KMUP-1HCl+simvastatin、KMUP-1-DL-ascorbic acid+simvastatin、Sildenafil+simvastatin、Tadalafil、simvastatin或其他实验所需的待测药物,于体重增加后进行生化分析。于预防组投予1mg/kg/day的KMUP-1HCl,收集肝脏测定3-羟基-3-甲基戊二酰辅酶A还原酶(3-hydroxy-3-methylglutaryl-CoA reductase,HMG CoA reductase,HMGR)的表现。各组从第1周至第14周期间,自由地饮用作为常态矿物质营养的自来水。
于高雄医学大学动物实验中心的日夜循环系统喂养上述动物。动物的全部照顾方式及实验室的使用规定遵守高雄医学大学委员会的核准指南,且依照美国国家卫生研究院的动物照顾与使用协定。
血液的生化分析
在2个月实验内,喂饲饲料3天后测量小鼠的平均重量。每组小鼠体重的增加量及血清脂肪含量(plasma lipid levels)均加以测量并与对照组进行比较。小鼠心脏穿刺后,将收集的血液以90×g速度的离心机(Benchtop Centrifuge,U.S.A.)离心,分离血清,随后于-80℃冻结,运用日立临床分析仪7070(Hitachi Clinical Analyzer 7070,日本),以默克公司(Merck&Co.,Kenilworth,NJ,U.S.A.)的试剂进行生化分析。运用临床常用方式测量小鼠血清的三酸甘油酯(Triglyceride)、总胆固醇(total cholesterol)、低密度脂蛋白胆固醇(low-density lipoprotein cholesterol,LDL cholesterol)及高密度脂蛋白胆固醇(high-density lipoprotein cholesterol,HDL cholesterol)。测量经分离的动物肝脏切片的肝脏三酸甘油酯。
细胞培养(Cell culture)
购自美国菌种保藏中心(American Type Culture Collection(ATCC),Manassas,VA,U.S.A.)的人类肝癌细胞株(human liver hepatocellular carcinoma)HepG2细胞培养于基础培养基(Dulbecco's Modified Eagle'Medium,DMEM)。所述基础培养基包含5%热灭活的胎牛血清(Fetal Bovine Serum,FBS)、100U/mL盘林西尼(penicillin)、100μg/mL链霉素(streptomycin)。细胞生长环境为37℃以20%氧气(20%O2,v/v)、5%二氧化碳(5%CO2)组成饱和湿度空气的140毫米汞柱(mmHg)培养箱。关于待测药物之间的溶解度差异性,应考虑各自适当溶媒的选择,因而将KMUP-1盐酸盐溶于蒸馏水,辛伐他汀(simvastatin)溶于丙二醇(propylene glycol)溶媒。将待测药物溶液与培养基一起培养24小时,接着进行蛋白质萃取。将待测药物分别加入溶媒或蒸馏水的最终浓度培养细胞后,在上述介质内,观察3-羟基-3-甲基戊二酰辅酶A还原酶(HMG CoA reductase)的丙二醇表现变化程度低于0.1%人类肝癌细胞株。
西方墨点法分析HepG2细胞以及肝脏的蛋白质表现
以各种浓度的待测药物处理HepG2细胞24小时后,以经冷PBS洗涤2次以终止反应,收集细胞。以冰冷的溶解缓冲溶液(lysis buffer)以及蛋白酶抑制剂(Sigma-Aldrich,St.Louis,MO,U.S.A.),将整个细胞溶解并均质化蛋白质。于4℃将均质化的蛋白质以90,000g离心15分钟,回收上清液作为总量细胞蛋白质(total cellular protein)。依照细胞质核膜分部蛋白质萃取套组(Cytosol Nuclear Membrane(CNM)compartmental proteinextraction kit,BioChain Institute Inc.,Hayward,CA,U.S.A.)的制造商操作指南,进行制备HepG2细胞的细胞质以及细胞膜部分。所有分馏的蛋白溶液存储于-80℃待用。为了测量药物影响的蛋白质表现,再以处理组培养24小时后萃取总细胞蛋白,进行如前述西方蛋白印迹方法。
观察SR-B1、HMG CoA reductase、PPARγ与ROCK II的表现
此是将分离的肝脏切成小片后置入萃取缓冲液(extraction buffer)来萃取肝脏的蛋白质,并于20,000×g离心30分钟。萃取缓冲液的组成为pH值为7.0的10mM三羟甲基氨基甲烷(Tris)、2mM的苯甲基磺酰氟(phenylmethylsulfonyl fluoride,PMSF)、140mM的氯化钠、5mM的二硫苏糖醇(Dithiothreitol,DTT)、0.5%的NP-40裂解液、0.05mM的抑肽素(pepstatin A)和0.2mM的亮肽素(leupeptin)。将获得的蛋白质萃取物以4:1比例与样本缓冲液煮沸成为样本。样本缓冲液的组成为100mM pH 6.8的三羟甲基氨基甲烷(Tris)、20%的甘油(glycerol)、4%的十二烷基硫酸钠(Sodium Dodecyl Sulfate,SDS)、0.2%的溴酚蓝(bromophenol blue)。使用10%十二烷基硫酸钠聚丙烯酰胺凝胶(SDS-polyacrylamidegel),以100V、40mA将各电泳孔洞的20μg蛋白质进行电泳(Electrophoresis)1小时。
被分离的蛋白质经3次离心以清除上层脂肪杂质,以5%脱脂奶粉转印至聚偏氟乙烯(Polyvinylidene Difluoride,PVDF)膜,于90分钟以100V阻隔非特异性的IgGs,以及与专一性蛋白质抗体培养。以连接碱性磷酸酶1:1000的抗山羊或抗小鼠抗体IgG培养所述印迹1小时。以量测SR-B1、3-羟基-3-甲基戊二酰辅酶A还原酶,PPAR与ROCK II的表现。
3-羟基-3-甲基戊二酰辅酶A还原酶与[14C]甲羟戊酸的形成
使用大肠杆菌菌株(H7039,Sigma-Adrich,MO,U.S.A.)中表现的人类基因重组3-羟基-3-甲基戊二酰辅酶A还原酶。使用经10%十二烷基硫酸钠聚丙烯酰胺凝胶(SDS-polyacrylamidegel)及纯度≥90%的蛋白质(拥有2-8units/mg蛋白质的活性及分子量约~76kDa)以测定3-羟基-3-甲基戊二酰辅酶A还原酶与[14C]甲羟戊酸的形成量。将KMUP-1及待测药物预培养于37℃、含有35ng/ml酶的pH 7.5磷酸缓冲液。藉由添加2.5μM[14C]3-羟基-3-甲基戊二酰辅酶A还原酶开始反应并另行培养20分钟,并于添加1N盐酸终止反应。经由管柱移除等分试样,以测定[14C]甲羟戊酸的形成(Co.Ltd.,Taipei,Taiwan)。
cGMP路径与RhoA/ROCK II
将RhoA激酶拮抗剂5μg/ml的C3胞外酶(exoenzyme)和ROCK拮抗剂10μM的Y27632分别溶于10%丙烯乙二醇(propylene glycol)溶液使ROCK II失活,分别将其添加于细胞培养液24小时。进行ROCK II的表现测量,并于HepG2细胞测量PPARγ、ABCA-1相关的表现。
将10μM的环磷酸鸟嘌呤核苷(cGMP)拮抗剂Rp-8-pCPT-cGMPs溶于10%丙二醇增加ROCK II活性,而Rp-8-pCPT-cGMPs诱导ROCK II活性的现象可被KMUP-1的类待测药物所抑制。于HepG2细胞以Rp-8-pCPT-cGMPs预培养30分钟作为对照组,再添加10μM的KMUP-1或待测药物培养24小时。
肝脏内低密度脂蛋白受体(LDLRs)的免疫组织化学染色
以10%的福尔马林(formalin)固定肝脏组织24小时,并经石蜡(paraffin)包埋。将石蜡所包埋的肝脏组织切成4μm厚的切片,先热封再以二甲苯(xylene)脱蜡,其次以梯次浓度的乙醇进行脱水,以蒸馏水洗涤。最后,以过碘酸希夫瓦(Periodic Acid-Schiff,PAS)和苏木精染液(Mayer’s hematoxylin)对组织切片进行染色。
于外源性LDL存在下LDLRs的表现与荧光染色
于存在500μg/ml外源性LDL的条件下,使用HepG2细胞株检测外源性低密度脂蛋白受体(LDLRs)细胞蛋白的表现。于4℃下以二级抗体共轭的红色荧光Cy3隔夜侦测HepG2细胞上的绿色氟荧光Bodipy 493/503和LDLRs,接着以获得的BODIPY影像和低密度脂蛋白影像合并来分析LDLRs位置。藉由以尼康显微镜(Eclipse TE200-S,Tokyo,Japan)扫描而收集及分析所有影像。
PKA/PKG的表现与PKA/HSL的免疫活性
将10-4M、10-5M或10-6M KMUP-1或待测药物与HepG2细胞培养24小时,使用免疫印迹法测量PKA/PKG的蛋白表现,或者以荧光染色法测量PKA/PKG和HSL的免疫活性,在添加或无添加200μg/ml的氧化型低密度脂蛋白(oxidized LDL,oxLDL)结合影像扫描,以评估待测化合物可否影响PKA。
脂肪性肝炎的油滴直径与数量的测量
将全肝脏切片白色条纹图像的直径订为100μM,以作为显微镜观测标准,借助Powerpoint PC计算机软件(微软,美国)以测量照片中油滴的直径,并以美国惠普(HP)打印机打印。油滴直径和细胞数目的增加表示肝脏脂肪变性增多,即视为脂肪性肝炎(steaotohepatitis)。相对地,脂肪性肝炎的形成受到抑制,呈现直径和脂肪细胞的数量减少。以尼康Eclipse TE200-S显微镜观察全肝切片的油滴。
肝脏和附睾脂肪垫的苏木精-伊红染色
将小鼠肝脏及附睾脂肪垫组织切片以福尔马林固定,梯度酒精脱水,石蜡包埋。肝脏及附睾脂肪垫组织标本以4%福尔马林固定,于4℃下经石蜡包埋切成4μm厚,经苏木精-伊红(Hematoxylin-Eosin,H&E)染色进行切片,以显微镜观察图像。
MMP-9/TNFα、HSL/p-HSL/ATGL以及eNOS/IL-10的免疫组织化学染色
以内含pH 9.0赋活溶液(Dako target retrieval solution)的蔬菜蒸锅(vegetable steamer)对于经脱蜡切片的基质金属蛋白酶-9(MMP-9)/肿瘤坏死因子(TNF-α)、激素敏感性脂肪酶(HSL)/p-HSL/脂肪甘油三酯脂肪酶(ATGL)、内皮型一氧化氮合酶(eNOS)和白细胞介素-10(IL-10)进行抗原修复(antigen retrieval),而后以含3.0%H2O2的甲醇溶液抑制其内源性过氧化物酶活性,再进行免疫组织化学染色(IHC)。在4℃恒温箱将切片与特定一级抗体培养过夜。使用的特定抗体包括经1:50倍稀释的兔多株抗eNOS抗体(Abcam,Cambridge,UK),或经1:50倍稀释的活化半胱胺酸蛋白酶蛋白-3兔单株抗体(rabbit monoclonal anti-cleaved caspase-3,Cell Signaling,U.S.A.)。使用DAKO检测试剂(DAKO REAL EnVisionTM Detection System kit,DAKO,Carpinteria,CA,U.S.A.)检测切片,再经苏木精(hematoxylin)复染,以尼康显微镜(Nikon Eclipse TE200-S)观察影像。
使用辣根过氧化物酶(horseradish peroxidase)–共轭二次抗体和随后的增强化学发光(Enhanced Chemiluminescence(ECL),GE Healthcare Bio-Sciences Corp.,Piscataway,NJ,U.S.A.)进行检测,使免疫反应的结合带呈现可视化。免疫印迹分析使用的抗小鼠或抗兔单株抗体包括抗ROCK II的抗体(Upstate,Lake Placid,NY,U.S.A.)、抗RhoA的抗体(Santa Cruze,Biotechnology,Santa Cruz,CA,U.S.A.)、抗HMG CoA reductase的抗体(Upstate,Lake Placid,NY,U.S.A.)、抗PPARγ的抗体(Abcam,Cambridge,UK)、抗ABCA-1的抗体(Cell Signaling,Boston,MA,U.S.A.)、抗ApoA-I的抗体(Abcam,Cambridge,UK)、抗LXRα的抗体(Santa Cruze,Biotechnology,Santa Cruz,CA,U.S.A.)、抗LDLR的抗体(Abcam,Cambridge,UK)、抗HSL的抗体(Cell Signaling,Boston,MA,U.S.A.)、抗eNOS的抗体(Abcam,Cambridge,UK)、抗MMP-9的抗体(Abcam,Cambridge,UK)、抗TNFα的抗体(Abcam,Cambridge,UK)、抗IL-10的抗体(Abcam,Cambridge,UK)和填注控制组蛋白质β-肌动蛋白(Sigma-Adrich,St.Louis,MO,U.S.A.)。以兔多株抗体进行辨识PPARγ1与PPARγ2的试验。Rp-8-pCPT-cGMPs与C3胞外酶购自Sigma-Adrich(St.Louis,Mo,U.S.A.)。高脂肪食品(HFD)为包含60%脂肪能量的基础纯化饲料(具有来自脂肪的60%能量,Blue:58G9Test Diet;Richmond,VA,U.S.A.)。荧光染色试验的LDL购自Abcam(Cambridge,UK),氧化低密度脂蛋白(oxidized LDL,oxLDL)购自Biomedical Technologies Inc.(Stoughton,MA,USA)。以Sigma-Adrich公司(H7039,Sigma-Adrich,St.Louis,MO.U.S.A.)纯度≥90%的蛋白质拥有2-8units/mg蛋白质的活性,其分子量约~76kDa的[14C]3-羟基-3-甲基戊二酰辅酶A还原酶([14C]HMG CoA reductase),以测定[14C]甲羟戊酸的形成。
统计分析
实验结果皆以平均值加减标准误差(Mean±SEM)表示。统计间的差异在非配对及配对样本中分别采用非相依性的配对t-检验(Student’s t-test)。当多个治疗组与一对照组相比较时,采用单因子变异数分析(one way ANOVA)或双因子重复测量变异数分析(twowayrepeated measures ANOVA)。当变异数分析(Analysis of variance,ANOVA)呈现统计学上的差异时,采用Dunnett's或Student-Newman-Keuls检验。P值小于0.05表示实验值具有统计学上显著性差异。在IBM计算机运用SigmaPlot软件(版本8.0,Chicago,IL,U.S.A.)和SigmaStat(版本2.03,Chicago,IL,U.S.A.)分析数据和图表的绘制。
实验例1:治疗脂质代谢紊乱的组合投药
KMUP-1盐酸盐(KMUP-1HCl) 8.6g
辛伐他汀钠盐(Simvastatin sodium salt) 4.6g
实验例2:治疗脂质代谢紊乱的组合投药
KMUP-1盐酸盐 8.6g
Pravastatin钠盐(Pravastatin sodium salt) 4.5g
实验例3:治疗脂质代谢紊乱的组合投药
KMUP-1盐酸盐 8.6g
辛伐他汀钠盐(Simvastatin sodium salt) 4.6g
实验例4:治疗脂质代谢紊乱的组合投药
KMUP-1坏血酸复合物(KMUP-1DL-ascorbic acid Complex) 11.5g
辛伐他汀钠盐 4.6g
实验例5:制备锭剂
依照于1994年10月25日公告的Bechard等人的U.S.Pat.No.5,358,941方法(其全文并入本文做为参考),分别依量秤取下列各成分,混合后充填于打锭机,制备成锭剂。
实验例6:治疗脂质代谢紊乱的组合投药
西地那非柠檬酸复合物(Sildenafil citrate Complex) 13.2g
Pravastatin钠盐 4.5g
实验例7:治疗脂质代谢紊乱的组合投药
阿伐那非(Avanafil) 9.6g
Pravastatin钠盐 4.5g
实验例8:治疗脂质代谢紊乱的组合投药
他达拉非(Tadalafil) 7.7g
辛伐他汀钠盐 4.6g
实验例9:治疗脂质代谢紊乱的组合投药
KMUP-1油酸复合物(KMUP-1oleic acid Complex) 13.7g
Pravastatin钠盐 4.5g
实验例10:制备锭剂
依照于1994年10月25日公告的Bechard等人的U.S.Pat.No.5,358,941方法(其全文并入本文做为参考),分别依量秤取下列各成分,混合后充填于打锭机,制备成锭剂。
实验例11:治疗脂质代谢紊乱的组合投药
KMUP-1油酸复合物 13.7g
Fluvastatin钠盐(Fluvastatin sodium salt) 4.4g
实验例12:治疗脂质代谢紊乱的组合投药
双嘧达莫(Dipyridamole) 9.9g
Fluvastatin钠盐 4.4g
实验例13:治疗脂质代谢紊乱的组合投药
KMUP-1坏血酸复合物 11.5g
Fluvastatin钠盐 4.4g
其他类型实施例
1、一种组合物的用途,其用于制备可缓减动物脂质代谢紊乱的组合物,所述组合物包含有效量选自第一类磷酸二酯酶类型5抑制剂与他汀类类似物所组成的药物组合物的主成分;及药学上可接受的赋形剂。
2、如实施例1所述的用途,其中脂质代谢紊乱包括非酒精性脂肪肝、过度肥胖(hyperadiposity)、血脂异常症(dyslipidemia)、肝脏脂肪变性(hepatic steaotosis)、高脂肪食品诱发肝脏脂质蓄积、高脂肪食品诱发肥胖、胰岛素抗性、高脂肪食品诱发脂质蓄积(lipid accumulation)并发炎症和肝脏损伤的后续症候其组合或其组合型式。
3、如实施例1或2所述的用途,其中动物选自人类、山羊(goat)、羔羊(lamb)、猪(pig)、牛(cow)、鸡(chicken)、鸭(duck)等温血动物其中之一。
4、如实施例1至3中任一实施例所述的用途,其中他汀类类似物选自阿伐他汀(Atorvastatin)、西立伐他汀(Cerivastatin)、氟伐他汀(Fluvastatin)、洛伐他汀(Lovastatin)、美伐他汀(Mevastatin)、普伐他汀(Pravastatin)、罗伐他汀(Rosuvastatin)、辛伐他汀(Simvastatin)和普玛他汀酸(Pravastatin acid)及其混合或药学上可接受的盐类。
5、如实施例1至4中任一实施例所述的用途,其中第一类磷酸二酯酶类型5抑制剂选自哌嗪类似物和哌嗪基复合类似物。
6、如实施例1至5中任一实施例所述的用途,其中哌嗪类似物选自KMUPs衍生物和西地那非(Sildenafil)类似物,而哌嗪基复合类似物(Piperazinyl Complex Analogue)选自KMUPs衍生物复合物和西地那非类似物复合物;而RX为羧酸基团提供者,选自D-抗坏血酸(D-ascorbic acid)、L-抗坏血酸(L-ascorbic acid)、DL-抗坏血酸(DL-ascorbic acid)、油酸(oleic acid)、磷酸(phosphoric acid)、柠檬酸(citric acid)、烟碱酸(nicotinicacid)、羧甲基纤维素钠(sodium carboxyl methylcellulose,sodium CMC)、玻尿酸(hyaluronic acid)、聚丙烯酸(polyacrylic acid,PAA)、聚甲基丙烯酸甲酯(polymethylmethacrylates,PMMA)、丙烯酸树脂(Eudragit)、葡聚糖硫酸(dextransulfate)、硫酸乙酰肝素(heparan sulfate)、聚乳酸或聚乳酸酯(polylactide,PLA)、聚乳酸钠、聚羟基磺酸钠(polyglycolic acid sodium,PGCA sodium)、聚-γ-聚麸胺酸钠(sodiumγ-polyglutamate,poly-γ-polyglutamic acid sodium,γ-PGA sodium)、γ-聚麸胺酸、海藻酸钠-聚-l-离胺酸-海藻酸钠(alginate-poly-l-lysine-alginate,APA)和聚γ-聚麸胺酸衍生物(poly-γ-polyglutamic acid derivative)及其群组其中之一。
7、如实施例1至6中任一实施例所述的用途,其中KMUPs衍生物选自KMUP-1、KMUP-2、KMUP-3、KMUP-4及其药学上可接受的盐类的群组其中之一。
8、一种组合物的用途,其用于制备可缓减动物脂质代谢紊乱的组合物,所述组合物包含有效量选自第二类磷酸二酯酶类型5抑制剂与他汀类类似物所组成的药物组合物的主成分;及药学上可接受的赋形剂。
9、如实施例8所述的用途,其中第二类磷酸二酯酶类型5抑制剂选自阿伐那非(Avanafil)、Benzamidenafil、Dasantafil、双嘧达莫(Dipyridamole)、E4021、淫羊藿苷(Icariin)、Rolipram、Piclamilast、他达拉非(Tadalafil)、苯氮嘌呤酮(Zaprinast)所组成的群组其中之一。
10、如实施例8或9所述的用途,其中脂质代谢紊乱包括非酒精性脂肪肝、过度肥胖(hyperadiposity)、血脂异常症(dyslipidemia)、肝脏脂肪变性(hepatic steaotosis)、高脂肪食品诱发肝脏脂质蓄积、高脂肪食品诱发肥胖、胰岛素抗性、高脂肪食品诱发脂质蓄积(lipid accumulation)并发炎症和肝脏损伤的后续症候其组合或其组合型式。
11、如8至10中任一实施例所述的用途,其中动物选自人类、山羊(goat)、羔羊(lamb)、猪(pig)、牛(cow)、鸡(chicken)、鸭(duck)等温血动物其中之一。
12.一种可缓减动物脂质代谢紊乱的组合物,包含:药学上可接受的载体;以及有效量选自第一类磷酸二酯酶类型5抑制剂以及有效量选自他汀类类似物的群组;其中第一类磷酸二酯酶类型5抑制剂选自哌嗪类似物和哌嗪基复合类似物。
13、如实施例12所述的组合物,其中他汀类类似物选自阿伐他汀(Atorvastatin)、西立伐他汀(Cerivastatin)、氟伐他汀(Fluvastatin)、洛伐他汀(Lovastatin)、美伐他汀(Mevastatin)、普伐他汀(Pravastatin)、罗伐他汀(Rosuvastatin)、辛伐他汀(Simvastatin)和普玛他汀酸(Pravastatinacid)及其组合以及其药学上可接受的盐类。
14、如实施例12或13所述的组合物,其中哌嗪类似物选自KMUPs衍生物和西地那非(Sildenafil)类似物,而哌嗪基复合类似物(Piperazinyl Complex Analogue)选自KMUPs衍生物复合物和西地那非类似物复合物;而RX为羧酸基团提供者,选自D-抗坏血酸(D-ascorbic acid)、L-抗坏血酸(L-ascorbic acid)、DL-抗坏血酸(DL-ascorbic acid)、油酸(oleic acid)、磷酸(phosphoric acid)、柠檬酸(citric acid)、烟碱酸(nicotinicacid)、羧甲基纤维素钠(sodium carboxyl methylcellulose,sodium CMC)、玻尿酸(hyaluronic acid)、聚丙烯酸(polyacrylic acid,PAA)、聚甲基丙烯酸甲酯(polymethylmethacrylates,PMMA)、丙烯酸树脂(Eudragit)、葡聚糖硫酸(dextransulfate)、硫酸乙酰肝素(heparan sulfate)、聚乳酸或聚乳酸酯(polylactide,PLA)、聚乳酸钠、聚羟基磺酸钠(polyglycolic acid sodium,PGCA sodium)、聚-γ-聚麸胺酸钠(sodiumγ-polyglutamate,poly-γ-polyglutamic acid sodium,γ-PGA sodium)、γ-聚麸胺酸、海藻酸钠-聚-l-离胺酸-海藻酸钠(alginate-poly-l-lysine-alginate,APA)和聚γ-聚麸胺酸衍生物(poly-γ-polyglutamic acid derivative)所组成的群组其中之一。
15、如实施例12至14中任一实施例所述的组合物,其中KMUPs衍生物选自KMUP-1、KMUP-2、KMUP-3、KMUP-4及其药学上可接受的盐类的群组其中之一。
16、如实施例12至15中任一实施例所述的组合物,其中脂质代谢紊乱包括非酒精性脂肪肝、过度肥胖(hyperadiposity)、血脂异常症(dyslipidemia)、肝脏脂肪变性(hepatic steaotosis)、高脂肪食品诱发肝脏脂质蓄积、高脂肪食品诱发肥胖、胰岛素抗性、高脂肪食品诱发脂质蓄积(lipid accumulation)并发炎症和肝脏损伤的后续症候其组合或其组合型式。
17、如实施例12至16中任一实施例所述的组合物,其中动物选自人类、山羊(goat)、羔羊(lamb)、猪(pig)、牛(cow)、鸡(chicken)、鸭(duck)等温血动物其中之一。
18、如实施例12至17中任一实施例所述的组合物,其中第二类磷酸二酯酶类型5抑制剂选自阿伐那非(Avanafil)、Benzamidenafil、Dasantafil、双嘧达莫(Dipyridamole)、E4021、淫羊藿苷(Icariin)、Rolipram、Piclamilast、他达拉非(Tadalafil)、苯氮嘌呤酮(Zaprinast)所组成的群组其中之一。
19、一种可缓减动物脂质代谢紊乱的组合物,包含:药学上可接受的载体;以及有效量选自第二类磷酸二酯酶类型5抑制剂以及有效量选自他汀类类似物的群组。
20、一种组合物的用途,其用于制备可缓减动物脂质代谢紊乱的组合物,所述组合物包含有效量个别选自第一类及第二类磷酸二酯酶类型5抑制剂与他汀类类似物所组成的药物组合物的主成分;以及药学上可接受的赋形剂;其中第一类磷酸二酯酶类型5抑制剂选自哌嗪类似物和哌嗪基复合类似物其中之一,第二类磷酸二酯酶类型5抑制剂选自阿伐那非(Avanafil)、Benzamidenafil、Dasantafil、双嘧达莫(Dipyridamole)、E4021、淫羊藿苷(Icariin)、Rolipram、Piclamilast、他达拉非(Tadalafil)、苯氮嘌呤酮(Zaprinast)所组成的群组其中之一。
21、一种组合物,包含:药学上可接受的载体;有效量个别选自第一类及第二类磷酸二酯酶类型5抑制剂与他汀类类似物所组成的药物组合物的主成分;以及药学上可接受的赋形剂;其中第一类磷酸二酯酶类型5抑制剂选自哌嗪类似物和哌嗪基复合类似物其中之一,第二类磷酸二酯酶类型5抑制剂选自阿伐那非(Avanafil)、Benzamidenafil、Dasantafil、双嘧达莫(Dipyridamole)、E4021、淫羊藿苷(Icariin)、Rolipram、Piclamilast、他达拉非(Tadalafil)、苯氮嘌呤酮(Zaprinast)所组成的群组其中之一。
参考文献
1.Dai Z.-K.,et al.,(2014)Xanthine Derivative KMUP-1ReducesInflammation and Hyperalgesia in a Bilateral Chronic Constriction InjuryModel by Suppressing MAPK and NFκBActivation.Mol.Pharm.,11,1621-1631.
2.Bivalacqua T.J.,et al.,(2013)Sildenafil citrate-restored eNOS andPDE5regulation in sickle cell mouse penis prevents Priapism via control ofoxidative/nitrosative stress.PLoSONE,8:e68028.
3.Chung H.-H.,et al.,(2010)The xanthine derivative KMUP-1inhibitsmodels of pulmonary artery hypertension via increased NO and cGMP-dependentinhibition of RhoA/Rho kinase.Br.J.Pharmacol.160,971-986.
4.Chung H.-H.,et al.,(2010)KMUP-1inhibits pulmonary arteryproliferation by targeting serotonin receptors/transporter and NO synthase,inactivating RhoA and suppressing AKT/ERK phosphorylation.Vascu.Pharmacol.53,239-249.
5.Kuo,K.-K.,et al.,(2015)Xanthine-based KMUP-1Improves HDL via PPARγ/SR-B1,LDL via LDLRs,and HSL via PKA/PKG for Hepatic Fat Loss.J.LipidRes.56(11):2070-2084.
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Claims (10)
1.一种组合物的用途,其用于制备可缓减动物脂质代谢紊乱的组合物,所述组合物包含:
有效量选自第一类磷酸二酯酶类型5抑制剂及他汀类类似物所组成的药物组合物的主成分;以及
药学上可接受的赋形剂,
其中所述第一类磷酸二酯酶类型5抑制剂选自哌嗪类似物和哌嗪基复合类似物所组成群组之一。
2.根据权利要求1所述的用途,其中所述脂质代谢紊乱包括至少非酒精性脂肪肝、过度肥胖(hyperadiposity)、血脂异常症(dyslipidemia)、肝脏脂肪变性(hepaticsteaotosis)、高脂肪食品诱发肝脏脂质蓄积、高脂肪食品诱发肥胖、胰岛素抗性、高脂肪食品诱发脂质蓄积(lipid accumulation)并发炎症或肝脏损伤的后续症候及其组合其中之一。
3.根据权利要求1所述的用途,其中所述动物为温血动物,所述温血动物包括至少人类、山羊(goat)、羔羊(lamb)、猪(pig)、牛(cow)、鸡(chicken)及鸭(duck)所组成的群组其中之一。
4.根据权利要求1所述的用途,其中所述他汀类类似物包括至少阿伐他汀(Atorvastatin)、西立伐他汀(Cerivastatin)、氟伐他汀(Fluvastatin)、洛伐他汀(Lovastatin)、美伐他汀(Mevastatin)、普伐他汀(Pravastatin)、罗伐他汀(Rosuvastatin)、辛伐他汀(Simvastatin)及普玛他汀酸(Pravastatin acid)及所述等他汀类类似物的药学上可接受的盐类其中之一。
5.根据权利要求1所述的用途,其中所述哌嗪类似物包括至少KMUPs衍生物和西地那非(Sildenafil)类似物其中之一,而所述哌嗪基复合类似物(Piperazinyl ComplexAnalogue)包括至少KMUPs衍生物复合物(KMUPs-RX)及西地那非类似物复合物(SildenafilAnalogue-RX)其中之一,其中:
RX是羧酸基团提供者,并选自D-抗坏血酸(D-ascorbic acid)、L-抗坏血酸(L-ascorbic acid)、DL-抗坏血酸(DL-ascorbic acid)、油酸(oleic acid)、磷酸(phosphoricacid)、柠檬酸(citric acid)、烟碱酸(nicotinic acid)、羧甲基纤维素钠(sodiumcarboxyl methylcellulose,sodium CMC)、玻尿酸(hyaluronic acid)、聚丙烯酸(polyacrylic acid,PAA)、聚甲基丙烯酸甲酯(polymethylmethacrylates,PMMA)、丙烯酸树脂(Eudragit)、葡聚糖硫酸(dextran sulfate)、硫酸乙酰肝素(heparan sulfate)、聚乳酸或聚乳酸酯(polylactide,PLA)、聚乳酸钠、聚羟基磺酸钠(polyglycolic acid sodium,PGCA sodium)、聚-γ-聚麸胺酸钠(sodiumγ-polyglutamate,poly-γ-polyglutamicacid sodium,γ-PGA sodium)、γ-聚麸胺酸、海藻酸钠-聚-l-离胺酸-海藻酸钠(alginate-poly-l-lysine-alginate,APA)和聚γ-聚麸胺酸衍生物(poly-γ-polyglutamic acid derivative)所组成群组之一。
6.一种组合物的用途,其用于制备可缓减动物脂质代谢紊乱的组合物,所述组合物包含:
有效量选自第二类磷酸二酯酶类型5抑制剂及他汀类类似物所组成的药物组合物的主成分;以及
药学上可接受的赋形剂,其中所述第二类磷酸二酯酶类型5抑制剂选自阿伐那非(Avanafil)、Benzamidenafil、Dasantafil、双嘧达莫(Dipyridamole)、E4021、淫羊藿苷(Icariin)、Rolipram、Piclamilast、他达拉非(Tadalafil)及苯氮嘌呤酮(Zaprinast)所组成群组其中之一。
7.一种组合物,包含:
药学上可接受的载体;以及
有效量选自第一类磷酸二酯酶类型5抑制剂及第二类磷酸二酯酶类型5抑制剂所组成群组其中之一;以及
有效量的他汀类类似物,其中所述第一类磷酸二酯酶类型5抑制剂包括至少哌嗪类似物和哌嗪基复合类似物其中之一。
8.根据权利要求7所述的组合物,其中所述他汀类类似物包括阿伐他汀(Atorvastatin)、西立伐他汀(Cerivastatin)、氟伐他汀(Fluvastatin)、洛伐他汀(Lovastatin)、美伐他汀(Mevastatin)、普伐他汀(Pravastatin)、罗伐他汀(Rosuvastatin)、辛伐他汀(Simvastatin)和普玛他汀酸(Pravastatin acid)及所述等他汀类类似物的药学上可接受的盐类所组成的群组至少其中之一。
9.根据权利要求7所述的组合物,其中所述第二类磷酸二酯酶类型5抑制剂选自阿伐那非(Avanafil)、Benzamidenafil、Dasantafil、双嘧达莫(Dipyridamole)、E4021、淫羊藿苷(Icariin)、Rolipram、Piclamilast、他达拉非(Tadalafil)及苯氮嘌呤酮(Zaprinast)所组成群组其中之一。
10.根据权利要求7所述的组合物,其中所述哌嗪类似物包括至少KMUPs衍生物及西地那非(Sildenafil)类似物其中之一,而所述哌嗪基复合类似物(Piperazinyl ComplexAnalogue)包括至少KMUPs衍生物复合物(KMUPs-RX)和西地那非类似物复合物(SildenafilAnalogs-RX)其中之一,其中:
RX是羧酸基团提供者,并是选自D-抗坏血酸(D-ascorbic acid)、L-抗坏血酸(L-ascorbic acid)、DL-抗坏血酸(DL-ascorbic acid)、油酸(oleic acid)、磷酸(phosphoricacid)、柠檬酸(citric acid)、烟碱酸(nicotinic acid)、羧甲基纤维素钠(sodiumcarboxyl methylcellulose,sodium CMC)、玻尿酸(hyaluronic acid)、聚丙烯酸(polyacrylic acid,PAA)、聚甲基丙烯酸甲酯(polymethylmethacrylates,PMMA)、丙烯酸树脂(Eudragit)、葡聚糖硫酸(dextran sulfate)、硫酸乙酰肝素(heparan sulfate)、聚乳酸或聚乳酸酯(polylactide,PLA)、聚乳酸钠、聚羟基磺酸钠(polyglycolic acid sodium,PGCA sodium)、聚-γ-聚麸胺酸钠(sodiumγ-polyglutamate,poly-γ-polyglutamicacid sodium,γ-PGA sodium)、γ-聚麸胺酸、海藻酸钠-聚-l-离胺酸-海藻酸钠(alginate-poly-l-lysine-alginate,APA)和聚γ-聚麸胺酸衍生物(poly-γ-polyglutamic acid derivative)所组成群组之一。
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Application publication date: 20171110 |