TW201300103A - 使用茉莉酸治療膀胱功能障礙 - Google Patents
使用茉莉酸治療膀胱功能障礙 Download PDFInfo
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- TW201300103A TW201300103A TW100145467A TW100145467A TW201300103A TW 201300103 A TW201300103 A TW 201300103A TW 100145467 A TW100145467 A TW 100145467A TW 100145467 A TW100145467 A TW 100145467A TW 201300103 A TW201300103 A TW 201300103A
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- Prior art keywords
- acid
- jasmonic acid
- bladder
- jasmonic
- dihydroxy
- Prior art date
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Classifications
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Abstract
一種含茉莉酸的配方或成份，用於調節哺乳動物的膀胱功能，和/或治療膀胱的功能障礙，尤其是人類的膀胱無力症狀，而使用本發明提供的茉莉酸，來治療膀胱的功能障礙。
Description
一種含茉莉酸的配方或成份，用於治療哺乳動物，尤其是人類膀胱無力的功能障礙。
膀胱功能障礙是因為膀胱組織的功能異常所引發，而導致尿痛、尿急、頻尿、夜尿和尿流量減少的梗阻症狀、排空不完全、憋尿和排尿時間增加。其中1種的膀胱功能障礙就是膀胱無力。膀胱無力有許多的因素。
膀胱無力的1個因素，就是老年人常見的良性的攝護腺肥大(BPH)症狀。50歲以上的男性中，大約80%具有不同程度的膀胱尿道梗阻現象，發生率僅次於BHP(Levin et al.,1999,泌尿外科期刊,53:446-450)。膀胱功能障礙的症狀，跟攝護腺肥大導致尿道阻塞有關。
攝護腺肥大導致的尿道阻塞，可能導致膀胱補償性的變化，包括增加膀胱壁厚度的增加、膀胱失調和逼尿肌神經遵失調，這藉由3個細胞轉化而促成：1)神經密度下降；2)線粒體功能障礙，和3)鈣儲存的失調，以及肌漿網釋出Ca2+ATPase的功能障礙(見US2003/0187059)。
膀胱功能障礙而導致良性攝護腺肥大症狀(BPH)的男性病患樣本中，相較於類似年齡無尿道阻塞者，其Ca2+ATPase的活性約低上40%(Levin et al.,1999,Urology 53:446-450)。肌漿網(SR)Ca2+儲存和釋放機制干擾下，造成膀胱收縮功能障礙，而導致尿道出口部份阻塞，其膀胱收縮功能障礙的程度，跟肌質網鈣質ATPase(SERCA)，使用本文舉例的酶活性和Western Blot分析下，發現到正比的相關性(如參見Zhao et al.,1997,Urology 49: 293-300)。
膀胱功能障礙，尤其在婦女中，膀胱無力、尿失禁和逼尿肌收縮功能差，更隨年齡而增長(見2009,泌尿外科期刊74:691-697)。美國泌尿系統疾病基金會的膀胱保健協會即表示，在美國1000萬的婦女中，超過85%具有尿失禁的問題，其中45歲以上的女性佔20%，而病例數量隨年齡而增加。
在女性中，一般認為雌性激素的變化，在膀胱無力，如因為尿道或骨盆底肌無力，以及低雌激素狀態下的逼尿平滑肌收縮無力，而導致的尿失禁、急尿、頻尿，在調節上，可能扮演重要的角色。功能障礙1個可能的解釋，就是雌激素量和血流量，對膀胱和尿道組織，增加其自由基的生成和氧化損傷上，具有關聯性。氧化損傷跟體內到達膀胱血流量的減少，而導致雌激素量變化，具有其相關性，可能在更年期的低雌激素狀態下，而降低跟膀胱和尿道功能作用有關的Ca2+ATPase量。在兔子切除卵巢(OX)28日後，在肌肉和粘膜的Ca2+ATPase的總活性降低，即顯示在OX後，鈣質的儲存和釋出量降(Li et al.,2009,泌尿外科期刊74:691-697)。
其他導致膀胱功能障礙的尿道出口阻塞，包括但不限於膀胱頸的癌症、硬化或纖維化、尿道結構的疾病、尿道瓣膜、平衡肌、橫紋肌和括約肌的功能失調(見US2006/0234939)。此外，兒童可能患有先天性的尿道阻塞疾病(US 6191156)。
膀胱無力可能是因為失調的神經損傷，包括但不限於中風、帕金森病、糖尿病、多發性硬化、周圍神經病變或脊髓病變。
對膀胱的功能障礙中，尤其是對膀胱無力，已有許多的療法。這些療法實例包括但不限於抗膽鹼能藥物、前列腺素抑製劑，β-腎上腺素受體激動劑、COX2酶抑製劑和鈣通道的調製器(如見美國專利案號6,444,685,6,19,156,6514,991,7,459,430)。此外，已有實驗觀察到，在膀胱肌質網中，出現有磷蛋白，為SERCA抑製劑，對膀胱的收縮具有重大的影響(Nobe et al.,2001,生理學期刊535: 867-878)。
茉莉酸
茉莉酸是植物激素，食用植物中只有微量，具有環戊酮的特性。本文揭露茉莉酸的不同用途。應用實例包括促進植物生長(美國專利案號5,436,226)、驅蟲(美國專利案號5,118711)、治療癌症(美國專利案號6,469,061)，以及營養不良和疾病引發骨骼肌肉功能不佳的治療(美國專利案號6,465,021、美國專利公佈案號201000003346)，疼痛紓解(WO2009019693)和消除心理壓力(美國專利申請案號200700420567)，睡眠治療補充療劑(JP2000355545)、皮膚乾燥的治療(美國專利申請案20110085999)、織物惡臭的防止(美國專利申請案號20110070181)，心臟衰竭和相關失調的治療(US2011.已發現到茉莉酸可增加肌漿網中的Ca2+Atpase含量(如參見Antipenko et al.,1997,生物化學期刊272:2852-60)，和治療骨骼肌肉(如參見Ioumaa et al.,2002,藥理學和實驗療法期刊300:638-46;Starling et al,1995,生物化學期刊308:343-6 and Starling et al.,1994,Biochemistry 15:3023-31)。
本文所揭露者，為某種用於調節膀胱收縮的方法，用劑含至少1種特定含量的茉莉酸，也可再含1種其他的物質成份，此物質為某種藥物或天然物質，而用於治療膀胱的功能障礙，可有效調節膀胱的收縮。在相關的應用方面中，本發明為某種治療膀胱功能障礙的方法，尤其是非心理壓力導致的膀胱功能障礙，而尤其是用於治療膀胱無力，含至少1種特定含量的茉莉酸，可有效治療非心理壓力導致的膀胱功能障礙，尤其是膀胱無力，特別是年齡相關的膀胱無力症狀，和/或非心理壓力造成的膀胱無力現象。在具體的專利實例中，實驗對象是哺乳動物，而在更為具體點實例中，其實驗對象為人類。
再者，本發明提供的成份，即用於調節哺乳動物(如人類)的膀胱收縮，含至少1種特定含量的茉莉酸，也可再含1種其他的物質成份，此物質為某種藥物或天然物質，而用於治療上述的膀胱功能障礙。此成份可為抗氧化劑、氨基酸和/或天然補充物。在更為具體的實例中，此成份含、精氨酸、瓜氨酸和牛磺酸。
在相關的應用方面中，本文揭露關於茉莉酸的使用中，此成份可再含至少1種的其他物質，而此物質可為藥劑或天然物質，而用於治療哺乳動物的膀胱功能障礙，尤其是膀胱無力(如年齡相關的膀胱無力症狀)，其配方用於調節哺乳動物(如人類)膀胱的收縮，和/或治療膀胱的功能障礙(如非心理壓力相關的膀胱功能障礙)，尤其是膀胱無力(如非心理壓力相關的膀胱無力)。
在本文提供的許多數值中，應瞭解到，除非本文內容另有詳細說明者，在上下限範圍內，各個相關值為其下限單位的十分之一，除非另外說明者，否則在該範圍上下限以內者，均屬本發明的範圍以內。這些較小範圍的上下限，也列入本發明較小的範圍中，也屬其他明確排除在外的規定範圍以外。本發明的申請範圍，可包括1種或兩種的限制範圍，此範圍即排除本發明中，兩者任一的範圍。
除非另有說明者，否則本文使用的所有技術和科學術語，即屬本發明所屬工藝中，一般熟知的相同語義內容。雖然任何跟本文類似或同等的方法和材料，皆可用於本發明的實作和測試中，本文提出的方法和材料，仍屬首選。
需注意到，除非另有明確說明者，否則本文和本發明聲明中，使用「此」和「該」字，可為複數的意義。
需注意到，除非另有明確說明者，否則本文和本發明範圍中，「成份」和「配方」可彼此交換互用。
定義
如本文所定義，「調節」為調整膀胱的收縮量和/或速率。尤其是，用於模擬膀胱收缩的情況。
如本文所定義，「膀胱無力」為不管長期和短暫的現象，或失去了部份的自主控制能力，或有無脫尿(尿失禁)現象，為任何排尿頻率增加，造成下尿道失調的現象。症狀包括但不限於尿急、尿失禁、急迫性尿失禁、頻尿和夜尿。
茉莉酸
本成份中使用的茉莉酸，以及本發明使用的方法，可能為配方1：
配方1
其中：n是0、1或2；R1是OH、烷氧基、O型葡萄糖或亞胺，R2是OH、O、烷氧基或O型葡萄糖，R3、R4和R5是H、OH、烷氧基或O型葡萄糖，和/或，其中的R1和R2，或R1和R4來自相同的內酯，而此成份中的C3:C7、C4:C5和C9:C10的鍵結。可能為雙鍵或單鍵，或是上述配方的衍生物，其中的衍生物至少含有下列1種的成份：C3上的低酰基側鏈(游離酸或酯或共軛物)、C6碳上的1個羰基團或羥基團(游離羥基團或酯基團)、或C7的1個n-戊烯基或N-戊基側鏈。
在更為具體的實例中，此茉莉酸成份可選自含甲基茉莉酸、茉莉酮酸、茉莉酮、7-異-茉莉酮酸、9,10-二羥基茉莉酮酸、2,3-二羥基茉莉酮酸、3,4-二羥基茉莉酮酸、3,7-二羥基茉莉酮酸、4,5-二羥基茉莉酮酸、4,5-二羥基-7-異-茉莉酮酸、南瓜酸、6-epi-南瓜酸、6-epi-南瓜酸內酯、12-羥基茉莉酮酸、12-羥基茉莉酮酸內酯、11-羥基茉莉酮酸、8-羥基茉莉酮酸、同-茉莉酮酸、雙同-茉莉酮酸、11-羥基-雙同-茉莉酮酸、8-羥基-雙同-茉莉酮酸、塊莖酮酸、塊莖酮酸-O-b-葡萄糖苷、塊莖酮酸-O-b-葡萄糖苷、5,6-二羥基茉莉酮酸、6,7-脫氫茉莉酮酸、7,8-雙脫氫茉莉酮酸、順式茉莉酮、甲基-二羥基茉莉酸、二羥基-茉莉酮、茉莉酸的氨基酸共軛物、茉莉酸的低烷基酯、載劑配體共軛物和立體異構體。
成份
此成份可含上述的茉莉酸。此外，此成份可再含至少1種的其他藥劑或天然物質，而用於調節膀胱收縮，和/或治療膀胱功能障礙，尤其是治療膀胱無力，甚至是年齡相關的膀胱無力。此類的藥劑或天然物質，包括但不限於可有效治療膀胱功能障礙，尤其是膀胱無力，和/或具有相關療效的茉莉酸物質。這些物質包括但不限於度洛西汀、單胺再攝取抑製劑、解痙藥、抗膽鹼能藥物，β-3腎上腺素受體激動劑(見美國專利案號6,444,685和6,569,873)、鈣增敏劑、抗氧化劑(見US 2003/0187059)和鈣通道調製器(見US 2006/0234939)。
此成份也可在藥劑或物質中，混合有茉莉酸，包括但不限於黃芪或其衍生物(如黃芪甲苷)、薑、綠茶或其衍生物(如兒茶素)。在更為具體的實例中，此成份可含甲基茉莉酸、精氨酸、瓜氨酸和牛磺酸。
尤其是，此成份為藥劑成份，可進行不同類型的藥劑調配使用，包括口服吸收、透皮吸收或胃腸道的吸收(皮下、腹腔、靜脈、動脈和肌肉注射的吸收)。此成份可調配為尿道部位治療用的栓劑(如見US 2006/0234939)。另外，此成份可調配為陰道部位治療用的栓劑、霜劑、膏劑、液劑、衛生棉條、凝膠、藥膏、泡沫劑或噴劑(如見US 2006/0234939)。
此成份的製備為藥劑業界熟知的方法，而含有本文發明中，至少1種的活性成份，作為藥劑業界可接受的賦形劑或載劑。本發明成份中的活性成份，其重量百分比的含量為0.5到100%。「藥劑業界可接受」者為美國聯邦政府、州政府或美國地區的藥典或其他普遍公認的藥典中，而核可用於動物或特別是人類者。可在例行施藥中，選定適當的藥劑，而用於日產的皮膚吸收治療上。顯見適當的載劑、溶劑、凝膠成份、散劑成份、抗氧化劑、色素、甜味劑、潤濕化合物、釋出控制成份和其他成份，通常也適用於本科技大領域中。此藥劑成份最好使用靜脈注射的藥劑調配方式。依據相同的藥劑配方，進行此活性成份的調配。另外，這些活性成份可調配為各別的藥劑。此藥劑的調配混合，可為單劑產品，或作為本發明療法的工具，或另外構成藥劑包裝，而註明有正確的用劑方法。
在本發明的另一個具體實例中，為藥劑產品，可混合和另外各別搭配有1種或多種的茉莉酸活性成份，或為藥劑業界可接受的鹽類，以及1種或多種的物質，用於降低哺乳動物中，其肌肉疲勞，和/或促進其骨骼肌肉功能的複合製劑。
在另一個具體實例中，此藥劑產品可含1種或多種上述的茉莉酸，作為各別的成份物。
治療和使用
如上所述，此類的1種或多種的茉莉酸成份，可含其他物質，而用於治療膀胱功能障礙，尤其是非心理壓力相關的膀胱功能障礙。在具體的專利實例中，此茉莉酸可混合其他物質，而用於治療膀胱無力，尤其是非心理壓力相關的膀胱無力。非心理壓力相關的膀胱無力症狀，包括但不限於年齡相關的膀胱無力或神經性的膀胱無力症狀。在更為具體的專利實例中，年齡相關的膀胱無力，可能是因為攝護腺肥大，良性攝護腺肥大引發的失調，或在另1個具體的專利實例中，為更年期相關的雌激素缺乏的相關症狀。在具體實例中，神經性的膀胱無力可能是因為失調造成的神經損傷，包括但不限於中風、帕金森病、糖尿病、多發性硬化、周圍神經病變或脊髓病變。
可同時、分別或依序施用此活性成份。此活性成份的例行治療施用，包括但不限於腸內吸收，如口腔或直腸的吸收，或腸外的吸收，如靜脈注射、肌肉注射、局部、腹腔或透皮的吸收。
再者，此活性成份的治療施用，可作為立即緩和的配方(此藥劑配方可在用藥後，立即緩和。)、控制緩和配方(此配方不會立即緩和)，或持續緩和配方(此藥劑配方後的一段時間後，才會促成緩和作用，而儘管在非必要的情況下，即會在用藥後的一段時間內，實質恒定血流量，此期間可約為用藥後72小時、66小時、60小時、54小時、48小時、42小時、36小時、30小時、24小時、18小時、12小時、10小時、8小時或4小時的期間。)。在更為具體的實例中，此成份可在活動前用藥，達到緩和膀胱無力症狀的所需療效。
此成份的使用，最好為每天口服1次。
依據本發明中，所建議的每日茉莉酸劑量，通常約0.01到50mg，可為約0.02到20mg，較適合的劑量約0.05到10mg，而更佳劑量約0.05 mg到0.10mg，依據病患的年齡、體重和情況而定。茉莉酸的有效劑量，取決於病患的治療情況、例行療法、年齡、體重和相關情況。也可使用其他的類似藥劑。
發明實例
上述的成份和方法再說明如下，其範圍不限於上述的實例中。本說明實例僅為說明用，而不限於本發明聲明中，其相關的各種材料、條件、重量比、工藝參數和引述內容。
本研究中，有5個實驗對象，即4男1女，同意參與本實驗研究。實驗對象的病患年齡自55到73歲，平均年齡為67歲。所有的參與本實驗的對象，都有明顯的膀胱功能障礙，包括頻尿、急尿和尿量減少。實驗對象每天服用50到100微克的茉莉酮一次持續30天。在2週後，約有1/2的實驗對象，發現膀胱功能得到改善。到了第30日，所有的實驗對象回報，頻尿、急尿和尿量減少的症狀得到改善。例如，許多的實驗對象注意到，在治療前，平均每晚夜尿2次，服用茉莉酮後，則降到1次和0次。其他的實驗對象中，甚至有更大的改善，原本每晚夜尿3-4次，而降到1次。白天排尿的次數，也降低約50%。許多病患也注意到，急尿次數也降低，此外旅行期間，可憋尿10到60分鐘。且許多的男性回報，尿量增加100%。
本發明可具體藉由其他方法的應用下，而無違本發明的精神和基本特性。本發明所揭露者，在所有方面即屬說明舉例所需，而未限定其應用範圍，而設計上的所有改變，即屬本發明用途的意義和範圍以內。
本文說明提及的許多參考內容中，即構成本文完整的說明內容。
Claims (12)
- 一種用於調節膀胱收縮的方法，該方法係於用劑中含至少1種特定含量的茉莉酸，可有效調節膀胱的收縮。
- 一種成份，該成份用於調節哺乳動物的膀胱收縮功能，和/或非心理壓力相關的膀胱功能障礙，其所需的茉莉酸成份。
- 依據申請專利範圍第2項所述之成分，其中非心理壓力相關的膀胱功能障礙，為膀胱無力。
- 依據申請專利範圍第2項所述之成分，其中茉莉酸結構(1)為：
- 依據申請專利範圍第2至4項所述之成分，其中的茉莉酸成份可選自含甲基茉莉酸、茉莉酮酸、茉莉酮、7-異-茉莉酮酸、9,10-二羥基茉莉酮酸、2,3-二羥基茉莉酮酸、3,4-二羥基茉莉酮酸、3,7-二羥基茉莉酮酸、4,5-二羥基茉莉酮酸、4,5-二羥基-7-異-茉莉酮酸、南瓜酸、6-epi-南瓜酸、6-epi-南瓜酸內酯、12-羥基茉莉酮酸、12-羥基茉莉酮酸內酯、11-羥基茉莉酮酸、8-羥基茉莉酮酸、同-茉莉酮酸、雙同-茉莉酮酸、11-羥基-雙同-茉莉酮酸、8-羥基-雙同-茉莉酮酸、塊莖酮酸、塊莖酮酸-O-b-葡萄糖苷、塊莖酮酸-O-b-葡萄糖苷、5,6-二羥基茉莉酮酸、6,7-脫氫茉莉酮酸、7,8-雙脫氫茉莉酮酸、順式茉莉酮、甲基-二羥基茉莉酸、二羥基-茉莉酮、茉莉酸的氨基酸共軛物、茉莉酸的低烷基酯、載劑配體共軛物和立體異構體。
- 依據申請專利範圍第3項所述之成分，其中膀胱無力為年齡相關的膀胱無力。
- 依據申請專利範圍第6項所述之成分，其中所謂年齡相關的膀胱無力，其成因為攝護腺肥大或雌激素缺乏。
- 依據申請專利範圍第2項所述之成分，其中該成份可再含至少1種的其他物質。
- 依據申請專利範圍第8項所述之成分，其中所謂的物質，可為抗氧化劑、維生素、氨基酸和/或營養補充物。
- 依據申請專利範圍第6項所述之成分，其中所謂的成份，含茉莉酸、精氨酸、瓜氨酸和牛磺酸的成份。
- 一種茉莉酸的使用，其係可再含至少1種其他的物質，而用於治療調節哺乳動物的膀胱功能障礙，和/或調節膀胱收縮的功能。
- 依據申請專利範圍第11項所述之使用，其中哺乳動物為人類。
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| KR20170008041A (ko) * | 2015-07-13 | 2017-01-23 | 엘지전자 주식회사 | 이동 단말기 및 그것의 제어 방법 |
| RU2743805C1 (ru) * | 2020-06-26 | 2021-02-26 | Государственное бюджетное учреждение здравоохранения Свердловской области "Центр специализированных видов медицинской помощи "Уральский институт травматологии и ортопедии имени В.Д. Чаклина" (ГБУЗ СО "ЦСВМП "УИТО им. В.Д. Чаклина") | Способ лечения нейрогенного мочевого пузыря |
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| CN103429234A (zh) | 2013-12-04 |
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| TWI489981B (zh) | 2015-07-01 |
| US20150005246A1 (en) | 2015-01-01 |
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