TW202118489A - 生物活性之植物性化學物質 - Google Patents
生物活性之植物性化學物質 Download PDFInfo
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Abstract
係描述一種用於製造包含(2R,3R,4R,5S)-3,4,5-三羥基哌啶-2-羧酸(idoBR1)之組成物的方法,該方法包含下列步驟:(a)提供來自包含葫蘆科(Cucurbitaceae)家族植物之植物性來源的植物材料;(b)將該植物材料進行分餾,以製造富含idoBR1之萃取物;(c)針對下述測定該萃取物:(i) 對於唾液酸酶的抑制活性;(ii) 對於TNF-α的抑制活性;或(iii) IL-10刺激活性;以及(d)將該測定的萃取物與化妝品上、營養品上或醫藥上可接受的賦形劑或載體一起配製,以製造化妝品組成物、營養品組成物或醫藥組成物。
Description
發明領域
本發明相關於一種製備包含(2R,3R,4R,5S)-3,4,5-三羥基哌啶-2-羧酸(idoBR1)之組成物、以及其各種產品、化合物、組成物、醫藥用途、以及以其為基礎之方法,以及將其用於製備各種醫藥用組成物之用途,包括治療發炎、感染、皮膚疾病、體內抑制唾液酸酶活性,並相關於從各種植物來源分離和純化該組成物之方法。
本發明亦相關於監測葫蘆科(Cucurbitaceae)萃取物(例如,黃瓜(Cucumis
)萃取物)品質的方法,相關於製造葫蘆科萃取物的方法,以及相關於藉由此種方法獲得的葫蘆科萃取物(尤其是黃瓜萃取物)。
發明背景
黃瓜(Cucumis sativus
))是葫蘆家族葫蘆科(Cucurbitaceae),其中包括南瓜,之一種廣泛種植的植物。黃瓜起源於印度,在西亞至少已有3000年的栽種歷史,可能是羅馬人將其引入歐洲的其他地區。黃瓜種植的記錄出現在9世紀的法國、14世紀的英國和16世紀中葉的北美。
黃瓜和黃瓜萃取物長期以來被認為具有抗發炎特性,且已局部用於各種類型的皮膚問題,包括眼下腫脹和曬傷。黃瓜在埃及、希臘和羅馬等古代文明中非常流行,在那裡不僅被用作食品,而且還具有皮膚治療特性。
亞胺醣酸(ISA)構成一群分佈更廣的植物性化學物質(稱之為亞胺醣)之子群。許多已知的ISA都是植物性化學物質,以植物組織中的次級代謝產物形式存在(在該處它們可能扮演防禦作用)。雖然亞胺醣廣泛分佈於植物中(Watson, A. et al. ,2001, Phytochemistry 56, 265),但亞胺醣酸的分佈窄許多,更難以分離和辨識(Martinez, R., et al., 2019, Amino acids 51, 991)。
亞胺醣酸idoBR1出現在較老的黃瓜品種中,但卻不存在於某些現代商業品種中。它已被證明是某些黃瓜果實的主要成分,且是黃瓜中唯一的亞胺醣酸。在某些南瓜和葫蘆中,它是次要成分。
WO2013/054070辨識出idoBR1為以黃瓜萃取物為基礎之抗發炎草藥中的重要生物活性主成分。草藥食品添加劑和藥物
目前,人們對使用草藥和補充劑非常感興趣,且食品製造業、保健食品業和醫學界越來越認可草藥產品具有價值,並可補充已建立的配方和治療方法。草藥食品添加劑和補充劑現已廣泛使用。
然而,由於植物材料的複雜性質和固有的不均勻性,使得草藥食品添加劑的品質難以控制。草藥和植物系食品添加劑中使用的材料通常為整株植物或其部分或萃取物。由於植物材料包含許多不同的化學成分,使這些材料為複雜性混合物。這使得材料品質的標準化和控制非常困難。此外,許多草藥食品添加劑為兩種或多種植物系成分的混合物,因此為混合物之混合物,因而引入更高度的複雜性。此外,所使用的配方和製造方法通常不統一,且可能未公開。這些因素使其難以確保從不同來源獲得且表面上相同之一特定產品的兩個樣本,實際上包含相同的成分混合物。這個問題導致此類材料的品質難以控制,因而限制某些草藥萃取物的使用,即使是中草藥從業人員亦如此。
其他問題來自於下列事實,用於草藥施用或作為食品補充劑/營養保健品的植物通常在當地無法獲得,因此需要與最終用戶距離遙遠的來源獲得。然而,從偏遠地區提供這種植物可能是不穩定且不準確的,特別是因為許多此類植物都沒有詳細的專論研究,包括品種和品質標準。藥用植物中各種成分的複雜混合物,其類型和濃度變化很大,取決於許多因素,包括植物來源、植物的生長位置、附近其他植物或微生物的生長情況、植物收穫時的時節、材料儲存和加工的條件,以及所使用的萃取程序。
因此,需要一種靈敏的方法,可對含有idoBR1的草藥產品進行分析,因此可建立植物衍生產品之活性相關標準規範,因而可允許草藥、食品添加劑、化妝品、營養食品和食品添加劑的生產品質控制,且可理想地定量(結構性及/或功能性)生物活性成分。
本發明人已發現idoBR1對於唾液酸酶和TNF-α具有抑制活性,同時具有IL-10刺激活性。此發現可開發出增進的方法,用於配製化妝品、營養品或醫藥組成物,其基於來自包含葫蘆科家族植物的植物性來源之植物材料的萃取物,由於相關的生物活性原理,現在idoBR1可在將植物材料分餾後,快速且輕易地進行功能性測定。
因此,極有助於提供符合標準規格的化妝品、營養品或醫藥組成物:本發明可允許萃取物功能品質快速測定法的進行。它也使得耗時和昂貴的物理性鑑定(例如藉由GC-MS及/或HPLC)成為選擇性。此外,由於萃取物的功能性進行測定,因此可監測共萃取部分可能的干擾/抑制影響。這在化妝品應用中特別重要,由於該萃取物被配製為用於局部應用。
發明概要
因此,本發明係提供一種用於製造包含(2R,3R,4R,5S)-3,4,5-三羥基哌啶-2-羧酸(idoBR1)之組成物的方法,該方法包含下列步驟:
(a) 提供來自包含葫蘆科(Cucurbitaceae)家族植物之植物性來源的植物材料;
(b) 將該植物材料進行分餾,以製造富含idoBR1之萃取物;
(c) 針對下述測定該萃取物:(i) 對於唾液酸酶的抑制活性; (ii) 對於TNF-α的抑制活性;或 (iii) IL-10刺激活性;以及
(d) 將該測定的萃取物與化妝品上、營養品上或醫藥上可接受的賦形劑或載體一起配製,以製造化妝品組成物、營養品組成物或醫藥組成物。
該植物性來源包含黃瓜屬(Cucumis
)或南瓜屬(Cucurbita
)植物。較佳的黃瓜屬(Cucumis
)植物為胡瓜種(Cucumis sativus
)植物(小黃瓜)。較佳的南瓜(Cucurbita
)屬植物為甜瓜南瓜種(Cucurbita melos
)或中國南瓜種(Cucurbita moschata
)。
較佳實施例之詳細說明
出於所有目的,本文中提及的所有文獻、專利、專利申請案和其他參考文獻,在此完整併入本案以作為參考資料,如同每一單獨文獻、專利或專利申請案被特定地且單獨地指出在此併入完整本案以作為參考資料。定義
在本文中使用時,除非另有明確說明,以下術語具有以下含義(除了具有本領域可能有的任何較寬(或較窄)含義外):
除非上下文另外要求,否則本文中的單數應理解為包括複數,反之亦然。關於實體使用的術語"一(a)"或"一(an)"應理解為是指該實體中的一個或多個。如此,術語"一(a)"(或"一(an)")、“一或多個”以及“至少一”在本文中可互換使用。
如本文所使用的,術語“包含(comprise)”或其變化,例如“包含(comprises)”或“包含(comprising)”,應理解為代表內含任何所列舉的整數(例如,特性、元素、特徵、性質、方法/過程步驟或限制)或整數組(例如,例如,特性、元素、特徵、性質、方法/過程步驟或限制),但不排除任何其他整數或整數組。因此,如本文所使用的,術語“包含”是內含性的或開放式的,且不排除額外的、未引用的整數或方法/過程步驟。
片語“基本上由...組成”在本文中用於要求指定的一或多個整數或步驟,以及實質上不影響申明的發明特徵或功能者。
如本文中所使用的,術語“由……組成”用於指示僅存在有所列舉的整數(例如,特性、元素、特徵、性質、方法/過程步驟或限制)或整數組(例如,特性、元素、特徵、性質、方法/過程步驟或限制)。
如本文所用,術語“疾病”用於定義任何損害生理功能並與特定症狀相關的異常狀況。該術語廣泛地用於涵蓋生理功能受損的任何病症、疾病、異常、病理學、疾病、症狀或症候群,而不論病因學的性質為何(或實際上該疾病的病因學基礎是否已建立)。因此,它涵蓋由感染、創傷、受傷、手術、放射線灼燒、中毒或營養缺乏引起的症狀。
如本文所用,術語“治療(treatment)”或“治療(treating)”是指一種干預措施(例如,投予個體藥劑),其可治癒、改善或減輕疾病症狀,或消除(或減輕其衝擊)其病因(例如,病理性斑點狀態)。在此情況下,該術語與術語“療法(therapy)”同義使用。
額外地,術語"治療(treatment)"或"治療(treating)"是一種干預措施(例如,投予個體藥劑),其可預防或延遲疾病的發作或進展,或是降低(或消除)治療群體中的發病率。在此情況下,術語“治療(treatment)”與術語“預防(prophylaxis)”係同義使用。
術語“個體”(在上下文允許的情況下應理解為包括“單獨個體(individual)”、“動物”、“患者”或“哺乳動物”)定義出需要對其進行治療的任何個體,特別是哺乳動物個體。哺乳動物個體包括但不限於人類、家畜、農場動物、動物園動物、運動動物和寵物。在較佳實施例中,該個體為人類。
本文中對糖尿病的治療應解釋為包括治療第1型和第2型糖尿病本身,以及糖尿病前期(初發性糖尿病)和胰島素抵抗性。術語“糖尿病前期”或“初發性糖尿病”定義為在沒有糖尿病的情況下,存在高位準的葡萄糖或醣基化血紅蛋白的症狀。
如本文所用,化合物或組成物的有效量定義為可投予個體而無過量毒性、刺激、過敏反應或其他問題或併發症的量,其與合理的受益/風險比相當,但足以提供希望的效果,例如永久性或暫時性改善個體症狀的治療或預防。該量依個體而異,取決於個體的年齡和一般症狀、投藥方式和其他因素。因此,儘管不可能指定確切的有效量,但本領域技術人員將能夠使用常規實驗和背景常識,在任何單獨案例中決定適當的“有效”量。在本文中,治療結果包括根除或減輕症狀、減輕疼痛或不適、延長生存期、改善活動力和其他臨床改善標誌。治療結果不必完全治癒。
本文中廣泛使用的術語 “植物性化學物質
” 包括植物的任何化學組成,包括大分子和小分子。重要範例包括生物鹼(例如亞胺醣和亞胺醣酸,例如選自以下結構類別:吡咯烷、哌啶、吡咯聯啶、吲啶、莨菪烷和正莨菪烷)、碳水化合物類似物、酚類化合物、萜類、酵素抑制劑、醣苷、核苷酸、胺基酸、脂質和糖類。
本文所用的術語“分離的
”在本文中用於表示該化合物存在於不同於自然發生的物理環境中。例如,相對於天然發生的複雜細胞環境,該分離的化合物可為實質上分離的(例如,富集或純化)。因此,分離出的化合物可採取本文所述任何植物性來源的富集分液或萃取物形式。
當該分離出的材料被富集或純化時,富集度或純度的絕對位準並非關鍵,且本領域技術人員可立即根據待載入材料的用途決定適當的位準。較佳的純度位準為至少0.1% w/w、0.2% w/w、0.3% w/w、0.4% w/w、0.5% w/w、0.6% w/w、0.7% w/w、0.8% w/w、0.9% w/w、1.0% w/w、1.1% w/w、1.2% w/w、1.3% w/w、1.4% w/w、1.5% w/w、1.6% w/w、 1.7% w/w、1.8% w/w、1.9% w/w或2.0% w/w。
尤佳為純度位準至少0.5至2.0% w/w,例如至少0.8至1.5% w/w,例如至少約1.0% w/w。若材料是從天然來源中分離出來,如果需要的話,可藉由適當的富集技術,例如離子交換層析法,立即獲得5至10% w/w的位準。
在某些情況下,分離出的化合物形成組成物(例如或多或少含有許多其他物質的粗萃取物)或緩衝系統的一部分,其可例如含有其他成分。在其他情況下,該分離出的化合物可純化至基本均質,例如以分光光譜法、藉由NMR或層析法(例如,三甲基甲矽烷基衍生物之GC-MS)測定。
本文使用的術語“ 草藥”
定義一種醫藥組成物,其中至少一種活性成分(例如該化合物)並非化學合成的,且為一植物的植物性化學組成。在大多數情況下,此非合成的活性成分並非分離出的(如本文所定義),而是與來源植物中與其結合的其他植物性化學物質一起存在。然而,在某些情況下,該植物衍生的生物活性主要成分
可能處於濃縮分液或被分離出(有時涉及高度純化)。然而,在許多情況下,該草藥包含植物中或多或少的粗萃取物、浸液或分液,或甚至未加工的整株植物(或其部分),儘管在這種情況下,該植物(或植物部分)通常至少經乾燥及/或研磨。該草藥可為食品補充劑、食品添加劑、營養保健品、飲料形式,或以草藥套組或草藥包的整體劑量存在。
本文中,術語“草本食品
”用於定義一種組成物,其中至少一種成分非化學合成的,而是一植物的植物性化學物質成分。在大多數情況下,這種非合成性成分不會被純化出,而是與來源植物中與其結合的其他植物性化學物質一起存在。但是,在某些情況下,該植物衍生的成分可能處於濃縮分液中或被分離出(有時至高度純化)。然而,在許多情況下,該草藥包含植物中或多或少的粗萃取物、浸液或分液,或甚至未加工的整株植物(或其部分),儘管在這種情況下,該植物(或植物部分)通常至少經乾燥及/或研磨。 因此,該術語包括與食品和飲料一起使用的添加劑和補充劑形式的草藥食品。
術語 “生物活性主要成分
” 在本文中用於定義一植物性化學物質,其對於其中所包含的草藥藥效是必需的或足夠的。在本發明的情況下,該生物活性主要成分包含idoBR1。
術語 “營養品
” 在本文中用於定義提供一食品(或其分離物),其提供對抗疾病之助益或預防作用。本發明較佳的保健食品為抗發炎性。
術語 “標準規範
”在本文中係用於定義一特徵或植物性化學物質概況,其與草藥、化妝品或營養品的可接受品質相關。在本文中,術語 “品質
”係用於定義該產品預定用途的總體適用性,包括在適當濃度下的ido BR1活性。
術語 “植物性化學物質概況
”在本文中係用於定義一組與不同植物性化學物質組成有關的特徵。功能性測定法
本發明的萃取物係測定其:(i)對於唾液酸酶或TNF-α的抑制活性;或(ii)IL-10刺激活性。該功能性測定法可包含生物學測定法。該生物學測定法可於體內或體外進行,且可包括酵素抑制測定法(例如唾液酸酶抑制作用)。其他生物學測定法包括受器結合測定法、細胞學測定法(包括細胞複製、細胞病原體和細胞間相互作用,以及細胞分泌測定法)、免疫測定法、抗微生物活性(例如細菌和病毒細胞結合及/或複製)測定法,以及毒性測定法(例如LD50
測定法)。
功能性鑑定亦可間接地以允許辨識一或多種生物活性指標之鑑定形式進行。
示範性技術將於下進行更詳細地描述。唾液酸酶
idoBR1或含其之萃取物對於唾液酸酶(神經胺酸酶)活性的抑制,可藉由酵素測定法來決定,其中神經胺酸酶活性可使用例如來自產氣莢膜梭菌(Clostridium perfringens
)的酵素(Sigma-Aldrich)來測量。該測定法基於酵素會切割2'-(4-甲基繖形酮)-α-D-N-乙醯神經胺酸(MUNANA)受質,釋放出螢光產物4-甲基繖形酮(4-MU)而測定。因此,抑制作用是根據降低50%的酵素活性時所需的idoBR1或萃取物的濃度(IC50
值)而定。
適當的方法如下:
1. 準備反應混合物。 磷酸鈉緩衝液(pH 4.5)、10 mmol MUNANA4MU-NeuAc (100 μl於緩衝液中)、0.1 mg酵素於100 μl溶液中、100 μl植物萃取物或化合物。
2. 於37 C下靜置10-30分鐘。
3. 加入1.25 ml之0.25 M甘胺酸-NaOH (pH 10.4)以終止反應。
4. 螢光測量釋放出的4-甲基繖形酮(4-MU)( 於448 nm放射,於365 nm激發)。TNF-α 與IL-10
萃取物降低TNF-α並增加IL-10,可使用ELISA法在細胞培養物(例如THP-1單核細胞)或全血樣本中進行測量。
THP-1細胞可於商業上購得。培養細胞可置於微量滴定盤中的RPMI完全培養基中(例如每孔5個細胞,於96孔盤中),培養24小時後,將PMA(10 ng/ml)加入96孔盤中,以分化THP-1細胞,並決定其對於TNF-α和IL-10製造的影響。細胞應使用200 μg/ml至25 μg/ml濃度的黃瓜萃取物進行預處理,然後進行LPS(100 ng/ml)刺激2小時。靜置後,將細胞上清液從每一孔中吸到無菌微量離心管中,並以1000 rpm離心2至3分鐘,以沉澱出任何存在的細胞。細胞上清液之後使用ELISA評估TNF-α或IL-10的存在。塗覆有適當抗體的夾層ELISA盤為廣泛可獲得的(例如,R&D Systems,USA)。
就全血測量而言,等分試樣(800 μl)的全血可與溶解在RPMI 1640中的萃取物一起預靜置48小時,然後添加LPS(10 μg/ml),之後在37°C下、空氣中含5% CO2
的濕潤(100%)大氣中繼續靜置20小時。靜置結束時,由血漿組成的上清液在室溫下以10,000 g離心30秒收集,並使用人類TNF-α和IL-10 ELISA測定法測量TNF-α和IL-10的位準(套組可得於例如BioSource Europe S.A., 比利時)。物理性鑑定
本發明的萃取物亦可經物理性鑑定(儘管這不是必需的)。此可採取以下形式:定量存在於過程中任何特定分液或任何其他階段的植物性化學物質成分、測量組成純度、決定分子量(或分子量分佈或各種統計函數,在包含多種不同植物性化學物質組成的分液之情況下)、分子式(e)的測定(例如藉由核磁共振)和各種光譜分析。
特別適用的光譜特性包括:
•質譜圖(例如,荷質比(m/z)值與豐富度的關係),及/或
•層析法數據(例如,光譜、管柱滯留時間、沖提曲線等),及/或
•光電二極管陣列(PDA)光譜(例如在紫外光和可見光範圍內),及/或
•電化學偵測(ED)或蒸發光散射(ELSD)偵測;及/或
•核磁共振(NMR)光譜(包括經由1
H和/或13
C NMR獲得的光譜數據組)。
光譜鑑定可與分餾步驟結合。例如,可使用GC-MS和HPLC-PDA-MS-ED-ELSD(如本文所述),將分餾與獲得的質譜、UV-可見光譜、電化學反應或分液質譜數據和層析光譜數據結合。
以上任何或所有特徵均可用於定義任一特定樣本(或其任何分液或其植物性化學物質組成)之“化學指紋”。化學鑑定
本發明萃取物亦可進行化學鑑定(儘管這不是必需的)。此可,尤其是測量植物性化學物質成分的化學反應性、其溶解度、穩定性和熔點進行測量。
本發明化合物之藥物用途贅瘤形成(Neoplasia)
本發明化合物為唾液酸酶抑制劑,因此可用於治療或預防由唾液酸酶活性及/或唾液酸介導的疾病和病症。
唾液酸酶參與多種病理過程,包括細菌和病毒感染以及贅瘤形成,這使得這些酵素成為有吸引力的治療靶標。唾液酸酶Neu1和Neu3的表現在糖尿病中出現變化(例如,Natori, Y., et al, 2013, Biol. Pharm., Bull., 36, 1027一文中討論的Neu1活性)。唾液酸酶亦與動脈粥樣形成(Sukhorukov, V.N., et al., 2017, Curr. Pharm. Des., 23, 4696)和骨關節炎(Katoh, S., et al., 1999, J Immunol., 162, 5058)有關。
因此,發現本發明化合物可用於治療或預防贅瘤形成/增生性疾病,如下文更詳細地描述。
如本文所用,術語“贅瘤形成(neoplasia)”被嚴格地用於定義涉及贅瘤細胞異常增殖的疾病。該術語包括良性、癌症前和惡性贅瘤形成(如上定義),與術語“增生性病症(proliferative disorder)”同義使用。
贅瘤形成是由於贅瘤細胞中不適當的高位準細胞分裂及/或低位準凋亡或衰老引起的,該贅瘤細胞已獲得基因性或表觀基因性改變,使它們脫離了正常的生理控制(即,細胞已經“轉型”)。贅瘤形成通常產生稱為 “贅瘤(neoplasms)”的結構:異常的組織塊,其生長超過正常組織的生長且與正常組織不協調,並在引起變化的刺激停止後,以相同的過量方式持續存在。大多數贅瘤形成大塊組織(實體瘤),而某些贅瘤則不形成這種分離的組織塊。這些包括子宮頸上皮內贅瘤形成、肛門上皮內贅瘤形成和白血病。
贅瘤形成可能是良性的、潛在惡性的或惡性的。良性贅瘤形成包括子宮肌瘤和黑色素細胞痣(皮膚痣),其非侵入性,不會轉移或發展為惡性贅瘤。潛在惡性(癌症前)贅瘤包括原位癌,其非侵入性,但會隨時間轉變成惡性贅瘤。
惡性贅瘤形成會產生贅瘤(腫瘤(tumor)),侵襲並破壞周圍組織,可形成轉移並最終殺死宿主。術語“惡性贅瘤形成(malignant neoplasia)”和“癌症(cancer)”在本文中為同義詞使用。
術語“增生性病症(proliferative disorder)”和“贅瘤形成(neoplasia)”在本文中可作為同義詞使用,以定義涉及體內細胞病理性生長的一類疾病。
因此,增生性病症包括癌症、癌症轉移、平滑肌細胞增殖、系統性硬化症、肝硬化、成人呼吸窘迫症候群、原發性心肌病、紅斑性狼瘡、視網膜病變(例如糖尿病型視網膜病變)、心組織增殖、良性前列腺增生、卵巢囊腫、肺纖維化、子宮內膜異位、纖維瘤病、錯構瘤、淋巴管瘤病、類肉瘤病和硬纖維瘤。涉及平滑肌細胞增殖的贅瘤形成包括血管系統中細胞的過度增殖(例如內膜平滑肌細胞增生、再狹窄和血管閉塞,尤其包括在生物性或機械性介導的血管損傷(例如血管成形術)後的狹窄)。此外,內膜平滑肌細胞過度增生可包括除了血管系統之外的平滑肌過度增生(例如,膽管、支氣管呼吸道阻塞,以及腎間質纖維化患者的腎臟過度增生)。非癌性增生性病症亦包括皮膚細胞過度增生,例如乾癬及其各種臨床形式、雷特氏症候群(Reiter's syndrome)、毛孔性紅糠疹和角質化疾病(包括光化性角化病、老年性角化病和硬皮病)的過度增生變異。
術語“贅瘤形成(neoplasia)”在本文中亦可用於定義涉及體內細胞異常生長及/或分化的疾病,因此涵蓋過度增生(hyperplasia)、轉化(metaplasia)和發育異常(dysplasia)。
“過度增生(Hyperplasia
)”係定義器官或組織內的正常(未轉型)細胞增殖至異常程度的情況。因此,它可能會導致器官的整體腫大、良性腫瘤的形成,或者可能僅在顯微鏡下可見。過度增生是對特定刺激的生理反應,過度增生的細胞仍受正常調節控制機制的作用(與贅瘤形成的生長不同,其中細胞以對正常生理控制無反應的異常方式增殖)。範例包括先天性腎上腺增生、子宮內膜增生、良性前列腺增生(前列腺腫大)、乳房過度增生(包括乳腺過度增生)、局部上皮過度增生(海克斯症(Heck's disease))、皮脂腺過度增生和肝過度增生。
“化生(Metaplasia
)”係定義為其中一種成熟、分化類型的細胞被另一種成熟、分化類型的細胞取代之情況。範例包括唾液腺管柱狀上皮細胞的鱗片狀化生(當有結石存在時)、膀胱移行上皮的鱗片狀化生(同樣地,當有結石存在或與感染有關時)、具胃酸逆流(巴瑞特食道症(Barrett's esophagus))食道腺癌患者的食道腺上皮化生,以及結締組織的骨化生。
“發育異常(Dysplasia
)” 係定義為以組織內細胞異常成熟為特徵的疾病。這通常是由未成熟細胞的擴增組成,其中成熟細胞的數量和位置相對應地減少。例如,子宮頸的上皮發育異常的特徵在於未成熟細胞的數量增加,它們侷限於黏膜表面。骨髓增生異常症候群或造血細胞發育異常,顯示骨髓中未成熟細胞數量增加,以及血液中成熟、功能性細胞數量減少。其他範例包括神經纖維瘤病。
過度增生、化生和發育異常通常是可逆的狀況,為刺激(例如損傷或受傷)的結果。相反地,贅瘤形成通常是不可逆的,且與細胞轉型有關。
發現本發明化合物可普遍用於治療任何贅瘤形成,包括增生性疾病、良性、癌症前和惡性贅瘤形成、過度增生、化生和發育異常。
因此,本發明可用於治療增生性疾病,包括但不限於癌症、癌症轉移、平滑肌細胞增殖、系統性硬化症、肝硬化、成人呼吸窘迫症候群、原發性心肌病、紅斑性狼瘡、視網膜病變(例如糖尿病型視網膜病變)、心組織增殖、良性前列腺增生、卵巢囊腫、肺纖維化、子宮內膜異位、纖維瘤病、錯構瘤、淋巴管瘤病、類肉瘤病和硬纖維瘤。涉及平滑肌細胞增殖的贅瘤形成包括血管系統中細胞的過度增殖(例如內膜平滑肌細胞增生、再狹窄和血管閉塞,尤其包括在生物或機械介導的血管損傷(例如血管成形術)後的狹窄)。此外,內膜平滑肌細胞過度增生可包括除了血管系統之外的平滑肌過度增生(例如,膽管、支氣管呼吸道,以及腎間質纖維化患者的腎臟阻塞)。非癌性增生性疾病亦包括皮膚細胞過度增生,例如乾癬及其各種臨床形式、雷特氏症候群(Reiter's syndrome)、毛孔性紅糠疹,以及角質化疾病(包括光化性角化病、老年性角化病和硬皮病)的過度增生變異。
尤佳者為惡性贅瘤形成(癌症)的治療。本發明可用於治療任何癌症,包括選自以下主要群組者:(a)癌;(b)母細胞瘤;(c)白血病;(d)淋巴瘤;(e)骨髓瘤;(f)肉瘤和(g)混合型癌症。
癌(carcinoma)是指上皮來源的惡性贅瘤,或體內襯或外襯的癌症。癌為上皮組織的惡性腫瘤,佔所有癌症病例的80%至90%。上皮組織遍布全身。它存在於皮膚,以及器官和內部通道,例如胃腸道,的覆蓋層和內襯層。在較佳實施例中,本發明可治療的癌選自於下列之癌:唾液腺;結腸;直腸;闌尾;肺;胸腺;乳房;子宮頸;膀胱和眼睛。
本發明可用於治療所有母細胞瘤,包括肝母細胞瘤(例如腎母細胞瘤、非上皮腎腫瘤、橫紋肌腎腫瘤、腎肉瘤和腎臟的pPNET)、髓母細胞瘤、胰腺母細胞瘤、肺母細胞瘤、胸膜母細胞瘤、神經母細細胞瘤(包括周邊神經細胞腫瘤,及神經節神經母細胞瘤和視網膜母細胞瘤)。
本發明可用於治療所有白血病、骨髓增生性疾病和骨髓增生異常疾病,包括:淋巴性白血病(例如前驅細胞白血病、成熟B細胞白血病、成熟T細胞白血病和NK細胞白血病);急性髓細胞性白血病;慢性骨髓增生性疾病;骨髓增生異常症候群和其他骨髓增生性疾病。因此,本發明可用於治療各種白血病,包括淋巴管、淋巴球或淋巴母細胞性白血病(淋巴組織和淋巴球血液細胞系列的惡性腫瘤)和真性紅血球增多症或紅血球過多症(各種血液細胞產物的惡性腫瘤,但以紅血球為主)。
淋巴瘤在淋巴系統的腺體或淋巴結中發育,淋巴系統是由血管、淋巴結和器官(特別是脾臟、扁桃腺和胸腺)組成的網絡,可淨化體液並產生對抗感染的白血球或淋巴細胞。與有時被稱為“液體癌症(liquid cancers)”的白血病不同,淋巴瘤是“實體癌症(solid cancers)”。淋巴瘤也可能發生在特定器官,例如胃、乳房或腦中。這些淋巴瘤被稱為結外淋巴瘤。淋巴瘤分為兩類:霍奇金淋巴瘤(Hodgkin lymphoma)和非霍奇金淋巴瘤。在霍奇金淋巴瘤中存在Reed-Sternberg細胞,可在診斷上將霍奇金淋巴瘤與非霍奇金淋巴瘤區分開來。本發明可用於治療所有此類淋巴瘤和網狀內皮贅瘤,包括:(a)霍奇金淋巴瘤;(b)非霍奇金淋巴瘤(例如前驅細胞淋巴瘤、成熟B細胞淋巴瘤、成熟T細胞淋巴瘤和NK細胞淋巴瘤;(c)伯基特淋巴瘤(Burkitt lymphoma)和(d)其他淋巴網狀贅瘤,包括被套細胞淋巴瘤。
因此,本發明可用於治療廣範圍的淋巴瘤,包括例如淋巴系統(包括脾臟、扁桃腺和胸腺)的腺體或淋巴結的腫瘤,以及胃、乳房和腦的結外淋巴瘤。
骨髓瘤是起源於骨髓漿細胞的癌症。因此,本發明可用於治療造血腫瘤和血液系統惡性腫瘤,包括淋巴譜系(例如白血病、急性淋巴細胞性白血病、慢性淋巴細胞性白血病、B細胞淋巴瘤(例如瀰漫性大B細胞淋巴瘤)、T細胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、毛細胞淋巴瘤和伯基特氏淋巴瘤),以及骨髓譜系的造血腫瘤(例如急性骨髓性白血病、慢性骨髓性白血病、骨髓性白血病及伊馬替尼(Imatinib)敏感性和難治性慢性骨髓性白血病、骨髓增生不良症候群、硼替左米(Bortezomib)敏感性和難治性多發性骨髓瘤、骨髓增生性疾病或早幼粒細胞白血病,以及甲狀腺濾泡癌症)。
本發明可用於治療所有肉瘤。肉瘤是指源於支持性和結締組織,例如骨骼、肌腱、軟骨、肌肉和脂肪的癌症。通常在年輕人中發生,最常見的肉瘤通常在骨骼上發展為疼痛的腫塊。肉瘤腫瘤通常類似於其生長的組織。本發明治療的示範性肉瘤包括骨肉瘤(或成骨肉瘤);軟骨肉瘤;平滑肌肉瘤(平滑肌);橫紋肌肉瘤(骨骼肌);間皮肉瘤或間皮瘤(體腔的膜狀內襯);纖維肉瘤(纖維組織);血管肉瘤或血管內皮瘤(血管);脂肪肉瘤;膠質瘤;星狀細胞瘤;黏液肉瘤(原始胚胎結締組織),以及間質型或混合型中胚層腫瘤(混合的結締組織類型)。纖維肉瘤包括周圍神經鞘瘤和其他纖維贅瘤,例如纖維母細胞和肌纖維母細胞腫瘤、神經鞘腫瘤和其他纖維贅瘤。亦包括卡波西肉瘤(Kaposi sarcoma)。亦包括軟組織肉瘤,例如軟組織的尤因腫瘤(Ewing tumour)和阿斯肯腫瘤(Askin tumour)、軟組織的pPNET、腎外橫紋肌樣瘤;纖維組織細胞瘤;滑膜肉瘤;軟組織的骨性和軟骨瘤性贅瘤和肺泡軟組織肉瘤。骨肉瘤(惡性骨腫瘤)包括:骨骼的惡性纖維贅瘤;惡性脊索瘤和牙源性惡性腫瘤。神經膠質瘤包括寡樹突膠質細胞瘤、混合型和非特異型膠質細胞瘤,以及神經上皮膠質細胞瘤。
本發明可用於治療混合型癌症,包括例如腺鱗狀癌、混合中胚層腫瘤、癌肉瘤和畸胎癌。因此,本發明可用於治療各種CNS、PNS以及各種顱內和脊柱內贅瘤,包括:星狀細胞瘤、神經母細胞瘤、神經膠質瘤、神經鞘瘤、室管膜瘤和脈絡叢腫瘤(例如室膜瘤和脈絡叢腫瘤);顱內和脊柱內胚胎腫瘤(例如,髓母細胞瘤、原始神經外胚層腫瘤(PNET)、髓上皮瘤、非典型類畸形/類瘤狀腫瘤,以及其他顱內和脊柱內贅瘤(例如,腦下腺瘤和癌、蝶鞍區腫瘤(顱咽管瘤)、松果體實質細胞瘤、神經元和混合型神經元-膠質細胞瘤、腦膜瘤以及一般顱內和脊柱內贅瘤)。
因此,本發明發現可特定應用於以下的治療:顱內和脊柱內生殖細胞腫瘤;顱內和脊柱內胚芽瘤;顱內和脊柱內畸胎瘤;顱內和脊柱內胚胎癌;顱內和脊柱內卵黃囊腫瘤;顱內和脊柱內絨毛膜癌,以及混合形式之顱內和脊柱內腫瘤。
本發明也可用於治療各種生殖細胞腫瘤、滋養細胞腫瘤,以及生殖腺贅瘤。因此,本發明可用於治療惡性顱外和性腺外生殖細胞腫瘤,包括,例如,顱外和性腺外部位的惡性生殖瘤、顱外和性腺外部位的惡性畸胎瘤、顱外和性腺外部位的胚胎癌、顱外和性腺外部位的卵黃囊癌;顱外和性腺外的絨毛膜癌,以及顱外和性腺外部位的一般惡性混合型生殖細胞瘤。本發明亦可用於治療惡性性腺生殖細胞腫瘤,包括例如惡性性腺生殖細胞瘤、精原細胞瘤、惡性性腺畸胎瘤、性腺胚胎癌、性腺卵黃囊瘤、性腺絨毛膜癌、混合形式之惡性性腺瘤和惡性性腺母細胞瘤。感染疾病
本發明化合物為唾液酸酶抑制劑,因此可用於治療或預防由唾液酸酶活性及/或唾液酸介導的疾病和病症。此類疾病和病症包括傳染性疾病(包括細菌和病毒感染)。
本發明化合物可具有對抗任何感染因子的抗感染(例如,抑病或殺菌)活性。因此,本發明化合物可靶向(即具有對抗活性)廣範圍的不同感染因子。因此,本發明可廣範圍地應用於治療或預防任何感染或傳染性疾病,包括涉及病毒、細菌,真菌、原生動物、普昂蛋白(prion)或後生動物的傳染性疾病。
因此,本發明可廣範圍地應用於治療或預防病毒感染;治療或預防細菌感染;治療或預防原生動物感染;治療或預防真菌感染;治療或預防普昂蛋白(prion)感染;及/或治療或預防後生動物(例如蠕蟲)感染或侵擾。本發明化合物亦發現可應用於治療或預防慢性、休眠或潛伏的病毒、細菌、原生動物、真菌、普昂蛋白(prion),或後生動物(例如蠕蟲)的感染或侵擾。
l病毒靶標
包括但不限於以下病毒(或病毒類別):逆轉錄病毒科(Retroviridae
)(例如,人類免疫缺陷病毒,包括HIV-1);小核醣核酸病毒科(Picornaviridae
)(例如小兒麻痺症病毒、A型肝炎病毒、腸病毒、人類克沙奇病毒(Coxsackie viruses)、鼻病毒、伊科病毒(echoviruses));杯狀病毒科(Calciviridae
)(例如引起腸胃炎的菌株);披膜病毒(Togaviridae
)(例如馬腦炎病毒、麻疹病毒);黃病毒科(Flaviridae
)(例如登革熱病毒、腦炎病毒、黃熱病病毒);冠狀病毒科(Coronoviridae
)(例如冠狀病毒);橫紋病毒科(Rhabdoviradae
)(例如水疱性口炎病毒、狂犬病毒);絲狀病毒科(Filoviridae
)(例如伊波拉病毒(ebola viruses));副黏病毒科(Paramyxoviridae
)(例如副流感病毒、腮腺炎病毒、麻疹病毒、呼吸道融合病毒);正黏病毒科(Orthomyxoviridae
)(例如流感病毒);繖形病毒科(Bungaviridae
)(例如漢他病毒(Hantaan viruses)、邦加病毒(bunga viruses)、沙蠅病毒(phleboviruses)和奈羅病毒(Nairo viruses));沙狀病毒(Arena viridae
)(出血熱病毒);呼腸孤病毒科(Reoviridae
)(例如呼腸孤病毒、單病毒和輪狀病毒);雙核醣核酸病毒科(Birnaviridae
);肝病毒科(Hepadnaviridae
)(B型肝炎病毒);細小病毒科(Parvoviridae)
(微小病毒);乳突多泡病毒科(Papovaviridae
)(乳突狀病毒、多瘤病毒);腺病毒科(Adenoviridae
)(大多數腺病毒);皰疹病毒科(Herpesviridae
)(單純皰疹病毒(HSV)1和2、水痘帶狀病毒科(varicella zoster virus)、巨細胞病毒(CMV)、皰疹病毒;痘病毒科(Poxviridae
)(天花病毒、牛痘病毒、痘病毒);和虹膜病毒科(Iridoviridae
)(例如非洲豬瘟病毒);以及未分類的病毒(例如,海綿狀腦炎的病原體、δ型肝炎的病原體(被認為是B型肝炎病毒的缺陷衛星病毒)、HCV病毒(引起非A型、非B型肝炎);諾沃克(Norwalk)和相關病毒,以及星狀病毒。在前文中,尤佳為HIV、A型肝炎病毒、B型肝炎病毒、C型肝炎病毒、狂犬病病毒、脊髓灰質炎病毒、流感病毒、腦膜炎病毒、麻疹病毒、腮腺炎病毒、德國麻疹病毒、百日咳病毒、腦炎病毒、乳突狀病毒、黃熱病毒、呼吸道融合病毒、細小病毒、屈公病毒(chikungunya virus)、出血熱病毒和皰疹病毒,特別是水痘、巨細胞病毒和艾斯坦-巴爾病毒(Epstein-Barr virus)。
l細菌靶標
包括但不僅限於革蘭氏陰性菌和革蘭氏陽性菌。可被本發明化合物靶向的細菌範例包括但不限於:幽門螺桿菌(Helicobacter pylori
)、伯氏疏螺旋體(Borelia burgdorferi
)、嗜肺性退伍軍人桿菌(Legionella pneumophilia
)、分枝桿菌屬(Mycobacterium
spp)(例如結核分枝桿菌(M. tuberculosis
)、麻風分枝桿菌(M. leprae
)、鳥分枝桿菌(M. avium
)、胞內分枝桿菌(M. intracellulare
)、堪薩斯分枝桿菌(M. kansaii
)和戈登分枝桿菌(M. gordonae
))、金黃色葡萄球菌(Staphylococcus aureus
)、淋病奈瑟氏球菌(Neisseria gonorrhoeae
)、腦膜炎奈瑟氏菌(Neisseria meningitidis
)、單核細胞增生李斯特菌(Listeria monocytogenes
)、化膿性鏈球菌(Streptococcus pyogenes
)(A群鏈球菌)、無乳鏈球菌(Streptococcus agalactia
)(B群鏈球菌)、弧菌鏈球菌(Streptococcus viridans
)、腸球菌屬鏈球菌(Streptococcus faecalis
)、牛鏈球菌(Streptococcus bovis
)、任一下列之厭氧菌屬:鏈球菌(Streptococcus
)、肺炎鏈球菌(Streptococcus pneumoniae
)、曲狀桿菌屬(Campylobacter
spp.)、腸球菌屬(Enterococcus
spp.)、流感嗜血桿菌(Haemophilus influenzae
)、炭疽桿菌(Bacillus anthracis
)、棒狀桿菌屬(Corynebacterium
spp.)(包括白喉棒狀桿菌(C. diphtheriae
))、豬丹毒桿菌(Erysipelothrix rhusiopathiae
)、產氣莢膜梭菌(Clostridium perfringens
)、破傷風梭菌(Clostridium tetani
)、產氣腸桿菌(Enterobacter aerogenes
)、克雷伯氏菌屬(Klebsiella
spp.)(包括肺炎克雷伯菌(K. pneumoniae
))、多殺性巴斯德氏菌(Pasturella multocida
)、類桿菌屬(Bacteroides
spp.)、梭桿菌屬(Fusobacterium nucleatum
)、念珠狀鏈桿菌(Streptobacillus monilijormis
)、梅毒螺旋體(Treponema pallidium
)、細弱密螺旋體(Treponema pertenue
)、鉤端螺旋體屬(Leptospira
spp.)、立克次體(Rickettsia
spp.)、放射線菌屬(Actinomyces
spp.)(包括伊氏放線菌(A. israelii
))。在體內形成生物膜的細菌是本發明化合物的特定靶標,這些細菌包括福賽斯坦納氏菌(Tannerella forsythia
)、齒垢坦納氏菌(Tannerella denticola
)、牙齦紫質單孢菌(Porphyromonas gingivalis
)或陰道加德納菌(Gardnerella vaginalis
)。
l真菌靶標
包括但不限於新隱球菌(Cryptococcus neoformans
)、莢膜組織胞漿菌(Histoplasma capsulatum
)、粗球黴菌(Coccidioides immitis
)、皮炎芽生菌(Blastomyces dermatitidis
)、砂眼衣原體(Chlamydia trachomatis
)和白色念珠菌(Candida albicans
)。
l原生動物靶標
包括但不限於瘧原蟲屬(包括惡性瘧原蟲(Plasmodium falciparum
)、三日瘧原蟲(Plasmodium malariae
)、卵形瘧原蟲(Plasmodium ovale
)和間日瘧原蟲(Plasmodium vivax
))、弓形蟲屬(Toxoplasma spp.
) (包括弓形蟲(T. gondii
)和克氏錐蟲(T. cruzii
))、利甚曼原蟲屬(Leishmania
spp.)、隱孢子蟲屬(Cryptosporidium
spp.) (包括微小隱孢子蟲(C. parvum
))、環孢子蟲屬(Cyclospora
spp.)(包括環孢子蟲(C. cayetanensis
))、內阿米巴屬(Entamoeba)(包括痢疾阿米巴原蟲(E. histolytica
))和鞭毛蟲屬(Giardia
spp.) (包括梨形鞭毛蟲(G. lamblia
))。
l後生動物靶標包括
寄生蟲或病原體,例如蠕蟲(如血吸蟲屬(Schistosoma
spp.))。 體內細菌生長的抑制
唾液酸酶活性是唾液酸共軛醣利用的關鍵,且涉及與細菌的宿主-病原體相互作用。當在生物膜中生長時,與醣蛋白相關的唾液酸已被提出為福賽斯坦納氏菌(Tannerella forsythia
)的關鍵體內營養源(Roy, S., 2011, Microbiology, 157, 3195)。本發明化合物的唾液酸酶抑制特性也可用於抑制體內共生及/或致病性細菌的生長,特別是用於破壞宿主-細菌細胞的相互作用,包括抑制或消除哺乳動物(例如人類)宿主之細菌生物膜的能力。
因此,該化合物可應用於治療或預防由於細菌生物膜(例如牙齦下斑塊生物膜和黏膜生物膜)的存在而介導或為其特徵的疾病和病症。
此類疾病包括牙周病、細菌性陰道病及/或由福賽斯坦納氏菌(Tannerella forsythia
)、齒垢坦納氏菌(Tannerella denticola
)、牙齦紫質單孢菌(Porphyromonas gingivalis
)或陰道加德納菌(Gardnerella vaginalis
)感染引起的疾病(後者與細菌性陰道病和早產有關)。共生細菌生長的調節
亦發現本發明化合物的唾液酸酶抑制性質可應用於調節宿主中微生物群(特別是共生細菌)的組成,例如調節哺乳動物(例如人類)宿主中共生細菌的組成。尤佳為腸道微生物群的調節。動脈粥樣形成
本發明化合物為唾液酸酶抑制劑,因此發現其可應用於治療或預防動脈粥樣形成的發生,因為唾液酸酶參與該過程(Sukhorukov, V.N., et al., 2017, Curr. Pharm. Des., 23, 4696);以及骨關節炎(Katoh, S., et al., 1999, J Immunol., 162, 5058)。因此,發現本發明化合物可應用於治療和預防動脈粥樣硬化。發炎反應
本發化合物會抑制唾液酸酶,唾液酸酶被認為與骨關節炎中TNF-α誘導的發炎過程有關(Gee, K. et al., 2003, J Biol Chem. 278, 37275)。此外,本發明化合物可壓制或抑制TNF-α活性。因此,它們可用於其中發炎反應在生理功能損害及/或症狀及/或疼痛上發揮作用的任何疾病中。例如,本發明化合物可作為抗發炎藥,例如減輕或消除急性、慢性、局部或系統性發炎。
當組織受到微生物、創傷、化學物質、熱、冷、曬傷或任何其他有害事件的傷害時,就會發生發炎反應。內源性化學物質(例如緩激肽、組織胺和5-羥色胺)會在受傷或受刺激時釋放出來,這些化學物質會活化並吸引組織巨噬細胞和其他白血球。在此過程中,諸如TNF-α的化學介質會被釋放出,引起發炎反應。
發炎性疾病是指持續或慢性發炎的疾病。在這種情況下,長時間的發炎會導致組織破壞,並導致廣泛的損害,最終使受影響的組織及/或器官衰竭。
因此,發現本發明化合物可應用於治療非局部發炎性疾病,例如影響不止一個器官的疾病。此類疾病包括由免疫功能障礙引起的疾病(且因此可能具有自體免疫作用)。此類疾病包括系統性紅斑性狼瘡(SLE)、硬皮病和過敏症。
越來越多的證據顯示發炎反應與第2型糖尿病的發展有關。
本發明化合物亦可應用於治療局部發炎性疾病,包括皮膚發炎和慢性前列腺炎、腎絲球腎炎、發炎性腸病、骨盆發炎疾病、再灌注損傷、類風濕性關節炎、移植排斥、血管炎、氣喘、痤瘡、骨關節炎、口腔黏膜、胃腸道發炎、眼、鼻和耳發炎,以及其他類固醇反應性發炎疾病。
特別地,發現本發明的化合物可應用於治療皮膚發炎疾病。這些疾病包括,例如光化性角化症、痤瘡(包括尋常性痤瘡、粉刺性痤瘡、潮紅性痤瘡、囊腫型痤瘡)、過敏性接觸性皮膚炎、血管性水腫、大疱性類天皰瘡(bullous pemiphigoid)、皮膚性藥物反應、多形性紅斑、紅斑性狼瘡、光照性皮膚炎、乾癬性關節炎、硬皮症與蕁麻疹、乾癬、皮膚炎(如異位性皮膚炎)、硬皮症、類固醇-反應性皮膚發炎病症(如尿毒性瘙癢症),以及與暴露於陽光、輻射、化學療法和環境刺激物有關的皮膚症狀。
本發明化合物亦可應用於治療發炎性自體免疫疾病。此類疾病可能涉及特定的組織或器官(例如肌肉骨骼組織,如類風濕關節炎和僵直性脊柱炎)、胃腸道(例如克隆氏症(Crohn's disease)和潰瘍性結腸炎)、中樞神經系統(例如阿茲海默症(Alzheimer's disease)、多發性硬化、運動神經元疾病、帕金森氏症(Parkinson's disease)和慢性疲勞症候群)、胰島β細胞(例如胰島素-依賴型糖尿病)、腎上腺(例如艾迪生氏症(Addison's disease))、腎臟(例如古德帕症候群(Goodpasture's syndrome)、IgA腎病和間質性腎炎)、外分泌腺(例如修格蘭氏症候群(Sjogren's syndrome)和自體免疫性胰腺炎),以及皮膚(例如乾癬和異位性皮膚炎)。
本發明可治療的其他發炎性疾病包括如骨關節炎、牙周病、糖尿病(包括第2型糖尿病和糖尿病性腎病)、慢性阻塞性肺病、動脈硬化、移植物對抗宿主疾病、慢性骨盆腔發炎疾病、子宮內膜異位、慢性肝炎和結核病。劑量學
本發明組成物和化合物可局部或口服或腸胃外投予,包括靜脈內、肌內、腹膜內、皮下、穿皮、呼吸道(氣霧劑)、直腸、陰道和局部(包括頰和舌下)投藥。
投予的量可根據所使用的特定劑量單位、治療期間、所治療患者的年齡和性別、所治療疾病的性質和程度,以及所選擇的特定化合物而有很大差異。
一般而言,所投予化合物的有效量通常為每天約0.01 mg/kg至500 mg/k。單位劑量可包含0.05至500 mg的化合物,且可每天服用一次或多次。如下所述,可使用常規劑量單位形式將化合物與藥物載體一起投藥,不論是口服、胃腸外或局部。
較佳的投予途徑為口服投予。通常,適當劑量將為每日0.01至500 mg每公斤接受者體重的範圍內,較佳為每日0.1至50 mg每公斤接受者體重的範圍內,最佳為每日1至5 mg每公斤接受者體重的範圍內。
期望劑量較佳地以單一劑量用於每日投予。然而,亦可採用一天中適當間隔投予二、三、四、五或六或更多個子劑量。這些子劑量可以單位劑型投予,例如每單位劑型包含0.001至100 mg,較佳0.01至10 mg,最佳0.5至1.0 mg活性成分。配方
當從天然來源分離時,idoBR1可被純化出。然而,本發明組成物可為草藥、食品補充劑、食品添加劑、營養品、飲料或作為草藥套組或包裝之單位劑量形式,如上文所定義。此類草藥較佳在使用前進行分析,以確定它們是否符合標準規格。
本發明使用的草藥可為乾燥的植物材料。替代地,該草藥可為加工過的植物材料,該加工涉及物理或化學預處理,例如粉末化、研磨、冷凍、蒸發、過濾、壓製、噴霧乾燥、擠出、超臨界溶劑萃取和酊劑生產。在該草藥以整株植物(或其一部分)的形式投予或販賣的情況下,該植物材料可在使用前乾燥。可使用任何方便的乾燥方式,包括冷凍乾燥、噴霧乾燥或風乾。
本發明化合物可藉由在極性溶劑(例如乙醇/水混合物,例如≥50% v/v(例如至多〜70% v/v)乙醇/水混合物)中萃取,與較高分子量的成分如蛋白質和多醣分離。其他適當的技術包括各種膜技術。這些技術包括微濾、超濾和奈米過濾。替代地或另外地,也可以使用電透析來濃縮帶電化合物。這些方法使用具有特定孔徑的膜,該孔徑僅允許特定尺寸以下的分子通過,或依賴於分子上的電荷以允許或不允許它們通過該膜。陰離子和陽離子交換樹脂亦可用於濃縮該化合物。
當從天然來源分離時,本發明使用的化合物可被純化出。在該化合物與醫藥上可接受的賦形劑一起配製的實施例中,可使用任何適當的賦形劑,包括例如惰性稀釋劑、崩解劑、黏合劑、潤滑劑、甜味劑、香味劑、著色劑和防腐劑。適當的惰性稀釋劑包括碳酸鈉和碳酸鈣、磷酸鈉和磷酸鈣,以及乳糖,而玉米澱粉和海藻酸則為適當的崩解劑。黏合劑可包括澱粉和明膠,而潤滑劑(如果存在)通常為硬脂酸鎂、硬脂酸或滑石。
該醫藥組成物可為任何適當的形式,且包括例如錠劑、酏劑、膠囊、溶液、懸浮液、粉末、顆粒劑和氣霧。
該醫藥組成物可採取各部分之套組形式,該套組可包含本發明組成物與使用說明書,及/或在單位劑型中的複數個不同成分。
口服錠劑可包括本發明使用的化合物,其與醫藥上可接受的賦形劑如惰性稀釋劑、崩解劑、黏合劑、潤滑劑、甜味劑、香味劑、著色劑和防腐劑,混合。適當的惰性稀釋劑包括碳酸鈉和碳酸鈣、磷酸鈉和磷酸鈣,以及乳糖,而玉米澱粉和海藻酸則為適當的崩解劑。黏合劑可包括澱粉和明膠,而潤滑劑(如果存在)通常為硬脂酸鎂、硬脂酸或滑石。如果需要,可使用如單硬脂酸甘油酯或二硬脂酸甘油酯的材料包覆該錠劑,以延遲在胃腸道中的吸收。口服用膠囊包括硬明膠膠囊,其中將本發明使用的化合物與固體稀釋劑混合;以及軟明膠膠囊,其中該活性成分與水或油例如花生油、液體石蠟或橄欖油混合。
直腸投藥的配方可以具有適當基質之栓劑形式存在,該基質包含如可可脂或水楊酸酯。適用於陰道投藥的製劑可為子宮托、棉塞、乳膏、凝膠、糊劑、泡沫或噴霧製劑的形式存在,該配方除了活性成分外尚包含本領域已知的適當載體。
對於肌內、腹膜內、皮下和靜脈內使用,本發明化合物通常以無菌水溶液或懸浮液提供,緩衝至適當的pH和等張性。適當的水性載劑包括林格氏溶液(Ringer's solution)和等張性氯化鈉。本發明的水性懸浮液可包括懸浮劑,例如纖維素衍生物、海藻酸鈉、聚乙烯吡咯烷酮和黃耆膠,以及潤濕劑如卵磷脂。用於水性懸浮液的適當防腐劑包括對-羥基苯甲酸乙酯和對羥基苯甲酸正丙酯。
本發明化合物亦可以脂質體配方形式存在。
對於口服投藥,可將化合物或化合物群配製成固體或液體製劑,例如膠囊、片劑、錠劑、口含錠、菱形錠、融化物、粉劑、顆粒劑、溶液、懸浮液、分散劑或乳劑(其中溶液、懸浮分散劑或乳劑可為水性或非水性)。該固體單位劑型可為膠囊,其可為普通的硬-或軟-殼明膠類型,其包含例如界面活性劑、潤滑劑和惰性填充劑,例如乳糖、蔗糖、磷酸鈣和玉米澱粉。
在另一實施例中,將本發明化合物與常規的錠劑基質如乳糖、蔗糖和玉米澱粉,係與黏合劑如阿拉伯膠、玉米澱粉或明膠;旨在幫助該錠劑投予後崩解和溶解之崩解劑例如馬鈴薯澱粉、海藻酸、玉米澱粉和瓜爾豆膠;旨在增進該錠劑顆粒的流動並防止錠劑材料黏附在錠劑模具和沖頭的表面之潤滑劑,例如滑石、硬脂酸酸、硬脂酸鎂、硬脂酸鈣或硬脂酸鋅;旨在提高錠劑的美觀品質並使患者更容易接受之染料、著色劑和香味劑,一同壓製。
用於口服液體劑型的適當賦形劑包括稀釋劑如水和醇,例如乙醇、苯甲醇和聚乙烯醇,添加或不添加醫藥上可接受的界面活性劑、懸浮劑或乳化劑。
本發明化合物亦可以腸胃外投藥,即皮下、靜脈內、肌內或腹膜內投藥。
在此實施例中,該化合物係以溶於生理上可接受之稀釋劑中的可注射劑量與藥物載體(可為無菌液體或液體混合物)一起提供。適當的液體包括水、生理食鹽水、葡萄糖水溶液和相關的醣類溶液、醇(例如乙醇、異丙醇或十六烷醇)、二醇(例如丙二醇或聚乙二醇)、甘油縮酮(例如2,2-二甲基-1,3-二氧戊環-4-甲醇)、醚(例如聚(乙二醇)-400)、油、脂肪酸、脂肪酸酯或甘油酯,或乙醯化脂肪酸甘油酯(添加或不添加醫藥上可接受的界面活性劑(如肥皂或去污劑))、懸浮劑(例如果膠、卡波姆(carhomer)、甲基纖維素、羥基丙基甲基纖維素或羧基甲基纖維素),或乳化劑和其他醫藥上的佐劑。適用於本發明的腸胃外製劑的適當油類為石油、動物、植物或合成來源者,例如花生油、大豆油、芝麻油、棉籽油、玉米油、橄欖油、凡士林和礦物油。適當的脂肪酸包括油酸、硬脂酸和異硬脂酸。適當的脂肪酸酯為例如油酸乙酯和肉荳蔻酸異丙酯。
適當的皂類包括脂肪族鹼金屬鹽、銨鹽和三乙醇胺鹽,以及適當的清潔劑包括陽離子清潔劑,例如二甲基二烷基鹵化銨、烷基吡啶鎓鹵化物(alkyl pyridinium halides)和烷基胺乙酸酯;陰離子清潔劑,例如烷基、芳基和烯烴磺酸鹽、烷基、烯烴、醚和甘油單酸酯硫酸鹽,以及磺基琥珀酸鹽;非離子型清潔劑,例如脂肪胺氧化物、脂肪酸烷醇醯胺,和聚氧乙烯-聚丙烯共聚物;以及兩性清潔劑,例如烷基-β-胺基丙酸酯和2-烷基咪唑啉季銨鹽,以及其混合物。
本發明的腸胃外組成物通常在溶液中含有約0.5至約25 重%之本發明使用的化合物。亦可使用防腐劑和緩衝劑。為了最小化或消除注射部位的刺激,此類組成物可包含親水性-親脂性平衡(HLB)為約12至約17的非離子型界面活性劑。此類配方中的界面活性劑量為約5至約15重%。該界面活性劑可為具有上述HLB的單一成分,或可為具有所需HLB的二或更多種成分的混合物。用於腸胃外配方的界面活性劑範例為聚乙烯脂肪酸去水山梨醣酯,例如單油酸去水山梨醣酯,以及環氧乙烷與疏水性鹼的高分子量加成物,其經由環氧丙烷與丙二醇縮合而形成。
本發明使用的一或多種化合物亦可局部投予,當這樣做時,該載體可適當地包含溶液、軟膏或凝膠基質。例如,該基質可包含以下一或多者:凡士林、羊毛脂、聚乙二醇、蜂蠟、礦物油、稀釋劑如水和酒精,以及乳化劑和穩定劑。局部配方可包含約0.1至約10% w/v(每單位體積的重量)之化合物濃度。
當輔助使用時,本發明使用的化合物或化合物群可配製為與一或多種其他藥物一同使用。因此,輔助用途可反映於設計成與其他藥物相容(或協同作用)的特定單位劑量,或其中該化合物或化合物群係與一或多種酵素混合的配方。輔助用途亦可反映於本發明醫藥套組的組成物中,其中本發明化合物與該酵素共包裝(例如作為單位劑量陣列的一部分)。輔助用途亦可反映於與化合物或化合物群及/或酵素的共投藥相關之資訊及/或說明中。化妝品配方
本發明的化妝品組成物可選自例如保濕組成物、清潔組成物或對皮膚提供助益的任何組成物。本發明的化妝品組成物可包含化妝品上可接受的賦形劑或載體,例如選自以下所述者。
在一實施例中,該化妝品組成物為清潔組成物。適當的清潔組成物在室溫下為固體或半固體。適用的清潔組成物範例包括但不限於脂肪酸皂、包括甘油皂、合成清潔劑和其混合物。固體清潔組成物在1990年版的Soap Technology中有大量揭示,在此併入本案以作為參考資料。較佳該清潔組成物為可流動的。
在本發明之一實施例中,該清潔組成物包含甘油皂。可用於本發明的甘油皂範例包括但不限於美國專利4,405,492和4,879,063中公開者,其在此併入本案以作為參考資料。
適當的脂肪酸皂範例包括衍生自約10至22(包括羧基碳)個烴鏈長度的皂類,且可為飽和或不飽和的。該皂類可為如鈉鹽、鉀鹽、銨鹽、三乙醇銨鹽及其混合物。
適當的合成清潔劑包括本領域已知用於所需目的者。用於個人清潔的清潔劑範例包括羥乙磺酸鹽、肌胺酸鹽和甘油醚磺酸鹽,其可為純鏈長變異物或衍生自商業油脂例如椰子油者。其他適當的清潔劑包括陰離子醯基肌胺酸鹽、甲基丙烯酸牛磺酸鹽、N-醯基麩胺酸鹽、烷基磺基琥珀酸鹽、烷基磷酸酯、乙氧基化烷基磷酸酯、十三烷基硫酸鹽、蛋白質縮合物、乙氧基化烷基硫酸鹽和烷基胺氧化物的混合物、甜菜鹼、磺基甜菜鹼和其混合物。包括具有1至12個乙氧基的烷基醚硫酸鹽,尤其是十二烷基醚硫酸銨和十二烷基醚硫酸鈉。
該化妝品組成物可為保濕組成物。
本發明化妝品組成物的其他任擇性成分包括但不限於香味劑、香料、防腐劑、著色劑、染料、抗結塊劑和個人護理成分,包括但不限於皮膚和頭髮護理成分。
可用於本發明的適當個人護理成分範例包括但不限於安全和有效量的:保濕劑、防曬活性劑、皮膚安撫劑、抗刺激劑、抗發炎劑、潤膚劑、調理劑、保濕劑、除臭劑、止汗劑、人工曬黑劑、抗菌劑、抗痤瘡劑、抗皺劑、抗皮膚萎縮劑、緊膚劑、止癢劑、抗真菌劑、局部麻醉劑、膚色平衡劑、活性天然成分、可使多餘毛髮出現最小化或阻止其再生的試劑、皮膚紋路修飾劑和其他清潔劑。
在一實施例中,該化合物可藉由使用油包水(w/o)乳液,自水或酒精性水萃取物中使用,例如用於治療皮膚乾燥治療和潤膚應用。
潤膚劑藉由其保留在皮膚表面或角質層中作為潤滑劑、減少剝落和改善皮膚外觀的能力而發揮作用。典型的潤膚劑包括脂肪酸酯、脂肪醇、礦物油、聚醚矽氧烷共聚物及類似物。適當的潤膚劑範例包括但不限於,聚丙二醇(“PPG”)-15硬脂基醚、PPG-10鯨蠟基醚、硬脂醇聚醚-10(steareth-10)、油醇聚醚(oleth-8)、PPG-4月桂基醚、維生素E乙酸酯、PEG- 7椰子油酸甘油酯、羊毛脂及其組合。較佳為維生素E乙酸酯、PEG-7椰子油酸甘油酯及其組合。
適當的保濕劑範例包括多元醇。 適當的多元醇包括但不限於丙三醇(也稱為甘油)、聚烷基二醇、亞烷基多元醇及其衍生物,包括丙二醇、二丙二醇、聚丙二醇、聚乙二醇及其衍生物、山梨醣醇、羥丙基山梨醣醇、己二醇、1,3-二丁二醇、1,2,6-己三醇、乙氧基化甘油、丙氧基化甘油,以及其混合物。
適當的皮膚安撫劑包括但不限於泛醇、比沙泊洛爾(bisabolol)、尿囊素、蘆薈及其組合。
適當的調理劑包括但不限於聚二甲基矽氧烷丙基PG-甜菜鹼、聚二甲基矽氧烷共聚多元醇、聚季銨鹽-10、瓜爾膠(guar)、瓜爾膠衍生物及其組合。適當的抗痤瘡活性成分包括但不限於水楊酸、硫、乳酸、乙醇酸、丙酮酸、尿素、間苯二酚、N-乙醯半胱胺酸、視黃酸、過氧化苯甲醯、吡羅克酮乙醇胺鹽(octopirox)、三氯沙(triclosan)、壬二酸、苯氧基乙醇、苯氧基丙醇、類黃酮,其衍生物及其組合。較佳為水楊酸和過氧化苯甲醯。範例
以下將以具體範例描述本發明。這些僅為示範性,且僅出於說明目的:它們並非以任何方式限制所申明或所描述的發明範圍。這些範例構成目前預期用於實施本發明的最佳模式。範例1 :idoBR1 對於唾液酸酶的抑制 引言
唾液酸酶或神經胺酸酶為可催化末端唾液酸從寡醣和醣共軛物上切割下的酵素。它們在調節生物系統中含唾液酸分子之代謝上扮演重要角色。它們亦為許多病毒和致病細菌(如福賽斯坦納氏菌(Tannerella forsythia
))的毒力因子。據報導,人類嗜中性顆粒細胞中的唾液酸酶活性在宿主發炎反應中扮演重要角色((Glanz, V.Y., 2019, European J. Pharmacol. 842, 345)。
方法
:唾液酸酶測定法係使用2.8 mM和0.28 mM抑制劑(或不加抑制劑的水)和2.5 nM唾液酸酶(包括來自福賽斯坦納氏菌(T. forsythia
)的NanH),靜置於20 mM磷酸鈉緩衝液中,其存在有0.1 mM甲基繖形酮-N-乙醯神經胺酸,pH 7.2。藉由加入pH 10.5之60 mM碳酸鈉緩衝液,在30秒和60秒時停止反應。螢光甲基繖形酮(MU)的釋放係藉由測量450 nm放光、350 nm激發的螢光放射來定量。唾液酸酶活性百分比係以在30秒和60秒間之螢光變化表示,與沒有抑制劑的反應相較。反應重複進行三次。結果
idoBR1非明顯劑量依賴地抑制唾液酸酶,在所使用的兩種濃度下皆具有超過30%的抑制作用(2.8 mM [36%]和0.28 mM [42%])。在兩種濃度下都觀察到相似的抑制作用,說明該抑制作用為非競爭性。範例2 :THP-1 細胞中內生性唾液酸酶活性測定法的抑制作用 引言
本研究目的為測定idoBR1或含有超過1% idoBR1的黃瓜萃取物(Q-actin批次B17CF001)是否會影響人類THP-1(單核細胞樣)細胞培養物中唾液酸酶的活性。此研究結果可能為唾液酸酶表現降低或該酵素被idoBR1抑制的組合。方法 處理THP-1 細胞株以進行 唾液酸酶活性測試
在補充有巰基乙醇和麩胺醯胺的RPMI培養基中培養THP-1細胞,使其在培養瓶中達到80%匯集度,之後抽出並以1500 rpm離心5分鐘。之後將細胞沉澱物重新懸浮於1 ml RPMI完全培養基中,並常規使用血球計計數。將細胞(5x106
)與PMA(10 ng/ml)在不同的培養皿中培養,以分化THP-1細胞。為了測定唾液酸酶活性,分別使用濃度為100 μg/ml至12.5 μg/ml及200 μg/ml至25 μg/ml的idoBR1和黃瓜萃取物-Q-actin(批號B17CF001)預處理THP-1細胞1小時,之後進行24小時LPS(1 μg/ml刺激)。培養後,細胞用於測定唾液酸酶活性。
將THP-1細胞以磷酸鹽緩衝液(PBS)洗滌,並重新懸浮於冰冷的緩衝液中,該緩衝液包含0.25 M蔗糖、1 mM EDTA和0.2 mM苯基甲基磺醯基氟。細胞懸浮液於冰上進行超音波處理15秒,在低設定(6%振幅)下(VibracellTM; Sonics and Materials Inc.,Newtown,CT),之後於4°C以25,000 g離心15分鐘。所得上清液用於測定溶酶體唾液酸酶活性。該上清液之蛋白質定量係使用Bio-Rad蛋白質測定套組進行。為了測定溶酶體的唾液酸酶活性,將200 μg總蛋白質與40 nmol之4-甲基繖形醯-α-N-乙醯基-D-神經胺酸(Sigma)、溶酶體唾液酸酶-特異性受質、10 μmol乙酸鈉緩衝液(pH 4.6),以及牛血清白蛋白200 μg,總體積為200 μl混合。唾液酸酶反應係於37℃下進行1小時,並以加入0.25 M甘胺酸NaOH,pH 10.4終止反應。在365 nm激發波長和448 nm放射波長下,以螢光法(Synergy 2 多模組微盤讀取儀)測量釋放出的4-甲基繖形酮。發現唾液酸酶活性在16小時細胞培養時間點達最大值。結果 IdoBR1 對於內源唾液 酸酶活性的抑制
黃瓜萃取物 批次 B17CF007(Q-Actin ) 對內源 性 唾液酸酶活性的抑制
唾液酸酶活性/mg蛋白質 時間(小時) | |||||
樣本 | 濃度 µg/ml | 4 | 8 | 16 | 24 |
培養基對照組 | 0 | 8.51 | 6.45 | 7.29 | 4.09 |
LPS (1μg/ml) | LPS | 100.00 | 154.17 | 208.33 | 125.00 |
IdoBR1 | 12.5μg/mL + LPS | 91.30 | 129.95 | 186.34 | 108.47 |
25μg/mL + LPS | 86.48 | 121.84 | 178.24 | 103.85 | |
50μg/mL + LPS | 79.35 | 109.77 | 130.21 | 88.83 | |
100μg/mL + LPS | 72.15 | 99.32 | 115.16 | 78.66 |
唾液酸酶活性/mg蛋白質 時間(小時) | |||||
樣本 | 濃度 µg/ml | 4 | 8 | 16 | 24 |
培養基對照組 | 0 | 8.51 | 6.45 | 7.29 | 4.09 |
LPS (1 μg/ml) | LPS | 100.00 | 154.17 | 208.33 | 125.00 |
黃瓜萃取物 B17CF007 | 25 μg/mL + LPS | 95.47 | 134.05 | 199.07 | 114.11 |
50 μg/mL + LPS | 88.94 | 124.25 | 187.50 | 109.16 | |
100 μg/mL + LPS | 81.80 | 113.87 | 145.83 | 92.82 | |
200μg/mL + LPS | 74.10 | 102.92 | 128.47 | 75.46 |
發現唾液酸酶活性在LPS(1 μg/ mL)處理後的16小時達到最高,因此該培養時間用於進一步評估idoBR1和黃瓜萃取物對THP-1細胞中唾液酸酶活性的影響。藉由IdoBR1 ,以測試樣本處理2 小時,之後以LPS 刺激16 小時的THP-1 細胞之相對唾液酸酶活性
藉由黃瓜萃取物批號B17CF007 (Q-Actin) ,以測試樣本處理2 小時,之後以LPS 刺激16 小時的THP-1 細胞之相對唾液酸酶活性
樣本 | 濃度 μg/ml | RFU | 唾液酸酶活性/mg蛋白質 | 相對唾液酸酶活性/mg蛋白質 時間(小時) |
培養基對照組 | 0 | 63 | 7.29 | 0.04 |
LPS 1μg/ml | 1800 | 208.33 | 1.00 | |
idoBR1 | 12.5 | 1610 | 186.34 | 0.89 |
25 | 1540 | 178.24 | 0.86 | |
50 | 1125 | 130.21 | 0.63 | |
100 | 995 | 115.16 | 0.55 |
樣本 | 濃度 μg/ml | RFU | 唾液酸酶活性/ mg蛋白 | 相對唾液酸酶活性/ mg蛋白 |
培養基對照組 | 0 | 63 | 7.29 | 0.04 |
LPS 1μg/ml | 1800 | 208.33 | 1.00 | |
黃瓜萃取物 | 25 | 1720 | 199.07 | 0.96 |
50 | 1620 | 187.50 | 0.90 | |
100 | 1260 | 145.83 | 0.70 | |
200 | 1110 | 128.47 | 0.62 |
與LPS對照組相較,於50 μg/ml和100 μg/ml測試的標準idoBR1,顯示出相對唾液酸酶活性的最大降低量分別為0.63和0.55。與對照組(LPS)相較,100 μg/ml和200 μg/ml的Q-Actin之相對唾液酸酶活性降低的最大值分別為0.7和0.62。範例3 :使用ELISA 測定經CD44-HA( 透明質酸 ) 處理之THP-1 細胞,在idoBR1 存在下的結合活性 引言
CD44已證明涉及造血、回歸至黏膜淋巴組織以及淋巴細胞浸入至發炎組織。透明質酸(HA)與CD44和CD168(RHAMM)的相互作用可誘導多種細胞行為,包括酪胺酸激酶、蛋白激酶C、FAK和PI3K、MAPK、NFκB和RAS,以及發炎與癌症所需的細胞骨架成分的活化。儘管大多數細胞會表現某種形式的CD44,但並非所有細胞都會構成性地結合至HA(Kryworuchko, M. et al., 1999, Cellular Immunol., 194, 54; Nandi et al., 2000, J. Biol. Chem., 275, 14939)。功能性活化的HA黏合劑CD44是經由MAPK活化誘導唾液酸酶而產生的。為了了解MAPK在LPS誘導的發炎反應中的作用而進行的研究顯示,MAPK p42/44介導的TNF-α產生以及隨後TNF-α介導的p38活化,會因唾液酸酶活性而產生HA黏附性CD44(Gee, K. et al., 2003, J Biol Chem. 278, 37275)。方法
在補充有巰基乙醇和麩胺醯胺的RPMI培養基中培養THP-1細胞,使其在培養瓶中達到80%匯集度,之後抽出並以1500 rpm離心5分鐘。之後將細胞沉澱物重新懸浮於1 ml RPMI完全培養基中,並常規使用血球計計數。在各單獨培養皿中將細胞(5x106
)與Phorbol 12-肉荳蔻酸酯13-乙酸酯(PMA)(10 ng/ml)一同培養,以引發THP-1細胞分化。為了測定CD44-HA的結合活性,將THP-1細胞分別以濃度為100 μg/ml至12.5 μg/ml及200 μg/ml至25 μg/ml的idoBR1或黃瓜萃取物-Q-actin(批號B17CF001)預處理1小時,之後進行LPS (1 μg/ml)刺激24小時。培養後,將細胞裂解物用於進一步分析。
將抗CD44單株抗體(Invitrogen,2 μg)溶於50 mM碳酸鹽/碳酸氫鹽緩衝液(pH 9.6)中,塗覆於96孔盤的每一孔中,並在4℃下靜置過夜。使用含0.05% Tween 20的PBS(PBS-T洗滌液)除去未結合的抗體。各孔使用1% BSA進行阻斷,並在37°C下靜置1小時。各孔使用200 μl之PBS-T洗滌液徹底洗滌三次。將50 μl細胞裂解物加入各孔中,並在37℃下靜置1小時。之後各孔以加入200 μl的PBS-T洗滌三次,在每次清洗之前將各孔浸泡30秒。加入生物素化透明質酸(HA)抗體,之後加入鏈親和素(Streptavidin)-HRP,形成一免疫複合物,並在37°C下靜置60分鐘。溶液抽出,並將各孔以200 μl洗滌溶液浸泡30秒進行洗滌三次。每孔中加入50 μl的色原質A和色原質B二者。將盤在37°C下避光靜置15分鐘。加入50 μl終止溶液終止反應,並在450 nm處讀取吸光度。結果 IdoBR1 對於CD44-HA 結合的抑制
黃瓜萃取物 批次 號 B17CF007(Q- Actin) 對於 CD44-HA 結合 的 抑制
樣本 | 濃度 μg/mL | CD44-HA (ng/mL) | CD44-HA位準的降低% |
對照組 | LPS | 110.45 | 0.00 |
idoBR1 | 12.5 | 101.48 | 8.12 |
25 | 94.93 | 14.05 | |
50 | 88.43 | 19.93 | |
100 | 81.04 | 26.62 |
樣本 | 濃度 μg/mL | CD44-HA (ng/mL) | CD44-HA位準的降低% |
對照組 | LPS | 110.45 | 0.00 |
黃瓜萃取物 | 12.5 | 103.13 | 6.63 |
50 | 97.78 | 11.47 | |
100 | 89.52 | 18.95 | |
200 | 76.65 | 30.60 |
在LPS刺激的(1 μg/ ml)的THP-1細胞中發現,與CD44結合的HA為110.45 ng/ml。在LPS-誘發發炎反應的THP-1細胞中,100 μg/ml的Ido-BR1表現出最高的CD44-HA位準降低(26.62%),與LPS對照組相較。200 μg/ml之黃瓜萃取物-Q-Actin顯示在THP-1細胞中LPS誘發之發炎反應中,CD44-HA位準的降低量最高(30.60%),與LPS對照組相較。範例4 :人類血液中idoBR1 和Q-Actin 黃瓜萃取物會減少TNF- α的產生 引言
TNF-α是由單核細胞(巨噬細胞)和T淋巴細胞產生的細胞因子,為產生發炎反應的一系列因素中之一關鍵元素,且在作為疾病狀態的主要協調者上,具有許多多效作用(Beutler, B. et al., 1989, Annual Review of Immunology, 7, 625)。TNF-α的生物學效應取決於其濃度和生成部位:在低濃度時,TNF-α可能會產生所需的體內平衡和防禦功能,但在高濃度下,系統性或在某些組織中,TNF-α可與其他細胞因子協同作用,尤其是介白素1(IL-1),而惡化許多發炎反應。本研究目的在於評估idoBR1或黃瓜萃取物與idoBR1一同的抗發炎活性,就調節人類全血中TNF-α位準的能力而言。方法
血液和白膜層(buffy coat)部分,係由Scottish National Blood Transfusion Service (SNBTS), Glasgow, UK提供。Ficoll Histopaque (1.077 g/l)、脂多醣(來自馬流產沙門氏菌(Salmonella abortus equi
))購自Sigma-Aldrich Co. Ltd.(英國)。PGE來自開曼化學公司(Ann Arbor, MI)。用於TNF-α ELISA測定法的人類TNF-α抗體對來自Invitrogen/Life Sciences Europe。所有藥物皆溶解於RPMI 1640培養基中(來自英國Gibco BRL)。
血液在捐血後即可使用,無需任何進一步處理。其由蘇格蘭國家輸血服務局(Scottish National Blood Transfusion Service)從正常健康捐獻者友善提供的,所有人經測試確認為HIV、B型肝炎和C型肝炎、CMV和寄生蟲病如瘧疾,呈陰性反應(由國家輸血服務局進行檢測)。本實驗室亦確認捐血者在採血時並無急性發炎疾病,藉由測量其TNF-α基礎位準,其始終< 50 pg/ml。刺激細胞並測定其TNF- α
如結果所示,將全血的等分試樣(800 μl)與溶解在RPMI 1640中的化合物,一同靜置適當的預靜置時間,之後添加LPS,並在37°C、含5%二氧化碳的潮濕大氣(100%)中,繼續靜置20小時。靜置期間結束時,在室溫下以10,000 g離心30秒收集血漿或培養基的上清液,並使用人類TNF-α ELISA系統(BioSource Europe S.A., Belgium,由Invitrogen提供)測量TNF-α的位準。結果
下列二表顯示黃瓜萃取物和idoBR1對於人類血液中LPS-誘發的TNF-α具有強活性。結果顯示,含有0.09% idoBR1的黃瓜萃取物(先導Q-Actin)可降低TNF-α,而idoBR1在低於10 µM時仍有效,並證實僅idoBR1便可發揮黃瓜萃取物的抗發炎作用。Q-actin所含的idoBR1比此處使用的先導萃取物中所含者多10至100倍。具有低10倍的idoBR1之Q-actin,對於TNF-α的作用低10倍(數據未顯示)。
第二項研究顯示,預靜置後人類血液中的idoBR1活性更高(在0.01 μM時即為顯著)。經過48小時預靜置的idoBR1之IC50
經計算,在血液中為182 nM,而用於抑制人類單核細胞株THP-1細胞產生TNF-α時為27 nM。測量台盼藍(trypan blue)攝入或MTT染料轉化時發現,idoBR1不會顯著改變THP-1細胞的存活率。idoBR1(10 μM)的抑制作用與進行同樣以地塞米松(dexamethasone)(50 µM)進行預處理,具有可比擬的抑制作用,分別抑制> 50%和> 65%。僅米非司酮(Mifepristone)(一種醣皮質激素受器拮抗劑)與LPS一同便會大幅增加THP-1細胞中的TNF-α產生,然而,在地塞米松(dexamethasone)的存在下,它會逆轉地塞米松(dexamethasone)的抑制作用,但無法逆轉idoBR1的抑制作用。數據清楚地顯示,idoBR1可抑制人類血液中TNF-α的產生。因此,顯示其可為有效的抗發炎劑。亦顯示其可能經由一種不同於類固醇受器途徑的新機制作用。
下表顯示各種idoBR1 濃度對於人類血液中LPS- 刺激的TNF- α產生之作用。全血與各種不同濃度的idoBR1 預靜置 48 小時,然後加入LPS(10 μg/ml) ,並繼續靜置20 小時。於37 °C 下(5% CO2 ,100% 濕度) 靜置後 ,經由離心從血液中收集血漿,並以ELISA 測量血漿樣本中TNF- α的位準
。
數值以平均值±s.d表示,n =3。*表示與單獨LPS(無idoBR1)相較,P < 0.05。
idoBR1 µM | 0 | 0.01 | 0.1 | 1 | 10 |
TNF-α pg/ml 血漿 (無LPS) | 200 | 200 | |||
TNF-α pg/ml 血漿 + LPS | 1650 | 1680 | 950* | 490* | 500* |
下表顯示各種黃瓜萃取物(0.09% idoBR1) 濃度對於人類血液中LPS- 刺激的TNF- α產生之作用。全血與各種不同濃度的黃瓜Q-Actin 萃取物預靜置48 小時,之後加入LPS(10 μg/ml) ,並繼續靜置20 小時。於37 °C(5% CO2 ,100% 濕度) 下靜置後 ,經由離心從血液中收集血漿,並以ELISA 測量血漿樣本中TNF- α的位準。數值以平均值± s.d 表示,n=3 。* 表示與單獨LPS 相較,P < 0.05
。
範例5 :idoBR1 和黃瓜萃取物對於經LPS 刺激的THP-1 細胞中的細胞因子IL-10 、IL-12 和IL-1 β的作用 引言
黃瓜萃取物濃度 mg/ml | 0 | 0.02 | 0.2 | 2 |
TNF-α pg/ml 血漿(無 LPS) | 200 | 200 | ||
TNF-α pg/ml 血漿 + LPS | 1650 | 1750 | 1250* | 650* |
IL-10為一種抗發炎細胞因子,且為一促發炎細胞因子的重要負調節劑。在不同的免疫活化條件下,包括T細胞、B細胞和單核細胞/巨噬細胞等多種細胞類型會分泌IL-10 (Moore, K. et al., 1993, Annu. Rev. Immunol., 11, 165)。體外研究顯示IL-10會抑制IL-1β、IL-6、TNF-α、顆粒細胞巨噬細胞集落-刺激因子和IL-12的釋放和功能(Casatella, M. et al., 1993, J. Exp. Med., 178, 2207; de Waal Malefyt, R. et al., 1991, J. Exp. Med., 174, 1209; Fiorentino, D. et al., 1991, J. Immunol., 147, 3815),因而提出一種控制免疫反應和發炎的正常內源性回饋機制(Asadullah, K. et al., 1998, J. Clin. Invest. 101, 783;, Joosten, L. et al., 1997, Arthritis Rheum., 40, 249)。研究顯示,IL-10對於IL-12、p40和p35以及TNF-a的基因表現發揮抑制作用,主要為轉錄層級 (Aste-Amezaga, M. et al., 1998, J. Immunol., 160, 5936)。在涉及數種自體免疫性疾病病理學的促發炎性細胞因子中,IL-12為產生IFN-γ和輔助T細胞(Th)1發展自體免疫反應的主要刺激物(Paunovic, V. et al., 2008, Rheumatology, 47, 771)。已證明IL-12與多種細胞因子可協同作用並誘導IFN-γ和促發炎細胞因子的產生。在感染或LPS刺激時,單核細胞/巨噬細胞會與TNF-α一起作用產生IL-1β而介導發炎反應。其獨立地或與其他介質組合而誘導發炎反應和分解代謝作用。IL-1β對細胞的生物性活化是藉由與膜受器,即IL-1R1(IL-1RI、CD121a)的相互作用而介導,該受器亦可與IL-1α(另一IL-1基團)結合。方法 THP-1 單核細胞的ELISA 測定 用於ELISA 測定法之樣本製備
吸出培養瓶中80%匯集度的細胞,並以1500 rpm離心5分鐘。然後將細胞沉澱物重新懸浮於1 ml RPMI完全培養基中,並將1×105
個細胞/孔接種到96孔微量滴定盤的每一孔中。靜置24小時後,將PMA(10 ng/ml)加入96孔盤中,以分化THP-1細胞,測定TNF-α的產生,將THP-1細胞以idoBR1或黃瓜萃取物-Q-actin(批號B17CF001),於200 μg/ ml至25 μg/ ml連續稀釋2倍之濃度下預處理1小時,之後以LPS(100 ng/ml)刺激2小時。靜置後,將每一孔的細胞上清液吸到無菌微量離心管中,並以1000 rpm離心2至3分鐘。之後使用ELISA評估細胞上清液中細胞因子的存在。夾層ELISA 測定法
塗覆有IL-12、IL-1β或IL-10抗體的ELISA盤(美國R&D Systems)係用於以下研究。充分混合後,於每孔中加入50 μL的Assay Diluent RD1F。每孔加入200 μL樣本(idoBR1或萃取物)或對照組,並以膠帶覆蓋。在室溫下靜置2小時後,吸出每孔溶液並以洗滌緩衝液(400 μl)洗滌4次。最後一次洗滌後,藉由抽吸或傾倒除去所有剩餘的洗滌緩衝液。將盤倒置並以乾淨的紙巾吸乾。每孔中加入200 μl適當的人類共軛物,之後以新的膠帶覆蓋,並在室溫下靜置1小時。之後重複抽吸/洗滌。然後加入200 μL受質溶液至每一孔中,並在室溫下進一步避光靜置20分鐘。加入50μL終止溶液至每一孔中。孔中的顏色從藍色變為黃色。在30分鐘內,於450 nm下測量OD值。結果
不同 IdoBR1 濃度下 , IL-12 的降低 值
在不同黃瓜萃取物( 批號B17CF007) 濃度下,IL-12 的降低值
在 不同 IdoBR1 濃度下 , IL-1 β的降低 值
在不同黃瓜萃取物( 批號B17CF007) 濃度下,IL-1 β 的降低值
樣本 | 濃度 μg/mL | IL-10 (pg/mL) | IL-10位準增加的倍數 |
對照組 | 0 | 14.16 | 1.00 |
idoBR1 | 12.5 | 19.02 | 1.34 |
25 | 29.34 | 2.07 | |
50 | 37.22 | 2.63 | |
100 | 43.08 | 3.04 |
樣本 | 濃度 μg/mL | IL-10 (pg/mL) | IL-10位準增加的倍數 |
對照組 | 0 | 14.16 | 1.00 |
黃瓜萃取物 批號 B17CF007 | 25 | 23.08 | 1.63 |
50 | 31.36 | 2.21 | |
100 | 36.88 | 2.60 | |
200 | 51.68 | 3.65 |
樣本 | 濃度 μg/mL | IL-12 (pg/mL) | IL-12位準降低% |
LPS對照組 | 0.1 | 117.4 | 0.00 |
IdoBR1 | 12.5 | 104.23 | 11.22 |
25 | 97.37 | 17.07 | |
50 | 92.89 | 20.88 | |
100 | 88.60 | 24.53 |
樣本 | 濃度 μg/mL | IL-12 (pg/mL) | IL-12位準降低% |
LPS對照組 | 0.1 | 117.4 | 0.00 |
黃瓜萃取物批號B17CF007 | 25 | 102.74 | 12.49 |
50 | 95.95 | 18.27 | |
100 | 89.60 | 23.68 | |
200 | 87.02 | 25.88 |
樣本 | 濃度 μg/mL | IL-1β (pg/mL) | IL-1 β位準降低% |
LPS對照組 | 0.1 | 146.89 | 0.00 |
IdoBR1 | 12.5 | 133.30 | 9.31 |
25 | 127.63 | 13.17 | |
50 | 120.36 | 18.12 | |
100 | 111.60 | 24.07 |
樣本 | 濃度 μg/mL | IL-1β (pg/mL) | IL-1 β位準降低% |
LPS對照組 | 0.1 | 146.89 | 0.00 |
黃瓜萃取物批號B17CF007 | 25 | 136.21 | 7.27 |
50 | 130.96 | 10.84 | |
100 | 121.89 | 17.02 | |
200 | 113.80 | 22.53 |
idoBR1和黃瓜萃取物的抗發炎標誌物IL-10分別增加3.04和3.65倍。IL-10結果指出有抗發炎作用。在THP-1細胞中LPS誘導的發炎反應中,與LPS對照組相較,100 μg/mL的IdoBR1可使IL-12位準降低24.53%。在THP-1細胞中LPS誘導的發炎反應中,與LPS對照組相較,200 μg/mL黃瓜萃取物Q-actin可使IL-12位準降低25.88%。在THP-1細胞中LPS誘導的發炎反應中,與LPS對照組相較,100 μg/mL的IdoBR1可使IL-1β位準降低24.07%。在THP-1細胞中LPS誘導的發炎反應中,與LPS對照組相較,200 μg/mL黃瓜萃取物Q-actin顯示出最高的IL-1β位準降低值(22.53%)。範例6 :以Q-actin 搭配重量訓練可增加人體血液中的IL-10 引言
我們已顯示idoBR1和黃瓜萃取物(Q-actin)對於THP-1細胞中抗發炎細胞因子IL-10的調節。在此測試服用Q-actin並進行劇烈運動下(其會自然導致肌肉發炎反應),人體內細胞因子的調節。方法
在運動恢復實驗中,使用7名安慰劑個體和10名Q-actin個體,測量血液樣本中的IL-10。從第0天起,每天兩次給予個體10 mg之Q-actin,或從第0天開始給予安慰劑(均在膠囊中),持續4天,並在第1、2、3和4天(即恢復日)進行劇烈運動。在第1、2、3天以及恢復的第4天結束時的運動前與運動後採集血液樣本。以ELISA分析測量IL-10。結果
一旦開始運動,接受Q-actin的個體便表現出IL-10顯著增加的趨勢,證實了經LPS刺激的THP-1細胞獲得的結果。下表顯示規律進行劇烈運動( 加入或減去Q-actin ,具有> 1%idoBR1 的黃瓜萃取物) 的個體血液中的IL-10 反應
D1-pre = 在運動前採集的血液樣本
D1-1H = 運動後1小時採集的血液樣本範例7 :idoBR1 和含有idoBR1 的黃瓜萃取物之MAPK 訊息傳遞作用 引言
基線 | D1-pre | D1-1H | D2-pre | D2-1H | D3-pre | D3-1H | D4-pre | ||
安慰劑 | 平均值 | 51.84 | 62.05 | 77.92 | 63.49 | 72.03 | 59.65 | 68.03 | 58.82 |
SD | 15.65 | 4.66 | 12.55 | 8.81 | 6.42 | 6.58 | 12.63 | 6.25 | |
SEM | 5.92 | 1.76 | 4.74 | 3.33 | 2.43 | 2.49 | 4.77 | 2.36 | |
Q-actin | 平均值 | 64.22 | 60.12 | 92.45 | 64.36 | 88.30 | 54.96 | 85.79 | 55.90 |
SD | 16.82 | 19.54 | 31.63 | 23.87 | 34.64 | 25.00 | 35.91 | 23.59 | |
SEM | 5.95 | 6.91 | 11.18 | 8.44 | 12.25 | 8.84 | 12.69 | 8.34 |
MAPK訊息級聯在發炎反應的啟動上扮演重要角色。發炎細胞因子基因的誘導需要活化MAPK,且刺激細胞外調節蛋白激酶/有絲分裂原-活化的蛋白激酶(ERK/MAPK)路徑對於下游發炎反應至關重要(Kaminska, B., 2005, Biochim. Biophys. Acta, 1754, 253; Buchholz, K. et al., 2007, Infection and Immunity, 75, 5924)。MAPK路徑對於表現發炎介導基因(包括COX-2、iNOS、IL-1β和TNF-α)也是必需的。據報導,ERK及/或p38 MAPK參與IL-1β的上調(Baldassare, J. et al., 1999, J. Immunol., 162, 5367)。方法
THP-1細胞係於補充巰基乙醇和麩胺醯胺的RPMI培養基中培養,使其在培養瓶中達到80%匯集度,然後將其吸出並以1500 rpm離心5分鐘。之後將細胞沉澱物重新懸浮於1 ml RPMI完全培養基中,並常規使用血球計計數。將細胞(5x106
)與PMA(10 ng/ml)在不同的培養皿中靜置,以分化THP-1細胞。為了測定p38和p42/44的蛋白質表現,將THP-1細胞以idoBR1-100 μg/ml和50 μg/ml,以及黃瓜萃取物(Q-actin批號B17CF001)-200 μg/ ml和100 μg/ml預處理1小時,之後以LPS(1 μg/ml)刺激2小時。靜置後,收獲細胞並分離出完整蛋白。西方印跡法流程
裂解細胞沉澱物,並使用Bio-Rad蛋白質測定法(Bio-Rad)測定蛋白質濃度。將總細胞蛋白進行8%聚丙烯醯胺SDS凝膠電泳,然後轉移到聚偏二氟乙烯膜(Thermoscientific)上。該膜以小鼠抗磷酸化-p38 mAb(Thermoscientific)或小鼠抗磷酸化-p42/44 mAb(Thermoscientific),之後使用辣根過氧化物酶偶聯的山羊抗小鼠多株抗體(Thermoscientific)進行探測。所有的免疫印跡均以ECL(Amersham Biosciences)顯化。與LPS對照組相較,100 μg/ ml和200 μg/ ml的Q-Actin樣本經測試顯示磷酸化p38的表現分別相對降低了0.92和0.83。與LPS對照組相較,50 μg/ml和100 μg/ml的idoBR1樣本經測試顯示分別降低磷酸化p38的表現0.88和0.80。與LPS對照組相較,100 μg/ml和200 μg/ml的Q-Actin樣本經測試顯示分別降低ERK 42/44的表現0.81和0.78。與LPS對照組相較,50 μg/ml和100 μg/ml的IdoBR1樣本經測試顯示分別降低ERK 42/44的表現0.80和0.76。下表顯示p42/44 的相對表現
下表顯示p38 的相對表現
。
測試樣本 | 濃度 (μg/ml) | 相對表現 |
LPS | 1 | 1.00 |
Q-actin | 100 | 0.81 |
Q-actin | 200 | 0.78 |
idoBR1 | 50 | 0.80 |
idoBR1 | 100 | 0.76 |
測試樣本 | 濃度 (μg/ml) | 相對表現 |
LPS | 1 | 1.00 |
Q-actin | 100 | 0.92 |
Q-actin | 200 | 0.83 |
idoBR1 | 50 | 0.88 |
idoBR1 | 100 | 0.80 |
因此,idoBR1和含idoBR1的黃瓜萃取物(Q-actin)均被證實能夠減少在發炎反應中扮演必要角色的MAPK訊息級聯反應。範例8 :idoBR1 的口服可利用性和體內穩定性 引言
此研究目的為研究食用黃瓜/小黃瓜中的idoBR1口服有效性,藉由測量尿液而進行。此項研究不僅顯示idoBR1的口服有效性和可能的系統性活性,同時亦支持該化合物通過膜的能力並未改變,因此亦支持其局部可利用性。方法
Parisien醃製黃瓜(種子購自Lidl 2013)是有機種植的,一名男性志願者和一名女性志願者各自在中午吃了三份。在每種情況下,消耗的新鮮重量均為260g,從所有消耗的黃瓜中取出比較用重量30g部分,並將其保存以進行分析。志願者在實驗前15小時內未吃葫蘆科(Cucurbitaceae)食物。在t=0的3小時內收集消耗前的尿液樣本,之後女性採集9小時,男性採集15小時。將30g黃瓜樣本在50%乙醇(水溶液)中均質化,萃取15小時後過濾,並將idoBR1分液與H+形式的陽離子交換樹脂IR120結合。以水洗滌管柱後,以2M氨水溶液置換出的物質遂進行乾燥(52.3 mg),並使用Pierce TriSil進行三甲基矽烷化後,以GC-MS進行分析。之後將剩餘的51 mg物質加入0.2 mg粟精胺(castanospermine),用於比較定量目的。整個尿液樣本都使用陽離子交換樹脂進行類似處理,不同之處在於,以氨水置換的材料第二次通過相同的陽離子交換樹脂(現在呈銨離子形式),以減少強鹼(其以銨離子形式結合至IR120上),僅維持未滯留的材料。將尿液idoBR1分液乾燥並加水至20 ml。每一樣本取500 μl,並加入0.025 mg的粟精胺。結果 黃瓜的GCMS 分析
此研究於Perkin Elmer Turbomass Gold GCMS上進行。光譜上於10.33分鐘處的主峰與真實的idoBR1(英國900288 PhytoQuest Ltd)的GCMS光譜匹配。真實BR1(900125, PhytoQuest Ltd)和粟精胺之間的相對反應倍數為1:2。假設反應倍數相同,則在30g樣品中idoBR1的量估計為1.5 mg,這表示志願者大約消耗了260/30 x 1.5 mg = 13 mg的idoBR1。尿液結果
在食用黃瓜之前收集的尿液樣本,在idoBR1的滯留時間點(10.33分鐘)並未出現明顯的尖峰。15小時後,與粟精胺參考峰面積相較,男性顯示出約2.4 mg的idoBR1排泄,但是為了確定質量平衡,需要更準確地測量攝入量和排泄量。女性排泄出約2.1 mg的idoBR1。此項研究證實idoBR1可以口服,且可在尿液中進行測定,這代表它可以經由口服攝入進入血流,且至少有明顯的一部分在尿液中的排泄量不改變。這說明該化合物可穿過消化道上的薄膜且在尿液中的量顯著。在尿液分析中並未觀察到明顯的共軛物。
剩餘的idoBR1似乎可在體內保留更長時間。因此,其顯示可為一種有效的抗發炎藥,且可為長效性。範例9 :idoBR1 對小膠質細胞的作用 引言
小膠質細胞是中樞神經系統(CNS)的常駐巨噬細胞。這些細胞是CNS中主動免疫防禦的主要形式。在神經退化性疾病中,例如阿茲海默症和帕金森氏症,小膠質細胞被慢性活化並促進促發炎細胞因子的釋放,因而進一步破壞正常的CNS活性。檢驗生物活性食品成分可藉由降低氧化壓力及/或減少促發炎基因表現而減輕發炎作用之程度,係引起高度關注。方法
0、20、40和80 μg/ml的idoBR1,加入或不加次最佳量之LPS,係用於小鼠小膠質細胞株BV-2的細胞培養物中。24小時後測量TNF-α和亞硝酸鹽的產生。有趣的是,發現來自Q-actin的idoBR1可有效減少受刺激的小膠質細胞產生TNF-α和亞硝酸鹽。
*計算出加/不加LPS的顯著性,以及針對LPS加0 idoBR1的測試樣本(n => 3)的顯著性
將細胞以化合物預處理30分鐘,然後再以LPS刺激24小時。所有實驗數據以至少3個實驗的平均值±SEM表示。數值係使用單向ANOVA和事後的學生紐曼·基爾斯測試進行比較。數據係使用GraphPad Prism軟體分析。 * p <0.05; ** p <0.01; *** p <0.001等效性
idoBR1 µg/ml | No LPS | 0 | 20 | 40 | 80 |
亞硝酸鹽產生µM | 3 | 14*** | 11* | 9** | 8** |
TNF-α產生pg/ml | 50 | 600*** | 500** | 470** | 410*** |
前面的描述詳述本發明目前的較佳實施例。在考慮這些描述後,本領域技術人員預期會在實施中進行許多修飾和變化。這些修飾和變化旨在包含於所附的申請專利範圍內。
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Claims (53)
- 一種用於製造包含(2R,3R,4R,5S)-3,4,5-三羥基哌啶-2-羧酸(idoBR1)之組成物的方法,該方法包含下列步驟: (a) 提供來自一植物性來源的植物材料,該植物性來源包含葫蘆科(Cucurbitaceae)家族植物; (b) 將該植物材料進行分餾,以製造富含idoBR1之萃取物; (c) 針對下述測定該萃取物:(i) 對於唾液酸酶之抑制活性;(ii)對於TNF-α之抑制活性;或(iii)IL-10刺激活性;以及 (d) 將該經測定的萃取物與化妝品上、營養品上或醫藥上可接受的賦形劑或載體一同配製,以製造化妝品組成物、營養品組成物或醫藥組成物。
- 如請求項1之方法,其中該植物性來源包含黃瓜屬(Cucumis ) 植物,例如胡瓜種(Cucumis sativus )。
- 如請求項1之方法,其中該植物性來源包含南瓜屬(Cucurbita )植物,例如,甜瓜南瓜種(Cucurbita melos )或中國南瓜種(Cucurbita moschata )。
- 如前述請求項中任一項之方法,其中該植物材料包含果實、果實部分、果實萃取物、果汁、種子及/或葉子。
- 如前述請求項中任一項之方法,其中該植物材料包含黃瓜,任擇地包含來自胡瓜種(Cucumis sativus )植物的黃瓜。
- 如前述請求項中任一項之方法,其中idoBR1係經分離的,例如以至少為下列的位準存在於該組成物中:1% w/w、5% w/w、10% w/w;15% w/w;20% w/w;25% w/w;30% w/w;35% w/w;40% w/w;45% w/w;50% w/w、60% w/w、70% w/w、80% w/w、90% w/w、99% w/w (以乾燥重量為基準)。
- 如前述請求項1至5中任一項之方法,其中idoBR1係以至多為5% w/w (以乾燥重量為基準)的位準存在於該組成物中。
- 如請求項7之方法,其中idoBR1係以至多為1% w/w (以乾燥重量為基準)的位準存在於該組成物中。
- 如前述請求項中任一項之方法,其中該步驟(d)之組成物為化妝品組成物。
- 如請求項1至8中任一項之方法,其中該步驟(d)之組成物為營養品組成物。
- 如請求項1至8中任一項之方法,其中該步驟(d)之組成物為醫藥組成物。
- 如請求項11之方法,其中該步驟(d)之組成物為:(i)呈醫藥包、套組或患者包(patient pack)的形式;或(ii)呈單位劑量形式。
- 如請求項11或12之方法,其中該配製步驟包含將該經測定的萃取物與醫藥上可接受的賦形劑混合。
- 如前述請求項中任一項之方法,其中在步驟(c)中,該萃取物係經測定其對於唾液酸酶的抑制活性。
- 如前述請求項中任一項之方法,其中在步驟(c)中,該萃取物係經測定其對於TNF-α的抑制活性。
- 如前述請求項中任一項之方法,其中在步驟(c)中,該萃取物係經測定其之IL-10刺激活性。
- 一種可由前述請求項中任一項之方法獲得或製造的組成物,係供使用於治療或預防中。
- 如請求項17所供使用的組成物,其係供使用於治療發炎病症之方法中。
- 如請求項18所供使用的組成物,其中該發炎病症係選自於:(a)非局部發炎病症(例如系統性紅斑性狼瘡(SLE)、硬皮病和過敏反應);(b)慢性前列腺炎;(c)腎絲球腎炎;(d)發炎性腸病;(e)骨盆發炎疾病;(f)再灌注損傷;(g)類風濕性關節炎;(h)移植排斥;(i)血管炎;(j)氣喘;(k)痤瘡;(l)骨關節炎;(m)口腔、黏膜或胃腸發炎;(n)眼部發炎;(o)鼻炎;(p)耳發炎;(q)類固醇-反應性發炎病症;(r)皮膚發炎疾病(例如光化性角化症、尋常性痤瘡、粉刺性痤瘡、潮紅性痤瘡、結節型痤瘡、過敏性接觸性皮膚炎、血管性水腫、大疱性類天皰瘡(bullous pemiphigoid)、皮膚性藥物反應、多形性紅斑、紅斑性狼瘡、光照性皮膚炎、乾癬性關節炎、硬皮症與蕁麻疹、乾癬、皮膚炎、異位性皮膚炎、硬皮症、類固醇-反應性皮膚發炎病症、尿毒性瘙癢症,以及與暴露於輻射、化學療法和環境刺激物有關的皮膚症狀);(s)發炎性自體免疫疾病(例如僵直性脊椎炎、克隆氏症(Crohn's disease)、潰瘍性結腸炎、阿茲海默症(Alzheimer's disease)、多發性硬化症、運動神經元症、帕金森氏症(Parkinson's disease)、慢性疲勞症候群、胰島素-依賴型糖尿病、愛迪生氏症(Addison's disease)、古巴司傑氏症候群(Goodpasture's syndrome)、IgA腎病、間質性腎炎、修格蘭氏症候群(Sjogren's syndrome),以及自體免疫性胰臟炎);(t)骨關節炎;(u)牙周疾病;(v)糖尿病腎病;(w)慢性阻塞性肺部疾病;(x)動脈粥樣硬化;(y)移植物對抗宿主疾病;(z)慢性骨盆腔發炎疾病;(a’)子宮內膜異位症;(b’)慢性肝炎;(c’)結核病和(d’)皮膚發炎,例如由於暴露於陽光、過敏原、刺激物或灼傷引起者。
- 如請求項18所供使用的組成物,其中該發炎病症為自體免疫疾病、氣喘或過敏。
- 如請求項20所供使用的組成物,其中該發炎病症為一種選自於下列的自體免疫疾病:葛瑞夫茲病(Grave’s disease);類風濕性關節炎;橋本甲狀腺炎(Hashimoto’s thyroiditis);白斑病;糖尿病(例如第I型糖尿病或第II型糖尿病);惡性貧血;多發性硬化症;腎絲球腎炎;系統性紅斑性狼瘡(SLE,狼瘡);修格蘭氏症候群(Sjogren syndrome);硬皮病;乾癬;僵直性脊椎炎;重症肌無力;天皰瘡;多發性肌炎;皮肌炎;葡萄膜炎;格林巴利症候群(Guillain-Barre syndrome);克隆氏症(Crohn's disease);潰瘍性結腸炎,以及發炎性腸病(IBD)。
- 如請求項20所供使用的組成物,其中該發炎病症為一種選自於下列的過敏:異位性過敏、過敏性鼻炎、過敏性結膜炎、異位性皮膚炎、嗜酸性粒細胞過多症(hypereosinophilia)、腸躁症候群、過敏原-誘發型偏頭痛、細菌性過敏、支氣管過敏(氣喘)、接觸性過敏(皮膚炎)、遲發型過敏、花粉過敏(花粉熱)、藥物過敏、螫刺過敏、叮咬過敏、胃腸道過敏;食物過敏;以及物理性過敏,例如寒冷性蕁麻疹、血管性水腫、膽素型蕁麻疹和光過敏症。
- 如請求項18所供使用的組成物,其中該發炎病症係選自於:移植物對抗宿主疾病;類肉瘤症;血管發炎性疾病,包括彌漫性血管內凝血、動脈粥樣硬化、川崎氏症(Kawasaki's pathology);血管炎;修格蘭氏症候群(Sjogren syndrome);乾癬關節炎;腸病性關節炎(enteropathic arthritis);反應性關節炎,以及與發炎性腸病有關的關節炎。
- 如請求項17所供使用的組成物,其係供使用於治療贅瘤形成(neoplasia)之方法中。
- 如請求項24所供使用的組成物,其中該贅瘤形成係選自於良性、癌症前和惡性贅瘤形成、過度增生(hyperlasia)、化生(metaplasia)和發育異常(dysplasia)。
- 如請求項25所供使用的組成物,其中該贅瘤形成為惡性贅瘤形成(癌症(cancer))。
- 如請求項26所供使用的組成物,其中該惡性贅瘤形成係選自於:(a)癌(carcinoma);(b)母細胞瘤;(c)白血病;(d)淋巴瘤;(e)骨髓瘤;(f)肉瘤,以及(g)混合型癌症。
- 如請求項26所供使用的組成物,其中該惡性贅瘤形成為一種選自於下列之癌的癌:膀胱、乳房(例如原發性乳房腫瘤、淋巴結陰性乳腺癌(node-negative breast cancer)、侵襲性乳房導管腺癌和非子宮內膜樣乳癌)、結腸(例如結腸直腸癌,如結腸腺癌和結腸腺瘤)、腎臟、表皮(例如惡性黑色素瘤)、肝、肺(例如腺癌、腎上腺皮質癌、鼻咽癌、小細胞肺癌和非小細胞肺癌)、食道、膽囊、卵巢、胰臟(例如外分泌胰臟癌)、胃、子宮頸、甲狀腺、前列腺、胃腸道系統(例如胃腸道間質瘤),或皮膚(例如鱗狀細胞癌)。
- 如請求項26所供使用的組成物,其中該惡性贅瘤形成為一種選自於淋巴樣白血病的白血病,例如前驅細胞白血病、成熟B細胞白血病、成熟T細胞白血病和NK細胞白血病、急性骨髓性白血病、慢性骨髓增生性疾病,以及骨髓增生異常症候群。
- 如請求項26所供使用的組成物,其中該惡性贅瘤形成為一種選自於下列的淋巴瘤:(a)霍奇金淋巴瘤(Hodgkin lymphoma);(b)非霍奇金淋巴瘤(Non-Hodgkin lymphoma),例如前驅細胞淋巴瘤、成熟B細胞淋巴瘤、成熟T細胞淋巴瘤,和NK細胞淋巴瘤;(c)博氏淋巴瘤(Burkitt lymphoma),以及(d)淋巴網狀贅瘤,例如被套細胞淋巴瘤。
- 如請求項26所供使用的組成物,其中該惡性贅瘤形成為一種選自於下列之肉瘤:骨肉瘤;軟骨肉瘤;平滑肌肉瘤;橫紋肌肉瘤;間皮瘤;纖維肉瘤;血管肉瘤或血管內皮瘤;脂肪肉瘤;膠質母細胞瘤;星狀細胞瘤;黏液肉瘤,以及間質型和混合型中胚層瘤。
- 如請求項17所供使用的組成物,其係供使用於治療病毒感染之方法中。
- 如請求項17所供使用的組成物,其係供使用於治療細菌感染之方法中。
- 如請求項33所供使用的組成物,其中該方法包含在體內抑制共生及/或致病細菌的生長。
- 如請求項34所供使用的組成物,其中該方法包含破壞宿主-細菌細胞的相互作用,及/或抑制或消除哺乳動物(例如人類)宿主中細菌生物膜的形成。
- 如請求項34或35所供使用的組成物,其中該方法包含治療或預防由細菌生物膜(例如牙齦下斑塊生物膜和黏膜生物膜)的存在而介導或為其特徵的疾病和病症。
- 如請求項17所供使用的組成物,其係供使用於治療牙周病、細菌性陰道病及/或由於福賽斯坦納氏菌(Tannerella forsythia )、齒垢坦納氏菌(Tannerella denticola )、牙齦紫質單孢菌(Porphyromonas gingivalis )或陰道加德納菌(Gardnerella vaginalis )感染引起的疾病之方法中。
- 如請求項17所供使用的組成物,其係供使用於治療動脈粥樣化形成例如動脈粥樣硬化之方法中。
- 如請求項17所供使用的組成物,其係供使用於調節哺乳動物宿主中共生細菌生長之方法中。
- 如請求項39所供使用的組成物,其中該方法包含調節哺乳動物例如人類宿主中共生細菌的組成。
- 一種如請求項17中所定義之組成物在製備一藥物的用途,該藥物係用於治療一疾病或係使用於如請求項18至40中任一項中所定義的方法中。
- 營養品、草藥或醫藥組成物,其包含可由請求項1至16中任一項的方法獲得或製造的組成物,任擇地更包含一化妝品上、營養品上或醫藥上可接受的賦形劑或載體。
- 一種用於減少皮膚腫脹或紅斑的美容方法,包含對個體投予如請求項42中所定義的組成物,例如藉由局部施用至皮膚上。
- 一種用於製造補給食品或飲料的方法,包含以下步驟:(a)提供如請求項42中所定義的組成物;以及(b)將步驟(a)的組成物添加到食品或飲料中,以製造補給食品或飲料。
- 一種用於監測化妝品、營養品或醫藥組成物的品質之方法,包含以下步驟:(a)提供該組成物之樣本;以及(b)對該樣本進行針對以下的測定:(i)對於唾液酸酶的抑制活性;(ii)對於TNF-α的抑制活性;或(iii)IL-10刺激活性。
- 如請求項45之方法,其中該化妝品、營養品或醫藥組成物包含idoBR1。
- 如請求項45或46之方法,其中該化妝品、營養品或醫藥組成物包含來自植物性來源的植物材料,該植物性來源包含葫蘆科(Cucurbitaceae)家族植物。
- 如請求項47之方法,其中該植物性來源包含黃瓜屬(Cucumis )植物,例如胡瓜種(Cucumis sativus )。
- 如請求項47或請求項48之方法,其中該植物材料包含果實、果實部分、果實萃取物、果汁、種子及/或葉子。
- 如請求項49之方法,其中該植物材料包含黃瓜。
- 如請求項50之方法,其中該植物材料包含來自胡瓜種(Cucumis sativus )植物的黃瓜。
- 一種IdoBR1,其係供使用於如請求項24至40中任一項中所定義之方法中。
- 一種如請求項24至40中任一項中所定義之治療方法,其包含向有此需要的個體投予有效量的idoBR1。
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PCT/GB2019/052098 WO2021019194A1 (en) | 2019-07-26 | 2019-07-26 | Bioactive phytochemicals |
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EP (1) | EP4003520A1 (zh) |
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CN (1) | CN114585415A (zh) |
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US4405492A (en) | 1982-03-22 | 1983-09-20 | The Procter & Gamble Company | Process for making high-glycerin soap bars |
DE3628486A1 (de) * | 1986-08-22 | 1988-02-25 | Bayer Ag | Piperidinderivate |
US4879063A (en) | 1987-06-05 | 1989-11-07 | The Dial Corporation | Process for making translucent soap bars |
CN102006869B (zh) | 2008-02-18 | 2013-11-06 | 萨米特公开有限公司 | 能量利用疾病的治疗 |
WO2010029313A1 (en) | 2008-09-11 | 2010-03-18 | Summit Corporation Plc. | Antiinfective compounds |
JP5730549B2 (ja) | 2010-11-29 | 2015-06-10 | 花王株式会社 | Cgrp応答性促進剤 |
GB201117490D0 (en) * | 2011-10-11 | 2011-11-23 | Phytoquest Ltd | Anti-inflammatory compounds |
GB2524806A (en) * | 2014-04-03 | 2015-10-07 | Invest Solutions Ltd B | Nutraceutical composition comprising a cucumber (cucumis sativus) extract |
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