TWI794200B - 預防或治療免疫發炎性皮膚疾病的方法及醫藥組合物 - Google Patents
預防或治療免疫發炎性皮膚疾病的方法及醫藥組合物 Download PDFInfo
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- TWI794200B TWI794200B TW107102071A TW107102071A TWI794200B TW I794200 B TWI794200 B TW I794200B TW 107102071 A TW107102071 A TW 107102071A TW 107102071 A TW107102071 A TW 107102071A TW I794200 B TWI794200 B TW I794200B
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- diacerein
- dermatosis
- berberine
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Abstract
一種預防或治療免疫發炎性皮膚疾病的方法。一種預防或治療免疫發炎性皮膚疾病的醫藥組合物。
Description
本發明係關於一種預防或治療免疫發炎性皮膚疾病的方法及醫藥組合物。
免疫發炎性皮膚疾病涵蓋各種類型，包括自體免疫皮膚疾病、增生性皮膚疾病、及發炎性皮膚病。免疫發炎性皮膚疾病經由發炎過程而造成健康組織的破壞、免疫系統失調、及不欲之細胞增生。
大疱性類天疱瘡(bullous pemphigoid，BP)是最常見的自體免疫起泡性皮膚疾病，通常發生在年長者身上，常約在70歲接近80歲時發病，且在高於80歲的年長者有大幅增高的發生率。
一般認為BP的致病機制包括補體活化作用、肥大細胞的去顆粒作用、嗜中性白血球及嗜伊紅性白血球的加入及活化、以及自這些作用細胞中釋放基底膜區(BMZ)降解蛋白酶。
儘管這些事件的確切順序絕大部分仍然未明，業經提出第一個導致BP形成水泡的步驟之中包括自體抗體(autoAbs)標定半胞橋小體跨膜蛋白
BP180，亦稱做膠原蛋白XVII(COL17)，其被認為是在真皮層-表皮層交界內的主要自體抗原(autoAg)。在和NC16A(BP180的細胞外區域)結合後，自體抗體啟動非Fc受器依存性的事件，導致介白素IL-6及IL-8以依存於濃度及時間的方式自基底角質細胞中釋放。此外，業經報導自體抗體與BP180結合會引發BP180的內化作用(internalization)，此內化作用在BP疾病致病機制的起始中扮演關鍵的角色(Bullous Pemphigoid IgG Induces BP180 Internalization via a Macropinocytic Pathway,Hiroyasu et al,The American Journal of Pathology,Vol.182,No.3,March 2013,p828-840)。
本案發明人發現雙醋瑞因(diacerein)及/或小蘗鹼(berberine)能夠抑制與免疫發炎性皮膚疾病相關之促發炎細胞激素的生成，以及抑制BP180的內化作用，因此具有治療免疫發炎性皮膚病(尤其是BP)的潛力。
於一實施態樣中，本發明提供一種預防或治療免疫發炎性皮膚疾病的方法，包含向有需要的個體投予一醫藥組合物，其包含醫療有效量之小蘗鹼或小蘗鹼之生物相等類似物或其醫藥上可接受的鹽類。
於另一實施態樣中，本發明提供一種預防或治療免疫發炎性皮膚疾病的方法，包含向有需要的個體投予一醫藥組合物，其包含一醫療有效量之選自以下群組之化合物：雙醋瑞因、大黃苷、單乙醯基大黃苷、或其醫藥上可接受鹽類或酯類或前驅藥。
本發明亦提供一種預防或治療免疫發炎性皮膚疾病的醫藥組合物，其包含醫療有效量之小蘗鹼或小蘗鹼之生物相等類似物或其醫藥上可接受的鹽類。
本發明亦提供一種預防或治療免疫發炎性皮膚疾病的醫藥組合物，其包含一醫療有效量之選自以下群組之化合物：雙醋瑞因、大黃苷、單乙醯基大黃苷、或其醫藥上可接受鹽類或酯類或前驅藥。
第1圖(a)所示為丙酸倍氯松(clobetasol propionate)對IL-6生成之抑制效果的統計直條圖。
第1圖(b)所示為丙酸倍氯松對IL-8生成之抑制效果的統計直條圖。
第2圖(a)所示為雙醋瑞因對IL-6生成之抑制效果的統計直條圖。
第2圖(b)所示為雙醋瑞因對IL-8生成之抑制效果的統計直條圖。
第3圖(a)所示為小蘗鹼對IL-6生成之抑制效果的統計直條圖。
第3圖(b)所示為小蘗鹼對IL-8生成之抑制效果的統計直條圖。
第4圖(a)所示為丙酸倍氯松對IL-6及IL-8之mRNA生成之抑制效果的統計直條圖。
第4圖(b)所示為雙醋瑞因對IL-6及IL-8之mRNA生成之抑制效果的統計直條圖。
第4圖(c)所示為小蘗鹼對IL-6及IL-8之mRNA生成之抑制效果的統計直條圖。
第5圖(a)所示為經螢光染色之角質細胞的共軛焦顯微鏡相片(細胞核：深藍色；BP180：亮綠色)，其經健康個體之IgG處理(右欄)或未經IgG處理(控制組，左欄)。
第5圖(b)所示為經螢光染色且經BP個體之IgG處理之角質細胞的共軛焦顯微鏡相片。
第5圖(c)所示為經螢光染色且經BP個體之IgG及不同濃度之小蘗鹼處理之角質細胞的共軛焦顯微鏡相片。
第6圖(a)所示為經螢光染色之角質細胞的共軛焦顯微鏡相片，其經健康個體之IgG處理(右欄)或未經IgG處理(控制組，左欄)。
第6圖(b)所示為經螢光染色且經BP個體之IgG處理之角質細胞的共軛焦顯微鏡相片。
第6圖(c)所示為經螢光染色且經BP個體之IgG及不同濃度之雙醋瑞因處理之角質細胞的共軛焦顯微鏡相片。
本文中「醫療上有效量」乙詞係指可在至少一個或多個病人身上減緩或減少疾病之一或多種症狀的量。
本文中「雙醋瑞因或其類似物」乙詞係指雙醋瑞因、大黃苷、單乙醯基大黃苷、或其醫藥上可接受鹽類或酯類或前驅藥。
本文中「前驅藥(prodrug)」乙詞係指任何可代謝成其原構化合物(parent compound)，並於體內以原構化合物的形式發揮其生理功能的化合物。
除非本文中另有定義，本文(尤其是申請專利範圍)中之「一」、「該」或類似用詞皆應視為包含單數及複數形式。
大黃苷(rhein)之化學名稱為9,10-二氫-4,5-二羥基-9,10-二側氧基-2-蒽羧酸，具有式(I)所示之結構，而雙醋瑞因為大黃苷的前驅藥之一，化學名稱為4,5-雙(乙醯基氧基)9,10-二氫-4,5-二羥基-9,10-二側氧基-2-蒽羧酸，具有式(II)所示之結構。雙醋瑞因於進入體循環前，會完全轉換成大黃苷，並於體內以大黃苷的形式發揮其生理功能。
雙醋瑞因係被廣泛用於治療骨關節炎的抗發炎劑，且經證實可抑制介白素-1(IL-1)的訊息傳遞。目前，可取得50毫克劑量之雙醋瑞因膠囊，其以各種商標名在不同國家銷售，包括Art 50®及Artrodar®等。
小蘗鹼(天然黃18，5,6-二氫-9,10-二甲氧基苯并(g)-1,3-苯并二氧戊環(5,6-a)喹啉鹽)為存在於藥用植物如黃連(coptidis rhizome)、黃柏、黃芩、尖頭葉十大功勞(Mahonia aquifolium)、及小檗屬中的異喹啉生物鹼。
已發現小蘗鹼及其衍生物具有抗微生物及抗瘧疾活性。其可對抗各種病原體，例如真菌、酵母菌、寄生生物、細菌及病毒。
本案發明人發現雙醋瑞因和小蘗鹼能夠抑制和免疫發炎性皮膚疾病相關之促發炎細胞激素的生成，以及抑制BP180的內化作用，而可被用於治療這些疾病。因此，本發明提供一種預防或治療免疫發炎性皮膚疾病的方法，包含向有需要的個體投予一醫藥組合物，其包含醫療有效量之小蘗鹼或小蘗鹼之生物相等類似物或其醫藥上可接受的鹽類。
在本發明方法中小蘗鹼的生物相等類似物，包括但不限於：藥根鹼(jatrorrhizine)、巴馬亭、黃連鹼、9-去甲基小蘗鹼、9-去甲基巴馬亭、13-羥基小蘗鹼、小檗紅鹼(berberrubine)、黃藤素紅鹼(palmatrubine)、9-氧-乙基小檗紅鹼、9-氧-乙基-13-乙基小檗紅鹼、13-甲基二氫小蘗鹼N-甲基鹽、四氫原小蘗鹼及其N-甲基鹽類、及9-月桂醯基小檗紅鹼氯鹽。
較佳地，該醫藥上可接受鹽類為氯化小蘗鹼(berberine chloride)。
於一實施態樣中，小蘗鹼或小蘗鹼之生物相等類似物或其醫藥上可接受的鹽類為本發明方法中主要的醫藥活性成分。
於另一實施態樣中，小蘗鹼或小蘗鹼之生物相等類似物或其醫藥上可接受的鹽類為本發明方法中唯一的醫藥活性成分。
本發明亦提供一種預防或治療免疫發炎性皮膚疾病的方法，包含向有需要的個體投予一醫藥組合物，其包含一醫療有效量之選自以下群組之化合物：雙醋瑞因、大黃苷、單乙醯基大黃苷、或其醫藥上可接受鹽類或酯類或前驅藥(即，雙醋瑞因及其類似物)。
於一實施態樣中，該化合物為雙醋瑞因。
於一實施態樣中，雙醋瑞因或其類似物為本發明方法中主要的醫藥活性成分。
於另一實施態樣中，雙醋瑞因或其類似物為本發明方法中唯一的醫藥活性成分。
於一實施態樣中，該化合物之醫療有效量為每日相當於10至200毫克之雙醋瑞因鹼。
較佳地，本發明中的個體為人類。
於一實施態樣中，所述免疫發炎性皮膚疾病係選自以下群組：急性發熱性嗜中性皮膚病、皮膚肌炎、剝落性皮膚炎、汗疱疹、嗜中性肝腺炎、無菌性膿疱症、孕婦的搔癢性蕁麻疹丘疹和斑塊、大疱性類天疱瘡、尋常型天皰瘡、疱疹性皮膚炎、妊娠期類天疱瘡、腸道疾病相關性皮膚病關節炎綜合症(bowel-associated dermatosis-arthritis syndrome)、類風濕性嗜中性皮膚病、手背嗜中性皮膚病、漿細胞性龜頭炎、龜頭包皮炎、貝賽特氏病(Behcet’s disease)、遠心性環狀紅斑、持續性色素異常性紅斑、多形性紅斑、環狀肉芽腫瘤、手部皮膚炎、光澤苔癬、扁平苔癬、硬化性萎縮性苔癬、慢性單純苔癬、小棘苔癬、錢幣狀皮膚炎、壞疽性膿皮症、肉狀瘤病、角膜下膿性皮膚病、蕁麻疹、掌蹠膿疱症、藥物性紅疹、急性廣泛性發疹性膿皰症、接觸性皮膚炎、以及暫時性棘層鬆解性皮膚病。
較佳地，該免疫發炎性皮膚疾病係大疱性類天疱瘡。
下文將參照以下實施例進一步說明本發明。惟，該等實施例僅係提供用於例示目的，而非限制本發明之範疇。
實施例
[實施例1]細胞激素生成抑制試驗
進行試驗觀察雙醋瑞因或小蘗鹼降低成人皮膚角質細胞(HaCaT細胞)內由抗BP-180(anti-BP180)免疫球蛋白G(IgG)刺激之BP相關促發炎細胞激素(IL-6或IL-8)的生成的效果。丙酸倍氯松係普遍用於治療BP及各種其他皮膚疾病的皮質類固醇，在此用作正控制(positive control)。
IgG係自正常人或BP病患血中純化而得。因此，於此試驗中，對健康捐血者或BP病患進行血液採集。經純化的IgG係用於刺激HaCaT細胞中促發炎細胞激素(如IL-6及IL-8)的生成。
血液採集
於國立臺灣大學醫學院附設醫院(NTUH)皮膚科接受診治的病患必須確診患有BP，該診斷係依據代表性的臨床發現以及偵測到IgG及/或C3在真皮層-表皮層交界處有線性沉積的證據(經由直接免疫螢光(DIF)電子顯微鏡或酵素連結免疫吸附分析法(ELISA)抗BP180 NC16A的流動的IgG自體抗體(MBL有限公司，名古屋，日本))。
自BP病患及健康志願者身上進行兩次採血。健康捐血者或BP病患的總採血量為40毫升，且每位個體單次最高的採血量為20毫升。
紀錄族群統計資料，包括年齡、性別、醫療歷史(包括BP及診斷資訊)、以及流動的正常IgG、抗BP180(anti-BP180)或抗BP230(anti-BP230)IgG自體抗體的量。
血液樣本的採集是由國立臺灣大學醫學院附設醫院的研究倫理委員會(REC)所核准，並根據赫爾辛基宣言取得受試者的告知後同意。
BP180-NC16A蛋白質的表現
BP180-NC16A表現質體係由清水弘及西江亙教授(北海道大學醫學研究所皮膚病學系，札幌，日本)所提供。將編碼有NC16A區域(77個胺基酸)的構築體插入至pGEX-6P1載體的MCS中。將質體轉形至DH5a勝任細胞中，並汲取出序列經確認為人類BP180 NC16A的DNA。為獲得大量的NC16A蛋白質，將BL21藉由引入質體來轉形，並根據製造商的指示使用Overnight Express Autoinduction System(Novagen)來表現NC16A區域蛋白質。
純化IgG
使用Hitrap Protein A HP管柱(GE Healthcare Life Sciences公司)純化健康捐血者的總血清IgG(Healthy-IgG)與經診斷患有BP之病患的總血清IgG(BP-IgG)。以0.1莫耳濃度NaPi pH 8.0(平衡)、0.1莫耳濃度檸檬酸鈉pH 6.0(清洗)、以及0.1莫耳濃度檸檬酸鈉pH 3.0(沖提)沖提出免疫球蛋白。接著，以經CNBr活化、結合有BP180-NC16A蛋白質的瓊脂糖管柱(GE Healthcare Life Sciences公司)進一步沖提出經濃縮的免疫球蛋白，即可純化出對NC16A有反應的經濃縮的特異IgG(Specific-IgG，Protein A Elu-NC16A-Elu)。藉由抗BP180-NC16A ELISA(MBL有限公司，名古屋，日本)確認經親合性純化之BP IgG配製品的免疫反應性。
細胞培養
將HaCaT細胞株(CLS Cell Lines Service，德國)培養於Dulbecco’s modified eagle medium(DMEM)培養基(補充有4.5公克/公升葡萄糖、2毫莫耳濃度L-麩胺酸、及10%胎牛血清)中。將細胞接種於24或12孔的盤內，並生長至80%的細胞融合狀態後用於之後的試驗。
細胞存活率或細胞毒性試驗
將繼代3至6次呈指數生長的細胞(3,000細胞/孔於100微升培養基內)置於96孔盤內過夜，使細胞貼附(80%細胞融合)，接著使細胞於37℃下接觸不同濃度的雙醋瑞因(0.1、1、10微莫耳濃度)或小蘗鹼(0.1、1、10微莫耳濃度)或丙酸倍氯松(0.1、1、10微莫耳濃度)，以及2毫克/毫升的Healthy-IgG、BP-IgG或Specific-IgG，時間達48小時。
在藥物處理之後，緩慢地移除細胞培養基。以溫培養基小心地清洗細胞三次，移除任何脫附及死掉的細胞。將細胞與MTT試劑(最終濃度1.0毫克/毫升)培養於細胞培養基中達2小時。使用ELISA微孔盤光譜分析儀紀錄在570奈米下吸收的變化，以測量三苯基甲脂(formazan)的量(大致直接和活細胞的數量成比例)。
促發炎細胞激素的測量
依據先前的試驗進行細胞激素的測量。簡言之，將細胞培養於單獨的培養基或添加有2毫克/毫升經純化的BP-IgG或Specific-IgG的培養基內，並在有或沒有雙醋瑞因、小蘗鹼或丙酸倍氯松(0.1、1、及10微莫耳濃度)的存在下進行培養，在培養48小時之後收集培養上清液，並儲存於-20℃以用於之後的分析。藉由ELISA(BD Biosciences公司)根據製造商的指示分析細胞培養上清液中IL-6及IL-8的量。
藉由定量即時聚合酶連鎖反應定量IL-6及IL-8 mRNA的表現
使用定量即時聚合酶連鎖反應(qPCR)定量IL-6及IL-8 mRNA的量。經BP-IgG處理過的HaCaT細胞在有或沒有雙醋瑞因、小蘗鹼或丙酸倍氯松的存在下培養48小時。使用TRIzol試劑(Life Technologies公司)依據製造商的指示自培養的HaCaT細胞中純化出全RNA。使用RevertAid First Strand cDNA
Synthesis Kit(Thermo Scientific公司)依據製造商指示溫育1微克的RNA，以自經純化的RNA反轉錄出互補DNA(cDNA)。使用SYBR® Select Master Mix(Life Technologies公司)在Mastercycler(Eppendorf)中進行定量RT-PCR。PCR混合物中含有各0.5微莫耳濃度的順向引子與反向引子。將各反應混合物置於50℃下達2分鐘及95℃下2分鐘，接著95℃下15秒及60℃下1分鐘進行40個循環。將資料與持家基因甘油醛-3-磷酸去氫酶(GAPDH)進行標準化。使用於RT-PCR的引子如下：IL-8 mRNA，5’-ACC GGA AGG AAC CAT CTC AC-3’(正向)及5’-AAA CTG CAC CTT CAC ACA GAG-3’(反向)；IL-6 mRNA，5’-GGT ACA TCC TCG ACG GCA TCT-3’(正向)及5’-GTG CCT CTT TGC TGC TTT CAC-3’(反向)；以及GAPDH，5’-ACA ACT TTG GTA TCG TGG AAG G-3’(正向)及5’-GCC ATC ACG CCA CAG TTT-3’(反向)。
統計分析
使用Student’s t test或單因子變異數分析(ANOVA)分析數據。P值小於0.05視為有統計上明顯的差異。
[結果]
於試驗期間共招募13位受試者。其中6位為正常的控制組，其他7位則最初經診斷為患有大疱性類天疱瘡(BP)。7名患有BP之病患中，有1名(案例編號第12號)因為陰性的DIF/IIF而被排除(screen-failure)。案例編號第1、2、3、4及13有升高的抗BP180 NC16A的流動的IgG自體抗體(依據ELISA)。
使用GST-Bulk Kit及B-PER Protein Extraction Reagents(Thermo公司)獲得大量的人類NC16A蛋白質，並使用PreScission Protease System進行GST-tag的切割。
為了自健康捐血者(Healthy-IgG)及經診斷確診患有BP之病患(BP-IgG)純化出血清IgG，使用Hitrap Protein A HP管柱，再利用經CNBr活化、與BP180-NC16A蛋白質偶合的瓊脂糖管柱進一步沖提出經濃縮的免疫球蛋白。藉由自初始步驟純化出之IgG(Protein A Elu)及對NC16A有反應的經濃縮的特異性IgG(Protein A Elu-NC16A-Elu，即Specific-IgG)的相對倍數變化來驗證純化效率，其最高純化倍數高達23.46及6,821IU/毫克特異性IgG。
藉由MTT試驗評估雙醋瑞因、小蘗鹼或丙酸倍氯松在不同濃度下的角質細胞細胞毒性。以0.1至10微莫耳濃度雙醋瑞因的處理對HaCaT細胞有明顯的細胞毒性，存活率降低至50%。以來自健康控制組(Healthy-IgG)、BP-IgG或BP Specific-IgG的血清樣本的處理提高HaCaT存活率至高達250%，但10微莫耳濃度雙醋瑞因的處理仍然大幅降低HaCaT的存活率。相反地，以0.1至10微莫耳濃度小蘗鹼及丙酸倍氯松的處理不會對HaCaT細胞造成明顯的細胞毒性。
HaCaT細胞與培養基單獨培養或與添加有2毫克/毫升經純化之BP-IgG或Specific-IgG之培養基一起培養，並以不同濃度雙醋瑞因、小蘗鹼或丙酸倍氯松(0、0.1、1及10微莫耳濃度)處理，且經48小時培養後收集培養上清液，再檢驗IL-6及IL-8的變化。丙酸倍氯松(正控制)的處理以劑量依存性的方式降低IL-6(第1圖(a))及IL-8(第1圖(b))的分泌。雙醋瑞因大幅降低以特異性抗BP180 IgG處理之HaCaT細胞內IL-6的分泌(第2圖(a))。相反地，0.1微莫耳濃度雙醋瑞因並未降低以特異性抗BP180 IgG處理之HaCaT細胞內IL-8的分泌。雙醋瑞因對IL-8分泌的抑制效果只有在1或10微莫耳濃度的濃度下較為顯著(第2圖(b))。
小蘗鹼未降低以特異性抗BP180 IgG處理之HaCaT細胞內IL-6的分泌(第3圖(a))。小蘗鹼以劑量依存性的方式降低經BP Specific-IgG處理之HaCaT細胞內IL-8的分泌。以BP Specific-IgG處理之細胞內的抑制效果明顯較佳(第3圖(b))。
將經BP IgG處理的HaCaT細胞與不同濃度(0、0.1、1及10微莫耳濃度)之雙醋瑞因、小蘗鹼或丙酸倍氯松一起培養達48小時。自培養的HaCaT細胞純化出全RNA，並進行定量RT-PCR(RT-qPCR)分析。結果顯示丙酸倍氯松大幅降低IL-6及IL-8 mRNA的表現量(第4圖(a))，儘管雙醋瑞因對IL-6 mRNA表現量有劑量依存性的抑制效果，但僅有在10微莫耳濃度對IL-8 mRNA有抑制作用(第4圖(b))。相反地，小蘗鹼對IL-6及IL-8的mRNA表現皆有劑量依存性的抑制效果(第4圖(c))。
以上試驗顯示雙醋瑞因及小蘗鹼對與免疫發炎性皮膚疾病相關的促發炎細胞激素的生成有抑制效果，因此具有治療免疫發炎性皮膚疾病的潛力。
[實施例2]BP180內化試驗
BP180係半胞橋小體的重要成分，其使角質細胞保持貼附於皮膚的基底膜。BP180損壞可導致角質細胞的貼附不佳，因此和皮膚疾病或起泡性疾病有關。BP180的內化作用(internalization)被認為是大疱性類天疱瘡致病機制中的關鍵角色，因此可被測量來評估此疾病。進行以下試驗以評估小蘗鹼、雙醋瑞因或大黃苷對於經BP-IgG處理之角質細胞內由自體抗體(BP-IgG)誘導之BP180內化作用及半胞橋小體破壞的效果。
方法：BP180內化作用的免疫螢光試驗
為了此BP180內化試驗，自BP病患純化出IgG及以不同IgG與藥物(雙醋瑞因或小蘗鹼)處理細胞培養物皆依照實施例1中描述的程序來進行。
將生長於玻璃蓋玻片上的角質細胞固定於4%三聚甲醛中，以磷酸鹽緩衝液(PBS)徹底清洗，再於PBS內的0.1%(v/v)Triton X-100中進行細胞透化達10分鐘。將初級抗體覆蓋於細胞上，再將製備品培養於室溫下達1小時。以PBS清洗蓋玻片上的細胞，再於室溫下施用螢光共軛次級抗體達1小時。以PBS清洗之後，將蓋玻片安裝於載玻片上。細胞核的螢光顏色是深藍色，BP180是亮綠色。以共軛焦顯微鏡檢視所有製備品。
[結果]
小蘗鹼處理
在控制組角質細胞(即，未經IgG處理)及經健康個體IgG處理之角質細胞中，BP180(亮綠色)的免疫螢光分析顯示顯著的細胞質和細胞膜的集中分布現象(第5圖(a))。相反地，在經BP-IgG處理的細胞中的BP180的細胞膜分布大幅地減少，且在細胞質中顯得更為分散，顯示發生由BP-IgG處理所引發之BP180內化作用和半胞橋小體破壞(第5圖(b))。當小蘗鹼濃度增加(0.1至10微莫耳濃度)，BP180的細胞膜集中現象也恢復了，顯示在小蘗鹼處理之後，抑制了BP180的內化作用並維持半胞橋小體的完整性(第5圖(c))。
雙醋瑞因處理
相較於控制組角質細胞(即，未經IgG處理)及經Healthy-IgG處理之角質細胞(第6圖(a))，經BP-IgG處理之角質細胞的BP180在細胞膜內的分布降低，且在細胞質內更為分散，顯示發生了由BP-IgG處理而引發的BP180內化作用(第6圖(b))。當雙醋瑞因濃度增加時(0.1至10微莫耳濃度)，BP180的細
胞膜集中現象也恢復了，顯示在雙醋瑞因處理之後，抑制了BP180的內化作用並維持半胞橋小體的完整性(第6圖(c))。
以上結果顯示雙醋瑞因及小蘗鹼皆能抑制BP180的內化作用，因此具有治療BP的潛力。
上述實施例僅係用以例示說明本發明之原理及功效，而非用於限制本發明。所屬技術領域具有通常知識者均可在不違背本發明之技術原理及精神的情況下，對上述實施例進行修改及變化。因此，本發明之權利保護範圍應如申請專利範圍所列者。
Claims (7)
- 一種醫藥組合物在製備預防或治療免疫發炎性皮膚疾病之藥物的用途，其中該醫藥組合物包括一化合物，且該化合物選自以下群組：雙醋瑞因、大黃苷及其鹽類。
- 如請求項1所述之用途，其中該免疫發炎性皮膚疾病係選自以下群組：急性發熱性嗜中性皮膚病、皮膚肌炎、剝落性皮膚炎、汗疱疹、嗜中性肝腺炎、無菌性膿疱症、孕婦的搔癢性蕁麻疹丘疹和斑塊、大疱性類天疱瘡、尋常型天皰瘡、疱疹性皮膚炎、妊娠期類天疱瘡、腸道疾病相關性皮膚病關節炎綜合症(bowel-associated dermatosis-arthritis syndrome)、類風濕性嗜中性皮膚病、手背嗜中性皮膚病、漿細胞性龜頭炎、龜頭包皮炎、貝賽特氏病(Behcet’s disease)、遠心性環狀紅斑、持續性色素異常性紅斑、多形性紅斑、環狀肉芽腫瘤、手部皮膚炎、光澤苔癬、扁平苔癬、硬化性萎縮性苔癬、慢性單純苔癬、小棘苔癬、錢幣狀皮膚炎、壞疽性膿皮症、肉狀瘤病、角膜下膿性皮膚病、蕁麻疹、掌蹠膿疱症、藥物性紅疹、急性廣泛性發疹性膿皰症、接觸性皮膚炎、以及暫時性棘層鬆解性皮膚病。
- 如請求項1所述之用途，其中該免疫發炎性皮膚疾病係大疱性類天疱瘡。
- 如請求項1所述之用途，其中該化合物係雙醋瑞因。
- 如請求項1所述之用途，其中該化合物是主要的醫藥活性成分。
- 如請求項1所述之用途，其中該化合物是唯一的醫藥活性成 分。
- 如請求項1所述之用途，其中該個體係人類。
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| CN112679492B (zh) * | 2019-10-17 | 2022-03-18 | 中国科学院上海药物研究所 | 小檗碱衍生物、其制备方法和用途 |
| CN112538081A (zh) * | 2020-12-15 | 2021-03-23 | 辽宁中医药大学 | 一种源于黄柏盐炙品的巴马红汀及其分离制备方法和用途 |
| CN114236132B (zh) * | 2021-11-26 | 2024-02-02 | 李小光 | 一种用于检测人BP180 IgG抗体的ELISA试剂盒及其应用 |
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| FR2842738B1 (fr) | 2002-07-23 | 2006-02-10 | Negma Lerads | Utilisation d'une rheine pour la preparation d'un medicament pour le traitement de l'inflammation chronique, la prevention et le traitement du rejet des transplantations d'organes et de tissus |
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| CA2566861A1 (en) * | 2004-05-17 | 2005-12-08 | Combinatorx, Incorporated | Methods and reagents for the treatment of immunoinflammatory disorders |
| CN100441183C (zh) * | 2005-08-29 | 2008-12-10 | 中国医学科学院皮肤病研究所 | 盐酸13-己基小檗碱和盐酸13-己基巴马汀制备治疗湿疹、皮炎和银屑病的药物用途 |
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| KR102275267B1 (ko) * | 2014-01-25 | 2021-07-09 | 주식회사 엘지생활건강 | 피부 개선용 조성물 |
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| JP2020505362A (ja) | 2020-02-20 |
| CN116919957A (zh) | 2023-10-24 |
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