TWI755524B - 抗過敏劑 - Google Patents
抗過敏劑 Download PDFInfo
- Publication number
- TWI755524B TWI755524B TW107114248A TW107114248A TWI755524B TW I755524 B TWI755524 B TW I755524B TW 107114248 A TW107114248 A TW 107114248A TW 107114248 A TW107114248 A TW 107114248A TW I755524 B TWI755524 B TW I755524B
- Authority
- TW
- Taiwan
- Prior art keywords
- quinolinone
- allergic
- based antibacterial
- antiallergic agent
- drug
- Prior art date
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- 239000000043 antiallergic agent Substances 0.000 title claims abstract description 38
- 239000003814 drug Substances 0.000 claims abstract description 17
- 229940079593 drug Drugs 0.000 claims abstract description 11
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims description 48
- 229930185107 quinolinone Natural products 0.000 claims description 48
- 229940124350 antibacterial drug Drugs 0.000 claims description 45
- 208000026935 allergic disease Diseases 0.000 claims description 24
- 238000002360 preparation method Methods 0.000 claims description 19
- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 claims description 18
- 229960003923 gatifloxacin Drugs 0.000 claims description 18
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- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 claims description 13
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 claims description 13
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Abstract
本發明的目的是提供新穎的抗過敏劑。
本發明提供含有喹啉酮系抗菌藥的抗過敏劑。
Description
本發明是關於具有β-己糖胺酶(β-hexosaminidase)游離抑制活性,可緩和過敏症狀的抗過敏劑。
近年,由於特定的花粉及食物等引發過敏症狀的人増加而成為社會問題,正開發緩和發作的過敏症狀的抗過敏劑及食品。
就過敏症狀的治療法而言,可大分為類固醇激素的投與等類固醇療法及抗組織胺劑等非類固醇系療法。類固醇療法對過敏症狀的緩和非常有效但長期間投與時,會有發生骨質疏鬆症、白內障、血栓症等副作用的情況。
就過敏症狀的機制而言,在嗜鹼性球及肥胖細胞等細胞內存在的顆粒中有組織胺等各種化學介質(chemical mediator)存在,在該等細胞表面上的特定部位接受抗原的刺激,引起脫顆粒化現象而化學介質被釋放於細胞外。已知由於化學介質的釋放,而引發噴嚏、流鼻水、流淚、皮膚炎、氣喘等過敏症狀。
過敏症狀的機制已經被解明,而在減少IgE 量之外,亦由天然萃取物等進行探索、研究非類固醇系療法的藥劑,其係抑制IgE與在肥胖細胞及嗜鹼性球的細胞表面上表現的高親和性的IgE受體(FcεRI)鍵結後,再由抗原橋聯而發生的肥胖細胞或嗜鹼性球的脫顆粒。
例如,可舉鳳果(mangosteen)的果皮萃取物的α-或γ-楝子素(α-或γ-mangostin)(參照專利文獻1)、黴的一種的卵苞菌屬(Oospora)菌株生產的二苯基酮衍生物的硫赭曲菌素(sulochrin)(參照專利文獻2)、由唇形花科植物萃取的雙萜(diterpene)的一種的毛喉素(forskolin)(參照專利文獻3)等。
[專利文獻1]日本特開2000-116356號公報
[專利文獻2]日本特開平8-92082號公報
[專利文獻3]日本特開2003-252786號公報
本發明的目的是提供新穎的抗過敏劑。
抗體IgE在與FcεRI鍵結後如能抑制肥胖細胞及嗜鹼性球的脫顆粒,則可直接導致過敏症狀的緩和。由於做為抑制細胞株的脫顆粒的指標,可使用β-己糖胺酶(LB Schwartz,KF Austen,and SI Wasserman,Immunologic release of beta-hexosaminidase and beta-glucuronidase from purified rat serosal mast cells,J.Immunol.,(1979)123:p.1445-1450),本發明者等,以嗜鹼性球細胞株的脫顆粒抑制做為指標而檢討β-己糖胺酶釋放抑制活性的結果,發現:以往雖未用於過敏性疾病的治療,但具有脫顆粒促進作用的報告(Furuhata等,Biol.Pharm.Bull.21(5)461-464(1998))的喹啉酮系抗菌劑具有抗過敏作用,而完成本發明。
即本發明是包含以下的〔1〕至〔4〕。
〔1〕含有喹啉酮系抗菌藥的抗過敏劑。
〔2〕如〔1〕所述的抗過敏劑,其過敏性疾病是由春季型黏膜炎(spring catarrh)、過敏性結膜炎、過敏性鼻炎、異位性皮膚炎、蕁麻疹及支氣管氣喘所成組群選出的至少1種。
〔3〕如〔1〕或〔2〕所述的抗過敏劑,其中的喹啉酮系抗菌藥是由加替沙星(gatifloxacin)、莫西沙星(moxifloxacin)、妥舒沙星(tosufloxacin)、司帕沙星(sparfloxacin)、西他沙星(sitafloxacin)、氟羅沙星(fleroxacin)、加雷沙星(garenoxacin)、左氧氟沙星(levofloxacin)、鹽酸洛美沙星(lomefloxacin hydrochloride)、鹽酸環丙沙星(ciprofloxacin hydrochloride)、依諾沙星(enoxacin)、歐氟沙星(ofloxacin)、諾氟沙星(norfloxacin)及那氟沙星(nadifloxacin)所成組群選出的1種以上的成分。
〔4〕如〔1〕至〔3〕中任一者所述的抗過敏劑,其
劑形是內服劑、軟膏劑、霜劑、液劑、點鼻劑、或點眼劑。
再者,本發明是包含以下的〔5〕至〔8-4〕。
〔5〕一種供使用之喹啉酮系抗菌藥,係用於治療過敏性疾病。
〔6〕一種過敏性疾病的治療方法,係將喹啉酮系抗菌藥投與包含人的動物。
〔7〕一種喹啉酮系抗菌藥的使用,係用於過敏性疾病的治療。
〔8〕一種喹啉酮系抗菌藥的使用,係用於製造過敏性疾病治療用醫藥。
〔5-2〕如〔5〕所述的供使用的喹啉酮系抗菌藥,其中,過敏性疾病是由春季型黏膜炎、過敏性結膜炎、過敏性鼻炎、異位性皮膚炎、蕁麻疹及支氣管氣喘所成組群選出的至少1種。
〔5-3〕如〔5〕或〔5-2〕所述的供使用的喹啉酮系抗菌藥,該喹啉酮系抗菌藥是由加替沙星、莫西沙星、妥舒沙星、司帕沙星、西他沙星、氟羅沙星、加雷沙星、左氧氟沙星、鹽酸洛美沙星、鹽酸環丙沙星,依諾沙星、歐氟沙星、諾氟沙星及那氟沙星所成組群選出的1種以上的成分。
〔5-4〕如〔5〕、〔5-2〕及〔5-3〕中任一者所述的供使用的喹啉酮系抗菌藥,其中,喹啉酮系抗菌藥是含在內服劑、軟膏劑、霜劑、液劑、點鼻劑、或點眼劑中。
〔6-2〕如〔6〕所述的過敏性疾病的治療方法,其中,
過敏性疾病是由春季型黏膜炎、過敏性結膜炎、過敏性鼻炎、異位性皮膚炎、蕁麻疹及支氣管氣喘所成組群選出的至少1種。
〔6-3〕如〔6〕或〔6-2〕所述的過敏性疾病的治療方法,其中,喹啉酮系抗菌藥是由加替沙星、莫西沙星、妥舒沙星、司帕沙星、西他沙星、氟羅沙星、加雷沙星、左氧氟沙星、鹽酸洛美沙星、鹽酸環丙沙星、依諾沙星、歐氟沙星、諾氟沙星及那氟沙星所成組群選出的1種以上的成分。
〔6-4〕如〔6〕、〔6-2〕及〔6-3〕中任一者所述的過敏性疾病的治療方法,其中,喹啉酮系抗菌藥是含在內服劑、軟膏劑、霜劑、液劑、點鼻劑、或點眼劑中。
〔7-2〕如〔7〕所述的喹啉酮系抗菌藥的使用,其中,過敏性疾病是由春季型黏膜炎、過敏性結膜炎、過敏性鼻炎、異位性皮膚炎、蕁麻疹及支氣管氣喘所成組群選出的至少1種。
〔7-3〕如〔7〕或〔7-2〕所述的喹啉酮系抗菌藥的使用,其中,喹啉酮系抗菌藥是由加替沙星、莫西沙星、妥舒沙星、司帕沙星、西他沙星、氟羅沙星、加雷沙星、左氧氟沙星、鹽酸洛美沙星、鹽酸環丙沙星、依諾沙星、歐氟沙星、諾氟沙星及那氟沙星所成組群選出的1種以上的成分。
〔7-4〕如〔7〕、〔7-2〕及〔7-3〕中任一者所述的喹啉酮系抗菌藥的使用,其中,喹啉酮系抗菌藥是含在內服
劑、軟膏劑、霜劑、液劑、點鼻劑、或點眼劑中。
〔8-2〕〔8〕所述的喹啉酮系抗菌藥的使用,其中,過敏性疾病是由春季型黏膜炎、過敏性結膜炎、過敏性鼻炎、異位性皮膚炎、蕁麻疹及支氣管氣喘所成組群選出的至少1種。
〔8-3〕如〔8〕或〔8-2〕所述的喹啉酮系抗菌藥的使用,其中,喹啉酮系抗菌藥是由加替沙星、莫西沙星、妥舒沙星、司帕沙星、西他沙星、氟羅沙星、加雷沙星、左氧氟沙星、鹽酸洛美沙星、鹽酸環丙沙星、依諾沙星、歐氟沙星、諾氟沙星及那氟沙星所成組群選出的1種以上的成分。
〔8-4〕如〔8〕、〔8-2〕及〔8-3〕中任一者所述的喹啉酮系抗菌藥的使用,其中,過敏性疾病治療用醫藥的劑形是內服劑、軟膏劑、霜劑、液劑、點鼻劑、或點眼劑。
在本發明中的喹啉酮系抗菌藥由於具有脫顆粒抑制作用,而有用於做為抗過敏劑。
[第1圖]第1圖是表示加替沙星的β-己糖胺酶的釋放抑制效果之圖。
[第2圖]第2圖是表示歐氟沙星的β-己糖胺酶的釋放抑制效果之圖。
[第3圖]第3圖是表示本發明在實驗性的大鼠過敏性結膜炎模型的加替沙星的抗過敏作用效果之圖。
[第4圖]第4圖是表示本發明的,在實驗性的大鼠過敏性結膜炎模型的歐氟沙星的抗過敏作用效果之圖。
本發明包括含有喹啉酮系抗菌藥的抗過敏劑。
本發明的喹啉酮系抗菌藥是合成抗菌藥的系列之一,是藉由抑制DNA旋轉酶(gyrase)而產生抗菌或殺菌作用的藥劑。本發明的喹啉酮系抗菌藥是含有狹義的喹啉酮系抗菌藥及新喹啉酮系抗菌藥。喹啉酮系抗菌藥的例子可列舉如加替沙星、莫西沙星、妥舒沙星、司帕沙星、西他沙星、氟羅沙星、加雷沙星、左氧氟沙星、鹽酸洛美沙星、鹽酸環丙沙星、依諾沙星、歐氟沙星、諾氟沙星、或那氟沙星,或其等之鹽等,其中尤以加替沙星或歐氟沙星,或其等之鹽為佳。鹽是以藥學上可容許的鹽或水合物為佳。例如,可舉鈉、鉀、鋰等的鹼金屬的鹽,鈣、鎂、錳等的鹼土金屬的鹽,或鹽酸、硫酸等的酸加成鹽等。喹啉酮系抗菌藥是沒有特別的限定,但做為在日本國內受承認的藥劑是以左氧氟沙星(商品名:可樂必(Cravit)),歐氟沙星(商品名:泰利必妥(Tarivid)),西他沙星(商品名:Gracevit),環丙沙星(商品名:Ciproxan),或加替沙星(商品名:Gatiflo)等做為代表的新喹啉酮為特佳。
喹啉酮系抗菌藥是有強的脫顆粒抑制作用, 做為抗過敏劑而有用。做為本發明的對象的過敏症狀或過敏性疾病而言,可舉春季型黏膜炎、過敏性結膜炎、過敏性鼻炎、異位性皮膚炎、蕁麻疹、支氣管氣喘、噴嚏、流鼻水,流淚、或發癢等。抗過敏劑也可稱為過敏性疾病的預防或治療劑。
相對於抗過敏劑,喹啉酮系抗菌藥的含有比率例如可為0.01至100質量%,可為0.1至10質量%,也可為0.1至5質量%。
本發明是包括含有本發明的抗過敏劑的醫藥品。相對於醫藥品,抗過敏劑的含有比率是例如可為0.01至100質量%,可為0.1至10質量%,也可為0.1至5質量%。
本發明的抗過敏劑可為喹啉酮系抗菌藥單獨,或與其他的醫藥(例如甲哌噻庚酮(ketotifen)或其鹽)、任意的製劑用載體或稀釋劑混合成為任意的劑形而做為醫藥品。前述成分在醫藥品的含有量並無特別的限制,但較佳者是0.01至5質量%,更佳者是0.05至3質量%,又更佳者是0.1至2質量%。喹啉酮系抗菌藥及其他醫藥的質量比(喹啉酮系抗菌藥:其他醫藥)可為約1:(0.1至10),也可為約1:(0.9至1.1)。本發明的抗過敏劑可含有甲哌噻庚酮(ketotifen)或其鹽或其他的醫藥成分,不含也可以。
本發明的抗過敏劑或醫藥品的劑形的例子可列舉內服劑、軟膏劑、霜劑、液劑、點鼻劑、或點眼劑等。
本發明的抗過敏劑或醫藥品,可藉由醫藥品 的一般製造方法,將喹啉酮系抗菌藥及製劑用載體、稀釋劑或其他的醫藥等直接混合、分散後,加工成所希望的形態即可獲得。具體而言,可添加例如醫藥品可容許的公知的溶劑、可溶化劑、等張化劑、保存劑、抗氧化劑、賦形劑、黏合劑、潤滑劑、乳化劑或安定劑等。
就本發明的抗過敏劑或醫藥品的劑形而言,為內服劑時,例如,可列舉錠劑、顆粒劑、細粒劑、硬膠囊劑、軟膠囊劑、散劑、口含錠劑、或經口用液體製劑等,為外用劑時,例如,可列舉點眼劑、注射劑、軟膏劑或霜劑等的皮膚外用劑,或栓劑等。
在本發明的抗過敏劑或醫藥品的劑形中,可各分別添加醫藥品可容許的載體或稀釋劑等。在內服劑中,例如,可添加賦形劑、崩壞劑、崩壞佐劑、黏合劑、潤滑劑、流動化劑、緩衝劑、持續化劑、安定化劑、抗氧化劑、還原劑、清涼化劑、甜味劑、調味劑、香料、着色劑、界面活性劑、可塑劑、可溶化劑、懸浮化劑、分散劑、乳化劑、溶解佐劑、光澤化劑、或被覆劑等。又,在外用劑而言,例如,可添加溶劑、溶解佐劑、乳化劑、等張化劑、緩衝劑、或pH調整劑等。再視必要,而可添加安定化劑、保存劑、或抗氧化劑等。
在本發明中,前述劑形中,以點眼劑為特佳。在點眼劑中可分別添加醫藥品可容許的載體或稀釋劑等,只要能解決本發明的課題,也可添加緩衝劑、等張化劑、溶解佐劑、保存劑、增稠劑、螯合劑、或pH調整劑等的 各種添加劑。
本發明的點眼劑的pH只要是在眼科可容許的範圍則無特別的限制,pH較佳者是3至12,更佳者是4至11,又更佳者是5至10,再更佳者是5至9,再更佳者是6至8。
本發明的點眼劑的滲透壓比是較佳者是0.5至5壓力比,更佳者是0.7至2壓力比,又更佳者是0.9至1.5壓力比。
pH調整劑並無特別的限定,例如,可列舉鹽酸、或氫氧化鈉等,pH調整劑是可在上述的範圍內適量添加。
等張化劑並無特別的限定,例如,可列舉葡萄糖、D-山梨醇、氯化鈉、D-甘露糖醇、或甘油等,而以甘油為佳。甘油的含有量是藉由計算對點眼劑全體成為等張之量而求得。
溶劑並無特別的限定,例如,可列舉精製水、乙醇、丙二醇、聚乙二醇、Macrogol、或食用油(芝麻油、玉米油、橄欖油等)等。溶解佐劑並無特別的限定,例如可列舉,丙二醇、D-甘露糖醇、苯甲酸苯甲酯、乙醇、三乙醇胺、碳酸鈉、或檸檬酸鈉等。
乳化劑並無特別的限定,例如,可列舉羧甲基纖維素(carmellose)、羥丙基纖維素、丙二醇、聚乙烯基吡咯酮、甲基纖維素、單硬脂酸甘油酯、聚乙烯醇、卵磷脂(卵黃卵磷脂、大豆卵磷脂),脫氧膽酸(deoxycholic acid) 類、聚氧乙烯蓖麻籽油、聚氧乙烯硬化蓖麻籽油類、聚氧伸乙基聚氧伸丙基二醇、單油酸聚氧伸乙基去水山梨醇酯(聚山梨醇酯80),或單月桂酸聚氧伸乙基去水山梨醇酯等,而以卵磷脂為佳,卵黃卵磷脂更佳。相對於抗過敏劑或醫藥品全體,乳化劑的含有量可為0.1至3.0質量%。
緩衝劑並無特別的限定,例如,可列舉檸檬酸鹽(檸檬酸三鈉二水合物、檸檬酸鈉、檸檬酸二鈉等)、磷酸鹽(磷酸二氫鈉、磷酸鈉、磷酸氫二鈉、磷酸二氫鉀、磷酸鉀、磷酸氫二鉀等)、硼酸鹽(硼酸鈉、硼酸鉀)、乙酸鹽(乙酸鈉三水合物、乙酸鈉、乙酸鉀等),或碳酸鹽(碳酸鈉、碳酸氫鈉等)等。相對於抗過敏劑或醫藥品全體,緩衝劑的含有量可為0.001至3.0質量%。
安定化劑並無特別的限定,例如可列舉EDTA,油酸鈉、酪蛋白,或酪蛋白鈉鹽等。EDTA包括EDTA-2Na、或EDTA-4Na等。相對於抗過敏劑或醫藥品全體,EDTA的含有量可為0.001至0.1質量%。
就保存劑並無特別的限定,例如,可舉4級銨鹽(氯化烷基二甲基苯甲基銨(benzalkonium chloride),氯化本索寧(benzethonium chloride)等)、對羥基苯甲酸酯(對羥基苯甲酸乙酯、對氧基苯甲酸甲酯、對羥基苯甲酸丙酯、對羥基苯甲酸丁酯)、氯丁醇、苯甲醇,去氫乙酸鈉、或山梨酸等。抗氧化劑並無特別的限定,例如,可列舉亞硫酸鈉、或抗壞血酸等。相對於抗過敏劑或醫藥品全體,保存劑的含有量可為0.001至3.0質量%。
黏稠劑並無特別的限定,例如,可列舉羧乙烯聚合物、軟骨素硫酸鈉、精製羊毛脂、玻尿酸鈉、羥乙基纖維素、或羧丙基甲基纖維素(hypromellose)等。相對於抗過敏劑或醫藥品全體,黏稠劑的含有量可為0.001至3.0質量%。
抗氧化劑例如可列舉多酚、抗壞血酸、三級丁基氫醌、丁基羥基茴香醚(butyl hydroxyanisole)、丁基羥基甲苯,L-半胱胺酸鹽酸鹽、亞硫酸氫鈉、或α-生育酚等,或該等的衍生物等。相對於抗過敏劑或醫藥品全體,抗氧化劑的含有量可為0.001至3.0質量%。
本發明的抗過敏劑或醫藥品的投與對象亦可為人或人以外的動物。人以外的動物並無特別的限定,可列舉牛、馬、豬、羊、山羊、駱馬(llama)、羊駝(alpaca)、駱駝、兔、貂、狐、粟鼠(chinchilla)、鵝、雞、鴨、狗、貓、或倉鼠等。
本發明的抗過敏劑或醫藥品的投與量是視劑型、投與路徑、投與對象、年齡、體重、投與間隔等而適宜選定。經口投與時,例如,成人(60kg)每日的本發明的抗過敏劑或醫藥品的投與量可為約0.0001mg至約100g,約0.001mg至約50g,約0.01mg至約20g,約0.1mg至約5g等。本發明的抗過敏劑或醫藥品的投與間隔是視劑型、投與對象等而適宜選定,例如,可為每日約1至3次,但每2或3個月約1至3次也可以。投與次數是視劑型、投與對象等而適宜選定,例如,投與1次也可以,但隔一定間隔而持 續投與等也可以。
以下,舉實施例更詳細說明本發明,但本發明不受該等的限定。又,在實施例中,濃度的「%」若無特別註明時是表示「質量/容量%」。
在本實施例中,藉由測定β-己糖胺酶的活性而評定細胞的脫顆粒。方法如下。
在本說明書中,M是表示mol/L,mM是表示mmol/L的意思。
<被驗物質的調製>
加替沙星(gatifloxacin)(LKT Laboratories,Inc.)及歐氟沙星(ofloxacin)(LKT Laboratories,Inc.)是以HEPES Tyrode BSA Buffer(140mM NaCl、2.7mM KCl、1.8mM CaCl2‧2H2O、12.1mM NaHCO3、0.4mM NaH2PO4‧2H2O、0.5mM MgCl2‧6H2O、5.7mM葡萄糖、25mM HEPES、0.1% BSA)溶解而各分別成為0.05w/v%、0.3w/v%及0.145w/v%,再稀釋到目的之濃度而使用。又,陽性對照係使用肉桂氨茴酸(Tranilast)(大和藥品工業股份公司)。
<試藥及試藥調製>
基本培養基是使用Dulbecco’s Modified Eagle’s Medium(以下DMEM,商品名:GIBCO,Thermo Fisher Scientific Co.,Ltd)。將脫顆粒誘導物質的A23187 (SIGMA-ALDRICH社),以二甲亞碸(DMSO,和光純藥工業股份公司)溶解後,以HEPES Tyrode BSA Buffer調製終濃度10μM的A23187溶液。基質溶液是使用將4-硝苯基N-乙醯基-β-D-葡萄胺糖苷(Nitrophenyl N-acetyl-β-D-glucosaminide)(SIGMA-ALDRICH社)溶解於0.4M檸檬酸緩衝液(pH4.5)成為2mM者,反應停止液是使用0.2M甘胺酸緩衝液(pH10.7)。
<試驗方法>
將嗜鹼性球樣細胞株(RBL-2H3細胞),以含有10v/v%牛胎兒血清(FCS;Fetal calf serum)的DMEM調整為3×105cells/mL,在96孔微量盤各播種200μL/well,在37℃,5v/v% CO2恆溫箱內培養一夜。翌日,將培養基吸引除去,以DMEM清洗後,添加MEM200μL/well,在37℃,5v/v% CO2恆溫箱培養3至4小時。培養後,將DMEM吸引除去,添加A23187溶液100μL/well,與添加A23187溶液同時,添加被驗物質使成為第1表及第2表所述的濃度,在37℃,5v/v% CO2恆溫箱培養30分鐘。培養後,將96孔微量盤氷冷10分鐘以停止反應,在別的96孔微量盤,在相對應的各孔回收培養上清液40μL×2,吸引除去殘液。其次,在該96孔微量盤添加0.1w/v% Triton X-100,100μL/well,超音波處理1分鐘後,同樣將培養上清液,在相對應的別的96孔微量盤的各孔回收細胞溶解液40μL×2。將所回收的培養上清液及細胞溶解液的96孔微量盤在37℃預保溫5 分鐘,添加基質溶液100μL/well,混合後,在37℃保溫30分鐘。繼而,添加反應停止液200μL/well並混合,以微量盤分析儀(microplate reader)(Power Scan MX,DS Pharma BioMedical股份公司)測定405nm的吸光度。
<算出方法>
β-己糖胺酶的游離率(%)是由下式算出。
【數1】β-己糖胺酶的游離率(%)=100×[(S-Sc)/{(S-Sc)+(CL-CLc)}]
S:培養上清液的吸光度
Sc:以反應停止液→基質溶液的順序添加時的培養上清液的吸光度
CL:細胞溶解液的吸光度
CLc:以反應停止液→基質溶液的順序添加時的細胞溶解液的吸光度
<結果>
將結果示於第1表及第2表。加替沙星及歐氟沙星對於脫顆粒反應顯示優異的抑制效果(*:p<0.05,對應緩衝液群2或7,Dunnett多重比較檢定)。
〔實施例2 過敏性結膜炎抑制試驗〕
在本實施例,使用實驗性的大鼠過敏性結膜炎模型評定喹啉酮系抗菌藥(加替沙星或歐氟沙星)及抗組織胺藥的甲哌噻庚酮(ketotifen)富馬酸鹽的併用投與。方法如下。
<檢體調製>
做為試驗液,準備下述的3群。
1.對照群(生理食鹽水)
2.單獨群(立敏停(Zaditen)(登錄商標)點眼液0.05w/v%(甲哌噻庚酮(ketotifen)0.05w/v%),日本Alcon社製)
3.併用群(各喹啉酮系抗菌醫療用點眼劑(在加替沙星(0.3w/v%)或歐氟沙星(0.3w/v%))中溶解或懸浮甲哌噻庚酮使成為0.05w/v%者)
<試藥及試藥調製>
引發溶液係使用1w/v%卵白白蛋白(Grade V,Sigma Aldrich社製)/生理食鹽液(大塚製藥工場社製)及1w/v% Evans Blue(和光純藥工業社製)/生理食鹽液的等量混合液。
萃取液係使用丙酮(和光純藥工業社製)/0.5w/v%硫酸鈉(和光純藥工業社製)水溶液(7:3)。
<試驗方法>
將大鼠(Wistar系,雄性,進貨時5週齡,由日本SLC社購入)以二乙醚吸入麻醉後,將預先製作的卵白白蛋白抗血清(ovalbumin antiserum)(抗體價4)在兩下眼瞼結膜下注射而被動敏化(passive sensitization)(20μL/眼,n=4至6/群)。在48小時後,在靜脈內投與引發溶液1mL,在結膜局部引發過敏反應。將試驗液在引發過敏15分鐘前及將引發之前點眼投與(計2次)。反應引發30分鐘後使大鼠安樂死,將下眼瞼結膜順著結膜圓蓋部取出,測定組織重量後,添加萃取液萃取一夜。將經過一夜的萃取液離心分離,測定上清液的620nm的吸光度。
由於過敏反應,血管透過性亢進時Evans Blue會漏出,因而漏出色素量越少,即血管透過性的亢進越受到抑制,可判斷具有抗過敏效果。由預先作成的標準曲線求得每單位組織的漏出色素量(μg/g),做為抑制效果的指標。
<結果>
將結果示於第3表及第4表。確認加替沙星及歐氟沙星的抗過敏作用在與甲哌噻庚酮富馬酸鹽併用時會呈現相加的抗過敏作用(*:p<0.05,對應對照群,無對應t檢定(Independent sample t-test))。
本發明是在過敏的治療等的醫藥領域中有用。
Claims (10)
- 一種抗過敏劑,係含有喹啉酮系抗菌藥,其中,前述喹啉酮系抗菌藥是由加替沙星(gatifloxacin)、莫西沙星(moxifloxacin)、妥舒沙星(tosufloxacin)、司帕沙星(sparfloxacin)、西他沙星(sitafloxacin)、氟羅沙星(fleroxacin)、加雷沙星(garenoxacin)、左氧氟沙星(levofloxacin)、鹽酸洛美沙星(lomefloxacin hydrochloride)、鹽酸環丙沙星(ciprofloxacin hydrochloride)、依諾沙星(enoxacin)、歐氟沙星(ofloxacin)、諾氟沙星(norfloxacin)及那氟沙星(nadifloxacin)所成組群選出的1種以上的成分。
- 如申請專利範圍第1項所述的抗過敏劑,其中,過敏性疾病是由春季型黏膜炎(spring catarrh)、過敏性結膜炎、過敏性鼻炎、異位性皮膚炎、蕁麻疹及支氣管氣喘所成組群選出的至少1種。
- 如申請專利範圍第1或2項所述的抗過敏劑,其具有脫顆粒抑制作用。
- 如申請專利範圍第1或2項所述的抗過敏劑,其劑形是內服劑、軟膏劑、霜劑、液劑、點鼻劑、或點眼劑。
- 如申請專利範圍第3項所述的抗過敏劑,其劑形是內服劑、軟膏劑、霜劑、液劑、點鼻劑、或點眼劑。
- 一種喹啉酮系抗菌藥的使用,係用於製造過敏性疾病治療用醫藥,其中,前述喹啉酮系抗菌藥是由加替沙星(gatifloxacin)、莫西沙星(moxifloxacin)、妥舒沙星 (tosufloxacin)、司帕沙星(sparfloxacin)、西他沙星(sitafloxacin)、氟羅沙星(fleroxacin)、加雷沙星(garenoxacin)、左氧氟沙星(levofloxacin)、鹽酸洛美沙星(lomefloxacin hydrochloride)、鹽酸環丙沙星(ciprofloxacin hydrochloride)、依諾沙星(enoxacin)、歐氟沙星(ofloxacin)、諾氟沙星(norfloxacin)及那氟沙星(nadifloxacin)所成組群選出的1種以上的成分。
- 如申請專利範圍第6項所述的喹啉酮系抗菌藥的使用,其中,過敏性疾病是由春季型黏膜炎,過敏性結膜炎,過敏性鼻炎,異位性皮膚炎,蕁麻疹及支氣管氣喘所成組群選出的至少1種。
- 如申請專利範圍第6項或第7項中所述的喹啉酮系抗菌藥的使用,其具有脫顆粒抑制作用。
- 如申請專利範圍第6或7項所述的喹啉酮系抗菌藥的使用,其中,過敏性疾病治療用醫藥的劑形是內服劑、軟膏劑、霜劑、液劑、點鼻劑、或點眼劑。
- 如申請專利範圍第8項所述的喹啉酮系抗菌藥的使用,其中,過敏性疾病治療用醫藥的劑形是內服劑、軟膏劑、霜劑、液劑、點鼻劑、或點眼劑。
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期刊韕Contact dermatitis from amlexanox eyedrops,Contact dermatitis 1991,Vol.25,p.255〜256 * |
期刊韕Contact dermatitis from amlexanox eyedrops,Contact dermatitis 1991,Vol.25,p.255〜256。韕 韕CONTACT DERMATITIS韕25韕SHORT COMMUNICATIONS韕1991韕256韕 |
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