CN1267091C - 抗流感药物 - Google Patents
抗流感药物 Download PDFInfo
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- CN1267091C CN1267091C CNB028170601A CN02817060A CN1267091C CN 1267091 C CN1267091 C CN 1267091C CN B028170601 A CNB028170601 A CN B028170601A CN 02817060 A CN02817060 A CN 02817060A CN 1267091 C CN1267091 C CN 1267091C
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- influenza virus
- influenza
- mice
- infection
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Abstract
一种抗流感药物,包含活性成分溴环己胺醇、溴苄环己铵或它们可药用盐。这种药物的特点是,它通过促进包含在呼吸道分泌液中并有抑制流感病毒增殖作用的生物因子的分泌而起到抗流感的作用。它还具有以下特点:通过促进可抑制呼吸道中导致流感病毒感染的蛋白酶的物质分泌,抑制呼吸道中流感病毒的增殖;通过促进粘膜免疫物质或IgA和IgG的分泌而来抑制呼吸道中流感病毒的增殖;及能够抑制呼吸道中炎性细胞因子的释放。本发明还涉及一种用于治疗或预防流感病毒感染疾病的药物。
Description
发明背景
本发明涉及一种抗流感药物。更具体地说,本发明涉及一种可用于治疗或预防流感病毒感染疾病的药物。
流感病毒是一种最常见的传染性病原体,它可产生相当普遍的流行和导致很高的死亡率,对于老年人、婴幼儿、慢性疾病患者及免疫缺陷疾病患者来说尤其如此(参考1、2)。
现已报道A、B和C三种流感病毒类型。就这点来说,现已发现A型流感病毒广为传染,并显示出强致病性;而B型和C型流感病毒只是地区或局域传染,并表现出弱致病性。但是这三种流感病毒在传染过程中却体现出相同的传染机制。
参考1:Kim HW,Brandt CD,Arrobio JO,Murphy B,Chanock RM,ParrottRH,Influenza A and B virus infection in infants and young children during theyears 1957-1976.
Am.J.Epidemiol 1979;109:464-479。
参考2:Barker WH,Mullooly JP,Impact of epidemic type A influenza in adefined adult population.
Am.J.Epidemiol 1980;112:798-813。
流感病毒的致病性取决于其单个病毒基因组和由呼吸道宿主细胞分泌的使病毒基因组侵入宿主细胞细胞质的胰蛋白酶型蛋白酶的多形性。这种胰蛋白酶型蛋白酶是受由病毒包膜糖蛋白[血凝素(HA)]的限定开裂(limitative cleavage)及相应的病毒膜和细胞质膜的融合引起的流感病毒的膜融合作用的诱导而被分泌的(参考3-5)。
参考3:Klenk HD,Garten W,Host cell protease controlling viruspathogenicity.
Trends Microbiol.1980;2:39-43。
参考4:Klenk HD,Rott R,The molecular biology of influenza viruspathogenicity.
Adv.Virus Res.1988;34:247-281。
参考5:Homma M,Ohuchi M,Trypsin action on the growth of Sendai virusin tissue culture cells.
J.Virol 1973;12:1457-1465。
病毒包膜糖蛋白的断裂发生在呼吸道和/或呼吸腔的上皮细胞膜上(参考6、7)。
参考6:Kido H,Yokogoshi Y,Sakai K,Tashiro M,Kishino Y,Fukutomi A,Kutunuma N,Isolation and characterization of a novel trypsin-like proteasefound in rat bronchiolar epithelial Clara cells,J.Biol.Chem,1992,267:13573-13579。
参考7:Tashiro M,Yokogoshi Y,Tobita K,Seto JT,Rott R,Kido H,Tryptase Clara,an activating protease for sendai virus in rat lungs,is involved inpneumopathogenicity,
J.Virol,1992,66:7211-7216。
能断裂病毒包膜糖蛋白的蛋白酶的活性由呼吸道分泌液中上述这些蛋白酶的内源抑制化合物严格控制,例如上呼吸道中的粘膜蛋白酶抑制剂(MPI;参考8)和肺的表面活性剂(PS;参考9)。肺PS中的表面活性蛋白质A(SP-A)属于被加入唾液酸的C型凝集素,这种蛋白质与流感病毒HA直接相连,并因此抑制病毒侵入细胞(参考10)。除了这些包含在呼吸道分泌液中的化合物之外,粘膜免疫系统作为主要的免疫防御系统可以预防病毒侵入到细胞中,更具体地说,诱导免疫球蛋白IgA和IgG的局部分泌与防止流感病毒的感染紧密相关(参考11-13)。这些结果表明,这些包含在呼吸道分泌液中的抗病毒生物防御性物质的浓度决定了个体对流感病毒感染的敏感性。
参考8:Beppu Y,Imamura Y,Tashiro M,Towatari T,Ariga H,Kido H,Human Mucus protease inhibitor in airway fluids is a potential defensivecompound aginst infection with influenza A and Sendai viruses,
J.Biochem.,1997,121:309-316。
参考9:Kido H,Sakai K,Kishino Y,Tshiro M,A pulmonary surfactant is apotential endogenous inhibitor of proteolytic activation of Sendai virus andinfluenza virus,
FFBS Lett.,1993,322:115-119。
参考10:Benne CA,Kraaijeveld CA,van Strijp JAG,Brouwer E,HarmsenM,Verhoef J,van GoldLMG,van Iwaarden JF,Interactions of surfactant proteinA with influenza A viruses:bindingand neutralization,
J.Infect.Dis.,1995,171:335-341。
参考11:Liew FY.Russell SM,Appleyard G,Brand CM,Beale J,Crossprotection in mice infected with influenza A virus by the respiratoty route iscorrelated with local IgA rather than serum antibody or cytotoxic T cellreactivity,
Eur.J.Immunol.,1984,14:350-356。
参考12:Tamura S,Funato H,Hirabayash Y等,Functional role ofrespiratory tract hemagglutinin-specific IgA antibodies in protection againstinfluenza,
Vaccine,1990,8:479-485。
参考13:Wright PF,Murphy Br,Kervina M,Lawrence EM,Phelan MA,Karzon DT,Secretory immunological response after intranasal inactivatedinfluenza A virus vaccinations:evidence for immunoglobulin A memory,
Infect. Immun.,1983,40:1092-1095。
已知作为祛痰剂或化痰剂的溴环己胺醇(ambroxol)(2-氨基-3,5-二溴-N-[反式-4-羟基环己基]苯甲基胺)可用于治疗新生儿慢性支气管炎和呼吸窘迫综合症(参考14)。
据报道,溴环己胺醇具有控制呼吸道腺细胞上的粘液和促进PS生成的药理学作用(参考15)。
除此之外,溴环己胺醇还显示出抗氧化作用(参考16),及与由支气管肺泡巨噬细胞、单核细胞和粒细胞释放的炎性细胞因子的减少相关的抗炎作用(参考17、18)。然而,溴环己胺醇对活体内流感病毒感染的作用还不为人知。
已知作为祛痰剂的溴苄环己铵(bromhexin)(2-氨基-3,5-二溴-N-环己基-N-甲基苯甲基胺)可用于治疗慢性支气管炎。但是,溴苄环己铵对活体内流感病毒感染的作用还不为人知。
参考14:Germouty J,Jirou-Najou J,Clinical efficacy of ambroxol in thetreatment of bronchial stasis,
Respiration,1987,51:37-41。
参考15:Heath MF,Jacobson W,The inhibition of lysosomal phospholipaseA from rabbit lung by ambroxol and its consequence for pulmonary surfactant,Lung,1985,163:337-44。
参考16:Gillissen A,Scharling B,Jaworska M,Bertling A,Rasche K,Schultze-Werninghaus G,Oxidant scavenger function of ambroxol in vitro:acomparison with N-acetylcysteine AC,
Res.Exp.Med(Berl),1997,196:389-398。
参考17:Pfeifer S,Zissel G,Kienast K,Muller-Quernheim J,Reduction ofcytokine release from blood and bronchoalveolar mononuclear cells byambroxol,
Eur.J.Med.Res,1997,2:129-132。
参考18:Gibbs BF,Schmutzler W,Vollrath IB,Brostharardt P,Braam U,Wolff HH,Zadlo-Klarwasser G,Ambroxol inhibits the release of histamine,leukotrienes and cytokines from human leukocytes and mast cells,
Inflamm. Res.,1999,48:86-93。
发明详述
本发明的目的是提供一种抗流感药物,或一种利用有抗氧化作用,并可作为化痰剂促进PS释放的溴环己胺醇和/或溴苄环己铵对流感病毒传染的防御作用,治疗或预防流感病毒感染疾病的药物。
本发明的要点在于一种包含溴环己胺醇或其可药用盐作为有效成分的抗流感药物。
本发明所述药物的特征在于它是通过促进分泌包含在呼吸道分泌液中,并显示出抗流感病毒作用的生物或机体内因子(机体防御物质群),而具备了抗流感作用。换言之,本发明提供了一种抗流感药物,其特征在于它包含有效成分溴环己胺醇、溴苄环己铵或它们的可药用盐,该药物是通过促进分泌被包含在呼吸道分泌液中,并显示出抗流感病毒作用的生物或机体内因子(机体防御物质群),而具备了抗流感作用。
此外,本发明药物的特征还在于呼吸道中流感病毒的增殖,是通过促进分泌可抑制呼吸道中导致流感病毒感染的蛋白酶的物质,和粘膜免疫物质如IgA和IgG而被控制的。更具体地说,本发明提供了一种抗流感药物,其特征在于,该抗流感药物包含有效成分溴环己胺醇、溴苄环己铵或其可药用盐,并且呼吸道流感病毒的增殖是通过促进分泌被包含在呼吸道分泌液中的具有抗流感病毒作用的生物因子,如MPI和PS,及粘膜免疫物质如IgA和IgG而被控制的。
进一步地,本发明药物的特征在于,它能抑制呼吸道中炎性细胞因子的释放,更具体地讲,本发明还提供一种抗流感药物,其特征在于,该药物包含有效成分溴环己胺醇、溴苄环己铵或它们的可药用盐,而且它能够通过促进分泌呼吸道分泌液中的抗流感病毒因子,例如MPI和/或PS,及促进分泌粘膜免疫物质,如IgA和/或IgG,而抑制流感病毒的增殖;它还能抑制呼吸道中炎性细胞因子的释放。
本发明所述的抗流感药物可作为治疗或防止流感病毒感染性疾病的药物。
本发明还提供溴环己胺醇、溴苄环己铵或它们的可药用盐在制备抗流感药物中的用途。
本发明进一步提供一种治疗流感病毒感染性疾病的方法,该方法包括给予患有这些疾病的患者含溴环己胺醇、溴苄环己铵或它们可药用盐作为有效成分的抗流感药物。
附图说明
图1显示了溴环己胺醇提高了被感染流感病毒A的小鼠的存活率。
图2显示了溴环己胺醇在BALF中对病毒增殖的抑制作用(A);和感染4天后在小鼠身上视觉观察到的肺部损伤(B)。
图3显示了溴环己胺醇对非感染小鼠组(A)和感染流感病毒A的小鼠组(B)的BALF中粘膜免疫球蛋白IgA分泌的刺激作用。
图4显示了溴环己胺醇对非感染小鼠组(A)和感染流感病毒A的小鼠组(B)的BALF中粘膜免疫球蛋白IgG分泌的刺激作用。
本发明的最佳实施方式
由以下化学式1表示的溴环己胺醇(2-氨基-3,5-二溴-N-[反式-4-羟基环己基]苯甲基胺),其盐酸(通用名:盐酸溴环己胺醇;化学名:反式-4-[(2-氨基-3,5-二溴-苯甲基)胺]环己醇盐酸盐),在全世界包括德国在内被广泛用作祛痰剂或化痰剂(sputum-dissolving agent),并且,它还被用于治疗新生儿慢性支气管炎和呼吸窘迫综合症。
[化学式1]
另外,由以下化学式2表示的溴苄环己铵(2-氨基-3,5-二溴-N-环己基-N-甲基苯甲基胺),其盐酸(通用名:盐酸溴苄环己铵;化学名2-氨基-3,5-二溴-N-环己基-N-甲基苯甲基胺盐酸盐),如上所述,在全世界包括德国在内被广泛用作祛痰剂,并且,它还被用于治疗慢性支气管炎。
[化学式2]
本发明的药物可以治疗和/或预防的病毒感染性疾病可以是任何由有外膜糖蛋白的病毒引起的呼吸道感染,具体的例子如流感病毒、副流感病毒、呼吸道合胞病毒、麻疹病毒和腮腺炎病毒。
与普通药物组合物一样,本发明所述的抗流感药物可以以多种形式给予病人,例如,口服固体药物制剂如片剂、散剂、微粒剂(fine granules)、颗粒剂、胶囊、悬浮液、含片和咀嚼制剂,及液体制剂例如酏剂和糖浆剂(包括干糖浆)。另外,如果其口服制剂对病人来说不适合或希望通过选择局部给药来保证该药物更快和更可靠的药效,该抗流感药物就可以按照传统方式例如液体制剂注入法、气雾喷雾或喷雾注入法、及用旋转吸入器(spinhaler)或盘式吸入器(diskhaler)通过干粉末吸入器(DPD)或通过计量喷雾式吸入器(MDI)等方法给药。此时,可根据例如方便性、可靠性和效率等方面的考虑而选择使用上述方法。
可以根据本发明抗流感药物的剂型适当地调整其给药物量或用量。
如果本发明的抗流感药物是口服固体制剂例如片剂或口服液体制剂,它可按每日剂量以分剂量形式每天一次或几次给予病人。如果其婴幼儿剂型是应被一次性服用,并通过内用同时满足其局部和全身作用的药物制剂,例如糖浆、含片及咀嚼片,那么在该药物中采用上述同样用途的剂型的每日剂量的1/2-1/10便足够了。这种情况下,其总剂量应小于每日剂量。与此相反,相当于一天剂量的有效成分可以调配到单剂量中,只要从药物剂型方面考虑,不会导致用量过多。另外,如果该药物是例如注射用液体制剂、经气雾喷射装置给药的药物、经喷雾器或粉末吸入给药的药物,那么可按有效成分含量为其内用口服药物剂量的1/10-1/100的量制备这些药物。
在制备这些药物时,可使用多种目前使用的添加剂,例如填料、增稠剂、粘合剂、崩解剂、表面活性剂、润滑剂、包衣剂、缓释剂、稀释剂和/或赋形剂。本发明所述药物制剂除含上述添加剂外,如有必要,还可进一步包含其他添加剂,例如助溶剂、缓冲剂、防腐剂、增溶剂、等渗剂、乳化剂、悬浮剂、分散剂、增粘剂、胶凝剂、固化剂、吸收剂、粘合剂、增弹剂、增塑剂、吸附剂、香料、着色剂、矫味剂、抗氧化剂、保湿剂、遮光剂、光亮剂和/或抗静电剂。
更具体地讲,上述添加剂的实例包括赋形剂,例如乳糖、玉米淀粉、甘露醇、D-山梨醇、结晶纤维素、赤藓醇和蔗糖;粘合剂例如羟丙基纤维素(HPC-L)、羟丙甲基纤维素、聚乙烯吡咯烷酮、甲基纤维素和胶化淀粉;崩解剂例如羧甲基纤维素钙、交联羧甲基纤维素钠和交联聚乙烯吡咯烷酮;润滑剂例如硬脂酸镁和滑石粉;香料例如食用香精或芳香油例如1-薄荷醇、香兰素、柠檬油、肉桂油和薄荷油;和/或吸附剂例如合成硅酸铝和轻质无水硅酸。此外,还可利用目前使用的包衣材料例如羟丙甲基纤维素、羟丙基纤维素、甲基纤维素或聚乙烯吡咯烷酮,来制备包衣药物制剂。如有必要,同样还可使用甜味剂,其中尤其加在含片、糖浆和咀嚼剂中。这类甜味剂的具体例子有甘露醇、葡萄糖、麦芽糖、淀粉糖浆、麦精、麦芽糖醇(maltitol)、山梨糖醇、蔗糖、非精制糖、果糖、乳糖、蜂蜜、木糖醇、八仙花茶(hydrangea tea)、糖精、天冬氨酰基苯丙氨酸酯和其他麦芽低聚糖类、及低聚糖类例如麦糖基蔗糖(maltosyl sucrose)、还原型isomaltyrose和蜜三糖。可以根据本领域公知的任何方法制备含有这些添加剂的药物制剂,该方法可以是通常使用的或普通的方法,这取决于该药物的剂型。
对于粉末和颗粒制剂例如散剂、微粒制剂和颗粒剂[包括那些通过计量吸入器(MPI)或粉末吸入器(DPD)给药的制剂],可在考虑各种性质例如飞散性和粘附性的同时适当地制备。例如,制备它们时优选要考虑粉末物质的物理性质例如体积,飞散性、粘附性、吸湿性、带电性、润湿性、溶解性,及其他性质例如粒度(颗粒直径),表面积和颗粒形状。具体来说,在粉末吸入法中,一定要特别注意药物成分的粒度,从而有效地使药物到达疾病部位,因此,其最适宜的粒度范围是0.5-5μm。此外,在制备该药物时还优选要考虑例如易处理性,并要防止吸湿、分解行为,变质及褪色。粉末可根据任何现有粉碎方法来制备,例如干法粉碎、湿法粉碎、低温粉碎、喷气粉碎、分批式粉碎和连续开放循环式粉碎以及连续封闭循环式粉碎法,它们可单独选用或任意联合使用,这依目的而定。
现已确认溴环己胺醇和溴苄环己铵具有促进分泌呼吸道抗病毒因子的作用,并因此具有抑制呼吸道流感病毒增殖的作用。溴环己胺醇的作用可从它可增加呼吸道中病毒增殖抑制性物质例如SP-A、MPI、IgA和IgG的浓度,及能够抑制呼吸道分泌液中炎性细胞因子的释放这些方面得到证实。
实施例
在此将用下列实施例对本发明做进一步具体说明,但本发明不受这些具体实施例的限制。
<概述>
利用小鼠检测作为化痰剂,具有抗氧化作用并能诱导释放PS的溴环己胺醇保护受试体不感染流感病毒的作用。
用致死量的流感病毒A/Aichi68(H3N2)感染小鼠鼻腔后,对其每天两次腹腔给药溴环己胺醇或赋形剂,然后测试分析其存活率、BALF中病毒滴度、BALF中的细胞因子和抗病毒因子或粘膜免疫球蛋白IgA和IgG,及PS和MPL浓度。
结果显示,溴环己胺醇显著抑制了病毒的增殖,并大大提高了被感染小鼠的存活率。测定存活率时,当溴环己胺醇剂量为10mg/kg/天时其作用达到最高水平,而当剂量高于此值时作用下降。但是,即使采用高剂量,与给予生理盐水作为对照的动物组相比,小鼠的存活率提高了。感染流感病毒导致呼吸道分泌液中抗病毒因子和炎性细胞因子的释放,溴环己胺醇进一步促进这些抗病毒因子的释放。然而,它同时也促进胰蛋白酶型蛋白酶的释放,这将促进病毒增殖。此外,溴环己胺醇一过性地抑制了呼吸道分泌液中细胞因子或肿瘤坏死因子-α(TNF-α),干扰素-γ(IFN-γ)及白细胞介素-2(IL-2)的释放。
现已确认溴环己胺醇具有一些涉及体内病毒增殖的副作用,但是整体来说,它能显著提高呼吸道中一组能控制病毒增殖的物质的水平,这表明它能作为一种治疗流感病毒感染患者的有效试剂而在临床上应用。
用致死量的小鼠适应型(mouse-aclaptive)流感病毒A/Aichi68(H3N2)感染小鼠鼻腔后,给它们施用溴环己胺醇,然后测试分析其存活率、病毒滴度、病毒增殖,及呼吸道分泌液中胰蛋白酶型蛋白酶、MPI、PS、IgA、IgG和细胞因子的浓度。
<受试体和方法>
1)动物和受试体
三周龄雌性oddY小鼠,每只体重为8-10g,并且不携带任何特异性病原体,购自日本SLC Inc.(Shizuoka,Japan)。对所有小鼠的处理都依据Guidelinefor Animal Experiments,Tokushima Universicy.进行。Boehringer Ingelheim向本发明人提供了溴环己胺醇。胰蛋白酶取自于猪脾,购于Sigma Company。小鼠适应型流感病毒A/Aichi68(H3N2)(参考19)是其在10天龄胚胎卵中增殖后才被使用的。
参考19:Ovcharenko AV,Zhirnov OP,Aprotinin aerosol treatment ofinfluenza and paramyxovirus bronchopneumonia of mice,
Antiviral Res.,1994,23:107-118。
2)病毒感染和溴环己胺醇的给药方法
在乙醚麻醉下,以6.6×104PFU(plague-forming units)的流感病毒A/Aichi68(H3N2)20μl感染小鼠鼻腔。病毒感染后10-15分钟立刻以2、5、10或15mg/kg体重的剂量给每组动物(每组10只)腹腔给药含有溴环乙胺醇的食盐水200μl。此后按照同样的步骤对试验动物组施用溴环乙胺醇,持续7-10天,每天2次。在测定或分析呼吸道分泌液中多种化合物及其预期病理效果的试验中,其中抽出三个试验动物组,分别对它们施用剂量为0、10和30mg/kg/天的溴环己胺醇。每组有80只动物。用现有报道(参考20)的免疫荧光细胞计数法测定BALF中的病毒水平。
参考20:Tashiro M,Homma M,Pneumotropism of Sendai virus in relationto protease-mediated activation in mouse lungs,
Infect.Immun.,1983,39:879-888。
3)BALF的制备
本实验所用动物被分为以下几组(每组有80只):接受溴环己胺醇治疗的组、不接受任何治疗的组、感染流感病毒的组和未感染流感病毒的组。每组每天抽取至少5只动物以收集BALF(根据Singh等的方法(参考21)),持续7天。BALF样品在-80℃储藏直至使用。
参考21:Singh G,Katyal SL,An immunologic study of the secretoryproducts of rat clara cells,
J.Histoche.Cytochem,1984,32:49-54。
4)BALF中SP-A、细胞因子和免疫球蛋白水平的测定
大鼠和小鼠的SP-A氨基酸序列有95%同源(参考22、23),分离的大鼠SP-A多克隆抗体(参考6、24)与小鼠SP-A反应。因此,用非生物素化和生物素化的大鼠SP-A特异性抗体建立酶联免疫吸附试验(ELISA)系统,并用小鼠SP-A作为对照物质绘制出校准曲线分析小鼠BALF中SP-A的浓度。根据制造商的方案,BALF中的细胞因子水平[TNF-α、IFN-γ、IL-2、白细胞介素-6(IL-6)、白细胞介素-4(IL-4)]用ELISA试剂盒测定(购自Bio-SourceInternational,CA,美国)。BALF中的IgA和IgG水平同样也用ELISA试剂盒(购自Bethy Company,TX,美国)测定,吸光率可用Immuno MiniNJ-2300Multi-plate-Reader在490nm和450nm处读取。
参考21:Singh G,Katyal SL,An immunologic study of the secretoryproducts of rat clara cells,
J.Histoche.Cytochem,1984,32:49-54。
参考22:Korfhagen TR,Bruno MD,Glasser SW等,Murine pulmonarysurfactant SP-A:gene cloning sequence,and transcripitional activity,
Am.J. Physiol,1992,263:L546-554。
参考23:Lacaze-Masmonteil T,Fraslon C,Bourban J,Raymondiean M,Kahn A,Characterization of the rat pulmonary surfactant protein A promoter,
Eur. J.Biochem.,1992,206:613-623。
参考24:Sakai K,Kweon MN,Kohri T,Kishino Y,Effects of a pulmonarysurfactant and surfactant protein A on phagocytosis of fractionate alveolarmacrophages:relationship to starvation,
Cell.Mol.Biol.,1992,38:123-130。
5)酶和抑制剂的测定
如前所述(Kido H,Yokogoshi Y,Sakai K,Tashiro M,Kishino Y,FukutomiA,Kutunuma N,Isolation and characterization of a novel trypsin-like proteasefound in rat bronchiolar epithelial Clara cells,J.Biol.Chem,1992,267:13573-13579),用与流感病毒HA的断裂部位识别共有基序(consensuscleavage motif)相似的下列序列测定胰蛋白酶型蛋白酶:N-叔丁氧基羰基-Gln-Ala-Arg-4-甲基-香豆素基(coumaryl)-7-酰胺。相当于抑制BALF中流感病毒HA-开裂蛋白酶的物质的90%的MPI的抑制活性可由下列方式测定:利用MPI对酸和热的稳定性,用5%(v/v)的高氯酸溶液处理MPI,将混合物离心以除去其中大部分蛋白质,然后收集BALF的上清液,并使后者在100℃沸腾10分钟。接着在1500×g条件下,将所得上清液离心15分钟,然后用4M的KOH将其pH值调到7.0,最后根据现有报道的方法(Beppu Y,Imamura Y,Tashiro M,Towatari T,Ariga H,Kido H,Human Mucus proteaseinhibitor in airway fluids is a potential defensive compound aginst infection withinfluenza A and Sendai viruses J.Biochem.,1997,121:309-316)测定上清液的蛋白酶抑制活性。
参考25:Stolk J,Rossie W,Dijkman JH,Apocynin improves the efficacy ofa secretory leukocyte protease inhibitor in experimental emphysema,
Am.J. Respir.Crit.Care Med.,1994,150:1628-1631。
参考26:Ohlsson K,Tegner H,Akesson U,Isolation and partialcharacterization of a low molecular weight acid stable protease inhibitor fromhuman bronchial secretion,Hoppe Seylers Z,
Physiol.Chem.,1977,358:583-589。
<统计学处理>
所有试验结果都用平均值±SD表示。用Paired Student’s t-Test评价溴环己胺醇治疗组与不接受该治疗的组或对照组之间的显著性差异,P<0.05则视为具有显著性。
<结果>
1)溴环己胺醇基本上提高了感染流感病毒的小鼠的存活率。
图1所示的结果清楚地表明,溴环己胺醇提高了感染流感病毒A/Aichi/68(H3N2)的小鼠的存活率。图1中,使小鼠感染6.6×104PFU的流感病毒A/Aichi/68(H3N2),随后腹腔注射食盐水(●)、溴环己胺醇4mg/kg/天(▲)、10mg/kg/天(■)、20mg/kg/天(△)、30mg/kg/天(□),对每组试验动物的存活率(每组10只)观察分析10天。
如前所述,现已报道了溴环己胺醇可以刺激肺部和主支气管分泌PS,并且具有抗氧化和抗炎特性。基于上述认识,测定或评价溴环己胺醇对感染了高传染性、强发展性的流感病毒A/Aichi/68(H3N2)的小鼠的作用。每只小鼠体重在8-10g范围内,用小鼠致死量的流感病毒A鼻使其鼻腔内受感染,然后以不同的剂量给它们每天两次腹腔注射溴环己胺醇。溴环己胺醇本身在30mg/kg/天以下的剂量是无毒性的。
病毒感染2天后就可观察到每只动物的体重都显著下降,所有没有接受溴环己胺醇治疗的受试动物(n=10)10天内死亡。接受溴环己胺醇治疗的组中,被感染小鼠的存活率随溴环己胺醇的剂量而提高。更具体地讲,存活率在10mg/kg/天的剂量时达到峰值,但是当剂量超过此值后,溴环己胺醇提高存活率的作用下降(参看图1)。当以10mg/kg/天的剂量用溴环己胺醇治疗小鼠时,尽管它们被感染了致死量的病毒,但是半数小鼠仍然存活下来。
2)接受溴环己胺醇治疗的受试动物组中,病毒增殖都被抑制。
图2显示了溴环己胺醇对BALF中病毒增殖的抑制作用(A)和流感病毒感染4天后在小鼠身上肉眼观察到的损伤(B)。
A:每组小鼠(每组80只)都被感染流感病毒A/Aichi/68(H3N2),然后如图1的解释所述,用食盐水溶液(●)、10mg/kg/天溴环己胺醇(△)和30mg/kg/天溴环己胺醇(▲)处理。感染和处理后,连续7天每天采集5只存活小鼠的BALF。根据前述免疫荧光细胞计数法(参考20)测定BALF中病毒的滴度,其结果用细胞感染单位(CTU)表示。这些数据用平均值±SD表示(n=5)。用Student’st-Test评价用食盐水处理的小鼠与接受溴环乙胺醇治疗的小鼠之间观察值的显著性差异。*P<0.01。
B:4天后,在没有被感染的组(n=5)动物肺部肉眼观察到的肺部损伤(1);在感染流感病毒并用食盐水处理的肺(2);在感染流感病毒并接受10mg/kg/天溴环己胺醇治疗的动物的肺(3);和用30mg/kg/天溴环己胺醇治疗的动物的肺(4)。
按照前述免疫荧光细胞计数法测定BALF中的病毒滴度,以分析溴环己胺醇提高被感染小鼠存活率的基本机制。
在小鼠鼻内感染流感病毒A两天后,BALF中的病毒滴度开始增大,在感染5天后达到最大值,BALF中的病毒滴度在第6天迅速下降,第7天观察到的滴度几乎与感染后2天所观察到的相同。由此可推知,这是宿主细胞中免疫反应的结果(参见图2A)。接受10mg/kg/天剂量的溴环己胺醇治疗的组中,病毒增殖被明显抑制,但是在接受30mg/kg/天剂量的溴环己胺醇治疗的组中观察到的病毒增殖抑制作用不如上述这组。病毒感染后第4天,观察了受试动物身上的病理学变化和肉眼观察到的肺部损伤(参见图2B)。在受感染小鼠的肺部观察到了严重的大面积肝样损伤,并伴有发红现象。另一方面,用10mg/kg/天剂量的溴环己胺醇治疗的组中,病理学变化大大减少,而且30mg/kg/天剂量的溴环己胺醇的损伤抑制作用不如上述这组。
受感染小鼠体内的病毒增殖几乎停止,并在第7天呼吸道中的病毒被清除了,但是即使在病毒增殖停止后,其肺部任然存在病理性变化,并有微弱的发展,动物在10天内死亡。为了阐明受感染小鼠存活率的提高机制及溴环己胺醇在抑制病毒增殖方面起到的作用,本发明人研究了溴环己胺醇对BALF中的多种细胞因子、炎性细胞因子及在控制流感病毒复制方面的作用。
3)溴环己胺醇对呼吸道分泌液中流感病毒增殖促进和抑制因子浓度的影响。
由呼吸道分泌的胰蛋白酶型蛋白酶例如Tryptase Clara使流感病毒HA断裂成HA1和HA2,由此激活病毒膜融合活性并促进病毒复制(参考6、7)。内源性抑制物质例如MPI(参考8)和PS(参考9)抑制这种蛋白酶活性。因此,本发明人研究了溴环己胺醇对BALF中这些抑制物质浓度的影响。研究结果归纳入下表1中(溴环己胺醇对受流感病毒A感染的小鼠BALF中胰蛋白酶型蛋白酶活性、PS和MPI的影响)。
一般来说,未受感染的小鼠或大鼠分泌的这种胰蛋白酶型蛋白酶远多于它们呼吸道分泌的蛋白酶抑制物质,因此,呼吸道随时可能受到流感病毒的感染(参考6、9)。当这些动物受到流感病毒感染,6天后其胰蛋白酶型蛋白酶的浓度达到峰值,是未受感染动物的6.4倍。接受10mg/kg/天剂量的溴环己胺醇治疗的组中,蛋白酶的分泌在第1天就已经加速,从接受治疗起第5天其蛋白酶水平达到峰值。接受30mg/kg/天剂量的溴环己胺醇治疗的组中,蛋白酶水平进一步提高,但是在更短的时间,或在自接受治疗起第4天达到峰值水平,随后有迅速下降的趋势。即使在未受感染的小鼠身上,也同样发现BALF中胰蛋白酶型蛋白酶的分泌被溴环己胺醇促进(参见表2中所列的数据)。在施用10mg/kg/天和30mg/kg/天剂量的溴环己胺醇的实验动物组中,胰蛋白酶型蛋白酶水平在第4天达到峰值,或达到在未受感染动物身上观察到的2.2倍和2.4倍。
本发明人还进一步研究了溴环己胺醇对SP-A和MPI水平的影响[参见表1和2中所列的数据(溴环己胺醇对受流感病毒感染组和未受感染组的小鼠BALF中胰蛋白酶样蛋白酶活性、PS和MTI的影响)]。
流感病毒的感染增加了生物保护性物质或SP-A和MPI的水平,它们都具有抗流感活性。更具体地讲,第6天它们达到峰值,该值是在未受感染的动物身上观测到的6倍和4.4倍。溴环己胺醇对受感染动物组的治疗使得MPI和SP-A浓度在施用溴环己胺醇后1天迅速显著地提高,并达到峰值,其值是在未受感染动物身上观察到的9-10倍和8.4倍。接受10mg/kg/天剂量的溴环己胺醇治疗的受感染的小鼠组中,在第1天其MPI和SP-A水平就迅速提高,并在其后逐渐提高,在第5天达到峰值,并持续保持其高水平直至第7天。然而,当用30mg/kg/天的溴环己胺醇治疗小鼠时,MPI和SP-A水平在第1天被提高,在第4天达到峰值,接着MPI和SP-A迅速下降。同时还发现,施用溴环己胺醇还可轻微促进未受感染小鼠的SP-A和MPI分泌。
表1
调节因子 | 溴环己胺醇的用量[mg/kg/天] | 病毒感染后的天数 | |||||||
0 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | ||
胰蛋白酶样蛋白酶活性[μU/ml] | 0 | 25.0±10.0 | 38.4±2.9 | 70.0±8.8 | 99.0±28.3 | 125.0±2.9 | 146.8±21.0 | 160.0±21.0 | 124.0±30.0 |
10 | 56.0±2.3* | 81.0±10.0 | 135.0±17.0 | 156.6±25.0 | 201.5±20.0* | 172.0±30.0 | 175.0±26.0 | ||
30 | 60.0±10.0* | 90.0±12.5 | 129.0±33.7 | 221.5±38.0* | 148.0±19.8 | 137.0±17.0* | 53.0±15.0* | ||
SP-A[ng/ml] | 0 | 2.1±0.6 | 2.3±0.1 | 6.0±2.1 | 8.6±3.2 | 9.2±4.6 | 10.4±2.2 | 12.5±1.5 | 7.3±1.9 |
10 | 9.4±3.9* | 14.5±2.6* | 14.8±2.9 | 15.6±3.4 | 19.1±3.5* | 16.5±3.1 | 15.1±3.1* | ||
30 | 11.3±1.1* | 14.5±3.3* | 16.0±5.1 | 21.1±6.0* | 12.4±1.2 | 12.1±1.7 | 4.9±1.5 | ||
MPI[μU/ml] | 0 | 110.0±56.0 | 123.0±25.0 | 188.6±61.0 | 256.0±71.4 | 360.0±97.0 | 425.0±120.0 | 143.0±69.0 | 329.0±81.0 |
10 | 200.0±20.0* | 396.7±62.6* | 480.0±120.0* | 587.6±147.0* | 933.0±170.0* | 600.0±98.0 | 660±180.0* | ||
30 | 305.0±18.3* | 518.3±183.0* | 753.0±216.0* | 929.2±95.0* | 800.0±134.0* | 500.0±61.0 | 156.0±30.0* |
本表中的数据都用平均值±SD表示。每组数据中n=5。用Student’s t-Test评价溴环己胺醇治疗组与不接受该治疗的组之间的显著性差异,*P<0.05。
表2
调节因子 | 溴环己胺醇的用量[mg/kg/天] | 病毒感染后的天数 | |||||||
0 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | ||
胰蛋白酶样蛋白酶活性[μU/ml] | 0 | 25.0±2.0 | 25.0±1.8 | 20.0±1.5 | 20.0±5.0 | 25.0±6.0 | 25.0±8.0 | 20.0±10.0 | 25.0±8.0 |
10 | 26.7±3.0 | 30.0±10.0 | 33.4±1.6* | 55.0±16.0* | 50.0±13.0* | 20.0±9.1 | 25.0±10.0 | ||
30 | 26.7±2.4 | 33.4±18.0 | 40.0±11.0* | 60.0±22.0* | 25.0±10.0 | 20.0±7.7 | 20.0±6.0 | ||
SP-A[ng/ml] | 0 | 2.2±0.3 | 2.4±0.8 | 2.7±1.1 | 2.4±1.0 | 2.7±0.9 | 2.3±0.7 | 2.7±0.8 | 2.5±1.0 |
10 | 3.0±0.9 | 3.4±1.1 | 4.3±2.2 | 5.6±1.4* | 6.8±3.0* | 6.2±2.2* | 7.4±3.1* | ||
30 | 3.9±1.7 | 5.2±1.0* | 5.6±1.9* | 8.3±1.2* | 7.2±3.1* | 6.9±2.8* | 6.6±2.1* | ||
MPI[μU/ml] | 0 | 112.5±30.0 | 125.0±26.0 | 130.0±50.0 | 167.0±40.0 | 200.0±98.0 | 130±32.0 | 200.0±50.0 | 165.0±50.0 |
10 | 150.0±40.0 | 200.0±50.0 | 250.0±60.0* | 300.0±50.0* | 500±70.0* | 470.8±50.0* | 430.0±100.0* | ||
30 | 200.0±60.0 | 250.0±70.0 | 458.5±60.0* | 550.0±80.0* | 500±60.0* | 250.0±80.0 | 167.0±70.0 |
本表中的数据都用平均值±SD表示。每组数据中n=5。用Student’s t-Test评价溴环己胺醇治疗组与不接受该治疗的组之间的显著性差异,*P<0.05。
研究溴环己胺醇对BALF中粘膜免疫球蛋白IgA和IgG分泌的作用(参见图3和4)。
图3显示了溴环己胺醇对未受感染小鼠组(A)和对感染流感病毒A的小鼠组(B)的BALF中粘膜免疫球蛋白IgA和IgG的分泌促进作用。图中,对(A)未受感染的组,和(B)受感染的组接受食盐水(白条)、10mg/kg/天(黑条)和30mg/kg/天/剂量的溴环己胺醇治疗的小鼠BALF中IgA水平检测观察了7天。这些数据都用平均值±SD(n=5)表示。通过Student’s t-Test,发现食盐水处理组与溴环己胺醇治疗组之间的显著性差异为*P<0.05、**P<0.01。
图4显示了溴环己胺醇对(A)未受感染的组,和(B)受流感病毒A感染的组的小鼠BALF中粘膜免疫球蛋白IgG的分泌促进作用。图中,对(A)未受感染的组,和(B)受感染的组接受食盐水(白条)、10mg/kg/天(黑条)和30mg/kg/天/剂量的溴环己胺醇治疗的小鼠BALF中IgA水平检测观察了7天。这些数据都用平均值±SD(n=5)表示。通过Student’s t-Test发现食盐水处理组与溴环己胺醇治疗组的之间显著性差异为*P<0.05。
鼻内接种流感病毒可大大促进粘膜免疫球蛋白IgA和IgG的分泌。这些抗体水平已被发现与病毒增殖抑制程度相互关联(Liew FY.Russell SM,Appleyard G,Brand CM,Beale J,Cross protection in mice infected withinfluenza A virus by the respiratoty route is correlated with local IgA rather thanserum antibody or cytotoxic T cell reactivity.Eur.J.Immunol.,1984,14:350-356;Tamura S,Funato H,Hirabayash Y等,Functional role of respiratorytract hemagglutinin-specific IgA antibodies in protection against influenza.Vaccine.,1990,8:479-485)。
从未受感染的小鼠组中得到的BALF中,IgA浓度很低,只有10.3±6.6ng/ml,而IgG浓度相对高一些,为460±26.2ng/ml。相对较高的IgG水平可能缘于其从血清到呼吸道分泌液中的扩散(参见图3A和4A)。对受感染的小鼠组进行的10和30mg/kg/天溴环己胺醇的治疗促进了IgA的分泌。更具体地讲,从开始治疗起第7和第5天,与未接受该治疗的组相比,这种治疗使IgA水平大约提高了10倍,IgG水平稍微升高,在第7和第6天提高了大约1.2倍。如果使小鼠感染流感病毒,那么自感染起1到2天后,BALF中IgA和IgG的浓度基本上得到提高,其水平在第7天达到峰值,并发现为400倍,第6天的IgG水平是未接受治疗的组的11倍(参见图3B和4B)。对未受感染小鼠进行的10和30mg/kg/天溴环己胺醇的治疗大大提高了其第7和第5天的IgA水平,并分别达到IgA基础浓度的大约600倍和700倍。另一方面,对受感染小鼠进行的10和30mg/kg/天溴环己胺醇的治疗中度刺激了受感染小鼠的IgG分泌,其第6和5天的浓度是其基础浓度的约16倍和15倍。这些结果是可以获得的,因为通过溴环己胺醇的治疗,由感染而诱导的粘膜免疫球蛋白IgA和IgG的分泌分别得到了大大和中度提高。因此,可以认定的是免疫球蛋白水平的提高源于溴环己胺醇对呼吸道中病毒增殖抑制的作用。
5)溴环己胺醇对细胞因子的作用
据报道,溴环己胺醇可体外抑制任何炎性细胞因子的释放,例如TNF-α、IL-2、IL-1、IL-4、IL-13和IFN-γ(Pfeifer S,Zissel G,Kienast K,Muller-Quernheim J,Reduction of cytokine release from blood andbronchoalveolar mononuclear cells by ambroxol.,Eur.J.Med.Res.,1997,2:129-132;Gibbs BF,Schmutzler W,Vollrath IB,Brostharardt P,Braam U,WolffHH,Zadlo-Klarwasser G,Ambroxol inhibits the release of histamine,leukotrienes and cytokines from human leukocytes and mast cells.Inflamm.Res.,1999,48:86-93)。为了测定溴环己胺醇对受流感病毒感染的小鼠的抗炎作用。本发明人研究或分析了粘膜免疫促进细胞因子的水平,例如TNF-α、IL-4和IFN-γ、IL-6和IL-12等炎性细胞因子(Boyaka PN,Marinaro M,Jachson R,Menon S,Kiyono H,Jirillo E,McGhee JR,IL-12 is an effective adjuvant forinduction of mucosal immunity,
J.Immunol.,1999,162:122-128)。上述所得结果被列在表3中(溴环己胺醇对感染流感病毒A/Aichi/68(H3N2)的小鼠BALF中细胞因子例如TNF-α、IL-12、IFN-γ和IL-6的作用)。
未受感染的小鼠BALF中细胞因子的水平比检测限低。尽管感染流感病毒后时间过程模式不同,但病毒感染明显诱导BALF中除IL-4外所有细胞因子的分泌。更具体地讲,当动物受到流感病毒感染,其TNF-α水平一开始被提高,或在第1天达到峰值,此后,该值会迅速下降并在第6天达到第二个最小峰值。IL-6水平同样在感染后第1天迅速升高,并一直保持这一高水平,第5天达到峰值,但在感染后第7天开始迅速下降。IFN-γ和IL-12的浓度在施用溴环己胺醇后逐渐上升,并在用药后第4和6天达到相对峰值。然而,7天检测中(没有显示该数据)未检测到受感染小鼠的BALF中的IL-4。当受用溴环己胺醇处理感染小鼠,分别在自用溴环己胺醇治疗起第3-5天、第1天和第4天观测了TNF-α、IFN-γ和IL-12的分泌抑制作用,但是在用溴环己胺醇治疗期间,没能经常观测该抑制作用。另一方面,受感染小鼠BALF中的IL-6水平自接受溴环己胺醇治疗起第4和6天得到了提高。
表3
调节因子(CK)(pg/ml) | 溴环己胺醇的用量(AM)(mg/kg/天) | 病毒感染后的天数 | ||||||
1 | 2 | 3 | 4 | 5 | 6 | 7 | ||
TNF-α | 0 | 155.5±36.2 | 124.2±27.8 | 67.7±7.3 | 28.9±0.2 | 57.1±15.8 | 64.1±29.3 | 12.3±5.2 |
10 | 150.6±21.3 | 108.9±17.3 | 57.8±20.2 | 23.1±8.3 | 29.0±8.5* | 61.1±24.0 | 9.8±2.3 | |
30 | 123.5±26.4 | 84.8±18.8 | 35.5±5.4* | 19.2±3.3* | 45.2±23.2 | 41.5±17.0 | 10.6±3.6 | |
IL-12 | 0 | 22.4±8.9 | 93.4±12.1 | 138.3±8.8 | 184.7±8.5 | 74.7±21.9 | 32.6±4.7 | 88.3±33 |
10 | 27.3±7.1 | 68.5±12.9* | 133.3±17.2 | 119.5±15.8* | 57.4±16.0 | 29.4±6.2 | 62.5±27.7 | |
30 | 22.4±4.1 | 108.2±33.3 | 141.5±15.1 | 118.6±11.4* | 62.4±13.6 | 44.3±29.1 | 95.8±52.2 | |
IFN-γ | 0 | 17.5±2.6 | 12.6±2.3 | 3.9±0.8 | 7.1±0.9 | 40.4±10.8 | 49.5±26.6 | 5.3±2.9 |
10 | 9.4±2.4* | 9.5±1.8 | 2.8±0.9 | 5.3±2.8 | 14.7±5.3* | 39.4±18.6 | 4.0±1.6 | |
30 | 10.4±2.7* | 9.8±2.4 | 4.0±1.1 | 10.2±5.5 | 32.8±11.1 | 61.8±21.7 | 5.1±1.8 | |
IL-6 | 0 | 139.1±45.2 | 196.0±22.6 | 268.0±75.2 | 216.2±60.2 | 459.8±127.1 | 430.0±63.6 | 72.1±13.0 |
10 | 174.8±35.0 | 191.8±51.9 | 280.2±54.2 | 339.2±57.1* | 540.9±84.2 | 503.23±61.4 | 73.7±14.7 | |
30 | 170.8±28.9 | 186.7±19.6 | 326.2±44.9 | 433.5±101.9* | 478.2±86.4 | 817.0±168.0* | 80.0±17.5 |
本表中的数据都用平均值±SD表示。每组数据中n=5。用Student’s t-Test评价溴环己胺醇治疗组与不接受该治疗的组之间的显著性差异,*P<0.05。
<讨论>
本项研究中,可得到的结论是溴环己胺醇明显抑制呼吸道中流感病毒的增殖,并同样提高被感染致死量流感病毒A/Aichi/68(H3N2)的小鼠的存活率。流感病毒对呼吸道表现出器官特异性,其病原性和复制是由多种源于宿主细胞的因子及T-细胞和B-细胞的免疫应答决定的。
据报道,在动物的呼吸道中,胰蛋白酶型蛋白酶例如胰蛋白酶Clara作为一种细胞因子促进流感病毒复制(Kido H,Yokogoshi Y,Sakai K,Tashiro M,Kishino Y,Fukutomi A,Kutunuma N,Isolation and characterization of a noveltrypsin-like protease found in rat bronchiolar epithelial Clara cells.J.Biol.Chem.,1992,267:13573-13579;Tashiro M,Yokogoshi Y,Tobita K,Seto JT,Rott R,Kido H,Tryptase Clara,an activating protease for sendai virus in ratlungs,is involved in pneumopathogenicit.J。Virol.,1992,66:7211-7216),另一方面,能够抑制病毒增殖的因子为作为蛋白酶抑制剂的MPI(Beppu Y,Imamura Y,Tashiro M,Towatari T,Ariga H,Kido H,Human Mucus proteaseinhibitor in airway fluids is a potential defensive compound aginst infection withinfluenza A and Sendai viruses.J.Biochem.,1997,121:309-316),和PS,它可吸收蛋白酶从而抑制其活性(Kido H,Sakai K,Kishino Y,Tshiro M,Apulmonary surfactant is a potential endogenous inhibitor of proteolytic activationof Sendai virus and influenza virus.FFBS Lett.,1993,322:115-119)。胰蛋白酶型蛋白酶的浓度在正常的呼吸道环境中维持在可以感染流感病毒并使其能增殖的水平,其高于抑制剂浓度。
覆盖在肺泡上皮上的PS与胰蛋白酶Clara结合并抑制其蛋白酶活性(Kido H,Sakai K,Kishino Y,Tshiro M,A pulmonary surfactant is a potentialendogenous inhibitor of proteolytic activation of Sendai virus and influenzavirus.FFBS Lett.,1993,322:115-119;Kido H,Murakami M,Oba K,Chen Y,Towatari T,Cellular proteinases trigger the infectivity of the influenza virus Aand Sendai viruses,
Mol.Cells.,1999,9:235-244)。流感病毒的感染促进了细胞增殖所需的胰蛋白酶型蛋白酶及其抑制剂的分泌。此外,当用溴环己胺醇治疗受感染的小鼠时,进一步大大促进上述物质的分泌,但是这种作用改变了蛋白酶和抑制剂的平衡。由病毒感染诱导的蛋白酶的浓度进一步提高到1.3-1.4倍的水平,而通过溴环己胺醇的治疗,SP-A和MPI的浓度分别提高到1.5-1.7倍和1.9倍。这些结果清楚地表明溴环己胺醇的治疗保证了受感染小鼠呼吸道分泌液中具有病毒增殖抑制作用的物质的比率,并以此改善了呼吸道环境,使其与未接受这种治疗的小鼠的呼吸道环境相比,具有更高的病毒增殖抑制倾向。
另外,溴环己胺醇还能够促进或增加受感染和不受感染的小鼠的粘膜免疫球蛋白IgA和IgG的分泌,如图3所示。该药物还可中度促进IgG的分泌(图4)。溴环己胺醇同样可促进IgA的释放,即使是在未受感染的小鼠中。更具体地讲,IgA的浓度提高到其基准浓度的大约10倍,IgG的浓度提高到其基准浓度的1.2倍。病毒感染后,BALF中IgA和IgG的浓度显著提高,但是用溴环己胺醇治疗受感染的小鼠可以分别将IgA和IgG的浓度提高到其由病毒感染诱导的最大浓度的约1.5-1.8倍和1.45倍。这清楚地说明了因溴环己胺醇的治疗而提高的IgA和IgG浓度在提高受感染小鼠的存活率方面起到了重要作用。
虽然现在还不能清楚地阐明溴环己胺醇促进分泌多种因子例如IgA、IgG、SP-A、MPI和胰蛋白酶型蛋白酶的确切机理,但是,上述事实表明溴环己胺醇能刺激上、下呼吸道的很多靶细胞。当小鼠接受最适剂量10mg/kg/天的溴环己胺醇治疗时,呼吸道中病毒增殖抑制物质和免疫球蛋白的浓度随时间而逐步上升,并在第7天当病毒复制停止时保持一个很高的值。然而,采用更高剂量的溴环己胺醇的治疗使这些物质的浓度迅速提高,并在第4-5天达到其峰值,但是整个病毒感染过程中不能一直保持这样的高水平。这是溴环己胺醇在30mg/kg/天剂量时病毒增殖抑制效果低的原因。这些结果表明溴环己胺醇促进呼吸道分泌液体中这些抑制物质和胰蛋白酶型蛋白酶的分泌,而不是促进这些物质的合成。此外,还应认识到的是,这些病毒增殖抑制物质应在7天内一直保持在一个高水平以提高受感染小鼠的存活率。
这种病毒增殖在第7天停止(参见图2),但是肺部炎症一直存在,并有缓慢发展。最近,很多研究表明溴环己胺醇具有抗炎作用(Gillissen A,Scharling B,Jaworska M,Bertling A,Rasche K,Schultze-Werninghaus G,Oxidant scavenger function of ambroxol in vitro:a comparison withN-acetylcysteine AC.Res.Exp.Med(Berl),1997,196:389-398),及降低炎性细胞因子产生的能力(Pfeifer S,Zissel G,Kienast K,Muller-Quernheim J,Reduction of cytokine release from blood and bronchoalveolar mononuclearcells by ambroxol.Eu r.J.Med.Res,1997,2:129-132;Gibbs BF,Schmutzler W,Vollrath IB,Brostharardt P,Braam U,WolffHH,Zadlo-Klarwasser G.,Ambroxolinhibits the release of histamine,leukotrienes and cytokines from humanleukocytes and mast cell.Inflamm.Res.1999,48:86-93)。在本研究中,还认识到溴环己胺醇抑制受感染小鼠呼吸道分泌液中炎性细胞因子或TNF-α和IFN-γ的水平,但是这一作用并不能在整个感染过程中被经常观测到。另外,据报道,IL-6和IL-12都具有促进粘膜免疫的作用,尤其是有报道指出IL-12具有促进生成粘膜免疫球蛋白IgA的作用(Boyaka PN,Marinaro M,JachsonR,Menon S,Kiyono H,Jirillo E,McGhee JR,IL-12is an efective adjuvant forinduction of mucosal immunity.J.Immunol.,1999,162:122-128)。用溴环己胺醇治疗受感染小鼠提高了第4和6天BALF中IL-6的水平,并在第4天暂时性地抑制了IL-12水平。
另一方面,溴环己胺醇对抵抗流感病毒的机体防御体系显示出一些负面作用,例如增加胰蛋白酶型蛋白酶的水平和短暂性地抑制IL-12释放的作用,但是总体来讲,采用溴环己胺醇的治疗显著提高了呼吸道分泌液中具有病毒增殖抑制作用的生物因子的浓度,并因此可抑制呼吸道中病毒的增殖,由此大大提高了受流感病毒感染的小鼠的存活率。其中,与抑制流感病毒增殖相关的溴环己胺醇作用可由其对例如SP-A、MPI、IgA和IgG这些呼吸道中物质浓度的提高及对呼吸道中炎性细胞因子释放的抑制来证实。这些结果表明溴环己胺醇可在临床上用来治疗或预防流感病毒A的感染。
总而言之,现在流感有流行趋势,而且其流行在大多数情况下都变成了重大新闻。因此,本发明所述的抗流感药物可在流感刚开始流行时,甚至当发生传染后,作为药物使用。尤其,根据本发明的记载,所述药物可用来治疗受流感病毒感染的患者或防止随之而来的传染,可用于以治疗或防止由原因病毒引起的疾病,这些病毒具有外膜糖蛋白,并通过感染呼吸道而增殖,例如流感病毒。
Claims (2)
1.溴环己胺醇、溴苄环己铵或它们的可药用盐在制备抗流感药物中的用途。
2.权利要求1的用途,其为溴环己胺醇、溴苄环己铵或它们的可药用盐在治疗或预防流感病毒感染疾病的药物中的用途。
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