CN102264222B - 抗病毒补剂 - Google Patents
抗病毒补剂 Download PDFInfo
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- CN102264222B CN102264222B CN200980148721.4A CN200980148721A CN102264222B CN 102264222 B CN102264222 B CN 102264222B CN 200980148721 A CN200980148721 A CN 200980148721A CN 102264222 B CN102264222 B CN 102264222B
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- ascorbic acid
- virus
- influenza
- ascorbate
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Abstract
本公开内容提供了口服抗病毒补剂组合物,其包含赖氨酸、抗坏血酸化合物、类黄酮糖苷、苏氨酸和吡哆醇。本公开内容还提供了减少细胞中病毒复制的方法,其包括用本公开内容的组合物处理病毒感染的细胞。本公开内容还提供了治疗和预防患者的病毒感染的方法,其包括施用本公开内容的组合物。
Description
与相关申请的交叉引用
本申请以Vymedic,LLC(美国公司,除美国外所有指定国的申请人)以及Kenneth E.Phillips和Cynthia A.Winning(均为美国公民,仅为指定国美国的申请人)的名义于2009年10月30日以PCT国际专利申请提交,并要求于2008年11月4日提交的美国临时专利申请序列号61/111,234的优先权,其通过整体引用并入本文。
发明背景
发明领域
本公开内容提供了包含赖氨酸、抗坏血酸化合物、类黄酮糖苷、苏氨酸和吡哆醇的口服抗病毒补剂组合物。
背景技术
流行性感冒(流感)是由流感病毒引起的传染性呼吸系统疾病。其可导致轻度至重度疾病,有时可致死亡。据CDC统计,多种亚型的流感病毒在世界范围内传播。估计约有306种已知的人流感病毒类型、亚型和毒株,以及约62种导致人流感样疾病的已知的非脊髓灰质炎肠道病毒。甲和乙型流感病毒是每年季节性流感流行的原因,其通常在十二月至四月暴发。非脊髓灰质炎肠道病毒为仅次于“普通感冒”病毒的最常见人病毒感染因素。肠道病毒最有可能发生在六月至十一月。为减少感染甲或乙型流感病毒的可能性,可在流感季节接种流感疫苗以提供保护措施。
预防流感的最好方法是每年接种流感疫苗。不过,接种仅对预防某些流感毒株有效。实际上,疫苗的一个关键缺点是它们具有毒株特异性。一旦患者被感染,则必须考虑其它选择。
在美国,两类药物获FDA批准用于治疗或预防流感病毒感染:M2离子通道阻断剂和神经氨酸酶抑制剂(NAI)。M2通道阻断剂(金刚烷类,如金刚烷胺和金刚乙胺)对甲型流感病毒有效,但对缺乏M2蛋白的乙型流感病毒无效。M2阻断剂的使用与人甲型流感病毒H3N2和H1N1亚型中的M2蛋白药物抗性突变的出现有关,并已在A/H5N1病毒中检测到抗性。因此,CDC已从2005年开始不推荐使用M2阻断剂,目前除了NAI抗性株的可能情况外,仅推荐使用NAI。病毒神经氨酸酶可方便病毒到达细胞表面并辅助新形成病毒颗粒从被感染细胞中释放,使病毒感染其它细胞。
如果患者感染了甲或乙型流感病毒株,NAI(如Relenza(扎纳米韦(zanamivir))和Tamiflu(奥司他韦(oseltamivir)))只能通过处方获得并应在出现症状后头48小时内开始服用。已证明NAI药物将通常的七天症状持续期减少约一天。为治疗2009 H1N1病毒感染,CDC目前推荐使用奥司他韦(Tamiflu)或扎纳米韦(Relenza)(http://www.cdc.gov/h1n1flu/recommendations.htm)。在症状出现后,还同时对症治疗流感病毒和非脊髓灰质炎肠道病毒以缓解不适。
Tamiflu(磷酸奥司他韦,Roche)是抗病毒处方药,其以口服胶囊或口服悬浮剂形式获批治疗和预防流行性感冒。磷酸奥司他韦是乙酯类前药,需要酯水解转变成活性形式的羧酸奥司他韦。羧酸奥司他韦是影响病毒颗粒的释放的流感病毒神经氨酸酶抑制剂。通过在存在不断增加的羧酸奥司他韦浓度的细胞培养物中连续传代病毒回收了对羧酸奥司他韦敏感性降低的甲型流感病毒分离株。在治疗自然获得的流感病毒感染的临床研究中,1.3%的成年和青年治疗后分离株和8.6%的1至12岁儿童治疗后分离株在细胞培养物中出现针对羧酸奥司他韦的神经氨酸酶敏感性降低的流感病毒变体。已在细胞培养物中发现了某些扎纳米韦抗性流感突变体与奥司他韦抗性流感突变体之间的交叉抗性。在2007至2008流感季节中,甲型(H1N1)流感病毒中的奥司他韦抗性在世界范围内首次显著增加(Dharan等,Infections with Oseltamivir-resistant influenza A(HlNl)virus in the United States,JAMA 301(10),1034-1041(2009))。对神经氨酸酶抑制剂敏感性降低的乙型流感病毒的增加频率不如抗性甲型流感病毒的高。不过,它们似乎在社区和家庭中传播(Hatakeyama等,Emergenceof influenza B viruses with reduced sensitivity to neuraminidase inhibitors.JAMA,297:13:1492-1493(2007))。
用NAI治疗也会产生副作用。例如,2008年3月Roche和FDA向医疗专业人士通告了与流感患者使用Tamiflu有关的神经精神方面事件。修订了标签以声明流行性感冒可与多种神经和行为症状有关,它们可包括如幻觉、精神错乱和异常行为事件,某些情况下可导致致死结果。这些事件主要在儿科患者中被报道,常为急性发病并快速消失。由于这些事件在临床实践中为自愿报告,所以很难估算频率,但基于Tamiflu使用数据,这些事件看来并不常见。无论如何,由于药物抗性流感病毒株的出现和Tamiflu的可能副作用,抗病毒治疗的替代方法受到关注。
Relenza(扎纳米韦,GlaxoSmithKline)是抗病毒处方药,以吸入粉剂形式获批用于治疗和预防流行性感冒。扎纳米韦作为流感病毒表面神经氨酸酶抑制剂发挥作用。病毒神经氨酸酶可促进病毒到达细胞表面并辅助新形成的病毒颗粒从被感染细胞中释放,使病毒感染其它细胞。对扎纳米韦敏感性降低的流感病毒通过在不断增加的药物浓度存在下传代病毒已经在体外回收。最近已鉴定到具有新型神经氨酸酶突变的扎纳米韦抗性流感病毒(Hurt等,J.Virology,83(20):10366-10373(Oct.2009))。
这些药物在流行中的有效性仍存有很大的不确定性,因为获取可能受限且可能产生药物抗性。显然,需要治疗和预防病毒感染的替代方法来帮助限制已知抗病毒药物的药物抗性的产生。
已知几种含有多种维生素和矿物质的抗病毒补剂,一些已上市。这些制剂中许多是由膳食补剂(联邦食品、药品和化妆品法,第II章第201节[21U.S.C.§321]第ff段定义)制成,因此可被归类为膳食补剂而非药物。
US 5,626,883Paul公开了提供增强的人免疫系统活性的抗坏血酸化合物。Paul组合物包含水溶性抗坏血酸盐、脂溶性抗坏血酸酯和至少一种选自以下的抗坏血酸代谢物:碱性氨基酸、抗坏血酸降解代谢副产物、类黄酮、含硫氨基酸、焦磷酸四钠和谷胱甘肽。
WO 2007/106675,Rath等和美国专利No.2007/0212426,Rath等均公开了阻碍病毒活性并减少病毒复制的组合物和方法,其包括施用含有多酚类、抗坏血酸化合物、赖氨酸和脯氨酸的组合物。
美国专利No.7,041,699,Netke等公开了包含多酚类的营养药物制剂以及在治疗癌症中的用途。Netke等公开了含有抗坏血酸化合物;赖氨酸、脯氨酸和N-乙酰半胱氨酸的氨基酸,以及至少一种多酚的制剂。
WO 92/15315,Wilkinson公开了疱疹感染的治疗方法,其包括施用含有赖氨酸、维生素C和橘皮苷的组合物。
美国专利No.5,650,418,Rath和Pauling公开了主要由抗坏血酸盐化合物和赖氨酸组成并具有有药物载体的药物组合物。Rath和Pauling还公开了通过施用含有抗坏血酸盐、烟酸、赖氨酸和药物载体的组合物治疗心血管疾病的方法。
已发现与其它膳食补剂和奥司他韦相比,含有赖氨酸、抗坏血酸化合物、类黄酮糖苷、苏氨酸和吡哆醇的新型抗病毒制剂在抑制甲型流感病毒和神经氨酸酶的体外表达中具有惊人的效果。
发明简述
在一个实施方案中,本公开内容提供了口服抗病毒补剂组合物,其包含赖氨酸、抗坏血酸化合物、类黄酮糖苷、苏氨酸和吡哆醇。在一个方面,所述赖氨酸选自:L-赖氨酸、L-赖氨酸单盐酸盐、L-赖氨酸二盐酸盐、L-赖氨酸琥珀酸盐、L-赖氨酸谷氨酸盐和L-赖氨酸乳清酸盐。在另一个方面,所述抗坏血酸化合物选自下列一种或更多种:抗坏血酸、抗坏血酸钙、抗坏血酸镁、抗坏血酸钾、抗坏血酸钠、抗坏血酸锰、抗坏血酸锌、抗坏血酸铁(iron ascorbate)、抗坏血酸铜、抗坏血酸硼、抗坏血酸钼、抗坏血酸铬、抗坏血酸棕榈酸酯、抗坏血酸花生四烯酸酯、抗坏血酸硬脂酸酯、抗坏血酸亚油酸酯、抗坏血酸亚麻酸酯(ascorbyl linoleneate)和抗坏血酸油酸酯。在另一些方面,所述类黄酮糖苷选自下列一种或更多种:橘皮苷、芸香苷、柚皮苷和槲皮苷。在一个具体方面,所述类黄酮糖苷为按重量计约1∶1的橘皮苷和芸香苷混合物。在一个方面,所述吡哆醇为盐酸吡哆醇。在另一个方面,所述组合物还包含牛磺酸。
在一个方面,所述组合物为粉剂、胶囊、锭剂、糖锭剂(troche)、片剂、液体或囊片剂形式。在一个方面,所述组合物包含L-赖氨酸单盐酸盐、抗坏血酸、橘皮苷、芸香苷、盐酸吡哆醇、苏氨酸和牛磺酸。在一个方面,所述组合物还包含抗坏血酸钙、抗坏血酸烟酰胺和抗坏血酸棕榈酸酯。
在一个具体方面,所述组合物的单剂量包含约2g至约3.5g L-赖氨酸单盐酸盐;约0.1g至约1.5g抗坏血酸;约0.2g至约0.8g橘皮苷;约0.1g至约0.5g芸香苷;约0.04g至约0.08g盐酸吡哆醇;约0.01g至约0.08g苏氨酸和约0.02g至约0.4g牛磺酸。在另一个特定方面,所述组合物还包含约0.5g至约0.75g抗坏血酸钙;约0.1g至约0.5g抗坏血酸烟酰胺和约0.01g至约0.1g抗坏血酸棕榈酸酯。在另一个特定方面,所述组合物的单剂量包含约3g L-赖氨酸单盐酸盐;约0.2g至约1.0g抗坏血酸;约0.3g橘皮苷;约0.3g芸香苷;约0.05g盐酸吡哆醇;约0.05g苏氨酸和约0.02g至约0.3g牛磺酸。在另一个方面,所述组合物的单剂量还包含约0.6g抗坏血酸钙;约0.3g抗坏血酸烟酰胺和约0.05g抗坏血酸棕榈酸酯。
在另一个实施方案中,本公开内容提供了减少细胞中病毒复制的方法,其包括用有效量的包含赖氨酸、抗坏血酸化合物、类黄酮糖苷、苏氨酸和吡哆醇的组合物处理病毒感染的细胞。在一个方面,所述方法采用的组合物中的赖氨酸选自L-赖氨酸、L-赖氨酸单盐酸盐、L-赖氨酸二盐酸盐、L-赖氨酸琥珀酸盐、L-赖氨酸谷氨酸盐和L-赖氨酸乳清酸盐。在另一个方面,所述方法采用的组合物中抗坏血酸化合物选自下列一种或更多种:抗坏血酸、抗坏血酸钙、抗坏血酸镁、抗坏血酸钾、抗坏血酸钠、抗坏血酸锰、抗坏血酸锌、抗坏血酸铁、抗坏血酸铜、抗坏血酸硼、抗坏血酸钼、抗坏血酸铬、抗坏血酸棕榈酸酯、抗坏血酸花生四烯酸酯、抗坏血酸硬脂酸酯、抗坏血酸亚油酸酯、抗坏血酸亚麻酸酯和抗坏血酸油酸酯。在另一个方面,所述方法采用的组合物中类黄酮糖苷选自下列一种或更多种:橘皮苷、芸香苷、柚皮苷和槲皮苷。在另一个方面,所述方法采用的组合物中的吡哆醇为盐酸吡哆醇。在另一个方面,所述方法采用的组合物还包含牛磺酸。
在另一个特定方面,本公开内容提供了减少细胞中病毒复制的方法,其包括用有效量的包含L-赖氨酸单盐酸盐、抗坏血酸、抗坏血酸钙、抗坏血酸烟酰胺、抗坏血酸棕榈酸酯、橘皮苷、芸香苷、盐酸吡哆醇、苏氨酸和牛磺酸的组合物处理病毒感染的细胞。
在另一个实施方案中,本公开内容提供了在有此需要的对象中治疗或预防病毒感染的方法,其包括向所述对象施用治疗有效量的包含赖氨酸、抗坏血酸化合物、类黄酮糖苷、苏氨酸和吡哆醇的组合物。在某些方面中,所述病毒感染为甲型流感、乙型流感、丙型流感或非脊髓灰质炎肠道病毒感染。在另一个方面中,所述方法采用的组合物中的赖氨酸选自L-赖氨酸、L-赖氨酸单盐酸盐、L-赖氨酸二盐酸盐、L-赖氨酸琥珀酸盐、L-赖氨酸谷氨酸盐和L-赖氨酸乳清酸盐。在另一个方面,所述方法采用的组合物中的抗坏血酸化合物选自下列一种或更多种:抗坏血酸、抗坏血酸钙、抗坏血酸镁、抗坏血酸钾、抗坏血酸钠、抗坏血酸锰、抗坏血酸锌、抗坏血酸铁、抗坏血酸铜、抗坏血酸硼、抗坏血酸钼、抗坏血酸铬、抗坏血酸棕榈酸酯、抗坏血酸花生四烯酸酯、抗坏血酸硬脂酸酯、抗坏血酸亚油酸酯、抗坏血酸亚麻酸酯和抗坏血酸油酸酯。在另一个方面,所述方法采用的组合物中的类黄酮糖苷选自下列一种或更多种:橘皮苷、芸香苷、柚皮苷和槲皮苷。在另一个方面,所述方法采用的组合物中的吡哆醇为盐酸吡哆醇。在另一个方面,所述方法采用的组合物还包含牛磺酸。在另一个方面中,所述方法采用的组合物包含L-赖氨酸单盐酸盐、抗坏血酸、抗坏血酸钙、抗坏血酸烟酰胺、抗坏血酸棕榈酸酯、橘皮苷、芸香苷、盐酸吡哆醇、苏氨酸和牛磺酸。在另一个方面中,所述方法采用的组合物还包含抗坏血酸钙、抗坏血酸烟酰胺和抗坏血酸棕榈酸酯。
在一个具体方面,所述在有此需要的对象中治疗或预防病毒感染的方法包括向所述对象施用治疗有效量的组合物,其中单剂量包含约2g至约3.5g L-赖氨酸单盐酸盐;约0.1g至约1.5g抗坏血酸;约0.2g至约0.8g橘皮苷;约0.1g至约0.5g芸香苷;约0.04g至约0.08g盐酸吡哆醇;约0.01g至约0.08g苏氨酸;和约0.02g至约0.4g牛磺酸。在另一个特定方面,所述方法采用的组合物的单剂量还包含约0.5g至约0.75g抗坏血酸钙;约0.1g至约0.5g抗坏血酸烟酰胺;和约0.01g至约0.1g抗坏血酸棕榈酸酯。在另一个特定方面,所述方法采用的组合物的单剂量包含约3g L-赖氨酸单盐酸盐;约0.2g至约1.0g抗坏血酸;约0.3g橘皮苷;约0.3g芸香苷;约0.05g盐酸吡哆醇;约0.05g苏氨酸;和约0.02g至约0.3g牛磺酸。在另一个特定方面中,所述方法采用的组合物的单剂量还包含约0.6g抗坏血酸钙;0.3g抗坏血酸烟酰胺和约0.05g抗坏血酸棕榈酸酯。
附图说明
图1显示了如实施例2所述在被感染细胞上清的支链DNA(bDNA)测定中用多种制剂处理时,体外抑制甲型流感感染Vero细胞的浓度(μM)/反应曲线。数据代表各数据点的平均值(n=3),为清楚表示省略误差线。
图2显示了如实施例2所述在bDNA测定中用多种制剂处理时,体外抑制甲型流感感染Vero细胞的浓度(μM)/反应曲线。数据代表各数据点的平均值(n=3);误差线代表平均值的标准误(SEM)。
图3显示如实施例3所述在Amplex Red神经氨酸酶测定中多种制剂对来自甲型流感病毒感染的Vero细胞上清的神经氨酸酶的体外抑制。数据代表各数据点的平均值(n=3),为清楚表示省略误差线。
图4显示如实施例3所述在Amplex Red神经氨酸酶测定中两种制剂对来自甲型流感病毒感染的Vero细胞上清的神经氨酸酶的体外抑制。数据代表各数据点的平均值(n=3);误差线代表平均值的标准误(SEM)。
图5显示如实施例4所述多种制剂(μM)对甲型流感病毒感染的Vero细胞中基质金属蛋白酶9(matrix metalloproteinase 9,MMP-9)表达的抑制。数据代表各数据点的平均值(n=3),为清楚表示省略误差线。
图6显示如实施例4所述两种制剂对甲型流感病毒感染的Vero细胞中基质金属蛋白酶9(MMP-9)表达的抑制。数据代表各数据点的平均值(n=3);误差线代表平均值的标准误(SEM)。
图7显示神经氨酸酶测定中测试的多种组合物的表格(表4)。
图8显示人流感病毒感染细胞在暴露于羧酸奥司他韦、配方V和表4的十种含有配方V多种成分的测试组合物之后的神经氨酸酶活性曲线。
图9显示人流感病毒感染细胞在暴露于羧酸奥司他韦、配方V和单独的赖氨酸(1)或赖氨酸联合抗坏血酸/抗坏血酸盐(1/2;9A)后的神经氨酸酶活性。
图10显示人流感病毒感染细胞在暴露于羧酸奥司他韦、配方V和赖氨酸/抗坏血酸盐/类黄酮糖苷(1/2/3;10A)或赖氨酸/抗坏血酸盐/吡哆醇(1/2/4;10B)后的神经氨酸酶活性。
图11显示人流感病毒感染细胞在暴露于羧酸奥司他韦、配方V和赖氨酸/抗坏血酸盐/苏氨酸(1/2/5;11A)或赖氨酸/抗坏血酸盐/牛磺酸(1/2/6;11B)后的神经氨酸酶活性。
图12显示人流感病毒感染细胞在暴露于羧酸奥司他韦、配方V和赖氨酸/抗坏血酸盐/盐酸吡哆醇/苏氨酸(1/2/4/5;12A)或赖氨酸/抗坏血酸盐/类黄酮糖苷/苏氨酸(1/2/3/5;12B)后的神经氨酸酶活性。
图13显示人流感病毒感染细胞在暴露于羧酸奥司他韦、配方V和赖氨酸/抗坏血酸盐/类黄酮糖苷/盐酸吡哆醇/苏氨酸(1/2/3/4/5;13A)或赖氨酸/抗坏血酸盐/类黄酮糖苷/盐酸吡哆醇/苏氨酸/牛磺酸(1/2/3/4/5/6;13B)后的神经氨酸酶活性。
发明详述
本公开内容提供了含有赖氨酸、抗坏血酸化合物、类黄酮糖苷、苏氨酸和吡哆醇的新型抗病毒补剂组合物。本公开内容提供了以粉剂、胶囊、片剂、锭剂、糖锭剂、液体或囊片剂形式的组合物。一个具体实施方案公开了含有赖氨酸、抗坏血酸、类黄酮糖苷、盐酸吡哆醇、牛磺酸和苏氨酸的粉剂。
本文所用术语“患者”或“对象”是指作为治疗对象的动物,例如哺乳动物如人。对象或患者可以为雄性或雌性。
本文所用术语“约”是指给定量+/-10%的数值范围。例如,术语“约50%”是指45%至55%,“约100mg”是指90mg至110mg。
本文所用术语“病毒”是指任何由蛋白质外壳包被的DNA或RNA区段组成的一大类亚显微物质。流感病毒和肠道病毒为RNA病毒。病毒是寄生生物,需要宿主细胞进行复制。由于病毒不能离开宿主进行复制,在通常的分类系统中不认为其是活生物。在能够进行复制和导致疾病时将其描述成“活的(live)”。因此,术语“病毒活性”是指病毒的任何活性状态或任何活力作用或动作或活性。因此,术语“病毒复制”是指遗传物质、单细胞生物或病毒繁殖或复制其本身的任何过程。
本文所用术语“神经氨酸酶”是指起水解酶作用的从粘蛋白上移除唾液酸的病毒神经氨酸酶蛋白,主要发现于呼吸道和肠道微生物中。神经氨酸酶使得新病毒颗粒与被感染细胞外部相连的键断裂。一旦该酶破坏这些键,新病毒被释放从而感染其他细胞并传播感染。
本文所用术语“神经氨酸酶抑制剂”(Neuraminidase inhibitor,NAI)是指阻断神经氨酸酶蛋白功能并因而阻止新病毒颗粒释放从而限制感染传播的药物或制剂。具体的NAI包括奥司他韦、扎纳米韦、金刚乙胺和帕拉米韦。
本文所用术语“Vero细胞”是指非洲绿猴肾细胞系,其是甲型流感病毒初步分离和培养的适合系统。已知Vero细胞还适于乙型流感病毒的分离和大量复制。
本文所用术语“感染”是指病毒在对象体内或体表的存在,若病毒复制延迟或病毒活性减弱,则有益于所述对象。因此,术语“感染”是指病原体在人或动物任何解剖学位点的存在。
本文中所用术语“治疗”是指向对象施用化合物或组合物以达到治疗目的。术语“施用”包括通过任何将药物递送至感染位点的适当方法向对象进行的递送。药物的施用可为经口、经鼻、肠胃外、局部、经眼或透皮施用或以固体、半固体、冻干粉或液体剂型递送。剂型包括片剂、胶囊、锭剂、粉剂、溶液、悬浮液、栓剂等,优选适于单次精确剂量施用的单位剂型。
本文所用术语“抗病毒补剂”包括任何专门用于治疗或预防病毒感染的组合物,特别是流感病毒或非脊髓灰质炎肠道病毒感染。一方面可通过多种神经氨酸酶测定评价本公开内容的组合物。另一方面,可通过在基于细胞的测定中延迟病毒生长或复制评估本公开内容的组合物。另一方面,可通过减少患者病毒感染持续时间评估本公开内容的组合物。另一方面,可通过降低患者病毒感染症状的严重性或持续时间评估本公开内容的组合物。
本文所用术语“可药用盐”是指保持生物化学组合物中必需的活性成分的生物有效性和特性的盐。可药用盐包括但不限于:钠盐、钾盐、钙盐、镁盐、铝盐等。
本文所用术语“有效量”是指当向有此需要的单个对象施用时,足以降低病毒活性和/或生长从而增强抗病毒活性的本公开内容组合物的量。
本文所用术语“治疗有效量”是指当向有此需要的人对象施用时,足以治疗或预防流感病毒感染或非脊髓灰质炎肠道病毒感染的本公开内容组合物的量。该治疗有效量取决于患者体型和性别、感染阶段和严重程度以及所需结果。对给定患者和病症,可通过本领域技术人员已知方法确定治疗有效量。例如,对于用本发明组合物治疗流感病毒感染,有效量是指具有以下效应的组合物量:(1)减少病毒释放,(2)减少感染持续时间,(3)降低传染性,和/或(4)降低(或者优选地消除)一种或更多种与感染相关的其它症状的严重性,例如发热、头痛、乏力、干咳、咽喉痛、肌肉酸痛、结膜炎、流鼻涕和/或鼻塞。这样的有效剂量通常取决于上述因素。预防性有效剂量是降低感染流感病毒或非脊髓灰质炎肠道病毒可能性的剂量。预防性有效剂量是治疗有效剂量的约20%至约100%,优选约40%至约60%。
一方面,施用为经口施用。通常,治疗有效剂量不少于表1所列单个成分量的约10%且不多于其的约200%。在某些方面,治疗病毒感染的治疗有效剂量为表1所列成分的约50%至约150%、或约80%至约120%、或约100%相同。另一方面,治疗有此需要对象的病毒感染的治疗有效剂量为醒着时每4至6小时、或每天约两至六次施用。另一方面,预防有此需要对象的病毒感染的治疗有效剂量为醒着时每8至12小时、或约每天一至三次施用。
本文所用术语“可药用载体”是指参与将本发明组合物从一个器官或身体部分携带或运输至另一个器官或身体部分而不影响其生物学作用的药学可接受的材料、组合物或载剂,如液体或固体填充剂、稀释剂、赋形剂、溶剂或封闭材料。各载体应在与组合物的其它成分可相容且对对象无害的意义上为“可接受”的。
流行性感冒的症状可包括发热、头痛、乏力、干咳、咽喉痛、肌肉酸痛、流鼻涕和/或鼻塞。还可能出现胃肠系统症状如恶心、呕吐和腹泻,但在儿童中比在成人中更为常见。
非脊髓灰质炎肠道病毒的症状包括发烧、肌肉酸痛、上呼吸道症状、疲劳以及伴随皮疹的流感样症状。
病毒主要通过咳嗽或喷嚏在人与人之间传播。人们还可通过接触被污染的表面或物体随后接触自己的口或鼻而被感染。大多数健康成人可在症状发展前约一天开始至患病后约五天感染其他人。
流感病毒为动态且持续进化的。流感病毒能够以两种方式变化:抗原性漂移和抗原性转变。流感病毒通过抗原性漂移不断地发生变化,但抗原性转变仅偶尔发生。甲型流感病毒经历两种类型的变化;而乙型流感病毒仅通过更逐步的抗原性漂移过程发生变化。抗原性漂移是指小的、逐渐的改变,其通过点突变在两个含有产生主要表面蛋白(血球凝集素和神经氨酸酶)的遗传物质基因的基因中发生。这些点突变的发生不可预知,且导致这些表面蛋白的微小改变。抗原性漂移产生可能不被之前流感病毒株抗体识别的新病毒株。
人可感染甲、乙和丙型流感病毒。甲、乙和丙型流感病毒产生306种人流感病毒。目前在世界范围内人群中传播的甲型流感病毒亚型包括H1N1、H1N2和H3N2病毒。
基于迄今的全球经验,2009 H1N1流感病毒可能是在即将来临的流感季中传播的病毒中(特别是在低龄人群中导致流感的那些病毒中)最常见的流感病毒。(CDC″Updated Interim Recommendations for the Use ofAntiviral Medications in the Treatment and Prevention of Influenza forthe 2009-2010Season,September 22,2009,http://www.cdc.gov/hlnlflu/recommendations.htm)
野生鸟类是已知甲型流感病毒亚型的天然宿主。通常,野生鸟类在感染甲型禽流感病毒时并不生病。不过,家禽会因禽流感而重病并死亡。
根据两种病毒表面蛋白质将甲型流感病毒划分成亚型并命名:血球凝集素(hemagglutinin,HA)和神经氨酸酶(neuraminidase,NA)。有16种已知HA亚型和9种已知NA亚型。HA和NA蛋白能有许多不同的组合。只有一些甲型流感病毒亚型(即H1N1“西班牙流感”或“猪流感”、H1N2和H3N2“香港流感”)目前在人群中普遍流行。只有甲型流感病毒感染鸟类,且所有已知甲型流感病毒亚型均可感染鸟类。不过,通常感染鸟类的甲型流感病毒亚型与感染人与鸟类的那些具有实质的遗传差异。已知三种主要甲型禽流感病毒亚型感染鸟类和人。
甲型H7流感病毒包括几种亚型。H7感染在人中不常见,但可在直接接触被感染鸟类的人中发生。症状可包括结膜炎和/或上呼吸道症状。已将H7病毒与LPAI(例如,H7N2、H7N7)和HPAI(例如,H7N3、H7N7)联系起来,其导致人轻度至重度甚至致死病症。
甲型H5流感病毒包括几种已知亚型,包括高致病性的H5N1。适应鸟类的H5N1毒株被称为HPAI H5N1(甲型H5N1亚型的高致病性禽流感病毒),通常称为“禽流感”或“鸟流感”。HPAI H5N1病毒目前在亚洲和欧洲流行,并可导致严重疾病或死亡。认为HPAI H5N1是潜在的农业生物武器。低致病性禽流感H5N1(LPAI H5N1)(也称为“北美”H5N1)发生在野生鸟类中并导致鸟类轻度疾病或无明显症状,对人类影响未知,但其能传播给家禽并可能突变成高致病性毒株。
低致病性甲型禽流感病毒(H9N2)在1999年被证实。已知几种可能的H9亚型;不过很少有关于甲型H9流感病毒感染人类的报道。所记载的该亚型仅为低致病性形式。
乙型流感病毒通常仅在人中发现。不同于甲型流感病毒,此类病毒不根据亚型分类。乙型流感病毒可导致人发病和死亡,但与甲型流感病毒相比通常与严重度较低的流行相关。虽然乙型流感病毒可导致人中的流行,但不导致大范围流行。
丙型流感病毒导致人类轻度疾病且不导致流行或大范围流行。此类病毒不根据亚型分类。
进一步将乙型流感病毒和甲型流感病毒亚型表征为毒株。乙型流感病毒和和甲型流感病毒亚型有许多不同毒株。流感病毒新毒株出现并取代旧毒株。该过程通过抗原性漂移发生。当新型人流感病毒毒株出现时,旧毒株感染或接种后产生的抗体保护可能不能提供针对新毒株的保护。
流感在孕妇中更为严重的证据来自于对之前大范围流行期间的观察和对患有季节性流感孕妇的研究。在1918-1919和1957-1958年大范围流行期间报道了孕妇大量的流感相关死亡。之前流感大范围流行后有关于不良妊娠结果的报道,报告了自发性流产和早产的比率上升,在患肺炎的妇女中尤其如此(http://www.cdc.gov/H1N1flu/clinician_pregnant.htm,June30,2009)。认为孕妇和产后2周妇女患流感感染并发症的风险更高。
奥司他韦、扎纳米韦、金刚烷胺和金刚乙胺是“妊娠C类”药物,这表明尚未进行这些药物对孕妇的安全性评价研究。已有金刚烷胺用于第三三月期(trimester)严重流感疾病的有限病例被报道。但是,金刚烷胺和金刚乙胺已在动物研究中被证实以相当高剂量施用时具致畸性和胚胎毒性。因为抗流感病毒药物对孕妇及胎儿的未知影响,这四种药物应当仅在对胚胎或胎儿的潜在益处大于潜在风险时在妊娠期使用(Prevention &Control of Influenza-Recommendations of the Advisory Committee onImmunization Practices(ACIP)2004.MMWR 2004 May 28;53(RR06);l-40.)。尽管如此,CDC声明,现有的风险-获益数据表明疑似或确诊流感的孕妇应及时接受抗病毒治疗。
基质金属蛋白酶(MMP)是在正常生理过程(如组织重塑、再生和胚胎发育)中参与细胞外基质降解的蛋白酶。MMP是组织重塑的重要酶,组织重塑是胎膜和胎盘发育的关键事件,并在妊娠早期建立胎儿-母体的相互交流。大部分MMP以非活性蛋白分泌,当被细胞外蛋白酶切割后激活。MMP-2(72kDa的IV型胶原酶)和MMP-9(明胶酶B,92kDa的IV型胶原酶)是细胞外基质重塑的关键作用物。研究表明MMP-2和MMP-9存在于第一三月期的胚胎外体腔液和妊娠全程的羊水中。主要MMP激活蛋白为MMP-2潜伏形式,发现其存在于羊水中,从第一到第二三月期浓度渐增(Riley等,Secretion of matrix metalloproteinase-2,matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases intothe intrauterine compartments during early pregnancy.Molecul.HumanReprod.5(4):676-381(1999))。如图5所示,Tamiflu抑制MMP-9的表达,这可导致孕期风险增加。
在一个实施方案中,本公开内容的组合物仅微弱抑制MMP-9的表达,这可使对孕妇的流感治疗安全性更高。数据见图5和图6。在另一实施方案中,本公开内容的组合物已被证实未显示对MMP-2表达的显著抑制,如实施例5中的所讨论的,这可使对孕妇的流感治疗安全性更高。
肠道病毒是由核糖核酸(RNA)和蛋白形成的小病毒。该类群包括脊髓灰质炎病毒、柯萨奇病毒、埃可病毒和其它肠道病毒。有62种可致人类疾病的非脊髓灰质炎病毒:23种A型柯萨奇病毒、6种B型柯萨奇病毒和28种埃可病毒以及5种其它肠道病毒。
非脊髓灰质炎肠道病毒非常常见,在人中最常见感染因子方面仅次于被称为鼻病毒的“普通感冒”病毒。每一个对特定肠道病毒无免疫性的人均有感染风险。肠道病毒爆发通常在夏季至秋季发生。
L-赖氨酸和抗坏血酸补剂的组合在减少病毒复制和降低病毒感染方面有些效果,本公开内容是基于此认识而开发的。在一个实施方案中,本公开内容提供了抗病毒补剂组合物,可出乎意料地进一步减少病毒复制并抑制病毒感染。特别地,本公开内容提供了含有赖氨酸、抗坏血酸化合物、类黄酮糖苷、吡哆醇、牛磺酸和苏氨酸的补剂组合物,发现其具有显著增强的抗病毒特性。
在另一实施方案中,本公开内容提供了通过施用所述组合物降低人流感病毒感染症状的严重程度和持续时间的方法。在该实施方案中,所述组合物在流感样疾病最初征兆出现时服用。一方面,所述组合物醒时每六小时以水送服直到症状消除。另一方面,所述组合物在最初症状出现后约每四小时施用。另一方面,所述组合物每天施用两次直至症状消除。
在另一实施方案中,本公开内容的组合物减少细胞的病毒感染。一方面,所述组合物作为神经氨酸酶抑制剂发挥作用。另一方面,本公开内容的组合物在体外微弱抑制MMP-9的表达。
已知维生素C(抗坏血酸)为人体一般健康所必需。人缺乏合成维生素C的生物化学机制,所以其必须以食物或补充物形式从膳食中提供(Englard,S.和Steifter,S.″The Biochemical functions of Ascorbic Acid,″Ann.Rev.Nutr.1986.)。除非存在天生代谢障碍(如胱氨酸尿症、草酸过多症和高尿酸血症),已知维生素C可以大剂量摄取而无毒副作用。参见Stanbury,J.B.,Wyngaarden,J.B.,Fredrickson,D.S.,1972,Themetabolic basis of inherited disease.第三版.McGraw Hill。
维生素C支持人免疫系统的功能。认为维生素C通过增强干扰素合成和淋巴细胞(尤其是称为自然杀伤(NK)细胞的一类淋巴细胞)活性来刺激人体免疫系统。Sigel,B.V.& Morton,J.I.″Vitamin C andImmunity:Natural Killer(NK)cell factor″Int.J.Vitamin & NutritionRes.1983,53:179-183;Lovzova,E.,Savary,C.A.,& Heberman,R.B.″Induction of NK cells activity against fresh human leukemia in culturewith interlukin 2″J.Immunology 1987,138:2718-2727。自然杀伤细胞是自发杀死肿瘤或病毒感染细胞的淋巴细胞。已将循环中NK细胞数量的减少与多种免疫缺陷、病毒感染、AIDS和癌症的发病和进展相联系。还认为维生素C作为抗氧化剂通过减少自由基损伤量而辅助免疫系统来提供更多益处,自由基损伤可作为正常身体代谢的结果而出现并可来自外源。
研究表明补充维生素C(例如500mg/天)增加血浆中谷胱甘肽的浓度。Johnston等,″Vitamin C Elevates Red Blood Cell Glutathione inHealthy Adults″Am.J.Clin.Nutr.1993,58:103-105。某些数据支持硫醇抗氧化剂谷胱甘肽(GSH)具有体外和体内抗流感病毒活性。因此氧化压力或耗尽口、鼻和上呼吸道的上皮中GSH的其它条件可增强感染流感的易感性。
已知RNA病毒感染在宿主细胞中诱导氧化压力。越来越多的证据表明细胞氧化还原状态在调节病毒复制和感染性方面起重要作用。某些数据支持硫醇抗氧化剂谷胱甘肽(GSH)具有体外和体内抗流感病毒活性。特别地,进行了试验以确定硫醇抗氧化剂谷胱甘肽(GSH)是否阻断Madin-Darby犬肾细胞或人小呼吸道上皮细胞培养物中流感病毒的感染。在低(0.05-0.1)感染复数(MOI)时观察针对活性病毒颗粒产生的保护。Cai等,2003,Inhibition of influenza infection by glutathione.Free Rad.Biol.And Med.34(7):928-936。还发现GSH抑制病毒基质蛋白的表达,并且抑制病毒引起的胱天蛋白酶激活和Fas上调。综上,数据表明硫醇抗氧化剂谷胱甘肽(GSH)具有体外和体内抗流感病毒活性。因此口、鼻和上呼吸道的上皮中耗尽GSH的氧化压力或其它条件增强感染流感的易感性。
在一个实施方案中,本公开内容的组合物包含作为抗坏血酸、抗坏血酸酯或抗坏血酸盐中一种或更多种形式的维生素C;总称抗坏血酸化合物(ascorbic compound)。一方面,所述一种或更多种抗坏血酸化合物选自抗坏血酸、抗坏血酸酯或抗坏血酸盐的任何生物可接受形式,包括水溶性和脂溶性形式中的一种或两种。抗坏血酸的水溶形式可选自抗坏血酸、抗坏血酸的生物可接受单价或二价金属离子盐和抗坏血酸烟酰胺,及其混合物。抗坏血酸的适当金属离子盐选自抗坏血酸钙、抗坏血酸镁、抗坏血酸钾和抗坏血酸钠的单独使用或其混合物。其它水溶性形式可包括抗坏血酸锰、抗坏血酸锌、抗坏血酸铁、抗坏血酸铜、抗坏血酸硼、抗坏血酸钼和抗坏血酸铬。脂溶性抗坏血酸酯优选地包括饱和或不饱和羧酸的脂肪酸酯,以抗坏血酸棕榈酸酯为优选形式。优选的其它脂溶性抗坏血酸酯包括:抗坏血酸棕榈酸酯、抗坏血酸花生四烯酸酯、抗坏血酸硬脂酸酯、抗坏血酸亚油酸酯、抗坏血酸亚麻酸酯和抗坏血酸油酸酯。
一方面,所述组合物包含按重量计共约15%至约35%、优选按重量计约20%至约30%的一种或更多种抗坏血酸化合物,或其等同物。在一个具体方面,所述组合物包含按重量计共约25%的抗坏血酸、抗坏血酸钙、抗坏血酸烟酰胺和抗坏血酸棕榈酸酯。另一方面,所述组合物每剂量包含按重量计共约0.5至约2.0g、优选约0.5至约1.5g的一种或更多种抗坏血酸化合物。一方面,某些组合物每剂量包含约0.1g至约1.5g抗坏血酸。另一方面,本公开内容的某些组合物每剂量包含约0.5g至约0.75g的抗坏血酸钙。另一方面,本公开内容某些组合物每剂量包含约0.1g至约0.5g的烟酰胺抗坏血酸。另一方面,本公开内容的某些组合物每剂量包含约0.01g至约0.1g抗坏血酸棕榈酸酯。
赖氨酸是蛋白质中发现的必需氨基酸之一。它是婴儿正常生长和成人氮平衡维持所需要的。L-赖氨酸在哺乳动物体内通过α-酮戊二酸的初始转氨作用代谢产生乙酰-CoA。赖氨酸是体内蛋白质合成所必需的。L-赖氨酸在钙吸收、肌蛋白构建、损伤恢复以及机体激素、酶和抗体的产生中起作用。已知L-赖氨酸用于治疗由单纯疱疹病毒引起的口腔和生殖器损伤以及由带状疱疹病毒引起的带状疱疹。服用赖氨酸补充物可加速恢复时间并降低疱疹病毒感染的复发机率。通常治疗疱疹病毒感染症状的赖氨酸剂量包括每天约3g至约9g的分次口服剂量。通常认为赖氨酸补充物是安全无毒的。建议每天服用约0.5g至约1.5g赖氨酸以预防复发(Griffith等.Success of L-lysine therapy in frequently recurrent herpes simplexinfection.Treatment and prophylaxis.Dermatologica.1987;175(4):183-190.)。单纯疱疹病毒蛋白富含L-精氨酸,组织培养研究表明当L-赖氨酸与L-精氨酸的比值高时,发现单纯疱疹病毒的病毒复制和细胞致病性被抑制。
在一个实施方案中,本公开内容的组合物包含赖氨酸。术语赖氨酸是指包括L-赖氨酸盐(包括赖氨酸盐酸盐、赖氨酸二盐酸盐、赖氨酸琥珀酸盐、赖氨酸谷氨酸盐、赖氨酸乳清酸盐盐)以及L-赖氨酸的任何可药用形式。赖氨酸的其它可接受形式包括赖氨酸衍生物如赖氨酸乙酸盐。一方面,所述组合物包含按重量计约40%至约80%、优选按重量计约50%至约70%的L-赖氨酸盐酸盐,或其等同物。在一个具体方面,所述组合物包含按重量计约60%的L-赖氨酸盐酸盐。一方面,本公开内容的组合物包含约1,000mg至约5,000mg、优选约2,000至约3,500mg的单剂量。
类黄酮是一类具有共同化学结构的由植物合成的化合物大家族。类黄酮基于化学结构进一步分成亚类。类黄酮在膳食的水果和蔬菜中发现。已知类黄酮与一种或更多种糖分子连接成为类黄酮糖苷,而不与糖分子连接的那些称为糖苷配基(aglycone)。除了黄烷醇(儿茶酚和原花青素)外,类黄酮均以糖苷配基存在于植物和大部分食物中。甚至在烹制后,大多数黄苷酮仍能完整地达到小肠。只有类黄酮糖苷元和黄酮葡糖苷(与葡萄糖相连)被小肠吸收,并在其中被快速代谢成甲基化、糖醛酸化或硫酸化代谢物。类黄酮螯合(结合)金属离子的能力似乎有助于其体外抗氧化活性。虽然最初假定类黄酮的生物学作用应与其抗氧化能力相关,现有的细胞培养试验证据支持类黄酮的许多生物学效应与其调节细胞信号通路的能力有关(Williams等,Flavonoids:antioxidants or signalling molecules?FreeRadic.Biol.Med.;36(7):838-849(2004))。
一方面,本公开内容的组合物包含一种或更多种类黄酮糖苷。类黄酮糖苷可包括任何糖基化的类黄酮。在特定方面,所述组合物包含选自于橘皮苷、芸香苷、柚皮苷和槲皮苷的一种或更多种类黄酮糖苷。在一个具体方面,所述组合物包含橘皮苷和芸香苷。
一方面,所述组合物包含按重量计共约5%至约20%、优选按重量计共约10%至约15%的一种或更多种类黄酮糖苷,或其等同物。在特定方面,所述组合物包含按重量计共约12%的橘皮苷复合物和/或芸香苷。一方面,所述组合物每单剂量包含约0.2g至约0.8g的橘皮苷。另一方面,所述组合物每剂量包含约0.1至约0.5g芸香苷。
苏氨酸是蛋白质结构单元所需的必需氨基酸。它促进胸腺生长,胸腺是调节对免疫防御关键的多种激素和细胞的小腺体。甚至膳食摄入中苏氨酸的中度减少就可导致免疫应答或抗体产生的减弱。Lotan.Humoral andcellular immune response in growing rats fed a 10%gluten diet.Isr.J.Med.Sci.1989Aug;25(8):437-41。最近的研究表明苏氨酸的作用与胸腺对该氨基酸的特殊需求以及其促进细胞免疫防御功能的能力有关。Braverman,Threonine:The Immunity Booster,The Healing NutrientsWithin,2003;13 201页。在一个实施方案中,本公开内容的组合物包含苏氨酸。所述苏氨酸可选自L-苏氨酸或任何其可药用盐或衍生物。
在一个具体方面,所述苏氨酸为L-苏氨酸。一方面,所述组合物包含按重量计约0.1%至约5%、优选约0.5%至约2%的L-苏氨酸,或其等同物。在一个具体方面,所述组合物包含按重量计约1%的L-苏氨酸。一方面,本公开内容的组合物每剂量包含约0.01至约0.08g苏氨酸。
在一个实施方案中,本公开内容的组合物包含吡哆醇。吡哆醇是维生素B6的一种形式。肝脏利用吡哆醇合成活性辅酶形式的磷酸吡哆醛(pyridoxal phosphate,PLP)。PLP是苏氨酸醛缩酶的辅因子,苏氨酸醛缩酶催化羟基-N-三甲基-L-赖氨酸转化成三甲基氨基丁醛(L-赖氨酸向L-肉毒碱转化的中间体)。已知吡哆醇缺乏导致血浆肉毒碱水平显著下降。Absorption and Utilization of Amino Acids,Vol.II,Mendel Friedman,CRC Press,1989,ISBN 0849360072,Ch.HI,p.48-49页。吡哆醇是水溶性B族维生素,其为辅因子并参与蛋白质、碳水组合物的代谢和胰岛素与红血细胞和白血细胞的产生。维生素B6在免疫系统的多种生物化学通路中很重要。吡哆醇缺乏导致免疫应答损伤(Trakatellis等,1997,Pyridoxinedeficiency:new approaches in immunosuppression and chemotherapy.Postgrad.Med.J.October;73(864):617-622(1997))。成人每天摄入多至200mg的维生素B6通常是安全的。
在一个实施方案中,本公开内容的组合物包含吡哆醇。在一个具体方面,吡哆醇为盐酸吡哆醇。一方面,所述组合物包含按重量计约0.1%至约2%、优选按重量计约0.5%至约1.5%重量的盐酸吡哆醇,或其等同物。在特定方面,所述组合物包含按重量计约1%的盐酸吡哆醇。一方面,本公开内容的组合物每剂量包含约0.04g至约0.08g盐酸吡哆醇。
在一个实施方案中,本公开内容的组合物包含牛磺酸。牛磺酸或2-氨基乙磺酸是含硫氨基酸半胱氨酸的代谢物。牛磺酸是已知为数不多的天然磺酸之一。牛磺酸的代谢作用包括缀合胆汁酸、解毒、膜稳定、渗透调节和调节细胞钙水平。牛磺酸能穿透血脑屏障。牛磺酸作为抗氧化剂发挥作用,并有针对多种物质的毒性的保护作用(Green等,Antioxidant roleand subcellular location of hypotaurine and taurine in human neutrophils.Biochimica et biophysica acta Jan 23;1073(l):91-7(1991))。已知牛磺酸还在免疫系统中发挥作用。例如,牛磺酸与次氯酸(在被刺激的巨噬细胞“氧化剂爆发”时产生)相互作用产生牛磺酸氯胺(TauCl)。该化合物可具有重要的免疫调节特性,并可能造成了之前归因于牛磺酸的特性。体外研究表明,牛磺酸浓度从生理至超生理浓度的增加对外周血单核细胞产生促炎性细胞因子无影响;不过,Tau-Cl调节促炎性细胞因子的合成,并因此可能在免疫应答开始和扩大中起作用(Chorazy等,Taurine chloraminemodulates cytokine production by human peripheral blood mononuclearcells.Amino Acids.23:407-13(2002))。Tau-Cl抑制核因子κB的激活和促炎性细胞因子的产生能力,从而产生抗炎作用(Huxtable RJ.,Taurine past,present,and future.AdvExp Med Biol.403:641-50(1996))。虽然膳食中牛磺酸的最大安全水平尚未确定,每天0.9至1.4克是尚未记载不利作用的可容忍水平(Braverman,Taurine:The Seizure Fighter,The HealingNutrients Within,Basic Health Publications,Inc.,Laguna Beach,California,Ch.8,132-133页(2003))。
在一个实施方案中,本公开内容的组合物任选地包含牛磺酸或其可药用盐或衍生物。在一个方面中,所述组合物包含按重量计约1%至约10%、优选约2%至约6%的牛磺酸,或其等价物。在一个具体方面,所述组合物包含按重量计约4%的牛磺酸。在一个方面中,本公开内容的组合物每剂量包含约0.02g至约0.4g牛磺酸。
本公开内容的组合物为口服组合物。在一个实施方案中,所述口服组合物可为粉剂、胶囊、片剂、糖锭剂、液体或囊片剂形式。粉剂可以用于填充胶囊,或以单剂量包装出售以与食物如苹果酱混合,或可以泡腾粉末制剂形式的单剂量包装出售以悬浮于液体中。在一方面中,胶囊、片剂或锭剂设计用于吞服摄取。在另一方面中,片剂、胶囊或锭剂是经口可崩解的。在一方面中,片剂、胶囊、锭剂或糖锭剂是缓释组合物。在另一方面中,片剂、锭剂、糖锭剂或胶囊是立即释放组合物。在另一方面中,口服组合物可以是预包装液体饮品,其中所述制剂悬浮于经调味的液体中。在一个优选的方面中,所述组合物是以与食物(如苹果酱)混合为目的的片剂、胶囊或粉剂形式。虽然本公开内容的组合物主要为口服形式,也已考虑其它施用方式如肠胃外形式或肛门栓剂。
本公开内容的片剂、胶囊和囊片剂形式除以上指明的那些化合物外可包含其它多种添加剂,如载剂、粘合剂、崩解剂、润滑剂、增稠剂、表面活性剂、渗透压调节剂、电解质、甜味剂、调味剂、香料、色素、pH调节剂和其它需要的恰当添加物。
特别地,所述添加剂包括淀粉如小麦淀粉、马铃薯淀粉、玉米淀粉和糊精;糖类如蔗糖、葡萄糖、果糖、麦芽糖、木糖和乳糖;糖醇如山梨醇、甘露醇、麦芽糖醇和木糖醇,Isotransposable glycoside如偶合糖和巴拉金糖;载剂如磷酸钙和硫酸钙;粘合剂和增稠剂如淀粉、糖、明胶、阿拉伯胶、糊精、甲基纤维素、聚乙烯吡咯烷酮、聚乙烯醇、羟丙基纤维素、黄原胶、果胶、黄蓍胶、酪蛋白和海藻酸;润滑剂如亮氨酸、异亮氨酸、缬氨酸、糖酯、硬化油、硬脂酸、硬脂酸镁、滑石和聚乙二醇;崩解剂如微晶纤维素粉(avicel)、CMC、CMC-Na和CMC-Ca;表面活性剂如多山醇酯和卵磷脂,以及甜味剂如糖、糖醇、阿斯巴甜、阿力甜、其他二肽、甜叶菊和糖精,并且可考虑与基本成分的关系、组合物特性、制造方法等选择性地适量使用这些添加剂。
在另一实施方案中,本公开内容的组合物可任选地另外包含一种或更多种调味剂。添加任选调味剂以增加患者对推荐给药方案的接受性和依从性。可用调味剂包括本领域专业人员已知的香料,如天然和人造香料。这些调味剂可选自合成香料油和调味芳香剂和/或油,源自植株、叶、花、果实等的油树脂和提取物,及其组合。非限定的代表性香料油包括留兰香油、肉桂油、冬青油(甲基水杨酸酯)、薄荷油、丁香油、月桂油、茴香油,桉树油、百里香油、雪松叶油、肉豆蔻油、多香果、鼠尾草油、苦杏仁油和肉桂油。并且可用的调味剂为人造、天然和合成的果味香料如香草,和柑桔油(包括但不限于柠檬、橙、酸橙、葡萄柚),以及包括苹果、梨、桃、葡萄、草莓、覆盆子、樱桃、李子、菠萝、杏等的果香香精。这些调味剂可以液体或固体形式使用,并可单独或混合使用。通常使用的香料包括单独或混合使用的薄荷如胡椒薄荷、薄荷醇、人造香草、肉桂衍生物和多种水果香料。其它可用的调味剂包括醛和酯,如可使用乙酸肉桂酯、肉桂醛、柠檬醛二乙缩醛、乙酸二氢香芹酯、丁香酚甲酸酯、p-methylamisol等。在一个具体方面,调味剂是留兰香油。香料任选地按重量计占抗病毒组合物的约0.1%至约5%。
片剂可以是模制片或压制片。片剂可通过湿法制粒、干法制粒或直接压制形成。这些技术为本领域技术人员已知,在例如United StatesPharmacopeia National Formulary USP XXII,1990,1696-1697页中描述。可向组合物中加入多种其它维生素。片剂可任选地另外包含调味剂或甜味剂。一方面,经增甜调味的片剂用作在口中溶解的含片。本公开内容的组合物还可以咀嚼片或泡腾片形式制备。对泡腾制剂,本公开内容的生产方法与常用泡腾制剂(如泡腾片)的制法基本相同。即,将成分称重、混合并通过粉末压缩方法、干法或湿法制粒压缩方法等直接制备。口服崩解片剂在如美国专利No.7,431,942(Shimuzu等,通过引用并入本文)中描述。可制备具有硬糖基的锭剂,例如通过美国专利No.6,316,008(Godfrey,通过引用并入本文)的技术。
液体组合物还可包含其他营养物。该液体组合物可如美国专利No.6,037,375(Sakamoto等,通过引用并入本文)所述的进行制备。本公开内容的营养液组合物含有赖氨酸、抗坏血酸化合物、类黄酮糖苷、苏氨酸和吡哆醇作为基本成分,并以与普通食品和饮料相同的方法制备,可适当加入其他食物原料。作为特别优选的食物原料,可使用甜味剂如有机酸和碳水化合物。有机酸成分包括柠檬酸、酒石酸、苹果酸和琥珀酸,特别优选柠檬酸。这些有机酸通常以100至1500mg/100ml、优选250至800mg/100ml加入,可制备饮料形式的原料组合物。
多种甜味剂可任选地用于本公开内容的片剂、液体、胶囊、锭剂或糖锭剂制剂中。碳水化合物和甜味剂的实例包括单糖如葡萄糖和果糖;二糖如麦芽糖、蔗糖;其它常见糖类;糖醇如木糖醇、山梨醇、甘油和赤藓糖醇;多糖如糊精和环糊精;以及寡聚糖如低聚果糖、低聚半乳糖和乳蔗糖。在糖类中,对于作为对脂类代谢无不利影响的成分,优选果糖和甘油。对寡聚糖,添加乳蔗糖为优选。本公开内容的饮料组合物能依靠乳蔗糖的掺入增加体内的双歧杆菌或减少腐败产物,以进一步增强免疫系统。其它甜味剂包括天然甜味剂(如索马甜、甜叶菊提取物、甜叶菊双糖甙A和甘草酸等)和合成甜味剂(如糖精、阿斯巴甜等)。这些碳水化合物也可作为碳水化合物的混合物(如异构糖和精制糖)添加。甜味剂可选地以按重量计约0.1%至约5%存在于固体组合物中。碳水化合物的混合可在每100ml本公开内容饮料组合物中含有约1至15g,优选约3至12g。低聚糖含量约为0.5至10g,优选1至3g。
本公开内容的营养液组合物除上述外还可包含多种营养物、维生素、包括微量元素的矿物质(电解质)、包括合成香料和天然香料的香料、色素、调味剂(水果味、香草味、巧克力味等)、果胶酸及其盐、海藻酸及其盐、有机酸、作为保护性胶质的增稠剂、pH调节剂、稳定剂、防腐剂、甘油类、醇类以及碳酸饮料的发泡成分。此外,本公开内容的组合物还可包含天然果汁或水果,以作为水果饮料或蔬菜饮料提供。这些可单独使用或是两种或更多种组合使用。这些添加剂的混合比例没有特别限制,通常选自每100份本公开内容组合物重量中的约0至20份重量范围内。
可选的另外的维生素包括(无论水溶性或脂溶性)硫胺素、尼克酸、视黄醇棕榈酸酯、双苯酰硫胺、核黄素、氰钴胺素、胆钙化醇、烟酰胺、泛酸钙,叶酸,生物素和酒石酸胆碱(choline ditartate),以及属于B族维生素的那些维生素。
通过混合这些成分制备本公开内容的液体营养组合物,制备方法没有特别限定,所有成分可同时混合,但更优选将脂溶性成分预先溶于油中,而水溶性成分溶于水中,然后通过使用乳化剂将溶液乳化以制备本公开内容的组合物。更优选地,将油溶液加入水中,用适合的乳化剂乳化,并加入水溶液并混合以得到乳化液。所述成分的混合操作可在常温下进行,或优选地通过稍加热操作来实施。
乳化作用可通过使用适当的乳化器来进行,例如,匀质混合器或高压力匀浆器,通过完全传递系统或循环系统。乳化作用得到的乳液通过常用方法过滤,倒入适当容器中并进行灭菌以得到所需的饮料产品。灭菌可通过加热、无菌过滤等实现。
为了将本公开内容组合物制备成碳酸饮料,通过常用方法将二氧化碳注入乳化剂中。该饮料优选地以约260至600mOsm/kg渗透压范围制备。
本公开内容的液体组合物还可以泡腾剂形式制备。泡腾剂形式除本公开内容的基本成分外应包含适量碳酸钠和/或碳酸氢钠以及中和剂作为发泡成分。本文所用中和剂为能通过中和碳酸钠或碳酸氢钠产生二氧化碳的酸性化合物。此类化合物包括,例如L-酒石酸、柠檬酸、富马酸、抗坏血酸和其它有机酸。优选的抗坏血酸同时具有中和剂作用和抗氧化剂作用。
出乎意料地发现本公开内容的组合物在体外抑制MDCK细胞中甲型流感病毒的复制。QuantiGene Plex 2.0测定利用支链DNA(bDNA)信号放大和多指标分析珠(multi-analyte profiling bead(xMAP)技术对甲型流感病毒的mRNA进行检测和定量。具体而言,发现配方V比其它已知制剂(如配方A2)更有效地减少甲型流感病毒mRNA。在另一个实施方案中,本公开内容提供了降低病毒活性和/或减少病毒复制的方法,其包括用有效量的含赖氨酸、抗坏血酸化合物、类黄酮糖苷、苏氨酸和吡哆醇的组合物治疗病毒感染细胞。
神经氨酸酶(也称为唾液酸酶)是非常常见的酶,其水解多糖链的末端唾液酸残基,大多数情况下暴露出半乳糖残基。虽然哺乳动物中发现有神经氨酸酶,但它主要是在微生物(如细菌和病毒)中表达。J.Biochem.Biophys.Methods 22,23(1991)。负链RNA流感病毒含有两个表面糖蛋白,血球凝集素(HA)和神经氨酸酶。认为神经氨酸酶通过其对靶细胞受体唾液酸部分的切割在靶细胞侵入和随后的流感病毒复制过程中起重要作用。该作用防止病毒与靶细胞进一步的交互作用并便于子代病毒粒从被感染细胞中的释放(Haskell等,Neuraminidase inhibition and viralchemotherapy.J.Med.Chem.13,697(1970);McKimm-Breschkin,Resistance of influenza viruses to neuraminidase inhibitors-a review.Antiviral Res.47,1(2000))。此外,病毒粒上新合成的神经氨酸酶和HA还可含有唾液酸残基,其可被神经氨酸酶切割以防止自聚集。还认为病毒对粘膜表层的穿透由神经氨酸酶对胎球蛋白(此类膜上主要成分)的水解作用而增强。这些基本活性使神经氨酸酶成为流感病毒药物开发的重要靶标。神经氨酸酶活性可通过使用市售试剂盒测定,如根据方案(通过引用并入本文)使用的分子探针AmplexRed神经氨酸酶测定试剂盒No.A22178。
Yeo等研究了A/Beijing/353/89(H3N2)流感病毒对两种不同类型上皮细胞中IV型胶原酶表达的影响(Yeo等.Influenza A virus infectionmodulates the expression of type IV collagenase in epithelial cells.Arch.Virol.144:1361-1370(1999))。根据所感染的细胞系,病毒感染导致IV型胶原酶表达的改变。Vero细胞中基质金属蛋白酶9(MMP-9;92kDa)而非基质金属蛋白酶2(MMP-2;72kDa)的表达被激活。在MDCK细胞中,MMP-2的产生随病毒感染而增加。确定取决于上皮细胞系,甲型流感病毒感染引起的MMP-9和-2的表达在转录水平上被调控。因此,抑制MMP-9和/或MMP-2表达的制剂由于其可具有或增强抗病毒活性而引起一些关注。然而应注意,在孕期强烈抑制这些酶可能是不利的。
在一个实施方案中,本公开内容的某些组合药剂显示出对神经氨酸酶的剂量依赖性抑制,出乎意料地比已知组合物更好。结果见图3-6。发现配方V比其它已知制剂(如配方A2)更有效地抑制神经氨酸酶。
在一个实施方案中,本公开内容提供了降低病毒活性的方法,其包括用有效量的包含赖氨酸、抗坏血酸化合物、类黄酮糖苷、苏氨酸和吡哆醇的已知抑制神经氨酸酶活性和/或仅微弱抑制MMP-9表达的组合物处理病毒感染的细胞。一方面,治疗或预防对象病毒感染的方法包括向对象施用治疗有效剂量的包含赖氨酸、抗坏血酸化合物、类黄酮糖苷、苏氨酸和吡哆醇的组合物。本公开内容组合物的一个关键优点为以非毒株特异方式降低病毒活性的能力。
实施例
实施例1.病毒生成方案
将Madin-Darby犬肾(MDCK)细胞(ATCC)培养在含有Earle’s盐(Gibco BRL,Grand Island,NY)、添加有2mM L-谷氨酰胺、100U/ml青霉素、100g/ml链霉素和10%热灭活胎牛血清(Hyclone)并添加HEPES缓冲液(pH 7.55,终浓度为10mM,Invitrogen)缓冲的最低基本培养基(MEM)中,。
将非洲绿猴肾细胞系Vero(ATCC)培养在含有Earle’s盐(Invitrogen)并添加2mM L-谷氨酰胺、100U/ml青霉素、100g/ml链霉素和10%热灭活胎牛血清(Hyclone)的最小必需培养基(MEM)中。
采用H1N1流感毒株A/WS/33(ATCC)通过在MDCK细胞中传代产生高滴度的病毒库。
实施例2.甲型流感病毒mRNA活性的体外bDNA测定
将100μL体积1e5细胞/mL的MDCK或Vero细胞铺在组织培养物处理的96孔板中。次日用病毒以10感染复数感染细胞并测定病毒活性。为了测试化合物,感染前1小时用化合物预孵育细胞。
对每个浓度一式三份测试所有制剂。所测试制剂见实施例5,表1。应注意配方A1为Airborne健康泡腾配方,配方T为Tamiflu。
孵育过夜后,收集细胞,裂解并根据制造商建议方案对上清进行QuantiGene Plex 2.0测定(Panomics,Inc.,Fremont,CA)以定量测定甲型流感病毒mRNA。QuantiGene Plex 2.0测定结合了支链DNA(bDNA)信号放大和多指标分析珠(xMAP)技术,能同时检测和定量多个mRNA靶标。通常认为该测定比用于监测流感病毒感染的传统方法(通常需要进行2-5天)快。
bDNA测定是基于杂交的靶标特异RNA定量法,它使用带标记的DNA探针放大信号而非靶RNA。QuantiGene Plex 2.0系统利用荧光微球(捕获珠)作为捕获特异性RNA分子的支持物。在单个样品中定量多个靶标特异性RNA分子的能力源自于探针集合的设计。对每个目的RNA分子,提供含有三类合成探针(捕获增强剂(CE)、标记增强剂(LE)和阻断剂(BL))并杂交和覆盖目的RNA邻接序列的寡核苷酸探针集合。CE通过协助杂交捕获靶RNA时区分珠阵列中不同的捕获珠。
信号放大通过与LE尾部杂交的DNA扩增分子介导。各个扩增单元含有多个结合链霉亲和素辍合的R-藻红素(SAPE)的生物素标记探针杂交位点。在Luminex流式细胞仪上读取与单个捕获珠相关的荧光信号结果。信号以平均荧光强度(MFI)报告,并与未处理样品中存在的靶RNA分子数量成比例。
甲型流感病毒感染的Vero细胞上清的结果见图1和图2。图1中,配方V和配方5以剂量依赖方式降低了甲型流感病毒mRNA的量。虽然配方A1在高剂量下降低了甲型流感病毒mRNA的量,这可解释为用于缓冲配方A1商业产品的泡腾化学物升高了pH,从而导致配方A1高浓度时由于pH效应引起的抑制。还发现A1在高剂量时具有细胞毒性。如图2所示,在本测定中显示配方V比配方A2更强。浓度以微摩尔(μM)浓度表示。
实施例3.体外分子探针AmplexRed神经氨酸酶(唾液酸酶)测定
根据制造商方案(通过引用并入本文)使用了分子探针AmplexRed神经氨酸酶测定试剂盒No.A22178。
分子探针AmplexRed神经氨酸酶测定利用Amplex Red检测半乳糖氧化酶氧化去唾液酸半乳糖(神经氨酸酶反应的最后结果)时产生的H2O2。H2O2随后在辣根过氧化物酶(HRP)存在下以1∶1的化学剂量与AmplexRed试剂反应产生红色荧光氧化产物试卤灵(Mohanty等,Ahighly sensitive fluorescent micro-assay of H2O2 release from activatedhuman leukocytes using a dihydroxyphenoxazine derivative.J.Immunol.Methods 202,133(1997))。试卤灵在约571nm和585nm处分别有最大吸收和荧光发射,由于消光系数高(54,000cm-1M-1),该测定可用荧光法或分光光度法进行。
将100μL体积1e5细胞/mL的MDCK或Vero细胞铺在组织培养物处理的96孔板中。次日用病毒以10感染复数感染细胞并测定病毒活性。为了测试化合物,感染前1小时用化合物预孵育细胞。孵育过夜后,收集细胞、裂解并将上清进行测定。
对每个浓度一式三份测试所有制剂。所测试制剂见表1。应注意配方A1为Airborne健康泡腾配方,配方T为Tamiflu。
甲型流感病毒感染的Vero细胞上清的结果见图3和图4。显示配方V以剂量依赖方式有效抑制了神经氨酸酶。虽然配方A1似乎在高剂量时有活性,可能用于缓冲商业产品(Airborne)的泡腾化学物升高了测定的pH,从而导致了配方A1仅在高浓度时由于pH效应引起的抑制。配方A1还在高剂量时表现出细胞毒性。
实施例4.基质金属蛋白酶9(MMP-9)的体外抑制
根据制造商方案(通过引用并入本文)使用Quantikine人(总)MMP-9免疫测定R&D系统定量被感染细胞中MMP-9的表达。
将100μL体积1e5细胞/mL的Vero细胞铺在组织培养物处理的96孔板中。次日用病毒以10感染复数感染细胞并测定病毒活性。为了测试化合物,感染前1小时用化合物预孵育细胞。孵育过夜后,收集细胞、裂解并将上清进行测定。
该MMP-9测定使用了定量夹心酶法免疫测定技术。将对MMP-9特异的单克隆抗体预先包被在微孔板上中。将标准品和样品吸入孔中,MMP-9与固定化抗体结合。洗去未结合底物后,向孔中加入对MMP-9特异的酶联多克隆抗体。洗去未结合的抗体-酶试剂后,向孔中加入底物溶液,显色与起始步骤中结合的总MMP-9量(前体和/或活性的)成比例。终止显色并测定颜色强度。
所测试制剂见实施例5,表1。应注意配方A1为Airborne健康泡腾配方,配方T为Tamiflu。甲型流感病毒感染的Vero细胞上清的结果见图5和图6。认为用于缓冲配方A1商业产品的泡腾化学物升高了测定的pH,从而导致配方A1仅在高浓度时由于pH效应干扰了本测定。
配方V以剂量依赖方式微弱抑制了MMP-9的表达。配方T(Tamiflu)对MMP-9表达表现出明显的剂量依赖抑制。认为对孕妇来说,与用Tamiflu治疗病毒感染相比,配方V存在时所表现的对MMP-9表达的明显微弱抑制可带来更低的孕期风险。
实施例5.基质金属蛋白酶2(MMP-2)的体外抑制
使用两种独立试剂盒确定本公开内容的制剂是否抑制MMP-2的表达。CalbiochemMMP-2 ELISA试剂盒是组织培养基人MMP-2蛋白体外定量的非同位素免疫测定。R&D Systems Quantikine(总)MMP-2免疫测定试剂盒用于定量检测细胞培养物上清中活性和前-基质金属蛋白酶2(总MMP-2)的浓度。所有制剂均用两种测定试剂盒一式三份地进行测定。当以最高约5μM的多种浓度进行测试时,本公开内容的制剂未显著抑制MMP-2表达。
实施例6.制剂:粉剂
多种测试制剂的成分见表1;显示了粉剂单一剂量包装的量。用所示量的五倍制备各制剂的测试量。将各种成分加入测试量中,彻底混匀,按重量分装并密封于五个包装中。或者,可将粉末装入硬壳胶囊中。
表1:制剂-粉剂的重量/剂量
实施例7.制剂:片剂
用表2所示成分制备片剂。所示成分量相当于一个剂量。五个片剂含有制剂的一个剂量。采用了湿法造粒技术并将压缩的片剂包被上表2所示的白色包衣。干燥片剂并在室温下存放。
实施例8.初步临床数据
在甲型流感暴发期间进行了初步试验。向对象施用实施例6的片剂FT,其中5片药片相当于一个剂量。指导研究对象在流感样症状第一次出现时服用一个剂量;每4至6小时重复服用直到症状消除。对象用水吞服各剂量。完成了对十四位患者的调查。表3显示对象报告流感样症状。此外,一些患者还表现出额外的干咳、咽喉痛或头疼症状。
表3:初步临床调查
八个对象在服用第一剂量的配方后约2小时内报告了症状消除。另三个对象在服用开始的两个剂量后约6小时内报告了症状完全消除。另三个对象在服用开始的三至四剂量后约18小时内报告了症状消除。
实施例9.预防性给药
在无对照研究(anecdotal study)中,要求在眼科中心进行日常工作的两个对象在上一季不接种流感疫苗,但以40%强度服用单次每日预防剂量的配方F(每剂量2片)。各对象均报告同事在此期间感染了流感。对象居住和工作的区域经受甲型流感大爆发,爆发期间两家当地医院禁止访客。两个对象均未感染流感。
实施例10.制剂成分的神经氨酸酶测定
为测定本公开内容组合物中各成分的相对贡献并确定加成和协同效应,用神经氨酸酶测试以与实施例3相似的方式评估多种组合中的各目的成分。测试组合物在体外测定中进行检测,以测定甲型流感病毒感染的MDCK细胞中的神经氨酸酶活性。Madin-Darby犬肾(MDCK)上皮细胞从获取自ATCC(Manassus,VA)并如供应商所述培养。细胞用人流感病毒(TC适应株A/WS/33,ATCC-1520)感染,并如前所述进行繁殖。依据ATCC的描述,该毒株显示与PR8和猪流感病毒的交叉反应。为检测神经氨酸酶活性,用病毒贮液感染MDCK细胞并用Amplex Red神经氨酸酶测定试剂盒(Invitrogen,Inc.Carlsbad CA)对神经氨酸酶活性进行定量。简言之,在37℃下存在表4所示组合物时用甲型流感病毒感染MDCK细胞。各条件以8点2倍的稀释系列测定三次。定量神经氨酸酶活性的Amplex Red法使用三种不同的酶:NA、半乳糖氧化酶和辣根过氧化物酶。过氧化物与HRP的组合作用使Amplex Red被氧化释放试卤灵,并在分光光度计上读取其OD 563nm值。
羧酸奥司他韦作为标准神经氨酸酶抑制剂(NAI)阳性对照供比较之用。Tamiflu(磷酸奥司他韦)是乙酯前药,需要酯水解转化成活性形式的羧酸奥司他韦。羧酸奥司他韦是影响病毒颗粒释放的流感病毒神经氨酸酶抑制剂。
图7,表4显示神经氨酸酶测定中测试的多种组合物。在神经氨酸酶测定中将每个测试组合物与配方V和羧酸奥司他韦比较。图8-13显示了神经氨酸酶测定中多种组合物的活性。图8-13中X轴显示的浓度代表每个测试组合物和配方V中盐酸L-赖氨酸的浓度,或羧酸奥司他韦的浓度。
图8显示人流感病毒感染细胞在暴露于羧酸奥司他韦、配方V和十种含有多种配方V成分的测试组合物之后的神经氨酸酶活性图。数字1-6用于表明配方V的各个主要成分。所有6个成分(赖氨酸、抗坏血酸/抗坏血酸盐、类黄酮糖苷、吡哆醇、苏氨酸和牛磺酸)均是神经氨酸酶活性的协同抑制所必需的。
图9显示人流感病毒感染细胞在暴露于羧酸奥司他韦、配方V和单独的赖氨酸(1)或赖氨酸与抗坏血酸/抗坏血酸盐(1/2;9A)后神经氨酸酶的活性。所有测试组合物均不是十分有效,直到采用最高浓度的赖氨酸/抗坏血酸盐(1/2;9B)。
图10显示人流感病毒感染细胞在暴露于羧酸奥司他韦、配方V和赖氨酸/抗坏血酸盐/类黄酮糖苷(1/2/3;10A)或赖氨酸/抗坏血酸盐/吡哆醇(1/2/4;10B)后神经氨酸酶的活性。在配方赖氨酸/抗坏血酸盐/类黄酮糖苷(1/2/3)最高的四个浓度中观察到神经氨酸酶活性的剂量依赖性降低。在赖氨酸/抗坏血酸盐/吡哆醇(1/2/4)配方最高的四个浓度中观察到神经氨酸酶活性的微弱剂量依赖性降低。
图11显示人流感病毒感染细胞在暴露于羧酸奥司他韦、配方V和赖氨酸/抗坏血酸盐/苏氨酸(1/2/5;11A)或赖氨酸/抗坏血酸盐/牛磺酸(1/2/6;11B)后神经氨酸酶的活性。在赖氨酸/抗坏血酸盐/苏氨酸最高浓度中观察到神经氨酸酶活性的微弱降低。
图12显示人流感病毒感染细胞在暴露于羧酸奥司他韦、配方V和赖氨酸/抗坏血酸盐/盐酸吡哆醇/苏氨酸(1/2/4/5;12A)或赖氨酸/抗坏血酸盐/类黄酮糖苷/苏氨酸(1/2/3/5;12B)后神经氨酸酶的活性。组合物赖氨酸/抗坏血酸盐/类黄酮糖苷/苏氨酸在最高的三个浓度中表现出对神经氨酸酶活性的剂量依赖性降低。
图13显示人流感病毒感染细胞在暴露于羧酸奥司他韦、配方V和赖氨酸/抗坏血酸盐/类黄酮糖苷/盐酸吡哆醇/苏氨酸(1/2/4/5;13A)或赖氨酸/抗坏血酸盐/类黄酮糖苷/盐酸吡哆醇/苏氨酸/牛磺酸(1/2/3/4/5/6;13B)后神经氨酸酶的活性。两种组合物均产生对神经氨酸酶活性的强、剂量依赖性抑制。然而,只有组合物赖氨酸/抗坏血酸盐/类黄酮糖苷/盐酸吡哆醇/苏氨酸牛磺酸与配方V作用相似。配方V和1/2/3/4/5/6的区别在于所用的抗坏血酸化合物的类型。如表1所示配方V包含抗坏血酸/混合抗坏血酸盐。如表4所示图13B中采用的组合物1/2/3/4/5/6包含单独的抗坏血酸而无混合物抗坏血酸盐。
本测定显示1/2/3/4/5/6六组分中的每个均对所需的神经氨酸酶活性完全剂量依赖性抑制是必需的。组合物赖氨酸/抗坏血酸盐/类黄酮糖苷/盐酸吡哆醇/苏氨酸(1/2/3/4/5)在所检测的全部浓度范围上显示剂量依赖性抑制。组合物1/2/3;1/2/4和1/2/3/5在本测定中均仅在较高的测试浓度下显示出对神经氨酸酶活性的剂量依赖性抑制。
Claims (14)
1.用于在有此需要的对象中治疗或预防甲型流感病毒感染的口服抗病毒补剂组合物,所述组合物包含赖氨酸、0.5至2g抗坏血酸化合物、0.2-0.8g橘皮苷、0.1-0.5g芸香苷、0.01-0.08g苏氨酸、0.02至0.4g牛磺酸和0.04-0.08g盐酸吡哆醇,所述赖氨酸的单剂量为1000mg至5000mg。
2.权利要求1的组合物,其中所述赖氨酸选自:L-赖氨酸、L-赖氨酸单盐酸盐、L-赖氨酸二盐酸盐、L-赖氨酸琥珀酸盐、L-赖氨酸谷氨酸盐和L-赖氨酸乳清酸盐。
3.权利要求1的组合物,其中所述抗坏血酸化合物选自下列一种或更多种:抗坏血酸、抗坏血酸钙、抗坏血酸镁、抗坏血酸钾、抗坏血酸钠、抗坏血酸锰、抗坏血酸锌、抗坏血酸铁、抗坏血酸铜、抗坏血酸硼、抗坏血酸钼、抗坏血酸铬、抗坏血酸棕榈酸酯、抗坏血酸花生四烯酸酯、抗坏血酸硬脂酸酯、抗坏血酸亚油酸酯、抗坏血酸亚麻酸酯和抗坏血酸油酸酯。
4.权利要求3的组合物,其中所述橘皮苷和芸香苷为按重量计1∶1的混合物。
5.前述权利要求1至4中任一项的组合物,其中所述组合物的形式选自粉剂、胶囊、锭剂、片剂、液体或囊片剂。
6.权利要求1的组合物,其包含L-赖氨酸单盐酸盐、抗坏血酸、橘皮苷、芸香苷、盐酸吡哆醇、苏氨酸和牛磺酸。
7.权利要求6的组合物,其还包含抗坏血酸钙、抗坏血酸烟酰胺和抗坏血酸棕榈酸酯。
8.权利要求6的组合物,其中单剂量包含2g至3.5g L-赖氨酸单盐酸盐;0.1g至1.5g抗坏血酸;0.2g至0.8g橘皮苷;0.1g至0.5g芸香苷;0.04g至0.08g盐酸吡哆醇;0.01g至0.08g苏氨酸和0.02g至0.4g牛磺酸。
9.权利要求8的组合物,其还包含0.5g至0.75g抗坏血酸钙;0.1g至0.5g抗坏血酸烟酰胺和0.01g至0.1g抗坏血酸棕榈酸酯。
10.权利要求9的组合物,其中所述单剂量包含3g L-赖氨酸单盐酸盐;0.2g至1.0g抗坏血酸;0.3g橘皮苷;0.3g芸香苷;0.05g盐酸吡哆醇;0.05g苏氨酸和0.02g至0.3g牛磺酸。
11.权利要求10的组合物,其还包含0.6g抗坏血酸钙;0.3g抗坏血酸烟酰胺和0.05g抗坏血酸棕榈酸酯。
12.前述权利要求1至4中任一项的组合物,其中所述组合物的形式为糖锭剂。
13.权利要求1至4或6至12中任一项的组合物在制备用于减少细胞中的病毒复制的药物中的用途。
14.权利要求1的用于在有此需要的对象中预防甲型流感病毒感染的口服抗病毒补剂组合物,其中预防有效剂量为治疗有效剂量的20%至100%。
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