CN101563075A - 糖尿病性神经病治疗剂 - Google Patents
糖尿病性神经病治疗剂 Download PDFInfo
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- CN101563075A CN101563075A CNA2007800469402A CN200780046940A CN101563075A CN 101563075 A CN101563075 A CN 101563075A CN A2007800469402 A CNA2007800469402 A CN A2007800469402A CN 200780046940 A CN200780046940 A CN 200780046940A CN 101563075 A CN101563075 A CN 101563075A
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- Prior art keywords
- diabetic neuropathy
- therapeutic agent
- agent
- suplatast tosilate
- acid
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Abstract
糖尿病性神经病的治疗剂，以式(1)表示的(±)－〔2－〔4－(3－乙氧基－2－羟基丙氧基)苯基氨基甲酰基〕乙基〕二甲基锍对甲苯磺酸盐作为有效成分。
Description
技术领域
本发明涉及糖尿病性神经病治疗剂。
背景技术
糖尿病是以由于胰岛素的不足等发病的慢性高血糖作为特征的代谢异常，根据发病原因分类为I型和II型。I型发病的原因是由于通过病毒或自己免疫等引起胰脏的胰岛素分泌细胞的破坏，年青者居多。II型的主要原因是包括过度饮食、肥胖、运动不足等的生活习惯的环境因子和高龄，在中年以后发病。日本的糖尿病患者数据说大约为740万人，其中90～95％为II型糖尿病。这些糖尿病患者如果没有充分地治疗，置之不理，长期持续高血糖状态的话，不仅显著损害患者的QOL，而且还发生与生命予后相关的严重的合并症。代表性的合并症是糖尿病性视网膜病、糖尿病性肾病、和与本发明相关的糖尿病性神经障碍。
糖尿病性神经障碍也称为糖尿病性神经病，据说糖尿病患者的约2/3并发各种形式的并发症。一般来说，从被长的神经纤维所支配的部位(手或足尖的神经)引起障碍，首先是手足的麻木和疼痛，异常的冷感，如果放置不理，症状发展，从足尖开始到膝，从手尖开始到肘，向身体的中心扩展。这样的症状的多样性的原因在于，受障碍的神经跨度到运动神经、感觉神经、以及自律神经等多方面，各自的神经所担当的功能是多样的，此外对糖尿性神经症的诊断以及治疗的困难也是主要原因。
糖尿病性神经障碍的发病机理目前还没有确定，但是假想多元醇经路的活性亢进和与其关联的肌醇代谢异常、蛋白激酶C(PKC)的活性异常、氧化应激等作为代谢性因素。另外，还提倡的说法是，作为血管性因素是由于神经内膜内微循环障碍所引起的向神经组织的氧、营养供给不十分。据说它们独立地并不异常，但在高血糖状态长期持续的条件下，代谢性因素和血管性因素相互参与导致了糖尿病性神经障碍的并发症和进展。
关于糖尿病性神经障碍的予防和治疗，与糖尿病的合并症相同，基本是控制危险因素、即糖尿病状态。另一方面，伴随发病机理的治疗药的开发也积极地进行着，正期待着作为代谢性因素的多元醇代谢活性亢进的限速酶-醛糖还原酶抑制剂的有用性。另外，发现糖尿病状态或者高葡糖条件下，PKC(β亚型)活性亢进，据说所选择的PKC-β抑制剂抑制作为糖尿病性神经障碍的成因之一的神经营养血管的血流降低。进一步，近年来报告了氧化应激亢进所导致的细胞损伤、NO产生的阻碍引起的血流降低产生神经功能的低下，从基础上报告了具有多样抗氧化作用的药剂和在氧化应激的下游所具有的转录因子的有效性。
但是，基于这些发病原因的治疗剂对于进一步发展的神经障碍缺乏有效性，现实上以改善患者的QOL为目的的对症疗法药的必要性很高。特别是，对于总称为所谓的糖尿性神经病的疼痛和麻木、痛觉过敏的非甾体抗炎症也没有适应的药。现状是据说三环性抗抑郁药、抗痉挛药、美西律有效，但是决定性的治疗法还没有确立，期待根据患者的状态选择恰当的对症疗法药剂的状况。
本发明的课题是提供副作用少，效果好的糖尿病性神经病治疗剂、特别是治疗糖尿病性神经病所伴随的疼痛等的自觉症状的药剂。
发明内容
本发明涉及以下的发明。
1.糖尿病性神经病的治疗剂，以式(1)表示的(±)-〔2-〔4-(3-乙氧基-2-羟基丙氧基)苯基氨基甲酰基〕乙基〕二甲基锍对甲苯磺酸盐作为有效成分，
【化1】
2.上述1所述的治疗剂，其中，糖尿病性神经病为多神经病。
3.上述1或2的任一项所述的治疗剂，其中，糖尿病性神经病的症状为疼痛和/或感觉异常。
4.式(1)的化合物在制备糖尿病性神经病治疗剂中的应用。
5.糖尿病性神经病的治疗方法，其特征在于，将式(1)的化合物的有效量给予哺乳动物。
式(1)所表示的(±)-[2-[4-(3-乙氧基-2-羟基丙氧基)苯基氨甲酰基]乙基]二甲基锍对甲苯磺酸盐(以下称为甲磺司特(spulatasttosylate))具有优良的抑制I gE抗体产生的作用，是已知的治疗支气管哮喘、特异反应性皮炎、过敏性鼻炎的药剂(特公平3-70698号公报：专利文献1)。而且，已知，该甲磺司特还可用作治疗排尿障碍的药剂(WO00/27383号公报：专利文献2)、治疗肾透析伴生的瘙痒的药剂(特开平11-315019号公报：专利文献3)、改善由C型或非B非C型肝炎病毒引起的肝功能异常的药剂(特开2002-114672号公报：专利文献4)、治疗化学物质过敏症的药剂(特开2004-292407号公报：专利文献5)、腹膜后纤维化治疗剂(特开2005-097220：专利文献6)、扁平苔癣的予防剂和/或治疗剂(特开2006-199642：专利文献7)、头痛的予防和/或治疗剂(特开2006-131521：专利文献8)、肾病综合征治疗剂(特开2006-076958：专利文献9)。但是，对于甲磺司特作为糖尿病性神经病治疗剂具有优异的效果还全然不知。
【非专利文献1】Pain clinic Vol.25，No.2，2004，P.158-165
【非专利文献2】治疗Vol.85，No.7，2003，P.2097-2104
【专利文献1】特公平3-70698号公报
【专利文献2】WO00/27383号公报
【专利文献3】特开平11-315019号公报
【专利文献4】特开2002-114672号公报
【专利文献5】特开2004-292407号公报
【专利文献6】特开2005-097220号公报
【专利文献7】特开2006-199642号公报
【专利文献8】特开2006-131521号公报
【专利文献9】特开2006-076958号公报
作为本发明的有效成分的甲磺司特是公知的化合物，可以用例如特公平3-70698号公报中所述的方法进行制造。
本发明中所谓的“治疗”是指为了预防疾病和治疗疾病、以及减轻伴有该疾病的症状和防止其复发的维持疗法。
根据本发明治疗剂可以治疗的“糖尿病性神经病”只要是由糖尿病合并引起的神经障碍，就不做特别的限定，可以是多神经病(感觉神经障碍和运动神经障碍)，也可以是自律神经障碍。另外，作为根据本发明治疗剂可以治疗的糖尿病性神经病的“症状”，作为多神经病的症状，可举出疼痛、感觉钝麻、感觉缺失、感觉异常(麻木、灼热感、冷感等)、腓肠绞痛等，作为自律神经障碍的症状，可举出胃肠障碍(便秘/痢疾)、发汗异常、直立性低血压、膀胱障碍、勃起功能障碍等。
在本发明中，作为可以在甲磺司特中并用的药剂，可以举出醛糖还原酶抑制剂、抗心律不齐药、维生素制剂、非类固醇性抗炎制剂、抗抑郁、抗精神病药、抗痉挛剂等。通过与这些中的一种以上并用，不仅可以进一步提高本发明治疗剂对伴有糖尿病性神经病的疼痛的治疗效果，而且，由于与可并用的药剂单独使用时相比可降低给药量，所以从减轻副作用的观点考虑也是适合的。另外，也可以和神经阻滞、针灸疗法、温热疗法、离子透入疗法、神经根阻滞、超声波疗法、红外线照射疗法、激光照射疗法等并用。
作为醛糖还原酶抑制剂，可举出依帕司他或者其药学上可接受的盐等。
作为抗心律不齐药，可举出美西律或者其药学上可接受的盐等。
作为维生素制剂可例举：维生素A、维生素D、维生素B类、(B1、B2、B6、B12)、烟酸、叶酸、泛酸、维生素C、维生素E、维生素H、维生素K等。更具体地可例举：视黄醇、α骨化二醇、钙三醇、他卡西醇、钙泊三醇、马沙骨化醇、氟骨三醇、钙三醇、硫胺素、辅羧酶、呋喃硫胺、丙硫硫胺、奥托硫胺、二硫化硫胺、二苯并噻唑、双硫丁异胺、苯磷胺、西托硫胺、核黄素、黄素腺嘌呤二核苷酸、抗皮炎维生素、吡哆醛、烟酸、烟酸胺、维生素B12、维生素B12辅酶、甲钴胺、叶酸、泛酸钙、泛酰醇、泛硫乙胺、维生素C、维生素E、维生素H、维生素K1、维生素K2或这些物质的药学上可接受的盐等。
作为非类固醇性抗炎制剂可例举：水杨酸钠、乙酰水杨酸、水杨酰胺、氟灭酸、甲灭酸、托灭酸、环氟拉嗪、苏灵大、联苯丁酮酸、中枢心奋药、消炎痛、丙谷美辛、阿西美辛、奈丁美酮、依托度酸、莫苯唑酸、布洛芬、酮洛芬、氟比洛芬、噁丙嗪、萘普生、苯噻丙酸、甲氧萘丙酸、双吡苯丙酸、洛索洛芬、阿明洛芬、扎托洛芬、布可隆、吡氧噻嗪、安吡昔康、替诺昔康、氯诺昔康、甲嘧啶唑、噻拉米特、エモルフアン(emorphan)、或这些物质的药学上可接受的盐等。
作为抗抑郁剂可例举：去甲替林、阿莫沙平、马普替林、丙咪嗪、阿密替林、曲米帕明、羟甲金霉素、洛非帕明、度硫平、托法尼、氟伏沙明、帕罗西丁、米那普仑、米安舍林、司普替林、舒必利或这些物质的药学上可接受的盐等。
作为抗精神病药，可举出氟奋乃静、氯丙嗪、或这些物质的药学上可接受的盐等。
作为抗痉挛剂可例举：苯妥英、乙基苯妥英、苯巴比妥、普里米酮、丙戊酸、氨甲酰氮三甲双酮、乙琥胺、乙酰苯丁脲、舒噻嗪、安定、氯硝安定、氯巴詹、唑尼沙胺、乙酰唑胺或这些物质的药学上可接受的盐等。
本发明中所谓药学上可接受的盐可例举例如：盐酸盐、硫酸盐、酒石酸盐、氢溴酸盐、硝酸盐、磷酸盐等无机酸盐，丙酸、二丙酸、戊酸、丁酸、特戊酸、醋酸盐、苯甲酸盐、甲磺酸、三氟醋酸盐、酒石酸盐、琥珀酸、棕榈酸、柠檬酸盐、苹果酸盐、马来酸盐、富马酸盐、甲磺酸盐、苯磺酸盐、甲苯磺酸盐、烟酸盐等有机酸盐，钾盐、钠盐、钙盐、铝盐等无机盐。有时根据化合物不同，形成水合物，这些水合物也属于本发明的范围。
本发明的糖尿病性神经病治疗剂，可以以各种方式给药于哺乳动物。其方式可以是例如口服剂、注射剂、直肠栓剂、外用剂(软膏剂、贴剂、滴眼剂等)中的任意一种，从业者利用众所周知的常用方法可以制造这些制剂。
在口服剂中，作为固体制剂，对甲磺司特加入赋形剂，根据需要加入粘合剂、崩解剂、润滑剂、着色剂、矫味剂、矫异味剂等后，用通常的方法进行处理，可以做成片剂、包衣片剂、颗粒剂、散剂、胶囊剂、干糖浆制剂等。另外，作为口服液剂，对甲磺司特使用矫味剂、缓冲剂、稳定化剂、矫异味剂等，根据常法处理，可以制成内服液剂、糖浆剂等。
作为注射剂，对甲磺司特加入pH调整剂、缓冲剂、稳定化剂、等渗剂、局部麻醉剂等，用常用方法进行处理，可以制成皮下注射剂、肌肉注射剂、静脉注射剂等。
作为直肠给药的栓剂，对甲磺司特加入赋形剂，进一步根据需要加入表面活性剂等后，用常用方法进行处理，可以制成栓剂。
外用剂中，软膏剂、例如糊剂、乳膏、凝胶等，可以在含有甲磺司特的基剂中根据需要配合稳定化剂、湿润剂、保存剂等，用常用方法进行处理，可以制成制剂。作为上述基剂可例举例如：白色凡士林、石蜡、甘油、纤维素衍生物、聚乙二醇、硅油、膨润土等。作为保存剂，可例举：对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯等。
另外，作为外用剂的贴剂，可以通过在通常的支持体上用常用方法涂敷上述软膏、乳膏、凝胶、糊剂等来制造。作为支持体，优选由棉、人造棉、化学纤维制成的纺布、无纺布或者软质氯乙烯、聚乙烯、聚氨酯等薄膜或发泡体片等。
在上述各种制剂中可以配合的甲磺司特的量，可以根据应该给予该制剂的患者的症状或其剂型等适当确定，一般情况下，每给药单位优选口服剂约5～1000mg、注射剂约0.1～500mg、栓剂和外用剂约5～1000mg。
另外，甲磺司特的每日给药量也可以根据患者的症状、体重、年龄、性别、其它条件而变动，优选约5～1000mg。
附图的简单说明
图1表示随着时间经过的脚底触觉敏感测量的镇痛试验结果的图。
具体实施方式
利用下面的实施例和试验例更详细地说明本发明，但本发明并不限定这些。
制剂例1(片剂)
甲磺司特 50mg
玉米淀粉 50mg
微结晶纤维素 50mg
羟丙基纤维素 15mg
乳糖 47mg
滑石 2mg
硬脂酸镁 2mg
乙基纤维素 30mg
不饱和甘油酯 2mg
二氧化钛 2mg
将由上述配合比例构成的组合物按照常用方法进行处理，制成每片含有甲磺司特50mg的片剂。
制剂例2(颗粒剂)
甲磺司特 300mg
乳糖 540mg
玉米淀粉 100mg
羟丙基纤维素 50mg
滑石 10mg
将由上述配合比例构成的组合物按照常用方法进行处理，制成每包含有甲磺司特300mg的颗粒剂。
制剂例3(胶囊剂)
甲磺司特 100mg
乳糖 30mg
玉米淀粉 50mg
微结晶纤维素 10mg
硬脂酸镁 3mg
将由上述配合比例构成的组合物按照常用方法进行处理，制成每个胶囊含甲磺司特100mg的胶囊剂。
制剂例4(注射剂)
甲磺司特 100mg
氯化钠 3.5mg
注射用蒸馏水 适量
将由上述配合比例构成的组合物按照常用方法进行处理，制成每安瓿(2ml)含甲磺司特100mg的注射剂。
制剂例5(干糖浆制剂)
甲磺司特 50mg
精制白糖 949mg
香料 适量
将由上述配合比例构成的组合物按照常用方法进行处理，制成每包含有甲磺司特50mg的干糖浆制剂。
制剂例6(糖浆制剂)
甲磺司特 50mg
精制白糖 1000mg
对羟基苯甲酸乙酯 1mg
精制水 适量
香料 适量
着色料 适量
将由上述配合比例构成的组合物按照常用方法进行处理，制成2ml中含甲磺司特50mg的糖浆制剂。
制剂例7(栓剂)
甲磺司特 300mg
ウイテツプゾ一ル(Witepsol)W-35* 1400mg
(*：注册商标，从月桂酸到硬脂酸的饱和脂肪酸的单、双和三-甘油酯的混合物，ダイナマイトノ一ベル社制)
将由上述配合比例构成的组合物按照常用方法进行处理，制成每个中含甲磺司特300mg的栓剂。
实施例1
甲磺司特对链唑霉素诱发的大鼠糖尿病性神经病的抑制效果
(1)糖尿病性神经病模型的制作
使用体重为160g以上的雄性大鼠，将链唑霉素(STZ，Sigma-Aldrich Co.)50mg/kg以2mL/kg的用量静脉内给药，制作STZ诱发糖尿病模型(Malcangio M.et al.，Pain，1998)。STZ给药7天后采用血糖值为200mg/dL以上的动物作为糖尿病模型。予以说明，血糖值的测定是将通过尾静脉采血的血液(2μL)利用测定芯片(GlutestSensor，Arkray，Inc.)和小型血糖测定仪Glutest PRO R(modelGT-1661、Arkray，Inc.)进行测定。
(2)脚底触觉敏感测量(von Frey test)
使用最大压力设定为30.0g、达到最大压力的时间设定为40秒的动态针刺测痛仪(Dynamic Planter Aesthesiometer)(Model No.37400，Ugo Basile，Inc.)，进行左右脚掌的脚底触觉敏感测量，测定疼痛阈值。STZ给药8天后，选择疼痛阈值达到一定以上的个体，使测定的疼痛阈值为各组均一，实施分组。将甲磺司特30mg/kg(腹腔内给药)或100mg/kg(口服给药)1周时间连续给药的STZ诱发糖尿病模型分别作为腹腔内给药组或口服给药组，将溶媒(蒸馏水)口服给予的STZ诱发糖尿病模型作为STZ对照组。予以说明，正常对照组使用将不给予STZ的无处置动物口服给予溶媒(蒸馏水)的动物。对于各组(各8只)，在给予开始后第1、4和7天，测定左右脚掌的疼痛阈值，通过肢体逃避反应阈值(左右脚掌的疼痛阈值的合计)评价镇痛效果。予以说明，疼痛阈值的测定时间在给予后1～1.5小时实施。平均值的显著性差异检验使用2组检验的Student的t检验，检验的显著性水平的表示为：
##(正常对照组对STZ对照组)：p值小于0.001％、和
**(STZ对照组对口服给药组或腹腔内给药组)：p值小于0.001％。口服给药组或腹腔内给药组分别与STZ对照组进行比较。另外，STZ对照组与正常对照组进行比较，判断糖尿病性神经病模型的建立。
结果：与正常对照组比较，STZ对照组发生显著的痛觉过敏，从测定开始日到第7天，其症状继续(p值小于0.001％)。从这些证实了STZ诱发糖尿病性神经病模型的建立。对于该模型动物，甲磺司特30mg/kg(腹腔内给药)和100mg/kg(口服给药)在测定开始日(初次给药时)都没有发现镇痛效果。另一方面，在测定第4天(甲磺司特给予4天后)和第7天(给予7天后)，30mg/kg(腹腔内给药)和100mg/kg(口服给药)都发现显著性的神经病抑制作用(p值小于0.001％)。
从以上结果可以知道甲磺司特发挥了对伴随糖尿病性神经病的疼痛优异的镇痛效果。
产业上的可利用性
本发明的治疗剂显示在糖尿病性神经病、特别是伴随糖尿病性神经病的疼痛的治疗上优异的效果，并且副作用小，非常有用。
Claims (5)
1.糖尿病性神经病的治疗剂，以式(1)表示的(±)-〔2-〔4-(3-乙氧基-2-羟基丙氧基)苯基氨基甲酰基〕乙基〕二甲基锍对甲苯磺酸盐作为有效成分，
【化1】
2.权利要求1所述的治疗剂，其中，糖尿病性神经病为多神经病。
3.权利要求1或2的任一项所述的治疗剂，其中，糖尿病性神经病的症状为疼痛和/或感觉异常。
4.式(1)表示的(±)-〔2-〔4-(3-乙氧基-2-羟基丙氧基)苯基氨基甲酰基〕乙基〕二甲基锍对甲苯磺酸盐在制备糖尿病性神经病治疗剂中的应用。
5.糖尿病性神经病的治疗方法，其特征在于，将式(1)表示的(±)-〔2-〔4-(3-乙氧基-2-羟基丙氧基)苯基氨基甲酰基〕乙基〕二甲基锍对甲苯磺酸盐的有效量给予哺乳动物。
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| JP349987/2006 | 2006-12-26 | ||
| JP2006349987 | 2006-12-26 | ||
| PCT/JP2007/075233 WO2008078826A1 (ja) | 2006-12-26 | 2007-12-20 | 糖尿病性ニューロパチー治療剤 |
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| CN112423742A (zh) * | 2018-06-27 | 2021-02-26 | 阿尔杰农制药股份有限公司 | 使用阿克他利预防或治疗肾纤维化或肾脏疾病 |
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| JPS59167564A (ja) | 1983-03-11 | 1984-09-21 | Taiho Yakuhin Kogyo Kk | スルホニウム化合物 |
| US4556737A (en) * | 1983-03-11 | 1985-12-03 | Taiho Pharmaceutical Company Limited | Sulfonium compounds, processes for preparing the compounds and pharmacological composiitons containing the same |
| JP3634622B2 (ja) * | 1998-05-01 | 2005-03-30 | 大鵬薬品工業株式会社 | 腎透析に伴うそう痒の治療剤 |
| CA2317530C (en) * | 1998-11-05 | 2004-04-27 | Taiho Pharmaceutical Co., Ltd. | Dysuria remedies |
| JP3885135B2 (ja) | 2000-10-10 | 2007-02-21 | 幸彦 松田 | Ｃ型又は非ｂ非ｃ型肝炎ウイルスによる肝機能異常の改善剤 |
| US7138140B2 (en) * | 2001-04-16 | 2006-11-21 | Taiho Pharmaceutical Co., Ltd. | Suplatast tosilate crystals |
| US20040087558A1 (en) * | 2002-10-24 | 2004-05-06 | Zeldis Jerome B. | Methods of using and compositions comprising selective cytokine inhibitory drugs for treatment, modification and management of pain |
| US20050203142A1 (en) * | 2002-10-24 | 2005-09-15 | Zeldis Jerome B. | Methods of using and compositions comprising immunomodulatory compounds for treatment, modification and management of pain |
| WO2004058709A1 (en) * | 2002-12-23 | 2004-07-15 | Millennium Pharmaceuticals, Inc. | Ccr8 inhibitors |
| JP4370117B2 (ja) * | 2003-03-28 | 2009-11-25 | 博夫 中山 | 化学物質過敏症治療薬 |
| ITMI20031467A1 (it) * | 2003-07-18 | 2005-01-19 | Acraf | Farmaco attivo nel dolore neuropatico |
| JP2005097220A (ja) * | 2003-09-26 | 2005-04-14 | Taiho Yakuhin Kogyo Kk | 後腹膜線維症治療剤 |
| US20070161696A1 (en) | 2004-04-23 | 2007-07-12 | Zeldis Jerome B | Methods of using and compositions comprising selective cytokine inhibitory drugs for treatment, modification and management of pain |
| JP4794148B2 (ja) * | 2004-09-10 | 2011-10-19 | 大鵬薬品工業株式会社 | ネフローゼ症候群治療剤 |
| JP4498101B2 (ja) * | 2004-11-04 | 2010-07-07 | 大鵬薬品工業株式会社 | 頭痛の予防及び／または治療剤 |
| JP4676770B2 (ja) * | 2005-01-21 | 2011-04-27 | 大鵬薬品工業株式会社 | 扁平苔癬の予防剤及び／又は治療剤 |
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| CN112423742A (zh) * | 2018-06-27 | 2021-02-26 | 阿尔杰农制药股份有限公司 | 使用阿克他利预防或治疗肾纤维化或肾脏疾病 |
| CN112423742B (zh) * | 2018-06-27 | 2024-03-19 | 阿尔杰农制药股份有限公司 | 使用阿克他利预防或治疗肾纤维化或肾脏疾病 |
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| KR20090096640A (ko) | 2009-09-11 |
| JPWO2008078826A1 (ja) | 2010-04-30 |
| EP2103305B1 (en) | 2011-09-28 |
| CA2674066A1 (en) | 2008-07-03 |
| AU2007339153B2 (en) | 2010-11-25 |
| EP2103305A4 (en) | 2010-08-18 |
| JP5023074B2 (ja) | 2012-09-12 |
| CN101563075B (zh) | 2011-09-28 |
| EP2103305A1 (en) | 2009-09-23 |
| ATE526014T1 (de) | 2011-10-15 |
| AU2007339153A1 (en) | 2008-07-03 |
| CA2674066C (en) | 2012-01-24 |
| WO2008078826A1 (ja) | 2008-07-03 |
| US20100041764A1 (en) | 2010-02-18 |
| KR101103157B1 (ko) | 2012-01-04 |
| US8247458B2 (en) | 2012-08-21 |
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