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1. 发明授权

US08949033B2 Method for quantification of neurotoxin 有权
标题翻译：神经毒素定量方法
公开(公告)号：US08949033B2
公开(公告)日：2015-02-03
申请号：US12298908
申请日：2006-04-28
申请人： Tetsuhiro Harakawa , Hirotoshi Nakano , Yasushi Torii , Sachio Okuda , Ryuji Kaji , Takashi Sakamoto , Motohide Takahashi , Setsuji Ishida
发明人： Tetsuhiro Harakawa , Hirotoshi Nakano , Yasushi Torii , Sachio Okuda , Ryuji Kaji , Takashi Sakamoto , Motohide Takahashi , Setsuji Ishida
IPC分类号： G01N33/50 , G01N33/94
CPC分类号： G01N33/5088 , G01N33/94
摘要： The present invention relates to a method for quantitatively measuring the muscular relaxing activity of a neurotoxin. Specifically, based on an extent of the activity of muscular relaxation of a neurotoxin from bacteria of Clostridium, the present invention relates to a method for quantification of the efficacy (potential and/or diffusion reaction) of a neurotoxin comprising the following steps of: (a) administering a neurotoxin to the hind leg muscle of one of hind legs of a non-human mammal; (b) applying electric stimulus to said non-human mammal; (c) measuring a compound muscle action potential (CMAP) by contraction of said hind leg muscle to which the neurotoxin is administered and/or of the hind leg muscle of the other hind leg to which the neurotoxin is not administered; and (d) taking amplitude data from the compound muscle action potential (CMAP) obtained by the measurement in step (c) and analyzing an extent of a decrease in amplitude to thereby quantify the efficacy of the muscular relaxing activity by the neurotoxin. In contrast to the mouse LD50 currently used as a potential unit of a botulinum toxin which is measurable at a level of only several units, the quantification method of the efficacy of a neurotoxin of the present invention allows for measurement at a level of as low as 0.01 to 1 unit and hence is a method with a high sensitivity, reproducibility and accuracy.
摘要翻译：本发明涉及一种定量测定神经毒素的肌肉松弛活性的方法。具体而言，本发明是基于梭菌属细菌的神经毒素的肌肉弛豫活动的程度，本发明涉及一种定量神经毒素的功效（潜在和/或扩散反应）的方法，包括以下步骤：（ a）将神经毒素施用于非人哺乳动物后腿之一的后腿肌肉; （b）对所述非人哺乳动物施加电刺激; （c）通过神经毒素施用的所述后腿肌肉的收缩和/或不施用神经毒素的另一后腿的后腿肌肉测定复合肌肉动作电位（CMAP）; 和（d）从步骤（c）中测定得到的复合肌肉动作电位（CMAP）获取振幅数据，分析振幅减小的程度，由此量化神经毒素对肌肉松弛活性的功效。与目前用作肉毒杆菌毒素的潜在单位的小鼠LD50相比，其可测量的水平仅为几个单位，本发明的神经毒素的功效的定量方法允许测量水平低至 0.01〜1单位，因此是具有高灵敏度，重现性和准确性的方法。

2. 发明授权

US08577618B2 Method for quantification of neurotoxin 有权
公开(公告)号：US08577618B2
公开(公告)日：2013-11-05
申请号：US12298908
申请日：2006-04-28
申请人： Tetsuhiro Harakawa , Hirotoshi Nakano , Yasushi Torii , Sachio Okuda , Ryuji Kaji , Takashi Sakamoto , Motohide Takahashi , Setsuji Ishida
发明人： Tetsuhiro Harakawa , Hirotoshi Nakano , Yasushi Torii , Sachio Okuda , Ryuji Kaji , Takashi Sakamoto , Motohide Takahashi , Setsuji Ishida
IPC分类号： G01N33/50
摘要： The present invention relates to a method for quantitatively measuring the muscular relaxing activity of a neurotoxin. Specifically, based on an extent of the activity of muscular relaxation of a neurotoxin from bacteria of Clostridium, the present invention relates to a method for quantification of the efficacy (potential and/or diffusion reaction) of a neurotoxin comprising the following steps of: (a) administering a neurotoxin to the hind leg muscle of one of hind legs of a non-human mammal; (b) applying electric stimulus to said non-human mammal; (c) measuring a compound muscle action potential (CMAP) by contraction of said hind leg muscle to which the neurotoxin is administered and/or of the hind leg muscle of the other hind leg to which the neurotoxin is not administered; and (d) taking amplitude data from the compound muscle action potential (CMAP) obtained by the measurement in step (c) and analyzing an extent of a decrease in amplitude to thereby quantify the efficacy of the muscular relaxing activity by the neurotoxin. In contrast to the mouse LD50 currently used as a potential unit of a botulinum toxin which is measurable at a level of only several units, the quantification method of the efficacy of a neurotoxin of the present invention allows for measurement at a level of as low as 0.01 to 1 unit and hence is a method with a high sensitivity, reproducibility and accuracy.

3. 发明申请

US20090297452A1 METHOD FOR QUANTIFICATION OF NEUROTOXIN 有权
标题翻译：神经毒素定量方法
公开(公告)号：US20090297452A1
公开(公告)日：2009-12-03
申请号：US12298908
申请日：2006-04-28
申请人： Tetsuhiro Harakawa , Hirotoshi Nakano , Yasushi Torii , Sachio Okuda , Ryuji Kaji , Takashi Sakamoto , Matohide Takahashi , Setsuji Ishida
发明人： Tetsuhiro Harakawa , Hirotoshi Nakano , Yasushi Torii , Sachio Okuda , Ryuji Kaji , Takashi Sakamoto , Matohide Takahashi , Setsuji Ishida
IPC分类号： A61K49/00 , A61P43/00 , G01N33/15 , G06F19/00 , G06F17/18
CPC分类号： G01N33/5088 , G01N33/94
摘要： The present invention relates to a method for quantitatively measuring the muscular relaxing activity of a neurotoxin. Specifically, based on an extent of the activity of muscular relaxation of a neurotoxin from bacteria of Clostridium, the present invention relates to a method for quantification of the efficacy (potential and/or diffusion reaction) of a neurotoxin comprising the following steps of: (a) administering a neurotoxin to the hind leg muscle of one of hind legs of a non-human mammal; (b) applying electric stimulus to said non-human mammal; (c) measuring a compound muscle action potential (CMAP) by contraction of said hind leg muscle to which the neurotoxin is administered and/or of the hind leg muscle of the other hind leg to which the neurotoxin is not administered; and (d) taking amplitude data from the compound muscle action potential (CMAP) obtained by the measurement in step (c) and analyzing an extent of a decrease in amplitude to thereby quantify the efficacy of the muscular relaxing activity by the neurotoxin. In contrast to the mouse LD50 currently used as a potential unit of a botulinum toxin which is measurable at a level of only several units, the quantification method of the efficacy of a neurotoxin of the present invention allows for measurement at a level of as low as 0.01 to 1 unit and hence is a method with a high sensitivity, reproducibility and accuracy.
摘要翻译：本发明涉及一种定量测定神经毒素的肌肉松弛活性的方法。具体而言，本发明是基于梭菌属细菌的神经毒素的肌肉弛豫活动的程度，本发明涉及一种定量神经毒素的功效（潜在和/或扩散反应）的方法，包括以下步骤：（ a）将神经毒素施用于非人哺乳动物后腿之一的后腿肌肉; （b）对所述非人哺乳动物施加电刺激; （c）通过神经毒素施用的所述后腿肌肉的收缩和/或不施用神经毒素的另一后腿的后腿肌肉测定复合肌肉动作电位（CMAP）; 和（d）从步骤（c）中测定得到的复合肌肉动作电位（CMAP）获取振幅数据，分析振幅减小的程度，由此量化神经毒素对肌肉松弛活性的功效。与目前用作肉毒杆菌毒素的潜在单位的小鼠LD50相比，其可测量的水平仅为几个单位，本发明的神经毒素的功效的定量方法允许测量水平低至 0.01〜1单位，因此是具有高灵敏度，重现性和准确性的方法。

4. 发明授权

US09278133B2 Highly purified type A botulinum toxin preparation from infant botulism pathogen 有权
标题翻译：来自婴儿肉毒杆菌病原体的高纯度A型肉毒杆菌毒素制剂
公开(公告)号：US09278133B2
公开(公告)日：2016-03-08
申请号：US12447351
申请日：2007-10-26
申请人： Tetsuhiro Harakawa , Hirotoshi Nakano , Yasushi Torii , Yoshitaka Goto , Miho Shinmura , Sachio Okuda , Ryuji Kaji , Shunji Kosaki
发明人： Tetsuhiro Harakawa , Hirotoshi Nakano , Yasushi Torii , Yoshitaka Goto , Miho Shinmura , Sachio Okuda , Ryuji Kaji , Shunji Kosaki
IPC分类号： A61K38/48 , A61K39/08 , A61K9/00 , A61K47/42 , A61K9/19
CPC分类号： A61K47/42 , A61K9/0019 , A61K9/19 , A61K38/4893 , Y02A50/469
摘要： A novel type A botulinum toxin preparation is provided. A neuromuscular transmission blocking agent comprising as an active ingredient a highly purified type A botulinum toxin from Clostridium botulinum as infant botulism pathogen and a medicament for treating a disease with a muscle overactivity comprising as an active ingredient said toxin. In particular, the medicament of the present invention, as compared to the conventional known botulinum toxin preparations, has rapid efficacy of potential and is less diffusive and thus, having a broader safety margin, may be used as therapeutic medicament for decreasing local, muscle overactivity in a disease with a muscle overactivity.
摘要翻译：提供了一种新型的A型肉毒杆菌毒素制剂。一种包含作为活性成分的来自肉毒梭菌的高度纯化的A型肉毒杆菌毒素作为婴儿肉毒杆菌病原体的神经肌肉阻滞剂和用于治疗肌肉过度活动的疾病的药物，其包含所述毒素作为活性成分。特别地，与常规已知的肉毒杆菌毒素制剂相比，本发明的药物具有快速的潜力和较少的扩散作用，因此具有较宽的安全性，可用作减少局部，肌肉过度活动的治疗药物在肌肉过度活动的疾病中。

5. 发明申请

US20100173841A1 Highly Purified Type A Botulinum Toxin Preparation From Infant Botulism Pathogen 有权
标题翻译：高纯度A型肉毒杆菌毒素从婴儿肉毒杆菌病原体制备
公开(公告)号：US20100173841A1
公开(公告)日：2010-07-08
申请号：US12447351
申请日：2007-10-26
申请人： Tetsuhiro Harakawa , Hirotoshi Nakano , Yasushi Torii , Yoshitaka Goto , Miho Shinmura , Sachio Okuda , Ryuji Kaji , Shunji Kosaki
发明人： Tetsuhiro Harakawa , Hirotoshi Nakano , Yasushi Torii , Yoshitaka Goto , Miho Shinmura , Sachio Okuda , Ryuji Kaji , Shunji Kosaki
IPC分类号： A61K38/16 , C07K14/33 , A61P25/06 , A61P13/10 , A61P25/14 , A61P25/00 , A61P21/00 , A61P29/00
CPC分类号： A61K47/42 , A61K9/0019 , A61K9/19 , A61K38/4893 , Y02A50/469
摘要： A novel type A botulinum toxin preparation is provided. A neuromuscular transmission blocking agent comprising as an active ingredient a highly purified type A botulinum toxin from Clostridium botulinum as infant botulism pathogen and a medicament for treating a disease with a muscle overactivity comprising as an active ingredient said toxin. In particular, the medicament of the present invention, as compared to the conventional known botulinum toxin preparations, has rapid efficacy of potential and is less diffusive and thus, having a broader safety margin, may be used as therapeutic medicament for decreasing local, muscle overactivity in a disease with a muscle overactivity.
摘要翻译：提供了一种新型的A型肉毒杆菌毒素制剂。一种包含作为活性成分的来自肉毒梭菌的高度纯化的A型肉毒杆菌毒素作为婴儿肉毒杆菌病原体的神经肌肉阻滞剂和用于治疗肌肉过度活动的疾病的药物，其包含所述毒素作为活性成分。特别地，与常规已知的肉毒杆菌毒素制剂相比，本发明的药物具有快速的潜力和较少的扩散作用，因此具有较宽的安全性，可用作减少局部，肌肉过度活动的治疗药物在肌肉过度活动的疾病中。

6. 发明申请

US20110105940A1 METHOD FOR QUANTIFICATION OF TITER OF NEUTRALIZING ANTIBODY TO NEUROTOXIN 审中-公开
标题翻译：中性抗体对神经毒素的定量的方法
公开(公告)号：US20110105940A1
公开(公告)日：2011-05-05
申请号：US12673980
申请日：2008-08-20
申请人： Yasushi Torii , Tetsuhiro Harakawa , Yoshitaka Goto , Akihiro Ginnaga , Ryuji Kaji , Shunji Kozaki , Motohide Takahashi
发明人： Yasushi Torii , Tetsuhiro Harakawa , Yoshitaka Goto , Akihiro Ginnaga , Ryuji Kaji , Shunji Kozaki , Motohide Takahashi
IPC分类号： A61B5/0488
CPC分类号： G01N33/6854 , A61B5/0488 , G01N2333/33 , G01N2469/20
摘要： A method for quantification of a titer of a neutralizing antibody to a neurotoxin is disclosed. The method comprises the steps: (a) mixing a standard sample containing a fixed amount of a neurotoxin and a test sample containing a neutralizing antibody to said neurotoxin; (b) administering the mixture obtained in step (a) into the muscle of a non-human mammal; (c) applying electric stimulus to said non-human mammal; (d) measuring a compound muscle action potential (CMAP) due to contraction of the muscle of said mammal by application of electric stimulus with an electromyograph; and (e) analyzing CMAP amplitude data obtained in step (d) for an extent of decrease in amplitude by a non-neutralized neurotoxin to thereby quantify a titer of the neutralizing antibody contained in the test sample.
摘要翻译：公开了定量神经毒素中和抗体滴度的方法。该方法包括以下步骤：（a）将含有固定量的神经毒素的标准样品和含有中和抗体的测试样品与所述神经毒素混合; （b）将步骤（a）中获得的混合物给予非人哺乳动物的肌肉; （c）对所述非人哺乳动物施加电刺激; （d）通过用肌电图仪施加电刺激来测量由于所述哺乳动物的肌肉收缩引起的复合肌肉动作电位（CMAP）; 和（e）通过未中和的神经毒素分析在步骤（d）中获得的CMAP振幅数据的幅度减小，从而定量测试样品中所含的中和抗体的滴度。

7. 发明申请

US20130252902A1 TYPE A2 BOTULINUM TOXIN PREPARATION 审中-公开
标题翻译： A2型BOTULINUM毒素制剂
公开(公告)号：US20130252902A1
公开(公告)日：2013-09-26
申请号：US13903731
申请日：2013-05-28
申请人： Shinji NAKAHIRA , Yasushi Torii , Yoshitaka Goto , Miho Shinmura , Satomi Munechika , Sachio Okuda , Shunji Kozaki
发明人： Shinji NAKAHIRA , Yasushi Torii , Yoshitaka Goto , Miho Shinmura , Satomi Munechika , Sachio Okuda , Shunji Kozaki
IPC分类号： A61K38/16
CPC分类号： A61K38/164 , A61K38/4893 , Y02A50/469
摘要： A method for treating a patient who has a neutralizing antibody to a type A1 botulinum toxin. The method includes administering 150 kDa type A neurotoxin from type A2 Clostridium botulinum (A2 NTX) to the patient. In accordance with the present invention, a problem can be solved of decrease in clinical response caused by a neutralizing antibody to a type A1 botulinum toxin produced when a patient is treated with a pharmaceutical preparation containing a type A1 botulinum toxin.
摘要翻译：一种治疗患有A1型肉毒杆菌毒素中和抗体的患者的方法。该方法包括从A2型肉毒杆菌（A2NTX）向患者施用150kDa的A型神经毒素。根据本发明，当患者用含有A1型肉毒杆菌毒素的药物制剂治疗时，可以解决由中和抗体对产生的A1型肉毒杆菌毒素引起的临床反应降低的问题。

8. 发明授权

US09623075B2 Type A2 botulinum toxin preparation 有权
公开(公告)号：US09623075B2
公开(公告)日：2017-04-18
申请号：US13903731
申请日：2013-05-28
申请人： Shinji Nakahira , Yasushi Torii , Yoshitaka Goto , Miho Shinmura , Satomi Munechika , Sachio Okuda , Shunji Kozaki
发明人： Shinji Nakahira , Yasushi Torii , Yoshitaka Goto , Miho Shinmura , Satomi Munechika , Sachio Okuda , Shunji Kozaki
IPC分类号： A61K38/48 , A61K38/16
CPC分类号： A61K38/164 , A61K38/4893 , Y02A50/469
摘要： A method for treating a patient who has a neutralizing antibody to a type A1 botulinum toxin. The method includes administering 150 kDa type A neurotoxin from type A2 Clostridium botulinum (A2 NTX) to the patient. In accordance with the present invention, a problem can be solved of decrease in clinical response caused by a neutralizing antibody to a type A1 botulinum toxin produced when a patient is treated with a pharmaceutical preparation containing a type A1 botulinum toxin.

9. 发明申请

US20110033431A1 TYPE A2 BOTULINUM TOXIN PREPARATION 审中-公开
标题翻译： A2型BOTULINUM毒素制剂
公开(公告)号：US20110033431A1
公开(公告)日：2011-02-10
申请号：US12935769
申请日：2009-03-31
申请人： Shinji Nakahira , Yasushi Torii , Yoshitaka Goto , Miho Shinmura , Satomi Munechika , Sachio Okuda , Shunji Kozaki
发明人： Shinji Nakahira , Yasushi Torii , Yoshitaka Goto , Miho Shinmura , Satomi Munechika , Sachio Okuda , Shunji Kozaki
IPC分类号： A61K35/74 , A61P21/00 , C12N1/20 , C07K14/33
CPC分类号： A61K38/164 , A61K38/4893 , Y02A50/469
摘要： A pharmaceutical preparation for use in a patient who has a neutralizing antibody to a botulinum toxin from type A1 Clostridium botulinum (type A1 botulinum toxin), said preparation comprising as an active ingredient 150 kDa type A neurotoxin from type A2 Clostridium botulinum (A2 NTX); a medicament for treating a disease with muscle overactivity for use in a patient who has a neutralizing antibody to a type A1 botulinum toxin, said medicament comprising as an active ingredient said A2 NTX; a method for treating a patient who has a neutralizing antibody to a type A1 botulinum toxin, said method comprising administering said A2 NTX to the patient; and a method for use of A2 NTX in a patient who has said neutralizing antibody. In accordance with the present invention, a problem can be solved of decrease in clinical response caused by a neutralizing antibody to a type A1 botulinum toxin produced when a patient is treated with a pharmaceutical preparation comprising a type A1 botulinum toxin.
摘要翻译：一种用于患有来自A1型肉毒毒素（A1型肉毒杆菌毒素）的肉毒毒素中和抗体的患者的药物制剂，所述制剂包含来自A2型肉毒毒素（A2NTX）的150kDa A型神经毒素作为活性成分， ; 用于治疗患有肌肉过度活动的疾病的药物，所述疾病用于患有A1型肉毒杆菌毒素的中和抗体的患者，所述药物包含所述A2NXX的活性成分; 用于治疗对A1型肉毒杆菌毒素具有中和抗体的患者的方法，所述方法包括向患者施用所述A2NXX; 以及在具有所述中和抗体的患者中使用A2NTX的方法。根据本发明，当患者用包含A1型肉毒杆菌毒素的药物制剂治疗时，可以解决由中和抗体对产生的A1型肉毒杆菌毒素引起的临床反应降低的问题。

10. 发明授权

US4689198A Austenitic stainless steel with high corrosion resistance and high strength when heat treated 失效
标题翻译：奥氏体不锈钢具有高耐蚀性和高强度的热处理
公开(公告)号：US4689198A
公开(公告)日：1987-08-25
申请号：US786960
申请日：1985-10-03
申请人： Kazuo Fujiwara , Yasushi Torii , Koujiro Kitahata , Tsuyoshi Inoue , Tadamasa Yokoyama, deceased
发明人： Kazuo Fujiwara , Yasushi Torii , Koujiro Kitahata , Tsuyoshi Inoue , Tadamasa Yokoyama, deceased
IPC分类号： C21D6/00 , C22C38/46 , C22C38/50 , C22C38/58 , C22C38/44
CPC分类号： C22C38/58 , C21D6/004 , C22C38/46 , C22C38/50
摘要： Disclosed herein is a high strength austenitic stainless steel with excellent corrosion resistance even in oxidative enviroments, and a method for producing such stainless steel, in which the kinds and proportions of the component elements are strictly restricted, especially limiting the contents of C and N to achieve solution strengthening while preventing degradations in corrosion resistance and defects of steel ingots which would be caused if they are added excessively. Besides, V is added under coexistence with Cr and Ni to increase the strength by precipitation of carbides and nitrides of V while preventing production of Cr carbides.
摘要翻译： PCT No.PCT / JP85 / 00051 Sec。 371日期：1985年10月3日 102（e）日期1985年10月3日PCT提交1985年2月7日PCT公布。出版物WO85 / 0352800 1985年8月15日。在此公开的是高强度奥氏体不锈钢，即使在氧化环境中也具有优异的耐腐蚀性，以及这种不锈钢的制造方法，其中组分元素的种类和比例被严格限制，特别是限制 C和N的含量实现溶液强化，同时防止如果过量加入会导致耐腐蚀性降低和钢锭缺陷。此外，在与Cr和Ni共存的情况下，通过与Cr和Ni共存而添加V，同时防止Cr碳化物的生成而提高V的碳化物和氮化物的强度。

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