CN101044200A - 治疗有机磷中毒的方法 - Google Patents
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Abstract
治疗有机磷(OP)中毒的方法，包括给处于OP中毒危险中的哺乳动物施用OP中毒－抑制量的加兰他敏。
Description
本申请要求享有2004年9月24日提交的美国临时专利申请号60/613,121的利益。
政府支持的声明
本文所述的发明至少部分地在美国军队的资助下完成，资助号为DAAD19-02-D-0001。因此，美国可具有本发明的某些权利。
发明的技术领域
本发明涉及治疗动物(尤其是哺乳动物，更具体为人)的有机磷中毒的方法。
发明背景
由于它们的物理状态和高亲脂性，有机磷化合物(OP)会迅速渗透并蓄积在中枢神经系统(CNS)中。战场上的军人的OP中毒、和例如在神经毒气恐怖袭击事件中的普通市民的OP中毒，近年来已经在世界范围内造成公共和政府当局的关注的增加，另外，对食物和观赏作物的增加需求，已经在发达国家和发展中国家导致有毒的基于抗胆碱酯酶(抗-ChE)的杀虫剂的使用增加，包括OP，例如对硫磷和马拉硫磷。这已经导致农民和花匠的意外中毒的增加。
长期以来已知，OP和其它抗-ChE剂的主要毒性作用源自对酶ChE(该酶负责灭活CNS和周围神经系统(PNS)中的神经递质乙酰胆碱(ACh))的抑制，从而异常地增加和延长毒蕈碱性和烟碱性胆碱能反应。不幸地，现有的治疗或预防OP的毒性作用的方法仍然远远不能令人满意，尤其是在急性暴露于高度可吸收的且容易进入脑的神经毒剂的情况下。
已经测试了可逆的ChE抑制剂，如溴化米斯他隆(PB)、毒扁豆碱和石杉碱，作为针对OP中毒的解毒治疗。PB已经用作战场上士兵的预防疗法。尽管它是一种有力的抗-ChE剂，它的作用主要限于PNS，这是由于下述事实，即它是一种几乎不能穿透CNS的带电荷的分子。因此，PB不能有效地保护脑ChE对抗神经毒气。毒扁豆碱比PB更有效，但是安全性较低。因此，目前没有保护脑免受OP对ChE的不可逆抑制的方法。已经暴露于OP的那些个体而是在暴露后用抗毒蕈碱剂如阿托品，ChE再活化剂如肟类例如吡啶-2-醛肟(2-PAM)，和抗惊厥剂例如地西泮进行治疗。
鉴于上述情况，本发明的一个目的是，提供治疗OP中毒的方法。从本文提供的详细描述中，可以明白该目的和其它目的和优点，以及另外的发明特征。
发明简述
本发明提供了治疗OP中毒的方法。该方法包括，给处于OP中毒危险中的哺乳动物施用OP中毒-抑制量的加兰他敏，从而保护该哺乳动物在暴露于OP后免于OP中毒。
发明详述
本发明至少部分地基于下述令人惊奇的且意外的发现，即可以将叔生物碱(tertiary alkaloid)如加兰他敏施用给处于OP中毒危险中的动物，尤其是哺乳动物，更具体为人，以保护该动物免于OP中毒。尽管与PB和毒扁豆碱相比，加兰他敏是一种较弱的ChE抑制剂，但它是一种不带电的分子，且因此具有穿过血脑屏障的能力。加兰他敏还会起烟碱性受体(nAChR)的变构增强配体(APL)的作用，且能″解救″一些烟碱性受体免于脱敏。在OP中毒的情况下(此时过量的ACh诱发nAChR的大量脱敏)，该性能是重要的。
鉴于上述内容，本发明提供了对OP中毒的解毒治疗的方法。该方法包括，给处于OP中毒危险中的哺乳动物施用OP中毒-抑制量的加兰他敏，从而保护该哺乳动物在随后暴露于OP时免于OP中毒。可以在暴露于OP之前或之后，给哺乳动物施用加兰他敏。如果在暴露之前施用加兰他敏，该方法还包括，随后给哺乳动物施用有效量的抗毒蕈碱剂，如阿托品。如果在暴露之后施用加兰他敏，该方法还包括，在暴露于OP之后、且施用OP-中毒抑制有效量的加兰他敏之前或同时，施用有效量的抗毒蕈碱剂，如阿托品。优选地，在暴露于OP后尽可能快地施用抗毒蕈碱剂和加兰他敏，以便使后-治疗的有效性最大化。取决于相对于暴露于OP的时间随后施用抗毒蕈碱剂和加兰他敏的时机，该实施方案也可以具有治疗作用。
如果哺乳动物当前暴露于高到足以毒害该哺乳动物的水平的OP，或它处于暴露于所述高到足以毒害它的水平的OP的危险中，则该哺乳动物是处于OP中毒的危险中。对于战场上的军人，在神经毒气恐怖袭击事件中的普通市民，和操作用基于抗-ChE的杀虫剂处理的食物和观赏作物的农民和花匠，存在这样的危险。
当加兰他敏的量足以显著地、优选地完全地减少由不健康的征象所证实的暴露于OP的毒害作用时，这样的量是″OP中毒-抑制量″或″有效量″，所述征象包括但不限于，OP中毒的任何外周的和中枢的高胆碱能征象，如分泌过多，肌肉收缩，呼吸困难，惊厥，或行为异常。根据本领域已知的剂量范围寻找技术，可以确定足以抑制OP中毒的加兰他敏的量。例如，在临床环境或在战场上，熟练的临床医师可以确定最佳剂量。通常，通过递增地改变起始剂量，直到达到该情形下的最佳效果，确定最佳剂量。当还施用10mg/kg阿托品(如硫酸阿托品)时，约5mg/kg至约8mg/kg的加兰他敏(如加兰他敏氢溴酸盐)剂量有效地预防由致死剂量的神经毒剂梭曼和沙林诱发的毒性和致死性。当在暴露于OP之前至多约1小时或暴露之后至多约5分钟紧急使用时，加兰他敏是有效的解毒治疗。
除了别的以外，加兰他敏特别可以从中国深圳的Hande Industry& Trade Holdings Co.，Ltd.购得。理想的是，加兰他敏适合作为药物组合物施用给动物，如哺乳动物，尤其是人。药物组合物的配制是本领域已知的(见，例如Remington：The Science and Practice ofPharmacy，Mack Pub.Co.)。目前，可以以商品名ReminylTM(Janssen-Cilag，Ltd.，UK)得到作为用于治疗阿尔茨海默氏病的药物组合物的加兰他敏。
可通过本领域已知的任何合适的给药途径，施用加兰他敏。优选的给药途径包括，但不限于，经口的和肌肉内的。给药途径部分地取决于暴露危险的情形。例如，对于预测暴露的预-治疗，如在有规律地(例如，每天)操作OP杀虫剂的农业工人和其它个体的情况下，经口给药可以是优选的，而对于战场上的军人和暴露于OP的市民(如在恐怖袭击的背景下)的后-治疗，肌肉内给药可以是优选的。
如果哺乳动物在施用加兰他敏后暴露于OP，优选地，在暴露于OP后尽可能快地给哺乳动物施用有效量的抗毒蕈碱剂，如阿托品。可以通过任何合适的途径施用抗毒蕈碱剂。肌肉内给药通常是优选的。当足以抑制(优选地预防)暴露于OP的任何不良作用时，抗毒蕈碱剂(如阿托品)的量是″有效量″。根据本领域已知的剂量范围寻找技术，可以确定抗毒蕈碱剂的有效量。例如，在临床环境或在战场上，熟练的临床医师可以确定最佳剂量。通常，通过递增地改变起始剂量，直到达到该情形下的最佳效果，确定最佳剂量。如上所述，当施用剂量为约5mg/kg至约8mg/kg的加兰他敏(如加兰他敏氢溴酸盐)时，约10mg/kg是阿托品(如硫酸阿托品)的最有效的剂量。
阿托品可以从Sigma Chemical Co.(St.Louis，MO)得到。理想的是，阿托品或其它抗毒蕈碱剂适合作为药物组合物(见，例如Remington，同上)施用给动物，如哺乳动物，尤其是人。
实施例
下面的实施例用于解释本发明，但是无意以任何方式限制它的范围。
实施例1
本实施例证实了在随后暴露于OP的哺乳动物中用加兰他敏预-治疗的有效性。
在将豚鼠暴露于1.5-2.0×50％致死剂量(LD50)的梭曼(42或56μg/kg皮下注射)或沙林(63或73.5μg/kg皮下注射)之前30分钟或之后5分钟，给豚鼠(幼龄雄性，重300-420g)(肌肉内地)施用加兰他敏(4-10mg/kg)。在施用神经毒剂梭曼或沙林后1-2分钟，给一些豚鼠(肌肉内地)施用硫酸阿托品(6-16mg/kg)。与施用阿托品同时或之后(例如在约4分钟内)，一些豚鼠接受加兰他敏(肌肉内地)。对照豚鼠接受加兰他敏(4-8mg/kg)，阿托品(6-16mg/kg)，其组合，或盐水。观察存活和体重至少1周。
发现加兰他敏保护豚鼠对抗致死剂量的梭曼或沙林。由5-8mg/kg加兰他敏和10mg/kg阿托品组成的治疗，完全保护豚鼠免于1.5×LD50的梭曼和沙林诱导的毒性和致死性。不仅加兰他敏完全保护豚鼠免于死亡，而且在OP注射后短时间内，豚鼠没有表现出OP中毒的任何外周的和中枢的高胆碱能征象，如分泌过多，肌肉收缩，呼吸困难，惊厥，或行为异常，且在长达1-2周的观察阶段内，它们没有表现出不健康的征象。接受梭曼或沙林、然后接受硫酸阿托品的那些豚鼠，都在10-20分钟内呈现出威及生命的症状，并根据IACUC-批准的动物护理和操作方案被实施了安乐死。
在前24小时，接受OP的所有豚鼠都表现出5-10％体重减轻；但是，在随后的几天中，豚鼠体重增加。以产生部分保护的加兰他敏剂量，有些豚鼠表现出OP中毒的迹象。在OP攻击后数小时或数天内，这些豚鼠具有威及生命的症状，并根据IACUC-批准的动物护理和操作方案被实施了安乐死。这样的豚鼠表现出不同程度的OP毒性，且不会恢复它们的体重。但是，在OP攻击后3-4天后，没有记录到进一步的死亡。接受加兰他敏(多至8mg/kg)或阿托品(6-10mg/kg)或2种保护剂的混合物的对照豚鼠，没有表现出体重减少或其它不良反应或中毒的迹象。
当在CO2深度麻醉后通过断头对豚鼠实施安乐死时，取出血样(通过心脏穿刺得到)和全脑，并立即在干冰中冷冻，用于随后的胆碱酯酶抑制和加兰他敏水平的分析。初始测量表明，肌内注射8mg/kg加兰他敏产生约1-3μM该试剂的血浆和脑浓度，这类似于在用临床上推荐用于治疗阿尔茨海默氏病的加兰他敏剂量治疗的人的血浆中观察到的加兰他敏浓度。加兰他敏在脑中的浓度足以预防由OP-诱发的对胆碱酯酶的不可逆抑制引起的升高的ACh水平对nAChR的脱敏。从加兰他敏的最高至最低的测量浓度，脑中的胆碱酯酶抑制是在20％至＜1％的范围内。甚至当脑胆碱酯酶抑制可忽略时，加兰他敏仍然阻止OP-诱发的毒性。
使用Fluoro Jade B染色，将通过加兰他敏预-治疗或后-治疗成功地保护免于OP中毒的那些豚鼠的脑与对照豚鼠的脑进行形态测定比较。在对照和(加兰他敏+阿托品)-治疗的、OP-攻击的动物的脑中，神经元的生存力和结构非常相似。
实施例2
本实施例证实了在已经暴露于OP的哺乳动物中用加兰他敏后-治疗的有效性。
将梭曼(42μg/kg)(皮下地)施用给豚鼠(幼龄雄性，重300-420g)。1分钟后，给动物(肌肉内地)施用阿托品(10mg/kg)。在施用阿托品的同时或之后(例如4分钟后)，给动物(肌肉内地)施用加兰他敏(8-10mg/kg)。在施用梭曼5分钟内施用8-10mg/kg加兰他敏，提供了100％保护。相比之下，在施用梭曼5分钟内施用6mg/kg加兰他敏，仅提供约35％存活。在前24小时，所有豚鼠表现出约5％体重减轻；但是，在随后的几天中，豚鼠以与未用OP攻击的对照动物相同的速度增加体重。
本文引用的所有文献，包括出版物、专利申请和专利，都特此引作参考，其程度与个别地且特别地指明每篇文献引作参考并整体在本文中阐明相同。
在描述本发明的上下文中(特别是在下面的权利要求书的上下文中)，术语“一”和“1”和“该”和类似的指示的使用，应当解释为涵盖单数和复数，除非本文另有说明或上下文清楚地抵触。除非本文另有说明，本文对数值范围的描述，仅仅用作个别地指示该范围内的每个单独值的简单方法，且将每个单独值引入本说明书中，如同在本文中单独地列举它。除非本文另有说明或上下文清楚地抵触，可以以任何合适的次序进行本文所述的所有方法。除非另有声明，本文提供的任意的和所有的实例或示例性的语言(例如″如″)的使用，仅仅用于更好地解释本发明，且不对本发明的范围施加限制。本说明书中的任何语言，都不应解释为指示任何未要求保护的元素是实现本发明所必需的。
本文描述了本发明的优选实施方案，包括发明人已知的实现本发明的最佳方式。应当理解，解释的实施方案仅仅是示例性的，不应当理解为限制本发明的范围。
Claims (7)
1.治疗有机磷(OP)中毒的方法，该方法包括，给处于OP中毒危险中的哺乳动物施用OP中毒-抑制量的加兰他敏，从而保护该哺乳动物在暴露于OP后免于OP中毒。
2.权利要求1的方法，其中在暴露于OP之前给哺乳动物施用加兰他敏。
3.权利要求2的方法，包括随后给哺乳动物施用有效量的抗毒蕈碱剂。
4.权利要求3的方法，其中所述抗毒蕈碱剂是阿托品。
5.权利要求1的方法，其中在暴露于OP之后给哺乳动物施用加兰他敏。
6.权利要求5的方法，还包括在暴露于OP之后且在加兰他敏之前或同时，施用有效量的抗毒蕈碱剂。
7.权利要求6的方法，其中所述抗毒蕈碱剂是阿托品。
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| CN113507895A (zh) * | 2018-09-24 | 2021-10-15 | 巴尔的摩马里兰大学 | 用于隔膜穿刺的设备和方法 |
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2012
- 2012-02-22 IL IL218241A patent/IL218241A/en not_active IP Right Cessation
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2013
- 2013-04-24 JP JP2013091045A patent/JP2013173773A/ja active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103041368A (zh) * | 2013-01-18 | 2013-04-17 | 新乡医学院 | 藻蓝蛋白在制备防治有机磷农药所致胚胎毒性的药物中的应用 |
| CN113507895A (zh) * | 2018-09-24 | 2021-10-15 | 巴尔的摩马里兰大学 | 用于隔膜穿刺的设备和方法 |
| CN113507895B (zh) * | 2018-09-24 | 2025-01-07 | 巴尔的摩马里兰大学 | 用于隔膜穿刺的设备和方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| US8703762B2 (en) | 2014-04-22 |
| WO2006036686A3 (en) | 2007-02-22 |
| EP2813225A1 (en) | 2014-12-17 |
| EP1791904B1 (en) | 2014-08-27 |
| AU2005289808A1 (en) | 2006-04-06 |
| WO2006036686A2 (en) | 2006-04-06 |
| CA2583439C (en) | 2016-05-10 |
| PL1791904T3 (pl) | 2015-02-27 |
| ES2519690T3 (es) | 2014-11-07 |
| JP5710092B2 (ja) | 2015-04-30 |
| CA2583439A1 (en) | 2006-04-06 |
| IL182048A0 (en) | 2007-07-24 |
| IL218241A0 (en) | 2012-04-30 |
| EP2813225B1 (en) | 2017-12-13 |
| IL218241A (en) | 2016-03-31 |
| PL2813225T3 (pl) | 2018-11-30 |
| US20110144093A1 (en) | 2011-06-16 |
| US20080070900A1 (en) | 2008-03-20 |
| JP2008514609A (ja) | 2008-05-08 |
| US7888346B2 (en) | 2011-02-15 |
| ES2662868T3 (es) | 2018-04-10 |
| JP2013173773A (ja) | 2013-09-05 |
| AU2005289808A2 (en) | 2008-07-31 |
| AU2005289808B2 (en) | 2011-11-03 |
| EP1791904A2 (en) | 2007-06-06 |
| EP1791904A4 (en) | 2009-01-21 |
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