CN1074920C - 止痛剂及其应用 - Google Patents

止痛剂及其应用 Download PDF

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CN1074920C
CN1074920C CN94193782A CN94193782A CN1074920C CN 1074920 C CN1074920 C CN 1074920C CN 94193782 A CN94193782 A CN 94193782A CN 94193782 A CN94193782 A CN 94193782A CN 1074920 C CN1074920 C CN 1074920C
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H·J·巴兹利
R·W·格里斯伍德
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
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Abstract

左旋丁哌卡因作为麻醉药对于患有心肌收缩力降低或可能有心肌收缩力降低倾向的病人是有用的。

Description

止痛剂及其应用
本发明涉及已知止痛剂，即丁哌卡因或1-丁基-N-(2,6-二甲基苯基)-2-哌啶甲酰胺新的治疗应用。
消旋丁哌卡因是有效的长效麻醉药，并且可以硬膜外给予。然而，消旋丁哌卡因具有心脏毒性，它对心脏的电生理和机械作用具有抑制作用。因此，心脏病患者要小心应用。
已知左旋丁哌卡因的心脏毒性可能小于右旋和消旋丁哌卡因的心脏毒性。例如见Vanhoutte等人，Br.J.Pharmacol.103:1275-1281(1991)，和Denson等人，Regional Anaesthesia,17:311-316(1992)。Vanhoutte等人研究了丁哌卡因对映体对荷兰猪离体乳头肌电生理特性的影响；这依据了他们的陈述，即“丁哌卡因的心脏毒性似乎主要源于电生理”。
很多需要止痛剂的病人伴随有其它药物，例如抗高血压剂的治疗。很多这样的药物是心脏抑制剂。尤其，最近已报道，在离体器官中，给予丁哌卡因和Ca2+通道抑制剂如维拉帕米后观察到心脏抑制作用。
已经意外地发现，左旋丁哌卡因对心脏的作用减小，这不简单地指电生理性质，而且包括机械性质减小。尽管消旋丁哌卡因可能对心脏兼有电生理和机械抑制作用，但没有证据表明这些作用有联系。
尤其，现已发现，在人类中，在旋丁哌卡因对心搏动，加速指数的作用小于消旋丁哌卡因。由于这些是心肌收缩力指数，所以该发现表明左旋丁哌卡因的心脏抑制作用小于丁哌卡因。该发现支持用左旋丁哌卡因作为较安全的长效局麻药用于患心肌收缩力降低或能有心肌收缩力降低倾向的病人，例如，一类患心脏病的病人和伴随使用具有心脏抑制作用的药物或使用具有细胞毒性的药物来治疗的病人。由于同样的原因，在某种外科手术后，当交感神经阻断要求心脏抑制作用最小时，左旋丁哌卡因也可能具有有益的治疗作用。
该止痛剂可以是单一的异构体，但有效地是不含右旋丁哌卡因，例如，其对映体含量至少为80％，更优选至少90％并且最优选至少99％。可使用任何常规性盐，如盐酸盐。
为实现本发明的目的，“心肌收缩力降低”是指病人患有或可能患心衰的程度为纽约心脏协会级别(New York Heart Association Scale)的2,3或4级。按照前面的知识，在有各种伴随心肌收缩力减小治疗指征的病人中，使用丁哌卡因或其异构体可能是禁忌的。在某些人中，心脏的机械力减小是主要的问题。
本发明所涉及的，并且适宜使用左旋丁哌卡因作为止痛剂的特定适应症包括高血压，肾病，病毒性疾病，酒精依赖或效应，严重的局部缺血和糖尿病。本发明也适用于老年和虚弱病人的麻醉，适用于梗塞后，中风、心脏手术或多器官衰竭后及能心肌梗塞后引起的其它危险的稳定。
例如，根据设想的过程，给予可有效利用的左旋丁哌卡因的浓度为0.25％、0.5％或0.75％。可以给予的单次剂量不超过60ml。所使用的给药途径为浸润，硬膜外，脊髓和外周神经阻断。根据麻醉惯例，也可以连续输注低浓度，例如0.125％的含或不含鸦片样物液的止痛剂。这在分娩期间是常见的并且与治疗慢性疼痛时连续输注几天而不是几小时不同。
左旋丁哌卡因相对消旋丁哌卡因另外的好处是它摄人心脏和脑中的量少。因此尤其适用于治疗慢性疼痛。在由本申请人ChiroscienceLimited等以同样题目同一天提出的其它国际专利申请中更充分地描述了这一点，其内容引入本文供参考。
下面提供作为本发明基础的证据。
在健康男性志愿者中，比较左旋丁哌卡因与消旋物(麻卡因)的心血管和中枢神经作用。用双盲交叉方法静脉内给予药物。每种药物的输注速度为10mg/min，并且连续输注至最大量为150mg或在第一次发现CNS作用(包括耳鸣，舌或唇麻木和口干)后停止输注。预先，通过给予试验剂量的利多卡因来确定志愿者局麻引起CNS作用的条件。测定一系列心血管参数，包括收缩期和舒张期血压，ECG，并且利用经胸腔电生物阻抗技术(with a Bo Med NCCOM3-R7)测定主动脉血流，允许测得心脏指数和心搏动指数。根据前面输注消旋丁哌卡因的研究结果可以预测，在给予丁哌卡因后所观察到的主要心血管改变与心肌收缩力有关。因此，用该项新研究测定加速指数(代表开始排出时，加速血流的初始最大值)来估测心肌收缩力。
同消旋物一样，左旋丁哌卡因具有很好的耐受性。所给予左旋丁哌卡因和消旋物的平均总剂量分别为54.0和45.6mg，并且在输液结束时的血浆浓度分别2.384ug/ml和1.87ug/ml(n=12)。尽管左旋丁哌卡因的平均总剂量和血浆浓度较高，但它引起的心脏变量的平均变化却比消旋物小得多。丁哌卡因引起的心肌收缩力指数从1.36S-2到1.18S-2显著减小，减小0.18S-2或13％。左旋丁哌卡因在给予前该值为1.34S-2并且在输液结束时该值只减小到1.28S-2，减小0.06S-2或4.5％。药物治疗之间的差异是非常显著的(P＜0.02,n=12)。心搏动指数(可反映心肌，收缩力变化的参数)的结果是类似的。丁哌卡因将该值从55.3ml/m2减小到44.4ml/m2，减小10.9ml/m2或20％。左旋丁哌卡因在给予前该值为52.4ml/m2并且在输液结束时为49.1ml/m2，减小3.3ml/m2或6％。药物治疗之间的差异在统计学上仍然是非常显著的(P＜0.01,n=12)。在其它变量方面产生的微小变化包括心率和平均血压(增加)以及排出成分和心脏指数(减小)。就加速指数和心搏动指数而言，丁哌卡因引起的变化是更大的。
利用尺骨阻滞技术已进行第二项研究来比较左旋丁哌卡因相对丁哌卡因的功效。在20名志愿者的双盲研究中，比较浓度为0.125％、0.25％和0.5％的左旋丁哌卡因与0.25％的丁哌卡因(体积均为5ml)。数据的初步分析表明，从感觉阻断方面来说，左旋丁哌卡因的功效类似于丁哌卡因，就感觉阻断的持续时间而言，0.25％丁哌卡因与0.25％左旋丁哌卡因类似。
左旋丁哌卡因的这些结果已提供证据，即与现在临床使用的消旋物相比，该局麻药引起人类心脏毒性的可能性较低。根据左旋丁哌卡因具有与丁哌卡因类似的麻醉作用，这表明左旋丁哌卡因将是临床更安全的局麻药。这对产科应用和偶然静脉内注射消旋物可能引起严重后果的巨大血管丛阻断可能尤其重要。另外，这种降低引起心肌抑制的倾向可能有益于心功能受损的病人。
根据用分离的对映体获得的临床前的结果，左旋丁哌卡因减小人类的心脏毒性可能由于对心脏的直接减小作用。然而另外的因素也可能导致心脏毒性减小。最近，其他人已报道，在人类中，丁哌卡因对映体与血浆的立体选择性结合，其中左旋丁哌卡因的血浆结合比右旋丁哌卡因的结合大约高50％。这种较高的结合可能减小偶然血管内给药产生的后果。

Claims (10)

1．利用左旋丁哌卡因或其盐来制备用于患有心肌收缩力降低或可能有心肌收缩力降低倾向的病人的麻醉药物。
2．权利要求1的应用，其中病人患高血压，肾病，心肌梗塞后，局部缺血，糠尿病，病毒或酒精依赖。
3．权利要求1的应用，其中病人已经历心脏手术，多器官衰竭或换瓣，或已安装起搏器。
4．前面任一权利要求的应用，其中病人伴随用心脏抑制药物的治疗。
5．权利要求1的应用，其中病人伴随有使用Ca2+通道阻滞剂来进行抗高血压治疗。
6．权利要求5的应用，其中Ca2+通道阻滞剂为维拉帕米。
7．权利要求1的应用，其中病人伴随用细胞毒性药物治疗。
8．权利要求1的应用，其中在对映体中相对右旋丁哌卡因而言，左旋丁哌卡因的含量至少为90％。
9．左旋丁哌卡因或其盐用于制备用作产科中的麻醉药物。
10．权利要求9的用途，其中相对于右旋丁哌卡因，左旋丁哌卡因至少在对映体中超过90％。
CN94193782A 1993-10-13 1994-10-13 止痛剂及其应用 Expired - Lifetime CN1074920C (zh)

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GB939321061A GB9321061D0 (en) 1993-10-13 1993-10-13 Analgestic agent and its use
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GB9408014.0 1994-04-22
GB9408014A GB9408014D0 (en) 1994-04-22 1994-04-22 Analgesic agent and its use

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EP0727210B1 (en) 2001-12-19
DE69402330D1 (de) 1997-04-30
HK1006420A1 (en) 1999-02-26
JPH09503778A (ja) 1997-04-15
NO961479L (no) 1996-06-11
ATE150643T1 (de) 1997-04-15
PT727210E (pt) 2002-06-28
AU694453B2 (en) 1998-07-23
ES2170179T3 (es) 2002-08-01
US5708011A (en) 1998-01-13
DK0727210T3 (da) 2002-04-15
CN1133010A (zh) 1996-10-09
KR100365979B1 (ko) 2003-07-22
ATE210982T1 (de) 2002-01-15
DE69429536T2 (de) 2002-06-20
NO961479D0 (no) 1996-04-12
EP0723445A1 (en) 1996-07-31

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