CN1249685A - 左布比卡因或罗哌卡因在治疗偏头痛中的用途 - Google Patents
左布比卡因或罗哌卡因在治疗偏头痛中的用途 Download PDFInfo
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- 229960001549 ropivacaine Drugs 0.000 title claims abstract description 10
- 208000019695 Migraine disease Diseases 0.000 title abstract description 8
- 206010027599 migraine Diseases 0.000 title abstract description 8
- 229960004288 levobupivacaine Drugs 0.000 title abstract 2
- LEBVLXFERQHONN-INIZCTEOSA-N levobupivacaine Chemical compound CCCCN1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-INIZCTEOSA-N 0.000 title abstract 2
- SIEYLFHKZGLBNX-NTISSMGPSA-N levobupivacaine hydrochloride (anhydrous) Chemical compound [Cl-].CCCC[NH+]1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C SIEYLFHKZGLBNX-NTISSMGPSA-N 0.000 claims description 27
- 239000003814 drug Substances 0.000 claims description 12
- LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 description 23
- 229960003150 bupivacaine Drugs 0.000 description 23
- 230000000694 effects Effects 0.000 description 10
- 229940079593 drug Drugs 0.000 description 9
- 210000003169 central nervous system Anatomy 0.000 description 5
- 238000011160 research Methods 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
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- 238000012360 testing method Methods 0.000 description 3
- 206010048610 Cardiotoxicity Diseases 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 231100000259 cardiotoxicity Toxicity 0.000 description 2
- 230000007681 cardiovascular toxicity Effects 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
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- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
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- 206010010774 Constipation Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 206010019468 Hemiplegia Diseases 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010034960 Photophobia Diseases 0.000 description 1
- 208000001407 Vascular Headaches Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000035606 childbirth Effects 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000007831 electrophysiology Effects 0.000 description 1
- 238000002001 electrophysiology Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000004217 heart function Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000002690 local anesthesia Methods 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000003533 narcotic effect Effects 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 206010030875 ophthalmoplegia Diseases 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- GOLXNESZZPUPJE-UHFFFAOYSA-N spiromesifen Chemical compound CC1=CC(C)=CC(C)=C1C(C(O1)=O)=C(OC(=O)CC(C)(C)C)C11CCCC1 GOLXNESZZPUPJE-UHFFFAOYSA-N 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- 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
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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
- A61P25/06—Antimigraine agents
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Abstract
用左布比卡因或罗哌卡因治疗偏头痛。
Description
发明领域
本发明涉及罗哌卡因和左布比卡因的治疗新用途。
发明背景
外消旋布比卡因是一种有效的长效局部麻醉药，并可硬膜外给药。但是，外消旋布比卡因是心脏毒性的，对心脏有抑制性电生理学或机械作用。因此，在心脏功能低下患者中应谨慎使用，而且禁止使用高剂量和高浓度。
具体地讲，布比卡因已在许多患者包括分娩妇女中引起死亡，并且当用于Bier’s阻滞技术时也会引起死亡。尽管死亡率相对不高，但是已足以引起注意而停止将0.75％布比卡因用于产科学并禁止将布比卡因用于Bier’s阻滞。
另外，在较高剂量时，由于其直接作用于神经系统的作用方式，已知布比卡因有不利的中枢神经系统(CNS)副作用，初步认为所述副作用与其麻醉活性有关。事实上，CNS副作用的出现是限制这种药物用于使用如局部浸润、神经传导阻滞、区域阻滞、硬膜外和脊柱阻滞技术之正常临床实践的一个主要因素。
已经表明左布比卡因的心脏毒性低于右旋布比卡因和外消旋布比卡因。参见，例如Vanhoutte等，英国药物学杂志(Br.J.Pharmacol.)103：1275-1281(1991)，和Denson等，局部麻醉(RegionalAnaesthesia)17：311-316(1992)。但是这些报告是以体外研究为基础的，而且不能必然推断至任何哺乳动物，当然也不能推断至人。
在WO-A-9510276、WO-A-9510277和Gristwood等药物开发与研究(Exp.Opin.Invest.Drugs)3(11)：1209-12(1994)中首次证明了左布比卡因在人体内的令人惊奇和有效的实用性。
通过输注0.2mg/kg的布比卡因已检测了治疗多偏头痛的效果。有一定程度的缓解。参见疼痛(Pain)(1984)，Suppl.2S269。这种可能性尚未得到进一步证实。
发明综述
尽管以前已表明在特定领域使用左布比卡因优于布比卡因，但是，没有证据表明它可用于治疗偏头痛。本发明是基于令人惊奇的发现左布比卡因和罗哌卡因是用于该目的的有效药物。
发明描述
在本说明书中，按Dorland’s Illustrated Medical Dictionary，27th Edition所述定义偏头痛，即一种周期性发作的家族性血管性头痛，通常暂时和一侧发作，并通常与易怒、恶心、呕吐、便秘、腹泻、畏光有关；发作前颅动脉收缩，通常产生前驱感觉性(特别是眼的)症状，并随之而发生血管舒张。可将偏头痛分成各种具体类型，包括腹型，无头型、急性精神混乱型、基底型、典型的、普通型、并发型、闪电状、Harris型、偏瘫型、眼型和眼肌麻痹型。
通过这两种药物之一或两种药物(它们是化学同系物)均可作为体外5HT1受体激动剂，或者在任何其他偏头痛体外试验中有治疗作用或者在偏头痛动物模型中有治疗偏头痛的作用而说明了治疗偏头痛的活性。适宜的模型用于下文所述的研究中。
在本发明方法中，可提供左布比卡因或罗哌卡因溶液用于如静脉内输注，或装置如滴眼液、滴鼻剂/喷雾剂，真皮内贴剂，注射，或者任何浸润制剂，外周或中枢给药，如局部、皮下或硬膜外给药。还可利用经口或直肠给药。
左布比卡因或罗哌卡因给药可以是连续给药或快速浓注给药。所述给药可利用常规装置如按需要给患者进行输注的装置来完成。给患者施用的每日剂量可相对低于施用外消旋布比卡因的剂量范围，但是由于左布比卡因的CNS副作用降低，所述每日剂量可高于外消旋药物的常规剂量。左布比卡因的总剂量为大约2mg/kg患者体重，或超过2mg/kg患者体重。
所施用的左布比卡因浓度可以是外消旋药物所用的常规浓度。但是，本发明药物的浓度通常比常规浓度高，例如至少0.75％w/v，并可高达2％w/v。但是，优选左布比卡因的浓度为0.8％-1.5％w/v，更优选使用1％、1.25％或1.5％w/v。溶液优选是水溶液。
通常以1-15ml，优选10毫升的单位剂量分装溶液。但是，单位剂量可更高，例如高达40毫升或更高。单位剂量可以是安瓿形式，所述安瓿可以用任何适宜的材料例如玻璃或适宜的不透性塑料材料制成，可施用含至少75mg，但优选低于200mg左布比卡因的单位剂量，更优选的单位剂量为80-150mg。
同样由于左布比卡因所产生的CNS副作用降低，因此，在显著长于目前的时间的时期内可施用高于目前用于外消旋药物浓度或上述更高浓度的左布比卡因。例如，可给患者安全施用左布比卡因至少24小时，常常高达72小时，甚至达一星期或两星期，或者更长的时间。当然，可将左布比卡因以与外消旋药物类似的时间施用，如0.5-6小时。
为了达到本发明目的，所述左布比卡因基本上不含右旋布比卡因，即左布比卡因至少为90％，最佳至少为99％对映体过量。在本发明说明书中，布比卡因和其对映体包括其可药用盐。
罗哌卡因可代替左布比卡因，后者已在上文讨论过。
为了比较左布比卡因、布比卡因和右旋布比卡因使人分离的脑血管平滑肌收缩的能力，进行了一项研究。更具体地讲，该项研究研究了左布比卡因、布比卡因和右旋布比卡因对离体人脑动脉环的基础紧张性的影响，每个化合物用来自三个不同供体的组织进行一式两份的试验。
将来自各供体的8种制备物以累积的方式用血栓烷A2模拟物(1nM-1μM)给药。所有制备物均以浓度-依赖方式通过收缩产生反应。
在来自各供体的两个不同制备物中，以1nM-10μM的浓度得到累积的浓度-效应曲线。受试化合物的最大剂量后，用所有制备物进一步得到浓度-效应曲线。用来自各供体的两种剩余制备物中，在不存在受试化合物的条件下得到第二浓度-效应曲线。
在来自三个供体的六份制备物中，布比卡因或右旋布比卡因甚至在浓度为10μM时，对基础紧张度没有显著影响。但是，对于左布比卡因，在浓度为10μM时，有明显的小的收缩。
存在布比卡因或右旋布比卡因的条件下，对于未用试验化合物处理的制备物，对TXA2模拟物的第二浓度-效应曲线与第一曲线没有显著差异。但是，在用左布比卡因处理的组织中，对模拟物的最大反应有适当的增加。
这些结果表明尽管布比卡因和右旋布比卡因对人分离的脑血管平滑肌的基础紧张度没有作用，或对TXA2模拟物没有反应，但是，左布比卡因却可增加基础紧张度并对随后施用的模拟物起反应。在该模型的基础上，左布比卡因在偏头痛的治疗中有有益的令人惊奇的特性。通过与同其相反对映体及其以外消旋形式混合的化合物相比，预期罗哌卡因也有这些特性。
Claims (1)
1.左布比卡因或罗哌卡因用于制备治疗偏头痛的药物的用途。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9704349.1A GB9704349D0 (en) | 1997-03-03 | 1997-03-03 | Levobupivacaine and its use |
| GB9704349.1 | 1997-03-03 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1249685A true CN1249685A (zh) | 2000-04-05 |
| CN1128620C CN1128620C (zh) | 2003-11-26 |
Family
ID=10808600
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98802995A Expired - Lifetime CN1128620C (zh) | 1997-03-03 | 1998-03-03 | 左布比卡因在制备治疗偏头痛的药物中的用途 |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US6019994A (zh) |
| EP (1) | EP0967979A1 (zh) |
| JP (1) | JP2001515479A (zh) |
| KR (1) | KR20000075895A (zh) |
| CN (1) | CN1128620C (zh) |
| AU (1) | AU731127B2 (zh) |
| BR (1) | BR9808299A (zh) |
| CA (1) | CA2280135A1 (zh) |
| GB (1) | GB9704349D0 (zh) |
| HU (1) | HUP0000756A3 (zh) |
| IL (1) | IL131085A0 (zh) |
| NO (1) | NO994258L (zh) |
| PL (1) | PL335562A1 (zh) |
| WO (1) | WO1998038998A1 (zh) |
| ZA (1) | ZA981781B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106214670A (zh) * | 2016-07-25 | 2016-12-14 | 上海璃道医药科技有限公司 | 酰胺类药物的新用途 |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4521117B2 (ja) * | 1997-07-21 | 2010-08-11 | ブルース・エイチ・レヴィン | 偏頭痛、群発性頭痛、緊張性頭痛、血管疾患に伴う頭痛、耳鳴りまたは筋肉性頭痛を治療するための医薬 |
| US7799337B2 (en) | 1997-07-21 | 2010-09-21 | Levin Bruce H | Method for directed intranasal administration of a composition |
| US6491940B1 (en) | 1999-01-27 | 2002-12-10 | Bruce H. Levin | Apparatus for administering composition for inhibiting cerebral neurovascular disorders and muscular headaches |
| US6432986B2 (en) | 1997-07-21 | 2002-08-13 | Bruce H. Levin | Compositions, kits, and methods for inhibiting cerebral neurovascular disorders and muscular headaches |
| AU2100901A (en) * | 1999-12-15 | 2001-06-25 | Bruce H. Levin | Compositions, kits, apparatus, and methods for inhibiting cephalic inflammation |
| US20070225781A1 (en) * | 2006-03-21 | 2007-09-27 | Nidus Medical, Llc | Apparatus and methods for altering temperature in a region within the body |
| DE102008037682A1 (de) * | 2008-08-14 | 2010-04-08 | Strackharn, Klaus, Dr.med. | Verwendung äquipotenter Dosierungen von Lokalanästetika oder Derivaten davon zur Therapie chronischer Schmerzen |
| CA2873138A1 (en) * | 2012-05-10 | 2013-11-14 | Cellixbio Private Limited | Compositions and methods for the treatment of local pain |
| WO2023215604A1 (en) | 2022-05-05 | 2023-11-09 | Pfof Llc | Anesthetic nerve block and method |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2135673A (en) * | 1983-02-25 | 1984-09-05 | Raychem Ltd | Curable fabric |
| US4695576A (en) * | 1984-07-09 | 1987-09-22 | Astra Lake Medel Aktiebolag | L-N-n-propylpipecolic acid-2,6-xylidide |
| GB9321061D0 (en) * | 1993-10-13 | 1993-12-01 | Chiroscience Ltd | Analgestic agent and its use |
| HU224226B1 (hu) * | 1995-04-13 | 2005-06-28 | Darwin Discovery Limited | Levobupivacaine alkalmazása terhesség esetén használható érzéstelenítő hatású gyógyszerkészítmény előállítására |
| GB2315673A (en) * | 1996-08-01 | 1998-02-11 | Merck & Co Inc | Treatment of migraine |
| JP4521117B2 (ja) * | 1997-07-21 | 2010-08-11 | ブルース・エイチ・レヴィン | 偏頭痛、群発性頭痛、緊張性頭痛、血管疾患に伴う頭痛、耳鳴りまたは筋肉性頭痛を治療するための医薬 |
-
1997
- 1997-03-03 GB GBGB9704349.1A patent/GB9704349D0/en active Pending
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1998
- 1998-03-03 IL IL13108598A patent/IL131085A0/xx unknown
- 1998-03-03 CA CA002280135A patent/CA2280135A1/en not_active Abandoned
- 1998-03-03 WO PCT/GB1998/000662 patent/WO1998038998A1/en not_active Application Discontinuation
- 1998-03-03 US US09/034,081 patent/US6019994A/en not_active Expired - Lifetime
- 1998-03-03 AU AU66308/98A patent/AU731127B2/en not_active Expired
- 1998-03-03 KR KR1019997007974A patent/KR20000075895A/ko not_active Application Discontinuation
- 1998-03-03 EP EP98908228A patent/EP0967979A1/en not_active Withdrawn
- 1998-03-03 CN CN98802995A patent/CN1128620C/zh not_active Expired - Lifetime
- 1998-03-03 BR BR9808299-0A patent/BR9808299A/pt not_active Application Discontinuation
- 1998-03-03 PL PL98335562A patent/PL335562A1/xx unknown
- 1998-03-03 JP JP53827498A patent/JP2001515479A/ja active Pending
- 1998-03-03 ZA ZA981781A patent/ZA981781B/xx unknown
- 1998-03-03 HU HU0000756A patent/HUP0000756A3/hu not_active Application Discontinuation
-
1999
- 1999-09-02 NO NO994258A patent/NO994258L/no not_active Application Discontinuation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106214670A (zh) * | 2016-07-25 | 2016-12-14 | 上海璃道医药科技有限公司 | 酰胺类药物的新用途 |
| CN106214670B (zh) * | 2016-07-25 | 2020-12-29 | 上海璃道医药科技有限公司 | 酰胺类药物的用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1128620C (zh) | 2003-11-26 |
| WO1998038998A1 (en) | 1998-09-11 |
| HUP0000756A2 (hu) | 2000-10-28 |
| IL131085A0 (en) | 2001-01-28 |
| NO994258D0 (no) | 1999-09-02 |
| GB9704349D0 (en) | 1997-04-23 |
| JP2001515479A (ja) | 2001-09-18 |
| AU6630898A (en) | 1998-09-22 |
| EP0967979A1 (en) | 2000-01-05 |
| HUP0000756A3 (en) | 2000-12-28 |
| KR20000075895A (ko) | 2000-12-26 |
| PL335562A1 (en) | 2000-05-08 |
| CA2280135A1 (en) | 1998-09-11 |
| BR9808299A (pt) | 2002-05-21 |
| ZA981781B (en) | 1999-03-03 |
| AU731127B2 (en) | 2001-03-22 |
| US6019994A (en) | 2000-02-01 |
| NO994258L (no) | 1999-11-02 |
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