CN1249684A - 左布比卡因在面部手术中的用途 - Google Patents
左布比卡因在面部手术中的用途 Download PDFInfo
- Publication number
- CN1249684A CN1249684A CN98802994A CN98802994A CN1249684A CN 1249684 A CN1249684 A CN 1249684A CN 98802994 A CN98802994 A CN 98802994A CN 98802994 A CN98802994 A CN 98802994A CN 1249684 A CN1249684 A CN 1249684A
- Authority
- CN
- China
- Prior art keywords
- chirocaine
- bupivacaine
- patient
- purposes
- medicine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000001356 surgical procedure Methods 0.000 title abstract description 3
- 230000001815 facial effect Effects 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
- 229960004288 levobupivacaine Drugs 0.000 title abstract 2
- 206010002091 Anaesthesia Diseases 0.000 claims abstract description 4
- 230000037005 anaesthesia Effects 0.000 claims abstract description 4
- 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 41
- 239000003814 drug Substances 0.000 claims description 19
- 230000000202 analgesic effect Effects 0.000 claims description 3
- 238000006386 neutralization reaction Methods 0.000 claims 1
- 238000001949 anaesthesia Methods 0.000 abstract 1
- 230000036592 analgesia Effects 0.000 abstract 1
- 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 18
- 229960003150 bupivacaine Drugs 0.000 description 18
- 230000000694 effects Effects 0.000 description 9
- 210000003169 central nervous system Anatomy 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 4
- 229930182837 (R)-adrenaline Natural products 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 229960005139 epinephrine Drugs 0.000 description 4
- 229960004194 lidocaine Drugs 0.000 description 4
- 210000005036 nerve Anatomy 0.000 description 4
- 230000009471 action Effects 0.000 description 3
- 230000002146 bilateral effect Effects 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000902 placebo Substances 0.000 description 3
- 229940068196 placebo Drugs 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 210000000515 tooth Anatomy 0.000 description 3
- 206010048610 Cardiotoxicity Diseases 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 206010029350 Neurotoxicity Diseases 0.000 description 2
- 208000009205 Tinnitus Diseases 0.000 description 2
- 206010044221 Toxic encephalopathy Diseases 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 210000001367 artery Anatomy 0.000 description 2
- 210000005252 bulbus oculi Anatomy 0.000 description 2
- 231100000259 cardiotoxicity Toxicity 0.000 description 2
- 230000007681 cardiovascular toxicity Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 210000001508 eye Anatomy 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 238000002690 local anesthesia Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 210000000214 mouth Anatomy 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 231100000228 neurotoxicity Toxicity 0.000 description 2
- 230000007135 neurotoxicity Effects 0.000 description 2
- 231100000886 tinnitus Toxicity 0.000 description 2
- 206010008479 Chest Pain Diseases 0.000 description 1
- 206010013911 Dysgeusia Diseases 0.000 description 1
- 229920001503 Glucan Polymers 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 230000035606 childbirth Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000002173 dizziness Diseases 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
- 238000000605 extraction Methods 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 210000004195 gingiva Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000004217 heart function Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 210000002698 mandibular nerve Anatomy 0.000 description 1
- 210000002295 maxillary tooth Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000003533 narcotic effect Effects 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 210000003254 palate Anatomy 0.000 description 1
- 208000035824 paresthesia Diseases 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000014860 sensory perception of taste 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
- 230000002269 spontaneous effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000004357 third molar Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
- A61P23/02—Local anaesthetics
-
- 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
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Anesthesiology (AREA)
- Pain & Pain Management (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Magnetic Resonance Imaging Apparatus (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Peptides Or Proteins (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
在人面部手术特别是牙科和眼科手术过程中和之后,用左布比卡因麻醉或止痛。
Description
发明领域
本发明涉及左布比卡因或(S)-1-丁基-N-(2，6-二甲基苯基)-2-哌啶甲酰胺的治疗新用途。
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。
有效、安全、作用时间长的麻醉剂在面部手术中是特别有用的。但是，目前施用用于局部麻醉和手术后止痛的化合物存在具体问题；由于例如眼周围和牙龈中丰富的神经和/或血管，应施用小体积麻醉剂。但这样效力低。因此，需要高浓度药物。
利多卡因被广泛使用，特别是用于牙科。但是该药物有神经毒性。为了产生足够深度的阻滞和足够长的作用时间，通常将利多卡因与肾上腺素同时施用。这会产生其他不利的影响如心悸和晕厥。因此，期待着更安全的药物出现。
发明综述
尽管已表明在特定区域中使用左布比卡因优于布比卡因，但还没有证据表明一般在面部手术，特别是在眼科和牙科方面，左布比卡因是有价值的。本发明是基于左布比卡因是一种有效并特别安全的麻醉剂这一惊人的发现，这也是本发明的目的。具体地讲，左布比卡因的神经毒性低于布比卡因并比利多卡因更安全(当单独给药或与葡聚糖或肾上腺素联用时)。该化合物有血管收缩作用。当给药位点有大量神经和/或血管时，这是非常有用的，因为这样就可以不需要或需要较少的肾上腺素。以临床剂量给药时，副作用降低。发明详述
在本发明方法中，提供左布比卡因溶液用于输注或注射至硬膜外或脊柱空间，或用于通过任何常规装置施用以获得神经或区域阻滞效果。除消旋物常规产生的麻醉阻滞外，左布比卡因还可用于在全身性暴露于药物并因此CNS副作用之危险特别高的身体部位提供阻滞作用。实例包括暴露的伤口和血管部位，例如对于后者要使用脉间阻滞。特别对于眼科应用，可局部施用该化合物。
左布比卡因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，例如0.25％w/v。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1.5％w/v。但是，优选左布比卡因的浓度为0.5％-1％w/v，溶液优选是水溶液。
通常以1-15ml，优选约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25mg，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25-100mg。
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，或更长。当然，可将左布比卡因施用与外消旋药物类型的时间，如3-10小时。左布比卡因对于保持手术后麻醉是特别有用的。
本发明方法在对仅需要手术，而其他情况均正常的患者进行手术时是特别有用的。患者还可患有心或CNS功能低下、易患心或CNS-相关疾病，即CNS阈值低。
根据本发明，在牙科手术，例如拔除智齿时，左布比卡因是适用的。在矫正性的眼科手术如除去白内障的过程中，可将左布比卡因用于眼球周和眼球后的阻滞。
左布比卡因和消旋物可以是等效的，但是左布比卡因可能有优选的特征如对神经血管系统的影响最小并具有良好的血液动力学图象。
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。
已经完成一项研究以比较0.75％左布比卡因与2％利多卡因(与肾上腺素)和安慰剂(0.9％NaCl)作为经历了单侧或双侧阻生的第3磨牙拔除患者的手术后疼痛缓解剂的效力并比较投药的安全性。这是一个单中心的随机的双盲试验。每组有30名随机患者，随机分单侧和双侧拔除。完成肉眼观察的类似级别疼痛记录。记录所有营救投药时间以及阻滞抵消的时间。
对于每个阻生下颌牙，施用2毫升作为下牙槽神经阻滞剂，然后施用1毫升作为口腔浸润。对于每个上颌齿，施用1毫升作为口腔浸润，用0.5ml作为腭浸润。
在经历了单侧或双侧阻生的第3磨牙拔除的患者中，左布比卡因、利多卡因和安慰剂有相似的安全图。但是，将营救投药时间设定为从完成手术到撤销的时间或者对于未进行营救投药的患者设定为48小时，在左布比卡因组中，需要进行第一次营救止痛的平均时间几乎是其他2个处理组的3倍。安慰剂组的中值最小(45分钟)，然后是利多卡因组(55分钟)，但比左布比卡因组(87.5分钟)高很多。左布比卡因组的标准偏差是其他组的约5倍，这是因为在该组中最大营救投药时间是48小时，而其他处理组的最大值在8小时以下。
在进一步的研究中，在经历了眼部动脉段手术的患者中，需进行眼球周围的阻滞，将0.75％左布比卡因与0.75％布比卡因进行比较以确定其相对效力。在阻滞开始的时间上，没有发现显著差异。左布比卡因的相对价值是另一项研究的结果，该研究对健康男性自愿者的QT分散和单平均ECG进行分析以比较0.5％左布比卡因和0.5％外消旋布比卡因的效力。
这项最后的研究包括以10mg/分钟的速度静脉内输注最多达150mg药物，两种药物分别给药。评估包括ECG监测。具体地讲，观察自发NS紊乱(面红)、中枢紊乱(头痛、胸痛)、中枢/外周NS紊乱(头晕、感觉减退、感觉异常)，听力失调(耳鸣)、其他失调(味觉反常)。
用左布比卡因后，观察到外周/中枢神经系统紊乱和听力失调(耳鸣)显著减少。这些症状在使用目前药物(在头和颈手术中，这些药物受到限制)的临床中是常见的。
在下列表中列出了所述事件的总频率。
| 布比卡因0.5％(n＝22) | 布比卡因0.5％(n＝11) | 左布比卡因0.5％(n＝11) | ||||
| n | ％ | n | ％ | n | ％ | |
| 未发生事件的患者 | - | - | 1 | 9 | 4 | 36 |
| 发生一起或多起事件的患者 | 22 | 100 | 10 | 91 | 7 | 64 |
对于接受75毫克以上药物的患者，QT结果是：
75毫克以上布比卡因 0.024
75毫克以上左布比卡因 0.003
P值 0.022
这些结果的重要性还在于说明了下列事实，即对于面部手术，可以施用大的单位剂量，如75毫克或更多，临床上，10毫升0.75％或1％左布比卡因是理想的。
Claims (5)
1.左布比卡因在制备提供人面部手术中和手术后之麻醉或止痛的药物中的用途。
2.权利要求1的用途，其中所述手术是牙科手术。
3.权利要求1的用途，其中所述手术是眼科手术。
4.根据前述任一权利要求的用途，包括施用单剂量左布比卡因。
5.根据权利要求4的用途，其中所述剂量含有至少75毫克左布比卡因。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9704352.5A GB9704352D0 (en) | 1997-03-03 | 1997-03-03 | Levobupivacaine and its use |
| GB9704352.5 | 1997-03-03 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1249684A true CN1249684A (zh) | 2000-04-05 |
| CN1089585C CN1089585C (zh) | 2002-08-28 |
Family
ID=10808603
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98802994A Expired - Lifetime CN1089585C (zh) | 1997-03-03 | 1998-03-03 | 左布比卡因在面部手术中的用途 |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US5919804A (zh) |
| EP (1) | EP0981347B1 (zh) |
| JP (1) | JP2001513812A (zh) |
| KR (1) | KR100516676B1 (zh) |
| CN (1) | CN1089585C (zh) |
| AT (1) | ATE240730T1 (zh) |
| AU (1) | AU730390B2 (zh) |
| BR (1) | BR9808303A (zh) |
| CA (1) | CA2279497C (zh) |
| DE (1) | DE69814851T2 (zh) |
| DK (1) | DK0981347T3 (zh) |
| ES (1) | ES2199423T3 (zh) |
| GB (1) | GB9704352D0 (zh) |
| HK (1) | HK1022651A1 (zh) |
| HU (1) | HU225151B1 (zh) |
| IL (1) | IL131084A0 (zh) |
| NO (1) | NO322446B1 (zh) |
| PL (1) | PL190900B1 (zh) |
| PT (1) | PT981347E (zh) |
| WO (1) | WO1998038996A1 (zh) |
| ZA (1) | ZA981779B (zh) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0998286A2 (en) * | 1997-07-21 | 2000-05-10 | Darwin Discovery Limited | Use of levobupivacaine |
| DK0998287T3 (da) * | 1997-07-22 | 2003-09-01 | Darwin Discovery Ltd | Anvendelse af levobupivacain |
| WO1999025319A1 (en) | 1997-11-14 | 1999-05-27 | Depotech Corporation | Production of multivesicular liposomes |
| ATE428371T1 (de) | 1998-07-17 | 2009-05-15 | Pacira Pharmaceuticals Inc | Biologisch abbaubare anordnungen zur kontrollierten freigabe eingeschlossener substanzen |
| EP1395243A2 (en) * | 2001-05-31 | 2004-03-10 | SkyePharma Inc. | Encapsulation of nanosuspensions in liposomes and microspheres |
| AU2003261304A1 (en) | 2002-07-30 | 2004-02-16 | Omeros Corporation | Ophthalmologic irrigation solutions and method |
| DE10260313A1 (de) * | 2002-12-20 | 2004-07-15 | Siemens Ag | Elektrische Maschine mit Wicklungen aus Litze |
| US20050176823A1 (en) * | 2004-02-10 | 2005-08-11 | Diaz Robert L. | Intra-operative procedure for post-operative pain control |
| AU2013201465B2 (en) | 2012-10-24 | 2016-03-03 | Rayner Surgical (Ireland) Limited | Stable preservative-free mydriatic and anti-inflammatory solutions for injection |
| TWI809304B (zh) | 2014-12-01 | 2023-07-21 | 奥默羅斯公司 | 用於抑制術後眼睛炎性病況的抗炎和散瞳前房溶液 |
| US11278494B1 (en) | 2021-01-22 | 2022-03-22 | Pacira Pharmaceuticals, Inc. | Manufacturing of bupivacaine multivesicular liposomes |
| US11357727B1 (en) | 2021-01-22 | 2022-06-14 | Pacira Pharmaceuticals, Inc. | Manufacturing of bupivacaine multivesicular liposomes |
| US11033495B1 (en) | 2021-01-22 | 2021-06-15 | Pacira Pharmaceuticals, Inc. | Manufacturing of bupivacaine multivesicular liposomes |
| WO2023215604A1 (en) | 2022-05-05 | 2023-11-09 | Pfof Llc | Anesthetic nerve block and method |
| US12070454B1 (en) | 2022-05-05 | 2024-08-27 | Pfof Llc | Anesthetic nerve block and method |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| DE69402330T2 (de) * | 1993-10-13 | 1997-07-03 | Chiroscience Ltd | Analgetisches mittel und dessen verwendung |
| EP0821588B1 (en) * | 1995-04-13 | 2003-06-18 | Darwin Discovery Limited | Levobupivacaine and its use as an anaesthetic in pregnant women |
-
1997
- 1997-03-03 GB GBGB9704352.5A patent/GB9704352D0/en active Pending
-
1998
- 1998-03-03 EP EP98908223A patent/EP0981347B1/en not_active Expired - Lifetime
- 1998-03-03 BR BR9808303-1A patent/BR9808303A/pt not_active Application Discontinuation
- 1998-03-03 HU HU0000873A patent/HU225151B1/hu unknown
- 1998-03-03 AU AU66304/98A patent/AU730390B2/en not_active Expired
- 1998-03-03 WO PCT/GB1998/000657 patent/WO1998038996A1/en active IP Right Grant
- 1998-03-03 DE DE69814851T patent/DE69814851T2/de not_active Expired - Lifetime
- 1998-03-03 CA CA002279497A patent/CA2279497C/en not_active Expired - Lifetime
- 1998-03-03 KR KR10-1999-7007975A patent/KR100516676B1/ko not_active IP Right Cessation
- 1998-03-03 DK DK98908223T patent/DK0981347T3/da active
- 1998-03-03 US US09/033,917 patent/US5919804A/en not_active Expired - Lifetime
- 1998-03-03 JP JP53826998A patent/JP2001513812A/ja active Pending
- 1998-03-03 ES ES98908223T patent/ES2199423T3/es not_active Expired - Lifetime
- 1998-03-03 IL IL13108498A patent/IL131084A0/xx not_active IP Right Cessation
- 1998-03-03 PT PT98908223T patent/PT981347E/pt unknown
- 1998-03-03 AT AT98908223T patent/ATE240730T1/de active
- 1998-03-03 PL PL335561A patent/PL190900B1/pl unknown
- 1998-03-03 ZA ZA981779A patent/ZA981779B/xx unknown
- 1998-03-03 CN CN98802994A patent/CN1089585C/zh not_active Expired - Lifetime
-
1999
- 1999-09-02 NO NO19994257A patent/NO322446B1/no not_active IP Right Cessation
-
2000
- 2000-03-21 HK HK00101738A patent/HK1022651A1/xx not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| NO994257D0 (no) | 1999-09-02 |
| JP2001513812A (ja) | 2001-09-04 |
| GB9704352D0 (en) | 1997-04-23 |
| KR20000075896A (ko) | 2000-12-26 |
| HU225151B1 (en) | 2006-07-28 |
| AU6630498A (en) | 1998-09-22 |
| HUP0000873A2 (hu) | 2000-09-28 |
| WO1998038996A1 (en) | 1998-09-11 |
| BR9808303A (pt) | 2000-05-16 |
| PL335561A1 (en) | 2000-05-08 |
| IL131084A0 (en) | 2001-01-28 |
| HK1022651A1 (en) | 2000-08-18 |
| NO994257L (no) | 1999-11-02 |
| DE69814851D1 (de) | 2003-06-26 |
| ZA981779B (en) | 1999-03-03 |
| US5919804A (en) | 1999-07-06 |
| EP0981347B1 (en) | 2003-05-21 |
| KR100516676B1 (ko) | 2005-09-22 |
| CA2279497C (en) | 2009-01-20 |
| CN1089585C (zh) | 2002-08-28 |
| EP0981347A1 (en) | 2000-03-01 |
| HUP0000873A3 (en) | 2002-10-28 |
| NO322446B1 (no) | 2006-10-09 |
| ATE240730T1 (de) | 2003-06-15 |
| PT981347E (pt) | 2003-09-30 |
| AU730390B2 (en) | 2001-03-08 |
| DE69814851T2 (de) | 2004-01-22 |
| ES2199423T3 (es) | 2004-02-16 |
| DK0981347T3 (da) | 2003-09-15 |
| PL190900B1 (pl) | 2006-02-28 |
| CA2279497A1 (en) | 1998-09-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1089585C (zh) | 左布比卡因在面部手术中的用途 | |
| Blanton et al. | Avoiding complications in local anesthesia induction: anatomical considerations | |
| DE60126265T2 (de) | Zusammensetzung bestehend aus Phentolaminmesylat und deren Verwendung | |
| US5849763A (en) | Use of levobupivacaine as an anesthetic agent | |
| Yalcin | Complications associated with local anesthesia in oral and maxillofacial surgery | |
| DE69934305T2 (de) | Verwendung von dexmedetomidine zur sedierung auf der intensivstation | |
| KR100535554B1 (ko) | 소아과 수술에서의 레보부피바카인의 용도 | |
| EP1731149A1 (en) | Use of 2-oxo-1-pyrrolidone derivatives for the treatment of diseases characterized by progressive myoclonic epilepsy | |
| CN1128620C (zh) | 左布比卡因在制备治疗偏头痛的药物中的用途 | |
| JPS5910585A (ja) | スピロスクシンイミド誘導体のアルツハイマ−型痴「ほう」の治療における使用 | |
| Owen-Falkenberg et al. | Continuous stellate ganglion blockade for reflex sympathetic dystrophy | |
| HU214629B (hu) | Eljárás műtét utáni hányinger és hányás kezelésére szolgáló gyógyszerkészítmény előállítására | |
| JPH09500620A (ja) | 極小の運動遮断で鎮痛効果を示す医薬の製造におけるロピバカインの使用 | |
| DE60117541T2 (de) | Candesartan zur Behandlung von Migräne | |
| White et al. | Evidence indicating central atropine-like actions of psychotogenic piperidyl benzilates | |
| DE10293600B4 (de) | Rezeptoradaptierter Nikotinentzug durch anticholinerge und noradrenerge Blockade | |
| Choudhary et al. | Effectiveness of Articaine, Single Buccal Infiltration Versus Lidocaine, Conventional Buccal and Palatal Infiltration in Maxillary Local Anesthesia: A Comparative Clinical Study | |
| Mahinrad | Complications and techniques of local anesthesia in oral and maxillofacial surgery | |
| MXPA99008055A (es) | Uso de levobupivacaina en cirugia facial | |
| RU2180847C1 (ru) | Способ лечения начальных клинических проявлений эссенциальной артериальной гипертензии в условиях дневного стационара | |
| GB2602123A (en) | Composition for procedural sedation and use thereof | |
| DE3348444C2 (de) | Analgetische und antiinflammatorische Mittel | |
| Singh | Understanding and Evaluating the Role of Local Anaesthesia in Dentistry: A Brief Review | |
| Uddin et al. | Comparison of Ondansetron and Granisetron for prevention of PONV following elective LUCS | |
| HU210322B (en) | Process for production of preparations containing ropivacaine for treatment of iontophoresis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| C10 | Entry into substantive examination | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CX01 | Expiry of patent term |
Granted publication date: 20020828 |
|
| CX01 | Expiry of patent term |