[go: up one dir, main page]

WO1998038997A1 - Utilisation de la levobupivacaine en association avec des opioides ou des alfa2-agonistes comme anesthesiants ou analgesiques - Google Patents

Utilisation de la levobupivacaine en association avec des opioides ou des alfa2-agonistes comme anesthesiants ou analgesiques Download PDF

Info

Publication number
WO1998038997A1
WO1998038997A1 PCT/GB1998/000658 GB9800658W WO9838997A1 WO 1998038997 A1 WO1998038997 A1 WO 1998038997A1 GB 9800658 W GB9800658 W GB 9800658W WO 9838997 A1 WO9838997 A1 WO 9838997A1
Authority
WO
WIPO (PCT)
Prior art keywords
levobupivacaine
another drug
analgesia
combination
fentanyl
Prior art date
Application number
PCT/GB1998/000658
Other languages
English (en)
Inventor
Brian Albert Gennery
Original Assignee
Darwin Discovery Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Darwin Discovery Limited filed Critical Darwin Discovery Limited
Priority to AU66305/98A priority Critical patent/AU6630598A/en
Publication of WO1998038997A1 publication Critical patent/WO1998038997A1/fr

Links

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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine

Definitions

  • This invention relates to a new formulation and a new use for levobupivacaine or (S)- 1 -butyl-N-(2, 6-dimethylphenyl)-2-piperidinecarboxamide.
  • Racemic bupivacaine is an effective long-acting local anaesthetic, and may be given as an epidural. However, racemic bupivacaine is cardiotoxic, having depressant electrophysiological and mechanical effects on the heart. It should therefore be used with caution in cardiac-compromised patients, and the use of high doses and high concentrations is contraindicated.
  • bupivacaine has produced death in a number of patients, including women in childbirth and when used in the Bier's block technique. Although the incidence of death has been relatively small, the concern has been sufficient to stop the use of 0.75% bupivacaine for obstetrics and the proscribing of bupivacaine for use in Bier's blocks.
  • CNS central nervous system
  • levobupivacaine is less cardiotoxic than dextrobupivacaine and racemic bupivacaine. See, for example, Vanhoutte et al, Br. J. Pharmacol.103 : 1275- 1281 ( 1991 ), and Denson et al, Regional Anaesthesia, 17:311-316
  • levobupivacaine is an effective and especially safe anaesthetic, in combination with another drug, i.e. an opioid or ⁇ 2-agonist, e.g. an agent selected from morphine, fentanyl and clonidine. Synergy between these drugs allows for the amount of either or each to be reduced, e.g. below conventional dosing.
  • another drug i.e. an opioid or ⁇ 2-agonist, e.g. an agent selected from morphine, fentanyl and clonidine.
  • levobupivacaine may be provided in solution, for infusion or injection into the epidural or spinal space, or for administration by any of the conventional means for obtaining a nerve or field block.
  • levobupivacaine may also be useful in providing blocks in areas of the body where the risk of systemic exposure to the drug, and therefore CNS side-effects, is particularly high. Examples include open wounds and vascular areas, for instance using intercostal blocks for the latter. For upper limb surgery at least, infusion into the body near the base of the limb may be appropriate. A regional or plexus block may also be used.
  • Levobupivacaine may be continuous or bolus administration. This may be done using conventional apparatus, e.g. including means for the patient to induce infusion as desired.
  • the daily dose administered to the patient may be in the relatively low range known for the administration of racemic bupivacaine, but, because of the decreased CNS side-effects of levobupivacaine, may be higher than the conventional dose for the racemic drug.
  • the total dose of levobupivacaine may be around, or in excess of, 2 mg per kg of patient body weight.
  • the concentration of levobupivacaine to be given can be that conventionally used for the racemic drug, e.g. from 0.25% w/v and typically about 0.5% w/v.
  • the amounts of levobupivacaine and of the other drug can each be lower than they would be if administered independently. True synergy may be seen.
  • the dosage of fentanyl or morphine can be halved, and 0.125% or 0.0625% w/v levobupivacaine can be used.
  • the solution of levobupivacaine is preferably aqueous.
  • the solution may typically be put up in unit doses of from 1 to 15 ml, and preferably of around 10 ml.
  • the unit doses may be higher, for instance up to 40 ml or higher.
  • the unit doses may be in the form of ampoules, which may be made of any suitable material, e.g. glass or an appropriately impervious plastics material.
  • Unit dosages comprising at least 75 mg, but preferably less than 200 mg, of levobupivacaine can be administered, and more preferably the unit dosage is in the range 80 to 150 mg.
  • the administration of levobupivacaine over a range of concentrations, including those currently used for the racemic drug and the higher concentrations described above, can be carried out for significantly longer periods than at present, again as a result of the reduced CNS side-effects experienced with levobupivacaine.
  • levobupivacaine can be administered to a patient safely for at least 24 hours, often up to 72 hours, and even for periods of up to a week or a fortnight, or longer. It can, of course, be administered for similar periods already used for the racemic drug, e.g. between 3 and 6 hours. Levobupivacaine may be particularly valuable for the maintenance of post-operative analgesia, e.g. over the period 8-24 hours after surgery.
  • the method of the present invention is particularly useful in surgical procedures carried out on patients who merely require surgery, and are otherwise healthy.
  • the patient may also be cardiac or CNS-compromised, or predisposed to cardiac or CNS- related conditions, i.e. having a low CNS threshold.
  • the levobupivacaine is substantially free of dextrobupivacaine, i.e. preferably in at least 90%, and most preferably at least 99%, enantiomeric excess.
  • reference to bupivacaine and its enantiomers includes pharmaceutically-acceptable salts thereof.
  • the other drug that is used in the invention may be formulated together with, or independently from, the levobupivacaine. It may be formulated in a manner that is already known for that drug.
  • the drugs may be administered sequentially or simultaneously, according to need. In one preferred embodiment, a mixture, e.g. a solution, of both drugs is administered.
  • the other drug is chosen for its ability to complement the utility of levobupivacaine, especially in post-operative pain control.
  • examples of such other drugs are opioids and ⁇ 2-agonists such as morphine, clonidine, fentanyl, alfentanyl, remifentanyl, diamorphone and dexmedetomidate.
  • the utility of the combination may be in any of the uses already described for levobupivacaine. See also the other Applications also filed 3rd March 1998, in the same name.
  • Efficacy The median time to first verbal request for rescue, the primary efficacy study endpoint, was approx. 3 times shorter (8 h) for the combination than the time (24 h) for single drug. Fewer patients in the combination arm than in the morphine alone arm requested any rescue analgesia. Compared to patients in the morphine treatment group, significantly fewer patients in the combination arm requested ketorolac.
  • Safety The 0.25% levobupivacaine/0.005% morphine combination was generally well tolerated and was associated with fewer study drug related adverse events than levobupivacaine or morphine alone. Cardiovascular adverse events reported were primarily reports of hypotension with similar incidence across treatment arms.
  • Clonidine was administered as a continuous infusion at a concentration of 50 ⁇ g.h "1 or in combination with 0.125% levobupivacaine, also at a concentration of 50 ⁇ g.h "1 given over 24 h.
  • Efficacy For the primary efficacy variable, i.e. the total dose of morphine administered, the greatest difference was seen between the levobupivacaine treatment group and the levobupivacaine plus clonidine group (the levobupivacaine alone group requested a median of 23 mg more), with a p-value of ⁇ 0.001. An analysis using the per-protocol population confirmed this assessment.

Landscapes

  • Health & Medical Sciences (AREA)
  • Emergency Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé pour fournir un anesthésiant ou un analgésique à l'homme. Ce procédé consiste à administrer simultanément, séparément ou en séquence de la lévobupivacaïne et également un autre produit sélectionné dans le groupe se composant d'opioïdes et d'α-2 agonistes.
PCT/GB1998/000658 1997-03-03 1998-03-03 Utilisation de la levobupivacaine en association avec des opioides ou des alfa2-agonistes comme anesthesiants ou analgesiques WO1998038997A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU66305/98A AU6630598A (en) 1997-03-03 1998-03-03 Use of levobupivacaine in combination with opiods or alfa2-agonists for providing anaesthesia or analgesia

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9704370.7A GB9704370D0 (en) 1997-03-03 1997-03-03 Levobupivacaine and its use
GB9704370.7 1997-03-03

Publications (1)

Publication Number Publication Date
WO1998038997A1 true WO1998038997A1 (fr) 1998-09-11

Family

ID=10808616

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1998/000658 WO1998038997A1 (fr) 1997-03-03 1998-03-03 Utilisation de la levobupivacaine en association avec des opioides ou des alfa2-agonistes comme anesthesiants ou analgesiques

Country Status (4)

Country Link
AU (1) AU6630598A (fr)
GB (1) GB9704370D0 (fr)
WO (1) WO1998038997A1 (fr)
ZA (1) ZA981782B (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000023066A3 (fr) * 1998-10-20 2001-08-23 Omeros Med Sys Inc Solution d'irrigation et procede d'inhibition de la douleur et de l'inflammation
US7091181B2 (en) 1994-12-12 2006-08-15 Omeros Corporation Method of inhibition of pain and inflammation during surgery comprising administration of soluble TNF receptors
EP1563838A3 (fr) * 1998-10-20 2009-11-04 Omeros Corporation Solution d'irrigation et méthodes pour inhiber la douleur et l'inflammation
US7973068B2 (en) 1998-10-20 2011-07-05 Omeros Corporation Arthroscopic irrigation solution and method for peripheral vasoconstriction and inhibition of pain and inflammation
US9254271B2 (en) 1998-10-20 2016-02-09 Omeros Corporation Arthroscopic irrigation solution and method for peripheral vasoconstriction and inhibition of pain and inflammation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995010276A1 (fr) * 1993-10-13 1995-04-20 Chiroscience Limited Levobupivacaine utilisee dans le traitement de la douleur chronique
WO1995010277A1 (fr) * 1993-10-13 1995-04-20 Chiroscience Limited Agent analgesique et son utilisation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995010276A1 (fr) * 1993-10-13 1995-04-20 Chiroscience Limited Levobupivacaine utilisee dans le traitement de la douleur chronique
WO1995010277A1 (fr) * 1993-10-13 1995-04-20 Chiroscience Limited Agent analgesique et son utilisation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GRISTWOOD R ET AL: "REDUCED CARDIOTOXICITY OF LEVOBUPIVACAINE COMPARED WITH RACEMIC BUPIVACAINE (MARCAINE): NEW CLINICAL EVIDENCE", EXPERT OPINION ON INVESTIGATIONAL DRUGS, vol. 3, no. 11, November 1994 (1994-11-01), pages 1209 - 1212, XP000610836 *
M.BARTH ET AL: "EFFECTS OF APPLICATION OF I.V. WITH LOAL ANAESTHESIA ON CHRONIC PAIN SYNDROMES, ESPECIALLY HEADACHE AND MIGRAINE", PAIN, 1984, AMSTERDAM, THE NETHERLANDS, pages S269, XP002068058 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7091181B2 (en) 1994-12-12 2006-08-15 Omeros Corporation Method of inhibition of pain and inflammation during surgery comprising administration of soluble TNF receptors
WO2000023066A3 (fr) * 1998-10-20 2001-08-23 Omeros Med Sys Inc Solution d'irrigation et procede d'inhibition de la douleur et de l'inflammation
EP1563838A3 (fr) * 1998-10-20 2009-11-04 Omeros Corporation Solution d'irrigation et méthodes pour inhiber la douleur et l'inflammation
US7973068B2 (en) 1998-10-20 2011-07-05 Omeros Corporation Arthroscopic irrigation solution and method for peripheral vasoconstriction and inhibition of pain and inflammation
US8450309B2 (en) 1998-10-20 2013-05-28 Omeros Corporation Arthroscopic irrigation solution and method for peripheral vasoconstriction and inhibition of pain and inflammation
US9254271B2 (en) 1998-10-20 2016-02-09 Omeros Corporation Arthroscopic irrigation solution and method for peripheral vasoconstriction and inhibition of pain and inflammation

Also Published As

Publication number Publication date
AU6630598A (en) 1998-09-22
ZA981782B (en) 1999-03-03
GB9704370D0 (en) 1997-04-23

Similar Documents

Publication Publication Date Title
US5849763A (en) Use of levobupivacaine as an anesthetic agent
CA2294921C (fr) Levobupivacine et son utilisation
US5910502A (en) Use of levobupivacaine in paediatric surgery
AU730390B2 (en) The use of levobupivacaine in facial surgery
AU731127B2 (en) The use of levobupivacaine or ropivacaine in treating migraine
JP3792251B2 (ja) 手術後の悪心および嘔吐の治療のためのグラニセトロンの使用
WO1998038997A1 (fr) Utilisation de la levobupivacaine en association avec des opioides ou des alfa2-agonistes comme anesthesiants ou analgesiques
AU5339596A (en) Levobupivacaine and its use as an anaesthetic in pregnant women
CZ283300B6 (cs) Použití ropivakcinu pro výrobu farmaceutického prostředku s analgetickou účinností s minimální motorickou blokádou
US6784194B2 (en) Therapeutic use of a thienylcyclohexylamine derivative
GB2189703A (en) Vinpocetine
HK1022649B (en) The use of levobupivacaine in paediatric surgery
MXPA99008056A (en) The use of levobupivacaine or ropivacaine in treating migraine
HK1022651B (en) The use of levobupivacaine in facial surgery

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM GW HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

NENP Non-entry into the national phase

Ref country code: JP

Ref document number: 1998538270

Format of ref document f/p: F

NENP Non-entry into the national phase

Ref country code: CA

122 Ep: pct application non-entry in european phase