CA2173207C - Levobupivacaine and its use as an anaesthetic in patients having or disposed to depressed myocardial contractility - Google Patents
Levobupivacaine and its use as an anaesthetic in patients having or disposed to depressed myocardial contractility Download PDFInfo
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- CA2173207C CA2173207C CA002173207A CA2173207A CA2173207C CA 2173207 C CA2173207 C CA 2173207C CA 002173207 A CA002173207 A CA 002173207A CA 2173207 A CA2173207 A CA 2173207A CA 2173207 C CA2173207 C CA 2173207C
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- levobupivacaine
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- anaesthetic
- myocardial contractility
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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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- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
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- General Health & Medical Sciences (AREA)
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Abstract
Levobupivacaine is useful as an anaesthetic in a human patient having or dis posed to depressed myocardial contractility.
Description
'. CA 02173207 2005-05-09 LSVOBUPIVACAINS AND ITS US$ As AN ANA$STHBTIC IN PATI$NTS HAVING
Field of the Inv'ention This invention relates to a new therapeutic use for a known analgesic agent, i.e. bupivacaine or 1-butyl-N-(2,6 dimethylphenyl)-2-piperidinecarboxamide.
~acl~qround of the Invention 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.
It is known that levobupivacaine is probably less cardiotoxic than dexbupivacaine and racemic bupivacaine.
See, for example, Vanhoutte _e~ a~, Br. J. Pharmacol.
,~0~:1275-1281 (1991), and Denson et a~, Regional Anaesthesia, x:311-316 (1992). Vanhoutte et al studied the effects of bupivacaine enantiomers on the electrophysiological properties of guinea pig isolated papillary muscle; this is based on their statement that nthe cardiotoxicity of bupivacaine seems to be mainly of electrophysiological origin".
Many patients who require analgesics are undergoing concomitant therapy with other drugs, e.g. anti hypertensive agents. Many such drugs are cardio depressant. In particular, it has recently been reported that cardio-depressant effects are observed in isolated organs, following administrations of bupivacaine and CaZ
channel inhibitors such as verapamil.
summ_~y of the Inv~;Iti ion Surprisingly, it has been found that the effect of levobupivacaine on the heart is reduced, in respect not simply of electrophysiological properties, but also mechanical properties. Although racemic bupivacaine may have both electrophysiological and mechanical depressant effects on the heart, there is no evidence to suggest that these effects are linked.
WO 95110277 ~ '~ PCT/GB94/02249 In particular, it has now been found that levobupivacaine in man has less effect on stroke, cardiac and acceleration indices than racemic bupivacaine. As these are indices of myocardial contractility, this finding indicates that levobupivacaine is less cardio-depressant than racemic bupivacaine. This finding supports the use of levobupivacaine as a safer long-acting local anaesthetic for use in patients having or disposed to depressed myocardial contractility, i.e. a class of cardiac-compromised patients and also patients undergoing concomitant therapy with medicines having a cardio-depressant effect or with cytotoxic drugs. For the same reasons, levobupivacaine may also have beneficial therapeutic effects after certain kinds of surgery when sympathetic blockade is required with minimal cardio-depressant effects.
The agent may be the single isomer, but is effectively free of dexbupivacaine, e.g. in at least 80%, more preferably at least 90%, and most preferably at least 99%, enantiomeric excess. Any conventional salt, e.g. the hydrochloride, may be used.
Description of the Invention For the purposes of the present invention, "depressed myocardial contractility" indicates that the patient is suffering from, or disposed to, heart failure at level 2, 3 or 4 of the New York Heart Association Scale. There are various therapeutic indications associated with reduced force of contraction of the heart, where the use of bupivacaine or its isomers, on the basis of prior knowledge, would have been contra-indicated. In certain populations, reduced mechanical effectiveness of the heart is a major problem.
Specific indications to which the present invention relates, and for which the use of levobupivacaine as an analgesic is thus appropriate, include hypertension, renal disease, viral illness, alcohol-dependence or effects, major ischaemia and diabetes. The invention is also applicable for providing anaesthesia in the old and frail, for stable post-infarct, shock, following cardiac surgery or multiple organ failure, and others at risk from post-myocardial infarcts.
The concentration of levobupivacaine to be given for effective utility, is for example, 0.25%, 0.5% or 0.75%, depending on the procedure envisaged. Up to 60 ml in a single dose can be given. The usual routes of administration are infiltration, epidural, spinal and peripheral nerve block. It is also possible to provide continuous infusion of agent at lower concentration, for example 0.125%, with or without opioid, depending on anaesthetic practice. This is common during labour and is distinct from the treatment of chronic pain when infusions can continue for days rather than hours.
An additional benefit of levobupivacaine over racemic bupivacaine is its reduced uptake into heart and brain. It is therefore particularly suitable for use in treating chronic paid. This is described more fully in International Patent Application No. PCT/GB94/02248 (Chiroscience Limited, October 13, 1994).
The following provides the evidence that is the basis of the present invention.
The cardiovascular and central nervous effects of levobupivacaine were compared with racemate (Marcaine) in healthy male volunteers. Drugs were administered by intravenous administration in a double-blind crossover manner. The infusion rate was 10 mg/min for each drug and infusion was continued up to a maximum of 150 mg or stopped following the first detection of CNS effects (including tinnitus, numb tongue or lips and dry mouth). Volunteers were previously conditioned to the CNS effects of local anaesthetics by administration of a test dose of lignocaine. A range of cardiovascular parameters were measured, including systolic and diastalic blood pressures, ECG, and, using the transthoracic electrical bioimpedance _' A
W0 95/10277 ~CT/GB94/02249 technique (with a BoMed NCCOM3-R7), aortic blood flow, allowing measurements of cardiac index and stroke index.
Based on results from a previous study in which racemic bupivacaine was infused it was anticipated that the major cardiovascular changes observed following bupivacaine administration would be related to myocardial contractility. Therefore, an acceleration index, representing the initial maximum acceleration of blood flow during the onset of ejection, was measured to estimate to myocardial contractility in this new study.
Levobupivacaine, like racemate, was well tolerated.
The mean total doses administered of levobupivacaine and racemate were 54.0 and 45.6 mg respectively and plasma concentrations at the end of infusion were 2.384 ~g/ml and 1.87 ~g/ml respectively (n.12). Despite the mean total dose and plasma concentration being higher with levobupivacaine, this produced much smaller mean changes in cardiac variables than the racemate. The myocardial contractility index was significantly reduced by bupivacaine from a value of 1.36 S!2 to 1.18 S 2, a decrease of 0.18 Sz or 13%. For levobupivacaine the pre-dose value was 1.34 S~Z and this only decreased to 1.28 Sz at the end of infusion, a decrease of 0.06 S~2 or 4.5%. The difference between drug treatments was highly significant (p <0.02, n=12). The results were similar for stroke index, a parameter likely to reflect changes in myocardial contractility. Bupivacaine reduced this from 55.3 ml/M2 to 44.4 ml/MZ, a decrease of 10.9 ml/MZ or 20%. For levobupivacaine the pre-dose value was 52.4 ml/MZ and 49.1 ml/MZ at the end of infusion, a decrease of 3.3 ml/MZ or 6%.
Again the difference between drug treatments was statistically highly significant (p <0.01, n=12). Small changes in other variables occurred including heart rate and mean blood pressure (increases) and ejection fraction and cardiac index (decreases). As with acceleration index and stroke index the changes tended to be greater with bupivacaine.
A second study has been carried out, to compare the efficacy of levobupivacaine against bupivacaine using the ulnar block technique. Concentrations of 0.125%, 0.25% and 0.5% levobupivacaine were compared with 0.25% bupivacaine 5 (all volumes 5 mls) in a double-blind study in 20 volunteers. A preliminary analysis of the data suggests that in terms of sensory block, levobupivacaine has comparable efficacy to bupivacaine, with the duration of sensory block to 0.25% bupivacaine being similar to that l0 seen with levobupivacaine 0.25%.
These results with levobupivacaine have provided evidence that this local anaesthetic, in comparison with the currently clinically-used racemate, has a lower potential to cause cardiotoxicity in man. This, along with evidence that levobupivacaine has a similar anaesthetic potency to the racemate, suggests that levobupivacaine will be a safer local anaesthetic in the clinic. This would be of particular importance for obstetrics use and large plexus blocks where accidental intravenous injection of the racemate can have grave consequences. In addition, the lower propensity to cause myocardial depression would be beneficial in patients with compromised cardiac function.
Based on preclinical results obtained with separated enantiomers, the reduced cardiotoxicity of levobupivacaine in man is likely due to reduced direct actions on the heart. However additional factors may contribute to the reduced cardiotoxicity. Recently, others have reported stereoselective plasma binding of bupivacaine enantiomers in man, with the plasma binding of levobupivacaine being about 50% higher than binding for dexbupivacaine. This higher binding would reduce the consequences of accidental intravascular administration.
Field of the Inv'ention This invention relates to a new therapeutic use for a known analgesic agent, i.e. bupivacaine or 1-butyl-N-(2,6 dimethylphenyl)-2-piperidinecarboxamide.
~acl~qround of the Invention 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.
It is known that levobupivacaine is probably less cardiotoxic than dexbupivacaine and racemic bupivacaine.
See, for example, Vanhoutte _e~ a~, Br. J. Pharmacol.
,~0~:1275-1281 (1991), and Denson et a~, Regional Anaesthesia, x:311-316 (1992). Vanhoutte et al studied the effects of bupivacaine enantiomers on the electrophysiological properties of guinea pig isolated papillary muscle; this is based on their statement that nthe cardiotoxicity of bupivacaine seems to be mainly of electrophysiological origin".
Many patients who require analgesics are undergoing concomitant therapy with other drugs, e.g. anti hypertensive agents. Many such drugs are cardio depressant. In particular, it has recently been reported that cardio-depressant effects are observed in isolated organs, following administrations of bupivacaine and CaZ
channel inhibitors such as verapamil.
summ_~y of the Inv~;Iti ion Surprisingly, it has been found that the effect of levobupivacaine on the heart is reduced, in respect not simply of electrophysiological properties, but also mechanical properties. Although racemic bupivacaine may have both electrophysiological and mechanical depressant effects on the heart, there is no evidence to suggest that these effects are linked.
WO 95110277 ~ '~ PCT/GB94/02249 In particular, it has now been found that levobupivacaine in man has less effect on stroke, cardiac and acceleration indices than racemic bupivacaine. As these are indices of myocardial contractility, this finding indicates that levobupivacaine is less cardio-depressant than racemic bupivacaine. This finding supports the use of levobupivacaine as a safer long-acting local anaesthetic for use in patients having or disposed to depressed myocardial contractility, i.e. a class of cardiac-compromised patients and also patients undergoing concomitant therapy with medicines having a cardio-depressant effect or with cytotoxic drugs. For the same reasons, levobupivacaine may also have beneficial therapeutic effects after certain kinds of surgery when sympathetic blockade is required with minimal cardio-depressant effects.
The agent may be the single isomer, but is effectively free of dexbupivacaine, e.g. in at least 80%, more preferably at least 90%, and most preferably at least 99%, enantiomeric excess. Any conventional salt, e.g. the hydrochloride, may be used.
Description of the Invention For the purposes of the present invention, "depressed myocardial contractility" indicates that the patient is suffering from, or disposed to, heart failure at level 2, 3 or 4 of the New York Heart Association Scale. There are various therapeutic indications associated with reduced force of contraction of the heart, where the use of bupivacaine or its isomers, on the basis of prior knowledge, would have been contra-indicated. In certain populations, reduced mechanical effectiveness of the heart is a major problem.
Specific indications to which the present invention relates, and for which the use of levobupivacaine as an analgesic is thus appropriate, include hypertension, renal disease, viral illness, alcohol-dependence or effects, major ischaemia and diabetes. The invention is also applicable for providing anaesthesia in the old and frail, for stable post-infarct, shock, following cardiac surgery or multiple organ failure, and others at risk from post-myocardial infarcts.
The concentration of levobupivacaine to be given for effective utility, is for example, 0.25%, 0.5% or 0.75%, depending on the procedure envisaged. Up to 60 ml in a single dose can be given. The usual routes of administration are infiltration, epidural, spinal and peripheral nerve block. It is also possible to provide continuous infusion of agent at lower concentration, for example 0.125%, with or without opioid, depending on anaesthetic practice. This is common during labour and is distinct from the treatment of chronic pain when infusions can continue for days rather than hours.
An additional benefit of levobupivacaine over racemic bupivacaine is its reduced uptake into heart and brain. It is therefore particularly suitable for use in treating chronic paid. This is described more fully in International Patent Application No. PCT/GB94/02248 (Chiroscience Limited, October 13, 1994).
The following provides the evidence that is the basis of the present invention.
The cardiovascular and central nervous effects of levobupivacaine were compared with racemate (Marcaine) in healthy male volunteers. Drugs were administered by intravenous administration in a double-blind crossover manner. The infusion rate was 10 mg/min for each drug and infusion was continued up to a maximum of 150 mg or stopped following the first detection of CNS effects (including tinnitus, numb tongue or lips and dry mouth). Volunteers were previously conditioned to the CNS effects of local anaesthetics by administration of a test dose of lignocaine. A range of cardiovascular parameters were measured, including systolic and diastalic blood pressures, ECG, and, using the transthoracic electrical bioimpedance _' A
W0 95/10277 ~CT/GB94/02249 technique (with a BoMed NCCOM3-R7), aortic blood flow, allowing measurements of cardiac index and stroke index.
Based on results from a previous study in which racemic bupivacaine was infused it was anticipated that the major cardiovascular changes observed following bupivacaine administration would be related to myocardial contractility. Therefore, an acceleration index, representing the initial maximum acceleration of blood flow during the onset of ejection, was measured to estimate to myocardial contractility in this new study.
Levobupivacaine, like racemate, was well tolerated.
The mean total doses administered of levobupivacaine and racemate were 54.0 and 45.6 mg respectively and plasma concentrations at the end of infusion were 2.384 ~g/ml and 1.87 ~g/ml respectively (n.12). Despite the mean total dose and plasma concentration being higher with levobupivacaine, this produced much smaller mean changes in cardiac variables than the racemate. The myocardial contractility index was significantly reduced by bupivacaine from a value of 1.36 S!2 to 1.18 S 2, a decrease of 0.18 Sz or 13%. For levobupivacaine the pre-dose value was 1.34 S~Z and this only decreased to 1.28 Sz at the end of infusion, a decrease of 0.06 S~2 or 4.5%. The difference between drug treatments was highly significant (p <0.02, n=12). The results were similar for stroke index, a parameter likely to reflect changes in myocardial contractility. Bupivacaine reduced this from 55.3 ml/M2 to 44.4 ml/MZ, a decrease of 10.9 ml/MZ or 20%. For levobupivacaine the pre-dose value was 52.4 ml/MZ and 49.1 ml/MZ at the end of infusion, a decrease of 3.3 ml/MZ or 6%.
Again the difference between drug treatments was statistically highly significant (p <0.01, n=12). Small changes in other variables occurred including heart rate and mean blood pressure (increases) and ejection fraction and cardiac index (decreases). As with acceleration index and stroke index the changes tended to be greater with bupivacaine.
A second study has been carried out, to compare the efficacy of levobupivacaine against bupivacaine using the ulnar block technique. Concentrations of 0.125%, 0.25% and 0.5% levobupivacaine were compared with 0.25% bupivacaine 5 (all volumes 5 mls) in a double-blind study in 20 volunteers. A preliminary analysis of the data suggests that in terms of sensory block, levobupivacaine has comparable efficacy to bupivacaine, with the duration of sensory block to 0.25% bupivacaine being similar to that l0 seen with levobupivacaine 0.25%.
These results with levobupivacaine have provided evidence that this local anaesthetic, in comparison with the currently clinically-used racemate, has a lower potential to cause cardiotoxicity in man. This, along with evidence that levobupivacaine has a similar anaesthetic potency to the racemate, suggests that levobupivacaine will be a safer local anaesthetic in the clinic. This would be of particular importance for obstetrics use and large plexus blocks where accidental intravenous injection of the racemate can have grave consequences. In addition, the lower propensity to cause myocardial depression would be beneficial in patients with compromised cardiac function.
Based on preclinical results obtained with separated enantiomers, the reduced cardiotoxicity of levobupivacaine in man is likely due to reduced direct actions on the heart. However additional factors may contribute to the reduced cardiotoxicity. Recently, others have reported stereoselective plasma binding of bupivacaine enantiomers in man, with the plasma binding of levobupivacaine being about 50% higher than binding for dexbupivacaine. This higher binding would reduce the consequences of accidental intravascular administration.
Claims (9)
1. Use of levobupivacaine or a salt thereof, for the manufacture of a medicament for use as an anaesthetic in a human patient having or disposed to depressed myocardial contractility.
2. Use of levobupivacaine or a salt thereof, for use as an anaesthetic in a human patient having or disposed to depressed myocardial contractility.
3. Use according to claim 1 or 2, wherein the patient is suffering from hypertension, renal disease, a post-myocardial infarct, ischaemia, diabetes, a virus or alcohol-dependence.
4. Use according to any one of claims 1 to 3, wherein the patient has undergone cardiac surgery, multiple organ failure or a valve replacement, or has been fitted with a pacemaker.
5. Use according to any one of claims 1 to 4, wherein the patient is undergoing concomitant therapy with a cardio-depressant drug.
6. Use according to any one of claims 1 to 5, wherein the patient is undergoing concomitant anti-hypertension therapy, by the administration of a Ca2+ channel blocker.
7. Use according to claim 6, wherein the Ca2+ channel blocker is verapamil.
8. Use according to any one of claims 1 to 4, wherein the patient is undergoing concomitant therapy with a cytotoxic drug.
9. Use according to any one of claims 1 to 8, wherein the levobupivacaine is in at least 90% enantiomeric excess with respect to dexbupivacaine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002505487A CA2505487C (en) | 1993-10-13 | 1994-10-13 | Levobupivacaine and its use as an anaesthetic in obstetrics |
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9321061.5 | 1993-10-13 | ||
| GB939321061A GB9321061D0 (en) | 1993-10-13 | 1993-10-13 | Analgestic agent and its use |
| GB9408014A GB9408014D0 (en) | 1994-04-22 | 1994-04-22 | Analgesic agent and its use |
| GB9408014.0 | 1994-04-22 | ||
| PCT/GB1994/002249 WO1995010277A1 (en) | 1993-10-13 | 1994-10-13 | Analgesic agent and its use |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002505487A Division CA2505487C (en) | 1993-10-13 | 1994-10-13 | Levobupivacaine and its use as an anaesthetic in obstetrics |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2173207A1 CA2173207A1 (en) | 1995-04-20 |
| CA2173207C true CA2173207C (en) | 2007-02-06 |
Family
ID=37734816
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002173207A Expired - Lifetime CA2173207C (en) | 1993-10-13 | 1994-10-13 | Levobupivacaine and its use as an anaesthetic in patients having or disposed to depressed myocardial contractility |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2173207C (en) |
-
1994
- 1994-10-13 CA CA002173207A patent/CA2173207C/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| CA2173207A1 (en) | 1995-04-20 |
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| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |
Effective date: 20141014 |