Note: Descriptions are shown in the official language in which they were submitted.
'. CA 02173207 2005-05-09
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LSVOBUPIVACAINS AND ITS US$ As AN ANA$STHBTIC IN PATI$NTS HAVING
OR DISP058D TO DSPRBSSLD MYOCARDIAL CONTRACTILITY
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
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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
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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
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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.
WO 95/10277 PCTIGB94102249
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.
