Levobupivacaine and its use

A method of anesthetizing a human patient prior to major surgery, which comprises the administration to the patient of at least 200 mg levobupivacaine.

FIELD OF THE INVENTION 
This invention relates to a new therapeutic use for levobupivacaine or 
(S)-1-butyl-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide, and to new 
formulations including it. 
BACKGROUND OF THE INVENTION 
Racemic bupivacaine is an effective long-acting local anesthetic, 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. 
In particular, 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. 
In addition, due to its mode of action, directly on the nervous system, at 
higher doses, bupivacaine is known to have undesirable central nervous 
system (CNS) side-effects which, prima facie, are connected to its 
anaesthetic activity. Indeed, the occurrence of CNS side-effects is one of 
the major factors limiting the use of this drug in normal clinical 
practice employing techniques such as local infiltration, nerve block, 
field block, epidural and spinal blocks. 
It has been suggested that 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 (1992). However, these reports are based on work 
in vitro, and cannot necessarily be extrapolated to any mammals, and 
certainly not to humans. 
The effective utility of levobupivacaine in man, in vivo, is evidenced for 
the first time in WO-A-9510276, WO-A-9510277 and Gristwood et al, Exp. 
Opin. Invest. Drugs 3(11): 1209-12 (1994). The latter documents indicate 
the potential utility of levobupivacaine in obstetrics, in part at least 
because of reduced CNS side-effects. 
Gristwood et al also disclose that bupivacaine has "a beneficial ratio of 
sensory to motor blockade. This ratio is particularly important for 
obstetric use as it affords appropriate sensory block and yet allows women 
to consciously participate in the childbirth". Gristwood et al then report 
experiments comparing bupivacaine and levobupivacaine, and conclude that 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 for 0.25% levobupivacaine being similar to that seen with 
bupivacaine 0.25%". 
WO-A-9500148 discloses that ropivacaine salts provide sensory block and 
"minimal motor blockade". It is suggested that this effect is desirable, 
because reduced motor blockade (compared to bupivacaine) allows the 
patient to move, say, legs soon after operation. 
There are of course many more major surgical procedures, where profound 
block is required, the need is for administration of high amounts and 
volumes of anesthetic, and where safety is a major consideration. Although 
racemic bupivacaine is an effective long-acting anaesthetic, large doses 
may be toxic. Further, particularly when administered as a bolus 
injection, where there is a real risk of accidentally administering the 
drug to the wrong site, safety is a critical consideration. For example, 
there is a risk of intravascular injection, in abdominal surgery, brachial 
plexus and femoral sciatic nerve blocks. 
SUMMARY OF THE INVENTION 
This invention is based on two surprising observations. The first is that, 
whereas a large dose of bupivacaine may be fatal in sheep, the same dose 
of levobupivacaine is not. It is therefore possible to administer much 
larger amounts of levobupivacaine, safely. Without wishing to be bound by 
theory, it may be that, because a given dose of levobupivacaine takes 
longer to reach T.sub.max than the same dose of racemate, a higher amount 
of levobupivacaine may safely be administered, that provides anaesthesia. 
The second observation is that levobupivacaine exhibits a different pathic 
handling compared with bupivacaine. This manifests itself as a faster 
plasma clearance rate within 0-4 hours post-administration. Therefore, for 
major surgical procedures, where aberrant injection may occur, the risk of 
harming the patient is reduced due to faster clearance in the problematic 
phase. 
In accordance with the present invention, levobupivacaine is administered 
as an anaesthetic for major surgery in an amount that could not be used by 
injection, with confidence, for bupivacaine, i.e. at least 200 mg, often 
at least 225 mg, and perhaps more than 250 mg, e.g. up to 300 mg. A novel 
unit dosage or delivery system, e.g., a syringe, may comprise such an 
amount of the drug. In terms of the amount of drug administered, this may 
be at least 3 mg/kg.

Bupivacaine was slightly more potent in inducing an arrhythmia; it was more 
than three times more potent in sustaining the arrhythmia. 
Study 2 
Reiz et al, Acta Anaesthesiol. Scand. (1989) 33: 93-98, reports that in 
vivo cardiotoxicity of local anaesthetics can be evaluated without 
interference by central mechanisms in a highly reproducible model 
(Pentobarbital-Anesthetized Swine) where the drug is injected directly 
into a coronary artery. When local anesthetics are injected in the left 
anterior descending artery (LAD), death occurs consistently by ventricular 
fibrillation (VF). The aim of this study was to determine the lethal dose 
of each of the local anesthetics levobupivacaine (L), bupivacaine (B) and 
ropivacaine (R) as well as to compare their respective effects on the QRS 
interval of the precordial ECG. Prolongation of the QRS has been shown to 
correlate highly with in vitro cardiotoxicity of bupivacaine and lidocaine 
(Reiz et al, supra). 
A total of 27 animals were randomized to receive a dose response injection 
of L, B or R into the LAD. A blinded randomized protocol was used. All 
calculations and exclusions were made prior to disclosure of treatment. 
The doses of each agent were 0.375, 0.75, 1.5, 3.0, 4.0 mg etc., in 
increments of 1 mg till death occurred. Each dose was made up in a volume 
of 3 ml plus the dead space of the catheter (1.2 ml), injected over 10 
sec. The time between doses was 5 min, or longer, if ECG, blood pressure 
or heart rate had not returned to pre-injection controls. A complete 
12-lead ECG was recorded on optical disk for later analysis. Statistical 
analysis was by ANOVA, Dunnett's and the Mann-Whitney-U test. Power 
analysis was performed (0.85 to 1.00). 
One animal died of myocardial infarction following acute embolization into 
the LAD. Of the 26 remaining animals, 6 were found to have been injected 
into the right coronary artery (RCA) following undetected reversal of the 
radiological image during coronary artery catheterization. Of the animals 
injected into the LAD, 7 had received L, 7 B and 6 R. All deaths following 
LAD injection were by VF and deaths following RCA injection were by A-V 
dissociation. The lethal doses of L (median 8 mg, range 7-9 mg) and R 
(median 8 mg, range 4-10 mg) were significantly higher (p&lt;0.01 and 0.05 
respectively) than that of bupivacaine (median 5 mg, range 4-6 mg). Death 
following RCA injection was within the same dose ranges and did not alter 
the difference between drugs. QRS prolongation was plotted versus log dose 
of each drug and revealed results for B and R identical to those 
previously obtained in the same model. In contrast to L and B, R did not 
produce more than 100% (approximately 60 msec) QRS prolongation (at the 6 
mg dose). To obtain the same degree of QRS prolongation, L had to be given 
in a significantly higher dose than B. The difference was 25% at 40 msec 
QRS prolongation and 47% at 90 msec QRS prolongation. The difference 
between L and R at 50 msec prolongation was insignificant. 
This study showed that the lethal doses of L and R were approximately 50% 
higher than that of B, regardless of whether the drugs were injected into 
the LAD or RCA causing death by VF or A-V dissociation. A similar 
difference between the drugs was observed for the doses producing 
comparable QRS prolongation. 
Study 3 
This study compared the efficacy, safety and pharmacokinetics of 0.75% 
levobupivacaine with 0.75% bupivacaine in 58 patients undergoing major 
abdominal surgery under epidural anaesthesia. Although 0.75% bupivacaine 
is no longer used in some situations (obstetrics) and 0.5% concentrations 
are usually adequate for lower extremity surgery, 0.75% is preferential 
for abdominal surgery because of the enhancement of motor blockade. Onset 
of sensory anaesthesia to T10 (mean.about.15 minutes), time to peak block 
height (T5, 25-30 min), and abdominal muscle relaxation (RAM score 3-5) 
were equivalent between the groups. Duration of total sensory anaesthesia 
was statistically longer with 0.75% levobupivacaine (levobupivacaine--551 
min, racemic bupivacaine--506 min). This shows that the improvement in 
safety is highly relevant. 
Study 4 
Contraction was measured in mycocytes and papillary muscle isolated from 
guinea-pig ventricle and pectinate muscle isolated from human right atrial 
appendage. 
Myocytes were isolated from guinea-pig left ventricle by an enzyme 
digestion procedure and placed in a chamber on the stage of an inverted 
microscope. Cells were superfused with Krebs-Henseleit buffer (KHB) at 
30.degree. C. and field stimulated at 1.0 Hz. Cell shortening was measured 
with a video camera and edge-detection system. Papillary and pectinate 
muscles were placed in KHB at 37.degree. C. and field stimulated at 1.0 
Hz. Isometric tension was recorded at maximum developed force (L.sub.max). 
Electrophysical parameters were recorded in papillary muscles superfused 
with KHB at 37.degree. C. and stimulated at 1.0 Hz. Standard action 
potential parameters were recorded, i.e. maximum rate of rise of membrane 
potential (V.sub.max); action potential amplitude (APA); and action 
potential duration to 90% repolarization (APD.sub.90). Developed force was 
measured by recording isometric tension in muscles stretched to 90% of 
L.sub.max. 
The effect of equimolar concentrations of levobupivacaine, bupivacaine and 
ropivacaine on developed force and action potential parameters were 
measured at steady-state. No significant differences were noted. 
The mean drug concentration producing a 50% reduction (CI-50) in cell 
shortening was calculated from cumulative dose-response curves. All data 
were analysed by an unpaired t-test (for control data comparison) or 
one-way ANOVA (for comparison between drug groups), assuming a Gaussian 
distribution. 
The most important observation was that, on washout of local anaesthetic 
from myocardium with drug-free perfusate, the recovery of contractility 
following levobupivacaine was significantly greater than that for 
bupivacaine (P&lt;0.05) in both cardiac mycocytes (see FIG. 3) and guinea-pig 
papillary muscle (see FIG. 4). Therefore, there is a potential for better 
reversibility after intravascular injection of levobupivacaine. 
Study 5 
20 adult patients scheduled for distal upper extremity orthopaedic surgical 
procedures with axillary brachial plexus neural blockade were studied. 
Patients received an axillary block using 50 ml of 0.5% levobupivacaine 
without epinephrine. Transarterial and/or nerve stimulator techniques were 
used to identify injection into the brachial plexus sheath. If after 10 
min patients required supplemental local anaesthetic to produce 
anaesthesia in a single peripheral nerve distribution, an additional 10 ml 
of 0.5% levobupivacaine could be administered as a single peripheral nerve 
block at the axilla or wrist. Patients were monitored for onset and 
duration of sensory and motor block using a 0-2 scale (0=no block, 
1=partial block, 2=complete block) for each major nerve distribution 
(median, musculocutaneous, radius, ulnar). Time to onset of adequate 
anaesthesia for surgery, time to first request for post-operative 
analgesics, as well as any subjective or objective signs of local 
anaesthetic toxicity were also collected. Blood samples for PK analysis 
were drawn from 10 patients. 
The patients ranged in age from 20-81 years, and body weight was 50-107 kg. 
Doses of 50-60 ml of levobupivacaine in these patients ranged from 3-5 
mg/kg. 18 patients had adequate onset of sensory/motor blockade for 
surgical anaesthesia within 30 min. In 2 patients, general anaesthesia was 
required due to inadequate sensory/motor block for surgery at 30 min 
post-injection. All patients had complete sensory and motor blockade in 
all four peripheral nerve distributions immediately post-operatively. Mean 
duration of sensory/motor block in at least two nerve distributions was 20 
h (14-24 h). Time to request for supplemental analgesics was 15 h (9-24 
h). No patient demonstrated any subjective or objective signs or symptoms 
of local anesthetic toxicity. 
The results of this study demonstrate the clinical efficacy of 0.5% 
levobupivacaine for axillary brachial plexus blockade. While the maximum 
tolerated dose of levobupivacaine for brachial plexus blockade cannot be 
determined from these results, doses in the range of 3-5 mg/kg were well 
tolerated in these patients for axillary block. By comparison, the 
recommended dose for bupivacaine is 2 mg/kg.