MXPA99008057A - The use of levobupivacaine in paediatric surgery - Google Patents

Abstract

Levobupivacaine is used for providing anaesthesia or analgesia in human paediatric surgery.

Description

USE D? L? VOBUPIVACAIN IN PEDRIATIC SURGERY DESCRIPTION OF THE INVENTION This invention relates to a new therapeutic use for levobupivacaine or (5) -1-butyl-N- (2,6-dimethylphenyl) -2-piperidinecarboxamide. Racemic bupivacaine is an effective long-acting local anesthetic, and can be given as an epidural. However, racemic bupivacaine is cardiotoxic, having electrophysical and repressive mechanical effects on the heart. Therefore, it should 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 when giving birth and when used in the Bier blocking technique.

Although the incidence of death has been relatively small, the concern has been enough to stop the use of 0. 75% bupivacaine for obstetrics and the prescription of bupivacaine to use Bier 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, mainly, are connected to its anesthetic activity. In fact, the occurrence of side effects in the central nervous system is one of the main factors that limit the use of this drug in normal clinical practice using techniques such as local infiltration, nerve block, field block, epidural blocks and spinal 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 Anesthesia, _17_: 311-316 (1992). However, these reports are based on work in vi tro, and necessarily can not be extrapolated to any mammal, and certainly not to humans. The surprising and effective use of levobupivacaine in man, in vivo, is evidenced for the first time in O-A-9510276, WO-A-9510277 and Gristwood et al, Exp. Opin. Invest. Drugs 3 (11): 1209-12 (1994). No long-acting anesthetic is approved for use in pediatrics. Children are particularly committed to surgery, making the control of anesthesia a particular problem. It is arranging a relatively narrow therapeutic window. In addition, there is the potential problem with intubation, because the airway is small and risks of damage are associated. Children have relatively undeveloped livers, therefore, they increase the risk of a drug interaction. All these problems mean that anesthetics in general of long action are not registered for use in pediatrics. Since a child is developing, and has cells in development / division, a particular aspect of using any of the drugs in a child is its long-term effect. Therefore, it is desirable to avoid the use of drugs that may have genotoxic properties, especially if the drugs are to be used frequently and for a prolonged period. Although it has been previously shown that the use of levobupivacaine may have advantages over bupivacaine in certain areas, nor is there any evidence to suggest that it could be of value in pediatrics. The invention is based on the surprising discovery that levobupivacaine is an effective and especially safe anesthetic for this purpose. In the method of the present invention, levobupivacaine can be provided in solution, for infusion or injection into the epidural or spinal space, or for administration through any conventional means to obtain a nerve or field block. In addition to the anesthetic blocks conventionally provided by the racemate, levobupivacaine may also be useful in providing blockages in areas of the body where the risk of systemic exposure to the drug, and therefore, side effects in the central nervous system is particularly high. Examples include open wounds and vascular areas, for example using side blocks for the latter. For surgery of upper extremities at least, infusion in the body near the base of the limb may be appropriate. A regional block or plexus can also be used. Blocking upper and lower extremities can be used. The interscalene, sciatica, lumbar or plexus auxiliary administration may be involved. The invention is also suitable for use in neonates, for example, up to 6 months or more, for example 2 years. For example, it can be used in caudal block, urological surgery or orchidopexy. In this context, low genotoxicity is particularly important. Epidural infusion (intravascular administration) is especially appropriate when the plasma threshold is low. For example, it is appropriate to treat subjects from 0.5 to 12 years of age. Levobupivacaine can be used with 'pentanyl; see the other application filed the same day on behalf of the same inventor whose title is "The Use of Levobupivacaine in Combination with Other Drugs". The administration of levobupivacaine can be with continuous or bolus administration. This can be done using a conventional apparatus, for example, which includes means for the patient to induce the infusion as desired. Daily administration to the patient may be on a relatively low scale known by the administration of racemic bupivacaine, but, due to the central nervous system side effects reduced by levobupivacaine, may be higher than the conventional dose for the racemic drug. The total dose of levobupivacaine may be around, or an excess of 2 mg per kg of the patient's body weight. The concentration of levobupivacaine that will be given may be that conventionally used for the racemic drug, for example 0.25% w / v. However, the concentration may be higher than this, for example, at least 0.75% w / v, and may be up to 2% w / v. Preferably, however, the concentration of levobupivacaine is about 0.5% w / v. The solution is preferably aqueous. Typically it can be placed in unit doses of 1 to 15 ml, and preferably about 10 ml. However, the unit doses may be higher, for example up to 40 ml or more. The unit doses may be in the form of ampoules, which may be made of any suitable material, for example glass or an appropriately waterproof plastic material. Unit doses comprising at least 75 ml, but preferably less than 200 mg of levobupivacaine can be administered, and most preferably the unit dose is in the range of 80 to 150 mg. In addition, low-dose infusions may be appropriate, for a few hours to a few days. The administration of levobupivacaine on a concentration scale, including those currently used in racemic drug and the higher concentrations described above, can be performed significantly longer than the current ones for a period, again as a result of reduced central nervous system side effects. Experienced with levobupivacaine. For example, levobupivacaine can be safely administered to a patient for at least 24 hours, up to 72 hours, and even for periods of up to a week or every two weeks, or longer. This can be administered, of course, during similar periods already used for the racemic drug, for example between 2 and 6 hours. Levobupivacaine may be particularly valuable for the maintenance of postoperative analgesia, for example, during a period of 8-24 hours after surgery. The method of the present invention is particularly useful in surgical procedures performed on patients who merely require surgery, and are otherwise healthy. The patient can also be cardiac or be involved in the central nervous system or predisposed to cardiac conditions or related to the central nervous system, that is, having a low threshold of the central nervous system. For the purposes of this specification, levobupivacaine is substantially free of dextrobupivacaine, i.e., at least 90%, and most preferably at least 99% enantiomeric excess relative to dextrobupivacaine. Through this specification, the reference to bupivacaine and its enantiomers includes their pharmaceutically acceptable salts. It has been found that, in the mouse lymphoma, the dose of bupivacaine was limited by cytotoxicity and was positive for genotoxicity, while levobupivacaine was completely negative. This surprising result indicates the value of levobupivacaine in pediatric use, whether for neonates, up to 12 months of age, or older children, for example up to 12 years of age. It is also indicative of utility for breastfeeding mothers, and more generally for women of childbearing age, especially those who do not use contraceptive devices or drugs. More specifically, levobupivacaine hydrochloride was analyzed for its ability to induce mutation in the tk site (5-trifluorothymidine resistance) in mouse lymphoma cells using a fluctuating protocol. The study consisted of a cytotoxicity scale finding followed by two independent experiments, each conducted in the absence and presence of metabolic activation by a post-mitochondrial fraction of rat liver induced by Aroclor 1254 (S-9). For reference, bupivacaine hydrochloride was triggered on the occurrence of the cytotoxicity scale. A wide range of concentration was selected for the cytotoxicity scale finding experiments, separated by two double ranges and varying from 31.25 to 1000 μg / ml for levobupivacaine hydrochloride and from 62.5 to 2000 μg / ml for bupivacaine hydrochloride (limited by the solubility in both cases). Cells that survived all doses of levobupivacaine hydrochloride produced 149.6% relative survival in the absence of S-9 and 9.1% relative survival in the presence of S-9 at the higher dose (1000 μg / ml). The two highest doses of bupivacaine hydrochloride (1000 and 2000 μg / ml) were completely toxic but the cells that survived were 500 μg / ml in the absence and presence of S-9, producing 100% and 12.4% relative survival respectively. Accordingly, six doses of levobupivacaine hydrochloride were chosen for the first experiment, separated by double intervals and varying from 31.25 to 1000 μg / ml. For reference, three doses of bupivacaine hydrochloride were tested in the absence of S-9 (250, 500 and 750 μg / ml), and two doses in the presence of S-9 (250, 500 μg / ml). The five lowest doses of levobupivacaine hydrochloride and all reference doses of bupivacaine hydrochloride were selected to determine the viability and resistance of 5-trifluorothymidine, two days after treatment. The highest dose of selected levobupivacaine hydrochloride (500 μg / ml) produced 80.9% and 41.3% relative survival in the absence and presence of S-9. The higher dose of bupivacaine hydrochloride in the presence of S-9 was excluded from the analysis due to the heterogeneity between the replicate cultures, attributable to a high toxicity evident during the period of expression. In this way, the upper doses analyzed were 7.50 and 250 μg / ml in the absence and presence of S-9, which produced 75.4% relative and 54.3% relative survival, respectively. In the second experiment, the dose scale was modified slightly for both levobupivacaine hydrochloride and bupivacaine hydrochloride. For levobupivacaine hydrochloride, the highest doses analyzed were 500 μg / ml and 1000 μg / ml in the absence and presence of S-9, which produced 85.8% and 44.6% relative survival, respectively. The highest doses of bupivacaine hydrochloride analyzed in this experiment were 750 and 500 μg / ml in the absence and presence of S-9, which produced 46.0% and 50.8% relative survival, respectively. Negative control (positive) and positive control treatments were included in each experiment of mutations in the absence and presence of S-9. Mutant frequencies in negative control cultures fell within normal range, and clear increases in mutation were induced by positive control chemicals, 1-oxide of 4-nitroquinoline (without S-9) and benzo [a] pyrene (with S-9). Therefore, the study was accepted as valid. No statistically significant increase in the mutant frequency was observed after treatment with levobupivacaine hydrochloride at any dose level, in these experiments, in the absence or presence of S-9. For bupivacaine hydrochloride, a statistically significant increase in the mutant frequency was observed at 750 μg / ml in the second experiment, in the absence of S-9. However, significant heterogeneity was observed in the survival among replicate cultures at that dose, and the finding was not seen in this first experiment. No statistically significant experiment was observed in the mutant frequency after treatment with bupivacaine hydrochloride and in the presence of S-9 (again only a limited number of doses were tested for references) it was concluded that, under the conditions used in this study , levobupivacaine hydrochloride is not mutagenic in this test system. In a clinical study, the suitability of levobupivacaine in pediatric surgery was evaluated. This was a randomized, double-blind, placebo-controlled study to determine the safety and effectiveness of levobupivacaine to block fields in children having external patient herniorrhaphy. More specifically, otherwise healthy children aged 6 months to 12 years presenting outpatient herniorrhaphy were randomized to receive either ilioinguinal / iliohypograstic nerve block (IIIH) with 0.25 ml / kg of levobupivacaine at 0.5% operated side , or without blockage, at the end of the surgery. It was concluded that levobupivacaine was safe and effective for blocking IIIH in children having herniorrhaphy, as demonstrated by a longer interval of rescue analgesia, lower analgesic doses of fever rescue, and CHEOPS lower than 15, -20, 30 and 60 minutes and in the absence of any adverse event specifically attributable to levobupivacaine. In a further study, using levobupivacaine in patients requiring hernia repair, 45% of patients in the 0.5% levobupivacaine group compared to 73.3% of patients in the nonblocking group required at least one dose of rescue analgesia ( p = 0.167). The majority of children who will require rescue (91.4%) required two or fewer rescue doses of analgesia. The time for the first request for rescue medication was significantly higher in the levobupivacaine group at 0.5% compared to the nonblocking group. The average patient in the 0.5% levobupivacaine group first requested rescue medication after at least 118 minutes, compared to 31 minutes in the nonblocking group (p = 0.041).

Claims (6)

1. CLAIMS 1. The use of levobupivacaine for the manufacture of a drug to provide anesthesia or analgesia in pediatric surgery of human beings.
2. 2. The use according to claim 1, characterized in that the subject is a neonate.
3. 3. The use according to claim 1, characterized in that the subject is from 0.5 to 12 years of age.
4. 4. The use according to any of the preceding claims, characterized in that the administration is through epidural infusion.
5. 5. The use according to any of the preceding claims, characterized in that the administration comprises a blockage of upper or lower extremities.
6. 6. The use according to any of the preceding claims, for use in pain control after the operation.