MXPA99008055A - The use of levobupivacaine in facial surgery - Google Patents

Abstract

Levobupivacaine is used for providing anaesthesia or analgesia in a human patient in and after facial surgery, especially dentistry or ophthalmics.

Description

USE OF L? VOBUP VACAINE IN FACIAL SURGERY DESCRIPTION OF THE INVENTION This invention relates to a new therapeutic use of levobupivacaine or (S) -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 electrophysiological and mechanical depressant 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 of childbearing age and when using 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 for use in Bier blocks. In addition, due to its mode of action, directly on the nervous system, at higher doses, bupivacaine is known to have unwanted central nervous system (CNS) side effects, which are mainly 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, blockage of fields, epidural and spinal blocks. . It has been suggested that levobupivacaine is less toxic than dextrob-upivacaine 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 utility of levobupivacaine in man, in vivo, is evidenced for the first time in WO-A-9510276, O-A-9510277 and Gristwood et al, Exp. Opin. Invest. Drugs 3 (11): 1209-12 (1994). A long-acting, safe, effective anesthetic may be particularly valuable for use in facial surgery. However, the administration of said compound for local anesthesia, and postoperative analgesia, presents particular problems; small volumes should be administered, due to the mass of nerves and / or blood vessels, for example, around the eyes and in the gums. This is associated with low efficiency. Therefore, high concentrations of the drug are necessary.

Lignocaine is widely used, especially by dentists. However, it is associated with neurotoxicity. In order to give adequate depth of blockage and duration of action, it is usually administered along with epinephrine. This gives rise to additional undesirable effects such as palpitations and syncope. A safer drug may be desirable. Although it has previously been shown that the use of levobupivacaine may have advantages over bupivacaine in certain areas, there is no evidence to suggest that it could be of value in facial surgery in general, and especially in the ophthalmic field and in dentistry. The invention is based on the surprising discovery that levobupivacaine is an effective and especially safe anesthetic for this purpose. In particular, it is less neurotoxic than bupivacaine and is safer in this respect than lignocaine (when given alone or in combination with dextrose or epinephrine). It can have a vasoconstrictor effect. This is useful when the site of administration has a large mass of nerves and / or blood vessels, since no epinephrine or less epinephrine is required. This is a reduced potential for side effects, in clinical dose scales. In the method of the present invention, levobupivacaine can be provided in solution, for infusion or injection into the epidural or spinal space, or to be administered through any of the conventional means to obtain a block of nerves or fields. In addition to the anesthetic blocks, conventionally provided by the racemate, levobupivacaine may also be useful for providing blockages in areas of the body where the risk of systemic exposure to the drug and, therefore, side effects of the central nervous system, is particularly high. . Examples include open wounds and vascular areas, for example, using intercostal blocks for the latter. Especially for ophthalmic use, it can be applied topically. The administration of levobupivacaine may be by continuous or bolus administration. This can be done using conventional apparatuses, for example, which include means for the patient to induce the infusion as necessary. The daily dose administered to the patient may be on a relatively low scale known for the administration of racemic bupivacaine, but, due to the reduced side effects in the central nervous system by levobupivacaine, it 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 the weight of the patient's body.

The concentration of levobupivacaine that will be given may be that conventionally used for the racemic drug, for example, 0.25% w / v. However, especially for the ophthalmic field, the concentration may be higher than this, for example, at less than 0.75% w / v, and may be up to 1.5% w / v. Preferably, however, the concentration of levobupivacaine is in the range of 0.5% to 1% w / v. The solution is preferably aqueous. The solution typically can be in unit doses of 1 to 15 ml, and preferably about 10 ml. However, 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 suitable material, for example, glass or an appropriately impermeable plastic material. Unit doses comprising at least 25 mg, but preferably less than 200 mg of levobupivacaine can be administered, and most preferably the unit dose is in the range of 25 to 100 mg. The administration of levobupivacaine over a variety of concentrations, including those currently used for the racemic drug and the higher concentrations described above, can be performed for significantly longer periods than current ones, again as a result of reduced side effects in the nervous system. Central experienced with levobupivacaine. For example, levobupivacaine can be safely administered to a patient for at least 24 hours, up to 72 hours, or longer. Of course, it can be administered during similar periods already used by the racemic drug, for example between 3 and 10 hours. Levobupivacaine may be particularly valuable for the maintenance of postoperative analgesia. 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 compromised in the central nervous system, or predisposed to cardiac or central nervous system related conditions, that is, having a low threshold of the central nervous system. Levobupivacaine is suitable for use, according to the invention, in relation to dental surgery, for example for the removal of a wisdom tooth. It can also be used during corrective eye surgery, for example in the removal of cataracts in perioral or retrovulvar blocks. Levobupivacaine and racemate may be equipotent, but levobupivacaine may have preferable characteristics such as a minimal effect on the neurovascular system, and a good haemodynamic profile. For the purposes of this specification, levobupivacaine is substantially free of dextrobupivacaine, ie, at least 90% and most preferably at least 99% enantiomeric excess. Through this specification, the reference bupivacaine and its enantiomers include their pharmaceutically acceptable salts. A study was conducted to compare the efficacy of levobupivacaine at 0.75% with 2% lignocaine (with adrenaline) and placebo (0.9% NaCl) as a relief of post-operative pain in patients who experience unilateral or bilateral impacted third molar extractions, and to compare the safety of the study medication. This was a double-blind, randomized, single-center study. 30 patients were randomized, and randomization was stratified for unilateral and bilateral extractions. Analogous visual scale pain measurements were conducted. The time of all rescue medication was recorded and the time of deviation from the blockage was recorded. For each impacted mandibular tooth, 2 ml was administered as a blockade of the inferior alveolar nerve and lml was administered as buccal infiltration. For each maxillary tooth, 1 ml was administered as buccal infiltration and 0.5 ml as infiltration of the palate. Levobupivacaine, lignocaine and placebo had similar safety profiles in patients who presented extractions of the 3rd. impacted molars unilateral or bilateral. However, by fixing the tissue to the rescue medication in time from the end of the surgery to the withdrawal or at 48 hours for patients who did not take rescue medication, the average time of the first requirement for rescue analgesia was almost three times higher. patients in the levobupivacaine group compared with those in the other two treatment groups. The mean level was the lowest for the placebo group (45 min.) And after the lignocaine group (55 min.) But was much higher for the levobupivacaine group (87.5 min.). The standard deviation was approximately 5 times higher for the levobupivacaine group than for the others, and this is due to the maximum time of rescue medication in this group that took 48 hours, while the maximum level was under 8 hours for the patients. other treatment groups. In other studies, 0.75% levobupivacaine with 0.75% bupivacaine was compared in patients undergoing ophthalmic anterior segment surgery, with peribulbar block, to determine its relative efficacy. No significant differences were found at the time of initiation of the block. The relative value of levobupivacaine was seen as a result of another study, comparing the effects of 0.5% levobupivacaine and 0.5% racemic bupivacaine on the QT dispersion and individual average ECG in healthy male volunteers. This last study involved intravenous infusion of 10 mg / min up to a maximum of 150 mg of drug, individually on 2 occasions. The evaluation involved verification by ECG. In particular, disorders of the autonomic nervous system (redness), central disorders (headache, chest pain) disorders of the central / peripheral nervous system (insomnia, hypoanesthesia, paraesthesia), disorders of the ear (tinnitus), and other disorders ( taste perception), were observed. Significantly reduced peripheral / nervous system disorders and ear disorders (tinnitus) were seen with levobupivacaine. These symptoms are commonly seen in clinical fixation, with agents currently used (for which there are restrictions on head and neck surgery). The total frequency of events was tabulated as presented below.

For those subjects who received more than 75 mg, the results of QTc are: Bupivacaine more than 75 mg 0.024 Levobupivacaine more than 75 mg 0.003 Value P 0.022 The importance of these results lies also in the fact that, for facial surgery, large individual doses of the drug can be given, for example 75 mg or more.

Clinically, 10 ml of levobupivacaine may be desirable 0. 75% or 1%.

Claims (5)

1. CLAIMS 1. The use of levobupivacaine for the manufacture of a drug to be used in the provision of anesthesia or analgesia in a human patient in and after facial surgery.
2. 2. The use according to claim 1, characterized in that the surgery is in dentistry.
3. 3. The use according to claim 1, characterized in that the surgery is in the ophthalmic field.
4. 4. The use according to any of the preceding claims, characterized in that it comprises administering a single dose of levobupivacaine.
5. 5. The use according to claim 4, characterized in that the dose comprises at least 75 mg of levobupivacaine.