Etidocaine Research Articles

DoE development of ionic gradient liposomes: A successful approach to improve encapsulation, prolong anesthesia and decrease the toxicity of etidocaine

Etidocaine (EDC) is a long-acting local anesthetic of the aminoamide family whose use was discontinued in 2008 for alleged toxicity issues. Ionic gradient liposomes (IGL) are nanostructured carriers for which an inner/outer gradient of ions increases drug upload. This work describes IGLEDC, a formulation optimized by Design of Experiments, composed of hydrogenated soy phosphatidylcholine:cholesterol:EDC, and characterized by DLS, NTA, TEM/Cryo-TEM, DSC and 1H NMR. The optimized IGL showed significant encapsulation efficiency (41 %), good shelf stability (180 days) and evidence of EDC interaction with the lipid bilayer (as seen by DSC and 1H NMR results) that confirms its membrane permeation. In vitro (release kinetics and cytotoxicity) tests showed that the encapsulation of EDC into the IGL promoted sustained release for 24 h and decreased by 50 % the intrinsic toxicity of EDC to Schwann cells. In vivo IGLEDC decreased the toxicity of EDC to Caenorhabditis elegans by 25 % and extended its anesthetic effect by one hour, after infiltrative administration, at clinically used (0.5 %) concentration, in rats. Thus, this novel drug delivery system is a promise for the possible reintroduction of EDC in clinics, aiming at the control of operative and postoperative pain.

Sustained Release from Ionic-Gradient Liposomes Significantly Decreases ETIDOCAINE Cytotoxicity.

Etidocaine (EDC) is a long lasting local anesthetic, which alleged toxicity has restricted its clinical use. Liposomes can prolong the analgesia time and reduce the toxicity of local anesthetics. Ionic gradient liposomes (IGL) have been proposed to increase the upload and prolong the drug release, from liposomes. First, a HPLC method for EDC quantification was validated. Then, large unilamellar vesicles composed of hydrogenatedsoy phosphatidylcholine:cholesterol with 250mM (NH4)2SO4 - inside gradient - were prepared for the encapsulation of 0.5% EDC. Dynamic light scattering, nanotracking analysis, transmission electron microscopy and electron paramagnetic resonance were used to characterize: nanoparticles size, polydispersity, zeta potential, concentration, morphology and membrane fluidity. Release kinetics and in vitro cytotoxicity tests were also performed. IGLEDC showed average diameters of 172.3 ± 2.6nm, low PDI (0.12 ± 0.01), mean particle concentration of 6.3 ± 0.5 × 1012/mL and negative zeta values (-10.2 ± 0.4mV); parameters that remain stable during storage at 4°C. The formulation, with 40% encapsulation efficiency, induced the sustained release of EDC (ca. 24h), while reducing its toxicity to human fibroblasts. A novel formulation is proposed for etidocaine that promotes sustained release and reduces its cytotoxicity. IGLEDC can come to be a tool to reintroduce etidocaine in clinical use.

Preferential location of lidocaine and etidocaine in lecithin bilayers as determined by EPR, fluorescence and 2H NMR

We have examined the effect of the uncharged species of lidocaine (LDC) and etidocaine (EDC) on the acyl chain moiety of egg phosphatidylcholine liposomes. Changes in membrane organization caused by both anesthetics were detected through the use of EPR spin labels (5, 7 and 12 doxyl stearic acid methyl ester) or fluorescence probes (4, 6, 10, 16 pyrene-fatty acids). The disturbance caused by the LA was greater when the probes were inserted in more external positions of the acyl chain and decreased towards the hydrophobic core of the membrane. The results indicate a preferential insertion of LDC at the polar interface of the bilayer and in the first half of the acyl chain, for EDC. Additionally, 2H NMR spectra of multilamellar liposomes composed by acyl chain-perdeutero DMPC and EPC (1:4 mol%) allowed the determination of the segmental order ( S mol) and dynamics ( T 1) of the acyl chain region. In accordance to the fluorescence and EPR results, changes in molecular orientation and dynamics are more prominent if the LA preferential location is more superficial, as for LDC while EDC seems to organize the acyl chain region between carbons 2–8, which is indicative of its positioning. We propose that the preferential location of LDC and EDC inside the bilayers creates a “transient site”, which is related to the anesthetic potency since it could modulate the access of these molecules to their binding site(s) in the voltage-gated sodium channel.

Spectrophotometric determination of etidocaine in pharmaceutical (dental) formulation

A spectrophotometric method was developed for the determination of etidocaine hydrochloride (EH) in injectable pharmaceutical preparation. The proposal of this work was to develop a rapid, simple, inexpensive, precise and accurate visible spectrophotometric method. The method is based on the formation of the ion-pair complex by the EH reaction with bromocresol green in the pH 4.6 which after chloroform extraction gives a yellow color that in basic medium change to blue color and exhibits a maximum absorbance at 625 nm. The calibration graph was linear over the range 2.0–6.0 μg ml −1 EH calculated on the final yellow solution. The R.S.D. of the slope of the four lines was 0.73%. This method can be applied to injectable pharmaceutical preparation dosage studied.

Anesthetic efficacy and heart rate effects of the intraosseous injection of 1.5% etidocaine (1:200,000 epinephrine) after an inferior alveolar nerve block

Objective. The purpose of this study was to determine the anesthetic efficacy and heart rate effects of an intraosseous (IO) injection of 1.5% etidocaine with 1:200,000 epinephrine after an inferior alveolar nerve block. Study design. In a repeated-measures designed study, 48 subjects randomly received 2 combinations of injections at 2 separate appointments. The combinations were an inferior alveolar nerve (IAN) block (with 3% mepivacaine) + IO injection with 1.8 mL of 1.5% etidocaine hydrochloride containing 1:200,000 epinephrine, and an IAN + mock IO injection. The first molar was blindly tested with a pulp tester at 2-minute cycles for 60 minutes after the injection. Anesthesia was considered successful when 2 consecutive 80 readings (no subject response) were obtained. Heart rate (pulse rate) was measured with a pulse oximeter. Results. Lip numbness occurred in 100% of the subjects with both the techniques. For the first molar, anesthetic success for the IAN + mock IO and the IAN + IO etidocaine hydrochloride groups, respectively, were 81% and 100%. The differences were significant ( P < .05) when the IAN + IO etidocaine hydrochloride technique was compared with the IAN + mock IO. A mean increase in heart rate of 32 beats/min occurred in 90% of the subjects with the IO injection of the etidocaine hydrochloride solution. In 89% of these subjects, the heart rate returned to within 5 beats of baseline values 4 minutes or less after solution deposition. Conclusions. The IO injection of 1.8 mL of 1.5% etidocaine hydrochloride with 1:200,000 epinephrine, when used to augment an inferior alveolar nerve block, significantly increased anesthetic success in the first molar. The majority of subjects receiving the IO injection of the etidocaine hydrochloride solution had a transient increase in heart rate. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;89:407-11)

Inclusion complexation of amide-typed local anaesthetics with β-cyclodextrin and its derivatives. ii. evaluation of affinity constants and in vitro transfer rate constants

The inclusion complex-forming abilities of five local anaesthetics of the amide-type (LAs), bupivacaine (BVC), etidocaine (EDC), lidocaine (LDC), mepivacaine (MVC) and prilocaine (PLC), with three cyclodextrins (CDs), β-cyclodextrin (βCD) and its alkylated derivatives 2-hydroxypropyl-β-cyclodextrin (HPβCD) and heptakis (2,6-di-omethyl)-β-cyclodextrin (DMβCD), were studied in aqueous solution at 25°C and 37°C using the solubility method of Higuchi and Connors (1965) (Adv. Anal. Chem. Instr., 4 (1965) 117–212) based on changes in the solubility of substrates (LAs) upon the addition of ligands (CDs). The interaction was quantified for each LA-CD system by determination of the stability constant, from the slope of the phase-solubility diagram. This second part of a study dealing with improvement in LA biopharmaceutics provided more evidence about LA-CD complexation. The solubility increase of the LAs in the presence of CDs was in the rank order DMβCD > HPβCD ⪢ βCD; BVC showed the greatest stability constant values of all LAs tested, for all CDs and there was an influence of the temperature upon the complexation, only with βCD. Then, the effect of DMβCD and HPβCD on transfer of BVC from an aqueous to an organic phase was investigated with a two-phase system, water with methylene chloride or n-octanol. The BVC-CDs complexation provided modifications in first-order transfer rate constants compared with BVC alone, showing a decrease in the transfer rate of BVC between the two phases.

Tetraphasic actions of local anesthetics on central nervous system electrical activities in cats.

The effects of seven local anesthetics, mepivacaine, bupivacaine, etidocaine, dibucaine, prilocaine, procaine, and tetracaine, on the central nervous system (CNS) electrical activities were studied in five cats with each agent. Brain electrodes were implanted chronically in the cortex, amygdala, hippocampus, and midbrain reticular formation. The cortical, amygdala, and hippocampus electroencephalograms (EEGs), reticular multiunit activity (R-MUA), and heart rate were recorded. Drugs were administered intravenously with constant rates of equipotent doses until EEG seizures appeared. Effects of lidocaine, 1 mg.kg-1.min-1, were studied for comparison. The rates of infusion were: mepivacaine, 1 mg.kg-1.min-1; procaine, 4 mg.kg-1.min-1; bupivacaine and tetracaine, 0.25 mg.kg-1.min-1; etidocaine, 0.5 mg.kg-1.min-1; dibucaine, 0.15 mg.kg-1.min-1; and prilocaine, 3 mg.kg-1.min-1. The effects of 10-15 times higher rates of infusion were also studied in two cats with each drug. During the slow rates of infusion, a tetraphasic sequence of changes, common to all agents, was observed: the initial stage represented by diffuse EEG slowing and a suppression of the R-MUA; the second stage by low voltage fast wave EEG and an activation of the R-MUA; the third stage by reappearance of slow wave EEG and a suppression of the R-MUA; and the fourth stage by an epileptiform EEG and an activation of the R-MUA. These changes in EEG were not typical in some cats administered procaine, bupivacaine, prilocaine, and dibucaine. During the high rates of infusion, suppressive stages in the R-MUA were less dominant and activations dominated. High rates of infusion of mepivacaine produced sudden epileptic activities in EEG. Tetracaine, procaine, etidocaine, and bupivacaine in the high rates of infusion produced slow waves for a short period, prior to seizure activities in the EEG. Dibucaine or prilocaine in high rates of infusion could not produce seizure activities in the EEG, but slow waves and isoelectrical EEG, which were accompanied with idioventricular rhythm followed by ventricular fibrillation. All local anesthetics have similar tetraphasic CNS actions and whether the expression of CNS intoxication with subconvulsive doses is excitation or suppression may possibly be dependent on the brain drug level and its rate of increase.

NMR Studies of Drugs. 1H and 13C NMR Chemical Shift Assignments in Etidocaine and Etidocaine Hydrochloride Determined by Two-Dimensional NMR Spectroscopy

Abstract 1H and 13C NMR chemical shift assignments were obtained for the local anesthetics etidocaine (1) and etidocaine hydrochloride (2) in CDCl3 solution, as well as for 2 in D2O solution. The COSY experiment was employed for proton-proton correlation, while onebond and long-range 2D heteronuclear techniques allowed the assignments of all 13C chemical shifts in each molecule. Etidocaine has a chiral carbon; etidocaine hydrochloride has, in addition to the natural chiral center, an acid-induced chirality at the protonated amine nitrogen, resulting in solvent-dependent diastereomers. Ten of the fourteen magnetically nonequivalent 13C nuclei of 2 exhibit doubled 13C resonance peaks (50.3 MHz, 20°C, CDCl3 solution) due to the presence of the two diastereomers.

Combining epidural fentanyl and lidocaine for postoperative pain

Fifteen patients undergoing total hip and total knee replacement were studied prospectively to evaluate postoperative pain relief provided by an epidural infusion of fentanyl citrate, with and without lidocaine hydrochloride, and changes in arterial flow to the lower extremities. The patients were randomly placed in three groups: group 1 received epidural fentanyl, 5 micrograms/mL; group 2 received epidural fentanyl, 5 micrograms/mL with 0.75% solution of lidocaine; and group 3 received epidural fentanyl, 5 micrograms/mL with 1.0% solution of lidocaine. All patients received 1.5% solution of epidural etidocaine hydrochloride with epinephrine 1:200,000 for intraoperative anesthesia. No clinical evidence of deep vein thrombosis, tachyphylactic reaction to lidocaine, orthostatic hypotension, or motor block was demonstrated in any patient. The addition of lidocaine to the epidural fentanyl infusion did not improve pain relief or allow a decrease in the rate of infusion. Patients in all groups had improved arterial flow to the lower extremities 24 hours postoperatively.

Etidocaine Hydrochloride in Surgical Procedures: Effects on Postoperative Analgesia

Because early research has established the prolonged duration of the effects of etidocaine, this study was performed to determine whether the long-acting local anesthetic can reduce the need for postoperative analgesics after oral surgery.

Etidocaine Aerosol for Laryngotracheal Anesthesia Clinical Evaluation Using Exploratory Data Analysis

Topical airway application of local anesthetics is used to blunt autonomic responses to intubation and to reduce coughing, bucking, and possible bronchospasm. In this study, laryngotracheal anesthesia (LTA) with etidocaine aerosol was evaluated. Techniques of Exploratory Data Analysis were used to illuminate the data and allow for interpretation of clinical relevance by the reader. Results indicate that etidocaine aerosol LTA blunted tachycardia response to intubation, 50 mg etidocaine appears to be the optimal dose, and etidocaine effects we observed are exerted topically rather than systemically.

Evaluation of etidocaine hydrochloride for local anesthesia and postoperative pain control in oral surgery

Etidocaine hydrochloride, an amide-type local anesthetic with prolonged duration of action, was evaluated and compared with a standard local anesthetic, lidocaine, to determine its efficacy as a local anesthetic and its effect on postoperative pain following removal of impacted third molars. The findings indicate that 1.5% etidocaine hydrochloride with 1:200,000 epinephrine, in comparison with 2% lidocaine hydrochloride with 1:100,000 epinephrine, suppresses the magnitude of postoperative pain, and results in anesthesia comparable with that obtained by lidocaine, but results in greater blood loss during surgery.

A Comparison of Etidocaine and Lidocaine for Retrobulbar Anesthesia

In this double-blind study of retrobulbar block for cataract surgery, 62 patients scheduled for cataract surgery were randomly assigned to treatment with either (1) lidocaine 2% with epinephrine 1:200,000 (21 patients); (2) etidocaine 1% plain (20 patients); or (3) etidocaine 1% with epinephrine 1:200,000 (21 patients). The time of onset of sensory and motor block after administration of the three drugs was the same. The duration of motor nerve block produced by etidocaine plain and by etidocaine with epinephrine was considerably longer than that produced by lidocaine with epinephrine, and fewer patients reported postoperative pain after either etidocaine plain or etidocaine with epinephrine than after lidocaine with epinephrine.

Use of Etidocaine Hydrochloride in Oral Surgery

Use of Etidocaine Hydrochloride in Oral Surgery

Disposition and placental transfer of etidocaine in pregnancy.

Following epidural administration of etidocaine hydrochloride to non-pregnant and pregnant patients, a similar rate of absorption was observed and there was no significant difference in total systemic blood clearance (Clsb) of etidocaine in the two groups. There were no major differences in the urinary excretion of etidocaine and metabolites in 48 h urine in both groups. The ability of pregnant women to form the N-glucuronide of the metabolite ABX (2-amino-2′-butyroxylidide) was similar to that of non-pregnant individuals. In vitro experiments showed that the blood/plasma concentration ratio (λ) of etidocaine was significantly higher in pregnant females than in males, presumably due to the lower haematocrit in females. The fraction unbound in plasma (fp) of etidocaine was low in control subjects (mean 0.057) and was not significantly different in pregnant women of 35 to 37 weeks gestation. A marked increase in fp was observed in pregnant women during delivery (mean 0.264). This finding has potentially serious clinical implications because it is the unbound drug in blood which is pharmacologically important. Placental transfer of etidocaine was rapid and the cord/maternal venous blood concentration ratio at delivery (CMb) was, with one exception, always less than unity (mean 0.342). Following epidural administration of etidocaine to pregnant women in labour, measurable concentrations of mono-dealkylated metabolites of etidocaine, PABX (2-N-propylamino-2′-butyroxylidide) and EABX (2-N-ethylamino-2′-butyroxylidide) were detectable in maternal blood within 5 min and cord blood within 30 min. The CMb for PABX and EABX was 0.401 and 0.658 respectively.

Bupivacaine and Etidocaine for Lumbar Epidural Anesthesia for Intra-abdominal Pelvic Surgery, A Double-blind Study

Bupivacaine and Etidocaine for Lumbar Epidural Anesthesia for Intra-abdominal Pelvic Surgery, A Double-blind Study

THE EFFECTS OF ADDING ADRENALINE TO ETIDOCAINE AND LIGNOCAINE IN EXTRADURAL ANAESTHESIA I: BLOCK CHARACTERISTICS AND CARDIOVASCULAR EFFECTS

The addition of adrenaline 5 mug/ml, 1 : 200 000 to 1% etidocaine hydrochloride administered extradurally (L2-3) shortened significantly the onset time for sensory blockade, particularly with respect to the spread of the analgesia from the injection site, and shortened the already rapid onset of motor block. Etidocaine hydrochloride 1% plain caused a slower onset of block, laster longer and produced more profound analgesia over the caudal dermatomes than did 2% lignocaine hydrochloride. The motor block from plain etidocaine was more profound in its extent and lasted longer than that caused by lignocaine. With regard to cardiovascular variables, there were no significant differences between subjects receiving the plain etidocaine and the plain lignocaine. However, subjects receiving etidocaine with adrenaline exhibited increased cardiac stimulation and a decrease in total peripheral resistance over the first 150 min.