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

PURPOSE: 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. METHODS: First, a HPLC method for EDC quantification was validated. Then, large unilamellar vesicles composed of hydrogenated soy phosphatidylcholine:cholesterol with 250 mM (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. RESULTS: IGLEDC showed average diameters of 172.3 ± 2.6 nm, low PDI (0.12 ± 0.01), mean particle concentration of 6.3 ± 0.5 × 1012/mL and negative zeta values (-10.2 ± 0.4 mV); parameters that remain stable during storage at 4°C. The formulation, with 40% encapsulation efficiency, induced the sustained release of EDC (ca. 24 h), while reducing its toxicity to human fibroblasts. CONCLUSION: 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.

Circadian phase-dependent protein and tissular binding of three local anesthetics (bupivacaine, etidocaine, and mepivacaine) in mice: a possible mechanism of their chronotoxicokinetics?

The aim of this study was to investigate the possible influence of the time of administration on bupivacaine (B), etidocaine (E), and mepivacaine (M) protein and tissue (brain and heart) binding. For each anesthetic agent, a single dose of B (20 mg/kg), E (40 mg/kg), or M (60 mg/kg) was administered intraperitoneally at 10:00, 16:00, 22:00, and 04:00 h. Blood and tissue samples were collected 15 min after drug administration. This study documents significant circadian variations in protein and tissue binding of the three local anesthetic agents. We did not demonstrate a temporal relationship between the respective free and tissue levels. Thus, the temporal variations of free plasma, brain, and heart levels do not seem to be involved in the temporal changes of induced mortality.

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.

Circadian phase dependent acute toxicity and pharmacokinetics of etidocaine in serum and brain of mice.

The aim of this study was to investigate the possible influence of the time of administration on etidocaine acute toxicity and kinetics in mice. Different groups of adult male NMRI mice maintained under controlled environmental conditions (lights on 06.00-18.00) were injected at one of the following times: 10.00, 16.00, 19.00, 22.00, 01.00 and 04.00 h with four doses of etidocaine at each time point to establish the acute toxicity (LD 50). To assess chronokinetics, a single 40 mg kg-1 i.p. dose of etidocaine was given to adult male NMRI mice at four fixed times: 10.00, 16.00, 22.00 and 04.00 h. Etidocaine serum levels were determined by GLC. The data showed significant 24 h variations of the Cmax only (highest value = 9.64 +/- 1.31 micrograms mL-1 at 10.00 P less than 0.05; amplitude, (maximum-minimum) mean x 100 = 84%) Vd, (amplitude = 59.7%), alpha and beta phase elimination half-lives (amplitude = 52 and 35%, respectively), clearance (amplitude = 23%) and AUC infinity 0 (amplitude = 22%) were not found to be significantly time dependent. Etidocaine kinetics in brain were determined similarly; a significant temporal variation was found for the elimination half life (amplitude, 161.9%) and AUC (amplitude, 133.2%) but not for Cmax. These data demonstrate a temporal pattern of etidocaine kinetics similar to those reported previously for other local anaesthetic agents, bupivacaine and mepivacaine. The temporal changes in etidocaine induced acute toxicity may result in part from its chronokinetic changes.

[Local anesthetics in the aqueous humor in local anesthesia of the eye]. / Lokalanaesthetika im Kammerwasser bei örtlicher Betäubung am Auge.

Local anesthetics injected retrobulbarly are detectable in the aqueous humor. From 40 patients who received a total dose of 140 mg lidocaine, 15 mg bupivacaine, and 30 mg etidocaine, samples of aqueous humor were taken between 30 and 90 minutes after administration (average 57 minutes). The mean lidocaine concentration was 1.02 micrograms/ml, that of bupivacaine 0.075 micrograms/ml. Etidocaine, used only for facial nerve block in front of the ear, could not be detected in the aqueous humor. All three substances were found in the central venous blood. It therefore appears unlikely that any of them are transported via the blood-aqueous barrier, whether actively or passively. Local anesthetics can inhibit corneal cell proliferation and result in lens opacification when administered into the conjunctival sac. It may be that local anesthetics detected in the aqueous humor have similar effects resulting from contact with the cornea and lens.

Temporal variations in the erythrocyte permeability to bupivacaine, etidocaine and mepivacaine in mice.

Temporal changes in membrane permeability to bupivacaine (B), etidocaine (E) and mepivacaine (M) documented by their erythrocytic penetration were studied in mice. Temporal variations of B, E and M erythrocytic penetration were demonstrated with a maximum at 04.00 h for B (amplitude = 148%), 10.00 h for E (amplitude = 146%) and at 10.00 h for M (amplitude = 75%). Differences in the circadian pattern of erythrocytic penetration of B, E and M are discussed according to physicochemical properties of these three agents.

Alterations in the pharmacokinetic properties of amide local anaesthetics following local anaesthetic induced convulsions.

The comparative pharmacokinetic properties of lidocaine, bupivacaine, etidocaine and mepivacaine were investigated in convulsing and non-convulsing dogs. The same dose of a given local anaesthetic was administered as either a 30-s intravenous (IV) bolus to produce convulsions or as a 15-min IV infusion producing no convulsions. Derived pharmacokinetic data were found to be different in convulsing and non-convulsing animals. Total body clearance was found to be significantly reduced for lidocaine (29%, P less than 0.05), bupivacaine (31%, P less than 0.05), etidocaine (60%, P less than 0.01) and mepivacaine (68%, P less than 0.01) in convulsing animals. Increases in elimination half-life only achieved statistical significance in mepivacaine-treated animals (non-convulsing 45.2 min, convulsing 105.4 min, P less than 0.01). Overall, the most profound effects of convulsions on pharmacokinetic data were seen with mepivacaine. Convulsions were associated with increases in heart rate ranging from 117% (lidocaine, P less than 0.05) to 129% (mepivacaine, P less than 0.05), increases in cardiac output ranging from 78% (mepivacaine) to 232% (bupivacaine, P less than 0.05) and increases in mean arterial pressure ranging from 45% (lidocaine, P less than 0.05) to 80% (bupivacaine, P less than 0.05). The results suggest that when local anaesthetic-induced seizures occur in man, it cannot be assumed that these drugs will be distributed and eliminated as predicted by intravenous infusion of non-toxic doses.