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.

High-performance liquid chromatographic method for an automated determination of local anaesthetics in human plasma.

A method is described that allows the rapid and precise determination of the local anaesthetics bupivacaine and etidocaine from biological fluids. This method uses a fully automated system with solid-phase extraction in combination with a column-switching technique. Both sample extraction on a LiChrocart pre-column and elution onto the analytical LiChrospher column, were performed automatically and concomitantly using conventional HPLC equipment in conjunction with an OSP-2 on-line sample preparator from Merck combined with UV detection. Recoveries were found to be 96.7 and 96.4% for 2 micrograms/ml bupivacaine and etidocaine, respectively. Lower limits of quantification were found to be 0.05 microgram/ml plasma for both of the compounds.

Etidocaine for Caesarean section--effects on mother and baby.

The effectiveness and safety of etidocaine during extradural anaesthesia for Caesarean section were evaluated in 81 patients. Adequate sensory analgesia occurred in 78 patients and muscle relaxation was excellent in all patients. The combined umbilical venous-umbilical arterial/maternal venous ratio was 0.28+/-0.2 following the administration of 1% etidocaine 25 ml with adrenaline and 0.38+/-0.2 following the administration of 1% etidocaine plain 25 ml. Neurobehavioural patterns of the newborn were not affected noticeably. Etidocaine, in appropriate dose and concentration, appears to be an excellent local anaesthetic agent for Caesarean section under extradural anaesthesia.

Observed and predicted accumulation of local anaesthetic agents during continuous extradural analgesia.

After lumbar extradural injections of ligocaine or etidocaine for surgical anaesthesia further accumulation in the plasma was minimal following top-up injections for pain relief after operation. The dose regimens were: 20 ml of 2% plain lignocaine HCl solution for surgical anaesthesia followed by 10 ml every 1 h until 4 h, and 20 ml of 1% plain etidocaine HCl solution for surgical anaesthesia followed by 10 ml every 2 h until 8 h. Plasma drug concentrations measured after initial doses were used to predict those following successive doses. Agreement between predicted and experimental values was good and further projections were made concerning the local accumulation of etidocaine.

[Plasma level of etidocaine within the first two hours after axillary plexus block in healthy adults and patients with renal insufficiency (author's transl)]. / Plasmakonzentration von Etidocain in den ersten zwei Stunden nach axillärer Blockade bei Gesunden und bei Patienten mit Niereninsuffizienz.

The plasma level of etidocaine was studied within the first two hours of axillary block in 7 patients with renal insufficiency and 7 healthy adults. After 15-20 min the maximum of plasma concentration was found in the group with renal failure and after 30-45 min in the healthy adults. 30 min after the block the plasma level was 1,26 +/- 0,62 mug/ml in the ill patients and only 0,73 +/- 0,31 in the normal group. Using a mathematical model the ratio of permeation into the blood is significantly higher in the group with renal failure than in the healthy adults. The main reason for these results seems to be the acidosis, which is often combined with renal insufficiency. The meaning of these results for regional anaesthesia in patients like these is discussed.

Evaluation of etidocaine in extradural block.

Etidocaine has been evaluated in extradural block with regard to its absorption, toxicity and clinical effectiveness, which have been compared with those of bupivacaine. Etidocaine is associated with lower plasma concentrations than bupivacaine and its absorption is decreased by the addition of adrenaline 1:200,000 to a greater extent than is the case with bupivacaine. Etidocaine causes motor paralysis more frequently than does bupivacaine, especially if adrenaline is added. The duration of action of the two drugs is similar when comparing etidocaine 1% and bupivacaine 0.5%. Bupivacaine 0.75%, however, acts for a significantly longer time than etidocaine 1%. The drug is a useful addition to the range of local anaesthetics, especially with regard to the degree of motor blockade it can achieve during surgical procedures.

Lidocaine, bupivacaine, etidocaine, and epinephrine-induced arrhythmias during halothane anesthesia in dogs.

Arrhythmogenic doses of epinephrine were determined in six mongrel dogs anesthetized at 1.4 MAC halothane initially in the absence of local anesthetics and then at increasing arterial plasma levels of lidocaine, bupivacaine, and etidocaine. The authors gave epinephrine intravenously at 5 microgram/kg/min and calculated the arrhythmogenic dose as a function of time until two or more premature ventricular contractions occurred within a 10-sec period. The control arrythmogenic dose of epinephrine was 4.66 +/- 0.46 microgram/kg (mean +/- SEM). Arrythmogenic doses of epinephrine were increased significantly after each dose of lidocaine, bupivacaine, and etidocaine. With the largest doses studied, local anesthetic plasma levels were frequently in the toxic range. The data show that lidocaine, bupivacaine, and etidocaine equally protect against epinephrine-induced arrhythmias in dogs anesthetized with halothane.

Epidural anesthesia for cesarean section: a comparison of bupivacaine, chloroprocaine, and etidocaine.

The authors studied three groups of patients undergoing elective cesarean section during lumbar epidural anesthesia with bupivacaine, 0.75 per cent (15 patients), chloroprocaine, 3 per cent (15 patients) or etidocaine, 1 per cent (ten patients). Excellent sensory and motor block were obtained with chloroprocaine and bupivacaine; sensory anesthesia was inadequate with etidocaine in most patients. Onset of anesthesia, induction--delivery interval, and stay in the recovery room were all longer with bupivacaine when compared with chloroprocaine. Fetal outcomes, as determined by Apgar scores, acid--base status and neurobehavioral testing, were equally good in all groups. At delivery, fetal/maternal concentration ratio of bupivacaine was 0.31 and that of etidocaine, 0.25. The umbilical artery--umbilical vein blood concentration difference for etidocaine was significantly higher than that for bupivacaine. Excellent clinical results were obtained using either bupivacaine, 0.75 per cent, alone, or chloroprocaine, 3 per cent- for induction and maintenance of anesthesia, supplemented with bupivacaine, 0.25 per cent, before removal of the catheter.

[The interaction of sedativa with etidocaine in patients with brachial plexus block (author's transl)]. / Die Beeinflussung der Plasmaetidocainspiegel durch Sedativa nach supraclaviculärer Plexusanaesthesie.

The influence of diazepam and phenobarbital on plasma etidocaine concentrations is studied. It is shown that there is no statistical relevant interaction. The mean peak levels occurred within 40 min after application of local anaesthetics and amounted to 1,439 micrograms/ml. The mean half times were calculated and are 135 min.

[Plasma concentrations of etidocaine after supraclavicular plexus block (author's transl)]. / Plasmakonzentrationen des Lokalanästhetikums Etidocain nach supraklavikulärer Plexusanästhesie.

10 patients without concomitant hepatic or renal diseases were given brachial plexus block (Winnie) with etidocaine and the plasma concentrations of the drug were measured. The quantity of local anaesthetic was determined solely by the body weight and amounted to 4 mg/kg body weight. The mean peak concentration was 1.39 microgram/ml, the highest single concentration measured was 1.74 microgram/ml. Peak levels were reached within 40 minutes after administration of the local anaesthetic.

Plasma concentrations of local anaesthetics after interscalene brachial plexus block.

Plasma concentrations of local anaesthetic agents have been measured after 40 interscalene brachial plexus blocks in 39 patients, using lignocaine, prilocaine, bupivacaine and etidocaine. Lignocaine produced greater concentrations than prilocaine, and bupivacaine greater concentrations than etidocaine. The addition of adrenaline resulted in much lower concentrations in the case of all four agents.

Plasma protein binding of etidocaine during pregnancy and labour.

Preliminary studies of the ultrafiltration method for measuring the extent of plasma protein binding of etidocaine showed that etidocaine binding was both pH and concentration dependent. Etidocaine (1 microgram/ml) was found to bind avidly to a physiological concentration (74 mg/dl) of alpha 1-acid glycoprotein (alpha 1-AGP) (7.23 +/- 0.64%, mean +/- SD, unbound). In vitro investigation of etidocaine binding in plasma obtained from blood bank donors and from 19 pregnant women prior to induction of labour, during early labour, mid-labour and delivery showed no difference in etidocaine binding (10.3 +/- 3.3%, 7.06 +/- 2.66%, 8.15 +/- 2.57%, 7.84 +/- 3.74% and 9.28 +/- 6.06% unbound respectively). There was a significant increase in the mean plasma total free fatty acid (FFA) concentration from pre-labour (0.535 +/- 0.240 mM) to delivery (0.948 +/- 0.28 mM), while plasma albumin and beta-lipoprotein concentrations remained constant. Alpha 1-Acid glycoprotein concentration tended to increase slightly from pre-labour to early labour (p less than 0.1) but was still within the normal physiological range. There was no correlation between etidocaine binding ratio and the concentrations of FFA or plasma proteins except for a poor correlation with the alpha 1-AGP concentration (r = 0.361, p less than 0.05). Storage of plasma and inadequate control of plasma pH during ultrafiltration appeared to give spurious binding values. These studies with the extensively bound basic drug etidocaine suggest that unlike many acidic drugs which are bound predominantly to serum albumin, the binding of alpha 1-AGP - bound basic drugs may be unaffected by pregnancy and labour.

Simultaneous measurement of bupivacaine, etidocaine, lidocaine, meperidine, mepivacaine, and methadone.

A gas-liquid chromatographic method for the simultaneous measurement of bupivacaine, etidocaine, lidocaine, meperidine, mepivacaine, and methadone in serum is described. The drugs and the internal standard, prilocaine, are extracted from 1 ml of serum. The procedure involves a two-step extraction and injection of the extract into a gas chromatograph equipped with a 10-ft OV-11 glass column and a nitrogen-phosphorus detector. The temperature gradient program results in a run time of 16 min and retention times for meperidine, prilocaine (internal standard), lidocaine, etidocaine, mepivacaine, methadone, and bupivacaine of 3.8, 5.4, 6.0, 8.7, 11.0, 11.7, and 14.8 min, respectively. Standard curves for all drugs were linear over the 80 to 2,000-ng/ml range and recovery of all components averaged 97 +/- 2% with the lowest detection limit of 10 ng/ml for all drugs except meperidine and methadone, which were 20 ng/ml. The within-day coefficients of variation ranged from 12 to 8% at 500 ng/ml. The day-to-day coefficients of variation of the slope and intercept values ranged from 2 to 0% and 130 to 3%, respectively. Response factors of the nitrogen-specific collector varied with the drug analyzed and resulted in peak area variation at constant offset and attenuation of 30%. This method is intended and adequate for therapeutic monitoring of chronically treated pain patients who are being given various combinations of local anesthetic and/or narcotic agents.

[The quantitative analysis of amide local anesthetics using high pressure liquid chromatography and ultraviolet detection (HPLC/UV)]. / Die quantitative Analyse von Amid-Lokalanaesthetika mittels Hochdruck-Flüssigkeits-Chromatographie und UV-Detektion (HPLC/UV).

This study was undertaken to develop a time- and cost-effective method for the detection of lidocaine, mepivacaine, prilocaine, bupivacaine, and etidocaine by HPLC/UV. The chromatographic system consisted of a C18-column (300 x 3.9 mm) for reversed-phase chromatography and a mobile phase of 30% acetonitrile and 70% 0.05 M sodium phosphate buffer. For the analysis of lidocaine, mepivacaine, and prilocaine, the buffer was adjusted to pH 5.8. The buffer for the analysis of bupivacaine and etidocaine was adjusted to pH 3.5. The flow rate was 1 ml/min. UV detection took place at a wavelength of 210 nm. All blood samples were taken from a central venous line. After plasma separation, 1 microgram (100 microliters) of internal standard was added to 1 ml plasma. The samples were alkalized and extracted with ether, followed by the extraction of the organic phase in 250 microliters 0.05 N sulphuric acid; 50 microliters of this solution was injected into the system. The chromatographic system allowed the separation of bupivacaine and etidocaine (pH 3.5) as well as lidocaine and mepivacaine or prilocaine (pH 5.8). Separation of prilocaine and mepivacaine in one run was not satisfactory. Recovery rates for all local anesthetic substances were about 90%, standard variations below 3%, and coefficients of variation below 2%. The detection limit was about 30 ng/ml. The method is suitable for clinical practice. Only minor methodological modifications are necessary for the detection of the amide local anesthetics in current clinical use.

Thoracic epidural analgesia III--prolongation in the early postoperative period by intermittent injections of etidocaine with adrenaline.

In 38 patients who had undergone elective upper abdominal surgery, postoperative analgesia was obtained by thoracic epidual analgesia, prolonged by intermittent injections of 3.0, 4.0 and 5.0 ml, respectively, of 1.0% etidocaine with adrenaline 1:200,000. The spread of analgesia after repeated doses is given, as are also the incidences of incomplete analgesia and urinary retention. Signs of tachyphylaxis were noticed. Decreases in the systolic blood pressure were evident, especially after the first injections in the three groups investigated. The falls in blood pressure in the 5 ml group were so pronounced that this part of the study had to be terminated. Accumulation of etidocaine in plasma was noticed in all groups. The clinical implications of the method are discussed.

The effects of adding adrenaline to etidocaine and lignocaine in extradural anaesthesia II: Pharmacokinetics.

The addition of adrenaline to solutions of etidocaine or lignocaine for extradural administration resulted in significantly lower plasma koncentrations in both the arterial blood (14% decrease for etidocaine and 43% decrease for lignocaine) and venous blood (35% and 60% decreases for etidocaine and lignocaine respectively). The nett absorption over the first 4 h after administration, measured from the area under the plasma concentration-time curve, was decreased by the addition of adrenaline (18% and 30% decreases for etidocaine and lignocaine respectively). Both drugs were absorbed in a biexponential manner, having similar fast absorption rates but with etidocaine having a longer absorption half-life in the slow absorption phase. It is concluded that the addition of adrenaline reduces the fraction of the dose being absorbed during the first (fast) phase rather than influencing the absorption rate constants.

Bupivacaine (Marcaine): an evaluation of its tissue and systemic toxicity in humans.

In countries other than the U.S.A., dosages of bupivacaine have been limited to 100 mg without epinephrine and 150 mg with epinephrine. A review of 7,688 regional block procedures employing bupivacaine in concentrations of 0.25, 0.5, and 0.75%, and in dosages as high as 600 mg, indicated that such stringent restrictions: (1) are unwarranted, (2) make comparisons with other local anesthetic agents difficult, and (3) are in need of revision.

Topical bupivacaine and etidocaine analgesia following fallopian tube banding.

The purpose of this study was to compare the effectiveness and safety of etidocaine and bupivacaine for postoperative analgesia after laparoscope sterilization. The study was performed in 22 healthy patients who received either one per cent etidocaine, 2 mg.kg-1, or bupivacaine 1.5 mg.kg-1 in a double-blind, randomized fashion. The local anaesthetic was dropped onto the fallopian tubes from uterus to fimbriae before tubal occlusion. To establish safety, blood concentrations of the parent drug and its metabolites were measured before application and at 1, 3, 6, 10, 15, 30, 60 and 120 min. The mean peak concentrations were 501.8 +/- 71.3 (SEM) for etidocaine with a range of 225 to 905 ng.ml-1. For bupivacaine, the mean peak concentration was 468 +/- 73.8 SEM with a range from 191 to 1005 ng.ml-1. The mean values are one eighth of the toxic convulsive dose for humans. Etidocaine was metabolized at a faster rate than bupivacaine with a rapid appearance of 2-amino-2'-butyroxylidide (ABX). The bupivacaine metabolite 2,6-pipecoloxylidide (PPX) was detected in low concentrations in the 60-minute samples. We conclude that the topical application of either etidocaine or bupivacaine is a safe procedure in the doses and concentrations used during general anaesthesia for laparoscopic tubal banding.

Paracervical block with etidocaine for out-patient abortion.

Paracervical block using etidocaine 0.5 % and 1.0 % without adrenaline proved to be an effective anaesthetic procedure for first trimester abortion performed by surgical dilatation of the cervix and subsequent vacuum suction. Three blocks out of 24 were inadequate, probably due to inaccurate deposition of the local anaesthetic. There were two adverse reactions, possibly as a result of inadvertant intravascular injection. The need for long-acting agents for the present indication is questioned.