Rate-dependent effects of lidocaine on cardiac dynamics: Development and analysis of a low-dimensional drug-channel interaction model.

State-dependent sodium channel blockers are often prescribed to treat cardiac arrhythmias, but many sodium channel blockers are known to have pro-arrhythmic side effects. While the anti and proarrhythmic potential of a sodium channel blocker is thought to depend on the characteristics of its rate-dependent block, the mechanisms linking these two attributes are unclear. Furthermore, how specific properties of rate-dependent block arise from the binding kinetics of a particular drug is poorly understood. Here, we examine the rate-dependent effects of the sodium channel blocker lidocaine by constructing and analyzing a novel drug-channel interaction model. First, we identify the predominant mode of lidocaine binding in a 24 variable Markov model for lidocaine-sodium channel interaction by Moreno et al. Specifically, we find that (1) the vast majority of lidocaine bound to sodium channels is in the neutral form, i.e., the binding of charged lidocaine to sodium channels is negligible, and (2) neutral lidocaine binds almost exclusively to inactivated channels and, upon binding, immobilizes channels in the inactivated state. We then develop a novel 3-variable lidocaine-sodium channel interaction model that incorporates only the predominant mode of drug binding. Our low-dimensional model replicates an extensive amount of the voltage-clamp data used to parameterize the Moreno et al. model. Furthermore, the effects of lidocaine on action potential upstroke velocity and conduction velocity in our model are similar to those predicted by the Moreno et al. model. By exploiting the low-dimensionality of our model, we derive an algebraic expression for level of rate-dependent block as a function of pacing frequency, restitution properties, diastolic and plateau potentials, and drug binding rate constants. Our model predicts that the level of rate-dependent block is sensitive to alterations in restitution properties and increases in diastolic potential, but it is insensitive to variations in the shape of the action potential waveform and lidocaine binding rates.

Assessment of Drug Delivery Kinetics to Epidermal Targets In Vivo.

It has proven challenging to quantify 'drug input' from a formulation to the viable skin because the epidermal and dermal targets of topically applied drugs are difficult, if not impossible, to access in vivo. Defining the drug input function to the viable skin with a straightforward and practical experimental approach would enable a key component of dermal pharmacokinetics to be characterised. It has been hypothesised that measuring drug uptake into and clearance from the stratum corneum (SC) by tape-stripping allows estimation of a topical drug's input function into the viable tissue. This study aimed to test this idea by determining the input of nicotine and lidocaine into the viable skin, following the application of commercialised transdermal patches to healthy human volunteers. The known input rates of these delivery systems were used to validate and assess the results from the tape-stripping protocol. The drug input rates from in vivo tape-stripping agreed well with the claimed delivery rates of the patches. The experimental approach was then used to determine the input of lidocaine from a marketed cream, a typical topical product for which the amount of drug absorbed has not been well-characterised. A significantly higher delivery of lidocaine from the cream than from the patch was found. The different input rates between drugs and formulations in vivo were confirmed qualitatively and quantitatively in vitro in conventional diffusion cells using dermatomed abdominal pig skin.

A weight of evidence assessment of the genotoxicity of 2,6-xylidine based on existing and new data, with relevance to safety of lidocaine exposure.

Lidocaine has not been associated with cancer in humans despite 8 decades of therapeutic use. Its metabolite, 2,6-xylidine, is a rat carcinogen, believed to induce genotoxicity via N-hydroxylation and DNA adduct formation, a non-threshold mechanism of action. To better understand this dichotomy, we review literature pertaining to metabolic activation and genotoxicity of 2,6-xylidine, identifying that it appears resistant to N-hydroxylation and instead metabolises almost exclusively to DMAP (an aminophenol). At high exposures (sufficient to saturate phase 2 metabolism), this may undergo metabolic threshold-dependent activation to a quinone-imine with potential to redox cycle producing ROS, inducing cytotoxicity and genotoxicity. A new rat study found no evidence of genotoxicity in vivo based on micronuclei in bone marrow, comets in nasal tissue or female liver, despite high level exposure to 2,6-xylidine (including metabolites). In male liver, weak dose-related comet increases, within the historical control range, were associated with metabolic overload and acute systemic toxicity. Benchmark dose analysis confirmed a non-linear dose response. The weight of evidence indicates 2,6-xylidine is a non-direct acting (metabolic threshold-dependent) genotoxin, and is not genotoxic in vivo in rats in the absence of acute systemic toxic effects, which occur at levels 35 × beyond lidocaine-related exposure in humans.

Prediction of inter-individual variability on the pharmacokinetics of CYP1A2 substrates in non-smoking healthy volunteers.

The activity of CYP1A2, a major drug-metabolizing enzyme, is known to be affected by various environmental factors. Our study aimed to predict inter-individual variability of AUC/Dose of CYP1A2 substrates in non-smoking healthy volunteers using the Monte Carlo simulation. Inter-individual variability in hepatic intrinsic clearance of CYP1A2 substrates (CLint,h,1A2) was estimated using dispersion model based on the inter-individual variability (N = 96) of the AUC of caffeine, a major CYP1A2 substrate. The estimated coefficient of variation (CV) of CLint,h,1A2 was 55%, similar to previously reported CLint,h,2D6 (60%) but larger than CLint,h,3A4 (33%). Then, this estimated CV was validated by predicting the CVs of AUC/Dose of tizanidine and phenacetin, which are mainly metabolized by CYP1A2 and have negligible renal clearance. As a result, reported CVs were successfully predicted within 2.5-97.5 percentile range of predicted values. Moreover, CVs for AUC/Dose of the CYP1A2 substrates theophylline and lidocaine, which are affected by other CYPs and renal clearance, were also successfully predicted. The inter-individual variability of AUC/Dose of CYP1A2 substrates was successfully predicted using 55% CV for CLint,h,1A2, and the results, along with those reported by our group for other CYPs, support the prediction of inter-individual variability of pharmacokinetics in the clinical setting.

Pharmacokinetics of pilsicainide hydrochloride for injection in healthy Chinese volunteers: a randomized, parallel-group, open-label, single-dose study.

BACKGROUND: Pilsicainide hydrochloride is a class IC antiarrhythmic agent used for the treatment of supraventricular and ventricular arrhythmias and atrial fibrillation. OBJECTIVE: The objective of the present study was to determine the pharmacokinetics (PK) of a pilsicainide hydrochloride injection in healthy Chinese adults. The study was conducted to meet China State Food and Drug Administration requirements for the marketing of the new generic formulation of pilsicainide hydrochloride. METHODS: This Phase I, randomized, parallel-group, open-label, single-dose PK study was conducted in healthy Chinese volunteers. Subjects were randomized to receive a single dose of 0.25-, 0.50-, and 0.75-mg/kg pilsicainide hydrochloride with a 10-minute intravenous infusion. Serial blood and urine samples were collected up to 24 hours after dosing; drug concentrations in plasma and urine were then determined by using LC-MS/MS. The PK parameters of pilsicainide were calculated from the plasma concentration-time data according to noncompartmental methods. Safety profile was evaluated by monitoring adverse events, clinical laboratory parameters, and the results of 12-lead ECGs. RESULTS: Thirty healthy volunteers (mean [SD] age, 28.0 [4.95] years; weight, 59.3 [6.51] kg; height, 165.0 [7.25] cm; body mass index, 21.7 [1.94] kg/m(2)) were randomly divided into 3 groups, each consisting of 5 men and 5 women. After single-dose intravenous administration of 0.25, 0.50, and 0.75 mg/kg of pilsicainide hydrochloride, mean Cmax was 0.34 (0.11), 0.54 (0.15), and 1.05 (0.19) µg/mL, respectively; AUC0-24 was 0.76 (0.12), 1.61 (0.37), and 2.61 (0.46) h · µg/mL; and AUC0-∞ was 0.79 (0.13), 1.71 (0.46), and 2.72 (0.50) h · µg/mL. The ranges for t½z, CL, and Vz were 5.19 to 5.98 hours, 4.73 to 5.44 mL/min/kg, and 2.23 to 0.58 L/kg, respectively. The mean urinary recovery rate within 24 hours was 75.0% (12.0%), 65.0% (19.2%), and 66.4% (14.1%). Men and women had significantly different AUC0-24 values in the 0.50-mg/kg dose group (P = 0.044), and Vz showed significant differences between men and women in all 3 dose groups (P = 0.001). According to ECG parameters, PR intervals were significantly prolonged after administration at all 3 doses (P = 0.034, P < 0.001, and P = 0.034); no significant changes were seen in QRS width, QTc interval, or other parameters. CONCLUSIONS: Pilsicainide hydrochloride demonstrated linear PK, and the increase in the exposure of pilsicainide (AUC0-24 and AUC0-∞) was dose proportional after single doses of 0.25, 0.50, and 0.75 mg/kg. All 3 pilsicainide hydrochloride doses were well tolerated in these Chinese volunteers. ChiCTR-ONC-13003546.

A microfluidic approach for in vitro assessment of interorgan interactions in drug metabolism using intestinal and liver slices.

Over the past two decades, it has become increasingly clear that the intestine, in addition to the liver, plays an important role in the metabolism of xenobiotics. Previously, we developed a microfluidic-based in vitro system for the perifusion of precision-cut liver slices for metabolism studies. In the present study, the applicability of this system for the perifusion of precision-cut intestinal slices, and for the sequential perifusion of intestinal and liver slices, all from rat, was tested to mimic the in vivo first pass situation. Intestinal and liver slices, exposed to the substrates 7-ethoxycoumarin (7-EC), 7-hydroxycoumarin (7-HC) and lidocaine (Li), exhibited similar metabolic rates in the biochip and in the well plates for periods of at least 3 h. The metabolic rate remained the same when two slices were placed in adjacent microchambers and perifused sequentially. In addition, the system has been adapted to sequentially perifuse intestinal and liver tissue slices in a two-compartment co-culture perfusion system with a continuous flow of medium. It becomes possible to direct metabolites or other excreted compounds formed by an intestinal slice in the first compartment to the second compartment containing a liver slice. The intestine does not influence liver metabolism for these substrates. The interplay between these two organs was demonstrated by exposing the slices to the primary bile acid, chenodeoxycholic acid (CDCA). CDCA induced the expression of fibroblast growth factor 15 (FGF15) in the intestinal slice, which resulted in a stronger down-regulation of the enzyme, cytochrome P450 7A1 (CYP7A1), in the liver slice in the second compartment than when the liver slice was exposed to CDCA in a single-microchamber biochip. We thus demonstrate in this paper that intestinal slices, in addition to liver slices, remain functional in the biochip under flow conditions, and that the two-microchamber biochip has great potential for the study of interorgan effects. This is the first example of the incorporation of both liver and intestinal slices in a microfluidic device. Use of this microfluidic system will improve our insight into interorgan interactions and elucidate as yet unknown mechanisms involved in toxicity, gene regulation and drug-drug interactions.

Simultaneous assessment of pharmacokinetics of pilsicainide transdermal patch and its electropharmacological effects on atria of chronic atrioventricular block dogs.

Pharmacokinetics of pilsicainide transdermal patch and its electropharmacological effects were simultaneously assessed using chronic atrioventricular block dogs. After application of the patch (9.8 mg/kg), pilsicainide was continuously absorbed through the skin with a C(max) of 0.49 +/- 0.13 microg/ml, while its plasma concentration was kept above the clinically reported minimum effective plasma concentration for 2 - 8 h. Inter-atrial conduction time was significantly prolonged, whereas statistically significant prolongation was not detected in the atrial effective refractory period. Prolongation of the cycle length of atrial fibrillation and anti-fibrillatory action were confirmed. Thus, pilsicainide can be absorbed transdermally to exert long-lasting electropharmacological effects leading to anti-atrial fibrillatory action.

Assessment of liver function in children with acute lymphoblastic leukemia in remission.

PURPOSE: Acute lymphoblastic leukemia (ALL) is the most common malignant neoplasm in children. Antineoplastic treatment alone or with coexisting chronic viral hepatitis may permanently impair liver function. The aim of this study was to examine the effect of ALL and chronic viral hepatitis on the pharmacokinetics of lidocaine and its metabolite MEGX. MATERIAL AND METHODS: We enrolled 17 children and young adults with ALL in remission. Mean remission time was 61 +/- 30 months. Eleven patients were also infected with chronic viral hepatitis type B and/or type C. The control group comprised 12 healthy children. Lidocaine and MEGX pharmacokinetics were studied after intravenous administration of 1 mg/kg lidocaine. Serum samples were obtained at 15, 30, 60, 120, 240, and 360 min. from drug administration and were processed for separation by high-performance liquid chromatography. Statistical analysis was performed with Student's t-test. RESULTS: Elevated serum concentrations of MEGX 30 min. after lidocaine administration were observed in patients with ALL and hepatitis. The remaining pharmacokinetic parameters of lidocaine and MEGX did not differ significantly between groups. Our results suggest that pharmacokinetics of lidocaine and MEGX remain essentialy unaltered in ALL with coexisting chronic hepatitis.

Porcine ear skin as a model for the assessment of transdermal drug delivery to premature neonates.

PURPOSE: The purpose of this study was (i) to validate differentially tape-stripped, porcine skin as an in vitro model for the evaluation of transdermal drug delivery (TDD) to premature neonates, (ii) to determine whether the model could estimate neonatal skin permeability as a function of postconceptional age (PCA), and (iii) to demonstrate that iontophoretic delivery permits precise control of drug input independent of skin barrier function. METHODS: Passive permeation of caffeine, phenobarbital, and lidocaine across tape-stripped porcine skin barriers was measured. Iontophoretic delivery of lidocaine across skins with different barrier competencies was also evaluated. RESULTS: For all drugs, passive permeation correlated with skin barrier function; that is, with transepidermal water loss (TEWL): Jss = A x exp[B x TEWL]. Combining this result with a previously derived dependence of TEWL upon the PCA of premature neonates in vivo allowed a relative value of Jss to be predicted for a given PCA. Comparison of these predictions showed excellent agreement with experimental data reported for diamorphine. Iontophoretic lidocaine delivery was precisely controllable independent of barrier competency. CONCLUSIONS: Porcine skin, in vitro, differentially tape-stripped to specific barrier competencies, is a useful model to explore TDD in premature neonates. The potential for iontophoresis to provide improved dose control and adjustment, irrespective of skin barrier maturity, is established.

Assessment of hepatic function in cystic fibrosis by lidocaine metabolism.

BACKGROUND: To determine hepatic drug metabolism in patients with cystic fibrosis, as measured by monoethylglycinexylidide formation after lidocaine injection and indocyanine green (ICG) clearance. METHODS: The following study is a case-control study, which included 19 patients with cystic fibrosis and 13 control subjects. Serum monoethylglycinexylidide concentration was measured after intravenous injection of 1 mg/kg (maximum, 50 mg) lidocaine. Indocyanine green (0.5 mg/kg) was injected concomitantly, and absorbance (805 nm) of serum was measured over time to determine its volume of distribution, serum half-life, and hepatic blood flow. RESULTS: Monoethylglycinexylidide formation was decreased in patients with cystic fibrosis compared with controls (39.4+/-16.9 microg/L versus 70.3+/-45.7 microg/L, mean +/- SD, respectively, P < 0.02). Indocyanine green half-life (4.6+/-2.7 min versus 3.0+/-1.0 min), volume of distribution (8.6+/-5.5 L versus 8.3+/-3.4 L), and hepatic blood flow (10.9+/-5.9 ml x kg(-1) x min(-1) versus 7.4+/-2.0 ml x kg(-1) x min(-1)) were similar in both groups. CONCLUSION: Monoethylglycinexylidide formation after lidocaine injection is impaired in patients with cystic fibrosis. This impairment may have clinical implications when using hepatically metabolized medications in patients with cystic fibrosis.

The MEGX test: a tool for the real-time assessment of hepatic function.

The dynamic liver function test based on the hepatic conversion of lidocaine to monoethylglycinexylidide (MEGX) can complement established static liver function tests if prognostic information is of particular interest. Because of its ease of use and rapid turnaround, the MEGX test has found widespread application for realtime assessment of hepatic function in transplantation, critical care medicine, and various experimental models. Lidocaine is metabolized primarily by the liver cytochrome P450 system through sequential oxidative N-dealkylation, the major initial metabolite in humans being MEGX. Because of the relatively high extraction ratio of lidocaine, this liver function test depends not only on hepatic metabolic capacity but also on hepatic blood flow. For the determination of MEGX in serum, an immunoassay based on the fluorescence polarization immunoassay technique high-performance liquid chromatography and gas liquid chromatography methods have been described. Whereas high-performance liquid chromatography and gas liquid chromatography are specific for MEGX, the fluorescence polarization immunoassay also cross-reacts with 3-OH-MEGX. Although this is not a problem in humans, some species, such as the rat, produce significant amounts of this metabolite. The findings of most studies published so far suggest that the MEGX test is a useful tool that can improve our decision-making process with respect to the selection of transplant candidates. Patients with a MEGX 15- or 30-minute test value <10 microg/L have a particularly poor 1-year survival rate. Serial monitoring of liver graft recipients early after transplantation with the MEGX test may initially alert the clinician to a major change in liver function; if used with other tests, such as serum hyaluronic acid concentrations, it may become more discriminatory. In critically ill patients, several studies have shown that an initially rapid decrease in MEGX test values is associated with an enhanced risk for the development of multiple organ dysfunction syndrome and a poor outcome. Further, this decrease appears to be associated with an enhanced systemic inflammatory response. The MEGX test has potential for investigating the pathogenesis of multiple organ dysfunction syndrome with regard to early hepatic functional impairment in critically ill patients after polytrauma or sepsis.

Assessment of rate of drug release from oil vehicle using a rotating dialysis cell.

The rate constants for transfer of model compounds (naproxen and lidocaine) from oily vehicle (Viscoleo) to aqueous buffer phases were determined by use of the rotating dialysis cell. Release studies were done for the partly ionized compounds at several pH values. A correlation between the overall first-order rate constant related to attainment of equilibrium, k(obs), and the pH-dependent distribution coefficient, D, determined between oil vehicle and aqueous buffer was established according to the equation: logk(obs)=-0.71 logD-0.22 (k(obs) in h(-1)). Based on this correlation it was suggested that the rate constant of a weak electrolyte at a specified D value could be considered equal to the k(obs) value for a non-electrolyte possessing a partition coefficient, P(app), the magnitude of which was equal to D. Specific rate constants k(ow) and k(wo) were calculated from the overall rate constant and the pH-dependent distribution coefficient. The rate constant representing the transport from oily vehicle to aqueous phase, k(ow), was found to be significantly influenced by the magnitude of the partition coefficient P(app) according to: logk(ow)=-0.71 logP(app)-log(P(app)+1)-0.22 (k(ow) in h(-1)).

Early assessment of transplanted liver function: lignocaine clearance test (MEGX).

The purpose of this study was to assess the value of lignocaine biotransformation into monoethylglycinexylidide (MEGX) and conventional liver function tests in the early post-operative period as an indicator of graft function and as a diagnostic tool for complications after hepatic transplantation. Monoethylglycinexylidide formation, plasma bilirubin, aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), factor V index (FVI) and prothrombin time index (PTI) were measured in 71 patients undergoing 80 liver transplantations respectively at 12 (T1), 24 (T2), 48 (T3) and 72 h (T4) after liver graft revascularization. Patients were divided into two group according to the post-operative outcome. Patients with favourable outcome (n = 59) had significantly higher monoethylglycinexylidide synthesis, higher factor V index and prothrombin time index plasma concentrations, lower bilirubin, ASAT and ALAT plasma concentration (P < 0.0001 at T2 and T3) than those with complicated time course (n = 21). Monoethylglycinexylidide synthesis was the best discriminant of a favourable outcome, whereas bilirubin and ALAT concentrations were associated with complications (bilirubin for primary non function [PNF], ALAT for acute rejection). Thus, the combination of parameters at T2 was a very efficient predictor of primary non function, acute rejection and an uncomplicated time course.

The low-dose monoethylglycinexylidide test: assessment of liver function with fewer side effects.

The hepatic metabolism of lidocaine (1 mg/kg intravenously) to its metabolite monoethylglycinexylidide (MEG-X) is the basis of the standard MEG-X test. To reduce the lidocaine-induced side effects, we evaluated the MEG-X formation after 0.5 and 1 mg/kg lidocaine intravenously in subjects with normal (n = 5) and severely impaired liver function (n = 7) (study I). From this study, a low-dose test (MEG-X concentration 30 minutes after 50 mg lidocaine intravenously [MEG-X30min] normalized to standard MEG-X test results) was developed. Sensory side effects from this low dose and from the standard MEG-X test were compared in a double-blind, randomized, cross-over study (study II) comprising 15 individuals with normal liver function and 45 patients with cirrhosis (15 Child A, 15 Child B, and 15 Child C). In study I, MEG-X formation rate was dose-independent in patients with severely impaired liver function. In study II, normalized MEG-X test results (ranging from < or = 4 to 120 microg/L) were virtually identical to the standard test results (mean difference: -1.9 microg/L; 95% confidence interval [CI]: -5.3; 1.5 microg/L). Fewer individuals experienced side effects (30% vs. 53%) with the low-dose test (P = .0013). In a multivariate analysis, the Child-Pugh score was inversely related to the occurrence of side effects. The low-dose MEG-X test gives almost identical results to the standard MEG-X test and is associated with fewer side effects, which occur less often in individuals with more severely compromised liver function.

Assessment of metabolic liver function and hepatic blood flow during cardiopulmonary bypass.

A modified monoethylglycinexylidide (MEGX) test was performed in 14 patients undergoing myocardial revascularization to evaluate liver function during cardiopulmonary bypass (CPB). MEGX is the principal metabolite of lidocaine. Different studies have shown a decrease in MEGX formation in patients with impaired liver function. Following a low-dose bolus application of 0.3 mg/kgBW lidocaine MEGX concentrations were measured in five-minute intervals for half an hour. This was done once before and once during CPB. Arterial and hepatic vein blood samples were obtained in order to avoid the effects of hemodilution by CPB priming. Hepatic blood was calculated using the indocyanine green (ICG) infusion extraction technique. MEGX formation during CPB decreased. After the 10 and 15 minutes measurement points the mean arterio-hepatic venous concentrations were 61 +/- 7.2 micrograms/L and 63 +/- 7.3 micrograms/L respectively in comparison to pre-CPB values of 36 +/- 5.8 micrograms/L and 42 +/- 5.1 micrograms/L. Hepatic blood flow increased insignificantly from a mean of 835 +/- 54 ml/min prior to CPB to 913 +/- 83 ml/min during CPB. As a result the MEGX clearance calculated 15 minutes after administration of lidocaine bolus application did not differ significantly before (51.2 +/- 6.4 micrograms/min) and during CPB (40.2 +/- 5.7 micrograms/min). In conclusion, a decrease in MEGX formation was found during CPB. However, due to increased hepatic blood flow there was no significant change in MEGX clearance before and during CPB.

Assessment of liver function: the current situation.

Hepatologists continue to search for a safe, accurate, and reliable method to quantify hepatic function similar in principle to the creatinine clearance for renal disease or spirometry for pulmonary disease. When evaluating patients with advanced decompensated chronic liver disease, there is little need for such tests and a decision for or against liver transplantation is all that is required. However, in patients with chronic compensated liver disease, an estimate of hepatic function based on objective criteria would be most valuable in establishing a prognosis and in determining a treatment plan. The best methods currently available for this purpose consist of the use of model drugs which are metabolized exclusively by the liver by cytochromes P-450 enzyme systems. The alterations in pharmacokinetic parameters (i.e., clearance rate of the parent compound or formation rate of one of its metabolites, etc.) produced as a result of liver disease can be quantitated. The results obtained can be utilized as a measure of hepatic function. The two drugs most commonly utilized for this purpose are lidocaine and caffeine. The advantages and disadvantages of each of these two drugs as probes of hepatic function are herein reviewed.

[Feasibility assessment of skin permeation for the local anesthetic lidocaine].

In this paper, the feasibility of skin permeation for lidocaine and pressure sensitive adhesive (PSA) tape formulation containing lidocaine for skin local anesthetic were assessed. Firstly, in vitro skin permeation of the molecular and ionic forms of lidocaine from water and silicone fluid suspensions was measured using a side-by-side two diffusion cells and excised hairless rat skin. Secondly, PSA tape containing lidocaine was prepared by a general casting method using styrene-isoprene-styrene block copolymer. The in vitro release and skin permeation were evaluated and compared with that of Japan marketed xylocaine jelly. The effect of lidocaine concentration on the steady-state flux of skin permeation from 10% to 60% lidocaine PSA tapes was also evaluated.

Valoración cinética y dinámica de la lidocaína y mepivacaína en odontopediatría / Kinetic and dynamic evaluation of lidocaine and mepivacaine in pediatric dentistry

En una población pediátrica de 20 niños se evalúa el comportamiento cinético y dinámico dela lidocaína y mepivacaína asociados con adrenalina, con referencia específica al período de latencia, profundidad y duración del efecto anestésico

The role of dynamic and morphological studies in the assessment of potential liver donors.

In a prospective study, 66 donor livers were evaluated by monoethylglycinexylidide (MEGX) dynamic clearance and semiquantitative scoring of pathological changes in liver biopsies. The median MEGX level in 63 donors was 89 mcg/L (range 16-250 mcg/L); fifteen had MEGX levels < 50 mcg/L, 17 between 50 and 90 mcg/L, and 31 > 90 mcg/L. There were no cases of primary nonfunction, and no deaths were related to poor graft function. There was no statistically significant difference in peak aspartate aminotransferase (AST), day 5 AST, peak bilirubin, or lowest prothrombin time among the 3 groups. Liver biopsies were assessed in 61 donors: 33 (54%) were normal and 17 (28%) showed mild, 8 (13%) showed moderate, and 3 (5%) showed severe steatosis. Postperfusion biopsy assessing the extent of preservation injury was essentially normal or showed minimal change in 16 (26%), mild change in 29 (48%), moderate in 13 (21%) and severe abnormalities in 3 (5%). The latter 3 biopsies all had severe steatosis. There was no significant difference in early graft function or outcome between moderate/severe groups and normal/minimal groups, although the former had a higher peak AST (P < 0.02) and peak bilirubin (P < 0.004). This detailed prospective analysis suggests that MEGX and the morphological studies may assist in the assessment of potential liver donors but they do not provide a basis on which grafts should be discarded.

Noninvasive assessment of anesthetic activity of topical lidocaine formulations.

The effectiveness of a series of lidocaine formulations in producing anesthesia after topical application was evaluated in human volunteers. The formulations, five suspensions in 20% propylene glycol and one cream, were applied to the forearms for 3 h with occlusion with Hilltop chambers. Testing for anesthesia was performed electrometrically. All lidocaine-containing formulations produced significantly greater anesthesia than the blanks. The formulation containing tetradecyltrimethylammonium bromide produced greater anesthesia than that containing octadecyltrimethylammonium chloride. Changing the pH of the formulation from 7.9 to 10.0 had no significant effect. Other formulations (sodium lauryl sulfate and the cream) were no more effective than the plain formulation without surfactants. The rank order for the suspension formulations was the same as for steady-state permeation in in vitro experiments. However, application of the cream formulation produced greater effect in vivo than was anticipated from in vitro flux values.