Jean-Christophe Boyer

A comparison of the pharmacodynamics and pharmacokinetics of bupivacaine, ropivacaine (with epinephrine) and their equal volume mixtures with lidocaine used for femoral and sciatic nerve blocks: a double-blind randomized study.

BACKGROUND: Mixtures of lidocaine with a long-acting local anesthetic are commonly used for peripheral nerve block. Few data are available regarding the safety, efficacy, or pharmacokinetics of mixtures of local anesthetics. In the current study, we compared the effects of bupivacaine 0.5% or ropivacaine 0.75% alone or in a mixed solution of equal volumes of bupivacaine 0.5% and lidocaine 2% or ropivacaine 0.75% and lidocaine 2% for surgery after femoral-sciatic peripheral nerve block. The primary end point was onset time. METHODS: In a double-blind, randomized study, 82 adults scheduled for lower limb surgery received a sciatic (20 mL) and femoral (20 mL) peripheral nerve block with 0.5% bupivacaine (200 mg), a mixture of 0.5% bupivacaine 20 mL (100 mg) with 2% lidocaine (400 mg), 0.75% ropivacaine (300 mg) or a mixture of 0.75% ropivacaine 20 mL (150 mg) with 2% lidocaine (400 mg). Each solution contained epinephrine 1:200,000. Times to perform blocks, onset times (end of injection to complete sensory and motor block), duration of sensory and motor block, and morphine consumption via IV patient-controlled analgesia were compared. Venous blood samples of 5 mL were collected for determination of drug concentration at 0, 5, 15, 30, 45, 60, and 90 min after placement of the block. RESULTS: Patient demographics and surgical times were similar for all four groups. Sciatic onset times (sensory and motor block) were reduced by combining lidocaine with the long-acting local anesthetic. The onset of bupivacaine-lidocaine was 16 ± 9 min versus 28 ± 12 min for bupivacaine alone. The onset of ropivacaine-lidocaine was 16 ± 12 min versus 23 ± 12 for ropivacaine alone. Sensory blocks were complete for all patients within 40 min for those receiving bupivacaine–lidocaine versus 60 min for those receiving bupivacaine alone and 30 min for those receiving ropivacaine–lidocaine versus 40 min for those receiving ropivacaine alone (P < 0.05). Duration of sensory and motor block was significantly shorter in mixture groups. There was no difference among groups for visual analog scale pain scores and morphine consumption during the 48 h postoperative period, except for bupivacaine alone (median: 9 mg) versus bupivacaine–lidocaine mixture (15 mg), P < 0.01. There was no difference in the incidence of adverse events among groups. Plasma concentrations of bupivacaine and ropivacaine were higher, and remained elevated longer, in patients who received only the long-acting local anesthetic compared to patients who received the mixture of long-acting local anesthetic with lidocaine (P < 0.01). CONCLUSION: Mixtures of long-acting local anesthetics with lidocaine induced faster onset blocks of decreased duration. Whether there is a safety benefit is unclear, as the benefit of a decreased concentration of long-acting local anesthetic may be offset by the presence of a significant plasma concentration of lidocaine.

Reversal of bupivacaine-induced cardiac electrophysiologic changes by two lipid emulsions in anesthetized and mechanically ventilated piglets.

BACKGROUND: Accidental IV administration of bupivacaine can compromise cardiovascular function by inducing lethal arrhythmias whose hemodynamic consequences may be alleviated by lipid emulsions. However, little is known about the electrophysiologic effects of lipid emulsions. In this study, we assessed whether 2 different lipid emulsions can reverse cardiac electrophysiologic impairment induced by the IV administration of bupivacaine in anesthetized and mechanically ventilated piglets. METHODS: Bupivacaine (4 mg · kg−1) was injected over a 30-second period in 26 piglets. Thirty seconds after the end of bupivacaine injection, 1.5 mL · kg−1 saline solution for the control group, and long-chain triglyceride emulsion (LCT group) or a mixture of long-chain and medium-chain triglyceride emulsion (LCT/MCT group) were infused over 1 minute. Cardiac conduction variables and hemodynamic variables were monitored for 30 minutes after injection. RESULTS: Bupivacaine induced similar electrophysiologic and hemodynamic changes. After 3 minutes, His ventricle intervals (median and interquartiles) were 100 (85–105), 45 (35–55), and 53 (48–73) milliseconds in the control, LCT, and LCT/MCT groups, respectively (P < 0.001 between control and both lipid emulsion groups). Lipid emulsions also reversed the effects on QRS duration, atrial-His, and PQ (the onset of the P wave to the Q wave of the QRS complex) intervals. LCT/MCT emulsion restored the decrease in maximal first derivative of left ventricular pressure (P < 0.01 after 3 minutes versus control group). CONCLUSIONS: LCT and LCT/MCT emulsions reversed the lengthening of His ventricle, QRS, atrial-His, and PQ intervals induced by the IV injection of 4 mg · kg−1 bupivacaine.

High-resolution melting analysis of sequence variations in the cytidine deaminase gene (CDA) in patients with cancer treated with gemcitabine.

Gemcitabine (2′,2′-difluorodeoxycytidine) is a major antimetabolite cytotoxic drug with a wide spectrum of activity against solid tumors. Hepatic elimination of gemcitabine depends on a catabolic pathway through a deamination step driven by the enzyme cytidine deaminase (CDA). Severe hematologic toxicity to gemcitabine was reported in patients harboring genetic polymorphisms in CDA gene. High-resolution melting (HRM) analysis of polymerase chain reaction amplicon emerges today as a powerful technique for both genotyping and gene scanning strategies. In this study, 46 DNA samples from gemcitabine-treated patients were subjected to HRM analysis on a LightCycler 480 platform. Residual serum CDA activity was assayed as a surrogate marker for the overall functionality of this enzyme. Genotyping of three well-described single nucleotide polymorphisms in coding region (c.79A>C, c.208G>A and c.435C>T) was successfully achieved by HRM analysis of small polymerase chain reaction fragments, whereas unknown single nucleotide polymorphisms were searched by a gene scanning strategy with longer amplicons (up to 622 bp). The gene scanning strategy allowed us to find a new intronic mutation c.246+37G>A in a female patient displaying marked CDA deficiency and who had an extreme toxic reaction with a fatal outcome to gemcitabine treatment. Our work demonstrates that HRM-based methods, owing to their simplicity, reliability, and speed, are useful tools for diagnosis of CDA deficiency and could be of interest for personalized medicine.

p53 and Follow-up of Colorectal Adenocarcinomas

Circulating p53 antibodies (ELISA method), p53genetic alterations (SSCP), and protein overexpression(immunohistochemistry) were studied in 41 patients withcolorectal adenocarcinomas and 10 control patients. Carcinoembryonic antigen (CEA) and carbohydrateantigen 19.9 (CA 19-9) were evaluated in parallel. Tenpatients with p53 antibodies and p53 overexpression wereselected. Tumor DNA extracts from these 10 patients were analyzed by SSCP. Of all 41patients, 10 (24%) showed significant levels of p53antibodies, and p53 accumulation was detected in 20(48%) patients. In six patients, p53 antibodieconcentrations decreased rapidly after surgery; in twopatients, these levels returned to normal values. Of the10 selected tumors, eight revealed TP53 gene mutations.Only two patients with high values of both CEA and CA 19-9 developed p53 antibodies. Inconclusion, beside classical tumor markers, circulatingp53 antibodies may be considered as additional markersfor the management of patients with colorectaladenocarcinomas.

Calcitonin gene-related peptide-induced relaxation of isolated human colonic smooth muscle cells through different intracellular pathways

Calcitonin gene-related peptide (CGRP) plays a significant role in the non-adrenergic non-cholinergic (NANC) regulation of intestinal tract motility. In this work, the contractile properties of enzymatically isolated circular smooth muscle cells (SMC) from human colon in response to CGRP were evaluated. Relaxation by CGRP (1 microM) was determined in cells maximally contracted by carbachol (CCh, 1 nM). Simultaneously, cGMP contents of SMC were measured by radioimmunoassay. CCh-induced contraction was inhibited by 1 microM CGRP (maximum: 69+/-5% within 60 sec); similarly, exposure of cells to sodium nitroprussiate (SNP), 1 microM, fully inhibited contraction (maximum: 89+/-8% within 30 sec). In the same time-course as for relaxation, CGRP and sodium nitroprussiate caused significant increase in intracellular cGMP levels (2- and 10-fold that of the basal level, respectively, P < 0.01). The nitric oxide synthase (NOS) inhibitor, L-N5(I-iminoethyl)ornithine, dihydrochloride, (L-NIO), 1 microM, partly inhibited SMC relaxation induced by CGRP (78.26%); the protein kinase inhibitor, N-(2-aminoethyl)-5-isoquinolinesulfonamide hydrochloride (H9), 1 microM, and the selective cAMP-dependent protein kinase inhibitor, adenosine-3,5-monophosphorothioate triethylammonium salt, Rp isomer, (Rp-cAMP(S)), 1 microM, also caused inhibition of relaxation (70.30% and 28.6%, respectively). In parallel, the increase in cGMP caused by CGRP was partly reduced by L-NIO (65.47%) and by H9 (55%). In conclusion, the nitric oxide generation following exposure of human colonic SMC to sodium nitroprussiate causes relaxation through the cGMP pathway; on the other hand, exposure of SMC to CGRP causes relaxation in part by activation of nitric oxide synthase and guanylate cyclase and in part through the cAMP pathway.

Effect of champagne compared to still white wine on peripheral neurotransmitter concentrations.

To evaluate how the peripheral release of neurotransmitters such as serotonin, dopamine, cholecystokinin, and beta-endorphin is involved in drinking behavior, blood concentrations of these neurotransmitters were followed in 40 healthy young volunteers during the first hour after ingestion of a moderate dose of some common alcoholic beverages (champagne, still white wine) as compared to water. Concerning serotonin levels, two groups of subjects are statistically distinct: one with low basal serotonin levels (< 620 nmol/L) which responded with an increase in serotonin (52% in 10 minutes), and a second group with higher basal serotonin levels (> 620 nmol/L) which responded with a decrease ( 190% in 60 minutes). Variations in serotonin concentrations appear to depend upon the alcoholic content of the beverage. A rapid increase in plasma dopamine concentrations after consumption of champagne seems to be due to the nonalcoholic content of the beverage. Cholecystokinin values were not significantly different between the three beverages: the observed increase can be explained by a moderate gastric distention. Beta-endorphin levels didnt change significantly after drinking. In conclusion, some significant blood variations of serotonin and dopamine appeared even after moderately dose of champagne or still white wine. These changes might be partially responsible for the different drinking behavior.

Differential Responsiveness to Contractile Agents of Isolated Smooth Muscle Cells from Human Colons as a Function of Age and Inflammation

To study the involvement of age and inflammationin motor colonic activity in man, contractile responsesto CCK, carbachol, and KCl of isolated colonic smoothmuscle cells (SMC) from normal and inflamed human colons were evaluated; the incidence ofsex and smoking on contraction was also analyzed.Contractile responses to the three agonists weresignificantly lower in tissues with a low degree ofinflammation than in tissues with high level of inflammationor normal tissues. This reduction in cell responsivenessappears to be nonspecific and nonreceptor mediated. Apositive correlation of the contractile responses to the three stimulants with the age ofpatients was observed. In contrast, no association wasfound between sex, smoking, and cell contraction. Inconclusion, contractions of SMC due to CCK, carbachol, and KCl were significantly modified duringlife; inflammation of the colon led to a loss of SMCresponsiveness.

CK-MB mass test in ischemic myocardial injury. Comparison of two tests: BioMerieux Vidas and sanofi access immunoassays.

The analytical and clinical performances of the new fluorescent immunoassay (CK‐MB mass Vidas‐BioMerieux) were examined and compared to the chemiluminescent test (CK‐MB mass Access‐Sanofi‐Pasteur). Assay precisions of the CK‐MB Vidas test within‐assay or between‐assay were less than 5.4 and 5.3%, respectively. Linearity was tested up to 214 μg/L. The CK‐MB Vidas test was free of interference with CK‐BB, CK‐MM, and macro‐CK. One hundred nineteen blood samples from patients with ischemic myocardial injury (IMI): acute myocardial infarction (AMI), suspected myocardial contusion (SMC), and unstable angina pectoris (UA), were tested using both immunoassays. In AMI, a good correlation was found (Y [CK‐MB Access] = 1.1372 × [CK‐MB Vidas] – 6.3902; r2 = 0.96). In UA and SMC, low values were observed and both methods were well correlated (Y [CK‐MB Access] = 1.3662 × [CK‐MB Vidas] + 0.0671; r2 = 0.97). Clinical data were in good agreement with both immunoassays. ROC analysis performed in AMI demonstrated that the clinical performances of the two assays were similar. J. Clin. Lab. Anal. 14:43–47, 2000.