[Interactions of melatonin with the central nervous system].
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Central Nervous System↗
Biomedical subjects
B Bruguerolle
Publications and source records attributed to B Bruguerolle.
Effect of lithium on norepinephrine metabolic pathways.
We investigated lithium-induced changes in norepinephrine (NE) catabolism. NE and its major metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3,4-dihydroxyphenyl glycol (DHPG), ions such as lithium (Li(+)), magnesium (Mg(2+)), and potassium (K(+)) were measured in rat plasma and cerebral cortex using an HPLC method with electrochemical detection for amines. The results obtained with a group of rats treated by lithium chloride (2 mmol/kg/IP) were compared with a control group receiving sodium chloride (2 mmol/kg/IP). Animals were killed at different times over a period of six hours in the morning following salt administration to minimize possible chronobiological effects. There are two pathways leading to MHPG formation: way A, without DHPG, and way B, with DHPG. In plasma and cerebral cortex of lithium treated rats, way A catabolism seems to be preferential. Lithium increases Mg(2+) and K(+) plasma levels. These results suggest that lithium may increase inactivation of NE and decrease NE available for adrenergic receptors.
Animals↗
Effects of three-hour restricted food access during the light period on circadian rhythms of temperature, locomotor activity, and heart rate in rats.
The effects of food on biological rhythms may influence the findings of chronopharmacological studies. The present study evaluated the influence of a restricted food access during the rest (light) span of nocturnally active Wistar rats on the 24 h time organization of biological functions in terms of the circadian rhythms of temperature (T), heart rate (HR), and locomotor activity (LA) in preparation for subsequent studies aimed at evaluating the influence of timed food access on the pharmacokinetics and pharmacodynamics of medications. Ten-wk-old male Wistar rats were housed under controlled 12:12 h light:dark (LD) environmental conditions. Food and water were available ad libitum, excepted during a 3 wk period of restriction. Radiotelemetry transmitters were implanted to record daily rhythms in T, HR, and LA. The study lasted 7 wk and began after a 21-d recovery span following surgery. Control baseline data were collected during the first wk (W1). The second span of 3 wk duration (W2 to W4) consisted of the restricted feeding regimen (only 3 h access to food between 11:00 and 14:00 h daily) during the L (rest span) under 12:12 h LD conditions. The third period of 3 wk duration (W5 to W7) consisted of the recovery span with ad libitium normal feeding. Weight loss in the amount of 5% of baseline was observed during W1 with stabilization of body weight thereafter during the remaining 2 wk of food restriction. The 3 h restricted food access during the L rest span induced a partial loss of circadian rhythmicity and the emergence of 12 h rhythms in T, HR, and LA. Return to ad libitum feeding conditions restored circadian rhythmicity in the manner evidenced during the baseline control span. Moreover, the MESORS and amplitudes of the T, HR, and LA 24 h patterns were significantly attenuated during food restriction (p < 0.001) and then returned to initial values during recovery. These changes may be interpreted as a masking effect, since T, HR, and LA are known to directly react to food intake. The consequences of such findings on the methods used to conduct chronokinetic studies, such as the fasting of animals the day before testing, are important since they may alter the temporal structure of the organism receiving the drug and thereby compromise findings.
Animals↗
High plasma ropivacaine concentrations after fascia iliaca compartment block in children.
BACKGROUND: The pharmacokinetic profile of local anaesthetics is influenced by the mode of administration. We sought to compare the pharmacokinetics of two doses of ropivacaine after fascia iliaca compartment (FIC) block in children. METHODS: In this prospective, double-blind study, children received an FIC block as a part of their anaesthetic management during elective orthopaedic surgery on the thigh. They were randomized to receive ropivacaine 0.7 ml x kg(-1) using either a 0.375% or 0.5% solution. Venous blood samples were drawn up to 6 h after injection. Plasma concentrations of ropivacaine were measured by gas-liquid chromatography. RESULTS: Six children (10.2 (range 5-15) yr, 35.6 (sd 10) kg were included. FIC block provided satisfactory peroperative pain relief. No signs of toxicity were observed, but high maximal plasma concentrations (C(max) 4.33-5.6 microg ml(-1)), were observed for three of four patients in the ropivacaine 0.5% group. The two patients in the 0.375% group showed values within the safe range (C(max) 0.66 and 0.98 microg ml(-1) respectively). Even though no toxic effects were observed, these results led us to discontinue the study. CONCLUSIONS: The administration of ropivacaine 3.5 mg x kg(-1) can be associated with sustained high plasma concentrations of ropivacaine, outside the tolerable range. In view of these results, we recommend the use of lower ropivacaine dosage during FIC block in children.
Adolescent↗
Air-stepping in neonatal rats: A comparison of L-dopa injection and olfactory stimulation.
The kinematic parameters of air-stepping induced by 2 methods known to elicit locomotion (olfactory stimulation vs. L-dopa injection) were compared in 3-day-old rats. In the 1st stage, suspended pups were induced to step with an olfactory stimulus of soiled shavings from the nest. In the 2nd stage, they received a subcutaneous injection of L-dopa. Their movements were faster, with a larger amplitude and a phase delay in ipsilateral coupling. Third, the olfactory stimulus was presented in conjunction with L-dopa. The characteristics of locomotion returned to the same level as with the olfactory stimulus alone. These results suggest that olfactory stimulation involves higher nerve centers able to modulate the dopaminergic pathways. They are discussed in relation to the neural structure involved in locomotion.
Animals↗
Lack of daily rhythms major modifications despite continuous infusion of melatonin in the rat.
The present study was conducted to evaluate the effect of melatonin on the daily rhythms of temperature, heart rate and locomotor activity in rats that received subcutaneously a continuous infusion of two different doses e.g. 1 and 5 mg/kg per day for seven days. Our results indicate that melatonin does not induce a loss of the daily rhythmicity of temperature, heart rate and locomotor activity. Whatever the dose, melatonin slightly modifies the main parameters of these rhythms e.g. a decrease of the amplitude of the daily rhythms of temperature and heart rate and an increase of the mesor of temperature. Taking into account these results obtained after constant rate delivery in normal rats, we plan now to investigate the effects of melatonin on our experimental model of Parkinson's disease (double bilateral intrastriatal 6-hydroxydopamine injection).
Analysis of Variance↗
Chronotherapy and compliance: impairment or improvement?
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Chronotherapy↗
A double blind parallel group placebo controlled comparison of sedative and mnesic effects of etifoxine and lorazepam in healthy subjects [corrected].
This paper describes the psychomotor and mnesic effects of single oral doses of etifoxine (50 and 100 mg) and lorazepam (2 mg) in healthy subjects. Forty-eight healthy subjects were included in this randomized double blind, placebo controlled parallel group study [corrected]. The effects of drugs were assessed by using a battery of subjective and objective tests that explored mood and vigilance (Visual Analog Scale), attention (Barrage test), psychomotor performance (Choice Reaction Time) and memory (digit span, immediate and delayed free recall of a word list). Whereas vigilance, psychomotor performance and free recall were significantly impaired by lorazepam, neither dosage of etifoxine (50 and 100 mg) produced such effects. These results suggest that 50 and 100 mg single dose of etifoxine do not induce amnesia and sedation as compared to lorazepam.
Adolescent↗
Continuous fascia iliaca compartment block in children: a prospective evaluation of plasma bupivacaine concentrations, pain scores, and side effects.
UNLABELLED: We sought to determine the plasma concentrations of bupivacaine and its main metabolite after continuous fascia iliaca compartment (FIC) block in children. Twenty children (9.9 +/- 4 yr, 38 +/- 19 kg) received a continuous FIC block for either postoperative analgesia (n = 16) or femoral shaft fracture (n = 4). A bolus dose of 0.25% bupivacaine (1.56 +/- 0.3 mg/kg) with epinephrine was followed by a continuous administration of 0.1% bupivacaine (0.135 +/- 0.03 mg. kg(-)(1). h(-)(1)) for 48 h. Plasma bupivacaine levels were determined at 24 h and 48 h by using gas liquid chromatography. Heart rate, arterial blood pressure, respiratory rate, side effects, and pain scores were recorded at 4-h intervals during 48 h. No significant differences were found between mean plasma bupivacaine levels at 24 h (0.71 +/- 0.4 microg/mL) and at 48 h (0.84 +/- 0.4 microg/mL) (P = 0.33). FIC block provided adequate analgesia in most cases. No severe adverse effects were noted. We conclude that the bupivacaine plasma concentrations during continuous FIC block in children are within the safety margins. FIC block is well tolerated, and provides satisfactory pain relief in most cases. IMPLICATIONS: In this study, we have shown that, in children, continuous fascia iliaca compartment block, a technique providing neural blockade of the thigh and the anterior part of the knee, was associated with safe plasma bupivacaine concentrations, was well tolerated, and provided satisfactory pain scores in most cases.
Adolescent↗
Effects of bilateral striatal 6-OHDA lesions on circadian rhythms in the rat: a radiotelemetric study.
The present work aims to document, in a previously described animal model of Parkinson (double bilateral striatal injection of 6-OHDA), the possible modifications of circadian markers rhythms i.e. temperature (T), heart rate (H) and locomotor activity (A) registered continuously by telemetry, in order to evaluate a possible perturbation of the circadian rythmicity. H, T and A were measured by radiotelemetry after surgical implantation of the transmitters (Data Sciences). After a recovery period, the study was divided into a control period (C) for baseline measurements of T, H and A daily rhythms. Then, the stereotaxic 6-OHDA striatal lesion was done to a group of 4 rats while the control rats were injected into striata with saline; a second period of four registration weeks was observed [D 1-7 (W1), D 8-14 (W2), D 15-21 (W3), D 22-28 (W4)]. Finally, at the end of this period the seven rats were decapited in order to determine their striatal dopamine (DA) content. Our data document that the circadian rhythms of H, T and A were differently affected according to time. Thus, a temporary loss of circadian periodicity was observed particularly for heart rate. 6-OHDA-induced modifications of H, T and A circadian rhythm characteristics were also observed: a significant decrease of the mesor was observed for the three rhythms as well as a phase advance. Concerning the amplitude of these rhythms, only H was significantly decreased. These perturbations were observed during the four weeks following the intervention, never reaching the initial control levels. Such observed perturbations would supply a basis for the future study of the chronopharmacology of antiparkinsonian drugs.
Animals↗
Effects of a seven-day continuous infusion of L-DOPA on daily rhythms in the rat.
The present study was conducted to evaluate the effect of L-3, 4-dihydroxyphenylalanine (L-DOPA) on the daily rhythms of temperature, heart rate and locomotor activity in rats that received a 7-day continuous infusion. Our results indicate that L-DOPA does not induce a loss of the daily rhythmicity of temperature, heart rate and locomotor activity but modifies the main parameters of these rhythms, e.g. it increased the MESOR (midline estimating statistic of rhythm) of temperature and heart rate and increased the amplitude of temperature but decreased the amplitude of heart rate. Taking into account these results obtained after constant rate delivery, we now plan to investigate the effects of DOPA therapy by changing the time of its administration.
Analysis of Variance↗
Cerebrospinal fluid penetration and pharmacokinetics of vancomycin administered by continuous infusion to mechanically ventilated patients in an intensive care unit.
Cerebrospinal fluid (CSF) penetration and the pharmacokinetics of vancomycin were studied after continuous infusion (50 to 60 mg/kg of body weight/day after a loading dose of 15 mg/kg) in 13 mechanically ventilated patients hospitalized in an intensive care unit. Seven patients were treated for a sensitive bacterial meningitis and the other six patients, who had a severe concomitant neurologic disease with intracranial hypertension, were treated for various infections. Vancomycin CSF penetration was significantly higher (P < 0.05) in the meningitis group (serum/CSF ratio, 48%) than in the other group (serum/CSF ratio, 18%). Vancomycin pharmacokinetic parameters did not differ from those obtained with conventional dosing. No adverse effect was observed, in particular with regard to renal function.
Adult↗
Oxidative metabolism of bupivacaine into pipecolylxylidine in humans is mainly catalyzed by CYP3A.
Bupivacaine is used to provide prolonged anesthesia and postoperative analgesia. The human cytochrome P450 (CYP) involved in bupivacaine degradation into pipecolylxylidine (PPX), its major metabolite, has, to our knowledge, never been described. Microsome samples were prepared from six human livers and incubated in the presence of bupivacaine. The concentrations of PPX in the microsomal suspensions were assessed, and K(m) and V(max) values were calculated. Bupivacaine incubations were then performed with specific CYP substrates and inhibitors. For each sample of hepatic microsomes, the correlation between the rate of PPX formation and the corresponding erythromycin N-demethylase activity was analyzed. Finally, an immunoinhibition study using an anti-rabbit CYP3A6 antibody and assays with cDNA-expressed human CYP were conducted. The apparent K(m) and V(max) values of bupivacaine were, respectively, 125 microM and 4.78 nmol/min/mg of microsomal protein. The strongest inhibition of bupivacaine metabolism was obtained for troleandomycin (-95% at 50 microM), a specific CYP3A inhibitor. The correlation between PPX formation and erythromycin N-demethylase activity showed an R value of 0.99 whereas anti-rabbit CYP3A6 antibody inhibited the degradation of bupivacaine into PPX by 99%. Finally, CYP1A2 and CYP2E1 cDNA-expressed forms of human CYP did not allow PPX formation, CYP2C19 and CYP2D6 produced only small amounts whereas CYP3A4 most efficiently metabolized bupivacaine into PPX. These results demonstrated that bupivacaine degradation into PPX was mediated in humans by CYP3A.
Anesthetics, Local↗
Caffeine-induced modifications of heart rate, temperature, and motor activity circadian rhythms in rats.
Even if the effects of caffeine on some physiological parameters are well known, its influence on circadian rhythmicity had not yet been investigated. This possible influence is of particular importance, introducing a possible bias in chronopharmacological studies. Thus, the aim of this study was to evaluate the effects of repeated caffeine administration on the circadian rhythms of heart rate "H," body temperature "T," and motor activity "A" in unrestrained rats maintained under controlled conditions (LD 12:12, light from 0600 to 1800 h) by using radiotelemetry transmitters. The study was divided into three 7-day observation spans: a 1-week control span "P1," a 1-week treatment span "P2," and a 1-week recovery span "P3." P1 was performed for assessing baseline measurements of H. T, and A. During P2, four rats received caffeine (25 mg/kg) at 0900 h, while four rats received saline in the same conditions every day of the observation span. H, T, and A were continuously monitored and plotted every 10 min. For P1, P2, and P3. a power spectrum analysis (Fourier transform) was applied to determine the dominant period of rhythmicity. If H, T, and A circadian rhythms were detected, the characteristics of these rhythms, i.e., mesors, amplitudes and acrophases, were determined by cosinor analysis, expressed as means +/- SEM and compared by analysis of variance. Our results indicated that caffeine did not suppress the circadian rhythmicity of H, T, and A, but significantly increased mesors and decreased amplitudes of the three rhythms and advanced acrophases of temperature and activity compared to the control group.
Animals↗
Excretion of lidocaine and bupivacaine in breast milk following epidural anesthesia for cesarean delivery.
BACKGROUND: There is a lack of information and knowledge about the practical importance of even low concentrations of the excretion of local anesthetics into breast milk, particularly concerning bupivacaine. The present work aims to confirm, under practical clinical conditions of admission of parturients, the passage of local anesthetics (lidocaine and bupivacaine) into breast milk after an epidural anesthesia. METHODS: Twenty-seven pregnant women admitted for cesarean delivery received epidural anesthesia with 0.5% bupivacaine and 2% lidocaine. Blood and milk samples were simultaneously collected at 2, 6 and 12 h after the beginning of the epidural infusion. Lidocaine, bupivacaine and its main metabolite, pipecolylxylidide (PPX), were determined in serum and milk by a gas-liquid chromatographic technique. APGAR scores were systematically performed at delivery and a clinical examination was done 24 h after delivery. RESULTS: Our data indicate that lidocaine and bupivacaine as well as PPX are excreted into breast milk. The milk/serum ratio based upon area under the curve values were 1.07 +/- 0.82, 0.34 +/- 0.24 and 1.37 +/- 0.61 mean +/- SD for lidocaine, bupivacaine and PPX, respectively. Most of the newborns had a maximal APGAR score. Our study does not reveal any adverse reactions related to the excretion of local anesthetics into breast milk. CONCLUSION: This study documents the magnitude of excreted lidocaine, bupivacaine and PPX in breast milk, and indicates that the use of both lidocaine and bupivacaine for epidural anaesthesia is safe with regard to breast-feeding.
Adult↗
Pharmacokinetic-pharmacodynamic analysis of mnesic effects of lorazepam in healthy volunteers.
AIMS: To describe the pharmacokinetic-pharmacodynamic modelling of the psychomotor and mnesic effects of a single 2 mg oral dose of lorazepam in healthy volunteers. METHODS: This was a randomized double-blind, placebo-controlled two-way cross-over study. The effect of lorazepam was examined with the following tasks: choice reaction time, immediate and delayed cued recall of paired words and immediate and delayed free recall and recognition of pictures. RESULTS: The mean calculated EC50 values derived from the PK/PD modelling of the different tests ranged from 12.2 to 15.3 ng ml-1. On the basis of the statistical comparison of the EC50 values, the delayed recall trials seemed to be more impaired than the immediate recall trials; similar observations were made concerning the recognition vs recall tasks. CONCLUSIONS: The parameter values derived from PK/PD modelling, and especially the EC50 values, may provide sensitive indices that can be used, rather than the raw data derived from pharmacodynamic measurements, to compare CNS effects of benzodiazepines.
Amnesia, Anterograde↗
Metabolic and hemodynamic changes during recovery and tracheal extubation in neurosurgical patients: immediate versus delayed recovery.
UNLABELLED: Delayed recovery has been advocated to limit the postoperative stress linked to awakening from anesthesia, but data on this subject are lacking. In this study, we measured oxygen consumption (V(O2)) and plasma catecholamine concentrations as markers of postoperative stress. We tested the hypothesis that delayed recovery and extubation would attenuate metabolic changes after intracranial surgery. Thirty patients were included in a prospective, open study and were randomized into two groups. In Group I, the patients were tracheally extubated as soon as possible after surgery. In Group II, the patients were sedated with propofol for 2 h after surgery. V(O2), catecholamine concentration, mean arterial pressure (MAP), and heart rate (HR) were measured during anesthesia, at extubation, and 30 min after extubation. V(O2) and noradrenaline on extubation and mean V(O2) during recovery were significantly higher in Group II than in Group I (V(O2) for Group I: preextubation 215 +/- 46 mL/min, recovery 198 +/- 38 mL/min; for Group II: preextubation 320 +/- 75 mL/min, recovery 268 +/- 49 mL/min; noradrenaline on extubation for Group I: 207 +/- 76 pg/mL, for Group II: 374 +/- 236 pg/ mL). Extubation induced a significant increase in MAP. MAP, HR, and adrenaline values were not statistically different between groups. In conclusion, delayed recovery after neurosurgery cannot be recommended as a mechanism of limiting the metabolic and hemodynamic consequences from emergence from general anesthesia. IMPLICATIONS: In this study, we tested the hypothesis that delayed recovery after neurosurgery would attenuate the consequences of recovery from general anesthesia. As markers of stress, oxygen consumption and noradrenaline blood levels were higher after delayed versus early recovery. Thus, delayed recovery cannot be recommended as a mechanism of limiting the metabolic and hemodynamic consequences from emergence after neurosurgery.
Aged↗
Clozapine monitoring: plasma or serum levels?
In this study, differences between plasma and serum levels of clozapine and norclozapine were quantified and correlations of these differences with myeloperoxidase (MPO) activities were examined. Fifty-seven patients (34 men and 23 women, mean age 36.6+/-11.4 years) taking clozapine in a daily doses varying from 75 to 800 mg entered the study. All patients were analyzed for clozapine level, 29 were analyzed for norclozapine level and 28 for MPO activity. Significant differences (p<0.001) between plasma and serum levels were found for clozapine (mean decrease 9.99+/-15.8%) and norclozapine (mean decrease 16.0+/-21.2%) and for MPO activities (mean increase 114.1+/-123.9%). No correlation was found between differences of MPO activities and differences of drug levels in plasma and serum. Differences in clozapine and norclozapine levels could reflect chemical instability of these drugs. These compounds should be quantified only in plasma because serum levels underestimate blood levels in patients.
Adult↗