Biomedical subjects

Bruno Megarbane

Publications and source records attributed to Bruno Megarbane.

4 recordsLinked to original sources

PubMed2005

Cerebral and plasma kinetics of a high dose of midazolam and correlations with its respiratory effects in rats.

Benzodiazepine poisoning causes coma and respiratory depression. Our objective was to determine whether, and to what extent, arterial blood gas disturbances correlated with blood or cerebral kinetics of midazolam. A 160 mgkg(-1) single dose of midazolam was infused intravenously over 20 min in catheterized male Sprague-Dawley rats. Midazolam kinetics was simultaneously determined in plasma and brain using striatal microdialysis. Midazolam concentrations were measured using a high-performance liquid chromatographic assay with ultraviolet detection. Midazolam (160 mgkg(-1)) reproducibly induced deep coma with respiratory acidosis. Plasma midazolam kinetics was well described by a bi-exponential model, with an elimination half-life of 6.4+/-1.8 h. The striatal dialysate concentration peaked at 50.0+/-8.9 min after the end of infusion, with a significant delay to peak concentration compared to plasma. Respiratory depression, assessed by the elevation in PaCO2, was more closely correlated with midazolam striatal dialysate rather than plasma kinetics. These results suggest a central mechanism for midazolam respiratory effects at toxic doses in rats. In conclusion, our study showed a delayed onset in peak PaCO2 and pH effects after the slow infusion of a toxic dose of midazolam in rats. The effects on arterial blood gases were better correlated with midazolam striatal concentrations than with plasma concentrations. This study may contribute to better understanding of benzodiazepine-induced respiratory depression in poisonings.

Acidosis↗

PubMed2005

Flunitrazepam does not alter cerebral distribution of buprenorphine in the rat.

Deaths have been reported among heroin addicts related to combined buprenorphine and flunitrazepam use. The aim of this study was to determine the existence of a drug-drug interaction during the distribution phase of buprenorphine. Arterial blood gases were measured after intravenous administration of buprenorphine alone (30 mg/kg), flunitrazepam alone (40 mg/kg) or both drugs in rats. Buprenorphine kinetics was studied in plasma and in striatum using cerebral microdialysis, both alone and after rat pretreatment with flunitrazepam. In contrast to buprenorphine or flunitrazepam alone, buprenorphine in combination with flunitrazepam induced a significant, rapid and sustained respiratory depression. Arterial PCO2 was increased at 1.5 min (6.7+/-0.2 versus 5.4+/-0.3 and 5.5+/-0.3 kPa, respectively, P=0.04) (mean+/-S.E.M.), and arterial pH decreased (7.37+/-0.02 versus 7.45+/-0.02 and 7.45+/-0.01, respectively, P=0.03). Plasma buprenorphine kinetics was well described by a three-compartment linear model, with a distribution half-life of 7.4+/-2.7 min and an elimination half-life of 463.9+/-152.3 min. However, neither plasma nor striatal buprenorphine kinetics were significantly altered by pre-administration of flunitrazepam. The adverse interaction between flunitrazepam and buprenorphine cannot be explained by a pharmacokinetic drug-drug interaction during the distribution phase of buprenorphine.

Animals↗

PubMed2005

Brain damage after heat stroke.

Cerebellar syndromes and radiologic cerebellar atrophy after hyperpyrexia have occasionally been reported, mostly in neuroleptic malignant syndromes, but neuropathologic studies are extremely rare. We studied 3 patients (a 74-year-old woman, a 63-year-old man, and an 80-year-old man) who had heat stroke during heat waves in France. One patient had generalized seizures and died 28 hours after admission. The other patients survived one month and 2 months after admission; both had palatal myoclonus, and in one case, magnetic resonance imaging showed high signal intensity in the cerebral peduncles. The main neuropathology in the 3 cases was severe diffuse loss of Purkinje cells associated with heat shock protein 70 expression by Bergmann glia. In situ end labeling was negative in surviving Purkinje cells, suggesting that the mechanism of neuronal death was not apoptosis. Degeneration of Purkinje cells axons resulted in myelin pallor of the white matter of the folia and of the hilum of the dentate nuclei. DNA internucleosomal breakages were identified by in situ end labeling in the dentate nuclei and centromedian nuclei of the thalamus and were associated with degeneration of the cerebellar efferent pathways: superior cerebellar peduncles, decussation of the superior cerebellar peduncles (Wernekinck commissure), and dentatothalamic tract. These findings suggest that the mechanisms of neuronal death in the dentate nuclei and centromedian nuclei of the thalamus was different from that in Purkinje cells and more likely resulted from deafferentation. Ammon's horn and other areas susceptible to hypoxia were spared. These observations confirm the selective vulnerability of Purkinje cells to heat-induced injury and involvement of the cerebellar efferent pathways in palatal myoclonus.

Aged↗

PubMed2003

[Interactions between benzodiazepines and opioids].

Benzodiazepines and opiates or opioids are used concomitantly in various circumstances, for example in anesthesiology, for the management of acute or chronic pain and for substitution therapy in heroin addiction. There are numerous interactions between these two families of substances. The objective of this review is to present the interactions identified in clinical and experimental studies reported in the literature dealing with their effects on pain, anxiety, sedation and respiration. The exact mechanism of benzodiazepine and opioid interactions remains to be established. It may depend on pharmacokinetic or pharmacodynamic mechanisms. Certain arguments would support the pharmacodynamic hypothesis: the co-location of GABA and opiate receptors in the central nervous system, the existence of possible cross-reactivity and common pathways of intracellular transduction. The deleterious interaction of benzodiazepines and opioids on respiration may take place at the level of the central command of ventilation or may be related to additive actions on the different neuromuscular components of the respiration. A better understanding of the exact mechanisms implicated in these interactions would increase the safety of prescription of these drugs.

Anti-Anxiety Agents↗