Brain PET imaging using 11C-flumazenil and 11C-buprenorphine does not support the hypothesis of a mutual interaction between buprenorphine and benzodiazepines at the neuroreceptor level.

Among opioids, buprenorphine presents a favorable safety profile with a limited risk of respiratory depression. However, fatalities have been reported when buprenorphine is combined to a benzodiazepine. Potentiation of buprenorphine interaction with opioid receptors (ORs) with benzodiazepines, and/or vice versa, is hypothesized to explain this drug-drug interaction (DDI). The mutual DDI between buprenorphine and benzodiazepines was investigated at the neuroreceptor level in nonhuman primates (n = 4 individuals) using brain PET imaging and kinetic modelling. The binding potential (BPND) of benzodiazepine receptor (BzR) was assessed using 11C-flumazenil PET imaging before and after administration of buprenorphine (0.2 mg, i.v.). Moreover, the brain kinetics and receptor binding of buprenorphine were investigated in the same individuals using 11C-buprenorphine PET imaging before and after administration of diazepam (10 mg, i.v.). Outcome parameters were compared using a two-way ANOVA. Buprenorphine did not impact the plasma nor brain kinetics of 11C-flumazenil. 11C-flumazenil BPND was unchanged following buprenorphine exposure, in any brain region (p > 0.05). Similarly, diazepam did not impact the plasma or brain kinetics of 11C-buprenorphine. 11C-buprenorphine volume of distribution (VT) was unchanged following diazepam exposure, in any brain region (p > 0.05). To conclude, our PET imaging findings do not support a neuropharmacokinetic or neuroreceptor-related mechanism of the buprenorphine/benzodiazepine interaction.

Developmental and neurochemical effects of early postnatal exposure to flumazenil in female and male mice / Efectos neuroquímicos y sobre el desarrollo de la exposición postnatal temprana al fulmazenil en ratones machos y hembras

The effect of the benzodiazepine antagonist flumazenil (10 and 20 mg/Kg) on righting reflex, body weight, body temperature, and proteins, cholesterol and phospholipids of the brain was examined in new born male and female mouse pups. In males, the level of brain cholesterol was increased by the low dose but diminished by the high dose. On the contrary, the amount of phospholipids and protein was diminished by the low dose and increased by the high dose. In females, the level of phospholipids was reduced by 10 mg/Kg but was increased by 20 mg/Kg. Flumazenil dose-dependently decreased the level of proteins, although the quantity of brain cholesterol was similar to males Postnatal exposure to flumazenil did not influence righting reflex, body weight and body temperature although prenatal exposure to the drug retarded the formermentioned response. Postnatal flumazenil clearly had a very profound effect on biochemical measures in mice, which could reflect the antagonist’s powerful fluidising effects on neuromembranes (AU)

Efectos neuroquímicos y sobre el desarrollo de la exposición postnatal temprana al flumazenil en ratones machos y hembras. Se estudia el efecto del antagonista benzodiacepínico flumazenil (10 y 20 mg/kg) en el "righting reflex" (incorporación), peso y temperatura corporal, proteínas, colesterol y fosfolípidos cerebrales en crías de ratones de ambos sexos. En los machos, la dosis baja incrementa el nivel de colesterol, disminuyendo los fosfolípidos y proteínas. En hembras, la dosis de 10 mg/kg disminuye el nivel de fosfolípidos, mientras que la de 20 mg/kg lo incrementa. El flumazenil disminuye de forma dosis-dependiente el nivel de proteínas, aunque con respecto al colesterol cerebral los resultados fueron similares a los machos. La exposición postnatal al flumazenil no afecta al "righting reflex", el peso corporal o la temperatura. La exposición postnatal tiene un profundo efecto en las medidas bioquímicas de los ratones lo cual podría reflejar una poderosa acción en la permeabilidad de las neuromembranas (AU)

Antídotos de uso reciente

Los antídotos son sustancias cuya función es contrarrestar el efecto farmacológico y tóxico de otras sustancias, teniendo en cuenta la importancia de las medidas generales en el manejo del intoxicado (baño general, emesis, lavado gástrico, carbón activado, catárticos). Cada día aparecen sustancias nuevas con dichas características. En el presente artículo se pretende dar información breve y detallada sobre las propiedades farmacológicas, indicaciones, dosificación, efectos secundarios y contraindicaciones de algunos de uso general (carbón activado, soluciones electrolíticas con polietilenglycol) y principalmente de algunos específicos de uso reciente: flumazenil, fragmentos Fab-antidigoxina, glucagón, naloxona, clonidina, N-acetil-cisteína, azul de metileno, nitrito y tiosulfato de sodio, ácido-2-3-dimercaptosuccínico, penicilina benzatínica, glicopirrolato y S-adenosil-metionina.