Flumazenil and bupivacaine-induced toxicity: inverse agonist type activity.

The purpose of this study was to investigate the influence of flumazenil on bupivacaine-induced acute toxicity, 10 groups of mice were previously treated by a 1, 0.5, 0.25 and 0.125 mg/kg single dose of flumazenil or saline 15 minutes before an injection of bupivacaine (50 mg/kg: exp. 1 and 60 mg/kg: exp.2). The convulsant activity, the period of latency to convulse and the induced mortality were assessed in each group. The bupivacaine-induced mortality was increased by flumazenil. Also, the convulsant activity was increased by flumazenil and the period of latency to convulse was proportionally decreased with increasing doses of flumazenil for the two tested doses of bupivacaine.

Local anesthetic-induced toxicity may be modified by low doses of flumazenil.

The purpose of this study was to investigate the influence of flumazenil on local anesthetic-induced acute toxicity. For each of the three tested anesthetics (etidocaine, mepivacaine and lidocaine) 6 groups of mice were treated by a single dose of flumazenil (0.125, 0.25, 0.5, 1 and 2 mg/kg), or an equal volume of saline, 15 minutes before the injection of the anesthetic (etidocaine: 50 mg/kg, mepivacaine: 110 mg/kg and lidocaine: 115 mg/kg). The convulsant activity, the time of latency to convulse and the mortality rate were assessed in each group. The local anesthetic-induced mortality was not significantly modified by flumazenil. The convulsant activity of lidocaine and mepivacaine was significantly increased by flumazenil but not for etidocaine. Also, increasing doses of flumazenil decreased the time of latency to obtain lidocaine-induced convulsions. This effect was not obtained with etidocaine or mepivacaine.

Ketamine effects on bupivacaine local anaesthetic activity and pharmacokinetics of bupivacaine in mice.

This study was designed to document possible changes in bupivacaine (B) local anaesthetic activity and pharmacokinetics in mice after a ketamine (K) injection. In the experiments, bupivacaine (8.25 mg.kg(-1)), was injected into the popliteal space of the right posterior limb: the local anaesthetic activity was assessed according to a sciatic nerve blockade method with three different doses (2, 10 and 40 mg/kg) of ketamine and the kinetics were studied after a 10 mg/kg dose. When ketamine was associated, the local anesthetic activity of bupivacaine was significantly enhanced as well as its elimination half-life. Significantly lower levels of the main metabolite, PPX, were observed, when ketamine was associated, suggesting a metabolic inhibition phenomenon. The ketamine-induced increase in the total anaesthetic effect of bupivacaine may thus be explained by kinetic modifications i.e. a possible inhibiting effect of ketamine on the metabolism of bupivacaine.

Flumazenil and lignocaine-induced toxicity: is the inverse agonist type activity circadian-time dependent?

We have investigated the possible influence of time of day on the activity of flumazenil on lignocaine-induced toxicity in mice. The circadian pattern of the period of latency for convulsions and the induced mortality for lignocaine alone and for lignocaine plus flumazenil was not statistically significant (cosinor or analysis of variance) but the influence of flumazenil on lignocaine-induced toxicity was circadian-time dependent (F = 27.8, P = 0.0001).

Bupivacaine acute toxicity protection by diazepam in mice.

1. The effects of acute and 8-day administration of diazepam (DZP) on the acute toxicity of bupivacaine in the mouse were studied. 2. Protection of bupivacaine-induced acute toxicity by DZP appears to be dose-dependent after treatment for 8 days but not after acute treatment.

Effects of metyrapone infusion on corticotropin-releasing factor and arginine vasopressin secretion into the hypophysial portal blood of conscious, unrestrained rams.

The effects of rapid changes of circulating cortisol levels on ACTH secretion and on corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) concentrations into hypophysial portal blood were studied in six adult rams. Pharmacological adrenalectomy was obtained by 3 h metyrapone infusion (100 mg.kg-1.h-1). Blockade of cortisol synthesis induced a tenfold increase of plasma ACTH levels accompanied by a moderate increase of CRF secretion (150% vs preinjection levels) and a large increment of AVP secretion (535% vs preinjection levels). ACTH levels remained high during the 3 h following the end of metyrapone infusion. During the same period, CRF secretion was still elevated (231% vs preinjection levels), while AVP secretion was further stimulated (2,151% vs preinjection levels). Subsequent hydrocortisone infusion (66 micrograms.kg-1.h-1) for 2 h induced a rapid decrease of both ACTH and AVP secretion, while CRF levels in hypophysial portal blood still remained elevated. These data suggest that changes in ACTH secretion induced by acute modifications of the negative glucocorticoid feedback are, in addition to the well documented direct effect of cortisol on the corticotropes, mainly mediated by variations of hypothalamic AVP secretion.