Bernard Bruguerolle

Temporal changes in bupivacaine kinetics.

The chronokinetics of bupivacaine have been examined in the mouse. Different groups of adult male NMRI mice maintained under controlled environmental conditions received a single intraperitoneal injection of bupivacaine (20 mg kg−1) at one of four different fixed time points in a 24 h period i.e. 1000, 1600, 2200 and 0400h. Blood samples were taken 0.25, 0.5, 0.75, 1, 1.5, 3, 4 and 6 h after drug administration and total serum levels of bupivacaine were determined by a gas‐liquid chromatography with a flame ionization detector. Statistically significant temporal changes were found in the following pharmacokinetic parameters: highest Cmax value = 0.900 ± 0.080 μg mL−1 at 2200h (amplitude, maximum‐minimum/mean × 100, is 64%); highest Cmax/Tmax ratio = 3.596 ± 0.339 at 2200h (amplitude = 85%); highest β elimination half‐life, T½β;, = 3.950 ± 0.246 h at 2200h (amplitude = 35%); area under concentration curve (AUC0∞) was not found to be significantly different among the hours of administration. The temporal kinetic changes demonstrated suggest a possible circadian difference in bupivacaine efficacy and/or toxicity.

Tyrosine kinase inhibitors and cycloheximide inhibit Li+ protection of cerebellar granule neurons switched to non-depolarizing medium

Recently, it has been shown that Li+ robustly enhances the survival of cerebellar granule neurons acutely switched to non-depolarizing medium after maturing in vitro, a condition which elicits massive apoptotic death in this cell type. Tyrosine protein phosphorylation is known to underlie the activity of a number of trophic factors. This prompted us to investigate whether specific tyrosine kinase inhibitors could modulate the Li+ protection of cultured granule neurons switched to non-depolarizing medium. Genistein and herbimycin A dose dependently abolished the Li+ effect. Furthermore, this effect was substantially prevented by the translational inhibitor cycloheximide, suggesting that it requires de novo protein synthesis. Overall, these results suggest that Li+ protection of cerebellar granule neurons switched to non-depolarizing medium involves tyrosine kinases and transcriptional activation.

Circadian phase‐dependent pharmacokinetics and acute toxicity of mepivacaine

Abstract— The aim of this study was to investigate the possible influence of the time of administration on mepivacaine acute toxicity and kinetics in mice. Four different groups of adult male NMRI mice maintained under controlled environmental conditions (lights on: = 0600–1800 h) were injected at one of the following times: 1000, 1600, 1900, 2200, 0100 and 0400 h with one of four doses of mepivacaine at each time point to establish the acute toxicity (LD50). To assess chronokinetics, a single 60 mg kg−1 i.p. dose of mepivacaine was given to adult male NMRI mice at four fixed times: 1000, 1600, 2200 and 0400 h. Mepivacaine plasma concentrations were determined by GLC. Our data showed significant 24 h variations in the following parameters: Highest tmax value = 0.366 ± 0.073 h at 1000 h (P < 0005, amplitude, maximum‐minimum/mean × 100, = 184%), highest Cmax/tmax ratio = 177.17 ± 9.49 at 2200 h (P < 0005, amplitude = 192%), highest Vd = 0.842 ± 0.23 L kg−1 at 2200 h (P < 0005, amplitude = 158%) and highest β phase elimination half‐life = 5.408 ± 1.36 h at 2200 h (P < 0.025, amplitude = 145%). Cmax (amplitude = 15%), AUCox (amplitude = 24%) and clearance (amplitude = 23%) were not significantly time‐dependent. These data demonstrate a temporal pattern of mepivacaine kinetics similar to those reported previously for bupivacaine. The temporal changes in mepivacaine‐induced acute toxicity may result in part from its chronokinetic changes.

Circadian phase dependent acute toxicity and pharmacokinetics of etidocaine in serum and brain of mice

Abstract— The aim of this study was to investigate the possible influence of the time of administration on etidocaine acute toxicity and kinetics in mice. Different groups of adult male NMRI mice maintained under controlled environmental conditions (lights on 06.00–18.00) were injected at one of the following times: 10.00, 16.00,19.00,22.00,01.00 and 04.00 h with four doses of etidocaine at each time point to establish the acute toxicity (LD 50). To assess chronokinetics, a single 40 mg kg−1 i.p. dose of etidocaine was given to adult male NMRI mice at four fixed times: 10.00,16.00,22.00 and 04.00 h. Etidocaine serum levels were determined by GLC. The data showed significant 24 h variations of the Cmax only (highest value = 9.64 ± 1.31 μg mL−1 at 10.00 P < 0.05; amplitude, (maximum‐minimum) mean × 100 = 84%) Vd, (amplitude = 59.7%), α and β phase elimination half‐lives (amplitude = 52 and 35%, respectively), clearance (amplitude = 23%) and AUC°8 (amplitude = 22%) were not found to be significantly time dependent. Etidocaine kinetics in brain were determined similarly; a significant temporal variation was found for the elimination half life (amplitude, 161.9%) and AUC (amplitude, 133.2%) but not for Cmax. These data demonstrate a temporal pattern of etidocaine kinetics similar to those reported previously for other local anaesthetic agents, bupivacaine and mepivacaine. The temporal changes in etidocaine induced acute toxicity may result in part from its chronokinetic changes.

Circadian phase dependent pharmacokinetics of L-dopa, its main metabolites (3-OMD, HVA, DOPAC) and carbidopa in rats

Summary— This study aims to evaluate whether or not the kinetics of L‐dopa, its main metabolites (3‐O‐methyldopa, 3‐OMD, homovanilic acid, HVA and 3,4‐dihydroxyphenylacetic acid, DOPAC) and carbidopa, vary according to the 24‐hour scale in rats. Four groups of seven adult male Wistar AF EOPS rats were used for these experiments; each group received L‐dopa (200 mg·kg−1 ip) and carbidopa (20 mg·kg−1 ip) at 1000, 1600, 2200 or 0400 hours. L‐dopa, 3‐OMD, DOPAC, HVA and carbidopa were simultaneously determined by specific ion‐pair reversed‐phase high performance liquid chromatography with electrochemical detection. A temporal variation of the kinetics of both L‐dopa and carbidopa was demonstrated with higher plasma clearance and lower area under concentration curve after the administration at 2200 hours. Moreover, a temporal variation of the metabolism of L‐dopa was indirectly documented by temporal variation in kinetics of 3‐OMD, DOPAC and HVA.

Effects of Clonidine Pretreatment on the Local Anaesthetic Activity of Bupivacaine in Mice

This study was designed to document possible changes in bupivacaine local anaesthetic activity in mice after a single injection of clonidine (0.1 or 1 mgkg−1, i.p.). The local anaesthetic activity was evaluated during 60 min, according to a previously reported technique, using sciatic nerve blockade by injection of bupivacaine in the area of the sciatic nerve.

Effects of Calcium Antagonists on Binding of Local Anesthetics to Plasma Proteins and Erythrocytes in Mice

This study was designed to document possible changes in the binding of bupivacaine (BV), lidocaine (LC) and their main metabolites desbutylbupivacaine (PPX) and monoethylglycinexylydide (MEGX), respectively, to plasma proteins and erythrocytes in mice after acute treatment with the calcium antagonists diltiazem (DZ), nicardipine (NP) and verapamil (VP). A significant plasma protein binding of BV, LC and PPX was measured, whereas no binding could be detected for MEGX. The binding of BV was not modified by DZ, NP and VP, however, the total plasma level was increased in the presence of VP. For PPX a significant increase in total and free plasma levels and a decrease in protein binding were demonstrated after DZ and VP treatment. Concerning LC, a significant increase in total and free plasma levels was documented for DZ, NP and VP suggesting an inhibition of the metabolism of LC by the calcium antagonists. An increased penetration of LC into erythrocytes was also demonstrated which is consistent with the calcium antagonist-induced increase in LC free plasma levels. These effects may contribute in part to the previously observed increase in toxicity of BV by calcium antagonists, but are not likely to be the sole mechanism.

Bupivacaine kinetic changes during the oestrous cycle in rats

Abstract— After a single 20 mg kg−1 i.p. dose during pro‐oestrus, oestrus or dioestrus, bupivacaine kinetics in rats were not significantly different except for Cmax which was significantly higher during dioestrus.

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

Abstract— 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 = 00001).

Kinetics of bupivacaine after levcromakalim treatment in mice

Previous workers have reported that 0.01 mg kg−1 of levcromakalim injected intraperitoneally did not modify bupivacaine‐induced neurotoxicity but increased the duration of action of bupivacaine. This study was designed to document possible changes in the pharmacokinetic behaviour of bupivacaine and its main metabolite, N‐desbutylbupivacaine in mice after a single 0.01 mg kg−1 intraperitoneal injection of levcromakalim.