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Local anesthetics-induced toxicity may be modified by low doses of flumazenil
Life Sciences, Vol. Printed in the USA
50, pp.
PL-185
- PL-187
PHARMACOLOGY Accelerated
Pergamon
Press
LETTERS
Communication
LOCAL ANESTHETICS-INDUCED TOXICITY MAY BE MODIFIED BY LOW DOSES OF FLUMAZENIL B.BRUGUEROLLE 1 and N.EMPERAIRE 2 1- Laboratoire de Pharmacologie M~dicale, Facult6 de M~decine de Marseille, 27 Bid J.Moulin F 13385 Marseille cedex 5, France. 2- Departement d'Anesth~sie-R~animation, Hbpital de la Conception, Marseille, France. (Submitted January 28, 1992; accepted February ii, received in final form March 20, 1992)
1992;
Abstract: The purpose of this study was to investigate the influence of flumazenil on local anesthetics-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).Theconvulsant activity, the time of latency to convulse and the mortality rate were assessed in each group.The local anesthetics-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 and mepivacaine.
Introduction Partial benzodiazepine agonist properties and inverse agonist properties of flumazenil, an imidazodiazepine initially characterized as a benzodiazepine receptor antagonist (1) have been reported (2,3,4,5); also, the antiepileptic activity of flumazenil have been reported both in animal and in man(l). Since local anesthetics are known to induce seizures and CNS toxicity, and benzodiazepines are often used to prevent local anesthetics-induced seizures or CNS toxicity, we have recently documented the action of flumazenil on bupivacaine-induced toxicity, one of the most widely used agent. Surprisingly, we demonstrated a partial inverse agonist activity of flumazenil (8). Thus, it was of interest to document if such findings would occur with three other often used local anesthetic agents, etidocaine, lidocaine and mepivacaine. Materials and methods Male NMRI adult mice weighing approximately 30 g each were used in this experiment. The mice were housed in groups of 10 per plastic cages; food and water were supplied ad libitum. All animals were maintained at a temperature of 25 o +_ 1 o C for a minimum period of 2 weeks in an environmental room equipped to distribute a cool white fluorescence light; the light cycle was automatically timed to last from 06.00 h to 18.00 h daily. The experience was conducted during November 1991.
Copyright
0024-3205/92 $5.00 + .00 © 1992 Pergamon Press Ltd All rights
reserved.
PL-186
Flumazenil
Latency(sec) 210 t
and A c u t e T o x i c i t y
Vol.
%
1O0
ETIDOCAINE Time of Latency
ANOVA:ns
50, No. 22, 1992
ETIDOCAINE
t
Mortality ratens Chl square:
180 ] 150 ] 50 120 90 0
60 C 0,125 0,25 0,5
1
C
2
0,125 0,25
0,5
1
2
% Latency(sec) 210
LIDOCAINE
100
LIDOCAINI= :e ns
180 150
50
120 90 60 C 0,125 0,25 0,5
Latenc 210
~'(sec)
1
C
2
MEPIVACAINE Time of latency ANOVA:ns ~
% 100
0,125 0,25
0,5
1
2
MEPIVACAINE Mortalityrate Chl square:ns
/-I
180 150 120 9060 C 0,125 0,25
0,5
1
2
C
0,125 0,25
0,5
1
2
FIG.1 Time of latency for convulsions and etidocaine, lidocaine or mepivacaine-induced mortality rate produced by increasing dose of flumazenil (0.125, 0.25, 0.5, 1 and 2 mg/kg) or saline (C = controls). When a significant difference was detected by the ANOVA test, the Dunnett test was used for comparison to controls. ns= non significant difference
Vol. 50, No. 22, 1992
Flumazenil and Acute Toxicity
PL-187
As for bupivacaine, lidocaine-induced time to convulse was decreased by increasing doses of flumazenil but this was not observed for etidocaine and mepivacaine;also, the convulsant activity was significantly increased both for lidocaine and mepivacaine but, conversely, the mortality induced by these agents was not significantly modified. One must notice that etidocaine-induced toxicity was not affected by flumazenil. The partial inverse agonist activity of flumazenil previously observed with bupivacaine was also observed with lidocaine but was not, surprisingly, demonstrated with etidocaine and mepivacaine. This activity does not seem to depend on the physicochemical properties of these agents since etidocaine which is the most lipophilic and the most potent of the local anesthetics would have react like bupivacaine. Acknowledgements This work was supported partly by a grant from The "Conseil Scientifique" of Medicine Faculty of Marseille, France. Special thanks to J. Mouchet for technical assistance. References .
2. 3. 4. 5. 6. 7. .
R.N. BROGDEN, K.L.GOA, Drugs 3,5 448-467 (1988). J. DE VRY, J.L. SLANGEN, Europ J Pharmacol 119 193-197 (1985). S.E.FILE, S.PELLOW, Br J Pharmacol 8_44103 P (1985). D.J. SANGER, Pharmacol Biochem Behav 2,5 537-541 (1986). J.A.WAGNER, R.J.KATZ, Neurosci Letters 4_38317-320 (1984). R.H. DE JONG, J.D. BONIN, Anesth Analg 60385-389 (1981). B.BRUGUEROLLE, N.EMPERAIRE, A.OTTOMANI, J.C.MANELLI, Clin Exp Pharmacol Physiol 1,5 563-564 (1988). B.BRUGUEROLLE, N.EMPERAIRE, Life Sci 4_99185-188 (1991).
50, pp.
PL-185
- PL-187
PHARMACOLOGY Accelerated
Pergamon
Press
LETTERS
Communication
LOCAL ANESTHETICS-INDUCED TOXICITY MAY BE MODIFIED BY LOW DOSES OF FLUMAZENIL B.BRUGUEROLLE 1 and N.EMPERAIRE 2 1- Laboratoire de Pharmacologie M~dicale, Facult6 de M~decine de Marseille, 27 Bid J.Moulin F 13385 Marseille cedex 5, France. 2- Departement d'Anesth~sie-R~animation, Hbpital de la Conception, Marseille, France. (Submitted January 28, 1992; accepted February ii, received in final form March 20, 1992)
1992;
Abstract: The purpose of this study was to investigate the influence of flumazenil on local anesthetics-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).Theconvulsant activity, the time of latency to convulse and the mortality rate were assessed in each group.The local anesthetics-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 and mepivacaine.
Introduction Partial benzodiazepine agonist properties and inverse agonist properties of flumazenil, an imidazodiazepine initially characterized as a benzodiazepine receptor antagonist (1) have been reported (2,3,4,5); also, the antiepileptic activity of flumazenil have been reported both in animal and in man(l). Since local anesthetics are known to induce seizures and CNS toxicity, and benzodiazepines are often used to prevent local anesthetics-induced seizures or CNS toxicity, we have recently documented the action of flumazenil on bupivacaine-induced toxicity, one of the most widely used agent. Surprisingly, we demonstrated a partial inverse agonist activity of flumazenil (8). Thus, it was of interest to document if such findings would occur with three other often used local anesthetic agents, etidocaine, lidocaine and mepivacaine. Materials and methods Male NMRI adult mice weighing approximately 30 g each were used in this experiment. The mice were housed in groups of 10 per plastic cages; food and water were supplied ad libitum. All animals were maintained at a temperature of 25 o +_ 1 o C for a minimum period of 2 weeks in an environmental room equipped to distribute a cool white fluorescence light; the light cycle was automatically timed to last from 06.00 h to 18.00 h daily. The experience was conducted during November 1991.
Copyright
0024-3205/92 $5.00 + .00 © 1992 Pergamon Press Ltd All rights
reserved.
PL-186
Flumazenil
Latency(sec) 210 t
and A c u t e T o x i c i t y
Vol.
%
1O0
ETIDOCAINE Time of Latency
ANOVA:ns
50, No. 22, 1992
ETIDOCAINE
t
Mortality ratens Chl square:
180 ] 150 ] 50 120 90 0
60 C 0,125 0,25 0,5
1
C
2
0,125 0,25
0,5
1
2
% Latency(sec) 210
LIDOCAINE
100
LIDOCAINI= :e ns
180 150
50
120 90 60 C 0,125 0,25 0,5
Latenc 210
~'(sec)
1
C
2
MEPIVACAINE Time of latency ANOVA:ns ~
% 100
0,125 0,25
0,5
1
2
MEPIVACAINE Mortalityrate Chl square:ns
/-I
180 150 120 9060 C 0,125 0,25
0,5
1
2
C
0,125 0,25
0,5
1
2
FIG.1 Time of latency for convulsions and etidocaine, lidocaine or mepivacaine-induced mortality rate produced by increasing dose of flumazenil (0.125, 0.25, 0.5, 1 and 2 mg/kg) or saline (C = controls). When a significant difference was detected by the ANOVA test, the Dunnett test was used for comparison to controls. ns= non significant difference
Vol. 50, No. 22, 1992
Flumazenil and Acute Toxicity
PL-187
As for bupivacaine, lidocaine-induced time to convulse was decreased by increasing doses of flumazenil but this was not observed for etidocaine and mepivacaine;also, the convulsant activity was significantly increased both for lidocaine and mepivacaine but, conversely, the mortality induced by these agents was not significantly modified. One must notice that etidocaine-induced toxicity was not affected by flumazenil. The partial inverse agonist activity of flumazenil previously observed with bupivacaine was also observed with lidocaine but was not, surprisingly, demonstrated with etidocaine and mepivacaine. This activity does not seem to depend on the physicochemical properties of these agents since etidocaine which is the most lipophilic and the most potent of the local anesthetics would have react like bupivacaine. Acknowledgements This work was supported partly by a grant from The "Conseil Scientifique" of Medicine Faculty of Marseille, France. Special thanks to J. Mouchet for technical assistance. References .
2. 3. 4. 5. 6. 7. .
R.N. BROGDEN, K.L.GOA, Drugs 3,5 448-467 (1988). J. DE VRY, J.L. SLANGEN, Europ J Pharmacol 119 193-197 (1985). S.E.FILE, S.PELLOW, Br J Pharmacol 8_44103 P (1985). D.J. SANGER, Pharmacol Biochem Behav 2,5 537-541 (1986). J.A.WAGNER, R.J.KATZ, Neurosci Letters 4_38317-320 (1984). R.H. DE JONG, J.D. BONIN, Anesth Analg 60385-389 (1981). B.BRUGUEROLLE, N.EMPERAIRE, A.OTTOMANI, J.C.MANELLI, Clin Exp Pharmacol Physiol 1,5 563-564 (1988). B.BRUGUEROLLE, N.EMPERAIRE, Life Sci 4_99185-188 (1991).