EFFECTS OF ACUTE AND CHRONIC ADMINISTRATION OF METHYLPHENIDATE ON LIDOCAINE CONVULSIONS IN MICE WATTANA KONTHIKAMEE, R. L. SPRECHER and P. A. MOORE Department of Pharmacology-Physiology, School of Dental Medicine. Pittsburgh, PA 15261, U.S.A.
University
of Pittsburgh,
Summary-The reports about lidocaine and methylphenidate interactions and the wide usage of both drugs suggest a possibility of convulsive interaction between lidocaine and methylphenidate. The dose-response curves of lidocaine, methylphenidate, lidocaine in combination with 30mg/kg methylphenidate, and lidocaine in mice chronically treated with 30mg/kg/per day methylphenidate were plotted and compared. The median convulsant dose (cD~J for lidocaine was determined to be 64mg/kg, for methylphenidate lOOmg/kg, for lidocaine in combination with methylphenidate 47.50 mg/kg and for lidocaine in chronically-treated mice 57.70 mg/kg. The first three curves did not significantly deviate from parallelism, but the relative potencies were significantly different from each other. The dose-response curve of lidocaine in chronically-treated mice did significantly deviate from the other curves. This study showed significant effects of acute and chronic administration of methylphenidate on lidocaine convulsions. These findings suggest a need for precaution against possible interactions between lidoCaine and methylphenidate.
INTRODUCTION
MATERIALS AND METHODS
Lidocaine is commonly used as a local anaesthetic agent and cardiac anti-arrhythmic agent. Methylphenidate is used for the treatment of various kinds of depression and for hyperkinetic syndromes in children. A toxic effect common to both drugs is their ability to stimulate the central nervous system and induce convulsions (Ritchie and Cohen, 1975; Franz, 1975). The convulsive response to lidocaine can be potentiated by other agents. In mice, the combination with promethazine or meperidine potentiates the convulsive action of lidocaine (Smudski, Sprecher and Elliott, 1964). Increasing pCOZ decreases the dose of lidocaine required to induce convulsions (Wagman, de Jong and Prince, 1967; de Jong, Wagman and Prince, 1967: Englesson and Grevsten, 1974). Interactions between methylphenidate and other agents have been reported. Pretreatment with methylphenidate decreases the dose of pentylenetetrazol or strychnine required to induce convulsions (Chen and Bohner, 1958). Methylphenidate can also interact with other agents by inhibiting liver drug-metabolizing enzymes (Garrettson, Perel and Dayton, 1969; Perel et al., 1969; Wharton et al., 1971.) As both lidocaine and methylphenidate are widely used for therapeutic purposes, there is a possibility that both drugs could be administered simultaneously and could interact to stimulate the central nervous system. This interaction could result from a change in the biotransformation of lidocaine as chronic administration of methylphenidate can inhibit liver drug metabolizing enzymes. Therefore, the following experiments were performed to determine the effects of acute and chronic administration of methylphenidate on lidocaine convulsions.
Male Swiss Webster mice, weighing 23-35 g, were housed in an animal room for at least 7 days before being used. They had free access to food and water at all times except during the experiments. The light was automatically turned on at 06.00 h and turned off at 18.00 h. As the physical reaction of animals to drugs may be modified by circadian rhythm (Haus and Halberg, 1959; Davis and Webb, 1963), all experiments were carried out at [email protected] h. A group of 20 mice was used to determine the response at each dose of the drugs. Many authors have reported that the toxic effects of central nervous system stimulants are more pronounced in the animals which are kept in groups rather than isolated (Chance, 1946; Greenblatt and Osterberg, 1961). Therefore, each mouse was isolated in a transparent cage, 114 x 7f x 5 in., after drug administration. A crystalline form of lidocaine HCl and methylphenidate HCl was dissolved and diluted in normal saline solutions. The combination of lidocaine and 30mg/‘kg methylphenidate was prepared by mixing appropiated concentrations of lidocaine and methylphenidate together before administration to the mice. In the acute administration studies, the selected doses of lidocaine, methylphenidate and lidocaine in combination with 30 mg/kg methylphenidate were administered intraperitoneally in a volume of 0.2 ml/30 g mouse. After administration, the convulsive responses were observed for 15 min. In the chronic administration studies, the dose of 30mg/kg per day methylphenidate in a volume of 0.1 ml/25 g mouse was administered subcutaneously to each mouse for 14 consecutive days between I7.0&20.00 h. After the administration of the drug, 579
Wattana Konthikamee,
580
R. L. Sprecher and P. A. Moore Table 1. The CD,, values with upper and lower limits
300-
200
coSO (mg/kg)
Drugs Lidocaine Methylphenidate Lidocaine + 30 mg/kg methylphenidate Lidocaine (in chronically-treated mice)
e!!i*
zo-
'02
I 5
I IO
I 20
III/II 30405060
Convuhons,
70 80
I 90
I 95
1 98
%
Fig. 1. Dose-response curves showing per cent convulsions plotted against the log of the mg/kg dose of lidocaine (O---O), methylphenidate (A--A), lidoeaine in combination with methylphenidate (O-O) and lidocaine in chronically-treated mice (a---+).
CDs,
Upper limit
Lower limit
64.00 100.00
69.71 105.66
5x.71 94.64
47.50
51.71
43.61
59.67
55.41
57.70
The dose that caused convulsions in 50 per cent of the mice was defined as CD,, (Table 1). Intraperitoneal administration and chronic subcutaneous administration of normal saline solution did not significantly modify lidocaine-induced convulsions. DISCUSSION
each mouse was isolated in a cage for approximately 2-3 h before they were housed together again. The administration of the drug was discontinued 72 h before the dose-convulsive response relationship for lidocaine was determined in the chronically-treated mice. The dose-response relationship were evaluated by a simplified method of evaluating dose-effect experiments (Litchfield and Wilcoxon, 1949). p < 0.05 was considered to be the level of significance. RESULTS
After intraperitoneal administration of a convulsive dose of lidocaine, the mice exhibited signs of either opisthotonus, tonic convulsion, clonic convulsion or a combination of these convulsions. After 15 min of observation, all mice showed some degree of sedation. The behavioural convulsive pattern of methylphenidate was different from convulsions induced by lidoCaine. After a convulsive dose of methylphenidate, the mice exhibited myoclonic jerking, jumping up and down and running around the cage very rapidly. After the observation period, the mice continued to show an increase in activities for 2-3 h. The combination of lidocaine and 30 mg/‘kg methylphenidate did not induce a consistent behavioural convulsive pattern. Some mice exhibited convulsions mimicking lidocaine convulsions whereas others exhibited convulsions similar to methylphenidate convulsions. The chronically-treated mice challenged with a convulsive dose of lidocaine only exhibited convulsions mimicking the lidocaine convulsions observed in untreated mice. Figure 1 shows the dose-response curves of lidoCaine, methylphenidate, lidocaine in combination with 30 mg/kg methylphenidate and lidocaine after chronic treatment with 30mgkg per day methylphenidate. The first three curves did not significantly deviate from parallelism, but the relative potencies were significantly different. The slope of the lidocaine curve in chronically-treated mice was significantly different from the other curves.
Although the mechanism of convulsions is not fully understood, the finding that the dose-response curves of hdocaine, methylphenidate and lidocaine in combination with 30mg/kg methylphenidate did not significantly deviate from parallelism suggests that these drugs may induce convulsions by the same mechanism. However, the difference in behavioural convulsive patterns suggests the opposite. On the other hand, the dose-response curves of lidocaine and lidoCaine in chronically-treated mice significantly deviated from parallelism though the behavioural convulsive patterns were not different. The effect of chronic treatment with 30mg,kg per day methylphenidate on the lidocaine dose-response curve could be explained by the findings by Garrettson et al. (1969) Perel et al. (1969) and Wharton et al. (1971), that chronic treatment with methylphenidate can inhibit liver microsomal enzymes which are responsible for biotransformation of some drugs. As liver microsomal enzymes are also responsible for lidocaine biotransformation (Hohunger, 1960) the chronic treatment with methylphenidate could have inhibited the liver drug metabolizing enzymes responsible for hdoCaine biotransformation. As a result, more lidocaine could have been present in the circulation after passing through the liver and more lidocaine could have been transported to the site of action and produced the increased effects. Our results indicate that in mice there are interactions between lidocaine and methylphenidate which enhance their ability to induce convulsions. There must be caution in extrapolating from experimental animals to man, but our findings suggest that in patients receiving methylphenidate, the risk of convulsions may be increased if lidocaine is administered intravenously, because the convulsive threshold of lidocaine might have been decreased by methylphenidate. Acknowledgements-We thank the Thai Government for their financial support to the first author and CIBA Phar-
Convulsive
interactions
of lidocaine
maceutical Co. for providing the methylphenidate hydrochloride (Ritalina), We are grateful for the advice of Dr. James W. Smudski. REFERENCES Chance M. R. A. 1946. Aggregation as a factor influencing the toxicity of sympathomimetic amines in mice. J. Pharmat. rup. Ther. 81, 216219. Chen G. and Bohner B. 1958. A study of central nervous svstem stimulants. J. Pharmac. ~.YD.Ther. 123. 212-215. DaCis W. M. and Webb 0. L. 196j. A circadian rhythm of chemoconvulsive response thresholds in mice. Medna exp. 9, 263-267. de Jong R. H.. Wagman 1. H. and Prince D. A. 1967. Effect of carbon dioxide on the cortical seizure threshold to lidocaine. Evpl Netrrol. 17. 221-232. Englesson S. and Grevsten S. 1974. The influence of acidbase changes on central nervous toxicity of local anaesthetic agents II. .4ctu anaesth. stand. 18, 88-103. Franz D. N. 1975. Central nervous system stimulants. In: ThP Phurmacological Basis qf Therapeutics (Edited by Gopdman L.. S. and Gilman A.). Chap. 18. p. 365. Macmillan. New York. Garrettson L. K.. Perel J. M. and Dayton P. G. 1969. Methylphenidate interaction with both anticonvulsants and ethyl biscoumacetate. J. .4m. med. Ass. 207, 2053. 20% Greenblatt E. N. and Osterberg A. C. 1961. Correlations of activating and lethal effects of excitatory drugs in
and methylphenidate
SRI
grouped and isolated mice. J. Pharmac. rrp. Ther. 131. 115-I 19. Haus E. and Halberg F. 1959. 24-Hour rhythm in susceptibility of C mice to a toxic dose of ethanol. J. UPPI. Phv siol.-14, 878-880. Hollunger G. 1960. On the metabolism of lidocaine I. The properties of the enzyme system responsible for the oxiaative metabolism of lidocaine. Arta phurmuc. lo\. 17, 356-364. Litchfield J. T. Jr. and Wilcoxon F. 1949. A simplified method of evaluating dose-effect experiments. J. Phtrrmat. exp. Ther. 96, 99-113. Perel J. M., Black N.. Wharton R. N. and Malitr S. 1969. Inhibition of Imipramine metabolism by methylphenidate. Fedn Proc. Fedn Am. Sots e\-p. Biol. 28. 41 X (abstract). Ritchie J. M. and Cohen P. J. 1975. Local anesthetics. In: The Pharmacological Basis of Therapeutics (Edited hy Goodman L. S. and Gilman A.). Chap. 20. p. 384. Macmillan, New York. Smudski J. W., Sprecher R. L. and Elliott H. W. 1964. Convulsive interactions of promethazine, meperidlne and lidocaine. Archs oral Biol. 9. 595-600. Wagman I. H., de Jong R. H. and Prince D. A. 1967. Effects of lidocaine on the central nervous system. .4ncsthesiology 28, 155-l 72. Wharton R. N., Perel J. M., Dayton P. G. and Malitz S. 1971. A potential clinical use for methylphenidate with 121. antidepressants. Am. J. Psychinr. tricyclic 1619-1625.
University
of Pittsburgh,
Summary-The reports about lidocaine and methylphenidate interactions and the wide usage of both drugs suggest a possibility of convulsive interaction between lidocaine and methylphenidate. The dose-response curves of lidocaine, methylphenidate, lidocaine in combination with 30mg/kg methylphenidate, and lidocaine in mice chronically treated with 30mg/kg/per day methylphenidate were plotted and compared. The median convulsant dose (cD~J for lidocaine was determined to be 64mg/kg, for methylphenidate lOOmg/kg, for lidocaine in combination with methylphenidate 47.50 mg/kg and for lidocaine in chronically-treated mice 57.70 mg/kg. The first three curves did not significantly deviate from parallelism, but the relative potencies were significantly different from each other. The dose-response curve of lidocaine in chronically-treated mice did significantly deviate from the other curves. This study showed significant effects of acute and chronic administration of methylphenidate on lidocaine convulsions. These findings suggest a need for precaution against possible interactions between lidoCaine and methylphenidate.
INTRODUCTION
MATERIALS AND METHODS
Lidocaine is commonly used as a local anaesthetic agent and cardiac anti-arrhythmic agent. Methylphenidate is used for the treatment of various kinds of depression and for hyperkinetic syndromes in children. A toxic effect common to both drugs is their ability to stimulate the central nervous system and induce convulsions (Ritchie and Cohen, 1975; Franz, 1975). The convulsive response to lidocaine can be potentiated by other agents. In mice, the combination with promethazine or meperidine potentiates the convulsive action of lidocaine (Smudski, Sprecher and Elliott, 1964). Increasing pCOZ decreases the dose of lidocaine required to induce convulsions (Wagman, de Jong and Prince, 1967; de Jong, Wagman and Prince, 1967: Englesson and Grevsten, 1974). Interactions between methylphenidate and other agents have been reported. Pretreatment with methylphenidate decreases the dose of pentylenetetrazol or strychnine required to induce convulsions (Chen and Bohner, 1958). Methylphenidate can also interact with other agents by inhibiting liver drug-metabolizing enzymes (Garrettson, Perel and Dayton, 1969; Perel et al., 1969; Wharton et al., 1971.) As both lidocaine and methylphenidate are widely used for therapeutic purposes, there is a possibility that both drugs could be administered simultaneously and could interact to stimulate the central nervous system. This interaction could result from a change in the biotransformation of lidocaine as chronic administration of methylphenidate can inhibit liver drug metabolizing enzymes. Therefore, the following experiments were performed to determine the effects of acute and chronic administration of methylphenidate on lidocaine convulsions.
Male Swiss Webster mice, weighing 23-35 g, were housed in an animal room for at least 7 days before being used. They had free access to food and water at all times except during the experiments. The light was automatically turned on at 06.00 h and turned off at 18.00 h. As the physical reaction of animals to drugs may be modified by circadian rhythm (Haus and Halberg, 1959; Davis and Webb, 1963), all experiments were carried out at [email protected] h. A group of 20 mice was used to determine the response at each dose of the drugs. Many authors have reported that the toxic effects of central nervous system stimulants are more pronounced in the animals which are kept in groups rather than isolated (Chance, 1946; Greenblatt and Osterberg, 1961). Therefore, each mouse was isolated in a transparent cage, 114 x 7f x 5 in., after drug administration. A crystalline form of lidocaine HCl and methylphenidate HCl was dissolved and diluted in normal saline solutions. The combination of lidocaine and 30mg/‘kg methylphenidate was prepared by mixing appropiated concentrations of lidocaine and methylphenidate together before administration to the mice. In the acute administration studies, the selected doses of lidocaine, methylphenidate and lidocaine in combination with 30 mg/kg methylphenidate were administered intraperitoneally in a volume of 0.2 ml/30 g mouse. After administration, the convulsive responses were observed for 15 min. In the chronic administration studies, the dose of 30mg/kg per day methylphenidate in a volume of 0.1 ml/25 g mouse was administered subcutaneously to each mouse for 14 consecutive days between I7.0&20.00 h. After the administration of the drug, 579
Wattana Konthikamee,
580
R. L. Sprecher and P. A. Moore Table 1. The CD,, values with upper and lower limits
300-
200
coSO (mg/kg)
Drugs Lidocaine Methylphenidate Lidocaine + 30 mg/kg methylphenidate Lidocaine (in chronically-treated mice)
e!!i*
zo-
'02
I 5
I IO
I 20
III/II 30405060
Convuhons,
70 80
I 90
I 95
1 98
%
Fig. 1. Dose-response curves showing per cent convulsions plotted against the log of the mg/kg dose of lidocaine (O---O), methylphenidate (A--A), lidoeaine in combination with methylphenidate (O-O) and lidocaine in chronically-treated mice (a---+).
CDs,
Upper limit
Lower limit
64.00 100.00
69.71 105.66
5x.71 94.64
47.50
51.71
43.61
59.67
55.41
57.70
The dose that caused convulsions in 50 per cent of the mice was defined as CD,, (Table 1). Intraperitoneal administration and chronic subcutaneous administration of normal saline solution did not significantly modify lidocaine-induced convulsions. DISCUSSION
each mouse was isolated in a cage for approximately 2-3 h before they were housed together again. The administration of the drug was discontinued 72 h before the dose-convulsive response relationship for lidocaine was determined in the chronically-treated mice. The dose-response relationship were evaluated by a simplified method of evaluating dose-effect experiments (Litchfield and Wilcoxon, 1949). p < 0.05 was considered to be the level of significance. RESULTS
After intraperitoneal administration of a convulsive dose of lidocaine, the mice exhibited signs of either opisthotonus, tonic convulsion, clonic convulsion or a combination of these convulsions. After 15 min of observation, all mice showed some degree of sedation. The behavioural convulsive pattern of methylphenidate was different from convulsions induced by lidoCaine. After a convulsive dose of methylphenidate, the mice exhibited myoclonic jerking, jumping up and down and running around the cage very rapidly. After the observation period, the mice continued to show an increase in activities for 2-3 h. The combination of lidocaine and 30 mg/‘kg methylphenidate did not induce a consistent behavioural convulsive pattern. Some mice exhibited convulsions mimicking lidocaine convulsions whereas others exhibited convulsions similar to methylphenidate convulsions. The chronically-treated mice challenged with a convulsive dose of lidocaine only exhibited convulsions mimicking the lidocaine convulsions observed in untreated mice. Figure 1 shows the dose-response curves of lidoCaine, methylphenidate, lidocaine in combination with 30 mg/kg methylphenidate and lidocaine after chronic treatment with 30mgkg per day methylphenidate. The first three curves did not significantly deviate from parallelism, but the relative potencies were significantly different. The slope of the lidocaine curve in chronically-treated mice was significantly different from the other curves.
Although the mechanism of convulsions is not fully understood, the finding that the dose-response curves of hdocaine, methylphenidate and lidocaine in combination with 30mg/kg methylphenidate did not significantly deviate from parallelism suggests that these drugs may induce convulsions by the same mechanism. However, the difference in behavioural convulsive patterns suggests the opposite. On the other hand, the dose-response curves of lidocaine and lidoCaine in chronically-treated mice significantly deviated from parallelism though the behavioural convulsive patterns were not different. The effect of chronic treatment with 30mg,kg per day methylphenidate on the lidocaine dose-response curve could be explained by the findings by Garrettson et al. (1969) Perel et al. (1969) and Wharton et al. (1971), that chronic treatment with methylphenidate can inhibit liver microsomal enzymes which are responsible for biotransformation of some drugs. As liver microsomal enzymes are also responsible for lidocaine biotransformation (Hohunger, 1960) the chronic treatment with methylphenidate could have inhibited the liver drug metabolizing enzymes responsible for hdoCaine biotransformation. As a result, more lidocaine could have been present in the circulation after passing through the liver and more lidocaine could have been transported to the site of action and produced the increased effects. Our results indicate that in mice there are interactions between lidocaine and methylphenidate which enhance their ability to induce convulsions. There must be caution in extrapolating from experimental animals to man, but our findings suggest that in patients receiving methylphenidate, the risk of convulsions may be increased if lidocaine is administered intravenously, because the convulsive threshold of lidocaine might have been decreased by methylphenidate. Acknowledgements-We thank the Thai Government for their financial support to the first author and CIBA Phar-
Convulsive
interactions
of lidocaine
maceutical Co. for providing the methylphenidate hydrochloride (Ritalina), We are grateful for the advice of Dr. James W. Smudski. REFERENCES Chance M. R. A. 1946. Aggregation as a factor influencing the toxicity of sympathomimetic amines in mice. J. Pharmat. rup. Ther. 81, 216219. Chen G. and Bohner B. 1958. A study of central nervous svstem stimulants. J. Pharmac. ~.YD.Ther. 123. 212-215. DaCis W. M. and Webb 0. L. 196j. A circadian rhythm of chemoconvulsive response thresholds in mice. Medna exp. 9, 263-267. de Jong R. H.. Wagman 1. H. and Prince D. A. 1967. Effect of carbon dioxide on the cortical seizure threshold to lidocaine. Evpl Netrrol. 17. 221-232. Englesson S. and Grevsten S. 1974. The influence of acidbase changes on central nervous toxicity of local anaesthetic agents II. .4ctu anaesth. stand. 18, 88-103. Franz D. N. 1975. Central nervous system stimulants. In: ThP Phurmacological Basis qf Therapeutics (Edited by Gopdman L.. S. and Gilman A.). Chap. 18. p. 365. Macmillan. New York. Garrettson L. K.. Perel J. M. and Dayton P. G. 1969. Methylphenidate interaction with both anticonvulsants and ethyl biscoumacetate. J. .4m. med. Ass. 207, 2053. 20% Greenblatt E. N. and Osterberg A. C. 1961. Correlations of activating and lethal effects of excitatory drugs in
and methylphenidate
SRI
grouped and isolated mice. J. Pharmac. rrp. Ther. 131. 115-I 19. Haus E. and Halberg F. 1959. 24-Hour rhythm in susceptibility of C mice to a toxic dose of ethanol. J. UPPI. Phv siol.-14, 878-880. Hollunger G. 1960. On the metabolism of lidocaine I. The properties of the enzyme system responsible for the oxiaative metabolism of lidocaine. Arta phurmuc. lo\. 17, 356-364. Litchfield J. T. Jr. and Wilcoxon F. 1949. A simplified method of evaluating dose-effect experiments. J. Phtrrmat. exp. Ther. 96, 99-113. Perel J. M., Black N.. Wharton R. N. and Malitr S. 1969. Inhibition of Imipramine metabolism by methylphenidate. Fedn Proc. Fedn Am. Sots e\-p. Biol. 28. 41 X (abstract). Ritchie J. M. and Cohen P. J. 1975. Local anesthetics. In: The Pharmacological Basis of Therapeutics (Edited hy Goodman L. S. and Gilman A.). Chap. 20. p. 384. Macmillan, New York. Smudski J. W., Sprecher R. L. and Elliott H. W. 1964. Convulsive interactions of promethazine, meperidlne and lidocaine. Archs oral Biol. 9. 595-600. Wagman I. H., de Jong R. H. and Prince D. A. 1967. Effects of lidocaine on the central nervous system. .4ncsthesiology 28, 155-l 72. Wharton R. N., Perel J. M., Dayton P. G. and Malitz S. 1971. A potential clinical use for methylphenidate with 121. antidepressants. Am. J. Psychinr. tricyclic 1619-1625.
