TOXICOLOGY
AND
APPLIED
Cyanide
PHARMACOLOGY
Intoxication:
36,93-97 (1976)
Protection
with
Chlorpromazine1
JAMESL. WAY AND GEORGE BURROWS Department
ef Pharmacology, Washington State University Received
August
Colleges of Veterinary Medicine and Pharmacy, University, Pullman, Washington 99163 of Idaho, Moscow, Idaho 83843 6 1975, accepted
October
15, 1975
CyanideIntoxication: Protection With Chlorpromazine.WAY, J. L. AND (1976). Toxicol. Appl. Pharmacol. 36, 93-97. Protection againstcyanideintoxication in micecan beenhancedby the administration of chlorpromazine, providing it is given with sodiumthiosulfate, or the sodium thiosulfate-sodiumnitrite antidotal combination. Potency ratios which werederived from the LD50 valueswerecomparedin groupsof mice premeditated with chlorpromazine(10 mg/kg) and/or sodiumthiosulfate (1 g/kg) and/or sodiumnitrite (100mg/kg). Theseresultsindicate that the administrationof chlorpromazinealoneprovidesno protection againstthe lethal effects of cyanide. Chlorpromazine also does not enhance the protective effect of sodium nitrite; however, it strikingly potentiatesthe effectivenessof sodium thiosulfate either alone or in combination with sodiumnitrite.
BURROWS, G.
Chlorpromazine has beenreported to antagonize the lethal effect of cyanide (Guth and Spirtes, 1958; Levine and Klein, 1959). This antidotal effect is attributed to a hypothermic response (Levine and Klein, 1959), as various drugs have been reported to protect against anoxia by a lowering of body temperature (Flacke et al., 1953). These studieswere initiated to investigate the antidotal properties of chlorpromazine when it is employed in combination with the classic cyanide antagonists, sodium nitrite and sodium thiosulfate (Chen et al., 1933; Hug, 1933). The present report clearly demonstrates that the administration of chlorpromazine alone in mice is of no value in antagonizing cyanide poisoning. However, when chlorpromazine is employed in combination with sodium thiosulfate, either alone or with sodium nitrite, a marked potentiation of the antidotal effect is observed against the lethality of potassiumcyanide. METHODS Potassium cyanide was purchased from the Mallinckrodt Chemical Works, and the cyanide was analyzed according to the method of Liebig (Kolthoff and Sandell, 1943). Sodium nitrite and sodium thiosulfate were Baker’s analyzed reagent grade chemicals, and chlorpromazine was obtained from Smith, Kline and French Laboratories. Solutions of potassium cyanide, sodium nitrite, sodium thiosulfate, and chlorpromazine were prepared just prior to use.Thesesolutions were dissolved in 0.9 ‘A sodium chloride, 1 This research was supported by Research Grant No. GM 21738 from the National Institute of General Medical Sciences, U.S. Department of Health, Education and Welfare. Copyright 0 1976 by Academic Press, Inc. 93 All rights of reproduction in any form reserved. Printed
in Great
Britain
94
WAY
AND
BURROWS
stored in glass-stoppered bottles, and were discarded daily. The cyanide solution was maintained at 0 to 2°C at all times. Swiss Webster mice weighing between 18 and 24 g were housed in air-conditioned rooms maintained at 20 to 23’C. The mice were randomly divided into five groups of 10 mice per group. Both groups of mice, i.e., groups receiving chlorpromazine and groups receiving no chlorpromazine, were treated on the same day. No gross toxic effect was observed from the administration of sodium nitrite, sodium thiosulfate, and chlorpromazine either alone or in various combinations. The LD50 values. which were based on 24-hr mortality, were analyzed statistically by the method of Litchfield and Wilcoxon (1949), and all experiments were repeated at least two times. The efficacy of chlorpromazine, sodium nitrite, and sodium thiosulfate in various combinations in antagonizing potassium cyanide was expressed as potency ratios. These potency ratios were derived from the LD50 values of potassium cyanide with and without antagonist. The dose and route of administration of antagonists were as follows: sodium nitrite, 100 mg/kg, SC; sodium thiosulfate, 1 g/kg, ip; chlorpromazine, 10 mg/kg, SC; potassium cyanide, 8 to 76 mg/kg, SC. The solutions were administered to the mice in a volume of less than I % of the body weight per injection. Sodium nitrite, chlorpromazine, and sodium thiosulfate were administered 45, 30, and 15 min respectively, prior to the SC injection of potassium cyanide. RESULTS The action of chlorpromazine (Table I), either sodium thiosulfate, in protecting against the lethal (Experiment 1) was compared with chlorpromazine was no significant difference observed. Although
alone or with sodium nitrite and/or effects of potassium cyanide alone pretreatment (Experiment 2); there sodium nitrite (Experiment 3) can
TABLE I THE EFFECT
OF CHLORPROMAZINE,
SODIUM NITRITE, AND SODIUM CYANIDE IN MICE
THIOSULFATE
ON THE
LD50
OF POTASSIUM
Treatment before KCN (SC) Experiment number
NaNOZ (SC) (wdkd
Chlorpromazine (SC) (n-cd@
0 0 100 100 0 0 100 100
0 10 0 10 0 IO 0 10
N&W3 (ipI (g/k)
LD50b IO.5 (9.50-l 1.60) 12.0 (10.81-13.32) 22.8 (21.80-23.78) 21.9 (20.89-22.95) 26.8 (25.30-28.68) 63.0 (60.40-65.70) 49.0(46.40-51.10) 68.0 (64.03-72.21)
“Dose schedule: NaNO,, chlorpromazine, and Na2S203 were administered 45, 30, and 15 min, respectively, prior to the administration of KCN. b Each LD50 value was obtained from five or more graded doses of KCN administered to five or more groups of 10 mice each. Numbers in parentheses are the 95 ‘A confidence limits.
ANTAGONISM
OF CYANIDE
INTOXICATION
95
protect against the lethal effects of potassium cyanide, the effect of sodium nitrite was not enhanced when combined with chlorpromazine (Experiment 4). Sodium thiosulfate (Experiment 5) was slightly more efficacious than sodium nitrite (Experiment 3) in protecting against the lethal effects of potassium cyanide. When sodium thiosulfate was administered in combination with chlorpromazine (Experiment 6), a striking enhancement in the antagonism of cyanide intoxication was observed. The combination of sodium thiosulfate and chlorpromazine (Experiment 6) was more efficacious than
FIG. 1. Dose-mortality regression lines for KCN in the presence of: (1) control; (2) chlorpromazine; (3) sodium nitrite; (4) sodium nitrite and chlorpromazine; (5) sodium thiosulfate; (6) sodium thiosulfate and chlorpromazine; (7) sodium nitrite and sodium thiosulfate; (8) sodium nitrite, sodium thiosulfate and chlorpromazine. POTENCY
RATIO
12345671 KCN
(CONTROL) KCN+Cz KCN+NaN02
KCN+NaN02+Cr KCN+Na2+03
2. Potency ratios of KCN with and without antagonist(s): LD50 of KCN with antagonist(s) Potency ratio = LD50 of KCN without antagonist’ KCN (control) in isotonic saline was employed as the “antagonist”. FIG.
the antidotal combination of sodium nitrite and sodium thiosulfate (Chen et al., 1933; Hug, 1933) (Experiment 7). When sodium nitrite and sodium thiosulfate (Experiment 7) were administered in combination with chlorpromazine (Experiment S), the LD50 value increased by 19 mg/kg or approx two times the LD50 dose of potassium cyanide. The LD50 values were plotted as log dose-response curves as shown in Fig. 1, and the slopes of these curves were found not to be significantly different from each other; therefore, the potency ratios could be computed. A general overall picture of the action of chlorpromazine against the lethal effects of potassium cyanide is best illustrated in Fig. 2. The protective effect of antagonized cyanide experiments are all compared to unantagonized potassium cyanide and
96
WAY
AND
BURROWS
expressed as potency ratios. It should be emphasized that Fig. 2 compares only~ cyanide alone to each combination of cyanide with antagonists. However, every possible combination (28) of these eight experimental groups were compared and expressed as potency ratios to ensure a statistically valid cross-comparison of the relative potency in all groups. Under these conditions chlorpromazine alone produced no protection against the lethal effects of potassium cyanide. Although sodium nitrite was shown to be more efficacious than chlorpromazine, there was no enhancement of sodium nitrite when chlorpromazine was combined with sodium nitrite. Sodium thiosulfate was more effective than sodium nitrite in protecting against the lethal effects ofpotassium cyanide, but when sodium thiosulfate was combined with chlorpromazine, a marked increase in the potency ratio was observed, as the ratio was increased by 3.4. The combination of chlorpromazine and sodium thiosulfate, with or without sodium nitrite, clearly protected against potassium cyanide lethality much better than the classic cyanide antidotal combination of sodium nitrite and sodium thiosulfate. DISCUSSION Guth and Spirtes (1958) reported that chlorpromazine and other phenothiazines can antagonize cyanide intoxication in pigeons. Subsequently, Levine and Klein (1959) indicated that chlorpromazine also can antagonize the lethal effect of cyanide in mice, and they concluded that the mechanism of cyanide antagonism can be attributed in a large part to hypothermia. This proposal is consistent with their experimental data; also, various drugs have been reported to protect against anoxia, presumably by a lowering of body temperature (Flacke et al., 1953). However, it should be emphasized that chlorpromazine does have many pharmacological properties and its antidotal activity, as a cyanide antagonist, may be due to other mechanisms besides hypothermia. We were unable to confirm earlier reports (Guth and Spirtes, 1958; Levine and Klein, 1959) that chlorpromazine alone can protect against the lethal effects of potassium cyanide. However, it should be emphasized that the inability to confirm the protective effect of chlorpromazine alone may be attributed to different experimental conditions. Our studies employed chlorpromazine at a dose of IO mg/kg, whereas the protective effect was elicited by the other laboratory at 50 mg/kg. Also, these studies were conducted in mice, and Guth and Spirtes (1958) employed pigeons in their studies. The inability of chlorpromazine alone to protect against cyanide would suggest that the predominant antidotal mechanism(s) involved is more complex than merely a lowering of body temperature. Also, in regard to our experimental design, the pretreatment time-interval employed with chlorpromazine may have been too short to produce appreciable hypothermia, as it has been reported by Schnell and Miya (1970) that maximal hypothermic response to chlorpromazine in rats does not occur until after 2-3 hr. It is of interest to note that cyanide can conversely antagonize the hypothermic response of chlorpromazine (LeBlanc, 1959). The striking results of chlorpromazine are surprising and similar, in many respects, to oxygen as a cyanide antagonist (Way et al., 1966 a, b); however, there also are some differences. Neither oxygen nor chlorpromazine antagonize the lethal effect of cyanide when used alone, and neither compound enhances the effect of sodium nitrite. However, oxygen enhances the protective effect of sodium thiosulfate only minimally, whereas
ANTAGONISM
OF CYANIDE
97
INTOXICATION
chlorpromazine produces a very marked synergistic effect. Furthermore, when sodium thiosulfate and the combination of sodium nitrite and sodium thiosulfate are compared with respect to chlorpromazine and oxygen, no significant difference between the two groups is observed with chlorpromazine, whereas oxygen elicits a very marked difference. These results indicate that the predominant beneficial effect of chlorpromazine is with sodium thiosulfate, while that of oxygen is with the sodium nitrite-sodium thiosulfate combination. It should be pointed out that these studies indicate that chlorpromazine is an effective cyanide antagonist only when it is administered prophylactically with sodium thiosulfate, or with sodium nitrite and sodium thiosulfate. It is important that similar studies be conducted under “therapeutic” conditions, i.e., the administration of chlorpromazine after signs and symptoms of cyanide poisoning are clearly delineated, prior to considering the feasibility of extending these experimental laboratory findings to clinica situations. ACKNOWLEDGMENT The authors would like to thank Smith, Kline and French for the chlorpromazine, and Susan
Gehant
for
technical
assistance.
REFERENCES K. K., ROSE, C. L. AND CLOWES, G. H. A. (1933). Methylene blue, nitrites and sodium thiosulfate against cyanide poisoning. Proc. Sot. Exp. Biol. Med. 31,250-252. FLACKE, W., M~~LKE, G. AND SCHULZ, R. (1953).Beitrag zur Wirkung von Pharmaka auf die Unterdrucktoleranz. Arch. Exp. Path. Pharm. 220,469476. GUTH, P. S. AND SPIRTES, M. A. (1958).Antagonism ofcyanide intoxication by chlorpromazine. CHEN,
Fed. Amer. Sot. Exp. Biol. 11, 374. HUG, E. (1933).Acci6n de1nitrito de sodioy de1hiposulfito de sodioen el tratamiento de la intoxicacibn provocada por el cianuro de potasio en el conejo. Reu. Sot. Argent. Biol. 9,91-97. KOLTHOFF, I. M. AND SANDELL, E. B. (1943). Textbook of Quantitative Inorganic Analysis, rev. ed. Macmillan, New York. LEBLANC, J. A. (1959). Effect of cyanide on some chlorpromazine responses. Proc. Sot. Exp.
Bioi. Med. 100,635-636. LEVINE,
S. AND
KLEIN,
M.
(1959).
Effect
of chlorpromazine
on cyanide
intoxication.
Proc.
Sot. Exp. Biol. Med. 102,192-194. LITCHFIELD, J. T., Jr. AND WILCOXON, F. (1949). A simplified method of evaluating dose-effect experiments. J. Pharmacol. Exp. Ther. 96,99-l 13. SCHNELL, R. C. AND MIYA, T. S. (1970). Influence of carbonic anhydrase inhibition on hypothermic response and brain distribution of chlorpromazine. Toxicof. Appl. Pharmacoi. 17, 239-243. WAY, J. L., GIBBON, S. L. AND SHEEHY, M. (1966a). Cyanide intoxication: Protection with oxygen. Science 152,210-211. WAY, J. L., GIBBON, S. L. AND SHEEHY, M. (1966b).Effect of oxygen on cyanide intoxication. II. Prophylactic protection. J. Pharmacol. Exp. Ther. 153,351-355.
AND
APPLIED
Cyanide
PHARMACOLOGY
Intoxication:
36,93-97 (1976)
Protection
with
Chlorpromazine1
JAMESL. WAY AND GEORGE BURROWS Department
ef Pharmacology, Washington State University Received
August
Colleges of Veterinary Medicine and Pharmacy, University, Pullman, Washington 99163 of Idaho, Moscow, Idaho 83843 6 1975, accepted
October
15, 1975
CyanideIntoxication: Protection With Chlorpromazine.WAY, J. L. AND (1976). Toxicol. Appl. Pharmacol. 36, 93-97. Protection againstcyanideintoxication in micecan beenhancedby the administration of chlorpromazine, providing it is given with sodiumthiosulfate, or the sodium thiosulfate-sodiumnitrite antidotal combination. Potency ratios which werederived from the LD50 valueswerecomparedin groupsof mice premeditated with chlorpromazine(10 mg/kg) and/or sodiumthiosulfate (1 g/kg) and/or sodiumnitrite (100mg/kg). Theseresultsindicate that the administrationof chlorpromazinealoneprovidesno protection againstthe lethal effects of cyanide. Chlorpromazine also does not enhance the protective effect of sodium nitrite; however, it strikingly potentiatesthe effectivenessof sodium thiosulfate either alone or in combination with sodiumnitrite.
BURROWS, G.
Chlorpromazine has beenreported to antagonize the lethal effect of cyanide (Guth and Spirtes, 1958; Levine and Klein, 1959). This antidotal effect is attributed to a hypothermic response (Levine and Klein, 1959), as various drugs have been reported to protect against anoxia by a lowering of body temperature (Flacke et al., 1953). These studieswere initiated to investigate the antidotal properties of chlorpromazine when it is employed in combination with the classic cyanide antagonists, sodium nitrite and sodium thiosulfate (Chen et al., 1933; Hug, 1933). The present report clearly demonstrates that the administration of chlorpromazine alone in mice is of no value in antagonizing cyanide poisoning. However, when chlorpromazine is employed in combination with sodium thiosulfate, either alone or with sodium nitrite, a marked potentiation of the antidotal effect is observed against the lethality of potassiumcyanide. METHODS Potassium cyanide was purchased from the Mallinckrodt Chemical Works, and the cyanide was analyzed according to the method of Liebig (Kolthoff and Sandell, 1943). Sodium nitrite and sodium thiosulfate were Baker’s analyzed reagent grade chemicals, and chlorpromazine was obtained from Smith, Kline and French Laboratories. Solutions of potassium cyanide, sodium nitrite, sodium thiosulfate, and chlorpromazine were prepared just prior to use.Thesesolutions were dissolved in 0.9 ‘A sodium chloride, 1 This research was supported by Research Grant No. GM 21738 from the National Institute of General Medical Sciences, U.S. Department of Health, Education and Welfare. Copyright 0 1976 by Academic Press, Inc. 93 All rights of reproduction in any form reserved. Printed
in Great
Britain
94
WAY
AND
BURROWS
stored in glass-stoppered bottles, and were discarded daily. The cyanide solution was maintained at 0 to 2°C at all times. Swiss Webster mice weighing between 18 and 24 g were housed in air-conditioned rooms maintained at 20 to 23’C. The mice were randomly divided into five groups of 10 mice per group. Both groups of mice, i.e., groups receiving chlorpromazine and groups receiving no chlorpromazine, were treated on the same day. No gross toxic effect was observed from the administration of sodium nitrite, sodium thiosulfate, and chlorpromazine either alone or in various combinations. The LD50 values. which were based on 24-hr mortality, were analyzed statistically by the method of Litchfield and Wilcoxon (1949), and all experiments were repeated at least two times. The efficacy of chlorpromazine, sodium nitrite, and sodium thiosulfate in various combinations in antagonizing potassium cyanide was expressed as potency ratios. These potency ratios were derived from the LD50 values of potassium cyanide with and without antagonist. The dose and route of administration of antagonists were as follows: sodium nitrite, 100 mg/kg, SC; sodium thiosulfate, 1 g/kg, ip; chlorpromazine, 10 mg/kg, SC; potassium cyanide, 8 to 76 mg/kg, SC. The solutions were administered to the mice in a volume of less than I % of the body weight per injection. Sodium nitrite, chlorpromazine, and sodium thiosulfate were administered 45, 30, and 15 min respectively, prior to the SC injection of potassium cyanide. RESULTS The action of chlorpromazine (Table I), either sodium thiosulfate, in protecting against the lethal (Experiment 1) was compared with chlorpromazine was no significant difference observed. Although
alone or with sodium nitrite and/or effects of potassium cyanide alone pretreatment (Experiment 2); there sodium nitrite (Experiment 3) can
TABLE I THE EFFECT
OF CHLORPROMAZINE,
SODIUM NITRITE, AND SODIUM CYANIDE IN MICE
THIOSULFATE
ON THE
LD50
OF POTASSIUM
Treatment before KCN (SC) Experiment number
NaNOZ (SC) (wdkd
Chlorpromazine (SC) (n-cd@
0 0 100 100 0 0 100 100
0 10 0 10 0 IO 0 10
N&W3 (ipI (g/k)
LD50b IO.5 (9.50-l 1.60) 12.0 (10.81-13.32) 22.8 (21.80-23.78) 21.9 (20.89-22.95) 26.8 (25.30-28.68) 63.0 (60.40-65.70) 49.0(46.40-51.10) 68.0 (64.03-72.21)
“Dose schedule: NaNO,, chlorpromazine, and Na2S203 were administered 45, 30, and 15 min, respectively, prior to the administration of KCN. b Each LD50 value was obtained from five or more graded doses of KCN administered to five or more groups of 10 mice each. Numbers in parentheses are the 95 ‘A confidence limits.
ANTAGONISM
OF CYANIDE
INTOXICATION
95
protect against the lethal effects of potassium cyanide, the effect of sodium nitrite was not enhanced when combined with chlorpromazine (Experiment 4). Sodium thiosulfate (Experiment 5) was slightly more efficacious than sodium nitrite (Experiment 3) in protecting against the lethal effects of potassium cyanide. When sodium thiosulfate was administered in combination with chlorpromazine (Experiment 6), a striking enhancement in the antagonism of cyanide intoxication was observed. The combination of sodium thiosulfate and chlorpromazine (Experiment 6) was more efficacious than
FIG. 1. Dose-mortality regression lines for KCN in the presence of: (1) control; (2) chlorpromazine; (3) sodium nitrite; (4) sodium nitrite and chlorpromazine; (5) sodium thiosulfate; (6) sodium thiosulfate and chlorpromazine; (7) sodium nitrite and sodium thiosulfate; (8) sodium nitrite, sodium thiosulfate and chlorpromazine. POTENCY
RATIO
12345671 KCN
(CONTROL) KCN+Cz KCN+NaN02
KCN+NaN02+Cr KCN+Na2+03
2. Potency ratios of KCN with and without antagonist(s): LD50 of KCN with antagonist(s) Potency ratio = LD50 of KCN without antagonist’ KCN (control) in isotonic saline was employed as the “antagonist”. FIG.
the antidotal combination of sodium nitrite and sodium thiosulfate (Chen et al., 1933; Hug, 1933) (Experiment 7). When sodium nitrite and sodium thiosulfate (Experiment 7) were administered in combination with chlorpromazine (Experiment S), the LD50 value increased by 19 mg/kg or approx two times the LD50 dose of potassium cyanide. The LD50 values were plotted as log dose-response curves as shown in Fig. 1, and the slopes of these curves were found not to be significantly different from each other; therefore, the potency ratios could be computed. A general overall picture of the action of chlorpromazine against the lethal effects of potassium cyanide is best illustrated in Fig. 2. The protective effect of antagonized cyanide experiments are all compared to unantagonized potassium cyanide and
96
WAY
AND
BURROWS
expressed as potency ratios. It should be emphasized that Fig. 2 compares only~ cyanide alone to each combination of cyanide with antagonists. However, every possible combination (28) of these eight experimental groups were compared and expressed as potency ratios to ensure a statistically valid cross-comparison of the relative potency in all groups. Under these conditions chlorpromazine alone produced no protection against the lethal effects of potassium cyanide. Although sodium nitrite was shown to be more efficacious than chlorpromazine, there was no enhancement of sodium nitrite when chlorpromazine was combined with sodium nitrite. Sodium thiosulfate was more effective than sodium nitrite in protecting against the lethal effects ofpotassium cyanide, but when sodium thiosulfate was combined with chlorpromazine, a marked increase in the potency ratio was observed, as the ratio was increased by 3.4. The combination of chlorpromazine and sodium thiosulfate, with or without sodium nitrite, clearly protected against potassium cyanide lethality much better than the classic cyanide antidotal combination of sodium nitrite and sodium thiosulfate. DISCUSSION Guth and Spirtes (1958) reported that chlorpromazine and other phenothiazines can antagonize cyanide intoxication in pigeons. Subsequently, Levine and Klein (1959) indicated that chlorpromazine also can antagonize the lethal effect of cyanide in mice, and they concluded that the mechanism of cyanide antagonism can be attributed in a large part to hypothermia. This proposal is consistent with their experimental data; also, various drugs have been reported to protect against anoxia, presumably by a lowering of body temperature (Flacke et al., 1953). However, it should be emphasized that chlorpromazine does have many pharmacological properties and its antidotal activity, as a cyanide antagonist, may be due to other mechanisms besides hypothermia. We were unable to confirm earlier reports (Guth and Spirtes, 1958; Levine and Klein, 1959) that chlorpromazine alone can protect against the lethal effects of potassium cyanide. However, it should be emphasized that the inability to confirm the protective effect of chlorpromazine alone may be attributed to different experimental conditions. Our studies employed chlorpromazine at a dose of IO mg/kg, whereas the protective effect was elicited by the other laboratory at 50 mg/kg. Also, these studies were conducted in mice, and Guth and Spirtes (1958) employed pigeons in their studies. The inability of chlorpromazine alone to protect against cyanide would suggest that the predominant antidotal mechanism(s) involved is more complex than merely a lowering of body temperature. Also, in regard to our experimental design, the pretreatment time-interval employed with chlorpromazine may have been too short to produce appreciable hypothermia, as it has been reported by Schnell and Miya (1970) that maximal hypothermic response to chlorpromazine in rats does not occur until after 2-3 hr. It is of interest to note that cyanide can conversely antagonize the hypothermic response of chlorpromazine (LeBlanc, 1959). The striking results of chlorpromazine are surprising and similar, in many respects, to oxygen as a cyanide antagonist (Way et al., 1966 a, b); however, there also are some differences. Neither oxygen nor chlorpromazine antagonize the lethal effect of cyanide when used alone, and neither compound enhances the effect of sodium nitrite. However, oxygen enhances the protective effect of sodium thiosulfate only minimally, whereas
ANTAGONISM
OF CYANIDE
97
INTOXICATION
chlorpromazine produces a very marked synergistic effect. Furthermore, when sodium thiosulfate and the combination of sodium nitrite and sodium thiosulfate are compared with respect to chlorpromazine and oxygen, no significant difference between the two groups is observed with chlorpromazine, whereas oxygen elicits a very marked difference. These results indicate that the predominant beneficial effect of chlorpromazine is with sodium thiosulfate, while that of oxygen is with the sodium nitrite-sodium thiosulfate combination. It should be pointed out that these studies indicate that chlorpromazine is an effective cyanide antagonist only when it is administered prophylactically with sodium thiosulfate, or with sodium nitrite and sodium thiosulfate. It is important that similar studies be conducted under “therapeutic” conditions, i.e., the administration of chlorpromazine after signs and symptoms of cyanide poisoning are clearly delineated, prior to considering the feasibility of extending these experimental laboratory findings to clinica situations. ACKNOWLEDGMENT The authors would like to thank Smith, Kline and French for the chlorpromazine, and Susan
Gehant
for
technical
assistance.
REFERENCES K. K., ROSE, C. L. AND CLOWES, G. H. A. (1933). Methylene blue, nitrites and sodium thiosulfate against cyanide poisoning. Proc. Sot. Exp. Biol. Med. 31,250-252. FLACKE, W., M~~LKE, G. AND SCHULZ, R. (1953).Beitrag zur Wirkung von Pharmaka auf die Unterdrucktoleranz. Arch. Exp. Path. Pharm. 220,469476. GUTH, P. S. AND SPIRTES, M. A. (1958).Antagonism ofcyanide intoxication by chlorpromazine. CHEN,
Fed. Amer. Sot. Exp. Biol. 11, 374. HUG, E. (1933).Acci6n de1nitrito de sodioy de1hiposulfito de sodioen el tratamiento de la intoxicacibn provocada por el cianuro de potasio en el conejo. Reu. Sot. Argent. Biol. 9,91-97. KOLTHOFF, I. M. AND SANDELL, E. B. (1943). Textbook of Quantitative Inorganic Analysis, rev. ed. Macmillan, New York. LEBLANC, J. A. (1959). Effect of cyanide on some chlorpromazine responses. Proc. Sot. Exp.
Bioi. Med. 100,635-636. LEVINE,
S. AND
KLEIN,
M.
(1959).
Effect
of chlorpromazine
on cyanide
intoxication.
Proc.
Sot. Exp. Biol. Med. 102,192-194. LITCHFIELD, J. T., Jr. AND WILCOXON, F. (1949). A simplified method of evaluating dose-effect experiments. J. Pharmacol. Exp. Ther. 96,99-l 13. SCHNELL, R. C. AND MIYA, T. S. (1970). Influence of carbonic anhydrase inhibition on hypothermic response and brain distribution of chlorpromazine. Toxicof. Appl. Pharmacoi. 17, 239-243. WAY, J. L., GIBBON, S. L. AND SHEEHY, M. (1966a). Cyanide intoxication: Protection with oxygen. Science 152,210-211. WAY, J. L., GIBBON, S. L. AND SHEEHY, M. (1966b).Effect of oxygen on cyanide intoxication. II. Prophylactic protection. J. Pharmacol. Exp. Ther. 153,351-355.
