Clinical Toxicology
ISSN: 0009-9309 (Print) (Online) Journal homepage: http://www.tandfonline.com/loi/ictx18
Arsenic Poisoning in Childhood an Unusual Case Report with Special Notes on Therapy with Penicillamine Abraham Kuruvilla, Paul S. Bergeson & Alan K. Done To cite this article: Abraham Kuruvilla, Paul S. Bergeson & Alan K. Done (1975) Arsenic Poisoning in Childhood an Unusual Case Report with Special Notes on Therapy with Penicillamine, Clinical Toxicology, 8:5, 535-540, DOI: 10.3109/15563657508988097 To link to this article: http://dx.doi.org/10.3109/15563657508988097
Published online: 25 Sep 2008.
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CLINICAL TOXICOLOGY 8(5), pp. 535-540 (1975)
Arsenic Poisoning in Childhood An Unusual Case Report With Special Notes on Therapy With Penicillamine
ABRAHAM KURWILIA, M.D. Maricopa County General Hospital Phoenix, Arizona PAUL S. BERGESON, M.D. Good Samaritan Hospital Phoenix, Arizona ALAN K. DONE Children's Hospital of Michigan Detroit, Michigan
Of 163,500 ingestion case reports to the National Clearinghouse for Poison Control Centers in 1973, 56 involved a substance contaiiing arsenic. Fifteen were in children under five years of age [ 13. The inorganic arsenic compound, arsenic trioxide (AszOs), is the third most common substance involved in arsenic ingestions [2]. Poisonings due to arsenic continue to be seen because of its widespread use in pesticides, in herbicides, and in industry. 535 Copyright 0 1976 by Marcel Dekker, Inc. All Rights Reserved. Neither this work nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher.
536
KURWILLA, BERGESON, AND DONE
Among arsenical herbicides there a r e greatly varying toxicities is less toxic than some more soluble herbicidal arsenicals, it has caused poisoning through ingestion, inhalation, o r skin contact of the dust [3, 41, and from vaginal suppositories [5]. The purpose of this article is to detail what we believe to be the first documented nonindustrial case of A s 2 4 poisoning involving the process of sublimation (preliminarily referred to previously) [2]. We will also comment on the adjunctive use of penicillamine in the treatment of arsenic poisoning, which appears to have been mentioned only once previously [6]
Downloaded by [NUS National University of Singapore] at 22:59 05 November 2015
[2]. Although As&
.
CASE R E P O R T
A nine-year-old boy was hospitalized with three of his brothers aged 6, 15, and 16, and a 15-year-old friend, for treatment of acute arsenic poisoning following a family cookout. An herbicide containing 47?6 arsenic trioxide* was inadvertently spilled over a barbecue grill and the underlying gravel. The grill itself was thoroughly scrubbed, and most of the underlying gravel and all loose herbicide were removed from the underlying barbecue base. Charcoal was then spread over the remaining herbicide and gravel, and a meal of chicken was cooked on the grill, with no direct contact with the underlying contents. Nine hours after ingestion of meat cooked in this setting, this nine- year-old boy experienced nausea and severe frontal headache, which were followed by five episodes of vomiting. Abdominal pain and tenderness were present. Complete blood count and urinalysis were normal. Arsenic level in urine obtained on admission was later reported to be 1.68 ml/liter. Intramuscular dimercaprol (BAL) was started in a dose of 3 mg/kg every 4 h r for 48 hr, every 6 h r for the next 24 hr, and every 8 h r for 48 hr, and discontinued a t the end of day 5. However, dimercaproI had to be restarted within 24 hr because of recurrence of the same symptoms. These symptoms promptly subsided with dimercaprol therapy given every 8 hr. The treatment was continued another 48 hr after which dimercaprol was discontinued (day 8). H i s arsenic level a t that time was 0.57 ml/liter. In the 24 hr after stopping dimercaprol the second time, the child had abdominal pain and vomited four times inspite of intravenous feedings, diphenhydramine hydrochloride by mouth and trimethobenzamide hydrochloride suppositories. He was, therefore, started on Dpenicillamine, 250 mg orally, every 6 hr. He experienced dramatic *Pax Crabgrass Control
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ARSENIC POISONING
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symptomatic relief with complete disappearance of nausea and vomiting, allowing discontinuation of supportive measures. The hospital courses of the 6- and 16-year-old siblings were marked by somewhat milder symptomatology. Their urine arsenic levels were 7.35 and 2.93 ml/liter, respectively. Seven days later this level was 0.3 ml/liter in each case. They were treated with dimercaprol for five days on the same dosage schedule as the nineyear-old. Dimercaprol was discontinued for the next two days. No drug treatment was given, but the children experienced continued nausea. Therefore, on day 8 they were started on D-penicillamine in the doses listed above. They promptly became asymptomatic. The 15-year-old friend and 15-year-old brother required no treatment. DISCUSSION Arsenic trioxide sublimes when sufficiently heated, i.e., vaporizes otherwise unchanged and condenses on cooling. In the present cases the herbicide that fell into the barbecue pit apparently underwent sublimation as the barbecuing progressed, and the vapor contaminated the meat. Subsequent ingestion of this meat, with its content of tasteless arsenic trioxide, resulted in the acute arsenic poisoning. The effect of sublimation on toxicity is unknown but may well increase the toxicity. As203 in powder form is not as toxic as some other more soluble arsenicals, and pulverizing As203 powder increases its toxicity [2]. The potential importance of the effect of sublimation on toxicity is evidenced by the fact that much A s 2 4 is commercially prepared by a process of sublimation [4]. The possibility of altered toxicity of A s 2 4 when sublimated should be kept in mind in future studies. The present cases presented with typical gastrointestinal manifestations of arsenic intoxication, including vomiting, abdominal pain, and diarrhea in various stages of severity. No circulatory embarrassment o r neurologic symptomatology was seen, possibly because of prompt use of dimercaprol. The antidotal treatment of choice for acute arsenic poisoning is dimercaprol (British Anti Lewisite, BAL), which forms a poorly dissociable complex with a variety of metals. Dimercaprol can also be used to protect against the toxic effects of those other metals that combine with sulfhydryl groups. Though dimercaprol has remained the treatment of choice since its discovery “7, 81, one must consider the painful intramuscular route of administration and certain unpleasant adverse effects, including nausea, vomiting, burning sensation in
Downloaded by [NUS National University of Singapore] at 22:59 05 November 2015
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KURWILLA, BERGESON, AND DONE
mucous membranes, generalized aches, and a sense of constriction in the chest. Dimercaprol has been used intermittently in less severe o r acute cases [9]. Our most severe case was treated with dimercaprol ineonventional doses (3 mg/kg every 4 hr for 48 hr, every 6 h r for 24 hr, and every 8 h r for 48 hr) for a total of five days. Symptoms of acute arsenic poisoning reappeared on its discontinuation so dramatically that dimercaprol was restarted on the sixth day for 48 hr, and the symptoms promptly subsided again. Symptoms recurred when dimercaprol was discontinued a second time. Thereafter, Dpenicillamine (Cuprimine), 250 mg orally, was given every 6 h r instead of intermittent dimercaprol injections, with dramatic relief of symptoms. This was continued 10 days. The other two cases of severe toxicity were also treated with D-penicillamine for 10 days after an initial eight days of dimercaprol, and had no recurrence of symptoms. Since its discovery in 1953, there has, to our knowledge, been only one report in the literature in which penicillamine was employed in the treatment of arsenic poisoning [6]. However, penicillin, which is degraded in part to penicillamine, has been used in at least one case of arsenic poisoning with apparent increased arsenic elimination [ 103. N-Acetyl DL penicillamine has been successfully used in mercury poisoning 211-151 and for removing excessive copper in the treatment of Wilson's disease (hepatolenticular degeneration) and has been studied in lead intoxication [ 161. It is effective in complexing certain metals by virtue of its thiol group and, therefore, is at least potentially reactive with the same compounds as dimercaprol [ 171. It is well absorbed from the gastrointestinal tract and rapidly excreted in the urine. Most common and serious untoward effects are the hypersensitivity reactions manifested by a maculopapular erythematous rash which may occasionally be accompanied by fever, leukopenia, thrombocytopenia, eosinophilia, arthralgia, o r lymphadenopathy. Optic neuropauy had been reported in patients using racemic penicillamine but not with the D-isomer, the form presently in common clinical usage [ 181. The neuropathy was found to be reversible on treatment with pyridoxine [ 191. The three patients reported herein treated with D-penicillamine (Cuprimine), after a course of dimercaprol, appeared clearly to benefit clinically. Unfortunately, no arsenic elimination studies were performed during treatment with penicillamine, so it cannot be stated whether the drug promoted arsenic elimination. Though the exact mode of action of penicillamine in arsenic toxicity is unknown, one would assume that the thiol group of penicillamine forms soluble complexes with arsenic, as with similar metals, which are excreted by the kidneys. More work needs to be done regarding the action of penicillamine
Downloaded by [NUS National University of Singapore] at 22:59 05 November 2015
ARSENIC POISONING
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in relation to arsenic in vivo. The oral route of administration and relatively fewer side effects a r e definite advantages over the intermittent intramuscular dimercaprol therapy. However, we feel that dimercaprol is the drug of choice for initiating treatment and that penicillamine a t present should be considered only to have possibilities as an adjunct mode of therapy. Whether and when penicillamine may be an acceptable alternative to dimercaprol requires further data. SUMMARY An unusual case of arsenic ingestion involving five children is reported, which involved the process of sublimation. A s 2 4 was inadvertently heated in a charcoal barbecue, and the meat cooked thereon was contaminated. It is possible that the sublimation may have potentiated the toxicity of the usually mildly toxic, relatively unsoluble Asz03. Penicillamine w a s used in the latter part of the therapy in three cases after initial dimercaprol, and the clinical effect of penicillamine was particularly dramatic in one case in which dimercaprol discontinuation had been accompanied by recurrent symptoms. Remarks on the mode of action of penicillamine are made. More work needs to be done to establish the possible role of penicillamine in arsenic poisoning.
REFERENCES National Clearinghouse for Poison Control Centers, Poison Control Statistics, 1973. A. K. Done and A. J. Peart, Clin. Toxicol., 4, 343 (1971). B. L. Valle, D. D. Ulmer, and W. E. C. Walker, AMA Arch. Ind. Health, 21, 132 (1960). S. S. Pinto B. M. Benette, Arch. Environ. Health, 1,583 (1963). Y. Chou and W. Chen, Chinese J. Int. Med., 2,278 (1959). English abstract, p. 27. C. R. Kjeldsberg and H. P. Ward, Ann. Int. Med., 77, 935 (1972). L. S. Goodman and A. Gilman, The Pharmacologic Basis of Therapeutics, 4th ed., MacMillan, 1970. L. A. Stocken and R. H. S. Thompson, Biochem. J., 40, 535 (1946).
an
Downloaded by [NUS National University of Singapore] at 22:59 05 November 2015
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KURWILLA, BERGESON, AND DONE
[91 J. St. Petery, 0. M. Rennert, H. Choi, and S. Wolfson, Clin. Toxicol., 3, 519 (1970). L. Perrot-and H. Gardere, Therapie, 14, 910 (1959). L. D. Pagnotto, Am. Ind. Hyg. Assoc.%, 21, 419 (1960). H. V. Aposhian and M. M. Aposhian, J. PGrmacol. Exptl. Therap., 126, 131 (1959). A. D. M. smith and J. W. Miller, -~ Lancet, 1961-1, 640. S. Z. Hirschman, M. Feingold, and G. Boylen, New Engl. J. Med.,269, 889 (1963). R. A. Pieterkark, D. C. Poskanzer, J. D. Bullock, and G. Boylen, New Engl. J. Med., 285, 10 (1971). L. F. Vitale, A. R. Bailon, D. Folland, J. F. Brennan, and B. McCormick, J. Pediat., 83, 1041 (1973). A. K. Done, Clin. Pharmacox Therap., 2, 750 (1961). AMA Drug Evaluation (2nd ed.), American Medical Association, Chicago, 1973, p. 890. J. Tu, R. Q. Blackwell, and P. F. Lee, JAMA, 185, 83 (1963).
ISSN: 0009-9309 (Print) (Online) Journal homepage: http://www.tandfonline.com/loi/ictx18
Arsenic Poisoning in Childhood an Unusual Case Report with Special Notes on Therapy with Penicillamine Abraham Kuruvilla, Paul S. Bergeson & Alan K. Done To cite this article: Abraham Kuruvilla, Paul S. Bergeson & Alan K. Done (1975) Arsenic Poisoning in Childhood an Unusual Case Report with Special Notes on Therapy with Penicillamine, Clinical Toxicology, 8:5, 535-540, DOI: 10.3109/15563657508988097 To link to this article: http://dx.doi.org/10.3109/15563657508988097
Published online: 25 Sep 2008.
Submit your article to this journal
Article views: 7
View related articles
Citing articles: 2 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ictx18 Download by: [NUS National University of Singapore]
Date: 05 November 2015, At: 22:59
Downloaded by [NUS National University of Singapore] at 22:59 05 November 2015
CLINICAL TOXICOLOGY 8(5), pp. 535-540 (1975)
Arsenic Poisoning in Childhood An Unusual Case Report With Special Notes on Therapy With Penicillamine
ABRAHAM KURWILIA, M.D. Maricopa County General Hospital Phoenix, Arizona PAUL S. BERGESON, M.D. Good Samaritan Hospital Phoenix, Arizona ALAN K. DONE Children's Hospital of Michigan Detroit, Michigan
Of 163,500 ingestion case reports to the National Clearinghouse for Poison Control Centers in 1973, 56 involved a substance contaiiing arsenic. Fifteen were in children under five years of age [ 13. The inorganic arsenic compound, arsenic trioxide (AszOs), is the third most common substance involved in arsenic ingestions [2]. Poisonings due to arsenic continue to be seen because of its widespread use in pesticides, in herbicides, and in industry. 535 Copyright 0 1976 by Marcel Dekker, Inc. All Rights Reserved. Neither this work nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher.
536
KURWILLA, BERGESON, AND DONE
Among arsenical herbicides there a r e greatly varying toxicities is less toxic than some more soluble herbicidal arsenicals, it has caused poisoning through ingestion, inhalation, o r skin contact of the dust [3, 41, and from vaginal suppositories [5]. The purpose of this article is to detail what we believe to be the first documented nonindustrial case of A s 2 4 poisoning involving the process of sublimation (preliminarily referred to previously) [2]. We will also comment on the adjunctive use of penicillamine in the treatment of arsenic poisoning, which appears to have been mentioned only once previously [6]
Downloaded by [NUS National University of Singapore] at 22:59 05 November 2015
[2]. Although As&
.
CASE R E P O R T
A nine-year-old boy was hospitalized with three of his brothers aged 6, 15, and 16, and a 15-year-old friend, for treatment of acute arsenic poisoning following a family cookout. An herbicide containing 47?6 arsenic trioxide* was inadvertently spilled over a barbecue grill and the underlying gravel. The grill itself was thoroughly scrubbed, and most of the underlying gravel and all loose herbicide were removed from the underlying barbecue base. Charcoal was then spread over the remaining herbicide and gravel, and a meal of chicken was cooked on the grill, with no direct contact with the underlying contents. Nine hours after ingestion of meat cooked in this setting, this nine- year-old boy experienced nausea and severe frontal headache, which were followed by five episodes of vomiting. Abdominal pain and tenderness were present. Complete blood count and urinalysis were normal. Arsenic level in urine obtained on admission was later reported to be 1.68 ml/liter. Intramuscular dimercaprol (BAL) was started in a dose of 3 mg/kg every 4 h r for 48 hr, every 6 h r for the next 24 hr, and every 8 h r for 48 hr, and discontinued a t the end of day 5. However, dimercaproI had to be restarted within 24 hr because of recurrence of the same symptoms. These symptoms promptly subsided with dimercaprol therapy given every 8 hr. The treatment was continued another 48 hr after which dimercaprol was discontinued (day 8). H i s arsenic level a t that time was 0.57 ml/liter. In the 24 hr after stopping dimercaprol the second time, the child had abdominal pain and vomited four times inspite of intravenous feedings, diphenhydramine hydrochloride by mouth and trimethobenzamide hydrochloride suppositories. He was, therefore, started on Dpenicillamine, 250 mg orally, every 6 hr. He experienced dramatic *Pax Crabgrass Control
Downloaded by [NUS National University of Singapore] at 22:59 05 November 2015
ARSENIC POISONING
537
symptomatic relief with complete disappearance of nausea and vomiting, allowing discontinuation of supportive measures. The hospital courses of the 6- and 16-year-old siblings were marked by somewhat milder symptomatology. Their urine arsenic levels were 7.35 and 2.93 ml/liter, respectively. Seven days later this level was 0.3 ml/liter in each case. They were treated with dimercaprol for five days on the same dosage schedule as the nineyear-old. Dimercaprol was discontinued for the next two days. No drug treatment was given, but the children experienced continued nausea. Therefore, on day 8 they were started on D-penicillamine in the doses listed above. They promptly became asymptomatic. The 15-year-old friend and 15-year-old brother required no treatment. DISCUSSION Arsenic trioxide sublimes when sufficiently heated, i.e., vaporizes otherwise unchanged and condenses on cooling. In the present cases the herbicide that fell into the barbecue pit apparently underwent sublimation as the barbecuing progressed, and the vapor contaminated the meat. Subsequent ingestion of this meat, with its content of tasteless arsenic trioxide, resulted in the acute arsenic poisoning. The effect of sublimation on toxicity is unknown but may well increase the toxicity. As203 in powder form is not as toxic as some other more soluble arsenicals, and pulverizing As203 powder increases its toxicity [2]. The potential importance of the effect of sublimation on toxicity is evidenced by the fact that much A s 2 4 is commercially prepared by a process of sublimation [4]. The possibility of altered toxicity of A s 2 4 when sublimated should be kept in mind in future studies. The present cases presented with typical gastrointestinal manifestations of arsenic intoxication, including vomiting, abdominal pain, and diarrhea in various stages of severity. No circulatory embarrassment o r neurologic symptomatology was seen, possibly because of prompt use of dimercaprol. The antidotal treatment of choice for acute arsenic poisoning is dimercaprol (British Anti Lewisite, BAL), which forms a poorly dissociable complex with a variety of metals. Dimercaprol can also be used to protect against the toxic effects of those other metals that combine with sulfhydryl groups. Though dimercaprol has remained the treatment of choice since its discovery “7, 81, one must consider the painful intramuscular route of administration and certain unpleasant adverse effects, including nausea, vomiting, burning sensation in
Downloaded by [NUS National University of Singapore] at 22:59 05 November 2015
538
KURWILLA, BERGESON, AND DONE
mucous membranes, generalized aches, and a sense of constriction in the chest. Dimercaprol has been used intermittently in less severe o r acute cases [9]. Our most severe case was treated with dimercaprol ineonventional doses (3 mg/kg every 4 hr for 48 hr, every 6 h r for 24 hr, and every 8 h r for 48 hr) for a total of five days. Symptoms of acute arsenic poisoning reappeared on its discontinuation so dramatically that dimercaprol was restarted on the sixth day for 48 hr, and the symptoms promptly subsided again. Symptoms recurred when dimercaprol was discontinued a second time. Thereafter, Dpenicillamine (Cuprimine), 250 mg orally, was given every 6 h r instead of intermittent dimercaprol injections, with dramatic relief of symptoms. This was continued 10 days. The other two cases of severe toxicity were also treated with D-penicillamine for 10 days after an initial eight days of dimercaprol, and had no recurrence of symptoms. Since its discovery in 1953, there has, to our knowledge, been only one report in the literature in which penicillamine was employed in the treatment of arsenic poisoning [6]. However, penicillin, which is degraded in part to penicillamine, has been used in at least one case of arsenic poisoning with apparent increased arsenic elimination [ 103. N-Acetyl DL penicillamine has been successfully used in mercury poisoning 211-151 and for removing excessive copper in the treatment of Wilson's disease (hepatolenticular degeneration) and has been studied in lead intoxication [ 161. It is effective in complexing certain metals by virtue of its thiol group and, therefore, is at least potentially reactive with the same compounds as dimercaprol [ 171. It is well absorbed from the gastrointestinal tract and rapidly excreted in the urine. Most common and serious untoward effects are the hypersensitivity reactions manifested by a maculopapular erythematous rash which may occasionally be accompanied by fever, leukopenia, thrombocytopenia, eosinophilia, arthralgia, o r lymphadenopathy. Optic neuropauy had been reported in patients using racemic penicillamine but not with the D-isomer, the form presently in common clinical usage [ 181. The neuropathy was found to be reversible on treatment with pyridoxine [ 191. The three patients reported herein treated with D-penicillamine (Cuprimine), after a course of dimercaprol, appeared clearly to benefit clinically. Unfortunately, no arsenic elimination studies were performed during treatment with penicillamine, so it cannot be stated whether the drug promoted arsenic elimination. Though the exact mode of action of penicillamine in arsenic toxicity is unknown, one would assume that the thiol group of penicillamine forms soluble complexes with arsenic, as with similar metals, which are excreted by the kidneys. More work needs to be done regarding the action of penicillamine
Downloaded by [NUS National University of Singapore] at 22:59 05 November 2015
ARSENIC POISONING
539
in relation to arsenic in vivo. The oral route of administration and relatively fewer side effects a r e definite advantages over the intermittent intramuscular dimercaprol therapy. However, we feel that dimercaprol is the drug of choice for initiating treatment and that penicillamine a t present should be considered only to have possibilities as an adjunct mode of therapy. Whether and when penicillamine may be an acceptable alternative to dimercaprol requires further data. SUMMARY An unusual case of arsenic ingestion involving five children is reported, which involved the process of sublimation. A s 2 4 was inadvertently heated in a charcoal barbecue, and the meat cooked thereon was contaminated. It is possible that the sublimation may have potentiated the toxicity of the usually mildly toxic, relatively unsoluble Asz03. Penicillamine w a s used in the latter part of the therapy in three cases after initial dimercaprol, and the clinical effect of penicillamine was particularly dramatic in one case in which dimercaprol discontinuation had been accompanied by recurrent symptoms. Remarks on the mode of action of penicillamine are made. More work needs to be done to establish the possible role of penicillamine in arsenic poisoning.
REFERENCES National Clearinghouse for Poison Control Centers, Poison Control Statistics, 1973. A. K. Done and A. J. Peart, Clin. Toxicol., 4, 343 (1971). B. L. Valle, D. D. Ulmer, and W. E. C. Walker, AMA Arch. Ind. Health, 21, 132 (1960). S. S. Pinto B. M. Benette, Arch. Environ. Health, 1,583 (1963). Y. Chou and W. Chen, Chinese J. Int. Med., 2,278 (1959). English abstract, p. 27. C. R. Kjeldsberg and H. P. Ward, Ann. Int. Med., 77, 935 (1972). L. S. Goodman and A. Gilman, The Pharmacologic Basis of Therapeutics, 4th ed., MacMillan, 1970. L. A. Stocken and R. H. S. Thompson, Biochem. J., 40, 535 (1946).
an
Downloaded by [NUS National University of Singapore] at 22:59 05 November 2015
540
KURWILLA, BERGESON, AND DONE
[91 J. St. Petery, 0. M. Rennert, H. Choi, and S. Wolfson, Clin. Toxicol., 3, 519 (1970). L. Perrot-and H. Gardere, Therapie, 14, 910 (1959). L. D. Pagnotto, Am. Ind. Hyg. Assoc.%, 21, 419 (1960). H. V. Aposhian and M. M. Aposhian, J. PGrmacol. Exptl. Therap., 126, 131 (1959). A. D. M. smith and J. W. Miller, -~ Lancet, 1961-1, 640. S. Z. Hirschman, M. Feingold, and G. Boylen, New Engl. J. Med.,269, 889 (1963). R. A. Pieterkark, D. C. Poskanzer, J. D. Bullock, and G. Boylen, New Engl. J. Med., 285, 10 (1971). L. F. Vitale, A. R. Bailon, D. Folland, J. F. Brennan, and B. McCormick, J. Pediat., 83, 1041 (1973). A. K. Done, Clin. Pharmacox Therap., 2, 750 (1961). AMA Drug Evaluation (2nd ed.), American Medical Association, Chicago, 1973, p. 890. J. Tu, R. Q. Blackwell, and P. F. Lee, JAMA, 185, 83 (1963).
