PEDIATRIC
PHARMACOLOGY
THERAPEUTICS
AND
Paul S. Lietman, Editor
Urinary D-glucaric acid excretion in children with dystonic reactions caused by antiemetic drugs Chr. Cassimos, J. Tsiuris, B. Danielides, and Keti Malaka-Zafiriu,
Thessaloniki, Greece
THE BIOTRANSFORMATION of drugs takes place mainly in the smooth endoplasmic reticulum of the liver. Some individuals, particularly children, have unusual drug responses or idiosyncrasies to various antiemetic drugs, e.g., phenothiazines and their derivatives 1, 2 and metodopromide, 3 and develop extrapyramidal signs and dystonic reactions. These extrapyramidal reactions are caused by an unusual sensitivity to the drugs. These individuals may have an inherited defect involving the hepatic detoxification of the drugs?' 3 Recently measurement of 24-hour urinary excretion of D-glucaric acid has been used as an index of the enzymatic activity of the smooth endoplasmic reticulum of the liver? -* In this paper the experiences with seven children who developed alarming reactions to recommended doses of various antiemetic drugs are presented. MATERIALS
AND METHODS
Urinary excretion of D-glucaric acid was studied in seven children who developed various extrapyramidal symptoms after the administration of antiemetic drugs (Table I). The drugs were given in recommended doses to c o u n teract nausea and vomiting. Previous neurologic examinations had been normal, and there was no history of hepatic disease. All reactions began within 24-48 hours of starting administration of the drugs. The symptoms consisted mainly of torticollis, anxiety, tremor, dysarthria, neck pain, akathisia and walking difficulties; the children From the Paediatric Clinic, University o f Thessaloniki, A H E P A Hospital. Reprint address: Pediatric Clinic, University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece.
were admitted to hospital with presumptive diagnoses of encephalitis or meningitis. Urinary excretion o f D-glucaric acid was measured at least 10 days after the last administered dose. A modification of the Marsh method". 10 was used for the determination of the total concentration of D-glucaric acid in this 24-hour excretion of urine. The concentration of creatinine was measured in each urine sample in order to express the amount of D-glucaric acid per gram creatinine. The standard error of the method was found to be _+ 0.19 m M / g m creatinine in ten determinations of the same urine under the same circumstances. Simultaneous measurements of concentrations of D-glucaric acid in 24-hour collections of urine were performed in 50 normal children over 5 years of age who had not received any known inducers of microsomal enzymes. RESULTS Low values of urinary excretion of D-glucaric acid were found in two of the 50 normal children, i.e., < 8 m M / g m creatinine (4%). Extremely low values were found in the seven children who developed dystonic reactions to given drugs (100%) (p < 0.001) with an average excretory value of 3.37 m M / g m creatinine (Table I and Fig. 1). Repeated measurements of urinary concentration of D-glucaric acid were performed at least six months after the dystonic reactions. The results were similar. COMMENT From the results of this study it is suggested that children who develop dystonic reactions to recommended doses of antiemetic drugs, specifically phenothiazines and their derivatives, have greatly decreased urinary excretion The Journal o f P E D I A T R I C S Vol. 87, No. 6, part 1, pp. 981-982
981
982
Cassirnos et al.
The Journal of Pediatrics December 1975
Table I. Administered drug, daily dosage, and D-glucaric acid values in seven children with dystonic reactions
Co e I A(yr) el ei(kg)h No. 1 2 3 4 5 6 7
7 11 !5 6 6/12 7 11 14
A min ere drug
36 36 40 34 15 25 40
Thiethylperazine Metoclopramide Metoclopramide Metoclopramide Metoclopramide Dimenhydrinate Chlorpromazine and haloperidol
Nonproprietary name and manufacturer Torecan, Sandoz Primperan, Delagrange Primperan, Delagrange Primperan, Delagrange Primperan, Delagrange Vomex A, Endofarm Largactil, Specia, and Aloperidin, Minerva
I
I ]
Total amount taken daily 6.5 mg x 3 10 mg x 3 10 mg 5 mg 25 mg 0.5 mg
x x x x
2 2 2 3
D-glucaric acid (l*M/ gm creatinine) 1.4 3.6 4.5 3.1 6.4 1.5 3.1
acquired defects which influence the hepatic detoxification of drugs.
30
REFERENCES
e-
..~2o 9
9
~ 1 4 9 1 4 9 ~176 9
10
"-"..'i
.~ A
9
L_
~
"" 1
2
, Contro s 2 Children with dystonic reactions to antiemetic drugs.
Fig. 1. Urinary D-glucaric acid excretion (#M/gm creatinine) m apparently normal children and those with dystonic reactions to administered antiemetic drugs.
o f D-glucaric acid. Perhaps this is associated with slower detoxification o f the drugs'and thus increased toxicity. Further studies are indicated in order to establish the significance o f urinary excretion of D-glucaric acid as a screening test to identify individuals with genetic or
1. Cotton D, and Newman CGH: Dystonic reaction to phenothiazine derivatives, Arch Dis Child 41:551, 1966. 2. Hunter P, Blackwood W, Smith M, and Cumings: Neuropathological findings in three cases of persistent dyskinesia following phenothiazine medication, J Neurol Sci 7:263, 1968. 3. Casteels-Van Dacle M, Jaeken J, Van der Schneren P, Zimmerman A, and Van Den Bon P: Dystonic reactions in children caused by metoclopramid, Arch Dis Child 45:130, 1970. 4. Darby FJ, Newnes W, and Price-Evance DA: Human liver microsomal drugs metabolism, Biochem Pharmacol 19:1514, 1970. 5. Kutt H, Wolk M, Scherman T, and McDowell F: Insufficient parahydroxylation as a cause of diphenylhydantoin toxicity, Neurology 14:542, 1964. 6. Black M, and Sherlock S: Treatment of Gilbert's syndrome with phenobarbitone, Lancet 1:1359, 1970. 7. Hunter J, Maxwell JD, Carrela W, Stewart DA, Williams P: Urinary D-glucaric acid excretion as a test for hepatic enzyme induction in man, Lancet 1:572, 1971. 8. Marsh J, Turner WJ, Janley J, and Field J: Clin Chem 20:1155, 1974. 9. Marsh CA: Metabolism of D-glucuronolactone in mammalian system Biochem J 86:77, 1963. 10. Davidson DC, Mclntosh WB, and Ford JA: Assessment of plasma Glutamyl Transpeptidase activity and urinary D-glucaric acid excretion as indices of enzymes induction, Clin Sci Mol Med 47:279, 1974.
PHARMACOLOGY
THERAPEUTICS
AND
Paul S. Lietman, Editor
Urinary D-glucaric acid excretion in children with dystonic reactions caused by antiemetic drugs Chr. Cassimos, J. Tsiuris, B. Danielides, and Keti Malaka-Zafiriu,
Thessaloniki, Greece
THE BIOTRANSFORMATION of drugs takes place mainly in the smooth endoplasmic reticulum of the liver. Some individuals, particularly children, have unusual drug responses or idiosyncrasies to various antiemetic drugs, e.g., phenothiazines and their derivatives 1, 2 and metodopromide, 3 and develop extrapyramidal signs and dystonic reactions. These extrapyramidal reactions are caused by an unusual sensitivity to the drugs. These individuals may have an inherited defect involving the hepatic detoxification of the drugs?' 3 Recently measurement of 24-hour urinary excretion of D-glucaric acid has been used as an index of the enzymatic activity of the smooth endoplasmic reticulum of the liver? -* In this paper the experiences with seven children who developed alarming reactions to recommended doses of various antiemetic drugs are presented. MATERIALS
AND METHODS
Urinary excretion of D-glucaric acid was studied in seven children who developed various extrapyramidal symptoms after the administration of antiemetic drugs (Table I). The drugs were given in recommended doses to c o u n teract nausea and vomiting. Previous neurologic examinations had been normal, and there was no history of hepatic disease. All reactions began within 24-48 hours of starting administration of the drugs. The symptoms consisted mainly of torticollis, anxiety, tremor, dysarthria, neck pain, akathisia and walking difficulties; the children From the Paediatric Clinic, University o f Thessaloniki, A H E P A Hospital. Reprint address: Pediatric Clinic, University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece.
were admitted to hospital with presumptive diagnoses of encephalitis or meningitis. Urinary excretion o f D-glucaric acid was measured at least 10 days after the last administered dose. A modification of the Marsh method". 10 was used for the determination of the total concentration of D-glucaric acid in this 24-hour excretion of urine. The concentration of creatinine was measured in each urine sample in order to express the amount of D-glucaric acid per gram creatinine. The standard error of the method was found to be _+ 0.19 m M / g m creatinine in ten determinations of the same urine under the same circumstances. Simultaneous measurements of concentrations of D-glucaric acid in 24-hour collections of urine were performed in 50 normal children over 5 years of age who had not received any known inducers of microsomal enzymes. RESULTS Low values of urinary excretion of D-glucaric acid were found in two of the 50 normal children, i.e., < 8 m M / g m creatinine (4%). Extremely low values were found in the seven children who developed dystonic reactions to given drugs (100%) (p < 0.001) with an average excretory value of 3.37 m M / g m creatinine (Table I and Fig. 1). Repeated measurements of urinary concentration of D-glucaric acid were performed at least six months after the dystonic reactions. The results were similar. COMMENT From the results of this study it is suggested that children who develop dystonic reactions to recommended doses of antiemetic drugs, specifically phenothiazines and their derivatives, have greatly decreased urinary excretion The Journal o f P E D I A T R I C S Vol. 87, No. 6, part 1, pp. 981-982
981
982
Cassirnos et al.
The Journal of Pediatrics December 1975
Table I. Administered drug, daily dosage, and D-glucaric acid values in seven children with dystonic reactions
Co e I A(yr) el ei(kg)h No. 1 2 3 4 5 6 7
7 11 !5 6 6/12 7 11 14
A min ere drug
36 36 40 34 15 25 40
Thiethylperazine Metoclopramide Metoclopramide Metoclopramide Metoclopramide Dimenhydrinate Chlorpromazine and haloperidol
Nonproprietary name and manufacturer Torecan, Sandoz Primperan, Delagrange Primperan, Delagrange Primperan, Delagrange Primperan, Delagrange Vomex A, Endofarm Largactil, Specia, and Aloperidin, Minerva
I
I ]
Total amount taken daily 6.5 mg x 3 10 mg x 3 10 mg 5 mg 25 mg 0.5 mg
x x x x
2 2 2 3
D-glucaric acid (l*M/ gm creatinine) 1.4 3.6 4.5 3.1 6.4 1.5 3.1
acquired defects which influence the hepatic detoxification of drugs.
30
REFERENCES
e-
..~2o 9
9
~ 1 4 9 1 4 9 ~176 9
10
"-"..'i
.~ A
9
L_
~
"" 1
2
, Contro s 2 Children with dystonic reactions to antiemetic drugs.
Fig. 1. Urinary D-glucaric acid excretion (#M/gm creatinine) m apparently normal children and those with dystonic reactions to administered antiemetic drugs.
o f D-glucaric acid. Perhaps this is associated with slower detoxification o f the drugs'and thus increased toxicity. Further studies are indicated in order to establish the significance o f urinary excretion of D-glucaric acid as a screening test to identify individuals with genetic or
1. Cotton D, and Newman CGH: Dystonic reaction to phenothiazine derivatives, Arch Dis Child 41:551, 1966. 2. Hunter P, Blackwood W, Smith M, and Cumings: Neuropathological findings in three cases of persistent dyskinesia following phenothiazine medication, J Neurol Sci 7:263, 1968. 3. Casteels-Van Dacle M, Jaeken J, Van der Schneren P, Zimmerman A, and Van Den Bon P: Dystonic reactions in children caused by metoclopramid, Arch Dis Child 45:130, 1970. 4. Darby FJ, Newnes W, and Price-Evance DA: Human liver microsomal drugs metabolism, Biochem Pharmacol 19:1514, 1970. 5. Kutt H, Wolk M, Scherman T, and McDowell F: Insufficient parahydroxylation as a cause of diphenylhydantoin toxicity, Neurology 14:542, 1964. 6. Black M, and Sherlock S: Treatment of Gilbert's syndrome with phenobarbitone, Lancet 1:1359, 1970. 7. Hunter J, Maxwell JD, Carrela W, Stewart DA, Williams P: Urinary D-glucaric acid excretion as a test for hepatic enzyme induction in man, Lancet 1:572, 1971. 8. Marsh J, Turner WJ, Janley J, and Field J: Clin Chem 20:1155, 1974. 9. Marsh CA: Metabolism of D-glucuronolactone in mammalian system Biochem J 86:77, 1963. 10. Davidson DC, Mclntosh WB, and Ford JA: Assessment of plasma Glutamyl Transpeptidase activity and urinary D-glucaric acid excretion as indices of enzymes induction, Clin Sci Mol Med 47:279, 1974.
