Breath tests using fatty acids labeled with a stable isotope (carbon 13) were carried out on epileptic patients treated with valproic acid in order to detect abnormal fatty acid metabolism. The patients were given 13C-octanoic acid or 13C-palmitic acid orally, and expired air was collected at appropriate intervals for the analysis of 13CO2 content by a mass spectrometer. Eight patients were tested in the palmitic acid breath test and nine patients in the octanoic acid breath test. Controls for these tests were patients treated with antiepileptic drugs other than valproic acid and unmedicated cerebral palsy patients. In the valproic acid-treated group, 13C recovery was reduced by 56% in seven hours on the 13C-palmitic acid breath test, while the octanoic acid breath test showed a 52% reduction in one hour. This suppression of fatty acid oxidation was significantly correlated with dose of valproic acid in both tests. No influence of other drugs was detected, and the effect of administered carnitine was not conclusive. This study demonstrates the usefulness of 13C-labeled fatty acid breath tests in clinical practice. (J Child Neurol 1988;3:250-257).
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References
1.
livanainen M. , Hiberg J.: Valproate and clonazepam in the treatment of severe progressive myoclonus epilepsy. Arch Neurol1982;39:236-238.
Gaskins JD, Holt RJ, Postelnick M.: Nondosage-dependent valproic acid-induced hyperammonemia and coma . Clin Pharm1984;3:313-316.
6.
Zaccara G., Paganini M., Campostrini R., et al: Hyperammonemia and valproate induced alterations of the state of consciousness. A report of 8 cases. Eur Neurol1984;23:104-112.
7.
Coulter DL, Allen RJ: Hyperammonemia with valproic acid therapy. J Pediatr1982;101:782-785.
8.
Zaret BS, Becker RR, Marini AM, et al: Sodium valproate induced hyperammonemia without clinical hepatic dysfunction. Neurology1982;32:206-208.
9.
Williams CA, Tiefenbach S., McReynolds JW: Valproic acid induced hyperammonemia in mentally retarded adults. Neurology1984;34:550-553.
10.
Rothehner AD : Valproic acid. A review of 23 fatal cases . Ann Neurol1981;10:287.
11.
Jeavons PM: Sodium valproate and acute hepatic failure. Dev Med Child Neurol1980;22:547-548.
12.
Hojer B., Rane A.: Fatal hepatic failure in a child treated with phenytoin and valproic acid . Dev Med Child Neurol1982;24: 846-849.
13.
Zah W., Rengeling M., Ruhl G., Hackenberg K.: [Acute liver necrosis caused by valproate]. Dtsch Med Wochenshr1985;110: 956-959.
14.
Thruston JH , Hauhart RE, Schulz DW, et al: Chronic valproate administration produces hepatic dysfunction and may delay brain maturation in infant mice. Neurology1981;31:1063-1069.
15.
Gerber N., Dickinson RG, Hartland RC, et al: Reye-like syndrome associated with valproic acid therapy. J Pediatr1979;95: 142-144.
16.
Sugimoto T. , Nishida N., Yasuhara A.: Reye-like syndrome associated with valproic acid. Brain Dev1983 ;5:334-337.
17.
Keene DL, Humphereys P., Carpenter B., Fletcher JP: Valproic acid producing a Reye-like syndrome. Can J Neurol Sci1982;9:435-437.
18.
Shumate JB, Dodson WE, Brook MH, Santiago J.: Suppression of fatty acid oxidation by valproic acid. Ann Neurol1981;10:88.
19.
Suehiro M., Ueda K., Iio M.: Application of 13C-fatty acid breath tests in myocardial metabolic studies , in Schmidt HL, Foerstel H, Heinzinger K (ed): Stable Isotopes. Amsterdam, Elsevier Science Publishers, 1982, pp 367-372.
20.
Schoeller DA , Schneider JG, Solomon NW, et al: Clinical diagnosis using the stable isotope 13C in CO2 breath tests: Methodology and fundamental considerations . J Lab Clin Med1977;90: 412.
21.
Suehiro M., Iuchi M., Kitani K., Iio M.: 13C-Aminopyrine breath test in aged patients with and without schistosomiasis japonica, in Kitani K (ed): Liver and Aging. Amsterdam, Elsevier Biomedical Press, 1982, pp 379-391.
22.
Craig H.: The geochemistry of the stable carbon isotopes. Geochim Cosmodrim Acta1953;3:53-92.
23.
Helge H., Gregg B., Jaeger E., et al: The 13CO2 breath test for the measurement of N-demethylation of 13C-dimethylaminopyrine in children, in Klein ER and Klein PD (ed): Stable Isotopes. Proceeding of the Third International Conference. Amsterdam, Elsevier Science Publishers, 1979, pp 495-505.
24.
Wittfoht W., Nau H., Tating D., Helge H.: 13C-Labelled valproic acid pulse dosing during steady state antiepileptic therapy for pharmacokinetic studies during pregnancy, in Schimidt HL, Foerstel H, Heinzinger K (ed): Stable Isotope. Amsterdam, Elsevier Science Publishers , 1982, pp 265-276.
25.
Suehiro M., Iio M.: [Techniques for utilization of stable isotope for life science (VI): 13CO2 analysis in breath test]. Radioisotopes1982 ;31:321-329.
26.
Pinder RM, Brogden RN, Speight TM, Avery GS: Sodium valproate, A review of its pharmacological properties and therapeutic efficacy in epilepsy. Drugs1977;13:81-123.
27.
Ferrandes B. , Eymard P.: Metabolism of valproate sodium in rabbit, rat, dog and man. Epilepsia1977;18:169-182.
28.
Kochen W., Schneider A., Ritz A.: Abnormal metabolism of valproic acid in fatal hepatic failure. Eur J Pediatr1983;141: 30-35.
29.
Trauner DA, Huttenlocher PR: Short chain fatty acid induced central hyperventilation in rabbits . Neurology1978;28:940-944.
30.
Young RSK , Bergman I., Gang DL, Richardson EP: Fetal Reye-like syndrome associated with valproic acid. Ann Neurol1980;7:389.
31.
Haas R., Chir B., Stumpf DA, et al: Inhibitory effects of sodium valproate on oxidative phosphorylation . Neurology1981;31: 1473-1476.
32.
Jezequel AM , Bonazzi P., Novelli G., et al: Early structural and functional changes in liver of rats treated with a single dose of valproic acid. Hepatology1984;4:1159-1166.
33.
Kuhara T., Inoue Y., Matsumoto M., et al: Altered metabolic profiles of valproic acid in a patient with Reye's syndrome. Clin Chim Acta1985;145:135-142.
34.
Sackellares JC, Lee SI, Dreifuss FE: Stupor following administration of valproic acid to patients receiving other antiepileptic drugs. Epilepsia1979;20:697-703.
35.
Marescaux C. , Warter JM, Brandt C., et al: Adaptation of hepatic ammonia metabolism after chronic valproate administration in epileptics treated with phenytoin . Eur Neurol1985;24:191-195.
36.
Zaccara G., Paganini M., Campostrini R., et al: Effect of associated antiepileptic treatment on valproate-induced hyperammonemia. Ther Drug Monit1985;7:185-190.
37.
Ohtani Y., Endo F., Matsuda I.: Carnitine deficiency and hyperammonemia associated with valproic acid therapy . J Pediatr1982;101:782-785.
38.
Bohles H., Richter K., Waagner-Thiessen E., Schafer H.: Decreased serum carnitine in valproate induced Reye syndrome. Eur J Pediatr1982;139:185-186.
39.
Thurston JH , Carroll JE, Hauhart RE, Schiro JA: A single therapeutic dose of valproate affects liver carbohydrate, fat, adenylate, amino acid, coenzyme A, and carnitine metabolism in infant mice: Possible clinical significance . Life Sci1985;36:1643-1651.
40.
Dodson WE, Tasch V.: Pharmacology of valproic acid in children with severe epilepsy: Clearance and hepatotoxicity. Neurology1981;31:1047-1050.
