Das bei der Behandlung mit Valproinsäure (VPA) bei Kindern auftretende irreversible Leberversagen ist in seinem Wirkungsmechanismus unbekannt. Es ist ebenso ungeklärt, ob den reversiblen und dosisabhängigen Leberschäden ein anderer biochemischer Mechanismus zu Grunde liegt.

A five-year-old, normally developed boy who had been healthy except for an absence epilepsy prior to valproate (VPA) treatment died 16 weeks after the introduction of VPA-monotherapy due to liver failure and intractable bleeding disorder. This case emphasizes that the restriction of VPA-therapy to children of more than two years of age, on monotherapy, and without evidence of other diseases or retardation does not exclude fatal complications. Until today world-wide about 100 patients have died during VPA-treatment.

Abstract Hepatotoxicity of valproic acid (VPA) is reported in a psychomotor retarded boy. A four-month antiepileptic therapy was followed by a combined VPA/phenytoin treatment where-upon, two months later, the patient died in a hepatic coma. In the final state the metabolic pattern of VPA was still found within the normal range with the exception of the two abnormal metabolites 4-en-VPA) (2-propyl-4-pentenoic acid) and 4.4'-dien-VPA (2-(2-propenyl-4-pentenoic acid) detected only in low concentration. The amino acid pattern in plasma was characterized by a decrease or branched chain amino acids by 50% in contrast to the increase of the aromatic amino acids. Methionine, however, was in the normal range. Due to lack of a biochemical parameter indicating a possibly irreversible development of VPA induced hepatotoxicity stopping of VPA therapy should be obligatory if abnormal unsaturated VPA metabolites are detected or if dien-VPA/3, a normal metabolic compound, is increased above the normal range. L-carnitine treatment is recommended as a prophylactic therapy.

Hepatotoxicity of valproic acid (VPA) is reported in a psychomotor retarded boy. A four-month antiepileptic therapy was followed by a combined VPA/phenytoin treatment where-upon, two months later, the patient died in a hepatic coma. In the final state the metabolic pattern of VPA was still found within the normal range with the exception of the two abnormal metabolites 4-en-VPA) (2-propyl-4-pentenoic acid) and 4.4'-dien-VPA (2-(2-propenyl-4-pentenoic acid) detected only in low concentration. The amino acid pattern in plasma was characterized by a decrease or branched chain amino acids by 50% in contrast to the increase of the aromatic amino acids. Methionine, however, was in the normal range. Due to lack of a biochemical parameter indicating a possibly irreversible development of VPA induced hepatotoxicity stopping of VPA therapy should be obligatory if abnormal unsaturated VPA metabolites are detected or if dien-VPA/3, a normal metabolic compound, is increased above the normal range. L-carnitine treatment is recommended as a prophylactic therapy.

The urine and plasma of epileptic patients receiving therapeutic doses of valproic acid (2-propyl- pentanoic acid) was found to contain five doubly unsaturated metabolites of valproic acid, which were identified as their trimethylsilyl derivatives by GC/MS. A series of reference substances was synthesized but only two of them were identical with native metabolites: 2(2-propenyl)-4-pentenoic acid (= 4.4'-diene) and E-2-propyl-2.4- pentadienoic acid (E-2.4-diene). The mass-spectra of the five native metabolites are given. Preliminary quantitative data obtained from four groups of patients indicate increased formation of doubly unsaturated metabolites when valproic acid-induced side-effects are present, and in cases of fatal hepatic failure. The 4.4'-diene has hitherto been found only in fatal cases with hepatic injury. Quantitative data are presented as % of the sum of valproic acid plus all its detected metabolites.

A 7-year-old boy developed a severe unilateral grand mal seizure at the age of 5 years (phenobarbitone therapy); 1.5 years later valproate (2-propylpentanoic acid, VPA) was added to the therapy. After a seizure-free period of 3 months the patient died from hepatic failure resembling Reye syndrome. Several plasma and urine samples from the final stage before and during peritoneal dialysis were analyzed by GC/MS.

Peritoneal transfer kinetics of substances differing in molecular size and lipophilic properties were studied in anuric adult rabbits with ligated ureters. In conscious animals, the dialysate/plasma concentration ratios of creatinine (Cr) and inulin (In) rose exponentially up to 200 min of dwelling. Peritoneal CIn was 0.24 ml/min/kg, and CCr was 0.10 ml/min/kg of body wt. The transfer rate for dipropyl acetic acid (VPA) was higher than for its more lipophilic analogue dibutyl acetic acid (DBA); the apparent equilibrium of the dialysate/plasma concentration ratio for VPA was 0.3 to 0.6 and 0.15 to 0.20 for DBA. Correspondingly, the peritoneal CVPA was higher (0.08 to 0.16 ml/min/kg) than CDBA (0.04 to 0.05 ml/min/kg); peritoneal clearances were 8% vs. 1.5% of the plasma clearances. The addition of nitroglycerin, dopamine, isoprenalin, fenoterol, and nitroprusside sodium to the dialysate did not increase significantly the peritoneal CCr and CIn during 30-min cycles. In conclusion, the peritoneal transport kinetics of creatinine, inulin, and protein are qualitatively similar to clinical data, but of different magnitude. The efficiency of peritoneal dialysis depends on the lipophilic characteristics of the substance to be transferred. The vasoactive drugs studied seem not to be promising for increasing the efficiency of peritoneal transport.

Seven metabolites of valproic acid (VPA), i.e. 2-en-VPA, 3-en-VPA, 4-en-VPA, 3-hydroxy-VPA, 4-hydroxy-VPA, 5-hydroxy-VPA and 3-keto-VPA and valproic acid itself were examined for their effects on the metabolism of γ-aminobutyric acid (GABA) in the brain and brain nerve endings (synaptosomes) in mice. Administered in anticonvulsant doses, valproic acid and its metabolites caused elevations of the synaptosomal GABA content which were correlated with their anticonvulsant potency. No relationship was observed between the relative anticonvulsant activity of the respective compounds and the increase of GABA in the whole brain. The synaptosomal activity of glutamate decarboxylase (GAD) was increased parallel to the elevation of GABA and the activity of GABA aminotransferase (GABA-T) was partly inhibited. The present results emphasise the usefulness of determining the in vivo effects of drugs on GABA metabolism in brain nerve terminals which is thought to be the critical factor controlling the functioning of the amino acid as a neurotransmitter.

A sensitive and reliable method for trace analysis of methylmalonic acid in amniotic fluid and urine is described using deuterated methylmalonic acid as the internal standard and capillary gas chromatography/mass fragmentography. The application of the method for the prenatal diagnosis of methylmalonic acidemia is demonstrated in three pregnancies at risk. In two pregnancies the fetuses were affected by methylmalonyl-CoA-mutase deficiency. Correspondingly, the excretion of methylmalonic acid in the maternal urine was elevated as early as at the 12/13th week of gestation, reaching its highest level shortly before abortion at the 19/20th week: 157 and 173 μmol/24h (excretion in normal pregnancies: 39±8 μmol/24h, n=8). In addition, the concentration of methylmalonic acid in amniotic fluid at the 16th week (13.4 and 33.8 μmol/l, normal range 0.31±0.10μmol/l, n=8) strongly suggested that the fetuses were affected. In the third pregnancy no increase of the methylmalonic acid excretion in maternal urine at 11–17 weeks of gestation could be found (42±10 μmol/24h, n=5). The cultured amniotic cells of this fetus showed normal enzyme activity. Nevertheless abortion was initiated without further biochemical investigation because of an elevated a1-fetoprotein value in the amniotic fluid. The fetus was anencephalic. The data suggest that it is possible to make a reliable prenatal diagnosis of methylmalonic acidemia even in those cases where cultured amniotic cells are not available.

19 pooled plasma specimens were sent as unknowns to 13 participating research laboratories. The interlaboratory variability between the results was very high. Only 4 out of 13 laboratories had 6--12% of their results within the 95% confidence limit for each sample. The precision of repeated determinations was fairly good. 6 out of 10 participating laboratories had a coefficient of variation of less then 5%. The reproducibility and the agreement between the different procedures for quantitative analysis of dipropylacetate is similar to that reported for other major antiepileptic drugs.

In 15 children with advanced chronic renal failure, glomerular filtration rate was determined by different methods. Inulin clearance correlated well with the mean of creatinine and urea clearance, and also with 51-chromium edetic acid (EDTA) clearance measured over 24 hours. The absolute values of creatinine clearance and of 51Cr-EDTA clearance measured up to 8 hours were higher than inulin clearance. In advanced renal failure both the 51Cr-EDTA clearance measured over 24 hours, and the mean of creatinine and urea clearance, provide acceptable estimates of true glomerular filtration rate.