Commentary on George JR, Davis GG. Comparison of antiepileptic drug levels in different cases of sudden death. J Forensic Sci 1998;43:595-603.
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Anticonvulsants↗
Biomedical subjects
B Rambeck
Publications and source records attributed to B Rambeck.
Comparison between premortem and postmortem serum concentrations of phenobarbital, phenytoin, carbamazepine and its 10,11-epoxide metabolite in institutionalized patients with epilepsy.
The last premortem serum concentrations of phenobarbital (PB), phenytoin (PHT), carbamazepine (CBZ) and its CBZ-10,11-epoxide metabolite (CE) were compared with the corresponding postmortem serum concentrations in 16 adult patients of an epilepsy centre. Based on complete postmortem examinations, 12 individuals showed a known cause of death (KCD) and four patients succumbed from sudden unexplained death (SUD). The last premortem and the postmortem serum levels of PB (r = 0.991), PHT (r = 0.986), CBZ (r = 0.985) and CE (r = 0.936) were highly correlated. However, the regression analysis indicated that, except for CE, the premortem concentrations were significantly higher than the postmortem concentrations, i.e. 65% for PB, 34% for PHT, and 16% for CBZ. Varying time lapses (4-62 h) between death and serum sampling during autopsy did not significantly influence the ratio of premortem to postmortem serum levels for PB, PHT, CBZ, and CE (p > 0.1). Furthermore we found no significant differences between the premortem and the postmortem serum concentration ratios CE/CBZ. Considering the above variables, the data of SUD and KCD patients were comparable. Postmortem decrease in anticonvulsant serum concentrations, especially for PB and PHT, should be considered in order to avoid misinterpretation in respect to so-called 'subtherapeutic' serum levels and noncompliance in context with SUD or fatal intoxication.
Adult↗
Influence of oxcarbazepine and methsuximide on lamotrigine concentrations in epileptic patients with and without valproic acid comedication: results of a retrospective study.
The aim of this retrospective study was to investigate the influence of oxcarbazepine (OCBZ) and methsuximide (MSM) on lamotrigine (LTG) serum concentrations. The effect of OCBZ compared to carbamazepine (CBZ) and the effect of MSM on LTG serum concentrations were examined in patients with and without valproic acid (VPA) comedication. Altogether, 376 samples from 222 patients were analyzed in routine drug monitoring. Two or more serum samples from the same patient were considered only if the comedication had been changed. For statistical evaluation, regression analytical methods and an analysis of variance were performed. For the analysis of variance, the LTG serum concentration in relation to LTG dose/ body weight--level-to-dose ratio (LDR), in (microg/mL)/(mg/kg)--was calculated and compared for different drug combinations. The nonlinear regression analysis including the LTG dose per body weight, age, gender, and the different kinds of comedication revealed that these variables have a significant influence on LTG serum concentration (r2 = 0.724). The relationship between LTG dose/body weight and serum concentration deviates only slightly from linearity, the LTG concentration was about 18% lower in women than in men, and age had a significant influence. The data indicate that children have significantly lower LTG concentrations than adults on a comparable LTG dose per body weight and that children may be more prone to enzyme induction by comedicated drugs. Methsuximide has a strong inducing effect on the LTG metabolism and decreases the LTG concentrations markedly (about 70% compared to LTG monotherapy). Carbamazepine also reduces the LTG concentrations considerably (by 54%). The inducing effect of OCBZ (29%) was less pronounced but also significant. The inducing effect of MSM, CBZ, and OCBZ was also seen in combination with VPA: VPA alone increases the LTG concentration approximately 211%, whereas in addition to MSM (8%), CBZ (21%), or OCBZ (111%), the increase of LTG was significantly smaller. The analysis of variance confirmed the results of the regression analysis. The effect of MSM on the LTG concentration should be considered if MSM is added or withdrawn in patients treated with LTG. Oxcarbazepine had a less pronounced inducing effect on LTG metabolism compared to CBZ. If CBZ is replaced by OCBZ as comedication, an increase in LTG serum concentrations should be expected.
Adolescent↗
Comparison of total and free phenytoin serum concentrations measured by high-performance liquid chromatography and standard TDx assay: implications for the prediction of free phenytoin serum concentrations.
The free fraction of phenytoin (PHT) in serum increases considerably in combination with valproic acid (VPA), depending on the VPA concentration. Equations to predict the free PHT concentration (PHTf) from the total PHT concentration (PHTt) and from the VPA concentration were developed by Haidukewych and colleagues. (equation 1: PHTf = 0.095 x PHTt + 0.001 x VPA x PHTt) and May and colleagues (equation 2: PHTf = 0.0792 x PHTt + 0.000636 x VPA x PHTt]; in both equations, PHTf, PHTt, and VPA are given in microg/ml. Obviously, the equations give different predictions. The aim of this study was to investigate whether different methods for the determination of PHTt and PHTf were responsible for the differences; equation 1 was calculated from standard TDx measurements and equation 2 from high-performance liquid chromatography (HPLC) values. A total of 52 samples from patients with VPA (n=26) or without VPA (n=26) were analyzed using HPLC and TDx. The concentrations measured by HPLC and TDx were highly correlated but TDx yields significantly higher PHTt (Y = 0.98 x X + 2.46; X = HPLC, Y = TDx, r2 = 0.957) and, in particular, higher PHTf concentrations (Y = 1.03 x X + 0.30; X = HPLC, Y = TDx, r2 = 0.919), compared with our HPLC method. The accuracy of the predictive equations depends on the method used for the determination of PHTt and PHTf. The best predictions of PHTf were obtained if equation 2 and HPLC measurements were used. However, the differences in the predicted PHTf could only partly be explained by the different methods of determination.
Chromatography, High Pressure Liquid↗
Concentrations of lamotrigine in a mother on lamotrigine treatment and her newborn child.
OBJECTIVE: To investigate the transfer of lamotrigine in pregnancy and during lactation from a mother on lamotrigine treatment to her child. METHODS: Concentrations of lamotrigine were measured by high-pressure liquid chromatography in umbilical cord serum and in serum samples of the mother and her child as well as in the mother's milk during the first five postpartum months. RESULTS: In the child lamotrigine serum concentrations (up to 2.8 micrograms ml-1) comparable to those usually achieved in active treatment with lamotrigine were found not only after birth, but also during lactation. A considerable amount of lamotrigine (2-5 mg per day) was excreted in breast milk. No adverse effects were seen in the child. CONCLUSION: The transfer of lamotrigine taking place during pregnancy and lactation should not be neglected. In this case the child should be thoroughly observed for potential adverse effects.
Adult↗
Post-mortem determination of anticonvulsant concentrations and lung oedema in the sudden, unexpected death of epileptics.
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Anticonvulsants↗
Lack of influence of histopathological changes on carbamazepine and carbamazepine-10, 11-epoxide concentrations in the brain cortex of epileptic patients.
Post-mortem concentrations of carbamazepine (CBZ) and its anticonvulsive metabolite carbamazepine-10,11-epoxide (CE) were determined in different lesions of the cerebral cortex and in the serum (total and free) from 13 epileptic patients. Twenty cortical specimens were obtained from the superior frontal gyrus, the temporopolar region and the neocerebellum. The cortical samples showed various pathological changes characterized by augmented glial cells, fibre gliosis or ulegyria as well as abundant corpora amylacea or encephalitic signs of viral type besides neuronal depletion. The CBZ and CE concentrations in the 20 cortical lesions were not significantly decreased when compared to the control specimens of 32 epileptic patients without essential histopathological alterations of the specified cortical areas (p < 0.05). A comparable result had been found in our former study on phenytoin (PHT) and phenobarbital (PB). Six patients with cortical lesions of the present series had already been included in this PHT/PB study. Five of these patients revealed unchanged CBZ and CE as well as PHT and PB concentrations. Only in one neocerebellar specimen the CE concentration was just above the upper 95% confidence limit of the control group. But, most probably this finding has no further relevance. The results greatly favour the nonspecific binding of CBZ and CE to cerebral tissue constituents.
Adult↗
Relationship between ischemic damage and concentrations of phenytoin and phenobarbital in the brain cortex of epileptic patients in vegetative state at death.
Post-mortem concentrations of phenytoin (PHT) and phenobarbital (PB) were determined by high-performance liquid chromatography in the cortical matter of specified brain regions and in the serum (total and free) from 3 epileptic males in vegetative state and compared to the data of 45 deceased epileptic control patients. The duration of the vegetative state was 12 days, 15 days or about 4 months until death and was associated with corresponding stages of generalized ischemic brain damage. The histological examination was completed by immunohistochemical and morphometric methods. According to other investigators nerve cells are the major binding sites for PHT and PB in the cerebral cortex of rodents. But, in the 3 comatose patients the PHT and PB concentrations of the isocortex and neocerebellum were not significantly decreased in comparison with the control patients despite necrosis and loss of neurons as well as other distinct tissue alterations. The results strongly favor the non-specific binding of PHT and PB to cells and subcellular structures of the brain-mainly based on simple physico-chemical principles.
Adult↗
Serum concentrations of lamotrigine in epileptic patients: the influence of dose and comedication.
Lamotrigine (LTG) is a new antiepileptic drug (AED), chemically unrelated to the drugs in current use. Previous studies have shown that LTG has only a limited effect on other AEDs, but its own metabolism can be strongly induced or inhibited by the comedication. We investigated the influences of carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB), valproic acid (VPA), and combinations of these drugs on the serum concentration of LTG. A total of 588 blood samples from 302 patients were analyzed. The mean duration of LTG therapy was 141 +/- 137 days (mean +/- SD). A patient was only considered twice in this study if his or her comedication had been changed. The LTG serum concentration in relation to LTG dose/body weight (level-to-dose ratio, LDR, microgram/ml/mg/kg) was calculated and compared for different drug combinations. The results showed that comedication had a highly significant (p < 0.001) influence on the LTG serum concentrations. The mean LDR for LTG was 0.32 (LTG + PHT) < 0.52 (LTG + PB) approximately equal to 0.57 (LTG + CBZ) < 0.98 (LTG mono) approximately equal to 0.99 (LTG + VPA + PHT) < 1.67 (LTG + VPA + CBZ) approximately equal to 1.80 (LTG + VPA + PB) < 3.57 (LTG + VPA (<, p < 0.05; approximately equal to, p > 0.05, multiple comparisons). The mean LTG concentrations in patients on comedication with VPA were about two times higher than on patients on LTG monotherapy or on comedication without VPA (5.0 vs. 2.6 micrograms/ml), despite the LTG doses being half as high (3.0 vs. 5.9 mg/kg). The correlations of the serum concentrations and doses of CBZ, PB, PHT, and VPA with the LDR of LTG were only weak or not significant. Furthermore, the distribution of LTG serum concentrations and dosages was compared with the tentative therapeutic range for the LTG concentration (1-4 micrograms/ml), proposed by some investigators, and the recommendations for the LTG dosage. Remarkable discrepancies were observed. The comedication has an important influence on the LTG concentration and should be considered in LTG dosage.
Adult↗
Fatal hepatotoxicity in a child treated with vigabatrin.
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Anticonvulsants↗
Fluctuations of 10-hydroxy-carbazepine during the day in epileptic patients.
Oxcarbazepine (OCBZ) is a new antiepileptic drug with a chemical structure similar to carbamazepine. We investigated the daily fluctuations of 10-OH-carbazepine (monohydroxy derivative, MHD), the clinically relevant metabolite of OCBZ, in patients with or without comedication. Twenty-two profiles of (total) serum concentrations of MHD from 18 epileptic patients on a b.i.d. OCBZ regimen were determined at 8.00, 11.00, 14.00, 17.00, 20.00 h (and 22.00 h/23.00 h). A patient was only considered twice if his comedication or OCBZ dosage had been changed. The maximal MHD concentrations were about 33% +/- 14% higher than the minimal MHD concentrations during the day. The free MHD concentrations were determined in 17 profiles. The mean free fraction of MHD was 56.7% +/- 5.5%. In combination with valproic acid the free fraction (64.0% +/- 1.4%) was slightly, but significantly higher (p < 0.05) than in monotherapy (52.3% +/- 0.9%) or in combination (58.0% +/- 2.6%) with other antiepileptic drugs (2 x phenobarbital, 2 x methsuximide, 1 x sulthiame). Further studies are necessary to clarify if the observed fluctuations of MHD are of clinical importance.
Adolescent↗
Pharmacokinetic interactions of the new antiepileptic drugs.
Therapy with traditional antiepileptic drugs is associated with a wide range of pharmacokinetic drug-drug interactions. In particular, enzyme induction, enzyme inhibition and displacement from protein binding may result in important changes in serum concentrations of antiepileptics. Relevant interactions have also been described for some new antiepileptics. Felbamate increases serum concentrations of phenytoin, phenobarbital and valproic acid (sodium valproate). On the other hand, it reduces concentrations of carbamazepine and increases concentrations of its metabolite carbamazepine-10,11-epoxide. Concentrations of felbamate itself are reduced by phenytoin and carbamazepine. Concentrations of lamotrigine are considerably increased by valproic acid and decreased by phenytoin, carbamazepine and phenobarbital (phenobarbitone). Vigabatrin reduces serum concentrations of phenytoin by approximately 20%. On the other hand, some new antiepileptics have the important advantage of not interfering with the metabolism of other antiepileptics; this is the case for gabapentin, lamotrigine and oxcarbazepine. Furthermore, the pharmacokinetics of gabapentin, oxcarbazepine and vigabatrin are independent of concomitant drugs. These aspects are especially important as, until now, new antiepileptics have been most often utilised as add-on therapy.
Anticonvulsants↗
Lack of effect of histological lesions on the phenytoin and phenobarbital concentrations in the brain cortex of epileptic patients.
Postmortem concentrations of phenytoin (PHT) and phenobarbital (PB) were determined in 24 specimens of the frontal, temporal, occipital or neocerebellar cortex with different pathological changes and in the serum (total and free) from 11 epileptic patients. The cortical lesions were characterized by various degrees of neuronal loss or necrosis associated with other changes such as proliferated gliocytes, fibre gliosis, Rosenthal fibres or numerous corpora amylacea. According to other investigators neurons are the main binding sites of PHT and PB in rodent brains. The PHT and PB concentrations in 20 cortical lesions from nine patients were not significantly reduced as compared to the data of 46 deceased epileptic control patients. A significantly decreased PB value could only be demonstrated in the temporal specimen of an old scarred infarction with complete demyelination. On the other hand a slight but significant increase of PB was observed in three neocortical samples from a child exhibiting severe brain oedema and thrombosis of the sinuses. The results favour the unspecific binding of PHT and PB to cerebral tissue constituents and do not support the hypothesis of major binding to specific receptors.
Aged↗
Pharmacokinetics of sulthiame in epileptic patients.
Sulthiame is an antiepileptic drug that was introduced approximately 30 years ago for the treatment of epilepsy. Currently it is rarely used, but recent studies show its efficacy, especially in the treatment of focal epilepsies in children. Because there are hardly any pharmacokinetic studies of sulthiame in humans, we studied the dose-level relationship, the elimination half-life, and the daily fluctuations in the concentration of sulthiame among children and adults with epilepsy. The evaluation of the sulthiame serum concentrations of 86 patients gave, considering age and comedication, a relatively high correlation (r = 0.82) between the sulthiame dose/body weight and the sulthiame serum concentration. Children on a comparable sulthiame dose per body weight have lower sulthiame concentrations than adults. In our study sulthiame was, with few exceptions, administered in combination with other antiepileptic drugs. The sulthiame serum concentrations were lower in comedication with carbamazepine than with valproic acid. The evaluation of the individual sulthiame dose-level relationship of 8 patients showed in most cases a close and linear relationship. After withdrawal of sulthiame in 11 patients, short elimination half-lives (8.65 +/- 3.10 h) were estimated. This was in accordance with the large daily fluctuations in the sulthiame concentrations (swing: 103.9 +/- 59.3%) of the nine patients examined. The shorter half-lives and higher daily fluctuations in children indicate a higher clearance of sulthiame among children.
Adolescent↗
Comparison of phenytoin and carbamazepine serum concentrations measured by high-performance liquid chromatography, the standard TDx assay, the enzyme multiplied immunoassay technique, and a new patient-side immunoassay cartridge system.
Steady-state concentrations of phenytoin (PHT) and carbamazepine (CBZ) were measured by a novel patient-side immunoassay system with a single-use cartridge (Biotrack 516). The Biotrack determinations were performed in whole blood and extrapolated to serum on the basis of the hemoglobin content. The results were compared with serum concentrations measured by high-performance liquid chromatography (HPLC) or the standard TDx and enzyme multiplied immunoassay (EMIT) techniques. A total of 222 samples from epileptic patients on PHT and 322 samples from patients on CBZ were analyzed. In the case of PHT there was a highly linear correlation [r = 0.985, y = 1.113x-0.589; x = HPLC, y = Biotrack] between HPLC and the Biotrack system in the concentration range of 2.5-30 micrograms/ml. In the case of CBZ, the correlation between HPLC and the Biotrack system in the concentration range of 2.0-20 micrograms/ml was somewhat lower [r = 0.931, y = 1.29x-0.136; x = HPLC, y = Biotrack]. Comparable results were also found for the correlation of the Biotrack system with the TDx assay or with the EMIT assay, respectively. Comedication had no influence, or only a minor influence (valproic acid), on the concentration of PHT and CBZ measured by the Biotrack system. Furthermore, the concentration of the metabolite carbamazepine-10, 11-epoxide had no influence on the concentration of CBZ measured by the Biotrack system. Since the automated cartridge system is simple, can be used rapidly, and is performed with only a few drops of blood, this technique offers some advantages for routine clinical use, especially under outpatient conditions.
Carbamazepine↗
Efficacy of carbamazepine with respect to distribution of carbamazepine and its metabolite 10,11-epoxide in cerebral tumours and paratumorous cortex.
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Adolescent↗
Concentrations of carbamazepine and carbamazepine-10, 11-epoxide in serum, brain tumors and paratumorous cortex: a prospective study of 37 neurosurgically treated epileptic patients.
Concentrations of carbamazepine (CBZ) and its metabolite carbamazepine-10, 11-epoxide (CE) were determined in serum (free and total), brain tumors and paratumorous cortex from 37 epileptic patients. Tumor biopsies were available from 25 different gliomas, 5 hamartomas and 1 angioma. The free serum concentrations of CBZ and CE were highly correlated with the corresponding paratumorous concentrations (r = 0.94 and r = 0.93) and to a lower extent with the tumorous concentrations (r = 0.78 and r = 0.75). For CBZ the concentration ratios paratumorous cortex/serum free and tumor/serum free showed no significant differences between CBZ-resistant and -nonresistant patients. Apart from histological grade a significant influence of type and site of the tumors on their CBZ and CE concentration was not recognizable. The results indicate that resistance to CBZ therapy cannot be sufficiently explained by decreased paratumorous or tumorous levels of CBZ and CE.
Adolescent↗
Acute encephalopathy with vigabatrin.
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4-Aminobutyrate Transaminase↗