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Biomedical subjects

B Rambeck

Publications and source records attributed to B Rambeck.

At least 37 records · Page 2Linked to original sources
PubMed1993

Postmortem concentrations of phenobarbital, carbamazepine, and its metabolite carbamazepine-10,11-epoxide in different regions of the brain and in the serum: analysis of autoptic specimens from 51 epileptic patients.

Postmortem concentrations of phenobarbital (PB), carbamazepine (CBZ), and its metabolite carbamazepine-10,11-epoxide (CE) were determined by high-performance liquid chromatography in the serum (total and free) and in specified areas of the brain (frontal, temporal, occipital cortex, and white matter, as well as cerebellum) of 51 deceased epileptic patients. The concentrations of PB and CBZ in the frontal cortex were approximately 1.4 times higher, and of CE were 1.1 times higher than the total concentrations in the serum. Furthermore, the concentrations of PB in the frontal cortex were approximately 2.1 times, of CBZ were 4.5 times, and of CE were 2.1 times higher than the free concentrations in the serum. The distribution of the three substances in the brain is rather homogeneous and seems to follow basic physicochemical principles. This means that the concentrations of the substances in the white matter are, depending on their lipophilicity, modestly but significantly higher than in the cortex. Small and in part statistically significant concentration differences between different regions of the cortex and also of the white matter may be explained by differences in the lipid content of the respective regions and by the lipophilicity of the respective substance. The concentrations in the cerebellar hemisphere (neocerebellum) were nearly identical to those in the frontal cortex. Remarkably increased or decreased concentrations were not observed in any region of the brain.

Adolescent↗
PubMed1993

Lamotrigine clinical pharmacokinetics.

Lamotrigine is a new antiepileptic agent chemically unrelated to any established drugs in use. The drug can be estimated in biological fluids by high performance liquid chromatography and immunoassays. It is rapidly absorbed, reaching peak concentrations within about 3 hours postdose. The bioavailability of the oral formulation is about 98%. The area under the plasma concentration-time curve indicates dose-linear pharmacokinetics. The degree of plasma protein binding is 56%. Saliva concentrations are 46% of the plasma concentration. The concentration of lamotrigine in the brain is similar to the total concentration in the plasma. Lamotrigine exhibits first-order linear kinetics during long term administration. 43 to 87% of a dose is recovered in the urine, predominantly as glucuronide metabolites. Mean half-lives of lamotrigine in healthy volunteers (single and multiple doses) as well as in epileptic patients receiving lamotrigine monotherapy range from 22.8 to 37.4 hours. Enzyme-inducing antiepileptic drugs such as phenytoin, phenobarbital (phenobarbitone) or carbamazepine reduce the half-life of lamotrigine (to mean values of 13.5 to 15 hours), whereas valproic acid increases the half-life of the drug (to mean values of 48.3 to 59 hours). Lamotrigine itself does not influence the plasma concentrations of concomitant antiepileptic drugs, except for causing an increase in concentrations of carbamazepine-10,11-epoxide, the main metabolite of carbamazepine. Other observations indicate that the interaction of carbamazepine and lamotrigine may be primarily pharmacodynamic rather than pharmacokinetic. Usual dosages of lamotrigine range from 50 to 400 mg/day depending on an enzyme-inducing or -inhibiting comedication. Therapeutic plasma concentrations of the drug are not known, but a putative therapeutic range of 1 to 4 mg/L has been proposed. Some patients have tolerated concentrations > 10 mg/L with benefit and without clinical toxicity. The value of measuring the concentrations of lamotrigine in helping to optimise the dosage or reduce the likelihood of adverse effects has not been established. Safety data from several large studies indicate that the incidence of adverse effects of the drug is low and that unwanted effects are reversible.

Anticonvulsants↗
PubMed1992

Postmortem concentrations of phenytoin in different regions of the brain and in the serum: analysis of autoptic specimens from 24 epileptic patients.

Postmortem concentrations of phenytoin (PHT) were determined by high-performance liquid chromatography in the serum (total and free) and in specified areas of the brain (frontal, temporal, occipital cortex and white matter, as well as cerebellum) of 18 epileptic patients who died following chronic diseases (group A) and of six otherwise healthy epileptic patients who died suddenly and unexpectedly (group B). The free concentrations in the serum correlated considerably better (r = 0.987) than the total concentrations in the serum (r = 0.871) with the concentrations in the frontal cortex. The concentrations in the frontal cortex were about nine times that of the free serum concentrations. The data show that the PHT concentrations in the frontal, temporal and occipital cortex largely agree. The concentrations in the white matter were significantly higher (frontal region 54%, temporal region 30%, occipital region 36%) than in the cortex. The concentrations in the cerebellar hemisphere (neocerebellum) were nearly identical with those in the frontal cortex. Regression analysis showed that on comparable total serum concentration the patients of group A had significantly higher free serum concentrations and significantly higher concentrations in the frontal cortex than the patients of group B. In respect of the concentration ratios cortex to serum free and in regard of the local distribution of PHT in the brain no difference, however, was found between those patients who died from chronic diseases and those who died suddenly.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Effects of withdrawal of phenytoin on cognitive and psychomotor functions in hospitalized epileptic patients on polytherapy.

The effects of the withdrawal of phenytoin (PT) on cognitive and psychomotor functions of long-term patients in an epilepsy centre were studied. The patients had been treated for many years (31.1 +/- 10.8 yrs.) with PT in combination with other antiepileptic drugs. The serum concentration of PT was in the lower to middle therapeutic range (6.8 +/- 3.1 mg/l). Only patients in which the efficacy of PT was questionable were included in the study. PT was withdrawn in 17 patients. The PT dose was not changed in 12 patients (control group). Psychological tests were carried out immediately before the withdrawal of PT and about 10 weeks later. Tests were also carried out with the control group at the same time. A significantly improved performance (using a composite score) was noted after the withdrawal of PT. The statistical evaluation of the different tests showed an significant improvement in one test of concentration and two tests of psychomotor function (tapping and pursuit rotor with the dominant hand). There was no significant change in the frequency of seizures.

Adult↗
PubMed1991

Nomogram for the prediction of unbound phenytoin concentrations in patients on a combined treatment of phenytoin and valproic acid.

The interpretation of the total phenytoin (PT) concentration can be problematic if valproic acid (VPA) is given as a comedication, because VPA displaces PT from the protein binding sites and can increase the free fraction of PT. In order to estimate the free or unbound PT concentration (PTf) from the total PT concentration (PTt) and VPA concentration, a nomogram was constructed and evaluated. Data of 84 patients on combined therapy with PT and VPA were used in drawing up the regression equation (PTf = 0.0792.PTt + 0.000636.PTt.VPA) from which the nomogram was constructed. The predictions were checked using another 33 patients whose serum concentrations were determined in the morning and in addition several times during the day. The results show that using this method the PTf concentrations can be accurately estimated from the PTt and VPA concentrations.

Adolescent↗
PubMed1990

Fluctuations of unbound and total phenytoin concentrations during the day in epileptic patients on valproic acid comedication.

The influence of daily fluctuations in the concentration of valproic acid (VPA) on the unbound and total concentration of phenytoin (PT) was examined in a prospective study. The serum concentrations of 28 patients with epilepsy (group PT + VPA) who were treated with PT and concurrently with VPA and 15 patients (group PT) who were treated with PT but without VPA comedication were determined at 8.00, 11.00, 14.00, 17.00, and in part at 20.00 h. The results show that there are significantly greater fluctuations in the total PT concentration among patients on VPA than those not on VPA. The fluctuations in the total PT concentration during the day correlated with the fluctuations in the VPA concentration. On the other hand, the fluctuations in the concentrations of unbound PT of patients on VPA were comparable with those not on VPA. In the absence of VPA, the diurnal fluctuations of the total PT concentration correlated highly significantly with the fluctuations of the unbound PT concentration. This is not the case in patients on VPA. Our data are a further indication of the smaller significance of the total PT concentration as compared with the unbound PT concentration in the combined treatment of PT and VPA.

Adolescent↗
PubMed1990

Postmortem serum protein binding and brain concentrations of antiepileptic drugs in autoptic specimens from 45 epileptic patients.

The free fraction of antiepileptic drugs can, in certain diseases, be greatly increased in the serum. In order to study the significance of this increase for the concentration in the brain, the postmortem concentrations of phenytoin (PT), phenobarbital (PB), carbamazepine (CBZ), and its metabolite carbamazepine-10,11-epoxide (CE) in the serum (total and free), as well as in specimens of the frontal cortex of 45 epileptic patients who died from various causes, were determined. The postmortem free fractions were higher than reported in the literature and varied considerably from subject to subject. For PT the free fraction was 21.7% (median), for PB 68.0%, for CBZ 33.4%, and for its metabolite CE 53.6%. The values for a control group of 236 otherwise healthy epileptic patients were in agreement with those given in the literature, namely 10.4% for PT, 55.6% for PB, 20.9% for CBZ, and 42.5% for CE. Using a nonparametric correlation coefficient (Kendall T), the concentrations in the frontal cortex of the autopsied patients correlated with the postmortem free serum concentrations, especially for the substances with high protein binding (PT and CBZ), better (PT r = 0.88, PB r = 0.86, CBZ r = 0.87, CE r = 0.79) than with the total concentrations (PT r = 0.69, PB r = 0.80, CBZ r = 0.77, CE r = 0.77). The study indicates that in critically ill patients the determination of the free concentration in serum is indispensable. If treatment is orientated solely on the total concentration, unexpectedly high concentrations in the brain and hence possible intoxication of the patient in the critical or final state can result.

Anticonvulsants↗
PubMed1990

Valproic acid-induced carbamazepine-10,11-epoxide toxicity in children and adolescents.

The study of 14 children and adolescents shows that the addition of carbamazepine (CBZ) to a basic valproic acid (VPA) therapy can result in unexpectedly high concentrations of carbamazepine-10,11-epoxide (CE) in the serum (up to 13 micrograms/ml). These concentrations were associated with marked side effects, especially vomiting and tiredness. The concentrations of CBZ were within the therapeutic range. Very high CE concentrations can largely be avoided at the commencement of the CBZ treatment if the CBZ dose is slowly increased. But high CE concentrations (4-8 micrograms/ml) associated with side effects can also be reached in later stages during the build up of CBZ treatment and under steady state conditions. The determination of the CE concentration is important when VPA and CBZ are administered together, especially when side effects occur.

Adolescent↗
PubMed1989

Fluctuations of carbamazepine concentrations during the day for two slow-release preparations.

Fluctuations in the carbamazepine (CBZ) concentration during the day were studied using the profiles of 88 patients on slow release CBZ preparations. Blood was taken at 800, 1100, 1400, 1700, 2000, 2200 and 800 hr of the following day. The CBZ dosage was divided into two equal doses and administered at 800 and 2000 h. The influence of different factors on the fluctuations in the CBZ concentration during the day was studied. The fluctuation correlated negatively (r = -0.51, p less than 0.001) with the level-dose ratio LDR (CBZ morning concentration-CBZ dose per body weight ratio). The co-medication and preparation had no additional significant influence on fluctuations in the CBZ concentration during the day. The maximal CBZ serum concentration during the day can be described for most patients as a function of the CBZ morning concentration and the level-dose ratio using a suitable regression equation (r = 0.93, standard error of estimate = 1.2 mg/L).

Adult↗
PubMed1987

Serum concentrations of carbamazepine and its epoxide and diol metabolites in epileptic patients: the influence of dose and comedication.

The influence of carbamazepine (CBZ) dose, CBZ preparation used, comedication (phenobarbital, phenytoin, primidone, valproate), and factors such as age, weight, and sex on the concentration of CBZ and its metabolites carbamazepine-10,11-epoxide (CBZ-epoxide) and 10,11-dihydro-10,11-dihydroxy-carbamazepine (CBZ-diol) in serum was investigated. A non-linear regression analysis using the data of 609 patients shows that other anti-epileptic drugs can influence the metabolism of CBZ in various ways. The mean serum concentration of CBZ is lower when the drug is given in combination with phenytoin (59.4%), primidone (58.2%), phenobarbital (65.7%), and valproate (83.0%) than when CBZ is given alone (100%), whereas the mean concentration of CBZ-epoxide is increased by valproate (144.8%), by primidone (118.5%), and by a combination of the latter (167.4%). The CBZ-diol concentrations are also increased during concomitant treatment with the other antiepileptic drugs. Our results indicate a nonlinear relationship between the CBZ dose and the CBZ concentration, but a linear relationship between the CBZ dose and the CBZ-diol concentration.

Adult↗
PubMed1985

Acute valproate intoxication with fatal outcome in an infant.

A healthy twenty-month-old boy ingested a maximal dose of valproate from which about 750 mg/kg were absorbed. Cerebral coma, which lasted for twenty hrs, was followed by an undisturbed period of approximately sixteen hrs. Death from cardiorespiratory failure due to severe bronchopneumonia occurred 46.5 hrs after the ingestion of the drug. The serum valproic acid concentration reached a peak of 1061 micrograms/ml within three hours, and fifteen minutes before death it had fallen to 187 micrograms/ml. The half-life of 16.6 hrs was within the range usually found. Metabolic acidosis, hypernatraemia and hyperosmolarity could be corrected, unlike the hypocalcaemia, which developed later. Bilirubin, GOT, GPT, gamma-GT, alkaline phosphatase, blood glucose, diastase, urea, creatinine, haemoglobin as well as PT and PTT and the platelet count were all normal. Leucopenia with 1,600 per microliter developed only during the bronchopneumonial stage. The histo-pathological findings were acute hypoxic damage of the myocardium, kidneys and certain neurones of vulnerable areas of the brain (neuronal microvesiculation and tigrolysis) in addition to a severe cerebral oedema in the final stage. A morphological substrate of an acute valproate encephalopathy was not demonstrable. The liver showed no necrosis or cholostasis. The vertebral marrow was inconspicuous. All the results indicate that liver function was not impaired in spite of the initial maximal concentration of valproic acid. In all probability the patient might have survived the acute valproate intoxication had it not been for the bronchopneumonia.

Brain↗
PubMed1985

Serum concentrations of valproic acid: influence of dose and comedication.

The influence of valproate (VPA) dose, VPA preparation used, comedication (phenobarbital, phenytoin, carbamazepine) and factors such as age, weight, height, and sex on the concentration of VPA in serum was investigated. Nonlinear regression analysis showed that about 63% of the variance in the VPA morning concentrations of 259 inpatients could be explained by the following variables: dose, body weight, sex, and comedication. Age, height, and kind of preparation had no important influence on the VPA concentration. The relationship between dose and concentration of VPA is nonlinear, as the concentration does not increase proportionally with the dose but increases to a lesser extent. The serum concentration of VPA is clearly lower when the drug is given in combination with phenytoin (49.5%), carbamazepine (66.2%), or phenobarbital (76.3%) than when given alone (100%).

Adolescent↗
PubMed1984

Urinary hydroxyphenytoin/creatinine ratios as an index of compliance in adult epileptic patients on phenytoin therapy.

The ratio of the concentration of the phenytoin metabolite hydroxyphenyl phenylhydantoin (HPPH) to the creatinine concentration in morning urine samples was used as an index of compliance in adult epileptic patients on phenytoin therapy. For this purpose, the phenytoin dose was estimated from the urinary HPPH/creatinine ratio with the help of a regression equation that took into consideration body weight, height, age, and sex. A high correlation (r = 0.927 for men and r = 0.954 for women) between the prescribed and estimated dose was found for a reference group (127 hospitalized patients on supervised drug regimen). Compliance was judged from the discrepancy between the prescribed and the estimated dose for 45 patients immediately after their admittance to an epilepsy clinic, as well as for 98 outpatients, who had been treated by neurologists. Noncompliance was suspected in 6.7% of patients admitted to the clinic, as well as in 28.6% of the outpatients.

Creatinine↗
PubMed1984

Systematic comparison of three basic methods of sample pretreatment for high-performance liquid chromatographic analysis of antiepileptic drugs using gas chromatography as a reference method.

Sera of epileptic patients which were routinely examined by gas chromatography (GC) were also analysed using high-performance liquid chromatography (HPLC). Three basic methods for the pretreatment of samples for HPLC analysis were compared: protein precipitation by adding acetonitrile to the serum, direct serum extraction using ethylacetate, and partitioning of serum and buffer solution over a stationary phase and extraction with dichloromethane/2-propanol. The analytical performance and practicability of the three methods were tested under routine conditions. The following anti-epileptic drugs and metabolites were used in the comparison of HPLC with GC: ethosuximide, primidone, phenobarbital, phenytoin, carbamazepine, N-desmethylmethsuximide, and phenylethylmalonediamide.

Anticonvulsants↗
PubMed1981

Systematic method of development in liquid chromatography applied to the determination of antiepileptic drugs.

The object of a liquid-chromatographic analysis is to separate, identify, and quantitate the constituents of interest in a sample mixture within an acceptable analysis time. This will be achieved by a systematic analysis development rather than by a trial-and-error approach. Such a systematic procedure requires a knowledge of the chromatographic parameters governing resolution and analysis time and their relative influences on resolution and its experimental implication. Furthermore, basic information about the mechanisms of the modes of liquid chromatography (adsorption, partition, ion exchange, and steric exclusion) and about the types of sample which can be preferentially analyzed by them is necessary. This information leads to a rational selection of the separation system that promises the best chance of success. In the subsequent experimental work, the analyst systematically measures and calculates resolution and analysis time as functions of selectivity, capacity, and efficiency of the phase system under selected chromatographic conditions. The essential chromatograms, tables, and graphs resulting from this systematic method of development are documented so that it is possible to replicate the analysis procedure in the laboratories involved. The result is a set of chromatographic conditions capable of achieving an optimum compromise between resolution and analysis time. The procedure is applied to routine therapeutic drug monitoring of antiepileptic drugs in patient serum.

Anticonvulsants↗