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Biomedical subjects

T Tomson

Publications and source records attributed to T Tomson.

At least 73 records · Page 4Linked to original sources

Electrophysiologic effects and clinical hazards of carbamazepine treatment for neurologic disorders in patients with abnormalities of the cardiac conduction system.

Carbamazepine, a first-line drug for the treatment of epilepsy and neuralgia, may exert hazardous effects on the cardiac conduction system. Standard ECG and long-term ECG monitoring and invasive electrophysiologic testing were carried out in 10 patients who required this drug for neurologic disorders, but in whom its safe use had been questioned because of symptoms of ECG abnormalities. We observed depression of sinus node function and an atrioventricular conduction delay with a significant prolongation of the PQ interval of 16 msec (9%; 95% confidence interval: 1.9% to 16.5%; p less than 0.05), of which the HV interval was significantly prolonged but not the PA and AH intervals. These effects are in accordance with previously shown class 1A properties. However, the lack of effects on QRS, JT, and QT intervals at normal heart rates is a class 1B characteristic. Thus carbamazepine seems to have composite electropharmacologic actions. A cause effect relationship between carbamazepine treatment and significant arrhythmias was established in five patients. Thus the negative chronotropic and dromotropic effects of carbamazepine may, at least in predisposed patients, induce symptoms confusingly similar to the epileptic seizures it is used to prevent.

Aged↗

Effect of phenobarbital on the pharmacokinetics of carbamazepine-10,11-epoxide, an active metabolite of carbamazepine.

The single oral dose kinetics of carbamazepine-10,11-epoxide (CBZ-E), the active metabolite of carbamazepine, were studied in six epileptic patients, stabilized on phenobarbital (PB) monotherapy, and in six drug-free health volunteers. The epoxide metabolite was administered as an enteric-coated tablet at the dose of 200 mg to the patients and at the dose of 100 mg to the volunteers. Patients had a significantly higher plasma clearance of CBZ-E than the control group (mean values +/- SD = 220.2 +/- 63.5 versus 112.5 +/- 46.0 ml/h/kg, p less than 0.007) and a significantly shorter plasma half-life (mean values +/- SD = 4.3 +/- 1.0 versus 6.7 +/- 0.8 h, p less than 0.0015). These results suggest that PB induces CBZ-E metabolism.

Adult↗

Carbamazepine-10,11-epoxide in epilepsy. A pilot study.

The effects of carbamazepine-10,11-epoxide, an active metabolite of carbamazepine, were evaluated in seven outpatients with frequent epileptic seizures. The study included an initial 4-week period with the carbamazepine dose optimized for each patient. Patients were then crossed over, dose by dose, to carbamazepine-10,11-epoxide and followed up for another 4 weeks. Dosing was single blind. The evaluation of the anticonvulsant effect was hampered by marked fluctuations in plasma levels during treatment with carbamazepine-10,11-epoxide. There was, however, no significant change in seizure control. During epoxide treatment, no subjective side effects were reported despite epoxide plasma concentrations up to 57 mumol/L. Neuropsychological assessment revealed a significant improvement in finger motor speed and logical reasoning during the carbamazepine-10,11-epoxide period. Subnormal serum sodium levels in two patients were normalized after switching from carbamazepine to the epoxide. Continued investigations with this active metabolite of carbamazepine in epilepsy are therefore justified.

Adult↗

Serum prolactin during status epilepticus.

The serum concentration of prolactin is frequently increased after single epileptic seizures and has therefore been used as a method to differentiate between hysterical attacks and epileptic seizures. We determined plasma prolactin concentrations in fifteen patients with status epilepticus. Seven patients had absence status, five complex partial and three generalised tonic-clonic status epilepticus. Prolactin levels were normal in all patients which indicates that, in contrast to single seizures, status epilepticus is not associated with an increase in serum prolactin.

Adult↗

Relationship of intraindividual dose to plasma concentration of carbamazepine: indication of dose-dependent induction of metabolism.

The effect of a dose change on the plasma concentration of carbamazepine (CBZ) was studied in 13 epileptic patients, all with a CBZ dose of at least 800 mg/day. A disproportionately small rise in the plasma concentration of CBZ was found in 10 of the patients. The ratio between the final metabolite 10,11-dihydro-10,11-trans-dihydroxy-CBZ and CBZ in plasma was higher after dose increase in the 10 patients with a small rise in CBZ levels, indicating a dose-dependent autoinduction of CBZ metabolism. The ratio between the active intermediary metabolite, CBZ-epoxide, and CBZ was unaltered by the dose change in all patients. This indicates that CBZ plasma level determinations can be used for prediction of the total effect of CBZ treatment during high as well as low dosage.

Adolescent↗

Impaired visual contrast sensitivity in epileptic patients treated with carbamazepine.

Critical flicker fusion frequencies and visual contrast sensitivity were determined in 27 adult epileptic patients receiving carbamazepine monotherapy and in 24 healthy, drug-free control subjects. Flicker fusion thresholds were the same in patients and control subjects, whereas the contrast sensitivity was significantly reduced in the patient group at all spatial frequencies. There was a significant negative correlation between the plasma concentration of carbamazepine and the contrast sensitivity at 11.4 and 22.8 cycles per degree, indicating that the reduced contrast sensitivity was due to the drug therapy.

Adolescent↗

Choreoathetosis induced by ordinary phenytoin levels, explained by high free fraction?--A case report.

Choreoathetosis was induced by phenytoin therapy in an 81-year-old epileptic woman. The plasma concentration of phenytoin was 59 to 80 mumol/L when side effects appeared. Choreoathetosis at ordinary plasma levels has previously been attributed to a preexisting brain damage. In this case, however, it may be explained by a high free fraction (19%) of the phenytoin plasma concentration.

Aged↗

Single-dose kinetics of an enteric-coated formulation of carbamazepine-10,11-epoxide, an active metabolite of carbamazepine.

The kinetics of an enteric-coated formulation of carbamazepine-10,11-epoxide (CBZ-E) were studied in healthy subjects. A single oral dose of 100 mg of CBZ-E was given to eight subjects. Four of them were also given a single oral dose of 200 mg of CBZ-E. Plasma concentrations of CBZ-E and urinary excretion of the end metabolite trans-10,11-dihydroxy-10,11-dihydro-carbamazepine (trans-CBZ-diol) were determined by high performance liquid chromatography. Plasma kinetics of CBZ-E fitted an open one-compartment model with plasma elimination half-life of 7.4 +/- 1.8 h (mean +/- SD). The clearance was 105 +/- 17 ml/kg/h and the apparent volume of distribution 1.1 +/- 0.2 L/kg assuming complete bioavailability. There was no indication of dose-dependent elimination of CBZ-E. The recovery of trans-CBZ-diol in urine collected for 3 days was 67 +/- 9% of the given dose. This enteric-coated formulation may thus in the future be used for the evaluation of the clinical effects of CBZ-E in patients.

Adult↗

The debrisoquin hydroxylation phenotype does not predict the metabolism of phenytoin.

Phenytoin plasma elimination kinetics and accrual of phenytoin metabolites in urine were studied in seven rapid and five slow hydroxylators of debrisoquin. There was no interphenotypic difference in phenytoin clearance, plasma half-life, volume of distribution, maximum rate of metabolism (Vmax), or Michaelis-Menton constant (Km). The total recovery of metabolites as percentage of given dose and the metabolite profiles in urine were similar for the two debrisoquin hydroxylator phenotypes. Similarly, no differences were observed between the groups with respect to stereoselective production of either dihydrodiol or para-phenolic metabolites of phenytoin. The debrisoquin hydroxylation phenotype was also investigated in 74 epileptic patients treated with phenytoin. Vmax and Km were graphically estimated from plasma concentrations at varying phenytoin dosage regimens in 36 of the patients. There was no correlation between the debrisoquin hydroxylation index and Vmax or Km. We conclude that the debrisoquin hydroxylation phenotype has no predictive value in guiding phenytoin dosage.

Adult↗

Interdosage fluctuations in plasma carbamazepine concentration determine intermittent side effects.

Fluctuations in plasma carbamazepine concentrations were related to side effects in five epileptics. One patient was receiving only carbamazepine; four were receiving carbamazepine plus phenobarbital sodium or phenytoin sodium. The patients were studied during two 12-hour periods: carbamazepine given (1) twice daily or (2) four times daily. Concomitant medication regimens were kept constant; administration was single-blind. Plasma concentrations of carbamazepine, carbamazepine's epoxide metabolite, phenobarbital, and phenytoin were determined hourly; side effects were assessed simultaneously. Fluctuations in carbamazepine concentrations were 79% +/- 29% higher than trough levels on a twice-daily dosage schedule and 40% +/- 13% higher during four-times-a-day administration. The appearance and intensity of side effects followed the fluctuations in carbamazepine levels and were thus substantially reduced during the four-times-daily regimen. The intrapatient reproducibility of the side effects was good, whereas the thresholds of carbamazepine concentrations at which side effects appeared ranged from 17 to 37 mumole/L.

Adult↗