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T Tomson

Publications and source records attributed to T Tomson.

90 records · Page 5Linked to original sources
PubMed1984

Potent therapeutic effect of carbamazepine-10,11-epoxide in trigeminal neuralgia.

The clinical effects of carbamazepine-10,11-epoxide were assessed in six patients with trigeminal neuralgia. The patients were first given an optimal therapeutic dose of carbamazepine. Part of or the entire carbamazepine dose was then exchanged for the metabolite carbamazepine-10,11-epoxide for three to six days. The patients were unaware of changes in the therapeutic regimen (single-blind). Carbamazepine dosages ranged from 400 to 1,400 mg/day and carbamazepine-10,11-epoxide dosages ranged from 300 to 1,000 mg/day. The clinical effects were assessed by the patients' recordings of pain attacks. When carbamazepine-10,11-epoxide and carbamazepine were given in similar doses, the pain control was comparable. On a plasma concentration basis, carbamazepine-10,11-epoxide had a considerably higher pain-relieving potency than carbamazepine. During carbamazepine treatment, the epoxide metabolite contributes to the antineuralgic effect to an extent that might be comparable to that of the parent drug. No side effects were seen during carbamazepine-10,11-epoxide therapy.

Aged↗
PubMed1983

Single-dose kinetics and metabolism of carbamazepine-10,11-epoxide.

Carbamazepine-(CBZ)-10,11-epoxide (CBZ-E) was found to decompose in gastric juice in vitro. An antacid did not affect the bioavailability of single CBZ doses given to three subjects and was therefore used to neutralize gastric juice when administering CBZ-E. CBZ-E was given orally as a suspension in two single doses ranging from 10 to 200 mg to each of four healthy subjects. Plasma concentrations of CBZ and CBZ-E were determined with high-performance liquid chromatography. Plasma concentrations and urinary excretion of the end metabolite trans-10,11-dihydroxy-10,11-dihydro-CBZ (trans-CBZ-diol) were measured by mass fragmentography. After dosing with CBZ-E, peak plasma concentrations of the parent compound were reached within 2 hr. Urinary recovery of trans-CBZ-diol was 90 +/- 11% (mean +/- SD) of the dose, indicating almost complete absorption. Plasma kinetics of the epoxide fitted an open one-compartment model with elimination half-lifes (t 1/2s) of 6.1 +/- 0.9 hr. Clearance was 89 +/- 25 ml x kg-1 x hr-1. The urinary excretion t 1/2 of the trans-CBZ-diol was 12.4 +/- 0.9 hr, which is longer (P less than 0.001) than the epoxide plasma t 1/2. There was no indication of dose-dependent kinetics of the epoxide. After 200 mg CBZ to the same subjects, plasma CBZ t 1/2 was 26.0 +/- 4.6 hr and clearance was 23.4 +/- 4.6 ml x kg -1 x hr -1. Of the CBZ dose, 20.5 +/- 2.9% was excreted as the trans-CBZ-diol, which gives an estimate of the percentage of CBZ that is metabolized by the epoxide-diol pathway in healthy subjects. These observations provide a basis for the administration of CBZ-E in patients to assess its clinical effects.

Absorption↗
PubMed1981

Trigeminal neuralgia: time course of pain in relation to carbamazepine dosing.

Eight in-patients with idiopathic trigeminal neuralgia (TN) were studied while receiving carbamazepine (CBZ) treatment. The aim was to study diurnal pain distribution, its relation to CBZ dosing and plasma concentration and the effect of decreasing the dose. All pain attacks were registered by the patients at three-hour intervals. CBZ was given b.i.d. in a single blind manner with the patient unaware of dose and dose changes. Plasma concentrations of CBZ were followed every fourth hour during a period of altogether sixteen dosage intervals. The diurnal pain distribution revealed marked intra-individual similarities with pain-free nights and a significant drop in pain during mid-day hours. The latter coincided in time with the peak plasma concentration of CBZ, thus indicating an effect of plasma concentration fluctuations on pain relief. Shorter dosage intervals might therefore be beneficial in problem cases. A significant increase in pain was detected within six to nine hours after a dose reduction, whereas the full effect of the dose change seemed to be established only after one day.

Aged↗
PubMed1980

Carbamazepine therapy in trigeminal neuralgia: clinical effects in relation to plasma concentration.

Seven patients with trigeminal neuralgia were treated with carbamazepine at three dose levels, each period lasting for six days. A single-blind technique was used, the patients being unaware of the dose changes. During the last three days of each dose treatment, the pain score was determined by the patients and the plasma concentrations of carbamazepine and its epoxide metabolite were measured. There was a correlation between the dose and plasma level of carbamazepine (r = .56; P < .01). At the carbamazepine doses studied (200 to 1,400 mg/day), no indication of saturation kinetics was seen. As the ratio between the plasma levels of the epoxide and carbamazepine was relatively low and constant, it was not possible to evaluate the potency of the epoxide. In six of the patients studied a plasma level-effect relationship was found. The best effect was seen at carbamazepine levels between 24 and 43 mu mole/L (5.7 and 10.1 microgram/mL). In one patient who was studied twice, the plasma level-response curve was different on the two occasions. Side effects were recorded in two patients, both with carbamazepine plasma levels above 33 mu mole/L (7.9 microgram/mL).

Carbamazepine↗
PubMed1980

Carbamazepine in trigeminal neuralgia: clinical effects in relation to plasma-concentration.

Seven patients (mean age 60 years) with idiopathic trigeminal neuralgia previously treated with Carbamazepine(CBZ) were studied as in patients. One patient was examined twice. CBZ (Tegretol) was given twice daily in three different dose-levels to each patient, six days on each level. A single-blind technique was used. The doses were individually chosen with previous dose requirements as a basis. Plasma samples were taken immediately before the morning dose the three last days on each dose-level. CBZ and CBZ-10, 11-epoxide were analysed using liquid chromatography. All pain paroxysms were graded and registered by the patient and pain scores were calculated. The CBZ-doses given ranged from 200 to 1 400 mg/day, the mean being 733 mg/day. In six courses of treatment, patients experienced complete or almost complete pain relief, achieved at CBZ-plasma-concentrations of 24-43 mumol/l. Patients with high pain-scores at plasma-concentrations of 30 mumol/l did not benefit from further dose increase. Small adjustments of plasma-concentration otherwise resulted in pronounced changes in pain-score. Side-effects were not reported below 34 mumol/l. No conclusions could be drawn as to the possible clinical effect of CBZ-10,11-epoxide.

Carbamazepine↗
PubMedDate not supplied

Pharmacokinetics: time-dependent changes--autoinduction of carbamazepine epoxidation.

Drugs labeled with stable isotopes have been useful to study time-dependent changes in kinetics. Early studies suggested that carbamazepine (CBZ) may induce its own metabolism, but this could not be proved until tetradeuterium-labeled CBZ (CBZ-D4) was synthesized and then given to patients. CBZ-D4 was administered to three children during long-term treatment of epilepsy with CBZ. After 17 to 32 days of treatment, the plasma clearance of CBZ-D4 was doubled, but during the next four months, there was no further increase, indicating that autoinduction was complete within one month. Two patients with chronic alcoholism were treated with CBZ for five days. Half of the first dose of 600 mg was comprised of CBZ-D4. The half-life of this CBZ-D4 dose in the two patients (20 and 26 hr, respectively) was similar to the post-steady-state half-life of CBZ (23 hr in both patients) measured later. A single dose of CBZ given one week after the last maintenance dose had a longer half-life (46 and 45 hr, respectively), which probably is close to the disposition of the drug before starting the treatment with CBZ. This shows that autoinduction of CBZ metabolism was completed during the very first doses of CBZ. Autoinduction also disappeared rapidly after stopping the treatment. We have shown that it is mainly the epoxide-diol pathway that is induced, both during autoinduction and after induction with other antiepileptic agents.

Biotransformation↗
PubMedDate not supplied

Nonconvulsive status epilepticus: high incidence of complex partial status.

Nonconvulsive status epilepticus may be subdivided into generalized (absence) status and complex partial status. The latter is regarded as a rarity, whereas the former constitutes the dominant part of the hitherto reported cases. We report 10 consecutive cases of adult patients with nonconvulsive status epilepticus, all documented by ictal electroencephalographic (EEG) recordings. Five had a complex partial status; the origin of the complex partial status appeared to be frontal in four of these patients. Three had recurrent complex partial seizures with incomplete recovery between seizures, and two had more continuous symptoms. One of the latter exhibited neither motor phenomena nor automatisms. The effect of diazepam or clonazepam was immediate in all 10 cases though transient in eight. A lasting control of the status was not achieved in six patients until i.v. phenytoin was added. The difficulties in the differentiation between complex partial status and absence status despite ictal EEG recordings are discussed, illustrated by a case with seizure discharges of a focal onset which rapidly generalized. The study indicates that complex partial status may be more common and the clinical expressions of absence status more variable than hitherto recognized.

Adult↗
PubMedDate not supplied

Nonconvulsive status epilepticus in adults: thirty-two consecutive patients from a general hospital population.

We studied all adult patients who between 1984 and 1989 were initially diagnosed at our hospital as having nonconvulsive status epilepticus. Thirty-two patients fulfilled the criteria, which included ictal EEG recordings. The annual incidence was 1.5 in 100,000 inhabitants. The median age at onset of status was 51 years. Ten patients had status as their first epileptic manifestation, but most patients had a previous history of epilepsy. Median duration of epilepsy at onset of status was 4 years. Fourteen patients had focal ictal seizure activity on EEG and thus met the criteria for complex partial status. Eighteen patients had generalized seizure activity on EEG, but only 6 of these had a history of absence epilepsy or juvenile myoclonic epilepsy. None had Lennox-Gastaut syndrome. The clinical features of status in the remaining 12 patients were in some respects similar to those of the patients with complex partial status. We hypothesize that the EEG seizure activity in these patients may have been generalized from an initial focus.

Adolescent↗
PubMedDate not supplied

Vertebral arch nonfusion and juvenile myoclonic epilepsy.

Neural tube defects (NTD) are known to occur at a higher rate in pregnancies of women with epilepsy. Antiepileptic drugs (AEDs), notably valproate (VPA) and carbamazepine (CBZ), have been identified as risk factors, but a familial aggregation of this condition also occurs in the absence of pharmacologic teratogens. Spina bifida occulta, defined as a nonsymptomatic nonfusion of vertebral arches, has been suggested to be genetically determined, with an increased prevalence in patients with primary generalized epilepsy, and that the presence of this trait in fetal development can be enhanced pharmacologically to produce NTD such as meningomyelocele. In this study, plain abdominal radiographs were obtained from 56 patients with juvenile myoclonic epilepsy (JME) and 56 age- and sex-matched controls. The radiographs were presented in a random order to an unbiased radiologist. No difference in prevalence of vertebral arch nonfusion (VAN) was noted between the two groups. Even if it has no increased frequency in patients with epilepsy, however, VAN is a common radiologic finding, and its relation to symptomatic neural tube defects should be clarified in future studies.

Adolescent↗
PubMedDate not supplied

Epilepsy and pregnancy: a prospective study of seizure control in relation to free and total plasma concentrations of carbamazepine and phenytoin.

Seizure control and plasma concentrations of antiepileptic drugs (AEDs) were determined in a prospective, population-based study of 93 pregnancies (cases) of 70 patients with epilepsy. Seventy-seven cases were treated with monotherapy, which in 70 cases consisted of carbamazepine (CBZ) or phenytoin (PHT). Dosage was kept constant unless poor seizure control prompted an increase. Plasma concentrations were determined at monthly intervals throughout pregnancy and compared with baseline levels obtained at least 10 weeks postpartum. Both free and total CBZ and PHT concentrations were analyzed. Seizure frequency during pregnancy for the group as a whole was not different as compared with the 9 pregestational months and was unaltered or improved in 85% of cases. Total CBZ concentration was slightly lower during the third trimester as compared with baseline, whereas free concentration was unchanged. In contrast, PHT levels decreased steadily as pregnancy progressed. Total plasma concentration was 39% of baseline during the third trimester, whereas free PHT concentration decreased far less, being 82% of baseline level during the third trimester. No clear-cut relation could be demonstrated between seizure control and plasma concentrations, which may be explained by the limited changes in free AED concentrations and the small number of cases with an increased seizure frequency. Our results indicate that total plasma concentrations may be misleading and that monitoring of free concentrations, in particular of PHT concentrations, may be advantageous during pregnancy.

Adult↗
PubMedDate not supplied

Disposition of carbamazepine and phenytoin in pregnancy.

Free and total plasma concentrations of phenytoin (PHT) and carbamazepine (CBZ) and its active metabolite carbamazepine-10, 11-epoxide (CBZ-E) were determined in a prospective study of 86 pregnant epileptic women. The pharmacokinetics of PHT and CBZ during the three trimesters were compared with kinetics at least 10 weeks postpartum. Plasma clearance and unbound CBZ clearance were slightly decreased during the last trimester. Total and free plasma CBZ-E concentrations did not change significantly during pregnancy. Plasma PHT clearance, on the other hand, increased from the first trimester. A less pronounced increase was observed for clearance of unbound PHT; the increase was statistically significant only during the third trimester.

Adult↗
PubMedDate not supplied

Carbamazepine metabolism in man. Induction and pharmacogenetic aspects.

The metabolism of carbamazepine (CBZ) was studied in 3 groups of subjects: (1) 6 healthy volunteers given a single dose of 200mg carbamazepine; (2) 4 epileptic patients on carbamazepine monotherapy; and (3) 5 patients receiving carbamazepine in combination with other anticonvulsants. Carbamazepine kinetics in the patients were investigated by use of 15N-CBZ. The mean plasma clearances of carbamazepine were 19.8, 54.6 and 113.3 ml/h/kg in groups 1, 2 and 3, respectively. The increased clearance in the patients was mainly due to an induction of the epoxide-diol pathway, as reflected by an increased urinary excretion of the trans-CBZ-diol metabolite. The urinary excretion (as a percentage of the administered dose) of 9-hydroxymethyl-10-carbamoyl-acridan (9-OH-CBZ) was also increased, whereas the excretion of 2-OH-CBZ and 3-OH-CBZ in groups 2 and 3 were decreased in comparison with group 1. As it has been suggested that 9-OH-CBZ is formed from carbamazepine-10,11-epoxide (CBZ-E) or trans-CBZ-diol, the formation of 9-OH-CBZ was investigated in 3 patients with trigeminal neuralgia treated with carbamazepine or CBZ-E as monotherapy on separate occasions. The urinary excretion of 9-OH-CBZ was 1.9, 3.3 and 4.0% of the trans-CBZ-diol excretion during CBZ-E therapy and 23, 32 and 24%, respectively, during carbamazepine administration. Thus only a minor part of the 9-OH-CBZ excreted in urine during carbamazepine therapy is formed via the epoxide-diol pathway. Data on plasma concentrations of carbamazepine and CBZ-E, and on urinary excretion of trans-CBZ-diol from 4 patients on carbamazepine therapy were used to calculate the plasma clearance of CBZ-E. The hydration of CBZ-E during carbamazepine therapy was found to be induced, but to a lesser extent than the epoxidation of carbamazepine. The interrelationship between carbamazepine-epoxidation and oxidative metabolic reactions of some other drugs was also studied in 8 healthy volunteers. Carbamazepine-epoxidation was not correlated to 4-hydroxylation of debrisoquine, oxidation of sparteine, 3- and 4-hydroxylation and demethylation of antipyrine, demethylation of amitriptyline, or total metabolism of theophylline.

Adult↗
PubMedDate not supplied

Clinical pharmacokinetics and pharmacological effects of carbamazepine and carbamazepine-10,11-epoxide. An update.

Carbamazepine is a first-line drug in the treatment of most forms of epilepsy and also the drug of first choice in trigeminal neuralgia. Furthermore, it is now frequently used in bipolar depression. Most oral formulations of carbamazepine are well absorbed with high bioavailability. The drug is 75% bound to plasma proteins. The degree of protein binding shows little variation between different subjects, and there is no need to monitor free rather than total plasma concentrations. Carbamazepine is metabolised in the liver by oxidation before excretion in the urine. A major metabolite is carbamazepine-10,11-epoxide which is further metabolised by hydration before excretion. This epoxide-diol pathway is induced during long term treatment with carbamazepine. Co-medication with phenytoin or phenobarbitone further induces this metabolic pathway. Some but not all studies indicate an increased metabolism of carbamazepine during pregnancy. The drug crosses the placenta, and the newborns who are exposed to the drug during fetal life eliminate the drug readily after birth. There seems to be no problem to nurse children during treatment with carbamazepine. Metabolism of carbamazepine is comparable in children and adults. Several studies have tried to establish a relationship between plasma carbamazepine and clinical effect in epilepsy, but very few of these are controlled. The best anticonvulsant effect seems to be obtained at plasma concentrations of 15 to 40 mumol/L and a similar optimal plasma concentration range was found in a controlled study in trigeminal neuralgia. Side effects are more frequent at higher plasma concentrations but are also seen within that range. In some patients, with pronounced fluctuation of plasma concentrations during the dosage interval, side effects may be avoided by more frequent dosing. Carbamazepine-10,11-epoxide is a potent anticonvulsant in animal models. During treatment with carbamazepine the plasma concentrations of this metabolite are usually 10 to 50% of those of the parent drug. It has not been possible to establish the relative contribution of the two compounds to the pharmacological effects. The epoxide has therefore been given to humans with the aim of determining the relative potency of the parent drug and its metabolite. After single oral doses of carbamazepine-10,11-epoxide to healthy subjects, the compound was rapidly absorbed. As a mean of 90% of the given dose was recovered in urine as trans-10,11-dihydroxy-10,11-dihydro-carbamazepine, a complete absorption of unchanged epoxide was shown.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMedDate not supplied

[Malformations in the offspring of pregnant women with epilepsy. Presentation of an international registry of antiepileptic drugs and pregnancy (EURAP)].

The interaction between epilepsy and pregnancy has been studied for many years; nonetheless the risk associated with individual antiepileptic drug has not been adequately characterized up to date. Moreover, virtually nothing is known about the possible human teratogenicity of the newer antiepileptic drugs. Because of the complexity of the mechanisms involved, the crucial evidence needed can only come from very large population based studies, and a collaborative European multicentre investigation has been set up to this purpose. Specific objectives include the evaluation of the risk of major foetal malformations and of delay in prenatal growth following exposure to antiepileptic drugs, assessment of the pattern of congenital abnormalities associated with older and newer antiepileptic drugs and their combinations, and identification of possible relationships with dosage and with a variety of other risk factors. All women exposed to antiepileptic drugs at the time of conception are eligible for entry. The protocol is purely observational and does not entail any change in prescribing pattern or management policies, which are left to the discretion of the treating physician. Data obtained during prospective monitoring for up to 1 year after birth are regularly collected in especially designed forms and entered into Regional Registries prior to transfer to a Central European Registry of Antiepileptic Drugs and Pregnancy (EURAP). Evaluations of incidence and prevalence of teratogenic endpoints will be based exclusively on cases enrolled before foetal outcome is known and in any case not after the 16th week of pregnancy. Cases enrolled after birth, after the 16th week of pregnancy or after prenatal diagnosis will only be reported descriptively. The study is being implemented gradually in 19 countries in Western and Eastern Europe. Wide participation from interested physicians is essential for the achievement of the study objectives, which are expected to lead to important advances in pre pregnancy counselling and overall clinical management of women with epilepsy.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Prevalence of cardiac conduction disturbances during carbamazepine treatment: preliminary data.

Twenty-five epileptic patients chronically treated with carbamazepine underwent 24 h electrocardiogram (ECG) monitoring in order to evaluate the prevalence of cardiac conduction abnormalities. Plasma levels of carbamazepine and its metabolite, carbamazepine-10,11-epoxide, were determined by liquid chromatography. Six patients had mild ECG abnormalities. These patients did not differ from the others with respect to plasma concentrations of the drug and its metabolite.

Adult↗