Concentration-effect relationships with carbamazepine and its epoxide on psychomotor and cognitive function in epileptic patients.

Gillham, R. A.; Williams, N. M.; Wiedmann, Klaus D.; Butler, Elaine; Larkin, John G.; Brodie, MJ

doi:10.1136/jnnp.51.7.929

Cited by 74 publications

(42 citation statements)

References 21 publications

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“…CRT = choice reaction time (1 = recognition time; 2 = complete manoeuvre). 1 6r I both substances, the relationship with the epoxide being the more impressive (Gillham et al, 1988).…”

Section: Discussionmentioning

confidence: 99%

A double‐blind comparison of conventional and controlled‐release carbamazepine in healthy subjects.

Larkin

McLellan

Munday

et al. 1989

Brit J Clinical Pharma

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1. Eight healthy subjects took part in a balanced, double‐blind, crossover comparison of conventional carbamazepine (Tegretol, Ciba‐ Geigy Ltd, CBZ‐C) and a novel controlled‐release formulation (Tegretol CR Divitabs, Ciba‐Geigy Ltd; CBZ‐CR). An initial single dose of either preparation was followed 1 week later by a 2 week course of 200 mg twice daily. 2. Following the single dose, CBZ‐CR produced a concentration plateau from 6‐56 h at 50‐60% of the CBZ‐CR peak. 3. After 2 weeks' treatment, CBZ daytime levels measured as area under the concentration‐time curve over a dosage interval were 7% lower with CBZ‐ CR, but this difference was not statistically significant. 4. CBZ‐CR showed less diurnal fluctuation (12%) of CBZ than CBZ‐C (24%; P less than 0.025) with less rapid changes in concentration (P less than 0.02). 5. Diurnal fluctuation of free CBZ and of CBZ 10,11 epoxide, the active metabolite, did not differ significantly between the two preparations. 6. Auto‐induction of CBZ metabolism resulted from the administration of both formulations. The mean elimination half‐life was 23 h (CBZ‐C) and 25 h (CBZ‐CR) after dose 29 compared with a base‐line value of 37 h (both P less than 0.02). Antipyrine metabolism was also induced to a similar extent in both legs of the study (P less than 0.01). 7. No significant alteration in psychomotor function was demonstrated with either preparation. 8. CBZ‐CR fulfils the criteria for a controlled‐release preparation with comparable apparent bioavailability to CBZ‐C. Further pharmacokinetic and, more importantly, pharmacodynamic studies are required in epileptic patients to confirm a clinical advantage over the currently available formulation.

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“…CRT = choice reaction time (1 = recognition time; 2 = complete manoeuvre). 1 6r I both substances, the relationship with the epoxide being the more impressive (Gillham et al, 1988).…”

Section: Discussionmentioning

confidence: 99%

A double‐blind comparison of conventional and controlled‐release carbamazepine in healthy subjects.

Larkin

McLellan

Munday

et al. 1989

Brit J Clinical Pharma

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“…OXC is a compound with similar anticonvulsant efficacy to CBZ, but which appears to have improved patient tolerability both with regard to allergic reactions and psychomotor impairment (Bulau etal., 1987;Dam etal., 1989;Houtkooper etal., 1987;Reinikainen etal., 1987). The latter potential advantage may be due to its lack of an epoxide metabolite, as this plays a major role in the neurotoxic side-effects associated with CBZ (Gillham et al, 1988;Patsalos et al, 1985).…”

Section: Oxc and Metabolitesmentioning

confidence: 99%

Lack of enzyme induction with oxcarbazepine (600 mg daily) in healthy subjects.

Larkin

Mckee

Forrest

et al. 1991

Brit J Clinical Pharma

114

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1 Oxcarbazepine (OXC), the 10-keto analogue of carbamazepine (CBZ), has similar anticonvulsant efficacy and possibly improved patient tolerability. Unlike CBZ, it is metabolised by reduction and may not induce hepatic monooxygenase enzymes. 2 Serum concentrations of OXC and its active metabolite 10-OH-carbazepine (10-OH-CZ) were followed after a single 300 mg dose and during and after 300 mg OXC twice daily for 29 doses in eight healthy male volunteers. 3 Antipyrine metabolism, urinary 6-,-hydroxycortisol excretion, sex hormone binding globulin (SHBG) levels and circulating androgens were measured as indices of hepatic enzyme induction before, during and after treatment with OXC. 4 Elimination half-lives (mean ± s.e. mean) of 10-OH-CZ were unaltered by 2 weeks' therapy with OXC (before 11.3 ± 1.1 h; after 13.9 ± 3 h). Trough plasma concentrations of 10-OH-CZ at steady-state (31 ± 2.2 ,umol 1-1) were higher than predicted (16.5 + 4 ,umol 1-1).5 Antipyrine metabolism, urinary 6-13-hydroxycortisol excretion, SHBG levels and circulating androgens were unaltered by treatment with OXC. 6 OXC (600 mg daily) does not induce hepatic monooxygenase enzymes and so is likely to have more predictable dose-concentration relationships and to produce fewer physiological and pharmacological interactions than CBZ.

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“…Carbamazepine A number of cognitive and psychomotor effects have been linked to carbamazepine [Gillham et al 1988]. A double-blind trial reported deterioration in measures of information processing speed and attention [Wesnes et al 2009].…”

Section: Phenytoinmentioning

confidence: 99%

The cognitive impact of antiepileptic drugs

Eddy¹,

Rickards²,

Cavanna³

2011

Ther Adv Neurol Disord

319

189

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Effective treatment of epilepsy depends on medication compliance across a lifetime, and studies indicate that drug tolerability is a significant limiting factor in medication maintenance. Available antiepileptic drugs (AEDs) have the potential to exert detrimental effects on cognitive function and therefore compromise patient wellbeing. On the other hand, some agents may serve to enhance cognitive function. In this review paper, we highlight the range of effects on cognition linked to a variety of newer and older AEDs, encompassing key alterations in both specific executive abilities and broader neuropsychological functions. Importantly, the data reviewed suggest that the effects exerted by an AED could vary depending on both patient characteristics and drug-related variables. However, there are considerable difficulties in evaluating the available evidence. Many studies have failed to investigate the influence of patient and treatment variables on cognitive functioning. Other difficulties include variation across studies in relation to design, treatment group and assessment tools, poor reporting of methodology and poor specification of the cognitive abilities assessed. Focused and rigorous experimental designs including a range of cognitive measures assessing more precisely defined abilities are needed to fill the gaps in our knowledge and follow up reported patterns in the literature. Longitudinal studies are needed to improve our understanding of the influence of factors such as age, tolerance and the stability of cognitive effects. Future trials comparing the effects of commonly prescribed agents across patient subgroups will offer critical insight into the role of patient characteristics in determining the cognitive impact of particular AEDs.

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Concentration-effect relationships with carbamazepine and its epoxide on psychomotor and cognitive function in epileptic patients.

Cited by 74 publications

References 21 publications

A double‐blind comparison of conventional and controlled‐release carbamazepine in healthy subjects.

A double‐blind comparison of conventional and controlled‐release carbamazepine in healthy subjects.

Lack of enzyme induction with oxcarbazepine (600 mg daily) in healthy subjects.

The cognitive impact of antiepileptic drugs

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