This prospective study was designed to ascertain whether measurement of lamotrigine (LTG) concentrations in the epilepsy clinic could be used to predict the onset of complete seizure control or the emergence of adverse effects. LTG was initiated in doses of 25 or 50 mg daily in 69 patients with newly diagnosed or poorly controlled epilepsy and was increased monthly in 50-mg increments until the patient became seizure-free for at least 6 months or developed adverse effects that abated after a reduction in dosage. LTG and other antiepileptic drug (AED) concentrations were measured at each clinic visit but were not supplied to the investigator examining the patients. Overall, 19 patients either withdrew due to lack of efficacy or defaulted from the clinic. Of the remaining 50 patients, 32 (19 monotherapy, 13 polytherapy) became seizure-free at widely varying daily LTG doses (median 200 mg, range 25-850 mg) and concentrations (median 3.8 mg/L, range 1.4-18.7 mg/L). Likewise, the 18 patients (5 monotherapy, 13 polytherapy) who experienced intolerable side effects showed substantial variations in daily LTG doses (median 300 mg, range 100-900 mg) and concentrations (median 4.0 mg/L, range 0.4-18.5 mg/L). No useful concentration-effect or concentration-toxicity relation with LTG could be demonstrated in this study; therefore, we believe that routine therapeutic drug monitoring with this new AED is not currently indicated.
Accumulation of VGB in the retina, with or without an increase in GABA, may be responsible for the visual field constriction reported clinically. In contrast, TGB had no effect on GABA concentrations and did not accumulate in the retina. These results suggest that TGB is unlikely to cause visual field defects in humans.
Dihydropyridine calcium antagonists are candidate anticonvulsants, but little is known of their penetration into brain. Nifedipine (NFD) and nimodipine (NMD) pharmacokinetics were compared in mouse blood and brain, and their activity against pentylenetetrazol (PTZ) was assessed. After intraperitoneal (i.p.) injection, both dihydropyridines achieved peak blood and brain concentrations in 5 min. Estimated blood and brain elimination half-lives (t1/2) of NMD (16.7 and 22.4 min) were slightly longer than those of NFD (11.2 and 14.7 min). Brain and blood concentrations correlated with both NFD (r = 0.701, p less than 0.001) and NMD (r = 0.572, p less than 0.001). Injection of the dihydropyridines as a suspension (Tween 80) did not alter brain penetration, although systemic absorption was more erratic. NFD (p less than 0.001), NMD (p less than 0.02), and carbamazepine (CBZ, p less than 0.001) i.p. inhibited PTZ-induced seizures. Brain concentrations of PTZ were not altered by NFD pretreatment. Combining NFD and CBZ was less effective than giving NFD alone (p less than 0.005). NFD (p less than 0.002) and NMD (p less than 0.001) inhibited PTZ seizures after 2-week oral dosing, but low dosing was more effective than high dosing (p less than 0.002). NFD and NMD cross the blood-brain barrier (BBB) in mice and inhibit PTZ seizures. A possible therapeutic window was identified, and NFD and CBZ were less effective in combination than singly. A pharmacodynamic interaction may exist, inhibiting effective use of dihydropyridines as adjunctive therapy in epileptic patients.
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.
Summary:Purpose: The antiepileptic drug (AED) vigabatrin (VGB), which exerts its pharmacologic effects on the γ -aminobutyric acid (GABA) system, causes concentric visual field constriction in >40% of exposed adults. This may be a class effect of all agents with GABArelated mechanisms of action. We compared the concentrationrelated effects of VGB in rat brain and eye with those of gabapentin (GBP) and topiramate (TPM), both of which have been reported to elevate brain GABA concentrations in humans.Methods: Adult male rats (n = 10) were administered 0.9% saline (control), VGB (250, 500, 1,000 mg/kg), GBP (50, 100, 200 mg/kg), or TPM (12.5, 25, 50, 100 mg/kg). At 2 h after dosing, animals were killed, a blood sample obtained, the brain dissected into eight distinct regions, and the retina and vitreous humor isolated from each eye. Samples were analyzed for several GABA-related neurochemical parameters, and serum and tissue drug concentrations determined.Results: VGB treatment produced a significant (p < 0.05) dose-related increase in GABA concentrations and decrease in GABA-transaminase activity in all tissues investigated. This effect was most pronounced in the retina, where VGB concentrations were 18.5-fold higher than those in brain. In contrast, GBP and TPM were without effect on any of the neurochemical parameters investigated and did not accumulate appreciably in the retina.Conclusions: These findings corroborate a previously reported accumulation of VGB in the retina, which may be responsible for the visual field constriction observed clinically. This phenomenon does not appear to extend to other GABAergic drugs, suggesting that these agents might not cause visual field defects.
Steady state carbamazepine (CBZ) plasma concentrations were similar in 15 epileptics receiving monotherapy and in 24 patients taking CBZ in combination with one other anticonvulsant. The ratio of CBZ 10, 11-epoxide (CBZ-E) to the parent drug was significantly higher (P < 0.01) in those patients taking concomitant phenytoin (n = 9), phenobarbitone or primidone (n = 9), and valproic acid (n = 6) than in the patients receiving CBZ alone. In the monotherapy group, there was a significant correlation between CBZ-E/CBZ ratio and the concentration of the parent drug (P < 0.05). If CBZ-E has equipotent anticonvulsant properties to CBZ in man as is the case in animal models, routine CBZ-E concentrations may provide further refinement in the therapeutic drug monitoring of CBZ.
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