Carbamazepine toxicity with lamotrigine: pharmacokinetic or pharmacodynamic interaction?

PURPOSE: To determine whether the toxicity that occurs in some patients when lamotrigine (LTG) is added to carbamazepine (CBZ) is the result of either a pharmacokinetic or a pharmacodynamic interaction. METHODS: Escalating LTG doses were added to ongoing CBZ treatment in 47 patients. All patients had blood samples collected for drug concentration measurement, including the epoxide metabolite of CBZ, before starting LTG treatment and after stabilising at each dose escalation. Patients also were examined for signs of toxicity. RESULTS: After LTG was introduced, nine patients demonstrated clinical signs of CNS toxicity, mainly diplopia and dizziness. There was no significant (p = 0.05) change in the serum concentrations of either CBZ or its epoxide metabolite when LTG was added either to the group as a whole or to the nine patients who experienced adverse CNS effects. LTG serum concentrations also were below the level at which the common signs of LTG toxicity, such as nausea, vomiting, or unsteadiness, are more likely to occur. In seven of the nine patients who exhibited CNS toxicity, CBZ serum concentrations were >8 mg/L on LTG introduction. CONCLUSIONS: Toxicity is more likely to occur when LTG is added to CBZ if the initial CBZ level is high, typically >8 mg/L. This appears to be the result of a pharmacodynamic interaction. A reduction of CBZ dose usually resolves the toxicity, allowing the LTG dose to be escalated to maximal effect. It is not usually necessary to stop either drug.

Analysis of desmethylmethsuximide using high-performance liquid chromatography.

Analysis of desmethylmethsuximide by high-performance liquid chromatography (HPLC) is described. After adding an internal standard (IS), 200 microliters of plasma was buffered to pH 4.5 and extracted with dichloroethane. The organic solvent was then evaporated to dryness and the residue reconstituted in 100 microliters of mobile phase prior to injecting a 20 microliters aliquot onto a Hypersil 5 MOS column, which was eluted with acetonitrile/acetate buffer (pH 5.5) 36:64 vol/vol. Constituents were separated in approximately 8 min. Using this method, down to 1.0 mg/L of desmethylmethsuximide in plasma can be accurately determined. The method is suitable for therapeutic monitoring of desmethylmethsuximide in patient samples.

The analysis of clobazam and its metabolite desmethylclobazam by high-performance liquid chromatography.

The analysis of clobazam and its metabolite desmethylclobazam by high-performance liquid chromatography is described. After adding an internal standard 500 microliters of plasma is extracted under basic conditions into dichloroethane. The organic solvent is then evaporated to dryness and the residue reconstituted in 100 microliters of mobile phase prior to injecting an aliquot (30 microliters) onto a Hypersil 5 MOS column, which is eluted with acetonitrile/acetate buffer (pH 5.4) 40:60 vol/vol. The components are separated in approximately 12 min. Using this method, 15 micrograms L-1 of clobazam and 30 micrograms L-1 of desmethylclobazam can be detected. The method is suitable for the therapeutic monitoring of these two drugs in patient samples.

Phenylethylmalonamide serum levels in patients treated with primidone and the effects of other antiepileptic drugs.

Data are presented for the serum levels of 2-ethyl-2-phenylmalonamide (PEMA) in patients receiving anticonvulsant medication. Statistical analysis of these data indicates that the serum level of PEMA, which is a metabolite of primidone, is affected not only by the dose of primidone but also by the serum levels of other prescribed anticonvulsant drugs. In particular, phenobarbitone is shown to be a major perturbation upon the PEMA serum level.

Investigation of the enzymatic digestion of plant cell walls using reflectance Fourier Transform Infrared spectroscopy.

A method has been developed to determine the reflectance Fourier Transform Infrared spectra of plant cells grown in vitro and of the protoplasts released from such cells by enzymatic digestion. It is demonstrated that there is a smooth and reproducible transition in spectral detail as enzymatic digestion procedes. Reflectance Fourier Transform Infrared spectroscopy has been used to monitor the progress of protoplast release during enzymatic digestion of cell wall material.