In recent years several new drugs (oxcarbazepine, lamotrigine, topiramate, gabapentin, zonisamide, tiagabine, fosphenytoin, vigabatrin and felbamate) have been added to the therapeutic armamentarium against epilepsy. Some of these represent structural modifications of pre-existing compounds, others were developed with the specific objective of modifying neurotransmitter function, and many more were found to be clinically useful even though their mode of action is unclear or differs from that originally planned. The pharmacokinetics of these drugs differ widely from one agent to another. Some (gabapentin and vigabatrin) are eliminated unchanged in urine and have little or no interaction potential; others (tiagabine, lamotrigine, topiramate, oxcarbazepine, zonisamide, felbamate) are subject to induction of metabolism by concomitant anticonvulsants; lamotrigine is vulnerable to metabolic inhibition by valproate, and felbamate is a powerful enzyme inhibitor in addition to being an inducer of the metabolism of carbamazepine and steroid oral contraceptives. All new antiepileptic drugs have been found to be effective in improving seizure control in patients with partial and secondarily generalized seizures. However, lamotrigine, topiramate, zonisamide and felbamate appear to have broader efficacy against both partial and many generalized seizure types, while vigabatrin is also valuable in the management of infantile spasms. In monotherapy studies, new drugs have not been found to be more efficacious than older agents, but some may offer limited advantages in terms of improved tolerability. On the other hand, serious toxicity restricts considerably the use of vigabatrin and felbamate. Overall, new drugs represent valuable tools in the fight against epilepsy, but because of limited experience and cost considerations their first-line use cannot be recommended in most situations.
The influence of age and administered daily dosage on the plasma concentrations of gabapentin (GBP) at steady state was evaluated in a group of 41 children and young adults (aged 3-30 years) receiving long-term adjunctive treatment with GBP for the management of refractory partial-onset seizures. For each patient, peak and trough concentrations were determined by a specific high-performance liquid chromatography (HPLC) method in samples obtained before the morning dose and 2.5 hours later, respectively. To assess within-subject relationship between plasma concentration and dosage, 30 patients were evaluated at more than one dosage level. Within the assessed dose range, plasma GBP concentrations were linearly related to dose. Apparent oral clearance values (mean +/- SD) in children aged 6 years or less (4.8 +/- 0.9 mL/kg/min) were comparable with those observed in children aged 7 to 15 years (4.6 + 1.5 mL/kg/min) and moderately higher than those found in young adults (3.9 + 0.9 mL/kg/min), even though differences among groups failed to reach statistical significance. There was, however, a significant difference in CL/F between children aged 10 years or less and older children (5.1 +/- 1.1 vs. 3.8 +/- 1.2 mL/kg/min, P < 0.005). Of the 41 patients who entered the study, 22 discontinued treatment, mostly due to insufficient efficacy. No significant difference in plasma GBP concentration was detected between patients showing a greater than 50% reduction in seizure frequency (4.1 +/- 1.9 microg/mL, n = 11, mean +/- SD) and those having no significant clinical improvement (4.4 +/- 1.7 microg/mL, n = 30). These results indicate that in children given dosages up to 50 mg/kg/d (mean, 25 mg/kg/d), GBP pharmacokinetic analyses show no important deviation from linearity. The data also suggest that, on average, children may need moderately higher dosages to reach plasma GBP concentrations comparable with those found in adults. There seems to be a large variation in the plasma concentrations of the drug associated with a favorable therapeutic response.
The enhanced platelet aggregation and thrombosis occurring in TTP is probably due to an unbalance between agents insulting endothelial integrity and natural antithrombotic factors, such as NO. Using a sensitive and specific HPLC assay, we tested the hypothesis of NO involvement in TTP, comparing NO production, as the stable end-products nitrites and nitrates, in the plasma of 29 TTP patients and of 29 healthy subjects matched for sex and age. Average nitrate titer was 25.868 μM/L in the TTP group vs 24.234 μM/L in the control group (p = n.s.), while nitrite were undetectable in both groups. Moreover, nitrate titers did not correlate with hemoglobin value, platelet count, LDH values, or with Rose and Eldor's severity score. In conclusion, even though the enhanced platelet aggregation observed in TTP could be due to reduced natural antithrombotic substances, NO involvement in the pathogenesis of TTP appears unlikely.
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