No abstract

Phenytoin has a widespread use in epilepsy treatment and is mainly metabolized by hepatic cytochrome P450 enzymes (CYP). We have investigated CYP2C9*2, CYP2C9*3, CYP2C19*2 and CYP2C19*3 allelic variants in a Turkish population of patients on phenytoin therapy. Patients on phenytoin therapy (n = 102) for the prevention of epileptic seizures were included. Polymorphic alleles were analyzed by restriction fragment length polymorphism method. Serum concentrations of phenytoin were measured by fluorescence polarization immune assay method. The most frequent genotype was detected for CYP2C9 wild-type alleles (78.43 %), whereas CYP2C19*2/*2 (5.88 %) was the least frequent genotype group. According to the classification made with both enzyme polymorphisms, CYP2C9*1/*1-CYP2C19*1/*1 (G1: 41.17 %) genotype group was the most frequent whereas CYP2C9*1/*2-CYP2C19*1/*3 (G7: 0.98 %) was the least frequent one. The highest mean phenytoin level (27.95 ± 1.85 µg/ml) was detected in the G8 genotype group (CYP2C9*1/*3-CYP2C19*2/*3) and the G1 genotype group showed the lowest mean phenytoin level (7.43 ± 0.73 µg/ml). The mean serum concentration of phenytoin of the polymorphic patients with epilepsy was higher than that for the wild-type alleles both in the monotherapy and polytherapy patients. These results show the importance of the genetic polymorphism analysis of the main metabolizing enzyme groups of phenytoin for the dose adjustment.

To assess changes in the pharmacokinetics of the anti-epileptic drug lamotrigine (LTG) during pregnancy, plasma LTG concentrations at steady-state were determined at different intervals during 11 pregnancies in 10 women with epilepsy stabilized on long-term LTG therapy. In the five pregnancies that could be assessed both during gestation and after delivery, plasma LTG concentrations increased on average by 164% (range +75 to +351%) between the last observation during pregnancy and the puerperium (P < 0.05). When all pregnancies monitored during pregnancy were considered, plasma LTG concentrations declined by an average of 20% (range -64% to +13%) between the first and the last assessment before delivery. These findings confirm that plasma LTG concentrations decrease markedly during pregnancy and that, at least in some cases, this effect occurs as early as the first trimester. Because there is a large interindividual variability in the magnitude and time course of the pregnancy-associated pharmacokinetic changes, it is desirable to establish baseline plasma LTG concentrations in all women of childbearing potential and to monitor LTG levels at frequent intervals during pregnancy and the puerperium.

Summary:Purpose: This study was planned to investigate the baroreflex responses (BRs) in kindled rats during seizure-free period to put forward new data on cardiac autonomic changes in epilepsy.Methods: Male Wistar rats were randomized into shamoperated (SO) and kindled groups where stimulation and recording electrodes were implanted stereotaxically into the basolateral amygdala and the cortex, respectively. For kindling process, rats were stimulated twice daily at their afterdischarge threshold current and accepted as being kindled after 10 grade 5 seizures. Six to 8 weeks after the establishment of the kindled state, mean arterial pressure (MAP) and heart rate (HR) were evaluated. BR was defined as the ratio of HR response to changes in MAP induced by i.v. nitroprusside (10, 25 µg/kg) or i.v. phenylephrine (10, 25 µg/kg). The sympathetic or parasympathetic component of the BR was evaluated in rats pretreated with atropine or atenolol where phenylephrine or nitroprusside was administered at 25 µg/kg.Results: Basal MAP and HR values were found to be similar in SO and kindled rats. Phenylephrine increased MAP more in the kindled group (p < 0.05), but the HR decreased similarly in both groups. Nitroprusside decreased MAP at similar rates, but the increase in HR was higher in the kindled rats (p < 0.05). BRs to phenylephrine and nitroprusside were abolished after pretreatment with atenolol and atropine, whereas phenylephrineand nitroprusside-induced changes in MAP remained unchanged in both groups.Conclusions: These results may indicate that amygdaloid kindling affects BRs in long-term seizure-free periods. Key Words: SUDEP-Baroreflex responses-KindlingEpilepsy-Autonomic dysfunction.The mortality rate is 2 to 3 times higher in the people with epilepsy than in the general population (1). Moreover, increased risk of sudden death occurs in 7.5-17 % of all deaths among patients with epilepsy (2). Although the mechanisms underlying sudden unexplained deaths in epilepsy patients (SUDEPs) have not been clearly established, seizure-related arrhythmias, cardiorespiratory pathology, and autonomic dysfunction have been suggested as the causes of SUDEP (3-6). Several experimental seizure and epileptogenesis models have been used to examine the physiopathologic mechanisms responsible for SUDEP (7-9).Kindling, an experimental model of temporal lobe epilepsy, is performed by daily application of short trains of high-frequency electrical pulses that induce initially focal but subsequently generalized convulsive seizures (10). It is characterized by the increase of electrographic afterdischarge duration and behavioral complexity produced by the repeated low-density electrical stimulation of several brain areas, mainly the limbic system. In previous studies, immediate effects of kindled seizures on cardiovascular function have shown a seizure-associated increase in blood pressure and bradycardia with a variety of arrhythmias during the seizures in unanesthetized and freely moving rats (10,11). Furthermore, seizure-induced cardiovasc...