SUMMARYPurpose: To evaluate the relative contribution of demographic and epilepsy-related variables, depressive symptoms, and adverse effects (AEs) of antiepileptic drugs (AEDs) to health-related quality of life (HRQOL) in adults with pharmacoresistant epilepsy. Methods: Individuals with epilepsy whose seizures failed to respond to at least one AED were enrolled consecutively at 11 tertiary referral centers. HRQOL was assessed by the Quality of Life in Epilepsy Inventory-31 (QOLIE-31), AEs by the Adverse Event Profile (AEP), and depressive symptoms by the Beck Depression Inventory-II (BDI-II). Multivariate linear regression models were used to identify variables associated with QOLIE-31 total score and subscale scores. Key Findings: Of 933 enrolled individuals aged 16 years or older, 809 (87%) were able to complete the selfassessment instruments and were included in the analysis. Overall, 61% of the variance in QOLIE-31 scores was explained by the final model. The strongest predictors of HRQOL were AEP total scores (b = )0.451, p < 0.001) and BDI-II scores (b = )0.398, p < 0.001). These factors were also the strongest predictors of scores in each of the seven QOLIE-31 subscales. Other predictors of HRQOL were age (b = )0.060, p = 0.008), lack of a driving license (b = )0.053, p = 0.018), pharmacoresistance grade, with higher HRQOL in individuals who had failed only one AED (b = 0.066, p = 0.004), and location of the enrolling center. Epilepsy-related variables (seizure frequency, occurrence of tonic-clonic seizures, age of epilepsy onset, disease duration) and number of AEDs had no significant predictive value on HRQOL. The AEP total score was the strongest negative predictor of HRQOL in the subgroup of 362 patients without depressive symptoms (BDI-II score <10), but even in this subgroup the BDI-II score was retained as a significant predictor. Significance: In individuals with pharmacoresistant epilepsy, AEs of medication and depressive symptoms are far more important determinants of HRQOL than seizures themselves. When seizure freedom cannot be achieved, addressing depressive comorbidity and reducing the burden of AED toxicity is likely to be far more beneficial than interventions aimed at reducing the frequency of seizures. KEY WORDS: Antiepileptic drugs, Pharmacoresistance, Depression, Adverse event profile.The primary objective of the management of epilepsy is to restore a normal health-related quality of life (HRQOL). To achieve this goal, complete seizure control without adverse effects (AEs) is the primary prerequisite, but other factors such as comorbidities and psychosocial constraints also need to be addressed (Perucca & Tomson, 2011;Taylor et al., 2011 To date, most studies of HRQOL in epilepsy have been conducted in relatively small or heterogenous populations of patients with controlled and uncontrolled seizures, and have focused on specific factors, most notably the impact of seizures and AEs of treatment (Baker et al., 1997;Gilliam et al., 2004a;Cramer et al., 2007) or seizures and comorbidities...

IdB 1016 is a complex of silybin (the main active component of silymarin) and phosphatidylcholine, which in animal models shows greater oral bioavailability and therefore greater pharmacological activity compared with pure silybin and silymarin. In order to assess its pharmacokinetic profile in man, plasma silybin levels were determined after administration of single oral doses of IdB 1016 and silymarin (equivalent to 360 mg silybin) to 9 healthy volunteers. Although absorption was rapid with both preparations, the bioavailability of IdB 1016 was much greater than that of silymarin, as indicated by higher plasma silybin levels at all sampling times after intake of the complex. Regardless of the preparation used, the terminal half-life was relatively short (generally less than 4 h). In a subsequent study, 9 healthy volunteers received IdB 1016 (120 mg b.i.d., expressed as silybin equivalents) for 8 consecutive days. The plasma silybin level profiles and kinetic parameters on day 1 were similar to those determined on day 8. Most of the silybin present in the systemic circulation was in conjugated form. Less than 3% of the administered dose was accounted for by urinary recovery of free plus conjugated silybin, a significant proportion of the dose probably being excreted in the bile. It is concluded that complexation with phosphatidylcholine in IdB 1016 greatly increases the oral bioavailability of silybin, probably by facilitating its passage across the gastrointestinal mucosa.

SUMMARYPurpose: To evaluate the adverse effects (AEs) of antiepileptic drugs (AEDs) in adults with refractory epilepsy and their relationship with number of coprescribed AEDs and AED load. Methods: Patients with refractory epilepsy were enrolled consecutively at 11 tertiary referral centers. AEs were assessed through unstructured interview and the Adverse Event Profile (AEP) questionnaire. AED loads were calculated as the sum of prescribed daily dose (PDD)/defined daily dose (DDD) ratios for each coprescribed AED. Results: Of 809 patients enrolled, 709 had localizationrelated epilepsy and 627 were on polytherapy. AED loads increased with increasing number of AEDs in the treatment regimen, from 1.2 ± 0.5 for patients on monotherapy to 2.5 ± 1, 3.7 ± 1.1, and 4.7 ± 1.1 for those on two, three, and ‡4 AEDs, respectively. The number of spontaneously reported AEs correlated with the number of AEs identified by the AEP (r = 0.27, p < 0.0001). AEP scores did not differ between patients with monotherapy and patients with polytherapy (42.8 ± 11.7 vs. 42.6 ± 11.2), and there was no correlation between AEP scores and AED load (r = )0.05, p = 0.16). Conclusions: AEs did not differ between monotherapy and polytherapy patients, and did not correlate with AED load, possibly as a result of physicians' intervention in individualizing treatment regimens. Taking into account the limitations of a cross-sectional survey, these findings are consistent with the hypothesis that AEs are determined more by individual susceptibility, type of AEDs used, and physicians' skills, than number of coprescribed AEDs and AED load.

The intracellular mechanisms regulating the process of evoked neurotransmitter release were studied in the cloned neurosecretory cell line PC12 . Various agents were employed that were known, from previous studies in other systems, to stimulate release in a manner either strictly dependent or independent of the concentration of extracellular Ca z+, [Caz+] . Three parameters were investigated in cells suspended in either Ca 2 '-containing or Ca 2 '-free Krebs-Ringer media: release of previously accumulated [3H]dopamine ; average free cytoplasmic Ca 2+ concentration, [Ca 2+]i (measured by the quin2 technique) ; and cell ultrastructure, with special reference to the number and structure of secretion granules . The release induced by the ionophores transporting monovalent cations, X537A and monensin, occurred concomitantly with profound alterations of secretory granule structure (swelling and dissolution of the dense core). These results suggest that the effect of these drugs is due primarily to leakage of dopamine from granules to the cytoplasm and extracellular space. In contrast, the changes induced by other stimulatory drugs used concerned not the structure but the number of secretory granules, indicating that with these drugs stimulation of exocytosis is the phenomenon underlying the increased transmitter release. The release response induced by the CaZ+-ionophore ionomycín was dependent on [Caz+ ]o, occurred rapidly, was concomitant with a marked rise of [Caz+ ]i, and ceased after 1-2 min even though [CaZ+] i remained elevated for many minutes. 12-O-tetradecanoylphorbol, 13-acetate and diacylglycerol (both of which are known as activators of protein kinase C) induced slow responses almost completely independent of [Caz+] and not accompanied by changes of [CaCombination of an activator of protein kinase C with a low concentration of ionomycin failed to modify the [Caz+] i rise induced by the ionophore, but elicited a marked potentiation of the release response, which was two-to fourfold larger than the sum of the responses elicited separately by either drugs . Thus, activation of protein kinase C seems to play an important role in the regulation of exocytosis in neurosecretory cells, possibly by increasing and maintaining the sensitivity to Ca 2+ of the intracellular apparatus regulating granule discharge by exocytosis .During the last two decades, considerable attention has been focused on the process of evoked transmitter release from nerve terminals and neurosecretory cells (see reference 33 for a recent review). Two important aspects of such a process now appear firmly established . The first concerns the mechanism of the release that in many (possibly all) systems has been demonstrated to occur in quanta by exocytosis, i.e ., (6,7,38). The second aspect concerns the key role played by Ca". Depolarization, whether induced by action potential invasion of synaptic terminals or by other means, is followed rapidly by the opening of the voltagedependent Ca 2+ channels. The consequent inward flow...

The serine/threonine kinase mTOR, the major sensor of cell growth along the PI3K/Akt pathway, can be activated by agents acting on microtubules. Damaged microtubules induce phosphorylation of the Bcl-2 protein and lower the threshold of programmed cell death, both of which are inhibited by rapamycin. In HEK293 cells expressing Akt mutants, the level of Bcl-2 phosphorylation and the threshold of apoptosis induced by taxol or by nocodazole are significantly modified. In cells expressing dominantnegative Akt (DN-Akt), Bcl-2 phosphorylation and p70S6KThr421/Ser424 phosphorylation induced by taxol or nocodazole were significantly enhanced as compared to cells expressing constitutively active Akt (CA-Akt) and inhibited by rapamycin. Moreover, DN-Akt cells were more sensitive to antitubule agents than CA-Akt cells. In nocodazole-treated HEK293 cells sorted according to cell cycle, the p70S6K Thr421/Ser424 phosphorylation was associated to the G2/M fraction. More relevant, nocodazole inhibited, in a dose-response manner, mTOR phosphorylation at Ser2448. This activity, potentiated in DN-Akt cells, was not detectable in CA-Akt cells. Our results suggest that death signals originating from damaged microtubules in G2/M can compete with G1 survival pathways at the level of mTOR. These findings have implications for cancer therapy and drug resistance.

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ICWCNS, Basel, and if1.P.A.S. SA, Stubio, Switzerland Summary: Purpose: To evaluate the effect of oxcarbazepine (OCBZ) on the pharmacokinetic profile of steroid oral contraceptives.Methods: Twenty-two healthy women aged 18-44 years were recruited, and 16 of them completed the study. By using a randomized double-blind crossover design, each woman was studied in two different menstrual cycles, during which placebo or OCBZ (maintenance dosage, 1,200 mglday) was given in randomized sequence for 26 consecutive days with a washout of at least one cycle in between. A steroid oral contraceptive containing 50 p,g ethinylestradiol (EE) and 250 tJ-g levonorgestrel (LN) was taken for the first 21 days of each cycle. Plasma concentrations of EE and LN were measured by gas chromatography-mass spectrometry in samples collected at regular intervals on days 21-23 of each cycle.Results: Compared with placebo, areas under the plasma concentration curves (AUC,,,,, geometric means) decreased by 47% for both EE (from 1,677 to 886 pgWml; p < 0.01) and LN(from 137 to 73 ngWml; p < 0.01), during OCBZ treatment. Peak plasma EE concentrations decreased from 180 pg/ml during the placebo cycle to 117 pg/ml during the OCBZ cycle (p < O.Ol), whereas peak plasma LN concentrations decreased from 10.2 to 7.7 ng/ml (p < 0.01). The half-lives of EE and LN also decreased from 13.6 to 7.9 h (p < 0.01) and from 28.8 to 15.8 h, respectively (p i 0.01).Conclusions: OCBZ reduces plasma concentrations of the estrogen and progestagen components of steroid oral contraceptives, presumably by stimulating their CYP3A-mediated metabolism in the liver or gastrointestinal tract or both. Because this may lead to a decreased efficacy of the contraceptive pill, women treated with OCBZ should receive preferentially a high-dosage contraceptive and should be monitored for signs of reduced hormonal cover.