Ralitoline: a reevaluation of anticonvulsant profile and determination of "active" plasma concentrations in comparison with prototype antiepileptic drugs in mice

Ralitoline (RLT) is a new thiazolidinone derivative with potent anticonvulsant activity in different seizure models. During Phase I studies, RLT was well tolerated in human volunteers and showed linear pharmacokinetics in the dose range tested (up to 150 mg). Since RLT will soon be entering clinical Phase II studies, we were interested in obtaining predictive data for effective plasma concentrations in patients. For this purpose, the anticonvulsant potency of RLT was determined in four seizure models in mice, and plasma levels were measured at time of peak drug effect. The four models were the threshold for maximal (tonic extension) electroshock seizures (MES), the threshold for clonic seizures determined by i.v. infusion of pentylenetetrazol (PTZ), the traditional MES test with supramaximal (50 mA) stimulation, and generalized clonic seizures induced by s.c. administration of PTZ. Furthermore, median minimal "neurotoxic" doses (TD50s) were determined by the rotorod and chimney test for calculation of protective indices. All data obtained for RLT were compared with data obtained with standard antiepileptic drugs: phenobarbital, phenytoin, valproate, and diazepam. The onset of anticonvulsant action after i.p. injection of RLT was very rapid, and the peak drug effect was already obtained after 2 min. In the MES models, RLT was the most potent compound. "Active" plasma levels ranged from approximately 300 ng/ml in the MES threshold test to approximately 1,300 ng/ml in the MES test. RLT was also capable of increasing the PTZ threshold, whereas, possibly because of its short duration of action in mice, it was not very active in the s.c. PTZ seizure test.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative pharmacokinetic analysis of USL255, a new once‐daily extended‐release formulation of topiramate

Purpose: To compare the pharmacokinetics of USL255, a once‐daily extended‐release (ER) formulation of topiramate (TPM), with Topamax (immediate‐release TPM) in healthy subjects after oral dosing and evaluate the effect of food on USL255 bioavailability and pharmacokinetics. Methods: This randomized, single‐center, open‐label, cross‐over design study had three dosing periods separated by 21 days of washout between treatments. Thirty‐six volunteers received single doses of USL255 (200 mg) in fasted and fed conditions and two doses of Topamax (100 mg) administered 12 h apart. TPM plasma samples were analyzed by liquid chromatography–mass spectroscopy. Pharmacokinetic parameters were calculated by noncompartmental methods. Key Findings: USL255 fasted pharmacokinetic parameters [point estimate (90% confidence interval, CI) compared to Topamax] were: relative bioavailability (F´) 91.2% (84–99%), peak plasma concentration (C_max) USL255/Topamax‐ratio 59% (53–65%), time to reach C_max (t_max) 19.5 ± 7.2 h, accumulation ratio (R_ac) 3.9 ± 1.2, effective half‐life (t_1/2,eff) 55.7 ± 19.9 h, terminal half‐life (t_1/2,z) 80.2 ± 14.2 h, and peak‐occupancy‐time (POT) 12.1 ± 4.0 h. Although the F´ and C_max were unaffected by food, R_ac and t_1/2,eff increased to 4.9 ± 0.9, and 72.5 ± 15.4 h, respectively. In contrast to t_1/2,z, t_1/2,eff reflects absorption rate; therefore, USL255’s t_1/2,eff was significantly longer than Topamax’s t_1/2,eff (37.1 ± 6.5 h). Significance: Although bioequivalent to Topamax in extent of absorption, USL255 had a slower absorption rate as reflected in its lower C_max and longer t_max, larger POT and longer t_1/2,eff, and similar R_ac values to that of Topamax (q12 h). This relative flat plasma profile allows for once‐daily dosing with diminished fluctuations in TPM plasma levels. In addition, neither USL255’s peak nor extent of plasma exposure of TPM was affected by food.     

Efficacy,safety, and tolerability of overnight switching from immediate‐ to once daily extended‐release pramipexole in early Parkinson's disease

The aim of this article is to test the feasibility, in early Parkinson's disease (PD), of an overnight switch from immediate‐release (IR) pramipexole to a new once‐daily extended‐release (ER) formulation. Nonfluctuating patients on pramipexole IR three‐times daily, alone or with levodopa, for early PD were randomly switched overnight to double‐blind IR three‐times daily (N = 52) or ER once‐daily (N = 104) at initially unchanged daily dosage. Successful switching (defined as no worsening >15% of baseline UPDRS II+III score and no drug‐related adverse event withdrawal) was assessed at 9 weeks, after optional dosage adjustments (primary endpoint), and at 4 weeks, before adjustment. Other secondary endpoints included adjusted mean changes from baseline in UPDRS scores and proportion of responders based on Clinical or Patient Global Impression (CGI/PGI). Absolute difference between percentage of successful switch to ER versus IR was tested for ER noninferiority, defined as a 95% confidence‐interval lower bound not exceeding ?15%. At 9 weeks, 84.5% of the ER group had been successfully switched, versus 94.2% for IR. Noninferiority was not demonstrated, with a difference of ?9.76% (95% CI: [?18.81%, +1.66%]). At 4 weeks, 81.6% of the ER group had been successfully switched, versus 92.3% for IR, a difference of ?10.75% (95% CI: [?20.51%, +1.48%]). UPDRS changes and CGI/PGI analyses showed no differences between the groups. Both formulations were safe and well tolerated. Pramipexole ER was not equivalent to IR, but the difference was marginal. The fact that >80% of the patients successfully switched overnight at unchanged dosage shows that this practice was feasible in most patients. © 2010 Movement Disorder Society     

Exposure to antiepileptic drugs and the risk of hip fracture: a case-control study

Purpose: To investigate whether the use of antiepileptic drugs (AEDs) increases the risk of hip fracture. Methods: We performed a case‐control study using data from the Funen County (population 2004: 475,000) hip fracture register. Cases (n = 7,557) were all patients admitted to county hospitals with a hip fracture during the period 1996–2004. Controls (n = 27,575) were frequency matched by age and gender. Information on use of AEDs, other drugs, and hospital contacts was available from local registers. Odds ratios (ORs) with 95% confidence intervals (CI) for hip fracture were estimated by unconditional logistic regression. Results: Fracture risk was increased with ever use of any AED (OR: 1.31; 95% CI: 1.16–1.48). The risk was also increased with use of only enzyme inducing (OR: 1.31; 95% CI: 1.14–1.51), but not with use of only noninducing AEDs (OR: 1.03; 95% CI: 0.77–1.37). Current (OR: 1.92; 95% CI: 1.58–2.33) and recent use, as well as high daily (OR: 1.50; 95% CI: 1.24–1.82) and cumulative dose increased fracture risk, but long treatment duration or previous use did not. The risk was modified by the presence of an epilepsy diagnosis. Conclusion: Use of AEDs modestly increases the risk of hip fracture. The risk increase is probably associated to a higher degree with a dose dependent effect on CNS with current and recent use, than with an effect on bone tissue.     

The ABCC2 c.-24C > T polymorphism increases the risk of resistance to antiepileptic drugs: A meta-analysis

Several studies examined a possible link between multidrug resistance-associated protein 2 (ABCC2) gene variants and the risk of resistance to antiepileptic drugs (AEDs) in epilepsy, but the results were contradictory. In this study, a meta-analysis was conducted to assess the relevance of ABCC2 common variants (c.-24C > T, c.1249G > A, c.3972C > T) with the response risk of AEDs. We searched Embase, PubMed, the Cochrane Library and CNKI databases for case-control studies published through May 2016 that evaluated the role of ABCC2 gene variants in pharmacoresistance to AEDs. Odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated to assess the strength of associations between the ABCC2 c.-24C > T, c.1249G > A and c.3972C > T variants and the risk of resistance to AEDs using an allele frequency model, dominant model and recessive model. Subgroup analyses were performed by ethnicity and the definition of drug-resistance. A total of 13 published studies involving 4300 patients (2261 patients with drug-resistant epilepsy and 2039 controls with drug-responsive epilepsy) met the selection criteria. We observed that the variant c.-24C > T was associated with a significantly increased risk of AED resistance (TT + CT vs CC: OR = 1.24, 95%CI = 1.06–1.46, p = 0.009; TT vs CT + CC: OR = 1.90, 95%CI = 1.31–2.76, p = 0.0008; T vs C: OR = 1.27, 95%CI = 1.11–1.46, p = 0.0006). However, we identified no significant association of the ABCC2 c.1249G > A, c.3972C > T variants and haplotypes with the response to anticonvulsant drug in the overall population. In summary, these observations suggest that the ABCC2 c.-24C > T polymorphism is a likely risk factor for resistance to AEDs.     

Effects of antiepileptic drugs on cortical excitability in humans: A TMS‐EMG and TMS‐EEG study

Brain responses to transcranial magnetic stimulation (TMS) recorded by electroencephalography (EEG) are emergent noninvasive markers of neuronal excitability and effective connectivity in humans. However, the underlying physiology of these TMS‐evoked EEG potentials (TEPs) is still heavily underexplored, impeding a broad application of TEPs to study pathology in neuropsychiatric disorders. Here we tested the effects of a single oral dose of three antiepileptic drugs with specific modes of action (carbamazepine, a voltage‐gated sodium channel (VGSC) blocker; brivaracetam, a ligand to the presynaptic vesicle protein VSA2; tiagabine, a gamma‐aminobutyric acid (GABA) reuptake inhibitor) on TEP amplitudes in 15 healthy adults in a double‐blinded randomized placebo‐controlled crossover design. We found that carbamazepine decreased the P25 and P180 TEP components, and brivaracetam the N100 amplitude in the nonstimulated hemisphere, while tiagabine had no effect. Findings corroborate the view that the P25 represents axonal excitability of the corticospinal system, the N100 in the nonstimulated hemisphere propagated activity suppressed by inhibition of presynaptic neurotransmitter release, and the P180 late activity particularly sensitive to VGSC blockade. Pharmaco‐physiological characterization of TEPs will facilitate utilization of TMS‐EEG in neuropsychiatric disorders with altered excitability and/or network connectivity.     

Estimation of the burden of active and life‐time epilepsy: A meta‐analytic approach

Purpose: To estimate the burden of lifetime epilepsy (LTE) and active epilepsy (AE) and examine the influence of study characteristics on prevalence estimates. Methods: We searched online databases and identified articles using prespecified criteria. Random‐effects meta‐analyses were used to estimate the median prevalence in developed countries and in urban and rural settings in developing countries. The impact of study characteristics on prevalence estimates was determined using meta‐regression models. Results: The median LTE prevalence for developed countries was 5.8 per 1,000 (5th–95th percentile range 2.7–12.4) compared to 15.4 per 1,000 (4.8–49.6) for rural and 10.3 (2.8–37.7) for urban studies in developing countries. The median prevalence of AE was 4.9 per 1,000 (2.3–10.3) for developed countries and 12.7 per 1,000 (3.5–45.5) and 5.9 (3.4–10.2) in rural and urban studies in developing countries. The estimates of burden for LTE and AE in developed countries were 6.8 million (5th–95th percentile range 3.2–14.7) and 5.7 million (2.7–12.2), respectively. In developing countries these were 45 (14–145) million LTE and 17 (10–133) million AE in rural areas and 17 (5–61) million LTE and 10 (5–17) million AE in urban areas. Studies involving all ages or only adults showed higher estimates than pediatric studies. Higher prevalence estimates were also associated with rural location and small study size. Conclusions: This study estimates the global burden of epilepsy and the proportions with AE, which may benefit from treatment. There are systematic differences in reported prevalence estimates, which are only partially explained by study characteristics.     

Critical determinants of the epilepsy treatment gap: A cross‐national analysis in resource‐limited settings

Purpose: Epilepsy is one of the most common serious neurologic disorders worldwide. Our objective was to determine which economic, health care, neurology, and epilepsy‐specific resources were associated with untreated epilepsy in resource‐constrained settings. Methods: A systematic review of the literature identified community‐based studies in resource‐constrained settings that calculated the epilepsy treatment gap, the proportion with untreated epilepsy, from prevalent active epilepsy cases. Economic, health care, neurology, and epilepsy‐specific resources were taken from existing datasets. Poisson regression models with jackknifed standard errors were used to create bivariate and multivariate models comparing the association between treatment status and economic and health resource indicators. Relative risks were reported. Key Findings: Forty‐seven studies of 8,285 individuals from 24 countries met inclusion criteria. Bivariate analysis demonstrated that individuals residing in rural locations had significantly higher risks of untreated epilepsy (relative risk [RR] 1.63; 95% confidence interval [CI] 1.26–2.11). Significantly lower risks of untreated epilepsy were observed for higher physician density (RR 0.65, 95% CI 0.55–0.78), presence of a lay (RR 0.74, 95% CI 0.60–0.91) or professional association for epilepsy (RR 0.73, 95% CI 0.59–0.91), or postgraduate neurology training program (RR 0.67, 95% CI 0.55–0.82). In multivariate models, higher physician density maintained significant effects (RR 0.67; 95% CI 0.52–0.88). Significance: Even among resource‐limited regions, people with epilepsy in countries with fewer economic, health care, neurology, and epilepsy‐specific resources are more likely to have untreated epilepsy. Community‐based epilepsy care programs have improved access to treatment, but in order to decrease the epilepsy‐treatment gap, poverty and inequalities of health care, neurology, and epilepsy resources must be dealt with at the local, national, and global levels.