非氨酯的合成

目的:合成非氨酯.方法:以2-苯基-1,3-丙二酸二乙酯为起始原料,经硼氢化钠还原后得到2-苯基-1,3-丙二醇,再与氯甲酸苯酯、氨水反应得到目标化合物非氨酯.结果:目标化合物经红外光谱、核磁共振氢谱、质谱确证其化学结构.非氨酯总收率达38.1%.结论:该法合成操作简便,适合于工业化生产.     

Felbamate produces antidepressant‐like actions in the chronic unpredictable mild stress and chronic social defeat stress models of depression

Felbamate is an anticonvulsant used in the treatment of epilepsy. In this study, we investigated the antidepressant‐like actions of felbamate in mice. The effects of felbamate were first assessed using the forced swimming test (FST) and tail suspension test (TST), and then investigated in the chronic unpredictable mild stress (CUMS) and chronic social defeat stress (CSDS) models of depression. The changes in the hippocampal brain‐derived neurotrophic factor (BDNF) signaling cascade after chronic stress and felbamate treatment were also examined. It was found that felbamate exhibited antidepressant‐like activities in the FST and TST without affecting the locomotor activity of mice. Felbamate was also effective in both the CUMS and CSDS models of depression. Moreover, felbamate administration fully restored the decreased hippocampal BDNF signaling pathway in both the CUMS‐stressed and CSDS‐stressed mice. Collectively, felbamate has antidepressant‐like actions in mice involving the hippocampal BDNF system.     

Single-dose pharmacokinetics of felbamate in patients with renal dysfunction

Aims The purpose of this study was to evaluate the effects of renal impairment on the single-dose pharmacokinetics of the antiepileptic felbamate.
Methods Twelve subjects with three levels of renal dysfunction (creatinine clearance >30–80, >10–30 or 5–10  m  min⁻¹ ) and four controls with normal renal function (creatinine clearance >80  ml min⁻¹ were studied). Plasma and urine samples were obtained for 144  h following administration of a single 1200  mg dose.
Results Compared with controls, apparent total body clearance, renal clearance and urinary excretion of felbamate were decreased, and half-life, C _max and AUC values were increased in subjects with renal dysfunction. The magnitude of these changes was associated with the degree of renal dysfunction. Nonrenal clearance and apparent volume of distribution values were also lower in renal dysfunction subjects, but there was no association between the extent of these changes and degree of renal dysfunction. Renal clearance of felbamate accounted for approximately 30% of apparent total body clearance in the control group and from 9–22% in the renal failure patients. Renal clearance of felbamate was significantly correlated with creatinine clearance ( r ²=0.75; P <0.001).
Conclusions These data suggest that initial dosage and titration of felbamate may require adjustment in patients with renal dysfunction.     

Efficacy and safety of felbamate in children under 4 years of age: a retrospective chart review

Background and purpose:  To review our experience of the efficacy and tolerability of felbamate in children younger than 4 years.
Methods:  We used a retrospective chart review to identify 53 children with seizures who were younger than 4 years. Efficacy was evaluated based on the occurrence of responsiveness, defined as seizure frequency reduction of more than 50% for a minimum period of 4 months. Tolerability was based on parent-reported side effects.
Results:  Twenty-two (41%) patients resulted to be responders and 31 (59%) did not. By univariate analysis, those achieving seizure remission were probably much older, to have a shorter history of epilepsy and a lower frequency of seizures before felbamate therapy. The number of antiepileptic drugs (AEDs) used before felbamate therapy was the only significant predictor of the duration of response to felbamate, with a longer responsiveness to the drug seen in those who were placed under fewer than three AEDs before felbamate compared with those who had taken more than three (median, 16 months vs. 7 months; P  < 0.0084). Side effects occurred in 30% of the subjects, but these did not require discontinuation of the drug.
Discussion:  Felbamate is an effective medication for a wide range of epilepsy syndromes in children younger than 4 years. Although caution is necessary when the drug is used in children, felbamate might represent a possible option for the treatment of epilepsy in this age group.     

Single and multiple dose pharmacokinetics of felbamate in the elderly

Aims The objective of this study was to compare the pharmacokinetics, safety and tolerability of the antiepileptic drug felbamate in young and elderly healthy vounteers.
Methods The single and multiple dose pharmacokinetics of felbamate were examined in an open-label two-dose level parallel group study in 24 elderly (66 to 78-year-old) and 11 young (18 to 45-year-old) healthy volunteer subjects. Pharmacokinetics were determined from blood samples obtained over 120  h after administration of single 600  mg or 1200  mg doses, and after multiple doses of 600  mg or 1200  mg administered every 12  h. Safety and tolerability were assessed through laboratory tests, ECGs, vital signs and reported adverse events.
Results Single dose felbamate pharmacokinetic parameters differed between young and elderly subjects; compared with young subjects, elderly subjects had lower mean clearance (31.2 vs 25.1  ml  min⁻¹; 90% CI −11.4 to −0.9; P =0.02) and a trend towards a greater half-life (18.6 vs 21.0  h; 90% CI −0.6 to 5.4; P =0.11). Mean AUC and C _max values were also higher in elderly subjects. No gender differences were noted for weight-adjusted pharmacokinetic variables. Felbamate was less well tolerated in elderly subjects compared with young subjects, as shown by higher rates of adverse event reporting and dropouts at the higher dose level. This may be due to age-related pharmacokinetic differences, to the rapid dose titration schedule used in this study, and/or to altered sensitivity to felbamate's pharmacodynamic effects.
Conclusions These findings imply that elderly subjects require lower initial dosing and slower dose titration of felbamate than non-elderly subjects.     

Effects of felbamate on brain polyamine changes following transient cerebral ischemia in the Mongolian gerbil

We sought to determine whether treatment with felbamate was capable to reduce the accumulation of putrescine induced by transient forebrain ischemia in the Mongolian gerbil. Gerbils underwent 10 min ligation of common carotid arteries followed by recirculation. Immediately after the release of the arterial occlusion, felbamate (75 and 150 mg kg(-1) i.p.) was administered. Putrescine and polyamine levels were measured in hippocampus and striatum at 1, 8, 24 and 48 h after recirculation. Putrescine levels appeared enhanced already 8 h after the release of the arterial occlusion and kept increasing up to 48 h in the hippocampus and striatum. No significant changes in spermidine levels during recirculation were detected. Conversely, spermine appeared to decrease in the hippocampus while it did not show changes in the striatum. Felbamate significantly reduced the ischemia induced changes in putrescine brain content only at the dose of 150 mg kg(-1) i.p.     

An assessment of rufinamide as an anti-epileptic in comparison with other drugs in clinical development

This article evaluates rufinamide, a new anti-epileptic drug (AED) in Phase III development. This review is done against the background of therapeutic challenges of epilepsy, old established AEDs, newly introduced AEDs and AEDs in clinical development. Pharmacological properties of 12 AEDs in clinical trials (Phases I - III) are compared: ADCI, AWD 131-138, DP-VPA, ganaxolone, levetiracetam, losigamone, pregabalin, remacemide hydrochloride, retigabine, rufinamide, soretolide and TV1901. One of these, levetiracetam has been approved in the USA and is waiting approval in other countries. The protective index of rufinamide, as shown in rodent models of epilepsy, is much higher than that of most common AEDs. Features which make it a desirable AED are: (i) a broad spectrum of anti-epileptic actions including both partial and symptomatic generalised epilepsy; (ii) a statistically significant reduction in seizure frequency in clinical trials; (iii) efficacy and safety shown in a broad range of age groups including children and the elderly; (iv) rapid oral absorption enabling quick titration to effective dose and (v) a benign adverse event profile. Most of the events did not lead to discontinuation in clinical trials. These features offer considerable advantages over the existing anti-epileptic drugs. It is one of the two drugs in development which have reached Phase III and is expected to be approved by the year 2001 - 2002.     

Changes in somatosensory evoked potentials following forebrain ischemia in the gerbils: effects of felbamate

Somatosensory evoked potentials (SEPs) as well as change following transient cerebral ischemia in the gerbil were characterized in this study. SEPs were measured in each gerbil before ischemia (day -1), during ischemia, 10 min, 2, 4, 8, 24, 48 h and 8 days after recirculation. During bilateral carotid occlusion, SEP amplitude was dramatically reduced and central conduction time was significantly increased. During recirculation these values showed an improvement when compared to ischemic but not to control values. Moreover at 8 days of recirculation they were still statistically different from control values. Felbamate administration at the dose of 150 mg kg(-1), immediately after recirculation was shown to ameliorate neurophysiological recovery following cerebral ischemia.