首页 | 本学科首页   官方微博 | 高级检索  
相似文献
 共查询到10条相似文献,搜索用时 46 毫秒
1.
L‐3,4‐dihydroxyphenylalanine (L‐DOPA)‐induced dyskinesia is a complication of dopaminergic treatment in Parkinson's disease. Lowering the L‐DOPA dose reduces dyskinesia but also reduces the antiparkinsonian benefit. A therapy that could enhance the antiparkinsonian action of low‐dose L‐DOPA (LDl) without exacerbating dyskinesia would thus be of considerable therapeutic benefit. This study assessed whether catechol‐O‐methyltransferase (COMT) inhibition, as an add‐on to LDl, might be a means to achieve this goal. Cynomolgus macaques were administered 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine. Dyskinesia was established by chronic treatment with L‐DOPA. Two doses of L‐DOPA were identified – high‐dose L‐DOPA (LDh), which provided good antiparkinsonian benefit but was compromised by disabling dyskinesia, and LDl, which was sub‐threshold for providing significant antiparkinsonian benefit, without dyskinesia. LDh and LDl were administered in acute challenges in combination with vehicle and, for LDl, with the COMT inhibitor entacapone (5, 15 and 45 mg/kg). The duration of antiparkinsonian benefit (ON‐time), parkinsonism and dyskinesia were determined. The ON‐time after LDh was ~170 min and the ON‐time after LDl alone (~98 min) was not significantly different to vehicle (~37 min). In combination with LDl, entacapone significantly increased the ON‐time (5, 15 and 45 mg/kg being ~123, ~148 and ~180 min, respectively). The ON‐time after LDl/entacapone 45 mg/kg was not different to that after LDh. However, whereas the percentage ON‐time that was compromised by disabling dyskinesia was ~56% with LDh, it was only ~31% with LDl/entacapone 45 mg/kg. In addition to the well‐recognized action of COMT inhibition to reduce wearing‐OFF, the data presented suggest that COMT inhibition in combination with low doses of L‐DOPA has potential as a strategy to alleviate dyskinesia.  相似文献   

2.
3.
4.
5.
6.
7.
8.
Purpose: To evaluate safety, tolerability, and seizure outcome data during long‐term treatment with once‐daily adjunctive perampanel (up to 12 mg/day) in patients with refractory partial‐onset seizures. Methods: Study 307 was an extension study for patients completing the double‐blind phase of three pivotal phase III trials (studies 304, 305, and 306). The study consisted of two phases: an open‐label treatment phase (including a 16‐week blinded conversion period and a planned 256‐week maintenance period) and a 4‐week follow‐up phase. Patients were blindly titrated during the conversion period to their individual maximum tolerated dose (maximum 12 mg/day). Adverse events (AEs) were monitored throughout the study and seizure frequency recorded. The interim data cutoff date for analyses was December 1, 2010. Key Findings: In total, 1,218 patients were enrolled in the study. At the interim cutoff date, 1,186 patients were in the safety analysis set; 1,089 (91.8%) patients had >16 weeks of exposure to perampanel, 580 (48.9%) patients had >1 year of exposure, and 19 (1.6%) patients had >2 years of exposure. At the interim analysis, 840 (70.8%) patients remained on perampanel treatment. The large majority of patients (n = 1,084 [91%]) were titrated to 10 mg or 12 mg/day. Median (range) duration of exposure was 51.4 (1.1–128.1) weeks. Treatment‐emergent AEs were reported in 87.4% of patients. The most frequent were dizziness (43.9%), somnolence (20.2%), headache (16.7%), and fatigue (12.1%). Serious AEs were reported in 13.2% of patients. In the intent‐to‐treat analysis set (n = 1,207), the frequency of all seizures decreased over the first 26 weeks of perampanel treatment in patients with at least 26 weeks of exposure to perampanel (n = 1,006 [83.3%]); this reduction was maintained in patients with at least 1 year of exposure (n = 588 [48.7%]). The overall median percent changes in seizure frequency in patients included in each 13‐week interval of perampanel treatment were ?39.2% for weeks 14–26 (n = 1,114), ?46.5% for weeks 40–52 (n = 731), and ?58.1% for weeks 92–104 (n = 59). Overall responder rates in patients included in each 13‐week interval of perampanel treatment were 41.4% for weeks 14–26 (n = 1,114), 46.9% for weeks 40–52 (n = 731), and 62.7% for weeks 92–104 (n = 59). During the blinded conversion period, the reduction in seizure frequency in patients previously randomized to placebo (?42.4%, n = 369) was similar to that in patients previously randomized to perampanel (?41.5%, n = 817). Significance: Consistent with pivotal phase III trials, these interim results demonstrated that perampanel had a favorable tolerability profile in patients with refractory partial‐onset seizures over the longer term. The decrease in seizure frequency was consistent and maintained in those patients over at least 1 year of perampanel exposure.  相似文献   

9.
Parkinson's disease (PD), a progressive neurodegenerative movement disorder, is known to be caused by diverse pathological conditions resulting from dysfunction of the ubiquitin‐proteasome system (UPS), mitochondria, and oxidative stress leading to preferential nigral dopamine (DA) neuron degeneration in the substantia nigra. In the present study, we evaluated the novel D3 receptor‐preferring agonist D‐264 in a mouse model of PD to evaluate its neuroprotective properties against both the nigrostriatal dopaminergic toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐ and the proteasome inhibitor lactacystin‐induced dopaminergic degeneration. C57BL/6 male mice either were given MPTP by intraperitoneal injection twice per day for 2 successive days at a dose 20 mg/kg or were microinjected with lactacystin bilaterally (1.25 μg/side) into the medial forebrain bundle (MFB). Pretreatment with D‐264 (1 mg/kg and 5 mg/kg, intraperitoneally, once per day), started 7 days before administration of MPTP or lactacystin. We found that D‐264 significantly improved behavioral performance, attenuated both MPTP‐ and lactacystin‐induced DA neuron loss, and blocked proteasomal inhibition and microglial activation in the substantia nigra (SN). Furthermore, D‐264 treatment was shown to increase the levels of brain‐derived neurotrophic factor (BDNF) and glial cell line‐derived factor (GDNF) in MPTP‐ and lactacystin‐treated mice, possibly indicating, at least in part, the mechanism of neuroprotection by D‐264. Furthermore, pretreatment with the D3 receptor antagonist U99194 significantly altered the effect of neuroprotection conferred by D‐264. Collectively, our study demonstrates that D‐264 can prevent neurodegeneration induced by the selective neurotoxin MPTP and the UPS inhibitor lactacystin. The results indicate that D‐264 could potentially serve as a symptomatic and neuroprotective treatment agent for PD. © 2010 Wiley‐Liss, Inc.  相似文献   

10.
Purpose: 2‐Deoxy‐d ‐glucose (2‐DG), a glucose analog that accumulates in cells and interferes with carbohydrate metabolism by inhibiting glycolytic enzymes, has anticonvulsant actions. Recognizing that severe glucose deprivation can induce seizures, we sought to determine whether acute treatment with 2‐DG can promote seizure susceptibility by assessing its effects on seizure threshold. For comparison, we studied 3‐methyl‐glucose (3‐MG), which like 2‐DG accumulates in cells and reduces glucose uptake, but does not inhibit glycolysis. Methods: Mice were treated with 2‐DG or 3‐MG and the seizure threshold determined in the 6‐Hz test, the mouse electroshock seizure threshold (MEST) test, and the intravenous pentylenetetrazol (i.v. PTZ) or kainic acid (i.v. KA) seizure threshold tests. 2‐DG was also tested in fully amygdala‐kindled rats. Results: 2‐DG (125–500 mg/kg, i.p., 30 min before testing) significantly elevated the seizure threshold in the 6‐Hz seizure test. 2‐DG (250–500 mg/kg) decreased the threshold in the MEST and i.v. PTZ and i.v. KA tests. 3‐MG had no effect on seizure threshold in the 6‐Hz test but, like 2‐DG, decreased seizure threshold in the i.v. PTZ test. 2‐DG (250 and 500 mg/kg, i.p., 30 min before testing) had no effect on amygdala‐kindled seizures. Conclusions: Although 2‐DG protects against seizures in the 6‐Hz seizure test, it promotes seizures in some other models. The proconvulsant action may relate to reduced glucose uptake, whereas the anticonvulsant action may require inhibition of glycolysis and shunting of glucose metabolism through the pentose phosphate pathway.  相似文献   

设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号