盐酸美金刚胶囊人体药代动力学研究

目的：进行健康志愿者盐酸美金刚胶囊单次和多次口服的药代动力学研究。方法：采用高效液相色谱串联质谱法测定美金刚血浓度,以DAS2.0计算其药代动力学参数。结果：盐酸美金刚胶囊5、10和15 mg单次口服,美金刚药代动力学参数tmax为（5.6±1.2）、（5.2±2.0）和（4.9±1.1）h;Cmax为（4.4±0.9）、（8.9±1.6）和（16.5±2.8）ng/mL;t1/2为（47±10）、（47±9）和（51±9）h。10 mg多次口服,美金刚药代动力学参数tmax为（6.0±1.4）h,Cmax为（31.8±6.0）ng/mL,t1/2为（46±8）h。结论：美金刚单次给药,Cmax和AUC有良好剂量相关性;多次给药可发生蓄积。     

Pre-ischemic treatment with memantine reversed the neurochemical and behavioural parameters but not energy metabolites in middle cerebral artery occluded rats

In the present study, Memantine (MN) an uncompetitive N-methyl-d-aspartate (NMDA) open channel blocker has been investigated for its suitable therapeutic time-window on the basis of its influence on behavioural and biochemical changes in rats subjected to transient focal ischemia. MN (20 mg/kg, ip) was administered at pre, during and post ischemic state and the extent of neuroprotection was compared to ascertain its therapeutic time-window in stroke treatment. Neuroprotective effect was assessed by measuring glutamate, glutamine synthetase, glutathione, Na⁺K⁺ATPase, adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NAD), lactate and pyruvate levels. Middle cerebral artery occlusion produced neurological deficits, anxiogenic behaviour, histological changes, increased glutamate levels along with depletion of Na⁺K⁺ATPase, energy stores such as ATP, NAD, lactate, and antioxidant glutathione. MN significantly restored glutamate, glutamine synthetase, Na⁺K⁺ATPase and lactate levels on preischemic administration. In addition, MN reversed the altered neurological and behavioural paradigms significantly and prevented the neurodegeneration on preischemic treatment. However, it failed to exert any effect on energy metabolite (ATP and NAD) levels irrespective of the treatment phase. Based on the present data, it is summarized that the suitable therapeutic time window of MN is preischemic phase in stroke and it possesses only a subjective role in reversing ischemic brain biochemical alterations preferentially in favor of neuronal homeostasis.     

Cognitive effects of memantine in postmenopausal women at risk of dementia: a pilot study

Background – To determine the effects of memantine on cognition in a normal population of postmenopausal women with putative risk factors for Alzheimer’s disease (AD) using a built‐in control for the genetic risk factor for AD (apoE‐?4 status). Methods – A prospective, open‐label, 6‐month pilot medication trial with memantine and follow‐up after discontinuance conducted at the Center for Neuroscience in Women’s Health, Stanford University School of Medicine. Neuropsychological data were collected on 22 community‐dwelling postmenopausal women (11 apoE‐?4 carriers and 11 apoE‐?4 non‐carriers) with at least one putative risk factor for AD. Results – ApoE‐?4 status was not a significant predictor of change in neuropsychological performance. Changes associated with memantine treatment for entire sample included significant declines in some variables associated with verbal learning and memory that improved upon medication withdrawal. A positive medication effect was noted with executive functions and possibly category fluency. Trend‐level improvements were seen in motor dexterity of the non‐dominant hand and maintained even after drug discontinuance. Conclusions – Treatment with memantine appeared to have differential effects on cognitive performance in a population of women with putative risk factors for AD. ApoE‐?4 carrier status did not account for observed changes in cognition.     

Effect of memantine on CBF and CMRO2 in patients with early Parkinson's disease

Objectives –  Parkinson's disease (PD) may be associated with increased energy metabolism in overactive regions of the basal ganglia. Therefore, we hypothesized that treatment with the N -methyl- d -aspartate receptor (NMDAR) antagonist memantine would decrease regional cerebral blood flow (rCBF) and oxygen metabolism in the basal ganglia of patients with early-stage PD.
Methods –  Quantitative positron emission tomography (PET) recordings were obtained with [¹⁵O]water and [¹⁵O]oxygen in 10 patients, scanned first in a baseline condition, and again 6 weeks after treatment with a daily dose of 20 mg memantine. Dynamic PET data were analyzed using volume of interest and voxel-based approaches.
Results –  The treatment evoked rCBF decreases in basal ganglia, and in several frontal cortical areas. The regional cerebral metabolic rate of oxygen (rCMRO₂) did not decrease in any of the a priori defined regions, and consequently the oxygen extraction fraction was increased in these regions. Two peaks of significantly decreased rCMRO₂ were detected near the frontal poles in both hemispheres, using a posteriori voxel-based analysis.
Conclusions –  Although we did not find the predicted decrease in basal ganglia oxygen consumption, our data suggest that treatment with memantine actively modulates neuronal activity and/or hemodynamic response in basal ganglia of PD patients. This finding may be relevant to the putative neuroprotective properties of NMDAR antagonists.     

Improvement in behavioural symptoms in patients with moderate to severe Alzheimer's disease by memantine: a pooled data analysis

INTRODUCTION: Behavioural disturbances are a common and distressing aspect of Alzheimer's disease (AD). This pooled analysis evaluated the specific benefits of memantine on behavioural disturbances in patients with moderate to severe AD. METHODS: Data were pooled from six 24/28-week, randomised, placebo-controlled, double-blind studies. Of the 2,311 patients included in these studies, 1,826 patients with moderate to severe AD (MMSE <20) were included in this analysis, corresponding to the extended indication for memantine in Europe. In this subgroup, 959 patients received memantine 20 mg/day and 867 received placebo. Behavioural symptoms were rated using the Neuropsychiatric Inventory (NPI) total and single-item scores at weeks 12 and 24/28. RESULTS: At weeks 12 and 24/28, ITT analysis demonstrated that memantine treatment produced statistically significant benefits over placebo treatment in NPI total score (p=0.001 and p=0.008), and in NPI single items: delusions (p=0.007 week 12, p=0.001 week 24/28), hallucinations (p=0.037 week 12), agitation/aggression (p=0.001 week 12, p=0.001 week 24/28), and irritability/lability (p=0.005 week 24/28), LOCF population. Analysis of the patients without symptoms at baseline indicated reduced emergence of agitation/aggression (p=0.002), delusions (p=0.047), and disinhibition (p=0.011), at week 12, and of agitation/aggression (p=0.002), irritability/lability (p=0.004), and night-time behaviour (p=0.050) at week 24/28 in those receiving memantine. OC analyses yielded similar results. CONCLUSIONS: The data suggest that memantine is effective in treating and preventing the behavioural symptoms of moderate to severe AD. Specific persistent benefits were observed on the symptoms of delusions and agitation/aggression, which are known to be associated with rapid disease progression, increased caregiver burden, early institutionalisation, and increased costs of care.     

Memantine agonist action at dopamine D2High receptors

Memantine is reported to improve symptoms in moderate cases of Alzheimer's disease and Parkinson's disease, but is also known to trigger psychosis in some Parkinson patients. Because these clinical features suggested a possible dopamine component of memantine action, we measured the potency of memantine on the functional high-affinity state of dopamine D2 receptors, or D2(High). Using [(3)H]domperidone to label D2 receptors, the memantine dissociation constant at D2(High) was 917 +/- 23 nM for rat striatal D2 receptors and 137 +/- 19 nM for human cloned D2Long receptors. The memantine dissociation constant for striatal N-methyl-D-aspartate (NMDA) receptors labeled by [(3)H]MK 801 was 2200 +/- 400 nM. Memantine stimulated the incorporation of [(35)S]GTP-gamma-S into D2-expressing Chinese Hamster Ovary cells with a dissociation constant of 1200 +/- 400 nM. Memantine, between 200 and 2000 nM, directly acted on D2(High) to inhibit the release of prolactin from isolated anterior pituitary cells in culture. Because the memantine potencies at NMDA receptors and dopamine D2(High) receptors are of a similar order of magnitude, it is likely that the clinical features of memantine can be attributed to its action at both types of receptors.     

美金刚对比多奈哌齐治疗帕金森病痴呆的Meta分析

目的 系统评价美金刚对比多奈哌齐治疗帕金森病痴呆的疗效与安全性。方法 检索中国学术期刊全文数据库（CNKI）、万方数据库（Wanfang Data）、维普中文期刊全文数据库（VIP）和中国生物医学文献数据库（SinoMed）、Cochrane Library、PubMed、Web of Science等数据库自建库起至2022年7月1日收录的有关美金刚、多奈哌齐分别联合多巴丝肼治疗帕金森病痴呆的临床随机对照试验（RCT）。评估偏倚风险,并收集患者治疗后的简易精神状态量表（MMSE）评分、蒙特利尔认知评估量表（MoCA）评分变化情况,临床总有效率及不良反应发生率,采用RevMan5.3软件进行Meta分析。结果 共纳入14项RCTs,总计1219名患者,其中美金刚联合多巴丝肼组610例、多奈哌齐联合多巴丝肼组609例。Meta分析结果显示,美金刚联合多巴丝肼在改善MMSE评分、改善MoCA评分、提高临床总有效率方面效果均优于多奈哌齐联合多巴丝肼,其差异有统计学意义（P＜0.05）;美金刚对比多奈哌齐治疗帕金森病痴呆的不良反应发生率更低。结论 美金刚对帕金森病痴呆患者的认知功能改善效果优于多奈哌齐,临床总有效率更高,且治疗后不良反应发生率低。     

Novel regimen through combination of memantine and tea polyphenol for neuroprotection against brain excitotoxicity

NMDA receptors are abundant, ubiquitously distributed throughout the brain, fundamental to excitatory neurotransmission, and critical for normal CNS function. However, excessive glutamate overstimulates NMDA receptors, leading to increased intracellular calcium and excitotoxicity. Mitochondrial dysfunction associated with loss of Ca(2+)homeostasis and enhanced cellular oxidative stress has long been recognized to play a major role in cell damage associated with excitotoxicity. In this experiment, we attempted to explore whether treatment with memantine (an NMDA receptor antagonist) and tea polyphenol (an antioxidant and anti-inflammatory agent), either alone or in combination, is effective in neuroprotection in a mouse excitotoxic injury model. Memantine (10 mg/kg/day), tea polyphenol (60 mg/kg/day), or a combination (memantine 5 mg/kg/day plus tea polyphenol 30 mg/kg/day) was administered by oral gavage for 2 consecutive days before causing excitotoxic injury. Mice received a 0.3-microL NMDA [335 mM (pH 7.2)] injection into the left striatum. Locomotor activity was assessed 24 hr before and after excitotoxic injury. Brain synaptosomes were harvested 24 hr after excitotoxic injury for assessment of Na(+), K(+)-ATPase and Mg(2+)-ATPase activity, reactive oxygen species production, mitochondrial membrane potential (Delta Psi m), mitochondrial reductase activity (MTT test), and Ca(2+)concentration. The results showed that treatment with memantine could significantly rescue mitochondrial function by attenuating the decreased mitochondrial membrane potential (Delta Psi m) and mitochondrial reductase activity in mouse excitotoxic injury. Treatment with tea polyphenol could significantly decrease the increased production of synaptosomal reactive oxygen species (ROS) and thus reduced the deteriorative ROS-sensitive Na(+), K(+)-ATPase and Mg(2+)-ATPase activity. However, neither memantine nor tea polyphenol alone could significantly improve the impaired locomotor activity unless treatment was combined. Combined treatment with memantine and tea polyphenol could significantly protect mice against excitotoxic injury by reducing the increased synaptosomal ROS production, attenuating the decreased Na(+), K(+)-ATPase and Mg(2+)-ATPase activity, the mitochondrial membrane potential (Delta Psi m), the mitochondrial reductase activity, and the increased synaptosomal Ca(2+)concentration. In addition, the impairment in locomotor activity was also significantly improved. Therefore, the combined treatment of memantine and tea polyphenol is more effective in neuroprotection than either memantine or tea polyphenol alone in mouse excitotoxic injury. These findings provide useful information about the potential application of memantine and tea polyphenols in preventing clinical excitotoxic injury such as brain trauma, brain ischemia, epilepsy, and Alzheimer's disease.     

The Treatment of Cognitive Impairment Associated with Parkinson's Disease

Cognitive impairment and dementia associated with Parkinson''s disease (PD) are common and often have devastating effects upon the patient and their family. Early cognitive impairment in PD is frequent, and the functional impact may be underestimated. Optimal management will rely upon better identification of the predominant symptoms and greater knowledge of their pathophysiological basis. The management of dementia in PD (PD‐D) also has to consider the significant neuropsychiatric burden that frequently accompanies the cognitive decline, as well as fluctuations in attention. Atypical anti‐psychotics have a limited role at present in treating PD‐D, although new drugs are under development. The mainstay of drug management for people with PD‐D is cholinesterase inhibitors, although recent trials have suggested that the N‐methyl‐D aspartate antagonist memantine may also have some benefit. Disease modification remains the ultimate goal for preventing the inexorable decline in PD‐D, although effective interventions are still some way off. Limited benefit may, however, be possible through exercise programmes and so‐called “medical foods”, although randomised trials are required to confirm largely anecdotal observations.