Effects of Rivastigmine Combined with Reinhartdt and Sea Cucumber Capsule in Patients with Mild-to-Moderate Parkinson’s Disease Dementia: A Pilot Study

Many patients with Parkinson’s disease suffer cognitive impairment or dementia. Cholinesterase inhibitors (ChEIs) have positive effects on patients with Parkinson’s Disease Dementia (PDD). But it is only improve symptoms. There is no etiological cure for PDD. So, In order to achieve the best outcomes, the combination of ChEIs and other therapeutic strategies is needed to study.?In the present study, we investigate the efficacy and safety of rivastigmine combined with Reinhartdt and Sea Cucumber Capsule (RSC) in patients with mild-to-moderate PDD, and its effect on thyroid function.?There were 52 patients were randomly assigned to receive either rivastigmine (3 mg/ day) or rivastigmine plus RSC (2.7 g/day) treatment for 24 weeks. Efficacy was investigated by the change of the scores of Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-Cog), Activities of Daily Life (ADL) and Unified Parkinson’s Disease Rating Scale (UPDRS) part III (motor scale). Meanwhile, thyroid hormone levels were detected before and after 12 weeks, 24 weeks treatment in all patients. Results showed that?the patients treated with rivastigmine plus RSC showed more improvement in the cognition and the daily life activities compared to those treated with rivastigmine alone. Significant difference was present after being treated for 12 weeks or more. However, no group difference was found on UPDRS part III, thyroid hormone level change and the incidence of adverse events (11.1% vs 16.0%) between the two groups of treatment. Adverse effects were nausea and vomiting which were the main reasons for the dropout. The finding suggests that Rivastigmine plus RSC may improves the treatment effects in cognition and the ADL of the patients with mild-to-moderate PDD, compared with the rivastigmine treatment alone. However, no effect was observed on the motor symptoms and thyroid hormone levels. In addition, this joint treatment is safe.

Rivastigmine Restores 5-HT_1AReceptor Levels in the Hippocampus of Olfactory Bulbectomized Mice

Rivastigmine, a dual acetylcholinesterase and butyrylcholinesterase inhibitor, is used for symptomatic treatment of patients with mild to moderately severe dementia in Alzheimer’s disease (AD) patients. In the present study, we found that 5-HT1A receptor (5-HT1AR) is downregulated, whereas 5-HT2A receptor (5-HT2AR) is upregulated in the hippocampal dentate gyrus (DG) and CA1 region by olfactory bulbectomy (OBX) in mice. Furthermore, chronic treatment with rivastigmine (1.0 mg/kg) for 2 weeks starting 2 weeks after OBX operation restored the decreased 5-HT1AR and the increased 5-HT2AR levels. To determine whether cholinergic receptor stimulation by rivastigmine is involved in the rivastigmine-induced regulation of 5-HTR levels, we treated the mice with mecamylamine (2.5 mg/kg), or atropine (5.0 mg/kg) with rivastigmine (1.0 mg/kg) once a day for 2 weeks. Notably, the rivastigmine-induced 5-HT1AR upregulation was eliminated by mecamylamine but not by atropine treatments. On the other hand, the restored 5-HT2AR level by rivastigmine was not affected by either mecamylamine or atropine. Treatment with 8-OH-DPAT, a selective 5-HT1AR agonist improved the decreased 5-HT1AR and the increased 5-HT2AR levels in OBX mice. On the other hand, treatment with TCB-2, a potent 5-HT2AR agonist had no effects on the 5-HT1AR and 5-HT2AR dysregulation in OBX mice. Taken together, nicotinic acetylcholine receptor (nAChR) stimulation mediates rivastigmine-induced upregulation of 5-HT1AR. Therefore, we speculate that the increased ACh levels by rivastigmine can stimulate nAChR located on serotonergic nerve terminals and stimulate 5-HT1AR by the enhanced 5-HT release in the hippocampus. The 5-HT1AR stimulation likely mediates the improvement of 5-HT1AR levels as auto-receptor in OBX hippocampus.

Randomized, Placebo-Controlled Trial of Transdermal Rivastigmine for the Treatment of Encephalopathy in Liver Cirrhosis (TREC Trial)

Objectives: Cognitive dysfunction in patients with hepatic encephalopathy (HE) may be caused by alterations in cholinergic neurotransmission. The objective of the study was to evaluate the efficacy and safety of transdermal rivastigmine in improving cognitive function in patients with overt HE. Design: Randomized, controlled pilot study in which patients with grade 2 or 3 HE were treated with lactulose and randomized to receive either transdermal rivastigmine or placebo for 21 days. The modified encephalopathy scale (MES), object recognition test (ORT), trail test (TT), and serum ammonia were assessed at baseline weekly. Electroencephalography was performed at baseline and the final week of the study. Results: Patients were treated with lactulose (20 g/30 mL three times per day) and either transdermal rivastigmine (4.6 mg/d;n = 15) or placebo (n = 15). Transdermal rivastigmine significantly improved MES, ORT, and TT results compared with placebo (P ≤ 0.0001 at all 3 weeks for all 3 assessments). Serum ammonia improved in both treatment groups, although there was significantly greater improvement with placebo than rivastigmine after 2 weeks of treatment (P What is already known about this subject? ? Current approaches to the management of HE are primarily designed to reduce the levels of ammonia and other gut-derived toxins. ? Traditional strategies for HE treatment have included non-absorbable disaccharides (to decrease bowel transit time) or rifamixin (non-absorbable antibiotics to reduce ammoniogenic flora). ? No transdermal cholinomimetic agents have been used with oral lactulose to date, in HE. What are the new findings? ? Transdermal rivastigmine is safe for use in patients with grade 2 & 3 HE. ? Transdermal rivastigmine in combination with oral lactulose in this study is far superior to lactulose alone in improving cognitive function. How might it impact on clinical practice in the foreseeable future? ? Transdermal rivastigmine in combination with oral lactulose can be used safely in clinical practice. ? Transdermal rivastigmine in combination with oral lactulose is efficacious in improving cognitive function in moderate HE (grade 2/3). Further validation through large randomized clinical trials is required before this is adopted in universal clinical practice of treating HE.

Rivastigmine可有效治疗AIPD

根据一项前瞻性、随机、安慰剂对照临床研究显示，胆碱酯酶抑制剂rivastigmine（I）可显著有效治疗酒精诱导性持续性痴呆（AIPD）且耐受性良好。

Rivastigmine透皮贴剂用于AD

小野公司有意在日本帮助Novartis公司开发和上市阿尔茨海默病（AD）治疗药rivastigmine（Ⅰ）的透皮贴剂。这种乙酰胆碱酯酶抑制剂在日本已处于Ⅱ期试验中，小野公司将协助完成剩下的临床项目以加速开发。这家中等规模的日本公司将获得在日本的共同上市权。（Ⅰ）有望成为第一个用于AD的透皮治疗药物，它可抑制乙酰胆碱酯酶和丁酰胆碱酯酶。这两家公司指出，在AD的疾病进程中丁酰胆碱酯酶的含量是增加的。

Sensitive Method for Enantioseparation of Rivastigmine with Highly Sulfated Cyclodextrin as Chiral Selector by Capillary Electrophoresis

A sensitive method for enantioseparation of a basic drug rivastigmine and determination of its optical impurity by capillary electrophoresis with highly sulfated β-cyclodextrin （HS-β-CD） as the chiral selector is described. In general, enantioseparation of basic chiral compounds is carried out in acidic condition （pH 2.5） to prevent analytes from adsorption on the capillary wall. However, in the case of rivastigmine, the detection sensitivity was too limited to determine the optical impurity of S-rivastigmine lower than 1% when buffer pH was 2.5. It was found that the detection sensitivity was improved 1.6 times just by raising the buffer pH value from 2.5 to 5.8. The poor column efficiency due to the adsorption of the analytes on the capillary wall was resolved by using dynamical coating of the capillary wall with the linear polyacrylamide solution. The experimental parameters such as the concentration of HS-β-CD, buffer pH and buffer ionic strength were optimized, respectively. The method was validated in terms of repeatability, linearity, limit of detection （LOD） and limit of quantitation （LOQ）. Using the present method, the optical purity of nonracemic rivastigmine with the enantiomeric excess （ee） value of 99.14% was determined.

Rivastigmine可能有助于治疗皮层下血管型痴呆

根据一项公开（open-label)研究报道，研制用于治疗阿尔茨海默病的Rivastigmine(Exelon)，同时也对皮层下血管痴呆有益。

Comparative efficacy and safety of cognitive enhancers for treating vascular cognitive impairment: systematic review and Bayesian network meta-analysis

Objective: To assess and compare the clinical efficacy and safety of cognitive enhancers(donepezil, galantamine, rivastigmine, and memantine) on cognition, behavior, function, and global status in patients with vascular cognitive impairment.Data sources: The initial literature search was performed with PubMed, EMBASE, the Cochrane Methodology Register, the Cochrane Central Register of Controlled Trials, and Cumulative Index to Nursing & Allied Health(CINAHL) from inception to January 2018 for studies regarding donepezil, galantamine, rivastigmine, and memantine for treatment of vascular cognitive impairment.Data selection: Randomized controlled trials on donepezil, galantamine, rivastigmine, and memantine as monotherapy in the treatment of vascular cognitive impairment were included. A Bayesian network meta-analysis was conducted. Outcome measures: Efficacy was assessed by changes in scores of the Alzheimer's Disease Assessment Scale, cognitive subscale, Mini-Mental State Examination, Neuropsychiatric Inventory scores and Clinician's Interview-Based Impression of Change Scale Plus Caregiver's Input, Activities of Daily Living, the Clinical Dementia Rating scale. Safety was evaluated by mortality, total adverse events(TAEs), serious adverse events(SAEs), nausea, vomiting. diarrhea, or cerebrovascular accidents(CVAs). Results: After screening 1717 citations, 12 randomized controlled trials were included. Donepezil and rivastigmine(mean difference(e) = –0.77, 95% confidence interval(CI): 0.25–1.32; MD = 1.05, 95% CI: 0.18–1.79) were significantly more effective than placebo in reducing Mini-Mental State Examination scores. Donepezil, galantamine, and memantine(MD = –1.30, 95% CI: –2.27 to –0.42; MD = –1.67, 95% CI: –3.36 to –0.06; MD = –2.27, 95% CI: –3.91 to –0.53) showed superior benefits on the Alzheimer's Disease Assessment Scale–cognitive scores compared with placebo. Memantine(MD = 2.71, 95% CI: 1.05–7.29) improved global status(Clinician's Interview-Based Impression of Change Scale Plus Caregiver's Input) more than the placebo. Safety results revealed that donepezil 10 mg(odds ratio(OR) = 3.04, 95% CI: 1.86–5.41) contributed to higer risk of adverse events than placebo. Galantamine(OR = 5.64, 95% CI: 1.31–26.71) increased the risk of nausea. Rivastigmine(OR = 16.80, 95% CI: 1.78–319.26) increased the risk of vomiting. No agents displayed a significant risk of serious adverse events, mortality, cerebrovascular accidents, or diarrhea.Conclusion: We found significant efficacy of donepezil, galantamine, and memantine on cognition. Memantine can provide significant efficacy in global status. They are all safe and well tolerated.

Acetylcholinesterase inhibitors in cognitive impairment in Huntington's disease: A brief review

Huntington's disease(HD) is a neurodegenerative disease associated with cognitive deficits. Cognitive dysfunction may be present in the early stages of the disease, even before the onset of motor symptoms. The cognitive dysfunction includes executive dysfunction, psychomotor symptoms, visuospatial deficits, perceptual deficits, memory loss and difficulty learning new skills. Acetylcholinesterase inhibitors have shown good effect in the treatment of other types of dementia and it is postulated that it might delay cognitive decline in HD. We reviewed the evidence for Acetylcholinesterase inhibitors in the treatment of cognitive decline and dementia associated with Huntington's disease. We identified 6 articles that investigated the role of Acetylcholinesterase inhibitors for treatment of cognitive deficits in Huntington's disease. Following the review, the authors concluded that there is limited evidence for the use of Acetylcholinesterase inhibitors for cognitive impairment in HD.

Rivasligmine被批准用于新适应证

2006年6月，美国FDA已正式批准Novarfis制药公司的可逆性胆碱酯酶抑制剂——Exelon（通用名为：枸橼酸Rivastigmine）也可用于治疗与帕金森病有关的轻、中度痴呆。虽然该药的此项适应证已在欧洲获得批准，在美国也已被批准用于阿尔茨海默病（早老性痴呆），但目前为止，Exelon还是第一个在美国被批准用于治疗帕金森病痴呆的药物。

魁北克补偿AD经皮贴片

魁北克已成为加拿大第一个能补偿Novartis公司的Exelon贴剂（内含酒石酸rivastigmine的乙酰胆碱酯酶抑制剂）（I）的省份。（I）是获准用于轻、中度阿尔茨海默病（AD）的唯一经皮贴片。

09032 IQWIG肯定胆碱脂酶抑制剂的疗效

德国医药评估局IQWIG有一次在对三个药品进行评估时指出，胆碱脂酶抑制剂（Ⅰ）可以减缓阿尔茨海默病（AD）患者的认知障碍进展。IQWIG评估了多奈哌齐（donepezil，卫材／Pfizer公司的Aricept）、加兰他敏（galantamine，Shire公司的Reminyl）和rivastigmine（Novartis公司的Exelon）。

Efficacy and Safety of Chinese Herbal Medicines Combined with Chemical Drugs for Alzheimer's Disease:A Systematic Review and Meta-Analysis

Objective:To evaluate the efficacy and safety of Chinese herbal medicines(CHMs)combined with chemical drugs for the treatment of Alzheimer's disease(AD).Materials and Methods:Databases were searched to retrieve randomized controlled trials(RCTs)of CHMs combined with tacrine,galantamine,rivastigmine,donepezil,or memantine,following strict inclusion and exclusion criteria.Only research papers published in English,Chinese,and Japanese were considered.The primary outcome was the mini-mental state examination(MMSE)score and the secondary outcomes were AD assessment scale cognitive subscale(ADAS-Cog)score and safety evaluation.Meta-analysis was carried out using Rev Man 5.3 and subgroup analysis was conducted to identify the sources of heterogeneity.Results:A total of 15 RCTs with 1386 participants were included in this study.Only donepezil was used in the retrieved literature.Meta-analyses showed that the combination of CHMs with donepezil led to significant improvement in the MMSE score(Z=9.45;P<0.00001;weighted mean difference[WMD]=2.68,95%confidence interval[CI]:2.12-3.24)and a significant decrease in the ADAS-Cog score(Z=5.53;P<0.00001;WMD=-3.79;95%CI:-5.13--2.44).Safety evaluation demonstrated that these combination treatments relieved adverse events such as insomnia(risk ratio[RR]=0.20,95%CI:0.06-0.68;P=0.01)and hive(RR=0.10;95%CI:0.01-0.73;P=0.02).Conclusions:The combination of CHMs with a chemical drug like donepezil led to significant improvements in patient cognition as well as a better safety profile when compared to the application of a chemical drug alone.

Design, synthesis and evaluation of genistein-polyamine conjugates as multi-functional anti-Alzheimer agents

A series of genistein-polyamine conjugates(4a–4h) were designed, synthesized and evaluated as multi-functional anti-Alzheimer agents. The results showed that these compounds had significant cholinesterases(Ch Es) inhibitory activity. Compound 4b exhibited the strongest inhibition to acetylcholinesterase(ACh E) with an IC_(50) value of 2.75 μmol/L, which was better than that of rivastigmine(5.60 μmol/L). Lineweaver–Burk plot and molecular modeling study showed that compound 4b targeted both the catalytic active site(CAS) and the peripheral anionic site(PAS) of ACh E. Besides, compound 4b showed potent metal-chelating ability. In addition, it was found that 4a–4h did not affect Hep G-2 cell viability at the concentration of 10 μmol/L.

Framework of treating Alzheimer’s dementia

Current treatment paradigm in Alzheimer’s disease(AD)involves multiple approaches combining pharmacological and nonpharmacological intervention to mitigate the clinical symptoms,slow the progressive loss of cognitive and functional abilities,or modify the disease course.So far,beyond anti-cholinesterase inhibitors(ACh EIs),donepezil,rivastigmine,galantamine,and antagonist of N-methyl-D-aspartic acid(NMDA)receptor,there are no newly approved medicines to treat AD.Under pharmacological treatment,the personal characteristic and the intra-individual therapeutic evaluations to examine various cognitive domains,behavioral and psychological problems,and global function should be considered when choosing any of ACh EIs.The use of optimal dosage referring to the expected clinical outcomes and currently reported deficits from patient with AD has become an important issue in clinical treatment.Establishing and maintaining a strong therapeutic alliance to physician,patient,and caregiver is crucial and central to the comprehensive care in AD.