Identification of responders and reactive domains to rivastigmine in Alzheimer's disease

PURPOSE: Presently, it is unclear which patients suffering from Alzheimer's Disease (AD) respond to rivastigmine and if rivastigmine acts on specific cognitive domains. The aims of this study are thus to investigate treatment effects of rivastigmine on specific cognitive domains and to find possible responsive subpopulations to rivastigmine cognitive effects. METHODS: Mini Mental State Examination (MMSE) and Cambridge Cognitive Examination (CAMCOG) were administered at baseline and after 6 months in 83 rivastigmine users and 96 historical controls, representing natural decline. Treatment effects on different subsections of the CAMCOG and in different subpopulations were investigated by linear regression analyses. RESULTS: Rivastigmine showed effectiveness on total CAMCOG (p < 0.001), CAMCOG non-memory subsection (p < 0.001) and subscales of language (p = 0.002), attention/calculation (p = 0.043), abstract thinking (p < 0.001) and perception (p = 0.031). In patients with baseline MMSE < or =19 rivastigmine showed significant and favourable effects compared to historical controls on total CAMCOG (p < 0.001) and both non-memory (p < 0.001) and memory subsections (p = 0.002). CONCLUSION: Rivastigmine showed primarily effectiveness on the non-memory section of the CAMCOG and patients with a baseline MMSE < or = 19 appeared to show greater responses to rivastigmine compared to patients with baseline MMSE > or = 20.     

A non-comparative assessment of tolerability and efficacy of duloxetine in the treatment of depressed patients with Parkinson's disease

Objective: Depression is a comorbidity affecting quality of life (QoL) in patients with Parkinson's disease (PD) and requires appropriate treatment. This study evaluated the tolerability, safety, and efficacy of duloxetine 60 mg once daily for 12 weeks in PD patients with major depressive disorder (MDD).

Research and design methods: Non-comparative, open-label, multi-center study.

Main outcome measures: Tolerability was evaluated by discontinuation rate (acceptable if ≤ 19%) due to treatment-emergent adverse events (TEAEs) and motor symptoms (UPDRS). Safety measures were TEAEs, the UKU side effect rating scale, vital signs, weight, laboratory tests, and ECG. Efficacy measures included HAMD-17, BDI, CGI-S, PGI-I, and pain VAS. QoL was measured by PDQ-39.

Results: Of the 151 patients enrolled, 8.6% (95% upper CI: 13.3%) discontinued the study due to TEAEs. Worsening in PD-related tremor and rigidity was not observed, activities of daily living significantly improved and UKU subscales progressively decreased. Clinically significant abnormalities in laboratory findings were limited to four cases of hypercholesterolemia and one increase of total bilirubin, CPK, and fasting glucose. Blood pressure, weight, and ECG did not change from baseline. HAMD-17 and PDQ-39 total score and individual domains, BDI, CGI-S, and PGI-I total scores significantly improved.

Conclusions: Duloxetine seems well tolerated and likely effective in the treatment of depression associated with PD, with no detrimental effects in PD signs and symptoms.     

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。     

Effect of age on response to rivastigmine or donepezil in patients with Alzheimer's disease

ABSTRACT

Background: Younger Alzheimer's disease (AD) patients appear to differ genetically and neuropathologically from older AD patients, and may experience a more aggressive disease course compared with older patients. A randomised trial investigated the efficacy and tolerability of rivastigmine, an inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and donepezil, an AChE-selective inhibitor, in patients with AD over a 2-year period. This retrospective analysis investigated whether younger and older patients showed differential tolerability and efficacy responses to cholinesterase inhibitor treatment.

Methods: For the current analysis, patients were divided according to age at baseline: those aged < 75 years and those aged ≥ 75 years. Efficacy measures were the Severe Impairment Battery (SIB), Neuropsychiatric Inventory (NPI), Global Deterioration Scale (GDS), Mini-Mental State Examination (MMSE) and the AD Cooperative Study Activities of Daily Living scale (ADCS‐ADL). Changes in efficacy parameters and adverse event frequencies were calculated for rivastigmine and donepezil-treated patients in both age groups. Exploratory analyses were also conducted on SIB, ADCS‐ADL and NPI in patients who consented to pharmacogenetic testing at baseline. Genotyping of the apolipoprotein E (APOE) ε4 allele and the BuChE K-variant was conducted using the TaqMan assay. Main efficacy analyses were based on an intent-to-treat last observation carried forward (ITT‐LOCF) population.

Results: Of the 994 patients who received the study drug, 362 (36.4%) were younger than 75 years and 632 (63.6%) were aged 75 years or over. Rivastigmine provided significant benefits in younger patients compared with donepezil on the NPI‐10, NPI‐12, NPI‐D, GDS and ADCS‐ADL (all p < 0.05, ITT‐LOCF). With the exception of the NPI‐D in favour of donepezil (?p < 0.05, ITT‐LOCF), no significant treatment differences were observed in older patients. Younger patients with two wild-type BuChE alleles had a significantly greater response to rivastigmine than donepezil on the ADCS‐ADL (?p < 0.01, ITT‐LOCF) and SIB (?p < 0.05, ITT‐LOCF). The most common adverse events were nausea and vomiting and these were more frequent in rivastigmine-treated patients.

Conclusion: In this sub group analysis, patients younger than 75 years of age showed greater treatment responses to rivastigmine than donepezil. Analysis of response by BuChE genotype suggests that this differential effect may be due to the inhibition of BuChE, in addition to AChE, by rivastigmine.     

Effect of rivastigmine in the treatment of behavioral disturbances associated with dementia: review of neuropsychiatric impairment in Alzheimer's disease

ABSTRACT

Cognitive decline is conventionally regarded as the defining clinical symptom of Alzheimer's disease (AD), but behavioral and neuropsychiatric symptoms are also present throughout the course of the disease. In fact, behavioral symptoms may appear before cognitive decline is diagnosed. The presence of these symptoms may predict an increasing need for community-based services or even nursing home placement. The characteristic behavioral and neuropsychiatric symptoms associated with AD may be related to the same pathophysiology that underlies the cognitive abnormalities. AD is characterized by a loss of cholinergic neurons as well as by the presence of neurofibrillary tangles (NFTs) and senile plaques in brain regions with cholinergic deficits, resulting in a deficiency in acetylcholine (ACh) in areas of the brain that modulate cognition, behavior, and emotion. Cholinesterase inhibitors are thought to augment or maximize the concentration of ACh in the synaptic cleft. Rivastigmine is a dual inhibitor of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), enzymes involved in hydrolysis of ACh. Literature searches using MEDLINE and EMBASE databases were performed to identify studies of rivastigmine (through August 2005) that assessed neuropsychiatric aspects of AD. Rivastigmine has been demonstrated to be safe and effective in stabilizing or improving the cognitive symptoms of AD in 3 large, well-controlled, randomized clinical trials, which also demonstrated that rivastigmine improves overall global functioning. Smaller studies and meta-analyses of pooled data from the 3 large trials have suggested that rivastigmine may improve the behavioral and neuropsychiatric symptoms associated with AD.     

Potential of ezetimibe in memory deficits associated with dementia of Alzheimer's type in mice

Background:

High cholesterol levels have been positively correlated with a higher incidence of memory impairment and dementia.

Aim:

The study was undertaken to investigate the potential of the lipid-lowering drug, ezetimibe, in memory deficits associated with dementia of Alzheimer''s (AD) type in mice.

Methods:

Dementia was induced with chronic administration of a high-fat diet (HFD) or intracebroventricular streptozotocin (ICV STZ, two doses of 3 mg/kg) in separate groups of animals. The memory of the animals was assessed by employing a Morris water maze. Brain thio barbituric acid-reactive species and reduced glutathione levels were measured to assess the total oxidative stress. Brain acetyl cholinesterase (AChE) activity and total serum cholesterol levels were also measured.

Results:

STZ/HFD produced a significant impairment of memory along with an increase in brain AChE activity and oxidative stress. HFD mice also showed an increase in cholesterol levels. Ezetimibe (10 mg/kg, orally for 15 days) significantly attenuated STZ/HFD-induced memory deficits and biochemical changes. It also prevented HFD-induced rise in the cholesterol level.

Conclusions:

The memory-restorative effect of ezetimibe can be attributed to its cholesterol-dependent as well as cholesterol-independent effects. The study highlights the potential of ezetimibe in memory dysfunctions associated with dementia of AD.     

Double-blind,placebo controlled study of acetyl-l-carnitine in patients with Alzheimer's dementia

Summary

A randomized, double-blind, placebo-controlled, parallel-group clinical trial was carried out to compare 24-week periods of treatment with I gacetyl-l-carnitine twice daily and placebo in the treatment of patients with dementia of the Alzheimer type. A total of 36 patients entered the trial, of whom 20 patients (7 active, 13 placebo) completed the full 24 weeks. Whilst several of the efficacy indices showed little change in either group during the trial, there was an apparent trend for more improvement in the acetyl-l-carnitine group in relation to the Names Learning Test and a computerized Digit Recall Test, both related to aspects of short-term memory. Similarly, there was a trend for reaction time in the computerized classification test to show less deterioration in the active treatment group. Changes within groups, and changes between groups, failed to reach statistical significance, at least partially because of the small number of patients available for analysis. Two indices of overall therapeutic benefit showed a trend for less deterioration in the active-treatment group than in the placebo group. Nausea and/or vomiting occurred in 5 patients in the acetyl-l-carnitine group. Laboratocy tests revealed no signs of drug toxicity. The results suggest that acetyl-l-carnitine may have a beneficial effect on some clinical features of Alzheimer-type dementia, particularly those related to short-term memory.     

Role of GPR40 in pathogenesis and treatment of Alzheimer's disease and type 2 diabetic dementia

Abstract

G-protein coupled receptor 40 (GPR40) is also known as free fatty acid receptor 1. It is a typical 7 transmembrane receptor and currently the natural receptor of the saturated or unsaturated long-chain fatty acids. It could trigger the intracellular signalling pathway when combined with the free long-chain fatty acids, thereby controlling cells physiological function. In this review, we summarised the relationships and the potential mechanisms between the promising target GPR40, and pathogenesis and treatment of Alzheimer's disease and type 2 diabetic dementia. It may provide a theoretical reference for the development of clinical drug targeting GPR40.     

Outcomes of Alzheimer's disease therapy with acetylcholinesterase inhibitors and memantine

Introduction: Alzheimer's disease (AD) is a world-wide health problem with implications for an increasing number of people and countries. Populations suffering from AD financially strain the healthcare budgets of rich and poor countries alike. Moreover, no effective treatment is available and current drugs merely slow the progression of cognitive function deterioration and overall health status toward an inevitable end point. An increasing number of novel approaches have been tested in numerous clinical trials, but none of them has proved safe and effective for treating AD.

Areas covered: This review summarizes all currently available compounds (donepezil, rivastigmine, galantamine, memantine) for the management of AD, concentrating on clinical aspects such as the mechanisms of action, pharmacokinetics, pharmacodynamics and clinical trials. This review also considers the mechanisms and side effects to provide perspective on current treatment options.

Expert opinion: Novel approaches in the treatment of AD are being intensively tested, but so far without any major success. Patients diagnosed with AD still mostly benefit from four compounds to significantly improve cognition functions and overall health and help manage other symptoms or even prolong the symptom-free period.     

白藜芦醇治疗阿尔茨海默病的研究进展

神经退行性疾病是一种慢性进展性疾病,其特点是中枢神经系统神经元的逐渐丧失。由于血脑屏障的存在,经典的抗炎药物如类固醇激素和非甾体类抗炎药,对神经系统疾病的治疗作用有限。因此,开发新的抗炎药物,对于预防和治疗神经系统疾病具有重要的意义。白藜芦醇是一种有很强活性的天然多酚类物质,目前研究已显示其具有心血管保护、神经保护、免疫调节、肿瘤的化学预防作用。近年来还发现其具有抗神经炎症作用,可用于治疗神经精神性疾病,如帕金森病、阿尔茨海默病(AD)和亨廷顿症等。综述白藜芦醇对AD的保护作用及其机制研究进展,为进一步推进白藜芦醇用于防治AD的研究提供参考。     

Rotigotine transdermal delivery for the treatment of Parkinson's disease

Background: Rotigotine is a non-ergot dopamine agonist that has been developed as a new transdermal formulation, and is indicated for use in early (USA and Europe) and advanced (Europe only) Parkinson's disease (PD). The potential advantages of the rotigotine patch include immediacy of effect onset as intestinal absorption in unneeded, constant drug delivery, and ease of use via application of a once-daily adhesive patch. An interesting element of this profile is constant drug delivery, which may avoid pulsatile dopaminergic stimulation, which has been postulated to be related to the development of motor complications. Objective: To consider the evidence surrounding the profile of rotigotine and, in particular, whether its constant delivery system offers significant benefits to the treatment of early and advanced PD. Methods: Source material was identified using a PubMed search for the term ‘rotigotine’ (up to March 2008). The review focuses only on publications related to the rotigotine indication for PD. Results/conclusion: The rotigotine transdermal patch demonstrates clinical efficacy, alongside a tolerability profile that appears to be well within the range of that observed with other non-ergot dopamine agonists. The once-daily patch formulation may favour compliance but, in similarity with the other theoretical advantages of constant drug delivery (for example reduced emergence of motor complications, improved tolerance to peripheral AEs), requires further detailed study.     

A review of compliance to treatment in Alzheimer's disease: potential benefits of a transdermal patch

ABSTRACT

Background: Following prescribed medication regimens is essential for the effective treatment of any medical condition. Unfortunately, patients often fail to follow recommendations, and treatment non-compliance represents a widespread, often underestimated problem, placing tremendous burden on the healthcare system. Compliance in Alzheimer's disease (AD), a chronic neurodegenerative disease typically afflicting older adults, is especially challenging.

Scope: To review factors contributing to poor treatment compliance in AD, considering the prominent role care­givers often play in treatment management; and acknowledging strategic approaches, particularly modern transdermal patches, to improve compliance in this particularly susceptible population. Articles were identified by searching MEDLINE in November 2006 (search limits: 1987–2007) using the terms: compliance; Alzheimer's; treatment; and transdermal. Additional resources included bibliographies of identified articles.

Findings: Strategic approaches to improving treatment compliance include: simplifying treatment regimens, using reminder packaging, and developing more patient- or caregiver-friendly modes of administration. To date, AD therapies have been administered orally. However, recent developments in alternative modes of drug delivery, such as transdermal patches, may offer effective, well-tolerated treatment options with the potential to enhance compliance. A patch containing rivastigmine (Exelon*), an established cholinesterase inhibitor, has been developed and demonstrated to have good efficacy and tolerability in patients with AD. In addition, initial caregiver experience suggests preference for the patch over oral administration.

Conclusion: Transdermal patches may be an effective way to optimize treatment compliance for AD, as well as an increasing number of other chronic conditions that typically afflict the older population, offering the possibility of more sustained clinical benefits.     

Fatigue in Parkinson's disease

Introduction: Non-motor symptoms of Parkinson's disease (PD) have become increasingly recognized as central to the disease. These include somatic symptoms, such as pain and autonomic dysfunction (bladder dysfunction, constipation, dipahoresis and orthostatic hypotension) and behavioral problems, such as dementia, depression, fatigue, sleep disorders and psychosis. Research on fatigue has focused on its epidemiology with only a single report of a beneficial treatment trial, which used methylphenidate.

Areas covered: This review was made of all articles related to fatigue in Parkinson's disease arising in PUBMED. It will cover the types of fatigue, epidemiology, pathophysiology and treatment of fatigue in PD.

Expert opinion: Fatigue is a common and severe problem in Parkinson's disease. Virtually nothing is known about it aside from its epidemiology. It is an area greatly in need of investigation.     

Plasma inositol is not elevated in Alzheimer's disease

Brain inositol levels have been previously reported as elevated in Alzheimer's disease (AD) in brain. Brain inositol levels may be reflected in plasma levels. We therefore studied plasma inositol levels in 20 AD patients and 20 controls. Plasma inositol levels in the AD patients did not differ from values found in the controls. © 1998 John Wiley & Sons, Ltd.     

Skin tolerability of transdermal patches

Introduction: Transdermal patch systems are an effective method of administering active ingredients through the skin, with considerable advantages over other drug delivery routes, for example, maintenance of constant plasma drug levels and avoidance of first-pass metabolism. However, repeated epicutaneous application may be associated with local skin reactions.

Areas covered: This review addresses current issues regarding the effective/safe use of transdermal patch systems, and provides a critical analysis of the addition of ‘skin-caring’ ingredients to patch systems. Effective use of transdermal systems includes choosing an appropriate body area for application, maintaining regular skin care regimens before application and not replacing a patch in the same area (rotation) within 7 days. Another strategy, developed in an attempt to improve the tolerability of transdermal systems, is the addition of assumed ‘skin-caring’ ingredients (e.g., Aloe Vera) to patch systems. However, at present there is neither proof nor clinical evidence of any benefit. On the contrary, plant-derived ingredients might be associated with allergenic potential.

Expert opinion: Transdermal systems are generally well tolerated; physicians must adequately inform patients of the most effective ways to use these formulations for maximum therapeutic benefit, while minimising local adverse events. Skin-caring agents, including Aloe Vera, cannot be recommended until well-controlled clinical trials with standardised extracts are available.     

Progress in acetylcholinesterase inhibitors for Alzheimer's disease: an update

Background: To date, the pharmacotherapy of Alzheimer's disease (AD) has been based on acetylcholinesterase inhibitors (AChEIs), and more recently on an N-methyl-d-aspartate receptor antagonist. By increasing acetylcholine concentration in the brain, AChEIs slow behavioral and functional impairments, improving cognitive function. Objective: The review provides an update on novel analogs of approved AChEIs, their combination with other anti-AD agents, natural AChEIs, and modern multitarget-directed ligands (MTDLs) able to hit different biological targets. Methods: We reviewed patents filed during 2005 – 2007 dealing with new AChEIs and their potential application for AD treatment. We point out new chemical structures and scaffolds for designing new AD therapeutic agents as well as new combinations or MTDLs. Results and conclusions: Compared to the limited number of novel commercially available AChEI analogs, many new natural compounds were patented for AD treatment. These might represent a starting point for the rational design of new MTDLs.