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Small G.,University of California at Los Angeles | Bullock R.,Kingshill Research Center
Alzheimer's and Dementia | Year: 2011

Despite growing recognition that Alzheimer's disease (AD) represents a global public health and social care crisis, diagnosis is frequently slow and many patients still receive no treatment at all. Of those who do receive treatment, many remain on lower than recommended doses. The Alzheimer's disease International Global Charter promotes awareness and understanding of AD, stressing the importance of optimal treatment. However, the definition of "optimal treatment" is unclear. Since cholinesterase inhibitors became available nearly 20 years ago, clinicians have developed a variety of protocols on the basis of clinical experiences. This review considers what is optimal for several aspects of cholinesterase inhibitor therapy, taking into account initiation strategies, dosages, modes of drug delivery (e.g., oral vs. transdermal), and treatment durations. Regardless of management approach, individuals with AD, their families, and caregivers have a right to a timely diagnosis and access to best available treatment. © 2011 The Alzheimer's Association. All rights reserved.

Emre M.,Istanbul University | Bernabei R.,Catholic University of the Sacred Heart | Blesa R.,Hospital de la Sta Creu i Sant Pau | Bullock R.,Kingshill Research Center | And 12 more authors.
CNS Neuroscience and Therapeutics | Year: 2010

Cholinesterase inhibitors constitute one of the mainstays of treatment of Alzheimer disease (AD). Gastrointestinal side effects, difficulty accessing therapeutic doses and poor patient compliance have been identified as barriers to effective treatment with these substances. The rivastigmine transdermal patch provides continuous delivery of drug through the skin into the bloodstream, avoiding the fluctuations in plasma concentration associated with oral administration. This pharmacokinetic profile is associated with reduced side effects, resulting in easier access to expected target doses. These benefits, along with other practical advantages of the transdermal patch, may contribute to enhanced patient compliance. Here, we present a review of the current literature on rivastigmine patch, and offer advice based on our own collective clinical experience. Rivastigmine patch provides an efficient option for managing patients with AD, to be considered among the first line therapies for the disease. © 2010 Blackwell Publishing Ltd.

Baker N.L.,Pfizer | Cook M.N.,Pfizer | Arrighi H.M.,LLC Epidemiology | Bullock R.,Kingshill Research Center
Age and Ageing | Year: 2011

Background: hip fractures result in a significant burden to the patient, their caregivers and the health care system. Patients with Alzheimer's disease (AD) have a higher incidence of hip fracture compared with other older people without AD, although it is not clear if AD is an independent risk factor for hip fracture. Methods: a retrospective cohort study was conducted using anonymised electronic medical records from primary care practices in the United Kingdom. Proportional hazards regression modelling with adjustment for potential confounders was used to evaluate AD as an independent risk factor for predicting hip fractures. Results: the incidence of hip fracture among patients with and without AD was 17.4 (95% CI, 15.7-19.2) and 6.6 (95% CI, 5.8-7.6) per 1,000 person years, respectively. Patients with AD had a hazard that was 3.2 (95% CI, 2.4-4.2) times that of non-AD patients after controlling for potential confounders. AD patients who experienced a hip fracture also had an increased mortality rate compared with non-AD patients who experienced a hip fracture (hazard ratio = 1.5; 95% CI, 1.1-1.9). Conclusion: patients with AD and their caregivers should be advised on how to prevent hip fractures and more attention should be given to AD patients who are undergoing rehabilitation following a hip fracture. © The Author 2010. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved.

Nordberg A.,Karolinska Institutet | Ballard C.,Kings College London | Bullock R.,Kingshill Research Center | Darreh-Shori T.,Karolinska Institutet | Somogyi M.,Novartis
Primary Care Companion to the Journal of Clinical Psychiatry | Year: 2013

Objective: To examine the role of butyrylcholinesterase (BuChE) in cholinergic signaling and neurologic conditions, such as Alzheimer's disease (AD). The rationale for inhibiting cholinesterases in the management of AD, including clinical evidence supporting use of the dual acetylcholinesterase (AChE) and BuChE inhibitor rivastigmine, is discussed. Data Sources: PubMed searches were performed using butyrylcholinesterase as a keyword. English-language articles referenced in PubMed as of September 2011 were included. Study Selection and Data Synthesis: English-language articles related to BuChE considered to be of clinical relevance to physicians were included. English-language articles specifically related to AChE were not included, as the role of AChE in cholinergic signaling and the underlying pathology of AD is well documented. Reference lists of included publications were used to supplement the search. Results: AChE and BuChE play a role in cholinergic signaling; BuChE can hydrolyze acetylcholine and compensate for AChE when levels are depleted. In the AD brain, AChE levels decrease, while BuChE levels are reportedly increased or unchanged, with changes becoming more pronounced during the disease course. Furthermore, BuChE genotype may influence AD risk and rate of disease progression. Strategies that increase acetylcholine levels (eg, cholinesterase inhibitors) demonstrate symptomatic efficacy in AD. Rivastigmine has proven cognitive efficacy in clinical trials, and data suggest that its action is mediated, in part, by inhibition of BuChE. Retrospective analyses of clinical trials provide evidence that BuChE genotype may also influence treatment response. Conclusions: AChE-selective inhibitors and a dual AChE and BuChE inhibitor demonstrate symptomatic efficacy in AD. Mounting preclinical and clinical evidence for a role of BuChE in maintaining normal cholinergic function and the pathology of AD provides a rationale for further studies investigating use of rivastigmine in AD and the influence of BuChE genotype on observed efficacy. © 2013 Physicians Postgraduate Press, Inc.

Rinne J.O.,Clinical Research Services Turku | Brooks D.J.,Medical Research Council Clinical science Center | Rossor M.N.,University College London | Fox N.C.,University College London | And 13 more authors.
The Lancet Neurology | Year: 2010

Background: Carbon-11-labelled Pittsburgh compound B (11C-PiB) PET is a marker of cortical fibrillar amyloid-β load in vivo. We used 11C-PiB PET to investigate whether bapineuzumab, a humanised anti-amyloid-β monoclonal antibody, would reduce cortical fibrillar amyloid-β load in patients with Alzheimer's disease. Methods: Patients with mild-to-moderate Alzheimer's disease were randomly assigned to receive intravenous bapineuzumab or placebo in a ratio of seven to three in three ascending dose groups (0·5, 1·0, or 2·0 mg/kg). Each dose group was enrolled after safety review of the previous group. Randomisation was by interactive voice response system; masking was achieved with numbered kit allocation. Patients, investigators, study site personnel, sponsor staff, and carers were masked to treatment. Patients received up to six infusions, 13 weeks apart, and had 11C-PiB PET scans at baseline and at weeks 20, 45, and 78. The primary outcome was the difference between the pooled bapineuzumab group and the pooled placebo group in mean change from screening to week 78 in 11C-PiB cortical to cerebellar retention ratio averaged across six cortical regions of interest. Analysis was by modified intention to treat. This study is registered with EudraCT, number 2004-004120-12; ISRCTN17517446. Findings: 28 patients were assigned to bapineuzumab (n=20) or placebo (n=8). 19 patients in the bapineuzumab group and seven in the placebo group were included in the modified intention-to-treat analysis. Estimated mean 11C-PiB retention ratio change from baseline to week 78 was -0·09 (95% CI -0·16 to -0·02; p=0·014) in the bapineuzumab group and 0·15 (95% CI 0·02 to 0·28; p=0·022) in the placebo group. Estimated mean difference in 11C-PiB retention ratio change from baseline to week 78 between the bapineuzumab group and the placebo group was -0·24 (95% CI -0·39 to -0·09; p=0·003). Differences between the bapineuzumab group and the placebo group in the individual regions of interest were similar to the overall mean difference. Adverse events were typically mild to moderate in severity and transient. Two patients in the 2·0 mg/kg bapineuzumab group had transient cerebral vasogenic oedema. Interpretation: Treatment with bapineuzumab for 78 weeks reduced cortical 11C-PiB retention compared with both baseline and placebo. 11C-PiB PET seems to be useful in assessing the effects of potential Alzheimer's disease treatments on cortical fibrillar amyloid-β load in vivo. Funding: Elan Pharmaceuticals and Wyeth Research. © 2010 Elsevier Ltd. All rights reserved.

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