Parkinson Disease: Schapira AH

Grosset DG, Schapira AH. · Institute of Neurological Sciences, Department of Neurology, Southern General Hospital, 1345 Govan Rd, Glasgow G51 4TF, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #18487552 No free full text.

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Tan EK, Schapira AH. · No affiliation provided · Eur J Neurol. · Pubmed #18290841 No free full text.

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Schapira AH. · No affiliation provided · Eur J Neurol. · Pubmed #18171385 No free full text.

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Schapira AH. · No affiliation provided · Arch Neurol. · Pubmed #16966498 No free full text.

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Chaudhuri KR, Schapira AH. · National Parkinson Foundation Centre of Excellence, King's College Hospital and University Hospital Lewisham, London, UK. · Lancet Neurol. · Pubmed #19375664 No free full text.

Abstract: Several studies, including work from the Parkinson's disease (PD) non-motor group and others, have established that the non-motor symptoms of PD are common, occur across all stages of PD, are under-reported, and are a key determinant of quality of life. Research suggests that the non-motor symptoms of the disease are frequently unrecognised by clinicians and remain untreated. Even when identified, there is a common perception that many of these symptoms are untreatable. The role of dopaminergic drugs in treating the various non-motor problems of PD, although clinically recognised, has received little attention. In this Review, we investigate the dopaminergic basis of the range of non-motor symptoms that occur in PD such as depression, apathy, sleep disorders (including rapid-eye movement sleep behaviour disorder), and erectile dysfunction. We discuss the evidence that these symptoms are treatable, at least in part, with various dopaminergic strategies and, where relevant, we also refer to the use of deep-brain stimulation of appropriate targets in the brain. This Review provides a comprehensive overview of the management of this challenging aspect of PD.

Schapira AH. · University Department of Clinical Neurosciences, Institute of Neurology, University College London, London, NW3 2PF, UK. · Neurology. · Pubmed #19221314 No free full text.

Abstract: During the last 20 years, an enormous research effort and hundreds of millions of dollars have been spent attempting to develop and prove that drugs may slow the rate of progression of Parkinson disease (PD). At the time of writing, no drug has yet satisfied the rigorous criteria set by clinicians and licensing authorities for a neuroprotective agent. Despite this apparent failure, numerous important lessons have been learned, and some areas for optimism have emerged. Dopaminergic drugs have, for 40 years, been the basis for the treatment of the predominant early motor features of PD. Several of these drugs have also demonstrated an ability to protect cells, including neurons, against a range of toxins that are of relevance to the pathogenesis of PD. Some have entered clinical trials for neuroprotection, and a few have produced a positive result according to the endpoint selected. The interpretation of these trials is the subject of some debate. A pattern has emerged in these and other clinical trials, which has lead to a novel concept for neuroprotection, and that is simply to treat early rather than delay. The basis for this may lie in the support of basal ganglia compensatory mechanisms and the restoration of normal dopaminergic transmission.

Olanow CW, Kieburtz K, Schapira AH. · Department of Neurology, Mount Sinai School of Medicine, New York, USA. · Ann Neurol. · Pubmed #19127580 No free full text.

Abstract: The development of a neuroprotective therapy that slows, stops, or reverses neurodegeneration in Parkinson's disease (PD) is the single most important unresolved issue in the management of this disorder. Current therapies provide effective control of symptoms, particularly in the early stages of the disease, but disease progression is associated with the development of "nondopaminergic" features such as postural instability, falling, and dementia that are not adequately controlled with existing medications. There are many promising candidate neuroprotective agents based on pathological and laboratory studies, but to date, it has not been possible to determine that any drug has a disease-modifying effect in PD. Obstacles to the development of a neuroprotective therapy in PD include: (1) uncertainty as to the precise cause of cell death in PD and what to target; (2) the lack of an animal model of PD that precisely reflects the etiopathogenesis of the disease, the pattern of dopaminergic and nondopaminergic pathology, and its chronic, progressive nature; (3) determination of the correct dose to use in clinical trials; and (4) delineation of a clinical end point that is an accurate measure of the underlying disease and is not confounded by potential symptomatic effects of a study intervention. New developments in understanding the cause of the disease, in the development of animal models of PD, and in clinical trial methodology will hopefully hasten the resolution of these problems.

Schapira AH. · University Department of Clinical Neurosciences, University College London, London NW3 2PF, UK. · Trends Pharmacol Sci. · Pubmed #19042040 No free full text.

Abstract: Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease and is an important cause of chronic disability. Numerous important advances have been made in our understanding of the aetiopathogenesis, pathology and clinical phenomenology of this disease, and these have underpinned advances in symptomatic treatment and the prospect that these might be extended into interventions that will slow progression. It is notable that the continuing characterisation of the downstream biochemical consequences of the genetic causes of PD serves only to reinforce this notion. Progress in the management of PD has continued, particularly in timing of drug initiation and the sequence and combinations in which drugs are used to improve long-term outcome and reduce drug-induced complications. Particular progress has been made in the field of neuroprotection, where novel therapies and clinical trial designs are being tested. This review will focus particularly upon this area.

Yamamoto M, Schapira AH. · Department of Neurology, Kagawa, Prefectural Central Hospital, Takamatsu, Japan. · Expert Rev Neurother. · Pubmed #18416667 No free full text.

Abstract: Dopamine agonists are established as effective drugs for the symptomatic treatment of Parkinson's disease (PD) throughout its course. As monotherapy, they produce effective control of motor symptoms and combine this with a low risk for motor complications. As an adjunct to levodopa, they improve motor control and limit the need for levodopa in those patients in whom this may be considered relevant. The non-ergot dopamine agonists in particular have a good safety profile, although as with other agonists, sedation, and cognitive and behavioral problems may be limiting in some patients. Pramipexole has shown benefit in improving depressive symptoms in PD. Ropinirole and pramipexole have both demonstrated a reduction in the rate of loss of nigrostriatal innervation as determined by imaging in PD patients, when compared with levodopa. Thus, dopamine agonists contribute to several dimensions of the management of PD and have become an integral part of the disease treatment algorithm.

Schapira AH. · University Department of Clinical Neurosciences, Institute of Neurology, University College London, London, UK. · Eur J Neurol. · Pubmed #18353131 No free full text.

Abstract: Slowing or aborting the progress of neurodegeneration in Parkinson's disease (PD) remains the most important unmet need of this disorder. There are several recent developments in trial design and also in drugs under investigation for possible neuroprotective effect. Emphasis has been placed on clinical as opposed to imaging end-points and these include change in a clinical rating scale, e.g. United Parkinson's disease Rating Scale (UPDRS), or time to additional therapy. The introduction of the delayed-start, or wash-in, trial design adds an additional dimension to drug evaluation for neuroprotection. Compounds that have been recently tested in clinical trial include the monoamine oxidase-B inhibitor rasagiline, the anti-apoptotic agents TCH346 and CEP1347, and the promitochondrial agent creatine. The dopamine agonists have been evaluated for a neuroprotective effect using imaging end-points. Perhaps the most important and simplest concept for neuroprotection has been the theory that early dopaminergic support for the degenerating dopaminergic system per se provides significant long-term clinical benefit for PD patients.

Schapira AH. · University Department of Clinical Neurosciences, Royal Free and University College Medical School, University College London, London, UK. · Mov Disord. · Pubmed #18175401 No free full text.

Abstract: The development of treatment for the symptoms of Parkinson's disease (PD) has been one of the most notable successes of neurology. Dopaminergic therapies in the form of levodopa, dopamine agonists, or monoamine oxidase B inhibitors significantly improve the characteristic motor symptoms of bradykinesia and rigidity, with a beneficial effect upon tremor in a proportion of patients. Novel delivery of dopaminergic drugs whether in the form of once a day sustained release preparations or transdermal applications ensures that they remain at the forefront of PD treatment. The development of drugs to slow the progression of PD has attracted considerable attention and there appears to be some measure of success although additional studies need to be performed. A range of nondopaminergic drugs including alpha 2-adrenergic antagonists, serotoninergics, and adenosine A2a antagonists are in late-stage development for PD and offer benefit for motor symptoms and motor complications.

Schapira AH. · University Department of Clinical Neurosciences and Institute of Neurology, University College London, London, UK. · Lancet Neurol. · Pubmed #18093566 No free full text.

Abstract: Several biochemical abnormalities have been described in the brains of patients with Parkinson's disease (PD), including oxidative stress and mitochondrial dysfunction. The identification of specific gene mutations that cause PD has reinforced the relevance of oxidative stress and mitochondrial dysfunction in the familial and the sporadic forms of the disease. The proteins that are associated with familial PD--PTEN-induced putative kinase 1 (PINK1), DJ-1, alpha-synuclein, leucine-rich repeat kinase 2, and, possibly, parkin--are either mitochondrial proteins or are associated with mitochondria, and all interface with the pathways of oxidative stress and free radical damage. Insights into the aetiology and pathogenesis of PD provide hope that drugs or cocktails of drugs that might successfully intervene in the pathogenesis and slow the progression of the disease can be derived from the study of the converging rather than diverging pathways to cell dysfunction and death.

Simonson W, Hauser RA, Schapira AH. · Commission for Certification in Geriatric Pharmacy. · Ann Pharmacother. · Pubmed #17878397 No free full text.

Abstract: OBJECTIVE: To evaluate the role of the practicing pharmacist in the identification and current treatment of the levodopa wearing-off phenomenon experienced by patients with Parkinson's disease (PD) who are receiving chronic levodopa therapy. DATA SOURCES: Literature retrieval was accessed through MEDLINE (1967-June 2007) using the terms levodopa, wearing-off, and Parkinson's disease. In addition, reference citations from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION: All articles that were identified from the data sources and written in English were evaluated. DATA SYNTHESIS: Levodopa is the most efficacious therapeutic agent in PD; however, the response of patients to levodopa changes over time. Eventually, the duration of response becomes shorter and more unpredictable, and complications emerge. One of the first complications observed with levodopa therapy is wearing-off, which can emerge within 1-3 years of initiation of levodopa treatment. Wearing-off is characterized by the predictable emergence of motor and nonmotor PD symptoms before the next scheduled dose of medication. Despite effective treatment options to tackle wearing-off, it remains underrecognized and under treated. With early identification and optimization of treatment, wearing-off can be managed effectively, resulting in improved quality of life for patients with PD. CONCLUSIONS: Owing to their training and accessibility, pharmacists play an increasingly important role in the management of patients with PD. Pharmacists are uniquely placed to identify wearing-off, offer timely advice, and facilitate the optimization of treatment regimens to improve patients' quality of life and enhance long-term outcomes.

Schapira AH. · University Department of Clinical Neurosciences, Institute of Neurology, University College London, England. · Arch Neurol. · Pubmed #17698697 No free full text.

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Schapira AH. · University Department of Clinical Neurosciences, Royal Free and University College Medical School, University College London, Rowland Hill Street, London NW3 2PF, UK. · Cell Death Differ. · Pubmed #17464321 links to  free full text

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Schapira AH. · University Department of Clinical Neurosciences, Royal Free and University College Medical School, University College London, London, UK. · J Neural Transm Suppl. · Pubmed #17447426 No free full text.

Abstract: Rasagiline is a novel, potent, irreversible inhibitor of monoamine oxidative B developed for the symptomatic treatment of Parkinson's disease. The drug has shown efficacy in improving motor features in both early and advanced Parkinson's disease patients. The drug appears to be well tolerated and its once daily fixed dose formulation should make for excellent compliance. Rasagiline has also demonstrated important neuroprotective properties in both in vitro and in vivo laboratory studies. A provisional study of neuroprotection in a delayed start clinical trial of early PD patients has also suggested that this benefit may be translated to the clinic. Additional clinical trials are underway to confirm this.

Schapira AH, Bezard E, Brotchie J, Calon F, Collingridge GL, Ferger B, Hengerer B, Hirsch E, Jenner P, Le Novère N, Obeso JA, Schwarzschild MA, Spampinato U, Davidai G. · University Department of Clinical Neurosciences, Royal Free and University College Medical School, University College London, Rowland Hill Street, London NW3 2PF, UK. · Nat Rev Drug Discov. · Pubmed #17016425 No free full text.

Abstract: Dopamine deficiency, caused by the degeneration of nigrostriatal dopaminergic neurons, is the cause of the major clinical motor symptoms of Parkinson's disease. These symptoms can be treated successfully with a range of drugs that include levodopa, inhibitors of the enzymatic breakdown of levodopa and dopamine agonists delivered by oral, subcutaneous, transcutaneous, intravenous or intra-duodenal routes. However, Parkinson's disease involves degeneration of non-dopaminergic neurons and the treatment of the resulting predominantly non-motor features remains a challenge. This review describes the important recent advances that underlie the development of novel dopaminergic and non-dopaminergic drugs for Parkinson's disease, and also for the motor complications that arise from the use of existing therapies.

Schapira AH, Obeso J. · University Department of Clinical Neurosciences, Royal Free and University College Medical School, University College London, UK. · Ann Neurol. · Pubmed #16489611 No free full text.

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Chaudhuri KR, Healy DG, Schapira AH, Anonymous00164. · Movement Disorders Unit, Kings College Hospital, Guy's King's and St Thomas' School of Medicine, London, UK. · Lancet Neurol. · Pubmed #16488379 No free full text.

Abstract: The clinical diagnosis of Parkinson's disease rests on the identification of the characteristics related to dopamine deficiency that are a consequence of degeneration of the substantia nigra pars compacta. However, non-dopaminergic and non-motor symptoms are sometimes present before diagnosis and almost inevitably emerge with disease progression. Indeed, non-motor symptoms dominate the clinical picture of advanced Parkinson's disease and contribute to severe disability, impaired quality of life, and shortened life expectancy. By contrast with the dopaminergic symptoms of the disease, for which treatment is available, non-motor symptoms are often poorly recognised and inadequately treated. However, attention is now being focused on the recognition and quantitation of non-motor symptoms, which will form the basis of improved treatments. Some non-motor symptoms, including depression, constipation, pain, genitourinary problems, and sleep disorders, can be improved with available treatments. Other non-motor symptoms can be more refractory and need the introduction of novel non-dopaminergic drugs. Inevitably, the development of treatments that can slow or prevent the progression of Parkinson's disease and its multicentric neurodegeneration provides the best hope of curing non-motor symptoms.

Schapira AH. · University Department of Clinical Neurosciences, Royal Free and University College Medical School, London NW3 2PF, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #16227533 links to  free full text

Abstract: Considerable advances made in defining the aetiology, pathogenesis, and pathology of Parkinson's disease (PD) have resulted in the development and rapid expansion of the pharmacopoeia available for treatment. Anticholinergics were used before the introduction of levodopa which is now the drug most commonly used. Dopamine agonists are effective when used alone or as an adjunct to levodopa, while monoamine oxidase B inhibitors improve motor function in early and advanced PD. However, treatment mainly addresses the dopaminergic features of the disease and leaves its progressive course unaffected; the drug treatment available for the management of non-motor symptoms is limited. This article seeks to set current treatment options in context, review emerging and novel drug treatments for PD, and assess the prospects for disease modification. Surgical therapies are not considered.

Schapira AH. · The Royal Free and University College Medical School, University College London, and Institute of Neurology, University College London, London, United Kingdom. · Neurology. · Pubmed #15505139 No free full text.

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Schapira AH. · Royal Free and University College Medical School and the Institute of Neurology, University College London, UK. · Lancet Neurol. · Pubmed #15157851 No free full text.

Abstract: Several separate gene mutations have now been identified in familial Parkinson's disease and important environmental influences modulating risk for the idiopathic form of the disease have also been recognised. These insights have provided important clues in the development of disease modifying therapies. Some compounds have already been shown to potentially delay disease progression in early clinical trials. The most important challenge, particularly for those drugs that might have a symptomatic effect, is defining appropriate markers that will confirm a neuroprotective effect.

Schapira AH, Olanow CW. · University Department of Clinical Neurosciences, Royal Free and University College Medical School, and Institute of Neurology, Queen Square, London, England. · JAMA. · Pubmed #14734599 No free full text.

Abstract: Parkinson disease is an age-related neurodegenerative disease that affects approximately 1 million persons in the United States. Current therapies provide effective control of symptoms, particularly in the early stages of the disease, but most patients develop motor complications with long-term treatment, and features develop such as postural instability, falling, and dementia that are not adequately controlled with existing medications. Accordingly, neuroprotective therapy that might slow, stop, or reverse disease progression is urgently needed. While many agents appear to be promising based on laboratory studies, selecting clinical end points for clinical trials that are not confounded by symptomatic effects of the study intervention has been difficult. More recently, neuroimaging end points have been used as biomarkers of disease progression, but again there are concerns that they may be influenced by regulatory effects of the drugs used. We review clinical trials aimed at detecting neuroprotection in Parkinson disease and address the controversies surrounding the interpretation of these studies.

Schapira AH. · University Department of Clinical Neurosciences, Royal Free and University College Medical School, and Institute of Neurology, UCL, London, United Kingdom. · Neurology. · Pubmed #14504378 No free full text.

This publication has no abstract.

Schapira AH, Olanow CW. · University Department of Clinical Neurosciences, Royal Free and University College Medical School, UCL, Queen Square, London, United Kingdom. · Ann Neurol. · Pubmed #12666106 No free full text.

This publication has no abstract.