Efficacy, safety, and tolerability of overnight switching from immediate- to once daily extended-release pramipexole in early Parkinson's disease.

The aim of this article is to test the feasibility, in early Parkinson's disease (PD), of an overnight switch from immediate-release (IR) pramipexole to a new once-daily extended-release (ER) formulation. Nonfluctuating patients on pramipexole IR three-times daily, alone or with levodopa, for early PD were randomly switched overnight to double-blind IR three-times daily (N = 52) or ER once-daily (N = 104) at initially unchanged daily dosage. Successful switching (defined as no worsening >15% of baseline UPDRS II+III score and no drug-related adverse event withdrawal) was assessed at 9 weeks, after optional dosage adjustments (primary endpoint), and at 4 weeks, before adjustment.

Rasagiline protects against alpha-synuclein induced sensitivity to oxidative stress in dopaminergic cells.

Rasagiline is a propargylamine and irreversible monoamine oxidase (MAO) B inhibitor used for the treatment of Parkinson's disease (PD). It has demonstrated neuroprotective properties in laboratory studies. Current concepts of PD aetiopathogenesis include the role of alpha-synuclein, protein aggregation, free radical metabolism and mitochondrial dysfunction in contributing to cell death.

Rationale for delayed-start study of pramipexole in Parkinson's disease: the PROUD study.

Perhaps the most important unmet need in Parkinson's disease (PD) is the ability to slow or prevent progression of the neurodegeneration that underlies the motor and nonmotor features of this disorder. Pramipexole, a dopamine agonist used for the symptomatic treatment of PD, has demonstrated neuroprotective properties in laboratory studies. The PRamipexole On Underlying Disease (PROUD) study is a randomized, double-blind clinical trial evaluating the ability of pramipexole to modify disease progression using a delayed-start design.

Missing pieces in the Parkinson's disease puzzle.

Parkinson's disease is a neurodegenerative process characterized by numerous motor and nonmotor clinical manifestations for which effective, mechanism-based treatments remain elusive. Here we discuss a series of critical issues that we think researchers need to address to stand a better chance of solving the different challenges posed by this pathology.

Mitochondrial matters of the brain: the role in Huntington's disease.

Even before the discovery of the mutant htt gene as the cause of Huntington's Disease (HD), abnormal energy metabolism and mitochondrial dysfunction had been suggested as a possible pathogenic mechanism in HD. These initial investigations described defects in energy metabolism using Positron Emission Tomography (PET) and Nuclear Magnetic Resonance (NMR) Spectroscopy in symptomatic and pre-symptomatic HD patients. Concurrently, 3-nitroproprionic acid, a mitochondrial complex II inhibitor, was found to replicate many of the pathological and clinical features of HD when administered to animals.

Molecular and clinical prodrome of Parkinson disease: implications for treatment.

The development of interventions to slow or prevent progression represents an important aim for current research into Parkinson disease (PD). General agreement prevails that success in this endeavor will depend on a clearer understanding of etiology and pathogenesis, and several important advances have recently been made, particularly in defining the genetic causes of PD. Studies of the biochemical consequences of the mutations that cause familial PD, and postmortem brain studies of idiopathic, sporadic PD, have highlighted mitochondrial dysfunction, oxidative stress, and protein metabolism by the ubiquitin-proteasomal and autophagy systems as being central to pathogenesis.

Analysis of the factors influencing the cardiac phenotype in Friedreich's ataxia.

Friedreich's ataxia (FRDA) has been associated with both cardiac hypertrophy and to a lesser degree dilated cardiomyopathy. We have conducted a cross sectional magnetic resonance imaging (MRI) study of 25 patients with clinically and genetically confirmed FRDA and 24 healthy controls to analyse how disease parameters influence cardiac features in FRDA. MR cine imaging in the long and short axis planes was performed alongside clinical assessments.

The nondeclaration of nonmotor symptoms of Parkinson's disease to health care professionals: an international study using the nonmotor symptoms questionnaire.

The nonmotor symptoms (NMS) of Parkinson's disease (PD) are less well recognised and can be more troublesome to patients and carers than classical motor features. NMS are frequently missed during routine consultations and such under-recognition may have implications on quality of care given that many NMS are treatable. To determine the proportion of patients not declaring NMS to healthcare professional (HCP) as assessed by self completion of the NMS questionnaire (NMSQuest), a validated, self-completing questionnaire with 30 items.

Complex I: inhibitors, inhibition and neurodegeneration.

Complex I is the first protein component of the mitochondrial respiratory chain and as such plays a crucial role in ATP production and mitochondrial function in general. Mitochondrial dysfunction has been identified in a number of neurodegenerative diseases. In some of these the mitochondrial abnormality is primary and in others secondary.

Future strategies for neuroprotection in Parkinson's disease.

The development of a drug or combination of drugs to slow or stop the progression of Parkinson's disease is the most important goal in this disease area. An understanding of the complex etiology and pathogenesis of the disorder is essential in this process. However, the current pathways to disease pathogenesis identified from the genetic causes of Parkinson's disease offer optimism in the sense that they appear to converge and interconnect rather than diverge.

Neuroprotection in Parkinson's disease.

A major focus in Parkinson's disease (PD) research is to produce drugs or other interventions that can slow or stop clinical progression. This should include an effect on both motor and non-motor symptoms and so target dopaminergic and non-dopaminergic pathways. It is logical to assume that the best chance of developing such therapies will be based on forming a better understanding of the aetiology and pathogenesis of PD and to identify critical molecular targets.

Parkinsonism in patients with chronic hepatitis C treated with interferon-alpha2b: a report of two cases.

Details of two patients with chronic hepatitis C infection who developed features of Parkinsonism when treated with IFN-alpha2b and ribavirin are reported. The symptoms resolved when treatment was discontinued in one patient but not in the other. Physicians should be alert to the possibility that drug-related Parkinsonism may complicate treatment of hepatitis C infection with antiviral agents; the agent most likely responsible is IFN-alpha2b.

Quantifying the evolution and impact of antimalarial drug resistance: drug use, spread of resistance, and drug failure over a 12-year period in Papua New Guinea.

BACKGROUND. Antimalarial use is a key factor driving drug resistance and reduced treatment effectiveness in Plasmodium falciparum malaria, but there are few formal, quantitative analyses of this process. METHODS.

Etiopathogenesis and treatment of Parkinson's disease.

Parkinson's disease (PD) is a complex neurodegenerative disorder characterised by dopaminergic cell loss in the substantia nigra. In addition, neurodegeneration occurs at a number of extra-nigral locations and involves a variety of non-dopaminergic neurotransmitter systems. Etiopathogenic mechanisms leading to cell death include oxidative stress and free radical generation, mitochondrial dysfunction, glutamate receptor mediated excitotoxicity, inflammation, oligodendrocytic interaction and neurotrophic factors, ubiquitin-proteosome system involvement, autophagy and apoptosis.

Perspectives on recent advances in the understanding and treatment of Parkinson's disease.

There have been numerous important recent advances in our understanding of the causes of Parkinson's disease (PD), the treatments available and how these are best applied for the long-term management of patients. Novel genes causing familial PD have been discovered and mechanisms leading to cell dysfunction and death identified. The PD prodrome is now a subject of great interest and clinical markers are being defined that may in future, together with biochemical markers, support an early, pre-motor diagnosis of PD.

Drug-induced fibrotic valvular heart disease.

The initial association between the development of valvular heart disease and drugs stems from observations made during the use of methysergide and ergotamine for migraine prophylaxis in the 1960s. Since then, the appetite suppressants fenfluramine and dexfenfluramine, the dopamine agonists pergolide and cabergoline, and more recently, the recreational drug ecstasy (3,4 methylenedioxymethamphetamine; MDMA) have been implicated. Results from clinical trials show that drug dose and treatment duration affect both the risk of developing the disease and its severity.

Early versus delayed initiation of entacapone in levodopa-treated patients with Parkinson's disease: a long-term, retrospective analysis.

Background: We analysed data from three clinical trials in Parkinson's disease (PD) patients with wearing-off to determine whether early enhancement of levodopa therapy with entacapone can lead to better long-term outcomes than delayed entacapone treatment.

Methods: Post-hoc analysis of pooled data from three randomized, double-blind, placebo-controlled studies and their long-term, open-label extension phases. In all three studies, patients on levodopa/dopa-decarboxylase inhibitor (DDCI) were first randomized to entacapone ('early-start' group) or placebo ('delayed-start' group) for the initial 6-month double-blind phase, after which all patients received open-label levodopa/DDCI and entacapone treatment for up to 5 years.

Etiology and pathogenesis of Parkinson disease.

The etiology of Parkinson disease (PD) is multifactorial and is likely to involve different causes in different patients. Several different genes have been identified as causes of familial PD, including alpha-synuclein gene mutations and multiplications, and mutations of parkin, PINK1, DJ1, and LRRK2. The biochemical consequences of these mutations have served to reinforce the relevance of the pathways to pathogenesis previously characterized, for example, mitochondrial dysfunction, oxidative stress, and protein misfolding and aggregation.

Levodopa in the treatment of Parkinson's disease.

The predominant motor features of Parkinson's disease (PD) are caused by degeneration of dopaminergic neurones and can be reversed in part or whole by dopamine replacement or augmentation strategies. Physicians have most experience with the use of levodopa, which remains the most potent oral dopaminergic treatment for PD. There are reservations about the long-term use of levodopa, most particularly in the context of its propensity to induce motor fluctuations and dyskinesias.

Differential effects of PINK1 nonsense and missense mutations on mitochondrial function and morphology.

Mutations of the PINK1 gene are a cause of autosomal recessive Parkinson's disease (PD). PINK1 encodes a mitochondrial kinase of unknown function which is widely expressed in both neuronal and non-neuronal cells. We have studied fibroblast cultures from four family members harbouring the homozygous p.

Relationship between alpha synuclein phosphorylation, proteasomal inhibition and cell death: relevance to Parkinson's disease pathogenesis.

Alpha synuclein can be phosphorylated at serine129 (P-S129), and the presence of highly phosphorylated alpha-synuclein in Lewy bodies suggests changes to its phosphorylation status has an important pathological role. We demonstrate that the kinase(s) responsible for alpha-synuclein S129 phosphorylation is constitutively active in SH-SY5Y cells and involves casein kinase 2 activity. Increased oxidative stress or proteasomal inhibition caused significant elevation of P-S129 alpha-synuclein levels.

Non-motor symptoms of Parkinson's disease: dopaminergic pathophysiology and treatment.

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.