169 research outputs found
New Approaches to Therapy
No full textL-DOPA-induced dyskinesia (LID) is a major complication of the treatment of Parkinson's disease (PD). LID comprises two major components, the priming process responsible for its onset and the expression of involuntary movements that underlies its clinical manifestation. The mechanisms responsible for these components are partially understood and their biochemical basis is being unraveled but avoidance and treatment remain an issue. In this chapter, we review what is known about the involvement of dopaminergic systems in LID and the way in which dopaminergic therapy can be used to avoid the onset of LID or to reverse or suppress involuntary movements once these have been established. The involvement of specific dopamine receptor subtypes, continuous dopaminergic stimulation (CDS) and continuous drug delivery (CDD) is reviewed. However, a major role is emerging in the avoidance and suppression of LID through the use of nondopaminergic mechanisms and we consider the present and future use of glutamatergic drugs, serotoninergic agents, adenosine antagonists and others as a means of improving therapy. There is compelling basic science supporting a role for nondopaminergic approaches to LID but at the moment the translational benefit to PD is not being achieved as predicted. There needs to be further consideration of why this is the case and how in future, both experimental models of dyskinesia and clinical trial design can be optimized to ensure success
The serotonergic system in levodopa-induced dyskinesia
No full textAn increasing body of experimental evidence suggests that serotonergic neurons play a major role in the production of levodopa-derived dopamine when dopaminergic neurons have degenerated, and that unregulated release of dopamine from serotonergic neurons is responsible for the appearance of levodopa-induced dyskinesia (LID) in animal models of Parkinson’s disease (PD).
Promising preclinical findings show that the activation of 5-HT1 receptors, induced by the administration of 5-HT1A and/or 5-HT1B receptor agonists, suppressed LID in 6-OHDA-lesioned rat, as well as in MPTP-treated nonhuman primate models of PD, suggesting a possible clinical application. This chapter will provide an overview of these preclinical findings concerning the role of serotonergic
neurons and serotonergic receptors in the appearance of LID, with a brief review of relevant clinical studies
Levodopa-induced dyskinesias
No full textLevodopa-induced dyskinesias (LID) are common and difficult to treat. This review focuses on three issues related to LID: clinical features, classification and rating, pathophysiology and pathogenesis, and management. The three primary clinical syndromes are OFF-period dystonia, peak-dose dyskinesia, and diphasic dyskinesia. Several other forms also occur, making the evaluation and choice of treatment complicated. A core component of the pathophysiology of LID is overactivity of the direct striatal output pathway. This pathway provides a direct GABAergic connection by which the striatum inhibits the output regions of the basal ganglia, i.e., the internal globus pallidus and the substantia nigra pars reticulata. Altering dopaminergic dosing and timing can abate dyskinesias, but usually impact the control of parkinsonism. Putative therapies to reduce the problem of dyskinesias could focus on the glutamatergic, GABAergic, alpha(2) adrenergic, serotonergic (5HT(1A), 5HT(2A)), opi oid, histamine H-3 adenosine A(2A) receptors, the monoamine transport or cannabinoid CB1 receptors systems. The only currently available drug with an evidence-based recommendation on efficacy for dyskinesia is amantadine. Therapy goals include the prevention of dyskinesia and treatment of dyskinesias that are troublesome clinically. New rating measures to assess severity and disability related to dyskinesia are in the process of development and clinimetric testing. (c) 2007 Movement Disorder Society
Phenomenology of levodopa-induced dyskinesia
No full textLevodopa has been effective against the motor features of Parkinson's disease for several decades. However, it is observed that long-term treatment with levodopa can be complicated by the development of various types of response fluctuations as well as dyskinesias. The latter, once established, tend to remain persistent although they can be reduced by some pharmacological and neurosurgical manipulations. These situations can lead to a significant source of disability, and their treatment options require significant expertise and costs. Therefore, efforts are made to minimize or prevent the appearance of long-term dyskinesia and fluctuations. In this chapter, we will consider the phenotypes of levodopa-induced dyskinesias
Experimental models of L-DOPA-induced dyskinesia
No full textStrategies to avoid or minimize dyskinesia and other motor complications of chronic dopamine replacement therapy in Parkinson's disease (PD) remain a significant unmet clinical need. As such, the refinement and development of animal models with which to delineate the underlying molecular mechanisms of dyskinesia and to find effective treatment paradigms remain as necessary as ever. Toxin-based models including the MPTP-lesioned primate and the 6-hydroxydopamine (6-OHDA) lesioned rodent continue to form the bedrock of current l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia modeling approaches. This chapter reviews these models, illustrating their origins, application and strengths as well as problems that accompany their use. We also describe new methodologies that, although still in their infancy, may offer powerful future alternatives by which to better model this debilitating complication of current PD treatment
Preclinical models of levodopa-induced dyskinesia
No full textL -DOPA-induced dyskinesia (LID) represents one of the major limitations in the current pharmacotherapy of Parkinson's disease (PD) and affects the majority of PD patients. Animal models are the most important preclinical tool for molecular investigations of LID mechanisms and therapeutic targets. Over the last two decades, models of LID have been developed in both nonhuman primate and rodent species, recapitulating several aspects of the human dyskinesia. This chapter will review and compare the main features of the rodent and nonprimate models of LID currently available and summarize some of the main neurobiological fi ndings obtained from these models
Alfred Jarry. Three Early Novels. Collected Works II. Absolute Love, Days and Nights, Exploits and Opinions of Doctor Faustroll, Pataphysician: Edited by Alastair Brotchie and Paul Edwards. Translations by Alexis Lykiard, Simon Watson Taylor, and Paul Edwards
No full textInternational audienceIn a short and legendary life, Alfred Jarry (1873-1907) created a unique and large body of work that included plays, novels, poetry, journalism and other less definable texts and speculations. His writings form the essential bridge between the European avant-garde of the 1890s (Symbolism) and those of the 20th century (Futurism, Dada, Surrealism). In the last fifty years his influence has scarcely faltered, and in particular his science of ’Pataphysics has informed the recent writings of Deleuze, Baudrillard and Eco, among many others. The College of ’Pataphysics, founded in his honour, has numbered among its members such luminaries as Cortazar, Duchamp, Ionesco, Leiris, Queneau and most of the other writers of the "Oulipo". Despite this influence, Jarry is still best known in English as the author of Ubu Roi; the aim of this three-volume Collected Works is to make the totality of his major writings available in English for the first time
Antidyskinetic actions of amantadine in Parkinson’s disease: are benefits maintained in the long term?
No full textAlfred Jarry. Adventures in ’Pataphysics. Collected Works I. Black Minutes, Caesar-Antichrist, Essays, Speculations: Edited by Alastair Brotchie and Paul Edwards. Translations by Paul Edwards and Antony Melville
No full textInternational audienceIn a short and legendary life, Alfred Jarry (1873-1907) created a unique and large body of work that included plays, novels, poetry, journalism and other less definable speculations and texts. His writings form the essential bridge between the European avant-garde of the 1890s (Symbolism) and those of the Twentieth century (Futurism, Dada, Surrealism). In the last fifty years his influence has scarcely faltered, in particular his science of ’Pataphysics has informed the recent writings of Deleuze, Baudrillard and Eco, among others. The College of ’Pataphysics, founded in Jarry’s honour, has numbered among its members luminaries such as Cortázar, Duchamp, Ionesco, Leiris, Queneau and most of the other writers of the “Oulipo".Despite this influence he is still best known in English as the author of Ubu Roi; the aim of this three volume Collected Works is to make the totality of his major writings available in English for the first time.This first volume presents his first two books, Black Minutes of Memorial Sand and Caesar-Antichrist, two apocalyptic Symbolist texts which already signal their self-destruction through the presence of Ubu.A series of essays follows: aesthetic (Time in Art), philosophical (To Be and To Live), political (perhaps: Visions of the Present and Future), and concludes with his famous treatise on how to actually construct a time machine (convincing enough to be taken seriously by contemporary scientists). Jarry’s own selection of his speculative journalism completes this volume
Adjuncts to dopamine replacement: A pragmatic approach to reducing the problem of dyskinesia in Parkinson's disease
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