Levodopa has been the mainstay of treatment for Parkinson's disease (PD) for more than 40 years. During this time, researchers have strived to optimize levodopa formulations to minimize side effects, ...enhance central nervous system (CNS) bioavailability, and achieve stable therapeutic plasma levels. Current strategies include concomitant treatment with inhibitors of dopa decarboxylase (DDC) and catechol-O-methyltransferase (COMT) to prolong the peripheral levodopa half-life and increase CNS bioavailability. Levodopa combined with DDC inhibition is the current standard method of delivering levodopa for symptomatic treatment of PD. Recent research suggests that continuous dopaminergic stimulation that more closely approximates physiological stimulation may delay or prevent the development of motor fluctuations ('wearing off') and dyskinesias. Strategies currently being used to achieve more continuous dopaminergic stimulation include the combination of an oral levodopa/DDC inhibitor with a COMT inhibitor and the enteral infusion of a levodopa gel formulation. Attempts are underway to develop oral and transdermal very long-acting levodopa preparations.
Fourteen years after transplantation into the striatum of an individual with Parkinson's disease, grafted nigral neurons were found to have Lewy body-like inclusions that stained positively for ...α-synuclein and ubiquitin and to have reduced immunostaining for dopamine transporter. These pathological changes suggest that Parkinson's disease is an ongoing process that can affect grafted cells in the striatum in a manner similar to host dopamine neurons in the substantia nigra. These findings have implications for cell-based therapies and for understanding the cause of Parkinson's disease.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Introduction It is now accepted that Parkinson's disease (PD) is not simply due to dopaminergic dysfunction, and there is interest in developing non-dopaminergic approaches to disease management. ...Adenosine A
2A
receptor antagonists represent a new way forward in the symptomatic treatment of PD.
Areas covered In this narrative review, we summarize the literature supporting the utility of adenosine A
2A
antagonists in PD with a specific focus on istradefylline, the most studied and only adenosine A
2A
antagonist currently in clinical use.
Expert opinion: At this time, the use of istradefylline in the treatment of PD is limited to the management of motor fluctuations as supported by the results of randomized clinical trials and evaluation by Japanese and USA regulatory authorities. The relatively complicated clinical development of istradefylline was based on classically designed studies conducted in PD patients with motor fluctuations on an optimized regimen of levodopa plus adjunctive dopaminergic medications. In animal models, there is consensus that a more robust effect of istradefylline in improving motor function is produced when combined with low or threshold doses of levodopa rather than with high doses that produce maximal dopaminergic improvement. Exploration of istradefylline as a 'levodopa sparing' strategy in earlier PD would seem warranted.
Since the work of Tower in the 1950s, we have come to expect lower neuron density in the cerebral cortex of larger brains. We studied dolphin brains varying from 783 to 6215g. As expected, average ...neuron density in four areas of cortex decreased from the smallest to the largest brain. Despite having a lower neuron density than smaller dolphins, the killer whale has more gray matter and more cortical neurons than any mammal, including humans. To begin a study of non-dolphin toothed whales, we measured a 596g brain of a pygmy sperm whale and a 2004g brain of a Cuvier's beaked whale. We compared neuron density of Nissl stained cortex of these two brains with those of the dolphins. Non-dolphin brains had lower neuron densities compared to all of the dolphins, even the 6215g brain. The beaked whale and pygmy sperm whale we studied dive deeper and for much longer periods than the dolphins. For example, the beaked whale may dive for more than an hour, and the pygmy sperm whale more than a half hour. In contrast, the dolphins we studied limit dives to five or 10 minutes. Brain metabolism may be one feature limiting dolphin dives. The brain consumes an oversized share of oxygen available to the body. The most oxygen is used by the cortex and cerebellar gray matter. The dolphins have larger brains, larger cerebellums, and greater numbers of cortex neurons than would be expected given their body size. Smaller brains, smaller cerebellums and fewer cortical neurons potentially allow the beaked whale and pygmy sperm whale to dive longer and deeper than the dolphins. Although more gray matter, more neurons, and a larger cerebellum may limit dolphins to shorter, shallower dives, these features must give them some advantage. For example, they may be able to catch more elusive individual high-calorie prey in the upper ocean.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The diagnosis of movement disorders including Parkinson's disease (PD) and essential tremor is determined through clinical assessment. The difficulty with diagnosis of early PD has been highlighted ...in several recent clinical trials. Studies have suggested relatively high clinical diagnostic error rates for PD and essential tremor. This review was undertaken to clarify the utility of DaT-SPECT imaging with ((123)I)ioflupane (DaTSCAN or DaTscan or ((123)I)FP-CIT) in assisting practitioners in their clinical decision making by visualising the dopamine transporter in parkinsonian cases. In some patients with suspected parkinsonian syndromes, SPECT imaging with ((123)I)ioflupane is useful to assist in the diagnosis and to help guide prognosis and treatment decisions, including avoiding medications that are unlikely to provide benefit. Clinicians ordering ((123)I)ioflupane SPECT should be aware of its limitations and pitfalls and should order scans when there is diagnostic uncertainty or when the scan will be helpful in clinical decision making.
Summary Background IPX066 is an oral, extended-release, capsule formulation of carbidopa-levodopa. We aimed to assess this extended-release formulation versus immediate-release carbidopa-levodopa in ...patients with Parkinson's disease and motor fluctuations. Methods We did a phase 3, randomised, double-blind, double-dummy study at 68 academic and clinical centres in North America and Europe. Patients with Parkinson's disease who had at least 2·5 h per day of off-time underwent 3 weeks of open-label immediate-release carbidopa-levodopa dose adjustment followed by 6 weeks of open-label extended-release carbidopa-levodopa dose conversion. These patients were then randomly allocated (1:1), by use of an interactive web-response system, to 13 weeks of double-blind treatment with extended-release or immediate-release carbidopa-levodopa plus matched placebos. The primary efficacy measure was off-time as a percentage of waking hours in all patients randomly allocated to treatment groups, adjusted for baseline value. This study is registered with ClinicalTrials.gov , number NCT00974974. Findings Between Sept 29, 2009, and Aug 16, 2010, we enrolled 471 participants, of whom 393 (83%) were randomly allocated in the double-blind maintenance period and were included in the main efficacy analyses. As a percentage of waking hours, 201 patients treated double-blind with extended-release carbidopa-levodopa (mean 3·6 doses per day SD 0·7) had greater reductions in off-time than did 192 patients treated double-blind with immediate-release carbidopa-levodopa (mean 5·0 doses per day 1·2). Covariate-adjusted end-of-study means were 23·82% (SD 14·91) for extended-release carbidopa-levodopa and 29·79% (15·81) for immediate-release carbidopa-levodopa (mean difference −5·97, 95% CI −9·05 to −2·89; p<0·0001). Extended-release carbidopa-levodopa reduced daily off-time by, on average, an extra −1·17 h (95% CI −1·69 to −0·66; p<0·0001) compared with immediate-release carbidopa-levodopa. During dose conversion with extended-release carbidopa-levodopa, 23 (5%) of 450 patients withdrew because of adverse events and 13 (3%) withdrew because of a lack of efficacy. In the maintenance period, the most common adverse events were insomnia (seven 3% of 201 patients allocated extended-release carbidopa-levodopa vs two 1% of 192 patients allocated immediate-release carbidopa-levodopa), nausea (six 3% vs three 2%), and falls (six 3% vs four 2%). Interpretation Extended-release carbidopa-levodopa might be a useful treatment for patients with Parkinson's disease who have motor fluctuations, with potential benefits including decreased off-time and reduced levodopa dosing frequency. Funding Impax Laboratories.
The approvals of the first two medications, valbenazine and deutetrabenazine, to treat tardive dyskinesia have ushered in a new era in neuropsychiatric care. Tardive syndromes are defined as delayed ...onset, persistent movement disorders or sensory phenomena that occur in association with exposure to dopamine receptor blocking agents (DRBAs). Their underlying pathophysiology remains to be fully elucidated, but clinicians can conceptualize tardive syndromes as persistent dopamine supersensitivity states. Tardive syndromes can potentially cause distress, disfigurement, embarrassment, and dysfunction, and are often permanent. Therefore, practitioners who prescribe DRBAs should be aware of this potential, carefully assess the risk/benefit ratio when considering the use of these medications, and be sure that patients are appropriately informed. Patients on DRBAs should be monitored for the development of tardive syndromes, including through the use of regularly scheduled Abnormal Involuntary Movement Scale (AIMS) (or similar) examinations. Clinicians prescribing DRBAs should be familiar with the diagnosis and management of tardive syndromes, and be able to institute treatment or refer patients when treatment is appropriate. Future research may focus on the potential benefit of earlier introduction of VMAT2 inhibitors to delay onset or progression of tardive syndromes. More effective treatments are still needed, as are effective, well-tolerated antipsychotics that do not cause tardive syndromes.
PDF
