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Parkinsons Treatment
Parkinsons DiseaseParkinson's disease (PD), a neurodegenerative disease of the substantia nigra, was first discovered and its symptoms ..... The best course of action to take sometimes isn't clear until you've listed and considered your alternatives. The article to follow will you see what those who know believe is important. If you have a particular interest in parkinsons treatment, then this informative article is much needed reading.
Medical Care: The goal of medical management of PD is to provide control of signs and symptoms for as long as possible while minimizing adverse effects. Medications usually provide good symptomatic control for 4-6 years. After this, disability progresses despite best medical management, and many patients develop long-term motor complications including fluctuations and dyskinesia. Additional causes of disability in late disease include postural instability (balance difficulty) and dementia.
Putative neuroprotective therapy: Neuroprotective therapies are defined as those that slow the underlying loss of dopamine neurons. Currently, no proven neuroprotective therapies exist for PD.
If a neuroprotective therapy were available for PD, it would be administered from the time of diagnosis onward.
Selegiline is the medication that first has garnered interest as a possible neuroprotective agent.
Laboratory investigations continue to provide evidence that selegiline affords a neuroprotective effect for dopamine neurons independent of MAO-B inhibition.
Selegiline has been demonstrated to protect cultured dopamine neurons from MPP+ toxicity, an effect that cannot be attributed to MAO-B inhibition. Tatton and Greenwood demonstrated that selegiline protects dopamine cells in mice from MPTP toxicity even when administered after a delay sufficient to allow the oxidation of MPTP to MPP+.
In cell-culture systems, selegiline's neuroprotective effect is mediated by new protein synthesis. Selegiline induces transcriptional events that result in increased synthesis of antioxidant and anti-apoptotic proteins. Recent evidence indicates that one of selegiline's metabolites, desmethylselegiline, is the active agent for neuroprotection.
Selegiline's amphetamine metabolites may interfere with its neuroprotective actions.
In the clinical study called deprenyl (selegiline) and tocopherol (vitamin E) antioxidative therapy of parkinsonism (DATATOP), the Parkinson Study Group evaluated the ability of these 2 medications to delay progression of clinical disability in early PD. Eight hundred patients were randomized to receive selegiline (10 mg/d) or placebo and tocopherol (2000 IU/d) or placebo. Patients assigned to receive selegiline, with placebo or with tocopherol, experienced a significant delay in the need for levodopa therapy (hazard ratio = 0.50, P <0.001). Patients assigned to receive placebo required levodopa at a projected median of 15 months from enrollment, while those who received selegiline required levodopa at a projected median of 24 months after enrollment. Tocopherol had no effect on progression of disability.
The study conclusively demonstrated that selegiline delays the need for levodopa therapy in early PD; this result is consistent with the hypothesis that selegiline may slow disease progression. However, the study also found that selegiline provided a small symptom-relieving effect, and whether the delay in the need for levodopa was due entirely or in part to this modest effect is not clear.
Parkinsons Disease ArticleHuman retina cell implants improved motor symptoms in a group of Parkinson's disease (PD) patients who participated in a recent study, and they ..... In one study, selegiline was associated with increased mortality rate in patients with PD. The Parkinson's Disease Research Group of the United Kingdom reported a 57% higher mortality rate in patients assigned to receive selegiline plus levodopa than in those who received levodopa alone (mortality ratio = 1.57, 95% confidence interval 1.09-2.30, P = 0.015). The difference in mortality rate emerged between the third and fifth years of treatment, and no obvious explanation regarding its cause was identified.
Many questions have been raised regarding the results and methodology of this study. Mortality rates were not significantly different between groups when the analysis was based on what patients actually were taking and not on intention to treat. In addition, the mortality rate was unusually high in both groups (28% in patients receiving selegiline, 18% in those not receiving selegiline).
Rasagiline is a new MAO-B inhibitor that exhibits neuroprotective effects in cell culture and animal models. In a clinical trial (TEMPO), treatment with rasagiline for 1 year provided significantly greater improvement than treatment with placebo for 6 months followed by rasagiline for 6 months.
Co-enzyme Q10 is another drug of interest. It is a scavenger of free radicals. In a preliminary study, co-enzyme Q10 1200 mg/d slowed progression of PD disability.
Further studies of rasagiline and co-enzyme Q10 are required.
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Symptomatic therapy
Levodopa, coupled with a peripheral decarboxylase inhibitor (PDI), remains the standard of symptomatic treatment for PD. It provides the greatest antiparkinsonian benefit with the fewest adverse effects in the short term.
Dopamine agonists provide symptomatic benefit comparable to levodopa/PDI in early disease but lack sufficient efficacy to control signs and symptoms by themselves in later disease.
Dopamine agonists cause more sleepiness, hallucinations, and edema than levodopa.
Prospective, double-blind studies have demonstrated that initial treatment with a dopamine agonist, to which levodopa can be added as necessary, causes less motor fluctuations and dyskinesias than levodopa alone.
Dopamine agonists can be used as initial symptomatic therapy in early disease, rather than levodopa/PDI, to delay the onset of motor fluctuations and dyskinesia. This strategy is usually reserved for younger individuals (<65-70 y) who are cognitively intact.
Levodopa and motor complications
As PD progresses, fewer dopamine neurons are available to store and release levodopa-derived dopamine. The patient's clinical status begins to fluctuate more and more closely in concert with plasma levodopa levels. Exposing striatal dopamine receptors to fluctuating dopamine concentrations may cause a hypersensitivity that is expressed clinically as peak-dose dyskinesia (twisting, turning movements). Fluctuating levodopa-derived dopamine concentrations in association with advancing disease therefore may be responsible for development of motor fluctuations and dyskinesia.
The Continuous Dopaminergic Stimulation (CDS) hypothesis posits that pulsatile dopamine receptor stimulation induces dyskinesia, whereas smoother more continuous dopamine receptor stimulation causes less dyskinesia.
Just MobilityDon’t be a prisoner in your own home. If you or a household member happens to be ..... In contrast to levodopa, the long-acting dopamine agonists (ie, bromocriptine, pergolide, pramipexole, ropinirole, cabergoline) provide relatively smooth and sustained receptor stimulation. In marmosets with MPTP-induced parkinsonism, levodopa administration causes significantly more dyskinesia than bromocriptine or ropinirole.
Prospective clinical trials have demonstrated that initial treatment with a dopamine agonist to which levodopa can be added causes less motor fluctuations and dyskinesia than levodopa alone.
A recent MPTP marmoset study found that the addition of entacapone (which increases the half-life of levodopa) was associated with less motor fluctuations and less dyskinesia than treatment with the same regimen of levodopa alone. This finding is consistent with the CDS hypothesis. A clinical trial (STRIDE-PD) is now underway to determine if levodopa plus entacapone (levodopa/carbidopa/entacapone) delays the occurrence of dyskinesia compared with levodopa/carbidopa when levodopa is first required.
Early disease treatment strategies
The younger the patient, the more emphasis the authors place on long-term considerations to guide early treatment. Young patients have a longer life expectancy and are more likely to develop motor fluctuations and dyskinesias.
For older patients and those with cognitive impairment, less emphasis is placed on long-term considerations; the focus is on providing adequate symptomatic benefit in the near term with as few adverse effects as possible.
At the time of diagnosis, a discussion is initiated to review current information regarding possible neuroprotective agents currently under study.
The younger the patient, the more critical the need for neuroprotection, and the more likely the authors are to recommend a possible neuroprotective agent.
Symptomatic therapy is introduced when the patient experiences functional disability. The selection of medication depends in part on the nature and cause of the disability.
If disability is due solely to tremor, a tremor-specific medication, such as an anticholinergic agent, can be used. Anticholinergic medications provide good tremor relief in approximately 50% of patients but do not improve bradykinesia or rigidity. Because tremor may respond to one anticholinergic medication and not another, a second anticholinergic usually is tried if the first is not successful. These medications should be introduced at a low dose and escalated slowly to minimize adverse effects, which include memory difficulty, confusion, and hallucinations. Adverse cognitive effects are relatively common, especially in the elderly.
If disability is due to a dopamine-responsive symptom such as bradykinesia, rigidity, decreased dexterity, slow speech, or shuffling gait, a dopaminergic medication, such as an MAO-B inhibitor, amantadine, dopamine agonist, or levodopa, should be introduced. MAO-B inhibitors provide mild symptomatic improvement but have few side effects. Amantadine also provides mild symptomatic improvement but may cause cognitive side effects or hallucinations, especially in older individuals and those with cognitive dysfunction. Dopamine agonists provide moderate benefit and cause less fluctuations and dyskinesias, but they have more side effects including sleepiness, hallucinations, and edema. Levodopa is the strongest symptomatic agent but its long-term use is associated with the development of fluctuations and dyskinesias.
Symptomatic medications are started at a low dose, escalated slowly, and titrated to control symptoms. Most patients require symptomatic dopaminergic therapy to ameliorate bradykinesia and rigidity within 1-2 years after diagnosis.
For patients younger than 65 years, the authors often utilize a dopamine agonist and then add levodopa/PDI when the dopamine agonist alone no longer controls symptoms adequately. Dopamine agonists provide antiparkinsonian efficacy comparable to levodopa/PDI for 6-18 months or longer and may control symptoms adequately for several years.
When the dopamine agonist no longer provides adequate symptomatic control despite titration to the usual maximum or highest tolerated dose, levodopa/PDI is added. The relatively sustained dopamine receptor stimulation provided by the dopamine agonist may buffer receptors from fluctuating levodopa-derived dopamine concentrations and afford a lower incidence of motor fluctuations and dyskinesia.
For patients who are demented or those older than 70 years, who may be prone to adverse effects from dopamine agonists, and for those likely to require treatment for only a few years, the authors may elect not to use a dopamine agonist and depend on levodopa/PDI as primary symptomatic therapy.
For patients aged 65-70 years, the authors make a judgment based on general health and cognitive status. The more robust and cognitively intact the patient, the more likely the authors are to start symptomatic treatment with a dopamine agonist and add levodopa/PDI when necessary.
When introducing a dopamine agonist, starting at a low dose and escalating slowly is important. The dose should be titrated upward until symptoms are controlled, the maximum dose is reached, or adverse effects become intolerable. The most common adverse effects of dopamine agonists are nausea, orthostatic hypotension, hallucinations, and somnolence. Nausea usually can be reduced by having the patient take the medication after meals. Domperidone, a peripheral dopamine agonist available outside the US, is very helpful in relieving refractory nausea.
Levodopa/PDI is introduced at a low dose and escalated slowly. Currently available levodopa preparations in the United States include levodopa/carbidopa, levodopa/carbidopa CR, levodopa/carbidopa orally disintegrating tablet, and levodopa/carbidopa/entacapone. The orally disintegrating tablet is bioequivalent to oral levodopa/carbidopa but dissolves on the tongue without the need to swallow it with water.
The levodopa dose is titrated to control clinical symptoms; most patients experience a good response on a daily dosage of 400-600 mg/d for 3-5 years or more. Doses higher than those necessary to control symptoms adequately should be avoided.
If nausea occurs, the dose may be taken following a meal. Additional measures to alleviate nausea include adding extra carbidopa or introducing domperidone.
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