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A neurologist fears that treatments for Parkinson's disease, called "levodopa phobia," do not cause potential side effects, to delay the use of these treatments.
However, evidence suggests that early initiation of adequate treatment with levodopa is safe, particularly for patients with increased functional disability, according to a presentation by Joseph Jankovic, MD, professor of neurology at Baylor College of Medicine, presented by the Parkinson Voice Project (PVP.)
Jankovic's conference, "New Emerging Treatments for Parkinson's Disease," was presented to patients and caregivers via Skype as part of Parkinson's Parkinson's Series of PVP, organized by Parkinson Education Center and Brigid Lund Parkinson. A video of the presentation is available online.
Modifying therapies
There is currently no treatment to slow or prevent Parkinson's progression, although many are in clinical trials. A Phase 3 trial (NCT00256204), called ADAGIO, completed in 2011, suggested that early treatment with Azilect (rasagiline) could delay the progression of the disease. However, the study included two dosages, 1 mg and 2 mg, and although the benefits were real for the lowest dose, they did not withstand the highest dose. Because the two doses were associated with different results, the results should be interpreted with caution, and the US Food and Drug Administration (FDA) did not approve Azilect as a disease modifying treatment.
Researchers are exploring several treatments that may alter the disease, including inosine (which increases urate levels) and isradipine (a calcium channel blocker). Both are in phase 3 testing (NCT02642393 and NCT02168842).
However, said Jankovic, the "most important strategy of development" is to reduce alpha-synuclein, a protein that does not work properly and that accumulates in the brains of patients with Parkinson's disease, resulting in neuronal death.
Jankovic and his colleagues Last year, we published a study based on a Phase 2 trial (NCT03100149) on an antibody – prasinezumab (PRX002 / RG7935) – designed to remove alpha-synuclein proteins. The dose-escalation study in 80 patients showed that the treatment was safe and that it reduced alpha-synuclein levels in the blood over 52 weeks, without any of the following. serious adverse reaction has been reported. The study supported the continuation of the Phase 2 trial.
Similar antibodies currently being tested include BIIB054 (NCT03318523) from Biogen, MEDI1341 (NCT03272165) from AstraZeneca (which is currently recruiting) and ABBV-951 (NCT03781167) from Abbie.
Early symptomatic therapies
When patients begin to experience symptoms severe enough to require treatment, their doctor and doctor may be reluctant to start levodopa or levodopa-carbidopa – the most commonly used treatment for Parkinson's symptoms – for fear of developing complications. motor such as dyskinesia.
Some patients may turn to natural supplements, such as bacopa extract or mucuna pruriens. Jankovic has "strongly discouraged" the use of these products for "many reasons", including among the supplements that some supplements contain levodopa in inconsistent doses.
Dopamine agonists such as Mirapex (pramipexole), Requip (ropinirole), Dostinex (cabergoline) and Permax (pergolide) are an alternative to patients and neurologists who fear starting levodopa too early. Instead of helping the brain to produce more dopamine than it lacks, these treatments directly stimulate the receptors on which dopamine would normally act.
A 2009 study comparing pramipexole with levodopa in patients who had not been treated with levodopa showed that 50% of pramipexole patients had dyskinesia, compared with 68.4% of patients treated with levodopa.
"There is no doubt that delaying treatment with levodopa by using dopamine agonists early may delay the onset of motor complications related to levodopa," said Jankovic.
Although levodopa has potential for side effects in vitro (or in the lab), Jankovic said that there was no evidence that this translates to the patients. Therefore, delaying the use of therapy, particularly in patients with increased functional disability, is not supported by currently available scientific evidence, he said.
However, he thinks that, as each patient is different, the timing, choice and dosage of treatment should be individualized according to the needs of each patient.
Emerging and experimental therapies
Almost all patients with severe Parkinson's who are taking levodopa or levodopa-carbidopa will experience motor fluctuations and dyskinesia over time. Thus, many emerging therapies are designed to make treatment more effective and reduce side effects.
Three treatments increase the effectiveness of levodopa by maintaining increased levels of dopamine in the brain. Xadago (safinamide) inhibits monoamine oxidase, an enzyme that normally breaks down dopamine. The opicapone works by preventing a different enzyme, catechol-O-methyltransferase (COMT), from degrading dopamine. Gocovri (amandine) prevents cells from recycling dopamine.
Several new formulations of levodopa are intended to extend the effects of a single dose or to act almost immediately to help patients recover from "off" episodes between doses.
Rytary, a capsule that can be taken orally, contains carbidopa-levodopa beads that dissolve and release the drug at different times. Since the treatment should be taken more than once a day, patients end up ingesting a higher dose of levodopa than they would otherwise have. But the effects start earlier and last longer than the usual carbidopa-levodopa formulation.
The researchers experimented with the administration of continuous treatment for 24 hours using an intestinal gel, surgically implanted in the small intestine and programmed to administer the treatment consistently to the appropriate dose.
But choosing this operation "can not be taken lightly," said Jankovic. Although patients increased their activation time without dyskinesia (4.11 hours for those who used the intestinal gel, versus 2.24 hours for those who took oral levodopa), almost all of 66 patients from a 2014 study reported gastrointestinal adverse effects result of the insertion of the device.
Jankovic also described the "accordion" pill currently being tested in a Phase 3 trial (NCT02605434). The pill, developed by Intec Pharma, is a multilayer film that unfolds in the stomach and stays there for 12 hours, releasing a combination of levodopa and carbidopa.
Rather than prolonging the lifespan of a levodopa dose, some companies are developing "life-saving therapies" that can be taken during off-peak periods or when treatment ends. These therapies take effect almost immediately and help the patient continue treatment until the next scheduled dose of levodopa. Several forms – approved and undergoing testing – are dopamine agonists injected under the skin.
Other companies are developing treatments they hope will be administered by less invasive methods, such as under the tongue in the case of APL-130277 or by inhalation, such as Inbrija, a powder levodopa approved in December 2018.
Surgical therapies are attracting more and more attention, with FDA approved end-point-of-care ultrasound scientists testing late 2018. However, they are available in very few centers and cost more than $ 4 million.
Also in 2018, researchers conducted a pilot study of five patients, suggesting that spinal cord stimulation could help patients improve gait.
Jankovic says it's too early to usefully discuss several other experimental therapies, such as gene therapies or stem-cell therapies. "Ask me in 10 years," he says.
Various agents are studied to treat non-motor symptoms, including Exelon (rivastigmine) and memantine (sold under the Namenda brand, among others) for cognitive disorders, paroxetine and venlafaxine for depression and SEP-363856 for psychosis. Nuplazid (pimavanserin) is the only treatment currently approved by the FDA for the treatment of hallucinations and delusions associated with Parkinson's disease.
In addition to all the therapies available on the market, Jankovic said he "could not overemphasize the importance of physiotherapy" and high-intensity exercise – "something that makes you really angry".
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