De Novo/early Stage Pd
A preliminary, open-label trial conducted in Japan suggested that a single administration of ZNS was efficacious in improving motor and sleep dysfunction in treatment-naive patients with early stage PD. Moreover, ZNS was recommended as adjunctive therapy in early stage/stable PD according to 2018 guidelines .
What Kinds Of Genetic Research Is Being Done
Researchers are investigating genes that code proteins responsible for producing dopamine. By increasing the amount of dopamine in the brain, Parkinson’s symptoms can be minimized if not prevented.
What other treatments are being researched?
- Drug treatments. Researchers are investigating drugs that block the action of glutamate, an amino acid that destroys nerve cells, as well as the role of the antioxidant coenzyme Q-10 in slowing the progression of Parkinson’s disease.
- Neural growth factor. Preliminary studies have shown that neural growth factor revives the dormant cells needed to produce dopamine, dramatically improving symptoms.
- Deep brain stimulation. Research is underway to better understand how deep brain stimulation works in Parkinson’s disease. Researchers are also studying improved ways of stimulating the brain.
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Symptomatic Treatment Of Motor Symptoms
Levodopa
A majority of patients with PD require levodopa therapy within 2 years of symptom onset. Levodopa, the most effective drug in the treatment of PD, is almost always combined with carbidopa or benserazide, aromatic acid decarboxylase inhibitors that prevent its peripheral metabolism and markedly reduce the risk of nausea. Increasing the ratio of carbidopa:levodopa from the current standard 1:4 has been shown to increase on time without dyskinesia and reduce off time.
The global antiparkinsonian efficacy of levodopa is so predictable that a positive therapeutic response is used to support the diagnosis of PD. Adverse effects of levodopa include nausea and vomiting, orthostatic hypotension, sedation, confusion, sleep disturbance, hallucinations and dyskinesias. There are many different types of dyskinesia but peak-dose chorea or stereotypy and wearing off dystonia are most common. About half of the patients experience wearing off, and a third experience dyskinesias within 2 years after initiation of levodopa therapy. Latency from ingestion of levodopa to observable therapeutic benefit can be shortened by taking levodopa on an empty stomach , avoiding or reducing protein intake, or by crushing the levodopa tablet and mixing it with a carbonated beverage.
Other drugs
Besides levodopa, there are many other types of medications available for the treatment of PD-related motor symptoms: anticholinergics, amantadine, MAOIs, COMTIs, dopamine agonists and istradefylline.
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Anticholinergics For Early On
The first pharmacological agents used in PD therapy were anticholinergic drugs. They reduce the activity of acetylcholine by acting as antagonists at choline receptors, hoping to restore the balance between dopamine and acetylcholine levels that was disturbed by PD. These drugs have largely been replaced by L-DOPA and other centrally acting dopaminergic agonists, but they still remain available for use in the treatment of PD. Benztropine, biperiden, diphenhydramine, ethopropazine, orphenadrine, procyclidine, and trihexyphenidyl are included in this therapeutic class of drugs, though there is little pharmacokinetic information available on them because of their low plasma drug concentrations. Typically, anticholinergic drugs have a greater role in tremor-predominant PD and can be a monotherapy in early stages, but are usually done in adjunct with L-DOPA or other prescribed medications.
Parkinsons Living Well Stories
- In a recent TODAY Sunday interview, Michael J. Fox shares details of the conversation he had with his wife, Tracy Pollan, when he told her about his Parkinsons diagnosis almost 30 years ago. One of the things Ill always love about Tracy for is that at that moment, she didnt blink.
- Veteran NASCAR driver and team owner Morgan Shepherd, who recently shared that he has been diagnosed with Parkinsons, is focusing on the positive and making plans for an inspired and successful 2021.
- At their TITLE Boxing Club in Florida, two veterans living with Parkinsons keep themselves and others motivated, reciting songs or answering trivia questions as they work out to strengthen their mind-body connection.
- Live well in 2021! Find holiday gifts for a loved one living with Parkinsons with ideas from Sherri Woodbridges A Gift Guide for Shopping from Home.
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Updates On Currently Approved Pd Treatments
Table 1 Approved dopaminergic drugs
Later, DA receptor agonists, such as those shown in Table , were developed either as monotherapies or combination therapies with L-DOPA for the treatment of PD. Five types of DA receptors, D1D5, exist in the brain. The D1 and D5 receptors are grouped together as D1-like receptors based on their stimulatory effects on adenylyl cyclase , and the D2, D3, and D4 receptors are classified as D2-like receptors due to their inhibition of cAMP activity. Many synthetic DA agonists, including pramipexole and apomorphine, activate D2-like receptors, and have a lower incidence of motor fluctuations and dyskinesia .
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Muscarinic And Nicotinic Acetylcholine Receptor Agonists
Cholinergic receptors contain muscarinic receptors and nicotinic receptors they function in somatic and autonomic signal transductions in the nervous system . We observed three trials that use muscarinic or nicotinic acetylcholine receptor agonists . ANAVEX2-73 is a small molecule that binds to muscarinic acetylcholine and sigma1 receptors in the low micromolar range developing by Anavex Life Sciences Corp . In October 2019, they started a phase II open-label extension to evaluate the effects of ANAVEX2-73 in 120 PD subjects with dementia on the safety and efficacy of daily treatment . Anavex Life Sciences Corp. estimates the study completion by 31 October 2021. Nicotine is used in two phase-II trials as a transdermal patch and a nasal spray for PD treatment. Unfortunately, the trial data for the nicotine transdermal patch in PD patients is unavailable . Another trial using nicotine nasal spray trial status shows complete under subject recruitment and no results posted . Although the high doses of transdermal nicotine were also tolerated, they failed to show significant improvements in UPDRS scores .
Moreover, the cholinergic drug treatment disadvantages might be less efficient than dopamine receptor agonists or carbidopa-levodopa treatment or even may cause adverse effects on parasympathetic nerve-related organs in PD .
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Pd Therapeutic Strategies In Clinical Trials
In Figure 2, we have classified these therapeutic strategies into 15 types: dopamine receptor agonists, anti–synuclein aggregation therapy, convalescent plasma therapy, cell-based therapy, gene therapy, serotonin receptor partial agonists or antagonists, monoamine reuptake inhibitors, muscarinic and nicotinic acetylcholine receptor agonists, N-methyl-d-aspartate receptor modulators, anti-apoptotic drugs, kinase inhibitors, myeloperoxidase inhibitors, adenosine A2A receptor antagonists, antioxidants/botanical-based medication, and others. Figure 3 depicts the type of drug or therapy, mechanisms, and the current drugs/treatments in PD.
The drug or therapy with its therapeutic strategy and trial status in the clinical trials for PD treatment. The blue and red text color indicates the trial status is unknown and discontinued, respectively .
Rapid Eye Movement Sleep Behaviour Disorder
REM sleep behaviour is associated with PD and is a prodromal symptom in many cases. Patients with REM sleep disorder often physically act out vivid dreams during REM sleep, which can affect their quality of life and that of their family and carers. NICE recommends the off-label use of clonazepam or melatonin . Benzodiazepines are cautioned in the elderly population therefore, this patient cohort must be monitored closely by their care team if started on clonazepam.
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How Could Stem Cells Help People With Parkinson’s
Stem cells are the parent cells of all tissues in the body. This means they can turn into any type of cell. The hope is that they will eventually be able to make these cells into specific types of cells, like dopamine-producing neurons, that can be used to treat Parkinson’s disease. However, there are concerns that patients may have the same risk of increased involuntary movements as those who undergo fetal cell transplantation. And, like fetal cell transplantation, stem cell therapy is surrounded by moral and ethical controversy.
Starting Treatment In Early Parkinsons Disease
The optimal time to start treatment in PD has been the source of much debate. In an open-label study of 198 patients with untreated PD, quality of life as measured by the Parkinsons Disease Questionnaire-39 worsened in those left untreated, but was stable or improved in patients receiving dopaminergic treatment. In an observational study comparing Italian patients with PD who started levodopa early with those in Ghana where therapy was delayed, motor fluctuations and dyskinesia occurred at similar disease duration. This showed that duration of disease rather than treatment is a key determinant of motor complications. Therefore, delaying dopaminergic therapy does not avoid the development of motor complications and may be associated with poorer QoL. The recent delayed-start LEAP study showed no disease-modifying effect of levodopa in patients diagnosed < 2 years prior, but PDQ-39 score was improved in the blinded phase in those receiving early vs delayed treatment.
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Diagnosis Of Parkinsons Disease
The diagnosis of PD is clinical and requires bradykinesia, defined as slowness of movement and decrement in amplitude or speed, usually assessed using finger tapping, foot tapping or pronationsupination hand movements. In addition, rest tremor or rigidity is required to confirm a parkinsonian syndrome. Tremor was absent at presentation in 30% in one series of pathologically proven PD. Patients with suspected PD should be referred quickly and untreated to a specialist in movement disorders for evaluation. Key points for discussion at diagnosis include the need to inform vehicle licensing agencies and insurers, signposting to written or web-based information on newly diagnosed PD, and provision of contact details for the local PD nurse specialist .
Current International Parkinson and Movement Disorder Society diagnostic criteria for Parkinsons disease adapted from Postuma RB, Berg D, Stern M et al. MDS clinical diagnostic criteria for Parkinsons disease. Mov Disord 2015 30:1591601. At least two supportive criteria and no red flags required for a diagnosis of clinically established Parkinsons disease. Conditions in italics should be considered if the corresponding exclusion criteria or red flags are present.
Parkinsons Surveys Clinical Trials And Volunteer Opportunities
PAIRing Up If you are a person with Parkinsons or a care partner to someone with Parkinsons, you are invited to participate in an online survey to address neuropsychiatric concerns in Parkinsons. The survey aims to learn about the needs and priorities for clinical care, education, support, and research as related to neuropsychiatric symptoms. To learn more and participate, .
The University of Oulu, along with collaborators from Aalborg University, Fraunhofer University, the University of Manchester, the University of Glasgow, the University of Lisbon, and the University of Melbourne, is conducting a survey for people with Parkinsons and Parkinsons care partners about self-care. Complete the survey here to share your self-care strategies and techniques. You can also review ideas submitted by others and add them to your own self-care toolbox.
Looking for a once-in-a-lifetime adventure? Pass to Pass, a nonprofit dedicated to raising Parkinsons awareness while supporting hikers living with Parkinsons, offers multi-day hiking trips on the Pacific Crest Trail in both Washington and Oregon. Participants are being recruited now for these summer 2021 events. For more details and information, visit www.PasstoPass.org or contact Bill Meyer at 509-991-1212 or .
Park Test University of Rochester
Project Euphonia LSVT Global and Project Euphonia
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Where Is Drug Development Headed
Overall, experts say the Parkinson’s disease field aims to develop therapies that can slow or stop disease progression. Kordower notes several promising gene therapy and stem cell therapy approaches are entering the early stages of clinical development.
Most ongoing PD trials are at the Phase II stage, according to GlobalDatas Clinical Trial Database. While institutions are sponsoring 84 trials of the 133 ongoing Phase II studies , pharma companies are running 44 trials of the 56 ongoing Phase I studies .
As the field awaits results from the slew of ongoing trials, experts agree that the PD trials reading out in the remainder of 2022 could have a substantial impact. These four trials are all very timely, Eidelberg says. The community of movement disorder specialists and neurologists would use these drugs because the indications we’re talking about are really very common.
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Parkinsons Disease: A Hopeful Future
Parkinsons disease is the fastest growing neurological condition in the world. Between 1990 and 2015, the number of people with this disease doubled to over 6 million . This number is predicted to double again to 12 million by 2040, primarily because of an ageing population . In the UK, the lifetime risk of developing Parkinsons disease is 2.7%, with approximately 17,300 new diagnoses made every year in people aged 45 and above .
Parkinsons disease is a progressive, neurodegenerative disorder of the brain . It is characterised by the death of certain brain cells , particularly in an area of the brain called the substantia nigra . A high proportion of neurons within this part of the brain use a chemical called dopamine to transmit signals between themselves and throughout the brain these signals act to coordinate movement .
As the neurons in the substantia nigra die off, the amount of dopamine falls, which results in some of the major features of Parkinsons disease, such as slowness and stiffness of movement .
Adapted from International Society for Stem Cell Research 2022.
These symptoms increase in severity over time as more neurons are lost, and eventually patients may experience a resting tremor and have problems walking . Approximately 80% of patients also develop dementia within 20 years of disease onset .
Current treatment options target the symptoms, but not the cause
A new era: Targets for the Parkinsons disease medication pipeline
Lewy body accumulation
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Irlab Celon Target Parkinsons Disease Motor Symptoms
While levodopa can reduce PD symptoms by increasing dopamine levels in the brain, prolonged use can cause increased bouts of dyskinesia during OFF time when the drug has reduced effects. IRLAB Therapeutics and Celon Pharma have Phase II trials aiming to reduce levodopa-induced dyskinesia using two different approaches.
IRLABs mesdopetam, which targets the dopamine D3 receptor, has placebo-controlled Phase II trial results expected the second half of this year. Mesdopetam has estimated peak sales of $226 million in 2026, according to GlobalDatas consensus forecast. GlobalData is the parent company of Clinical Trials Arena.
As a primary endpoint, the Phase II mesdopetam trial assesses change in ON time, defined as hours in the day where patients experience the positive effects of levodopa without the negative effects of dyskinesia. Before and after 12 weeks of treatment, patients record their hours of ON time over the course of 24 hours.
Meanwhile, Celons CPL500036, which targets phosphodiesterase 10A , also has placebo-controlled Phase II results expected this year. The four-week study uses a primary endpoint of the Unified Dyskinesia Rating Scale , which measures the severity of dyskinesia side effects.
Of the two primary endpoints, change in ON time is a better measure than the UDyRS, Kordower says. My understanding is that patients would much rather have less time spent in dyskinesias than decreased magnitude of dyskinesia, he explains.
Drug And Medication Therapies
The purpose of treating Parkinsons is to reduce the effect of symptoms on your daily life. Without treatment, you will eventually find that the symptoms make it hard to perform daily activities. Symptoms, such as shaking and stiffness, may cause discomfort the risk of injury from falls may increase, and swallowing may become more difficult. People are encouraged to maintain open and ongoing discussions with their Parkinsons healthcare team when exploring treatment options.
Medication will help you function, but may cause side effects. It is important to find the right balance between the medications benefits and side effects. Everyone with Parkinsons is unique and will experience different symptoms, which means the treatment you receive will be geared to your specific needs. Drugs for Parkinsons work on the brains complex chemistry and may need to be taken several times a day. Use them as prescribed and do not alter your doses without consulting your doctor. Current treatment neither cures Parkinsons nor stops it from advancing.
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Lifestyle And Other Protective Factors
Cigarette smoking and caffeine consumption are the two most consistent protective factors associated with a reduced risk of PD. Other reported associations include higher serum urate, ibuprofen use and exercise, among others. The negative association between cigarette smoking and PD is most intriguing. This inverse relationship is not easily explained, but some have suggested that PD-related cautious personality predisposes some individuals to quitting neuroprotective smoking as the biological mechanism involved in PD. The other hypothesis links nicotine to dopaminergic neuronal protection since it has been shown to stimulate the release of dopamine in the striatum and preserve dopaminergic function in experimental models. It is also possible that there are other unidentified neuroprotective components in cigarette smoke.
The relative risk reduction of PD among caffeine drinkers is between 0.5 and 0.8 and, similar to smoking, a dose-dependent effect has been consistently demonstrated in most studies. Caffeine, an antagonist of adenosine A2a receptor, has been postulated to exert neuroprotective role by blocking this receptor. In addition to caffeine, it is possible that antioxidants present in some beverages may contribute to a protective effect among black tea drinkers, independent of caffeine.
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What Causes Parkinson’s Disease
Parkinson’s Disease is caused by a loss of nerve cells in the brain. This loss of nerve cells within the brain results in a reduced amount of dopamine being created which acts as a messenger between the parts of your brain that control voluntary and involuntary movement. Therefore without that vital connection, your brain starts losing the ability to effectively control movement. Currently, it is unknown what causes the deterioration of nerve cells associated with Parkinson’s Disease . Currently, it is believed that both environmental factors, as well as genetic factors, may play a role in the loss of nerve cells.
Parkinson’s Disease is a lifelong condition that can greatly impair the ability of one’s daily functions. Traditional treatments only address the symptoms of the condition, but researchers are excited about the possibilities of certain gene therapies and stem cell therapy, which may have the ability to reverse damage and halt the progression of the disease.
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