Tuesday, November 22, 2022

Recent Developments In Parkinson’s Disease

Common Scale Of Motor Symptom Severity May Have Flaws: Study

Latest developments in symptomatic treatment of Parkinsons disease

A commonly used measure of how motor symptoms are affecting daily life could also for people in early stages of Parkinsons disease be taking into account the contribution of their non-motor symptoms, a study suggests. This is a likely reason for the discrepancies seen in evaluations made by patients

New Medications For Off Time

A number of new medications approved recently are designed to reduce OFF time. These medications fall into two major categories:

  • Medications that lengthen the effect of a carbidopa/levodopa dose
  • Medications that are used as needed if medication effects wear off

Well give specific examples below. In general, new medications that extend the length of a carbidopa/levodopa dose are used if OFF time is somewhat predictable and occurs prior to next dose. New medications that are used as needed are most beneficial when OFF time is not predictable.

New medications that lengthen the effect of a dose of carbidopa/levodopa

  • Istradefylline is an adenosine A2A receptor antagonist which was approved in the US in 2019 as an add-on therapy to levodopa for treatment of OFF time in PD. Unlike many of the other medications, it has a novel mechanism of action and is the first medication in its class to be approved for PD. It acts on the adenosine receptor, which modulates the dopaminergic system, but is not directly dopaminergic. The drug was developed in Japan and underwent clinical trials both in Japan and in the US.
  • Opicapone is a catechol-O-methyltransferase inhibitor that is taken once a day. It was approved in the US in 2020 as an add-on therapy to levodopa for motor fluctuations.

New formulations of levodopa designed to be used as needed if medication effects wear off

Other medications used as needed if medication effects wear off

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Levodopa In The Treatment Of Parkinson’s Disease: Current Status And New Developments

Article type: Review Article

Authors: Salat, David | Tolosa, Eduardo

Affiliations: Universitat Autònoma de Barcelona, Barcelona, Spain | Parkinson’s Disease and Movement Disorders Unit, Neurology Service, Hospital Clínic, University of Barcelona Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas Barcelona, Spain

Note: Correspondence to: Eduardo Tolosa MD, FRCP, Neurology Service, Hospital Clinic, University of Barcelona, Villarroel 170, Barcelona 080036, Spain. Tel.: +34 93 227 57 85 Fax: +34 93 227 57 83 E-mail:

Keywords: Levodopa/carbidopa, Parkinson’s disease, wearing-off, dyskinesia, entacapone

DOI: 10.3233/JPD-130186

Journal: Journal of Parkinson’s Disease, vol. 3, no. 3, pp. 255-269, 2013

Abstract

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What Is Fetal Cell Transplantation

Fetal cell transplantation is a procedure in which fetal cells are implanted into the brains of people with Parkinson’s disease to replace the dopamine-producing cells in the substantia nigra. Although promising, this area of research is one of the most controversial. Some studies have found that fetal cell transplantation caused an increase in severe involuntary movements due to too much dopamine in the brain. There are also moral and ethical objections to the use of fetal cell implants. As a result, other methods of treatment are being explored.

The Shift From Research On Symptomatic Therapy To The Search For Parkinsons Disease

Frontiers

Based on these findings, the majority of cases with PD were assumed to present an alpha-synucleinopathy. Drug development shifted its focus from transmitters, transmitter-related receptor agonists and antagonists, and transmitter-synthesizing and -degrading enzymes to the protein chemistry, synthesis, transport, aggregation, and degradation of alpha-synuclein and other proteins related to neurodegenerative disorders, such as MAP-Tau or beta-amyloid. A now-20-year-long effort in neuroscience and drug development appears to provide the first results.

This article summarizes the recent achievements to further improve symptomatic therapy of motor PD symptoms, the still-limited attempts to provide symptomatic therapy for NMSs in PD, and the advances in the development and clinical testing of compounds, which promise to offer disease modification in already-manifest PD. However, prevention is still a dream and one reason for this is that we have no consensus on primary endpoints for clinical trials, which reflect the progression in prodromal stages of PD, such as in rapid eye movement sleep behavior disorder , the most specific prodromal stage of PD a methodological challenge to be met in the future.

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A Little Bit Of History

A new important breakthrough took place in 1983 when Langston and colleagues reported a group of drug users who developed acute parkinsonism after MPTP exposure . These patients developed an acute syndrome indistinguishable from PD. This is due because the MPTP metabolite, MPP+, destroys the dopaminergic neurons in the substantia nigra after a series of alterations in the mitochondrial matrix and the electron transport chain. The SNc of Parkinson patients was also described as exhibiting a marked decrease in complex I activity . The fact that some PD patients have certain polymorphisms in genes that express subunits of complex I suggests that this could be a vulnerability factor in PD . New models based on MPTP intoxication allowed researchers to ascertain PD hallmarks both in vitro and in vivo . Due to the achievements of pharmacological DA treatments, search of cell-based DA replacement approaches were initiated with largely disappointing results . From the surgical and therapeutic point of view, discrete lesions of the BG improved parkinsonism . A monkey model of PD showed motor signs improvement as a result of the chemical destruction of the subthalamic nucleus , with evidence of reversal of experimental parkinsonism by STN lesions. This same year deep brain stimulation of the STN became effective for PD treatment .

Figure 1. Breakthroughs in Parkinsons disease history.

Aptinyx Focuses On Parkinsons Disease Cognitive Impairment

Aptinyx is amid a Phase II trial targeting one of the biggest unmet needs in Parkinson’s disease treatment: cognitive impairment and dementia.

In patients with PD, Lewy bodies and alpha-synuclein, which are implicated in the pathology of PD, can spread into the cortex, causing forms of cognitive impairment and dementia in a large percentage of patients, Kordower explains. Theres no current treatment, so any clinical trial that has some benefit is incredibly valuable, he says.

Aptinyxs NYX-458, which targets the N-methyl-D-aspartate receptor, has placebo-controlled Phase II results expected at the end of 2022 or early 2023. The trial lists eight primary endpoints, ranging from the incidence adverse events to reductions in scales of psychosis and suicidal ideation.

“There’s no current treatment, so any clinical trial that has some benefit is incredibly valuable.”

Jeffrey Kordower

Targeting NMDA is a good start, says Dr David Eidelberg, neurologist at the Feinstein Institutes for Medical Research. However, showing reduction in cognitive impairment may be more difficult in PD than in Alzheimers disease, where changes are typically more pronounced, he notes.

Nevertheless, experts are encouraged that a trial is taking aim at this substantial unmet need. According to GlobalData consensus forecasts, NYX-458 has expected peak sales of $323 million in 2028.

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Recent Advances In Parkinson’s Disease

Brain neurotransmitters.

Parkinson.org

Parkinsons disease is a progressive neurodegenerative disease that induces symptoms of shaking, stiffness, uncontrollable movement, poor coordination, and balance. Development of Parkinsons disease occurs at the age of 60 onward. This brain disorder develops as early as 50 years old in 5-10% of cases. Parkinsons affects nerve cells deep in the brain called basal ganglia. These cells are responsible for producing dopamine and transmitting messages for bodily functions.

Current treatments replace dopamine to the brain of a patient. Such treatments have been successful at reducing symptoms of nausea. At present, there is no cure for this brain disorder. It is important to manage Parkinsons early on, one new discovery that may help is the use of diagnostic tools.

Early detection of Parkinsons Disease

Biomarkers can be used as a diagnostic tool for identifying the stage of a disease in a patient with abnormal conditions. Researchers at Kobe and Hiroshima University developed a biomarker that detects early Parkinsons in patients’ blood serum samples such it is a quick and inexpensive process as outlined in figure 1.

Figure 1. Changes in P450 expression

https://neurosciencenews.com/parkinsons-biomarker-20673/

Figure 2. P450 inhibition assay process

https://neurosciencenews.com/parkinsons-biomarker-20673/

Model Analysis

Figure 3. Results of analysis using Parkinsons disease model rats and humans with Parkinsons … disease.

Levodopa In The Treatment Of Parkinsons Disease: Current Status And New Developments

New Advances Make DBS Therapy More Effective For Treating Parkinson’s Disease

Article type: Review Article

Authors: Salat, David | Tolosa, Eduardo

Affiliations: Universitat Autònoma de Barcelona, Barcelona, Spain | Parkinsons Disease and Movement Disorders Unit, Neurology Service, Hospital Clínic, University of Barcelona Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas Barcelona, Spain

Note: Correspondence to: Eduardo Tolosa MD, FRCP, Neurology Service, Hospital Clinic, University of Barcelona, Villarroel 170, Barcelona 080036, Spain. Tel.: +34 93 227 57 85 Fax: +34 93 227 57 83 E-mail:

Keywords: Levodopa/carbidopa, Parkinsons disease, wearing-off, dyskinesia, entacapone

DOI: 10.3233/JPD-130186

Journal: Journal of Parkinsons Disease, vol. 3, no. 3, pp. 255-269, 2013

Abstract

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The State Of The Field

Understanding of Parkinson’s has grown substantially over the past two decades. The Michael J. Fox Foundation is building on this momentum to explore prevention of the disease and transform diagnosis and treatments.

Years of work spent uncovering Parkinsons secrets defining the highly variable patient experience, shedding light on genetic origins of disease, mapping molecular pathways are now paying off in a tangible quickening tempo of scientific progress. Investigators are increasingly linking cellular pathology to outward clinical symptoms to identify new therapeutic and biomarker targets. This has positioned drug makers to make rapid inroads toward treatments that have the potential to slow or stop progression of Parkinson’s disease . The field also is closer than ever to arriving at therapies that can treat all the symptoms of PD, including the less well understood non-motor aspects, such as cognitive impairment and mood disorders, sleeping and digestive issues, and speech and swallowing difficulties.

While the Parkinson’s pipeline is more active than at any previous point in the modern era of drug development, much work remains to be done in the quest to better understand the connection between pathological “bad actors” and the daily lived experience of the disease and to translate understanding of basic Parkinson’s biology into new therapies.

Table 2 Therapy With Compounds Of Disease

Compound
Oertel et al. 2016100Quik et al. 2008101Hong et al. 2009102

Modified from Oertel and Schulz17 .

The second approach relates to the groundbreaking genetic discoveries in PD. In fact, a dramatic shift in the strategy for developing a new PD therapy has taken place: pharmaceutical efforts now target alpha-synuclein protein synthesis, degradation , protein aggregation, and propagation in the nervous system. Finally, 20 years after the discovery of PARK1, the academic and pharmaceutical industrial scientific community can offer the first candidates with a potential for a disease-modifying effect in PD.

Three different principles of therapeutic action are addressed: active or passive immunotherapy, modulation of alpha-synuclein aggregation, and enhancement of autophagy of alpha-synuclein .

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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.

The Decades Of Focus On The Nigrostriatal System And Dopamine Replacement Therapy

Micro

Parkinsons disease is a devastating disorder of the human nervous system and the second most common progressive chronic neurodegenerative disease. The three cardinal motor symptoms, akinesia in combination with either tremor at rest or rigidity , are200 years after their descriptionstill the basis of the clinical diagnosis. Up to 2016, we still have no treatment to slow down or even stop the progression of the disease. Available therapy is symptomatic. This article presents evidence that for the first time in history substances with a potentially disease-modifying effect for PD are under development and thus offer hope for the patient, the spouse, and the treating physician.

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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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The Challenge Of Treating Motor And Non

In summary, neurologists, and especially movement disorder experts, can choose from a large number of compounds to treat the motor symptoms in PD effectively for several years, if not decades. In addition, owing to advances in the field of internal medicine, the surgical disciplines, and anesthesia, patients with PD live longer, but with a price or rather trade off to find the optimal therapeutic balance between motor- and non-motor symptoms with a minimum of adverse effects:

1) With increasing age and duration of PD, gait problemsnon-responsive to dopamimetic therapy, combined with the increased risk to fall and to incur fracturesand other NMSs appear. These NMSs include autonomic dysfunctions , sleep impairment, pain syndromes, and most important, neuropsychiatric symptoms, including depression, impulse control disorders, punding, hallucinations, overt psychosis , and cognitive impairment progressing to dementia. The NMSs substantially impair the quality of life not only of the PD-patient but also of their family. Thus, in the very advanced stages, the family and the physician facein many casesa disoriented, often demented PD patient, who either is mobile, if not hypermobile , and may hallucinate and even endanger him- or herself or others or who is akinetic-rigid.

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Advances In Deep Brain Stimulation

Deep brain stimulation is another established treatment for PD that is useful in treating dopamine-dependent motor symptoms when levodopa-induced side effects become particularly problematic. DBS involves the surgical implantation of electrodes that stimulate subcortical structures including the subthalamic nucleus and globus pallidus internus9194. DBS offers significant improvements in motor symptoms and fluctuations in comparison to best medical therapy in some advanced PD patients, but dopamine-resistant symptoms other than tremor respond poorly95. It has also been suggested in an open-label trial that DBS is beneficial in early PD patients, with improved tremor scores and reduced development ofde novo tremor96. In addition to surgical complications, DBS strategies may cause cognitive and neuropsychiatric adverse effects as well as speech dysfunction. Novel DBS approaches, including adaptive DBS, targeting different regions, and refined intra-operative imaging techniques promise to offer improved clinical applicability and reduce the impact of adverse effects97.

Search For Primary Endpoints Reflecting The Progression Of Parkinsons Disease In The Prodromal Stages

Can we prevent falls in Parkinson’s?

Taking together the discoveries on the genetic background of PD and the Braak staging hypothesis, new avenues for drug development and clinical testing have opened up. For clinical testingat least in the next few yearspotential disease-modifying compounds are and will be tested in the early stage of motor PD that is, very earlyde novo PD patients, who never received a symptomatic therapy will be recruited and should present with a unilateral asymmetric very mild motor symptomatology.

However, for true neuroprevention , parameters and biomarkers which reflect the progression of the alpha-synucleinopathy in the prodromal stage have to be discovered. In addition, such a parameter must be responsive to therapy, even in the prodromal stage, in order to qualify as a primary endpoint for pivotal registration trials. At present, such a parameter has not been identified. Respective research ranges from studies on biomarkers in the cerebrospinal fluid, peripheral blood, saliva, and sweat and in biopsies of the colonic enteric nervous system, the salivary gland, or the skin. Major efforts are placed into different imaging techniques with sophisticated magnetic resonance methods, nuclear medical ligands for the dopamine transporter single-positron emission computed tomography or fluoro-desoxyglucose positron emission tomography.

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Updates On The Clinical Progress Of Dopaminergic Pd Treatments

Despite the intensive efforts in PD research and development, there are clear unmet medical needs for the development of additional dopaminergic treatment options to improve current DA-centered treatment. Most currently used dopaminergic drugs selectively activate D2-like DA receptors , but no D1-like selective agonists have been successfully approved even though the D1 receptor is a known target for PD treatment. Recently, important progress has been made in the clinical development of D1 selective agonists and allosteric modulators. All active dopaminergics since 2012 on the clinical trial website are summarized in Fig. and Table .

Fig. 2

Current Parkinsons Treatments Cant Slow Down Onset Of Disease

Parkinsons is a long-term degenerative disorder of the central nervous system, which mainly the area of the brain that controls movement leading to a slow onset of symptoms including tremors, rigidity and slow movement.

More than 10 million people worldwide are estimated to be living with Parkinsons disease, according to the US-based Parkinsons Foundation, with the Parkinsons News Today website saying it affects 1,900 per 100,000 among those aged over 80,

Typically, by the time people are diagnosed with the condition, they have already lost between 70% and 80% of their dopamine-producing cells, which are involved in co-ordinating movement.

While current treatments mask the symptoms, there is nothing that can slow down its progression or prevent more brain cells from being lost.

As dopamine levels continue to fall, symptoms get worse and new symptoms can appear.

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