Posts

Nourianz Reduces Duration of ‘Off Periods’ in Parkinson’s Patients with and without Dyskinesia, Analysis Finds

Nourianz analysis

When used as an add-on treatment to carbidopa-levodopa, Nourianz (istradefylline) reduced the duration of “off periods” — when symptoms are not adequately controlled — and increased the duration of “on periods” in Parkinson’s disease patients with and without pre-existing dyskinesia, a pooled analysis of several clinical trials has found.

The findings, “Impact of Baseline Dyskinesia on the Safety and Efficacy of Istradefylline, an Adenosine A2A Receptor Antagonist, in Patients with Parkinson’s Disease: a Pooled Analysis of 8 Clinical Studies,” were presented at the 6th Congress of the European Academy of Neurology (EAN), which took place virtually May 23–26.

Carbidopa-levodopa is one of the mainstay treatments used to alleviate the symptoms of Parkinson’s. The combination therapy works by increasing the levels of dopamine, which is a brain chemical essential for balance and movement coordination whose levels are very low in patients with Parkinson’s.

However, over time and as the disease progresses, treatment may become less effective at preventing symptoms. When that happens, many patients start experiencing so-called “off episodes,” or periods of time when treatment is no longer effective at keeping disease symptoms at bay.

Nourianz, marketed by Kyowa Hakko Kirin Pharma, is an add-on treatment approved by the U.S. Food and Drug Administration (FDA) to treat off episodes in patients receiving carbidopa-levodopa. Involuntary muscle movement, also known as dyskinesia, is the most common side effect of Nourianz.

Investigators at Kyowa now have presented the findings of a pooled analysis of several clinical trials they conducted to evaluate the possible impact of pre-existing dyskinesia (baseline dyskinesia) on the safety and effectiveness of Nourianz.

The analysis was based on data from eight randomized, placebo-controlled trials involving 2,719 patients with Parkinson’s who experienced off episodes while taking levodopa/carbidopa.

During the trials, patients were assigned randomly to receive either Nourianz at a daily dose of 20 mg, or 40 mg, or a placebo, for a period of 12 or 16 weeks.

The analysis included those with baseline dyskinesia, as well as those who did not have dyskinesia before adding Nourianz or a placebo to their treatment regimen.

Data revealed that compared to placebo, Nourianz reduced the duration of off periods and increased the duration of on periods without troublesome dyskinesia, as reported by patients.

This was true for patients with and without baseline dyskinesia, suggesting that pre-existing dyskinesia did not compromise Nourianz’s overall effectiveness.

A post hoc subanalysis also found that troublesome dyskinesia was reported more frequently by patients with baseline dyskinesia, regardless of whether they were being treated with Nourianz or a placebo, compared to those who did not have pre-existing dyskinesia.

The most common adverse side effects seen among patients receiving Nourianz in the trials included dyskinesia, dizziness, constipation, nausea, hallucinations, and insomnia.

“The results being presented at EAN suggest that dyskinesia is observed more often in patients with baseline dyskinesia before [Nourianz] was added to the treatment regimen and that the overall efficacy of [Nourianz] was not affected by patients’ baseline status,” Stuart Isaacson, MD, said in a press release. Issacson is a neurologist at the Parkinson’s Disease and Movement Disorders Center of Boca Raton, Florida.

“We believe these data can be helpful to physicians as they make treatment decisions and may provide insight into the appropriate use of Nourianz in the treatment of ‘OFF’ time in patients with PD [Parkinson’s disease],” Isaacson said.

The post Nourianz Reduces Duration of ‘Off Periods’ in Parkinson’s Patients with and without Dyskinesia, Analysis Finds appeared first on Parkinson’s News Today.

Study Suggests Mechanism Behind Levodopa-induced Dyskinesia in Parkinson’s

dyskinesia

The protein RasGRP1 is a key culprit for involuntary movements that arise from dopamine replacement therapies used to treat Parkinson’s disease, a new study done in animals suggests.

Targeting this protein may be a therapeutic strategy to prevent these motor problems, while still receiving the benefits of treatment.

The study, “RasGRP1 is a causal factor in the development of l-DOPA–induced dyskinesia in Parkinson’s disease,” was published in Science Advances.

Parkinson’s disease is caused by the death of nerve cells in the brain that make the neurotransmitter dopamine. Therapies designed to increase the amount of dopamine in the brain, including levodopa (l-DOPA) and its derivatives, are staples of Parkinson’s treatment.

Although the effectiveness of these treatments is well-established, long-term use is associated with the development of involuntary movements called dyskinesia. However, exactly which molecular mechanisms are responsible for this side effect is not clear.

Previous research implicated a protein called Rhes in the development of  dyskinesia. In the new study, researchers examined the role of a related protein, RasGRP1 (Ras-guanine nucleotide-releasing factor 1). This protein is known to activate Rhes, and it has been shown to be active in certain blood cells. But its role in the brain is less clear.

Researchers first used a mouse model of Parkinson’s in which dopamine-producing neurons are killed by means of a specific toxin (6-hydroxydopamine). The researchers modeled Parkinson’s both in wild-type mice and in mice that had been genetically engineered to lack RasGRP1.

Both types of mice displayed similar Parkinson’s-like symptoms, and l-DOPA treatment resulted in similar improvement in these symptoms in both types. However, mice lacking RasGRP1 displayed significantly fewer abnormal involuntary movements with long-term l-DOPA treatment.

Additionally, in wild-type mice, l-DOPA treatment induced significantly higher levels of RasGRP1 in the mice’s brains. This finding also was replicated in a macaque (a type of monkey) model of Parkinson’s disease.

“Since monkey model for PD [Parkinson’s disease] can mimic more signs and symptoms of human PD, our finding strengthens the translational relevance of RasGRP1 in PD treatment,” the researchers wrote.

Additional biochemical studies indicated that RasGRP1 is involved in dyskinesia through the activation of the proteins mTOR and ERK (as well as other associated proteins).

These proteins have been implicated previously in l-DOPA-induced dyskinesia (LID). However, they play many important roles in different types of cells throughout the body, so it’s difficult to therapeutically target them without significant side effects. In contrast, the lack of functional RasGRP1 in mice did not result in noteworthy physiological problems, apart from some mild deficits related to the development of cells in the thymus, an organ that’s part of the immune system.

Because of this, “… we think that blocking RasGRP1 with drugs, or even with gene therapy, may have very little or no major side effects,” study co-author Srinivasa Subramaniam, PhD, a professor at Scripps Research, said in a press release.

Since mice and humans are biologically distinct in many important respects, further research will be needed to determine the safety profile of treatments intended to block RasGRP1. Nonetheless, this study provides a theoretical foundation for the possible utility of such treatment strategies.

“There is an immediate need for new therapeutic targets to stop LID,” Subramaniam said. “The treatments now available work poorly and have many additional unwanted side effects. We believe this represents an important step toward better options for people with Parkinson’s.”

The post Study Suggests Mechanism Behind Levodopa-induced Dyskinesia in Parkinson’s appeared first on Parkinson’s News Today.

Clinical Model Predicts Risk of Levodopa-induced Dyskinesia in Parkinson’s

dyskinesia

Some clinical features of Parkinson’s disease patients — such as age at disease onset, disease duration, initial motor symptom, and use of dopaminergic agonists — can predict with high accuracy which patients will experience dyskinesia (abnormal involuntary movements) induced by levodopa treatment, a study found.

The study, “Diagnostic prediction model for levodopa-induced dyskinesia in Parkinson’s disease,” was published in the Brazilian journal Arquivos de Neuro-Psiquiatria.

Parkinson’s disease is a central nervous system disorder characterized by low levels of dopamine, causing tremors, stiffness, or slowing of movement.

Levodopa, a medication that helps counteract the shortage of dopamine in the brain, is the gold standard for treating Parkinson’s patients. But more than half the patients who use levodopa experience abnormal, involuntary movements — dyskinesia — within the first five years of treatment.

Many clinical and genetic features have been pointed to as predictors of levodopa-induced dyskinesia, but a model that incorporates all these features to accurately predict the risk of dyskinesia does not exist. Such a tool would be useful to choose patients for clinical trials testing therapies that prevent dyskinesia.

As research progresses toward precision medicine, “a more effective decision-making process in [n]eurology and medical therapy in [Parkinson’s ] seems suitable to be tailored based on prediction models, regarding the prevention of [levodopa-induced dyskinesia],” the researchers wrote

Seeking to develop one such model, researchers examined clinical and genetic data from a group of 430 Brazilian patients receiving levodopa for Parkinson’s disease. Among them, 232 had dyskinesia — defined as a score of one or higher on the “time spent with dyskinesias” item of the International Parkinson and Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS).

Compared to patients with dyskinesia, those without were significantly older at disease onset, older at evaluation, had a shorter disease duration, had been taking levodopa for fewer years and at lower doses, and had experienced tremor as their first symptom of Parkinson’s. They also used dopaminergic agonists, amantadine (brand name Gocovri, among others) and COMT inhibitors less frequently.

Statistical analysis showed that only four of these factors were significantly associated with dyskinesia: age of disease onset, disease duration, initial motor symptom, and use of dopaminergic agonists. When used together, these clinical factors could distinguish patients with and without dyskinesia with an accuracy of 81.5%.

While all these clinical factors had been associated with prior studies, none had demonstrated such a strong association with the initial motor symptom. In fact, patients with tremor as initial motor symptom were about 70% less likely to develop dyskinesia compared to people with other motor symptoms at disease onset.

Another model taking both clinical and genetic factors into account was only slightly better than this first model (correctly identifying about 81.7% of cases). This model also included four factors: age at disease onset, disease duration, initial motor symptom, and a specific genetic variant of the ADORA2A gene called rs2298383.

This gene provides instructions for making a receptor present in certain brain nerve cells that has been targeted to lessen motor symptoms in mouse models of Parkinson’s disease without increasing dyskinesia.

While both models could identify patients with dykinesia with high accuracy, “we suggest the use of the clinical prediction model, because its predictors are more easily assessed,” the researchers wrote.

This prediction model testing for the risk of dyskinesia is already available for free as a mobile application called DysKalc (only for Android operating system).

The post Clinical Model Predicts Risk of Levodopa-induced Dyskinesia in Parkinson’s appeared first on Parkinson’s News Today.

NLX-112 Eases L-dopa Dyskinesia in Marmosets With Parkinson’s, Study Says

dyskinesia

An investigational therapy known as NLX-112 (befiradol) may hold promise to treat levodopa-induced dyskinesia, a complication of long-term levodopa therapy that affects people with Parkinson’s disease, a study found.

The study, “The selective 5-HT1A receptor agonist, NLX-112, exerts anti-dyskinetic and anti-parkinsonian-like effects in MPTP-treated marmosets,” was published in Neuropharmacology.

Motor symptoms of Parkinson’s disease include tremor; slow movement (bradykinesia); stiffness (rigidity); uncontrolled, involuntary movements that can affect the arms, legs, head, or the whole body (dyskinesia); and poor balance.

As the disease progresses, patients typically need to gradually increase treatment doses for maximum benefit. Even after that, symptoms sometimes reappear or worsen due to the dopaminergic therapy’s gradual loss of efficiency.

Dyskinesia is one of the complications of long-term levodopa therapy that affects many patients with advanced Parkinson’s disease. Currently, the main medication available to manage dyskinesia is amantadine. However, it can have side effects and may not be effective for every patient.

Studies indicate that Parkinson’s progression and symptoms may be associated with impaired signals from another important brain chemical, serotonin. Serotonin is involved in smooth muscle contraction, and serves as the “feel-good” chemical in the brain, influencing one’s sense of well-being and happiness.

Serotonin-producing neurons have an enzyme that is crucial to producing dopamine. This enzyme can be stored in vesicles and released as a “false neurotransmitter.” This results in excessive and inappropriate dopamine release, which generates dyskinesia.

NLX-112 (also known as befiradol or F13640) is an experimental medicine being developed by Neurolixis that activates a type of serotonin receptor called 5-HT1A. This investigational therapy has been shown to inhibit the “false neurotransmitter” release, thereby minimizing or even abolishing dyskinesia in rodent models of Parkinson’s disease.

In a study funded by Parkinson’s Virtual Biotech, the drug development arm of Parkinson’s UK, researchers tested NLX-112 in a marmoset model of levodopa-induced dyskinesia.

Animals were treated with 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that induces the death of dopamine-producing neurons and mimics Parkinson’s symptoms. Dyskinesia was then induced by chronic levodopa/benserazide combination therapy administered up to twice daily for up to a month.

NLX-112 treatment was administered alone or in combination with levodopa twice a week. Scientists also tested levodopa therapy combined with (+)8-OH-DPAT, another compound that activates the serotonin receptor 5-HT1A.

When administered together with levodopa at three different doses (0.025, 0.1 and 0.4 mg/kg ), NLX-112 reduced dyskinesia in a time and dose-dependent manner. The most prominent effects were at a dosage of 0,4 mg/kg.

In addition, NLX-112 was found to marginally interfere with the anti-parkinsonian effects of levodopa, unlike (+)8-OH-DPAT, which lessened levodopa-induced dyskinesia but also eliminated levodopa’s therapeutic efficacy.

When given alone (not combined with dopaminergic therapy), NLX-112 elicited anti-parkinsonian-like activity, easing disease-related motor disability in marmosets modeling Parkinson’s.

“Interestingly, the higher dose of NLX-112 (0.4 mg/kg) appeared less active than the lower doses, only reducing disability at a single, early time-point, suggesting an inverted dose-response relationship,” the researchers wrote.

Both NLX-112 and (+)8-OH-DPAT produced dose-dependent unusual behavior in marmosets, including sedation, scratching, wet-dog shakes, and sustained muscle contractions in the tail. These manifestations are all consistent with serotonin syndrome, a disorder that can occur when taking serotonin-boosting medications, and manifests itself with both behavioral and other general symptoms such as sweating and diarrhea.

Despite its effects, NLX-112 was not kept in animals’ blood circulation for long, which may limit its pharmacological effects in this particular species.

“This promising research on NLX-112 offers hope that we can find a treatment that can tackle dyskinesia, which can make everyday tasks, such as eating, writing, and walking, extremely difficult,” Arthur Roach, PhD, director of research at Parkinson’s UK, said in a press release.

“People with Parkinson’s tell us it is one of the most critical issues that impacts quality of life, so we’re delighted that this project is progressing so positively,” Roach said. “With 145,000 people living with Parkinson’s in the UK, we are desperately in need of a breakthrough treatment, and we’re committed to delivering one by 2024.”

“It is vital we continue to work with biotech companies like Neurolixis to drive forward new treatments that may slow, stop, or reverse Parkinson’s, and also those, like NLX-112, that could bring relief from symptoms or side effects,” said Roach.

“We are excited that NLX-112 has shown such positive results in reducing dyskinesia in marmosets,” said Adrian Newman-Tancredi, PhD, co-founder and CEO of Neurolixis. “If the striking preclinical data are reproduced in clinical trials, NLX-112 could significantly alleviate the troubling dyskinesia that prevent many Parkinson’s patients from performing routine daily tasks, thereby improving their quality of life.”

“We are currently making plans and seeking funding to take NLX-112 into clinical trials, and hope to be able to initiate these before the end of 2020,” Newman-Tancredi said.

The post NLX-112 Eases L-dopa Dyskinesia in Marmosets With Parkinson’s, Study Says appeared first on Parkinson’s News Today.

A Tale of a Beating Heart and the Will to Move Forward

heart

With Parkinson’s disease, a progressive nervous system disorder that affects movement, some days you need a little nudge to keep going. Other days require a huge push.

I recently watched a video that told the story of a pastor who asks his friend, a heart surgeon, if he can observe one of his heart surgeries. According to Randy Philips of the musical group Philips, Craig & Dean, the physician makes the arrangements. The pastor watches as the patient’s chest is cut open, the damaged heart is repaired, and is returned to the chest cavity.

The heart is massaged, and doctors wait for it to begin working. But nothing happens. The heart refuses to beat. So the heart surgeon massages the heart again. 

Still nothing.

After a few more attempts to restart the heart, it still refuses to beat.

Finally, the heart surgeon does something unconventional. He removes his mask, kneels beside his patient, and speaks to her.

“Mrs. Johnson, this is your surgeon. The operation went perfectly. Your heart has been repaired. Now tell your heart to beat again.”

A few seconds and her heart begins beating. It needed a little “nudge.”

Just like the patient on the operating table, our hearts need a little nudge — sometimes a big push — to get going again after we receive a diagnosis of Parkinson’s disease (or any chronic illness, for that matter).

We want to get better, but our fortitude is failing and we slowly begin to give up. We don’t want to isolate ourselves from others, but we can feel so self-conscious when we are out in public dealing with tremors, dyskinesia, drooling, and choking. 

We want to get up, go out, and exercise, but our legs freeze on us before we even get to the front door. Eventually, we quit trying.

Sometimes life with Parkinson’s can be so hard.

Former “American Idol” contestant Danny Gokey was inspired by the story of the pastor and the heart surgeon to write his hit single, “Tell Your Heart to Beat Again.” The beginning of the song illustrates how we can feel broken and shattered, as if we will never get back to the life we once knew or the person we used to be. It’s about the person who is traveling on a new and unfamiliar journey.

We may have to tell our heart to beat again, like the doctor told his patient. It may be time to say goodbye to the past, look forward, and move in the new direction we have been given. It may not be the life you once knew or dreamed of, but we’ve been set on a new journey — and it might even be a better one.

***

Note: Parkinson’s News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of Parkinson’s News Today or its parent company, BioNews Services, and are intended to spark discussion about issues pertaining to Parkinson’s disease.

The post A Tale of a Beating Heart and the Will to Move Forward appeared first on Parkinson’s News Today.

Long-term Gocovri Lessens Parkinson’s Motor Symptoms for at Least 2 Years, Final Phase 3 Data Show

Gocovri (amantadine)

Long-term treatment with Gocovri (amantadine) extended-release capsules was safe and led to sustained reductions in dyskinesia — involuntary, jerky movements — and off episodes in people with Parkinson’s disease, final data from a two-year Phase 3 clinical trial show.

“As the longest-running amantadine study to date, this open-label trial suggests Gocovri may provide sustained improvement in both dyskinesia and OFF [episodes] to a wide cohort of patients with Parkinson’s disease living with motor complications,” Caroline Tanner, MD, professor in the department of neurology at the University of California San Francisco, said in a press release.

“These results expand not only our knowledge of Gocovri efficacy but also of its long-term safety in these patients,” Turner said.

The study, “EASE LID 2: A 2-Year Open-Label Trial of Gocovri (Amantadine) Extended Release for Dyskinesia in Parkinson’s Disease,” was published in the Journal of Parkinson’s Disease.

While levodopa is one of the gold standard treatment to manage Parkinson’s motor symptoms, long-term use may lead to off-episodes, which are moments in which the therapy’s effects wear off and symptoms, including dyskinesia, re-emerge.

Adamas Pharmaceuticals’ Gocovri, a long-acting and extended-release oral capsule amantadine formulation, is the only U.S.-approved treatment for dyskinesia in Parkinson’s patients who receive levodopa-based therapy, with or without other dopaminergic medications. It also is the only therapy clinically proven to lessen both Parkinson’s dyskinesia and off episodes.

Taken once daily at bedtime, Gocovri levels rise slowly overnight and achieve their peak in the morning (before the patient’s first levodopa dose), maintaining its high levels throughout the waking day.

The two-year, open-label Phase 3 EASE LID 2 clinical trial (NCT02202551) evaluated the long-term safety, tolerability, and effectiveness of Gocovri in Parkinson’s patients with levodopa-induced dyskinesia for two years.

The study was designed to reflect conditions closer to a “real-world” clinical setting by including not only patients who completed previous Gocovri trials — EASED (NCT01397422), EASE LID (NCT02136914) and EASE LID 3 (NCT02274766 ) — but also those excluded from these trials because they had deep brain stimulation (DBS) therapy. It also allowed clinicians to adjust doses of levodopa and other Parkinson’s medications.

DBS is the most common surgery used to treat Parkinson’s symptoms by delivering electrical pulses to brain cells.

A total of 223 patients were recruited, including 138 who transitioned directly from previous clinical trials (60 receiving Gocovri and 78 a placebo), 61 with prior DBS surgery, and 24 who had a time gap between the prior trial and the EASE LID 2 study.

Among them, 32 patients (24 who underwent DBS and eight among those with a time gap between trials) were switched directly from amantadine immediate-release to Gocovri when entering EASE LID 2.

Most patients were white (93.3%) and more than half (58.7%) were men. Participants’ mean (average) age was 63.7 years at enrollment and they had been diagnosed with Parkinson’s for a mean of 11.8 years. Patients had been taking levodopa for a mean of 9.3 years, with reports of dyskinesia for about 5.3 years.

During the trial, participants received Gocovri once daily at bedtime for a median of 1.9 years, with 75.8% of them having completed one year of treatment and 57.8% completing two years of treatment.

The therapy’s effectiveness was assessed using the Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part IV (focused on motor complications). Higher scores indicate greater impact of Parkinson’s symptoms, and changes of at least one point in the MDS-UPDRS Part IV score are considered clinically important.

Results showed that Gocovri was effective in lowering dyskinesia and off episodes in all groups of patients, including those who continued treatment from prior trials and those initiating Gocovri in this trial (patients switching from placebo or amantadine immediate release, and those under DBS therapy).

Low levels of motor complications were maintained in patients continuing Gocovri treatment from prior trials. Those initiating Gocovri in this trial showed marked reductions (between two and four points) in the MDS-UPDRS Part IV score, reaching the same levels as those with continuous treatment after eight weeks (the first scheduled effectiveness assessment). These improvements were maintained throughout the two-year trial.

“The present long-term trial provides supportive evidence that 274 mg Gocovri, taken once daily at bedtime, durably reduces the daily duration, severity, and functional impact of dyskinesia as well as OFF episodes throughout 100 weeks of continued use,” the researchers wrote.

Gocovri’s safety profile and rate of treatment discontinuations (22%) were consistent with those reported in previous clinical trials. Common adverse side effects included falls (32.7%), hallucinations (24.2%), swelling in the legs or arms (16.1%), constipation (13.5%), and urinary tract infections (10.3%).

Not surprisingly, adverse side effects’ onset and related treatment discontinuations tended to occur earlier among those just beginning Gocovri treatment than among those continuing treatment from a prior trial.

Jean Hubble, MD, Adamas’ vice president of medical affairs, said that “given the chronic nature of Parkinson’s disease, both patients and physicians seek treatments that are effective long-term.”

“This study further demonstrates that the only FDA-approved medicine for dyskinesia may help people with PD who are struggling to manage these levodopa-related motor complications over this long period of time,” Hubble said.

The post Long-term Gocovri Lessens Parkinson’s Motor Symptoms for at Least 2 Years, Final Phase 3 Data Show appeared first on Parkinson’s News Today.

FDA Clears Way for Phase 2 Trial of AV-101 for Levodopa-Induced Dyskinesia

AV-101

VistaGen Therapeutics will begin a Phase 2 clinical trial to evaluate its lead candidate AV-101 as a potential treatment to reduce dyskinesia (abnormal involuntary movements) induced by levodopa in patients with Parkinson’s disease, after the U.S. Food and Drug Administration (FDA) cleared the company’s investigational new drug (IND) application.

Parkinson’s is characterized by the loss of neurons that produce the neurotransmitter dopamine. Treatment with levodopa, or L-DOPA — a precursor to dopamine — is one of the gold standards for Parkinson’s. However, as the disease progresses, patients need larger doses.

Dyskinesia — sudden, involuntary movement — is one of the complications of long-term levodopa therapy that affects many patients with advancing Parkinson’s.

Amantadine (brand names Gocovri, Symmetrel, Symadine) can be used to treat dyskinesia, though it is often accompanied by side effects such as depression and cognitive impairment.

Amantadine acts on a specific part of NMDA (N-methyl-D-aspartate) receptors  — molecular structures involved in neuronal communication — in the brain, enhancing dopamine levels.  AV-101 is an oral NMDA receptor antagonist (inhibitor) that acts on a different part of the receptor.

Preclinical data from a non-human, primate model of Parkinson’s showed that AV-101 lessened dyskinesia without affecting the timing, extent, or duration of the therapeutic benefits of levodopa. Researchers observed none of the adverse effects with AV-101 often associated with amantadine, such as hallucinations, dizziness, and falls.

In a Phase 1b clinical study performed in collaboration with Baylor College of Medicine, researchers tested AV-101’s potential in seven healthy U.S. military veteran volunteers. Participants were randomly assigned a single (either high or low) dose of AV-101 (720 mg or 1440 mg) or a placebo.

The results showed that the higher dose of AV-101 could block NMDA activity, confirming the therapy’s target engagement. Moreover, both doses were well tolerated, without any adverse side effects.

“Current drug treatment options for levodopa-induced dyskinesia, or LID, may cause serious side effects, including hallucinations and sedation,” VistaGen CEO Shawn Singh said in a press release. “In all clinical studies to date, AV-101 has not been associated with any psychotomimetic [inducing psychotic alteration of behavior and personality] side effects or drug-related serious adverse events.”

“With its exceptional safety profile, recently successful preclinical studies in the leading primate model for LID, and the successful Phase 1b NMDAR target engagement clinical study conducted by Baylor College of Medicine in healthy volunteer U.S. military veterans, we are excited by AV-101’s potential as a novel therapy for LID,” Singh said.

VistaGen said it also received a notice of allowance from the U.S. Patent and Trademark Office covering to the use of AV-101 for levodopa-induced dyskinesia. The patent, once issued, will be in effect until at least 2034, the company said.

The post FDA Clears Way for Phase 2 Trial of AV-101 for Levodopa-Induced Dyskinesia appeared first on Parkinson’s News Today.

Parkinson’s Foundation, Zelira Crafting Survey on Cannabis Use and Possible Benefits

medical cannabis

Zelira Therapeutics, an Australia-based medical cannabis company, has partnered with the Parkinson’s Foundation to learn more about patients’ usage and understanding of medical cannabis and hemp-derived treatments.

Zelira and the organization are developing a survey looking at current use and perceived benefits of medical cannabis among those with Parkinson’s (PD).

The partnership marries the nonprofit’s scientific understanding of this disease with Zelira’s experience in pharmaceutical and condition-specific medical cannabis product development. The company participated in the foundation’s first conference  focused on medical marijuana and PD last year.

“The challenge for people with Parkinson’s is clear, as there is a lack of definitive studies informing clinicians and patients with Parkinson’s about the safety and efficacy of medical cannabis,” said Tom Borger, Zelira’s chief business officer, in a press release.

“One of the objectives of the survey and this collaboration is to provide guidance to people with Parkinson’s about the need for clinically validated medical marijuana and hemp-derived [cannabidiol] CBD treatment alternatives,” he said.

Zelira and the foundation will jointly develop the survey — which will be sent to patients — and review results in preparation for a clinical trial on the safety and efficacy of medical cannabis in PD.

Separately, Zelira will use survey results to inform development of clinically validated medical cannabis and hemp-derived cannabidiol medicines for PD patients, and to help guide patients in considering such alternative treatments. (Cannabidiol, or CBD, is a non-psychoactive marijuana extract.)

“Many people with Parkinson’s disease are seeking help with their symptoms by trying various forms of medical cannabis,” said John Lehr, president and CEO of the Parkinson’s Foundation. “The volume and frequency of questions Parkinson’s Foundation receive from people with Parkinson’s regarding the safety and impact of medical cannabis and CBD has led us to examine this public health issue more fully, and to seek collaborations with leaders in the field from academia, government, advocacy groups and industry to provide the most accurate information possible.”

Zelira, he added, is devoted to helping patients understand the role that medical cannabis might play in managing daily symptoms.

“This effort is consistent with our focus on patients and our desire to provide them with as many treatment options as possible,” said Osagie Imasogie, Zelira’s founder and chairman.

Currently, evidence is lacking to support the use of medical marijuana in managing Parkinson’s symptoms. The issue is being researched, but mostly in small studies with and without control groups, so that results are conflicting, the foundation said in an article that followed the 2019 conference and cites a need for larger and more rigorously conducted research.

Observational studies have shown that cannabinoids — the active molecules in marijuana — may help with non-motor PD symptoms, including pain, anxiety, weight loss and problems sleeping. Controlled clinical trials have reported mixed results for treating motor symptoms such as tremor and rigidity.

In related news, an animal study reported that a compound affecting some of the same brain receptors as cannabis could help ease dyskinesia, the uncontrolled and involuntary movements that can follow levodopa treatment in Parkinson’s.

This disease is estimated to affect about 1 million U.S. residents and 10 million people globally.

The post Parkinson’s Foundation, Zelira Crafting Survey on Cannabis Use and Possible Benefits appeared first on Parkinson’s News Today.

Deep Brain Stimulation: Time for a Tuneup

tuneup

My sister, Dad, and I waited in the doctor’s office before Christmas for his deep brain stimulation (DBS) appointment. Dad underwent DBS last fall, and it’s time for a “tuneup,” as he likes to call them. I imagine his doctor with a wrench in her hand, manipulating Dad’s brain like a mechanic fixes a car.

If she works on the suspension on the left side, maybe it’ll change the tremors in his left foot. And it does. His doctor punches the instructions into her computer and my dad’s foot stops shaking. It’s an immediate change. We don’t have to wait for medications to kick in or his body to adjust.

His medication dosage is about the same. He experiments to see if a half-dose is enough to keep him going. He thinks it is; his doctor doesn’t.

While we’re in the office, I try to mediate. His doctor — my dad calls her “The General” — tells him that he needs to take his medications regularly and as prescribed. Dad’s face sinks because he has been clinging to the hope that he can reduce them. She explains that patients don’t develop a tolerance to Sinemet (carbidopa/levodopa), but as Parkinson’s disease progresses, a higher dosage is needed. She reassures him that an increase in dosage won’t cause adverse effects. Dad is in it for the long-run, and he hopes that if he plays his cards right, his symptoms will ease later in his life. But his quality of life is suffering now because he is undermedicating.

Sometimes having a window into someone’s life can be heart-wrenching. While I’m looking through the glass panes of my dad’s mind, I realize that he is determined to fight Parkinson’s for as long as he can. And I’m proud of him for being so determined. I know that you can’t give someone the desire to put Parkinson’s in its place, but I also worry that undermedicating is compromising his quality of life.

What has changed?

Dad tells me that he has noticed some subtle changes since the surgery. His eyes are dull with disappointment as he shares that he had hoped for more improvements. He didn’t have a honeymoon period like others do despite his longing for a week without symptoms. This grueling disease has been chasing my Dad since 2013, and he was comforted by the idea of a break. Everything short of a cure is a little heartbreaking. But he does admit to the positive changes, including the following:

  • Parkinson’s patients can experience a strong urge to urinate frequently. Since his surgery, the urge has disappeared.
  • He decided to undergo DBS because his dyskinesia can be debilitating. But since the surgery, the worst of it is gone.
  • His hair is so thick that he jokes about having a ponytail, like the one he had during his youth.

He tells me that his freezing has gotten worse. I observe him walking and notice that he freezes for longer. But he only freezes when he’s trying to navigate a choppy situation — like our Christmas presents all over the floor. It’s as if fear paralyzes him. He worries about stepping on something. But when his path is a straight shot, he zooms away. I wonder if managing our fears can affect freezing.

Sweet relief

I felt a brief sense of relief upon seeing my dad at Christmas. He is 20 pounds heavier than he was before the surgery. He seems to be in good spirits. It’s like a victory among bouts of tremendous loss. It feels as if the surgery has provided us with a deep breath of air after going without it for a long time.

***

Note: Parkinson’s News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of Parkinson’s News Today or its parent company, BioNews Services, and are intended to spark discussion about issues pertaining to Parkinson’s disease.

The post Deep Brain Stimulation: Time for a Tuneup appeared first on Parkinson’s News Today.

Activating Cannabis Receptors Could Help Treat L-DOPA-induced Dyskinesia, Mouse Study Finds

dyskinesia

A compound that affects some of the same receptors in the brain as cannabis could help reduce dyskinesia — involuntary muscle movement — that develops following levodopa treatment in Parkinson’s disease, a new study done in mice suggests.

The mice were treated with HU-308, an agonist, or activator that binds to a cannabinoid receptor in the brain. It was found to reduce tremors without causing the “high” associated with cannabis.

Titled “Targeting the cannabinoid receptor CB2 in a mouse model of l-dopa induced dyskinesia,” the study was published in Neurobiology of Disease

Parkinson’s is characterized by the loss of neurons that make the neurotransmitter dopamine. Treatment with levodopa, or L-DOPA — a precursor to dopamine — has long been one of the gold standards for Parkinson treatment. However, this medicine can lead to uncontrollable movements, a condition called levodopa-induced dyskinesia, or LID.

The only treatment currently available for LID is Gocovri (amantadine). This is thought to reduce dyskinesia through a few different mechanisms, namely by reducing inflammation in the brain (neuroinflammation) and affecting glia, brain cells that serve a variety of specialized functions. Since glia function as the primary immune system in the brain, they play a role in neuroinflammation.

“If targeting neuroinflammation, and or glial signalling, offers a potential strategy, then cannabinoid based therapies could be an option for treating LIDs,” the researchers said. They explained that “cannabinoid-based therapies can exert effects on glia, are thought to suppress neuroinflammation, and have neuroprotective effects in preclinical animal models of several neurodegenerative disorders.”

However, cannabis itself is ill-suited to such therapeutic uses.

“Currently there is limited evidence about the effectiveness of medicinal cannabis,” Bryce Vissel, PhD, director of the Centre for Neuroscience and Regenerative Medicine at the University of Technology Sydney (UTS) and a study co-author, said in a press release. “One problem is that no cannabis preparation is the same and cannabis has numerous effects, some of which may not be beneficial in Parkinson’s disease.”

The compounds in cannabis act primarily via two chemical receptors in the brain, CB1 and CB2. Since CB1 is primarily responsible for the “high” cannabis can impart, which is not desirable in a medicine, the researchers investigated whether specifically activating CB2 could reduce LID without this adverse effect.

To test this, mice with modeled LID — essentially, modeled Parkinson’s disease followed by L-DOPA treatment to the development of LID — were treated with HU-308, a CB2 agonist (activator). Compared with mice that did not receive such treatment, LID was significantly decreased in the HU-308-treated mice, as evidenced both by behavioral observation and by decreased levels of FosB, a marker of LID in the brain.

To confirm that this effect was the result of CB2 activation, the researchers treated mice with both HU-308 and SR144528, which is an antagonist, or blocker, of CB2. This co-treatment eliminated the benefits imparted by HU-308 alone, suggesting that the effect is indeed due to CB2 activation.

In the same model, Gocovri also reduced LID, to a similar extent as HU-308. And, when both HU-308 and Gocovri were given simultaneously, the reduction in LID was greater than that seen with either treatment alone.

“The fact that amantadine [Gocovri] has its own set of side effects, may not work in the long term, and is still the only drug available on the market that is approved for dyskinesias makes our study really exciting,” said Sandy Stayte, PhD, a researcher at UTS and a study co-author.

“First, our study shows HU-308 is equally affective so a drug like HU-308 will be useful for those people who can’t take amantadine. Second, for those who can tolerate amantadine, taking the combination may have even greater benefits than taking either drug alone,” Stayte said. “That means we may end up with a much more powerful treatment than currently available by ultimately prescribing both.”

Further analysis revealed that both treatments — separately and combined — reduced neuroinflammation, as evidenced by decreased levels of inflammatory signaling molecules in the brain. Additionally, both treatments reduced the numbers of inflammatory glia cells.

“By reducing inflammation in the brain — such as with HU-308 — these immune cells [glia] can support normal neural function again, rather than inhibiting it,” Vissel said.

Interestingly, though, treatment with both HU-308 and Gocovri together did not affect neuroinflammation to a greater extent than either therapy alone. This suggests that the additive effect seen at the behavioral level may be due to other mechanisms. However, the team said their “measures in this paper are too rudimentary to explore these various mechanisms, and much further research is needed.”

Nonetheless, the study does support using CB2 agonists as a treatment strategy for LID.

The researchers said approximately 52-78% of patients may develop LIDs within 10 years of starting levodopa treatment.

“Accordingly, clinical trials investigating [CB2 agonists’] efficacy for neurodegenerative diseases is currently in high demand,” the investigators said.

The post Activating Cannabis Receptors Could Help Treat L-DOPA-induced Dyskinesia, Mouse Study Finds appeared first on Parkinson’s News Today.