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Deep Brain Stimulation Technique Lessens Parkinson’s Dyskinesia, Study Finds

deep brain stimulation, dyskinesia

Using a parameter called interleaving stimulation (ILS) in deep brain stimulation (DBS) eased dyskinesia — involuntary, jerky movements — in patients with Parkinson’s, according to a new study.

In contrast, the benefits in people with tremor or dystonia — abnormal muscle tone — or in mitigating DBS-induced adverse side effects were not as evident.

The study, “Interleaving Stimulation in Parkinson’s Disease, Tremor, and Dystonia,” was published in the journal Stereotactic and Functional Neurosurgery.

DBS is a surgical treatment for Parkinson’s motor symptoms that involves implanting a device to stimulate specific brain regions using electrical impulses generated by a battery-operated neurostimulator.

ILS is a variant of DBS that enables alternating stimulation with two contacts on different brain regions set with specific measures — amplitude, or wave height, and pulse width. ILS may be applied to lessen stimulation-induced adverse side effects and to simultaneously target different brain regions to ease specific symptoms.

Researchers assessed the applications and outcomes of ILS in clinical practice for patients with Parkinson’s, tremor, and dystonia. The team conducted a review through June 2015, by searching the electronic database at Toronto Western Hospital for all patients receiving DBS and ILS.

ILS was preformed in 50 patients — 27 with Parkinson’s (19 men), seven with tremor (three men), and 16 with dystonia (three men). Mean age at diagnosis was 48 for patients with Parkinson’s, 48.6 for people with tremor, and 23.8 for those with dystonia. Age at surgery was 58, 57.8 and 37.8, respectively.

Pre- and post-operative assessments (at six months) were performed with validated scales, including the Unified Parkinson’s Disease Rating Scale part III (motor section), the Fahn-Tolosa-Marin Tremor Rating Scale for patients with tremor, and the Toronto Western Spasmodic Torti-collis Rating Scale and the Burke-Fahn-Marsden Dystonia Rating Scale specifically for those with dystonia.

Twenty-nine patients underwent ILS to manage stimulation-induced adverse effects, mainly to reduce the volume of activated tissue (the amount of brain tissue that is stimulated by electrical activity in DBS). Nineteen participants — 14 with Parkinson’s, two with tremor and three with dystonia — experienced a reduction of symptoms, while 10 (seven with Parkinson’s, one with tremor and two with dystonia) saw no change.

Overall, the benefit of using ILS was predominantly noted in the lessening of dyskinesia — the involuntary, jerky movements — in patients with Parkinson’s disease, and occurred soon after the switch. The average duration of ILS in the six Parkinson’s patients who continued on this approach was 206 days.

Six additional patients also experienced easing of dyskinesia but discontinued the therapy due to worsened pain or mood, temporary benefit, and worsened motor function.

Of the nine Parkinson’s patients receiving ILS for other stimulation-induced adverse effects, only one who tried ILS for dysarthria (slurred or slow speech) continued the treatment with further improvement in parkinsonism.

Three patients with tremor and five with dystonia were receiving ILS for stimulation-induced adverse events. Among these, the approach had mixed results, with only three participants with dystonia showing improvements.

A total of 21 participants tried ILS to improve DBS clinical effectiveness (six Parkinson’s; four tremor; 11 dystonia). Of these, all six Parkinson’s patients and three with dystonia demonstrated benefits. Of the patients with Parkinson’s (mean ILS duration 420 days), four had ILS to reduce tremor, one to lower bradykinesia (slowness of movement), and one to lessen freezing of gait. ILS was not effective in people with tremor and only two patients with dystonia continued with the treatment.

“We identified 2 reasons for attempting ILS: to mitigate adverse effects and to improve disease signs and symptoms,” researchers wrote. “The most impressive finding was improvement of dyskinesias with ILS …  In tremor and dystonia, marginal effects in terms of mitigation of adverse effects and improvement of clinical outcomes were evident,” they added.

“Overall, ILS appears to have limited benefits in the treatment of other stimulation-induced adverse effects potentially due to minimal adjustment of the VAT [volume of activated tissue] and would unlikely be effective to salvage a misplaced electrode,” they concluded.

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The ABCs of Parkinson’s: It’s Not Just About Shaking

tremor, shaking

Sherri Journeying Through

The next letter in a series on the ABCs of Parkinson’s is “N.” This is because the disease is not just about shaking.

When the topic of Parkinson’s disease comes up, it’s often met with a misunderstanding of what it really is. People immediately think of someone who shakes, if indeed they know much about the disease at all. But that’s not what Parkinson’s is. It does entail tremors, or shaking, but it is so much more than that.

Parkinson’s is not just shaking in one or more of the extremities (hands, arms, legs, and feet). While shaking can occur in only one extremity, it also can happen with all of them. It can include other parts of the body such as the head, the neck, the “insides,” the eyelids, or the mouth.

But again, Parkinson’s is not just about shaking.

When someone sees a person flailing about as they are walking/shuffling down the street, they may assume the person may have had a bit too much to drink. This is not necessarily true. Parkinson’s may (and has been known to) take the appearance of a drunken sailor, but the flailing about is not PD. It is a side effect of the medications taken to cope with the disease. Sad, but true.

Parkinson’s disease is unpredictable. PD is not a disease you can define other to say that it is ever-changing from one person to another. You may know someone with Parkinson’s, yet you will not find another who experiences the disease in the same way. There is nothing certain about the disease. It is not predictable. 

Most people do not, and cannot, understand this often misunderstood disease. They focus on the tremors or the dyskinesia (flailing about). They do not understand it may (or may not) entail other lesser-known symptoms such as depression, apathy, constipation, and irritable bowel syndrome, drooling, and skin concerns. Other invisible symptoms can include sleep disorders, loss of smell, cognitive issues, moderate to extremely severe pain, dystonia, facial masking, visual and speech issues, mood changes, blood pressure irregularities, tripping, a shuffling gait, restless leg syndrome, and urinary dysfunctions, to name a few more. Yet, these still are not all of the symptoms.

The symptoms of Parkinson’s disease are misunderstood because basically, they are not visible and therefore can’t be evidenced in most people who have PD.

We often do not believe in something we can’t see, diseases included. Many times we choose to believe a person is not struggling or suffering because we can’t see below the skin to where the real pain is occurring. That’s because Parkinson’s is not just about shaking. It’s so much more than that. 

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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 The ABCs of Parkinson’s: It’s Not Just About Shaking appeared first on Parkinson’s News Today.

IRL790 Is Safe, Reduces Levodopa-induced Dyskinesia in Parkinson’s, Phase 1b Trial Shows

IRL790 and Parkinson's

IRL790, Integrative Research Laboratories‘ investigational treatment for Parkinson’s disease patients, was safe and reduced levodopa-induced dyskinesia, a Phase 1b trial shows.

The results were published in the journal npj Parkinson’s Disease in the study, “Safety and tolerability of IRL790 in Parkinson’s disease with levodopa-induced dyskinesia—a phase 1b trial.”

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 treatment of Parkinson’s patients. But more than half the patients who use levodopa experience abnormal, involuntary movements — dyskinesia — within the first five years of treatment.

Studies have shown that long-term treatment with levopoda increases levels of a dopamine receptor, called dopamine D3 receptor, that seems to correlate with levodopa-induced dyskinesia.

IRL790 is a central nervous system medication that mainly targets the dopamine D3 receptor. In rat models of Parkinson’s disease, the treatment reduced involuntary movements caused by levodopa treatment without compromising the animals’ locomotion. Also, IRL790 showed anti-psychotic properties, suggesting its potential for treating both dyskinesia and psychosis in Parkinson’s patients.

In a prior Phase 1 trial, researchers tested ascending doses of IRL790 in healthy male volunteers. The treatment had a very good safety profile, with no serious adverse events reported, even at doses higher than those planned for patients.

Now, a team at the Karolinska Institutet in Sweden conducted a Phase 1b trial to determine the treatment’s safety and efficacy in Parkinson’s patients experiencing levodopa-induced dyskinesia.

The study (NCT03531060) included 15 Parkinson’s patients (nine men and six women) who randomly received oral capsules of IRL790 (11 patients) or an oral placebo (four patients) for four weeks. During the trial, all patients continued receiving their regular medication.

The study’s main objective was to assess the treatment’s safety — measured through the number of adverse events, physical examination, electrocardiogram, heart rate, blood pressure, and other laboratory measurements — after four weeks.

Secondary measures included changes from baseline in dyskinesia, measured with the Unified Dyskinesia Rating Scale (UDysRS), and Parkinson’s scores, measured with the Unified Parkinson’s Disease Rating Scale (UPDRS) and Parkinson’s Kinetigraph.

Thirteen patients completed the 4-week study, with IRL790 given at an average daily dose of 18 mg.

Overall, 14 patients (93.3%) reported 62 adverse effects. Most were reported during the first two weeks — when the dose of IRL790 was adjusted to each patient — and were mild to moderate, easily mitigated by dose adjustments. No serious adverse effects were reported in any of the groups.

Patients taking IRL790 had a mean reduction of 8.2 percent in dyskinesia scores compared to those taking a placebo.

“Among patients treated with IRL790, 55.5% were assessed as having an improved global clinical condition, as compared with baseline (much improved/minimally improved),” researchers stated.

There were no changes in symptoms relating to parkinsonism, either in the UPDRS or in measurements from the Parkinson’s Kinetigraph, a wrist-worn device that evaluates bradykinesia (slowness of movement) and dyskinesia during activities of daily living.

The results show that “IRL790 can be safely administered to patients with advanced PD,  which will now “be of guidance for the design of phase 2 studies,” researchers said.

IRL790 is already being tested in a Phase 2 trial (NCT03368170), which will assess whether the treatment can reduce dyskinesia in a larger population (74 patients). The trial will also help establish the optimal dose for further testing.

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24-hour Levodopa-carbidopa Intestinal Gel Lessened Dyskinesia, Parkinson’s Study Finds

dyskinesia, levodopa-carbidopa intestinal gel

A 24-hour treatment with a levodopa-carbidopa intestinal gel (LCIG) lessened the duration and functional effect of dyskinesia — involuntary, jerky movements — in Parkinson’s patients, according to a small study.

The research, “24-hour levodopa-carbidopa intestinal gel may reduce troublesome dyskinesia in advanced Parkinson’s disease,” was published in npj Parkinson’s disease.

Continuous intra-jejunal (the middle part of the small intestine) infusion with a LCIG has been shown to efficiently treat Parkinson’s motor fluctuations. The gel normally is administered with a portable pump directly into the duodenum or upper jejunum by a permanent tube inserted surgically.

Currently, it is mainly used as a 16-hour per day continuous infusion, and is licensed for use in this way. However, additional benefits have been observed when used as a continuous 24-hour infusion in the treatment of severe nocturnal akinesia (losing the ability to move muscles voluntarily), daytime falls and freezing of gait (FOG), as well as poor sleep quality.

Clinical trials have shown that a 16-hour treatment with LCIG can effectively reduce levodopa-induced dyskinesia (LID), which typically occurs after long-term therapy, despite an increase in daily levodopa dose. Current treatments options for LID, such as deep brain stimulation and Gocovri (amantadine, by Adamas Pharmaceuticals) are not uniformly available or are not suitable for all patients.

Researchers from Movement Disorder Unit at Westmead Hospital, in Australia, have now described their clinical experience with a 24-hour LCIG infusion to treat dyskinesia in Parkinson’s patients.

Of 74 patients treated with LCIG for motor fluctuations, 12 (10 men) were treated with 24-hour daily infusion intended to control troublesome daytime dyskinesia and with sufficient data pre- and post- initiation of continuous treatment. Patients’ mean age at the start of 24-hour LCIG was 69 years and mean duration of Parkinson’s was 18 years. Two had a mutation in the PRKN gene, whose mutations are associated with the juvenile form of Parkinson disease.

Among these 12 patients, four took 24-hour LCIG infusion due to lack of response to 16-hour therapy; two due to troublesome dyskinesia and levodopa-unresponsive FOG; three due to levodopa-unresponsive FOG with non-troublesome dyskinesia; two more had troublesome dyskinesia and nocturnal akinesia; and one self-initiated 24-hour therapy. Two transitioned from oral levodopa, without an in-between 16-hour infusion.

Patients’ clinical characteristics, as well as dyskinesia severity and incidence, were analyzed before and after therapy using the Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) – part 3, part 4 (motor complications) total scores and sub-scores 4.1 (time spent with dyskinesias) and 4.2 (functional impact of dyskinesias). All evaluations were performed at baseline and at six months after starting 16- and 24-hour LCIG.

Daytime dyskinesia was reduced in nine patients (75%) following 24-hour therapy, including seven who were first treated with 16-hour infusion and the two patients who transitioned from oral levodopa.

Of the three patients without decrease in dyskinesia, one could not tolerate 24-hour infusion due to worsening of hallucinations and agitation, and shifted back to 16-hour therapy after two months. After six months, the patient’s neurocognitive function returned to baseline. A second 24-hour therapy was initiated 11 months later, but again led to no benefit. The remaining two patients had no change in dyskinesia despite eased FOG and nocturnal akinesia.

Combining the results from all 12 patients, both the time spent with dyskinesia and its functional impact were reduced during 24-hour LCIG treatment. In contrast, the MDS-UPDRS part 3 “ON” scores — control of motor symptoms — did not change.

Five patients showed lessened dyskinesia despite an overall increase in the total daily levodopa dose. No patient had worsened dyskinesia after a median follow-up of 27.5 months.

A total of three patients had worsening of nocturnal hallucinations, which diminished after lowering the night-time LCIG continuous rate. One patient developed asymptomatic peripheral neuropathy (nerve damage) within six months of 24-hour therapy, which remained stable during 18 months of follow-up.

Ten patients experienced vitamin B6 deficiency requiring supplementation, while seven developed vitamin B12 deficiency during therapy (16- or 24-hour). Two patients had hyperhomocysteinaemia (excess blood level of homocysteine), a condition associated with cardiovascular problems and neuropathy.

Of note, no patient elected to return to 16-hour infusion due to difficulty managing the pump, or technical difficulties with the jejunal tube.

Overall, if future studies confirm these findings, “24-[hour] LCIG may offer a novel approach to the treatment of troublesome dyskinesias which persist despite an adequate trial of 16-[hour] therapy,” researchers wrote.

Although further research is necessary to assess the mechanisms involved, the researchers hypothesized that the benefits with 24-hour treatment in patients not responding to 16-hour infusion may be due to continuous levodopa delivery to the brain.

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Phase 3 Trial of Accordion Pill in Treating Parkinson’s ‘Off’ Periods Fully Enrolled

medications

Intec Pharma announced the complete enrollment of a Phase 3 clinical trial evaluating the safety and effectiveness of its Accordion Pill Carbidopa/Levodopa (AP-CD/LD) in easing motor fluctuations in people with advanced Parkinson’s disease.

The investigative treatment will be compared to immediate release Sinemet, an approved combination of levodopa and carbidopa marketed by Merck, and to placebo in the study.

Levodopa is considered the most effective and widely used treatment for Parkinson’s motor symptoms, and is almost always given in combination with carbidopa — a molecule that helps ease levodopa’s side effects.

Together, these two components increase the level of dopamine in the brain, which normally is low in Parkinson’s patients, leading to the motor impairments associated with the disease.

However, patients with advanced disease being treated with levodopa (or Sinemet) often develop motor fluctuations, which result from “off” periods (a return of symptoms) between levodopa doses due to its short-term effects.

This limited effectiveness is associated with the restricted absorption of levodopa in the upper part of the gastrointestinal tract, meaning that it has a short period of absorption.

Intec Pharma’s AP-CD/LD was created to solve this problem through a specific gastric retention and release system containing carbidopa and levodopa. This system is intended to allow the therapy to be released in both immediate and controlled-release modes.

Controlled release enables a slow discharge of the therapy in the stomach over 8 to 12 hours, potentially allowing for more steady absorption in the upper gastrointestinal tract, where levodopa is absorbed.

Previous results from a randomized Phase 2 clinical study in 60 Parkinson’s patients showed that AP-CD/LD treatment was safe and significantly reduced “off” times by 45%, giving patients two extra hours a day of controlled motor function. AP-CD/LD treatment also significantly reduced the total number of levodopa doses per day.

“By providing more uniform levodopa plasma [blood] concentrations than those provided by currently available orally-administered levodopa products, we expect to improve the duration and consistency of symptom relief provided by levodopa with a simpler dosing regimen,” R. Michael Gendreau, MD, PhD, Intec Pharma’s chief medical officer, said in a press release.

The multi-center, randomized, double-blind, Phase 3 clinical trial (NCT02605434), named ACCORDANCE, is comparing the safety and effectiveness of AP-CD/LD and Sinemet (immediate release of carbidopa-levodopa) in hundreds of adults with advanced Parkinson’s.

Prior to the 13-week randomized part of the study — which includes placebo groups — 462 patients were first stabilized and optimized on Sinemet and then on AP-CD/LD during two open-label periods lasting six weeks.

About 300 of these patients are now receiving either an AP-CD/LD capsule — containing 50 mg of carbidopa with 400 or 500 mg of levodopa — twice or three times a day or a matching placebo. Or they are being given an immediate release Sinemet tablet — consisting of 25 mg of carbidopa and 100 mg of levodopa — or a matching placebo at least four times a day.

The study’s primary goal is the reduction in the percentage of daily “off” time during waking hours, which will be considered statistically significant if it leads to at least one-hour difference between Sinemet and AP-CD/LD.

Secondary goals include the reduction of involuntary movements during “on” periods, and improvement in the scores of the Clinical Global Impression Scale-Improvement (CGI-I) — as recorded by the physician and patient — and the Unified Parkinson’s Disease Rating Scale (UPDRS), which assesses both motor and non-motor symptoms.

ACCORDANCE is taking place at about 90 clinical sites throughout the U.S., Europe and Israel (some 32% of participants were enrolled in the U.S.). At enrollment, 65% of patients were men with a mean age of 63, who have lived with the disease for a mean of 8.8 years. Participants’ mean daily “off” time was 6.1 hours, and over 40% were taking more than 800 mg of levodopa daily.

Participants who complete the 13-week randomized period can chose to move to an open-label extension study, where all patients will receive AP-CD/LD for one year. To date, more than 90% of eligible patients have chosen to enter the extension study, the company reports.

According to an Israel newspaper, results of the ACCORDANCE study are expected in mid-2019.

Intec Pharma believes these results, along with the long-term data provided by the extension study and the results of a Phase 2 clinical study (NCT03576638) evaluating how the most common dose of AP-CD/LD in the ACCORDANCE study is processed by the human body, will be essential for regulatory submission and AP-CD/LD launch.

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Parkinson’s Study Analyzes Levodopa‐induced Dyskinesia’s Effect on Sleep

sleep study

When a person is awake, brain circuit activity is constantly “on.” This activity needs to be normalized during sleep. Researchers now report that neuronal activity in Parkinson’s disease patients with levodopa-induced dyskinesia fails to decrease during sleep.

The study, “Levodopa-induced dyskinesia in Parkinson’s disease: sleep matters,” was published in Annals of Neurology.

The brain’s structure and functional networks are constantly changing/evolving in a biological process scientists call “neuronal plasticity,” which affects the brain’s learning and memory abilities.

Levodopa (L-Dopa), one of the main therapies used to treat Parkinson’s symptoms, “successfully controls motor symptoms for several years and then induces motor fluctuation and abnormal involuntary movements, i.e. levodopa-induced dyskinesias (LIDs),” researchers wrote.

This long-term, therapy-related complication results in important functional disability, often requiring complex pharmacological or surgical interventions.

Although LDIs are believed to be associated with changes in neuronal plasticity in the striatum — a brain area involved in multiple aspects of cognition — studies have demonstrated abnormal motor cortex plasticity in LID patients. The motor cortex is the brain area involved in the planning, control, and execution of voluntary movements.

In addition, changes in cortical slow wave activity (SWA) — the major characteristic of deep sleep key for both cortical restructuring and functioning, which, in turn, supports cognition — have been described in animal models of Parkinson’s disease with LID.

SWA increases with wake duration, peaks in early sleep, and declines in late sleep. Animal studies have shown that “rodents exposed to combined levodopa treatment and sleep deprivation developed earlier and more severe LID than animals that were not sleep deprived,” authors noted.

The team at Neurocenter of Southern Switzerland investigated if sleep could influence clinical presentation of Parkinson’s in humans, as previously observed in animals.

A total of 27 Parkinson’s patients (50-65 years old) were divided into three groups:

  • de novo: seven recently diagnosed patients who had received only azilect (rasagiline, by Teva) as dopaminergic therapy;
  • advanced: nine subjects without LID using their usual therapy, but demonstrating the end-of-dose or wearing-off phenomenon;
  • dyskinetic: 11 advanced patients with LID.

Seven healthy and age-matched participants also were recruited as controls.

Researchers evaluated subjects’ mood and sleep complaints as well as their Parkinson’s motor symptoms, using a series of rating scales, and asked them to maintain regular sleep-wake schedules.

A wristwatch-like device was attached to individuals’ non-dominant wrist to monitor their sleep/wake cycles for one week. This method is known as actigraphy. Because of technical failure, one patient from each of the Parkinson’s groups could not undergo rest/activity cycles monitoring.

Additionally, participants were submitted to whole night video polysomnography-high-density electroencephalogram (EEG) recording, meaning those studied had their brain waves, blood oxygen level, heart rate, breathing patterns, eye and leg movements monitored while they were asleep. Recording data was corrupted by artifacts in two de novo patients and one dyskinetic participant, and as a result was excluded from the SWA analysis.

Subjects were followed for at least six months.

Results showed there was a decline in SWA in the de novo, advanced and control groups, but not in dyskinetic patients, who had their SWA persistently elevated during the night.

In accordance, all groups except the dyskinetic one, manifested a significant decrease in SWA between early and late sleep, further supporting the investigators’ hypothesis that dyskinetic patients have their much-needed overnight brain activity normalization process compromised.

In all Parkinson’s patients, total sleep time and sleep efficiency were negatively correlated with disease duration, which is consistent with previous studies.

However, “while the correlation between [deep sleep] and disease duration was positive in both [de novo and advanced] patients, it was surprisingly negative in [dyskinetic] patients,” researchers wrote.

A possible explanation is there may be biological compensatory mechanisms in the de novo and advanced sample that can be compromised in the dyskinetic one, making dyskinetic patients unable to sleep efficiently as disease progresses.

Because levodopa dose influences dyskinesia onset, investigators performed a correlation analysis between sleep parameters and levodopa-equivaled daily dose.

A negative correlation of total sleep time and sleep efficiency with levodopa-equivalent daily dose was observed in all patients with motor fluctuations, i.e., in both advanced and dyskinetic groups. Importantly, slow wave (or deep) sleep was negatively correlated with levodopa-equivalent daily dose only in patients  experiencing LID.

“In conclusion, these results support our preclinical findings of a clear association between sleep and LID at the electrophysiological, behavioral, and biochemical levels,” researchers wrote.

“Although our findings do not imply a causative role for the lack of SWA reduction in the emergence of LID … they do suggest an association between sleep and some clinical [features] of PD and suggest a relationship between sleep disruption and LID,” they concluded.

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Chinese Compound Helps Reduce Levodopa-induced Dyskinesia, Eases Motor Symptoms in Parkinson’s, Study Finds

traditional Chinese compound

The traditional Chinese compound Zishenpingchan can be used as an add-on treatment to levodopa for improvements in motor symptoms and quality of life in patients with Parkinson’s disease, according to researchers.

The study, “Zishenpingchan granules for the treatment of Parkinson’s disease: a randomized, double-blind, placebo-controlled clinical trial,” was published in the journal Neural Regeneration Research.

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

The current standard for treatment is levodopa, which the body uses as a building block to make dopamine. But long-term treatment with levodopa can lead to abnormal, involuntary movements — a condition called dyskinesia — in more than half of treated patients.

As a result, there is a lack of treatments in Western medicine that can effectively and safely treat Parkinson’s in the long-term.

Several researchers have explored traditional Chinese medicine to find remedies that can help improve the quality of patients’ lives.

A Chinese professor, Jian-hua Hu, conducted a thorough clinical investigation into the effects of Zishenpingchan — a mixture of Chinese roots and herbs — in Parkinson’s disease.

In China, Zishenpingchan has been applied clinically to treat the disease and has been shown to improve patients’ dyskinesia and nonmotor symptoms, as well as delay disease worsening.

But to date, no clinical trials have been conducted to address the effects of the compound in a controlled environment.

Chinese researchers set out to evaluate the clinical efficacy and safety of this treatment in a clinical trial (ChiCTR-INR-1701194) in patients with Parkinson’s disease.

Researchers recruited 128 patients from the Department of Neurology of Longhua Hospital and Shuguang Hospital, affiliated with Shanghai University of Traditional Chinese Medicine in China.

Patients were already being treated with levodopa. They were randomized to either receive add-on treatment of Zishenpingchan granules or a placebo for 24 weeks. Researchers then evaluated the effects of the treatment across a variety of factors, including function, sleep, cognition, and quality of life.

First, researchers showed that administration of Zishenpingchan granules was significantly linked to a decrease in unified Parkinson’s disease rating scale (UPDRS) III score compared to patients treated with placebo, which suggests an improvement in dyskinesia and motor symptoms in treated patients.

While cognitive scores and experiences of daily living scores were not significantly different between the groups, depression and anxiety scores were significantly improved in the treatment group.

The UPDRS IV score, which measures motor complications, was significantly higher at 24 weeks compared to baseline in the control group, while the reverse was true in the treatment group. This suggests that Zishenpingchan granules reduces the severity of motor complications.

Additionally, quality of life, which was measured using the Parkinson’s Disease Quality of Life Questionnaire (PDQ-39), was significantly improved in the treatment group, suggesting treatment with Zishenpingchan improved patient’s quality of life.

And, the levodopa dosage had significantly increased at 24 weeks in the control group while there was no significant change in levodopa dosage in the treatment group.

Finally, researchers determined that all the adverse reactions to the treatment were mild, and no patients were lost due to the adverse reactions.

“This combination of Chinese and Western medicine has the potential to reduce levodopa dosages, and no obvious side effects were found,” researchers wrote.

These findings indicate that Zishenpingchan granules can help alleviate some of the symptoms of Parkinson’s disease, reduce toxic side effects of levodopa, and improve the quality of life of patients.

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Source: Parkinson's News Today

Ketamine Studied for Relief of Levodopa-associated Involuntary Movements

ketamine study

A Phase 1 trial will test the potential of ketamine — an analgesic medicine used for depression and pain — at reducing the uncontrollable, jerky movements that arise in Parkinson’s disease patients after long-term treatment with levopoda.

Levodopa, probably the most common treatment for Parkinson’s disease, is effective at improving the stiffness and slowness of movement that characterize the disease.

However, up to 40 percent of long-term users eventually experience dyskinesia, which is the uncontrollable and involuntary movements that may be restricted to certain parts of the body, such as head, arms or legs, or affect the whole body.

“The problem is levodopa works great for a few years — we call that the ‘honeymoon’ period — but then you start getting these side effects,” Scott Sherman, MD, PhD, a neurologist at the University of Arizona College of Medicine – Tucson, said in a press release.

The severity of dyskinesia varies among patients, with some experiencing small jerky movements and others being affected by strong, constant bursts. Unfortunately, these side effects go away only after a patient stops taking levodopa.

So, researchers at the University of Arizona will conduct a small Phase 1 clinical trial with 10 Parkinson’s patients to determine the potential of ketamine for rescuing levopoda-induced dyskinesia.

The trial follows earlier work by Sherman and Torsten Falk, PhD, the scientists leading the study. They were using ketamine to relieve pain in Parkinson’s disease patients when they noticed an unexpected effect — the treatment also reduced the patients’ uncontrolled movements. One patient was actually free of the jerky movements for several weeks.

The same results were seen in animal models, where treatment led to a significant reduction in abnormal involuntary movements. The reduction was sustained for three days, and 10 days passed before baseline involuntary movements returned.

Ketamine increases blood pressure, but may cause a sensation of “out-of-body” experience, also known as dissociation, Sherman said. “When people describe it, they have told me that they feel like they are in fish bowl,” said Sherman. Ketamine actually has been used as a psychedelic recreational drug, Sherman said, adding that researchers have established preventive measures and he is hopeful those side effects will not affect the clinical trial.

“We are going to monitor blood pressure closely to make sure it doesn’t get high,” Sherman said. “And we know at what dosage ketamine causes this disassociation; we expect that the dosage needed in Parkinson’s disease will stay well below that level.”

Parallel to the Phase 1 trial, researchers will undertake a rodent study to assess the mechanisms underlying the effects of ketamine in the brain.

“We want to find out exactly what ketamine is doing to have this effect,” Sherman added.

Positive results in both the human trial and the animal study could help researchers establish ketamine as a therapy for patients with Parkinson’s disease.

“Ketamine has been long overlooked. Now it could prove very useful for Parkinson’s patients,” Sherman said.

The Phase 1 human and the animal study are both supported by a $750,000 three-year grant from the Arizona Biomedical Research Commission.

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Gocovri Reduces Transitions Between Dyskinesia and ‘Off’ Episodes, Trial Results Show

Gocovri, dyskinesia

Treatment with Gocovri (amantadine) reduced Parkinson’s dyskinesia — involuntary, jerky movements — and so-called “off” episodes, leading to longer periods of controlling motor symptoms, Phase 3 clinical trial results show.

Parkinson’s motor fluctuations (off episodes) occur when the benefits of treatments such as levodopa wear off and symptoms re-emerge. About half of patients taking levodopa experience off periods, which become more frequent and severe as the disease progresses.

In August 2017, Gocovri, a long-acting and extended-release oral capsule formulation,  became the first and only treatment approved by the U.S. Food and Drug Administration for the treatment of dyskinesia in Parkinson’s patients receiving levodopa, with or without other dopaminergic medications.

According to developer Adamas Pharmaceuticals, Gocovri — designed to be taken once daily at bedtime — also is the first FDA-approved therapy to improve dyskinesia while reducing off periods in Parkinson’s patients.

During the study, 162 patients — 77 taking Gocovri and 85 placebo — provided a complete Parkinson’s home diary (either on or off states) at both baseline and week 12.

“The Parkinson’s disease home diary data from the Gocovri Phase 3 pivotal studies clearly show that the entire waking day may be impacted by troublesome dyskinesia,” Rajiv Patni, MD, chief medical officer at Adamas, said in a press release. Dyskinesia may happen after the patient takes the first daily dose of levodopa in the morning, he added.

Reductions in dyskinesia and off episodes with Gocovri at week 12 resulted in markedly longer on periods (when patients can control muscle symptoms) without dyskinesia.

Compared to placebo, Gocovri led to a 3.2-hour increase in the first on episode without troublesome dyskinesia.

Patients taking Gocovri also experienced 4.2 fewer transitions between diary states per day compared to 2.0 fewer transitions with placebo. Approximately 17% of Gocovri-treated patients did not experience any transitions during the day, compared with only 1% of those who took placebo.

The results, “ADS-5102 Reduces ON Time with Troublesome Dyskinesia and OFF Time Throughout the Waking Day-Time Course Analysis,” were presented recently at the 2nd Pan American Parkinson’s Disease and Movement Disorders Congress (MDS-PAS) in Miami.

“Gocovri-treated patients experienced a decrease in the number of transitions between these diary states, resulting in longer periods of uninterrupted on time without troublesome dyskinesia,” Patni commented, while noting that the 17% of Gocovri-treated patients who were transition-free throughout the waking day is “particularly noteworthy”.

“This new analysis provides a useful definition of transitions that reinforces the previously reported data of Gocovri on dyskinesia and off (periods),” Patni said.

Of note, safety results were consistent with the overall population of the pivotal trials for Gocovri, Adamas noted. The most frequent side effects, occurring in more than 10% of patients, were hallucination, dizziness, dry mouth, peripheral edema, constipation, falls, and orthostatic (or postural) hypotension.

Gocovri’s benefits are in line with those of the EASE LID 2 (NCT02202551) open-label study, which evaluated the safety, tolerability, and effectiveness of a two-year treatment with Gocovri in Parkinson’s patients with levodopa-induced dyskinesia. Results showed that Gocovri could lead to long-term improvements of motor complications.

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Deep Brain Stimulation Device That Can Self-Tune Show Promise in Small Parkinson’s Study

adaptive DBS trial

A new and experimental deep brain stimulation (DBS) system uses feedback from the brain to fine-tune its signaling in response to signs of dyskinesia, potentially offering a more refined way to ease motor problems in Parkinson’s patients, a small feasibility study reports.

The research, “Adaptive deep brain stimulation for Parkinson’s disease using motor cortex sensing,” was published in the Journal of Neural Engineering. Larger studies of the devices potential effectiveness, as well as its safety, may follow.

DBS is a treatment strategy for people with advanced Parkinson’s disease, whose movement problems do not benefit from medications.

The procedure as now used consists in surgically implanting one or more thin wires into the brain, and an area known as the basal ganglia is constantly stimulated to ease symptoms. Adjustments in intensity are done manually by clinicians in response to changes in symptoms.

While it can be effective, DBS can also cause side effects that include dyskinesia, or uncontrolled movements, which has led to attempts to improve the technique.

In a small and short-term study, two Parkinson’s patients were implanted with an adaptive DBS device. The implant wire was inserted over the primary motor cortex — a key part of the brain that controls movement.

Signals collected from this lead were fed to a computer program embedded in the device, which would determine whether to stimulate the brain — rather than provide continuous stimulation.

“Other adaptive deep brain stimulation designs record brain activity from an area adjacent to where the stimulation occurs, in the basal ganglia, which is susceptible to interference from stimulation current,” Philip Starr, MD, PhD, the study’s senior author at the University of California, San Francisco, said in a news release. “Instead, our device receives feedback from the motor cortex, far from the stimulation source, providing a more reliable signal.”

The computer program was instructed to identify a pattern of brain activity that has been linked to dyskinesia.

Specifically, stimulation was reduced upon identification of dyskinesia-related brain activity, and increased when no dyskinesia was found, in this way minimizing side effects.

Initial results indicated that the adaptive system improved patients’ movement as effectively as traditional, constant DBS set manually by the researchers.

Because the new adaptive approach did not continuously stimulate the brain, it required about 40 percent battery energy over traditional DBS.

“This is the first demonstration of adaptive DBS in Parkinson’s disease using a fully implanted device,” the researchers wrote.

Although researchers were not able to compare the incidence of dyskinesia using either system, they hope that the adaptive system will lead to fewer adverse effects over longer time periods.

“The novel approach taken in this small-scale feasibility study may be an important first step in developing a more refined or personalized way for doctors to reduce the problems patients with Parkinson’s disease face every day,” Nick B. Langhals, PhD, program director at National Institute of Neurological Disorders and Stroke (NINDS) and team leader for the Brain Research through Advancing Innovative Technologies (BRAIN) Initiative.

Because too much stimulation could cause dyskinesia, an adaptive DBS system that responds to brain activity may represent an effective and safer alternative, the investigators believe.

“Here we have demonstrated the feasibility of adaptive [DBS],” Starr said. “We are now planning larger, longer-term trials to determine how effective this system is in managing the symptoms of patients with Parkinson’s.”

Both NINDS and the Brain Initiative supported the study.

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