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Pain May Be Early Detector of Parkinson’s, Study Suggests

pain in early Parkinson's

Patients likely to have prodromal, or early, Parkinson’s disease tend to have a higher prevalence of pain, according to a new study.

The findings indicate that pain may be a relevant disease marker before the appearance of motor disturbances.

The study, “Pain: A marker of prodromal Parkinsons disease?” was presented at the recent 2018 World Congress on Parkinson’s Disease and Related Disorders (IAPRD), held in Lyon, France.

Disease-related changes in patients with Parkinson’s can start decades before the onset of motor symptoms and may include pain, among other non-motor changes.

Researchers at the Bangur Institute of Neurosciences in India conducted a combined hospital and community-based study to evaluate whether pain could be an early clinical marker of future development of Parkinson’s in people with no motor impairment.

The study included a total of 500 individuals (314 men, 186 women) older than 50 from an urban community, who were examined for the prevalence of different types of pain by interviewing patients and relatives, and analyzing medical records.

The likelihood ratio (LR) of prodromal Parkinson’s — according to the research criteria of the Movement Disorder Society — were estimated in these patients divided into two groups: a control group (LR under 80%) and a prodromal, or early, Parkinson’s group (LR above 80%).

Presence of pain was assessed in 95 patients with less than two years of disease duration and who were attending a neurology outpatient department (clinical group). Different pain syndromes were classified according to the U.S. ICD-9-CM system of diagnostic codes (the official system of assigning codes to diagnoses and procedures associated with hospital utilization in the U.S.).

Thirty-two of the 500 individuals (6.4%) had a LR consistent with early Parkinson’s. These patients showed a significantly higher prevalence of pain than the controls — 23 (71.8%) vs. 144 (30.76%), respectively.

Pain prevalence in the clinical group was 63.15%, which was comparable to the prodromal group, researchers observed.

The data also revealed that both the clinical and the prodromal groups had a higher prevalence of cervicalgia (neck pain), shoulder pain, pelvic pain, pain in the thigh joint, backache, and low back pain compared to controls.

Individuals in the clinical and prodromal groups also had more frequent frozen shoulder — characterized by stiffness and pain in the shoulder joint — restless legs syndrome (discomfort in the legs and an irresistible urge to move them), and nocturnal leg cramps.

“This is an indirect evidence that pain can be an important early clinical marker of [Parkinson’s],” the authors wrote.

However, they noted that longitudinal studies are needed to better assess the predictive value of pain in Parkinson’s disease.

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Source: Parkinson's News Today

Phase 2 Trial Shows Nilotinib Potential to Modulate Dopamine in Parkinson’s

Nilotinib Phase 2 trial

Nilotinib can modulate dopamine levels and metabolism, as well as prevent the formation of toxic alpha-synuclein aggregates, according to recent data from a Phase 2 clinical trial.

These findings suggest that Novartis’ investigational therapy has the potential to promote long-term benefits in patients with Parkinson’s disease.

The study, “Nilotinib increases dopamine metabolism and reduces oligomeric: total alpha-synuclein ratio in Parkinson’s disease,” was recently presented during the 2018 World Congress on Parkinson’s Disease and Related Disorders (IAPRD), Lyon, France.

Nilotinib is available under the brand name Tasigna as an approved treatment for certain types of leukemia. It blocks the activity of a protein called BCR-ABL that is known to support cancer development. But this protein also is intimately linked to several mechanisms in the brain, such as oxidative stress and alpha-synuclein-induced neurodegeneration, which play critical roles in Parkinson’s and other brain disorders.

Results of a small proof-of-concept Phase 1 trial (NCT02281474) performed at Georgetown University in Washington, D.C., revealed that treatment with two different doses of Nilotinib — 150 mg and 300 mg — could improve Parkinson’s patients’ motor skills and cognitive abilities. In addition, the treatment showed the potential to reduce levels of the protein alpha-synuclein, which is believed to contribute to destruction of brain nerve cells in Parkinson’s disease.

In the ongoing Phase 2 trial (NCT02954978) a total of 75 patients with mid-stage Parkinson’s disease with mild cognitive impairment were randomized to take one of four tested oral doses of Nilotinib -—150 mg, 200 mg, 300 mg, and 400 mg — or a placebo.

After a single treatment researchers evaluated several biomarkers of the disease, including the levels of alpha-synuclein and dopamine derivate compounds in patients’ cerebrospinal fluid (CSF).

The data revealed a significant increase in homovanillic acid (HVA) and DOPAC levels, suggestive of enhanced production and metabolism of dopamine just one to four hours after treatment.

Although researchers could not find significant changes in CSF total alpha-synuclein levels, low-dose Nilotinib therapy (150 mg and 200 mg) resulted in a reduction of the levels of abnormally clustered and toxic alpha-synuclein.

“The significant reduction of oligomeric alpha-synuclein, which is expected to increase in the CSF of Parkinson’s disease patients as the disease progresses, suggests that Nilotinib may reduce misfolded alpha-synuclein accumulation and have a long-term disease modifying effect,” researchers wrote.

“These results suggest Nilotinib, in a dose dependent manner, may have a symptomatic effect through modulation of brain dopamine levels. Additionally, the significant reduction of oligomeric alpha-synuclein, which is expected to increase in the CSF of PD patients as the disease progresses, suggests that Nilotinib may reduce misfolded alpha-synuclein accumulation and have a long-term disease modifying effect,” researchers wrote.

The team will continue the analysis of the collected data to further explore the impact of Nilotinib treatment on disease biomarkers’ levels both in the blood and CSF, after a single administration and 52-week daily treatment regimen.

A new Phase 2 trial, NILO-PD (NCT03205488), currently recruiting 135 participants, will further investigate the potential of Nilotinib in patients with moderate-to-advanced Parkinson’s symptoms.

The study will take place at 25 sites across the United States. It will compare the safety and effects on patients’ motor functions of once-daily Nilotinib versus placebo treatment, for up to 12 months.

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Source: Parkinson's News Today

Opicapone Superior to Comtan in Providing Motor Benefits to Parkinson’s Patients, Phase 3 Study Shows

opicapone

Once-daily treatment with opicapone provides continued reductions of off periods in Parkinson’s patients taking levodopa, Neurocrine Biosciences’ Phase 3 clinical study shows.

The findings also reveal that opicapone’s effectiveness was superior to that of Comtan (entacapone, marketed by Novartis).

The results were presented in three scientific posters at the 2018 World Congress on Parkinson’s Disease and Related Disorders (IAPRD), taking place in Lyon, France.

Opicapone is designed as a once-daily add-on therapy to levodopa for adults with Parkinson’s and end-of-dose motor fluctuations. It is an inhibitor of the enzyme catechol-o-methyltransferase, or COMT, which breaks down levodopa. This leads to prolonged levodopa effects, as it reduces the time when the medication wears off before the next dose — s0-called off periods.

It is currently marketed in Europe as Ongentys. The company is intending to start the U.S. regulatory review in early 2019, which could lead to the medication’s approval.

“Neurocrine Biosciences is committed to bringing innovative and effective treatments to patients living with movement disorders,” Eiry W. Roberts, MD, Neurocrine’s chief medical officer, said in a press release. Roberts added that these findings will help healthcare providers further understand “the potential of opicapone to help [Parkinson’s] patients.”

Neurocrine compared the effectiveness and safety of 5, 25 and 50 mg doses of opicapone over a three-week treatment to that of 200 mg of Comtan (also a COMT inhibitor) and placebo. Primary results from BIPARK I as well as data from its open-label extension phase already had been published.

The multi-center, double-blind Phase 3 study (NCT01568073) included patients 30 to 83 years old, with a three-year diagnosis of idiopathic Parkinson’s, Hoehn and Yahr (H-Y) stage — a system used to assess the worsening of Parkinson’s symptoms — of 1 to 3 (meaning minimal or no functional disability, to mild-to-moderate disability), and receiving treatment with levodopa for at least one year.

In the study, “Efficacy of Opicapone in Parkinson’s Disease Patients with Motor Fluctuations: A Phase III, Randomized, Double-Blind, Placebo- and Active-Controlled Study – BIPARK I,” researchers analyzed data from 590 patients — 119 taking 5 mg of opicapone, 116 receiving 25 mg, 115 taking 50 mg, 120 on 200 mg Comtan, and 120 on placebo.

Results showed that both 50 mg opicapone and Comtan significantly decreased the duration of daily off periods and increased “on time” (periods when symptoms are controlled) without troublesome dyskinesia, which are involuntary, jerky movements. However, the higher dose of opicapone led to a 51% greater reduction in off periods (50.8 minutes vs. 40.3 minutes).

The data further revealed that, unlike Comtan, 50 mg opicapone was associated with significant improvement in the proportion of both off and on responders (minimum of one hour improvement) compared to placebo. Also, unlike Comtan and placebo, opicapone led to favorable ratings in both Patient Global Impression of Change (PGI-C) and Clinical Global Impression of Change (CGI-C).

This was further addressed in the study, “Opicapone as Adjunctive Therapy to Levodopa in Patients with Parkinson’s Disease and Motor Fluctuations: Global Impressions of Change Compared to Placebo and Entacapone,” which reported that, for PGI-C, the proportion of patients reporting improvement ranged between 63.8% to 72.2% for opicapone groups, vs. 50.8% for placebo, and 52.5% for Comtan.

As for CGI-C, the proportion of patients assessed as improved ranged between 60.3% to 73.0% for opicapone, in comparison to 50.0% for placebo and 50.8% for Comtan.

Treatment-emergent adverse events (TEAEs) were reported by 51.6%-54.6% of patients taking opicapone, 56.6% on Comtan, and 49.6% on placebo.

Compared to placebo, opicapone led to more common dyskinesia, insomnia, and dizziness. TEAEs were similar between opicapone and Comtan.

“[Opicapone] 50 mg once-daily was effective in the treatment of motor fluctuations with a favorable profile compared to [Comtan],” researchers wrote.

The study, “Switch of Double-Blind Opicapone, Entacapone, or Placebo to Open-Label Opicapone: Efficacy Results of the 1-Year Extension of Study BIPARK I,” reported the efficacy results of a one-year extension study of BIPARK I. This trial included patients who completed BIPARK I or the Phase 3 study BIPARK II (NCT01227655).

All patients included in study began with a 25 mg dose of opicapone for a minimum of one week, regardless of prior double-blind treatment.

Compared to the start of the trial (baseline), mean off time was reduced by 34 minutes. If comparing to the start of BIPARK I, this represented a decrease superior to two hours (127 minutes).

Opicapone reduced off periods by 65 minutes and 39 minutes and increased on periods without troublesome dyskinesia by 43 minutes and 46 minutes, when compared to BIPARK I participants’ taking placebo or Comtan, respectively.

Overall, opicapone “maintained its efficacy over the 1-year treatment period,” researchers wrote.

The medication was originally developed by Portugal-based BIAL, which licensed the North American rights to Neurocrine in February 2017.

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Source: Parkinson's News Today

Deep Brain Stimulation is a Long-term, Effective, Safe Treatment for Parkinson’s, New Studies Show

deep brain stimulation

Subthalamic deep brain stimulation (STN-DBS) seems to be a long-term, effective, and safe therapeutic option for patients with advanced Parkinson’s disease, new studies report.

STN-DBS is a non-destructive surgical treatment for Parkinson’s, in which a battery-operated device that generates electrical impulses is implanted to specific regions of the patient’s brain. Since its implementation, it has become an accepted and effective therapeutic option to treat the motor symptoms associated with Parkinson’s and other complications caused by prolonged dopaminergic treatment in advanced forms of the disease.

However, research documenting the long-term effects of STN-DBS on the clinical state of patients with advanced Parkinson’s disease is still scarce. Now, researchers presented two studies during the IAPRD World Congress 2018, held August 19-22 in Lyon, France, where they revealed the effects of STN-DBS after long-term follow-up.

In the study, “Subthalamic deep brain stimulation for advanced Parkinson’s disease beyond the 5-year follow-up,” (abstract e-book, page 11) Russian researchers evaluated the long-term safety and effectiveness of STN-DBS in a group of patients for at least seven years after surgery.

The study enrolled 33 patients with advanced Parkinson’s disease who had undergone STN-DBS surgery with a minimum follow-up period of five years. Several parameters, including motor function, disease impact on daily activities and quality of life, were assessed using the UPDRS-2,3,4, the Schwab & England scale and the PDQ-39 questionnaire, respectively.

After a follow-up period of seven years, there was a significant improvement in patients’ motor functions (42% in UPDRS-3, 24% in UPDRS-2 and 58% in UPDRS-4), ability to perform regular daily activities (23% in Schwab & England scale) and quality of life (9% in PDQ-39 questionnaire).

In addition, researchers also found that 41% of patients who underwent STN-DBS reduced their intake of levodopa and three even completely withdrew from the medication in the course of the study.

“In advanced PD-patients, STN-DBS could provide significant improvement in OFF-state [when medications fail to suppress disease symptoms] and diminish dopaminergic medication up to seven postoperative years,” the authors wrote.

In another study, “Long-term effect of subthalamic deep brain stimulation in young- and late-onset Parkinson’s disease: 10-year follow-up study,” (abstract e-book, page 13) Korean researchers evaluated the long-term safety and effectiveness of STN-DBS in patients with young disease onset (YOPD) and compared it to those who developed the condition later (LOPD) for a follow-up period of 10 years.

The study analyzed motor symptoms (UPDRS scores) of 24 patients with advanced Parkinson’s disease (13 YOPD and 11 LOPD) who underwent STN-DBS between March 1, 2002 and March 31, 2007 at the Asan Medical Center in Seoul, South Korea.

Ten years after STN-DBS, the reduction in the scores of levodopa equivalent dose (a rough technique to compare different medications, LED) and levodopa-induced dyskinesia (measures levodopa side effects, LID) were significantly lower in YOPD compared to LOPD patients.

Levodopa-induced dyskinesia improvement remained statistically significant until five years after the surgery in both groups, but after 10 years, its severity increased substantially in LOPD patients.

However, the decrease in motor symptoms (measured by UPDRS scores), visual hallucinations and adverse effects did not differ between the two groups.

“This study shows that STN DBS showed higher effect on LED reduction in LOPD and LID improvement in YOPD at 10 years after DBS surgery. These results may have clinical implications for tailored application of STN DBS in patients with PD,” the authors wrote.

Altogether, these data suggest that STN-DBS is a long-term beneficial treatment option for patients with advanced Parkinson’s disease.

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Source: Parkinson's News Today