Stable Doses Of Levodopa Research Articles

CVN424, a GPR6 inverse agonist, for Parkinson's disease and motor fluctuations: a double-blind, randomized, phase 2 trial

CVN424 is a GPR6 inverse agonist that provides selective pharmacological control of the indirect striatopallidal pathway. We assessed the safety and efficacy of CVN424 as an adjunctive treatment to levodopa for reducing OFF-time in individuals with Parkinson's disease (PD) experiencing motor-fluctuations. This was a randomised, double-blind, placebo-controlled study conducted at 21 sites across the United States to evaluate two doses of CVN424 (NCT04191577). Patients with PD (Hoehn and Yahr stages 2-4) who were on a stable dose of levodopa and experiencing ≥2h of daily OFF-time were randomised (1:1:1) to receive either once-daily CVN424 (50mg or 150mg) or placebo for a 28-day treatment period. The primary endpoints were safety and tolerability. The key secondary endpoint was the change from baseline to Day 27 in OFF-time. The study was conducted from December 23, 2019, to October 14, 2021. Out of 198 participants screened, 141 eligible participants were randomised to one of the three treatment groups (n=47 per group), and 127 participants completed the 28-day treatment period. The most common treatment emergent adverse events (TEAEs) were headache (2% with CVN424 50mg, 9% with CVN424 150mg, and 2% with placebo) and nausea (4% with CVN424 50mg, 6% with CVN424 150mg and 2% with placebo). No serious treatment-related adverse events were reported. On Day 27, the mean±standard deviation (SD) change from baseline in daily OFF-time was-1.3±3.0h in the CVN424 50mg group,-1.6±2.5h in the CVN424 150mg group, and-0.5±2.9h in the placebo group. The placebo-adjusted LS mean±standard error (SE) treatment difference was significant for the CVN424 150mg dose (1.3±0.56h, [95 CI%-2.41 to-0.19], nominal p=0.02). Treatment with CVN424 was safe and well-tolerated. Despite the short study duration and small sample size, the 150mg CVN424 dose provided a clinically meaningful reduction in daily OFF-time. This study supports the development of CVN424 for the treatment of PD. Cerevance.

Effectiveness and safety of safinamide in the Toledo Movement Disorders Unit.

The management of motor fluctuations in Parkinson's disease (PD) can be challenging, and current therapeutic options include the use of monoamine oxidase B inhibitors (MAO-B inhibitors), among others. The aim of this study was to evaluate the effectiveness and safety of safinamide in the clinical practice carried out in the Toledo Movement Disorders Unit. This is a retrospective study in which data were collected at baseline and at six months from PD patients who were started on safinamide as an add-on therapy with a stable dose of levodopa in line with standard clinical practice. An analysis was performed by subgroups: patients who were given low-dose safinamide and patients who previously received rasagiline. Ninety patients (47 previously received rasagiline) completed the six-month follow-up. A statistically significant decrease in morning akinesia, nocturnal akinesia, wearing off, unpredictable off phenomenon and Unified Parkinson's Disease Rating Scale-III was observed both in those who previously received rasagiline and in those treated with low doses of safinamide. No variation was found in the dyskinesias. The adverse events described were mild, with generalised weakness, dizziness, nausea, headache and alopecia. Safinamide has been shown to be effective and safe in improving motor fluctuations, motor symptoms and the subjective perception of disease severity in PD patients previously receiving rasagiline and in those receiving low-dose safinamide, all of which is accompanied by a good safety profile.

A Study to Evaluate the Efficacy and Safety of Safinamide, as add-on Therapy, in Idiopathic Chinese Parkinson's Disease (PD) Patients With Motor Fluctuations Treated With Stable Doses of Levodopa

A Study to Evaluate the Efficacy and Safety of Safinamide, as add-on Therapy, in Idiopathic Chinese Parkinson's Disease (PD) Patients With Motor Fluctuations Treated With Stable Doses of Levodopa

Correction of non-motor vegetative fluctuations with parkinson’s disease based on levodopa treatment

The influence of dopamine receptor agonists in the transdermal and oral forms of drugs and amantadine for a non-motor autonomic fluctuations of patients with different duration of the disease during the treatment of Parkinson's in a stable dose of levodopa were established. It was analysed, that the use of dopamine receptor agonists in the transdermal and oral forms of drugs reduce the frequency and duration of vegetative non-motor fluctuations of patients with Parkinson's disease. The use of amantadine sulphate has little effect in a decrease of non-motor autonomic fluctuations.

The relationship between temperament and depression in Parkinson's disease patients under dopaminergic treatment.

The risk factors for depressive symptoms in patients with Parkinson's disease (PD) under dopaminergic drug treatment are unclear. In this study, we examined whether some temperament traits are related to the presence of comorbid depression in PD patients, independent of the characteristics of illness and drug treatment. The participants in this study were 74 patients with idiopathic PD who were already treated with stable doses of levodopa or dopamine agonists. Depressive (n = 20) and non-depressive (n = 52) PD patients were assessed by means of the Unified Parkinson's Disease Rating Scale, Beck Depression Inventory, and Temperament Evaluation of Memphis, Pisa, Paris and San Diego Auto-questionnaire. The doses of levodopa and dopamine agonists were converted into levodopa equivalent daily dose. The duration of treatment in the depressive group was significantly longer than in the non-depressive group (P = 0.03). The depressive patients had significantly higher scores on the Unified Parkinson's Disease Rating Scale than the non-depressive patients. Depressive (P < 0.0001), cyclothymic (P < 0.0001), anxious (P < 0.0001), and irritable (P = 0.02) temperament scores were significantly higher in depressive than in non-depressive patients. Hyperthymia scores were significantly higher in non-depressive patients than in depressive patients (P = 0.01). Logistic regression analysis revealed that depressive temperament traits (P = 0.03) significantly predicted the diagnosis of depression. In contrast, hyperthymic temperament seemed to be associated with the absence of depression (P = 0.006). Our results indicated that the severity of PD and duration of dopaminergic treatment were not predictive of the development of depression in PD patients. Depressive temperament strongly predicted the development of depression in our sample. Hyperthymic temperament seemed to be associated with patients without depression. We suggest that depressive temperament traits seem to be related to depression, while hyperthymic temperament may have a protective role in the risk of depression in PD patients.

Adjunctive preladenant: A placebo-controlled, dose-finding study in Japanese patients with Parkinson's disease

BackgroundPreladenant, an adenosine 2A antagonist, reduced daily OFF time when administered as adjunctive treatment in a previous phase 2 trial in non-Japanese Parkinson's disease (PD) patients on stable doses of levodopa. This study aimed to evaluate preladenant as adjunctive therapy in Japanese patients with PD. MethodsIn this randomized, placebo-controlled, double-blind, 12-week, dose-ranging, phase 2 study, Japanese patients with moderate to severe PD on a stable regimen of levodopa were randomly assigned 1:1:1:1 to preladenant 2 mg, 5 mg, or 10 mg BID or placebo. The primary efficacy end point was change from baseline to week 12 in mean OFF time, recorded using a PD diary. Safety and tolerability were also assessed. ResultsIn total, 111 patients were randomly assigned to receive preladenant 2 mg, and 113 each received preladenant 5 mg, 10 mg, or placebo. In contrast to previous data, preladenant in this study did not demonstrate statistically significant efficacy; the primary outcome was −0.7 h (P = 0.0564), –0.5 h (P = 0.1844), and −0.3 h (P = 0.3386), respectively, for preladenant 2 mg, 5 mg, and 10 mg BID versus placebo. Overall, preladenant was well tolerated, and the frequency of adverse events appeared to be dose related. ConclusionsIn this phase 2 study, preladenant used as adjunctive therapy in PD patients on stable doses of levodopa did not reduce mean OFF time; treatment was well tolerated at doses between 2 and 10 mg BID.

Effects of a single dose levodopa on heart rate variability in Parkinson's disease

To explore the effects of levodopa on heart rate variability (HRV) in Parkinson's disease (PD). A total of 48 PD patients (M:F = 35: 13, mean age: 59 ± 6 years, duration of illness: 4.7 ± 1.8 years, Hoehn & Yahr stage: 2.2 ± 0.3) on a stable dose of levodopa were recruited from January 2012 to May 2014.For confirming autonomic dysfunction, the baseline patient data (12 hours off-medication) were compared with a control group consisting of 48 age and gender-matched healthy subjects (M: F = 35: 13, mean age 58 ± 6 years). Resting lead II electrocardiogram (ECG) was recorded at baseline and continuously after two tablets of 100/10 mg levodopa/carbidopa.However, 5-min segments were selected from every quarter, i.e., Q1 (0-15 min), Q2 (15-30 min), Q3 (30-45 min) and Q4 (45-60 min). Artifact-free 5-min segments of ECG were analyzed offline to acquire the parameters of heart rate variability in time and frequency domains. At baseline, PD patients had a significantly reduced standard deviation of normal-to-normal intervals (SDRR) [(24 ± 4) vs (26 ± 4) ms, P < 0.01)] and total power (TP) [(569 ± 180) vs (652 ± 205) ms², P < 0.05] when compared to controls. Comparing of HRV in PD patients at baseline and during first hour after drug administration, we observed significant increase in SDRR [(29 ± 12) vs (24 ± 8) ms, P < 0.05)], TP [(708 ± 253) vs (569 ± 180) ms², P < 0.01], low frequency power (LF) [(203 ± 98) vs (168 ± 60) ms², P < 0.05) ] and high frequency power (HF) [158 ± 86) vs (114 ± 90) ms², P < 0.05] in Q3. The results suggest an improvement in the overall variability of heart rate resulting from an enhanced vagal tone.

CORRECTION OF NON-MOTOR VEGETATIVE FLUCTUATIONS WITH PARKINSON’S DISEASE BASED ON LEVODOPA TREATMENT

The influence of dopamine receptor agonists in the transdermal and oral forms of drugs and amantadine for a non-motor autonomic fluctuations of patients with different duration of the disease during the treatment of Parkinson's in a stable dose of levodopa were established. It was analysed, that the use of dopamine receptor agonists in the transdermal and oral forms of drugs reduce the frequency and duration of vegetative non-motor fluctuations of patients with Parkinson's disease. The use of amantadine sulphate has little effect in a decrease of non-motor autonomic fluctuations.

A Randomized Study of Rotigotine Dose Response on ‘Off’ Time in Advanced Parkinson's Disease

Previous phase III studies in patients with advanced Parkinson's disease (PD) not adequately controlled on levodopa demonstrated significant reduction of 'off' time with rotigotine transdermal system up to 16 mg/24 h. However, the minimal effective dose has not been established. This international, randomized, double-blind, placebo-controlled study (SP921; NCT00522379) investigated rotigotine dose response up to 8 mg/24 h. Patients with advanced idiopathic PD (≥2.5 h of daily 'off' time on stable doses of levodopa) were randomized 1:1:1:1:1 to receive rotigotine 2, 4, 6, or 8 mg/24 h or placebo, titrated over 4 weeks and maintained for 12 weeks. The primary efficacy variable was change from baseline to end of maintenance in absolute time spent 'off'. 409/514 (80%) randomized patients completed maintenance. Mean (±SD) baseline daily 'off' times (h/day) were placebo: 6.4 (±2.5), rotigotine 2-8 mg/24 h: 6.4 (±2.6). Rotigotine 8 mg/24 h was the minimal dose to significantly reduce 'off' time versus placebo. LS mean (±SE) absolute change in daily 'off' time (h/day) from baseline was -2.4 (±0.28) with rotigotine 8 mg/24 h, and -1.5 (±0.26) with placebo; absolute change in 'off' time in the 8 mg/24 h group compared with placebo was -0.85 h/day (95% CI -1.59, -0.11; p = 0.024). There was an apparent dose-dependent trend. Adverse events (AEs) reported at a higher incidence in the rotigotine 8 mg/24 h group versus placebo included application site reactions, nausea, dry mouth, and dyskinesia; there was no worsening of insomnia, somnolence, orthostatic hypotension, confusional state or hallucinations, even in patients ≥75 years of age. The minimal statistically significant effective dose of rotigotine to reduce absolute 'off' time was 8 mg/24 h. The AE profile was similar to previous studies.

A phase 2, placebo-controlled, randomized, double-blind trial of tozadenant (Syn-115) in patients with Parkinson's disease with wearing-off fluctuations on levodopa

A phase 2, placebo-controlled, randomized, double-blind trial of tozadenant (Syn-115) in patients with Parkinson's disease with wearing-off fluctuations on levodopa