Morning Dose Of Levodopa Research Articles

Early‐morning OFF and levodopa dose failures in patients with Parkinson's disease attending a routine clinical appointment using Time‐to‐ON Questionnaire

In patients with Parkinson's disease (PD) with motor fluctuations, total daily OFF time is comprised of both end-of-dose time and the time taken to turn ON with medication. However, little is known about the impact of delays in ON time. This was a single-visit pilot study of fluctuating patients with PD attending a routine appointment. During a single visit, adult patients with idiopathic PD who were treated with levodopa for at least 1year completed a questionnaire evaluating the time waiting for ON and the symptoms experienced while waiting to turn ON. Patients then completed a 5-day home time-to-ON diary, where they documented how long it took to turn ON following their first morning dose of levodopa in 5-min increments. A total of 151 consecutive patients completed the study survey, of whom 97 (64.2%) experienced motor fluctuations. Of the patients experiencing motor fluctuations, 54 (56%) reported delays in ON time (latency >30min) following their first morning dose of levodopa. Half (51%) reported that they had experienced delayed ON at least once in the previous week and 21% reported having delayed ON during all seven mornings of the previous week. In addition, 10% of patients reported having dose failures on four or more mornings during the previous week. The most common symptoms experienced while waiting for ON were slowness (94.8%), fatigue (87.6%), reduced dexterity (82.5%), problems in walking (66.0%) and problems with balance (59.8%). Early-morning OFF problems such as delays in time to ON and dose failures are common in levodopa-treated patients with PD.

Apomorphine Subcutaneous Injection for the Management of Morning Akinesia in Parkinson's Disease.

BackgroundIn patients with motor fluctuations complicating Parkinson's disease (PD), delays in time‐to‐ON with levodopa are common. This open‐label study aimed to assess the effect of apomorphine on time‐to‐ON in PD patients with morning akinesia.MethodsThe safety population included 127 enrolled patients, and the full analysis set (FAS) included 88 patients. Patients completed a 7‐day levodopa baseline period recording their time‐to‐ON following each morning dose of levodopa. Patients were titrated to an optimal dose of apomorphine (2–6 mg) while taking trimethobenzamide antiemetic therapy. Apomorphine was injected each morning for a 7‐day treatment period and time‐to‐ON was self‐recorded in 5‐minute blocks. The primary efficacy variable was time‐to‐ON in the apomorphine treatment period versus the baseline levodopa period. Secondary assessments included and global impression scales. Safety and tolerability were assessed through adverse events (AEs).ResultsPatients receiving apomorphine achieved mean ± standard deviation (SD) time‐to‐ON 23.72 ± 14.55 minutes, reduced from 60.86 ± 18.11 minutes with levodopa (P < 0.0001). Dose failures (defined as time‐to‐ON >60 minutes) were more commonly reported with levodopa versus apomorphine (46% vs. 7% of diary entries, respectively).Secondary endpoints supported the primary efficacy findings, with significant improvements from levodopa baseline to apomorphine treatment period (all P < 0.0001). The most common AEs were nausea and dizziness. Most patients who discontinued because of AEs did so in the titration phase.ConclusionsApomorphine injections significantly reduced time‐to‐ON in PD patients experiencing delayed onset of their morning levodopa dose, and was well tolerated in most patients. After apomorphine treatment, fluctuating patients with morning akinesia experienced rapid and reliable improvement of time‐to‐ON.

Effects of pallidotomy and levodopa on walking and reaching movements in Parkinson's disease

We examined the effects of levodopa and unilateral pallidotomy on quantitative measures of walking and reaching in Parkinson's disease (PD). We also compared quantitative measures of movement with standard clinical rating scales. We used kinematic measures and the Unified Parkinson's Disease Rating Scale (UPDRS) motor subscale (subscale III) to evaluate the movement of 10 people with PD. Subjects were tested after withholding PD medications for at least 8 hours and again 30 to 45 minutes after taking the first morning dose of levodopa. They were studied in this manner before unilateral pallidotomy and then 3.5 to 10 months after surgery. The UPDRS motor subscale was performed in each state. Kinematic data were collected as subjects reached to a target and walked. The UPDRS motor subscale ratings were similar to those reported in the literature: pallidotomy improved the overall motor score and the contralateral bradykinesia + rigidity score, but not the gait + posture score. In contrast, kinematic measures demonstrated that levodopa and pallidotomy had different effects on walking and reaching speed. Both treatments improved walking speed, and the effect was additive. Levodopa improved reaching speed before pallidotomy but did not improve it as much after pallidotomy. Additionally, pallidotomy had inconsistent effects on reaching; some subjects were faster and others were slower. The subjects who initially reached more slowly improved after pallidotomy; the subjects who initially reached more normally (faster) worsened after pallidotomy. On the basis of our results, we speculate that basal ganglia output pathways that control walking and reaching may be distinct, such that bilateral projections to the pedunculopontine area influence walking, whereas ipsilateral thalamocortical projections influence reaching.

Levodopa pharmacokinetics and motor performance during activities of daily living in patients with Parkinson's disease on individual drug combinations.

Pharmacokinetics and pharmacodynamics of levodopa were evaluated at a high-resolution level in a heterogeneous group of 10 patients with idiopathic Parkinson's disease during their normal daily activity. A physician and a nurse spent 10 hours with each patient from the first morning dose of levodopa during daily activities at home and at work. Plasma samples were obtained every 20 minutes for analysis of levodopa and 3-O-methyldopa by high-performance liquid chromatography. To assess clinical response, mobility was rated on every test occasion by patients and by investigators. Food and fluid intake and physical activity were also monitored. There was a large intra- and interindividual variability in the pharmacokinetics of levodopa regardless of the different drug combinations used. Mean plasma levodopa concentration ranged between 0.45 to 7.07 microg/mL and peak concentrations between 0.95 to 13.75 microg/mL. In 44 of 58 dosing events, an oral dose of levodopa was related to a peak in plasma concentration. Assessment of the clinical effects was more sensitive when given by patients than when given by the investigators. The fluctuations of the levodopa concentration in plasma had a clear effect on the clinical parameters assessed, even during early disease stages. Variation in levodopa concentration is the determining factor for motor fluctuations also in patients on clinically optimized combinations with dopamine agonists and enzyme inhibitors.

High‐speed memory scanning in Parkmson's disease: Adverse effects of levodopa

High-speed memory scanning as assessed by the Sternberg paradigm was studied in 12 nondemented patients with fluctuating Parkinson's disease and 13 age-matched healthy controls. Patients were first assessed before taking their morning dose of levodopa ("off") and again after that dose had produced full clinical effect ("on") after that dose had produced full clinical effect ("on"). Although motor components of the measured choice reaction time were slower in patients when off than in control subjects, memory scanning speed was not different. After levodopa (on), patients' motor time normalized, but cognitive processing speed became significantly slower when compared with previous performance in the off condition and with controls. Contrary to previous concepts of bradyphrenia in patients with Parkinson's disease, these results indicate that dopaminergic stimulation can reduce cognitive processing speed.

Effect of duration of levodopa/decarboxylase inhibitor therapy on the pharmacokinetic handling of levodopa in elderly patients with idiopathic Parkinson's disease

We address, from a pharmacokinetic viewpoint, the important question of why some patients with clinical idiopathic Parkinson's disease experience a fall off in benefit from levodopa maintenance therapy. Thirteen such patients, of mean age 78 y, without overt fluctuations in motor control in temporal relation to dosing with a levodopa/decarboxylase inhibitor combination, were studied. Levodopa (currently 400 to 800 mg daily) had been started at between 61 and 81 y of age, the mean duration of therapy being 54 months. Plasma concentrations of levodopa and its peripheral metabolite, 3-0-methyldopa, were measured before a morning dose of levodopa (100 mg)/carbidopa (25 mg) and at hourly intervals for 6 h after. There was a significant negative regression between duration of levodopa therapy (but not age or severity of disease) and the area under the plasma concentration/time curve (AUC) for levodopa attributed to the test dose. A significant negative regression was also seen of duration of therapy on the dose absorbed per unit distribution volume, but not on the elimination rate constant, indicating a decrease in bioavailability and/or an increase in distribution volume with duration. There was a tendency for the plasma 3-0-methyldopa concentration, standardised for daily dose, [30MD], to increase with duration of therapy. Although, the regression of duration on [30MD] did not reach statistical significance, that on the ratio, [30 MD]/AUC, did so at the 0.01 level. The amount by, and time for which, the plasma levodopa concentration exceeds any critical threshold for the competitive active uptake process into the brain may thus decrease with duration of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

CQA 206-291 in Parkinson's Disease: An Acute Single Escalating Dosage Study

CQA 206-291, a new ergot derivative with a "biphasic" dopaminergic profile, was studied in 6 patients with longstanding Parkinson's disease suffering from pronounced fluctuations in hourly mobility. On alternate days, up to seven single doses, escalating from 0.2 to 20 mg, were given as replacement for the usual first morning dose of levodopa. At the most effective dosage, four of the six patients obtained as good a peak response to CQA (8-20 mg) as to L-dopa. Side effects were common and similar to other ergot derivatives, suggesting that the initial weak dopamine antagonist properties of the parent compound, documented in animals, may be of little clinical significance. However, comparative studies will be needed to confirm this suspicion. The addition of domperidone successfully reduced the incidence and severity of side effects. CQA 206-291 has potent anti-parkinsonian properties; further longer-term treatment trials are indicated.