A randomized, double-blind, placebo-controlled trial of subcutaneously injected apomorphine for parkinsonian off-state events.

OBJECTIVE: To assess the safety and efficacy of subcutaneous apomorphine hydrochloride administration for off-state (poor motor function) periods in patients with Parkinson disease with motor fluctuations under both inpatient titration and outpatient therapeutic conditions. PATIENTS AND METHODS: Twenty-nine patients had advanced Parkinson disease with 2 hours or more off time despite aggressive oral therapy. Patients randomly received titrated doses of subcutaneous apomorphine hydrochloride (2-10 mg, n = 20) or pH-matched vehicle placebo (n = 9) during an inpatient and 1-month outpatient phase. A change in the United Parkinson Disease Rating Scale motor score 20 minutes after inpatient dosing during a practically defined off-state event and the percentage of injections successfully aborting off-state events were the primary inpatient and outpatient efficacy factors. RESULTS: The average (SEM) levodopa equivalent dose of apomorphine hydrochloride was 5.4 +/- 0.5 mg and the mean placebo dose was 1.0 mL. Mean inpatient United Parkinson Disease Rating Scale motor scores were reduced by 23.9 and 0.1 points (62% and 1%) by apomorphine treatment and placebo, respectively (P<.001). The mean percentage of outpatient injections resulting in successful abortion of off-state events was 95% for apomorphine and 23% for placebo (P<.001). Inpatient response was significantly correlated with and predictive of outpatient efficacy (P<.001). The levodopa dose was not predictive of the apomorphine dose requirement. Frequent adverse events included dyskinesia, yawning, and injection site reactions. CONCLUSION: Apomorphine by intermittent subcutaneous injection is effective and safe for outpatient use to reverse off-state events that occur despite optimized oral therapy.

Transdermal dopaminergic D(2) receptor agonist therapy in Parkinson's disease with N-0923 TDS: a double-blind, placebo-controlled study.

N-0923 is a non-ergot, dopaminergic D(2) agonist designed to be transdermally available. It has anti-parkinsonian effects when infused intravenously. An adhesive matrix patch was developed to deliver N-0923 transdermally (N-0923 TDS). In this phase II trial, we evaluated the effectiveness of various doses of N-0923 TDS at replacing levodopa. Eighty-five Parkinson's disease (PD) patients were randomized to placebo or one of four doses of N-0923 TDS for 21 days. Change in daily levodopa dose was the primary efficacy measure. Significantly greater reductions in levodopa dose were achieved as compared to placebo for the two highest doses of N-0923 TDS. Patients treated with 33.5 mg and 67 mg N-0923 TDS decreased levodopa use by 26% and 28%, vs. 7% for placebo. N-0923 TDS was safe and well tolerated.

Immediate-release and controlled-release carbidopa/levodopa in PD: a 5-year randomized multicenter study. Carbidopa/Levodopa Study Group.

OBJECTIVE: To compare effects of immediate-release (IR) and sustained-release (CR) carbidopa/levodopa in levodopa-naive PD patients. BACKGROUND: It was hypothesized that the long-acting preparation would be associated with fewer long-term complications. METHODS: A total of 618 patients were studied in 36 centers worldwide in a blinded, randomized parallel study. Measures of efficacy and adverse reactions were recorded at 3-month intervals for 5 years. Motor fluctuations and dyskinesias were evaluated by a patient diary and a physician-recorded questionnaire. The Nottingham Health Profile (NHP) was used to evaluate quality of life. RESULTS: Approximately 60% of patients completed the trial. After 5 years, the mean dose of IR was 426 mg/day, and the bioavailable dose of CR was 510 mg/day (mean dose, 736 mg/day). After 5 years, 20.6% of the IR group and 21.8% of the CR group had motor fluctuations or dyskinesia. Sixteen percent of both groups had changes in motor response by the questionnaire's definition. There was no significant difference between the two treatment groups. Disability scores and the motor score of the Unified Parkinson Disease Rating Scale (UPDRS) were highest at baseline, improved with therapy, and thereafter worsened over time to reach baseline scoring at the end of 5 years. The CR group was superior to IR for the Activities of Daily Living subsection of the UPDRS for all 5 years and for emotional reactivity and social isolation on the NHP; however, this may have resulted from higher doses of CR that were used. CONCLUSION: Despite the progressive nature of PD, both the immediate-release and sustained-release carbidopa/levodopa formulations maintained a similar level of control in PD after 5 years compared with baseline. Additionally, the low incidence of motor fluctuations or dyskinesia was not significantly different between the treatment groups and may be partly attributed to the relatively low doses of levodopa used throughout the 5-year study.

Visual contrast sensitivity in Parkinson's disease is worsened with cabergoline treatment.

Parkinson's disease (PD) is associated with abnormal visual contrast sensitivity (CS) and frequent complaints of visual disturbance. Cabergoline is a potent D(2) agonist that is efficacious for the treatment of PD and is marketed throughout Europe. We studied the effect of cabergoline on the CS of PD patients. Twenty-two patients with PD participated in this placebo-controlled double-blind study. Contrast thresholds for seven spatial frequencies were determined prior to and again during treatment. The mean CS scores for the cabergoline group worsened significantly at 6, 9, and 12c/d. These changes with cabergoline may relate to reduced perception of visual detail.

Multicenter, placebo-controlled trial of cabergoline taken once daily in the treatment of Parkinson's disease.

Cabergoline is a dopaminergic agonist relatively specific for the D2 receptor and much longer-acting than other dopamine agonists. We conducted a randomized, placebo-controlled, double-blind study of cabergoline in 188 levodopa/carbidopa-treated patients with suboptimally controlled Parkinson's disease (PD). The cabergoline patients had significantly better Activities of Daily Living (p = 0.032) and Motor Examination (p = 0.031) scores at the conclusion of the trial compared with the placebo group. The daily levodopa dose for the cabergoline patients decreased 18% compared with a 3% reduction for the placebo group (p < 0.001). The amount of time in the "on" state increased more in the cabergoline group (p = 0.022). The side-effect was similar to that seen with other dopamine agonists, and cabergoline was generally well tolerated. We conclude that cabergoline is an effective adjunct to levodopa for the treatment of PD.

Postural finger tremor exhibited by Parkinson patients and age-matched subjects.

Physiological correlates of postural tremor of the finger seen in Parkinson's disease patients are different from those seen in age-matched control subjects. A significant correlation between the spectral peak of acceleration and the spectral peak of rectified electromyographic activity from the muscle responsible for finger extension was found in Parkinson's disease patients. This correlation was not seen in age-matched control subjects. Any neural drive imposed on the motoneuron pool from supraspinal levels would enhance the electromyographic activity. Likewise, any feedback effects via spinal stretch reflexes or supraspinal stretch responses would be mediated through the motoneuron pool and electromyographic activity. The results of this research support the theory that Parkinson tremor is a centrally driven rhythm that may be influenced by feedback effects, whereas physiological tremor is due to a complex interaction of central, feedback, and mechanical effects.

Assessment of intellectual functioning of patients with Parkinson's disease using the Satz-Mogel (1962) short form of the Wechsler Adult Intelligence Scale.

The purpose of the present study was to compare the Satz-Mogel (S-M) short form of the Wechsler Adult Intelligence Scale--Revised (WAIS-R) with the full-scale WAIS-R to establish its utility in the assessment of intellectual functioning in patients with Parkinson's disease (PD). PD patients and elderly control subjects were administered a neuropsychological test battery that included the complete WAIS-R or the S-M. Results indicated that the S-M was a reliable measure of IQ. The PD subjects' Verbal, Performance, and Full-Scale IQ scores were inferior to that of controls, regardless of test form. Adjustments for depression and age did not alter these results. PD patients with more severe disease scored lower on some visual-spatial measures. Verbal decrements among PD patients may relate to problems in verbal fluency, categorical thinking, and impaired retrieval of verbal material. PD patients may experience patterns of subtle cognitive changes that include deterioration of some specific abilities as the disease progresses.

Contrast sensitivity dysfunction in Alzheimer's disease.

We compared the spatial contrast sensitivity of six patients with mild to moderate Alzheimer's disease (AD) and six age-matched control subjects in a parametric design. Results demonstrate reduced contrast sensitivity in patients with AD at all but the lowest frequency tested. The results suggest that the effect of AD on spatial contrast sensitivity is stronger at higher frequencies and provide a rationale for complaints of poor vision in AD patients.

Levodopa improves spatial contrast sensitivity in Parkinson's disease.

OBJECTIVE: To study the effect of levodopa on the visual contrast sensitivity of patients with Parkinson's disease. DESIGN: Contrast sensitivity of patients was measured before and after levodopa administration. Patient contrast sensitivity was compared with that of normal controls by repeated-measures analyses of variance. SETTING: Parkinson's disease research center associated with private neurology practice. PATIENTS: Fifteen patients with idiopathic Parkinson's disease (eight men, seven women; mean age, 71.8 years) and 22 normal controls (10 men, 12 women; mean age, 68.0 years) volunteered for the study. INTERVENTION: Levodopa/carbidopa (Sinemet). MAIN OUTCOME MEASURE: Change in contrast sensitivity of parkinsonian patients. RESULTS: Following levodopa treatment, the contrast sensitivity of parkinsonian patients improved significantly at the three lowest spatial frequencies tested (0.4, 1, and 2 cycles per degree). CONCLUSIONS: Levodopa improves low-frequency contrast sensitivity in parkinsonian patients. Initially deficient contrast sensitivity in such patients may be restored to near normal levels by levodopa therapy.

Controlled study of the antiparkinsonian activity and tolerability of cabergoline.

Cabergoline, a new ergoline derivative, is a D2-specific dopaminergic agonist that is more potent and longer-acting than other agonist agents. We conducted a randomized, double-blind study of increasing doses of cabergoline taken once a day. Twenty-five patients with Parkinson's disease taking stable doses of levodopa began cabergoline at 0.5 mg. The dose was escalated at weekly intervals to 1.0 mg in 19 patients, 1.5 mg in 14 patients, 2.0 mg in nine patients, and 2.5 mg in four patients. Treatment continued for 8 weeks after titration. Unified Parkinson's Disease Rating Scale scores, Hoehn and Yahr stage of disease, and computerized measures of motor performance improved significantly with cabergoline treatment. Dose-response effects were not significant. No serious adverse experiences occurred during the 13-week trial, and the side-effect profile mirrored other dopaminergic agonists. Cabergoline appears to be a promising agent in the treatment of Parkinson's disease.

Long-acting carbidopa-levodopa in the management of moderate and advanced Parkinson's disease.

Parkinson's disease patients treated chronically with levodopa often develop fluctuations in motor response. Motor fluctuations can be attributed in part to oscillating plasma levodopa concentrations. A controlled-release formulation containing 200 mg of levodopa and 50 mg of carbidopa provides superior plasma levodopa profiles compared with the standard preparation. A multicenter, double-blind trial involving 202 patients with fluctuating motor response found controlled-release carbidopa-levodopa to be safe and tolerable, with improved efficacy compared with the standard formulation. Long-term exposure to the controlled-release formulation, at least for a period of 3 years, does not appear to be associated with any increase in the incidence of adverse side effects.

Long-term evaluation of Sinemet CR in parkinsonian patients with motor fluctuations.

The safety and efficacy of Sinemet CR, a controlled-release formulation of carbidopa/levodopa, were investigated in a three year, open-label trial involving 18 parkinsonian patients with fluctuating motor response. The average daily levodopa dosing frequency did not change significantly during long-term treatment. Efficacy measures generally revealed a gradual progression of parkinsonian disability. Patient diaries of motor fluctuations revealed relative stability of time "on" but with a tendency toward increased time "on with dyskinesias" over the 36 month follow-up period. There were no adverse laboratory results deemed to be related to Sinemet CR and no unexpected side effects were observed.

Spatial contrast sensitivity is reduced in bilateral Parkinson's disease.

We studied the contrast sensitivity functions of 41 patients with idiopathic Parkinson's disease (PD) with a wide range of parkinsonian symptomatology (Hoehn and Yahr stages 1 to 4) and 22 age-matched control subjects in a parametric design. Results demonstrated reduced contrast sensitivity in PD patients but only in those patients who had progressed beyond Hoehn and Yahr stage 1. Furthermore, there were deficits in contrast sensitivity related to the severity of PD.

Multicenter controlled study of Sinemet CR vs Sinemet (25/100) in advanced Parkinson's disease.

Controlled-release carbidopa/levodopa 50/200 (Sinemet CR) and standard carbidopa/levodopa (Sinemet 25/100) were compared in a multicenter double-blind trial involving 202 patients with advanced Parkinson's disease and motor response fluctuations. Treatment with Sinemet CR significantly reduced daily "off" time. According to both physician and patient global ratings, patients showed significant improvements with Sinemet CR compared to treatment with standard Sinemet. Patients preferred Sinemet CR treatment by a ratio of approximately 2 to 1. Daily dosing frequency was 33% less with Sinemet CR, while daily intake of levodopa required was increased by 25%. The safety profiles of the 2 formulations were similar. We conclude that Sinemet CR is superior to standard Sinemet for many patients with advanced Parkinson's disease, although it does not solve the problem of fluctuating motor performance.

Changes in the performance of parkinsonian patients and normal aged on the Benton Visual Retention Test.

Performance on the Benton Visual Retention Test was compared between those with Parkinson's disease (PD) and age-equivalent controls. The major difference between groups was that those with PD showed an increase in figural reproduction errors between test periods spaced six months apart, while controls showed little increase in errors over this time and made fewer errors at each time of testing. Age and IQ accounted for major proportions of variance in performance for both groups (about 50%), far more than that attributable to group membership. Within the PD group, however, age and disease onset were confounded (r = .92), indicating that age as a variable is quite when disease onset is considered. The results support the notion that PD is associated with change in visual-spatial memory, beyond that predicted by age per se.

Treatment of chronic Parkinson's disease with controlled-release carbidopa/levodopa.

Controlled-release carbidopa/levodopa 50/200 (SINEMET CR) and standard carbidopa/levodopa (SINEMET 25/100) were compared in a double-blind, six-month, crossover study involving 21 patients with chronic Parkinson's disease and motor response fluctuations. Daily dosage frequency was significantly reduced with SINEMET CR compared with SINEMET 25/100, while the daily amount of levodopa required with SINEMET CR was significantly greater. No significant differences in disability ratings, motor response fluctuations, or safety were detected during double-blind conditions. In the open-label, dose-finding phase of the study, SINEMET CR was superior to standard SINEMET 25/100 in patient ratings of percent "on" time (good motor function), clinical assessments of motor function, and activities of daily living. This finding resulted from a depreciation of the value of the "old drug" rather than an overestimation of the value of the experimental drug. This double-blind study also suggested that elderly male patients with Parkinson's disease derived the greatest benefit from SINEMET CR.

Prolonged serum levodopa levels with controlled-release carbidopa-levodopa in the treatment of Parkinson's disease.

Twenty parkinsonian patients (Hoehn and Yahr scale, I through III) were treated with controlled-release carbidopa-levodopa (CR-2 or CR-3) and standard carbidopa-levodopa (Sinemet, 25 mg/100 mg) in a double-blind, crossover pharmacokinetic and clinical efficacy study. The controlled-release agents had a slower rise to peak plasma values and flatter pharmacokinetic curves than did the standard. The area under the curve for CR-3 was significantly increased by 55.5% as compared with standard agent and by 84.2% as compared with CR-2. No differences in clinical efficacy were found between controlled-release agents and the standard agent for this group of parkinsonian patients with mild to moderate severity. The dissociation between the prolonged serum levodopa levels and unimproved clinical efficacy may have resulted from the absence of patients with prominent motor fluctuations and/or substantial serum levodopa variability that was especially prominent with CR-3.