BACKGROUND:The best way to initiate dopaminergic therapy for early Parkinson disease remains unclear.OBJECTIVE:To compare initial treatment with pramipexole vs levodopa in early Parkinson disease, followed by levodopa supplementation, with respect to the development of dopaminergic motor complications, other adverse events, and functional and quality-of-life outcomes.DESIGN:Multicenter, parallel-group, double-blind, randomized controlled trial.SETTING:Academic movement disorders clinics at 22 sites in the United States and Canada.PATIENTS:Patients with early Parkinson disease (N = 301) who required dopaminergic therapy to treat emerging disability, enrolled between October 1996 and August 1997 and observed until August 2001.INTERVENTION:Subjects were randomly assigned to receive 0.5 mg of pramipexole 3 times per day with levodopa placebo (n = 151) or 25/100 mg of carbidopa/levodopa 3 times per day with pramipexole placebo (n = 150). Dosage was escalated during the first 10 weeks for patients with ongoing disability. Thereafter, investigators were permitted to add open-label levodopa or other antiparkinsonian medications to treat ongoing or emerging disability.MAIN OUTCOME MEASURES:Time to the first occurrence of dopaminergic complications: wearing off, dyskinesias, on-off fluctuations, and freezing; changes in the Unified Parkinson's Disease Rating Scale and quality-of-life scales; and adverse events.RESULTS:Initial pramipexole treatment resulted in a significant reduction in the risk of developing dyskinesias (24.5% vs 54%; hazard ratio, 0.37; 95% confidence interval [CI], 0.25-0.56; P<.001) and wearing off (47% vs 62.7%; hazard ratio, 0.68; 95% CI, 0.49-0.63; P =.02). Initial levodopa treatment resulted in a significant reduction in the risk of freezing (25.3% vs 37.1%; hazard ratio, 1.7; 95% CI, 1.11-2.59; P =.01). By 48 months, the occurrence of disabling dyskinesias was uncommon and did not significantly differ between the 2 groups. The mean improvement in the total Unified Parkinson's Disease Rating Scale score from baseline to 48 months was greater in the levodopa group than in the pramipexole group (2 +/- 15.4 points vs -3.2 +/- 17.3 points, P =.003). Somnolence (36% vs 21%, P =.005) and edema (42% vs 15%, P<.001) were more common in pramipexole-treated subjects than in levodopa-treated subjects. Mean changes in quality-of-life scores did not differ between the groups.CONCLUSIONS:Initial treatment with pramipexole resulted in lower incidences of dyskinesias and wearing off compared with initial treatment with levodopa. Initial treatment with levodopa resulted in lower incidences of freezing, somnolence, and edema and provided for better symptomatic control, as measured by the Unified Parkinson's Disease Rating Scale, compared with initial treatment with pramipexole. Both options resulted in similar quality of life. Levodopa and pramipexole both appear to be reasonable options as initial dopaminergic therapy for Parkinson disease, but they are associated with different efficacy and adverse-effect profiles.

Background: Oral dopamine agonists are effective for treating early Parkinson's disease (PD). Rotigotine is a dopamine agonist delivered through a silicone-based transdermal patch that is replaced every 24 hours.Objectives: To assess the efficacy and safety of rotigotine in patients with PD not receiving dopaminergic medications.Design: Randomized, double-blind, placebo-controlled study.Patients: Two hundred forty-two patients with early PD.Intervention: Treatment with patches containing either 4.5, 9.0, 13.5, or 18.0 mg of rotigotine or placebo for 11 weeks.Main Outcome Measure; The change in the sum of the scores of the activities of daily living and motor components of the Unified Parkinson's Disease Rating Scale from baseline to the end of treatment.Results: There was a significant dose-related improvement in the motor and activities of daily living Unified Parkinson's Disease Rating Scale score between baseline and week 11 for the 13.5- and 18.0-mg groups compared with placebo (placebo, 0.3 +/- 7.7; 13.5-mg group, 5.1 +/- 7.0, P = .001; 18.0-mg group, 5.3 +/- 7.0, P < .001). Adverse experiences that occurred more commonly among subjects randomized to active treatment vs placebo included nausea, application site reactions, dizziness, insomnia, somnolence, vomiting, and fatigue.Conclusions: Rotigotine can be safely administered once daily transdermally and improves parkinsonian signs in patients with early PD.

Context Pramipexole and levodopa are effective medications to treat motor symptoms of early Parkinson disease (PD). In vitro and animal studies suggest that pramipexole may protect and that levodopa may either protect or damage dopamine neurons. Neuroimaging offers the potential of an objective biomarker of dopamine neuron degeneration in PD patients.Objective To compare rates of dopamine neuron degeneration after initial treatment with pramipexole or levodopa in early PD by means of dopamine transporter imaging using single-photon emission computed tomography (SPECT) with 2beta-carboxymethoxy-3beta(4-iodophenyl)tropane (beta-CIT) labeled with iodine 123.Design Substudy of a parallel-group, double-blind randomized clinical trial.Setting and Patients Eighty-two patients with early PD who were recruited at 17 clinical sites in the United States and Canada and required dopaminergic therapy to treat emerging disability, enrolled between November 1996 and August 1997.Interventions Patients were randomly assigned to receive pramipexole, 0.5 mg 3 times per day with levodopa placebo (n=42), or carbidopa/levodopa, 25/100 mg 3 times per day with pramipexole placebo (n=40). For patients with residual disability, the dosage was escalated during the first 10 weeks, and subsequently, open-label levodopa could be added. After 24 months of follow-up, the dosage of study drug could be further modified.Main Outcome Measures The primary outcome variable was the percentage change from baseline in striatal [I-123]beta-CIT uptake after 46 months. The percentage changes and absolute changes in striatal, putamen, and caudate [I-123]beta-CIT uptake after 22 and 34 months were also assessed. Clinical severity of PD was assessed using the Unified Parkinson Disease Rating Scale (UPDRS) 12 hours off anti-PD medications.Results Sequential SPECT imaging showed a decline in mean (SD) [I-123]beta-CIT striatal uptake from baseline of 10.3% (9.8%) at 22 months, 15.3% (12.8%) at 34 months, and 20.7% (14.4%) at 46 months-approximately 5.2% per year. The mean (SD) percentage loss in striatal [I-123] beta-CIT uptake from baseline was significantly reduced in the pramipexole group compared with the levodopa group: 7.1% (9.0%) vs 13.5% (9.6%) at 22 months (P=.004); 10.9% (11.8%) vs 19.6% (12.4%) at 34 months (P=.009); and 16.0% (13.3%) vs 25.5% (14.1%) at 46 months (P=.01). The percentage loss from baseline in striatal [I-123]beta-CIT uptake was correlated with the change from baseline in UPDRS at the 46-month evaluation (r=-0.40; P=.001).Conclusions Patients initially treated with pramipexole demonstrated a reduction in loss of striatal [I-123]beta-CIT uptake, a marker of dopamine neuron degeneration, compared with those initially treated with levodopa, during a 46-month period. These imaging data highlight the need to further compare imaging and clinical end points of PD progression in long-term studies.

Context: Long-term levodopa therapy for Parkinson disease commonly results in motor complications including "on-off" fluctuations and dyskinesias, but it is still unclear how best to assess treatment effects on dyskinesias in clinical trials.Objective: To compare several methods of rating levodopa-induced dyskinesias to evaluate the effect of remacemide hydrochloride treatment in patients with advanced Parkinson disease.Design: Two-week multicenter randomized, double-blind, placebo-controlled, parallel-group study.Setting: Five academic sites of the Parkinson Study Group.Patients: Thirty-nine subjects at least 30 years old with idiopathic Parkinson disease and disabling dyskinesias.Interventions: Randomly received daily doses of 150 mg, 300 mg, or 600 mg of remacemide hydrochloride or matching placebo for 2 weeks.Main Outcome Measures: The dyskinesia rating scales used were the Modified Goetz Dyskinesia Rating scale (MGDRS), a newly created Lang-Fahn Activities of Daily Living Dyskinesia scale (LFADLDS), and diary dyskinesia ratings.Results: Patient and investigator diaries showed excellent agreement in dyskinesia ratings. The MGDRS score correlated with clinic diary ratings of the percentage of "on" time with dyskinesias, and the LFADLDS score correlated with home and clinic diary assessments of percentage of on time with severe dyskinesias. The MGDRS score did not correlate highly with the LFADLDS score. This pilot study also validated previous results demonstrating the safety and tolerability of remacemide treatment for advanced Parkinson disease but did not result in any demonstrable improvement or worsening in dyskinesia measures.Conclusions: Diaries may provide a valid means of evaluating dyskinesias in clinical trials for Parkinson disease, but there remain other aspects of dyskinesias, as assessed by the MGDRS and LFADLDS, that are not reflected in diary ratings.

BACKGROUND:Preclinical studies suggest that glutamate antagonists help ameliorate motor fluctuations in patients with PD treated with levodopa.METHODS:In a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study, the authors assessed the safety, tolerability, and efficacy of the glutamate receptor blocker remacemide hydrochloride in 279 patients with motor fluctuations treated with levodopa. The primary objective was to assess the short-term tolerability and safety of four dosage levels of remacemide during 7 weeks of treatment. Patients were also monitored with home diaries and the Unified PD Rating Scale (UPDRS) to collect preliminary data on treatment efficacy.RESULTS:Remacemide was well tolerated up to a dosage of 300 mg/d on a twice daily schedule and 600 mg/d on a four times daily schedule. The most common dosage-related adverse events were dizziness and nausea, as observed in previous studies of remacemide. The percent "on" time and motor UPDRS scores showed trends toward improvement in the patients treated with 150 and 300 mg/d remacemide compared with placebo-treated patients, although these improvements were not significant.CONCLUSION:Remacemide is a safe and tolerable adjunct to dopaminergic therapy for patients with PD and motor fluctuations. Although this study had limited power to detect therapeutic effects, the observed improvement is consistent with studies of non-human primates with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian signs and symptoms. Additional studies are warranted to confirm these results over an extended period of observation, and to explore the potential neuroprotective effects of remacemide in slowing the progression of PD.

Objectives: To determine whether chronic treatment with coenzyme Q(10) or remacemide hydrochloride slows the functional decline of early Huntington's disease (HD). Methods: The authors conducted a multicenter, parallel group, double-blind, 2 X 2 factorial, randomized clinical trial. Research participants with early HD (n = 347) were randomized to receive coenzyme Q(10) 300 mg twice daily, remacemide hydrochloride 200 mg three times daily, both, or neither treatment, and were evaluated every 4 to 5 months for a total of 30 months on assigned treatment. The prespecified primary measure of efficacy was the change in total functional capacity (TFC) between baseline and 30 months. Safety measures included the frequency of clinical adverse events. Results: Neither intervention significantly altered the decline in TFC. Patients treated with coenzyme Q(10) showed a trend toward slowing in TFC decline (13%) over 30 months (2.40- versus 2.74-point decline, p = 0.15), as well as beneficial trends in some secondary measures. There was increased frequency of nausea, vomiting, and dizziness with remacemide and increased frequency of stomach upset with coenzyme Q(10). Conclusions: Neither remacemide nor coenzyme Q(10), at the dosages studied, produced significant slowing in functional decline in early HD.

Background: Preclinical evidence suggests that manipulation of the glutamatergic system may provide an alternative strategy for therapeutic intervention in PD. Remacemide hydrochloride is a low affinity NMDA channel blocker that might improve parkinsonian symptoms by modulating glutamatergic overactivity in the basal ganglia or slow worsening by decreasing excitotoxicity. Methods: The authors performed a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study of remacemide in patients with early PD who were not yet receiving levodopa or dopamine agonists. The primary objective was to assess the short-term tolerability and safety of three dosage levels of remacemide. Two hundred patients were randomized to receive either remacemide 150 mg, 300 mg, or 600 mg, or matching placebo daily for 5 weeks. Results: Significantly fewer patients receiving remacemide 600 mg daily were able to tolerate 5 weeks of their assigned treatment on a BID schedule compared with patients receiving placebo (64% versus 94%,p = 0.0002). Most patients who experienced intolerable side effects on the BID schedule, however, could tolerate the same daily dosage on a QID schedule. The most common adverse events were dizziness and nausea. There were no serious adverse events or clinically significant treatment-related changes in vital signs, laboratory values, or electrocardiograms. There was no evidence of improvement in PD signs or symptoms associated with remacemide monotherapy. Conclusion: Remacemide was generally well tolerated and safe in this 5-week trial. There was no evidence for a symptomatic effect of remacemide monotherapy in patients with early PD. Based on its favorable safety profile and several animal studies, further studies of remacemide are warranted as symptomatic therapy in levodopa-treated patients and as a neuroprotective agent.

CONTEXTSince there is no diagnostic biological marker for Parkinson disease (PD), the diagnosis is based on the results of clinical assessment. The accuracy of diagnosis improves with time and repeated assessments. Studies that require only inclusion of early cases of PD present a diagnostic challenge. Previous studies concluded that initial diagnoses of PD made by general neurologists were incorrect in 24% to 35% of the cases when patients were examined at autopsy. Experts in movement disorders are expected to have greater accuracy of initial diagnosis of PD.OBJECTIVETo determine the evolution of clinical diagnosis in patients with early PD made initially by experts in PD.DESIGNEight hundred patients with mild parkinsonian symptoms (Hoehn and Yahr stage 1 or 2) who received a diagnosis of PD less than 5 years before the beginning of the study were included in the original Deprenyl and Tocopherol Antioxidative Therapy for Parkinson's Disease study. These patients were followed up prospectively with repeated clinical assessments. The following clinical criteria were used to reassess the initial diagnosis: investigator's confidence in the diagnosis of PD, presence of atypical clinical features, findings of imaging studies, response to levodopa, and results of autopsy examinations.RESULTSThe mean +/- SD duration of illness in the 800 cases at enrollment was 2.2+/-1.3 years, and the mean +/- SD Hoehn and Yahr stage was 1.6+/-0.5. The mean +/- SD follow-up was 6.0+/-1.4 years (range, 0.2-7.6 years). In 5 cases, PD was not confirmed at autopsy, and in 15 patients, the results of imaging studies indicated the presence of other pathological conditions. Of the 550 cases treated with levodopa, 49 (8.9%) had little or no improvement; 6 of these cases overlap with either autopsy or imaging study exclusion criteria. Two other cases had at least 4 of the 6 atypical clinical features arguing against the diagnosis of PD. Thus, of the 800 patients, 65 (8.1%) did not have PD according to the study criteria. Compared with those patients with the final diagnosis of PD, in the diagnoses of 60 patients without autopsy, the duration of symptoms (mean +/- SD, 7.2+/-2.0 years vs. 8.3+/-1.9 years; P<.001) and the duration of follow-up (5.3+/-1.6 years vs. 6.1+/-1.3 years; P<.001) were shorter.CONCLUSIONSWe found that 65 (8.1%) of patients initially diagnosed as having PD were later found to have an alternate diagnosis based on multifactorial clinical diagnostic criteria. This alternate diagnosis indicated that experts in PD changed their diagnoses infrequently during the 7.6-year follow-up.

CALM-PD (Comparison of the agonist pramipexole with levodopa on motor complications of Parkinson's disease) is a randomized, multicenter, double-blind, controlled clinical trial designed to compare the policy of initial treatment of pramipex ole with the policy of initial treatment with levodopa in early, symptomatic Parkinson's disease with regard to the development of dopamineragic motor complications. At 22 American and Canadian sites, 301 eligible subjects requiring antiparkinsonian therapy to treat emerging disability were enrolled in CALM-PD and randomized to (i) active pramipexole and placebo levodopa or (ii) placebo pramipexole and active levodopa. Subjects are being evaluated systematically at regular intervals during a 23.5-month period to determine if and when dopaminergic motor complications (wearing off, dyskinesias, "on-off " effects) occur. In addition, quality-of-life outcomes, economic outcomes, and functional imaging outcomes are being assessed in standard fashion with [I-123]beta-CIT and SPECT imaging throughout the trial. The study design contains many provisions to approximate routine clinical practice and to produce data about clinical effectiveness, tolerability, and cost to facilitate the evidence-based practice of neurology.

Thirty-seven HIV-positive women were recruited in a 2-year prospective investigation into the role of depression in HIV disease progression. All participants had CD4+ cell counts of 200 or less at baseline and at least 3 CD4+ cell counts during follow-up. Participants were evaluated semiannually for CD4+ lymphocyte counts, B2Microglobulin (B2M), hemoglobin data, and new AIDS-defining illnesses. The Center for Epidemiologic Studies Depression Scale was used to assess for depressed mood. Over time, average rates of change in CD4+ counts did not differ significantly between depressed and nondepressed women, even after adjustment for age, antiretroviral use, and baseline CD4 count, and depressed women did not differ from nondepressed women in numbers of new AIDS-defining illnesses. The authors concluded that depression may not be a significant determinant of disease progression in women with advanced disease and called for further investigations with larger samples and women at earlier stages of the infection.

Cognitive impairment is a frequent manifestation of advanced human immunodeficiency virus (HIV) infection. The response to antiretroviral medication is often partial and poorly sustained. Recent studies suggest that free radical production within the CNS and neuronal apoptosis may play important roles in the pathogenesis of HN dementia. We conducted a randomized double-blind, placebo-controlled trial using a parallel group, 2 x 2 factorial design evaluating deprenyl, a monoamine oxidase B inhibitor and putative anti-apoptotic agent, and thioctic acid, an antioxidant, in 36 patients with HIV-associated cognitive impairment. Both deprenyl and thioctic acid were well tolerated with few adverse events. Deprenyl recipients showed significant improvement on tests of verbal memory compared with patients not taking deprenyl. Thioctic acid treatment did not improve cognitive function. These results suggest that deprenyl treatment is associated with cognitive improvement in subjects with mild HN-associated cognitive impairment, whereas thioctic acid has no benefit. A larger efficacy trial is needed to assess the long-term effect of deprenyl on cognitive performance in patients with HIV infection.

Context.-Monotherapy with dopamine agonists may be useful in early Parkinson disease.Objective.-To evaluate dose-response relationships for tolerability, safety, and efficacy of the synthetic dopamine agonist pramipexole.Design.-Multicenter, multidosage, parallel-group, double-blind, placebo-controlled, randomized clinical trial.Setting.-University or academically based movement disorder clinics.Patients.-A total of 264 patients with early Parkinson disease (PD) who were not requiring or receiving levodopa or other dopamine agonists were enrolled.Intervention.-Subjects were randomized to 1 of 5 treatment groups: pramipexole doses of 1.5 mg/d, 3.0 mg/d, 4.5 mg/d, and 6.0 mg/d, or matching placebo. A 6-week dosage escalation period was followed by a 4-week maintenance period and a 1-week period during which active treatment was withdrawn.Main Outcome Measures.-The primary measure of tolerability was the proportion of subjects completing the study on the assigned treatment. The primary measure of efficacy was the change from baseline to 10 weeks in the total score on the Unified Parkinson's Disease Rating Scale (UPDRS).Results.-Pramipexole was generally safe and well tolerated in this 10-week study. The proportion of subjects completing the study on the originally assigned dosage was 98% for placebo and 81% for the 1.5-mg/d, 92% for the 3.0-mg/d, 78% for the 4.5-mg/d, and 67% for the 6.0-mg/d treatment groups. There was a trend toward increased frequency of adverse experiences, particularly somnolence, in the 6.0-mg/d group. After 10 weeks of treatment, pramipexole-treated subjects showed a 20% improvement in total UPDRS scores, with mean improvements in scores ranging from 5.9 to 7.0 units among active treatment groups, compared with 0.9 units for the placebo group (P<.005 for each comparison with placebo). There was also evidence that the treatment effects were more pronounced in subjects with worse UPDRS scores at baseline.Conclusions.-Pramipexole is safe and effective as short-term monotherapy in patients with early PD who are not receiving levodopa. Further study is warranted to determine the long-term impact of pramipexole on the progression of disability in PD and its value in comparison with levodopa therapy and other dopamine agonists.

Cognitive impairment is a common and disabling complication of advanced HIV infection. Antiretroviral agents are the only proven therapies currently used for the treatment of HIV dementia, but the response to these agents is frequently unsatisfactory, short-lived, or complicated by intolerable side effects. We hypothesized that OPC-14117, a lipophilic antioxidant that acts to scavenge superoxide anion radicals, might ameliorate the toxic interactions between HIV infected macrophages and neurons. We conducted a double-blind, placebo-controlled, randomized clinical trial to assess the safety and tolerability of OPC-14117 240 mg per day. All 30 patients enrolled (15 per group) had cognitive impairment based on performance on neuropsychological tests. The primary outcome was tolerability of the study drug as measured by the proportion of subjects able to complete the study on their assigned dosage of experimental medication. Overall OPC-14117 was as well tolerated as placebo. Five subjects withdrew because of adverse experiences (two placebo, three OPC-14117). The OPC-14117-treated group had better scores on a clinical global impression scale, compared with the placebo group. There were trends toward improvement in the cognitive test scores; however, these changes were not statistically significant. These results demonstrate that this antioxidant intervention is well tolerated in cognitively impaired patients with advanced HIV infection, and suggest that a larger efficacy trial to assess the impact of OPC-14117 on cognitive performance is warranted.

Motor fluctuations associated with levodopa therapy are common problems encountered in the long-term treatment of Parkinson's disease (PD). Entacapone, a peripherally acting, reversible inhibitor of catechol-O-methyltransferase, slows the elimination of levodopa in humans by reducing the formation of 3-O-methyldopa. We conducted a placebo-controlled, double-blind, parallel-group, multicenter trial of entacapone in PD patients with motor fluctuations. Two hundred five patients were randomized to receive either entacapone 200 mg or matching placebo with each dose of levodopa and were followed for 24 weeks. The primary measure of efficacy was the change in percentage of ''on'' time (relief of parkinsonism) while awake, as recorded by subjects at home in diaries completed at 30-minute intervals. At baseline, patients averaged approximately 10 hours of ''on'' time per day while awake (60.5% ''on'' time), and entacapone treatment increased the percent ''on'' time by 5.0 percentage points. The effect of entacapone was more prominent in patients with a smaller percent ''on'' time (<55%) at baseline, and increased as the day wore on. Entacapone is effective at increasing the duration of response to levodopa and at relieving parkinsonism in patients experiencing motor fluctuations and was well tolerated during the 24 weeks of treatment.