Selegiline slows the progression of the symptoms of Parkinson disease. Does selegiline modify the progression of early Parkinson's disease? Results from a five-year study. The Norwegian-Danish Study Group. Selegiline as the primary treatment of Parkinson's disease--a long-term double-blind study. The effect of deprenyl (selegiline) on the natural history of Parkinson's disease. Zydis selegiline reduces off time in Parkinson's disease patients with motor fluctuations: a 3-month, randomized, placebo-controlled study. Investigation by Parkinson's Disease Research Group of United Kingdom into excess mortality seen with combined levodopa and selegiline treatment in patients with early, mild Parkinson's disease: further results of randomised trial and confidential inquiry. Rasagiline mesylate, a new MAO-B inhibitor for the treatment of Parkinson's disease: a double-blind study as adjunctive therapy to levodopa. Five-year follow-up of early lisuride and levodopa combination therapy versus levodopa monotherapy in de novo Parkinson's disease. The French Lisuride Study Group. Alzheimer-type dementia and verbal memory performances: influence of selegiline therapy. SELEDO: a 5-year long-term trial on the effect of selegiline in early Parkinsonian patients treated with levodopa. Survival in Parkinson disease: thirteen-year follow-up of the DATATOP cohort.
To study the long-term effects of selegiline in monotherapy and in combination with levodopa in the early phase of Parkinson disease (PD).
                One hundred fifty-seven de novo PD patients were randomized in a double-blind, placebo-controlled study of 7 years' duration. In the monotherapy part, selegiline significantly delayed the initiation of levodopa therapy vs placebo. The authors now report the results from the combination part of the study, in which 140 patients received selegiline or placebo in addition to individually tailored levodopa therapy.
                Compared with placebo, selegiline slowed the progression of disease disability as measured by the Unified Parkinson Disease Rating Scale (UPDRS) total score (p = 0.003) or by motor (p = 0.002) and Activities of Daily Living (p = 0.0002) subscores. After 5 years in combination therapy, the mean difference in the UPDRS total score was nearly 10 points, with patients receiving placebo having 35% higher scores. Simultaneously, patients receiving placebo needed progressively higher doses of levodopa than patients receiving selegiline; after 5 years, the mean dosage of levodopa was 19% higher with placebo than with selegiline (p = 0.0002). Considering the entire (monotherapy and combination therapy) 7-year study time, there was a trend for selegiline to delay the start of wearing-off fluctuations (hazard ratio 0.55, p = 0.08). In both phases of the study, selegiline was safe and well tolerated.
                The results of this long-term study confirm earlier findings indicating that selegiline delays the progression of the signs and symptoms of Parkinson disease. The objective of this study was to examine the effect of long-term treatment with selegiline on the progression of Parkinson's disease (PD). One hundred and sixty-three patients with early PD were treated with levodopa and benserazide, combined with selegiline or placebo in a five-year randomized, placebo-controlled, double-blind, parallel group study followed by a one-month wash-out of selegiline or placebo. The main outcome measures were assessments of the severity of parkinsonism, levodopa requirements and the development of end-of-dose motor fluctuations over time and after wash-out at the end of the study period. Results indicated that patients treated with the combination of selegiline and levodopa developed markedly less severe parkinsonism and required lower doses of levodopa during the five-year study period than patients treated with levodopa and placebo. There was no trend towards worsening during wash-out among patients previously treated with selegiline. The results cannot easily be explained by a symptomatic effect of selegiline.
                Copyright Lippincott Williams & Wilkins To assess the therapeutic efficacy of selegiline combined with levodopa in the long-term treatment of Parkinson's disease (PD).
                A randomized, prospective, double-blind study on 44 patients with PD needing levodopa therapy after the initial double-blind treatment with placebo or selegiline was carried out. The patients were followed-up for 5 years under combination therapy.
                Selegiline induced a significant (P < 0.001) slowing in the need to increase the daily levodopa dose in order to compensate for the progression of the disease. After 5 years of combination therapy the mean dose of levodopa was on average 320 mg lower in the selegiline group (405 +/- 59 mg vs 725 +/- 78 mg). The difference in the levodopa doses between the two groups increased along with follow-up time, as also the ratio of the levodopa doses (placebo/selegiline group). The number of daily levodopa doses needed to compensate for the occurrence of motor fluctuations was significantly lower in the selegiline group. The parkinsonian disability did not differ between the two groups because the clinical condition was kept as optimal as possible by adjusting the levodopa dosage. Nine patients in the placebo group needed initiation of additional dopaminergic therapy in comparison to one in the selegiline group (P = 0.004). During the 5-year follow-up period 11 patients were withdrawn from the selegiline group, 7 due to adverse events. There was no difference in mortality between the two groups.
                Selegiline therapy offers beneficial long-term effets in the treatment of PD. The effects of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a neurotoxin that produces the symptoms of Parkinson's disease, can be fully prevented in experimental animals by inhibiting monoamine oxidase B. On the basis of this observation, a double-blind, placebo-controlled study in patients with early Parkinson's disease was initiated to determine whether deprenyl (a selective monoamine oxidase B inhibitor) would delay the need for L-dopa therapy by slowing the progression of the disease. Fifty-four patients were randomly assigned to deprenyl (10 mg/day) or placebo treatment groups and followed until L-dopa therapy was indicated or until the patient had been in the study for 3 years. Analysis of Kaplan-Meier survival curves for each group showed that deprenyl delayed the need for L-dopa therapy; the average time until L-dopa was needed was 312.1 days for patients in the placebo group and 548.9 days for patients in the deprenyl group. Disease progression, as monitored by five different assessment scales, was slowed (by 40 to 83% per year) in the deprenyl group compared to placebo. Therefore, early deprenyl therapy delays the requirement for antiparkinsonian medication, possibly by slowing progression of the disease. Zydis selegiline dissolves on contact with saliva and undergoes pregastric absorption. This minimizes first-pass metabolism and provides high plasma concentrations of selegiline. In this study, the efficacy and safety of Zydis selegiline was assessed in Parkinson's disease (PD) patients who were experiencing motor fluctuations with levodopa. Patients were randomly assigned to either drug or placebo in a 2:1 ratio in this double-blind, multicenter trial. Significant reductions in daily off time occurred at 4 to 6 weeks with the 1.25 mg dose (9.9%, P = 0.003) and 10 to 12 weeks with the 2.5 mg dose (13.2%, P < 0.001). The total number of off hours was reduced by 2.2 hours at Week 12 from baseline (compared with 0.6 hours in the placebo group). The average number of dyskinesia-free on hours for the Zydis selegiline patients increased by 1.8 hours at Week 12. There was no change in mean percentage of "Asleep" time throughout the study. No apparent differences were detected in the occurrence of drug-related adverse events between the Zydis selegiline group and placebo-treated groups. Adverse events were consistent with known effects of levodopa therapy. Zydis selegiline safely reduces daily off time when used as adjunctive therapy with levodopa in patients with PD.
                Copyright 2004 Movement Disorder Society To determine whether the excess mortality observed in patients who received both levodopa and selegiline in a randomised trial could be explained by revised diagnosis of Parkinson's disease, autonomic or cardiovascular effects, more rapid disease progression, or drug interactions.
                Open randomised trial and blind comparison and reclassification of the cause of death of patients who were recruited from 93 hospitals between 1985 and 1990 and who had died before December 1993 in arms 1 and 2.
                United Kingdom.
                624 patients with early Parkinson's disease who were not receiving dopaminergic treatment and a subgroup fo 120 patients who died during the trial.
                Levodopa and a dopa carboxylase inhibitor (arm 1), levodopa and a dopa decarboxylase inhibitor in combination with selegiline (arm 2), or bromocriptine alone (arm 3).
                All cause mortality for 520 subjects in arms 1 and 2 and for 104 subjects who were randomised into these arms from arm 3. Cause specific mortality for people who died in the original arms 1 and 2 on the basis of the opinion of a panel, revised diagnosis and disability ratings, evidence from clinical records of either autonomic or cardiovascular episodes, other clinical features before death, and drug interactions.
                After extended follow up (mean 6.8 years) until the end of September 1995, when arm 2 was terminated, the hazard ratio for arm 2 compared with arm 1 was 1.32 (95% confidence interval 0.98 to 1.79). For subjects who were randomised from arm 3 the hazard ratio for arm 2 was 1.54 (0.83 to 2.87). When all subjects were included the hazard ratio was 1.33 (1.02 to 1.74) and after adjustment for other baseline factors it was 1.30 (0.99 to 1.72). The excess mortality seemed to be greatest in the third and fourth year of follow up. Cause specific death rates showed an excess of deaths from Parkinson's disease only (hazard ratio 2.5 (1.3 to 4.7)). No significant differences were found for revised diagnosis, disability rating scores, autonomic or cardiovascular events, other clinical features, or drug interactions. Patients who died in arm 2 were more likely to have had possible dementia and a history of falls before death compared with those who died in arm 1.
                The results consistently show excess mortality in patients treated with combined levodopa and selegiline. Revised diagnosis, autonomic or cardiovascular events, or drug interactions could not explain this finding, but falls and possible dementia were more common in arm 2. The results do not support combined treatment in patients with newly diagnosed Parkinson's disease. In more advanced disease, combined treatment should perhaps be avoided in patients with postural hypotension, frequent falls, confusion, or dementia. Rasagiline mesylate (TVP-1012) is a potent, selective, non-reversible MAO-B inhibitor, without the tyramine-potentiating effect and with neuroprotective activities. The benefit of rasagiline as monotherapy in patients with early Parkinson's disease (PD) has already been reported. To evaluate the safety, tolerability, and clinical effect of rasagiline as adjunctive therapy to levodopa, a multicenter, double-blind, randomized, placebo-controlled, parallel-group study (0.5, 1, and 2 mg/d) was conducted for 12 weeks in 70 patients with PD (mean age, 57.4 y; mean disease duration, 5.7 y; 32 patients had motor fluctuations). A beneficial clinical effect was observed in fluctuating patients treated with rasagiline (all doses), expressed as a decrease in total Unified Parkinson's Disease Rating Scale (UPDRS) score (23.0% vs 8.5% in the placebo group). The treatment effect was still evident 6 weeks after drug discontinuation (in all doses). The safety and tolerability of rasagiline were good. Adverse events were no different than those of patients taking placebo. Almost complete platelet MAO-B inhibition was obtained at all rasagiline doses. This study has demonstrated that rasagiline (up to 2 mg/day) has a good safety profile and a beneficial clinical effect in fluctuating patients with PD when given as an add-on to chronic levodopa therapy. The value of an early initial coadministration of levodopa (L-dopa) and lisuride in Parkinson's disease was the main goal of the present study. Eighty-two patients with recently diagnosed idiopathic Parkinson's disease were randomized into two groups for treatment with L-dopa alone or L-dopa + lisuride. The trial was double-blinded for the first year and open for the following 4 years. Selegiline (10 mg/day b.i.d.) was added in both groups at the end of the first year. Outcome measures were evolution of L-dopa dosage and Unified Parkinson's Disease Rating Scale scores and subscores, and incidence of motor complications. The dropout rate was higher in the L-dopa group (63.4%) than in the combination group. Motor improvement was better (p < 0.01) in the L-dopa + lisuride group. Expected motor complications were rare, moderate and equivalent in the two groups despite a difference in L-dopa dosage (446.7 vs. 387.5 mg/day). Long-term follow-up demonstrated the L-dopa-sparing effect of lisuride (average 1 mg/day), the beneficial effect of early combination therapy on motor status and the paucity of motor complications in both groups.
                Copyright 2000 S. Karger AG, Basel In a double blind randomized crossover trial lasting 6 months selegiline, a selective MAO-B inhibitor, was tested against placebo for activity on verbal memory performances in Alzheimer-type dementia (DAT). Verbal memory was assessed with the Rey-Auditory-Verbal Learning Test at the start of treatment, at the time scheduled for crossover (90 days) and at the end of the trial (180 days). The results suggest that selegiline possesses significant activity on some memory parameters, which seems to depend on an improvement both in information processing abilities and in learning strategies at the moment of acquisition. The SELEDO (from selegiline plus levodopa) study was carried out as a randomized, prospective, placebo-controlled, double- blind, multicenter long-term, 5-year trial to evaluate the possible advantages of combining selegiline and levodopa in the early treatment of Parkinson's disease. One-hundred-and-sixteen patients were randomized either to selegiline or placebo. Before starting the study medication, the levodopa dose was titrated to the individual requirements of each patient. The primary study end point (time when levodopa had to be increased by >50% of the titrated dose) was reached in 23 of 59 patients in the selegiline group and 26 of 48 patients in the placebo group. At the end of the 5 years' treatment period the rates derived from a life-table analysis were 50.4% in the selegiline group and 74.1% in the placebo group (P = 0.027, log-rank test). The median time to reach the primary end point was 4.9 years in the selegiline group and 2.6 years in the placebo group. In patients treated with selegiline, the mean levodopa dose changed only slightly over the 5 years of treatment compared to the initially titrated dose, but rose markedly in the placebo group, where the dose of levodopa had to be adjusted earlier than in the selegiline group. At the same time, the lower levodopa dosage in the selegiline group was accompanied by at least equal therapeutic efficacy (which is necessary for an unambiguous interpretation). Subgroup analyses showed greater benefit for selegiline treated) patients in the earlier stages. Long-term side effects appeared later in the selegiline group, although the difference was not significant. The early combination of selegiline and levodopa proved to be clearly superior to levodopa monotherapy.
                Copyright 1999 Lippincott Williams & Wilkins. To investigate predictors of survival in Parkinson disease (PD).
                Vital status was determined in 800 subjects enrolled in a clinical trial of deprenyl (selegiline) and tocopherol 13 years earlier.
                Two hundred ninety-six deaths were recorded. There was no difference in the standardized mortality ratios across gender or age group. In univariate analyses, PD-specific variables associated with mortality were increased symmetry of parkinsonism, gait dysfunction as an initial symptom, severity of parkinsonism, and rate of worsening of parkinsonism prior to study enrollment. Cumulative exposure to deprenyl was not associated with mortality. In multivariable analysis, severity of parkinsonism and rate of worsening of parkinsonism remained associated with mortality. A poorer response to levodopa was associated with increased mortality independent of disease severity or dosage of levodopa. Results were unchanged when the analysis was restricted to 747 subjects maintaining a most likely diagnosis of PD throughout 6 years of active follow-up.
                Parkinson disease did not affect survival differently across gender or age groups in this selected group of otherwise healthy clinical trial participants. Severity and rate of worsening of parkinsonism and response to levodopa are strongly related to survival.
MAO-B inhibitors (more specifically selegiline which contributes most of the data) do not appear to delay disease progression in terms of improved survival but may reduce later motor fluctuations. At present, we do not feel these drugs can be recommended for routine use in the treatment of early Parkinson's disease.