Selegiline as initial treatment in de novo parkinsonian patients.

To investigate the efficacy and safety of selegiline in the early phase of Parkinson's disease (PD), we carried out a placebo-controlled, double-blind, parallel trial. De novo PD patients were randomized to receive either selegiline (10 mg/d) or matching placebo. We continued selegiline or placebo until levodopa therapy became necessary and assessed the disability using three different rating scales at baseline, after 3 weeks, at 2, 4, 8, and 12 months, and at every 4 months thereafter. Fifty-two patients were eligible for the analysis, 27 in the selegiline group and 25 in the placebo group. The median duration of time before levodopa had to be initiated was 545 +/- 90 days with selegiline and 372 +/- 28 days with placebo (p = 0.03). Disability was significantly less in the selegiline group than in the placebo group up to 12 months. The period of time during which the mean total Columbia University Rating Scale score stayed below the baseline was used to express the initial symptomatic effect of the treatments. The difference in this initial improvement time between the two groups was about 3 months and did not alone explain the difference in the delay of the need to start levodopa therapy. Selegiline was well tolerated and there were no severe side effects. We conclude that selegiline delays the need to start levodopa in de novo PD patients, has symptomatic efficacy, and possibly retards the progression of the disease.     

Selegiline as the primary treatment of Parkinson's disease — a long-term double-blind study

Introduction – To assess the therapeutic efficacy of selegiline combined with levodopa in the long-term treatment of Parkinson's disease (PD). Material and methods – 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. Results – 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. Conclusion – Selegiline therapy offers beneficial long-term effects in the treatment of PD.     

Does selegiline modify the progression of early Parkinson's disease? Results from a five-year study

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     

Experience with selegiline and levodopa in advanced Parkinson's disease

We compared the results of treatment with selegiline (deprenyl, Eldepryl) in 17 patients with advanced Stage 4 Parkinson Disease (PD) who were on levodopa (as Sinemet) with 65 Stage 2 or 3 patients with early PD who were also on levodopa. The first group consisted of 17 patients with advanced Stage 4 PD without response fluctuations ("wearing off" or "on off" phenomena). Their mean age was 72.1 ± 7.5 years, their mean duration of PD was 7.4 ± 3.2 years. The second group consisted of 65 patients with Stage 2 or 3 PD who had recently been started on levodopa. Their mean age was 63 ± 12.1 years, their mean duration of PD was 7.4 ± 3.2 years. The mean dose of selegiline was 10.0 ± 1.8 mg per day (range 5–20 mg). The mean duration of treatment was 1.5 ± 0.8 years.
During the four years of observation 55.3 ± 8.0% of the Stage 2 or 3 patients improved while only 14.3 ± 13.5% of the Stage 4 patients improved. This difference was significant (p<0.05). During this time 22.0 ± 6.7% of the Stage 2 or 3 patients worsened and 60.7 ± of the Stage 4 patients worsened. This degree of worsening was significant (p<0.05). Adverse effects were minor and reversible.
Our observations suggest that selegiline is more effective (higher percent of patients improving, lower percent of patients worsening) when it is added earlier with patients on levodopa than when it is added later.     

The effects of early selegiline therapy on long-term levodopa treatment and parkinsonian disability: An interim analysis of a norwegian–danish 5-year study

In this study, we investigated the effects of selegiline on levodopa treatment and parkinsonian disability over several years of treatment in patients with early Parkinson's disease (PD). The 163 patients were randomized to receive either selegiline or placebo in addition to levodopa in a double-blind, parallel-group study design, and the patients were to be followed up until a defined termination point or for 5 years. All patients had previously either never (two thirds) or for <6 months (one third) received levodopa. After 1 year of treatment or at withdrawal from study or both, the patients were divided according to specified diagnostic criteria into groups of definite, probable, possible, or unlikely PD. The efficacy parameters were levodopa therapy, Unified Parkinson's Disease Rating Scale (UPDRS) with subscales, and the time to develop wearing-off fluctuations or reaching the termination point. Evaluation of efficacy was performed for all patients with PD and for patients with a definite and probable disease. The results of this study are based on an interim analysis when 80% of the 163 randomized patients had been followed up for ≥3 years. Nine patients were excluded from the study because of protocol violations or because the patients were diagnosed as unlikely PD. At the time of interim analysis, 39 patients had been withdrawn from the study because of adverse effects or their own wish. Eighteen patients had reached the termination point, and 97 patients (observation time, 30–54 months) were still in the study. Among the patients receiving selegiline, we found a rather stable daily levodopa dose during 54 months of therapy, compared with an anticipated increase among patients with levodopa monotherapy. Concurrently, patients in the selegiline group showed a trend to develop less severe parkinsonian disability and a lower frequency of motor fluctuations and need for additional antiparkinsonian medication. The results of this study indicate that early combination therapy of selegiline and levodopa compared with levodopa monotherapy has an increasingly favorable impact on the long-term daily levodopa dose and may possibly delay the development of disability in PD.     

Early selegiline therapy reduces levodopa dose requirement in Parkinson's disease

In an earlier report of our placebo-controlled selegiline trial on de novo parkinsonian patients, we have shown that the need to start additional levodopa therapy is significantly postponed by using selegiline monotherapy. Now we report the two-year interim results of the double-blind continuation of the trial in 44 patients after the introduction of levodopa to the earlier therapy with placebo or selegiline (21 and 23 patients, respectively). The clinical disability was assessed by three rating scales. The daily dose of levodopa needed to maintain an optimal condition had to be increased progressively up to a 52% higher level in the placebo group than in the selegiline group (543 ± 150 and 358 ± 117 mg, respectively, p<0.001). The number of daily doses of levopoda was also statistically significantly higher in the placebo group during the 24 months' observation period (p<0.01). The ratio of levodopa doses that was expected to stay the same contrarily significantly increased suggesting that selegiline would, besides having the levodopa potentiating effect, also have a beneficial influence on the progression of the basic cerebral dopamine deficiency. The combination of selegiline and levodopa was well tolerated, and the adverse event profiles did not differ from each other. In conclusion, early selegiline therapy allows a significant saving in the subsequent levodopa dosage. This saving seems to become even stronger along with the treatment time.     

Zydis selegiline reduces off time in Parkinson's disease patients with motor fluctuations: a 3-month, randomized, placebo-controlled study.

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.     

SELEDO: a 5-y-ear long-term trial on the effect of selegiline in early parkinsonian patients treated with levodopa

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.     

Selegiline as primary treatment in early phase Parkinson's disease — an interim report

Abstract– We are carrying out a double-blind parallel trial comparing the effect of selegiline monotherapy and placebo in de novo parkinsonian patients. Fifty-six patients (28 in both groups) are included in the trial. This interim analysis reports the results of the first 52 evaluable patients who have had at least one follow-up visit after entering the trial. The efficacy of treatment was assessed using the Columbia University Rating Scale, the North-Western University Disability Scale and the Webster Rating Scale and followed until the addition of levodopa therapy became necessary. The data were analysed at follow-up times of up to twelve months (34 patients evaluable at the end of the period). The overall disability scores of all the rating scales used were significantly smaller in the selegiline group than in the placebo group. Levodopa treatment had become necessary in 12 patients (46%) in the selegiline group and in 14 patients (54%) in the placebo group. The side-effects were mild and similar in both treatment groups. According to the present results selegiline monotherapy seems to have therapeutic efficacy in the early phase of Parkinson's disease. Whether selegiline is able to slow down the progression of Parkinson's disease needs further clarification.     

Selegiline in the treatment of daily fluctuations in disability of parkinsonian patients with long-term levodopa treatment

Abstract– In order to evaluate in a double-blind manner the therapeutic efficacy of selegiline in the treatment of late-phase Parkinson's disease, 19 patients with end-of-dose type fluctuations were randomized for a double-blind cross-over trial receiving either selegiline 10 mg or placebo. Each period lasted 12 weeks. During a two week prestudy period the dose of levodopa was titrated to optimal levels. The disability was evaluated using the Columbia University Disability Scale (CUDS). The patients kept a daily diary to monitor closely the frequency and severity of their fluctuations and the side-effects of treatment. Their parkinsonian disability and all main symptoms improved significantly during selegiline treatment. The mean duration of action of a levodopa dose was significantly longer and there was significantly less daily end-of-dose and early morning akinesia during selegiline treatment. The side-effects were similar in both treatments. This double-blind study confirms the findings of earlier open studies that selegiline potentiates and prolongs the therapeutic effects of levodopa and thus its use is particularly beneficial in patients with end-of-dose type fluctuations in disability.     

The effects of acute loading with levodopa and levodopa with selegiline on blood pressure and plasma norepinephrine levels in chronic Parkinson's disease patients

OBJECTIVES: Contradictory possible cardiovascular side effects of selegiline have been reported. Therefore, we studied the effect of acute administration of selegiline with levodopa (LD) compared with LD alone, on blood pressure, pulse and norepinephrine (NE) plasma levels, during an orthostatic test on chronically treated Parkinson's disease patients (PDpts) and controls. MATERIALS AND METHODS: Twelve PDpts treated with LD (group D), 12 PDpts treated with selegiline and LD (group S) and eight volunteers (CTRL) underwent the orthostatic test. Patients repeated the test twice, before and after acute loading with 125 mg LD (group D) and 125 mg LD +5 mg selegiline (group S). RESULTS: Group S showed more episodes of postural hypotension (n = 10; two symptomatic) than group D (n = 4) and CTRL (n = 2), however not statistically significant. Plasma NE also rose significantly higher (P < 0.001) in group S. CONCLUSION: PD patients treated with selegiline showed more orthostatism and higher plasma NE after submission to the orthostatic test. These findings may be relevant to explain its deleterious effect.     

Selegiline and cognitive function in Parkinson''s disease

Eighteen patients with Parkinson's disease were treated with placebo for 4 weeks and with the MAO-B inhibitor selegiline for 8 weeks without levodopa in a randomized double-blind clinical study. The maximum dose of selegiline was 30 mg/day and the patients' cognitive functions were evaluated before treatment and at week 12 when they were either on 30 mg selegiline or placebo. A series of neuropsychological tests were used to study general cognitive reasoning, memory, visuospatial abilities, attention, cognitive flexibility, motor functions and depression. Specific cognitive effects were not observed. Slight improvement occurred mainly in learning (easy word associations) which may reflect a limited, nonspecific arousal effect.     

Selegiline in Parkinson''s disease

Twenty patients with Parkinson's disease were treated with the MAO-B inhibitor selegiline (l-deprenyl) and placebo without levodopa (L-dopa) in a randomized double-blind clinical cross-over study to analyze relative importances of dopamine (DA) synthesis and metabolism. The daily dose of selegiline was gradually increased to a maximum of 30 mg in all patients. The clinical neurological disability (Columbia score) was about 10% less on selegiline (30 mg/day) than on placebo. This difference was neither statistically nor clinically significant. The results are compatible with the possibility that treatment with selegiline without concomitant L-dopa does not significantly increase DA concentration which remains low and is determined mainly by tyrosine hydroxylase activity. At low DA levels the DA re-uptake mechanism recaptures most of the released DA and DA deamination is of minor significance. The pathway of DA oxidation becomes more important only at higher DA concentrations, accomplished by bypassing the rate limiting step of tyrosine hydroxylation using L-dopa.     

Lisuride plus selegiline in the treatment of early Parkinson''s disease

We treated 20 early Parkinson's disease subjects with the dopamine agonist lisuride in combination with the MAO-B inhibitor selegiline (L-deprenyl). We started with lisuride alone for one month, then we added selegiline versus placebo to lisuride in double-blind conditions for 3 months; finally all patients received lisuride and selegiline for another 3 months. Lisuride alone (1.43 +/- 0.10 mg) significantly improved PD. When selegiline (10 mg/day) was added in the double-blind phase the mean lisuride dosage could be reduced by 22.8% without deterioration of the clinical effects, and the same occurred in the former placebo group when selegiline was added. The combination of both drugs was well tolerated. These data are of interest for the interpretation of the effects of selegiline.     

Double-blind, crossover placebo controlled trial of selegiline in Parkinson's disease — an interim analysis

Abstract– The response to selegiline was assessed in ten (2 females, 8 males) idiopathic parkinsonian patients with the wearing off response. Selegiline was compared to placebo in each patient in a double blind crossover study carried out over ten months. After 16 weeks of therapy selegiline significantly prolonged response to levodopa, extending response to 3 hours (p < 0.05) in most patients and to 4 hours (p < 0.001) in some patients. Baseline scores (zero time: 12 hours after their previous dose of medication) were also significantly better after selegiline therapy (p < 0.05). Selegiline did not improve peak response (1 hour after medication) to levodopa indicating that these patients were on optimum therapy prior to receiving selegiline. Adverse effects (nausea (2), dyskinesia (2), fear reaction (1) and postural dizziness (1)) occurred in 5 patients during the trial.     

Selegiline as an adjunct to conventional levodopa therapy in Parkinson's disease. Experience with this type B monoamine oxidase inhibitor in 200 patients

Two hundred patients at a median age of 63 years, receiving conventional levodopa therapy for 8 years, who had had Parkinson's disease for 10 years, tried a regimen of selegiline (L-deprenyl), a type B monoamine oxidase inhibitor, at a daily dose of 10 mg, for varying periods from less than 6 months to more than 24 months (28% over 24 months). Selegiline does improve parkinsonism during the initial 6 months to 12 to 24 months of combined therapy in one third to almost half of patients with an end-of-dose type of response to long-term levodopa therapy. However, even this particular class of patients is unable to maintain such an improvement by 36 months, much less by 48 months, from the start of the selegiline trial. About one quarter of poor responders to levodopa and those with random deterioration show improvement in their parkinsonian status in the first 6 months of the selegiline trial, but their conditions quickly deteriorate by 1 year. The predominant pattern of response to previous levodopa therapy and the severity of the total disability score at the initiation of the selegiline trial were the two variables that were predictive of risk of failure with the drug. No evidence suggested that selegiline decreases the excess mortality rate of Parkinson's disease above that achieved with the use of levodopa alone. Selegiline as an adjunctive agent to conventional levodopa therapy was not unduly impressive with regard to preventing progression of Parkinson's disease.     

Selegiline (deprenyl) treatment and death of nigral neurons in Parkinson's disease

We studied the effect of selegiline (deprenyl) treatment on the number of Lewy bodies and neuron counts in the substantia nigra in patients with Parkinson's disease (PD). The number of medial nigral neurons was greater and the number of Lewy bodies fewer in those PD patients who had been treated with selegiline in combination with levodopa as compared with patients who had received levodopa alone. This suggests that selegiline treatment may retard the death of nigral neurons, but alternative explanations, such as the reduction of levodopa dosage in selegiline-treated patients, are possible.     

Efficacy and safety of entacapone in Parkinson's disease patients with suboptimal levodopa response: a 6-month randomized placebo-controlled double-blind study in Germany and Austria (Celomen study)

OBJECTIVES: To determine the efficacy and safety of the catechol-O-methyltransferase (COMT) inhibitor entacapone, used as an adjunct to levodopa, in Parkinson's disease (PD) patients. PATIENTS AND METHODS: In this parallel group, randomized, double-blind study, 301 PD patients, the majority with motor fluctuations, received entacapone (200 mg) or placebo with each daily dose of standard or controlled-release (CR) levodopa. The 24-week treatment period was followed by 2 weeks of entacapone withdrawal. Efficacy was determined by home diaries ('on' and 'off' times), Unified Parkinson's Disease Rating Scale (UPDRS) and changes in levodopa dosage, and safety by adverse-event inquiry, vital signs, electro cardiography (ECG) and laboratory tests. RESULTS: In the total population, the UPDRS activities of daily living and motor scores were significantly improved (P < 0.05) by entacapone vs placebo. In fluctuating patients, 'on' time increased (1.7 h) and 'off' time decreased (1.5 h) significantly more with entacapone than with placebo (0.5 and 0.6 h, respectively; P < 0.05), and the daily levodopa dose was reduced by 54 mg with entacapone and increased by 27 mg with placebo (P < 0.05). Entacapone benefit was lost on withdrawal. Entacapone efficacy was comparable between patients using CR and standard levodopa preparations. Increased dyskinesias (entacapone 34%, placebo 26%) and nausea (10 and 5%, respectively), mostly occurring shortly after treatment initiation, were generally managed by reducing the levodopa dose. Diarrhoea (entacapone 8%, placebo 4%) was seldom severe. There were no differences in vital signs, ECG or laboratory results. CONCLUSION: Entacapone is an effective and safe levodopa extender and enhancer, improving the symptomatic efficacy of levodopa in PD and adding to the patients' benefit.     

Therapeutic factors causing hallucination in Parkinson's disease patients, especially those given selegiline

Selegiline protects nigral dopaminergic neurons and is recommended for the treatment of patients in the early stage of Parkinson's disease (PD). We treated 112 PD patients and noted that those given selegiline had a high incidence of hallucination. Our objective was to determine which clinical therapeutic factors cause such hallucinations. The Kruskal-Wallis and chi-square test showed that in 94 patients, the severity of the hallucinations was significantly related to the duration of illness, Hoehn and Yahr stage, doses of levodopa and cabergoline, whether or not selegiline was used, and whether or not medication for constipation was required. In addition, patients who were treated with a low dose of levodopa (< or =300 mg/day), who had a low Hoehn and Yahr stage, and a short duration of illness (< or =8 years) together with a high dose of selegiline or cabergoline also tended to have hallucinations. MRI findings were not related to the incidence of hallucination. When selegiline is given to patients who have PD of long duration and a high Hoehn and Yahr stage, and who already are receiving levodopa and a dopamine agonist, the doses of levodopa and the dopamine agonists given, as well as the presence of constipation, may be related to the incidence of hallucination.     

Efficacy of methylprednisolone pulse therapy on neuroleptic malignant syndrome in Parkinson's disease

BACKGROUND: Neuroleptic malignant syndrome (NMS) is a dangerous complication in patients with Parkinson's disease (PD). AIMS: To evaluate the efficacy of methylprednisolone pulse therapy compared to placebo in PD patients with NMS. METHODS: In a double blind, placebo controlled study, 20 PD patients with NMS received steroid pulse therapy for three days, and 20 PD patients received placebo. Both groups received levodopa, bromocriptine, and dantrolene. RESULTS: NMS in the steroid group healed within 10 days in 17 patients; median value of duration of illness of NMS in this group was 7 days (range 4-20). NMS in the placebo group healed within 10 days in five patients; in the remaining 15, it persisted for 12-27 days after the onset of NMS; median value of duration illness of NMS in this group was 18 days. Hyperthermia, rigidity, and consciousness improved within 10 days in many patients in the steroid group; these signs persisted more than 10 days in many patients in the placebo group. CONCLUSIONS: Steroid pulse therapy is useful in NMS for reducing the illness duration and improving symptoms.