Clinical evaluation of deprenyl (selegiline) in the treatment of Parkinson's disease

ABSTRACT — The experiences of a seven-year study on deprenyl in the treatment of Parkinson's disease are summarized. It was found that the main advantage of deprenyl was that it permitted the reduction of die dose of levodopa in optimally treated patients. In the initial stage of Parkinson's disease deprenyl is only partially sufficient as monotherapy. Deprenyl can administered successfully for correcting the "wearing off" effect.     

Treatment of Parkinson's disease in Japan

In this paper, the course of therapy for Parkinson's disease is outlined. The rationale for the use of DA-receptor-agonist (DA agonist) monotherapy or early combination therapy using levodopa and a DA agonist is that these therapies are asociated with a lower incidence of motor complications. However, the disease progresses, the use of levodopa in combination with a DA agonist results in motor complications and development of levodopa dependency in parkinsonian patients, because the effect of levodopa on parkinsonism is very strong. In this study, a positive correlation between the Hoehn-Yahr severity score at off-periods and duration of illness was observed in parkinsonian patients with long duration of illness. This indicates that responsiveness to dopaminergic therapy still exists even in patients in advanced stages of Parkinson's disease, indicating that continuous stimulation of DA receptors and reducing the excessive fluctuation in the plasma levodopa level possibly improve motor complications. If the dose of the DA agonist is simply increased without reduction of levodopa doses, dyskinesia worsens. Although levodopa therapy is essential in the case of patients in advanced stages of Parkinson's disease, the therapeutic principle, which depends on levodopa efficacy, must be changed. Reduction of the levodopa dose and administration of a sufficient dose of a DA agonist, which is equivalent to levodopa dose reduction, is one of the possible means of effective therapy of the disease.     

Recent observations on the clinical pharmacology of (-)deprenyl

Summary Serial tyramine challenges were given to 4 patients with Parkinson's disease who had taken 10 mg of a selective monoamine oxidase B inhibitor, (-)deprenyl, for up to eighteen months. In doses sufficient for complete inhibition of the platelet enzyme, no clinically significant adverse pressor reactions (cheese effects) occurred nor were any significant tyramine responses seen when higher doses of deprenyl (40–60 mg daily) were given for three weeks.A balanced crossover study in six healthy young male adults showed that (-)deprenyl was associated with a significant increase in the frequency of periods of wakefulness and stage 2 sleep and a significant decrease in REM sleep and sleep stages 3 and 4.In 85 patients with Parkinson's disease taking 10 mg of (–) deprenyl daily with levodopa and carbidopa for up to eighteen months, a mean dosage reduction of 200 mg levodopa daily was possible; 19 of the 39 patients who had end-of-dose akinesia responded favourably and only one of the 10 patients with on-off oscillations improved. On 10 mg (-)deprenyl daily only 4 patients showed an amphetamine response, but this was more frequent when 40 mg deprenyl was given daily. In 5 patients taking 40 mg (-)deprenyl daily without other medications a mild antiparkinsonian response occurred comparable to that seen with amphetamine.     

A randomised controlled study comparing bromocriptine to which levodopa was later added, with levodopa alone in previously untreated patients with Parkinson''s disease: a five year follow up.

This pilot study was performed to compare the occurrence of long term motor complications in Parkinson's disease when the introduction of levodopa was delayed by an initial treatment with high doses of bromocriptine alone. The trial was a prospective randomised controlled study comparing 31 previously untreated patients with Parkinson's disease initially given bromocriptine alone to which levodopa was later added (group B/D) and 29 other previously untreated patients with Parkinson's disease immediately given levodopa alone (group D). The end point was the occurrence of the first motor complications (wearing off or dyskinesia). Group B/D patients received bromocriptine (52 (SEM 5) mg/day) for 2.7 years, to which levodopa was later added (471 (SEM 46) mg/day). Group D patients received a comparable dose of levodopa alone (569 (SEM 47) mg/day). Both had similar disability scores at the end of the study. Motor complications were fewer and appeared later in group B/D than in group D (56% after 4.9 (SEM 0.5) years of treatment v 90% after 2.7 (SEM 0.5) years, p < 0.01). Wearing off appeared later (p < 0.01) in group B/D (4.5 (SEM 0.6) years) than in group D (2.9 (SEM 0.6) years). Peak dose dyskinesia occurred less often in group B/D patients (three v 14 cases, p < 0.01). This study showed that a three year initial monotherapy with high doses of bromocriptine followed by addition of levodopa delayed the occurrence of long term motor complications usually found in patients with Parkinson's disease treated with levodopa alone from the beginning.     

Does combined levodopa and bromocriptine therapy in Parkinson's disease prevent late motor complications?

Levodopa-carbidopa (LD) in low dosages adequately controls symptoms in most patients with Parkinson's disease and delays the appearance of fluctuations and dyskinesias. It has been suggested that early combination therapy with bromocriptine and levodopa delays or prevents the onset of late treatment complication associated with LD monotherapy in Parkinson's disease. We have conducted this study to assess the possible benefit of combined therapy compared with levodopa monotherapy. Seventy-eight previously untreated patients with Parkinson's disease were recruited over a period of 54 months and randomly allocated to either a levodopa-carbidopa (LD) Group or a levodopa-carbidopa in combination with low-dose bromocriptine (LD-Br) Group. The appearance of motor complications determined the end point of the study. We gradually increased the doses of bromocriptine (2.5–15 mg/d) or levodopa (125–500 mg/d) until the maximum "on" time was reached. In six patients, the doses of levodopa had to be increased up to the optimal dose (625–1000 mg/day). In the last evaluation the on-time and parkinsonian disability were similar in both treatment groups. We did not find statistically significant differences in the frequency of motor complications when comparing the two groups of treatment. Our study suggests that early combination of levodopa and bromocriptine does not confer any clinical benefit over levodopa alone in treating early Parkinson's disease, nor will it influence the evolution of the disease.     

Motor response to acute dopaminergic challenge with apomorphine and levodopa in Parkinson''s disease: implications for the pathogenesis of the on-off phenomenon.

OBJECTIVES--To evaluate the contribution of postsynaptic changes to motor fluctuations, three groups of parkinsonian patients with differing responses to treatment were acutely challenged with two dopaminergic drugs-apomorphine and levodopa-having different mechanisms of action. METHODS--Forty two patients with Parkinson's disease (14 untreated, eight with a stable response to levodopa, and 20 with levodopa induced motor fluctuations) were challenged on two consecutive days with apomorphine and levodopa. The latency, duration, and magnitude of motor response was measured. RESULTS--A progressive shortening of mean latency after levodopa challenge was found passing from the untreated to the stable and fluctuating groups; the difference between untreated and fluctuating patients was statistically significant (P < 0.01). Response duration after levodopa challenge was similar in untreated and stable patients, whereas it showed a significant shortening in patients with motor fluctuations (P < 0.05 v both untreated and stable patients). When subcutaneous apomorphine was given, untreated patients had a longer response duration than those who had developed motor fluctuations (P < 0.05). Although baseline disability was significantly greater in the fluctuating patients than in the untreated and stable patients, the severity of residual parkinsonian signs after both apomorphine and levodopa challenge was similar for all three groups; as a result, the degree of improvement in parkinsonian signs after dopaminergic stimulation was substantially greater in more advanced than in early cases. Linear regression analysis also indicated that latency and duration after apomorphine challenge did not significantly correlate with those after levodopa challenge, whereas magnitude of response to apomorphine showed a strong positive correlation with that after levodopa challenge (r = 0.9, P < 0.001). CONCLUSION--The progressive shortening of motor response after both apomorphine and levodopa suggests that pharmacodynamic factors play an important part in determining the duration of motor response and argue against altered central pharmacokinetics of levodopa being principally responsible for the on-off effect. The widening response amplitude and increasing off phase disability occurring during disease progression are also critical factors in determining the appearance of motor fluctuations.     

Levodopa-induced dyskinesias in Parkinson's disease: is sensitization reversible?

Levodopa-induced dyskinesias (LIDs) in patients with Parkinson's disease are considered to result from the severity of dopaminergic denervation in the striatum, which is an irrevocable phenomenon, and sensitization induced by long-term intermittent administration of levodopa. Taking advantage of the 64% reduction of levodopa treatment allowed in 12 Parkinson's disease patients by continuous high-frequency stimulation of the subthalamic nucleus, we evaluated the severity of parkinsonian motor disability and LIDs during two levodopa challenges performed before the surgical implantation of the stimulation electrodes and after 8.8 months of continuous bilateral subthalamic nucleus stimulation that was interrupted 2 hours before the levodopa test. Motor disability during the "off" and "on" drug periods was unchanged. The severity of LIDs during the "on" period and dystonia during the "off" period decreased by 54% and 62%, respectively. The reduced severity of LIDs in the absence of subthalamic nucleus stimulation demonstrates that the sensitization phenomenon resulting from long-term intermittent levodopa administration is partially reversible.     

Problems associated with long-term levodopa treatment of Parkinson's disease

ABSTRACT — Levodopa treatment improves significantly not only the parkinsonian disability but also the mortality rate. However, during long-term levodopa treatment the therapeutic benefit gradually declines. Furthermore, most cognitive skills improve initially, but long-term levodopa treatment is associated with declining intellectual capacity and dementia.
In patients on long-term levodopa treatment there seems to be a low threshold for certain clinical side-effects, especially postural hypotension, psychiatric disturbances and various types of fluctuations in disability. Low age at onset of Parkinson's disease, and at the commencement of levodopa therapy, the duration of levodopa treatment and a high dose of levodopa seem to be significant risk factors for the development of response fluctuations, but not the pretreatment duration of Parkinson's disease nor the disability of the patients.
A readjustment of the levodopa dosage, and as an adjuvant drug treatment, deprenyl, a specific inhibitor of MAO type B, or a direct-acting dopamine agonist may prove helpful in the management of fluctuations in disability. It is important, moreover, to try to prevent these phenomena by taking into account the predictive risk factors of response fluctuations in the treatment strategy of Parkinson's disease.     

Deprenyl (selegiline) in the treatment of Parkinson''s disease

ABSTRACT — The effects of deprenyl were investigated in 45 parkinsonian patients suffering from fluctuations in disability under long-term levodopa treatment. During a 1 to 3 month period of treatment, 5–10 mg of deprenyl caused a significant reduction in response fluctuations in 26 out of 45 patients (58 %). This improvement was only moderate (58 %) or minimal (42 %). Of 11 parkinsonian patients taking deprenyl with levodopa and benserazide for up to 4 years, 6 patients (55 %) showed moderate and 5 patients (45 %) minimal improvement initially. The improvement in response fluctuations was maintained during the follow-up period, although there was a clear decline in the degree of improvement. The addition of deprenyl to levodopa treatment also caused a further improvement in parkinsonian disability, which, however, decreased during the treatment period. Deprenyl appears to be a useful adjuvant to levodopa in patients with daily fluctuations in disability.     

Impact of deprenyl and tocopherol treatment on Parkinson's disease in DATATOP patients requiring levodopa

The Deprenyl and Tocopherol Antioxidant Therapy of Parkinsonism (DATATOP) trial was designed to test outcomes from treatment with 10 mg of deprenyl and/or 2,000 mg of tocopherollday in 800 untreated patients with Parkinson's disease. The need of subjects for symptomatic treatment with levodopa and the conversion of all subjects to open-label deprenyl made it possible to study the long-term effect of early deprenyl and tocopherol treatment on the later development of levodopa-associated side effects. The rate of developing these side effects did not differ among the original treatment groups (early versus late deprenyl and tocopherol versus nontocopherol). About 50% of subjects developed “wearing off,” 30% dyskinesias, and 25% “freezing” in each group. At the end of the study, the groups were similarly disabled on the Hoehn-Yahr, Schwab-England, and Unified Parkinsonapos;s Disease Rating scales and took similar amounts of levodopa. Young subjects were more likely to develop wearing off, women to develop dyskinesias, and older subjects with rapidly progressive disease to develop freezing. We conclude that prior treatment with deprenyl or tocopherol did not reduce the occurrence of subsequent levodopa-associated adverse effects in this population.