Early combination of bromocriptine and levodopa in the treatment of Parkinson's disease: a 5-year follow-up

Compared with levodopa, long-term bromocriptine treatment of parkinsonian patients for 5 years resulted in fewer fluctuations of disability and peak-dose dyskinesias, but also less improvement in parkinsonian disability. Combination of low-dose bromocriptine and levodopa resulted in a therapeutic response equal to that of levodopa alone but with fewer end-of-dose disturbances and peak-dose dyskinesias. I believe that treatment should begin promptly with a low dose of levodopa, combined with a dopamine agonist such as bromocriptine.     

Combination therapy with lisuride and L-dopa in the early stages of Parkinson's disease decreases and delays the development of motor fluctuations. Long-term study over 10 years in comparison with L-dopa monotherapy

A randomized, prospective study was carried out in order to investigate the efficacy of a dopamine agonist, lisuride, alone or in combination with levodopa, to minimize or postpone the development of motor fluctuations, compared with levodopa alone during 10 years' treatment of 90 patients with early Parkinson's disease. Only a small, and with time gradually decreasing number of patients obtained enough therapeutic benefit during long-term treatment with lisuride alone. Consequently, levodopa had to be added to the patients' regimen. During combined treatment with lisuride and levodopa the daily dose of levodopa needed for optimal therapeutic response was significantly lower than when using levodopa alone. The addition of levodopa to the lisuride regimen either from the beginning or at any time during long-term treatment according to clinical need, resulted in a therapeutic response in parkinsonian disability equal to that achieved with levodopa alone, but significantly decreased and postponed the development of motor fluctuations, end-of-dose failure and dyskinesias. Severe dopaminergic adverse events leading to withdrawal of the treatment were more frequent during treatment with lisuride and levodopa than with levodopa alone, but the lower mortality rate did not reach the level of statistical significance. In conclusion, according to the results obtained, it seems reasonable to consider a treatment strategy in early Parkinson's disease using a dopamine agonist, like lisuride, as the primary treatment and to delay the addition of levodopa until parkinsonian disability cannot be adequately controlled by a dopamine agonist.     

Combination of a dopamine agonist, MAO-B inhibitor and levodopa — a new strategy in the treatment of early Parkinson's disease

Abstract– During 3 years'treatment of de novo parkinsonian patients with lisuride in combination with selegiline and levodopa the optimal therapeutic dose of levodopa was significantly lower than that when given alone or together with lisuride. The improvement in parkinsonian disability was equal in all these patient groups, but treatment with an early combination of lisuride and levodopa without or with selegiline resulted in significantly and equally reduced end-of-dose disturbances and dyskinesias than treatment with levodopa alone. This finding, together with the possible retardation of the progression of the disease with selegiline suggests that dopaminergic treatment in early Parkinson's disease should be initiated using a dopamine agonist such as lisuride in combination with selegiline and levodopa.     

Combined bromocriptine-levodopa therapy early in Parkinson's disease

Compared with levodopa, treatment of parkinsonism for 3 years with bromocriptine alone resulted in less fluctuation and peak-dose dyskinesia, but also less improvement in parkinsonian disability. Only a few of the 76 patients had long-term benefit on chronic bromocriptine therapy. However, combined bromocriptine and levodopa therapy had a therapeutic response equal to that of levodopa alone, with fewer fluctuations and peak-dose dyskinesias. Treatment should begin with a low dose of levodopa and a dopamine agonist.     

Lisuride, a dopamine agonist in the treatment of early Parkinson's disease

A randomized, prospective trial in 90 de novo parkinsonian patients showed that 4 years' treatment with lisuride resulted in significantly fewer end-of-dose disturbances and peak-dose dyskinesias, but also less improvement in parkinsonian disability, than with levodopa. Early combination of lisuride and a low dose of levodopa, during a 4-year follow-up, resulted in a therapeutic response equal to that achieved with high-dose levodopa alone, but significantly fewer end-of-dose failures and dyskinesias. Thus it seems advisable that treatment should begin in the early phase of the disease with a dopamine agonist such as lisuride combined with a low dose of levodopa.     

New strategies in the treatment of early Parkinson's disease

Over recent years I have been studying whether dopamine agonist treatment alone, or in early combination with levodopa, might institute a better long-term treatment in Parkinson's disease than levodopa alone. Indeed, early combination of levodopa with bromocriptine, pergolide or lisuride has indicated that this kind of treatment results in better management of Parkinson's disease with fewer fluctuations in disability, especially end-of-dose disturbances and dyskinesias, than treatment with levodopa alone. Furthermore, similar results were obtained by using lisuride in combination with selegiline and levodopa. However, during long-term treatment the changes in parkinsonian disability were equal in all treatment groups with or without selegiline. Thus, the possible efficacy of selegiline in slowing down the progression of Parkinson's disease requires further investigations. As a new treatment strategy it appears advisable to initiate the dopaminergic treatment in early Parkinson's disease by using initially selegiline and a dopamine agonist and by adding levodopa when the therapeutic response is insuifficient. Another alternative would be to start with selegiline alone, then add a dopamine agonist and, finally, levodopa.     

Bromocriptine and lisuride in Parkinson disease

Lisuride was compared with bromocriptine in 25 parkinsonian patients in whom the response to levodopa had diminished; 19 had “wearing off,” “on-off” phenomena, or both. At the time bromocriptine was added to levodopa, the mean age of the patients was 62.7 years and mean disease duration was 8.9 years. Disability decreased by 34% in the on period and by 20% in the off period, and the number of hours the patients were on increased from 9.6 to 12.8. All these changes were significant (p ≤ 0.01 to 0.05). Bromocriptine, however, had to be discontinued in 11 patients because of adverse effects. In the remaining 14 patients, bromocriptine was eventually discontinued because of decreased efficacy. Mean dose of bromocriptine was 55 mg (range, 20 to 100 mg). At the time lisuride was added to levodopa the patients were older (65.4 years), had had the disease longer (11.4 years), and were more disabled. Nonetheless, disability decreased in the on period by 33% and in the off period by 17%, and the number of hours the patients were on increased from 3.9 to 8.9. All these changes were significant (p ≤ 0.01 to 0.05). The mean dose of lisuride was 2.8 mg (range, 0.6 to 5.0 mg). Lisuride was discontinued in 8 patients because of adverse effects. Both bromocriptine and lisuride are useful in managing patients with advanced Parkinson disease whose response to levodopa has diminished. While it is presently not possible to state which of the drugs is more effective, ultimately their usage will probably be determined by their relative cost.     

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.     

Brain dopamine receptor stimulation and the relief of parkinsonism: Relationship between bromocriptine and levodopa

The relationship between brain dopamine receptor stimulation by bromocriptine or levodopa and the relief of parkinsonism was studied in 24 patients with Parkinson disease. Bromocriptine, 30 mg daily for 20 weeks, elicited an improvement in the parkinsonian clinical features, but this was less than the subsequent improvement with levodopa and benserazide, 800 mg and 200 mg daily, respectively. There was a negative correlation between the pretreatment severity of the disease or changes in cerebrospinal fluid homovanillic acid (HVA) and improvement in parkinsonian disability during bromocriptine treatment. Furthermore, it was found that clinical improvement and HVA responses in the cerebrospinal fluid after dopamine receptor stimulation by bromocriptine may predict the clinical response to levodopa.     

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.     

Comparison of pergolide and bromocriptine therapy in parkinsonism

Twenty-four parkinsonian patients compared pergolide and bromocriptine therapy in a randomized double-blind, two-period crossover study. Both drugs were adjusted to an optimal balance between benefits and side effects. The mean daily dose and dose range for pergolide and bromocriptine were 3.3 mg (0.7 to 7.2) and 42.7 mg (5.8 to 87.5), respectively. Adjunctive medications, which for most patients included levodopa (plus carbidopa), were not altered during the study. A similar spectrum of clinical effects was found with both drugs and with lisuride, which was used to treat 13 of the patients in a previous study. Despite neurochemical differences in the antiparkinsonian ergots, their clinical utility is quite similar. We draw attention to hepatotoxicity and pleural reactions that may occur rarely with these drugs.     

Bromocryptine in levodopa response-losing parkinsonism. A double blind study.

23 patients with advanced Parkinson's disease were allocated in a double-blind study of bromocryptine. These patients had an insufficient or deteriorating response to levodopa treatment. The dosages of levodopa were optimal and stabilized 3 months prior to and during this 5-month study. The addition of bromocryptine in high doses (average daily dose 71 mg) induced a significant improvement in the total score of the Webster and the NUDS scales. The global assessment, both by the investigator and by the patients, also showed significant improvement. The efficacy of bromocryptine in these type of parkinsonian patients in a double-blind trial has not yet been established. The conclusion of this trial is that bromocryptine significantly increases the therapeutic effectiveness in these poorly levodopa responding parkinsonian patients.     

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.     

Lisuride in the treatment of Parkinsonism

Lisuride 1.2–4.8 mg daily was given to 10 patients with severe Parkinsonism for up to 9 months. All had been taking bromocriptine and eight had been taking levodopa combined with carbidopa. Total replacement of bromocriptine by lisuride was achieved in every case, but partial or total levodopa replacement was possible only in five patients. Lisuride 1 mg has approximately the same antiparkinsonian activity as bromocriptine 15 mg or levodopa 250–500 mg combined with carbidopa, but the duration of action of each dose is short, and gastro-intestinal and neuropsychiatric side effects are common. However, lisuride i.v. may be of considerable value in the emergency treatment of severe Parkinsonism.     

The use of lisuride, a potent dopamine and serotonin agonist, in the treatment of progressive supranuclear palsy.

Seven patients with progressive supranuclear palsy were treated with lisuride. Mean age was 62 years (range, 52 to 68 years), and duration of disease was 4.4 years (range, 1 to 7 years). All seven had been treated with levodopa/carbidopa and three with bromocriptine; four had, at one time, shown a partial response to levodopa. One patient had also shown a partial response to bromocriptine. Lisuride was used alone in four patients, and combined with levodopa/carbidopa in three patients. Mean dose of lisuride was 2.5 mg (range, 1.5 to 5.0 mg). Mean duration of treatment was 4 months (range, 1 to 10 months). While two patients showed a reduction in rigidity, one in tremor and two in bradykinesia, in only one of them was there an overall improvement. It is postulated that the relative lack of response to lisuride may be due to a loss of both the dopaminergic and serotonergic receptors in progressive supranuclear palsy.     

Therapeutic effect of lisuride in advanced Parkinson's disease

The therapeutic effects of lisuride hydrogen maleate, a central dopamine agonist, were examined in 15 patients with advanced Parkinson's disease no longer satisfactorily responding to levodopa. A significant improvement (p less than 0.01) in the total Parkinson's disease disability score was obtained by the addition of lisuride to levodopa therapy. The clinical assessment in the follow-up was performed with 2 different disability scales that yielded a more precise evaluation of the efficacy of lisuride, an efficacy that, as with other dopaminergic drugs, showed a slight decrease in time after a mean of 3 months. No important adverse effects were noticed. The only limitation of the use of lisuride was the occurrence of reversible psychic disturbances. It is concluded from this study that lisuride is a valuable tool in the management of advanced Parkinson's disease that allows for a reduction of the side effects of levodopa therapy in the long-term treatment of the disease.     

Effect of a slow release preparation of levodopa on Parkinson''s disease in combination with a peripheral decarboxylase inhibitor

Plasma concentrations of levodopa were determined after therapeutic oral levodopa-carbidopa doses. The wide fluctuations observed in plasma levodopa levels could be considerably reduced by the addition of a slow release levodopa preparation. This kind of combination medication was given to 15 parkinsonian patients, whose earlier therapy had proved inadequate. With the combination medication, levodopa-carbidopa, on an average 420 mg/42 mg combined with 950 mg of levodopa in slow release form, a statistically significant improvement in parkinsonian signs could be achieved without any worsening of the side effects. The results suggest that parkinsonian patients may tolerate much higher daily levodopa doses if the fluctuations in plasma levels of the drug can be diminished.     

High-dose treatment with pergolide in Parkinson's disease patients with motor fluctuations and dyskinesias

Motor complications arising after long-term treatment with levodopa remain one of the main challenges in the treatment of patients with Parkinson's disease (PD). Monotherapy with dopamine agonists may delay the onset of motor complications or reduce their severity when added to levodopa treatment. Here, we retrospectively analyzed data from 62 patients with advanced PD who presented with moderate to severe response fluctuations in whom we increased the dose of oral treatment with pergolide beyond 4.5mg daily. Patients had been treated with levodopa for 10.7+/-4.8 years. Pergolide was increased to 8.2+/-4.3 mg per day over a median titration period of 13.5 weeks. Mean daily dose of levodopa prior to pergolide high-dose treatment was 733+/-468 mg and decreased to 348+/-186 mg after pergolide titration. The duration of OFF times decreased from 7.3+/-3.8 to 1.7+/-0.9 h per day (p < 0.001) measured by patients' diaries. Dyskinesias, present for 5.0+/-3.3 h per day at baseline, were reduced to 1.4+/-0.8 h per day (p < 0.001) and the total daily duration of motor fluctuations (off-time duration plus dyskinesia duration) decreased from 10.5+/-7.0 to 2.8+/-2.2 h (p < 0.001). There was a significant improvement in parkinsonian symptoms (baseline to endpoint reduction of UPDRS III from a median of 36 to 8; p < 0.001). To reduce gastrointestinal side effects 23 patients required concomitant treatment with domperidone. Seven patients developed hallucinations during the titration period, six patients required treatment with clozapine. Our data indicate that increasing the dose of pergolide above 5mg per day can dramatically reduce the need for levodopa, motor fluctuations and severity of clinical symptoms. Controlled trials are needed to further substantiate the efficacy and safety of this treatment strategy.     

The L-dopa test in Parkinson's disease

Seventy parkinsonian patients (mean age: 59.6 +/- 1.2 years; duration of disease: 9 +/- 0.6 years) with severe fluctuations of disability under L-Dopa treatment received a single dose of L-Dopa (200 mg + benserazide, a peripheral decarboxylase inhibitor) after 24-72 h interruption of treatment. The delay and duration of action of a single dose of L-Dopa, and the percentage of improvement of the parkinsonian symptoms were 39 +/- 2 and 162 +/- 6 minutes, and 57 +/- 2 p. 100 respectively. Estimation of the difference between the basal parkinsonian score and the score during maximum clinical improvement under levodopa treatment, and the score under levodopa treatment may reflect the severity of dopaminergic and of non dopaminergic lesions in the brain respectively. Modification of the treatment to obtain continuous clinical improvement can be performed according to the delay and duration of action of a single dose of L-Dopa.     

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.