Bromocriptine in Parkinsonism: long-term treatment, dose response, and comparison with levodopa.

Thirty-seven patients with Parkinsonism were treated with bromocriptine 2.5-300 mg daily. Bromocriptine, alone or combined with levodopa, caused a 20-30% reduction in disability scores in 11 patients treated for one year. Tolerance did not develop during this period. Bromocriptine treatment was not of value in six patients who had previously not responded or who had lost their response to levodopa. However, in four of five patients with response swings on levodopa due to rapid changes in plasma dopa levels, the addition of bromocriptine caused a more stable response. Dose response curves to bromocriptine 12.5, 25, 50, and 100 mg and to levodopa 250, 500, 1000, and 2000 mg were studied in seven patients. Levodopa 2 g had a greater therapeutic effect and caused a greater rise in plasma growth hormone concentration than bromocriptine 100 mg. Levodopa caused emesis more commonly and hallucinations less commonly than bromocriptine. Bromocriptine appears to be a less potent stimulant than dopamine, and has both pre- and post-synaptic effects. Metoclopramide 60 mg oral was given 30 minutes before bromocriptine or levodopa to establish whether this caused dopamine-receptor blockade. Metoclopramide acted as a competitive antagonist to the anti-Parkinsonism and growth hormone effect of both drugs and in individual cases prevented emesis and hallucinations. The fall in blood pressure due to bromocriptine or levodopa was not antagonised by metoclopramide. Central and peripheral vascular dopamine receptors may be different in nature.     

Low-dose bromocriptine therapy in severe Parkinson's disease

We present an interim report of an ongoing, single-blind study of the effectiveness and safety of bromocriptine mesylate (Parlodel) in 15 patients, 14 of whom had severe idiopathic Parkinson's disease (Stages 4 and 5 on the Hoehn and Yahr Scale). The patients had never received levodopa, amantadine, or bromocriptine. Gradually increasing doses of bromocriptine were assessed: Initial daily dosage was 1.25 mg, with weekly increments of 1.25 mg/day until either the clinical response was satisfactory or a maximum of 15 mg/day was reached. The patients were on no other antiparkinsonian agents, except trihexyphenidyl HCl (Artane). Response to treatment was scored on the Columbia Scale. The patients discussed in this report had been in the study for varying times, ranging from 1 month to 3 years. Only one patient who entered this study dropped out because his response to bromocriptine was unsatisfactory; he had taken the drug for 2 weeks. No serious adverse reactions were noted with the gradually increasing dosage regimen. Response on the whole was very satisfactory; patients improved by at least two stages on the Hoehn and Yahr Scale. Improvement began within 48 h of onset of treatment with 1.25 mg daily. The preliminary results of this study indicate that low-dose bromocriptine as a first-line drug in severe Parkinson's disease is definitely warranted.     

Bromocriptine: long-term low-dose therapy in Parkinson's disease

Low-dose bromocriptine therapy (average dose 14.5 mg/day at 2 years) produced significant improvement in 25 of 39 parkinsonian patients. Bradykinesia was less in de novo subjects; tremor and rigidity improved most in the levodopa subjects. Five of six patients improved after a low-dose bromocriptine drug "holiday." After the addition of bromocriptine any reductions in levodopa dosage were small, with repeated cuts made gradually over months preventing the deterioration commonly seen with larger sudden reductions in levodopa dosage. Five patients withdrew because of intolerable adverse effects, two because of worsening response. Adverse effects were mild and generally dose dependent, and in some patients they disappeared without reduction in continuing bromocriptine therapy. Eighty percent of those who tolerated bromocriptine maintained response over 2 years. Bromocriptine did not induce dyskinesia, the wearing-off response, or the on-off phenomenon in de novo subjects and was used as a first choice drug in these parkinsonian patients. Best results were obtained from a combination of bromocriptine and levodopa.     

Comparison of bromocriptine and levodopa as first line treatment of Parkinson's disease: results of a 3-year prospective randomized study

The long term effects of a first line treatment with levodopa or bromocriptine were compared in 36 previously untreated patients with Parkinson's disease in a prospective randomized trial: 18 patients were treated with levodopa alone (mean dose: 485 +/- 71 mg daily) whereas 18 others received bromocriptine alone (mean dose: 55 +/- 6 mg daily) during 36 +/- 3 and 31 +/- 3 months respectively. We observed a similar decrease in the Columbia rating scale but the nature of long term side effects was different in the two groups: patients on levodopa developed peak-dose dyskinesias (5 cases), wearing off akinesia (1 case) and on-off effects (1 case). Under bromocriptine treatment, 2 patients developed severe psychosis whereas one suffered from primary lack of drug effectiveness and 5 others from late decrease of drug effectiveness. These results suggest the potential value of relatively high doses of D2 dopamine agonists (such as bromocriptine) in the first line treatment of Parkinson's disease: however, their use can be limited by their decrease of effectiveness after several years and/or the occurrence of severe neuropsychiatric side-effects.     

Low-dose bromocriptine in the early phases of Parkinson's disease

The effect of bromocriptine at doses up to 20 mg/day was studied in a single-blind format with a placebo phase in 15 Parkinson's disease patients with mild-to-moderate disability who had not been previously treated with levodopa. For the 11 patients who completed the 9 month trial, both Northwestern University Disability Scale and Columbia University Rating Scale scores were significantly reduced during bromocriptine therapy, when compared with either baseline or placebo scores. Two patients improved greater than 50% and had no side effects. Transient side effects appeared in four patients. Bromocriptine at doses of 20 mg/day or below may yield effective symptomatic improvement in de novo parkinsonism and may be considered as the initial treatment in young parkinsonian patients with only mild-to-moderate disability.     

Low dosages of bromocriptine added to levodopa in Parkinson's disease

Thirty-six patients with Parkinson's disease, on levodopa, were admitted to a double-blind, parallel, 40-week study of adjunct bromocriptine in dosages increased by 2.5 mg every 4 weeks. A 37% improvement of the mean neurologic deficit score was obtained at the maximal daily dosage of 20 mg. Improvement was greatest in patients with mild disease. The wearing-off effect, off-dose abnormal involuntary movements, and leg pains, associated with levodopa, improved in over 70% of patients at an average dosage of 13 mg. Only 15% of patients had adverse reactions severe enough to necessitate discontinuance of the drug. Abnormalities of mental state were less severe than expected, but two patients had exacerbations of angina pectoris.     

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.     

Bromocriptine in Parkinson disease: further studies

Bromocriptine was administered to 66 patients with advanced Parkinson disease (PD) and increasing disability despite optimal treatment with levodopa/carbidopa (Sinemet). Forty-five patients tolerated at least 25 mg per day of bromocriptine (the "adequately treated" group) in addition to Sinemet and had significantly decreased rigidity, tremor, bradykinesia, gait disturbance, and total score, but increased involuntary movements. Twenty-five of these 45 patients improved by at least one stage. Among the 45 patients, 27 had "on-off" effects, and in 19 the "on-off" effects decreased on bromocriptine. The mean dose of bromocriptine in adequately treated patients las 47 mg, permitting a 10 percent reduction in the dose of levodopa. Twelve adequately treated patients received bromocriptine for at least 1 year, and 8 continued for longer than this. Bromocriptine was discontinued in 29 of 66 patients because of adverse effects, including mental changes (14 patients) and involuntary movements (9 patients). All adverse effects were reversible. Despite adverse effects, expense, and scarcity, bromocriptine, when added to levodopa, is useful in patients with advanced disease who no longer respond satisfactorily to levodopa, and for whom no other treatment is available.     

Long-term bromocriptine treatment of de novo patients with Parkinson''s disease. A seven-year follow-up

Thirty-nine de novo patients with Parkinson's disease were treated with bromocriptine alone and followed on average for 5.9 years. Fifteen of the 39 patients did not complete the first year of observation, 12 of them because of drug intolerance. The symptomatology was tolerated well by other 24 for the first 2 years treatment. During the third year of follow-up levodopa treatment had to be instituted because of loss of response to bromocriptine. The number of fluctuations in disability was smaller in the patients whose symptomatology was controlled by bromocriptine monotherapy than in those requiring levodopa, either alone or combined with bromocriptine.     

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.     

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.     

A double-blind crossover, placebo-controlled study of the adenosine A2A antagonist theophylline in Parkinson's disease

Blockade of the adenosine A2A receptor potentiates the effects of levodopa in experimental animals and may offer a novel nondopaminergic target for drug therapy in Parkinson's disease (PD). Open-label trials suggest that the nonspecific adenosine antagonist theophylline improves parkinsonian symptoms and increases ON time in advanced patients with PD. In a double-blind, crossover, placebo-controlled trial, the authors investigated the ability of stable plasma levels of theophylline (between 10-20 microg/mL after 15 days of treatment) to modulate the long-duration response and the short-duration response of levodopa in 10 patients with PD. Although theophylline induced a longer duration of the effect of levodopa in all Unified Parkinson's Disease Rating Scale variables considered, including dyskinesias, maximal levodopa-induced improvement and the duration of the effect of levodopa did not differ significantly from placebo. Only the secondary variable "akinesia" showed a statistical tendency to a more prolonged beneficial response with theophylline during an acute levodopa test (short-duration response), and tremor worsened with theophylline during levodopa withdrawal (long-duration response). No differences were observed during the subacute course of study medication added to levodopa. During this exploratory study, the effects of theophylline were not strong enough to potentiate clearly the antiparkinsonian action of levodopa or to increase ON time in patients with advanced PD.     

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.     

Sustained-release Madopar HBS® compared with standard Madopar® in the long-term treatment of de novo parkinsonian patients

In this Danish-Norwegian randomized double-blind parallel-group multicentre study, we compared the therapeutic response of slow-release Madopar HBS® to standard Madopar® in 134 de novo patients with idiopathic Parkinson's disease during a 5-year period. The drugs were dosed according to the individual need of the patients. The Webster, NUDS, UPDRS and Hoehn & Yahr scales were used for evaluation of symptoms. Addition of a morning dose of standard Madopar 62.5 mg was allowed after 6 months. Bromocriptine could be administered but not Selegiline. Sixty-five patients got Madopar HBS and 69 standard Madopar. Surprisingly, no differences were found as to the mean daily levodopa dose, the mean number of daily doses or the use of and doses of bromocriptine. Unexpectedly, we found a trend towards a more frequent use of a morning dose of standard Madopar in the group treated with the standard formulation. No differences were observed in the occurrence of motor fluctuations or dyskinesia, the incidence of which was relatively low. Sustained-release Madopar (HBS) thus proved to be as effective as standard Madopar in the long-term treatment of de novo parkinsonian patients, but the drug showed no advantage in postponing or reducing the long-term levodopa treatment problems.     

Amphetamines in the treatment of Parkinson's disease.

Twenty-two patients with Parkinsonism were treated with levoamphetamine and 12 of these with dextroamphetamine. Levoamphetamine resulted in a significant improvement in disability from Parkinsonism, although the reduction in total disability, tremor, akinesia, and rigidity scores was slight (ca 20 percent). Dextroamphetamine in lower dosage also reduced disability by some 17 percent. The most disabled patients, including those also on levodopa, showed the greatest response to amphetamines. Previously, amphetamines have been reported to be a selective treatment for the oculogyric crises of post-encephalitic Parkinsonism. Amphetamines are thought to cause the release of catecholamines from central neurones. Their action in Parkinson's disease may be limited because of pre-existing striatal dopamine deficiency. Side-effects of amphetamines, anorexia, and CNS stimulation are different from those caused by levodopa in patients with Parkinson's disease.     

Therapeutic experience with the new dopamine agonist CU 32-085 in advanced Parkinson's disease

Twenty patients with advanced progressing Parkinson's disease have been treated with the 8-alpha-ergoline CU 32-085 in combination therapy for 3 months. With a mean daily dose of 12.65 mg, CU 32-085 together with levodopa plus a decarboxylase inhibitor produced a significant reduction in akinesia, rigor and tremor. Adverse reactions were rare and mild; in one case the drug was discontinued because of dyskinetic movements. Many of the pre-existing side effects were reduced or eliminated, particularly the involuntary movements and the levodopa response swings. The compound was considered useful in the treatment of advanced, progressing Parkinson's disease.     

Three-year observation of mesulergine (CU 32-085) in advanced and newly treated parkinsonism

Summary In 15 patients (8 men, 7 women), aged 44–81 years, with idiopathic parkinsonism, the effects of mesulergine (CU 32-085) were observed for up to 3 years. Of these patients, four had been without previous levodopa treatment, five had been on levodopa/decarboxylase inhibitor for 6.4 years and six patients had been on levodopa/decarboxylase inhibitor and bromocriptine for a period of 7.5 years. Mesulergine proved to be effective in all three groups of patients and for each main symptom of the disease. Rigidity and tremor showed a better response than akinesia. A decline in efficacy could be observed after 18 months of treatment. By increasing the levodopa dosage, the worsening of the symptomatology could be reduced again and after 3 years patients were slightly better off than before the introduction of mesulergine. Fine motor performance showed a longer-lasting improvement than walking, which was affected by an increase of freezing. Mesulergine was not fully sufficient when given in monotherapy and the levodopa saving effect was only temporary. Parallel with the decline in the therapeutic response as assessed by the rating scales, there was a worsening in the on/off symptomatology. The on/off symptoms, evaluated by patients themselves, had shown very small or no improvement at the beginning of mesulergine administration, contrasting with the findings reflected in the assessment scales. The most frequent side-effects were hallucinations and dyskinesias. Orthostatic hypotension did not prove a problem. Dyskinesias were not seen during monotherapy with mesulergine in de novo patients.     

Pergolide in late-stage Parkinson disease

Twenty-six patients with late-stage Parkinson disease were given 0.4 to 15 mg of pergolide mesylate daily in addition to, or as replacement for, levodopa or bromocriptine therapy. Despite treatment with individually determined optimum doses of levodopa, bromocriptine, and anticholinergics, they had shown response failure or fluctuating response. Forty percent (11 patients) were unable to tolerate pergolide. Nausea and vomiting, somnolence, and psychiatric disturbances were the most frequent side effects. Eleven of the remaining patients improved on pergolide, 2 were unchanged, and 2 were slightly worse. Among the patients who benefited, pergolide improved dose-related response fluctuations more than non-dose-related fluctuations, with a reduction in number and duration of “off” periods and improvement in quality of sleep and early morning akinesia but little change in freezing episodes. Despite treatment failure in many cases, pergolide is at present the best available drug for specific latestage management problems.     

Bromocriptine blood levels after the concomitant administration of levodopa, amantadine and biperiden in Parkinson''s disease

We recently demonstrated that when different drugs (mainly used for the treatment of Parkinson's disease) are administered in combination they interfere with the availability of bromocriptine in the brain of rats (striatum and hypothalamus). In the present study performed with parkinsonian patients, we measured plasma levels of bromocriptine (RIA) over 4 h after giving orally 5 mg bromocriptine alone; together with levodopa 250 mg plus 25 mg DCI (10 patients); with 100 mg amantadine HCl (5 patients) and with biperiden 5 mg (5 patients). Amantadine and biperiden did not interfere with the pharmacokinetics of bromocriptine. However, levodopa significantly diminished plasma levels (a mean increment of 1.78 mg +/- 0.30 vs 0.92 +/- 0.18 mg/ml). We postulate that levodopa may interfere with the metabolism of bromocriptine in the liver. Although we did not observe substantial clinical differences among the patients (Webster scale), this study supports our previous findings and suggests that one of the advantages of combined treatment may result from a modification of the plasma levels of bromocriptine by levodopa. A "smoothing" of the plasma bromocriptine curve possibly avoids sudden oscillations of the drug availability and enables a more "stable" penetrability of the medication into the central nervous system.     

Antiparkinsonian activity of CY 208-243, a partial D-1 dopamine receptor agonist, in MPTP-treated marmosets and patients with Parkinson's disease

The effect of stimulation of cerebral dopamine D-1 receptors by CY 208-243 on motor disability was tested in MPTP-treated parkinsonian marmosets and patients with Parkinson's disease. CY 208-243 (0.5-1.25 mg/kg s.c.) produced a dose-related reversal of akinesia and rigidity in the marmosets, lasting some 2 h. Single morning doses of CY 208-243 (5-40 mg) were compared with the usual morning dose of levodopa in eight patients with Parkinson's disease on long-term levodopa therapy who had developed motor fluctuations from immobility with akinesia and rigidity (off) to mobility often with dyskinesias (on). CY 208-243 alone was capable of switching such patients from off to on; five of the eight patients responded to the highest dose (40 mg), sometimes with dyskinesias. The response to CY 208-243 was comparable to that produced by levodopa in these cases. Drugs designed to stimulate both dopamine D1 and D2 receptors in the brain may improve the therapy of Parkinson's disease.