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.     

Comparison between lergotrile and bromocriptine in parkinsonism

The therapeutic and adverse effects of two ergot derivatives, bromocriptine and lergotrile, were compared in idiopathic parkinsonism. At both low (50 mg daily) and high (150 mg daily) dosage there was a similar but not identical profile of response. Initially, lergotrile tended to induce more severe but always transient hypotension. At higher doses, bromocriptine caused more dyskinesia. Neurological deficits improved with increasing doses up to an average daily level of 80 to 150 mg of ergot derivatives combined with levodopa, 450 to 1,150 mg, and carbidopa, 45 to 115 mg. However, efficacy often declined at the highest doses of antiparkinsonian agents. Adverse effects caused by ergot derivatives are more common with dosages greater than 100 mg per day. In general, the best overall therapeutic results with bromocriptine and lergotrile were obtained in the dose range of 50 to 100 mg daily for each. It is concluded that bromocriptine and lergotrile are similar in their therapeutic properties and that both are comparable in efficacy to levodopa plus carbidopa (though optimal results are commonly obtained by combining submaximal doses of levodopa with ergot derivatives). The role for each drug in the treatment of parkinsonism is likely to be determined by factors such as cost (bromocriptine) and hepatotoxicity (lergotrile).     

Amantadine for levodopa resistant parkinsonism

A 65-year-old woman with stigmata of Parkinsonism was resistant to therapy with levodopa, bromocriptine and anticholinergics. However, administration of amantadine (Symmetrel), (200 mg/day) produced significant improvement in her motor disability as well as in her mental status. The mechanisms of amantadine's therapeutic effects in this unusual case are discussed.     

Chemotherapy-induced parkinsonism responsive to levodopa: an underrecognized entity.

Parkinsonism is a rare neurological complication of cancer treatment. Although individual case reports of this syndrome have been reported, the clinical features and prevalence of this syndrome are unknown. We present 3 patients, encountered over 6 months at one institution, who developed parkinsonism after treatment with various chemotherapeutic agents. Parkinsonism was severe in 2 patients, affecting postural reflexes, speech, and swallowing. All 3 patients responded dramatically to treatment with levodopa, and parkinsonism spontaneously improved or remitted over months. This unusual complication of cancer therapy is treatable and may be underappreciated.     

Mesulergine and bromocriptine in long-term treatment of advanced parkinsonism

Summary 24 levodopa pretreated patients with advanced parkinsonism were splitted into two equal groups receiving mesulergine or bromocriptine respectively as an adjuvant therapy. The trial was carried out under double blind conditions the first three months and then continued as an open trial for one year. Clinical benefit was similar in both groups with minor differences in regard to single symptoms. While bromocriptine showed a beginning decline in efficacy after one year, mesulergine showed no decline. The mean mesulergine-dose, necessary to achieve good clinical improvement, was about half of bromocriptine. Side-effects were similar, except orthostatic hypotension requiring vasopressor medication, which was less frequent in mesulergine treated patients. This advantage of mesulergine might be explained by its special pharmacological pattern with biphasic action on dopaminergic receptors.     

The role of bromocriptine in the treatment of parkinsonism

Fifty-three patients with parkinsonism, either with intractable symptoms despite optimum-dosage levodopa therapy or with adverse effects from levodopa limiting its usefulness, were treated with bromocriptine, with gradually increasing doses until benefit or adverse effect was encountered. All were initially maintained on optimal levodopa therapy. Improvement was seen in 26 patients, of whom 19 (36 percent of the total 53 patients) had sustained improvement. Effective doses of bromocriptine ranged from 5 to 90 mg per day. Improvement occurred in all categories of clinical problems, including patients who lost some benefit from chronic levodopa therapy as well as those with adverse effects from levodopa. A high incidence (70 percent) of adverse effects of bromocriptine limited the usefulness of this drug. Since one cannot predict which patients might benefit from bromocriptine, this drug is worth a trial in patients not doing well on levodopa therapy if other means to improve their condition are not successful.     

Four-year treatment of patients with parkinsonism using amantadine alone or with levodopa.

Half of 94 parkinsonian patients improved on amantadine therapy during acute double-blind trials. In a four-year follow-up, amantadine given alone or added to a stable dose of levodopa had its greatest effect in the first month and helped few patients after six months. Levodopa either alone or added to a stable dose of amantadine had a beneficial effect lasting three years or more. The side-effects of edema and livido reticularis occurred twice as often in women. Confusion and hallucinations appeared sooner on a regimen of 300 mg of amantadine a day, but the ultimate incidence was the same on 200 mg a day. Withdrawal effects from amantadine are no less frequent or serious than from other antiparkinson medications and are not evidence that amantadine is still helping the patient. Considering the years of exposure, the morbidity and mortality do not indicate any risks peculiar to amantadine. Our mortality in all groups combined was 2.4 times that of the age- and sex-matched United States population.     

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.     

Akinetic mutism from recurrent hydrocephalus: successful treatment with levodopa, bromocriptine and trihexyphenidyl

A case of akinetic mutism was reported with reference to a marked improvement by levodopa, bromocriptine and trihexyphenidyl. A 39-year-old male, first seen on February 2, 1981, had an occipitalgia, accompanied by nausea and vomiting. For several months before this consultation, the patient had suffered from asthenopia. Brain CT scan and cerebral angiogram demonstrated internal hydrocephalus due to aqueduct stenosis of unknown etiology. After a ventriculoperitoneal shunt operation on February 20, 1981, he completely recovered. Two years and a half after the shunt insertion he had no difficulty in his daily life. He reentered the hospital on December 21, 1983, because of personality change, mental deterioration and bradykinesia. Brain CT scan showed recurrent hydrocephalus resulting from shunt blockage. Following the shunt revision, hydrocephalus was resolved. Nevertheless, the patient did not return to his previous state. And he became bed-ridden, incontinent of urine, and unable to take fluids or foods, following which he went into a state of akinetic mutism. Other neurological findings were as follows: upward gaze palsy, impaired convergence, convergence nystagmus, plastic rigidity of neck and all four limbs, and diffuse hyperreflexia with right Babinski's sign. Abnormal involuntary movement was not seen. On March 27, 1984, levodopa therapy was instituted and on April 2, trihexyphenidyl was combined with levodopa. Shortly after administration of levodopa and trihexyphenidyl, akinetic mutism began to improve, but upward gaze palsy was not affected. He began to speak and could walk unassisted by the end of July.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of the effects of bromocriptine and levodopa in Parkinson''s disease.

The effects of bromocriptine and levodopa were compared in a blind trial in 18 patients with Parkinson's disease. Optimal doses of the two drugs were given in identical capsules: there was no significant difference between the therapeutic effects. There were wide individual differences in response to the two drugs. Side effects were more common with bromocriptine because of side effects.     

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.     

Duodenal and gastric delivery of levodopa in parkinsonism

To clarify the influence of gastric emptying on levodopa-related motor fluctuations in Parkinson's disease, we assessed mobility and plasma levodopa concentrations in 10 patients during five modes of levodopa administration: (1) standard intermittent oral (SIO), (2) intermittent duodenal (ID), (3) continuous duodenal infusion (CDI), (4) continuous gastric infusion (CGI), and (5) controlled-release Sinemet (CR-4). The rank order from greatest to least for both percentage of time "on" and average mobility score was CDI, CGI, ID, CR-4, and SIO. The rank order for variance of means, a measure of fluctuation, from least to greatest for mobility was CDI, CGI, CR-4, ID, SIO, and for plasma levodopa concentrations was CDI, CGI, ID, SIO, and CR-4. The results demonstrate that it is possible to produce very steady plasma concentrations of levodopa with a corresponding reduction in motor fluctuations by continuous intraduodenal administration of the drug. This mode of delivery is an ideal model for the development of optimal continuous-release preparations of levodopa. Other enteral routes have produced a more variable plasma levodopa concentration and clinical response.     

Long-term duodenal infusion of levodopa for motor fluctuations in parkinsonism

We report the long-term clinical responses of 2 parkinsonian patients with severe "on-off" phenomena who have been receiving continuous duodenal levodopa (LD) infusions. The rate of LD infusion needed to keep the patients just "on" declined gradually during the initial 60 days of infusion and then remained constant. Total LD intake declined rapidly during the first several days and gradually for another 60 days, after which it remained stable. Motor fluctuations virtually disappeared in both patients during the time of the day when the pump was in use. This was accompanied by a decline in the plasma LD concentration needed to just maintain the "on" stage in one patient.     

Ropinirole as an adjunct to levodopa in the treatment of Parkinson's disease: a 16-week bromocriptine controlled study

Background: and objectives Ropinirole is a non-ergoline, selective dopamine D₂ agonist. The aim of this study was to evaluate the efficacy and safety of ropinirole as an adjunct to levodopa in the treatment of Parkinson's disease (PD) complicated by motor fluctuations. Methods: A total of 76 patients with PD (Hoehn and Yahr stage II to IV) were included in this trial. Each patient was randomly allocated to receive either ropinirole (n = 37) or bromocriptine (n = 39) as an adjunct to levodopa over a 16-week period. Ropinirole and bromocriptine were titrated for optimal efficacy and tolerability. This optimal dose was then maintained for the rest of the study. Response rate was defined as the percentage of patients who achieved at least a 20 % reduction in levodopa dose. Clinical status was also assessed using the Unified Parkinson's Disease Rating Scale (UPDRS), Clinical Global Impression (CGI), and reduction in time spent ‘off’. Results: Ropinirole produced a significantly greater response rate than bromocriptine (odds ratio 2.995, 95 % C. I. (1.157, 7.751) p < 0.05). There was also a statistically significant difference between the groups in the proportion of patients who were ‘improved’ on the CGI improvement scale (91.9 % for ropinirole, 74.3 % for bromocriptine, p = 0.046). Other measures, including at least a 20 % improvement in the UPDRS motor score (70 % for ropinirole and 63.3 % for bromocriptine), and a 20 % reduction in ‘off’ duration (81 % for ropinirole and 52.4 % for bromocriptine) showed a trend in favour of ropinirole. There was no significant difference between the two groups in the overall incidence of adverse effects (ropinirole, 59.5 %; bromocriptine, 59 %). In each group, the most common side-effects were dizziness, dyskinesia and nausea/vomiting. No patients were withdrawn from the study because of side-effects. Conclusion: Ropinirole was found to be safe and well-tolerated. Ropinirole as an adjunct to levodopa in the treatment of PD with motor fluctuation was associated with more significant reduction of levodopa dose and, on one form of analysis, with significantly greater improvement in CGI ratings than bromocriptine. On the other efficacy measures the two drugs were comparable. Received: 4 September 2001, Received in revised form: 8 May 2002, Accepted: 31 July 2002 This study was supported by SmithKline Beecham Korea and presented at the XIII International Congress on Parkinson's Disease, Vancouver, Canada, July 24–28, 1999. Correspondence to Joo-Hyuk Im, MD     

The influence of bromocriptine on the pharmacokinetics of levodopa in Parkinson's disease.

Several hypotheses have explained the beneficial effect of adding bromocriptine (BR) to levodopa (LD) in Parkinson's disease (PD) by interaction at the striatal level. In the present study we show the influence of BR on plasma LD values in an acute loading experiment (125 mg LD + 12.5 mg carbidopa [DCI] given alone and together with 2.5 mg BR at 0 time; 4 h observation). On the basis of this influence we have been able to differentiate between three groups of patients: (a) in six patients (five of them with frequent off episodes) LD values were significantly lower (p less than 0.05) when both drugs were given together (area under the curve [AUC] +/- SE 2.10 +/- 0.42 micrograms/ml/h vs. 4.96 +/- 1.10 micrograms/ml/h); (b) in eight patients (one with frequent akinesia) LD levels were significantly higher (p less than 0.003) when both drugs were given together (AUC +/- SE 4.05 +/- 0.51 micrograms/ml/h vs. 1.94 +/- 0.19 micrograms/ml/h); (c) in six patients (without motor fluctuations) no difference in LD levels was noted (AUC +/- SE 3.91 + 0.62 micrograms/ml/h vs. 3.81 +/- 0.70 micrograms/ml/h). The clinical evaluation (Webster scale) did not show substantial differences, except for increased dyskinesia, which correlated with higher LD levels. In summary, we suggest that the diminution of motor fluctuations and the occurrence of dyskinesias when BR is added to LD may stem from changes in LD plasma levels. These findings would be taken into consideration in the interpretation of therapeutic response fluctuations under combined treatment.     

Duodenal delivery of levodopa for on-off fluctuations in parkinsonism: preliminary observations

The pathogenesis of on-off motor fluctuations in parkinsonism remains incompletely understood, but slowed or erratic gastric emptying of orally administered levodopa may be involved. In 3 patients with resistant on-off fluctuations, direct duodenal continuous infusion of levodopa via a nasoduodenal tube resulted in a heightened therapeutic effect, including a reduction in motor fluctuations. In 1 of these patients, continuous duodenal levodopa infusion produced greater benefit than did intermittent duodenal levodopa administration. Direct duodenal delivery of levodopa lessens the problems with gastric emptying and may be suitable for long-term therapy in selected patients with resistant on-off motor fluctuations.