Comparing dopamine agonists in Parkinson's disease

Dopamine agonists are effective in the management of both advanced and early-stage Parkinson's disease. Unfortunately, randomized head-to-head comparative studies between the many different dopamine agonists now available are sparse. Indirect comparisons of dopamine agonists show that ergot derivatives, such as pergolide and cabergoline, are as effective as non-ergot derivatives, such as ropinirole and pramipexole, in ameliorating Parkinson's disease symptoms in patients in early or advanced stages of the condition. As far as safety and tolerability are concerned, no significant differences between dopamine agonists are found. However, some specific adverse events, such as somnolence and sleep attacks, seem less frequent in monotherapy studies with pergolide than in those with the non-ergot dopamine agonists; however, because of the lack of direct-comparison studies this cannot be proved conclusively. Randomized, controlled comparative studies between dopamine agonists are necessary to verify any possible differences in their effectiveness and tolerability in the treatment of Parkinson's disease.     

Rationale for dopamine agonist use as monotherapy in Parkinson's disease

Dopamine agonists are increasingly being used in the initial treatment of patients with de-novo Parkinson's disease because they provide symptom relief and a low risk of the dyskinesia frequently associated with levodopa. Evidence is also mounting in preclinical models that dopamine agonists protect dopaminergic neurons from the toxic effects of oxidative stress and the by-products of dopamine and L-dopa metabolism. Ergot derivatives, such as pergolide, induce minor side-effects and provide significant and sustained improvements in motor function in patients with early Parkinson's disease. Dopamine agonists also appear to reduce the loss of functional dopamine transporters when used early in the disease course, and these factors combine to build a case for the use of dopamine agonists in early-stage Parkinson's disease.     

Bromocriptine and CF 25-397 in the treatment of tardive dyskinesia

Dopamine agonist therapy using selected drugs at particular dosage levels has been found to have therapeutic benefit in certain dyskinetic syndromes. Two ergot derivatives with dopamine agonist properties were administered at relatively low doses to eight neuroleptic-free schizophrenic patients with tardive dyskinesia. Neither agent significantly improved dyskinetic symptoms; no symptoms worsened. Dopamine agonists likely vary in their selective activation of functionally distinct dopamine receptors.     

Ergoline and non-ergoline derivatives in the treatment of Parkinson’s disease

Journal of Neurology - There are a large variety of dopamine agonists available. Especially de novo patients are treated with dopamine agonists to avoid dyskinesia. Dopamine agonists can be...     

Acute complications of dopamine agonist treatment for macroprolactinoma – how uncommon?

Dopamine agonists are first line treatment for prolactinomas. This treatment can cause serious complications in patients with invasive macroprolactinomas. This study reviewed 195 patients attending the endocrine clinic and/or undergoing surgery for pituitary tumours at The Royal Melbourne Hospital in a seven-year period (1996-2002). Thirty three patients had macroprolactinoma (diameter >10 mm). Eleven of them were treated with dopamine agonist prior to surgery and four developed severe complications. This study suggests that the severe complications of dopamine agonist therapy may be higher than previously reported. All patients should be educated about these complications and their early recognition.     

The putative neuroprotective role of dopamine agonists in parkinson’s disease

Parkinson's disease is probably caused by a combination of genetic and environmental factors, which trigger a cascade of events that lead to the cell death of the dopamine-containing neurons of the substantia nigra pars compacta. These processes include oxidative stress, mitochondrial dysfunction, excitotoxicity with excess of nitric oxide formation, glial and inflammatory abnormalities and apoptosis. Dopamine agonists are chemical compounds that act directly on the dopamine receptors without any previous enzymatic biotransformation. Besides their symptomatic antiparkinsonian effect, these drugs may have neuroprotective properties in Parkinson's disease through different possible mechanisms: (a) stimulation of dopamine auoreceptors, reducing thereby dopamine turnover; (b) direct antioxidant effects; (c) reduction of excitotoxicity induced by excessive subthalamic nucleus firing; (d) inhibition of mitochondrial permeability; (e) induction of trophic factors. Dopamine agonists have already shown neuroprotective effects on dopaminergic cells against a variety of neurotoxins in several in vitro and in vivo studies. Clinical studies to detect changes in the progression of the underlying neurodegenerative process in patients with Parkinson's disease treated with dopamine agonists, by assessing the dopamine terminal function in the striatum by means of PET and SPECT techniques are under way.     

Progressive supranuclear palsy: clinical features and response to treatment in 16 patients

Among 415 patients with parkinsonism, 16 (3.9%) had findings of progressive supranuclear palsy (PSP). This report reviews the clinical features and response to drug therapy in those 16 patients. Anticholinergic drugs failed to benefit any of the 5 patients treated, while presynaptic dopaminergic drugs (Sinemet or amantadine) were beneficial in only 5 of 22 patient trials. Alternatively, dopamine agonists (bromocriptine and pergolide) caused improvement in 9 of 14 patient trials despite the fact that all but 1 of these patients had previously failed to respond to presynaptic dopaminergic drugs. Dopamine agonists such as bromocriptine and pergolide may be useful in some patients with PSP.     

Treatment of Parkinson's disease should begin with a dopamine agonist.

The occurrence of side effects with long-term levodopa therapy, such as fluctuations in motor performance or abnormal movements, led to a search for new antiparkinsonian drugs. Dopamine agonists include ergot derivatives such as bromocriptine, lisuride, pergolide, and cabergoline and other agents which do not possess the ergot structure such as pramipexole and ropinirole. They all are powerful stimulators of the D2 dopamine receptor which probably underlies their therapeutic effects. The clinical consequences of their binding to other dopamine receptor subtypes (D1 or D3) remains unknown. They are usually prescribed in combination with levodopa when late side effects begin to occur. This review summarizes the available pharmacologic and clinical data to support the early use of dopamine agonists in Parkinson's disease. Several strategies can be used, such as monotherapy or "early" or "late" combination with levodopa. Results of recent well-performed, modern clinical trials show that early use of the new dopamine agonists is able to effectively control the clinical symptoms for more than 3 years thereby offering the possibility of delaying the occurrence of levodopa-induced late motor side effects.     

Morphologic changes of prolactin-producing pituitary adenomas after short treatment with dopamine agonists

Treatment of patients with prolactin (PRL)-producing pituitary adenomas with dopamine agonists has proved successful for most cases. Dopamine agonists inhibit PRL secretion, suppress cell proliferation, and may induce apoptosis to adenoma cells. Dopamine agonists induce striking morphologic changes in the majority of treated PRL-producing adenomas. To date, these morphologic effects have been primarily described only after long-term treatment. To the best of our knowledge, no similar studies have investigated apoptotic alterations induced after short-term therapy. The purpose of this report is to describe the morphologic changes seen in PRL-producing adenomas after short-term dopamine agonist treatment. We present two cases of PRL-producing macroadenomas, both from male patients who received treatment with dopamine agonists, the first for 5 and the second for 8 days. In contrast to long-term treatment, no striking reduction of PRL immunoreactivity was noted. Slight stromal fibrosis was noted in case 1, which contained several cells all in late phase of apoptosis. In addition to typical apoptotic cells, numerous dark cells representing another common form of cell death were also noted. These novel findings represent characteristic features of short-term dopamine agonist treatment, which are not seen in long-term treatment.     

Dopamine agonist‐induced antecollis in Parkinson's disease

Few cases of dopamine agonist‐induced antecollis in Parkinson's disease (PD) have been reported. Literature review of 16 PD patients including our 3 cases with dopamine agonist‐induced antecollis showed predominance of (1) Japanese, (2) women, and (3) Hoehn‐Yahr stage of ≥3. We experienced three Japanese PD patients who subacutely exhibited antecollis following increased dopamine agonist dose that improved just after withdrawal of the agonist. One patient developed antecollis during increasing pramipexole dose in combination with cabergoline. Antecollis in another patient appeared during increasing pramipexole dose; it worsened after substituting pergolide for pramipexole, but improved after withdrawal of pergolide. Our cases indicate that there is no specific dopamine agonist causing antecollis, and it is possibly caused by a number of single dopamine agonists or a combination of them. Dopamine agonist‐induced antecollis should be considered when encountering antecollis in PD patients being treated with dopamine agonists and withdrawal of the agonist can improve symptoms. © 2009 Movement Disorder Society     

Dopamine autoreceptor agonists in the treatment of schizophrenia and major depression.

Dopamine autoreceptor agonists reduce the firing rate, synthesis, and release of dopamine in dopaminergic neurons by means of a negative feedback mechanism via stimulation of autoreceptors. Moreover, dopamine autoreceptor agonists are able to stimulate supersensitive but not normosensitive postsynaptic receptors. For dopamine autoreceptor agonists, therapeutic effects by readjustment of excessive or deficient dopaminergic function have been postulated for positive and negative schizophrenic symptomatology as well as for subtypes of depressive disorders. Investigations on the therapeutic effects of autoreceptor-nonselective dopamine agonists in schizophrenia or depression have yielded inconsistent results. In order to reduce the excess of central dopaminergic activity postulated by the dopamine hypothesis of schizophrenia, dopamine autoreceptor agonists have been tested in open clinical trials in positive schizophrenic symptomatology. However, administration of selective dopamine autoreceptor agonists like talipexole or roxindole did not result in a significant improvement of positive psychotic symptoms. In negative schizophrenic symptomatology, a dopamine deficit rather than an excess has been hypothesized. Current evidence from pilot studies suggests that dopamine autoreceptor agonists like roxindole may produce a minor to moderate improvement of symptoms like affective flattening, depressed mood, alogia, and avolition, possibly by stimulation of supersensitive postsynaptic dopamine receptors. For certain subgroups of depression, a reduction of functional dopamine activity has been postulated. In an open pilot study in patients with a major depression, roxindole demonstrated antidepressive properties comparable to those of standard antidepressants, justifying further double-blind controlled trials against reference drugs.     

Dopamine agonists, receptor selectivity and dyskinesia induction in Parkinson's disease

Levodopa and the dopamine agonists are effective symptomatic treatments for Parkinson's disease, and all patients receive at least one of these agents during their illness. Long-term use of levodopa is commonly associated with motor complications such as dyskinesia, and both the dosing frequency and total daily dose of levodopa determine the rate of onset and severity. Dopamine agonists have gained popularity as first-line monotherapy in Parkinson's disease, as they effectively reverse motor deficits and reduce the risk of motor complications. Long-acting dopamine agonists providing continuous, rather than pulsatile, dopaminergic stimulation appear able to avoid dyskinesia induction. Current treatments act predominantly on D2 receptors, but drugs acting on both the D1 and D2 receptor families may produce an additive motor response, although this remains to be proven in patients with Parkinson's disease. Most currently used dopamine agonists are selective for D2-like receptors, with only pergolide and apomorphine potentially interacting with D1 receptor populations.     

Pleuropulmonary fibrosis after long-term treatment with the dopamine agonist pergolide for Parkinson Disease

Dopamine agonists are increasingly used in the treatment of Parkinson disease, but they may cause serious adverse effects. In December 1983, symptoms of Parkinson disease developed in a 55-year-old man with no history of pulmonary disease, smoking, or asbestos exposure. He began treatment with dopamine agonists bromocriptine mesylate (in 1984) and pergolide mesylate (in 1989). In late 2000, pulmonary symptoms developed. Chest radiographs and computed tomographic findings showed a mass in the right upper lobe and effusion. A biopsy specimen showed pleural and parenchymal fibrosis. This syndrome resolved after cessation of pergolide therapy and a switch to pramipexole dihydrochloride. This case draws attention to the association of long-term ergot dopamine agonist therapy with pleuropulmonary fibrosis, which can develop as late as 11 years after the initiation of therapy. We also review evidence that the risk of this complication is substantially lower with the newer nonergot dopamine agonists.     

How to succeed in using dopamine agonists in Parkinson's disease

Dopamine receptor agonists are assuming increased importance in the treatment of both early and advanced symptoms of Parkinson's disease (PD). However, tolerability of these drugs can be a problem. Identifying patients who are at increased risk of adverse effects is central to using dopamine agonists in PD. The newer agonists, pramipexole and ropinirole, are generally adequate without levodopa for early symptoms and carry the hope for a more acceptable profile of long-term side-effects. In the patient with advanced disease, all four dopamine agonists significantly augment the response to levodopa, which reduces the problems of motor fluctuations and drug related dyskinesia. Understanding the common pitfalls when prescribing these drugs will facilitate their safety and efficacy.     

Cardiac and noncardiac fibrotic reactions caused by ergot‐and nonergot‐derived dopamine agonists

There is growing evidence that the ergot‐derived dopamine agonists cabergoline and pergolide can cause fibrotic cardiac valvulopathy. Data on other fibrotic reactions and nonergot‐derived dopamine agonists are sparse. Aim of this study was to investigate whether there are signals that dopamine agonists are related to cardiac and other fibrotic reactions. We identified all reports of fibrotic reactions at the heart, lung, and retroperitoneal space associated with dopamine agonists within the US Adverse Event Reporting System database. Disproportionality analyses were used to calculate adjusted reporting odds ratios (RORs). For ergot‐derived dopamine agonists (bromocriptine, cabergoline, pergolide), the RORs of all reactions under study were increased, whereas no such increases were observed for nonergot‐derived drugs (apomorphine, pramipexole, ropinirole, rotigotine). Fibrotic reactions due to ergot‐derived dopamine agonists may not be limited to heart valves. For nonergot‐derived dopamine agonists, no drug safety signals were evident. © 2008 Movement Disorder Society     

Levodopa-induced dyskinesias in Parkinson's disease: clinical and pharmacological classification.

Levodopa-induced dyskinesias (LID) in Parkinson's disease (PD) may be classified into three main categories: "On" dyskinesias, diphasic dyskinesias (DD), and "off" periods. The study of 168 parkinsonian patients showed that about half (n = 84) showed one pattern of LID only. A combination of two was present in 68, and 16 had the three presentation patterns. A fairly good correlation between type of dyskinesia and presentation pattern was established. Chorea, myoclonus, and dystonic movements occurred during the "on" period. Dystonic postures, particularly affecting the feet, were mainly present in the "off" period, but a few patients had a diphasic presentation. Repetitive stereotyped movements of the lower limbs always corresponded to DD. Acute pharmacological tests using dopamine agonists (subcutaneous apomorphine 3-8 mg; intravenous lisuride 0.1-0.15 mg) and dopamine antagonists (intravenous sulpiride 200-400 mg and intravenous chlorpromazine 25 mg) were performed in 40 patients. Dopamine agonists enhanced "on" dyskinesias and markedly reduced or abolished "off" period dystonia and DD. Dopamine antagonists reduced all types of LID but usually aggravated parkinsonism. These clinical and pharmacological results indicate that LID in PD are a heterogeneous phenomenon difficult to explain on the basis of a single pathophysiological mechanism.     

Dopamine agonists in Parkinson's disease

Dopamine agonists are established as effective drugs for the symptomatic treatment of Parkinson's disease (PD) throughout its course. As monotherapy, they produce effective control of motor symptoms and combine this with a low risk for motor complications. As an adjunct to levodopa, they improve motor control and limit the need for levodopa in those patients in whom this may be considered relevant. The non-ergot dopamine agonists in particular have a good safety profile, although as with other agonists, sedation, and cognitive and behavioral problems may be limiting in some patients. Pramipexole has shown benefit in improving depressive symptoms in PD. Ropinirole and pramipexole have both demonstrated a reduction in the rate of loss of nigrostriatal innervation as determined by imaging in PD patients, when compared with levodopa. Thus, dopamine agonists contribute to several dimensions of the management of PD and have become an integral part of the disease treatment algorithm.     

Guanine nucleotides reveal differential actions of ergot derivatives at D-2 receptors labelled by [3H]spiperone in striatal homogenates

The specific binding of [3H]spiperone (35 pM), as defined by the D-2 antagonist sulpiride, was potently displaced by ergot derivatives of both the ergoline and ergopeptine type, and by dopamine agonists and antagonists. The potency of the ergot derivatives ranged widely from an IC50 value of 3 nM for bromocriptine to a value of 1000 nM for the partial ergoline, LY-141865. GTP and its stable analogue, guanyl-5'-yl-imidodiphosphate (Gpp(NH)p), did not affect the affinity (100 pM) or density (30 pmol/g wet wt) of [3H]spiperone binding sites, but did decrease the potency of a number of ergoline compounds including pergolide, lergotrile and LY-141865, as well as dopamine agonists to displace [3H]spiperone binding. The affinities of the ergopeptines, bromocriptine and dihydroergocryptine, and of the isolysergic acid ergoline, lisuride, and dopamine antagonists were unaltered by the presence of guanine nucleotides. The effect was specific for guanine nucleotides, with near maximal effects on agonist affinity observed in the presence of a 100 microM concentration of nucleotide. The relative decrease in affinity found in the presence of GTP or Gpp(NH)p varied widely for individual ergot derivatives and dopamine agonists. The largest decrease was seen with dopamine itself, and agonists such as the tetralins and with LY-141865. Many ergolines had shifts in potency between those seen for agonists and antagonists, suggesting a partial agonist action at D-2 receptors. Guanine nucleotide sensitivity may represent a valuable in vitro method for studying the agonist/antagonist properties of dopaminergic drugs, such as the semi-synthetic ergoline compounds.     

Cocaine abuse and adult attention deficit disorder

Cocaine increases dopaminergic tone in the central nervous system, and hyperprolactinemia has been found in chronic cocaine abusers. Dopamine depletion is believed to result from chronic cocaine abuse. Dopamine deficiency has also been associated with attention deficit disorder (ADD) in adults, and dopamine agonists have been effective in the treatment of ADD. Four case reports of cocaine addiction and ADD are presented. ADD was assumed to play an etiologic role in cocaine abuse, and it was postulated that the patients might in part have been self-medicating a dopamine-deficient state. In addition, cocaine addicts without a premorbid history of ADD may experience a temporary cocaine-induced ADD state. In both cases, the dopamine agonist bromocriptine was highly effective for treating ADD and promoting cocaine abstinence. Restoration of the presumed dopamine deficit may permit an easier course of rehabilitation by improving the patient's ability to participate in therapeutic programs.