Dopamine agonists in the treatment of Parkinson's disease

Dopamine agonists are highly effective as adjunctive therapy to levodopa in advanced Parkinson's disease and have rapidly gained popularity as a monotherapy in the early stages of Parkinson's disease for patients less than 65-70 years old. In the latter case, dopamine agonists are about as effective as levodopa but patients demonstrate a lower tendency to develop motor complications. However, dopamine agonists lose efficacy over time and the number of patients remaining on agonist monotherapy decreases to less than 50% after 3 years of treatment. Thus, after a few years of treatment the majority of patients who started on dopamine agonists will be administered levodopa, in a combined dopaminergic therapy, in order to achieve a better control of motor symptoms.     

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.     

Dopamine agonists

Dopamine agonists provide an effective means of treating early, middle, and late stages of Parkinson's disease. This article outlines the advantages and disadvantages of dopamine agonists as compared with levodopa therapy. The features and costs of the four Food and Drug Administration-approved agonists (bromocriptine, pergolide, pramipexole, and ropinirole) and apomorphine, another agonist presently under investigation, are discussed.     

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.     

Treatment of Parkinson''s disease

The aim of current treatment of Parkinson's disease is to ameliorate the symptoms while seeking to lessen the potential development of late levodopa complications. To this end, there is ample evidence that the early use of dopamine agonists is beneficial in younger Parkinsonian patients but monotherapy with dopamine agonists is for only a select few. Nonergot dopamine agonists offer the potential for fewer side effects. Lower dose levodopa therapy delays the onset and reduces severity of dyskinesia and end of dose failure. However levodopa remains the treatment of choice in Parkinson's disease and should not be restricted unnecessarily in patients with disability. There is no evidence that levodopa is toxic to dopaminergic neurons in people with Parkinson's disease. As yet, no drugs are of proven neuroprotective value. Dopamine agonists, catechol-o-methyltransferase inhibitors, amantadine and apomorphine have differing but beneficial roles in the management of levodopa side effects. Ablative surgery and deep brain stimulation of thalamus, globus pallidus and subthalamic nucleus are increasingly available but choice of procedure depends not just on patient symptomatology, but also on local experience and results. Ideally, deep brain stimulation is the treatment of choice as it offers less morbidity than bilateral ablative surgery, the possibility of postoperative adjustments and the potential for reversibility if better treatments become available.     

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.     

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.     

Dopamine agonists and neuroprotection in Parkinson's disease

Dopamine agonists are effective in reversing the motor symptoms of Parkinson's disease (PD). They have also shown that they can delay or prevent the onset of motor complications associated with levodopa use. Recent attention has focused on the possible role for dopamine agonists in neuroprotection. Numerous studies have demonstrated that a variety of dopamine agonists can protect dopaminergic neuronal function in several toxin model systems. Pramipexole in particular has shown efficacy in reducing toxicity to MPTP, MPP, rotenone and 6-hydroxydopamine. Recent studies in early PD using imaging parameters as a surrogate marker of dopaminergic neuronal integrity have shown that pramipexole and ropinirole can apparently retard the rate of cell loss. These observations are of considerable interest, but additional studies are required to confirm a neuroprotective function for these dopamine agonists.     

Pramipexole in the treatment of Parkinson's disease: new developments

The nonergot dopamine agonist pramipexole is an efficient and safe drug for the treatment of Parkinson's disease. Clinicians may favor pramipexole over other dopamine agonists because of its suggested higher tolerability with respect to peripheral dopaminergic side effects. Importantly, nonergot dopamine agonists such as pramipexole may not cause restrictive valvular heart disease and may therefore represent the first choice in patients with valvular lesions under treatment with ergot dopamine agonists. However, particular caution has to be exercised in younger Parkinson's disease patients with a shorter disease duration regarding the occurrence of sudden onset of sleep. In light of cost-effectiveness and quality-of-life issues, its final significance for the initial treatment of patients with early Parkinson's disease remains to be determined.     

Disease-related and drug-induced changes in dopamine transporter expression might undermine the reliability of imaging studies of disease progression in Parkinson's disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder. Standard therapeutic interventions are aimed at replenishment of empty dopamine stores with levodopa or substitution with dopamine receptor agonists. However, in the long term this symptomatic therapy fails. Currently, various neuroprotective agents are being developed, with the intention to slow down the degeneration of dopaminergic neurons. In this context, the early identification of persons at risk to develop the disease as well as the assessment of the effectiveness of putative neuroprotective agents, are critical issues. Dopamine transporter (DAT) scintigraphy with single photon emission computed tomography (SPECT) has been used to assess the dopaminergic function in PD. Initial studies with several radioligands show significant loss of DAT binding in PD patients as compared to controls. In this paper we review the evidence on the utility of DAT imaging with SPECT in early PD detection as well as in monitoring neurprotection.     

Arguments for the use of dopamine receptor agonists in clinical and preclinical Parkinson's disease

On the basis of experimental studies which have demonstrated deleterious effects of L-DOPA (L-3,4-dihydroxyphenylalanine) in vivo and in vitro, it has been suggested that L-DOPA itself may contribute to the progression of Parkinson's disease. This hypothesis is, for many clinicians, the rationale for postponing the employment of and reducing the applied dosage of L-DOPA and for beginning therapy with dopamine receptor agonists or the monoamine oxidase type B (MAO-B) inhibitor selegiline. Furthermore, clinical studies have demonstrated that early treatment with dopamine receptor agonists is associated with a lower incidence of motor fluctuations and dyskinesia. Dopamine receptor agonists exert their symptomatic effect by directly activating dopamine receptors, bypassing the presynaptic synthesis of dopamine and the degenerating nigro-striatal dopaminergic system. They can thus also be of benefit late in the therapy of the disorder. In addition, the pharmacological profile of dopamine receptor agonists suggests a possible neuroprotective effect. This paper reviews briefly the pharmacology of dopamine receptor agonists and basic knowledge concerning the dopamine receptor stimulation which underlies their therapeutic effect. Preclinical approaches for demonstrating neuroprotective effects and their clinical relevance are also discussed.     

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.     

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.     

Role of dopamine agonists in Parkinson's disease: an update

At present, dopamine agonists play an important role in antiparkinsonian therapy since they were proved effective in the management of both advanced- and early-stage Parkinson's disease. In the latter, they are often regarded as first-choice medication to delay the introduction of levodopa therapy. Despite sharing the capacity to directly stimulate dopamine receptors, dopamine agonists show different pharmacological properties as they act on different subsets of dopamine receptors. This, in theory, provides the advantage of obtaining a different antiparkinsonian activity or safety profile with each agent. However, there is very little evidence that any of the marketed dopamine agonists should be consistently preferred in the management of patients with Parkinson's disease. Pergolide and cabergoline are now considered a second-line choice after the proven association with valvular fibrosis. Transdermal administration (rotigotine) and subcutaneous infusion (apomorphine) of dopamine receptor agonists are now available alternatives to oral administration and provide continuous dopaminergic stimulation. Continuous subcutaneous apomorphine infusion during waking hours leads to a large reduction in daily 'off' time, dyskinesias and levodopa daily dose. Almost all currently used dopamine agonists are able to provide neuroprotective effects towards dopaminergic neurons during in vitro and in vivo experiments. This neuroprotection may be the result of different mechanisms including antioxidation, scavenging of free radicals, suppression of lipid peroxidation and inhibition of apoptosis. However, the disease-modifying effect of these agents in Parkinson's disease remains to be ascertained.     

Levodopa or dopamine agonists, or deprenyl as initial treatment for Parkinson's disease. A randomized multicenter study

Objectives: levodopa improves the quality of life in parkinsonian patients, however long term response is compromised by the emergence of motor fluctuations and dyskinesias. The aim of this study was to compare the occurrence of motor fluctuations and dyskinesias in previously untreated patients assigned to receive levodopa, a dopamine agonist or deprenyl.Thirty-five neurological departments in Italian hospitals participated in this randomized open trial. Patients with Parkinson's disease, who required the initiation of an effective antiparkinsonian treatment, were randomly assigned to receive levodopa, dopamine agonists or deprenyl. The end-points were motor dyskinesias and motor fluctuations occurring in a median follow-up period of about 3years.After a median follow-up of 34months, motor fluctuations and dyskinesias were less frequent in patients assigned to a dopamine agonist or deprenyl than in patients assigned to levodopa (relative risk [RR] 0.5, 95% confidence interval [95% CI] 0.3-0.8, and RR=0.6, 95% CI 0.3-0.9, respectively), but dopamine agonists were less effective and less well tolerated than levodopa. The lower frequency of motor fluctuations in patients assigned to deprenyl was no longer statistically significant when prognostic predictors were considered in a multivariable analysis. Long-term mortality did not differ in the three arms of the study. Dopamine agonists and deprenyl can be considered as an alternative to levodopa for starting treatment in Parkinson's disease patients. However, on clinical grounds, only small advantages are expected over the traditional therapy initiation with levodopa.     

Drug therapy for Parkinson's disease

The fundamental concepts of the medical treatment of Parkinson's disease are simple, and remain based on the enhancement of dopaminergic transmission by means of levodopa and dopamine agonists. Recently published practice parameters from the American Academy of Neurology and an evidence-based review under the auspices of the Movement Disorder Society provide guidance on motor complications and also cognitive and psychiatric issues associated with Parkinson's disease. The choices of medications are increasing as are the routes of administration, with the arrival of injectable and transdermal dopamine agonists and a monoamine inhibitor absorbed via the buccal mucosa. Although simple conceptually, the actual care of patients with Parkinson's disease is often complex, requiring consideration of potential future complications and individualized medication regimens, and minimizing the adverse effects of medications that range from unpleasant to seriously disturbing.     

Dopamine: a key regulator to adapt action, emotion, motivation and cognition

Dopamine is expressed in restricted brain areas involved in numerous integrative functions contributing to automated behaviours that are highly adaptive. During ontogenesis, dopamine can have a trophic action, which influences cortical specification directly, especially in prefrontal areas. Such a role is attested by the close relationships existing between the development of dopamine cortical innervation and cognitive abilities. Interestingly, such a proposal is reinforced by phylogenetic data. During the last stages of evolution in mammals, the characteristic extension of dopamine cortical innervation is also correlated with the development of cognitive capacities. More generally, the contribution of dopamine will be to increase the processing of cortical information through basal ganglia, either during the course of evolution or development. In this respect, dysmaturation suspected in schizophrenia and attention deficit-hyperactivity disorder in children can emphasize such a defect in basal ganglia processing. Remarkably, these diseases are improved by dopamine antagonists and agonists, respectively. In this line of evidence, experimental studies showed that selective lesions of the dopamine neurones in rats or primates can actually provide motor, limbic and cognitive deficits, in later cases especially when the mesocorticolimbic dopamine pathways are altered. Data resulting from lesion studies also showed significant alteration in attentional processes, thus raising the question of the direct involvement of dopamine in regulating attention. Dopamine can act as a powerful regulator and integrator of different aspects of brain functions. For example, in Parkinson's disease, besides motor impairment, dopamine degeneration is also expressed by alterations of both limbic, executive and cognitive functions, both improved by dopamine receptor agonists and dopa therapy. Dopamine has thus to be considered as a key regulator that contributes to behavioural adaptation and to the anticipatory processes necessary for preparing voluntary action consequent upon intention. In this respect, the alteration of dopamine transmission with age could contribute to cognitive impairment. Therefore, to normalize dopamine transmission pharmacologically could actually improve the cognitive and limbic deficits during normal aging, as it does in psychiatric and neurological disorders.     

Dopaminergic induced changes in cognitive and motor processing in Parkinson''s disease: an electrophysiological investigation.

Event-related potentials and reaction time measures to auditory discrimination tasks of graded difficulty were used to separate cognitive from motor processing time in 27 patients with newly diagnosed, previously untreated Parkinson's disease and later on optimal levodopa treatment. Before treatment event-related potential P3 and task performance were normal but the reaction time was prolonged compared with age matched controls. After treatment P3 latency was significantly prolonged and the reaction time reduced suggesting a dopamine induced dissociation between cognitive and motor processing. In early Parkinson's disease cognitive processing time remains normal but the motor processing time is prolonged. Dopamine replacement is followed by significantly reduced motor processing time despite increased cognitive processing time. Motor processing may reflect the dopamine status of the putamen whereas dopaminergic over-stimulation of other regions may adversely affect cognitive processing in patients treated with levodopa.     

Workshop IV: drug treatment guidelines for the long-term management of Parkinson's disease

An attempt was made to establish a decision algorithm for the treatment of idiopathic Parkinson's disease at various stages and in different subgroups such as akinetic-rigid or tremor dominance type. We suggest treating young patients with selegiline and a dopamine agonist. In the tremor dominance type we use either budipine or a dopamine agonist. Due to levodopa-induced dyskinesia, we try to avoid levodopa in the early stages of the disease and use it only later in more advanced situations in a combination therapy with dopamine agonists. Since IPS is not only based upon dopamine deficiency but also on resulting glutamatergic overstimulation, we advocate the use of a glutamate antagonist such as amantadine or budipine. Catechol-O-methyl inhibitors are very helpful when wearing-off occurs. Anticholinergics are only used in the early stages of tremor-dominant IPS because we fear enhancing the risk of dementia.