Short-acting Dopamine Agonist Research Articles

Impulsivity in Patients with Parkinson’s Disease

Summary In recent years focus has been increasingly placed on impulse control disorders (ICDs) in patients with Parkinson’s disease (PD). ICDs include pathological attraction to gambling, compulsive shopping, compulsive eating and compulsive sexual behaviour and are associated mostly with the intake of dopamine agonists. Another impulsive and compulsive behaviour in PD is the dopamine dysregulation syndrome, which is associated with compulsive intake of L-dopa, and short-acting dopamine agonists. Diagnostics and prevention of this group of disorders is essential, considering the difficulties related to their treatment and their negative impact on the patients themselves as well as on their relatives.

Dopaminergic Augmentation in Restless Legs Syndrome/Willis-Ekbom Disease: Identification and Management.

Augmentation is the main clinical complication of long-term dopaminergic treatment of restless legs syndrome (RLS)/Willis-Ekbom disease and also the main reason for treatment failure of this class of drugs. It involves an increase in the severity (or frequency) of RLS symptoms during treatment. There is some preliminary evidence that the incidence of augmentation is higher when short-acting dopamine agonists are used. Prevention strategies include managing lifestyle changes and keeping dopaminergic load low. This might include, whenever feasible, to postpone any dopaminergic medication and perform a treatment trial with nondopaminergic agents (ie, alpha-2 delta ligand) first. Treatment of augmentation might require switching to longer-acting dopaminergic agents, to alpha-2 delta ligands or to opiates.

TLC–surface enhanced Raman scattering of apomorphine in human plasma

Apomorphine is a well-known short-acting dopamine agonist typically used in the treatment of patients with advanced Parkinson's disease. In this work we propose a method for detection of apomorphine in blood plasma through Surface Enhanced Raman Scattering (SERS) technique. Detection can be achieved in a few minutes by simply depositing a drop of the blood plasma containing Apofin® on silica Thin Layer Chromatography (TLC) substrates and dropping the silver colloid on it. The Raman measurements carried out on the edges of the stain reveal the presence of the drug through its SERS signal which is found to significantly differ from the normal Raman spectrum. We propose a Density Functional Theory (DFT) model for the interpretation of the major SERS signatures of apomorphine in terms of the interaction of the drug molecule with silver.

Induction and expression of abnormal involuntary movements is related to the duration of dopaminergic stimulation in 6‐OHDA‐lesioned rats

Dyskinesia induction in Parkinson's disease (PD) appears less marked with long-acting dopamine agonists than with short-acting L-Dopa, but the relationship to duration of drug action is unknown. It is also unclear whether the duration of drug action affects the expression of established dyskinesia. This study compared the ability of L-Dopa and four dopamine agonists of different duration of action to induce abnormal involuntary movements (AIMs) in 6-hydroxydopamine (6-OHDA)-lesioned rats, and their ability to express established AIMs following prior exposure to L-Dopa. 6-OHDA-lesioned rats were treated with saline, L-Dopa/benserazide, apomorphine, ropinirole, pramipexole or pergolide once daily for 15 days. Repeated administration of the short-acting dopamine agonists, apomorphine (duration 80 min) and ropinirole (duration 90 min) induced marked axial, limb and orolingual AIMs at peak effect. L-Dopa (duration 100 min) produced moderate AIMs at peak effect, while administration of the long-acting dopamine agonists, pramipexole (duration 150 min) and pergolide (duration 240 min) resulted in mild AIMs. In rats primed to exhibit severe AIMs following repeated L-Dopa administration, acute administration of apomorphine, ropinirole and L-Dopa induced severe AIMs. By contrast, pramipexole and pergolide evoked only mild-moderate AIMs. Again, there was a negative correlation between duration of effect and the severity of AIMs expressed. These studies show that both the induction and expression of AIMs in 6-OHDA-lesioned rats are related to the duration of action of dopaminergic drugs. These findings suggest that continuous dopaminergic stimulation could be used both to avoid dyskinesia induction and to improve motor function in late-stage PD when troublesome dyskinesia is evident.

Spectrum of addictions in Parkinson’s disease: from dopamine dysregulation syndrome to impulse control disorders

There is an increasing awareness that addictive disorders may occur in Parkinson's disease (PD), either typical substance-related addictions that are commonly known as dopamine dysregulation syndrome (DDS) or behavioral addictive syndromes, usually presenting as impulse control disorders (ICDs) that include pathological gambling, hypersexuality, compulsive eating and buying. DDS is characterized by the use of dopaminergic drugs in doses larger than those required to treat motor symptoms, despite the development of disabling dyskinesias. Case reporting and prospective studies have reported an association between ICDs and the use of dopamine-agonists (DAs) at greater doses, while DDS has been associated with levodopa at greater doses or short-acting DAs. Risk factors for addictions in PD include male sex, younger age or younger age at PD onset, history of substance use or bipolar disorder, and a personality profile characterized by impulsiveness. Functional neuroimaging studies such as functional MRI and PET have investigated in vivo the neurobiological basis of these pathologic behaviors. The management for clinically significant ICD symptoms should consist of modifications to dopamine replacement therapy (DRT), particularly DAs, which is usually associated with an improvement of ICDs, whereas there is no empiric evidence supporting the use of psychiatric drugs in ICDs in PD. Management of DDS is not easy, mainly because balancing the drugs in the long term could represent a difficult problem. Hypomanic and psychotic episodes are best managed with a reduction of DRT performed in hospital also by using atypical antipsychotics low dose.

Impulse control disorders in Parkinson's disease: prevalence and possible risk factors

There is an increasing awareness that impulse control disorders (ICDs), including compulsive gambling, buying, sexual behavior and eating, can occur as a complication of Parkinson's disease (PD). In addition, other impulsive or compulsive disorders including dopamine dysregulation syndrome (DDS) and punding are reported. Case reporting and prospective studies documented an association between ICDs and the use of dopamine agonists (DAs), and to a lesser extent levodopa use, while DDS occurs with higher dosages of levodopa or short-acting DAs. Data suggest that risk factors for an ICD may include male sex, younger age or younger age at PD onset, a pre-PD history of ICD symptoms, personal or family history of substance abuse or bipolar disorder, and a personality style characterized by impulsiveness. It is important that PD patients be aware that DA use may lead to the development of one or more ICDs, and clinicians monitor patients as part of routine clinical care.

Dopamine and impulse control disorders in Parkinson's disease.

There is an increasing awareness that impulse control disorders (ICDs), including compulsive gambling, buying, sexual behavior, and eating, can occur as a complication of Parkinson's disease (PD). In addition, other impulsive or compulsive disorders have been reported to occur, including dopamine dysregulation syndrome (DDS) and punding. Case reporting and prospective studies have reported an association between ICDs and the use of dopamine agonists (DAs), particularly at greater dosages, whereas dopamine dysregulation syndrome has been associated with greater dosages of levodopa or short-acting DAs. Data suggest that risk factors for an ICD may include male sex, younger age or younger age at PD onset, a pre-PD history of ICD symptoms, personal or family history of substance abuse or bipolar disorder, and a personality style characterized by impulsiveness. Although psychiatric medications are used clinically in the treatment of ICDs, there is no empiric evidence supporting their use in PD. Therefore, management for clinically significant ICD symptoms should consist of modifications to dopamine replacement therapy, particularly DAs, and there is emerging evidence that such management is associated with an overall improvement in ICD symptomatology. It is important that PD patients be aware that DA use may lead to the development of an ICD, and that clinicians monitor patients as part of routine clinical care. As empirically validated treatments for ICDs are emerging, it will be important to examine their efficacy and tolerability in individuals with cooccurring PD and ICDs.

Effect of subcutaneous apomorphine on tremor in idiopathic Parkinson's disease

Among the cardinal symptoms of Parkinson's disease (PD) rest tremor is the least responsive to dopaminergic treatment, raising the assumption that it may not be directly related to the loss of dopaminergic neurons. Apomorphine is a potent short-acting dopamine agonist that rapidly ameliorates symptoms of PD. The aim of this study was to evaluate the extent to which apomorphine can suppress tremor in patients with idiopathic PD compared to other symptoms. The study group included 18 patients with Parkinson's disease. Increasing doses of 1 mg, 2 mg, and 4 mg of subcutaneous apomorphine were used. Treatment response was assessed with the motor section of the unified Parkinson's disease rating scale (UPDRS). Tremor, rigidity and bradykinesia were scored using specific items of the UPDRS. UPDRS motor score improved from 31.5 ± 9 at baseline to 20.0 ± 6.4 after treatment. The scores for tremor, bradykinesia and rigidity improved after administration of apomorphine. The improvement in each of these scores for each individual patient was not significantly different, i.e., the magnitude of improvement was similar for all symptoms. These results indicate that subcutaneous apomorphine appears to be as effective in the treatment of tremor in Parkinson's disease as compared to the other symptoms.

Cerebrospinal fluid leakage as complication of treatment with cabergoline for macroprolactinomas

Treatment of patients with prolactinomas consists primarily of dopamine agonists (DA). Cerebrospinal fluid (CSF) leakage has sporadically been reported in patients with macroprolactinomas treated with short-acting DA such as bromocriptine. Little is known on the incidence of this complication in patients treated with the long-acting D2 specific DA cabergoline. We report three patients with CSF leakage shortly after initiation of cabergoline treatment for macroprolactinoma. All three patients responded rapidly to cabergoline (CAB) by shrinkage of the tumor and release of the optic chiasm compression. The CSF leakage occurred within 10 days after initiation of treatment. CAB treatment was not discontinued. In one patient the CSF leakage ceased spontaneously, with no additional therapy. The second patient had a surgical repair of the CSF fistula, permitting cabergoline to be continued without a recurrence of the CSF leakage. The third patient refused surgical repair of the sellar defect. In this patient the cabergoline dosage was temporarily decreased with no effect on the CSF leakage. Four years later, the CSF leakage is unchanged in this patient, whilst no other complications occurred during the follow-up. No infectious complications occurred in these three patients. In conclusion, patients with large, invasive macroprolactinomas are at risk of CSF leakage during medical treatment with CAB. It is advisable to warn these patients for occurrence of this complication and to monitor them closely especially during the first months of treatment.

Rotigotine for the treatment of Parkinson’s disease

Dopaminergic therapies, including levodopa and dopamine agonists, are the mainstays of therapy in Parkinson’s disease. With the exception of the injectable short-acting dopamine agonist apomorphine, there is no other widely available non-oral dopaminergic therapy. Rotigotine is a lipid-soluble, non-ergot, D3, D2, D1 dopamine receptor agonist that has demonstrated efficacy as an alternative therapeutic option in both early and advanced Parkinson’s disease. More importantly, it is uniquely formulated as a transdermal patch delivery system allowing for continuous, once-daily administration and better patient compliance. Preclinical and clinical trials have shown rotigotine to be a well-tolerated and effective treatment for early-stage Parkinson’s disease. Rotigotine has also shown promise as adjunctive therapy with levodopa for the treatment of advanced Parkinson’s disease.

Drug Insight: continuous dopaminergic stimulation in the treatment of Parkinson's disease

Continuous dopaminergic stimulation is a therapeutic strategy for the management of Parkinson's disease, which proposes that dopaminergic agents that provide continuous stimulation of striatal dopamine receptors will delay or prevent the onset of levodopa-related motor complications. Dopaminergic neurons in the basal ganglia normally fire in a random but continuous manner, so that striatal dopamine concentrations are maintained at a relatively constant level. In the dopamine-depleted state, however, intermittent oral doses of levodopa induce discontinuous stimulation of striatal dopamine receptors. This pulsatile stimulation leads to molecular and physiologic changes in basal ganglia neurons and the development of motor complications. These effects are reduced or avoided when dopaminergic therapies are delivered in a more continuous and physiologic manner. Studies in primate models and patients with Parkinson's disease have shown that continuous or long-acting dopaminergic agents are associated with a decreased risk of motor complications compared with short-acting dopamine agonists or levodopa formulations. Continuous dopaminergic stimulation can be achieved with a continuous infusion, but infusion therapies are cumbersome and not likely to be acceptable to patients with early disease. The current challenge is to develop a long-acting oral formulation of levodopa that provides comparable anti-parkinsonian benefits without motor complications.

Avoidance of dyskinesia: preclinical evidence for continuous dopaminergic stimulation.

Current concepts suggest that avoidance of pulsatile stimulation of dopamine receptors in Parkinson's disease (PD) can prevent the onset of dyskinesia. In MPTP-treated primates, repeated administration of levodopa or other short-acting dopamine agonist drugs leads to the onset of marked involuntary movements. In contrast, treatment with long-acting dopamine agonists leads to a much lower level of dyskinesia. Similar results have been obtained in PD patients, although the introduction of levodopa is a requirement in virtually all patients and this leads to further increases in motor complications. The concept of continuous dopaminergic stimulation should also apply to levodopa, such that reduced dyskinesia would be expected if it could be administered in a manner that avoids pulsatile receptor stimulation. In MPTP monkeys, administration of multiple small doses of levodopa in conjunction with the peripheral COMT inhibitor entacapone removes much of the pulsatility of motor function seen with standard levodopa treatment regimens and, at the same time, results in a lower incidence and intensity of dyskinesia. Furthermore, the addition of multiple small doses of levodopa plus entacapone to dopamine agonist treatment also avoids dyskinesia induction in MPTP-treated primates. These results suggest that administering of levodopa with entacapone as either initial or supplemental therapy for PD patients might reduce the risk for motor complications. Clinical trials to assess this hypothesis and determine if the results in MPTP monkeys can be duplicated in PD patients are warranted.

P.4.028 Efficacy of bio-normalizer in stroke patients: EEG-mapping, neuropsychological and clinical study

The current concept of dyskinesia is that pulsatile stimulation of D-1 or D-2 receptors by l-DOPA or short-acting dopamine agonists is more likely to induce dyskinesia compared to long-acting drugs producing more continuous receptor stimulation. We now investigate the ability of two mixed D-1/D-2 agonists, namely pergolide (long-acting) and apomorphine (short-acting), to induce dyskinesia in drug-naı̈ve MPTP-lesioned primates, compared to l-DOPA. Adult common marmosets (Callithrix jacchus) were lesioned with MPTP (2 mg/kg/day sc for 5 days) and subsequently treated with equieffective antiparkinsonian doses of l-DOPA, apomorphine, or pergolide for 28 days. l-DOPA, apomorphine, and pergolide reversed the MPTP-induced motor deficits to the same degree with no difference in peak response. l-DOPA and apomorphine had a rapid onset of action and short duration of effect producing a pulsatile motor response, while pergolide had a slow onset and long-lasting activity producing a continuous profile of motor stimulation. l-DOPA rapidly induced dyskinesia that increased markedly in severity and frequency over the course of the study, impairing normal motor activity by day 20. Dyskinesia in animals treated with pergolide or apomorphine increased steadily, reaching mild to moderate severity but remaining significantly less marked than that produced by l-DOPA. There was no difference in the intensity of dyskinesia produced by apomorphine and pergolide. These data suggest that factors other than duration of drug action may be important in the induction of dyskinesia but support the use of dopamine agonists in early Parkinson's disease, as a means of delaying l-DOPA therapy and reducing the risk of developing dyskinesia.

Both Short- and Long-Acting D-1/D-2 Dopamine Agonists Induce Less Dyskinesia than l-DOPA in the MPTP-Lesioned Common Marmoset ( Callithrix jacchus)

The current concept of dyskinesia is that pulsatile stimulation of D-1 or D-2 receptors by l-DOPA or short-acting dopamine agonists is more likely to induce dyskinesia compared to long-acting drugs producing more continuous receptor stimulation. We now investigate the ability of two mixed D-1/D-2 agonists, namely pergolide (long-acting) and apomorphine (short-acting), to induce dyskinesia in drug-naı̈ve MPTP-lesioned primates, compared to l-DOPA. Adult common marmosets ( Callithrix jacchus) were lesioned with MPTP (2 mg/kg/day sc for 5 days) and subsequently treated with equieffective antiparkinsonian doses of l-DOPA, apomorphine, or pergolide for 28 days. l-DOPA, apomorphine, and pergolide reversed the MPTP-induced motor deficits to the same degree with no difference in peak response. l-DOPA and apomorphine had a rapid onset of action and short duration of effect producing a pulsatile motor response, while pergolide had a slow onset and long-lasting activity producing a continuous profile of motor stimulation. l-DOPA rapidly induced dyskinesia that increased markedly in severity and frequency over the course of the study, impairing normal motor activity by day 20. Dyskinesia in animals treated with pergolide or apomorphine increased steadily, reaching mild to moderate severity but remaining significantly less marked than that produced by l-DOPA. There was no difference in the intensity of dyskinesia produced by apomorphine and pergolide. These data suggest that factors other than duration of drug action may be important in the induction of dyskinesia but support the use of dopamine agonists in early Parkinson's disease, as a means of delaying l-DOPA therapy and reducing the risk of developing dyskinesia.

Long-duration effect and the postsynaptic compartment: study using a dopamine agonist with a short half-life.

A possible reason why levodopa induces a sustained, stable motor benefit during the first months to years of therapy may be its long duration of action. This long-duration effect may be due either to a presynaptic storage mechanism or to postsynaptic pharmacodynamic changes. We previously reported that the dopamine agonist ropinirole induced a long-duration response (LDR) in levodopa-naive patients with Parkinson's disease. In this study, we investigated motor responses to the short half-life dopamine agonist lisuride in a group of levodopa naive parkinsonian patients. Once lisuride reached its maximum effect, it was substituted, in randomized order, with placebo. Neither investigators nor patients knew when the active drug was switched to placebo. When patients were switched from lisuride to placebo, their Unified Parkinson's Disease Rating Scale (UPDRS) motor scores and tapping test and screw scores declined to baseline values within a mean 9.0 +/- 1.9 days. The results confirmed that, like ropinirole and levodopa, the short-acting dopamine agonist lisuride induces a long-duration response, probably due to postsynaptic changes.

Pathophysiology and biochemistry of dyskinesia: clues for the development of non-dopaminergic treatments.

Levodopa-induced dyskinesia is a major therapeutic problem in the long-term treatment of Parkinson's disease. The development of dyskinesia is dependent on the extent of nigral denervation but can be induced through both D-1 and D-2 dopamine receptors. Short-acting dopamine agonists producing pulsatile receptor stimulation are more likely to induce dyskinesia than long-acting drugs that produce continuous receptor stimulation. However, there are no consistent changes in dopamine receptors which explain the occurrence of dyskinesia. Rather, dyskinesia may originate from an imbalance between the major striatal output pathways. Indeed, levodopa and dopamine agonist drugs show a differential ability to alter striatal output as judged by mRNA for colocalised neuropeptides. The involvement of striatal output pathways raises the possibility of utilising a range of non-dopaminergic receptors within the striatum and in output nuclei as targets for novel drug therapies which may be antiparkinsonian without eliciting dyskinesia. For example, the A2a adenosine antagonist KW6002 reverses motor deficits in primates treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) without provoking an established dyskinesia. Similarly, manipulation of muscarinic cholinergic receptors in the striatum can alter the intensity and components of dyskinesia. Neurotrophic therapies diminish dyskinesia since glial cell line-derived neurotrophic factor (GDNF) produces a decrease in motor disability in MPTP-treated primates associated with a reduced intensity of levodopa-induced dyskinesia. The mechanisms underlying the manifestations and the priming process for dyskinesia remain unknown, but non-dopaminergic approaches to therapy may provide an effective way of preventing, or limiting, the expression of involuntary movements in Parkinson's disease.

The role of pulsatile versus continuous dopamine receptor stimulation for functional recovery in Parkinson's disease.

More effective measures to control and replace the dopaminergic deficit of Parkinson's disease are being actively sought. One basic problem is how the striatal dopamine loss should be replaced in order to mimic most accurately the physiological state. Animal electrophysiology indicates that the dopaminergic nigrostriatal pathway has a dual tonic and phasic action. Intermittent dopaminergic stimulation is associated with behavioural hyposensitivity both in animal models and in patients with Parkinson's disease. Continuous dopaminergic stimulation provides a tonic background and improves some clinical problems but is also associated with tolerance. None of the available pharmacological approaches can restore the dopamine deficiency of Parkinson's disease to physiological levels. Continuous dopaminergic stimulation for < 24 h, associated with small doses of levodopa or a short-acting dopamine agonist, appears to be the best, albeit imperfect, therapeutic approach until other, more efficacious remedies are developed.