Continuous Stimulation Of Dopamine Receptors Research Articles

DOPAMINE DYSREGULATION SYNDROME IN PARKINSON’S DISEASE AND APPROACHES TO ITS CORRECTION WITH DRUGS

The objective is to describe a clinical case of dopamine dysregulation syndrome (DDS) with compulsive intake of large doses of levodopa in a patient with Parkinson’s disease (PD). Materials and methods. Male patient R., born in 1956, has had PD since 2004 when he noticed changes in his handwriting, difficulties to perform small movements with the right hand. Therapy with levodopa/benserazide was started at 300 mg/day. With time symptoms of the disease escalated: gait impairment and motor fluctuations started. Action duration after administration of levodopa/benserazide sin gle dose shortened to 2 hours, peak dose dyskinesia developed, as well as instability with frequent falls. In 2012, clinical picture of the disease included symptoms of DDS. The patient independently increased the drug dose, decreased time between doses, didn’t follow the doctor’s recommendations. Relatives noticed a state of euphoria in the patient after taking a dose of levodopa/benserazide. At the time of visiting the Department of Neurology of the Russian Medical Academy of Continuous Professional Education in the beginning of 2016, the daily equivalent levodopa dose was 2000 mg, and 800 mg of it were taken at night. Results. The patient was transferred to a three-component modern levodopa drug Stalevo (levodopa + carbidopa + entacapone) 150 mg + levodopa/benserazide 50 mg 6 times a day (daily dose 1200 mg). Decreased levodopa daily dose achieved by transferring the patient to a three-component drug with better bioavailability lead to significant reduction of motor and non-motor symptoms, significant increase in effect duration after a single dose of levodopa. In a year of follow-up, DDS symptoms gradually regressed, time between drug administration increased, the patient stopped taking the drug at night, fluctuations and drug-induced dyskinesias significantly decreased. Conclusion. In this clinical case, manifestations of DDS caused by long-term compulsive levodopa intake at doses significantly exceeding daily dose (necessary for control of motor symptoms) are described. One of the approaches to reduction of high doses of levodopa and control of motor fluctuations is prescription of Stalevo which stabilizes levodopa level in plasma and provides a more continuous stimulation of dopamine receptors in the striatum.

Modern treatment in Parkinson's disease, a personal approach.

There are many guidelines available concerning the treatment of Parkinson's disease. Most of these advocate treating young-onset patients with a dopamine agonist and older patients with levodopa. The rationale behind this recommendation has its origins in the side effects associated with each of these drug classes: whilst levodopa leads to dyskinesia, which may not be relevant for patients with a limited life-expectancy, dopamine agonists have a much longer plasma half life which probably leads to more continuous dopamine receptor stimulation and thus decreases the occurrence and severity of dyskinesia. However, the side effects associated with the use of dopamine agonists, such as sleepiness, orthostatic problems, hallucinations and impulse control disorders are a drawback. In this overview, the hypothesis will be put forward that perhaps such a strict distinction is no longer needed. A new idea may be the early combination of levodopa with a dopamine agonist which would provide good clinical efficacy and, because of the relatively low doses involved, would reduce the side effects associated with both substances. MAO-B inhibitors may be a good option for early treatment and especially for patients who experience first motor fluctuations. Similarly, and particularly if a wearing-off symptom is present, COMT inhibitors smoothen and prolong the action of levodopa. More invasive escalation therapy comes into play when patients reach the advanced stages with problems of insufficient motor control, such as bradykinesia, rigidity and resting tremor, combined with on-time dyskinesia. The use of all oral and invasive treatment has to be individualized to gain a good motor and non-motor control and especially a good quality of life.

A commentary on: "A 12-year population-based study of freezing of gait in Parkinson's disease".

A commentary on: "A 12-year population-based study of freezing of gait in Parkinson's disease".

Dropped head sign induced by transdermal application of the dopamine agonist rotigotine in parkinsonian syndrome: a case report

Introduction‘Dropped head sign’ relates to a severe disproportionate antecollis in parkinsonism. We present the first report of a rotigotine-induced dropped head sign in a patient with suspected idiopathic Parkinson’s disease, which was later defined as multiple system atrophy. The ‘dropped head sign’ is considered a rare symptom of unknown etiology in parkinsonian disorders, though a disproportionate antecollis is frequently observed in multiple system atrophy. It has also been described as a side effect of dopamine agonist medication with cabergoline and pramipexole. Rotigotine is a transdermally applied, non-ergot dopamine agonist, resulting in a continuous stimulation of dopamine receptors, which is widely used in the treatment of patients with Parkinson’s disease.Case presentationWe report a case of a 64-year-old Caucasian woman with a rapidly progressive two-and-a-half-year history of a hypokinetic Parkinson’s syndrome with asymmetric development of symptoms and an initially good response to levodopa medication. Due to side effects of other dopamimetic medications the patient was switched to rotigotine medication five weeks before clinical admission. Progressive antecollis without muscle weakness and prominent paraspinal muscle contraction developed within two weeks of treatment and resolved within a week after discontinuation of rotigotine and initiation of levodopa/cabergoline medication.ConclusionWhile the pathophysiology still remains unresolved, this case supports the concept of a dopaminergic imbalance as a cause of certain axial dystonias like disproportionate antecollis including the ‘dropped head sign’. We believe this case is specifically useful for neurologists and general practitioners, as the easily recognizable symptom should prompt a thorough reevaluation of diagnosis and medication in patients with Parkinson’s disease.

Drugs and drug delivery in PD: optimizing control of symptoms with pramipexole prolonged‐release

Intermittent or pulsatile dopamine-receptor stimulation is postulated to induce plastic changes in motor systems that are responsible for the development of motor fluctuations and dyskinesia, complicating long-term levodopa therapy of Parkinson's disease (PD). Continuous dopamine stimulation (CDS) is a concept that refers to the hypothesis that more continuous dopamine-receptor stimulation will reduce the risk of motor complications, particularly dyskinesias, and may also treat established dyskinesias. In line with this hypothesis, the intermittent administration of dopaminergic agents with short half-lives induce motor complications in animal models, whilst the continuous administration of the same compounds via mini-pumps substantially reduces such symptoms. Continuous drug delivery (CDD) strategies are therefore explored in clinical trials to prevent or manage motor complications. The early use of a dopamine agonist reduces the risk of motor fluctuations compared with levodopa. Conversely, the early combination of the catechol-O-methyltransferase inhibitor entacapone with levodopa has failed to demonstrate a comparable advantage. Outcomes of uncontrolled long-term studies of PD patients with motor complications treated for several months with subcutaneous continuous infusion of apomorphine or intraduodenal levodopa are compatible with CDS. New once-daily prolonged-release formulations of dopamine agonists have demonstrated antiparkinsonian efficacy in randomized trials conducted in early as well as advanced patients with PD. Once-daily administration is convenient and may improve compliance. Other theoretical advantages in terms of efficacy or tolerability deserve further exploration.

Rationale Therapie der Parkinsonerkrankung mit Dopaminagonisten

Idiopathic Parkinson's disease is one of the most frequent neurological diseases. Besides L-dopa dopamine agonists play a major role in therapy of this condition. In most guidelines it is advocated to use dopamine agonists proferentially in monotherapy or in combination in de novo patients younger than 70 years old. To avoid dyskinesias continuous dopamine receptor stimulation should be achieved. This may be very well accomplished by the use of a transdermally applicated dopamine agonist which results in constant plasma levels over the whole day.

Continuous delivery of rotigotine decreases extracellular dopamine suggesting continuous receptor stimulation

Rotigotine, a non-ergolinic dopamine receptor agonist for treatment of Parkinson's disease was continuously administered over 48 h (0.5 mg/kg s.c., slow release formulation) to conscious rats striatally implanted with a microdialysis probe. Subsequently, the levels of rotigotine increased to a maximum of 3.42 + 2.1 nmol/l and remained at a level of 2.81 +/- 0.82 nmol/l for 48 h. Concomitantly, the dopamine levels consistently decreased to 20% of the control level. This suggests that the sustained administration of rotigotine provides stable extracellular drug levels in the striatum resulting in continuous stimulation of dopamine receptors.

Dopamine depletion and subsequent treatment with l‐DOPA, but not the long‐lived dopamine agonist pergolide, enhances activity of the Akt pathway in the rat striatum

Dysregulation of signaling pathways is believed to contribute to Parkinson's disease pathology and l-DOPA-induced motor complications. Long-lived dopamine (DA) agonists are less likely to cause motor complications by virtue of continuous stimulation of DA receptors. In this study, we compared the effects of the unilateral 6-hydroxydopamine lesion and subsequent treatment with l-DOPA and DA agonist pergolide on signaling pathways in rats. Pergolide caused less pronounced behavioral sensitization than l-DOPA (25 mg/kg, i.p., 10 days), particularly at lower dose (0.5 and 0.25 mg/kg, i.p.). Pergolide, but not l-DOPA, reversed lesion-induced up-regulation of preproenkephalin and did not up-regulate preprodynorphine or DA D3 receptor in the lesioned hemisphere. Pergolide was as effective as l-DOPA in reversing the lesion-induced elevation of ERK2 phosphorylation in response to acute apomorphine administration (0.05 mg/kg, s.c.). Chronic l-DOPA significantly elevated the level of Akt phosphorylation at both Thr(308) and Ser(473) and concentration of phosphorylated GSK3alpha, whereas pergolide suppressed the lesion- and/or challenge-induced supersensitive Akt responses. The data indicate that l-DOPA, unlike pergolide, exacerbates imbalances in the Akt pathway caused by the loss of DA. The results support the hypothesis that the Akt pathway is involved in long-term actions of l-DOPA and may be linked to l-DOPA-induced dyskinesia.

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

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 subdivided into ergoline and non-ergoline derivatives. This distinction raises the question whether there are differences in the effects to treat symptoms, not only in the side effects between the individual dopamine agonists but also between these two groups. Pergolide is now considered a second line drug because of its particularly high tendency towards valvular heart disease. Some authors claim that all ergoline-derivatives may cause this problem, while own results do not necessarily support this view. We recommend performing echocardiography on those patients being treated with an ergot-derivative. New data support the view that all dopaminergic drugs may cause somnolence and that there is no preference for non-ergots. It may be that the number of gamblers is slightly higher among patients treated with pramipexole than in others. Dopamine agonists with a high affinity to D3 receptors have a good anti-anhedonic potency. In cell culture all dopamine agonists studied so far show neuroprotective properties in cell culture. The introduction of a slow-release formulation for ropinirole and the rotigotine and lisuride patches have opened new ways of continuous dopamine receptor stimulation. Taken together, dopamine agonists show individual properties and there are differences between ergot and non-ergot derivatives.

Entacapone in the treatment of Parkinson's disease

The development of fluctuations in motor response and involuntary movements commonly complicate the treatment of Parkinson's disease (PD). Catechol-O-methyltransferase (COMT) inhibitors delay the breakdown of levodopa, which leads to an increase in levodopa bioavailability and more stable concentrations of plasma levodopa. The addition of a COMT inhibitor therefore combines the rapid onset of levodopa with prolonged efficacy, and theoretically provides a more continuous stimulation of dopamine receptors with reduced risk of motor complications. Randomised, controlled trials have shown that in patients with PD who have motor fluctuations, the addition of the COMT-inhibitor entacapone results in an improvement in motor fluctuations, particularly of the "wearing-off" type, with about 1.0-1.7 h more on-time and less off-time per day, reduced required levodopa dose, modest improvement in motor and disability scores (mean total unified PD rating scale [UPDRS] scores of about 4.5), and in some but not all studies improvement of health-related quality of life [HRQOL] scores. Patients with stable PD, without motor fluctuations, also have improved HRQOL scores on treatment with entacapone in addition to levodopa with a dopa-decarboxylase inhibitor. However, in a recent large multicentre study, UPDRS motor and disability scores were not improved despite significant improvements in HRQOL scores. The disparity between results on clinical rating scales and HRQOL scores suggests that these scales give different and potentially complementary information on health status changes in PD, and that entacapone provides benefit that may not be captured with standard clinical rating scales. Whether entacapone combined with levodopa can delay dyskinesia or motor fluctuations in patients with untreated PD is unknown; however, in animal studies, a decrease in motor complications has been reported in drug-naive animals given frequent doses of levodopa combined with entacapone. WHERE NEXT?: Clinical studies are underway to address the hypothesis that motor complications in PD can be delayed if entacapone is given from the start of treatment. Until the results of these trials are available, entacapone is indicated as a useful adjunct to levodopa in the symptomatic treatment of patients with PD with and without motor fluctuations. In addition, future trials should specifically assess the effect of entacapone on HRQOL in PD.

Early administration of entacapone prevents levodopa-induced motor fluctuations in hemiparkinsonian rats

The purpose of this study was to investigate the effect of the catechol- O-methyltransferase (COMT) inhibitor, entacapone, in the reversal and prevention of “wearing-off” phenomena in hemiparkinsonian rats. Catechol- O-methyltransferase (COMT) inhibitors increase the half-life and bioavailability of levodopa, providing more continuous dopamine receptor stimulation. This raises the possibility of using levodopa and a COMT inhibitor not only to treat motor complications, but also to prevent their development. Male Sprague-Dawley rats received a unilateral 6-hydroxydopamine (6-OHDA) administration in the nigrostriatal pathway. Two sets of experiments were performed. First, animals were treated with levodopa (50 mg/kg/day with benserazide 12.5 mg/kg/day, twice daily (b.i.d.), intraperitoneally (i.p.) for 22 days. On day 23, animals received either entacapone (30 mg/kg, i.p.) or vehicle with each levodopa dose. In the second set, animals were treated either with levodopa (50 mg/kg/day, i.p.) plus entacapone (30 mg/kg/day, i.p.) or levodopa (50 mg/kg/day, i.p.) plus vehicle, administered two or three times daily [b.i.d. or thrice daily (t.i.d.), respectively] for 22 consecutive days. Entacapone both reversed and prevented the shortening of the motor response duration that defines “wearing-off” motor fluctuations. Entacapone also decreased the frequency of failures to levodopa. The combination of levodopa and entacapone may reduce the likelihood of motor fluctuation development and may thus become a valuable approach to treat Parkinson disease whenever levodopa is needed.

1061 Continuous stimulation of dopamine receptors by a continuous delivery of rotigotine in a rat model

1061 Continuous stimulation of dopamine receptors by a continuous delivery of rotigotine in a rat model

Levodopa in the treatment of Parkinson's disease: current controversies.

Levodopa is the most effective symptomatic agent in the treatment of Parkinson's disease (PD) and the "gold standard" against which new agents must be compared. However, there remain two areas of controversy: (1) whether levodopa is toxic, and (2) whether levodopa directly causes motor complications. Levodopa is toxic to cultured dopamine neurons, and this may be a problem in PD where there is evidence of oxidative stress in the nigra. However, there is little firm evidence to suggest that levodopa is toxic in vivo or in PD. Clinical trials have not clarified this situation. Levodopa is also associated with motor complications. Increasing evidence suggests that they are related, at least in part, to the short half-life of the drug (and its potential to induce pulsatile stimulation of dopamine receptors) rather than to specific properties of the molecule. Treatment strategies that provide more continuous stimulation of dopamine receptors provide reduced motor complications in MPTP monkeys and PD patients. These studies raise the possibility that more continuous and physiological delivery of levodopa might reduce the risk of motor complications. Clinical trials to test this hypothesis are underway. We review current evidence relating to these areas of controversy.

The pharmacokinetics of pergolide in Parkinson's disease.

Three decades of research have led to a fuller understanding of the pharmacokinetics of pergolide. Pergolide is rapidly absorbed following oral dosing, reaching peak plasma concentrations within 2-3 h. It is about 90% protein bound yet has negligible drug interactions. Pergolide undergoes extensive first-pass metabolism and is completely eliminated within 4-5 days. The metabolism/elimination profile varies between patients but is consistent within the individual, highlighting the importance of careful titration to an effective dose. Pergolide has a long half-life of about 21 h; this has interesting implications, as it should produce a more physiological or continuous stimulation of dopamine receptors, avoiding or delaying the induction of dyskinesia.

Levodopa-Induced Response Fluctuations in Patients with Parkinson???s Disease

Fluctuations in response to levodopa in patients in the advanced stages of idiopathic Parkinson's disease occur frequently and are a difficult problem to treat. Patients who are treated with levodopa have an additional 10% risk of experiencing response fluctuations with each year of treatment: 50% of patients have this problem after 5 years of receiving levodopa therapy and almost 100% of patients after 10 years. The mechanisms by which response fluctuations occur are only partially understood and can be divided into three main types: (i) presynaptic neuronal degeneration leading to a lack of buffering of released levodopa, which is mainly related to wearing-off phenomena; (ii) postsynaptic changes in dopamine receptor sensitivity and number, partially caused by the presynaptic changes, which are clinically related to at-random response fluctuations; and (iii) pharmacokinetic and pharmacodynamic influences of exogenously administered dopaminergic agents. Several oral and parenteral treatment strategies are recommended to manage response fluctuations, such as optimisation of dopamine receptor agonist therapy in combination with a reduction of the levodopa load; use of slow-release levodopa formulations; use of catechol-O-methyltransferase inhibitors; an increase of levodopa dose frequency; use of high-dose amantadine; and intermittent or continuous use of apomorphine and/or levodopa. Continuous stimulation of dopamine receptors with dopaminergic agents is one of the crucial basic steps in the treatment of patients at an advanced stage of Parkinson's disease, and the preferential use of dopamine receptor agonists has proven to be successful in the prevention and treatment of response fluctuations.

Neostriatal mechanisms in Parkinson's disease.

Normal motor function is dependent on the highly regulated synthesis and release of dopamine (DA) by neurons projecting from substantia nigra to corpus striatum. Cardinal symptoms of Parkinson's disease (PD) arise as a consequence of a deficiency in striatal DA due to the progressive degeneration of this neuronal system. Under such circumstances, the subunit composition and/or phosphorylation state of glutamatergic receptors of the N-methyl-D-aspartate (NMDA) subtype expressed on the dendritic spines of medium-sized striatal neurons changes in ways that compromise motor performance. Although levodopa acts, after conversion to DA, to reverse these changes by restoring striatal dopaminergic transmission, significant differences exist between the normally functioning DA system and the restoration of function provided by standard levodopa therapy. The nonphysiologic stimulation of DA receptors on striatal spiny neurons associated with current levodopa regimens now appears to contribute to the motor response complications that ultimately affect most parkinsonian patients. Current evidence suggests that alterations in signaling systems linking dopaminergic and glutamatergic receptors within these GABAergic efferent neurons induce NMDA receptor modification. Functionally, the resultant long-term change in glutamatergic synaptic efficacy leads to alterations in spiny neuron output, favoring the appearance of motor complications. Although dopaminomimetic replacement strategies that provide more continuous DA receptor stimulation should alleviate these disabling complications, more innovative approaches to the interdiction of pathologic changes in signal transduction components or glutamate receptor sensitivity could ultimately prove safer and more effective for the treatment of all stages of PD.

Levodopa therapy: consequences of the nonphysiologic replacement of dopamine.

Normal motor function is dependent on the highly regulated synthesis and release of the transmitter dopamine by neurons projecting from the substantia nigra to the corpus striatum. Parkinson's disease involves the progressive degeneration of these neurons. Its core symptoms are a direct consequence of a striatal insufficiency of intrasynaptic dopamine. Levodopa, the standard of care for the treatment of PD, acts after its conversion to dopamine by restoring striatal dopaminergic transmission. However, there are significant differences between the normally functioning dopamine system and the restoration of function provided by standard levodopa treatment. Increasing clinical and preclinical evidence suggests that the intermittent stimulation of dopamine receptors resulting from current therapeutic regimens contributes to the response complications that ultimately affect most parkinsonian patients. It now appears that chronic nonphysiologic stimulation of dopaminergic receptors on striatal GABAergic neurons activates characteristic signaling pathways, leading to a potentiation of the synaptic efficacy of adjacent glutamatergic receptors of the N-methyl-D-aspartate (NMDA) subtype. As a result, function of these GABAergic efferent neurons changes in ways that favor the appearance of motor complications. Conceivably, use of dopaminomimetic replacement strategies that provide more continuous dopamine receptor stimulation will act to prevent or alleviate these disabling complications. A number of promising approaches to achieving this goal are now under development.

The significance of continuous dopaminergic stimulation in the treatment of Parkinson's disease.

Levodopa continues to be the most effective agent for the symptomatic treatment of Parkinson's disease. No other drug matches its ability to suppress parkinsonian symptoms, especially in patients with advanced disease. But over time, initial benefits begin to wane, not so much because of a decline in efficacy against core symptoms, but rather because of a rise in adverse effects. Most common are the motor response complications that appear within a few years of treatment initiation and ultimately affect most parkinsonian patients. These progressively disabling complications include response fluctuations and abnormal involuntary movements. Current evidence indicates that 'wearing-off' fluctuations, typically the first motor complication to become clinically evident, initially reflect the loss of buffering normally provided by striatal dopaminergic terminals. Thus, with increasing degeneration of the nigrostriatal system, swings in plasma levodopa concentrations associated with standard dosage regimens produce nonphysiological fluctuations in intrasynaptic dopamine. As a result of long term discontinuous stimulation, secondary changes occur at sites downstream from the dopamine system and now appear to underlie the progressive worsening of 'wearing-off' phenomena as well as the eventual appearance of other response complications. Chronic intermittent stimulation of normally tonically active dopaminergic receptors activates specific signalling cascades in striatal dopaminoceptive medium spiny neurons, and this evidently results in long term potentiation of the synaptic efficacy of glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype on these GABAergic efferents. As a consequence of their increasing sensitivity to excitation by cortical glutamatergic projections, it would, however, appear that medium spiny neuron function changes to favour the appearance of response fluctuations of the 'on-off' type and peak dose dyskinesias. The inability of standard levodopa treatment to restore striatal dopaminergic function in a more physiological manner clearly contributes to the appearance of motor complications. Continuous dopaminergic replacement not only reverses these complications in parkinsonian patients but also prevents their development in animal models of Parkinson's disease. Thus, pharmaceutical approaches that provide relatively continuous dopamine receptor stimulation might confer both prophylactic and palliative benefit to parkinsonian patients. Several such strategies are currently under development, and include various methods to prolong the duration of action of levodopa as well as the use of transdermally administered or very long acting dopamine agonists.

Management of Motor Fluctuations in Parkinson’s Disease

A complication of chronic levodopa therapy is a shortening of benefit of each dose. Peripheral pharmacokinetics, central pharmacokinetics, and central pharmacodynamics are involved in the pathophysiology of motor fluctuations. Strategies to improve 'wearing-off' fluctuations attempt to provide more constant plasma levodopa levels or more continuous stimulation of dopamine receptors. Controlled-release levodopa preparations are very effective for mild to moderate fluctuations. The addition of direct-acting dopamine agonists or the MAO-B inhibitor selegiline is helpful for short-term improvement. Liquid levodopa is beneficial for some patients with severe fluctuations. Apomorphine injections will provide immediate 'rescue' from 'off' states. Catechol-O-methyl transferase inhibitors are a new class of drugs which appear to improve motor fluctuations. Manipulations of dieting protein may reduce fluctuations in some patients. It is possible that motor fluctuations may be delayed by the early use of sustained release levodopa preparations or early combinations of levodopa with a dopamine agonist.