Continuous Dopaminergic Stimulation Research Articles

Rotigotine polyoxazoline conjugate SER‐214 provides robust and sustained antiparkinsonian benefit

Currently available dopaminergic drugs such as levodopa and dopamine (DA) receptor agonists impart considerable improvement in Parkinson's disease (PD) motor symptoms but often lead to significant motor complications including "wearing-off" and dyskinesia. Such complications are believed to stem from the pulsatile nature of dopaminergic stimulation with these agents. Continuous dopaminergic drug delivery using polyoxazoline (POZ) polymer conjugation may improve motor symptoms, while avoiding development of side effects. The purposes of the current study are to characterize the in vitro and in vivo pharmacokinetics of POZ conjugation of a U.S. Food and Drug Administration (FDA)-approved DA agonist, rotigotine, and to evaluate their effects in an established rat model of PD. After determination of release profiles of several POZ-conjugated constructs ("fast": SER-212; "moderate": SER-213; and "slow": SER-214) using in vitro hydrolysis, normal male Sprague-Dawley rats were used for determination of the pharmacokinetic profile of both acute and chronic exposure. Finally, a separate group of rats was rendered hemiparkinsonian using intracranial 6-hydroxydopamine (6-OHDA) infusions, treated acutely with POZ-rotigotine, and assessed for rotational behavior and antiparkinsonian benefit using the cylinder test. POZ-rotigotine formulations SER-213 and SER-214 led to substantial pharmacokinetic improvement compared to unconjugated rotigotine. In addition, SER-214 led to antiparkinsonian effects in DA-lesioned rats that persisted up to 5 days posttreatment. Repeated weekly dose administration of SER-214 to normal rats for up to 12 weeks demonstrated highly reproducible pharmacokinetic profiles. The continuous dopaminergic stimulation profile afforded by SER-214 could represent a significant advance in the treatment of PD, with potential to be a viable, once-per-week therapy for PD patients.

Application of the concept of continuous dopaminergic stimulation for the management of Parkinson’s disease

Continuous dopaminergic stimulation (CDS) is a prominent therapeutic concept for the treatment of Parkinson's disease (PD), which proposes that continuous brain dopamine-receptor stimulation, rather than intermittent doses of oral L-dopa, prevents or manages L-dopa-induced dyskinesias (LIDs). In the normal situation, dopaminergic neurons in the substantia nigra pars compacta fire tonically to keep the dopamine receptor stimulation at a steady-state level. But when the dopaminergic pathway is impaired, the dopamine receptor stimulation becomes intermittent or pulsatile. This pulsatile stimulation causes a series of gene and protein changes in striatal neurons, leading to alterations in the fi ring patterns of basal ganglia neurons that result in LIDs. Studies in animal models and clinical trials of PD have shown that approaches providing CDS, currently including patches, extended-release formulations of L-dopa or dopamine agonists, continuous delivery of apomorphine and duodenal L-dopa infusion, are associated with a decreased risk of LIDs. In this review, we summarize both preclinical and clinical evidence for the five methods that may provide CDS in theory and compare the advantages and disadvantages of these methods.

Motor and nonmotor complications in Parkinson’s disease: an argument for continuous drug delivery?

The complications of long-term levodopa therapy for Parkinson’s disease (PD) include motor fluctuations, dyskinesias, and also nonmotor fluctuations—at least equally common, but less well appreciated—in autonomic, cognitive/psychiatric, and sensory symptoms. In seeking the pathophysiologic mechanisms, the leading hypothesis is that in the parkinsonian brain, intermittent, nonphysiological stimulation of striatal dopamine receptors destabilizes an already unstable system. Accordingly, a major goal of PD treatment in recent years has been the attainment of continuous dopaminergic stimulation (CDS)—or, less theoretically (and more clinically verifiable), continuous drug delivery (CDD). Improvements in the steadiness of the plasma profiles of various dopaminergic therapies may be a signal of progress. However, improvements in plasma profile do not necessarily translate into CDS, or even into CDD to the brain. Still, it is reassuring that clinical studies of approaches to CDD have generally been positive. Head-to-head comparative trials have often failed to uncover evidence favoring such approaches over an intermittent therapy. Nevertheless, the findings among recipients of subcutaneous apomorphine infusion or intrajejunal levodopa/carbidopa intestinal gel suggest that nonmotor PD symptoms or complications may improve in tandem with motor improvement. In vivo receptor binding studies may help to determine the degree of CDS that a dopaminergic therapy can confer. This may be a necessary first step toward establishing whether CDS is, in fact, an important determinant of clinical efficacy. Certainly, the complexities of optimal PD management, and the rationale for an underlying strategy such as CDS or CDD, have not yet been thoroughly elucidated.

José Obeso: on a pilgrimage to unravel Parkinson's disease

José Obeso: on a pilgrimage to unravel Parkinson's disease

Three-month subchronic intramuscular toxicity study of rotigotine-loaded microspheres in SD rats

Continuous dopaminergic stimulation (CDS) has been an important strategy of drug development for the treatment of Parkinson's disease (PD). Rotigotine is a non-ergoline D3/D2/D1 dopamine agonist for treating PD. As a new treatment option for CDS, rotigotine-loaded microspheres (RoMS), a long-acting sustained-release microspheres for injection with poly(lactide-co-glycolide) as drug carrier, are now being evaluated in clinical trial. In this study, subchronic toxicity of RoMS in SD rats has been characterized via intramuscular administration with RoMS (0-240 mg/kg/week) on a consecutive weekly dosing schedule for 3 months followed by 1-month recovery period. The No Observed Adverse Effect Level (NOAEL) was 45 mg/kg/week. One male at 240 mg/kg died from an extensive pulmonary embolism. The major toxicological effects were associated with the dopamine agonist-related pharmacodynamic properties of rotigotine (e.g. hyperactivity and stereotype, enlarged ovary, sporadic gastric mucous membrane lesions, decreased body weight, food consumption and prolactin, and increased mononuclear cell, neutrophil granulocyte, aspartate aminotransferase and alanine aminotransferase) and foreign body removal reaction induced by poly(lactide-co-glycolide) and carboxymethycellulose sodium. At the end of recovery period, all findings had recovered to a normal level or to a certain degree except foreign body reaction at injection sites. RoMS has exhibited high safety on SD rats.

Selecting deep brain stimulation or infusion therapies in advanced Parkinson’s disease: an evidence-based review

Motor complications in Parkinson’s disease (PD) result from the short half-life and irregular plasma fluctuations of oral levodopa. When strategies of providing more continuous dopaminergic stimulation by adjusting oral medication fail, patients may be candidates for one of three device-aided therapies: deep brain stimulation (DBS), continuous subcutaneous apomorphine infusion, or continuous duodenal/jejunal levodopa/carbidopa pump infusion (DLI). These therapies differ in their invasiveness, side-effect profile, and the need for nursing care. So far, very few comparative studies have evaluated the efficacy of the three device-aided therapies for specific motor problems in advanced PD. As a result, neurologists currently lack guidance as to which therapy could be most appropriate for a particular PD patient. A group of experts knowledgeable in all three therapies reviewed the currently available literature for each treatment and identified variables of clinical relevance for choosing one of the three options such as type of motor problems, age, and cognitive and psychiatric status. For each scenario, pragmatic and (if available) evidence-based recommendations are provided as to which patients could be candidates for either DBS, DLI, or subcutaneous apomorphine.

Levodopa-induced dyskinesias in Parkinson's disease: emerging treatments.

Parkinson’s disease therapy is still focused on the use of L-3,4-dihydroxyphenylalanine (levodopa or L-dopa) for the symptomatic treatment of the main clinical features of the disease, despite intensive pharmacological research in the last few decades. However, regardless of its effectiveness, the long-term use of levodopa causes, in combination with disease progression, the development of motor complications termed levodopa-induced dyskinesias (LIDs). LIDs are the result of profound modifications in the functional organization of the basal ganglia circuitry, possibly related to the chronic and pulsatile stimulation of striatal dopaminergic receptors by levodopa. Hence, for decades the key feature of a potentially effective agent against LIDs has been its ability to ensure more continuous dopaminergic stimulation in the brain. The growing knowledge regarding the pathophysiology of LIDs and the increasing evidence on involvement of nondopaminergic systems raises the possibility of more promising therapeutic approaches in the future. In the current review, we focus on novel therapies for LIDs in Parkinson’s disease, based mainly on agents that interfere with glutamatergic, serotonergic, adenosine, adrenergic, and cholinergic neurotransmission that are currently in testing or clinical development.

Rasagilina en monoterapia en pacientes en fases tempranas de la enfermedad de Parkinson y en terapia combinada y coadyuvante a levodopa en fases moderada y avanzada

Rasagiline is effective in the early stages of the disease and has shown a possible effect of modifying disease progression at a dose of 1 mg. The accurate management of dopaminergic drugs in Parkinson's disease is able to delay the appearance of motor fluctuations and dyskinesias. The combination of different drugs that provide a more continuous dopaminergic stimulation (rasagiline, dopamine agonists) not only exerts a benefit through diminishing the impact of pulsatile stimulation on post-synaptic dopamine receptors, but allows to decrease total daily levodopa requirements. The combination of rasagiline with other dopaminergic drugs has demonstrated to be as efficacious as entacapone for improving both the frequency and severity of motor fluctuations. Likewise, new evidences have shown that the earlier introduction of rasagiline is associated with a delay in introducing other dopaminergic drugs, thus indicating that the symptomatic benefit of rasagiline on daily motor function is not only present in the early Parkinson's disease stages, but is maintained over time.

Efectos locales del tratamiento transdérmico con rotigotina

Rotigotine is the first transdermal non-ergolinic dopaminergic agonist used in the treatment of Parkinson's disease. It has several important advantages such as once-daily administration, absence of interactions with food, steady levels in plasma and continuous dopaminergic stimulation. Although its systemic side effects are similar to those seen in other dopaminergic agonists, rotigotine also has local side effects derived from the site of application. The aim of this paper is to review those local problems. A retrospective analysis was carried out in order to identify the first 165 patients treated with rotigotine. Patients with intracranial lesions, psychiatric pathology or dementia were excluded. Patients were evaluated before and at two, four and six months after beginning treatment with rotigotine. In all, 94 males and 71 females were identified, with an average age of 65.2 and an average rotigotine daily dose of 11.3 mg. Local side effects were present in 21 patients and they were usually mild. Two patients abandoned the treatment because of these local adverse events, presenting erythema and prurigo. Thirty patients complained about lack of adherence of the patch, specially when it was hot, and 36 about the formation of wrinkles in the patch. None of these problems was associated to motor fluctuations or other complications. Local complications of transdermal rotigotine are mild but frequent. We consider it is necessarily to take them into account to get a better treatment of patients suffering from Parkinson's disease.

The Management of Orthostatic Hypotension in Parkinson’s Disease

Orthostatic hypotension (OH) is a common and disabling symptom affecting Parkinson’s disease (PD) patients. We present the effect of the different therapies commonly used to manage PD on this clinical manifestation. For this purpose, we describe the relationship between OH and the current treatments employed in PD, such as L-DOPA, dopaminergic agonists, and continuous dopaminergic stimulation therapies. Additionally, we review the therapeutic measures that could be used to ameliorate OH. There are different approaches to deal with this manifestation, including pharmacological and non-pharmacological treatments, although none of them is specifically aimed for treating OH in PD.

Three-month subchronic intramuscular toxicity study of rotigotine-loaded microspheres in Cynomolgus monkeys

Continuous dopaminergic stimulation (CDS) is an important drug development strategy in the treatment of Parkinson’s disease (PD). Rotigotine is a non-ergoline D3/D2/D1 dopamine receptor agonist for treating PD. As a new treatment option for CDS, rotigotine-loaded microspheres (RoMS), long-acting sustained-release microspheres with poly(lactide-co-glycolide) as drug carrier, are now being evaluated in clinical trial. In the present study, the subchronic toxicity in Cynomolgus monkeys has been characterized via intramuscular administration with RoMS at 0, 10, 40 and 160mg/kg, weekly for 3months with a 1-month recovery period. The NOAEL was 10mg/kg/week. One male at 160mg/kg died from an extensive pulmonary embolism. The major toxicological effects were associated with dopamine agonist-related pharmacodynamic properties of rotigotine (e.g., hyperactivity and stereotype, decreased serum prolactin level) and foreign body removal reaction induced by poly(lactide-co-glycolide) and carboxymethycellulose sodium (e.g., increased mononuclear cells and neutrophils, thymus atrophy and vacuolar degeneration of adrenal cortex, foreign body granuloma with foam cells accumulation at injection sites and foam cells accumulation in spleen and multiple lymph sinuses). At the end of recovery period, above findings recovered to a normal level or to a certain degree except vacuolar degeneration of adrenal gland. RoMS has exhibited high safety on monkeys.

Experimental reappraisal of continuous dopaminergic stimulation against L‐dopa‐induced dyskinesia

The concept of ‘‘continuous dopaminergic stimulation’’ (498 occurrences on PubMed, of which 46 feature these words in their title) emerged in the 1980s primarily for managing the complex fluctuations in motor performances 1‐3 that are the major problem in the long-term management of Parkinson’s disease. Although motor fluctuations were the first targeted issues of the concept (and its pharmacological consequences), levodopa-induced dyskinesia was rapidly encompassed as a possible manifestation controllable by continuous dopaminergic stimulation. 4 The short plasma half-life of levodopa and the ensuing pulsatile stimulation of striatal dopamine receptors were thought to underlie the propensity of the drug to induce dyskinesia. Late-stage parkinsonian patients indeed benefit from continuous dopaminergic stimulation with notable improvement of established dyskinesia, 5 but large trials in de novo parkinsonian patients with either continuous delivery of levodopa in early Parkinson’s disease using Sinemet CR (CR-FIRST) 6 or the combination of levodopa with the C-O-methyltransferase inhibitor entacapone (STRIDE-PD) 7 failed to reduce the risk of dyskinesia induction. Because the experimental evidence on continuous dopaminergic stimulation has been skeletal, Papathanou et al report in this issue of Movement Disorders on the effect of duodenal compared with intraperitoneal levodopa administration on the induction and expression of abnormal involuntary movements in 6-hydroxydopamine (6-OHDA)‐lesioned rats. Their experimental data confirm that more continuous delivery of levodopa by intraduodenal infusion can exert a beneficial effect on the expression of established dyskinesia. Probably more interesting is their second claim: that continuous dopaminergic stimulation may not reduce the risk of dyskinesia induction, at least in this rodent model. This second claim contradicts both the concept of providing continuous dopaminergic stimulation for preventing dyskinesia incidence and the conclusions made by previous experimental studies obtained in the very same 6-OHDA-lesioned rat model 8 and in the MPTP-treated marmoset model of dyskinesia. 9 Those studies indeed showed that levodopa combined with entacapone delayed the onset of abnormal involuntary movements or dyskinesia, respectively and reduced their severity. 8,9 The question thus arises as to why the previous and current studies reached different conclusions, if they actually did. Two studies were performed in the medial forebrain bundle 6-OHDA-lesioned rat model 8,10 that produced extensive nigrostriatal lesions (more than 90%). They differed in their screening method, with one challenging the unlesioned hemisphere with amphetamine 10 and the other priming the

Morbus Parkinson: Aktuelle Standards in Diagnostik und Therapie

Idiopathic Parkinson's disease is still a clinical diagnosis. However, modern imaging and nuclear techniques allow very early diagnosis and lead to higher security in the differential diagnosis between idiopathic Parkinson's disease and atypical Parkinson syndromes. At early stages of the disease, modification of disease progression and symptom control are key factors of the therapy. Continuous dopaminergic stimulation is even more important at later stages with first fluctuations. In stages where conservative medical options have been exhausted continuous pump therapies with Duodopa and apomorphine are attractive options. Deep brain stimulation in the subthalamic nucleus has turned out in the last years, especially in younger patients, to be a highly successful treatment option. Deep drain stimulation requires, however, a close preoperative work-up and individual consideration of potential effects and side effects.

Preparation of Rotigotine-Loaded Microspheres and Their Combination Use with L-DOPA to Modify Dyskinesias in 6-OHDA-Lesioned Rats

To prepare rotigotine loaded microspheres (RoMS) to achieve continuous dopaminergic stimulation (CDS) for the treatment of Parkinson's disease (PD) and investigate both the therapeutic benefit and inducibility of AIMs of administration of RoMS combination with L-DOPA in 6-OHDA-leisioned rats. Rotigotine was encapsulated into poly(lactic-co-glycolic acid) (PLGA) microspheres by an oil-in-water emulsion solvent evaporation technique. In vitro characteristics and in vivo pharmacokinetics of RoMS either in rat blood or brain (by microdialysis) were investigated. Contraversive rotations and AIMs were observed to investigate the therapeutic benefit and the propensity to induce dyskinesia of RoMS or RoMS combination with L-DOPA in 6-OHDA-lesioned rats. RoMS displayed continuous-release characteristics of rotigotine in animals and exhibited a steady efficacy lasted for 2weeks in 6-OHDA-lesioned rats. No significant difference of the therapeutic benefit between the treatment of RoMS and pulsatile L-DOPA combination and mono L-DOPA was found. While the dyskinesia was significantly decreased with the treatment of RoMS and pulsatile L-DOPA combination compared to mono L-DOPA. RoMS could supply an alternative of CDS for the treatment of PD and the study indicates a potential advantage of RoMS for the treatment of mild and advanced PD patient in combination with L-DOPA.

Upper limb tremor

Tremor is a common clinical problem in middle-aged and older patients, and Parkinson disease (PD) is one of the commonest causes. Careful history-taking and physical examination is usually sufficient for diagnosis of PD; extensive investigation is generally not required. Treatment of PD should be individualised, taking into account the patient's age, lifestyle, severity of motor symptoms, level of disability, comorbidities, expectations of treatment and PD subtype (eg, akinetic rigid or tremor dominant). In PD, optimal medical therapy often involves a combination of dopaminergic medications, aiming for doses that provide adequate symptom relief without adverse effects such as dyskinesias and impulse-control disorders. Continuous dopaminergic stimulation and deep brain stimulation should be considered for patients with PD whose motor symptoms cannot be adequately controlled with oral medication, especially those aged less than 70 years.

Sustained-release pramipexole in the treatment of Parkinson’s disease

Dopamine (DA) receptor agonists ensure stimulation of DA receptors in the brain, by compensating for dopaminergic deficiency in Parkinson’s disease (PD). Since 1996, pramipexole has been used to treat early and extensive PD stages; its clinical efficacy has been proven in many double-blind randomized placebo-controlled and open-labeled trials. Since 2009 the European countries and the USA has used extendedrelease pramipexole (ERP) that is given once daily. Its benefits are stabilized plasma drug concentrations, 24-hour action, which provides continuous dopaminergic stimulation ofpostsynaptic receptors for the prevention and therapy of already existing motor fluctuations and drug-induced dyskinesias. Once-daily dosing of ERP increases the adherence of a patient with PD to regular treatment. Two (extended- and immediate-release) formulations of pramipexole differ only in the release rate for the active ingredient from the contents of a tablet. Both formulations contain the same active ingredient, have the similar profile of interacting with DA receptors, and show pharmacotherapeutic efficacy.

Oral formulations of L dopa and continuous dopaminergic stimulation

Oral formulations of <scp>L</scp> dopa and continuous dopaminergic stimulation

Moving from continuous dopaminergic stimulation to continuous drug delivery in the treatment of Parkinson’s disease

Motor fluctuations and motor complications are a major consequence of the treatment and progression of Parkinson's disease (PD) and they have, in particular, been linked to L-dopa therapy. Using continuous dopaminergic stimulation (CDS) by employing longer acting dopaminergic drugs has been proposed as a means of avoiding or lowering their occurrence. However, both the preclinical and clinical evidence base suggest that this concept does not fully explain the differences between L-dopa and dopamine (DA) agonist drugs and that their pharmacological profiles may also be important. In addition, the way in which drugs are delivered in PD appears to have a marked influence on both efficacy and side-effect profile. As a consequence, the concept of continuous drug delivery (CDD) has arisen to explain the differences between the intermittent and continuous delivery of both L-dopa and DA agonists. This review presents the evidence for using CDD as a working concept for the early and later stages of PD and in the treatment of motor complications and motor fluctuations. CDD as an approach to the treatment of PD may improve the outcome of therapy and explain the differences between drug classes and the delivery systems employed.

Continuous Dopaminergic Stimulation – The Evolving Management of Advanced Parkinson’s Disease

Continuous Dopaminergic Stimulation – The Evolving Management of Advanced Parkinson’s Disease

Update on Levodopa/Carbidopa Intestinal Gel Infusion

Recent data on levodopa/carbidopa intestinal gel (LCIG) infusion are discussed in this article. LCIG infusion provides improvements in ‘off’ time and dyskinesia via continuous dopaminergic stimulation (CDS). In the long-term, LCIG infusion appears to maintain efficacy without the need to increase dosages. The growing number of publications on LCIG infusion shows the increasing experience and interest in this therapy. The new data demonstrate the effects of using LCIG infusion in combination with catechol-O-methyl transferase inhibitors, and technical improvements to the pump system (e.g., to the tubing). Despite the invasive nature of LCIG infusion, nearly all patients would recommend this treatment. Furthermore, a number of larger-scale studies on this particular CDS therapy are in progress.