Dopamine Receptor Agonist Pramipexole Research Articles

Quantification of Non-Motor Symptoms in Parkinsonian Cynomolgus Monkeys.

Parkinson's disease (PD) is a neurodegenerative disorder that features motor and non-motor deficits. The use of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine neuron degeneration has been widely practiced to produce reliable animal models of PD. However, most previous preclinical studies focused on motor dysfunction, and few non-motor symptoms were evaluated. Thus far, there is a lack of comprehensive investigations of the non-motor symptoms in animal models. In this study, we aim to use a battery of behavioral methods to evaluate non-motor symptoms in MPTP-induced non-human primate PD models. Cognitive function, sleep, and psychiatric behaviors were evaluated in MPTP-treated cynomolgus monkeys. The tests consisted of a delayed matching-to-sample (DMTS) task, the use of a physical activity monitor (PAM), an apathy feeding task (AFT), the human intruder test (HIT), novel fruit test (NFT), and predator confrontation test (PCT). In addition, we tested whether the dopamine receptor agonist pramipexole (PPX) can improve these non-motor symptoms. The present results show that the MPTP-treated monkeys exhibited cognitive deficits, abnormal sleep, and anxiety-like behaviors when compared to the control monkeys. These symptoms were relieved partially by PPX. These results suggest that MPTP-induced PD monkeys displayed non-motor symptoms that were similar to those found in PD patients. PPX treatment showed moderate therapeutic effects on these non-motor symptoms. This battery of behavioral tests may provide a valuable model for future preclinical research.

Effects of different doses of dopamine receptor agonist pramipexole on neurobehaviors and changes of mitochondrial membrane potentials in rats with global cerebral ischemia-reperfusion injury

ObjectiveTo explore the effects of different doses of dopamine receptor agonist pramipexole on neurobehaviors and changes of mitochondrial membrane potential in rats with global cerebral ischemia-reperfusion injury. MethodsA total of 75 SPF Sprague-Dawley male rats were randomly divided into sham group (n=20), model group (n=20), pramipexole administration group (n=35). The rat model of global cerebral ischemia-reperfusion injury was prepared by the modified Pulsinelli's four-vessel occlusion method. Pramipexole administration group was administered intraperitoneally in rats with global cerebral ischemia-reperfusion injury at different doses of pramipexole 0.25 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, once a day for 14 consecutive days. Based on the results of modified neurological severity scores, open field test and morphology by Nissl's staining to determine the optimal dose of pramipexole. Mitochondrial membrane potential in the optimal dose of pramipexole administration group were measured by the JC-1 fluorescent probe staining method. Results1. Different doses of pramipexole 0.25 mg/kg, 0.5 mg/kg, 1 mg/kg, and 2 mg/kg, were used as drug administration in rats with global cerebral ischemia-reperfusion injury for 14 consecutive days, and we found that all four doses of pramipexole could improve the modified neurological severity scores of rats with global cerebral ischemia-reperfusion injury to varying degrees, but only 0.5 mg/kg pramipexole at 1, 3, 7 and 14 days consistently reduced modified neurological severity scores and improved neurological function in rats with global cerebral ischemia-reperfusion injury. In the open-field test, only 0.5 mg/kg pramipexole increased the number of entries into the central zone, duration spent in the central zone, total distance travelled in the open field and average velocity, which improved the spontaneous activities and reduced anxiety and depression of rats with global cerebral ischemia-reperfusion injury. 2. Different doses of pramipexole 0.25 mg/kg, 0.5 mg/kg, 1 mg/kg, and 2 mg/kg for 14 consecutive days significantly increased the number of surviving neurons in the hippocampal CA1 subfield in rats with global cerebral ischemia-reperfusion injury to varying degrees. Based on these results, we tentatively found that 0.5 mg/kg pramipexole may be the optimal dose in all of the above. 3. We found that 0.5 mg/kg pramipexole significantly increased the mitochondrial membrane potential in rats after global cerebral ischemia-reperfusion injury. ConclusionDifferent doses of dopamine receptor agonist pramipexole improved neurological function of rats with global cerebral ischemia-reperfusion injury to varying degrees, and 0.5 mg/kg pramipexole may be the optimal dose in all of the above. Pramipexole may produce neuroprotective effects by protecting neurons in the hippocampus and improving the mitochondrial membrane potential after global cerebral ischemia-reperfusion injury.

Pramipexole inhibits astrocytic NLRP3 inflammasome activation via Drd3-dependent autophagy in a mouse model of Parkinson’s disease

Inflammation is one of the pathogenic processes in Parkinson’s disease (PD). Dopamine receptor agonist pramipexole (PPX) is extensively used for PD treatment in clinics. A number of studies show that PPX exerts neuroprotection on dopaminergic (DA) neurons, but the molecular mechanisms underlying the protective effects of PPX on DA neurons are not fully elucidated. In the present study, we investigated whether PPX modulated PD-related neuroinflammation and underlying mechanisms. PD model was established in mice by bilateral striatum injection of lipopolyssaccharide (LPS). The mice were administered PPX (0.5 mg·kg−1·d−1, i.p.) 3 days before LPS injection, and for 3 or 21 days after surgery, respectively, for biochemical and histological analyses. We showed that PPX administration significantly alleviated the loss of DA neurons, and suppressed the astrocyte activation and levels of proinflammatory cytokine IL-1β in the substantia nigra of LPS-injected mice. Furthermore, PPX administration significantly decreased the expression of NLRP3 inflammasome-associated proteins, i.e., cleaved forms of caspase-1, IL-1β, and apoptosis-associated speck-like protein containing a caspase recruit domain (ASC) in the striatum. These results were validated in LPS+ATP-stimulated primary mouse astrocytes in vitro. Remarkably, we showed that PPX (100–400 μM) dose-dependently enhanced the autophagy activity in the astrocytes evidenced by the elevations in LC3-II and BECN1 protein expression, as well as the increase of GFP-LC3 puncta formation. The opposite effects of PPX on astrocytic NLRP3 inflammasome and autophagy were eliminated by Drd3 depletion. Moreover, we demonstrated that both pretreatment of astrocytes with autophagy inhibitor chloroquine (40 μM) in vitro and astrocyte-specific Atg5 knockdown in vivo blocked PPX-caused inhibition on NLRP3 inflammasome and protection against DA neuron damage. Altogether, this study demonstrates an anti-neuroinflammatory activity of PPX via a Drd3-dependent enhancement of autophagy activity in astrocytes, and reveals a new mechanism for the beneficial effect of PPX in PD therapy.

Impulse control disorders associated with dopaminergic drugs: A disproportionality analysis using vigibase

BackgroundDopamine receptor agonist drugs, which are used, for example, to treat Parkinson's disease (PD), increase the risk for impulse control disorders (ICDs), potentially resulting in devastating psychosocial consequences. It is unknown whether other drugs with dopaminergic properties also increase the risk for ICDs. This study assesses the disproportionality of reporting ICDs between drugs with dopaminergic properties and selected non-dopaminergic drugs. MethodsA case/non-case disproportionality analysis was performed, using data from VigiBase (1968–2020). Reports on ICDs as suspected adverse drug reactions (ADRs) were cases (n=852), and those with ADRs other than ICDs were non-cases (n=281,720). Relative reporting frequencies were expressed as adjusted reporting odds ratios (aRORs). Within the dopamine receptor agonists, the relationship between reporting odds ratios and dopamine receptor occupancy was explored. ResultsA high disproportionality was found for reporting ICDs for all dopaminergic drugs (aROR 20.4 [95% CI 17.4–24.1]) compared to non-dopaminergic drugs. In pharmacotherapeutic subgroups, a high disproportionality was found for primary dopaminergic agents used in PD (aROR 52.1 [95% CI 44.1–61.5]), and to a lesser extent for ADHD psychostimulants and antidepressants (aROR 5.8 [95% 4.1–8.3] and aROR 3.9 [95% CI 2.9–5.6], respectively). There was no difference in reporting by consumers and healthcare professionals. The highest disproportionality was found for the dopamine receptor agonists pramipexole and ropinirole. ConclusionsA signal of disproportion in ICD occurrence was found among all investigated drugs with dopaminergic properties, highlighting the importance of counselling and monitoring for ICDs when prescribing dopaminergic drugs.

3D printed extended release tablets for once daily use: An in vitro and in vivo evaluation study for a personalized solid dosage form

Fused deposition modeling (FDM)-3D printing enables the manufacturing of dosage forms with personalized doses and controllable release profiles. Parkinson’s disease is a neurodegenerative disorder that causes motor complications. In the treatment of the disease, the nonergot dopamine receptor agonist pramipexole is used in gradually increasing doses depending on patient’s needs. Hence, there are various dosed commercial products of pramipexole and it is a suitable model drug for the preparation of personalized-dose 3D printed dosage forms. In this study, we prepared extended release 3D tablets of pramipexole for once daily use in Parkinson’s disease. Herein, 12 different 3D tablet formulations were prepared and in vitro characterizations were performed on these formulations. The formulations were compared with the marketed tablet and the optimum formulation was selected. The chosen formulation was prepared with commercially available doses of pramipexole and also with intermediate doses which are not available in the market to demonstrate the applicability of 3D printing in personalized dosing. Stability studies, which have innovative features for 3D tablets, were conducted in optimum 3D tablet formulation for 6 months at 25 °C/60% relative humidity (RH) and 40 °C/75% RH conditions. After oral administration of the optimum 3D tablets and the marketed tablets (in the same dose) to the rats, 24-hour plasma profiles were obtained and pharmacokinetic parameters were calculated. 3D tablets were successfully prepared in personalized doses and their properties were similar for almost all doses. The optimum 3D tablet formulation was found to be stable during the stability tests. 3D tablet and marketed tablet performed similar plasma profiles. The relative bioavailability of 3D tablet formulation was calculated as 107.6% compared with the marketed tablet. Briefly, in vitro and in vivo evaluations demonstrated that FDM-3D printing is a promising technology for the development of personalized dosage forms with extended release property and comparable to conventional ones.

Efficacy of pramipexole combined with levodopa for Parkinson's disease treatment and their effects on QOL and serum TNF-α levels.

PurposeTo investigate the efficacy of combining the dopamine receptor agonist pramipexole with levodopa for Parkinson’s disease (PD) treatment and to measure their effects on quality of life and tumor necrosis factor (TNF)-α levels in PD patients.Basic ProcedureIn total, 160 PD patients who were admitted to our hospital were equally randomized into a control treatment group (levodopa alone) and the study group (pramipexole combined with levodopa). Both groups were treated for 12 weeks.FindingsAfter treatment, scores from the Unified Parkinson’s Disease Rating Scales (1–3), the Hamilton Depression Scale, and the Parkinson’s Disease Questionnaire (PDQ-39) were significantly decreased in both groups, whereas Mini-Mental State Examination scores were significantly increased. After treatment, the study group had significantly lower scores for all scales except the Mini-Mental State Examination, for which those who received combined treatment had significantly higher scores than the control group. The incidence of adverse reactions was significantly lower in the study group than in the control group. Furthermore, after treatment, serum TNF-α levels were significantly decreased in both groups compared with pre-treatment levels.ConclusionPramipexole combined with levodopa relieved PD symptoms and improved the quality of life of PD patients, potentially by suppressing serum TNF-α levels.

P.414 Influence of the dopamine receptor agonist pramipexole on serum levels of pro- and anti-inflammatory cytokines

P.414 Influence of the dopamine receptor agonist pramipexole on serum levels of pro- and anti-inflammatory cytokines

P.411 Investigating the effects of the dopamine receptor agonist pramipexole on learning and memory in rats with lipopolysaccharide-induced memory impairment

P.411 Investigating the effects of the dopamine receptor agonist pramipexole on learning and memory in rats with lipopolysaccharide-induced memory impairment

Development and in vitro safety evaluation of pramipexole-loaded hollow mesoporous silica (HMS) particles

In this study, spherical hollow mesoporous silica (HMS) particles with average size of 550 nm were loaded with dopamine-receptor agonist pramipexole, as a model drug. High drug loading (55%) was achieved by its incorporation in the reservoir structure of HMS. The newly developed drug-delivery systems were further double-coated with bioadhesive polymers chitosan and sodium alginate to achieve sustained release. The double chitosan/sodium alginate coating diminished the initial burst effect and lowered pramipexole release at two pH values (1.2 and 6.8) as shown by in vitro release studies. The haemolytic assay and MTT-test in human neuroblastoma SH-SY5Y cells showed good safety profile of the novel pramipexole-loaded HMS particles. Moreover, a more pronounced protection of human neuroblastoma SH-SY5Y cells against H2O2-induced oxidative damage was observed upon treatment with pramipexole-loaded (non-coated or chitosan-coated) HMS particles compared to the free drug. In conclusion, we found that HMS particles might be of great interest as a promising drug-delivery system for pramipexole. The coating with biopolymer chitosan modified both the drug-delivery process and the in vitro protection against oxidative stress in neuroblastoma SH-SY5Y cells.

Backing into the future: pharmacological approaches to the management of resistant depression.

Pragmatic studies indicate that a substantial number of depressed patients do not remit with current first-line antidepressant treatments and after two failed treatment steps the chance of remission with subsequent therapies is around 15%. This paper focuses on current evidence for pharmacological treatments in resistant depression as well as possible future developments. For patients who have failed to respond to two antidepressant trials, augmentation with atypical antipsychotic drugs, specifically quetiapine and aripiprazole, has the best evidence for efficacy, though older treatments such as lithium and triiodothyronine still have utility. The striking antidepressant effect of ketamine in resistant depression has stimulated research into glutamatergic compounds; however, capturing the efficacy of ketamine with drugs suitable for continuous use has proved challenging. Growing knowledge of the pathophysiological role of inflammation in depression offers great opportunities for future treatment in terms of repurposing anti-inflammatory agents from general medicine and pre-treatment stratification of those depressed patients in whom such interventions are likely to be beneficial. Finally an older drug, the dopamine receptor agonist pramipexole, if used carefully may well improve the prospects of depressed patients who are refractory to current approaches.

Effects of pramipexole treatment on the α-synuclein content in serum exosomes of Parkinson's disease patients.

Advances approaches in the treatment of Parkinson's disease are needed. The study was aimed to evaluate the therapeutic value of the new dopamine receptor agonist pramipexole. The effects of pramipexole on serum exosomes were investigated, and the possible mechanisms of action of the drug were explored. Initially, 68 patients were included in the study, of whom 3 cases did not complete the study. The remaining 65 patients were administered pramipexole at increasing doses starting at 0.25 mg twice a day for the 1st week, and reaching 1.5 mg three times daily at the 8th week. The doses were tapered during the course of the following 4 weeks. The total scores of the motor examination of the unified Parkinson's disease rating scale III (UPDRS III) and the total scores of the daily life activity in UPDRS II were compared before and after treatment. The relative expression amounts of α-synuclein in serum exosomes were then calculated by western blot analysis. Scores of UPDRS III and UPDRS II following treatment were significantly lower than the scores prior to treatment, and the difference was statistically significant (P<0.05). The relative expression of α-synuclein in serum exosomes was also found to be significantly lower after treatment (P<0.05). The relative expression of α-synuclein in the effective treatment group was significantly lower than that in the ineffective treatment group, and the difference was statistically significant (P<0.05). The relative expression of α-synuclein in serum exosomes was significantly correlated with treatment effects (P<0.05). In conclusion, pramipexole was effective and safe as a treatment for Parkinson's disease. The therapeutic effect of pramipexole may be associated with its reducing effect on the relative expression of α-synuclein in serum exosomes.

Multi-facetted impulsivity following nigral degeneration and dopamine replacement therapy

Impulse control disorders (ICDs) are debilitating side effects of dopamine replacement therapy (DRT) in Parkinson’s disease (PD) that severely affect the quality of life of patients. While DRT, the pattern and extent of neurodegeneration, and prodromic factors of vulnerability (e.g. impulsivity) have all been hypothesized to play a role in the development of ICDs, their respective, and potentially interacting, contributions remain to be established. High impulsive (HI), Intermediate (Int) or low impulsive (LI) rats were identified based on their performance in both a differential reinforcement of low rate of responding (DRL) and a fixed consecutive number (FCN) schedules, that operationalize two independent facets of impulsivity, waiting and action inhibition (motor impulsivity). We investigated whether high impulsivity trait influenced the progressive development of a parkinsonian state induced by viral-mediated overexpression of α-synuclein, and whether impulsivity trait and nigrostriatal neurodegeneration independently or jointly influenced the effects of DRT on impulse control. α-synuclein-induced nigrostriatal neurodegeneration increased both waiting and motor impulsivity. The D2/D3 dopamine receptor agonist pramipexole exacerbated motor impulsivity more than waiting. However, the pramipexole-induced increase in waiting impulsivity observed in both sham and lesioned rats, was more pronounced in HI lesioned rats, which displayed a restricted α-synuclein-induced dopaminergic neurodegeneration. Thus, a PD-like nigrostriatal lesion increases both motor and waiting impulsivity, but its interaction with a pre-existing impulsivity trait, which, at the cellular level, confers resilience to dopaminergic neurodegeneration, worsens the detrimental effects of D2/D3 dopamine receptor agonists on inhibitory control.

A successful treatment of buprenorphine withdrawal with the dopamine receptor agonist pramipexole

Buprenorphine, used for treating opioid dependence, may have a withdrawal syndrome requiring treatment. Modulation of the dopamine system, which has been implicated in opioid withdrawal, may be a target for withdrawal for opioids such as buprenorphine. A case is reported of a buprenorphine withdrawal syndrome with predominant symptoms of restlessness that were resistant to clonidine and benzodiazepines. It was successfully treated with the dopamine agonist pramipexole. Dopamine receptor agonists may have a place in the treatment of restlessness associated with opioid withdrawal and may have value for the broader spectrum of opioid withdrawal symptoms.

Anterior ventral tegmental area dopaminergic neurons are not involved in the motivational effects of bromocriptine, pramipexole and cocaine in drug-free rats

Dopamine dysregulation syndrome in Parkinson's disease has been attributed to dopamine replacement therapies and/or a lesion of the dopaminergic system. Dopaminergic neuronal loss targets the substantia nigra and the ventral tegmental area (VTA). We hypothesize that dopamine replacement therapy is responsible for the potential reinforcement effect in Parkinson's disease, by acting on the neuronal reward circuitry. We previously demonstrated that the posterior (p) VTA, which projects to the nucleus accumbens (NAc), is implicated in the motivational effect of dopamine receptor agonists in 6-OHDA bilateral pVTA-lesioned drug-free animals. In the present study we investigated the implication of the anterior (a) VTA in the potential reinforcement effect of dopamine receptor agonists. Using the conditioned place preference (CPP) behavioral paradigm, we investigated the motivational effects of dopamine receptor agonists (bromocriptine and pramipexole), and cocaine in rats with a 6-OHDA bilateral lesion of the aVTA. Bromocriptine and pramipexole did not induce a significant CPP at 1mg/kg in both sham and bilateral 6-OHDA-lesioned rats. However bromocriptine induced CPP only at a dose of 3mg/kg in both animal groups. Moreover cocaine, which is known to increase dopamine release, induced reinforcing effects in both 6-OHDA-lesioned and sham rats. Our data show a lack of involvement of aVTA dopamine neurons in the motivational effects of bromocriptine, pramipexole and cocaine.

Capacities of the dopamine receptor agonist pramipexole in the treatment of patients with Parkinson’s disease

Dopaminergic stimulation with levodopa, a biological precursor of dopamine precursor, and dopamine receptor agonists (DRA) remains the leading pharmacotherapeutic strategy for Parkinson’s disease (PD). The long-term use of levodopa is associated with the development of characteristic fluctuations in its symptoms and drug-induced dyskinesias so DRA are the drugs of choice and may be used alone and as part of combination therapy in a number of cases of parkinsonism in young patients in particular. Pramipexole (mirapex) is one of the most effective representatives of non-ergoline DRA, which has an extensive evidence base. The paper analyzes the heterodirectional properties of pramipexole in detail and its effect on motor (including tremor) and nonmotor (depression) manifestations of PD and discusses the possible neuroprotective action of the drug. It also separately considers the potential of the new unique 24-hour controlled release formulation: the administration of the drug considerably reduces the dose titration period and enhances patient compliance.

Parkinson's disease fatigability and its correction with the dopamine receptor agonist pramipexole

Fatigability is a common nonmotor symptom in Parkinson's disease (PD), which worsens quality of life in patients. Objective: to analyze the association of fatigability with the duration of PD and the degree of movement and neuropsychic (depression, nocturnal sleep disorders, daytime sleepiness) disorders; to evaluate changes in the manifestations of fatigability during therapy with the dopamine receptor agonist pramipexole (Mirapex). Patients and methods. Sixty patients with PD (disease duration 6.02±3.47 years; stage 2.68±0.62) without dementia were examined using the PD fatigue scale (PFS-16), unified PD rating scale (Part 2), the Beck depression inventory, the PD sleep scale, and the Epworth sleeping scale. Results. 66% of the patients were found to consider fatigability to be one of the three most daily life-limiting manifestations of the disease. The integrated rating of fatigability significantly correlated with total depression scores and sleep scores. During pramipexole therapy, there were statistically significant positive changes in fatigability, which did not correlate with those in motor functions, depression, and sleep problems. It is concluded that fatigability substantially impairs the daily activities of patients with PD and is associated with neuropsychic symptoms to a greater extent than with the degree of movement disorders in PD. This may be due to both the common pathophysiological mechanisms of these abnormalities and their comorbidity in PD. The fact that there is no significant association of the time course of changes in fatigability with alterations in the parameters of other neuropsychic functions during therapy conceivably indicated the independent genesis of this symptom.

Adenosine Receptor Antagonists Do Not Disrupt Rodent Prepulse Inhibition: An Improved Side Effect Profile in the Treatment of Parkinson's Disease

Parkinson's disease (PD) is characterized by loss of dopaminergic neurons in the substantia nigra. Current treatments for PD focus on dopaminergic therapies, including L-dopa and dopamine receptor agonists. However, these treatments induce neuropsychiatric side effects. Psychosis, characterized by delusions and hallucinations, is one of the most serious such side effects. Adenosine A2A receptor antagonism is a nondopaminergic treatment for PD with clinical and preclinical efficacy. The present studies assessed A2A antagonists SCH 412348 and istradefylline in rodent prepulse inhibition (PPI), a model of psychosis. Dopamine receptor agonists pramipexole (0.3–3 mg/kg), pergolide (0.3–3 mg/kg), and apomorphine (0.3–3 mg/kg) significantly disrupted PPI; ropinirole (1–30 mg/kg) had no effect; L-dopa (100–300 mg/kg) disrupted rat but not mouse PPI. SCH 412348 (0.3–3 mg/kg) did not disrupt rodent PPI; istradefylline (0.1–1 mg/kg) marginally disrupted mouse but not rat PPI. These results suggest that A2A antagonists, unlike dopamine agonists, have an improved neuropsychiatric side effect profile.

Neural mechanisms of antidepressant efficacy of the dopamine receptor agonist pramipexole in treatment of bipolar depression

The D₂/D₃ receptor agonist pramipexole has clinical efficacy as an antidepressant, but its neural mechanisms are unknown. We used ¹⁸FDG-PET to investigate the cerebral metabolic effects of pramipexole augmentation of mood stabilizers in bipolar II depression. Fifteen bipolar II depressed patients on mood stabilizers were imaged at baseline and following 6 wk of pramipexole (n=7) or placebo (n=8) augmentation. Relative to placebo, pramipexole treatment was associated with reductions in normalized metabolism in bilateral orbitofrontal cortex, left ventrolateral prefrontal cortex (PFC), and right anteromedial PFC. Voxel-wise analyses additionally showed decreased normalized metabolism in the left inferior parietal cortex and medial frontopolar cortical (BA 10P) area of the anteromedial PFC following pramipexole treatment. These pramipexole-induced effects on regional metabolism suggest a mechanism of antidepressant action distinct from that previously reported under serotonin reuptake inhibitor treatment and appear compatible with evidence that the central dopaminergic system plays a role in the pathophysiology of bipolar depression.

Dopamine receptor agonists and depression in Parkinson's disease

Depression is one of the most common non-motor symptoms in Parkinson's disease (PD). It is associated with a more rapid progression of physical symptoms, greater decline in cognitive skills, and a poorer quality of life. Despite the high prevalence of depression and antidepressant use in PD, validated guidelines for the treatment of PD-associated depression (dPD) are lacking. Several methodological limitations have been recognized in the available studies examining the treatment of dPD. Some studies support a relevant role of the catecholaminergic systems in the pathogenesis of dPD. In open-label studies, the dopamine receptor agonists pramipexole and pergolide have shown antidepressant effects in PD patients. A placebo-controlled study of pramipexole in dPD is ongoing. The combined results of data from animal models and evidence in human studies support the strategy of dopaminergic stimulation as a treatment of depression. Treatment strategies for depressive symptoms in PD should include optimization of dopaminergic treatment prior to the addition of classic antidepressant drugs, thus reducing the risk of side-effects associated with multi-drug therapies.

Cost Effectiveness of Rasagiline and Pramipexole as Treatment Strategies in Early Parkinsonʼs Disease in the UK Setting

Levodopa is the most effective treatment for the symptoms of Parkinson's disease (PD). However, after an initial period of benefit, several limitations become apparent, including motor complications such as dyskinesia. Dyskinesia can severely affect patients' quality of life and increases healthcare resource use. Thus, delaying the need for levodopa, and therefore the onset of levodopa-induced dyskinesia, is important. The aim of this study was to compare the cost effectiveness, from a UK healthcare payer perspective, of two antiparkinsonian treatment strategies in early PD: first-line monotherapy with rasagiline, a novel monoamine oxidase B inhibitor; and the non-ergoline dopamine receptor agonist pramipexole. An economic Markov model was developed as a pragmatic tool to derive comparative information on the effectiveness, utility and costs of these two strategies over a 5-year period. Model input data were obtained from the TEMPO study for rasagiline and from a study by the Parkinson Study Group for pramipexole. Effectiveness outcomes were time to levodopa and time to levodopa-induced dyskinesia. Cost and quality-adjusted life-year (QALY) data were derived from published sources. Rasagiline was the dominant strategy. Compared with pramipexole, use of the rasagiline strategy was estimated to reduce costs by 18% per patient over 5 years and was associated with an additional 10% delay in dyskinesia onset (0.41 years; 95% CI 0.27, 0.55). This strategy was also found to prolong the time to levodopa initiation by 25% through a gain of 0.83 levodopa-free years (95% CI 0.56, 1.1). In addition, use of the rasagiline strategy was found to generate a 5% gain in QALYs over 5 years compared with the pramipexole strategy (3.7 +/- 0.02 vs 3.51 +/- 0.03). Sensitivity analyses confirmed that the model was robust. Rasagiline represents a cost-effective alternative to pramipexole in the treatment of early PD in the UK.