Pramipexole Research Articles

Effects of a Dopamine Agonist on the Pharmacodynamics of Levodopa in Parkinson Disease

Treatment of Parkinson disease commonly includes levodopa and dopamine agonists; however, the interaction of these 2 drugs is poorly understood. To examine the effects of a dopamine agonist on the motor response to levodopa. Double-blind, randomized, placebo-controlled, crossover clinical trial. Ambulatory academic referral center. Patients Thirteen patients with idiopathic Parkinson disease taking levodopa and experiencing motor fluctuations and dyskinesia. Eligible individuals were randomly assigned to receive pramipexole dihydrochloride or placebo for 4 weeks followed by a 2-hour intravenous levodopa infusion on consecutive days at 2 rates and with blinded assessments. They were then crossed over to the alternate oral therapy for 4 weeks followed by levodopa infusion and reassessment. Change in finger-tapping speed, measured using the area under the curve (AUC) for finger taps per minute across time; peak finger-tapping speed; duration of response; time to "ON" (defined as a 10% increase in finger-tapping speed above baseline); walking speed; and dyskinesia AUC. Pramipexole with levodopa infusion increased finger-tapping speed beyond the change in baseline by a mean (SE) of 170 (47.2) per minute x minutes (P = .006) and more than doubled the AUC for finger-tapping speed. Pramipexole increased peak finger-tapping speed by a mean (SE) of 18 (8.5) taps per minute (P = .02) and improved mean (SE) walking speed (15.9 [0.70] vs 18.9 [0.70] seconds, P = .004). Pramipexole prolonged duration of response after levodopa infusion and shortened time to ON. Pramipexole increased mean (SE) baseline dyskinesia scores (26.0 [5.85] vs 12.1 [5.85] points, P = .05) and peak dyskinesia scores with levodopa infusion. Pramipexole augmented the motor response to levodopa beyond a simple additive effect and increased the severity of levodopa-induced dyskinesia. When considering a combination of these therapies, an appropriate balance should be maintained regarding gain of motor function vs worsening of dyskinesia. Trial Registration clinicaltrials.gov Identifier: NCT00666653.

Pramipexole Acts as Antidepressant in PD

Pramipexole Acts as Antidepressant in PD

Reply: long-term retention rate of pramipexole in the treatment of Parkinson’s disease

To the editor: Keranen and colleagues have investigated the retention rate on pramipexole (PRX) among patients diagnosed with idiopathic Parkinson’s disease (PD) in a University Hospital in Finland. Moreover, they investigated reasons for PRX discontinuation, and they tried to identify determinants for PRX discontinuation. We welcome their study as a first initiative to identify reasons for discontinuation and possible determinants. The authors pointed out that they found a retention rate of PRX in PD patients that was higher (63% at 3 years) than we found in our cohort (40% at 3 years) [1], despite similarities in patient characteristics. We agree that differences in study methods may have contributed to variation in findings. In our study, we assessed the (dis)continuation of PRX treatment with prescription data from pharmacies whereas Keranen et al. used records of physicians. In our opinion, several factors have to be taken into account. Firstly, it is possible that not all changes in medication (discontinuation, dose changes) are written down in medical records. Therefore, some patients that have discontinued could be missed. Secondly, there remains a possibility that some patients have discontinued their medication without informing their physician. There is evidence for non-adherence in patients with PD measured with a computerised monitoring system [2]. However, studies investigating whether patients actually get their medication from the pharmacy are lacking. Lastly, the number of visits to the treating physician (in the study of Keranen et al.) or to the pharmacy (in our study) could be a factor in the precision of the estimation of discontinuation. The mean length of PRX prescriptions in our study was 47 days. This implies that we had an evaluation moment (use or no use) every 47 days. We do not know the frequency of visits to the treating physician in the study of Keranen et al. Keranen et al. found two non-genetic factors that were associated with PRX discontinuation: orthostatic hypotension and entacapone treatment prior to PRX treatment. These findings are an interesting supplement to our study. We think, however, that genetic factors should also be studied in the future [3].

Long-term retention rate of pramipexole in the treatment of Parkinson’s disease

To the editor: In a recent retrospective study, Arbouw et al. [1] reported that 60% of patients treated with pramipexole (PRX) due to Parkinson’s disease (PD) discontinued the drug within 3 years. The patients were identified from a neurology department of a large teaching hospital in The Netherlands, and the discontinuation rates were based on prescription data from community pharmacies. We have assessed longterm retention rate of patients on PRX therapy based on hospital records and sought to identify risk factors underlying the discontinuation of PRX. Using the patient records of Tampere University Hospital (Finland), we retrospectively identified all patients with idiopathic PD treated either as inor outpatients at the Department of Neurology between 1 January 1999 and 31 December 2005. We included patients who had been prescribed PRX and for whom data were available from at least one follow-up visit. From the hospital records on patient demographics, age at onset and duration of PD, we obtained information on possible motor (treatment-related fluctuations, dyskinesia) and non-motor complications (e.g. orthostatic hypotension, hallucinations etc.) and previous concomitant PD drugs and their doses prior to and during PRX treatment. The cause and time of possible discontinuation of PRX was recorded. The retention rate (i.e. the proportion of patients continuing on PRX medication) was estimated using the Kaplan–Meyer method [2]. Follow-up commenced at the introduction of PRX into the treatment program and ended at the discontinuation of treatment or closing date. The effect of different factors on retention rate was examined using Cox regression analysis [3]. A total of 94 patients (33 women, 61 men) fulfilled the study criteria. The mean age of the patient cohort at the onset of PD was 59 (standard deviation 11) years, and the duration of the disorder before the initiation of PRX therapy was 6.5 (SD 6) years. Motor fluctuations prior to the introduction of PRX were recorded in 37 patients (39%). At the initiation of PRX treatment, 66 patients (70%) were on levodopa, 30 (32%) used selegiline, 19 (20%) used entacapone and 15 (16%) used other antiparkinsonian drugs. At the last followup, 72 patients were still using PRX. Figure 1 shows the estimated rate of patient continuation on PRX. At 1 year, 76% of the patients were still on PRX; the rate at 3 and 6 years was 63%. The mean maintenance dose of PRX was 1.05 mg/day (as base; corresponding approximately to 1.5 mg as salt). Of the 94 patients, 14 (15%) discontinued PRX due to adverse effects, and eight (9%) discontinued due to insufficient therapeutic effects. The most common adverse effects leading to discontinuation were confusion (three patients), hallucinations (three patients) and nausea (two patients). Other reasons of discontinuation included dyskinesia, orthostatic hypotension and miscellaneous symptoms. Eur J Clin Pharmacol (2009) 65:955–956 DOI 10.1007/s00228-009-0661-4

Long-term Effect of Initiating Pramipexole vs Levodopa in Early Parkinson Disease

To compare the long-term outcomes of subjects initially treated with pramipexole dihydrochloride with those of subjects initially treated with levodopa in the Comparison of the Agonist Pramipexole With Levodopa on Motor Complications of Parkinson's Disease (CALM-PD) trial. Up to 2 years of open extended follow-up of the CALM-PD subjects. Academic movement disorders clinics at 22 sites in the United States and Canada. Patients Patients with early Parkinson disease (N = 301) who required dopaminergic therapy to treat emerging disability were enrolled between October 1996 and August 1997, a subset of whom consented to extended follow-up until August 2003 (n = 222). Intervention Subjects were randomized to receive initial treatment with either pramipexole (n = 151) or levodopa (n = 150). Investigators were permitted to add open-label levodopa or other antiparkinsonian medications to treat ongoing or emerging disability. The primary outcome variable was the time-weighted average of self-reported disability scores in the "on" and "off" states as measured by the Schwab and England Activities of Daily Living Scale at the final visit. Secondary outcomes included the Unified Parkinson's Disease Rating Scale score, the presence and severity of dopaminergic motor complications, quality-of-life scale scores, Geriatric Depression Scale score, Epworth Sleepiness Scale score, and adverse events. After a mean (SD) follow-up of 6.0 (0.2) years, mean (SD) self-reported weighted Schwab and England Activities of Daily Living Scale scores were similar in the initial pramipexole (79.9 [16.2]) and initial levodopa (82.5 [14.6]) groups (P = .19). Dopaminergic motor complications (wearing off, on-off effects, or dyskinesias) were more common in the initial levodopa group (68.4%) than in the initial pramipexole group (50.0%) (P = .002), although disabling dyskinesias were uncommon in both groups. The mean (SD) Epworth Sleepiness Scale score was significantly higher in the initial pramipexole group (11.3 [5.8]) than in the initial levodopa group (8.6 [4.7]) (P < .001). Mean (SD) changes from baseline in the total Unified Parkinson's Disease Rating Scale score did not significantly differ between the initial pramipexole (2.4 [17.4]) and initial levodopa (0.5 [17.1]) groups (P = .11). The policies of initial pramipexole and initial levodopa use followed by open-label levodopa use resulted in similar self-reported disability 6 years after randomization. Persistent differences favoring initial pramipexole were seen in the rates of dopaminergic motor complications, with less severe somnolence favoring initial levodopa. Trial Registration clinicaltrials.gov Identifier: NCT00804479.

Long-term Effect of Initiating Pramipexole vs Levodopa in Early Parkinson Disease

<h3>Objective</h3> To compare the long-term outcomes of subjects initially treated with pramipexole dihydrochloride with those of subjects initially treated with levodopa in the Comparison of the Agonist Pramipexole With Levodopa on Motor Complications of Parkinson's Disease (CALM-PD) trial. <h3>Design</h3> Up to 2 years of open extended follow-up of the CALM-PD subjects. <h3>Setting</h3> Academic movement disorders clinics at 22 sites in the United States and Canada. <h3>Patients</h3> Patients with early Parkinson disease (N = 301) who required dopaminergic therapy to treat emerging disability were enrolled between October 1996 and August 1997, a subset of whom consented to extended follow-up until August 2003 (n = 222). <h3>Intervention</h3> Subjects were randomized to receive initial treatment with either pramipexole (n = 151) or levodopa (n = 150). Investigators were permitted to add open-label levodopa or other antiparkinsonian medications to treat ongoing or emerging disability. <h3>Main Outcome Measures</h3> The primary outcome variable was the time-weighted average of self-reported disability scores in the “on” and “off” states as measured by the Schwab and England Activities of Daily Living Scale at the final visit. Secondary outcomes included the Unified Parkinson's Disease Rating Scale score, the presence and severity of dopaminergic motor complications, quality-of-life scale scores, Geriatric Depression Scale score, Epworth Sleepiness Scale score, and adverse events. <h3>Results</h3> After a mean (SD) follow-up of 6.0 (0.2) years, mean (SD) self-reported weighted Schwab and England Activities of Daily Living Scale scores were similar in the initial pramipexole (79.9 [16.2]) and initial levodopa (82.5 [14.6]) groups (<i>P</i> = .19). Dopaminergic motor complications (wearing off, on-off effects, or dyskinesias) were more common in the initial levodopa group (68.4%) than in the initial pramipexole group (50.0%) (<i>P</i> = .002), although disabling dyskinesias were uncommon in both groups. The mean (SD) Epworth Sleepiness Scale score was significantly higher in the initial pramipexole group (11.3 [5.8]) than in the initial levodopa group (8.6 [4.7]) (<i>P</i> &lt; .001). Mean (SD) changes from baseline in the total Unified Parkinson's Disease Rating Scale score did not significantly differ between the initial pramipexole (2.4 [17.4]) and initial levodopa (0.5 [17.1]) groups (<i>P</i> = .11). <h3>Conclusions</h3> The policies of initial pramipexole and initial levodopa use followed by open-label levodopa use resulted in similar self-reported disability 6 years after randomization. Persistent differences favoring initial pramipexole were seen in the rates of dopaminergic motor complications, with less severe somnolence favoring initial levodopa. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT00804479 Published online March 9, 2009 (doi:10.1001/archneurol.2009.32).

Critical review of ropinirole and pramipexole - putative dopamine D3-receptor selective agonists - for the treatment of RLS

Ropinirole hydrochloride (REQUIP, ADARTREL) and pramipexole dihydrochloride (MIRAPEX, SIFROL) are two putative dopamine D(3) receptor subtype-selective agonists recently approved by the FDA for the treatment of 'restless legs syndrome' (RLS). RLS is a difficult to define condition that is possibly more prevalent than previously thought. Direct-to-consumer advertising has raised public and professional awareness of RLS, but questions, even skepticism about the very existence of the condition, persist. The drugs have adverse effects that can negatively impact on quality of life and thus, as true for all drugs, require consideration of the benefit : risk ratio. We review the definition, diagnostic criteria, pathophysiology, and treatment of RLS, and assess the clinical and preclinical evidence for a pharmacologic rationale for D(3) agonism in general and of the claimed D(3) selectivity of ropinirole and pramipexole in particular.

Pharmacotherapy of Restless Legs Syndrome with Pramipexole

The dopamine agonist pramipexole (PRA) ((S)-2-Amino-4,5,6,7-tetrahydro-6-(propylamino) benzothiazole dihydrochloride; molecular formula C10H17N3S-2(HCl), is a D3 selective compound, approved in 1997 for the treatment of Parkinson disease and in 2006 for that of idiopathic restless legs syndrome (RLS). Because of its tolerability, safety and half-life, PRA is favored over levodopa and on the other ergot derivate dopamine agonists, and it is considered nowadays one of the first choices in the therapy of RLS. PRA is rapidly and completely absorbed after oral administration, its protein binding is around 15%, it is almost unaffected by hepatic metabolism and excreted by urine unchanged. PRA has a linear pharmacokinetics, with a half-life ranging between 8 and 14 hours. Double-blind, placebo-controlled studies demonstrated that PRA, even at low dosages and since the first nights of administration, is significantly effective on the typical sensitive symptoms of RLS, on the periodic leg movements during sleep, and in improving the quality of life of patients with RLS. A subjective improvement of sleep quality is usually also reported by the patients, but the polysomnographic assessment gave less solid results on objective sleep parameters. The most common PRA related side effects include headache, nausea and orthostatic hypotension. Data on the long-term therapy of PRA in RLS, and on the efficacy of PRA in symptomatic forms of RLS are warranted to better delineate the role of PRA in RLS treatment.

KNS‐760704 [(6R)‐4,5,6,7‐tetrahydro‐N6‐propyl‐2, 6‐benzothiazole‐diamine dihydrochloride monohydrate] for the Treatment of Amyotrophic Lateral Sclerosis

Developing effective treatments for chronic neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) has proven extremely difficult. ALS is universally fatal, characterized by progressive weakness due to the degeneration of upper and lower motor neurons, and leads eventually to respiratory failure which is the usual cause of death. Only a single treatment has been approved, the modestly effective nonspecific neuroprotectant Rilutek (riluzole; 2-amino-6-(trifluoromethoxy)benzothiazole). KNS-760704 [(6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine dihydrochloride, RPPX], a synthetic amino-benzothiazole with demonstrated activity in maintaining mitochondrial function, is being developed as a treatment for ALS. It has proven to be effective in multiple in vitro and in vivo assays of neuroprotection, including the G93A-SOD1 mutant mouse model; however, its specific mechanism of action remains unknown. The potential of KNS-760604 as a treatment for ALS was first suggested by studies showing that its optical enantiomer, Mirapex[(6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine; pramipexole dihydrochloride; PPX], a high-affinity agonist at dopamine D2, D3, and D4 receptors, exhibits important neuroprotective properties independent of its dopamine receptor agonism. In cell-based assays, both RPPX and PPX reduce the production of reactive oxygen species (ROS), attenuate the activation of apoptotic pathways, and increase cell survival in response to a variety of neurotoxins. However, PPX has limited utility as a clinical neuroprotective agent because the drug concentrations required for neuroprotection would likely produce unacceptable dopaminergic side effects. RPPX, on the other hand, while possessing the same neuroprotective potential as PPX, is a much lower-affinity dopamine receptor agonist and may therefore be more useful in the treatment of ALS. This review will examine the data supporting the hypothesis that the RPPX may have therapeutic potential for the treatment of neurodegenerative disorders including ALS. In addition, we will briefly review recent preclinical data in support of RPPX, and discuss the current status of its clinical development.

Corrections

Corrections

1.277 Holmes' tremor and treatment with pramipexole

1.277 Holmes' tremor and treatment with pramipexole

Pramipexole Okayed for Restless Legs

Pramipexole Okayed for Restless Legs

Factors Associated With the Development of Motor Fluctuations and Dyskinesias in Parkinson Disease

Motor fluctuations and dyskinesias can cause disability and reduce quality of life for patients with Parkinson disease (PD). To evaluate factors associated with the development of motor fluctuations and dyskinesias and to assess the sequence in which they occur in individual patients. We performed a retrospective analysis of data from a randomized clinical trial comparing pramipexole dihydrochloride and levodopa as initial treatment for PD. Subjects were followed up for 48 to 58 months and evaluated at 3-month intervals for the presence of motor fluctuations and dyskinesias. Academic and private practices. Patients Three hundred one patients with early Parkinson disease were enrolled in this study between October 2, 1996, and August 21, 1997, and were observed through August 24, 2001, when the last patient enrolled completed 4 years of follow-up. Order of appearance of motor fluctuations and dyskinesias, time to the first occurrence of motor fluctuations, and time to the first occurrence of dyskinesias. One hundred eighty-nine subjects (62.8%) developed motor complications. Of these, 71 (37.6%) developed fluctuations but not dyskinesias, 23 (12.2%) developed dyskinesias but not fluctuations, 48 (25.4%) developed fluctuations before dyskinesias, 33 (17.5%) developed dyskinesias before fluctuations, and 14 (7.4%) developed both at the same time. Factors significantly associated with earlier occurrence of dyskinesia were Hoehn and Yahr stage of 2 or higher, cumulative levodopa dose, cumulative levodopa equivalent dose (levodopa plus pramipexole), and occurrence of motor fluctuations. Pramipexole treatment was associated with later occurrence of dyskinesias. Factors associated with earlier occurrence of motor fluctuations were cumulative levodopa dose, cumulative levodopa equivalent dose, and occurrence of dyskinesias. Factors associated with later occurrence of motor fluctuations were age at onset of 65 years or older and pramipexole treatment. Higher cumulative levodopa doses and higher cumulative levodopa equivalent doses (levodopa plus pramipexole) were associated with the earlier occurrence of motor complications. Motor fluctuations and dyskinesias appear to be interrelated because the presence of one is associated with the earlier development of the other.

Pramipexole: a prime performer in RLS

Pramipexole: a prime performer in RLS

Validated chiral liquid chromatographic method for the enantiomeric separation of Pramipexole dihydrochloride monohydrate

A chiral liquid chromatographic method was developed for the enantiomeric resolution of Pramipexole dihydrochloride monohydrate, ( S)-2-amino-4,5,6,7-tetra-hydro-6-(propylamino) benzothiazole dihydrochloride monohydrate, a dopamine agonist in bulk drugs. The enantiomers of Pramipexole dihydrochloride monohydrate were resolved on a Chiralpak AD (250 mm × 4.6 mm, 10 μm) column using a mobile phase system containing n-hexane:ethanol:diethylamine (70:30:0.1, v/v/v). The resolution between the enantiomers was found not less than eight. The presence of diethylamine in the mobile phase has played an important role in enhancing chromatographic efficiency and resolution between the enantiomers. The developed method was extensively validated and proved to be robust. The limit of detection and limit of quantification of ( R)-enantiomer were found to be 300 and 900 ng/ml, respectively for 20 μl injection volume. The percentage recovery of ( R)-enantiomer was ranged from 97.3 to 102.0 in bulk drug samples of Pramipexole dihydrochloride monohydrate. Pramipexole dihydrochloride monohydrate sample solution and mobile phase were found to be stable for at least 48 h. The proposed method was found to be suitable and accurate for the quantitative determination of ( R)-enantiomer in bulk drugs.

Pramipexole reduces pain in patients with fibromyalgia

Pramipexole reduces pain in patients with fibromyalgia

Pleuropulmonary Fibrosis After Long-term Treatment With the Dopamine Agonist Pergolide for Parkinson Disease

Dopamine agonists are increasingly used in the treatment of Parkinson disease, but they may cause serious adverse effects. In December 1983, symptoms of Parkinson disease developed in a 55-year-old man with no history of pulmonary disease, smoking, or asbestos exposure. He began treatment with dopamine agonists bromocriptine mesylate (in 1984) and pergolide mesylate (in 1989). In late 2000, pulmonary symptoms developed. Chest radiographs and computed tomographic findings showed a mass in the right upper lobe and effusion. A biopsy specimen showed pleural and parenchymal fibrosis. This syndrome resolved after cessation of pergolide therapy and a switch to pramipexole dihydrochloride. This case draws attention to the association of long-term ergot dopamine agonist therapy with pleuropulmonary fibrosis, which can develop as late as 11 years after the initiation of therapy. We also review evidence that the risk of this complication is substantially lower with the newer nonergot dopamine agonists.

Pathological Gambling Caused by Drugs Used to Treat Parkinson Disease

Pathological gambling is a rare potential complication related to treatment of Parkinson disease (PD). However, the etiology of this behavior is poorly understood. To examine the relationship between medical therapy for PD and pathological gambling. In our routine movement disorders practice (2002-2004), we encountered 11 patients with idiopathic PD who had recently developed pathological gambling. We assessed the relationship to their medical therapy and compared them with cases identified by systematic review of the existing literature on pathological gambling and PD. All 11 patients with PD and pathological gambling were taking therapeutic doses of a dopamine agonist; 3 of these patients were not treated with levodopa. In 7 patients, pathological gambling developed within 3 months of starting to take or escalating the dose of the agonist; in the other 4 with a longer latency, gambling resolved after the agonist use was discontinued. Pramipexole dihydrochloride was the agonist in 9 of 11 cases in our series and 10 of 17 in the literature (68% in total). Dopamine agonist therapy was associated with potentially reversible pathological gambling, and pramipexole was the medication predominantly implicated. This may relate to disproportionate stimulation of dopamine D(3) receptors, which are primarily localized to the limbic system.

Pramipexole provides prolonged improvement of RLS

Pramipexole provides prolonged improvement of RLS

Legs can rest easy with pramipexole

Legs can rest easy with pramipexole