Mirapex

Mov Disord. 2005 May;20(5):602-10.
Long-term efficacy and safety of pramipexole in advanced Parkinson's disease: Results from a European multicenter trial.
Moller JC, Oertel WH, Koster J, Pezzoli G, Provinciali L.
Department of Neurology, Philipps-University Marburg, Germany.

A double-blind, placebo-controlled study with a subsequent open-label phase was conducted in 354 patients with Parkinson's disease (PD) and motor fluctuations under individually adjusted therapy with levodopa. During the double-blind phase 174 patients received pramipexole and 180 placebo. In agreement with previous studies, pramipexole treatment improved UPDRS sum scores of parts II and III by 30% and off times by approximately 2.5 hours per day. Differences between the treatment groups became significant at a daily dose of 0.75 mg of pramipexole dihydrochloride. We, furthermore, performed post hoc analyses with respect to resting tremor and depression. Patients with pronounced resting tremor derived a clear benefit from pramipexole treatment compared with placebo. In addition, pramipexole significantly improved the subitems motivation/initiative and depression in a subpopulation with increased Unified Parkinson's Disease Rating Scale I scores at the time of inclusion. There were 262 patients who were subsequently enrolled into the open-label study featuring a maximum duration of up to 57 months. Statistical analysis revealed good long-term efficacy and tolerability of pramipexole. Overall, only a low prevalence of somnolence was found. In summary, this study provides additional level I evidence of the usefulness of pramipexole, suggests a particular tremorlytic and a possible antidepressant action of this compound, and addresses for the first time its efficacy and safety during long-term administration in advanced PD. (c) 2005 Movement Disorder Society.

Neurosci Lett. 2005 Mar 29;377(2):106-9.
Biological effects of pramipexole on dopaminergic neuron-associated genes: relevance to neuroprotection.
Pan T, Xie W, Jankovic J, Le W.
Department of Neurology, Parkinson Disease Research Laboratory, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.

Pramipexole (PRX) is a non-ergot dopamine (DA) D2/D3 receptor agonist. Experimental studies have provided evidence that PRX may exert neuroprotective effects on the nigro-striatal system. Recent studies have demonstrated a slower decline of DAT density in Parkinson's disease patients treated with PRX as measured by SPECT. The aim of this study is to determine whether PRX has direct biological effects on DAergic neuron-associated genes expression, including DAT, VMAT2, and Nurr1. The human neuroblastoma SH-SY5Y cells were treated with PRX for various time periods and harvested to measure the mRNA and protein products of these genes. Treatment with PRX at 10 microM significantly increased DAT mRNA levels by 54-130% in 4-8 h, VMAT2 mRNA levels by 34% in 4 h, and Nurr1 mRNA levels by 31-39% in 2-4 h, which was the earliest induction among these three genes. The protein levels of DAT, VMAT2, and Nurr1 were markedly increased after PRX treatment, among which the increase of Nurr1 protein level was the highest at first 2 h treatment of PRX. Nafadotride, a D3 DA receptor antagonist, blocked the increase of Nurr1 gene expression induced by PRX, while eticlopride, a D2 DA receptor antagonist, didn't show this effect. Our findings that PRX has biological regulatory effects on DAergic neuron-associated genes may explain both the slower decline of imaged DAT and the neuroprotective effect of PRX. Furthermore, our results suggest that the induction of Nurr1 gene expression by PRX may be mediated by D3 DA receptor.

Eur J Neurol. 2005 Jun;12(6):432-6.
A pilot double-blind placebo-controlled trial of low-dose pramipexole in sleep-related eating disorder.
Provini F, Albani F, Vetrugno R, Vignatelli L, Lombardi C, Plazzi G, Montagna P.
Department of Neurological Sciences, University of Bologna, Bologna, Italy.

Sleep-related eating disorder (SRED) is characterized by recurrent arousals from sleep associated with compulsive ingestion of food. No controlled therapeutic trials are available for SRED. We assessed the safety, tolerability and efficacy of pramipexole, a dopamine D3-receptor agonist, in the treatment of SRED. Eleven consecutive patients with SRED in the absence of concurrent daytime eating disorders underwent actigraphic recording and subjective sleep diary evaluation for a week before and every week for 2 weeks of treatment with pramipexole 0.18-0.36 mg or placebo, administered in a double-blind crossover randomized sequence. The primary outcomes of the trial were actigraphic measures of night sleep parameters (sleep efficiency, motor activity mean and median, number and duration of wake episodes), secondary outcomes were the number of good sleep nights/weekly, number and duration of nocturnal awakenings/night, and visual analogue preference score. Pramipexole was well tolerated without any patient withdrawing from the study. Pramipexole reduced night-time activity median (P = 0.02) and increased the number of nights of good sleep/week (P = 0.02). All other measurements remained unaffected. Pramipexole at low doses was well tolerated, improving some measures of sleep quality and reducing median night activity in SRED. Further studies with higher dosages and for longer time-periods are warranted.

Addiction. 2005 Mar;100 Suppl 1:12-22.
Efficacy screening trials of paroxetine, pentoxifylline, riluzole, pramipexole and venlafaxine in cocaine dependence.
Ciraulo DA, Sarid-Segal O, Knapp CM, Ciraulo AM, Locastro J, Bloch DA, Montgomery MA, Leiderman DB, Elkashef A.
Division of Psychiatry, Boston University School of Medicine and VA Boston Healthcare System Medication Development Research Unit (MDRU), Boston, MA, USA.

ABSTRACT Aims The two studies presented here were conducted to assess the efficacy of paroxetine, pentoxifylline, riluzole, venlafaxine and pramipexole as medications for the treatment of cocaine dependence. Design A multi-arm, modified blinded, placebo-controlled design was used. Setting The studies were conducted at the Boston VA Healthcare System and the Boston University School of Medicine Medication Development Research Unit (MDRU). Participants Participants met criteria for cocaine dependence during a 2-week screening period. Intervention Following random assignment to one of the treatment groups, subjects received active medication or placebo for 8 weeks in combination with cognitive behavioral counseling. In the first study the efficacy of the antidepressant paroxetine (20 mg daily), the phosphodiesterase inhibitor pentoxifylline (1200 mg daily) and the glutamate release inhibitor riluzole (100 mg daily) was assessed. The antidepressant venlafaxine (150 mg daily) and the dopamine agonist pramipexole (1.5 mg daily) were evaluated in the second study. Measurements Urine benzoylecgonine (BE) concentrations, self-report of cocaine use and global impression scores served as primary outcome measures. Secondary measures included assessments of cocaine craving and psychiatric functioning. Adverse events were monitored during the treatment period. Findings None of the active medications produced greater reductions in urine BE concentrations over the treatment period than did placebo. There were trends for BE levels to become reduced in the pentoxifylline group during the first 4 weeks of treatment and for Addiction Severity Index (ASI) drug composite scores to be lower in the pentoxyfylline group at end-point compared to the placebo group. Significant within-group reductions in reported cocaine use and craving were found for all treatment groups, but none of the active medications were superior to placebo on these measures. The accuracy of self-reported cocaine use declined over the study period. Overall, the active medications were well tolerated. Conclusions This study does not support the use of paroxetine, pentoxifylline, riluzole, venlafaxine or pramipexole for the treatment of cocaine dependence. However, these results need to be interpreted with caution because of the small size and lack of homogeneity of the experimental groups.

Arch Neurol. 2004 Jul;61(7):1044-53.
Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial.
Holloway RG, Shoulson I, Fahn S, Kieburtz K, Lang A, Marek K, McDermott M, Seibyl J, Weiner W, Musch B, Kamp C, Welsh M, Shinaman A, Pahwa R, Barclay L, Hubble J, LeWitt P, Miyasaki J, Suchowersky O, Stacy M, Russell DS, Ford B, Hammerstad J, Riley D, Standaert D, Wooten F, Factor S, Jankovic J, Atassi F, Kurlan R, Panisset M, Rajput A, Rodnitzky R, Shults C, Petsinger G, Waters C, Pfeiffer R, Biglan K, Borchert L, Montgomery A, Sutherland L, Weeks C, DeAngelis M, Sime E, Wood S, Pantella C, Harrigan M, Fussell B, Dillon S, Alexander-Brown B, Rainey P, Tennis M, Rost-Ruffner E, Brown D, Evans S, Berry D, Hall J, Shirley T, Dobson J, Fontaine D, Pfeiffer B, Brocht A, Bennett S, Daigneault S, Hodgeman K, O'Connell C, Ross T, Richard K, Watts A; Parkinson Study Group.
Department of Neurology, University of Rochester, 1351 Mt. Hope Avenue, Suite 220, Rochester, NY 14620, USA. robert.holloway@ctcc.rochester.edu
BACKGROUND: The best way to initiate dopaminergic therapy for early Parkinson disease remains unclear. OBJECTIVE: To compare initial treatment with pramipexole vs levodopa in early Parkinson disease, followed by levodopa supplementation, with respect to the development of dopaminergic motor complications, other adverse events, and functional and quality-of-life outcomes. DESIGN: Multicenter, parallel-group, double-blind, randomized controlled trial. SETTING: 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, enrolled between October 1996 and August 1997 and observed until August 2001. INTERVENTION: Subjects were randomly assigned to receive 0.5 mg of pramipexole 3 times per day with levodopa placebo (n = 151) or 25/100 mg of carbidopa/levodopa 3 times per day with pramipexole placebo (n = 150). Dosage was escalated during the first 10 weeks for patients with ongoing disability. Thereafter, investigators were permitted to add open-label levodopa or other antiparkinsonian medications to treat ongoing or emerging disability. MAIN OUTCOME MEASURES: Time to the first occurrence of dopaminergic complications: wearing off, dyskinesias, on-off fluctuations, and freezing; changes in the Unified Parkinson's Disease Rating Scale and quality-of-life scales; and adverse events. RESULTS: Initial pramipexole treatment resulted in a significant reduction in the risk of developing dyskinesias (24.5% vs 54%; hazard ratio, 0.37; 95% confidence interval [CI], 0.25-0.56; P<.001) and wearing off (47% vs 62.7%; hazard ratio, 0.68; 95% CI, 0.49-0.63; P =.02). Initial levodopa treatment resulted in a significant reduction in the risk of freezing (25.3% vs 37.1%; hazard ratio, 1.7; 95% CI, 1.11-2.59; P =.01). By 48 months, the occurrence of disabling dyskinesias was uncommon and did not significantly differ between the 2 groups. The mean improvement in the total Unified Parkinson's Disease Rating Scale score from baseline to 48 months was greater in the levodopa group than in the pramipexole group (2 +/- 15.4 points vs -3.2 +/- 17.3 points, P =.003). Somnolence (36% vs 21%, P =.005) and edema (42% vs 15%, P<.001) were more common in pramipexole-treated subjects than in levodopa-treated subjects. Mean changes in quality-of-life scores did not differ between the groups. CONCLUSIONS: Initial treatment with pramipexole resulted in lower incidences of dyskinesias and wearing off compared with initial treatment with levodopa. Initial treatment with levodopa resulted in lower incidences of freezing, somnolence, and edema and provided for better symptomatic control, as measured by the Unified Parkinson's Disease Rating Scale, compared with initial treatment with pramipexole. Both options resulted in similar quality of life. Levodopa and pramipexole both appear to be reasonable options as initial dopaminergic therapy for Parkinson disease, but they are associated with different efficacy and adverse-effect profiles.

Biol Psychiatry. 2004 Jul 1;56(1):54-60.
Pramipexole for bipolar II depression: a placebo-controlled proof of concept study.
Zarate CA Jr, Payne JL, Singh J, Quiroz JA, Luckenbaugh DA, Denicoff KD, Charney DS, Manji HK.
Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institute of Health, Department of Human and Health Services, Bethesda, Maryland, USA.
BACKGROUND: The original serotonergic and noradrenergic hypotheses do not fully account for the neurobiology of depression or mechanism of action of effective antidepressants. Research implicates a potential role of the dopaminergic system in the pathophysiology of bipolar disorder. The current study was undertaken as a proof of the concept that dopamine agonists will be effective in patients with bipolar II depression. METHODS: In a double-blind, placebo-controlled study, 21 patients with DSM-IV bipolar II disorder, depressive phase on therapeutic levels of lithium or valproate were randomly assigned to treatment with pramipexole (n = 10) or placebo (n = 11) for 6 weeks. Primary efficacy was assessed by the Montgomery-Asberg Depression Rating Scale. RESULTS: All subjects except for one in each group completed the study. The analysis of variance for total Montgomery-Asberg Depression Rating Scale scores showed a significant treatment effect. A therapeutic response (>50% decrease in Montgomery-Asberg Depression Rating Scale from baseline) occurred in 60% of patients taking pramipexole and 9% taking placebo (p =.02). One subject on pramipexole and two on placebo developed hypomanic symptoms. CONCLUSIONS: The dopamine agonist pramipexole was found to have significant antidepressant effects in patients with bipolar II depression.

Nippon Yakurigaku Zasshi. 2004 Jun;123(6):429-40.
Pharmacological profiles and clinical effects of antiparkinsonian agent, pramipexole
Kohno Y, Takeuchi S.
Product Information Department of Marketing Division.
Pramipexole hydrochloride (pramipexole) is a nonergot dopamine D(2) agonist, and the S(-)enantiomer is used for the treatment of Parkinson's disease (PD). Pramipexole possessed the highest affinity with the D(3) subtype among the D(2) receptor subfamily members (D(2), D(3), D(4)), lacking affinity with the D(1) and D(5) subtype. Pramipexole ameliorated the motor disturbances in PD animal models, induced contralateral rotational behavior reflecting post-synaptic D(2) receptor stimulation in the striatum, and showed a variety of neuroprotective effects in vitro and in vivo experimental systems. The neuroprotective effects of pramipexole seemed to be derived from several mechanisms: stimulation of D(2) autoreceptor, stimulation of D(3) receptor, inhibition of oxidative reaction and following radical production, increase of Bcl-2 protein and inhibition of apoptotic cell death, and production of neurotrophic factor. Clinical efficacy of pramipexole both in monotherapy and combined use with L-DOPA were confirmed evaluating by UPDRS (Unified Parkinson's Disease Rating Scale) II (Activities of daily living) and III (Motor), in the results of clinical studies mainly performed in USA and European countries and partly in Japan. In addition, patients initially treated with pramipexole demonstrated reduction in problematic symptoms and in loss of striatal [(123)I]2beta-carboxymethoxy-3beta-(4-idodophenyl)tropan uptake, a marker of dopamine neuron degeneration, compared with those initially treated with L-DOPA.

Am J Psychiatry. 2004 Mar;161(3):564-6.
Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression.
Goldberg JF, Burdick KE, Endick CJ.
Department of Psychiatry, Weill Medical College of Cornell University, New York, NY, USA. jgoldber1@lij.edu
OBJECTIVE: Previous studies suggest that the dopamine agonist pramipexole may possess antidepressant properties. The authors conducted a preliminary randomized, placebo-controlled trial to determine the safety and antidepressant efficacy of pramipexole in treatment-resistant bipolar depression. METHOD: Twenty-two depressed outpatients with DSM-IV nonpsychotic bipolar disorder were randomly assigned to receive placebo or flexibly dosed pramipexole (mean maximum dose=1.7 mg/day, SD=1.3) added to existing mood stabilizers for 6 weeks. The primary outcome measure was response, defined as improvement in Hamilton Depression Rating Scale score of 50% or more over the baseline score; secondary analyses involved changes in Clinical Global Impression (CGI) severity scores. RESULTS: More patients given pramipexole (10 [83%] of 12) than patients given placebo (six [60%] of 10) completed the study. Eight (67%) of 12 patients taking pramipexole and two (20%) of 10 taking placebo had an improvement of at least 50% in their Hamilton depression scale scores. The mean percentage of improvement from baseline Hamilton depression scale scores was greater for patients taking pramipexole (48%) than for those taking placebo (21%). Mean improvements in CGI severity were also greater with pramipexole than placebo. No patients discontinued the study because of adverse events except for one patient who became hypomanic while taking pramipexole. CONCLUSIONS: Pramipexole was a safe and effective antidepressant among patients with bipolar depression. Larger randomized, controlled trials are needed to affirm these initial observations.

Clin Neuropharmacol. 2004 Mar-Apr;27(2):87-9.
Restless legs symptoms in a patient with above knee amputations: a case of phantom restless legs.
Hanna PA, Kumar S, Walters AS.
New Jersey Neuroscience Institute, JFK Medical Center, Edison, NJ, USA. phanna@solarishs.org
We describe a 78-year-old gentleman who, following bilateral above-knee amputations, developed symptoms of restless legs syndrome in the absent portions of his lower extremities. These symptoms improved with dopamine agonist therapy. In addition, he later developed parkinsonism with prominent rest tremor on metoclopramide. This suggests that this individual had a dopamine-deficient state which predisposed him to both restless legs syndrome and drug-induced or drug-exacerbated parkinsonism. We propose expanding the spectrum of phantom limb phenomena to include phantom restless legs.

J Neurol. 2004 Mar;251(3):335-9.
Conversion from dopamine agonists to pramipexole. An open-label trial in 227 patients with advanced Parkinson's disease.
Linazasoro G; Spanish Dopamine Agonists Study Group.
Centro de Neurologia y Neurocirugia funcional, Clinica Quiron, Parque Alcolea s/n, 20012 San Sebastian, Guipuzcoa, Spain. glinazasoro@terra.es
BACKGROUND: Pramipexole is a nonergoline dopamine agonist with D2 and preferential D3 dopamine receptor activity. This selective activity may result in clinically different effects. Small clinical trials indicate that overnight switching from one agonist to another can be performed safely. Objective To determine safety and efficacy of overnight switching from dopamine agonists to pramipexole in patients with advanced Parkinson's disease (PD). OBJECTIVE: To determine safety and efficacy of overnight switching from dopamine agonists to pramipexole in patients with advanced Parkinson's disease (PD). METHODS: Patients with advanced PD and motor complications not optimally controlled by levodopa and a stable dose of bromocriptine, pergolide or ropinirole were converted to pramipexole overnight. Clinical assessments were performed just prior to conversion and after 2, 6 and 12 weeks of treatment, when an optimal dose of pramipexole was achieved. RESULTS: Two hundred and seventeen patients were included in the trial. One hundred and twenty five were converted from pergolide to pramipexole, 58 from bromocriptine and 34 from ropinirole. After 12 weeks, the average dose of pramipexole was 2.8, 2.9 and 3.4 mg/d in patients converted from bromocriptine, pergolide, and ropinirole, respectively. UPDRS II, III and IV scores were reduced by 26-30% in all patients (p<0.0001). Mean levodopa dose was slightly reduced in all groups (p: NS). No serious or unexpected side effects were reported. The dose equivalences calculated from this trial were: bromocriptine:pramipexole 6.9:1, pergolide:pramipexole 0.9:1, ropinirole:pramipexole 1.5:1. CONCLUSION: Switching from bromocriptine, pergolide or ropinirole to pramipexole in an overnight schedule is safe. The observed clinical improvement may be related to a placebo effect, to the use of low doses of dopamine agonists or to a direct effect of pramipexole.

Arch Neurol. 2004 Jan;61(1):97-102.
Predictors of impaired daytime sleep and wakefulness in patients with Parkinson disease treated with older (ergot) vs newer (nonergot) dopamine agonists.
Razmy A, Lang AE, Shapiro CM.
Divisions of Psychiatry and Neurology, Department of Medicine, University of Toronto, Toronto Western Hospital, 399 Bathurst Street, Toronto, Ontario, Canada M5T 2S8.
BACKGROUND: Patients with Parkinson disease (PD) treated with the nonergot dopamine agonists pramipexole dihydrochloride and ropinirole hydrochloride have been reported to have sleep attacks without warning. OBJECTIVE: To perform a systematic evaluation of excessive daytime sleepiness using standard polysomnographic techniques. DESIGN: Two overnight studies and daytime sleep tests were performed on a prospective sample. Pathologic daytime sleep latency was indexed by a mean Multiple Sleep Latency Test score of no greater than 5 minutes or a mean Maintenance of Wakefulness Test latency of no greater than 20 minutes. PATIENTS AND SETTING: Eighty nondemented, independent PD patients treated with dopamine agonists at the Toronto Western Hospital Sleep Research Unit, Toronto, Ontario. RESULTS: Patients treated with pramipexole dihydrochloride (n = 29), ropinirole (n = 28), or bromocriptine mesylate or pergolide mesylate (n = 23) did not differ with respect to mean Multiple Sleep Latency Test scores (overall, 12.1 minutes [SD, 5.1 minutes], F(2,77) = 0.11; P =.90) or mean Maintenance of Wakefulness Test latencies (overall, 26.7 minutes [SD, 5.4 minutes]; F(2,77) = 1.1; P =.29). Fifteen patients (18.8%) exhibited pathologic daytime sleep latencies. The main risk factor associated with pathologic daytime sleep latency was high levodopa dosage equivalents (>867.5 mg; odds ratio, 4.2; 95% confidence interval, 1.3-13.7). Subjective accounts of daytime sleep and wakefulness, as indexed by scores on the Epworth Sleepiness Scale, were not related to impaired daytime sleepiness or wakefulness (chi(2)(1) [n = 80], 0.13; P =.72). CONCLUSIONS: Total dopaminergic drug dose rather than the specific dopamine agonist used is the best predictor of daytime sleepiness in PD patients receiving dopamine agonist therapy. Physicians concerned with daytime hypersomnolence in PD patients treated with dopamine agonists and receiving high levodopa dosage equivalents should consider polysomnographic monitoring for impaired daytime sleep latency.

Mov Disord. 2004 Jan;19(1):22-8.
Quality of life in early Parkinson's disease: impact of dyskinesias and motor fluctuations.
Marras C, Lang A, Krahn M, Tomlinson G, Naglie G; Parkinson Study Group.
Division of Neurology, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.
The impact of dyskinesias and motor fluctuations on quality of life (QOL) at various stages in the course of Parkinson's disease (PD) is not well understood. In 301 subjects with early PD enrolled in a clinical trial (CALM-PD), we quantified the impact of motor complications on QOL and investigated how this changes over time. We also compared QOL related to demographic and treatment characteristics. The presence of dyskinesias was associated with visual analogue scale (VAS) scores 3.0 of 100 points higher (better) than those without dyskinesias in years 1 to 2, even when adjusting for Unified Parkinson's Disease Rating Scale (UPDRS) motor scores. The positive association between dyskinesias and QOL scores was more marked in older patients. In years 3 to 4, dyskinesias no longer had a significant relationship with QOL. Younger subjects had higher VAS scores. Gender, motor fluctuations, and treatment regimen had no significant association with QOL, although a trend was found toward a small negative effect of motor fluctuations on QOL. We conclude that motor complications that occur within the first 4 years of treatment of PD do not have a significant negative effect on quality of life as measured by a visual analogue scale for most patients. Copyright 2003 Movement Disorder Society

Neuropsychobiology. 2004;50(1):65-70.
Low-dose pramipexole in the management of restless legs syndrome. An open label trial.
Stiasny-Kolster K, Oertel WH.
Department of Neurology, Center of Nervous Diseases, Philipps University, Marburg, Germany. stiasny@staff.uni-marburg.de
Dopaminergic agents are considered the treatment of choice for restless legs syndrome (RLS); levodopa is the only substance licensed for this disorder in some European countries. However, in a substantial proportion of patients symptoms are not adequately controlled for a whole night due to the short half-life of levodopa or because symptom augmentation may develop. To further investigate the impact of pramipexole on the management of RLS we performed a short-term open label trial with pramipexole in 17 patients who were being insufficiently treated with levodopa or for whom pramipexole was primarily being considered because of the severity of the RLS symptoms. A single dose of 0.125-0.75 mg pramipexole (mean 0.3 +/- 0.2 mg) in the evening resulted in a significant improvement of subjective RLS symptoms as rated by the International RLS Study Group Severity Scale (IRLS scores: 29.8 +/- 4.7 baseline vs. 7.3 +/- 5.9 endpoint; p = 0.0001). Polysomnographic recordings showed a significant improvement of the periodic leg movements (PLM) index, PLM sleep arousal index, sleep-onset latency, total sleep time and sleep efficiency. All patients who had developed a worsening of RLS symptoms under levodopa recovered from daytime symptoms after their medication was switched to pramipexole. Since pramipexole was well tolerated, an ideal dosage to control RLS symptoms could be reached rapidly. Pramipexole has proven a suitable alternative in patients with moderate to severe RLS, particularly when their therapy has to be switched to a dopamine agonist. Copyright 2004 S. Karger AG, Basel

Sleep Med. 2004 Jan;5(1):9-14.
Augmentation and tolerance with long-term pramipexole treatment of restless legs syndrome (RLS).
Winkelman JW, Johnston L.
Departments of Medicine and Psychiatry, Brigham and Women's Hospital, Harvard Medical School, 1400 Centre Street, Suite 109, Newton Center, MA 02459, USA. jwinkelman@sleephealth.com
BACKGROUND: Dopaminergic agents have become first-line treatments for restless legs syndrome (RLS). The most common serious complications of L-Dopa treatment of RLS are "augmentation", in which RLS symptoms appear earlier during the day, and tolerance, in which medication effectiveness wanes over time. The aims of this study were to assess rates of augmentation and tolerance, and their interrelationship, with pramipexole treatment of RLS. PATIENTS AND METHODS: Retrospective assessment of all patients (N=59) treated for RLS with pramipexole for at least 6 months (mean duration=21.2+/-11.4 months) by the senior author. Pramipexole dosing and clinical follow-up were performed in a standardized fashion. L-Dopa was discontinued and other medications for RLS were tapered as tolerated. Rates of augmentation (need for earlier administration of the same dose of pramipexole) and tolerance (need for an increase in pramipexole dose) were determined. RESULTS: Augmentation developed in 32% (19/59), and tolerance occurred in 46% (27/59), of patients. These two complications were statistically related (P<0.05). The only clinical predictors of these complications were previous augmentation or tolerance to L-Dopa. CONCLUSIONS: Augmentation and tolerance are more common with extended pramipexole treatment of RLS than has been previously reported in preliminary studies. However, these complications are generally manageable by earlier dosing or small dose increases of this agent, and only rarely require medication discontinuation.

Zh Nevrol Psikhiatr Im S S Korsakova. 2004;104(1):24-30.
A comparative study of efficacy of dopamine receptors agonists and catechol-O-methyltransferase in the treatment of late stages of Parkinson's disease
Krivonos OV, Fedorova NV, Chigir' IP.
Dopamine receptors agonists and catechol-O-methyltransferase (COMT) inhibitors are the novel classes of the drugs for Parkinson's disease (PD) treatment in both early and late stages. In the latter one, there is an increase of substantia nigra neurons degeneration, striatum denervation, changes of dopamine receptors state, dysregulation of Levadopa uptake, dopamine synthesis and storage, decrease of dopamine receptors density in striatum that results in clinical picture alteration and development of pharmaco-therapeutic side-effects, as well as motor fluctuations and drug diskinesias. The use of dopamine receptors agonists and COMT inhibitors at the late PD stages in combination with other antiparkinsonian medications allows improving pharmaco-therapeutic efficacy, along with patient's daily activity and quality of life.

CNS Drugs. 2003;17(13):965-73.
Pramipexole in routine clinical practice: a prospective observational trial in Parkinson's disease.
Reichmann H, Brecht MH, Koster J, Kraus PH, Lemke MR.
Department of Neurology, Technical University of Dresden, Dresden, Germany.
OBJECTIVE: The mixed dopamine D2/D3 receptor agonist pramipexole is effective as monotherapy in early Parkinson's disease and as adjunctive therapy in advanced disease. Clinical trials suggest that the benefits of pramipexole may extend beyond the relief of motor symptoms (akinesia, rigidity and tremor at rest) to amelioration of depressive symptoms in Parkinson's disease. The aim of this study was to confirm the beneficial effects of pramipexole on the core symptoms of Parkinson's disease (with a focus on tremor), as well as to assess its antidepressant activity, during routine clinical practice. The study also aimed to demonstrate the practicability of the Snaith-Hamilton Pleasure Scale (SHAPS-D), the Tremor Impact Scale (TIS) and the Short Parkinson's Evaluation Scale (SPES) under conditions of routine clinical practice. STUDY DESIGN: This was a prospective observational study. PATIENTS: Data for 657 outpatients with Parkinson's disease were collected from German hospitals and specialist practices. The majority of patients were in Hoehn & Yahr stage II or III and were receiving levodopa. METHODS: Pramipexole (Sifrol) was initiated at a dosage of 0.375 mg/day (using a three-times-daily schedule) and titrated upwards, as required, at weekly intervals over a 4-week period to a maximum dosage of 4.5 mg/day (three times daily). Clinical evaluation was performed at baseline, at the end of the titration phase and at the end of maintenance therapy. Patients were assessed via the German questionnaire versions of the physician-assessed SPES, the self-evaluated TIS and the SHAPS-D. Changes in scale scores were evaluated nonparametrically, using the Wilcoxon-matched pairs test. Cronbach's alpha was used as a measure for item consistency. RESULTS: Pramipexole significantly improved SPES subscores for motor symptoms, complications of therapy, psychological status and activities of daily living. Pramipexole also reduced the detrimental effect of tremor on activities of daily living and social interactions, as assessed by patients via the TIS. As indicated by the results of the SHAPS-D questionnaire, pramipexole significantly reduced anhedonia in patients who had associated depression. Internal consistency of SPES subscales was found to be unaltered between the initial evaluation and follow-up. Likewise, internal consistency for TIS and SHAPS-D was demonstrated. Pramipexole was well tolerated and accepted by the vast majority of physicians and patients. CONCLUSION: In addition to ameliorating the core symptoms of akinesia and rigidity in Parkinson's disease, pramipexole improves tremor and depressive symptoms in routine clinical practice. The SPES, TIS and SHAPS-D were found to be useful instruments with validity in this study.

Amyotroph Lateral Scler Other Motor Neuron Disord. 2003 Jun;4(2):90-5.
Reduction of oxidative stress in amyotrophic lateral sclerosis following pramipexole treatment.
Pattee GL, Post GR, Gerber RE, Bennett JP Jr.
Department of Neurology, University of Nebraska Medical Center/Neurology Associates, Lincoln, NE, USA.
Oxidative abnormalities have been identified both in familial amyotrophic lateral sclerosis (FALS) and the more prevalent sporadic ALS (SALS). Mitochondria dysfunction and toxic free radicals may play a role in this disease process, although the exact pathogenesis of both forms of ALS remains unknown. 2,3-DHBA is a hydroxylated salicylate by product that has been shown to be a reliable marker of increased free radical activity and is reliably assayed by HPLC. Following an oral salicylate load, we found elevated serum levels of 2, 3-dihydroxybenzoic acid (2,3-DHBA) and DHBA/salicylate in SALS subjects. Pramipexole has been shown to reduce oxidative stress and be neuroprotective in cell and animal models of neurodegeneration. We studied 12 SALS patients to determine the levels of 2,3-DHBA both before and after treatment with pramipexole. We found that pramipexole treatment up to 6 mg/day was well tolerated. The mean 2,3-DHBA serum levels were reduced by 45% and DHBA/salicylate ratios declined by 59% following treatment with pramipexole. SALS patients show apparent increases in systemic oxygen radical production that are reduced by pramipexole treatment at conventional doses, suggesting that pramipexole or related compounds may interrupt free radical production in SALS.

Ideggyogy Sz. 2003 May 20;56(5-6):166-72.
Asymptomatic ischemic cerebrovascular disorders and neuroprotection with vinpocetine.
Hadjiev D.
University Hospital of Neurology and Psychiatry, St. Naum Compl. Javorov, B-1504 Bulgaria, Sofia, bl. 21. A.
The asymptomatic ischemic cerebrovascular disorders (AICVD) is an early manifestation of cerebrovascular disease. It is also known as latent insufficiency of the cerebrovascular circulation or as asymptomatic cerebrovascular disorders. Recently, the term subclinical disease, detected noninvasively, has been introduced by American Heart Association. The diagnosis is based on the following criteria: evidence of vascular risk factors; episodic nonspecific complaints without any focal cerebral symptoms; mild cognitive deficit, detected by neuropsychological tests; carotid ultrasonography often shows intimal-medial thickening, atherosclerotic plaques and carotid stenosis; CT and MRI occasionally reveal silent cerebral infarctions, white matter hyperintensities or cerebral atrophy; regional hypoperfusion above the ischemic threshold is also seen by rCBF measurements. Treatment of the AICVD, modifying the vascular risk factors and using neuroprotective agents, should be the cornerstone of primary prevention of ischemic stroke and cognitive decline, caused by cerebrovascular disorders. Vinpocetine has been found to interfere with various stages of the ischemic cascade: ATP depletion, activation of voltage-sensitive Na(+)- and Ca(++)-channels, glutamate and free radicals release. The inhibition of the voltage-sensitive Na(+)-channels appears to be especially relevant to the neuroprotective effect of vinpocetine. Pronounced antioxidant activity of the drug could also contribute to the neuroprotection. PET studies in primates and man showed that 11C labelled vinpocetine passes the blood-brain barrier rapidly. Heterogeneous brain distribution of the compound was observed mainly in the thalamus, basal ganglia, occipital, parietal and temporal cortex, regions which are closely related to the cognitive functions. PET studies in chronic ischemic stroke patients revealed favourable effects of vinpocetine on rCBF and glucose metabolism in the thalamus, basal ganglia and primary visual cortex. It seems, vinpocetine, affecting the multiple mechanisms of the AICVD, could be of benefit for the treatment in this early stage of cerebrovascular disease. Vinpocetine may also become a new therapeutic approach to prophylactic neuroprotection in patients at high risk of ischemic stroke.

Orv Hetil. 2003 May 18;144(20):973-8.
Effect of vinpocetin on the hemorheologic parameters in patients with chronic cerebrovascular disease
Szapary L, Horvath B, Alexy T, Marton Z, Kesmarky G, Szots M, Nagy F, Czopf J, Toth K.
Pecsi Tudomanyegyetem, Altalanos Orvostudomanyi Kar, Neurologiai Klinika.
INTRODUCTION: Data collected from large number of multicenter, randomized trials in acute and chronic stroke patients provide evidence, that incidence and high mortality of cerebrovascular disorders can be decreased mainly by prevention and that the effectiveness of acute stroke treatment is limited. The terminology of "chronic cerebrovascular diseases" involves many pathologic entities and often atypical clinical symptoms refer to the focal or global hypoperfusion of the brain. However, hemorheological disturbances seem to be important factors of the complex pathomechanism. Vinpocetine has successfully been used in the treatment of cerebrovascular diseases, the part of the mechanism of action are the favourable rheological effects demonstrated after oral administration in more previous studies. AIMS AND METHODS: In this study the hemorheological changes after administration of small (30 mg/day) and high dose (increased to 70 mg/day) intravenous vinpocetine for 7 days in 30 patients in chronic phase of ischemic cerebrovascular disease were investigated. RESULTS: High dose parenteral vinpocetine treatment significantly (p < 0.05-0.005) decreased the hematocrit, the whole blood and plasma viscosity and red blood cell aggregation compared to the values before the treatment. Only red blood cell aggregation was improved significantly (p < 0.05) by small dose treatment. CONCLUSION: This study and other hemorheological studies in cerebrovascular patients demonstrated persistent rheological abnormalities despite the preventive therapy. The beneficial rheological effect of high dose parenteral vinpocetine indicates the use of this drug in the treatment of chronic cerebrovascular diseases.

Cochrane Database Syst Rev. 2003;(1):CD003119.
Vinpocetine for cognitive impairment and dementia.
Szatmari SZ, Whitehouse PJ.
4300, Targu Mures, str. Gral I., Dumitrache 22, Romania.
BACKGROUND: Vinpocetine is a synthetic ethyl ester of apovincamine, a vinca alkaloid obtained from the leaves of the Lesser Periwinkle (Vinca minor) and discovered in the late 1960s. Although used in human treatment for over twenty years, it has not been approved by any regulatory body for the treatment of cognitive impairment. Basic sciences studies have been used to claim a variety of potentially important effects in the brain. However, despite these many proposed mechanisms and targets, the relevance of this basic science to clinical studies is unclear. OBJECTIVES: To assess the efficacy and safety of vinpocetine in the treatment of patients with cognitive impairment due to vascular disease, Alzheimer's disease, mixed (vascular and Alzheimer's disease) and other dementias. SEARCH STRATEGY: The Cochrane Dementia & Cognitive Improvement Group's Specialized Register was searched using the terms vinpocetin*, cavinton, kavinton, Rgh-4405, Tcv-3B, "ethyl apovincaminate", vinRx, periwinkle, "myrtle vincapervinc" and cezayirmeneksesi. The manufacturers of vinpocetine were asked for information on trials of vinpocetine for dementia. In addition we tried to collect articles not listed in MEDLINE or other sources on the Internet (e.g. articles in Hungarian and Romanian). SELECTION CRITERIA: All human, unconfounded, double-blind, randomized trials in which treatment with vinpocetine was administered for more than a day and compared to control in patients with vascular dementia, Alzheimer's dementia or mixed Alzheimer's and vascular dementia and other dementias. Non-randomized trials were excluded. DATA COLLECTION AND ANALYSIS: Data were independently extracted by the two reviewers (SzSz and PW) and cross-checked. Data from "washout" periods were not used for the analysis. For continuous or ordinal variables, such as cognitive test results, the main outcomes of interest were the change in score from baseline. The categorical outcome of global impression was transformed to binary data (improved or not improved) as was the occurrence of adverse effects; here the endpoint itself was of interest the Peto method of the "typical odds ratio" was used. A test for heterogeneity of treatment effects between the trials was made if appropriate. Data synthesis and analysis were performed using the Cochrane Review Manager software (RevMan version 4.1). MAIN RESULTS: All identified studies were performed before the 1990s and used various terms and criteria for cognitive decline and dementia. The three studies included in the review involved a total of 583 people with dementia treated with vinpocetine or placebo. The reports of these studies did not make possible any differentiation of effects for degenerative or vascular dementia. The results show benefit associated with treatment with vinpocetine 30mg/day and 60 mg/day compared with placebo, but the number of patients treated for 6 months or more was small. Only one study extended treatment to one year. Adverse effects were inconsistently reported and without regard for relationship to dose. The available data do not demonstrate many problems of adverse effects but intention-to-treat data were not available for any of the trials. REVIEWER'S CONCLUSIONS: Although the basic science is interesting, the evidence for beneficial effect of vinpocetine on patients with dementia is inconclusive and does not support clinical use. The drug seems to have few adverse effects at the doses used in the studies. Large studies evaluating the use of vinpocetine for people suffering from well defined types of cognitive impairment are needed to explore possible efficacy of this treatment.

Acta Pharm Hung. 2002;72(2):84-91.
Neuroprotective effects of vinpocetine in vivo and in vitro. Apovincaminic acid derivatives as potential therapeutic tools in ischemic stroke
Dezsi L, Kis-Varga I, Nagy J, Komlodi Z, Karpati E.
Richter Gedeon Vegyeszeti Gyar Rt., Budapest, Gyomroi ut 19-21.-1103.
The aim of the present study was to review neuroprotective therapy from the preclinical point of view as a potential tool for the treatment of stroke, as well as to discuss neuroprotective effects of the apovincaminic acid derivative vinpocetine (Cavinton). Our own in vivo and in vitro experiments were aimed at further characterizing pharmacological effects involved in the vinpocetine-induced neuroprotection. The effect of vinpocetine on infarct volume (obtained by 2,3,5-triphenyltetrazolium-chloride staining) was studied in permanent middle cerebral artery occlusion (MCAO) in rats (3 mg/kg i.p., 30 min postischemia). Vinpocetine treatment significantly decreased infarct volume (by 42%, p < 0.05) compared to control, which was better than the effect of nimodipine (17%) or MK-801 (18%). Neurotoxicity measurements were made in primary cortical cell culture using LDH release as an indicator. Vinpocetine dose-dependently inhibited prolonged (24 h) or transient (15 min) glutamate, and transient N-metil-D-aspartate (NMDA) or veratridine (0.1-1 mM) induced excitotoxicity (IC50 = 2-7 x 10(-6) M). In these tests the neuroprotective potency of vinpocetine was lower than that of MK-801, but it was similar to those of flunarizine or nimodipine. These results together with former literature data indicate that apovincaminic acid derivatives possessing strong neuroprotective potential may play an important role in the therapy of ischemic stroke.