Mirapexin scientific update |
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2010 Jun;67(6):632-44.
Ersche KD, Bullmore ET, Craig KJ, Shabbir SS, Abbott S, Müller U, Ooi C, Suckling J, Barnes A, Sahakian BJ, Merlo-Pich EV, Robbins TW.
University of Cambridge, Behavioural and Clinical Neuroscience Institute, Department of Psychiatry, Cambridge, England.
Influence of compulsivity of drug abuse on dopaminergic modulation of attentional bias in stimulant dependence.
CONTEXT: There are no effective pharmacotherapies for stimulant dependence but there are many plausible targets for development of novel therapeutics. We hypothesized that dopamine-related targets are relevant for treatment of stimulant dependence, and there will likely be individual differences in response to dopaminergic challenges. OBJECTIVE: To measure behavioral and brain functional markers of drug-related attentional bias in stimulant-dependent individuals studied repeatedly after short-term dosing with dopamine D(2)/D(3) receptor antagonist and agonist challenges. DESIGN: Randomized, double-blind, placebo-controlled, parallel-groups, crossover design using pharmacological functional magnetic resonance imaging. SETTING: Clinical research unit (GlaxoSmithKline) and local community in Cambridge, England. PARTICIPANTS: Stimulant-dependent individuals (n = 18) and healthy volunteers (n = 18). INTERVENTIONS: Amisulpride (400 mg), pramipexole dihydrochloride (0.5 mg), or placebo were administered in counterbalanced order at each of 3 repeated testing sessions. MAIN OUTCOME MEASURES: Attentional bias for stimulant-related words was measured during functional magnetic resonance imaging by a drug-word Stroop paradigm; trait impulsivity and compulsivity of dependence were assessed at baseline by questionnaire. RESULTS: Drug users demonstrated significant attentional bias for drug-related words, which was correlated with greater activation of the left prefrontal and right cerebellar cortex. Attentional bias was greater in people with highly compulsive patterns of stimulant abuse; the effects of dopaminergic challenges on attentional interference and related frontocerebellar activation were different between high- and low-compulsivity subgroups. CONCLUSIONS: Greater attentional bias for and greater prefrontal activation by stimulant-related words constitute a candidate neurocognitive marker for dependence. Individual differences in compulsivity of stimulant dependence had significant effects on attentional bias, its brain functional representation, and its short-term modulation by dopaminergic challenges.
2010 Jan;67(1):27-32.
Brodsky MA, Park BS, Nutt JG.
Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, OP-32, Portland, OR 97239. brodskym@ohsu.edu.
Effects of a dopamine agonist on the pharmacodynamics of levodopa in Parkinson disease.
BACKGROUND: Treatment of Parkinson disease commonly includes levodopa and dopamine agonists; however, the interaction of these 2 drugs is poorly understood. OBJECTIVE: To examine the effects of a dopamine agonist on the motor response to levodopa. DESIGN: Double-blind, randomized, placebo-controlled, crossover clinical trial. SETTING: Ambulatory academic referral center. Patients Thirteen patients with idiopathic Parkinson disease taking levodopa and experiencing motor fluctuations and dyskinesia. INTERVENTIONS: 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. MAIN OUTCOME MEASURES: 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. RESULTS: 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. CONCLUSIONS: 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.
Exp Clin Psychopharmacol. 2010 Jun;18(3):267-76.
Madden GJ, Johnson PS, Brewer AT, Pinkston JW, Fowler SC.
Department of Applied Behavioral Science, University of Kansas, Lawrence, KS 66045, USA. gmadden@ku.edu
Effects of pramipexole on impulsive choice in male wistar rats.
Clinical reports, primarily with Parkinson's disease patients, note an association between the prescribed use of pramipexole (and other direct-acting dopamine agonist medications) and impulse control disorders, particularly pathological gambling. Two experiments examined the effects of acute pramipexole on rats' impulsive choices where impulsivity was defined as selecting a smaller-sooner over a larger-later food reward. In Experiment 1, pramipexole (0.1 to 0.3 mg/kg) significantly increased impulsive choices in a condition in which few impulsive choices were made during a stable baseline. In a control condition, in which impulsive choices predominated during baseline, pramipexole did not significantly change the same rats' choices. Experiment 2 explored a wider range of doses (0.01 to 0.3 mg/kg) using a choice procedure in which delays to the larger-later reinforcer delivery increased across trial blocks within each session. At the doses used in Experiment 1, pramipexole shifted choice toward indifference regardless of the operative delay. At lower doses of pramipexole (0.01 and 0.03 mg/kg), a trend toward more impulsive choice was observed at the 0.03 mg/kg dose. The difference in outcomes across experiments may be due to the more complex discriminations required in Experiment 2, that is, multiple discriminations between changing delays within each session.
2009 Oct;34(5):493-505.
Varga LI, Ako-Agugua N, Colasante J, Hertweck L, Houser T, Smith J, Watty AA, Nagar S, Raffa RB.
Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA, USA.
Critical review of ropinirole and pramipexole - putative dopamine D(3)-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.
Parkinsonism Relat Disord. 2009 Dec;15 Suppl 4:S93-6.
Reichmann H.
Department of Neurology, Dresden University of Technology, Dresden, Germany. Heinz.Reichmann@uniklinikum-dresden.de
Transdermal delivery of dopamine receptor agonists.
Conceptually, continuous dopaminergic stimulation is universally accepted to be the preferred therapeutic strategy to prevent or postpone dyskinesia in Parkinson's disease (PD). L-dopa has a short half-life of 2 hours and causes dyskinesia, whereas dopamine receptor agonists usually have a much longer half-life. Of the latter agents, cabergoline has the longest half-life of 68 hours and is ideal for the prevention of dyskinesia; but this is also true for other dopamine receptor agonists such as ropinirole or pramipexole, which have a shorter half-life of about 6-8 hours. Due to the possible development of valvular fibrosis, cabergoline is, however, only approved as a second-line treatment in PD, and patch technology has therefore gained major interest. So far, rotigotine is the only dopamine receptor agonist available as a patch. There is good evidence that once-daily patch usage provides patients with constant dopaminergic stimulation, and that patches are of equal potency to other oral non-ergot derivatives such as ropinirole and pramipexole. The disadvantages of patches are skin irritation and crystallization of the drug if not kept in the refrigerator.
Parkinsonism Relat Disord. 2009 Dec;15 Suppl 4:S81-4.
Picillo M, Rocco M, Barone P.
Department of Neurological Sciences, University of Naples Federico II, Naples, Italy.
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.
2008 Fall;14(3):215-26.
Gribkoff VK, Bozik ME.
Knopp Neurosciences, Inc., Pittsburgh, PA 15203, USA. valentin.gribkoff@knoppneurosciences.com
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.
Neurol Sci. 2008 Dec;29 Suppl 5:S371-4.
Antonini A, Barone P.
Istituti Clinici di Perfezionamento, Parkinson Institute, Via Bignami 1, Milan, Italy. angelo3000@yahoo.com
Dopamine agonist-based strategies in the treatment of Parkinson's disease.
More therapeutic options have become available for Parkinson's disease (PD) in recent years, leading to significant improvements in motor control both at early and advanced disease stages. More importantly, the need to expand disease management beyond motor symptom control has been recently highlighted and contribution of non-motor features to quality of life is now relevant. Dopamine agonists represent a valid therapeutic option in PD and their effect on non-motor domains like mood or cognition is now acknowledged as a key factor in fully addressing patients' needs. Pramipexole is a well established dopamine agonist that is currently being investigated for its potential disease-modifying effect and action on mood in PD. In this review we will examine factors contributing to treatment decision-making and discuss how a proper balance between motor and non-motor features should be aimed for in approaching PD therapy.
No To Hattatsu. 2008 Nov;40(6):473-7.
Mohri I, Kato-Nishimura K, Kagitani-Shimono K, Tachibana N, Ozone K, Taniike M.
Department of Mental Health and Environmental Effects Research, the Molecular Research Center for Children's Mental Development.
[Restless-leg syndrome--possible unrecognized cause for insomnia and irritability in children] [Article in Japanese]
Restless legs syndrome (RLS) has gradually been recognized as a cause for insomnia in adults, but there have been few reports about children with RLS in Japan. Here we described seven pediatric RLS patients. All of the parents of our patients had difficult times to make their children sleep due to irritability, restlessness, and demanding bedtime routines. All patients had asked their parents to rub their feet in bed, and it took more than half an hour to soothe them until they fell asleep. Their mothers had been exhausted from this night-time routine. However, they did not consider the routine abnormal, as it had been their habitual behavior since infancy. Some parents were too distressed or embarrassed to describe the symptoms of their child properly. Five patients had clear family history and none had obvious periodic leg movements during sleep. All patients showed low levels of ferritin and iron supplementation was effective in five cases. In the severest two cases, pramipexole, but not iron, was dramatically effective. Both patients started to show RLS symptoms in the early days of infancy, which may suggest more severe hereditary dopaminergic dysfunction. RLS does occur in childhood and pediatricians should bear it in mind as one of the differential diagnoses when seeing children who are irritated and/or having difficulty in initiating their sleep.
Neuropsychiatr Dis Treat. 2008 Aug;4(4):707-10.
Kano O, Ikeda K, Kiyozuka T, Iwamoto K, Ito H, Kawase Y, Sato R, Fujioka T, Araki Y, Baba S, Iwasaki Y.
Department of Neurology, Methodist Neurological Institute Houston, TX, USA.
Beneficial effect of pramipexole for motor function and depression in Parkinson's disease.
We examined whether pramipexole (PPX) can influence depressive scale in normal and mild depressive parkinsonian patients. In an open study of PPX as an add-on to L-dopa therapy or single administration, 36 nondemented outpatients with Parkinson's disease (PD) were entered first. All were in the stage II or III of Hoehn and Yahr scale (H&Y). PPX were started at 0.125 mg/day and daily doses were increased to 1.5 mg/day. At 3 months after PPX treatment, patients were re-evaluated. Hamilton Depression Rating Scale (HAM-D), Unified Parkinson's Disease Rating Scale III, H&Y stage, and freezing of gait questionnaire were compared in patients before and after PPX treatment. These scores were significantly improved after PPX administration. There were no correlations between HAM-D and those motor functions. We suggest that PPX treatment has antidepressant effects in depressive PD patients and also ameliorates HAM-D score in nondepressive PD patients in addition to motor function.
Can J Neurol Sci. 2007 Nov;34(4):438-42.
de Bie RM, Miyasaki J, Lang AE, Fox SH.
Movement Disorders Centre, Division of Neurology University of Toronto, Toronto, Ontario, Canada.
Clinical practice regarding dopamine-agonist use and driving in Parkinson's disease.
BACKGROUND: Current Health Canada instructions for use of the dopamine agonists (DA), pramipexole and ropinirole, state that Parkinson's disease (PD) patients should be told not to drive. The objective was to assess neurologists' actual clinical practice concerning driving advice they give to PD patients starting a DA. METHODS: An online survey was created consisting of 4 items regarding demographics, 5 regarding PD and driving, and 9 regarding DA use and driving. The survey was distributed to 563 neurologists. RESULTS: In total 96 neurologists (17.9%) responded. 4.4% tell patients with PD not to drive, solely because they are taking a DA. Respondents assess the patient's tendency for excessive daytime sleepiness and sleep attacks after starting a DA more frequently than after starting other dopaminergic drugs (p < 0.001). DISCUSSION: A minor proportion of the clinicians responding to our survey advise PD patients not to drive, solely because they use a DA. Such being the case, we propose that current Health Canada guidelines need revision.
CNS Drugs. 2007;21(12):1039-55.
Baldwin CM, Keating GM.
Wolters Kluwer Health | Adis, Auckland, New Zealand. demail@dis.co.nz
Rotigotine transdermal patch: a review of its use in the management of Parkinson's disease.
A transdermal patch formulation of the non-ergolinic dopamine agonist rotigotine (Neupro) is indicated for use as monotherapy in the treatment of early-stage Parkinson's disease or, in the EU, as an adjunct to levodopa across all disease stages. Transdermal rotigotine is an effective and generally well tolerated addition to the armamentarium for the control of Parkinson's disease, with the once-daily transdermal patch system offering several practical advantages and the possible benefits of avoiding pulsatile dopaminergic stimulation. Transdermal rotigotine was superior to placebo in patients with early-stage and advanced Parkinson's disease, although noninferiority to the oral dopamine agonists ropinirole or pramipexole was not consistently demonstrated. Additional active comparator trials would be of interest. In the meantime, transdermal rotigotine offers a convenient new treatment option for patients with Parkinson's disease.
Neurol Neurochir Pol. 2007 Mar-Apr;41(2 Suppl 1):S29-33.
Sławek J.
Oddział Neurologii, Szpital Specjalistyczny św. Wojciecha w Gdońsku, Zakład Pielegniarstwa Neurologiczno-Psychiotrycznego, Akademia Medyczna w Gdańsku. jaroslawek@amg.gda.pl
[Dopamine agonists in the treatment of motor complications in advanced Parkinson's disease] [Article in Polish]
Dopamine agonists are a relatively new group of medications, which are the second group after levodopa in terms of clinical efficacy in reduction of parkinsonian symptoms. When added to levodopa in patients with motor fluctuations they significantly prolong the on time with reduction of off periods. In patients with dyskinesias they may also be useful, because the reduction of levodopa may decrease the severity of dyskinesias as well. Agonists of the new generation, like the non-ergotamine derivatives ropinirol and pramipexol, but also the older ergoline derivative pergolide, fulfill the criterion of efficacy in classification according to evidence-based medicine regulations.
Neurol Neurochir Pol. 2007 Mar-Apr;41(2 Suppl 1):S22-8.
Szczudlik A, Rudzińska M.
Klinika Neurologii Collegium Medicum Uniwersytetu Jagiellońskiego w Krakowie. szczudlik@neuro.cm-uj.krakow.pl
[Neuroprotective effect of dopamine agonists] [Article in Polish]
Neuroprotection in Parkinson's disease is defined as halting or slowing of the progression of neurodegeneration. Neuroprotective properties of dopamine agonists may be mediated via several mechanisms, (levodopa-sparing effect, decreased dopamine turnover, antioxidant activity or inhibition of the subthalamic nucleus). Many preclinical studies demonstrate that bromocriptine, pergolide, pramipexole, ropinirole and other dopamine agonists provide significant protection against neuronal loss in experimental models. Only a few studies have investigated the potential neuroprotective effect of dopamine agonists at the clinical level. Several recent trials have used neuroimaging biomarkers to assess the rate of dopamine neuron loss in dopamine agonist-treated versus levodopa-treated patients using fluoro-dopa PET or beta-CIT SPECT. Ropinirole slowed the decline of putaminal dopamine storage capacity and pramipexole reduced decline in striatal beta-CIT uptake to a similar extent, compared to levodopa. It is not possible to exclude, however, some pharmacologic or pharmacodynamic effects of drugs on imaging markers in these studies, as well as symptomatic effects of dopamine agonist treatment in clinical outcomes.
Clin Neuropharmacol. 2007 Sep-Oct;30(5):256-65.
LeWitt PA, Boroojerdi B, MacMahon D, Patton J, Jankovic J.
Department of Neurology, Wayne State University School of Medicine, and Henry Ford Hospital-Franklin Pointe Medical Center, 26400 West 12 Mile Road, Southfield, MI 48034, USA. plewitt@ameritech.net
Overnight switch from oral dopaminergic agonists to transdermal rotigotine patch in subjects with Parkinson disease.
OBJECTIVE: To assess safety, tolerability, and efficacy outcomes of an overnight switch from oral ropinirole, pramipexole, or cabergoline to rotigotine, a dopaminergic agonist with transdermal delivery over 24 hours in subjects with established Parkinson disease (PD). METHODS: In this open-label multicenter study, we hypothesized that the selected doses of transdermal rotigotine would provide at least equivalent antiparkinsonian actions in subjects with idiopathic PD not adequately controlled with oral ropinirole (up to 9 mg/d), pramipexole (up to 2 mg/d), or cabergoline (up to 3 mg/d). The tolerability of the rotigotine switch was evaluated by the number of subjects completing the scheduled 28-day treatment period, need for rotigotine dose reductions, and dropouts due to adverse events. Efficacy assessment relied on changes in Unified Parkinson's Disease Rating Scale from the baseline to the end of treatment in PD symptoms and subject preference of dopaminergic agonist. RESULTS: Of 116 PD subjects enrolled, 104 completed the 28-day rotigotine treatment. Fifteen subjects required rotigotine dose adjustment; of these, 11 completed the trial. The most common adverse events (generally mild or moderate in intensity) were application site reactions, nausea, and somnolence. The change to rotigotine was well tolerated. Rotigotine was preferred by 77% of subjects who were not adequately controlled by their previous oral dopaminergic agonist. The predetermined rotigotine substitutions provided improvements over baseline in Unified Parkinson's Disease Rating Scale II and III subscales. CONCLUSIONS: Subjects and clinicians found the overnight switch to rotigotine convenient, well tolerated, and effective for control of PD signs and symptoms for subjects previously receiving low-to-moderate doses of oral dopaminergic agonists.
Eur J Neurol. 2003 Jul;10(4):399-406.
Rektorova I, Rektor I, Bares M, Dostal V, Ehler E, Fanfrdlova Z, Fiedler J, Klajblova H, Kulist'ak P, Ressner P, Svatova J, Urbanek K, Veliskova J.
First Department of Neurology, Masaryk University, St Anne's Teaching Hospital, Brno, Czech Republic.
Pramipexole and pergolide in the treatment of depression in Parkinson's disease: a national multicentre prospective randomized study.
An 8-month multicentre prospective randomized study aimed at comparing the effects of dopamine receptor agonists pramipexole (PPX; Mirapexin) and pergolide (PRG; Permax) as add-on to L-dopa therapy on depression [Montgomery and Asberg Depression Rating Scale (MADRS)] in 41 non-demented patients (25 men, 16 women) suffering from both mild or moderate depression and advanced Parkinson's disease (PD). The assessment was performed by a blinded independent observer. Motor symptoms (UPDRS III), motor complications (UPDRS IV), activities of daily living (UPDRS II and VI) and depressive symptoms as measured by Self - Rating Depression Scale by Zung were evaluated in an open-label design. The average value of Zung scores decreased significantly in both groups with no statistical difference between both groups. A significant decrease in the average value of MADRS scores was present only in the PPX group. The average UPDRS scores decreased significantly with no statistical difference between both groups at the comparable average total daily dose of both preparations. In both cases, the total daily dose of L-dopa decreased significantly but the decrease was statistically more pronounced in the PRG group. Our results demonstrate the antidepressant effect of PPX in patients with PD while we can't make any conclusions with regard to antidepressant effect of PRG.
Zh Nevrol Psikhiatr Im S S Korsakova. 2004;104(1):24-30.
Krivonos OV, Fedorova NV, Chigir IP.
A comparative study of efficacy of dopamine receptors agonists and catechol-O-methyltransferase in the treatment of late stages of Parkinsons disease.
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.
Neuropsychobiology. 2004;50(1):65-70.
Stiasny-Kolster K, Oertel WH.
Department of Neurology, Center of Nervous Diseases, Philipps University, Marburg, Germany.
Low-dose pramipexole in the management of restless legs syndrome. An open label trial.
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.
Depress Anxiety. 2004;20(3):131-8.
Cassano P, Lattanzi L, Soldani F, Navari S, Battistini G, Gemignani A, Cassano GB.
Department of Psychiatry, Neurobiology, Pharmacology and Biotechnology, University of Pisa, Pisa, Italy.
Pramipexole in treatment-resistant depression: an extended follow-up.
We evaluated the long-term antidepressant safety and response of adjunctive pramipexole, a D2-D3 dopamine agonist, in the course of drug-resistant depression. Twenty-three patients with treatment-resistant major depressive episode (MDE) were followed up after a 16-week pramipexole add-on trial. Pramipexole was added to current treatment with TCA or SSRI, at increasing doses from 0.375-1.500 mg/day. The LIFE scale was administered at baseline of the acute trial, at Weeks 16, 32, and 48. Patients were analyzed for sustained remission (score= <2 at LIFE for at least 8 weeks) and recurrence (after remission score > =3 at LIFE for at least 2 weeks) of depression. Of 23 patients, 12 had major depression and 11 had bipolar depression (16 women; mean age=52.8 years). Mean age of onset and median duration of current MDE were 35.1 years and 6 months, respectively; all subjects had at least two prior MDEs. Mean pramipexole dose was 0.990 mg/day. Median duration of follow-up was 28 weeks. Mean baseline MADRS and CGI-S scores were 33.7+/-8.4 (sd) and 4.6+/-0.8, respectively. Median time to sustained remission from baseline was 10 weeks and overall 60.9% (14/23) of subjects recovered within Week 22. Recurrence of depression occurred in 35.7% (5/14) of remitters after Week 24 and within Week 28 from remission. Although there were no sleep attacks, two cases of hypomania and one case of psychotic mania occurred at Weeks 22, 24, and 30, respectively. Pramipexole augmentation of antidepressant treatment was relatively safe and presumably effective in the long-term course of treatment resistant depression. (c) 2004 Wiley-Liss, Inc.
J Neurochem. 2004 Dec;91(5):1075-81.
Gu M, Iravani MM, Cooper JM, King D, Jenner P, Schapira AH.
Royal Free and University College Medical School, University College London, London, UK.
Pramipexole protects against apoptotic cell death by non-dopaminergic mechanisms.
We have investigated the ability of pramipexole, a dopamine agonist used in the symptomatic treatment of Parkinson's disease (PD), to protect against cell death induced by 1-methyl-4-phenylpyridinium (MPP+) and rotenone in dopaminergic and non-dopaminergic cells. Pre-incubation with either the active (-)- or inactive (+)-enantiomer forms of pramipexole (10 microm) decreased cell death in response to MPP+ and rotenone in dopaminergic SHSY-5Y cells and in non-dopaminergic JK cells. The protective effect was not prevented by dopamine receptor blockade using sulpiride or clozapine. Protection occurred at concentrations at which pramipexole did not demonstrate antioxidant activity, as shown by the failure to maintain aconitase activity. However, pramipexole reduced caspase-3 activation, decreased the release of cytochrome c and prevented the fall in the mitochondrial membrane potential induced by MPP+ and rotenone. This suggests that pramipexole has anti-apoptotic actions. The results extend the evidence for the neuroprotective effects of pramipexole and indicate that this is not dependent on dopamine receptor occupation or antioxidant activity. Further evaluation is required to determine whether the neuroprotective action of pramipexole is translated to a disease-modifying effect in PD patients.
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Drug category:Antiparkinson agents
 Mirapexin scientific update
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