Pramipexole in Treatment Resistant Depression: A Case Review

Pramipexole is a dopamine agonist used in the treatment of Parkinson’s disease and Restless legs syndrome. Although off-label, the use of Pramipexole as an adjunct therapy in treatment resistant depression has recently been documented in the literature with promising results. We present a 75-year-old male with MDD who has failed trials of SSRIs, SNRIs, TCAs, SGA, TMS, Ketamine, and ECT who was initiated on Pramipexole. We discuss, based on existing literature, the probability of a favorable long-term response to Pramipexole and the potential side effects for our patient. We also highlight the need for future studies designed to test the efficacy of Pramipexole in geriatric patients with TRD.

Pramipexole, a dopamine D3/D2 receptor-preferring agonist, attenuates reserpine-induced fibromyalgia-like model in mice

Fibromyalgia(FM) is a complex pathology described as persistent hyperalgesia including somatic and mood dysfunctions, depression and anxiety. Although the etiology of FM is still unknown, a significant decrease in biogenic amines is a common characteristic in its pathogenesis. Here, our main objective was to investigate the role of dopamine D3/D2 receptor during the reserpine-induced pain in mice. Our results showed that pramipexole(PPX) – a dopaminergic D3/D2 receptor agonist – inhibited mechanical allodynia and thermal sensitivity induced by reserpine. Relevantly, PPX treatment decreased immobility time and increased the number of grooming in the forced swimming test and splash test, respectively. Animals that received PPX remained longer in the open arms than the reserpine group using elevated plusmaze apparatus. The repeated PPX administration, given daily for 4 days, significantly blocked the mechanical and thermal allodynia during FM model, similarly to pregabalin, although it failed to affect the reserpine-induced thermal nociception. Reserpine administration induced significant downregulation of dopamine concentration in the central nervous system, and repeated treatment with PPX restored dopamine levels in the frontal cortex and spinal cord tissues. Moreover, PPX treatment inhibited oxidants production such as DCFH(2′,7′-dichlorodihydrofluorescein) and nitrite, also decreased oxidative damage(carbonyl), and upregulated the activity of superoxide dismutase in the spinal cord. Together, our findings demonstrated the ability of dopamine D3/D2 receptor-preferring agonist in reducing pain and mood dysfunction allied to FM in mice. All experimental protocols were approved by the Universidade Federal de Santa Catarina(UFSC) Ethics Committee(approval No. 2572210218) on May 10, 2018.

Efficacy of Pramipexole for Treatment of Apathy in Parkinson’s Disease

Background: Apathy occurs frequently in patients with Parkinson’s disease (PD), and has a negative impact on activities of daily living through loss of motivation. Pramipexole (PPX), which shows preferential affinity for D3 dopamine receptor in the mesolimbic system, is thought to influence mood and motivation. Therefore, we conducted an open-label case-control study to examine the effect of PPX on apathy in PD. Methods: We studied 36 PD patients (mean age, 70.4 ± 8.1 years), who had been treated only with L-DOPA. PPX was added to L-DOPA treatment in 24 patients (PPX group) and other 12 patients continued with L-DOPA alone (non-PPX group). The study period was 8 weeks. Apathy was assessed using the revised apathy scale for Japanese. Motor function was assessed with part III of the Unified Parkinson’s Disease Rating Scale (UPDRS). Results: Seventeen of 36 patients (47%) were diagnosed as having apathy. In the PPX group, apathy scale significantly improved from 17.3 to 13.8 at week 8 (p < 0.05). Motor function also improved significantly from 16.1 to 7.6 at week 8 (p < 0.0001). In the non-PPX group, apathy scale and UPDRS both showed no change during the study period. There was no correlation between changes in apathy scale and UPDRS in either the PPX or non-PPX group. Conclusion: PPX may be effective for treating apathy as well as motor dysfunction in PD.

Establishment of inherent stability of pramipexole and development of validated stability indicating LC-UV and LC-MS method

Pramipexole belongs to a class of nonergot dopamine agonist recently approved for the treatment of early and advanced Parkinson＇s disease.A validated specific stability indicating reversed-phase liquid chromatographic method has been developed for the quantitative determination of pramipexole in bulk as well as in pharmaceutical dosage forms in the presence of degradation products.Forced degradation studies were performed by exposition of drug to hydrolytic（acidic and basic）,oxidative and photolytic stress conditions,as defined under ICH guideline Q1A（R2）.Significant degradation was observed under hydrolytic,oxidative and photolytic conditions and the degradation products formed were identified by LC-MS.

Self-Reported Adherence after Overnight Switching from Immediate- to Extended-Release Pramipexole in Parkinson’s Disease

Background: Drug adherence decreased in patients with Parkinson’ s disease (PD) because of taking many different types of drugs. We evaluated drug adherence after switching from immediate-release (IR) to once-daily extended-release (ER) pramipexole (PPX) in PD. Methods: This study included 35 PD patients (20 men, 15 women);10 were taking oral PPX alone, and 25 were also using another anti-PD drug. PPX-IR was switched overnight to PPX-ER without gradual tapering. One month after switching, improvement in timing adherence and reduction in medication burden were evaluated by a questionnaire using a visual analog scale (VAS) (0: No change;10: Better). Motor function was assessed using part III of the Unified Parkinson’s Disease Rating Scale (UPDRS). Results: The VAS score for improvement in timing adherence was 8.1 ± 0.5 (mean ± standard error), and that for reduction in medication burden was 7.3 ± 0.6. There was a significant negative correlation (ρ = -0.43, p = 0.01) between the VAS score and number of types of medications. The UPDRS part III score improved significantly after switching

Alpha-Dihydroergocryptine vs. Pramipexole as Adjunct Symptomatic Treatment of Idiopathic Parkinson’s

A randomized, double blind, and active reference-controlled study was carried out among 116 patients suffering from idiopathic Parkinson’s disease (PD). The aim of the study was to compare the safety and efficacy of alpha-dihydroergocryptine (DHEC) vs. pramipexole (PRAM) as an adjunct symptomatic therapy to levodopa in PD patients. The motor symptoms, assessed by the Unified Parkinson’s Disease Rating Scale (UPDRS) III subscale, was identified as efficacy target. Fifty-six patients were randomized to DHEC and 60 to PRAM. Patients included were under constant levodopa dose for at least 3 months before entering the study, with baseline UPDRS III ≥14. They underwent a 16-week treatment. Out of the 116 included patients, 85 (39 in DHEC group and 46 in PRAM group, respectively) completed the study protocol. In DHEC group, UPDRS III decreased by 24.2% from baseline at week 10 and by 28.1% at week 16. In PRAM group, UPDRS III decreased by 27.1% from baseline at week 10 and by 29.2% at week 16. The data were highly significant

Pathological Gambling after Administration of Pramipexole

Parkinson’s disease is a common condition usually treated by dopaminergic agents and many behavioral abnormalities such as impulse control disorders (ICD) are connected with that usage. Pathological gambling, a form of ICD includes is a clinical condition that disrupts personal, family and occupational activity. Pramipexole a D2 AND D3 agonist may be associated with pathological gambling. We present a case of 74-year-old male patient who was diagnosed with Parkinson’s disease (PD). His doctor advised him to take pramipexole 0.18 mg/p.o./day. A month after the onset of treatment he manifested a behavior of pathological gambling. After the discontinuation of the drug all this behavior was interrupted.

The efficacy and safety of pramipexole ER versus IR in Chinese patients with Parkinson’s disease: a randomized, double-blind, double-dummy, parallel-group study

Objective:To evaluate the non-inferiority of pramipexole extended-release(ER)versus immediate-release(IR)in Chinese patients with Parkinson’s disease(PD)in a double-blind,randomized,parallel-group study.Methods:Subjects were Chinese patients with idiopathic PD with diagnosis≥2 years prior to trial,age≥30 years old at diagnosis,and Modified Hoehn and Yahr score 2-4 during‘on’-time.Subjects received treatment with pramipexole ER(n=234)or IR(n=239).Non-inferiority was based on the primary endpoint,the change from baseline to end of maintenance(week 18)in the UPDRS(Parts II+III)total score.Results:For the primary endpoint,the adjusted mean changes(standard error)of UPDRS Parts II+III at week 18 were−13.81(0.655)and−13.05(0.643)for ER and IR formulations,respectively,using ANCOVA adjusted for treatment and centre(fixed effect)and baseline(covariate).The adjusted mean between group difference was 0.8 for the 2-sided 95%CI(−1.047,2.566).Since the lower limit of the 2-sided 95%CI(−1.047)for treatment difference was higher than the non-inferiority margin of−4,non-inferiority between pramipexole ER and IR was demonstrated.The incidence of adverse events(AEs)was 68.8%in the ER arm and 73.6%in the IR arm with few severe AEs(ER:2.1%;IR:3.8%).Conclusion:Based on the UPDRS II+III score,pramipexole ER was non-inferior to pramipexole IR.The safety profiles of pramipexole ER and IR were similar.These results were based on comparable mean daily doses and durations of treatment for both formulations.

Reassessment subacute MPTP-treated mice model of Parkinson disease

OBJECTIVE(1) To estimate the value of the subacute MPTP mouse model in aspects of behavioral performance,biochemical changes and pathological abnormalities.(2) To find effective positive drugs.METHODS Male C57 BL/6 mice were injected with MPTP(30 mg·kg^(-1)·d^(-1),ip) for 5 consecutive days.Three days before MPTP injection,the mice were orally administered selegiline(3 mg·kg^(-1)·d^(-1)),pramipexole(3 mg·kg^(-1)·d^(-1)),or medopar(100 mg·kg^(-1)·d^(-1)) for 18 d.Behavioral performance was assessed in the open field test,pole test and rotarod test.Neurotransmitters in the striatum were detected using HPLC.Protein levels were measured by Western blot.Pathological characteristics were examined by immunohistochemistry.Ultrastructure changes were observed by electron microscopy.RESULTS The subacute MPTP treatment did not induce evident motor defects despite severe injuries in the dopaminergic system.Additionally,MPTP significantly increased the α-synuclein levels and the number of astrocytes in the striatum,and destroyed the blood-brain barrier(BBB) in the substantianigra pars compacta.Both selegiline and pramipexole were able to protect the mice against MPTP injuries.CONCLUSION The subacute MPTP mouse model does not show visible motor defects;it is not enough to evaluate the validity of a candidate just based on behavioral examination,much attention should also be paid to the alterations in neurotransmitters,astrocytes,α-synuclein and the BBB.In addition,selegiline or pramipexole is a better choice than medopar as an effective positive control for the subacute MPTP model.

Problems Associated with Non-Ergot Dopamine Agonist Maintenance Therapy in Patients with Advanced Parkinson’s Disease

Non-ergot dopamine agonists have become popular for treating motor complications associated with long-term use of levodopa-containing drugs. We conducted a retrospective study in which we identified clinical problems related to use of non-ergot dopamine agonists. The study included 38 patients with Parkinson’s disease (PD) who suffered the wearing-off phenomenon and had thus been under non-ergot dopamine receptor agonist therapy for 1 - 2 years. Some presented with problems such as major symptoms of PD (30.3%), psychiatric symptoms (24.2%), and postural dysfunction (21.2%). Comparison between two different non-ergot drugs showed the levodopa dosage to be greater among patients taking ropinirole than among those taking pramipexole. In patients with advanced PD, various problematic symptoms can develop early after administration of a non-ergot dopamine agonist to treat the wearing-off phenomenon, necessitating identification and treatment of such symptoms on a patient-to-patient basis.

欧洲委员会批准Beehringer公司的Sifrol上市用于治疗帕金森病

欧洲委员会批准Boehringer Ingelheim公司的Sifrol（盐酸普拉克索，pramipexole hydrochloride）缓释、每日1次片剂用于治疗早期和晚期自发性帕金森病。此项批准基于提交的临床试验结果，结果表明新剂型的有效性和安全性与每日服用3次的速释片剂相当。其他研究结果显示服用速释片剂的患者可转为服用每日剂量相同的缓释片剂。