Comparison of the effectiveness, safety, and costs of anti-Parkinson drugs: A multiple-center retrospective study.

AIMS: This study aimed to systematically compare the effectiveness, safety, and costs of different anti-Parkinson drugs (APDs). METHODS: This is a multi-center study that retrospectively analyzed the data of 8420 outpatients with PD from 2014 to 2019 across 30 tertiary hospitals in China. The effectiveness was evaluated by changes in total dosages of APDs, normalized by levodopa equivalent dose (LED) and presented as ΔLEDs; levodopa equivalent dose cost (LEDc) represented the daily cost of APDs; and newly added diagnostics were represented as APDs-related adverse events. RESULTS: A total of 384 patients with eligible medical records for three consecutive years were enrolled. Patients treated with carbidopa/levodopa or levodopa/benserazide had significantly lower mean ΔLEDs than other groups (p < 0.01), followed by pramipexole and selegiline. The piribedil group had the highest ΔLEDs, with mean differences of 112.56-355.04 mg compared to other groups (p < 0.01). Meanwhile, LEDc in the levodopa/benserazide, carbidopa/levodopa, and piribedil groups were significantly lower than those in pramipexole or selegiline groups ($0.088-0.135/day for levodopa/benserazide; $0.070-0.126/day for carbidopa/levodopa; $0.112-0.138/day for piribedil; $0.290-0.332/day for pramipexole; $0.229-0.544/day for selegiline; p < 0.01). Patients with piribedil had more adverse events, with an incidence rate of 35.7%, followed by levodopa/benserazide (25.6%), selegiline (23.5%), carbidopa/levodopa (23.3%), and pramipexole (16.4%). Pramipexole showed a lower incidence rate of adverse events than piribedil, including neuropsychiatric symptoms (p = 0.006), headache/dizziness (p = 0.016), and gastrointestinal symptoms (p = 0.031). CONCLUSIONS: Carbidopa/levodopa or levodopa/benserazide might exhibit better clinical improvement with less medical cost, while piribedil presented less clinical improvement but a higher risk of headache/dizziness, gastrointestinal, and neuropsychiatric symptoms.

[Motor and autonomic disorders influence on pain syndrome of patients with Parkinson's disease of the I-III H&Y stages]. / Vliyanie motornykh i vegetativnykh narushenii na vyrazhennost' bolevogo sindroma u patsientov s I­III stadiyami bolezni Parkinsona.

OBJECTIVE: To evaluate the influence of motor and autonomic disorders on the pain of patients with PD of the I-III H&Y stages and possibility of correcting the pain with dopamine receptor agonists (ADR). MATERIAL AND METHODS: 252 patients (128 women and 124 men, 42-80 years old) with PD of I-III Hoehn and Yahr stages (H&Y) were examined using the following scales: UPDRS, daily activity Sch&En, quality of life PDQ-39, MMSE, BDI, PFS-16, NMSQuest, GSRS, AUA; 53 patients were piribedil treated during 6 months. RESULTS: Our results indicated a wide prevalence of pain syndrome in PD patients (58.6%), starting from the early stages (50% for the Ist stage). The most stable pain associations were found with the PD stage, levodopa doses, severity of motor symptoms (postural disorders and hypokinesia manifestations) and motor complications («off-periods¼ and dyskinesias), as well as non-motor PD manifestations depression and autonomic dysfunctions (constipation, swallowing disorders, and frequent urination). The regression analysis showed, that the severity of motor complications and depression were the predictors of pain occurrence. The pain syndrome in patients with PD of I-III stages underwent significant regression (by 51% and 62%, after 1.5 and 6 months of therapy, respectively) after ADR (piribedil) addition to their therapy; it's probably due to improving the motor component and decreasing depressive disorders. CONCLUSIONS: The piribedil inclusion contributes to the reduction of pain syndrome, regardless is it used in monotherapy or in conjunction with levodopa preparations.

The Efficacy and Safety of Piribedil Relative to Pramipexole for the Treatment of Early Parkinson Disease: A Systematic Literature Review and Network Meta-Analysis.

OBJECTIVES: Patients with early Parkinson disease (PD) frequently defer initiation of levodopa treatment to minimize long-term complications. Nonergoline dopamine agonists, such as pramipexole and piribedil, are frequent first-line therapies for early PD patients, yet limited head-to-head randomized controlled trial (RCT) evidence exists for dopamine agonists in this population. We therefore conducted a systematic literature review and network meta-analysis. METHODS: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were systematically searched (until January 7, 2020), identifying RCTs assessing the efficacy of piribedil or pramipexole in early PD. Eligible trial data were incorporated into fixed- and random-effects Bayesian network meta-analyses. RESULTS: No RCTs were identified directly comparing piribedil with pramipexole, but 6 trials provided data for pramipexole versus placebo and 2 compared piribedil versus placebo, facilitating indirect comparisons. Across all time points assessed, no significant differences were found between pramipexole and piribedil for change in the Unified Parkinson's Disease Rating Scale (UPDRS) score from baseline. Piribedil and pramipexole demonstrated superiority relative to placebo for UPDRS II/III change at weeks 22 to 30. No significant differences were noted between the treatments at weeks 20 to 35 for anxiety, constipation, hypotension, nausea, and somnolence. Sensitivity analyses on adjustment for dose titration periods and baseline risk yielded the same pattern of results. CONCLUSIONS: No significant differences were found for pramipexole versus piribedil in the UPDRS II/III scores from baseline in early PD, with similar safety profiles.

Protective effects of dopamine D2/D3 receptor agonist piribedil on learning and memory of rats exposed to global cerebral ischemia-reperfusion.

Global cerebral ischemia-reperfusion (GCI/R) may occur after any of several clinical conditions such as cardiac arrest and anesthetic accident. Some dopamine receptor agonists possess neuroprotective effects. However, some of them may produce side effects during treatment. Piribedil, which is a dopamine D2/D3 receptor agonist, has fewer side effects and is well tolerated. This study investigated the effects of piribedil on learning and memory of rats with GCI/R according to modified neurological severity score (mNSS) scoring and Morris water maze test (MWM). Rats with GCI/R were treated with piribedil 25 or 50 mg/kg/d, and mNSS was performed at 6 h, 1 day, 3 days, and 1 and 2 weeks after injury. The MWM test was employed to evaluate learning and memory of rats at 1 and 2 weeks after injury. The results showed treatment with piribedil reduced the mNSS score and prolonged the time in the target quadrant compared with untreated rats although no obvious differences of the 25 and 50 mg/kg/d piribedil intervention groups were observed statistically. Piribedil is effective in improving the neurological function and learning and memory of rats after GCI/R.

[The agonist of dopamine receptors piribedil in treatment of Parkinson's disease]. / Agonist dofaminovykh retseptorov piribedil v terapii bolezni Parkinsona.

In this paper, the authors review the current foreign and domestic literature on a role of the agonist of dopamine receptors piribedil in the treatment of Parkinson's disease. The results of the main studies of the efficacy and safety of piribedil, mechanisms of actions and a comparative characteristics with other dopamine receptors agonist are reviewed.

[Current approaches to management of patients with mild cognitive impairment]. / Sovremennye podkhody k vedeniiu patsientov s umerennymi kognitivnymi narusheniiami.

Mild cognitive impairment (MCI) is an intermediate stage between normal aging and dementia. The prevalence of MCI among elderly people is 12-17% but the risk of progression of cognitive impairment and development of dementia during 5 years is up to 70%. Cerebral vascular diseases and initial stages of neurodegenerative processes are the cause of MCI. Clinical characteristics of MCI depend on the main etiological factor. To decrease the severity of symptoms and prevent the progression of cognitive impairment in MCI patients, pharmacotherapy and non-medication methods, including diet optimization, stimulation of mental and physical activity, are used. Dopaminergic and noradrenergic therapy is most prevalent among pharmacological methods.

Piribedil for the Treatment of Motor and Non-motor Symptoms of Parkinson Disease.

Dopamine agonists are well-established symptomatic medications for treating early and advanced Parkinson disease (PD). Piribedil was one of the first agonists to be marketed (1969) and is widely used as an extended-release oral formulation in European, Latin-American, and Asian countries. Piribedil acts as a non-ergot partial dopamine D2/D3-selective agonist, blocks alpha2-adrenoreceptors and has minimal effects on serotoninergic, cholinergic, and histaminergic receptors. Animal models support the efficacy of piribedil to improve parkinsonian motor symptoms with a lower propensity than levodopa to induce dyskinesia. In PD patients, randomized double-blind studies show that piribedil (150-300 mg/day, three times daily) is superior to placebo in improving motor disability in early PD patients. Based on such evidence, piribedil was considered in the last Movement Disorder Society Evidence-Based Medicine review as "efficacious" and "clinically useful" for the symptomatic treatment of PD, either as monotherapy or in conjunction with levodopa, in non-fluctuating early PD patients. This effect appears comparable to what is known from other D2 agonists. However, randomized controlled trials are not available to assess the effect of piribedil in managing levodopa-induced motor complications. Pilot clinical studies suggest that piribedil may improve non-motor symptoms, such as apathy, but confirmatory trials are needed. The tolerability and safety profile of piribedil fits with that of the class of dopaminergic agonists. As for other non-ergot agonists, pneumo-pulmonary, retroperitoneal, and valvular fibrotic side effects are not a concern with piribedil. The original combination of piribedil D2 dopaminergic and alpha-2 adrenergic properties deserve further investigations to better understand its antiparkinsonian profile.

[The use of piribedil in early and late stages of Parkinson's disease].

In this article, we present clinical cases at an early stage of Parkinson's disease with mild affective and cognitive disorders, and at a later stage with motor fluctuations and levodopa-induced dyskinesia. The efficacy of dopamine receptor agonists in treatment of Parkinson's disease in the early and late stages is illustrated by the example of piribedil.

Rhythmic auditory stimulation with visual stimuli on motor and balance function of patients with Parkinson's disease.

OBJECTIVE: Discuss the effect of rhythmic auditory stimulation with visual stimuli on motor and balance function in patients with Parkinson's disease (PD). PATIENTS AND METHODS: One hundred and sixteen patients with PD participated in this study. The control group used a routine drug treatment for eight weeks. The comprehensive treatment group used conventional drug treatment with sound rhythm metronome released as the rhythmical auditory stimulation, in accordance with the ground fixed ribbon rhythmic visual stimulation walking training for eight weeks. After four and eight weeks, the two groups of subjects took the walking parameters test, and used the disease Parkinson score scale to assess the damaged degree of motor function of PD patients. The Berg Balance Scale was used to evaluate the balance function of the PD patients. A six minute walk test was used to evaluate the walking motor function of the patients. RESULTS: The comparison between the groups suggests that after treatment of rhythmic auditory stimulation with visual stimulation group, the step size increased, frequency decreased, pace increased, and PD score scale part II decreased. As well, the PD score scale part III reduced, the six minute walking distance increased, and the Berg Balance Scale score increased significantly. There were significant differences compared with the control group after the treatment (p < 0.01). Comparison of time points suggests that after rhythmic auditory stimulation with visual stimulation group trained for eight weeks, the step size increased, frequency decreased, pace increased, and PD score scale part II were reduced. As well the PD score scale part III reduced, six minute walking distance increased, Berg Balance Scale increased. There were significant differences compared with the parameters of training for four weeks (p < 0.01). CONCLUSIONS: Rhythmic auditory stimulation with visual stimulation can improve motor and balance function of patients with PD.

[USAGE OF PRONORAN® FOR TREATMENT OF ELDERLY PATIENTS WITH MILD COGNITIVE IMPAIRMENT].

Evaluated the effectiveness of Pronoran® for treatment of elderly patients with syndrome of mild cognitive impairment (MCI) with underlying dyscirculatory encephalopathy. The study involved 48 people: I (main) group--27 patients who in addition to basic therapy received Pronoran®, II (control) group--21 patients, received only basic therapy. We found that exposure to a 3-month treatment course for patients of the I (main) group showed significant improvement in terms of indicators characterizing orientation in space, short-term memory, counting ability, concentration, psychomotor pace, ability to learn. In addition, the treatment course was accompanied by improved emotional state, positive changes in the coefficients of the spectral power qEEG for patients. At the same time, the patients in the II (control) group didn't show significant changes in the studied parameters.

Treatment for mild cognitive impairment: systematic review.

BACKGROUND: More people are presenting with mild cognitive impairment (MCI), frequently a precursor to dementia, but we do not know how to reduce deterioration. AIMS: To systematically review randomised controlled trials (RCTs) evaluating the effects of any intervention for MCI on cognitive, neuropsychiatric, functional, global outcomes, life quality or incident dementia. METHOD: We reviewed 41 studies fitting predetermined criteria, assessed validity using a checklist, calculated standardised outcomes and prioritised primary outcome findings in placebo-controlled studies. RESULTS: The strongest evidence was that cholinesterase inhibitors did not reduce incident dementia. Cognition improved in single trials of: a heterogeneous psychological group intervention over 6 months; piribedil, a dopamine agonist over 3 months; and donepezil over 48 weeks. Nicotine improved attention over 6 months. There was equivocal evidence that Huannao Yicong improved cognition and social functioning. CONCLUSIONS: There was no replicated evidence that any intervention was effective. Cholinesterase inhibitors and rofecoxib are ineffective in preventing dementia. Further good-quality RCTs are needed and preliminary evidence suggests these should include trials of psychological group interventions and piribedil.

Evaluation on the efficacy and safety of Chinese herbal medication Xifeng Dingchan Pill in treating Parkinson's disease: study protocol of a multicenter, open-label, randomized active-controlled trial.

BACKGROUND: Parkinson's disease (PD) is a complicated disease, commonly diagnosed among the elderly, which leads to degeneration of the central nervous system. It presently lacks an effective therapy for its complex pathogenesis. Adverse effects from Western drug-based medical intervention prevent long-term adherence to these therapies in many patients. Traditional Chinese medicine (TCM) has long been used to improve the treatment of PD by alleviating the toxic and adverse effects of Western drug-based intervention. Therefore, the aim of this study is to evaluate the efficacy and safety of Xifeng Dingchan Pill (XFDCP), a compound traditional Chinese herbal medicine, taken in conjunction with Western medicine in the treatment of PD patients at different stages in the progression of the disease. METHODS AND DESIGN: This is a multicenter, randomized controlled trial. In total, 320 patients with early- (n = 160) and middle-stage PD (n = 160) will be enrolled and divided evenly into control and trial groups. Of the 160 patients with early-stage PD, the trial group (n = 80) will be given XFDCP, and the control group (n = 80) will be given Madopar. Of the 160 patients with middle-stage PD, the trial group (n = 80) will be given XFDCP combined with Madopar and Piribedil, and the control group (n = 80) will be given Madopar and Piribedil. The Unified Parkinson's Disease Rating Scale scores, TCM symptoms scores, quality of life, change of Madopar's dosage and the toxic and adverse effects of Madopar will be observed during a 3-month treatment period and through a further 6-month follow-up period. DISCUSSION: It is hypothesized that XFDCP, combined with Madopar and Piribedil, will have beneficial effects on patients with PD. The results of this study will provide evidence for developing a comprehensive therapy regimen, which can delay the progress of the disease and improve the quality of life for PD patients in different stages. TRIAL REGISTRATION: This trial has been registered in the Chinese Clinical Trial Registry with the identifer ChiCTR-TRC-12002150.

Parkinsonian apathy responds to dopaminergic stimulation of D2/D3 receptors with piribedil.

Apathy is one of the most common symptoms encountered in Parkinson's disease, and is defined as a lack of motivation accompanied by reduced goal-directed cognition, behaviour and emotional involvement. In a previous study we have described a delayed withdrawal syndrome after successful motor improvement related to subthalamic stimulation allowing for a major decrease in dopaminergic treatment. This withdrawal syndrome correlated with a diffuse mesolimbic dopaminergic denervation. To confirm our hypothesis of parkinsonian apathy being related to mesolimbic dopaminergic denervation, we performed a randomized controlled study using piribedil, a relatively selective D2/D3 dopamine agonist to treat parkinsonian apathy, using the model of postoperative apathy. A 12-week prospective, placebo-controlled, randomized, double-blinded trial was conducted in 37 patients with Parkinson's disease presenting with apathy (Starkstein Apathy Scale score > 14) following subthalamic nucleus stimulation. Patients received either piribedil up to 300 mg per day (n = 19) or placebo (n = 18) for 12 weeks. The primary end point was the improvement of apathy under treatment, as assessed by the reduction of the Starkstein Apathy Scale score in both treatment groups. Secondary end points included alleviation in depression (Beck Depression Inventory), anxiety (Beck Anxiety Inventory), improvement of quality of life (PDQ39) and anhedonia (Snaith-Hamilton Pleasure Scale). Exploratory endpoints consisted in changes of the Robert Inventory score and Hamilton depression scales. An intention to treat analysis of covariance analysis was performed to compare treatment effects (P < 0.05). The number of premature study dropouts was seven in the placebo and five in the piribedil groups, mostly related to intolerance to hypodopaminergic symptoms. At follow-up evaluation, the apathy score was reduced by 34.6% on piribedil versus 3.2% on placebo (P = 0.015). With piribedil, modifications in the Beck depression and anxiety scores were -19.8% and -22.8%, respectively versus +1.4% and -8.3% with placebo, without reaching significance level. Piribedil led to a trend towards improvement in quality of life (-16.2% versus +6.7% on placebo; P = 0.08) and anhedonia (-49% versus -5.6% on the placebo; P = 0.08). Apathy, assessed by the Robert Inventory score, improved by 46.6% on piribedil and worsened by 2.3% on placebo (P = 0.005). Depression, measured by the Hamilton score, improved in the piribedil group (P = 0.05). No significant side effects were observed. The present study provides a class II evidence of the efficacy of the dopamine agonist piribedil in the treatment of apathy in Parkinson's disease.

The effect of piribedil on L-DOPA-induced dyskinesias in a rat model of Parkinson's disease: differential role of α(2) adrenergic mechanisms.

Piribedil is a non-ergoline, dopamine D(2)/D(3) receptor agonist with α(2) adrenoceptor antagonist properties that has been used in the treatment of Parkinson's disease (PD). Noradrenergic neurotransmission may be involved in the pathogenesis of dyskinesias induced by chronic treatment with L-DOPA (3,4-dihydroxyphenylalanine, levodopa), but its role in the in vivo action of piribedil or on different subclasses of abnormal involuntary movements (AIMs) remains unclear. The aims of this study were therefore (1) to investigate the anti-dyskinetic effects of piribedil on L-DOPA-induced contralateral turning behaviour, locomotive dyskinesias (LD), axial dystonia (AD), orolingual dyskinesia (OD) and forelimb dyskinesia (FD) and (2) to compare these effects to the α(2) adrenoceptor antagonist, idazoxan, or the α(2) adrenoceptor agonist, clonidine. Rats were unilaterally lesioned with 6-hydroxydopamine (6-OHDA) and injected intraperitoneally twice daily with L-DOPA methylester (12.5 mg/kg) and benserazide (3.25 mg/kg). After 3 weeks, the effects of piribedil (5, 15, 40 mg/kg), clonidine (0.15 mg/kg), idazoxan (10 mg/kg) and combinations of these drugs were scored during 2 h. Pre-treatment with 5 and 40 mg/kg, but not 15 mg/kg, of piribedil reduced turning behaviour and AD, OD and FD, but piribedil increased LD at the 40 mg/kg doses compared to the L-DOPA group. Idazoxan induced similar effects as piribedil (40 mg/kg), except that it had no effect on LD. Idazoxan blocked the effect of piribedil on AD and FD. Clonidine reduced all AIMs except OD, possibly because of its sedative effect. Clonidine blocked the effect of piribedil on AD, OD and FD. These data suggest a differential involvement of α(2) adrenergic receptors in the action of piribedil on different subclasses of L-DOPA-induced dyskinesias.

From the cell to the clinic: a comparative review of the partial D2/D3receptor agonist and α2-adrenoceptor antagonist, piribedil, in the treatment of Parkinson's disease.

Though L-3,4-dihydroxyphenylalanine (L-DOPA) is universally employed for alleviation of motor dysfunction in Parkinson's disease (PD), it is poorly-effective against co-morbid symptoms like cognitive impairment and depression. Further, it elicits dyskinesia, its pharmacokinetics are highly variable, and efficacy wanes upon long-term administration. Accordingly, "dopaminergic agonists" are increasingly employed both as adjuncts to L-DOPA and as monotherapy. While all recognize dopamine D(2) receptors, they display contrasting patterns of interaction with other classes of monoaminergic receptor. For example, pramipexole and ropinirole are high efficacy agonists at D(2) and D(3) receptors, while pergolide recognizes D(1), D(2) and D(3) receptors and a broad suite of serotonergic receptors. Interestingly, several antiparkinson drugs display modest efficacy at D(2) receptors. Of these, piribedil displays the unique cellular signature of: 1), signal-specific partial agonist actions at dopamine D(2)and D(3) receptors; 2), antagonist properties at α(2)-adrenoceptors and 3), minimal interaction with serotonergic receptors. Dopamine-deprived striatal D(2) receptors are supersensitive in PD, so partial agonism is sufficient for relief of motor dysfunction while limiting undesirable effects due to "over-dosage" of "normosensitive" D(2) receptors elsewhere. Further, α(2)-adrenoceptor antagonism reinforces adrenergic, dopaminergic and cholinergic transmission to favourably influence motor function, cognition, mood and the integrity of dopaminergic neurones. In reviewing the above issues, the present paper focuses on the distinctive cellular, preclinical and therapeutic profile of piribedil, comparisons to pramipexole, ropinirole and pergolide, and the core triad of symptoms that characterises PD-motor dysfunction, depressed mood and cognitive impairment. The article concludes by highlighting perspectives for clarifying the mechanisms of action of piribedil and other antiparkinson agents, and for optimizing their clinical exploitation.

Impulse control disorder and piribedil: report of 5 cases.

Recent studies suggest that impulse control disorders (ICD) in Parkinson disease are not uncommon, and antiparkinsonian therapy, mainly the use of dopaminergic agonists, plays a causal role in the development of these symptoms. Pramipexole has been mainly related to the occurrence of ICDs, although these disorders may occur when any dopaminergic agonist-based therapy is administered.In this paper, we describe 4 patients with Parkinson disease and 1 with multisystem atrophy who presented a history (several months or years) of pathological gambling, hypersexuality, punding, and pathological use of the Internet secondary to piribedil. This previously undescribed association suggests that the development of these disorders might be also related to piribedil administration. It is also the first report of a patient with multisystem atrophy developing such adverse effects.

Tinnitus treatment with piribedil guided by electrocochleography and acoustic otoemissions.

INTRODUCTION: Tinnitus is a frequent disorder and very difficult to treat. Both animal studies and clinical observations suggest that dopaminergic substances might have potential for the treatment of tinnitus. Here, we investigated the dopamine agonist piribedil for the treatment of chronic tinnitus. In all participants, we performed audiometry, electrocochleography (ECoG), and otoacoustic emissions before treatment began. OBJECTIVE: To assess the efficacy and safety of the dopaminergic drug piribedil for the treatment of tinnitus and to evaluate whether ECoG and acoustic otoemissions might be useful for predicting treatment response. STUDY DESIGN: Prospective randomized double-blind crossover study. SUBJECTS AND METHOD: One hundred patients with tinnitus were randomized into a double-blind, placebo-controlled, prospective crossover study. All patients underwent distortion product acoustic otoemissions with and without contralateral suppression and ECoG. Patients received 50 mg piribedil and placebo for 90 days each, separated by a 30-day washout period. Treatment effects were assessed by using the Tinnitus Handicap Inventory and a visual analog scale. Fifty-six patients completed the trial. RESULTS: There was no significant improvement of Tinnitus Handicap Inventory and visual analog scale score after piribedil treatment as compared with placebo. However, results were characterized by high interindividual variability. Post hoc analysis of piribedil effects revealed that piribedil treatment responders differed from nonresponders by the occurrence of a double peak in the ECoG. In addition, normal distortion product acoustic otoemission suppression patterns indicated better treatment response with piribedil. The incidence of side effects during piribedil treatment was 23.3%, leading to interruption of treatment in all cases. CONCLUSION: Piribedil is not superior to placebo in the treatment of tinnitus. Piribedil treatment responders differed from nonresponders by specific findings in the ECoG and in the distortion product acoustic otoacoustic emissions, suggesting a beneficial effect of piribedil in an electrophysiologically characterized tinnitus subgroup.