Hypotension and bradycardia, a serious adverse effect of piribedil, a case report and literature review.

BACKGROUND: Dopamine agonists (DAs) are efficacious for the treatment of motor and nonmotor symptoms in patients with Parkinson's disease (PD). The treatment of PD with DAs is often complicated by adverse drug reactions (ADRs) of dopaminergic and non-dopaminergic origins. The DA piribedil is widely used in Asian, European, and Latin American countries; therefore, its ADRs are pertinent to clinicians. Here we present a rare case of hypotension and bradycardia that is significantly related to the dosage of piribedil. CASE PRESENTATION: A middle-aged male, diagnosed with PD, received dopamine replacement with piribedil. When taking 50 mg piribedil daily dose, the patient didn't feel any discomfort. Two hours after taking 100 mg piribedil he presented with serious concomitant hypotension and bradycardia with a blood pressure (BP) reading of 85/48 mmHg and a heart rate (HR) of 45 beats/min when sitting. After taking 75 mg piribedil, the patient showed the same symptoms with BP reading at 70/45 mmHg and HR of 47 beats/min in the same position. Upon replacing treatment with pramipexole 0.125 mg, 0.25 mg, and 0.375 mg three times a day, no further cardiovascular effects persisted. CONCLUSIONS: No studies have previously reported the simultaneous observation of position-unrelated hypotension and bradycardia after taking small doses of piribedil. More studies are needed to explore the effects of DAs on BP and HR, especially piribedil. Piribedil is efficacious for the treatment of PD, but it is important to weigh the potential risk of hypotension and bradycardia against the clinical benefits of this drug.

Piribedil: sleep attacks, also in patients without Parkinson's disease.

Piribedil is a dopamine agonist used in Parkinson's disease and a variety of other clinical situations although its efficacy has not been demonstrated. A study based on the French national pharmacovigilance database identified and analysed 7 reports of sleep attacks attributed to piribedil in patients without Parkinson's disease. The case reports are detailed and indicate that piribedil has a direct role in the onset of sleep attacks. To spare patients unnecessary exposure to the adverse effects of piribedil, it is better to avoid using piribedil and to choose drugs with demonstrated efficacy instead.

Pathological gambling in a patient on piribedil: A case report.

RATIONALE: Piribedil is an orally active dopamine agonist that has been widely used for Parkinson disease (PD), with its partial D2/D3 agonistic functions and alpha2-adrenoreceptor antagonistic effects, piribedil has been proved to be efficacious in the relief of motor symptoms in PD, while it can also lead to impulse control disorders such as pathological gambling due to its dopamine agonistic effects. PATIENT CONCERNS: A 28-year-old Chinese female patient with Parkinson disease and a history of taking piribedil finally developed pathological gambling and depressive episode. DIAGNOSES: After a careful clinical observation and evaluation, the patient met the criteria of severe depressive episode and pathological gambling due to antiparkinson therapy. INTERVENTIONS: We discontinued piribedil and picked bupropion, a dopamine reuptake inhibitor, to alleviate the depressive symptom. Benzhexol and selegiline were also added for the control of motor fluctuations. OUTCOMES: After 3 weeks' treatment, the patient's depressive mood was significantly alleviated and her recurring PD symptoms were also relieved. She was no more addicted to network gambling, and there was no recurrence during the 1-year follow-up. LESSONS: Piribedil-induced problem gambling and impulse control disorders are side effects needed to be evaluated when commencing a patient on piribedil. This case further emphasizes the importance of monitoring and controlling Parkinson symptoms after drug reduction or withdrawal. Anticipation of this risk strengthens the significance of detailed medical history-taking and targeted clinical management.

Design and evaluation of thermo-responsive nasal in situ gelling system dispersed with piribedil loaded lecithin-chitosan hybrid nanoparticles for improved brain availability.

Piribedil (PBD) is a compound that has shown efficacy in clinical trials to treat motor and non-motor symptoms of Parkinson's disease. However, drug delivery issues like low oral bioavailability, high dosing frequency (3-5 tablets/day), gastrointestinal side-effects reduced the clinical use of PBD. In this work, we have developed lecithin-chitosan hybrid nanoparticles (PBD-LCNs) to improve the direct nose to brain uptake of PBD. PBD-LCNs were optimized using hybrid design approach based on DoE. The mean particle size and drug loading of PBD-LCNs were 147 nm, and 12%, respectively. The PBD-LCNs showed good stability and were found to be nearly spherical in shape. Further, the optimized LCNs were loaded in methylcellulose thermo-responsive in situ gel (PBD-LCN-ISG) to overcome rapid mucociliary clearance upon intranasal administration. Plasma and brain pharmacokinetic studies in rats showed that PBD-LCN-ISG increased the relative bioavailability of PBD in brain (AUCbrain) by about 6.4-folds and reduced the (Cmax)plasma by 3.7-folds when compared to plain intranasal suspension of PBD (PBD-Susp). Further, PBD-Susp showed limited direct nose to brain uptake with DTP values less than 0, while the optimized PBD-LCNs showed DTP value of 56% indicating efficient direct nose to brain uptake. Overall, the development of nanoformulations significantly improved the direct nose to brain uptake of PBD.

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.

Effects of a dopamine agonist piribedil in depressed patients: relationship of pretreatment homovanillic acid to antidepressant response.

Piribedil, a compound that stimulates dopamine receptors in a relatively specific fashion, was administered to 11 hospitalized depressed patients. The dopamine agonist significantly decreased rapid eye movement (REM) sleep and percent REM sleep and increased REM latency. Piribedil decreased the probenecid-induced accumulation of the dopamine metabolite homovanillic acid (HVA) in CSF. A range of mild to moderate antidepressant effects was noted; one patient worsened and one developed recurrent manic episodes. The degree of improvement in depression was negatively correlated with pretreatment values of HVA in CSF (r = -.66, P less than .05). These data suggest that the heterogeneity of clinical response may be related to biological differences in depressed patients and that those with low initial dopaminergic function respond best to increased dopamine receptor stimulation.

Piribedil and pathological gambling in six parkinsonian patients.

UNLABELLED: Impulse control disorders (ICD) in Parkinson's disease (PD) have attracted increasing interest. They are characterized by the inability to control the impulse to perform an act that can be detrimental to them or to others. Although dopamine agonists (DA), as a group, have been associated with impulse control disorders (ICD), piribedil has rarely been reported to cause them. METHOD: Case reports of six parkinsonian patients on piribedil presenting pathological gambling (PG). RESULTS: All of the patients presented ICD associated with piribedil use. Two of them received this medication as first treatment and four of them who had developed ICDs secondary to other DA that reappeared with piribedil. CONCLUSION: Despite piribedil is commercially available in only a few countries, it should be considered in the differential diagnosis of PG in patients with PD.

Piribedil: its synergistic effect in multidrug regimens for parkinsonism.

Piribedil, a dopamine agonist, was administered to 13 patients with long-standing Parkinson's disease whose major symptoms were not well controlled on levodopa, anticholinergics, alpha-methyldopa, amantadine, or a combination of these agents. Twelve of the 13 clearly benefited from the addition of Piribedil although side effects precluded long term use in two cases. Beneficial results were obtained by using a combination of Piribedil, levodopa, and anticholinergic drugs. Side effects (hallucinations, confusion, dyskinesias) were frequent, but were usually reversible by lowering the dosage of levodopa or the accompanying anticholinergic medication. The synergistic effect of Piribedil and other antiparkinsonian drugs emphasizes the need for careful titration of all available medications in difficult cases and demonstrates the usefulness of dopamine receptor stimulators when drugs acting presynaptically have failed.

Parkinsonism by haloperidol and piribedil.

Three groups of schizophrenic patients were treated with haloperidol, with a low dose of piribedil (a dopamine agonist), and with a combination of the two treatments, respectively. After a few days, all 7 patients treated with the drug combination showed marked rigidity and akinesia, while patients treated with haloperidol alone (4) and piribedil alone (4) showed either mild or no symptoms of parkinsonism. The drug combination induced mainly an akinetic-hypertonic syndrome, while tremors were absent or mild. The results suggest that low doses of the DA-agonist potentiate the extrapyramidal side effects of haloperidol by acting on self-inhibitory DA receptors, thereby blocking the compensatory increase in dopaminergic firing elicited by the neuroleptic agent.

Effect of a dopaminergic agonist, piribedil (Trivastal 50 mg LP), on visual and spatial integration in elderly subjects.

Dopamine acts as a neuromodulator in the retina. Dopaminergic deficiency of any origin, as observed in elderly subjects, is associated with altered visual performances, and more specifically with altered perception of contrasts. The goal of this study was to compare contrast vision in elderly subjects and young subjects (first phase, n = 20), then to compare this function in elderly subjects before and after 3 months of treatment with a dopaminergic agonist, piribedil (Trivastal 50 mg LP), administered once daily (second phase, n = 20). The perception of contrast was analysed using a test measuring sensitivity to colour contrast yielding threshold values for sensitivity to contrast in eight spatial frequencies and three colours (red, green, blue) and in two directions (horizontal and vertical). The results of the first phase of the study demonstrated that elderly subjects showed a decrease in contrast perception in comparison with young subjects, primarily in the high frequency range, and over the full range of stimulation for direction and colour. In the second phase, elderly subjects, in comparison with young subjects, showed altered visual contrast, again in the high frequency range, but also in the low frequency range for horizontal simulation with red and blue. After 3 months of treatment with piribedil the mean contrast sensitivity threshold, over the entire frequency range, had significantly increased (P less than 0.05) for all stimulations, apart for red in the vertical direction. These results underline the value of treatment with a dopaminergic agonist, piribedil in visual disturbances in patients with dopaminergic deficiency (Parkinson patients or elderly subjects).

Activity and acceptability of piribedil in Parkinson's disease: a multicentre study.

Several controlled trials have shown that the dopamine agonist, Trivastal (piribedil), is active in the treatment of Parkinson's disease, particularly with regard to tremor. To determine its efficacy as monotherapy in patients previously untreated with levodopa, a 3-month multicentre study was conducted with Trivastal 50 mg LP in 113 patients with idiopathic Parkinson's disease. The study population consisted of 66 men and 47 women, aged 63.1, SD 0.6 (43-79) years with a 2.1, SD 0.2 (1-15) year history of Parkinson's disease. Mean disease stage was 1.82 (1-4) by the Hoehn and Yahr classification. Tremor was the predominant clinical feature in 42 patients; the remaining 71 patients displayed the full parkinsonian syndrom. Trivastal 50 mg LP was prescribed stepwise up to doses of 150-250 (207, SD 6.4) mg/day at the end of 3 months. No concomitant anti-parkinsonian medication was given. Patients were clinically assessed at 1, 2 and 3 months on the Webster scale, a specific tremor scale and the HARD depression scale. Mean results were as follows in the 90 patients completing the study. On the Webster scale, tremor fell from 1.7 to 1 (-41%, P less than 0.001), bradykinesia from 1.5 to 0.8 (-47%, P less than 0.001) and rigidity from 1.3 to 0.9 (-31%, P less than 0.001); on the specific scale, rest tremor decreased in daily duration and amplitude from 3.9 to 2.4 (-39%, P less than 0.001) and from 2.9 to 2.1 (-35%, P less than 0.001), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Piribedil-induced sleep attacks in Parkinson's disease.

'Sleep attacks', episodes of sudden onset of sleep without any prodromal symptoms, were initially described in patients with Parkinson's disease (PD) taking the newer dopamine agonists pramipexole and ropinirole. Piribedil, a nonergot agonist with both D2 and D3 agonist action, is an effective antiparkinsonian medication. However, there are very few reports of Piribedil-induced sleep attacks in PD. Among 50 PD patients seen at our Movement Disorder Clinic who had recently taken Piribedil, we identified three (6%) who satisfied the clinical description of sleep attacks. Here we provide details of the clinical characteristics of Piribedil-induced sleep attacks in these PD patients.

Psychomotor and cognitive effects of piribedil, a dopamine agonist, in young healthy volunteers.

Piribedil is a dopamine agonist acting on D2 and D3 central nervous system dopamine receptors. This drug has been administered to 12 young healthy male volunteers (age 22 +/- 2 years) according to a single center randomized, double-blind, two ways cross-over, placebo controlled trial, including a washout period of one week. Placebo and piribedil were administered by a single intravenous infusion over 2 h (3 mg). Psychomotor performance and cognitive functions were assessed through a standardized and computerized psychometric tests battery and a continuous electroencephalogram (EEG) mapping. Piribedil improved simple reaction time (P=0.02), immediate (P=0.045 and 0.004), and delayed free recall (P=0.05), dual coding test (P=0.02) and increased theta and fast beta waves on the EEG (P < 0.05 and 0.001, respectively). No deleterious effect was observed on the tests exploring attention and concentration via the other procedures. It is concluded that a single intravenous perfusion of piribedil 3 mg improves alertness and the information processing speed within the central nervous system, in healthy volunteers.

Piribedil therapy in Parkinson's disease. Use of the drug in the retard form.

We conducted a 20-week nonblind study to evaluate the efficacy of piribedil in 30 patients with idiopathic Parkinson's disease (PD). Prior to the study 17 of these patients were under L-Dopa treatment alone or in combination with anticholinergics and/or amantadine, while 13 patients who had never taken L-Dopa were treated only with anticholinergics and/or amantadine, or were without any medication. Piribedil (in the retard form) was administered orally at a gradually increasing dose up to 200 mg daily, while previous antiparkinsonian medication remained unchanged. Twenty-five patients showed statistically significant improvement. Among the cardinal symptoms of parkinsonism, tremor responded the best. Depression also appeared to respond favorably. Our results indicate that piribedil may be a useful adjuvant in the treatment of PD.

Dopaminergic agonist effects on Parkinsonian clinical features and brain monamine metabolism.

The effect of a new dopaminergic agonist, piribedil, was studied in 16 patients with Parkinson's disease and compared with placebo and L-DOPA. Piribedil appeared to have a moderate therapeutic effect that was significantly less than that of L-DOPA. Tremor appeared to be the main clinical feature to benefit. Nausea, vomiting, and somnolence were most frequent during the buildup of treatment and confusion and hallucinations during long-term treatment. Piribedil caused a significant decrease in probenecid-induced accumulation of HVA in the CSF, suggesting reduced turnover of endogenous dopamine in the brain. There was a significant relationship between dopamine receptor activation by piribedil and improvement of parkinsonian disability.

Pharmacological exploration of dopamine hypersensitivity in migraine patients.

Patients with migraine show a hypersensitivity to dopamine or its agonists. One of these, piribedil, was administered as 0.1 mg/kg intravenously over 30 min to subjects with either migraine or other types of headache. This test provoked in migraine patients an increase of the cerebral blood flow and the peripheral signs of dopamine hypersensitivity:- nausea or vomiting and a rapid fall in blood pressure. In contrast, in those subjects with chronic non-migrainous headache, the administration of piribedil had no effect. The piribedil test appears to possess good specificity vis à vis migraine, enabling a differential diagnosis from atypical periodic headache, a condition difficult to consider as migraine or psychogenic headache on clinical grounds alone.

[The effectiveness and tolerance of piribedil as adjunct therapy to levodopa in patients with Parkinson's disease: a nine month follow up]. / Eficacia y tolerancia del piribedil como terapia adjunta a la levodopa en pacientes con enfermedad de Parkinson: seguimiento de nueve meses.

INTRODUCTION: Piribedil is a D2 D3 dopamine agonist, which has been shown to be well tolerated and to improve Parkinsonian symptoms, particularly tremor. However, few studies have been published about this Dopamine Agonist as an adjunct to levodopa therapy in patients with Parkinson's disease (PD). This placebo controlled, parallel group study was undertaken to investigate the effects of piribedil in PD patients insufficiently controlled with levodopa in a nine months follow up. PATIENTS AND METHODS: We included 62 PD patients insufficiently controlled with levodopa and needed an increase in dopamine stimulation. Patients were randomized in two similar groups, one of them taking Piribedil and levodopa and the other group taking a placebo and levodopa. The primary efficacy measures were the items II and III of the UPDRS. The patients were evaluated prior to the start of therapy, and 3, 6 and 9 months after the start of the study. RESULTS: Patients taking Piribedil showed an average of improvement of 37,8% (p < 0.01) in the part II and 63,2% (p < 0.01) in the part III of the UPDRS at the end of the study. At 9 month evaluation, tremor at rest showed an average improvement of 68,6%, rigidity, fingers taps and legs agility improved substantially in their respective items of the UPDRS at the end of the study. CONCLUSIONS: We concluded that PD patients with functional worsening while on stable levodopa doses exhibit a steady improvement of the UPDRS part II and III with the adjunction of Piribedil 150 mg mean daily dose for 9 months.