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.

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.

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.

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 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: 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.

Dose-dependent impulse control disorders in piribedil overdose.

We describe a 73-year-old female patient with Parkinson disease who developed impulse control disorders (ICDs) and dopamine dysregulation syndrome (DDS) owing to piribedil overdose. She was initially put on piribedil 150 mg; and owing to disease progression, levodopa was added 4 years later. Three years later, piribedil was raised to 200 mg; but presumably owing to a misunderstanding, she took 400 mg/d, which was well tolerated and produced an improvement in her parkinsonian symptoms.However, over the next few weeks, she started shopping compulsively, buying unnecessary clothes and food. In addition, she visited her dog's veterinarian several times a day with nonsense queries. She began to have financial problems and family disruption. During an examination, mild dyskinesia was evident.We diagnosed ICDs and most likely dopamine dysregulation syndrome DDS. Piribedil doses were decreased to 200 mg/d and levodopa increased up to 750 mg/d, with a clear improvement in compulsive behavior without worsening of the dyskinesia.Our case shows that even in cases in which regular doses of dopamine agonists are harmless, dose increments can induce these unwanted effects.

Piribedil-induced sleep attacks in patients without Parkinson disease: a case series.

BACKGROUND: Sleep attacks were initially described in 1999 in patients with Parkinson disease (PD) treated by dopamine agonists (DAs). Because the respective role of DAs or PD-induced excessive daytime sleepiness is still unclear, reports of sleep attacks in non-PD patients treated with DA would support the specific role of these drugs. Piribedil, a nonergot dopamine D2/D3 agonist with alpha(2)-noradrenergic properties, is indicated in the treatment of PD as well as in patients with circulatory disorders. After a spontaneous report of sleep attack associated with piribedil use in a non-PD patient, we reviewed other cases from the French pharmacovigilance database. MATERIALS AND METHODS: Cases of piribedil associated with sleep attacks recorded between 1988 and December 2008 were identified in the French Pharmacovigilance database. Cases were retained for analysis only if patients were treated for conditions other than PD. RESULTS: Overall, a total of 35 cases of piribedil-induced sleep disorders were retrieved, and 7 cases suggestive of sleep attacks were retained for analysis. The mean time to onset after starting piribedil was 2.5 days. Piribedil was the only suspected drug in all but 1 patient. Complete recovery was noticed after piribedil discontinuation in all patients, and recurrence of symptoms was observed after piribedil reintroduction in 1 patient. CONCLUSIONS: Our series suggests that piribedil may be associated with sleep attack disorders independently of the treated disease and supports the prominent role of DAs in sleep disorders.

[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.

[Use of pronoran (piribedil) in Parkinson's disease: the results of a multicenter study]. / Primenenie pronorana (piribedila) pri bolezni Parkinsona: rezul'taty mul'titsentrovogo issledovaniia.

The study of 99 patients has been conducted in 5 Russian centers. Pronoran ("Servier", France) combined with levodopa was used in dosage 50-150 mg daily during 6 months. The treatment was placebo-controlled. Significant differences (p < 0.001) between the study and control groups in expression of all main symptoms of the disease were found.

Efficacy of piribedil as early combination to levodopa in patients with stable Parkinson's disease: a 6-month, randomized, placebo-controlled study.

Piribedil is a non-ergot D2/D3 agonist with a significant antagonist action on alpha2A and alpha2C adrenergic receptor subtypes. This double-blind placebo-controlled study was undertaken to confirm the efficacy of 150 mg/day piribedil po in improving motor symptoms of idiopathic Parkinson's disease (PD) in nonfluctuating patients insufficiently controlled by a stable daily dose of levodopa (L-dopa). Efficacy was assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) III score as primary criterion over 4 months. A second comparison was planned at 6 months, after possible adjustment of L-dopa. At 4 months, the rate of response, defined as a 30% decrease from baseline on UPDRS III score, was significantly greater with piribedil compared with placebo (56.4% vs. 37.7%; P = 0.040). At 6 months, the better efficacy of piribedil was maintained (61.8% of responders vs. 39.6% on placebo; P = 0.020). The difference between groups on UPDRS III change from baseline reached statistical significance only at 6 months: -10.0 points in the piribedil group vs. -6.7 points in the placebo group (P = 0.037). Secondary end-points were not significantly different. The most frequently reported adverse events were gastrointestinal symptoms (27 of 61 patients in the piribedil group vs. 13 of 54 patients in the placebo group). In conclusion, a 6-month oral administration of 150 mg/day piribedil in combination with L-dopa is well tolerated, except for minor gastrointestinal symptoms at the beginning of the treatment and significantly improves motor symptoms compared with placebo in PD nonfluctuating patients.

Piribedil and bromocriptine in Parkinson's disease: a single-blind crossover study.

INTRODUCTION: Clinicians switch from one dopamine agonist to another for various reasons. However, each change may inadvertently result in certain potential risks such as decreased medication efficacy or new side-effects. OBJECTIVE: We evaluated the tolerability of a switch of bromocriptine to piribedil using two conversion ratios as a primary outcome measure, with motor function as a secondary outcome measure, in patients with mild to moderate Parkinson's disease (PD). METHODS: Twenty consecutive patients with mild to moderate PD (Hoehn and Yahr, stage II-III) on treatment with stable doses of bromocriptine and levodopa were randomized to two groups of 10 patients each, to receive piribedil based on 1:5 or 1:10 conversion ratios. Blinded evaluations were performed: 1) United Parkinson's Diseased Rating Scale (UPDRS) scores both in 'on' and 'off', 2) Open-ended interviews for adverse events, 3) Epworth Sleepiness Scale, 4) Purdue Pegboard assessment during 'on' and 'off', 5) Hand-arm movement test during 'on' and 'off', and 6) Walking test during 'on' and 'off'. RESULTS: Major adverse events included 'sleep attacks' in one patient and minor side-effects included giddiness, nausea, hallucinations, sleepiness and lethargy. However, these were mild and 19 (95%) of the 20 patients completed the study. There was a significant improvement in both the UPDRS 'off' total and motor scores at 1 month compared with baseline for the group on 1:10 ratio. The walking times during the 'off' state at 1 and 2 months were significantly better compared with baseline in the 1:5 group. There were otherwise no significant differences in the rating tests during both 'off' and 'on' states before and after the bromocriptine switch. CONCLUSIONS: We demonstrated that patients with mild to moderate PD who were on relatively low doses of bromocriptine can be safely switched to piribedil based on a conversion ratio of either 1:5 or 1:10. However, the higher conversion ratio has to be carried out with caution in patients with daytime somnolence.

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.

Repeated administration of piribedil induces less dyskinesia than L-dopa in MPTP-treated common marmosets: a behavioural and biochemical investigation.

Piribedil ([1-(3,4-methylenedioxybenzyl)-4-(2-pyrimidinyl)piperazine]; S 4200) is a dopamine agonist with equal affinity for D(2)/D(3) dopamine receptors effective in treating Parkinson's disease as monotherapy or as an adjunct to levodopa (L-dopa). However, its ability to prime basal ganglia for the appearance of dyskinesia is unknown. We now report on the ability of repeated administration of piribedil to induce dyskinesia in drug naïve 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) -lesioned common marmosets compared with L-dopa and its actions on the direct and indirect striatal outflow pathways. Administration of piribedil (4.0-5.0 mg/kg orally) or L-dopa (12.5 mg/kg orally plus carbidopa 12.5 mg/kg orally twice daily) produced equivalent increases in locomotor activity and reversal of motor deficits over a 28-day study period. Administration of L-dopa resulted in the progressive development of marked dyskinesia over the period of study. In contrast, administration of piribedil produced a significantly lower degree and intensity of dyskinesia. Surprisingly, piribedil caused an increase in vigilance and alertness compared to L-dopa, which may relate to the recently discovered alpha(2)-noradrenergic antagonist properties of piribedil. The behavioural differences between piribedil and L-dopa are reflected in the biochemical changes associated with the direct striatal output pathway. Administration of L-dopa or piribedil did not reverse the MPTP-induced up-regulation of preproenkephalin A mRNA in rostral or caudal areas of the putamen or caudate nucleus. In contrast, administration of either piribedil or L-dopa reversed the downregulation of preprotachykinin mRNA induced by MPTP in rostral and caudal striatum. L-dopa, but not Piribedil, reversed the decrease in preproenkephalin B mRNA produced by MPTP treatment.

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 for restless legs syndrome: a pilot study.

Thirteen consecutive patients with restless legs syndrome (RLS) were treated with piribedil and were rated using an RLS rating scale (0-10) and subjective response (0-100%); 11/13 (85%) had improvement of their mean RLS scores with subjective response ranging from 30% to 100% (mean 74.6%). This pilot study suggests that piribedil is effective for RLS.