Piribedil 50mg modified-release tablets

Background: Non-ergot dopamine agonists (NEDAs) have been used as monotherapy or as an adjunctive therapy to levodopa for many years. Novel long-acting formulations of NEDAs including pramipexole extended-release (ER), ropinirole prolonged-release (PR), and rotigotine transdermal patch have been developed. However, there is no strong evidence that a given NEDA is more potent than another. We performed a systematic review and network meta-analysis to evaluate the efficacy, tolerability and safety of six commonly used NEDAs in early Parkinson's disease (PD). Methods: Six NEDAs including piribedil, rotigotine transdermal patch, pramipexole immediate-release (IR)/ER, and ropinirole IR/PR were investigated. The efficacy outcomes including Unified Parkinson's Disease Rating Scale activities in daily life (UPDRS-II), motor function (UPDRS-III), and their subtotal (UPDRS-II + III), tolerability and safety outcomes were analyzed. Results: A total of 20 RCTs (5,355 patients) were included in the current study. The result indicated that compared with placebo, all six investigated drugs had statistically significant differences in the improvement of UPDRS-II, UPDRS-III, and UPDRS-II + III (except ropinirole PR in UPDRS-II). There were no statistically significant differences between six NEDAs for the UPDRS-II and UPDRS-III. For UPDRS-II + III, the improvement of ropinirole IR/PR and piribedil were higher than that of rotigotine transdermal patch, and piribedil was higher than that of pramipexole IR. The surface under the cumulative ranking curve (SUCRA) indicated that piribedil resulted in best improvement in UPDRS-II and UPDRS-III (0.717 and 0.861, respectively). For UPDRS-II + III, piribedil and ropinirole PR exhibited similar improvement and both had high rates (0.858 and 0.878, respectively). Furthermore, piribedil performed better as monotherapy, ranking first in the improvement of UPDRS-II, III, and II + III (0.922, 0.960, and 0.941, separately). With regard to tolerability, there was a significant increase in overall withdrawals with pramipexole ER (0.937). In addition, the incidence of adverse reaction of ropinirole IR was relatively high (nausea: 0.678; somnolence: 0.752; dizziness: 0.758; fatigue: 0.890). Conclusions: In this systematic review and network meta-analysis of six NEDAs, piribedil exhibited better efficacy, especially as monotherapy, and ropinirole IR was associated with a higher incidence of adverse events in patients with early PD.

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We read with interest the systematic review on treatment options for Parkinson's disease (PD) motor fluctuations, published as an International Parkinson and Movement Disorder Society (MDS) evidence-based medicine (EBM) review article.1 We appreciate the authors' motivation to provide guidance in determining which therapeutic options are safe and efficacious to reduce patients' disease burden. The article appears intrinsically consistent, following the strict Grading of Recommendations Assessment, Development and Evaluation (GRADE)-based methodology. Having recently evaluated the literature on the same subject while developing the German Society of Neurology Guidelines for PD,2, 3 we wish to share some comments on this article.1 First, rapid-release (dispersible/soluble) oral levodopa is still among the most frequently prescribed off-rescue medication. This option is not mentioned in the MDS review.1 In the absence of randomized controlled trials to demonstrate superiority over other therapeutic options, there is still robust clinical experience supporting this safe and efficacious option. Inhaled levodopa is not mentioned either in the MDS review,1 although the criteria set forth by the authors appear to qualify consideration of the pivotal study demonstrating its efficacy to significantly reduce motor fluctuations.4 It might have been omitted since daily off-time was not the primary readout. The drug is still approved for this indication by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Likewise, the commonly used dopamine agonist piribedil is not mentioned.1 Intermittent application of apomorphine, either subcutaneous or sublingual, has been declassified by “insufficient evidence” in the MDS review,1 although published evidence may suggest otherwise5, 6 and these treatment options are approved, reimbursed, and administered successfully in many countries. The classification of istradefylline as “likely efficacious” is interesting, since the EMA issued a negative opinion in 2021,7 refusing approval for istradefylline as an add-on treatment for motor fluctuations, considering the available evidence as inconsistent and not satisfactorily showing effectiveness to reduce ‘off’ time. A pooled analysis of eight phase IIb/III trials suggested that istradefylline reduces daily off-time by only 0.38 or 0.45 hr more than placebo at 20 or 40 mg/day, respectively.8 These discrepancies between the conclusions reached in this article1 and the current options approved and available to aid patients with motor fluctuations demonstrate the striking limitations of the GRADE methodology, when stringently applied. Obviously, there is no possibility to consider other than the specified endpoints, relative effect sizes, or clinical experience in the absence of formal data for “old” drugs, and regional availabilities. The article also does not comment on the specific medical conditions in which the different options might be advantageous for individual patients (eg, continuous vs. on-demand medications, enteral vs. parenteral administration, different half-lives, renal or hepatic elimination, and so on). These aspects, however, are very important when making treatment decisions. Furthermore, the choice of options should also consider individual patient's side effect profiles, which in reality often become decisive factors. Thus, the strict EBM methodology apparently may deliver conclusions that are strikingly distinct from the options available and meaningful in reality for patients and caring neurologists in different regions. Therefore, a reconsideration of the EBM methodology used by the MDS Task Forces to provide true guidance for clinical practice may be warranted. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique. G.H.: 3A, 3B. P.L.: 3B. M.H.: 3B. C.T.: 3B. G.H. participated in industry-sponsored research projects from AbbVie, Biogen, Biohaven, Novartis, Roche, Sanofi, and UCB; has ongoing research collaborations with AbbVie, Ferrer, Roche, and UCB; serves as a consultant for AbbVie, Alzprotect, Amylyx, Bayer, Bial, Biogen, Biohaven, Ferrer, Lundbeck, Merz, Novartis, Roche, Sanofi, Takeda, TEVA, and UCB; and received honoraria for scientific presentations from AbbVie, Bayer, Bial, Biogen, Merz, Roche, TEVA, UCB, and Zambon. P.L. participated in industry-sponsored research projects from Alexion, Biogen, Blue Rock Therapeutics, Corcept Therapeutics, Mitsubishi Tanabe, Novartis, Theranexus, and Trace Neuroscience; serves as a consultant for AbbVie, Novartis, ITF Pharma, Raya Therapeutics, Stadapharm, Trace Neuroscience, Woolsey Pharmaceuticals, and Zambon; and received honoraria for scientific presentations from Bial, Desitin, ITF Pharma, and Zambon. M.H. participated in industry-sponsored research projects from AbbVie, Biogen, and Roche; serves as a consultant for AbbVie and Teitur Trophics; and received honoraria for scientific presentations from AbbVie and DESITIN. C.T. served as consultant for AbbVie, Roche, Boehringer, UCB, Bial, and Convatec; and has received honoraria for lectures from AbbVie, Bial, Esteve, and STADA. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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BACKGROUND AND PURPOSE: Non-ergot dopamine agonists (NEDAs) have been used as an adjunct therapy to levodopa in advanced Parkinson's disease (PD) for many years. However, there is no strong evidence that a given NEDA is more potent than another. To compare and rank the efficacy, tolerability, and safety of six commonly used NEDAs as an adjunct to levodopa in advanced PD, which includes long-acting and standard formulations, a network meta-analysis was performed. METHODS: The MEDLINE, Embase, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, and Wanfang databases were searched from January 1996 to June 2022 for eligible randomized controlled trials (RCTs). Six NEDAs, including rotigotine transdermal patch, ropinirole immediate-release (IR)/prolonged-release (PR), pramipexole IR/extended-release (ER), and piribedil, were investigated. RESULTS: A total of 34 RCTs (7868 patients) were included in the current study. The surface under the cumulative ranking curve indicated that ropinirole PR was associated with the best improvement in Unified Parkinson's Disease Rating Scale (UPDRS)-II, UPDRS-III, and UPDRS-II + III (0.811, 0.742, and 0.827). For OFF time reduction, pramipexole IR ranked first (0.979), and ropinirole PR ranked first in OFF time responder rate (0.927). Pramipexole ER ranked first in overall withdrawals, and rotigotine transdermal patch ranked first in the incidence of adverse events (≥1 AEs). CONCLUSIONS: This network meta-analysis suggests six commonly used NEDAs are effective as an adjunct to levodopa in advanced PD. In comprehensive consideration of better symptomatic management, ropinirole PR may be a better choice than other NEDAs in advanced PD. Six NEDAs showed different profiles of AEs.

Abstract licence: CC BY-NC-ND

With rapidly growing rates of prevalence, disability, and mortality, Parkinson’s disease (PD) has become a global healthcare burden. Increasing elderly population increases the incidence of neurodegenerative diseases in China. Hence, PD poses a huge burden to Chinese economic and healthcare system. PD is a movement disorder that affects the motor and nonmotor functions. Dopamine agonists are used in the management of PD. Piribedil is an antiparkinsonian drug and piperazine derivative, which acts as D2/D3 receptor agonist. Piribedil is one of the non-ergot dopamine receptor (DR) agonists and has been used in China for many years as monotherapy or in combination with levodopa. In this paper, we present a review of clinical application of piribedil, management of adverse events, and drug interactions, and discuss the results of clinical trials of piribedil on motor and non-motor symptoms of PD.

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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.

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Objective: This study focuses on improving the delivery of Piribedil, a poorly soluble drug, to the brain through the nasal route using a nanosuspension in a nasal in-situ gel. Methods: The nanosuspension was prepared using the sonoprecipitation method. Quality-by-Design (QbD) principles were used to optimize both the formulation and process parameters. The optimal process parameters were determined as sonication time (7.09 min), sonication amplitude (83.44%), and infusion rate (2.41 mL/min) with a desirability value of 0.970. Results: The nanosuspension exhibited an average particle size ranging from 46.7 nm to 50.1 nm, and polydispersity index values between 0.393 and 0.425. Zeta potential values ranged from -33.78 ± 1.86 mV to -35.06 ± 2.12 mV, indicating favorable stability. FTIR studies revealed molecular interactions between Piribedil and stabilizers. XRPD and DSC analyses showed the transition from a crystalline to an amorphous state in the nanosuspension. Dissolution studies demonstrated significantly accelerated dissolution for the Piribedil nanosuspension, attributed to its nanosize and improved wettability. Stability assessments confirmed the robustness of the nanosuspension. Conclusion: This innovative approach offers potential solutions for drug solubility challenges and blood-brain barrier penetration, holding promise for effective brain-targeted treatments.

Abstract licence: CC BY