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.

Association of Multiple Dopamine D3 Receptor Gene 3'UTR Polymorphisms with Susceptibility to Parkinson's Disease and Clinical Efficacy of Piribedil Therapy.

Objective: To investigate the correlation between the Dopamine D3 receptor (DRD3) 3'untranslated region (3'UTR) gene polymorphism and susceptibility to Parkinson's disease (PD) and the clinical effect of the DRD2 and DRD3 agonist piribedil treatment. Methods: Sanger sequencing was used to analyze the single nucleotide polymorphisms (SNPs) within the 3'UTR rs76126170, rs9868039, rs9817063, and rs3732790 loci of the DRD3 gene in 284 PD patients and 284 controls. PD patients were treated with piribedil sustained-release tablets (50 mg) combined with levodopa and benserazide hydrochloride tablets, three times daily (patients with first-diagnosed PD were only administrated with piribedil sustained-release tablets) for 3 months. The Unified Parkinson's Disease Rating Scale (UPDRS) and the Hoehn and Yahr disease stage were evaluated at baseline and after 3 months of treatment. Results: The T allele carriers of the DRD3 gene rs76126170 locus were more susceptible to PD than the C allele carriers (odds ratio [OR] = 3.44, 95% confidence interval [CI]: 2.46-4.80, p < 0.01). Carriers of the rs9868039 A allele had a decreased risk of PD compared to those with G allele (OR = 0.67, 95% CI: 0.53-0.86, p < 0.01). C allele carriers at rs9817063 were less likely to develop PD than those with T allele (OR = 0.74, 95% CI: 0.58-0.94, p = 0.02). No significant correlation was observed between the alleles or genotypes of the rs3732790 locus and PD susceptibility (p > 0.05). The various genotypes of the DRD3 gene loci rs76126170, rs9868039, and rs9817063 in PD patients were associated with significant differences with regard to reduction of UPDRS scores and Hoehn and Yahr stage after 3 months of treatment (p < 0.05). Conclusion: The alleles and genotypes of the DRD3 gene 3' UTR SNP loci rs76126170, rs9868039, and rs9817063 are associated with PD susceptibility and the clinical efficacy of piribedil treatment.

Ultrasonography after pharmacological stimulation of erection for the diagnosis and therapeutic follow-up of erectile dysfunction due to cavernovenous leakage.

The goal of this work was to demonstrate that Doppler ultrasound (DUS) after pharmacological stimulation of erection (PSE) can be used to evaluate the presence and intensity of a cavernovenous leak (CVL) suspected in erectile dysfunction (ED) patients. The study was built around 50 DUS-PSE exams of penile arteries and veins, which were carried out 3, 5, 10 and 20minutes after pharmacological stimulation. Measured parameters were end diastolic velocity of the cavernous arteries and mean velocity of the deep penile vein and/or penile superficial veins. A score from 0 to 3 was attributed to each according to the recorded velocities. A final score from 0 to 9 was established by adding the three values: patients quoting 0 and 1 were classified as "no leak" (n=8); from 2 to 9 (n=42) as "leaking". Penile computed tomography (CT-scan) under identical pharmacological stimulation identified the cavernovenous leak to be compared with the DUS-PSE results, which were valid in 47 cases (94%), with 97.6% sensitivity and 77.7% specificity. The kappa correlation coefficient for CT-scan diagnosis of suspected CVL was 0.7875 (P<0.001). In addition, we found that end diastolic velocity in the cavernous artery, considered up until now as the gold standard in cases of suspected CVL was insufficient (negative predictive value=47%). In addition to its well-known diagnostic value regarding ED of arterial origin, DUS-PSE is an excellent screening test for CVL, especially in young patients without vascular risk factors who are resistant to medical treatments. For those with well-established CVL, confirmation by CT-scan to discuss possible surgery should be the next step. Moreover, DUS-PSE is useful in postoperative monitoring.

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.

Optimization of piribedil mucoadhesive tablets for efficient therapy of Parkinson's disease: physical characterization and ex vivo drug permeation through buccal mucosa.

OBJECTIVE: The aim of this study was optimization of buccal piribedil (PR) mucoadhesive tablets to improve its low bioavailability and provide controlled release for the treatment of Parkinson's disease. METHODS: Buccal tablets were prepared by direct compression method using carbomer (CP), carboxymethyl cellulose (CMC), and hydroxypropyl methylcellulose (HPMC) as mucoadhesive polymers. Physical properties of powder mixtures and buccal tablets were evaluated. Physicochemical compatibility between ingredients was investigated with infrared spectroscopy and differential scanning calorimetry analysis. In vitro dissolution profiles and drug release kinetics of buccal tablets were investigated. Mucoadhesion and ex vivo permeation studies were performed using sheep buccal mucosa. RESULTS: Powder mixtures demonstrated sufficient flow properties and physical characteristics of all tablet formulations were within compendia limits. Tablet ingredients were absent of any chemical interactions. CP tablets displayed slower drug release compared to HPMC tablets with zero order release, while CMC tablets lost their integrity and released entire drug after 6 h following Higuchi model. All formulations displayed adequate mucoadhesion and steady state flux of PR through buccal mucosa were higher with HPMC compared to CP-containing tablets. CONCLUSION: Overall, HPMC was found to combine desired controlled release and mucoadhesion characteristics with sufficient pharmaceutical quality for optimization of buccal tablets. Piribedil mucoadhesive buccal tablets designed for the first time may introduce a new alternative for the treatment of Parkinson's disease.

Persistence, distribution, and impact of distinctly segmented microparticles on cochlear health following in vivo infusion.

Delivery of pharmaceuticals to the cochleae of patients with auditory dysfunction could potentially have many benefits from enhancing auditory nerve survival to protecting remaining sensory cells and their neuronal connections. Treatment would require platforms to enable drug delivery directly to the cochlea and increase the potential efficacy of intervention. Cochlear implant recipients are a specific patient subset that could benefit from local drug delivery as more candidates have residual hearing; and since residual hearing directly contributes to post-implantation hearing outcomes, it requires protection from implant insertion-induced trauma. This study assessed the feasibility of utilizing microparticles for drug delivery into cochlear fluids, testing persistence, distribution, biocompatibility, and drug release characteristics. To allow for delivery of multiple therapeutics, particles were composed of two distinct compartments; one containing polylactide-co-glycolide (PLGA), and one composed of acetal-modified dextran and PLGA. Following in vivo infusion, image analysis revealed microparticle persistence in the cochlea for at least 7 days post-infusion, primarily in the first and second turns. The majority of subjects maintained or had only slight elevation in auditory brainstem response thresholds at 7 days post-infusion compared to pre-infusion baselines. There was only minor to limited loss of cochlear hair cells and negligible immune response based on CD45+ immunolabling. When Piribedil-loaded microparticles were infused, Piribedil was detectable within the cochlear fluids at 7 days post-infusion. These results indicate that segmented microparticles are relatively inert, can persist, release their contents, and be functionally and biologically compatible with cochlear function and therefore are promising vehicles for cochlear drug delivery. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1510-1522, 2016.

[The use of piribedil for the prevention of falls in elderly patients with metabolic syndrome].

Effects of pirebedil used to prevent falls in elderly patients with metabolic syndrome are discussed. A prospective controlled study showed that therapy with pirebedil significantly decreases the frequency of falls, reduces severity of pro-inflammatory and pro-oxidative activities, improves cognitive abilities. Prevention of falls by virtue of improved cognitive abilities is a new clinical effect of pirebedil and gives reason to recommend it for the treatment of geriatric patients with metabolic syndrome.

[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.

Pre-treatment with dopamine agonists influence L-dopa mediated rotations without affecting abnormal involuntary movements in the 6-OHDA lesioned rat.

L-dopa induced dyskinesia is a complication of long-term L-dopa administration in patients with Parkinson's disease. This study uses the rodent model of dyskinesia to determine whether prior dopamine agonist treatment causes long-term changes that influence the development of L-dopa mediated behaviours. Rats with unilateral 6-OHDA lesions were injected with dopamine agonists (ropinirole, piribedil bromocriptine, all 1mg/kg) or saline (0.9%) daily for 21 days. Following a 1-week drug free interval L-dopa was administered for 15 days (10mg/kg with benserazide 15 mg/kg in saline s.c.). Rotational behaviour and abnormal involuntary movements (AIMs) were recorded at regular intervals. All dopamine agonists induced a contralateral rotational response on day 1, which increased in response to repeated administration but did not by themselves induce overt dyskinesias. On day 1 of L-dopa administration animals pre-treated with piribedil and ropinirole produced a more severe rotational response. In the saline pre-treated group, AIMs developed with repeated L-dopa administration, which was reflected in the increased expression of PPE-B mRNA. There was a trend for the same pattern in the dopamine agonist treated groups but this was non-significant. Therefore, while locomotor sensitivity is altered by the pre-treatment with dopamine agonists, there appears to be no increased risk of developing AIMs.

Orodispersible sublingual piribedil to abort OFF episodes: a single dose placebo-controlled, randomized, double-blind, cross-over study.

S90049, a novel sublingual formulation of the non-ergoline D(2)-D(3) agonist piribedil, has a pharmacokinetic profile promising to provide rapid relief on motor signs in Parkinson's disease (PD). We assessed the efficacy and safety of S90049 in aborting OFF episodes responding to subcutaneous apomorphine in PD patients with motor fluctuations. This was a single-dose double-blind double-placebo 3 x 3 cross-over study. Optimal tested doses were determined during a previous open-label titration phase (S90049 median dose: 60 mg, apomorphine: 5 mg). Primary endpoint was the maximal change versus baseline in UPDRS motor score (Delta UPDRS III) assessed after drug administration following an overnight withdrawal of antiparkinsonian medications. Thirty patients (age: 60 +/- 8 years, PD duration: 12 +/- 6 years, UPDRS III OFF: 37 +/- 15) participated. S90049 was superior to placebo on Delta UPDRS III (-13 +/- 12 versus -7 +/- 9 respectively; estimated difference -5.2, 95% Confidence Interval (CI)[-10.4;0.05], P = 0.05). This was also true for secondary outcomes: number of patients switching from OFF to ON (17 on S90049 vs. 8 on placebo, P = 0.03), time to turn ON (P = 0.013) and duration of the ON phase (P = 0.03). In the 17 patients who switched ON on S90049, Delta UPDRS III was similar on S90049 (-21.2 +/- 10.1) and apomorphine (-23.6 +/- 14.1) (estimated difference: 4.0 95% CI [-2.9;10.9]). S90049 was well tolerated: no serious or unexpected adverse event occurred. A single dose of up to 60 mg of S90049 given sublingually was superior to placebo in improving UPDRS III and aborting a practical OFF in patients with advanced PD. Testing greater doses might improve response rate.

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.

Comparative effects of the dopaminergic agonists piribedil and bromocriptine in three different memory paradigms in rodents.

The potential memory-enhancing properties of two dopamine agonists currently used in patients with Parkinson's disease, piribedil (1, 10 mg/kg/day, subcutaneously) and bromocriptine (5 mg/kg/day, subcutaneously), were evaluated in three experiments. Although piribedil (10 mg/kg) and bromocriptine equally enhanced spontaneous object recognition in young adult rats (experiment A), only piribedil displayed beneficial effects against aging-related memory impairments in two radial-maze experiments in mice. First (experiment B), a two-stage paradigm of spatial discrimination was used to assess relational/declarative memory in aged mice; piribedil (1 and 10 mg/kg) selectively and significantly improved the performances of aged mice in the critical tests for relational/declarative memory, whereas bromocriptine had no effect. Second, in a novel working memory task (experiment C), vehicle- or bromocriptine-treated aged mice displayed, compared with (vehicle) younger controls, a severe and persistent deficit in short-term retention of successive arm-visits, performing close to chance whichever the retention interval. Performances of piribedil (10 mg/kg) group remarkably improved across testing-days and reached young adults' level. The restoration of specific mnemonic impairments, in aged mice, highlights the memory-enhancing properties of piribedil. The efficacy of this drug in treating cognitive impairment of Parkinson's disease should now be assessed in more specific models.This work was published in an abstract form: ECNP Abstracts, 2005 (P8060 & P8065).

[Effect of dopamine deficiency on the preparation of visually guided saccadic eye movements].

Parameters of saccadic eye movements were studied in patients with Parkinson's disease and control subjects. In parkinsonian patients, the number of slow regular saccades was shown to be increased, and the number of express saccades was shown to be decreased. As a result the mean of saccade latency in patients was longer than in the control group. Moreover, the percentage of multistep saccades in patients with Parkinson's disease. In this case, not one but two or three saccades were performed with smaller amplitude to the target. We point, that the multistep saccades occurred mainly among the express saccades. Obviously, the dopamine deficiency distinguishing parkinsonian patients takes the primary part in the development of saccadic disorders. Degeneration of the nigrostriatal dopamine pathway results in imbalance in activity of the direct and indirect output pathways of the striatum. We suppose that this leads to inhibition of neurons activity in the superior colliculus during the saccade performance, which results in the early saccade interruption. In support of this reasoning, the mean of saccade latency and the percentage of the multistep saccades decreased in patients with Parkinson's disease after dopamine D2/D3 agonist (piribedil) treatment, due to activity restoration of the indirect pathway.

The dopamine agonist piribedil with L-DOPA improves attentional dysfunction: relevance for Parkinson's disease.

Cognitive deficits are often associated with motor symptoms in Parkinson's disease. This study investigates the ability of piribedil ([(methylenedioxy-3,4 benzyl)-4 pyperazinyl-1]-2 pyrimidine), a D(2)/D(3) dopamine (DA) receptor agonist with antagonist activity at alpha(2A)-adrenoceptors, to restore motor and attentional deficits in nigrostriatal 6-hydroxydopamine-lesioned rats. Subjects were trained to depress a lever, detect a stimulus occurring after variable foreperiods, and release the lever quickly afterward. Striatal DA depletions produce deficits in the timing of foreperiods and prolong reaction times. Although a subchronic treatment with piribedil (0.1-2 mg/kg) is not effective, a dose of 0.3 mg/kg administered for 3 weeks significantly reverses the akinetic deficits produced by the striatal dopamine depletion and progressively improves attentional deficits. When coadministered with the dopamine prodrug l-3,4-dihydroxyphenylalanine (l-DOPA) (3 mg/kg), piribedil (0.3 mg/kg) promotes a rapid and full recovery of preoperative performance. These results suggest that administration of l-DOPA in combination with piribedil in a chronic treatment as either initial or supplemental therapy for Parkinson's disease might improve cognitive functions while reducing the risk for motor complications.

Switching from levodopa to the long-acting dopamine D2/D3 agonist piribedil reduces the expression of dyskinesia while maintaining effective motor activity in MPTP-treated primates.

BACKGROUND: The control of motor complications following dopaminergic medication in late-stage Parkinson disease remains problematic. OBJECTIVE: We now investigate the potential of oral administration of the long-acting dopamine D2/D3 agonist piribedil to decrease the expression of dyskinesia induced by prior exposure to levodopa in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-treated primates. METHODS: MPTP-treated common marmosets were treated with equieffective doses of levodopa (10.0-12.5 mg/kg PO, twice daily) or piribedil (3.0-4.0 mg/kg PO, once daily) for 30 days and then switched to the alternative treatment for a further 35 days. RESULTS: Levodopa administration markedly improved motor function, but dyskinesia rapidly appeared and intensified as treatment progressed. Administration of piribedil produced a similar reversal of MPTP-induced motor deficits but with comparatively mild dyskinesia. On switching from levodopa to piribedil, the intensity of dyskinesia decreased without altering the improvement in motor deficits. However, on switching from piribedil to levodopa, the rapid increase in dyskinesia despite the improvement in motor function being maintained suggests that piribedil also primes for but does not markedly express dyskinesia. CONCLUSION: The study confirms the low dyskinesia expression resulting from piribedil treatment compared with an equieffective dose of levodopa. Importantly, the results show that switching from levodopa to piribedil rapidly results in a sustained decrease in dyskinesia intensity.

Enhancement in dissolution pattern of piribedil by molecular encapsulation with beta-cyclodextrin.

The aim of this study was to improve the dissolution behavior of piribedil by molecular encapsulation with beta-cyclodextrin (beta-CD). Toward this aim, physical mixing, co-grinding, and spray-drying methods were used to prepare solid binary systems. Differential scanning calorimetry, X-ray diffractometry, and particle size analysis were used to characterize the binary systems obtained. Complexes of piribedil and beta-CD could be prepared using the spray-drying method. Dissolution of piribedil was improved to a great extent by the complex prepared.

[Efficacy of pronoran in age-related memory impairment].

Thirty patients aged 45-62 years (mean 54.8 +/- 3.7) have been studied. Pronoran (piribedil) was used for treatment of age-related memory impairment in dosage 50 mg per day during 30 and 90 days (2 groups of 15 patients). Psychophysiological examination included a study of sensomotor activity (time for visual-motor reactions--simple and complex) and functional lability of visual analyzer as well as evaluation of cognitive processes--memory and attention. Patients were examined before and after therapy of different duration. Pronoran exerted a positive effect on psychophysiological state of elderly people, improving memory and attention and increasing the velocity of psychomotor reactions and lability of nervous processes. The longer was the therapy, the more improved were above traits. Along with cogniotropic and mnemotoric (an influence on operative memory) effects of pronoran, its non-specific activating impact is described.

[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.

Efficacy and safety of piribedil in early combination with L-dopa in the treatment of Parkinson's disease: a 6-month open study.

BACKGROUND: Piribedil is a non-ergot D2/D3 dopamine agonist with antagonistic effect on alpha2-adrenoceptors and lack of agonist properties at 5-HT2A/2C receptors. Previous studies indicated its efficacy in monotherapy as well as in combinatio' s disease in L-dopa-treated parkinsonian patients. PATIENTS AND METHOD: A 6-month, open-labeled, multicenter study was conducted in Thai Parkinsonian patients who were insufficiently controlled by L-dopa (< or = 600 mg/day). Piribedil 50 mg in retard form was titrated upward to 150 mg/day (50 mg tid) by the 5th week and up to 6 months as an add-on treatment. L-dopa daily dose was kept stable until the 3rd month and could be adjusted afterwards. The main efficacy parameter was the change in UPDRS part III score versus baseline over Full Analysis Set, score variation, and percentage of responders defined by at least 30% decrease from baseline of total UPDRS part III score. The secondary efficacy criteria were changes in L-dopa dose between the third month and the end of the study, UPDRS part II score variation, Hoehn and Yahr stage variation and Schwab and England Activities of Daily Living Scale variation. The acceptability of piribedil was assessed by physical examination, weight, blood pressure and heart rate as well as the reported adverse events. RESULTS: Twenty-nine patients (55.2% male) with the mean age of 64.0 +/- 7.2 years and mean duration of disease of 18.3 +/- 8.2 months were recruited The mean UPDRS part III score at baseline was 19.8 +/- 11.4. After 6-month treatment with piribedil, mean UPDRS part III score significantly decreased to 6.6 +/- 4.7 (p < 0.0001) with mean score variation of 13.3 +/- 10.3. Twenty-seven patients (93.1%) were responders. Mean UPDRS part II score was significantly decreased from 7.2 +/- 5.4 at baseline to 2.7 +/- 2.1 at the end of 6 months (p < 0.0001). Hoehn and Yahr stage and Schwab and England Activities of Daily Living Scale were also significantly improved Reported adverse events were mainly gastrointestinal symptoms. Blood pressure and heart rate were not significantly changed during the study period. Peak dose dyskinesia was reported only in one patient. Two patients (6.9%) were withdrawn because of adverse events. CONCLUSION: Piribedil was effective on motor symptoms during a 6-month treatment in early parkinsonian patients insufficiently controlled by L-dopa and it was well tolerated.