RESUMEN
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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Levodopa , Enfermedad de Parkinson , Humanos , Levodopa/efectos adversos , Carbidopa/efectos adversos , Benserazida/efectos adversos , Estudios Retrospectivos , Pramipexol/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Piribedil/uso terapéutico , Selegilina/uso terapéutico , Mareo/inducido químicamente , Mareo/tratamiento farmacológico , Antiparkinsonianos/efectos adversos , Cefalea/inducido químicamente , Cefalea/tratamiento farmacológicoRESUMEN
The article is of an overview nature and is devoted to movement disorders in Parkinson's disease. The article discusses the existing problems according to the latest literature data, a review on the treatment and rehabilitation of postural instability. Special attention in the article is paid to dopamine receptor agonists - namely, piribedil, prescribed for the correction of these disorders.
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Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/complicaciones , Piribedil , Agonistas de Dopamina , Caminata , Equilibrio PosturalRESUMEN
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.
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Enfermedades del Sistema Nervioso Autónomo , Enfermedad de Parkinson , Masculino , Humanos , Femenino , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/diagnóstico , Levodopa/uso terapéutico , Piribedil/uso terapéutico , Calidad de Vida , Agonistas de Dopamina/uso terapéutico , Enfermedades del Sistema Nervioso Autónomo/etiología , Enfermedades del Sistema Nervioso Autónomo/complicacionesRESUMEN
OBJECTIVE: To evaluate the main symptoms of the upper gastrointestinal dysfunction (salivation and swallowing disorders) and to determine their impact on the quality of life for patients with PD of stages I-III, as well as the possibility of their correction by dopamine receptor agonists. MATERIAL AND METHODS: 252 patients (128 women and 124 men, 42-80 years old) with PD of stages I-III were examined using: UPDRS items «salivation¼, «swallowing¼ and «anorexia¼, scale of daily activity (Schwab and England ADL scale), questionnaire quality of life (PDQ-39), measurement of saliva amount, BMI, MMSE scale; 53 patients were treated with piribedil during 6 months. RESULTS: The upper gastrointestinal tract dysfunction of mild to moderate severity was detected in 51.2% of patients. The prevalence of sialorrhea was 38.9, 42.9 and 46.2%, and that of dysphagia was 22.2, 24.3 and 17.3% at stages I-III, respectively. According to the results of the correlation analysis dysphagia is associated with a long history of PD, low BMI, high doses of levodopa and low Sch & En score; and sialorrhea is also associated with low BMI and with old age. For the early stages of PD we can tell, that the quality of patients' life deteriorates, and this to a large extent is due to impaired salivation and swallowing, which manifest themselves in daily activity and communication difficulties. CONCLUSIONS: The inclusion of piribedil (150-250 mg/day) in the 6-months therapy reduces the dysfunction of the upper gastrointestinal tract (by 61 and 74% of the initial level of dysphagia and sialorrhea, respectively) regardless the drug use in monotherapy or in complex therapy with levodopa.
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Trastornos de Deglución , Enfermedades Gastrointestinales , Enfermedad de Parkinson , Sialorrea , Tracto Gastrointestinal Superior , Masculino , Humanos , Femenino , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Agonistas de Dopamina/uso terapéutico , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/diagnóstico , Piribedil , Levodopa/uso terapéutico , Sialorrea/tratamiento farmacológico , Sialorrea/etiología , Trastornos de Deglución/etiología , Trastornos de Deglución/diagnóstico , Calidad de VidaRESUMEN
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.
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Encéfalo/metabolismo , Quitosano , Composición de Medicamentos/métodos , Sistemas de Liberación de Medicamentos , Diseño de Fármacos , Lecitinas , Nanopartículas , Mucosa Nasal/metabolismo , Piribedil/administración & dosificación , Piribedil/farmacocinética , Administración Intranasal , Disponibilidad Biológica , Transporte Biológico , Estabilidad de Medicamentos , Geles , Metilcelulosa , Depuración Mucociliar , Enfermedad de Parkinson/tratamiento farmacológico , Tamaño de la Partícula , Piribedil/efectos adversosRESUMEN
Piribedil (PBD) is an anti-Parkinson's drug that gained interest recently due to its unique pharmacological profile. But its clinical use is severely limited by drug delivery issues like high dosing frequency (up to 5 tablets/day), low oral bioavailability (<10%), severe GI side-effects, etc. In this work, we have developed solid lipid nanoparticles (PBD-SLNs) to access the nose to brain pathways for direct uptake of PBD. PBD-SLNs were optimized using design of experiments approach to a mean particle size of 358 nm, and drug loading of 15%. The optimized PBD-SLNs were found to be nearly spherical in shape and showed good stability. Further, the SLNs were loaded in thermoresponsive Methyl Cellulose in situ gel (PBD-SLN-ISG) to delay mucociliary clearance upon intranasal administration in rats. Intranasal administration at the olfactory region was achieved with a cannula-microtip setup. In vivo pharmacokinetic studies showed that PBD-SLN-ISG increased the PBD (AUC)brain by about 4-folds and reduced the (Cmax)plasma by 2.3-folds when compared to plain intranasal suspension of PBD (PBD-Susp). Further, PBD-Susp showed limited direct nose to brain uptake with direct transport percentage (DTP) values less than 0, while the optimized PBD-SLN-ISG showed DTP value of 27% indicating efficient direct nose to brain uptake.
Asunto(s)
Nanopartículas , Enfermedad de Parkinson , Administración Intranasal , Animales , Disponibilidad Biológica , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Geles , Lípidos , Enfermedad de Parkinson/tratamiento farmacológico , Tamaño de la Partícula , Piribedil , RatasRESUMEN
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.
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Antiparkinsonianos/efectos adversos , Trastorno Depresivo Mayor/inducido químicamente , Juego de Azar/inducido químicamente , Piribedil/efectos adversos , Adulto , Femenino , HumanosRESUMEN
Methyl cellulose (MC) based nasal in situ gels were developed to enhance the brain delivery of piribedil (PBD), an anti-Parkinson's drug. Different grades of MC and several solutes (NaCl, KCl, Na.Citrate, STPP, PEG-6000, sucrose, etc.) were screened to formulate thermo-responsive nasal in situ gelling systems. Formulations were evaluated for their sol-gel transition temperature and time, rheological behaviour, in vitro drug release, mucociliary clearance (MCC), ex vivo nasal toxicity, and in vivo brain availability studies in Wistar rats. Intranasal (i.n.) administration was carried out using a cannula-microtip setup to deliver PBD at the olfactory region of the nose. The concentration and viscosity grade of MC and also the concentration and type of solute used were found to affect the rheological behaviour of the formulations. Among the solutes tested, NaCl was found to be effective for formulating MC in situ gels. The developed in situ gels significantly delayed the MCC of PBD from the site of administration when compared with conventional suspension (p < 0.05). Further, formulations with higher gel strength showed lower in vitro drug release rate and longer intranasal residence (delayed MCC) (p < 0.05). The absolute brain availability (brain AUC0-t) of PBD increased to 35.92% with i.n. delivery when compared to 4.71% with oral administration. Overall, it can be concluded that intranasal delivery of PBD is advantageous when compared to the currently practiced oral therapy. Graphical abstract.
Asunto(s)
Mucosa Nasal , Piribedil , Administración Intranasal , Animales , Disponibilidad Biológica , Encéfalo , Sistemas de Liberación de Medicamentos , Geles , Mucosa Nasal/metabolismo , Piribedil/metabolismo , Piribedil/farmacología , Ratas , Ratas WistarRESUMEN
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.
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Regiones no Traducidas 3' , Predisposición Genética a la Enfermedad , Enfermedad de Parkinson , Piribedil/administración & dosificación , Polimorfismo de Nucleótido Simple , Receptores de Dopamina D3/genética , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/genéticaRESUMEN
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.
Asunto(s)
Antiparkinsonianos/uso terapéutico , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/tratamiento farmacológico , Piribedil/uso terapéutico , Pramipexol/uso terapéutico , Antiparkinsonianos/efectos adversos , Agonistas de Dopamina/efectos adversos , Agonistas de Dopamina/uso terapéutico , Enfermedades Gastrointestinales/inducido químicamente , Humanos , Metaanálisis en Red , Piribedil/efectos adversos , Pramipexol/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Resultado del TratamientoRESUMEN
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.
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Atropina/administración & dosificación , Dipiridamol/administración & dosificación , Disfunción Eréctil/diagnóstico por imagen , Papaverina/administración & dosificación , Erección Peniana , Pene/irrigación sanguínea , Pene/diagnóstico por imagen , Piperidinas/administración & dosificación , Piribedil/administración & dosificación , Ultrasonografía Doppler de Pulso , Yohimbina/administración & dosificación , Adulto , Anciano , Velocidad del Flujo Sanguíneo , Angiografía por Tomografía Computarizada , Combinación de Medicamentos , Disfunción Eréctil/fisiopatología , Disfunción Eréctil/cirugía , Humanos , Masculino , Persona de Mediana Edad , Pene/cirugía , Valor Predictivo de las Pruebas , Recuperación de la Función , Flujo Sanguíneo Regional , Reproducibilidad de los Resultados , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
G protein-coupled receptors (GPCRs) are currently the target of more than 30% of the marketed medicines. However, there is an important medical need for ligands with improved pharmacological activities on validated drug targets. Moreover, most of these ligands remain poorly characterized, notably because of a lack of pharmacological tools. Thus, there is an important demand for innovative assays that can detect and drive the design of compounds with novel or improved pharmacological properties. In particular, a functional and screening-compatible GPCR-G protein interaction assay is still unavailable. Here, we report on a nanoluciferase-based complementation technique to detect ligands that promote a GPCR-G protein interaction. We demonstrate that our system can be used to profile compounds with regard to the G proteins they activate through a given GPCR. Furthermore, we established a proof of applicability of screening for distinct G proteins on dopamine receptor D2 whose differential coupling to Gαi/o family members has been extensively studied. In a D2-Gαi1versus D2-Gαo screening, we retrieved five agonists that are currently being used in antiparkinsonian medications. We determined that in this assay, piribedil and pergolide are full agonists for the recruitment of Gαi1 but are partial agonists for Gαo, that the agonist activity of ropinirole is biased in favor of Gαi1 recruitment, and that the agonist activity of apomorphine is biased for Gαo We propose that this newly developed assay could be used to develop molecules that selectively modulate a particular G protein pathway.
Asunto(s)
Luciferasas/metabolismo , Nanopartículas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Células Cultivadas , Células HEK293 , Humanos , Ligandos , Luciferasas/química , Nanopartículas/química , Pergolida/química , Pergolida/farmacología , Piribedil/química , Piribedil/farmacología , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/químicaRESUMEN
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.
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Bradicardia/inducido químicamente , Hipotensión/inducido químicamente , Piribedil/efectos adversos , Dopamina/metabolismo , Agonistas de Dopamina/administración & dosificación , Agonistas de Dopamina/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/tratamiento farmacológico , Piribedil/administración & dosificación , Pramipexol/administración & dosificaciónRESUMEN
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.
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Isquemia Encefálica/tratamiento farmacológico , Agonistas de Dopamina/uso terapéutico , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Piribedil/uso terapéutico , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D3/agonistas , Animales , Isquemia Encefálica/fisiopatología , Agonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Masculino , Aprendizaje por Laberinto/fisiología , Memoria/fisiología , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Piribedil/farmacología , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/fisiopatología , Resultado del TratamientoRESUMEN
Simple, selective and sensitive high-performance liquid chromatographic (HPLC) bioanalytical methods using fluorescence (FL) and photodiode array (PDA) detectors were developed and validated for determination of piribedil (PBD), an anti-Parkinson's drug, in rat plasma and brain samples, with telmisartan as internal standard (IS). Protein precipitation technique was used to extract PBD from both biological matrices. Chromatographic separation was achieved on a Phenomenex Kinetex C18 end-capped column (250 × 4.6 mm, 5 µm), with 38:62 v/v acetonitrile and ammonium acetate buffer (pH 5.0) as mobile phase at 1.0 mL/min flow rate. Linear response in the concentration ranges 5-300 and 150-3000 ng/mL in plasma, and 15-900 and 450-9000 ng/g in brain tissue were achieved in FL and PDA detectors, respectively. The chromatograms were extracted at 239 nm in case of PDA detection and at excitation wavelength of 239 nm and emission wavelength of 385 nm in case of FL detection. FL detection was found to be more sensitive compared with PDA detection. The developed methods were successfully employed in determining the plasma time course, brain distribution and the pharmacokinetic parameters of PBD following intravenous bolus administration of the drug in male Wistar rats.
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Química Encefálica , Cromatografía Líquida de Alta Presión/métodos , Piribedil/análisis , Piribedil/farmacocinética , Espectrometría de Fluorescencia/métodos , Animales , Encéfalo/metabolismo , Estabilidad de Medicamentos , Límite de Detección , Modelos Lineales , Piribedil/química , Piribedil/aislamiento & purificación , Ratas , Reproducibilidad de los ResultadosRESUMEN
Targeting WT MLL for the treatment of MLL-r leukemia, which is highly aggressive and resistant to chemotherapy, has been shown to be a promising strategy. However, drug treatments targeting WT MLL are lacking. We used an in vitro histone methyltransferase assay to screen a library consists of 592 FDA-approved drugs for MLL1 inhibitors by measuring alterations in HTRF signal and found that Piribedil represented a potent activity. Piribedil specifically inhibited the proliferation of MLL-r cells by inducing cell-cycle arrest, apoptosis and myeloid differentiation with little toxicity to the non-MLL cells. Mechanism study showed Piribedil blocked the MLL1-WDR5 interaction and thus selectively reduced MLL1-dependent H3K4 methylation. Importantly, MLL1 depletion induced gene expression that was similar to that induced by Piribedil and rendered the MLL-r cells resistant to Piribedil-induced toxicity, revealing Piribedil exerted anti-leukemia effects by targeting MLL1. Furthermore, both the Piribedil treatment and MLL1 depletion sensitized the MLL-r cells to doxorubicin-induced apoptosis. Our study support the hypothesis that Piribedil could serve as a new drug for the treatment of MLL-r AML and provide new insight for further optimization of targeting MLL1 HMT activity.
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Apoptosis , Doxorrubicina/farmacología , N-Metiltransferasa de Histona-Lisina/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Piribedil/farmacología , Animales , Antineoplásicos/farmacología , Ciclo Celular , Diferenciación Celular , Proliferación Celular/efectos de los fármacos , Agonistas de Dopamina/farmacología , Regulación hacia Abajo , Sinergismo Farmacológico , Regulación Leucémica de la Expresión Génica , Histonas/química , Humanos , Péptidos y Proteínas de Señalización Intracelular , Células K562 , Ratones , Ratones Desnudos , Trasplante de Neoplasias , ARN Interferente Pequeño/metabolismoRESUMEN
Sleep disorders increase pain sensitivity and the risk of developing painful conditions; however, the underlying mechanisms are poorly understood. It has been suggested that nucleus accumbens (NAc) influences sleep-wake cycle by means of a balance between adenosine activity at A2A receptors and dopamine activity at D2 receptors. Because the NAc also plays an important role in pain modulation, we hypothesized that the NAc and its A2A and D2 receptors mediate the pronociceptive effect of rapid eye movement (REM) sleep deprivation (SD). We found that 24 hours of REM-SD induced an intense pronociceptive effect in Wistar rats, which decreases progressively over a sleep rebound period. Although the level of fecal glucocorticoid metabolites increased with SD within group, it did not differ between sleep-deprived group and control group, indicating a stress response with similar magnitude between groups. The pronociceptive effect of REM-SD was prevented by excitotoxic lesion (N-Methyl-D-aspartate, 5.5 µg) of NAc and reverted by its acute blockade (Qx-314, 2%). The administration of an A2A receptor antagonist (SCH-58261, 7 ng) or a D2 receptor agonist (piribedil, 6 µg) into the NAc increased home cage activity and blocked the pronociceptive effect of REM-SD. Complementarily, an A2A receptor agonist (CGS-21680, 24 ng) impaired the reversal of the pronociceptive effect and decreased home cage activity, as it did a D2 receptor antagonist (raclopride, 5 µg). Rapid eye movement SD did not affect the expression of c-Fos protein in NAc. These data suggest that SD increases pain by increasing NAc adenosinergic A2A activity and by decreasing NAc dopaminergic D2 activity.
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Nocicepción/fisiología , Núcleo Accumbens/fisiopatología , Dolor/fisiopatología , Privación de Sueño/fisiopatología , Sueño REM/efectos de los fármacos , Adenosina/análogos & derivados , Adenosina/farmacología , Agonistas del Receptor de Adenosina A2/farmacología , Animales , Masculino , Actividad Motora , Nocicepción/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Fenetilaminas/farmacología , Piribedil/farmacología , Antagonistas de Receptores Purinérgicos P1/farmacología , Pirimidinas/farmacología , Ratas , Ratas Wistar , Receptor de Adenosina A2A/fisiología , Receptores de Dopamina D2/fisiología , Triazoles/farmacologíaRESUMEN
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.
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Resinas Acrílicas/química , Rastreo Diferencial de Calorimetría/métodos , Derivados de la Hipromelosa/química , Mucosa Bucal/química , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/fisiopatología , Piribedil/administración & dosificación , Piribedil/metabolismo , Comprimidos/química , Adhesividad , Administración Bucal , Animales , Química Farmacéutica , Preparaciones de Acción Retardada , Piribedil/química , OvinosRESUMEN
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.
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Antiparkinsonianos/uso terapéutico , Agonistas de Dopamina/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Piribedil/uso terapéutico , Antiparkinsonianos/farmacología , Agonistas de Dopamina/farmacología , Humanos , Actividad Motora/efectos de los fármacos , Neuroprotección , Piribedil/farmacología , Receptores Dopaminérgicos/metabolismo , Resultado del TratamientoRESUMEN
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.