Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 717
Filtrar
1.
AAPS PharmSciTech ; 20(8): 312, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31529266

RESUMO

To enhance efficiency, convenience, and safety of Parkinson's disease (PD) treatment for geriatric patients, an advanced suspension of Levodopa/Benserazide hydrochloride (LD/BH) has been prepared by cation-exchange resin and used to synchronize sustained release of LD and BH by optimizing coating parameters and prescription. For the purpose, LD and BH were immobilized on the surface of cation-exchange resin, respectively. Based on HPLC results, the cation-exchange resin showed high loading capacity. The studies on drug loading mechanism indicated that both drugs were immobilized by electrostatic interaction rather than physical adsorption. After PEG modification, pretreated drug-resin complexes were coated by emulsion-solvent evaporation method. In order to control drug release in a sustained manner, coating parameters of drug-resin microcapsules were optimized respectively by single-factor analysis. Further, coating prescription of the microcapsules was optimized to synchronize sustained release of LD and BH in vitro by orthogonal design. Utilizing optimal LD-resin microcapsules and BH-resin microcapsules, LD/BH suspension, containing both of them, was prepared by an optimal formulation and characterized by accelerated test and pharmacokinetic study in vivo. The accelerated test confirmed high stability of LD/BH suspension. According to pharmacokinetic results in vivo, in contrast with LD/BH commercial tablets, LD/BH suspensions did not only synchronize sustained release of both drugs but also show good bioequivalence. As LD/BH sustained release suspension can synchronize sustained release of multiple active ingredients by oral administration, the suspension presents promising oral dosage forms for geriatric patients with PD. An advanced Levodopa/Benserazide hydrochloride (LD/BH) suspension, prepared by cation-exchange resin and optimized microencapsulation, synchronizes sustained releases of LD and BH in vivo to benefit Parkinson's disease treatment for geriatric patients.


Assuntos
Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/química , Benserazida/administração & dosagem , Benserazida/química , Levodopa/administração & dosagem , Levodopa/química , Administração Oral , Animais , Antiparkinsonianos/farmacocinética , Benserazida/farmacocinética , Cápsulas , Resinas de Troca de Cátion , Preparações de Ação Retardada , Combinação de Medicamentos , Composição de Medicamentos , Levodopa/farmacocinética , Lipídeos/química , Masculino , Ratos , Suspensões , Comprimidos com Revestimento Entérico
2.
Clin Neuropharmacol ; 42(4): 111-116, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31192808

RESUMO

OBJECTIVES: Although commercially available levodopa (LD) formulations include carbidopa (CD) or benserazide for gastrointestinal L-aromatic amino acid decarboxylase inhibition, little is known how manipulating CD delivery affects the pharmacokinetics of LD. Our research systematically evaluated the peripheral and central pharmacokinetics of LD during continuous subcutaneous CD delivery. METHODS: We conducted pharmacokinetic experiments in pigs, mice, and humans to characterize effects of continuous subcutaneous CD delivery co-administered with LD as compared with oral LD/CD administration on LD pharmacokinetics. The porcine and human studies compared peripheral LD pharmacokinetic parameters (area under the curves [AUCs], peak plasma concentrations [Cmax], and plasma elimination half-life [t1/2]) and the mouse studies compared brain LD and dopamine concentrations. RESULTS: In the pig, supplementary subcutaneous CD delivery significantly increased the LD t1/2 and AUC versus LD/CD alone and versus additional oral CD administration. In mice, administration of supplementary subcutaneous CD substantially increased mean plasma concentrations of both LD and CD versus oral LD/CD alone at all time points. These increases were mirrored by increased brain dopamine levels for at least the 7 hours of study. In healthy human subjects, continuous subcutaneous CD administration, 3.33 mg/h x24h, increased the plasma LD t1/2, Cmax, and AUC by 17.4%, 40.5%, and 22.3%, respectively (P < 0.003). CONCLUSIONS: This series of studies demonstrates that small continuous dosing of subcutaneous CD has an unexpected effect on LD pharmacokinetics greater than the extent of decarboxylase inhibition achieved by additional oral CD administration.


Assuntos
Antiparkinsonianos/administração & dosagem , Inibidores das Descarboxilases de Aminoácidos Aromáticos/administração & dosagem , Carbidopa/administração & dosagem , Levodopa/farmacocinética , Adulto , Animais , Quimioterapia Combinada , Feminino , Voluntários Saudáveis , Humanos , Levodopa/administração & dosagem , Levodopa/sangue , Masculino , Camundongos , Pessoa de Meia-Idade , Suínos
3.
Pharmacol Res Perspect ; 7(2): e00473, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30977301

RESUMO

A new levodopa-carbidopa intestinal gel (LCIG) system featuring a higher levodopa/carbidopa (LD/CD) concentration and viscosity, LCIG-HV, is being developed to reduce the intrajejunal volume of LD/CD that is administered as compared to the current commercial formulation, LCIG-LV. This study characterizes the LCIG-HV formulation and compares it to the LCIG-LV formulation via dissolution testing and a clinical pharmacokinetic bioequivalence study. In vitro release profiles of LD/CD were determined using a USP Dissolution Apparatus 2 with 500 mL of phosphate buffer (pH 4.5) operating at 25 RPM. A single dose, open-label study was conducted according to a two-period, randomized, crossover design in 28 healthy subjects. The point estimate (PE) of the levodopa Cmax geometric mean for the LCIG-HV formulation was 4% higher than that of the LCIG-LV formulation. PEs of levodopa AUCt and AUCinf geometric means were comparable for both formulations. PEs of carbidopa Cmax , AUCt and AUCinf geometric means for the LCIG-HV formulation were 3%-5% higher than those of the LCIG-LV formulation. For both formulations, the median Tmax for levodopa was 1.0 and 3.0 hours for carbidopa. The levodopa half-life harmonic mean was 1.6 hour for both formulations. The carbidopa half-life harmonic mean was 1.9 and 2.0 hour, respectively, for the LCIG-HV and LCIG-LV formulations. Cmax , AUCt and AUCinf of LD/CD carbidopa were comparable for both formulations. The current study demonstrates that the LCIG-LV and LCIG-HV formulations are clinically bioequivalent for LD/CD according to FDA guidance. However, the dissolution method was over discriminatory of formulation differences.


Assuntos
Antiparkinsonianos/química , Antiparkinsonianos/farmacocinética , Carbidopa/química , Carbidopa/farmacocinética , Levodopa/química , Levodopa/farmacocinética , Adulto , Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/sangue , Carbidopa/efeitos adversos , Carbidopa/sangue , Estudos Cross-Over , Combinação de Medicamentos , Liberação Controlada de Fármacos , Feminino , Géis , Humanos , Levodopa/efeitos adversos , Levodopa/sangue , Masculino , Pessoa de Meia-Idade , Equivalência Terapêutica
4.
Drugs ; 79(6): 593-608, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30905034

RESUMO

Parkinson's disease (PD) is a chronic, progressive condition affecting around 1% of the population older than 60 years. Upon long-term treatment with levodopa, the mainstay of treatment in PD, most patients, especially younger ones exposed to higher doses, will experience symptoms related to end-of-dose deterioration, peak-dose dyskinesias, and other motor fluctuations. Therapeutic strategies are grounded on modification of oral levodopa pharmacokinetics to extend levodopa benefit and development of new routes of drug delivery (e.g., levodopa/carbidopa intestinal gel infusion) or long-acting formulations of existing dopaminergic drugs to prolong the duration of striatal dopamine receptors stimulation. As our understanding of the pathophysiology of motor complications evolves, our therapeutic armamentarium is actively expanding and the focus of research is now actively pointing to the new non-dopaminergic agents acting both within the basal ganglia and in other brain regions (e.g., drugs acting on glutamate, GABA, serotonin, and calcium channels). Despite the fact that trials comparing the different therapeutic strategies are lacking, we aimed at devising practical evidence- and experience-guided suggestions for the clinical management of motor complications, emphasizing that this should always be an individualized endeavor. This review summarizes the pharmacological management of motor complications in PD, including new formulations and routes of delivery, and the newer released drugs such as istradefylline, opicapone, safinamide, and zonisamide. Advanced therapeutic strategies for selected cases such as treatment with apomorphine and surgical techniques (deep brain stimulation) are also discussed. A comprehensive knowledge of the available options and evidence is fundamental for the successful management of these challenging complications.


Assuntos
Antiparkinsonianos/uso terapêutico , Carbidopa/farmacocinética , Carbidopa/uso terapêutico , Levodopa/farmacocinética , Levodopa/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/farmacocinética , Gânglios da Base/efeitos dos fármacos , Carbidopa/administração & dosagem , Carbidopa/efeitos adversos , Agonistas de Dopamina/farmacologia , Portadores de Fármacos/química , Combinação de Medicamentos , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Humanos , Levodopa/administração & dosagem , Levodopa/efeitos adversos , Levodopa/farmacologia , Receptores Dopaminérgicos/efeitos dos fármacos , Transdução de Sinais
5.
Nat Commun ; 10(1): 310, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-30659181

RESUMO

Human gut microbiota senses its environment and responds by releasing metabolites, some of which are key regulators of human health and disease. In this study, we characterize gut-associated bacteria in their ability to decarboxylate levodopa to dopamine via tyrosine decarboxylases. Bacterial tyrosine decarboxylases efficiently convert levodopa to dopamine, even in the presence of tyrosine, a competitive substrate, or inhibitors of human decarboxylase. In situ levels of levodopa are compromised by high abundance of gut bacterial tyrosine decarboxylase in patients with Parkinson's disease. Finally, the higher relative abundance of bacterial tyrosine decarboxylases at the site of levodopa absorption, proximal small intestine, had a significant impact on levels of levodopa in the plasma of rats. Our results highlight the role of microbial metabolism in drug availability, and specifically, that abundance of bacterial tyrosine decarboxylase in the proximal small intestine can explain the increased dosage regimen of levodopa treatment in Parkinson's disease patients.


Assuntos
Antiparkinsonianos/farmacologia , Bactérias/enzimologia , Levodopa/farmacocinética , Doença de Parkinson/tratamento farmacológico , Tirosina Descarboxilase/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Antiparkinsonianos/metabolismo , Bactérias/isolamento & purificação , Feminino , Microbioma Gastrointestinal/fisiologia , Humanos , Intestino Delgado/metabolismo , Intestino Delgado/microbiologia , Levodopa/metabolismo , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/microbiologia , Ratos
6.
Mov Disord ; 34(3): 425-429, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30653246

RESUMO

BACKGROUND: Laboratory and clinical evidence indicate that continous delivery of levodopa is associated with reduced motor complications compared to standard intermittent levodopa. OBJECTIVE: To assess the pharmacokinetics and efficacy of continuous oral delivery of l-dopa/carbidopa in PD patients with motor fluctuations. METHODS: Eighteen PD patients with motor fluctuations were enrolled in an open-label study comparing pharmacokinetics and efficacy measures between standard intermittent oral l-dopa/carbidopa and "continuous" oral l-dopa/carbidopa. Continuous treatment was operationally defined as sips of an l-dopa dispersion at 5- to 10-minute intervals. On day 1, patients received their usual oral l-dopa/carbidopa doses. On day 2, patients received l-dopa/carbidopa dose by "continuous" oral administration. On day 3, patients received a single dose of oral l-dopa/carbidopa followed by continuous administration of l-dopa/carbidopa. Each study period was 8 hours, and the total l-dopa/carbidopa dose administered was the same on each day. Analyses of variability were primarily-based samples drawn between 4 and 8 hours when subjects were in a relative steady state. RESULTS: There was less variability in plasma l-dopa concentration with continuous versus intermittent oral l-dopa/carbidopa treatment (fluctuation index was 0.99 ± 0.09 vs. 1.38 ± 0.12 [P < 0.001] and coefficient of variation was 0.35 ± 0.03 vs. 0.49 ± 0.04 [P < 0.001]). Mean OFF time was decreased by 43% (P < 0.001) with continuous oral l-dopa therapy. No safety or tolerability issues were observed. CONCLUSIONS: Continuous oral delivery of l-dopa/carbidopa was associated with less plasma variability and reduced off time in comparison to standard intermittent oral l-dopa/carbidopa therapy. © 2019 International Parkinson and Movement Disorder Society.


Assuntos
Antiparkinsonianos/uso terapêutico , Carbidopa/uso terapêutico , Levodopa/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Administração Oral , Adulto , Idoso , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/farmacocinética , Carbidopa/administração & dosagem , Carbidopa/efeitos adversos , Carbidopa/farmacocinética , Esquema de Medicação , Combinação de Medicamentos , Feminino , Humanos , Levodopa/administração & dosagem , Levodopa/efeitos adversos , Levodopa/farmacocinética , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
7.
Clin Neuropharmacol ; 42(1): 4-8, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30520758

RESUMO

OBJECTIVE: IPX203 is an investigational oral extended-release capsule formulation of carbidopa-levodopa (CD-LD). The aim of this study was to characterize the single-dose pharmacodynamics, pharmacokinetics, and safety of IPX203 in subjects with advanced Parkinson disease compared with immediate-release (IR) CD-LD and extended-release CD-LD (Rytary). METHODS: This was a randomized, open-label, rater-blinded, multicenter, single-dose crossover study. Blinded clinicians assessed subject's motor state and Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III scores for up to 10 hours postdose. Duration of effect was determined using improvement thresholds in the MDS-UPDRS part III. RESULTS: Levodopa concentrations increased rapidly and similarly across all 3 treatments and were sustained for a longer duration after IPX203 dosing. All treatments exhibited a rapid onset of pharmacodynamic effect, whereas IPX203 had a significantly longer duration of effect based on MDS-UPDRS part III scores compared with IR CD-LD (P < 0.0001) and Rytary (P ≤ 0.0290). IPX203 had a 2.7-hour advantage over IR CD-LD (P < 0.0001) and a 0.9-hour advantage over Rytary in "off" time (P = 0.023) and in "good on" time (2.6 hours more than IR CD-LD, P < 0.0001; 0.9 hours more than Rytary, P = 0.0259) as measured by the Investigator Assessment of Subject's Motor State. Subjects were 77% more likely to require rescue following IR CD-LD treatment compared with IPX203 (hazard ratio, 0.23; P < 0.0001). More subjects reported treatment-emergent adverse effects during IR CD-LD (28.0%) and IPX203 (19.2%) than during Rytary (8.0%) treatment. CONCLUSIONS: Compared with Rytary and IR CD-LD, IPX203 had a longer pharmacodynamic effect consistent with LD pharmacokinetics for the 3 treatments. The safety and tolerability of IPX203 were similar to those of IR CD-LD and Rytary.


Assuntos
Carbidopa/administração & dosagem , Carbidopa/farmacocinética , Levodopa/administração & dosagem , Levodopa/farmacocinética , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Idoso , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/farmacocinética , Cápsulas , Carbidopa/efeitos adversos , Estudos Cross-Over , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Esquema de Medicação , Combinação de Medicamentos , Feminino , Humanos , Levodopa/efeitos adversos , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade
8.
Biomed Chromatogr ; 33(1): e4382, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30203852

RESUMO

A simple, accurate, and reproducible HPLC-UV method has been developed and validated for the quantification of levodopa (l-Dopa) in human plasma. The method involves a simple protein precipitation procedure to extract both l-Dopa and methyldopa, the internal standard. The chromatographic analysis was achieved on a Shimadzu LC 20A HPLC system equipped with a Zorbax Eclipse XDB C18 column and an isocratic mobile phase consisting of 20 mm KH2 PO4 (pH 2.5) and methanol (95:5, v/v) run at a flow rate of 1 mL/min. The UV detection wavelength was set at 230 nm. The method exhibited good linearity (R2 > 0.999) over the assayed concentration range (0.1-10 µg/mL) and demonstrated good intra- and inter-day precision and accuracy (relative standard deviations and the deviation from predicted values were <15%). This method was also successfully applied for studying the potential effect of ketogenic diet on the pharmacokinetics of l-Dopa in Parkinson's participants. Our data analysis indicates that ketogenic diet does not significantly affect the pharmacokinetics of l-Dopa.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Dieta Cetogênica , Levodopa/sangue , Levodopa/farmacocinética , Doença de Parkinson/metabolismo , Animais , Humanos , Levodopa/química , Limite de Detecção , Modelos Lineares , Doença de Parkinson/tratamento farmacológico , Ratos , Reprodutibilidade dos Testes
9.
Expert Opin Drug Metab Toxicol ; 14(12): 1189-1195, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30479171

RESUMO

INTRODUCTION: Levodopa (LD), in combination with a decarboxylase inhibitor, is a mainstay and the most effective therapeutic agent in the treatment of Parkinson's disease (PD). Unfortunately, during chronic treatment with this agent, ON-OFF phenomena and dyskinesia appear. Despite the many medical treatment options available, unpredictable OFF episodes can still occur and be severe and disabling. A rescue therapy that provides a rapid and predictable ON response for patients with OFF periods would be of great value for such patients. Areas covered: CVT-301 is a self-administered dry powder aerosol inhaled formulation of LD that is being developed as a self-administered treatment for OFF periods. The PK profile of CVT-301, the efficacy, and the safety highlighted in randomized clinical trials will be reviewed. Expert opinion: CVT-301 may offer several potential advantages including increased systemic bioavailability through pulmonary absorption, rapid onset of action, avoidance of first-pass drug metabolism and less plasma-level variability. List of Abbreviations: PD: Parkinson's disease; LD: Levodopa; CD: Carbidopa; AADC: aromatic L-amino acid decarboxylase; IR: immediate-release; FPD: fine particle dose; GI: gastrointestinal; PK: pharmacokinetic; CVs: coefficient of variation; UPDRS: Unified Parkinson's Disease Rating Scale; AEs: adverse events; FEV: forced expiratory volume; FVC: forced vital capacity; DLCO: diffuse lung CO ; tmax: time to maximum concentration.


Assuntos
Antiparkinsonianos/administração & dosagem , Levodopa/administração & dosagem , Doença de Parkinson/tratamento farmacológico , Administração por Inalação , Aerossóis , Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/farmacocinética , Disponibilidade Biológica , Dopaminérgicos/administração & dosagem , Dopaminérgicos/efeitos adversos , Dopaminérgicos/farmacocinética , Humanos , Levodopa/efeitos adversos , Levodopa/farmacocinética , Ensaios Clínicos Controlados Aleatórios como Assunto
10.
Bioanalysis ; 10(19): 1567-1576, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30295551

RESUMO

AIM: The combination of levodopa with carbidopa has been used for treatment of Parkinson's disease being an important therapy in dopamine level control in the brain. Both are very polar compounds becoming a challenge for analysis by LC-MS/MS. MATERIALS & METHODS: In this work, it was developed and validated a sensitive bioanalytical method by UHPLC-MS/MS for simultaneous levodopa and carbidopa quantification in human plasma using a fast protein precipitation method. Moreover, the bioanalytical method was applied to a pharmacokinetic study in healthy volunteers. RESULTS/CONCLUSION: The results demonstrated a sensitive and adequate method for application to pharmacokinetic/bioequivalence studies.


Assuntos
Análise Química do Sangue/métodos , Carbidopa/sangue , Carbidopa/farmacocinética , Levodopa/sangue , Levodopa/farmacocinética , Limite de Detecção , Adolescente , Adulto , Métodos Analíticos de Preparação de Amostras , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem , Adulto Jovem
11.
PLoS One ; 13(7): e0200266, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29990324

RESUMO

Drug delivery to the brain is challenging due to the presence of the blood-brain barrier. Mathematical modeling and simulation are essential tools for the deeper understanding of transport processes in the blood, across the blood-brain barrier and within the tissue. Here we present a mathematical model for drug delivery through capillary networks with increasingly complex topologies with the goal to understand the scaling behavior of model predictions on a coarse-to-fine sequence of grids. We apply our model to the delivery of L-Dopa, the primary drug used in the therapy of Parkinson's Disease. Our model replicates observed blood flow rates and ratios between plasma and tissue concentrations. We propose an optimal network grain size for the simulation of tissue volumes of 1 cm3 that allows to make reliable predictions with reasonable computational costs.


Assuntos
Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Sistemas de Liberação de Medicamentos , Levodopa/farmacocinética , Modelos Biológicos , Transporte Biológico , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Simulação por Computador
12.
Br J Clin Pharmacol ; 84(10): 2422-2432, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29959802

RESUMO

AIMS: SD-1077, a selectively deuterated precursor of dopamine (DA) structurally related to L-3,4-dihydroxyphenylalanine (L-DOPA), is under development for treatment of motor symptoms of Parkinson's disease. Preclinical models have shown slower metabolism of central deuterated DA. The present study investigated the peripheral pharmacokinetics (PK), metabolism and safety of SD-1077. METHODS: Plasma and urine PK of drug and metabolites and safety after a single oral 150 mg SD-1077 dose were compared to 150 mg L-DOPA, each in combination with 37.5 mg carbidopa (CD) in a double-blind, two-period, crossover study in healthy volunteers (n = 16). RESULTS: Geometric least squares mean ratios (GMRs) and 90% confidence intervals (90% CI) of SD-1077 vs. L-DOPA for Cmax , AUC0-t , and AUC0-inf were 88.4 (75.9-103.1), 89.5 (84.1-95.3), and 89.6 (84.2-95.4), respectively. Systemic exposure to DA was significantly higher after SD-1077/CD compared to that after L-DOPA/CD, with GMRs (90% CI) of 1.8 (1.45-2.24; P = 0.0005) and 2.06 (1.68-2.52; P < 0.0001) for Cmax and AUC0-t and a concomitant reduction in the ratio of 3,4-dihydroxyphenylacetic acid/DA confirming slower metabolic breakdown of DA by monoamine oxidase (MAO). There were increases in systemic exposures to metabolites of catechol O-methyltransferase (COMT) reaction, 3-methoxytyramine (3-MT) and 3-O-methyldopa (3-OMD) with GMRs (90% CI) for SD-1077/CD to L-DOPA/CD for 3-MT exposure of 1.33 (1.14-1.56; P = 0.0077) and 1.66 (1.42-1.93; P < 0.0001) for Cmax and AUC0-t , respectively and GMRs (90% CI) for 3-OMD of 1.19 (1.15, 1.23; P < 0.0001) and 1.31 (1.27, 1.36; P < 0.0001) for Cmax and AUC0-t . SD-1077/CD exhibited comparable tolerability and safety to L-DOPA/CD. CONCLUSIONS: SD-1077/CD demonstrated the potential to prolong exposure to central DA at comparable peripheral PK and safety to the reference L-DOPA/CD combination. A single dose of SD-1077 is safe for further clinical development in Parkinson's disease patients.


Assuntos
Antiparkinsonianos/farmacocinética , Carbidopa/farmacocinética , Levodopa/farmacocinética , Pró-Fármacos/farmacocinética , Administração Oral , Adulto , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/química , Área Sob a Curva , Carbidopa/administração & dosagem , Carbidopa/efeitos adversos , Estudos Cross-Over , Deutério/química , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Feminino , Voluntários Saudáveis , Humanos , Levodopa/administração & dosagem , Levodopa/efeitos adversos , Levodopa/química , Masculino , Doença de Parkinson/tratamento farmacológico , Pró-Fármacos/administração & dosagem , Pró-Fármacos/efeitos adversos , Pró-Fármacos/química
13.
Expert Opin Pharmacother ; 19(9): 1003-1011, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29913079

RESUMO

INTRODUCTION: Parkinson's disease is a chronic, neurodegenerative disease. Its symptoms and course are heterogeneous. After several years of investigative drug studies, levodopa remains the most efficacious drug despite its long-term limitations. Consequently, research into new drug delivery modes is ongoing. AREAS COVERED: This review summarizes past and current advances of levodopa therapy with a focus on long-term patient management. Current research aims to increase drug bioavailability and to deliver it to the brain continuously. Reduced fluctuations improve drug efficacy and levodopa-associated motor complications. Less considered metabolic long-term consequences of levodopa are impaired methylation capacity and antioxidant defense. Both may contribute to disease progression and weaken physiological available human neuronal repair mechanisms. EXPERT OPINION: New developed formulations will improve pharmacokinetic and pharmacodynamic behavior. The authors suggest the regular supplementation with methyl group-donating and free radical scavenging substrates to weaken the metabolic consequences of chronic and high levodopa dosing. Many patients perform this nutrient supplementation in their diet already.


Assuntos
Antiparkinsonianos/uso terapêutico , Levodopa/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Antioxidantes/metabolismo , Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/farmacocinética , Inibidores das Descarboxilases de Aminoácidos Aromáticos/farmacocinética , Inibidores das Descarboxilases de Aminoácidos Aromáticos/uso terapêutico , Encéfalo/metabolismo , Inibidores de Catecol O-Metiltransferase/farmacocinética , Inibidores de Catecol O-Metiltransferase/uso terapêutico , Quimioterapia Combinada , Humanos , Levodopa/efeitos adversos , Levodopa/farmacocinética , Estresse Oxidativo , Doença de Parkinson/patologia
14.
Eur J Clin Pharmacol ; 74(10): 1299-1307, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29882153

RESUMO

OBJECTIVES: Low dose, dispersible, levodopa/carbidopa microtablets with an automatic dose dispenser have been developed to facilitate individualized levodopa treatment. The aim of this study was to characterize the pharmacokinetics (PK) of levodopa and carbidopa after microtablet administration, and evaluate the impact of potential covariates. METHODS: The population PK analysis involved data from 18 healthy subjects and 18 Parkinson's disease patients included in two single-dose, open-label levodopa/carbidopa microtablet studies. The analysis was carried out using non-linear mixed effects modeling. Bodyweight was included on all disposition parameters according to allometric scaling. Potential influence of additional covariates was investigated using graphical evaluation and adjusted adaptive least absolute shrinkage and selection operator. RESULTS: Dispositions of levodopa and carbidopa were best described by a two- and one-compartment model respectively. Double-peak profiles were described using two parallel absorption compartments. Levodopa apparent clearance was found to decrease with increasing carbidopa dose (15% lower with 75 compared to 50 mg of carbidopa) and disease stage (by 18% for Hoehn and Yahr 1 to 4). Carbidopa apparent clearance was found to decrease with age (28% between the age of 60 and 80 years). An external evaluation showed the model to be able to reasonably well predict levodopa concentrations following multiple-dose microtablet administration in healthy subjects. CONCLUSIONS: The presented models adequately described the PK of levodopa and carbidopa, following microtablet administration. The developed model may in the future be combined with a pharmacokinetic-pharmacodynamic target and used for individualized dose selection, utilizing the flexibility offered by the microtablets.


Assuntos
Antiparkinsonianos/administração & dosagem , Carbidopa/administração & dosagem , Levodopa/administração & dosagem , Modelos Biológicos , Doença de Parkinson/tratamento farmacológico , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antiparkinsonianos/farmacocinética , Carbidopa/farmacocinética , Estudos de Casos e Controles , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Feminino , Humanos , Levodopa/farmacocinética , Masculino , Pessoa de Meia-Idade , Dinâmica não Linear , Comprimidos , Adulto Jovem
15.
Rev Neurol ; 67(1): 1-5, 2018 Jul 01.
Artigo em Espanhol | MEDLINE | ID: mdl-29923594

RESUMO

INTRODUCTION: Treatment with intraduodenal levodopa-carbidopa infusion is one of the three therapies currently available for advanced Parkinson's disease. It optimizes the benefit of antiparkinsonian treatment by counteracting the negative effect of erratic gastric emptying on the absorption of oral levodopa. The purpose is to describe our outpatient protocol of treatment establishment. PATIENTS AND METHODS: In our unit we have implemented a protocol for the treatment with intradoudenal levodopa-carbidopa infusion without admission based on the development of a multidisciplinary circuit among the Neurology Service, the Digestive Endoscopy Unit and the Home Hospitalization Unit. RESULTS: Over one and a half year, we treated five patients with advanced Parkinson's disease. All of them remain on the medication and no significant side effect has taken place. CONCLUSION: The outpatient onset install of this treatment saves costs and avoids the negative impact of admission on the patient with advanced Parkinson's disease, in the same way that favors their adaptation and tolerability to it.


Assuntos
Assistência Ambulatorial/métodos , Antiparkinsonianos/uso terapêutico , Carbidopa/uso terapêutico , Levodopa/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Idoso , Algoritmos , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/farmacocinética , Carbidopa/administração & dosagem , Carbidopa/farmacocinética , Protocolos Clínicos , Gerenciamento Clínico , Combinação de Medicamentos , Duodeno , Feminino , Gastrostomia/métodos , Humanos , Infusões Parenterais , Absorção Intestinal , Intubação Gastrointestinal , Levodopa/administração & dosagem , Levodopa/farmacocinética , Masculino
16.
New Phytol ; 219(1): 287-296, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29754447

RESUMO

The key enzymatic step in betalain biosynthesis involves conversion of l-3,4-dihydroxyphenylalanine (l-DOPA) to betalamic acid. One class of enzymes capable of this is 3,4-dihydroxyphenylalanine 4,5-dioxygenase (DODA). In betalain-producing species, multiple paralogs of this gene are maintained. This study demonstrates which paralogs function in the betalain pathway and determines the residue changes required to evolve a betalain-nonfunctional DODA into a betalain-functional DODA. Functionalities of two pairs of DODAs were tested by expression in beets, Arabidopsis and yeast, and gene silencing was performed by virus-induced gene silencing. Site-directed mutagenesis identified amino acid residues essential for betalamic acid production. Beta vulgaris and Mirabilis jalapa both possess a DODA1 lineage that functions in the betalain pathway and at least one other lineage, DODA2, that does not. Site-directed mutagenesis resulted in betalain biosynthesis by a previously nonfunctional DODA, revealing key residues required for evolution of the betalain pathway. Divergent functionality of DODA paralogs, one clade involved in betalain biosynthesis but others not, is present in various Caryophyllales species. A minimum of seven amino acid residue changes conferred betalain enzymatic activity to a betalain-nonfunctional DODA paralog, providing insight into the evolution of the betalain pigment pathway in plants.


Assuntos
Beta vulgaris/fisiologia , Betalaínas/biossíntese , Mutação com Ganho de Função , Proteínas de Plantas/genética , Arabidopsis/efeitos dos fármacos , Arabidopsis/genética , Arabidopsis/fisiologia , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Betalaínas/metabolismo , Caryophyllales/genética , Dioxigenases/genética , Dioxigenases/metabolismo , Evolução Molecular , Regulação da Expressão Gênica de Plantas , Levodopa/farmacocinética , Levodopa/farmacologia , Mirabilis/genética , Filogenia , Pigmentação/genética , Pigmentos Biológicos/biossíntese , Pigmentos Biológicos/genética , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas , Piridinas/metabolismo , Leveduras/genética
17.
AAPS PharmSciTech ; 19(7): 2843-2850, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29845498

RESUMO

Despite extensive research in the field of gastroretentive dosage forms, this "holy grail" of oral drug delivery yet remained an unmet goal. Especially under fasting conditions, the reproducible retention of dosage forms in the stomach seems to be an impossible task. This is why such systems are often advised to be taken together with food. But also the postprandial motility can contribute significantly to the failure of gastroretentive dosage forms. To investigate the influence of postprandial pressure conditions on drug release from such systems, we used a novel in vitro dissolution tool, the dissolution stress test device. With the aid of this device, we simulated three different intragastric pressure profiles that may occur after postprandial intake. These transit scenarios were based on recently obtained, postprandial SmartPill® data. The tested systems, Glumetza® 1000 and Madopar® HBS 125, are marketed dosage forms that are based on different approaches to achieve proper gastric retention. All three transit scenarios revealed a highly pressure-sensitive drug release behavior, for both drugs. For Madopar® HBS 125, nearly complete drug release was observed even after early occurring pressures. Glumetza® 1000 seemed to be more resistant to these, most likely due to incomplete wetting of the system. On the contrary to these findings, data from standard dissolution tests using the paddle apparatus displayed controlled drug release for both systems for about 6 h. Based on these results, it can be doubted that established gastroretentive systems stay intact over a longer period of time, even under postprandial conditions.


Assuntos
Benserazida/farmacocinética , Liberação Controlada de Fármacos/fisiologia , Levodopa/farmacocinética , Período Pós-Prandial/fisiologia , Estômago/fisiologia , Benserazida/administração & dosagem , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/metabolismo , Formas de Dosagem , Combinação de Medicamentos , Sistemas de Liberação de Medicamentos/métodos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Jejum/metabolismo , Humanos , Levodopa/administração & dosagem , Período Pós-Prandial/efeitos dos fármacos , Pressão , Estômago/efeitos dos fármacos
18.
Neuromolecular Med ; 20(2): 262-270, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29696585

RESUMO

Oral administration of levodopa (LD) is the gold standard in managing Parkinson's disease (PD). Although LD is the most effective drug in treating PD, chronic administration of LD induces levodopa-induced dyskinesia. A continuous and sustained provision of LD to the brain could, therefore, reduce peak-dose dyskinesia. In commercial oral formulations, LD is co-administrated with an AADC inhibitor (carbidopa) and a COMT inhibitor (entacapone) to enhance its bioavailability. Nevertheless, patients are known to take up to five tablets a day because of poor sustained-releasing capabilities that lead to fluctuations in plasma concentrations. To achieve a prolonged release of LD with the aim of improving its bioavailability, floatable spray-coated microcapsules containing all three PD drugs were developed. This gastro-retentive delivery system showed sustained release of all PD drugs, at similar release kinetics. Pharmacokinetics study was conducted and this newly developed formulation showed a more plateaued delivery of LD that is void of the plasma concentration fluctuations observed for the control (commercial formulation). At the same time, measurements of LD and dopamine of mice administered with this formulation showed enhanced bioavailability of LD. This study highlights a floatable, sustained-releasing delivery system in achieving improved pharmacokinetics data compared to a commercial formulation.


Assuntos
Antiparkinsonianos/administração & dosagem , Levodopa/administração & dosagem , Administração Oral , Animais , Antiparkinsonianos/análise , Antiparkinsonianos/farmacocinética , Disponibilidade Biológica , Química Encefálica , Cápsulas , Carbidopa/administração & dosagem , Carbidopa/análise , Carbidopa/farmacocinética , Catecóis/administração & dosagem , Catecóis/análise , Catecóis/farmacocinética , Dopamina/análise , Composição de Medicamentos , Feminino , Interações Hidrofóbicas e Hidrofílicas , Levodopa/análise , Levodopa/farmacocinética , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Varredura , Nitrilos/administração & dosagem , Nitrilos/análise , Nitrilos/farmacocinética , Doença de Parkinson/tratamento farmacológico
19.
Colloids Surf B Biointerfaces ; 167: 415-424, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29704742

RESUMO

Magnetic responsive hydrogels composed of alginate (Alg) and xanthan gum (XG), crosslinked with Ca2+ ions, were modified by in situ magnetic nanoparticles (MNP) formation. In comparison to magnetic Alg hydrogels, magnetic Alg-XG hydrogels presented superior mechanical and swelling properties, due to the high charge density and molecular weight of XG. The loading efficiency of levodopa (LD), an important antiparkinson drug, in the Alg-XG/MNP hydrogels was the highest (64%), followed by Alg/MNP (56%), Alg-XG (53%) and Alg (28%). A static external magnetic field (EMF) of 0.4 T stimulated the release of LD from Alg-XG/MNP hydrogels achieving 64 ±â€¯6% of the initial loading after 30 h. The viability, proliferation and expression of dopaminergic markers of human neuroblastoma SH-SY5Y cell on the LD loaded magnetic hydrogels were successful, particularly under EMF, which stimulated the release of LD. Overall, the results of this study provided the rational design of magnetic hydrogels for the delivery of drugs, which combined with external magnetic stimulus, might improve cell proliferation and specific differentiation.


Assuntos
Hidrogéis/química , Levodopa/química , Campos Magnéticos , Magnetismo , Alginatos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dopaminérgicos/administração & dosagem , Dopaminérgicos/química , Dopaminérgicos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Ácido Glucurônico/química , Ácidos Hexurônicos/química , Humanos , Concentração de Íons de Hidrogênio , Levodopa/administração & dosagem , Levodopa/farmacocinética , Microscopia Eletrônica de Varredura , Polissacarídeos Bacterianos/química
20.
Int J Med Inform ; 112: 137-142, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29500011

RESUMO

BACKGROUND AND OBJECTIVE: To achieve optimal effect with continuous infusion treatment in Parkinson's disease (PD), the individual doses (morning dose and continuous infusion rate) are titrated by trained medical personnel. This study describes an algorithmic method to derive optimized dosing suggestions for infusion treatment of PD, by fitting individual dose-response models. The feasibility of the proposed method was investigated using patient chart data. METHODS: Patient records were collected at Uppsala University hospital which provided dosing information and dose-response evaluations. Mathematical optimization was used to fit individual patient models using the records' information, by minimizing an objective function. The individual models were passed to a dose optimization algorithm, which derived an optimized dosing suggestion for each patient model. RESULTS: Using data from a single day's admission the algorithm showed great ability to fit appropriate individual patient models and derive optimized doses. The infusion rate dosing suggestions had 0.88 correlation and 10% absolute mean relative error compared to the optimal doses as determined by the hospital's treating team. The morning dose suggestions were consistency lower that the optimal morning doses, which could be attributed to different dosing strategies and/or lack of on-off evaluations in the morning. CONCLUSION: The proposed method showed promise and could be applied in clinical practice, to provide the hospital personnel with additional information when making dose adjustment decisions.


Assuntos
Algoritmos , Antiparkinsonianos/administração & dosagem , Hospitalização/estatística & dados numéricos , Levodopa/administração & dosagem , Doença de Parkinson/tratamento farmacológico , Antiparkinsonianos/farmacocinética , Simulação por Computador , Relação Dose-Resposta a Droga , Feminino , Humanos , Infusões Parenterais , Levodopa/farmacocinética , Masculino , Doença de Parkinson/metabolismo , Distribuição Tecidual
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA