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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.
Drug Deliv ; 26(1): 700-707, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31290705

RESUMO

Efficient delivery of brain-targeted drugs is highly important for successful therapy in Parkinson's disease (PD). This study was designed to formulate borneol and lactoferrin co-modified nanoparticles (Lf-BNPs) encapsulated dopamine as a novel drug delivery system to achieve maximum therapeutic efficacy and reduce side effects for PD. Dopamine Lf-BNPs were prepared using the double emulsion solvent evaporation method and evaluated for physicochemical and pharmaceutical properties. In vitro cytotoxicity studies indicated that treatment with dopamine Lf-BNPs has relatively low cytotoxicity in SH-SY5Y and 16HBE cells. Qualitative and quantitative cellular uptake experiments indicated that Lf modification of NPs increased cellular uptake of SH-SY5Y cells and 16HBE cells, and borneol modification can promote the cellular uptake of 16HBE. In vivo pharmacokinetic studies indicated that AUC0-12 h in the rat brain for dopamine Lf-BNPs was significantly higher (p < .05) than that of dopamine nanoparticles. Intranasal administration of dopamine Lf-BNPs effectively alleviated the 6-hydroxydopamine-induced striatum lesion in rats as indicated by the contralateral rotation behavior test and results for striatal monoamine neurotransmitter content detection. Taken together, intranasal administration of dopamine Lf-BNPs may be an effective drug delivery system for Parkinson's disease.


Assuntos
Antiparkinsonianos/administração & dosagem , Encéfalo/metabolismo , Dopamina/administração & dosagem , Lactoferrina , Nanopartículas/química , Administração Intranasal , Animais , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/farmacologia , Células Cultivadas , Dopamina/farmacocinética , Dopamina/farmacologia , Sistemas de Liberação de Medicamentos , Nanopartículas/toxicidade , Doença de Parkinson/tratamento farmacológico , Ratos , Ratos Sprague-Dawley
3.
Expert Opin Drug Metab Toxicol ; 15(5): 429-435, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31017021

RESUMO

INTRODUCTION: Brain function depends considerably on the neurotransmission of biogenic monoamines. Their metabolism employs monoamine oxidase-B in neuronal and glial cells. Inhibition of monoamine oxidase-B elevates biogenic amine levels. Accordingly, monoamine oxidase-B inhibitors provide a symptomatic effect via dopamine on motor symptoms in patients with Parkinson's disease. Areas covered: This narrative review aims to describe the pharmacokinetic characteristics of the available reversible and irreversible monoamine oxidase B inhibitors for the treatment of Parkinson's disease in daily practice. All these compounds are administered on a daily basis. Expert opinion: Reversibility or irreversibility of available monoamine oxidase-B inhibition is not relevant, due to their daily intake and half-life in clinical practice. Irreversible monoamine oxidase-B inhibitors slowed the progression of neuronal dying in experimental models of Parkinson's disease. In patients, concomitant inhibition of monoamine oxidase-B caused less increase of levodopa dosages over five years. The curve of levodopa increment diverged from the placebo curve. This reduced need for L-dopa monotherapy may be discussed as an indirect biomarker for disease severity and reflects a disease-modifying effect. In case of a symptomatic effect only, parallel curves would have occurred. Long-term L-dopa treatment should be combined with monoamine oxidase-B inhibitors when tolerated by patients.


Assuntos
Antiparkinsonianos/administração & dosagem , Inibidores da Monoaminoxidase/administração & dosagem , Doença de Parkinson/tratamento farmacológico , Antiparkinsonianos/farmacocinética , Progressão da Doença , Dopamina/metabolismo , Humanos , Levodopa/administração & dosagem , Monoaminoxidase/efeitos dos fármacos , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacocinética , Doença de Parkinson/fisiopatologia , Índice de Gravidade de Doença
4.
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
5.
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
6.
Drugs Aging ; 36(3): 189-202, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30623310

RESUMO

Dopamine agonists (DAs) are frequently used in the management of Parkinson's disease (PD), a complex multisystem disorder influenced substantially by age-related factors. Over 80% of PD patients present after age 60 years and may have clinical features exacerbated by age-related comorbidities or decline in physiological compensatory mechanisms. Pharmacotherapy for motor symptoms in older persons is more likely to involve exclusive use of levodopa combined with a peripheral decarboxylase inhibitor throughout the course of the illness. Non-ergot DAs, such as pramipexole, rotigotine and ropinirole, may be used as de novo monotherapy for the control of motor symptoms in older persons, although they are less efficacious than levodopa therapy. DAs may also be considered as adjunct therapy in older persons when motor symptoms are no longer adequately controlled by levodopa or when motor fluctuations and dyskinesia appear. DAs may be used cautiously in older persons with cognitive impairment and orthostatic hypotension but should be avoided when there is a history or risk of psychosis or impulse control disorders.


Assuntos
Antiparkinsonianos/administração & dosagem , Agonistas de Dopamina/administração & dosagem , Doença de Parkinson/tratamento farmacológico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/farmacocinética , Agonistas de Dopamina/efeitos adversos , Agonistas de Dopamina/farmacocinética , Feminino , Humanos , Levodopa/administração & dosagem , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto
7.
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
8.
J Pharm Biomed Anal ; 165: 73-81, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30503895

RESUMO

In this study, an antiparkinson drug Entacapone (ENP) is electrochemically investigated under optimized conditions using NH2 functionalized multi walled carbon nanotubes (NH2fMWCNT) decorated over glassy carbon electrode (GCE). The surface morphology of the NH2fMWCNT/GCE was probed by scanning electron microscopy (SEM) armed with EDX analysis. Electrochemical impedance spectroscopy (EIS) was employed to investigate the electron transfer capability of modified and bare electrodes. Cyclic voltammetry was used to compare the redox response of ENP on the surface of modified and unmodified electrodes. The influence of interfering agents was also studied to examine the selectivity of the designed sensor. For the purpose of practical applicability of the proposed method, differential pulse voltammetric method was applied for the investigation of ENP in real samples i.e., tablet, human serum and urine. Almost 100% recovery percentages were obtained from tablet, serum and urine samples with RSD% values of less than 2% for all the samples, thus, suggesting promising applicability of the designed electrochemical sensing platform (NH2fMWCNT/GCE) for determination of ENP in pharmaceutical dosage and real samples.


Assuntos
Antiparkinsonianos/análise , Catecóis/análise , Espectroscopia Dielétrica/métodos , Nanotubos de Carbono , Nitrilos/análise , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/farmacocinética , Inibidores de Catecol O-Metiltransferase/administração & dosagem , Inibidores de Catecol O-Metiltransferase/análise , Inibidores de Catecol O-Metiltransferase/farmacocinética , Catecóis/administração & dosagem , Catecóis/farmacocinética , Técnicas Eletroquímicas/métodos , Eletrodos , Humanos , Microscopia Eletrônica de Varredura , Nitrilos/administração & dosagem , Nitrilos/farmacocinética , Oxirredução , Comprimidos
9.
J Pharm Biomed Anal ; 164: 32-40, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30342394

RESUMO

FLZ is a novel anti-Parkinson's disease candidate drug. The main active metabolite is FLZ O-dealkylation (M1) in preclinical studies. A reliable ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) quantitation method was developed for the simultaneous determination of FLZ and M1 with low limits of quantitation in human plasma (0.1 ng/mL) and urine (0.5 ng/mL). The plasma and urine samples were both purified by full-automatic solid phase extraction (SPE) method with ensured high extraction recovery and little matrix effect for both analytes, and then separated on a BEH C18 column (2.1 × 50 mm, 1.7 µm). Detection and quantification were performed using an electrospray ionization (ESI) source in positive mode by multiple reaction monitoring (MRM). The precursor to product ion transitions were monitored at m/z 450.3+→313.2+ for FLZ, m/z 436.3+→299.1+ for M1, m/z 462.6+→142.0+ for [D12]-FLZ (internal standard of FLZ) and m/z 447.2+→125.2+ for [D11]-M1 (internal standard of M1), respectively. This method showed good linearity, accuracy, precision and stability in the range of 0.1-100 ng/mL in plasma and 0.5-500 ng/mL in urine of two analytes. Finally, the developed method was successfully applied to a pharmacokinetic research in Chinese healthy volunteers after oral administration of FLZ tablets.


Assuntos
Antiparkinsonianos/análise , Benzenoacetamidas/análise , Fenóis/análise , Extração em Fase Sólida/métodos , Administração Oral , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/farmacocinética , Benzenoacetamidas/administração & dosagem , Benzenoacetamidas/farmacocinética , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão/métodos , Voluntários Saudáveis , Humanos , Masculino , Fenóis/administração & dosagem , Fenóis/farmacocinética , Extração em Fase Sólida/instrumentação , Espectrometria de Massas por Ionização por Electrospray , Comprimidos , Espectrometria de Massas em Tandem/instrumentação , Espectrometria de Massas em Tandem/métodos
10.
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
11.
Basic Clin Pharmacol Toxicol ; 124(3): 273-284, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30218626

RESUMO

As of March 2018, rasagiline is approved for the treatment of Parkinson disease in 55 countries including Japan. The present study evaluated the pharmacokinetics (PK) and safety of rasagiline in healthy Japanese and Caucasian subjects following single and multiple administrations of three rasagiline doses. In this double-blind, placebo-controlled study, 64 healthy subjects (32 Japanese and 32 Caucasian) received either rasagiline (0.5, 1.0, or 2.0 mg) or placebo for 10 days with PK sampling for single-dose administration on day 1 and for multiple administration on day 10. Regardless of administration schedule, rasagiline plasma concentrations and dose-related increases in exposure parameters were similar between Japanese and Caucasians. Rasagiline accumulation (2-fold for 0.5 mg and 3-fold for 1.0 mg and 2.0 mg doses) following multiple administration was similar across the ethnic groups. Geometric mean ratios (GMR) comparing Japanese to Caucasians for AUC0-24 , Cmax and AUCinf following single administration were 1.38, 1.17 and 1.38 for 0.5 mg; 1.22, 1.20 and 1.22 at 1.0 mg; and 1.02, 1.00 and 1.02 at for 2.0 mg. GMR for AUCtau and Cmax,ss following multiple administration were 1.43 and 1.06 at 0.5 mg, 1.06 and 1.00 at 1.0 mg, and 1.09 and 1.07 at 2.0 mg. Safety measures were unremarkable and similar between Caucasian and Japanese subjects. Comparable systemic exposure and safety parameters were demonstrated for rasagiline administered to healthy Japanese and Caucasian subjects.


Assuntos
Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/farmacocinética , Indanos/administração & dosagem , Indanos/farmacocinética , Adulto , Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/sangue , Grupo com Ancestrais do Continente Asiático , Método Duplo-Cego , Esquema de Medicação , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Indanos/efeitos adversos , Indanos/sangue , Masculino , Adulto Jovem
12.
Clin Pharmacokinet ; 58(1): 77-88, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29777529

RESUMO

BACKGROUND: Preclinical and clinical studies suggest amantadine immediate-release (IR) may reduce dyskinesia in Parkinson's disease (PD), although higher doses are associated with increased CNS adverse events (AEs). ADS-5102 is an extended release amantadine capsule formulation, designed for once-daily dosing at bedtime (qhs) to provide high concentrations upon waking and throughout the day, with lower concentrations in the evening. The pharmacokinetics (PK) of ADS-5102 were assessed in two phase I studies in healthy subjects, and a blinded, randomized phase II/III dose-finding study in PD patients. METHODS: The first phase I study assessed single ADS-5102 doses (68.5, 137, and 274 mg) in a crossover design, whereas the second phase I study evaluated ADS-5102 137 mg for 7 days followed by amantadine IR 81 mg twice daily (or reverse order). In the phase II/III double-blind study, PD patients with dyskinesia were randomized to ADS-5102 (210, 274, or 338 mg) or placebo for 8 weeks. RESULTS: Single ADS-5102 doses resulted in a slow initial rise in amantadine plasma concentration, with delayed time to maximum concentration (12-16 h). Amantadine plasma concentrations were higher in PD patients versus healthy volunteers. The steady-state profile of once-daily ADS-5102 was significantly different from that of twice-daily amantadine IR, such that the two formulations are not bioequivalent. PK modeling suggested the recommended daily ADS-5102 dosage (274 mg qhs) resulted in 1.4- to 2.0-fold higher amantadine plasma concentrations during the day versus amantadine IR. CONCLUSIONS: ADS-5102 can be administered once-daily qhs to achieve high amantadine plasma concentrations in the morning and throughout the day, when symptoms of dyskinesia occur.


Assuntos
Amantadina/administração & dosagem , Amantadina/farmacocinética , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/farmacocinética , Discinesias/metabolismo , Doença de Parkinson/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Cross-Over , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Método Duplo-Cego , Esquema de Medicação , Discinesias/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/tratamento farmacológico , Adulto Jovem
13.
Pharm. pract. (Granada, Internet) ; 16(4): 0-0, oct.-dic. 2018. tab, graf
Artigo em Inglês | IBECS | ID: ibc-180980

RESUMO

Objective: The objective of this study is to compute the potential benefit of Pramipexole ER on total levodopa equivalent dose (LED) and Unified Parkinson Disease Rating Score (UPDRS-III) compared to mono- or combined therapy of pramipexole IR and/or carbidopa/levodopa. Methods: This is a retrospective observational study conducted in a specialized PD (Parkinson Disease) and movement disease center in Lebanon between January and December 2017. Results: A total of 176 patient's record was reviewed. Pramipexole ER showed a significant difference on the mean changes in LED and UPDRS-III score. After 13 weeks of initiating Pramipexole ER, the mean decrease in LED was -49.42 mg for all patients (p < 0.001, CI 95% [35.28-63.55]) and the mean decrease in UPDRS-III score for all patients was -6 points (P< 0.001). According to the subgroup analysis, patients aged 65 years and below, the change in mean total LED from baseline ( 350.80 mg) was a decrease of 63.19 mg with a p<0.001, CI 95% [42.07-84.31]. In patients aged more than 65 years and shifted to mono or combined pramipexole ER therapy, the change in mean total LED from baseline (559.25 mg) was a decrease of 34.67 mg with a p<0.001 CI 95% [16.16-53.18]. In addition the results showed that in patients having an UPDRS-III score of less than or equal to 33, the change in mean total LED from baseline (436.73 mg) was a decrease of 56.76 mg (p<0.001; CI 95% [41.32-72.20]). However, in patients having an UPDRS-III score of more than 33 the change in mean total LED from baseline (545.06 mg) was a decrease of 2.96 mg with a p value < 0.844 CI 95% [27.32-33.15]. Conclusions: This study demonstrated the efficacy of Pramipexole ER on decreasing the total levodopa equivalent dose (LED).The role of health care professionals is to maintain the patient on the lowest effective levodopa equivalent daily dose and optimize the treatment therapy, thus decreasing the side effects that might arise from overdosing of antiparkinsonian drugs


No disponible


Assuntos
Humanos , Masculino , Feminino , Adulto , Idoso , Idoso de 80 Anos ou mais , Pramipexol/farmacocinética , Doença de Parkinson/tratamento farmacológico , Levodopa/administração & dosagem , Resultado do Tratamento , Antiparkinsonianos/farmacocinética , Estudos Retrospectivos , Relação Dose-Resposta a Droga , Líbano/epidemiologia
14.
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
15.
Nanomedicine ; 14(8): 2609-2618, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30171904

RESUMO

Selegiline, a well-known anti-Parkinson agent, is reported to be associated with poor oral bioavailability and safety. Therefore, we formulated selegiline as chitosan nanoparticles and evaluated its pharmacokinetics and pharmacodynamics after intranasal administration to rats relative to those after oral administration. The optimized formulation exhibited spherical nanoparticles with more than 90% drug loading and steady in vitro and ex vivo drug release. Selegiline concentrations in the brain and plasma were 20- and 12-fold higher, respectively, after intranasal administration than after oral administration. Treatment with intranasal nanoparticles was also associated with better performance in locomotor activity, catalepsy, and stride length tests and significantly increased dopamine, catalase activity, and glutathione content in the brain. Therefore, intranasally administered selegiline nanoparticles holds superior therapeutic value compared to oral administration and can be a promising approach for the treatment of Parkinson's disease.


Assuntos
Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Liberação Controlada de Fármacos , Nanopartículas/administração & dosagem , Doença de Parkinson/tratamento farmacológico , Selegilina/farmacologia , Selegilina/farmacocinética , Administração Intranasal , Animais , Antiparkinsonianos/química , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/farmacologia , Comportamento Animal/efeitos dos fármacos , Disponibilidade Biológica , Encéfalo/metabolismo , Quitosana/química , Portadores de Fármacos , Masculino , Nanopartículas/química , Doença de Parkinson/metabolismo , Ratos , Ratos Sprague-Dawley , Selegilina/química , Distribuição Tecidual
16.
J Pharmacol Exp Ther ; 367(2): 373-381, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30087157

RESUMO

Dyskinesia is a common motor complication associated with the use of levodopa to treat Parkinson's disease. Numerous animal studies in mice, rats, and nonhuman primates have demonstrated that the N-methyl-d-aspartate antagonist, amantadine, dose dependently reduces levodopa-induced dyskinesia (LID). However, none of these studies characterized the amantadine plasma concentrations required for a therapeutic effect. This study evaluates the pharmacokinetic (PK)/pharmacodynamic (PD) relationship between amantadine plasma concentrations and antidyskinetic efficacy across multiple species to define optimal therapeutic dosing. The PK profile of amantadine was determined in mice, rats, and macaques. Efficacy data from the 6-hydroxydopamine rat and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine macaque model of LID, along with previously published antidyskinetic efficacy data, were used to establish species-specific PK/PD relationships using a direct-effect maximum possible effect model. Results from the PK/PD model were compared with amantadine plasma concentrations and antidyskinetic effect in a phase 2 study in patients with Parkinson's disease treated with ADS-5102, an extended-release amantadine capsule formulation. Outcomes from each of the species evaluated indicate that the EC50 of amantadine for reducing dyskinesia range from 1025 to 1633 ng/ml (1367 ng/ml for an all-species model). These data are consistent with the mean amantadine plasma concentrations observed in patients with Parkinson's disease (∼1500 ng/ml) treated with ADS-5102 at doses that demonstrated a statistically significant reduction in dyskinesia. These results demonstrate that the EC50 of amantadine for reducing dyskinesia is consistent across multiple species and supports a plasma concentration target of ∼1400 ng/ml to achieve therapeutic efficacy.


Assuntos
Amantadina/farmacologia , Amantadina/farmacocinética , Discinesia Induzida por Medicamentos/tratamento farmacológico , Levodopa/farmacologia , Animais , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/farmacologia , Modelos Animais de Doenças , Discinesia Induzida por Medicamentos/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Ratos , Ratos Sprague-Dawley
17.
Eur J Pharm Sci ; 124: 80-88, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30076954

RESUMO

The purpose of the study was to improve transdermal delivery of pramipexole via nanocrystals and investigate the enhancement micro-mechanism. Pramipexole nanocrystals were prepared using wet media milling method and incorporated into carbomer gel. In vitro permeation studies through rabbit ear skin indicated that the cumulative permeation amount of pramipexole from nanocrystals in 24 h was 2.75 times more than that from coarse suspension. Investigations of selective follicular closing technique indicated that approximately 33.88% of the total permeation from nanocrystals was contributed to the follicular pathway, which was confirmed by scanning electron microscopy images. In vitro permeation and in vivo pharmacokinetic studies indicated that pramipexole from nanocrystal gel showed a higher permeation profile than that from coarse suspension gel. Overall, nanocrystals could improve transdermal delivery of pramipexole through transepidermal and transfollicular pathways by the nanosized particles.


Assuntos
Antiparkinsonianos/administração & dosagem , Agonistas de Dopamina/administração & dosagem , Sistemas de Liberação de Medicamentos , Nanopartículas/administração & dosagem , Pramipexol/administração & dosagem , Administração Cutânea , Animais , Antiparkinsonianos/farmacocinética , Agonistas de Dopamina/farmacocinética , Masculino , Pramipexol/farmacocinética , Coelhos , Pele/metabolismo , Absorção Cutânea
18.
Neurodegener Dis Manag ; 8(5): 349-360, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29975112

RESUMO

In the past 4 years, two adjunctive treatment options to levodopa have been licensed for use in the UK in patients with Parkinson's disease (PD) and motor fluctuations: opicapone, a third-generation catechol-O-methyl transferase inhibitor, and safinamide, a monoamine oxidase B inhibitor. This clinical consensus outlines the practical considerations relating to motor fluctuations and managing wearing-off in patients with PD, and provides a clinical insight to adjunctive treatment options, including opicapone and safinamide. Practice-based opinion was provided from a multidisciplinary steering Group of eight UK-based movement disorder and PD specialists, including neurologists, geriatricians and a nurse specialist, from England, Scotland and Wales.


Assuntos
Antiparkinsonianos/administração & dosagem , Doença de Parkinson/tratamento farmacológico , Antiparkinsonianos/farmacocinética , Humanos
19.
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
20.
Rev. neurol. (Ed. impr.) ; 67(1): 1-5, 1 jul., 2018. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-175165

RESUMO

Introducción. El tratamiento con infusión intraduodenal de levodopa-carbidopa es una de las tres terapias de que disponemos en la actualidad en la enfermedad de Parkinson avanzada. Optimiza el beneficio del tratamiento antiparkinsoniano al contrarrestar el efecto negativo que provoca el vaciado gástrico errático sobre la absorción de la levodopa oral. El objetivo es describir nuestro protocolo de instauración del tratamiento de modo ambulatorio. Pacientes y métodos. En nuestra unidad hemos implementado un protocolo de instauración del tratamiento con infusión continua de levodopa-carbidopa intestinal sin necesidad de ingreso hospitalario gracias al desarrollo de un circuito multidisciplinar entre el propio servicio de neurología, la unidad de endoscopia digestiva y la unidad de hospitalización a domicilio. Resultados. En año y medio se trató a cinco pacientes con enfermedad de Parkinson avanzada. Todos ellos continúan con el tratamiento y no han tenido complicaciones significativas. Conclusión. La instauración ambulatoria del tratamiento ahorra costes y evita el impacto negativo del ingreso en el paciente con enfermedad de Parkinson avanzada, de la misma manera que favorece su adaptación y tolerancia a aquél


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 levodopacarbidopa 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
Humanos , Masculino , Feminino , Idoso , Assistência Ambulatorial/métodos , Antiparkinsonianos/uso terapêutico , Carbidopa/uso terapêutico , Carbidopa/administração & dosagem , Levodopa/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Algoritmos , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/farmacocinética , Carbidopa/farmacocinética , Protocolos Clínicos , Levodopa/administração & dosagem , Combinação de Medicamentos , Gastrostomia , Infusões Parenterais , Intubação Gastrointestinal
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