Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 210
Filtrar
1.
Int J Pharm ; 577: 119046, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31982559

RESUMO

A rotigotine (ROT)-loaded polymer micelles thermosensitive gel (ROT-PM-TSG) delivery system was engineered to enhance the solubility of the drug, prolong the residence time, and increase the concentration of the drug in the brain tissue. First, ROT-loaded polymer micelles (ROT-PM) were tailored and optimized. The average particle size, encapsulation efficiency, and drug loading of the ROT-PM were (88.62 ± 1.47) nm, (93.5 ± 0.79) %, and (19.9 ± 0.60) %. The optimal ROT-PM-TSG formulation contained 22% P407 and 2% P188 with a gelation temperature of about 32.3 °C and a pH of 5.186. In vivo, the MRT of ROT-PM and ROT-PM-TSG nasal administration was 1.43 and 1.79 times extended than that of the intravenous. In comparison with the intravenous group, the distribution of ROT in olfactory bulb, cerebrum, cerebellum and striatum was 276.6%, 170.5%, 166.5% and 184.4%, respectively. In conclusion, the ROT-PM-TSG system has proven to be a potential application prospect as a ROT nose-to-brain delivery system.


Assuntos
Agonistas de Dopamina/administração & dosagem , Sistemas de Liberação de Medicamentos , Polímeros/química , Tetra-Hidronaftalenos/administração & dosagem , Tiofenos/administração & dosagem , Administração Intranasal , Animais , Encéfalo/metabolismo , Agonistas de Dopamina/farmacocinética , Portadores de Fármacos/química , Feminino , Hidrogéis , Masculino , Micelas , Tamanho da Partícula , Coelhos , Ratos , Ratos Sprague-Dawley , Solubilidade , Temperatura , Tetra-Hidronaftalenos/farmacocinética , Tiofenos/farmacocinética
2.
Eur J Pharm Sci ; 134: 1-6, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30959104

RESUMO

Rotigotine is a dopamine receptor agonist that can improve motor function in Parkinson's disease (PD) patients. Rotigotine extended-release microsphere (RoMS) is an extended-release intramuscular formulation that exhibits a sustained release of rotigotine over a 14-day period. The clinical trials of RoMS has been carried out in USA and China. The purpose of this study is to observe the effects of RoMS therapy on myocardial ischemic injury in mice, to know whether RoMS alleviate or deteriorate the myocardial ischemic injury while PD patient has onset of myocardial ischemia concurrent after administered with RoMS. A mouse model of myocardial ischemia was established using isoproterenol, and mice were pretreated with rotigotine or RoMS before inducing myocardial ischemic injury. The effects of rotigotine or RoMS therapy on the degree of myocardial ischemic injury were studied by evaluating troponin I level, creatine kinase-MB (CK-MB) activity, and histopathological changes in cardiomyocytes. The dopamine receptor blocker chlorpromazine was used to further investigate the effects of rotigotine or RoMS on myocardial ischemic injury. Furthermore, serum rotigotine concentrations were also assayed. When myocardial ischemia occurred during rotigotine or RoMS administration, troponin I level and CK-MB activity were decreased, and ischemia-induced histopathological changes in cardiomyocytes were alleviated. The effects of rotigotine were maintained only 12 h and after that no protective effect was observed. RoMS releases continuously into the circulation after intramuscular injection. The cardioprotective effects of RoMS were maintained 14 days after a single RoMS administration. When combined with chlorpromazine, the protective effects of rotigotine on myocardial ischemic injury were eliminated, and the protective effects of RoMS were also partially abolished. In the animal model of myocardial ischemia, pretreatment with rotigotine or RoMS does not deteriorate, but can alleviate cardiomyocyte injury. Furthermore, RoMS pretreatment show long-term and continuous protective effects on cardiomyocyte injury. RoMS therapy in PD patients at high risk for cardiovascular diseases may attenuate the degree of cardiomyocyte injury caused by ischemia.


Assuntos
Cardiotônicos/farmacocinética , Agonistas de Dopamina/farmacocinética , Microesferas , Isquemia Miocárdica/tratamento farmacológico , Tetra-Hidronaftalenos/farmacocinética , Tiofenos/farmacocinética , Animais , Cardiotônicos/administração & dosagem , Cardiotônicos/uso terapêutico , Clorpromazina/antagonistas & inibidores , Creatina Quinase Forma MB/efeitos dos fármacos , Creatina Quinase Forma MB/metabolismo , Agonistas de Dopamina/administração & dosagem , Agonistas de Dopamina/uso terapêutico , Isoproterenol/farmacologia , Masculino , Camundongos , Modelos Animais , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Doença de Parkinson/tratamento farmacológico , Tetra-Hidronaftalenos/administração & dosagem , Tetra-Hidronaftalenos/uso terapêutico , Tiofenos/administração & dosagem , Tiofenos/uso terapêutico , Troponina I/efeitos dos fármacos , Troponina I/metabolismo
3.
Biol Pharm Bull ; 42(3): 448-452, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30828077

RESUMO

Combination therapy is often an effective strategy to treat cancer. In this study, we examined the growth-inhibitory effects of Am80 (tamibarotene), a specific retinoic acid receptor (RAR) α/ß agonist, in combination with a histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), or a DNA methyl transferase (DNMT) inhibitor, 5-aza-2'-deoxycytidine, on androgen receptor (AR)-positive and AR-negative prostate cancer cell lines (LNCaP and PC-3, respectively). We found that the combination therapy of SAHA and Am80 showed an enhanced growth-inhibitory effect on LNCaP cells. Further studies with various HDAC isotype-selective inhibitors showed that SAHA and KD5170 (a selective class I and II HDAC inhibitor) each increased the RARα protein level in LNCaP cells. Our results indicate that the target of the enhancing effect belongs to the Class IIb HDACs, especially HDAC6. Dual targeting of Class IIb HDAC and RARα may be a candidate therapeutic strategy for prostate cancer.


Assuntos
Benzoatos/uso terapêutico , Decitabina/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Piridinas/farmacologia , Sulfonamidas/farmacologia , Tetra-Hidronaftalenos/uso terapêutico , Vorinostat/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Benzoatos/administração & dosagem , Benzoatos/farmacocinética , Linhagem Celular Tumoral , Decitabina/administração & dosagem , Sinergismo Farmacológico , Quimioterapia Combinada , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/farmacologia , Humanos , Masculino , Piridinas/administração & dosagem , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Sulfonamidas/administração & dosagem , Tetra-Hidronaftalenos/administração & dosagem , Tetra-Hidronaftalenos/farmacocinética , Vorinostat/administração & dosagem
4.
J Med Chem ; 62(5): 2265-2285, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30785748

RESUMO

Recently, our research group reported the identification of BMS-986104 (2) as a differentiated S1P1 receptor modulator. In comparison to fingolimod (1), a full agonist of S1P1 currently marketed for the treatment of relapse remitting multiple sclerosis (RRMS), 2 offers several potential advantages having demonstrated improved safety multiples in preclinical evaluations against undesired pulmonary and cardiovascular effects. In clinical trials, 2 was found to exhibit a pharmacokinetic half-life ( T1/2) longer than that of 1, as well as a reduced formation of the phosphate metabolite that is required for activity against S1P1. Herein, we describe our efforts to discover highly potent, partial agonists of S1P1 with a shorter T1/2 and increased in vivo phosphate metabolite formation. These efforts culminated in the discovery of BMS-986166 (14a), which was advanced to human clinical evaluation. The pharmacokinetic/pharmacodynamic (PK/PD) relationship as well as pulmonary and cardiovascular safety assessments are discussed. Furthermore, efficacy of 14a in multiple preclinical models of autoimmune diseases are presented.


Assuntos
Ensaios Clínicos como Assunto , Naftalenos/farmacologia , Receptores de Esfingosina-1-Fosfato/agonistas , Tetra-Hidronaftalenos/farmacologia , Animais , Líquido da Lavagem Broncoalveolar , Relação Dose-Resposta a Droga , Meia-Vida , Humanos , Naftalenos/química , Naftalenos/farmacocinética , Ratos , Ratos Endogâmicos Lew , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/farmacocinética
5.
Parkinsonism Relat Disord ; 61: 111-117, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30446407

RESUMO

INTRODUCTION: Pramipexole (PRA), ropinirole (ROP) and rotigotine (ROT) are non-ergoline dopaminergic agonists (DAs) used to treat Parkinson's disease (PD). Clinical pharmacokinetics of DAs is poorly characterized in PD. The main purpose of our study was to investigate the effect of dose, age and sex on steady-state plasma concentrations of DAs in real life PD patients on chronic DAs therapy. METHODS: The study was single center, open and prospective. Blood samples for measurement of DAs plasma concentrations were drawn in the morning, at a median 18-h distance from the last DA dose. RESULTS: Ninety-one patients treated with PRA, 50 with ROP and 37 with ROT were enrolled in the study. Plasma concentration of DAs significantly correlated with weight-adjusted daily dose in all subgroups, although at a given dose, matched plasma concentrations highly varied among patients. Median PRA plasma concentration-to-daily dose ratio (C/D) [(ng/mL)/(mg/kg/d)] was 68% higher in patients >65 years than ≤65 years (158 vs 94, p < 0.001), while was not affected by age in ROP and ROT subgroups. No sex-mediated differences in C/D ratios were observed in any group. CONCLUSION: These are the first observations on DAs pharmacokinetics in PD patients' everyday clinical practice. Of relevance, patients over 65yrs may require about one third of PRA dose compared to under 65yrs to achieve the same plasma concentration. Due to the high intersubject variability in plasma concentrations at the same dosage, we speculate that monitoring of plasma DAs might be helpful in the individualization of treatment in selected patients.


Assuntos
Agonistas de Dopamina/farmacocinética , Indóis/farmacocinética , Doença de Parkinson/tratamento farmacológico , Pramipexol/farmacocinética , Tetra-Hidronaftalenos/farmacocinética , Tiofenos/farmacocinética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Preparações de Ação Retardada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais
6.
Bioorg Med Chem Lett ; 28(21): 3425-3430, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30274694

RESUMO

Vesicular acetylcholine transporter (VAChT) is a reliable biomarker for assessing the loss of cholinergic neurons in the brain that is associated with cognitive impairment of patients. 5-Hydrotetralin compound (±)-5-OH-VAT is potent (Ki = 4.64 ±â€¯0.32 nM) and selective for VAChT (>1800-fold and 398-fold for σ1 and σ2 receptor, respectively) with favorable hydrophilicity (LogD = 1.78), while (-)-5-OH-VAT originally serves as the radiolabeling precursor of (-)-[18F]VAT, a promising VAChT radiotracer with a logD value of 2.56. To evaluate (-)-5-OH-[18F]VAT as a radiotracer for VAChT, we performed in vitro binding assay to determine the potency of the minus enantiomer (-)-5-OH-VAT and plus enantiomer (+)-5-OH-VAT, indicating that (-)-5-OH-VAT is a more potent VAChT enantiomer. Radiosynthesis of (-)-5-OH-[18F]VAT was explored using three strategies. (-)-5-OH-[18F]VAT was achieved with a good yield (24 ±â€¯6%) and high molar activity (∼37 GBq/µmol, at the end of synthesis) using a microwave assisted two-step one-pot procedure that started with di-MOM protected nitro-containing precursor (-)-6. MicroPET studies in the brain of nonhuman primate (NHP) suggest that (-)-5-OH-[18F]VAT readily penetrated the blood brain barrier and specifically accumulated in the VAChT-enriched striatum with improved washout kinetics from striatum compared to [18F]VAT. Nevertheless, the lower target to non-target ratio may limit its use for in vivo measurement of the VAChT level in the brain.


Assuntos
Piperidinas/metabolismo , Compostos Radiofarmacêuticos/metabolismo , Tetra-Hidronaftalenos/metabolismo , Proteínas Vesiculares de Transporte de Acetilcolina/metabolismo , Animais , Corpo Estriado/metabolismo , Radioisótopos de Flúor , Cinética , Ligantes , Macaca fascicularis , Masculino , Piperidinas/síntese química , Piperidinas/química , Piperidinas/farmacocinética , Tomografia por Emissão de Pósitrons , Ligação Proteica , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Estereoisomerismo , Tetra-Hidronaftalenos/síntese química , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/farmacocinética
7.
Bioorg Chem ; 81: 481-493, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30243239

RESUMO

Type 2 diabetes (T2D) is a severe disease and it is one of the most raising problems worldwide. This study deals with design, synthesis and in vivo determination of a new set of tetralin-sulfonamide derivatives as anti-diabetic and dipeptidyl peptidase-IV (DPP-4) inhibiting agents. Most of the new compounds exhibited significant hypoglycemic effect alongside with DPP-4 suppression potency considering sitagliptin as a reference drug. The most promising compounds 4, 15 showed 2.80 nM DPP-4 IC50 with 20-40 folds selectivity over DPP-8 and DPP-9. 2D and 3D QSAR models were performed using auto QSAR of Schrödinger, QuaSAR of MOE and 3D Field-based QSAR of Schrödinger, respectively. The experimental results revealed that the alignment-independent descriptors, electrostatic and steric field descriptors were significantly correlated with the antidiabetic activity of the new derivatives. In addition, the new compounds were docked in the active site of DPP-4 in reference to sitagliptin to rationalize the binding modes of the compounds with the amino acid residues of the enzyme. Furthermore, 131I-compound 4 complex was selected to evaluate the pharmacokinetic behavioral profile of compound 4 and its body organs uptakes alongside its elimination pathway as a representative example for the rest of the analogues. The bio distribution pattern of the tracer proved the selective accumulation of 131I-substrate in the pancreas and rapid clearance from most of the body organs.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/uso terapêutico , Sulfonamidas/uso terapêutico , Tetra-Hidronaftalenos/uso terapêutico , Animais , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Inibidores da Dipeptidil Peptidase IV/farmacologia , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Masculino , Simulação de Acoplamento Molecular , Relação Quantitativa Estrutura-Atividade , Ratos , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/farmacocinética , Tetra-Hidronaftalenos/farmacologia , Distribuição Tecidual
8.
Clin Ther ; 40(7): 1108-1121.e8, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30098648

RESUMO

PURPOSE: The pharmacokinetic (PK) profile of the rotigotine transdermal patch is well characterized in Caucasian patients with Parkinson's disease (PD) but not in Chinese subjects. This article reports the PK variables, safety, and tolerability of the rotigotine transdermal patch (2 mg/24 hours and 4 mg/24 hours cold-chain PR2.1.1 formulation) in healthy Chinese subjects (SP0913; NCT01675024). A second study (PD0011; NCT02070796) evaluated the relative bioavailability of cold-chain (PR2.1.1) and room temperature-stable (PR2.2.1) formulations of rotigotine in healthy Chinese men. METHODS: In treatment period 1 of SP0913, subjects received a single application of rotigotine 2 mg/24 hours on day 1 followed by a washout period (days 2-6); treatment period 2 (days 6-14) involved multiple doses of rotigotine 2 mg/24 hours (days 7-9) followed by multiple doses of rotigotine 4 mg/24 hours (days 10-12), with patches applied for 24 hours each. In PD0011, subjects received a single dose (2 mg/24 hours) of each rotigotine formulation (PR2.2.1 and PR2.1.1) for 24 hours each in a crossover design. Blood samples were collected at scheduled time points to determine rotigotine plasma concentrations. Safety and tolerability were evaluated by adverse events monitoring. RESULTS: Twenty-four healthy Chinese subjects (12 males, 12 females) were enrolled and completed SP0913. Geometric mean plasma concentrations of unconjugated and total rotigotine increased to a plateau beginning at ∼8 hours (multiple dose) to 16 hours (single dose) postdose; no characteristic Tmax was observed for unconjugated and total rotigotine. The respective geometric mean Cmax, Cmax,ss, AUC from zero up to the last analytically quantifiable concentration, and AUC0-24,ss values for unconjugated and total rotigotine were similar when rotigotine 2 mg/24 hours was applied as a single dose or multiple-dose regimen. During the multiple-dose period, geometric mean Cmax,ss and AUC0-24,ss of both unconjugated and total rotigotine were ∼2-fold higher for rotigotine 4 mg/24 hours than for rotigotine 2 mg/24 hours. Forty-seven of 50 male Chinese subjects completed PD0011. Primary PK parameters for the room temperature-stable formulation of rotigotine were highly comparable to the cold-chain formulation. Common adverse events included application site pruritus, nausea, dizziness, and constipation (SP0913 only), with no clinically significant changes in other safety measures. IMPLICATIONS: PK profiles and derived PK parameters of unconjugated and total rotigotine in healthy Chinese subjects were consistent with findings from other ethnic groups receiving single and multiple doses of the rotigotine transdermal patch. Single and repeated daily doses of the rotigotine transdermal patch were well tolerated. Room temperature-stable and cold-chain formulations were bioequivalent. ClinicalTrials.gov identifiers: NCT01675024 and NCT02070796.


Assuntos
Tetra-Hidronaftalenos/farmacocinética , Tiofenos/farmacocinética , Adolescente , Adulto , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático , Disponibilidade Biológica , China , Estudos Cross-Over , Agonistas de Dopamina/administração & dosagem , Agonistas de Dopamina/sangue , Agonistas de Dopamina/farmacocinética , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/tratamento farmacológico , Tetra-Hidronaftalenos/administração & dosagem , Tetra-Hidronaftalenos/sangue , Equivalência Terapêutica , Tiofenos/administração & dosagem , Tiofenos/sangue , Adesivo Transdérmico , Adulto Jovem
9.
Artif Cells Nanomed Biotechnol ; 46(sup1): 1131-1137, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29504426

RESUMO

A compound (WJD-A-1) was previously reported as a candidate prodrug of Am80 (tamibarotene), which was approved in Japan in 2005 as a therapeutic agent for recurrent refractory acute promyelocytic leukaemia. A rapid, selective and sensitive ultra high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed for the first time to simultaneously determine WJD-A-1 and its major phase-I metabolites AM80 in rat plasma. After a simple sample preparation procedure by protein precipitation with methanol and acetonitrile, WJD-A-1, AM80 and the internal standard were chromatographed on an ACQUITY UPLCTM BEH C18 column. The mobile phase consisted of methanol-0.1% formic acid (80:20, v/v) and the flow rate was 0.20 mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode via electrospray ionization (ESI) source. Each plasma sample was chromatographed within 2.6 min. The linear calibration curves for WJD-A-1 and the AM80 were obtained in the concentration range of 5.40-5.40 × 103 and 5.08-5.08 × 103 ng/mL, respectively (r ≥ 0.99). The intra- and inter-day precision (relative standard deviation, RSD) values were less than 8% and the accuracy (relative error, RE) was within ±6.8%, determined from quality control (QC) samples for the analytes. The method herein described was fully validated and successfully applied to pharmacokinetic study of WJD-A-1 following an intravenous administration of 300 µg/kg WJD-A-1 to rats.


Assuntos
Benzoatos/sangue , Benzoatos/farmacocinética , Análise Química do Sangue/métodos , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas em Tandem/métodos , Tetra-Hidronaftalenos/sangue , Tetra-Hidronaftalenos/farmacocinética , Métodos Analíticos de Preparação de Amostras , Animais , Calibragem , Modelos Lineares , Controle de Qualidade , Ratos , Fatores de Tempo
10.
Int J Nanomedicine ; 13: 273-281, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29391788

RESUMO

Introduction: Efficient delivery of rotigotine into the brain is crucial for obtaining maximum therapeutic efficacy for Parkinson's disease (PD). Therefore, in the present study, we prepared lactoferrin-modified rotigotine nanoparticles (Lf-R-NPs) and studied their biodistribution, pharmacodynamics, and neuroprotective effects following nose-to-brain delivery in the rat 6-hydroxydopamine model of PD. Materials and methods: The biodistribution of rotigotine nanoparticles (R-NPs) and Lf-R-NPs after intranasal administration was assessed by liquid extraction surface analysis coupled with tandem mass spectrometry. Contralateral rotations were quantified to evaluate pharmacodynamics. Tyrosine hydroxylase and dopamine transporter immunohistochemistry were performed to compare the neuroprotective effects of levodopa, R-NPs, and Lf-R-NPs. Results: Liquid extraction surface analysis coupled with tandem mass spectrometry analysis, used to examine rotigotine biodistribution, showed that Lf-R-NPs more efficiently supplied rotigotine to the brain (with a greater sustained amount of the drug delivered to this organ, and with more effective targeting to the striatum) than R-NPs. The pharmacodynamic study revealed a significant difference (P<0.05) in contralateral rotations between rats treated with Lf-R-NPs and those treated with R-NPs. Furthermore, Lf-R-NPs significantly alleviated nigrostriatal dopaminergic neurodegeneration in the rat model of 6-hydroxydopamine-induced PD. Conclusion: Our findings show that Lf-R-NPs deliver rotigotine more efficiently to the brain, thereby enhancing efficacy. Therefore, Lf-R-NPs might have therapeutic potential for the treatment of PD.


Assuntos
Encéfalo/efeitos dos fármacos , Nanopartículas/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Tetra-Hidronaftalenos/administração & dosagem , Tiofenos/administração & dosagem , Administração Intranasal , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Agonistas de Dopamina/administração & dosagem , Agonistas de Dopamina/farmacocinética , Agonistas de Dopamina/farmacologia , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Lactoferrina/química , Masculino , Nanopartículas/química , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacocinética , Nariz/efeitos dos fármacos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Tetra-Hidronaftalenos/farmacocinética , Tiofenos/farmacocinética , Distribuição Tecidual
11.
Eur J Drug Metab Pharmacokinet ; 43(4): 475-481, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29332198

RESUMO

BACKGROUND AND OBJECTIVE: Pharmacokinetic studies using deconvolution methods and non-compartmental analysis to model clinical absorption of drugs are not well represented in the literature. The purpose of this research was (1) to define the system of equations for description of rotigotine (a dopamine receptor agonist delivered via a transdermal patch) absorption based on a pharmacokinetic model and (2) to describe the kinetics of rotigotine disposition after single and multiple dosing. METHODS: The kinetics of drug disposition was evaluated based on rotigotine plasma concentration data from three phase 1 trials. In two trials, rotigotine was administered via a single patch over 24 h in healthy subjects. In a third trial, rotigotine was administered once daily over 1 month in subjects with early-stage Parkinson's disease (PD). A pharmacokinetic model utilizing deconvolution methods was developed to describe the relationship between drug release from the patch and plasma concentrations. Plasma-concentration over time profiles were modeled based on a one-compartment model with a time lag, a zero-order input (describing a constant absorption via skin into central circulation) and first-order elimination. Corresponding mathematical models for single- and multiple-dose administration were developed. RESULTS: After single-dose administration of rotigotine patches (using 2, 4 or 8 mg/day) in healthy subjects, a constant in vivo absorption was present after a minor time lag (2-3 h). On days 27 and 30 of the multiple-dose study in patients with PD, absorption was constant during patch-on periods and resembled zero-order kinetics. CONCLUSION: Deconvolution based on rotigotine pharmacokinetic profiles after single- or multiple-dose administration of the once-daily patch demonstrated that in vivo absorption of rotigotine showed constant input through the skin into the central circulation (resembling zero-order kinetics). Continuous absorption through the skin is a basis for stable drug exposure.


Assuntos
Sistemas de Liberação de Medicamentos , Absorção Cutânea , Tetra-Hidronaftalenos/sangue , Tetra-Hidronaftalenos/farmacocinética , Tiofenos/sangue , Tiofenos/farmacocinética , Adesivo Transdérmico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Disponibilidade Biológica , Ensaios Clínicos Fase I como Assunto/estatística & dados numéricos , Agonistas de Dopamina/sangue , Agonistas de Dopamina/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Modelos Teóricos , Adulto Jovem
12.
AAPS PharmSciTech ; 19(1): 275-283, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28702817

RESUMO

Tamibarotene (Am80) has good curative effect on advanced hepatocellular carcinoma (HCC). To improve the therapeutic efficacy furtherly, we prepared tamibarotene-loaded PLGA microspheres (Am80-PLGA-MS) for intratumoral injection. Firstly, Am80-PLGA-MS were prepared by emulsion-solvent evaporation method. Subsequently, microspheres were characterized by particle size analysis, drug loading (DL), and entrapment efficiency (EE). Finally, the drug release characteristics in vitro, pharmacokinetic, and pharmacodynamics were studied separately. According to results obtained, microspheres were spherical with a uniform particle size 7.04 ± 0.03 µm and its EE and DL were 82.23 ± 0.74 and 11.74 ± 0.11%, respectively. In vitro, Am80-PLGA-MS can release drug for 14 days and its release behavior was fitted with the Higuchi equation. In pharmacokinetic studies, the t1/2ß, MRT, and AUC of microspheres were 15.43-fold, 8.62-fold, and 9.98-fold those of Am80 solution, respectively, which revealed that the utilization of drug was improved obviously. The pharmacodynamics studies showed that the tumor doubling time, growth inhibition rate, and specific growth rate of tumor of Am80-PLGA-MS were 1.34 times, 2.63 times, and 0.72 times those of drug solution, respectively, indicating that the inhibitory effect on tumor by the microspheres was significantly improved. In summary, Am80-PLGA-MS are promising carrier to enhance the inhibitory effect on tumor, which will provide significantly clinical value for treatment of HCC.


Assuntos
Antineoplásicos/uso terapêutico , Benzoatos/uso terapêutico , Ácido Láctico , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Ácido Poliglicólico , Tetra-Hidronaftalenos/uso terapêutico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Benzoatos/administração & dosagem , Benzoatos/farmacocinética , Liberação Controlada de Fármacos , Feminino , Injeções Intralesionais , Neoplasias Hepáticas Experimentais/metabolismo , Camundongos , Microesferas , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Tetra-Hidronaftalenos/administração & dosagem , Tetra-Hidronaftalenos/farmacocinética
13.
Bioorg Med Chem ; 26(4): 798-814, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29288071

RESUMO

A ligand-based virtual screening exercise examining likely bioactive conformations of AM 580 (2) and AGN 193836 (3) was used to identify the novel, less lipophilic RARα agonist 4-(3,5-dichloro-4-ethoxybenzamido)benzoic acid 5, which has good selectivity over the RARß, and RARγ receptors. Analysis of the medicinal chemistry parameters of the 3,5-substituents of derivatives of template 5 enabled us to design a class of drug-like molecules with lower intrinsic clearance and higher oral bioavailability which led to the novel RARα agonist 4-(3-chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoic acid 56 that has high RARα potency and excellent selectivity versus RARß (2 orders of magnitude) and RARγ (4 orders of magnitude) at both the human and mouse RAR receptors with improved drug-like properties. This RARα specific agonist 56 has high oral bioavailability (>80%) in both mice and dogs with a good PK profile and was shown to be inactive in cytotoxicity and genotoxicity screens.


Assuntos
Aminobenzoatos/química , Benzoatos/química , Desenho de Fármacos , Receptor alfa de Ácido Retinoico/agonistas , Tetra-Hidronaftalenos/química , Administração Oral , Aminobenzoatos/farmacocinética , Aminobenzoatos/toxicidade , Animais , Benzoatos/farmacocinética , Benzoatos/toxicidade , Células COS , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Meia-Vida , Células Hep G2 , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Ratos , Receptores do Ácido Retinoico/agonistas , Receptores do Ácido Retinoico/metabolismo , Receptor alfa de Ácido Retinoico/metabolismo , Relação Estrutura-Atividade , Tetra-Hidronaftalenos/farmacocinética , Tetra-Hidronaftalenos/toxicidade
14.
Anal Bioanal Chem ; 409(22): 5217-5223, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28702764

RESUMO

The direct analysis of drug distribution of rotigotine-loaded microspheres (RoMS) from tissue sections by liquid extraction surface analysis (LESA) coupled with tandem mass spectrometry (MS/MS) was demonstrated. The RoMS distribution in rat tissues assessed by the ambient LESA-MS/MS approach without extensive or tedious sample pretreatment was compared with that obtained by a conventional liquid chromatography tandem mass spectrometry (LC-MS/MS) method in which organ excision and subsequent solvent extraction were commonly employed before analysis. Results obtained from the two were well correlated for a majority of the organs, such as muscle, liver, stomach, and hippocampus. The distribution of RoMS in the brain, however, was found to be mainly focused in the hippocampus and striatum regions as shown by the LESA-imaged profiles. The LESA approach we developed is sensitive enough, with an estimated LLOQ at 0.05 ng/mL of rotigotine in brain tissue, and information-rich with minimal sample preparation, suitable, and promising in assisting the development of new drug delivery systems for controlled drug release and protection. Graphical abstract Workflow for the LESA-MS/MS imaging of brain tissue section after intramuscular RoMS administration.


Assuntos
Microesferas , Tetra-Hidronaftalenos/farmacocinética , Tiofenos/farmacocinética , Animais , Agonistas de Dopamina/sangue , Agonistas de Dopamina/química , Agonistas de Dopamina/farmacocinética , Extração Líquido-Líquido , Masculino , Estrutura Molecular , Ratos , Propriedades de Superfície , Espectrometria de Massas em Tandem , Tetra-Hidronaftalenos/sangue , Tetra-Hidronaftalenos/química , Tiofenos/sangue , Tiofenos/química , Distribuição Tecidual
15.
Sleep Med ; 32: 48-55, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28366342

RESUMO

OBJECTIVE: To investigate the pharmacokinetics (PK) of rotigotine transdermal system in adolescents with moderate-to-severe idiopathic restless legs syndrome (RLS). METHODS: This multicenter, open-label, dose-escalation study enrolled patients ≥13 to <18 years of age. Rotigotine transdermal patches were applied daily and up-titrated weekly: 0.5, 1, 2, 3 mg/24 h. Blood samples were collected on the final day of each dose step. Primary PK variables were the apparent total body clearance (CL/f; L/h) and volume of distribution at steady state (VSS/f; L) of unconjugated rotigotine for each dose step, calculated for the PK per-protocol set (PKPPS). Other PK, safety, and efficacy variables (International RLS Study Group Rating Scale [IRLS]; Clinical Global Impressions Item 1 [CGI-1]) were assessed. RESULTS: Of 24 patients who received rotigotine, 23 completed all dose steps and 17 formed the PKPPS. Least-squares mean (95% confidence interval) CL/f and VSS/f values were broadly similar across all dose steps (CL/f: 0.5 mg/24 h: 676.86 [408.50-1121.51]; 1 mg/24 h: 671.72 [459.11-982.80]; 2 mg/24 h: 937.56 [658.50-1334.89]; 3 mg/24 h: 1088.77 [723.47-1638.53]; VSS/f: 5403.16 [2850.67-10,241.17]; 6220.79 [3842.05-10,072.28]; 7114.01 [4547.88-11,128.07]; 6037.92 [3598.36-10,131.41]). Among 23 patients with efficacy data, mean IRLS and CGI-1 scores improved at each dosage level. Adverse events reported by ≥3 patients were nausea (seven) and application site reactions (four). CONCLUSIONS: Key PK properties of rotigotine in adolescent patients with moderate-to-severe idiopathic RLS were comparable to those previously observed in adults. Rotigotine improved RLS symptoms and was well tolerated. ClinicalTrials.gov: NCT01495793.


Assuntos
Agonistas de Dopamina/farmacocinética , Síndrome das Pernas Inquietas/tratamento farmacológico , Tetra-Hidronaftalenos/farmacocinética , Tiofenos/farmacocinética , Adolescente , Agonistas de Dopamina/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Tetra-Hidronaftalenos/administração & dosagem , Tiofenos/administração & dosagem , Adesivo Transdérmico
16.
Biomed Chromatogr ; 31(9)2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28168729

RESUMO

A novel ultra-high-pressure liquid chromatography-tandem mass spectrometry method was developed and validated for the determination of the dopamine receptor agonist rotigotine in human plasma. Following liquid-liquid extraction with tert-butyl methyl ether from 500 µL plasma, the chromatographic analysis was performed on a Gemini NX3 column using 5 mm pH 5.0 ammonium acetate-5 mm ammonium acetate in methanol as binary gradient mobile phase, at a flow rate of 0.3 mL/min. The MS/MS ion transitions were 316.00 → 147.00 for rotigotine and 256.10 → 211.00 for the internal standard (lamotrigine). The lower limit of quantitation was 50 pg/mL and the linearity was determined from 50 to 2500 pg/mL. The mean recovery was 96.9%. Both intra- and interassay imprecision and inaccuracy were ≤15% at all quality control concentrations. The method was successfully applied to measure morning trough plasma rotigotine concentrations in a series of patients with Parkinson's disease on chronic treatment. The present study describes the first fully validated method for rotigotine determination in human plasma.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Agonistas de Dopamina/sangue , Doença de Parkinson/tratamento farmacológico , Espectrometria de Massas em Tandem/métodos , Tetra-Hidronaftalenos/sangue , Tiofenos/sangue , Agonistas de Dopamina/química , Agonistas de Dopamina/farmacocinética , Agonistas de Dopamina/uso terapêutico , Humanos , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/farmacocinética , Tetra-Hidronaftalenos/uso terapêutico , Tiofenos/química , Tiofenos/farmacocinética , Tiofenos/uso terapêutico
17.
Bioorg Med Chem Lett ; 27(3): 437-442, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28043796

RESUMO

We report on the discovery of two new lead series for the development of glucocorticoid receptor agonists. Firstly, the discovery of tetrahydronaphthalenes led to metabolically stable and dissociated compounds. Their binding mode to the glucocorticoid receptor could be elucidated through an X-ray structure. Closer inspection into the reaction path and analyses of side products revealed a new amino alcohol series also addressing the glucocorticoid receptor and demonstrating strong anti-inflammatory activity in vitro.


Assuntos
Anti-Inflamatórios/química , Receptores de Glucocorticoides/agonistas , Tetra-Hidronaftalenos/química , Amino Álcoois/química , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Sítios de Ligação , Genes Reporter , Meia-Vida , Células HeLa , Humanos , Ligação de Hidrogênio , Concentração Inibidora 50 , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Monócitos/citologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Ligação Proteica , Receptores de Glucocorticoides/metabolismo , Relação Estrutura-Atividade , Tetra-Hidronaftalenos/farmacocinética , Tetra-Hidronaftalenos/farmacologia , Ativação Transcricional/efeitos dos fármacos
18.
J Nucl Med ; 58(1): 123-128, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27469360

RESUMO

Cholinergic alterations in dementia with Lewy bodies (DLB) have been widely documented in postmortem studies, whereas in vivo studies are sparse, particularly at the subcortical level. We used 123I-iodobenzovesamicol, a SPECT radiotracer of the vesicular acetylcholine transporter, to evaluate in vivo in DLB the integrity of the 3 main cholinergic pathways-the Ch1 (septohippocampal), the Ch4 (innominatocortical), and the Ch5 (pontothalamic) cholinergic pathways-as well as the striatal cholinergic interneurons. In addition, we assessed the involvement of the cholinergic system in cognitive and neuropsychiatric disorders in DLB patients. METHODS: Twelve healthy volunteers (median age, 72 y; interquartile range, 6.25 y) and 11 DLB patients (median age, 76 y; interquartile range, 10.50 y) underwent a dynamic 123I-iodobenzovesamicol SPECT scan and an MRI scan. MR images were automatically segmented, providing the volumes of several regions of interest, including the striatum and cholinergic terminals in Ch1 (hippocampus), Ch4 (cortical lobes), and Ch5 (thalamus). For each region of interest and each subject, pharmacokinetic modeling allowed calculation of the nondisplaceable binding potential (BPND) values for the binding of 123I-iodobenzovesamicol to the vesicular acetylcholine transporter. A neuropsychological evaluation of participants was performed with the Mini-Mental State Examination and the Grober-Buschke, Set, visual discrimination, Benton, and Wechsler tests, and cognitive fluctuations and apathy were also assessed. RESULTS: Compared with BPND values for healthy subjects, BPND values for DLB patients were significantly lower in the Ch4 terminal regions of the anterior cingulate cortex and the superior and inferior parietal cortices (P = 0.0006, 0.0015, and 0.0023, respectively), in the Ch5 terminal region of the thalamus (P = 0.0003), and in the striatum (P = 0.0042). All of the neuropsychological test scores were significantly lower in DLB patients than in healthy subjects. Four DLB patients with apathy and 4 DLB patients without apathy were identified. For the anterior cingulate cortex, compared with BPND values in healthy subjects, BPND values were significantly lower in patients with apathy (P = 0.004) and were unchanged in patients without apathy. CONCLUSION: Our results confirm the existence in DLB of cholinergic alterations, reaching both cortical and subcortical levels, including the Ch5 pathway and the striatum. Alterations in cholinergic transmission in the anterior cingulate cortex could be closely associated with the development of apathy.


Assuntos
Encéfalo/diagnóstico por imagem , Neurônios Colinérgicos/patologia , Doença por Corpos de Lewy/diagnóstico por imagem , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Idoso , Idoso de 80 Anos ou mais , Encéfalo/metabolismo , Neurônios Colinérgicos/metabolismo , Feminino , Humanos , Doença por Corpos de Lewy/metabolismo , Masculino , Vias Neurais/diagnóstico por imagem , Vias Neurais/metabolismo , Piperidinas/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Tetra-Hidronaftalenos/farmacocinética , Distribuição Tecidual , Proteínas Vesiculares de Transporte de Acetilcolina/metabolismo
19.
J Cereb Blood Flow Metab ; 37(4): 1286-1298, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27354093

RESUMO

P-glycoprotein is a protective efflux transporter at the blood-brain barrier showing altered function in many neurological disorders. The purpose of this study was to validate [18F]MC225 as a radiotracer for measuring P-glycoprotein function with positron emission tomography. Three groups of Sprague-Dawley rats were used to assess tracer uptake at baseline (group 1), after inhibition of P-glycoprotein (group 2), and after inhibition of both P-glycoprotein and breast cancer resistance protein (Bcrp, group 3). A two-tissue compartment model with a metabolite-corrected plasma input function provided the best fit to the positron emission tomography data, but parameter estimates were more reliable in a one-tissue compartment model, which was selected as the preferred model. Regional distribution volumes ( VT) in the control group ranged from 6 to 11, which is higher than for other radiotracers. [18F]MC225 showed transporter selectivity, since inhibition of P-glycoprotein caused a two to fourfold increase in the cerebral VT values, but additional inhibition of Bcrp did not cause any further increase. Metabolic stability of [18F]MC225 was moderate (at 1 h post-injection 15% of plasma radioactivity and 76% of brain radioactivity represented intact parent). Thus, [18F]MC225 may be a useful radiotracer to measure especially increases of P-glycoprotein function at the blood-brain barrier.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Barreira Hematoencefálica/metabolismo , Isoquinolinas/química , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/química , Tetra-Hidronaftalenos/química , Animais , Barreira Hematoencefálica/diagnóstico por imagem , Radioisótopos de Flúor , Isoquinolinas/síntese química , Isoquinolinas/farmacocinética , Cinética , Masculino , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Ratos Sprague-Dawley , Tetra-Hidronaftalenos/síntese química , Tetra-Hidronaftalenos/farmacocinética , Distribuição Tecidual
20.
J Dermatol ; 44(2): 135-142, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27543197

RESUMO

Safety, tolerability, pharmacokinetics and efficacy of bexarotene, a novel retinoid X receptor (RXR)-selective retinoid, were evaluated in Japanese patients with stage IIB-IVB and relapsed/refractory stage IB-IIA cutaneous T-cell lymphomas (CTCL). This study was conducted as a multicenter, open-label, historically controlled, single-arm phase I/II study. Bexarotene was p.o. administrated once daily at a dose of 300 mg/m2 for 24 weeks in 13 patients, following an evaluation of safety and tolerability for 4 weeks at a dose of 150 mg/m2 in three patients. Eight of 13 patients (61.5%) with an initial dose of 300 mg/m2 met the response criteria using the modified severity-weighted assessment tool (mSWAT) at 24 weeks or discontinuation. Dose-limiting toxic effects (DLT) were present in four of 13 patients (31%) at a dose of 300 mg/m2 : two neutropenia, one abnormal hepatic function and one hypertriglyceridemia. No DLT was observed in patients received 150 mg/m2 bexarotene. In the 13 patients at 300 mg/m2 , common drug-related adverse events (AE) included hypothyroidism (92%), hypercholesterolemia (77%), leukopenia or neutropenia (39%), nasopharyngitis or anemia (31%). The treatment-related grade 3 AE included hypertriglyceridemia (4/16 patients, 25%), increased alanine aminotransferase, increased aspartate aminotransferase, dyslipidaemia, leukopenia and neutropenia (1/16 patients, 6%), and one of 16 patients experienced grade 4 hypertriglyceridemia. No patients discontinued bexarotene due to the AE during the study, but dose reduction or suspension was required. Bexarotene was shown to be well tolerated at 300 mg/m2 once daily and effective in Japanese patients with CTCL.


Assuntos
Anticarcinógenos/uso terapêutico , Linfoma Cutâneo de Células T/tratamento farmacológico , Receptores X Retinoide/agonistas , Tetra-Hidronaftalenos/uso terapêutico , Adulto , Idoso , Anticarcinógenos/farmacocinética , Bexaroteno , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tetra-Hidronaftalenos/farmacocinética , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...