RESUMEN
Parkinson's disease (PD), affecting about ten million people globally, presents a significant health challenge. Rotigotine (RTG), a dopamine agonist, is currently administered as a transdermal patch (Neupro®) for PD treatment, but the daily application can be burdensome and cause skin irritation. This study introduces a combinatorial approach of dissolving microarray patch (MAP) and nanosuspension (NS) for the transdermal delivery of RTG, offering an alternative to Neupro®. The RTG-NS was formulated using a miniaturized media milling method, resulting in a nano-formulation with a mean particle size of 274.09 ± 7.43 nm, a PDI of 0.17 ± 0.04 and a zeta potential of -15.24 ± 2.86 mV. The in vitro dissolution study revealed an enhanced dissolution rate of the RTG-NS in comparison to the coarse RTG powder, under sink condition. The RTG-NS MAPs, containing a drug layer and a 'drug-free' supporting baseplate, have a drug content of 3.06 ± 0.15 mg/0.5 cm2 and demonstrated greater amount of drug delivered per unit area (â¼0.52 mg/0.5 cm2) than Neupro® (â¼0.20 mg/1 cm2) in an ex vivo Franz cell study using full-thickness neonatal porcine skin. The in vivo pharmacokinetic studies demonstrated that RTG-NS MAPs, though smaller (2 cm2 for dissolving MAPs and 6 cm2 for Neupro®), delivered drug levels comparable to Neupro®, indicating higher efficiency per unit area. This could potentially avoid unnecessarily high plasma levels after the next dose at 24 h, highlighting the benefits of dissolving MAPs over conventional transdermal patches in PD treatment.
Asunto(s)
Administración Cutánea , Agonistas de Dopamina , Nanopartículas , Absorción Cutánea , Tetrahidronaftalenos , Tiofenos , Parche Transdérmico , Animales , Tiofenos/administración & dosificación , Tiofenos/farmacocinética , Tiofenos/química , Tetrahidronaftalenos/administración & dosificación , Tetrahidronaftalenos/farmacocinética , Tetrahidronaftalenos/química , Agonistas de Dopamina/administración & dosificación , Agonistas de Dopamina/farmacocinética , Agonistas de Dopamina/química , Nanopartículas/química , Porcinos , Suspensiones , Piel/metabolismo , Liberación de Fármacos , Masculino , Solubilidad , Tamaño de la PartículaRESUMEN
AIMS: Rotigotine extended-release microspheres is a weekly intramuscular injection formulation to treat Parkinson's disease. This study aimed to develop a population pharmacokinetics (PK) model for rotigotine extended-release microspheres to investigate its PK ethnic differences. METHODS: Data for the study were obtained from three studies in China, Japan and the US. The population PK model was developed using the Phoenix NLME 8.3.5 software. Two parallel absorption models were created to include both zero- and first-order absorptions. The elimination phase was evaluated for one- and two-compartment linear models. Moreover, covariates including sex, body weight, body mass index, albumin, creatinine clearance and race were input into the model using a stepwise covariate method. RESULTS: We constructed a one-compartment linear model with the first parallel absorption model identified as the best-fitting model. Simulation results in patients with lighter body weight (45 kg) exhibited a 27% increase in Cmax,ss and a 31% increase in AUCtau,ss compared to those with median body weight (65 kg). Patients with heavier body weight (103 kg) showed a 27% decrease in Cmax,ss and a 29% decrease in AUCtau,ss compared to the median body weight group. Asian patients displayed only a 21% increase in Cmax,ss and a 6% increase in AUCtau,ss compared to non-Asian. While we could not fully conclude that race does not affect rotigotine exposure, dosage adjustments based on race were not deemed necessary. CONCLUSIONS: Exposure differences were mainly attributed to body weight, while dose adjustments were not needed for patients of different racial identities.
Asunto(s)
Enfermedad de Parkinson , Tiofenos , Humanos , Inyecciones Intramusculares , Enfermedad de Parkinson/tratamiento farmacológico , Microesferas , Tetrahidronaftalenos/efectos adversos , Tetrahidronaftalenos/farmacocinética , Peso CorporalRESUMEN
Drug resistant tuberculsosis (TB) is global health crisis that demands novel treatment strategies. Bacterial ATP synthase inhibitors such as bedaquiline and next-generation analogues (such as TBAJ-876) have shown promising efficacy in patient populations and preclinical studies, respectively, suggesting that selective targeting of this enzyme presents a validated therapeutic strategy for the treatment of TB. In this work, we report tetrahydronaphthalene amides (THNAs) as a new class of ATP synthase inhibitors that are effective in preventing the growth of Mycobacterium tuberculosis (M.tb) in culture. Design, synthesis and comprehensive structure-activity relationship studies for approximately 80 THNA analogues are described, with a small selection of compounds exhibiting potent (in some cases MIC90 <1 µg/mL) in vitro M.tb growth inhibition taken forward to pharmacokinetic and off-target profiling studies. Ultimately, we show that some of these THNAs possess reduced lipophilic properties, decreased hERG liability, faster mouse/human liver microsomal clearance rates and shorter plasma half-lives compared with bedaquiline, potentially addressing of the main concerns of persistence and phospholipidosis associated with bedaquiline.
Asunto(s)
Amidas/química , Antituberculosos/síntesis química , Mycobacterium tuberculosis/efectos de los fármacos , Tetrahidronaftalenos/síntesis química , Animales , Antituberculosos/efectos adversos , Antituberculosos/farmacocinética , Diarilquinolinas/farmacología , Diarilquinolinas/normas , Descubrimiento de Drogas , Humanos , Hígado , Ratones , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad , Tetrahidronaftalenos/efectos adversos , Tetrahidronaftalenos/farmacocinéticaRESUMEN
A hollow fiber liquid phase microextraction (HF-LPME) based on a reversed lipid micelle as the extraction phase was proposed and combined with high performance liquid chromatography (HPLC) for the determination of rotigotine in biological matrix. In the proposed procedure, pieces of hollow fibers were fastened on a magnetic stir bar using a thread to provide better precision. Rotigotine was extracted from 5â¯mL of diluted plasma sample phase with pH 6 into reversed lipid micelle (5â¯mmol/L of dipalmitoyl phosphatidyl choline in n-octanol/water) impregnated in both the wall pores and the lumen of the hollow fiber. After the extraction at 900â¯rpm and room temperature for 30â¯min, the acceptor phase of reversed lipid micelle was collected for HPLC analysis. Various parameters affecting the extraction efficiency, such as type of surfactant and organic solvent, surfactant concentration, sample phase pH, salt amount, extraction time, stirring rate, and dilution factor of the plasma sample, were investigated and optimized. Furthermore, the formed reversed lipid micelle was characterized by fluorescence method. Under the optimal conditions, the linear range of rotigotine was between 2â¯ng/mL and 100â¯ng/mL with determination coefficient (r2)â¯≥â¯0.9913. It is shown from results of method validation that the satisfactory accuracy (the relative errors between -8.5% and 3.3%), precision (the relative standard deviations from 3.8% to 8.9%), stability and matrix effect were obtained. The enrichment factor (EF) of the reversed lipid micelle-based HF-LPME for rotigotine reached 126. And the feasibility of the proposed method was confirmed by the application to the pharmacokinetic study of rotigotine in rat plasma.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Microextracción en Fase Líquida/métodos , Tetrahidronaftalenos/sangre , Tiofenos/sangre , Animales , Diseño de Equipo , Límite de Detección , Modelos Lineales , Microextracción en Fase Líquida/instrumentación , Masculino , Micelas , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Tetrahidronaftalenos/química , Tetrahidronaftalenos/farmacocinética , Tiofenos/química , Tiofenos/farmacocinéticaRESUMEN
BACKGROUND: An efficient, fast and sensitive ultra high-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) method for simultaneous determination of celecoxib (CEL), dezocine (DEZ) and dexmedetomidine (DEX) in beagle plasma were established. METHODS: The beagle dogs plasmawas precipitated by acetonitrile. The column was Acquity UPLC BEH C18 column and the mobile phase was acetonitrile-formic acid with gradient mode, and the flow rate was set at 0.4 mL/min. Under the positive ion mode, CEL, DEZ, DEX and Midazolam (internal standard, IS) were monitored by multiple reaction monitoring (MRM) as the following mass transition pairs: m/z 381.10â282.10 for CEL, m/z 246.20â147.00 for DEZ, m/z 201.10â94.90 for DEX, and m/z 326.10â291.10 for IS. RESULTS: This UPLC-MS/MS method had good linearity for CEL, DEZ and DEX. The RSDs of inter-day and intra-day precision were the values of 0.31-7.66% and 0.11-9.63%, respectively; the RE values were from -6.05% to 10.98%. The extraction recovery was more than 79%, and the matrix effect was around 100%. The RSDs of stability were less than 8.96%. All of them met the acceptance standard of biological analysis method recommended by FDA. CONCLUSION: This UPLC-MS/MS method is an effective tool for the simultaneous determination of CEL, DEX and DEX, and has been successfully applied to the study of pharmacokinetics in beagle dogs.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Celecoxib/farmacocinética , Cromatografía Líquida de Alta Presión/métodos , Dexmedetomidina/farmacocinética , Espectrometría de Masas en Tándem/métodos , Tetrahidronaftalenos/farmacocinética , Analgésicos/administración & dosificación , Analgésicos/farmacocinética , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Celecoxib/administración & dosificación , Dexmedetomidina/administración & dosificación , Perros , Quimioterapia Combinada , Reproducibilidad de los Resultados , Tetrahidronaftalenos/administración & dosificaciónRESUMEN
PURPOSE: Tamibarotene is a synthetic retinoid that inhibits proliferation and induces differentiation of malignant cells by binding to the retinoic acid receptor α/ß. Previous in vitro studies have shown that some pediatric solid tumors with retinoic acid receptors differentiate in response to retinoic acid. We conducted a phase I dose-escalation study to determine the recommended dose of tamibarotene for further study in pediatric and young adult patients with recurrent/refractory solid tumors. METHODS: Pediatric and young adult patients with recurrent/refractory solid tumors were administered tamibarotene at 4, 6, 8, 10, and 12 mg/m2/day for 14 or 21 days of a 28 day cycle. Safety, efficacy, and pharmacokinetics of tamibarotene were evaluated. RESULTS: Twenty-two patients (median age 8 years) were enrolled in this study. No dose-limiting toxicity (DLT) was encountered, and tamibarotene was generally well tolerated. Two patients experienced severe adverse events (AEs), leading to discontinuation of the treatment. One grade 4 venous thrombosis and one grade 2 erythema multiforme were observed, which promptly resolved after tamibarotene discontinuance. The grade 4 venous thrombosis was a severe AE but not DLT because it occurred after the evaluation period. Pharmacokinetic analyses showed a dose-dependent increase in the maximum drug concentration (Cmax) and area under the concentration-time curve (AUC). None of the patients achieved a complete response or partial response. Seven patients had stable disease lasting longer than 18 weeks. CONCLUSIONS: The recommended dose for phase II study of tamibarotene in pediatric and young adult patients with refractory solid tumors is 12 mg/m2/day for 21 days in a 28 day cycle.
Asunto(s)
Antineoplásicos/administración & dosificación , Benzoatos/administración & dosificación , Neoplasias/tratamiento farmacológico , Tetrahidronaftalenos/administración & dosificación , Adolescente , Adulto , Antineoplásicos/farmacocinética , Benzoatos/farmacocinética , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Tetrahidronaftalenos/farmacocinética , Adulto JovenRESUMEN
PURPOSE: This phase I study (RAD1901-005; NCT02338349) evaluated elacestrant, an investigational oral selective estrogen receptor degrader (SERD), in heavily pretreated women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer, including those with estrogen receptor gene alpha (ESR1) mutation. The primary objective was to determine the maximum tolerated dose and/or recommended phase II dose (RP2D). METHODS: The study consisted of a 3 + 3 design (elacestrant capsules) followed by expansion at RP2D (400-mg capsules, then 400-mg tablets) for the evaluation of safety and antitumor activity. Elacestrant was taken once daily until progression or intolerability. RESULTS: Of 57 postmenopausal women enrolled, 50 received RP2D (400 mg once daily): median age, 63 years; median three prior anticancer therapies, including cyclin-dependent kinase 4,6 inhibitors (CDK4/6i; 52%), SERD (52%), and ESR1 mutation (circulating tumor DNA; 50%). No dose-limiting toxicities occurred; the most common adverse events at RP2D (400-mg tablet; n = 24) were nausea (33.3%) and increased blood triglycerides and decreased blood phosphorus (25.0% each). Most adverse events were grade 1-2 in severity. The objective response rate was 19.4% (n = 31 evaluable patients receiving RP2D), 15.0% in patients with prior SERD, 16.7% in patients with prior CDK4/6i, and 33.3% in patients with ESR1 mutation (n = 5/15). The clinical benefit rate (24-week) was 42.6% overall (n = 47 patients receiving RP2D), 56.5% (n = 23, ESR1 mutation), and 30.4% (n = 23, prior CDK4/6i). Elacestrant clinical benefit was associated with decline in ESR1 mutant allele fraction. CONCLUSION: Elacestrant 400 mg orally once daily has an acceptable safety profile and demonstrated single-agent activity with confirmed partial responses in heavily pretreated patients with estrogen receptor-positive metastatic breast cancer. Notably, responses were observed in patients with ESR1 mutation as well as those with prior CDK4/6i and prior SERD. A phase III trial investigating elacestrant versus standard endocrine therapy is ongoing.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Receptor ErbB-2/análisis , Receptores de Estrógenos/análisis , Tetrahidronaftalenos/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/química , Neoplasias de la Mama/genética , Receptor alfa de Estrógeno/genética , Femenino , Humanos , Persona de Mediana Edad , Mutación , Tetrahidronaftalenos/efectos adversos , Tetrahidronaftalenos/farmacocinéticaRESUMEN
AMPK is an energy sensor modulating metabolism, inflammation, and a target for metabolic disorders. Metabolic dysfunction results in lower AMPK activity. PXL770 is a direct AMPK activator, inhibiting de novo lipogenesis (DNL) and producing efficacy in preclinical models. We aimed to assess pharmacokinetics, safety, and pharmacodynamics of PXL770 in humans with metabolic syndrome-associated fatty liver disease. In a randomized, double-blind four-week trial, 12 overweight/obese patients with non-alcoholic fatty liver disease (NAFLD) and insulin resistance received PXL770 500 mg QD; 4 subjects received matching placebo. Endpoints included pharmacokinetics, hepatic fractional DNL, oral glucose tolerance testing, additional pharmacodynamic parameters, and safety. PK parameters show adequate plasma exposure in NAFLD patients for daily oral dosing. PXL770 decreases DNL-both peak and AUC are reduced versus baseline-and improves glycemic parameters and indices of insulin sensitivity versus baseline. Assessment of specific lipids reveals decrease in diacyglycerols/triacylglycerols. Safety/tolerability are similar to placebo. These results unveil initial human translation of AMPK activation and support this therapeutic strategy for metabolic disorders.
Asunto(s)
Adenilato Quinasa/metabolismo , Resistencia a la Insulina , Enfermedad del Hígado Graso no Alcohólico/enzimología , Enfermedad del Hígado Graso no Alcohólico/patología , Piridonas/farmacología , Tetrahidronaftalenos/farmacología , Activación Enzimática/efectos de los fármacos , Activadores de Enzimas , Femenino , Glucosa/metabolismo , Humanos , Lípidos/sangre , Lipogénesis/efectos de los fármacos , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Piridonas/efectos adversos , Piridonas/sangre , Piridonas/farmacocinética , Tetrahidronaftalenos/efectos adversos , Tetrahidronaftalenos/sangre , Tetrahidronaftalenos/farmacocinéticaRESUMEN
Sphingosine-1-phosphate (S1P) binding to the S1P-1 receptor (S1P1R) controls the egress of lymphocytes from lymphoid organs and targets modulation of immune responses in autoimmune diseases. Pharmacologic modulation of S1P receptors has been linked to heart rate reduction. BMS-986166, a prodrug of the active phosphorylated metabolite BMS-986166-P, presents an improved cardiac safety profile in preclinical studies compared to other S1P1R modulators. The pharmacokinetics, safety, and pharmacodynamics of BMS-986166 versus placebo after single (0.75-5.0 mg) and repeated (0.25-1.5 mg/day) oral administration were assessed in healthy participants after a 1-day lead-in placebo period. A population model was developed to jointly describe BMS-986166 and BMS-986166-P pharmacokinetics and predict individual exposures. Inhibitory sigmoid models described the relationships between average daily BMS-986166-P concentrations and nadir of time-matched (day -1) placebo-corrected heart rate on day 1 (nDDHR, where DD represents ∆∆) and nadir of absolute lymphocyte count (nALC). Predicted decreases in nDDHR and nALC were 9 bpm and 20% following placebo, with maximum decreases of 10 bpm in nDDHR due to drug effect, and approximately 80% in nALC due to drug and placebo. A 0.5-mg/day dose regimen achieves the target 65% reduction in nALC associated with a 2-bpm decrease in nDDHR over placebo.
Asunto(s)
Modelos Biológicos , Tetrahidronaftalenos/farmacocinética , Adulto , Simulación por Computador , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Voluntarios Sanos , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Receptores de Esfingosina-1-Fosfato , Tetrahidronaftalenos/administración & dosificación , Adulto JovenRESUMEN
Rotigotine-loaded microspheres (RoMS) are sustained-release formulations with prolonged anti-Parkinson's effects. Given that pain is a non-motor symptom of Parkinson's disease, this study investigated the antinociceptive effects of RoMS and their synergistic effects with analgesics on inflammatory pain. A model of inflammatory pain was prepared by intraplantarly injecting male Sprague-Dawley rats with carrageenan. The antinociceptive effects of RoMS, acetaminophen, and tramadol, both alone and in combination, were evaluated using the hind paw withdrawal latency in the hot plate test and Randall-Selitto test. The rotigotine concentrations in serum and tissues were assayed using ultra-performance liquid chromatography-tandem mass spectrometry. Isobolographic analysis was performed to evaluate the nature of the interactions of RoMS with acetaminophen or tramadol. The results showed that hind paw withdrawal latency to thermal and mechanical stimuli was significantly increased on day 3 and 7 after administered RoMS. Rotigotine could be detected in serum and tissues 3 and 7 days after an intramuscular injection of RoMS. However, the rotigotine concentration fell the detection limit of the assay on day 14 after administration. RoMS produced synergistic antinociceptive effects in the inflammatory pain model when RoMS is combined with acetaminophen or tramadol. These findings suggest that RoMS can relieve inflammatory pain in rats. Furthermore, the combination of RoMS with acetaminophen or tramadol produces synergistic antinociception, which may be clinically worthy because combination therapies may reduce the drug doses required for antinociception.
Asunto(s)
Acetaminofén/farmacología , Analgésicos/farmacología , Hiperalgesia/prevención & control , Dolor Nociceptivo/prevención & control , Umbral del Dolor/efectos de los fármacos , Tetrahidronaftalenos/farmacología , Tiofenos/farmacología , Tramadol/farmacología , Analgésicos/química , Analgésicos/farmacocinética , Animales , Conducta Animal/efectos de los fármacos , Carragenina , Preparaciones de Acción Retardada , Modelos Animales de Enfermedad , Composición de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Hiperalgesia/inducido químicamente , Hiperalgesia/fisiopatología , Locomoción/efectos de los fármacos , Masculino , Microesferas , Dolor Nociceptivo/inducido químicamente , Dolor Nociceptivo/fisiopatología , Prueba de Campo Abierto/efectos de los fármacos , Ratas Sprague-Dawley , Tetrahidronaftalenos/química , Tetrahidronaftalenos/farmacocinética , Tiofenos/química , Tiofenos/farmacocinéticaRESUMEN
BACKGROUND: Elacestrant is an oral selective estrogen receptor (ER) degrader. This phase 1b open-label, non-randomized study (RAD1901-106) was initiated to determine the effect of elacestrant on the availability of ER in lesions from postmenopausal women with ER+ advanced breast cancer (ABC) using 16α-18F-fluoro-17ß-estradiol positron emission tomography with low-dose computed tomography (FES-PET/CT). METHODS: Eligible patients were postmenopausal women with ER+, HER2- ABC; tumor progression after ≥ 6 months of 1-3 lines of endocrine treatment for ABC; and measurable or evaluable disease. Two 8-patient cohorts were enrolled: one treated with 400 mg elacestrant once daily (QD) and one treated with 200 mg elacestrant QD with dose escalation to 400 mg QD after 14 days. Elacestrant was dosed continuously until progressive disease, toxicity, or withdrawal. FES-PET/CT was performed pre-dose at baseline and 4 h post-dose on day 14. The primary endpoint was the percentage difference in FES uptake in tumor lesions (maximum 20) after 14 days of treatment compared to baseline. Overall response was investigator-assessed by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1. RESULTS: Patients (n = 16; median age, 53.5 years) had ABC with a median 2.5 prior lines of endocrine therapy. Median reduction in tumor FES uptake from baseline to day 14 was 89.1% (Q1, Q3: 75.1%, 94.1%) and was similar in both cohorts (89.1% [Q1, Q3: 67.4%, 94.2%], 200/400 mg and 88.7% [Q1, Q3: 79.5%, 94.1%], 400 mg). Residual ER availability (> 25% persistence in FES uptake) on day 14 was observed in 3 patients receiving 200/400 mg (3/78, 37.5%) and 1 patient receiving 400 mg (1/8, 12.5%). The overall response rate (ORR) was 11.1% (1 partial response), and clinical benefit rate (CBR) was 30.8%. Median percentage change in FES uptake did not correlate with ORR or CBR. Adverse events occurring in > 20% of the patients were nausea (68.8%), fatigue (50.0%), dyspepsia (43.8%), vomiting (37.5%), and decreased appetite, dysphagia, and hot flush (31.3% each). Most events were grade 2 in severity. CONCLUSION: Elacestrant 200 mg and 400 mg QD greatly reduced ER availability measured by FES-PET/CT. In a heavily pretreated population, elacestrant was associated with antitumor activity. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02650817 . Registered on 08 January 2016.
Asunto(s)
Neoplasias de la Mama/patología , Estradiol/metabolismo , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Receptores de Estrógenos/metabolismo , Tetrahidronaftalenos/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Femenino , Radioisótopos de Flúor/metabolismo , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Seguridad del Paciente , Radiofármacos/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/farmacocinética , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Tetrahidronaftalenos/farmacocinética , Distribución Tisular , Resultado del TratamientoRESUMEN
[18F]MC225 has been developed as a weak substrate of P-glycoprotein (P-gp) aimed to measure changes in the P-gp function at the blood-brain barrier with positron emission tomography. This study evaluates [18F]MC225 kinetics in non-human primates and investigates the effect of both scan duration and P-gp inhibition. Three rhesus monkeys underwent two 91-min dynamic scans with blood sampling at baseline and after P-gp inhibition (8 mg/kg tariquidar). Data were analyzed using the 1-tissue compartment model (1-TCM) and 2-tissue compartment model (2-TCM) fits using metabolite-corrected plasma as the input function and for various scan durations (10, 20, 30, 60, and 91 min). The preferred model was chosen according to the Akaike information criterion and the standard errors (%) of the estimated parameters. For the 91-min scan duration, the influx constant K1 increased by 40.7% and the volume of distribution (VT) by 30.4% after P-gp inhibition, while the efflux constant k2 did not change significantly. Similar changes were found for all evaluated scan durations. K1 did not depend on scan duration (10 min-K1 = 0.2191 vs 91 min-K1 = 0.2258), while VT and k2 did. A scan duration of 10 min seems sufficient to properly evaluate the P-gp function using K1 obtained with 1-TCM. For the 91-min scan, VT and K1 can be estimated with a 2-TCM, and both parameters can be used to assess P-gp function.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Barrera Hematoencefálica/metabolismo , Radioisótopos de Flúor/farmacocinética , Isoquinolinas/farmacocinética , Primates/metabolismo , Radiofármacos/farmacocinética , Tetrahidronaftalenos/farmacocinética , Animales , Encéfalo/metabolismo , Cinética , Macaca mulatta , Masculino , Tomografía de Emisión de Positrones/métodos , Quinolinas/farmacocinética , Cintigrafía/métodosRESUMEN
OBJECTIVE: We developed and validated a sensitive and reliable UPLC-MS/MS method for simultaneous determination of dezocine (DEZ), midazolam (MDZ) and its metabolite 1-hydroxymidazolam (1-OH-MDZ) in beagle plasma and investigated the effect of dexmedetomidine (DEX) on the pharmacokinetics of DEZ, MDZ and 1-OH-MDZ in beagles. MATERIALS AND METHODS: Diazepam was used as the internal standard (IS); the three analytes and IS were extracted by acetonitrile precipitation and separated on an Acquity UPLC BEH C18 column using acetonitrile-0.1% formic acid as mobile phase in gradient mode. In positive ion mode, the three analytes and IS were monitored by multiple reaction monitoring (MRM). Six beagles were designed as a double cycle self-control experiment with 0.15 mg/kg in the first cycle (Group A). After a 1-week washout period, the same six beagles were slowly injected intravenously with 2 µg/kg DEX in the second cycle (Group B), with continuous injection for 7 days. On the seventh day, 0.5 hr after intravenous injection of 2 µg/kg DEX, the six beagles were intramuscularly given with DEZ 0.33 mg/kg and MDZ 0.15 mg/kg. RESULTS: Under the conditions of this experiment, this method exhibited a good linearity for each analyte. The accuracy and precision were all within the acceptable limits in the bioanalytical method, and the results of recovery, matrix effect and stability have also met the requirements. CONCLUSION: The developed UPLC-MS/MS method for simultaneous determination of DEZ, MDZ and 1-OH-MDZ in beagles plasma was accurate, reproducible, specific, and suitable. DEX could inhibit the metabolism of DEZ and MDZ and increase the exposure of DEZ and MDZ in beagles. Therefore, the change of therapeutic effect and the occurrence of adverse reactions caused by drug-drug interaction should be paid attention to when the drugs were used in combination.
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Compuestos Bicíclicos Heterocíclicos con Puentes/sangre , Dexmedetomidina/sangre , Midazolam/análogos & derivados , Midazolam/sangre , Tetrahidronaftalenos/sangre , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/metabolismo , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Cromatografía Líquida de Alta Presión , Dexmedetomidina/metabolismo , Dexmedetomidina/farmacocinética , Perros , Femenino , Masculino , Midazolam/metabolismo , Midazolam/farmacocinética , Espectrometría de Masas en Tándem , Tetrahidronaftalenos/metabolismo , Tetrahidronaftalenos/farmacocinéticaRESUMEN
BACKGROUND AND OBJECTIVES: Advanced estrogen receptor-positive (ER+) breast cancer is currently treated with endocrine therapy. Elacestrant is a novel, nonsteroidal, selective estrogen receptor degrader with complex dose-related ER agonist/antagonist activity that is being developed as a treatment option for ER+ breast cancer. METHODS: Two first-in-human phase 1 studies of elacestrant in healthy postmenopausal women (Study 001/Study 004) were conducted to determine its pharmacokinetic and pharmacodynamic profile as well as its safety and maximum tolerated dose. RESULTS: In total, 140 postmenopausal subjects received at least one dose of study drug (114 received elacestrant and 26 received placebo). Single-ascending dose and multiple-ascending dose assessments showed that doses up to 1000 mg daily were safe and well tolerated, and the maximum tolerated dose was not reached. Oral administration of elacestrant had an absolute bioavailability of 10% and a mean half-life ranging from 27 to 47 h, reaching steady state after 5-6 days. Mean occupancy of the ER in the uterus after seven daily doses was 83% for 200 mg and 92% for 500 mg daily. The median ratio of elacestrant concentrations in the cerebral spinal fluid vs. plasma was 0.126% (500 mg dose) and 0.205% (200 mg dose). Most adverse events were related to the upper gastrointestinal tract. CONCLUSIONS: These data demonstrate that elacestrant has good bioavailability when administered orally with a half-life that supports once-daily administration. Engagement of the ER and some ability to cross the blood-brain barrier was demonstrated in addition to an acceptable safety profile.
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Posmenopausia , Moduladores Selectivos de los Receptores de Estrógeno/administración & dosificación , Tetrahidronaftalenos/administración & dosificación , Administración Oral , Anciano , Disponibilidad Biológica , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Femenino , Semivida , Humanos , Dosis Máxima Tolerada , Persona de Mediana Edad , Moduladores Selectivos de los Receptores de Estrógeno/farmacocinética , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Tetrahidronaftalenos/farmacocinética , Tetrahidronaftalenos/farmacologíaRESUMEN
Background: Safety, pharmacokinetics and pharmacodynamics of BMS-986166, a novel sphingosine-1-phosphate receptor 1 modulator, were assessed.Research design and methods: Two double-blind, placebo-controlled, randomized Phase l studies were conducted in healthy participants. In the single ascending dose study (N = 70), BMS-986166 was administered as a single dose, upwardly titrated daily doses or a single dose in participants who were fed, fasted or administered famotidine. In the multiple ascending dose study (N = 32), BMS-986166 was administered daily for 28 days. Safety, pharmacokinetics and pharmacodynamics (absolute lymphocyte count [ALC]) were assessed.Results: BMS-986166 was generally well tolerated; treatment-related adverse events were mild. Dose-related, clinically insignificant reductions in time-matched heart rate were recorded versus placebo. Pharmacokinetics were linear and stationary with approximately dose-related increases in blood exposure of BMS-986166. Decreases in ALC percent change from baseline with multiple doses of BMS-986166 versus placebo were dose-related. Between Day 0 and 35, median nadir lymphocyte reductions were 53.7%, 75.9% and 81.9% with 0.25-, 0.75- and 1.5-mg BMS-986166 doses. ALC recovery began 14, 14-21 and 7 days after last dose of 0.25, 0.75 and 1.5 mg.Conclusions: BMS-986166 was generally well tolerated in this population and warrants further investigation.Trial registration: ClinicalTrials.gov: NCT02790125, NCT03038711.
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Receptores de Esfingosina-1-Fosfato , Tetrahidronaftalenos/administración & dosificación , Adulto , Grasas de la Dieta/administración & dosificación , Método Doble Ciego , Famotidina/administración & dosificación , Ayuno/metabolismo , Voluntarios Sanos , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Recuento de Linfocitos , Persona de Mediana Edad , Tetrahidronaftalenos/efectos adversos , Tetrahidronaftalenos/farmacocinética , Adulto JovenRESUMEN
Rotigotine, a non-ergoline dopamine agonist, has been shown to be highly effective for the treatment of Parkinson's disease (PD). However, despite its therapeutic potential, its' clinical applications were hindered due to low aqueous solubility, first-pass metabolism and low bioavailability. Therefore, we developed rotigotine-loaded chitosan nanoparticles (RNPs) for nose-to-brain delivery and evaluated its neuronal uptake, antioxidant and neuroprotective effects using cell-based studies. The pharmacological effects of nose-to-brain delivery of the RNPs were also evaluated in an animal model of PD. The average particle size, particle size distribution and entrapment efficiency of the RNPs were found to be satisfactory. Exposure of RNPs for 24 h did not show any cytotoxicity towards SH-SY5Y human neuroblastoma cells. Furthermore, the RNPs caused a decrease in alpha-synuclein (SNCA) and an increase in tyrosine hydroxylase (TH) expression in these cells, suggestion that the exposure alleviated some of the direct neurotoxic effects of 6-OHDA. Behavioral and biochemical testing of RNPs in haloperidol-induced PD rats showed a reversal of catalepsy, akinesia and restoration of swimming ability. A decrease in lactate dehydrogenase (LDH) and an increase in catalase activities were also observed in the brain tissues. The results from the animal model of PD show that intranasally-administered RNPs enhanced brain targeting efficiency and drug bioavailability. Thus, RNPs for nose-to-brain delivery has significant potential to be developed as a treatment approach for PD.
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Quitosano/química , Agonistas de Dopamina/administración & dosificación , Portadores de Fármacos/química , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Tetrahidronaftalenos/administración & dosificación , Tiofenos/administración & dosificación , Administración Intranasal , Animales , Barrera Hematoencefálica/citología , Barrera Hematoencefálica/metabolismo , Línea Celular Tumoral , Quitosano/toxicidad , Modelos Animales de Enfermedad , Agonistas de Dopamina/farmacocinética , Femenino , Haloperidol/toxicidad , Humanos , Masculino , Nanopartículas/química , Nanopartículas/toxicidad , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Oxidopamina/toxicidad , Enfermedad de Parkinson Secundaria/inducido químicamente , Tamaño de la Partícula , Ratas , Tetrahidronaftalenos/farmacocinética , Tiofenos/farmacocinética , Pruebas de Toxicidad Aguda , alfa-Sinucleína/metabolismoRESUMEN
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.
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Agonistas de Dopamina/administración & dosificación , Sistemas de Liberación de Medicamentos , Polímeros/química , Tetrahidronaftalenos/administración & dosificación , Tiofenos/administración & dosificación , Administración Intranasal , Animales , Encéfalo/metabolismo , Agonistas de Dopamina/farmacocinética , Portadores de Fármacos/química , Femenino , Hidrogeles , Masculino , Micelas , Tamaño de la Partícula , Conejos , Ratas , Ratas Sprague-Dawley , Solubilidad , Temperatura , Tetrahidronaftalenos/farmacocinética , Tiofenos/farmacocinéticaRESUMEN
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 12â¯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 14â¯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.
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Cardiotónicos/farmacocinética , Agonistas de Dopamina/farmacocinética , Microesferas , Isquemia Miocárdica/tratamiento farmacológico , Tetrahidronaftalenos/farmacocinética , Tiofenos/farmacocinética , Animales , Cardiotónicos/administración & dosificación , Cardiotónicos/uso terapéutico , Clorpromazina/antagonistas & inhibidores , Forma MB de la Creatina-Quinasa/efectos de los fármacos , Forma MB de la Creatina-Quinasa/metabolismo , Agonistas de Dopamina/administración & dosificación , Agonistas de Dopamina/uso terapéutico , Isoproterenol/farmacología , Masculino , Ratones , Modelos Animales , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Enfermedad de Parkinson/tratamiento farmacológico , Tetrahidronaftalenos/administración & dosificación , Tetrahidronaftalenos/uso terapéutico , Tiofenos/administración & dosificación , Tiofenos/uso terapéutico , Troponina I/efectos de los fármacos , Troponina I/metabolismoRESUMEN
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.
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Benzoatos/uso terapéutico , Decitabina/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Piridinas/farmacología , Sulfonamidas/farmacología , Tetrahidronaftalenos/uso terapéutico , Vorinostat/farmacología , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Benzoatos/administración & dosificación , Benzoatos/farmacocinética , Línea Celular Tumoral , Decitabina/administración & dosificación , Sinergismo Farmacológico , Quimioterapia Combinada , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Masculino , Piridinas/administración & dosificación , Receptores de Ácido Retinoico/genética , Receptores de Ácido Retinoico/metabolismo , Sulfonamidas/administración & dosificación , Tetrahidronaftalenos/administración & dosificación , Tetrahidronaftalenos/farmacocinética , Vorinostat/administración & dosificaciónRESUMEN
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.