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1.
Pharmacol Res Perspect ; 8(1): e00563, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-32030892

RESUMEN

SARM-2f a selective androgen receptor (AR) modulator, increases skeletal muscle mass and locomotor activity in rats. This study aimed to clarify its pharmacological effects in monkeys. In reporter assays, the EC50 values of SARM-2f for rat, monkey, and human AR were 2.5, 3, and 3.6 nmol/L, respectively; those of testosterone were 12, 3.2, and 11 nmol/L, respectively. A single oral administration (10 mg/kg SARM-2f) produced a maximal plasma concentration of 3011 ng/mL, with an area under the 24 hours concentration-time curve of 8152 ng·h/mL in monkeys. Body weight (BW), lean body mass (LBM), and plasma levels of total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, lipoprotein (a), alanine aminotransferase, and asparagine aminotransferase were measured after 4 weeks of treatment with SARM-2f (1, 3, and 10 mg/kg/day, QD, p.o.) or testosterone enanthate (TE; 2 mg/kg/2 weeks, s.c.) in monkeys. BW and LBM were significantly increased by 12% each by SARM-2f at 10 mg/kg, and by 5% and 8%, respectively, by TE, but these effects were not statistically significant. Plasma levels of all lipids were either decreased or showed a tendency to be decreased by SARM-2f. TE decreased the triglyceride level and increased the low-density lipoprotein cholesterol level. Liver marker levels were not changed by either SARM-2f or TE. Our data demonstrated that SARM-2f exerted anabolic effects and produced a lipid profile that differed from that produced by testosterone in monkeys, suggesting that SARM-2f might be useful for diseases such as sarcopenia.


Asunto(s)
Metabolismo de los Lípidos/efectos de los fármacos , Pirrolidinonas/administración & dosificación , Receptores Androgénicos/metabolismo , Administración Oral , Animales , Índice de Masa Corporal , Peso Corporal/efectos de los fármacos , Células COS , Chlorocebus aethiops , Femenino , Humanos , Macaca fascicularis , Masculino , Pirrolidinonas/farmacocinética , Ratas
2.
J Pharmacol Exp Ther ; 372(1): 1-10, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31619465

RESUMEN

Padsevonil is an antiepileptic drug (AED) candidate synthesized in a medicinal chemistry program initiated to rationally design compounds with high affinity for synaptic vesicle 2 (SV2) proteins and low-to-moderate affinity for the benzodiazepine binding site on GABAA receptors. The pharmacological profile of padsevonil was characterized in binding and electrophysiological experiments. At recombinant SV2 proteins, padsevonil's affinity for SV2A was greater than that of levetiracetam and brivaracetam (pKi 8.5, 5.2, and 6.6, respectively). Unlike the latter AEDs, both selective SV2A ligands, padsevonil also displayed high affinity for the SV2B and SV2C isoforms (pKi 7.9 and 8.5, respectively). Padsevonil's interaction with SV2A differed from that of levetiracetam and brivaracetam; it exhibited slower binding kinetics: dissociation t 1/2 30 minutes from the human protein at 37°C compared with <0.5 minute for levetiracetam and brivaracetam. In addition, its binding was not potentiated by the allosteric modulator UCB1244283. At recombinant GABAA receptors, padsevonil displayed low to moderate affinity (pIC50≤6.1) for the benzodiazepine site, and in electrophysiological studies, its relative efficacy compared with zolpidem (full-agonist reference drug) was 40%, indicating partial agonist properties. In in vivo (mice) receptor occupancy studies, padsevonil exhibited SV2A occupancy at low ED50 (0.2 mg/kg) and benzodiazepine site occupancy at higher doses (ED50 36 mg/kg), supporting in vitro results. Padsevonil's selectivity for its intended targets was confirmed in profiling studies, where it lacked significant effects on a wide variety of ion channels, receptors, transporters, and enzymes. Padsevonil is a first-in-class AED candidate with a unique target profile allowing for presynaptic and postsynaptic activity. SIGNIFICANCE STATEMENT: Padsevonil is an antiepileptic drug candidate developed as a single molecular entity interacting with both presynaptic and postsynaptic targets. Results of in vitro and in vivo radioligand binding assays confirmed this target profile: padsevonil displayed nanomolar affinity for the three synaptic vesicle 2 protein isoforms (SV2A, B, and C) and micromolar affinity for the benzodiazepine binding site on GABAA receptors. Furthermore, padsevonil showed greater affinity for and slower binding kinetics at SV2A than the selective SV2A ligands, levetiracetam, and brivaracetam.


Asunto(s)
Anticonvulsivantes/farmacocinética , Agonistas del GABA/farmacocinética , Imidazoles/farmacocinética , Glicoproteínas de Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Pirrolidinonas/farmacocinética , Receptores de GABA-A/metabolismo , Tiadiazoles/farmacocinética , Animales , Anticonvulsivantes/química , Células COS , Chlorocebus aethiops , Agonistas del GABA/química , Células HEK293 , Humanos , Imidazoles/química , Cinética , Masculino , Ratones , Ratones Endogámicos C57BL , Unión Proteica , Pirrolidinonas/química , Ratas , Ratas Sprague-Dawley , Tiadiazoles/química
3.
Expert Opin Pharmacother ; 20(14): 1755-1765, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31264486

RESUMEN

Introduction: Antiseizure drugs (ASDs) play a central and crucial role in the treatment of epilepsy patients, as the majority require anticonvulsant treatment for an extended period of time. Since up to 30% of patients are refractory to medical treatment, new therapeutic options are necessary. Perampanel (PER) and brivaracetam (BRV) are the latest approved ASDs that may be considered in a variety of epilepsy syndromes. PER has a distinct and selective mode of action on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and is licensed for use in focal and generalized epilepsies. BRV is a derivative of levetiracetam but exhibits a 20-fold higher affinity and a faster brain entry time as a synaptic vesicle glycoprotein 2A (SV2A) ligand. Areas covered: This article reviews the advances in the epileptic treatment and provides a comparison of PER and BRV. Both drugs have shown comparable results in randomized controlled trials, and both are well tolerated. Expert opinion: PER and BRV have the potential to perform as important, broad-spectrum ASDs with significant market shares. BRV's intravenous formulation and fast penetration into the brain and PER's unique mode of action will result in the more frequent use of both drugs in status epilepticus.


Asunto(s)
Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Piridonas/uso terapéutico , Pirrolidinonas/uso terapéutico , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/farmacocinética , Ensayos Clínicos como Asunto , Epilepsia/patología , Semivida , Humanos , Piridonas/efectos adversos , Piridonas/farmacocinética , Pirrolidinonas/efectos adversos , Pirrolidinonas/farmacocinética , Receptores AMPA/química , Receptores AMPA/metabolismo , Estado Epiléptico/tratamiento farmacológico , Resultado del Tratamiento
4.
PLoS One ; 14(4): e0215612, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31002681

RESUMEN

Understanding the effects of cognitive enhancing drugs is an important area of research. Much of the research, however, has focused on restoring memory following some sort of disruption to the brain, such as damage or injections of scopolamine. Aniracetam is a positive AMPA-receptor modulator that has shown promise for improving memory under conditions when the brain has been damaged, but its effectiveness in improving memory in neurologically healthy subjects is unclear. The aim of the present study was to examine the effects of aniracetam (100mg/kg and 200 mg/kg) on short-term memory in "neurologically healthy" pigeons. Pigeons were administered aniracetam via either intramuscular injection or orally, either 30 or 60 minutes prior to testing on a delayed matching-to-sample task. Aniracetam had no effect on the pigeons' memory performance, nor did it affect response latency. These findings add to the growing evidence that, while effective at improving memory function in models of impaired memory, aniracetam has no effect in improving memory in healthy organisms.


Asunto(s)
Encéfalo/efectos de los fármacos , Columbidae/fisiología , Memoria a Corto Plazo/efectos de los fármacos , Pirrolidinonas/farmacología , Administración Oral , Animales , Encéfalo/fisiología , Cognición/efectos de los fármacos , Cognición/fisiología , Inyecciones Intramusculares , Memoria a Corto Plazo/fisiología , Nootrópicos/administración & dosificación , Nootrópicos/farmacocinética , Nootrópicos/farmacología , Desempeño Psicomotor/efectos de los fármacos , Pirrolidinonas/administración & dosificación , Pirrolidinonas/farmacocinética , Factores de Tiempo
5.
Epilepsia ; 60(5): 958-967, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30924924

RESUMEN

OBJECTIVE: Brivaracetam (BRV) and levetiracetam (LEV) are antiepileptic drugs that bind synaptic vesicle glycoprotein 2A (SV2A). In vitro and in vivo animal studies suggest faster brain penetration and SV2A occupancy (SO) after dosing with BRV than LEV. We evaluated human brain penetration and SO time course of BRV and LEV at therapeutically relevant doses using the SV2A positron emission tomography (PET) tracer 11 C-UCB-J (EP0074; NCT02602860). METHODS: Healthy volunteers were recruited into three cohorts. Cohort 1 (n = 4) was examined with PET at baseline and during displacement after intravenous BRV (100 mg) or LEV (1500 mg). Cohort 2 (n = 5) was studied during displacement and 4 hours postdose (BRV 50-200 mg or LEV 1500 mg). Cohort 3 (n = 4) was examined at baseline and steady state after 4 days of twice-daily oral dosing of BRV (50-100 mg) and 4 hours postdose of LEV (250-600 mg). Half-time of 11 C-UCB-J signal change was computed from displacement measurements. Half-saturation concentrations (IC50 ) were determined from calculated SO. RESULTS: Observed tracer displacement half-times were 18 ± 6 minutes for BRV (100 mg, n = 4), 9.7 and 10.1 minutes for BRV (200 mg, n = 2), and 28 ± 6 minutes for LEV (1500 mg, n = 6). Estimated corrected half-times were 8 minutes shorter. The SO was 66%-70% for 100 mg intravenous BRV, 84%-85% for 200 mg intravenous BRV, and 78%-84% for intravenous 1500 mg LEV. The IC50 of BRV (0.46 µg/mL) was 8.7-fold lower than of LEV (4.02 µg/mL). BRV data fitted a single SO versus plasma concentration relationship. Steady state SO for 100 mg BRV was 86%-87% (peak) and 76%-82% (trough). SIGNIFICANCE: BRV achieves high SO more rapidly than LEV when intravenously administered at therapeutic doses. Thus, BRV may have utility in treating acute seizures; further clinical studies are needed for confirmation.


Asunto(s)
Anticonvulsivantes/farmacocinética , Levetiracetam/farmacocinética , Glicoproteínas de Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neuroimagen/métodos , Tomografía de Emisión de Positrones , Pirrolidinonas/farmacocinética , Administración Oral , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/sangre , Anticonvulsivantes/metabolismo , Radioisótopos de Carbono , Femenino , Voluntarios Sanos , Humanos , Concentración 50 Inhibidora , Inyecciones Intravenosas , Levetiracetam/administración & dosificación , Levetiracetam/sangre , Levetiracetam/metabolismo , Imagen por Resonancia Magnética , Masculino , Unión Proteica , Pirrolidinonas/administración & dosificación , Pirrolidinonas/sangre , Pirrolidinonas/metabolismo
6.
Mol Imaging Biol ; 21(5): 888-897, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-30460626

RESUMEN

PURPOSE: [18F]UCB-H is a specific positron emission tomography (PET) biomarker for the Synaptic Vesicle protein 2A (SV2A), the binding site of the antiepileptic drug levetiracetam. With a view to optimising acquisition time and simplifying data analysis with this radiotracer, we compared two parameters: the distribution volume (Vt) obtained from Logan graphical analysis using a Population-Based Input Function, and the Standardised Uptake Value (SUV). PROCEDURES: Twelve Sprague Dawley male rats, pre-treated with three different doses of levetiracetam were employed to develop the methodology. Three additional kainic acid (KA) treated rats (temporal lobe epilepsy model) were also used to test the procedure. Image analyses focused on: (i) length of the dynamic acquisition (90 versus 60 min); (ii) correlations between Vt and SUV over 20-min consecutive time-frames; (iii) and (iv) evaluation of differences between groups using the Vt and the SUV; and (v) preliminary evaluation of the methodology in the KA epilepsy model. RESULTS: A large correlation between the Vt issued from 60 to 90-min acquisitions was observed. Further analyses highlighted a large correlation (r > 0.8) between the Vt and the SUV. Equivalent differences between groups were detected for both parameters, especially in the 20-40 and 40-60-min time-frames. The same results were also obtained with the epilepsy model. CONCLUSIONS: Our results enable the acquisition setting to be changed from a 90-min dynamic to a 20-min static PET acquisition. According to a better image quality, the 20-40-min time-frame appears optimal. Due to its equivalence to the Vt, the SUV parameter can be considered in order to quantify [18F]UCB-H uptake in the rat brain. This work, therefore, establishes a starting point for the simplification of SV2A in vivo quantification with [18F]UCB-H, and represents a step forward to the clinical application of this PET radiotracer.


Asunto(s)
Encéfalo/metabolismo , Piridinas/farmacocinética , Pirrolidinonas/farmacocinética , Animales , Encéfalo/diagnóstico por imagen , Cinética , Tomografía de Emisión de Positrones , Ratas Sprague-Dawley
7.
Molecules ; 24(1)2018 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-30577480

RESUMEN

ZL-004, a promising small molecule that increases white blood cell counts, was developed for extended-release nanosuspensions to improve low solubility and compliance of patients. In vivo pharmacokinetic studies of nanosuspensions with different particle sizes and administration volumes were conducted. Unexpectedly, Cmax of NS-PC-L (1156 nm) was 1.3 fold higher than NS-PB-L (836 nm), and area under plasma concentration-time curve (AUC) was similar. It suggested that in vivo behavior of nanosuspensions was influenced significantly by the original dissolved drug, which did not only rely on the particle size but also the amount of the free stabilizers. In addition, smaller administration volume (0.1 mL) achieved significantly lower Cmax and AUC than the higher volume (0.5 mL), due to the reduced amount of dissolved drug. DSC and XPRD demonstrated that the crystal forms of nanosuspensions prepared by the precipitation method and high-pressure homogenization were similar; therefore, in vivo behaviors did not show significant differences. An additional 0.15% PEG 4000 enhanced the redispersity and maintained the particle size for 3 months. Finally, a nanosuspensions with the desired initial release was achieved, which lasted approximately 32 days steadily after a single dose. AUC and t1/2 were 161.2 fold and 22.9 fold higher than oral administration.


Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Pirrolidinonas/química , Pirrolidinonas/farmacocinética , Suspensiones/química , Liberación de Fármacos , Tamaño de la Partícula , Solubilidad
8.
Bioorg Med Chem Lett ; 28(20): 3404-3408, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-30217415

RESUMEN

Small molecule inhibitors of the p53-MDM2 protein complex are under intense investigation in clinical trials as anti-cancer agents, including our first generation inhibitor NVP-CGM097. We recently described the rational design of a novel pyrazolopyrrolidinone core as a new lead structure and now we report on the synthesis and optimization of this to provide a highly potent lead compound. This new compound displayed excellent oral efficacy in our preclinical mechanistic in vivo model and marked a significant milestone towards the identification of our second generation clinical candidate NVP-HDM201.


Asunto(s)
Antineoplásicos/farmacología , Multimerización de Proteína/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Pirazoles/farmacología , Pirrolidinonas/farmacología , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Perros , Haplorrinos , Humanos , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/farmacocinética , Pirrolidinonas/síntesis química , Pirrolidinonas/química , Pirrolidinonas/farmacocinética , Ratas Sprague-Dawley , Estereoisomerismo
9.
Cancer Chemother Pharmacol ; 82(4): 723-732, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30128950

RESUMEN

PURPOSE: Tyrosine kinase inhibitors (TKI) that target MET signaling have shown promise in various types of cancer, including lung cancer. Combination strategies have been proposed and developed to increase their therapeutic index. Based on preclinical synergy between inhibition of MET and topoisomerase I, a phase I study was designed to explore the combination of topotecan with the MET TKI tivantinib. METHODS: Eligible patients with advanced solid malignancies for which there was no known effective treatment received topotecan at doses of 1.0-1.5 mg/m2/day for five consecutive days in 21-day cycles with continuous, oral tivantinib given at escalating doses of 120-360 mg orally twice daily. Pharmacokinetic analyses of tivantinib were included. Circulating tumor cells (CTC) were collected serially to identify peripheral changes in MET phosphorylation. RESULTS: The trial included 18 patients, 17 of whom received treatment. At the planned doses, the combination of topotecan and tivantinib was not tolerable due to thrombocytopenia and neutropenia. The addition of G-CSF to attenuate neutropenia did not improve tolerability. Greater tivantinib exposure, assessed through pharmacokinetic analysis, was associated with greater toxicity. No responses were seen. MET phosphorylation was feasible in CTC, but no changes were seen with therapy. CONCLUSIONS: The combination of topotecan and oral tivantinib was not tolerable in this patient population.


Asunto(s)
Neoplasias/tratamiento farmacológico , Neutropenia , Pirrolidinonas , Quinolinas , Trombocitopenia , Topotecan , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Monitoreo de Drogas/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias/clasificación , Neoplasias/metabolismo , Neoplasias/patología , Neutropenia/inducido químicamente , Neutropenia/diagnóstico , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-met/metabolismo , Pirrolidinonas/administración & dosificación , Pirrolidinonas/efectos adversos , Pirrolidinonas/farmacocinética , Quinolinas/administración & dosificación , Quinolinas/efectos adversos , Quinolinas/farmacocinética , Trombocitopenia/inducido químicamente , Trombocitopenia/diagnóstico , Topotecan/administración & dosificación , Topotecan/efectos adversos , Topotecan/farmacocinética , Insuficiencia del Tratamiento , Resultado del Tratamiento
10.
Rev Neurol ; 66(s02): S21-S25, 2018 06 05.
Artículo en Español | MEDLINE | ID: mdl-29876908

RESUMEN

We report the most notable pharmacokinetic and pharmacodynamic characteristics of the antiepileptic drugs commercialised in the last four years (eslicarbazepine acetate, brivaracetam and perampanel). Their efficacy and safety are analysed in open-label clinical trials, which are the ones that reproduce their use in everyday life, without the rigid protocols used in clinical trials.


Asunto(s)
Anticonvulsivantes/farmacología , Dibenzazepinas/farmacología , Piridonas/farmacocinética , Pirrolidinonas/farmacocinética , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapéutico , Dibenzazepinas/farmacocinética , Dibenzazepinas/uso terapéutico , Epilepsia/tratamiento farmacológico , Humanos , Piridonas/farmacología , Piridonas/uso terapéutico , Pirrolidinonas/farmacología , Pirrolidinonas/uso terapéutico
11.
Rev. neurol. (Ed. impr.) ; 66(supl.2): S21-S25, 5 jun., 2018.
Artículo en Español | IBECS | ID: ibc-175386

RESUMEN

Se refieren las características farmacocinéticas y farmacodinámicas más destacadas de los fármacos antiepilépticos comercializados en los cuatro últimos años (acetato de eslicarbacepina, brivaracetam y perampanel). Se analiza su eficacia y tolerabilidad en estudios clínicos abiertos, que son los que reproducen su utilización en la vida diaria, sin los protocolos rígidos de los ensayos clínicos


We report the most notable pharmacokinetic and pharmacodynamic characteristics of the antiepileptic drugs commercialised in the last four years (eslicarbazepine acetate, brivaracetam and perampanel). Their efficacy and safety are analysed in open-label clinical trials, which are the ones that reproduce their use in everyday life, without the rigid protocols used in clinical trials


Asunto(s)
Humanos , Anticonvulsivantes/farmacología , Dibenzazepinas/farmacología , Piridonas/farmacocinética , Pirrolidinonas/farmacocinética , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapéutico , Dibenzazepinas/farmacocinética , Dibenzazepinas/uso terapéutico , Piridonas/farmacología , Piridonas/uso terapéutico , Pirrolidinonas/farmacología , Pirrolidinonas/uso terapéutico
12.
PLoS One ; 12(12): e0189480, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29216311

RESUMEN

Sarcopenia and cachexia present characteristic features of a decrease in skeletal muscle mass and strength, anorexia, and lack of motivation. Treatments for these diseases have not yet been established, although selective androgen receptor modulators (SARMs) are considered as therapeutic targets. We previously reported that a novel SARM compound, SARM-2f, exhibits anabolic effect on muscles, with less stimulatory effect on prostate weight compared with testosterone, in rat Hershberger assays and cancer cachexia models. In this study, we studied the mechanism of action for SARM-2f selectivity and also assessed whether the muscle increase by this compound might lead to improvement of muscle function and physical activity. First, we examined the tissue distribution of SARM-2f. Tissue concentration was 1.2-, 1.6-, and 1.9-fold as high as the plasma concentration in the levator ani muscle, brain, and prostate, respectively. This result showed that the tissue-selective pharmacological effect did not depend on SARM-2f concentration in the tissues. The ability of SARM-2f to influence androgen receptor (AR)-mediated transcriptional activation was examined by reporter assays using human normal prostate epithelial cells (PrEC) and skeletal muscle cells (SKMC). SARM-2f exerted higher activity against AR in SKMC than in PrEC. Mammalian two hybrid assays showed different co-factor recruitment patterns between SARM-2f and dihydrotestosterone. Next, we studied the effect of SARM-2f on motivation and physical functions such as sexual behavior and motor activities in castrated rat or mouse models. SARM-2f restored the sexual behavior that was lost by castration in male rats. SARM-2f also increased voluntary running distance and locomotor activities. These results suggest that tissue-specific AR regulation by SARM-2f, but not tissue distribution, might account for its tissue specific androgenic effect, and that the muscle mass increase by SARM-2f leads to improvement of physical function. Together, these findings suggest that SARM-2f might represent an effective treatment for sarcopenia and cachexia.


Asunto(s)
Actividad Motora , Orquiectomía , Pirrolidinonas/farmacología , Receptores Androgénicos/efectos de los fármacos , Conducta Sexual Animal , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Pirrolidinonas/farmacocinética , Ratas , Ratas Sprague-Dawley , Receptores Androgénicos/fisiología , Distribución Tisular , Transcripción Genética
13.
Epilepsy Res ; 137: 95-100, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-28982069

RESUMEN

Brivaracetam is a selective, high-affinity ligand for synaptic vesicle protein 2A, recently approved as adjunctive therapy in the treatment of focal (partial-onset) seizures in patients 16 years of age and older with epilepsy. The goal of the present analysis was to determine if the dose-response of brivaracetam as monotherapy would fall within the range associated with brivaracetam efficacy as adjunctive therapy. An existing brivaracetam population pharmacokinetic model consisting of first-order absorption, single compartment distribution, and first-order elimination components was extended by estimating the clearance changes due to co-administration of 12 widely prescribed AEDs. Data for the population pharmacokinetic analysis originated from three Phase III add-on trials and two terminated Phase III monotherapy trials. An existing population model of daily seizure rate versus brivaracetam daily average concentration was applied to the data from the three add-on trials. Simulations allowed the assessment of the combined impact of covariate effects on both the pharmacokinetics and the pharmacodynamics of brivaracetam, and indicated that in the absence of other AEDs, only marginal changes in the overall dose-response relationship would be expected. This suggests that brivaracetam can be used as monotherapy without dose modifications.


Asunto(s)
Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapéutico , Pirrolidinonas/farmacocinética , Pirrolidinonas/uso terapéutico , Convulsiones/sangre , Convulsiones/tratamiento farmacológico , Adolescente , Adulto , Anciano , Simulación por Computador , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Humanos , Persona de Mediana Edad , Modelos Biológicos , Adulto Joven
14.
J Pharmacol Exp Ther ; 363(3): 377-393, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28954811

RESUMEN

(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169) and the phosphate prodrug 4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl dihydrogen phosphate (BMS-986163) were identified from a drug discovery effort focused on the development of novel, intravenous glutamate N-methyl-d-aspartate 2B receptor (GluN2B) negative allosteric modulators (NAMs) for treatment-resistant depression (TRD). BMS-986169 showed high binding affinity for the GluN2B subunit allosteric modulatory site (Ki = 4.03-6.3 nM) and selectively inhibited GluN2B receptor function in Xenopus oocytes expressing human N-methyl-d-aspartate receptor subtypes (IC50 = 24.1 nM). BMS-986169 weakly inhibited human ether-a-go-go-related gene channel activity (IC50 = 28.4 µM) and had negligible activity in an assay panel containing 40 additional pharmacological targets. Intravenous administration of BMS-986169 or BMS-986163 dose-dependently increased GluN2B receptor occupancy and inhibited in vivo [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ([3H]MK-801) binding, confirming target engagement and effective cleavage of the prodrug. BMS-986169 reduced immobility in the mouse forced swim test, an effect similar to intravenous ketamine treatment. Decreased novelty suppressed feeding latency, and increased ex vivo hippocampal long-term potentiation was also seen 24 hours after acute BMS-986163 or BMS-986169 administration. BMS-986169 did not produce ketamine-like hyperlocomotion or abnormal behaviors in mice or cynomolgus monkeys but did produce a transient working memory impairment in monkeys that was closely related to plasma exposure. Finally, BMS-986163 produced robust changes in the quantitative electroencephalogram power band distribution, a translational measure that can be used to assess pharmacodynamic activity in healthy humans. Due to the poor aqueous solubility of BMS-986169, BMS-986163 was selected as the lead GluN2B NAM candidate for further evaluation as a novel intravenous agent for TRD.


Asunto(s)
Antidepresivos/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Organofosfatos/uso terapéutico , Piperidinas/uso terapéutico , Profármacos/uso terapéutico , Pirrolidinonas/uso terapéutico , Receptores de N-Metil-D-Aspartato/metabolismo , Administración Intravenosa , Regulación Alostérica , Animales , Antidepresivos/efectos adversos , Antidepresivos/farmacocinética , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatología , Ondas Encefálicas/efectos de los fármacos , Trastorno Depresivo Mayor/fisiopatología , Trastorno Depresivo Mayor/psicología , Trastornos Disociativos/inducido químicamente , Macaca fascicularis , Masculino , Memoria a Corto Plazo/efectos de los fármacos , Ratones , Actividad Motora/efectos de los fármacos , Organofosfatos/efectos adversos , Organofosfatos/farmacocinética , Piperidinas/efectos adversos , Piperidinas/farmacocinética , Profármacos/efectos adversos , Profármacos/farmacocinética , Pirrolidinonas/efectos adversos , Pirrolidinonas/farmacocinética , Ensayo de Unión Radioligante , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Xenopus
15.
Expert Opin Drug Discov ; 12(11): 1169-1178, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-28829199

RESUMEN

INTRODUCTION: Brivaracetam (BRV) is a new AED currently licensed for the adjunctive treatment of adult patients with focal epilepsies. It is a ligand of the ubiquitous synaptic vesicle glycoprotein 2A (SV2A). Areas covered: This paper covers the preclinical and subsequent clinical development of BRV focusing on the discovery of the SV2A protein as the main target for levetiracetam (LEV) and the main similarities and differences between LEV and BRV in terms of pharmacodynamic and pharmacokinetic properties. Phase II and Phase III studies are also presented and data from post-marketing phase IV studies are discussed. Expert opinion: The preclinical development of BRV is quite unique and has raised several doubts on current methodologies adopted for AED development, reinforcing the need for new approaches. The preclinical and clinical profile suggest that BRV is potentially an ideal compound in the emergency setting given the rapid onset of action associated with being water soluble and, therefore, available in intravenous formulation. In addition, data from Phase III studies have already suggested that BRV may be effective not only in focal epilepsies but also in generalised syndromes. Further data from special populations such as children and women of child bearing age are urgently needed.


Asunto(s)
Anticonvulsivantes/uso terapéutico , Epilepsias Parciales/tratamiento farmacológico , Pirrolidinonas/uso terapéutico , Adulto , Animales , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/farmacología , Descubrimiento de Drogas/métodos , Epilepsias Parciales/fisiopatología , Humanos , Levetiracetam , Ligandos , Glicoproteínas de Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Piracetam/análogos & derivados , Piracetam/farmacocinética , Piracetam/farmacología , Piracetam/uso terapéutico , Pirrolidinonas/farmacocinética , Pirrolidinonas/farmacología , Solubilidad
16.
J Pharmacol Exp Ther ; 362(3): 413-423, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28642233

RESUMEN

Monoamine oxidase B (MAO-B) has been implicated in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders. Increased MAO-B expression in astroglia has been observed adjacent to amyloid plaques in AD patient brains. This phenomenon is hypothesized to lead to increased production of hydrogen peroxide and reactive oxygen species (ROS), thereby contributing to AD pathology. Therefore, reduction of ROS-induced oxidative stress via inhibition of MAO-B activity may delay the progression of the disease. In the present study we report the pharmacological properties of sembragiline, a novel selective MAO-B inhibitor specifically developed for the treatment of AD, and on its effect on ROS-mediated neuronal injury and astrogliosis in MAO-B transgenic animals. Sembragiline showed potent and long-lasting MAO-B-selective inhibition and did not inhibit MAO-A at doses where full inhibition of MAO-B was observed. Such selectivity should translate into a favorable clinical safety profile. Indeed, sembragiline neither induced the serotonin syndrome when administered together with the serotonin precursor l-5-hydroxytryptophan in combination with antidepressants such as fluoxetine, nor potentiated the pressor effect of tyramine. Additionally, in experiments using a transgenic animal model conditionally overexpressing MAO-B in astroglia, sembragiline protected against neuronal loss and reduced both ROS formation and reactive astrogliosis. Taken together, these findings warrant further investigation of the potential therapeutic benefit of MAO-B inhibitors in patients with AD and other neurologic disorders.


Asunto(s)
Acetamidas/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Monoaminooxidasa/uso terapéutico , Monoaminooxidasa/efectos de los fármacos , Pirrolidinonas/uso terapéutico , 5-Hidroxitriptófano/farmacología , Acetamidas/farmacocinética , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Gliosis/tratamiento farmacológico , Gliosis/patología , Humanos , Hipertensión/inducido químicamente , Hipertensión/prevención & control , Masculino , Monoaminooxidasa/genética , Monoaminooxidasa/metabolismo , Inhibidores de la Monoaminooxidasa/farmacocinética , Actividad Motora/efectos de los fármacos , Neurotransmisores/metabolismo , Pirrolidinonas/farmacocinética , Ratas , Ratas Transgénicas , Especies Reactivas de Oxígeno/metabolismo , Especificidad por Sustrato , Distribución Tisular
17.
Artículo en Inglés | MEDLINE | ID: mdl-28600961

RESUMEN

Brivaracetam (BVR) is a novel antiepileptic drug (AED), approved clinically for the treatment of partial onset seizures in adults and adolescents. It has some abuse potential and assigned to Schedule V category under the Controlled Substance Act by the Drug Enforcement Administration. Being an AED and drug of abuse, a sensitive and robust assay is necessary for determination of BVR in biological fluids. Herein, we report a sensitive and validated UPLC-MS/MS assay for identification and quantification of BVR in plasma samples. The samples were prepared by one step liquid liquid extraction method using tert-Butyl methyl ether as extracting solvent. BVR and internal standard (carbamazepine) were separated on Aquity BEH™ C-18 column and eluted by using gradient mobile phase combination of acetonitrile and 0.1% formic acid in water. The precursor to product ion transition of m/z 213.12→54.95 (qualifier), 213.12→168.10 (quantifier) for BVR, and m/z 237.06→193.25 for IS were used for MRM detection and quantification. The assay was validated according to USFDA and SWGTOX guidelines for method validation and all parameter results were within the acceptable limits. The calibration curves were found to be linear in concentration range of 1.98-2000ng/mL (r2≥0.995) having LOD and LLOQ of 0.80 and 1.98ng/mL, respectively. The assay was successfully employed in BVR pharmacokinetic study in rats and can be suitable for therapeutic drug monitoring, pharmacokinetic study and forensic analysis.


Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Pirrolidinonas/sangre , Pirrolidinonas/farmacocinética , Espectrometría de Masas en Tándem/métodos , Animales , Límite de Detección , Modelos Lineales , Extracción Líquido-Líquido , Masculino , Pirrolidinonas/química , Ratas , Ratas Wistar , Reproducibilidad de los Resultados
18.
Pediatr Blood Cancer ; 64(11)2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28449393

RESUMEN

BACKGROUND: The c-Met receptor tyrosine kinase is dysregulated in many pediatric cancers. Tivantinib is an oral small molecule that inhibits the c-Met receptor tyrosine kinase. A phase 1 and pharmacokinetic (PK) trial evaluating tivantinib was conducted in children with relapsed/refractory solid tumors. METHODS: Oral tivantinib capsules were administered twice daily with food, continuously in 28-day cycles. Dose levels 170, 200, and 240 mg/m2 /dose were evaluated using a rolling-six design (Part A). In Part B, subjects received tivantinib powder sprinkled on food at the recommended phase 2 dose (RP2D) from Part A. PK, CYP2C19 genotyping, and baseline tumor tissue c-Met expression were analyzed. RESULTS: Thirty-six patients were enrolled: 20 in Part A, 6 in a PK expansion cohort, and 10 in Part B. Fifteen patients had primary central nervous system tumors and 21 had solid tumors. In Part A, there were no dose-limiting toxicities. One grade 4 intracranial hemorrhage occurred in a patient with a progressive brain tumor in the expanded PK cohort (240 mg/m2 ). PK analysis showed marked interpatient variability (20-fold) in the Cmax and AUC0-8h across all dose levels. Sprinkling tivantinib powder over food did not alter exposure. Membranous and total c-Met expression was moderate (2), low (4), or not detected (26). Two patients had stable disease as the best response. CONCLUSIONS: The RP2D of tivantinib given with food in children with refractory solid tumors is 240 mg/m2 /dose. PK of tivantinib in children demonstrated high variability. Objective responses were not observed in this phase 1 trial.


Asunto(s)
Resistencia a Antineoplásicos/efectos de los fármacos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Pirrolidinonas/farmacología , Quinolinas/farmacología , Terapia Recuperativa , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Dosis Máxima Tolerada , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Neoplasias/patología , Proyectos Piloto , Pronóstico , Pirrolidinonas/farmacocinética , Quinolinas/farmacocinética , Distribución Tisular , Adulto Joven
19.
J Control Release ; 255: 54-61, 2017 06 10.
Artículo en Inglés | MEDLINE | ID: mdl-28288895

RESUMEN

Among a broad spectrum of medical treatments, protein therapeutics holds tremendous opportunities for the treatment of metabolic disorders, cancer, autoimmune diseases and etc. Broad adaption of protein therapeutics, however, still remain challenging, not only because of poor protein stability, but they also experience fast clearance after administrated and elicit immune responses, resulting in undesirable biodistribution and short blood residence time. In this study, we demonstrate a novel protein delivery method via encapsulating therapeutic proteins within thin shells of poly(N-vinylpyrrolidone) (PVP), which leads to significantly improved protein stability, reduced macrophage uptake, prolonged circulation time and reduced immunogenicity. Exemplified with urate oxidase (UOx), the enzyme used for hyperuricemia treatment, as-formed UOx nanocapsules, n(UOx), exhibits enhanced stability, more significant therapeutic effects, and a more than 10-fold improvement in circulation time when compared with native UOx. This technology not only demonstrates the use of UOx nanocapsules for hyperuricemia management, but also provides a general approach for a broad spectrum of therapeutic proteins for in vivo applications.


Asunto(s)
Hiperuricemia/tratamiento farmacológico , Nanocápsulas/administración & dosificación , Urato Oxidasa/administración & dosificación , Animales , Línea Celular , Proliferación Celular/efectos de los fármacos , Estabilidad de Medicamentos , Endocitosis , Células HeLa , Humanos , Hiperuricemia/sangre , Hiperuricemia/metabolismo , Inmunoglobulina E/sangre , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Masculino , Ratones Endogámicos BALB C , Nanocápsulas/química , Nanocápsulas/uso terapéutico , Pirrolidinonas/administración & dosificación , Pirrolidinonas/química , Pirrolidinonas/farmacocinética , Pirrolidinonas/uso terapéutico , Distribución Tisular , Tripsina/química , Urato Oxidasa/química , Urato Oxidasa/farmacocinética , Urato Oxidasa/uso terapéutico
20.
Eur J Clin Pharmacol ; 73(6): 727-733, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28280887

RESUMEN

PURPOSE: The aims of the study were to develop a population pharmacokinetic model of orally administered brivaracetam in paediatric patients and to provide dosing suggestions. METHODS: Analysis included 600 brivaracetam plasma concentrations from a phase 2a study (NCT00422422; N01263) in 96 paediatric patients with epilepsy aged 1 month to 16 years, taking one to three concomitant antiepileptic drugs (AEDs). Pharmacokinetic analysis was performed using non-linear mixed effects modelling, and a stepwise covariate search was used to determine factors influencing brivaracetam clearance. Simulations were performed to investigate dosing regimens. RESULTS: The final model consisted of first-order absorption, single compartment distribution and first-order elimination components with allometric scaling of clearance and volume using lean body weight and fixed allometric exponents. Co-administration with phenobarbital or carbamazepine was associated with a 29% (95%CI 17%/39%) and 32% (22%/42%) decrease in exposure, respectively. Co-administration with valproate was associated with an 11% (1%/23%) increase in exposure. Simulations demonstrated that the majority of children were predicted to have an exposure similar to that in adults, using an age-independent dosing regimen of 2.0 mg/kg bid with a maximum of 100 mg bid for body weight >50 kg. CONCLUSIONS: A paediatric dose adaptation of 2.0 mg/kg twice daily with a maximum of 100 mg twice daily for body weight >50 kg is predicted to ensure steady-state plasma concentrations in the same range as in adult patients receiving 100 mg twice daily (highest recommended dose). Data suggest no need to change brivaracetam dosing when used concomitantly with carbamazepine, phenobarbital or valproate.


Asunto(s)
Anticonvulsivantes/administración & dosificación , Epilepsia/tratamiento farmacológico , Modelos Biológicos , Pirrolidinonas/administración & dosificación , Administración Oral , Adolescente , Factores de Edad , Anticonvulsivantes/farmacocinética , Carbamazepina/administración & dosificación , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Femenino , Humanos , Lactante , Masculino , Dinámicas no Lineales , Fenobarbital/administración & dosificación , Pirrolidinonas/farmacocinética , Ácido Valproico/administración & dosificación
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