RESUMEN
Parenteral chemotherapy is usually administered intravenously, although patient preference and health economics suggest the subcutaneous (sc) route could be an attractive alternative. However, due to the low aqueous solubility of hydrophobic drugs and injection volume limitations, the total amount of drug that can be administered in a single sc injection is frequently insufficient. We have developed hyaluronidase coated nanoparticles (NPs) that efficiently encapsulate such drugs, thus addressing both issues and allowing sufficient amounts of hydrophobic drug to be administered and absorbed effectively. CUDC-101, a poorly water-soluble multitargeted anticancer drug that simultaneously inhibits the receptor tyrosine kinases (RTKs) EGFR and HER2, as well as histone deacetylase (HDAC), was encapsulated in polymeric Molecular Envelope Technology (MET) NPs. The role of polymer chemistry, formulation parameters, and coating with hyaluronidase (HYD) on MET-CUDC-101 NP formulations was examined and optimized to yield high drug loading and colloidal stability, and, after freeze-drying, stable storage at room temperature for up to 90 days. The pharmacokinetic studies in healthy rats showed that plasma AUC0-24h after sc administration correlates tightly with formulation physical chemistry, specifically in vitro colloidal stability. Compared to uncoated NPs, the HYD-coating doubled the drug plasma exposure. In a murine A431 xenograft model, the coated HYD-MET-CUDC-101 NPs at a dose equivalent to 90 mg kg-1 CUDC-101 increased the survival time from 15 days (control animals treated with hyaluronidase alone) to 43 days. Polymer MET nanoparticles coated with hyaluronidase enabled the subcutaneous delivery of a hydrophobic drug with favorable therapeutic outcomes.
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Antineoplásicos/administración & dosificación , Carcinoma de Células Escamosas/tratamiento farmacológico , Sistemas de Liberación de Medicamentos/métodos , Inhibidores de Histona Desacetilasas/farmacología , Hialuronoglucosaminidasa/química , Ácidos Hidroxámicos/administración & dosificación , Nanopartículas/química , Polímeros/química , Quinazolinas/administración & dosificación , Animales , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Quitosano/análogos & derivados , Quitosano/química , Portadores de Fármacos/química , Femenino , Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/sangre , Histona Desacetilasas , Histonas/metabolismo , Interacciones Hidrofóbicas e Hidrofílicas , Ácidos Hidroxámicos/sangre , Ácidos Hidroxámicos/farmacocinética , Ratones , Ratones Desnudos , Microscopía Electrónica de Transmisión , Nanopartículas/ultraestructura , Tamaño de la Partícula , Quinazolinas/sangre , Quinazolinas/farmacocinética , Ratas , Solubilidad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Chidamide is a new subtype-selective histone deacetylase inhibitor (HDACi), which has been approved for the treatment of recurrent or refractory peripheral T-cell lymphoma (PTCL) in China. However, there are few studies about the application of chidamide in PTCL with central nervous system (CNS) involvement. It is essential to investigate the penetration of chidamide in the blood brain barrier (BBB). LC-MS methods were established firstly to determine the concentration of chidamide in rat plasma and CSF. Then five rats were anaesthetized and the plasma and CSF samples were collected at the time of 5, 15, 30, 60, 120, 180, 240, 360 and 480â¯min after being administered 1â¯mg/kg chidamide by intravenous injection, respectively. All samples were analyzed with the established LC-MS method by using the precursor/product transitions (m/z) of 391.1/265.1 for chidamide and 441.1/138.2 for internal standard (IS). The PK parameters were calculated after both of the concentrations of chidamide in plasma and CSF were determined. The penetration ratio of chidamide in BBB ranged from 0.19% to 0.67%. Result indicated chidamide could pass through the BBB, enter into the CNS and have the potential to be utilized in PTCL with CNS involvement.
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Aminopiridinas/sangre , Aminopiridinas/líquido cefalorraquídeo , Antineoplásicos/sangre , Antineoplásicos/líquido cefalorraquídeo , Benzamidas/sangre , Benzamidas/líquido cefalorraquídeo , Inhibidores de Histona Desacetilasas/sangre , Inhibidores de Histona Desacetilasas/líquido cefalorraquídeo , Aminopiridinas/farmacocinética , Animales , Antineoplásicos/farmacocinética , Benzamidas/farmacocinética , Inhibidores de Histona Desacetilasas/farmacocinética , Masculino , Ratas Sprague-DawleyRESUMEN
PURPOSE: This was an open label, phase I (3 + 3 design), multi-centre study evaluating panobinostat in pediatric patients with refractory solid tumors. METHODS: Primary endpoints were to establish MTD, define and describe associated toxicities, including dose limiting toxicities (DLT) and to characterize its pharmacokinetics (PK). Secondary endpoints included assessing the anti-tumour activity of panobinostat, and its biologic activity, by measuring acetylation of histones in peripheral blood mononuclear cells. RESULTS: Nine patients were enrolled and treated with intravenous panobinostat at a dosing level of 15 mg/m2 which was tolerated. Six were evaluable for adverse events. Two (33%) patients experienced Grade 3-4 thrombocytopenia, 1 (17%) experienced Grade 3 anemia, and 2 (33%) experienced Grade 3 neutropenia. Grade 4 drug related pain occurred in 2 (33%) of the patients studied. Two (33%) patients experienced a Grade 2 QTcF change (0.478 ± 0.006 ms). One cardiac DLT (T wave changes) was reported. PK values for 15 mg/m2 (n = 9) dosing were: Tmax 0.8 h, Cmax 235.2 ng/mL, AUC0-t 346.8 h ng/mL and t1/2 7.3 h. Panobinostat significantly induced acetylation of histone H3 and H4 at all time points measured when compared to pre-treatment samples (p < 0.05). Pooled quantitative Western blot data confirmed that panobinostat significantly induced acetylation of histone H4 at 6 h (p < 0.01), 24 h (p < 0.01) and 28-70 h (p < 0.01) post dose. CONCLUSION: A significant biological effect of panobinostat, measured by acetylation status of histone H3 and H4, was achieved at a dose of 15 mg/m2. PK data and drug tolerability at 15 mg/m2 was similar to that previously published.
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Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Panobinostat/administración & dosificación , Acetilación , Adolescente , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/sangre , Western Blotting , Neoplasias del Sistema Nervioso Central/sangre , Niño , Preescolar , Citometría de Flujo , Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/efectos adversos , Inhibidores de Histona Desacetilasas/sangre , Histonas/metabolismo , Humanos , Inmunohistoquímica , Masculino , Neoplasias/sangre , Panobinostat/efectos adversos , Panobinostat/sangreRESUMEN
PURPOSE: Belinostat is a second-generation histone deacetylase inhibitor (HDI) predominantly metabolized by UGT1A1-mediated glucuronidation. Two common polymorphisms (UGT1A1*28 and UGT1A1*60) were previously associated with impaired drug clearance and thrombocytopenia risk, likely from increased drug exposure. This latter phenomenon has been observed with other HDIs such as abexinostat, panobinostat, romidepsin, and vorinostat. It was the intention of this brief report to expand a population pharmacokinetic (PPK) model to include a pharmacodynamic (PD) model describing the change in platelet levels in patients with cancer administered belinostat as a 48-h continuous intravenous infusion, along with cisplatin and etoposide. METHODS: The PPK/PD model developed here introduced an additional rate constant to a commonly used mechanistic myelosuppression model to better describe the maturation of megakaryocytes into platelets before degradation and a feedback mechanism. The model employed a proportional error model to describe the observed circulating platelet data. RESULTS: Several covariates were explored, including sex, body weight, UGT1A1 genotype status, liver, and kidney function, but none significantly improved the model. Platelet levels rebounded to baseline within 21 days, before the next cycle of therapy. Simulations predicted that higher belinostat drug exposure does cause lower thrombocyte nadirs compared to lower belinostat levels. However, platelet levels rebound by the start of the next belinostat cycle. CONCLUSIONS: This model suggests a q3week schedule allows for sufficient platelet recovery before the next belinostat infusion is optimal.
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Plaquetas/efectos de los fármacos , Ácidos Hidroxámicos/efectos adversos , Ácidos Hidroxámicos/farmacocinética , Modelos Biológicos , Sulfonamidas/efectos adversos , Sulfonamidas/farmacocinética , Plaquetas/metabolismo , Plaquetas/patología , Ensayos Clínicos Fase I como Asunto , Simulación por Computador , Femenino , Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/efectos adversos , Inhibidores de Histona Desacetilasas/sangre , Inhibidores de Histona Desacetilasas/farmacocinética , Humanos , Ácidos Hidroxámicos/administración & dosificación , Ácidos Hidroxámicos/sangre , Infusiones Intravenosas , Masculino , Sulfonamidas/administración & dosificación , Sulfonamidas/sangreRESUMEN
Alzheimer's disease (AD) is a dreadful neurodegenerative disease that leads to severe impairment of cognitive function, leading to a drastic decline in the quality of life. The primary pathological features of AD include senile plaques (SPs) and intracellular neurofibrillary tangles (NFTs), comprising aggregated amyloid ß (Aß) and hyperphosphorylated tau protein, respectively, in the hippocampus of AD patients. Histone deacetylase 6 (HDAC6) is a key enzyme in this neurodegenerative disease, in particular, as it relates to tau hyperphosphorylation. This study aimed to investigate the protective effects and mechanism of the novel HDAC6 inhibitor, MPT0G211, using an AD model. Our results indicated that MPT0G211 significantly reduced tau phosphorylation and aggregation, the processes highly correlated with the formation of NFTs. This HDAC6 inhibitory activity resulted in an increase in acetylated Hsp90, which decreased Hsp90 and HDAC6 binding, causing ubiquitination of phosphorylated tau proteins. In addition, a significant increase of phospho-glycogen synthase kinase-3ß (phospho-GSK3ß) on Ser9 (the inactive form) through Akt phosphorylation was associated with the inhibition of phospho-tau Ser396 in response to MPT0G211 treatment. In AD in vivo models, MPT0G211 appeared to ameliorate learning and memory impairment in animals. Furthermore, MPT0G211 treatment reduced the amount of phosphorylated tau in the hippocampal CA1 region. In summary, MPT0G211 treatment appears to be a promising strategy for improving the AD phenotypes, including tau hyperphosphorylation and aggregation, neurodegeneration, and learning and memory impairment, making it a valuable agent for further investigation.
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Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Benzamidas/farmacología , Benzamidas/uso terapéutico , Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/metabolismo , Inhibidores de Histona Desacetilasas/uso terapéutico , Quinolinas/farmacología , Quinolinas/uso terapéutico , Proteínas tau/metabolismo , Enfermedad de Alzheimer/complicaciones , Animales , Apoptosis/efectos de los fármacos , Benzamidas/sangre , Benzamidas/química , Línea Celular Tumoral , Trastornos del Conocimiento/complicaciones , Modelos Animales de Enfermedad , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Inhibidores de Histona Desacetilasas/sangre , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacología , Trastornos de la Memoria/complicaciones , Trastornos de la Memoria/tratamiento farmacológico , Modelos Biológicos , Fármacos Neuroprotectores/farmacología , Fosforilación/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/metabolismo , Agregado de Proteínas , Proteolisis/efectos de los fármacos , Quinolinas/sangre , Quinolinas/química , Ratas Sprague-Dawley , Ubiquitinación/efectos de los fármacosRESUMEN
AIM/HYPOTHESIS: Combination therapy targeting the major actors involved in the immune-mediated destruction of pancreatic beta cells appears to be an indispensable approach to treat type 1 diabetes effectively. We hypothesised that the combination of an orally active pan-histone deacetylase inhibitor (HDACi: givinostat) with subtherapeutic doses of CD3 antibodies may provide ideal synergy to treat ongoing autoimmunity. METHODS: NOD mice transgenic for the human CD3ε (also known as CD3E) chain (NOD-huCD3ε) were treated for recent-onset diabetes with oral givinostat, subtherapeutic doses of humanised CD3 antibodies (otelixizumab, 50 µg/day, 5 days, i.v.) or a combination of both drugs. Disease remission, metabolic profiles and autoreactive T cell responses were analysed in treated mice. RESULTS: We demonstrated that givinostat synergised with otelixizumab to induce durable remission of diabetes in 80% of recently diabetic NOD-huCD3ε mice. Remission was obtained in only 47% of mice treated with otelixizumab alone. Oral givinostat monotherapy did not reverse established diabetes but reduced the in situ production of inflammatory cytokines (IL-1ß, IL-6, TNF-α). Importantly, the otelixizumab + givinostat combination strongly improved the metabolic status of NOD-huCD3ε mice; the mice recovered the capacity to appropriately produce insulin, control hyperglycaemia and sustain glucose tolerance. Finally, diabetes remission induced by the combination therapy was associated with a significant reduction of insulitis and autoantigen-specific CD8+ T cell responses. CONCLUSIONS/INTERPRETATION: HDACi and low-dose CD3 antibodies synergised to abrogate in situ inflammation and thereby improved pancreatic beta cell survival and metabolic function leading to long-lasting diabetes remission. These results support the therapeutic potential of protocols combining these two drugs, both in clinical development, to restore self-tolerance and insulin independence in type 1 diabetes.
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Diabetes Mellitus Tipo 1/tratamiento farmacológico , Inhibidores de Histona Desacetilasas/uso terapéutico , Inmunoterapia/métodos , Células Secretoras de Insulina/metabolismo , Linfocitos T/fisiología , Administración Oral , Animales , Anticuerpos Monoclonales Humanizados/uso terapéutico , Células Cultivadas , Diabetes Mellitus Tipo 1/metabolismo , Femenino , Citometría de Flujo , Inhibidores de Histona Desacetilasas/sangre , Células Secretoras de Insulina/efectos de los fármacos , Interferón gamma/sangre , Interleucina-10/sangre , Interleucina-1beta/sangre , Interleucina-6/sangre , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Purpose This phase I trial evaluated epigenetic modulation of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor by using a histone deacetylase abexinostat in combination with pazopanib to enhance response and reverse resistance. Patients and Methods Pazopanib was administered once a day on days 1 to 28 and abexinostat was administered orally twice a day on days 1 to 5, 8 to 12, and 15 to 19 (schedule A) or on days 1 to 4, 8 to 11, and 15 to 18 (schedule B). Dose escalation (3 + 3 design) in all solid tumors was followed by dose expansion in renal cell carcinoma (RCC). Results Fifty-one patients with RCC (N = 22) were enrolled, including 30 (59%) with one or more lines of prior VEGF-targeting therapy. Five dose-limiting toxicities, including fatigue (n = 2), thrombocytopenia (n = 2), and elevated AST/ALT (n = 1), were observed with schedule A; one dose-limiting toxicity was observed (elevated AST/ALT) was observed with schedule B. Grade ≥ 3 related adverse events included fatigue (16%), thrombocytopenia (16%), and neutropenia (10%). The recommended phase II dose was established as abexinostat 45 mg/m2 twice a day administered per schedule B plus pazopanib 800 mg/d. Objective response rate was 21% overall and 27% in the RCC subset. Median duration of response was 9.1 months (1.2 to > 49 months). Eight patients (16%) had durable control of disease for > 12 months. Durable tumor regressions were observed in seven (70%) of 10 patients with pazopanib-refractory disease, including one patients with RCC with ongoing response > 3.5 years. Peripheral blood histone acetylation and HDAC2 gene expression were associated with durable response to treatment. Conclusion Abexinostat is well tolerated in combination with pazopanib, allowing prolonged exposure and promising durable responses in pazopanib- and other VEGF inhibitor-refractory tumors, which supports epigenetically mediated reversal of treatment resistance.
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Inhibidores de la Angiogénesis/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Renales/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Renales/tratamiento farmacológico , Acetilación , Adulto , Anciano , Alanina Transaminasa/sangre , Inhibidores de la Angiogénesis/administración & dosificación , Aspartato Aminotransferasas/sangre , Benzofuranos/administración & dosificación , Benzofuranos/sangre , Benzofuranos/farmacocinética , Carcinoma de Células Renales/genética , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Resistencia a Medicamentos , Epigénesis Genética , Fatiga/inducido químicamente , Femenino , Expresión Génica , Histona Desacetilasa 2/genética , Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/sangre , Inhibidores de Histona Desacetilasas/farmacocinética , Histonas/metabolismo , Humanos , Ácidos Hidroxámicos/administración & dosificación , Ácidos Hidroxámicos/sangre , Ácidos Hidroxámicos/farmacocinética , Indazoles , Neoplasias Renales/genética , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neutropenia/inducido químicamente , Pirimidinas/administración & dosificación , Sulfonamidas/administración & dosificación , Trombocitopenia/inducido químicamente , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular/sangre , Factor A de Crecimiento Endotelial Vascular/genética , Adulto JovenRESUMEN
Histone deacetylase inhibitors (HDAC inhibitors) are used to treat malignancies such as cutaneous T cell lymphoma and peripheral T cell lymphoma. Only four drugs are approved by the US Food and Drug Administration, namely vorinostat, romidepsin, panobinostat and belinostat, while chidamide has been approved in China. There are a number of bioanalytical methods reported for the measurement of HDAC inhibitors in clinical (human plasma and serum) and preclinical (mouse plasma, rat plasma, urine and tissue homogenates, etc.) studies. This review covers various HDAC inhibitors such as vorinostat, romidepsin, panobinostat, belinostat and chidamide. In addition to providing a comprehensive review of the available methods for the above mentioned HDAC inhibitors, it also provides case studies with perspectives for chosen drugs. Based on the review, it is concluded that the published methodologies using either HPLC or LC-MS/MS are well suited for the quantification of HDAC inhibitors in various biological fluids to delineate pharmacokinetic data.
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Cromatografía Líquida de Alta Presión/métodos , Inhibidores de Histona Desacetilasas/farmacocinética , Espectrometría de Masas en Tándem/métodos , Aminopiridinas/sangre , Aminopiridinas/farmacocinética , Aminopiridinas/orina , Animales , Benzamidas/sangre , Benzamidas/farmacocinética , Benzamidas/orina , Depsipéptidos/sangre , Depsipéptidos/farmacocinética , Depsipéptidos/orina , Inhibidores de Histona Desacetilasas/sangre , Inhibidores de Histona Desacetilasas/orina , Humanos , Ácidos Hidroxámicos/sangre , Ácidos Hidroxámicos/farmacocinética , Ácidos Hidroxámicos/orina , Indoles/sangre , Indoles/farmacocinética , Indoles/orina , Neoplasias/tratamiento farmacológico , Panobinostat , Sulfonamidas/sangre , Sulfonamidas/farmacocinética , Sulfonamidas/orina , VorinostatRESUMEN
A sensitive and rapid LC-MS/MS method was developed and validated for the simultaneous quantitation of four HDAC inhibitors, namely belinostat (BST), panobinostat (PST), rocilinostat (RST) and vorinostat (VST), in mouse plasma as per regulatory guidelines. The analytes and internal standard were extracted from 50 µL mouse plasma by protein precipitation, followed by chromatographic separation using an Atlantis C18 column with an isocratic mobile phase comprising 0.1% formic acid-acetonitrile (25:75, v/v) at a flow rate of 0.5 mL/min within 2.5 min. Detection and quantitation were done by multiple reaction monitoring on a triple quadrupole mass spectrometer following the transitions: m/z 319 â 93, 350 â 158, 434 â 274 and 265 â 232 for BST, PST, RST and VST, respectively, in the positive ionization mode. The calibration curves were linear from 2.92 to 2921 ng/mL for BST and PST and from 1.01 to 1008 ng/mL for RST and VST with r2 ≥ 0.99 for all of the analytes. The intra- and inter-batch accuracy and precision (CV) across quality controls varied from 85.5 to 112% and from 2.30 to 12.5, respectively, for all of the analytes. Analytes were found to be stable under different stability conditions. The method was applied to an i.v. pharmacokinetic study in mice.
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Cromatografía Liquida/métodos , Inhibidores de Histona Desacetilasas/sangre , Espectrometría de Masas en Tándem/métodos , Animales , Calibración , Inhibidores de Histona Desacetilasas/farmacocinética , Límite de Detección , Masculino , Ratones , Ratones Endogámicos BALB C , Estándares de Referencia , Reproducibilidad de los ResultadosRESUMEN
Histone deacetylase inhibitors (HDACi) are approved for treating rare cancers and are of interest as potential therapies for neurodegenerative disorders. We evaluated a triple combination formulation (TCF) comprising the pan-HDACi vorinostat, the caging agent 2-hydroxypropyl-ß-cyclodextrin (HPBCD), and polyethylene glycol (PEG) for treating a mouse model (the Npc1(nmf164) mouse) of Niemann-Pick type C (NPC) disease, a difficult-to-treat cerebellar disorder. Vorinostat alone showed activity in cultured primary cells derived from Npc1(nmf164) mice but did not improve animal survival. However, low-dose, once-weekly intraperitoneal injections of the TCF containing vorinostat increased histone acetylation in the mouse brain, preserved neurites and Purkinje cells, delayed symptoms of neurodegeneration, and extended mouse life span from 4 to almost 9 months. We demonstrate that the TCF boosted the ability of HDACi to cross the blood-brain barrier and was not toxic even when used long term. Further, the TCF enabled dose reduction, which has been a major challenge in HDACi therapy. TCF simultaneously treats neurodegenerative and systemic symptoms of Niemann-Pick type C disease in a mouse model.
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Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/uso terapéutico , Enfermedad de Niemann-Pick Tipo C/tratamiento farmacológico , 2-Hidroxipropil-beta-Ciclodextrina , Animales , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Inhibidores de Histona Desacetilasas/sangre , Ácidos Hidroxámicos/administración & dosificación , Ácidos Hidroxámicos/sangre , Ácidos Hidroxámicos/uso terapéutico , Inflamación/sangre , Inflamación/complicaciones , Inflamación/patología , Hígado/efectos de los fármacos , Hígado/patología , Ratones , Mutación/genética , Degeneración Nerviosa/sangre , Degeneración Nerviosa/complicaciones , Degeneración Nerviosa/tratamiento farmacológico , Degeneración Nerviosa/patología , Enfermedad de Niemann-Pick Tipo C/sangre , Enfermedad de Niemann-Pick Tipo C/complicaciones , Enfermedad de Niemann-Pick Tipo C/patología , Polietilenglicoles/química , Células de Purkinje/efectos de los fármacos , Células de Purkinje/metabolismo , Células de Purkinje/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Bazo/efectos de los fármacos , Bazo/patología , Análisis de Supervivencia , Vorinostat , beta-Ciclodextrinas/químicaRESUMEN
Novel selective histone deacetylase 6 (HDAC6) inhibitors using the quinazoline as the cap were designed, synthesized, and evaluated for HDAC enzymatic assays. N-Hydroxy-4-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)butanamide, 23bb, was the most potent selective inhibitor for HDAC6 with an IC50 of 17 nM and showed 25-fold and 200-fold selectivity relative to HDAC1 and HDAC8, respectively. In vitro, 23bb presented low nanomolar antiproliferative effects against panel of cancer cell lines. Western blot analysis further confirmed that 23bb increased acetylation level of α-tubulin in vitro. 23bb has a good pharmacokinetic profile with oral bioavailability of 47.0% in rats. In in vivo efficacy evaluations of colorectal HCT116, acute myelocytic leukemia MV4-11, and B cell lymphoma Romas xenografts, 23bb more effectively inhibited the tumor growth than SAHA even at a 4-fold reduced dose or ACY-1215 at the same dose. Our results indicated that 23bb is a potent oral anticancer candidate for selective HDAC6 inhibitor and deserves further investigation.
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Antineoplásicos/química , Antineoplásicos/uso terapéutico , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/uso terapéutico , Histona Desacetilasas/metabolismo , Neoplasias/tratamiento farmacológico , Quinazolinas/química , Quinazolinas/uso terapéutico , Acetilación/efectos de los fármacos , Animales , Antineoplásicos/sangre , Antineoplásicos/farmacología , Línea Celular Tumoral , Femenino , Histona Desacetilasa 6 , Inhibidores de Histona Desacetilasas/sangre , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Ratones SCID , Simulación del Acoplamiento Molecular , Neoplasias/metabolismo , Neoplasias/patología , Quinazolinas/sangre , Quinazolinas/farmacología , Ratas , Tubulina (Proteína)/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Chidamide (epidaza), a new oral isotype-selective histone deacetylase inhibitor (HDACi), which is just approved in China for the treatment of recurrent or refractory peripheral T-cell lymphoma (PTCL) in December 2014, is the first listed benzamide class of HDACi in the world, and is currently undergoing global clinical trials for solid tumor treatments. Here, we report a sensitive, rapid and robust HPLC-MS/MS method for determination of chidamide in human plasma. Plasma sample was subjected to a simple acetonitrile protein precipitation containing MS-275 used as an internal standard (IS). Chromatography was performed on a Hypersil GOLD C18 analytical column, using a gradient methanol/water mobile phase containing 0.1% formic acid. A tandem mass spectrometer equipped with electrospray ionization source was used as detector and operated in the positive-ion mode. Selected reaction monitoring (SRM) using the precursor/ product transitions (m/z) of 391.1/265.1 for chidamide and 377.1/359.2 for IS were used for quantification, respectively. Good linearity was obtained in the range of 1-1000ng/mL. The method gave R.S.D.% values for precision always lower than 13.8% and R.E.% values for accuracy between -3.7 and 9.1%. In addition, the specificity, recovery, stability and matrix effect were satisfactory too. The method is now being successfully applied to plasma samples as part of an ongoing chidamide phase Ib clinical trial in patients with solid tumors, and had demonstrated consistent AUClast and t1/2 results with the published phase I pharmacokinetic data, which was also analyzed by this method, thus further confirming the reproducibility and accuracy during its clinical application. Considering the excellent performance of this method, it will continue being utilized for future clinical developments of chidamide and for routine monitoring of plasma exposure of chidamide during its clinical therapy.
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Aminopiridinas/sangre , Benzamidas/sangre , Cromatografía Líquida de Alta Presión/métodos , Inhibidores de Histona Desacetilasas/sangre , Espectrometría de Masas en Tándem/métodos , Aminopiridinas/química , Aminopiridinas/farmacocinética , Aminopiridinas/uso terapéutico , Benzamidas/química , Benzamidas/farmacocinética , Benzamidas/uso terapéutico , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacocinética , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Límite de Detección , Modelos Lineales , Neoplasias/tratamiento farmacológico , Reproducibilidad de los ResultadosRESUMEN
IKH12 is a novel histone deacetylase 6 selective inhibitor. A rapid and sensitive liquid chromatography tandem mass spectrometry method was developed and validated for the quantification of IKH12 in rat plasma and tissue with kendine 91 as internal standard (IS). The samples were prepared by liquid-liquid extraction with tert-butyl methyl ether. The chromatographic separation was accomplished by using a Zorbax Extend C18 4.6 × 150 mm, 5 µm column, with a mobile phase consisting of methanol and 0.1% formic acid (75:25 v/v). Multiple reaction monitoring, using electrospray ionization in positive ion mode, was employed to quantitatively detect IKH12 and IS. The monitored transitions were set at m/z 418 â 252 and 444 â 169 for IKH12 and kendine 91, respectively. The calibration curve was linear over the concentration range 2-1000 ng mL(-1) . The intra- and inter-assay precision and accuracy of the quality controls and the limit of quantification were satisfactory in all cases (according to European Medicines Agency guidelines). Stability studies showed that plasma samples were stable in the chromatography rack for 24 h and at -80°C for 2 months and also after three freeze-thaw cycles. This method was successfully applied to a pharmacokinetic study of IKH12 in rat.
Asunto(s)
Antineoplásicos/sangre , Inhibidores de Histona Desacetilasas/sangre , Ácidos Hidroxámicos/sangre , Prolina/análogos & derivados , Espectrometría de Masa por Ionización de Electrospray/métodos , Animales , Cromatografía Líquida de Alta Presión/métodos , Límite de Detección , Extracción Líquido-Líquido/métodos , Masculino , Éteres Metílicos/química , Prolina/sangre , Ratas Wistar , Espectrometría de Masas en Tándem/métodosRESUMEN
PURPOSE: This study assessed the pharmacokinetics and safety of oral panobinostat and its metabolite BJB432 in patients with advanced solid tumors and normal to severely impaired renal function. METHODS: Patients with varying degrees of renal impairment, defined by their 24-h baseline urine creatinine clearance (as normal, mild, moderate or severe), received a single oral dose of 30 mg panobinostat. Serial plasma samples were collected pre-dose and up to 96-h post-dose. Serial urine samples were collected for 24-h post-dose. Following the serial PK sampling, patients received 30 mg oral panobinostat thrice weekly for as long as the patient had benefit. Pharmacokinetic parameters were derived using non-compartmental analysis. RESULTS: Thirty-seven patients were enrolled, and median age was 64 (range 40-81) years. Eleven patients had normal renal function; 10, 10, and 6 patients had mild, moderate, and severe renal impairment, respectively. Geometric means of AUC(0-∞) in the normal, mild, moderate, and severe groups were 224.5, 144.3, 223.1, and 131.7 ng h/mL, respectively. Geometric mean ratio of BJB432 to parent drug plasma AUC(0-∞) was 0.64 in the normal group and increased to 0.81, 1.13, and 1.20 in the mild, moderate, and severe groups, respectively. The fraction excreted as unchanged panobinostat was small (<2 %), with a large variability. The renal clearance of panobinostat and tolerability was similar across all four groups. CONCLUSION: Systemic exposure to panobinostat did not increase with severity of renal impairment, and the drug was tolerated equally; thus, patients with renal impairment do not require starting dose adjustments.
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Antineoplásicos/farmacocinética , Drogas en Investigación/farmacocinética , Inhibidores de Histona Desacetilasas/farmacocinética , Ácidos Hidroxámicos/farmacocinética , Indoles/farmacocinética , Neoplasias/tratamiento farmacológico , Insuficiencia Renal/complicaciones , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/sangre , Antineoplásicos/uso terapéutico , Biotransformación , Monitoreo de Drogas , Drogas en Investigación/efectos adversos , Drogas en Investigación/metabolismo , Drogas en Investigación/uso terapéutico , Semivida , Inhibidores de Histona Desacetilasas/efectos adversos , Inhibidores de Histona Desacetilasas/sangre , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Ácidos Hidroxámicos/efectos adversos , Ácidos Hidroxámicos/sangre , Ácidos Hidroxámicos/metabolismo , Ácidos Hidroxámicos/uso terapéutico , Indoles/efectos adversos , Indoles/sangre , Indoles/metabolismo , Indoles/uso terapéutico , Riñón/efectos de los fármacos , Riñón/fisiopatología , Tasa de Depuración Metabólica , Persona de Mediana Edad , Clasificación del Tumor , Neoplasias/complicaciones , Neoplasias/metabolismo , Neoplasias/fisiopatología , Panobinostat , Pacientes Desistentes del Tratamiento , Insuficiencia Renal/fisiopatología , Índice de Severidad de la EnfermedadRESUMEN
Vorinostat (suberoylanilide hydroxamic acid) is the first approved histone deacetylase (HDAC) inhibitor for the treatment of cutaneous T-cell lymphoma after progressive disease following two systemic therapies. Intracellular access of vorinostat is essential to exert its epigenetic effects. Therefore, we studied the relationship between vorinostat extracellular (plasma) and intracellular (peripheral blood mononuclear cells, PBMCs) concentration and assessed its concentration-effect relationship by HDAC activity testing. Assays were developed and validated for the low nanomolar quantification of vorinostat and two inactive metabolites in human plasma and PBMCs. For the vorinostat extraction from plasma and PBMCs solid-phase extraction and liquid-liquid extraction methods were applied. Extraction recoveries ranged from 88.6% to 114.4% for all analytes and extraction methods. Extracts were chromatographed on a Phenomenex Luna column isocratically (plasma) or by gradient (PBMCs) consisting of acidic ammonium acetate, acetonitrile, and methanol. The analytes were quantified using deuterated internal standards and positive electrospray tandem mass spectrometry (multiple reaction monitoring) with lower limits of quantification of 11.0 ng/mL (plasma) and 0.1 ng/3 × 10(6) cells (PBMCs). The calibrated ranges were linear for vorinostat in plasma 11.0-1100 (11,000) ng/mL (metabolites) and PBMCs 0.1-10.0 ng/3 × 10(6) cells with correlation coefficients >0.99, an overall accuracy varying between -6.7% and +3.8% in plasma, -8.1% and -1.5% in PBMCs, and an overall precision ranging from 3.2% to 6.1% in plasma and 0.8% to 4.0% in PBMCs (SD batch-to-batch). The application to blood samples from healthy volunteers incubated with vorinostat revealed accumulation of vorinostat in PBMCs, effective intracellular HDAC inhibition at therapeutic vorinostat concentrations and a direct vorinostat concentration dependency to HDAC inhibition.
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Inhibidores de Histona Desacetilasas/análisis , Inhibidores de Histona Desacetilasas/sangre , Ácidos Hidroxámicos/análisis , Ácidos Hidroxámicos/sangre , Leucocitos Mononucleares/química , Cromatografía Liquida/métodos , Inhibidores de Histona Desacetilasas/metabolismo , Histona Desacetilasas/metabolismo , Humanos , Ácidos Hidroxámicos/metabolismo , Límite de Detección , Extracción Líquido-Líquido/métodos , Extracción en Fase Sólida/métodos , Espectrometría de Masas en Tándem/métodos , VorinostatRESUMEN
Mocetinostat (MGCD0103) is a benzamide histone deacetylase inhibitor undergoing clinical trials for treatment of various cancers including Hodgkin's lymphoma, follicular lymphoma and acute myelogenous leukemia. A sensitive and selective liquid chromatography mass spectrometry method for determination of MGCD0103 in rat plasma was developed. After addition of midazolam as internal standard (IS), protein precipitation by acetonitrile was used as sample preparation. Chromatographic separation was achieved on a C18 (2.1 mm×50 mm, 3.5 µm) column with acetonitrile-0.1% formic acid in water as mobile phase with gradient elution. An electrospray ionization source was applied and operated in positive ion mode; selective ion monitoring (SIM) mode was used for quantification using target fragment ions m/z 397 for MGCD0103 and m/z 326 for the IS. Calibration plots were linear over the range of 5-5000 ng/mL for MGCD0103 in rat plasma. Mean recoveries of MGCD0103 in rat plasma were in the range of 89.7-96.1%. RSD of intra-day and inter-day precision were both<11%. The accuracy of the method ranged from 96.5% to 109.7%. The matrix effects for MGCD0103 were between 94.5% and 97.4%. The method was successfully applied to pharmacokinetic study of MGCD0103 after oral (15 mg/kg) and intravenous (3 mg/kg) administration in rats. The bioavailability of MGCD0103 was 29.3% in rats.
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Benzamidas/sangre , Benzamidas/farmacocinética , Inhibidores de Histona Desacetilasas/sangre , Inhibidores de Histona Desacetilasas/farmacocinética , Pirimidinas/sangre , Pirimidinas/farmacocinética , Animales , Disponibilidad Biológica , Calibración , Cromatografía Liquida , Masculino , Espectrometría de Masas , Control de Calidad , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: A phase I study to assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and antitumor activity of vorinostat in combination with bortezomib in patients with advanced solid tumors. METHODS: Patients received vorinostat orally once daily on days 1-14 and bortezomib intravenously on days 1, 4, 8 and 11 of a 21-day cycle. Starting dose (level 1) was vorinostat (400 mg) and bortezomib (0.7 mg/m(2)). Bortezomib dosing was increased using a standard phase I dose-escalation schema. PKs were evaluated during cycle 1. RESULTS: Twenty-three patients received 57 cycles of treatment on four dose levels ranging from bortezomib 0.7 mg/m(2) to 1.5 mg/m(2). The MTD was established at vorinostat 400 mg daily and bortezomib 1.3 mg/m(2). DLTs consisted of grade 3 fatigue in three patients (1 mg/m(2),1.3 mg/m(2) and 1.5 mg/m(2)) and grade 3 hyponatremia in one patient (1.5 mg/m(2)). The most common grade 1/2 toxicities included nausea (60.9%), fatigue (34.8%), diaphoresis (34.8%), anorexia (30.4%) and constipation (26.1%). Objective partial responses were observed in one patient with NSCLC and in one patient with treatment-refractory soft tissue sarcoma. Bortezomib did not affect the PKs of vorinostat; however, the Cmax and AUC of the acid metabolite were significantly increased on day 2 compared with day 1. CONCLUSIONS: This combination was generally well-tolerated at doses that achieved clinical benefit. The MTD was established at vorinostat 400 mg daily × 14 days and bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11 of a 21-day cycle.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Ácidos Borónicos/administración & dosificación , Bortezomib , Femenino , Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/sangre , Inhibidores de Histona Desacetilasas/farmacocinética , Humanos , Ácidos Hidroxámicos/administración & dosificación , Ácidos Hidroxámicos/sangre , Ácidos Hidroxámicos/farmacocinética , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/sangre , Pirazinas/administración & dosificación , Vorinostat , Adulto JovenRESUMEN
The fatty acids, n-butyric acid (BA), 4-phenylbutyric acid (PBA) and valproic acid (VPA, 2-propylpentanoic acid) have been used for many years in the treatment of a variety of CNS and peripheral organ diseases including cancer. New information that these drugs alter epigenetic processes through their inhibition of histone deacetylases (HDACs) has renewed interest in their biodistribution and pharmacokinetics and the relationship of these properties to their therapeutic and side effect profiles. In order to determine the pharmacokinetics and biodistribution of these drugs in primates, we synthesized their carbon-11 labeled analogues and performed dynamic positron emission tomography (PET) in six female baboons over 90 min. The carbon-11 labeled carboxylic acids were prepared by using (11)CO2 and the appropriate Grignard reagents. [(11)C]BA was metabolized rapidly (only 20% of the total carbon-11 in plasma was parent compound at 5 min post injection) whereas for VPA and PBA 98% and 85% of the radioactivity were the unmetabolized compound at 30 min after their administration respectively. The brain uptake of all three carboxylic acids was very low (<0.006%ID/cc, BA>VPA>PBA), which is consistent with the need for very high doses for therapeutic efficacy. Most of the radioactivity was excreted through the kidneys and accumulated in the bladder. However, the organ biodistribution between the drugs differed. [(11)C]BA showed relatively high uptake in spleen and pancreas whereas [(11)C]PBA showed high uptake in liver and heart. Notably, [(11)C]VPA showed exceptionally high heart uptake possibly due to its involvement in lipid metabolism. The unique biodistribution of each of these drugs may be of relevance in understanding their therapeutic and side effect profile including their teratogenic effects.
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Inhibidores de Histona Desacetilasas/farmacocinética , Tomografía de Emisión de Positrones , Animales , Proteínas Sanguíneas/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Ácido Butírico/sangre , Ácido Butírico/metabolismo , Ácido Butírico/farmacocinética , Radioisótopos de Carbono , Femenino , Inhibidores de Histona Desacetilasas/sangre , Inhibidores de Histona Desacetilasas/metabolismo , Marcaje Isotópico , Papio , Fenilbutiratos/sangre , Fenilbutiratos/metabolismo , Fenilbutiratos/farmacocinética , Radioquímica , Distribución Tisular , Ácido Valproico/sangre , Ácido Valproico/metabolismo , Ácido Valproico/farmacocinéticaRESUMEN
Nonspecific histone deacetylase (HDAC) inhibition has been shown to facilitate the extinction of drug-seeking behavior in a manner resistant to reinstatement. A key open question is which specific HDAC is involved in the extinction of drug-seeking behavior. Using the selective HDAC3 inhibitor RGFP966, we investigated the role of HDAC3 in extinction and found that systemic treatment with RGFP966 facilitates extinction in mice in a manner resistant to reinstatement. We also investigated whether the facilitated extinction is related to the enhancement of extinction consolidation during extinction learning or to negative effects on performance or reconsolidation. These are key distinctions with regard to any compound being used to modulate extinction, because a more rapid decrease in a defined behavior is interpreted as facilitated extinction. Using an innovative combination of behavioral paradigms, we found that a single treatment of RGFP966 enhances extinction of a previously established cocaine-conditioned place preference, while simultaneously enhancing long-term object-location memory within subjects. During extinction consolidation, HDAC3 inhibition promotes a distinct pattern of histone acetylation linked to gene expression within the infralimbic cortex, hippocampus, and nucleus accumbens. Thus, the facilitated extinction of drug-seeking cannot be explained by adverse effects on performance. These results demonstrate that HDAC3 inhibition enhances the memory processes involved in extinction of drug-seeking behavior.
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Acrilamidas/farmacología , Cocaína , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Extinción Psicológica/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Fenilendiaminas/farmacología , Acetilación/efectos de los fármacos , Acrilamidas/sangre , Acrilamidas/farmacocinética , Análisis de Varianza , Animales , Inmunoprecipitación de Cromatina , Técnica del Anticuerpo Fluorescente , Inhibidores de Histona Desacetilasas/sangre , Inhibidores de Histona Desacetilasas/farmacocinética , Histonas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Fenilendiaminas/sangre , Fenilendiaminas/farmacocinética , Reacción en Cadena en Tiempo Real de la Polimerasa , Factores de TiempoRESUMEN
A pediatric study has established a maximum tolerated dose (MTD) for temsirolimus (Tem) of more than 150 mg/m intravenously/week. A phase I trial was conducted to establish the MTD for Tem in combination with valproic acid (VPA) in children and adolescents with refractory solid tumors. The secondary aims included expression of mammalian target of rapamycin (mTOR) markers on archival tumor tissue; Tem pharmacokinetics; assessment of histone acetylation (HA); and tumor response. Patients were treated with VPA (5 mg/kg orally three times daily) with a target serum level of 75-100 mcg/ml. Tem was started at an initial dose of 60 mg/m/week. Pharmacokinetics and HA measurements were performed during weeks 1 and 5. Two of the first three patients experienced dose-limiting toxicity (grade 3 mucositis). Tem at 35 mg/m/week was found to be tolerable. Peak Tem concentrations were higher in all patients compared with those in previously published reports of single agent Tem. Increases in HA are correlated with VPA levels. All tumor samples expressed mTORC1 and mTORC2. An objective response was observed in one patient (melanoma), whereas transient stable disease was observed in four other patients (spinal cord ependymoma, alveolar soft part sarcoma, medullary thyroid carcinoma, and hepatocellular carcinoma). The MTD of Tem when administered with VPA is considerably lower than when used as a single agent, with mucositis the major dose-limiting toxicity. The combination merits further study and may have activity in melanoma. Attention to drug-drug interactions will be important in future multiagent trials including Tem.