RESUMEN
OBJECTIVE: Epilepsy patients often report memory deficits despite normal objective testing, suggesting that available measures are insensitive or that non-mnemonic factors are involved. The Visual Paired Comparison Task (VPCT) assesses novelty preference, the tendency to fixate on novel images rather than previously viewed items, requiring recognition memory for the "old" images. As novelty preference is a sensitive measure of hippocampal-dependent memory function, we predicted impaired VPCT performance in epilepsy patients compared to healthy controls. METHODS: We assessed 26 healthy adult controls and 31 epilepsy patients (16 focal-onset, 13 generalized-onset, 2 unknown-onset) with the VPCT using delays of 2 or 30 s between encoding and recognition. Fifteen healthy controls and 17 epilepsy patients (10 focal-onset, 5 generalized-onset, 2 unknown-onset) completed the task at 2-, 5-, and 30-minute delays. Subjects also performed standard memory measures, including the Medical College of Georgia (MCG) Paragraph Test, California Verbal Learning Test-Second Edition (CVLT-II), and Brief Visual Memory Test-Revised (BVMT-R). RESULTS: The epilepsy group was high functioning, with greater estimated IQ (p = 0.041), greater years of education (p = 0.034), and higher BVMT-R scores (p = 0.024) compared to controls. Both the control group and epilepsy cohort, as well as focal- and generalized-onset subgroups, had intact novelty preference at the 2- and 30-second delays (p-values ≤ 0.001) and declined at 30 min (p-values > 0.05). Only the epilepsy patients had early declines at 2- and 5-minute delays (controls with intact novelty preference at p = 0.003 and p ≤ 0.001, respectively; epilepsy groups' p-values > 0.05). CONCLUSIONS: Memory for the "old" items decayed more rapidly in overall, focal-onset, and generalized-onset epilepsy groups. The VPCT detected deficits while standard memory measures were largely intact, suggesting that the VPCT may be a more sensitive measure of temporal lobe memory function than standard neuropsychological batteries.
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Epilepsia , Trastornos de la Memoria , Pruebas Neuropsicológicas , Reconocimiento en Psicología , Humanos , Masculino , Femenino , Adulto , Epilepsia/psicología , Epilepsia/diagnóstico , Epilepsia/fisiopatología , Epilepsia/complicaciones , Reconocimiento en Psicología/fisiología , Trastornos de la Memoria/diagnóstico , Trastornos de la Memoria/etiología , Persona de Mediana Edad , Adulto Joven , Tecnología de Seguimiento Ocular , Estimulación Luminosa/métodosRESUMEN
The standard of care for the treatment of chronic hepatitis B (CHB) is typically lifelong treatment with nucleos(t)ide analogs (NAs), which suppress viral replication and provide long-term clinical benefits. However, infectious virus can still be detected in patients who are virally suppressed on NA therapy, which may contribute to the failure of these agents to cure most CHB patients. Accordingly, new antiviral treatment options are being developed to enhance the suppression of hepatitis B virus (HBV) replication in combination with NAs ("antiviral intensification"). Here, we describe GS-SBA-1, a capsid assembly modulator (CAM) belonging to class CAM-E, that demonstrates potent inhibition of extracellular HBV DNA in vitro (EC50 [50% effective concentration] = 19 nM) in HBV-infected primary human hepatocytes (PHHs) as well as in vivo in an HBV-infected immunodeficient mouse model. GS-SBA-1 has comparable activities across HBV genotypes and nucleos(t)ide-resistant mutants in HBV-infected PHHs. In addition, GS-SBA-1 demonstrated in vitro additivity in combination with tenofovir alafenamide (TAF). The administration of GS-SBA-1 to PHHs at the time of infection prevents covalently closed circular DNA (cccDNA) formation and, hence, decreases HBV RNA and antigen levels (EC50 = 80 to 200 nM). Furthermore, GS-SBA-1 prevents the production of extracellular HBV RNA-containing viral particles in vitro. Collectively, these data demonstrate that GS-SBA-1 is a potent CAM that has the potential to enhance viral suppression in combination with an NA.
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Hepatitis B Crónica , Hepatitis B , Animales , Ratones , Humanos , Hepatitis B Crónica/tratamiento farmacológico , Cápside , Virus de la Hepatitis B , Antivirales/farmacología , Antivirales/uso terapéutico , Proteínas de la Cápside/genética , ARN , ADN Viral/genética , ADN Circular , Hepatitis B/tratamiento farmacológicoRESUMEN
Drugs with prolonged on-target residence times often show superior efficacy, yet general strategies for optimizing drug-target residence time are lacking. Here we made progress toward this elusive goal by targeting a noncatalytic cysteine in Bruton's tyrosine kinase (BTK) with reversible covalent inhibitors. Using an inverted orientation of the cysteine-reactive cyanoacrylamide electrophile, we identified potent and selective BTK inhibitors that demonstrated biochemical residence times spanning from minutes to 7 d. An inverted cyanoacrylamide with prolonged residence time in vivo remained bound to BTK for more than 18 h after clearance from the circulation. The inverted cyanoacrylamide strategy was further used to discover fibroblast growth factor receptor (FGFR) kinase inhibitors with residence times of several days, demonstrating the generalizability of the approach. Targeting of noncatalytic cysteines with inverted cyanoacrylamides may serve as a broadly applicable platform that facilitates 'residence time by design', the ability to modulate and improve the duration of target engagement in vivo.
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Acrilamidas/farmacocinética , Linfocitos B/efectos de los fármacos , Cianoacrilatos/farmacocinética , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Acrilamidas/síntesis química , Agammaglobulinemia Tirosina Quinasa , Animales , Linfocitos B/enzimología , Linfocitos B/patología , Línea Celular Tumoral , Cristalografía por Rayos X , Cianoacrilatos/síntesis química , Dasatinib , Femenino , Expresión Génica , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Estructura Terciaria de Proteína , Proteínas Tirosina Quinasas/química , Proteínas Tirosina Quinasas/genética , Pirimidinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Células Sf9 , Spodoptera , Relación Estructura-Actividad , Especificidad por Sustrato , Tiazoles/farmacocinética , Factores de TiempoRESUMEN
Leucine-rich repeat kinase 2 (LRRK2) has been implicated in the pathogenesis of Parkinson's disease (PD). Inhibition of LRRK2 kinase activity is a therapeutic approach that may lead to new treatments for PD. Herein we report the discovery of a series of [1,2,4]triazolo[4,3-b]pyridazines that are potent against both wild-type and mutant LRRK2 kinase activity in biochemical assays and show an unprecedented selectivity towards the G2019S mutant. A structural rational for the observed selectivity is proposed.
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Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Piridazinas/farmacología , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Piridazinas/síntesis química , Piridazinas/química , Relación Estructura-ActividadRESUMEN
Leucine rich repeat kinase 2 (LRRK2) has been implicated in the pathogenesis of Parkinson's disease (PD). Inhibition of LRRK2 kinase activity is a therapeutic approach that may lead to new treatments for PD. Herein we report the discovery of a series of cinnoline-3-carboxamides that are potent against both wild-type and mutant LRRK2 kinase activity in biochemical assays. These compounds are also shown to be potent inhibitors in a cellular assay and to have good to excellent CNS penetration.
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Compuestos Heterocíclicos con 2 Anillos/química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Amidas/síntesis química , Amidas/química , Amidas/metabolismo , Animales , Sitios de Unión , Células HEK293 , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Ratones , Simulación del Acoplamiento Molecular , Mutación , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Estructura Terciaria de Proteína , TransfecciónRESUMEN
Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with familial Parkinson's disease (PD). The kinase activity of this complex protein is increased by pathogenic mutations. Inhibition of LRRK2 kinase activity has therefore emerged as a promising approach for the treatment of PD. Herein we report our findings on a series of 4-alkylamino-7-aryl-3-cyanoquinolines that exhibit kinase inhibitory activity against both wild type and G2019S mutant LRRK2. Activity was determined in both biochemical and cellular assays. Compound 14 was further evaluated in an in vivo pharmacodynamic study and found to significantly inhibit Ser935 phosphorylation after oral dosing.
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Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Quinolinas/farmacología , Animales , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Ratones , Ratones Noqueados , Ratones Transgénicos , Modelos Moleculares , Estructura Molecular , Mutación , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Quinolinas/síntesis química , Quinolinas/química , Relación Estructura-ActividadRESUMEN
Utilizing a structure based design approach, combined with extensive medicinal chemistry execution, highly selective, potent and novel BACE1 inhibitor 8 (BACE1 Alpha assay IC50=8nM) was made from a weak µM potency hit in an extremely efficient way. The detailed SAR and general design approaches will be discussed.
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Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Diseño de Fármacos , Isoquinolinas/farmacología , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Tiofenos/farmacología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Isoquinolinas/química , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteasas/química , Relación Estructura-Actividad , Tiofenos/químicaRESUMEN
The structure-activity relationship of a series of dihydroisoquinoline BACE-1 inhibitors is described. Application of structure-based design to screening hit 1 yielded sub-micromolar inhibitors. Replacement of the carboxylic acid of 1 was guided by X-ray crystallography, which allowed the replacement of a key water-mediated hydrogen bond. This work culminated in compounds such as 31, which possess good BACE-1 potency, excellent permeability and a low P-gp efflux ratio.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Ácido Aspártico/química , Diseño de Fármacos , Isoquinolinas/farmacología , Inhibidores de Proteasas/farmacología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Catálisis , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Isoquinolinas/síntesis química , Isoquinolinas/química , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/química , Relación Estructura-ActividadRESUMEN
Polo-like kinase-2 (Plk-2) is a potential therapeutic target for Parkinson's disease and this Letter describes the SAR of a series of dihydropteridinone based Plk-2 inhibitors. By optimizing both the N-8 substituent and the biaryl region of the inhibitors we obtained single digit nanomolar compounds such as 37 with excellent selectivity for Plk-2 over Plk-1. When dosed orally in rats, compound 37 demonstrated a 41-45% reduction of pS129-α-synuclein levels in the cerebral cortex.
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Diseño de Fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Administración Oral , Animales , Encéfalo/metabolismo , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/metabolismo , Células HEK293 , Semivida , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/metabolismo , Pteridinas/síntesis química , Pteridinas/química , Pteridinas/farmacocinética , Ratas , Relación Estructura-Actividad , Quinasa Tipo Polo 1RESUMEN
Objectives: In response to the coronavirus disease 2019 (COVID-19) pandemic, neuropsychologists rapidly adopted teleneuropsychology (TeleNP) services to ensure continued clinical care. Prior to COVID-19, TeleNP was not widely used nor was it included in the majority of traditional practice or training models across graduate, internship, and postdoctoral programs. Out of necessity, the pandemic was a catalyst that promoted greater adoption of TeleNP services. In response, neuropsychological guidelines for modified assessments were developed and further empirical studies have been published. Numerous surveys in response to service delivery changes during COVID-19 now exist, but what follows is a commentary based on neuropsychologists' experiences with adapting clinical practice to TeleNP. Methods: Co-authors represent settings across academic medical centers, Veterans Affairs hospitals, and private practices that serve multiculturally diverse pediatric, adult, and geriatric populations in the United States. Results: The perspectives within this commentary aim to highlight the growth of TeleNP and highlight lessons learned from implementation across practice settings. Conclusions: Our goal is to help foster the development of further empirical studies through candid discussion of various TeleNP experiences and approaches. Through this reflective process, TeleNP presents both opportunities and challenges but it ultimately has potential to reduce healthcare disparities and enhance patient care.
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COVID-19 , Telemedicina , Adulto , Anciano , Niño , Humanos , Pruebas Neuropsicológicas , Neuropsicología , Pandemias , Encuestas y Cuestionarios , Estados UnidosRESUMEN
Chronic hepatitis B (CHB) is a global health care challenge and a major cause of liver disease. To find new therapeutic avenues with a potential to functionally cure chronic Hepatitis B virus (HBV) infection, we performed a focused screen of epigenetic modifiers to identify potential inhibitors of replication or gene expression. From this work we identified isonicotinic acid inhibitors of the histone lysine demethylase 5 (KDM5) with potent anti-HBV activity. To enhance the cellular permeability and liver accumulation of the most potent KDM5 inhibitor identified (GS-080) an ester prodrug was developed (GS-5801) that resulted in improved bioavailability and liver exposure as well as an increased H3K4me3:H3 ratio on chromatin. GS-5801 treatment of HBV-infected primary human hepatocytes reduced the levels of HBV RNA, DNA and antigen. Evaluation of GS-5801 antiviral activity in a humanized mouse model of HBV infection, however, did not result in antiviral efficacy, despite achieving pharmacodynamic levels of H3K4me3:H3 predicted to be efficacious from the in vitro model. Here we discuss potential reasons for the disconnect between in vitro and in vivo efficacy, which highlight the translational difficulties of epigenetic targets for viral diseases.
Asunto(s)
Virus de la Hepatitis B , Hepatitis B Crónica , Humanos , Animales , Ratones , Antivirales/farmacología , Hepatitis B Crónica/tratamiento farmacológico , EpigenómicaRESUMEN
Bruton's tyrosine kinase (BTK), a Tec family tyrosine kinase, is critical in immune pathways as an essential intracellular signaling element, participating in both adaptive and immune responses. Currently approved BTK inhibitors are irreversible covalent inhibitors and limited to oncology indications. Herein, we describe the design of covalent reversible BTK inhibitors and the discoveries of PRN473 (11) and rilzabrutinib (PRN1008, 12). These compounds have exhibited potent and durable inhibition of BTK, in vivo efficacy in rodent arthritis models, and clinical efficacy in canine pemphigus foliaceus. Compound 11 has completed phase 1 trials as a topical agent, and 12 is in phase 3 trials for pemphigus vulgaris and immune thrombocytopenia.
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Inhibidores de Proteínas Quinasas , Transducción de Señal , Agammaglobulinemia Tirosina Quinasa , Animales , Perros , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
A novel series of potent inhibitors of glucosylceramide synthase are described. The optimization of biochemical and cellular potency as well as ADME properties led to compound 23c. Broad tissue distribution was obtained following oral administration to mice. Thus 23c could be another useful tool compound for studying the effects of GCS inhibition in vitro and in vivo.
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Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Glucosiltransferasas/antagonistas & inhibidores , Glucosiltransferasas/metabolismo , Administración Oral , Animales , Descubrimiento de Drogas , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacocinética , Humanos , Ratones , Ratones Endogámicos C57BL , Relación Estructura-ActividadRESUMEN
Development of curative therapies for chronic hepatitis B virus (HBV) infection will likely require new animal models. Here, we evaluate HBV infection in squirrel monkeys based on the high-sequence homology of the HBV receptor, Na+/taurocholate co-transporting peptide (NTCP), between humans and squirrel monkeys. HBV PreS1 peptide was examined for binding human and squirrel monkey NTCP. Immunodeficient Fah -/- , NOD, Rag1 -/- , Il2Rg null (FNRG) mice engrafted with human or squirrel monkey hepatocytes were challenged with HBV or Woolly Monkey HBV (WMHBV). In addition, adult squirrel monkeys were inoculated with HBV, WMHBV, adeno-associated virus containing an infectious genome of HBV (AAV-HBV), and AAV-WMHBV. Finally, neonate squirrel monkeys were assessed for the potential of chronic infection with WMHBV. PreS1 peptide efficiently bound to human and squirrel monkey NTCP but not to mouse or capuchin NTCP. FNRG mice engrafted with squirrel monkey hepatocytes were susceptible to infection by WMHBV but not human HBV. Similarly, adult squirrel monkeys could be infected with WMHBV but not human HBV, whereas chimeric mice engrafted with human hepatocytes were susceptible to HBV but not WMHBV. Infection of squirrel monkeys with AAV-WMHBV yielded maximum viremia of 108 genomes/mL with detectable virus for up to 8 months. Notably, covalently closed circular DNA was detected in the liver of these animals. Infection of neonates with WMHBV led to detectable viremia for up to 6 months. Conclusions: Adult and neonate squirrel monkeys exhibited prolonged WMHBV viremia lasting 6-8 months. This is greater than twice the duration of viremia achieved in other nonhuman primates and suggests that squirrel monkeys may be a suitable model for testing HBV therapeutics.
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Malformations of neocortical development are associated with cognitive dysfunction and increased susceptibility to epileptogenesis. Rodent models are widely used to study neocortical malformations and have revealed important genetic and environmental mechanisms that contribute to neocortical development. Interestingly, several inbred mice strains commonly used in behavioral, anatomical, and/or physiological studies display neocortical malformations. In the present report we examine the cytoarchitecture and myeloarchitecture of the neocortex of 11 inbred mouse strains and identified malformations of cortical development, including molecular layer heterotopia, in all but one strain. We used in silico methods to confirm our observations and determined the transcriptional profiles of cells found within heterotopia. These data indicate cellular and transcriptional diversity present in cells in malformations. Furthermore, the presence of dysplasia in nearly every inbred strain examined suggests that malformations of neocortical development are a common feature in the neocortex of inbred mice.
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Perfilación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Ratones Endogámicos , Neocórtex/anomalías , Neocórtex/fisiología , Animales , Animales no Consanguíneos , Coristoma/genética , Coristoma/patología , Bases de Datos Genéticas , Canales Iónicos/genética , Ratones , Ratones Endogámicos A , Ratones Endogámicos AKR , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Receptores de Neurotransmisores/genética , Especificidad de la Especie , Transcripción GenéticaRESUMEN
Neuropsychologists regularly conduct sport-related concussion (SRC) evaluations, although research has not tracked these assessment practices. As part of a survey of neuropsychological test usage, we analyzed data from 215 neuropsychologists who conduct SRC evaluations. Only 15% reported conducting baseline assessments of athletes as part of a sports program and 92% evaluate athletes' post-concussion without baseline data. The majority of respondents use a full battery, considered the most reliable approach for assessing concussion symptoms in athletes. Only 6% use computerized tests exclusively (>50% ImPACT). We discuss the implications of these results and address challenges faced by neuropsychologists who perform SRC evaluations.
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Traumatismos en Atletas/diagnóstico , Conmoción Encefálica/diagnóstico , Pruebas Neuropsicológicas , Atletas , Femenino , Humanos , Masculino , DeportesRESUMEN
Aberrant signaling of the FGF/FGFR pathway occurs frequently in cancers and is an oncogenic driver in many solid tumors. Clinical validation of FGFR as a therapeutic target has been demonstrated in bladder, liver, lung, breast, and gastric cancers. Our goal was to develop an irreversible covalent inhibitor of FGFR1-4 for use in oncology indications. An irreversible covalent binding mechanism imparts many desirable pharmacological benefits including high potency, selectivity, and prolonged target inhibition. Herein we report the structure-based design, medicinal chemistry optimization, and unique ADME assays of our irreversible covalent drug discovery program which culminated in the discovery of compound 34 (PRN1371), a highly selective and potent FGFR1-4 inhibitor.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias/tratamiento farmacológico , Piridonas/farmacología , Pirimidinas/farmacología , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Perros , Diseño de Fármacos , Estabilidad de Medicamentos , Femenino , Humanos , Absorción Intestinal , Macaca fascicularis , Masculino , Piridonas/administración & dosificación , Piridonas/síntesis química , Piridonas/farmacocinética , Pirimidinas/administración & dosificación , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Ratas Sprague-Dawley , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Solubilidad , Relación Estructura-ActividadRESUMEN
An increasing number of cancers are known to harbor mutations, translocations, or amplifications in the fibroblast growth factor receptor (FGFR) family of kinases. The FGFR inhibitors evaluated in clinical trials to date have shown promise at treating these cancers. Here, we describe PRN1371, an irreversible covalent inhibitor of FGFR1-4 targeting a cysteine within the kinase active site. PRN1371 demonstrated strong FGFR potency and excellent kinome-wide selectivity in a number of biochemical and cellular assays, including in various cancer cell lines exhibiting FGFR alterations. Furthermore, PRN1371 maintained FGFR inhibition in vivo, not only when circulating drug levels were high but also after the drug had been cleared from circulation, indicating the possibility of sustained FGFR inhibition in the clinic without the need for continuous drug exposure. Durable tumor regression was also obtained in multiple tumor xenografts and patient-derived tumor xenograft models and was sustained even using an intermittent dosing strategy that provided drug holidays. PRN1371 is currently under clinical investigation for treatment of patients with solid tumors. Mol Cancer Ther; 16(12); 2668-76. ©2017 AACR.
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Piridonas/uso terapéutico , Pirimidinas/uso terapéutico , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Proliferación Celular , Humanos , Ratones , Piridonas/farmacología , Pirimidinas/farmacología , Transducción de Señal , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OPINION STATEMENT: Cognitive impairment (CI) is an inclusive term to describe trouble with memory, learning, concentration, or decision-making. CI is highly prevalent in patients with heart failure (HF) and is known to be associated with a variety of poor outcomes. While published HF guidelines recommend screening for CI, they do not indicate how, due to a lack of consensus in the literature about which instrument to use. Our recommendation is to use the Mini-Cog for this purpose because of its brevity and utility in identifying patients with HF at high risk for hospitalization or mortality. At this time, there is minimal published clinical trial evidence about how to manage CI in patients with HF. Reasonable approaches to management may include following guideline-directed medical therapy for HF, treatment of hypertension and atrial fibrillation, management of depression, proactive diagnosis and treatment of sleep apnea, and encouragement of aerobic exercise and weight loss. Left ventricular assist device (LVAD) therapy in patients with Stage D HF may improve CI in the short term after implantation, though there is a risk of worsening CI in the intermediate and long term. Clinicians who care for patients with HF should routinely screen for CI and when identified should encourage interventions to support self-care, increase family involvement, and arrange for more frequent follow-up.
RESUMEN
Troglitazone, a thiazolidinedione containing compound, was widely used to treat non-insulin dependent-diabetes. Unfortunately, troglitazone was associated with a sporadic liver toxicity that led to a cessation of its use clinically. Here we show that troglitazone induces a rapid and dose-dependent drop of mitochondrial membrane potential in liver HepG2 cells. The decrease in mitochondrial membrane potential induced by 100 microM troglitazone was completed after 5 min and similar in magnitude to that caused by carbonyl cyanide m-chloro phenylhydrazone. The troglitazone-induced loss of mitochondrial membrane potential preceded changes in cell permeability and cell count. In addition, troglitazone-induced a rise of intracellular calcium, subsequent to the drop in mitochondrial membrane potential, which was blocked by EGTA and the Na+/Ca2+ exchange inhibitor bepridil. Finally, application of 100 microM troglitazone for 24h to HepG2 cells resulted in activation of caspase 3. The results of this study shed light on the molecular mechanisms by which troglitazone can cause cytotoxicity.