RESUMEN
OBJECTIVE: Nutritional rehabilitation and weight restoration are often critical for the treatment of eating disorders (ED), yet are restricted by the potential risk of refeeding syndrome (RFS). The primary objective was to determine the incidence of RFS. Secondary objectives were to explore predictive factors of RFS and describe its impact on treatment goals for patients with ED. METHOD: This retrospective observational study reviewed the nutrition management for patients admitted to a quaternary hospital for ED treatment from 2018 to 2020. Data were collected during the first 4 weeks of admission and included anthropometry, energy prescription, incidence and severity of RFS, and electrolyte and micronutrient prescription. Outcomes included incidence of RFS, energy prescription and advancement, and weight change. RESULTS: Of 423 ED admissions, 217 patients (median [interquartile range, IQR] age 25 [21-30.5] years; 210 [97%] female) met inclusion criteria. Median (IQR) body mass index (BMI) on admission was 15.5 (14.1-17.3) kg/m2 . The mean (standard deviation) length of admission was 35 (7.3) days. Median (IQR) initial energy prescription was 1500 (930-1500) kcal/day. Seventy-three (33%) patients developed RFS; 34 (16%) mild, 27 (12%) moderate, and 12 (5%) severe. There was no association between RFS severity and admission BMI, energy prescription, or prescription of prophylactic electrolytes or micronutrients. Lower admission weight was associated with RFS (odds ratio 0.96, 95% confidence interval [0.93-1.00], p = .035). Less than half of the participants met the weight gain target (>1 kg per week) in the first 3 weeks of admission. DISCUSSION: The incidence of severe RFS was low in this cohort and was associated with lower admission weight. PUBLIC SIGNIFICANCE: This study is one of the largest studies to utilize consensus-defined criteria to diagnose RFS among adult patients admitted for treatment of an ED. This population is still considered to be at risk of RFS and will require close monitoring. The results add to the growing body of research that restriction of energy prescription to prevent RFS may not require the level of conservatism traditionally practiced.
Asunto(s)
Anorexia Nerviosa , Trastornos de Alimentación y de la Ingestión de Alimentos , Síndrome de Realimentación , Adulto , Humanos , Femenino , Masculino , Síndrome de Realimentación/terapia , Síndrome de Realimentación/epidemiología , Pacientes Internos , Incidencia , Trastornos de Alimentación y de la Ingestión de Alimentos/terapia , Trastornos de Alimentación y de la Ingestión de Alimentos/complicaciones , Hospitalización , Anorexia Nerviosa/terapiaRESUMEN
Histone deacetylases (HDACs) play diverse roles in many diseases including cancer, sarcopenia, and Alzheimer's. Different isoforms of HDACs appear to play disparate roles in the cell and are associated with specific diseases; as such, a substantial effort has been made to develop isoform-selective HDAC inhibitors. Our group focused on developing HDAC1/HDAC2-specific inhibitors as a cancer therapeutic. In the course of characterizing the mechanism of inhibition of a novel HDAC1/2-selective inhibitor, it was determined that it did not exhibit classical Michaelis-Menten kinetic behavior; this result is in contrast to the seminal HDAC inhibitor SAHA. Enzymatic assays, along with a newly developed binding assay, were used to determine the rates of binding and the affinities of both the HDAC1/2-selective inhibitor and SAHA. The mechanism of action studies identified a potential conformational change required for optimal binding by the selective inhibitor. A model of this putative conformational change is proposed.
Asunto(s)
Antineoplásicos/química , Benzoatos/química , Histona Desacetilasa 1/antagonistas & inhibidores , Histona Desacetilasa 2/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/química , Ácidos Hidroxámicos/química , Xantenos/química , Animales , Antineoplásicos/farmacología , Benzoatos/farmacología , Línea Celular Tumoral , Femenino , Fluoresceína-5-Isotiocianato , Colorantes Fluorescentes , Xenoinjertos , Histona Desacetilasa 1/química , Histona Desacetilasa 2/química , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Ácidos Hidroxámicos/farmacología , Cinética , Ratones , Ratones Desnudos , Modelos Moleculares , Unión Proteica , Conformación Proteica , Especificidad por Sustrato , Vorinostat , Xantenos/farmacologíaAsunto(s)
Angioedemas Hereditarios/diagnóstico , Angioedemas Hereditarios/patología , Disfunciones Sexuales Psicológicas/etiología , Disfunciones Sexuales Psicológicas/patología , Enfermedades de la Vulva/diagnóstico , Enfermedades de la Vulva/patología , Angioedemas Hereditarios/complicaciones , Femenino , Humanos , Vulva/patología , Enfermedades de la Vulva/complicaciones , Adulto JovenRESUMEN
OBJECTIVE: A number of organic conditions may mimic the symptoms of an eating disorder, however, gastric outlet obstruction mimicking anorexia nervosa has rarely been reported. METHOD: We report the case of a 51-year-old female admitted to an eating disorders unit with an initial diagnosis of anorexia nervosa. RESULTS: The patient's upper gastrointestinal symptoms and weight loss were found to be secondary to gastric outlet obstruction from a gastric adenocarcinoma. Coincidental psychosocial stressors and past psychiatric history, among other factors, had confounded the diagnosis. DISCUSSION: Organic causes of weight loss and upper gastrointestinal symptoms need to be fully excluded prior to making the diagnosis of an eating disorder, particularly when there are atypical features in the presentation.
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Adenocarcinoma/diagnóstico , Anorexia Nerviosa/diagnóstico , Errores Diagnósticos , Neoplasias Gástricas/diagnóstico , Adenocarcinoma/psicología , Anorexia Nerviosa/psicología , Índice de Masa Corporal , Trastorno Depresivo Mayor/diagnóstico , Trastorno Depresivo Mayor/psicología , Dispepsia/etiología , Ingestión de Energía , Femenino , Obstrucción de la Salida Gástrica/diagnóstico , Obstrucción de la Salida Gástrica/psicología , Gastroscopía , Humanos , Persona de Mediana Edad , Neoplasias Gástricas/psicología , Delgadez/diagnóstico , Delgadez/psicología , Tomografía Computarizada por Rayos X , Vómitos/etiología , Pérdida de PesoRESUMEN
We report the preparation and structure-activity relationships of phosphorus-containing histone deacetylase inhibitors. A strong trend between decreasing phosphorus functional group size and superior mouse pharmacokinetic properties was identified. In addition, optimized candidates showed tumor growth inhibition in xenograft studies.
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Antineoplásicos/farmacocinética , Inhibidores Enzimáticos/farmacocinética , Inhibidores de Histona Desacetilasas , Organofosfonatos/farmacocinética , Proteínas Represoras/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Histona Desacetilasa 1 , Histona Desacetilasa 2 , Histona Desacetilasas/metabolismo , Ratones , Ratones Desnudos , Organofosfonatos/síntesis química , Organofosfonatos/química , Proteínas Represoras/metabolismo , Trasplante HeterólogoRESUMEN
The successful application of both solid and solution phase library synthesis, combined with tight integration into the medicinal chemistry effort, resulted in the efficient optimization of a novel structural series of selective HDAC1/HDAC2 inhibitors by the MRL-Boston Parallel Medicinal Chemistry group. An initial lead from a small parallel library was found to be potent and selective in biochemical assays. Advanced compounds were the culmination of iterative library design and possess excellent biochemical and cellular potency, as well as acceptable PK and efficacy in animal models.
Asunto(s)
Inhibidores de Histona Desacetilasas , Animales , Técnicas Químicas Combinatorias , Perros , Diseño de Fármacos , Histona Desacetilasa 1 , Histona Desacetilasa 2 , Humanos , Estructura Molecular , Ratas , Proteínas Represoras/antagonistas & inhibidores , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Ongoing clinical studies indicate that inhibitors of Class I and Class II histone deacetylase (HDAC) enzymes show great promise for the treatment of cancer. Zolinza (SAHA, Zolinza) was recently approved by the FDA for the treatment of the cutaneous manifestations of cutaneous T-cell lymphoma. As a part of an ongoing effort to identify novel small molecules to target these important enzymes, we have prepared several classes of amino acid-derived HDAC1 inhibitors. The design rationale and in vitro activity against the HDAC1 enzyme and HCT116 cell line are described in this letter.
Asunto(s)
Aminoácidos/química , Aminoácidos/farmacología , Inhibidores de Histona Desacetilasas , Aminoácidos/síntesis química , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Histona Desacetilasa 1 , Humanos , Piperazinas/síntesis química , Piperazinas/química , Piperazinas/farmacología , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/química , Tiofenos/farmacologíaRESUMEN
A class of biaryl benzamides was identified and optimized as selective HDAC1&2 inhibitors (SHI-1:2). These agents exhibit selectivity over class II HDACs 4-7, as well as class I HDACs 3 and 8; providing examples of selective HDAC inhibitors for the HDAC isoforms most closely associated with cancer. The hypothesis for the increased selectivity is the binding of a pendant aromatic group in the internal cavity of the HDAC1&2 enzymes. SAR development based on an initial lead led to a series of potent and selective inhibitors with reduced off-target activity and tumor growth inhibition activity in a HCT-116 xenograft model.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Proteínas Represoras/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Inhibidores Enzimáticos/química , Histona Desacetilasa 1 , Histona Desacetilasa 2 , Ratones , Relación Estructura-Actividad , Trasplante HeterólogoRESUMEN
An HTS screening campaign identified a series of low molecular weight phenols that showed excellent selectivity (>100-fold) for HDAC1/HDAC2 over other Class I and Class II HDACs. Evolution and optimization of this HTS hit series provided HDAC1-selective (SHI-1) compounds with excellent anti-proliferative activity and improved physical properties. Dose-dependent efficacy in a mouse HCT116 xenograft model was demonstrated with a phenylglycine SHI-1 analog.
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Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Glicina/análogos & derivados , Inhibidores de Histona Desacetilasas , Fenilalanina/química , Acetilación , Amidas , Animales , Neoplasias del Colon/enzimología , Neoplasias del Colon/patología , Perros , Canal de Potasio ERG1 , Inhibidores Enzimáticos/farmacocinética , Canales de Potasio Éter-A-Go-Go/metabolismo , Glicina/química , Histona Desacetilasa 1 , Humanos , Macaca mulatta , Ratones , Estructura Molecular , Relación Estructura-Actividad , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A potent family of spirocyclic nicotinyl aminobenzamide selective HDAC1/HDAC2 inhibitors (SHI-1:2) is profiled. The incorporation of a biaryl zinc-binding motif into a nicotinyl scaffold resulted in enhanced potency and selectivity versus HDAC3, but also imparted hERG activity. It was discovered that increasing polar surface area about the spirocycle attenuates this liability. Compound 12 induced a 4-fold increase in acetylated histone H2B in an HCT-116 xenograft model study with acute exposure, and inhibited tumor growth in a 21-day efficacy study with qd dosing.
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Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Canales de Potasio Éter-A-Go-Go/metabolismo , Inhibidores de Histona Desacetilasas , Niacinamida/síntesis química , Niacinamida/farmacología , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Animales , Antineoplásicos/química , Benzamidas/síntesis química , Benzamidas/química , Benzamidas/farmacología , Técnicas Químicas Combinatorias , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Células HCT116 , Histona Desacetilasas , Histonas/análisis , Humanos , Ratones , Ratones Desnudos , Estructura Molecular , Niacinamida/química , Isoformas de Proteínas , Compuestos de Espiro/química , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We report herein the initial exploration of novel selective HDAC1/HDAC2 inhibitors (SHI-1:2). Optimized SHI-1:2 structures exhibit enhanced intrinsic activity against HDAC1 and HDAC2, and are greater than 100-fold selective versus other HDACs, including HDAC3. Based on the SAR of these agents and our current understanding of the HDAC active site, we postulate that the SHI-1:2 extend the existing HDAC inhibitor pharmacophore to include an internal binding domain.
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Derivados del Benceno/síntesis química , Derivados del Benceno/farmacología , Inhibidores de Histona Desacetilasas , Modelos Moleculares , Derivados del Benceno/química , Sitios de Unión/efectos de los fármacos , Histona Desacetilasa 1 , Histona Desacetilasa 2 , Histona Desacetilasas/química , Histona Desacetilasas/metabolismo , Humanos , Estructura Molecular , Isoformas de Proteínas , Proteínas Represoras , Relación Estructura-ActividadRESUMEN
The identification and in vitro and in vivo characterization of a potent SHI-1:2 are described. Kinetic analysis indicated that biaryl inhibitors exhibit slow binding kinetics in isolated HDAC1 and HDAC2 preparations. Delayed histone hyperacetylation and gene expression changes were also observed in cell culture, and histone acetylation was observed in vivo beyond disappearance of drug from plasma. In vivo studies further demonstrated that continuous target inhibition was well tolerated and efficacious in tumor-bearing mice, leading to tumor growth inhibition with either once-daily or intermittent administration.
RESUMEN
To investigate the safety and tolerability of the atypical antipsychotic quetiapine in anorexia nervosa patients, and to determine the effect of quetiapine treatment on anorexic psychopathology and other key outcome measures including weight and body image, we conducted a naturalistic, open-label, 12-week randomized controlled trial of low-dose (100-400 mg/day) quetiapine treatment versus treatment as usual in 33 anorexia nervosa patients from our Eating Disorder Clinics. To monitor the effects of treatment over the medium term, the participants were then followed up with assessment visits at 6 and 12 months after the end of the treatment phase. Low-dose quetiapine treatment resulted in both psychological and physical improvements, with minimal associated side-effects. Given the overall trend toward improvement that we observed, quetiapine appears to be a promising candidate for the treatment of anorexia nervosa. Further large-scale placebo-controlled clinical trials will be necessary to fully evaluate the benefits of quetiapine treatment for this disorder.
Asunto(s)
Anorexia Nerviosa/tratamiento farmacológico , Anorexia Nerviosa/fisiopatología , Antipsicóticos/uso terapéutico , Dibenzotiazepinas/uso terapéutico , Adolescente , Adulto , Análisis de Varianza , Anorexia Nerviosa/rehabilitación , Protocolos Clínicos , Femenino , Estudios de Seguimiento , Humanos , Masculino , Proyectos Piloto , Escalas de Valoración Psiquiátrica , Psicoterapia/métodos , Fumarato de Quetiapina , Encuestas y Cuestionarios , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
Histone deacetylase (HDAC) inhibitors that target Class I and Class II HDACs are of synthetic and therapeutic interest and ongoing clinical studies indicate that they show great promise for the treatment of cancer. Moreover, Zolinza (vorinostat) was recently approved by the FDA for the treatment of the cutaneous manifestations of cutaneous T-cell lymphoma [Nat. Rev. Drug Disc. 2007, 6, 21]. As part of a broader effort to more fully explore the structure-activity relationships (SAR) of HDAC inhibitors, we sought to identify novel HDAC inhibitor structures through iterative design by utilizing low affinity ligands as synthetic starting points for SAR development. Novel and potent HDAC inhibitors have been identified using this approach and herein we report the optimization of the recognition elements of a novel series of malonyl-derived HDAC inhibitors.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Inhibidores de Histona Desacetilasas , Diseño de Fármacos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
This communication highlights the development of a nicotinamide series of histone deacetylase inhibitors within the benzamide structural class. Extensive exploration around the nicotinamide core led to the discovery of a class I selective HDAC inhibitor that possesses excellent intrinsic and cell-based potency, acceptable ancillary pharmacology, favorable pharmacokinetics, sustained pharmacodynamics in vitro, and achieves in vivo efficacy in an HCT116 xenograft model.
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6-Aminonicotinamida/análogos & derivados , 6-Aminonicotinamida/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , 6-Aminonicotinamida/síntesis química , Animales , Área Bajo la Curva , Benzamidas/química , Disponibilidad Biológica , Línea Celular Tumoral , Permeabilidad de la Membrana Celular/efectos de los fármacos , Perros , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/farmacocinética , Semivida , Humanos , Isoenzimas/antagonistas & inhibidores , Modelos Moleculares , Trasplante de Neoplasias , Unión Proteica , Ratas , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
The design of a human immunodeficiency virus-1 (HIV-1) immunogen that can induce broadly reactive neutralizing antibodies is a major goal of HIV-1 vaccine development. Although rare human monoclonal antibodies (mAbs) exist that broadly neutralize HIV-1, HIV-1 envelope immunogens do not induce these antibody specificities. Here we demonstrate that the two most broadly reactive HIV-1 envelope gp41 human mAbs, 2F5 and 4E10, are polyspecific autoantibodies reactive with the phospholipid cardiolipin. Thus, current HIV-1 vaccines may not induce these types of antibodies because of autoantigen mimicry of the conserved membrane-proximal epitopes of the virus. These results may have important implications for generating effective neutralizing antibody responses by using HIV-1 vaccines.
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Anticuerpos Monoclonales/inmunología , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Cardiolipinas/inmunología , Anticuerpos Anti-VIH/inmunología , Proteína gp41 de Envoltorio del VIH/inmunología , VIH-1/inmunología , Vacunas contra el SIDA/inmunología , Animales , Especificidad de Anticuerpos , Autoanticuerpos/química , Enfermedades Autoinmunes/inmunología , Línea Celular Tumoral , Epítopos , Anticuerpos Anti-VIH/química , Proteína gp41 de Envoltorio del VIH/química , Infecciones por VIH/inmunología , Humanos , Ratones , Imitación Molecular , Pruebas de NeutralizaciónRESUMEN
Fibroblasts from patients with thiamine-responsive megaloblastic anemia (TRMA) syndrome with diabetes and deafness undergo apoptotic cell death in the absence of supplemental thiamine in their cultures. The basis of megaloblastosis in these patients has not been determined. Here we use the stable [1,2-13C2]glucose isotope-based dynamic metabolic profiling technique to demonstrate that defective high-affinity thiamine transport primarily affects the synthesis of nucleic acid ribose via the nonoxidative branch of the pentose cycle. RNA ribose isolated from TRMA fibroblasts in thiamine-depleted cultures shows a time-dependent decrease in the fraction of ribose derived via transketolase, a thiamine-dependent enzyme in the pentose cycle. The fractional rate of de novo ribose synthesis from glucose is decreased several fold 2 to 4 days after removal of thiamine from the culture medium. No such metabolic changes are observed in wild-type fibroblasts or in TRMA mutant cells in thiamine-containing medium. Fluxes through glycolysis are similar in TRMA versus control fibroblasts in the pentose and TCA cycles. We conclude that reduced nucleic acid production through impaired transketolase catalysis is the underlying biochemical disturbance that likely induces cell cycle arrest or apoptosis in bone marrow cells and leads to the TRMA syndrome in patients with defective high-affinity thiamine transport.
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Anemia Megaloblástica/metabolismo , Fibroblastos/metabolismo , ARN/biosíntesis , Ribosa/biosíntesis , Tiamina/farmacología , Anemia Megaloblástica/etiología , Anemia Megaloblástica/patología , Isótopos de Carbono , Fibroblastos/patología , Glucosa/metabolismo , Humanos , Proteínas de Transporte de Membrana/deficiencia , Proteínas de Transporte de Membrana/genética , Mutación , Trazadores RadiactivosRESUMEN
Thiamine-responsive megaloblastic anemia with diabetes and deafness (TRMA) is an autosomal recessive disease caused by mutations in the high-affinity thiamine transporter gene SLC19A2. To study the role of thiamine transport in the pathophysiology of TRMA syndrome and of each of the component disorders, we created a targeted disruption of the Slc19a2 gene in mice. Slc19a2 -/- mice are viable and females are fertile. Male -/- mice on a pure 129/Sv background are infertile with small testes (testis/body weight=0.13 +/- 0.04 knockout vs. 0.35 +/- 0.05 wild type, P<0.000005). The lack of developing germ cells beyond primary spermatocytes suggests an arrest in spermatogenesis prior to meiosis II. Nuclear chromatin changes indicative of apoptosis are present. No mature sperm are found in the tubules or epididymis. This phenotype suggests a previously unknown role for thiamine transport in spermatogenesis and male fertility. Slc19a2 -/- mice on a pure 129/Sv background develop reticulocytopenia after two weeks on thiamine-depleted chow with a virtual absence of reticulocytes in the peripheral blood (0.12% knockout vs. 2.58% wild type, P=0.0079). Few erythroid precursors are found in the bone marrow. Contrary to human TRMA syndrome, we see no evidence of megaloblastosis or ringed sideroblasts in the bone marrow of Slc19a2 -/- mice in thiamine-replete or thiamine-deficient dietary states. Phenotypic differences between TRMA patients and Slc19a2 -/- mice might be explained by dissimilar tissue expression patterns of the transporter, as well as by differing metabolic needs and possible different species-specific contributions of the related thiamine transporter Slc19a3.