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1.
Lancet Neurol ; 23(5): 477-486, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38631764

RESUMEN

BACKGROUND: Facioscapulohumeral muscular dystrophy is a hereditary progressive myopathy caused by aberrant expression of the transcription factor DUX4 in skeletal muscle. No approved disease-modifying treatments are available for this disorder. We aimed to assess the safety and efficacy of losmapimod (a small molecule that inhibits p38α MAPK, a regulator of DUX4 expression, and p38ß MAPK) for the treatment of facioscapulohumeral muscular dystrophy. METHODS: We did a randomised, double-blind, placebo-controlled phase 2b trial at 17 neurology centres in Canada, France, Spain, and the USA. We included adults aged 18-65 years with type 1 facioscapulohumeral muscular dystrophy (ie, with loss of repression of DUX4 expression, as ascertained by genotyping), a Ricci clinical severity score of 2-4, and at least one skeletal muscle judged using MRI to be suitable for biopsy. Participants were randomly allocated (1:1) to either oral losmapimod (15 mg twice a day) or matching placebo for 48 weeks, via an interactive response technology system. The investigator, study staff, participants, sponsor, primary outcome assessors, and study monitor were masked to the treatment allocation until study closure. The primary endpoint was change from baseline to either week 16 or 36 in DUX4-driven gene expression in skeletal muscle biopsy samples, as measured by quantitative RT-PCR. The primary efficacy analysis was done in all participants who were randomly assigned and who had available data for assessment, according to the modified intention-to-treat principle. Safety and tolerability were assessed as secondary endpoints. This study is registered at ClinicalTrials.gov, number NCT04003974. The phase 2b trial is complete; an open-label extension is ongoing. FINDINGS: Between Aug 27, 2019, and Feb 27, 2020, 80 people were enrolled. 40 were randomly allocated to losmapimod and 40 to placebo. 54 (68%) participants were male and 26 (33%) were female, 70 (88%) were White, and mean age was 45·7 (SD 12·5) years. Least squares mean changes from baseline in DUX4-driven gene expression did not differ significantly between the losmapimod (0·83 [SE 0·61]) and placebo (0·40 [0·65]) groups (difference 0·43 [SE 0·56; 95% CI -1·04 to 1·89]; p=0·56). Losmapimod was well tolerated. 29 treatment-emergent adverse events (nine drug-related) were reported in the losmapimod group compared with 23 (two drug-related) in the placebo group. Two participants in the losmapimod group had serious adverse events that were deemed unrelated to losmapimod by the investigators (alcohol poisoning and suicide attempt; postoperative wound infection) compared with none in the placebo group. No treatment discontinuations due to adverse events occurred and no participants died during the study. INTERPRETATION: Although losmapimod did not significantly change DUX4-driven gene expression, it was associated with potential improvements in prespecified structural outcomes (muscle fat infiltration), functional outcomes (reachable workspace, a measure of shoulder girdle function), and patient-reported global impression of change compared with placebo. These findings have informed the design and choice of efficacy endpoints for a phase 3 study of losmapimod in adults with facioscapulohumeral muscular dystrophy. FUNDING: Fulcrum Therapeutics.


Asunto(s)
Distrofia Muscular Facioescapulohumeral , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ciclopropanos/efectos adversos , Ciclopropanos/uso terapéutico , Método Doble Ciego , Piridinas/efectos adversos , Piridinas/uso terapéutico , Resultado del Tratamiento
2.
Environ Health Perspect ; 128(11): 115001, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-33170741

RESUMEN

BACKGROUND: Modeling suggests that climate change mitigation actions can have substantial human health benefits that accrue quickly and locally. Documenting the benefits can help drive more ambitious and health-protective climate change mitigation actions; however, documenting the adverse health effects can help to avoid them. Estimating the health effects of mitigation (HEM) actions can help policy makers prioritize investments based not only on mitigation potential but also on expected health benefits. To date, however, the wide range of incompatible approaches taken to developing and reporting HEM estimates has limited their comparability and usefulness to policymakers. OBJECTIVE: The objective of this effort was to generate guidance for modeling studies on scoping, estimating, and reporting population health effects from climate change mitigation actions. METHODS: An expert panel of HEM researchers was recruited to participate in developing guidance for conducting HEM studies. The primary literature and a synthesis of HEM studies were provided to the panel. Panel members then participated in a modified Delphi exercise to identify areas of consensus regarding HEM estimation. Finally, the panel met to review and discuss consensus findings, resolve remaining differences, and generate guidance regarding conducting HEM studies. RESULTS: The panel generated a checklist of recommendations regarding stakeholder engagement: HEM modeling, including model structure, scope and scale, demographics, time horizons, counterfactuals, health response functions, and metrics; parameterization and reporting; approaches to uncertainty and sensitivity analysis; accounting for policy uptake; and discounting. DISCUSSION: This checklist provides guidance for conducting and reporting HEM estimates to make them more comparable and useful for policymakers. Harmonization of HEM estimates has the potential to lead to advances in and improved synthesis of policy-relevant research that can inform evidence-based decision making and practice. https://doi.org/10.1289/EHP6745.


Asunto(s)
Contaminación del Aire , COVID-19 , Coronavirus , Síndrome Respiratorio Agudo Grave , Cambio Climático , Brotes de Enfermedades , Estudios Epidemiológicos , Humanos , SARS-CoV-2
4.
Cell ; 150(3): 575-89, 2012 Aug 03.
Artículo en Inglés | MEDLINE | ID: mdl-22863010

RESUMEN

The mechanism by which cells decide to skip mitosis to become polyploid is largely undefined. Here we used a high-content image-based screen to identify small-molecule probes that induce polyploidization of megakaryocytic leukemia cells and serve as perturbagens to help understand this process. Our study implicates five networks of kinases that regulate the switch to polyploidy. Moreover, we find that dimethylfasudil (diMF, H-1152P) selectively increased polyploidization, mature cell-surface marker expression, and apoptosis of malignant megakaryocytes. An integrated target identification approach employing proteomic and shRNA screening revealed that a major target of diMF is Aurora kinase A (AURKA). We further find that MLN8237 (Alisertib), a selective inhibitor of AURKA, induced polyploidization and expression of mature megakaryocyte markers in acute megakaryocytic leukemia (AMKL) blasts and displayed potent anti-AMKL activity in vivo. Our findings provide a rationale to support clinical trials of MLN8237 and other inducers of polyploidization and differentiation in AMKL.


Asunto(s)
Azepinas/farmacología , Descubrimiento de Drogas , Leucemia Megacarioblástica Aguda/tratamiento farmacológico , Megacariocitos/metabolismo , Poliploidía , Pirimidinas/farmacología , Bibliotecas de Moléculas Pequeñas , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/farmacología , Animales , Aurora Quinasa A , Aurora Quinasas , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Humanos , Leucemia Megacarioblástica Aguda/genética , Megacariocitos/citología , Megacariocitos/patología , Ratones , Ratones Endogámicos C57BL , Mapas de Interacción de Proteínas , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Quinasas Asociadas a rho/metabolismo
5.
Hepatol Int ; 6(1): 379-85, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21557024

RESUMEN

PURPOSE: Some studies have suggested that autoantibodies might define a subcategory and phenotype of nonalcoholic fatty liver disease (NAFLD) associated with advanced histological features. We evaluated the relationship between the presence of serum autoantibodies and liver histology in a large cohort of well-characterized patients with NAFLD. METHODS: A total of 864 NAFLD patients participating in two prospective multicentre clinical studies underwent testing for serum autoantibodies within 24 months of a liver biopsy. Liver histology was compared between the patients with and without ANA ≥ 1:160 or ASMA ≥ 1:40 or both. RESULTS: Autoantibodies were present in 182 patients (21%). There was no difference in age, gender, race, body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR), or history of diabetes between the two groups. Biopsies in subjects with autoantibodies were less likely to have moderate-to-severe steatosis (i.e., >33%) compared to controls (57.1 vs. 43.0%, P value = 0.0006). Lobular inflammation (46.7 vs. 47.5%), ballooning degeneration (38.5 vs. 42.5%), and advanced fibrosis (33.2 vs. 29.3%) were not different between the two groups. Histologic evidence of 'definite' NASH did not differ significantly between the two groups (55.5 vs. 58.9%). After adjusting for age, gender, BMI, race, and diabetes, the presence of autoantibodies was independently associated with lower prevalence of moderate-to-severe steatosis [odds ratio (OR), 0.58; 95% confidence interval (CI), 0.41-0.82; P = 0.01]. CONCLUSION: Autoantibodies are frequently positive in NAFLD in the absence of autoimmune hepatitis and their occurrence is not associated with more advanced histologic features.

8.
Eur J Pharmacol ; 623(1-3): 96-102, 2009 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-19766109

RESUMEN

The triptans, serotonin 5-HT(1B/1D) receptor agonists exemplified by sumatriptan, are a mainstay migraine therapy but have class labeling contraindicating their use in patients with coronary artery disease. Triptans constrict human coronary artery in vitro, and there are case reports of myocardial infarction in patients using sumatriptan. However, preclinical studies with sumatriptan in normal dogs have failed to demonstrate effects on resting coronary flow. Calcitonin gene-related peptide (CGRP) receptor antagonism, exemplified by the prototype CGRP receptor antagonist peptide CGRP(8-37), is a new antimigraine mechanism which also has been reported to have no effect on coronary flow in normal, non-stressed animals. The goal of the present studies was to compare the effects of sumatriptan (10microg/kg/min i.v.) and CGRP(8-37) (30microg/kg/min i.v.) on systemic and coronary hemodynamics in conscious dogs under resting conditions and during myocardial reactive hyperemia following a brief 15s of coronary artery occlusion. Neither CGRP(8-37) nor sumatriptan affected resting coronary flow. However, whereas CGRP(8-37) had no effect on myocardial reactive hyperemic response, sumatriptan reduced peak reactive hyperemic coronary artery blood flow (baseline vs treatment: 75.4+/-12.7 vs 60.0+/-10.3ml/min, P<0.05), reactive hyperemic flow (16.7+/-5.2 vs 11.6+/-3.3ml, P<0.05) and the repayment of coronary blood flow debt following coronary artery occlusion (484+/-76 vs 369+/-57%, P<0.05), indicating an impairment in coronary blood flow reserve. The positive control nitric oxide synthase inhibitor L-NNA (30mg/kg/30min i.v.) likewise significantly attenuated myocardial reactive hyperemic response. These findings provide evidence for a differentiation between CGRP receptor antagonism and triptan effects on coronary vascular function.


Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Péptido Relacionado con Gen de Calcitonina/farmacología , Circulación Coronaria/efectos de los fármacos , Hiperemia/tratamiento farmacológico , Fragmentos de Péptidos/farmacología , Agonistas del Receptor de Serotonina 5-HT1 , Agonistas de Receptores de Serotonina/farmacología , Sumatriptán/farmacología , Animales , Péptido Relacionado con Gen de Calcitonina/administración & dosificación , Catéteres de Permanencia , Estado de Conciencia/fisiología , Enfermedad de la Arteria Coronaria/complicaciones , Oclusión Coronaria/fisiopatología , Estudios Cruzados , Perros , Hemodinámica , Infusiones Intraarteriales , Trastornos Migrañosos/complicaciones , Trastornos Migrañosos/tratamiento farmacológico , Fragmentos de Péptidos/administración & dosificación , Agonistas de Receptores de Serotonina/administración & dosificación , Agonistas de Receptores de Serotonina/sangre , Sumatriptán/administración & dosificación , Sumatriptán/sangre , Factores de Tiempo
9.
Proc Natl Acad Sci U S A ; 106(12): 4617-22, 2009 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-19255428

RESUMEN

Most small-molecule probes and drugs alter cell circuitry by interacting with 1 or more proteins. A complete understanding of the interacting proteins and their associated protein complexes, whether the compounds are discovered by cell-based phenotypic or target-based screens, is extremely rare. Such a capability is expected to be highly illuminating--providing strong clues to the mechanisms used by small-molecules to achieve their recognized actions and suggesting potential unrecognized actions. We describe a powerful method combining quantitative proteomics (SILAC) with affinity enrichment to provide unbiased, robust and comprehensive identification of the proteins that bind to small-molecule probes and drugs. The method is scalable and general, requiring little optimization across different compound classes, and has already had a transformative effect on our studies of small-molecule probes. Here, we describe in full detail the application of the method to identify targets of kinase inhibitors and immunophilin binders.


Asunto(s)
Sondas Moleculares/metabolismo , Preparaciones Farmacéuticas/metabolismo , Proteínas/metabolismo , Carbazoles/metabolismo , Células HeLa , Humanos , Inmunofilinas/química , Inmunofilinas/metabolismo , Alcaloides Indólicos/metabolismo , Marcaje Isotópico , Ligandos , Microesferas , Proteínas Asociadas a Microtúbulos/metabolismo , Inhibidores de Proteínas Quinasas/metabolismo , Proteínas Quinasas/metabolismo , Proteómica , Solubilidad
10.
J Pharmacol Exp Ther ; 310(2): 488-97, 2004 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-15051800

RESUMEN

Antagonists of the B1 bradykinin receptor (B1R) offer the promise of novel therapeutic agents for the treatment of inflammatory and neuropathic pain. However, the in vivo characterization of the pharmacodynamics of B1R antagonists is hindered by the low level of B1R expression in healthy tissue and the profound species selectivity exhibited by many compounds for the human B1R. To circumvent these issues, we generated a transgenic rat expressing the human B1R under the control of the neuron-specific enolase promoter. Membranes prepared from whole brain homogenates of heterozygous transgenic rats indicate a B1R expression level of 30 to 40 fmol/mg; there is no detectable B1R expression in control nontransgenic rats. The pharmacological profile of the B1R expressed in the transgenic rat matches that expected of the human, but not the rat receptor. The mapping of the transgene insertion site to rat chromosome 1 permitted the development of a reliable assay for the identification of homozygous transgenic rats. Significantly, homozygous transgenic rats express 2-fold more B1R than heterozygous animals. Autoradiographic analyses of tissue sections from transgenic rats reveal that the B1R is broadly expressed in both the brain and spinal cord. The human B1R expressed in the transgenic rat functions in an in vitro contractile assay and thus has the potential to elicit a functional response in vivo. Using the humanized B1R transgenic rat, an assay was developed that is suitable for the routine evaluation of a test compound's ability to occupy the human B1R in the central nervous system.


Asunto(s)
Animales Modificados Genéticamente/genética , Modelos Animales , Ratas/genética , Receptor de Bradiquinina B1/biosíntesis , Receptor de Bradiquinina B1/genética , Animales , Animales Modificados Genéticamente/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Células CHO , Cricetinae , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Íleon/efectos de los fármacos , Íleon/metabolismo , Masculino , Fragmentos de Péptidos/farmacología , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología
11.
J Cardiovasc Pharmacol ; 42(5): 656-61, 2003 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-14576515

RESUMEN

Whether endogenous calcitonin gene-related peptide (CGRP) plays a role in heart failure is unclear. Seven dogs were instrumented with left ventricular (LV) pressure gauges, pacers, coronary occluder and aortic, atrial, and coronary sinus catheters. Hemodynamic recordings and response to alpha-CGRP challenge were obtained for baseline in the conscious state. Rapid pacing (240 beats/min) was then initiated. The coronary artery was occluded for 90 minutes followed by reperfusion after 2 weeks of pacing. After 6 weeks of pacing, LV pressure (-11 +/- 6%), LV dP/dt (-53 +/- 5%), and mean arterial pressure (-15 +/- 4%) decreased (P < 0.01), while left atrial pressure (+19 +/- 3 mm Hg from 7 +/- 1 mm Hg) and heart rate (+53 +/- 16%) increased (P < 0.01). Infusion of the alpha-CGRP receptor antagonist alpha-CGRP[8-37] (30 microg/kg/min, i.v.), which blocked the exogenous alpha-CGRP challenge, did not affect any of these indices. Regional blood flow, as measured by the microsphere technique, in the nonischemic myocardium, as well as cerebral and renal vasculatures were unaltered during the infusion of alpha-CGRP[8-37]. Plasma concentrations of CGRP from both arterial and coronary sinus samples were unchanged after 6 weeks of pacing as compared with control. Thus, we conclude that endogenous alpha-CGRP does not appear to play a major role in the regulation of cardiac and peripheral vascular dynamics in the late stage of heart failure.


Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Péptido Relacionado con Gen de Calcitonina/farmacología , Insuficiencia Cardíaca/fisiopatología , Fragmentos de Péptidos/farmacología , Función Ventricular Izquierda/fisiología , Animales , Circulación Cerebrovascular/efectos de los fármacos , Circulación Cerebrovascular/fisiología , Enfermedad Crónica , Perros , Femenino , Masculino , Receptores de Péptido Relacionado con el Gen de Calcitonina/fisiología , Flujo Sanguíneo Regional/efectos de los fármacos , Flujo Sanguíneo Regional/fisiología , Circulación Renal/efectos de los fármacos , Circulación Renal/fisiología , Función Ventricular Izquierda/efectos de los fármacos
12.
J Pharmacol Exp Ther ; 306(2): 815-20, 2003 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-12750438

RESUMEN

To determine the functional role of growth hormone (GH) secretagogue in myocardium with ischemia, left ventricular (LV) pressure gauge, wall thickness crystals, coronary occluder, pacers, and catheters were implanted in 26 dogs. Beginning 1 week after ventricular pacing (240 beats/min) was initiated, dogs were treated (s.c.) with GH releasing peptide-6 (GHRP-6, n = 8, 0.2 mg/kg/day), GH (n = 7, 0.06 mg/kg/day), or vehicle (n = 11). Two weeks of pacing was associated with similar decreases in LV pressure, rate of change of LV pressure, systolic wall thickening (WT), and an increase in left atrial pressure in all groups. Coronary artery occlusion (CAO) resulted in a similar loss of WT in ischemic regions, which did not recover during reperfusion period in all groups. WT in nonischemic regions, however, was enhanced in the GHRP-6 group compared with the GH and vehicle groups, e.g., increase of WT after 1 h of reperfusion was greater (p <0.05) in the GHRP-6 (+53 +/- 8%) than in the GH (+14 +/- 12%) or (+14 +/- 6%). There were no differences in myocardial blood flow, hemodynamics, or arrhythmic beats among all groups during CAO and reperfusion periods. Strikingly, no dogs in the GHRP-6 group died during CAO, whereas the survival rates for GH and vehicle groups were 57 and 55%, respectively. Our data demonstrate, for the first time, that chronic therapy with a GH secretagogue prevents sudden death in dogs with dilated cardiomyopathy subjected to acute ischemia. This seems to be related to an enhanced nonischemic compensatory mechanism mediated by the GH secretagogue receptors rather than via the GH/insulin growth factor-1 pathway.


Asunto(s)
Cardiomiopatía Dilatada/complicaciones , Hormona del Crecimiento/uso terapéutico , Isquemia Miocárdica/complicaciones , Oligopéptidos/uso terapéutico , Daño por Reperfusión/prevención & control , Animales , Cardiomiopatía Dilatada/mortalidad , Enfermedad Crónica , Estenosis Coronaria/complicaciones , Modelos Animales de Enfermedad , Perros , Ventrículos Cardíacos/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Mortalidad , Contracción Miocárdica , Isquemia Miocárdica/mortalidad , Reperfusión Miocárdica
13.
Bioorg Med Chem Lett ; 12(3): 319-23, 2002 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-11814787

RESUMEN

The synthesis and biological evaluation of a series of nonpeptidic small molecule antagonists of the human platelet thrombin receptor (PAR-1) are described. Optimization of the 5-amino-3-arylisoxazole lead resulted in an approximate 100-fold increase in potency. The most potent of these compounds (54) inhibits platelet activation with IC(50)s of 90 nM against the thrombin receptor agonist peptide (TRAP) and 510 nM against thrombin as the agonist. Further, antagonist 54 fully blocks platelet aggregation stimulated by 1 nM thrombin for 10 min.


Asunto(s)
Azepinas/síntesis química , Azepinas/farmacología , Plaquetas/metabolismo , Isoxazoles/síntesis química , Isoxazoles/farmacología , Receptores de Trombina/antagonistas & inhibidores , Plaquetas/efectos de los fármacos , Diseño de Fármacos , Humanos , Técnicas In Vitro , Indicadores y Reactivos , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/farmacología , Piperidinas/síntesis química , Piperidinas/química , Activación Plaquetaria/efectos de los fármacos , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/farmacología , Receptor PAR-1 , Relación Estructura-Actividad , Trombina/antagonistas & inhibidores
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