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BACKGROUND: The aim of this study was to pool multiple data sets to build a patient-centric, data-informed, natural history model (NHM) for Duchenne muscular dystrophy (DMD) to estimate disease trajectory across patient lifetime under current standard of care in future economic evaluations. The study was conducted as part of Project HERCULES, a multi-stakeholder collaboration to develop tools to support health technology assessments of new treatments for DMD. METHODS: Health states were informed by a review of NHMs for DMD and input from clinicians, patients and caregivers, and defined using common outcomes in clinical trials and real-world practice. The primary source informing the NHM was the Critical Path Institute Duchenne Regulatory Science Consortium (D-RSC) database. This was supplemented with expert input obtained via an elicitation exercise, and a systematic literature review and meta-analysis of mortality data. RESULTS: The NHM includes ambulatory, transfer and non-ambulatory phases, which capture loss of ambulation, ability to weight bear and upper body and respiratory function, respectively. The NHM estimates patients spend approximately 9.5 years in ambulatory states, 1.5 years in the transfer state and the remainder of their lives in non-ambulatory states. Median predicted survival is 34.8 years (95% CI 34.1-35.8). CONCLUSION: The model includes a detailed disease pathway for DMD, including the clinically and economically important transfer state. The NHM may be used to estimate the current trajectory of DMD in economic evaluations of new treatments, facilitating inclusion of a lifetime time horizon, and will help identify areas for further research.
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The clinical benefit of PD-1 blockade can be improved by combination with CTLA4 inhibition but is commensurate with significant immune-related adverse events suboptimally limiting the doses of anti-CTLA4 mAb that can be used. MEDI5752 is a monovalent bispecific antibody designed to suppress the PD-1 pathway and provide modulated CTLA4 inhibition favoring enhanced blockade on PD-1+ activated T cells. We show that MEDI5752 preferentially saturates CTLA4 on PD-1+ T cells versus PD-1- T cells, reducing the dose required to elicit IL2 secretion. Unlike conventional PD-1/CTLA4 mAbs, MEDI5752 leads to the rapid internalization and degradation of PD-1. Moreover, we show that MEDI5752 preferentially localizes and accumulates in tumors providing enhanced activity when compared with a combination of mAbs targeting PD-1 and CTLA4 in vivo. Following treatment with MEDI5752, robust partial responses were observed in two patients with advanced solid tumors. MEDI5752 represents a novel immunotherapy engineered to preferentially inhibit CTLA4 on PD-1+ T cells. SIGNIFICANCE: The unique characteristics of MEDI5752 represent a novel immunotherapy engineered to direct CTLA4 inhibition to PD-1+ T cells with the potential for differentiated activity when compared with current conventional mAb combination strategies targeting PD-1 and CTLA4. This molecule therefore represents a step forward in the rational design of cancer immunotherapy.See related commentary by Burton and Tawbi, p. 1008.This article is highlighted in the In This Issue feature, p. 995.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma de Células Claras/tratamiento farmacológico , Antígeno CTLA-4/metabolismo , Humanos , Inmunoterapia , Neoplasias Renales/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Linfocitos T/inmunologíaAsunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Antiinflamatorios/uso terapéutico , Bevacizumab/uso terapéutico , Dexametasona/uso terapéutico , Retinopatía Diabética/tratamiento farmacológico , Edema Macular/tratamiento farmacológico , Humanos , Estimación de Kaplan-Meier , Modelos de Riesgos ProporcionalesRESUMEN
The integrity of the genome is maintained by a host of surveillance and repair mechanisms that are pivotal for cellular function. The tumour suppressor protein p53 is a major component of the DNA damage response pathway and plays a vital role in the maintenance of cell-cycle checkpoints. Here we show that a microRNA, miR-486, and its host gene ankyrin-1 (ANK1) are induced by p53 following DNA damage. Strikingly, the cytoskeleton adaptor protein ankyrin-1 was induced over 80-fold following DNA damage. ANK1 is upregulated in response to a variety of DNA damage agents in a range of cell types. We demonstrate that miR-486-5p is involved in controlling G1/S transition following DNA damage, whereas the induction of the ankyrin-1 protein alters the structure of the actin cytoskeleton and sustains limited cell migration during DNA damage. Importantly, we found that higher ANK1 expression correlates with decreased survival in cancer patients. Thus, these observations highlight ANK1 as an important effector downstream of the p53 pathway.
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Ancirinas/genética , Ancirinas/metabolismo , Daño del ADN , Proteína p53 Supresora de Tumor/metabolismo , Regulación hacia Arriba/genética , Citoesqueleto de Actina/metabolismo , Ancirinas/antagonistas & inhibidores , Antibióticos Antineoplásicos/farmacología , Western Blotting , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Línea Celular , Movimiento Celular/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Reparación del ADN , Doxorrubicina/farmacología , Femenino , Humanos , MicroARNs/antagonistas & inhibidores , MicroARNs/genética , MicroARNs/metabolismo , Microscopía Fluorescente , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Interferencia de ARN , ARN Mensajero/metabolismo , ARN Interferente Pequeño/metabolismo , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/genéticaAsunto(s)
Bevacizumab/administración & dosificación , Dexametasona/administración & dosificación , Retinopatía Diabética/tratamiento farmacológico , Edema Macular/tratamiento farmacológico , Agudeza Visual , Inhibidores de la Angiogénesis/administración & dosificación , Retinopatía Diabética/complicaciones , Relación Dosis-Respuesta a Droga , Implantes de Medicamentos , Femenino , Estudios de Seguimiento , Glucocorticoides/administración & dosificación , Humanos , Inyecciones Intravítreas , Edema Macular/etiología , Masculino , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVE: To report the effect of bevacizumab versus dexamethasone on hard exudates (HEX) in diabetic macular oedema (DME). DESIGN: Post hoc analysis of 24-month data from the Randomised clinical trial of BEVacizumab OR DEXamethasone for diabetic macular oedema (BEVORDEX) phase 2 multicentre randomised clinical trial. Eyes with centre-involving DME resistant to or unlikely to benefit from macular laser therapy were included. Eyes were randomly assigned to bevacizumab every 4â weeks or Ozurdex dexamethasone implant (DEX) every 16â weeks, both as required. The 68 eyes from 48 patients that completed 24-month follow-up were analysed. Two masked graders assessed extent and location of HEX on baseline, 12-month and 24-month foveal-centred colour fundus photographs using validated grading software. RESULTS: Macular HEX was present in 60% of study eyes. Of these, 21 eyes were treated with DEX and 20 eyes with bevacizumab. Both treatments led to reduction in area of macular HEX at 12 months and 24 months. There was greater regression of HEX from the foveal centre in DEX-treated eyes (median change +890â µm, IQR=1040â µm) than bevacizumab-treated eyes (median change +7.0â µm, IQR=590â µm) at 12 months (p=0.04) but the difference was no longer statistically significant (p=0.10) by 24 months (DEX +1400â µm, IQR=1590â µm; bevacizumab +20â µm, IQR=2680â µm). Reassuringly, no study eye developed HEX at the foveal centre, a visually devastating consequence of diabetic maculopathy. CONCLUSIONS: Bevacizumab and DEX were effective in reducing area of HEX in eyes with DME. DEX provided more rapid regression of HEX from the foveal centre although bevacizumab-treated eyes started to catch up by 24 months. Distance from the foveal centre as well as total area of macular HEX should be assessed when evaluating treatments for foveal-threatening HEX. TRIAL REGISTRATION NUMBER: NCT01298076; Post-results.
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Bevacizumab/administración & dosificación , Dexametasona/administración & dosificación , Retinopatía Diabética/tratamiento farmacológico , Edema Macular/tratamiento farmacológico , Adulto , Anciano , Inhibidores de la Angiogénesis/administración & dosificación , Retinopatía Diabética/complicaciones , Retinopatía Diabética/diagnóstico , Relación Dosis-Respuesta a Droga , Femenino , Angiografía con Fluoresceína , Estudios de Seguimiento , Fondo de Ojo , Glucocorticoides/administración & dosificación , Humanos , Inyecciones Intravítreas , Edema Macular/diagnóstico , Edema Macular/etiología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Tiempo , Tomografía de Coherencia Óptica , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Agudeza VisualRESUMEN
BACKGROUND: Diabetic macular oedema (DMO) is the commonest cause of vision loss in people with diabetes. Laser photocoagulation can be effective in the treatment of DMO; however, its mechanism of action is still poorly understood. A better understanding of these mechanisms may allow the development of therapeutic approaches that could avoid the deleterious adverse events associated with photocoagulation. METHODS: We have used proteomic techniques to identify the protein changes induced by threshold intensity retinal laser treatment in a rodent model of diabetic retinopathy. Retinae were obtained from diabetic Dark Agouti rats 8 weeks following laser treatment. Extracted proteins from lasered and non-lasered diabetic retinae were separated and compared using two-dimensional gel electrophoresis. RESULTS: Image analysis revealed 24 protein spots with decreased expression after laser treatment and 9 spots with increased expression. On lasered retinal gels, four spots were uniquely expressed, with eight unique spots on non-lasered gels. Twenty-two protein spots of interest were identified using matrix-assisted desorption ionization-mass spectrometry with database matching. Following laser, Wnt-5 beta, LEK-1, GADPH, claudin-12 and calretinin were significantly down-regulated in expression. CONCLUSIONS: The present study provides a proteomic insight into the underlying biological basis for the therapeutic effects of laser for DMO. We provide further evidence of the involvement of Wnt pathway signalling in the neural retina in DMO, and for up to 2 months following laser treatment. Changes in LEK-1 and claudin-12 may have effector roles, and changes in glyceraldehyde-3-phosphate dehydrogenase and calretinin may reflect the altered retinal microenvironment resulting from laser treatment.
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Diabetes Mellitus Experimental/cirugía , Retinopatía Diabética/cirugía , Proteínas del Ojo/metabolismo , Coagulación con Láser/métodos , Proteoma/metabolismo , Vía de Señalización Wnt/fisiología , Animales , Diabetes Mellitus Experimental/metabolismo , Retinopatía Diabética/metabolismo , Electroforesis en Gel Bidimensional , Masculino , Proteómica , Ratas , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
Widespread drug resistance due to empiric use of broad-spectrum antibiotics has stimulated development of bacteria-specific strategies for prophylaxis and therapy based on modern monoclonal antibody (mAb) technologies. However, single-mechanism mAb approaches have not provided adequate protective activity in the clinic. We constructed multifunctional bispecific antibodies, each conferring three mechanisms of action against the bacterial pathogen Pseudomonas aeruginosa by targeting the serotype-independent type III secretion system (injectisome) virulence factor PcrV and persistence factor Psl exopolysaccharide. A new bispecific antibody platform, BiS4, exhibited superior synergistic protection against P. aeruginosa-induced murine pneumonia compared to parent mAb combinations or other available bispecific antibody structures. BiS4αPa was protective in several mouse infection models against disparate P. aeruginosa strains and unexpectedly further synergized with multiple antibiotic classes even against drug-resistant clinical isolates. In addition to resulting in a multimechanistic clinical candidate (MEDI3902) for the prevention or treatment of P. aeruginosa infections, these antibody studies suggest that multifunctional antibody approaches may be a promising platform for targeting other antibiotic-resistant bacterial pathogens.
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Anticuerpos Antibacterianos/uso terapéutico , Anticuerpos Biespecíficos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Infecciones por Pseudomonas/terapia , Pseudomonas aeruginosa/inmunología , Animales , Antibacterianos/farmacología , Anticuerpos Antibacterianos/química , Anticuerpos Biespecíficos/química , Anticuerpos Monoclonales/química , Antígenos Bacterianos/inmunología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Farmacorresistencia Bacteriana , Humanos , Ratones , Conformación Molecular , Fagocitosis , Infecciones por Pseudomonas/inmunologíaRESUMEN
OBJECTIVE: To report the 12-month results of the first head-to-head comparison of a dexamethasone implant (Ozurdex; Allergan, Inc., Irvine, CA) versus bevacizumab (Avastin; Genentech, South San Francisco, CA) for center-involving diabetic macular edema (DME). DESIGN: Phase 2, prospective, multicenter, randomized, single-masked clinical trial (clinicaltrials.gov identifier NCT01298076). PARTICIPANTS: We enrolled 88 eyes of 61 patients with center-involving DME. METHODS: Forty-two eyes were randomized to receive bevacizumab every 4 weeks and 46 eyes were randomized to receive a dexamethasone implant every 16 weeks, both pro re nata. Results were analyzed using linear regression with generalized estimation equation methods to account for between-eye correlation. MAIN OUTCOME MEASURES: The primary outcome was the proportion of eyes that improved vision by 10 logarithm of minimum angle of resolution letters. Secondary outcomes included mean change in best-corrected visual acuity (BCVA), change in central macular thickness (CMT), injection frequency, and adverse events. Patient-reported outcomes were measured using the Impact of Vision Impairment (IVI) questionnaire. RESULTS: Improvement in BCVA of 10 or more letters was found in 17 of 42 eyes (40%) treated with bevacizumab compared with 19 of 46 dexamethasone implant-treated eyes (41%; P = 0.83). None of the 42 bevacizumab eyes lost 10 letters or more, whereas 5 of 46 (11%) dexamethasone implant eyes did, mostly because of cataract. Mean CMT decreased by 122 µm for bevacizumab eyes and by 187 µm for dexamethasone implant eyes (P = 0.015). Bevacizumab-treated eyes received a mean of 8.6 injections compared with 2.7 injections for dexamethasone implant eyes. Significant improvement in IVI scores occurred for both treatment groups. CONCLUSIONS: Dexamethasone implant achieved similar rates of visual acuity improvement compared with bevacizumab for DME, with superior anatomic outcomes and fewer injections. Both treatments were associated with improvement in visual quality-of-life scores. However, more dexamethasone implant-treated eyes lost vision, mainly because of cataract.
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Inhibidores de la Angiogénesis/administración & dosificación , Antiinflamatorios/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Dexametasona/administración & dosificación , Retinopatía Diabética/tratamiento farmacológico , Edema Macular/tratamiento farmacológico , Anciano , Bevacizumab , Preparaciones de Acción Retardada/uso terapéutico , Retinopatía Diabética/fisiopatología , Implantes de Medicamentos , Femenino , Humanos , Inyecciones Intravítreas , Mácula Lútea/patología , Edema Macular/etiología , Edema Macular/fisiopatología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Análisis de Regresión , Encuestas y Cuestionarios , Agudeza Visual/fisiologíaRESUMEN
MicroRNAs (miRNAs) control gene expression through both translational repression and degradation of target messenger RNAs (mRNAs). However, the interplay between these processes and the precise molecular mechanisms involved remain unclear. Here, we show that translational inhibition is the primary event required for mRNA degradation. Translational inhibition depends on miRNAs impairing the function of the eIF4F initiation complex. We define the RNA helicase eIF4A2 as the key factor of eIF4F through which miRNAs function. We uncover a correlation between the presence of miRNA target sites in the 3' untranslated region (3'UTR) of mRNAs and secondary structure in the 5'UTR and show that mRNAs with unstructured 5'UTRs are refractory to miRNA repression. These data support a linear model for miRNA-mediated gene regulation in which translational repression via eIF4A2 is required first, followed by mRNA destabilization.
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Factor 4A Eucariótico de Iniciación/biosíntesis , Regulación de la Expresión Génica , MicroARNs/metabolismo , Biosíntesis de Proteínas , Estabilidad del ARN , ARN Mensajero/metabolismo , Células HEK293 , Células HeLa , HumanosRESUMEN
INTRODUCTION AND HYPOTHESIS: Information on the prevalence, risk factors and social consequences of pelvic floor dysfunction (PFD) affecting women in 16 low-income and lower middle-income countries is reviewed. METHODS: Medline searches were performed for articles dealing with prevalence of PFD. RESULTS: Thirty studies were identified. The mean prevalence for pelvic organ prolapse was 19.7% (range 3.4-56.4%), urinary incontinence (UI) was 28.7% (range 5.2-70.8%) and faecal incontinence (FI) was 6.9% (range 5.3-41.0%). Risk factors for PFD are similar to those in more affluent countries particularly increased age and parity, but additionally, PFD is associated with other factors including poor nutrition and heavy work. The social consequences of PFD conditions can be devastating. CONCLUSIONS: Pelvic organ prolapse and urinary and faecal incontinence are significant problems in developing countries. Access to health care to manage these conditions is often limited, and women usually have to live with the consequences for the rest of their lives.
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Incontinencia Fecal/epidemiología , Prolapso de Órgano Pélvico/epidemiología , Incontinencia Urinaria/epidemiología , Países en Desarrollo , Incontinencia Fecal/prevención & control , Incontinencia Fecal/psicología , Femenino , Humanos , Prolapso de Órgano Pélvico/prevención & control , Prolapso de Órgano Pélvico/psicología , Prevalencia , Factores de Riesgo , Incontinencia Urinaria/prevención & control , Incontinencia Urinaria/psicologíaRESUMEN
The Afrotropical mosquito Anopheles gambiae sensu stricto, a major vector of malaria, is currently undergoing speciation into the M and S molecular forms. These forms have diverged in larval ecology and reproductive behavior through unknown genetic mechanisms, despite considerable levels of hybridization. Previous genome-wide scans using gene-based microarrays uncovered divergence between M and S that was largely confined to gene-poor pericentromeric regions, prompting a speciation-with-ongoing-gene-flow model that implicated only about 3% of the genome near centromeres in the speciation process. Here, based on the complete M and S genome sequences, we report widespread and heterogeneous genomic divergence inconsistent with appreciable levels of interform gene flow, suggesting a more advanced speciation process and greater challenges to identify genes critical to initiating that process.
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Anopheles/genética , Especiación Genética , Genoma de los Insectos , Animales , Anopheles/clasificación , Evolución Molecular , Femenino , Flujo Génico , Masculino , Modelos Genéticos , Polimorfismo de Nucleótido SimpleRESUMEN
3,4-Methylenedioxymethamphetamine (MDMA) is an amphetamine derivative that elicits complex biological effects in humans. One plausible mechanism for this phenomenon is that racemic MDMA is composed of two stereoisomers that exhibit qualitatively different pharmacological effects. In support of this, studies have shown that R(-)-MDMA tends to have hallucinogen-like effects, whereas S(+)-MDMA tends to have psychomotor stimulant-like effects. However, relatively little is known about whether these stereoisomers engender different endocrine and neurochemical effects. In the present study, the endocrine and neurochemical effects of each stereoisomer and the racemate were assessed in four rhesus monkeys after intravenous delivery at doses (1-3 mg/kg) that approximated voluntary self-administration by rhesus monkeys and human recreational users. Specifically, fluorescence-based enzyme-linked immunosorbent assay was used to assess plasma prolactin concentrations, and in vivo microdialysis was used to assess extracellular dopamine and serotonin concentrations in the dorsal striatum. R(-)-MDMA, but not S(+)-MDMA, significantly increased plasma prolactin levels and the effects of S,R(+/-)-MDMA were intermediate to each of its component stereoisomers. Although S(+)-MDMA did not alter prolactin levels, it did significantly increase extracellular serotonin concentrations. In addition, S(+)-MDMA, but not R(-)-MDMA, significantly increased dopamine concentrations. Furthermore, as in the prolactin experiment, the effects of the racemate were intermediate to each of the stereoisomers. These studies demonstrate the stereoisomers of MDMA engender qualitatively different endocrine and neurochemical effects, strengthening the inference that differences in these stereoisomers might be the mechanism producing the complex biological effects of the racemic mixture of MDMA in humans.
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Estimulantes del Sistema Nervioso Central/farmacología , Cuerpo Estriado/efectos de los fármacos , Dopamina/metabolismo , Alucinógenos/farmacología , N-Metil-3,4-metilenodioxianfetamina/farmacología , Prolactina/metabolismo , Serotonina/metabolismo , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Estimulantes del Sistema Nervioso Central/química , Cuerpo Estriado/metabolismo , Espacio Extracelular/metabolismo , Femenino , Alucinógenos/química , Ácido Homovanílico/metabolismo , Macaca mulatta , Microdiálisis , N-Metil-3,4-metilenodioxianfetamina/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The purpose of this study was to examine the efficacy of continuous resistance training (3 days/wk) compared to interrupted resistance training where 20-24 h separated an exercise bout (i. e. 6 days/wk) for enhancing bone mineral density (BMD) in growing male rats. The total volume of work performed per week between the two resistance training programs was equivalent by design. Young male rats were randomly divided into Control (Con, n=9), 3 days/wk resistance trained group (RT3, n=9), and 6 days/wk resistance trained group (RT6, n=9). The RT3 and RT6 groups were conditioned to climb a vertical ladder with weights appended to their tail for a total of 6 wks. After 6 wks, BMD (assessed via DXA) from the left tibia was significantly greater for RT3 (0.242+/-0.004 g/cm (2)) and RT6 (0.244+/-0.004 g/cm (2)) compared to Con (0.226+/-0.003 g/cm (2)). Further, serum osteocalcin (oc, in ng/ml) was significantly greater for RT3 (75.8+/-4.4) and RT6 (73.5+/-3.8) compared to Con (53.4+/-2.4). There was no significant difference in BMD or serum OC between RT3 and RT6 groups. The results indicate that both resistance training programs were equally effective in elevating bone mineral density in young, growing rats.
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Densidad Ósea/fisiología , Condicionamiento Físico Animal/métodos , Entrenamiento de Fuerza/métodos , Aminoácidos/orina , Animales , Masculino , Osteocalcina/sangre , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Tibia/metabolismo , Factores de TiempoRESUMEN
A resistance training program, where the exercise was uninterrupted (UT, i.e. continuous repetitions) was compared against another resistance training program where the exercise was interrupted (IT, i.e. 2 exercise sessions during a training day) for enhancing bone modeling and bone mineral density (BMD) in maturating animals. The total volume of work performed between the two resistance training programs was equivalent by design. Young male rats (approximately 8 weeks old) were randomly divided into Control (Con, n=8), UT (n=8) and IT (n=7) resistance trained groups. The UT and IT groups were conditioned to climb a vertical ladder with weights appended to their tail 3 days/week for 6 weeks. After the 6 week training regimen (Mean+/-SD), tibial BMD (assessed via DXA) was significantly greater for UT (0.237+/-0.008 g/cm(2)) and IT (0.238+/-0.005 g/cm(2)) compared to Con (0.223+/-0.004 g/cm(2)). Further, serum osteocalcin (OC) was significantly greater for UT (45.65+/-2.83 ng/ml) and IT (46.33+/-4.60 ng/ml) compared to Con (37.86+/-4.04 ng/ml). There was no significant difference in BMD or serum OC between UT and IT groups. The results indicate that both resistance training programs were equally effective in elevating BMD in growing animals.
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Densidad Ósea , Contracción Muscular/fisiología , Músculo Esquelético/fisiología , Entrenamiento de Fuerza , Absorciometría de Fotón , Aminoácidos/sangre , Animales , Fenómenos Biomecánicos , Colágeno Tipo I , Masculino , Fuerza Muscular/fisiología , Osteocalcina/sangre , RatasRESUMEN
Attention deficit hyperactivity disorder (ADHD) often persists into adulthood. Stimulant drugs, including methylphenidate, have showed efficacy in trials for ADHD in adults. Adult psychiatrists are likely to encounter increasing numbers of adult patients who may benefit from methylphenidate. A systematic review of the literature was made to examine the evidence on the safety of methylphenidate, when used therapeutically in adults. Twenty-six placebo-controlled trials were found, in which 811 adults received methylphenidate for ADHD and other conditions. In the short term, methylphenidate was well tolerated and no serious side effects were observed. There is little information on the long-term safety of methylphenidate in adults, although the number of serious adverse effects reported to regulatory authorities has, so far, been low. Methylphenidate is associated with a modest rise in blood pressure and heart rate. Surveys of stimulant use in US universities show that misuse of prescribed medication, for recreation or to enhance study, is fairly common although the level of harm that arises from this practice is unclear.
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Estimulantes del Sistema Nervioso Central/efectos adversos , Metilfenidato/efectos adversos , Adulto , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Estimulantes del Sistema Nervioso Central/administración & dosificación , Estimulantes del Sistema Nervioso Central/uso terapéutico , Medicina Basada en la Evidencia , Humanos , Metilfenidato/administración & dosificación , Metilfenidato/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Trastornos Relacionados con Sustancias/diagnóstico , Trastornos Relacionados con Sustancias/epidemiologíaRESUMEN
We have employed proteomics to establish a proteome map of the normal rat retina. This baseline map was then used for comparison with the early diabetic rat retinal proteome. Diabetic rat retinae were obtained from Dark Agouti rats after 10 wk of streptozotocin-induced hyperglycaemia. Extracted proteins from normal and diabetic rat retinae were separated and compared using 2-DE. A total of 145 protein spots were identified in the normal rat retina using MALDI-MS and database matching. LC-coupled ESI-MS increased the repertoire of identified proteins by 23 from 145 to 168. Comparison with early diabetic rat retinae revealed 24 proteins unique to the diabetic gels, and 37 proteins absent from diabetic gels. Uniquely expressed proteins identified included the HSPs 70.1A and 8, and platelet activating factor. There were eight spots with increased expression and 27 with decreased expression on diabetic gels. Beta catenin, phosducin and aldehyde reductase were increased in expression in diabetes whilst succinyl coA ligase and dihydropyrimidase-related protein were decreased. Identification of such changes in protein expression has given new insights and a more comprehensive understanding of the pathogenesis of diabetic retinopathy, widening the scope of potential avenues for new therapies for this common cause of blindness.
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Diabetes Mellitus Experimental/metabolismo , Retinopatía Diabética/etiología , Mapeo Peptídico/métodos , Proteoma/análisis , Retina/química , Animales , Glucemia/análisis , Bases de Datos de Proteínas , Diabetes Mellitus Experimental/sangre , Retinopatía Diabética/patología , Electroforesis en Gel Bidimensional , Masculino , Proteómica/métodos , Ratas , Ratas Endogámicas , Espectrometría de Masa por Ionización de Electrospray , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
Utilization of N-substituted-4-hydroxy-3-methylsulfonanilidoethanolamines 1 as selective beta(3) agonists is complicated by their propensity to undergo metabolic oxidative N-dealkylation, generating 0.01-2% of a very potent alpha(1) adrenergic agonist 2. A summary of the SAR for this hepatic microsomal conversion precedes presentation of strategies to maintain the advantages of chemotype 1 while mitigating the consequences of N-dealkylation. This effort led to the identification of 4-hydroxy-3-methylsulfonanilidopropanolamines 15 for which the SAR for the unique stereochemical requirements for binding to the beta adrenergic receptors culminated in the identification of the potent, selective beta(3) agonist 15f.