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1.
Am J Physiol Endocrinol Metab ; 314(4): E406-E412, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29138226

RESUMO

Sitagliptin, a dipeptidyl peptidase-IV inhibitor (DPP-4), sustains activity of the incretin hormones GLP-1 and GIP and improves hyperglycemia in Type 2 diabetes mellitus (T2DM). It has however proven challenging to quantify the effect of sitagliptin on rates of insulin secretion (ISR) during a prandial challenge. The tight feedback governance of ISR by plasma glucose means that in the face of treatment-related lowering of postprandial glycemia, corresponding stimulation of ISR is lessened. We postulated that sustaining a stable level of moderate hyperglycemia before and during a meal challenge (MC) would be a platform that enables greater clarity to assess the effect of sitagliptin on ISR and an approach that could be valuable to evaluate novel targets that increase insulin secretion directly and by augmenting incretins. A hyperglycemic clamp (HGC) at 160 mg/dl was conducted in 12 healthy volunteers (without diabetes) for 6 h; 3 h into the HGC, MC was administered while maintaining stable hyperglycemia of the HGC for an additional 3 h. Modeling of C-peptide response was used to calculate ISR. In crossover design of three periods (sitagliptin twice and placebo once), the effect of sitagliptin vs. placebo on ISR and the reproducibility of the response to sitagliptin were assessed. Sitagliptin increased ISR compared with placebo by 50% and 20% during the HGC alone and the HGC-MC phases, respectively ( P < 0.001 for both). There was an associated significant treatment-based increase in circulating insulin, as well as active levels of GLP-1. Robust reproducibility of the sitagliptin-mediated ISR response was observed; the intraclass correlation value was 0.94. The findings delineate the effect of sitagliptin to stimulate insulin secretion, and these benchmark data also demonstrate that an HGC-MC can be a useful platform for interrogating therapeutic targets that could potentially modulate ISR via direct action on beta-cells as well as by augmenting release or action of incretins.


Assuntos
Técnica Clamp de Glucose/métodos , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Insulina/metabolismo , Refeições/fisiologia , Fosfato de Sitagliptina/farmacologia , Adolescente , Adulto , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Estudos Cross-Over , Método Duplo-Cego , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Células Secretoras de Insulina/metabolismo , Masculino , Pessoa de Meia-Idade , Via Secretória/efeitos dos fármacos , Adulto Jovem
2.
Am J Physiol Endocrinol Metab ; 310(11): E865-73, 2016 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-27072496

RESUMO

The graded glucose infusion (GGI) examines insulin secretory response patterns to continuously escalating glycemia. The current study series sought to more fully appraise its performance characteristics. Key questions addressed were comparison of the GGI to the hyperglycemic clamp (HGC), comparison of insulin secretory response patterns across three volunteer populations known to differ in ß-cell function (healthy nonobese, obese nondiabetic, and type 2 diabetic), and characterization of effects of known insulin secretagogues in the context of a GGI. Insulin secretory response was measured as changes in insulin, C-peptide, insulin secretion rates (ISR), and ratio of ISR to prevailing glucose (ISR/G). The GGI correlated well with the HGC (r = 0.72 for ISR/G, P < 0.01). The insulin secretory response in type 2 diabetes (T2DM) was significantly blunted (P < 0.001), whereas it was significantly increased in obese nondiabetics compared with healthy nonobese (P < 0.001). Finally, robust (P < 0.001 over placebo) pharmacological effects were observed in T2DM and healthy nonobese volunteers. Collectively, the findings of this investigational series bolster confidence that the GGI has solid attributes for assessing insulin secretory response to glucose across populations and pharmacology. Notably, the coupling of insulin secretory response to glycemic changes was distinctly and uniformly linear across populations and in the context of insulin secretagogues. (Clinical Trial Registration Nos. NCT00782418, NCT01055340, NCT01373450).


Assuntos
Diabetes Mellitus/metabolismo , Teste de Tolerância a Glucose/métodos , Glucose/administração & dosagem , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Obesidade/sangue , Método Duplo-Cego , Glucose/farmacocinética , Humanos , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Modelos Lineares , Modelos Biológicos , Dinâmica não Linear , Efeito Placebo , Taxa de Sobrevida
3.
Curr Ther Res Clin Exp ; 77: 83-9, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26543510

RESUMO

BACKGROUND: Insulin resistance heightens the risk for type 2 diabetes mellitus and cardiovascular disease. Amelioration of insulin resistance may reduce this risk. The thiazolidinedone class of insulin sensitizers improves insulin action in individuals with insulin-resistant diabetes and nondiabetic individuals. However, there are few reports on the time of onset of such effects independent of reversal of glucotoxicity. OBJECTIVE: The goal of our study was to test whether the thiazolidinedione pioglitazone has prominent early metabolic effects that can be detected in an obese, nondiabetic, insulin-resistant population. METHODS: We conducted a randomized, double-blind, placebo-controlled, parallel-group trial in men with nondiabetic insulin resistance using a hyperinsulinemic euglycemic clamp technique (at low and high doses of insulin at 10 and 40 mU/m(2)/min, respectively). The patients were given 30 mg daily oral pioglitazone or placebo for 28 days. Patients underwent a baseline clamp before initiation of treatment, and again at 14 and 28 days of treatment. RESULTS: Compared with placebo, under high-dose hyperinsulinemia, pioglitazone led to significant increases in glucose disposal rates (GDR) of 1.29 mg/kg/min (90% CI, 0.43-2.15; 39%; P=0.008) that were detectable at 2 weeks of treatment and persisted at 4 weeks of treatment. Under low-dose hyperinsulinemia, significant increases in GDR of 0.40 mg/kg/min (90% CI, 0.17-0.62; 95%; P=0.003) were observed at 4 weeks of treatment. These responses were accompanied by robust suppression of free fatty acids under hyperinsulinemic conditions, and by significant increases in circulating basal total adiponectin at 2 and 4 weeks of treatment. CONCLUSIONS: Significant changes in insulin action across multiple insulin-sensitive tissues can be detected within 2 weeks of initiation of insulin-sensitizing therapy with pioglitazone in obese patients with nondiabetic insulin resistance. ClinicalTrials.gov identifier: NCT01115712.

4.
J Transl Med ; 12: 178, 2014 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-24952610

RESUMO

BACKGROUND: Single-cell network profiling (SCNP) is a multiparametric flow cytometry-based approach that simultaneously measures evoked signaling in multiple cell subsets. Previously, using the SCNP approach, age-associated immune signaling responses were identified in a cohort of 60 healthy donors. METHODS: In the current study, a high-dimensional analysis of intracellular signaling was performed by measuring 24 signaling nodes in 7 distinct immune cell subsets within PBMCs in an independent cohort of 174 healthy donors [144 elderly (>65 yrs); 30 young (25-40 yrs)]. RESULTS: Associations between age and 9 immune signaling responses identified in the previously published 60 donor cohort were confirmed in the current study. Furthermore, within the current study cohort, 48 additional immune signaling responses differed significantly between young and elderly donors. These associations spanned all profiled modulators and immune cell subsets. CONCLUSIONS: These results demonstrate that SCNP, a systems-based approach, can capture the complexity of the cellular mechanisms underlying immunological aging. Further, the confirmation of age associations in an independent donor cohort supports the use of SCNP as a tool for identifying reproducible predictive biomarkers in areas such as vaccine response and response to cancer immunotherapies.


Assuntos
Envelhecimento/imunologia , Voluntários Saudáveis , Transdução de Sinais , Adulto , Idoso , Estudos de Coortes , Humanos
5.
J Magn Reson Imaging ; 34(4): 947-55, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21751289

RESUMO

PURPOSE: To conduct a rigorous evaluation of the repeatability of liver stiffness assessed by MR elastography (MRE) in healthy and hepatitis-C-infected subjects. MATERIALS AND METHODS: A biopsy-correlated repeatability study using four-slice MRE was conducted in five healthy and four HCV-infected subjects. Subjects were scanned twice on day 1 and after 7-14 days. Each slice was acquired during a 14-s breath-hold with a commercially available acquisition technique (MR-Touch, GE Healthcare). Results were analyzed by two independent analysts. RESULTS: The intraclass correlation coefficient (ICC) was 0.85 (90% confidence interval [CI]: 0.71 to 0.98) for the between-scan average of maximum stiffness within each slice and 0.88 (90% CI: 0.78 to 0.99) for the average of mean stiffness within each slice for the primary analyst. For both analysts, the average of the mean liver stiffness within each slice was highly reproducible with ICC of 0.93 and 0.94. Within-subject coefficients of variation ranged from 6.07% to 10.78% for HCV+ and healthy subjects. CONCLUSION: MRE is a highly reproducible modality for assessing liver stiffness in HCV patients and healthy subjects and can discriminate between moderate fibrosis and healthy liver. MRE is a promising modality for noninvasive assessment of liver fibrosis (CLINICALTRIALS.GOV IDENTIFIER: NCT00896233).


Assuntos
Técnicas de Imagem por Elasticidade/métodos , Hepatite C Crônica/diagnóstico , Processamento de Imagem Assistida por Computador , Cirrose Hepática/diagnóstico , Imageamento por Ressonância Magnética/métodos , Adulto , Biópsia por Agulha , Estudos de Casos e Controles , Feminino , Hepatite C Crônica/complicações , Humanos , Imuno-Histoquímica , Cirrose Hepática/etiologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Valores de Referência , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Adulto Jovem
6.
Diabetes ; 67(6): 1105-1112, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29545266

RESUMO

Oxyntomodulin (OXM), an enteroendocrine hormone, causes appetite suppression, increased energy expenditure, and weight loss in obese humans via activation of GLP-1 and glucagon receptors. However, the effects of OXM on glucose homeostasis remain ill defined. To address this gap, we evaluated the effects of an i.v. infusion of native OXM on insulin secretion rates (ISRs) and glycemic excursion in a graded glucose infusion (GGI) procedure in two separate randomized, placebo (PBO)-controlled, single-dose crossover trials in 12 overweight and obese subjects without diabetes and in 12 obese subjects with type 2 diabetes mellitus (T2DM), using the GLP-1 analog liraglutide (LIRA) as a comparator in T2DM. In both groups, in the GGI, 3.0 pmol/kg/min of OXM significantly increased ISR and blunted glycemic excursion relative to PBO. In T2DM, the effects of OXM were comparable to those of LIRA, including restoration of ß-cell glucose responsiveness to that of nonobese subjects without diabetes. Our findings indicate that native OXM significantly augments glucose-dependent insulin secretion acutely in obese subjects with and without diabetes, with effects comparable to pharmacologic GLP-1 receptor activation and independent of weight loss. Native OXM has potential to improve hyperglycemia via complementary and independent induction of insulin secretion and weight loss.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hiperglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Obesidade/tratamento farmacológico , Sobrepeso/tratamento farmacológico , Oxintomodulina/uso terapêutico , Adulto , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/efeitos adversos , Índice de Massa Corporal , Estudos de Coortes , Estudos Cross-Over , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Relação Dose-Resposta a Droga , Método Duplo-Cego , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Glucose/administração & dosagem , Glucose/efeitos adversos , Humanos , Hiperglicemia/induzido quimicamente , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Infusões Intravenosas , Insulina/sangue , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Obesidade/sangue , Obesidade/complicações , Sobrepeso/sangue , Sobrepeso/complicações , Oxintomodulina/administração & dosagem , Oxintomodulina/efeitos adversos , Receptores de Glucagon/agonistas , Receptores de Glucagon/metabolismo , Adulto Jovem
7.
BMC Obes ; 4: 10, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28265415

RESUMO

BACKGROUND: Glucose homeostasis improves within days following Roux-en-Y gastric bypass (RYGB) surgery. The dynamic metabolic response to caloric intake following RYGB has been assessed using liquid mixed meal tolerance tests (MMTT). Few studies have evaluated the glycemic and hormonal response to a solid mixed meal in subjects with diabetes prior to, and within the first month following RYGB. METHODS: Seventeen women with type 2 diabetes of less than 5 years duration participated. Fasting measures of glucose homeostasis, lipids and gut hormones were obtained pre- and post-surgery. MMTT utilizing a solid 4 oz chocolate pudding performed pre-, 2 and 4 weeks post-surgery. Metabolic response to 4 and 2 oz MMTT assessed in five diabetic subjects not undergoing surgery. RESULTS: Significant reductions in fasting glucose and insulin at 3 days, and in fasting betatrophin, triglycerides and total cholesterol at 2 weeks post-surgery. Hepatic insulin clearance was greater at 3 days post-surgery. Subjects exhibited less hunger and greater feelings of fullness and satisfaction during the MMTT while consuming 52.9 ± 6.5% and 51.0 ± 6.5% of the meal at 2 and 4 weeks post-surgery respectively. At 2 weeks post-surgery, glucose and insulin response to MMTT were improved, with greater GLP-1 and PYY secretion. Improved response to solid MMTT not replicated by consumption of smaller pudding volume in diabetic non-surgical subjects. CONCLUSIONS: With a test meal of size and composition representative of the routine diet of post-RYGB subjects, improved glycemic and gut hormone responses occur which cannot be replicated by reducing the size of the MMTT in diabetic subjects not undergoing surgery. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT00957957 August 11, 2009.

8.
Lancet Infect Dis ; 16(8): 915-22, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27061887

RESUMO

BACKGROUND: The licensed live, attenuated varicella-zoster virus vaccine prevents herpes zoster in adults older than 50 years. We aimed to determine whether intradermal administration of zoster vaccine could enhance vaccine immunogenicity compared with conventional needle subcutaneous administration. METHODS: In this randomised, dose-ranging study, adults aged 50 years or older who had a history of varicella or who had resided in a country with endemic varicella-zoster virus infection for 30 years or more were eligible. Participants received the approved full or a 1/3 dose of zoster vaccine given subcutaneously or one of four intradermal doses (full, 1/3, 1/10, or 1/27 dose) using the MicronJet600 device. The two subcutaneous doses and the four intradermal doses were randomised (1·5:1:1:1:1:1) by computer generated sequence with randomisation stratified by age (50-59 years or 60 years or older). The primary immunogenicity endpoint was the change from baseline in IgG antibody to varicella-zoster virus-specific glycoproteins (gpELISA) measured at 6 weeks. All patients were included in the primary and safety analyses. This study is registered with ClinicalTrials.gov, number NCT01385566. FINDINGS: Between Sept 2, 2011, and Jan 13, 2012, 224 participants were enrolled from three clinics in the USA and 223 were randomly assigned: 52 to receive the full dose subcutaneous zoster vaccine, 34 to receive the 1/3 dose subcutaneous zoster vaccine, 34 to receive the full dose intradermal zoster vaccine, 35 to receive the 1/3 dose intradermal zoster vaccine, 34 to receive the 1/10 dose intradermal zoster vaccine, and 34 to receive the 1/27 dose intradermal zoster vaccine. Full dose zoster vaccine given subcutaneously resulted in a gpELISA geometric mean fold-rise (GMFR) of 1·74 (90% CI 1·48-2·04) at 6 weeks post-vaccination compared with intradermal administration which resulted in a significantly higher gpELISA GMFR of 3·25 (2·68-3·94; p<0·0001), which also remained high at 18 months. An apparent dose-response relation was observed with intradermal administration (1/3 dose subcutaneous GMFR 1·64 [90% CI 1·36-1·99], 1/3 dose intradermal 2·58 (2·13-3·13), 1/10 dose intradermal 2·22 [1·83-2·69], and 1/27 dose intradermal 1·64 [1·35-2·00]). Each partial dose of zoster vaccine given intradermaly had a gpELISA GMFR comparable to that of full dose zoster vaccine given subcutaneously. Transient erythema and induration were more common after intradermal administration (31% erythema for full subcutaneous dose and 77% for intradermal dose). INTERPRETATION: Intradermal zoster vaccine showed a greater increase in varicella-zoster virus gpELISA antibody compared with subcutaneous zoster vaccine at comparable doses. Larger and longer studies of intradermal administration of live, attenuated zoster vaccine are needed to provide convincing evidence of improved cell mediated immunity. FUNDING: Merck & Co Inc.


Assuntos
Relação Dose-Resposta Imunológica , Vacina contra Herpes Zoster/administração & dosagem , Herpes Zoster/prevenção & controle , Injeções Intramusculares/métodos , Injeções Subcutâneas/métodos , Idoso , Varicela/imunologia , Eritema/etiologia , Herpes Zoster/imunologia , Vacina contra Herpes Zoster/imunologia , Herpesvirus Humano 3/imunologia , Humanos , Esquemas de Imunização , Pessoa de Meia-Idade , Estados Unidos , Vacinação , Vacinas Atenuadas
9.
Nat Commun ; 7: 10369, 2016 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-26742691

RESUMO

Aging is associated with hyporesponse to vaccination, whose mechanisms remain unclear. In this study hepatitis B virus (HBV)-naive older adults received three vaccines, including one against HBV. Here we show, using transcriptional and cytometric profiling of whole blood collected before vaccination, that heightened expression of genes that augment B-cell responses and higher memory B-cell frequencies correlate with stronger responses to HBV vaccine. In contrast, higher levels of inflammatory response transcripts and increased frequencies of pro-inflammatory innate cells correlate with weaker responses to this vaccine. Increased numbers of erythrocytes and the haem-induced response also correlate with poor response to the HBV vaccine. A transcriptomics-based pre-vaccination predictor of response to HBV vaccine is built and validated in distinct sets of older adults. This moderately accurate (area under the curve≈65%) but robust signature is supported by flow cytometry and cytokine profiling. This study is the first that identifies baseline predictors and mechanisms of response to the HBV vaccine.


Assuntos
Envelhecimento/imunologia , Linfócitos B/fisiologia , Antígenos de Superfície da Hepatite B/imunologia , Vacinas contra Hepatite B/imunologia , Inflamação/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/metabolismo , Biomarcadores/sangue , Estudos de Coortes , Contagem de Eritrócitos , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Transcriptoma , Vacinação
10.
J Am Coll Cardiol ; 62(10): 909-17, 2013 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-23727083

RESUMO

OBJECTIVES: The study sought to test whether high-dose statin treatment would result in greater reductions in plaque inflammation than low-dose statins, using fluorodeoxyglucose-positron emission tomography/computed tomographic imaging (FDG-PET/CT). BACKGROUND: Intensification of statin therapy reduces major cardiovascular events. METHODS: Adults with risk factors or with established atherosclerosis, who were not taking high-dose statins (n = 83), were randomized to atorvastatin 10 versus 80 mg in a double-blind, multicenter trial. FDG-PET/CT imaging of the ascending thoracic aorta and carotid arteries was performed at baseline, 4, and 12 weeks after randomization and target-to-background ratio (TBR) of FDG uptake within the artery wall was assessed while blinded to time points and treatment. RESULTS: Sixty-seven subjects completed the study, providing imaging data for analysis. At 12 weeks, inflammation (TBR) in the index vessel was significantly reduced from baseline with atorvastatin 80 mg (% reduction [95% confidence interval]: 14.42% [8.7% to 19.8%]; p < 0.001), but not atorvastatin 10 mg (% reduction: 4.2% [-2.3% to 10.4%]; p > 0.1). Atorvastatin 80 mg resulted in significant additional relative reductions in TBR versus atorvastatin 10 mg (10.6% [2.2% to 18.3%]; p = 0.01) at week 12. Reductions from baseline in TBR were seen as early as 4 weeks after randomization with atorvastatin 10 mg (6.4% reduction, p < 0.05) and 80 mg (12.5% reduction, p < 0.001). Changes in TBR did not correlate with lipid profile changes. CONCLUSIONS: Statin therapy produced significant rapid dose-dependent reductions in FDG uptake that may represent changes in atherosclerotic plaque inflammation. FDG-PET imaging may be useful in detecting early treatment effects in patients at risk or with established atherosclerosis.


Assuntos
Aorta Torácica/diagnóstico por imagem , Aterosclerose/tratamento farmacológico , Artérias Carótidas/diagnóstico por imagem , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inflamação/tratamento farmacológico , Placa Aterosclerótica/tratamento farmacológico , Pirróis/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Aorta Torácica/patologia , Aterosclerose/diagnóstico por imagem , Atorvastatina , Artérias Carótidas/patologia , Método Duplo-Cego , Estudos de Viabilidade , Feminino , Fluordesoxiglucose F18 , Ácidos Heptanoicos/administração & dosagem , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inflamação/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Imagem Multimodal/métodos , Placa Aterosclerótica/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Pirróis/administração & dosagem , Resultado do Tratamento
11.
Clin Ther ; 34(3): 580-92, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22385927

RESUMO

BACKGROUND: The development of antihypertensives requires efficient and accurate tools for identifying pedal edema. Methodologies used to gauge the potential of an agent to induce pedal edema in short-term (<4-week) clinical trials have not been reported in the literature. OBJECTIVE: The purpose of this study was to identify a robust and practical method for measuring drug-induced pedal edema for use in the clinical development of antihypertensives. The efficacy of segmental bioimpedance in the detection of increased pedal edema was compared with that of clinical pitting assessment, ankle circumference, and water displacement volumetry. METHODS: The study population consisted of male and female healthy subjects and patients with stage 1 or 2 hypertension who were otherwise healthy. Participants were randomly assigned to receive amlodipine 10 mg or placebo once daily in this 6-week, double-blind, parallel-group study. Amlodipine was used as a means of inducing ankle edema, and not for the treatment of hypertension. Patients with hypertension were required to undergo a washout of antihypertensive therapies. Edema was evaluated using segmental bioimpedance at 10 kHz, clinical pitting assessment, ankle circumference, and water displacement at weeks 2, 4, and 6. The ANOVA model used included treatment and baseline values as covariates, with treatment pairs compared via t tests derived from the model. RESULTS: A total of 47 individuals were randomized (49% male; 29 [62%] with hypertension; mean [SD] age, 59 [5.9] years; baseline body mass index, 28.6 kg/m(2) [2.8]; blood pressure 146.6 [10.7]/93.5 [6.5] and 139.3 [8.3]/89.5 [4.5] in individuals with and without hypertension, respectively; amlodipine 10 mg, n = 24; placebo, n = 23). At weeks 2, 4, and 6, statistically significant treatment differences in changes from baseline were detected using water displacement (mean [90% CI] treatment differences, +39.0 g [+17.9 to +60.1], +61.9 g [+36.1 to +87.6], and +72.2 g [+42.3 to +102.1], respectively; all, P ≤ 0.001), ankle circumference (+4.74 mm [+2.38 to +7.11; P < 0.001], +2.92 mm [+0.33 to +5.49; P = 0.032], and +5.16 mm [+2.21 to +8.11; P = 0.002]), and bioimpedance (-11.7 Ω [-18.1 to -5.4], -18.3 Ω [-26.2 to -10.4], and -20.9 Ω [-29.7 to -12.0]; all, P≤0.001), but no significant differences were detected using clinical assessment of pitting. CONCLUSION: In this population of healthy subjects and patients with hypertension, segmental bioimpedance was comparable to water displacement and ankle circumference and outperformed clinical assessment of pitting for the detection of ankle edema, supporting the use of segmental bioimpedance as a drug-development tool to objectively quantify amlodipine-induced pedal edema.


Assuntos
Anlodipino/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Edema/induzido quimicamente , Edema/diagnóstico , Anlodipino/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Impedância Elétrica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
12.
Arthritis Res Ther ; 14(5): R198, 2012 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-22972032

RESUMO

INTRODUCTION: We aimed to investigate the sensitivity and reliability of two-dimensional ultrasonographic endpoints at the metacarpophalageal joints (MCPJs) and their potential to provide an early and objective indication of a therapeutic response to treatment intervention in rheumatoid arthritis (RA). METHODS: A randomized, double-blind, parallel-group, two-center, placebo-controlled trial investigated the effect on ultrasonographic measures of synovitis of repeat dose oral prednisone, 15 mg or 7.5 mg, each compared to placebo, in consecutive two-week studies; there were 18 subjects in a 1:1 ratio and 27 subjects in a 2:1 ratio, respectively. All subjects met the 1987 American College of Rheumatology criteria for the diagnosis of RA, were ≥18 years-old with RA disease duration ≥6 months, and had a Disease Activity Score 28 based on C-reactive protein (DAS28(CRP)) ≥3.2. Subjects underwent high-frequency (gray-scale) and power Doppler ultrasonography at Days 1 (baseline), 2, 8 and 15 in the dorsal transverse and longitudinal planes of all 10 MCPJs to obtain summated scores of quantitative and semi-quantitative measures of synovial thickness as well as vascularity. The primary endpoint was the summated score of power Doppler area measured quantitatively in all 10 MCPJs in the transverse plane at Day 15. Clinical efficacy was assessed at the same time points by DAS28(CRP). RESULTS: All randomized subjects completed the trial. The comparison between daily 15 mg prednisone and placebo at Day 15 yielded a statistically significant treatment effect (effect size = 1.17, P = 0.013) in change from baseline in the primary endpoint, but borderline for prednisone 7.5 mg daily versus placebo (effect size = 0.61, P = 0.071). A significant treatment effect for DAS28(CRP) was only observed at Day 15 in the prednisone 15 mg group (effect size = 0.95, P = 0.032). However, significant treatment effects at all time points for a variety of ultrasound (US) endpoints were detected with both prednisone doses; the largest observed effect size = 2.33. Combining US endpoints with DAS28(CRP) improved the registration of significant treatment effects. The parallel scan inter-reader reliability of summated 10 MCPJ scores were good to excellent (ICC values >0.61) for the majority of US measures. CONCLUSIONS: Ultrasonography of MCPJs is an early, reliable indicator of therapeutic response in RA with potential to reduce patient numbers and length of trials designed to give preliminary indications of efficacy. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00746512.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/tratamento farmacológico , Determinação de Ponto Final , Articulação Metacarpofalângica/diagnóstico por imagem , Prednisona/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/sangue , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Resultado do Tratamento , Ultrassonografia
13.
Arthritis Care Res (Hoboken) ; 62(7): 932-7, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20589702

RESUMO

OBJECTIVE: Magnetic resonance imaging (MRI) and radiography are established imaging modalities for the assessment of knee osteoarthritis (OA). The objective of our study was to compare the responsiveness of radiographic joint space width (JSW) with MRI-derived measures of cartilage morphometry for OA progression in participants from the Osteoarthritis Initiative (OAI). METHODS: This study examined the baseline and 12-month visits of a subset of 150 subjects from the OAI. Measurement of radiographic JSW was facilitated by the use of automated software that delineated the femoral and tibial margins of the joint. Measures of medial compartment minimum JSW and JSW at fixed locations were compared with cartilage morphometry measures derived from MRI. The results were stratified by Kellgren/Lawrence (K/L) scale grade and by tibiofemoral anatomic axis angle. In order to examine the relative responsiveness of various techniques, we calculated the standardized response mean (SRM) between the 2 visits. RESULTS: The SRM for radiographic JSW measured at the optimal location was -0.32 compared with -0.39 for the most responsive MRI measure. For the subgroup with a K/L scale grade of 2 or 3, the most responsive SRM values were -0.34 for radiographic JSW and -0.42 for MRI. CONCLUSION: Our study demonstrates that new measures using a software analysis of digital knee radiographic images are comparable with MRI in detecting OA progression, and potentially superior when considering the cost-effectiveness of the 2 imaging modalities.


Assuntos
Interpretação de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Meniscos Tibiais/diagnóstico por imagem , Meniscos Tibiais/patologia , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/patologia , Idoso , Antropometria , Feminino , Fêmur/diagnóstico por imagem , Fêmur/patologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Radiografia , Tíbia/diagnóstico por imagem , Tíbia/patologia
14.
J Biol Chem ; 277(50): 48664-76, 2002 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-12351631

RESUMO

The nuclear localization and transcriptional activity of the NF-ATc family of transcription factors, essential to many developmental, differentiation, and adaptation processes, are determined by the opposing activities of the phosphatase calcineurin, which promotes nuclear accumulation of NF-ATc, and several kinases, which promote cytoplasmic accumulation. Many reports suggest that protein kinase A (PKA) negatively modulates calcineurin-mediated NF-ATc activation. Here we show that overexpression of PKA causes phosphorylation and cytoplasmic accumulation of NF-ATc1 in direct opposition to calcineurin by phosphorylating Ser-245, Ser-269, and Ser-294 in the conserved serine-proline repeat domain, and that mutation of these serines blocks the effect of PKA. Activation of endogenous PKA is similarly able to promote phosphorylation of these sites on NF-ATc1 in two lymphoid cell lines. We further show that a complete block of NF-ATc1 nuclear localization by PKA requires a second kinase activity that can be supplied by glycogen synthase kinase-3 (GSK-3), and that mutation of either the PKA phosphorylation sites or the upstream GSK-3 sites prevents the effect of PKA. Thus, we propose that PKA functions cooperatively as a priming kinase for further phosphorylation by GSK-3 to oppose calcineurin-mediated nuclear accumulation and transcriptional activity of NF-ATc1 and that, through this mechanism, PKA may be an important modulator of many NF-ATc-dependent processes.


Assuntos
Núcleo Celular/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Proteínas de Ligação a DNA/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Proteínas Nucleares , Fatores de Transcrição/metabolismo , Sequência de Aminoácidos , Cálcio/metabolismo , Linhagem Celular , Núcleo Celular/efeitos dos fármacos , AMP Cíclico/metabolismo , Proteínas de Ligação a DNA/química , Humanos , Ionomicina/farmacologia , Dados de Sequência Molecular , Fatores de Transcrição NFATC , Fosforilação , Serina/metabolismo , Fatores de Transcrição/química , Transcrição Gênica , Transfecção
15.
Science ; 302(5646): 875-8, 2003 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-14593182

RESUMO

Because of its requirement for signaling by multiple cytokines, Janus kinase 3 (JAK3) is an excellent target for clinical immunosuppression. We report the development of a specific, orally active inhibitor of JAK3, CP-690,550, that significantly prolonged survival in a murine model of heart transplantation and in cynomolgus monkeys receiving kidney transplants. CP-690,550 treatment was not associated with hypertension, hyperlipidemia, or lymphoproliferative disease. On the basis of these preclinical results, we believe JAK3 blockade by CP-690,550 has potential for therapeutically desirable immunosuppression in human organ transplantation and in other clinical settings.


Assuntos
Rejeição de Enxerto/prevenção & controle , Transplante de Coração , Imunossupressores/farmacologia , Transplante de Rim , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Pirróis/farmacologia , Animais , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Inibidores Enzimáticos/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Imunossupressores/toxicidade , Interleucina-2/imunologia , Janus Quinase 3 , Ativação Linfocitária/efeitos dos fármacos , Contagem de Linfócitos , Teste de Cultura Mista de Linfócitos , Subpopulações de Linfócitos/efeitos dos fármacos , Macaca fascicularis , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Miocárdio/metabolismo , Piperidinas , Proteínas Tirosina Quinases/metabolismo , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêutico , Pirimidinas/toxicidade , Pirróis/administração & dosagem , Pirróis/uso terapêutico , Pirróis/toxicidade , Transplante Heterotópico , Transplante Homólogo , Células Tumorais Cultivadas
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