Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 18 de 18
Filtrar
1.
Am J Gastroenterol ; 116(9): 1929-1937, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34465695

RESUMO

INTRODUCTION: Linaclotide improves abdominal pain and constipation in patients with constipation-predominant irritable bowel syndrome (IBS-C). Patients report additional bothersome abdominal symptoms of bloating and discomfort. The intention of this study was to evaluate linaclotide's efficacy in relieving IBS-C-related abdominal symptoms (bloating, discomfort, and pain) using a novel multi-item Abdominal Score (AS). METHODS: Patients with IBS-C with abdominal pain ≥3 (0-10 scale) were randomized to linaclotide 290 µg or placebo daily for 12 weeks. The AS, derived from the Diary for IBS Symptoms-Constipation, is the average of abdominal bloating, discomfort, and pain at their worst (0 = none, 10 = worst possible). The primary end point was overall change from baseline (CFB) in AS. Secondary end points included CFB in 12-week AS evaluated using cumulative distribution function and 6-week/12-week AS responder (AS improvement ≥2 points for ≥6-week/12-week). RESULTS: Overall, 614 patients (mean age 46.7 years; 81% female) were randomized. All prespecified end points showed significant benefit of linaclotide vs placebo. The mean overall CFB AS reduction for linaclotide was -1.9 vs -1.2 for placebo (P < 0.0001); the 6-week/12-week AS responder rate was 40.5% for linaclotide vs 23.4% for placebo (odds ratio = 2.2 [95% confidence interval, 1.55-3.12; P < 0.0001]). Diarrhea was the most common treatment-emergent adverse event (linaclotide = 4.6%, placebo = 1.6%). DISCUSSION: Linaclotide significantly reduced multiple abdominal symptoms important to patients with IBS-C (bloating, discomfort, and pain) compared with placebo, as measured by a novel multi-item AS. The AS, derived from the Diary for IBS Symptoms-Constipation, should be considered for use in future IBS-C clinical studies to measure clinically meaningful improvements beyond traditional end points.


Assuntos
Dor Abdominal/tratamento farmacológico , Constipação Intestinal/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Agonistas da Guanilil Ciclase C/uso terapêutico , Peptídeos/uso terapêutico , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do Tratamento
2.
PLoS One ; 16(1): e0243318, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33428631

RESUMO

INTRODUCTION: Chronic idiopathic constipation (CIC) is a prevalent functional gastrointestinal disorder diagnosed based on patient-reported symptoms and the absence of structural gastrointestinal abnormalities. Individuals with CIC typically institute dietary changes and use stool softeners or over-the-counter (OTC) laxatives, possibly at the direction of a healthcare provider, before prescription medications for CIC are initiated. Although highly prevalent, there is limited information regarding CIC patient experiences with OTC medications. METHODS: This post-hoc analysis used patient-reported data from a questionnaire administered during patient screening for a prospective linaclotide Phase 3b clinical trial in patients with CIC (N = 1482 screened). The questionnaire asked patients to report their experiences with OTC CIC medications over the preceding 6 months. RESULTS: Among patients with screening responses (N = 1423), most were female (85%) and white (66%), with a mean age of 48.9 years. A high proportion of patients had used one or more OTC medications (70% had ≥1 OTC; 19% had ≥3 OTCs), with the majority being bisacodyl (33%) and polyethylene glycol (30%). The most commonly cited reason for stopping an OTC medication was insufficient symptom relief (17-40%). The majority of patients taking OTC medications reported no or little satisfaction with the medication's effect on their constipation (62%) and CIC-specific abdominal symptoms (78%). Many patients had little to no confidence in bowel movement (BM) frequency after taking OTC medications and their confidence in their ability to predict BM timing was also low (49-81% not at all confident). CONCLUSIONS: Treatment effects on individual CIC symptoms, predictability of bowel habits, and satisfaction with treatment are all important factors for healthcare providers and patients to consider when establishing an effective treatment regimen for CIC. TRIAL REGISTRATION NUMBER: NCT01642914.


Assuntos
Constipação Intestinal/tratamento farmacológico , Medicamentos sem Prescrição/uso terapêutico , Adolescente , Adulto , Idoso , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Peptídeos/uso terapêutico , Inquéritos e Questionários , Fatores de Tempo , Adulto Jovem
3.
Am J Gastroenterol ; 116(2): 354-361, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33065589

RESUMO

INTRODUCTION: Immediate-release (IR) formulation of linaclotide 290 µg improves abdominal pain and constipation (APC) in patients with irritable bowel syndrome (IBS) with constipation. Delayed-release (DR) formulations were developed on the premise that targeting the ileum (delayed-release formulation 1 [DR1]) or ileocecal junction and cecum (MD-7246, formerly DR2) would modulate linaclotide's secretory effects while preserving pain relief effects. METHODS: This phase 2b study randomized patients with IBS with constipation to placebo or 1 of 7 once-daily linaclotide doses (DR1 30, 100, or 300 µg; MD-7246 30, 100, or 300 µg; or IR 290 µg) for 12 weeks. Key efficacy endpoints were change from baseline in abdominal pain and complete spontaneous bowel movement frequency, and 6/12-week combined APC+1 responder rate. RESULTS: Overall, 532 patients were randomized; mean age was 45.1 years, and most were women (83.3%) and White (64.7%). All linaclotide DR1 and MD-7246 groups experienced greater improvements in abdominal pain from baseline and vs placebo throughout treatment. Linaclotide DR1 and IR led to numerically greater improvements from baseline in complete spontaneous bowel movement frequency and higher APC+1 responder rates compared with placebo; MD-7246 results were similar to placebo. Diarrhea was the most common adverse event with DR1 and IR; rates were similar between MD-7246 and placebo. DISCUSSION: Altering the site of drug delivery in the intestine might uncouple linaclotide's pain relief from secretory effects. Persistent, modest abdominal pain improvement with limited impact on bowel symptom parameters, as seen across MD-7246 doses, warrants further study of MD-7246 as a novel treatment for abdominal pain, regardless of IBS subtype.


Assuntos
Constipação Intestinal/tratamento farmacológico , Agonistas da Guanilil Ciclase C/administração & dosagem , Síndrome do Intestino Irritável/tratamento farmacológico , Peptídeos/administração & dosagem , Dor Abdominal/fisiopatologia , Adulto , Constipação Intestinal/fisiopatologia , Defecação , Preparações de Ação Retardada , Diarreia/induzido quimicamente , Método Duplo-Cego , Feminino , Humanos , Síndrome do Intestino Irritável/fisiopatologia , Masculino , Pessoa de Meia-Idade
4.
Sci Rep ; 9(1): 19099, 2019 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-31836823

RESUMO

Vampyroteuthis infernalis Chun, 1903, is a widely distributed deepwater cephalopod with unique morphology and phylogenetic position. We assessed its habitat and trophic ecology on a global scale via stable isotope analyses of a unique collection of beaks from 104 specimens from the Atlantic, Pacific and Indian Oceans. Cephalopods typically are active predators occupying a high trophic level (TL) and exhibit an ontogenetic increase in δ15N and TL. Our results, presenting the first global comparison for a deep-sea invertebrate, demonstrate that V. infernalis has an ontogenetic decrease in δ15N and TL, coupled with niche broadening. Juveniles are mobile zooplanktivores, while larger Vampyroteuthis are slow-swimming opportunistic consumers and ingest particulate organic matter. Vampyroteuthis infernalis occupies the same TL (3.0-4.3) over its global range and has a unique niche in deep-sea ecosystems. These traits have enabled the success and abundance of this relict species inhabiting the largest ecological realm on the planet.


Assuntos
Ecologia , Comportamento Alimentar , Isótopos de Nitrogênio/análise , Octopodiformes/fisiologia , Animais , Mudança Climática , Ecossistema , Geografia , Oxigênio/metabolismo , Filogenia
5.
J Am Assoc Nurse Pract ; 31(12): 714-722, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31169783

RESUMO

Lesbian, gay, bisexual, transgender, and queer/questioning (LGBTQ) persons account for 3.5% of the population. Nursing programs in the United States provide a median of 2.13 hours of formal content regarding LGBTQ health, which contributes to iatrogenic barriers to care. Patient experiences related to inadequate provider preparation include misguided treatment strategies, impedance of communication, and abuse. A pilot educational project was developed to provide advanced practice nursing (APRN) students meaningful clinical interactions with LGBTQ-identifying standardized patients (SPs) to better prepare them to care for LGBTQ patients with cultural humility. This project was determined to be Exempt by the Institutional Review Board at the University of Michigan. Implemented in an advanced health assessment course with 99 APRN students, components of the project included course readings, lecture content, laboratory activities, an SP experience, and both large and small debriefing sessions. The SP experience itself was a 15-minute clinical encounter with a patient presenting with "abdominal pain," with an emphasis on history-taking, communication, and cultural humility. Qualitative data analysis was performed using the constant comparison method to interpret the results from student evaluations and other written feedback. This pilot project has promise to inform future educational offerings and set the standard for LGBTQ health content and application for APRN students. Further research is needed to evaluate the quality of LGBTQ content in APRN curricula to improve the ability of APRN students to provide care to LGBTQ patients.


Assuntos
Prática Avançada de Enfermagem/normas , Disparidades em Assistência à Saúde , Minorias Sexuais e de Gênero , Padrão de Cuidado , Adulto , Prática Avançada de Enfermagem/educação , Idoso , Educação de Pós-Graduação em Enfermagem , Feminino , Humanos , Masculino , Michigan , Pessoa de Meia-Idade , Projetos Piloto , Avaliação de Programas e Projetos de Saúde
6.
Expert Rev Gastroenterol Hepatol ; 13(4): 397-406, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30791771

RESUMO

BACKGROUND: Linaclotide is approved for treating irritable bowel syndrome with constipation (IBS-C; 290 µg QD) and chronic idiopathic constipation (CIC; 145 µg or 72 µg QD). These analyses aimed to assess linaclotide safety in a large, pooled Phase 3 population. METHODS: In six randomized controlled trials (RCTs), patients received linaclotide (72 µg, 145 µg, 290 µg) or placebo daily for 12-26 weeks; in two long-term safety (LTS) studies, patients received open-label linaclotide for ≤78 additional weeks. Laboratory values, vital signs, and treatment-emergent adverse events (TEAEs) were assessed. RESULTS: Overall, 3853 patients received ≥1 dose of linaclotide. The most common TEAE was diarrhea (majority [90.5% in RCTs] mild/moderate). Linaclotide patients experienced 1.1 diarrhea TEAE per patient-year in the RCTs (0.2 in placebo), and 0.3 in the LTS studies. In RCTs, 6.9% linaclotide and 3.0% placebo patients discontinued due to any adverse event (AE); 4.0% linaclotide and 0.3% placebo patients discontinued due to diarrhea. In LTS studies, 9.4% patients discontinued due to any AE, and 3.8% due to diarrhea. Serious AEs (SAEs) were rare and similar across treatment groups; there were no SAEs of diarrhea. CONCLUSION: These pooled analyses of patients treated for ≤104 weeks confirm linaclotide's overall safety.


Assuntos
Constipação Intestinal/tratamento farmacológico , Defecação/efeitos dos fármacos , Agonistas da Guanilil Ciclase C/uso terapêutico , Síndrome do Intestino Irritável/tratamento farmacológico , Peptídeos/uso terapêutico , Doença Crônica , Ensaios Clínicos Fase III como Assunto , Constipação Intestinal/diagnóstico , Constipação Intestinal/fisiopatologia , Diarreia/induzido quimicamente , Diarreia/fisiopatologia , Agonistas da Guanilil Ciclase C/efeitos adversos , Humanos , Síndrome do Intestino Irritável/diagnóstico , Síndrome do Intestino Irritável/fisiopatologia , Peptídeos/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Recuperação de Função Fisiológica , Fatores de Risco , Resultado do Tratamento
7.
Curr Biol ; 28(4): R144-R145, 2018 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-29462576

RESUMO

Cirrate octopods (Cephalopoda: Cirrata) are among the largest invertebrates of the deep sea. These organisms have long been known to lay single, large egg capsules on hard substrates on the ocean bottom [1], including cold-water octocorals (Anthozoa: Octocorallia). The egg capsule is comprised of an external egg case as well as the chorion and developing embryo. Development in cirrates proceeds for an extended time without parental care [2]. Although juveniles have previously been collected in the midwater [3], cirrate hatchlings have so far never been observed. Here, we provide the first video of a living hatchling and use magnetic resonance imaging (MRI) to analyze its anatomy and assign the specimen to the genus Grimpoteuthis, the so-called dumbo octopods. The specimen's behavior and advanced state of organ development show that cirrate hatchlings possess all morphological features required for movement via fin-swimming, for visually and chemically sensing their environment, and for prey capture. In addition, the presence of a large internal yolk sac reduces the risk of failure at first feeding. These data provide evidence that dumbo octopods hatch as competent juveniles.


Assuntos
Animais Recém-Nascidos/crescimento & desenvolvimento , Octopodiformes/crescimento & desenvolvimento , Animais , Animais Recém-Nascidos/anatomia & histologia , Animais Recém-Nascidos/fisiologia , Imageamento por Ressonância Magnética , Octopodiformes/anatomia & histologia , Octopodiformes/fisiologia , Percepção Olfatória , Comportamento Predatório , Natação , Gravação em Vídeo , Percepção Visual
8.
United European Gastroenterol J ; 4(3): 413-22, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27403308

RESUMO

BACKGROUND: Regulatory and treatment guidelines focus on individual conditions, yet clinicians often see patients with overlapping conditions. OBJECTIVE: This cross-sectional survey study assesses the impact of overlapping functional dyspepsia (FD), gastroesophageal reflux disease (GERD), irritable bowel syndrome with constipation (IBS-C), and chronic idiopathic constipation (CIC) on symptom burden and consulting behavior. METHODS: Survey participants met Rome III criteria for FD, IBS-C, and/or CIC, and/or reported GERD; participants answered questions about symptom frequency and bothersomeness, work and productivity, and consulting behavior. RESULTS: Of 2641 respondents, 1592 (60.3%) had one condition; 832 (31.5%) had two; and 217 (8.2%) had three; 57.3% of 1690 FD, 54.6% of 1337 GERD, 82.6% of 328 IBS-C, and 62.5% of 552 CIC respondents had condition overlap. Overall GI symptoms were very/extremely bothersome in 28.6% of single-condition respondents, 50.7% of two-condition, and 69.6% of three-condition respondents (p < 0.001, chi square). Symptom frequency and productivity losses both increased with condition overlap. Over 12 months, 43.7% of single-condition, 49.9% of two-condition, and 66.5% of three-condition respondents consulted a physician about GI symptoms (p < 0.001, chi square). CONCLUSION: Functional GI disorders frequently overlap with each other and with GERD. Condition overlap is associated with greater symptom burden and increased physician consultations.

9.
Am J Gastroenterol ; 110(4): 580-7, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25781368

RESUMO

INTRODUCTION: The irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) are associated with substantial symptom and disease burden. Although typically classified as distinct diseases, symptoms frequently overlap. AIM: The objective of this study was to characterize symptom and disease burden in IBS-C and CIC sufferers and examine a subset of CIC sufferers with abdominal symptoms. METHODS: In a US population-based survey, respondents meeting the Rome III criteria for IBS-C or CIC rated symptom frequency and bothersomeness, missed work and disrupted productivity, and degree of obtaining and satisfaction with physician care. CIC respondents were analyzed in two subgroups: those with abdominal symptoms ≥once weekly (CIC-A) and those without (CIC-NA). RESULTS: Of the 10,030 respondents, 328 met the criteria for IBS-C and 552 for CIC (363 CIC-A; 189 CIC-NA). All symptoms were significantly more frequent in IBS-C vs. CIC respondents (P<0.0001). Constipation was extremely/very bothersome in 72% of IBS-C respondents, 62% of CIC-A, and 40% of CIC-NA (P<0.01 all pairs). All 11 other measured symptoms were significantly more bothersome in IBS-C and CIC-A vs. CIC-NA respondents. In IBS-C vs. CIC-A, abdominal discomfort, bloating, straining, and pellet-like stools were also significantly more bothersome, with other remaining symptoms similar. Gastrointestinal symptoms disrupted productivity a mean of 4.9 days per month in IBS-C respondents, 3.2 in CIC-A, and 1.2 in CIC-NA (P<0.001 all pairs); missed days were similar in IBS-C and CIC-A respondents. CONCLUSION: CIC respondents with abdominal symptoms experience greater disease burden compared with CIC respondents without frequent abdominal symptoms and have a disease burden profile that is similar to IBS-C respondents.


Assuntos
Constipação Intestinal/epidemiologia , Constipação Intestinal/etiologia , Efeitos Psicossociais da Doença , Trato Gastrointestinal/fisiopatologia , Comportamentos Relacionados com a Saúde , Síndrome do Intestino Irritável/complicações , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Adulto , Idoso , Doença Crônica , Estudos de Coortes , Constipação Intestinal/economia , Constipação Intestinal/fisiopatologia , Eficiência , Feminino , Inquéritos Epidemiológicos , Humanos , Incidência , Síndrome do Intestino Irritável/economia , Síndrome do Intestino Irritável/epidemiologia , Síndrome do Intestino Irritável/fisiopatologia , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Fatores de Tempo , Estados Unidos/epidemiologia
10.
Ann Allergy Asthma Immunol ; 110(3): 168-72, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23548526

RESUMO

BACKGROUND: Effective treatment of acute attacks is critical in managing hereditary angioedema (HAE). Ecallantide, a plasma kallikrein inhibitor, is approved for the treatment of HAE attacks. Occasionally, a second dose is needed when treating attacks of HAE. OBJECTIVE: To evaluate the characteristics of HAE attacks requiring a second dose (dose B) of ecallantide. METHODS: Data from all ecallantide clinical trials (EDEMA2, EDEMA4, and DX-88/19) that allowed an open-label dose B were included in this analysis. Patient and attack characteristics potentially predictive of dose B after ecallantide were analyzed by logistic regression. A multivariate model was built using a backward selection process, incorporating variables from the univariate model with P < .20 and removing factors with the highest P value until only significant (P < .05) factors remained. RESULTS: The analysis included 732 ecallantide-treated HAE attacks in 179 patients. Dose B was required in 88 attacks (12.0%), most (80.5%) for incomplete response. By attack location, 31 of 325 abdominal attacks (9.5%), 17 of 158 laryngeal attacks (10.8%), and 40 of 242 peripheral attacks (16.5%) required dose B. On the basis of the univariate analysis, baseline severity (odds ratio = 1.33, P = .15) and peripheral attack (odds ratio = 1.80, P = .01) were identified as potential predictive factors; abdominal attacks had an inverse correlation (odds ratio = 0.64, P = .055). However, the multivariate analysis identified only peripheral attacks as statistically significantly correlated (P < .05) with dose B requirement. CONCLUSION: A single, 30-mg dose of ecallantide was effective for most HAE attacks (88.0%). Patients with peripheral attacks of HAE were more likely to require a second dose of ecallantide after 4 hours. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: not applicable for EDEMA2 (trial was conducted before registration requirements were implemented), NCT00457015 for EDEMA4, and NCT00456508 for DX-88/19.


Assuntos
Angioedemas Hereditários/diagnóstico , Angioedemas Hereditários/tratamento farmacológico , Anti-Inflamatórios não Esteroides/administração & dosagem , Peptídeos/administração & dosagem , Adulto , Angioedemas Hereditários/fisiopatologia , Anti-Inflamatórios não Esteroides/efeitos adversos , Progressão da Doença , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeos/efeitos adversos , Valor Preditivo dos Testes , Prognóstico , Resultado do Tratamento , Adulto Jovem
11.
PLoS One ; 5(11): e13832, 2010 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-21124960

RESUMO

BACKGROUND: In contrast to the well-studied continental shelf region of the Gulf of Maine, fundamental questions regarding the diversity, distribution, and abundance of species living in deep-sea habitats along the adjacent continental margin remain unanswered. Lack of such knowledge precludes a greater understanding of the Gulf of Maine ecosystem and limits development of alternatives for conservation and management. METHODOLOGY/PRINCIPAL FINDINGS: We use data from the published literature, unpublished studies, museum records and online sources, to: (1) assess the current state of knowledge of species diversity in the deep-sea habitats adjacent to the Gulf of Maine (39-43°N, 63-71°W, 150-3000 m depth); (2) compare patterns of taxonomic diversity and distribution of megafaunal and macrofaunal species among six distinct sub-regions and to the continental shelf; and (3) estimate the amount of unknown diversity in the region. Known diversity for the deep-sea region is 1,671 species; most are narrowly distributed and known to occur within only one sub-region. The number of species varies by sub-region and is directly related to sampling effort occurring within each. Fishes, corals, decapod crustaceans, molluscs, and echinoderms are relatively well known, while most other taxonomic groups are poorly known. Taxonomic diversity decreases with increasing distance from the continental shelf and with changes in benthic topography. Low similarity in faunal composition suggests the deep-sea region harbours faunal communities distinct from those of the continental shelf. Non-parametric estimators of species richness suggest a minimum of 50% of the deep-sea species inventory remains to be discovered. CONCLUSIONS/SIGNIFICANCE: The current state of knowledge of biodiversity in this deep-sea region is rudimentary. Our ability to answer questions is hampered by a lack of sufficient data for many taxonomic groups, which is constrained by sampling biases, life-history characteristics of target species, and the lack of trained taxonomists.


Assuntos
Antozoários/crescimento & desenvolvimento , Biodiversidade , Crustáceos/crescimento & desenvolvimento , Peixes/crescimento & desenvolvimento , Moluscos/crescimento & desenvolvimento , Animais , Antozoários/classificação , Oceano Atlântico , Crustáceos/classificação , Ecossistema , Peixes/classificação , Geografia , Maine , Biologia Marinha , Moluscos/classificação , Oceanos e Mares , Especificidade da Espécie , Movimentos da Água
12.
Ann Allergy Asthma Immunol ; 104(4): 314-20, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20408341

RESUMO

BACKGROUND: Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by recurrent acute attacks of swelling of the larynx, abdomen, and periphery. OBJECTIVE: To assess the economic burden associated with acute attacks and long-term management of HAE. METHODS: Burden was assessed via a Web-based survey of HAE patients (> or = 18 years old) that solicited information on attack characterization, short-term treatment, long-term disease management, impact on work, and patient costs. A standardized instrument, the Work Productivity and Activity Impairment questionnaire, was included to assess impact on work productivity. Standard medical costs and US average wage costs were assigned to survey items to assess direct medical and indirect costs, respectively. RESULTS: Total annual per-patient costs are estimated at $42,000 for the average HAE patient, with costs totaling $14,000 for patients with mild attacks, $27,000 for patients with moderate attacks, and $96,000 for patients with severe attacks. Hospital costs account for 67% of direct medical costs. Respondents reported high rates of missed work, lost productivity, and lost income, contributing to indirect costs totaling $16,000 annually for the average patient. Almost all costs increase with disease severity, although the distribution varies with severity: indirect costs account for 75% of costs for patients with mild attacks, whereas emergency department and hospital costs account for 68% of costs for patients with severe attacks. CONCLUSIONS: HAE results in considerable economic burden to patients, payers, and society in terms of direct medical and indirect costs and compounds the substantial humanistic burdens, which will be reported separately.


Assuntos
Angioedemas Hereditários/economia , Efeitos Psicossociais da Doença , Custos de Cuidados de Saúde/estatística & dados numéricos , Doença Aguda/economia , Doença Aguda/terapia , Adulto , Angioedemas Hereditários/diagnóstico , Angioedemas Hereditários/terapia , Custos de Medicamentos/estatística & dados numéricos , Serviços Médicos de Emergência/economia , Serviços Médicos de Emergência/estatística & dados numéricos , Feminino , Pesquisas sobre Serviços de Saúde , Custos Hospitalares/estatística & dados numéricos , Hospitalização/economia , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Inquéritos e Questionários
13.
Metabolism ; 59(5): 658-63, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-19922964

RESUMO

Increased nonenzymatic glycation of apolipoprotein (apo) B-containing lipoproteins impairs uptake and metabolism by the high-affinity low-density lipoprotein receptor and is one of the postsecretory modifications contributory to accelerated atherosclerosis in diabetes. The present study evaluated in vitro and in vivo effects of 2,2-chlorophenylaminophenylacetate to probe the influence of glycated lipoprotein on cholesterol homeostasis. This compound prevented the increased formation of glycated products in low-density lipoprotein incubated with 200 mmol/L glucose and the increased cholesteryl ester synthesis in THP-1 macrophages induced by apo B-containing lipoproteins preincubated with high glucose concentration. The elevated circulating concentrations of glycated lipoprotein and cholesterol and higher vascular levels of lipid peroxidation products observed in streptozotocin diabetic rats compared with nondiabetic controls were significantly reduced in diabetic animals treated for 6 months with test compound. These results are the first to demonstrate that inhibiting nonenzymatic glycation of apo B-containing lipoproteins ameliorates abnormalities contributory to hypercholesterolemia and atherogenic risk in diabetes.


Assuntos
Apolipoproteínas B/sangue , Aterosclerose/sangue , Ésteres do Colesterol/biossíntese , Diabetes Mellitus Experimental/sangue , Hipercolesterolemia/sangue , Macrófagos/metabolismo , Animais , Ésteres do Colesterol/sangue , Diclofenaco/análogos & derivados , Diclofenaco/farmacologia , Glicosilação/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Lipoproteínas LDL/farmacologia , Macrófagos/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
14.
Ophthalmic Res ; 40(1): 5-9, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18025835

RESUMO

BACKGROUND: This study evaluated the postulate that the vitreous of diabetic db/db mice, a genetic model of type 2 diabetes that manifests hyperglycemia and insulin resistance, exhibits alterations in angiogenic and metabolic factors that reflect abnormalities in the retinal microvasculature participatory in the pathogenesis of diabetic retinopathy. METHODS: Vitreous obtained from db/db and age-matched nondiabetic db/m mice was analyzed by Western blot for pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor (VEGF), by immunoassay for type IV collagen, and by measurement of TBARs for lipid peroxide products. RESULTS: Compared to nondiabetic db/m controls, vitreous from db/db mice contained decreased PEDF and increased VEGF (VEGF:PEDF relative ratio 2.2 +/- 0.3 and 1.0 +/- 0.1 in db/db vs. db/m, respectively; p < 0.05), and elevated concentrations of lipid peroxide products (187 +/- 43 and 84 +/- 15 ng/ml in db/db vs. db/m, respectively; p < 0.05) and type IV collagen (5.2 +/- 0.7 and 3.1 +/- 0.4 nmol/ml in db/db vs. db/m, respectively; p < 0.05). These changes were observed at age 18-20 weeks, consistent with an early stage in the development of retinal microvascular pathology. CONCLUSIONS: The findings support the potential usefulness of vitreous from the db/db mouse as a model tissue for investigation of pathogenetic factors and assessment of therapeutic interventions in early diabetic retinopathy.


Assuntos
Moduladores da Angiogênese/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Retinopatia Diabética/metabolismo , Modelos Animais de Doenças , Corpo Vítreo/metabolismo , Animais , Western Blotting , Colágeno Tipo IV/metabolismo , Proteínas do Olho , Imunoensaio , Peróxidos Lipídicos/metabolismo , Masculino , Camundongos , Fatores de Crescimento Neural , Concentração Osmolar , Serpinas , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Fator A de Crescimento do Endotélio Vascular
15.
Am J Physiol Renal Physiol ; 292(2): F789-95, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17018845

RESUMO

Glomerular cells in culture respond to albumin containing Amadori glucose adducts (the principal serum glycated protein), with activation of protein kinase C-beta(1), increased expression of transforming growth factor (TGF)-beta1, the TGF-beta type II signaling receptor, and the extracellular matrix proteins alpha(1)(IV) collagen and fibronectin and with decreased production of the podocyte protein nephrin. Decreasing the burden of glycated albumin in diabetic db/db mice significantly reduces glomerular overexpression of TGF-beta1 mRNA, restores glomerular nephrin immunofluorescence, and lessens proteinuria, mesangial expansion, renal extracellular matrix protein production, and increased glomerular vascular endothelial growth factor (VEGF) immunostaining. In the present study, db/db mice were treated with a small molecule, designated 23CPPA, that inhibits the nonenzymatic condensation of glucose with the albumin protein to evaluate whether increased glycated albumin influences the production of VEGF receptors (VEGFRs) and type IV collagen subchains and ameliorates the development of renal insufficiency. Renal levels of VEGF and VEGFR-1 proteins and serum creatinine concentrations were significantly higher and renal levels of alpha(3)(IV) collagen and nephrin proteins and endogenous creatinine clearance values were significantly lower in control diabetic than in age-matched nondiabetic (db/m) mice. These changes were significantly attenuated in db/db littermate mice treated from 9 to 18 wk of age with 23CPPA. The findings indicate that inhibiting excess nonenzymatic glycation of serum albumin improves renal molecular biology abnormalities and protects against the development of renal insufficiency in the db/db mouse.


Assuntos
Colágeno Tipo IV/biossíntese , Diclofenaco/análogos & derivados , Glicosilação/efeitos dos fármacos , Rim/efeitos dos fármacos , Insuficiência Renal/prevenção & controle , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Albuminas/química , Animais , Creatinina/sangue , Diabetes Mellitus Experimental/fisiopatologia , Diclofenaco/farmacologia , Masculino , Proteínas de Membrana/biossíntese , Camundongos , Camundongos Obesos
16.
Kidney Int ; 68(4): 1554-61, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16164632

RESUMO

BACKGROUND: Albumin modified by Amadori-glucose adducts has been linked to the development of diabetic nephropathy through its ability, independent of hyperglycemia, to activate protein kinase C-beta (PKC-beta), up-regulate the transforming growth factor-beta (TGF-beta) system, and stimulate expression of extracellular matrix proteins in glomerular cells, and by the demonstration that reducing the burden of glycated albumin ameliorates renal structural and functional abnormalities in the db/db mouse. METHODS: To probe whether the salutary effects consequent to lowering glycated albumin, which include reduction of albuminuria, relate to an influence of the Amadori-modified protein on nephrin, the podocyte protein critical to regulation of protein excretion, and on the angiogenic vascular endothelial growth factor (VEGF), which induces microvascular permeability, diabetic db/db mice were treated with a small molecule that inhibits the nonenzymatic glycation of albumin. RESULTS: Compared to nondiabetic db/m mice, diabetic controls exhibited increased urinary excretion of albumin and type IV collagen, elevated renal TGF-beta1 protein levels, reduced glomerular nephrin immunofluorescence and nephrin protein by immunoblotting, and increased glomerular VEGF immunostaining and renal VEGF protein content. Diabetic animals receiving test compound showed significant lowering of proteinuria, normalization of renal TGF-beta1 protein, and significant restoration of altered glomerular nephrin and VEGF expression. CONCLUSION: The findings causally implicate the increased glycated albumin associated with the diabetic state in the abnormal renal nephrin and VEGF expression found in diabetes, thereby promoting proteinuria and glomerulosclerosis.


Assuntos
Nefropatias Diabéticas/metabolismo , Glomérulos Renais/metabolismo , Proteínas de Membrana/metabolismo , Proteinúria/metabolismo , Albumina Sérica/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Albuminúria/metabolismo , Animais , Colágeno Tipo IV/urina , Imunofluorescência , Masculino , Camundongos , Camundongos Mutantes , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1
17.
J Lab Clin Med ; 141(4): 242-9, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12677169

RESUMO

Albumin modified by Amadori glucose adducts has been shown to modulate signal transduction and induce alterations in renal glomerular cells that contribute to the development of diabetic nephropathy. However, the participation of this nonenzymatically glycated protein in the pathobiology of atherosclerotic cardiovascular disease in diabetes has not been established. To probe this issue, we used macrophage RAW cells to assess the effects of glycated albumin on molecular events implicated in the pathogenesis of diabetes-related vascular complications. RAW cells were cultured in medium containing 5.5 mmol/L glucose and glycated or nonglycated albumin, with and without the addition of PD98059, a specific inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK), followed by analysis of phosphorylated ERK and the nuclear translocation of nuclear factor (NF)-kappa B and measurement of cellular content of thiobarbituric acid-reactive substances and the concentration of transforming growth factor (TGF)-beta(1) in the spent medium. We demonstrate, for the first time, that glycated albumin activates RAW cell ERK and promotes ERK-dependent increases in TGF-beta(1) production, oxidative stress, and NF-kappa B activation. Preincubation with the antioxidant alpha-lipoic acid partially prevented the glycated albumin-induced increase in NF-kappa B activation. These findings indicate that Amadori-modified glycated albumin modulates macrophage cell biology independent of high glucose concentration. The effects of glycated albumin on RAW cell molecular mediators and cytokine production may have pathophysiologic significance with respect to the accelerated atherosclerosis that occurs in diabetes.


Assuntos
Macrófagos/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/biossíntese , NF-kappa B/biossíntese , Estresse Oxidativo/efeitos dos fármacos , Albumina Sérica/farmacologia , Fator de Crescimento Transformador beta/biossíntese , Animais , Antioxidantes/farmacologia , Linhagem Celular , Meios de Cultivo Condicionados/química , Inibidores Enzimáticos/farmacologia , Flavonoides/farmacologia , Glicosilação , Macrófagos/metabolismo , Camundongos , Albumina Sérica/química , Substâncias Reativas com Ácido Tiobarbitúrico/análise , Ácido Tióctico/farmacologia , Fator de Crescimento Transformador beta1
18.
Metabolism ; 51(7): 901-5, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12077739

RESUMO

Increased excretion of type IV collagen accompanies the accumulation of mesangial matrix, which leads to compromise in the glomerular filtration surface area, during the development of diabetic nephropathy. We postulated that the response of urinary collagen IV would be useful in evaluating possible treatment strategies to arrest the nephropathic process while still at a reversible stage. To test this hypothesis, we examined the effect of a small molecule (22CPPA) that inhibits the formation of glycated albumin, which is causally linked to the pathogenesis of diabetic nephropathy, on collagen IV excretion, albuminuria, and renal function in db/db mice. Compared to nondiabetic db/m mice, db/db animals showed markedly increased urinary collagen IV and albumin, significantly elevated serum glycated albumin and creatinine concentrations, and a significantly reduced creatinine clearance. Treatment of db/db mice with test compound, which normalized glycated albumin concentrations, significantly lowered collagen IV and albumin excretion and ameliorated the fall in creatinine clearance and the rise in serum creatinine despite persistent hyperglycemia. The findings indicate that reduction of elevated collagen IV excretion in diabetes reflects a salutary influence on developing glomerulosclerosis, and that glycated albumin has an important nephropathogenic role that can be therapeutically addressed independent of glycemic status.


Assuntos
Colágeno Tipo IV/urina , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Albumina Sérica/metabolismo , Albuminúria , Animais , Peso Corporal , Creatinina/sangue , Creatinina/urina , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/fisiopatologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/fisiopatologia , Modelos Animais de Doenças , Hiperglicemia/sangue , Hiperglicemia/etiologia , Testes de Função Renal , Masculino , Camundongos , Camundongos Mutantes , Fenilacetatos/farmacologia , Albumina Sérica/antagonistas & inibidores , Tempo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...