RESUMO
Cenderitide is a novel designer natriuretic peptide (NP) composed of C-type natriuretic peptide (CNP) fused to the C-terminus of Dendroaspis natriuretic peptide (DNP). Cenderitide was engineered to coactivate the two NP receptors, particulate guanylyl cyclase (pGC)-A and -B. The rationale for its design was to achieve the renal-enhancing and antifibrotic properties of dual receptor activation, but without clinically significant hypotension. Here we report the first clinical trial on the safety, tolerability, and cyclic guanosine monophosphate (cGMP) activating properties of Cenderitide in subjects with stable heart failure (HF). Four-hour infusion of Cenderitide was safe, well-tolerated, and significantly increased plasma cGMP levels and urinary cGMP excretion without adverse effects with no change in blood pressure. Thus, Cenderitide has a favorable safety profile and expected pharmacological effects in stable human HF. Our results support further investigations of Cenderitide in HF as a potential future cGMP-enhancing therapeutic strategy.
Assuntos
Fármacos Cardiovasculares/uso terapêutico , AMP Cíclico/sangue , Insuficiência Cardíaca/tratamento farmacológico , Peptídeos Natriuréticos/uso terapêutico , Venenos de Serpentes/uso terapêutico , Idoso , Biomarcadores/sangue , Biomarcadores/urina , Fármacos Cardiovasculares/efeitos adversos , Doença Crônica , AMP Cíclico/urina , Método Duplo-Cego , Esquema de Medicação , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/urina , Humanos , Infusões Intravenosas , Rim/efeitos dos fármacos , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Minnesota , Peptídeos Natriuréticos/efeitos adversos , Estudos Prospectivos , Eliminação Renal , Venenos de Serpentes/efeitos adversos , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: The Perioperative Surgical Home is a novel care model designed to provide patient-centered, high-quality surgical care. In 2013, we implemented POSH, a pilot Peri-Operative Surgical Home at Phoenix Indian Medical Center (PIMC), an Indian Health Service hospital, as a quality improvement project. After 2 y, we sought to quantify the impact of POSH on the quality of surgical care at PIMC. MATERIALS AND METHODS: We conducted a retrospective review of 33 surgical patients who underwent surgery at PIMC through the POSH process between 2013 and 2015 matched to 64 historical controls with similar operations. Study patients underwent surgery via the POSH treatment process. Primary outcomes were composite measures of (1) care standards and (2) care goals. Success was defined as meeting seven of nine care standards and six of eight care goals. RESULTS AND DISCUSSION: The mean number of care standards met was 8.1 ± 1.0 versus 4.2 ± 1.4 (P < 0.001) and the mean number of care goals met was 6.7 ± 0.8 versus 6.1 ± 1.1 (P = 0.005) for POSH patients and historical controls, respectively. Patients participating in the POSH model were 8.6 (95% confidence interval: 3.5-22.3) and 1.5 (95% confidence interval: 1.2-1.9) times more likely to meet the minimum number of care standards and goals, respectively. Fourteen of the study patients (42%) would not have been offered surgery at PIMC before POSH due to elevated surgical risk. CONCLUSIONS: POSH may have improved quality of surgical care at PIMC while expanding services to more complex patients. POSH may present an opportunity for improved surgical quality in resource-constrained environments.
Assuntos
Serviços de Saúde do Indígena/organização & administração , Indígenas Norte-Americanos , Equipe de Assistência ao Paciente/organização & administração , Assistência Centrada no Paciente/organização & administração , Assistência Perioperatória/normas , Melhoria de Qualidade/organização & administração , Cirurgiões/organização & administração , Adulto , Idoso , Arizona , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Processos e Resultados em Cuidados de Saúde , Assistência Perioperatória/métodos , Assistência Perioperatória/estatística & dados numéricos , Projetos Piloto , Melhoria de Qualidade/estatística & dados numéricos , Estudos RetrospectivosRESUMO
BACKGROUND: Aberrant right subclavian artery (ARSA) is the most common congenital arch anomaly, which can be complicated by aneursymal dilation at its ostium. We describe a successful repair of an ARSA with a three-stage operative procedure using a left carotid to subclavian bypass, coiling of the ARSA, and thoracic endovascular aortic repair with long-term clinical and radiographic follow-up.
Assuntos
Aorta Torácica/cirurgia , Implante de Prótese Vascular/métodos , Artéria Subclávia/cirurgia , Idoso , Angiografia , Aorta Torácica/patologia , Implante de Prótese Vascular/instrumentação , Artéria Braquial , Feminino , Humanos , Artéria Subclávia/anormalidades , Artéria Subclávia/patologia , Fatores de Tempo , Resultado do Tratamento , Malformações Vasculares/patologia , Malformações Vasculares/cirurgiaRESUMO
A case of unusual reactions consisting of involuntary abnormal facial movements in a child following exposure to the 5-HT3 receptor antagonists for prophylaxis against chemotherapy-induced vomiting is presented. Potential mechanisms for these reactions are discussed.
Assuntos
Músculos Faciais/efeitos dos fármacos , Ondansetron/efeitos adversos , Antagonistas da Serotonina/efeitos adversos , Antieméticos/efeitos adversos , Antieméticos/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Criança , Músculos Faciais/fisiopatologia , Humanos , Masculino , Ondansetron/uso terapêutico , Rabdomiossarcoma/tratamento farmacológico , Antagonistas do Receptor 5-HT3 de Serotonina , Antagonistas da Serotonina/uso terapêutico , Vômito/induzido quimicamente , Vômito/prevenção & controleRESUMO
BACKGROUND: EUR-1008 (Zenpep [pancrelipase]) is a new, enteric-coated, porcine-derived pancreatic enzyme product (PEP) developed for the treatment of cystic fibrosis (CF) patients with malabsorption associated with exocrine pancreatic insufficiency (EPI). Unlike currently marketed PEPs, EUR-1008 contains the label-claimed lipase content. Safety and efficacy were assessed in younger (<7 years) and older (> or =7 years) CF patients with EPI. METHODS: Two multicenter studies were conducted: a randomized, double-blind, placebo-controlled, crossover trial in patients > or =7 years of age (N=34) and a supplemental, open-label study in children <7 years of age (N=19). Use of any medications altering gastric pH/motility was prohibited during the studies. Outcome measures in the randomized trial included changes in the coefficient of fat absorption (CFA), coefficient of nitrogen absorption (CNA), and signs/symptoms of malabsorption for EUR-1008 vs. placebo. Outcome measures in the supplemental study included safety and response (defined as no steatorrhea and no overt signs/symptoms of malabsorption) to EUR-1008 vs. previous enzyme treatment. RESULTS: In the randomized trial, EUR-1008 treatment compared to placebo resulted in a significantly higher mean CFA (88.3% vs. 62.8%, respectively) and CNA (87.2% vs. 65.7%, respectively) (both p<0.001) and reduced the incidence of malabsorption signs and symptoms in 32 evaluable patients. In the supplemental study, 11 of 19 patients met the criteria for responder with EUR-1008 at the end of the study vs. 10 of 19 patients at screening (previous PEP), and improvements in clinical symptoms were reported with EUR-1008 treatment. EUR-1008 was safe and well tolerated, and no serious drug-related AEs were reported in either study. CONCLUSIONS: EUR-1008 was safe, well tolerated, and effective in CF patients of all ages with EPI-associated malabsorption in two clinical trials. Treatment led to clinically and statistically significant improvements in CFA and CNA in the randomized study, and control of malabsorption and clinical symptoms in both studies.
Assuntos
Fibrose Cística/complicações , Insuficiência Pancreática Exócrina/tratamento farmacológico , Insuficiência Pancreática Exócrina/etiologia , Pancrelipase/administração & dosagem , Adolescente , Criança , Colesterol/sangue , Estudos Cross-Over , Feminino , Humanos , Síndromes de Malabsorção/tratamento farmacológico , Síndromes de Malabsorção/etiologia , Masculino , Pancrelipase/efeitos adversos , Comprimidos com Revestimento Entérico , Resultado do Tratamento , Vitaminas/sangue , Adulto JovemRESUMO
Alternative RNA splicing may provide unique opportunities to identify drug targets and therapeutics. We identified an alternative spliced transcript for B-type natriuretic peptide (BNP) resulting from intronic retention. This transcript is present in failing human hearts and is reduced following mechanical unloading. The intron-retained transcript would generate a unique 34 amino acid (aa) carboxyl terminus while maintaining the remaining structure of native BNP. We generated antisera to this carboxyl terminus and identified immunoreactivity in failing human heart tissue. The alternatively spliced peptide (ASBNP) was synthesized and unlike BNP, failed to stimulate cGMP in vascular cells or vasorelax preconstricted arterial rings. This suggests that ASBNP may lack the dose-limiting effects of recombinant BNP. Given structural considerations, a carboxyl-terminal truncated form of ASBNP was generated (ASBNP.1) and was determined to retain the ability of BNP to stimulate cGMP in canine glomerular isolates and cultured human mesangial cells but lacked similar effects in vascular cells. In a canine-pacing model of heart failure, systemic infusion of ASBNP.1 did not alter mean arterial pressure but increased the glomerular filtration rate (GFR), suppressed plasma renin and angiotensin, while inducing natriuresis and diuresis. Consistent with its distinct in vivo effects, the activity of ASBNP.1 may not be explained through binding and activation of NPR-A or NPR-B. Thus, the biodesigner peptide ASBNP.1 enhances GFR associated with heart failure while lacking the vasoactive properties of BNP. These findings demonstrate that peptides with unique properties may be designed based on products of alternatively splicing.
Assuntos
Processamento Alternativo/efeitos dos fármacos , Desenho de Fármacos , Rim/efeitos dos fármacos , Peptídeo Natriurético Encefálico/genética , Peptídeos/farmacologia , Sequência de Aminoácidos , Animais , Bovinos , Cães , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Humanos , Dados de Sequência Molecular , Peptídeo Natriurético Encefálico/química , Peptídeo Natriurético Encefálico/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores do Fator Natriurético Atrial/metabolismoRESUMO
Since the discovery of atrial natriuretic factor by de Bold et al., there has been tremendous progress in our understanding of the physiologic, diagnostic and therapeutic roles of the natriuretic peptides (NPs) in health and disease. Natriuretic peptides are endogenous hormones that are released by the heart in response to myocardial stretch and overload. Three mammalian NPs have been identified and characterized, including atrial natriuretic peptide (ANP or atrial natriuretic factor), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). In addition, Dendroaspis natriuretic peptide (DNP) has been isolated from the venom of Dendroaspis angusticeps (the green mamba snake), and urodilatin from human urine. These peptides are structurally similar and they consist of a 17-amino-acid core ring and a cysteine bridge. Both ANP and BNP bind to natriuretic peptide receptor A (NPR-A) that are expressed in the heart and other organs. Activation of NPR-A generates an increase in cyclic guanosine monophosphate, which mediates natriuresis, inhibition of renin and aldosterone, as well as vasorelaxant, anti-fibrotic, anti-hypertrophic, and lusitropic effects. The NP system thus serves as an important compensatory mechanism against neurohumoral activation in heart failure. This provides a strong rationale for the use of exogenous NPs in the management of acutely decompensated heart failure. In this article, the therapeutic applications of NPs in the acute heart failure syndromes are reviewed. Emerging therapeutic agents and areas for future research are discussed.