RESUMO
BACKGROUND: The role of oral vasodilators in the management of acute decompensated heart failure (ADHF) is not clearly defined. We evaluated the use of captopril vs hydralazine-isosorbide dinitrate (H-ISDN) in the transition from sodium nitroprusside (SNP) in patients with ADHF. METHODS AND RESULTS: A retrospective chart review was performed of 369 consecutive adult patients in the intensive care unit with ADHF and reduced ejection fraction, who received either a captopril or an H-ISDN protocol to transition from SNP. Captopril patients were matched 1:2 to H-ISDN patients, based on serum creatinine and race (Black vs non-Black). Baseline demographics, serum chemistry and use of angiotensin converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) were similar in both groups. Time to SNP discontinuation (46.9 vs 40.4 hours, Pâ¯=â¯0.11) and length of hospital stay (9.86 vs 7.99 days, Pâ¯=â¯0.064) were similar in both groups. Length of hospital stay in the intensive care unit was statistically shorter in the H-ISDN group (4.11 vs 3.96 days, Pâ¯=â¯0.038). Fewer H-ISDN protocol patients were discharged on ACEis/ARBs (82.9 % vs 69.9%, Pâ¯=â¯0.003) despite similar kidney function at time of discharge (serum creatinine 1.1 vs 1.2, Pâ¯=â¯0.113). No difference was observed in rates of readmission (40.7% vs 50%, Pâ¯=â¯0.09) or mortality (16.3% vs 17.5 %, Pâ¯=â¯0.77) at 1 year postdischarge. CONCLUSION: Similar inpatient and 1-year outcomes were observed between patients using H-ISDN vs ACEi when transitioning from SNP, even though fewer H-ISDN protocol patients were discharged taking ACEis/ARBs despite similar kidney function.
Assuntos
Captopril , Insuficiência Cardíaca , Adulto , Assistência ao Convalescente , Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Hidralazina , Dinitrato de Isossorbida , Nitroprussiato/efeitos adversos , Alta do Paciente , Estudos Retrospectivos , Vasodilatadores/efeitos adversosRESUMO
Induction of lipogenesis in response to insulin is critically dependent on the transcription factor, sterol regulatory element-binding protein-1c (SREBP-1c). FoxO1, a forkhead box class-O transcription factor, is an important mediator of insulin action, but its role in the regulation of lipid metabolism has not been clearly defined. We examined the effects of FoxO1 on srebp1 gene expression in vivo and in vitro. In vivo studies showed that constitutively active (CA) FoxO1 (CA-FoxO1) reduced basal expression of SREBP-1c mRNA in liver by â¼60% and blunted induction of SREBP-1c in response to feeding. In liver-specific FoxO knock-out mice, SREBP-1c expression was increased â¼2-fold. Similarly, in primary hepatocytes, CA-FoxO1 suppressed SREBP1-c expression and inhibited basal and insulin-induced SREBP-1c promoter activity. SREBP-1c gene expression is induced by the liver X receptor (LXR), but CA-FoxO1 did not block the activation of SREBP-1c by the LXR agonist TO9. Insulin stimulates SREBP-1c transcription through Sp1 and via "feed forward" regulation by newly synthesized SREBP-1c. CA-FoxO1 inhibited SREBP-1c by reducing the transactivational capacity of both Sp1 and SREBP-1c. In addition, chromatin immunoprecipitation assays indicate that FoxO1 can associate with the proximal promoter region of the srebp1 gene and disrupt the assembly of key components of the transcriptional complex of the SREBP-1c promoter. We conclude that FoxO1 inhibits SREBP-1c transcription via combined actions on multiple transcription factors and that this effect is exerted at least in part through reduced transcriptional activity of Sp1 and SREBP-1c and disrupted assembly of the transcriptional initiation complex on the SREBP-1c promoter.
Assuntos
Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica/fisiologia , Fígado/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Fator de Transcrição Sp1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Animais , Células Cultivadas , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/genética , Hepatócitos/metabolismo , Insulina/genética , Insulina/metabolismo , Receptores X do Fígado , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Receptores Nucleares Órfãos/genética , Receptores Nucleares Órfãos/metabolismo , Ratos , Elementos de Resposta/fisiologia , Fator de Transcrição Sp1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Transcrição Gênica/fisiologiaRESUMO
Tacrolimus is a core component of immunosuppressive regimens. This study compared active pharmaceutical ingredient (API) and dissolution kinetics of branded tacrolimus and formulations from three generic manufacturers (Mylan, Dr. Reddy's, Intas) including samples from patients who suffered acute cardiac allograft rejection. Generic samples showed similar API content compared to branded samples with no major impurities. Capsules that underwent uniformity testing had consistent capsule-to-capsule API. Dissolution testing showed similar profiles between branded tacrolimus and Mylan, but notable differences with Dr. Reddy's and Intas. The approximate maximal inhibitory concentration (IC50) was highest in branded tacrolimus (29 minutes), followed by Mylan (26 minutes), Dr. Reddy's (19 minutes), and Intas (14 minutes) (Student-Newman-Keuls Multiple Comparisons Test; overall ANOVA: pâ¯=â¯0.0199, Fâ¯=â¯6.469). This study suggests that the bioavailability of certain generic tacrolimus formulations peak significantly earlier than branded tacrolimus. Further study is needed to determine whether these differences are clinically relevant.
Assuntos
Medicamentos Genéricos/farmacocinética , Rejeição de Enxerto/prevenção & controle , Transplante de Coração , Tacrolimo/farmacocinética , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/metabolismo , Humanos , Imunossupressores/farmacocinéticaRESUMO
PURPOSE OF REVIEW: A multidisciplinary approach is vital to reduce mortality and hospitalizations in patients with heart failure. As members of the multidisciplinary team, pharmacists are uniquely positioned to care for patients across the spectrum of heart failure. This comprehensive review explores the different facets in which pharmacists can be utilized to impact the care for patients with heart failure, including those with cardiac transplant and left ventricular assist devices (LVADs), in the outpatient setting. RECENT FINDINGS: Pharmacists can see heart failure patients in a variety of settings to reduce drug therapy-related issues, increase use of guideline-directed medical therapy (GDMT), and reduce hospitalizations. Although there is limited data available, pharmacists have also been described in aiding the therapeutic drug monitoring of warfarin for patients with LVADs and immunosuppression agents in the transplant population. Through collaborative practice agreements, pharmacists can provide progressive services such as titration of GDMT and lab monitoring, in addition to medication reconciliation, education, and review for potential drug-related problems. Pharmacists can increase access to patient care by providing services through distance-visits, shared medical appointments, and home visits.
RESUMO
Although heat shock proteins are thought to function primarily as intracellular chaperones, the release and potential extracellular functions of heat shock proteins have been the focus of an increasing number of studies. Our particular interest is HspB1 (Hsp25/27) and as astrocytes are an in vivo source of HspB1 it is a reasonable possibility they could release HspB1 in response to local stresses. Using primary cultures of rat cortical astrocytes, we investigated the extracellular release of HspB1 with exposure to amyloid-ß (Aß). In order to assess potential mechanisms of release, we cotreated the cells with compounds that can modulate protein secretion including Brefeldin A, Methyl ß-cyclodextrin, and MAP kinase inhibitors. Exposure to Aß (0.1, 1.0, 2.0 µM) for 24-48âh resulted in a selective release of HspB1 that was insensitive to BFA treatment; none of the other inhibitors had any detectable influence. Protease protection assays indicated that some of the released HspB1 was associated with a membrane bound fraction, and analysis of exosomal preparations indicated the presence of HspB1 in exosomes. Finally, immunoprecipitation experiments demonstrated that the extracellular HspB1 was able to interact with extracellular Aß. In summary, Aß can stimulate release of HspB1 from astrocytes, this release is insensitive to Golgi or lipid raft disruption, and HspB1 can be found either free in the medium or associated with exosomes. This release suggests that there is a potential for extracellular HspB1 to be able to bind and sequester extracellular Aß.
Assuntos
Peptídeos beta-Amiloides/farmacologia , Astrócitos/metabolismo , Proteínas de Choque Térmico HSP27/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Células Cultivadas , Transporte Proteico , RatosAssuntos
Analgesia/métodos , Analgésicos Opioides/farmacologia , Insuficiência Cardíaca/cirurgia , Coração Auxiliar , Dor Pós-Operatória/tratamento farmacológico , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Manejo da Dor/métodos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Clinical studies have revealed that social support improves the outcome of cancer patients, whereas epidemiologic studies suggest that social isolation increases the risk of death associated with several chronic diseases. However, the precise molecular consequences of an unfavorable social environment have not been defined. To do so, robust, reproducible preclinical models are needed to study the mechanisms whereby an adverse environment affects gene expression and cancer biology. Because random assignment of inbred laboratory mice to well-defined social environments allows accurate and repeated measurements of behavioral and endocrine parameters, transgenic mice provide a preclinical framework with which to begin to determine gene-environment mechanisms. In this study, we found that female C3(1)/SV40 T-antigen mice deprived of social interaction from weaning exhibited increased expression of genes encoding key metabolic pathway enzymes in the premalignant mammary gland. Chronic social isolation was associated with up-regulated lipid synthesis and glycolytic pathway gene expression-both pathways are known to contribute to increased breast cancer growth. Consistent with the expression of metabolic genes in premalignant mammary tissue, isolated mice subsequently developed a significantly larger mammary gland tumors burden compared with group-housed mice. Endocrine evaluation confirmed that isolated mice developed a heightened corticosterone stress response compared with group-housed mice. Together, these transdisciplinary studies show for the first time that an adverse social environment is associated with altered mammary gland gene expression and tumor growth. Moreover, the identification of specific alterations in metabolic pathways gene expression favoring tumor growth suggests potential molecular biomarkers and/or targets (e.g., fatty acid synthesis) for preventive intervention in breast cancer.