Population pharmacokinetics of carvedilol in patients with congestive heart failure.

The aim of this study was to derive population pharmacokinetic (PK) model for clearance (CL) of carvedilol in adult patients with chronic heart failure (CHF). Medication and demographic data were obtained from 52 Caucasian patients with CHF taking carvedilol. Population PK analysis was performed by nonlinear mixed-effects modeling (NONMEM) to estimate and identify different factors that could affect carvedilol CL. A total of 55 plasma concentrations were collected from 52 patients with mean age of 63.02 ± 11.95 years and total body weight (TBW) of 77.96 ± 13.46 kg. Total daily doses of carvedilol in the target population had wide range of variability (6.25-50 mg), followed by high variability of drug plasma concentrations (1-59.07 ng/mL). The typical mean value for carvedilol CL, estimated by the base model, in the target population was 43.8 L/h. The TBW, concomitant therapy with digoxin, and tobacco using were determinants of a derived population model. The final regression model for the CL of carvedilol is: [Formula: see text] Our results suggest that the TBW, concomitant therapy with digoxin, and tobacco using are the main subjects of carvedilol PK variability.

An inverse correlation between TNF alpha serum levels and heart rate variability in patients with heart failure.

BACKGROUND: Recent evidence indicates that chronic heart failure (CHF) is accompanied by both activation of the immune system and autonomic imbalance. There is a growing body of evidence that increased levels of proinflammatory cytokines and other inflammatory markers have important roles as mediators of disease progression and markers of mortality in patients with CHF. OBJECTIVE: The aim of this study was to investigate connection between autonomic imbalance [obtained by analysis of heart rate variability (HRV)] and activation of the immune system [as measured by serum levels of tumor necrosis factor (TNF)-α] in patients with chronic heart failure. MATERIALS AND METHODS: This cross-sectional study included 21 patients with CHF and 8 age- and gender-matched healthy control subjects. We assessed HRV by 24-hour electrocardiographic Holter monitoring and measured serum levels of TNF-α using an enzyme-linked immunosorbent assay. Clinical assessment and echocardiography were also performed. RESULTS: There was an inverse correlation between serum level of TNF-α and a time-domain parameter of HRV - SDNN (r=-0.542, p<0.05). A similar result was found for HRV triangular index, a geometric measure of HRV (r=-0.556; p<0.05). The correlation was stronger for subjects with a diabetes mellitus, females, and TNFA2 allele carriers (an "A" at position -308A). The pNN50, indirect marker of cardiac vagal activity, was not significantly associated with serum concentration of TNF-α. CONCLUSIONS: In conclusion, the results of the present study indicate that increased serum TNF-α level is significantly associated with reduced HRV indices, suggesting that activation of the immune system in patients with CHF is closely related to autonomic imbalance.

Population pharmacokinetics of bisoprolol in patients with chronic heart failure.

PURPOSE: The aim of the study was to develop a population pharmacokinetic (PK) model for clearance of bisoprolol in patients with congestive heart failure (CHF). METHODS: Parameters associated with the plasma concentrations of bisoprolol at steady-state were analyzed in 61 patients (mean age 66.21 ± 9.49 years; mean total body weight 8.90 ± 12.26 kg) with CHF using non-linear mixed-effect modeling (NONMEM). A validation set of 17 patients with heart failure was used to estimate the predictive performance of the pharmacokinetic model. RESULTS: The typical mean value for bisoprolol clearance (CL), estimated by the base model (without covariates), in our population was 11.4 l h(-1). In the full model, covariates such as bisoprolol total daily dose (DD) and creatinine clearance were included. The final regression model for the clearance of bisoprolol was the following: CL (l h(-1)) = 4.68 + 0.859 * DD. CONCLUSION: The derived PK model describes the clearance of bisoprolol in patients with CHF, showing that the total daily dose of bisoprolol is the most important covariate. This finding will provide the basis for future PK studies on beta blockers in this specific patient population and lead to better overall management of heart failure.

A Deficiência de vitamina d está associada com níveis aumentados de il-17 e tnfα em pacientes com insuficiência cardíaca crônica / Vitamin d deficiency is associated with increased il-17 and tnfα levels in patients with chronic heart failure / La deficiencia de vitamina D está asociada a niveles aumentados de IL-17 y Tnfα en pacientes con insuficiencia cardíaca crónica

FUNDAMENTO: Estudos recentes revelaram uma forte associação entre o estado de vitamina D (VD) e a insuficiência cardíaca crônica (ICC). Hoje, é normalmente aceito que a resposta imune pró-inflamatória é subjacente ao desenvolvimento de ICC. OBJETIVO: Uma vez que a VD possui propriedades anti-inflamatórias, pesquisamos o seu impacto sobre as citocinas envolvidas na ICC, como TNFα e IL-17, em pacientes portadores de ICC. MÉTODOS: Foi extraído sangue de quarenta pacientes com ICC secundária à hipertensão arterial e/ou doença coronariana. Os níveis de VD status, IL-17 e TNFαforam avaliados através de 25-hidroxi VD3 EIA e ELISA de citocinas. Também foram realizadas avaliação clínica e ecocardiograma. RESULTADOS: Pacientes idosos com ICC em Nis (Sudeste da Europa, latitude 43ºN) apresentaram níveis de 25-hidroxi VD3 abaixo do normal. Nossos dados demonstraram que pacientes com ICC secundária à hipertensão arterial têm níveis significativamente menores de 25-hidroxi VD3, e maiores de TNFαe IL-17A, se comparados com os níveis de pacientes com ICC secundária à doença coronariana. CONCLUSÃO: É demonstrado aqui que, mesmo em regiões com muitos dias ensolarados a deficiência de VD é motivo de preocupação. Os dados sugerem que o déficit de VD contribui para os elevados níveis de IL-17 e TNFα e, assim, contribuir ao desenvolvimento de ICC.

BACKGROUND: Recent studies revealed a strong association between vitamin D (VD) status and chronic heart failure (CHF). It is now commonly considered that proinflammatory immune response underlies CHF development. OBJECTIVE: Since VD expresses anti-inflammatory properties, we investigated its impact on cytokines implicated in CHF, such as TNFα and IL-17, in patients suffering from CHF. METHODS: Blood was obtained from forty patients with CHF secondary to hypertension and/or coronary heart disease. VD status, IL-17 and TNFαlevels were assessed using 25-hydroxy VD3 EIA and cytokine ELISAs. Clinical assessment and echocardiography was also performed. RESULTS: Elderly patients with CHF in Nis (Southeast Europe, latitude 43ºN) exhibited 25-hydroxy VD3 levels below normal. Our data identified that patients with CHF secondary to hypertension have significantly lower 25-hydroxy VD3, increased TNFα and IL-17A levels in comparison to donors with CHF secondary to coronary disease. CONCLUSION: This study reveals that even in regions with a lot of sunny days VD deficiency represents a concerning issue. Data suggest that impaired VD status contributes to high IL-17 and TNFα levels and thereby may support CHF development.

FUNDAMENTO: Estudios recientes revelaron una fuerte asociación entre el estado de la vitamina D (VD) y la insuficiencia cardíaca crónica (ICC). Hoy, es normalmente aceptado que la respuesta inmune pro-inflamatoria es subyacente al desarrollo de ICC. OBJETIVO: Una vez que la VD posee propiedades antiinflamatorias, investigamos su impacto sobre las citocinas envueltas en la ICC, como TNFα y IL-17, en pacientes portadores de ICC. MÉTODOS: Fue extraída sangre de cuarenta pacientes con ICC secundaria a la hipertensión arterial y/o enfermedad coronaria. Los niveles de VD status, IL-17 y TNFα fueron evaluados a través de 25-hidroxi VD3 EIA y ELISA de citocinas. También fueron realizadas evaluación clínica y ecocardiograma. RESULTADOS: Pacientes añosos con ICC en Nis (Sudeste de Europa, latitud 43ºN) presentaron niveles de 25-hidroxi VD3 debajo de lo normal. Nuestros datos demostraron que pacientes con ICC secundaria a la hipertensión arterial tienen niveles significativamente menores de 25-hidroxi VD3, y mayores de TNFα y IL-17A, si son comparados con los niveles de pacientes con ICC secundaria a la enfermedad coronaria. CONCLUSIONES: Es demostrado aquí que, aun en regiones con muchos días de sol la deficiencia de VD es motivo de preocupación. Los datos sugieren que el déficit de VD contribuye para los elevados niveles de IL-17 y TNFα y, así, al desarrollo de ICC.

Vitamin D deficiency is associated with increased IL-17 and TNFα levels in patients with chronic heart failure.

BACKGROUND: Recent studies revealed a strong association between vitamin D (VD) status and chronic heart failure (CHF). It is now commonly considered that proinflammatory immune response underlies CHF development. OBJECTIVE: Since VD expresses anti-inflammatory properties, we investigated its impact on cytokines implicated in CHF, such as TNFα and IL-17, in patients suffering from CHF. METHODS: Blood was obtained from forty patients with CHF secondary to hypertension and/or coronary heart disease. VD status, IL-17 and TNFα levels were assessed using 25-hydroxy VD3 EIA and cytokine ELISAs. Clinical assessment and echocardiography was also performed. RESULTS: Elderly patients with CHF in Nis (Southeast Europe, latitude 43ºN) exhibited 25-hydroxy VD3 levels below normal. Our data identified that patients with CHF secondary to hypertension have significantly lower 25-hydroxy VD3, increased TNFα and IL-17A levels in comparison to donors with CHF secondary to coronary disease. CONCLUSION: This study reveals that even in regions with a lot of sunny days VD deficiency represents a concerning issue. Data suggest that impaired VD status contributes to high IL-17 and TNFα levels and thereby may support CHF development.