RESUMO
BACKGROUND: Treatment of patients with heart failure with reduced ejection fraction (HFrEF) and renal dysfunction (RD) is challenging owing to the risk of further deterioration in renal function, especially after acute decompensated HF (ADHF). METHODS AND RESULTS: We assessed the effect of RD (estimated glomerular filtration rate of ≥30 to <60 mL/min/1.73 m2) on initiation, up-titration, and tolerability of sacubitril/valsartan in hemodynamically stabilized patients with HFrEF admitted for ADHF (RD, nâ¯=â¯476; non-RD, nâ¯=â¯483). At week 10, the target dose of sacubitril/valsartan (97/103 mg twice daily) was achieved by 42% patients in RD subgroup vs 54% in non-RD patients (P < .001). Sacubitril/valsartan was associated with greater estimated glomerular filtration rate improvements in RD subgroup than non-RD (change from baseline least squares mean 4.1 mL/min/1.73 m2, 95% confidence interval 2.2-6.1, P < .001). Cardiac biomarkers improved significantly in both subgroups; however, compared with the RD subgroup, the improvement was greater in those without RD (N-terminal pro-brain natriuretic peptide, -28.6% vs -44.8%, high-sensitivity troponin T -20.3% vs -33.9%) (P < .001). Patients in the RD subgroup compared with those without RD experienced higher rates of hyperkalemia (16.3% vs 6.5%, P < .001), investigator-reported cardiac failure (9.7% vs 5.6%, Pâ¯=â¯.029), and renal impairment (6.4% vs 2.1%, Pâ¯=â¯.002). CONCLUSIONS: Most patients with HFrEF and concomitant RD hospitalized for ADHF tolerated early initiation of sacubitril/valsartan and showed significant improvements in estimated glomerular filtration rate and cardiac biomarkers. CLINICAL TRIAL REGISTRATION: NCT02661217.
Assuntos
Insuficiência Cardíaca , Nefropatias , Disfunção Ventricular Esquerda , Humanos , Aminobutiratos/efeitos adversos , Antagonistas de Receptores de Angiotensina , Biomarcadores , Compostos de Bifenilo , Combinação de Medicamentos , Volume Sistólico , Tetrazóis/efeitos adversos , Resultado do Tratamento , Valsartana , Disfunção Ventricular Esquerda/tratamento farmacológicoRESUMO
Everolimus (EVR) is a semi-synthetic mammalian target of rapamycin inhibitor currently under development for liver transplantation (LTx) in combination with reduced exposure tacrolimus (rTAC). The relative potency of EVR was assessed in order to generate evidence for concomitant EVR+rTAC exposure in LTx recipients (LTxR). Twelve month data from study H2304 (NCT00622869), a 24-month, randomized, multicenter study in 719 de novo LTxR comparing EVR+rTAC to standard TAC demonstrated superior renal function and comparable efficacy, including fewer and less severe biopsy proven acute rejections with EVR+rTAC. Relative potency (p) of EVR was defined as factor by which the effect of 1 ng/mL of EVR must be multiplied to get comparable immunosuppression as with TAC: p = (TACcon - TACred)/EVRred. Relative efficacy of EVR in 4 different subpopulatlons was consistently 0.64, 0.60, 0.69, and 0.62, respectively. This assessment determined the relative potency of EVR as 0.64 compared to TAC in LTx indicating that EVR and TAC are not equipotent per ng/mL exposure. Knowledge about relative potency will help to rationalize co-exposure of EVR and TAC.
Assuntos
Imunossupressores/administração & dosagem , Transplante de Fígado , Sirolimo/análogos & derivados , Serina-Treonina Quinases TOR/antagonistas & inibidores , Everolimo , Humanos , Sirolimo/administração & dosagemRESUMO
The roles of protein kinase C (PKC) isoenzymes in the differentiation process of THP-1 cells are investigated. Inhibition of PKC by RO 31-8220 reduces the phagocytosis of latex particles and the release of superoxide, prostaglandin E(2) (PGE(2)), and tumour necrosis factor (TNF)-alpha. The proliferation of THP-1 cells is slightly enhanced by RO 31-8220. Stable transfection of THP-1 cells with asPKC-alpha, and incubation of THP-1 cells with antisense (as) PKC-alpha oligodeoxynucleotides reduces PKC-alpha levels and PKC activity. asPKC-alpha-transfected THP-1 cells show a decreased phagocytosis and a decreased release of superoxide, PGE(2) and TNF-alpha. The proliferation of asPKC-alpha-transfected THP-1 cells is enhanced. Stable transfection of THP-1 cells with asPKC-beta, and incubation of THP-1 cells with asPKC-beta oligodeoxynucleotides, reduces PKC-beta levels and PKC activity. asPKC-beta-transfected THP-1 cells show a decreased phagocytosis, a decreased TNF-alpha release, and a decreased proliferation. However, no difference is measured in the release of superoxide and PGE(2). These results suggest that: (1) PKC-alpha but not PKC-beta is involved in the release of superoxide and PGE(2); (2) TNF-alpha release and the phagocytosis of latex particles are mediated by PKC-alpha, PKC-beta, and other PKC isoenzymes; and (3) PKC-alpha and PKC-beta play antagonistic roles in the differentiation process of THP-1 cells. PKC-alpha promotes the differentiation process of THP-1 cells, PKC-beta retards the differentiation of THP-1 cells into macrophage-like cells.
Assuntos
Isoenzimas/metabolismo , Monócitos/citologia , Monócitos/enzimologia , Proteína Quinase C/metabolismo , Transdução de Sinais/imunologia , Western Blotting , Diferenciação Celular/fisiologia , Divisão Celular/fisiologia , Inibidores Enzimáticos/farmacologia , Humanos , Indóis/farmacologia , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Leucemia Monocítica Aguda , Oligonucleotídeos Antissenso/farmacologia , Plasmídeos , Prostaglandinas/fisiologia , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/genética , Proteína Quinase C beta , Proteína Quinase C-alfa , Transfecção , Células Tumorais CultivadasAssuntos
Ácido Araquidônico/metabolismo , Isoenzimas/fisiologia , Fígado/metabolismo , Macrófagos/metabolismo , Lipídeos de Membrana/metabolismo , Proteínas Quinases Ativadas por Mitógeno , Fosfolipases A/fisiologia , Animais , Calcimicina/farmacologia , Cálcio/fisiologia , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Células Cultivadas , Citosol/enzimologia , Diglicerídeos/metabolismo , Ativação Enzimática/efeitos dos fármacos , Ionóforos/farmacologia , Lipopolissacarídeos/farmacologia , Lipase Lipoproteica/metabolismo , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno , Modelos Biológicos , Fosfatidilinositol Diacilglicerol-Liase , Fosfolipases A2 , Fosforilação/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/fisiologia , Ratos , Ratos Wistar , Transdução de Sinais/fisiologia , Acetato de Tetradecanoilforbol/farmacologia , Fosfolipases Tipo C/fisiologia , Zimosan/farmacologiaAssuntos
Acetilmuramil-Alanil-Isoglutamina/análogos & derivados , Citotoxicidade Imunológica/efeitos dos fármacos , Eicosanoides/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Óxido Nítrico/fisiologia , Fosfatidiletanolaminas/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Acetilmuramil-Alanil-Isoglutamina/administração & dosagem , Acetilmuramil-Alanil-Isoglutamina/farmacologia , Animais , Células Cultivadas , Diglicerídeos/metabolismo , Portadores de Fármacos , Lipopolissacarídeos/farmacologia , Lipossomos , Macrófagos/metabolismo , Fosfatidiletanolaminas/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Células Tumorais CultivadasAssuntos
Colecalciferol/farmacologia , Eicosanoides/biossíntese , Leucemia Monocítica Aguda/patologia , Acetato de Tetradecanoilforbol/farmacologia , Tretinoína/farmacologia , Calcimicina/farmacologia , Diferenciação Celular/efeitos dos fármacos , Dinoprostona/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Isoenzimas/biossíntese , Isoenzimas/genética , Leucemia Monocítica Aguda/metabolismo , Receptores de Lipopolissacarídeos/biossíntese , Receptores de Lipopolissacarídeos/genética , Lipopolissacarídeos/farmacologia , Antígeno de Macrófago 1/biossíntese , Antígeno de Macrófago 1/genética , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Fagocitose/efeitos dos fármacos , Fosfolipases A/biossíntese , Fosfolipases A/genética , Superóxidos/metabolismo , Células Tumorais Cultivadas/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Human THP-1 leukemia cells differentiate along the monocytic lineage following exposure to phorbol-12-myristate-13-acetate (PMA) or 1,25-dihydroxyvitamin D3 (VD3). In the monocytic cell line THP-1, PMA treatment resulted in a more differentiated phenotype than VD3, according to adherence, loss of proliferation, phagocytosis of latex beads, and expression of CD11b and CD14. Both differentiating substances induced similar effects in the release of superoxide anions (O2-). VD3-differentiated cells did not release prostaglandin E2 (PGE2), in contrast to PMA-differentiated cells, and in PMA-differentiated cells phospholipase A2 (PLA2) activity and expression was increase. Lipopolysaccharide (LPS)-stimulated tumor necrosis factor-alpha (TNF-alpha) release was higher in PMA-treated cells. PMA- but not VD3-differentiation resulted in a translocation of protein kinase C (PKC) isoenzymes to membrane fractions. Both differentiating agents up-regulated the expression of PKC isoenzymes. Whereas VD3 elevated mainly the expression of PKC-beta, PMA caused a strong increase in PKC-delta and a weak increase in PKC-alpha, PKC-epsilon, and PKC-zeta expression. These results indicate that phorbol ester and the active metabolite of vitamin D induce different signal pathways, which might result in different achievement of differentiation.
Assuntos
Calcitriol/farmacologia , Carcinógenos/farmacologia , Leucemia Monocítica Aguda/patologia , Acetato de Tetradecanoilforbol/farmacologia , Western Blotting , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Citosol/enzimologia , Dinoprostona/metabolismo , Ativação Enzimática , Humanos , Isoenzimas/metabolismo , Leucemia Monocítica Aguda/induzido quimicamente , Leucemia Monocítica Aguda/metabolismo , Receptores de Lipopolissacarídeos/biossíntese , Antígeno de Macrófago 1/biossíntese , Fagocitose/efeitos dos fármacos , Fosfolipases A/metabolismo , Fosfolipases A2 , Proteína Quinase C/metabolismo , Superóxidos/metabolismo , Células Tumorais Cultivadas , Fator de Necrose Tumoral alfa/metabolismoRESUMO
LPS and liposome-encapsulated MTP-PE induce liver macrophages cytotoxicity against tumor target cells and a release of TNF-alpha, nitric oxide, and eicosanoids but not a generation of superoxide anions. Neither agent elicits a formation of inositol phosphates, a change in intracellular free calcium, or a translation of protein kinase C-beta. Inhibition or down-regulation of protein kinase C does not inhibit the release of TNF-alpha and nitric oxide but inhibits the formation of prostanoids. In contrast to LPS, liposome -encapsulated MTP-PE induces an elevation of diacylglycerol mass and an enhanced expression of protein kinase C-delta. LPS, but not liposome-encapsulated MTP-PE, elicits an enhanced expression of cytosolic phospholipase A2 and a predominant formation of PGE2. Both agents elicit different responses when given to cells pretreated with one of the immunomodulators, with dexamethasone, or with PGE2. In contrast, to liposome-encapsulated MTP-PE, LPS induces only cytotoxicity when added to liver macrophages simultaneously or a maximum of 2 h before the addition of tumor target cells. The observed differences might reflect partly differences in the potencies of LPS and some liposome-encapsulated MTP-PE as immunomodulators.
Assuntos
Acetilmuramil-Alanil-Isoglutamina/análogos & derivados , Citotoxicidade Imunológica/efeitos dos fármacos , Eicosanoides/metabolismo , Lipopolissacarídeos/farmacologia , Fígado/citologia , Macrófagos/efeitos dos fármacos , Óxido Nítrico/metabolismo , Fosfatidiletanolaminas/administração & dosagem , Fator de Necrose Tumoral alfa/metabolismo , Acetilmuramil-Alanil-Isoglutamina/administração & dosagem , Animais , Células Cultivadas , Dinoprostona/biossíntese , Portadores de Fármacos , Lipossomos , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacosRESUMO
In contrast with protein kinase C (PKC)-beta, PKC-delta is exclusively detectable in the membrane fraction of liver macrophages. After long-term treatment with phorbol 12-myristate 13-acetate (PMA) PKC-beta is depleted faster (within 3 h) than PKC-delta (> 7h). Simultaneously, pretreatment with PMA for 3 h inhibits the PMA- and zymosan-induced generation of superoxide and the PMA-induced formation of prostaglandin (PG) E2, whereas a preincubation of more than 7 h is required to affect the zymosan-induced release of PGE2 and inositol phosphates. These results support an involvement of PKC-beta in the PMA-induced activation of the arachidonic acid cascade and in superoxide formation and imply an involvement of PKC-delta in zymosan-induced phosphoinositide hydrolysis and PGE2 formation. Two phorbol ester derivates, sapintoxin A (SAPA) and 12-deoxyphorbol 13-phenylacetate 20-acetate (DOPPA), which have been previously reported to activate preferentially PLC-beta but not PKC-delta in vitro [Ryves, Evans, Olivier, Parker and Evans (1992) FEBS Lett. 288, 5-9], induce the formation of PGE2 and superoxide, down-regulate PKC-delta and potentiate inositol phosphate formation in parallel SAPA, but not DOPPA, down-regulates PKC-beta and inhibits the PMA-induced formation of eicosanoids and superoxide.