RESUMO
Proprotein convertase subtilisin/kexin 9 (PCSK9) is a protein that plays a key role in the metabolism of low-density lipoprotein (LDL) cholesterol. The gain-of-function mutations of the PCSK9 gene lead to a reduced number of surface LDL receptors by binding to them, eventually leading to endosomal degradation. This, in turn, is the culprit of hypercholesterolemia, resulting in accelerated atherogenesis. The modern treatment for hypercholesterolemia encompasses the use of biological drugs against PCSK9, like monoclonal antibodies and gene expression modulators such as inclisiran-a short, interfering RNA (siRNA). Peptide nucleic acid (PNA) is a synthetic analog of nucleic acid that possesses a synthetic peptide skeleton instead of a phosphate-sugar one. This different structure determines the unique properties of PNA (e.g., neutral charge, enzymatic resistance, and an enormously high affinity with complementary DNA and RNA). Therefore, it might be possible to use PNA against PCSK9 in the treatment of hypercholesterolemia. We sought to explore the impact of three selected PNA oligomers on PCSK9 gene expression. Using a cell-free transcription/translation system, we showed that one of the tested PNA strands was able to reduce the PCSK9 gene expression down to 74%, 64%, and 68%, as measured by RT-real-time PCR, Western blot, and HPLC, respectively. This preliminary study shows the high applicability of a cell-free enzymatic environment as an efficient tool in the initial evaluation of biologically active PNA molecules in the field of hypercholesterolemia research. This cell-free approach allows for the omission of the hurdles associated with transmembrane PNA transportation at the early stage of PNA selection.
Assuntos
Hipercolesterolemia , Inibidores de PCSK9 , Ácidos Nucleicos Peptídicos , Humanos , Expressão Gênica , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/genética , Ácidos Nucleicos Peptídicos/farmacologia , Pró-Proteína Convertase 9/efeitos dos fármacos , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertases/genética , Receptores de LDL/genética , Receptores de LDL/metabolismo , Subtilisina/genética , Inibidores de PCSK9/farmacologiaRESUMO
Cardiovascular disease is the leading cause of death worldwide, and its prevalence is increasing due to the aging of societies. Atherosclerosis, a type of chronic inflammatory disease that occurs in arteries, is considered to be the main cause of cardiovascular diseases such as ischemic heart disease or stroke. In addition, the inflammatory response caused by atherosclerosis confers a significant effect on chronic inflammatory diseases such as psoriasis and rheumatic arthritis. Here, we review the mechanism of action of the main causes of atherosclerosis such as plasma LDL level and inflammation; furthermore, we review the recent findings on the preclinical and clinical effects of antibodies that reduce the LDL level and those that neutralize the cytokines involved in inflammation. The apolipoprotein B autoantibody and anti-PCSK9 antibody reduced the level of LDL and plaques in animal studies, but failed to significantly reduce carotid inflammation plaques in clinical trials. The monoclonal antibodies against PCSK9 (alirocumab, evolocumab), which are used as a treatment for hyperlipidemia, lowered cholesterol levels and the incidence of cardiovascular diseases. Antibodies that neutralize inflammatory cytokines (TNF-α, IL-1ß, IL-6, IL-17, and IL-12/23) have shown promising but contradictory results and thus warrant further research.
Assuntos
Anticorpos/farmacologia , Aterosclerose/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , Imunização Passiva/métodos , Animais , Anticorpos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Anticolesterolemiantes/uso terapêutico , Apolipoproteínas B , Autoanticorpos , LDL-Colesterol/sangue , Citocinas/imunologia , Humanos , Inflamação/tratamento farmacológico , Fragmentos de Peptídeos , Pró-Proteína Convertase 9/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológicoRESUMO
Hypercholesterolemia has been documented to drive hormone-dependent breast cancer (BC) progression and resistance to hormonal therapy. Proprotein convertase subtilisin/kexin type-9 (PCSK9) regulates cholesterol metabolism through binding to LDL receptor (LDLR) and targeting the receptor for lysosomal degradation. Inhibition of PCSK9 is an established strategy to treat hypercholesterolemia. Pseurotin A (PS) is a unique spiro-heterocyclic γ-lactam alkaloid isolated from the fungus Aspergillus fumigatus. Preliminary studies indicated that PS lowered PCSK9 secretion in cultured HepG2 hepatocellular carcinoma cells, with an IC50 value of 1.20 µM. Docking studies suggested the ability of PS to bind at the PCSK9 narrow interface pocket that accommodates LDLR. Surface plasmon resonance (SPR) showed PS ability to inhibit the PCSK9-LDLR interaction at a concentration range of 10-150 µM. PS showed in vitro dose-dependent reduction of PCSK9, along with increased LDLR levels in hormone-dependent BT-474 and T47D breast cancer (BC) cell lines. In vivo, daily oral 10 mg/kg PS suppressed the progression of the hormone-dependent BT-474 BC cells in orthotopic nude mouse xenograft model. Immunohistochemistry (IHC) investigation of BT-474 breast tumor tissue proved the PS ability to reduce PCSK9 expression. PS also effectively suppressed BT-474 BC cells locoregional recurrence after primary tumor surgical excision. Western blot analysis showed decreased PCSK9 expression in liver tissues of PS-treated mice compared to vehicle-treated control group. PS treatment significantly reduced PCSK9 expression and normalized LDLR levels in collected primary and recurrent breast tumors at the study end. PS-treated mice showed reduced plasma cholesterol and 17ß-estradiol levels. Inhibition of tumor recurrence was associated with significant reductions in plasma level of the human BC recurrence marker CA 15-3 in treated mice at the study end. Histopathological examination of various PS-treated mice organs indicated lack of metastatic tumor cells and any pathological changes. The results of this study provide the first evidence for the suppression of the hormone-dependent breast tumor progression and recurrence by targeting the PCSK9-LDLR axis. PS is a novel first-in-class PCSK9-targeting lead appropriate for the use to control hormone-dependent BC progression and recurrence.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Pró-Proteína Convertase 9/metabolismo , Pirrolidinonas/farmacologia , Receptores de LDL/efeitos dos fármacos , Animais , Antibióticos Antineoplásicos/uso terapêutico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Colesterol/sangue , Progressão da Doença , Relação Dose-Resposta a Droga , Estradiol/sangue , Feminino , Células Hep G2 , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Camundongos Nus , Estrutura Molecular , Pró-Proteína Convertase 9/efeitos dos fármacos , Pirrolidinonas/uso terapêutico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Several changes have occurred during last few years in diagnostics and treatment of the ischemic heart disease, especially due to introduction of so called high-sensitive troponins, implementation of new antiplatelet drugs, using of drug-eluting stents in percutaneous coronary interventions or novel definitions of acute myocardial infarction types. The European Society of Cardiology and Czech Society of Cardiology established new recommendations for management of both acute and chronic forms of the ischemic heart disease. Recently discovered inhibitors of the PCSK9 molecule that have been slowly introduced in the clinical practice represent a breakthrough in the treatment of dyslipidemia. Future research will certainly aim at detection of early forms of the atherosclerotic involvement of the coronary arteries.
Assuntos
Isquemia Miocárdica , Humanos , Isquemia Miocárdica/diagnóstico , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/genética , Pró-Proteína Convertase 9/efeitos dos fármacosRESUMO
Alcohol use disorder (AUD) is a common and chronic disorder with substantial effects on personal and public health. The underlying pathophysiology is poorly understood but strong evidence suggests significant roles of both genetic and epigenetic components. Given that alcohol affects many organ systems, we performed a cross-tissue and cross-phenotypic analysis of genome-wide methylomic variation in AUD using samples from 3 discovery, 4 replication, and 2 translational cohorts. We identified a differentially methylated region in the promoter of the proprotein convertase subtilisin/kexin 9 (PCSK9) gene that was associated with disease phenotypes. Biological validation showed that PCSK9 promoter methylation is conserved across tissues and positively correlated with expression. Replication in AUD datasets confirmed PCSK9 hypomethylation and a translational mouse model of AUD showed that alcohol exposure leads to PCSK9 downregulation. PCSK9 is primarily expressed in the liver and regulates low-density lipoprotein cholesterol (LDL-C). Our finding of alcohol-induced epigenetic regulation of PCSK9 represents one of the underlying mechanisms between the well-known effects of alcohol on lipid metabolism and cardiovascular risk, with light alcohol use generally being protective while chronic heavy use has detrimental health outcomes.
Assuntos
Alcoolismo/genética , Pró-Proteína Convertase 9/efeitos dos fármacos , Pró-Proteína Convertase 9/genética , Adulto , Alcoolismo/fisiopatologia , Animais , LDL-Colesterol/metabolismo , Metilação de DNA/genética , Epigênese Genética/genética , Epigenômica/métodos , Etanol/efeitos adversos , Etanol/metabolismo , Feminino , Regulação da Expressão Gênica/genética , Humanos , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Masculino , Camundongos , Fenótipo , Regiões Promotoras Genéticas/genética , Pró-Proteína Convertase 9/fisiologia , Ratos , Ratos WistarRESUMO
BACKGROUND: The natural farnesoid X receptor (FXR) agonist chenodeoxycholic acid (CDCA) suppresses hepatic cholesterol and bile acid synthesis and reduces biliary cholesterol secretion and triglyceride production. Animal studies have shown that bile acids downregulate hepatic LDL receptors (LDLRs); however, information on LDL metabolism in humans is limited. METHODS: Kinetics of autologous 125 I-LDL were determined in 12 male subjects at baseline and during treatment with CDCA (15 mg kg-1 day-1 ). In seven patients with gallstones treated with CDCA for 3 weeks before cholecystectomy, liver biopsies were collected and analysed for enzyme activities and for specific LDLR binding. Serum samples obtained before treatment and at surgery were analysed for markers of lipid metabolism, lipoproteins and the LDLR modulator proprotein convertase subtilisin/kexin type 9 (PCSK9). RESULTS: Chenodeoxycholic acid treatment increased plasma LDL cholesterol by ~10% as a result of reduced clearance of plasma LDL-apolipoprotein (apo)B; LDL production was somewhat reduced. The reduction in LDL clearance occurred within 1 day after initiation of treatment. In CDCA-treated patients with gallstones, hepatic microsomal cholesterol 7α-hydroxylase and HMG-CoA reductase activities were reduced by 83% and 54%, respectively, and specific LDLR binding was reduced by 20%. During treatment, serum levels of fibroblast growth factor 19 and total and LDL cholesterol increased, whereas levels of 7α-hydroxy-4-cholesten-3-one, lathosterol, PCSK9, apoA-I, apoC-III, lipoprotein(a), triglycerides and insulin were reduced. CONCLUSIONS: Chenodeoxycholic acid has a broad influence on lipid metabolism, including reducing plasma clearance of LDL. The reduction in circulating PCSK9 may dampen its effect on hepatic LDLRs and plasma LDL cholesterol. Further studies of the effects of other FXR agonists on cholesterol metabolism in humans seem warranted, considering the renewed interest for such therapy in liver disease and diabetes.
Assuntos
Apolipoproteína C-III/efeitos dos fármacos , Ácido Quenodesoxicólico/farmacologia , LDL-Colesterol/efeitos dos fármacos , Lipoproteína(a)/efeitos dos fármacos , Pró-Proteína Convertase 9/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/agonistas , Apolipoproteína C-III/sangue , Ácido Quenodesoxicólico/uso terapêutico , LDL-Colesterol/sangue , Cálculos Biliares/tratamento farmacológico , Humanos , Fígado/enzimologia , Masculino , Pró-Proteína Convertase 9/sangue , Receptores de LDL/metabolismoAssuntos
Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/epidemiologia , Pandemias/prevenção & controle , Pneumonia Viral/epidemiologia , Pneumonia Viral/prevenção & controle , Pró-Proteína Convertase 9/efeitos dos fármacos , Adulto , Fatores Etários , COVID-19 , Causas de Morte , China , Comorbidade , Feminino , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Incidência , Masculino , Pessoa de Meia-Idade , Pandemias/estatística & dados numéricos , Prognóstico , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/uso terapêutico , Medição de Risco , Fatores Sexuais , Análise de Sobrevida , Resultado do TratamentoRESUMO
The proprotein convertase subtilisin/kexin-type 9 (PCSK9) binds to low-density lipoprotein receptors (LDLR), thereby trafficking them to lysosomes upon endocytosis and enhancing intracellular degradation to prevent their recycling. As a result, the levels of circulating LDL cholesterol (LDL-C) increase, which is a prominent risk factor for developing atherosclerotic cardiovascular diseases (ASCVD). Thus, PCSK9 has become a promising therapeutic target that offers a fertile testing ground for new drug modalities to regulate plasma LDL-C levels to prevent ASCVD. In this review, we have discussed the role of PCSK9 in lipid metabolism and briefly summarized the current clinical status of modalities targeting PCSK9. In particular, a detailed overview of peptide-based PCSK9 inhibitors is presented, which emphasizes their structural features and design, therapeutic effects on patients, and preclinical cardiovascular disease (CVD) models, along with PCSK9 modulation mechanisms. As a promising alternative to monoclonal antibodies (mAbs) for managing LDL-C, anti-PCSK9 peptides are emerging as a prospective next generation therapy.
Assuntos
Hipercolesterolemia , Inibidores de PCSK9 , Humanos , LDL-Colesterol/química , LDL-Colesterol/metabolismo , Inibidores de PCSK9/química , Inibidores de PCSK9/farmacologia , Pró-Proteína Convertase 9/efeitos dos fármacos , Hipercolesterolemia/tratamento farmacológicoRESUMO
The advent of monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) ushered in a new era of dyslipidemia pharmacotherapy. The first two antibodies targeting PCSK9 (evolocumab, alirocumab) approved by the United States Food and Drug Administration (FDA) provided significant and sustained reductions in atherogenic lipids and a reduced risk of atherosclerotic cardiovascular disease (ASCVD) events. More recently, phase 3 trials of inclisiran-a small interfering RNA-based agent targeting PCSK9-reported similar lipid-lowering effects and preliminary evidence of ASCVD risk reduction, although significant questions remain regarding the extent of benefits across cardiovascular outcomes. We conducted a systematic review and meta-analysis (random-effects model) of the available data on lipid lowering, incidence of atherosclerotic cardiovascular disease (ASCVD) events, and safety of pharmacologic agents targeting PCSK9. A significant and consistent reduction in low-density lipoprotein cholesterol (LDL-C) was observed across all agents (-51% [95% confidence interval {CI}: -61%, -41%]). Despite the impressive reduction in LDL-C, the individual effects on mortality, cardiovascular death, myocardial infarction (MI), and stroke remained nonsignificant. However, a consistent reduction was observed in the composite outcomes of MI, stroke, and cardiovascular death [relative risk {RR} (95% CI): 0.80 (0.73-0.87)] and MI, stroke, unstable angina (requiring revascularization), and cardiovascular death [RR (95% CI): 0.85 (0.74-0.97)]. In terms of safety outcomes, there was no significant difference in severe adverse events, new onset diabetes, neurocognitive disorders, or myalgia. Meanwhile, injection site reaction was more frequent in patients receiving these agents compared to placebo [RR 2.11 (95% CI): 1.26-3.54]. These findings suggest a class effect for favorable lipid changes and a low risk of serious adverse events among pharmacologic agents targeting PCSK9. Although there is compelling evidence that PCSK9-targeting agents reduce the risk of some cardiovascular outcomes, adequately powered studies with longer follow-up may be needed to fully characterize the magnitude of benefits across the cardiovascular spectrum.
Assuntos
Aterosclerose , Doenças Cardiovasculares , Pró-Proteína Convertase 9 , Aterosclerose/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , Humanos , Pró-Proteína Convertase 9/efeitos dos fármacos , Pró-Proteína Convertase 9/metabolismo , Resultado do TratamentoRESUMO
The choice of lipid-modifying treatment is largely based on the absolute level of cardiovascular risk and baseline lipid profile. Statins are the first-line treatment for most patients requiring reduction of low-density-lipoprotein cholesterol (LDL-C) and ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors can be added to reach LDL-C targets. Statins have some adverse effects that are somewhat predictable based on phenotypic and genetic factors. Fibrates or omega-3 fatty acids can be added if triglyceride levels remain elevated. The RNA-targeted therapeutics in development offer the possibility of selective liver targeting for specific lipoproteins such as lipoprotein(a) and long-term reduction of LDL-C with infrequent administration of a small-interfering RNA may help to overcome the problem of adherence to therapy.
Assuntos
Dislipidemias/tratamento farmacológico , Dislipidemias/fisiopatologia , Hipolipemiantes/farmacologia , Hipolipemiantes/uso terapêutico , Medicina de Precisão/métodos , Fatores Etários , Índice de Massa Corporal , LDL-Colesterol/efeitos dos fármacos , Comorbidade , Dislipidemias/genética , Ácidos Graxos Ômega-3/uso terapêutico , Ácidos Fíbricos/uso terapêutico , Predisposição Genética para Doença , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipolipemiantes/efeitos adversos , Lipoproteína(a)/efeitos dos fármacos , Pró-Proteína Convertase 9/efeitos dos fármacos , RNA Interferente Pequeno , Fatores Sexuais , Triglicerídeos/metabolismoRESUMO
The hypolipidemic effect of 10-DHGD was previously reported owing to its anti-inflammatory and anti-oxidant properties. We further investigated the anti-inflammatory role of 10-DHGD in modulating atherogenicity by targeting proproteinconvertasesubtilisinkexin-9 (PCSK-9). Rabbits fed high cholesterol diet (HCD) containing 0.2% w/w cholesterol for12-weeks received either 10-DHGD (10-mg/kg), pentoxifylline (PTX, 40-mg/kg) or their combination concurrently with HCD. Lipid profile, serum PCSK-9, macrophage migration inhibitory factor (MIF), aorta tumor necrosis factor- alpha (TNF-α) and glycosaminoglycans (GAGs) were measured. Atherogenicity and increased PCSK-9, MIF and TNF-α and GAGs (p < 0.001) was proved HCD-fed rabbits. The concurrent administration of 10-DHGD or PTX with HCD feeding prevented this atheogenicity by modulating the release of PCSK-9, inflammatory markers and GAGs. The combined PTX and 10-DHGD in HCD fed rabbits not only lowered hyperlipidemia, but also targeted arterial inflammation to a better extent. In conclusion PTX and 10-DHGD can prevent hyperlipidemia and associated inflammatory process modifying factors predisposing to atherosclerosis.
Assuntos
Glicosaminoglicanos/metabolismo , Guaiacol/análogos & derivados , Hiperlipidemias/prevenção & controle , Pentoxifilina/farmacologia , Pró-Proteína Convertase 9/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Aterosclerose/prevenção & controle , Colesterol , Guaiacol/farmacologia , Masculino , Pró-Proteína Convertase 9/sangue , CoelhosRESUMO
Quantitative systems pharmacology (QSP) models are often implemented using a wide variety of technical workflows and methodologies. To facilitate reproducibility, transparency, portability, and reuse for QSP models, we have developed gQSPSim, a graphical user interface-based MATLAB application that performs key steps in QSP model development and analyses. The capabilities of gQSPSim include (i) model calibration using global and local optimization methods, (ii) development of virtual subjects to explore variability and uncertainty in the represented biology, and (iii) simulations of virtual populations for different interventions. gQSPSim works with SimBiology-built models using components such as species, doses, variants, and rules. All functionalities are equipped with an interactive visualization interface and the ability to generate presentation-ready figures. In addition, standardized gQSPSim sessions can be shared and saved for future extension and reuse. In this work, we demonstrate gQSPSim's capabilities with a standard target-mediated drug disposition model and a published model of anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) treatment of hypercholesterolemia.
Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertase 9/efeitos dos fármacos , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/uso terapêutico , Simulação por Computador , Desenvolvimento de Medicamentos/instrumentação , Descoberta de Drogas/instrumentação , Humanos , Hipercolesterolemia/metabolismo , Modelos Biológicos , Inibidores de PCSK9 , Padrões de Referência , Reprodutibilidade dos Testes , Software , Incerteza , Interface Usuário-Computador , Fluxo de TrabalhoRESUMO
Background: The proprotein convertase subtilisin/kexin type 9 (PCSK9) has been implicated in the pathogenesis of inflammatory diseases. We sought to investigate the role of PCSK9 in the pathogenesis of Graves' orbitopathy (GO) and whether it may be a legitimate target for treatment. Methods: The PCSK9 was compared between GO (n=11) and normal subjects (n=7) in orbital tissue explants using quantitative real-time PCR, and in cultured interleukin-1ß (IL-1ß)-treated fibroblasts using western blot. Western blot was used to identify the effects of PCSK9 inhibition on IL-1ß-induced pro-inflammatory cytokines production and signaling molecules expression as well as levels of adipogenic markers and oxidative stress-related proteins. Adipogenic differentiation was identified using Oil Red O staining. The plasma PCSK9 concentrations were compared between patients with GO (n=44) and healthy subjects (n=26) by ELISA. Results: The PCSK9 transcript level was higher in GO tissues. The depletion of PCSK9 blunted IL-1ß-induced expression of intercellular adhesion molecule 1 (ICAM-1), IL-6, IL-8, and cyclooxygenase-2 (COX-2) in GO and non-GO fibroblasts. The levels of activated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and phosphorylated forms of Akt and p38 were diminished when PCSK9 was suppressed in GO fibroblasts. Decreases in lipid droplets and attenuated levels of peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein ß (C/EBPß), and leptin as well as hypoxia-inducible factor 1α (HIF-1α), manganese superoxide dismutase (MnSOD), thioredoxin (Trx), and heme oxygenase-1 (HO-1) were noted when PCSK9 was suppressed during adipocyte differentiation. The plasma PCSK9 level was significantly higher in GO patients and correlated with level of thyrotropin binding inhibitory immunoglobulin (TBII) and the clinical activity score (CAS). Conclusions: PCSK9 plays a significant role in GO. The PCSK9 inhibition attenuated the pro-inflammatory cytokines production, oxidative stress, and fibroblast differentiation into adipocytes. PCSK9 may serve as a therapeutic target and biomarker for GO.
Assuntos
Fibroblastos/metabolismo , Oftalmopatia de Graves/genética , Órbita/citologia , Pró-Proteína Convertase 9/genética , Adipócitos , Adipogenia/genética , Adulto , Moléculas de Adesão Celular/metabolismo , Diferenciação Celular/genética , Células Cultivadas , Citocinas/metabolismo , Feminino , Oftalmopatia de Graves/metabolismo , Humanos , Interleucina-1beta/farmacologia , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/genética , Pró-Proteína Convertase 9/efeitos dos fármacos , Pró-Proteína Convertase 9/metabolismo , Adulto JovemRESUMO
Nephrotic syndrome is sometimes refractory; however, it is rarely accompanied by acute pancreatitis. A 47-year-old Japanese woman complaining of limb edema was diagnosed with nephrotic syndrome. Blood and urine examinations suggested minimal change nephrotic syndrome (MCNS), and pulse intravenous methylprednisolone was administered, followed by oral prednisolone. Although proteinuria improved, the patient's condition remained unchanged, and diuresis was insufficient. As in patients with other nephrotic syndromes, this patient showed significant dyslipidemia. Atorvastatin was started for remarkable dyslipidemia since her admission, but her low-density lipoprotein cholesterol (LDL-C) level did not improve significantly. During the clinical course, she developed acute pancreatitis, and large-volume fluid replacement was performed. Although diuretic levels were increased in response to the increased fluid volume, diuresis was not enough, and lung edema developed. Extracorporeal ultrafiltration was started to ameliorate the lung edema. With the onset of pancreatitis, oral intake, including atorvastatin, was discontinued, and prednisolone was administered intravenously. To treat the high-LDL cholesterolemia, 140 mg of evolocumab was injected subcutaneously. Nausea slightly decreased on the following day, and the administration of 150 mg cyclosporine was initiated. LDL-C levels, proteinuria, and renal function promptly ameliorated. The results of a renal biopsy suggested MCNS. On the 44th day of hospitalization, she had complete remission. Evolocumab is potentially effective for severe nephrotic syndrome with uncontrollable dyslipidemia.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , LDL-Colesterol/análise , Nefrose Lipoide/complicações , Nefrose Lipoide/tratamento farmacológico , Pancreatite/etiologia , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/uso terapêutico , Povo Asiático/etnologia , LDL-Colesterol/efeitos dos fármacos , Ciclosporina/administração & dosagem , Ciclosporina/uso terapêutico , Quimioterapia Combinada , Dislipidemias/tratamento farmacológico , Feminino , Hidratação/métodos , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Injeções Subcutâneas , Pessoa de Meia-Idade , Nefrose Lipoide/metabolismo , Inibidores de PCSK9 , Pancreatite/terapia , Pró-Proteína Convertase 9/efeitos dos fármacos , Indução de Remissão , Índice de Gravidade de DoençaRESUMO
Importance: Little is known about the heterogeneity in low-density lipoprotein cholesterol levels (LDL-C) lowering with proprotein convertase subtilisin kexin 9 (PCSK9) inhibitor medications. Objective: To evaluate the interindividual variability in LDL-C reduction with the PCSK9 inhibitor drug evolocumab. Design, Setting, and Participants: We examined the percentage change in LDL-C levels from baseline in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, a placebo-controlled randomized clinical trial of the PCSK9 inhibitor evolocumab in patients with stable atherosclerotic cardiovascular disease who were taking statin medications. Patients in either treatment arm who had high baseline LDL-C variability during screening and either did not receive the study drug, altered their background lipid-lowering therapy regimen, or had no LDL-C level sample in week 4 were excluded from the primary analysis. Analyses in the patients were stratified by treatment arm. Data was collected from 2013 to 2016, and data were analyzed from January 2018 to November 2018. Main Outcomes and Measures: Interindividual variation in percent reduction in LDL-C with evolocumab. Results: There were 27â¯564 individuals in the cohort; after exclusions for baseline variability (n = 3524) or alterations in background lipid therapy and other causes (n = 2272), 21â¯768 patients remained. At week 4, the median percent reduction in LDL-C levels from baseline was 66% (interquartile range, 54%-76%; median [interquartile range] baseline value, 90 [79-105] mg/dL; postchange value, 31 [21-44] mg/dL) with evolocumab. During the first year, a total of 10â¯325 of 10902 patients in the evolocumab group (94.7%) had a reduction 50% or greater in LDL-C levels, 10â¯669 of 10â¯902 (97.9%) had a reduction 30% or more, and 10â¯849 of 10â¯902 (99.5%) had any reduction in LDL-C levels. Fifty-three patients (0.5%) had no apparent reduction in LDL-C levels. In the placebo arm, the median LDL-C reduction was 4% (interquartile range, 6% increase to 13% reduction; baseline median [IQR] value, 90 [79-106] mg/dL; postchange value, 87 [74-103] mg/dL) at 4 weeks. Waterfall plots showed notable variability in the top and bottom 5% of patients for both evolocumab and placebo groups, with large changes in LDL-C levels in the placebo group (increases of ≥25%, 531 patients [4.9%]; decreases of ≥25%, 985 patients [9.1%]). At 4 weeks, the placebo-adjusted reductions in LDL-C levels with evolocumab were 50% or greater in 9839 of 10â¯866 patients (90.5%) and 30% or greater in 10â¯846 of 10â¯866 patients (99.8%). Results were consistent across clinically relevant subgroups. Conclusions and Relevance: There appears to be a highly consistent robust reduction in LDL-C levels with evolocumab use. Trial Registration: ClinicalTrials.gov identifier: NCT01764633.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , LDL-Colesterol/efeitos dos fármacos , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticolesterolemiantes/administração & dosagem , Variação Biológica da População , Doença da Artéria Coronariana/tratamento farmacológico , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Inibidores de PCSK9 , Placebos/administração & dosagem , Pró-Proteína Convertase 9/efeitos dos fármacos , Pró-Proteína Convertase 9/metabolismoRESUMO
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition by monoclonal antibodies has been shown to reduce low density lipoprotein (LDL-C) but its effects on cardiovascular (CV) outcomes have not been fully described. The aim of this study is to assess the impact of PCSK9 inhibition on mortality and CV outcomes by pooling data from all available randomized clinical trials (RCT) of PCSK9 inhibitors. We conducted a comprehensive search of electronic databases, up to December 1, 2018, for all RCTs comparing PCSK9 inhibition to placebo or ezetimibe in patients with hypercholesterolemia or coronary artery disease receiving maximally tolerated statin for primary or secondary prevention of mortality and cardiovascular outcomes. We used random-effects meta-analyses to summarize the studies. We retained 23 RCTs having included 88,041 patients in primary and secondary prevention. The follow-up ranged from 6 to 36 months. PCSK9 inhibition was not significantly associated with reductions in total mortality (odds ratio [OR] 0.91, 95% confidence interval [CI] 078 to 1.06; pâ¯=â¯0.22) and CV mortality (OR 0.95, 95% CI 0.84 to 1.07; pâ¯=â¯0.37). In contrast, PCSK9 inhibition was associated with reductions in myocardial infarction (OR 0.80, 95% CI 0.71 to 0.91; p <0.0001), stroke (OR 0.75, 95% CI 0.65 to 0.85; p <0.0001), and coronary revascularization (OR 0.82, 95% CI 0.77 to 0.88; p <0.0001). In conclusion, PCSK9 inhibition was associated with reductions in myocardial infarction, stroke, and coronary revascularization. Future analyses may identify high-risk patients who may benefit more from these agents and longer follow-up of current or new trials may show a mortality benefit.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Doença das Coronárias/sangue , Doença das Coronárias/tratamento farmacológico , Infarto do Miocárdio/sangue , Infarto do Miocárdio/tratamento farmacológico , Pró-Proteína Convertase 9/efeitos dos fármacos , Idoso , Biomarcadores/sangue , Causas de Morte , Doença das Coronárias/mortalidade , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Pró-Proteína Convertase 9/sangue , Ensaios Clínicos Controlados Aleatórios como Assunto , Valores de Referência , Medição de Risco , Prevenção Secundária/métodos , Análise de Sobrevida , Resultado do TratamentoRESUMO
Monoclonal antibodies inhibiting proprotein convertase subtilisin-kexin type 9 constitute a new class of lipid-lowering drugs. Currently, evolocumab and alirocumab are marketed. A recent cardiovascular outcome study with evolocumab has shown a cardiovascular (CV) event reduction of 15% in high-risk individuals at very low levels of low-density lipoproteins. The adverse event profile up to two years is mild. Treatment is very costly, and data on CV endpoints are still limited. Treatment is restricted to patients at very high risk of getting CV diseases and on a maximal tolerated statin and ezetimibe treatment in addition to dietary intervention.
Assuntos
Anticolesterolemiantes , Doenças Cardiovasculares , Hipercolesterolemia , Pró-Proteína Convertase 9 , Anticorpos Monoclonais Humanizados , Anticolesterolemiantes/farmacologia , Colesterol , LDL-Colesterol , Humanos , Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertase 9/efeitos dos fármacos , Resultado do TratamentoRESUMO
Clinical trials have unequivocally shown that inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) efficaciously and safely prevents cardiovascular events by lowering levels of LDL cholesterol. PCSK9 in the circulation is derived mainly from the liver, but the protein is also expressed in the pancreas, the kidney, the intestine and the central nervous system. Although PCSK9 modulates cholesterol metabolism by regulating LDL receptor expression in the liver, in vitro and in vivo studies have suggested that PCSK9 is involved in various other physiological processes. Although therapeutic PCSK9 inhibition could theoretically have undesired effects by interfering with these non-cholesterol-related processes, studies of individuals with genetically determined reduced PCSK9 function and clinical trials of PCSK9 inhibitors have not revealed clinically meaningful adverse consequences of almost completely eradicating PCSK9 from the circulation. The clinical implications of PCSK9 functions beyond lipid metabolism in terms of wanted or unwanted effects of therapeutic PCSK9 inhibition therefore appear to be limited. The objective of this Review is to describe the physiological role of PCSK9 beyond the LDL receptor to provide a rational basis for monitoring the effects of PCSK9 inhibition as these drugs gain traction in the clinic.
Assuntos
LDL-Colesterol/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Pró-Proteína Convertase 9/efeitos dos fármacos , Pró-Proteína Convertase 9/metabolismo , Receptores de LDL/efeitos dos fármacos , Biomarcadores/metabolismo , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/efeitos dos fármacos , Feminino , Humanos , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/prevenção & controle , Masculino , Receptores de LDL/metabolismo , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Alirocumab undergoes target-mediated clearance via binding of proprotein convertase subtilisin/kexin type 9 (PCSK9). Statins increase PCSK9 levels; the effects of nonstatin lipid-lowering therapies are unclear. Every-4-weeks dosing of alirocumab may be appropriate for some patients in absence of background statin but is not yet approved. METHODS AND RESULTS: Low-density lipoprotein cholesterol (LDL-C), PCSK9, and alirocumab levels were assessed in subjects (LDL-C >130 mg/dL, n=24/group) after a 4-week run-in taking oral ezetimibe, fenofibrate, or ezetimibe placebo, when alirocumab 150 mg every 4 weeks (days 1, 29, and 57) was added. Maximal mean LDL-C reductions from day -1 baseline (prealirocumab) occurred on day 71 in all groups: alirocumab plus placebo, 47.4%; alirocumab plus ezetimibe, 56.6%; and alirocumab plus fenofibrate, 54.3%. LDL-C reductions were sustained through day 85 with alirocumab plus placebo (47.0%); the duration of effect was slightly diminished at day 85 versus day 71 with ezetimibe (49.6%) or fenofibrate combinations (43.2%). Free PCSK9 concentrations were lowest at day 71 in all groups, then increased over time; by day 85, free PCSK9 concentrations were higher, and alirocumab levels lower, with alirocumab plus fenofibrate, and to a lesser extent alirocumab plus ezetimibe, versus alirocumab plus placebo. CONCLUSIONS: Alirocumab 150 mg every 4 weeks produced maximal LDL-C reductions of 47% in combination with placebo and 54% to 57% in combination with ezetimibe or fenofibrate. The oral lipid-lowering therapies appear to increase PCSK9 levels, leading to increased alirocumab clearance. Although the duration of effect was modestly diminished with alirocumab plus ezetimibe/fenofibrate versus placebo, the effect was less than observed in trials with background statins, and it would not preclude the use of alirocumab every 4 weeks in patients taking these nonstatin lipid-lowering therapies concomitantly. CLINICAL TRIAL REGISTRATION: URL: http://www.Clinicaltrials.gov. Unique identifier: NCT01723735.