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1.
Clin Pharmacol Drug Dev ; 8(5): 628-636, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30240132

RESUMO

CSL112 (Apolipoprotein A-I [human]) is an intravenous preparation of apolipoprotein A-I (apoA-I), formulated with phosphatidylcholine (PC) and stabilized with sucrose, in development to prevent early recurrent cardiovascular events following acute myocardial infarction (AMI). This phase 1 study was designed to determine if moderate renal impairment (RI) influenced the pharmacokinetics (PK) and safety of CSL112. Thirty-two subjects, 16 with moderate RI (estimated glomerular filtration rate [eGFR] ≥ 30 and < 60 mL/min/1.73 m2 ) and 16 age-, sex-, and weight-matched subjects with normal renal function (eGFR ≥ 90 mL/min/1.73 m2 ) were randomized 3:1 to receive a single infusion of CSL112 2 g (n = 6) or placebo (n = 2), or CSL112 6 g (n = 6) or placebo (n = 2). PK sampling was at prespecified times from 48 hours prior to 144 hours following infusions, with final safety assessments at 90 days. Renal and hepatic safety, and adverse events (AEs) were monitored throughout the study. Plasma apoA-I and PC PK profiles were similar between renal function cohorts at both doses. For CSL112 6 g mean ± SD apoA-I AUC0 - last was 7670 ± 1900 and 9170 ± 2910 mg·h/dL in normal renal function and moderate RI subjects, respectively. Renal apoA-I clearance was <1% of CSL112 dose. In moderate RI, sucrose clearance was slower; however, approximately 70% was excreted within 48 hours in both renal function cohorts. No CSL112-related serious AEs or clinically significant renal or hepatic safety changes were observed. Dose adjustment of CSL112 is not required in subjects with moderate RI, supporting its further investigation in AMI patients with moderate RI.

2.
J Clin Pharmacol ; 59(3): 427-436, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30452776

RESUMO

CSL112 (apolipoprotein A-I [human]) is a novel intravenous formulation of plasma-derived apolipoprotein A-I (apoA-I) that enhances cholesterol efflux capacity. Renal impairment is a common comorbidity in acute myocardial infarction patients and is associated with impaired lipid metabolism. The aim of this phase 1 study was to assess the impact of moderate renal impairment on the pharmacokinetic and pharmacodynamic profile of CSL112. Sixteen subjects with moderate renal impairment and 16 age-, sex-, and weight-matched subjects with normal renal function participated in the study. Within each renal function cohort, subjects were randomized 3:1 to receive a single intravenous infusion of CSL112 2 g (n = 6) or placebo (n = 2) or CSL112 6 g (n = 6) or placebo (n = 2). At baseline, subjects with moderate renal impairment versus normal renal function had higher total cholesterol efflux, ABCA1-dependent cholesterol efflux capacity, and pre-ß1-high-density lipoprotein (HDL) levels. Infusing CSL112 resulted in similar, immediate, robust, dose-dependent elevations in apoA-I and cholesterol efflux capacity in both renal function cohorts and significantly greater elevations in pre-ß1-HDL (P < .05) in moderate renal impairment. Lecithin-cholesterol acyltransferase activity, demonstrated by a time-dependent change in the ratio of unesterified to esterified cholesterol, did not differ by renal function. No meaningful changes in proatherogenic lipid levels were observed. Moderate renal impairment did not impact the ability of CSL112 to enhance cholesterol efflux capacity. CSL112 may represent a novel therapy to reduce the risk of early recurrent cardiovascular events following acute myocardial infarction in patients with or without moderate renal impairment.

3.
Am Heart J ; 208: 81-90, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30580130

RESUMO

BACKGROUND: CSL112 (apolipoprotein A-I [human]) is a plasma-derived apolipoprotein A-I developed for early reduction of cardiovascular risk following an acute myocardial infarction (AMI). The safety of CSL112 among AMI subjects with moderate, stage 3 chronic kidney disease (CKD) is unknown. METHODS: CSL112_2001, a multicenter, placebo-controlled, parallel-group, double-blind, randomized phase 2 trial, enrolled patients with moderate CKD within 7 days following AMI. Enrollment was stratified on the basis of estimated glomerular filtration rate and presence of diabetes requiring treatment. Patients were randomized in a 2:1 ratio to receive 4 weekly infusions of CSL112 6 g or placebo. The co-primary safety end points were renal serious adverse events (SAEs) and acute kidney injury, defined as an increase ≥26.5 µmol/L in baseline serum creatinine for more than 24 hours, during the treatment period. RESULTS: A total of 83 patients were randomized (55 CSL112 vs 28 placebo). No increase in renal SAEs was observed in the CSL112 group compared with placebo (CSL112 = 1 [1.9%], placebo = 4 [14.3%]). Similarly, no increase in acute kidney injury events was observed (CSL112 = 2 [4.0%], placebo = 4 [14.3%]). Rates of other SAEs were similar between groups. CSL112 administration resulted in increases in ApoA-I and cholesterol efflux similar to those observed in patients with AMI and normal renal function or stage 2 CKD enrolled in the ApoA-I Event Reducing in Ischemic Syndromes I trial. CONCLUSIONS: These results demonstrate the acceptable safety of the 6-g dose of CSL112 among AMI subjects with moderate stage 3 CKD and support inclusion of these patients in a phase 3 cardiovascular outcomes trial powered to assess efficacy.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Lipoproteínas HDL/efeitos adversos , Infarto do Miocárdio/complicações , Infarto do Miocárdio/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Lesão Renal Aguda/sangue , Idoso , Apolipoproteína A-I/sangue , Biomarcadores/sangue , Colesterol/sangue , Creatinina/sangue , Feminino , Taxa de Filtração Glomerular , Humanos , Análise de Intenção de Tratamento , Lipoproteínas HDL/administração & dosagem , Masculino , Infarto do Miocárdio/sangue , Insuficiência Renal Crônica/sangue , Tamanho da Amostra , Fatores de Tempo
4.
Clin Transl Sci ; 10(6): 455-469, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28795506

RESUMO

A single dose of the apolipoprotein (apo)A-I mimetic peptide D-4F rendered high-density lipoprotein (HDL) less inflammatory, motivating the first multiple-dose study. We aimed to assess safety/tolerability, pharmacokinetics, and pharmacodynamics of daily, orally administered D-4F. High-risk coronary heart disease (CHD) subjects added double-blinded placebo or D-4F to statin for 13 days, randomly assigned 1:3 to ascending cohorts of 100, 300, then 500 mg (n = 62; 46 men/16 women). D-4F was safe and well-tolerated. Mean ± SD plasma D-4F area under the curve (AUC, 0-8h) was 6.9 ± 5.7 ng/mL*h (100 mg), 22.7 ± 19.6 ng/mL*h (300 mg), and 104.0 ± 60.9 ng/mL*h (500 mg) among men, higher among women. Whereas placebo dropped HDL inflammatory index (HII) 28% 8 h postdose (range, 1.25-0.86), 300-500 mg D-4F effectively halved HII: 1.35-0.57 and 1.22-0.63, respectively (P < 0.03 vs. placebo). Oral D-4F peptide dose predicted HII suppression, whereas plasma D-4F exposure was dissociated, suggesting plasma penetration is unnecessary. In conclusion, oral D-4F dosing rendered HDL less inflammatory, affirming oral D-4F as a potential therapy to improve HDL function.


Assuntos
Apolipoproteína A-I/administração & dosagem , Apolipoproteína A-I/uso terapêutico , Inflamação/tratamento farmacológico , Lipoproteínas HDL/metabolismo , Administração Oral , Adulto , Idoso , Apolipoproteína A-I/efeitos adversos , Apolipoproteína A-I/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores de Tempo
5.
Am Heart J ; 181: 130-136, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27823684

RESUMO

BACKGROUND: The 2013 American College of Cardiology/American Heart Association cholesterol management guidelines represented a paradigm shift from the National Cholesterol Education Program Adult Treatment Panel III guidelines, replacing low-density lipoprotein cholesterol targets with a risk assessment model to guide statin therapy. Our objectives are to compare provider prescription of high-intensity statin therapy in patients hospitalized with acute coronary syndrome (ACS) or cerebrovascular accident (CVA) before and after the publication of the 2013 cholesterol guidelines, determine potential predictors of high-intensity statin utilization, and identify targets for improvement in cardiovascular risk reduction among these high-risk populations. METHODS: A single-center retrospective cohort study of 695 patients discharged with a diagnosis of ACS or CVA in the 6months before (n=359) and after (n=336) the release of the 2013 American College of Cardiology/American Heart Association cholesterol guidelines. Patient characteristics were compared using analysis of variance and χ2 tests. Multivariable logistic regression models were used to assess clinical predictors of provider utilization of high-intensity statins. RESULTS: After the 2013 cholesterol guidelines, the rate of prescribing high-intensity statins was greater for statin-naïve patients compared with those already on statin therapy (odds ratio [OR]0.51, P=.02). Prescription of high-intensity statins was higher for patients with ACS compared with CVA (OR 8.4, P<.001-pre-2013 guidelines; OR 4.5, P<.001-post-2013 guidelines). Prescription of high-intensity statins steadily improved over the study period, significantly among patients with CVA (P<.001). CONCLUSIONS: Physicians were more likely to prescribe high-intensity statins in statin-naïve patients as compared with intensifying existing statin therapy, and their prescription pattern was lower after CVA vs ACS.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Angina Instável/tratamento farmacológico , Atorvastatina/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Guias de Prática Clínica como Assunto , Rosuvastatina Cálcica/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Síndrome Coronariana Aguda/sangue , Idoso , American Heart Association , Angina Instável/sangue , Cardiologia , LDL-Colesterol/sangue , Estudos de Coortes , Feminino , Fidelidade a Diretrizes/estatística & dados numéricos , Hospitalização , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Infarto do Miocárdio/sangue , Razão de Chances , Padrões de Prática Médica/estatística & dados numéricos , Estudos Retrospectivos , Sociedades Médicas , Acidente Vascular Cerebral/sangue , Estados Unidos
6.
J Clin Lipidol ; 10(5): 1223-9, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27678440

RESUMO

BACKGROUND: In the US familial hypercholesterolemia (FH), patients are underidentified, despite an estimated prevalence of 1:200 to 1:500. Criteria to identify FH patients include Simon Broome, Dutch Lipid Clinic Network (DLCN), or Make Early Diagnosis to Prevent Early Deaths (MEDPED). The use of these criteria in US clinical practices remains unclear. OBJECTIVE: To characterize the FH diagnostic criteria applied by US lipid specialists participating in the FH Foundation's CASCADE FH (CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia) patient registry. METHODS: We performed an observational, cross-sectional analysis of diagnostic criteria chosen for each adult patient, both overall and by baseline patient characteristics, at 15 clinical sites that had contributed data to the registry as of September 8, 2015. A sample of 1867 FH adults was analyzed. The median age at FH diagnosis was 50 years, and the median pretreatment low-density lipoprotein cholesterol (LDL-C) value was 238 mg/dL. The main outcome was the diagnostic criteria chosen. Diagnostic criteria were divided into five nonexclusive categories: "clinical diagnosis," MEDPED, Simon Broome, DLCN, and other. RESULTS: Most adults enrolled in CASCADE FH (55.0%) received a "clinical diagnosis." The most commonly used formal criteria was Simon-Broome only (21%), followed by multiple diagnostic criteria (16%), MEDPED only (7%), DLCN only (1%), and other (0.5%), P < .0001. Of the patients with only a "clinical diagnosis," 93% would have met criteria for Simon Broome, DLCN, or MEDPED based on the data available in the registry. CONCLUSIONS: Our findings demonstrate heterogeneity in the application of FH diagnostic criteria in the United States. A nationwide consensus definition may lead to better identification, earlier treatment, and ultimately CHD prevention.


Assuntos
Hiperlipoproteinemia Tipo II/diagnóstico , Adulto , LDL-Colesterol/sangue , Estudos Transversais , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Médicos , Sistema de Registros , Estados Unidos
7.
Circ Cardiovasc Genet ; 9(3): 240-9, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27013694

RESUMO

BACKGROUND: Cardiovascular disease burden and treatment patterns among patients with familial hypercholesterolemia (FH) in the United States remain poorly described. In 2013, the FH Foundation launched the Cascade Screening for Awareness and Detection (CASCADE) of FH Registry to address this knowledge gap. METHODS AND RESULTS: We conducted a cross-sectional analysis of 1295 adults with heterozygous FH enrolled in the CASCADE-FH Registry from 11 US lipid clinics. Median age at initiation of lipid-lowering therapy was 39 years, and median age at FH diagnosis was 47 years. Prevalent coronary heart disease was reported in 36% of patients, and 61% exhibited 1 or more modifiable risk factors. Median untreated low-density lipoprotein cholesterol (LDL-C) was 239 mg/dL. At enrollment, median LDL-C was 141 mg/dL; 42% of patients were taking high-intensity statin therapy and 45% received >1 LDL-lowering medication. Among FH patients receiving LDL-lowering medication(s), 25% achieved an LDL-C <100 mg/dL and 41% achieved a ≥50% LDL-C reduction. Factors associated with prevalent coronary heart disease included diabetes mellitus (adjusted odds ratio 1.74; 95% confidence interval 1.08-2.82) and hypertension (2.48; 1.92-3.21). Factors associated with a ≥50% LDL-C reduction from untreated levels included high-intensity statin use (7.33; 1.86-28.86) and use of >1 LDL-lowering medication (1.80; 1.34-2.41). CONCLUSIONS: FH patients in the CASCADE-FH Registry are diagnosed late in life and often do not achieve adequate LDL-C lowering, despite a high prevalence of coronary heart disease and risk factors. These findings highlight the need for earlier diagnosis of FH and initiation of lipid-lowering therapy, more consistent use of guideline-recommended LDL-lowering therapy, and comprehensive management of traditional coronary heart disease risk factors.


Assuntos
Doença das Coronárias/prevenção & controle , Heterozigoto , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Padrões de Prática Médica , Lacunas da Prática Profissional , Adulto , Idoso , Biomarcadores/sangue , Distribuição de Qui-Quadrado , LDL-Colesterol/sangue , Comorbidade , Doença das Coronárias/epidemiologia , Doença das Coronárias/genética , Estudos Transversais , Diabetes Mellitus/epidemiologia , Regulação para Baixo , Diagnóstico Precoce , Feminino , Predisposição Genética para Doença , Fidelidade a Diretrizes , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/epidemiologia , Hiperlipoproteinemia Tipo II/genética , Hipertensão/epidemiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Fenótipo , Guias de Prática Clínica como Assunto , Padrões de Prática Médica/normas , Valor Preditivo dos Testes , Prevalência , Lacunas da Prática Profissional/normas , Sistema de Registros , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Estados Unidos
8.
Del Med J ; 87(8): 238-43, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26402926

RESUMO

INTRODUCTION: The familial hypercholesterolemias (FH) are a group of undertreated genetically inherited disorders of lipid metabolism that lead to severely elevated cholesterol levels and early onset cardiovascular disease. Aggressive lifestyle modifications and lipid-lowering medications such as statins and bile acid sequestrants are the backbone of current treatment. Despite these interventions, homozygous FH (HoFH) patients are unable to reach LDL-C targets and remain at significantly increased risk of cardiovascular disease. Recently, two novel lipid-lowering medications, lomitapide and mipomersen, have been approved for the treatment of HoFH. CASE DESCRIPTIONS: We present two patients with HoFH who have been unable to reach target LDL-C goals on standard therapy. Patient A is a 41-year-old male and patient B is a 64-year-old female, both of whom have complex histories of multi-vessel coronary artery disease. In attempt to improve their LDL-C levels and lower their cardiovascular risk, lomitapide and mipomersen were initiated in patient A and B, respectively. DISCUSSION/CONCLUSION: Through inhibition of the microsomal triglyceride transfer protein, lomitapide prevents the formation of triglyceride rich lipoproteins. Mipomersen is an antisense oligonucleotide that inhibits the translation of apolipoprotein B-100. Both medications employ novel mechanisms developed through advances in pharmacogenetic technology and achieve unprecedented LDL-C reductions.


Assuntos
Anticolesterolemiantes/uso terapêutico , Benzimidazóis/uso terapêutico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/genética , Oligonucleotídeos/uso terapêutico , Farmacogenética , Adulto , LDL-Colesterol/sangue , Feminino , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Masculino , Pessoa de Meia-Idade
9.
Pract Radiat Oncol ; 5(3): 162-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25957186

RESUMO

PURPOSE: Deep inspiration breath hold (DIBH) dramatically reduces radiation dose to the heart during radiation therapy (RT) for left-sided breast cancer, but the subsequent risk of radiation-related ischemic heart disease (IHD) is unknown. Our primary objective was to quantify the risk of IHD following RT with DIBH using modeled risk estimates (MRE). METHODS AND MATERIALS: Patients with stage 0-III left-sided breast cancer who received RT with DIBH were retrospectively studied. Computed tomography simulations were performed with DIBH and during free breathing (FB) for comparison of dosimetry. Patients were classified as high risk, at risk, or at optimal risk for IHD and baseline risk estimates for IHD were obtained from historic controls. The excess relative risk of IHD because of left breast RT was calculated using patient-specific dosimetry and an existing dose-effect model. MRE were determined from the sum of baseline risk estimates and excess risk. RESULTS: Between 2002 and 2011, 111 patients were treated using DIBH and 104 were available for analysis. MRE for 10-year risk of IHD with DIBH and FB were 3.25% (interquartile range [IQR], 1.20-3.44) and 3.64% (IQR, 1.43-3.81) (P < .0001), respectively. MRE for lifetime risk of IHD with DIBH and FB were 9.71% (IQR, 1.98-16.62) and 10.28% (IQR, 2.05-16.97) (P < .0001), respectively. MRE were significantly reduced by use of DIBH in all risk groups. The largest absolute risk reduction resulting from the DIBH technique was observed in patients at high risk for IHD. The median relative risk reduction in MRE resulting from DIBH was 11.4% (range, 0-32.0) and 6.4% (range, 0-23.4) at 10 years and throughout the patients' lifetime, respectively. After a median follow-up of 7.0 years (range, 1.3-11.2), the estimated 10-year freedom from IHD was 99.0% (95% confidence interval 93.4-99.8). CONCLUSIONS: RT with DIBH may provide breast cancer survivors a clinically significant reduction in the risk of IHD.


Assuntos
Neoplasias da Mama/radioterapia , Suspensão da Respiração , Modelos Teóricos , Isquemia Miocárdica/etiologia , Adulto , Idoso , Neoplasias da Mama/mortalidade , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Dosagem Radioterapêutica , Respiração , Fatores de Risco , Tomografia Computadorizada por Raios X
10.
Curr Atheroscler Rep ; 17(5): 502, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25736345

RESUMO

Robust epidemiologic and genetic studies have solidified the role of lipoprotein (a) [Lp(a)] as an independent and causal risk factor for cardiovascular disease. The increased cardiovascular risk of Lp(a) is mediated through both proatherogenic and prothrombotic/antifibrinolytic mechanisms. Several societies recommend Lp(a) screening for patients with high cardiovascular risk, although no consensus exists on the management of patients with elevated Lp(a). However, numerous pharmacologic approaches are being evaluated that have the potential to reduce Lp(a) and will be the focus of this review. The majority of these interventions have been developed for other lipid-lowering indications, but also lower Lp(a). There are also novel therapies in development that specifically target Lp(a). The efficacy of these therapies varies, and their role in the evolving lipoprotein therapeutic landscape has yet to be determined. Nevertheless, targeted Lp(a) reduction is certainly intriguing and will likely continue to be an active area of investigation in the future.


Assuntos
Doenças Cardiovasculares/genética , Lipoproteína(a)/genética , Doenças Cardiovasculares/sangue , Gerenciamento Clínico , Humanos , Lipoproteína(a)/metabolismo
11.
Trends Cardiovasc Med ; 25(4): 340-7, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25435519

RESUMO

The 2013 American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults represents a major shift from prior cholesterol management guidelines. The new guidelines include data from individual randomized trials as well as the most comprehensive meta-analyses, and introduce several major paradigm shifts, which include: aiming for ASCVD risk reduction as opposed to targeting LDL-C levels, advocating for the use of evidence-based doses of statins as first line therapy, and utilizing a new risk calculator and risk cut point to guide initiation of statin therapy. These major changes have created controversy and confusion among the medical community, with some clinicians hesitant to embrace the shift. We review the evidence that forms the basis for these major changes, compare them to other major lipid guidelines, and recommend an integrated approach to managing dyslipidemia to decrease atherosclerotic cardiovascular disease risk.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , LDL-Colesterol/sangue , Doença da Artéria Coronariana/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , American Heart Association , Biomarcadores/sangue , Cardiologia , Doenças Cardiovasculares/sangue , Doença da Artéria Coronariana/sangue , Guias como Assunto , Humanos , Metanálise como Assunto , Doença Arterial Periférica , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Comportamento de Redução do Risco , Acidente Vascular Cerebral/prevenção & controle , Resultado do Tratamento , Estados Unidos
12.
Expert Rev Cardiovasc Ther ; 12(11): 1251-60, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25300316

RESUMO

Prescribed in patients with a history of myocardial infarction, stroke, transient ischemic attack, coronary intervention or bypass surgery, aspirin is one of the medications most commonly used in the secondary prevention of cardiovascular diseases. It has become a mainstay of therapy after years of solid evidence supporting its efficacy in clinical trials. However, a number of risks and side effects accompany its benefits, including the notable risk of bleeding and gastrointestinal side effects. Numerous mechanisms have been proposed to attenuate these effects to promote adherence and to expand the population for which aspirin is a reasonable treatment option. A polypill or combination formulation that includes a proton pump inhibitor, a drug commonly prescribed alongside aspirin, is one potential avenue of therapy. One such combination pill, PA32540, has undergone Phase I and Phase III trials and shows promising safety and efficacy results in these preliminary trials.


Assuntos
Aspirina/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Inibidores da Agregação de Plaquetas/uso terapêutico , Prevenção Secundária , Úlcera Gástrica , Doenças Cardiovasculares/tratamento farmacológico , Quimioterapia Combinada , Humanos , Úlcera Gástrica/complicações , Úlcera Gástrica/tratamento farmacológico
13.
Pharmacotherapy ; 34(9): 961-72, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24899514

RESUMO

The familial hypercholesterolemias (FHs) are inherited disorders of lipoprotein metabolism that are among the most prevalent genetically inherited disorders. Various genetic mutations ultimately lead to greatly increased low-density lipoprotein-cholesterol (LDL-C) levels over a lifetime. Consequently, patients with FH develop coronary artery disease at significantly earlier ages and at a greater frequency than the general population. Current therapies revolve around aggressive lifestyle modifications, cholesterol-lowering medications, and in some cases LDL apheresis. Despite maximal medical therapy, LDL-C is not sufficiently reduced in some patients, and they remain at a substantially increased risk of coronary heart disease. Recent advances in genetic-based pharmacology have enabled the development of three novel classes of medications for FH. Two of those compounds, mipomersen and lomitapide, result in decreased LDL-C production and were approved by the Food and Drug Administration in the past 18 months for treatment of homozygous FH. Mipomersen is an antisense oligonucleotide that inhibits the translation of apolipoprotein B-100, and lomitapide is an inhibitor of the microsomal triglyceride transfer protein, which prevents the incorporation of triglycerides into lipoproteins. A third class of drugs, the proprotein convertase subtilisin/kexin type 9 inhibitors, is still in development, although studies in patients with heterozygous or receptor-defective homozygous FH have demonstrated substantial reductions in LDL-C by decreasing the degradation of LDL receptors. Development of these novel treatments for hypercholesterolemia resulted from the application of known genetic mutations and is the focus of this review.


Assuntos
Anticolesterolemiantes/uso terapêutico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Farmacogenética , Anticolesterolemiantes/farmacologia , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , LDL-Colesterol/sangue , Desenho de Drogas , Humanos , Hiperlipoproteinemia Tipo II/genética , Mutação , Oligonucleotídeos/farmacologia , Oligonucleotídeos/uso terapêutico
14.
Pharmacotherapy ; 34(3): 227-39, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24734312

RESUMO

STUDY OBJECTIVE: To characterize the effects of two doses (10 and 60 mg) of lomitapide­a microsomal triglyceride transfer protein inhibitor approved as adjunct treatment to lower low-density lipoprotein cholesterol levels in patients with homozygous familial hypercholesterolemia­on the pharmacokinetics of several lipid-lowering therapies: atorvastatin, simvastatin, rosuvastatin, fenofibrate, ezetimibe, and niacin. DESIGN: Two prospective open-label studies (study 1 and study 2). SETTING: Two clinical research units. SUBJECTS: A total of 130 healthy volunteers (114 subjects in study 1 and 16 subjects in study 2). INTERVENTION: In study 1, subjects were enrolled sequentially to one of the following eight open-label treatment arms (probe drug + lomitapide): atorvastatin 20 mg + lomitapide 10 mg, atorvastatin 20 mg + lomitapide 60 mg, simvastatin 20 mg + lomitapide 10 mg, rosuvastatin 20 mg + lomitapide 10 mg, rosuvastatin 20 mg + lomitapide 60 mg, fenofibrate 145 mg + lomitapide 10 mg, ezetimibe 10 mg + lomitapide 10 mg, and extended-release niacin 1000 mg + lomitapide 10 mg. Study 2 consisted of the ninth treatment arm: simvastatin 40 mg + lomitapide 60 mg. Subjects received one dose of the probe drug on the morning of day 1. On days 2­7, subjects took their dose of lomitapide once/day in the morning. On day 8, subjects received one dose of lomitapide simultaneously with the same probe drug they took on day 1. Subjects returned 1 week later (day 15) for a final visit to check safety laboratory parameters. MEASUREMENTS AND MAIN RESULTS: A full pharmacokinetic profile was performed for the probe drug on day 1 and day 8 (after 7 days of dosing with lomitapide [i.e., at steady state]). Pharmacokinetic parameters were calculated from the plasma concentration-time data for each day by using noncompartmental methods. Analysis of variance was applied to the ln-transformed maximum concentration (Cmax) and area under the plasma concentration-time curve from time 0­t (AUC0­t) values, and ratios of the means were compared for day 8 versus day 1. Lomitapide increased exposure to the statin medications. The percent least squares means ratios (LSMR%) (90% confidence intervals [CIs]) for AUC0­t of the statin medications with lomitapide at the 60 mg dose were as follows: 129 (115­144) for the sum of the active atorvastatin moieties, 168 (139­203) for simvastatin acid, and 132 (112­157) for rosuvastatin. The LSMR% (90% CI) for Cmax was 138 (120­160) for the sum of the active atorvastatin moieties, 157 (133­186) for simvastatin acid, and 104 (82­32) for rosuvastatin. The LSMRs were not appreciably altered for the other probe drugs. CONCLUSION: This study shows that lomitapide is a weak inhibitor of CYP3A4 and increased the exposure of statin medications. Careful monitoring of adverse events of CYP3A4-metabolized statins should be used when initiating therapy with lomitapide.


Assuntos
Anticolesterolemiantes/farmacocinética , Benzimidazóis/farmacocinética , Proteínas de Transporte/antagonistas & inibidores , Interações de Medicamentos , Hipercolesterolemia/tratamento farmacológico , Adolescente , Adulto , Idoso , Anticolesterolemiantes/administração & dosagem , Benzimidazóis/administração & dosagem , Gerenciamento Clínico , Relação Dose-Resposta a Droga , Interações de Medicamentos/fisiologia , Quimioterapia Combinada , Feminino , Humanos , Hipercolesterolemia/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
15.
Postgrad Med ; 126(1): 18-28, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24393748

RESUMO

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in North America. Aspirin therapy has proven clinical effectiveness in the prevention and treatment of CVD and is one of the most widely used drugs nationwide. However, despite the medication's popularity and utility, adherence to a proper aspirin regimen is suboptimal, resulting in adverse health outcomes and increased health care costs. Our review outlines current knowledge on aspirin therapy adherence, causes of nonadherence, and strategies available to increase adherence to aspirin and medications in general. We demonstrate that, indeed, aspirin adherence rates are suboptimal, ranging from 72% to 92%, and that a combination of patient- and medication-related factors contribute to nonadherence. A multidimensional approach involving patient education and medication innovations to reduce aspirin side effects is imperative to improving rates of aspirin therapy adherence.


Assuntos
Aspirina/administração & dosagem , Doenças Cardiovasculares/prevenção & controle , Adesão à Medicação/psicologia , Inibidores da Agregação de Plaquetas/administração & dosagem , Fatores Etários , Comorbidade , Comportamentos Relacionados com a Saúde , Humanos , Saúde Mental , Educação de Pacientes como Assunto , Sistemas de Alerta , Fatores Sexuais , Apoio Social , Fatores Socioeconômicos
16.
Am J Cancer Ther Pharmacol ; 2(1): 21-32, 2014 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-25580468

RESUMO

BACKGROUND: Digoxin was found to inhibit prostate cancer (PCa) growth via the inhibition of HIF-1α synthesis in a mouse model. We hypothesized that a therapeutic dose of digoxin could inhibit human PCa growth and disease progression. METHODS: An open label, single arm pilot study was performed. Patients (pts) with non-metastatic, biochemically relapsed PCa with prostate specific antigen doubling time (PSADT) of 3-24 months and no hormonal therapy within the past 6 months were enrolled. All pts had testosterone > 50 ng/dL at baseline. Digoxin was taken daily with dose titration to achieve a target therapeutic level (0.8 - 2 ng/ml); patients had routine follow-up including cardiac monitoring with 12-lead electrocardiograms (ECGs) and digoxin levels. The primary endpoint was the proportion of pts at 6 months post-treatment with a PSADT ≥ 200% from the baseline. HIF-1α downstream molecule vascular endothelial growth factor (VEGF) was measured in plasma. RESULTS: Sixteen pts were enrolled and 14 pts finished the planned 6 months of treatment. Twenty percent (3/15) of the pts had PSA decrease >25% from baseline with a medium duration of 14 months. At 6 months, 5 of 13 (38%) pts had PSADT ≥ 200% of the baseline PSADT and were continued on study for an additional 24 weeks of treatment. Two patients had durable PSA response for more than 1 year. Digoxin was well tolerated with possible relation of one grade 3 back pain. No patients had evidence of digoxin toxicity. The digoxin dose was lowered in 2 patients for significant ECGs changes (sinus bradycardia and QT prolongation), and there were probable digoxin-related ECG changes in 3 patients. Plasma VEGF was detected in 4 (25%) patients. CONCLUSIONS: Digoxin was well tolerated and showed a prolongation of PSDAT in 38% of the patients. However, there was no significant difference comparing that of similar patients on placebo from historical data. Digoxin at the dose used in this study may have limited benefit for patients with biochemically relapsed prostate cancer.

17.
Am Heart J ; 163(4): 705-13, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22520538

RESUMO

BACKGROUND: Low serum high-density lipoprotein cholesterol (HDL-C) level is a potent risk factor for developing atherosclerosis, yet it is uncertain if HDL-C level at the time of non-ST-segment elevation myocardial infarction (NSTEMI) has downstream prognostic importance. METHODS: We evaluated 24,805 patients with NSTEMI aged ≥ 65 years enrolled at 434 Can Rapid Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology/American Heart Association Guidelines (CRUSADE) participating hospitals between February 15, 2003, and December 30, 2006, who had clinical data linked to Medicare files through December 31, 2008. Unadjusted and adjusted hazard ratios (HRs) were calculated to determine the association between HDL-C level at initial hospitalization and all-cause mortality, as well as a combined outcome of all-cause mortality or recurrent myocardial infarction (MI). RESULTS: Overall, 50% of patients had low HDL-C (≤ 40 mg/dL) and 18% had very low HDL-C (≤ 30 mg/dL). The rate of all-cause mortality was 39.5% during a median follow-up of 2.9 years; death or recurrent MI occurred in 43% in this older population with NSTEMI. Compared with patients who had normal HDL-C, those with very low HDL-C had a modest but significantly higher long-term mortality risk (adjusted HR 1.12, 95% CI 1.06-1.19, P = .0001). The adjusted HR for mortality or recurrent MI was the same. When modeled as a continuous variable, every 5-mg/dL decrement in HDL-C below 40 mg/dL was associated with a 5% increased risk of long-term mortality, as well as the combined end point. CONCLUSIONS: Older patients with NSTEMI with low levels of HDL-C are at increased risk for downstream mortality or recurrent MI. Future studies are needed to evaluate strategies to reduce this residual risk.


Assuntos
Lipoproteínas HDL/sangue , Infarto do Miocárdio/sangue , Idoso , Idoso de 80 Anos ou mais , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/mortalidade , Feminino , Humanos , Masculino , Infarto do Miocárdio/mortalidade , Prognóstico , Recidiva , Fatores de Risco
18.
Nat Rev Cardiol ; 6(7): 455-63, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19488077

RESUMO

Low levels of HDL cholesterol are a significant predictor of atherosclerotic cardiovascular events. HDL is believed to protect against atherosclerosis by promoting reverse cholesterol transport, and potentially through anti-inflammatory, antioxidative, antithrombotic and nitric oxide effects. The multiple mechanisms of action, as well as a limited ability to measure these properties, make HDL a complex therapeutic target, albeit one with immense potential for the treatment of patients with atherosclerosis. Here, we discuss new therapeutic strategies currently being developed, which have the potential to increase plasma levels of HDL cholesterol and/or improve HDL function.


Assuntos
Aterosclerose/terapia , Doenças Cardiovasculares/prevenção & controle , HDL-Colesterol/sangue , Dislipidemias/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Animais , Aterosclerose/sangue , Aterosclerose/etiologia , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etiologia , Dislipidemias/sangue , Dislipidemias/complicações , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Resultado do Tratamento , Regulação para Cima
19.
Arterioscler Thromb Vasc Biol ; 29(1): 140-6, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18988892

RESUMO

OBJECTIVE: The study of PPAR-alpha activation on apoA-I production in humans has been limited to fibrates, relatively weak PPAR-alpha agonists that may have other molecular effects. We sought to determine the effect of a potent and highly specific PPAR-alpha agonist, LY518674, on apoA-I, apoA-II, and apoB-100 kinetics in humans with metabolic syndrome and low levels of HDL cholesterol (C). METHODS AND RESULTS: Subjects were randomized to receive LY518674 (100 microg) once daily (n=13) or placebo (n=15) for 8 weeks. Subjects underwent a kinetic study using a deuterated leucine tracer to measure apolipoprotein production and fractional catabolic rates (FCR) at baseline and after treatment. LY518674 significantly reduced VLDL-C (-38%, P=0.002) and triglyceride (-23%, P=0.002) levels whereas LDL-C and HDL-C levels were unchanged. LY518674 significantly reduced VLDL apoB-100 (-12%, P=0.01) levels, attributable to an increased VLDL apoB-100 FCR with no change in VLDL apoB-100 production. IDL and LDL apoB-100 kinetics were unchanged. LY518674 significantly increased the apoA-I production rate by 31% (P<0.0001), but this was accompanied by a 33% increase in the apoA-I FCR (P=0.002), resulting in no change in plasma apoA-I. There was a 71% increase in the apoA-II production rate (P<0.0001) accompanied by a 25% increase in the FCR (P<0.0001), resulting in a significant increase in plasma apoA-II. CONCLUSIONS: Activation of PPAR-alpha with LY518674 (100 microg) in subjects with metabolic syndrome and low HDL-C increased the VLDL apoB-100 FCR consistent with enhanced lipolysis of plasma triglyceride. Significant increases in the apoA-I and apoA-II production rates were accompanied by increased FCRs resulting in no change in HDL-C levels. These data indicate a major effect of LY518674 on the production and clearance of apoA-I and HDL despite no change in the plasma concentration. The effect of these changes on reverse cholesterol transport remains to be determined.


Assuntos
Apolipoproteína A-I/sangue , Síndrome Metabólica/sangue , PPAR alfa/agonistas , Propionatos/farmacologia , Triazóis/farmacologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Apolipoproteína A-I/genética , HDL-Colesterol/sangue , VLDL-Colesterol/sangue , Deutério , Método Duplo-Cego , Feminino , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Placebos , Triglicerídeos/sangue , Adulto Jovem
20.
J Lipid Res ; 49(6): 1344-52, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18323573

RESUMO

Patients with coronary heart disease or equivalent risk received a single dose of 30, 100, 300, or 500 mg of unformulated D-4F (n = 8, each dose) or placebo (n = 8) under fasting conditions. An additional 10 patients received 500 mg (n = 8) or placebo (n = 2) with a low-fat meal. There were no significant trends in any safety parameter. D-4F was detectable in plasma at all doses with a T(max) of 30 min, 1 h, and 2 h for 30, 100, and > or = 300 mg, respectively. The area under the curve((0-t)) was 27.81 ng/hr/ml and 54.71 ng/hr/ml for the 300 mg and 500 mg dose groups, respectively, and 17.96 ng/hr/ml for the 500 mg dose given with food. HDL from each time point for each subject was tested for its ability to inhibit LDL-induced monocyte chemotactic activity in cultures of human aortic endothelial cells. The values obtained were normalized to 1.0 for LDL alone to obtain the HDL inflammatory index. This index significantly improved at 4 h at the 300 mg dose and at 2 h at the 500 mg dose compared with placebo (P < 0.05). There were no changes in plasma lipid or lipoprotein levels. We conclude that unformulated D-4F has low bioavailability that is improved under fasting conditions, and that a single dose of D-4F is safe and well tolerated and may improve the HDL anti-inflammatory index.


Assuntos
Apolipoproteína A-I/administração & dosagem , Doenças Cardiovasculares/metabolismo , Mimetismo Molecular , Peptídeos/administração & dosagem , Administração Oral , Adulto , Idoso , Sequência de Aminoácidos , Apolipoproteína A-I/efeitos adversos , Apolipoproteína A-I/química , Apolipoproteína A-I/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Peptídeos/efeitos adversos , Peptídeos/química , Peptídeos/farmacocinética
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