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1.
Expert Opin Drug Metab Toxicol ; 15(11): 897-911, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31648563

RESUMO

Introduction: Statins are prescribed widely for cholesterol-lowering therapy, but it is known that their efficacy and safety profiles vary, despite the shared pharmacophore and pharmacological target. The immense body of related clinical and preclinical data offers a unique opportunity to explore the possible factors underlying inter-statin and inter-individual variabilities.Area covered: Clinical and preclinical data from various statins were compiled with regard to the efficacy (cholesterol-lowering effect) and safety (muscle toxicity). Based on the compiled data, dose- and exposure-response relationships were explored to obtain mechanistic and quantitative insights into the variations in the efficacy and safety profiles of statins.Expert opinion: Our analyses indicated that the inter-statin variability in the cholesterol-lowering effect may be mainly attributable to variations in potency of inhibition of the pharmacological target, rather than variations in drug exposure at the site of drug action. However, the drug exposure at the sites of drug action (i.e., the liver for efficacy and the muscle for safety) may contribute to the differences in the efficacy and safety observed in individual patients.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hipercolesterolemia/tratamento farmacológico , Doenças Musculares/induzido quimicamente , Animais , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/efeitos adversos , Relação Dose-Resposta a Droga , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Doenças Musculares/epidemiologia
2.
Medicine (Baltimore) ; 98(43): e17664, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31651893

RESUMO

RATIONALE: Atherosclerotic cardiovascular disease (ASCVD), including coronary heart disease (CHD), atherosclerotic stroke and peripheral vascular disease, has become the most deadly chronic noncommunicable disease throughout the world in recent decades, while plaque regression could reduce the occurrence of ASCVD. Traditional Chinese Medicine (TCM) has been widely used for prevention and treatment of these diseases. In the perspective of TCM, phlegm and blood stasis are considered to be leading pathogenesis for CHD. Hence, activating blood circulation and dissipating phlegm, which is of great benefit to regress plaque, have been regarded as general principles in treatment. PATIENT CONCERNS: A 36-year-old man presented with a 3-month history of intermittent exertional chest pain. Coronary angiography revealed 60% stenosis of the proximal left anterior descending coronary artery. Liver function showed: alanine transaminase (ALT):627U/L, aspartate transaminase (AST):243U/L. DIAGNOSES: CHD and hepatitis B with severe liver dysfunction. INTERVENTIONS: The patient should have been treated with high-intensity statin therapy. Actually, due to severe liver dysfunction, Huazhirougan granule instead of statins was administered. In addition, he was treated with TCM according to syndrome differentiation for two and a half years. OUTCOMES: The chest pain disappeared and other symptoms alleviated as well after treatment. Coronary computed tomographic angiography revealed no stenosis in the proximal left anterior descending coronary artery. ALT and AST level returned to normal (ALT:45U/L,AST:24U/L). LESSONS: For patients with CHD and severe hepatic dysfunction, antilipidemic drugs such as statins are not recommended. This case suggested that TCM might fill a gap in lipid-lowering therapy. Thus, we could see that statins were not the only drug for plaque regression and the effect of TCM in treating coronary artery disease cannot be ignored.


Assuntos
Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/tratamento farmacológico , Hepatite B/diagnóstico , Hepatite B/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Medicina Tradicional Chinesa , Adulto , Diagnóstico Diferencial , Humanos , Testes de Função Hepática , Masculino
6.
Expert Opin Drug Saf ; 18(12): 1191-1201, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31623472

RESUMO

Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are novel drugs that have been developed since the discovery of the PCSK9 protein in 2003. In addition to background statin treatment, they reduce low-density lipoprotein cholesterol (LDL-C) to unprecedented levels and have shown encouraging results in improving cardiovascular events. Concerns regarding the safety of PCSK9 inhibitors and very low LDL-C have somewhat been allayed after several longer-term prospective studies.Areas covered: A comprehensive literature search was carried out including article searches in electronic databases (EMBASE, PUBMED, OVID) and reference lists of relevant articles. This review examines novel research concerning PCSK9 monoclonal antibodies and cardiovascular outcomes with a special focus on their safety and tolerability. The safety of very low LDL-C concentrations and the link between LDL-C lowering and diabetes is also discussed.Expert opinion: PCSK9 monoclonal antibodies when added to background statin therapy, lowers LDL-C to previously unattainable levels. This is safe with little undesirable effects and impacts positively on cardiovascular disease. Current guidance limits their use to primary prevention. Cost effectiveness should be taken into consideration before allowing a wider use of this new class of cholesterol lowering therapy and more data on their long-term safety is welcome.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticolesterolemiantes/administração & dosagem , Pró-Proteína Convertase 9/antagonistas & inibidores , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/farmacologia , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/sangue , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Prevenção Primária , Pró-Proteína Convertase 9/imunologia
7.
Endocrinol. diabetes nutr. (Ed. impr.) ; 66(8): 512-519, oct. 2019. tab, graf
Artigo em Inglês | IBECS | ID: ibc-184145

RESUMO

Introduction: The use of statins in non-selected type 1 diabetes (T1D) populations is low. We assessed the prevalence and factors associated with statin treatment in patients meeting criteria for this therapy for primary prevention of cardiovascular disease (CVD). Material and Methods: From 2015 to 2018, T1D patients from a tertiary hospital were selected. Inclusion criteria were: ≥40 years-old, diabetic nephropathy, or T1D duration ≥10 years with ≥1 cardiovascular risk factor (CVRF). A standardized cardiovascular risk evaluation protocol was performed. Prevalence of statin treatment was evaluated according to presence of several CVRFs, and multivariable models were constructed to assess independent determinants of statin use. Results: We included 241 patients (50% women, age 48.2 ± 9.9 years, T1D duration 26.6 ± 9.0 years). Diabetic retinopathy and nephropathy, active smoking, and hypertension were present in 38%, 12%, 28%, and 27%, respectively. Overall, 43% of patients were on statins and 27% had LDL-cholesterol < 100 mg/dl. Statin users were older, and had higher body mass index (BMI), prevalence of kidney dysfunction, and hypertension (p < 0.05 for all). However, among both T1D-related and classical CVRFs, only hypertension (odds ratio [OR], 2.96; 95% confidence interval [CI] 1.48-5.91) and BMI (OR, 1.08; CI, 1.01-1.16) were independently associated with statin use in multiple regression analysis. Conclusions: Less than half of T1D patients from a tertiary hospital who met criteria for statin use were on treatment. Hypertension and BMI emerged as the only CVRFs independently associated with statin therapy. New strategies are needed to better address CVD prevention in this very high-risk population


Introducción: El uso de estatinas en población con diabetes tipo 1 (DT1) general es bajo. Estudiamos la prevalencia y factores asociados con su uso en pacientes que cumplían los criterios para esta terapia para la prevención primaria de la enfermedad cardiovascular (ECV). Material y métodos: Del 2015-2018 seleccionamos a pacientes con DT1 de un hospital terciario. Los criterios de inclusión fueron: ≥ 40 años, nefropatía diabética, o duración de DT1≥10 años con ≥ 1 factor de riesgo cardiovascular (FRCV). Se realizó un protocolo estandarizado de evaluación del riesgo cardiovascular. Finalmente, estudiamos el uso de estatinas en función de diferentes FRCV y los factores independientemente asociados con su uso (modelos multivariantes). Resultados: Incluimos 241 pacientes (50% mujeres, edad 48,2 ± 9,9 años, duración de diabetes 26,6 ± 9 años). La presencia de retinopatía, nefropatía, tabaquismo e hipertensión fue del 38, 12, 28 y 27%, respectivamente. Un 43% tomaba estatinas y un 27% presentó un colesterol-LDL<100 mg/dL. Los usuarios de estatinas tenían mayor edad, índice de masa corporal (IMC), deterioro de la función renal e hipertensión (p < 0,05). Entre todos los FRCV clásicos y específicos de la DT1, únicamente la hipertensión (odds ratio [OR], 2,96; intervalo de confianza al 95% [IC], 1,48-5,91) y el IMC (OR, 1,08; IC, 1,01-1,16) fueron los que se asociaron independientemente con su uso. Conclusiones: Menos de la mitad de pacientes con DT1 que cumplen criterios para estatinas de un hospital terciario están en tratamiento. Únicamente la hipertensión y el IMC se asociaron independientemente con su uso. Nuevas estrategias son necesarias para la prevención cardiovascular en esta población de alto riesgo


Assuntos
Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Adulto , Diabetes Mellitus Tipo 1/epidemiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Fatores de Risco , Análise Multivariada , Retinopatia Diabética/complicações , Razão de Chances , Inibidores de Hidroximetilglutaril-CoA Redutases/metabolismo
8.
J Clin Neurosci ; 69: 1-6, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31521472

RESUMO

Thrombolysis-induced haemorrhagic transformation is the most challenging preventable complication in thrombolytic therapy. This condition is often associated with poor functional outcome and long-term disease burden. Statins, or 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, are controversially suggested to either increase or decrease the odds of better primary outcomes compared to treatment without statins after thrombolysis in patients or animals; statins are thought to act by influencing lipid levels, the inflammatory response, blood brain barrier permeability and cell apoptosis. Statins are the cornerstone of secondary prevention of cardiovascular and cerebrovascular diseases. However, the role of statins in acute phase stroke, and the necessity of their use, remains unclear. Currently, whether statins can increase the risk of haemorrhagic transformation is of great concern for patients treated with tissue plasminogen activator (t-PA). Herein, we thoroughly summarize the recent advances that address whether the administration of statins in ischaemic stroke increases haemorrhagic transformation in patients or animals who received thrombolysis at an early stage and the related mechanisms. This review will provide more clinical and preclinical evidence to address questions regarding the exercise of caution in the use of high dose statins in patients who received thrombolysis and if low dose statins may be beneficial in decreasing thrombolysis-induced haemorrhagic transformation.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hemorragias Intracranianas/etiologia , Acidente Vascular Cerebral/etiologia , Terapia Trombolítica/efeitos adversos , Animais , Relação Dose-Resposta a Droga , Acidente Vascular Cerebral/patologia , Terapia Trombolítica/métodos , Ativador de Plasminogênio Tecidual/efeitos adversos
9.
N Engl J Med ; 381(12): 1114-1123, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31532959

RESUMO

BACKGROUND: Persons with low socioeconomic status and nonwhite persons in the United States have high rates of cardiovascular disease. The use of combination pills (also called "polypills") containing low doses of medications with proven benefits for the prevention of cardiovascular disease may be beneficial in such persons. However, few data are available regarding the use of polypill therapy in underserved communities in the United States, in which adherence to guideline-based care is generally low. METHODS: We conducted a randomized, controlled trial involving adults without cardiovascular disease. Participants were assigned to the polypill group or the usual-care group at a federally qualified community health center in Alabama. Components of the polypill were atorvastatin (at a dose of 10 mg), amlodipine (2.5 mg), losartan (25 mg), and hydrochlorothiazide (12.5 mg). The two primary outcomes were the changes from baseline in systolic blood pressure and low-density lipoprotein (LDL) cholesterol level at 12 months. RESULTS: The trial enrolled 303 adults, of whom 96% were black. Three quarters of the participants had an annual income below $15,000. The mean estimated 10-year cardiovascular risk was 12.7%, the baseline blood pressure was 140/83 mm Hg, and the baseline LDL cholesterol level was 113 mg per deciliter. The monthly cost of the polypill was $26. At 12 months, adherence to the polypill regimen, as assessed on the basis of pill counts, was 86%. The mean systolic blood pressure decreased by 9 mm Hg in the polypill group, as compared with 2 mm Hg in the usual-care group (difference, -7 mm Hg; 95% confidence interval [CI], -12 to -2; P = 0.003). The mean LDL cholesterol level decreased by 15 mg per deciliter in the polypill group, as compared with 4 mg per deciliter in the usual-care group (difference, -11 mg per deciliter; 95% CI, -18 to -5; P<0.001). CONCLUSIONS: A polypill-based strategy led to greater reductions in systolic blood pressure and LDL cholesterol level than were observed with usual care in a socioeconomically vulnerable minority population. (Funded by the American Heart Association Strategically Focused Prevention Research Network and the National Institutes of Health; ClinicalTrials.gov number, NCT02278471.).


Assuntos
Anti-Hipertensivos/administração & dosagem , Combinação de Medicamentos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hipercolesterolemia/tratamento farmacológico , Hipertensão/tratamento farmacológico , Área Carente de Assistência Médica , Adesão à Medicação/estatística & dados numéricos , Adulto , Alabama , Anlodipino/administração & dosagem , Atorvastatina/administração & dosagem , LDL-Colesterol/sangue , Centros Comunitários de Saúde , Feminino , Humanos , Hidroclorotiazida/administração & dosagem , Hipercolesterolemia/sangue , Hipercolesterolemia/complicações , Hipertensão/complicações , Losartan/administração & dosagem , Masculino , Pessoa de Meia-Idade
10.
Expert Rev Clin Pharmacol ; 12(9): 825-830, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31474169

RESUMO

Introduction: 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are widely used for cardiovascular disease (CVD) prevention. Long-term use of statins has been linked to the development of diabetes mellitus (DM) which increases CVD risk. Areas covered: We discussed the reported incidence of DM in statin users, various possible mechanisms responsible for the development of DM and the clinical implications of this association on CVD risk. Relevant supporting literature was identified using MEDLINE/EMBASE search. Expert opinion: Data from available RCTs and observational studies suggest a 10-45% higher risk of new-onset DM with statin use compared to nonusers. Several cellular, molecular, and genetic mechanisms, and lifestyle changes have been studied and discussed as potential underlying mechanisms responsible for this elevated DM risk with statin therapy. The mode of the diabetogenic action of statins is still unclear and an interplay of pancreatic and peripheral effects in the pathogenesis of DM is a possibility. Despite these observations, the CVD preventative benefit of statin treatment outweighs the CVD risk associated with of development of new DM. There is a need for further research to identify the exact mechanisms involved so as to specifically target causative factors and individualize treatment.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus/etiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Diabetes Mellitus/epidemiologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Incidência , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco
11.
Medicine (Baltimore) ; 98(34): e16931, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31441882

RESUMO

Several studies have shown that statin users have a lower risk of new-onset dementia (NOD) compared nonusers. However, other studies have shown opposite results. In this study, we investigated the association between the use of statins and the development of NOD.This was a longitudinal cohort study using data from claim forms submitted to the Taiwanese Bureau of National Health Insurance. The study included patients with NOD and non-NOD subjects from January 2002 to December 2013. We estimated the hazard ratios (HRs) of NOD associated with statin use, whereas nonuser subjects were used as a reference group.A total of 19,522 NOD cases were identified in 100,610 hyperlipidemic patients during the study period. The risk of NOD, after adjusting for sex, age, comorbidities, and concurrent medication, was lower among statin users than nonusers (HR 0.95, 95% CI [confidence interval] 0.94-0.96; P < .001). The adjusted HRs for NOD were 1.53 (95% CI, 1.45-1.62), 0.63 (95% CI, 0.57-0.71), and 0.34 (95% CI, 0.30-0.38) when the cumulative defined daily doses ranged from 28 to 365, 366 to 730, and more than 730 relative to nonusers, respectively.We concluded that statin use is associated with a decreased NOD risk. The protective effect of statins for NOD seemed to be related to high exposure to statins. This study also highlights that high exposure to statins has a dose-response effect on lowering NOD risk.


Assuntos
Cognição/efeitos dos fármacos , Demência/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hiperlipidemias/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Comorbidade , Demência/epidemiologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Estimativa de Kaplan-Meier , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taiwan/epidemiologia
12.
Int J Pharm ; 569: 118605, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31400433

RESUMO

A promising strategy for treatment of EGFR-dependent tumours is EGFR signal transduction suppression via inhibition of HMG-CoA reductase using high doses of statins, popular cholesterol-lowering drugs. The main purpose of this study was to obtain targeted long circulating immunoliposomes containing simvastatin (tLCLS) with anti-EGFR antibody attached to their surface and to test whether they can be effective in treatment of TNBC. The designed tLCLS were characterized in terms of physicochemical properties and long-term stability. In vitro experiments conducted on MDA-MB-231 cells demonstrated that tLCLS induced apoptosis and are characterized by IC50 of 7.5 µM. Treatment of studied cells with tLCLS led to a decrease in membrane order and inhibited PI3K/Akt signalling. Analyses of efficacy of the tLCLS in in vivo experiments in model animals indicate that immunoliposomes were effectively delivered to tumours. Our results showed that regardless of whether tLCLS were administered before or after tumour formation, at the tested dose they inhibited tumour growth by an average of 25% in comparison to the control. However, the results were not statistically significant. The experiments described above allowed us to test the possibility of using immunoliposomes as simvastatin carriers delivering increased amounts of the drug to tumour cells.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Cetuximab/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Neoplasias Mamárias Experimentais/tratamento farmacológico , Sinvastatina/administração & dosagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Receptores ErbB/imunologia , Feminino , Humanos , Lipossomos , Neoplasias Mamárias Experimentais/imunologia , Camundongos SCID , Neoplasias de Mama Triplo Negativas/imunologia
13.
Molecules ; 24(15)2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31344834

RESUMO

In recent years, advances in pharmaceutical processing technologies have resulted in development of medicines that provide therapeutic pharmacokinetic exposure for a period ranging from weeks to months following a single parenteral administration. Benefits for adherence, dose and patient satisfaction have been witnessed across a range of indications from contraception to schizophrenia, with a range of long-acting medicines also in development for infectious diseases such as HIV. Existing drugs that have successfully been formulated as long-acting injectable formulations have long pharmacokinetic half-lives, low target plasma exposures, and low aqueous solubility. Of the statins that are clinically used currently, atorvastatin, rosuvastatin, and pitavastatin may have compatibility with this approach. The case for development of long-acting injectable statins is set out within this manuscript for this important class of life-saving drugs. An overview of some of the potential development and implementation challenges is also presented.


Assuntos
Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Fenômenos Químicos , Preparações de Ação Retardada/farmacocinética , Monitoramento de Medicamentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Concentração Inibidora 50 , Nanopartículas/química , Solubilidade
14.
Drugs Aging ; 36(10): 947-955, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31317420

RESUMO

BACKGROUND: Although compelling evidence exists supporting statins (HMG-CoA reductase inhibitors) for secondary prevention in older patients with clinical atherosclerotic diseases, the same cannot be said for primary prevention. OBJECTIVES: The objectives of this study were to estimate the frequency of potential statin overuse in older patients, the potential drug cost savings if corrected, and the associated factors. METHODS: A retrospective cross-sectional study was conducted in Alsace and Lorraine (France) from 1 January to 30 April 2017. All statin users aged 80 years or over living in the community (including nursing homes) and identified from the French health insurance database were analyzed. Potential statin overuse was defined according to the STOPP/START (Screening Tool of Older People's Prescriptions/Screening Tool to Alert to Right Treatment) criteria. RESULTS: Among the 38,268 aged insured, 23,228 (60.7%) had potential statin overuse. Of those living in the community, 22,132 (60.0%) patients had potential statin overuse: 12,352 (55.8%) for primary and 9780 (44.2%) for secondary prevention. Among nursing home residents, 1096 (79.0%) had potential statin overuse: 394 (35.9%) for primary and 702 (64.1%) for secondary prevention. The potential drug cost savings associated with the adjustment of potential statin overuse were €924,100 for the study period. Living in nursing home [adjusted odds ratio (ORadjusted) 3.91, 95% confidence interval (CI) 2.82-5.41] and being a female (ORadjusted 2.84, 95% CI 2.54-3.17) were the main risk factors associated with potential statin overuse. CONCLUSION: The frequency of potential statin overuse is very high among older people aged 80 years or over, highlighting the need to re-evaluate statin therapy and consider deprescribing, particularly for primary prevention and in nursing homes.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Fatores Etários , Idoso de 80 Anos ou mais , Aterosclerose/tratamento farmacológico , Aterosclerose/epidemiologia , Aterosclerose/prevenção & controle , Estudos Transversais , Bases de Dados Factuais , Desprescrições , Feminino , França/epidemiologia , Humanos , Seguro Saúde/estatística & dados numéricos , Masculino , Prevenção Primária , Estudos Retrospectivos , Prevenção Secundária
15.
Clin Drug Investig ; 39(10): 967-978, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31321631

RESUMO

BACKGROUND: Non-clinical study data suggest that DS-8500a, a G protein-coupled receptor 119 agonist, exhibits antidiabetic activity, inhibition of some transporters and induction of cytochrome P450 (CYP) 3A. Statins are substrates for some transporters and CYP3A that may be coadministered with DS-8500a in clinical practice. OBJECTIVE: To determine the potential effects of DS-8500a on the pharmacokinetics of statins, we evaluated the effects of repeated oral administration of DS-8500a 75 mg on the pharmacokinetics of rosuvastatin and atorvastatin in healthy adults. METHODS: We performed two single-center, open-label, single-sequence studies. In Study I, subjects received single-dose rosuvastatin 10 mg (Period A) and DS-8500a 75 mg once daily + single-dose rosuvastatin 10 mg (Period B). In Study II, subjects received single-dose atorvastatin 10 mg (Period A) and DS-8500a 75 mg once daily + single-dose atorvastatin 10 mg (Period B). Primary pharmacokinetic endpoints were maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of rosuvastatin and atorvastatin. Safety was evaluated. RESULTS: In Study I, the Cmax and AUC of rosuvastatin increased by 66% and 33%, respectively, when coadministered with DS-8500a, versus rosuvastatin alone. In Study II, the Cmax of atorvastatin increased by 28%, but AUC remained unchanged following coadministration with DS-8500a, versus atorvastatin alone. Treatment-emergent adverse events were mild to moderate and mostly unrelated to the study drugs. CONCLUSIONS: Multiple doses of DS-8500a increased exposure to rosuvastatin and atorvastatin. This short-term study suggests that the impact of DS-8500a coadministration on atorvastatin exposure is limited and may not be clinically relevant. Nevertheless, caution may be necessary when patients are coadministered rosuvastatin with DS-8500a. CLINICALTRIALS. GOV IDENTIFIER: NCT03699774. JAPAN PHARMACEUTICAL INFORMATION CENTER IDENTIFIER: JapicCTI-152878.


Assuntos
Atorvastatina/farmacocinética , Benzamidas/farmacocinética , Ciclopropanos/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Hipoglicemiantes/farmacocinética , Oxidiazóis/farmacocinética , Receptores Acoplados a Proteínas-G/agonistas , Rosuvastatina Cálcica/farmacocinética , Adulto , Atorvastatina/administração & dosagem , Benzamidas/administração & dosagem , Estudos Cross-Over , Ciclopropanos/administração & dosagem , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Interações de Medicamentos/fisiologia , Feminino , Voluntários Saudáveis , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hipoglicemiantes/administração & dosagem , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Oxidiazóis/administração & dosagem , Rosuvastatina Cálcica/administração & dosagem
16.
Int J Clin Pharmacol Ther ; 57(10): 489-499, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31272527

RESUMO

BACKGROUND AND OBJECTIVES: Statin/ezetimibe fixed-dose combination is often used as statin monotherapy; however, no study has analyzed its adverse effect (AE) signals. We comparatively analyzed the AE status of statin and statin/ezetimibe fixed-dose combination and compared the signal information using a 12-year AE reporting database. MATERIALS AND METHODS: We used data from the Korea Adverse Events Reporting System database from 2005 to 2016. Drug-AE pairs corresponded to drugs and AEs for analysis of demographic characteristics, causality, number, and type of serious AEs. Metrics, including proportional reporting ratio (PRR), reporting odds ratio (ROR), and information component (IC) were used to detect signals. Signals were compared with drug labels in the USA and Korea. RESULTS: Of the 4,569 AE cases identified, 4,130 and 442 were of statin and statin/ezetimibe fixed-dose combination, respectively. There were no statistically significant differences in AE report characterization for statin and the statin/ezetimibe fixed-dose combination. The number of AE signal detections for statin, statin/ezetimibe fixed-dose combination, and both, based on PRR and ROR, was 16, 4, and 2, respectively, and the number of cases not included on the label was 3, 2, and 0, respectively. The number of AE signals that only met IC indicators was greater in statin/ezetimibe fixed-dose combination (33) than in statin (4), and 12 of the 33 cases in statin/ezetimibe fixed-dose combination were not included on the drug label. CONCLUSION: The combination of statin and ezetimibe exhibited greater AE signal detection than statin alone, and the inclusion of AEs on the drug label was insufficient.


Assuntos
Ezetimiba/administração & dosagem , Ezetimiba/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Anticolesterolemiantes , Bases de Dados Factuais , Quimioterapia Combinada/efeitos adversos , Humanos , República da Coreia
17.
J Pak Med Assoc ; 69(7): 1006-1013, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31308572

RESUMO

OBJECTIVE: To review evidence-based data with respect to safety and efficacy of alternate-day statin therapy in dyslipidaemia compared to the standard daily dose. METHODS: The literature review was conducted at Aga Khan University Hospital, Karachi from July, 2016 to August, 2017. Electronic database search was carried out to compile available literature using PubMed, Excerpta Medica database and Google Scholar. The most relevant evidence-based research articles published over 10 years were selected. The latest search was dated August 03, 2017. RESULTS: A total of 2,074 articles were initially located. Alternate day statin regimen was reported in 53% of articles. Adverse effects on muscle and tendon were reported in 69% of articles. After scrutiny, 19(0.9%) studies covering alternate-day statin-mediated muscle and tendon disorders and 9(0.4%) studies encompassing the potential pathophysiological mechanisms of statin-associated muscle and tendon injury were selected. Except pravastatin and lovastatin, alternate-day statin therapy was almost as effective in lowering total cholesterol, low-density lipoprotein cholesterol and triglycerides as the daily dosing with low incidence of muscle toxicity and tends in opathy. CONCLUSIONS: Alternate-day statin regimen was found to be very well tolerated and might be an effective and safe remedy in clinical practice.


Assuntos
Dislipidemias/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Cãibra Muscular/induzido quimicamente , Mialgia/induzido quimicamente , Tendinopatia/induzido quimicamente , Humanos , Doenças Musculares/induzido quimicamente
18.
J Microencapsul ; 36(4): 317-326, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31159613

RESUMO

Aims: Lipid-core nanocapsules (LNCs) loaded with simvastatin (SV, SV-LNC) or lovastatin (LV, LV-LNC) were formulated for pulmonary administration. Methods: The LNC suspensions were characterized physicochemically, their stability was evaluated, and drug delivery by the pulmonary route was tested in vitro. Results: The loaded LNCs had a particle size close to 200 nm, a low polydispersity index, and a zeta potential around -20 mV. The encapsulation efficiency was high for SV (99.21 ± 0.7%) but low for LV (20.34 ± 1.2%). SV release from nanocapsules was slower than it was from SV in solution, with a monoexponential release profile, and the drug emitted and aerosol output rate was higher for SV-LNCs (1.58 µg/s) than for SV in suspension (0.54 µg/s). Conclusions: SV-LNCs had a median aerodynamic diameter of 3.51 µm and a highly respirable fraction (61.9%), indicating that nanoparticles are a suitable system for efficient delivery of simvastatin to the lung.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Lovastatina/administração & dosagem , Nanocápsulas/química , Sinvastatina/administração & dosagem , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Lipídeos/química , Lovastatina/química , Nebulizadores e Vaporizadores , Tamanho da Partícula , Sinvastatina/química
20.
Anesthesiology ; 131(2): 315-327, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31246609

RESUMO

BACKGROUND: This study aimed to examine the association between preadmission statin use and 90-day mortality in critically ill patients and to investigate whether this association differed according to statin type and dose. We hypothesized that preadmission statin use was associated with lower 90-day mortality. METHODS: This retrospective cohort study analyzed the medical records of all adult patients admitted to the intensive care unit in a single tertiary academic hospital between January 2012 and December 2017. Data including preadmission statin use, statin subtype, and daily dosage were collected, and the associations between these variables and 90-day mortality after intensive care unit admission were examined. The primary endpoint was 90-day mortality. RESULTS: A total of 24,928 patients (7,396 statin users and 17,532 non-statin users) were included. After propensity score matching, 5,354 statin users and 7,758 non-statin users were finally included. The 90-day mortality rate was significantly higher in non-statin users (918 of 7,758; 11.8%) than in statin users (455 of 5,354; 8.5%; P < 0.001). In Cox regression analysis, the 90-day mortality rate was lower among statin users than among non-statin users (hazard ratio: 0.70, 95% CI: 0.63 to 0.79; P < 0.001). Rosuvastatin use was associated with 42% lower 90-day mortality (hazard ratio: 0.58, 95% CI: 0.47 to 0.72; P < 0.001). There were no specific significant differences in the association between daily statin dose and 90-day mortality. In competing risk analysis, the risk of noncardiovascular 90-day mortality in statin users was 32% lower than that in non-statin users (hazard ratio: 0.68, 95% CI: 0.60 to 0.78; P < 0.001). Meanwhile, cardiovascular 90-day mortality was not significantly associated with statin use. CONCLUSIONS: Preadmission statin use was associated with a lower 90-day mortality. This association was more evident in the rosuvastatin group and with noncardiovascular 90-day mortality; no differences were seen according to daily dosage intensity.


Assuntos
Cuidados Críticos/métodos , Mortalidade Hospitalar , Hospitalização , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Idoso , Estudos de Coortes , Estado Terminal , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida
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