RESUMO
BACKGROUND: Dyslipidemia is the primary risk factor for cardiovascular disease, and statins have been effective in controlling lipid levels. Sex differences in the pharmacokinetics and pharmacodynamics of statins contribute to interindividual variations in drug efficacy and toxicity. OBJECTIVE: To evaluate the presence of sexual dimorphism in the efficacy and safety of simvastatin/atorvastatin treatment. METHODS: Lipid levels of 495 patients (331 women and 164 men) were measured at baseline and after 6 ± 3 months of simvastatin/atorvastatin treatment to assess the efficacy and safety profiles of both drugs. RESULTS: Women had higher baseline levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) compared with men (p < 0.0001). After treatment, women exhibited a greater decrease in plasma TC and LDL-C levels compared with men. After adjustment for covariates, baseline levels of TC and LDL-C influenced more than 30% of the efficacy of lipid-lowering therapy (p < 0.001), regardless of sex. Myalgia [with or without changes in creatine phosphokinase (CPK) levels] occurred more frequently in women (25.9%; p = 0.002), whereas an increase in CPK and/or abnormal liver function was more frequent in in men (17.9%; p = 0.017). CONCLUSIONS: Our results show that baseline TC and LDL-C levels are the main predictors of simvastatin/atorvastatin therapy efficacy, regardless of sex. In addition, they suggest the presence of sexual dimorphism in the safety of simvastatin/atorvastatin. The effect of sex differences on receptors, transporter proteins, and gene expression pathways needs to be better evaluated and characterized to confirm these observations.
Assuntos
Anticolesterolemiantes/farmacologia , Ácidos Heptanoicos/farmacologia , Hipercolesterolemia/tratamento farmacológico , Hipolipemiantes/farmacologia , Pirróis/farmacologia , Fatores Sexuais , Sinvastatina/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticolesterolemiantes/efeitos adversos , Atorvastatina , Brasil , Colesterol/sangue , Creatina Quinase/efeitos dos fármacos , Feminino , Ácidos Heptanoicos/efeitos adversos , Humanos , Hipercolesterolemia/sangue , Hipolipemiantes/efeitos adversos , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Masculino , Pessoa de Meia-Idade , Mialgia/etiologia , Estudos Prospectivos , Pirróis/efeitos adversos , Sinvastatina/efeitos adversosRESUMO
Background: Dyslipidemia is the primary risk factor for cardiovascular disease, and statins have been effective in controlling lipid levels. Sex differences in the pharmacokinetics and pharmacodynamics of statins contribute to interindividual variations in drug efficacy and toxicity. Objective: To evaluate the presence of sexual dimorphism in the efficacy and safety of simvastatin/atorvastatin treatment. Methods: Lipid levels of 495 patients (331 women and 164 men) were measured at baseline and after 6 ± 3 months of simvastatin/atorvastatin treatment to assess the efficacy and safety profiles of both drugs. Results: Women had higher baseline levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) compared with men (p < 0.0001). After treatment, women exhibited a greater decrease in plasma TC and LDL-C levels compared with men. After adjustment for covariates, baseline levels of TC and LDL-C influenced more than 30% of the efficacy of lipid-lowering therapy (p < 0.001), regardless of sex. Myalgia [with or without changes in creatine phosphokinase (CPK) levels] occurred more frequently in women (25.9%; p = 0.002), whereas an increase in CPK and/or abnormal liver function was more frequent in in men (17.9%; p = 0.017). Conclusions: Our results show that baseline TC and LDL-C levels are the main predictors of simvastatin/atorvastatin therapy efficacy, regardless of sex. In addition, they suggest the presence of sexual dimorphism in the safety of simvastatin/atorvastatin. The effect of sex differences on receptors, transporter proteins, and gene expression pathways needs to be better evaluated and characterized to confirm these observations. .
Fundamento: A dislipidemia é o principal fator de risco para doenças cardiovasculares e as estatinas são efetivas no controle do perfil lipídico. Diferenças sexuais na farmacocinética e farmacodinâmica contribuem para a variação interindividual na eficácia e toxicidade de fármacos. Objetivo: Avaliar a existência de dimorfismo sexual na eficácia e segurança do tratamento com sinvastatina/atorvastatina. Métodos: 495 sujeitos (331 mulheres e 164 homens) tiveram seus níveis lipídicos mensurados antes e após 6±3 meses de tratamento com sinvastatina/atorvastatina para avaliação dos perfis de eficácia e segurança. Resultados: As mulheres apresentaram maiores níveis basais de colesterol total, LDL-C e HDL-C quando comparadas aos homens (p < 0,0001). Após o tratamento, mulheres tiveram uma maior redução dos níveis de colesterol total e de LDL-C que homens. Após ajuste para covariáveis, foi observado que os níveis basais de colesterol total e de LDL-C são responsáveis por cerca de 30% da eficácia (p < 0,001), independentemente do sexo. Mialgia (com ou sem alteração de creatina fosfoquinase - CPK) ocorreu mais frequentemente em mulheres (25,9%) (p = 0,002), enquanto o aumento isolado de CPK e alterações de função hepática foram mais frequentemente observados em homens (17,9%) (p = 0,017). Conclusões: Nossos resultados demonstram que os níveis basais de colesterol total e LDL-C são os maiores preditores da eficácia do tratamento, independente do sexo. Adicionalmente, sugerimos que existe dimorfismo sexual na segurança do tratamento com sinvastatina/atorvastatina. O efeito das diferenças sexuais em receptores, proteínas transportadoras e rotas de expressão gênica devem ser avaliados ...
Assuntos
Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Anticolesterolemiantes/farmacologia , Ácidos Heptanoicos/farmacologia , Hipercolesterolemia/tratamento farmacológico , Hipolipemiantes/farmacologia , Pirróis/farmacologia , Fatores Sexuais , Sinvastatina/farmacologia , Anticolesterolemiantes/efeitos adversos , Brasil , Colesterol/sangue , Creatina Quinase/efeitos dos fármacos , Ácidos Heptanoicos/efeitos adversos , Hipercolesterolemia/sangue , Hipolipemiantes/efeitos adversos , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Mialgia/etiologia , Estudos Prospectivos , Pirróis/efeitos adversos , Sinvastatina/efeitos adversosRESUMO
OBJECTIVE: The aim of the present study was investigate the association between six genetic variants in the nuclear receptor genes PPARA, RXRA, NR1I2 and NR1I3 and the lipid-lowering efficacy and safety of statin therapy. SUBJECTS AND METHODS: The study was carried out on 240 Brazilian hypercholesterolemic patients on simvastatin and atorvastatin therapy. The polymorphisms were analyzed by PCR-based methods. RESULTS: The NR1I3 rs2307424 genotype distribution was different between subjects with and without adverse drug reactions. Among subjects in the ADR group, no T/T homozygotes were observed for this polymorphism, while in the non-ADR group the frequency of this genotype was 19.4% (P = 0.007, after multiple testing corrections P = 0.042). CONCLUSION: The polymorphisms investigated in PPARA (rs1800206), RXRA (rs11381416), and NR1I2 (rs1523130) did not influence the lipid-lowering efficacy and safety of statin. Our results show the possible influence of NR1I3 genetic variant on the safety of statin.
Assuntos
Anticolesterolemiantes/uso terapêutico , Dislipidemias/tratamento farmacológico , PPAR alfa/genética , Polimorfismo Genético , Receptores Citoplasmáticos e Nucleares/genética , Receptores de Esteroides/genética , Receptor X Retinoide alfa/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Anticolesterolemiantes/efeitos adversos , Atorvastatina , Receptor Constitutivo de Androstano , Dislipidemias/genética , Feminino , Genótipo , Ácidos Heptanoicos/efeitos adversos , Ácidos Heptanoicos/uso terapêutico , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Receptor de Pregnano X , Pirróis/efeitos adversos , Pirróis/uso terapêutico , Fatores de Risco , Sinvastatina/efeitos adversos , Sinvastatina/uso terapêutico , Resultado do TratamentoRESUMO
OBJECTIVE: The aim of the present study was investigate the association between six genetic variants in the nuclear receptor genes PPARA, RXRA, NR1I2 and NR1I3 and the lipid-lowering efficacy and safety of statin therapy. SUBJECTS AND METHODS: The study was carried out on 240 Brazilian hypercholesterolemic patients on simvastatin and atorvastatin therapy. The polymorphisms were analyzed by PCR-based methods. RESULTS: The NR1I3 rs2307424 genotype distribution was different between subjects with and without adverse drug reactions. Among subjects in the ADR group, no T/T homozygotes were observed for this polymorphism, while in the non-ADR group the frequency of this genotype was 19.4% (P = 0.007, after multiple testing corrections P = 0.042). CONCLUSION: The polymorphisms investigated in PPARA (rs1800206), RXRA (rs11381416), and NR1I2 (rs1523130) did not influence the lipid-lowering efficacy and safety of statin. Our results show the possible influence of NR1I3 genetic variant on the safety of statin.
OBJETIVO: O objetivo deste estudo foi investigar a associação de seis variantes genéticas nos genes de receptores nucleares PPARA, RXRA, NR1I2 e NR1I3 na eficácia hipolipemiante e na segurança da terapia com estatinas. SUJEITOS E MÉTODOS: O estudo foi realizado com 240 pacientes hipercolesterolêmicos em terapia com sinvastina e atorvastatina. Os polimorfismos foram analisados por meio de métodos baseados em PCR. RESULTADOS: A distribuição da frequência genotípica do polimorfismo NR1I3 rs2307424 foi diferente entre os pacientes com e sem efeito adverso à medicação; entre os sujeitos do grupo com efeitos adversos, nenhum homozigoto T/T foi observado, enquanto no grupo de indivíduos sem efeitos adversos a frequência desse genótipo foi 19,4% (P = 0,007, após correção para múltiplos testes P = 0,042). CONCLUSÃO: Os polimorfismos investigados nos genes PPARA (rs1800206), RXRA (rs11381416) e NR1I2 (rs1523130) não foram associados com eficácia hipolipemiante e segurança da terapia com estatinas. Nossos resultados mostram uma possível influência de variantes do gene NR1I3 (rs2307424) no desenvolvimento de efeitos adversos à terapia com estatinas.
Assuntos
Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Anticolesterolemiantes/uso terapêutico , Dislipidemias/tratamento farmacológico , Polimorfismo Genético , PPAR alfa/genética , Receptores Citoplasmáticos e Nucleares/genética , Receptores de Esteroides/genética , Receptor X Retinoide alfa/genética , Alelos , Anticolesterolemiantes/efeitos adversos , Dislipidemias/genética , Genótipo , Ácidos Heptanoicos/efeitos adversos , Ácidos Heptanoicos/uso terapêutico , Lipídeos/sangue , Reação em Cadeia da Polimerase , Pirróis/efeitos adversos , Pirróis/uso terapêutico , Fatores de Risco , Sinvastatina/efeitos adversos , Sinvastatina/uso terapêutico , Resultado do TratamentoRESUMO
The aim of this study was to evaluate the effects of atorvastatin on left atrial (LA) function in paroxysmal atrial fibrillation patients. Fifty-eight paroxysmal atrial fibrillation patients were divided into two groups (treatment and control groups). The echocardiography parameters, including LA active emptying volume (LAAEV), LA active emptying fraction, LA maximum volume, LA total emptying volume, LA total emptying fraction, and LA ejection force (LAEF), were measured before treatment, and then 12 and 18 months after treatment. Compared to pre-treatment levels, the parameters reflecting LA pump function, such as LAAEV and LAEF, decreased significantly in treatment groups 12 months after treatment (P < 0.05). LAAEV and LAEF significantly increased 18 months after treatment (P < 0.05), and the indicators reflecting LA reservoir function, such as maximum volume, total emptying volume, and total emptying fraction increased significantly 18 months after treatment (P < 0.05). Compared with pre-treatment levels, LAAEV and LAEF decreased significantly 18 months after treatment in the control group (P < 0.05). These results demonstrated that long-term atorvastatin treatment could ameliorate the function of the atrium sinistrum.
Assuntos
Fibrilação Atrial/fisiopatologia , Função do Átrio Esquerdo/efeitos dos fármacos , Ácidos Heptanoicos/efeitos adversos , Pirróis/efeitos adversos , Adulto , Atorvastatina , Fibrilação Atrial/tratamento farmacológico , Ecocardiografia/efeitos dos fármacos , Feminino , Átrios do Coração/fisiopatologia , Ácidos Heptanoicos/administração & dosagem , Humanos , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Pirróis/administração & dosagemRESUMO
Statins are inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting step in cholesterol biosynthesis. Statins effectively prevent and reduce the risk of coronary artery disease through lowering serum cholesterol, and also exert anti-thrombotic, anti-inflammatory and antioxidant effects independently of changes in cholesterol levels. On the other hand, clinical and experimental evidence suggests that abrupt cessation of statin treatment (i.e. statin withdrawal) is associated with a deleterious rebound phenomenon. In fact, statin withdrawal increases the risk of thrombotic vascular events, causes impairment of endothelium-dependent relaxation and facilitates experimental seizures. However, evidence for statin withdrawal-induced detrimental effects to the brain parenchyma is still lacking. In the present study adult male Wistar rats were treated with atorvastatin for seven days (10mg/kg/day) and neurochemical assays were performed in the cerebral cortex 30 min (atorvastatin treatment) or 24h (atorvastatin withdrawal) after the last atorvastatin administration. We found that atorvastatin withdrawal decreased levels of nitric oxide and mitochondrial superoxide dismutase activity, whereas increased NADPH oxidase activity and immunoreactivity for the protein nitration marker 3-nitrotyrosine in the cerebral cortex. Catalase, glutathione-S-transferase and xanthine oxidase activities were not altered by atorvastatin treatment or withdrawal, as well as protein carbonyl and 4-hydroxy-2-nonenal immunoreactivity. Immunoprecipitation of mitochondrial SOD followed by analysis of 3-nitrotyrosine revealed increased levels of nitrated mitochondrial SOD, suggesting the mechanism underlying the atorvastatin withdrawal-induced decrease in enzyme activity. Altogether, our results indicate the atorvastatin withdrawal elicits oxidative/nitrosative damage in the rat cerebral cortex, and that changes in NADPH oxidase activity and mitochondrial superoxide dismutase activities may underlie such harmful effects.
Assuntos
Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Ácidos Heptanoicos/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Pirróis/efeitos adversos , Síndrome de Abstinência a Substâncias/etiologia , Síndrome de Abstinência a Substâncias/metabolismo , Animais , Atorvastatina , Córtex Cerebral/enzimologia , Ácidos Heptanoicos/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Masculino , Óxido Nítrico/metabolismo , Oxirredução , Pirróis/administração & dosagem , Ratos , Ratos Wistar , Síndrome de Abstinência a Substâncias/enzimologia , Superóxido Dismutase/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismoRESUMO
In this study, simvastatin, atorvastatin, ezetimibe, and ezetimibe + simvastatin combination were administered to arthritic rats, first to determine their effects on the inflammatory response, employing a low-dose adjuvant-induced arthritis model in rats. Arthritis was induced by the subcutaneous injection of a suspension of Mycobacterium tuberculosis (100 µg) in mineral oil [complete Freund's adjuvant used (CFA)] into the plantar surface of the hind paws. Simvastatin(40 mg/kg), atorvastatin(10 mg/kg), ezetimibe(10 mg/kg), ezetimibe(10 mg/kg) + simvastatin(20 mg/kg or 40 mg/kg) were given intragastrically and the treatment began on the day of CFA injection and continued daily up to the 28th day after arthritis induction. The ezetimibe + simvastatin combination was more effective in reducing the inflammatory response in arthritic rats than in atorvastatin, simvastatin, or ezetimibe monotherapy. The observed effect seems to be cholesterol-independent as there were no changes in plasma cholesterol levels. In spite of the benefits on joint lesions, treatment with ezetimibe + simvastatin combination caused a marked increment in liver, kidneys, spleen size, and plasma transaminases activities. Therefore, animals treated with the ezetimibe(10 mg/kg) + simvastatin(40 mg/kg) combination were also submitted to liver perfusion experiments. In this regard, ezetimibe + simvastatin did not improve the liver metabolic alterations seen in control arthritic rats, on the contrary, a worsening was observed in liver production of glucose from alanine, as well as in oxygen uptake. All of these metabolic changes appear to be induced by treatment with ezetimibe + simvastatin combination, as the same metabolic effects were observed in normal and treated arthritic animals.
Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Azetidinas/uso terapêutico , Ácidos Heptanoicos/uso terapêutico , Fígado/metabolismo , Pirróis/uso terapêutico , Sinvastatina/uso terapêutico , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Artrite Experimental/sangue , Artrite Experimental/metabolismo , Atorvastatina , Azetidinas/administração & dosagem , Quimioterapia Combinada , Ezetimiba , Ácidos Heptanoicos/administração & dosagem , Ácidos Heptanoicos/efeitos adversos , Contagem de Leucócitos , Leucócitos/citologia , Leucócitos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Testes de Função Hepática , Perfusão , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Ratos , Ratos Sprague-Dawley , Sinvastatina/administração & dosagem , Sinvastatina/efeitos adversosRESUMO
Menopause is associated with changes in lipid levels resulting in increased risk of atherosclerosis and cardiovascular events. Hormone therapy (HT) and atorvastatin have been used to improve lipid profile in postmenopausal women. Effects of HT, atorvastatin and APOE polymorphisms on serum lipids and APOE and LXRA expression were evaluated in 87 hypercholesterolemic postmenopausal women, randomly selected for treatment with atorvastatin (AT, n=17), estrogen or estrogen plus progestagen (HT, n=34) and estrogen or estrogen plus progestagen associated with atorvastatin (HT+AT, n=36). RNA was extracted from peripheral blood mononuclear cells (PBMC) and mRNA expression was measured by TaqMan(®) PCR. APOE É2/É3/É4 genotyping was performed using PCR-RFLP. Total cholesterol (TC), LDL-c and apoB were reduced after each treatment (p<0.001). Triglycerides, VLDL-c and apoAI were reduced only after atorvastatin (p<0.05), whereas triglycerides and VLDL-c were increased after HT (p=0.01). HT women had lower reduction on TC, LDL-c and apoB than AT and HT+AT groups (p<0.05). APOE mRNA expression was reduced after atorvastatin treatment (p=0.03). Although LXRA gene expression was not modified by atorvastatin, it was correlated with APOE mRNA before and after treatments. Basal APOE mRNA expression was not influenced by gene polymorphisms, however the reduction on APOE expression was more pronounced in É3É3 than in É3É4 carriers. Atorvastatin down-regulates APOE mRNA expression and it is modified by APOE genotypes in PBMC from postmenopausal women.