Sintomas musculares relacionados ao uso de estatinas / Statin-associated muscle symptoms

Nas últimas duas décadas, comprovou-se que a terapia com estatinas é o instrumento isolado mais potente para atenuar o risco cardiovascular, e seu uso frequente foi enfatizado como um dos elementos mais importantes para reduzir a mortalidade cardiovascular nos países desenvolvidos. Uma incidência igualmente frequente de sintomas musculares em usuários de estatinas levanta a possibilidade de um nexo de causalidade, que leva a uma entidade patológica conhecida como sintomas musculares associados a estatinas (SMAS). Estudos e ensaios clínicos mecanicistas destinados a estudar os SMAS levaram a uma definição clara da sua história natural e incidência exata. Essa informação é essencial para evitar riscos desnecessários de formas graves de SMAS. Ao mesmo tempo, essa compreensão concreta dos SMAS evita o diagnóstico exagerado e a suspensão desnecessária de uma das mais poderosas estratégias de prevenção atuais. Nesse contexto, este artigo de revisão reuniu todas as informações disponíveis sobre o assunto, que são apresentadas em detalhe neste documento como a base da identificação e tratamento dos SMAS

In the last 2 decades, statin therapy has proved to be the most potent isolated instrument for attenuating cardiovascular risk, and its frequent use has been highlighted as one of the most important elements for reducing cardiovascular mortality in developed countries. An equally frequent incidence of muscle symptoms in statin users raises the possibility of a causal link, leading to a disease entity known as statin-associated muscle symptoms (SAMS). Mechanistic studies and clinical trials designed to the study of SAMS have led to a clear definition of its natural history and accurate incidence. This information is vital for avoiding unnecessary risk of severe forms of SAMS. At the same time, this concrete understanding of SAMS prevents over-diagnosis and unnecessary suspension of one of the most powerful prevention strategies available today. In this context, this review has gathered all the available information on the issue, which is presented in detail, in this document, as the basis for the identification and management of SAMS

Randomized clinical trial of lovastatin in HIV-infected, HAART naïve patients (NCT00721305).

BACKGROUND: Evidence suggests that statins may modify the immune response against HIV. The aim was to evaluate the antiretroviral and immunomodulatory effects of lovastatin in HIV-infected patients, naïve for antiretroviral therapy. METHODS: Randomized, double-blinded, placebo-controlled, phase-II clinical trial. Primary outcomes were plasma viral load and circulating CD4+ T cell count, after 6 and 12 months of treatment; secondary outcomes were CD8+ T cell count, expression of activation markers (CD38 and HLA-DR) on T cells, and clinical outcomes. With a power of 90% to detect both a decrease of 0.3 log10 in plasma HIV-1 RNA copies and an increase of 20% in the CD4+ T cell count, we estimated a required sample size of 110 HIV-infected patients (55 per group). The results were analyzed by a model of repeated measurements using Generalized Estimating Equations. RESULTS: Patients were randomized to receive either lovastatin (n = 55) or placebo (n = 57). During the 12-month follow-up, there was no effect of lovastatin either on viral load (estimated average change = 0.157 copies/mL; CI 95% = -0.099 to 0.414), or on the CD4+ T cell count (estimated average change = -26.1 cells/µL; CI 95% = -89.8 to 37.6). Moreover, there were no significant differences in secondary outcomes. CONCLUSIONS: Daily administration of lovastatin (40 mg) for one year in HIV-infected patients, naïve for antiretroviral therapy, had no significant effect on HIV replication, the CD4+ T cell count, or the activation level of T cells. (www.clinicaltrials.gov; ID NCT00721305).

Tratamento hipolipemiante em situações especiais: pós-transplante e/ou terapia imunossupressora / Hypolipidemic treatment under special conditions: posttransplant and/or immunosupressive therapy

Existem dados limitados sobre o uso concomitante de agentes hipolipemiantes e drogas imunosupressoras. As melhores evidências provêm do uso de estatinas e ciclosporina. Em termos farmacodinâmicos, estas duas drogas têm substratos diferentes. No tocante a farmacocinética, as estatinas não modificam as concentrações plasmáticas de ciclosporina. Entretanto, quando combinada a qualquer estatina, um controle rigoroso dos níveis de ciclosporina é recomendado, levando-se em conta o seu estreito intervalo terapêutico. Ciclosporina afeta a área sob a curva de muitas estatinas, pela inibição do CYP450 3A4, aumentando a exposição sistêmica dessas drogas. Pravastatina se apresenta como o composto de maior segurança, uma vez que é glucuronidado. A área sob a curva para as outras estatinas (sinvastatina, lovastatina, atorvastatina, cerivastatina e rosuvastatina) pode aumentar em graus variáveis de acordo com o seu sítio de metabolização, extração hepática pelo OATP-transportador, secreção biliar, excreção renal, e extrusão da droga pelo sistema MDR.

[Hypolipidemic treatment under special conditions: posttransplant and/or immunosuppressive therapy]. / Tratamento hipolipemiante em situações especiais--pós-transplante e/ou terapia imunossupressora.

There are limited data regarding the use of hypolipidemic agents concomitantly with immunosuppressive drugs. Best evidence is provided for the use of statins and cyclosporine. In terms of pharmacodynamics, these two drugs have different substrates. In respect to pharmacokinetics, statins usually do not modify serum concentrations of cyclosporine, however when combined with any statin a careful monitoring of cyclosporine levels is recommended, due to a narrow therapeutic window of the immunosuppressive agent. Conversely, cyclosporine does affect the area under the curve for many statins, by inhibiting the CYP450 3A4, thus increasing systemic exposure to statins. Pravastatin appears to be the safest compound, once it is glucuronized. The area under the curve for the other statins (simvastatin, lovastatin, atorvastatin, cerivastatin, and rosuvastatin) can be increased in variable degrees according to the site of metabolization, liver extraction by OATP-C transporter, biliary secretion, renal excretion, and drug extrusion by the MDR system.

High lovastatin doses combined with hypercholesterolemic diet induce hepatic damage and are lethal to the CD-1 mouse.

The addition of 1% lovastatin (LVT) to hypercholesterolemic diets [1% cholesterol or 1% cholesterol plus 0.1% sodium deoxycholate (HD)] induced hepatic damage and was lethal to CD-1 mice in the first days of treatment; the females were more resistant than males. LVT or HD administered alone was harmless to male or female mice. After a 3-day treatment all groups that received LVT (1%, 0.1% or 0.05%) plus HD showed a higher percentage of liver weight, with respect to whole body weight. Cholesterol serum levels increased in males with HD, but remained low in female mice. In the liver, total lipids and cholesterol levels increased in male mice with HD, but cholesterol remained unchanged in females. The addition of LVT to HD prevented the increase of serum and liver cholesterol levels in male mice. These results allow us to propose the CD-1 male-mouse as a model to evaluate the toxicity of LVT or other vastatins.

Comparative study of the efficacy and tolerability of policosanol and lovastatin in patients with hypercholesterolemia and noninsulin dependent diabetes mellitus.

This randomized, double-blind study was undertaken to compare the efficacy and tolerability of policosanol (10 mg/day) and lovastatin (20 mg/day) in patients with hypercholesterolemia and noninsulin dependent diabetes mellitus. After 6 weeks on a lipid lowering diet, 53 patients were randomized to receive either policosanol or lovastatin tablets that were taken o.i.d. for 12 weeks under double-blind conditions. Both groups were similar at randomization. Policosanol significantly (p < 0.001) lowered low-density lipoprotein (LDL)-cholesterol (20.4%), total cholesterol (14.2%) and the ratio of LDL-cholesterol to high-density lipoprotein (HDL)-cholesterol (23.7%). Lovastatin significantly (p < 0.01) lowered LDL-cholesterol (16.8%), total cholesterol (14.0%) and the ratio (p < 0.05) of LDL-cholesterol to HDL-cholesterol (14.9%). Triglyceride levels did not significantly change after therapy. Policosanol, but not lovastatin, significantly increased (p < 0.01) levels of HDL-cholesterol (7.5%). Comparison between groups showed that changes in HDL-cholesterol induced by policosanol were significantly greater (p < 0.01) than those induced by lovastatin. Both treatments were safe and well tolerated. Lovastatin moderately but significantly (p < 0.05) increased levels of aspartate aminotransferase, creatine phosphokinase and alkaline phosphatase. Adverse reactions were more frequent in the lovastatin group (p < 0.01) than in the policosanol group. In conclusion, policosanol administered at 10 mg/day produces more advantageous changes in HDL-cholesterol and has a better safety and tolerability profile than lovastatin 20 mg/day.

Hipolipemiantes e alterações musculares / Antilipemic drugs and muscular disorders

Distúbios musculares e elevações de creatinofosfoquinase säo os mais comuns entre os efeitos adversos das drgas hipolipemiantes mais frequentemente usadas, vastatinas e fibratos.Mialgia, fadiga, miosite e, em grau mais avançado, rabdomiólise säo as possíveis complicações observadas; entretanto, sua incidência é relativamente baixa, principalmente com os fibratos.Pacientes com funçäo renal diminuída e pós-transplantados têm maior risco de apresentar tais manifestações, cujo desencadeamento pode ser facilitado pela associaçäo com outros fármacos que utilizam via metabólica comum.A associaçäo desses medicamentos é outro fator que favorece os efeitos musculares, embora seu uso possa ser eventualmente substituído por vastatinas mais potentes capazes de diminuir os triglicerídeos.Estudos populacionais de prevençäo, envolvendo grande número de participantes, evidenciam a boa tolerância a esses fármacos.Os autores apresentam ainda dados relativos à funçäo muscular de pacientes tratados com sinvastatina e à tolerância a longo prazo em idosos recebendo o mesmo tratamento.

Significant increase of high-density lipoprotein2-cholesterol under prolonged simvastatin treatment.

In a contribution to a prolonged multicenter study 15 patients with primary hypercholesterolemia were treated with simvastatin, a competitive inhibitor of HMG-CoA reductase. The first part of the study was done in a double-blind fashion comparing the effect of this new drug with that of gemfibrozil during 12 weeks, and after this period on open-label treatment was started with the administration to all the patients of simvastatin in doses ranging from 2.5 to 40 mg q.p.m. Persistent and significant reductions (P less than 0.001) were achieved for total serum cholesterol (TC), LDL-cholesterol (LDL-C), apo B and triglycerides: by 38, 49, 44 and 33%, respectively, after 40 weeks of the open-label extension. From week 12, LDL-C levels were maintained at a cut point less than or equal to 140 mg/dl in every patient throughout the study. At week 40, cholesterol values of HDL subfractions showed a significant increase in HDL2-C (28%, P less than 0.01) and a concomitant reduction in HDL3-C (12%, P less than 0.01) in spite of a nonsignificant elevation of total HDL-C (by 6%). The HDL2-C/HDL3-C ratio rose by 47% (P less than 0.001) and the TC/HDL-C ratio was significantly reduced by 43%: from 6.1 +/- 1.2 to 3.5 +/- 0.7 (mean +/- SD, P less than 0.001). No adverse effects were detected. Our results suggest a conversion of HDL3 into HDL2, which could imply a beneficial effect of simvastatin upon the so-called reverse cholesterol transport, in addition to the striking reduction in atherogenic lipoproteins.