Manejo médico · CHEMM

Traduzido de Statins - Medical Countermeasures Database ↗ (CHEMM, HHS/ASPR — domínio público), fonte capturada em 2026-08-25. Em caso de dúvida, vale o original.

Statins (estatinas) — banco de contramedidas médicas

• Name of Chemical Defense therapeutic agent/deviceno original (inglês)
• Chemical Defense therapeutic areano original (inglês)
• Evidence-based medicine for Chemical Defenseno original (inglês)
• Pharmacokinetic and toxicokinetics datano original (inglês)
• Indication/dosingno original (inglês)
• Formulation/shelf lifeno original (inglês)
• Off-label use & dosingno original (inglês)
• Route of administrating/monitoringno original (inglês)
• Adverse effectsno original (inglês)
• Contraindicationsno original (inglês)
• Clinical studies in progressno original (inglês)
• Non-clinical studies in progressno original (inglês)
• Needed studies for Chemical Defenseno original (inglês)
• Needed studies for non-Chemical Defenseno original (inglês)
• Study-related ethical concernsno original (inglês)
• Global regulatory statusno original (inglês)
• Other potentially useful informationno original (inglês)
• Publicationsno original (inglês)
• Web sitesno original (inglês)

1. Nome do agente terapêutico/dispositivo de defesa química

Statinsdose/fármaco conforme a fonte ↗

2. Área(s) terapêutica(s) de defesa química

As statins podem ser usadas como tratamento anti-inflamatório da lesão pulmonar aguda (ALI) e da síndrome do desconforto respiratório agudo (ARDS) induzidas por agente pulmonar, como o fosgênio.dose/fármaco conforme a fonte ↗

3. Medicina baseada em evidência para defesa química

A. Resumo

Estrutura

US NLM. ChemIDplus Lite. Atorvastatinno original (inglês)

US NLM. ChemIDplus Lite. Fluvastatinno original (inglês)

US NLM. ChemIDplus Lite. Lovastatinno original (inglês)

US NLM. ChemIDplus Lite. Rosuvastatinno original (inglês)

US NLM. ChemIDplus Lite. Simvastatinno original (inglês)

US NLM.ChemIDplus Lite. Pitavastatinno original (inglês)

US NLM. ChemIDplus Lite. Pravastatinno original (inglês)

Mecanismo de ação

• Statins are 3-hydroxy-3-methylglutaryl-co-enzyme A reductase inhibitors of cholesterol biosynthesis, and have been reported to exert pleiotropic effects on cellular signalling and cellular functions involved in inflammation. Recent reports have demonstrated that previous statin therapy reduced the risk of pneumonia or increased survival in patients with community-acquired pneumonia. However, the precise mechanisms responsible for these effects are unclear. In the present study, we examined the effects of statins on cytokine production from lipopolysaccharide (LPS)-stimulated human bronchial epithelial cells (BEAS-2B). Interleukin (IL)-6 and IL-8 mRNA expression and protein secretion in LPS-stimulated cells were inhibited significantly by the lipophilic statin pitavastatin and the hydrophilic statin pravastatin. As these inhibitory effects of statin were negated by adding mevalonate, the anti-inflammatory effects of statins appear to be exerted via the mevalonic cascade. In addition, the activation levels of Ras homologue gene family A (RhoA) in BEAS-2B cells cultured with pitavastatin were significantly lower than those without the statin. These results suggest that statins have anti-inflammatory effects by reducing cytokine production through inhibition of the mevalonic cascade followed by RhoA activation in the lung.dose/fármaco conforme a fonte ↗no original (inglês)

Iwata A, Shirai R, Ishii H, Kushima H, Otani S, Hashinaga K, Umeki K, Kishi K, Tokimatsu I, Hiramatsu K, Kadota J. Inhibitory effect of statins on inflammatory cytokine production from human bronchial epithelial cells. Clin Exp Immunol. 2012 May;168(2):234-40. [PubMed Citation]dose/fármaco conforme a fonte ↗no original (inglês)

• The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have potent anti-inflammatory, vasodilatory and anti-platelet effects that are independent of the lipid-lowering effects. These non-lipid-lowering or pleiotropic effects are dependent on HMG-CoA reductase inhibition in tissues other than the liver. In animal models, high-dose statins upregulate cytosolic phospholipase A(2) and cyclooxygenase-2, leading to increased production of prostacyclin and 15-deoxy-PGJ(2). In addition, statins activate protein kinase A, which phosphorylates 5-lipoxygenase, resulting in decreased production of the pro-inflammatory leukotrienes and increased production of 15-epi-lipoxin A4, an eicosanoid with potent anti-inflammatory and inflammation-resolution properties. It is unclear, however, whether these effects occur in the clinical setting and whether these effects (partially) explain the anti-inflammatory effects of statins in patients.dose/fármaco conforme a fonte ↗no original (inglês)

Birnbaum Y, Ye Y. Pleiotropic effects of statins: the role of eicosanoid production. Curr Atheroscler Rep. 2012 Apr;14(2):135-9. [PubMed Citation]dose/fármaco conforme a fonte ↗no original (inglês)

• Results from large-scale clinical trials of lipid lowering with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have led to a revolution in the management of atherosclerosis. In addition to their potent effect on serum lipid levels, statins influence several other cellular pathways, including those involving inflammatory, oxidative, and thrombotic processes. These effects clearly have the potential to beneficially modify the atherogenic process, and it has been suggested that they contribute to the impressive results seen in the clinical trials. We review the clinical evidence for benefits of statin therapy that are distinct from their effect on lipid biology. In particular, we address three key issues: the role of statins in diseases not traditionally associated with elevated cholesterol levels; whether clinical benefits are seen with statin therapy before an effect on lipid levels; and whether the magnitude of clinical benefit observed with statin therapy is unrelated to the degree of cholesterol reduction. At present, low-density-lipoprotein lowering seems to be the primary mechanism underlying the clinical benefits of statin therapy and should remain the focus of risk-reduction strategies in clinical practice.dose/fármaco conforme a fonte ↗no original (inglês)

Halcox JP, Deanfield JE. Beyond the laboratory: clinical implications for statin pleiotropy. Circulation. 2004 Jun 1;109(21 Suppl 1):II42-8. [PubMed Citation]no original (inglês)

Resumo dos estudos clínicos e não clínicos

Acute lung injury is a life-threatening condition defined by intense pulmonary inflammation and alveolar collapse triggering respiratory failure and multi-organ dysfunction; the more severe form of this is acute respiratory distress syndrome (Ware and Matthay; 2000). Statins have anti-inflammatory properties, for example the ability to directly mediate endothelial cell signaling and induce characteristic actin cytoskeletal rearrangement leading to endothelial cell barrier protection (Jacobson; 2009), making them a good candidate as a supportive therapy in the acute treatment of ALI and ARDS stemming from toxic exposure. Pravastatin and Pitavastatin suppress the production of cytokines thereby reducing inflammation (Iwata et al; 2012). In mice pravastatin inhibited TGF-β1, CTGF, RhoA and cyclin D1 pathways attenuating the bleomycin induced ALI and pulmonary fibrosis (Kim et al; 2010). Simvastatin inhibited the production of IL-6 by human monocytes in a dose-dependent manner (Li and Chen; 2003). A double blind placebo study was done to test the effects of statins on patients with ALI using 80mg simvastatin. Patients with ALI were given 80mg simvastatin or a placebo while on mechanical ventilation for no longer than 14 days. Treatment with simvastatin reduced pulmonary and systemic inflammation and also improved pulmonary function and systemic organ dysfunction. Although 80mg is no longer the prescribed dose for prolonged use in the treatment of hypercholesterolemia, it was well tolerated in the patients participating in the study (Craig et al; 2011).dose/fármaco conforme a fonte ↗no original (inglês)

B. Link para os estudos clínicos

Adulto

• Preclinical studies suggest that HMG-CoA reductase inhibitors (statins) may attenuate organ dysfunction. Investrigators evaluated whether statins are associated with attenuation of lung injury and prevention of associated organ failure in patients with ALI/ARDS. From a database of patients with ALI/ARDS, we determined the presence and timing of statin administration. Main outcome measures were the development and progression of pulmonary and nonpulmonary organ failures as assessed by changes in PaO2/FiO2 ratio and Sequential Organ Failure Assessment score (SOFA) between days 1 and 7 after the onset of ALI/ARDS. Secondary outcomes included ventilator free days, ICU and hospital mortality, and lengths of ICU and hospital stay. From 178 patients with ALI/ARDS, 45 (25%) received statin therapy. From day 1 to day 7, the statin group showed less improvement in their PaO2/FiO2 ratio (27 vs. 55, P = 0.042). Ventilator free days (median 21 vs. 16 days, P = 0.158), development or progression of organ failures (median ΔSOFA 1 vs. 2, P = 0.275), ICU mortality (20% vs. 23%, P = 0.643), and hospital mortality (27 vs. 37%, P = 0.207) were not significantly different in the statin and non-statin groups. After adjustment for baseline characteristics and propensity for statin administration, there were no differences in ICU or hospital lengths of stay. In this retrospective cohort study, statin use was not associated with improved outcome in patients with ALI/ARDS. Investigators were unable to find evidence for protection against pulmonary or nonpulmonary organ dysfunction (Class IV).dose/fármaco conforme a fonte ↗no original (inglês)

Kor DJ, Iscimen R, Yilmaz M, Brown MJ, Brown DR, Gajic O. Statin administration did not influence the progression of lung injury or associated organ failures in a cohort of patients with acute lung injury. Intensive Care Med. 2009 Jun;35(6):1039-46. [PubMed Citation]no original (inglês)

• There is no effective pharmacological treatment for acute lung injury (ALI). Statins are a potential new therapy because they modify many of the underlying processes important in ALI. The objective of this study was to test whether simvastatin improves physiological and biological outcomes in ALI. Researchers conducted a randomized, double-blinded, placebo-controlled trial in patients with ALI. Patients received 80 mg simvastatin or placebo until cessation of mechanical ventilation or up to 14 days. Extravascular lung water was measured using thermodilution. Measures of pulmonary and nonpulmonary organ function were assessed daily. Pulmonary and systemic inflammation was assessed by bronchoalveolar lavage fluid and plasma cytokines. Systemic inflammation was also measured by plasma C-reactive protein. Sixty patients were recruited. Baseline characteristics, including demographics and severity of illness scores, were similar in both groups. At Day 7, there was no difference in extravascular lung water. By Day 14, the simvastatin-treated group had improvements in nonpulmonary organ dysfunction. Oxygenation and respiratory mechanics improved, although these parameters failed to reach statistical significance. Intensive care unit mortality was 30% in both groups. Simvastatin was well tolerated, with no increase in adverse events. Simvastatin decreased bronchoalveolar lavage IL-8 by 2.5-fold (P = 0.04). Plasma C-reactive protein decreased in both groups but failed to achieve significance in the placebo-treated group. Treatment with simvastatin appears to be safe and may be associated with an improvement in organ dysfunction in ALI. These clinical effects may be mediated by a reduction in pulmonary and systemic inflammation (Class III).dose/fármaco conforme a fonte ↗no original (inglês)

Craig TR, Duffy MJ, Shyamsundar M, McDowell C, O'Kane CM, Elborn JS, McAuley DF. A randomized clinical trial of hydroxymethylglutaryl- coenzyme a reductase inhibition for acute lung injury (The HARP Study). Am J Respir Crit Care Med. 2011 Mar 1;183(5):620-6. [PubMed Citation]no original (inglês)

Estudos em gravidez e amamentação

• Cholesterol and other products of the cholesterol biosynthetic pathway are essential for fetal development, including synthesis of steroids and cell membranes. Because of the ability of statins to decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthetic pathway, these agents may cause fetal harm when administered to pregnant women. ... Severe congenital skeletal malformation, tracheoesophageal fistula, and atresia were reported in a neonate whose mother received lovastatin concomitantly with dextroamphetamine sulfate during the first trimester of pregnancy (Class IV).dose/fármaco conforme a fonte ↗no original (inglês)

McEvoy GK, ed. Drug Information 2012. Bethesda, MD: American Society of Health-System Pharmacists, 2012 p.1747-1784no original (inglês)

• Pravastatin is distributed into human milk and pitavastatin is distributed into milk in animals (Class IV).no original (inglês)

McEvoy GK, ed. Drug Information 2012. Bethesda, MD: American Society of Health-System Pharmacists, 2012 p.1747-1784no original (inglês)

C. Link para os estudos não clínicos (por exemplo, em animais)

Modelos em animais adultos

• Therapies to limit the life-threatening vascular leak observed in patients with acute lung injury (ALI) are currently lacking. We explored the effect of simvastatin, a 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor that mediates endothelial cell barrier protection in vitro, in a murine inflammatory model of ALI. C57BL/6J mice were treated with simvastatin (5 or 20 mg/kg body wt via intraperitoneal injection) 24 h before and again concomitantly with intratracheally administered LPS (2 μg/g body wt). Inflammatory indexes [bronchoalveolar lavage (BAL) myeloperoxidase activity and total neutrophil counts assessed at 24 hr with histological confirmation] were markedly increased after LPS alone but significantly reduced in mice that also received simvastatin (20 mg/kg; ~35-60% reduction). Simvastatin also decreased BAL albumin (~50% reduction) and Evans blue albumin dye extravasation into lung tissue (100%) consistent with barrier protection. Finally, the sustained nature of simvastatin-mediated lung protection was assessed by analysis of simvastatin-induced gene expression (Affymetrix platform). LPS-mediated lung gene expression was significantly modulated by simvastatin within a number of gene ontologies (e.g., inflammation and immune response, NF-κB regulation) and with respect to individual genes implicated in the development or severity of ALI (e.g., IL-6, Toll-like receptor 4). Together, these findings confirm significant protection by simvastatin on LPS-induced lung vascular leak and inflammation and implicate a potential role for statins in the management of ALI.dose/fármaco conforme a fonte ↗no original (inglês)

Jacobson JR, Barnard JW, Grigoryev DN, Ma SF, Tuder RM, Garcia JG. Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury. Am J Physiol Lung Cell Mol Physiol. 2005 Jun;288(6):L1026-32. [PubMed Citation]no original (inglês)

• Lung infections are associated with acute lung injury (ALI), systemic inflammation, and vascular events. Clinical studies suggest that statins improve health outcomes of patients with pneumonia and ALI. The mechanisms by which this occurs are unknown. The aim of this study was to determine whether statins attenuate systemic inflammation and cardiovascular dysfunction related to ALI in mice. Simvastatin (SS; 20 mg/kg) or vehicle solution was instilled intraperitoneally into mice 24 h before and again just prior to intratracheal LPS instillation (1 μg/g). These mice were then anesthetized with 2.0% isoflurane and underwent a short surgical procedure to instill LPS. Four hours later, IL-6 levels in bronchoalveolar lavage fluid and in arterial and venous serum were measured. Cardiac function was evaluated using 2-D echocardiography, and endothelial function was determined using wire myography on aortic sections. LPS induced a significant increase in serum IL-6 levels. SS reduced venous (P = 0.040) but not arterial concentrations of IL-6 (P = 0.112). SS improved the maximal vasodilatory response of the aorta to ACh (P = 0.004) but not to sodium nitroprusside (P = 1.000). SS also improved cardiac output (P = 0.023). Vasodilatory response to ACh was impaired when aorta from untreated mice was incubated with ex vivo IL-6 (P = 0.004), whereas in the aorta from mice pretreated with SS, the vasodilatory response did not change with IL-6 incubation (P = 0.387). SS significantly improved LPS-induced cardiovascular dysfunction possibly by reducing systemic expression of IL-6 and its downstream signaling pathways. These findings may explain how statins improve health outcomes in patients with ALI.dose/fármaco conforme a fonte ↗no original (inglês)

Suda K, Eom J, Jaw JE, Mui T, Bai N, Or C, Ngan D, Li Y, Wang X, Tsuruta M, Tam S, Man SP, Van Eeden S, Sin DD. Endotoxin-induced cardiovascular dysfunction in mice: effect of simvastatin. J Appl Physiol. 2011 Oct;111(4):1118-24. [PubMed Citation]no original (inglês)

• Objectives to elicit whether pre-treatment with pravastatin will prevent or ameliorate the acute lung injury that occurs following lower torso ischemia-reperfusion (IR) in an experimental animal model. Male Sprague-Dawley rats were randomized into three groups (n=7/group). The control group underwent a sham laparotomy and aortic dissection. The second group underwent infrarenal aortic cross clamping for 30 min followed by reperfusion for 120 min. The third group pre-treated with pravastatin sodium (0.4 mg/kg/day over 5 days) were again subjected to an ischemia-reperfusion (IR) injury. The parameters used to assess lung injury included: Wet to dry lung weight ratio (W:D), myeloperoxidase activity (MPO), protein concentration (BALprot) and neutrophil count (BAL PMN) of bronchoaveolar lavage fluid. Western blotting was used to determine the expression of constitutive endothelial nitric oxide synthase (ecNOS) within lung tissue. IR causes an acute lung injury as indicated by statistically significant differences in W:D lung weight ratios, MPO activity, neutrophil count and BAL protein concentration in the IR group over that of controls. Pre-treatment with pravastatin attenuated this neutrophil infiltration and microvascular leakage. The pravastatin group showed a marked increased expression of ecNOS over that of the IR group and controls. This data indicates that pre-treatment with pravastatin protects against ischemia-reperfusion induced lung injury in an experimental animal model. We believe that its mechanism of action involves an upregulation of ecNOS, which increases basal expression of nitric oxide providing protective effects on the pulmonary circulation against microvascular injury.dose/fármaco conforme a fonte ↗no original (inglês)

Joyce M, Kelly CJ, Chen G, Bouchier-Hayes DJ. Pravastatin attenuates lower torso ischaemia-reperfusion-induced lung injury by upregulating constitutive endothelial nitric oxide synthase. Eur J Vasc Endovasc Surg. 2001 Apr;21(4):295-300. [PubMed Citation]no original (inglês)

• The present study was designed to determine whether pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, could attenuate acute lung injury (ALI) induced by lipopolysaccharide (LPS) in BALB/c mice. Acute lung injury was induced successfully by intratracheal administraiton of LPS (3 mg/g) in BALB/c mice. Pravastatin (3, 10 and 30 mg/kg, i.p.) was administered to mice 24 hr prior to and then again concomitant with LPS exposure. Challenge with LPS alone produced a significant increase in lung index and the wet/dry weight ratio compared with control animals. Pulmonary microvascular leakage, as indicated by albumin content in the bronchoalveolar lavage fluid (BALF) and extravasation of Evans blue dye albumin into lung tissue, was apparently increased in LPS-exposed mice. Lipopolysaccharide exposure also produced a significant lung inflammatory response, reflected by myeloperoxidase activity and inflammatory cell counts in BALF. Furthermore, histological examination showed that mice exposed to LPS also exhibited prominent inflammatory cell infiltration and occasional alveolar hemorrhage. Pravastatin (3, 10 or 30 mg/kg, i.p.) produced a significant reduction in multiple indices of LPS-induced pulmonary vascular leak and inflammatory cell infiltration into lung tissue. Elevated tumor necrosis factor (TNF)-a levels in lung tissue homogenates of ALI mice were significantly decreased after administration of 10 or 30 mg/kg pravastatin. These findings confirm significant protection by pravastatin against LPS-induced lung vascular leak and inflammation and implicate a potential role for statins in the management of ALI. The inhibitory effect of pravastatin was associated with its effect in decreasing TNF-a.dose/fármaco conforme a fonte ↗no original (inglês)

Yao HW, Mao LG, Zhu JP. Protective effects of pravastatin in murine lipopolysaccharide-induced acute lung injury. Clin Exp Pharmacol Physiol. 2006 Sep;33(9):793-7.[PubMed Citation]no original (inglês)

• Pravastatin is best known for its antilipidemic action. Recent studies have shown that statins have immunomodulatory and anti-inflammatory effects. The present study aimed to determine whether or not pravastatin can attenuate acute lung injury and fibrosis in a mouse model. Bleomycin was given to C57BL6 mice through intratracheal instillation. Pravastatin was given through intraperitoneal injection. To study the effect of pravastatin on the early inflammatory phase and the late fibrotic phase, mice were killed on days 3, 7, 14 and 21. Pravastatin attenuated the histopathological change of bleomycin- induced lung injury and fibrosis. The accumulation of neutrophils and increased production of tumor necrosis factor-a in bronchoalveolar lavage fluid were inhibited in the early inflammatory phase. Pravastatin effectively inhibited the increase of lung hydroxyproline content induced by bleomycin. Furthermore, pravastatin reduced the increased expression of transforming growth factor (TGF)-b1, connective tissue growth factor (CTGF), RhoA and cyclin D1. The increased levels of TGF-b1 and CTGF mRNA expression were also significantly inhibited by pravastatin. Pravastatin effectively attenuated bleomycin-induced lung injury and pulmonary fibrosis in mice. Our results provide evidence for the therapeutic potential of pravastatin in the treatment of acute lung injury and pulmonary fibrosis.dose/fármaco conforme a fonte ↗no original (inglês)

Kim JW, Rhee CK, Kim TJ, Kim YH, Lee SH, Yoon HK, Kim SC, Lee SY, Kwon SS, Kim KH, Kim YK. Effect of pravastatin on bleomycin-induced acute lung injury and pulmonary fibrosis. Clin Exp Pharmacol Physiol. 2010 Nov;37(11):1055-63. [PubMed Citation]no original (inglês)

Outros estudos não clínicos

• The accumulating evidence suggests that C-reactive protein (CRP) may have direct inflammatory effects on the vascular wall and that statin therapy may have important non-lipid anti-inflammatory effects confirmed by decreasing serum inflammatory markers, such as CRP. However, the effect of simvastatin on interleukin-6 (IL-6) release in cultured human monocytes was not investigated. Design A prospective, human monocyte culture, simvastatin intervention study. Methods Monocytes were isolated from blood of healthy volunteers by the Ficoll density gradient and stimulated by broad concentrations of CRP (1-20 lg/ml) and lipopolysaccharide (LPS, 1-10 ng/ml) at indicated time points (0, 2, 4, 8, 16 and 24 hr). Also 10-8-10-6 mol/l simvastatin was coincubated with cells in the presence of CRP and LPS. Measurements of IL-6 were performed from supernatants of cultured medium in duplicate, using a commercial assay kit. Results CRP and LPS induced the rapid release of IL-6, with significantly elevated levels in cultured supernatants at 4 hr in the CRP group and at 2 h in the LPS group. The effects of CRP and LPS on IL-6 release of monocytes were dose and time dependent. A greater than 11-fold increase of IL-6 in the CRP group (20 lg/ml) and a greater than 26- fold increase in the LPS group (10 ng/ml) were observed at 24 h compared with the control group (945.7&plusmn; 98.3 pg/ml compared with 94.3&plusmn; 12.4 pg/ml and 1720.4 &plusmn; 690.1 pg/ml compared with 70.1&plusmn; 16.7pg/ml, P < 0.001, respectively). However, 10-8-10-6 mol/l simvastatin inhibited significantly the production of IL-6 in monocytes stimulated by CRP and LPS in a dose-dependent manner, with the maximal inhibiting effect at a concentration of 10-6 mol/L (945.7 &plusmn; 98.3 pg/ml compared with 180.9 &plusmn; 31.2 pg/ml and 1720.4 &plusmn;690.1 pg/ml compared with 824.0 &plusmn; 206.2 pg/ml, P < 0.001 respectively). Conclusions CRP and LPS could induce IL-6 release in human monocytes and simvastatin could inhibit this response in a dose-dependent manner, which may provide an insight into the mechanisms of anti-inflammatory or anti-atherosclerotic actions of simvastatin.dose/fármaco conforme a fonte ↗no original (inglês)

Li JJ, Chen XJ. Simvastatin inhibits interleukin-6 release in human monocytes stimulated by C-reactive protein and lipopolysaccharide. Coron Artery Dis. 2003 Jun;14(4):329-34.[PubMed Citation]no original (inglês)

• The statins, hydroxy-3-methylglutaryl-CoA reductase inhibitors that lower serum cholesterol, exhibit myriad clinical benefits, including enhanced vascular integrity. One potential mechanism underlying increased endothelial cell (EC) barrier function is inhibition of geranylgeranylation, a covalent modification enabling translocation of the small GTPases Rho and Rac to the cell membrane. While RhoA inhibition attenuates actin stress fiber formation and promotes EC barrier function, Rac1 inhibition at the cell membrane potentially prevents activation of NADPH oxidase and subsequent generation of superoxides known to induce barrier disruption. We examined the relative regulatory effects of simvastatin on RhoA, Rac1, and NADPH oxidase activities in the context of human pulmonary artery EC barrier protection. Confluent EC treated with simvastatin demonstrated significantly decreased thrombin-induced FITC-dextran permeability, a reflection of vascular integrity, which was linked temporally to simvastatin-mediated actin cytoskeletal rearrangement. Compared with Rho inhibition alone (Y-27632), simvastatin afforded additional protection against thrombin-mediated barrier dysfunction and attenuated LPS-induced EC permeability and superoxide generation. Statin-mediated inhibition of both Rac translocation to the cell membrane and superoxide production were attenuated by geranylgeranyl pyrophosphate (GGPP), indicating that these effects are due to geranylgeranylation inhibition. Finally, thrombin-induced EC permeability was modestly attenuated by reduced Rac1 expression (small interfering RNA), whereas these effects were made more pronounced by simvastatin pretreatment. Together, these data suggest EC barrier protection by simvastatin is due to dual inhibitory effects on RhoA and Rac1 as well as the attenuation of superoxide generation by EC NADPH oxidase and contribute to the molecular mechanistic understanding of the modulation of EC barrier properties by simvastatin.dose/fármaco conforme a fonte ↗no original (inglês)

Chen W, Pendyala S, Natarajan V, Garcia JG, Jacobson JR. Endothelial cell barrier protection by simvastatin: GTPase regulation and NADPH oxidase inhibition. Am J Physiol Lung Cell Mol Physiol. 2008 Oct;295(4):L575-83. [PubMed Citation]no original (inglês)

• The statins, a class of HMG-CoA reductase inhibitors, directly affect multiple vascular processes via inhibition of geranylgeranylation, a covalent modification essential for Rho GTPase interaction with cell membrane-bound activators. We explored simvastatin effects on endothelial cell actomyosin contraction, gap formation, and barrier dysfunction produced by the edemagenic agent, thrombin. Human pulmonary artery endothelial cells exposed to prolonged simvastatin treatment (5 microM, 16 h) demonstrated significant reductions in thrombin-induced (1 U/ml) barrier dysfunction ( approximately 70% inhibition) with accelerated barrier recovery, as measured by transendothelial resistance. Furthermore, simvastatin attenuated basal and thrombin-stimulated (1 U/ml, 5 min) myosin light chain diphosphorylation and stress fiber formation while dramatically increasing peripheral immunostaining of actin and cortactin, an actin-binding protein, in conjunction with increased Rac GTPase activity. As both simvastatin-induced Rac activation and barrier protection were delayed (maximal after 16 h), we assessed the role of gene expression and protein translation in the simvastatin response. Simultaneous treatment with cycloheximide (10 microg/ml, 16 h) abolished simvastatin-mediated barrier protection. Robust alterations were noted in the expression of cytoskeletal proteins (caldesmon, integrin beta4), thrombin regulatory elements (PAR-1, thrombomodulin), and signaling genes (guanine nucleotide exchange factors) in response to simvastatin by microarray analysis. These novel observations have broad clinical implications in numerous vascular pathobiologies characterized by alterations in vascular integrity including inflammation, angiogenesis, and acute lung injury.dose/fármaco conforme a fonte ↗no original (inglês)

Jacobson JR, Dudek SM, Birukov KG, Ye SQ, Grigoryev DN, Girgis RE, Garcia JG. Cytoskeletal activation and altered gene expression in endothelial barrier regulation by simvastatin. Am J Respir Cell Mol Biol. 2004 May;30(5):662-70. [PubMed Citation]no original (inglês)

Revisões não clínicas

• Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) represent a spectrum of diseases that are commonly encountered in the intensive care unit and are associated with high mortality. Although significant advances have been made with respect to the ventilatory management of patients with ALI/ARDS with proven beneficial effects on outcomes, pharmacologic therapies remain nonexistent. Because the cardinal feature of ALI/ARDS is an increase in lung vascular permeability, often precipitated by an exuberant inflammatory response with subsequent endothelial barrier disruption, strategies aimed at promoting endothelial barrier function could serve as novel therapies in this setting. We have identified several promising agonists in this regard including sphingosine 1-phosphate, activated protein C, and statins, a class of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. These agonists all have in common the ability to directly mediate endothelial cell signaling and induce characteristic actin cytoskeletal rearrangement leading to endothelial cell barrier protection. Our in vitro findings have been extended to animal models of ALI/ARDS and suggest that effective pharmacologic therapies for patients with ALI/ARDS may soon be available.dose/fármaco conforme a fonte ↗no original (inglês)

Jacobson JR. Pharmacologic therapies on the horizon for acute lung injury/acute respiratory distress syndrome. J Investig Med. 2009 Dec;57(8):870-3. [PubMed Citation]no original (inglês)

4. Dados farmacocinéticos e toxicocinéticos

Adulto

• Pitavastatin calcium is a new addition to the class of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") approved for use in the United States for the treatment of primary hyperlipidemia and mixed dyslipidemia. ... Based on findings from pharmacokinetic studies, pitavastatin may be given at any time of the day, with or without food. The drug had a mean plasma elimination t(1/2) of 12 hours, is expected to be associated with minimal drug-drug interactions because it is not metabolized by the cytochrome P450 3A4 isozyme, and is primarily excreted unchanged in the bile with little renal elimination. ...dose/fármaco conforme a fonte ↗no original (inglês)

Yee LL, Wright EA. Pitavastatin calcium: clinical review of a new antihyperlipidemic medication. Clin Ther. 2011 Aug; 33 (8): 1023-42. [PubMed Citation]no original (inglês)

• Elucidation of the rate-determining process in the overall hepatic elimination of drugs is critical for predicting their intrinsic hepatic clearance and the impact of variation of sequestration clearance on their systemic concentration. The present study investigated the rate-determining process in the overall hepatic elimination of the HMG-CoA reductase inhibitors pravastatin, pitavastatin, atorvastatin, and fluvastatin both in rats and humans. The uptake of these statins was saturable in both rat and human hepatocytes. Intrinsic hepatic clearance obtained by in vivo pharmacokinetic analysis in rats was close to the uptake clearance determined by the multiple indicator dilution method but much greater than the intrinsic metabolic clearance extrapolated from an in vitro model using liver microsomes. In vivo uptake clearance of the statins in humans (pravastatin, 1.44; pitavastatin, 30.6; atorvastatin, 12.7; and fluvastatin, 62.9 ml/min/g liver), which was obtained by multiplying in vitro uptake clearance determined in cryopreserved human hepatocytes by rat scaling factors, was within the range of overall in vivo intrinsic hepatic clearance (pravastatin, 0.84-1.2; pitavastatin, 14-35; atorvastatin, 11-19; and fluvastatin, 123-185 ml/min/g liver), whereas the intrinsic metabolic clearance of atorvastatin and fluvastatin was considerably low compared with their intrinsic hepatic clearance. Their uptake is the rate-determining process in the overall hepatic elimination of the statins in rats, and this activity likely holds true for humans. In vitro-in vivo extrapolation of the uptake clearance using a cryopreserved human hepatocytes model and rat scaling factors will be effective for predicting in vivo intrinsic hepatic clearance involving active uptake.dose/fármaco conforme a fonte ↗no original (inglês)

Watanabe T, Kusuhara H, Maeda K, Kanamaru H, Saito Y, Hu Z, Sugiyama Y. Investigation of the rate-determining process in the hepatic elimination of HMG-CoA reductase inhibitors in rats and humans. Drug Metab Dispos. 2010 Feb; 38 (2): 215-22. [PubMed Citation]no original (inglês)

5. Indicações e posologia atualmente aprovadas pela FDA/EUA

Adultos (FDA)

• Hiperlipidemia (statins): a dose das statins deve ser cuidadosamente ajustada conforme as necessidades e a resposta individuais. Como doses mais altas se associam a risco aumentado de miopatia, o painel consultivo clínico sobre statins do American College of Cardiology (ACC), da American Heart Association (AHA) e do National Heart, Lung and Blood Institute (NHLBI) afirma que as doses de statin em geral não devem exceder as necessárias para atingir a meta terapêutica de LDL-colesterol. O fabricante da simvastatin afirma que doses mais altas do fármaco (isto é, 80 mg ao dia) devem ser restritas a pacientes que já vinham em terapia de longo prazo (por exemplo, 12 months (12 meses) ou mais) nessa dose, sem evidência de toxicidade muscular. As concentrações séricas de lipoproteínas devem ser determinadas periodicamente durante a terapia com statin. A dose deve ser aumentada em intervalos não menores que 4 weeks (4 semanas), até que se observe o efeito desejado sobre as concentrações de lipoproteínas; a redução da dose de statin pode ser considerada em pacientes cujas concentrações séricas de colesterol caiam abaixo da faixa-alvo desejada. A terapia com statins, junto com medidas dietéticas, deve continuar por toda a vida do paciente, na pendência de novos dados que definam um período de tratamento mais apropriado. O uso de certas statins com inibidores potentes da isoenzima 3A4 do citocromo P-450 (CYP), imunossupressores (por exemplo, cyclosporine), derivados do ácido fíbrico, doses antilipêmicas (acima de 1 g daily) de niacin, danazol, amiodarone, diltiazem ou verapamil pode se associar a risco aumentado de miopatia ou rabdomiólise. Se essas combinações forem usadas, doses iniciais menores dos fármacos devem ser administradas, e a titulação para doses mais altas deve ser feita com cautela.dose/fármaco conforme a fonte ↗

McEvoy GK, ed. Drug Information 2012. Bethesda, MD: American Society of Health-System Pharmacists, 2012 p.1747-1784no original (inglês)

• Hiperlipidemia (pitavastatin): a dose de pitavastatin calcium é expressa em termos de pitavastatin e deve ser cuidadosamente ajustada conforme as necessidades e a resposta individuais. A dose inicial adulta recomendada de pitavastatin para o manejo da hipercolesterolemia primária ou da dislipidemia mista é de 2 mg uma vez ao dia. A dose usual de manutenção é de 1-4 mg uma vez ao dia. A dose máxima de pitavastatin é de 4 mg uma vez ao dia. Em adultos que recebem pitavastatin junto com erythromycin, a dose de pitavastatin não deve exceder 1 mg uma vez ao dia. Em adultos que recebem pitavastatin junto com rifampin, a dose de pitavastatin não deve exceder 2 mg uma vez ao dia. Em adultos que recebem pitavastatin junto com doses antilipêmicas de niacin, deve-se considerar a redução da dose de pitavastatin. A dose inicial usual de pravastatin sodium em adultos é de 40 mg ao dia. Se a resposta antilipêmica for inadequada com a dose inicial, o fabricante afirma que a dose pode ser aumentada para 80 mg ao dia.dose/fármaco conforme a fonte ↗

McEvoy GK, ed. Drug Information 2012. Bethesda, MD: American Society of Health-System Pharmacists, 2012 p.1747-1784no original (inglês)

• Terapia concomitante com cyclosporine: pelo risco aumentado de miopatia durante a terapia concomitante, pacientes que recebem imunossupressores como a cyclosporine junto com pravastatin devem receber dose inicial de pravastatin sodium de 10 mg ao dia, ao deitar; a titulação para doses mais altas deve ser feita com cautela. A maioria dos pacientes tratados com essa combinação recebeu dose máxima de pravastatin sodium de 20 mg ao dia.dose/fármaco conforme a fonte ↗
• Terapia concomitante com sequestrantes de ácidos biliares: os efeitos redutores de colesterol do pravastatin sodium e dos sequestrantes de ácidos biliares (por exemplo, cholestyramine) são aditivos ou sinérgicos. Contudo, como os sequestrantes de ácidos biliares podem ligar e retardar a absorção do pravastatin sodium, o fabricante recomenda que o pravastatin sodium seja administrado 1 hour (1 hora) ou mais antes e pelo menos 4 hours (4 horas) depois do sequestrante de ácidos biliares, quando esses fármacos forem usados juntos.dose/fármaco conforme a fonte ↗

McEvoy GK, ed. Drug Information 2012. Bethesda, MD: American Society of Health-System Pharmacists, 2012 p.1747-1784no original (inglês)

• Hiperlipidemia (simvastatin): a dose inicial usual de simvastatin em adultos é de 10 ou 20 mg uma vez ao dia, à noite.1 Em pacientes com DAC ou equivalentes de risco de DAC (por exemplo, diabetes mellitus, doença arterial periférica, história de AVC ou outra doença cerebrovascular), a dose inicial recomendada de simvastatin é de 40 mg ao dia. A dose usual de manutenção de simvastatin é de 5-40 mg uma vez ao dia, à noite;1 pacientes idosos podem responder a doses de manutenção de 20 mg ou menos ao dia. Como doses mais altas de simvastatin (por exemplo, 80 mg ao dia) se associaram a risco maior de miopatia, incluindo rabdomiólise, particularmente no primeiro ano de tratamento, o fabricante afirma que os pacientes que não conseguem atingir a meta de LDL-colesterol com a dose de 40-mg ao dia de simvastatin não devem ser titulados para a dose de 80-mg ao dia, mas trocados por agentes antilipêmicos alternativos que ofereçam maior redução do LDL-colesterol. O fabricante afirma também que o uso da dose de 80-mg ao dia de simvastatin deve ser restrito a pacientes que já vinham em terapia de longo prazo (por exemplo, 12 months (12 meses) ou mais) nessa dose, sem evidência de efeitos musculares adversos. Pacientes que atualmente toleram a dose de 80-mg ao dia de simvastatin e que precisem de terapia com um fármaco interagente (isto é, um fármaco cujo uso concomitante é contraindicado ou implica limite de dose para a simvastatin) devem ser trocados para uma statin alternativa com menor potencial de interação medicamentosa.dose/fármaco conforme a fonte ↗
• Hipercolesterolemia familiar homozigótica: a dose recomendada de simvastatin é de 40 mg ao dia, à noite. A simvastatin deve ser usada como adjuvante de outro tratamento hipolipemiante (por exemplo, aférese de LDL) nesses pacientes, ou como alternativa se essa terapia não estiver disponível.dose/fármaco conforme a fonte ↗
• Terapia concomitante (simvastatin): pelo risco aumentado de miopatia, incluindo rabdomiólise, durante a terapia concomitante, particularmente com doses mais altas de simvastatin, o fabricante da simvastatin afirma que é contraindicado o uso concomitante de simvastatin com inibidores potentes da isoenzima 3A4 do citocromo P-450 (CYP3A4) (por exemplo, itraconazole, ketoconazole, posaconazole, inibidores da protease do HIV, clarithromycin, erythromycin, telithromycin, nefazodone), cyclosporine, danazol ou gemfibrozil. Deve-se evitar o consumo de grandes quantidades (mais de um quarto de galão por dia) de suco de toranja. Em pacientes que recebem amiodarone, diltiazem ou verapamil junto com simvastatin, a dose de simvastatin não deve exceder 10 mg ao dia. Em pacientes que recebem amlodipine ou ranolazine junto com simvastatin, a dose de simvastatin não deve exceder 20 mg ao dia.dose/fármaco conforme a fonte ↗
• Pacientes chineses: o risco de miopatia parece ser maior em pacientes chineses do que em não chineses que recebem simvastatin 40 mg ao dia junto com preparações contendo doses antilipêmicas (1 g daily ou mais) de niacin. A causa do risco aumentado de miopatia não é conhecida, e não se sabe se esses achados se aplicam a pacientes de outras ascendências asiáticas. Por esse risco aumentado, recomenda-se cautela quando pacientes chineses recebem doses de simvastatin acima de 20 mg ao dia com preparações contendo doses antilipêmicas de niacin. Como o risco de miopatia é dose-dependente, pacientes de ascendência chinesa devem evitar o uso concomitante de simvastatin 80 mg ao dia com preparações contendo doses antilipêmicas de niacin.dose/fármaco conforme a fonte ↗

McEvoy GK, ed. Drug Information 2012. Bethesda, MD: American Society of Health-System Pharmacists, 2012 p.1747-1784no original (inglês)

Crianças (FDA)

• Hiperlipidemia: a dose recomendada de pravastatin sodium em crianças de 8-13 or 14-18 years (8 a 13 ou 14 a 18 anos) de idade é de 20 ou 40 mg uma vez ao dia, respectivamente. A segurança e a eficácia de doses acima de 20 ou 40 mg ao dia em crianças de 8-13 ou 14-18 years de idade, respectivamente, não foram avaliadas. O fabricante afirma que crianças e adolescentes tratados com pravastatin devem ser reavaliados na vida adulta, e a terapia antilipêmica então modificada de forma apropriada para atingir as metas adultas de LDL-colesterol.dose/fármaco conforme a fonte ↗

McEvoy GK, ed. Drug Information 2012. Bethesda, MD: American Society of Health-System Pharmacists, 2012 p.1747-1784no original (inglês)

• Hipercolesterolemia familiar heterozigótica: a dose inicial recomendada de simvastatin para o tratamento da hipercolesterolemia familiar heterozigótica em meninos e meninas pós-menarca de 10-17 years (10 a 17 anos) de idade é de 10 mg uma vez ao dia, à noite. A dose deve ser aumentada em intervalos de 4 weeks (4 semanas) ou mais, até que se observe o efeito desejado sobre as concentrações de lipoproteínas ou até atingir a dose máxima de 40 mg ao dia.1 A segurança e a eficácia de doses de simvastatin acima de 40 mg ao dia não foram avaliadas nessa população de pacientes.dose/fármaco conforme a fonte ↗

McEvoy GK, ed. Drug Information 2012. Bethesda, MD: American Society of Health-System Pharmacists, 2012 p.1747-1784no original (inglês)

Gravidez (FDA)

• O colesterol e outros produtos da via de biossíntese do colesterol são essenciais ao desenvolvimento fetal, incluindo a síntese de esteroides e de membranas celulares. Pela capacidade das statins de reduzir a síntese de colesterol e, possivelmente, de outros produtos da via de biossíntese do colesterol, esses agentes podem causar dano fetal quando administrados a gestantes. ... Malformação esquelética congênita grave, fístula traqueoesofágica e atresia foram relatadas em um neonato cuja mãe recebeu lovastatin junto com dextroamphetamine sulfate durante o primeiro trimestre da gravidez.dose/fármaco conforme a fonte ↗

McEvoy GK, ed. Drug Information 2012. Bethesda, MD: American Society of Health-System Pharmacists, 2012 p.1747-1784no original (inglês)

Lactantes (FDA)

• A pravastatin é distribuída no leite humano e a pitavastatin é distribuída no leite em animais.

McEvoy GK, ed. Drug Information 2012. Bethesda, MD: American Society of Health-System Pharmacists, 2012 p.1747-1784no original (inglês)

Insuficiência renal (FDA)

• Como a maior parte das statins (por exemplo, atorvastatin, fluvastatin, lovastatin, rosuvastatin, simvastatin) não sofre excreção renal substancial, os fabricantes afirmam que a modificação da dose não deve ser necessária em pacientes com insuficiência renal leve (clearance de creatinina de 61-90 mL/minute por 1.73 m 2 ). Contudo, a pitavastatin e a pravastatin sofrem eliminação renal e hepática, com a excreção renal atingindo 15 e 20-47% da dose administrada, respectivamente. Como não se pode descartar a possibilidade de acúmulo da pravastatin e de outras statins, esses fármacos devem ser administrados com cautela em pacientes com insuficiência renal moderada a grave (clearance de creatinina menor que 60 mL/minute por 1.73 m 2 ), iniciando a terapia sob monitorização estreita e com doses diárias reduzidas.dose/fármaco conforme a fonte ↗

McEvoy GK, ed. Drug Information 2012. Bethesda, MD: American Society of Health-System Pharmacists, 2012 p.1747-1784no original (inglês)

Insuficiência hepática (FDA)

• Como as statins são parcialmente metabolizadas no fígado e podem se acumular no plasma de pacientes com insuficiência hepática, esses fármacos devem ser usados com cautela em pacientes que consomem quantidades substanciais de álcool e/ou que tenham história de doença hepática; esses pacientes devem ser monitorados de perto enquanto recebem terapia com statin. As statins não devem ser usadas em pacientes com doença hepática ativa ou com aumentos persistentes e inexplicados das concentrações séricas de aminotransferases.dose/fármaco conforme a fonte ↗

McEvoy GK, ed. Drug Information 2012. Bethesda, MD: American Society of Health-System Pharmacists, 2012 p.1747-1784no original (inglês)

Autorização de uso emergencial (FDA/CDC)

Nenhuma Autorização de Uso Emergencial para as Statins foi emitida pela Food and Drug Administration sob a seção 564 do Federal Food, Drug and Cosmetic Act (FD&C Act) (21 U.S.C. 360bbb-3), alterado pelo Project Bioshield Act of 2004 (Public Law 108-276).dose/fármaco conforme a fonte ↗

[DHHS/FDA; Emergency Preparedness and Response - Counterterrorism and Emerging Threats (01/12/2011)]

6. Formulações disponíveis atualmente / prazo de validade

Formulação

Atorvastatin calcium, 5mg, 10mg, 20mg, 40mgdose/fármaco conforme a fonte ↗

Fluvastatin sodium, cápsulas, 20mg, 40mgdose/fármaco conforme a fonte ↗

Lovastatin, 10mg, 20mg, 40mgdose/fármaco conforme a fonte ↗

Rosuvastatin calcium, 5mg, 10mg, 20mg, 40mgdose/fármaco conforme a fonte ↗

Pitavastatin calcium, comprimidos 1mg, 2mg, 4mgdose/fármaco conforme a fonte ↗

Simvastatin, comprimidos 5mg, 10mg, 20mg, 40, 80mgdose/fármaco conforme a fonte ↗

Pravastatin sodium, comprimidos 10mg, 20mg, 40mg, 80mgdose/fármaco conforme a fonte ↗

McEvoy GK, ed. Drug Information 2012. Bethesda, MD: American Society of Health-System Pharmacists, 2012 p.1747-1784no original (inglês)

Prazo de validade

Prazo de validade

Guardadas a 5-30&deg;C, as statins são estáveis por 24 months (24 meses) após a data de fabricação.dose/fármaco conforme a fonte ↗

McEvoy GK, ed. Drug Information 2012. Bethesda, MD: American Society of Health-System Pharmacists, 2012 p.1747-1784no original (inglês)

7. Utilização e posologia off-label atuais

• Nenhum dado disponível no momento.

8. Via de administração / monitorização

• Todas as statins são administradas por via oral.dose/fármaco conforme a fonte ↗
• As concentrações séricas de lipoproteínas devem ser determinadas periodicamente durante a terapia com statin.

McEvoy GK, ed. Drug Information 2012. Bethesda, MD: American Society of Health-System Pharmacists, 2012 p.1747-1784no original (inglês)

9. Efeitos adversos

• Doses de simvastatin de até 100 g/sq m em cães foram associadas a êmese e muco nas fezes.dose/fármaco conforme a fonte ↗

McEvoy GK, ed. Drug Information 2012. Bethesda, MD: American Society of Health-System Pharmacists, 2012 p.1747-1784no original (inglês)

• A U.S. Food and Drug Administration (FDA) recomenda limitar o uso da maior dose aprovada do medicamento hipolipemiante simvastatin (80 mg), pelo risco aumentado de dano muscular. A simvastatin 80 mg deve ser usada apenas em pacientes que já vinham tomando essa dose por 12 months (12 meses) ou mais sem evidência de lesão muscular (miopatia). A simvastatin 80 mg não deve ser iniciada em novos pacientes, inclusive nos que já tomam doses menores do fármaco. Além dessas novas limitações, a FDA está exigindo mudanças na bula da simvastatin, para acrescentar novas contraindicações (não deve ser usada com certos medicamentos) e limites de dose para o uso da simvastatin com certos medicamentos.dose/fármaco conforme a fonte ↗

FDA Drug Safety Communication: New restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury. June 8, 2011 (FDA)no original (inglês)

10. Contraindicação(ões)

• As statins são contraindicadas em pacientes com hipersensibilidade a qualquer componente das formulações. Esses fármacos também são contraindicados em pacientes com doença hepática ativa ou com elevações persistentes e inexplicadas das transaminases séricas. As statins são contraindicadas em gestantes ou lactantes e em mulheres em idade fértil, a menos que a chance de engravidar seja muito baixa.dose/fármaco conforme a fonte ↗

McEvoy GK, ed. Drug Information 2012. Bethesda, MD: American Society of Health-System Pharmacists, 2012 p.1747-1784no original (inglês)

• Fármacos contraindicados com a simvastatin: Itraconazole, Ketoconazole, Posaconazole (novo), Erythromycin, Clarithromycin, Telithromycin, inibidores da protease do HIV, Nefazodone, Gemfibrozil, Cyclosporine, Danazol

FDA Drug Safety Communication: New restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury. June 8, 2011 (FDA)no original (inglês)

11. Estudos clínicos em andamento

Title: Statins for Acutely Injured Lungs From Sepsis (SAILS) – Study Terminated, Results Availabledose/fármaco conforme a fonte ↗no original (inglês)

Condition: Sepsis for Acutely Injured Lungs From Sepsis Induced ALIno original (inglês)

Intervention: Drug: Rosuvastatin Drug: Placebono original (inglês)

ClinicalTrials.gov Statinsdose/fármaco conforme a fonte ↗no original (inglês)

12. Estudos não clínicos em andamento

• Nenhum dado disponível no momento.

13. Estudos necessários para a indicação clínica de defesa química

• Nenhum dado disponível no momento.

14. Estudos necessários para indicações clínicas fora da defesa química

• Nenhum dado disponível no momento.

15. Questões éticas relacionadas aos estudos

• Nenhum dado disponível no momento.

16. Situação regulatória global

EUA

• As statins são uma classe de medicamentos de prescrição /aprovados para serem/ usados junto com dieta e exercício para reduzir os níveis sanguíneos de colesterol de lipoproteína de baixa densidade (LDL) ("colesterol ruim")/ São comercializadas como produtos de ingrediente único, incluindo ... Livalo (pitavastatin), Pravachol (pravastatin), Crestor (rosuvastatin) e Zocor (simvastatin). Também são comercializadas como produtos em combinação, incluindo ... Simcor (simvastatin/niacin de liberação prolongada) e Vytorin (simvastatin/ezetimibe).dose/fármaco conforme a fonte ↗

FDA Drugs: Statins. April 19, 2012 (FDA)dose/fármaco conforme a fonte ↗no original (inglês)

UE

• Decisão do tipo W: decisão que concede uma dispensa (waiver) em todas as faixas etárias para as condições listadas — diabetes mellitus tipo 2 e hipercolesterolemia. A dispensa se aplica a: todos os subgrupos da população pediátrica, do nascimento até menos de 18 years (18 anos) de idade, para sitagliptin phosphate mono-hidratado / simvastatin, comprimido revestido, uso oral, sob o fundamento de que os estudos clínicos não podem atender a uma necessidade terapêutica da população pediátrica.dose/fármaco conforme a fonte ↗

European Medicines Agency Decision: Granting of a product specific waiver. August 28, 2009. EMEA/531540/2009, P/170/2009 (EMEA)no original (inglês)

17. Outras informações potencialmente úteis

• Statins represent a class of drugs that effectively lowers cholesterol, however they also possess pleiotropic effects, like promotion of angiogenesis, prevention of bone loss, immunomodulatory and anti-inflammatory effects. Thus, the aim of this study was to investigate the activity of simvastatin topically applied in mice in acute and chronic skin inflammation models. Skin inflammation was induced in mice ears by topical application of 12-O-tetradecanoyl-phorbol acetate (TPA). In the acute model, ear edema was measured by the increase of ear thickness 6 h after TPA (2.5 mg/ear). The chronic inflammatory process was induced by multiple applications of TPA (2.0 mg/ear) for nine alternate days, and the edema was measured daily as the increase in ear thickness. Topical treatment was applied immediately after TPA in acute model or started at 5th day of chronic experiment. For acute model treatment was simvastatin (0.24, 0.71 and 2.40 mM), dexamethasone (0.13 mM), both in acetone or vehicle alone (acetone). In chronic model simvastatin (1% and 3%) and dexamethasone (0.5%) were incorporated in ointment preparations, and a group received ointment alone (vehicle). Samples of ear tissue (6 mm) were taken from acute and chronic models, weighted and prepared for histological analysis and myeloperoxidase (MPO) enzymatic activity evaluation. Application of simvastatin in acetone reduced the ear edema after a single TPA application in a dose dependent manner [ID50 of 0.47 (0.22-1.13) mM], and the MPO enzymatic activity up to 61 +/- 10%. Also, both simvastatin ointment preparations 1% and 3% reduced acute TPA-induced ear edema in 55 +/- 7% and 65 +/- 8%, respectively. In the chronic model, simvastatin ointment 1% was able to reduce ear edema (25 +/- 3%) and ear weight (10 +/- 1%), though 3% formulation augmented both parameters. Histological analysis revealed a reduction of swelling and leukocyte migration in the acute model for both the formulations of simvastatin (1% and 3%), while in chronic model simvastatin 1% decreased ear swelling and epidermal thickness, but simvastatin 3% increased both parameters. The results confirm the anti-inflammatory activity of simvastatin when applied topically in both acute and chronic models of skin inflammation. Besides, the formulation of simvastatin ointment 1% shows to be a very effective formulation for a chronic usage.dose/fármaco conforme a fonte ↗no original (inglês)

Adami M, Prudente Ada S, Mendes DA, Horinouchi CD, Cabrini DA, Otuki MF. Simvastatin ointment, a new treatment for skin inflammatory conditions. J Dermatol Sci. 2012 May;66(2):127-35. [PubMed Citation]no original (inglês)

• Coeficiente de partição octanol/água: log Kow = 4.68

HSDB. Simvastatinno original (inglês)

18. Publicações

Adami M, Prudente Ada S, Mendes DA, Horinouchi CD, Cabrini DA, Otuki MF. Simvastatin ointment, a new treatment for skin inflammatory conditions. J Dermatol Sci. 2012 May;66(2):127-35. [PubMed Citation]no original (inglês)

Birnbaum Y, Ye Y. Pleiotropic effects of statins: the role of eicosanoid production. Curr Atheroscler Rep. 2012 Apr;14(2):135-9. [PubMed Citation]dose/fármaco conforme a fonte ↗no original (inglês)

Chen W, Pendyala S, Natarajan V, Garcia JG, Jacobson JR. Endothelial cell barrier protection by simvastatin: GTPase regulation and NADPH oxidase inhibition. Am J Physiol Lung Cell Mol Physiol. 2008 Oct;295(4):L575-83. [PubMed Citation]no original (inglês)

ClinicalTrials.gov Statinsdose/fármaco conforme a fonte ↗no original (inglês)

Craig TR, Duffy MJ, Shyamsundar M, McDowell C, O'Kane CM, Elborn JS, McAuley DF. A randomized clinical trial of hydroxymethylglutaryl- coenzyme a reductase inhibition for acute lung injury (The HARP Study). Am J Respir Crit Care Med. 2011 Mar 1;183(5):620-6. [PubMed Citation]no original (inglês)

Clinical trial registered with www.controlled-trials.com (ISRCTN70127774)no original (inglês)

[DHHS/FDA; Emergency Preparedness and Response- Counterterrorism and Emerging Threats (12/01/2011)]no original (inglês)

European Medicines Agency Decision: Granting of a product specific waiver. August 28, 2009. EMEA/531540/2009, P/170/2009 (EMEA)no original (inglês)

FDA Drugs: Statins. April 19, 2012 (FDA)dose/fármaco conforme a fonte ↗no original (inglês)

FDA Drug Safety Communication: New restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury. June 8, 2011 (FDA)no original (inglês)

Halcox JP, Deanfield JE. Beyond the laboratory: clinical implications for statin pleiotropy. Circulation. 2004 Jun 1;109(21 Suppl 1):II42-8. [PubMed Citation]no original (inglês)

HSDB. Simvastatinno original (inglês)

Iwata A, Shirai R, Ishii H, Kushima H, Otani S, Hashinaga K, Umeki K, Kishi K, Tokimatsu I, Hiramatsu K, Kadota J. Inhibitory effect of statins on inflammatory cytokine production from human bronchial epithelial cells. Clin Exp Immunol. 2012 May;168(2):234-40. [PubMed Citation]dose/fármaco conforme a fonte ↗no original (inglês)

Jacobson JR. Pharmacologic therapies on the horizon for acute lung injury/acute respiratory distress syndrome. J Investig Med. 2009 Dec;57(8):870-3. [PubMed Citation]no original (inglês)

Jacobson JR, Barnard JW, Grigoryev DN, Ma SF, Tuder RM, Garcia JG. Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury. Am J Physiol Lung Cell Mol Physiol. 2005 Jun;288(6):L1026-32. [PubMed Citation]no original (inglês)

Jacobson JR, Dudek SM, Birukov KG, Ye SQ, Grigoryev DN, Girgis RE, Garcia JG. Cytoskeletal activation and altered gene expression in endothelial barrier regulation by simvastatin. Am J Respir Cell Mol Biol. 2004 May;30(5):662-70. [PubMed Citation]no original (inglês)

Joyce M, Kelly CJ, Chen G, Bouchier-Hayes DJ. Pravastatin attenuates lower torso ischaemia-reperfusion-induced lung injury by upregulating constitutive endothelial nitric oxide synthase. Eur J Vasc Endovasc Surg. 2001 Apr;21(4):295-300. [PubMed Citation]no original (inglês)

Kim JW, Rhee CK, Kim TJ, Kim YH, Lee SH, Yoon HK, Kim SC, Lee SY, Kwon SS, Kim KH, Kim YK. Effect of pravastatin on bleomycin-induced acute lung injury and pulmonary fibrosis. Clin Exp Pharmacol Physiol. 2010 Nov;37(11):1055-63. [PubMed Citation]no original (inglês)

Kor DJ, Iscimen R, Yilmaz M, Brown MJ, Brown DR, Gajic O. Statin administration did not influence the progression of lung injury or associated organ failures in a cohort of patients with acute lung injury. Intensive Care Med. 2009 Jun;35(6):1039-46. [PubMed Citation]no original (inglês)

Li JJ, Chen XJ. Simvastatin inhibits interleukin-6 release in human monocytes stimulated by C-reactive protein and lipopolysaccharide. Coron Artery Dis. 2003 Jun;14(4):329-34.[PubMed Citation]no original (inglês)

McEvoy GK, ed. Drug Information 2012. Bethesda, MD: American Society of Health-System Pharmacists, 2012 p.1747-1784no original (inglês)

Suda K, Eom J, Jaw JE, Mui T, Bai N, Or C, Ngan D, Li Y, Wang X, Tsuruta M, Tam S, Man SP, Van Eeden S, Sin DD. Endotoxin-induced cardiovascular dysfunction in mice: effect of simvastatin. J Appl Physiol. 2011 Oct;111(4):1118-24. [PubMed Citation]no original (inglês)

US NLM. ChemIDplus Lite. Pravastatinno original (inglês)

US NLM.ChemIDplus Lite. Pitavastatinno original (inglês)

Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000 May 4;342(18):1334-49. [PubMed Citation]no original (inglês)

Watanabe T, Kusuhara H, Maeda K, Kanamaru H, Saito Y, Hu Z, Sugiyama Y. Investigation of the rate-determining process in the hepatic elimination of HMG-CoA reductase inhibitors in rats and humans. Drug Metab Dispos. 2010 Feb; 38 (2): 215-22. [PubMed Citation]no original (inglês)

Yao HW, Mao LG, Zhu JP. Protective effects of pravastatin in murine lipopolysaccharide-induced acute lung injury. Clin Exp Pharmacol Physiol. 2006 Sep;33(9):793-7. [PubMed Citation]no original (inglês)

Yee LL, Wright EA. Pitavastatin calcium: clinical review of a new antihyperlipidemic medication. Clin Ther. 2011 Aug; 33 (8): 1023-42. [PubMed Citation]no original (inglês)

19. Sites

NIH CounterACT Program (HHS/NIH)no original (inglês)

NIH RePORTER (HHS/NIH)no original (inglês)

ClinicalTrials.gov (HHS/NIH)no original (inglês)

PubMed (HHS/NIH)no original (inglês)

DailyMed (HHS/NIH)no original (inglês)

Record last updated 1/2/2013no original (inglês)