Fenofibrate

Abstract

The AS04-adjuvanted human papillomavirus (HPV) 16/18 vaccine (Cervarix®) is a noninfectious recombinant vaccine produced using purified virus-like particles (VLPs) that induce a strong immunogenic response eliciting high levels of anti-L1 VLP antibodies that persist at levels markedly greater than those observed with natural infection. The vaccine adjuvant (AS04) is composed of monophosphoryl-lipid A, which enhances cellular and humoral immune response, adsorbed to aluminium hydroxide. The vaccine is indicated for the prevention of premalignant cervical lesions and cervical cancer causally related to certain oncogenic HPV types in females aged ≥10 years. The AS04-adjuvanted HPV 16/18 vaccine administered in a three-dose schedule over 6 months elicits a high immunogenic response and is highly protective against cervical intraepithelial neoplasia and infection causally related to high-risk oncogenic HPV types. In well designed clinical trials in young women aged 15-25 years who were HPV 16/18 seronegative and DNA negative to 14 HPV high-risk types, high levels of immunogenicity and protection were sustained for follow-up periods of up to 8.4 years. High and persistent immunogenicity against infection with HPV 16/18 has also been demonstrated in older and younger females (aged 10-55 years) who were seronegative for vaccine HPV types. The AS04-adjuvanted HPV 16/18 vaccine elicited a greater immunogenic response than the quadrivalent HPV vaccine in women aged 18-45 years who were seronegative and DNA negative for HPV 16/18. The AS04-adjuvanted HPV 16/18 vaccine confers cross protection against certain non-vaccine, high-risk HPV types. A rapid and strong anamnestic humoral immune response was elicited following a fourth dose of the vaccine. The AS04-adjuvanted HPV 16/18 vaccine is generally well tolerated, and pharmacoeconomic analyses have demonstrated the potential for public health benefits and cost effectiveness when vaccination programmes are run in conjunction with screening programmes. Thus, the AS04-adjuvanted HPV 16/18 vaccine prevents cervical disease associated with certain oncogenic HPV types, thereby reducing the burden of premalignant cervical lesions and, very likely, cervical cancer.

Fenofibrate unexpectedly induces cardiac hypertrophy in mice lacking MuRF1

“…Given that loss-of-function MuRF1 mutations are found in human disease causing human hypertrophic cardiomyopathy [37], understanding the relationship between MuRF1 and hypertrophy is needed. Clinically, fenofibrate is used to treat dyslipidemia and is therapeutically valuable in lowering serum triglycerides in patients [20]. In the present study, we identified an unexpected link between fenofibrate and cardiac hypertrophy in MuRF1−/− hearts at doses that effectively lowered serum triglyceride levels after 8 weeks of treatment (Fig.…”

“…The lipid-modifying effects of fenofibrate are mediated by its activation of PPARα in the liver [inhibiting the synthesis and release of very low density lipoproteins and increasing apolipoprotein A-I (apoA-I) and apolipoprotein A-II (apoA-II)] and small intestine (stimulating apoA-I), and an increase in lipoprotein lipase in skeletal muscle [19]. Fenofibrate also has more pleiotropic effects, not related to lipid metabolism including the reduction of fibrinogen, C-reactive protein, and other inflammatory markers that may contribute to its clinical efficacy, particularly microvascular disease [20]. MuRF1−/− mice were fed a standard mouse chow with 0.05% fenofibrate continuously for 8 weeks and followed by conscious echocardiography for function (Fig.…”

“…However, a series of studies over the past few years have elucidated fenofibrate's pleiotropic activities beyond PPARα agonism [20,32], including down-regulation of complement and inflammatory responses [32–34] and alterations in proteases [35,36]. These studies may offer some insight in the finding that MuRF1−/− hearts had significant decreases in genes categorized as protease inhibitors (Fig.…”

Secondary Prevention After Coronary Artery Bypass Graft Surgery

“…Compared with statin monotherapy, fenofibrate monotherapy tends to improve triglyceride and HDL cholesterol levels to a greater extent, whereas statins improve LDL and total cholesterol levels to a larger degree. 175 In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, 9797 patients with diabetes mellitus who were not taking statins were randomized to micronized fenofibrate 200 mg daily or matching placebo for 5 years. Treatment with fenofibrate did not significantly reduce the risk of the primary outcome of cardiovascular death or nonfatal MI (HR, 0.89; 95% CI, 0.75-1.05; P=0.…”

“…Moreover, potential benefits with fenofibrate therapy were suggested in terms of decreasing cardiovascular risk among patients with the most pronounced dyslipidemia, including those with the highest levels of triglycerides and lowest levels of HDL. 159,160,175,176 After CABG, elevated triglyceride levels may increase the risk of postoperative adverse outcomes. In an observational study of >25 000 patients who underwent primary isolated CABG between 1971 and 1998, investigators noted that a higher baseline triglyceride level at the time of surgery was significantly associated with a higher risk of repeat coronary revascularization (stent or reoperation) during long-term follow-up (P=0.002).…”