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Lipoprotein glomerulopathy (LPG) is an uncommon cause of nephrotic syndrome and/or kidney failure. At microscopy, LPG is characterized by the presence of lipoprotein thrombi in dilated glomerular capillaries due to different ApoE mutations. ApoE gene is located on chromosome 19q13.2, and can be identified in almost all serum lipoproteins. ApoE works as a protective factor in atherosclerosis due its interaction with receptor-mediated lipoprotein clearance and cholesterol receptor. Most common polymorphisms include ApoE2/2, ApoE3/2, ApoE3/3, ApoE4/2, ApoE4/3, and ApoE4/4. All age-groups can be affected by LPG, with a discrete male predominance. Compromised patients typically reveal dyslipidemia, type III hyperlipoproteinemia, and proteinuria. LPG treatment includes fenofibrate, antilipidemic drugs, steroids, LDL aphaeresis, plasma exchange, antiplatelet drugs, anticoagulants, urokinase, and renal transplantation. Recurrence in kidney graft suggests a pathogenic component(s) of extraglomerular humoral complex resulting from abnormal lipoprotein metabolism and presumably associated to ApoE. Resumo A glomerulopatia por lipoproteínas (GLP) é uma patologia rara que causa síndrome nefrótica e/ou insuficiência renal. Na microscopia, a GLP é caracterizada pela presença de trombos de lipoproteínas em capilares glomerulares dilatados devido a diferentes mutações no gene da ApoE. O gene da ApoE está localizado no cromossomo 19q13.2 e pode ser identificado em quase todas as lipoproteínas séricas. A ApoE age como fator de proteção na arterioesclerose por conta de sua interação com a depuração de lipoproteínas mediada por receptores e com o receptor de colesterol. Dentre os polimorfismos mais comuns destacam-se ApoE2/2, ApoE3/2, ApoE3/3, ApoE4/2, ApoE4/3 e ApoE4/4. A GLP pode acometer indivíduos de todas as faixas etárias, com discreta predominância do sexo masculino. Pacientes afetados tipicamente apresentam dislipidemia, hiperlipoproteinemia tipo III e proteinúria. O tratamento da GLP é conduzido com fenofibrato, antilipêmicos, corticosteroides, LDL-aferese, troca de plasma, antiplaquetários, anticoagulantes, uroquinase e transplante renal. Recidiva no enxerto renal indica a existência de componentes patogênicos do complexo humoral extraglomerular resultante de metabolismo lipoproteico anômalo, possivelmente associado a ApoE.

La enfermedad de Chagas, causada por Trypanosoma cruzi (T. cruzi), es la principal causa de miocardiopatía dilatada en el continente americano. El tratamiento antiparasitario recae mayormente en benznidazol (Bzl) dado que el otro fármaco utilizado, el Nifurtimox, escasea o no se encuentra disponible en muchos países. Ambos inducen efectos adversos de variada severidad en muchos pacientes, que pueden llevar a la interrupción del tratamiento. Dado que la aparición de efectos adversos está, en muchos casos, relacionada con la dosis, en el primer capítulo de esta tesis estudiamos la eficacia de Bzl en términos de su actividad parasiticida y antiinflamatoria, usando dosis más bajas que las usualmente reportadas. Ratones BALB/c fueron infectados con la cepa de T. cruzi RA, altamente virulenta, y tratados con distintas dosis de Bzl. Se evaluaron la parasitemia, la mortalidad y el peso corporal. La carga parasitaria, el infiltrado tisular y mediadores inflamatorios fueron estudiados en el corazón. La actividad sérica de la creatina kinasa (CK) fue determinada como un marcador de injuria cardíaca. Asimismo, las propiedades antiinflamatorias de Bzl, independientemente de su capacidad parasiticida, fueron evaluadas en un modelo in vitro de cardiomiocitos en cultivo estimulados con LPS. La dosis elegida para el tratamiento fue de 25 mg/kg/día de Bzl. Esta dosis negativizó los parámetros parasitológicos, indujo un significativo descenso de IL-1β, IL-6 y NOS2 en el corazón y de la actividad sérica de CK, a valores normales. No se observó mortalidad en los ratones tratados. Cultivos primarios de cardiomiocitos tratados con Bzl mostraron disminución de la expresión de mediadores inflamatorios a través de la inhibición de la vía NF-κB. Desde el punto de vista funcional, T. cruzi induce serias alteraciones cardíacas en la etapa crónica de la enfermedad. La fibrosis y miocardiopatía dilatada y su consecuencia, la insuficiencia cardíaca congestiva, constituyen la principal causa de muerte de pacientes con infección crónica por T. cruzi. Este fenómeno se asocia a lapersistencia parasitaria que se acompaña de un intenso infiltrado inflamatorio que, secundariamente, desemboca en remodelación cardíaca con agrandamiento de las cámaras, adelgazamiento parietal y fibrosis intersticial. Los receptores activados por factores de proliferación peroxisomal α (PPARα), son factores de transcripción dependientes de ligando que participan en la regulación de la inflamación. Esta regulación conlleva la inhibición de la producción de citoquinas y mediadores inflamatorios y la reducción de depósitos de colágeno, modulando la fibrosis en diversas patologías. Por lo tanto, en el segundo capítulo de este trabajo, investigamos si el fenofibrato (Fen), agonista sintético de PPARα, mejoraba los parámetros inflamatorios y la disfunción ventricular en un modelo murino de infección con T. cruzi. Para ello, ratones BALB/c fueron secuencialmente infectados con dos cepas de T. cruzi de diferente contexto genético. Bzl 25 mg/kg/día eliminó los parásitos, pero no logró prevenir la patología cardíaca, de manera similar a lo que sucede en la cardiomiopatía chagásica crónica humana. Mediante ecocardiografìa Doppler, observamos que el tratamiento con Fen restableció a valores normales el diámetro de fin de sístole, la fracción de eyección y de acortamiento, y el tiempo de relajación isovolumétrico. Además, Fen redujo la inflamación cardíaca y la fibrosis, la expresión de mediadores proinflamatorios (IL-6, TNF-α y NOS2) y de remodelación cardíaca (MMP-9 y CTGF), y disminuyó la actividad sérica de CK. La degradación citosólica de IkBα fue inhibida por Fen, lo que sugiere que la vía NF-kB participa de los efectos de Fen. En síntesis, en esta tesis mostramos que, por un lado, una dosis baja de Bzl ejerce una adecuada actividad parasiticida y antiinflamatoria, llevando a la eliminación de los parásitos y a la recuperación del tejido. Esto puede ser relevante para actualizar la dosis utilizada para el tratamiento de la enfermedad de Chagas humana, minimizando los efectos adversos. Asimismo, nuestros resultados demuestran que el tratamiento combinado de Fen y Bzl elimina los parásitos y revierte la disfunción ventricular asociada a la respuesta inflamatoria y fibrótica, en un modelo experimental de la enfermedad de Chagas. Chagas disease, caused by Trypanosoma cruzi, is the main cause of dilated cardiomyopathy in the Americas. Antiparasitic treatment mostly relies on benznidazole (Bzl) due to Nifurtimox shortage or unavailability. Both induce adverse drug effects (ADE) of varied severity in many patients, leading to treatment discontinuation or abandonment. Since dosage may influence ADE, in the first part of this thesis we aimed to assess Bzl efficacy in terms of parasiticidal and antiinflammatory activity, using doses lower than those previously reported for acute mouse model. BALB/c mice, infected with the T. cruzi RA strain, were treated with different doses of Bzl. Parasitaemia, mortality and weight change were assessed. Parasite load, tissue infiltrates and inflammatory mediators were studied in the heart. Serum creatine kinase (CK) activity was determined as a marker of heart damage. The infection-independent antiinflammatory properties of Bzl were studied in an in vitro model of LPS-treated cardiomyocyte culture. The chosen dose for the treatment was 25 mg/Kg/day Bzl. This dose turned negative the parasitological parameters, induced a significant decrease in IL-1β, IL-6 and NOS2 in the heart and returned serum CK activity to normal levels. No mortality was observed in infected benznidazole-treated mice. Primary culture cardiomyocytes treated with Bzl showed that inflammatory mediators were reduced via inhibition of the NF-κB pathway. Besides, T. cruzi induces serious cardiac alterations during the chronic infection. Fibrosis and dilated cardiomyopathy, and it consequence, the congestive heart failure, are the main cause of death in patients with chronic infection with T. cruzi. This phenomenon is associated to the parasite persistence that is accompanied by an intense inflammatory infiltrate, which secondarily leads to cardiac remodeling with enlarged chambers, parietal thinning and interstitial fibrosis. Peroxisome proliferator-activated receptors (PPAR)-α, are ligand-dependent transcription, that participate in the regulation of inflammation. This regulation involves the inhibition of production of proinflammatory cytokines and mediators, and to the reduction of collagen deposits modulating the fibrosis in diverse pathologies. Thus, in the second part of this work, we investigated whether the PPAR-α agonist, fenofibrate (Fen), improves cardiac function and inflammatory parameters in a murine model of T. cruzi infection. BALB/c mice were sequentially infected with two T. cruzi strains of different genetic background. Bzl 25 mg/Kg/day cleared parasites but did not preclude cardiac pathology, resembling what is found in human chronic chagasic cardiomyopathy. Through echocardiography, we observed that Fen treatment restored to normal the ejection and shortening fractions, left ventricular end-systolic diameter, and isovolumic relaxation time. Moreover, it reduced cardiac inflammation and fibrosis, decreased the expression of proinflammatory (IL-6, TNF-α and NOS2) and heart remodeling mediators (MMP-9 and CTGF), and reduced serum creatine kinase activity. The fact that IκBα cytosolic degradation was inhibited by Fen suggests that the NFκB pathway has a role in its effects. Summarizing, in this work we show that a Bzl dose lower than that previously reported for treatment of experimental Chagas disease, exerts adequate antiparasitic and antiinflammatory effects leading to parasite clearance and tissue healing. This may be relevant to reassess the dose currently used for the treatment of human Chagas disease, aiming to minimize ADE. Moreover, we demonstrate that combined treatment with Fen plus Bzl is able both to reverse the cardiac dysfunction associated with the ongoing inflammatory response and fibrosis and to attain parasite clearance in an experimental model of Chagas disease. Fil: Cevey, Ágata Carolina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.

Resumen Aunque el colesterol unido a lipoproteinas de baja densidad (cLDL) es el objetivo primario de tratamiento para reducir el riesgo cardiovascular, el incremento de trigliceridos y el descenso del colesterol unido a lipoproteinas de alta densidad (cHDL) constituyen el denominado riesgo cardiovascular residual. El tratamiento con estatinas asociado a fibratos es una posibilidad real de tratamiento del riesgo cardiovascular total. Sin embargo, esta asociacion puede con frecuencia asociarse a efectos adversos, especialmente musculares y hepaticos. Por sus caracteristicas farmacologicas, la asociacion de pravastatina con fenofibrato puede ser eficaz y segura, con escasos efectos secundarios. Analizamos en esta revision los estudios de seguridad disponibles, obteniendo como conclusion que Pravafenix®, combinacion de pravastatina 40 mg con fenofibrato 160 mg, consigue beneficios complementarios sobre el perfil lipidico aterogenico global, es bien tolerado y presenta escasos efectos secundarios, similares a la monoterapia de cada uno de sus componentes. Todavia queda por dilucidar si esta asociacion confiere beneficios adicionales a largo plazo en pacientes tratados con estatinas.

Com a finalidade de avaliar possíveis interações existentes entre os fármacos ciprofibrato, fenofibrato e citalopram e os excipientes comumente empregados nas formulações comerciais, os excipientes e as misturas binárias entre cada fánnaco e excipiente foram avaliados por Calorimetria Exploratória Diferencial (DSC), Difração de raios X em pó (DRXP), Espectroscopia na Região do Infravermelho Médio com Transformada de Fourier (FTIR) e Ressonância Magnética Nuclear no estado sólido (ssNMR). Os excipientes estudados foram o amido, celulose microcristalina, crospovidona, estearato de magnésio, hidroxipropilmetilcelulose, lactose mono-hidratada, lauril sulfato de sódio. As misturas binárias de excipientes com citalopram não apresentaram indícios de interação por DSC, apesar da mistura com lactose ter mostrado alterações no perfil térmico. Entretanto, o ciprofibrato apresentou uma possível interação com o excipiente hidroxipropilmetilcelulose e o fenofibrato com o estearato de magnésio. O estudo de compatibilidade empregando FTIR. não evidenciou qualquer modificação no espectro de ciprofibrato das misturas binárias, mas evidenciaram interação química entre fenofibrato e estearato de magnésio. As análises por ssNMR não indicaram interações químicas entre citalopram e excipientes. O estudo por DRXP mostrou que os excipientes avaliados não alteram a forma cristalina dos fármacos fenofibrato, ciprofibrato e citalopram. In order to assess possible existing interactions of ciprofibrate, fenofibrate and citalopram drugs with the commonly used excipients in commercial formulations, each (1:1 m/m) binary mixtures were evaluated by Differential Scanning Calorimetry (DSC), X-ray Powder Diffraction (XRPD), Fourier Transform Infrared Spectroscopy (FTIR) and Solid State Nuclear Magnetic Resonance (ssNMR). The excipients studied were starch, microcrystalline cellulose, crospovidone, magnesium stearate, hydroxyl propyl methylcellulose, lactose monohydrate and sodium lauryl sulfate. The binaries for citalopram has shown no evidences of any interaction by DSC, nevertheless, blending it with lactose show visible changes in the thermal behavior profile. However, ciprofibrate have presented a possible interaction with hydroxylpropylmethylcellulose and fenofibrate with magnesium stearate. The FTER. compatibility study of ciprofibrate has shown no spectrum change for its binaries, the only observable effect was on the binary of fenofibrate with magnesium stearate. The ssNMR analyses did not indicate chemical interactions between citalopram and the chosen excipients. XRPD show that those excipients do not alter the crystalline form of the drugs fenofibrate, ciprofibrate and citalopram in (1:1 m/m) binary mixtures.

The aim of this study is to develop a new process for manufacturing a nano-sized form of the popular cholesterol-reducing drug fenofibrate which can be implemented on industrial scale with minimal changes of currently used production schemes.Salt-assisted milling was used to reduce particle size of commercial fenofibrate from micron-sized particles to nanometer domains.The optimal parameters for the salt milling are reported, allowing one to reduce the particle size from tens of micrometers to a hundred of nanometers. Dissolution of nano-sized fenofibrate was studied in various formulations and compared against the micron-sized commercially available fenofibrate.The nano-sized fenofibrate demonstrates faster dissolution kinetics in aqueous media, simulating stomach environment, within the first 60 min as compared to the micronized form. The highest dissolution rate is achieved with the nano-sized fenofibrate when surfactants, such as sodium dodecyl sulfate or inclusion complex forming agents such as alpha-cyclodextrin, are used.

Fenofibrate (FF) has previously been shown to induce hepatocellular neoplasia in a conventional mouse bioassay (NDA 1993), but there has been no report to examine the carcinogenic susceptibility of rasH2 mice to this chemical. In the present study, male rasH2 mice were subjected to a two-thirds partial hepatectomy (PH), followed by an N-diethylnitrosamine (DEN) initiation twenty-four hours after PH, and given a diet containing 0, 1200, or 2400 ppm FF for seven weeks. The incidences of preneoplastic foci were significantly increased in mice from the FF-treated groups. Immunohistochemistry revealed that significant increases in proliferating cell nuclear antigen (PCNA)-positive cells and cytokeratin 8/18 positive foci were observed in FF-treated groups. In addition, the transgene and several downstream molecules such as c- myc, c- jun, activating transcription factor 3 (ATF3), and cyclin D1 were overexpressed in these groups. These results suggest that the hepatocarcinogenic activity of rasH2 mice to FF can be detected in this hepatocarcinogenesis model and that up-regulation of genes for the ras/MAPK pathway and cell cycle was probably involved in the hepatocarcinogenic mechanism of rasH2 mice.

Submitted by Boris Flegr (boris@uerj.br) on 2021-01-05T18:13:48Z No. of bitstreams: 1 Tamiris Lima Rachid Dissertacao completa.pdf: 1692719 bytes, checksum: 5389693a5c0d750f7d09c32a61739cf3 (MD5) Made available in DSpace on 2021-01-05T18:13:48Z (GMT). No. of bitstreams: 1 Tamiris Lima Rachid Dissertacao completa.pdf: 1692719 bytes, checksum: 5389693a5c0d750f7d09c32a61739cf3 (MD5) Previous issue date: 2015-02-19 The current situation of obesity in the world encourages the study for its treatment. Fenofibrate, a PPAR-α agonist, is currently used to treat dyslipidemia. However, its pleiotropic effects upon body mass loss and fat pads reduction remain to be unraveled. This study aimed to examine the effects of PPAR-α agonist fenofibrate on energy expenditure, body mass, carbohydrate metabolism, secretory profile of adipokines, plasticity and thermogenesis in adipose tissue in diet-induced obese mice. Male C57BL/6 mice were fed a standard chow (SC; 10% lipids) diet or a high-fat (HF; 50% lipids) diet for 10 weeks. Afterwards, groups were subdivided into: SC, SC-F, HF and HF-F (n=10, each). Treatment with fenofibrate (100 mg/kg BM, mixed into the diet) was maintained for five weeks, totalizing fifteen weeks of experiment. All procedures were approved by the Animal Ethics Committee of UERJ (CEUA/032/2013). The differences among the groups were tested by one-way analysis of variance (ANOVA), followed by the Holm-Sidak post-hoc test. Two-way ANOVA was applied to test interactions between diet and treatment upon the evaluated outcomes. In all cases, P

Background: Rhabdomyolysis is a condition defined by necrosis of muscle cell and release of its contents into the systemic circulation. The fibric acid derivative fenofibrate is indicated in the treatment of hyperlipidaemia in adults. Fenofibrate monotherapy-induced rhabdomyolysis is rare. The presence of chronic renal failure and hypothyroidism are among the primary factors for rhabdomyolysis. Case: Our case study is about an adolescent with chronic renal failure, severe hypertriglyceridemia and hypothyroidism who developed rhabdomyolysis and irreversible deterioration of kidney function after monotherapy with fenofibrate. The patient required renal replacement therapy using haemodialysis and kidney transplant. Conclusion: This case study is of the highest importance to warn against the adverse events associated with fenofibrate therapy and to alert to the need of a rigorous control of its use when risk factors are present. Introdução: A rabdomiólise é uma patologia definida pela necrose da célula muscular com posterior extravasão do seu conteúdo para a circulação sistémica. O fenofibrato é um derivado do ácido fíbrico indicado no tratamento da dislipidémia do adulto. A rabdomiólise provocada pelo fenofibrato em monoterapia é rara. A insuficiência renal crónica e o hipotiroidismo são factores precipitantes de rabdomiólise provocada pelo fenofibrato. Caso clínico: Descrevemos o caso de uma adolescente com insuficiência renal crónica e hipotiroidismo que teve rabdomiólise após terapêutica com fenofibrato em monoterapia e agravamento irreversível da função renal com necessidade de hemodiálise e posterior transplante renal. Conclusão: Este caso alerta para os efeitos adversos associados à utilização de fenofibrato e para a necessidade do seu controlo rigoroso sobretudo na presença de factores de risco.

Fenofibrate, a fibric acid derivative, is used as adjunctive therapy with diet for treatment of hyperlipidemia. Side effects include gastrointestinal complaints and, rarely, elevations in liver function tests. According to the drug's package insert, elevations in serum creatinine may occur; although, no postmarketing case reports of fenofibrate-induced elevations in serum creatinine are on file with the manufacturer. Fenofibrate was the probable cause of elevations in serum creatinine concentrations in six patients at our clinic. As the implications of these elevations may be serious, routine serum creatinine monitoring is recommended at baseline and 1-2 months after starting fenofibrate.

Orientador: Maria Helena de Melo Lima Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas Resumo: Amputações e úlceras no pé de pacientes diabéticos, além de comprometer a qualidade de vida, são também um problema de saúde pública. A insulina tem sido usada topicamente para tratar feridas diabéticas e mostrou acelerar o processo de cicatrização tecidual. Um estudo recente demonstrou que o fenofibrato está associado à um menor número de amputações de membros inferiores em pacientes com diabetes do tipo 2, provavelmente através de mecanismos não lipídicos. O objetivo deste estudo foi investigar a associação e os efeitos do fenofibrato sistêmico em relação à insulina tópica na cicatrização de feridas de ratos diabéticos induzidos por estreptozotocina. O diabetes foi induzido em ratos utilizando estreptozotocina. Depois de quatro dias, foi realizada uma lesão no dorso dos animais diabéticos e estas lesões foram tratadas com insulina ou fenofibrato ou insulina mais fenofibrato ou placebo como controle. Nos dias 3 e 9 os animais foram sacrificados e as lesões foram extraídas. Portanto, os resultados deste estudo indicam que o tratamento sistêmico com fenofibrato por via oral em doses terapêuticas não acelera a taxa de cicatrização de feridas em ratos diabéticos, porém existe uma maior ativação do IR, ERK-1 na fase inflamatória; e do IR e GSK-3 na fase proliferativa, além da melhora da expressão de TGF-ß e TNF-'alfa'. O tratamento combinado do fenofibrato com o creme enriquecido de insulina apresentou uma aceleração da taxa de cicatrização, promovendo a ativação da via da PI3-K, além do aumento da expressão de citocinas (TNF-'alfa' e SDF1-'alfa') e fatores de crescimento (VEGF e TGF-ß) na fase inflamatória; e melhora de TGF-ß e TNF-'alfa' durante a fase proliferativa. Neste sentido, podemos concluir que o uso do creme enriquecido de insulina mostrou-se mais eficaz na aceleração da cicatrização quando utilizada sozinha, pois houve um aumento do infiltrado inflamatório, da maturação das fibras de colágeno e da angiogênese na derme, bem como a ativação da sinalização de insulina e melhora da expressão de SDF- 1'alfa', VEGF, TGF-ß e TNF-'alfa' tanto na fase inflamatória quanto na proliferativa Abstract: Amputations and foot ulcerations in patients with diabetes impairs their quality of life and is also a problematic public health issue. Insulin has been topically used to treat diabetic wounds and has shown acceleration of the healing process. A previous study of fenofibrate was associated with fewer lower-limb amputations in patients with type 2 diabetes, probably through non-lipid mechanism. The aim of this study was to investigate the association and the effect of systemic fenofibrate in relation to topical insulin on wound healing in streptozotocin-diabetic rats. Diabetes was induced in rats using streptozotocin. After 4 days, diabetic animals were wounded and the wounds were treated with insulin or fenofibrate or insulin plus fenofibrate or a placebo as the control. At days 3 and 9 animals were sacrificed and wounds were excised. Therefore, the results of this study indicate that systemic treatment with oral fenofibrate in therapeutic dose does not accelerate the rate of wound healing in diabetic rats, however there is a greater activation of IR, ERK-1 in the inflammatory phase, and IR and GSK-3 in the proliferative phase, besides the improvement of the expression of TGF-ß and TNF- 'alfa'. The combination of fenofibrate with insulin enriched cream showed an increased rate of wound healing by promoting the activation of the PI3-K, as well as increased expression of cytokines (TNF-'alfa' and SDF1-'alfa') and growth factors (VEGF and TGF-ß) in the inflammatory phase, and enhanced TGF-ß and TNF-'alfa' during the proliferative phase. We can conclude that the use of the insulin enriched cream was more effective in accelerating the healing when used alone, demonstrated by an increased inflammatory infiltrate, the maturation of collagen fibers in the dermis and angiogenesis, as well as activation of insulin signaling and the enhanced expression of SDF-1?, VEGF, TGF-ß and TNF-'alfa' in both the proliferative and inflammatory phases Mestrado Enfermagem e Trabalho Mestre em Enfermagem

Facultad de Ciencias Médicas y Biológicas. Maestría en Ciencias de la Salud Metabolic syndrome (MS) has become a true public health problem due to its high prevalence and because it increases the risk of diabetes development and cardiovascular disease. One of its components is the atherogenic dyslipidaemia which is constituted by hypoalphalipoproteinemia, hypertriglyceridaemia and C-LDL in variable or even normal levels, however the international guidelines point at C-LDL as treatment primary target which often results in clinical practice in failure to correct TG and C-HDL levels and this maintains a residual risk in these patients. This has been demonstrated in coronary patients but there are not studies in MS patients with hypoalphalipoproteinemia, hypertriglyceridaemia and C-LDL in goal that evaluate their cardiovascular state and the response to fibrate treatment. In order to determine the effect of fenofibrate on lipid profile and vascular status of patients with MS and its dyslipidaemia 12 patients were included in a prospective, longitudinal, crossover, double blind, placebo-controlled study based on fenofibrate 160 mg daily during 8 weeks. El síndrome metabólico por su elevada frecuencia a nivel nacional se ha convertido en un verdadero problema de salud pública, además de que aumenta el riesgo de desarrollar diabetes y eventos cardiovasculares. Uno de sus componentes es la dislipidemia aterogénica la cual está constituida por hipoalfalipoproteinemia, hipertrigliceridemia y C-LDL en niveles variables incluso normales, sin embargo las guías internacionales señalan al C-LDL como el objetivo primario del tratamiento, lo que ocasiona que en la práctica clínica con frecuencia se omita corregir los niveles de TG y C-HDL lo que mantiene un riesgo residual en estos pacientes. Esto ha sido demostrado en pacientes coronarios pero no existe un estudio en pacientes con SM hipertrigliceridemia, hipoalfalipoproteinemia y C-LDL en meta, es decir una fase más temprana, donde se evalúe su condición vascular y la respuesta al tratamiento con un fibrato. Con el objeto de determinar el efecto del fenofibrato sobre el perfil de lípidos y el estado vascular de pacientes con SM y la dislipidemia descrita se incluyeron 12 pacientes en un estudio prospectivo, longitudinal, cruzado, doble ciego, controlado con placebo a base de fenofibrato 160 mg diarios durante 8 semanas.

Fibrates are used to manage mixed dyslipidemia. However, these drugs have the potential risk of inducing rhabdomyolysis. This paper gives an overview of the literature on rhabdomyolysis associated with fibrate therapy.We reported a case of rhabdomyolysis induced by fenofibrate and reviewed the published rhabdomyolysis cases associated with fibrate therapy.Seventy-six published rhabdomyolysis cases associated with fibrates were evaluated, and a nondiabetic, nonhypertensive patient who presented with rhabdomyolysis caused by fenofibrate was reported. The onset time of the reaction varied between 36 h and 6 months. Gemfibrozil was the most frequent agent associated with rhabdomyolysis, followed by bezafibrate, fenofibrate, ciprofibrate, and clofibrate. Twenty-three cases were associated with fibrate monotherapy and 54 with fibrate therapy combined with statins or other drugs potentially interacting with fibrates. Sixteen cases had chronic renal failure before fibrate therapy, and 6 had hypothyroidism. Fifty-four complicated acute renal failure. After discontinuation of the fibrates and hydration, most patients recovered.Chronic renal failure may be a risk factor for rhabdomyolysis associated with fibrates. Although rhabdomyolysis usually occurred when fibrates were combined with statins, a well-known class of agents that potentially induce rhabdomyolysis, precautions against serious adverse effects should also be taken with fibrate monotherapy.

A novel lipid formulation containing fenofibrate in omega-3 oil was developed using a novel high-throughput screening platform. The optimized formulation combines the cardiovascular health benefits from omega-3 oil with the potent lipid-regulating effect of fenofibrate. When tested against the current marketed product Tricor® in healthy human volunteers, the new formulation was shown to be equivalent to Tricor®.

Este trabalho teve por finalidade estudar os efeitos do fenofibrato, ativador do PPARá (receptor nuclear ativado pelos proliferadores de peroxissomos-á) e da esteatose hepática, induzida pela administração dietética de ácido orótico, sobre o metabolismo do tecido adiposo (TA) e fígado de ratos. Ratos Wistar machos foram divididos em 4 grupos experimentais: 1) alimentados com dieta balanceada (C); 2) Alimentados com dieta balanceada adicionada de 100 mg.Kg-1PC.dia-1 de fenofibrato (C+F) 3) alimentados com a dieta C suplementada com 1% de ácido orótico (AO); 4) alimentados com dieta balanceada contendo 1% de AO adicionado de 100 mg.Kg-1PC.dia-1 de fenofibrato (AO+F). Os animais foram alimentados por um período de 9 dias.O tratamento com fenofibrato reduziu o ganho de peso corporal, a adiposidade, a concentração plasmática de triacilglicerol (TAG) e de colesterol total mas não influenciou a ingestão alimentar e as concentrações plasmáticas de leptina, glicose, glicerol, ácidos graxos einsulina quando comparado aos animais controles. A atividade da enzima lípase lipoprotéica (LPL) do TA epididimal apresentou-se diminuída nos animais tratados com fenofibrato em relação aos controles. Além disso, pode ser verificada uma redução de 34 % na lipogênese de novo do tecido adiposo induzida pelo tratamento com fenofibrato quando comparada aos controles. A captação de glicose por adipócitos foi avaliada a partir da incubação dessas células com 2- deoxi [3H]glicose (2-DG), e os resultados mostraram que o tratamento com fenofibrato aumentou a captação de glicose tanto no estado basal quanto estimulada pela insulina por adipócitos quando comprada ao controle. Esse efeito não foi devido ao aumento no conteúdo da proteína GLUT-4 (transportador de glicose) no TA. Os resultados também demonstraram que o fenofibrato aumentou a expressão do mRNA da enzima acil CoA oxidase (ACO) e do PPARá no fígado e da enzima carnitina palmitoil transferase1 (CPT-1) e ACO no TA em relação aos controles. A administração dietética de AO aos animais durante 9 dias induziu um aumento Resumo ii significante no conteúdo hepático de gordura total (160%) e redução na concentração plasmática de TAG (30%) e colesterol total (28%) comparado aos controles. A dministraçãode fenofibrato aos animais alimentados também com AO (AO+F) impediu o acúmulo de gordura hepática e reduziu a concentração plasmática de TAG (50%) e colesterol (46%) em relação ao grupo não tratado com fenofibrato(AO). Consistentemente, a análise histológica dofígado dos animais AO mostrou um acentuado acúmulo de gordura ao passo que o tratamento com fenofibrato nesses animais impediu o desenvolvimento da esteatose. O tratamento com AO não alterou a lipogênese de novo, entretanto, a administração de fenofibrato diminuiu as taxas lipogênicas no tecido adiposo dos animais AO+F. Os resultados mostraram um aumento de 40% na atividade da enzima LPL do tecido adiposo dos animais AO comparado aos controles ao passo que o tratamento com fenofibrato (OA+F) reduziu em 50% a atividadedessa enzima em relação ao grupo AO. A suplementação com AO aumentou a captação de glicose no estado basal e estimulado com insulina por adipócitos em relação ao C. Esse efeito foi devido, pelo menos em parte, ao aumento no conteúdo da proteína GLUT-4 no TA dos animais AO. O tratamento com fenofibrato (OA+F) não alterou a captação basal ou estimulada pela insulina por adipócitos comparado ao grupo AO. A expressão hepática do mRNA para o PPARá e a enzima ACO foram 85% e 68% reduzidas nos animais AO comparada aos controles, respectivamente. O tratamento com fenofibrato (OA+F) aumentou a expressão hepática do PPARá e da enzima ACO ao passo que a expressão da CPT-1 não foi alterada quando comparado ao grupo não tratado, AO. Em resumo, esse trabalho fornece evidências de que o fenofibrato impede o desenvolvimento da esteatose hepática induzida pela administração dietética de AO através do aumento no catabolismo hepático de lipídios. Esse efeito é provavelmente mediado peloPPARá, principalmente através da indução da expressão da enzima alvo ACO envolvida no metabolismo de lipídios. Embora os compartimentos mitocondriais e peroxissomais contribuam para a oxidação dos AG, nossos dados não apontam a mitocôndria como um sítio Resumoiii importante para a oxidação de lipídios induzida pelo tratamento com fenofibrato. Além dos efeitos no fígado, o fenofibrato tem influência relevante no metabolismo do tecido adiposo que contribui, por sua vez, para a redução da adiposidade, a qual parece ser conseqüente aoaumento da oxidação local de ácidos graxos, e melhora da captação celular de glicose. The experiments reported here were designed to study the effect of fenofibrate (stimulant of peroxisome proliferator-activated receptor á - PPARá) and hepatic steatosis induced by orotic acid administration on the metabolism of adipose tissue and liver. Wistar male rats were divided into 4 experimental groups: 1) fed a balanced diet (C); 2) fed a balanced diet plus 100 mg.Kg-1bw.day-1 fenofibrate (C+F) 3) fed a balanced dietsupplemented with 1% orotic acid (OA); 4) fed C diet containing 1% OA plus 100 mg.Kg-1 bw.day-1 fenofibrate (OA+F), which were fed during 9 days. Fenofibrate lowered body weight gain and adiposity, plasma triglyceride and total cholesterol but had no influence on food intake, plasma leptin, glucose, glycerol, free fatty acid (FFA) and insulin levels when compared to control animals. The activity of lipoprotein lípase (LPL) of treated animals decreased 50 % in epididymal adipose tissue. In this study, we have shown a 34 % decrease of epididymal adipose tissue de novo lipogenesis by fenofibrate compared to C. The glucose uptake was also evaluated by adipocyte incubation with deoxyglucose (2-DG). Fenofibrate treatment increased the glucose uptake in basal or insulinstimulated adipocytes when compared to C. This effect was not due to increased GLUT-4 protein content on adipose tissue. The results also demonstrate that fenofibrate increased the mRNA expression of ACO and PPARá in the liver and CPT-1and ACO in the adipose tissuewhen compared to control animals. The administration of OA to rats for 9 days induced significant increase in total fat liver content (160%) and decreases in plasma TG concentration (30%) and total cholesterol(28%) compared to control animals. Fenofibrate administration to rats fed OA (OA+F) prevented fat liver induction and reduced the plasma triglyceride (50%), and cholesterol (46%) concentrations in relation to the not treated group (OA). Consistently, histological examination of the liver from OA rats showed marked lipid accumulation whereas the treatment with fenofibrate in these animals prevented the development of fat liver. OA Abstract v treatment did not change de novo lipogenesis, however, fenofibrate administration caused a 40% decrease in the lipogenic rates in adipose tissue from OA+F treated rats. The results showed 40% increase in LPL activity in epididymal adipose tissue from OA treated rats when compared to C group while the fenofibrate treatment (OA+F) reduced in 50% the LPL activity in relation to OA group. OA administration enhanced the adipocyte glucose uptake in basal or insulin-stimulated conditions compared to control group. This effect was due, at leastin part, to an increase in the adipose tissue GLUT-4 protein content of OA treated rats. The fenofibrate treatment (OA+F) did not change the glucose uptake in basal or stimulated adipocyte when compared to OA animals. The liver mRNA expression of PPARá and ACO were 85% and 68% decreased in OA treated group when compared to control group,respectively. The fenofibrate treatment (OA+F) increased the liver PPARá and ACO expression whereas the CPT-1 expression was not altered when compared to the not treated group OA.In summary, we provide evidence that fenofibrate decreases the hepatic steatosis induced by orotic acid administration through enhancement of lipid catabolism in rat liver. This effect is probably mediated by PPARá, mainly through the induction of the target enzyme ACO involved in hepatic lipid metabolism. Although both the peroxisomal and the mitochondrial compartments contribute to increased oxidation of fatty acids, our data did not support a role of mitochondria in wasting energy, which is instead an intrinsic property of peroxisomal â-oxidation. Besides its effects on liver, fenofibrate seems to play a relevant role on the metabolism of adipose tissue which may contribute to decrease adiposity, probably as a result of the local increased fatty acid oxidation in the tissue, and improve the Glucose uptake by adipocyte.

Os receptores ativados por proliferadores de peroxissomos (PPAR) são fatores de transcrição regulados por ligantes que controlam a expressão de diversos genes por meio da interação direta com seqüências específicas do DNA. Os agonistas desses receptores foramoriginalmente aprovados para o tratamento do diabetes mellitus tipo 2 e de dislipdemias. Diversos estudos demonstraram que os agonistas de PPAR, em adição aos seus efeitos sobre o metabolismo de carboidratos e lipídeos, apresentam algumas propriedades antiinflamatórias. Entretanto, muitos desses estudos foram conduzidos in vitro, sendo que os efeitos dessas drogas em modelos experimentais de nocicepção, edema, febre e granuloma ainda não foramamplamente investigados. Assim, o presente estudo teve como objetivo avaliar o efeito da pioglitazona (agonista PPARg) e do fenofibrato (agonista PPARa) em modelos experimentais de edema, nocicepção, febre e granuloma, de forma a obter um conhecimento mais amplosobre o potencial efeito antiinflamatório dessas drogas. O tratamento agudo com pioglitazona (50 ou 100 mg/kg, i.p.) ou os tratamentos agudo e prolongado com fenofibrato (100 ou 300 mg/kg, p.o.) não inibiram a resposta nociceptiva induzida pelo calor no modelo de placaquente em camundongos. De forma semelhante, a pioglitazona e o fenofibrato não inibiram a primeira fase da resposta nociceptiva induzida por formaldeído em camundongos. Entretanto, a segunda fase dessa resposta foi inibida pelo tratamento agudo com pioglitazona (1, 5 ou 25mg/kg, i.p.) ou pelo tratamento prolongado com fenofibrato (100 ou 300 mg/kg.dia, p.o., sete dias). O tratamento agudo com pioglitazona (10 ou 50 mg/kg, i.p.) ou com fenofibrato (100 ou 300 mg/kg, p.o.) não inibiu a alodínia mecânica induzida por carragenina em ratos. Entretanto, a fase inicial dessa resposta foi inibida pelo tratamento prolongado comfenofibrato (100 ou 300 mg/kg.dia, p.o., sete dias). O tratamento agudo com pioglitazona (10, 25 ou 50 mg/kg, i.p.) e o tratamento agudo (100 ou 300 mg/kg, p.o.) ou prolongado (100 ou 300 mg/kg.dia, p.o., sete dias) com o fenofibrato inibiram o edema de pata induzido porcarragenina em ratos. Embora pioglitazona e fenofibrato tenham inibido o edema e a alodínia induzidos por carragenina, os efeitos sobre as respostas induzidas por PDD, um ativador de proteína quinase C, não foram muito expressivos. A alodínia mecânica induzida pelo PDD emratos não foi inibida por nenhum dos agonistas. Entretanto, o edema de pata induzido por esse estímulo inflamatório foi parcialmente atenuado pelo tratamento agudo com pioglitazona (50 mg/kg, i.p.). Em um modelo de uma manifestação sistêmica da inflamação, a resposta febrilinduzida por LPS em ratos, observou-se que o tratamento agudo ou prolongado com fenofibrato (100 ou 300 mg/kg, p.o.) não induziu efeito antipirético. Entretanto, o tratamento agudo com pioglitazona (10 ou 50 mg/kg, i.p.) aumentou a magnitude da resposta febril induzida por LPS e elevou a temperatura colônica per se. O tratamento prolongado compioglitazona (10 ou 25 mg/kg.dia, i.p., sete dias) ou com fenofibrato (100 ou 300 mg/kg.dia, p.o., sete dias) não inibiu o granuloma induzido pelo implante subcutâneo de algodão em ratos. Concluindo, os resultados do estudo demonstram que a pioglitazona e o fenofibrato, agonistas de PPARg e PPARa, respectivamente, apresentam atividades antinociceptiva e antiedematogênica em diferentes modelos experimentais. Os resultados representam a primeira demonstração da atividade antinociceptiva e antiedematogênica do fenofibrato e dapioglitazona e fornecem suporte adicional ao potencial uso dos agonistas de PPARa e PPARg no tratamento de diferentes condições inflamatórias. Peroxisome proliferator activated receptors (PPAR) are ligand-regulated transcription factors that control the expression of many genes by interacting directly with specific DNA sequences. The agonists of these receptors were originally approved for the treatment of type 2 diabetes mellitus and dislipidemia. Many studies have demonstrated that PPAR agonists, in addition to their effects on carbohydrate and lipid metabolism, present some antiinflammatory properties. However, many of these studies have been carried out in vitro and the effects of these drugs in experimental models of nociception, edema, fever e granulomahave not been fully investigated. Thus, the objective of the present study was to evaluate the effect of pioglitazone (PPARg agonist) and fenofibrate (PPARa agonist) on experimental models of nociception, edema, fever and granuloma, in order to obtain a wider knowledge of the potential anti-inflammatory effect of these drugs. Acute treatment with pioglitazone (50 or 100 mg/kg, i.p.) or acute and prolonged treatment with fenofibrate (100 or 300 mg/kg, p.o.) did not inhibit the nociceptive response induced by heat in the hot plate model in mice. Similarly, pioglitazone and fenofibrate did not inhibit the first phase of formaldehyde-inducednociceptive response in mice. However, the second phase of this response was inhibited by treatment with pioglitazone (5 or 25 mg/kg, i.p.) or fenofibrate (100 or 300 mg/kg.day, seven days). Acute treatment with pioglitazone (10 or 50 mg/kg, i.p.) or fenofibrate (100 or 300 mg/kg, p.o.) also did not inhibit mechanical allodynia induced by carrageenan in rats.However, the initial phase of this response was inhibited by the prolonged treatment with fenofibrate (100 ou 300 mg/kg.day, seven days). Acute treatment with pioglitazone (10, 25 or 50 mg/kg, i.p.) and the acute (100 or 300 mg/kg, p.o.) or prolonged treatment (100 or 300 mg/kg.day, seven days) with fenofibrate inhibited the paw edema induced by carrageenan in rats. Although pioglitazone and fenofibrate inhibited the edema and allodynia induced by carrageenan, the effects induced by PDD, a protein kinase C activator, were not very expressive. Mechanical allodynia induced by PDD in rats was not inhibited by any of theagonists. However, paw edema induced by carrageenan was partially reduced by treatment with pioglitazone (50 mg/kg, i.p.). In the investigation of the effects of these drugs in a model of a systemic manifestation of inflammation, the febrile response induced by LPS in rats, itwas observed that acute or prolonged treatment with fenofibrate (100 or 300 mg/kg, p.o.) did not induce an antipyretic effect. On the other hand, acute treatment with pioglitazone (10 or 50 mg/kg, i.p.) augmented the magnitude of febrile response induced by LPS and increasedthe colonic temperature per se. Prolonged treatment with pioglitazone (10 or 25 mg/kg.day, i.p., seven days) or fenofibrate (100 or 300 mg/kg.day, p.o., seven days) did not inhibit the granuloma induced by the subcutaneous implant of cotton in rats. In conclusion, the resultsdemonstrate that pioglitazone and fenofibrate, agonist of PPARg and PPARa, respectively, present antinociceptive and antiedematogenic activity in different experimental models. These results represent the first demonstration of the antinociceptive and antiedematogenic activitiesof fenofibrate and pioglitazone and give further support to the potential use of these PPAR agonists in the treatment of different inflammatory diseases.

Resume Introduction Les rhabdomyolyses au cours des traitements par fibrates sont essentiellement le fait de leur association aux statines ou de la presence d'une insuffisance renale ou d'une hypothyroidie. Fait clinique Il s'agit d'un patient diabetique traite depuis plusieurs annees par fenofibrate en monotherapie. Quarante-huit heures apres l'introduction du gliclazide, survient une rhabdomyolyse. Discussion Le role de la deshydratation et/ou de l'interaction avec le gliclazide est discute.

The aim of this study was to evaluate the possibility of cross-reactivity between ketoprofen, fenofibrate and benzophenones because of their structural similarities. Seven patients presenting photodermatitis from ketoprofen underwent patch and photopatch tests. Ketoprofen, fenofibrate, benzophenone 3, benzophenone 10, benzophenone 4, personal medications and topical creams were tested. All patients had positive patch or photopatch tests to ketoprofen and fenofibrate, four patients had positive UVA photopatch tests to benzophenone 3, and two to benzophenone 10. Patients presenting photosensitization to ketoprofen may also have cross-reactivity to fenofibrate and some benzophenones.

During the past 20 years, fibric acid derivatives have been the drugs most commonly used in the treatment of hyperlipidemia. Among them, fenofibrate is the most frequently prescribed. 1 Side effects of these drags are mainly gastrointestinal, but skin manifestations also occur in approximately 2% of patients. 2-6 Only a few instances of photosensitivity have been reported. 7-11 In these reports, the results of photopatch testing have been variable. 8, 9 Thus systemic photochallenge may be a more appropriate test to determine fenofabrate-induced photosensitivity. W e describe three patients in whom photosensitivity caused by fenofibrate was proved by systemic photochallenge.

Case Reports; Journal Article; Research Support, Non-U.S. Gov't; Assigning causality in drug-induced liver injury is challenging particularly when more than one drug could be responsible. We report a woman on long-term therapy with raloxifen who developed acute cholestasis shortly after starting fenofibrate. The picture evolved into chronic cholestasis. We hypothesized that an interaction at the metabolic level could have triggered the presentation of hepatotoxicity after a very short time of exposure to fenofibrate in this patient. The findings of an overexpression of vascular endothelial growth factor in the liver biopsy suggest that angiogenesis might play a role in the persistence of toxic cholestasis. Yes