RESUMO
BACKGROUND: Solid Dispersions (SDs) have been extensively used to increase the dissolution of poorly water-soluble drugs. However, there are few studies exploring SDs properties that must be considered during tablet development, like tabletability. Poorly water-soluble drugs with poor compression properties and high therapeutic doses, like gemfibrozil, are an additional challenge in the production of SDs-based tablets. OBJECTIVE: This study evaluates the applicability of SDs to improve both tabletability and dissolution rate of gemfibrozil. A SD-based tablet formulation was also proposed. METHODS: SDs were prepared by ball milling, using hydroxypropyl methylcellulose (HPMC) as a carrier, according to a 23 factorial design. The formulation variables were gemfibrozil:HPMC ratio, milling speed, and milling time. The response in the factorial analysis was the tensile strength of the compacted SDs. Dissolution rate and solid-state characterization of SDs were also performed. RESULTS: SDs showed simultaneous drug dissolution enhancement and improved tabletability when compared to corresponding physical mixtures and gemfibrozil. The main variable influencing drug dissolution and tabletability was the gemfibrozil:HPMC ratio. Tablets containing gemfibrozil- HPMC-SD (1:0.250 w/w) and croscarmellose sodium showed fast and complete drug release, while those containing the same SD and sodium starch glycolate exhibited poor drug release due to their prolonged disintegration time. CONCLUSION: SDs proved to be effective for simultaneously improving tabletability and dissolution profile of gemfibrozil. Tablets containing gemfibrozil-HPMC-SD and croscarmellose sodium as disintegrating agent showed improved drug release and good mechanical strength, demonstrating the potential of HPMC-based SDs to simultaneously overcome the poor dissolution and tabletability properties of this drug.
Assuntos
Genfibrozila , Comprimidos , Composição de Medicamentos , Liberação Controlada de Fármacos , Genfibrozila/química , SolubilidadeRESUMO
Hypercholesterolemia, also called high cholesterol, is a form of hyperlipidemia, which may be a consequence of diet, obesity or diabetes. In addition, increased levels of low-density lipoprotein (LDL) and reduced levels of high-density lipoprotein (HDL) cholesterol are associated with a higher risk of atherosclerosis and coronary heart disease. Thus, controlling cholesterol levels is commonly necessary, and fibrates have been used as lipid-lowering drugs. Gemfibrozil is a fibrate that acts via peroxisome proliferator-activated receptor alpha to promote changes in lipid metabolism and decrease serum triglyceride levels. However, anemia and leukopenia are known side effects of gemfibrozil. Considering that gemfibrozil may lead to anemia and that gemfibrozil acts via peroxisome proliferator-activated receptor alpha, we treated wild-type and peroxisome proliferator-activated receptor alpha-knockout mice with gemfibrozil for four consecutive days. Gemfibrozil treatment led to anemia seven days after the first administration of the drug; we found reduced levels of hemoglobin, as well as red blood cells, white blood cells and a reduced percentage of hematocrits. PPAR-alpha-knockout mice were capable of reversing all of those reduced parameters induced by gemfibrozil treatment. Erythropoietin levels were increased in the serum of gemfibrozil-treated animals, and we also observed an increased expression of hypoxia-inducible factor-2 alpha (HIF-2α) and erythropoietin in renal tissue, while PPAR-alpha knockout mice treated with gemfibrozil did not present increased levels of serum erythropoietin or tissue HIF-2α and erythropoietin mRNA levels in the kidneys. We analyzed bone marrow and found that gemfibrozil reduced erythrocytes and hematopoietic stem cells in wild-type mice but not in PPAR-alpha-knockout mice, while increased colony-forming units were observed only in wild-type mice treated with gemfibrozil. Here, we show for the first time that gemfibrozil treatment leads to anemia and leukopenia via peroxisome proliferator-activated receptor alpha in mice.
Assuntos
Anemia/induzido quimicamente , Genfibrozila/efeitos adversos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Hipolipemiantes/efeitos adversos , Leucopenia/induzido quimicamente , PPAR alfa/metabolismo , Anemia/metabolismo , Animais , Contagem de Células , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/metabolismo , Leucopenia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Gemfibrozil (GFZ) is a derivative of fibric acid and is used in the treatment of dyslipidemia. GFZ may affect the metabolism of various drugs, including statins, by inhibiting the sinusoidal influx transporter OATP1B1 and also CYP2C9 and CYP2C8 enzymes. This study presents the development and validation of a rapid, simple, sensitive and reproducible method of GFZ analysis in human plasma using UPLC-MS/MS. The method was applied in a pharmacokinetic study following administration of multiple doses of 600â¯mg GFZ every 12â¯h in healthy volunteers (nâ¯=â¯15). GFZ was separated on a C18 column using a mixture of 0.01% formic acid and acetonitrile (40:60, v/v) as the mobile phase at a flow rate of 0.4â¯mL/min. The method showed linearity in the range from 0.01⯵g/mL to 100⯵g/mL plasma. The coefficients of variation and the relative standard errors of the accuracy and precision analyses were <15%. The method allowed quantification of plasma concentrations of GFZ in the dose interval of the sixth day of administration of multiple oral doses of GFZ every 12â¯h. The pharmacokinetic parameters are presented as mean (95% CI): area under the plasma concentration versus time curve 88.84 (72.72-104.96) µg·h/mL, steady state mean plasma concentration 7.40 (6.06-8.75) µg/mL, minimum plasma concentration 1.24 (0.87-1.61) µg/mL, maximum plasma concentration 26.73 (21.31-32.15) µg/mL, time to reach maximum plasma concentration 2.28 (1.42-3.13) h, elimination half-life 2.81 (2.22-3.40) h, apparent total clearance 7.72 (5.85-9.58) L/h, apparent distribution volume 33.97 (18.41-49.53) L. In conclusion, the method for analysis of GFZ in human plasma showed sensitivity, linearity, precision and accuracy compatible with application in pharmacokinetic studies of multiple oral dose of 600â¯mg GFZ every 12â¯h.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Genfibrozila/sangue , Hipolipemiantes/sangue , Espectrometria de Massas em Tandem/métodos , Brasil , Genfibrozila/farmacocinética , Voluntários Saudáveis , Humanos , Hipolipemiantes/farmacocinética , MasculinoRESUMO
Sepsis is a serious condition characterized by an infectious process that induces a severe systemic inflammatory response. In this study, the effects of gemfibrozil (GFZ) on the inflammatory response associated with abdominal sepsis were investigated using a rat model of cecal-ligation and puncture (CLP). Male Wistar rats were randomly divided into three groups: Sham-operated group (sham), where laparotomy was performed, the intestines were manipulated, and the cecum was ligated but not punctured; control group, subjected to CLP; and GFZ group, which received GFZ prior to undergoing CLP. The groups were then subdivided into three different time-points: 2, 4 and 24 h, indicating the time at which blood samples were obtained for analysis. Serum concentrations of tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), malondialdehyde (MDA), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) were determined. The LDH, AST and ALT values were significantly elevated following CLP compared with those in the sham group, and GFZ treatment was able to reduce these elevations. GFZ also reduced the sepsis-induced elevations of TNF-α and IL-1. In conclusion, GFZ treatment was able to attenuate the inflammatory response associated with CLP-induced sepsis, by diminishing the release of inflammatory cytokines, thereby reducing tissue injury and oxidative stress.
RESUMO
El abuso de la ingestión de drogas y la creación de nuevos medicamentos, ha producido un aumento en la aparición de reacción adversa a medicamentos (RAM), los que deben ser siempre informados dada la importancia de su registro. Un tipo de RAM es la erupción fija medicamentosa (EFM). Se revisará un caso de EFM asociada al gemfibrozilo (GMZ) en un paciente chileno de 75 años, quien presentó en dos ocasiones lesiones dermatológicas en la misma localización anatómica, tras la ingestión de GMZ. EFM representa el 5-10% de las RAM y pueden manifestarse en piel y/o mucosas y suelen recurrir en el mismo sitio, cada vez que el paciente consume la droga. Los medicamentos más comunes que producen esta reación son: los antibióticos, analgésicos-anti-inflamatorios no esteroides e hipnóticos. No hemos encontrado publicados casos de EFM a causa de GM. Una EFM ampollar generalizada, es importante diferenciarla clínica e histológicamente del síndrome de Stevens-Johnson o de la necrólisis epidérmica tóxica. Los síntomas, signos, evolución y la histología del caso, nos hace pensar en una EFM bulosa generalizada debido a GMZ.(AU)
RESUMO
El abuso de la ingestión de drogas y la creación de nuevos medicamentos, ha producido un aumento en la aparición de reacción adversa a medicamentos (RAM), los que deben ser siempre informados dada la importancia de su registro. Un tipo de RAM es la erupción fija medicamentosa (EFM). Se revisará un caso de EFM asociada al gemfibrozilo (GMZ) en un paciente chileno de 75 años, quien presentó en dos ocasiones lesiones dermatológicas en la misma localización anatómica, tras la ingestión de GMZ. EFM representa el 5-10% de las RAM y pueden manifestarse en piel y/o mucosas y suelen recurrir en el mismo sitio, cada vez que el paciente consume la droga. Los medicamentos más comunes que producen esta reación son: los antibióticos, analgésicos-anti-inflamatorios no esteroides e hipnóticos. No hemos encontrado publicados casos de EFM a causa de GM. Una EFM ampollar generalizada, es importante diferenciarla clínica e histológicamente del síndrome de Stevens-Johnson o de la necrólisis epidérmica tóxica. Los síntomas, signos, evolución y la histología del caso, nos hace pensar en una EFM bulosa generalizada debido a GMZ.
RESUMO
OBJECTIVE: To determine the effectiveness of lipid-lowering therapy in a sample of patients affiliated with the Sistema General de Seguridad Social en Salud (the Colombian health system). METHODS: A cross-sectional study was conducted from 1 January 2010-30 June 2011. From a total of 8 316 patients in 10 cities, a random sample of 600 was stratified according to dyslipidemia. Information on sociodemographic and anthropometric characteristics, risk factors, and pharmacological and laboratory variables were obtained from medical records. RESULTS: Subjects were predominantly female (56.2%), with a mean age of 65.1 ± 11.5 years; 93.2% had hypertension; 29.0%, diabetes mellitus; and 10.2%, a history of myocardial infarction. The patients were being treated with lovastatin (84.1%) or gemfibrozil (12.3%)-both at doses below what is recommended-or atorvastatin (1.8%). In patients with high cardiovascular risk, 38.6% achieved goals for low-density lipoprotein cholesterol (LDL-C) levels (<100 mg/dL). Among those at moderate risk, 49.4% reached the target level (< 130 mg/dL). On average, there was a 4.9% reduction in LDL-C. Sex, age, history of cardiovascular disease and/or diabetes mellitus, use of hydrochlorothiazide, and poor therapy adherence were statistically associated with a lack of dyslipidemia control. CONCLUSIONS: Because a lack LDL-C control occurred in patients with two or more of the following variables: male, more than 55 years of age, diabetes and/or a history of cardiovascular disease, received lower doses of lovastatin, or non-adherent to treatment, it is recommended that medication be increased based on clearly-defined therapeutic goals and that comorbidities be assessed and effectively treated.
OBJETIVO: Determinar la eficacia del tratamiento hipolipemiante en una muestra de pacientes afiliados al Sistema General de Seguridad Social en Salud de Colombia. MÉTODOS: Se llevó a cabo un estudio transversal desde el 1 de enero del 2010 al 30 de junio del 2011. De un total de 8 316 pacientes de 10 ciudades seleccionadas, se estratificó una muestra aleatoria de 600 pacientes en función de la dislipidemia. A partir de los expedientes médicos, se obtuvo información sobre las características sociodemográficas y antropométricas, los factores de riesgo y las variables farmacológicas y de laboratorio. RESULTADOS: En la muestra predominaban las mujeres (56,2%) y la media de la edad era de 65,1 ± 11,5 años; 93,2% de los pacientes eran hipertensos; 29,0% eran diabéticos; y 10,2% tenían antecedentes de infarto de miocardio. Los pacientes recibían tratamiento con lovastatina (84,1%) o gemfibrozilo (12,3%) -ambos a dosis inferiores a las recomendadas- o atorvastatina (1,8%). El 38,6% de los pacientes con alto riesgo de enfermedad cardiovascular alcanzaron los objetivos de reducción de los niveles de colesterol unido a lipoproteínas de baja densidad (C-LDL) (< 100 mg/dL). El 49,4% de los pacientes que presentaban un riesgo moderado también alcanzaron los niveles fijados como objetivo (< 130 mg/dL). En promedio, hubo una reducción de 4,9% del C-LDL. El sexo, la edad, los antecedentes personales de enfermedad cardiovascular y diabetes, la administración de hidroclorotiazida y la deficiente adherencia al tratamiento se asociaron estadísticamente con una falta de control de la dislipidemia. CONCLUSIONES: Dado que se produjo un control deficitario del C-LDL en pacientes con dos o más de las siguientes variables: varones, mayores de 55 años, diabéticos o con antecedentes de enfermedad cardiovascular, que recibían dosis bajas de lovastatina, o mostraban falta de adherencia al tratamiento, se recomienda que se aumente la medicación con base en objetivos terapéuticos claramente definidos y que se evalúen y se traten eficazmente las comorbilidades.
Assuntos
Humanos , Masculino , Feminino , Idoso , Dislipidemias/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Colômbia , Estudos Transversais , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Se estudió la regulación del receptor de lipoproteína de muy baja densidad (VLDLR) en dos tipos de células que intervienen en la respuesta inflamatoria: hepatocitos (HepG2) y células linfocitarias de bazo de ratón (CMB) por agentes implicados en la inflamación: VLDL o Gemfibrozil, lipopolisacárido bacteriano (LPS) para HepG2 o Concanavalina A (ConA) para CMB. Se determinaron por citometría de flujo las subpoblaciones de CMB y de HepG2 en distintas fases del ciclo celular (G1 y G2/M) con ioduro de propidio y las VLDLR+ con VLDL fluorescente. Entre 10 a 60 por ciento de células expresaron VLDLR dependiendo de las condiciones experimentales. El enfrentamiento con LPS o ConA produjo un aumento de células VLDLR+. El tratamiento con Gemfibrozil disminuyó el número de hepatocitos en reposo VLDLR+ pero incrementó significativamente (más de dos veces) los hepatocitos VLDLR+ en fase G2/M. En los cultivos de CMB Gemfibrozil aumentó por igual el porcentaje de células VLDLR+ quiescentes y en G2/M. El comportamiento de estos tipos celulares con VLDL fue distinto: CMB no mostró cambios en las subpoblaciones VLDLR+, los hepatocitos mostraron disminución de VLDLR+ tanto en fase G1 como en fase G2/M. Se concluyó que el estudio de la regulación de VLDLR en distintas células facilitará el diseño de fármacos específicos para el tratamiento de enfermedades de etiología inflamatoria.
The regulation of the VLDL receptor (VLDLR) by molecules involved in the inflammation process (lipopolysaccharide, LPS; Concanavalin A, ConA, VLDL or Gemfibrozil) in two cellular types implied in the inflammatory response, hepatocytes (HepG2) and lymphocitary cells from mice spleen (CMB), was studied. Different subpopulations of CMB and HepG2 in different cell cycle phases (G1 and G2/M) were analyzed using flow citometry techniques with propidium iodide, and the VLDLR+ with fluorescent VLDL. In cultures of both cell types, it was observed that 10 to 60% of the cells expressed the VLDLR (VLDLR+ cells) indistinctly of the culture conditions. VLDLR+ cells belonged equally to cells in the quiescent and in the synthesis or mitosis phase of the cell cycle. Challenging them with LPS or ConA an increase in the percentage of VLDLR+ cells was produced. Gemfibrozil treatment decreased the number of resting hepatocytes VLDLR+ but increased significantly (more than twice) the number of hepatocytes VLDLR+ in phase G2/M. In hepatocytes there was almost the same proportion of VLDLR+ cells that were in the G1 or in the G2/M phase of the cell cycle. It is concluded that the study of VLDLR regulation will facilitate the design of new drugs to treat inflammatory diseases.
Assuntos
Genfibrozila , Inflamação , LipoproteínasRESUMO
PURPOSE--To evaluate the effects of gemfibrozil and pravastatin in coronary artery disease patients with HDL-cholesterol (HDL-C) < 35 mg/dl). METHODS--Twenty-nine patients (20 males, 60 +/- 9) were divided in a gemfibrozil group (G) (1200 mg/day n = 15) and a pravastatin group (P) (10 or 20 mg n = 10 and 4, respectively). The plasma lipid profile (LP) e.g. total cholesterol (TC), fractions and triglycerides (TG) was determined at 4 and 12 weeks of treatment. RESULTS--HDL-C was not affected in P, TC and LDL-cholesterol (LDL-C) reductions were superior to those in G (31.3 vs 13.4 and 38.7 and 11.5, p < 0.05 and < 0.01 respectively). In G HDL-C raised by 50 (12th week p < 0.01). Gemfibrozil reduced TG levels in 44.7 while in P it varied -32.2 (12th week p < 0.01 and < 0.05 respectively). CONCLUSION--Gemfibrozil is more effective in reducing TG and raising HDL-C than pravastatin. On the other hand, pravastatin was more potent in reducing LDL-C levels.
Objetivo - Comparar os efeitos do gemfibrozil e pravastatina no perfil lipídico (PL) de pacientes coronarianos com HDL-colesterol (HDL-C) <35 mg/dl Métodos - Vinte e nove pacientes (20 homens, 60 9 anos) divididos em grupo gemfibrozil (G) (1200mg/dia n=15) e grupo pravastatina (P) (10mg e 20mg, 10 e 4 pacientes, respectivamente). O perfil lipídico plasmático [colesterol total (CT), frações e triglicérides (TG)] foi avaliado a 4 e 12 semanas de tratamento. Resultados - Em P, o HDL-C não se alterou, as reduções de CT e LDL-colesterol (LDL-C) foram superiores às de G (31,3% vs 13,4% e 38,7 e 11,5%, respectivamente p<0,05 e <0,01). Em G. o HDL-C elevou-se em até 50% (12º semana, p<0,01). O gemfibrozil reduziu os TG em 44,7% (p<0,01) enquanto que em P, a variação foi de -32,2% na 12º semana (p<0,05). Conclusão - O gemfibrozil é mais eficaz que a pravastatina para reduzir os TG e elevar o HDL-C, porém a pravastatina é um redutor mais potente do LDLC
Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Genfibrozila , Pravastatina , Doença das Coronárias , Anticolesterolemiantes/uso terapêutico , Hipolipemiantes/uso terapêutico , Colesterol , Doença das Coronárias , HDL-Colesterol , LDL-Colesterol , Análise de VariânciaRESUMO
Purpose - To compare the effects of lovastatin and gemfibrozil in patients with primary hyperlipidemias. Patients and Methods - Forty patients with cholesterolemia over 200 mgldl and triglyceridemia not higher than 350 mp/dl, excluded secondary causes, were selected. Twenty patients received lovastatin and 20 gemfibrozil. In order to establish the lipid profile, blood samples were taken after 2 months without medication, after 4 weeks of diet and placebo and after 6 and 12 weeks active treatment. Biochemic profile was determined before and after the treatment with active drug. Results - Thirty nine patients completed the study. Total and LDL-cholesterol were significantly reduced (p < 0.05) by both drugs but lovastatin had greater effect. Only gemfibrozil reduced triglycerides significantly. Neither drug had significant effects on HDL-cholesterol. The tolerance was satisfactory; only one patient (using gemfibrozil) needed to stop the treatment due to gastrointestinal side effects. The biochemic profïle did not present any significant alteration. Conclusion - Both drugs produced useful effects on the lipid profile. Lovastatin produced greater reductions of total and LDL-cholesterol, while gemfibrozil was more active reducing triglycerides. Neither drug changed significantly the HDL-cholesterol