Metodología de investigación en farmacogenética: estudios de casos y controles / Methodology for research in pharmacogenetics: Case-control studies

RESUMEN La farmacogenética estudia la asociación entre el fenotipo farmacológico de un individuo con su constitución genética, y el diseño de estudios de casos y controles es una metodología de uso frecuente. Este diseño consiste en que se analiza la frecuencia de las variantes genéticas en los casos, es decir, de los pacientes que presentan el fenotipo (desenlaces o resultados) comparado con los controles. Para obtener una calidad metodológica adecuada en este tipo de estudios es importante trabajar con fenotipos precisos, adecuada selección de los casos y controles y tamaño de la muestra; seleccionar una metodología adecuada para la identificación de variantes genéticas; y en el momento del análisis de resultados utilizar el Equilibrio de Hardy-Weinberg (EHW) e interpretar los resultados considerando la posibilidad de un fenómeno de fenoconversión.

ABSTRACT Pharmacogenetics studies the association between the pharmacological phenotype of an individual with his/her genetic constitution. Case-control studies is a commonly used methodology when performing pharmacogenetics research. This design analyses the frequency of genetic variants in cases; that is, of those patients who have a particular phenotype (outcomes or results) compared with controls. For obtaining adequate methodological quality in pharmacogenetic case-control studies, it is important to work with precise phenotypes, have adequate case and control selection and appropriate sample size; select an adequate methodology for the identification of genetic variants, analyze the results using Hardy-Weinberg Equilibrium (HWE); and interpret the results considering the possibility of a phenoconversion phenomenon.

Phenoconversion of drug-metabolizing enzymes and its mechanism during inflammatory conditions / 国际药学研究杂志

Inflammatory conditions are associated with most diseases. Phenoconversion of drug-metabolizing enzymes(DME) leads to altered drug metabolism and disposition. It has profound impact on the pharmacotherapy of widely used clinically relevant medications in terms of safety and efficacy. More and more evidence has proved that elevated levels of proinflammatory cytokines may downregulate the expression and the activity of many Phase Ⅰ and Phase Ⅱ DME, which are involved in complex regulation mechanisms of drug disposition. The aim of this review is to present the recent findings in this area. Clinical practice based on personalized medicine according to DME phenotype with improved safety and efficiency can yield robust efficacy outcomes of drug treatment and has promising future prospects.

Phenoconversion of drug-metabolizing enzymes and its mechanism during inflammatory conditions / 国际药学研究杂志

Inflammatory conditions are associated with most diseases. Phenoconversion of drug-metabolizing enzymes (DME) leads to altered drug metabolism and disposition. It has profound impact on the pharmacotherapy of widely used clinically relevant medications in terms of safety and efficacy. More and more evidence has proved that elevated levels of proinflammatory cytokines may downregulate the expression and the activity of many Phase I and Phase “DME, which are involved in complex regulation mechanisms of drug disposition. The aim of this review is to present the recent findings in this area. Clinical practice based on personalized medicine according to DME phenotype with improved safety and efficiency can yield robust efficacy outcomes of drug treatment and has promising future prospects.

Signaling Mechanisms Regulating Fibroblast Activation, Phenoconversion and Fibrosis in the Heart.

Cardiac fibroblasts (CFs) maintain the cardiac extracellular matrix (ECM) through myocardial remodelling. The remodelling process can become dysregulated during various forms of heart disease  which leads to an overall accumulation of ECM. This results in cardiac fibrosis which increases the risk of heart failure in many patients. During heart disease, quiescent CFs undergo phenoconversion to an activated cell type called cardiac myofibroblasts (CMFs). Factors influencing phenoconversion include transforming growth factor β (TGF-β) which via SMADs (small mothers against decapentaplegic) activates the myofibroblast marker gene αSMA (α smooth muscle actin). Signaling molecules as diverse as NAD(P)H oxidase 4 (Nox4) and Wnt have been found to interact with TGF-β signalling via SMADs. Pathways, including FAK/TAK/JNK and PI3K/Akt/rac have also been implicated in activating phenoconversion of fibroblasts. Another major contributor is mechanical stress exerted on CFs by ECM changes, which involves activation of ERK and subsequent αSMA expression. Other factors, such as the mast cell protease tryptase and the seeding density also affect the phenoconversion of fibroblast cultures in vitro. Further, reversal of myofibroblast phenotype has been reported by a negative regulator of TGF-β, Ski, as well as the hormone relaxin and the second messenger cAMP. Targeting the signaling molecules involved in promoting phenoconversion of CFs to CMFs presents a possible method of controlling cardiac fibrosis. Here, we provide a brief review of signaling mechanisms responsible for phenoconversion and identify critical targets for the treatment of cardiac fibrosis.