ABSTRACT
Las enfermedades cardiovasculares constituyen un importante problema de salud pública al ser la principal causa de morbilidad y mortalidad en el mundo. Por ello, existe la creciente necesidad de tratamientos farmacoterapéuticos más eficaces y seguros. Sin embargo, a pesar de que los médicos prescriben fármacos sobre la base de las características farmacológicas del medicamento y la probabilidad de obtener resultados clínicamente reproducibles, muchos de los fármacos son eficaces sólo entre 25-60% de los pacientes. En este sentido es que la Farmacogenómica, a través del estudio de variantes genéticas de proteínas involucradas en la farmacocinética y farmacodinamia de los medicamentos, persigue maximizar su eficacia y seguridad, Este trabajo pretende dar una visión general acerca de farmacogenómica cardiovascular y la posibilidad de utilizar, en la consulta clínica, herramientas genéticas para apoyar la decisión farmacoterapéutica, con el objeto de mejorar la respuesta al tratamiento de enfermedades cardiovasculares, un paso hacia la medicina personalizada en Chile.
Cardiovascular disease is a major public health problem being the leading cause of morbidity and mortality worldwide. Therefore, there is a growing need for safer and more effective pharmacotherapeutic treatments. However, although physicians prescribe drugs based on pharmacological properties of each drug and the probability of obtaining clinically reproducible results, many drugs are effective only in 25-60% of patients. In this respect, pharmacogenomics, through the study of genetic variants of proteins involved in the pharmacokinetics and pharmacodynamics of drugs, pursues to maximize their efficacy and safety, This paper aims to give an overview of cardiovascular pharmacogenomics and the possibility to use, in clinical practice, genetic tools to support pharmacotherapeutical decisions, in order to improve the response to treatment of cardiovascular diseases, a step toward personalized medicine in Chile.
Subject(s)
Humans , Pharmacogenetics , Cardiovascular Agents/therapeutic use , Cardiovascular Diseases/drug therapy , Cardiovascular Agents/pharmacokinetics , Cardiovascular Diseases/epidemiology , Risk Factors , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacokinetics , Anticoagulants/therapeutic use , Anticoagulants/pharmacokineticsABSTRACT
Introducción: Entre los factores de riesgo para cáncer laríngeo (CL) son relevantes el consumo de tabaco y alcohol. Estos xenobióticos son metabolizados por un grupo de enzimas, entre las cuales están CYP1A1 y GSTM1, cuyas variantes polimórficas se postulan como factores de riesgo para esta enfermedad. Objetivos: Describir la frecuencia de las variantes de los polimorfismos de CYP1A1 y GSTM1 en un grupo de pacientes diagnosticados con CL. Analizar la posible correlación entre las variantes genéticas de ambas enzimas y la presencia de CL. Evaluar la influencia del hábito tabáquico en el riesgo de aparición de cáncer escamoso de laringe en pacientes con genotipos de riesgo. Material y método: Se seleccionaron 35 pacientes con CL entre los años 2000 y 2010 en Servicio de Otorrinolaringología del HBLT y 124 controles reclutados en el Centro de Investigaciones Farmacológicas y Toxicológicas (IFT). A todos los individuos se les registraron datos demográficos y extrajo una muestra de sangre para analizar las variantes polimórficas de CYP1A1 y GSTM1, mediante PCR-RFLP. Resultados: De un total de 35pacientes 54,3% presentan el genotipo GSTM1 (-/-) y 17,1% el genotipo CYP1A1*2A C/C. En el grupo control (n =140) estas frecuencias fueron de 19,35°% y 10,48%o, respectivamente. Se observó una correlación entre GSTM1 y el CL, estratificado por el hábito tabáquico y alcohólico. No se encontraron relaciones estadísticamente significativas con el hábito alcohólico y/o tabáquico. No se observaron asociaciones entre la patología y la combinación de genotipos o entre genotipos y el hábito tabáquico o alcohólico. Conclusiones: Los resultados muestran una asociación estadísticamente significativa entre la deleción de GSTM1 (-/-) y el riesgo de presentar CL, lo que refleja el importante papel que juega esta enzima en la desintoxicación de compuestos cancerígenos. Sin embargo, se requiere incrementar el número de pacientes para establecer apropiadamente la relación genético-ambiental que permite adjudicar un papel relevante a estos biomarcadores.
Introduction: Tobacco and alcohol consumption are recognized risk factors for squamous cell carcinoma of the larynx. These xenobiotics are metabolized by numerous enzymes, among which, CYP1A1 and GSTM1 gene polymorphisms have been identified as risk factors for developing tobacco related cancers as lung and laryngeal carcinomas. Nevertheless, these polymorphisms have not been studied in Chilean patients with squamous cell carcinoma of the larynx. Aim: To describe, for the first time, the frequency of CYP1A1 and GSTM1 gene polymorphisms in Chilean patients with squamous cell carcinoma of the larynx. Material and method: We conducted a case-control study. The case group consisted of 35 Chilean patients with squamous cell carcinoma of the larynx; the control group was formed by 124 Chilean subjects without cancer diagnosis. Demographic data as age, sex and quantification of tobacco smoking and alcohol consumption were recorded in all individuals. CYP1A1 and GSTM1 gene polymorphisms were evaluated by polymerase chain reaction and restriction enzymes (PCR-RFLP). Results: The frequency of CYP1A1*2A C/C genotype was 54, 3°% among laryngeal cancerpatients and 17,1%% among control subjects. The frequency ofGSTM1 (-/-) genotype was 19,35 %% among laryngeal cancer patients and 10,48%% among control subjects. There were no statistically significant relationships between this gene polymorphisms and tobacco smoking or alcohol consumption. There were no associations between the presence of both gene polymorphisms in the same individual and the presence of laryngeal cancer. Interestingly we found an OR of 8.69 (CI 2.90 to 26.01) for GSTM1 (-/-) polymorphism and laryngeal cancer, stratified by tobacco smoking and alcohol consumption. Conclusions: Our work shows that the deletion of GSTM1 could be an important risk factor for squamous cell carcinoma of the larynx in Chilean patients. This finding reflects the important role that detoxification of carcinogenic compounds plays in Chilean population. However, it is necessary to increase the number of studied patients to properly establish the genetic-environmental relationship ascribed to these biomarkers.
Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Carcinoma, Squamous Cell/genetics , Laryngeal Neoplasms/genetics , Tobacco Smoking/adverse effects , Polymorphism, Genetic , Polymorphism, Restriction Fragment Length , Carcinoma, Squamous Cell/enzymology , Biomarkers , Case-Control Studies , Chile/epidemiology , Pilot Projects , Laryngeal Neoplasms/enzymology , Risk Factors , Cytochrome P-450 CYP1A1/genetics , Tobacco Smoking/genetics , Glutathione Transferase/geneticsABSTRACT
Background: The bioequivalence of different formulations of a same pharmaceutical product must be tested empirically. Aim: To evaluate the relative bioavailability for an oralformulation of mycophenolate mofetil (MMF) (Linfonex) compared to the reference formulation (Cellcept) to determine the bioequivalence between both formulations. Material and Methods: A randomized, crossover, double-blind trial in 22 healthy male volunteers, who received a single oral dose of 1000 mg of Linfonex and Cellcept with a washout period of 10 days. Plasma levels of the drug were determined by high performance liquid chr ornatography. Plasma concentrations were plotted and maximum concentration, area under the plasma concentration versus time between 0 and 12 hours after administration and área under plasma concentration curve versus time after administration between 0 and infinity, were calculated for both products. Results: The active compound, mycophenolic acid, was similarly absorbed in both formulations. No statistically significant differences were found in calculated pharmacokinetic parameters between both formulations. Conclusions: Linfonex 500 mg is bioequivalent to Cellcept 500 mg.
Subject(s)
Adult , Humans , Male , Immunosuppressive Agents/pharmacokinetics , Mycophenolic Acid/analogs & derivatives , Administration, Oral , Area Under Curve , Biological Availability , Chromatography, High Pressure Liquid , Cross-Over Studies , Double-Blind Method , Immunosuppressive Agents/administration & dosage , Mycophenolic Acid/administration & dosage , Mycophenolic Acid/pharmacokinetics , Therapeutic EquivalencyABSTRACT
En el presente trabajo se hace un análisis de los conceptos, normativas y propuestas sobre la equivalencia terapéutica de medicamentos similares con respecto a los innovadores, desde una perspectiva internacional y nacional, explicando las bases científicas de los estudios de bioexención in vitro para determinar la intercambiabilidad de aquellos medicamentos similares provenientes de diferentes fuentes que se han liberado de los estudios de bioequivalencia (in vivo). Además, se presentan algunos resultados de estudios de test de disolución para dar a conocer la metodología usada en la bioexención y se detallan los requisitos para aprobar un Centro de Bioequivalencia in vitro.
In this review, the concepts, guidelines and proposals regarding the determination of therapeutic equivalence of similar drug products are analyzed from a national and international point of view. The scientific background of the in vitro biowaiver studies that may result in the interchange ability of multisource drug product that have been waived from the demonstration of in vivo bioequivalence studies is also explained. In order to explain the methods in biowaiver studies, results of dissolution kinetics are shown as well as the requirements to approve an in vitro biopharmaceutic center.
Subject(s)
Biological Availability , Pharmaceutical Preparations , Therapeutic Equivalency , Chile , SolubilityABSTRACT
Cytochrome P450 enzymes are very important to metabolize anti-carcinogenic agents. Therefore, understanding the role of these enzymes and their allele variants in the bioactivation or detoxification of drugs could greatiy benefit antineoplastic pharmacotherapy. The aim of thís manuscrípt is to give information about metabohzing enzymes for antineoplastic agents and to relate the current situation in antitumoral pharmacotherapy with recent knowledge about cytochrome P450 enzymes. This is crucial for the future perspectives towards personalized pharmacotherapy. We summarize the role of cytochrome P450 enzymes in the resistance and bioactivation of several antitumor agents, their induction and repression mechanisms and the effect of genetic polymorphisms on variability of drug metabolization. The understanding of genetic variability will help to develop new research Unes on innovative therapeutic possibilities.
Subject(s)
Humans , Antineoplastic Agents/metabolism , /physiology , Neoplasms/metabolism , Polymorphism, Genetic , Antineoplastic Agents/therapeutic use , /antagonists & inhibitors , /genetics , Drug Interactions , Enzyme Induction/physiology , Enzyme Inhibitors/pharmacology , Neoplasms/drug therapyABSTRACT
Pharmacokinetics corresponds to the branch of pharmacology that studies the absorption, distribution, biotransformation and excretion of drugs in the body, in order to proportionate a reference line for interpretation of drug concentration in biological fluids, fundamental for clinical therapy. While adult pharmacology has increase greatly, advances in pediatric pharmacology have been poor. Therefore, drug prescription in children is essentially empirical on the basis of an inmature organism. An effective, secure and rational pediatric pharmacology requires exhaustive knowledgement of the developmental changes in relation to absorption, distribution, metabolism and excretion affecting pharmacokinetics parameters; therefore, the effective dose. This review describes fundamental differences between adult and pediatric pharmacokinetics. These differences must be considered when therapeutic strategies develop for newborns and children.
La farmacocinética, rama de la farmacología que estudia el paso de las drogas a través del organismo en función del tiempo y la dosis tiene por finalidad el proporcionar un marco de referencia para interpretar la concentración de los fármacos en los líquidos biológicos por el bien del paciente, lo que es fundamental para una correcta terapéutica clínica. Mientras los avances en farmacología clínica del adulto en las últimas décadas tuvieron un gran adelanto, no ha ocurrido lo mismo en farmacología pediátrica donde la mayoría de las veces la prescripción de medicamentos se realiza sobre una base empírica en un organismo inmaduro. Una terapéutica farmacológica efectiva, segura y racional en neonatos, lactantes y niños requiere el exhaustivo conocimiento de las diferencias en la absorción, distribución, metabolismo y excreción, las que aparecen durante el crecimiento y desarrollo, debido a que virtualmente, todos los parámetros farmacocinéticos se modifican con la edad. Esta revisión describe las diferencias fundamentales en la farmacocinética de los medicamentos en el niño cuando se compara con el adulto. Estas diferencias y los cambios en estos procesos deben ser cuidadosamente considerados cuando se desarrollan estrategias terapéuticas en recién nacidos y niños pequeños.
Subject(s)
Humans , Child , Drug Therapy , Child Development/physiology , Pediatrics , PharmacokineticsABSTRACT
Once drug patents expire, the health authorities can approve the registry of similar products. They must request to the manufacturer, the bibliographic background of the original product and the analytical results that certify drug quality. An inspection of the premises of the manufacturer is also required. The main goal of this approval is to decrease cost, considering that the original product is usually more expensive. This is a current situation due to the imminent expiration of the patents of many biopharmaceutical products. Therefore, in Chile, the Public Health (ISP) and the Ministry of Health should consider that for this kind of products, until now, there are no interchangeable generic drugs, and that the similar drugs that are offered have a different chemical composition, since they have been manufactured through different processes. In the case of biological drugs (e.g. erythropoietir, somatotropin, heparin) the quality and homogeneity depend from the manufacture process. Its complete composition can not be absolutely elucidated; therefore small impurities or conformational variants can elicit an altered immune response or unexpected adverse reactions. This indicates that the approval of a biogeneric drug requires in addition to pharmacokinetic studies, preclinical and clinical analytical studies such as physicochemical assays, biological and immunological test. This issues have been established by WHO and have been incorporated for the main drug registry entities all over the world (FDA, EMEA, ANVISA) to approve biogeneric products.
Subject(s)
Humans , Biological Products/adverse effects , Chile , Product Surveillance, PostmarketingABSTRACT
Background: Gastric cancer (GaC) is the second cause of death by cancer in the world and one of the first causes in Chile. However, the burden of this disease shows remarkable worldwide variation probably explained by environmental and genetic factors. The role of susceptibility low penetrance genes and environmental and dietary factors in the etiology of gastric cancer is not well-known. Aim: To analyze the possible association between CaG susceptibility, genetic (CYP1A1 and GSTM1 polymorphisms) and environmental (tobacco and alcohol) factors. Patients and Methods: In a case-control study, we included 73 patients with a pathologically diagnosed GaC and 263 controls. DNA was extracted from peripheral blood to detect allele variants for CYP1A1 and GSTM1, using polymerase chain reactions and digestion with restriction enzymes. Results: There was a clear association of smoking and alcohol ingestion with GaC with odds ratios (OR) of 2.54 (95 percent confidence intervals (CI) of 1.45-4.46 and OR of 3.36 (95 percent CI 1.76-6.41), respectively. Polymorphic variants of CYP1A1 and GSTM1 had no association with GaC. However, the m2 variant of CYP1A1 significantly modifies the risk induced by tobacco or alcohol (OR 13.65; 95 percent CI 3.15-59.05 y 8.37; 95 percent CI 1.86-37.64, respectively). Conclusions: Subjects that carry the m2 allelic variant of CYP1A1 and are exposed to tobacco smoke or alcohol have a significantly higher risk of developing gastric cancer.
Subject(s)
Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Alcohol Drinking/adverse effects , /genetics , Glutathione Transferase/genetics , Polymorphism, Genetic , Smoking/adverse effects , Stomach Neoplasms/genetics , Alcohol Drinking/genetics , Case-Control Studies , Chile , Gene Frequency , Genetic Markers , Genetic Predisposition to Disease , Genotype , Odds Ratio , Risk Factors , Smoking/geneticsABSTRACT
Background: The role of susceptibility low penetrance genes and environmental factors in the etiology of prostate cancer (PCa) is unclear, but may involve in some cases multiple alleles at multiple loci. Aim: To evaluate the association of gene-gene and gene-environment interactions with PCa. Patients and methods: One hundred three subjects with biopsy proven PCa were studied, using a case-only design. All were interrogated about smoking habits. Polymorphisms for Glutathione-S-transferase (GST) and Cytochrome P4501A1 (CYP1A1), were measured in DNA extracted from peripheral Iymphocytes, using a restriction fragment length polymorphism analysis. Results: Our findings suggest that gene-gene interactions between GSTT1 and CYP1A1 high risk genotypes were positive modifiers and had a high predictive value for the presence of PCa, compared with non-susceptibility genotypes. The interaction between susceptibility genotypes and smoking did not modify the risk for PCa. Conclusions: Gene-gene interactions may play a role modulating the susceptibility to PCa in a proportion of affected individuals (Rev Méd Chile 2004; 132: 961-66).
Subject(s)
Male , Humans , Aged , Environment , Polymorphism, Genetic/genetics , Genetic Predisposition to Disease , /genetics , Risk Factors , Genotype , HabitsSubject(s)
Humans , Male , Female , Carbon Monoxide Poisoning/mortality , Environmental Exposure/adverse effects , Carbon Monoxide/adverse effects , Carboxyhemoglobin/adverse effects , Carboxyhemoglobin/analysis , Tobacco Smoke Pollution/adverse effects , Vehicle Emissions/toxicity , Inhalation Exposure/analysis , Inhalation Exposure/adverse effects , Hypoxia-Ischemia, Brain/physiopathology , Carbon Monoxide/toxicity , Reperfusion Injury/physiopathologyABSTRACT
Actualmente se sabe que la calidad del aire intradomiciliario puede ser un factor tanto o más importante que la contaminación exterior en términos de salud de la población, lo que se debe principalmente al uso de fuentes de energía altamente contaminantes. Problema que adquiere gran importancia en aquellas ciudades con clima frío y lluvioso en donde las personas permanecen preferentemente en lugares cerrados. Por lo tanto, la elección de una determinada alternativa energética para calefacción debe considerar variables cualitativas y cuantitativas tales como: el beneficio entregado, el costo y los potenciales riesgos en salud y medioambiente. Con el objetivo de integrar la mayoría de los criterios de decisión, definidos sobre la base de su importancia relativa, se aplicó a 10 usuarios (incluidos los autores) una moderna y flexible herramienta de análisis multicriterio usada en la toma de decisiones denominada Analytic Hierarchy Process (AHP). Las alternativas energéticas analizadas fueron: gas, parafina, leña CL (combustión lenta), Leña N (combustión normal), electricidad (sistema oleolítico) y carbón. El análisi del conjunto de los criterios muestra que la electricidad es la mejor alternativa (49 por ciento) seguida del gas (30 por ciento), ambos sistemas fueron significativamente mejores que los otros. este estudio sugiere que el uso de herramientas modernas aplicadas como apoyo en la toma de decisiones en gestión ambiental, permiten evaluar objetivamente un importante problema de salud pública
Subject(s)
Humans , Air Pollution, Indoor/prevention & control , Heating/methods , Air Pollutants/adverse effects , Air Pollutants/analysis , Heating/adverse effects , Coal/adverse effects , Coal , Fossil Fuels/adverse effects , Fossil Fuels , Fires , Decision Making , Electricity/adverse effects , Electric Power Supplies/adverse effects , Electric Power Supplies , Risk Assessment/methods , Paraffin/adverse effects , Risk FactorsABSTRACT
La prueba de Ames ensayada con diferentes cepas de salmonella Typhimurium fue utilizada para determinar el poder mutagénico de extractos orgánicos de muestras provenientes del material particulado del aire de Santiago tomadas en una de las estaciones de la Red MACAM, (monitoreo automático de conmtaminantes atmosféricos y variables meteorológicas), entre los meses de Marzo y Agosto de 1990. Los ensayos se realizaron con las cepas TA98, TA98NR y TA98/I DNP6 en presencia o ausencia de fracción 89. Las muestras analizadas presentaron un alto poder mutagénico cuando se utilizó la cepa TA98 en presencia o ausencia de fracción 89, indicando que el aire de Santiago contiene agentes mutagénicos, indirectos principalmente hidrocarburos aromáticos y policíclicos (HAPs) y agentes mutagénicos directos que no requieren activación metabólica. La mutagenicidad de las muestras de Santiago fue mucho mayor que la obtenida en investigaciones realizadas en otros países. Estudios con la cepa TA 98 NR, deficiente en nitroreductasas y en enzimas que esterifican hidroxilamina, revelan que los extractos analizados contienen también mononitro y dinitroarenos. Estos últimos compuestos que se pueden generar por reacciones fotoquímicas entre HAPs, ozono y óxidos de nitrógeno o en la combustión de motores Diesel, han sido descritos como de muy alta actividad mutagénica. La presencia de HAPs y nitroarenos en los extractos permiten concluir que el aire de Santiago contiene agente químicos que potencialmente presentan un grave riesgo para la salud de la población