Advanced Search
Now showing items 1-10 of 1130
Polimorfismos en el Gen de la deshidrogenasa alcohólica 1C (ADH1C) aumentan el riesgo de alcoholismo en la población chilena
(Universidad de ChilePrograma Cybertesis, 2008)
El riesgo individual de alcoholismo tiene un componente hereditario de 40 a 60%. Los únicos factores genéticos bien establecidos para una susceptibilidad diferenciada al alcoholismo son polimorfismos en los genes de las principales enzimas del...
Prevalencia del alcoholismo durante tres décadas en Chile (1952-1982)
(1989)
Mediante el método de Jellinek se estudió la evolución del número de alcohólicos y de la tasa de prevalencia de alcoholismo en Chile y sus variaciones entre los años 1952 y 1982. Se señalan los sesgos y limitaciones de la metodología empleada y se...
Alcoholism and heredity. A critical update Alcoholismo y herencia. Una actualizacion critica.
(1994)
Alcoholism and heredity. A critical update Alcoholismo y herencia. Una
actualizacion critica.
Rothhammer,
Moreno,
Llop,
The etiology of alcoholism is under constant revision. This work critically examines...
Terapia Génica por Vectores Adenovirales en Modelos Animales de Alcoholismo: Inhibición de la Expresión del Gen de la Deshidrogenasa Aldehídica Mitocondrial Mediante un Gen Antisentido
(Universidad de Chile, 2006)
El alcoholismo es una enfermedad de etiología multifactorial que causa un número de
problemas sociales, laborales, legales y médicos. El riesgo de un individuo de
desarrollar alcoholismo está influenciado por varios genes. Algunos genes permiten el...
Alcoholism is defined by the compulsive excessive use of alcohol despite of negative consequences perceived by the subject. It is not only one of major public health problems due to the morbidity caused by the alcohol abuse disorder but it is also a major social problem. The risk of developing this disease is genetically influenced, with some genes being permissive and other genes protective. Most of the elimination of ethanol occurs by oxidation to acetaldehyde and further into acetate. The reactions are sequentially catalyzed by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). The oxidation of acetaldehyde to acetate is catalyzed primarily by ALDH2, the low Km isozyme of ALDH present in mitochondria. A mutation in the gene coding for ALDH2 present in some Asian populations, lowers or abolishes the activity of this enzyme and results in marked elevations in blood acetaldehyde upon ethanol consumption. The resulting phenotype greatly protects against alcohol abuse and alcoholism. The protective Asian phenotype can be elicited in alcoholics who are administered the aversive medication disulfiram (Antabuse®), affording these individuals the same protection from alcohol abuse. However, disulfiram is a non-specific drug that binds to sulfhydryl groups, has a short half-life, cannot be metabolized by some patients into its active metabolite, and has marked toxicity side effects, as it nonspecifically binds to sulfhydryl groups in other proteins. Gene therapy, as a new approach, opens the possibility of developing a specific aversive medication for alcoholism. This new treatment, based on the reduction of Aldh2 mRNA transduction, provides a means by which gene expression can be specifically inhibited to yield the low-ALDH2 Asian phenotype. The aim of the work presented in this thesis is to reduce Aldh2 mRNA translation in the rat by the intracellular generation of an antisense aldehyde dehydrogenase RNA coded by an antisense gene (Aldh2 cDNA in a 3´ to 5´ orientation) contained in an adenoviral vector. Rat hepatoma cells were transduced with the antisense coding gene against ALDH2 carried by the adenoviral vector, leading to the generation of high levels of antisense mRNA. The cells infected with this vector, reduced their ALDH2 activity by 60 to 70% and, in the presence of ethanol, increased 8-fold the levels of acetaldehyde (10 μM to 80 μM). In studies in vivo, the adenoviral vector coding for the antisense-Aldh2 RNA was administered to UChB rats (University of Chile alcohol dependent rats). The rats infected with a single dose of the vector (1012 vp/kg) by tail vein injection inhibited its ALDH2 activity in 90% and reduced its alcohol consumption in 50%. The reduction in alcohol consumption lasted 34 days, time at which the study was terminated. A parallel study in which rats were infected 10 days earlier with a single dose of the vector carrying the antisense gene showed a 37.5% reduction in hepatic ALDH2 activity, while acetaldehyde plasma levels following the administration of ethanol increased 6-8 fold over controls (5-10 μM to 40-60 μM) (p<0,01). Overall, rats treated with an Aldh2- antisense coding gene show significant reductions in hepatic ALDH2 activity and elevations in systemic acetaldehyde upon ethanol administration, which are accompanied by marked reductions in ethanol voluntary consumption in alcohol dependent animals. These preclinical studies suggest that a long-lasting specific gene therapy against alcoholism may be developed...
Alcoholism is defined by the compulsive excessive use of alcohol despite of negative consequences perceived by the subject. It is not only one of major public health problems due to the morbidity caused by the alcohol abuse disorder but it is also a major social problem. The risk of developing this disease is genetically influenced, with some genes being permissive and other genes protective. Most of the elimination of ethanol occurs by oxidation to acetaldehyde and further into acetate. The reactions are sequentially catalyzed by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). The oxidation of acetaldehyde to acetate is catalyzed primarily by ALDH2, the low Km isozyme of ALDH present in mitochondria. A mutation in the gene coding for ALDH2 present in some Asian populations, lowers or abolishes the activity of this enzyme and results in marked elevations in blood acetaldehyde upon ethanol consumption. The resulting phenotype greatly protects against alcohol abuse and alcoholism. The protective Asian phenotype can be elicited in alcoholics who are administered the aversive medication disulfiram (Antabuse®), affording these individuals the same protection from alcohol abuse. However, disulfiram is a non-specific drug that binds to sulfhydryl groups, has a short half-life, cannot be metabolized by some patients into its active metabolite, and has marked toxicity side effects, as it nonspecifically binds to sulfhydryl groups in other proteins. Gene therapy, as a new approach, opens the possibility of developing a specific aversive medication for alcoholism. This new treatment, based on the reduction of Aldh2 mRNA transduction, provides a means by which gene expression can be specifically inhibited to yield the low-ALDH2 Asian phenotype. The aim of the work presented in this thesis is to reduce Aldh2 mRNA translation in the rat by the intracellular generation of an antisense aldehyde dehydrogenase RNA coded by an antisense gene (Aldh2 cDNA in a 3´ to 5´ orientation) contained in an adenoviral vector. Rat hepatoma cells were transduced with the antisense coding gene against ALDH2 carried by the adenoviral vector, leading to the generation of high levels of antisense mRNA. The cells infected with this vector, reduced their ALDH2 activity by 60 to 70% and, in the presence of ethanol, increased 8-fold the levels of acetaldehyde (10 μM to 80 μM). In studies in vivo, the adenoviral vector coding for the antisense-Aldh2 RNA was administered to UChB rats (University of Chile alcohol dependent rats). The rats infected with a single dose of the vector (1012 vp/kg) by tail vein injection inhibited its ALDH2 activity in 90% and reduced its alcohol consumption in 50%. The reduction in alcohol consumption lasted 34 days, time at which the study was terminated. A parallel study in which rats were infected 10 days earlier with a single dose of the vector carrying the antisense gene showed a 37.5% reduction in hepatic ALDH2 activity, while acetaldehyde plasma levels following the administration of ethanol increased 6-8 fold over controls (5-10 μM to 40-60 μM) (p<0,01). Overall, rats treated with an Aldh2- antisense coding gene show significant reductions in hepatic ALDH2 activity and elevations in systemic acetaldehyde upon ethanol administration, which are accompanied by marked reductions in ethanol voluntary consumption in alcohol dependent animals. These preclinical studies suggest that a long-lasting specific gene therapy against alcoholism may be developed...
Un modelo de programa de rehabilitación de drogas y alcohol desde una perspectiva junguiana
(Universidad de Chile, 2021)
Producción y purificación de vectores adenovirales y adenoasociados para terapia génica contra el alcoholismo
(Universidad de Chile, 2016)
purificación de vectores virales adenovirus y adenoasociados, centrándose en su uso para una terapia génica contra el alcoholismo. Se realizó la purificación de los vectores adenovirales rAd5V que contenían la secuencia de ARN antisentido de la enzima ALDH2, y...
Evaluación in vitro de la toxicidad de alda-1, un compuesto experimental para el tratamiento del alcoholismo
(Universidad de Chile, 2022)
El alcohol es una sustancia psicoactiva con propiedades tóxicas y productoras de dependencia. La OMS estima que 3 millones de muertes anuales son atribuibles al consumo de alcohol. El tratamiento farmacológico actual del alcoholismo se basa en tres...
Alcohol is a psychoactive substance with toxic and dependency-producing properties. WHO estimates that 3 million deaths per year are attributable to alcohol consumption. Current pharmacological treatment of alcoholism is based on three FDA-approved drugs: disulfiram, acamprosate and naltrexone, however, its clinical use is limited due to its low efficacy and serious side effects. In the brain, ethanol is metabolized to acetaldehyde by the enzyme catalase, and further oxidized to acetate by mitochondrial aldehyde dehydrogenase (ALDH2). A number of studies support that acetaldehyde generated in the brain has positive reinforcing properties. Therefore, regulating the brain concentration of this metabolite may constitute a potential pharmacological target in the treatment of alcohol dependence. Recent studies in animals have shown that Alda-1 administration, an organic compound that activates ALDH2 and promotes the elimination of acetaldehyde, results in a reduction in both the acquisition of the habit of drinking alcohol and chronic consumption in rats. These results suggest that Alda-1 could be a new pharmacological alternative for the treatment of alcoholism. Although Alda-1 has shown protective effects in various animal models of ischemia/reperfusion, there are no studies on its toxicity in cellular or animal models. The aim of this thesis was to evaluate the cytotoxicity and genotoxicity of Alda-1 in vitro and determine if this compound exerts protection against the toxicity induced by H2O2. Alda-1 cytotoxicity was verified using 5 different concentrations (0.2; 2; 20; 50 and 100 μM) after incubation for 24 and 48 hours in HepG2, SH-SY5Y, C3H/10T1/2 and HEK-293 cell lines, by trypan blue exclusion, MTS reduction, and LDH release assays. The evaluation of the genotoxicity was performed using the comet assay in SH-SY5Y and HepG2 cells after 1 and 6 hours of incubation with Alda-1 (20-100 μM). To measure the genotoxic protection cells were preincubated for 6 hours with Alda-1 followed by 1 hour of treatment with H2O2. The results showed that Alda-1 does not have cytotoxic or genotoxic effects on cell lines at the times studied but does not exert a protective effect against DNA damage produced by H2O2. Therefore, Alda-1 would not be a toxic compound at in vitro level...
Alcohol is a psychoactive substance with toxic and dependency-producing properties. WHO estimates that 3 million deaths per year are attributable to alcohol consumption. Current pharmacological treatment of alcoholism is based on three FDA-approved drugs: disulfiram, acamprosate and naltrexone, however, its clinical use is limited due to its low efficacy and serious side effects. In the brain, ethanol is metabolized to acetaldehyde by the enzyme catalase, and further oxidized to acetate by mitochondrial aldehyde dehydrogenase (ALDH2). A number of studies support that acetaldehyde generated in the brain has positive reinforcing properties. Therefore, regulating the brain concentration of this metabolite may constitute a potential pharmacological target in the treatment of alcohol dependence. Recent studies in animals have shown that Alda-1 administration, an organic compound that activates ALDH2 and promotes the elimination of acetaldehyde, results in a reduction in both the acquisition of the habit of drinking alcohol and chronic consumption in rats. These results suggest that Alda-1 could be a new pharmacological alternative for the treatment of alcoholism. Although Alda-1 has shown protective effects in various animal models of ischemia/reperfusion, there are no studies on its toxicity in cellular or animal models. The aim of this thesis was to evaluate the cytotoxicity and genotoxicity of Alda-1 in vitro and determine if this compound exerts protection against the toxicity induced by H2O2. Alda-1 cytotoxicity was verified using 5 different concentrations (0.2; 2; 20; 50 and 100 μM) after incubation for 24 and 48 hours in HepG2, SH-SY5Y, C3H/10T1/2 and HEK-293 cell lines, by trypan blue exclusion, MTS reduction, and LDH release assays. The evaluation of the genotoxicity was performed using the comet assay in SH-SY5Y and HepG2 cells after 1 and 6 hours of incubation with Alda-1 (20-100 μM). To measure the genotoxic protection cells were preincubated for 6 hours with Alda-1 followed by 1 hour of treatment with H2O2. The results showed that Alda-1 does not have cytotoxic or genotoxic effects on cell lines at the times studied but does not exert a protective effect against DNA damage produced by H2O2. Therefore, Alda-1 would not be a toxic compound at in vitro level...
Clinical study of disulfiram in intravenous suspension. A new alternative in the treatment of alcoholism Estudio clínico de disulfiram en suspensión inyectable. Una nueva alternativa en el tratamiento del alcoholismo.
(1990)
Clinical study of disulfiram in intravenous suspension. A new alternative in the
treatment of alcoholism Estudio clínico de disulfiram en suspensión inyectable.
Una nueva alternativa en el tratamiento del alcoholismo...
Protección contra el alcoholismo por el polimorfismo ARG47HIS de la deshidrogenasa alcohólica : desarrollo de un modelo animal
(Universidad de ChileCyberDocs, 2009)