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1.
Drug Alcohol Depend ; 61(2): 163-72, 2001 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-11137281

RESUMEN

This study explored the acute and long-term consequences of ultrarapid opioid detoxification (URD) in individuals with opioid dependence. In an open case series, seven patients underwent URD and subsequent treatment with daily naltrexone. Structured interviews, integrated rehabilitation and hair sampling were employed in the 12-week course of longitudinal follow-up. Cardiac and pulmonary physiology did not change significantly during the anesthesia phase of URD, but plasma ACTH and cortisol levels increased 15- and 13-fold, respectively. Marked withdrawal and tachypnea in all patients and respiratory distress in one patient occurred during the acute post-anesthesia phase. Withdrawal scores were significantly elevated for 3 weeks compared with baseline in the face of minimal self-reported craving for opioids. Anxiety, depression and vegetative symptoms improved gradually. Four patients remained abstinent of opioid use, two reported a brief period of opioid intake and one relapsed into daily opioid consumption. Given its effect on breathing and stress hormones, this procedure should be conducted by experienced anesthesiologists. The fact that URD and subsequent naltrexone treatment appears to cause a dissociation effect in the usual relationship between withdrawal and craving has implications for behavioral pharmacology. Further research is needed on the efficacy, safety, mechanisms and neurobiological sequelae of the procedure.


Asunto(s)
Hormona Adrenocorticotrópica/sangre , Analgésicos Opioides/uso terapéutico , Anestesia General , Hidrocortisona/sangre , Antagonistas de Narcóticos/uso terapéutico , Trastornos Relacionados con Opioides/tratamiento farmacológico , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Hormona Adrenocorticotrópica/efectos de los fármacos , Adulto , Analgésicos Opioides/farmacología , Análisis de Varianza , Anestesia General/métodos , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Femenino , Fentanilo/farmacología , Fentanilo/uso terapéutico , Estudios de Seguimiento , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Humanos , Masculino , Persona de Mediana Edad , Naltrexona/farmacología , Naltrexona/uso terapéutico , Antagonistas de Narcóticos/farmacología , Trastornos Relacionados con Opioides/psicología , Respiración/efectos de los fármacos , Estadísticas no Paramétricas , Síndrome de Abstinencia a Sustancias/psicología
2.
Cell Death Dis ; 1: e49, 2010 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-21364655

RESUMEN

X-linked inhibitor of apoptosis protein (XIAP) is a potent inhibitor of caspases 3, 7 and 9, and mitochondrial Smac (second mitochondria-derived activator of caspase) release during apoptosis inhibits the activity of XIAP. In this study we show that cytosolic XIAP also feeds back to mitochondria to impair Smac release. We constructed a fluorescent XIAP-fusion protein by labelling NH(2)- and COOH-termini with Cerulean fluorescent protein (C-XIAP-C). Immunoprecipitation confirmed that C-XIAP-C retained the ability to interact with Smac and impaired extrinsically and intrinsically activated apoptosis in response to tumour necrosis factor-related apoptosis-inducing ligand/cycloheximide and staurosporine. In C-XIAP-C-expressing cells, cytochrome c release from mitochondria proceeded normally, whereas Smac release was significantly prolonged and incomplete. In addition, physiological expression of native XIAP prolonged or limited Smac release in HCT-116 colon cancer cells and primary mouse cortical neurons. The Smac-binding capacity of XIAP, but not caspase inhibition, was central for mitochondrial Smac retention, as evidenced in experiments using XIAP mutants that cannot bind to Smac or effector caspases. Similarly, the release of a Smac mutant that cannot bind to XIAP was not impaired by C-XIAP-C expression. Full Smac release could however be provoked by rapid cytosolic C-XIAP-C depletion upon digitonin-induced plasma membrane permeabilization. Our findings suggest that although mitochondria may already contain pores sufficient for cytochrome c release, elevated amounts of XIAP can selectively impair and limit the release of Smac.


Asunto(s)
Apoptosis , Proteínas Portadoras/metabolismo , Mitocondrias/metabolismo , Proteínas Mitocondriales/metabolismo , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismo , Animales , Proteínas Reguladoras de la Apoptosis , Permeabilidad de la Membrana Celular , Proliferación Celular , Células Cultivadas , Citocromos c/metabolismo , Digitonina/farmacología , Humanos , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Ratones , Neuronas/metabolismo , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Proteína Inhibidora de la Apoptosis Ligada a X/genética
3.
Cell Death Differ ; 17(3): 459-68, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19779495

RESUMEN

Prolonged seizures (status epilepticus) are associated with brain region-specific regulation of apoptosis-associated signaling pathways. Bcl-2 homology domain 3-only (BH3) members of the Bcl-2 gene family are of interest as possible initiators of mitochondrial dysfunction and release of apoptogenic molecules after seizures. Previously, we showed that expression of the BH3-only protein, Bcl-2 interacting mediator of cell death (Bim), increased in the rat hippocampus but not in the neocortex after focal-onset status epilepticus. In this study, we examined Bim expression in mice and compared seizure damage between wild-type and Bim-deficient animals. Status epilepticus induced by intra-amygdala kainic acid (KA) caused extensive neuronal death within the ipsilateral hippocampal CA3 region. Hippocampal activation of factors associated with transcriptional and posttranslational activation of Bim, such as CHOP and c-Jun NH(2)-terminal kinases, was significant within 1 h. Upregulation of bim mRNA was evident after 2 h and Bim protein increased between 4 and 24 h. Hippocampal CA3 neurodegeneration was reduced in Bim-deficient mice compared with wild-type animals after seizures in vivo, and short interfering RNA molecules targeting bim reduced cell death after KA treatment of hippocampal organotypic cultures. In contrast, neocortical Bim expression declined after status epilepticus, and neocortex damage in Bim-deficient mice was comparable with that in wild-type animals. These results show region-specific differential contributions of Bim to seizure-induced neuronal death.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Hipocampo/metabolismo , Proteínas de la Membrana/metabolismo , Neocórtex/metabolismo , Fármacos Neuroprotectores/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Estado Epiléptico/metabolismo , Animales , Antracenos/metabolismo , Proteínas Reguladoras de la Apoptosis/genética , Proteína 11 Similar a Bcl2 , Hipocampo/citología , Hipocampo/patología , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas JNK Activadas por Mitógenos/genética , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Ácido Kaínico/farmacología , Masculino , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neocórtex/citología , Proteínas Proto-Oncogénicas/genética , Ratas , Estado Epiléptico/inducido químicamente , Factor de Transcripción CHOP/genética , Factor de Transcripción CHOP/metabolismo
4.
Alcohol Clin Exp Res ; 21(4): 627-30, 1997 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-9194915

RESUMEN

Patient self-report in evaluations involving alcohol and other drug abuse has generally been found to be reliable and valid. However, little is known about the variables associated with greater or lesser degrees of reliability and validity. This study was conducted to determine how motivation and satisfaction ratings obtained under anonymous conditions would compare with ratings obtained under nonanonymous conditions. Over the course of 12 months, 1397 subjects in the Boston Target Cities Project were assigned to either confidential or fully anonymous data collection procedures in an interrupted time-series design. Anonymity had either no effect on ratings or accounted for < 1% of the variance. Satisfaction and motivation ratings obtained under confidential conditions are probably as reliable and valid as ratings obtained under fully anonymous conditions.


Asunto(s)
Alcoholismo/rehabilitación , Cocaína , Confidencialidad , Dependencia de Heroína/rehabilitación , Motivación , Satisfacción del Paciente/estadística & datos numéricos , Trastornos Relacionados con Sustancias/rehabilitación , Adulto , Alcoholismo/psicología , Boston/epidemiología , Recolección de Datos , Femenino , Dependencia de Heroína/psicología , Humanos , Masculino , Persona de Mediana Edad , Inventario de Personalidad/estadística & datos numéricos , Trastornos Relacionados con Sustancias/psicología , Resultado del Tratamiento
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