RESUMEN
BACKGROUND: The concept of brain death (BD) is not well understood in the general population; this lack of knowledge is one of the main factors that generates an attitude against organ donation. Older people are a population group that has rarely been studied in relation to organ donation and transplantation (ODT), and it is important to investigate the most important aspects of ODT, such as people's concept of BD. OBJECTIVES: To analyze the level of understanding of the concept of BD in people > 65 years of age and the factors that influence their mode of thinking. METHODS: A multicenter study was carried out with a representative sample of people > 65 years of age, stratified by sex and geographic location in the southeast of Spain (n = 420). Knowledge of BD as well as the influence of other variables were analyzed through a validated questionnaire about ODT. SPSS version 21.0 (IBM Corp, Armonk, NY, United States) software was used for statistical analysis. Descriptive analysis included Student t test and the χ2 test. RESULTS: The questionnaire had a completion rate of 84% (n = 351). In 36% (n = 127) of cases, people Ë 65 years of age understood the concept of BD. In general, knowledge of this concept has not been associated with other variables including social-family interaction about ODT (P > .05). CONCLUSIONS: Older people do not understand the concept of BD. It is, therefore, necessary to carry out informative campaigns on ODT explaining this concept. This would improve organ donation awareness in this particular group of people.
Asunto(s)
Muerte Encefálica , Conocimientos, Actitudes y Práctica en Salud , Trasplante de Órganos/psicología , Obtención de Tejidos y Órganos , Anciano , Anciano de 80 o más Años , Comprensión , Femenino , Humanos , Relaciones Interpersonales , Masculino , España , Encuestas y CuestionariosRESUMEN
BACKGROUND: Worldwide population aging has resulted in changes in the approach to the organ donation and transplantation (ODT) process, forcing us to include older people on transplant waiting lists and to assess older patients as potential donors. However, this is a sector of the population that has not been studied in great detail in terms of the information they receive about ODT. OBJECTIVES: To analyze what kinds of media provide people > 65 years of age with information about ODT and which sources of information affect their attitude about this subject. METHODS: A multicentric study was undertaken using a sample of people > 65 years of age stratified by sex and geographic location in southeastern Spain (n = 420). Questions about ODT and methods of receiving information were analyzed using a questionnaire. Statistical analysis was performed using SPSS version 21.0 (IBM Corp, Armonk, NY, United States). Descriptive analyses were performed with a Student t test and χ2 test. RESULTS: The questionnaire completion rate was 84% (n = 351). People aged > 65 years received information about ODT, mainly positive, from the television (82%), followed by films (35%), the radio (30%), the press (26%), family (26%), and friends (17%). Receiving information through one of the following sources was associated with a more favorable attitude toward organ donation: the family (76% vs 45%; P < .001), friends (77% vs 48%; P = .01), and the press (62% vs 49%; P = .034). CONCLUSIONS: Older people mainly receive information about ODT from the mass media. However, social and family circles have the greatest influence on their attitudes toward organ donation.
Asunto(s)
Conocimientos, Actitudes y Práctica en Salud , Medios de Comunicación de Masas , Trasplante de Órganos/psicología , Donantes de Tejidos/psicología , Obtención de Tejidos y Órganos , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , España , Encuestas y Cuestionarios , TelevisiónRESUMEN
BACKGROUND: Living donation is a potential source of organs that could help to reduce the organ transplant deficit. Given that we have a worldwide aging population, it is important to assess the opinion of older people toward this type of donation. OBJECTIVES: To analyze the attitude of people aged > 65 years toward living kidney donation (LKD) and living liver donation (LLD) and to investigate the variables affecting their attitudes. METHODS: A multicentric study was carried out using a representative sample of people > 65 years stratified by sex and geographic location in southeastern Spain (n = 420). The measurement instrument was a validated questionnaire about LKD and LLD. Statistics were analyzed using SPSS version 21.0 (IBM Corp, Armonk, NY, United States) software. Descriptive analysis was carried out using Student t test, χ2 test, and a multivariate analysis. RESULTS: The questionnaire completion rate was 84% (n = 351) with 88% (n = 310) in favor of LKD, and 89% (n = 311) in favor of LLD. Favorable attitude decreased to 3% when the donation under consideration was unrelated. Attitudes toward LKD and LLD were associated with having received information from the television (P = .016 and P = .045) and from friends (P = .017 and P = .03); accepting an autopsy after death (P = .001 and P = .002); and not being worried about scars (P = .015 and P = .044). In the multivariate analysis, the following variables continued to be significant: having received information from the television (odds ratio [OR], 2) and from friends (OR, 10.3); and the acceptance of an autopsy (OR, 2). CONCLUSIONS: Older people are in favor of both LKD and LLD, assuming it is a related donation. In addition, the information the elderly population receives regarding organ donation and transplantation affects their attitudes.
Asunto(s)
Conocimientos, Actitudes y Práctica en Salud , Donadores Vivos , Trasplante de Órganos/psicología , Obtención de Tejidos y Órganos , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Análisis Multivariante , Oportunidad Relativa , España , Encuestas y Cuestionarios , Recolección de Tejidos y Órganos/métodos , Recolección de Tejidos y Órganos/psicologíaRESUMEN
Stenotrophomonas maltophilia is an opportunistic pathogen with increasing prevalence, which is able to cause infections in immunocompromised patients or in those with a previous pathology. The treatment of the infections caused by this bacterium is often complicated due to the several intrinsic antibiotic resistance mechanisms that it presents. Multidrug efflux pumps are among the best-studied mechanisms of S. maltophilia antibiotic resistance. Some of these efflux pumps have a basal expression level but, in general, their expression is often low and only reaches high levels when the local regulator is mutated or bacteria are in the presence of an effector. In the current work, we have developed a yellow fluorescent protein (YFP)-based sensor with the aim to identify effectors able to trigger the expression of SmeVWX, an efflux pump that confers resistance to quinolones, chloramphenicol, and tetracycline when it is expressed at high levels. With this purpose in mind, we tested a variety of different compounds and analyzed the fluorescence signal given by the expression of YFP under the control of the smeVWX promoter. Among the tested compounds, vitamin K3, which is a compound belonging to the 2-methyl-1,4-naphthoquinone family, is produced by plants in defense against infection, and has increasing importance in human therapy, was able to induce the expression of the SmeVWX efflux pump. In addition, a decrease in the susceptibility of S. maltophilia to ofloxacin and chloramphenicol was observed in the presence of vitamin K3, in both wild-type and smeW-deficient strains.
Asunto(s)
Antibacterianos/farmacología , Transporte Biológico Activo/fisiología , Farmacorresistencia Bacteriana Múltiple/fisiología , Proteínas de Transporte de Membrana/biosíntesis , Stenotrophomonas maltophilia/metabolismo , Vitamina K 3/metabolismo , Proteínas Bacterianas , Técnicas Biosensibles , Cloranfenicol/farmacología , Humanos , Proteínas Luminiscentes , Pruebas de Sensibilidad Microbiana , Ofloxacino/farmacología , Quinolonas/farmacología , Stenotrophomonas maltophilia/efectos de los fármacos , Tetraciclina/farmacologíaRESUMEN
Stenotrophomonas maltophilia is the only known bacterium in which quinolone-resistant isolates do not present mutations in the genes encoding bacterial topoisomerases. The expression of the intrinsic quinolone resistance elements smeDEF, smeVWX and Smqnr was analysed in 31 clinical S. maltophilia isolates presenting a minimum inhibitory concentration (MIC) range to ciprofloxacin between 0.5 and > 32 µg/mL; 11 (35.5%) overexpressed smeDEF, 2 (6.5%) presenting the highest quinolone MICs overexpressed smeVWX and 1 (3.2%) overexpressed Smqnr. Both strains overexpressing smeVWX presented changes at the Gly266 position of SmeRv, the repressor of smeVWX. Changes at the same position were previously observed in in vitro selected S. maltophilia quinolone-resistant mutants, indicating this amino acid is highly relevant for the activity of SmeRv in repressing smeVWX expression. For the first time SmeVWX overexpression is associated with quinolone resistance of S. maltophilia clinical isolates.
Asunto(s)
Antibacterianos/farmacología , Proteínas Bacterianas/biosíntesis , Farmacorresistencia Bacteriana , Expresión Génica , Quinolonas/farmacología , Stenotrophomonas maltophilia/efectos de los fármacos , Stenotrophomonas maltophilia/genética , Proteínas Bacterianas/genética , Perfilación de la Expresión Génica , Humanos , Pruebas de Sensibilidad Microbiana , Proteínas Mutantes/genética , Mutación Missense , Proteínas Represoras/genéticaRESUMEN
THOC5 is a member of the THO complex that is involved in processing and transport of mRNA. We have shown previously that hematopoietic stem cells have an absolute requirement for THOC5 for survival and that THOC5 is phosphorylated on tyrosine 225 as a consequence of leukemogenic protein tyrosine kinase (PTK) action. We have investigated pathways for THOC5 phosphorylation to develop an understanding of THO complex modulation by tyrosine kinase (TK) oncogenes in leukemias. We demonstrate that THOC5 phosphorylation is mediated by Src PTK and CD45 protein tyrosine phosphatase action and that this event is sensitive to oxidative status. We show that THOC5 phosphorylation is elevated in stem cells from patients with chronic myeloid leukemia (CML) and that this phosphorylation is sensitive to the frontline drugs used in CML treatment. Further we show that THOC5 Y225 phosphorylation governs mRNA binding. In addition, CXCL12 is shown to induce THOC5 Y225 phosphorylation, and site-directed mutagenesis demonstrates that this modulates motile response. In conclusion, we delineate a signaling pathway stimulated by leukemogenic PTKs, chemokines and oxidative stress that can affect THO complex mediation of gene expression describing mechanisms for post-transcriptional regulation of protein levels.
Asunto(s)
Quimiocinas/metabolismo , Leucemia/genética , Proteínas Nucleares/genética , Oncogenes , Procesamiento Postranscripcional del ARN , Células Madre/metabolismo , Humanos , Inmunohistoquímica , Proteínas Nucleares/metabolismo , Fosforilación , Transducción de Señal , Tirosina/metabolismoRESUMEN
Most of the bacterial species that form part of the biosphere have never been cultivated. In this situation, a comprehensive study of bacterial communities requires the utilization of non-culture-based methods, which have been named metagenomics. In this paper we review the use of different metagenomic techniques for understanding the effect of antibiotics on microbial communities, to synthesize new antimicrobial compounds and to analyse the distribution of antibiotic resistance genes in different ecosystems. These techniques include functional metagenomics, which serves to find new antibiotics or new antibiotic resistance genes, and descriptive metagenomics, which serves to analyse changes in the composition of the microbiota and to track the presence and abundance of already known antibiotic resistance genes in different ecosystems.
Asunto(s)
Antibacterianos/administración & dosificación , Bacterias/efectos de los fármacos , Biota , Tracto Gastrointestinal/microbiología , Metagenoma , Metagenómica/métodos , Farmacorresistencia Bacteriana , HumanosRESUMEN
ß-Amyloid (Aß) plaques in Alzheimer (AD) brains are surrounded by severe dendritic and axonal changes, including local spine loss, axonal swellings and distorted neurite trajectories. Whether and how plaques induce these neuropil abnormalities remains unknown. We tested the hypothesis that oligomeric assemblies of Aß, seen in the periphery of plaques, mediate the neurodegenerative phenotype of AD by triggering activation of the enzyme GSK-3ß, which in turn appears to inhibit a transcriptional program mediated by CREB. We detect increased activity of GSK-3ß after exposure to oligomeric Aß in neurons in culture, in the brain of double transgenic APP/tau mice and in AD brains. Activation of GSK-3ß, even in the absence of Aß, is sufficient to produce a phenocopy of Aß-induced dendritic spine loss in neurons in culture, while pharmacological inhibition of GSK-3ß prevents spine loss and increases expression of CREB-target genes like BDNF. Of note, in transgenic mice GSK-3ß inhibition ameliorated plaque-related neuritic changes and increased CREB-mediated gene expression. Moreover, GSK-3ß inhibition robustly decreased the oligomeric Aß load in the mouse brain. All these findings support the idea that GSK3ß is aberrantly activated by the presence of Aß, and contributes, at least in part, to the neuronal anatomical derangement associated with Aß plaques in AD brains and to Aß pathology itself.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Neuritas/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/genética , Animales , Encéfalo/patología , Células Cultivadas , Espinas Dendríticas/metabolismo , Espinas Dendríticas/patología , Glucógeno Sintasa Quinasa 3 beta , Ratones , Ratones Transgénicos , Neuritas/patología , Neuronas/metabolismo , Neuronas/patología , Proteínas tau/genética , Proteínas tau/metabolismoRESUMEN
OBJECTIVES: To compare the incidence of gastrointestinal side effects of two enteral feeding formulas with changes in the origin of protein (casein and isolated soy protein) in hospitalised elderly patients. METHOD: A cross sectional survey was done among a sample of elderly patients carrying nasogastric tube admitted to the Reina Sofia General Hospital (Murcia) during a period of 6 months. A formula based on casein or soybean protein was randomly assigned. The variables studied were: age, sex, cause for indication of EN, duration of the EN and maximum amount of EN administered per day. Nutritional status at admission and discharge, mortality and gastrointestinal side effects (diarrhoea, constipation, vomits or regurgitation) were also collected. Statistical analyses were performed with the Student's T and chi 2 tests, with a significance of 95%. RESULTS: Sample conformed by 50 patients over 65 years (48% casein, 52% soybean) without statistically significant differences in age nor cause of indication of the EN. Either there were no differences in the nutritional status at the admission and discharge in both groups. Significant differences were observed in the incidence of diarrhoea (C: 45.83%, S: 7.69%, p = 0.009) and vomits (C: 41.66%, S: 15.38%, p = 0.05). CONCLUSIONS: A significant reduction in the incidence of gastrointestinal complications, a reduction in the incidence of ulcers by pressure and less mortality occurred on the group that took formula based on the soybean protein. The individualized nutritional evaluation must be performed routinely when the patient is admitted to the hospital for detection and treatment of early signs of malnutrition.
Asunto(s)
Caseínas/efectos adversos , Nutrición Enteral , Alimentos Formulados/efectos adversos , Enfermedades Gastrointestinales/etiología , Hospitalización , Proteínas de Soja/efectos adversos , Anciano , Estudios Transversales , Femenino , Enfermedades Gastrointestinales/epidemiología , Humanos , Incidencia , MasculinoRESUMEN
Inflammation has been associated with the two classic lesions in the Alzheimer's (AD) brain, amyloid deposits and neurofibrillary tangles. Recent data suggest that Triflusal, a compound with potent anti-inflammatory effects in the central nervous system in vivo, might delay the conversion from amnestic mild cognitive impairment to a fully established clinical picture of dementia. In the present study, we investigated the effect of Triflusal on brain Abeta accumulation, neuroinflammation, axonal curvature and cognition in an AD transgenic mouse model (Tg2576). Triflusal treatment did not alter the total brain Abeta accumulation but significantly reduced dense-cored plaque load and associated glial cell proliferation, proinflammatory cytokine levels and abnormal axonal curvature, and rescued cognitive deficits in Tg2576 mice. Behavioral benefit was found to involve increased expression of c-fos and BDNF, two of the genes regulated by CREB, as part of the signal transduction cascade underlying the molecular basis of long-term potentiation. These results add preclinical evidence of a potentially beneficial effect of Triflusal in AD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Fármacos del Sistema Nervioso Central/farmacología , Salicilatos/farmacología , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Animales , Axones/efectos de los fármacos , Axones/patología , Encéfalo/patología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/metabolismo , Trastornos del Conocimiento/patología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuroglía/efectos de los fármacos , Neuroglía/patología , Placa Amiloide/efectos de los fármacos , Placa Amiloide/metabolismo , Placa Amiloide/patología , Proteínas Proto-Oncogénicas c-fos/metabolismoRESUMEN
Amyloid deposits, neurofibrillary tangles, and neuronal cell death in selectively vulnerable brain regions are the chief hallmarks in Alzheimer's (AD) brains. Glycogen synthase kinase-3 (GSK-3) is one of the key kinases required for AD-type abnormal hyperphosphorylation of tau, which is believed to be a critical event in neurofibrillary tangle formation. GSK-3 has also been recently implicated in amyloid precursor protein (APP) processing/Abeta production, apoptotic cell death, and learning and memory. Thus, GSK-3 inhibition represents a very attractive drug target in AD and other neurodegenerative disorders. To investigate whether GSK-3 inhibition can reduce amyloid and tau pathologies, neuronal cell death and memory deficits in vivo, double transgenic mice coexpressing human mutant APP and tau were treated with a novel non-ATP competitive GSK-3beta inhibitor, NP12. Treatment with this thiadiazolidinone compound resulted in lower levels of tau phosphorylation, decreased amyloid deposition and plaque-associated astrocytic proliferation, protection of neurons in the entorhinal cortex and CA1 hippocampal subfield against cell death, and prevention of memory deficits in this transgenic mouse model. These results show that this novel GSK-3 inhibitor has a dual impact on amyloid and tau alterations and, perhaps even more important, on neuronal survival in vivo further suggesting that GSK-3 is a relevant therapeutic target in AD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Inhibidores Enzimáticos/farmacología , Neuronas/efectos de los fármacos , Neuronas/patología , Tiadiazoles/farmacología , Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Astrocitos/efectos de los fármacos , Astrocitos/patología , Astrocitos/fisiología , Muerte Celular/efectos de los fármacos , Corteza Entorrinal/efectos de los fármacos , Corteza Entorrinal/patología , Inhibidores Enzimáticos/sangre , Femenino , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3 beta , Hipocampo/efectos de los fármacos , Hipocampo/patología , Humanos , Masculino , Memoria/efectos de los fármacos , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/patología , Ratones , Ratones Transgénicos , Nexinas de Proteasas , Receptores de Superficie Celular/genética , Percepción Espacial/efectos de los fármacos , Tiadiazoles/sangre , Proteínas tau/genéticaRESUMEN
The time from the start of incubation to a positive reading of blood cultures (time-to-positivity; TTP) is related to the concentration of bacteria in blood. Information concerning the correlation of TTP with clinical parameters, and its usefulness as a prognostic factor in patients with Escherichia coli bacteraemia, is limited. To investigate the relationship of TTP to clinical parameters, 459 cases of monomicrobial E. coli bloodstream infections from a single institution between 1997 and 2005 were reviewed. All cases involved patients who were not undergoing antibiotic treatment at the time of blood sampling. The in-hospital mortality rate was 6.3%. Median TTP was significantly shorter for patients who died than for those who survived (9.7 h, inter-quartile range 7.85-11.05 h vs. 11.2 h, inter-quartile range 10.1-11.4 h; p <0.001). Patients with TTP in the lowest quartile were more likely to be female, to have a non-urinary tract or an unknown origin of bacteraemia, to have severe sepsis or shock, and to subsequently die. In a multivariable Cox regression model, the hazard ratio for death from any cause for patients with a short TTP was 3.13 (95% CI 1.28-7.64; p 0.01). TTP in patients with E. coli bacteraemia provides prognostic information beyond that provided by the presence of haematological illness, a Charlson score > or =3, a non-urinary tract origin of bacteraemia, and the presence of severe sepsis or shock.
Asunto(s)
Bacteriemia/microbiología , Infecciones por Escherichia coli/microbiología , Escherichia coli/crecimiento & desarrollo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Bacteriemia/sangre , Escherichia coli/aislamiento & purificación , Infecciones por Escherichia coli/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
INTRODUCTION: Although 10 second generation new antiepileptic drugs are currently available on the market, 30% of patients are resistant to pharmacological treatment. In addition, today's antiepileptic drugs avert or suppress seizures but do not prevent the appearance of epilepsy or its progression. DEVELOPMENT: The foundations of the aetiopathogenesis of epilepsy and the main targets of antiepileptic drugs are described. Describing the important role of gamma-aminobutyric and glutamic acid in the genesis and proliferation of the seizures has allowed for the development of new antiepileptic drugs that increase the inhibitory tone of GABA or inhibit the excitatory tone of glutamate. The discovery that some epilepsies may be due to channelopathies is now making it possible to conduct research into drugs that inhibit calcium channels, activate potassium channels or inhibit abnormal AMPA/KA receptor channels. Recent reports describing a specific attachment of some antiepileptic drugs to the a2d subunits of the calcium channel and to the synaptic vesicles proteins SV2A open up new perspectives. Moreover, research is also being carried out on new drugs that are capable of preventing epileptogenesis, stemming the progression of epilepsy or overcoming the resistance to pharmacological treatment displayed by some epilepsies. CONCLUSIONS: The identification of new pharmacological targets in the aetiopathogenesis of epilepsies has made it possible to develop second generation antiepileptic drugs and it is allowing for the development of third generation antiepileptic drugs.
Asunto(s)
Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Resistencia a Medicamentos , Epilepsia/etiología , Epilepsia/metabolismo , Epilepsia/fisiopatología , HumanosRESUMEN
The aim of this study was to identify the risk factors for bacteremia in patients with limb cellulitis. Using the administrative and microbiology laboratory databases of a community teaching hospital, a review was conducted of all cases of community-acquired limb cellulitis that occurred during the period 1997-2004 and in which blood cultures had been performed. A comparison of demographical, clinical, and analytical data of patients with bacteremia versus patients without bacteremia was performed by univariate and multivariate analyses. Of 2,678 patients with cellulitis who presented to the hospital's emergency department, 308 were diagnosed with limb cellulitis and had blood cultures. Of these, 57 (18.5%) had bacteremia. In 24 of the 57 (42.1%) patients with bacteremia, the microorganism isolated in blood cultures was non-group-A beta-hemolytic Streptococcus, and in another 14 (24.6%), the microorganism identified was a gram-negative bacterium. Staphylococcus aureus was determined as the cause of bacteremia in just 6 (10.5%) patients and group A Streptococcus in 2 (3.5%). By logistic regression analysis, the following factors were associated with bacteremia: absence of previous antibiotic treatment (OR 5.3, 95% CI 1.4-20.3), presence of two or more comorbid factors simultaneously (OR 4.3, 95% CI 1.6-11.7), length of illness<2 days OR 2.44, 95% CI 1.07-5.56), and proximal limb involvement (OR 6, 95% CI 3.03-12.04). Patients with limb cellulitis who exhibit any of these characteristics are at increased risk of bacteremia. In such patients, it is imperative that blood cultures be performed.
Asunto(s)
Bacteriemia/microbiología , Celulitis (Flemón)/microbiología , Extremidades/microbiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Bacteriemia/sangre , Celulitis (Flemón)/sangre , Femenino , Bacterias Gramnegativas/aislamiento & purificación , Infecciones por Bacterias Gramnegativas/sangre , Infecciones por Bacterias Gramnegativas/microbiología , Bacterias Grampositivas/aislamiento & purificación , Infecciones por Bacterias Grampositivas/sangre , Infecciones por Bacterias Grampositivas/microbiología , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Introducción. A pesar de la comercialización de 10 antiepilépticosnuevos de segunda generación, hay un 30% de pacientesresistentes al tratamiento farmacológico. Además, los antiepilépticosactuales previenen o suprimen las crisis pero no evitan laaparición de epilepsia ni su progresión. Desarrollo. Se describenlos fundamentos de la etiopatogenia de la epilepsia y las principalesdianas de los antiepilépticos. La descripción del importante papeldel ácido gamma-aminobutírico y el glutámico en la génesis yla propagación de las crisis han permitido desarrollar nuevos antiepilépticosque aumenten el tono inhibidor gabérgico o inhiban eltono excitador glutamérgico. El descubrimiento de que algunasepilepsias pueden deberse a canalopatías está permitiendo investigarfármacos que inhiban canales de calcio, activen canales depotasio o inhiban canales anómalos de receptores AMPA/KA. Recientementese ha descrito una fijación específica de algunos antiepilépticosa las subunidades a2d del canal de calcio y a las proteínasde las vesículas sinápticas SV2A que abren nuevas perspectivas.Por otra parte, se investigan fármacos nuevos que puedanprevenir la epileptogénesis, evitar la progresión de la epilepsia ovencer la resistencia al tratamiento farmacológico de algunas epilepsias.Conclusión. La identificación de nuevas dianas farmacológicasen la etiopatogenia de las epilepsias ha permitido el desarrollode los antiepilépticos de segunda generación y está permitiendodesarrollar nuevos antiepilépticos de tercera generación
Introduction. Although 10 second generation new antiepileptic drugs are currently available on the market, 30% ofpatients are resistant to pharmacological treatment. In addition, todays antiepileptic drugs avert or suppress seizures but do notprevent the appearance of epilepsy or its progression. Development. The foundations of the aetiopathogenesis of epilepsy and themain targets of antiepileptic drugs are described. Describing the important role of gamma-aminobutyric and glutamic acid in thegenesis and proliferation of the seizures has allowed for the development of new antiepileptic drugs that increase the inhibitorytone of GABA or inhibit the excitatory tone of glutamate. The discovery that some epilepsies may be due to channelopathies isnow making it possible to conduct research into drugs that inhibit calcium channels, activate potassium channels or inhibitabnormal AMPA/KA receptor channels. Recent reports describing a specific attachment of some antiepileptic drugs to the a2d subunits of the calcium channel and to the synaptic vesicles proteins SV2A open up new perspectives. Moreover, research is alsobeing carried out on new drugs that are capable of preventing epileptogenesis, stemming the progression of epilepsy orovercoming the resistance to pharmacological treatment displayed by some epilepsies. Conclusions. The identification of newpharmacological targets in the aetiopathogenesis of epilepsies has made it possible to develop second generation antiepilepticdrugs and it is allowing for the development of third generation antiepileptic drugs
Asunto(s)
Humanos , Epilepsia/tratamiento farmacológico , Anticonvulsivantes/farmacología , Anticonvulsivantes/farmacocinética , Resistencia a MedicamentosRESUMEN
AIMS: Antiepileptic drugs, which often have to be used in patients with cancer, can have important effects on the results offered by antineoplastic agents. Here, we review the influence of antiepileptic drugs on antineoplastic agents and the influence of antineoplastic agents on antiepileptic drugs; measures to prevent such interactions are also suggested. DEVELOPMENT: Antiepileptic drugs that induce cytochrome P450, such as carbamazepine, phenytoin and phenobarbital, can reduce the levels and effects of antineoplastics that metabolise by means of this enzyme, for example, taxanes, Vinca alkaloids, methotrexate, teniposide and camptothecin. Furthermore, enzyme-inducing antiepileptic drugs diminish the levels and effects of many other drugs that can be administered to oncology patients, such as other antiepileptic drugs used in polytherapy, narcotic analgesics, antidepressants, antipsychotics or antibiotics. In contrast, valproate can increase the toxicity of etoposide or nitrosoureas. Moreover, antineoplastic agents like cisplatin or corticoids can lower the effectiveness of phenytoin and methotrexate has a similar effect on valproate. In contrast, 5-fluorouracil can increase the toxicity of phenytoin. Pharmacodynamic interactions are also possible. CONCLUSIONS: Information about the clinical consequences of the interactions between antiepileptics and antineoplastic agents is often based on cases or series of cases, but a growing body of evidence from pharmacokinetic studies shows that enzyme-inducing antiepileptics exert an important influence on the effectiveness of the antineoplastic agents. It is therefore recommendable to avoid them and replace them with non-enzyme-inducing antiepileptics, such as gabapentin, lamotrigine, levetiracetam, pregabalin, topiramate or zonisamide. When enzyme-inducing antiepileptics have to be used, it is likely that higher doses of antineoplastic agents or other inducible drugs will have to be utilised.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Antineoplásicos/uso terapéutico , Interacciones Farmacológicas , Epilepsia/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Monitoreo de Drogas , Humanos , PolifarmaciaRESUMEN
Objetivo. Los antiepilépticos, que con frecuencia se tienenque utilizar en el paciente oncológico, pueden interferir de formaimportante con los efectos de los antineoplásicos. Se revisa lainfluencia de los antiepilépticos sobre los antineoplásicos y la delos antineoplásicos sobre los antiepilépticos, y se sugieren medidaspara evitarlas. Desarrollo. Los antiepilépticos que inducen el citocromoP450, como carbamacepina, fenitoína y fenobarbital, puedenreducir los niveles y los efectos de los antineoplásicos que semetabolizan mediante esta enzima como taxanos, alcaloides de lavinca, metotrexato, tenipósido y camptotecina. Además, los antiepilépticosinductores reducen los niveles y los efectos de muchosotros fármacos que se pueden administrar en el paciente oncológico,como otros antiepilépticos utilizados en la politerapia, analgésicosnarcóticos, antidepresivos, antipsicóticos o antibióticos. Ensentido opuesto, el valproato puede aumentar la toxicidad del etopósidoo las nitrosureas. A su vez, los antineoplásicos como el cisplatinoo los corticoides pueden reducir la eficacia de la fenitoína yel metotrexato la del valproato. En sentido opuesto, el 5-fluoruracilo puede aumentar la toxicidad de la fenitoína. También hay posibilidadde interacciones farmacodinámicas. Conclusiones. La informaciónsobre las consecuencias clínicas de las interacciones entreantiepilépticos y antineoplásicos se basan con frecuencia en casoso series de casos, pero hay cada vez más estudios farmacocinéticosque demuestran una importante influencia de los antiepilépticosinductores sobre la eficacia de los antineoplásicos que hace recomendableevitarlos y sustituirlos por antiepilépticos no inductores,como gabapentina, lamotrigina, levetiracetam, pregabalina, topiramatoo zonisamida. Cuando sea necesario utilizar antiepilépticosinductores, es probable que haya que utilizar dosis mayores delos antineoplásicos o de otros fármacos que sean inducibles
Aims. Antiepileptic drugs, which often have to be used in patients with cancer, can have important effects on theresults offered by antineoplastic agents. Here, we review the influence of antiepileptic drugs on antineoplastic agents and theinfluence of antineoplastic agents on antiepileptic drugs; measures to prevent such interactions are also suggested.Development. Antiepileptic drugs that induce cytochrome P450, such as carbamazepine, phenytoin and phenobarbital, canreduce the levels and effects of antineoplastics that metabolise by means of this enzyme, for example, taxanes, Vinca alkaloids,methotrexate, teniposide and camptothecin. Furthermore, enzyme-inducing antiepileptic drugs diminish the levels and effectsof many other drugs that can be administered to oncology patients, such as other antiepileptic drugs used in polytherapy,narcotic analgesics, antidepressants, antipsychotics or antibiotics. In contrast, valproate can increase the toxicity of etoposideor nitrosoureas. Moreover, antineoplastic agents like cisplatin or corticoids can lower the effectiveness of phenytoin andmethotrexate has a similar effect on valproate. In contrast, 5-fluorouracil can increase the toxicity of phenytoin. Pharmacodynamicinteractions are also possible. Conclusions. Information about the clinical consequences of the interactions betweenantiepileptics and antineoplastic agents is often based on cases or series of cases, but a growing body of evidence frompharmacokinetic studies shows that enzyme-inducing antiepileptics exert an important influence on the effectiveness of theantineoplastic agents. It is therefore recommendable to avoid them and replace them with non-enzyme-inducing antiepileptics,such as gabapentin, lamotrigine, levetiracetam, pregabalin, topiramate or zonisamide. When enzyme-inducing antiepilepticshave to be used, it is likely that higher doses of antineoplastic agents or other inducible drugs will have to be utilised
Asunto(s)
Humanos , Interacciones Farmacológicas/fisiología , Anticonvulsivantes/farmacocinética , Antineoplásicos/farmacocinética , Evaluación Preclínica de MedicamentosRESUMEN
OBJECTIVE: Bipolar disorder is a chronic disease difficult to treat that generates a high degree of incapacity. Although lithium remains the first choice drug, some patients do not respond and others show adverse reactions. One alternative to lithium is the use of certain antiepileptic drugs. Data on the efficacy of old and new antiepileptic drugs in bipolar disorder obtained in controlled clinical trials are reviewed. DEVELOPMENT: Results in many clinical trial support the use of some old antiepileptic drugs such as carbamazepine and sodium valproate in monotherapy in the acute treatment of severe, mixed or mild manic episodes as well as in the management treatment of bipolar disorder. Overall, new antiepileptic drugs show a better profile of adverse reactions with fewer interactions than lithium, but data on their efficacy in bipolar disorder remain scarce. Oxcarbazepine efficacy in mania is similar to that of the carbamazepine. Lamotrigine is becoming the best alternative to lithium in depressive episodes. Topiramate does not appear to be effective in acute treatment of manic episodes. Levetiracetam seems to produce some benefits, but controlled, randomized and double blind clinical trials are not yet available. Data on gabapentin efficacy are controversial. CONCLUSIONS: Although lithium is still the first choice for the treatment of bipolar disorder, carbamazepine and valproate are also first choice drugs. Oxcarbazepine and lamotrigine may be a good option in some patients. Other new antiepileptic drugs may also be effective in bipolar disorder but more solid evidence of their efficacy is needed.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Trastorno Bipolar/tratamiento farmacológico , Humanos , Resultado del TratamientoRESUMEN
Of 41 patients with bone-related infections who were treated for > or =10 days with piperacillin-tazobactam, 14 (34%) developed neutropenia. Cumulative doses of piperacillin administered to neutropenic patients were higher than those administered to nonneutropenic ones (330 vs. 237 g; P=.008), and an inverse correlation was detected between the absolute neutrophil count at the end of treatment and the cumulative dose of piperacillin (r=-0.47, P=.002). Moreover, the incidence of piperacillin-tazobactam-induced neutropenia increased with an increase in the cumulative dose of piperacillin: 0% of patients in the first quartile of cumulative piperacillin doses, 33.3% in the second quartile, 40% in the third quartile, and 66.7% in the fourth quartile.