RESUMO
BACKGROUND: Changes in the epidemiology of traumatic brain injury (TBI) in older patients have received attention, but limited data are available on the outcome of these patients after admission to intensive care units (ICUs). The aim of this study was to evaluate the outcomes of patients over 65 years of age who were admitted to an ICU for TBI. METHODS: This was a multicentre, retrospective, observational study conducted from January 2013 to February 2019 in the surgical ICUs of 5 level 1 trauma centres in France. Patients aged ≥ 65 years who were hospitalized in the ICU for TBI with or without extracranial injuries were included. The main objective was to determine the risk factors for unfavourable neurological outcome at 3 months defined as an Extended Glasgow Outcome Scale (GOSE) score < 5. RESULTS: Among the 349 intensive care patients analysed, the GOSE score at 3 months was ≤ 4 and ≥ 5 in 233 (67%) and 116 (33%) patients, respectively. The mortality rate at 3 months was 157/233 (67%), and only 7 patients (2%) fully recovered or had minor symptoms. Withdrawal or withholding of life-sustaining therapies in the ICU was identified in 140 patients (40.1%). Multivariate analysis showed that age (OR 1.09, CI 95% 1.04-1.14), male sex (OR 2.94, CI95% 1.70-5.11), baseline Glasgow Coma Scale score (OR 1.20, CI95% 1.13-1.29), injury severity score (ISS; OR 1.04, CI95% 1.02-1.06) and use of osmotherapy (OR 2.42, CI95% 1.26-4.65) were associated with unfavourable outcomes (AUC = 0.79, CI 95% [0.74-0.84]). According to multivariate analysis, the variables providing the best sensitivity and specificity were age ≥ 77 years, Glasgow Coma Scale score ≤ 9 and ISS ≥ 25 (AUC = 0.79, CI 95% [0.74-0.84]). CONCLUSIONS: Among intensive care patients aged ≥ 65 years suffering from TBI, age (≥ 77 years), male sex, baseline Glasgow coma scale score (≤ 9), ISS (≥ 25) and use of osmotherapy were predictors of unfavourable neurological outcome. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04651803. Registered 03/12/2020. Retrospectively registered.
Assuntos
Lesões Encefálicas Traumáticas , Idoso , Humanos , Masculino , Estudos Retrospectivos , Lesões Encefálicas Traumáticas/diagnóstico , Lesões Encefálicas Traumáticas/epidemiologia , Lesões Encefálicas Traumáticas/terapia , Cuidados Críticos , Escala de Coma de Glasgow , Escala de Resultado de GlasgowRESUMO
Breast cancer is the most frequent cancer in women while it is the second cause of cancer death. Estrogens are well recognized to play the predominant role in breast cancer development and growth and much efforts have been devoted to the blockade of estrogen formation and action. The most widely used therapy of breast cancer which has shown benefits at all stages of the disease is the use of the antiestrogen Tamoxifen. This compound, however, possesses mixed agonist and antagonist activity and major efforts have been devoted to the development of compounds having pure antiestrogenic activity in the mammary gland and endometrium. Such a compound would avoid the problem of stimulation of the endometrium and the risk of endometrial carcinoma. We have thus synthesized an orally active non-steroidal antiestrogen, EM-652 (SCH 57068) and the prodrug EM-800 (SCH57050) which are the most potent of the known antiestrogens. EM-652 is the compound having the highest affinity for the estrogen receptor, including estradiol. It has higher affinity for the ER than ICI 182780, hydroxytamoxifen, raloxifene, droloxifene and hydroxytoremifene. EM-652 has the most potent inhibitory activity on both ER alpha and ER beta compared to any of the other antiestrogens tested. An important aspect of EM-652 is that it inhibits both the AF1 and AF2 functions of both ER alpha and ER beta while the inhibitory action of hydroxytamoxifen is limited to AF2, the ligand-dependent function of the estrogen receptors. AF1 activity is constitutive, ligand-independent and is responsible for mediation of the activity of growth factors and of the ras oncogene and MAP-kinase pathway. EM-652 inhibits Ras-induced transcriptional activity of ER alpha and ER beta and blocks SRC-1-stimulated activity of the two receptors. EM-652 was also found to block the recruitment of SRC-1 at AF1 of ER beta, this ligand-independent activation of AF1 being closely related to phosphorylation of the steroid receptors by protein kinase. Most importantly, the antiestrogen hydroxytamoxifen has no inhibitory effect on the SRC-1-induced ER beta activity while the pure antiestrogen EM-652 completely abolishes this effect, thus strengthening the need to use pure antiestrogens in breast cancer therapy in order to control all known aspects of ER-regulated gene expression. In fact, the absence of blockade of AF2 by hydroxytamoxifen could explain why the benefits of tamoxifen observed up to 5 years become negative at longer time intervals and why resistance develops to tamoxifen. EM-800, the prodrug of EM-652, has been shown to prevent the development of dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma in the rat, a well-recognized model of human breast cancer. It is of interest that the addition of dehydroepiandrosterone, a precursor of androgens, to EM-800, led to complete inhibition of tumor development in this model. Not only the development, but also the growth of established DMBA-induced mammary carcinoma was inhibited by treatment with EM-800. An inhibitory effect was also observed when medroxyprogesterone was added to treatment with EM-800. Uterine size was reduced to castration levels in the groups of animals treated with EM-800. An almost complete disappearance of estrogen receptors was observed in the uterus, vaginum and tumors in nude mice treated with EM-800. EM-652 was the most potent antiestrogen to inhibit the growth of human breast cancer ZR-75-1, MCF-7 and T-47D cells in vitro when compared with ICI 182780, ICI 164384, hydroxytamoxifen, and droloxifene. Moreover, EM-652 and EM-800 have no stimulatory effect on the basal levels of cell proliferation in the absence of E2 while hydroxytamoxifen and droloxifene had a stimulatory effect on the basal growth of T-47D and ZR-75-1 cells. EM-652 was also the most potent inhibitor of the percentage of cycling cancer cells. (ABSTRACT TRUNCATED)
Assuntos
Endométrio/efeitos dos fármacos , Antagonistas de Estrogênios/farmacologia , Glândulas Mamárias Animais/efeitos dos fármacos , Piperidinas/farmacologia , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Endométrio/metabolismo , Antagonistas de Estrogênios/administração & dosagem , Antagonistas de Estrogênios/metabolismo , Feminino , Humanos , Glândulas Mamárias Animais/metabolismo , Piperidinas/administração & dosagemRESUMO
HPLC assays were developed and validated for the quantitation of the novel orally active nonsteroidal antiestrogen EM-800 ¿(S)-(+)-4-[7-(2,2-dimethyl-l-oxopropoxy)-4-methyl-2-[4-[2-(1-pipe ridinyl)- ethoxy]phenyl]-2H-l-benzopyran-3-yl]-phenyl 2,2-dimethylpropanoate¿. The assay involves reversed-phase C18 or C4 columns using different mobile phases with ammonium acetate buffers and UV detection at lambda = 240 nm. The standard curve was linear over the concentration range of 10-1100 micrograms/ml. The precision (% relative standard deviation) values of these methods were in the range of 0.38-0.52 and 1.89-3.45% with C4 and C18 reversed phases, respectively. The limit of detection was found to be 1 microgram/ml. Enantiomeric separation was also obtained using a chiral method (ChiralPak AD column) using a mixture of hexane-reagent alcohol-diethylamine (94.9:5.0:0.1) as mobile phase. These methods were applied to stability studies, evaluation of pharmaceutical dosage forms and in the framework of toxicological studies. Details of some of these applications will be presented.
Assuntos
Benzopiranos/análise , Cromatografia Líquida de Alta Pressão/métodos , Antagonistas de Estrogênios/análise , Propionatos/análise , Ração Animal/análise , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrofotometria Ultravioleta , EstereoisomerismoRESUMO
An improved high-performance liquid chromatographic assay for the determination of procainamide and N-acetylprocainamide (NAPA) at concentrations observed up to 32 h after a single oral dose administration of procainamide to human subjects is reported. Following liquid-liquid extraction of plasma samples, procainamide, NAPA, and the internal standard (N-propionylprocainamide) are separated on a reversed-phase C8 column with retention times of 4.0, 6.7, and 13.2 min, respectively. The ultraviolet detection limit (wavelength, 280 nm) of procainamide and NAPA is 2 ng/mL (signal-to-noise ratio, 3:1), and the quantitation limit is 4 ng/mL (signal-to-noise ratio, 5:1). Intra- and interday coefficients of variation are less than 8% in the range of 20-500 ng/mL.
Assuntos
Acecainida/sangue , Antiarrítmicos/sangue , Procainamida/sangue , Acetilação , Antiarrítmicos/farmacocinética , Calibragem , Cromatografia Líquida de Alta Pressão , Humanos , Indicadores e Reagentes , Procainamida/farmacocinética , Análise de Regressão , Espectrofotometria UltravioletaRESUMO
An ultrastructural study of the action of peptidoglycans on malignant lymphocytes was made. Glycans acted upon lysosomes labilizing and rupturing the lysosomal membrane. Lysosomal enzymes were discharged directly into the cell cytoplasm. Nucleus, mitochondria and all organelles were digested in situ, resulting in a completely structureless cell. Finally, cancerous cells disintegrated by the detachment of cytoplasmic fragments.