RESUMEN
The overall goal of therapy for patients with rheumatoid arthritis (RA) is to achieve low disease activity or remission and to prevent or control joint damage, prevent loss of function, and decrease pain. However, many patients with RA do not have the disease adequately controlled, and only a minority attain consistent remission. To successfully treat to target, rheumatologists need practical guidance to select monotherapy and combination therapy regimens based on available data. Differences in study design, dosing regimens, and data from defined and specific patient populations pose challenges to clinicians who treat patients with diverse characteristics and needs. Because clinical trial results are not always translated into real-life clinical practice, this article synthesizes evidence from all sources, including meta-analyses of clinical trial data, data from patient registries in RA, and results of pragmatic trial designs. Practical guidance with these strategies is demonstrated using application in patient case scenarios, which will enable rheumatology health care professionals to more easily compare the effectiveness and safety of RA treatment strategies as experienced in real-life practice settings. Combination therapy is important for most patients with RA; however, there remain no clear guidelines for selecting the most appropriate combination strategy.
RESUMEN
A synthesis of 5-substituted cyclopentylamine precursors for 5'-substituted carbocyclic nucleoside analogues was developed. We show that the stereochemistry of the OsO4-catalyzed hydroxylation of an apically brominated lactam, 7-bromo-2-azabicyclo[2.2.1]hept-5-en-3-one, can be controlled through the appropriate selection of the lactam N-H protecting group. Sterically large groups direct the hydroxylation to the exo-face of the olefin, yielding hydroxylation products that can be converted into analogues of carbocyclic ribosides. Conversely, a sterically small protecting group permits OsO4 approach from the endo-face, yielding hydroxylation products analogous to carbocyclic lyxosides. A key intermediate for carbocyclic sugar production, (1S,2S,3R, 4R,5S)-1-(tert-butyloxycarbonyl)amino-5-bromo-2,3-(dimethylmethylene)dioxy-4-hydroxymethylcyclopentane, was synthesized starting from a commercially available enantiomerically pure lactam, (1S)-(+)-2-azabicyclo[2.2.1]hept-5-en-3-one, in seven steps in an overall yield of 21%.
Asunto(s)
Ácidos Carbocíclicos/síntesis química , Amino Azúcares/síntesis química , Ribosa/análogos & derivados , Hidroxilación , Lactamas/química , Ribosa/síntesis química , EstereoisomerismoRESUMEN
STUDY OBJECTIVE: We conduct a study to determine the rate of adverse events (anaphylactoid and cardiorespiratory) associated with the use of oral N-acetylcysteine by the intravenous route for the treatment of suspected acetaminophen poisoning and to examine specific variables that may be associated with adverse events. METHODS: We conducted a retrospective medical record review with explicit criteria. All patients who received oral N-acetylcysteine by the intravenous route from September 1995 to September 2001 were included. Patients were identified by cross-matching 3 databases. Adverse events were divided into categories of cutaneous, systemic, or life threatening. Five reviewers abstracted charts by using a standardized data collection form. Interrater reliability was calculated by using 24 medical records abstracted by all 5 reviewers. RESULTS: There were 7 adverse events identified in 187 patients (3.7%; 95% confidence interval 1.0% to 6.5%). Six adverse events were cutaneous and responded rapidly to antihistamines. One adverse event was life threatening but not clearly related to N-acetylcysteine. A high rate of antihistamine exposure (53%) was identified before the administration of N-acetylcysteine. Interrater agreement was higher than 95%. CONCLUSION: Intravenous administration of an oral solution of N-acetylcysteine is associated with a low rate of adverse events and should be considered for selected patients with suspected acetaminophen poisoning.
Asunto(s)
Acetaminofén/envenenamiento , Acetilcisteína/administración & dosificación , Acetilcisteína/efectos adversos , Anafilaxia/epidemiología , Hipersensibilidad a las Drogas/epidemiología , Depuradores de Radicales Libres/administración & dosificación , Depuradores de Radicales Libres/efectos adversos , Administración Oral , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Niño , Preescolar , Erupciones por Medicamentos/epidemiología , Erupciones por Medicamentos/etiología , Hipersensibilidad a las Drogas/etiología , Interacciones Farmacológicas , Sobredosis de Droga , Femenino , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Humanos , Indiana/epidemiología , Lactante , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Enfermedades Respiratorias/epidemiología , Enfermedades Respiratorias/etiología , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
Polyadenosine diphosphoribose glycohydrolase (PARG) catalyzes the intracellular hydrolysis of adenosine diphosphoribose polymers. Because structure-activity data are lacking for PARG, the specific inhibitor adenosine diphosphate (hydroxymethyl)pyrrolidinediol (ADP-HPD) was utilized to determine the effects of structure on inhibitor potency using PARG isolated from bovine thymus (bPARG) and recombinant bovine PARG catalytic fragment (rPARG-CF). Both enzymes were strongly inhibited by submicromolar levels of ADP-HPD, but ADP and the phosphorylated pyrrolidine displayed no activity. Utilizing ADP-HPD analogues containing 2-, N(6), or 8-adenosyl substituents or guanine instead of adenine, the importance of adenine ring recognition as well as a correlation between loss of PARG inhibition and the length and bulkiness of 8-adenosyl substituents was shown. Utilization of ADP-HPD analogues lacking one or both pyrrolidine cis-hydroxyls demonstrated their importance for inhibitor binding. Last, the similarity between naturally occurring bPARG and heterologously expressed rPARG-CF was demonstrated. Therefore, readily available rPARG-CF is suitable for use in future studies to determine the structural aspects of PARG.