RESUMO
PURPOSE: In 2013, the FDA placed a black box warning on the usage of opioid pain medications in the post-operative setting after pediatric adenotonsillectomy. Since then, alternative pain management regimens have been employed. Some have advocated for post-operative oral steroids, in part due to the effectiveness of intraoperative intravenous steroids in reducing post-operative pain and nausea. The evidence regarding the efficacy and safety of post-operative oral steroids is not as clear. The purpose of this study was to examine whether post-tonsillectomy hemorrhage rates in pediatric patients were affected by post-operative oral steroid usage. MATERIALS AND METHODS: Case-control retrospective chart review using a deidentified data set of patients undergoing tonsillectomy with or without adenoidectomy at a single academic medical center between June 2012 and November 2015. RESULTS: A total of 1416 patients were included in the study, with 704 in the no post-operative oral steroids group and 712 in the group who did receive post-operative oral steroids. The rate of post-tonsillectomy hemorrhage in the post-operative oral steroid group was 3.1 % compared to 1.8 % in the group who did not receive post-operative oral steroids, however, this was not a statistically significant difference (P = .132). CONCLUSIONS: Our study suggests that post-operative oral steroids are safe and do not increase the risk of post-operative hemorrhage after pediatric tonsillectomy.
Assuntos
Tonsilectomia , Analgésicos Opioides/efeitos adversos , Criança , Humanos , Hemorragia Pós-Operatória/epidemiologia , Hemorragia Pós-Operatória/etiologia , Hemorragia Pós-Operatória/prevenção & controle , Estudos Retrospectivos , Esteroides/efeitos adversos , Tonsilectomia/efeitos adversosRESUMO
BACKGROUND: Primary MALT lymphoma of the larynx is a rare condition first described in 1990. There have been only 43 reported cases as of 2015. The disease appears to be indolent in nature and responds well to radiation therapy. Symptoms are non-specific and may be limited to a combination of hoarseness, sore throat, shortness of breath, or cough. METHODS: We describe two cases of subglottic laryngeal MALT lymphoma identified from one academic medical center within five years of each other. Though identical in pathology, the presentation of the two cases were distinct in both patient demographic and tumor appearance. One patient required dilation of a subglottic stenosis caused by tumor, and the other required surgical debulking of a ball-valve-like mass. Neither patient presented with B-symptoms (fever, night sweats, weight loss) that often characterize other lymphomas. RESULTS: In both cases, histopathological exam revealed extensive infiltration of mucosa with atypical monomorphous lymphocytes, consistent with MALT lymphoma. CONCLUSION: MALT lymphoma of the larynx may present with non-specific symptoms such as cough and/or hoarseness. Thorough evaluation including flexible laryngoscopy should be performed should these symptoms persist without a known cause. Surgical biopsy and histopathological exam are crucial to determine the etiology of unknown subglottic masses.
Assuntos
Neoplasias Laríngeas/patologia , Linfoma de Zona Marginal Tipo Células B/patologia , Doenças Raras , Idoso , Idoso de 80 Anos ou mais , Biópsia , Tosse/etiologia , Dispneia/etiologia , Feminino , Rouquidão/etiologia , Humanos , Neoplasias Laríngeas/complicações , Neoplasias Laríngeas/diagnóstico , Neoplasias Laríngeas/cirurgia , Laringoscopia , Laringoestenose/etiologia , Laringoestenose/cirurgia , Linfoma de Zona Marginal Tipo Células B/complicações , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Linfoma de Zona Marginal Tipo Células B/cirurgia , Masculino , Faringite/etiologiaRESUMO
We employ single-molecule fluorescence resonance energy transfer (smFRET) to study structural dynamics over the first two elongation cycles of protein synthesis, using ribosomes containing either Cy3-labeled ribosomal protein L11 and A- or P-site Cy5-labeled tRNA or Cy3- and Cy5-labeled tRNAs. Pretranslocation (PRE) complexes demonstrate fluctuations between classical and hybrid forms, with concerted motions of tRNAs away from L11 and from each other when classical complex converts to hybrid complex. EF-Gâ GTP binding to both hybrid and classical PRE complexes halts these fluctuations prior to catalyzing translocation to form the posttranslocation (POST) complex. EF-G dependent translocation from the classical PRE complex proceeds via transient formation of a short-lived hybrid intermediate. A-site binding of either EF-G to the PRE complex or of aminoacyl-tRNAâ EF-Tu ternary complex to the POST complex markedly suppresses ribosome conformational lability.
Assuntos
Transferência Ressonante de Energia de Fluorescência/métodos , Simulação de Dinâmica Molecular , Proteínas Ribossômicas/metabolismo , Ribossomos/metabolismo , Trifosfato de Adenosina/metabolismo , Carbocianinas/química , Cinética , Modelos Químicos , Modelos Genéticos , Modelos Moleculares , Fator G para Elongação de Peptídeos/metabolismo , Biossíntese de Proteínas/genética , RNA de Transferência/química , RNA de Transferência/metabolismo , Proteínas Ribossômicas/química , Ribossomos/química , Ribossomos/genéticaRESUMO
MOTIVATION: Collaborative analysis of massive imaging datasets is essential to enable scientific discoveries. RESULTS: We developed Cytomine to foster active and distributed collaboration of multidisciplinary teams for large-scale image-based studies. It uses web development methodologies and machine learning in order to readily organize, explore, share and analyze (semantically and quantitatively) multi-gigapixel imaging data over the internet. We illustrate how it has been used in several biomedical applications. AVAILABILITY AND IMPLEMENTATION: Cytomine (http://www.cytomine.be/) is freely available under an open-source license from http://github.com/cytomine/ A documentation wiki (http://doc.cytomine.be) and a demo server (http://demo.cytomine.be) are also available. CONTACT: info@cytomine.be SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Assuntos
Interpretação de Imagem Assistida por Computador , Estatística como Assunto , Internet , SoftwareRESUMO
We report that 4-(3-(benzyloxy)phenyl)-2-ethylsulfinyl-6-(trifluoromethyl)pyrimidine (BETP), which behaves as a positive allosteric modulator at the glucagon-like peptide-1 receptor (GLP-1R), covalently modifies cysteines 347 and 438 in GLP-1R. C347, located in intracellular loop 3 of GLP-1R, is critical to the activity of BETP and a structurally distinct GLP-1R ago-allosteric modulator, N-(tert-butyl)-6,7-dichloro-3-(methylsulfonyl)quinoxalin-2-amine. We further show that substitution of cysteine for phenylalanine 345 in the glucagon receptor is sufficient to confer sensitivity to BETP.
Assuntos
Pirimidinas/química , Receptores de Glucagon/metabolismo , Animais , Células CHO , Cricetulus , Cisteína/química , Peptídeo 1 Semelhante ao Glucagon/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1 , Humanos , Ligantes , Pirimidinas/metabolismo , Receptores de Glucagon/químicaRESUMO
Identification of orally active, small molecule antagonists of the glucagon receptor represents a novel treatment paradigm for the management of type 2 diabetes mellitus. The present work discloses novel glucagon receptor antagonists, identified via conformational constraint of current existing literature antagonists. Optimization of lipophilic ligand efficiency (LLE or LipE) culminated in enantiomers (+)-trans-26 and (-)-trans-27 which exhibit good physicochemical and in vitro drug metabolism profiles. In vivo, significant pharmacokinetic differences were noted with the two enantiomers, which were primarily driven through differences in clearance rates. Enantioselective oxidation by cytochrome P450 was ruled out as a causative factor for pharmacokinetic differences.
Assuntos
Benzamidas/química , Pirimidinas/química , Receptores de Glucagon/antagonistas & inibidores , Administração Intravenosa , Administração Oral , Animais , Benzamidas/farmacocinética , Benzamidas/farmacologia , Células Cultivadas , Cães , Ligantes , Conformação Molecular , Estrutura Molecular , Oxirredução , Ligação Proteica/efeitos dos fármacos , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Ratos Wistar , EstereoisomerismoRESUMO
Glucagon-like peptide-1 (GLP-1)(7-36)amide is a 30-amino acid peptide hormone that is secreted from intestinal enteroendocrine L-cells in response to nutrients. GLP-1(7-36)amide possesses potent insulinotropic actions in the augmentation of glucose-dependent insulin secretion. GLP-1(7-36)amide is rapidly metabolized by dipeptidyl peptidase-IV to yield GLP-1(9-36)amide as the principal metabolite. Contrary to the earlier notion that peptide cleavage products of native GLP-1(7-36)amide [including GLP-1(9-36)amide] are pharmacologically inactive, recent studies have demonstrated cardioprotective and insulinomimetic effects with GLP-1(9-36)amide in mice, dogs and humans. In the present work, in vitro metabolism and pharmacokinetic properties of GLP-1(9-36)amide have been characterized in dogs, since this preclinical species has been used as an animal model to demonstrate the in vivo vasodilatory and cardioprotective effects of GLP-1(9-36)amide. A liquid chromatography tandem mass spectrometry assay was developed for the quantitation of the intact peptide in hepatocyte incubations as opposed to a previously reported enzyme-linked immunosorbent assay. Although GLP-1(9-36)amide was resistant to proteolytic cleavage in dog plasma and bovine serum albumin (t1/2>240 min), the peptide was rapidly metabolized in dog hepatocytes with a t1/2 of 110 min. Metabolite identification studies in dog hepatocytes revealed a variety of N-terminus cleavage products, most of which, have also been observed in human and mouse hepatocytes. Proteolysis at the C-terminus was not observed in GLP-1(9-36)amide. Following the administration of a single intravenous bolus dose (20 µg/kg) to male Beagle dogs, GLP-1(9-36)amide exhibited a mean plasma clearance of 15 ml/min/kg and a low steady state distribution volume of 0.05 l/kg, which translated into a short elimination half life of 0.05 h. Following subcutaneous administration of GLP-1(9-36)amide at 50 µg/kg, systemic exposure of GLP-1(9-36)amide as ascertained from maximal plasma concentrations and area under the plasma concentration-time curve from zero to infinity was 44 ng/ml and 32 ng h/ml, respectively. The subcutaneous bioavailability of GLP-1(9-36)amide in dogs was 57%. Our findings raise the possibility that the cardioprotective effects of GLP-1(9-36)amide in the conscious dog model of pacing-induced heart failure might be due, at least in part, to the actions of additional downstream metabolites, which are obtained from proteolytic cleavage of the peptide backbone in the parent compound in the liver.
Assuntos
Cardiotônicos/farmacocinética , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Peptídeos/farmacocinética , Animais , Cardiotônicos/sangue , Cromatografia Líquida , Cães , Peptídeo 1 Semelhante ao Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/farmacocinética , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Insulina/metabolismo , Secreção de Insulina , Masculino , Camundongos , Peptídeos/sangue , Espectrometria de Massas em TandemRESUMO
During protein synthesis, deacylated transfer RNAs leave the ribosome via an exit (E) site after mRNA translocation. How the ribosome regulates tRNA dissociation and whether functional linkages between the aminoacyl (A) and E sites modulate the dynamics of protein synthesis have long been debated. Using single molecule fluorescence resonance energy transfer experiments, we find that, during early cycles of protein elongation, tRNAs are often held in the E site until being allosterically released when the next aminoacyl tRNA binds to the A site. This process is regulated by the length and sequence of the nascent peptide and by the conformational state, detected by tRNA proximity, prior to translocation. In later cycles, E-site tRNA dissociates spontaneously. Our results suggest that the distribution of pretranslocation tRNA states and posttranslocation pathways are correlated within each elongation cycle via communication between distant subdomains in the ribosome, but that this correlation between elongation cycle intermediates does not persist into succeeding cycles.
Assuntos
Biossíntese de Proteínas/fisiologia , RNA de Transferência/metabolismo , Sítio Alostérico , Sequência de Aminoácidos , Sequência de Bases , Transporte Biológico Ativo , Fenômenos Biofísicos , Transferência Ressonante de Energia de Fluorescência , Cinética , Dados de Sequência Molecular , Conformação de Ácido Nucleico , Elongação Traducional da Cadeia Peptídica/fisiologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA de Transferência/química , Ribossomos/metabolismoRESUMO
PURPOSE: Twin-twin transfusion syndrome (TTTS) is a condition wherein monochorionic twins share a common placenta with placental anastomoses between the two foetal circulations. Most infants who survive TTTS are born prematurely. This study aimed to determine whether fetoscopic laser ablation (FLA) can reduce the risk of retinopathy of prematurity (ROP) and whether TTTS was a risk factor for ROP. METHODS: This single-centre, retrospective, comparative study included 32 monochorionic twins with TTTS matched for gestational age, birthweight and sex to premature twins and singletons without TTTS (n = 68; twins, n = 34; and singletons, n = 34) born between 2003 and 2022. A single ophthalmologist recorded the fundus findings. FLA was performed using Solomon's technique to separate the vascular systems of the twins with TTTS. RESULTS: The gestational age and weight of premature infants with TTTS treated with FLA were significantly higher than those of untreated infants (p = 0.001 and p = 0.001, respectively); however, the hyaline membrane grade was lower (p = 0.004). A significant increase in weight (g/day) (p = 0.002) and lesser avascular area in the peripheral temporal retina (p = 0.045) was observed at postnatal week 4. The risk of ROP in the FLA group was 2.6 times (13.3% vs. 35.3%) lower than that in the non-FLA group; however, this difference was not significant. The incidence of any stage of ROP (25% vs. 18%) and treatment for ROP type 1 (6.25% vs. 5.9%) did not differ significantly between monochorionic twins with TTTS and premature infants without TTTS. CONCLUSION: The gestational age of premature infants with TTTS treated with FLA was higher than that of untreated infants. Moreover, a reduction in complications of prematurity was also observed. Laser fetoscopy in twin-twin transfusion syndrome may reduce the risk of ROP, but the difference was not statistically significant in this small study.
Assuntos
Transfusão Feto-Fetal , Fetoscopia , Idade Gestacional , Terapia a Laser , Retinopatia da Prematuridade , Humanos , Transfusão Feto-Fetal/cirurgia , Feminino , Retinopatia da Prematuridade/cirurgia , Retinopatia da Prematuridade/diagnóstico , Estudos Retrospectivos , Gravidez , Fetoscopia/métodos , Recém-Nascido , Masculino , Terapia a Laser/métodos , Fatores de Risco , Incidência , Peso ao NascerRESUMO
Bloom syndrome (BS) is a rare genetic disorder characterized by genomic instability and a high predisposition to cancer. The gene defective in BS, BLM, encodes a member of the RecQ family of 3'-5' DNA helicases, and is proposed to function in recombinational repair during DNA replication. Here, we have utilized single-molecule fluorescence resonance energy transfer microscopy to examine the behaviour of BLM on forked DNA substrates. Strikingly, BLM unwound individual DNA molecules in a repetitive manner, unwinding a short length of duplex DNA followed by rapid reannealing and reinitiation of unwinding in several successions. Our results show that a monomeric BLM can 'measure' how many base pairs it has unwound, and once it has unwound a critical length, it reverses the unwinding reaction through strand switching and translocating on the opposing strand. Repetitive unwinding persisted even in the presence of hRPA, and interaction between wild-type BLM and hRPA was necessary for unwinding reinitiation on hRPA-coated DNA. The reported activities may facilitate BLM processing of stalled replication forks and illegitimately formed recombination intermediates.
Assuntos
DNA/metabolismo , RecQ Helicases/metabolismo , Síndrome de Bloom/genética , Síndrome de Bloom/metabolismo , DNA/química , DNA Helicases/química , DNA Helicases/genética , Reparo do DNA , Replicação do DNA , Transferência Ressonante de Energia de Fluorescência , Humanos , Modelos Genéticos , Conformação de Ácido Nucleico , Oligonucleotídeos/química , Ligação ProteicaRESUMO
Previous studies have revealed that the glucoincretin hormone glucagon-like peptide-1 (GLP-1)(7-36)amide is metabolized by dipeptidyl peptidase-IV (DPP-IV) and neutral endopeptidase 24.11 (NEP) to yield GLP-1(9-36)amide and GLP-1(28-36)amide, respectively, as the principal metabolites. Contrary to the previous notion that GLP-1(7-36)amide metabolites are pharmacologically inactive, recent studies have demonstrated cardioprotective and insulinomimetic effects with both GLP-1(9-36)amide and GLP-1(28-36)amide in animals and humans. In the present work, we examined the metabolic stability of the two GLP-1(7-36)amide metabolites in cryopreserved hepatocytes, which have been used to demonstrate the in vitro insulin-like effects of GLP-1(9-36)amide and GLP-1(28-36)amide on gluconeogenesis. To examine the metabolic stability of the GLP-1(7-36)amide metabolites, a liquid chromatography-tandem mass spectrometry assay was developed for the quantitation of the intact peptides in hepatocyte incubations. GLP-1(9-36)amide and GLP-1(28-36)amide were rapidly metabolized in mouse [GLP-1(9-36)amide: t(1/2) = 52 minutes; GLP-1(28-36)amide: t(1/2) = 13 minutes] and human hepatocytes [GLP-1(9-36)amide: t(1/2) = 180 minutes; GLP-1(28-36)amide: t(1/2) = 24 minutes), yielding a variety of N-terminal cleavage products that were characterized using mass spectrometry. Metabolism at the C terminus was not observed for either peptides. The DPP-IV and NEP inhibitors diprotin A and phosphoramidon, respectively, did not induce resistance in the two peptides toward proteolytic cleavage. Overall, our in vitro findings raise the intriguing possibility that the insulinomimetic effects of GLP-1(9-36)amide and GLP-1(28-36)amide on gluconeogenesis and oxidative stress might be due, at least in part, to the actions of additional downstream metabolites, which are obtained from the enzymatic cleavage of the peptide backbone in the parent compounds.
Assuntos
Peptídeo 1 Semelhante ao Glucagon/metabolismo , Hepatócitos/metabolismo , Fragmentos de Peptídeos/metabolismo , Animais , Gluconeogênese/fisiologia , Humanos , Camundongos , Estresse Oxidativo/fisiologiaRESUMO
4-(3-(Benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine (BETP) represents a novel small-molecule activator of the glucagon-like peptide-1 receptor (GLP-1R), and exhibits glucose-dependent insulin secretion in rats following i.v. (but not oral) administration. To explore the quantitative pharmacology associated with GLP-1R agonism in preclinical species, the in vivo pharmacokinetics of BETP were examined in rats after i.v. and oral dosing. Failure to detect BETP in circulation after oral administration of a 10-mg/kg dose in rats was consistent with the lack of an insulinotropic effect of orally administered BETP in this species. Likewise, systemic concentrations of BETP in the rat upon i.v. administration (1 mg/kg) were minimal (and sporadic). In vitro incubations in bovine serum albumin, plasma, and liver microsomes from rodents and humans indicated a facile degradation of BETP. Failure to detect metabolites in plasma and liver microsomal incubations in the absence of NADP was suggestive of a covalent interaction between BETP and a protein amino acid residue(s) in these matrices. Incubations of BETP with glutathione (GSH) in buffer revealed a rapid nucleophilic displacement of the ethylsulfoxide functionality by GSH to yield adduct M1, which indicated that BETP was intrinsically electrophilic. The structure of M1 was unambiguously identified by comparison of its chromatographic and mass spectral properties with an authentic standard. The GSH conjugate of BETP was also characterized in NADPH- and GSH-supplemented liver microsomes and in plasma samples from the pharmacokinetic studies. Unlike BETP, M1 was inactive as an allosteric modulator of the GLP-1R.
Assuntos
Pirimidinas/química , Receptores de Glucagon/metabolismo , Regulação Alostérica/efeitos dos fármacos , Animais , Células CHO , Cricetinae , Cricetulus , Estabilidade de Medicamentos , Receptor do Peptídeo Semelhante ao Glucagon 1 , Glutationa/química , Humanos , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Ratos , Ratos WistarRESUMO
Glucokinase (hexokinase IV) continues to be a compelling target for the treatment of type 2 diabetes given the wealth of supporting human genetics data and numerous reports of robust clinical glucose lowering in patients treated with small molecule allosteric activators. Recent work has demonstrated the ability of hepatoselective activators to deliver glucose lowering efficacy with minimal risk of hypoglycemia. While orally administered agents require a considerable degree of passive permeability to promote suitable exposures, there is no such restriction on intravenously delivered drugs. Therefore, minimization of membrane diffusion in the context of an intravenously agent should ensure optimal hepatic targeting and therapeutic index. This work details the identification a hepatoselective GKA exhibiting the aforementioned properties.
Assuntos
Ativadores de Enzimas/química , Glucoquinase/química , Hipoglicemiantes/química , Regulação Alostérica , Animais , Células Cultivadas , Diabetes Mellitus Tipo 2/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Ativadores de Enzimas/metabolismo , Ativadores de Enzimas/uso terapêutico , Glucoquinase/metabolismo , Hepatócitos/citologia , Hepatócitos/enzimologia , Humanos , Hipoglicemiantes/metabolismo , Hipoglicemiantes/uso terapêutico , Imidazóis/química , Injeções Intravenosas , Niacina/análogos & derivados , Niacina/química , Ratos , Distribuição TecidualRESUMO
A novel and potent small molecule glucagon receptor antagonist for the treatment of diabetes mellitus is reported. This candidate, (S)-3-[4-(1-{3,5-dimethyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenoxy}butyl)benzamido]propanoic acid, has lower molecular weight and lipophilicity than historical glucagon receptor antagonists, resulting in excellent selectivity in broad-panel screening, lower cytotoxicity, and excellent overall in vivo safety in early pre-clinical testing. Additionally, it displays low in vivo clearance and excellent oral bioavailability in both rats and dogs. In a rat glucagon challenge model, it was shown to reduce the glucagon-elicited glucose excursion in a dose-dependent manner and at a concentration consistent with its rat in vitro potency. Its properties make it an excellent candidate for further investigation.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Fármacos , Propionatos/farmacologia , Receptores de Glucagon/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Físico-Química , Cães , Relação Dose-Resposta a Droga , Células Epiteliais/efeitos dos fármacos , Haplorrinos , Humanos , Fígado/citologia , Camundongos , Estrutura Molecular , Propionatos/administração & dosagem , Propionatos/síntese química , Ratos , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/síntese química , Relação Estrutura-AtividadeRESUMO
A novel series of glucagon receptor antagonists has been discovered. These pyrazole ethers and aminopyrazoles have lower molecular weight and increased polarity such that the molecules fall into better drug-like property space. This work has culminated in compounds 44 and 50 that were shown to have good pharmacokinetic attributes in dog, in contrast to rats, in which clearance was high; and compound 49, which demonstrated a dose-dependent reduction in glucose excursion in a rat glucagon challenge experiment.
Assuntos
Diabetes Mellitus/tratamento farmacológico , Pirazóis/química , Receptores de Glucagon/antagonistas & inibidores , Animais , Química Farmacêutica/métodos , Cães , Relação Dose-Resposta a Droga , Desenho de Fármacos , Éter/química , Glucagon/química , Glucose/química , Humanos , Cinética , Modelos Químicos , Peso Molecular , Ratos , TemperaturaRESUMO
INTRODUCTION: The American Association of Colleges of Pharmacy (AACP) has emphasized the need to prepare pharmacy students for practicing amidst the opioid crisis. This research aimed to identify patterns and predictors of pharmacy program participation in skills-based education, research, and service activities designed to address this crisis. METHODS: Opioid-related activities were identified from the AACP opioid-related activities database and classified by two independent reviewers. The final activities included: (1) direct participation in drug disposal and/or naloxone outreach, (2) opioid-focused research, and (3) skills-based training in the doctor of pharmacy curriculum. Latent class analysis was used to identify classes of program involvement in these activities. Differences in class membership based on program and geographic characteristics were examined using multivariable logistic regression. RESULTS: Of the 106 schools included, a minority reported opioid-focused research (38.7%), drug disposal or naloxone outreach (30.2%), or hands-on learning (22.6%). A "highly engaged" class (34.9%) and a "limited engagement" class (65.1%) were identified. "Highly engaged" programs were more likely to report opioid-related research (65.9% vs. 24.6%, P < .001), drug disposal or naloxone outreach events (86.5% vs. 0%, P < .001), and skills-based education (40.5% vs. 13%, P = .001) than "limited engagement" programs. No school or geographic factors were significantly associated with class membership. CONCLUSIONS: Nearly two-thirds of schools and colleges of pharmacy reported limited involvement in skills-based education, research, and outreach efforts. Future research should explore other predictors of school-level opioid-related activities, including faculty expertise and institutional priorities.
Assuntos
Epidemia de Opioides , Farmácia , Humanos , Estados Unidos , Analgésicos Opioides , Faculdades de Farmácia , Naloxona/uso terapêuticoRESUMO
The design and synthesis of a GPR119 agonist bearing a 2-(2,3,6-trifluorophenyl)acetamide group is described. The design capitalized on the conformational restriction found in N-ß-fluoroethylamide derivatives to help maintain good levels of potency while driving down both lipophilicity and oxidative metabolism in human liver microsomes. The chemical stability and bioactivation potential are discussed.
Assuntos
Acetamidas/química , Acetamidas/farmacologia , Desenho de Fármacos , Receptores Acoplados a Proteínas G/agonistas , Acetamidas/síntese química , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Receptores Acoplados a Proteínas G/químicaRESUMO
Audience: This simulation provides training for emergency medicine residents in the stepwise management of a patient who presents with bleeding from a tracheoinnominate artery fistula. Additional learners who might benefit from this simulation are otolaryngology and general surgery residents as well as critical care fellows. Introduction: Hemorrhage from a tracheoinnominate artery fistula (TIAF) is a rare but life-threatening complication in a patient with a recent tracheostomy. This complication occurs in 0.7% of tracheostomy patients with a mortality of 50-70%.1 Seventy-five percent of patients with a TIAF will present within the first three weeks of surgery and 50% of patients will present with a sentinel bleed that briefly resolves.1 Key elements of a history and exam that should raise a provider's concern for this diagnosis include a recent tracheostomy (within the last 4 weeks), a percutaneous tracheostomy, prior radiation, chronic steroid use, a neck or chest deformity or a sentinel bleed.2 Survival from a TIAF hinges upon emergent, operative repair by an otolaryngologist and cardiothoracic surgeon. Cuff hyperinflation and the Utley Maneuver are critical bedside interventions to temporize this massive bleed and stabilize the patient for definitive, operative repair. Educational Objectives: By the end of this simulation, learners will be able to: 1) perform a focused history and physical exam on any patient who presents with bleeding from the tracheostomy site, 2) describe the differential diagnosis of bleeding from a tracheostomy site, including a TIAF, 3) demonstrate the stepwise management of bleeding from a suspected TIAF, including cuff hyperinflation and the Utley Maneuver, 4) verify that definitive airway control via endotracheal intubation is only feasible in the tracheostomy patient when it is clear, upon history and exam, that the patient can be intubated from above, 5) demonstrate additional critical actions in the management of a patient with a TIAF, including early consultation with otolaryngology and cardiothoracic surgery as well as emergent blood transfusion and activation of a massive transfusion protocol. Educational Methods: This case was written with a modified, low-fidelity manikin, traditionally used for training in nasogastric tube placement and tracheostomy care. We modified this manikin to simulate a hemorrhage from the tracheostomy site.3 The patient in our case had a history of laryngeal cancer, and thus we occluded his larynx for this simulation. As a result of this obstruction, he was unable to be intubated from above. We provided confederates, a bedside nurse and family member, to assist the learners throughout the case. We also utilized a simulation technician to operate dynamic vital signs on a simulated cardiac monitor. It would be technically challenging to adapt this case to a high-fidelity simulator due to potential for damage of the internal electrical elements by the large amount of artificial blood from the tracheostomy tube. However, a mechanical pump provided a useful means of active bleeding in this low-fidelity manikin. Research Methods: We provided a pre- and post-simulation questionnaire for the 33 emergency medicine residents who participated in this simulation. There were 11 residents from each of the PGY-1, PGY-2 and PGY-3 year-groups. Thirty-two residents (97%) completed the pre-survey and 33 residents (100%) completed the post-survey. For our questions, we used a 5-point Likert Scale to assess a resident's knowledge of the learning objectives within this simulation. Results: Responses from our pre- and post- survey indicated a significant improvement in knowledge about a tracheoinnominate artery fistula as well as the general management of tracheostomy complications in the emergency department. Discussion: This simulation is a useful educational tool for instructing emergency medicine residents on optimal management of tracheostomy emergencies such as a TIAF. The interprofessional teaching by an emergency medicine attending and mid-level (PGY-3) otolaryngology resident allowed for a richer and more detailed discussion during the debriefing. Throughout the case, the emergency medicine attending played the role of a bedside nurse and offered supportive, clinical cues when bleeding recurred. The otolaryngology resident played the role of a family member and offered helpful cues during the history and exam portion of the case. Following the case, both content experts provided useful clinical insight during the debriefing. If staffing availability permits, it might be advantageous to use additional simulation-trained personnel to play the roles of the nurse and family member, thus allowing the emergency medicine attending and otolaryngology content experts to simply view the case from the control room and perform the debriefing. Topics: Tracheostomy, surgical airway, tracheoinnominate artery fistula, bleeding from tracheostomy site, complications with tracheostomies, hemorrhagic shock.
RESUMO
Probiotics are heavily advertised to promote a healthy gastrointestinal tract and boost the immune system. This review article summarizes the history and diversity of probiotics, outlines conventional in vitro assays and in vivo models, assesses the pharmacologic effects of probiotic and pharmaceutical co-administration, and the broad impact of clinical probiotic utilization for gastrointestinal disease indications.
RESUMO
Previous studies on the in vitro metabolism of 4-alkylsulfonyl-2-pyridone-based glucokinase activators revealed a facile, non-enzymatic displacement of the 4-alkylsulfonyl group by glutathione. In the present studies, a role for glutathione-S-transferases (GST) as catalysts in the desulfonylation reaction was demonstrated using a combination of human liver microsomes, human liver cytosol and human GSTs. The identification of a glutathione conjugate in circulation following intravenous administration of a candidate 4-methylsulfonyl-2-pyridone to rats confirmed the relevance of the in vitro findings.