RESUMEN
The virally encoded 3C-like protease (3CLpro) is a well-validated drug target for the inhibition of coronaviruses including Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Most inhibitors of 3CLpro are peptidomimetic, with a γ-lactam in place of Gln at the P1 position of the pseudopeptide chain. An effort was pursued to identify a viable alternative to the γ-lactam P1 mimetic which would improve physicochemical properties while retaining affinity for the target. Discovery of a 2-tetrahydrofuran as a suitable P1 replacement that is a potent enzymatic inhibitor of 3CLpro in SARS-CoV-2 virus is described herein.
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Antivirales , Inhibidores de Proteasa de Coronavirus , Furanos , Antivirales/química , Antivirales/farmacología , Lactamas , Péptido Hidrolasas , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/química , SARS-CoV-2 , Furanos/química , Inhibidores de Proteasa de Coronavirus/químicaRESUMEN
BACKGROUND: Leicester was the first city in the UK to have 'local lockdown' measures imposed in response to high community rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission. As part of this response, a directive was issued by NHS England to offer testing of asymptomatic healthcare workers (HCWs) at University Hospitals of Leicester NHS Trust (UHL) for SARS-CoV-2 infection. METHODS: Between 20 July and 14 August 2020, we invited all HCWs at UHL to attend for SARS-CoV-2 testing by nucleic acid amplification (NAAT). We combined the result of this assay with demographic information from the electronic staff record. RESULTS: A total of 1150 staff (~8% of the workforce) volunteered. The median age was 46 years (IQR 34-55), 972 (84.5%) were female; 234 (20.4%) were of South Asian and 58 (5.0%) of Black ethnicity; 564 (49.0%) were nurses/healthcare assistants. We found no cases of asymptomatic infection. In comparison, average community test positivity rate in Leicester city was 2.6%. CONCLUSIONS: Within the context of local lockdowns due to high community transmission rates, voluntary testing of asymptomatic staff has low uptake and low yield and thus its premise and cost-effectiveness should be re-considered.
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COVID-19 , COVID-19/epidemiología , Prueba de COVID-19 , Control de Enfermedades Transmisibles , Atención a la Salud , Femenino , Personal de Salud , Humanos , Transmisión de Enfermedad Infecciosa de Paciente a Profesional , Masculino , Persona de Mediana Edad , SARS-CoV-2RESUMEN
BACKGROUND: Although evidence suggests that demographic characteristics including minority ethnicity increase the risk of infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), it is unclear whether these characteristics, together with occupational factors, influence anti-SARS-CoV-2 IgG seroprevalence in hospital staff. METHODS: We conducted cross-sectional surveillance examining seroprevalence of anti-SARS-CoV-2 IgG amongst staff at University Hospitals of Leicester (UHL) NHS Trust. We quantified seroprevalence stratified by ethnicity, occupation and seniority of practitioner and used logistic regression to examine demographic and occupational factors associated with seropositivity. RESULTS: A total of 1148/10662 (10.8%) hospital staff members were seropositive. Compared to White staff (seroprevalence 9.1%), seroprevalence was higher in South Asian (12.3%) and Black (21.2%) staff. The occupations and department with the highest seroprevalence were nurses/healthcare assistants (13.7%) and the Emergency Department (ED)/Acute Medicine (17.5%), respectively. Seroprevalence decreased with seniority in medical/nursing practitioners. Minority ethnicity was associated with seropositivity on an adjusted analysis (South Asian: aOR 1.26; 95%CI: 1.07-1.49 and Black: 2.42; 1.90-3.09). Anaesthetics/ICU staff members were less likely to be seropositive than ED/Acute medicine staff (0.41; 0.27-0.61). CONCLUSIONS: Ethnicity and occupational factors, including specialty and seniority, are associated with seropositivity for anti-SARS-Cov-2 IgG. These findings could be used to inform occupational risk assessments for front-line healthcare workers.
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COVID-19 , SARS-CoV-2 , Anticuerpos Antivirales , COVID-19/epidemiología , Estudios Transversales , Demografía , Personal de Salud , Humanos , Inmunoglobulina G , Personal de Hospital , Estudios SeroepidemiológicosRESUMEN
BACKGROUND: Healthcare workers (HCWs) and ethnic minority groups are at increased risk of COVID-19 infection and adverse outcomes. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is now available for frontline UK HCWs; however, demographic/occupational associations with vaccine uptake in this cohort are unknown. We sought to establish these associations in a large UK hospital workforce. METHODS AND FINDINGS: We conducted cross-sectional surveillance examining vaccine uptake amongst all staff at University Hospitals of Leicester NHS Trust. We examined proportions of vaccinated staff stratified by demographic factors, occupation, and previous COVID-19 test results (serology/PCR) and used logistic regression to identify predictors of vaccination status after adjustment for confounders. We included 19,044 HCWs; 12,278 (64.5%) had received SARS-CoV-2 vaccination. Compared to White HCWs (70.9% vaccinated), a significantly smaller proportion of ethnic minority HCWs were vaccinated (South Asian, 58.5%; Black, 36.8%; p < 0.001 for both). After adjustment for age, sex, ethnicity, deprivation, occupation, SARS-CoV-2 serology/PCR results, and COVID-19-related work absences, factors found to be negatively associated with vaccine uptake were younger age, female sex, increased deprivation, pregnancy, and belonging to any non-White ethnic group (Black: adjusted odds ratio [aOR] 0.30, 95% CI 0.26-0.34, p < 0.001; South Asian: aOR 0.67, 95% CI 0.62-0.72, p < 0.001). Those who had previously had confirmed COVID-19 (by PCR) were less likely to be vaccinated than those who had tested negative. Limitations include data being from a single centre, lack of data on staff vaccinated outside the hospital system, and that staff may have taken up vaccination following data extraction. CONCLUSIONS: Ethnic minority HCWs and those from more deprived areas as well as younger staff and female staff are less likely to take up SARS-CoV-2 vaccination. These findings have major implications for the delivery of SARS-CoV-2 vaccination programmes, in HCWs and the wider population, and should inform the national vaccination programme to prevent the disparities of the pandemic from widening.
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Vacunas contra la COVID-19/farmacología , COVID-19/prevención & control , Personal de Salud/estadística & datos numéricos , SARS-CoV-2/patogenicidad , Vacunación/estadística & datos numéricos , COVID-19/epidemiología , Atención a la Salud/estadística & datos numéricos , Humanos , Grupos Minoritarios , Reino Unido/epidemiologíaRESUMEN
Lead optimization of piperidine amide HTS hits, based on an anilino-thiazole core, led to the identification of analogs which displayed low nanomolar blocking activity at the canonical transient receptor channels 3 and 6 (TRPC3 & 6) based on FLIPR (carbachol stimulated) and electrophysiology (OAG stimulated) assays. In addition, the anilino-thiazole amides displayed good selectivity over other TRP channels (TRPA1, TRPV1, and TRPV4), as well as against cardiac ion channels (CaV1.2, hERG, and NaV1.5). The high oxidation potential of the aliphatic piperidine and aniline groups, as well as the lability of the thiazole amide group contributed to the high clearance observed for this class of compounds. Conversion of an isoquinoline amide to a naphthyridine amide markedly reduced clearance for the bicyclic piperidines, and improved oral bioavailability for this compound series, however TRPC3 and TRPC6 blocking activity was reduced substantially. Although the most potent anilino-thiazole amides ultimately lacked oral exposure in rodents and were not suitable for chronic dosing, analogs such as 14-19, 22, and 23 are potentially valuable in vitro tool compounds for investigating the role of TRPC3 and TRPC6 in cardiovascular disease.
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Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Canales Catiónicos TRPC/antagonistas & inhibidores , Tiazoles/química , Tiazoles/farmacología , Diglicéridos/metabolismo , Descubrimiento de Drogas , Células HEK293 , Humanos , Canales Catiónicos TRPC/metabolismo , Canal Catiónico TRPC6RESUMEN
BACKGROUND/AIMS: Data concerning differences in demographics/disease severity between the first and second waves of COVID-19 are limited. We aimed to examine prognosis in patients presenting to hospital with COVID-19 amongst different ethnic groups between the first and second waves in the UK. METHODS: In this retrospective cohort study, we included 1763 patients presenting to a regional hospital centre in Leicester (UK) and compared those in the first (n = 956) and second (n = 807) waves. Admission National Early Warning Scores, mechanical ventilation and mortality rate were lower in the second wave compared with the first. RESULTS: Thirty-day mortality risk in second wave patients was approximately half that of first wave patients [adjusted hazard ratio (aHR) 0.55, 95% confidence interval (CI) 0.40-0.75]. In the second wave, Black patients were at higher risk of 30-day mortality than White patients (4.73, 1.56-14.3). CONCLUSION: We found that disporportionately higher risks of death in patients from ethnic minority groups were not equivalent across consecutive waves of the pandemic. This suggests that risk factors for death in those from ethnic minority groups are malleable and potentially reversible. Our findings need urgent investigation in larger studies.
RESUMEN
E1A binding protein (p300) and CREB binding protein (CBP) are two highly homologous and multidomain histone acetyltransferases. These two proteins are involved in many cellular processes by acting as coactivators of a large number of transcription factors. Dysregulation of p300/CBP has been found in a variety of cancers and other diseases, and inhibition has been shown to decrease Myc expression. Herein, we report the identification of a series of highly potent, proline-based small-molecule p300/CBP histone acetyltransferase (HAT) inhibitors using DNA-encoded library technology in combination with high-throughput screening. The strategy of reducing ChromlogD and fluorination of metabolic soft spots was explored to improve the pharmacokinetic properties of potent p300 inhibitors. Fluorination of both cyclobutyl and proline rings of 22 led to not only reduced clearance but also improved cMyc cellular potency.
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Proteína de Unión a CREB , Ensayos Analíticos de Alto Rendimiento , Prolina , Histona Acetiltransferasas , Proteínas E1A de Adenovirus/metabolismo , Factores de Transcripción p300-CBP , ADN , TecnologíaAsunto(s)
Reacción Leucemoide/diagnóstico , Mieloma Múltiple/diagnóstico , Neutrófilos/patología , Granulocitos/patología , Humanos , Reacción Leucemoide/complicaciones , Reacción Leucemoide/patología , Masculino , Microscopía , Persona de Mediana Edad , Mieloma Múltiple/complicaciones , Mieloma Múltiple/patología , Células Plasmáticas/patologíaRESUMEN
The previously reported pyrrolidine class of progesterone receptor partial agonists demonstrated excellent potency but suffered from serious liabilities including hERG blockade and high volume of distribution in the rat. The basic pyrrolidine amine was intentionally converted to a sulfonamide, carbamate, or amide to address these liabilities. The evaluation of the degree of partial agonism for these non-basic pyrrolidine derivatives and demonstration of their efficacy in an in vivo model of endometriosis is disclosed herein.
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Pirrolidinas/química , Receptores de Progesterona/agonistas , Animales , Sitios de Unión , Carbamatos/química , Cristalografía por Rayos X , Canal de Potasio ERG1 , Endometriosis/tratamiento farmacológico , Canales de Potasio Éter-A-Go-Go/metabolismo , Femenino , Humanos , Pirrolidinas/síntesis química , Pirrolidinas/farmacocinética , Ratas , Receptores de Progesterona/metabolismo , Sulfonamidas/químicaRESUMEN
GSK3527497, a preclinical candidate for the inhibition of TRPV4, was identified starting from the previously reported pyrrolidine sulfonamide TRPV4 inhibitors 1 and 2. Optimization of projected human dose was accomplished by specifically focusing on in vivo pharmacokinetic parameters CLu, Vdssu, and MRT. We highlight the use of conformational changes as a novel approach to modulate Vdssu and present results that suggest that molecular-shape-dependent binding to tissue components governs Vdssu in addition to bulk physicochemical properties. Optimization of CLu within the series was guided by in vitro metabolite identification, and the poor FaSSIF solubility imparted by the crystalline properties of the pyrrolidine diol scaffold was improved by the introduction of a charged moiety to enable excellent exposure from high crystalline doses. GSK3527497 is a preclinical candidate suitable for oral and iv administration that is projected to inhibit TRPV4 effectively in patients from a low daily clinical dose.
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Pirrolidinas/química , Sulfonamidas/química , Canales Catiónicos TRPV/antagonistas & inhibidores , Administración Oral , Animales , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Concentración 50 Inhibidora , Pirrolidinas/metabolismo , Ratas , Ratas Sprague-Dawley , Solubilidad , Relación Estructura-Actividad , Sulfonamidas/metabolismo , Canales Catiónicos TRPV/metabolismoRESUMEN
GSK2798745, a clinical candidate, was identified as an inhibitor of the transient receptor potential vanilloid 4 (TRPV4) ion channel for the treatment of pulmonary edema associated with congestive heart failure. We discuss the lead optimization of this novel spirocarbamate series and specifically focus on our strategies and solutions for achieving desirable potency, rat pharmacokinetics, and physicochemical properties. We highlight the use of conformational bias to deliver potency and optimization of volume of distribution and unbound clearance to enable desirable in vivo mean residence times.
RESUMEN
OBJECTIVE: To evaluate complications and outcomes associated with surgical placement of gastrojejunostomy feeding tubes in dogs with naturally occurring disease. DESIGN: Prospective study. ANIMALS: 26 dogs. Multiple preoperative, intraoperative, and postoperative variables were evaluated. Daily postoperative abdominal radiographic examinations were performed to determine the presence of the following mechanical tube complications: kinking, coiling, knotting, and migration. Tube stoma abnormalities (erythema, cellulitis, and discharge) were observed daily and recorded by use of a standardized visual analog grading scale. Additionally, presence of complications was compared with median survival times. RESULTS: The most common indication for gastrojejunostomy tube placement was gastrointestinal disease (n = 11), with confirmed septic peritonitis in 8 of 11 dogs. Other indications for gastrojejunostomy tube placement included extrahepatic biliary surgery (n = 6) and pancreatic disease (9). Mean +/- SD surgical time required for tube placement was 26 +/- 14 minutes. Overall, mechanical tube complication rate was 46% (12/26), including coiling (7), migration (4), and kinking (2). Overall minor tube stoma complication rate was 77% (20/26) and included erythema (16), cellulitis (13), and discharge (17). Dislodgement or self-induced tube trauma resulted in accidental tube removal in 2 of 26 dogs, and inadvertent tube damage necessitated premature removal by the clinician in 1 of 26 dogs. Kaplan-Meier median survival time was 39 days with 13 of 26 dogs still alive. CONCLUSIONS AND CLINICAL RELEVANCE: Gastrojejunostomy tube placement affords flexibility in the postoperative nutritional regimen by allowing for postgastric feeding with simultaneous access to the stomach.
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Enfermedades de los Perros/cirugía , Derivación Gástrica/veterinaria , Enfermedades Gastrointestinales/veterinaria , Enfermedades Pancreáticas/veterinaria , Complicaciones Posoperatorias/veterinaria , Animales , Perros , Femenino , Derivación Gástrica/efectos adversos , Derivación Gástrica/instrumentación , Derivación Gástrica/métodos , Enfermedades Gastrointestinales/cirugía , Estimación de Kaplan-Meier , Masculino , Enfermedades Pancreáticas/cirugía , Complicaciones Posoperatorias/epidemiología , Estudios Prospectivos , Radiografía Abdominal/veterinaria , Resultado del TratamientoRESUMEN
Pancreatitis is recognized as an important and common problem in dogs, but diagnosis can be challenging. Recently, new assays for the measurement of trypsin-a1-proteinase inhibitor complexes and canine pancreatic lipase immunoreactivity (cPLI and Spec cPL) have been developed and analytically validated. This is the first report of a direct comparison of the sensitivity of these and other more traditional serum markers for the diagnosis of canine pancreatitis in a subset of dogs with this disease (i.e., dogs with both macroscopic and microscopic changes characteristic of pancreatitis). Serum cPLI and Spec cPL concentrations showed the highest sensitivity for the diagnosis of pancreatitis in this group of patients. Further studies will be required to compare the specificity of these serum markers and thus determine their overall clinical utility.
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Amilasas/sangre , Enfermedades de los Perros/sangre , Enfermedades de los Perros/diagnóstico , Lipasa/sangre , Pancreatitis/veterinaria , Animales , Biomarcadores/sangre , Enfermedades de los Perros/patología , Perros , Páncreas/enzimología , Pancreatitis/sangre , Pancreatitis/diagnóstico , Pancreatitis/patología , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Índice de Severidad de la EnfermedadRESUMEN
We developed an automated countercurrent chromatography (CCC) process to isolate anthocyanins from black currant extract utilizing a solvent system of methyl-t-butyl ether, n-butanol, acetonitrile and water with pH adjusted by addition of trifluoroacetic acid in normal phase mode. The process has excellent repeatability as indicated by the high purity of isolated products (90% or better) and the low retention time variability (<10% RSD overall and <5% RSD at constant mass loading). In addition, we determined solvent system ratios to facilitate independent preparation of stationary and mobile phases which enabled us to reduce solvent waste by 70%.
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Antocianinas/aislamiento & purificación , Técnicas de Química Analítica/métodos , Distribución en Contracorriente , Solventes/químicaRESUMEN
A novel series of pyrrolidine sulfonamide transient receptor potential vanilloid-4 (TRPV4) antagonists was developed by modification of a previously reported TRPV4 inhibitor (1). Several core-structure modifications were identified that improved TRPV4 activity by increasing structural rigidity and reducing the entropic energy penalty upon binding to the target protein. The new template was initially discovered as a minor regio-isomeric side product formed during routine structure-activity relationship (SAR) studies, and further optimization resulted in highly potent compounds with a novel pyrrolidine diol core. Further improvements in potency and pharmacokinetic properties were achieved through SAR studies on the sulfonamide substituent to give an optimized lead compound GSK3395879 (52) that demonstrated the ability to inhibit TRPV4-mediated pulmonary edema in an in vivo rat model. GSK3395879 is a tool for studying the biology of TRPV4 and an advanced lead for identifying new heart failure medicines.
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Diseño de Fármacos , Pirrolidinas/química , Sulfonamidas/química , Sulfonamidas/farmacología , Canales Catiónicos TRPV/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Ratas , Relación Estructura-Actividad , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacocinéticaRESUMEN
Analysis of cis-regulatory elements is central to understanding the genomic program for development. The scl/tal-1 transcription factor is essential for lineage commitment to blood cell formation and previous studies identified an scl enhancer (the +18/19 element) which was sufficient to target the vast majority of hematopoietic stem cells, together with hematopoietic progenitors and endothelium. Moreover, expression of scl under control of the +18/19 enhancer rescued blood progenitor formation in scl(-/-) embryos. However, here we demonstrate by using a knockout approach that, within the endogenous scl locus, the +18/19 enhancer is not necessary for the initiation of scl transcription or for the formation of hematopoietic cells. These results led to the identification of a bifunctional 5' enhancer (-3.8 element), which targets expression to hematopoietic progenitors and endothelium, contains conserved critical Ets sites, and is bound by Ets family transcription factors, including Fli-1 and Elf-1. These data demonstrate that two geographically distinct but functionally related enhancers regulate scl transcription in hematopoietic progenitors and endothelial cells and suggest that enhancers with dual hematopoietic-endothelial activity may represent a general strategy for regulating blood and endothelial development.
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Proteínas de Unión al ADN/metabolismo , Elementos de Facilitación Genéticos , Hematopoyesis/fisiología , Células Madre Hematopoyéticas/fisiología , Proteínas Proto-Oncogénicas/metabolismo , Factores de Transcripción/metabolismo , Animales , Secuencia de Bases , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Linaje de la Célula , Proteínas de Unión al ADN/genética , Embrión de Mamíferos/anatomía & histología , Embrión de Mamíferos/fisiología , Regulación del Desarrollo de la Expresión Génica , Genes Reporteros , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Datos de Secuencia Molecular , Proteínas Nucleares , Proteína Proto-Oncogénica c-fli-1 , Proteínas Proto-Oncogénicas/genética , Alineación de Secuencia , Proteína 1 de la Leucemia Linfocítica T Aguda , Transactivadores/metabolismo , Factores de Transcripción/genética , Transcripción GenéticaRESUMEN
CASE DESCRIPTION: 2 dogs were evaluated because of vomiting and lethargy (a Toy Poodle; dog 1) and acute respiratory distress, vomiting, and anorexia (a Chihuahua; dog 2). Dog 1 had been exposed to a commercial hydrocarbon waterproofing spray 24 hours before the development of clinical signs, and dog 2 was examined 18 hours after exposure to a waterproofing spray containing heptane, a highly flammable liquid hydrocarbon. CLINICAL FINDINGS: In both dogs, major gastrointestinal tract abnormalities were ruled out but respiratory status worsened. Thoracic radiography revealed a diffuse interstitial pulmonary pattern, and hypoxemia was detected. TREATMENT AND OUTCOME: Hospitalization for monitoring and care was required for both dogs. The dogs recovered with supportive care, which included administration of oxygen, fluids, and bronchodilators. Additionally, dog 1 received glucocorticoids via inhalation and supplemental enteral nutrition, whereas dog 2 was treated with an antimicrobial. CLINICAL RELEVANCE: The dogs of this report developed hydrocarbon pneumonitis following exposure to waterproofing sprays. Such sprays contain potentially toxic hydrocarbons. The severity of the adverse effects associated with exposure may have been amplified because the dogs were physically small and were exposed to a relatively large amount of aerosolized spray within small areas. Development of chemical pneumonitis in pet animals is best prevented by application of waterproofing sprays in well-ventilated or outdoor areas from which pets have been excluded. With prolonged hospitalization and considerable monitoring and care, affected dogs can recover from these exposures.
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Enfermedades de los Perros/inducido químicamente , Polímeros de Fluorocarbono/toxicidad , Hipoxia/veterinaria , Exposición por Inhalación/efectos adversos , Enfermedades Pulmonares Intersticiales/veterinaria , Aerosoles/toxicidad , Contaminantes Atmosféricos/toxicidad , Animales , Enfermedades de los Perros/diagnóstico , Enfermedades de los Perros/terapia , Perros , Femenino , Hipoxia/inducido químicamente , Hipoxia/diagnóstico , Hipoxia/terapia , Enfermedades Pulmonares Intersticiales/inducido químicamente , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/terapia , Resultado del TratamientoRESUMEN
Few studies of the prevalence of histologic lesions of the exocrine pancreas in dogs have been reported, and none of them systematically evaluate the localization of these lesions. The purpose of this study was to describe the anatomic localization of pancreatic inflammation, necrosis, and fibrosis in dogs presented for postmortem examination. Seventy-three pancreata from dogs presented for postmortem examination were evaluated and investigated for the presence of suppurative inflammation (SI), pancreatic necrosis (PN), and lymphocytic inflammation (LI). Sections that showed evidence of SI, PN, or LI also were evaluated for pancreatic fibrosis (F). The tendency for a preferred localization for SI, PN, and LI was evaluated by chi-square analysis. A total of 47 pancreata with histologic evidence of pancreatitis (SI, PN, or LI; F alone was not considered evidence of pancreatitis) were identified. Twenty-four (51.1%) had SI, 23 (48.9%) had PN, and 34 (72.3%) had LI. Of the 47 dogs with SI, PN, or LI, 28 (59.6%) had F. The distribution of SI, PN, and LI between the right and the left limb of the pancreas and among the 5 anatomic regions was random, based on a goodness-of-fit test. We conclude that pancreatic inflammation tends to occur in discrete areas within the pancreas rather than diffusely throughout the whole organ. These findings suggest that a single biopsy is insufficient to exclude subclinical pancreatitis and that there is no preferred site for pancreatic biopsy collection unless gross lesions are apparent.
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Enfermedades de los Perros/epidemiología , Enfermedades de los Perros/patología , Pancreatitis/veterinaria , Animales , Autopsia , Enfermedades de los Perros/etiología , Perros , Femenino , Masculino , Necrosis , New York/epidemiología , Páncreas/patología , Pancreatitis/epidemiología , Pancreatitis/patologíaRESUMEN
OBJECTIVE: To evaluate pituitary-adrenal function in a population of critically ill dogs by measuring serial plasma concentrations of basal cortisol, ACTH-stimulated cortisol, and endogenous ACTH. DESIGN: Prospective study. ANIMALS: 20 critically ill dogs admitted to an intensive care unit (ICU). PROCEDURE: Basal plasma cortisol, ACTH-stimulated cortisol, and endogenous ACTH concentrations were measured for each dog within 24 hours of admission and daily until death, euthanasia, or discharge from the ICU. Established reference ranges for healthy dogs were used for comparison. Survival prediction index (SPI) scores were calculated for each dog within 24 hours of admission. RESULTS: No significant difference was found between initial concentrations of basal cortisol, ACTH-stimulated cortisol, and endogenous ACTH in 13 dogs that survived and those in 7 dogs that died. High initial basal endogenous ACTH concentrations were correlated with subsequent high values. Low basal ACTH-stimulated cortisol concentrations were predictive of higher subsequent values. All basal and ACTH-stimulated cortisol concentrations were within or above the reference range in the 52 plasma samples collected from the 20 dogs during hospitalization. The SPI scores correlated with outcome (ie, alive or dead), but none of the plasma hormone concentrations correlated with SPI score or outcome. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicate that none of the critically ill dogs in our study population developed adrenal insufficiency during hospitalization in the ICU.