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Even in large systems, the effect of noise arising from when populations are initially small can persist to be measurable on the macroscale. A deterministic approximation to a stochastic model will fail to capture this effect, but it can be accurately approximated by including an additional random time-shift to the initial conditions. We present a efficient numerical method to compute this time-shift distribution for a large class of stochastic models. The method relies on differentiation of certain functional equations, which we show can be effectively automated by deriving rules for different types of model rates that arise commonly when mass-action mixing is assumed. Explicit computation of the time-shift distribution can be used to build a practical tool for the efficient generation of macroscopic trajectories of stochastic population models, without the need for costly stochastic simulations. Full code is provided to implement the calculations and we demonstrate the method on an epidemic model and a model of within-host viral dynamics.
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Simulación por Computador , Epidemias , Conceptos Matemáticos , Modelos Biológicos , Dinámica Poblacional , Procesos Estocásticos , Humanos , Epidemias/estadística & datos numéricos , Dinámica Poblacional/estadística & datos numéricos , Factores de TiempoRESUMEN
BACKGROUND: The central nervous system contains steroid receptors, particularly in the hypothalamic and limbic systems. These systems are responsible for driving certain emotions in humans, especially stress, anxiety, motivation, energy levels, and mood. Thus, corticosteroids may precipitate patients to experience these emotions. Most existing studies report neuropsychiatric side effects after oral or intravenous corticosteroids rather than epidural. OBJECTIVES: This study examines the neuropsychiatric side effects after epidural steroid injections (ESIs), with a focus on whether certain factors in patients' histories further exacerbate symptomatology. STUDY DESIGN: Prospective observational cohort study. SETTING: Fluoroscopy suite at an urban academic teaching hospital. METHODS: Patients were called 24 hours and one week after their ESIs and asked if they experienced certain neuropsychiatric symptoms more than usual compared to baseline. PATIENTS: Seventy-four patients undergoing a lumbosacral ESI (interlaminar (ILESI), caudal or transforaminal (TFESI)) were invited to take part in the study the day of his or her procedure. INTERVENTION/MEASUREMENT: Assessed whether psychiatric history, gender, race, type of ESI, or the number of levels injected affected frequency and duration of neuropsychiatric symptoms at one day and one week after an ESI. RESULTS: Significantly (P < 0.05) more patients with a psychiatric history experienced restlessness and irritability at day one than those without a psychiatric history. At week one, male gender (IRR 2.29, 95% CI 1.37, 3.83, P = 0.002), ILESI (IRR 7.75, 95% CI 1.03, 58.6, P = 0.047), and 2-level injections (IRR 2.14, 95% CI 1.13, 4.06, P = 0.019) were significantly associated to more total symptoms. LIMITATIONS: Single center study, reliance on subjective responses from patients, lack of follow-up after one week post-ESI. CONCLUSION(S): This study demonstrates that neuropsychiatric symptoms are rare overall after an ESI, though certain factors may influence patients experiencing these symptoms. Restlessness and irritability were more likely to occur one day after an ESI in those with a psychiatric history. Those who had a 2-level injection were more likely to keep experiencing most symptoms by week one, suggesting a possible correlation between corticosteroid dose and neuropsychiatric symptoms.
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Ansiedad , Agitación Psicomotora , Humanos , Femenino , Masculino , Estudios Prospectivos , Corticoesteroides , EsteroidesRESUMEN
BACKGROUND: Since electronic cigarettes (E-Cigs) were introduced to the United States (US) in 2007 its use has increased. Like other tobacco products, E-Cigs too pose health risks. Studies have shown a correlation between pain and tobacco use, with the association being bidirectional. However, there is limited data on the effect of E-Cig use on chronic pain, as well as its association with opioid use. OBJECTIVES: To evaluate the use of tobacco products, including E-Cigs in a chronic pain population. STUDY DESIGN: This study was designed as a cross sectional survey. SETTING: This study was set in an urban academic teaching center. METHODS: After IRB approval, surveys of established chronic pain patients were conducted over 4 months. The survey and results were anonymous, without the collection of any identifiable information. The adult patients who had been treated in the pain practice for over 3 months were included in this study. The survey collected the patients' age, gender, history of tobacco usage, cigarette smoking, E-Cig and opioid use. RESULTS: A total of 312 patients were surveyed. 198 women (63.5%) and 114 men (36.5%). The average age was 58.2; ~59 years for men and ~58 years for women. Eighty-four patients (26.9%) were managing pain using chronic opioids; 46 women and 38 men. Nine women (4.5%) had tried E-Cigs in the past, but none (0%) were active users. Eighteen men (15.8%) had tried E-Cigs in the past with 9 (7.8%) being active users. Among the opioid managed patients, 6 (9.1%) had and were active users of E-Cigs and all 6 were men (20%). LIMITATIONS: The anonymous results collected through the survey may not be accurate as they cannot be validated. In addition to the small sample size, the entire study population is from an urban academic center which may not be generalizable to all chronic pain patients. Finally, the study does not evaluate the impact of tobacco or E-Cig use on pain level or functional status. CONCLUSION: In this study of chronic pain patients, cigarette smoking and E-Cig use was similar to the reported use in the general adult population in the US. The study showed a strong correlation between tobacco use, especially cigarettes and E-Cigs, and opioid use. As the use of E-Cigs becomes more mainstream, the association between E-Cig use, chronic pain, and opioid use should be monitored.
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Dolor Crónico , Sistemas Electrónicos de Liberación de Nicotina , Vapeo , Humanos , Adulto , Masculino , Femenino , Estados Unidos/epidemiología , Persona de Mediana Edad , Dolor Crónico/epidemiología , Estudios Transversales , Analgésicos Opioides/uso terapéuticoRESUMEN
A series of macrocyclic PKCθ inhibitors based on a 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hinge binder has been studied. Different aromatic and heteroaromatic substituents have been explored in order to optimize potency, isoform selectivity as well as DMPK properties. The importance of the length of the macrocyclic linker has also been analyzed. In particular, it has been found that methyl substitutions on the linker can have a profound influence on both potency and metabolic stability. Several compounds showing very good profiles, suitable for in vivo testing, are disclosed.
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BACKGROUND: Lower limb injuries constitute a problem in the sport of football. Our aim is to explore patterns and trends of lower limb injuries in an English professional football club. METHODS: This is a descriptive epidemiological study. Reports provided by the club's physical therapy team were screened for injuries among professional football players sustained over four seasons, from 2015/2016 to 2018/2019. Data included setting of injury (in-match or training), anatomical location of injury, type of injury, number of days off and month of injury. RESULTS: A total of 296 lower limb injuries were recorded in our study, with a rate of 11.14 per 1000 football hours. Injury rate during games was 51.38 per 1000 football hours, significantly greater than that during training at 3.81 per 1000 football hours (p = 0.021). The thigh was significantly the most commonly injured location at 4.67 per 1000 football hours (p < 0.001). Grade I tears were the most common injury type at 1.73 per 1000 football hours, significantly greater than grade III tears (p = 0.027), contusions (p = 0.043), fractures (p = 0.02), and lacerations (p = 0.019). Injury rates were found to be greatest during preseason and declined as season progressed. On average, an injury sidelined the affected footballer for a total of 20 days. CONCLUSION: Lower limb injuries were more common during matches than training. The thigh is the most common injury location, and grade I muscle tear was the most common type of injury. Injury rates were higher early on in the season. Potential prevention strategies include spacing out competition, adopting training and exercise regimens that cater for recovery, and increasing research regarding injury mechanisms.
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Traumatismos en Atletas , Fútbol , Esguinces y Distensiones , Humanos , Incidencia , Extremidad Inferior/lesiones , Fútbol/lesionesRESUMEN
BACKGROUND: Autopsy studies of former contact sports athletes, including soccer and rugby players, frequently report chronic traumatic encephalopathy, a neurodegenerative pathology associated with traumatic brain injury. Nevertheless, little is known about the risk of neurodegenerative disease in these populations. We hypothesised that neurodegenerative disease risk would be higher among former elite rugby union players than the general population. METHODS: We conducted a retrospective cohort study accessing national electronic records on death certification, hospital admissions and dispensed prescriptions for a cohort of 412 male Scottish former international rugby union players and 1236 members of the general population, matched to former players by age, sex and area socioeconomic status. Mortality and incident neurodegenerative disease diagnoses among former rugby players were then compared with the matched comparison group. RESULTS: Over a median 32 years follow-up from study entry at age 30 years, 121 (29.4%) former rugby players and 381 (30.8%) of the matched comparison group died. All-cause mortality was lower among former rugby players until 70 years of age with no difference thereafter. During follow-up, 47 (11.4%) former rugby players and 67 (5.4%) of the comparison group were diagnosed with incident neurodegenerative disease (HR 2.67, 95% CI 1.67 to 4.27, p<0.001). CONCLUSIONS: This study adds to our understanding of the association between contact sports participation and the risk of neurodegenerative disease. While further research exploring this interaction is required, in the meantime strategies to reduce exposure to head impacts and head injuries in sport should be promoted.
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Traumatismos en Atletas , Conmoción Encefálica , Fútbol Americano , Enfermedades Neurodegenerativas , Humanos , Masculino , Adulto , Fútbol Americano/lesiones , Traumatismos en Atletas/epidemiología , Enfermedades Neurodegenerativas/epidemiología , Estudios Retrospectivos , Rugby , Conmoción Encefálica/diagnósticoRESUMEN
The cessation of amateur and recreational sport has had significant implications globally, impacting economic, social and health facets of population well-being. As a result, there is pressure to resume sport at all levels. The ongoing prevalence of SARS-CoV-2 and subsequent 'second waves' require urgent best practice guidelines to be developed to return recreational (non-elite) sports as quickly as possible while prioritising the well-being of the participants and support staff.This guidance document describes the need for such advice and the process of collating available evidence. Expert opinion is integrated into this document to provide uniform and pragmatic recommendations, thereby optimising on-field and field-side safety for all involved persons, including coaches, first responders and participants.The nature of SARS-CoV-2 transmission means that the use of some procedures performed during emergency care and resuscitation could potentially be hazardous, necessitating the need for guidance on the use of personal protective equipment, the allocation of predetermined areas to manage potentially infective cases and the governance and audit of the process.
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COVID-19 , Pandemias , Consenso , Primeros Auxilios , Humanos , SARS-CoV-2RESUMEN
INTRODUCTION: COVID-19 has forever impacted health care in the U.S. Changes to health and hospital policies led to disruptions to both patient care and medical training. There is limited understanding of the impact on urology resident training across the U.S. Our aim was to examine trends in urological procedures, as captured by the Accreditation Council for Graduate Medical Education resident case logs, throughout the COVID-19 pandemic. METHODS: Retrospective review of publicly available urology resident case logs between July 2015 and June 2021 was performed. Average case numbers were analyzed via linear regression with different models specifying different assumptions regarding the impact of COVID-19 on procedure in 2020 and onward. Statistical calculations utilized R (version 4.0.2). RESULTS: Analysis favored models which assumed the impact of COVID-related disruptions were specific to 2019-2020. Analysis of procedures performed indicate an average upward trend of urology cases nationally. An average annual increase of 26 procedures between 2016 and 2021 was noted, except for 2020 which saw an average drop of approximately 67 cases. However, in 2021 case volume dramatically increased to the same rate as projected had there not been a disruption in 2020. Stratifying by category of urology procedure revealed evidence for variability between categories in the magnitude of the 2020 decrease. CONCLUSIONS: Despite widespread pandemic-related disruptions in surgical care, urological volume has rebounded and increased, likely having minimal detriment to urological training over time. Urological care is essential and in high demand as evidenced by the uptick in volume across the U.S.
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Importance: Neurodegenerative disease mortality is higher among former professional soccer players than general population controls. However, the factors contributing to increased neurodegenerative disease mortality in this population remain uncertain. Objective: To investigate the association of field position, professional career length, and playing era with risk of neurodegenerative disease among male former professional soccer players. Design, Setting, and Participants: This cohort study used population-based health record linkage in Scotland to evaluate risk among 7676 male former professional soccer players born between January 1, 1900, and January 1, 1977, and 23â¯028 general population control individuals matched by year of birth, sex, and area socioeconomic status providing 1â¯812â¯722 person-years of follow-up. Scottish Morbidity Record and death certification data were available from January 1, 1981, to December 31, 2016, and prescribing data were available from January 1, 2009, to December 31, 2016. Database interrogation was performed on December 10, 2018, and data were analyzed between April 2020 and May 2021. Exposures: Participation in men's soccer at a professional level. Main Outcomes and Measures: Outcomes were obtained by individual-level record linkage to national electronic records of mental health and general hospital inpatient and day-case admissions as well as prescribing information and death certification. Risk of neurodegenerative disease was evaluated between former professional soccer players and matched general population control individuals. Results: In this cohort study of 30â¯704 male individuals, 386 of 7676 former soccer players (5.0%) and 366 of 23â¯028 matched population control individuals (1.6%) were identified with a neurodegenerative disease diagnosis (hazard ratio [HR], 3.66; 95% CI, 2.88-4.65; P < .001). Compared with the risk among general population control individuals, risk of neurodegenerative disease was highest for defenders (HR, 4.98; 95% CI, 3.18-7.79; P < .001) and lowest for goalkeepers (HR, 1.83; 95% CI, 0.93-3.60; P = .08). Regarding career length, risk was highest among former soccer players with professional career lengths longer than 15 years (HR, 5.20; 95% CI, 3.17-8.51; P < .001). Regarding playing era, risk remained similar for all players born between 1910 and 1969. Conclusions and Relevance: The differences in risk of neurodegenerative disease observed in this cohort study imply increased risk with exposure to factors more often associated with nongoalkeeper positions, with no evidence this association has changed over the era studied. While investigations to confirm specific factors contributing to increased risk of neurodegenerative disease among professional soccer players are required, strategies directed toward reducing head impact exposure may be advisable in the meantime.
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Enfermedades Neurodegenerativas/epidemiología , Fútbol , Adulto , Atletas , Estudios de Cohortes , Humanos , Masculino , Estudios Retrospectivos , Factores de Riesgo , Escocia , Factores de TiempoRESUMEN
BACKGROUND: There is growing concern surrounding the role of repetitive sub-concussive head impacts, such as football heading, on brain health. OBJECTIVES: Three questions were addressed while only considering studies that observed heading exposure directly: (1) how frequently does heading occur within football training and matches, (2) what are the biomechanical characteristics of heading, and (3) is cognitive function affected by heading? METHODS: This review followed the steps described in the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Electronic databases including MEDLINE and SPORTDiscus were searched from the earliest entry to July 2020. Studies that reported independently quantified heading exposure, biomechanical characteristics of heading or the relationship between heading and cognitive function were included. Data were extracted and used to populate summary tables with reference to each research question. RESULTS: Heading incidence ranged between one to nine headers per player per match. The number of headers observed in small-sided games during training varied depending on the exact format used but generally speaking ranged between zero to one per player per game. The three most commonly reported biomechanical variables were head acceleration, head rotational velocity and overall movement kinematics during the heading action. Average head acceleration ranged from approximately four to 50 g. Nine out of 12 included studies did not observe a negative impact on cognitive test performance following exposure to heading and while three did, these negative effects were limited to specific outcome measures: reaction time and memory function. CONCLUSION: The current weight of evidence summarised herein does not support the notion that heading is deleterious to cognitive performance in the short term; however, this conclusion is tentative due to methodological shortcomings in the existing evidence base.
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Conmoción Encefálica , Fútbol Americano , Fútbol , Aceleración , Fenómenos Biomecánicos , Conmoción Encefálica/epidemiología , Cognición , Humanos , IncidenciaRESUMEN
The COVID-19 pandemic has necessitated many novel responses in healthcare including sport and exercise medicine. The cessation of elite sport almost globally has had significant economic implications and resulted in pressure to resume sport in very controlled conditions. This includes protecting pitch-side medical staff and players from infection. The ongoing prevalence of SARS-CoV-2 and the desire to resume professional sport required urgent best practice guidelines to be developed so that sport could be resumed as safely as possible. This set of best practice recommendations assembles early evidence for managing SARS-CoV-2 and integrates expert opinion to provide a uniform and pragmatic approach to enhance on-field and pitch-side safety for the clinician and player. The nature of SARS-CoV-2 transmission creates new hazards during resuscitation and emergency care and procedures. Recommendations for the use and type of personal protective equipment during on-field or pitch-side emergency medical care is provided based on the clinical scenario and projected risk of viral transmission.
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INTRODUCTION: There is growing recognition of an association between contact sports participation and increased risk of neurodegenerative disease, including Alzheimer's disease and chronic traumatic encephalopathy. In addition to cognitive impairment, a range of mental health disorders and suicidality are proposed as diagnostic features of traumatic encephalopathy syndrome, the putative clinical syndrome associated with chronic traumatic encephalopathy. However, to date, epidemiological data on contact sport participation and mental health outcomes are limited. METHODS: For a cohort of former professional soccer players (n=7676) with known high neurodegenerative mortality and their matched general population controls (n=23 028), data on mental health outcomes were obtained by individual-level record linkage to national electronic records of hospital admissions and death certification. RESULTS: Compared with matched population controls, former professional soccer players showed lower risk of hospital admission for anxiety and stress related disorders, depression, drug use disorders, alcohol use disorders and bipolar and affective mood disorders. Among soccer players, there was no significant difference in risk of hospitalisation for mental health disorders between outfield players and goalkeepers. There was no significant difference in rate of death by suicide between soccer players and controls. CONCLUSIONS: Among a population of former professional soccer players with known high neurodegenerative disease mortality, hospital admissions for common mental health disorders were lower than population controls, with no difference in suicide. Our data provide support for the reappraisal of currently proposed diagnostic clinical criteria for traumatic encephalopathy syndrome, in particular the inclusion of mental health outcomes.
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Atletas/estadística & datos numéricos , Hospitalización/estadística & datos numéricos , Trastornos Mentales/epidemiología , Fútbol , Suicidio/estadística & datos numéricos , Adulto , Anciano , Alcoholismo/epidemiología , Trastornos de Ansiedad/epidemiología , Atletas/psicología , Trastorno Bipolar/epidemiología , Estudios de Cohortes , Trastorno Depresivo/epidemiología , Humanos , Masculino , Trastornos Mentales/psicología , Salud Mental , Persona de Mediana Edad , Trastornos Relacionados con Sustancias/epidemiologíaRESUMEN
The clinical success of anti-IL-17 monoclonal antibodies (i.e., Cosentyx and Taltz) has validated Th17 pathway modulation for the treatment of autoimmune diseases. The nuclear hormone receptor RORγt is a master regulator of Th17 cells and affects the production of a host of cytokines, including IL-17A, IL-17F, IL-22, IL-26, and GM-CSF. Substantial interest has been spurred across both academia and industry to seek small molecules suitable for RORγt inhibition. A variety of RORγt inhibitors have been reported in the past few years, the majority of which are orthosteric binders. Here we disclose the discovery and optimization of a class of inhibitors, which bind differently to an allosteric binding pocket. Starting from a weakly active hit 1, a tool compound 14 was quickly identified that demonstrated superior potency, selectivity, and off-target profile. Further optimization focused on improving metabolic stability. Replacing the benzoic acid moiety with piperidinyl carboxylate, modifying the 4-aza-indazole core in 14 to 4-F-indazole, and incorporating a key hydroxyl group led to the discovery of 25, which possesses exquisite potency and selectivity, as well as an improved pharmacokinetic profile suitable for oral dosing.
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BACKGROUND: Neurodegenerative disorders have been reported in elite athletes who participated in contact sports. The incidence of neurodegenerative disease among former professional soccer players has not been well characterized. METHODS: We conducted a retrospective cohort study to compare mortality from neurodegenerative disease among 7676 former professional soccer players (identified from databases of Scottish players) with that among 23,028 controls from the general population who were matched to the players on the basis of sex, age, and degree of social deprivation. Causes of death were determined from death certificates. Data on medications dispensed for the treatment of dementia in the two cohorts were also compared. Prescription information was obtained from the national Prescribing Information System. RESULTS: Over a median of 18 years, 1180 former soccer players (15.4%) and 3807 controls (16.5%) died. All-cause mortality was lower among former players than among controls up to the age of 70 years and was higher thereafter. Mortality from ischemic heart disease was lower among former players than among controls (hazard ratio, 0.80; 95% confidence interval [CI], 0.66 to 0.97; P = 0.02), as was mortality from lung cancer (hazard ratio, 0.53; 95% CI, 0.40 to 0.70; P<0.001). Mortality with neurodegenerative disease listed as the primary cause was 1.7% among former soccer players and 0.5% among controls (subhazard ratio [the hazard ratio adjusted for competing risks of death from ischemic heart disease and death from any cancer], 3.45; 95% CI, 2.11 to 5.62; P<0.001). Among former players, mortality with neurodegenerative disease listed as the primary or a contributory cause on the death certificate varied according to disease subtype and was highest among those with Alzheimer's disease (hazard ratio [former players vs. controls], 5.07; 95% CI, 2.92 to 8.82; P<0.001) and lowest among those with Parkinson's disease (hazard ratio, 2.15; 95% CI, 1.17 to 3.96; P = 0.01). Dementia-related medications were prescribed more frequently to former players than to controls (odds ratio, 4.90; 95% CI, 3.81 to 6.31; P<0.001). Mortality with neurodegenerative disease listed as the primary or a contributory cause did not differ significantly between goalkeepers and outfield players (hazard ratio, 0.73; 95% CI, 0.43 to 1.24; P = 0.24), but dementia-related medications were prescribed less frequently to goalkeepers (odds ratio, 0.41; 95% CI, 0.19 to 0.89; P = 0.02). CONCLUSIONS: In this retrospective epidemiologic analysis, mortality from neurodegenerative disease was higher and mortality from other common diseases lower among former Scottish professional soccer players than among matched controls. Dementia-related medications were prescribed more frequently to former players than to controls. These observations need to be confirmed in prospective matched-cohort studies. (Funded by the Football Association and Professional Footballers' Association.).
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Atletas , Enfermedades Neurodegenerativas/mortalidad , Fútbol , Adulto , Anciano , Anciano de 80 o más Años , Lesiones Encefálicas , Estudios de Casos y Controles , Causas de Muerte , Femenino , Cardiopatías/mortalidad , Humanos , Incidencia , Modelos Logísticos , Longevidad , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Nootrópicos/uso terapéutico , Estudios Retrospectivos , Escocia/epidemiologíaRESUMEN
INTRODUCTION: In the past decade, evidence has emerged suggesting a potential link between contact sport participation and increased risk of late neurodegenerative disease, in particular chronic traumatic encephalopathy. While there remains a lack of clear evidence to test the hypothesis that contact sport participation is linked to an increased incidence of dementia, there is growing public concern regarding the risk. There is, therefore, a pressing need for research to gain greater understanding of the potential risks involved in contact sports participation, and to contextualise these within holistic health benefits of sport. METHODS AND ANALYSIS: Football's InfluencE on Lifelong health and Dementia risk is designed as a retrospective cohort study, with the aim to analyse data from former professional footballers (FPF) in order to assess the incidence of neurodegenerative disease in this population. Comprehensive electronic medical and death records will be analysed and compared with those of a demographically matched population control cohort. As well as neurodegenerative disease incidence, all-cause, and disease-specific mortality, will be analysed in order to assess lifelong health. Cox proportional hazards models will be run to compare the data collected from FPFs to matched population controls. ETHICS AND DISSEMINATION: Approvals for study have been obtained from the University of Glasgow College of Medical, Veterinary and Life Sciences Research Ethics Committee (Project Number 200160147) and from National Health Service Scotland's Public Benefits and Privacy Panel (Application 1718-0120).
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Atletas , Demencia/epidemiología , Trastornos Mentales/epidemiología , Enfermedades Neurodegenerativas/epidemiología , Exposición Profesional , Fútbol , Estudios de Casos y Controles , Causas de Muerte , Enfermedad Crónica , Encefalopatía Traumática Crónica , Humanos , Incidencia , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Escocia/epidemiologíaRESUMEN
According to the World Health Organization (WHO), approximately 1.7 million deaths per year are caused by tuberculosis infections. Furthermore, it has been predicted that, by 2050, antibacterial resistance will be the cause of approximately 10 million deaths annually if the issue is not tackled. As a result, novel approaches to treating broad-spectrum bacterial infections are of vital importance. During the course of our wider efforts to discover unique methods of targeting multidrug-resistant (MDR) pathogens, we identified a novel series of amide-linked pyrimido[4,5-b]indol-8-amine inhibitors of bacterial type II topoisomerases. Compounds from the series were highly potent against gram-positive bacteria and mycobacteria, with excellent potency being retained against a panel of relevant Mycobacterium tuberculosis drug-resistant clinical isolates.
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Antibacterianos/farmacología , Girasa de ADN/metabolismo , Diseño de Fármacos , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Inhibidores de Topoisomerasa II/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Bacterias Grampositivas/metabolismo , Células Hep G2 , Humanos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Inhibidores de Topoisomerasa II/síntesis química , Inhibidores de Topoisomerasa II/químicaRESUMEN
Interleukin-1 receptor associated kinase 4 (IRAK4) has been implicated in IL-1R and TLR based signaling. Therefore selective inhibition of the kinase activity of this protein represents an attractive target for the treatment of inflammatory diseases. Medicinal chemistry optimization of high throughput screening (HTS) hits with the help of structure based drug design led to the identification of orally-bioavailable quinazoline based IRAK4 inhibitors with excellent pharmacokinetic profile and kinase selectivity. These highly selective IRAK4 compounds show activity in vivo via oral dosing in a TLR7 driven model of inflammation.
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Inflamación/tratamiento farmacológico , Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/farmacología , Administración Oral , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ensayos Analíticos de Alto Rendimiento , Imidazoles/farmacología , Inflamación/enzimología , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Interleucina-6/antagonistas & inhibidores , Interleucina-6/biosíntesis , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Quinazolinas/administración & dosificación , Quinazolinas/química , Ratas , Ratas Endogámicas Lew , Relación Estructura-ActividadRESUMEN
The inhibition of aldosterone synthase (CYP11B2) may be an effective treatment of hypertension and heart failure, among other ailments. Previously reported benzimidazole CYP11B2 inhibitors led the way for bioisosteric imidazopyridines that are both potent and selective over CYP11B1.
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Citocromo P-450 CYP11B2/antagonistas & inhibidores , Imidazoles/farmacología , Piridinas/farmacología , Animales , Cricetulus , Humanos , Imidazoles/síntesis química , Imidazoles/química , Imidazoles/farmacocinética , Macaca mulatta , Masculino , Microsomas Hepáticos/metabolismo , Piridinas/síntesis química , Piridinas/química , Piridinas/farmacocinética , Ratas Wistar , Esteroide 11-beta-Hidroxilasa/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
There is an urgent and unmet medical need for new antibacterial drugs that tackle infections caused by multidrug-resistant (MDR) pathogens. During the course of our wider efforts to discover and exploit novel mechanism of action antibacterials, we have identified a novel series of isothiazolone based inhibitors of bacterial type II topoisomerase. Compounds from the class displayed excellent activity against both Gram-positive and Gram-negative bacteria with encouraging activity against a panel of MDR clinical Escherichia coli isolates when compared to ciprofloxacin. Representative compounds also displayed a promising in vitro safety profile.
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Antibacterianos/química , ADN-Topoisomerasas de Tipo II/metabolismo , Tiazoles/química , Tiazolidinas/química , Inhibidores de Topoisomerasa II/química , Antibacterianos/síntesis química , Antibacterianos/farmacología , Supervivencia Celular/efectos de los fármacos , ADN-Topoisomerasas de Tipo II/química , Evaluación Preclínica de Medicamentos , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Escherichia coli/aislamiento & purificación , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Células Hep G2 , Humanos , Pruebas de Sensibilidad Microbiana , Mutación , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/farmacología , Tiazolidinas/síntesis química , Tiazolidinas/farmacología , Inhibidores de Topoisomerasa II/síntesis química , Inhibidores de Topoisomerasa II/farmacologíaRESUMEN
The ERK/MAPK pathway plays a central role in the regulation of critical cellular processes and is activated in more than 30% of human cancers. Specific BRAF and MEK inhibitors have shown clinical efficacy in patients for the treatment of BRAF-mutant melanoma. However, the majority of responses are transient, and resistance is often associated with pathway reactivation of the ERK signal pathway. Acquired resistance to these agents has led to greater interest in ERK, a downstream target of the MAPK pathway. De novo design efforts of a novel scaffold derived from SCH772984 by employing hydrogen bond interactions specific for ERK in the binding pocket identified 1-(1H-pyrazolo[4,3-c]pyridin-6-yl)ureas as a viable lead series. Sequential SAR studies led to the identification of highly potent and selective ERK inhibitors with low molecular weight and high LE. Compound 21 exhibited potent target engagement and strong tumor regression in the BRAF(V600E) xenograft model.