RESUMEN
BACKGROUND: The mechanism of motorcycle accidents (high speeds, pelvis behind fuel tank) may predispose to genitourinary injury (GUI) but the epidemiology is poorly understood. Previous studies have assessed GUI patterns in cyclists, and road traffic accident victims in general, but no study has analyzed GUI patterns in a large cohort of motorcyclists. OBJECTIVES: We aimed to better understand patterns of urological injuries among motorcyclists admitted to hospital. We aimed to determine any relationship between pelvic fracture and GUI patterns or severity. METHODS: The Trauma Audit Research Network was reviewed to identify motorcyclists admitted between January 2012 and December 2016 (n = 12,374). Cases were divided into riders (n = 11,926) and pillion passengers (n = 448), and the data analyzed to identify urological injuries and their associations. The associations between pelvic fracture and other injury types were tested for significance by one- and two-way χ 2. RESULTS: GUI was identified in 6%. Renal trauma was the most common GUI among riders (4%) and pillions (2%). There was no statistically significant relationship between grade of renal trauma and presence of pelvic fracture. Urethral injury occurred in 0.2% of riders and passengers, and bladder injury in 0.4% of riders and 0.7% of pillions. Urethral and bladder injuries were positively associated with pelvic fracture, which was present in 81 and 92%, respectively. Testicular trauma occurred in 0.4% of riders and 0.7% of pillions. Body armor was recorded in 3% of casualties with urological trauma, and 3% overall. CONCLUSIONS: A significant proportion of motorcyclists brought to accident and emergency department have GUI, most commonly renal trauma. Pelvic fracture is more common in pillion passengers than riders, and associated with urethral and bladder injuries, but it does not predict severity of renal trauma. External genital injuries are rare, but we recommend examination in the tertiary survey, as consequences of missed injury are severe. Further research is needed to explore protective effects of motorcyclist clothing.
RESUMEN
Doravirine is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) that has demonstrated good efficacy, tolerability, and safety for the treatment of patients with human immunodeficiency virus (HIV)-1 infection in phase III clinical trials. Doravirine achieved non-inferiority when compared with efavirenz- and darunavir/ritonavir-based regimens. Fewer adverse effects, including neuropsychiatric effects were observed with doravirine compared with efavirenz. Key pharmacodynamic and pharmacokinetic characteristics as well as drug-drug interactions and the resistance profile were assessed in this clinical review. Doravirine is a pyridinone NNRTI with potent antiviral activity against wild-type HIV-1 virus and common NNRTI variants. Studies in healthy volunteers and HIV-infected individuals have shown that doravirine has a favorable pharmacokinetic profile for once-daily dosing, with an elimination half-life of around 15 h, median time to maximum plasma concentrations of 1-4 h, and time to steady-state concentration of 7 days. The pharmacokinetics of doravirine are not greatly influenced by sex, age, race, or hepatic impairment. Although no dose adjustment is required for doravirine in renal impairment when given as a single tablet, the fixed-dose combination tablet of doravirine/lamivudine/tenofovir disoproxil fumarate is not recommended in patients with a creatinine clearance of < 50 mL/min. Doravirine has a low potential for drug-drug interactions and does not impact on the pharmacokinetics of other drugs. However, it is metabolized via cytochrome P450 (CYP) 3A enzymes and is thus susceptible to interactions with CYP3A inhibitors and inducers. Strong CYP3A inhibitors can significantly increase doravirine exposure; however, this is not considered to be clinically relevant. Conversely, strong CYP3A inducers, such as rifampin, are contraindicated with doravirine owing to a significant reduction in exposure with potential for impaired virological efficacy. Moderate CYP3A inducers, such as rifabutin, may be co-administered if the doravirine dose is increased to 100 mg twice daily. Doravirine has a unique resistance profile and has demonstrated in vitro activity against some of the most common, clinically relevant NNRTI-resistant mutations. Prevalence of baseline NNRTI resistance to doravirine appears to be low in treatment-naïve cohorts. Further data on the efficacy of doravirine in patients with previous treatment experience and/or transmitted NNRTI resistance are required to further inform its place in the current armamentarium of drugs for the treatment of HIV infection.
Asunto(s)
Infecciones por VIH/tratamiento farmacológico , Piridonas/administración & dosificación , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Triazoles/administración & dosificación , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/farmacocinética , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , VIH-1/efectos de los fármacos , Humanos , Piridonas/efectos adversos , Piridonas/farmacocinética , Inhibidores de la Transcriptasa Inversa/efectos adversos , Inhibidores de la Transcriptasa Inversa/farmacocinética , Triazoles/efectos adversos , Triazoles/farmacocinéticaRESUMEN
Differentiating actions of short chain fatty acids (SCFAs) at free fatty acid receptor 2 (FFA2) from other free fatty acid-responsive receptors and from non-receptor-mediated effects has been challenging. Using a novel chemogenetic and knock-in strategy, whereby an engineered variant of FFA2 (FFA2-DREADD) that is unresponsive to natural SCFAs but is instead activated by sorbic acid replaced the wild-type receptor, we determined that activation of FFA2 in differentiated adipocytes and colonic crypt enteroendocrine cells of mouse accounts fully for SCFA-regulated lipolysis and release of the incretin glucagon-like peptide-1 (GLP-1), respectively. In vivo studies confirmed the specific role of FFA2 in GLP-1 release and also demonstrated a direct role for FFA2 in accelerating gut transit. Thereby, we establish the general principle that such a chemogenetic knock-in strategy can successfully define novel G-protein-coupled receptor (GPCR) biology and provide both target validation and establish therapeutic potential of a 'hard to target' GPCR.
Asunto(s)
Ácidos Grasos Volátiles/metabolismo , Receptores de Superficie Celular/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animales , Humanos , Ratones , Receptores de Superficie Celular/química , Receptores de Superficie Celular/genética , Receptores Acoplados a Proteínas G/genéticaRESUMEN
The short chain fatty acid receptor FFA2 is able to stimulate signaling via both Gi- and Gq/G11-promoted pathways. These pathways are believed to control distinct physiological end points but FFA2 receptor ligands appropriate to test this hypothesis have been lacking. Herein, we characterize AZ1729, a novel FFA2 regulator that acts as a direct allosteric agonist and as a positive allosteric modulator, increasing the activity of the endogenously produced short chain fatty acid propionate in Gi-mediated pathways, but not at those transduced by Gq/G11 Using AZ1729 in combination with direct inhibitors of Gi and Gq/G11 family G proteins demonstrated that although both arms contribute to propionate-mediated regulation of phospho-ERK1/2 MAP kinase signaling in FFA2-expressing 293 cells, the Gq/G11-mediated pathway is predominant. We extend these studies by employing AZ1729 to dissect physiological FFA2 signaling pathways. The capacity of AZ1729 to act at FFA2 receptors to inhibit ß-adrenoreceptor agonist-promoted lipolysis in primary mouse adipocytes and to promote chemotaxis of isolated human neutrophils confirmed these as FFA2 processes mediated by Gi signaling, whereas, in concert with blockade by the Gq/G11 inhibitor FR900359, the inability of AZ1729 to mimic or regulate propionate-mediated release of GLP-1 from mouse colonic preparations defined this physiological response as an end point transduced via activation of Gq/G11.
Asunto(s)
Depsipéptidos/farmacología , Subunidades alfa de la Proteína de Unión al GTP Gi-Go , Subunidades alfa de la Proteína de Unión al GTP Gq-G11 , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Receptores de Superficie Celular , Receptores Acoplados a Proteínas G , Regulación Alostérica/efectos de los fármacos , Animales , Colon/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/antagonistas & inhibidores , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/genética , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/antagonistas & inhibidores , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/genética , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/metabolismo , Humanos , Lipólisis/efectos de los fármacos , Lipólisis/genética , Sistema de Señalización de MAP Quinasas/genética , Ratones , Ratones Noqueados , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Neutrófilos/metabolismo , Receptores de Superficie Celular/agonistas , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
Despite some blockbuster G protein-coupled receptor (GPCR) drugs, only a small fraction (â¼ 15%) of the more than 390 nonodorant GPCRs have been successfully targeted by the pharmaceutical industry. One way that this issue might be addressed is via translation of recent deorphanization programs that have opened the prospect of extending the reach of new medicine design to novel receptor types with potential therapeutic value. Prominent among these receptors are those that respond to short-chain free fatty acids of carbon chain length 2-6. These receptors, FFA2 (GPR43) and FFA3 (GPR41), are each predominantly activated by the short-chain fatty acids acetate, propionate, and butyrate, ligands that originate largely as fermentation by-products of anaerobic bacteria in the gut. However, the presence of FFA2 and FFA3 on pancreatic ß-cells, FFA3 on neurons, and FFA2 on leukocytes and adipocytes means that the biologic role of these receptors likely extends beyond the widely accepted role of regulating peptide hormone release from enteroendocrine cells in the gut. Here, we review the physiologic roles of FFA2 and FFA3, the recent development and use of receptor-selective pharmacological tool compounds and genetic models available to study these receptors, and present evidence of the potential therapeutic value of targeting this emerging receptor pair.
Asunto(s)
Ácidos Grasos Volátiles/farmacología , Ácidos Grasos Volátiles/fisiología , Receptores Acoplados a Proteínas G/fisiología , Animales , Ácidos Grasos Volátiles/química , Humanos , Inmunidad Celular/fisiología , Receptores de Superficie Celular/química , Receptores de Superficie Celular/fisiología , Receptores Acoplados a Proteínas G/químicaRESUMEN
BACKGROUND AND PURPOSE: Glucagon-like peptide-1 (GLP-1) is secreted from enteroendocrine L-cells after food intake. Increasing GLP-1 signalling either through inhibition of the GLP-1 degrading enzyme dipeptidyl-peptidase IV or injection of GLP-1-mimetics has recently been successfully introduced for the treatment of type 2 diabetes. Boosting secretion from the L-cell has so far not been exploited, due to our incomplete understanding of L-cell physiology. Elevation of cyclic adenosine monophosphate (cAMP) has been shown to be a strong stimulus for GLP-1 secretion and here we investigate the activities of adenylate cyclase (AC) and phosphodiesterase (PDE) isozymes likely to shape cAMP responses in L-cells. EXPERIMENTAL APPROACH: Expression of AC and PDE isoforms was quantified by RT-PCR. Single cell responses to stimulation or inhibition of AC and PDE isoforms were monitored with real-time cAMP probes. GLP-1 secretion was assessed by elisa. KEY RESULTS: Quantitative PCR identified expression of protein kinase C- and Ca²+-activated ACs, corresponding with phorbolester and cytosolic Ca²+-stimulated cAMP elevation. Inhibition of PDE2, 3 and 4 were found to stimulate GLP-1 secretion from murine L-cells in primary culture. This corresponded with cAMP elevations monitored with a plasma membrane targeted cAMP probe. Inhibition of PDE3 but not PDE2 was further shown to prevent GLP-1 secretion in response to guanylin, a peptide secreted into the gut lumen, which had not previously been implicated in L-cell secretion. CONCLUSIONS AND IMPLICATIONS: Our results reveal several mechanisms shaping cAMP responses in GLP-1 secreting cells, with some of the molecular components specifically expressed in L-cells when compared with their epithelial neighbours, thus opening new strategies for targeting these cells therapeutically.