Búsqueda de nuevos analgésicos mediante modulación del canal iónico TRPV1 implicado en mecanismos de transducción de señales nociceptivas

El canal iónico TRPV1 constituye una diana terapéutica potencial en la búsqueda de nuevos analgésicos debido a su implicación en mecanismos de transducción de señales nociceptivas. En concreto, participa en la detección de estímulos nocivos de naturaleza mecánica, térmica y química, dando lugar a la sensación de dolor nociceptivo. Adicionalmente, su actividad se ha visto incrementada bajo condiciones patológicas de dolor e inflamación, por ello su modulación supone un desafío en la generación de nuevas terapias más seguras y efectivas. A lo largo de este trabajo, se ha avanzado en la caracterización farmacológica de compuestos derivados de la capsaicina, todos ellos moduladores de este receptor, ya sean con actividad agonista como antagonista. Las técnicas de cribado de alto rendimiento han permitido su identificación inicial, a partir de la cual continuar con el estudio de propiedades importantes para su posible aplicación clínica, entre ellas potencia, citotoxicidad, modelado molecular y selectividad. Como resultado de estos experimentos, los moduladores C12 y C49 han mostrado ser potenciales candidatos para proseguir con su desarrollo como futuros fármacos analgésicos.The TRPV1 ion channel is a potential therapeutic target in the search for new analgesics due to its involvement in mechanisms of nociceptive signal transduction. Specifically, they participate in the detection of noxious stimuli (mechanical, thermal and chemical), giving rise to nociceptive pain sensation. Additionally, its activity is increased under pathological conditions of pain and inflammation, thus its modulation is a challenge in the generation of new safer and more effective therapies. Throughout this work, there has been progress in the pharmacological characterization of compounds derived from capsaicin, all of them modulators of this receptor, either with agonist or antagonist activity. High throughput screening techniques have allowed an initial identification, from which to continue the study of important properties for its possible clinical application, including potency, cytotoxicity, molecular modeling and selectivity. As a result, modulators C12 and C49 have shown to be potential candidates to continue their development as future analgesic drugs

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Evaluation of Changes in Gut Microbiota in Patients with Crohn’s Disease after Anti-Tnfα Treatment: Prospective Multicenter Observational Study

Background: Crohn’s disease is believed to result from the interaction between genetic susceptibility, environmental factors and gut microbiota, leading to an aberrant immune response. The objectives of this study are to evaluate the qualitative and quantitative changes in the microbiota of patients with Crohn’s disease after six months of anti-tumor-necrosis factor (anti-TNFα) (infliximab or adalimumab) treatment and to determine whether these changes lead to the recovery of normal microbiota when compared to a control group of healthy subjects. In addition, we will evaluate the potential role of the Faecalibacterium prausnitzii/Escherichia coli and Faecalibacterium prausnitzii/Clostridium coccoides ratios as indicators of therapeutic response to anti-TNFα drugs. Methods/Design: This prospective multicenter observational study will comprise a total of 88 subjects: 44 patients with Crohn’s disease scheduled to start anti-TNFα treatment as described in the drug specifications to control the disease and 44 healthy individuals who share the same lifestyle and eating habits. The presence of inflammatory activity will be determined by the Harvey-Bradshaw index, analytical parameters in blood, including C-reactive protein, and fecal calprotectin levels at commencement of the study, at three months and at six months, allowing the classification of patients into responders and non-responders. Microbiota composition and the quantitative relationship between Faecalibacterium prausnitzii and Escherichia coli and between Faecalibacterium prausnitzii and Clostridium coccoides group as indicators of dysbiosis will be studied at inclusion and six months after initiation of treatment using ultra sequencing with Illumina technology and comparative bioinformatics analysis for the former relationship, and digital droplet PCR using stool samples for the latter. Upon inclusion, patients will complete a survey of dietary intake for the three days prior to stool collection, which will be repeated six months later in a second collection to minimize dietary bias. Discussion: In this study, massive sequencing, a reliable new tool, will be applied to identify early biomarkers of response to anti-TNF treatment in patients with Crohn’s disease to improve clinical management of these patients, reduce morbidity rates and improve efficiency