Metabolomic Evaluation of N-Acetyl-p-Benzoquinone Imine Protein Adduct Formation with Therapeutic Acetaminophen Administration: Sex-based Physiologic Differences.

BACKGROUND: Acetaminophen (APAP)-associated transaminase elevation, induced by N-acetyl-p-benzoquinone imine (NAPQI) protein adduction, remains an area of research interest. Distinct from known genetic, physiologic, and dosage associations dictating severity of hepatic injury, no known factors predict an absence of protein adduct formation at therapeutic APAP dosing. HYPOTHESIS: Sex-based physiology is predictive of APAP-induced protein adduct formation and differential metabolite expression at therapeutic doses. METHODS: This retrospective study interrogated serum samples collected for a prior study investigating fluctuations of alanine aminotransferase (ALT) over time with 4G daily APAP dosing for ≥ 16 days in subjects from Denver, Colorado. Subjects were grouped by adduct formation (n = 184) vs no adducts (n = 20). Samples were run on ultra-high-performance liquid chromatography mass spectrometry from study days 0, 7, 16, and 31. Significant metabolite expressions were identified using t-tests with false discovery rate correction (FDR), partial least squares discriminant, and ANOVA simultaneous comparison analyses. Demographic and clinical data were explored using t-tests with FDR (age, weight, BMI, ALT) and Chi-square (sex, ethnicity, race) analyses. RESULTS: In pre-treatment samples, relative quantitation caprylic acid was expressed ninefold higher and 6-carboxyhexanoate was expressed threefold lower in subjects who did not develop adducts. Lactate had greater expression in the no adducts group (p = 0.001). Using absolute quantitation, glutathione was expressed 2.6-fold greater among no adduct subjects. Odds of males developing NAPQI protein adducts at therapeutic APAP dosing were 5.91 times lower than females (95% CI = 2.3-14.9; p = 0.0001). CONCLUSION: Multiple metabolites were differentially expressed based on adduct group and sex. Metabolites were identified unique to adduct development independent of sex. At therapeutic APAP dosing, males were less likely to develop APAP protein adducts. Further research into lipid biosynthesis and metabolism may provide further insight into physiology associated with adduct production.

ɑO-Conotoxin GeXIVA isomers modulate N-type calcium (CaV 2.2) channels and inwardly-rectifying potassium (GIRK) channels via GABAB receptor activation.

αO-Conotoxin GeXIVA is a 28 amino acid peptide derived from the venom of the marine snail Conus generalis. The presence of four cysteine residues in the structure of GeXIVA allows it to have three different disulfide isomers, that is, the globular, ribbon or bead isomer. All three isomers are active at α9α10 nicotinic acetylcholine receptors, with the bead isomer, GeXIVA[1,2], being the most potent and exhibiting analgesic activity in animal models of neuropathic pain. The original report of GeXIVA activity failed to observe any effect of the isomers on high voltage-activated (HVA) calcium channel currents in rat dorsal root ganglion (DRG) neurons. In this study, we report, for the first time, the activity of globular GeXIVA[1,3] at G protein-coupled GABAB receptors (GABAB R) inhibiting HVA N-type calcium (Cav2.2) channels and reducing membrane excitability in mouse DRG neurons. The inhibition of HVA Ba2+ currents and neuroexcitability by GeXIVA[1,3] was partially reversed by the selective GABAB R antagonist CGP 55845. In transfected HEK293T cells co-expressing human GABAB R1 and R2 subunits and Cav2.2 channels, both GeXIVA[1,3] and GeXIVA[1,4] inhibited depolarization-activated Ba2+ currents mediated by Cav2.2 channels, whereas GeXIVA[1,2] had no effect. The effects of three cyclized GeXIVA[1,4] ribbon isomers were also tested, with cGeXIVA GAG being the most potent at human GABAB R-coupled Cav2.2 channels. Interestingly, globular GeXIVA[1,3] also reversibly potentiated inwardly-rectifying K+ currents mediated by human GIRK1/2 channels co-expressed with GABAB R in HEK293T cells. This study highlights GABAB R as a potentially important receptor target for the activity of αO-conotoxin GeXIVA to mediate analgesia.

Impact of dexmedetomidine supplemented analgesia on delirium in patients recovering from orthopedic surgery: A randomized controlled trial.

BACKGROUND: Dexmedetomidine promotes normal sleep architecture; the drug also improves analgesia. We therefore tested the hypothesis that supplementing intravenous analgesia with dexmedetomidine reduces delirium in older patients recovering from orthopedic surgery. METHODS: In this double-blinded randomized controlled trial, we enrolled 712 older (aged 65-90 years) patients scheduled for major orthopedic surgery. Postoperative analgesia was provided by patient-controlled intravenous sufentanil, supplemented by randomly assigned dexmedetomidine (1.25 µg/mL) or placebo, for up to three days. The primary outcome was the incidence of delirium assessed twice daily with the Confusion Assessment Method. Among secondary outcomes, pain severity was assessed twice daily and sleep quality once daily, each with an 11-point scale where 0 = no pain/the best possible sleep and 10 = the worst pain/the worst possible sleep. RESULTS: The incidence of postoperative delirium was 7.3% (26 of 354) with placebo and 4.8% (17 of 356) with dexmedetomidine; relative risk 0.65, 95% CI 0.36 to 1.18; P = 0.151. Dexmedetomidine reduced pain both at rest (median difference -1 to 0 points, P ≤ 0.001) and with movement (-1 points, P < 0.001) throughout the first 5 postoperative days; it also improved subjective sleep quality during the first 3 postoperative days: day one median difference -1 point (95% CI -1 to 0), P = 0.007; day two 0 point (-1 to 0), P = 0.010; and day three 0 point (-1 to 0), P = 0.003. The incidence of adverse events was similar in each group. CONCLUSIONS: Supplementing sufentanil intravenous analgesia with low-dose dexmedetomidine did not significantly reduce delirium, but improved analgesia and sleep quality without provoking adverse events. TRIAL REGISTRATION: www.chictr.org.cn : ChiCTR1800017182 (Date of registration: July 17, 2018); ClinicalTrials.gov: NCT03629262 (Date of registration: August 14, 2018).

Nalbuphine and dexmedetomidine as adjuvants to ropivacaine in ultrasound-guided erector spinae plane block for video-assisted thoracoscopic lobectomy surgery: A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Adjuvants to local anesthetics, such as nalbuphine and dexmedetomidine, can be used to improve the quality and duration of peripheral nerve block effects. Dexmedetomidine has been successfully used as an adjuvant of erector spinae plane block (ESPB) with ropivacaine in video-assisted thoracoscopic lobectomy surgeries (VATLS). This study aimed to compare the effects of nalbuphine and dexmedetomidine used as adjuvants to ropivacaine for ESPB in VATLS. METHODS: A total of 102 patients undergoing VATLS with ESPB were enrolled and randomized into 3 groups, each of which received a different adjuvant to ropivacaine. The visual analogue scale score, onset and duration of sensory block, use of patient-controlled analgesia (PCA), rate of rescue analgesia, duration of postoperative hospitalization, incidence of postoperative nausea and vomiting, and chronic pain were measured and observed. RESULTS: The visual analogue scale score, total PCA use, rate of rescue analgesia, and postoperative chronic pain in the ropivacaine with dexmedetomidine (RD), and ropivacaine with nalbuphine (RN) groups were lower than those in the ropivacaine (RC) group (P < .05). The duration of sensory block was longer and the first use of PCA occurred later in the RD and RN groups than they did in the RC group (P < .05). CONCLUSIONS: As an adjuvant to ropivacaine in ESPB, nalbuphine and dexmedetomidine are comparable in terms of the associated analgesia, sensory block duration, need for rescue analgesia, and incidence of chronic pain in patients after VATLS.

Pain Relieving and Neuroprotective Effects of Non-opioid Compound, DDD-028, in the Rat Model of Paclitaxel-Induced Neuropathy.

Chemotherapy-induced neuropathy (CIN) is a major dose-limiting side effect of anticancer therapy that can compel therapy discontinuation. Inadequate analgesic efficacy of current pharmacological approaches requires the identification of innovative therapeutics and, hence, the purpose of this study is to conduct a preclinical evaluation of the efficacy of DDD-028, a versatile pentacyclic pyridoindole derivative, against paclitaxel-induced neuropathic pain. In two separate experiments, DDD-028 was administered per os acutely (1-25 mg kg-1) or repeatedly (10 mg kg-1) in paclitaxel-treated rats. The response to mechanical noxious stimulus (paw pressure) as well as to non-noxious mechanical (von Frey) and thermal (cold plate) stimuli was investigated. Acute administration of DDD-028 induced a dose-dependent anti-neuropathic pain effect in all tests performed. Further, repeated daily treatment for 18 consecutive days (starting the first day of paclitaxel administration) significantly reduced the development of pain over time without the development of tolerance to the anti-hyperalgesic effect. Ex vivo analysis showed that DDD-028 was able to reduce oxidative damage of dorsal root ganglia as evidenced by the increase in the level of carbonylated proteins and the decrease in catalase activity. In the lumbar spinal cord, periaqueductal gray matter, thalamus, and somatosensory cortex 1, DDD-28 significantly prevented the activation of microglia and astrocytes. The pharmacodynamic study revealed that the pain-relieving effects of DDD-028 were fully blocked by both the non-selective nicotinic receptor (nAChR) antagonist mecamylamine and by the selective α7 nAChR antagonist methyllycaconitine. In conclusion, DDD-028 was active in reducing paclitaxel-induced neuropathic pain after single or repeated administrations without tolerance development and displaying a double symptomatic and neuroprotective profile. DDD-028 could represent a valuable candidate for the treatment of CIN.

The strategy of physiological arousal of athletes in sports competition based on drug intervention / A estratégia da excitação fisiológica de atletas em competições esportivas com base em intervenção medicamentosa / Deportistas basados en intervenciones farmacéuticas, estrategia fisiológica de despertar

ABSTRACT Generally speaking, the physiological index of the human body is in a relatively stable state, which refers to the function of various organ systems with the characteristics of high-tide period, low-tide period and critical period. However, for competitive athletes, it is necessary to maintain physiological activation in both training and competition. In view of this, this study will analyze the physiological arousal degree of aspirin and acetaminophen in order to provide a reference for athletes to take analgesic drugs. In this study, the analytic hierarchy process (AHP), principal component analysis and factor analysis, were used to construct a scientific evaluation system of physiological arousal level, and the medication and non-medication status of 90 athletes were evaluated. The results showed that aspirin was better than acetaminophen in blood urea and serum creatine kinase, and the comprehensive score of some athletes was higher than 0.95. Aspirin is better in arousing athletes' physiology. The research results will provide scientific guidance for athletes to take antipyretic and analgesic drugs.

RESUMO Em termos gerais, o índice fisiológico do corpo humano encontra-se num estado relativamente estável, que se refere à função de vários sistemas de órgãos no corpo humano, com as características do período de altas, período de baixas e período crítico. No entanto, para atletas competitivos, é necessário manter a ativação fisiológica em treinamento e competição. Em vista disso, este estudo irá analisar o grau fisiológico de excitação de aspirina e acetaminofeno, a fim de fornecer referência para os atletas a tomar medicamentos analgésicos. Neste estudo, o Analytic Hierarchy Process (AHP), análise de componentes principal e análise de fatores foram usados para construir um sistema de avaliação científica de nível de excitação fisiológica, e o estado de medicação e de não medicação de 90 atletas foram avaliados. Os resultados mostraram que a aspirina foi melhor do que o acetaminofeno na ureia sanguínea e na creatina quinase sérica, e o escore abrangente de alguns atletas foi maior do que 0.95. A aspirina é melhor no despertar da fisiologia dos atletas. Os resultados da pesquisa fornecerão orientação científica para os atletas tomarem medicamentos antipiréticos e analgésicos.

RESUMEN En términos generales, el índice fisiológico del cuerpo humano se encuentra en un estado relativamente estable, que se refiere a la función de varios sistemas de órganos en el cuerpo humano, con las características del período de altas, período de bajas y período crítico. Mientras tanto, para atletas competitivos, es necesario mantener la activación fisiológica en entrenamiento y competición. En vista de eso, este estudio analizará el grado fisiológico de excitación de aspirina y acetaminofeno, a fin de proveer referencia para los atletas para tomar medicamentos analgésicos. En este estudio, el Analytic Hierarchy Process (AHP), análisis de componentes principal y análisis de fatores fueron usados para construir un sistema de evaluación científica de nivel de excitación fisiológica, y el estado de medicación y de no medicación de 90 atletas fueron evaluados. Los resultados mostraron que la aspirina fue mejor que el acetaminofeno en la urea sanguínea y en la creatina quinasa sérica, y el escore abarcador de algunos atletas fue mayor de 0.95. La aspirina es mejor en el despertar de la fisiología de los atletas. Los resultados de la investigación proveerán orientación científica para que los atletas tomen medicamentos antipiréticos y analgésicos.

Effect of Dexmedetomidine on Postoperative Sleep Quality: A Systematic Review.

In this article, we conduct a systematic review of the literature to explore the specific role of dexmedetomidine (DEX) on postoperative sleep and its associated mechanisms at present. The electronic database Embase, MEDLINE/PubMed, the Cochrane Library, Web of Science, and Google Scholar were searched. The restriction terms included "dexmedetomidine", "sleep" and "surgery". The inclusion criteria were as following: 1) patients 18 years old or older; 2) DEX used in the perioperative period not just for critically ill patients in the intensive care unit (ICU); 3) prospective or retrospective studies. The review articles, conference abstracts, and animal studies were excluded. Out of the 22 articles which met the above criteria, 20 of them were randomized controlled studies and 2 of them were retrospective cohort studies. Infusion of DEX including during the surgery and after surgery at a low or high dose was shown to improve subjective and objective sleep quality, although 2 studies showed there is no evidence that the use of DEX improves sleep quality and 1 showed less sleep efficiency and shorter total sleep time in the DEX group. Other postoperative outcomes evaluated postoperative nausea and vomiting, pain, postoperative delirium bradycardia and hypotension. Outcomes of our systematic review showed that DEX has advantages in improving patients' postoperative sleep quality. Combined with the use of general anesthetic, DEX provides a reliable choice for procedural sedation.

Analysis of Remifentanil-Based Fast-Track Anesthesia Combined with Dexmedetomidine for Transthoracic Device Closure of Atrial Septal Defect in Pediatric Patients.

BACKGROUND: To investigate the safety and efficacy of remifentanil combined with dexmedetomidine in fast-track cardiac anesthesia (FTCA) for transthoracic device closure of atrial septal defect (ASD) in pediatric patients. METHODS: A retrospective analysis was performed on 61 cases of children undergoing ASD closure through a small thoracic incision from January 2018 to January 2020. According to whether FTCA was administered, they were divided into group F (fast-track anesthesia, n = 31) and group R (routine anesthesia, n = 30). RESULTS: There was no significant difference in general preoperative data, perioperative hemodynamics, or postoperative pain scores between the 2 groups (P > .05). The postoperative sedation score of group F was higher than that of group R 1 and 4 hours after extubation. Meanwhile, duration of mechanical ventilation and length of postoperative intensive care unit (ICU) stay of group F were significantly shorter than those of group R (P < .05). No serious anesthesia-related complications occurred. CONCLUSION: Remifentanil combined with dexmedetomidine in FTCA for transthoracic device closure of ASD in pediatric patients is safe and effective, is worthy of clinical promotion, and can benefit more children.

Dexmedetomidine attenuates myocardial ischemia-reperfusion injury in vitro by inhibiting NLRP3 Inflammasome activation.

BACKGROUND: Myocardial ischemia-reperfusion injury (MIRI) is the most common cause of death worldwide. The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome plays an important role in the inflammatory response to MIRI. Dexmedetomidine (DEX), a specific agonist of α2-adrenergic receptor, is commonly used for sedation and analgesia in anesthesia and critically ill patients. Several studies have shown that dexmedetomidine has a strong anti-inflammatory effect in many diseases. Here, we investigated whether dexmedetomidine protects against MIRI by inhibiting the activation of the NLRP3 inflammasome in vitro. METHODS: We established an MIRI model in cardiomyocytes (CMs) alone and in coculture with cardiac fibroblasts (CFs) by hypoxia/reoxygenation (H/R) in vitro. The cells were treated with dexmedetomidine with or without MCC950 (a potent selective NLRP3 inhibitor). The beating rate and cell viability of cardiomyocytes, NLRP3 localization, the expression of inflammatory cytokines and NLRP3 inflammasome-related proteins, and the expression of apoptosis-related proteins, including Bcl2 and BAX, were determined. RESULTS: Dexmedetomidine treatment increased the beating rates and viability of cardiomyocytes cocultured with cardiac fibroblasts. The expression of the NLRP3 protein was significantly upregulated in cardiac fibroblasts but not in cardiomyocytes after H/R and was significantly attenuated by dexmedetomidine treatment. Expression of the inflammatory cytokines IL-1ß, IL-18 and TNF-α was significantly increased in cardiac fibroblasts after H/R and was attenuated by dexmedetomidine treatment. NLRP3 inflammasome activation induced the increased expression of cleaved caspase1, mature IL-1ß and IL-18, while dexmedetomidine suppressed H/R-induced NLRP3 inflammasome activation in cardiac fibroblasts. In addition, dexmedetomidine reduced the expression of Bcl2 and BAX in cocultured cardiomyocytes by suppressing H/R-induced NLRP3 inflammasome activation in cardiac fibroblasts. CONCLUSION: Dexmedetomidine treatment can suppress H/R-induced NLRP3 inflammasome activation in cardiac fibroblasts, thereby alleviating MIRI by inhibiting the inflammatory response.

Dexmedetomidine-soaked nasal packing can reduce pain and improve sleep quality after nasal endoscopic surgery: a double-blind, randomized, controlled clinical trial.

STUDY OBJECTIVE: Bilateral endoscopic nasal surgery is usually associated with pain and sleep disturbance. The aim of this study was to evaluate the effects of dexmedetomidine-soaked nasal packing on analgesia and improvement of sleep quality in patients undergoing this surgery. METHOD: Eighty patients were enrolled and randomly allocated into 4 groups. At the end of surgery, dexmedetomidine-soaked nasal packings were applied to three groups with a dosage of 1 µg kg-1 (D1), 2µg kg-1 (D2), 4 µg kg-1 (D4) and normal saline-soaked nasal packing (NS) was applied to a fourth group. The primary outcome was postoperative pain scores using a visual analog scale (VAS) recorded at six time points: before the surgery (T1); 2 h (T2), 8 h (T3), 24 h (T4), 48 h (T5) after surgery; and at the moment of nasal packing removal (T6). Secondary outcomes were postoperative sleep status evaluated by the Pittsburgh sleep quality index (PSQI) and subjective sleep quality value (SSQV). Factors affecting sleep, hemodynamic changes, and adverse events were also recorded. RESULTS: Compared with the NS group, dexmedetomidine-soaked nasal packing significantly relieved postoperative pain and improved sleep quality. The effect was similar between D2 and D4, which was greater than in D1. However, D2 was associated with fewer adverse events. CONCLUSIONS: Dexmedetomidine-soaked nasal packing not only offers effective analgesia but also improves postoperative sleep quality in patients undergoing bilateral endoscopic nasal surgery. Taking effect and adverse events into consideration, a dosage of 2µg kg-1 may be optimal. TRIAL REGISTRATION: www.chictr.org.cn/index.aspx (ChiCTR1900025692) Retrospectively registered 5 September 2019.

Dexmedetomidine inhibits cell malignancy in osteosarcoma cells via miR-520a-3p-YOD1 interactome.

BACKGROUND: Osteosarcoma is a common malignant tumor in adolescents with a low 5-year survival rate. Dexmedetomidine (DEX) has been widely used for surgery of osteosarcoma patients. MiR-520a-3p and YOD1 expression was abnormal in osteosarcoma cells. However, whether DEX affects osteosarcoma progression via miR-520a-3p-YOD1 interactome needs to be explored. METHODS: We detected osteosarcoma cells biological behavior by CCK-8 assay, BrdU assay, cell adhesion assay, and apoptosis assay, respectively. The miR-520a-3p and YOD1 levels was explored in osteosarcoma cell lines by RT-qPCR or western blotting assay. RESULTS: In this study, we found that DEX treating osteosarcoma cells inhibited cell viability, proliferation and adhesion, while it promoted cell apoptosis. Moreover, miR-520a-3p targeting to YOD1 also functionally repressed cell malignancy in osteosarcoma cells. Notably, DEX treatment could inhibit YOD1 expression via upregulating miR-520a-3p, thereby suppressing cell malignancy in osteosarcoma. CONCLUSIONS: Our study first revealed that DEX inhibited malignancy of osteosarcoma cells via miR-520a-3p/YOD1 axis.

Effects of intravenous lidocaine, dexmedetomidine, and their combination on IL-1, IL-6 and TNF-α in patients undergoing laparoscopic hysterectomy: a prospective, randomized controlled trial.

BACKGROUND: Surgical-related inflammatory responses have negative effects on postoperative recovery. Intravenous (IV) lidocaine and dexmedetomidine inhibits the inflammatory response. We investigated whether the co-administration of lidocaine and dexmedetomidine could further alleviate inflammatory responses compared with lidocaine or dexmedetomidine alone during laparoscopic hysterectomy. METHODS: A total of 160 patients were randomly allocated into four groups following laparoscopic hysterectomy: the control group (group C) received normal saline, the lidocaine group (group L) received lidocaine (bolus infusion of 1.5 mg/kg over 10 min, 1.5 mg/kg/h continuous infusion), the dexmedetomidine group (group D) received dexmedetomidine (bolus infusion of 0.5 µg/kg over 10 min, 0.4 µg/kg/h continuous infusion), and the lidocaine plus dexmedetomidine group (group LD) received a combination of lidocaine (bolus infusion of 1.5 mg/kg over 10 min, 1.5 mg/kg/h continuous infusion) and dexmedetomidine (bolus infusion of 0.5 µg/kg over 10 min, 0.4 µg/kg/h continuous infusion). The levels of plasma interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) at different time points were the primary outcomes. Secondary outcomes included hemodynamic variables, postoperative visual analogue scale (VAS) scores, time to first flatus, and incidence of nausea and vomiting after surgery. RESULTS: The levels of plasma IL-1, IL-6, and TNF-α were lower in groups D and LD than in group C and were lowest in group LD at the end of the procedure and 2 h after the operation (P < 0.05). The VAS scores were decreased in groups D and LD compared with group C (P < 0.05). The heart rate (HR) was decreased at the end of the procedure and 2 h after the operation in groups D and LD compared to groups C and L (P < 0.001). The mean blood pressure (MBP) was lower at 2 h after the operation in groups L, D, and LD than in group C (P < 0.001). There was a lower incidence of postoperative nausea and vomiting (PONV) in group LD than in group C (P < 0.05). CONCLUSIONS: The combination of lidocaine and dexmedetomidine significantly alleviated the inflammatory responses, decreased postoperative pain, and led to fewer PONV in patients undergoing laparoscopic hysterectomy. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT03276533 ), registered on August 23, 2017.

The Impact of Transversus Abdominis Plane Block Within an Enhanced Recovery After Surgery Protocol on Length of Stay.

BACKGROUND: Multimodal, narcotic-sparing analgesic strategies are an important part of enhanced recovery after surgery protocols. Within such protocols, regional anesthetics have proven to be superior to narcotics. OBJECTIVE: This study aimed to evaluate the impact of the transversus abdominis plane block within an enhanced recovery after surgery protocol on length of stay. DESIGN: A retrospective analysis of patients who underwent colorectal surgery in 2015 to 2016 was completed. The primary end points for this analysis were total length of stay and total narcotics consumed during hospitalization. Length of stay and total narcotic use were compared for patients who received a transversus abdominis plane block versus those that did not. DATA SOURCE: The data were obtained from the data warehouse of a university teaching hospital. SETTINGS: This study took place at a university teaching hospital. PATIENTS: The patients were 18 years or older. MAIN OUTCOME MEASURES: The primary outcomes measured were length of stay and the total narcotics used. RESULTS: A total of 347 patients underwent colorectal procedures under the enhanced recovery protocol. Among these, 186 (54%) received a transversus abdominis plane block. Overall, the mean length of stay was 5.8 days (SD ±5.6), and median length of stay was 4 days. These values compare to a mean length of stay of 9.6 days and median length of stay of 7 days before implementing the enhanced recovery protocol. Patients who received a transversus abdominis plane block had a mean length of stay of 5.1 days compared to 6.6 days for those who did not receive one (p < 0.01). Patients who received a transversus abdominis plane block consumed 736.5 morphine milligram equivalents of opioids compared to 1150.3 morphine milligram equivalents of opioid consumed by those without a transversus abdominis plane block (p < 0.05), a 36% decrease in opioid use. When comparing patients who had a mean length of stay of 4 days with those whose length of stay was >4 days, there was an 80% decrease in opioid use. The readmission rate was 7.8%. LIMITATIONS: The lack of randomization of patients was a limitation of this study. CONCLUSION: The use of transversus abdominis plane block in the setting of a well-structured enhanced recovery protocol was associated with a statistically significant decrease in length of stay by 1.5 days and a 36% decrease in narcotic use. See Video Abstract at http://links.lww.com/DCR/B432. IMPACTO DE LA ANESTESIA DEL PLANO MUSCULAR DE LOS TRANSVERSOS ABDOMINALES EN LA ESTADA DENTRO UN PROTOCOLO ERAS: ANTECEDENTES:La estrategia analgésica multimodal que consume poco medicamento de tipo narcótico es parte importante en los protocolos de recuperación mejorada postoperatoria. Dentro de dichos protocolos, los anestésicos regionales han demostrado ser superiores a la administración de medicamentos narcóticos.OBJETIVO:Estudiar el impacto del bloqueo del plano muscular de los transversos del abdomen sobre la duración de la estadía dentro de un protocolo de recuperación mejorada postoperatoria.DISEÑO:Se realizó un análisis retrospectivo de los pacientes que se sometieron a cirugía colorrectal entre 2015-2016. Los criterios principales de valoración en el presente análisis fueron la duración total de la estadía y el total de medicamentos narcóticos consumidos durante la hospitalización. Se comparó la duración de la estadía y el uso total de narcóticos en los pacientes que recibieron un bloqueo anestésico del plano muscular de los transversos del abdomen con los que no lo recibieron.FUENTE DE DATOS:Banco de datos de un hospital universitario docente.AMBIENTE:Hospital Universitario Docente.PACIENTES:Adultos desde los 18 años o mayores.PRINCIPALES MEDIDAS DE RESULTADO:Duración de la estadía, cantidad total de medicamentos narcóticos administrados.RESULTADOS:Un total de 347 pacientes se sometieron a procedimientos colorrectales bajo el protocolo ERAS. Entre ellos, 186 (54%) recibieron un bloqueo del plano muscular de los transversos del abdomen. En la globalidad, la duración media de la estadía fué de 5,8 días (DE ± 5,6) y la duración media de la estadía fué de 4 días. Estos resultados fueron comparados con la estadía media de 9,6 días y una estadía media de 7 días antes de implementar el protocolo ERAS. Los pacientes que recibieron un bloqueo del plano muscular de los transversos del abdomen tuvieron una estadía media de 5,1 días en comparación con los 6,6 días de los que no recibieron el mencionado bloqueo (p <0,01). Los pacientes que recibieron el bloqueo del plano muscular consumieron 736,5 miligramos de morfina o su equivalente en opioides, comparados con los 1150,3 de aquellos sin bloqueo del plano muscular (p <0,05) lo que significó una disminución del 36% en la administración de opioides. Al comparar los pacientes que tuvieron una estadía media de 4 días con aquellos cuya estadía fue mayor a 4 días, se evidenció una disminución en el 80% de la administración de opioides. La tasa de reingreso fue del 7,8%.LIMITACIONES:Estudio sin sin aleatorización de pacientes.CONCLUSIÓN:El bloqueo anestésico del plano muscular de los transversos del abdomen dentro un contexto protocolar tipo ERAS o de recuperación mejorada bien estructurada, se asoció con la disminución estadísticamente significativa de la duración de la estadía en 1,5 días y una disminución del 36% en la administración de medicamentos narcóticos. Consulte Video Resumen en http://links.lww.com/DCR/B432.

Delayed peaks of acetaminophen in overdose patients with concomitant abdominal trauma.

OBJECTIVE: To present two cases of delayed acetaminophen absorption in abdominal trauma patients with concomitant acetaminophen overdose. CASES: Case 1. A 25-year-old female arrived to the emergency department with multiple stab wounds. She had ingested an unknown amount of acetaminophen and was then stabbed by her boyfriend in a suicide pact. Initial acetaminophen concentration was 211.7 mcg/mL and the patient was started on N-Acetylcysteine (NAC) therapy. She was found to have injuries and was taken for operative repair. Acetaminophen concentrations were down trending and nearly undetectable until 58 h post-presentation when concentrations began to rise again. CASE 2: A 41-year-old female ingested approximately 500 tablets of acetaminophen prior to jumping from a four-story building in a suicide attempt. She was found to have multiple traumatic injuries as well as an initial acetaminophen concentration of 225 mcg/mL and was started on NAC therapy. The patient underwent multiple interventions to treat her traumatic injuries. Despite receiving no acetaminophen while inpatient, the patient's acetaminophen concentrations peaked a second time on her third hospital day. CONCLUSIONS: In this case series, two patients with abdominal trauma and coexistent massive acetaminophen ingestions were described. Both cases demonstrated a delayed rise in serum acetaminophen concentrations and required extended NAC therapy.

Global Trends in Cannabis and Cannabidiol Research from the Year 1940 to 2019.

Legalization of Cannabis in countries, like Canada, and global demand for non-hallucinating chemical components, such as Cannabidiols (CBD), have stimulated the increased interest from academics, industry, and regulatory agencies. Subsequent research publications in scientific journals in this field are expected to grow rapidly. However, there have been few research reviews that have quantified patterns in research publications concerning cannabis, nor a literature-based perspective on the historical development, current status, and future direction of cannabis research. Here, a bibliometric analysis is performed to address this gap in the scientific literature. A total of 1167 relevant articles (Supplementary file 1) were screened and analyzed using three software tools: HistCite, CiteSpace, and Bibliometric Online Analysis Platform. The performances of relevant countries, institutions, authors, and journals were presented, and the evolutionary trends of different categories were revealed. The historical development of cannabis and CBD research can be clearly divided into three stages, which focus on the chemistry, pharmacology, and molecular biology aspects of Cannabis sativa in general and then a focus on CBD related publications. A timeline was drawn to highlight the major trends in the literature, including scientific discoveries. In the end, several suggestions for future research directions in this field are provided.

III. Detecting Treatment Effects in Clinical Trials With Different Indices of Pain Intensity Derived From Ecological Momentary Assessment.

Pain intensity represents the primary outcome in most pain clinical trials. Identifying methods to measure aspects of pain that are most sensitive to treatment may facilitate discovery of effective interventions. In this third of 3 articles examining alternative indices of pain intensity derived from ecological momentary assessments (EMA), we compare treatment effects based on Average Pain, Maximum Pain, Minimum Pain, Pain Variability, Time in High Pain, Time in Low Pain, and Pain After Wake-Up. We also examine which indices contribute to Patient Global Impressions of Change (PGIC). Data came from 2 randomized, double-blind, placebo-controlled trials examining the efficacy of milnacipran for fibromyalgia treatment; 2,084 patients provided >1 million EMA pain intensity ratings over 24 (Study 1) or 26 (Study 2) treatment weeks. Pain Variability and Time in High Pain produced significantly smaller treatment effects than Average Pain; other pain indices showed effects that were numerically smaller, but not significantly different from Average Pain. Changes in all pain indices were significantly associated with PGIC, with improvements in Maximum Pain and in Pain Variability offering small incremental contributions to understanding PGIC over Average Pain. Results suggest that different pain indices could be used to detect treatment effects in pain clinical trials. PERSPECTIVE: Alternative summary measures of pain intensity derived from EMA may broaden the scope of outcomes useful in pain clinical trials. In this analysis of a pharmacological treatment for fibromyalgia, most pain summary measures indicated similar effects; improvements in Maximum Pain and Pain Variability contributed to understanding PGIC over Average Pain.

Analgesic Effects of Topical Amitriptyline in Patients With Chemotherapy-Induced Peripheral Neuropathy: Mechanistic Insights From Studies in Mice.

Oral amitriptyline hydrochloride (amitriptyline) is ineffective against some forms of chronic pain and is often associated with dose-limiting adverse events. We evaluated the potential effectiveness of high-dose topical amitriptyline in a preliminary case series of chemotherapy-induced peripheral neuropathy patients and investigated whether local or systemic adverse events associated with the use of amitriptyline were present in these patients. We also investigated the mechanism of action of topically administered amitriptyline in mice. Our case series suggested that topical 10% amitriptyline treatment was associated with pain relief in chemotherapy-induced peripheral neuropathy patients, without the side effects associated with systemic absorption. Topical amitriptyline significantly increased mechanical withdrawal thresholds when applied to the hind paw of mice, and inhibited the firing responses of C-, Aß- and Aδ-type peripheral nerve fibers in ex vivo skin-saphenous nerve preparations. Whole-cell patch-clamp recordings on cultured sensory neurons revealed that amitriptyline was a potent inhibitor of the main voltage-gated sodium channels (Nav1.7, Nav1.8, and Nav1.9) found in nociceptors. Calcium imaging showed that amitriptyline activated the transient receptor potential cation channel, TRPA1. Our case series indicated that high-dose 10% topical amitriptyline could alleviate neuropathic pain without adverse local or systemic effects. This analgesic action appeared to be mediated through local inhibition of voltage-gated sodium channels. PERSPECTIVE: Our preliminary case series suggested that topical amitriptyline could provide effective pain relief for chemotherapy-induced peripheral neuropathy patients without any systemic or local adverse events. Investigation of the mechanism of this analgesic action in mice revealed that this activity was mediated through local inhibition of nociceptor Nav channels.

Effect of Dexmedetomidine on Perioperative Stress Response and Immune Function in Patients With Tumors.

OBJECTIVE: This study aims to investigate the effect of dexmedetomidine on perioperative stress response and immune function in patients with tumors. METHODS: Sixty patients who underwent selective radical gastrectomy for cancer were randomly divided into 3 groups: remifentanil group (group R), dexmedetomidine group (group D), and sufentanil group (group S). Remifentanil, dexmedetomidine, and sufentanil were used as general anesthetics. Endotracheal intubation and mechanical ventilation were performed after the spontaneous respiration disappeared. Then, the data were recorded, and blood samples were collected at all time points. RESULTS: The heart rate significantly increased (P < 0.05) at T1 in group S, and both heart rate and mean arterial pressure significantly increased (P < 0.05) in group R when compared to group D. The heart rate significantly increased (P < 0.05) at T2 in group S and group R. Furthermore, the heart rate significantly increased (P < 0.05) at T3 and T4 in group S and group R. Intra-group comparison: The heart rate at T1-T4 and mean arterial pressure at T1-T4 significantly increased (P < 0.05) in group S, and the heart rate at T1 and T4, and mean arterial pressure at T2-T4 significantly increased (P < 0.05) in group R when compared to T0. The serum IL-6, IFN-γ, and ß-EP significantly increased (P < 0.05) at T0' in group S and group R when compared to group D. Blood glucose, and serum IL-10, IFN-γ, and ß-EP significantly increased (P < 0.05), while IL-18 significantly decreased (P < 0.05) at T1' in group S and group R. CONCLUSION: Continuous infusion of dexmedetomidine in combination with the inhalation of sevoflurane is superior to sevoflurane + remifentanil or sufentanil in patients undergoing tumor surgery.

Gene Expression Signatures in AML-12 Hepatocyte Cells upon Dengue virus Infection and Acetaminophen Treatment.

Dengue is an acute viral disease caused by Dengue virus (DENV) and is considered to be the most common arbovirus worldwide. The clinical characteristics of dengue may vary from asymptomatic to severe complications and severe organ impairment, particularly affecting the liver. Dengue treatment is palliative with acetaminophen (APAP), usually known as Paracetamol, being the most used drug aiming to relieve the mild symptoms of dengue. APAP is a safe and effective drug but, like dengue, can trigger the development of liver disorders. Given this scenario, it is necessary to investigate the effects of combining these two factors on hepatocyte homeostasis. Therefore, this study aimed to evaluate the molecular changes in hepatocytes resulting from the association between DENV infection and treatment with sub-toxic APAP concentrations. Using an in vitro experimental model of DENV-2 infected hepatocytes (AML-12 cells) treated with APAP, we evaluated the influence of the virus and drug association on the transcriptome of these hepatocytes by RNA sequencing (RNAseq). The virus-drug association was able to induce changes in the gene expression profile of AML-12 cells and here we highlight and explore these changes and its putative influence on biological processes for cellular homeostasis.