Concentration profiles and safety of topically applied betulinic acid and NVX-207 in eight healthy horses-A randomized, blinded, placebo-controlled, crossover pilot study.

The naturally occurring betulinic acid (BA) and its derivative NVX-207 show anticancer effects against equine malignant melanoma (EMM) cells and a potent permeation in isolated equine skin in vitro. The aim of the study was to determine the in vivo concentration profiles of BA and NVX-207 in equine skin and assess the compounds' local and systemic tolerability with the intent of developing a topical therapy against EMM. Eight horses were treated percutaneously in a crossover design with 1% BA, 1% NVX-207 or a placebo in a respective vehicle twice a day for seven consecutive days with a seven-day washout period between each formulation. Horses were treated at the neck and underneath the tail. Concentration profiles of the compounds were assessed by high-performance liquid chromatography in the cervical skin. Clinical and histopathological examinations and blood analyses were performed. Higher concentrations of NVX-207 were found in the skin compared to BA. Good systemic tolerability and only mild local adverse effects were observed in all three groups. This study substantiates the topical application of BA and NVX-207 in further clinical trials with horses suffering from EMM; however, penetration and permeation of the compounds may be altered in skin affected by tumors.

ß2-AR blockade potentiates MEK1/2 inhibitor effect on HNSCC by regulating the Nrf2-mediated defense mechanism.

The ß2-Adrenergic receptor (ß2-AR) is a G protein-coupled receptor (GPCR), involved in the development of many cancers, among which HNSCC. In this contest, ß2-AR signaling interacts with different pathways, such as PI3K and MAPK, commonly activated by TK receptors. For this reason, TK blockade is one of the most adopted therapeutic strategies in HNSCC patients. In our study we investigated the effects of the ß2-AR blocking in HNSCC cell lines, using the selective inhibitor ICI118,551 (ICI), in combination with the MAPK inhibitor U0126. We found that ICI leads to the blocking of p38 and NF-kB oncogenic pathways, strongly affecting also the ERK and PI3K pathways. Cotreatment with U0126 displays a synergic effect on cell viability and pathway alteration. Interestingly, we found that the ß2-AR blockade affects Nrf2-Keap1 stability and its nuclear translocation leading to a drastic ROS increase and oxidative stress. Our results are confirmed by a TCGA dataset analysis, showing that NFE2L2 gene is commonly overexpressed in HNSC, and correlated with a lower survival rate. In our system, the PI3K pathway inhibition culminated in the blocking of pro-survival autophagy, a mechanism normally adopted by cancer cells to became less responsive to the therapies. The mTOR expression, commonly upregulated in HNSC, was reduced in patients with disease-recurrence. It is well known that mTOR has a strong autophagy inhibition effect, therefore its downregulation promoted pro-survival autophagy, with a related increase recurrence rate. Our findings highlight for the first time the key role of ß2-AR and related pathway in HNSCC cell proliferation and drug resistance, proposing it as a valuable therapeutic molecular target.

Core-crosslinked nanomicelles based on crosslinkable prodrug and surfactants for reduction responsive delivery of camptothecin and improved anticancer efficacy.

As an important DNA topoisomerase I inhibitor in oncotherapy, camptothecin (CPT) with traditional formulation only shows a limited clinical application mainly because of its poor solubility. In this study, a novel redox responsive nanoscaled delivery system was developed to overcome the inherent defect of CPT. Firstly, a CPT prodrug (CPT-LA) and two crosslinkable surfactants (SO-LA and MPEG-LA) was synthesized, all of which contained the same lipoic acid (LA) structure. In the preparation, highly core-crosslinked structure was formed by adding a thiol crosslinker, which can induce LA ring opening polymerization and disulfide crosslinking. The resulting CPT-LA core-crosslinked nanomicelles (CPT-LA CNM) were formulated with a highly crosslinked core and a PEG hydrophilic shell. Dynamic light scattering (DLS) characterization indicated that CPT-LA CNM possessed a narrow size distribution (184.6 ± 3.6 nm) and negatively charged zeta potential (-3.5 ± 1.2 mV). The storage and physiological stabilities showed that the size distribution of CPT-LA CNM was relatively stable in both conditions which were neutral PBS at 4 °C (1 week period) and PBS containing 10% serum at 37 °C (24 h period). Moreover, the effective CPT release behavior of CPT-LA CNM was confirmed in the reducing circumstances containing dithiothreitol (DTT). Under confocal laser scanning microscopy (CLSM), CPT-LA CNM demonstrated a rapid cellular uptake behavior against cancer cells when compared to CPT suspension. Finally, the enhanced anticancer efficacy of CPT-LA CNM was also detected by in vitro cytotoxicity and cell apoptosis assay. In summary, the core-crosslinked CPT-LA CNM could be a promising CPT delivery system because of high stability, effectively controlled release as well as improved anticancer activity.

Effects of dexmedetomidine and esmolol on otoacoustic emissions during controlled hypotensive anesthesia: randomized clinical trial.

PURPOSE: The aim of this study was to investigate the ability of esmolol and dexmedetomidine to achieve controlled hypotension on cochlea by measuring otoacoustic emission and stapedius reflex. METHODS: In this prospective, double-blind pilot study, patients scheduled for elective tympanoplasty, rhinoplasty and endoscopic sinus surgery operation were randomly assigned to two groups, and received either dexmedetomidine (n=23) or esmolol (n=24) during surgery to maintain a mean arterial blood pressure between 55 and 65 mmHg. Distortion product otoacoustic emission tests (DPOAE) were performed 24 hours before and after the operation and during surgery (in the 20th and 40th minutes of the operation). RESULTS: In the intra-group comparison, a statistically significant decrease was present at t20 (2,000 and 4,000 Hz frequency band) and t40 (1,000 and 1,500 Hz) according to the baseline value in the dexmedetomidine group (n=23); in the esmolol group (n=24), a statistically significant decrease (relative to the baseline value) was also detected at t20 and t40 for the 1,000 Hz frequency band. No damage was found on stapes reflexes with the infusion of these drugs. CONCLUSIONS: Infusion of dexmedetomidine and esmolol decreased DPOAE levels during the operations, but DPOAE levels returned to normal in the postoperative period, and had no effect on stapes reflexes. Studies with larger groups of patients are needed to confirm these results in tympanoplasty and other surgeries.

The effect of intraoperative lidocaine versus esmolol infusion on postoperative analgesia in laparoscopic cholecystectomy: a randomized clinical trial.

BACKGROUND: As a part of multimodal analgesia for laparoscopic cholecystectomy, both intraoperative lidocaine and esmolol facilitate postoperative analgesia. Our objective was to compare these two emerging strategies that challenge the use of intraoperative opioids. We aimed to assess if intraoperative esmolol infusion is not inferior to lidocaine infusion for opioid consumption after laparoscopic cholecystectomy. METHODS: In this prospective, randomized, double-blind, non-inferiority clinical trial, 90 female patients scheduled for elective laparoscopic cholecystectomy received either intravenous (IV) lidocaine bolus 1.5 mg/kg at induction followed by an infusion (1.5 mg/ kg/h) or IV bolus of esmolol 0.5 mg/kg at induction followed by an infusion (5-15 µg/kg/min) till the end of surgery. Remaining aspect of anesthesia followed a standard protocol apart from no intraoperative opioid supplementation. Postoperatively, patients received either morphine or tramadol IV to maintain visual analogue scale (VAS) scores ≤3. The primary outcome was opioid consumption (in morphine equivalents) during the first 24 postoperative hours. Pain and sedation scores, time to first perception of pain and void, and occurrence of nausea/vomiting were secondary outcomes measured up to 24 h postoperatively. RESULTS: Two patients in each group were excluded from the analysis. The postoperative median (IQR) morphine equivalent consumption in patients receiving esmolol was 1 (0-1.5) mg compared to 1.5 (1-2) mg in lidocaine group (p = 0.27). The median pain scores at various time points were similar between the two groups (p > 0.05). More patients receiving lidocaine were sedated in the post-anesthesia care unit (PACU) than those receiving esmolol (p < 0.05); however, no difference was detected later. CONCLUSION: Infusion of esmolol is not inferior to lidocaine in terms of opioid requirement and pain severity in the first 24 h after surgery. Patients receiving lidocaine were more sedated during their stay in PACU than those receiving esmolol. TRIAL REGISTRATION: ClinicalTrials.gov - NCT02327923. Date of registration: December 31, 2014.

Successful management of persistent tachycardia using esmolol in 2 dogs with septic shock.

OBJECTIVE: To describe the successful management of 2 dogs with septic shock and persistent tachycardia using norepinephrine and esmolol, a short-acting beta receptor antagonist. SERIES SUMMARY: Two cases are reviewed. In the first case, septic shock with ventricular tachycardia was diagnosed in a 4-year-old neutered female Great Dane that underwent jejunoileal resection and anastomosis for a partial mesenteric torsion. The patient's tachyarrhythmias failed to respond to lidocaine, and an esmolol infusion was used for heart rate control. The condition of the dog improved and she was discharged after 4 days of hospitalization. The second case was a 7-year-old neutered female Cavalier King Charles Spaniel with septic peritonitis. Following surgery for intestinal resection and anastomosis, supraventricular tachycardia developed that was not responsive to volume resuscitation and was treated with an esmolol infusion. The condition of the dog improved and she was discharged after 6 days of hospitalization. Both patients were doing well at the time of long-term follow-up. NEW OR UNIQUE INFORMATION PROVIDED: This case series highlights a novel method of managing dogs in septic shock with persistent tachycardia based on recently published data in the human literature. The use of esmolol may be considered in certain veterinary patients with septic shock to improve persistent tachycardia not related to hypovolemia.

Effect of esmolol and lidocaine on agitation in awake phase of anesthesia among children: a double-blind, randomized clinical study.

BACKGROUND: Sevoflurane is widely used to anesthetize children because of its rapid action with minimal irritation of the airways. However, there is a high risk of agitation after emergence from anesthesia. Strabismus surgery, in particular, can trigger agitation because patients have their eyes covered in the postoperative period. The aim of this study was to determine whether or not esmolol and lidocaine could decrease emergence agitation in children. METHODS: Eighty-four patients aged 3 to 9 years undergoing strabismus surgery were randomly assigned to a control group (saline only), a group that received intravenous lidocaine 1.5 mg/kg, and a group that received intravenous esmolol 0.5 mg/kg and lidocaine 1.5 mg/kg. Agitation was measured using the objective pain score, Cole 5-point score, and Richmond Agitation Sedation Scale score at the end of surgery, on arrival in the recovery room, and 10 and 30 min after arrival. RESULTS: The group that received the combination of esmolol and lidocaine showed lower OPS and RASS scores than the other two groups when patients awoke from anesthesia (OPS = 0 (0-4), RASS = -4 [(-5)-1]) and were transferred to the recovery room (OPS = 0 (0-8), RASS = -1 [(-5)-3]) (P < 0.05). There was no significant difference in the severity of agitation among the three groups at other time points (P > 0.05). CONCLUSIONS: When pediatric strabismus surgery is accompanied by sevoflurane anesthesia, an intravenous injection of esmolol and lidocaine could alleviate agitation until arrival in the recovery room. TRIAL REGISTRATION: Clinical Research Information Service, No. KCT0002925; https://cris.nih.go.kr/cris/en/search/search_result_st01.jsp?seq=11532.

Effects of Intraoperative Infusion of Esmolol on Systemic and Pulmonary Inflammation in a Porcine Experimental Model of Lung Resection Surgery.

BACKGROUND: Lung resection surgery (LRS) is associated with systemic and pulmonary inflammation, which can affect postoperative outcomes. Activation of ß-adrenergic receptors increases the expression of proinflammatory and anti-inflammatory mediators, and their blockade may attenuate the systemic inflammatory response. The aim of this study was to analyze the effect of a continuous perioperative intravenous perfusion of esmolol on postoperative pulmonary edema in an experimental model of LRS requiring periods of one-lung ventilation (OLV). METHODS: Twenty-four large white pigs were randomly assigned to 3 groups: control (CON), esmolol (ESM), and sham. The ESM group received an intravenous esmolol bolus (0.5 mg/kg) and then an esmolol infusion (0.05 mg·kg·minute) throughout the procedure. The CON group received the same volume of 0.9% saline solution as the ESM group plus a continual infusion of saline. The sham group underwent a left thoracotomy without LRS or OLV. At the end of the LRS, the animals were awakened, and after 24 hours, they underwent general anesthesia again. Lung biopsies and plasma samples were obtained to analyze the levels and expression of inflammatory mediators, and the animals also received a bronchoalveolar lavage. RESULTS: At 24 hours after the operation, the ESM group had less lung edema and lower expression of the proinflammatory biomarkers tumor necrosis factor (TNF) and interleukin (IL)-1 compared to the CON group for both lung lobes. For the mediastinal lobe biopsies, the mean difference and 95% confidence interval (CI) between the groups for edema, TNF, and IL-1 were 14.3 (95% CI, 5.6-23.1), P = .002; 0.19 (95% CI, 0.07-0.32), P = .002; and 0.13 (95% CI, 0.04-0.22), P = .006, respectively. In the left upper lobe, the mean differences for edema, TNF, and IL-1 were 12.4 (95% CI, 4.2-20.6), P = .003; 0.25 (95% CI, 0.12-0.37), P < .001; and 0.3 (95% CI, 0.08-0.53), P = .009. CONCLUSIONS: Our results suggest that esmolol reduces lung edema and inflammatory responses in the intraoperative and postoperative periods in animals that underwent LRS with OLV.

Efficacy and safety of intravenous esmolol for cardiac protection in non-cardiac surgery. A systematic review and meta-analysis.

Haemodynamic instability predisposes patients to cardiac complications in non-cardiac surgery. Esmolol, a short-acting cardioselective beta-adrenergic blocker might be efficient in perioperative cardiac protection, but could affect other vital organs, such as the kidneys, and post-discharge survival. We performed a systematic review on the use of esmolol for perioperative cardiac protection. We searched PubMed, Ovid Medline and Cochrane Central Register for Controlled trials. Eligible randomized controlled studies (RCTs) reported a perioperative esmolol intervention with at least one of the primary (major cardiac or renal complications during the first 30 postoperative days) or secondary (postoperative adverse effects and all-cause mortality) outcomes. We included 196 adult patients from three RCTs. Esmolol significantly reduced postoperative myocardial ischaemia, RR =0.43 [95% confidence interval, CI: 0.21-0.88], p = .02. No association with clinically significant bradycardia and hypotension compared to patients receiving control treatment could be confirmed (RR =7.4 [95% CI: 0.29-139.81], p = .18 and RR =2.21 [95% CI: 0.34-14.36], p = .41, respectively). No differences regarding other outcomes were observed. No study reported postoperative renal outcomes. Esmolol seems promising for the prevention of perioperative myocardial ischaemia. However, the association with bradycardia and hypotension remains unclear. Randomized trials investigating the effect of ß1-selective blockade on clinically relevant outcomes and non-cardiac vital organs are warranted. Key messages Short-acting cardioselective esmolol seems efficient in the prevention of perioperative myocardial ischaemia. The possibly increased risk of bradycardia and hypotension with short-acting intravenous beta blockade could not be confirmed or refuted by available data. Future adequately powered trials investigating the effect of ß1-selective blockade on clinically relevant outcomes and non-cardiac vital organs are warranted.

Esmolol does not improve quality of postsurgical recovery after ambulatory hysteroscopy: A prospective, randomized, double-blinded, placebo-controlled, clinical trial.

INTRODUCTION: Intraoperative systemic esmolol has been shown to reduce postsurgical pain. Nonetheless, it is unknown whether the use of intraoperative systemic esmolol can improve patient-reported postsurgical quality of recovery. The main objective of the current investigation was to evaluate the effect of intraoperative esmolol on postsurgical quality of recovery. We hypothesized that patients receiving intraoperative esmolol would report better quality of postsurgical recovery than the ones receiving saline. METHODS: The study was a prospective randomized double-blinded, placebo-controlled, clinical trial. Healthy female subjects undergoing outpatient hysteroscopic surgery under general anesthesia were randomized to receive intravenous esmolol administered at a rate of 0.5 mg/kg bolus followed by an infusion of 5 to 15 µg/kg/min or the same volume of saline. The primary outcome was the Quality of Recovery 40 (QOR-40) questionnaire at 24 hours after surgery. Other data collected included postoperative opioid consumption and pain scores. Data were analyzed using group t tests and the Wilcoxon exact test. RESULTS: Seventy subjects were randomized and 58 completed the study. There was not a clinically significant difference in the global QoR-40 scores between the esmolol and saline groups at 24 hours, median (interquartile range) of 179 (171-190) and 182 (173-189), respectively, P = .82. In addition, immediate post-surgical data in the post-anesthesia care unit did not show a benefit of using esmolol compared to saline in regard to pain scores, morphine consumption, and postoperative nausea and vomiting. CONCLUSIONS: Despite current evidence in the literature that intraoperative esmolol improves postsurgical pain, we did not detect a beneficial effect of intraoperative esmolol on patient-reported quality of recovery after ambulatory surgery. Our results confirm the concept that the use of patient-centered outcomes rather than commonly used outcomes (e.g., pain scores and opioid consumption) can change the practice of perioperative medicine.

Esmolol, Antinociception, and Its Potential Opioid-Sparing Role in Routine Anesthesia Care.

ß-Adrenergic blockade is an important mechanism for reducing morbidity and mortality in patients with hypertension and heart failure. Esmolol has been used widely for its chronotropic and antihypertensive effects. However, there has been recent inquiry regarding perioperative esmolol use and nociceptive modulation. Conventional postoperative analgesic treatment has relied primarily on opioids, which present their own adverse effects and pharmacoepidemiologic repercussions. Esmolol, to date, has not shown any direct analgesic or anesthetic properties; however, recent studies suggest that esmolol may have antinociceptive and postoperative opioid-sparing effects. In this Daring Discourse narrative, we describe the role of esmolol in current perioperative ß-blockade guidelines (related to noncardiac surgery), briefly describe studies supporting the antinociceptive effects of esmolol, propose mechanisms for esmolol antinociception, and forecast potential routine esmolol use intraoperatively (as part of a multimodal total intravenous anesthetic) and its effects on opioid sparing. The reading audience of regional anesthesiologists and acute pain medicine physicians is uniquely positioned to take a lead role in promulgating this care advance amid (i) the unwanted effects of the opioid epidemic and (ii) the uncertain notion of whether routine general anesthesia care (with fentanyl) may indirectly be contributing to the epidemic.

Short-Term Treatment with Esmolol Reverses Left Ventricular Hypertrophy in Adult Spontaneously Hypertensive Rats via Inhibition of Akt/NF-κB and NFATc4.

Our group has previously demonstrated that short-term treatment with esmolol reduces left ventricular hypertrophy (LVH) in spontaneously hypertensive rats (SHRs). The present study aimed to assess the molecular mechanisms related to this effect. Fourteen-month-old male SHRs were treated intravenously with saline as vehicle (SHR) or esmolol (SHR-E) (300 µg/kg/min). Age-matched vehicle-treated male Wistar-Kyoto (WKY) rats served as controls. After 48 hours of treatment, the hearts were harvested and left ventricular tissue was separated and processed for Western blot analysis to determine the levels of Akt, NF-κB, NFATc4, Creb1, Serca2a, Erk1/2, and Sapk/Jnk. Biomarkers of oxidative stress, such as catalase, protein carbonyls, total thiols, and total antioxidant capacity were evaluated. Esmolol reversed the levels of p-NFATc4, p-Akt, and p-NF-κB in SHRs to the phospholevels of these proteins in WKY rats without modifying p-Erk1/2, p-Sapk/Jnk, p-Creb1, or Serca2a in SHR. Compared with SHR, esmolol increased catalase activity and reduced protein carbonyls without modifying total thiols or total antioxidant capacity. Short-term treatment with esmolol reverses LVH in aged SHRs by downregulation of Akt/NF-κB and NFATc4 activity. Esmolol treatment also increases catalase activity and reduces oxidative stress in SHRs with LVH.

Use of low-dose neostigmine intravenously in the treatment of thyroid storm-induced severe tachycardia in patient during huge pelvic mass resection: A case report and review of literature.

RATIONALE: Thyroid storm is a rare and life-threatening metabolic crisis because of an emergent release of excess thyroid hormone. Sinus tachycardia induced by excess thyroid hormone may result in congestive heart failure due to decreased diastolic filling time. PATIENT CONCERNS: A controlled hyperthyroidism patient with severe sinus tachycardia. DIAGNOSES: A controlled hyperthyroidism patient was induced thyroid storm during huge pelvic mass resection. INTERVENTIONS: Application of low-dose neostigmine and ß-antagonist esmolol to control the heart rate (HR) avoided hemodynamic collapse. OUTCOMES: The patient improved dramatically following application of low-dose neostigmine instead of esmolol to control the HR avoided hemodynamic collapse. LESSONS: Our case suggests that neostigmine, an acetylcholinesterase inhibitor, may warrant further investigation in patients with thyroid storm-induced severe sinus tachycardia.

Ultra-Short-Acting ß-Blockers (Esmolol and Landiolol) in the Perioperative Period and in Critically Ill Patients.

ß-Blockers are useful drugs in several clinical cardiologic scenarios. Their use in the perioperative period and in critically ill patients is increasing, but their effect on clinically relevant outcomes remains controversial. Long-acting ß-blockers can have detrimental effects that are difficult to be counteracted in these settings. The authors describe the possible clinical uses of ultra-short-acting ß-blockers (esmolol and landiolol) in the perioperative period and in critically ill patients because these drugs have the beneficial effects of ß-blockers, but do not have the detrimental effects of long-acting agents. This narrative review focuses on ultra-short-acting ß-blockers in the following clinical settings: prevention and treatment of arrhythmias and myocardial ischemia in noncardiac and cardiac surgery, usage as cardioplegia adjuvants or to test the reversibility of systolic anterior motion of the mitral valve in cardiac surgery, medical treatment of aortic dissection before surgery, improvement of microcirculation and oxygenation in critically ill patients experiencing sepsis or undergoing extracorporeal membrane oxygenation, anesthesia induction, and coronary computed tomography angiography.

Two-year results from a phase 2 extension study of oral amiselimod in relapsing multiple sclerosis.

BACKGROUND: Amiselimod, an oral selective sphingosine-1-phosphate 1 receptor modulator, suppressed disease activity dose-dependently without clinically relevant bradyarrhythmia in a 24-week phase 2, placebo-controlled study in relapsing-remitting multiple sclerosis. OBJECTIVE: To assess safety and efficacy of amiselimod over 96 weeks. METHODS: After completing the core study, patients on amiselimod continued at the same dose, whereas those on placebo were randomised 1:1:1 to amiselimod 0.1, 0.2 or 0.4 mg for another 72 weeks. Most patients receiving 0.1 mg were re-randomised to 0.2 or 0.4 mg upon availability of the core study results. RESULTS: Of 415 patients randomised in the core study, 367 (88.4%) entered and 322 (77.6%) completed the extension. One or more adverse events were reported in 303 (82.6%) of 367 patients: 'headache', 'lymphocyte count decreased', 'nasopharyngitis' and 'MS relapse' were most common (14.7%-16.9%). No serious opportunistic infection, macular oedema or malignancy was reported and no bradyarrhythmia of clinical concern was observed by Holter or 12-lead electrocardiogram. The dose-dependent effect of amiselimod on clinical and magnetic resonance imaging-related outcomes from the core study was sustained in those continuing on amiselimod and similarly observed after switching to active drug. CONCLUSION: For up to 2 years of treatment, amiselimod was well tolerated and dose-dependently effective in controlling disease activity.

Intraoperative Esmolol as an Adjunct for Perioperative Opioid and Postoperative Pain Reduction: A Systematic Review, Meta-analysis, and Meta-regression.

BACKGROUND: Esmolol is an ultrashort ß-1 receptor antagonist. Recent studies suggest a role for esmolol in pain response modulation. The authors performed a meta-analysis to determine if the intraoperative use of esmolol reduces opioid consumption or pain scores. METHODS: PubMed, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, pubget, and Google Scholar were searched. Studies were included if they were randomized, placebo- or opioid-controlled trials written in English, and performed on patients 18 years of age or older. For comparison of opioid use, included studies tracked opioid consumption intraoperatively and/or in the postanesthesia care unit. Pain score comparisons were performed during the first hour after surgery. RESULTS: Seventy-three studies were identified, 23 were included in the systematic review, and 19 were eligible for 1 or more comparisons. In 433 patients from 7 trials, intraoperative esmolol decreased intraoperative opioid consumption (Standard Mean Difference [SMD], -1.60; 95% confidence interval [CI], -2.25 to -0.96; P ≤ .001). In 659 patients from 12 trials, intraoperative esmolol decreased postanesthesia care unit opioid consumption (SMD, -1.21; 95% CI, -1.66 to -0.77; P ≤ .001). In 688 patients from 11 trials, there was insufficient evidence of change in postoperative 1 hour pain scores (SMD, -0.60; 95% CI, -1.44 to 0.24; P = .163). CONCLUSIONS: This meta-analysis demonstrates that intraoperative esmolol use reduces both intraoperative and postoperative opioid consumption, with no change in postoperative pain scores.

Alternative Treatment Options for Atrioventricular-Nodal-Reentry Tachycardia: An Emergency Medicine Review.

BACKGROUND: Atrioventricular-nodal-reentry tachycardia (AVNRT) is a form of supraventricular tachycardia (SVT) that is relatively common in the emergency department (ED). It is rarely indicative of underlying electrical or structural pathology. OBJECTIVE: This review evaluates the literature and controversies concerning treatment of AVNRT in the ED. DISCUSSION: For treatment of narrow-complex tachycardia, Advanced Cardiovascular Life Support guidelines recommend the use of vagal maneuvers, followed by adenosine. Recent literature suggests that nondihydropyridine calcium channel blockers, such as verapamil and diltiazem, may be as effective as adenosine, without the negative short-term side effects. Multiple studies have demonstrated that although adenosine is rapid acting, there is no statistically significant difference in conversion rate between adenosine and calcium channel blockers. Both medications result in a conversion rate above 90%, but there are significantly more minor adverse effects, such as flushing or chest discomfort, with adenosine. Calcium channel blockers are a viable option for treatment for AVNRT, especially in refractory states. Beta-blockers have been evaluated but should not be used routinely due to lower efficacy. AVNRT is the most common tachydysrhythmia in pregnancy, and vagal maneuvers and adenosine are first line. Electrical cardioversion should be utilized for hemodynamically unstable patients. Most patients with AVNRT may be discharged with appropriate follow-up. CONCLUSION: Several studies demonstrate that nondihydropyridine calcium channels (verapamil and diltiazem) are equally as efficacious as adenosine in converting AVNRT to sinus rhythm, without the negative (albeit short-lived) side effects. If given over 20 min, the risk for hypotension is low.

Apoptosis in human liver carcinoma caused by gold nanoparticles in combination with carvedilol is mediated via modulation of MAPK/Akt/mTOR pathway and EGFR/FAAD proteins.

In cancers, apoptosis signaling pathways and cell survival and growth pathways responsible for resistance to conventional treatments, such as Pi3K/Akt/mTOR and mitogen-activated protein kinase (MAPK) become dysregulated. Recently, alternative treatments to promote tumor cell death have become important. The present study reports on the antitumor and cytoprotective action of gold nanoparticles (GNPs) and carvedilol in combination and in isolated application. Apoptosis was analyzed by FITC/propidium iodide staining flow cytometry; caspase-3, caspase-8, Bcl-2 and MAPK/ERK activity by immunofluorescence microscopy; gene expression of proteins related to cell death as Akt, mTOR, EGFR, MDR1, survivin, FADD and Apaf, by the real-time PCR; and western blot analysis for MAPK/ERK, Akt and mTOR. Oxidative stress evaluation was performed by reduced glutathione (GSH) and malondialdehyde (MDA) levels. Intracellular GNPs targets were identified by transmission electron microscopy. After exposure to a combination of GNPs (6.25 µg/ml) and carvedilol (3 µM), death as promoted by apoptosis was detected using flow cytometry, for expression of pro-apoptotic proteins FADD, caspase-3, caspase-8 and sub-regulation of anti-apoptotic MAPK/ERK, Akt, mTOR, EGFR and MDR1 resistance. Non-tumor cell cytoprotection with GSH elevation and MDA reduction levels was detected. GNPs were identified within the cell near to the nucleus when combined with carvedilol. The combination of GNP and carvedilol promoted downregulation of anti-apoptotic and drug resistance genes, over-regulation of pro-apoptotic proteins in tumor cells, as well as cytoprotection of non-tumor cells with reduction of apoptosis and oxidative stress.

Effect of Continuous Systemic Administration of Esmolol on Intraocular Pressure During Surgery in a Sustained Steep Trendelenburg Position.

PURPOSE: To investigate the effects of continuous systemic administration of esmolol on intraocular pressure (IOP) during laparoscopic and robotic surgeries for recto-sigmoid cancer in a steep Trendelenburg position. MATERIALS AND METHODS: A total of 50 patients undergoing laparoscopic surgery in a steep Trendelenburg position were included. Patients in the esmolol (E) group received a 0.25 mg/kg IV loading dose of esmolol before anesthesia, followed by an infusion of 15 µg/kg/min throughout the operation. Patients in the saline (S) group were infused with the same volume of normal saline. IOP and ocular perfusion pressure were measured 16 times: before anesthetic induction (T1), before administration of the study drug (T2), after administration of anesthetic induction agents (T3), after tracheal intubation (T4), 1, 3, 5, and 10 minutes after tracheal intubation (T5-T8), immediately after intraperitoneal CO2 insufflation (T9), immediately after the steep Trendelenburg position (T10), 1, 2, and 4 hours after the steep Trendelenburg position (T11-T13), just before the supine position (T14), and 10 and 30 minutes after the supine position (T15, T16). RESULTS: The IOP increased markedly after adopting the steep Trendelenburg position, reaching 28.8±4.4 mm Hg in group S. The IOP at T13 in group S was ∼5.7 mm Hg higher than in group E. The IOP at T13 was ∼10.6 mm Hg higher than in T1 in group S, but only ∼4.4 mm Hg higher than in group E. CONCLUSIONS: Continuous systemic administration of esmolol can alleviate the increase in IOP during a sustained steep Trendelenburg position without adverse cardiovascular effects.