Efficacy and Safety of Vibegron for Persistent Symptoms of Overactive Bladder in Men Being Pharmacologically Treated for Benign Prostatic Hyperplasia: Results From the Phase 3 Randomized Controlled COURAGE Trial.

PURPOSE: The efficacy and safety of vibegron, a ß3-adrenergic receptor agonist, was assessed among men with symptoms of overactive bladder (OAB) receiving pharmacologic treatment for benign prostatic hyperplasia (BPH) in a phase 3 randomized controlled trial. MATERIALS AND METHODS: Men ≥ 45 years with OAB symptoms and BPH, treated with α-blocker with/without 5α-reductase inhibitors, were randomized 1:1 to vibegron or placebo for 24 weeks. Coprimary end points were change from baseline at week 12 in mean daily micturitions and urgency episodes. Secondary end points were change from baseline at week 12 in mean nightly nocturia and daily urge urinary incontinence episodes, International Prostate Symptom Score‒storage score, and volume voided per micturition. Safety was evaluated via adverse events (AEs). RESULTS: Of 1105 participants randomized, 965 (87.3%) completed the trial. At week 12, vibegron was associated with significant reductions vs placebo in daily micturitions (least squares mean difference [95% CI], -0.74 [-1.02, -0.46]; P < .0001) and urgency episodes (-0.95 [-1.37, -0.54]; P < .0001). Vibegron was also associated with significant improvements vs placebo at week 12 in nocturia episodes (least squares mean difference, -0.22 [-0.36, -0.09]; P = .002), urge urinary incontinence episodes (-0.80 [-1.33, -0.27]; P = .003), International Prostate Symptom Score‒storage scores (-0.9 [-1.2, -0.6]; P < .0001), and volume voided (15.07 mL [9.13-21.02]; P < .0001). AE rates were similar in vibegron (45.0%) and placebo (39.0%) arms; AEs occurring in ≥ 2% of participants were hypertension (9.0% vs 8.3%), COVID-19 (4.0% vs 3.1%), UTI (2.5% vs 2.2%), and hematuria (2.0% vs 2.5%). CONCLUSIONS: In this trial, vibegron met all primary and secondary end points and was safe and well tolerated in men with OAB symptoms and pharmacologically treated BPH.

Oral Clonidine-Based Strategy to Reduce Opiate Use During Cooling for Neonatal Encephalopathy: An Observational Study.

OBJECTIVE: To determine whether an enteral, clonidine-based sedation strategy (CLON) during therapeutic hypothermia (TH) for hypoxic-ischemic encephalopathy would decrease opiate use while maintaining similar short-term safety and efficacy profiles to a morphine-based strategy (MOR). STUDY DESIGN: This was a single-center, observational study conducted at a level IV neonatal intensive care unit from January 1, 2017, to October 1, 2021. From April 13, 2020, to August 13, 2020, we transitioned from MOR to CLON. Thus, patients receiving TH for hypoxic-ischemic encephalopathy were grouped to MOR (before April 13, 2020) and CLON (after August 13, 2020). We calculated the total and rescue morphine milligram equivalent/kg (primary outcome) and frequency of hemodynamic changes (secondary outcome) for both groups. RESULTS: The MOR and CLON groups (74 and 25 neonates, respectively) had similar baseline characteristics and need for rescue sedative intravenous infusion (21.6% MOR and 20% CLON). Both morphine milligram equivalent/kg and need for rescue opiates (combined bolus and infusions) were greater in MOR than CLON (P < .001). As days in TH advanced, a lower percentage of patients receiving CLON needed rescue opiates (92% on day 1 to 68% on day 3). Patients receiving MOR received a greater cumulative dose of dopamine and more frequently required a second inotrope and hydrocortisone for hypotension. MOR had a lower respiratory rate during TH (P = .01 vs CLON). CONCLUSIONS: Our CLON protocol is noninferior to MOR, maintaining perceived effectiveness and hemodynamic safety, with an apparently reduced need for opiates and inotropes.

Treating asthma in the time of COVID.

The Precision Interventions for Severe and/or Exacerbation-Prone Asthma clinical trials network is actively assessing novel treatments for severe asthma during the coronavirus disease (COVID-19) pandemic and has needed to adapt to various clinical dilemmas posed by the COVID-19 pandemic. Pharmacologic interactions between established asthma therapies and novel drug interventions for COVID-19 infection, including antivirals, biologics, and vaccines, have emerged as a critical and unanticipated issue in the clinical care of asthma. In particular, impaired metabolism of some long-acting beta-2 agonists by the cytochrome P4503A4 enzyme in the setting of antiviral treatment using ritonavir-boosted nirmatrelvir (NVM/r, brand name Paxlovid) may increase risk for adverse cardiovascular events. Although available data have documented the potential for such interactions, these issues are largely unappreciated by clinicians who treat asthma, or those dispensing COVID-19 interventions in patients who happen to have asthma. Because these drug-drug interactions have not previously been relevant to patient care, clinicians have had no guidance on management strategies to reduce potentially serious interactions between treatments for asthma and COVID-19. The Precision Interventions for Severe and/or Exacerbation-Prone Asthma network considered the available literature and product information, and herein share our considerations and plans for treating asthma within the context of these novel COVID-19-related therapies.

Long-term safety of once-daily indacaterol acetate/glycopyrronium bromide/mometasone furoate high-dose, and indacaterol acetate/mometasone furoate high-dose, in Japanese patients with inadequately controlled asthma: Results from two open-label, 52-week studies.

INTRODUCTION: The 52-week long-term safety of once-daily indacaterol acetate/glycopyrronium bromide/mometasone furoate (IND/GLY/MF) high-dose (150/50/160 µg) and IND/MF high-dose (150/320 µg) was evaluated in two studies enrolling Japanese patients with inadequately controlled asthma. METHODS: Study 1 (IND/GLY/MF) and Study 2 (IND/MF) were 52-week, phase III, open-label, single-arm, multicenter studies conducted in Japanese adult patients with inadequately controlled asthma. The primary endpoint was incidence and severity of treatment-emergent adverse events (AEs) over 52-weeks. RESULTS: In Study 1, 94 patients received IND/GLY/MF high-dose and 84 (89.4%) patients completed the 52-week study treatment; in Study 2, 51 patients received IND/MF high-dose and 48 (94.1%) patients completed the 52-week study treatment. In Study 1, 68.1% and 6.4% of 94 patients reported ≥1 AE and ≥1 serious AE (SAE) respectively. In Study 2, 78.4% of 51 patients reported ≥1 AE; no patients reported SAEs. The most commonly reported AEs were asthma (exacerbation; 30.9% and 54.9%) and nasopharyngitis (18.1% and 29.4%) in Study 1 and Study 2, respectively. Severe AEs including asthma (exacerbation) were reported in 13.8% and 13.7% of patients in Study 1 and Study 2, respectively. In Study 1, 10 patients (10.6%) reported treatment-related AEs, of which dysphonia (9 patients [9.6%]) was the most commonly reported; no treatment-related AEs were reported in Study 2. In Study 1, one death (not study drug-related) was reported after study discontinuation (92 days after last dose of study medication). CONCLUSIONS: Once-daily IND/GLY/MF and IND/MF high-dose were well-tolerated in Japanese patients with inadequately controlled asthma. No unexpected safety findings were observed.Supplemental data for this article is available online at.

Economic Consequences of the Overuse of Short-Acting ß-Adrenergic Agonists in the Treatment of Asthma in Spain.

BACKGROUND AND OBJECTIVE: To determine the relationship between short-acting ß-adrenergic agonist (SABA) overuse and health care resource use and costs in asthma patients in routine clinical practice. METHODS: A longitudinal retrospective study was conducted in Spanish primary and specialized care centers using the BIG-PAC medical records database. The study population comprised asthma patients ≥12 years of age who attended ≥2 consultations during 2017 and had 1-year follow-up data available. The main outcomes were demographics, comorbidities, medication, and clinical and health care resource use and costs. The relationship between SABA overuse and health care costs and between asthma severity and health care costs was determined. RESULTS: The SABA use IN Asthma (SABINA) study included 39 555 patients, with a mean (SD) age of 49.8 (20.7) years (64.2% female). The Charlson comorbidity index was 0.7 (1.0). SABA overuse (≥3 canisters/y) was 28.7% (95%CI, 27.7-29.7), with a mean of 3.3 (3.6) canisters/y. Overall, 5.1% of patients were prescribed ≥12 canisters/y. SABA overuse was correlated with health care costs (ρ=0.621; P<.001). The adjusted mean annual cost/patient according to the Global Initiative for Asthma (GINA 2019) classification of asthma severity was €2231, €2345, €2735, €3473, and €4243 for steps 1-5, respectively (P<.001). Regardless of asthma severity, SABA overuse yielded a significant increase in health care costs per patient and year (€5702 vs €1917, P<.001) compared with recommended use (<2 canisters/y). CONCLUSION: SABA overuse yields high costs for the Spanish National Health System. Costs increased with severity of asthma.

Management of treatment-resistant nocturnal enuresis.

Nocturnal enuresis is defined as intermittent urinary incontinence during sleep in children 5 years of age and older, occurring at least once a month for at least 3 months. In Japan, pediatricians who do not specialize in nocturnal enuresis have become more proactive in treating the condition since 2016, when the guidelines for treating it were revised for the first time in 12 years. For monosymptomatic nocturnal enuresis, the first step is lifestyle guidance, with a focus on the restriction of fluid intake at night; however, if lifestyle guidance does not decrease the frequency of nocturnal enuresis, aggressive treatment should be added. The first choice of aggressive treatment is oral desmopressin, an antidiuretic hormone preparation, or alarm therapy. However, there remain patients whose wet nights do not decrease with oral desmopressin or alarm therapy. In such cases, it is necessary to reconfirm the method of desmopressin administration and check for factors that may decrease the efficacy of desmopressin. If alarm therapy does not increase the number of dry nights, it is possible that the patient is fundamentally unsuitable for alarm therapy. If dry nights do not increase with oral desmopressin or alarm therapy, the next treatment strategy should be considered immediately to keep the patient motivated for treatment.

Optimizing drug inhibition of IgE-mediated anaphylaxis in mice.

BACKGROUND: Administering allergens in increasing doses can temporarily suppress IgE-mediated allergy and anaphylaxis by desensitizing mast cells and basophils; however, allergen administration during desensitization therapy can itself induce allergic responses. Several small molecule drugs and nutraceuticals have been used clinically and experimentally to suppress these allergic responses. OBJECTIVES: This study sought to optimize drug inhibition of IgE-mediated anaphylaxis. METHODS: Several agents were tested individually and in combination for ability to suppress IgE-mediated anaphylaxis in conventional mice, FcεRIα-humanized mice, and reconstituted immunodeficient mice that have human mast cells and basophils. Hypothermia was the readout for anaphylaxis; therapeutic efficacy was measured by degree of inhibition of hypothermia. Serum mouse mast cell protease 1 level was used to measure extent of mast cell degranulation. RESULTS: Histamine receptor 1 (HR1) antagonists, ß-adrenergic agonists, and a spleen tyrosine kinase (Syk) inhibitor were best at individually inhibiting IgE-mediated anaphylaxis. A Bruton's tyrosine kinase (BTK) inhibitor, administered alone, only inhibited hypothermia when FcεRI signaling was suboptimal. Combinations of these agents could completely or nearly completely inhibit IgE-mediated hypothermia in these models. Both Syk and BTK inhibition decreased mast cell degranulation, but only Syk inhibition also blocked desensitization. Many other agents that are used clinically and experimentally had little or no beneficial effect. CONCLUSIONS: Combinations of an HR1 antagonist, a ß-adrenergic agonist, and a Syk or a BTK inhibitor protect best against IgE-mediated anaphylaxis, while an HR1 antagonist plus a ß-adrenergic agonist ± a BTK antagonist is optimal for inhibiting IgE-mediated anaphylaxis without suppressing desensitization.

Systemic toxicity from subcutaneous brimonidine injection successfully treated with naloxone.

Brimonidine is a topical ophthalmic alpha-2 adrenergic agonist solution used to treat glaucoma. The toxidrome includes drowsiness, lethargy, hypotension, bradycardia, and respiratory depression when ingested in infants. We report a case of intentional subcutaneous injection of brimonidine in an elderly patient resulting in hypotension and CNS depression that responded to naloxone. A 73-year-old female with a past medical history significant for glaucoma, hypertension, and indwelling pacemaker presented to the emergency department after injecting her brimonidine tartrate ophthalmic solution subcutaneously (SQ). The patient was not taking any antihypertensive medications or opioids. Initial presentation consisted of lethargy, a paced rhythm of 60 bpm, and blood pressure of 91/24 mmHg with a MAP of 46. Due to central nervous system depression, 3 mg of intranasal naloxone was administered. The patient was treated with intravenous fluids and escalating doses of naloxone and required a continuous infusion. Mental status and vital signs subsequently improved. The patient was admitted to the ICU and naloxone was subsequently weaned over 12 h. Systemic central alpha-2 adrenergic agonist toxicity resulted from SQ brimonidine injection. Central alpha-2 adrenergic agonist overdoses present as sympatholytic effects including CNS depression, bradycardia, hypotension, and may mimic the opioid toxidrome. Brimonidine SQ injection has not previously been reported and this case has similar findings to other central alpha-2 adrenergic agonist poisonings. Naloxone has previously shown variable reversal of CNS depression in central alpha-2 overdose. In this case, high-dose naloxone was useful for reversing CNS depression and hemodynamic instability.

All-trans Retinoic Acids Synergistically and Beneficially Affect In Vitro Glaucomatous Trabecular Meshwork (TM) Models Using 2D and 3D Cell Cultures of Human TM Cells.

We report herein on the effects of all-trans retinoic acid (ATRA) on two-dimensional (2D) and three-dimensional (3D) cultures of human trabecular meshwork (HTM) cells that were treated with transforming growth factor ß2 (TGF-ß2). In the presence of 5 ng/mL TGF-ß2, the effects of ATRA on the following were observed: (1) the barrier function of the 2D HTM monolayers, as determined by trans-endothelial electrical resistance (TEER) and fluorescein isothiocyanate (FITC) dextran permeability measurements; (2) a Seahorse cellular bio-metabolism analysis; (3) physical properties, including the size and stiffness, of 3D spheroids; (4) the gene expression of extracellular matrix (ECM) molecules, ECM modulators including tissue inhibitor of metalloproteinases (TIMPs), matrix metalloproteinases (MMPs), tight junction (TJ)-related molecules, and endoplasmic reticulum (ER)-stress-related factors. ATRA significantly inhibited the TGF-ß2-induced increase in the TEER values and FITC dextran permeability of the 2D monolayers, while an ATRA monotreatment induced similar effects as TGF-ß2. A real-time metabolic analysis revealed that ATRA significantly inhibited the TGF-ß2-induced shift in metabolic reserve from mitochondrial oxidative phosphorylation to glycolysis in 2D HTM cells, whereas ATRA alone did not induce significant metabolic changes. In contrast, ATRA induced the formation of substantially downsized and softer 3D spheroids in the absence and presence of TGF-ß2. The different effects induced by ATRA toward 2D and 3D HTM cells were also supported by the qPCR analysis of several proteins as above. The findings reported here indicate that ATRA may induce synergistic and beneficial effects on TGF-ß2-treated 2D- and 3D-cultured HTM cells; those effects varied significantly between the 2D and 3D cultures.

Effects of acepromazine and dexmedetomidine, followed by propofol induction and maintenance with isoflurane anaesthesia, on the microcirculation of Beagle dogs evaluated by sidestream dark field imaging: an experimental trial.

OBJECTIVE: To investigate the effects of intramuscularly administered acepromazine or dexmedetomidine on buccal mucosa microcirculation in Beagle dogs. STUDY DESIGN: Experimental, blinded, crossover study. ANIMALS: A group of seven Beagle dogs aged 7.5 ± 1.4 years (mean ± standard deviation). METHODS: Microcirculation was assessed on buccal mucosa using sidestream dark field videomicroscopy. After baseline measurements, 5 µg kg-1 dexmedetomidine or 30 µg kg-1 acepromazine were administered intramuscularly. After 10, 20 and 30 minutes, measurements were repeated. At 40 minutes after premedication, anaesthesia was induced with propofol intravenously and maintained with isoflurane. Measurements were repeated 50, 60 and 65 minutes after the injection of the investigated drugs. Analysed microcirculatory variables were: Perfused de Backer density, Perfused de Backer density of vessels < 20 µm, Proportion of perfused vessels and Proportion of perfused vessels < 20 µm. Heart rate (HR), systolic, diastolic (DAP) and mean (MAP) arterial pressures were recorded at the same time points. Macro- and microcirculatory variables were analysed using a linear mixed model with baseline as a covariate, treatment, trial period and repetition as fixed effects and time and dog as random effect. Results are presented as effect size and confidence interval; p values < 0.05 were considered significant. RESULTS: After acepromazine, Perfused de Backer density was greater during sedation and anaesthesia [3.71 (1.93-5.48 mm mm-2, p < 0.0001) and 2.3 (0.86-3.75 mm mm-2, p < 0.003)], respectively, than after dexmedetomidine. HR was significantly lower, whereas MAP and DAP were significantly higher with dexmedetomidine during sedation and anaesthesia (p < 0.0001 for all) compared with acepromazine. CONCLUSIONS AND CLINICAL RELEVANCE: The sedative drugs tested exerted a significant effect on buccal mucosal microcirculation with a higher Perfused de Backer density after the administration of acepromazine compared with dexmedetomidine. This should be considered when microcirculation is evaluated using these drugs.

Prolonged ß2-adrenergic agonist treatment improves glucose homeostasis in diet-induced obese UCP1-/- mice.

Prolonged supplementation with the ß2-agonist clenbuterol improves glucose homeostasis in diabetic rodents, likely via ß2-adrenoceptor (ß2-AR)-mediated effects in the skeletal muscle and liver. However, since rodents have, in contrast to-especially diabetic-humans, substantial quantities of brown adipose tissue (BAT) and clenbuterol has affinity to ß1- and ß3-ARs, the contribution of BAT to these improvements is unclear. Therefore, we investigated clenbuterol-mediated improvements in glucose homeostasis in uncoupling protein 1-deficient (UCP1-/-) mice, lacking thermogenic BAT, versus wild-type (WT) mice. Anesthetized WT and UCP1-/- C57Bl/6 mice were injected with saline or clenbuterol and whole body oxygen consumption was measured. Furthermore, male WT and UCP1-/- C57Bl/6 mice were subjected to 17-wk of chow feeding, high-fat feeding, or high-fat feeding with clenbuterol treatment between weeks 13 and 17. Body composition was measured weekly with MRI. Oral glucose tolerance and insulin tolerance tests were performed in week 15 and 17, respectively. Clenbuterol increased oxygen consumption approximately twofold in WT mice. This increase was blunted in UCP1-/- mice, indicating clenbuterol-mediated activation of BAT thermogenesis. High-fat feeding induced diabetogenic phenotypes in both genotypes. However, low-dose clenbuterol treatment for 2 wk significantly reduced fasting blood glucose by 12.9% in WT and 14.8% in UCP1-/- mice. Clenbuterol treatment improved glucose and insulin tolerance in both genotypes compared with HFD controls and normalized to chow-fed control mice independent of body mass and composition alterations. Clenbuterol improved whole body glucose homeostasis independent of UCP1. Given the low human abundancy of BAT, ß2-AR agonist treatment provides a potential novel route for glucose disposal in diabetic humans.NEW & NOTEWORTHY Improvements in whole body glucose homeostasis of rodents upon prolonged ß2-adrenergic agonist supplementation could potentially be attributed to UCP1-mediated BAT thermogenesis. Indeed, we show that acute injection with the ß2-AR agonist clenbuterol induces BAT activation in mice. However, we also demonstrate that prolonged clenbuterol supplementation robustly improves whole body glucose and insulin tolerance in a similar way in both DIO WT and UCP1-/- mice, indicating that ß2-AR agonist supplementation improves whole body glucose homeostasis independent of UCP1-mediated BAT thermogenesis.

Rosacea: An Update in Diagnosis, Classification and Management.

The diagnosis and classification of rosacea has been modified to reflect presenting features. On exclusion of differentials, the diagnosis of rosacea is based on the presence of either (1) phymatous changes, or (2) centrofacial persistent erythema. In their absence, diagnosis can be established by presence of any two of: flushing/transient erythema, papules and pustules, telangiectases, or ocular manifestations. Management of rosacea depends on presenting feature(s), their severity, and impact. General management includes gentle skin care, sun protection, and trigger avoidance. Evidence-based treatment recommendations include topical brimonidine and oxymetazoline for persistent erythema; topical azelaic acid, ivermectin, metronidazole, minocycline and oral doxycycline, tetracycline and isotretinoin for papules and pustules; vascular lasers and light devices for telangiectases; and omega-3 fatty acids and cyclosporine ophthalmic emulsion for ocular rosacea. While surgical or laser therapy can be considered for clinically noninflamed phyma, there are no trials on their utility. Combination therapies include topical brimonidine with topical ivermectin, or topical metronidazole with oral doxycycline. Topical metronidazole, topical ivermectin, and topical azelaic acid are appropriate for maintenance therapy. In conclusion, the updated phenotype approach, based on presenting clinical features, is the foundation for current diagnosis, classification, and treatment of rosacea.

Evaluation of the perioperative stress response from dexmedetomidine infusion alone, with butorphanol bolus or remifentanil infusion compared with ketamine and morphine infusions in isoflurane-anesthetized horses.

OBJECTIVE: To evaluate perioperative stress-related hormones in isoflurane-anesthetized horses administered infusions of dexmedetomidine alone or with butorphanol or remifentanil, compared with ketamine-morphine. STUDY DESIGN: Randomized, prospective, nonblinded clinical study. ANIMALS: A total of 51 horses undergoing elective surgical procedures. METHODS: Horses were premedicated with xylazine, anesthesia induced with ketamine-diazepam and maintained with isoflurane and one of four intravenous infusions. Partial intravenous anesthesia (PIVA) was achieved with dexmedetomidine (1.0 µg kg-1 hour-1; group D; 12 horses); dexmedetomidine (1.0 µg kg-1 hour-1) and butorphanol bolus (0.05 mg kg-1; group DB; 13 horses); dexmedetomidine (1.0 µg kg-1 hour-1) and remifentanil (3.0 µg kg-1 hour-1; group DR; 13 horses); or ketamine (0.6 mg kg-1 hour-1) and morphine (0.15 mg kg-1, 0.1 mg kg-1 hour-1; group KM; 13 horses). Infusions were started postinduction; butorphanol bolus was administered 10 minutes before starting surgery. Blood was collected before drugs were administered (baseline), 10 minutes after ketamine-diazepam, every 30 minutes during surgery and 1 hour after standing. Mean arterial pressure (MAP), pulse rate, end-tidal isoflurane concentration, cortisol, nonesterified fatty acids (NEFA), glucose and insulin concentrations were compared using linear mixed models. Significance was assumed when p < 0.05. RESULTS: Within D, cortisol was lower at 120-180 minutes from starting surgery compared with baseline. Cortisol was higher in KM than in D at 60 minutes from starting surgery. Within all groups, glucose was higher postinduction (except DR) and 60 minutes from starting surgery, and insulin was lower during anesthesia and higher after standing compared with baseline. After standing, NEFA were higher in KM than in DB. In KM, MAP increased at 40-60 minutes from starting surgery compared with 30 minutes postinduction. CONCLUSIONS AND CLINICAL RELEVANCE: Dexmedetomidine suppressed cortisol release more than dexmedetomidine-opioid and ketamine-morphine infusions. Ketamine-morphine PIVA might increase catecholamine activity.

Prolonged ocular exposure leads to retinal lesions in mice.

Retinal lesions in the posterior pole of laboratory mice occur due to native, developmental abnormalities or as a consequence of environmental or experimental conditions. In this study, we investigated the rate and extent of retinal lesions as a result of prolonged ocular exposure following general anesthesia. Following experimental preparation induction procedures (EPIP) involving general anesthesia, mydriasis/cycloplegia, and topical anesthesia to the cornea, two ocular recovery conditions (protected and unprotected) were tested within two different animal recovery chambers (open or closed). The anterior and posterior poles were evaluated for the development of retinal lesions using digital color photography, scanning laser ophthalmoscopy, and spectral-domain optical coherence during anesthesia recovery and up to 2.5 months thereafter. In some mice, electroretinograms, histological and immunohistological evaluations were performed to assess functional and structural changes that accompanied the retinal lesions detected by in vivo imaging. Our data suggests that prolonged ocular surface exposure to circulating ambient room air leads to significant anterior and posterior segment ocular complications. The most abundant, semi-reversible complication observed was the development of lesions in the outer retina, which had a 90% probability of occurring after 45 min of exposure. The lesions mostly resolved short-term, but functional and imaging evidence suggest that some perturbations to the outer retina may persist one or more months following initial development.

Differential Effects of Isoproterenol on Regional Myocardial Mechanics in Rat Using Three-Dimensional Cine DENSE Cardiovascular Magnetic Resonance.

The present study assessed the acute effects of isoproterenol on left ventricular (LV) mechanics in healthy rats with the hypothesis that ß-adrenergic stimulation influences the mechanics of different myocardial regions of the LV wall in different ways. To accomplish this, magnetic resonance images were obtained in the LV of healthy rats with or without isoproterenol infusion. The LV contours were divided into basal, midventricular, and apical regions. Additionally, the midventricular myocardium was divided into three transmural layers with each layer partitioned into four segments (i.e., septal, inferior, lateral, and anterior). Peak systolic strains and torsion were quantified for each region. Isoproterenol significantly increased peak systolic radial strain and circumferential-longitudinal (CL) shear strain, as well as ventricular torsion, throughout the basal, midventricle, and apical regions. In the midventricle, isoproterenol significantly increased peak systolic radial strain, and induced significant increases in peak systolic circumferential strain and longitudinal strain in the septum. Isoproterenol consistently increased peak systolic CL shear strain in all midventricular segments. Ventricular torsion was significantly increased in nearly all segments except the inferior subendocardium. The effects of isoproterenol on LV systolic mechanics (i.e., three-dimensional (3D) strains and torsion) in healthy rats depend on the region. This region dependency is also strain component-specific. These results provide insight into the regional response of LV mechanics to ß-adrenergic stimulation in rats and could act as a baseline for future studies on subclinical abnormalities associated with the inotropic response in heart disease.

Photoelectrochemical determination of ractopamine based on inner filter effect between gold nanoparticles and graphitic carbon nitride-copper(II) polyphthalocyanine coupled with 3D DNA stabilizer.

Copper(II) polyphthalocyanine (CuPPc) was combined with graphitic carbon nitride (g-C3N4) to form a heterojunction with enhanced photoelectrochemical (PEC) signal. A sensitive PEC method was developed for determination of ractopamine based on a PEC inner filter effect between gold nanoparticles (AuNPs) and the g-C3N4/CuPPc. A gold electrode was modified with g-C3N4/CuPPc and the DNA was linked to the AuNPs. Initially, the PEC signal is weak due to the inner filter effect between the AuNPs and g-C3N4/CuPPc. In the presence of ractopamine, it interacts with the aptamer and the complementary chain (C chain) is released. This triggers the entropy-driven cyclic amplification and results in the release of the substrate B chain (SB chain) from three-dimensional DNA stabilizer. The probe is released from the electrode due to the interaction of probe DNA and the SB chain. As a result, the PEC signal increases linearly in the 0.1 pmol·L-1 to 1000 pmol·L-1 ractopamine concentration range. The detection limit is 0.03 pM, and the relative standard deviation is 3.4% (at a 10 pmol·L-1 level; for n = 11). The method has been successfully applied to the determination of ractopamine in pork samples. Graphical abstract Schematic presentation of detection method based on PEC inner filter effect between AuNPs and the g-C3N4/CuPPc being fabricated for ractopamine. 3D DNA was used as stabilizer to decrease the PEC blank signal.

Toxicity From Unintentional Pediatric Ingestion of a Performance-Enhancing Drug: A Case Report With Review of Clenbuterol Toxicity and Treatment.

BACKGROUND: Clenbuterol is a long-acting ß-adrenergic agonist that is not Food and Drug Administration-approved for use in the United States, but may be obtained without a prescription from various unregulated sellers. It has seen increasing use as a performance-enhancing drug for sports. Literature on pediatric toxicity and treatment is limited. CASE REPORT: We report a case of a 2-year-old female presenting after an exploratory ingestion of clenbuterol. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Use of performance-enhancing agents is increasing and physicians should be aware of the potential toxicity of intentional and unintentional ingestions of ß-adrenergic agonists. Patients may exhibit nausea, vomiting, tremor, tachycardia, and hypotension, along with laboratory abnormalities, including hyperglycemia, hypophosphatemia, hypokalemia, and hyperglycemia. Hypotension might not respond to adrenergic agents and may require administration of ß-adrenergic antagonists to maintain adequate perfusion.

[Pharmacotherapy of most severe forms of alcohol withdrawal]. / Pharmacothérapie des formes sévères du sevrage éthylique en milieu hospitalier.

Acute alcohol withdrawal is a frequent medical condition among hospitalized patients. Severe forms are associated with significant morbidity and mortality, which can be sharply reduced with proper drug therapy. A good understanding of the pathophysiology as well as the pharmacokinetic and pharmacodynamic properties of the various drug used is paramount. The medications must target the imbalance between inhibitory and excitatory neurotransmitter systems responsible for the clinical picture. Proper drug therapy allows not only rapid symptomatic relief but also limit disease progression and complications while diminishing resource use, notably invasive ventilation and stay duration in the intensive care unit. GABA agonist drugs are the first line treatment, notably benzodiazepines and barbiturates. Other class, such as alpha-2 adrenoreceptor agonists may be used to control the dysautonomic features of the disease but are at best adjunctive.

Le sevrage éthylique est une condition fréquemment rencontrée chez les patients hospitalisés. Les formes sévères sont causes de morbidité et de mortalité significatives, qui peuvent être drastiquement réduites par un traitement médicamenteux adapté. Une bonne compréhension, tant de la physiopathologie que des propriétés pharmacocinétiques et pharmacodynamiques des médicaments utilisés, est cruciale. Les médicaments doivent agir sur le déséquilibre entre les systèmes de neurotransmetteurs inhibiteurs et excitateurs à l'origine des manifestations cliniques. Un traitement pharmacologique bien conduit permet, non seulement, le contrôle rapide des symptômes, mais limite aussi la progression de la maladie et de ses complications. Il diminue ainsi la consommation de ressources médicales, notamment les besoins en ventilation mécanique et les séjours en soins intensifs. Les agonistes GABAergiques sont les médicaments de première ligne, notamment les benzodiazépines, mais également les barbituriques. D'autres classes médicamenteuses, comme les agonistes alpha2-adrénergiques, pourraient être utiles au contrôle des manifestations dysautonomiques, mais leur place est, au mieux, secondaire.

Effect of brimonidine, an α2 adrenergic agonist, on human meibomian gland epithelial cells.

We recently discovered that the anti-glaucoma pharmaceuticals timolol, a ß adrenergic antagonist, and pilocarpine, a cholinergic compound, negatively influence the morphology, proliferative capacity and survival of human meibomian gland epithelial cells (HMGECs). We hypothesize that another class of anti-glaucoma drugs, the α2 adrenergic agonists, also acts directly on HMGECs to affect their structure and function. We tested this hypothesis. Immortalized (i) HMGECs were cultured with brimonidine, as well as clonidine (α2 agonist), phenylephrine (α1 agonist), RX821002 (inverse α2 agonist) and MK912 (neutral α2 agonist) for up to 7 days. Cells were counted with a hemocytometer, and evaluated for morphology, signaling pathway activity, protein biomarker expression, and the accumulation of neutral lipids, phospholipids and lysosomes. Our findings demonstrate that brimondine treatment induces a dose-dependent decrease in Akt signaling and proliferation of iHMGECs. In contrast, brimonidine also promotes a dose-dependent differentiation of iHMGECs, including an increase in neutral lipid, phospholipid and lysosome levels. These effects were paralleled by an inhibition of p38 signaling, and duplicated by cellular exposure to clonidine, but not phenylephrine. Brimonidine also enhanced the cellular content of sterol regulatory binding protein-1, a master regulator of lipid synthesis. Of particular interest, the putative α2 antagonists, RX821002 and MK912, did not interfere with brimonidine action, but rather stimulated IHMGEC differentiation. Our results support our hypothesis and demonstrate that α2 adrenergic agonists act directly on iHMGECs. However, these compounds do not elicit an overall negative effect. Rather, the α2 agonists promote the differentiation of iHMGECs.

Dexmedetomidine-induced fever and delirium: A case report.

WHAT IS KNOWN AND OBJECTIVE: Dexmedetomidine is a selective alpha-2 agonist used for sedation in the intensive care unit (ICU). CASE DESCRIPTION: A 41-year-old woman intubated in the ICU and being treated for acute respiratory distress syndrome (ARDS) received dexmedetomidine following successful extubation to treat increasing agitation thought to be secondary to a history of polysubstance abuse. Following initiation of the dexmedetomidine, the patient became febrile as well as increasingly more agitated and delirious. All potential fever or delirium causes were evaluated. Following discontinuation of dexmedetomidine, her fever, agitation and delirium ceased. WHAT IS NEW AND CONCLUSION: We depict the first known case of dexmedetomidine causing high fevers and delirium.