Selective Alpha-2 Adrenergic Receptor Agonist Research Articles

Number Needed to Treat and Number Needed to Harm From Two Phase 3 Studies of Sublingual Dexmedetomidine for Treating Acute Agitation in Patients With Schizophrenia and Bipolar Disorder

AbstractBackgroundEpisodes of acute agitation can occur in individuals who suffer from schizophrenia or bipolar disorder and these can be a significant challenge for patients and for those who provide care to them. Sublingual dexmedetomidine is a selective alpha2-adrenergic receptor agonist that was recently approved by the US Food and Drug Administration for the treatment of agitation in adults with schizophrenia or bipolar disorder. The sublingual form of dexmedetomidine does not undergo first-pass hepatic metabolism, thus resulting in greater absorption than when ingested. In two Phase 3 studies of adults with schizophrenia or bipolar disorder, sublingual dexmedetomidine significantly reduced acute agitation at 2 hours, as measured by the five-item Positive and Negative Syndrome Scale-Excited Component (PEC). When initially appraising the potential utility of a new medication, number needed to treat (NNT) and needed to harm (NNH) can be helpful to assess the size of the treatment effect and, hence, clinical relevance.ObjectiveCalculation of NNT and NNH through post hoc analysis of Phase 3 data.MethodsPost hoc analysis of data were performed on data from two double-blind, randomized, placebo-controlled studies of sublingual dexmedetomidine in adults with schizophrenia or bipolar disorder experiencing acute agitation. Patients were randomized to a single dose of sublingual dexmedetomidine 180 μg, 120 μg, or placebo. The primary endpoint was mean change from baseline in the PEC total score. A therapeutic response was defined as a ≥40% reduction from baseline in PEC total score at 2 hours. NNT was calculated for PEC response rate for sublingual dexmedetomidine versus placebo. NNH was calculated using the incidence of adverse events for sublingual dexmedetomidine versus placebo. Likelihood to be helped or harmed (LHH) was calculated as the ratio of NNH to NNT.ResultsNNT (95% CI) was 3 (2, 3) for 180 mcg and 3 (3, 4) for 120 ug in patients with schizophrenia and 3 (2, 3) for 180 mcg and 4 (3, 6) for 120 ug in patients with bipolar disorder. NNH was greater than 10 for all AEs except somnolence, where NNH was 7 (5, 10) for all doses pooled from both studies. LLH values were greater than 1 for efficacy versus applicable tolerability outcomes in all cases.ConclusionsThis post hoc analysis demonstrated favorable NNT and NNH values for sublingual dexmedetomidine. In all instances therapeutic response was encountered more frequently than any adverse event. These values compare favorably to similar analyses for other approved agents for the treatment of agitation associated with schizophrenia or bipolar disorder, including intramuscular and inhaled formulations.FundingBioXcel Therapeutics, Inc.

Sublingual dexmedetomidine: repurposing an anesthetic as an anti-agitation agent

ABSTRACT Introduction Especially when acutely ill, individuals with schizophrenia and bipolar disorder can present with agitated behavior. The initial approach to agitation management are non-pharmacologic strategies such as verbal de-escalation techniques; however, pharmacologic interventions may be needed. Dexmedetomidine is a selective alpha-2 adrenergic receptor agonist, and a sublingual formulation has been approved in the US for the treatment of agitation associated with schizophrenia and bipolar disorder in adults. Areas covered The authors review the published literature on sublingual dexmedetomidine using the US National Library of Medicine’s PubMed.gov resource. Pharmacodynamics, pharmacokinetics, and efficacy and tolerability findings are summarized. The authors also provide a discussion to its potential place in the treatment armamentarium. Expert opinion Sublingual dexmedetomidine is an effective and well-tolerated pharmacologic option for the treatment of agitation associated with schizophrenia and bipolar disorder. The sublingual method of administration allows for a rapid onset of action with treatment effects beginning as early as 20 minutes after administration. Adverse effects include somnolence, hypotension, oral paresthesia, hypoesthesia, and dry mouth. Further study will be needed to evaluate sublingual dexmedetomidine in real-world patients receiving concomitant psychotropic medications.

Compared Dexmedetomidine and Fentanyl on Sensory-Motor Block in Unilateral Intrathecal Anesthesia of Lower-limbs Orthopedic Surgeries: A Randomized Duble-blind Trials

Background: One of the alternatives for lower-limb orthopedic surgery is spinal anesthesia. It can affect the hemodynamic status and cause the prolonged motor and sensory blocks, as well as urinary retention, which are less common in the unilateral technique. Different drugs are used to improve the quality of the block and reduce its complications. Dexmedetomidine, a selective alpha-2 adrenergic receptor agonist, and fentanyl, an opioid medication, could administration as an adjuvant to increase the intrathecal block quality. Hence, this study aimed to compare unilateral spinal anesthesia with bupivacaine/dexmedetomidine (BD) and bupivacaine/fentanyl (BF) regimes on the sensory-motor block among patients with lower-limb orthopedic surgeries. Materials and Method: This randomized, double-blind clinical trial was performed on 36 patients who underwent lower-limb orthopedic surgeries in Qaem Hospital, Mashhad, Iran. The patients were randomly divided into two groups. Patients who received 5.7 mg hyperbaric bupivacaine 0.5% plus 10 µg fentanyl (BF group) or 5 µg dexmedetomidine (BD group) were administered for inducing unilateral spinal anesthesia. Patients and investigators responsible for data collection were not awarded from allocation groups. The sensory-motor block level, duration, postoperative analgesia, and complications were recorded and compared between the two groups. Results: No significant difference was observed between the two groups in hemodynamic changes (i.e., systolic and diastolic blood pressure and heart rate) before and after the blockage (P˃0.05). Also, there was no difference in the sensory-motor block level and anesthesia-related complications between BF and BD groups (P˃0.05). Conclusion: In patients for whom the use of opioids for unilateral spinal anesthesia is contraindicated, dexmedetomidine could be considered an appropriate alternative.

Dexmedetomidine alleviates intestinal barrier dysfunction and inflammatory response in mice via suppressing TLR4/MyD88/NF-κB signaling in an experimental model of ulcerative colitis.

Ulcerative colitis (UC) is a nonspecific intestinal inflammatory disease. Dexmedetomidine (DEX) is a selective alpha 2-adrenergic receptor agonist commonly used for analgesia and sedation in intensive care units. Herein, the role and mechanism of DEX in dextran sulfate sodium (DSS)-induced colitis was explored. A murine model of DSS-induced colitis was established by adding 3.5% (w/v) DSS in drinking water to C57BL/6J female mice. The severity of colitis was measured by the disease activity index (DAI) score, colon length and body weight of mice. The serum concentration and mRNA levels of inflammatory cytokines in colon tissues were assessed by ELISA and RT-qPCR, respectively. Protein levels of apoptotic markers, tight junction proteins and genes involved in the TLR4/MyD88/NF-κB signaling were quantified utilizing Western blotting. The pathological changes of colon tissues were evaluated by hematoxylin-eosin (HE) staining and histological score. Intestinal permeability in vivo was assessed by fluorescein isothiocyanate (FITC)-dextran (FITC-D) administration. TUNEL assay was used to determine cell apoptosis in the intestinal epithelium. DSS administration resulted in weight loss, shortening of the colon, increased DAI score, histological abnormalities, and increased serum FITC-D levels in mice, all of which were reversed by DEX injection. Moreover, DEX attenuated DSS-triggered inflammatory response, intestinal barrier injury and intestinal epithelial cell apoptosis. Mechanically, DEX inactivated the TLR4/MyD88/NF-κB signaling in the colon tissues. DEX exerts beneficial effects against the intestinal barrier dysfunction, inflammatory response, and apoptosis of intestinal epithelial cells via inactivation of the TLR4/MyD88/NF-κB signaling in mice with DSS-induced colitis.

The effects of dexmedetomidine against ruptured abdominal aortic aneurysm injury to myocardial tissue induced by abdominal aorta clamping

Objectives: This study aims to examine the potential protective effect of the selective alpha-2 adrenergic receptor agonist dexmedetomidine (DEX) against aortic occlusion-induced myocardial injury. Patients and methods: A total of 30 rats were randomly assigned into three groups of 10 animals each as control, ischemia+reperfusion (I/Rep), and I/Rep+DEX. In the I/Rep and I/Rep+DEX groups, after the completion of the shock stage, 60-min lower torso ischemia was induced with the application of cross-clamps to the abdominal aorta, followed by 120-min reperfusion. The I/Rep+DEX group received intraperitoneal 100 μg/kg DEX 30 min before the ischemia period. Results: Malondialdehyde (MDA) levels in myocardial tissue increased with the application of I/Rep, while glutathione (GSH) levels decreased. We also observed swollen, degenerative, apoptotic cardiac myofibrils exhibiting caspase-3 positivity, widespread edematous areas, vascular congestion, and an increase in the heart damage scores. The MDA levels decreased with DEX administration, while the GSH levels increased. Degenerative, apoptotic cardiac myofibrils exhibiting loss of cytoplasm content, and vascular congestion also decreased. Conclusion: Our study results suggest that DEX may have a future role in the treatment of myocardial damage occurring due to reperfusion, following ruptured abdominal aortic aneurysm surgery.

Dexmedetomidine had neuroprotective effects on hippocampal neuronal cells via targeting lncRNA SHNG16 mediated microRNA-10b-5p/BDNF axis

Dexmedetomidine (DEX), a highly selective alpha2 adrenergic receptor agonist, is a commonly used anesthetic drug in surgical procedures. Previous studies have indicated that DEX exerts neuroprotective effects while the detailed mechanism has not been fully elucidated. Here, we aim to study the role of lncRNA SHNG16 in DEX-induced brain protection and its underlying molecular mechanism. The rats underwent middle cerebral artery occlusion (MCAO) surgery and oxygen–glucose deprivation (OGD)-treated HT22 hippocampal neurons were treated with DEX, respectively. CCK8 was used to evaluate cell viability. sh-SHNG16 as well as miR-10b-5p mimics were transfected into hippocampal neurons to further explore the bio-function of SNHG16 and miR-10b-5p in vitro. Furthermore, the interactions between SHNG16 and miR-10b-5p, miR-10b-5p and BDNF gene were confirmed by dual-luciferase report assay. Our data revealed that DEX attenuated neurological damage of the MCAO rats and also increased the cell viability of the neurons significantly. Besides, expression of SHNG16 and BDNF were both downregulated while miR-10b-5p was upregulated in MCAO brain tissues or OGD treated neurons. DEX inhibited miR-10b-5p expression but increased SHNG16 and BDNF levels with a dosage effect. After transfection with sh-SHNG16 or miR-10b-5p mimics, the expression of BDNF protein was downregulated, accompanied with decreased neuron viability. Dual-luciferase assay showed that SHNG16 targeted on miR-10b-5p, which also could bind directly to the 3′-UTR sites of BDNF and negatively regulate its expression. In conclusion, DEX exerts neuroprotective in ischemic stroke via improving neuron damage, the underlying mechanism may be upregulating SHNG16 and BDNF via sponging miR-10b-5p.

AB227. Tackling a challenging intubation in a child: awake fibre-optic intubation using dexmedetomidine

: Awake fibre-optic intubation is uncommon, particularly in children. Dexmedetomidine is the sedating agent of choice in our centre for adult awake fibre-optic intubation. However, it has not been licensed for use in patients of less than 18 years and consequently, there is scarce research available concerning its use in this cohort. Nevertheless, dexmedetomidine is commonly used as a pre-medication in children in the intensive care setting. It is a selective alpha-2 adrenergic receptor agonist with both sedative and analgesic effects. Unlike most sedatives however, it causes minimal respiratory depression. Its duration of action is 30 minutes, and with its extended recovery time, post-sedation agitation is lessened. These factors contribute to the use of dexmedetomidine as our agent of choice for awake-fibre optic intubation; a procedure not deemed to be overly painful, but requires sedation. The case to be discussed is that of a 14-year-old male who presented to a hospital in the west of Ireland with a 3-day history of reduced mouth-opening, left-sided jaw stiffness, and coryzal symptoms. Following a variety of antimicrobial regimes and investigation by X-ray, nasoendoscopy, ultrasound and computed tomography, the patient was found to have a left lateral pterygoid abscess which required surgical drainage, under general anaesthesia. This posed obvious difficulties from an airway point of view, with the child’s mouth opening at less than one finger breadth. This challenge was overcome with the use of a dexmedetomidine infusion of 1.5 micrograms per kilogram per hour to perform an awake-fibre optic intubation. This procedure was atraumatic and performed without patient distress.

Effect of Dexmedetomidine on duration of mechanical ventilation in septic patients: a systematic review and meta-analysis

BackgroundBecause of its analgesic and light sedative properties, the highly selective alpha-2 adrenergic receptor agonist dexmedetomidine (DEX) has been suggested for the treatment of septic patients, but its effect on the duration of mechanical ventilation remains unclear. The present study was conducted to review the extant literature in DEX and determine its influence on ventilation time in adult septic patients.MethodsDatabases of PubMed, Cochrane, and EMBASE were applied till 20th January 2019 without language restriction. The searching strategy as following: sepsis OR septic AND mechanical ventilation AND dexmedetomidine. Two authors screened titles, abstracts, and even articles to meet the including criterion independently. In addition, references of related articles or reviews were also referred. Data was recorded in a table and analyzed using the software of Review Manager 5.0.ResultsFour studies with a total of 349 patients were included. Three trials with 267 patients revealed the effect of DEX on duration of mechanical ventilation, two trials with 264 patients on ventilator-free days and four trials with 334 patients on 28-day mortality. The analyzed results indicated that DEX was not associated with significantly different durations of mechanical ventilation (MD 0.65, 95% CI, − 0.13 to 1.42, P = 0.10). However, there were significant differences in ventilator-free days (MD 3.57, 95% CI, 0.26 to 6.89, P = 0.03) and 28-day mortality (RR 0.61, 95% CI, 0.49 to 0.94, P = 0.02) in the septic patients.ConclusionAdministration of DEX for sedation in septic patients was not associated with the duration of mechanical ventilation, but it increased the ventilator-free days and reduced 28-day mortality.

Dexmedetomidine modulates transient receptor potential vanilloid subtype 1

Dexmedetomidine, a highly selective alpha-2 adrenergic receptor agonist and novel sedative drug with minimal respiratory suppression, have shown anti-nociceptive activity in various pain models by poorly understood mechanisms. Because alpha-2 adrenergic receptor is co-localized with TRPV1 polymodal nociceptive receptor in dorsal root ganglion neurons and up-regulated in neuropathic pain animal models, the analgesic activity might be mediated through inhibition of TRPV1 in the peripheral nervous system. In an effort to elucidate whether modulatory effect of dexmedetomidine on TRPV1 activity could be the potential peripheral mechanism underlying the antinociceptive effect of dexmedetomidine, intracellular calcium concentration after capsaicin application was investigated in mice dorsal root ganglion (DRG) neurons, with and without pretreatment of dexmedetomidine. Dexmedetomidine (10 μM) reduced capsaicin-induced calcium responses by 29.7 ± 7.39% (n = 34, p < 0.0001), in dose-dependent manner. Higher level of inhibition was observed with increased dose of dexmedetomidine (50 μM, 45.1 ± 8.58%, n = 15, p = 0.0002), and lower inhibition by decreased dose (1 μM, 18.8 ± 1.48%, n = 148, p = 0.004). RT-PCR analysis revealed expression of TRPV1 and alpha-2A, alpha-2B and alpha-2C subtypes of adrenergic receptor in mice DRG neurons, and immunocytochemical analysis revealed co-expression of TRPV1 and alpha-2A receptors in primary cultured DRG neurons. In summary, these results suggested the inhibition of TRPV1 expressed in the primary sensory neurons as a potential mechanism that contributes to the anti-nociceptive action of dexmedetomidine.

Dexmedetomidine attenuates the increase of ultrasonographic optic nerve sheath diameter as a surrogate for intracranial pressure in patients undergoing robot-assisted laparoscopic prostatectomy

Background:Pneumoperitoneum and steep Trendelenburg position during robot-assisted laparoscopic prostatectomy (RALP) can increase intracranial pressure (ICP). Dexmedetomidine, a highly selective alpha-2 adrenergic receptor agonist, can cause cerebral vasoconstriction and decrease cerebral blood flow by stimulating the postsynaptic alpha-2 adrenergic receptors on cerebral blood vessels. However, the effects of dexmedetomidine on ICP are controversial and have not been evaluated during RALP under the establishment of pneumoperitoneum in the steep Trendelenburg position. Therefore, we evaluated the effect of dexmedetomidine on optic nerve sheath diameter (ONSD) as a surrogate for assessing ICP during RALP.Methods:Patients were randomly allocated to receive dexmedetomidine (n = 63) (loading dose, 1 μg/kg for 10 minutes and continuous infusion, 0.4 μg/kg/hr) or normal saline (n = 63). The ONSD was measured at 10 minutes after induction of anesthesia in the supine position (T1), 30 minutes (T2) and 60 minutes (T3) after establishment of pneumoperitoneum in the steep Trendelenburg position, and at closing the skin in the supine position (T4). Hemodynamic and respiratory variables were measured at every time point.Results:ONSDs at T2, T3, and T4 were significantly smaller in the dexmedetomidine group than in the control group (5.26 ± 0.25 mm vs 5.71 ± 0.26 mm, 5.29 ± 0.24 mm vs 5.81 ± 0.23 mm, and 4.97 ± 0.24 mm vs 5.15 ± 0.28 mm, all P <.001). ONSDs at T2, T3, and T4 were significantly increased compared to T1 in both groups. Hemodynamic and respiratory variables, except heart rate, did not significantly differ between the 2 groups. The bradycardia and atropine administration were not significantly different between the 2 groups.Conclusion:Dexmedetomidine attenuates the increase of ONSD during RALP, suggesting that intraoperative dexmedetomidine administration may effectively attenuate the ICP increase during pneumoperitoneum in the Trendelenburg position.

Identification of Candidate Genes and Pathways in Dexmedetomidine-Induced Cardioprotection in the Rat Heart by Bioinformatics Analysis.

Dexmedetomidine (DEX), a highly selective alpha2 adrenergic receptor agonist, directly protects hearts against ischemia/reperfusion (I/R) injury. However, the detailed mechanism has not been fully elucidated. We studied differentially expressed mRNAs and miRNAs after DEX administration in rat hearts by comprehensive analysis. Additionally, bioinformatics analysis was applied to explore candidate genes and pathways that might play important roles in DEX-induced cardioprotection. The results of microarray analysis showed that 165 mRNAs and 6 miRNAs were differentially expressed after DEX administration. Through bioinformatics analysis using differentially expressed mRNAs, gene ontology (GO) terms including MAP kinase tyrosine/serine/threonine phosphatase activity and pathways including the p53 pathway were significantly enriched in the down-regulated mRNAs. Dusp1 and Atm were associated with the GO term of MAP kinase tyrosine/serine/threonine phosphatase activity and the p53 pathway, respectively. On the other hand, no significant pathway was found in the target mRNAs of deregulated miRNAs. The results indicated some possible key genes and pathways that seem to be of significance in DEX-induced cardioprotection, although miRNAs seem to be unlikely to contribute to cardioprotection induced by DEX.

Effect of Dexmedetomidine on Maintaining Perioperative Hemodynamic Stability in Elderly Patients: A Systematic Review and Meta-analysis

ObjectiveDexmedetomidine is a highly selective alpha-2 adrenergic receptor agonist with sedative and analgesic properties but without respiratory depression effect and has been widely used in perioperative anesthesia. Here we performed a systematic review and meta-analysis to evaluate the effect of dexmedetomidine on maintaining perioperative hemodynamic stability in elderly patients. MethodsPubMed, Web of Science, the Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang Data were searched for randomized-controlled trials (RCTs) on the application of dexmedetomidine in maintaining perioperative hemodynamic stability in elderly patients from their inception to September, 2021. The standardized mean differences (SMD) with 95% confidence interval (CI) were employed to analyze the data. The random-effect model was used for the potential clinical inconsistency. ResultsA total of 12 RCTs with 833 elderly patients (dexmedetomidine group, 546 patients; control group, 287 patients) were included. There was no significant increase in perioperative heart rate (HR), mean arterial pressure (MAP), and diastolic blood pressure (DBP) in the dexmedetomidine group before and during the operation. In addition, the variations of hemodynamic indexes including HR, MAP, SBP (systolic blood pressure), and DBP were significantly lower in the dexmedetomidine group compared with the control group (HR: SMD = −0.87, 95% CI: −1.13 to −0.62; MAP: SMD = −1.12, 95% CI: −1.60 to −0.63; SBP: SMD = −1.27, 95% CI: −2.26 to −0.27; DBP: SMD = −0.96, 95% CI: −1.33 to −0.59). Subgroup analysis found that with the prolongation of 1.0 μg/kg dexmedetomidine infusion, the patient's heart rate declined in a time-dependent way. ConclusionDexmedetomidine provides more stable hemodynamics during perioperative period in elderly patients. However, further well-conducted trials are required to assess the effective and safer doses of dexmedetomidine in elderly patients.

Dexmedetomidine does not interfere with meta-iodobenzylguanidine (MIBG) uptake at clinically relevant concentrations.

Neuroblastoma is a pediatric malignancy, and most tumor cells express the norepinephrine transporter (NET) enabling uptake of NET ligands. Meta-iodobenzylguanidine (MIBG) is a NET-specific ligand used as a highly specific imaging agent and targeted radiotherapeutic. Patients with neuroblastoma frequently require sedation during targeted radiotherapy. Dexmedetomidine has been increasingly used to achieve efficacious sedation. There are theoretical concerns that this highly selective alpha-2 adrenergic receptor agonist may interfere with active uptake of MIBG through the NET transporter. In this study, we analyzed the impact of [125-iodine]-labeled MIBG ([125 I]MIBG) uptake in the presence of dexmedetomidine in human neuroblastoma-derived cellular models. Carrier-free [125 I]MIBG was synthesized using UltraTrace® resin (Molecular Insight Pharmaceuticals, Inc., Tarrytown, NY) through radioiododestannylation from a tin precursor bound by a solid-state polymer. NET (SLC6A2) protein expression was determined in human neuroblastoma cell lines (BE2C, SKNSH and IMR5). [125 I]MIBG internalization studies were performed using [125 I]MIBG alone or in combination with either desipramine or dexmedetomidine. Dexmedetomidine and desipramine competitive inhibition studies were performed and concentration at 50% maximal inhibition was calculated. Finally, NET inhibitor dissociation studies were performed in which after pre-incubation with either desipramine or dexmedetomidine, cells were washed and [125 I]MIBG was added. We show dose-dependent inhibition of [125 I]MIBG uptake by dexmedetomidine, but at several logs lower potency than the known NET inhibitor desipramine. A review of pediatric dexmedetomidine pharmacokinetic data shows that the concentrations achieved in the serum are much lower than those required to block MIBG uptake. We conclude that dexmedetomidine will not interfere with therapeutic [131 I]MIBG efficacy.

The newer aspect of dexmedetomidine use in dentistry: As an additive to local anesthesia, initial experience, and review of literature.

Introduction:Despite the availability of a wide variety of pharmacological agents in the field of anesthesia, there has always been a continuous search for newer local anesthetic agents with improved efficacy, potency, and better handling properties. Dexmedetomidine, a selective alpha-2 adrenergic receptor agonist, is an emerging agent for provision of additive local anesthetic effect if used with conventional local anesthetics, which can be implicated in dentistry for performing many minor oral surgical procedures. The present paper reports a pilot study comparing clinical efficacy and potency of this newer emerging drug in combination with lignocaine.Materials and Methods:Ten patients undergoing orthodontic extraction for correction of malocclusion and other dentofacial deformities requiring orthodontic treatment were locally infiltrated with 2% lignocaine plus dexmedetomidine 1μ/ml and 2% lignocaine plus adrenaline in 1:200,000 dilution at two different appointments. The onset of action, duration of action, and pain threshold were assessed.Results:Onset of action was found to be faster with longer duration of action with the newer drug dexmedetomidine and lignocaine combination when compared with combination of lignocaine and adrenaline.Conclusion:The study demonstrated that the combination of dexmedetomidine with lignocaine enhances the local anesthetic potency of lignocaine without significant systemic effects when locally injected into oral mucosa.

Dexmedetomidine: The Anesthetic as an Antiarrythmic

Cardiac arrhythmias are significant cause of morbidity and mortality during perioperative period as well as in critically ill patients in intensive care units (ICU).These rhythm disturbances that may be well tolerated in normal heart can cause significant hemodynamic instability in patients with a congenital or acquired heart problem. Management of these arrhythmias possess a challenge because currently available antiarrhythmic have several disadvantages. Dexmedetomidine (DEX) is a highly selective alpha-2 adrenergic receptor agonist with sympatholytic, sedative, amnesic and analgesic properties. Growing evidences has been suggested the potential therapeutic application of DEX in the management of cardiac rhythm disturbances. This work has an intention to review and update the application of DEX for management of various cardiac arrhythmias. A comprehensive review of pharmacology, mechanism of antiarrhythmic action and side effects of this drug is presented.

Noradrenergic function in generalized anxiety disorder: impact of treatment with venlafaxine on the physiological and psychological responses to clonidine challenge

Serotonin and noradrenaline reuptake inhibitor (SNRI) antidepressants have evidence of efficacy in the treatment of generalized anxiety disorder (GAD); however, it is not clear whether there is an advantage over selective serotonin reuptake inhibitor (SSRI) medicines and there is limited evidence for noradrenergic dysfunction in GAD. We tested whether a dysfunctional alpha-2 adrenoceptor system is present in patients with GAD and the effects of SNRI treatment on this system. The method used was an infusion of clonidine (a selective alpha-2 adrenergic receptor agonist) on psychological and physiological outcomes in three subject groups: 10 untreated GAD patients, five SNRI-treated GAD patients and seven normal controls. The clonidine challenge elicited sedation, a rise in growth hormone, decrease in blood pressure, decline in saccadic eye movement (SEM) variables, and improvement in verbal fluency as anticipated in the 22 subjects examined. Lower cortisol levels were found in controls and higher blood pressure readings in GAD-treated subjects, as well as evidence that GAD-treated subjects had SEMs that were intermediate between control and GAD subjects' scores and have less clonidine-induced sedation. The implications of these findings with reference to the study hypothesis in this small study are discussed.

Determination of the pharmacodynamic interaction of propofol and dexmedetomidine during esophagogastroduodenoscopy in children

Propofol is a sedative-hypnotic drug commonly used to anesthetize children undergoing esophagogastroduodenoscopy (EGD). Dexmedetomidine is a highly selective alpha-2 adrenergic receptor agonist that has been utilized in combination with propofol to provide anesthesia. There is currently no information regarding the effect of intravenous dexmedetomidine on the propofol plasma concentration-response relationship during EGD in children. This study aimed to investigate the pharmacodynamic interaction of propofol and dexmedetomidine when used in combination for children undergoing EGD. A total of 24 children undergoing EGD, ages 3-10 years, were enrolled in this study. Twelve children received dexmedetomidine 1 microg x kg(-1) given over 10 min as well as a continuous infusion of propofol delivered by a computer-assisted target-controlled infusion (TCI) system with target plasma concentrations ranging from 2.8 to 4.0 microg x ml(-1) (DEX group). Another group of 12 children undergoing EGD also received propofol administered by TCI targeting comparable plasma concentrations without dexmedetomidine (control group). We used logistic regression to predict plasma propofol concentrations at which 50% of the patients exhibited minimal response to stimuli (EC50 for anesthesia). The EC50 +/- SE values in the control and DEX groups were 3.7 +/- 0.4 microg x ml(-1) and 3.5 +/- 0.2 microg x ml(-1), respectively. There was no significant shift in the propofol concentration-response curve in the presence of dexmedetomidine. The EC50 of propofol required to produce adequate anesthesia for EGD in children was unaffected by a concomitant infusion of dexmedetomidine 1 microg x kg(-1) given over 10 min.

Effects of Dexmedetomidine on Regulating Pulmonary Inflammation in a Rat Model of Ventilator-induced Lung Injury

We sought to elucidate the effects of dexmedetomidine, a selective alpha2-adrenergic receptor agonist, on the regulation of pulmonary inflammation in ventilator-induced lung injury (VILI) in a rat model. A total of 64 adult male Sprague-Dawley rats were assigned to receive either standard ventilation (tidal volume 10 mL/kg; respiratory rate 50 breaths/minute), high-tidal volume ventilation (HVT: tidal volume 20 mL/kg; respiratory rate 50 breaths/minute), HVT plus dexmedetomidine (0.5, 2.5 or 5.0 microg/kg per hour), or HVT plus dexmedetomidine (0.5, 2.5 or 5.0 microg/kg per hour) and yohimbine (the alpha2-adrenergic receptor antagonist) (n = 8 in each group). The doses of dexmedetomidine were chosen to correspond to 1, 5 and 10 times the clinical dose (0.5 microg/kg per hour). After maintaining ventilation for 4 hours, rats were sacrificed and pulmonary inflammatory changes as well as the upregulation of pulmonary inflammatory molecules were evaluated. Histological and arterial blood gas analyses confirmed that HVT induced significant lung injury. HVT also significantly increased the pulmonary concentrations of chemokines (e.g. macrophage inflammatory protein-2), cytokines (e.g. tumor necrosis factor-alpha, interleukin [IL]-1beta, and IL-6), inducible nitric oxide synthase/nitric oxide, cyclooxygenase-2/prostaglandin E2. Dexmedetomidine at the dose of 5.0 microg/kg per hour, but not at 0.5 and 2.5 microg/kg per hour, significantly attenuated the effects of HVT. Moreover, these effects of dexmedetomidine were significantly attenuated by yohimbine. Dexmedetomidine at clinically relevant doses had no significant effect in attenuating VILI. In contrast, dexmedetomidine at a dose approximately 10 times higher than the clinical dose significantly attenuated VILI. These effects of dexmedetomidine were mediated, at least in part, by the alpha2-adrenergic receptor.

Brimonidine-induced Anterior Uveitis and Conjunctivitis

Brimonidine tartarate is a selective alpha2-adrenergic receptor agonist that is indicated for use in the treatment of glaucoma and ocular hypertension. Since its introduction in 1997 there have been a small number of case reports concerning granulomatous anterior uveitis as a late adverse reaction to long-term brimonidine therapy. We report a case of bilateral anterior uveitis and granulomatous papillary conjunctivitis in a 78-year-old gentleman after 2 years of brimonidine therapy. Cessation of brimonidine lead to rapid termination of uveitis. The histologic features of the conjunctiva are described. This has not been previously reported.

Variation in the ??2B-adrenergic receptor gene (ADRA2B) and its relationship to vascular response in vivo

The alpha2B-adrenergic receptor (ADRA2B) plays an important role in vasoconstriction and blood pressure regulation. One common variant in the ADRA2B gene (del 301--303) has been identified, and results in markedly decreased receptor desensitization in vitro but does not alter vascular sensitivity in vivo. Therefore, we fully characterized genetic variations in ADRA2B and related them to phenotype in vivo. We examined 5812 bp of contiguous sequence of ADRA2B (promoter, exonic, and 3'-untranslated region; 3'-UTR) using the polymerase chain reaction to amplify the genomic target followed by bidirectional sequencing (n=68). Haplotypes were inferred using an expectation maximization algorithm. Vasoconstriction in response to increasing doses of the highly selective alpha2-adrenergic receptor agonist, dexmedetomidine (0.01--1000 ng/min) was measured in the dorsal hand vein using a linear variable differential transformer. The dose that produced 50% (ED50) of maximum venoconstriction (Emax) was determined for each subject from the individual dose--response curves. ED50 and Emax were compared in subjects with and without variant alleles and haplotypes of interest. We identified 24 variable sites, 12 in the promoter region, five in the coding region (including two previously described as non-synonymous variants) and seven in the 3'-UTR region. Four haplotypes were inferred, representing approximately 95% of the cohort. One haplotype, characterized by two single nucleotide polymorphisms in the promoter region, and one in the 3'-UTR, occurred in seven of 38 African-Americans, and was associated with a lower Emax, 61.3% [95% confidence interval (CI) 39.5--83.0, n=7] compared to 78.1% (CI 73.8--82.5) in wild-types (n=61) (P=0.02). There was no association between the nine common variants and dexmedetomidine ED50. We have described novel variants and haplotypes of the ADRA2B gene. These do not alter sensitivity to a selective alpha2-adrenergic receptor agonist but some may decrease maximal venoconstriction in vivo.