By E. Lester. Ithaca College. 2018.

Forest plot of maintenance of sinus rhythm for PVI versus drug therapy Study name Odds ratio and 95% CI Odds Lower Upper ratio l i mi t l i mi t Krittayaphong discount 15mg mobic otc, 2003 5 buy 15mg mobic free shipping. CV Hospitalizations 222 discount 7.5 mg mobic otc,226 Two studies reported generally on CV hospitalizations during 12 months of followup buy 7.5 mg mobic free shipping. During 12 months of followup the rate of AF hospitalization was significantly higher in the AAD arm (15 out of 35) than in the PVI arm (3 out of 32; p<0. Quality of Life/Functional Status Six studies evaluated the impact of transcatheter PVI versus antiarrhythmic drugs on quality 222,226,253,262,273,293 of life or functional status. The metrics for assessing these outcomes were too variable to allow quantitative synthesis, but of the six studies, four demonstrated a statistically 222,253,273,293 significant better quality of life or functional status in the PVI group. The other two studies, which represented both the smallest (30 patients) and largest (198 patients) studies, did 226,262 not demonstrate significant differences. Given the inconsistency in metrics and findings 222,226,293 amongst the good-quality studies, we were unable to estimate the direction of impact of transcatheter PVI versus antiarrhythmic drugs on quality of life or functional status (insufficient strength of evidence). Mixed Embolic Events Including Stroke 222,273 Only two studies reported on mixed embolic events including stroke. In both studies, no embolic events occurred in the PVI arm or the AAD arm during 12 months of followup (low strength of evidence). Bleeding Events 273 Only one study reported on bleeding events. During 1 year of followup, there was no significant difference in the rate of bleeding between the PVI group (2 out of 32) and the AAD arm (1 out of 35; p=0. Other Outcomes None of these studies reported on cardiovascular mortality, or restoration of sinus rhythm, cardiovascular mortality, or heart failure symptoms. Adverse Events 262 In one study, PVI resulted in one stroke and one groin hematoma, while amiodarone caused the following adverse effects in 7 patients (46. Incidence of documented bradycardia was higher in the AAD group (3 [8. Asymptomatic moderate (50%–70%) pulmonary vein (PV) stenosis was documented in 1 (3%) of 32 patients in the PVI group, affecting only one vein; no patient developed severe (>70%) PV stenosis. Significant adverse events leading to permanent drug withdrawal occurred in 23 patients. Proarrhythmia developed in 3 patients in the flecainide group (hypotensive wide QRS tachycardia in 2 patients and 1:1 atrial flutter in 1); thyroid dysfunction occurred in 7 patients in the amiodarone group requiring drug discontinuation; and sexual impairment in 11 patients in the sotalol group. In the AAD arm, one patient had a TIA, two patients had cancer (one died), and one patient died suddenly. Two episodes of cardiac tamponade requiring pericardiocentesis and two groin hematomas were reported; one in each group (one crossover patient), with a favorable outcome in all. A stenosis of the left superior PV that required dilatation and stent implantation occurred in one crossover patient, with an uneventful course thereafter. One case of hyperthyroidism was observed in the AAD group, as well as two deaths that were not deemed related to AADs (acute myeloid leukemia and myocardial infarction). Symptomatic bradycardia requiring a dosage reduction or a change to an alternative drug occurred in five patients, all known to have hypertension. One of the patients underwent implantation of a dual-chamber pacemaker for symptomatic sinus nodal dysfunction. Another patient developed 1:1 atrial flutter while on flecainide. One patient in the catheter ablation group who had undergone PV isolation alone died 284 days after the procedure due to acute myocardial infarction deemed unrelated to the procedure. Transcatheter PVI Using Different Types of Ablation Catheters Overview Although we identified three studies comparing types of catheter, these were deemed inappropriate for a meta-analysis given that each study compared different types of catheter, 217 making heterogeneity insurmountable. One study compared an 8 mm tip catheter with a 210 cooled tip catheter. A second study compared a multipolar circular ablation catheter with 207 point-by-point PVI using an irrigated-tip ablation catheter. One study compared a new circular 64 ablation catheter with point-by-point conventional ablation catheter. Results for outcomes of interest are accordingly described qualitatively below.

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This protein component re- constitutes strong attenuation of B2AR-mediated activation of adenylyl cyclase when added back to highly purified frac- tions of BARK (25 purchase mobic 15 mg without prescription,26) order mobic 15 mg visa. The protein cofactor involved in desensitization of the B2AR turned out to be a protein simi- lar to visual arrestin and was therefore named -arrestin or barrestin generic 15mg mobic. Two nomenclatures are currently in common use for these molecules proven 7.5mg mobic. In one, the originally iden- tified -arrestin is denoted barrestin 1, and additional hom- ologues are named sequentially barrestin 2, and so on. In another nomenclature, all members of this protein family are referred to as arrestins, with visual arrestin denoted ar- C restin 1, -arrestin as arrestin 2, and subsequently identified FIGURE 5. Paradigms for phosphorylation-dependent desensi- family members numbered sequentially thereafter. B: GRK2- members of the arrestin family of protein cofactors have mediateddesensitizationofthe B2AR. As noted above, an important feature of many GRKs is that their kinase activity is highly sensitive to the conforma- tion of the receptor that they phosphorylate. Thus, GRK-mediated phosphory- GRK-Mediated Phosphorylation of the B2AR: a lation is generally considered to be a paradigm for homolo- Model for Homologous Desensitization gous desensitization (Fig. Studies of functional reconstitution of B2AR-mediated acti- vation of adenylyl cyclase provided compelling evidence for Protein Kinase A-Mediated Phosphorylation of a role of phosphorylation in mediating rapid desensitization the B2AR: a Model of Heterologous of a ligand-activated GPCR (22). Biochemical purification Desensitization of the cytoplasmic activity responsible for this phosphoryla- tion identified a kinase called -adrenergic receptor kinase Other kinases, such as the so-called second messenger-regu- (BARK), and it was noted that this kinase preferentially lated kinases, are also implicated in mediating desensitiza- phosphorylates agonist-occupied receptors (23). For example, the B2AR can be phosphory- quencing and cyclic DNA (cDNA) cloning later indicated lated by cyclic adenosine monophosphate (cAMP)- that this kinase is closely similar in structure to rhodopsin dependent protein kinase (PKA). Furthermore, cDNA-cloning experiments in ylation of a single residue located in the third intracellular which reduced stringency hybridization was used identified loop of the B2AR impairs the ability of the receptor to additional kinases homologous to rhodopsin kinase and couple to Gs and subsequently activate adenylyl cyclase BARK (19). Collectively, these observations led to the dis- (27–29). Phosphorylation of this residue is thought to im- covery of the family of G protein-coupled receptor kinases pair receptor–G protein coupling directly, without a re- (GRKs). According to this nomenclature, rhodopsin is de- quirement for any known protein cofactor such as an ar- noted GRK-1, the originally identified BARK enzyme is restin. An important feature of PKA is that this kinase can denoted GRK-2, and other members of this family of pro- phosphorylate B2ARs whether or not they have been acti- Chapter 5: Regulation of G Protein-Coupled Receptors 63 vated by ligand, in contrast to the preferential phosphoryla- This dynamic cycling of the B2AR was also suggested by tion of agonist-activated receptors by GRK-2. Because PKA elegant studies in which subcellular fractionation and ra- is activated by cAMP, a signaling intermediate produced as dioligand binding techniques were used (33). In addition, because activation tors in the plasma membrane, from a relatively diffuse distri- of any other receptor that stimulates adenylyl cyclase can bution throughout the plasma membrane to a pronounced also activate PKA, phosphorylation of the B2AR by PKA concentration of agonist-activated receptors in structures is generally considered to be a paradigm for heterologous resembling clathrin-coated pits when examined by immu- desensitization (Fig. Furthermore, this process of ligand- regulated concentration of B2ARs in coated pits of the plasma membrane was shown to be mechanistically distinct Rapid Desensitization and from the subsequent endocytosis of receptors by membrane Resensitization Mediated by Regulated fission, which can occur even in the absence of continued Endocytosis of Receptors ligand-induced activation of receptors (34). A protein that Endocytosis of GPCRs by Clathrin-Coated Pits is required for this latter step of endocytic membrane fission is the cytoplasmic guanosine triphosphatase dynamin (35, Studies conducted in cultured cells indicate that many 36). Consistent with this, agonist-induced endocytosis of GPCRs can be regulated by ligand-induced endocytosis. Subse- with respect to endocytic membrane trafficking. Early evi- quent studies have demonstrated that regulated endocytosis dence for agonist-induced endocytosis of the B2AR was sug- of several other GPCRs is also mediated by a dynamin- gested by observations from subcellular fractionation and dependent mechanism, which suggests a conserved role of radioligand binding assays conducted with membrane-im- clathrin-coated pits in the endocytosis of many GPCRs (Fig. Endocytosis by Clathrin-Coated Pits The development of receptor-specific antibodies allowed the application of immunocytochemical methods to visual- Studies elucidating the mechanism mediating the key step ize the subcellular localization of the B2AR and directly of regulated concentration of GPCRs in clathrin-coated pits demonstrate agonist-induced internalization of the receptor were initiated by the observation that GRK-mediated phos- protein. Internalization of the B2AR was observed to repre- phorylation of the M2 muscarinic acetylcholine receptor sent a steady state of a highly dynamic process involving can promote agonist-induced endocytosis of the receptor, continuous endocytosis and recycling of receptors through whereas a kinase-defective mutant form of GRK inhibits an endocytic pathway similar to that mediating constitutive this process (39). Similar observations were made for other (ligand-independent) endocytosis of nutrient receptors (32). Regulated endocytosis of the 2-adrenergic receptor (B2AR) by clathrin-coated pits. G protein-coupled re- ceptor kinase-mediated phosphorylation of the B2AR promotes receptor interaction with nonvisual arrestins, which cause un- coupling of heterotrimeric G proteins and also promote interaction of arrestin–re- ceptor complexes with clathrin coats. Once concentrated in clathrin-coated pits bythis mechanism, receptors undergo endocyto- sis rapidly(even if agonist is removed from the receptor in the coated pit) via a consti- tutive (ligand-independent) mechanism of endocytic membrane fission that requires the cytoplasmic guanosine triphosphatase dynamin.

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Dopamine reuptake diazepine receptor levels and novelty-induced fearfulness in the site densities in patients with social phobia buy generic mobic 15 mg on line. Chapter 63: Neurobiological Basis of Anxiety Disorders 929 291 mobic 7.5mg with visa. Serotonin and anxiety mine D(2) receptor binding potential in social phobia safe mobic 15 mg. Effects of the serotonin agonist MCPP in ness: in vivo correlation with serotonin order mobic 7.5 mg without prescription. Pharmacol Biochem panic disorder patients and healthy subjects. Trends Pharmacol Sci 1993;14: knockout: an animal model of anxiety-related disorder. Regulation of seroto-´ genic effects of CCK-4 in panic disorder patients. Am J Psychia- nin1A, glucocorticoid, and mineralocorticoid receptor in rat and try 1994;151:261–263. Elevated basal trough CCK receptor antagonist, in patients with panic disorder. Arch levels of corticosterone suppress hippocampal 5-HT1A receptor Gen Psychiatry 1994;51:486–493. Autoradiographic analyses of the with posttraumatic stress disorder. Biol Psychiatry 2000;47: effects of restraint-induced stress on 5-HT1A, 5-HT1C and 107–111. Transcriptional regulation of hippo- panic attacks in patients with panic disorder. Neuropsychophar- campal 5-HT1A receptors by glucocorticoid hormones. Stress and antidepres- nan concentrations in patients with panic disorder and normal sant effects on hippocampal and cortical 5-HT and 5-HT comparison subjects. Platelet serotonin levels in trial of the CCK-B antagonist, CI-988 in panic disorder. Serotonin changes in central opioid levels and pain responsiveness in the uptake in panic disorder and agoraphobia. Brain Res 1989;476: imipramine binding in patients with panic disorder. Differential 3H imipra- competing motivational state theory of stress analgesia. Ann NY mine platelet binding in patients with panic disorder and depres- Acad Sci 1986;467:40–54. Stressor controllability and stress induced analgesia. Naloxone-reversible and agoraphobia with panic attacks. Biol Psychiatry 1987;21: analgesic response to combat-related stimuli in posttraumatic 3–41. Cerebrospinal fluid and ders: the effects of intravenous tryptophan in healthy subjects plasma beta endorphin in combat veterans with post traumatic and panic disorder patients before and after alprazolam treat- stress disorder. Behavioral, neuroendocrine, phin in posttraumatic stress disorder. Aust NZ J Psychiatry 1989; and biochemical effects of 5-hydroxytryptophan administration 23:268–273. Carbon dioxide hypersensitiv- pal neuropeptide Y overexpression. Proc Natl Acad Sci USA ity, hyperventilation, and panic disorder. Ventilatory physiology peptide-Y concentrations in humans exposed to military survival of children and adolescents with anxiety disorders. Ventilatory physiology neuropeptide Y in patients with panic disorder.

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The greatest improvement during Other Agents (Trazodone mobic 7.5mg fast delivery, Nefazodone buy mobic 7.5mg lowest price, the first 2 weeks occurred in the group receiving the benzo- Anticonvulsants order 7.5 mg mobic with mastercard, Partial GABA Agonists) diazepine purchase mobic 7.5mg line,as expected by the early relief of physical anxiety In a randomized,placebo-controlled comparator trial of tra- symptoms and insomnia provided by this class of medica- zodone,diazepam,and imipramine in the treatment of 230 tion. However,from the fourth week forward,the paroxe- patients with GAD,trazodone was found to be superior tine and imipramine groups demonstrated superior benefits, to placebo yet somewhat less effective than diazepam and particularly in the area of psychic symptoms of anxiety. The antidepressant More recently,the efficacy of paroxetine was demonstrated nefazodone,which antagonizes the 5-HT receptor and 2C in a large,fixed-dose study of more than 500 patients with inhibits the reuptake of both serotonin and NE,has shown a DSM-IV diagnosis of GAD without major depression promise in the treatment of GAD in an open trial (102). Patients were randomized to receive paroxetine 20 mg/ Anticonvulsants such as valproate and carbamazepine have day,paroxetine 40 mg/day,or placebo for 8 weeks. Patients been used in the treatment of GAD; however,evidence of receiving both doses of paroxetine demonstrated significant their efficacy is primarily anecdotal,as there are no con- differences in the primary outcome measure,reduction in trolled clinical trials for either of these medications in the HAM-A score,versus placebo,with 68% on 20 mg paroxet- treatment of GAD (103). Other agents such as the partial ine and 81% on 40 mg paroxetine rated as responders based GABA agonist abecarnil have not demonstrated significant on a Clinical Global Impression (CGI-I) score of 1 or 2, efficacy versus placebo in GAD (101). In summary,although the benzodiazepines have been the mainstay of pharmacotherapy for GAD since their intro- Venlafaxine duction,significant concerns regarding their long-term use in GAD have fueled the search for other effective treat- Venlafaxine is an inhibitor of SNRI. Given the chronic nature of GAD,medications such cently been demonstrated in humans,using peripheral mea- as buspirone,and the antidepressants venlafaxine and parox- sures,to have primarily 5-HT reuptake inhibition properties etine,which have fewer effects on cognitive and psychomo- at low doses (75 mg/day),with increasing norepinephrine tor function,now represent first-line therapies for GAD. Shown to be effective in the treatment of anxiety symptoms associated with major depression (98,99), the extended release (XR) form of venlafaxine has been SOCIAL PHOBIA shown to be effective in the treatment of GAD (DSM-IV criteria) in several placebo-controlled studies (100,101). In Social phobia (SP) (or social anxiety disorder) is reported a placebo-controlled multicenter comparator trial,405 pa- to be the most common anxiety disorder with a 1-year prev- tients with GAD were randomized to receive venlafaxine alence of 7% to 8% and a lifetime prevalence of 13% to XR (75 or 150 mg/day),buspirone (30 mg/day),or placebo 14% in patients aged 15 to 54 years. For the 365 patients for whom efficacy mea- can be classified into two subtypes—discrete and general- sures were obtained,there was no significant difference be- ized. Level of disability with SP can be high,and 70% to tween groups in improvement on the primary outcome 80% of patients have comorbid psychiatric disorders,partic- measure,the HAM-A. However,both doses of venlafaxine ularly depression and substance abuse (104). Given the high were shown to be superior to placebo in improving HAM- degree of burden of illness in SP,its treatment has become A psychic anxiety and anxious mood scores at the endpoint a major priority. Historical Notes More robust efficacy findings for venlafaxine were reported in a recent large,multicenter trial,involving 377 outpatients Liebowitz et al. Patients (106),had a specific responsivity to the MAOIs,whereas were randomly assigned to receive either placebo or venla- TCAs,although effective for PD and 'typical' major faxine XR at one of three doses (75,150,or 225 mg/day) depression,were not effective for SP (107). Of the 349 patients included in the efficacy the MAOIs,which block reuptake of dopamine in addition analysis,those receiving 225 mg/day demonstrated signifi- to NE and serotonin,prompted speculation about a poten- 974 Neuropsychopharmacology: The Fifth Generation of Progress tial 'dopaminergic' component to the neurobiology of SP. As is the case with PD,buspirone does not appear effec- Several open clinical studies have attempted to utilize the tive for SP as monotherapy in placebo-controlled double- 'dopamine component' concept in phamacotherapy with blind studies (123). It may,however,have a role in augmen- some success,e. However,as data accumulated,other systems were also im- plicated,and the pharmacologic dissection approach seemed Serotonin/Norepinephrine Reuptake less applicable (see above). Positive results with the high- Inhibitors potency benzodiazepine clonazepam (110) suggested a GABAergic component. However,the suitability of benzo- One open label study (124) aimed to evaluate the clinical diazepines for long-term treatment of a chronic condition response to venlafaxine in SP in 12 patients who were nonre- such as social anxiety disorder has been questioned. In addi- sponders to SSRIs,and to assess how the response could be tion,the benzodiazepines are ineffective against comorbid influenced by Axis II comorbidity with avoidant personality depression. The duration of the study was 15 weeks using an open flexible-dosing regimen in individuals with or without concomitant APD. Venlafaxine improved SP RIMAs (Reversible Inhibitor of and/or APD symptomatology,as demonstrated by decreas- Monoamine Oxidase A) ing LSAS total scores. Similar favorable open-labeled results Although phenelzine demonstrated efficacy,the need for have been reported for nefazodone (125,126). Placebo-con- dietary restrictions severely limited its use.

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