Y. Hamil. Kean University.
Interest- peptide secretion from the anterior and intermediate lobes ingly purchase ketoconazole cream 15 gm on line topical antibiotics for acne in pregnancy,the putative antagonists for CRF receptors 15 gm ketoconazole cream otc antibiotics for pcos acne,D- of the pituitary order ketoconazole cream 15gm on line antibiotics ointment for acne. PheCRF(12-41) and -helical CRF(9-41) exhibited ap- Receptor autoradiography and binding studies in discrete proximately equal affinity for the two receptor subtypes areas of rat and primate CNS demonstrate that,in general, either in inhibiting [125I]sauvagine binding or inhibiting the highest concentration of CRF binding sites are distrib- sauvagine-stimulated cAMP production (34). These data uted in brain regions involved in cognitive function (cere- clearly indicated that although distinct pharmacologic dif- bral cortex),limbic areas involved in emotion and stress ferences exist between the two receptor subtypes of the same responses (amygdala,nucleus accumbens,and hippocam- family (in terms of their rank order profile),they still must pus),brainstem regions regulating autonomic function share some structural similarities. Further study is required (locus ceruleus and nucleus of the solitary tract),and olfac- to determine the precise common structural features of these tory bulb. In addition,there is a high density of CRF1 two family members. Although there is as yet no direct red pulp and marginal zones. The localization of [125I]oCRF evidence,this modulation of the binding of [125I]sauvagine binding sites in mouse spleen to regions known to have to the human CRF2 receptor by guanine nucleotides sug- a high concentration of macrophages suggests that CRF gests that this receptor exists in two affinity states for ago- receptors are present on resident splenic macrophages. The nists coupled through a guanine nucleotide binding protein absence of specific [125I]oCRF-binding sites in the periarter- to its second messenger system. Unfortunately to date,the iole and peripheral follicular white pulp regions of the spleen only ligands available for the biochemical study of these suggests that neither T nor B lymphocytes have specific receptors have been agonists,making it very difficult to high-affinity CRF receptors comparable to those localized examine the proportions and affinities of high- and low- in the marginal zone and red pulp areas of the spleen or in affinity states of these receptors. CRF2 receptors has allowed a detailed examination of the The high affinity of the nonmammalian CRF analogues regional and cellular distribution of CRF receptor subtype for this subtype has raised the possibility that other endoge- mRNA expression utilizing both RNAse protection assays nous mammalian ligands exist that have high affinity and and in situ hybridization histochemistry. A comparison of selectivity for this receptor subtype. As described,the recent the distribution of CRF1 and CRF2 mRNA and receptor discovery of urocortin (36),although not selective for the protein defined by ligand autoradiography is demonstrated CRF2 subtype,has provided the first evidence for one such in adjacent horizontal sections of rat brain (Fig. With the increase in the complexity of the CRF that of the CRF1 and exhibits a distinct subcortical pattern. For example, the lateral septum,by virtue of widespread reciprocal con- nections throughout the brain,is implicated in a variety of physiologic processes. These range from higher cognitive functions such as learning and memory to autonomic regu- lation,including food and water intake (38). In addition, the septum plays a central role in classical limbic circuitry and thus is important in a variety of emotional conditions, including fear and aggression. Thus,the lack of CRF1 recep- tor expression in these nuclei suggests that CRF2 receptors may solely mediate the postsynaptic actions of CRF inputs to this region and strongly suggests a role for CRF2 receptors in modulating limbic circuitry at the level of septal activity. In addition,the selective expression of CRF2 receptor mRNA within hypothalamic nuclei indicates that the anxio- genic and anorexic actions of CRF in these nuclei may likely be CRF2 receptor-mediated. In contrast,within the pitui- tary,there is a predominance of CRF1 receptor expression with little or no CRF2 expression in either the intermediate and anterior lobes,indicating that it is the CRF1 receptor that is primarily responsible for CRF regulation of the HPA axis. In addition to the differences in distribution between the CRF1 and CRF2 receptor subtypes,there exists a distinct pattern of distribution between the CRF2 isoforms (CRF2 and CRF2 ) as well. The CRF2 isoform is primarily ex- pressed within the CNS,whereas the CRF2 form is found both centrally and peripherally. Digitized, color-coded images of CRF1 (Panel A) and CRF form is the predominant one,whereas the CRF CRF (Panel B) receptor mRNA expression and receptor autoradi- 2 2 2 ography in adjacent horizontal sections of rat brain. The highest form is localized primarily to non-neuronal structures,the levels of mRNA expression are coded in red, whereas the lowest choroid plexus of the ventricular system,and cerebral arteri- concentrations are coded in blue. The identification of the CRF form in cere- of receptors labeled with either [125I]oCRF (CRF only; Panel C)or 2 1 [125I]sauvagine (CRF and CRF ; Panel D) are coded in red. There bral arterioles suggests a mechanism through which CRF 1 2 was a good correspondence between the message for a particular may directly modulate cerebral blood flow. Peripherally,the receptor subtype and its protein localization; the pharmacologic highest detectable levels of mRNA were found in heart and selectivity was retained for the two radioligands. Taken together, the results of these studies demonstrating a distinct heterogeneous distribution pattern of CRF receptor subtypes in brain and peripheral tissues, strongly suggest that these receptor subtypes subserve very erally corresponded to the previously reported distribution specific physiological roles in CRF related function both of [125I]oCRF binding sites (Fig. Using the radioligand [125I]sauvagine described, Receptors CRF2 receptors could be localized to areas of high CRF2 Radioligand binding studies have demonstrated that CRF message. In addition,because [125I]sauvagine has equal af- receptors in the brain-endocrine-immune axis are coupled finity for both receptor subtypes (34),the autoradiography to a guanine nucleotide regulatory protein. In all of these revealed the localization of both the CRF1 and CRF2 recep- tissues,the primary second messenger system involved in tor subtypes,demonstrating the utility of this novel radioli- transducing the actions of CRF is stimulation of cAMP Chapter 7: Corticotropin-Releasing Factor 99 production (29,31–33,40). CRF initiates a cascade of enzy- cDNA and Amino Acid Sequences matic reactions in the pituitary gland beginning with the The CRF-BP was first isolated and purified to near homoge- receptor-mediated stimulation of adenylate cyclase,which neity for sequencing and generation of oligonucleotide ultimately regulates POMC-peptide secretion and possibly probes (47). Screening a human liver cDNA library using synthesis. POMC-derived peptide secretion mediated by the probes generated from the original amino acid sequence activation of adenylate cyclase in the anterior and neuroin- revealed a full-length cDNA containing a 1. Similarly in the brain and putative N-linked glycosylation site was found at amino spleen,the pharmacologic rank order profile of CRF-related acid 203,which agrees with the previous observation of the peptides for stimulation of adenylate cyclase is analogous presence of asparagine-linked sugar moieties on the native to the profile seen in pituitary and in keeping with the protein (49). Subsequent screening of a rat cerebral cortical affinities of these compounds for receptor binding. In addi- cDNA library,revealed the presence of a single clone con- tion,the putative CRF receptor antagonist -hel ovine taining a 1. The transduction mechanisms may be involved in the actions of pharmacology of these proteins appears to be similar with CRF. For example,CRF has been shown to increase protein both the rat and human binding proteins having high affin- carboxyl methylation,and phospholipid methylation in ity for the rat/human CRF (Kd 0. Preliminary evidence suggests that CRF affinity for the ovine form of CRF (Kd 250 nM). Al- may regulate cellular responses through products of arachi- though there may be some similarities in the binding do- donic acid metabolism (42). Furthermore,although the evi- mains of the binding protein and the CRF receptor (as dence in anterior pituitary cells suggests that CRF does not evidenced by the equal affinity of r/hCRF),these are distinct directly regulate phosphatidylinositol turnover or protein proteins,each with unique characteristics and distributions. Thus, the effects of CRF on anterior pituitary cells and possibly Although the human and rat forms of the CRF-BP are ho- in neurons and other cell types expressing CRF receptors mologous (as indicated),there is a somewhat different ana- are likely to involve complex interactions among several in- tomic distribution pattern in the two species. Peripheral expres- sion of the binding protein may have its greatest utility in CRF and Its Binding Protein in Human the modulation and control of the elevated levels of CRF Plasma in circulating plasma induced by various normal physiologic Under normal conditions,the plasma levels of CRF remain conditions (see the preceding). In addition,expression of low; however,CRF levels are markedly elevated in plasma this binding protein in the brain and pituitary offers addi- during the late gestational stages of pregnancy (43–45). The tional mechanisms by which CRF-related neuronal or neu- source of the pregnancy-associated CRF is most likely the roendocrine actions may be modulated. The CRF in brain regions including neocortex,hippocampus (primarily the maternal plasma is bioactive in releasing ACTH from in the dentate gyrus),and olfactory bulb. In spite of the high levels of brain,mRNA is localized to the amygdaloid complex with CRF in the maternal plasma,there is no evidence of mark- a distinct lack of immunostained cells in the medial nucleus. A plausible explanation for this paradoxic the brainstem particularly in the auditory,vestibular,and situation could be the presence of a binding protein in the trigeminal systems,raphe nuclei of the midbrain and pons, plasma of pregnant women that could specifically inhibit and reticular formation (50). In addition,high expression the biological actions of CRF (44,45). This hypothesis was levels of binding protein mRNA are seen in the anterior validated by the isolation of a CRF-binding protein (CRF- pituitary,predominantly restricted to the corticotrope cells.
Modu- tion facilitates acetylcholine release in rat frontal cortex order ketoconazole cream 15gm line virus treatment. Neu- lation of phencyclidine-induced changes in locomotor activity roreport 1994;5:1230–1232 order ketoconazole cream 15 gm mastercard bacteria organelle. A critical role for antagonist- than dopamine agonist-induced hyperactivity in D1 receptors in the 5-HT1A-mediated facilitation of in vivo mice 15 gm ketoconazole cream otc treatment for demodex dogs. Increase of in the core and shell of the nucleus accumbens. Eur Neuropsycho- cortical acetylcholine release after systemic administration of pharmacol 1996;6:29–38. Systemic and striatal dopamine release elicited in vivo by dorsal raphe chlorophenylpiperazine increases acetylcholine release from rat nucleus electrical stimulation. J Neurochem 1999;73(3): hippocampus-implication of 5-HT2C receptors. Curr tor blockade increases cortical DA release via of 5-HT1A recep- Opin Neurobiol 1997;7:243–254. A pharmacological analysis of serotonergic induced cortical dopamine release. J Neurochem 2001;76: receptors: effect of their activation of blockade in learning. DOI, a 5-HT2a/2c receptor agonist, three 5-HT receptor antagonists on the performance of rats in potentiates amphetamine-induced dopamine release in rat stria- attentional and working memory tasks. Differential modula- serotonin enhances the release of dopamine in the striatum only tion of the 5-HT4 receptor agonist on rat learning and memory. Rodent data and general effects on a delayed conditional task in the rat: involvement of hypothesis: antipsychotic action exerted through 5-HT2A re- the 5-HT receptor in working memory. J Psychopharmacol 1A ceptor antagonism is dependent on increased serotonergic tone. J Clin Psychopharmacol 2000;20: action of hallucinogenic and antipsychotic drugs in pyramidal 386–388. Serotonin model of schizophrenia: adrenoceptor antagonism in the anti-cataleptic properties of the emerging role of glutamate mechanisms. Brain Res Rev 2000; atypical neuroleptic agent, clozapine, in the rat. The current status of the dopamine hypothesis of 117. Acute effects of typical and atypical pharmacol 1996;11:201–207. Treatment of cortex, nucleus accumbens, and striatum of the rat: an in vivo neuroleptic-induced akathisia with the 5-HT2 antagonist mi- microdialysis study. Effects of serotonergic cortex and nucleus accumbens. J Pharmacol Exp Ther 1999; agents on the up-regulation of dopamine D2 receptors induced 288:774–781. Chapter 58: Mechanism of Action of Atypical Antipsychotic Drugs 831 120. Opposite on extracellular serotonin levels in rat medial prefrontal cortex role of central 5-HT2a and 5-HT2c receptors subtypes in the and nucleus accumbens. Serotonin receptors in the in the rat frontal cortex: role of 2-adrenoceptor antagonism. Autoradiographic mapping of serotonin-2 Neuropsychopharmacology 1997;17:44–55. Serotonin (5-HT)2C recep- coordinated movement induced by D2 receptor blockade does tors tonically inhibit dopamine (DA) and noradrenaline (NA), not depend upon antagonism of 2 adrenoceptors. Naunyn but not 5-HT, release in the frontal cortex in vivo. Serotonin and dopamine pine and its effect on plasma homovanillic acid and norepineph- receptor affinities predict atypical antipsychotic drug (AAD) rine concentrations in schizophrenia. Idazoxan and response potentiate apomorphine-induced locomotor activity in rats by to typical neuroleptics in treatment-resistant schizophrenia. Comparison with the atypical neuroleptic, clozapine. The (2) antagonist ida- col Biochem Behav 1990;26:901–906. Effects of pindolol on the L-5-HTP- in patients with dementia of frontal type. Psychopharmacology induced increase in plasma prolactin and cortisol concentrations 1996;123:239–249. Direct injections of 5-HT2a receptor specific (2)-adrenoceptor antagonist, atipamezole, on cogni- agonists into the medial prefrontal cortex produces a head- tive performance and brain neurochemistry in aged Fisher 344 twitch response in rats. Antipsychotic-like properties of the 5-HT1a agonist ergic receptor polymorphisms on schizophrenia and antipsy- 8-OH-DPAT in the rat. Enhanced cortical do- bined treatment with raclopride and 8-OH-DPAT in the rat: enhancement of antipsychotic-like effects without catalepsy. J pamine output and antipsychotic-like effects of raclopride by Neural Transm 1991;83:43–53. Idazoxan preferentially onists in a two-way active avoidance procedure in rats: interac- increases dopamine output in the rat medial prefrontal cortex tions with 8-OH-DPAT, ritanserin, and prazosin. Antagonism by 8-OH-DPAT, but not ritans- drugs induce similar effects on the release of dopamine and erin, of catalepsy induced by SCH 23390 in the rat. J Neural noradrenaline in the medial prefrontal cortex of the rat brain. Noradrenergic influ- dorsal, raphe 5-HT autoreceptors by the local application of ences on prefrontal cortical cognitive function: opposing actions 1a 8-OH-DPAT reverses raclopride-induced catalepsy in the rat. Noradrenergic mecha- a 5-HT receptor agonist, inhibits amphetamine-induced sero- nisms in the prefrontal cortex. J Psychopharmacol 1997;11: 1a tonin and dopamine release in rat striatum and nucleus accum- 163–168. Clozapine for the treatment-resistant schizo- release in prefrontal cortex by 5-HT1a receptor activation. Eur phrenic: a double-blind comparison with chlorpromazine. Improvement in cogni- 100135, an antagonist of 5-HT1A serotonin receptors, atten- tive functions and psychiatric symptoms in treatment-refractory uates psychotomimetic effects of MK-801. The reduction of suicidality during levels in the nucleus accumbens by a dopamine receptor-inde- clozapine treatment in neuroleptic-resistant schizophrenia: im- pendent mechanism. WEINBERGER MARC LARUELLE Over the last 15 years, the ability to measure specific mole- This chapter also critically summarizes results obtained cules and proteins in the living human brain underwent using neurochemical imaging techniques in schizophrenia enormous developments, opening direct windows into neu- research, and the various insights on the pathophysiology rotransmitter functions and cellular processes associated and treatment of schizophrenia gained by these results. These techniques are based either first consider PET and SPECT investigations, and then on the injection of radioactive moieties whose distribution MRS studies. Although lacking the level of resolution of postmortem The principles of PET and SPECT neurochemical imaging studies and limited by the relatively small number of targets are reviewed elsewhere in this volume.
Pulmonary venous isolation versus additional substrate modification as treatment for paroxysmal atrial fibrillation order generic ketoconazole cream on line antibiotic list drugs. Biphasic energy selection for transthoracic cardioversion of atrial fibrillation order 15 gm ketoconazole cream with visa antibiotic eye ointment. Does intensity of rate control influence outcome in persistent atrial fibrillation? The effect of rate control on quality of life in patients with permanent atrial fibrillation: data from the RACE II (Rate Control Efficacy in Permanent Atrial Fibrillation II) study order ketoconazole cream overnight virus 66. Impact of rate versus rhythm control on quality of life in patients with persistent atrial fibrillation. Sinus rhythm is associated with fewer heart failure symptoms: insights from the AFFIRM trial. Effect of rate or rhythm control on quality of life in persistent atrial fibrillation. Results from the Rate Control Versus Electrical Cardioversion (RACE) Study. Determinants of sudden cardiac death in patients with persistent atrial fibrillation in the rate control versus electrical cardioversion (RACE) study. Effect of rate and rhythm control on left ventricular function and cardiac dimensions in patients with persistent atrial fibrillation: results from the RAte Control versus Electrical Cardioversion for Persistent Atrial Fibrillation (RACE) study. Changes in atrial fibrillation cycle length and inducibility during catheter ablation and their relation to outcome. Conversion of atrial fibrillation to sinus rhythm during treatment with intravenous esmolol or diltiazem: a prospective, randomized comparison. Verapamil versus digoxin and acute versus routine serial cardioversion for the improvement of rhythm control for persistent atrial fibrillation. Techniques, evaluation, and consequences of linear block at the left atrial roof in paroxysmal atrial fibrillation: a prospective randomized study. Effects of a high dose intravenous bolus amiodarone in patients with atrial fibrillation and a rapid ventricular rate. Rhythm or rate control in atrial fibrillation-- Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial. The effect of digitalis or a beta-blocker, alone or in combination, on atrial fibrillation at rest and during exercise. Catheter ablation versus antiarrhythmic drugs for atrial fibrillation: the A4 study. Quality of life in atrial fibrillation: the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. A randomized study of combining maze surgery for atrial fibrillation with mitral valve surgery. Initial energy for elective external cardioversion of persistent atrial fibrillation. A prospective, randomized controlled trial comparing the efficacy and safety of sotalol, amiodarone, and digoxin for the reversion of new-onset atrial fibrillation. Conversion efficacy of intravenous ibutilide compared with intravenous amiodarone in patients with recent-onset atrial fibrillation and atrial flutter. Comparative effects of carvedilol and amiodarone on conversion and recurrence rates of persistent atrial fibrillation. Freedom from atrial tachyarrhythmias after catheter ablation of atrial fibrillation: a randomized comparison between 2 current ablation strategies. Katritsis DG, Ellenbogen KA, Panagiotakos DB, et al. Ablation of superior pulmonary veins compared to ablation of all four pulmonary veins. Comparison of effectiveness of carvedilol versus bisoprolol for maintenance of sinus rhythm after cardioversion of persistent atrial fibrillation. Monophasic versus biphasic waveform shocks for atrial fibrillation cardioversion in patients with concomitant amiodarone therapy. Pulmonary-vein isolation for atrial fibrillation in patients with heart failure. Carvedilol alone or in combination with digoxin for the management of atrial fibrillation in patients with heart failure?. Saline-irrigated, cooled-tip radiofrequency ablation is an effective technique to perform the maze procedure. Biphasic versus monophasic cardioversion in shock-resistant atrial fibrillation. A randomized controlled trial of the efficacy and safety of electroanatomic circumferential pulmonary vein ablation supplemented by ablation of complex fractionated atrial electrograms versus potential-guided pulmonary vein antrum isolation guided by intracardiac ultrasound. Role of residual potentials inside circumferential pulmonary veins ablation lines in the recurrence of paroxysmal atrial fibrillation. Anterior-posterior versus anterior-lateral electrode positions for external cardioversion of atrial fibrillation: a randomised trial. A trial of self-adhesive patch electrodes and hand-held paddle electrodes for external cardioversion of atrial fibrillation (MOBIPAPA). Cardiac rate normalization in chronic atrial fibrillation: comparison of long-term efficacy of treatment with amiodarone versus AV node ablation and permanent His-bundle pacing. Epicardial microwave ablation of permanent atrial fibrillation during a coronary bypass and/or aortic valve operation: Prospective, randomised, controlled, mono-centric study. Sotalol versus propafenone for long-term maintenance of normal sinus rhythm in patients with recurrent symptomatic atrial fibrillation. C-7 Kochiadakis GE, Igoumenidis NE, Hamilos MI, et al. Long-term maintenance of normal sinus rhythm in patients with current symptomatic atrial fibrillation: amiodarone vs propafenone, both in low doses. Low dose amiodarone and sotalol in the treatment of recurrent, symptomatic atrial fibrillation: a comparative, placebo controlled study. Sotalol vs metoprolol for ventricular rate control in patients with chronic atrial fibrillation who have undergone digitalization: a single-blinded crossover study. Amiodarone, sotalol, or propafenone in atrial fibrillation: which is preferred to maintain normal sinus rhythm?. Korantzopoulos P, Kolettis TM, Papathanasiou A, et al. Propafenone added to ibutilide increases conversion rates of persistent atrial fibrillation. Krittayaphong R, Raungrattanaamporn O, Bhuripanyo K, et al. A randomized clinical trial of the efficacy of radiofrequency catheter ablation and amiodarone in the treatment of symptomatic atrial fibrillation. A short-term, randomized, double-blind, parallel-group study to evaluate the efficacy and safety of dronedarone versus amiodarone in patients with persistent atrial fibrillation: the DIONYSOS study.