An overview of the efficacy and safety of ß2-adrenoceptor antagonists for the treatment of chronic obstructive pulmonary disease.

INTRODUCTION: The safety of ß2-AR antagonists in the treatment of patients with COPD continues to be a topic of research and discussion within the medical community. Emerging evidence suggests potentially benefits in the management of this complex respiratory condition. However, antagonists that display a preference for ß2-AR over ß1-AR present a complex therapeutic challenge in COPD management, necessitating an understanding of differences in their pharmacological profiles and clinical implications. AREAS COVERED: An overview of the mechanisms of action of ß2-AR antagonists and their potential impact on respiratory function, their pharmacological interactions, clinical implications, and future perspectives in COPD. EXPERT OPINION: ß-Blockers have the potential to become a versatile class of therapeutic agents with benefits beyond their original cardiovascular use. However, the one-size-fits-all approach of prescribing ß-blockers regardless of their receptor selectivity to COPD patients with concomitant heart disease may not be appropriate. Instead, it is advisable to develop an individualized treatment strategy based on a thorough assessment of the patient's overall health. The use of non selective ß2-AR antagonists, functioning as inverse agonists at ß2-ARs, has garnered interest and debate, but further research efforts should focus on elucidating the optimal use of ß-AR antagonists in COPD, balancing cardiovascular benefits with potential respiratory risks to enhance outcomes and quality of life for individuals living with this debilitating respiratory condition.

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

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

Over-expression of microRNA-145 drives alterations in ß-adrenergic signaling and attenuates cardiac remodeling in heart failure post myocardial infarction.

BACKGROUND: Numerous studies have highlighted the crucial role of microRNA-145 (miR-145) in coronary atherosclerosis and myocardial ischemia reperfusion injury. However, effects of miR-145 on ß-adrenergic signaling and cardiac remodeling in heart failure (HF) remains unclarified. METHODS AND RESULTS: We established HF model in rats with left anterior descending coronary artery (LAD) occlusion. Four weeks after LAD ligation, rats showed substantial aggravation of cardiac dilation and electrophysiological instability. Up-regulation of miR-145 ameliorated HF-induced myocardial fibrosis and prolonged action potential duration. Echocardiography revealed increased basal contractility and decreased left ventricular inner-diameter in miR-145 over-expressed heart, while cardiac response to ß-adrenergic receptor (ßAR) stimulation was reduced. Furthermore, miR-145 increased L-type calcium current (ICa) density while decreased ICa response to ß-adrenergic stimulation with isoproterenol. The alterations in ßAR signaling might be predominant due to miR-145-mediated activation of Akt/CREB cascades. At high frequency pacing, Ca2+ transient, cell shortening and frequency of Ca2+ waves were significantly improved in AD-miR-145 group. Western blotting revealed that increased expression of Cav1.2, Ca2+-ATPase, ß2AR, GNAI3 and decreased level of CaMKII might be attributed to the cardioprotective effects of miR-145. CONCLUSION: miR-145 effectively alleviates HF-related cardiac remodeling by improving cardiac dilation, fibrosis, intracellular Ca2+ mishandling and electrophysiological instability.

La prescripción con visado de la triple terapia en combinación a dosis fija en España / Controlled Prescription of Triple Fixed-Dose Combination Therapy in Spain

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What drives inhaler prescription for asthma patients? Results from a real-life retrospective analysis.

BACKGROUND: The choice of inhaler device for asthma patients depends upon multiple attributes. We investigated factors that may drive general practitioners (GPs) and respiratory specialists in the prescription of inhaler devices for asthma patients who initiated inhalation therapy. METHODS: We retrospectively analysed prescriptions by GPs and respiratory specialists to asthma patients commencing inhaled corticosteroid/long-acting ß2-agonist combination therapy available as both pressurised metered-dose inhalers (pMDIs) and dry powder inhalers (DPIs). Patient characteristics were compared by device and multivariate analysis was used to model the likelihood of receiving a pMDI as opposed to a DPI in order to identify drivers for prescription. A sample of the respiratory specialists completed an ad-hoc survey of their perceived success in achieving asthma control in their patients and barriers to attaining full control. RESULTS: Prescription of a particular inhaler device was unrelated to the characteristics of the patients. Multivariate analysis revealed that the main driver for the choice of inhaler device was the medication (Odds Ratio and 95% Confidence Interval, respectively for GPs and specialists: 0.19 [0.16-0.23]; 0.17 [0.08-0.37]). Specialists perceived asthma as being inadequately controlled in 41% of their patients, and considered patients' difficulties in using DPIs and pMDIs as instrumental in this, citing a need for a novel, more effective inhaler technology. CONCLUSION: Physicians choose inhaler devices according to the prescribed drugs and not to the characteristics of the individual patient. This may reflect a lack of confidence in existing inhaler devices and underlines the need for technologies, which are more reliable and easier to use by patients.

Postnatal ß2 adrenergic treatment improves insulin sensitivity in lambs with IUGR but not persistent defects in pancreatic islets or skeletal muscle.

KEY POINTS: Previous studies in fetuses with intrauterine growth restriction (IUGR) have shown that adrenergic dysregulation was associated with low insulin concentrations and greater insulin sensitivity. Although whole-body glucose clearance is normal, 1-month-old lambs with IUGR at birth have higher rates of hindlimb glucose uptake, which may compensate for myocyte deficiencies in glucose oxidation. Impaired glucose-stimulated insulin secretion in IUGR lambs is due to lower intra-islet insulin availability and not from glucose sensing. We investigated adrenergic receptor (ADR) ß2 desensitization by administering oral ADRß modifiers for the first month after birth to activate ADRß2 and antagonize ADRß1/3. In IUGR lambs ADRß2 activation increased whole-body glucose utilization rates and insulin sensitivity but had no effect on isolated islet or myocyte deficiencies. IUGR establishes risk for developing diabetes. In IUGR lambs we identified disparities in key aspects of glucose-stimulated insulin secretion and insulin-stimulated glucose oxidation, providing new insights into potential mechanisms for this risk. ABSTRACT: Placental insufficiency causes intrauterine growth restriction (IUGR) and disturbances in glucose homeostasis with associated ß adrenergic receptor (ADRß) desensitization. Our objectives were to measure insulin-sensitive glucose metabolism in neonatal lambs with IUGR and to determine whether daily treatment with ADRß2 agonist and ADRß1/ß3 antagonists for 1 month normalizes their glucose metabolism. Growth, glucose-stimulated insulin secretion (GSIS) and glucose utilization rates (GURs) were measured in control lambs, IUGR lambs and IUGR lambs treated with adrenergic receptor modifiers: clenbuterol atenolol and SR59230A (IUGR-AR). In IUGR lambs, islet insulin content and GSIS were less than in controls; however, insulin sensitivity and whole-body GUR were not different from controls. Of importance, ADRß2 stimulation with ß1/ß3 inhibition increases both insulin sensitivity and whole-body glucose utilization in IUGR lambs. In IUGR and IUGR-AR lambs, hindlimb GURs were greater but fractional glucose oxidation rates and ex vivo skeletal muscle glucose oxidation rates were lower than controls. Glucose transporter 4 (GLUT4) was lower in IUGR and IUGR-AR skeletal muscle than in controls but GLUT1 was greater in IUGR-AR. ADRß2, insulin receptor, glycogen content and citrate synthase activity were similar among groups. In IUGR and IUGR-AR lambs heart rates were greater, which was independent of cardiac ADRß1 activation. We conclude that targeted ADRß2 stimulation improved whole-body insulin sensitivity but minimally affected defects in GSIS and skeletal muscle glucose oxidation. We show that risk factors for developing diabetes are independent of postnatal catch-up growth in IUGR lambs as early as 1 month of age and are inherent to the islets and myocytes.

ß-adrenergic modulation of discrimination learning and memory in the auditory cortex.

Despite vast literature on catecholaminergic neuromodulation of auditory cortex functioning in general, knowledge about its role for long-term memory formation is scarce. Our previous pharmacological studies on cortex-dependent frequency-modulated tone-sweep discrimination learning of Mongolian gerbils showed that auditory-cortical D1/5 -dopamine receptor activity facilitates memory consolidation and anterograde memory formation. Considering overlapping functions of D1/5 -dopamine receptors and ß-adrenoceptors, we hypothesised a role of ß-adrenergic signalling in the auditory cortex for sweep discrimination learning and memory. Supporting this hypothesis, the ß1/2 -adrenoceptor antagonist propranolol bilaterally applied to the gerbil auditory cortex after task acquisition prevented the discrimination increment that was normally monitored 1 day later. The increment in the total number of hurdle crossings performed in response to the sweeps per se was normal. Propranolol infusion after the seventh training session suppressed the previously established sweep discrimination. The suppressive effect required antagonist injection in a narrow post-session time window. When applied to the auditory cortex 1 day before initial conditioning, ß1 -adrenoceptor-antagonising and ß1 -adrenoceptor-stimulating agents retarded and facilitated, respectively, sweep discrimination learning, whereas ß2 -selective drugs were ineffective. In contrast, single-sweep detection learning was normal after propranolol infusion. By immunohistochemistry, ß1 - and ß2 -adrenoceptors were identified on the neuropil and somata of pyramidal and non-pyramidal neurons of the gerbil auditory cortex. The present findings suggest that ß-adrenergic signalling in the auditory cortex has task-related importance for discrimination learning of complex sounds: as previously shown for D1/5 -dopamine receptor signalling, ß-adrenoceptor activity supports long-term memory consolidation and reconsolidation; additionally, tonic input through ß1 -adrenoceptors may control mechanisms permissive for memory acquisition.

Methylglyoxal Impairs ß2-Adrenoceptor-Mediated Vasodilatory Mechanisms in Rat Retinal Arterioles.

Methylglyoxal, a highly reactive dicarbonyl compound, is formed as a by-product of glycolysis and plays an important role in the pathogenesis of diabetic complications, including diabetic retinopathy. However, it remains to be determined how methylglyoxal affects the regulatory mechanisms of retinal blood flow. In this study, we examined the effects of methylglyoxal on ß2-adrenoceptor-mediated vasodilatory mechanisms in rat retinal arterioles. The retinal vasodilator responses were assessed by measuring the diameter of retinal arterioles in the fundus images. Intravitreal injection of methylglyoxal significantly diminished the vasodilation of retinal arterioles induced by the ß2-adrenoceptor agonist salbutamol. The vasodilator effect of BMS-191011, a large-conductance Ca2+-activated K+ (BKCa) channel opener, on retinal arterioles was also attenuated by methylglyoxal. In contrast, methylglyoxal had no significant effect on retinal vasodilator response to forskolin. Methylglyoxal attenuated retinal vasodilator response to salbutamol under blockade of BKCa channels with iberiotoxin, an inhibitor of the channels. These results suggest that methylglyoxal attenuates ß2-adrenoceptor-mediated retinal vasodilation by impairing the coupling of the ß2-adrenoceptor to the guanine nucleotide-binding protein (Gs protein) and the function of the BKCa channel. Increased methylglyoxal in the eyes may contribute to the impairment of regulatory mechanisms of retinal blood flow in patients with diabetic retinopathy.

Cardiovascular outcomes with an inhaled beta2-agonist/corticosteroid in patients with COPD at high cardiovascular risk.

OBJECTIVES: Cardiovascular disease (CVD) and chronic obstructive pulmonary disease (COPD) often coexist. We assessed the effect of inhaled COPD treatments on CVD outcomes and safety in patients with COPD and at heightened CVD risk. METHODS: The SUMMIT (Study to Understand Mortality and MorbidITy) was a multicentre, randomised, double-blind, placebo-controlled, event-driven trial in 16 485 patients with moderate COPD who had or were at high risk of CVD. Here, we assessed the prespecified secondary endpoint of time to first on-treatment composite CVD event (CVD death, myocardial infarction, stroke, unstable angina or transient ischaemic attack (TIA)) by Cox regression and by clinician-reported CVD adverse events across the four groups: once-daily inhaled placebo (n=4111), long-acting beta2-agonist (vilanterol (VI) 25 µg; n=4118), corticosteroid (fluticasone furoate (FF) 100 µg; n=4135) and combination therapy (FF/VI; n=4121). RESULTS: Participants were predominantly middle-aged (mean 65 (SD 8) years) men (75%) with overt CVD (66%). The composite CVD endpoint occurred in 688 patients (first event: sudden death (35%), acute coronary syndrome (37%) and stroke or TIA (23%), and was not reduced in any treatment group versus placebo: VI (HR 0.99, 95% CI 0.80 to 1.22), FF (HR 0.90, 95% CI 0.72 to 1.11) and their combination (HR 0.93, 95% CI 0.75 to 1.14). Outcomes were similar among all subgroups. Adverse events, including palpitations and arrhythmias, did not differ by treatment. CONCLUSIONS: In patients with COPD with moderate airflow limitation and heightened CVD risk, treatment with inhaled VI, FF or their combination has an excellent safety profile and does not impact CVD outcomes. TRIAL REGISTRATION NUMBER: NCT01313676.

Combination of glycopyrronium and indacaterol inhibits carbachol-induced ERK5 signal in fibrotic processes.

BACKGROUND: Airway fibrosis is one of the pathological features of chronic obstructive pulmonary disease (COPD), and recent studies revealed that acetylcholine plays an important role in the development of airway remodeling by stimulating proliferation and collagen synthesis of lung fibroblasts. This study was designed to examine the effects of a long-acting muscarinic receptor antagonist (LAMA) glycopyrronium and a long-acting ß2 adrenergic receptor agonist (LABA) indacaterol on acetylcholine-mediated fibrotic responses in lung fibroblasts. METHODS: After carbachol (CCh) or transforming growth factor-ß1 (TGF-ß1) exposure, the response to glycopyrronium and indacaterol was determined in vitro in fibroblasts isolated from mild-to-moderate COPD lung tissue. The ability of fibroblasts to mediate the contraction of collagen gels was assessed. The expression of α-smooth muscle actin (α-SMA) and the phosphorylation of extracellular-signal-regulated kinase 5 (ERK5) were determined by immunoblot. TGF-ß1 was quantified by ELISA and acetylcholine was quantified by liquid chromatography tandem-mass spectrometry. RESULTS: CCh stimulated fibroblast-mediated collagen gel contraction and α-SMA expression and TGF-ß1 release by fibroblasts. Blockade of autocrine TGF-ß1 attenuated CCh-mediated fibrotic responses, while TGF-ß1 did not stimulate acetylcholine release. Glycopyrronium plus indacaterol significantly attenuated CCh- and TGF-ß1-mediated fibrotic responses through inhibition of ERK5 phosphorylation. Notably, the magnitudes of CCh- and TGF-ß1-stimulated gel contraction, CCh-induced TGF-ß1 release, and ERK5 phosphorylation were greater in fibroblasts isolated from COPD subjects than in those from non-smokers. CONCLUSIONS: CCh induced TGF-ß1 self-sustaining signaling loops by potentiating ERK5 signaling and promoted myofibroblast activity. This autocrine signaling mechanism may be an attractive therapeutic target to block the fibrotic response, which was modulated by the combination of glycopyrronium and indacaterol.

Zero-order metoprolol pharmacokinetics after therapeutic doses: severe toxicity and cardiogenic shock.

OBJECTIVE: Acute beta-blocker overdose can cause severe cardiac dysfunction. Chronic toxicity is rare but potentially severe. We report therapeutic dosing of metoprolol resulting in unusual pharmacokinetics and toxicity, given high-dose insulin therapy for treatment. CASE DETAILS: A 90-year-old female presented with hypotension, tachycardia and severe cardiac dysfunction after commencing a rapidly increasing metoprolol dose of 250 mg split daily. She was admitted to intensive care and given high-dose insulin therapy (10 U/kg/h), noradrenaline, adrenaline and dobutamine for severe cardiac dysfunction (cardiac index, 0.76 L/min/m2). She developed acute renal failure, ischaemic hepatitis and disseminated intravascular coagulopathy. Inotropes and high-dose insulin were weaned over four days with complete recovery. Metoprolol was quantified with liquid chromatography-tandem mass spectrometry and concentration-time data were analysed using MONOLIX® vs 4.3 ( www.lixoft.com ). Admission metoprolol concentration was 2.39 µg/mL (therapeutic reference range: 0.035-0.5 µg/mL). Data best fitted a one compartmental model with Michaelis-Menten kinetics and zero order elimination at high concentrations. Final parameter estimates were V, 63.4 L, maximum rate [Vm], 9.57 mg h-1, Michaelis constant [Km], 1.97 mg L-1. Predicted elimination half-life decreased from 20 h over time until there was first order elimination with a half-life 9 h. CONCLUSION: The time course of cardiac dysfunction was longer than acute overdose but consistent with prolonged zero order elimination of metoprolol, suggesting the patient was a poor CYP2D6 metaboliser. High-dose insulin euglycaemia appeared to be effective in combination with vasoconstrictors/inotropes.

Effect of formoterol, a long-acting ß2-adrenergic agonist, on muscle strength and power output, metabolism, and fatigue during maximal sprinting in men.

The aim was to investigate the effect of the long-acting ß2-adrenergic agonist formoterol on muscle strength and power output, muscle metabolism, and phosphorylation of CaMKII Thr(287) and FXYD1 during maximal sprinting. In a double-blind crossover study, 13 males [V̇o2 max: 45.0 ± 0.2 (means ± SE) ml·min(-1)·kg(-1)] performed a 30-s cycle ergometer sprint after inhalation of either 54 µg of formoterol (FOR) or placebo (PLA). Before and after the sprint, muscle biopsies were collected from vastus lateralis and maximal voluntary contraction (MVC), and contractile properties of quadriceps were measured. Oxygen uptake was measured during the sprint. During the sprint, peak power, mean power, and end power were 4.6 ± 0.8, 3.9 ± 1.1, and 9.5 ± 3.2% higher (P < 0.05) in FOR than in PLA, respectively. Net rates of glycogenolysis and glycolysis were 45.7 ± 21.0 and 28.5 ± 13.4% higher (P < 0.05) in FOR than in PLA, respectively, and the decrease in ATP content was lower (P < 0.05) in FOR than in PLA (3.7 ± 1.5 vs. 8.0 ± 1.6 mmol/kg dry weight). There was no difference in breakdown of phosphocreatine and oxygen uptake between treatments. Before and after the sprint, MVC and peak twitch force were higher (P < 0.05) in FOR than in PLA. No differences were observed in phosphorylation of CaMKII Thr(287) and FXYD1 between treatments before the sprint, whereas phosphorylation of CaMKII Thr(287) and FXYD1 was greater (P < 0.05) in FOR than in PLA after the sprint. In conclusion, formoterol-induced enhancement in power output during maximal sprinting is associated with increased rates of glycogenolysis and glycolysis that may counteract development of fatigue.

Dissociation of ß1- and ß2-adrenergic receptor subtypes in the retrieval of cocaine-associated memory.

Drug seeking is maintained by encounters with drug-associated cues, and disrupting retrieval of these drug-cue associations would reduce the risk of relapse. Retrieval of cocaine-associated memories is dependent on ß-adrenergic receptor (ß-AR) activation, and blockade of these receptors induces a persistent retrieval deficit. Whether retrieval of cocaine-associated memory is mediated by a specific ß-AR subtype, however, remains unclear. Using a cocaine conditioned place preference (CPP) procedure, we examined whether retrieval of a cocaine CPP memory is mediated collectively by ß1- and ß2-ARs, or by one of these ß-AR subtypes alone. We show that co-blockade of ß1- and ß2-ARs abolished CPP expression on that and subsequent drug-free CPP tests, resulting in a long-lasting retrieval deficit that prevented subsequent cocaine-induced reinstatement. To dissociate the necessity of either ß1- or ß2-ARs alone, we administered subtype-specific antagonists prior to retrieval. Administration of a ß1-AR antagonist before the initial CPP trial dose-dependently reduced expression of a CPP on that and subsequent drug-free trials as compared to vehicle administration. In contrast, administration of a ß2-AR antagonist had no effect on initial CPP expression, although the highest dose reduced subsequent CPP expression. Importantly, either ß1- or ß2-AR blockade prior to an initial retrieval trial prevented subsequent cocaine-induced reinstatement. Our findings indicate that the ß1-AR subtype mediates retrieval of a cocaine CPP, and that acutely blocking either ß1- or ß2-ARs can prevent subsequent cocaine-induced reinstatement. Thus, ß-AR antagonists, particularly ß1-ARs antagonists, could serve as adjuncts for addiction therapies to prevent retrieval of drug-associated memories and provide protection against relapse.

ß2-Adrenergic receptor-dependent attenuation of hypoxic pulmonary vasoconstriction prevents progression of pulmonary arterial hypertension in intermittent hypoxic rats.

In sleep apnea syndrome (SAS), intermittent hypoxia (IH) induces repeated episodes of hypoxic pulmonary vasoconstriction (HPV) during sleep, which presumably contribute to pulmonary arterial hypertension (PAH). However, the prevalence of PAH was low and severity is mostly mild in SAS patients, and mild or no right ventricular hypertrophy (RVH) was reported in IH-exposed animals. The question then arises as to why PAH is not a universal finding in SAS if repeated hypoxia of sufficient duration causes cycling HPV. In the present study, rats underwent IH at a rate of 3 min cycles of 4-21% O2 for 8 h/d for 6 w. Assessment of diameter changes in small pulmonary arteries in response to acute hypoxia and drugs were performed using synchrotron radiation microangiography on anesthetized rats. In IH-rats, neither PAH nor RVH was observed and HPV was strongly reversed. Nadolol (a hydrophilic ß(1, 2)-blocker) augmented the attenuated HPV to almost the same level as that in N-rats, but atenolol (a hydrophilic ß1-blocker) had no effect on the HPV in IH. These ß-blockers had almost no effect on the HPV in N-rats. Chronic administration of nadolol during 6 weeks of IH exposure induced PAH and RVH in IH-rats, but did not in N-rats. Meanwhile, atenolol had no effect on morphometric and hemodynamic changes in N and IH-rats. Protein expression of the ß1-adrenergic receptor (AR) was down-regulated while that of ß2AR was preserved in pulmonary arteries of IH-rats. Phosphorylation of p85 (chief component of phosphoinositide 3-kinase (PI3K)), protein kinase B (Akt), and endothelial nitric oxide synthase (eNOS) were abrogated by chronic administration of nadolol in the lung tissue of IH-rats. We conclude that IH-derived activation of ß2AR in the pulmonary arteries attenuates the HPV, thereby preventing progression of IH-induced PAH. This protective effect may depend on the ß2AR-Gi mediated PI3K/Akt/eNOS signaling pathway.

Administration of a selective ß2 adrenergic receptor antagonist exacerbates neuropathology and cognitive deficits in a mouse model of Alzheimer's disease.

Currently, there are no available approaches to cure or slow down the progression of Alzheimer's disease (AD), which is characterized by the accumulation of extracellular amyloid-ß (Aß) deposits and intraneuronal tangles that comprised hyperphosphorylated tau. The ß2 adrenergic receptors (ß2ARs) are expressed throughout the cortex and hippocampus and play a key role in cognitive functions. Alterations in the function of these receptors have been linked to AD; however, these data remain controversial as apparent contradicting reports have been published. Given the current demographics of growing elderly population and the high likelihood of concurrent ß-blocker use for other chronic conditions, more studies into the role of this receptor in AD animal models are needed. Here, we show that administration of ICI 118,551 (ICI), a selective ß2AR antagonist, exacerbates cognitive deficits in a mouse model of AD, the 3xTg-AD mice. Neuropathologically, ICI increased Aß levels and Aß plaque burden. Concomitantly, ICI-treated 3xTg-AD mice showed an increase in tau phosphorylation and accumulation. Mechanistically, these changes were linked to an increase in amyloidogenic amyloid precursor protein processing. These results suggest that under the conditions used here, selective pharmacologic inhibition of ß2ARs has detrimental effects on AD-like pathology in mice. Overall, these studies strengthen the notion that the link between ß2ARs and AD is likely highly complex and suggest caution in generalizing the beneficial effects of ß blockers on AD.

[Novel drugs for COPD treatment]. / Neue Pharmaka zur Behandlung der chronisch-obstruktiven Lungenerkrankung (COPD).

Currently, numerous new compounds and inhaler types are reaching the market for the treatment of chronic obstructive pulmonary disease (COPD). They comprise new long-acting beta-2 agonists, muscarinic antagonists and inhaled corticosteroids. Most of them are for combination treatment in new fixed-dose inhalers. Even the combination of three components in one inhaler is under development. Thus, management of COPD are getting more differentiated but also much more complex. This review gives an overview of the state of art of pharmaceutical research in this area and offers a glimpse into the proximate future.

Noradrenergic ß-receptor antagonism within the central nucleus of the amygdala or bed nucleus of the stria terminalis attenuates the negative/anxiogenic effects of cocaine.

Cocaine has been shown to produce both initial rewarding and delayed anxiogenic effects. Although the neurobiology of cocaine's rewarding effects has been well studied, the mechanisms underlying its anxiogenic effects remain unclear. We used two behavioral assays to study these opposing actions of cocaine: a runway self-administration test and a modified place conditioning test. In the runway, the positive and negative effects of cocaine are reflected in the frequency of approach-avoidance conflict that animals develop about entering a goal box associated with cocaine delivery. In the place conditioning test, animals develop preferences for environments paired with the immediate/rewarding effects of cocaine, but avoid environments paired with the drug's delayed/anxiogenic actions. In the present study, these two behavioral assays were used to examine the role of norepinephrine (NE) transmission within the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST), each of which has been implicated in drug-withdrawal-induced anxiety and stress-induced response reinstatement. Rats experienced 15 single daily cocaine-reinforced (1.0 mg/kg, i.v.) runway trials 10 min after intracranial injection of the ß1 and ß2 NE receptor antagonists betaxolol and ICI 118551 or vehicle into the CeA or BNST. NE antagonism of either region dose dependently reduced approach-avoidance conflict behavior compared with that observed in vehicle-treated controls. In addition, NE antagonism selectively interfered with the expression of conditioned place aversions while leaving intact cocaine-induced place preferences. These data suggest a role for NE signaling within the BNST and the CeA in the anxiogenic actions of cocaine.