Synergistic anti-tumor effects of lenalidomide and gefitinib by upregulating ADRB2 and inactivating the mTOR/PI3K/AKT signaling pathway in lung adenocarcinoma.

Gefitinib is commonly used to be the first-line therapy for advanced non-small cell lung cancer (NSCLC). Therapeutic effect of gefitinib is reduced due to acquired resistance, and combined treatment is recommended. In this research, we planned to explore the impacts of combined treatment of lenalidomide and gefitinib on gefitinib-sensitive or -resistant NSCLC cells. The co-treatment results demonstrated that enhanced antitumor impact on NSCLC cell growth, migration, invasion, cell cycle process and apoptosis. The tumor-bearing mouse models were established using PC9/GR cells. In vivo assays also showed that lenalidomide and gefitinib synergistically inhibited mouse tumor growth along increased the survival of mice. ADRB2 was identified as a lowly expressed gene in PC9/GR cells and LUAD tumor tissues. LUAD patients with high ADRB2 expression were indicated with favorable survival outcomes. Moreover, ADRB2 was upregulated in lenalidomide and/or gefitinib-treated PC9/GR cells. ADRB2 deficiency partially offsets the suppressive impacts of lenalidomide and gefitinib co-treatment on the viability and proliferation of PC9/GR cells. Additionally, lenalidomide and gefitinib cotreatment significantly inactivated the mTOR/PI3K/AKT signaling pathway compared with each treatment alone. Rescue assays were performed to explore whether lenalidomide and gefitinib synergistically inhibited the growth of PC9/GR cells via the PI3K/AKT pathway. PI3K activator SC79 significantly restored reduced cell proliferation, migration and invasion along with elevated cell cycle arrest and apoptosis caused by lenalidomide and gefitinib cotreatment. In conclusion, lenalidomide and gefitinib synergistically suppressed LUAD progression and attenuated gefitinib resistance by upregulating ADRB2 and inactivating the mTOR/PI3K/AKT signaling pathway in lung adenocarcinoma.

Compromised trigemino-coerulean coupling in migraine sensitization can be prevented by blocking beta-receptors in the locus coeruleus.

BACKGROUND: Migraine is a disabling neurological disorder, characterized by recurrent headaches. During migraine attacks, individuals often experience sensory symptoms such as cutaneous allodynia which indicates the presence of central sensitization. This sensitization is prevented by oral administration of propranolol, a common first-line medication for migraine prophylaxis, that also normalized the activation of the locus coeruleus (LC), considered as the main origin of descending noradrenergic pain controls. We hypothesized that the basal modulation of trigeminal sensory processing by the locus coeruleus is shifted towards more facilitation in migraineurs and that prophylactic action of propranolol may be attributed to a direct action in LC through beta-adrenergic receptors. METHODS: We used simultaneous in vivo extracellular recordings from the trigeminocervical complex (TCC) and LC of male Sprague-Dawley rats to characterize the relationship between these two areas following repeated meningeal inflammatory soup infusions. Von Frey Hairs and air-puff were used to test periorbital mechanical allodynia. RNAscope and patch-clamp recordings allowed us to examine the action mechanism of propranolol. RESULTS: We found a strong synchronization between TCC and LC spontaneous activities, with a precession of the LC, suggesting the LC drives TCC excitability. Following repeated dural-evoked trigeminal activations, we observed a disruption in coupling of activity within LC and TCC. This suggested an involvement of the two regions' interactions in the development of sensitization. Furthermore, we showed the co-expression of alpha-2A and beta-2 adrenergic receptors within LC neurons. Finally propranolol microinjections into the LC prevented trigeminal sensitization by desynchronizing and decreasing LC neuronal activity. CONCLUSIONS: Altogether these results suggest that trigemino-coerulean coupling plays a pivotal role in migraine progression, and that propranolol's prophylactic effects involve, to some extent, the modulation of LC activity through beta-2 adrenergic receptors. This insight reveals new mechanistic aspects of LC control over sensory processing.

Advances in adrenergic receptors for the treatment of chronic obstructive pulmonary disease: 2023 update.

INTRODUCTION: Strong scientific evidence and large experience support the use of ß2-agonists for the symptomatic alleviation of COPD. Therefore, there is considerable effort in discovering highly potent and selective ß2-agonists. AREAS COVERED: Recent research on novel ß2-agonists for the treatment of COPD. A detailed literature search was performed in two major databases (PubMed/MEDLINE and Scopus) up to September 2023." EXPERT OPINION: Compounds that preferentially activate a Gs- or ß-arrestin-mediated signaling pathway via ß- adrenoceptors (ARs) are more innovative. Pepducins, which target the intracellular region of ß2-AR to modulate receptor signaling output, have the most interesting profile from a pharmacological point of view. They stabilize the conformation of the ß2-AR and influence its signaling by interacting with the intracellular receptor-G protein interface. New bifunctional drugs called muscarinic antagonist-ß2 agonist (MABA), which have both muscarinic receptor (mAChR) antagonism and ß2-agonist activity in the same molecule, are a new opportunity. However, all tested compounds have been shown to act predominantly as mAChR antagonists or ß2-agonists. An intriguing idea is to utilize allosteric modulators that bind to ß2-ARs at sites different than those bound by orthosteric ligands to augment or reduce the signaling transduced by the orthosteric ligand.

Cost-effectiveness of Arg16Gly in ADRB2 pharmacogenomic-guided treatment for pediatric asthma.

OBJECTIVES: To assess the cost-effectiveness of Arg16Gly ADRB2 pharmacogenomic testing compared with no Arg16Gly ADRB2 testing to guide the use of long-acting ß2 receptor agonist (LABA) in asthma patients aged 1 to 5 years in China. METHODS: This economic evaluation developed a Markov model with four health states (no exacerbation, mild exacerbation, moderate-to-severe exacerbation, and death). Transition probabilities were estimated from the rate of exacerbations, the case-fatality rate of patients hospitalized for exacerbations, and natural mortality. Costs included drug costs and exacerbation management costs. Cost inputs and utilities for each health state were gained from public databases and the literatures. Costs and quality-adjusted life years (QALYs) were estimated for ten years. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: In the base case analysis, in contrast to the group without the genotype test, the incremental total cost was -¥334.7, and the incremental QALY was 0.001 in the Arg16Gly ADRB2 genotyping group. Therefore, the Arg16Gly ADRB2 test group was the dominant strategy for children with asthma in China. The sensitivity analyses showed that the model was relatively stable. CONCLUSION: Arg16Gly ADRB2 testing before using LABA is a cost-effective approach compared with no gene testing for pediatric asthma.

10-Gingerol Enhances the Effect of Taxol in Triple-Negative Breast Cancer via Targeting ADRB2 Signaling.

Purpose: Although paclitaxel is widely used in cancer treatment, severe side effects and drug resistance limit its clinical use. 10-gingerol (10-G) is a natural compound isolated from ginger, which displays anti-inflammatory, antioxidant, and antiproliferative properties. However, the chemotherapy-sensitization effect of 10-G on triple-negative breast cancer (TNBC) has not been fully clarified. This study is aimed at investigating the effect of 10-G on the paclitaxel sensitivity in TNBC, and its underlying mechanism. Methods: The study was determined through in vitro and in vivo experiments. Cell viability and proliferation were detected by cell counting kit 8 (CCK-8) and colony formation. To detect cell apoptosis, flow cytometry and TUNEL were used. The expression of proteins was detected by Western blotting and immunohistochemistry. The molecular docking and gene knockout were corroborated by interactions between 10-G and adrenoceptor Beta 2 (ADRB2). The body weight of mice, histopathology and organs (kidney and spleen) coefficients were used to monitor the drug toxicities. Results: In vitro, 10-G increased the sensitivity of TNBC cells to paclitaxel, and could synergistically promote the apoptosis of TNBC cells induced by paclitaxel. In combination with molecular docking and lentivirus knockdown studies, ADRB2 was identified as a 10-G binding protein. 10-G inhibited ADRB2 by binding to the active site of ADRB2. Knockdown of ADRB2 reduces the proliferation activity of TNBC cells but also attenuates the sensitizing effects of 10-G to paclitaxel. Western blotting and immunohistochemistry showed that 10-G played an anti-proliferation and chemotherapy-sensitizing role by inhibiting the ADRB2/ERK signal. Toxicity evaluation showed that 10-G would not increase hepatorenal toxicity with paclitaxel. Conclusion: This data suggests that 10-G may be used as a new chemotherapeutic synergist in combination with paclitaxel to enhance anticancer activity. The potential value of ADRB2 as a target for improving chemotherapy sensitivity was also emphasized.

Clinical course of COPD in patients with Arg16Gly (rs1042713) polymorphism of ADRB2 gene.

The ADBR2 gene has been studied for its possible relationship with the development and clinical course of chronic obstructive pulmonary disease (COPD), including response to beta-2 agonists, with existing data being contentious on the subject. So, the purpose of this study was to look into the potential impact of the arginine-16-glycine (Arg16Gly) polymorphism on the clinical course and drug utilization in COPD patients. Data show that patients with Arg16Arg have a lower number of hospital admissions for exacerbations (p=0.048), but only in the total number of exacerbations, including those treated out-patients (p=0.086). Each glycine (Gly) copy was associated with a higher number of exacerbations (OR: 0.25; 95% CI: 0.00-055; p=0.048). The number of exacerbations after LABA/LAMA treatment was similar across groups, indicating that all ADRB2 variants responded well to the treatment. Furthermore, there were no statistically significant differences in mMRC and CAT values across all study visits. Interestingly, groups differed in their use of antibiotics (AB) at all visits, with Arg16Arg being associated with the least amount of AB use. There was also a link discovered between clycine copies and increased use of glucocorticoids. As a result, Arg16Gly is involved in the clinical course of COPD as well as the utilization of drug groups. Based on the findings, we can speculate that the cross-talk between the ADRB2 gene and the corticosteroid receptor is altered in patients with the Gly16Gly genotype.

Antidiabetics, Anthelmintics, Statins, and Beta-Blockers as Co-Adjuvant Drugs in Cancer Therapy.

Over the last years, repurposed agents have provided growing evidence of fast implementation in oncology treatment such as certain antimalarial, anthelmintic, antibiotics, anti-inflammatory, antihypertensive, antihyperlipidemic, antidiabetic agents. In this study, the four agents of choice were present in our patients' daily treatment for nonmalignant-associated pathology and have known, light toxicity profiles. It is quite common for a given patient's daily administration schedule to include two or three of these drugs for the duration of their treatment. We chose to review the latest literature concerning metformin, employed as a first-line treatment for type 2 diabetes; mebendazole, as an anthelmintic; atorvastatin, as a cholesterol-lowering drug; propranolol, used in cardiovascular diseases as a nonspecific inhibitor of beta-1 and beta-2 adrenergic receptors. At the same time, certain key action mechanisms make them feasible antitumor agents such as for mitochondrial ETC inhibition, activation of the enzyme adenosine monophosphate-activated protein kinase, amelioration of endogenous hyperinsulinemia, inhibition of selective tyrosine kinases (i.e., VEGFR2, TNIK, and BRAF), and mevalonate pathway inhibition. Despite the abundance of results from in vitro and in vivo studies, the only solid data from randomized clinical trials confirm metformin-related oncological benefits for only a small subset of nondiabetic patients with HER2-positive breast cancer and early-stage colorectal cancer. At the same time, clinical studies confirm metformin-related detrimental/lack of an effect for lung, breast, prostate cancer, and glioblastoma. For atorvastatin we see a clinical oncological benefit in patients and head and neck cancer, with a trend towards radioprotection of critical structures, thus supporting the role of atorvastatin as a promising agent for concomitant association with radiotherapy. Propranolol-related increased outcomes were seen in clinical studies in patients with melanoma, breast cancer, and sarcoma.

Association between beta-2 adrenergic receptor variants and clinical outcomes in children and adolescents with acute asthma.

OBJECTIVE: To investigate whether different genotypes of p.Arg16Gly, p.Gln27Glu, p.Arg19Cys and p.Thr164Ile variants interfere in response to treatment in children and adolescents with moderate to severe acute asthma. METHODS: This sample comprised patients aged 2 to 17 years with a history of at least two wheezing episodes and current moderate to severe asthma exacerbation. All patients received multiple doses of albuterol and ipratropium bromide delivered via pressurized metered-dose inhaler with holding chamber and systemic corticosteroids. Hospital admission was defined as the primary outcome. Secondary outcomes were changes in forced expiratory volume in the first second after 1 hour of treatment, and for outpatients, length of stay in the emergency room. Variants were genotyped by sequencing. RESULTS: A total of 60 patients were evaluated. Hospital admission rates were significantly higher in carriers of the genotype AA relative to those with genotype AG or GG, within the p.Arg16Gly variant (p=0.03, test χ2, alpha=0.05). Secondary outcomes did not differ between genotypes. CONCLUSION: Hospital admission rates were significantly higher among carriers of the genotype AA within the p.Arg16Gly variant. Trial registration: ClinicalTrials.gov: NCT01323010.

Association between beta-2 adrenergic receptor variants and clinical outcomes in children and adolescents with acute asthma

ABSTRACT Objective To investigate whether different genotypes of p.Arg16Gly, p.Gln27Glu, p.Arg19Cys and p.Thr164Ile variants interfere in response to treatment in children and adolescents with moderate to severe acute asthma. Methods This sample comprised patients aged 2 to 17 years with a history of at least two wheezing episodes and current moderate to severe asthma exacerbation. All patients received multiple doses of albuterol and ipratropium bromide delivered via pressurized metered-dose inhaler with holding chamber and systemic corticosteroids. Hospital admission was defined as the primary outcome. Secondary outcomes were changes in forced expiratory volume in the first second after 1 hour of treatment, and for outpatients, length of stay in the emergency room. Variants were genotyped by sequencing. Results A total of 60 patients were evaluated. Hospital admission rates were significantly higher in carriers of the genotype AA relative to those with genotype AG or GG, within the p.Arg16Gly variant (p=0.03, test χ2, alpha=0.05). Secondary outcomes did not differ between genotypes. Conclusion Hospital admission rates were significantly higher among carriers of the genotype AA within the p.Arg16Gly variant. Trial registration: ClinicalTrials.gov: NCT01323010

Effects of Inhaled Corticosteroid/Long-Acting ß2-Agonist Combination on the Airway Microbiome of Patients with Chronic Obstructive Pulmonary Disease: A Randomized Controlled Clinical Trial (DISARM).

Rationale: Inhaled corticosteroids (ICS) are commonly prescribed with long-acting ß2-agonists (LABA) in chronic obstructive pulmonary disease (COPD). To date, the effects of ICS therapy on the airway microbiome in COPD are unknown. Objectives: To determine the effects of ICS/LABA on the airway microbiome of patients with COPD. Methods: Clinically stable patients with COPD were enrolled into a 4-week run-in period during which ICS was discontinued and all participants were placed on formoterol (Form) 12 µg twice daily (BID). The participants were then randomized to budesonide/formoterol (Bud + Form; 400/12 µg BID), fluticasone/salmeterol (Flu + Salm; 250/50 µg BID), or formoterol only (12 µg BID) for 12 weeks. Participants underwent bronchoscopy before and after the 12-week treatment period. The primary endpoint was the comparison of changes in the airway microbiome over the trial period between the ICS/LABA and LABA-only groups. Measurements and Main Results: Sixty-three participants underwent randomization: Bud + Form (n = 20), Flu + Salm (n = 22), and Form (n = 21) groups; 56 subjects completed all visits. After the treatment period, changes in α-diversity were significantly different across groups, especially between Flu + Salm and Form groups (Δrichness: P = 0.02; ΔShannon index: P = 0.03). Longitudinal differential abundance analyses revealed more pronounced microbial shifts from baseline in the fluticasone (vs. budesonide or formoterol only) group. Conclusions: Fluticasone-based ICS/LABA therapy modifies the airway microbiome in COPD, leading to a relative reduction in α-diversity and a greater number of bacterial taxa changes. These data may have implications in patients who develop pneumonia on ICS. Clinical trial registered with www.clinicaltrials.gov (NCT02833480).

A Systematic Review of Inverse Agonism at Adrenoceptor Subtypes.

As many, if not most, ligands at G protein-coupled receptor antagonists are inverse agonists, we systematically reviewed inverse agonism at the nine adrenoceptor subtypes. Except for ß3-adrenoceptors, inverse agonism has been reported for each of the adrenoceptor subtypes, most often for ß2-adrenoceptors, including endogenously expressed receptors in human tissues. As with other receptors, the detection and degree of inverse agonism depend on the cells and tissues under investigation, i.e., they are greatest when the model has a high intrinsic tone/constitutive activity for the response being studied. Accordingly, they may differ between parts of a tissue, for instance, atria vs. ventricles of the heart, and within a cell type, between cellular responses. The basal tone of endogenously expressed receptors is often low, leading to less consistent detection and a lesser extent of observed inverse agonism. Extent inverse agonism depends on specific molecular properties of a compound, but inverse agonism appears to be more common in certain chemical classes. While inverse agonism is a fascinating facet in attempts to mechanistically understand observed drug effects, we are skeptical whether an a priori definition of the extent of inverse agonism in the target product profile of a developmental candidate is a meaningful option in drug discovery and development.

Alveolar liquid clearance in lung injury: Evaluation of the impairment of the ß2-adrenergic agonist response in an ischemia-reperfusion lung injury model.

While alveolar liquid clearance (ALC) mediated by the ß2-adrenergic receptor (ß2-AR) plays an important role in lung edema resolution in certain models of lung injury, in more severe lung injury models, this response might disappear. Indeed, we have shown that in an ischemia-reperfusion-induced lung injury model, ß2-agonists do not enhance ALC. The objective of this study was to determine if downregulation of the ß2-AR could explain the lack of response to ß2-agonists in this lung injury model. In an in vivo canine model of lung transplantation, we observed no change in ß2-AR concentration or affinity in the injured transplanted lungs compared to the native lungs. Furthermore, we could not enhance ALC in transplanted lungs with dcAMP + aminophylline, a treatment that bypasses the ß2-adrenergic receptor and is known to stimulate ALC in normal lungs. However, transplantation decreased αENaC expression in the lungs by 50%. We conclude that the lack of response to ß2-agonists in ischemia-reperfusion-induced lung injury is not associated with significant downregulation of the ß2-adrenergic receptors but is attributable to decreased expression of the ENaC channel, which is essential for sodium transport and alveolar liquid clearance in the lung.

TPI 1020, a novel anti-inflammatory, nitric oxide donating compound, potentiates the bronchodilator effects of salbutamol in conscious guinea-pigs.

Inhaled corticosteroids are regularly co-administered with beta(2)-adrenoceptor agonists. This study evaluates in conscious guinea-pigs the bronchodilator effect, alone or combined with salbutamol, of TPI 1020, a novel anti-inflammatory corticosteroid and nitric oxide (NO) donor derived from budesonide. Guinea-pigs received inhaled histamine (3 mM) and specific airway conductance (sG(aw)) measured. Responses to histamine were measured before and on the next day 15 min after a 15 min inhalation of vehicle, salbutamol, TPI 1020, budesonide, the NO-donor, S-nitroso-N-acetylpenicillamine (SNAP), or combinations of these drugs. Salbutamol and TPI 1020 caused concentration-dependent bronchodilatation measured as inhibition of histamine-induced bronchoconstriction. TPI 1020-induced bronchodilatation was blocked by the guanylyl cyclise inhibitor, ODQ, indicating cGMP-dependence through released NO. While salbutamol at 80 microM did not exert significant bronchodilatation, significant inhibitions were observed when co-administered with TPI 1020, 0.11 and 0.33 mM. The combined effects of TPI 1020 and salbutamol lasted significantly longer than either drug alone. Inhaled budesonide was a weak bronchodilator and when co-administered with salbutamol there was enhanced bronchodilatation. Addition of the NO-donor, SNAP (0.1 mM), to the budesonide/salbutamol combination, also improved the inhibition of histamine-induced bronchoconstriction. This study has shown that TPI 1020 potentiates the bronchodilator activity of salbutamol, and their combination lasted longer than either drug administered individually. Both the corticosteroid and NO-releasing activities of TPI 1020 appear to be required for the potentiation of salbutamol. Combination of TPI 1020 with a beta(2)-adrenoceptor agonist may therefore be useful against acute bronchoconstriction episodes in asthma, and may offer an opportunity for reducing doses of inhaled beta(2)-adrenoceptor agonists.

Responses to inhaled long-acting beta-agonist and corticosteroid according to COPD subtype.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is a complex and heterogeneous disorder in which a number of different pathological processes lead to recognition of patient subgroups that may have individual characteristics and distinct responses to treatment. OBJECTIVES: We tested the hypothesis that responses of lung function to 3 months of combined inhalation of long-acting beta-agonist and corticosteroid might differ among patients with various COPD subtypes. METHODS: We classified 165 COPD patients into four subtypes according to the severity of emphysema and airflow obstruction: emphysema-dominant, obstruction-dominant, mild-mixed, and severe-mixed. The emphysema-dominant subtype was defined by an emphysema index on computed tomography of more than 20% and FEV(1) more than 45% of the predicted value. The obstruction-dominant subtype had an emphysema index < or = 20% and FEV(1) < or = 45%, the mild-mixed subtype had an emphysema index < or = 20% and FEV(1) > 45%, and the severe-mixed subtype had an emphysema index > 20% and FEV(1) < or = 45%. Patients were recruited prospectively and treated with 3 months of combined inhalation of long-acting beta-agonist and corticosteroid. RESULTS: After 3 months of combined inhalation of long-acting beta-agonist and corticosteroid, obstruction-dominant subtype patients showed a greater FEV(1) increase and more marked dyspnea improvement than did the emphysema-dominant subgroup. The mixed-subtype patients (both subgroups) also showed significant improvement in FEV(1) compared with the emphysema-dominant subgroup. Emphysema-dominant subtype patients showed no improvement in FEV(1) or dyspnea after the 3-month treatment period. CONCLUSION: The responses to 3 months of combined inhalation of long-acting beta-agonist and corticosteroid differed according to COPD subtype.

Combined therapy of pentastarch, dexamethasone, and dibutyryl-cAMP or beta 2-agonist attenuates ischaemia/reperfusion injury of rat lung.

We hypothesised that combined therapy with macromolecules that seal endothelial damage [pentastarch (Penta)], an anti-inflammatory agent [dexamethasone (Dex)], and an agent that reabsorbs alveolar fluid [beta(2)-agonist or dibutyryl-cAMP (Bt(2)-cAMP)] would have additive ameliorating effects on ischaemia/reperfusion (I/R) injury of the lung. We perfused one of the following solutions into isolated rat lungs in a closed circulating system, either prior to I/R injury (groups 1-5) or following 60 min of ischaemia (groups 6-10): (1) 0.9% normal saline (NS), (2) Penta, (3) Penta+Dex, (4) Penta+Bt(2)-cAMP, (5) Penta+beta(2)-agonist inhalation, (6) Penta+Dex, (7) Penta+Bt(2)-cAMP, (8) Penta+beta(2)-agonist inhalation, (9) Penta+Dex+Bt(2)-cAMP, or (10) Penta+Dex+beta(2)-agonist inhalation. Haemodynamics, lung weight gain (LWG), capillary filtration coefficient (K(fc)), cytokine mRNA levels, and lung pathology were assessed. Results showed that Dex, Bt(2)-cAMP, or beta(2)-agonist as an additive to Penta decreased K(fc) and LWG below values seen with Penta alone. Furthermore, LWG and K(fc) values in groups with three protective agents were lower than those in groups with two protective agents. Significantly lower levels of TNF-alpha and IL-1 mRNAs were observed in groups treated with Dex. Histopathological studies showed decreased injury profiles for all combined therapy groups. We conclude that the addition of Dex, Bt(2)-cAMP, or beta(2)-adrenergic agonist to Penta solution promoted attenuation of I/R injury. Furthermore, combination therapy with three protective agents (Penta+Dex+beta(2)-adrenergic agonist) caused the greatest attenuation of I/R.

Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline from the American College of Physicians.

RECOMMENDATION 1: In patients with respiratory symptoms, particularly dyspnea, spirometry should be performed to diagnose airflow obstruction. Spirometry should not be used to screen for airflow obstruction in asymptomatic individuals. (Grade: strong recommendation, moderate-quality evidence.) RECOMMENDATION 2: Treatment for stable chronic obstructive pulmonary disease (COPD) should be reserved for patients who have respiratory symptoms and FEV1 less than 60% predicted, as documented by spirometry. (Grade: strong recommendation, moderate-quality evidence.) RECOMMENDATION 3: Clinicians should prescribe 1 of the following maintenance monotherapies for symptomatic patients with COPD and FEV1 less than 60% predicted: long-acting inhaled beta-agonists, long-acting inhaled anticholinergics, or inhaled corticosteroids. (Grade: strong recommendation, high-quality evidence.) RECOMMENDATION 4: Clinicians may consider combination inhaled therapies for symptomatic patients with COPD and FEV1 less than 60% predicted. (Grade: weak recommendation, moderate-quality evidence.) RECOMMENDATION 5: Clinicians should prescribe oxygen therapy in patients with COPD and resting hypoxemia (Pao2 < or =55 mm Hg). (Grade: strong recommendation, moderate-quality evidence.) RECOMMENDATION 6: Clinicians should consider prescribing pulmonary rehabilitation in symptomatic individuals with COPD who have an FEV1 less than 50% predicted. (Grade: weak recommendation, moderate-quality evidence.).

Management of stable chronic obstructive pulmonary disease: a systematic review for a clinical practice guideline.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common and disabling condition in adults. Information about therapeutic effectiveness and adverse effects of common treatment options and how clinical and spirometric characteristics affect outcomes is not well known but is important for clinicians caring for patients with stable COPD. PURPOSE: To evaluate the effectiveness of COPD management strategies. DATA SOURCES: English-language publications in MEDLINE and the Cochrane Library through March 2007. STUDY SELECTION: Randomized, controlled trials (RCTs) and previous systematic reviews of inhaled therapies, pulmonary rehabilitation, disease management, and supplemental oxygen in adults with COPD. DATA EXTRACTION: Participant, study, and intervention characteristics; exacerbations; deaths; respiratory health status; exercise capacity; hospitalizations; and adverse effects. DATA SYNTHESIS: Eight meta-analyses and 42 RCTs examined inhaled therapies: short-acting anticholinergics (n = 7), long-acting anticholinergics (n = 10), long-acting beta2-agonists (n = 22), corticosteroids (n = 14), dual D2 dopamine receptor-beta2-agonist (n = 3), or short-acting beta2-agonist plus ipratropium (n = 3). Evidence for nonpharmacologic therapies included 3 reviews of 39 RCTs plus 6 additional RCTs of pulmonary rehabilitation, 2 reviews of 13 RCTs plus 2 additional RCTs of disease management, and 8 RCTs of oxygen. Overall, long-acting inhaled therapies, used alone or in combination, reduced exacerbations more than placebo by 13% to 25% and had similar effectiveness to each other. Average improvements in health status scores were less than what is considered to be clinically noticeable. Inhaled monotherapy did not reduce mortality rates. Inhaled corticosteroids plus long-acting beta2-agonists reduced deaths in relative terms compared with placebo (relative risk, 0.82 [95% CI, 0.69 to 0.98]) and inhaled corticosteroids alone (relative risk, 0.79 [CI, 0.67 to 0.94]) but not compared with long-acting beta2-agonists alone (relative risk, 0.82 [CI, 0.52 to 1.28]). Absolute reductions were 1% or less and were not statistically significant. Pulmonary rehabilitation improved health status and dyspnea but not walking distance. Neither disease management nor ambulatory oxygen improved measured outcomes. Supplemental oxygen reduced mortality rates among symptomatic patients with resting hypoxia (relative risk, 0.61 [CI, 0.46 to 0.82]). Insufficient evidence supports using spirometry to guide therapy. LIMITATIONS: Articles were limited to those in the English language. Treatment adherence, adverse effects, and effectiveness may differ among clinical settings. Short-acting inhalers for "rescue therapy" were not evaluated. CONCLUSION: Long-acting inhaled therapies, supplemental oxygen, and pulmonary rehabilitation are beneficial in adults who have bothersome respiratory symptoms, especially dyspnea, and FEV1 less than 60% predicted.

[Eosinophil apoptosis and asthma]. / Apoptoza eozynofilów w astmie oskrzelowej.

Eosinophils play an important role in airway inflammation in asthma. Eosinophils are believed through the release of their mediators to develop the irreversible structural airway changes. Dysregulation of apoptosis can lead to pathological accumulation of eosinophils in bronchial tissue. Apoptosis (programmed cell death) leads to the characteristic morphologic changes including reduction of the cellular volume, blebbing of the membrane, condensation of the nuclear chromatin, DNA laddering, mitochondrial dysregulation and finally to apoptotic bodies. Apoptosis can be induced by oncogenes, specific ligands and some cytokines. On the other hand IL-5, IL-3 and GM-CSF (granulocyte-macrophage-colony stimulating factor) dramatically increase the life span of eosinophils. Glucocorticoids promote eosinophil apoptosis and totally reverse the delayed death cased by beta2-agonists.

Therapeutic responses in asthma and COPD. Corticosteroids.

The effects of inhaled corticosteroids (ICSs) in asthma include reduced severity of symptoms, improved pulmonary function, diminished bronchial hyperresponsiveness (BHR), prevention of exacerbations, and possible prevention of airway wall remodeling. Compared with an inhaled beta(2)-agonist, ICSs improve airway function and BHR, reduce bronchial-epithelium abnormalities, decrease bronchial inflammation, and reduce inflammatory-cell infiltration into the bronchial lamina propria; thus, they may prevent airway remodeling. In children, early use of ICSs may result in improved airway function over time. ICSs reduce use of prednisone, asthma medications, hospitalizations, and urgent-care visits. The primary side effects of ICSs in children are limited to transient reduction in growth. Compared with a leukotriene receptor antagonist (LTRA), ICSs produced a greater change from baseline in FEV(1) and greater reductions in symptoms. A long-acting beta(2)-agonist (LABA) combined with an ICS produced greater improvements than does therapy with ICSs even at higher doses. In COPD, the therapeutic value of ICSs is not as clear. While clinical trials in patients with mild COPD have not shown a reduction in decline in FEV(1) over time, other studies have shown that ICS therapy reduces exacerbations in patients with more severe COPD. Combination therapy with both ICS and LABA has recently been shown to be effective in COPD, where studies have documented additive improvement in FEV(1). Overall, the same therapeutic approaches show clinical effectiveness in both asthma and COPD. This supports the hypothesis that there are some similarities in these obstructive airway diseases. Future approaches should further define phenotypes, perhaps based in part on pharmacogenetic factors that will guide anti-inflammatory therapy in asthma and COPD.