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Respiratory Research Sep 2016Identifying patients at risk of exacerbations and managing them appropriately to reduce this risk represents an important clinical challenge. Numerous treatments have... (Review)
Review
Identifying patients at risk of exacerbations and managing them appropriately to reduce this risk represents an important clinical challenge. Numerous treatments have been assessed for the prevention of exacerbations and their efficacy may differ by patient phenotype. Given their centrality in the treatment of COPD, there is strong rationale for maximizing bronchodilation as an initial strategy to reduce exacerbation risk irrespective of patient phenotype. Therefore, in patients assessed as frequent exacerbators (>1 exacerbation/year) we propose initial bronchodilator treatment with a long-acting muscarinic antagonist (LAMA)/ long-acting β2-agonist (LABA). For those patients who continue to experience >1 exacerbation/year despite maximal bronchodilation, we advocate treating according to patient phenotype. Based on currently available data on adding inhaled corticosteroids (ICS) to a LABA, ICS might be added to a LABA/LAMA combination in exacerbating patients who have an asthma-COPD overlap syndrome or high blood eosinophil counts, while in exacerbators with chronic bronchitis, consideration should be given to treating with a phosphodiesterase (PDE)-4 inhibitor (roflumilast) or high-dose mucolytic agents. For those patients who experience frequent bacterial exacerbations and/or bronchiectasis, addition of mucolytic agents or a macrolide antibiotic (e.g. azithromycin) should be considered. In all patients at risk of exacerbations, pulmonary rehabilitation should be included as part of a comprehensive management plan.
Topics: Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Anti-Bacterial Agents; Bronchodilator Agents; Disease Progression; Drug Therapy, Combination; Expectorants; Humans; Lung; Mucociliary Clearance; Muscarinic Antagonists; Phenotype; Phosphodiesterase 4 Inhibitors; Pulmonary Disease, Chronic Obstructive; Time Factors; Treatment Outcome
PubMed: 27613392
DOI: 10.1186/s12931-016-0425-5 -
Molecular Neurobiology Nov 2022Impairments in mitochondrial physiology play a role in the progression of multiple neurodegenerative conditions, including peripheral neuropathy in diabetes. Blockade of...
Antagonism of the Muscarinic Acetylcholine Type 1 Receptor Enhances Mitochondrial Membrane Potential and Expression of Respiratory Chain Components via AMPK in Human Neuroblastoma SH-SY5Y Cells and Primary Neurons.
Impairments in mitochondrial physiology play a role in the progression of multiple neurodegenerative conditions, including peripheral neuropathy in diabetes. Blockade of muscarinic acetylcholine type 1 receptor (MR) with specific/selective antagonists prevented mitochondrial dysfunction and reversed nerve degeneration in in vitro and in vivo models of peripheral neuropathy. Specifically, in type 1 and type 2 models of diabetes, inhibition of MR using pirenzepine or muscarinic toxin 7 (MT7) induced AMP-activated protein kinase (AMPK) activity in dorsal root ganglia (DRG) and prevented sensory abnormalities and distal nerve fiber loss. The human neuroblastoma SH-SY5Y cell line has been extensively used as an in vitro model system to study mechanisms of neurodegeneration in DRG neurons and other neuronal sub-types. Here, we tested the hypothesis that pirenzepine or MT7 enhance AMPK activity and via this pathway augment mitochondrial function in SH-SY5Y cells. MR expression was confirmed by utilizing a fluorescent dye, ATTO590-labeled MT7, that exhibits great specificity for this receptor. MR antagonist treatment in SH-SY5Y culture increased AMPK phosphorylation and mitochondrial protein expression (OXPHOS). Mitochondrial membrane potential (MMP) was augmented in pirenzepine and MT7 treated cultured SH-SY5Y cells and DRG neurons. Compound C or AMPK-specific siRNA suppressed pirenzepine or MT7-induced elevation of OXPHOS expression and MMP. Moreover, muscarinic antagonists induced hyperpolarization by activating the M-current and, thus, suppressed neuronal excitability. These results reveal that negative regulation of this MR-dependent pathway could represent a potential therapeutic target to elevate AMPK activity, enhance mitochondrial function, suppress neuropathic pain, and enhance nerve repair in peripheral neuropathy.
Topics: AMP-Activated Protein Kinases; Acetylcholine; Electron Transport; Fluorescent Dyes; Humans; Membrane Potential, Mitochondrial; Mitochondrial Proteins; Muscarinic Antagonists; Neuroblastoma; Neurons; Peripheral Nervous System Diseases; Pirenzepine; RNA, Small Interfering; Receptors, Muscarinic
PubMed: 36002781
DOI: 10.1007/s12035-022-03003-1 -
The Journal of Allergy and Clinical... May 2024Findings from CAPTAIN (NCT02924688) suggest that treatment response to fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) differs according to baseline type 2... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Findings from CAPTAIN (NCT02924688) suggest that treatment response to fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) differs according to baseline type 2 inflammation markers in patients with moderate to severe asthma. Understanding how other patient physiologic and clinical characteristics affect response to inhaled therapies may guide physicians toward a personalized approach for asthma management.
OBJECTIVE
To investigate, using CAPTAIN data, the predictive value of key demographic and baseline physiologic variables in patients with asthma (lung function, bronchodilator reversibility, age, age at asthma onset) on response to addition of the long-acting muscarinic antagonist UMEC to inhaled corticosteroid/long-acting β-agonist combination FF/VI, or doubling the FF dose.
METHODS
Prespecified and post hoc analyses of CAPTAIN data were performed using categorical and continuous variables of key baseline characteristics to understand their influence on treatment outcomes (lung function [trough FEV], annualized rate of moderate/severe exacerbations, and asthma control [Asthma Control Questionnaire]) following addition of UMEC to FF/VI or doubling the FF dose in FF/VI or FF/UMEC/VI.
RESULTS
Adding UMEC to FF/VI led to greater improvements in trough FEV versus doubling the FF dose across all baseline characteristics assessed. Doubling the FF dose was generally associated with numerically greater reductions in the annualized rate of moderate/severe exacerbations compared with adding UMEC, independent of baseline characteristics. Adding UMEC and/or doubling the FF dose generally led to improvements in Asthma Control Questionnaire scores irrespective of baseline characteristics.
CONCLUSIONS
Unlike previous findings with type 2 biomarkers, lung function, bronchodilator reversibility, age and age at asthma onset do not appear to predict response to inhaled therapy.
Topics: Humans; Asthma; Male; Female; Adult; Middle Aged; Benzyl Alcohols; Quinuclidines; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Muscarinic Antagonists; Chlorobenzenes; Administration, Inhalation; Treatment Outcome; Drug Combinations; Androstadienes; Aged; Anti-Asthmatic Agents; Bronchodilator Agents; Young Adult
PubMed: 38309696
DOI: 10.1016/j.jaip.2024.01.039 -
Neuroscience Letters Jan 2023Acetylcholine signaling can strengthen associations between environmental cues and reward availability. Diverse subtypes (M1-M5) of the muscarinic acetylcholine receptor...
Acetylcholine signaling can strengthen associations between environmental cues and reward availability. Diverse subtypes (M1-M5) of the muscarinic acetylcholine receptor (mAChR) family may have distinct roles in different learning and memory processes, such as encoding cue-reward associations and consolidating these associations in long-term memory. Using an operant discrimination learning task in which mice are trained to nose poke during a tone to receive a food reward, we found that acquisition of the task requires mAChR signaling in the central nervous system. In addition, post-session injections of a broad mAChR antagonist, scopolamine impaired consolidation of the cue-reward memory. Further, after successful learning of a cue-reward contingency across multiple training sessions, mice that received a single pre-session injection of scopolamine were unable to use the learned cue association to receive rewards. Taken together, these data demonstrate distinct roles for muscarinic signaling in acquisition, consolidation and recall of the operant discrimination learning task. Understanding mechanisms underlying natural reward-related responding may provide insight into other maladaptive forms of reward learning such as addiction.
Topics: Mice; Animals; Muscarinic Antagonists; Discrimination Learning; Scopolamine; Learning; Memory; Receptors, Muscarinic; Reward; Conditioning, Operant
PubMed: 36529388
DOI: 10.1016/j.neulet.2022.137025 -
BMC Pulmonary Medicine Jan 2021In chronic obstructive pulmonary disease (COPD) patients, combination treatment with long-acting muscarinic antagonist (LAMA) and long-acting β2 agonist (LABA)... (Comparative Study)
Comparative Study Randomized Controlled Trial
A randomized controlled trial of long-acting muscarinic antagonist and long-acting β2 agonist fixed-dose combinations in patients with chronic obstructive pulmonary disease.
BACKGROUND
In chronic obstructive pulmonary disease (COPD) patients, combination treatment with long-acting muscarinic antagonist (LAMA) and long-acting β2 agonist (LABA) increases forced expiratory volume in one second and reduces symptoms compared to monotherapy. In Japan, three different once-daily fixed-dose combinations (FDCs) have been prescribed since 2015, although a direct comparison of these FDCs has never been performed. The objective of the present study was to compare the effectiveness, preference, and safety of three LAMA/LABA FDCs-glycopyrronium/indacaterol (Gly/Ind), umeclidinium/vilanterol (Ume/Vil), and tiotropium/olodaterol (Tio/Olo)-in patients with COPD.
METHODS
We enrolled 75 COPD outpatients (male:female ratio, 69:6; 77.4 ± 6.9 years). A prospective, randomized, crossover study was conducted on three groups using three FDCs: Gly/Ind; Ume/Vil; and Tio/Olo. Each medication was administered for 4 weeks before crossover (total 12 weeks). After each FDC administration, a respiratory function test and questionnaire survey were conducted. A comparative questionnaire survey of all three LAMA/LABA FDCs was conducted after 12 weeks (following administration of final FDC).
RESULTS
No significant differences in COPD Assessment Test or modified Medical Research Council dyspnea questionnaire were reported in the surveys completed after each FDC administration; no significant differences in spirometric items were observed. In the final comparative questionnaire survey, patients reported better actual feeling of being able to inhale following Gly/Ind administration compared with Tio/Olo, although no significant differences in adverse events or other evaluations were reported.
CONCLUSIONS
The three LAMA/LABA FDCs administered to COPD patients show similar effects and safety, although some minor individual preference was reported. Trial registration This study retrospectively registered with the University Hospital Medical Information Network Clinical Trials Registry (number UMIN000041342, registered on August 6, 2020).
Topics: Adrenergic beta-2 Receptor Agonists; Aged; Aged, 80 and over; Benzoxazines; Cross-Over Studies; Disease Progression; Drug Administration Schedule; Drug Combinations; Female; Forced Expiratory Volume; Humans; Japan; Male; Middle Aged; Muscarinic Antagonists; Nebulizers and Vaporizers; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Tiotropium Bromide; Treatment Outcome
PubMed: 33441146
DOI: 10.1186/s12890-021-01403-y -
Drug Design, Development and Therapy 2013An increasing body of evidence suggests that the long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) combination appears to play an important role in... (Review)
Review
An increasing body of evidence suggests that the long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) combination appears to play an important role in maximizing bronchodilation, with studies to date indicating that combining different classes of bronchodilators may result in significantly greater improvements in lung function compared to the use of a single drug, and that these combinations are well tolerated in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). An inhaled, fixed-dose combination of two 24-hour bronchodilators, the LAMA umeclidinium and the LABA vilanterol, is under development as a once-daily treatment for COPD. The efficacy of both mono-components has already been demonstrated. The information currently available suggests that umeclidinium/vilanterol is an effective once-daily dual bronchodilator fixed-dose combination in the treatment of COPD. However, it remains to be seen if it compares favorably with current therapies. Moreover, the question remains whether umeclidinium/vilanterol fixed-dose combination, which significantly improves FEV1, is also associated with improvements in other outcome measures that are important to COPD patients.
Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Delayed-Action Preparations; Drug Combinations; Forced Expiratory Volume; Humans; Muscarinic Antagonists; Outcome Assessment, Health Care; Pulmonary Disease, Chronic Obstructive; Quinuclidines
PubMed: 24143077
DOI: 10.2147/DDDT.S39449 -
Journal of Applied Physiology... May 2022Exercise intolerance in chronic obstructive pulmonary disease (COPD) is associated with dyspnea, reduced inspiratory capacity (IC) and occurs with a neuromuscular "power... (Randomized Controlled Trial)
Randomized Controlled Trial
Exercise intolerance in chronic obstructive pulmonary disease (COPD) is associated with dyspnea, reduced inspiratory capacity (IC) and occurs with a neuromuscular "power reserve," i.e., an acute ability to increase isokinetic locomotor power. This power reserve is associated with resting forced expiratory volume in 1 s (FEV)/forced vital capacity (FVC) suggesting that treatments to target pulmonary function may protect neuromuscular performance and extend whole body exercise in COPD. We, therefore, tested whether combination long-acting β-agonist and muscarinic antagonist bronchodilator therapy [long-acting muscarinic antagonist (LAMA) + long-acting β-agonist (LABA); Stiolto Respimat] would ameliorate the decline in neuromuscular performance and increase endurance time during constant power cycling at 80% peak incremental power. Fourteen patients with COPD (4 female; 64 [58, 72] yr; FEV 67% [56%, 75%] predicted; median [25th, 75th percentile]) participated in a randomized, placebo-controlled crossover trial (NCT02845752). Pulmonary function and cardiopulmonary exercise responses were assessed before and after 1 wk of treatment, with 2 wk washout between conditions. Performance fatigue was assessed using an ∼4-s maximal isokinetic cycling effort at preexercise, isotime, and intolerance. Isotime was the shorter exercise duration of the two treatment conditions. Significance was assessed using ANOVA with treatment as fixed factor and subject as random factor. FEV was greater with LAMA + LABA versus placebo (1.81 [1.58, 1.98] L vs. 1.72 [1.29, 1.99] L; = 0.006), but IC at isotime, performance fatigue at isotime, and constant power endurance time were not different between conditions (each > 0.05). A modest (∼95 mL) increase in FEV following 1 wk of combination LAMA + LABA treatment did not alleviate neuromuscular performance fatigue or enhance cycle exercise tolerance in patients with mild-to-severe COPD with largely preserved "static" lung volumes. Bronchodilation is known to increase forced expiratory volume in 1 s (FEV) and reduce hyperinflation in COPD. In a randomized controlled trial, we investigated whether combined inhaled long-acting β-agonist and muscarinic antagonist would alleviate maximal voluntary neuromuscular performance fatigue or enhance maximal muscle activation during cycling in patients with COPD. Despite increased FEV, combination bronchodilator therapy did not reduce neuromuscular performance fatigue or enhance muscle activity or exercise tolerance in patients with mild-to-severe COPD.
Topics: Benzoxazines; Bronchodilator Agents; Cross-Over Studies; Drug Combinations; Fatigue; Female; Humans; Male; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide
PubMed: 35323052
DOI: 10.1152/japplphysiol.00332.2021 -
International Journal of Chronic... 2017The combination of a long-acting muscarinic antagonist (LAMA) and a long-acting β-agonist (LABA) in a single inhaler is a viable treatment option for patients with... (Review)
Review
OBJECTIVE
The combination of a long-acting muscarinic antagonist (LAMA) and a long-acting β-agonist (LABA) in a single inhaler is a viable treatment option for patients with chronic obstructive pulmonary disease (COPD). Here, we systematically review the current knowledge on double bronchodilation for the treatment of COPD, with a specific focus on its efficacy versus placebo and/or monotherapy bronchodilation.
METHODS
A systematic review of clinical trials investigating LABA/LAMA combination therapies was conducted. Articles were retrieved from PubMed, Embase, and Scopus on June 26, 2016. We specifically selected clinical trials with a randomized controlled or crossover design published in any scientific journal showing the following characteristics: 1) comparison of different LABA/LAMA combinations in a single inhaler for patients with COPD, 2) dose approved in Europe, and 3) focus on efficacy (versus placebo and/or bronchodilator monotherapy) in terms of lung function, respiratory symptoms, or exacerbations.
RESULTS
We analyzed 26 clinical trials conducted on 24,338 patients. All LABA/LAMA combinations were consistently able to improve lung function compared with both placebo and bronchodilator monotherapy. Improvements in symptoms were also consistent versus placebo, showing some lack of correlation for some clinical end points and combinations versus monotherapy bronchodilation. Albeit being an exploratory end point, exacerbations showed an improvement with LABA/LAMA combinations over placebo in some trials; however, scarce information was available in comparison with bronchodilator monotherapy in most studies.
CONCLUSION
Our data show consistent improvements for LABA/LAMA combinations, albeit with some variability (depending on the clinical end point, the specific combination, and the comparison group). Clinicians should be aware that these are average differences. All treatments should be tailored at the individual level to optimize clinical outcomes.
Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Clinical Trials as Topic; Disease Progression; Drug Combinations; Forced Expiratory Volume; Humans; Lung; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Treatment Outcome
PubMed: 28694697
DOI: 10.2147/COPD.S132962 -
British Journal of Pharmacology May 19991. In this study we have evaluated the pharmacological profile of the muscarinic antagonist glycopyrrolate in guinea-pig and human airways in comparison with the... (Comparative Study)
Comparative Study
1. In this study we have evaluated the pharmacological profile of the muscarinic antagonist glycopyrrolate in guinea-pig and human airways in comparison with the commonly used antagonist ipratropium bromide. 2. Glycopyrrolate and ipratropium bromide inhibited EFS-induced contraction of guinea-pig trachea and human airways in a concentration-dependent manner. Glycopyrrolate was more potent than ipratropium bromide. 3. The onset of action (time to attainment of 50% of maximum response) of glycopyrrolate was similar to that obtained with ipratropium bromide in both preparations. In guinea-pig trachea, the offset of action (time taken for response to return to 50% recovery after wash out of the test antagonist) for glycopyrrolate (t1/2 [offset]=26.4+/-0.5 min) was less than that obtained with ipratropium bromide (81.2+/-3.7 min). In human airways, however, the duration of action of glycopyrrolate (t1/2 [offset]>96 min) was significantly more prolonged compared to ipratropium bromide (t1/2 [offset]= 59.2+/-17.8 min). 4. In competition studies, glycopyrrolate and ipratropium bromide bind human peripheral lung and human airway smooth muscle (HASM) muscarinic receptors with affinities in the nanomolar range (K1 values 0.5-3.6 nM). Similar to ipratropium bromide, glycopyrrolate showed no selectivity in its binding to the M1-M3 receptors. Kinetics studies, however, showed that glycopyrrolate dissociates slowly from HASM muscarinic receptors (60% protection against [3H]-NMS binding at 30 nM) compared to ipratropium bromide. 5. These results suggest that glycopyrrolate bind human and guinea-pig airway muscarinic receptors with high affinity. Furthermore, we suggest that the slow dissociation profile of glycopyrrolate might be the underlying mechanism by which this drug accomplishes its long duration of action.
Topics: Animals; Binding, Competitive; Electric Stimulation; Glycopyrrolate; Guinea Pigs; Humans; In Vitro Techniques; Ipratropium; Kinetics; Lung; Male; Muscarinic Antagonists; Muscle Contraction; Receptors, Muscarinic; Respiratory System; Time Factors; Trachea
PubMed: 10385241
DOI: 10.1038/sj.bjp.0702573 -
Neuroscience Mar 2014Activation of the dopaminergic mesolimbic reward circuit that originates in the ventral tegmental area (VTA) is postulated to preferentially suppress emotional responses...
Activation of the dopaminergic mesolimbic reward circuit that originates in the ventral tegmental area (VTA) is postulated to preferentially suppress emotional responses to noxious stimuli, and presumably contributes to the addictive liability of strong analgesics. VTA dopamine neurons are activated via cholinergic afferents and microinjection of carbachol (cholinergic agonist) into VTA is rewarding. Here, we evaluated regional differences within VTA in the capacity of carbachol to suppress rats' affective response to pain (vocalization afterdischarges, VADs) and to support conditioned place preference (CPP) learning. As carbachol is a non-specific agonist, muscarinic and nicotinic receptor involvement was assessed by administering atropine (muscarinic antagonist) and mecamylamine (nicotinic antagonist) into VTA prior to carbachol treatment. Unilateral injections of carbachol (4μg) into anterior VTA (aVTA) and posterior VTA (pVTA) suppressed VADs and supported CPP; whereas, injections into midVTA failed to effect either VADs or CPP. These findings corroborate the hypothesis that the neural substrates underlying affective analgesia and reward overlap. However, the extent of the overlap was only partial. Whereas both nicotinic and muscarinic receptors contributed to carbachol-induced affective analgesia in aVTA, only muscarinic receptors mediated the analgesic action of carbachol in pVTA. The rewarding effects of carbachol are mediated by the activation of both nicotinic and muscarinic receptors in both aVTA and pVTA. The results indicate that analgesia and reward are mediated by separate cholinergic mechanisms within pVTA. Nicotinic receptor antagonism within pVTA failed to attenuate carbachol-induced analgesia, but prevented carbachol-induced reward. As addictive liability of analgesics stem from their rewarding properties, the present findings suggest that these processes can be neuropharmacologically separated within pVTA.
Topics: Analgesia; Animals; Atropine; Carbachol; Cholinergic Agonists; Male; Mecamylamine; Muscarinic Antagonists; Nicotinic Antagonists; Pain Threshold; Rats; Rats, Long-Evans; Reward; Ventral Tegmental Area
PubMed: 24434773
DOI: 10.1016/j.neuroscience.2014.01.009