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Advances in Pharmacology (San Diego,... 2020Scopolamine is a nonselective muscarinic antagonist that has shown relatively rapid antidepressant effects, although to date the results are from limited clinical... (Review)
Review
Scopolamine is a nonselective muscarinic antagonist that has shown relatively rapid antidepressant effects, although to date the results are from limited clinical studies. Scopolamine reportedly has downstream signaling effects thought to be linked to neuroplasticity within glutamatergic synapses and consequent antidepressant action. In psychiatry, clinically validated pathways are unusual and thus merit further research in an effort develop more effect medicines for patients with mood disorders. Thus, we are faced with a unique opportunity to build on the clinical observation associated with scopolamine through reverse translation to identify of targets that retain the clinical efficacy while reducing the side effect profile. This chapter reviews the clinical antidepressant findings with scopolamine, including discussion of differential response across patient subgroups, as well as a review of biomarkers that predict clinical outcome. The preclinical data associated with scopolamine also are reviewed and convey a vision for narrowing in on the therapeutic muscarinic receptor subtype(s) that support the antidepressant effects to guide the development of next generation antimuscarinic drug targets for depression.
Topics: Animals; Antidepressive Agents; Choline; Depression; Humans; Muscarinic Antagonists; Scopolamine; Treatment Outcome
PubMed: 32616213
DOI: 10.1016/bs.apha.2020.04.002 -
Expert Opinion on Therapeutic Patents Jan 2009The proven efficacy of several anti-cholinergics and beta(2)-agonists and their combinations in both chronic obstructive pulmonary disease (COPD) and asthma strongly... (Review)
Review
BACKGROUND
The proven efficacy of several anti-cholinergics and beta(2)-agonists and their combinations in both chronic obstructive pulmonary disease (COPD) and asthma strongly validates this therapeutic approach. As a consequence and although technically challenging, over the past 4 years there has been a growing interest in the generation of dual pharmacology Muscarinic-receptor antagonists-beta(2)-adrenergic receptor agonists (MABAs) for the treatment of COPD.
OBJECTIVE/METHODS
This article surveys and reviews the research activity in the MABA area to the end of August 2008.
RESULTS/CONCLUSION
Although the activity in this field seems to still be limited to a few companies, significant progress in the discovery of a MABA has been achieved with the progression of at least one candidate (GSK-961081) to the clinic.
Topics: Adrenergic beta-Agonists; Animals; Asthma; Bronchodilator Agents; Drug Design; Humans; Muscarinic Antagonists; Patents as Topic; Pulmonary Disease, Chronic Obstructive
PubMed: 19441894
DOI: 10.1517/13543770802630331 -
The Annals of Pharmacotherapy Aug 2017To compare the available literature regarding the use of long-acting muscarinic antagonist (LAMA)/long-acting β agonists (LABA) and inhaled corticosteroid (ICS)/LABA... (Review)
Review
OBJECTIVE
To compare the available literature regarding the use of long-acting muscarinic antagonist (LAMA)/long-acting β agonists (LABA) and inhaled corticosteroid (ICS)/LABA combination inhaler therapy in chronic obstructive pulmonary disease (COPD) maintenance therapy management.
DATA SOURCES
A MEDLINE literature search from database inception to February 2017 was conducted using the search terms chronic obstructive pulmonary disease, adrenergic beta-agonist, muscarinic antagonist, and inhaled corticosteroid. References from extracted sources were further searched for any relevant, missed data sources.
STUDY SELECTION AND DATA EXTRACTION
All English-language randomized-controlled trials comparing LAMA/LABA and ICS/LABA combination inhaler therapy were evaluated.
DATA SYNTHESIS
A total of 10 randomized controlled trials have reviewed the use of LAMA/LABA compared with ICS/LABA therapy for COPD maintenance therapy. Results of clinical trials that evaluated LAMA/LABA and ICS/LABA maintenance therapy demonstrated superior improvements in pulmonary function tests via spirometry and improved clinical outcomes with LAMA/LABA therapy, specifically reduction in COPD exacerbation rates. The safety of LAMA/LABA combination therapy also is favorable compared with ICS/LABA combination therapy because of the increased infection risk with ICS therapy.
CONCLUSIONS
COPD is a disease state with significant morbidity and mortality in the United States and is the third leading cause of death. Long-acting inhalers are recommended for the majority of COPD severities, and combination therapy is typically utilized. LAMA/LABA combination therapy has demonstrated superior improvements in pulmonary function and reduction in COPD exacerbation rates compared with ICS/LABA. LAMA/LABA combination therapy will have a larger future role in COPD maintenance management.
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Drug Therapy, Combination; Humans; Muscarinic Antagonists; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Spirometry
PubMed: 28410560
DOI: 10.1177/1060028017705149 -
International Journal of Chronic... 2018COPD is characterized by persistent airflow limitation, progressive breathlessness, cough, and sputum production. Long-acting muscarinic antagonists (LAMAs) are one of... (Review)
Review
COPD is characterized by persistent airflow limitation, progressive breathlessness, cough, and sputum production. Long-acting muscarinic antagonists (LAMAs) are one of the recommended first-choice therapeutic options for patients with COPD, and several new agents have been developed in recent years. A literature search identified 14 published randomized, placebo-controlled studies of the efficacy and safety of LAMAs in patients with COPD, with improvements seen in lung function, exacerbations, breathlessness, and health status. A greater weight of evidence currently exists for glycopyrronium (GLY) and tiotropium than for umeclidinium and aclidinium, especially in terms of exacerbation reductions. To date, there have been few head-to-head clinical studies of the different LAMAs. Available data indicate that GLY and aclidinium have similar efficacy to tiotropium in terms of improving lung function, dyspnea, exacerbations, and health status. Overall, evidence demonstrates that currently available LAMAs provide effective and generally well-tolerated therapy for patients with COPD. Delivery devices for the different LAMAs vary, which may affect individual patient's adherence to and preference for treatment. Subtle differences between individual therapeutic options may be important to individual patients and the final treatment choice should involve physician's and patient's experiences and preferences.
Topics: Bronchodilator Agents; Clinical Decision-Making; Drug Administration Schedule; Drug Prescriptions; Forced Expiratory Volume; Health Status; Humans; Lung; Medication Adherence; Muscarinic Antagonists; Patient Preference; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Recovery of Function; Risk Factors; Time Factors; Treatment Outcome
PubMed: 29670345
DOI: 10.2147/COPD.S160577 -
Behavioural Pharmacology Jun 2020This study aimed to use central and peripheral assays to compare the effects of the muscarinic antagonist scopolamine with those of a novel muscarinic antagonist,... (Comparative Study)
Comparative Study
This study aimed to use central and peripheral assays to compare the effects of the muscarinic antagonist scopolamine with those of a novel muscarinic antagonist, L-687,306 [(3R,4R)-3-(3-cyclopropyl-1,2,4,oxadiazol[5-yl]-1-azabicyclo[2.2.1]heptane. Groups of rats were trained to discriminate the stimulus effects of the muscarinic agonist, arecoline (1.0 mg/kg); concomitant measures of response rate were recorded. Separate groups were prepared with telemetery devices for recording bradycardia induced by arecoline (10 mg/kg). Methyl arecoline and arecoline were nearly equally potent in producing a brief but profound bradycardia, indicative of an equivalent effect in the heart. L-687,306 and scopolamine were both able to block this peripheral effect of arecoline. L-687,306 produced a surmountable antagonism of both the discriminative and rate-suppressing effects of arecoline. Scopolamine, however, was unable to antagonize the rate-reducing effects of arecoline in the discrimination assay. This limited the number of rats that could respond to the discriminative stimulus effects of arecoline, as well as the amount of arecoline stimulus effects they were able to report. The data suggest that L-687,306 may be a more generally effective muscarinic antagonist than scopolamine and support earlier reports that this antagonist has less direct effect on behavior.
Topics: Animals; Arecoline; Bradycardia; Bridged Bicyclo Compounds, Heterocyclic; Discrimination Learning; Male; Muscarinic Antagonists; Oxadiazoles; Rats; Scopolamine
PubMed: 31922966
DOI: 10.1097/FBP.0000000000000537 -
The Journal of Asthma : Official... Sep 2023To review the evidence for the use of open-inhaler (inhaled corticosteroid [ICS] plus long-acting β-agonist [LABA] with separate add-on long-acting muscarinic... (Review)
Review
Open-inhaler versus single-inhaler triple therapy (long-acting muscarinic antagonist, inhaled corticosteroid, and long-acting β-agonist) in asthma patients: a narrative review.
OBJECTIVE
To review the evidence for the use of open-inhaler (inhaled corticosteroid [ICS] plus long-acting β-agonist [LABA] with separate add-on long-acting muscarinic antagonist [LAMA]) versus single-inhaler triple therapy (ICS/LABA/LAMA combination) and the merits of add-on LAMA to ICS/LABA in patients with uncontrolled asthma.
DATA SOURCES
Original research articles were identified from PubMed using the search term "triple therapy asthma." Information was also retrieved from the ClinicalTrials.gov website.
STUDY SELECTIONS
Articles detailing the use of add-on LAMA to ICS plus LABA (open-inhaler triple therapy), and closed triple therapy compared with ICS plus LABA dual therapy, addressing patient symptoms, exacerbations, and health-related quality of life.
RESULTS
Open-inhaler triple therapy was associated with a significantly reduced incidence of hospitalizations and emergency department visits and a decrease in ICS dose, oral corticosteroids use, and antibiotics use. Exacerbations and acute respiratory events were also reduced. Single-inhaler triple therapy showed a greater improvement in lung function, asthma control, and health status and was noninferior to open-inhaler triple therapy for Asthma Quality of Life Questionnaire scores. Single-inhaler triple therapy may also lead to improved therapy adherence.
CONCLUSION
Add-on LAMA to ICS plus LABA (open- or single-inhaler triple therapy) improves the response in patients who remain symptomatic and provides a reasonable alternative to ICS dose escalation in treatment-refractory patients.
Topics: Humans; Asthma; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality of Life; Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Nebulizers and Vaporizers; Drug Therapy, Combination; Adrenal Cortex Hormones
PubMed: 36964764
DOI: 10.1080/02770903.2023.2188556 -
BioMed Research International 2018Severe asthma is associated with substantial morbidity and mortality. Therapies must be maximized to gain control of a patient's severe asthma; however, avoiding... (Review)
Review
Severe asthma is associated with substantial morbidity and mortality. Therapies must be maximized to gain control of a patient's severe asthma; however, avoiding overtreatment is also important. The mainstays of asthma maintenance treatment are inhaled corticosteroids (ICS) and long-acting -agonsits (LABAs), with the option of supplementary add-on treatments. New add-on treatments for severe asthma have emerged over the past two decades, including personalized biological therapies that are guided by a patient's asthma phenotype. In addition, the long-acting muscarinic antagonist tiotropium has been recommended as an add-on treatment for severe asthma. Phase III clinical trials have shown tiotropium in combination with ICS/LABA to be efficacious in patients with severe asthma. Further analyses of clinical trial data have indicated that there is no benefit in stratifying patients by phenotype to predict tiotropium efficacy. Furthermore, health economic studies suggest tiotropium to be a cost-effective treatment in patients with severe asthma. This review will present the evidence surrounding the role of tiotropium in severe asthma and will discuss the use of tiotropium add-on therapy before personalized medicine strategies in the stepwise process of gaining asthma control.
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Asthma; Clinical Trials, Phase III as Topic; Drug Therapy, Combination; Humans; Muscarinic Antagonists; Tiotropium Bromide
PubMed: 30474042
DOI: 10.1155/2018/7473690 -
Postgraduate Medicine Mar 2020Long-acting inhaled bronchodilator medications are recommended as initial maintenance therapy for many patients with COPD. These medications include long-acting... (Review)
Review
Long-acting inhaled bronchodilator medications are recommended as initial maintenance therapy for many patients with COPD. These medications include long-acting muscarinic antagonists (LAMA) and long-acting β-agonists (LABA). Combinations of long-acting bronchodilator agents (LAMA/LABA) and inhaled corticosteroids combined with LABA (ICS/LABA) are also used as initial or follow-up therapy in patients with more severe symptoms or at risk of COPD exacerbations. This review summarizes the position of LAMA/LABA combinations in treatment recommendations, and the evidence supporting their placement relative to LAMA monotherapy and ICS/LABA combination therapy, as well as differences within the LAMA/LABA class. Most studies show that LAMA/LABA treatment leads to greater improvements in lung function and symptoms than LAMA monotherapy or ICS/LABA treatment. There are fewer studies comparing the impact of different medication classes on patients' risk of exacerbations; however, the available evidence suggests that LAMA/LABA treatment and LAMA monotherapy lead to a similar reduction in exacerbation risk, while the effect of LAMA/LABA compared with ICS/LABA remains unclear. The incidence of adverse events is similar with LAMA/LABA and LAMA alone. There is a lower risk of pneumonia with LAMA/LABA compared with ICS/LABA. This evidence supports the use of LAMA/LABA combinations as an initial maintenance therapy option for symptomatic patients with low exacerbation risk and severe breathlessness or patients with severe symptoms who are at risk of exacerbations, and as follow-up treatment in patients with uncontrolled symptoms or exacerbations on bronchodilator monotherapy.
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Delayed-Action Preparations; Drug Combinations; Drug Therapy, Combination; Humans; Muscarinic Antagonists; Practice Guidelines as Topic; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory Function Tests; Severity of Illness Index
PubMed: 31900019
DOI: 10.1080/00325481.2019.1702834 -
The Annals of Pharmacotherapy Mar 2019To review the pharmacology, efficacy, and safety of the first nebulized long-acting muscarinic antagonist (LAMA), glycopyrrolate (GLY)/eFlow closed system (CS)... (Review)
Review
OBJECTIVE
To review the pharmacology, efficacy, and safety of the first nebulized long-acting muscarinic antagonist (LAMA), glycopyrrolate (GLY)/eFlow closed system (CS) nebulizer, approved for maintenance treatment of chronic obstructive pulmonary disease (COPD).
DATA SOURCES
A PubMed search was conducted (January 2000 to July 2018) using the following terms/phrases: nebulized glycopyrrolate, inhalation devices in COPD, long-acting muscarinic antagonists COPD, and COPD survey. Retrieved articles were reviewed to identify additional references.
STUDY SELECTION AND DATA EXTRACTION
Primary and review articles on GLY/eFlow CS and other treatment options for patients with COPD were selected.
DATA SYNTHESIS
Guidelines recommend the use of LAMAs, alone or in combination with long-acting β-agonists, as maintenance therapy for the majority of patients with COPD. With the range of different devices and bronchodilators now available, treatment can be tailored based on individual needs. The eFlow CS nebulizer delivers GLY rapidly over a 2- to 3-minute period and provides bronchodilation within 30 minutes, lasting 12 hours. Phase 2 dose-finding and phase 3 studies demonstrated sustained statistically significant and clinically important improvements in pulmonary function and patient-reported outcomes with GLY/eFlow CS. Relevance to Patient Care and Clinical Practice: GLY/eFlow CS provides a novel, portable, efficient, and rapid drug delivery system.
CONCLUSIONS
The recently approved GLY/eFlow CS drug-device combination provides a viable treatment option for patients with COPD, particularly those with conditions that may impair proper use of traditional handheld inhalers.
Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Drug Delivery Systems; Female; Glycopyrrolate; Humans; Male; Muscarinic Antagonists; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Treatment Outcome
PubMed: 30175596
DOI: 10.1177/1060028018798753 -
Palliative Medicine May 2022Patients with chronic obstructive pulmonary disease (COPD) face limited treatment options and inadequate access to palliative care. (Review)
Review
BACKGROUND
Patients with chronic obstructive pulmonary disease (COPD) face limited treatment options and inadequate access to palliative care.
AIM
To provide a pragmatic overview of clinical guidelines and produce evidence-based recommendations for severe COPD. Interventions for which there is inconsistent evidence to support their use and areas requiring further research were identified.
DESIGN
Practice review of guidelines supported by scoping review methodology to examine the evidence reporting the use of guideline-recommended interventions.
DATA SOURCES
An electronic search was undertaken in MEDLINE, EMBASE, PsycINFO, CINAHL and The Cochrane Database of Systematic Reviews, complemented by web searching for guidelines and publications providing primary evidence (July 2021). Guidelines published within the last 5 years and evidence in the last 10 years were included.
RESULTS
Severe COPD should be managed using a multidisciplinary approach with a holistic assessment. For stable patients, long-acting beta-agonist/long-acting muscarinic antagonist and pulmonary rehabilitation are recommended. Low dose opioids, self-management, handheld fan and nutritional support may provide small benefits, whereas routine corticosteroids should be avoided. For COPD exacerbations, systematic corticosteroids, non-invasive ventilation and exacerbation action plans are recommended. Short-acting inhaled beta-agonists and antibiotics may be considered but pulmonary rehabilitation should be avoided during hospitalisation. Long term oxygen therapy is only recommended for patients with chronic severe hypoxaemia. Short-acting anticholinergic inhalers, nebulised opioids, oral theophylline or telehealth are not recommended.
CONCLUSIONS
Recommended interventions by guidelines are not always supported by high-quality evidence. Further research is required on efficacy and safety of inhaled corticosteroids, antidepressants, benzodiazepines, mucolytics, relaxation and breathing exercises.
Topics: Adrenal Cortex Hormones; Analgesics, Opioid; Humans; Muscarinic Antagonists; Practice Guidelines as Topic; Pulmonary Disease, Chronic Obstructive
PubMed: 35311415
DOI: 10.1177/02692163221079697