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Drugs Jun 2019Tiotropium/olodaterol (Stiolto Respimat; Spiolto Respimat) is an inhaled fixed-dose combination of the long-acting muscarinic antagonist tiotropium bromide (hereafter... (Review)
Review
Tiotropium/olodaterol (Stiolto Respimat; Spiolto Respimat) is an inhaled fixed-dose combination of the long-acting muscarinic antagonist tiotropium bromide (hereafter referred to as tiotropium) and the long-acting β-adrenergic agonist olodaterol. It is available in several countries, including the USA, Japan, China and those of the EU, where it is indicated for the long-term maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). The efficacy of tiotropium/olodaterol 5/5 μg/day in patients with COPD was evaluated in phase III or IV trials of 6-52 weeks' duration. Tiotropium/olodaterol improved lung function to a greater extent than each of its individual components or placebo in 12- and 52-week trials. In 6-week trials, tiotropium/olodaterol provided greater lung function benefits over 24 h than the individual components, placebo or twice-daily fluticasone propionate/salmeterol. Tiotropium/olodaterol also demonstrated beneficial effects on health-related quality of life (HR-QoL), dyspnoea, inspiratory capacity, exercise endurance and the need for rescue medication. In an 8-week open-label trial, umeclidinium/vilanterol was superior to tiotropium/olodaterol for the primary endpoint of trough forced expiratory volume in 1 s. The tolerability profile of tiotropium/olodaterol was generally similar to that of the individual components. In conclusion, tiotropium/olodaterol provides a useful option for the maintenance treatment of COPD, with the convenience of once-daily administration via a single inhaler.
Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Benzoxazines; Clinical Trials, Phase III as Topic; Clinical Trials, Phase IV as Topic; Drug Combinations; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality of Life; Tiotropium Bromide; Treatment Outcome
PubMed: 31119643
DOI: 10.1007/s40265-019-01133-w -
ELife Aug 2020How the brain dynamics change during anesthetic-induced altered states of consciousness is not completely understood. The α2-adrenergic agonists are unique. They...
How the brain dynamics change during anesthetic-induced altered states of consciousness is not completely understood. The α2-adrenergic agonists are unique. They generate unconsciousness selectively through α2-adrenergic receptors and related circuits. We studied intracortical neuronal dynamics during transitions of loss of consciousness (LOC) with the α2-adrenergic agonist dexmedetomidine and return of consciousness (ROC) in a functionally interconnecting somatosensory and ventral premotor network in non-human primates. LOC, ROC and full task performance recovery were all associated with distinct neural changes. The early recovery demonstrated characteristic intermediate dynamics distinguished by sustained high spindle activities. Awakening by the α2-adrenergic antagonist completely eliminated this intermediate state and instantaneously restored awake dynamics and the top task performance while the anesthetic was still being infused. The results suggest that instantaneous functional recovery is possible following anesthetic-induced unconsciousness and the intermediate recovery state is not a necessary path for the brain recovery.
Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Brain; Consciousness; Dexmedetomidine; Electroencephalography; Humans; Hypnotics and Sedatives; Imidazoles; Macaca; Male; Unconsciousness; Wakefulness
PubMed: 32857037
DOI: 10.7554/eLife.57670 -
Current Neuropharmacology 2023Congenital myasthenic syndromes (CMS) refer to a series of inherited disorders caused by defects in various proteins. Mutation in the collagen-like tail subunit of... (Review)
Review Meta-Analysis
BACKGROUND
Congenital myasthenic syndromes (CMS) refer to a series of inherited disorders caused by defects in various proteins. Mutation in the collagen-like tail subunit of asymmetric acetylcholinesterase () is the second-most common cause of CMS. However, data on pharmacological treatments are limited.
OBJECTIVE
In this study, we reviewed related reports to determine the most appropriate pharmacological strategy for CMS caused by mutations. A literature review and meta-analysis were also performed. PubMed, MEDLINE, Web of Science, and Cochrane Library databases were searched to identify studies published in English before July 22, 2022.
RESULTS
A total of 42 studies including 164 patients with CMS due to 72 different mutations were selected for evaluation. Most studies were case reports, and none were randomized clinical trials. Our meta-analysis revealed evidence that β-adrenergic agonists, including salbutamol and ephedrine, can be used as first-line pharmacological treatments for CMS patients with mutations, as 98.7% of patients (74/75) treated with β-adrenergic agonists showed positive effects. In addition, AChEIs should be avoided in CMS patients with mutations, as 90.5% (105/116) of patients treated with AChEIs showed either no or negative effects.
CONCLUSION
(1) β-adrenergic agonist therapy is the first pharmacological strategy for treating CMS with mutations. (2) AChEIs should be avoided in patients with CMS with mutations.
Topics: Humans; Myasthenic Syndromes, Congenital; Acetylcholinesterase; Muscle Proteins; Mutation; Adrenergic beta-Agonists; Collagen
PubMed: 36703579
DOI: 10.2174/1570159X21666230126145652 -
Expert Opinion on Therapeutic Patents Oct 2019: Glaucoma is a neurodegenerative disease of the eye characterized by selective retinal ganglion cell loss that provokes progressive defects in the visual field.... (Review)
Review
: Glaucoma is a neurodegenerative disease of the eye characterized by selective retinal ganglion cell loss that provokes progressive defects in the visual field. Elevated intraocular pressure (IOP) is an important contributor for the progression of glaucoma. The current therapeutic arsenal for reducing IOP includes prostaglandin analogs, β-blockers, carbonic anhydrase inhibitors, α-adrenergic agonist, miotics, rho-kinase inhibitors and combinations thereof, generally administered as eye drops. : This manuscript reviews the state of art on adrenergic modulators for treating glaucoma. Both monotherapy and fixed-drugs combinations including α-adrenergic agonists and β-blockers are discussed as well as drug delivery systems where these classes of drugs are used. The review then covers the patent literature involving adrenoceptors modulators over the period 2013-2019. : While the scientific community is moving forward novel targets and related modulators for treating glaucoma and ocular hypertension, adrenergic modulators held a prominent position in the therapy of glaucoma and related disorders. Indeed, though not embodying anymore the first-choice monotherapy, they are widely marketed worldwide ordinarily in combination with other drugs, are subjects of many studies for identifying new drug compositions and have been assessed as active ingredients in several innovative ocular drug delivery systems.
Topics: Adrenergic alpha-2 Receptor Agonists; Adrenergic beta-Antagonists; Animals; Drug Combinations; Drug Delivery Systems; Drug Design; Glaucoma; Humans; Intraocular Pressure; Ocular Hypertension; Patents as Topic
PubMed: 31486689
DOI: 10.1080/13543776.2019.1665023 -
The Journal of Allergy and Clinical... Feb 2022Administering allergens in increasing doses can temporarily suppress IgE-mediated allergy and anaphylaxis by desensitizing mast cells and basophils; however, allergen...
BACKGROUND
Administering allergens in increasing doses can temporarily suppress IgE-mediated allergy and anaphylaxis by desensitizing mast cells and basophils; however, allergen administration during desensitization therapy can itself induce allergic responses. Several small molecule drugs and nutraceuticals have been used clinically and experimentally to suppress these allergic responses.
OBJECTIVES
This study sought to optimize drug inhibition of IgE-mediated anaphylaxis.
METHODS
Several agents were tested individually and in combination for ability to suppress IgE-mediated anaphylaxis in conventional mice, FcεRIα-humanized mice, and reconstituted immunodeficient mice that have human mast cells and basophils. Hypothermia was the readout for anaphylaxis; therapeutic efficacy was measured by degree of inhibition of hypothermia. Serum mouse mast cell protease 1 level was used to measure extent of mast cell degranulation.
RESULTS
Histamine receptor 1 (HR1) antagonists, β-adrenergic agonists, and a spleen tyrosine kinase (Syk) inhibitor were best at individually inhibiting IgE-mediated anaphylaxis. A Bruton's tyrosine kinase (BTK) inhibitor, administered alone, only inhibited hypothermia when FcεRI signaling was suboptimal. Combinations of these agents could completely or nearly completely inhibit IgE-mediated hypothermia in these models. Both Syk and BTK inhibition decreased mast cell degranulation, but only Syk inhibition also blocked desensitization. Many other agents that are used clinically and experimentally had little or no beneficial effect.
CONCLUSIONS
Combinations of an HR1 antagonist, a β-adrenergic agonist, and a Syk or a BTK inhibitor protect best against IgE-mediated anaphylaxis, while an HR1 antagonist plus a β-adrenergic agonist ± a BTK antagonist is optimal for inhibiting IgE-mediated anaphylaxis without suppressing desensitization.
Topics: Adrenergic beta-Agonists; Anaphylaxis; Animals; Drug Therapy, Combination; Histamine Antagonists; Immunoglobulin E; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Protein Kinase Inhibitors; Protein-Tyrosine Kinases
PubMed: 34186142
DOI: 10.1016/j.jaci.2021.06.022 -
The Annals of Pharmacotherapy Mar 2018To review and summarize topical oxymetazoline's pharmacology, pharmacokinetics, efficacy, safety, cost, and place in therapy for persistent redness associated with... (Review)
Review
OBJECTIVE
To review and summarize topical oxymetazoline's pharmacology, pharmacokinetics, efficacy, safety, cost, and place in therapy for persistent redness associated with erythematotelangiectatic rosacea.
DATA SOURCES
Literature searches of MEDLINE (1975 to September 2017), International Pharmaceutical Abstracts (1975 to September 2017), and Cochrane Database (publications through September 2017) using the terms rosacea, persistent redness, α -agonist, and oxymetazoline.
STUDY SELECTION AND DATA EXTRACTION
Results were limited to studies of human subjects, English-language publications, and topical use of oxymetazoline. Relevant materials from government sources, industry, and reviews were also included.
DATA SYNTHESIS
Data support the efficacy of oxymetazoline for persistent facial redness. Little study beyond clinical trials cited in the drug approval process has been conducted. Current data suggest that oxymetazoline is similar in safety and efficacy to brimonidine. Head-to-head comparisons of topical α-agonists for erythema caused by rosacea are needed.
CONCLUSION
The topical α-agonist, oxymetazoline, is safe and effective for reducing persistent facial redness associated with erythematotelangiectatic subtype of rosacea. Health care practitioners selecting among treatments should consider not only the subtype of rosacea but also individual patient response, preference, and cost.
Topics: Administration, Topical; Adrenergic alpha-Agonists; Drug Interactions; Erythema; Humans; Oxymetazoline; Rosacea; Treatment Outcome
PubMed: 29094614
DOI: 10.1177/1060028017740139 -
Biomolecules Jun 2021Adrenergic receptors are G protein-coupled receptors for epinephrine and norepinephrine. They are targets of many drugs for various conditions, including treatment of... (Review)
Review
Adrenergic receptors are G protein-coupled receptors for epinephrine and norepinephrine. They are targets of many drugs for various conditions, including treatment of hypertension, hypotension, and asthma. Adrenergic receptors are intensively studied in structural biology, displayed for binding poses of different types of ligands. Here, we summarized molecular mechanisms of ligand recognition and receptor activation exhibited by structure. We also reviewed recent advances in structure-based ligand discovery against adrenergic receptors.
Topics: Adrenergic Agonists; Adrenergic Antagonists; Amino Acid Sequence; Animals; Crystallography, X-Ray; Epinephrine; Humans; Ligands; Norepinephrine; Protein Binding; Protein Conformation; Protein Structure, Secondary; Protein Structure, Tertiary; Receptors, Adrenergic
PubMed: 34202543
DOI: 10.3390/biom11070936 -
Current Opinion in Allergy and Clinical... Oct 2020Epinephrine is the agreed-upon first line treatment for anaphylaxis, yet it continues to be underused by patients/caregivers and providers alike. (Review)
Review
PURPOSE OF REVIEW
Epinephrine is the agreed-upon first line treatment for anaphylaxis, yet it continues to be underused by patients/caregivers and providers alike.
RECENT FINDINGS
There are unfortunately limited data on how epinephrine can best be utilized in anaphylaxis, which hinders how best to inform patients and providers. Studies reporting underuse suggest various barriers and themes on why this may happen.
SUMMARY
Continued education of patients, caregivers, and providers is needed; however, is not likely to be enough to close the gap. Thus, novel studies on how to increase use; increase availability in a cost-effective manner; and newer, effective delivery routes are still needed.
Topics: Adrenergic Agonists; Adult; Aftercare; Anaphylaxis; Animals; Child; Disease Models, Animal; Drug Utilization; Epinephrine; Guideline Adherence; Humans; Injections, Intramuscular; Treatment Outcome
PubMed: 32739981
DOI: 10.1097/ACI.0000000000000680 -
Cancer Chemotherapy and Pharmacology Dec 2023Globally breast cancer accounts for 24.5% in incidence and 15.5% in cancer deaths in women. The triple-negative subtype lacks any specific therapy and is treated with...
PURPOSE
Globally breast cancer accounts for 24.5% in incidence and 15.5% in cancer deaths in women. The triple-negative subtype lacks any specific therapy and is treated with chemotherapy, resulting in significant side-effects. We aimed to investigate if the dose of chemotherapeutic drugs could be diminished by co-administering it with the β2-agonist salbutamol.
METHODS
Cell proliferation was measured by thymidine incorporation; gene expression, by real-time PCR and protein phosphorylation by WB. Apoptosis was assessed by acridine orange / ethidium bromide and TUNEL tests. Public patient databases were consulted. Cells were inoculated to nude mice and their growth assessed.
RESULTS
The β-agonist salbutamol synergizes in MDA-MB-231 cells in vitro with paclitaxel and doxorubicin on cell proliferation through ADRB2 receptors, while the β-blocker propranolol does not. The expression of this receptor was assessed in patient databases and other cell lines. Triple negative samples had the lowest expression. Salbutamol and paclitaxel decreased MDA-MB-231 cell proliferation while their combination further inhibited it. The pathways involved were analyzed. When these cells were inoculated to nude mice, paclitaxel and salbutamol inhibited tumor growth. The combined effect was significantly greater. Paclitaxel increased the expression of MDR1 while salbutamol partially reversed this increase.
CONCLUSION
While the effect of salbutamol was mainly on cell proliferation, suboptimal concentrations of paclitaxel provoked a very important enhancement of apoptosis. The latter enhanced transporter proteins as MDR1, whose expression were diminished by salbutamol. The expression of ADRB2 should be assessed in the biopsy or tumor to eventually select patients that could benefit from salbutamol repurposing.
Topics: Animals; Mice; Humans; Female; Paclitaxel; Breast Neoplasms; Triple Negative Breast Neoplasms; Mice, Nude; Albuterol; Cell Line, Tumor; Cell Proliferation; Propranolol; Adrenergic Agonists; Apoptosis
PubMed: 37725114
DOI: 10.1007/s00280-023-04586-9 -
Expert Opinion on Pharmacotherapy Jan 2021Vibegron is a very selective new β3-adrenergic receptor agonist introduced recently to clinical practice for OAB patients, which offers an alternative option for to... (Review)
Review
INTRODUCTION
Vibegron is a very selective new β3-adrenergic receptor agonist introduced recently to clinical practice for OAB patients, which offers an alternative option for to antimuscarinic drugs.
AREAS COVERED
This review presents the current knowledge concerning the mechanism of action, pharmacokinetics, and pharmacodynamics of vibegron. Moreover, it presents an overview of preclinical and phase II and phase III clinical studies on the efficacy, tolerability, and safety of this agent in patients suffering from OAB.
EXPERT OPINION
Clinical studies confirmed efficacy and safety of vibegron in OAB patients. Vibegron differ from well-known mirabegron with regards to its pharmacological profile because it is metabolized independently from CYP3A4, 2D6, or 2C9 and therefore is less likely to cause a drug-drug interaction. Moreover, since this drug does not penetrate the blood-brain barrier, it could become the drug of choice in OAB patients with cognitive impairment. These properties have paved the way in near future for better-tailored treatments for OAB patients.
Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Humans; Muscarinic Antagonists; Pyrimidinones; Pyrrolidines; Thiazoles; Treatment Outcome; Urinary Bladder, Overactive
PubMed: 32993398
DOI: 10.1080/14656566.2020.1809652