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Neville A. Mcbrien - One of the best experts on this subject based on the ideXlab platform.
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The Mx Muscarinic Antagonist Pirenzepine Reduces Myopia and Eye Enlargement in the Tree Shrew
2013Co-Authors: Charles L. Cottriall, Neville A. McbrienAbstract:Purpose. To determine the efficacy of the Mi-selective Muscarinic Antagonist, pirenzepine, in preventing experimentally induced myopia in a mammalian model, the tree shrew. Methods. Tree shrews were monocularly deprived (MD) using translucent goggles or negative lenses for a period of 12 days. In two of the MD groups, tree shrews received daily subconjunctival administration of either pirenzepine (17.7 fimol; re = 9) or vehicle control (re = 6). Control groups (re = 6) were used to assess the effects of MD, injection regimen, and drug effects. Results. In sham-injected and saline-injected MD tree shrews, 12 days of MD produced —13.2 D ± 0.8 D and —14.1 D ± 0.5 D of axial myopia, respectively. In pirenzepine-injected MD tree shrews, 12 days of MD induced an axial myopia of only —2.1 D ± 1.4 D. The significant reduction in myopia in pirenzepine-injected MD tree shrews was caused by significantly less vitreous chamber elongation of the deprived eye (0.05 mm ± 0.04 mm) relative to the contralateral control eye when compared to sham-injected and saline-injected MD tree shrews (0.24 mm ± 0.02 mm and 0.29 mm ± 0.01 mm). Mean equatorial enlargement and increased eye weight were prevented in pirenzepine-injected MD tree shrews (P < 0.01). Pirenzepine also was found to reduce myopia and ocular enlargement in lens defocus-induced myopia
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Muscarinic Antagonist control of myopia evidence for m4 and m1 receptor based pathways in the inhibition of experimentally induced axial myopia in the tree shrew
Investigative Ophthalmology & Visual Science, 2012Co-Authors: Baskar Arumugam, Neville A. McbrienAbstract:PURPOSE: The broadband Muscarinic Antagonist atropine is effective in stopping the progression of myopia in animals and humans. The partially selective M(1)/M(4) Antagonist pirenzepine also slows progression of myopia, although not as effectively as atropine. Due to the supra maximal doses utilized in these studies, it is unclear if this antimyopia effect occurs through a receptoral-based mechanism, and if so, which receptors are involved. Studies in chicks indicate the involvement of the M(4) Muscarinic receptor. The current study investigated the effect of the highly selective Muscarinic Antagonists Muscarinic Toxin 3 (MT3) (M(4) selective) and Muscarinic Toxin 7 (MT7) (M(1) selective) on experimental myopia in a mammalian model. METHODS: Tree shrews (n = 23) underwent daily intravitreal injections of MT3, MT7, or vehicle (phosphate buffered saline) for five days in the treated eye, combined with deprivation of vision with a translucent occluder (MD). The contralateral eye was unocccluded and underwent intravitreal injections of vehicle for the same period. Two additional groups (n = 10) underwent daily intravitreal injections of MT7 or vehicle for 10 days in the treated eye combined with negative lens (-9.5 diopter [D]) defocus (LIM). The control eye was injected with saline and wore a plano lens. RESULTS: Both MT3 and MT7 treatment reduced the development of deprivation-induced myopia (treated-control eye [T-C]; vehicle-MD; -4.3 ± 0.6 D versus MT3-MD; -0.7 ± 0.2 D and MT7-MD; -0.7 ± 0.4 D; P < 0.001). MT7 treatment was effective at inhibiting lens-induced myopia (T-C; vehicle-LIM; -4.6 ± 0.5 D versus MT7-LIM; 0.2 ± 0.2 D; P < 0.05). CONCLUSIONS: The findings demonstrate that inhibition of form-deprivation myopia by Muscarinic Antagonists involves both M(4) and M(1) Muscarinic receptor signaling pathways in mammals.
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The M4 Muscarinic Antagonist MT‐3 inhibits myopia in chick: evidence for site of action
Ophthalmic & physiological optics : the journal of the British College of Ophthalmic Opticians (Optometrists), 2011Co-Authors: Neville A. Mcbrien, Baskar Arumugam, Alex Gentle, Anna Chow, Srujana SahebjadaAbstract:Purpose: It is well established that the broad-band Muscarinic Antagonist, atropine is effective at inhibiting the progression of myopia and does so by preventing the elongation of the vitreous chamber of the eye. However, uncertainty remains as to whether this effect occurs through a receptoral mechanism and, if so, which Muscarinic receptor subtype mediates this effect. Previous work, in avian and mammalian models of myopia, implicates the M1 and M4 receptors as potential targets. The current study used physiologically relevant concentrations of highly selective Muscarinic Antagonists (MT-3 and MT-7) to further characterise the role of the M4 receptor in the control of myopia in the chick model of refractive development. Methods: Nine groups of week-old chicks underwent 5 days of monocular deprivation, with a translucent occluder, to induce myopia. These animals had either no injection, scleral puncture with a needle, or daily intravitreal injections of MT-3 (M4-selective), MT-7 (M1-selective) or vehicle. Three concentrations of each Antagonist were delivered (250 nm, 2.5 lm and 10 lm). After the treatment period, keratometry, retinoscopy and A-Scan ultrasound were used to assess ocular biometry. Results: MT-3 treatment produced a significant dose-dependent reduction in relative myopia (treated)control eye) compared to vehicle treatment (vehicle )10.1 ± 1.1 D vs 10 lm MT-3 )4.0 ± 1.5 D, p < 0.01). The majority of this effect was due to reduced relative vitreous chamber elongation in drug treated eyes (vehicle +0.26 ± 0.04 mm, 10 lm MT-3 +0.08 ± 0.07 mm, p < 0.05). In contrast, MT-7 had no significant effect on the development of myopia (MT-7 10 lm: myopia, )12.1 ± 0.8 D and vitreous chamber depth, +0.23 ± 0.07 mm). Calculations indicate that the experimentally achieved concentrations of MT-3 at intraocular receptors necessary to inhibit 50% of myopia development (between 5 and 50 nm) were consistent with published in vitro affinity constants for the M4 receptor and below those for the M1 receptor. Histology demonstrated that MT-3 at the doses used had no gross effects on the retina, indicating a non-toxic mode of action. Conclusions: In the chick, which lacks a homologue of the mammalian M1 receptor, the above findings represent compelling evidence that Muscarinic Antagonists prevent myopia progression through an M4-receptor mediated mechanism, most likely located in the retina.
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The M1 Muscarinic Antagonist pirenzepine reduces myopia and eye enlargement in the tree shrew.
Investigative ophthalmology & visual science, 1996Co-Authors: Charles L. Cottriall, Neville A. McbrienAbstract:Purpose. To determine the efficacy of the Mi-selective Muscarinic Antagonist, pirenzepine, in preventing experimentally induced myopia in a mammalian model, the tree shrew. Methods. Tree shrews were monocularly deprived (MD) using translucent goggles or negative lenses for a period of 12 days. In two of the MD groups, tree shrews received daily subconjunctival administration of either pirenzepine (17.7 fimol; re = 9) or vehicle control (re = 6). Control groups (re = 6) were used to assess the effects of MD, injection regimen, and drug effects. Results. In sham-injected and saline-injected MD tree shrews, 12 days of MD produced —13.2 D ± 0.8 D and —14.1 D ± 0.5 D of axial myopia, respectively. In pirenzepine-injected MD tree shrews, 12 days of MD induced an axial myopia of only —2.1 D ± 1.4 D. The significant reduction in myopia in pirenzepine-injected MD tree shrews was caused by significantly less vitreous chamber elongation of the deprived eye (0.05 mm ± 0.04 mm) relative to the contralateral control eye when compared to sham-injected and saline-injected MD tree shrews (0.24 mm ± 0.02 mm and 0.29 mm ± 0.01 mm). Mean equatorial enlargement and increased eye weight were prevented in pirenzepine-injected MD tree shrews (P < 0.01). Pirenzepine also was found to reduce myopia and ocular enlargement in lens defocus-induced myopia. Control experiments demonstrated that pirenzepine did not cause a significant reduction in amplitude of carbachol-induced accommodation. Conclusions. Findings demonstrate that chronic administration of the M,-selective Muscarinic Antagonist, pirenzepine, prevents experimentally induced myopia in this mammalian model by a nonaccommodative mechanism. Invest Ophthalmol Vis Sci. 1996; 37:1368-1379.
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atropine reduces experimental myopia and eye enlargement via a nonaccommodative mechanism
Investigative Ophthalmology & Visual Science, 1993Co-Authors: Neville A. Mcbrien, Hadi O Moghaddam, A P ReederAbstract:PURPOSE To determine whether the Muscarinic Antagonist atropine effectively reduces or prevents experimentally induced myopia via a nonaccommodative mechanism. METHODS Chicks were monocularly deprived (MD) of pattern vision by placement of a translucent occluder over the left eye. In two of the three MD groups, chicks received a series of intravitreal injections of atropine (n = 8) or saline vehicle (n = 8) with MD. Control groups (n = 8) of chicks were employed to assess the effects of MD, intravitreal injections, and drug effects. RESULTS In sham-injected or saline-injected MD chicks, 8 days of MD produced -18.5 D and -20.9 D of experimental myopia, respectively. In atropine-injected MD chicks, 8 days of MD produced only -2.8 D of experimental myopia. This significant reduction in experimentally induced myopia in atropine-injected MD chicks was associated with a marked reduction in the relative axial elongation of the deprived eye (0.21 mm) when compared to saline-injected or sham-injected MD chicks (1.04 mm and 1.00 mm). This reduction in axial length in atropine-injected MD chicks was predominantly the result of a reduction in vitreous chamber elongation, although a reduction in anterior segment depth also was observed. Mean equatorial diameter was significantly reduced in atropine-injected MD chicks compared to saline-injected and sham-injected MD chicks, although to a lesser extent. Control experiments demonstrated that intravitreally injected atropine did not reduce carbachol-induced accommodation or light-induced pupil constriction in the skeletal intraocular muscles of the chick eye. CONCLUSIONS These findings demonstrate that chronic administration of the Muscarinic Antagonist atropine prevents experimentally induced myopia in chick via a nonaccommodative mechanism.
Sharath S. Hegde - One of the best experts on this subject based on the ideXlab platform.
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discovery of r 1 3 2 chloro 4 2 hydroxy 2 8 hydroxy 2 oxo 1 2 dihydroquinolin 5 yl ethyl amino methyl 5 methoxyphenyl amino 3 oxopropyl piperidin 4 yl 1 1 biphenyl 2 ylcarbamate td 5959 gsk961081 batefenterol first in class dual pharmacology multival
Journal of Medicinal Chemistry, 2015Co-Authors: Adam Hughes, Alexander Mcnamara, Sharath S. Hegde, Yan Chen, Jeffrey R Jasper, Sarah Jawtsai, Taeweon Lee, Teresa M Pulidorios, Tod Steinfeld, Mathai MammenAbstract:Through application of our multivalent approach to drug discovery we previously reported the first discovery of dual pharmacology MABA bronchodilators, exemplified by 1. Herein we describe the subsequent lead optimization of both Muscarinic Antagonist and β2 agonist activities, through modification of the linker motif, to achieve 24 h duration of action in a guinea pig bronchoprotection model. Concomitantly we targeted high lung selectivities, low systemic exposures and identified crystalline forms suitable for inhalation devices. This article culminates with the discovery of our first clinical candidate 12f (TD-5959, GSK961081, batefenterol). In a phase 2b trial, batefenterol produced statistical and clinically significant differences compared to placebo and numerically greater improvements in the primary end point of trough FEV1 compared to salmeterol after 4 weeks of dosing in patients with moderate to severe chronic obstructive pulmonary disease (COPD).
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In vivo pharmacological characterization of TD-4208, a novel lung-selective inhaled Muscarinic Antagonist with sustained bronchoprotective effect in experimental animal models.
Journal of Pharmacology and Experimental Therapeutics, 2013Co-Authors: Mt Pulido-rios, Alexander Mcnamara, Glenmar P. Obedencio, S. Jaw-tsai, William J. Martin, Sharath S. HegdeAbstract:Tiotropium is currently the only once-daily, long-acting Muscarinic Antagonist (LAMA) approved in the United States and other countries for the treatment of chronic obstructive pulmonary disease (COPD). Glycopyrronium has shown promise as a LAMA and was recently approved for once-daily maintenance treatment of COPD in the European Union. Here, we describe the in vivo preclinical efficacy and lung selectivity of a novel inhaled Muscarinic Antagonist, TD-4208 (biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester) and compare its profile to tiotropium and glycopyrronium. In anesthetized dogs, TD-4208, along with tiotropium and glycopyrronium, produced sustained inhibition of acetylcholine-induced bronchoconstriction for up to 24 hours. In anesthetized rats, inhaled TD-4208 exhibited dose-dependent 24-hour bronchoprotection against methacholine-induced bronchoconstriction. The estimated 24-hour potency (expressed as concentration of dosing solution) was 45.0 µg/ml. The bronchoprotective potencies of TD-4208 and tiotropium were maintained after 7 days of once-daily dosing, whereas glycopyrronium showed a 6-fold loss in potency after repeat dosing. To assess systemic functional activity using a clinically relevant readout, the antisialagogue effect of compounds was also evaluated. The calculated lung selectivity index (i.e., ratio of antisialagogue and bronchoprotective potency) of TD-4208 was superior to glycopyrronium after both single and repeat dosing regimens and was superior to tiotropium after repeat dosing. In conclusion, the in vivo preclinical profile suggests that TD-4208 has the potential to be a long-acting bronchodilator for once-daily treatment of respiratory diseases. Its greater functional selectivity for the lung in preclinical models may translate to an improved tolerability profile compared with marketed Muscarinic receptor Antagonists.
Dave Singh - One of the best experts on this subject based on the ideXlab platform.
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reply to evaluating triple ics laba lama therapies for copd patients a network meta analysis of ethos kronos impact and trilogy studies
Expert Review of Respiratory Medicine, 2021Co-Authors: Meilan K Han, Dave Singh, David A Lipson, Fernando J MartinezAbstract:Dear Editors, We read with interest the recent network meta-analysis of inhaled corticosteroid/long-acting Muscarinic Antagonist/long-acting β2-agonist (ICS/LAMA/LABA) in chronic obstructive pulmon...
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triple inhaled therapy at two glucocorticoid doses in moderate to very severe copd
The New England Journal of Medicine, 2020Co-Authors: Klaus F Rabe, Gary T. Ferguson, Dave Singh, Fernando J Martinez, Chen Wang, Jadwiga A Wedzicha, Roopa Trivedi, Earl St Rose, Shaila Ballal, Julie MclarenAbstract:Abstract Background Triple fixed-dose regimens of an inhaled glucocorticoid, a long-acting Muscarinic Antagonist (LAMA), and a long-acting β2-agonist (LABA) for chronic obstructive pulmonary diseas...
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pharmacodynamics pharmacokinetics and safety of revefenacin td 4208 a long acting Muscarinic Antagonist in patients with chronic obstructive pulmonary disease copd results of two randomized double blind phase 2 studies
Pulmonary Pharmacology & Therapeutics, 2018Co-Authors: Dean Quinn, Edmund Moran, Chris N Barnes, David L Bourdet, Brett Haumann, Wayne Yates, Peter Potgieter, Andrew Nicholls, Dave SinghAbstract:Abstract Background Revefenacin (TD-4208) is a potent, lung-selective, long-acting Muscarinic Antagonist currently in development as a once-daily nebulized therapy for chronic obstructive pulmonary disease (COPD). We evaluated the pharmacodynamics (bronchodilator activity), pharmacokinetics (PK) and safety of single- and multiple-dose administrations of revefenacin in two clinical trials (Study 0059 and Study 0091) in patients with moderate to severe COPD. Methods In Study 0059, 32 patients were randomized to receive a single dose of revefenacin (350 or 700 μg), active control ipratropium (500 μg) or placebo inhalation solution administered via standard jet nebulizer in a double-blind, crossover fashion. In Study 0091, 59 patients were randomized to receive once-daily inhalations of revefenacin (22, 44, 88, 175, 350 or 700 μg) or placebo for 7 days in a double-blind, incomplete block, five-way crossover design. The primary efficacy endpoint was change from baseline in peak (0–6 h) forced expiratory volume in 1 s (FEV1) in Study 0059, and trough FEV1 after the final dose (Day 7) in Study 0091. In both studies, secondary endpoints included area under the FEV1-time curve (FEV1 AUC) values from time 12–24 h post dose and FEV1 AUC values from time zero to 24 h post dose. Results Revefenacin demonstrated a rapid onset and sustained duration of bronchodilator action in both studies. In Study 0059, mean peak FEV1 was significantly higher (p Conclusions Following single or multiple nebulized-dose administration in patients with COPD, revefenacin demonstrates a rapid onset and sustained duration of bronchodilator effect over 24 h following once-daily administration, with a PK profile that is commensurate with low systemic exposure.
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efficacy and safety of nebulized glycopyrrolate for administration using a high efficiency nebulizer in patients with chronic obstructive pulmonary disease
British Journal of Clinical Pharmacology, 2015Co-Authors: Brian Leaker, Peter J Barnes, Richard C Jones, Ahmet Tutuncu, Dave SinghAbstract:Aims To establish the dose−response for pharmacodynamics (bronchodilatation), safety and pharmacokinetics for a nebulized formulation of the long acting Muscarinic Antagonist glycopyrrolate (EP-101) with a high efficiency nebulizer in patients with chronic obstructive pulmonary disease (COPD).
William A. Fahy - One of the best experts on this subject based on the ideXlab platform.
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a randomized parallel group study to evaluate the efficacy of umeclidinium vilanterol 62 5 25 μg on health related quality of life in patients with copd
International Journal of Chronic Obstructive Pulmonary Disease, 2016Co-Authors: Thomas Siler, Alison Church, Alison Donald, Dianne Odell, William A. FahyAbstract:Background The combination of the inhaled Muscarinic Antagonist umeclidinium (UMEC) with the long-acting β2-agonist vilanterol (VI) has been shown to provide significant improvements in lung function compared with UMEC, VI, or placebo (PBO) in patients with chronic obstructive pulmonary disease (COPD). This study was specifically designed to support these findings by assessing health-related quality of life and symptomatic outcomes in a similar population.
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dual bronchodilator therapy with umeclidinium vilanterol versus tiotropium plus indacaterol in chronic obstructive pulmonary disease a randomized controlled trial
Drugs in R & D, 2016Co-Authors: Chris Kalberg, Dianne Odell, Dmitry V Galkin, Amy Newlands, William A. FahyAbstract:Introduction The fixed-dose, long-acting bronchodilator combination of umeclidinium/vilanterol (UMEC/VI) has not previously been compared with a combination of a long-acting Muscarinic Antagonist and long-acting β2-agonist in patients with chronic obstructive pulmonary disease (COPD).
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triple therapy of umeclidinium inhaled corticosteroids long acting beta2 agonists for patients with copd pooled results of randomized placebo controlled trials
Pulmonary Therapy, 2016Co-Authors: Thomas Siler, Edward Kerwin, Lee Tombs, William A. Fahy, Ian NayaAbstract:Introduction Data on triple therapy (long-acting Muscarinic Antagonist [LAMA] + inhaled corticosteroid/long-acting beta2-agonist [ICS/LABA]) in symptomatic patients with chronic obstructive pulmonary disease (COPD) are limited. This post hoc analysis aimed to determine the efficacy of once-daily umeclidinium (UMEC; 62.5 μg) or placebo (PBO) plus open-label fixed-dose ICS/LABA in symptomatic patients with COPD.
Gary T. Ferguson - One of the best experts on this subject based on the ideXlab platform.
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triple inhaled therapy at two glucocorticoid doses in moderate to very severe copd
The New England Journal of Medicine, 2020Co-Authors: Klaus F Rabe, Gary T. Ferguson, Dave Singh, Fernando J Martinez, Chen Wang, Jadwiga A Wedzicha, Roopa Trivedi, Earl St Rose, Shaila Ballal, Julie MclarenAbstract:Abstract Background Triple fixed-dose regimens of an inhaled glucocorticoid, a long-acting Muscarinic Antagonist (LAMA), and a long-acting β2-agonist (LABA) for chronic obstructive pulmonary diseas...
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efficacy of budesonide glycopyrronium formoterol fumarate metered dose inhaler bgf mdi versus other inhaled corticosteroid long acting Muscarinic Antagonist long acting β 2 agonist ics lama laba triple combinations in copd a systematic literature rev
Advances in Therapy, 2020Co-Authors: Gary T. Ferguson, Shaila Ballal, Patrick Darken, M K Siddiqui, Barinder Singh, Sumeet Attri, Ulf Holmgren, Enrico De NigrisAbstract:Triple inhaled corticosteroid/long-acting Muscarinic Antagonist/long-acting β2-agonist (ICS/LAMA/LABA) combination therapy is recommended for patients with chronic obstructive pulmonary disease (COPD) who experience further exacerbations/symptoms on dual LAMA/LABA or ICS/LABA therapy. The relative efficacy of budesonide/glycopyrronium/formoterol fumarate metered dose inhaler 320/18/9.6 µg (BGF MDI) in COPD was compared with other ICS/LAMA/LABA fixed-dose and open combination therapies in a network meta-analysis (NMA). A systematic literature review was conducted to identify randomized controlled trials of at least 10-week duration, including at least one fixed-dose or open combination triple therapy arm, in patients with moderate to very severe COPD. Studies were assessed for methodological quality and risk of bias. A three-level hierarchical Bayesian NMA model was used to determine the exacerbation rate per patient per year as well as the following outcomes at week 24: changes from baseline in pre-dose trough forced expiratory volume in 1 s (FEV1), post-dose peak FEV1, and St. George’s Respiratory Questionnaire (SGRQ) total score; proportion of SGRQ responders; and Transition Dyspnea Index focal score. Change from baseline in rescue medication use over weeks 12–24 was also analyzed. Meta-regression and sensitivity analyses were used to assess heterogeneity across studies. Eighteen studies (n = 29,232 patients) contributed to the NMA. ICS/LABA dual combinations were combined as a single treatment group to create a connected network. Across all outcomes, there were no statistically significant differences between BGF MDI and other triple ICS/LAMA/LABA fixed-dose (fluticasone furoate/umeclidinium/vilanterol and beclomethasone dipropionate/glycopyrronium/formoterol fumarate) and open combinations with data available within the network. Results from sensitivity analyses and meta-regression were consistent with the base-case scenario. This NMA suggested that BGF MDI has comparable efficacy to other ICS/LAMA/LABA fixed-dose and open triple combination therapies in reducing exacerbations and improving lung function and symptoms in patients with moderate to very severe COPD. Further research is warranted as additional evidence regarding triple therapies, especially fixed-dose combinations, becomes available.
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efficacy of tiotropium olodaterol in patients with chronic obstructive pulmonary disease by initial disease severity and treatment intensity a post hoc analysis
Advances in Therapy, 2015Co-Authors: Gary T. Ferguson, L Gronke, Lawrence Korducki, Matjaž Fležar, Roger Abrahams, Stephanie Korn, Roland BuhlAbstract:Introduction The once-daily long-acting Muscarinic Antagonist (LAMA) tiotropium and once-daily long-acting β2-agonist (LABA) olodaterol have been studied as a once-daily fixed-dose combination (FDC) in patients with chronic obstructive pulmonary disease (COPD). Two large, 52-week, double-blind, parallel-group studies in patients with moderate–very severe COPD demonstrated that tiotropium + olodaterol significantly improved lung function and symptoms versus the monocomponents. This post hoc analysis determined effects on lung function by prior LAMA or LABA maintenance treatment and initial disease severity.
