Human Receptor Kinetics, Tissue Binding Affinity, and Stability of Mometasone Furoate

Valotis, Anagnostis; Neukam, K.; Elert, O.; Högger, Petra

doi:10.1002/jps.20049

Cited by 55 publications

(62 citation statements)

References 30 publications

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“…This was most likely due to the high association and low dissociation rate constants of fluticasone and mometasone with the glucocorticoid receptor. 33 Furthermore, silencing the cellular expression levels of the glucocorticoid receptor completely abolished the ability of mometasone to protect against tunicamycin-induced apoptosis (Figure 2f), thus confirming the existence of a crosstalk between glucocorticoid receptor signaling and ER stress-induced apoptosis.…”

Section: Resultssupporting

confidence: 53%

The transrepression arm of glucocorticoid receptor signaling is protective in mutant huntingtin-mediated neurodegeneration

et al. 2015

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The unfolded protein response (UPR) occurs following the accumulation of unfolded proteins in the endoplasmic reticulum (ER) and orchestrates an intricate balance between its prosurvival and apoptotic arms to restore cellular homeostasis and integrity. However, in certain neurodegenerative diseases, the apoptotic arm of the UPR is enhanced, resulting in excessive neuronal cell death and disease progression, both of which can be overcome by modulating the UPR. Here, we describe a novel crosstalk between glucocorticoid receptor signaling and the apoptotic arm of the UPR, thus highlighting the potential of glucocorticoid therapy in treating neurodegenerative diseases. Several glucocorticoids, but not mineralocorticoids, selectively antagonize ER stress-induced apoptosis in a manner that is downstream of and/or independent of the conventional UPR pathways. Using GRT10, a novel selective pharmacological modulator of glucocorticoid signaling, we describe the importance of the transrepression arm of the glucocorticoid signaling pathway in protection against ER stress-induced apoptosis. Furthermore, we also observe the protective effects of glucocorticoids in vivo in a Drosophila model of Huntington's disease (HD), wherein treatment with different glucocorticoids diminished rhabdomere loss and conferred neuroprotection. Finally, we find that growth differentiation factor 15 has an important role downstream of glucocorticoid signaling in antagonizing ER stress-induced apoptosis in cells, as well as in preventing HD-mediated neurodegeneration in flies. Thus, our studies demonstrate that this novel crosstalk has the potential to be effectively exploited in alleviating several neurodegenerative disorders.

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Section: Resultssupporting

confidence: 53%

The transrepression arm of glucocorticoid receptor signaling is protective in mutant huntingtin-mediated neurodegeneration

et al. 2015

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“…MF shows a high receptor-binding affinity and high proteinbinding (98%) [25] and exhibits a large volume of distribution, high lipophilicity, oral bioavailability and first-pass metabolism similar to that of FP [20,64]. Although initial PK studies suggested that the bioavailability of MF was ,1% [64], its systemic activity may be higher, potentially due to the presence of a number of active metabolites that are usually not detected [20,[69][70][71].…”

Section: Modern and Emerging Inhaled Corticosteroidsmentioning

confidence: 99%

“…Although the RRA of BUD is lower than those of MF, FP and des-CIC [21,24,25], clinical studies have demonstrated that BUD has a good safety profile and is effective in the treatment of asthma [75][76][77]. Moreover, Bud forms fatty acid conjugates, thus allowing for once-daily dosing [61,63].…”

Section: Modern and Emerging Inhaled Corticosteroidsmentioning

confidence: 99%

Relevance of pharmacokinetics and pharmacodynamics of inhaled corticosteroids to asthma

Nave²,

et al. 2006

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The pharmacokinetic and pharmacodynamic effects of inhaled corticosteroids (ICS) have shaped the efficacy and safety of these agents in the treatment of asthma.Important pharmacokinetic and pharmacodynamic characteristics that can enhance the efficacy of ICS include small particle size, high glucocorticoid-receptor-binding affinity, long pulmonary residence time and lipid conjugation. These characteristics can increase or prolong the antiinflammatory effects of an ICS. Important pharmacokinetic characteristics that can enhance the safety of ICS include on-site activation in the lung, low oropharyngeal exposure, negligible oral bioavailability, high protein-binding and rapid systemic clearance.The degree of oropharyngeal exposure is relevant to local side-effects, such as oropharyngeal candidiasis, dysphonia and coughing. Pharmacokinetic properties that influence the degree of systemic exposure are relevant to the pharmacodynamic effect of ICS-induced hypothalamicpituitary-adrenal axis suppression and cortisol suppression, an indicator of potential long-term systemic side-effects, such as reduced growth velocity and bone density, fractures, and skin bruising and thinning.Therefore, significant differences in the pharmacokinetic and pharmacodynamic characteristics of the currently available inhaled corticosteroids warrant careful consideration when used in clinical practice as they may result in differences in efficacy and local and systemic safety profiles.

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“…Both these actions have as a result an altered transcription of pro-and anti-inflammatory genes. The main pharmacokinetic/dynamic properties [9][10][11] depend on (a) receptor affinity [12]; (b) particle size and formulation [13,14]; (c) oral, pulmonary, and systemic bioavailability [15][16][17][18]; (d) half-life [17]; (e) protein binding [19]; (f) bioactivation [17,20]; (g) lipophilicity; (h) lipid conjugation [8]; and (i) metabolism [17].…”

Section: Pharmacokinetics and Pharmacodynamics Of Icssmentioning

confidence: 99%

Erratum to: Safety Considerations of Inhaled Corticosteroids in the Elderly

et al. 2015

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Inhaled corticosteroids (ICSs) are widely used in the treatment of patients with chronic obstructive pulmonary diseases. However, high-dose regimens and longterm use of ICSs have the potential to cause a variety of local and systemic side effects such as candidiasis, cataracts, glaucoma, and osteoporosis. The use of ICSs can also be associated with the risk of bone fractures, diabetes mellitus and pneumonia. These ICS-related side effects are of particular importance in elderly patients due to the presence of comorbidities and age-related behavioral, cognitive, and psychological problems, which can all interact with inhaled treatment. We reviewed the available literature on the clinically relevant side effects of ICSs in the elderly to provide practical measures to properly monitor and manage the risk of ICSs in the geriatric population. Inspection of the mouth, monitoring of ocular pressure, and use of bone-protective drugs may be necessary in patients on prolonged ICS therapy. Above all, the use of the lowest possible ICS dose and a careful re-assessment of the inhalation procedure should be recommended. Taken together, these observations suggest that physicians should use ICSs appropriately for those patients in whom the benefit will outweigh the risk, especially chronic obstructive pulmonary disease (COPD) patients with previous frequent exacerbations. Given the paucity of information on the topic and the need to extrapolate the results from studies with broader age ranges, we strongly encourage the design of specifically tailored clinical studies in the elderly. Key PointsAsthma and chronic obstructive pulmonary disease (COPD) are inflammatory disorders of the airways. The pharmacological management of these chronic diseases is based on persistent and long-term use of inhaled corticosteroids (ICSs).Asthma and COPD are among the most common chronic diseases in clinical settings, and physicians are expected to diagnose and manage those diseases in the geriatric population on a daily basis. The management of chronic obstructive respiratory diseases in the geriatric population is complicated by the increased occurrence of comorbidities and associated treatment, and by age-associated physiological and structural changes of the lung.The chronic use of ICSs in the elderly is associated with the increased risk of local and systemic side effects such as candidiasis, cataract, glaucoma, diabetes mellitus, bone fractures, and pneumonia. Physicians should be aware of this in order to select those patients in whom the benefits will outweigh the risks.The online version of the original article can be found under

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Human Receptor Kinetics, Tissue Binding Affinity, and Stability of Mometasone Furoate

Cited by 55 publications

References 30 publications

The transrepression arm of glucocorticoid receptor signaling is protective in mutant huntingtin-mediated neurodegeneration

The transrepression arm of glucocorticoid receptor signaling is protective in mutant huntingtin-mediated neurodegeneration

Relevance of pharmacokinetics and pharmacodynamics of inhaled corticosteroids to asthma

Erratum to: Safety Considerations of Inhaled Corticosteroids in the Elderly

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