Corticosteroid pharmacokinetics in asthma

Lane, S. J.; Palmer, Jamie; Skidmore, I.F.; Lee, TakH.

doi:10.1016/0140-6736(90)92886-m

Cited by 24 publications

(6 citation statements)

References 4 publications

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“…The initial suggestion of Schwartz and colleagues (527) was that defective responses to steroids were due to increased clearance of the glucocorticoid, resulting in reduced clinical and eosinopenic response. There is no evidence for altered bioavailability or plasma clearance of prednisolone or methylprednisolone in patients with SR asthma (535)(536)(537). Metabolism of corticosteroids may be increased by induction of P-450 enzymes in response to certain drugs, which may thus lead to a secondary steroid resistance (538).…”

Section: Mechanisms Of Steroid Resistancementioning

confidence: 99%

Efficacy and Safety of Inhaled Corticosteroids

Barnes

Pedersen

Busse

1998

Am J Respir Crit Care Med

700

406

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Section: Mechanisms Of Steroid Resistancementioning

confidence: 99%

Efficacy and Safety of Inhaled Corticosteroids

Barnes

Pedersen

Busse

1998

Am J Respir Crit Care Med

700

406

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“…We and others have shown that GC resistance in asthma is not attributable to altered GC pharmacokinetics [10,11]. The clinical sensitivity of asthmatics to GC therapy can be correlated with the sensitivity of their peripheral blood T-lymphocytes to GC inhibition of proliferation and cytokine synthesis in vitro [10,12,13].…”

mentioning

confidence: 99%

Glucocorticoid resistant asthma: T-lymphocyte steroid metabolism and sensitivity to glucocorticoids and immunosuppressive agents

Corrigan

Bungre²,

Assoufi³

et al. 1996

Eur Respir J

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G Gl lu uc co oc co or rt ti ic co oi id d r re es si is st ta an nt t a as st th hm ma a: : T T--l ly ym mp ph ho oc cy yt te e s st te er ro oi id d m me et ta ab bo ol li is sm ma an nd d s se en ns si it ti iv vi it ty y t to o g gl lu uc co oc co or rt ti ic co oi id ds s a an nd d i im mm mu un no os su up pp pr re es ss si iv ve e a ag ge en nt ts s with dexamethasone for their antiproliferative effects on T-lymphocytes from GC sensitive and resistant asthmatics, and also to compare the rates of steroid metabolism by T-lymphocytes from these patients. Antiproliferative activity of the drugs was measured on peripheral blood T-lymphocytes activated with phytohaemagglutinin (PHA) and anti-CD3 antibody in vitro. The rates of total steroid metabolism and 20α-hydroxylation by T-cell homogenates were measured using radiolabelled progesterone as an established probe substrate.Over a wide concentration range, T-lymphocytes from GC resistant asthmatics were significantly less inhibited by all four GCs as compared with cells from GC sensitive asthmatics. The median inhibitory concentrations (IC50) for inhibition of T-lymphocytes from the GC resistant asthmatics exceeded those likely to be achieved therapeutically by systemic administration (although higher concentrations might in theory be achieved locally in the bronchial mucosa by inhaled administration). In contrast, all three immunosuppressive drugs at putative therapeutic concentrations inhibited T-lymphocytes both from GC sensitive and resistant asthmatics with equivalent potency. The rates of total metabolism and 20α-hydroxylation of steroid by homogenates of T-lymphocytes from GC sensitive and resistant asthmatics were equivalent.Thus, relative GC resistance in T-lymphocytes from GC resistant as compared with sensitive asthmatics is: 1) manifest with GC molecules of variable molecular structure; 2) not accompanied by elevated intracellular metabolism of steroids; and 3) overcome by immunosuppressive drugs which inhibit T-lymphocytes by non-GC-mediated mechanisms. We conclude that current anti-asthma glucocorticoids at therapeutic concentrations are unlikely to be of benefit for the therapy of glucocorticoid resistant asthma, and that other immunosuppressive drugs may have potential as therapeutic agents in these patients.

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“…The particle size of dry powder fluticasone propionate is increased in the presence of tobacco smoke and based on this finding it has been postulated that cigarette smoking could prevent the dispersion of corticosteroid into the small airways of the lung and hence inhaler efficacy [66]. The pharmacokinetics of oral prednisolone in asthma is similar to healthy controls [67]. …”

mentioning

confidence: 67%

Addressing corticosteroid insensitivity in adults with asthma

Thomson

2016

Expert Review of Respiratory Medicine

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Corticosteroids are the most effective treatment for asthma, but the therapeutic response varies markedly between individuals, with up to one third of patients showing evidence of insensitivity to corticosteroids. This article summarizes information on genetic, environmental and asthma-related factors as well as demographic and pharmacokinetic variables associated with corticosteroid insensitivity in asthma. Molecular mechanisms proposed to explain corticosteroid insensitivity are reviewed including alterations in glucocorticoid receptor subtype, binding and nuclear translocation, increased proinflammatory transcription factors and defective histone acetylation. Current therapies and future interventions that may restore corticosteroid sensitivity in asthma are discussed, including small molecule drugs and biological agents. In the future, biomarkers may be used in the clinic to predict corticosteroid sensitivity in patients with poorly controlled asthma. Word count: 120 wordsKey words: Adherence; asthma; biological agents; biomarkers; cigarette smoking; corticosteroids; corticosteroid insensitivity; corticosteroid resistance; small molecule drugs. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 IntroductionAsthma is a chronic inflammatory disease of the airways that affects 300 million people worldwide. Both national and international guidelines recommend daily inhaled corticosteroid as the preferred controller treatment for adults and adolescents with asthma who have poor symptom control or who at risk of exacerbations [201, 202]. Inhaled corticosteroid use in asthma reduces symptoms, improves quality of life and increases lung function as well as decreases the rate of exacerbations [201, 202]. The majority of the therapeutic benefits of inhaled corticosteroids are achieved at low to medium doses [1], although higher doses are often required in patients with more severe asthma [2] [202]. Short courses of oral corticosteroids are administered to treat severe exacerbations and daily oral corticosteroids are used in the lowest dose providing adequate control to treat patients with severe asthma when symptoms are uncontrolled despite maximal therapy [201, 202].Guideline recommendations for inhaled and oral corticosteroid use in asthma are based on average therapeutic responses from clinical trial populations that may not be representative of 'real-life' patients [3]. Numerous studies in adults and children with asthma have noted a considerable patient-to-patient variability in improvements in lung function and airway hyperreactivity with inhaled and oral corticosteroid treatment in patients with apparently similar levels of disease severity [4][5][6] (Figure 1). The findings from these studies suggest that corticosteroid insensitivity may be present in approximately one third of patients with asthma.Inhaled corticosteroids exhib...

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Corticosteroid pharmacokinetics in asthma

Cited by 24 publications

References 4 publications

Efficacy and Safety of Inhaled Corticosteroids

Efficacy and Safety of Inhaled Corticosteroids

Glucocorticoid resistant asthma: T-lymphocyte steroid metabolism and sensitivity to glucocorticoids and immunosuppressive agents

Addressing corticosteroid insensitivity in adults with asthma

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