Budesonide Attains Its Wide Clinical Profile by Alternative Kinetics.

The introduction of inhaled corticosteroids (ICSs) changed over a few decades the treatment focus of mild-to-moderate asthma from bronchodilation to reduction in inflammation. This was achieved by inhaling a suitable corticosteroid (CS), giving a high, protracted airway concentration at a low total dose, thereby better combining efficacy and tolerance than oral therapy. Successful trials with the potent, lipophilic "skin" CS beclomethasone dipropionate (BDP) paved the way, suggesting that ICSs require a very low water solubility, prolonging their intraluminal dissolution within airways. The subsequent ICS development, with resulting clinical landmarks, is exemplified here with budesonide (BUD), showing that a similar efficacy/safety relationship is achievable by partly alternative mechanisms. BUD is much less lipophilic, giving it a 100-fold higher water solubility than BDP and later developed ICSs, leading to its more rapid intraluminal dissolution and faster airway and systemic uptake rates. In airway tissue, a BUD fraction is reversibly esterified to intracellular fatty acids, a lipophilic conjugate, which prolongs airway efficacy. Another mechanism is that the rapidly absorbed bulk fraction, via short plasma peaks, adds anti-inflammatory activity at the blood and bone marrow levels. Importantly, these plasma peaks are too short to provoke systemic adverse actions. Controlled clinical trials with BUD changed the use of ICS from a last resort to first-line treatment. Starting ICS treatment immediately after diagnosis ("early intervention") became a landmark for BUD. An established dose response made BUD suitable for the treatment of patients with all degrees of asthma severity. With the development of the budesonide/formoterol combination inhaler (BUD/FORM), BUD contributed to the widely used BUD/FORM maintenance and reliever therapy (MART). Recent studies demonstrated the value of BUD/FORM as a generally recommended as-needed therapy for asthma ("anti-inflammatory reliever", AIR). These abovementioned qualities have all influenced international asthma management and treatment guidelines.

May a different kinetic mode explain the high efficacy/safety profile of inhaled budesonide?

The claimed functional basis for ICSs in asthma and COPD is airway selectivity, attained by inhaling a potent, lipophilic compound with long local dissolution/absorption time. The development has been empirically based, resulting in five widely used ICSs. Among them, budesonide (BUD) deviates by being less lipophilic, leading to a more rapid systemic uptake with plasma peaks with some systemic anti-inflammatory activity. By this, BUD fits less well into the current pharmacological dogma of optimal ICS profile. In this review we compared the physicochemical, pharmacological and clinical properties of BUD, fluticasone propionate (FP) and fluticasone furoate (FF), representing different levels of lipophilicity, airway and systemic kinetics, focusing on their long-acting ß2-agonist (LABA) combinations, in line with current GINA and GOLD recommendations. We are aware of the differences between formoterol (FORM) and the not rapid acting LABAs such as e.g. salmeterol and vilanterol but our comparisons are based on currently available combination products. A beclomethasone dipropionate (BDP)/FORM combination is also commented upon. Based on clinical comparisons in asthma and COPD, we conclude that the BUD/formoterol (BUD/FORM) combination is as effective and safe as the FP and FF combinations, and is in some cases even better as it can be used as "maintenance plus reliever therapy" (MART) in asthma and as maintenance in COPD. This is difficult to explain by current views of required ICS's/LABAs pharmacokinetic profiles. We propose that BUD achieves its efficacy by a combination of airway and systemic activity. The airway activity is dominating. The systemic activity contributes by plasma peaks, which are high enough for supportive anti-inflammatory actions at the blood and bone marrow levels but not sufficiently long to trigger a similar level of systemic adverse effects. This may be due to BUD's capacity to exploit a systemic differentiation mechanism as programmed for cortisol's various actions. This differentiation prospect can be reached only for an ICS with short plasma half-life. Here we present an alternative mode for an ICS to reach combined efficacy and safety, based on a poorly investigated and exploited physiological mechanism. A preference of this mode is broader versatility, due to that its straighter dose-response should allow a better adaptation to disease fluctuations, and that its rapid activity enables use as "anti-inflammatory reliever".

Correction to: Benefit:Risk Profile of Budesonide in Obstructive Airways Disease.

Page 5, Fig. 2 Key milestones in the development of budesonide.

Benefit:Risk Profile of Budesonide in Obstructive Airways Disease.

Airway inflammation is a major contributing factor in both asthma and chronic obstructive pulmonary disease (COPD) and represents an important target for treatment. Inhaled corticosteroids (ICS) as monotherapy or in combination therapy with long-acting ß2-agonists or long-acting muscarinic antagonists are used extensively in the treatment of asthma and COPD. The development of ICS for their anti-inflammatory properties progressed through efforts to increase topical potency and minimise systemic potency and through advances in inhaled delivery technology. Budesonide is a potent, non-halogenated ICS that was developed in the early 1970s and is now one of the most widely used lung medicines worldwide. Inhaled budesonide's physiochemical and pharmacokinetic/pharmacodynamic properties allow it to reach a rapid and high airway efficacy due to its more balanced relationship between water solubility and lipophilicity. When absorbed from the airways and lung tissue, its moderate lipophilicity shortens systemic exposure, and its unique property of intracellular esterification acts like a sustained release mechanism within airway tissues, contributing to its airway selectivity and a low risk of adverse events. There is a large volume of clinical evidence supporting the efficacy and safety of budesonide, both alone and in combination with the fast- and long-acting ß2-agonist formoterol, as maintenance therapy in patients with asthma and with COPD. The combination of budesonide/formoterol can also be used as an as-needed reliever with anti-inflammatory properties, with or without regular maintenance for asthma, a novel approach that is already approved by some country-specific regulatory authorities and currently recommended in the Global Initiative for Asthma (GINA) guidelines. Budesonide remains one of the most well-established and versatile of the inhaled anti-inflammatory drugs. This narrative review provides a clinical reappraisal of the benefit:risk profile of budesonide in the management of asthma and COPD.

20α- and 20ß-dihydrocortisone may interfere in LC-MS/MS determination of cortisol in saliva and urine.

Background LC-MS/MS methods offer high selectivity in cortisol determinations. However, endogenous steroid metabolites may still interfere and compromise the results, for example in the diagnosis of Cushing's syndrome. Erroneously elevated cortisol may, in particular, be misleading at the low concentrations found in salivary samples obtained at late night and after dexamethasone suppression. Methods Interferences in our LC-MS/MS method used for determination of cortisol in saliva and urine were identified by comparing their retention times and mass spectra with those of pure candidate substances. The chromatographic conditions used in our LC-MS/MS method, including column and mobile phase gradient, were varied in order to separate the target compound from the interferences. Results Two interferences, which were co-eluting or eluting close to cortisol in our original method, were successfully separated from cortisol by adjustment of the chromatographic conditions. These interferences were found in both urine and saliva and were identified as the two endogenous cortisol isomers 20α- and 20ß-dihydrocortisone. The isomers share molecular mass and mass spectrometric fragmentation pattern with cortisol using electrospray ionization in the positive-ion mode. Both give rise to the transitions m/z 363.1>121.1, 363.1>115.1 and 363.1>97.1. In our original LC-MS/MS setup, the 20ß-dihydrocortisone co-eluted with cortisol in the chromatography step resulting in false high determinations. Conclusions Cortisol determination by LC-MS/MS may suffer from erroneously elevated results unless 20α- and 20ß-dihydrocortisone are chromatographically separated from cortisol.

The role of intracellular esterification in budesonide once-daily dosing and airway selectivity.

BACKGROUND: Since their introduction in the 1970s, inhaled corticosteroids (ICSs) have been used to control airway inflammation associated with asthma. Budesonide is one of the ICSs recommended as first-line therapy for mild to moderate persistent asthma. OBJECTIVE: This article describes the esterification of budesonide and how it results in prolonged, location-specific retention of drug in the airways, allowing once-daily dosing. RESULTS: Studies conducted over the past decade have shown that budesonide forms reversible fatty acid esters within the cells of airway tissue, resulting in the formation of an intracellular depot pool of inactive drug. As the intracellular concentration of free budesonide decreases, these budesonide esters are hydrolyzed back to their active state. This process increases budesonide's retention in the airways, prolongs its duration of action, and lowers the risk of systemic effects. CONCLUSIONS: By extending budesonide's local anti-inflammatory effect and increasing its airway selectivity, the esterification process appears to contribute to the drug's efficacy, particularly during once-daily administration. Reducing the number of required daily inhalations may increase patient compliance with asthma therapy, although this remains to be evaluated.

Design and synthesis of dihydrofolate reductase inhibitors encompassing a bridging ester group. Evaluation in a mouse colitis model.

Crohn's disease is a chronic inflammatory bowel disease characterized by inflammation of both the small and large intestines. Methotrexate (MTX), a classical dihydrofolate reductase (DHFR) inhibitor, has been used as a therapeutic agent in the treatment of patients with Crohn's disease in recent years. We sought to develop antifolates similar in structure to MTX that would be effective in reducing inflammation in a mouse disease model of colitis. Four classical DHFR inhibitors encompassing ester bridges in the central parts of the molecules were synthesized. These antifolates were efficient inhibitors of the DHFR enzyme derived from rat. They were also tested in vitro for their ability to inhibit induced proliferation of lymphocytes from mouse spleen. Inhibition of cell proliferation was achieved only in the micromolar range, whereas MTX was effective at low nanomolar concentrations. One of the DHFR inhibitors (1), with an IC(50) value for rlDHFR approximately 8 times higher than that of methotrexate, was selected for in vivo experiments in an experimental colitis model in mice. This compound demonstrated a clear antiinflammatory effect after topical administration, comparable to the effect achieved with the glucocorticoid budesonide. Three parameters were evaluated in this model: myeloperoxidase activity, colon weight, and inflammation scoring. A favorable in vivo effect of compound 1 (15 mg/(kg.day)) was observed in all three inflammatory parameters. However, the results cannot be explained fully by DHFR inhibition or by inhibition of lymphocyte cell proliferation, suggesting that other yet unidentified mechanisms enable reduction of inflammation in the colitis model. The mechanism of action of methotrexate analogues encompassing a bridging ester group is not well understood in vivo but seems to lend itself well to further development of similar compounds.

Budesonide fatty-acid esterification: a novel mechanism prolonging binding to airway tissue. Review of available data.

AIMS: Evidence is accumulating that budesonide (BUD) forms intracellular esters in airways. which may affect both duration of action and therapeutic ratio of this drug. The aim of the present paper is to review the preclinical and human experimental evidence supporting the esterification of BUD, and to discuss the clinical implications this may have on asthma and rhinitis treatment. RESULTS: After inhalation, intact BUD binds primarily to available steroid receptors, and mainly excess (unbound) BUD is esterified. Esterification of BUD is a rapid process: within 20 minutes of inhalation in the rat of radiolabeled BUD, approximately 80% of radioactivity within the trachea and main bronchi was associated with BUD esters, primarily BUD oleate. After 4 hours, the proportion of BUD esters/total cellular BUD was typically 40 to 50% for lung, 70 to 90% for trachea, and only 10 to 15% for peripheral muscle. Comparative in vitro and in vivo studies have shown that esterification prolongs BUD's anti-inflammatory activity longer than that of corticosteroids that can not form esters. Clinical studies have confirmed the prolonged presence of BUD esters, as well as intact BUD, in human airway tissues: 6 hours postdosing, nasal biopsy concentrations of intact BUD were >10-fold greater than those of fluticasone propionate and at 24 hours BUD was detectable in threefold more biopsies than fluticasone propionate. The impact of esterification on airway selectivity of BUD has also been demonstrated in vivo and using pharmacokinetic/pharmacodynamic models. CONCLUSIONS: BUD is retained in airways as esters, a novel kinetic mechanism for synthetic glucocorticoids. In preclinical studies this esterification is correlated to a prolonged local tissue binding and efficacy, which is not found when the esterification is inhibited by an esterification blocker. Because less esters are formed in the systemic compartment than in airways/lung, the local benefit:systemic risk ratio may also be improved by this mechanism. BUD possesses favorable clinical properties, including its approved once-daily efficacy in asthma, which is probably in part attributable to esterification. However, a direct proof of the latter in patients requires effective and safe inhibitors of the esterification, which are not yet available. Therefore, evidence to support the therapeutic impact of esterification is still circumstantial.

Molecular mechanisms of decreased steroid responsiveness induced by latent adenoviral infection in allergic lung inflammation.

BACKGROUND: We recently reported that allergic lung inflammation in guinea pigs became steroid resistant in the presence of latent adenoviral infection. OBJECTIVE: We sought to investigate the molecular mechanisms that underlie steroid resistance in adenoviral infection. METHODS: Guinea pigs with a latent adenoviral infection were sensitized and challenged with ovalbumin (OVA) and given daily injections of budesonide (20 mg/kg administered intraperitoneally). Sham-infected animals received either saline challenge without budesonide injection or OVA challenge with or without budesonide. The inflammatory response in the lung was measured by means of quantitative histology. Eotaxin, monocyte chemoattractant protein 1 (MCP-1), and RANTES expression in the lung were analyzed by means of Northern blotting, and the binding activity of activator protein 1 (AP-1) and nuclear factor kappaB in nuclear extracts from the lung was analyzed with electrophoretic mobility shift assays. RESULTS: OVA challenge increased eosinophil infiltration and eotaxin and MCP-1 mRNA expression in the lungs, and glucocorticoids reduced these increases in the sham-infected, but not the adenovirus-infected, animals. Changes in binding activity of AP-1, but not nuclear factor kappaB, paralleled changes in eotaxin and MCP-1 mRNA. CONCLUSION: We conclude that latent adenoviral infection inhibits the anti-inflammatory effects of glucocorticoids on allergen-induced eotaxin and MCP-1 expression through AP-1, leading to steroid-resistant allergic lung inflammation.