Glucocorticoids GC

Current effective therapies for asthma have focused on treating the symptoms of the disease. Asthma is characterized by inflammation of the lung; thus, the most prescribed agents to date are the glucocorticoids (GC), due to their widespread anti-inflammatory properties [70-72]. The glucocorticoid drugs budesonide (25), beclomethasone dipropionate (26), and triamcinolone (27) have long been employed for use in treating asthma.

Fluticasone propionale (28) is a more recent addition, and mometasone furoate (29), which is currently under review by regulatory authorities worldwide, has recently been formulated for use in asthma [73]. Many of the adverse effects of elevated systemic glucocorticoid levels have been reduced through the use of inhalation as a method of drug delivery [74]. Inhalation therapy targets the local affected area, where it maximizes local efficacy while reducing systemic bioavailability. Therefore, at therapeutic doses of inhaled glucocorticoids, the risk of systemic effect is considerably reduced when compared to oral glucocorticoid therapy. Mometasone furoate (29) is a synthetic glucocorticoid that is structurally similar to the adrenocorticosteroids and prednisolone. The structure was designed to optimize potency; the furoate group at position C17 greatly increases lipid solubility, while the 21-chloromoiety is important for maximum potency and topical activity [75].

Recent studies have shown that intact budesonide (25) after inhalation binds primarily to available steroid receptors, and mainly excess unbound budesonide is esterified [76,77]. Esterification of budesonide is a rapid process. Thus, in the rat, within 20 minutes of inhalation of radiolabeled budesonide, approximately 80% of the radioactivity within the trachea and main bronchi was associated with budesonide esters, primarily budesonide oleate [78]. The efficacy of topical glucocorticoids in rhinitis and asthma is likely to depend on drug retention in the airway mucosa. With fluticasone propionate (28), retention may be achieved exclusively by its inherent lipophilicity, whereas for budesonide an additional possibility may be provided by its ability to form fatty acid esters in the airway mucosa that release the active drug [79]. Recent studies have investigated the role of inhaled corticosteroids in the long-term management of chronic obstructive pulmonary disease (COPD) [80,81]. This disease is characterized by the presence of airflow obstruction due to chronic bronchities or emphysema; in this respect, the airflow obstruction may be partially reversible, in contrast with asthma, which is largely a reversible disease. Although inflammation seems to be present in the airway of patients with COPD, the specific immunopathology is thought to be different from that of asthma [82]. There is conflicting information on the ability of glucocorticoids to modulate the progression of COPD [83]. Short-term treatment with both inhaled and systemic glucocorticoids may have beneficial effects on symptoms and lung function in subgroups of COPD patients, in particular those with partially reversible airways obstruction [84].

Glucocorticoid mimics the action of the endogenous hormones (i.e., Cortisol) that are involved in the regulation of the inflammatory response in the airway. The sequence of events in glucocorticoid action begins when this lipophilic corticosteroid molecule crosses the cell membrane and binds to the intracellular GR receptor that is located in the cytoplasm. Glucocorticoids bind to GR receptor with different affinities, for example, triamcinolone acetonide (27), budesonide (25), and dexamethasone are 10-90-fold less potent than mometasone furoate in activating transcription [74,85]. Thus, large differences in potency between GC can be observed in in vitro systems.

Combinations of medications has been common practice for the treatment of COPD. There is evidence of increased efficacy of combinations of the b-adrenoceptors agonists and cholinergic receptor antagonists. Such combined therapy has recently been introduced, e.g., Combivent®, which is an aerosol formulation of the b-adrenoceptor agonist, salbutamol, and ipratropium [86].

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