Selective asthma therapy

Underlying the discovery of a selective asthma therapy are numerous advances in analytical and instrumental techniques as well as synthetic methods that allow the construction of complex molecules. Practical catalytic, stereospecific, and organometallic methods that permit a high level of stereochemical control have enabled production at the multiton level of molecules previously inaccessible even at the gram scale. 

Dr David Graham from the FDA, speaking to the US senate in 2004, controversially raised concerns (refuted by the respective Pharmaceutical Companies) over the safety of the retinoid, isotretinoin (used in the treatment of cancer), the statin, rosuvastatin (used to lower cholesterol), a long-acting p2-receptor antagonist, salmeterol (used in asthma therapy), and a selective serotonin reuptake inhibitor, paroxetine (used as an antidepressant) (21). 

Bronchodilators Mabuteml is an adrenergic jS-2 agonist. It is more selective and potent than salbutamol, the reference bronchodilator used in asthma therapy (Figure 8.49). 

The principal asthma therapies have all been in clinical practice since the early 1970s and before, yet their mechanisms and potential hazards in many cases remain obscure. The trend towards inhaled corticosteroids continues to raise concerns about their long-term side-effects. This has fuelled efforts to develop safer anti-inflammatory therapies, despite the advent of fluticasone, which is 100 per cent first-pass metabolized in the liver and has fewer systemic effects (Harding, 1990). Suggestions that the long-actingy 2-agonists (salmeterol, formoterol) may be anti-inflammatory appear to be unfounded, but the possibility of an antiinflammatory effect of theophylline (Ward et al., 1993) has accelerated development of selective phosphodiesterase (PDE IV) inhibitors, which may have reduced side-effects and a better therapeutic index than theophylline itself. The immunosuppressants, such as cyclosporin A which prevents expression of IL-2 and IL-2R in T cells, are limited by toxicity to a small minority of very severe corticosteroid-dependent asthmatics. 

Consistent with an important role of PDF4 in obstructive lung disease, selective PDF4 inhibitors have been evaluated in clinical trials for the treatment of asthma and COPD. In one study, cilomilast (Ariflo, 15 mg twice daily for 10 weeks) decreased inflammatory cell infiltration sigifificantly in bronchial biopsies of patients with COPD. Further studies are needed to define the role of PDF4 inhibitors in asthma and COPD, but these drugs are promising candidates for new approaches to asthma therapy. 

Montelukast sodium (1, 2-[l-[[(lR)-l-[3-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulphanyhnethyl] cyclopropyl]acetic acid, sodium salt, Singulair , originator Merck Co.), a once-a-day oral antagonist of leukotriene D4 (LTD4) was selected for chnical development in 1991, and introduced in 1997 for the treatment of both adult and pediatric chronic asthma. This compound is recognized as one of the most significant advances in asthma therapy in the last 25 years [1] and is commonly used for the treatment of nocturnal asthma. 

Non-selective 3-blockers, including those in ophthalmic preparations, may cause asthma symptoms, and these agents should be avoided in asthmatics unless the benefits of therapy outweigh the risks.1 In asthmatic patients requiring 3-blocker therapy, a Pi-selective agent should be chosen. Because selectivity... 

In AIT, patient selection is critical. The allergic cause of AR should be verified by history and skin or blood tests. Additionally, the responsible antigen(s) must be identified. Patients who may benefit from AIT include those who do not tolerate traditional drug therapy (e.g., nosebleeds with intranasal steroids and sedation with antihistamines), suffer from severe symptoms, have comorbid conditions (e.g., asthma and sinusitis), fail drug therapy, or prefer not to take long-term medication.11 22"24... 

Adrenaline but not noradrenaline is useful in the therapy of bronchial asthma since the dilatory effects on the smooth muscle in this area are mediated via /82-adrenoceptors. Furthermore, a swelling of the mucosa, which might considerably contribute to the airway resistance, is reduced by /82-adrenoceptor activation. In this indication selective /82-mimetics are useful due to less circulatory side effects. 

It is newer long acting selective P2 adrenergic agonist with slow onset of action, used for maintenance therapy in asthma, nocturnal asthma and asthma induced by exercise. 

One of the most important uses of sympathomimetic drugs is in the therapy of bronchial asthma. This use is discussed in Chapter 20. Nonselective drugs (epinephrine), -selective agents (isoproterenol), and B2-selective agents (albuterol, metaproterenol, terbutaline) all are available for this indication. Sympathomimetics other than the 32-selective drugs are now rarely used because they are likely to have more adverse effects than the selective drugs. 

Dolovich MB, Ahrens RC, Hess DR, et al. Device selection and outcomes of aerosol therapy evidence-based guidelines American College of Chest Physicians/American College of Asthma, Allergy, and Immunology. Chest. 2005 127 335-371. 

Metoprolol, atenolol, and several other drugs (see Table 10-2) are members of the Di-selective group. These agents may be safer in patients who experience bronchoconstriction in response to propranolol. Since their Bi selectivity is rather modest, they should be used with great caution, if at all, in patients with a history of asthma. However, in selected patients with chronic obstructive lung disease the benefits may exceed the risks, eg, in patients with myocardial infarction. Betai-selective antagonists may be preferable in patients with diabetes or peripheral vascular disease when therapy with a 6-blocker is required since B2 receptors are probably important in liver (recovery from hypoglycemia) and blood vessels (vasodilation). 

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