INDEX asthmatics

In asthmatic human patients, fluticasone propionate improves asthma symptoms and parameters, improves pulmonary function and reduces pulmonary inflammation and airway reactivity (Barnes et al 1998). Regular fluticasone reduces or eliminates the need for rescue 2 agonist therapy and produces progressive improvement in airway reactivity and pulmonary function. In clinical studies, equivalent efficacy is demonstrated with one-quarter of the dose of fluticasone compared with flunisolide and budesonide, and equivalent efficacy is demonstrated with one-half of the dose of fluticasone compared with beclometasone. Adrenal function is less affected by fluticasone propionate at therapeutic doses than with beclometasone, flunisolide or budesonide. Although all aerosolized corticosteroids are considered safe, fluticasone has the least potential for adverse systemic effects and has the most favorable therapeutic index. 

In initial studies in which substance P was administered to subjects by intravenous infusion, no effect on airway caliber could be demonstrated. It is possible that potent cardiovascular side effects resulted in homeostatic reflexes with secondary effects on the airways that masked the effects of substance P (Fuller et al., 1987). However, when changes in the partial flow volume curve, a highly sensitive index of airway caliber, were used as the index of airway obstruction, inhaled NkA - and, to a lesser extent, inhaled substance P - caused airway obstruction in healthy people (Joos et al., 1987). NkA is approximately 10-100 times more potent as a bronchocon-strictor in asthmatic than in non-asthmatic subjects (Cheung et al., 1992, 1993) this ratio of potency is similar to that observed for other agonists. 

Figure 4 Determination of airway reactivity using an aerosolized broncho-constrictor. Incrementally increasing concentrations of bronchoconstrictor agonist aerosol are administered to a subject. The decrease in forced expiratory volume in one second (FEV1.0) is measured after each concentration. The dose of bronchoconstrictor that induces a 20% decrease in FEV10 is then interpolated from the dose-response curve obtained in the subject. This concentration provides an index of airway sensitivity or reactivity. Severe asthmatics are extremely sensitive to bronchoconstrictor stimuli (i.e., respond to a lower concentration of bronchoconstrictor), more so than mild asthmatics and nonasthmatic subjects.

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. 

A 1-year observational study of 73 asthmatic children, who were newly started on ICS (fluticasone 250 gg/day, gradually decreased to 125 ng/day) in China, did not suggest any delay in the increase of height, weight and bone age of ulna, radius, and short finger bones, compared to reference ranges pi ]. Furthermore, no difference was observed in Body Mass Index (BMI) before and after one year of treatment. However, the carpal bone age was delayed during the treatment period. 

---