Such concerns do not apply to
Such concerns do not apply to the anti-inflammatory actions shown by the agent, given that CR3465 proved effective in various models of inflammation including guinea pig, rat, and human. Airway inflammation, involving a complex network of local mediators, cytokines, and effector mln0128 (Bradley et al., 1991), is believed to play a central role in the pathogenesis as well as in the clinical manifestations of asthma. Thus, a speculative inference suggests that additional antiinflammatory properties shown by a prospective antiasthmatic drug would potentially represent an added value for the management of such a multifactorial condition (Roquet et al., 1997). In our study, CR3465 administration was associated with a dramatic reduction of total leukocytes and eosinophils in the bronchoalveolar lavage fluid after antigen challenge of actively sensitized guinea pigs, its effect being greater than that of the reference compound montelukast. These results are in agreement with those published in a recent manuscript (Wu et al., 2003), reporting that doses of montelukast higher than 10 mg/kg were necessary to produce a significant decrease of inflammatory cell infiltrates. Moreover, intravenous administration of CR3465 was able to functionally inhibit histamine-induced bronchoconstriction in vivo. An inhibitory action versus histaminergic stimulus was detected as well in guinea pig isolated tracheal strips, where the compound also exhibited a synergic effect in combination with the PDE4 inhibitor rolipram. These findings are in line with previous studies (Bernareggi et al., 1999) showing that, in histamine-challenged guinea pig tracheal strips, an antispasmogenic effect was only observed with agents exhibiting a mixed PDE3/PDE4 inhibitory action. In experiments performed in the presence of both CR3465 and rolipram, the enhanced inhibition of the contractile response to the agonist can most likely be explained by the fact that CR3465 appears to be a 2.5-fold more potent inhibitor of PDE3, compared with PDE4. Clinical outcomes have recently pointed out that administration of leukotriene CysLT1 receptor antagonists decreases the need for rescue treatment with β-adrenoceptor agonists, and that the additive effects of these two drug classes may be required while treating patients with asthmatic bronchoconstriction (Drazen et al., 1999). Considering the interest in PDE4 as a molecular target for new anti-inflammatory and antiasthmatic pharmacotherapies (Giembycz, 1992), the fact that CR3465 also possesses a phosphodiesterase inhibitory action seems in agreement with this scenario, where cAMP levels in airway smooth muscle are at issue. Consistent with previous reports on antiinflammatory effects shown by PDEs inhibitors (Thorphy and Undem, 1991), CR3465 was effective in reducing fMLP-induced degranulation of human neutrophils; even more importantly, oral administration of the compound proved active in decreasing ex vivo TNF-α release from rat whole blood stimulated with lipopolysaccharide. This latter result denotes high bioavailability after oral dosing in the rat because antiinflammatory actions of CR3465 are exerted at concentrations that exceed by far those needed to function as a cysteinyl–leukotriene antagonist. This is consistent with our pharmacokinetic data, which demonstrated an approximate 100% bioavailability after oral administration of the compound in rats. In this respect, Wu et al. (2003) verified that high-dose montelukast was required to produce antiinflammatory effects in an animal model of acute asthma, mediated through the suppression of T helper type-2 (Th2) cytokines. Finally, antiinflammatory properties displayed by CR3465 can be positively weighed up from the larger perspective of the clinical employment of leukotriene antagonists. Recent literature primarily describes leukotriene CysLT1 receptor antagonists as antiinflammatory drugs, their use being more preventive rather than rescue therapy for asthma exacerbations (Devillier et al., 1999). Long-term clinical trials have successfully evaluated the effectiveness of leukotriene antagonists in diminishing the incidence of acute asthmatic outbreaks and the need for glucocorticoid rescue treatment (Spector et al., 1994, Reiss et al., 1996). Nonetheless, a severe condition such as asthma requires a continuous research effort in order to develop new agents allowing better disease management.