Disease relevance of Cilomilast

• Cilomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease: a randomised, dose-ranging study [1].
• However, the PDE4 inhibitors cilomilast and roflumilast have recently shown efficacy in asthma and COPD, with a reduced propensity to cause nausea and emesis [2].
• These results suggest that cilomilast may be a potentially effective therapeutic agent in diseases characterized by excessive tissue destruction, such as emphysema [3].
• At 1, 3 and 6 hr after SB 207499 (30 mg/kg p.o.), OA-induced bronchospasm was inhibited by 92%, 70% and 58%, respectively, corresponding to elevated plasma concentrations of 1.62 +/- 0.19, 1.65 +/- 0.29 and 0 [4].
• The ability of SB 207499 to modulate interleukin-4 production in vivo was assessed in a chronic oxazolone-induced contact sensitivity model in Balb/c mice [5].

High impact information on Cilomilast

• INTERPRETATION: Cilomilast 15 mg twice daily might be an effective maintenance treatment for COPD [1].
• Phosphodiesterase 4 inhibitors, such as Ariflo, possibly represent the most important advance in pulmonary medicine in recent years [6].
• The role of PDE4 inhibitors in modulating cytokines, lipid mediators and in mucociliary clearance, along with clinical efficacy in asthma and/or COPD demonstrated with roflumilast and cilomilast, suggest a broad anti-inflammatory spectrum for these compounds [7].
• Compared with placebo, analysis of variance (ANOVA) of the change from baseline showed that cilomilast did not alter any sputum endpoint or FEV1 [8].
• Cilomilast is the first drug to demonstrate a reduction of tissue cells considered central to the ongoing inflammatory process (macrophages and CD8+ lymphocytes) in patients with stable COPD.Cilomilast is completely absorbed following oral administration and has negligible first-pass metabolism [9].

Chemical compound and disease context of Cilomilast

• Using a rat model of lipopolysaccharide (LPS)-induced pulmonary inflammation, the antiinflammatory activity of SB 207499 was evaluated and compared to that of the prototypic type-4 phosphodiesterase (PDE4) inhibitor, rolipram [10].
• We investigated the safety and potential pharmacodynamic interactions arising from the co-administration of inhaled beta(2)-agonist salbutamol and cilomilast (Ariflo), a new oral phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease and asthma [11].
• OBJECTIVE: To demonstrate a lack of effect of steady-state concentrations of cilomilast, a new oral phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease, on warfarin-induced anticoagulation [12].

Biological context of Cilomilast

• Cilomilast has not shown a propensity for any of the serious cardiac or neurological adverse effects associated with theophylline.Cilomilast exhibits favourable and predictable pharmacokinetics, has few clinically relevant drug-drug interactions and has demonstrated effects on measures of inflammation of potential benefit in the treatment of COPD [9].
• Supernatants of sputum cells and bronchial epithelial cells treated with cilomilast significantly decreased neutrophil chemotaxis (p<0.006 and p<0.008, respectively) [13].
• Clinical pharmacology of Cilomilast [9].
• In anesthetized guinea pigs, SB 207499 inhibited OA-induced bronchoconstriction with i.v. and p.o. ID50 values of 1.7 and 17 mg/kg, respectively [4].
• The potency of these inhibitors was RP 73401 > SB 207499 > rolipram which is correlated with their rank order of potency at inhibiting the catalytic site of purified neutrophil PDE4 [14].

Anatomical context of Cilomilast

• CONCLUSIONS: Cilomilast inhibits the production of some neutrophil chemoattractants by airway cells [13].
• METHODS: Bronchial epithelial cells obtained by bronchial brushing and sputum cells isolated from induced sputum samples were cultured for 24 hours in the presence or absence of cilomilast (1 micro M) [13].
• The current study evaluated the effects of the phosphodiesterase (PDE)4 inhibitor, cilomilast, and other PDE inhibitors on the ability of fibroblasts to degrade extracellular matrix [3].
• Ovalbumin (OA)-induced contractions of guinea pig isolated tracheal strips were inhibited by SB 207499 with an EC50 of 1 microM but had little or no effect on exogenous agonist-induced contraction, which suggests that its effect on OA-induced contraction in vitro is primarily due to inhibition of mediator release from mast cells [4].
• 2. The rank order of potency for inhibition of PDE4 activity in guinea-pig eosinophil, neutrophil and macrophage, and human neutrophil lysates was RP73401 > SB207499 >CDP840 > rolipram > LAS31025 [15].

Associations of Cilomilast with other chemical compounds

• These PDE4 inhibitors also inhibited contraction of three-dimensional collagen gels (control: 100% versus cilomilast: 167.7 +/- 6.9% versus rolipram: 129.9 +/- 1.9% of initial size; P < 0.05, both comparisons) [16].
• Digoxin did not appear to markedly affect cilomilast steady-state pharmacokinetics [17].
• The increase in RANTES was diminished in mouse ears pretreated with cilomilast or diflorasone diacetate [18].
• Two of these studies explored the drug interaction potential of cilomilast with the nonselective PDE inhibitor, theophylline, and a third study compared the pharmacokinetic profile of cilomilast in smokers and nonsmokers [19].
• The aim of the present study was to characterise a mouse model of airways inflammation induced by cigarette smoke and to compare it with a lipopolysaccharide (LPS) model with regards to the efficacy of a PDE4 inhibitor (cilomilast), a corticosteroid (dexamethasone) and macrophage metalloelastase (MMP)-12 gene deletion [20].

Gene context of Cilomilast

• SB 207499, a specific phosphodiesterase type 4 inhibitor, augmented the inhibitory effects of PGE(2) and forskolin on TNF-alpha-induced RANTES [21].
• Upregulation of surface CD11b expression and ERK-1/2 phosphorylation were blocked by cilomilast or rolipram+/-salmeterol for PMNs activated by LTB(4), but not for cells stimulated by TNF-alpha [22].
• Rolipram and cilomilast also increase ABCA1 protein expression in THP-1 and J774.A1 macrophages [23].
• These results indicate that CI-1044 inhibits in vitro LPS-induced TNF-alpha release in whole blood from COPD patients better than rolipram and cilomilast and suggested that it could be a useful anti-inflammatory therapy in COPD [24].
• We describe the high-resolution crystal structures of the catalytic domains of PDE4B, PDE4D, and PDE5A with ten different inhibitors, including the drug candidates cilomilast and roflumilast, for respiratory diseases [25].

Analytical, diagnostic and therapeutic context of Cilomilast

• Cilomilast (Ariflo, SB 207499, SmithKline Beecham), the most advanced member of the class in Phase III clinical trials, was reported to have a limited therapeutic window [26].
• In this model, topical administration of SB 207499 (1000 microgram) inhibited intralesional concentrations of interleukin-4 (55%; P <.01) [5].
• Effects of cilomilast, a selective phosphodiesterase 4 inhibitor, on esophageal motility and pH, and orocecal and colonic transit: two single-center, randomized, double-blind, placebo-controlled, two-part crossover studies in healthy volunteers [27].
• The point estimate (90% CI) for the difference in day 24 INR values between cilomilast and placebo (adjusted for baseline) was 0.02 (90% CI-0.13 to 0.17), which translates to an INR ratio of 1.02 (90% CI 0.91 to 0.13) [12].
• STUDY SELECTION AND DATA EXTRACTION: All clinical trials evaluating cilomilast and published in English were included in this review [28].

References