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Research Area
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Description
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Dry eyes , Inflammation |
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Biological Activity
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Description
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Cilomilast (SB-207499) is a potent LPDE4 and HPDE4 inhibitor with IC50 of 100 nM and 120 nM, respectively. |
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Targets
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LPDE4 |
HPDE4 |
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IC50 |
100 nM |
120 nM [1] |
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In Vitro
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Cilomilast produces a concentration-dependent increase in cAMP content in U937 cells. Cilomilast produces a concentration-dependent increase in cAMP content in U937 cells. [2] In isolated human monocytes, Cilomilast and (R)-rolipram are equipotent at suppressing LPS-induced TNF-α formation with -log (IC50) of 7.0 and 7.2, respectively. Both Cilomilast and (R)-rolipram produces a modest prevention of fMLP-induced degranulation of human neutrophils. Cilomilast and (R)-rolipram are equipotent at suppressing neutrophil activation with -log (IC50) of 7.1 and 6.4, respectively. [2] Cilomilast significantly decreases the expression of TNF-α in the cornea and IL-1α, IL-1β, and TNF-α in the conjunctivaas compared to vehicle control. Cilomilast treatment markedly decreases the presence of CD11b+ antigen-presenting cells in the central and peripheral cornea, and leads to decreased conjunctival expression of cytokines IL-6, IL-23, and IL-17. Moreover, Cilomilast decreases the expression of IL-17 and IL-23 in the draining lymph nodes. [3] Cilomilast reduces TLR4 expression, IL-8 release and neutrophil chemotactic activity as well as it increased IP-10 release and lymphocyte chemotactic activity. [4] |
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In Vivo
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Cilomilast inhibits human TNFα production with oral ED50 of 4.9 mg/kg. In contrast to their equipotent activity against TNFα production, Cilomilast (ED50 = 2.3 mg/kg, p.o.) is 10-fold less potent than R-rolipram (ED50 = 0.23 mg/kg, p.o.) in reversing reserpine-induced hypothermia, a model of antidepressant activity. [1] In time course studies, Cilomilast (30 mg/kg, p.o.) suppresses TNFα production for at least 10 hour. The ability of Cilomilast to modulate interleukin-4 productionin vivo is assessed in a chronic oxazolone-induced contact sensitivity model in Balb/c mice. Topical administration of Cilomilast (1000 μg) inhibits intralesional concentrations of interleukin-4. [1] Orally administered cilomilast dose-dependently inhibits production of interleukin-4, TNF-α, and cysteinyl leukotrienes, as well as leukocyte infiltration in bronchoalveolar lavage fluid from the airways of ovalbumin-sensitized Brown Norway rats [5]. |
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Clinical Trials
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A phase III clinical trial of Cilomilast for the treatment of emphysema and bronchitis has been completed. |
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Features
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Cilomilast has been used to treat chronic obstructive pulmonary disease (COPD) for centuries. |
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Protocol
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Cell Assay
[2]
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| Cell Lines |
U937 cells |
| Concentrations |
0.1-10 μM |
| Incubation Time |
5 min |
| Methods |
U937 cells (1-2 × 10 6) are incubated at 37 °C in a shaking water bath with Cilomilast for 1 min before the addition of 0.1 μM PGE 2 (total volume of 200 μL). The incubation proceeds for an additional 4 min and is stopped by the addition of 0.1 mL of HClO4 (17.5%), neutralized with 0.15 ml of K23 (1.0 M) and diluted to 1 mL with sodium acetate buffer. Samples are centrifuged at 3000 × g for 10 min. Aliquots of the supernatant fraction are assayed for cAMP content by radioimmunoassay using commercially available kits. |
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Animal Study
[1]
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| Animal Models |
Balb/c, CD-1 and C57B1/6 male mice weighing from 18 to 25 g with human monocytes or endotoxin-induced shock |
| Formulation |
Olive oil |
| Doses |
3, 6, 12, 25, 50 mg/kg |
| Administration |
Gavage |
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References |
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[1] Griswold DE,et al. J Pharmacol Exp Ther. 1998, 287(2),705-711.
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[2] Barnette MS, et al. J Pharmacol Exp Ther. 1998, 284(1), 420-426.
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[3] Sadrai Z, et al. Invest Ophthalmol Vis Sci. 2012.
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[4] Pace E, et al. Cell Immunol. 2011, 268(1), 47-53.
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[5] Kobayashi M, et al. Int Immunopharmacol. 2011, 11(6), 732-739.
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