title: Cilomilast.
abstract: The central role of cyclic nucleotides as intracellular second messengers dates back almost 50 years. The importance of phosphodiesterase in regulating this system was recognized early, and the potential therapeutic role of phosphodiesterase inhibitors in modulating pathologic conditions was also suggested. At that time, the methylxanthines represented major pharmacologic agents capable of inhibiting cyclic nucleotides and were widely used in respiratory medicine. Initially, bronchodilator effects were considered their major mechanism of action, but subsequent studies suggested other potential roles including an anti-inflammatory one. A number of developments led to the decline in popularity of this class of agents, the foremost being their side-effect profile. The discovery of multiple phosphodiesterase isoforms paired with a better understanding of the physiologic and clinical properties of the phosphodiesterases has re-awakened interest in therapeutic agents in this area and in particular the potential for the development of selective phosphodiesterase inhibitors. Cilomilast is a systemically available, second- generation, selective phosphodiesterase-4 inhibitor. It retains the therapeutic activity of the first generation phosphodiesterase-4 inhibitors (such as rolipram) but is believed to have less of an emetic effect. Cilomilast causes a reduction of tissue cells considered central to the ongoing inflammatory process (macrophages and CD8+ lymphocytes) in patients with chronic obstructive pulmonary disease. Chronic obstructive pulmonary disease is now considered a chronic inflammatory disease of the lungs resulting from prolonged exposure to inflammatory agents in cigarette smoke and other environmental and occupational pollutants, and it is currently the principal target of cilomilast. It is characterized by progressive destruction of parenchymal tissue and punctuated by acute exacerbations. The inflammation is thought to begin in the peripheral airways and lung parenchyma. Chronic obstructive pulmonary disease is a progressive disease, leading to disability and eventual death despite conventional therapy. Cilomilast is completely absorbed following oral administration and has negligible first-pass metabolism. It exhibits low between-subject variability. Cilomilast is predominantly protein bound. Plasma clearance is almost entirely metabolic, through multiple parallel pathways. Its terminal elimination half-life is approximately 6.5 hours, and steady state is rapidly achieved. A dose of 15 mg twice daily has been found to be clinically effective. Smoking and age have no clinically relevant effects on cilomilast pharmacokinetics. Most drugs frequently used in patients with chronic obstructive pulmonary disease do not alter its side effect profile. Initial concerns of arteritis involving the gastrointestinal tract in rodent animal models have not been reported in clinical trials. Nausea, presumably of central origin, is the principal adverse reaction seen in healthy subjects taking cilomilast. It has not been associated with the serious cardiac or neurological adverse effects seen with theophylline. Preliminary clinical studies suggest a favorable clinical effect in chronic obstructive pulmonary disease. Cilomilast is generally well tolerated and has not generated safety concerns in reported clinical studies.
authors.affiliation: Division of Pulmonary Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA. neil.schachter@mssm.edu
authors.forename: E Neil
authors.initials: EN
authors.lastname: Schachter
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002264:Carboxylic Acids / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000242:Cyclic AMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003509:Cyclohexanecarboxylic Acids; D004334:Drug Administration Schedule; D004347:Drug Interactions; D006801:Humans; D009570:Nitriles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000378:metabolism; D016032:Randomized Controlled Trials as Topic
chemical_list: D001993:Bronchodilator Agents; D002264:Carboxylic Acids; D003509:Cyclohexanecarboxylic Acids; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors; C433247:Cilomilast; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4