tetomilast and Colitis--Ulcerative

Ulcerative colitis (UC) is an idiopathic inflammatory condition of the large intestine. Recent advances in our understanding of the pathogenesis of UC have led to the development of novel treatments for this often debilitating condition. Aside from aminosalicylates and corticosteroids, drugs that have been used for decades in the treatment of UC, biologic agents, in addition to medications targeting specific effector mechanisms involved in the inflammatory cascade, have been used in patients with UC with varying degrees of success. Clinicians have never had as many therapeutic options for UC as they do today. Herein we review the variety of treatment options, both standard and investigational, that are available for patients with UC.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Butyrates; Colitis, Ulcerative; Cyclosporine; Epidermal Growth Factor; Glucocorticoids; Humans; Immunosuppressive Agents; Infliximab; Interferons; Mercaptopurine; Plasmapheresis; Probiotics; Remission Induction; Thiazoles

Tetomilast (OPC-6535), a novel thiazole compound, inhibits phosphodiesterase-4 and proinflammatory functions of leukocytes including superoxide production and cytokine release.. One hundred eighty-six patients with mildly to moderately active ulcerative colitis (Disease Activity Index [DAI] 4-11 points) from 35 centers were randomized to receive an oral, once-daily dose of placebo or tetomilast 25 mg or 50 mg for 8 weeks.. Percentages of patients reaching the primary end point (improvement as defined by reduction in DAI > or =3 at week 8) were not significantly different between placebo (35%) and either the 25 mg tetomilast (52%) or the 50 mg tetomilast (39%) groups (intent-to-treat population). Remission rates (DAI 0-1) were 7%, 16%, and 21%, respectively (not significant). Mean reduction in DAI at week 8 was greater in the 25-mg group than under placebo (2.8 +/- 0.4 vs 1.7 +/- 0.36, respectively, P = .041) and approached statistical significance in the 50-mg group (2.8 +/- 0.46, P = .056). A post hoc analysis focusing on patients with high activity scores (baseline DAI 7-11) suggested differences between tetomilast and placebo that will require further investigation. No significant safety concerns were raised. Main adverse effects included gastrointestinal problems (nausea, vomiting) and were preferentially seen in the 50-mg tetomilast group.. This phase II trial of tetomilast in ulcerative colitis did not achieve statistical significance for the primary end point. Secondary end points indicate a potential clinical activity of tetomilast. The post hoc analysis suggests that further clinical development should focus on patients with objective parameters of inflammation.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Inflammatory Agents; Colitis, Ulcerative; Cyclic Nucleotide Phosphodiesterases, Type 4; Female; Humans; Male; Middle Aged; Phosphodiesterase Inhibitors; Placebos; Remission Induction; Sigmoidoscopy; Thiazoles; Treatment Outcome

Otsuka is developing a once-daily oral formulation of the phosphodiesterase-4 inhibitor tetomilast for the potential treatment of ulcerative colitis (phase III) and chronic obstructive pulmonary disease (phase II).

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Anti-Inflammatory Agents, Non-Steroidal; Clinical Trials as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Colitis, Ulcerative; Contraindications; Cyclic Nucleotide Phosphodiesterases, Type 4; Humans; Phosphodiesterase Inhibitors; Pulmonary Disease, Chronic Obstructive; Structure-Activity Relationship; Thiazoles

Topics: Azepines; Cholinergic Agents; Colitis, Ulcerative; Crohn Disease; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Isoquinolines; Pyridazines; Tacrolimus; Thiazoles