Biology Reference
In-Depth Information
2006 ). Ibudilast is registered in Japan for the treatment of asthma and poststroke
dizziness (Ketas ® and Pinatos ® , delayed release capsules) as well as for the treatment
of ocular allergies with 0.01% ibudilast ophthalmic solution. The approved oral dose
is 10 mg administered twice (for asthma) or three times daily (for the cerebrovascular
condition).
Bronchodilator, vasodilator, antithrombotic, and anti-inflammatory effects are
attributed to the drug. The rationale for the use of ibudilast in poststroke dizziness
appears to be based on the assumption that this condition results from ongoing
ischemia and that the vasodilating activity of ibudilast may improve this condition
(Rolan et al. 2009 ).
In vitro effects of ibudilast include attenuation of leukotriene release (Ohtsu
et al. 1989 ), diminished TNF- a or interferon (IFN)- g production from T-cells
(Feng et al. 2004 ), and decreased histamine release from mast cells (Choi et al.
1989 ). Recently, it was revealed that ibudilast is an allosteric inhibitor of macro-
phage migration inhibitory factor (MIF), besides inhibiting PDEs (Cho et al. 2010 ).
2.3 Tetomilast
Tetomilast (OPC-6535; Otsuka) (3) is a comparably weak PDE4 inhibitor (IC 50 of
380 nM) with only about tenfold selectivity toward PDE3, which has been in clinical
development for ulcerative colitis. In a phase II study in mild-to-moderate, active
ulcerative colitis, the primary end point (reduction in “disease activity index”, a
composite score, by at least three points within 8 weeks of treatment), was not
achieved with a once-daily, oral dose of 25 or 50 mg per day (Keshavarzian et al.
2007 ). However, post hoc analyses in the subgroup with moderate activity revealed
some symptomatic benefit. Tetomilast was advocated as being well tolerated by most
individuals; however, 29% of patients assigned to the higher dose group experienced
nausea and 6.5% vomiting, although these adverse events were mostly transient over
the first weeks (Keshavarzian et al. 2007 ). In two more recent phase III trials (FACT 1
and FACT 2) in patients with moderately severe active ulcerative colitis, again the
primary end point (a composite symptom score indicative of clinically meaningful
improvement) was failed. Nausea was reported as the most common, dose-dependent
adverse event (Keshavarzian et al. 2007 ). According to the company's website,
tetomilast remains under investigations in clinical studies for Crohn's disease, but
more recently, a clinical study in COPD has also been registered.
2.4 Cilomilast
Cilomilast (Ariflo, SB 207499, GSK) (4) is a second-generation, selective PDE4
inhibitor originally developed for the treatment of asthma, later for COPD, that was
finally abandoned by GSK.
Cilomilast is more potent at inhibiting PDE4D (IC 50 of 20 nM) compared to
PDE4B (IC 50 of 140 nM) (Giembycz 2001 ).
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