PDE4 inhibitors have been in development as a novel anti‐inflammatory therapy since the 1980s with asthma and chronic obstructive pulmonary disease (COPD) being primary indications. Despite initial optimism, none have yet reached the market. In most cases, the development of PDE4 inhibitors of various structural classes, including cilomilast, filaminast, lirimilast, piclamilast, tofimilast, AWD‐12‐281 (aka GSK 842470), CDP840, CI‐1018, D‐4418, IC485, L‐826,141, SCH 351391 and V11294A has been discontinued due to lack of efficacy. A primary problem is the low therapeutic ratio of these compounds, which severely limits the dose that can be given. Indeed, for many of these compounds it is likely that the maximum tolerated dose is either sub‐therapeutic or at the very bottom of the efficacy dose‐response curve. Therefore, the challenge is to overcome this limitation. It is, therefore, encouraging that many ‘new(er)’ PDE4 inhibitors in development are reported to have an improved therapeutic window including tetomilast, oglemilast, apremilast, ONO 6126, IPL‐512602 and IPL‐455903 (aka HT‐0712), although the basis for their superior tolerability has not been disclosed. In addition, other approaches are possible that may allow the anti‐inflammatory activity of PDE inhibitors to be realized. Accordingly, this Commentary endorses the view of Spina (2008), published in the current issue of the British Journal of Pharmacology, that the therapeutic utility of PDE4 inhibitors to suppress inflammation still remains a viable concept.British Journal of Pharmacology (2008) 155, 288–290; doi:fn1; published online 28 July 2008

01 Mar 2008·BJU InternationalQ2 · MEDICINE

The effects of a type 4 phosphodiesterase inhibitor and the muscarinic cholinergic antagonist tolterodine tartrate on detrusor overactivity in female rats with bladder outlet obstruction

Q2 · MEDICINE

Article

Author: Peter B. Snyder ; Michael B. Chancellor ; Jun Nishiguchi ; Dong Duek Kwon ; Yasuhiro Kaiho ; Naoki Yoshimura ; Yoichi Arai

OBJECTIVETo investigate the effects of the selective phosphodiesterase (PDE) type 4 inhibitor IC485 and the widely used antimuscarinic drug tolterodine tartrate on bladder activity in rats with bladder outlet obstruction (BOO), as inhibition of PDE4 leads to elevation of intracellular cAMP levels and relaxation of smooth muscle.MATERIALS AND METHODSBOO was induced in female Sprague‐Dawley rats by tying a silk ligature around the urethra. Six weeks after inducing BOO, conscious rats were assessed by cystometry with the urethral ligature intact. The effects of IC485 (5, 10 and 50 mg/kg intravenous, i.v.) were examined and compared with those of tolterodine (0.01, 0.1 and 1 mg/kg i.v.).RESULTSIC485 (5–50 mg/kg i.v.) decreased the number and amplitude of non‐voiding contractions during the storage phase by 63–88% and 49–83%, respectively; IC485 also increased bladder capacity by 28–37%. There was no change in blood pressure after applying IC485. Tolterodine tartrate (0.1 and 1.0 mg/kg) significantly decreased the number and amplitude of non‐voiding contractions by 38–74% and 29–44%, respectively, and increased bladder capacity by 19–51%. Whereas voiding efficiency and maximum voiding pressure were not altered by IC485 at any dose, tolterodine significantly reduced both, by 35–67% and 19–34%, respectively.CONCLUSIONBoth IC485 and tolterodine tartrate reduced detrusor overactivity in rats with BOO. In addition, doses of IC485 that suppressed non‐voiding contractions had no effect on voiding function. Therefore, selective PDE4 inhibitors deserve further study as potential agents for treating detrusor overactivity in patients with BOO.

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