Tuesday, September 11, 2012

Future Pharmacologic Therapies of OAB


Recent advances in understanding the pathophysiology of OAB have highlighted potential roles of the urothelium, the suburothelium, and afferent sensory pathways in the symptoms of OAB. The urothelium has been demonstrated to generate and release acetylcholine, adenosine triphosphate, nitricoxide, urothelial-derived inhibitory factor, and other factors (Birder & de Groat, 2007; de Groat, 2004). Afferent receptors and nerves have been demonstrated in the urothelium and the suburothelium, and thus, release of such substances from the urothelium may alter the excitability of the bladder afferent nerves. Muscarinic receptors have been identified in the urothelium and the interstitium; antimuscarinic agents may exert their effects at the level of the afferent pathway as well as at the level of the detrusor muscle. There are two antimuscarinic agents currently in phase II trials for OAB: PSD-506 (Plethora Solutions, London, UK) an M2, M3 selective agent, and SMP-986 (Dainippon Sumitomo Pharma Europe Ltd.). Experimentally, ß-3-adreno receptor agonists reduce detrusor muscle contractility in animal models of OAB (Igawa et al., 2001; Nomiya & Yamaguchi, 2003; Woods, Carson, Norton, Sheldon, & Argentieri, 2001), and several ß-agonists are currently under investigation, including GW-427353 (Solabegron®, GlaxoSmithKline), YM-178 (Acetanilide®, Astellas), and KUC-7483 (Kissei Pharmaceuticals Co., Ltd.).
Phasic contractions of the detrusor muscle are dependent on calcium entry through L-type calcium channels, and thus, calcium channel blockers may have a role in modulating detrusor muscle activity (Darblade et al., 2006). Calcium channel blockers have been used in the management of OAB in the past. For example, terodiline, a non-specific calcium antagonist and an antimuscarinic agent, was approved by the FDA; however, it was withdrawn in 1991 due to serious ventricular arrhythmias and prolongation of the QT interval (Thomas et al., 1995).
The opening of potassium channels stabilizes cell membranes and decreases excitability. In animal models, pinacidil, ZD6169, and NS309 have been shown to affect detrusor overactivity (Darblade et al., 2006; Pandita & Andersson, 1999; Pandita, Rønn, Jensen, Anderssen, 2006). However, clinical use has been limited by significant hypotension with systemic administration.
Ongoing studies evaluate a variety of other pathways that affect detrusor muscle contractility. The Rho-kinase pathway is involved in detrusor stiffness, which can affect bladder compliance in detrusor overactivity (Drake, 2008). Elocalcitol (BXL-628) is a vitamin D3 analogue, which has affects on the Rho-A pathway (Morelli et al.,2007). Elocalcitol is currently in phase III trials.
Investigation is also ongoing regarding potential agents that may affect OAB via modulation of the CNS. Cizolirtine citrate (E-4018, Laboratories Dr. Esteve SA) is a substance P and calcitonin gene-related peptide (CGRP) modulator with antagonistic effects on neurokinin-1 and CGRP receptors at the spinal level (Ballet et al., 2001). Phase II studies have been performed in Europe. Other neurokinin-1 antagonists undergoing evaluation in phase II trials include SSR-240600 (Sanofi-Aventis) and TA-5538 (Mitsubishi Tanabe). Other pathways being evaluated include those modulated by 5-HT receptors, purinergic mediated pathways, and vanilloid mediated pathways. Many agents affecting these pathways are in the earlier phases of clinical trials.

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