AV608

An extensive body of scientific literature supports the potential therapeutic application of NK-1 antagonists to the treatment of anxiety disorders. At a biological level, there is a close anatomical association between Substance P, NK-1 receptors and monoamines. More specifically, ~50% of ascending serotonin neurons in the brain also co-express substance P, and norepinephrine cell bodies in the locus coeruleus express NK-1 receptors. In addition, it has been demonstrated that NK-1 receptor blockade can alter the firing pattern of both serotonin and norepinephrine neurons and increase hippocampal neurogenesis. At a functional level, NK-1 antagonists (including AV608) have broadly demonstrated activity in nearly all of the traditionally used preclinical assays to identify anxiolytic agents, including those assays that are predictive for both benzodiazepines and selective serotonin reuptake inhibitors (SSRIs). Clinically, anxiety remains a high priority target for Industry, as evidenced by recent development activity in this area. It is known that the human intestinal mucosa expresses NK-1 receptors. These receptors are also found in the smooth muscle, arterioles, venules and cells associated with lymph nodules and co-localized with substance P, which is found throughout the gastrointestinal tract. Nerve fibers, including sensory fibers, come into close contact with mast cells, which also express NK-1 receptors. Furthermore, approximately 80% of visceral sensory afferents in the gut express substance P, and it is known that NK-1 receptors in the spinal cord mediate visceral hyperalgesia. Tachykinins are potent secretagogues at the small and large intestinal mucosa in several animal models as well as in the human colon, where there is a direct NK-1 receptor mediated response. Perhaps most important with respect to IBS is the observation that stimulation of sensory fibers or mast cells in the human intestinal tract causes the release of substance P and a consequent increase in epithelial ion transport through the activation of NK-1 receptors. The response to colorectal distension has often been used as a proxy for IBS. In this model, colorectal distension increases abdominal flinching, which is an indicator of pain. This procedure also activates a rectocolonic inhibitory reflex characterized by a decrease in colonic pressure and an increase in fluid transport. Several authors have now observed that NK-1 receptors mediate this rectocolonic inhibitory reflex. Decreased colonic pressure is related to increased colonic transit and these findings are therefore consistent with reports that stress increases intestinal transit, an effect blocked by NK-1 receptor antagonists. Overactive bladder is a common and distressing condition that has a profound effect on the daily living of affected individuals. This common cause of urinary incontinence describes a cluster of symptoms typified by urinary urgency, frequency, and urge urinary incontinence. Whereas the currently available anticholinergic drugs used to treat overactive bladder act on efferent nerves to counteract overactive bladder, essentially after it occurs, NK-1 antagonists appear to have promising therapeutic potential in their ability to affect the afferent nerves that modulate bladder contraction. A key potential advantage of NK-1 antagonists is that there may be essentially no decrement of detrusor contractility and no urinary retention risk, as is seen with current anticholinergic agents. This is because NK-1 antagonists inhibit sensory afferent nerves but not efferent nerves, which are important for normal and complete voiding of urine. Furthermore, NK-1 antagonists have a more favorable tolerability profile than observed with anticholinergic medications.