F3c

Aprepitant 5

Ezlopitant 6

NK2, which preferentially bind NKs A and B, are located predominantly on sensory neurons. However, these receptors are also involved in mediating GI motor activity. The NK2 antagonist nepadutant suppressed the stimulatory effects of NKA, but did not affect basal migrating motor complexes. In animal studies, saredutant, another NK2 antagonist, dose-dependently reduced agonist-induced fecal excretion and abdominal contractions in response to colorectal distension. However, no data are available on the effects of NK2 modulation in human subjects and patients with IBS.192

NK3 receptors are present within intrinsic neurons of the spinal cord and are also distributed to excitatory and inhibitory motor neurons and secretomotor neurons in the myenteric plexus and to secretomotor neurons in the submucosal plexus. These receptors appear to play a role in disrupted, but not normal, intestinal motility and also in visceral nociception.202 Selective NK3 antagonists administered systemically reduced rat behavioral responses to colorectal distension.196 A similar antinociceptive effect was noted with administration of talnetant, an antagonist that crosses the blood-brain barrier, and SB-235375 7 , an antagonist that is restricted to the periphery, suggesting a peripheral site of action of NK3 antagonists.194'202 Studies on the effects of NK3 antagonism in IBS in humans are underway.

6.29.7.4 Opioid Receptor Antagonists

Opioid receptor agonists have an inhibitory effect on enteric motility and secretion and hence have a constipating effect. The actions of opiates on GI motility are due to the suppression of excitability and neurotransmitter release from enteric neurons, which disrupts the normal coordinated contractions and relaxations necessary for propulsion of intraluminal content. Opiates also suppress the activity of intestinal secretomotor neurons, thus inhibiting intestinal secretions.200

^-Opioid receptors are expressed widely on enteric neurons, as well as on nociceptive pathways conducting pain to the CNS. m-Opioid receptor antagonists are currently most therapeutically promising in patients in whom long-term opioid therapy for relief of pain produces constipation and patients with postoperative ileus. Alvimopan 8 is a selective m-opioid receptor antagonist that does not cross the blood-brain barrier. Postsurgical use of alvimopan speeds recovery of GI function and reduces the length of hospitalization. To date, studies on the effects of alvimopan in patients with IBS have not been performed.204

SB-235375 7 Alvimopan S

In contrast to available opioid agonists that relieve pain, but also result in constipation and central adverse effects, k-opioid receptor agonists appear to be selective visceral analgesics. Asimadoline 9 is a k-opioid receptor agonist that does not cross the blood-brain barrier. Pharmacodynamic studies of humans suggest that asimadoline can reduce colonic sensation at subnoxious levels of colonic distension and decrease satiation and postprandial fullness in humans without altering GI motor reflexes or transit.191 Further support for investigation of asimadoline for treating visceral hypersensitivity in patients with IBS is derived from a preliminary study of patients with IBS-C in which asimadoline reduced hypersensitivity in response to colonic distension without affecting compliance or tone.194

Asimadoline 9

6.29.7.5 CRF-1 Antagonists

A key alteration in patients with IBS is increased responsiveness to stress, leading to excessive release of neurohormones and autonomic dysfunction.126 CRF is a stress hormone that affects colonic sensorimotor function. CRF-1 receptors localized in the CNS and GI tract are involved in CRF-stimulated changes in GI function, including colonic motility, epithelial water transport, and permeability.210 A recent demonstration of the role of this system in colorectal hyperalgesia has further increased interest in its potential as a therapeutic target.211

A selective CRF-1 antagonist, astressin, when injected intracerebrally, reduces visceral discomfort induced in animals by administration of CRF.195 The CRF-1 antagonist antalarmin also decreases the visceromotor response to colonic distension in rats genetically predisposed to hyperanxiety coupled with a high basal level of CRF. Thus, CRF-1 antagonism could be an effective treatment for the motility disturbance, abdominal pain, and comorbid CNS symptoms experienced by patients with IBS.

6.29.7.6 Clonidine

The sensorimotor disturbances in patients with IBS may be caused in part by adrenergic dysfunction. Functional polymorphisms in a2-adrenoceptors may be associated with IBS-C.192 The a2-adrenoceptor agonist clonidine reduces colonic pain sensation in response to distension and reduces colonic motor activity. Clonidine also increases gut-wall compliance without altering motility, suggesting it may be beneficial in patients with urgency as the major symptom. In an initial study of patients with IBS-D, treatment with clonidine reduced bowel dysfunction and enhanced the proportion of patients achieving satisfactory relief of IBS, but did not alter GI transit.207 However, adverse effects such as hypotension and somnolence may limit its use in patients with IBS. Agents in this class with greater GI selectivity would be advantageous.

6.29.7.7 Cholecystokinin Receptor Antagonists

An excessive gastrocolonic response has been associated with postprandial symptoms in patients with IBS. Cholecystokinin (CCK) is a neuropeptide released by duodenal and jejunal cells that modulates gastric relaxation in response to feeding. CCK may also contribute to abnormal colonic motility in patients with IBS. Endogenously released CCK acts at CCK-1 in gastric mucosa and the CNS to alter gastric motility.192

Dexloxiglumide is a potent CCK-1 antagonist that blocks CCK-induced delays in gastric emptying in rats and reverses lipid-induced delays in gastric emptying in healthy subjects.204 This agent has been tested in patients with IBS-C. In a 12-week placebo-controlled trial, a significantly greater proportion of patients with IBS-C reported improvement in global symptoms after treatment with dexloxiglumide than with placebo. However, these preliminary results of a superiority of dexloxiglumide over placebo in improving global assessment scores were not confirmed in larger phase III trials. The development of this drug for patients with IBS-C has therefore been discontinued. Further studies of CCK-1 antagonists using different patient populations may be warranted.

6.29.7.8 Chloride Channel Openers

Chloride channels are proteins that control cell membrane transport of chloride ions and hence modulate intestinal fluid secretion. Chloride channel openers, such as lubiprostone 10, are currently under development for the treatment of patients with constipation, IBS-C, and postoperative ileus. By activating the specific chloride channel CIC2 in cells lining the gut, lubiprostone increases intestinal fluid secretion, which softens the stool, promotes bowel movement, and thus indirectly decreases abdominal discomfort and bloating.201 To date, two phase III trials of lubiprostone in patients with constipation showed that, relative to placebo, treatment with lubiprostone significantly improved symptoms of constipation, including stool frequency, stool consistency, and straining. The main adverse events were nausea, diarrhea, and headache. A phase III trial of lubiprostone in patients with IBS-C was initiated in mid-20 05.201

Lubiprostone 10
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