Postoperative ileus (POI) is the most common gastrointestinal (GI) motility disorder managed by surgeons in their clinical practice. The term ileus reflects a state of absence or reduced peristalsis. This failure of peristalsis can lead to an accumulation of gastrointestinal secretions, resulting in abdominal distension and vomiting. POI is seen commonly following gastrointestinal and other types of surgery (e.g. gynecological, orthopedic, and urological surgery), leading to increased patient morbidity, 30-day readmission rates and hospital costs3. Although ileus classically refers to dysmotility of the small bowel, postoperative ileus can selectively affect the small intestine, stomach or colon. The economic burden is considerable and is reviewed by Johnson & Walsh4. A retrospective review from 2002 of more than 800,000 patients who underwent surgery in the United States found a rate of postoperative ileus of 4.25% according to International Classification of Diseases–Ninth Revision (ICD-9) codes. The mean hospital length of stay was 9.3 days in patients with POI compared to 5.3 days in those without it. The difference in the mean total hospital costs was $6,300 per patient4. Other studies have recorded the incidence of POI to be as high as 50%5. Current treatments are less than satisfactory and there is a large unmet need that remains to be addressed4. The pathogenesis is complex but is thought to firstly involve a neural phase. The incisions result in stimulation of mechanoreceptors and nociceptors that results in a neural reflex and the release of mediators that inhibit gastrointestinal motility. There is then a second more prolonged inflammatory phase initiated by mast cell activation that ultimately results in the release of cytokines and other inflammatory mediators that inhibit gastrointestinal motility6. Surgery creates a stressful stimulus that activates the hypothalamic pituitary adrenal (HPA) axis resulting in elevated levels of stress hormones7,8,9. In addition, local stimulation of CRF receptors has been shown to increase mast cell activation in the intestine and is implicated in gastrointestinal inflammation, barrier function and motility responses10,11. Indeed, CRF has been shown to decrease both gastric emptying and small intestinal transit time providing a strong rationale for the utility of CRF antagonists in POI12. Moreover, peripherally administered astressin completely blocked surgery-induced gastric stasis in rats13. Furthermore, in mice after an operative procedure of the gut (a midline celiotomy and cecal exteriorization and palpation), gastric emptying was significantly reduced up to 30.3 ± 1.4%. Administration of a CRF1 antagonist, CP-154,526 (20 mg/kg subcutaneously), completely blocked the 30-second cecal palpation–induced delayed gastric emptying. Also, cecal palpation did not delay gastric emptying in CRF1 deficient mice but gastric emptying was decreased significantly in wild type animals14. Moreover, surgery increased glucose levels by 46% compared with sham operated wild-type mice, while glycemia remained unchanged in CRF1- deficient mice14. Thus, astressins offer the opportunity to treat POI by a non-oral mode of administration with long-acting effects1.

1 Erchegyi et. al., (2016) J. Med. Chem., 59, 854-866
3 Bragg et. al., (2015) Clin. Nutr., 34, 367-376
4 Johnson & Walsh, (2009) Cleve. Clin. J. Med., 76, 641-648
5 Senagore, (2007). Am. J. Health-Syst. Pharm., 64, Suppl. 13, S3-S7

6 Lubbers et. al., (2010) World J. Gastroenterol., 16, 1683-1687
7 Calogero et. al., (1992) Metabolism, 41, 839-845
8 Donald et. al., (1993) Clinical Endocrinol., 38, 609-615
9 Naito et. al., (1991) J. Clin. Endocrinol. Metab., 73, 111-117
10 Kokkotou et. al., (2006) J. Immunol., 177, 3355-3361
11 Overman et. al., (2012) PloS ONE, 7, e39935, 1-9
12 Stengel and Taché, (2009) Annu. Rev. Physiol., 71, 219–239
13 Martinez et. al., (1999) JPET, 290, 629-634
14 Luckey et. al., (2003) Gastroenterol., 125, 654-659

Consolidated References