Project: Development of Carbon Monoxide Releasing Molecules for the Treatment of Post-operative Ileus

This project aims to take the first steps in developing a novel class of drugs to treat or prevent post-operative ileus (POI). Its CO motivation is the severe health care and economic burden caused by POI; its rationale is based on the early promise shown by carbon monoxide (CO), and in particular CO-releasing molecules (CO-RMs) for the treatment of POI._x000D__x000D_Post-operative ileus or POI is a temporary impairment of gastrointestinal (GI) function and motility that happens as a consequence of most surgical procedures (Baig & Wexner, 2004). POI causes abdominal pain and distention, nausea and vomiting, and delayed passage of flatus or stool. Prolonged POI is associated with delayed enteral feeding and an increased morbidity, which in turn leads to extended hospital stays (Kehlet & Holte, 2001) and a very significant economic impact._x000D__x000D_GI recovery is particularly difficult after surgeries that involve manipulation of the GI tract. In Europe POI leads to a 45% increase in length of hospital stay (Msika et al., 2004), and 30% of the 46 million inpatient surgical procedures in the U.S. (2002) were performed on the GI tract (see www.cdc.gov/nchs/fastats/insurg.htm). It can thus be concluded that POI is a widespread, common problem in industrialized nations. Clear figures for Europe are scarce, in part due to the lack of efficient diagnoses and therapies, but several reports state that the net cost represented by POI in the United States surpasses US$1 billion per year (see Hocking et al., 2002)._x000D__x000D_No unrestricted treatments for POI have been approved by the FDA or the EMEA to date. The development of therapies for POI has been slow, mostly due to the multifactorial etiology of the condition. The occurrence of POI seems to involve both an activation of inhibitory neural reflexes and - according to more recent studies - an inflammatory process (Bauer, 2004). The use of opioids seems to contribute to an aggravation of POI, but treatments involving opioid receptor antagonists - though partially effective - do not solve the problem. Thus surgeons have opted for methods involving reduced bowel manipulation, minimally invasive surgery, reduced opioid use, early post-operative feeding/mobilization, and regional or epidural anesthetics as the way to prevent POI. Perhaps the best-known drug-based approach to treating POI so far has been the use of peripheral-acting mu-opioid receptor antagonists such as alvimopan (Entereg), which showed benefit in several POI endpoints in controlled trials (see Viscusi et al., 2006). The methodologies of these trials were later questioned (Buchler et al., 2008), however, as was the safety of alvimopan intake. The use of this drug is today severely restricted. A more recent therapeutic approach is the use of ghrelin agonists such as TZP-101, which is in Phase II clinical trials (Ejskjaer et al., 2009; Wargin et al., 2009), and ipamorelin (Venkova et al., 2009). Ghrelin agonists have been shown to restore gastric motility and accelerate GI transit in rodent models of ileus (Fraser et al., 2009; Sallam et al., 2007). Nevertheless, it is clear that new, better therapeutics for POI are a serious medical and economic need (Wittbrodt, 2006)._x000D__x000D_Carbon monoxide (CO) is an endogenous mediator that plays important roles in mammalian physiology. Inhalation of CO doses well below toxic levels has been shown to prevent inflammation, thrombosis, oxidative stress and apoptosis (see Ryter and Otterbein, 2004). Of direct relevance to POI are the observations that CO reduces ischemia/reperfusion injury of intestinal grafts and chronic colitis in IL-10-/- mice (Nakao et al., 2003; Hegazi et al., 2005) and in fact protects against the development of POI and necrotizing enterocolitis (Moore et al., 2005; Zuckerbraun et al., 2005)._x000D__x000D_To circumvent the fact that inhaled CO - despite its obvious potential - is difficult to use in the clinical setting (because it is a gas and because it binds strongly to hemoglobin after inhalation), several efforts have been undertaken in recent years to generate molecules which deliver CO in a more specific way to diseased tissues. A plethora of carbon monoxide-releasing molecules (CO-RMs) has been produced by various groups and used in animal proof-of-concept studies (see Motterlini, 2005). Various CO-RMs have been shown to reproduce and/or improve on the therapeutic effects of CO seen in inflammatory and other diseases. Recently it was shown that some water-soluble CO-RMs reduce the development of POI (De Backer et al., 2009). These and other existing CO-RMs, however, are only experimental and not suitable as pharmaceutical compounds due to inadequate physical-chemical properties. The next step in the development of drugs against POI - and the central aim of this project - is the production and development of clinically-acceptable, "drug-like" CO-RMs that can be used in clinical trials and eventually placed in the market.

Acronym	CORMPOI (Reference Number: 5507)
Duration	01/06/2010 - 30/11/2011
Project Topic	Post-operative ileus (POI) is a major economic and medical problem. Experimental carbon monoxide-releasing molecules (CO-RMs) have shown great promise for the treatment of this condition. The project proposes the chemical preparation and testing of candidate CO-RMs for the clinical treatment of POI.
Project Results (after finalisation)	The CO results of the project were, in this chronological order: (1) the generation of chemically adequate CO-releasing compounds (CO-RMs) to be tested in vitro for drug-like properties; (2) the selection of CO-RMs fulfilling the basic physical and chemical criteria of a drug; (3) the further selection of CO-RMs that displayed a very good safety and pharmaceutical activity profile in vitro; and (4), albeit as an indirect consequence of the work, the identification of lead candidate molecules for clinical development in liver disease.
Network	Eurostars
Call	Eurostars Cut-Off 4

Project partner

Number	Name	Role	Country
2	Alfama - Investigacao e Desenvolvimento de Produtos Framaceuticos, Lda.	Coordinator	Portugal
2	GalChimia, S.L.	Partner	Spain