Treatments against TNF exhibit a remarkable

Treatments against TNF-α exhibit a remarkable clinical response in some UC patients (Danese et al., 2013), but the majority of emerging selective ADAM17 inhibitors which target TNF-α shedding in human inflammatory diseases are not successful (Duffy et al., 2011). The information in the present study that epithelial cell-derived ADAM17 is required for colonic epithelial regeneration and barrier function indicates that remedies targeting specifically stromal cells, but not epithelial cells, would be necessary to avoid negative consequences during clinical trials of ADAM17 inhibitors in UC patients. In addition, this work provides important mechanistic insight for goblet cell- and mucin-based therapy to protect the epithelial barrier and compensate for impaired epithelial regenerative activity when ADAM17 inhibitors are introduced.
Conflict of Interest Statement
Author Contributions Study concept and design, M.S. and Y.O.; generation and maintenance of Adam17-deficient mice, K.H., M.S. and A.S.; acquisition, analysis and interpretation of data, M.S., A.S. and Y.O.; writing the manuscript, M.S. and Y.O.; contribution to analysis on human samples, M.S., A.S., K.O., H.H. and Y.K.; technical or material support, K.H. and T.T.
Acknowledgments
Background Gastrointestinal side effects are common with antipsychotics, particularly clozapine, ranging in severity from mild constipation to fatal bowel obstruction and/or ischemia. Constipation is reported in up to 60% of clozapine-treated patients (Hayes and Gibler, 1995) and up to 50% of those receiving other antipsychotics (Ozbilen and Adams, 2009) and is reflected in the high utilization of laxative in clozapine-treated patients (Bailey et al., 2015). The mechanism is considered to be anticholinergic inhibition of gastrointestinal smooth muscle contraction and order Cyclopamine (Ozbilen and Adams, 2009), but serotonin receptor antagonism likely compounds the problem (Palmer et al., 2008), with serotonin playing a crucial role in regulating gastrointestinal motility (Crowell, 2001). Symptoms of slow transit may include low stool frequency, lack of urge to defecate, abdominal distension, bloating, and abdominal discomfort (Foxx-Orenstein et al., 2008). A systematic search of AMED, BIOSIS, CINAHL, EMBASE, MEDLINE, PsycINFO and PubMed databases with no language restrictions from inception to August 2015 revealed 61 case reports, five large case series and one cohort study on the serious or life-threatening clozapine-induced gastrointestinal effects. For every 1000 patients treated with clozapine, between 300 and 600 will develop constipation and four will develop serious gastrointestinal complications (including ileus, bowel obstruction, bowel ischemia and necrosis) from which one will die. Pharmacovigilance data shows soil amongst antipsychotics, clozapine has the highest constipation-related mortality. Seventy such deaths were reported in the USA between 1997 and 2009, with a mortality rate three times that of clozapine-induced agranulocytosis (De Hert et al., 2011). A large prospective cohort study showed treatment with clozapine conferred the greatest risk of fatal ileus compared with other psychoactive medication (OR: 6.73; 95% CI 1.55–29.17) (Nielsen and Meyer, 2012). While these complications have been described as arising from ‘gastrointestinal hypomotility’ (Palmer et al., 2008; Flanagan and Ball, 2011; Nguyen et al., 2014), gastrointestinal transit times in antipsychotic-treated patients have not been measured previously. There is consensus that clozapine\'s effect on gastrointestinal function is important, but poorly understood and under-researched.
Objectives This study sought to ascertain:
Research Design and Methods Methods were pre-specified in the protocol (Every-Palmer et al., 2013 available at http://hdl.handle.net/10523/6070).
Results
Discussion
Conclusions The results suggest that all clozapine-treated patients are at risk of gastrointestinal hypomotility, which needs to become part of the consent process. We recommend starting prophylactic laxative treatment when commencing clozapine in the same way as is recommended for long-term opioids (Caraceni et al., 2012). Given our observation that patients prescribed prn (as required) laxatives did not use them, we suggest prescribing regular laxatives.