title: FK778 does not impair intestinal allograft absorption in a preclinical model of total small bowel transplantation.
abstract: Malononitrilamide 715 (FK778), a new low-molecular weight immunosuppressant, inhibits both T-cell and B-cell function by acting on the pathway for de novo pyrimidine biosynthesis. Pyrimidines are important for intestinal trophism; their inhibition may predispose to metabolic and functional impairments, such as diarrhea and malabsorption. In this study we assessed the absorptive capacity of intestinal allografts in a large-animal model of small bowel transplantation (SBTx) in pigs chronically treated with FK778. Ten outbred pigs underwent total orthotopic SBTx. Immunosuppression consisted of oral tacrolimus (trough levels 5-15 ng/mL) and oral FK778 (4 mg/kg per day) administered for 60 days. The D-xylose absorption test was performed at day 60 to evaluate carbohydrate absorption. Results were compared to normal controls. Eight of the 10 animals were alive and in good condition at day 60. All of their allografts were free of rejection. The animals had a mean maximal weight loss of 6.4% during the study period; the final weight was comparable to the initial weight (P > .05). Diarrhea was present in all animals (mean 16% of postoperative days). The D-xylose curves showed that absorption in the transplanted animals at day 60 was similar to that in the untreated controls (P > .05). The absence of differences was confirmed by the statistical analysis. In conclusion, our preclinical study in pigs showed that chronic treatment with FK778 in combination with tacrolimus did not impair carbohydrate absorption by the allograft after SBTx.
authors.affiliation: Department of Surgery, University of Pavia School of Medicine and I.R.C.C.S. Policlinico San Matteo Hospital, Piazzale Golgi 2, 27100 Pavia, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Zonta
authors.forename: M
authors.initials: M
authors.lastname: Doni
authors.forename: M
authors.initials: M
authors.lastname: Alessiani
authors.forename: F
authors.initials: F
authors.lastname: Abbiati
authors.forename: M
authors.initials: M
authors.lastname: Bardone
authors.forename: F
authors.initials: F
authors.lastname: Lovisetto
authors.forename: L
authors.initials: L
authors.lastname: Cobianchi
authors.forename: J
authors.initials: J
authors.lastname: Vigano
authors.forename: M
authors.initials: M
authors.lastname: De Martino
authors.forename: D
authors.initials: D
authors.lastname: Kabiri
authors.forename: T
authors.initials: T
authors.lastname: Dominioni
authors.forename: M
authors.initials: M
authors.lastname: Scaglione
authors.forename: A
authors.initials: A
authors.lastname: Bottazzi
authors.forename: P
authors.initials: P
authors.lastname: Poggi
authors.forename: P
authors.initials: P
authors.lastname: Dionigi
mesh_terms: D000480:Alkynes; D000818:Animals; D001835:Body Weight; D006085:Graft Survival; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D007421:Intestine, Small / Q000637:transplantation*; D007555:Isoxazoles / Q000494:pharmacology*; D023421:Models, Animal; D009570:Nitriles; D013552:Swine; D014994:Xylose / Q000378:metabolism
chemical_list: D000480:Alkynes; D007555:Isoxazoles; D009570:Nitriles; C115284:2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide; D014994:Xylose