5-ASA-glutamate protects rats from inflammatory bowel disease induced by intracolonic administration of trinitrobenzensulfonic acid.
OBJECTIVE
A new amino acid derivative of 5-aminosalicylic acid, 5-ASA-glutamate, releases 5-aminosalicylic acid independently of the action of bacterial azoreductases or adapt intestinal pH. In this study, 5-ASA-glutamate was compared with sulphasalazine with respect to: 1) therapeutic action, 2) effects on the synthesis of eicosanoids, 3) regional release of 5-aminosalicylic acid in the intestine.


METHODS
Colitis was induced in 29 rats by intracolonic administration of trinitrobenzensulfonic acid. Nine animals received an equal amount of saline. Three days after induction of colitis, animals were randomly assigned to equimolecular doses of 5-aminosalicylic acid as sulphasalazine (1040 mg/kg bw day) or 5-ASA-glutamate (850 mg/kg bw day) or arabic gum in water, given intragastrically. Arabic gum was also administered to animals that had received a saline enema (control group). The guts of 3 rats from the 5-ASA-glutamate group and 3 from the sulphasalazine group were used to assess regional release of 5-ASA, while in all the others, after 21 days of treatment, macroscopic and histologic lesions were assessed and eicosanoids and leukotriene determinations were performed.


RESULTS
The 5-ASA-glutamate group had macroscopic (2.20 +/- 0.58) and histologic (2.80 +/- 1.24) significantly lower scores than the trinitrobenzensulfonic acid group (3.40 +/- 0.22 and 6.50 +/- 1.2 respectively). 5-ASA-glutamate group had reduced PGE2 (-31%) and TXB2 (-25%) more effectively than the sulphasalazine group. LTB4 release was not affected by 5-ASA-glutamate treatment, while sulphasalazine produced a non significant, but quite consistent, reduction in LTB4 release (-37%). The release of 5-ASA after sulphasalazine was higher in the small intestine, lower in the colon compared to that following 5-ASA-glutamate administration.


CONCLUSIONS
5ASA-glutamate was effective in reducing the macroscopic and histologic score in the trinitrobenzensulfonic acid induced colitis. It also had some effect in reducing eicosanoid synthesis and could be a promising drug for the treatment of inflammatory bowel disease.
Clerici
C
C
Gastroenterology and Endoscopy Clinic, University of Perugia, Italy.
Gentili
G
G
Pellicciari
R
R
Gresele
P
P
Mezzasoma
A M
AM
Giansanti
M
M
Clementi
M
M
Bartoli
G
G
Balò
S
S
Modesto
R
R
Aburbeh
A G
AG
Morelli
O
O
Morelli
A
A
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D003106:Colon / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D015777:Eicosanoids / Q000096:biosynthesis; D005971:Glutamates / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015289:Leukotrienes / Q000096:biosynthesis; D011453:Prostaglandins / Q000096:biosynthesis; D011863:Radioimmunoassay; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric; D012460:Sulfasalazine / Q000494:pharmacology / Q000627:therapeutic use; D014302:Trinitrobenzenesulfonic Acid
C116459:5-ASA-glutamate; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015777:Eicosanoids; D005971:Glutamates; D015289:Leukotrienes; D011453:Prostaglandins; D012460:Sulfasalazine; D014302:Trinitrobenzenesulfonic Acid