5-Aminosalicylic acid concentration in mucosal interstitium of cat small and large intestine

Uncertainty regarding the concentration of 5-ASA within the mucosal interstitium has been a major limitation of defining the protective mechanisms of 5-ASA in intestinal inflammation. Therefore, we measured the concentration of 5-ASA in intestinal lymph and venous plasma during luminal perfusion of the cat small and large intestine with 10 mM 5-ASA. Blood and lymph flows were measured in each segment. 5-ASA and N-acetyl-5-ASA were extracted from plasma and lymph and quantified using fluorescence spectroscopy. Luminal perfusion of the terminal ileum with 5-ASA resulted in the following concentration profile: intestinal venous plasma (143 +/- 30 micrograms/ml) much greater than lymph (43 +/- 17 micrograms/ml) = systemic arterial plasma (40 +/- 11 micrograms/ml). In the colon the local venous plasma concentration of 5-ASA was 20 +/- 6 micrograms/ml compared to 2.0 +/- 1.0 micrograms/ml in systemic arterial plasma. N-Acetyl-5-ASA was found to comprise less than 5% of the total metabolite concentration in both ileum and colon. We also found that 58% of luminal 5-ASA was absorbed per minute in the terminal ileum, whereas only 3%/min was absorbed from the colon. The results of this study suggest that: (1) the mucosal interstitial concentration of 5-ASA in the terminal ileum and colon are approximately 100 micrograms/ml (654 microM) and 20 micrograms/ml (164 microM), respectively; and (2) the rate of 5-ASA absorption in the terminal ileum is approximately seven times greater than that in the colon.     

Pharmacology and pharmacokinetics of 5-aminosalicylic acid

There is accumulating clinical evidence that 5-aminosalicylic acid (5-ASA), a primary metabolite of sulfasalazine (SAS), represents the therapeutic active moiety of the azo-compound SAS in the treatment of chronic inflammatory bowel disease (IBD). Since it is presumed that 5-ASA acts from the lumen of the intestine, it is important to know how much 5-ASA is released from its special galenic formulations. After liberation of 5-ASA in the terminal ileum (only slow release oral preparations of 5-ASA) and colon (5-ASA suppositories and enemas), 5-ASA is only partly absorbed. A major part of this 5-ASA is presystemically eliminated, eg, N-acetylated during its first passage through the intestinal mucosa and liver. Mean steady state plasma levels of unchanged 5-ASA are rather low (range 0.02 to 1.2 μg/ml) whereas those of Ac-5-ASA are always higher (range 0.1 to 2.9 μg/ml). This is due to the rapid elimination of 5-ASA (t1/2=0.4 to 2.4h) and the slightly slower renal excretion of the Ac-5-ASA (t1/2=6 to 9h, renal clearance=200 to 300 ml/min). The knowledge of the pharmacokinetic properties of 5-ASA from different drug formulations might contribute to a better understanding of its mode of action in IBD.     

Concentrations of 5-ASA and Ac-5-ASA in human ileocolonic biopsy homogenates after oral 5-ASA preparations.

Intramucosal 5-aminosalicylic acid (5-ASA) and acetylated 5-ASA (Ac-5-ASA) concentrations were determined in ileocolonic biopsy specimens from 61 patients with irritable bowel syndrome treated for one week with near equimolar doses of different slow release preparations of 5-ASA (Claversal, Asacol, or Pentasa) or azo-bound drugs (Salazopyrin, Dipentum). The transit time in these patients was accelerated by a laxative, metoclopramide, and colonic lavage. The presence of 5-ASA in the mucosa was confirmed by autofluorescence. The highest concentrations of 5-ASA were obtained after Asacol (mean (SEM), 298.5 (37.3) ng/mg wet wt), followed by Claversal 500 mg (108.8 (11.7) ng/mg wet wt) and Pentasa (25.7 (2.2) ng/mg wet wt). Very low concentrations only were observed after Claversal 250 mg (0.3 (0.03) ng/mg wet wt), Salazopyrine (1.2 (0.1) ng/mg wet wt), and Dipentum (11.0 (3.2) ng/mg wet wt). The results for Ac-5-ASA were similar but the concentrations were generally lower. Serum concentration-time curves over eight hours were obtained from 34 healthy volunteers after a single oral dose of 400 to 500 mg of the different drugs. For the slow release forms, an apparently inverse relationship was found between the area under the curve of the serum concentrations and the intramucosal concentrations, supporting the importance of the local availability of the drug. This inverse relationship was absent for the azo-bound drugs. Colonic washout induced mechanical removal of intraluminal 5-ASA with a secondary disturbance in absorption resulting in a rapid decline in the serum concentrations. However, only for Dipentum did this result in significantly lower 5-ASA mucosal concentrations. This is the first reported attempt to evaluate the mucosal availability of 5-ASA after different oral preparations. It shows that where transit time is accelerated higher mucosal concentrations occur after slow release preparations (except for Claversal 250 mg) than after azo-bound drugs. Additional studies are necessary to correlate these concentrations with clinical effects.     

Effect of aminophenols (5-ASA and 4-ASA) on colonic interleukin-1 generation.

The effect of 5-ASA and 4-ASA, drugs used for the treatment of inflammatory bowel disease, on modulation of experimental colitis and on colonic generation of interleukin-1 was evaluated. Three weeks of treatment with 5-ASA or 4-ASA (50 micrograms/kg) and one week of treatment with 5-ASA significantly decreased colonic interleukin-1 generation and the extent and severity of inflammation in a rat model of colitis induced by trinitrobenzene sulphonic acid. Colonic biopsies were obtained from patients with active ulcerative colitis and organ cultured 24 hours in the absence or presence of the following drugs: sulphasalazine, sulphapyridine, 5-ASA and 4-ASA (25-100 micrograms/ml). Interleukin-1 content in tissue cultured in the presence of 5-ASA (100 micrograms/ml) was two-thirds of its content in tissue cultured in drug free medium and its release into the medium was decreased by 50%. Sulphasalazine 50 micrograms/ml significantly decreased by 33% the tissue content but did not affect interleukin-1 release and a higher dose was not more effective. Sulphapyridine and 4-ASA in doses up to 100 micrograms/ml did not affect either interleukin-1 colonic content or its release into the culture medium. We conclude that pharmacological suppression of colonic interleukin-1 generation may be one, although not the sole mechanism to explain the therapeutic efficacy of 5-ASA in the treatment of inflammatory bowel disease.     

Absorption, Enterohepatic Circulation, and Excretion of 5-Aminosalicylic Acid in Rats

After oral administration of sulfasalazine, the majority of the administered dose reaches the colon, where it is split into 5-aminosalicylic acid (5-ASA) and sulfapyridine. 5-ASA is believed to be the effective component in the treatment of inflammatory bowel disease. After intraduodenal administration of 5-ASA (20 mg) in rats, 91% of the drug was absorbed in the proximal small intestine. Peak serum 5-ASA concentration (55 μg/ml) was reached in 1 h. Approximately 61 and 6% of the administered dose were excreted in the urine and bile, respectively, in 24 h, almost exclusively in the acetylated form. When sulfapyridine (20 mg) was administered in addition to 5-ASA, 70% of the sulfapyridine was absorbed in the small intestine, peak serum concentration (50 jug/ml) was reached in 1 b, and 30% of the administered dose was excreted in the urine in 24 b. The results indicate that after oral administration of 5-ASA, a therapeutically significant concentration of the drug is not expected in the terminal ileum which is a common site of involvement in Crohn's disease. The therapeutic implications of these findings are discussed herein.     

Intestinal luminal pH in inflammatory bowel disease: possible determinants and implications for therapy with aminosalicylates and other drugs

Measurements of luminal pH in the normal gastrointestinal tract have shown a progressive increase in pH from the duodenum to the terminal ileum, a decrease in the caecum, and then a slow rise along the colon to the rectum. Some data in patients with ulcerative colitis suggest a substantial reduction below normal values in the right colon, while limited results in Crohn's disease have been contradictory. Determinants of luminal pH in the colon include mucosal bicarbonate and lactate production, bacterial fermentation of carbohydrates and mucosal absorption of short chain fatty acids, and possibly intestinal transit. Alterations in these factors, as a result of mucosal disease and changes in diet, are likely to explain abnormal pH measurements in inflammatory bowel disease (IBD). It is conceivable that reduced intracolonic pH in active ulcerative colitis impairs bioavailability of 5-aminosalicylic acid from pH dependent release formulations (Asacol, Salofalk) and those requiring cleavage by bacterial azo reductase (sulphasalazine, olsalazine, balsalazide), but further pharmacokinetic studies are needed to confirm this possibility. Reports that balsalazide and olsalazine may be more efficacious in active and quiescent ulcerative colitis, respectively, than Asacol suggest that low pH may be a more critical factor in patients taking directly pH dependent release than azo bonded preparations. Reduced intracolonic pH also needs to be considered in the development of pH dependent colonic release formulations of budesonide and azathioprine for use in ulcerative and Crohn's colitis. This paper reviews methods for measuring gut pH, its changes in IBD, and how these may influence current and future therapies.     

Effect of drugs on colonic eicosanoid accumulation in active ulcerative colitis.

The effect of immunosuppressive drugs, 4-aminosalicylic acid (4-ASA), acetyl 5-aminosalicylic acid (5-ASA), and ketotifen on human colonic eicosanoid accumulation was evaluated in view of enhanced accumulation in patients with active ulcerative colitis. Azathioprine (100 micrograms/ml), cyclosporin (100 micrograms/ml), and methotrexate (100 micrograms/ml) significantly inhibited, by 25-35%, prostaglandin E2 (PGE2) accumulation by organ-cultured colonic mucosa of ulcerative colitis patients. Methotrexate was the only immunosuppressive drug that inhibited leukotriene B4 (LTB4) accumulation (50%), whereas azathioprine inhibited the accumulation of leukotriene C4 (LTC4) (25%). 5-ASA and its metabolite, acetyl 5-ASA, inhibited by 20-70% PGE2, LTB4, and LTC4 accumulation in the culture, supporting the contention that acetyl 5-ASA is as active as 5-ASA in these respects. 4-ASA had no effect on any of the eicosanoids. Ketotifen, a mast cell stabilizer, significantly inhibited the accumulation of PGE2, LTB4, and LTC4 by 33-60%. These results suggest a potential, new, unrecognized mode by which the immunomodulators induce part of their therapeutic effects in inflammatory bowel disease and support the contention that acetyl 5-ASA is as active as 5-ASA. The results obtained also indicate that ketotifen, used effectively in the prevention of bronchial asthma, inhibits the accumulation of colonic eicosanoids and, thus, may be of value in the treatment of inflammatory bowel disease.     

In vitro immunomodulatory effects of sulfasalazine and its metabolites

We assessed the in vitro effects of sulfasalazine and its 2 main metabolites, sulfapyridine (SP) and 5-aminosalicylic acid (5-ASA) on functional aspects of peripheral blood lymphocytes (PBM) of normal controls and patients with rheumatoid arthritis (RA). Sulfasalazine, but not its 2 main metabolites, inhibited mitogen induced proliferative responses of PMB at high drug concentrations (100 micrograms/ml). Similar results were obtained with purified B lymphocytes. Sulfasalazine depressed, in a dose dependent manner, pokeweed mitogen induced Ig synthesis by PBM of normals and patients with RA. Moreover, synthesis of IgM rheumatoid factor was depressed to a greater degree than total IgM at low sulfasalazine concentrations (10-25 micrograms/ml). Both SP and 5-ASA were not inhibitory at the concentrations tested. Experiments with purified lymphocyte subpopulations indicated that sulfasalazine exerted its major inhibitory activity on the B lymphocyte. These studies indicate that sulfasalazine, but not its 2 main metabolites, has immunomodulatory characteristics which may be related to its therapeutic activity in RA.     

Colon-specific drug delivery systems based on cyclodextrin prodrugs： In vivo evaluation of 5-aminosalicylic acid from its cyclodextrin conjugates

AIM: To investigate the release of cyclodextrin-5-amino-salicylic acid (CyD-5-ASA) in cecum and colon. METHODS: An anti-inflammatory drug 5-ASA was conjugated onto the hydroxyl groups of α-,β- and γ-cyclodextrins (CyDs) through an ester linkage, and the in vivo drug release behavior of these prodrugs in rat' s gastrointestinal tract after the oral administration was investigated. RESULTS: The 5-ASA concentration in the rat's stomach and small intestine after the oral administration of CyD-5-ASA conjugate was much lower than that after the oral administration of 5-ASA alone. The lower concentration was attributable to the passage of the conjugate through the stomach and small intestine without significant degradation or absorption, followed by the degradation of the conjugate site-specific in the cecum and colon. The oral administration of CyD-5-ASA resulted in lower plasma and urine concentration of 5-ASA than that of 5-ASA alone. CONCLUSION: CyD-5-ASA conjugates may be used as prodrugs for colon-specific drug delivery system.     

Anastomotic configuration and mucosal 5-aminosalicyclic acid (5-ASA) concentrations in patients with Crohn's disease: a GISC study. Gruppo Italiano per lo Studio del Colon e del Retto

OBJECTIVE: Recurrence of Crohn's disease quite inevitably occurs after resection of distal small bowel and proximal colon, involving the neoterminal ileum close to the anastomosis. Oral 5-aminosalicylic acid (5-ASA) administered soon after surgery delays recurrence and reduces its severity. We recently observed that in operated patients submitted to prophylactic treatment with oral 5-ASA the rate of recurrence was significantly higher in those with end-to-end anastomosis than in those with other types of anastomosis (end-to-side, side-to-side). The hypothesis investigated in the present study was that patients with end-to-side or side-to-side anastomosis would benefit from a higher mucosal concentration of 5-ASA with respect to patients with end-to-end anastomosis. Therefore, the mucosal 5-ASA concentration was measured in the perianastomotic area of both groups. METHODS: The study was carried out in 19 patients submitted to radical surgery for Crohn's ileitis or ileocolitis, under oral prophylactic treatment with 5-ASA (Asacol). All patients were on regular endoscopic follow-up and were free of recurrence. Two biopsies were collected 3 cm from the anastomosis, in the neoterminal ileum, and two biopsies were collected at the colonic site 3 cm below the anastomosis. 5-ASA concentrations (ng/mg) were measured in tissue homogenates by high-performance liquid chromatography (HPLC) with electrochemical detection. RESULTS: The mucosal concentration of 5-ASA in the neoterminal ileum was significantly lower in patients with end-to-end anastomosis than in those with other types of anastomosis (median values: 29.4 ng/mg vs 92.9 ng/mg respectively; p < 0.001). Six of 10 patients (60%) with end-to-end anastomosis, but none of the nine patients with other types of anastomosis, showed 5-ASA mucosal concentrations <40 ng/mg at the neoterminal ileum. On the contrary, no patients with end-to-end anastomosis showed mucosal concentrations of 5-ASA >90 ng/mg, compared with the 57% of patients in the group with other types of anastomosis. No differences were observed for colonic biopsies. CONCLUSIONS: The different mucosal concentrations in these two groups may be explained by the difference in segmental transit time induced by the different anastomotic configurations. A slower preanastomotic transit time, demonstrated in patients with end-to-side or side-to-side anastomosis, could offer a prolonged contact time between the intestinal content and the mucosa, resulting in an increase in drug absorption.     

A comparison of intraduodenally and intracolonically administered nutrients on the release of peptide-YY in the dog

The objective of this study was to compare the effects of various nutrients (fats, proteins, amino acids, and carbohydrates), given directly into the duodenum or the colon, on the release of peptide-YY (PYY) in conscious dogs. As reported previously, this study showed that plasma levels of PYY increased significantly (P less than 0.05) within 15 min in response to an oral mixed meal. Intraduodenal (ID) administration of a fatty acid (oleic acid; 100 mmol/L; 100 ml/h) stimulated a robust release of PYY, whereas ID administration of an amino acid mixture (phenylalanine plus tryptophan; 100 mmol/L each; 100 ml/h), glucose (1 g/kg), or a liver extract (10%; 100 ml/h) failed to elevate plasma levels of PYY. ID administration of glucose at 2 g/kg caused a mild but significant elevation in plasma PYY levels. Intracolonic administration of saline, a fatty acid, an amino acid mixture, glucose, or a liver extract significantly stimulated PYY release. This study suggests that as chyme moves from the stomach to the proximal bowel, fat is the primary constituent of food that stimulates the prompt release of PYY. However, unabsorbed nutrients can release PYY by a direct contact with the PYY-containing cells lining the intestinal lumen of the terminal ileum, colon, and rectum. Both mechanisms probably participate in the release of PYY.     

Sulfasalazine metabolites and dapsone attenuate formyl-methionyl-leucyl-phenylalanine-induced mucosal injury in rat ileum

The effects of 5-aminosalicylic acid (5-ASA), 4-ASA, N-acetyl-5-ASA, and sulfapyridine on mucosal permeability were determined in an experimental model of acute ileitis. In addition, the antiinflammatory drug dapsone was tested. The distal 10 cm of rat ileum was perfused with formyl-methionyl-leucyl-phenylalanine (FMLP) (10(-5) M), a bacterial peptide that activates and attracts neutrophils. Changes in mucosal permeability were assessed using the blood-to-lumen clearance of 51Cr-ethylene-diamineacetate. Luminal FMLP increased 51Cr-labeled ethylenediamineacetate clearance twofold and fourfold in the first and second hour, respectively. Addition of 5-ASA (10 mM), 4-ASA (10 mM), or dapsone (4 mM) to the luminal perfusate after 60 min of FMLP perfusion greatly attenuated the increased mucosal permeability observed after 120 min of FMLP perfusion. Neither N-acetyl-5-ASA (10 mM) nor sulfapyridine (5 mM) had an effect on the FMLP-induced increase in mucosal permeability. We characterized the inhibitory effect of these drugs on the catalytic activity of myeloperoxidase and tested their ability to scavenge hypochlorous acid in vitro. 5-Aminosalicylic acid, 4-ASA, and dapsone demonstrated a powerful inhibitory effect on the catalytic activity of myeloperoxidase, whereas all drugs were equally effective in scavenging HOCl. In additional in vitro experiments we were unable to demonstrate an inhibitory effect of either of the drugs on the catalytic activity of neutrophilic elastase. Our results indicate that inhibition of neutrophilic myeloperoxidase may be an important mechanism by which 5-ASA, 4-ASA, and dapsone attenuate FMLP-induced mucosal injury.     

Effects of olsalazine in the jejunum of the rat.

Olsalazine (ADS) is the azo-linked dimer of 5-aminosalicylic acid (5-ASA). It is of value for the management of patients with ulcerative colitis but may be associated with increasing diarrhoea in a few. This study examines the effect of 5-ASA and ADS on small intestinal transport systems of the rat. Krebs-Ringer-bicarbonate solution was circulated through the lumen of a jejunal segment and the appearance of fluid, glucose and lactate on the serosal surface was shown to be linear over a two hour period. Addition of 5-ASA (10 mmol/l) or ADS (5 mmol/l and 10 mmol/l) caused a significant inhibition both of fluid transport (p less than 0.001), and of the appearance of glucose (p less than 0.001) and lactate (p less than 0.001 for 5 mmol/l and 10 mmol/l ADS, p less than 0.01 for 10 mmol/l 5-ASA). The uptake of glucose by rings of rat jejunum was shown to be markedly reduced by ADS. Experiments substituting glucose with either sucrose of 2-aminoisobutyric acid showed that ADS (5 mmol/l, 10 mmol/l) also inhibited the serosal appearance of fructose and the amino acid. These results show that 5-ASA and ADS, at concentrations which could be expected in the jejunum of patients receiving therapeutic doses, are able to inhibit small intestinal transport systems. The resulting increase in load on the diseased colon could be important for the pathogenesis of diarrhoea.     

Bioavailability of 5-aminosalicylic acid from slow release 5-aminosalicylic acid drug and sulfasalazine in normal children

The bioavailability of a controlled release 5-aminosalicylic acid preparation (Pentasa) was investigated in nine healthy children after a medication period of six days (1000 mg/day) and compared with sulfasalazine (Salazopyrin) (2000 mg/day). The local bioavailability in the distal gut lumen, reflected by the 5-aminosalicylic acid concentration in the fecal water, showed comparable values after Pentasa (4.44 mmol/liter) and Salazopyrin (6.25 mmol/liter). The concentration ofN-acetyl-5-ASA was significantly higher after Pentasa, reflecting the more proximal release of 5-aminosalicylic acid compared with Salazopyrin. No relation was found between the 5-aminosalicylic acid fecal water concentration and the 5-aminosalicylic acid dose per kilogram of body weight. The urinary excretion of 5-aminosalicylic acid andN-acetyl-5-aminosalicylic acid was higher after Pentasa than after Salazopyrin (32% vs 25%). Dose interval plasma concentration curves showed low values after both preparations. Based on the concept that the fecal water concentration is decisive for the efficacy of 5-aminosalicylic acid in distal inflammatory bowel disease, Pentasa treatment offers a relevant alternative in cases of Salazopyrin intolerance or allergy in children. The higher systemic bioavailability from Pentasa warrants monitoring of the renal function.     

A dynamic model of once-daily 5-aminosalicylic acid predicts clinical efficacy

New once daily mesalamine formulations may improve adherence to medication usage.Response to Asacol and other forms of 5-aminosalicyclic acid(5-ASA)is better correlated with tissue concentrations and best predicted by concentrations of the drug within the lumen of the colon.Our group used computer simulation to predict colonic 5-ASA levels after Asacol administration.In our study,the model simulated Asacol distribution in the healthy colon,and during quiescent and active ulcerative colitis.An Asacol dosage ...     

A dynamic model of once-daily 5-aminosalicylic acid predicts clinical efficacy

New once daily mesalamine formulations may improve adherence to medication usage.Response to Asacol and other forms of 5-aminosalicyclic acid(5-ASA)is better correlated with tissue concentrations and best predicted by concentrations of the drug within the lumen of the colon.Our group used computer simulation to predict colonic 5-ASA levels after Asacol administration.In our study,the model simulated Asacol distribution in the healthy colon,and during quiescent and active ulcerative colitis.An Asacol dosage ...     

Intestinal hypersecretion of the refed starved rat: a model for alimentary diarrhoea.

Fluid transport was gravimetrically measured in vivo in the duodenum, jejunum, and ileum of anaesthetised fed, 72 hour starved and 72 hour starved rats refed for up to five days after starvation. Basal unstimulated fluid transport was monitored by instilling 0.9% NaCl into the lumen and measuring the gain or loss in weight of the closed intestinal loop. Fluid was absorbed in all the areas of the intestine in the fed rats. Increasing basal fluid absorption was observed in the duodenum over the three days of starvation but in the jejunum there was no significant change. In the ileum, the pattern was very different, on day 1 the fluid was absorbed but on days 2 and 3 there was an increasing secretion of fluid. Refeeding the rats with their normal diet restored the basal absorption of fluid in the duodenum within 24 hours, had no effect in the jejunum but in the case of the ileum the hypersecretion of fluid observed in the day 3 starved rat was maintained on day 1 of refeeding, increased further on day 2, decreased on day 3 but returned to absorption on day 4. The normal absorption was restored to the ileum on day 5 of refeeding. Fluid secretion was induced in all the rat groups by bethanechol (ip 60 micrograms/kg bw) a stable cholinergic agonist, PGE2 (ip 10 micrograms/kg (bw) and E coli STa (luminally instilled, 500 ng/ml) a secretory enterotoxin. All the secretagogues gave enhanced secretion compared with the fed by day 2 of starvation which increased considerably on day 3. Refeeding returned their secretion back to the fed level in the duodenum within 24 hours, in the jejunum within 48 hours but in the ileum their induced secretion on day 2 of refeeding was greater than that of the day 2 of refeeding was greater than that of day 3 starved and took until day 4 to return to the fed levels for behanechol and PGE2 and until day 5 for E. coli STa. This behaviour of rat small intestine showing even greater hypersecretion in the refed state than the starved mimics the human condition of alimentary induced diarrhoea where incautious feeding of starved humans induces severe, often lethal diarrhoea. The refed starved rat appears to be a possible model for this condition.     

Topical administration of 5-aminosalicylic acid enemas in patients with ulcerative colitis. Studies on rectal absorption and excretion.

5-aminosalicylic acid (5-ASA) is a new treatment for patients suffering from ulcerative colitis but only limited information is available about its rectal absorption. We therefore studied seven patients with ulcerative colitis in remission, and five with active disease to determine acetylated and free 5-ASA plasma concentrations and urinary acetyl 5-ASA after the administration of three different types of enemas: (2 g 5-ASA/100 ml, 4 g/100 ml, and 200 ml). In patients in remission urinary acetyl 5-ASA excretion was dose and volume dependent (p less than 0.01; p less than 0.05) but this correlation was absent in active disease. Because aminosalicylates are usually eliminated through the kidney, these low values (10% in active disease and 19% in those in remission) suggest that the beneficial action may be local. Urinary recovery was significantly lower in patients with active disease (p less than 0.01; p less than 0.02). No accumulation of 5-ASA was found in plasma after repeated daily administration.     

Measurement of colonic mucosal concentrations of 5-aminosalicylic acid is useful for estimating its therapeutic efficacy in distal ulcerative colitis: comparison of orally administered mesalamine and sulfasalazine

OBJECTIVES: Oral 5-aminosalicylic acid (5-ASA) preparations have been used frequently in the treatment of ulcerative colitis. However, there have been few reports investigating the relationship between colonic mucosal concentrations of 5-ASA and its clinical efficacy when oral sulfasalazine or 5-ASA compounds were administered. The aim of this study is to compare the mucosal concentrations of 5-ASA ensured by sulfasalazine or mesalamine, and to define the clinical significance of the measurement of 5-ASA concentrations in the treatment of distal ulcerative colitis. MATERIALS AND METHODS: Biopsies were taken from the rectum and sigmoid colon of the oral sulfasalazine group (n = 13) and the slow-release 5-ASA (mesalamine) group with (n = 5) or without (n = 11) rectal administration of 5-ASA. High-pressure liquid chromatography was used to measure the tissue concentrations of 5-ASA and its metabolites. We compared the 5-ASA concentrations of the sulfasalazine group with the mesalamine group. Furthermore, we analyzed the relationship between tissue 5-ASA concentrations and the Disease Activity Index (DAI). RESULTS: The concentrations of 5-ASA and acetyl-5-ASA in the sulfasalazine group were higher than those in the group taking oral mesalamine alone (p < 0.01). The concentration of 5-ASA was much higher in the patients who received oral and rectal mesalamine in an enema than in the patients who had oral mesalamine alone. There was a significant inverse correlation between the DAI and concentrations of 5-ASA in the rectum (r = 0.712, p < 0.001). CONCLUSIONS: We demonstrated that the colonic mucosal concentration of 5-ASA was significantly higher in the sulfasalazine group than in the mesalamine group. Furthermore, the concentrations of mucosal 5-ASA may be a good marker for the estimation of its efficacy in the treatment of ulcerative colitis.     

Human distribution and release of a putative new gut hormone, peptide YY

A radioimmunoassay has been developed for the new intestinal hormonal peptide tyrosine tyrosine [peptide YY (PYY)]. Peptide YY concentrations were measured in separated layers of the human gastrointestinal tract, where PYY was found exclusively in the mucosal epithelium which contained the endocrine cells. Peptide YY was found throughout the small intestine, in very low concentrations (5 pmol/g) in duodenum (6 pmol/g) and jejunum (5 pmol/g), but in higher concentrations in the terminal ileum (84 pmol/g). High concentrations were found throughout the colon (ascending 82 pmol/g, sigmoid 196 pmol/g), being maximum in the rectum (480 pmol/g). The major molecular form of PYY-like immunoreactivity in human intestine appeared to be identical to pure porcine hormone, both as judged by gel permeation chromatography and by reverse-phase high-pressure liquid chromatography. Basal plasma concentrations of PYY were low but rose in response to food, remaining elevated for several hours postprandially. The known potent biologic actions of PYY, its high concentrations in gut endocrine cells, and its release into the circulation after a normal meal suggest that this peptide may function physiologically as a circulating gut hormone.