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PubMedDate not supplied

Immunopharmacology of 5-aminosalicylic acid and of glucocorticoids in the therapy of inflammatory bowel disease.

Glucocorticoids as well as 5-aminosalicylic acid have been used successfully in different formulations during the past 40 years for the treatment of both acute and chronic inflammation in inflammatory bowel disease. The mechanism by which the drugs exert their actions are only partially known. Recent studies of the immunoregulation in the lamina propria provide evidence that numerous therapeutic mechanisms contribute to the efficacy of these drugs including the inhibition of arachidonic acid metabolism, a decrease in radical formation by oxygen radical scavenging, an inhibition of both in vivo and in vitro activation of peripheral and intestinal lymphocytes. Moreover direct immunoregulatory effects exerted by the drug may be important in influencing the complex balance of pro-inflammatory mechanisms during active intestinal inflammation. Such effects are the inhibition of both peripheral and intestinal B lymphocyte immunoglobulin secretion as well as the inhibition of pro-inflammatory cytokine production and their binding to receptors. Some of these immunoregulatory effects appear to be mediated by an inhibition of the activation of the nuclear factor kappa B transcription factor family by steroids and (less potent) aminosalicylic acid. Activation of nuclear factor kappa B appears to be pivotal for the sustained upregulation of inflammation molecule expression in many inflammatory diseases. It seems, therefore, most likely that the enormous therapeutic potency of steroids, as well as the anti-inflammatory properties of 5-aminosalicylic acid, are not achieved by a single action of the drug. The complex orchestration of numerous inhibitory interactions with pro-inflammatory principles will add to the therapeutic potential of steroids and of 5-aminosalicylic acid in the treatment of both acute and chronic intestinal inflammation.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1983

Treatment of Crohn's disease with peroral 5-aminosalicylic acid.

Eighteen patients with active Crohn's disease entered an open trial with 5-aminosalicylic acid in a slow-release preparation. All had lesions of the small bowel. Ten of them also had Crohn's disease of the colon. 5-Aminosalicylic acid, 500 mg three times daily, was administered for 6 wk. Even with meticulous monitoring, no side effects of any kind were observed, particularly no cases of renal affection, which could have been expected from animal studies. The clinical course was estimated as improved in 13 patients (72%), unchanged in 2 patients (11%), and aggravated in 3 patients (17%); 2 of these 3 were withdrawn from the study and switched to alternative treatment. The Crohn's disease activity index decreased from a median of 226 points to 99 points. On the basis of these results, large-scale controlled therapeutic trails seem warranted in order to establish clinical evidence for the benefit of peroral treatment with 5-aminosalicylic acid in patients with Crohn's disease.

Administration, Oral↗
PubMed1997

Basic studies on 5-(7-hydroxy-3-O-phosphonocholyl)aminosalicylic acid for the evaluation of microbial overgrowth.

A newly synthesized conjugate of 7-hydroxy-3-O-phosphonocholic acid (ursodeoxycholic acid monophosphate) with 5-aminosalicylic acid (5-ASA-UDCA monophosphate) was investigated to determine its suitability for the evaluation of enteric bacteria. This compound, 5-ASA-UDCA monophosphate, was efficiently deconjugated by cholylglycine hydrolase to release 5-ASA, whereas it was completely resistant to deconjugation by pancreatic and intestinal mucosal enzymes. In everted gut sac experiments, 5-ASA-UDCA monophosphate was not actively absorbed from any part of the small intestine. In animal experiments, urinary excretions of N-acetyl-5-ASA (Ac-5ASA) were measured for 24 h following the oral administration of 20 mg of 5-ASA-UDCA monophosphate. Control rats excreted 276.3 +/- 89.0 micrograms (mean +/- S.E.) of Ac-5ASA, whereas the rats with intestinal bacterial overgrowth excreted more (1224.1 +/- 231.5 micrograms; p < 0.01). These basic studies indicate that this compound is likely to offer a simple method for the evaluation of microbial overgrowth without the use of radioisotopes or expensive, special apparatus.

Aminosalicylic Acids↗
PubMed1987

5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis.

The efficacy and safety of 4-g 5-aminosalicylic acid enemas were assessed in 153 patients with ulcerative colitis involving up to 50 cm of distal colon. Seventy-six patients received active medication and 77 received a placebo. There were 20 dropouts (6 in the active group and 14 in the placebo group) during the study because of insufficient efficacy. After 6 wk of therapy, 48 of the 76 patients (63%) receiving 5-aminosalicylic acid were considered to be "much improved" by the study physician compared to 22 of the 77 patients (29%) on placebo (p = 0.001). A disease activity index based on patient symptoms and sigmoidoscopic appearance was used to assess efficacy. Mean disease activity index declined 55% for patients on 5-aminosalicylic acid and 24% for patients on placebo (p = 0.0001). Analysis of subgroups indicated that patients most likely to respond were those with disease confined to the 20-40 cm from the anus. Response was not affected by concurrent sulfasalazine, but patients requiring concurrent oral steroids had a diminished response. Rapid onset of efficacy was shown by a significant reduction in rectal bleeding within 3 days of treatment initiation. 5-Aminosalicylic acid enemas are well tolerated and are of benefit in the treatment of ulcerative colitis confined to the distal colon.

Adult↗
PubMed1984

A stable isotope method for the quantification of N-acetyl-5-aminosalicylic acid in plasma and urine.

The synthesis of a number of N-acyl-5-aminosalicylic acids and their derivatives is described. These compounds allow the sensitive and specific mass spectrometric determination of unlabelled or deuterium-labelled N-acetyl-5-aminosalicylic acid in biological samples. An in vivo study shows that the labelled compound, administered to rats, is excreted isotopically unchanged to at least 97%, and that no significant deacetylation/acetylation mechanism exists for this metabolite N-acetyl-5-aminosalicylic acid of salicylazosulphapyridine.

Aminosalicylic Acids↗
PubMed1986

5-Aminosalicylic acid or sulphapyridine. Which is the active moiety of sulphasalazine in rheumatoid arthritis?

Thirty patients with active rheumatoid arthritis participated in an open study of 6 months' treatment with either 5-aminosalicylic acid or sulphapyridine, the two moieties of sulphasalazine. Patients were assessed at regular intervals using a number of clinical and biochemical tests designed to detect specific antirheumatic activity. Patients taking sulphasalazine showed significant improvement in most parameters of disease activity, but those taking 5-aminosalicylic acid did not improve despite the fact that high serum concentrations of 5-aminosalicylic acid and acetyl 5-aminosalicylic acid were achieved. These results suggest that sulphapyridine is the active moiety of sulphasalazine. Its possible mode of action is discussed. Nausea was a frequent problem in patients taking sulphapyridine. Unless this problem can be overcome, sulphapyridine is unlikely to offer any therapeutic advantages over sulphasalazine in the treatment of rheumatoid arthritis.

Adult↗
PubMed1987

Evaluation of an enteric-coated delayed-release 5-aminosalicylic acid tablet in patients with inflammatory bowel disease.

Gastrointestinal transit of an enteric coated delayed release 5-aminosalicylic acid tablet radiolabelled with 111indium has been monitored in a total of 13 patients with Crohn's disease and ulcerative colitis. More than 70% of the tablets disintegrated in the small intestine, on average 3.2 hours after emptying from the stomach. Dispersed preparation was detected in the proximal colon of all the patients, except one with an ileostomy. Mean peak plasma concentrations of 5-aminosalicylic acid and its metabolite acetyl-5-aminosalicylic acid occurred 3-4 hours after gastric emptying. The tablets provide a reliable means of drug delivery to the ileum and proximal colon.

Adult↗
PubMed1999

Oral desensitization to 5-aminosalicylic acid medications.

BACKGROUND: Although hypersensitive subjects have been desensitized to oral sulfasalazine, the feasibility of oral desensitization to the drug's active moiety, 5-aminosalicylic acid has been questioned and never been reported. METHODS: We devised a 5-aminosalicylic acid desensitization protocol and administered the drug to two hypersensitive subjects on three occasions. RESULTS: Both 5-aminosalicylic acid hypersensitive subjects were successfully desensitized without complications and were able to tolerate therapeutic doses. CONCLUSION: Despite changing the drug's properties by crushing it for incrementally increasing administration, we successfully desensitized two patients on three occasions with 5-aminosalicylic acid.

Administration, Oral↗
PubMed2001

Anti-inflammatory effects of 5-aminosalicylic acid conjugates with chenodeoxycholic acid and ursodeoxycholic acid on carrageenan-induced colitis in guinea-pigs.

Two epimeric bile acid conjugates, 5-aminosalicylic acid-chenodeoxycholic acid (5-ASA-CDCA) and 5-aminosalicylic acid-ursodeoxycholic acid (5-ASA-UDCA), were synthesized to deliver 5-ASA to the large intestine by oral administration. The movement of the conjugates down the gastrointestinal tract and the anti-inflammatory effects on ulcerative colitis were investigated by administering the conjugates to guinea-pigs with an inflammatory bowel disease induced by 2% degraded carrageenan solution. The conjugates were protected from deconjugation in stomach and small intestine and reached the caecum and the colon, where 5-ASA was more easily liberated from 5-ASA-CDCA than from 5-ASA-UDCA. The conjugates at doses equivalent to 50 or 150 mg kg(-1) 5-ASA were orally administered once a day for 4 weeks from the 15th day after starting carrageenan treatment. The body weights and the bleeding scores of occult blood in faeces were measured during the experiment. The number of ulcers in the caecum and the colon were counted after killing the guinea-pigs at the end of the experiment. Rapid onset of efficacy was shown by a significant reduction in bleeding scores within a week after administration of the conjugates. Treatment with the lower dose of 5-ASA-CDCA showed a recovery of body weight and a significantly decreased number of ulcers in the caecum, and the ulcers in the colon had completely disappeared bythe end of the experiment. There was a good correlation found between the number of ulcers in the caecum and the bleeding scores of occult blood in faeces. The findings indicate that both conjugates were sufficiently delivered to the large intestine without deconjugation and that the lower dose of 5-ASA-CDCA is enough for treatment of ulcerative colitis in colonic inflammatory bowel diseases.

Animals↗
PubMed1991

Inhibition of red cell membrane lipid peroxidation by sulphasalazine and 5-aminosalicylic acid.

The effects of sulphasalazine, 5-aminosalicylic acid (5-ASA), and sulphapyridine on peroxidation of red cell membrane lipids, measured as malondialdehyde production, were assessed. Sulphasalazine and 5-ASA, at concentrations of 10(-5)-10(-3) M significantly inhibit lipid peroxidation, suggesting an antioxidant action that may explain the efficacy of these drugs in treating inflammatory bowel disease. Sulphapyridine, which is not effective in inflammatory bowel disease inhibited malondialdehyde production at a concentration of 10(-3) M only.

Aminosalicylic Acids↗
PubMed1990

The release profile of a controlled release preparation of 5-aminosalicylic acid (Rowasa I) in humans.

5-Aminosalicylic acid and its metabolite, N-ac-5-ASA, were measured in the plasma, urine, and ileostomy effluent of 24 ileostomates who ingested 750 mg Rowasa I following an overnight fast. Twelve subjects previously had a small-bowel resection or had part of their small bowel out of circuit (mean 95 cm) (Group I) while 12 had an intact small bowel (Group II). The mean peak plasma concentration of N-ac-5-ASA was 1.11 micrograms/ml in Group 1 subjects compared with 2.80 micrograms/ml in Group II subjects (P = N.S.). On average, 53.0 percent of the ingested Rowasa I was detected in the 24-hr ileostomy effluent of Group I subjects compared with 45.3 percent in the Group II subjects (P = N.S.). The mean recovery of 5-ASA and N-ac-5-ASA in urine was 8.5 percent in Group I and 35.6 percent in Group II subjects (P less than 0.001). These studies demonstrate that 5-ASA is released and present in the small bowel following oral ingestion of Rowasa I in patients who have or have not had small bowel resections.

Administration, Oral↗
PubMed2003

Direct lung delivery of para-aminosalicylic acid by aerosol particles.

Para-aminosalicylic acid (PAS), a tuberculostatic agent, was formulated into large porous particles for direct delivery into the lungs via inhalation. These particles possess optimized physical properties for deposition throughout the respiratory tract, a drug loading of 95% by weight and physical stability over 4 weeks at elevated temperatures. Upon insufflation in rats, PAS concentrations were measured in plasma, lung lining fluid and homogenized whole lung tissue. Systemic drug concentrations peaked at 15 min, with a maximum plasma concentration of 11+/-1 microg/ml. The concentration in the lung lining fluid was 148+/-62 microg/ml at 15 min. Tissue concentrations were 65+/-20 microg/ml at 15 min and 3.2+/-0.2 microg/ml at 3h. PAS was cleared within 3 h from the lung lining fluid and plasma but was still present at therapeutic concentrations in the lung tissue. These results suggest that inhalation delivery of PAS can potentially allow for a reduction in total dose delivered while providing for higher local and similar peak systemic drug concentrations as compared to those obtained upon oral PAS dosing. Similar particles could potentially be used for the delivery of additional anti-tuberculosis agents such as rifampicin, aminoglucosides or fluoroquinolones.

Administration, Inhalation↗
PubMed1988

5-Aminosalicylic acid protects against ischemia/reperfusion-induced gastric bleeding in the rat.

The aim of the present study was to determine whether the split products of sulfasalazine, sulfapyridine, and 5-aminosalicylic acid can ameliorate ischemia/reperfusion-induced injury to the gastric mucosa. Gastric mucosal damage was assessed by measuring (a) 51Cr-labeled red blood cell leakage into the gastric lumen, (b) the area of gross mucosal lesions, and (c) the extent of histologically demonstrable mucosal damage. In rats treated with 5-aminosalicylic acid, but not in those treated with sulfapyridine, the leakage of 51Cr-labeled red blood cells and the area of gross mucosal lesions after ischemia/reperfusion were significantly reduced as compared with untreated (control) rats. Inasmuch as 5-aminosalicylic acid (the therapeutic moiety of sulfasalazine) has been reported to be a hydroxyl radical scavenger, we also assessed the effects of dimethylsulfoxide (another hydroxyl radical scavenger) on ischemia/reperfusion-induced gastric mucosal injury. In rats treated with dimethylsulfoxide, leakage of 51Cr-labeled red blood cells and the area of gross mucosal lesions after ischemia/reperfusion were significantly reduced as compared with control rats. The results of this study support the contention that ischemia/reperfusion-induced gastric bleeding involves the hydroxyl radical and indicate that 5-aminosalicylic acid significantly attenuates this vascular injury.

Aminosalicylic Acids↗