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PubMed1998

[Ulcerative colitis--colon delivery of 5-aminosalicylic acid].

Ulcerative colitis, Crohn's disease and hemorrhage colitis are typical example of colon specific diseases. The targeting of the drugs for these colon specific diseases was attempted by a new technology, where ethylcellulose (EC) was used as pharmaceutical material. Especially, pressure-controlled colon delivery capsule (PCDC) made of EC is a unique system. PCDC was prepared by coating the inner surface of gelatin capsule with water-insoluble polymer, EC. By adjusting the coating thickness of EC membrane to be approximately 40 microns, colon delivery of dug were obtained both in beagle dogs and human volunteers. PCDC containing 5-ASA was prepared and was administered orally to beagle dogs. After administration, 5-ASA appeared into the systemic circulation at 3-5 h which corresponds to the colon arrival time confirmed with sulfasalazine.

Animals↗
PubMed1994

Superoxide inhibition following different stimuli of respiratory burst and metabolism of aminosalicylates in neutrophils.

Reactive oxygen species such as superoxide radicals have been proposed to play an important role in the pathogenesis of inflammatory bowel disease. Some of the antiinflammatory actions of aminosalicylates have been ascribed to their capability to scavenge superoxide radicals directly or to inhibit its production in stimulated neutrophils. However, as a controversy still exists with regard to the precise mechanisms of inhibition and the metabolism within inflammatory cells, we compared scavenger properties of 5-aminosalicylic acid, 4-aminosalicylic acid, N-acetyl aminosalicylic acid, olsalazine, and benzalazine in systems with defined superoxide radical generation such as the dimethyl sulfoxide-NaOH and the potassium superoxide system. We also studied possible inhibition of the superoxide production following different stimuli of the respiratory burst in neutrophils and investigated the uptake and potential metabolism (N-acetylation) of 5-aminosalicylic acid in lipopolysaccharide-primed and resting neutrophils. We found that 5-aminosalicylic acid and 4-aminosalicylic acid had defined scavenger properties in the dimethyl sulfoxide-NaOH or potassium superoxide systems, respectively, whereas compounds with a modified aminophenolic structure had no effects. At the cellular level, 5-aminosalicylic acid inhibited phorbol myristate acetate (100 ng/ml)-activated superoxide generation to 82.3 +/- 9.3%, the formylmethionyl leucyl peptide (10(-5) M) to 61.0 +/- 6.8%, and the NaF (20 mM)-stimulated production to 32.3 +/- 3.2% (mean +/- SD, P < 0.01). The actions of the other drugs were less pronounced. Almost identical retention times (Rt = 11.2 min) of 3H-labeled phorbol myristate acetate in the presence and absence of 5-aminosalicylic acid revealed no in vitro interactions.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylation↗
PubMed1994

Restoration of postburn impaired lymphocyte responsiveness by nonsteroidal anti-inflammatory drugs is independent of prostaglandin E2 inhibition.

Prostaglandin E2 (PGE2) has been implicated in postburn immunosuppression, which is responsible for septic complications. In the present work, seven non-steroidal anti-inflammatory drugs (NSAIDs), differing by their capacity to inhibit the cyclooxygenase pathway, were compared for their ability to restore T lymphocyte proliferative responses evaluated 4 days after thermal injury in rats. Salicylic acid, 5-aminosalicylic acid, and niflumic acid, given daily, fully restored spleen cell responses to concanavalin A (Con A) and phytohemagglutinin. These drugs were active only at doses that were below the anti-inflammatory doses and did not modify normal spleen cell responses. In these conditions, indomethacin slightly restored lymphocyte reactivity, whereas acetylsalicylic acid, ketoprofen, and piroxicam were ineffective. PGE2 production by Con A-stimulated spleen cells from untreated burned rats and after treatment with niflumic acid or 5-aminosalicylic acid did not correlate with the intensity of the proliferative response. Indomethacin, niflumic acid, and 5-aminosalicylic acid were added in vitro to spleen cells from normal and burned rats, at concentrations from 10(-7) to 10(-4) M. PGE2 production was strongly depressed by indomethacin and niflumic acid and not modified by 5-aminosalicylic acid. The proliferative response of normal spleen cells was depressed in a concentration-dependent manner by niflumic acid and slightly inhibited at the highest concentrations of indomethacin. In contrast, indomethacin concentration dependently restored the burn-impaired proliferative response, whereas niflumic acid further depressed it and 5-aminosalicylic acid had no effect. These results demonstrate that only some NSAIDs are able to restore T lymphocyte reactivity impaired after thermal injury and that this property is not related to inhibition of PGE2 production.

Administration, Oral↗
PubMed2002

Is your patient taking the medicine? A simple assay to measure compliance with 5-aminosalicylic acid-containing compounds.

BACKGROUND: Poor compliance with 5-aminosalicylic acid therapy has been reported amongst patients with inflammatory bowel disease. Currently, there is no easy method to monitor 5-aminosalicylic acid; however, the chemical similarity between 5-aminosalicylic acid and salicylate might provide a solution. AIM: To determine the feasibility of using salicylate levels to monitor compliance with 5-aminosalicylic acid medication. METHODS: Thirty-six patients with inflammatory bowel disease, taking maintenance 5-aminosalicylic acid, provided either a paired serum and urine sample or an intestinal biopsy. Samples were split into two: half were sent to the hospital biochemistry department for salicylate measurement, and half were analysed for 5-aminosalicylic acid and its metabolite, N-acetyl-5-aminosalicylic acid, using high performance liquid chromatography. Correlation between the results was calculated. RESULTS: Serum and urine were available for 25 patients. Serum salicylate was undetectable, but urinary salicylate ranged from 31 to 3254 microg/mL. The correlations between urinary salicylate and 5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid were 0.96 (95% confidence interval, 0.91-0.98) and 0.9 (95% confidence interval, 0.77-0.96), respectively. Sixteen biopsies were available from 13 patients. The 5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid concentrations were 0.2-657 ng/mg and 1.6-1598 ng/mg, respectively; there was no correlation with bowel salicylate. CONCLUSIONS: The close correlation between 5-aminosalicylic acid and salicylate levels offers a simple method to assess compliance with 5-aminosalicylic acid therapy.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2006

Microbial transformation of aniline derivatives: regioselective biotransformation and detoxification of 2-phenylenediamine by Bacillus cereus strain PDa-1.

A bacterial isolate, strain PDa-1, grew well on basal medium supplemented with 2-phenylenediamine, sucrose, and ammonium nitrate and completely transformed 2-phenylenediamine. The isolate was identified as Bacillus cereus. The product formed from 2-phenylenediamine was identified by EI-MS and NMR as 2-aminoacetanilide; whole cells converted 2-phenylenediamine to the product with a 76% molar yield. Whole cells also showed a broad substrate specificity toward 20 of 26 tested arylamines with substituent groups of various size and positions. Especially 2-aminobenzoic acid, 4-aminosalicylic acid, 5-aminosalicylic acid, and 2-aminofluorene were converted completely to the corresponding product with an aminoacetyl group. Cell extracts of strain PDa-1 had a high arylamine N-acetyltransferase activity. The partially purified enzyme converted 2-phenylenediamine to 2-aminoacetanilide. Strain PDa-1 constitutively expressed the enzyme in the absence of 2-phenylenediamine. Effects of 2-phenylenediamine and 2-aminoacetanilide on growth indicated that this enzyme probably plays a role in the detoxification of toxic arylamines in this strain.

Aniline Compounds↗
PubMedDate not supplied

N-acetylation pharmacogenetics. Michaelis-Menten constants for arylamine drugs as predictors of their N-acetylation rates in vivo.

Michaelis-Menten constants for two in vivo monomorphically N-acetylated substrates, p-aminobenzoic acid and p-aminosalicylic acid, and two in vivo polymorphically N-acetylated substrates, sulfamethazine and procainamide, were determined with an improved assay procedure using liver N-acetyltransferase from rapid and slow acetylator rabbit. The slow rabbit liver isozyme proves to be a Vmax and a Km variant for p-aminobenzoic acid and p-aminosalicylic acid. Mean differences in the apparent Vmax for rapid acetylators were 39-fold greater for p-aminobenzoic acid and 16-fold greater for p-aminosalicylic acid. The apparent Km values for the slow acetylator enzyme were lower than 5 microM, whereas the apparent Km values for the rapid acetylator phenotype were at least 15 times higher, with a value of 105 +/- 21 microM for p-aminobenzoic acid and 74 +/- 16 microM for p-aminosalicylic acid. In contrast, for the polymorphic substrates, sulfamethazine and procainamide, rapid rabbit liver N-acetyltransferase was only a Vmax variant with a mean specific activity that was 13-fold higher than that for slow acetylator.

4-Aminobenzoic Acid↗
PubMed1990

The chlorinating activity of human myeloperoxidase: high initial activity at neutral pH value and activation by electron donors.

The steady-state activity of myeloperoxidase in the chlorination of monochlorodimedone at neutral pH was investigated. Using a stopped-flow spectrophotometer we were able to show that the enzymic activity at pH 7.2 rapidly declined in time. During the first 50-100 ms after addition of H2O2 to the enzyme, a turnover number of about 320 s-1 per haem was observed. However, this activity decreased rapidly to a value of about 25s-1 after 1 s. This shows that in classical steady-state activity measurements, the real activity of the enzyme at neutral pH is grossly underestimated. By following the transient spectra of myeloperoxidase during turnover it was shown that the decrease in activity was probably caused by the formation of an enzymically inactive form of the enzyme, Compound II. As demonstrated before (Bolscher, B.G.J.M., Zoutberg, G.R., Cuperus, R.A. and Wever, R. (1984) Biochim. Biophys. Acta 784, 189-191) reductants such as ascorbic acid and ferrocyanide convert Compound II, which accumulates during turnover, into active myeloperoxidase. Activity measurements in the presence of ascorbic acid showed, indeed, that the moderate enzymic activity was higher than in the absence of ascorbic acid. With 5-aminosalicylic acid present, however, the myeloperoxidase activity remained at a much higher level, namely about 150 s-1 per haem during the time interval from 100 ms to 5 s after mixing. From combined stopped-flow/rapid-scan experiments during turnover it became clear that in the presence of 5-aminosalicylic acid the initially formed Compound II was rapidly converted back to native enzyme. Presteady-state experiments showed that 5-aminosalicylic acid reacted with Compound II with a K2 of 3.2 x 10(5) M-1.s-1, whereas for ascorbic acid a K2 of 1.5 x 10(4) M-1.s-1 was measured at pH 7.2. In the presence of 5-aminosalicylic acid during the time interval in which the myeloperoxidase activity remained constant, a Km for H2O2 at pH 7.2 was determined of about 30 microM at 200 mM chloride. In the absence of reductants the same value was found during the first 100 ms after addition of H2O2 to the enzyme. The physiological consequences of these findings are discussed.

Aminosalicylic Acids↗
PubMed2004

Comparative pharmacokinetics of equimolar doses of 5-aminosalicylate administered as oral mesalamine (Asacol) and balsalazide: a randomized, single-dose, crossover study in healthy volunteers.

BACKGROUND: Existing pharmacokinetic data are insufficient to determine whether a delayed-release formulation of mesalamine (Asacol) results in greater systemic exposure to 5-aminosalicylic acid and its major metabolite N-acetyl-5-aminosalicylic acid than a prodrug (balsalazide). AIM: To determine the pharmacokinetic parameters of 5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid from equimolar doses of 5-aminosalicylic acid administered as Asacol and balsalazide. METHODS: Nineteen healthy volunteers completed an open-label, single-dose, randomized, crossover study comparing the pharmacokinetics of 5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid from equimolar doses of 5-aminosalicylic acid (800 mg) administered as Asacol (800 mg) and balsalazide (2250 mg). Plasma and urine samples were analysed for 5-aminosalicylic acid, N-acetyl-5-aminosalicylic acid, and balsalazide (urine only) using high-performance liquid chromatography methods with mass spectrometric detection. Pharmacokinetic parameters assessed for 5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid included: percentage of dose excreted in urine (A(e)%), area under the plasma concentration-time curve (AUCt(last)); and maximum plasma concentration (C(max)). RESULTS: The geometric mean total (5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid) urinary excretion values (A(e)%) of Asacol and balsalazide were 19.26 and 19.31% (P = 0.98). The geometric mean A(e)% values of 5-aminosalicylic acid for Asacol and balsalazide were 0.39 and 0.37% (P = 0.78); the geometric mean A(e)% values of N-acetyl-5-aminosalicylic acid for Asacol and balsalazide were 18.78 and 18.83% (P = 0.98). The geometric mean 5-aminosalicylic acid AUC(t(last)) values for Asacol and balsalazide were 3295 and 3449 ng h/mL (P = 0.85); the geometric mean N-acetyl-5-aminosalicylic acid AUC(t(last)) values for Asacol and balsalazide were 15 364 and 16 050 ng h/mL (P = 0.69). The geometric mean 5-5-aminosalicylic acid C(max) values for Asacol and balsalazide were 319 and 348 ng/mL (P = 0.80); the geometric mean N-acetyl-5-aminosalicylic acid C(max) values for Asacol and balsalazide 927 and 1009 ng/mL (P = 0.67). CONCLUSIONS: The systemic absorption of 5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid from Asacol and balsalazide are comparable based upon plasma pharmacokinetic parameters and urinary excretion values.

Administration, Oral↗
PubMed2003

The effect of 5-aminosalicylic acid-containing drugs on sulfide production by sulfate-reducing and amino acid-fermenting bacteria.

The toxic, bacterial metabolite sulfide is implicated in ulcerative colitis. Ulcerative colitis patients taking 5-aminosalicylic acid-containing drugs have lower fecal sulfide levels than those not taking these drugs. The effects of sulfasalazine, balsalazide, olsalazine, and 5-aminosalicylic acid on sulfide production were studied in a three-stage chemostat pulsed on days 1 to 3 with 5 g sulfasalazine (40 mM) and in pure cultures of amino acid-fermenting and sulfate-reducing bacteria. By the third day of sulfasalazine addition to the chemostat, sulfide concentrations in vessels 1 through 3 had dropped from 1.73, 1.78, and 1.43 mM to 0.01, 0.15, and 0.9 mM, respectively. In pure cultures, 50% inhibition of sulfide production from amino acids occurred at 2.5 +/- 0.05 mM for sulfasalazine, 5 +/- 0.2 mM for olsalazine, 6 +/- 1 mM for balsalazide, and more than 20 mM for 5-aminosalicylic acid. Fifty percent inhibition of sulfide production from sulfate occurred at 0.25 +/- 0.05 mM for sulfasalazine, 0.7 +/- 0.2 mM for balsalazide, and 9.0 +/- 1.0 mM for 5-aminosalicylic acid. The order of effectiveness of equimolar concentrations of drugs (most effective first) in this assay was sulfasalazine, then olsalazine (though given clinically at half the dose of other 5-aminosalicylic acid prodrugs) and balsalazide, and lastly 5-aminosalicylic acid. Inhibition of sulfide production by 5-aminosalicylic acid-containing drugs may contribute to their therapeutic effect in ulcerative colitis.

Amino Acids↗
PubMedDate not supplied

A comparison of effects of sulfasalazine and its metabolites on the metabolism of endogenous vs. exogenous arachidonic acid.

Sulfasalazine and, to a lesser extent, 5-aminosalicylic acid and N-acetyl-aminosalicylic acid, were found to block production of 5-hydroxy-6,8,11,14-eicosatetraenoic acid, leukotriene B4 (LTB4), and LTB4 stereoisomers from both exogenous and endogenous [14C]arachidonic acid (14C-AA) in ionophore A23187 (1 microgram/ml)-stimulated human neutrophils. Lipids were assessed by thin-layer chromatography and reverse-phase high-pressure lipid chromatography. Sulfasalazine blocked the synthesis of these metabolites from both exogenous and endogenous AA, but was more effective in blocking the metabolism of exogenous than endogenous AA. The IC50 for sulfasalazine in blocking the synthesis of LTB4 was 0.8 mM when exogenous AA was the substrate and 2.8 mM when endogenous AA was the substrate. N-Acetyl-aminosalicylic acid showed a similar pattern, but was less effective than sulfasalazine (IC50 for exogenous AA was 5.4 mM, and for endogenous AA was 8.0 mM). 5-Aminosalicylic acid had similar effects with an IC50 of 6.0 and 6.4 mM respectively. Sulfasalazine but not 5-aminosalicylic acid inhibited the incorporation of arachidonic acid into phospholipids and triglycerides. Sulfasalazine, but not its metabolites, inhibited the release of 14C-AA from membrane phospholipids in a dose-dependent manner (46.0% inhibition with 4 mM sulfasalazine). Sulfasalazine also blocked the metabolism of exogenously added LTB4 to 20-OH LTB4 and 20-COOH LTB4 with an IC50 of 2 mM. Our findings suggest that under physiologic conditions, with endogenous AA as a substrate, sulfasalazine acts as an inhibitor of lipoxygenase, of phospholipase A2 and of LTB4 metabolism, whereas 5-aminosalicylic acid and N-acetyl-aminosalicylic acid inhibit only lipoxygenase.

Aminosalicylic Acids↗