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PubMed1998

Substrate selectivity of mouse N-acetyltransferases 1, 2, and 3 expressed in COS-1 cells.

Two human acetyl-CoA:arylamine N-acetyltransferases (NAT1 and NAT2) have been identified. Therapeutic and carcinogenic agents that are substrates for these isoenzymes (including isoniazid, sulfamethazine, p-aminobenzoic acid, 5-aminosalicyclic acid, and 2-aminofluorene) have been used to evaluate the role of the N-acetylation polymorphisms of NAT1 and NAT2 in the treatment of disease and differential risk of various cancers among individuals of differing acetylator phenotypes. The mouse is frequently used as a model of the human acetylator polymorphism. As three Nat isoenzymes have been identified in mouse, it is necessary to determine the selectivity of mouse Nats toward common NAT substrates. In the present study, Nat1*, Nat2*8, and Nat3* were expressed in COS-1 cells, and their substrate selectivity was evaluated with various substrates. Under the conditions used, mouse Nat2 had 20-, 2.4-, and 5.4-fold higher catalytic activity for p-aminobenzoic acid, 5-aminosalicylic acid, and 2-aminofluorene, respectively, than Nat1. Isoniazid N-acetylation was catalyzed only by mouse Nat1. For the substrates tested in this study, mouse Nat3 exhibited activity only toward 5-aminosalicylic acid and only at 1/20 the activity shown by Nat2. In addition, p-aminobenzoylglutamate, the first endogenous NAT substrate identified, was selective for mouse Nat2. These results further support the functional analogy of mouse Nat2 and human NAT1.

4-Aminobenzoic Acid↗
PubMedDate not supplied

Stability of disodium azodisalicylate (olsalazine) and metabolites in urine and faeces stored at different temperatures.

METHODS: The stability of disodium azodisalicylate, 5-aminosalicylic acid and acetyl-5-aminosalicylic acid dissolved in distilled water and in urine or mixed with faeces to which HgCl2 was added, was studied at -20 degrees C, 4 degrees C and room temperature. RESULTS: In water, no marked differences were found between the three storage regimens. In urine, disodium azodisalicylate and acetyl-5-aminosalicylic acid were stable, while the 5-ASA concentration decreased when stored at 4 degrees C and room temperature. In faeces stored during seven days, a marked decrease in 5-aminosalicylic acid concentration to about zero was found when it was kept at 4 degrees C and room temperature. No marked change in the concentration of disodium azodisalicylate and 5-aminosalicylic acid added to the faeces-HgCl2-mixtures appeared.

Aminosalicylic Acids↗
PubMed1998

5-ASA-glutamate protects rats from inflammatory bowel disease induced by intracolonic administration of trinitrobenzensulfonic acid.

BACKGROUND AND AIMS: 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.

Animals↗
PubMed2002

Comparison between nasal and intravenous desmopressin for the treatment of aminosalicylic acid-induced platelet dysfunction.

BACKGROUND AND OBJECTIVE: The study was conducted to compare the standard intravenous route with the intranasal route of desmopressin application and to establish the best time for initiating treatment with desmopressin with the use of the Born test and the PFA 100-Analyzer for monitoring the therapeutic effect. METHODS: Thirty healthy volunteers (ASA I) with no known bleeding disorder were randomly assigned to an intravenous or an intranasal group in a cross-over design fashion. After obtaining baseline values, the volunteers were given 500 mg aminosalicylic acid for 3 days. On day 4, platelet function tests were performed and desmopressin (0.3 microg kg(-1) body weight) was administered either intravenously or intranasally. Born tests (aggregation after stimulation with epinephrine and collagen) were conducted at 30 and 240 min, and PFA 100 bleeding time measurements were conducted at 30, 120 and 240 min after desmopressin administration. Wilcoxon signed rank sum tests or non-parametric ANOVA for repeated measures were used for statistical evaluation. RESULTS: All volunteers showed a marked decreased platelet function in the Born test (especially if stimulation with epinephrine was used) and an increased PFA 100 bleeding time after treatment with aminosalicylic acid. Platelet function was improved by intravenous as well as intranasal application of desmopressin (P < 0.001) after 30 min. The effect diminished after 4 h in both groups. CONCLUSIONS: Intravenous as well as intranasal desmopressin improved platelet function in healthy volunteers with aminosalicylic acid-induced platelet dysfunction at least 30 min after application. The effect lasts up to 4 h.

Administration, Intranasal↗
PubMed1995

Experimental studies on the pharmacokinetics and toxicity of 5-aminosalicylic acid-O-sulfate following local and systemic application.

5-Aminosalicylic acid-O-sulfate (5-ASA sulfate), a new agent for the treatment of ulcerative colitis and Crohn's disease of the large intestine, was investigated for its pharmacokinetic and toxicological properties, following local and systemic application. 5-ASA sulfate can be considered as a non-toxic agent after single oral intake in rats (14-day LD50 > 6000 mg/kg b.w.). Oral application of 2500 mg 5-ASA sulfate/kg b.w./d for 28 days to rats resulted in significantly increased body weight gain and food and water consumption. Alanine aminotransferase and alkaline phosphatase values were elevated in high-dosed (2500 mg/kg b.w./d p.o.) males. Relative liver weights were significantly increased in high-dosed males and females and the macroscopical inspection revealed thickened liver margins. The no-effect level following 28 days of oral application to rats was determined as 500 mg 5-ASA sulfate/kg b.w./d. In acute local tolerance studies in rabbits, 5-ASA sulfate is rated as non-irritant to the skin and the eye. After a single oral administration of 1800 mg 5-ASA sulfate to 5 healthy human test subjects, 5-ASA sulfate was almost completely metabolized by all test subjects within 3 days; mean urinary and faecal excretion of unchanged 5-ASA sulfate amounted to only 6.7% of the administered dose. A high faecal excretion of the active metabolite 5-aminosalicylic acid (5-ASA) (21.2% of the administered dose) and a low urinary excretion (1.4% of the administered dose) were observed.

Aminosalicylic Acids↗
PubMed1980

Para-aminosalicylic acid-induced hypoglycaemia in a patient with diabetic nephropathy.

A 62-year-old Indian with diabetic nephropathy controlled with metformin, developed miliary tuberculosis for which he was treated with rifampicin, isoniazid and ethambutol. Soon afterwards he developed cholestatic hepatitis and visual disturbance. Rifampicin and ethambutol were stopped. Streptomycin caused vertigo and had to be stopped. The introduction of para-aminosalicylic acid (PAS) led to hypoglycaemic coma. Metformin was stopped. Hypoglycaemic coma recurred. PAS was stopped and the patient's blood glucose concentrations became normal. Treatment with isoniazid and ethambutol led to total recovery from pulmonary tuberculosis. The induction of hypoglycaemia with PAS in this patient suggests a potential role for PAS in the treatment of diabetes mellitus.

Aminosalicylic Acid↗
PubMed1975

The effect of p-aminosalicyclic acid on iron transport and assimilation in mycobacteria.

p-Aminosalicylic acid inhibits growth of Mycobacterium bovis BCG and Mycobacterium smegmatis more effectively if cells are growing with a sufficiency of iron (more than 1 mu g Fe/ml) in the medium than if cells are deficient in iron (smaller than 0.1 mu g Fe/ml). In iron-deficient cultures formation of mycobactin, an ionophore for iron transport, is strongly inhibited by p-aminosalicylic acid. Uptake of iron into cell suspensions is also inhibited and the activity of several iron-containing enzymes declines in cells exposed to p-aminosalicylic acid during their growth. p-Aminosalicylic acid is about 50 times more effective towards a mutant of M. smegmatis which required mycobactin under iron-deficient growth conditions than towards the wild-type parent. p-Aminosalicylate is taken up into cells by an active process independent of the salicylate uptake system, possibly by the route used for assimilation of p-aminobenzoate. (This could account for why p-aminobenzoic acid, but not salicylic acid, antagonizes the action of p-aminosalicylic acid.) With iron-deficient cells, salicylate assimilation is about 50 times greater than either p-aminosalicylate or p-aminobenzoate but with iron-sufficient cells and with the mycobactin mutant salicylate uptake is negligible whereas p-aminobenzoate and p-aminosalicylate uptakes are unaffected. p-Aminosalicylic acid at 3.3 mM (500 mu g/ml) partially inhibits the uptake of both p-aminobenzoate and, if it is occurring, that of salicylate as well. As p-aminosalicylic acid is always more effective when the intracellular concentration of salicylic acid is low, it probably acts as an anti-metabolite of salicylic acid, not, however, by inhibiting the conversion of salicylic acid to mycobactin, but probably somewhere along the metabolic pathway of iron uptake.

Aminobenzoates↗
PubMed1989

Treatment of experimental acute uranium poisoning by chelating agents.

Sixteen chelating agents were examined to determine their relative efficacy as antidotes in acute uranyl acetate intoxication in mice after subcutaneous administration. Chelators were administered intraperitoneally to male Swiss mice at a dose equal to one-fourth of their respective LD50 and the therapeutic effectiveness was calculated. Eight compounds resulted in a significant enhancement of the survival rate: Tiron, gallic acid, DTPA, p-aminosalicylic acid, sodium citrate, EDTA, 5-aminosalicylic acid and EGTA. Therapeutic indices (TI) were then determined for these chelating agents. Tiron (TI: 158), gallic acid (TI: 116) and DTPA (TI: 44.9) were the most effective antidotes. In subsequent experiments, uranyl acetate dihydrate was administered subcutaneously (10 mg/kg) in a 24 hr excretion and distribution study. The previous eight chelators were given intraperitoneally ten min. after the uranium administration. 5-Aminosalicylic acid and tiron were consistently the most effective in increasing the urinary and faecal excretion of uranium respectively. A decrease of the uranium concentration in kidneys and bone was also noted with tiron. Tiron appears to be the most effective agent of those tested in the prevention of acute uranium intoxication.

Animals↗
PubMed2004

Azathioprine formulation optimizes metabolite profile in inflammatory bowel disease.

BACKGROUND: Recent studies have suggested that mercaptopurine metabolism is influenced by drug formulation (mercaptopurine vs. azathioprine) and concomitant use of 5-aminosalicylic acid medications. AIM: To determine the influence of dose, formulation and 5-aminosalicylic acid use on mercaptopurine metabolism. METHODS: Metabolites from 131 inflammatory bowel disease patients were analysed. Logistic regression was used to analyse correlations between dose and metabolite levels. Multivariate analysis was used to determine the effects of drug formulation and 5-aminosalicylic acid use. RESULTS: A positive correlation was detected between dose and 6-tioguanine nucleotides levels for azathioprine/Imuran formulation (P = 0.005) but not for mercaptopurine formulation. Adjusted mean 6-tioguanine nucleotides levels were similar for both formulations. Adjusted mean 6-methylmercaptopurine levels were higher for mercaptopurine formulation than for azathioprine formulation (1950 vs. 1056, P = 0.04). 5-Aminosalicylic acid use: 6-tioguanine nucleotides levels did not differ based on concomitant 5-aminosalicylic acid use. However, 5-aminosalicylic acid use did result in higher adjusted mean 6-methylmercaptopurine levels: 2078 on 5-aminosalicylic acid vs. 991 off 5-aminosalicylic acid (P = 0.004). CONCLUSIONS: (i) Azathioprine may have metabolic benefits by achieving a correlation of dose with 6-tioguanine nucleotides levels and by leading to lower mean 6-methylmercaptopurine levels. (ii) 5-aminosalicylic acid use does not significantly impact 6-tioguanine levels and may lead to higher 6-methylmercaptopurine levels.

Adolescent↗
PubMed1999

Antioxidant effects of aminosalicylates and potential new drugs for inflammatory bowel disease: assessment in cell-free systems and inflamed human colorectal biopsies.

BACKGROUND: The therapeutic efficacy of 5-aminosalicylic acid in inflammatory bowel disease may be related to its antioxidant properties. AIM: To compare in vitro the antioxidant effects of conventional drugs (5-aminosalicylic acid, corticosteroids, metronidazole), with new aminosalicylates (4-aminosalicylic acid, balsalazide) and other potential therapies (ascorbate, N-acetylcysteine, glutathione, verapamil). METHODS: Compounds were assessed for efficacy in reducing the in vitro production of reactive oxygen species by cell-free systems (using xanthine/xanthine oxidase, with or without myeloperoxidase) and by colorectal biopsies from patients with ulcerative colitis using luminol-amplified chemiluminescence. RESULTS: 5-aminosalicylic acid and balsalazide were more potent antioxidants than 4-aminosalicylic acid or N-acetyl-5-aminosalicylic acid in cell-free systems. 5-aminosalicylic acid (20 mM) and balsalazide (20 mM) inhibited rectal biopsy chemiluminescence by 93% and 100%, respectively, compared with only 59% inhibition by 4-aminosalicylic acid (20 mM). Hydrocortisone, metronidazole and verapamil had no significant effect on chemiluminescence in any system. Ascorbate (20 mM) inhibited chemiluminescence by 100% in cell-free systems and by 60% in rectal biopsies. N-acetyl cysteine (10 mM), and both oxidized and reduced glutathione (10 mM), completely inhibited chemiluminescence in cell-free systems, but not with rectal biopsies. CONCLUSIONS: The antioxidant effects of compounds varies between cell-free systems and inflamed colorectal biopsies. The effect of drugs on the chemiluminescence produced by these two assay systems is useful for screening potentially new antioxidant treatments for inflammatory bowel disease. Ascorbate seems worth further study as a novel therapy.

Adrenal Cortex Hormones↗
PubMed1987

Inheritance of acetylator genotype-dependent arylamine N-acetyltransferase in hamster bladder cytosol.

Acetyl coenzyme A-dependent arylamine N-acetyltransferase (EC 2.3.1.5) was examined in bladder cytosol derived from inbred Syrian hamsters. Expression of N-acetyltransferase activity towards p-aminobenzoic acid, p-aminosalicylic acid and 2-aminofluorene was acetylator genotype-dependent. Highest levels of bladder N-acetyltransferase activity were expressed in homozygous rapid acetylator hamsters (Bio. 87.20), lowest levels in homozygous slow acetylator hamsters (Bio. 82.73/H), and intermediate levels in Bio. 87.20 X Bio. 82.73/H F1 generation progeny. The N-acetyltransferase activity was acetylator genotype-dependent in both epithelial and non-epithelial bladder tissue. Genetic crosses using p-aminobenzoic acid and p-aminosalicylic acid as substrates indicated that bladder N-acetyltransferase activity is controlled via simple autosomal Mendelian inheritance of two codominant alleles at a single genetic locus. Acetylator genotype as assessed by bladder N-acetyltransferase activity was completely concordant with acetylator genotype as assessed by liver N-acetyltransferase activity. N-Acetyltransferase in slow acetylator bladder cytosol was both an apparent Km and Vmax variant compared to N-acetyltransferase in rapid acetylator bladder cytosol. These results suggest that genetic control of arylamine N-acetyltransferase in bladder urothelium may be a factor in hereditary predisposition to arylamine-induced bladder cancer.

Acetylation↗
PubMed1989

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.

Aminosalicylic Acid↗
PubMed2004

A novel anti-oxidant and anti-cancer strategy: a peptoid anti-inflammatory drug conjugate with SOD mimic activity.

Activation of reactive oxygen and nitrogen species (RONS) by redox-active metal ions has been proposed to contribute to oxidative damage in inflamed tissues. Here, we report a dual-function anti-oxidant conjugate comprising an anti-inflammatory agent (5-aminosalicylic acid) and a chelator with potential as a superoxide dismutase mimic. The conjugate ethylenediaminetetraacetic acid bis-(5-aminosalicylic acid methyl ester) [EBAME] chelates Cu(II) ions in a 1:1 ratio, as assessed spectrophotometrically using Job's method. Superoxide dismutase (SOD) activity was determined for the Mn(II)-conjugate as 0.758+/-0.130 U at a concentration of 0.99 microM. In inflamed tissues, peptidase mediated release of active 5-ASA would also release the EDTA chelator which has significant SOD mimic activity when complexed to Cu(II) ions. Thus, EBAME has potential as a dual-function anti-inflammatory agent with reduced gastric irritability.

Aminosalicylic Acids↗
PubMed1997

5-Aminosalicylic acid-associated renal tubular acidosis with decreased renal function in Crohn's disease.

The use of 5-aminosalicylic acid (5-ASA, mesalazine) in Crohn's disease is usually well tolerated. Nevertheless, the occasional occurrence of nephrotoxic side effects has been described in several case reports. We present the case of a 34-year-old female in whom chronic use of 5-ASA may have caused renal damage which manifested with tubular acidosis, severe weight loss, shortness of breath and fatigue. For 17 years the patient has suffered from Crohn's disease. She received sulfasalazine (3 g/day) for 12 years and was treated with resin-coated mesalazine (3 g/day) for the last 72 months. Onset of weight loss of 10 kg over a 6-month period, accompanied by progressive shortness of breath and fatigue, lead to a diagnosis of metabolic acidosis and renal bicarbonate loss due to damage to the tubular epithelium. Kidney biopsy demonstrated acute interstitial nephritis which may be related to 5-ASA.

Acidosis, Renal Tubular↗
PubMed1989

Pharmacokinetics of sulfasalazine metabolites in rats following concomitant oral administration of riboflavin.

Sulfasalazine, 60 mg/kg, was administered orally to groups of rats (n = 4) along with 1, 5, or 10 mg/kg of riboflavin. Plasma and urine were assayed for 5-aminosalicylic acid, acetyl-5-aminosalicylic acid, sulfapyridine, and acetyl-sulfapyridine using an HPLC method. The mean percent of dose recovered as total metabolites in urine was significantly greater (alpha = 0.01) for the group receiving 10 mg/kg riboflavin compared to the controls or the group receiving 1 mg/kg riboflavin. Plasma AUC and Cmax values were also significantly greater (alpha = 0.05) for the 10 mg/kg riboflavin group. These results suggest that at higher doses, a significant fraction of riboflavin reaches the colon intact and stimulates more efficient reduction of the azo bond in sulfasalazine. Since the concentrations of 5-ASA achieved in the colon may be directly related to the efficacy of sulfasalazine in treating inflammatory bowel disease, concomitant administration of riboflavin may enhance sulfasalazine's efficacy in humans.

Administration, Oral↗
PubMed1978

Treatment of hypertriglyceridemia with para-aminosalicylic acid-C: a possible mechanism of action.

The effect of para-aminosalicylic acid-C (PAS-C, 8 g/day) on lipid metabolism was studied on a metabolic ward in nine subjects with primary endogenous hypertriglyceridemia. During 2 wk on a basal isocaloric liquid formula diet (40% fat, 45% carbohydrate), PAS-C reduced plasma triglyceride (-41.9 +/- 18.9%, p less than .01, -x +/- SD), cholesterol (-22.8 +/- 12.9%, p less than .005), and a very low density lipoprotein triglyceride (p less than .001) and cholesterol (p less than .01) levels without changing the cholesterol content of low density or high density lipoproteins. Similar effects occurred on a fat-free, 85% carbohydrate diet. Decreases in very low density lipoproteins correlated with changes in both total triglyceride (r = .99, p less than .01) and cholesterol (r = .70, p less than .05). Treatment with PAS-C reduced the plasma triglyceride removal rate related to lipoprotein lipase (-14.6 +/- 14.1%, p less than .02), but did not alter plasma postheparin lipolytic activity or the apparent Km for substrate-enzyme interaction. Kinetic data obtained during the prolonged heparin infusion fit the linearized Michaelis-Menten model for subjects with endogenous hypertriglyceridemia. The reduction in the plasma triglyceride concentration during PAS-C treatment was a function of the decrease in triglyceride removal rate (r = .74, p less than .025) without alternation in the maximal removal capacity related to lipoprotein lipase. This suggests that under the steady state conditions of these studies, the decrease in plasma triglyceride concentration was due to a reduction in endogenous triglyceride production. Free fatty acid metabolism, glucose homeostasis, fat absorption, and thyroid function did not change. These results suggest that PAS-C lowers plasma triglyceride and cholesterol levels in hypertriglyceridemic subjects reducing endogenous very low density lipoprotein production and/or secretion into the circulation.

Adult↗
PubMed1987

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.

Aminoisobutyric Acids↗
PubMed2001

Once versus divided daily dosing with delayed-release mesalazine: a study of tissue drug concentrations and standard pharmacokinetic parameters.

BACKGROUND: Delayed-release mesalazine is traditionally taken as three divided doses. However, it is well-recognized that dosing frequency has a significant impact on compliance and that once daily dosing is preferable. METHODS: We measured serum, urinary, faecal and rectal tissue concentrations of 5-aminosalicylic acid and N-acetyl 5-aminosalicylic acid in 24 healthy volunteers following dosing with delayed-release mesalazine, 1.2 g or 2.4 g daily, given as either a single daily dose at 08:00 hours or in three divided doses at 08:00, 13:00 and 18:00 hours. RESULTS: Urinary and faecal excretion and rectal tissue concentrations of 5-aminosalicylic acid and N-acetyl 5-aminosalicylic acid were similar following single or divided daily dosing, at both doses studied. Peak serum concentrations were found at 06:00-09:00 following divided dosing and at 17:00-20:00 following once daily dosing. However, peak and trough serum levels and serum area under curve values (AUC) were similar with both regimens and at both doses. CONCLUSIONS: Urinary, faecal and rectal tissue concentrations are similar following single or divided daily dosing. Minor differences in serum levels were apparent but maximum, minimum and AUC values were similar. Clinical trials should examine the efficacy and toxicity of once daily dosing in patients with ulcerative colitis.

Adolescent↗