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PubMed1999

Intestinal metabolism and transport of 5-aminosalicylate.

The purpose of this study was to determine the characteristics of intestinal absorption and metabolism of 5-aminosalicylic acid (5ASA). Regional perfusions of 5ASA in the anesthetized rat resulted in the appearance of N-acetyl-5-aminosalicylic acid in the intestinal lumen. Lumenal metabolite appearance was proportional to 5ASA permeability, which was 5-fold higher in the jejunum than in the ileum. Intestinal elimination significantly decreases 5ASA absorption at low lumenal drug concentrations and this process is saturated at high drug concentrations. Metabolite levels in intestinal tissue were higher than plasma levels at low perfusion drug concentrations, whereas the reverse was observed at high concentrations. Transport and metabolism of 5ASA was studied in Caco-2 monolayers. At low drug concentrations, 5ASA was preferentially transported in the basolateral (BL) to apical (AP) direction. With 5ASA incubation in either the AP or BL chamber, the N-acetyl metabolite appeared only in the AP compartment. Transport of N-acetyl-5-aminosalicylic acid was also exclusively observed in the BL to AP direction. Clinical data indicate that anti-inflammatory response to oral 5ASA correlates with the amount of 5ASA delivered to the intestinal tissue. This study shows that at lumenal levels below 200 microg/ml (concentrations that are typically achieved by controlled release dosage forms), intestinal secretion of 5ASA accounts for more than 50% of the total elimination and can significantly affect tissue levels and, therefore, may be an important factor in determining the response to 5ASA therapy.

Animals↗
PubMed1980

Effects of sulphasalazine and its metabolites on prostaglandin synthesis, inactivation and actions on smooth muscle.

1 We have investigated the effects of sulphasalazine and of its principal colonic metabolites (5-aminosalicylic acid and sulphapyridine) on prostaglandin inactivation, synthesis and actions on gastrointestinal smooth muscle.2 Sulphasalazine inhibits prostaglandin F(2alpha) breakdown in 100,000 g supernatants in all organs so far tested from 7 species with an ID(50) of approx. 50 muM; it has a selective action on prostaglandin 15-hydroxydehydrogenase and does not inhibit prostaglandin Delta-13 reductase, prostaglandin 9-hydroxydehydrogenase or ;enzyme X' at millimolar concentrations. Enzyme activities were measured radiochemically or by bioassay.3 Sulphapyridine and 5-aminosalicylic acid do not inhibit prostaglandin inactivation in vitro (4 species tested). A methyl analogue of sulphasalazine is a more potent inhibitor than the parent compound. Rabbit colon prostaglandin F(2alpha) metabolism in vitro was inhibited by the following drugs with ID(50) values (muM) of: diphloretin phosphate 20, sulphasalazine 50, indomethacin 220, frusemide 1000 and aspirin 10,000. A similar rank order of potencies was obtained with rabbit kidney.4 Sulphasalazine at 50 to 100 muM inhibited inactivation of prostaglandin E(2) in the perfused rat and guinea-pig lung by 3 to 40% (rat) and 32 to 100% (guinea-pig) when measured by superfusion cascade bioassay and of prostaglandin F(2alpha) by 43.6 +/- 6.5% in rat lung perfused with 50 muM sulphasalazine and assayed radiochemically.5 Prostaglandins E(1) and E(2) were 97.0 +/- 8.2% and 92.3 +/- 6.8% inactivated in the lungs after intravenous injection in the anaesthetized rat as measured by reference to their vasodepressor potencies when injected intra-arterially. Prostaglandin A(2) was not similarly inactivated. Pulmonary inactivation was prevented in the presence of an intravenous infusion of 16.3 mug kg(-1) min(-1) sulphasalazine and partially inhibited at a lower infusion rate.6 Prostaglandin biosynthesis from arachidonic acid was measured in microsomal preparations from four sources by bioassay and radiochemical methods. Indomethacin was a potent inhibitor (ID(50) 0.8 to 4.1 muM) but sulphasalazine and its methyl analogue were very weak inhibitors (ID(50) 1500 to > 5000 muM), 5-aminosalicylic acid was weaker still and sulphapyridine inactive.7 Sulphasalazine at 50 muM did not affect the actions of prostaglandins on five smooth muscle preparations; at 500 muM there was a rapidly reversible and probably non-specific antagonism of responses to low doses of prostaglandins.8 The specificity and selectivity of the interaction of sulphasalazine and its metabolites with the formation, breakdown and actions of prostaglandins are discussed.

Aminosalicylic Acids↗
PubMed1992

Distribution of mesalamine enemas in patients with active distal ulcerative colitis.

Mesalamine (5-aminosalicylic acid), a topically administered anti-inflammatory agent, is effective treatment by enema for distal ulcerative colitis; it lacks many of the side effects of orally administered sulfasalazine. In this study, we determined the colonic distribution of a 60-ml mesalamine enema in eight patients (five women and three men, 18 to 48 years old) with active distal ulcerative colitis that ranged from 12 to 40 cm proximal to the anal verge. On 3 consecutive days, each patient self-administered a 4-g (60-ml) 5-aminosalicylic acid enema that contained 3.7 MBq of [99mTc]technetium-sulfur colloid. Anterior and posterior images were obtained at 0, 30, 60, 120, and 240 minutes. During the 4-hour study period, all patients retained the enemas. The enemas spread to the sigmoid region in 24 of 24 studies, to the splenic flexure region in 22 of 24, and to the transverse colon in 1 of 24. Most of the enema was retained in the sigmoid colon. Therefore, we conclude that a 60-ml enema, when administered as recommended clinically, routinely flows retrograde as far as the splenic flexure but rarely spreads beyond this point. These results support the use of intrarectally administered 5-aminosalicylic acid for segmental colitis of the descending colon.

Adolescent↗
PubMed1985

In vitro effects of sulphasalazine, azodisal sodium, and their metabolites on Clostridium difficile and some other faecal bacteria.

The effects of sulphasalazine (SASP), azodisal sodium (ADS), and their metabolites were tested in vitro on aerobic and anaerobic faecal bacterial strains. Sulphapyridine (SP) had a mild to moderate effect on Escherichia coli and Streptococcus faecalis. SASP also had a growth-inhibitory effect on Strep. faecalis. The other substances had no effect on the aerobic strains. SASP, SP, 5-aminosalicylic acid, and, to a certain extent, N-acetyl-5-aminosalicylic acid exerted a growth-inhibitory effect on the anaerobic strains. Of special interest was the inhibitory effect on Clostridium difficile strains. In recent years the possibility that overgrowth of Cl. difficile could cause flare-ups of inflammatory bowel disease has been discussed. Some studies suggested that SASP treatment could predispose to Cl. difficile superinfection, whereas others found SASP more probable to exert a prophylactic effect. Our findings support the theory that SASP treatment reduces rather than promotes the risk of Cl. difficile superinfection.

Aminosalicylic Acids↗
PubMed2026

MIC-based tuberculosis drug susceptibility testing using Sensititre MYCOTB: a diagnostic accuracy meta-analysis.

Accurate drug susceptibility testing (DST) is crucial for designing effective regimens for multidrug-resistant (MDR) and pre-extensively drug-resistant tuberculosis (pre-XDR TB). Sensititre MYCOTB enables simultaneous determination of minimum inhibitory concentrations (MICs) for multiple drugs, but its diagnostic performance varies across studies. This meta-analysis evaluated the diagnostic performance of Sensititre MYCOTB for key MDR and pre-XDR TB drugs. The protocol was registered in PROSPERO (CRD420251230599). PubMed, Cochrane, Google Scholar, Scopus, ONOS, Web of Science, ScienceDirect, and registries were systematically searched for studies published between 2010 and 2025. Studies comparing the Sensititre MYCOTB with reference DST for Mycobacterium tuberculosis complex (MTBC) were included. Bias assessment and pooled diagnostic accuracy estimates were generated. Fourteen studies, including 1,728 isolates, were analyzed. Rifampicin and isoniazid demonstrated high sensitivity (0.976 [95% CI: 0.94-0.99] and 0.977 [95% CI: 0.95-0.99]) and specificity (0.958 [95% CI: 0.84-0.98] and 0.957 [95% CI: 0.83-0.99], respectively) with low heterogeneity. Amikacin, kanamycin, and ofloxacin demonstrate good diagnostic accuracy, with high specificity (>0.98 [95% CI]). Moderate diagnostic accuracy was observed for ethambutol, streptomycin, ethionamide, and rifabutin. Cycloserine, moxifloxacin, and para-aminosalicylic acid showed inconsistent performance despite excellent specificity (>0.97 [95% CI]). Sensitivity analysis partially improved pooled sensitivity for moxifloxacin 0.801 (95% CI: 0.585-0.924) and para-aminosalicylic acid 0.76 (95% CI: 0.518-0.894), whereas cycloserine remained at 0.436 (95% CI: 0.190-0.725), although heterogeneity persisted. Sensititre MYCOTB DST demonstrates high diagnostic accuracy for MDR-TB and pre-XDR-TB drugs, while caution is required with cycloserine, moxifloxacin, and para-aminosalicylic acid. These findings support the integration of MIC-based testing into clinical decision-making.

Microbial Sensitivity Tests↗
PubMed1986

Pharmacological and biochemical actions of sulphasalazine.

This review considers recent pharmacological and biochemical studies of sulphasalazine and its colonic metabolites, 5-aminosalicylic acid and sulphapyridine, in relation to the use of the parent drug for the treatment of ulcerative colitis and, more recently, rheumatoid arthritis. Several factors make it difficult to analyse the mode of action of sulphasalazine, such as the aetiology and variable course of the conditions it is used to treat, lack of suitable animal models, and the question of which moiety of the drug is active. An important feature of the pharmacokinetics of the drug after oral administration is the significance of the azo cleavage of sulphasalazine due to bacterial action. The effects of sulphasalazine on the metabolism of arachidonic acid to prostaglandins and leukotrienes have been widely studied because of the evidence that these substances are formed in increased amounts in inflammatory bowel diseases. The effects are complex, but it appears that sulphasalazine and 5-aminosalicylic acid are weak and very weak inhibitors, respectively, of both cyclo-oxygenase- and lipoxygenase-dependent pathways. The overall pharmacological profile may favour a more marked inhibition of the lipoxygenase pathway because of the additional ability of 5-aminosalicylic acid to enhance prostanoid production and of sulphasalazine to inhibit prostaglandin inactivation. Drugs with selective lipoxygenase inhibitory actions in the colon should thus be sought so as not to compromise the prostaglandin pathway. Other properties of sulphasalazine, including its immunosuppressive, antifolate, lymphocyte inhibitory and leucocyte modulatory actions, are also discussed in the context of the therapeutic uses of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1990

Salicylazosulfapyridine (Salazopyrin) effect on endotoxin-induced production of interleukin-1-like factor from human monocytes in vitro.

Monocytes (M phi) were simultaneously preincubated with salicylazosulfapyridine (Salazopyrin) (SAZ), 0.78-12.5 mM, and lipopolysaccharide from E. coli, 1 X 10(-9) g/ml. Presence of SAZ resulted in a dose-dependent decrease in the co-stimulatory activity in M phi culture supernatants, corresponding to a 50% reduction by SAZ, 2.0 mM. Co-stimulatory activity was estimated by the mitogen-induced thymocyte proliferation assay (THY assay). The results indicate an inhibitory effect of SAZ in vitro on the production of IL-1 and other possible co-stimulatory factors. This inhibitory effect was not due to decreased M phi viability, production of suppressive substances, or to drug interference with the THY assay. Equimolar preincubations with sulfapyridine, 5-aminosalicylic acid and N-acety-1-5-aminosalicylic acid were without effect on the production of co-stimulatory factors.

Animals↗
PubMed1988

Adverse effects with oral 5-aminosalicyclic acid.

Two patients with ulcerative colitis and a past history of allergic reactions to sulfasalazine had similar reactions when treated with 5-aminosalicylic acid. This suggests that, at least in some patients, the adverse effects of sulfasalazine are due to 5-aminosalicylic acid rather than sulfapyridine. Desensitization to sulfasalazine was successfully carried out in one patient but was not attempted in a second.

Adult↗
PubMed1985

[Effect of nontoxic inhibitors on the nitrosation of drugs under conditions simulating the human stomach].

The influence of sulphamic acid, sulfanilamide, p-aminosalicylic acid and ascorbic acid on the nitrosation behaviour of Analgin (active agent: noramidopyrinmethane sulfonate) was investigated in the pH range between 1.2 and 6.0 under simulated conditions of the human stomach. Using a colorimetric measuring method, the three last-mentioned compounds proved suitable as nitrosation inhibitors; preference should be given to ascorbic acid because of its better inhibitory capacity in the very weakly acidic pH range. Sulphamic acid is inadequate because it stimulates nitrosation in this pH range. The distinct inhibitory action of ascorbic acid was verified under simulated conditions of the human stomach in further 9 drugs undergoing nitrosation at different rates, which contain the active agents: aminophenazone, clomipramine, imipramine, desipramine, ampicilline, oxacilline, phenoxymethylpenicilline, ethambutole or piperazine. Despite the use of high doses of ascorbic acid, no complete inhibition of nitrosation could be achieved in the majority of drugs investigated.

Aminopyrine↗
PubMed1986

Sulphasalazine: a review of 40 years' experience.

Sulphasalazine, devised by Dr Nana Svartz for the treatment of 'infective polyarthritis', has been used in the treatment of inflammatory bowel disease for more than 40 years. Many controlled trials have shown that sulphasalazine 4g daily will induce remissions in between one-half and three-quarters of patients with acute attacks of ulcerative colitis. When given in a dosage of 2g daily it will prevent relapses in quiescent colitis. Relapses are 5 times more likely in untreated patients. It is less effective in Crohn's disease, where it exerts only a transient benefit in patients with active colonic disease and fails to prevent relapse or recurrence. Sulphasalazine is absorbed from the small intestine, re-excreted in bile and carried to the colon, where its azo bond is split by bacteria to release sulphapyridine, which is absorbed and is responsible for most of the drug's side effects, and 5-aminosalicylic acid, which is the active therapeutic moiety of the drug and exerts a beneficial topical action on the colonic mucosa. Side effects are common but are mainly reversible and not serious. Those related to high concentrations of sulphapyridine and to poor acetylation of the drug include gastrointestinal intolerance, malaise, headache, arthralgia, drug fever, effects on red blood cells and reversible male infertility. More serious, idiosyncratic side effects are skin rashes, leucopenia and agranulocytosis. Rarely, neurotoxicity, hepatotoxicity, polyarteritis, pulmonary fibrosis, a lupus-like syndrome and haemorrhagic colitis are produced. It is possible to desensitise most patients with drug-induced skin rashes. A number of less toxic alternatives to sulphasalazine have been devised and are undergoing trial. They either convey 5-aminosalicylic acid in a coated tablet to the colon or, when conjugated to a non-toxic carrier, release 5-aminosalicylic acid by bacterial cleavage there. Sulphasalazine remains a most useful drug in the treatment of inflammatory bowel disease after 40 years of use.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2004

Halomonas organivorans sp. nov., a moderate halophile able to degrade aromatic compounds.

A group of moderately halophilic bacteria able to degrade aromatic organic compounds contaminating hypersaline habitats in southern Spain have been isolated and characterized. The taxonomic position of these strains was determined using phenotypic, phylogenetic and genotypic methods. The G + C content of their DNA ranged from 61.0 to 62.9 mol%. DNA-DNA hybridization studies showed that they constitute a genospecies, having DNA-DNA hybridization values of 90-100 %. Analysis of the complete 16S rRNA gene sequence revealed a high level of similarity with members of the genus Halomonas, sharing 98 % 16S rRNA gene sequence similarity with the type strains of Halomonas salina and Halomonas halophila. However, phenotypic differences and the low level of DNA-DNA hybridization suggest the placement of these strains as a novel species within the genus Halomonas. The name Halomonas organivorans sp. nov. is proposed, with strain G-16.1T (= CECT 5995T = CCM 7142T) as the type strain. This novel species of Halomonas is characterized by its ability to use a wide range of organic compounds (benzoic acid, p-hydroxybenzoic acid, cinnamic acid, salicylic acid, phenylacetic acid, phenylpropionic acid, phenol, p-coumaric acid, ferulic acid and p-aminosalicylic acid), and it could be useful for the decontamination of polluted saline habitats.

Aminosalicylic Acid↗
PubMed1954

Current views on genitourinary tuberculosis.

Tubercle bacilli are spread by the blood stream to the kidney in miliary fashion from the primary pulmonary lesion. Activation, followed by arrest, may delay development of the disease in the kidney for many years or "healing" may occur. Renal ulcerative lesions are the most frequent source of infection of other genitourinary organs. In pyelograms there is no particular characteristic of lesions of tuberculosis. Cellular elements in the urine of a patient with tuberculosis of other organs should lead to urine culture and guinea pig inoculation for mycobacterium tuberculosis. Treatment with streptomycin, isonicotinic acid and/or para-aminosalicylic acid should be started as soon as genitourinary tuberculosis is proved. Patients with advanced lesions usually receive great benefit from these medications; even though organisms may not be eliminated they are definitely diminished in activity. Excision of diseased organs or tissue may be necessary in a few cases.

Aminosalicylic Acid↗
PubMed2004

Effect of 5-substituted benzylideneaminosalicylic acid on carrageenan-induced ulcerative colitis.

Mesalazine, a drug of choice in the management of ulcerative colitis, was chemically modified as 5-(E)-substituted benzylideneaminosalicylic acid by condensing 5-aminosalicylic acid with selected aryl aldehydes with an intention to improve its pharmacological profile. The tests were performed to study their anti-inflammatory effect on carrageenan-induced ulcerative colitis in albino rats. The histopathological findings, serum transaminase level and lipid peroxide content in the intestine and liver were taken as indices of pharmacological activity. The azomethine derivative formed from salicylaldehyde (5-ASASB3) was found to have maximum activity and it reversed the disease symptoms in experimental animals The azomethine derivative markedly reduces the ulcerative colitis when compared with parent molecule, mesalazine.

Aminosalicylic Acids↗
PubMed1991

Aspirin-like drugs, ethanol-induced rat gastric injury and mucosal eicosanoid release.

The effect of oral administration of various non-steroidal antiinflammatory drugs on ethanol-induced rat gastric injury and mucosal release of leukotriene C4, 6-keto-prostaglandin F1 alpha and 15-hydroxy-5,8,11,13-eicosatetraenoic acid was investigated. It was found that besides sodium salicylate and high doses of aspirin, other salicylate-type drugs, such as diflunisal, 4-aminosalicylic acid, 2,4-dihydroxybenzoic acid and methyl salicylate, and several non-acidic compounds, such as proquazone, benzydamine and paracetamol, were gastroprotective. All these drugs inhibited ex vivo leukotriene C4 formation by ethanol-stimulated gastric mucosa. However, naproxen, lonazolac, ibuprofen, gentisic acid and 5-aminosalicylic acid also inhibited leukotriene C4 formation, but were not protective. Gastroprotection was independent of 6-keto-prostaglandin F1 alpha formation. Both protective and non-protective drugs inhibited the ethanol-stimulated, but not the basal, release of 15-hydroxy-5,8,11,13-eicosatetraenoic acid. The results indicate that the differential effects of various non-steroidal antiinflammatory drugs on gastroprotection against ethanol are not correlated with specific effects on mucosal cyclooxygenase, 5-lipoxygenase or 15-lipoxygenase activity.

6-Ketoprostaglandin F1 alpha↗
PubMed1980

Inhibition of neutral proteases from polymorphonuclear (PMN) neutrophils by salicylazosulfapyridine (SASP).

Cytochemical methods were used to demonstrate the inhibitory effect of salicylazosulfapyridine (SASP) on the activity of neutral proteases produced by neutrophilic granulocytes (PMN proteases). The SASP metabolites (5-aminosalicylic acid and sulfapyridine), produced by splitting of SASP by bacteria in the colon, did not inhibit the activity of PMN proteases. Paradoxically, sulfapyridine intensified PMN protease activity. A similar effect however could not be demonstrated for 5-aminosalicylic acid.

Adult↗
PubMed1997

Colonic spread of 5-ASA enemas in healthy individuals, with a comparison of their physical and chemical characteristics.

BACKGROUND: 5-aminosalicylic acid (5-ASA) is widely used as topical treatment in patients with distal inflammatory bowel disease. The enema spread and retention time are considered to be important factors in the efficacy of this therapeutic agent. Whereas colonic spread is widely investigated in selected patient populations and volunteers, much less attention has been given to the in vitro differences of physical and chemical properties, although they may influence the in vivo characteristics. METHODS: Two different brand enemas, Salofalk and Asacol, both containing 2 g mesalazine, were compared with respect to their in vivo and in vitro characteristics. The retrograde spread, maximum distribution and wall adhesion, as well as the retention time of the enemas, was examined by the addition of a technetium tracer dose in 12 healthy volunteers on two separate occasions. In addition, several chemical properties such as pH, viscosity, particle size, dispersion rate, specific surface area and residual volume after application were analysed and compared. RESULTS: With its larger volume and higher viscosity the Asacol preparation reached a substantially larger proportion of the colon and produced a significantly higher retention time in the proximal parts of the large intestine. In addition, more than double the amount of 5-aminosalicylic acid was not expelled from the semi-rigid Salofalk enema container after application. With respect to chemical properties it was demonstrated that the Asacol preparation showed a significantly smaller size of micronized 5-aminosalicylic acid particles, better homogeneity and much less aggregation of the drug. This resulted in an almost threefold higher specific surface area per g active compound. CONCLUSIONS: The Asacol enema appears to be superior in several aspects of the galenical formulation. The better dispersion and larger specific surface area, in conjunction with a larger distribution, better bowel wall adherence and retention time in vivo, constitute a clear theoretical and possible clinical advantage.

Adult↗
PubMed1990

Postprandial exocrine pancreatic function during long-term treatment with the somatostatin analogue SMS 201-995 in acromegalic patients.

Long-term treatment with the somatostatin analogue SMS 201-995 (SMS) might impair exocrine pancreatic function, secretion of cholecystokinin (CCK) and pancreatic polypeptide (PP), and pancreatic size. In five acromegalics on chronic treatment with SMS, we investigated postprandial 6-h urinary excretion of p-aminobenzoic acid (PABA) and p-aminosalicylic acid (PAS) after s.c. injection of 100 micrograms SMS or placebo and after ingestion of 2 mmol nBT-PABA and 2 mmol PAS. In the acromegalics, urinary PABA/PAS ratio (reflecting exocrine pancreatic function) after SMS was similar to that after placebo (P greater than 0.10) and higher than in healthy volunteers (n = 8, P = 0.05). The initial inhibition of plasma CCK secretion by SMS was cancelled during the 3rd h after the meal, whereas PP release remained completely abolished. Pancreatic size as measured by ultrasonography, was not reduced in seven acromegalics compared with 14 healthy volunteers. It is concluded that despite a blunted release of the trophic hormone CCK, long-term treatment with SMS 201-995 neither induces an abnormally small pancreas nor deterioration of postprandial exocrine pancreatic function in patients with acromegaly.

4-Aminobenzoic Acid↗
PubMed1984

Reversible male infertility due to sulphasalazine: studies in man and rat.

Sulphasalazine treatment for inflammatory bowel disease in man causes oligospermia, reduced sperm motility and an increased proportion of abnormal forms. On withdrawal of sulphasalazine these effects are found to be reversible and 15 pregnancies occurred at a median of 2.5 months after stopping sulphasalazine therapy. Seminal plasma concentrations of acid phosphatase fructose and PGE2 as well as the hormone profiles of patients on sulphasalazine for three months were found to be within normal limits. Sulphasalazine fed to male Sprague Dawley rats caused a dose dependent and reversible infertility with a significant reduction in litter size. Rats fed the metabolite sulphapyridine also had a reduced litter size when mated, while those fed the metabolite 5'aminosalicylic acid and a polymer of 5'aminosalicylic acid did not. It seems likely that the sulphapyridine moiety of sulphasalazine is responsible for the infertility seen, the effect being mediated at a late stage in sperm maturation.

Adult↗