A study to determine the active moiety of sulphasalazine in rheumatoid arthritis

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

The metabolism of salicylazosulphapyridine in ulcerative colitis: II The relationship between metabolites and the progress of the disease studied in outpatients

Serum concentrations of salicylazosulphapyridine (SASP), sulphapyridine (SP), and 5-aminosalicylic acid (5-ASA) were measured in 64 outpatients with ulcerative colitis. About 90% of the patients in remission had serum total SP concentrations above 20 μg/ml. Seven patients, however, had active disease despite a serum total SP concentration > 20 μg/ml. The SASP and the individual SP metabolites did not show any correlation with the disease state. Three g per day seems to be the most effective dose. Plain and enteric-coated tablets produced similar concentrations at equivalent dosage. Side effects due to SASP were frequent in patients who had a total SP concentration > 50 μg/ml of serum.     

Influence of salazosulphapyridine and 5-aminosalicylic acid on seminal qualities and male sex hormones

Seminal abnormalities are a common side effect of salazosulphapyridine (SASP) treatment. We evaluated semen qualities and sex hormone concentrations in 11 patients with inflammatory bowel disease (IBD) during SASP treatment and 4 months after replacing SASP with an oral slow-release preparation of 5-aminosalicylic acid (5-ASA). Significant improvement in sperm count (p less than 0.01), morphology (p less than 0.02), and motility (p less than 0.02) could be observed during 5-ASA therapy, in comparison with SASP treatment. Three pregnancies occurred during the study period. The serum concentrations of gonadotrophins, prolactin, and sex hormone-binding globulin were normal in all patients and not significantly different in the two treatment periods. The mean total testosterone concentration decreased significantly (p less than 0.02) after 5-ASA substitution, together with serum albumin (p less than 0.005), although all values remained within normal limits. The apparent free testosterone concentration was not significantly different in the two treatment periods. It is concluded that a significant improvement in semen quality can be obtained in male patients with IBD after replacing SASP with 5-ASA.     

克罗恩病临床特征以及诊断和治疗选择

目的 分析克罗恩病的临床表现、误诊原因和诊疗方法,以促进与提高对本病的认识及诊治效果。方法 对近期诊治31例患者的发病情况、临床表现、内镜及实验室检查结果,结合文献报道,分析本病的临床特征与诊治方案。结果 患者以表中年为主,女略多于男。病变侵犯胃肠道任一部位,呈节段性分布,常同时侵犯多个部位,以结肠及小肠为主;腹痛与腹泻为主要的肠道症状;但尚有低热、消瘦、贫血及皮肤、关节与肛周疾病等多系统症状。内镜可见跳跃式分布的黏膜充血、水肿、溃疡、息肉、狭窄或铺路石征等破坏与增殖病变并存的特点,诊断正确率为62.9%。活检肉芽肿检出率为30.8%。B超可探查出肠道并发症。误衣原因：对本病认识不足;肠道病变多部位性,致使临床症状多样化;过于强调病理学检查及肉芽肿的诊断意义。口服泼尼松对轻－中型患者诱导缓解较氨基水杨酸盐类更迅速;免疫制剂为二线药物,个体间疗效不一;20例接受强化性营养支持治疗,具有辅助治疗作用。16例手术治疗收到较好疗效。结论 本病发病数明显增多,临床表现缺乏特异性;内镜联合活检,加强临床与病理医师沟通是及时和正确诊断的关键。治疗宜个体化选择方案,手术具有积极意义。     

EFFECT OF SULPHASALAZINE AND ITS METABOLITES ON MITOGEN INDUCED TRANSFORMATION OF LYMPHOCYTES--CLUES TO ITS CLINICAL ACTION?

The effects of sulphasalazine (SASP), sulphapyridinc (SP), and5-aminosalicylic acid (5-ASA) have been studied on mouse spleencells cultured in the presence of phytohaemagglutmin (PHA),concanavalin A (Con A), pokeweed mitogen (PWM) and lipopolysaccharide(LPS). SASP exhibited a significant degree of suppression, at dosesin the range 25–100 .µg/ml (p < 0.01), this suppressionbeing >50% at 50 µg/ml. SP exhibited only a minor degreeof suppression (10% at 75 µg/ml. p < 0.01). Coadministrationof a non-steroidal anti-inflammatory drug (NSAID), indomethacin,produced no evidence of further suppression in the presenceof SASP or SP. Administration of SP plus 5-ASA to parallel culturesthat were profoundly suppressed by the molecular equivalentamount of SASP resulted in no suppression. This implied requirementof the intact parent molecule (SASP) to produce this effect,at these concentrations. The concentration of SASP required to produce more than 50%suppression was higher than that ever attained in the peripheralblood of humans receiving therapeutic doses of the drug. Humanlymphocytes are similarly suppressed by SASP, but only at higherconcentrations than are required for murine cells. Thus, ifthe parent drug is the active moiety and requires these concentrationsto be effective in vivo, it follows that the site where theseeffects may be mediated is likely to be the intestinal tract.The effects described would suggest the gut associated lymphoidtissue as a likely target. KEY WORDS: 5-Aminosalicylic acid, Small intestine, Rheumatoid arthritis, Reactive arthritis, Ankylosing spondylitis     

The metabolism of salicylazosulphapyridine in ulcerative colitis: I The relationship between metabolites and the response to treatment in inpatients

The metabolism of salicylazosulphapyridine was studied in 16 patients with ulcerative colitis admitted to hospital. The acetylator phenotype was determined on admission. The mean serum concentration (mug/ml) (at steady state eight +/- two days in patients responding to treatment) of SASP, total SP, and 5-ASA were 18.7 +/- 12.8; 53.7 +/- 23.1; and 1 +/- 0.9 for slow acetylators and 17.6 +/- 7.1; 31 +/- 9.0 and 1 +/- 0.9 for fast acetylators respectively. Twenty-four hour urinary excretion of SASP, total SP, and 5-ASA were 4.6% +/- 3.1; 52% +/- 9.6 and 22.3 +/- 6.7% of the administered dose respectively.Serum total SP concentration of 20 to 50 mug/ml appeared to coincide with clinical improvement in the absence of any side effects related to salicylazosulphapyridine. No such relationship could be shown with serum SASP, individual metabolites, or 5-aminosalicyclic acid.     

Effect of azodisal sodium on the distribution of a transit marker in the small bowel of the fasted rat

The effect of azodisal sodium (ADS) on the transit of a radioactive marker in the small bowel was compared with that of 5-ASA and sulfasalazine (SASP). The bile-excreted radiopharmaceutic 99mTc-HIDA was infused intravenously for 1 h into conscious rats with an intact alimentary tract and the radioactivity along the excised gastrointestinal specimen was subsequently determined. After administration of ADS (12.5 mg/rat), 5-ASA and SASP, the distribution of radioactivity was characterized by localized peaks of radioactivity separated by fairly long empty regions. As judged from experience this pattern represents the fasting state under control conditions. Administration of ADS (60 and 120 mg/rat) resulted in a distribution along the small bowel without any apparent peaks or empty regions. The transport rate of the front of the tracer was enhanced by ADS at higher doses but not by 5-ASA or SASP. Intravenous administration of ADS did not affect the transit, indicating the importance of the presence of ADS in the gut lumen. Prostaglandin release does not seem to be a probable mediating mechanism since pretreatment with indomethacin did not abolish the effect of ADS on the interdigestive transit pattern.     

Effect of sulphasalazine and its metabolites on the generation of reactive oxygen species.

The relative in vitro anti-oxidant efficacy of sulphasalazine (salicylazosulphapyridine, SASP) and its metabolites (5-aminosalicylic acid, 5-ASA; sulphapyridine, SP) was examined by studying their effects on the generation of reactive oxygen species (ROS) using zymosan-stimulated polymorphonuclear leucocytes (PMNs) and a cell free, xanthine-xanthine oxidase system. Salicylazosulphapyridine, 5-ASA, and SP showed anti-oxidant effects to the various degrees. In particular, production of OH, which is one of the most potent reactive oxygen species, was remarkably suppressed by 5-ASA dose relatedly. These findings suggest that SASP and its metabolites play an important role in the inhibition of respiratory bursts. As the potent products of the respiratory burst by polymorphonuclear leucocytes are thought to be important inflammatory mediators, suppression of toxic reactive oxygen species generation by these agents may partly explain the therapeutic efficacy of SASP in ulcerative colitis, which is characterised by an acute mucosal inflammation dominated by polymorphonuclear leucocytes accumulation.     

Disposition of 5-aminosalicylic acid from 5-aminosalicylic acid-delivering drugs during accelerated intestinal transit in healthy volunteers

In eight healthy volunteers accelerated intestinal transit time was induced with bisacodyl, and urinary and faecal excretion of sulphasalazine, olsalazine, 5-aminosalicylic acid (5-ASA), and acetyl-5-ASA was studied after a single oral dose of 3.3 mmol sulphasalazine, olsalazine, Pentasa, and Salofalk and 2.6 mmol of Asacol. The faecal and urinary excretion of acetyl-5-ASA was lowest after intake of sulphasalazine and olsalazine and highest after intake of Pentasa and Salofalk. The figures for Asacol were intermediate. This indicates insufficient release of 5-ASA from sulphasalazine and olsalazine. When the results of this study are compared with those of a previous study without accelerated transit time, the disposition of 5-ASA from all the 5-ASA-delivering drugs is influenced unfavourably by an accelerated gut transit but most pronounced in the case of sulphasalazine, olsalazine, and Asacol. The impaired release from the azo compounds sulphasalazine and olsalazine is a result of far less complete splitting of the diazo bond.     

Steady-state kinetics of 5-aminosalicylic acid and sulfapyridine during sulfasalazine prophylaxis in ulcerative colitis

Fifteen adult and 19 pediatric outpatients with ulcerative colitis were studied to determine the steady-state kinetics of 5-aminosalicylic acid (5-ASA) released from salazosulfapyridine (SASP). Results of excretion in adults (mean 24-h recovery of 5-ASA, 21% in urine and 57% in feces) were compatible with those of healthy volunteers. Since mean SASP dose/kg body weight (about 50 mg/kg) and compliance (reflected in sulfapyridine recovery) were equal in adults and pediatric patients, the results of the patient groups could be compared. Near-complete azo reduction of SASP occurs in children. Absorption and excretion of 5-ASA and metabolism to acetyl-5-ASA did not differ statistically between pediatric and adult patients. However, the fecal excretion of the drug and its metabolites was significantly lower in young patients, although fecal concentrations were the same. The present results demonstrate that SASP is an excellent sustained-release drug for the delivery of 5-ASA to the lower part of the bowel system and provide a reference for comparison of 5-ASA kinetics after treatment with newer 5-ASA preparations.     

Compliance to therapy in patients on a maintenance dose of sulfasalazine

In patients with inflammatory bowel disease using a maintenance dose of sulfasalazine (SASP), compliance to therapy was studied by measuring serum sulfapyridine (SP) levels. Serum SP levels were determined in 51 patients both during hospitalization and at outpatient follow-up 1-6 months later. In 21 patients (41.2%) the serum SP level was considerably lower at outpatient follow-up than the serum level before discharge. In 21 (12%) of 175 outpatients taking a maintenance dose of SASP, SP in serum was not detectable at all at repeated determination during follow-up. These results indicate that a substantial number of patients on maintenance therapy with SASP do not take the prescribed dose. Drug trials in these patients should therefore incorporate methods of detecting defaulters.     

5-Aminosalicylic Acid Enemas in Patients with Active Ulcerative Colitis

Enemas containing 1000 mg 5-ASA were administered to patients with active distal colitis in three separate studies: as a single dose in a neutral solution (pH 7.4); as a single dose in a slightly acidic, buffered suspension (pH 4.8); and as multiple doses once a day for 10 days with the acidic enema. 5-ASA was relatively rapidly absorbed from the neutral solution, resulting in plasma concentrations of 5-ASA sometimes two to three times higher than those found after peroral salazosulfapyridine (SASP) treatment. In contrast, absorption from the acidic enema was reduced and/or prolonged, giving plasma concentrations similar to those found during oral SASP treatment. After repeated doses of the acidic enema, plasma concentrations after an enema resembled those seen after the single dose. Urinary excretion was significantly lower, suggesting a reduced fraction of absorption at steady-state conditions. No side effects were observed, and no local irritation was reported. An acidic buffer suspension with 5-ASA seems to be safe for use as enema and deserves further clinical testing for treatment of distal ulcerative colitis.     

5-Aminosalicylic acid enemas in patients with active ulcerative colitis. Influence of acidity on the kinetic pattern

Enemas containing 1000 mg 5-ASA were administered to patients with active distal colitis in three separate studies: as a single dose in a neutral solution (pH 7.4); as a single dose in a slightly acidic, buffered suspension (pH 4.8); and as multiple doses once a day for 10 days with the acidic enema. 5-ASA was relatively rapidly absorbed from the neutral solution, resulting in plasma concentrations of 5-ASA sometimes two to three times higher than those found after peroral salazosulphapyridine (SASP) treatment. In contrast, absorption from the acidic enema was reduced and/or prolonged, giving plasma concentrations similar to those found during oral SASP treatment. After repeated doses of the acidic enema, plasma concentrations after an enema resembled those seen after the single dose. Urinary excretion was significantly lower, suggesting a reduced fraction of absorption at steady-state conditions. No side effects were observed, and no local irritation was reported. An acidic buffer suspension with 5-ASA seems to be safe for use as enema and deserves further clinical testing for treatment of distal ulcerative colitis.     

5-Aminosalicylic acid suppositories in the management of ulcerative colitis

5-aminosalicylic acid (5-ASA) suppositories have been used in the author's out-patient clinic in Bologna for the treatment of distal ulcerative colitis (UC). One hundred fifty-six patients with mild or moderate attacks of UC were treated using different protocols for controlling active disease. Improvement was observed in 88.5 percent of the therapeutic cycles after one month. A small preliminary maintenance study using only 400-mg suppositories of 5-ASA twice a day for 6 or 12 months showed a remission percentage similar to salicylazosulfapyridine (SASP).     

Treatment of spondyloarthropathy with 5-aminosalicylic acid (mesalazine): an open trial

OBJECTIVE: Ankylosing spondylitis (AS) and spondyloarthropathy (SpA) are inflammatory diseases of unknown etiology. Various exogenous and endogenous (inherited) factors play a role in their development. Sulfasalazine (SSZ) is generally accepted as a disease modifying drug in the treatment of AS and SpA. Which part of SSZ, 5-acetylsalicylic acid (5-ASA, mesalazine) or sulfapyridine (SP), is the effective moiety is unknown. As the bowel, colon, and the ileum play an important role in the development of AS and SpA, it may be possible that 5-ASA is the effective moiety, with a similar mode of action as in the treatment of inflammatory bowel disease. To determine the efficacy of 5-ASA an open pilot study was done in 2 groups of patients with SpA. METHODS: Twenty patients with SpA, who were taking SSZ, were switched to 5-ASA (Pentasa), and 19 patients with active SpA were treated with 5-ASA without previous administration of SSZ. RESULTS: In the first group, 17 (85%) patients responded with respect to the physician global clinical assessment compared to the previous SSZ treatment period; whereas in the second patient group a statistically significant improvement was obtained in erythrocyte sedimentation rate. CONCLUSION: The results support our hypothesis that 5-ASA might be the active moiety of SSZ in the treatment of SpA.     

The contribution of sulphate reducing bacteria and 5-aminosalicylic acid to faecal sulphide in patients with ulcerative colitis

BACKGROUND: Butyrate oxidation within the colonocyte is selectively inhibited by hydrogen sulphide, reproducing the metabolic lesion observed in active ulcerative colitis. AIMS: To study generation of hydrogen sulphide by sulphate reducing bacteria (SRB) and the effects of 5-aminosalicylic acid (5-ASA) in patients with ulcerative colitis in order to identify a role of this noxious agent in pathogenesis. PATIENTS: Fresh faeces were obtained from 37 patients with ulcerative colitis (23 with active disease) and 16 healthy controls. METHODS: SRB were enumerated from fresh faecal slurries and measurements made of sulphate reducing activity, and sulphate and hydrogen sulphide concentrations. The effect of 5-ASA on hydrogen sulphide production was studied in vitro. RESULTS: All controls and patients with active ulcerative colitis carried SRB and total viable counts were significantly related to the clinical severity grade. SRB were of two distinct types: rapidly growing strains (desulfovibrios) which showed high sulphate reduction rates, present in 30% of patients with ulcerative colitis and 44% of controls; and slow growing strains which had little activity. In vitro, 5-ASA inhibited sulphide production in a dose dependent manner; in patients with ulcerative colitis not on these drugs faecal sulphide was significantly higher than in controls (0.55 versus 0.25 mM, p=0.027). CONCLUSIONS: Counts and carriage rates of SRB in faeces of patients with ulcerative colitis are not significantly different from those in controls. SRB metabolism is not uniform between strains and alternative sources of hydrogen sulphide production exist in the colonic lumen which may be similarly inhibited by 5-ASA. The evidence for hydrogen sulphide as a metabolic toxin in ulcerative colitis remains circumstantial.     

Modulation of arachidonic acid metabolism by olsalazine and other aminosalicylates in leukocytes.

We investigated the action of the new aminosalicylate olsalazine (disodium azodisalicylate) on arachidonic acid metabolism in comparison with 5-aminosalicylic acid (5-ASA) and sulphasalazine (SASP) by in vitro incubation of cellular homogenates from human polymorphonuclear (PMNL) and mononuclear (MNL) leukocytes with 14C-labelled arachidonic acid. Olsalazine reduced the synthesis of leukotriene B4 (LTB4), 5-hydroxyeicosatetraenoic acid (5-HETE), 11-HETE, 12-HETE, and 15-HETE in PMNL and MNL slightly less than SASP. 5-ASA was significantly less inhibitory than olsalazine and SASP on the formation of lipoxygenase products in PMNL and on LTB4 synthesis in MNL. In contrast, in MNL the formation of 5-HETE was unaffected, and the production of 11-HETE, 12-HETE, and 15-HETE was even slightly activated by 5-ASA. Total prostaglandin synthesis was dose-dependently reduced by the aminosalicylates (SASP greater than olsalazine greater than 5-ASA), but only SASP markedly altered the prostaglandin (PG) profile, with an increase in PGE2 and PGF2 alpha at the expense of other cyclooxygenase products. It may be concluded that olsalazine resembled SASP with regard to the inhibition of the lipoxygenase but had effects intermediate between the other salicylates on cyclooxygenase. Furthermore, the alteration of the prostaglandin profile by SASP points to an overlying cofactor effect of this drug.     

Optimum dosage of 5-aminosalicylic acid as rectal enemas in patients with active ulcerative colitis.

5-Aminosalicylic acid (5-ASA), the active moiety of sulphasalazine (SASP), was given as a rectal enema to patients with mild to moderate distal ulcerative colitis to determine the minimum effective dosage. A double blind study was carried out using enemas containing 1, 2, or 4 g or 5-ASA or placebo for a one month treatment period. One hundred and thirteen patients with ulcerative colitis attending our outpatient clinic volunteered to participate. Clinical, sigmoidoscopic, and histological assessments were carried out at the beginning of the study and after 15 and 30 days of treatment. All patients who received 5-ASA enemas showed significantly better results than those who received a placebo enema (p less than 0.001) but no difference was detected among the patients receiving differing concentrations of 5-ASA. This study suggests that 1 g 5-ASA (in a 100 ml enema) is a sufficient dosage for patients with a mild to moderate attack of ulcerative colitis.     

Dose-dependent influence of 5-aminosalicylates on thiopurine metabolism

INTRODUCTION: Studies indicated that 5-aminosalicylates (5-ASA) may influence the metabolism of thiopurines; however, conclusions were restricted as a result of number of patients or study design. AIM: To determine the influence of 5-ASA on thiopurine metabolism, we performed a prospective multicenter pharmacokinetic interaction study of two different 5-ASA dosages (2 g daily followed by 4 g daily) in 26 inflammatory bowel disease (IBD) patients during steady-state AZA or 6-MP therapy. RESULTS: The 4-wk coadministration of 2 g 5-ASA daily, followed by a 4-wk period of 4 g 5-ASA daily, led to a statistical significant increase of 40% (absolute 84 pmol/8x10(8) RBC) and 70% (absolute 154 pmol/8x10(8) RBC) in 6-thioguaninenucleotide levels (6-TGN), respectively. A rise in 6-TGN levels was observed in 100% of patients after a 4-wk period of 4 g 5-ASA daily. The 6-methylmercaptopurine-ribonucleotide levels did not change. Signs of myelotoxicity were observed in 7.7% of patients (N=2). CONCLUSIONS: The level of the pharmacologically active 6-TGN significantly increases in a dose-dependent manner during 5-ASA coadministration. IBD patients who are unresponsive or refractory to standard thiopurine therapy may benefit from the coadministration of 5-ASA, leading to an increase in 6-TGN levels.     

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.