Effects of mesalazine substitution on salicylazosulfapyridine-induced seminal abnormalities in men with ulcerative colitis

Some semen characteristics of eight male patients with clinically inactive ulcerative colitis were investigated. Semen analysis was carried out twice during salicylazosulfapyridine (SASP) treatment and repeated twice after at least 3 months' treatment with mesalazine. The motility variables all showed significant improvement during mesalazine treatment: the graded motility (p less than 0.05), motility in percentage (p less than 0.01), and the penetration in egg white (p less than 0.05). The semen plasma was analyzed for mesalazine and the metabolite Ac-mesalazine during both regimens. There was no difference in the semen plasma concentration of mesalazine during the two regimens, whereas Ac-mesalazine was significantly higher during mesalazine treatment than during SASP treatment, indicating that other SASP metabolites, most likely sulfapyridine, are the agent causing the abnormal sperm characteristics. We suggest that pure mesalazine preparations are a safer alternative in young men with chronic inflammatory bowel disease.     

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.     

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.     

Disposition of 5-aminosalicylic acid by olsalazine and three mesalazine preparations in patients with ulcerative colitis: comparison of intraluminal colonic concentrations, serum values, and urinary excretion.

To compare the disposition of 5-aminosalicylic acid (5-ASA) and its acetylated metabolite during treatment with olsalazine and mesalazine, 14 patients with inactive ulcerative colitis were randomly assigned to olsalazine (1 g twice daily) and the mesalazines, Asacol (800 + 400 + 800 mg daily), Pentasa (750 + 500 + 750 mg daily), and Salofalk (750 + 500 + 750 mg daily) in a crossover design trial so that all received each drug for seven days. Intraluminal colonic concentrations of 5-ASA were estimated after five days by the method of equilibrium in vivo dialysis of faeces. A predose serum sample and a 24 hour urine collection were obtained on day seven. The 5-ASA and acetyl-5-aminosalicylic acid (Ac-5-ASA) values were determined by high performance liquid chromatography. Olsalazine almost doubled the colonic concentrations (mean 23.7 (SEM) (1.9) mmol/l) of its therapeutically active ingredient (5-ASA) compared with equimolar doses of Pentasa (12.6 (2.2) mmol/l; p less than 0.0003) and Salofalk (15.0 (2.0) mmol/l; p less than 0.003). At the same time, olsalazine treatment was associated with lower serum concentrations and urinary excretions (p less than 0.05) of 5-ASA and Ac-5-ASA compared with the mesalazine preparations. The low systemic load of 5-ASA provided by olsalazine reduces the potential risk of nephrotoxicity during long term treatment.     

Topical administration of 5-aminosalicylic acid enemas in patients with ulcerative colitis. Studies on rectal absorption and excretion.

5-aminosalicylic acid (5-ASA) is a new treatment for patients suffering from ulcerative colitis but only limited information is available about its rectal absorption. We therefore studied seven patients with ulcerative colitis in remission, and five with active disease to determine acetylated and free 5-ASA plasma concentrations and urinary acetyl 5-ASA after the administration of three different types of enemas: (2 g 5-ASA/100 ml, 4 g/100 ml, and 200 ml). In patients in remission urinary acetyl 5-ASA excretion was dose and volume dependent (p less than 0.01; p less than 0.05) but this correlation was absent in active disease. Because aminosalicylates are usually eliminated through the kidney, these low values (10% in active disease and 19% in those in remission) suggest that the beneficial action may be local. Urinary recovery was significantly lower in patients with active disease (p less than 0.01; p less than 0.02). No accumulation of 5-ASA was found in plasma after repeated daily administration.     

Influence of intestinal transit time on azo-reduction of salicylazosulphapyridine (Salazopyrin).

During a normal and an accelerated intestinal transit, in seven healthy volunteers, the recoveries of salicylazosulphapyridine (SASP) and its split products sulphapyridine (SP) and 5-aminosalicylic acid (5-ASA) were determined in urine and faeces. The azo-reduction of SASP and consequently the recovery of 5-ASA in the faeces was found to be substantially decreased during an accelerated intestinal transit. In addition, in 18 patients with inflammatory disease of the colon during maintenance therapy of SASP it could be demonstrated that the serum SP levels were related to the diarrhoeal state and did not correlate with disease activity. As recent studies have reported that 5-ASA is possibly the active therapeutic moiety of SASP, the ineffectiveness of SASP therapy in patients with active colitis may be ascribed to the reduced azo reduction of SASP as the result of profuse diarrhoea.     

5-Aminosalicylates and renal function in inflammatory bowel disease: a systematic review

Nephrotoxicity has been described in some patients with inflammatory bowel disease (IBD) treated with 5-aminosalicylic acid (5-ASA). Studies with 5-ASA treatment in which serum creatinine or creatinine clearance was measured regularly show that nephrotoxicity is exceptional (mean rate of only 0.26% per patient-year). There have been several case reports, including 46 patients, of renal disease associated with 5-ASA treatment in patients with IBD. 5-ASA treatment-related nephrotoxicity is reported most often within the first 12 months, but also delayed presentation after several years has been shown. The absence of a clear relationship between 5-ASA dose and the risk of nephrotoxicity suggests that this complication is idiosyncratic rather than dose-related. Most of the patients with renal disease associated with 5-ASA treatment suffered interstitial nephritis, with symptoms and signs being nonspecific, which may delay detection for many months. The nephrotoxicity potential of mesalazine and sulfasalazine seems to be similar. The risk with different oral preparations of 5-ASA is probably too small to influence the choice of agent. Mesalazine should be withdrawn when renal impairment manifests in a patient with IBD; if this does not result in a fall in serum creatinine, then renal biopsy should be considered. A trial of high-dose steroid may be recommended in patients whose renal function does not respond to drug withdrawal. The optimal monitoring schedule of serum creatinine in patients receiving 5-ASA treatment remains to be established, as there is no evidence to date that either the test, or the frequency of testing, improves patient outcomes.     

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.     

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.     

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.     

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.     

Aminosalicylates and steroids in the treatment ot chronic inflammatory bowel diseases--consensus paper of the Working Group for Chronic Inflammatory Bowel Diseases of the OGGH

5-aminosalicylates (5-ASA) and steroids constitute a cornerstone of medical therapy in patients with inflammatory bowel diseases (IBD). Whereas the efficacy of 5-ASA in Crohn's disease (CD) is equivocal, ulcerative colitis (UC) is the main indication for this drug. In UC, 5-ASA is effective in the treatment of mild to moderate acute disease and in maintenance of remission. Furthermore, 5-ASA topical therapy is an important treatment option in patients with mild to moderate proctitis and/or left-sided UC and shows additive efficacy to oral therapy. From retrospective data a chemo-preventative activity of long-term 5-ASA therapy in UC is delineated. Steroids are treatment of first choice for moderate to severe cases of CD and UC. Budesonide, a modified steroid with less side effects, plays a major role in the treatment of ileocolonic CD +/- involvement of the right colon and is used as treatment of choice in mild-to-moderate cases. In case of acute, severe disease conventional steroids are superior compared to budesonide and therefore budesonide should only be used after considerable improvement of disease activity. The necessity to apply steroids in a given patient represents a negative prognostic indicator for the course of disease and should incite the early introduction of immunosuppressive therapy in this case. Steroids are only effective as short term therapy of IBD and are to be avoided for maintenance treatment. In all cases of steroid therapy an osteoporosis prophylaxis with calcium and vitamin D is recommended. Topical steroid treatment is less effective in left-sided UC compared to 5-ASA.     

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.     

Pharmacology and pharmacokinetics of 5-aminosalicylic acid

There is accumulating clinical evidence that 5-aminosalicylic acid (5-ASA), a primary metabolite of sulfasalazine (SAS), represents the therapeutic active moiety of the azo-compound SAS in the treatment of chronic inflammatory bowel disease (IBD). Since it is presumed that 5-ASA acts from the lumen of the intestine, it is important to know how much 5-ASA is released from its special galenic formulations. After liberation of 5-ASA in the terminal ileum (only slow release oral preparations of 5-ASA) and colon (5-ASA suppositories and enemas), 5-ASA is only partly absorbed. A major part of this 5-ASA is presystemically eliminated, eg, N-acetylated during its first passage through the intestinal mucosa and liver. Mean steady state plasma levels of unchanged 5-ASA are rather low (range 0.02 to 1.2 μg/ml) whereas those of Ac-5-ASA are always higher (range 0.1 to 2.9 μg/ml). This is due to the rapid elimination of 5-ASA (t1/2=0.4 to 2.4h) and the slightly slower renal excretion of the Ac-5-ASA (t1/2=6 to 9h, renal clearance=200 to 300 ml/min). The knowledge of the pharmacokinetic properties of 5-ASA from different drug formulations might contribute to a better understanding of its mode of action in IBD.     

5-Aminosalicylic Acid Enemas in Refractory Distal Ulcerative Colitis: A Randomized, Controlled Trial

5-Aminosalicylic acid (5-ASA), the presumed active moiety of sulfasalazine, has shown clinical efficacy when administered per rectum as initial therapy to patients with distal ulcerative colitis. We report the results of a randomized double-blind trial comparing nightly retention of a 4-g 5-ASA enema with continued administration of hydrocortisone enemas in 18 patients with persistent active distal ulcerative colitis after at least a 3-wk course of treatment with 100-mg hydrocortisone enemas with or without oral sulfasalazine. Continuation of hydrocortisone enemas rather than placebo was used in the control group to reflect the realistic alternative therapy likely to be employed in current practice. Response to therapy was assessed after 3 wk by comparing pretreatment and posttreatment point scores of clinical, sigmoidoscopic, and histological severity. Improvement in clinical score was achieved in seven of nine 5-ASA enema-treated patients versus one of nine hydrocortisone enema-treated patients (p less than 0.05). Sigmoidoscopic and histological improvement generally paralleled clinical improvement. We conclude that in patients with distal ulcerative colitis unresponsive to standard therapy, treatment with 5-ASA enemas results in significant short-term clinical and sigmoidoscopic improvement in a majority of cases. Moreover, a significantly greater number of refractory patients improve when switched to 5-ASA enemas than when continued on standard therapy.     

Effect of D-thyroxine on serum sex hormone binding globulin (SHBG), testosterone, and pituitary-thyroid function in euthyroid subjects

Concentrations of serum sex hormone binding globulin (SHBG) and free testosterone (T) were examined in 10 euthyroid subjects (5 men and 5 women) before, during and after 30 days of the daily ingestion of 1 or 4 mg D-thyroxine (D-T4), the thyroxine analog that has only 1-15% of the calorigenic effect of L-thyroxine (L-T4). No changes in serum L-T4 or triiodothyronine (T3), serum cholesterol, SHBG, T, progesterone, estradiol-17 beta, or free T concentrations were observed in response to the 1 mg dose, but there was a slight elevation in the free thyroxine index (FTI) and a significant (p less than 0.02) suppression of the thyrotropin (TSH) response to thyrotropin releasing hormone (TRH). The 4 mg dose of D-T4 induced an increase in SHBG levels in all but one man. There was a significant negative correlation between the SHBG and percent free T (p less than 0.05) although the mass of free T did not change. As a group, the women responded with a greater increase in SHBG and decrease in percent free T than the men. Serum cholesterol decreased (p less than 0.01), all serum thyroid hormone values measured by RIA were increased (p less than 0.01), and the TSH response to TRH was completely suppressed. Despite these changes, the subjects remained clinically euthyroid. Concentrations of testosterone, progesterone and estradiol-17 beta remained unchanged. Serum luteinizing hormone (LH), which was evaluated in the men only, also did not change during the daily administration of 4 mg D-T4.     

Azathioprine and mesalazine-induced effects on the mucosal flora in patients with IBD colitis

BACKGROUND: The impact of azathioprine and 5-aminosalicylic acid (5-ASA) on the innate immunity and mucosal flora is unknown. The study investigated the influence of IBD treatment on the concentrations and spatial organization of mucosal bacteria using fluorescence in situ hybridization with 16s r-RNA targeting probes. METHODS: We prospectively investigated colonoscopic biopsies from five groups of 20 subjects each: patients with ulcerative or indeterminate colitis treated with azathioprine (group 1), azathioprine and 5-ASA (group 2), 5-ASA (group 3), untreated IBD (group 4), and healthy controls. RESULTS: The elevated numbers of leukocytes in mucus of IBD patients were reduced nearly to norm in patients treated with azathioprine alone. In contrast, 5-ASA therapy had no influence on mucus leukocyte migration and was associated with the lowest concentrations of mucosal bacteria of all IBD groups. The suppressed migration of leukocytes in azathioprine-treated patients was accompanied by a 28-fold higher concentration of mucosal bacteria when compared with the 5-ASA group or a 1000-fold increase when compared with healthy controls. The percent of the epithelial surface covered with adherent bacteria (P < 0.001) and the amenability of mucosal bacteria (P = 0.01) were also significantly increased in the azathioprine-treated group compared with all other IBD groups. The patients receiving both 5-ASA and azathioprine did not differ statistically from untreated IBD patients either in mucus leukocyte migration or in bacterial concentrations. CONCLUSIONS: Azathioprine and 5-ASA induce opposite effects on the mucus barrier. Concomitant therapy of 5-ASA and azathioprine mutually neutralizes the effects of both on the mucosal flora and the barrier function.     

罗格列酮联合氨基水杨酸治疗溃疡性结肠炎

目的研究罗格列酮联合5-氨基水杨酸（ASA）对轻、中度活动期溃疡性结肠炎（UC）的疗效及相关细胞因子表达。方法参照2000年全国炎症性肠病学术研讨会制定的对炎症性肠病诊断治疗规范的建议,纳入2004年7—11月四川大学华西医院门诊确诊的慢性轻、中度活动期UC,1个月内未使用激素及免疫抑制剂的病例,排除感染性结肠炎、肠道阿米巴病、心肝肾功能不全者。治疗前后行血粪常规、肝肾功能、结肠镜检查。随机分为治疗组和对照组,均口服5-ASA 2g／d;治疗组加服罗格列酮4mg／d,临床观察期4周,4周后乙状结肠镜复查,进行疾病活动度、组织学评价,并观察治疗前后结肠上皮过氧化物酶增殖物激活受体γ（PPARγ）、NF-κB p65的表达。结果UC疾病活动指数积分在治疗组由平均5．87下降到1．86,完全缓解率为71．4％,部分缓解率为23．8％;对照组从6．05下降到2．57,完全缓解率为57．1％,部分缓解率为19．0％。组织学分级下降也高于对照组;PPARγ表达明显增加,NF—κB核阳性率明显降低,且两者之间有相关性。结论罗格列酮与5-ASA或柳氮磺吡啶联合应用较后者单独应用能够提高UC的治疗效果;UC时PPARγ表达降低,PPARγ配体可促进其表达增加;PPARγ缓解结肠炎症可能是通过抑制NF—κB活化完成,并可能代表UC治疗的一个新动向。     

Effect of polymer coating on faecal recovery of ingested 5-amino salicylic acid in patients with ulcerative colitis.

It has been suggested that polymer coating might retard jejunal absorption of 5-amino salicylic acid (5-ASA) and thus promote delivery to its colonic site of action. Twenty three patients with active (nine), or quiescent (14) ulcerative colitis were given either uncoated or coated 5-ASA (Asacol) 400 mg qds for one to three weeks, after which they ingested five 1.5 ml dialysis membrane sachets which were recovered from the stool in the next 72 hours. After one week of treatment the concentration of 5-ASA in the faecal dialysate, urine, and fasting plasma in those receiving the coated and uncoated preparations were respectively: 25.4 +/- 5.1 compared with 1.2 +/- 0.4 mmol/l (p less than 0.001); 0.34 +/- 0.21 compared with 0.70 +/- 0.29 mmol/24h (NS) and 11.1 +/- 4.2 compared with 0.07 +/- 0.03 mumol/l (p less than 0.02). Faecal excretion of the drug appeared to be greater in patients with active colitis than in those with quiescent disease. Thus coating with pH dependent methacrylic acid copolymer B is a very effective method of promoting delivery of 5-ASA to the colon, stool dialysate concentrations being 20 fold more than those in controls. Increased trough plasma concentrations in the polymer coating group probably reflect delayed intestinal absorption but no evidence of plasma accumulation after 21 days of therapy was found.