Comparison of the absorption and metabolism of sulphasalazine and acrylic-coated 5-amino salicylic acid in normal subjects and patients with colitis.

Serum levels of 5-amino salicylic acid ( 5ASA ) and acetyl 5ASA have been measured in volunteers after ingestion of sulphasalazine (6 g) and compared with levels after an equivalent dose of acrylic coated 5ASA (2.4 g). The serum levels of both 5ASA and acetyl 5ASA were similar after each preparation apart from an early peak of 5ASA following acrylic coated 5ASA . Serum and urinary levels for 5ASA and acetyl 5ASA have been measured in colitic patients following equivalent doses of sulphasalazine and acrylic coated 5ASA . Serum levels were similar; 25% of the calculated ingested 5ASA was excreted in the urine after sulphasalazine compared with 20% following acrylic coated 5ASA .     

The systemic load and efficient delivery of active 5-aminosalicylic acid in patients with ulcerative colitis on treatment with olsalazine or mesalazine

BACKGROUND: There have been reports of nephrotoxic reactions in patients with ulcerative colitis treated with 5-aminosalicylic acid (5-ASA) preparations. AIM: To compare the efficacy in delivery of active 5-ASA to the colon and the systemic load as the basis for potential long-term toxicity during treatment with olsalazine or mesalazine in patients with ulcerative colitis in remission. PATIENTS AND METHODS: Fifteen patients with ulcerative colitis were treated with olsalazine or mesalazine, each for 7 days in an open, randomized, crossover design study. 5-ASA and acetyl-5-ASA (Ac-5-ASA) in plasma and urine were measured by high performance liquid chromatography. RESULTS: The plasma concentration of 5-ASA was 1.2 +/- 0.1 micromol/L (mean +/- S.E.M.) for olsalazine and 8.0 +/- 1.9 micromol/L for mesalazine, while the plasma concentration of Ac-5-ASA was 2.8 +/- 0.2 micromol/L for olsalazine and 10.8 +/- 1.6 micromol/L for mesalazine. The amount of 5-ASA excreted in the urine was 68 +/- 30 micromol/24 h for olsalazine and 593 +/- 164 micromol/24 h for mesalazine. The amount of Ac-5-ASA in the urine was 1260 +/- 102 micromol/24 h for olsalazine and 3223 +/- 229 micromol/24 h for mesalazine. The urinary recovery of total 5-ASA plus Ac-5-ASA (as a percentage of the given dose) was 23 +/- 2.1% for olsalazine and 39 +/- 3.6% for mesalazine. The ratio between the plasma concentrations of mesalazine and olsalazine differed significantly both for 5-ASA (5.1) and Ac-5-ASA (3.6); for 5-ASA (9. 9) and Ac-5-ASA (2.6) in urine, and for the urinary recovery of total 5-ASA plus Ac-5-ASA (1.7). Moreover, in the mesalazine group there was a large variation in the individual plasma concentrations of 5-ASA and Ac-5-ASA, with maximal values 5-6-fold higher than that in the olsalazine group. CONCLUSION: The systemic load of active 5-ASA is significantly higher for mesalazine than for olsalazine, when based on the dosages given and when calculated on an equimolar basis. Some of the patients in the mesalazine group showed unexpected high levels of plasma and urinary 5-ASA concentrations, a finding which may have long-term safety implications.     

国产奥沙拉秦钠胶羹治疗溃疡性结肠炎149例

目的 验证国产奥沙拉秦钠胶囊治疗轻、中度溃疡性结肠炎（活动期）的治疗效果,比较国产奥沙拉秦钠胶囊与水杨酸柳氨磺胺吡啶（ＳＡＳＰ）对轻、中度溃疡性结肠炎（活动期）的疗效和不良反应。方法 采用多中心随机双盲对照验证１０７例轻、中度溃疡性结肠炎（活动期）的疗效和不良反应,同时,治疗４２例作为开放组,疗程为８周。结果 国产奥沙拉秦钠胶囊的总有效率达 ８４．６％,双盲组中,其临床完全缓解率、内镜完全缓解率和组织学完全缓解率在治疗８周后均比治疗前明显改善,分别各自达７５．００％,３４．６２％,５５．７７其疗效与开放组和对照组ＳＡＳＰ均类同。国产奥沙拉秦钠胶囊不良反应主要为腹泻。结论 国产奥沙拉秦钠胶囊治疗活动期轻、中度溃疡性结肠炎有效,其结果与ＳＡＳＰ相当,主要不良反应为腹泻,宜与控制腹泻药物合用。     

Colonic release of 5-amino salicylic acid from an oral preparation in active ulcerative colitis

5-amino salicylic acid coated with acrylic based resin was given orally to eight patients with active ulcerative colitis. Abdominal X-rays confirmed that the preparation released its contents in the terminal ileum and proximal colon. Differences between individuals were marked; the plasma 'concentration-time profile' reflected variations in the time taken for tablets to reach the terminal ileum.     

Adverse reactions to sulphasalazine and 5-amino salicylic acid in the same patient

We report a patient who developed sulphasalazine-related hepatitis with a subsequent adverse reaction to rectal 5-amino salicylic acid, in the form of pain and fever without associated liver dysfunction, suggesting reactions to both components of sulphasalazine. Included is a review of the literature. Caution should be observed when prescribing 5-amino salicylic acid to sulphasalazine-intolerant patients.     

Balsalazide in the maintenance treatment of patients with ulcerative colitis, a double-blind comparison with sulphasalazine

Balsalazide (BSZ) is a pro-drug which releases 5-aminosalicylic acid (5ASA) and 4-aminobenzoyl-beta-alanine (an inert carrier) in the colon of various species including man. BSZ was compared with sulphasalazine (SASP) (both 1 g b.d. orally) in the maintenance of remission in patients with ulcerative colitis (UC). Seventy-nine patients (53 male, 26 female), mean age 49 years (range 19-79 years), with UC were randomly allocated to either treatment (41 BSZ, 38 SASP) for 6 months. The groups were similar in respect of age, sex, duration and extent of disease. Seven patients defaulted (3 BSZ, 4 SASP) leaving 38 on BSZ and 34 on SASP. Two male patients, both receiving SASP, were withdrawn because of severe side-effects. One of these patients, with an exfoliative rash, was maintained satisfactorily on open BSZ. Remission rates at 6 months (51% BSZ, 63% SASP) were not significantly different (life-table analysis P less than 0.1). Twelve patients (15%) reported troublesome side-effects (2 BSZ 5%, 10 SASP 26%, P = 0.017 Fisher Exact Test). Mean haemoglobin concentrations, similar on entry, increased after 6 months with BSZ (0.2 g/dl) but decreased with SASP (0.5 g/dl) (P less than 0.0002). BSZ was not significantly different from SASP in maintaining remission in patients with UC but had fewer side-effects.     

5-氨基水杨酸肠溶片治疗溃疡性结肠炎

目的 :比较 5 氨基水杨酸肠溶片和柳氮磺吡啶 (SASP)治疗溃疡性结肠炎的疗效和安全性。方法 :采用随机对照、双盲双模拟的临床试验设计。试验组 2 0例病人服 5 氨基水杨酸肠溶片 ,0 .8g ,tid ;对照组 19例病人服SASP片 1g ,qid。疗程均为 6wk。结果 :试验组无效 3例 ,有效 1例 ,显效 8例 ,临床治愈 8例 ,总有效率为 80 % ;对照组无效 5例 ,有效 4例 ,显效 8例 ,临床治愈 2例 ,总有效率为5 3%。 2组不良反应发生率分别为 10 %和 2 5 %。结论 :5 氨基水杨酸肠溶片和SASP对溃疡性结肠炎具有明显治疗作用 ,前者的疗效好于后者 ,两者的安全性相似     

Retrograde spread of mesalazine (5-aminosalicylic acid)-containing enema in patients with ulcerative colitis

In order to investigate the retrograde spread in the colon and its relationship to the extent of the diseased area, the authors evaluated a 100ml enema of mesalazine (5-aminosalicylic acid, Pentasa') lg in a consecutive series of 30 patients with ulcerative colitis. The enema was labelled with 10 MBq 99mtechnetium-human serum albumin microcolloid. Sequential scintigraphic imaging was performed in all patients, and the results compared with the extension of the disease as found by colonoscopy. If the enema reached the entire affected area it was interpreted as 'topically adequate'. In 80% of the patients there was retrograde spread of the enema beyond the rectosigmoid, thus reaching the affected area in ulcerative colitis. No relationship was found between the extent of dispersion of the enema and the time of defecation prior to scintigraphy. The authors conclude that a 100ml 'Pentasa' enema may be adequate for treatment of ulcerative colitis extending up to the splenic flexure.     

Actions of sulphasalazine and analogues on mucosal eicosanoid formation and metabolism in patients with ulcerative colitis

Sulphasalazine is the most widely prescribed drug for ulcerative colitis. Following oral administration sulphasalazine practically unabsorbed reaches the colon where it is split by colonie bacteria to 5-aminosalicylic acid and sulphapyridine. Although there is no doubt that 5-aminosalicylic acid is the active ingredient of sulphasalazine in ulcerative colitis, indications of disease-modifying effects of the intact molecule exist in rheumatoid arthritis. A substantial amount of evidence has accumulated that sulphasalazine and its analogues exert their therapeutic benefit in patients with ulcerative colitis through modulation of the formation and metabolism of eicosanoids, in particular leukotrienes, but they may also reduce inflammation by acting as inhibitors of platelet activating factor, interleukins, intestinal mast cell- and basophil cell-stimulated histamine release, in addition to being effective scavengers of the active oxygen species, suppressors of buturate metabolism, and modulators of polymorphonuclear leukocyte and lymphocyte functions. Although the mode of action of sulphasalazine and its analogues in ulcerative colitis is still incompletely understood, basic and clinical research into these multiactive compounds have paved the road for new drug development. Until then, sulphasalazine remains an effective means for the oral delivery to the colonie mucosa of the anti-inflammatory actions provided by mesalazine.     

Further studies of sulphasalazine metabolism in the treatment of ulcerative colitis.

Sixty-four outpatients with ulcerative colitis receiving maintenance treatment with sulphasalazine were studied to relate disease activity to serum concentrations of sulphapyridine. Of 43 patients in remission, 32 had serum sulphapyridine levels over 20 microgram/ml. Ten of the 21 patients with active disease were for various reasons taking inadequate doses of sulphasalazine, as indicated by low serum sulphapyridine levels, and of the remaining 11 patients, who had serum levels over 20 microgram/ml, nine had faecal stasis proximal to active distal colitis and went into remission when treated with hydrophilic colloid or bran and an unchanged sulphasalazine dosage. This suggests that to be effective the metabolites of sulphasalazine must be delivered in the faeces to the lumen of the diseased distal segment of the colon. High serum concentrations of sulphapyridine produce side effects; therefore slow acetylators of sulphapyridine need lower doses of sulphasalazine. Estimations of serum sulphapyridine concentrations, as well as identifying the patient's acetylation phenotype, can also be useful in assessing his compliance with treatment.     

Paracetamol metabolism in patients with ulcerative colitis

Aims The capacity for sulphation of phenols appears to be impaired in the colonic mucosa of patients with ulcerative colitis. The aim of the present study was to investigate the systemic capacity for sulphation of phenols in patients with ulcerative colitis assessed by the metabolic clearances of paracetamol to the sulphate, glucuronide and glutathione derived metabolites.
Methods Ten patients with ulcerative colitis and 10 control subjects received a single oral dose of paracetamol (1  g). Venous blood samples were collected frequently for pharmacokinetic determinations (one compartment model). Urine was collected for 24  h. Plasma samples were analysed for parent drug and urine samples for parent drug and metabolites by h.p.l.c. Partial metabolic clearances were calculated as the fractional urinary recovery of each conjugate multiplied by the apparent oral clearance of paracetamol.
Results The apparent oral clearance of paracetamol and the partial clearances of its metabolites were not significantly different between the two study groups. Median value and the corresponding 25th and 75th percentiles for the clearance of the sulphate metabolites were 93.6 (82.5–138.8)  ml  kg⁻¹  h⁻¹ and 77.4 (75.5–99.1), patients with ulcerative colitis and control subjects, respectively.
Conclusions These results do not indicate a general impairment of the systemic capacity for sulphation of paracetamol in patients with ulcerative colitis.     

Distribution of mesalazine enemas in active and quiescent ulcerative colitis.

BACKGROUND: The efficacy of mesalazine enemas depends on intraluminal concentration of the drug and is therefore limited by the enema distribution in the colon. Active ulcerative colitis changes colon motility and this leads to uncertainty about enema spread. AIM: To assess the influence of disease activity on enema distribution, we conducted a physician-blinded, longitudinal study of the retrograde spread of three mesalazine enemas. METHODS: Thirty-one patients with mild to moderate ulcerative colitis were subdivided into three groups, and treated with 2 g mesalazine in 30 mL (group I, n = 10), 4 g mesalazine in 60 mL (group II, n = 12) or 1 g mesalazine in 100 mL (group III, n = 9). All patients received oral mesalazine 500 mg t.d.s. Enemas were labelled by adding 10 MBq (99mTc)technetium-sulphur colloid. Anterior scintigraphic images were taken at the start of the study and after 12 weeks of therapy; retrograde spread was assessed by calculating the percentage of the enema in each colonic segment. RESULTS: The activity score of ulcerative colitis diminished significantly after 12 weeks of treatment, but five patients dropped out of the study. At the start of treatment enema activity in group I was mainly concentrated in the sigmoid (99%); in group II activity was found in the rectum (9%), the sigmoid (61%) and the descending colon (15%); in group III activity was distributed between the sigmoid (66%) and descending colon (25%). The colonic distribution of mesalazine enemas was not influenced by disease activity. CONCLUSION: Volume, but not disease activity, is the important determinant of retrograde colonic spread of mesalazine enemas in ulcerative colitis.     

Experimental colitis induced by dextran sulphate sodium in mice: beneficial effects of sulphasalazine and olsalazine

Background:

Animal models of inflammatory bowel disease are artificial and more or less representative of human disease. However, the dextran sulphate sodium (DSS) induced intestinal inflammation model has recently been shown to fulfil some pathological criteria for an adequate experimental model.

Aim:

To determine whether this form of experimental intestinal inflammation responds to established therapy used for human inflammatory bowel disease.

Methods:

DSS was used to induce intestinal inflammation in conventional Balb/c mice and athymic nu/nu CD-1(BR) mice, and the well-documented 5-aminosalicylic acid (5-ASA) based anticolitis drugs sulphasalazine (SASP) and olsalazine (OLZ) were used to study therapeutic effects. Parameters which have been shown to reflect DSS-induced intestinal inflammation (body weight, colon length, spleen weight, diarrhoea, and rectal bleeding) were measured in the Balb/c mice.

Results:

Significant amelioration was seen on these parameters after different treatment protocols. Survival in nu/nu CD-1 mice was studied, and after 16 days a death rate of 50% was noted in the DSS group. SASP (100 mg/kg/day) and OLZ (50 mg/kg/day) significantly prolonged the survival to 29 and 38 days, respectively. SASP and OLZ showed a dose-dependent effect in the range between 10 and 100 mg/kg/day, doses closely corresponding to those used in humans.

Conclusions:

SASP and OLZ are able to ameliorate the DSS-induced intestinal inflammation. The dose-response patterns suggested that the active therapeutic moiety for the two drugs appears to be mainly the liberated 5-ASA molecule.

     

美沙拉嗪和柳氮磺吡啶对溃疡性结肠炎患者血清炎性因子表达的影响

目的 探讨美沙拉嗪与柳氮磺吡啶治疗对溃疡性结肠炎患者血清炎性因子表达的影响.方法 选取本院2012年1月至2015年1月收治的溃疡性结肠炎患者200例作为研究的对象,随机分为两组,每组100例,A组采用美沙拉嗪治疗,B组采用柳氮磺吡啶治疗.比较两组患者治疗8周后的总疗效,测定体内主要炎性因子含量,记录治疗中的不良反应的发生情况,并进行统计学分析.结果 两组共200例均完成了为期2个月的观察和治疗,美沙拉嗪治疗组治疗总体有效率91.0％,明显高于柳氮磺吡啶治疗组的71.0％,差异有统计学意义(x2=8.273,P＜0.05).柳氮磺吡啶治疗组患者治疗后血清中IL-13、IL-6、IL-8和TNF-α分别为(47.07±8.63) ng/L、(68.96±18.46) ng/L、(27.9±8.01)ng/L、(23.70±5.12)ng/L,美沙拉嗪治疗组患者治疗后IL-13、IL-6 、IL-8和TNF-α分别为(36.99±11.27)ng/L、(44.29±10.76) ng/L、(20.71±4.29) ng/L、(15.32±4.88) ng/L,均较治疗前明显下降(P＜0.05),且美沙拉嗪治疗组患者下降更为明显.结论 美沙拉嗪可降低血中IL-1 β、IL-6、IL-8和TNF-α等炎性因子水平,治疗溃疡性结肠炎临床疗效明显优于柳氮磺吡啶,而且不良反应发生率低,值得临床应用与推广.     

Allopurinol in addition to 5-aminosalicylic acid based drugs for the maintenance treatment of ulcerative colitis

Background:

To investigate the value of combined treatment with allopurinol and 5‐aminosalicylic (5‐ASA) based drugs as maintenance treatment for ulcerative colitis (UC).

Methods:

199 patients with UC in remission but with active disease during the preceding 3 years were included. Allopurinol 100 mg twice daily or placebo was added to the 5‐ASA based maintenance treatment. Clinical and endoscopic follow up was performed after 1, 6 and 12 months.

Results:

Intention‐to‐treat analysis after 6 and 12 months showed similar results in both groups. A log‐rank test showed that 77% in the allopurinol compared to 59% in the placebo group were still in remission after 6 months (P=0.0083) and 62% and 53% after 12 months, respectively (P=0.0936). This was mainly due to a higher than expected number of relapses during the first 3 months in the placebo group. After the first 3 months, the rate of relapse in each group was similar.

Conclusions:

It appears possible that allopurinol in combination with 5‐ASA is better than 5‐ASA alone for a 6‐month, but not a 12‐month period. This has to be verified in further dose‐ranging studies.

     

Comparative pharmacokinetics of sulphasalazine and sulphapyridine after rectal and oral administration to patients with ulcerative colitis

Summary Rectal administration of sulphasalazine to patients with ulcerative colitis has recently been shown to have similar therapeutic activity but fewer side effects than oral treatment. The present study is a comparison of the pharmacokinetics of sulphasalazine (SASP) and its metabolite sulphapyridine (SP) after rectal and oral administration of SASP to 6 patients with ulcerative colitis. The areas under the concentration-time curves (AUC) and the maximum concentrations (C_max) of SASP and SP were significantly lower after rectal than oral administration of SASP (p<0.05). These findings support the view that the lower frequency of side effects after rectal administration of SASP may result from the lower plasma levels of SASP and SP.