Synthesis and intestinal metabolism of ursodeoxycholic acid conjugate with an antiinflammatory agent, 5-aminosalicylic acid

5-Aminosalicylic acid conjugate of ursodeoxycholic acid was synthesized in above 90% yield by adding a basic solution of 5-aminosalicylic acid into the mixed anhydride formed with ursodeoxycholic acid and ethyl chloroformate. The 5-aminosalicylic acid conjugate of ursodeoxycholic acid was poorly secreted into the bile and was deconjugated with cholylglycine hydrolase and Clostridium perfringens, that deconjugate naturally occurring glycine and taurine conjugates of bile acids. However, ursodeoxycholic acid 5-aminosalicylic acid conjugate was not absorbed from the duodenum but was concentrated in the colon where it was partially hydrolyzed by the intestinal bacteria to ursodeoxycholic acid and 5-aminosalicylic acid. We believe that this unique conjugation of ursodeoxycholic acid with 5-aminosalicylic acid may facilitate the transport of both 5-aminosalicylic acid and ursodeoxycholic acid to the colon and may be useful for the treatment of colonic inflammatory bowel diseases, ulcerative colitis and Crohn's disease.     

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.     

Factors associated with the adaptation of parents with a chronically ill child

Improvement and standardization of the conservative therapy of inflammatory bowel disease has lead to a better prognosis for the patients. During the acute flare of Crohn's disease steroids are still the standard therapy, whereas 5-aminosalicylic acid (5-ASA) preparations are used for maintenance therapy during remission. In contrast ulcerative colitis may be treated with 5-ASA also for acute exacerbations. The development of new drugs as for example the topical steroids helps to improve life quality of the patients by reducing adverse side effects. Potent immunosuppressants as azathioprine and methotrexate are useful in chronic active and refractory disease. Cyclosporin A plays a role in severe steroid refractory colitis. In the future immunomodulation by application of antiinflammatory cytokines or antibodies to inflammatory cytokines may have its place in the treatment of IBD patients. In some cases, however, the conservative therapy reaches its limits. Mistakes in the therapy are made, when these limits are not recognized and complications are not discovered in time.     

Hyperprolactinemia: an inductor of neoplastic changes in endometrium? A report of two cases

Mast cell stabilizers are commonly used in the treatment of asthma and allergic disorders. Although the role of mucosal mast cells in the pathogenesis of inflammatory bowel disease remains uncertain, mast cell stabilizers have been shown in animal models to attenuate the severity of experimental colitis. The authors' experience with ketotifen in three patients--one each with Crohn's disease, ulcerative colitis and collagenous colitis--who had demonstrated allergy to, or intolerance of, 5-aminosalicylic acid is reported.     

Effects of ropivacaine on eicosanoid release from human granulocytes and endothelial cells in vitro

OBJECTIVE: To examine the effects of ropivacaine, currently being investigated for treatment of ulcerative colitis, on the release of arachidonic acid metabolites. MATERIAL: Human granulocytes and endothelial cells. TREATMENT: Ropivacaine, lidocaine, hydrocortisone, 5-aminosalicylic acid or acetylsalicylic acid (10-1000 microM). METHODS: Leukotriene B4, 5-hydroxyeicosatetraenoic acid, 6-keto PGF1 alpha and 15-hydroxyeicosatetraenoic acid were measured using immuno assays. Wilcoxon signed rank test was used for statistical calculations. RESULTS: Ropivacaine dose-dependently inhibited zymosan-induced release of leukotriene B4 and 5-hydroxyeicosatetraenoic acid whereas the release after ionophore stimulation was not affected. Ropivacaine was more potent than 5-aminosalicylic acid but less potent compared to hydrocortisone. Ropivacaine had only a weak inhibitory effect on the release of 15-hydroxyeicosatetraenoic acid from zymosan- or ionophore-stimulated cells. In contrast to hydrocortisone and 5-aminosalicylic acid, ropivacaine only weakly affected the release of 6-keto PGF1 alpha after stimulation with thrombin. CONCLUSIONS: The inhibited release of 5-lipoxygenase products may account for some of the anti-inflammatory effects of ropivacaine seen in the treatment of ulcerative colitis.     

Combined therapy with 5-aminosalicylic acid tablets and enemas for maintaining remission in ulcerative colitis: a randomized double-blind study

OBJECTIVES: To assess the efficacy of a combination of oral and topical 5-aminosalicylic acid (5-ASA) for the maintenance treatment of ulcerative colitis, we undertook a double-blind randomized clinical trial. METHODS: Patients aged 18 to 65 yr (with disease extent greater than proctitis only) were eligible for inclusion in the study if they met the following criteria: (a) history of two or more relapses in the last year; (b) achievement of remission in the last 3 months (with maintenance of remission for at least 1 month). Patients enrolled in the study were randomly assigned to one of the two following 1-yr treatments: (1) combined therapy with 5-ASA tablets 1.6 g/day and 5-ASA enemas 4 g/100 ml twice weekly; (2) oral therapy with 5-ASA tablets 1.6 g/day and placebo enemas/twice weekly. The main end point of the study was the maintenance of remission at 12 months. RESULTS: Upon completion of the study, relapse occurred in 13 of 33 patients in the combined treatment group versus 23 of 36 patients in the oral treatment group (39 vs 69%; p = 0.036). No significant side effects related to treatment were observed in either group. A simplified pharmacoeconomic analysis shows that this form of combined treatment can have a favorable cost-effectiveness ratio. CONCLUSIONS: Our results indicate that 5-ASA given daily by oral route and intermittently by topical route can be more effective than oral therapy alone. This form of combination treatment can be appropriate for patients at high risk of relapse.     

Prenatal diagnosis of congenital toxoplasmosis: comparative value of fetal blood and amniotic fluid using serological techniques and cultures

The management of patients with acute, severe ulcerative colitis requires careful in-hospital assessment of the patient and the coordinated treatment of a team of experienced gastroenterologists and surgeons. Complete understanding of the potential complications and their management, especially toxic megacolon, is essential. We review the current medical arsenal and advocate a standardized approach to management that includes continuous, high dose intravenous hydrocortisone, more aggressive use of topical steroids as well as feeding the patients and continuing (but not initiating) oral 5-aminosalicylic acid (5-ASA) agents. For those patients whose disease proves refractory to intravenous steroids, intravenous cyclosporin (with an acute response rate of 82%) is an essential component in the medical management of these patients. Antibiotics should be used only when specifically indicated. Total parenteral nutrition has not been shown to be helpful in the acute setting. Air contrast barium enema and colonoscopy have been used to predict response but may be dangerous diagnostic modalities in these acutely ill patients and are no better than good clinical judgement. We review and advocate long-term management of acute response using 6-mercaptopurine or azathioprine. The surgical experience and the postoperative complications of the ileal pouch anal anastomosis, which include acute pouchitis in 50-60%, chronic pouchitis in 5-10% and recent reports of dysplasia among patients with chronic pouchitis, must be considered before colectomy is advised. Over 80% of patients with acute severe colitis can be spared colectomy using our current arsenal of medical therapies.     

Forensic child and adolescent psychiatry: a review of the past 10 years

BACKGROUND AND METHODS: Risk factors for recurrence of Crohn's disease and the evidence for progress in reducing recurrence following resection were reviewed. A Medline based literature review was carried out. RESULTS AND CONCLUSION: Only smoking has been confirmed as a significant adverse risk factor for recurrence. Evidence for differing recurrence rates in fibrostenosing disease and perforating disease is inconclusive, but such a classification along with the endoscopic findings of recurrence may have a place in the analysis of therapeutic trials. Minimal resectional surgery with clearing of only macroscopic disease seems to be justified, with no clear benefits from different anastomotic techniques. Recent trials offer encouraging evidence of the usefulness of 5-aminosalicylic acid, particularly higher-dose regimens started early after resection, although the long-term benefits are uncertain. The oral steroid, budesonide, offers a potent treatment with minimal side-effects, but evidence of its prevention of recurrence is presently weak.     

Ulcerative colitis and intestinal bleeding

Ulcerative colitis is a nonspecific inflammatory disease of large intestine. Its inflammation is limited to intestinal mucosa. The most essential symptom is hematochezia, bloody stool and intestinal bleeding. Differential diagnosis among diseases having intestinal bleeding is clinically important. These diseases include Crohn disease, ischemic colitis, intestinal Beh?et disease, Enterohemorrhagic E. coli including O157, antibiotics associated hemorrhagic colitis and so on. Drugs for the treatment of ulcerative colitis are sulphapyridine, 5-aminosalicylic acid, prednisolone, betamethasone and immunosuppressive drugs. Recently, leukocytapheresis and massive immunoglobulin 7S treatment are available for the treatment of ulcerative colitis.     

Pericarditis in chronic inflammatory bowel disease: underlying disease or side effects of therapy? Clinical problem solving

Pericarditis and myocarditis are rare extraintestinal manifestations of chronic inflammatory bowel disease (ulcerative colitis and Crohn's disease). Pericarditis as a side effect induced by sulfasalazine or 5-aminosalicylic acid, drugs used in the therapy of these diseases, was first described only 7 years ago. In older case reports the relationship between the use of these drugs and pericarditis is unclear. We analyze the reported cases of 68 patients (38 men, 24 women) with ulcerative colitis (n = 45) or Crohn's disease (n = 15) who had one or more episodes of pericarditis or myopericarditis. Pericarditis was not associated with high activity of bowel disease in all cases. In most cases therapy with corticosteroids led to uneventful recovery. In drug induced pericarditis omission of the 5-ASA therapy was sufficient in a few cases. There was one fatal case (with myocarditis). The decision whether pericarditis is a symptom of the underlying disease or a side effect of the drug used for the treatment of the disease is not always easy. We present an analysis (clinical problem solving) of a pertinent observation in a patient with Crohn's disease and pericarditis, showing the dilemma of pericarditis in chronic inflammatory bowel disease and its therapy.     

Antenatal diagnosis of velamentous umbilical cord insertion and vasa previa with color Doppler imaging

The effect of various anionic surfactants on the initial rate of 5-aminosalicylic acid peroxidation with horseradish peroxidase was studied. With increasing surfactant concentration, this rate first decreased, then increased, and again decreased. We conclude that these changes were due to an inhibition of the enzyme, a subsequent change in the enzyme conformation accompanied by the enhanced accessibility of its active site to the substrate, and the final protein denaturation, respectively.     

Ulnar styloid malunion with dislocation of the distal radioulnar joint

AIMS: Delayed-release formulations of mesalazine often rely on the gastrointestinal luminal pH profile to deliver 5-aminosalicylic acid (5ASA) to the colon. The aim of this study was to examine the influence of luminal pH on mesalazine release. METHODS: We studied the effect of co-administration of omeprazole and lactulose on the steady-state pharmacokinetics of Eudragit S-coated mesalazine in healthy volunteers. RESULTS: No significant changes in urinary or faecal levels of 5ASA or its main metabolite, N-acetyl 5ASA, were apparent. CONCLUSIONS: This study suggests that co-administration of omeprazole and lactulose does not impair the release of delayed-release mesalazine.     

Application of a colon delivery capsule to 5-aminosalicylic acid and evaluation of the pharmacokinetic profile after oral administration to beagle dogs

Pressure-controlled colon delivery capsule (PCC) containing 5-aminosalicylic acid (5-ASA) for the treatment of inflammatory bowel disease (IBD) was prepared and evaluated by an in vivo experiment using beagle dogs. As a reference drug, sulfasalazine (SASP), prodrug of 5-ASA, was used as a plain gelatin capsule preparation. After the oral administration of SASP at the does of 25.0 mg/kg, the mean time when the plasma 5-ASA concentration reaches to its maximum (Tmax) was 9.0 hr. In the case of 5-ASA administered in PCC, at the doses of 12.5 and 25.0 mg/kg, Tmaxs were 5.3 and 5.3 hr, respectively. Although the time for the first appearance of 5-ASA into the systemic circulation was almost the same value between SASP capsule and PCC containing 5-ASA, longer Tmax was observed from SASP capsule than from PCC. These results suggest that this 5-ASA preparation would be an useful dosage form for the therapy of IBD from the point of avoiding the side effect of sulfapyridine, one of the metabolites of SASP.     

Guidelines for the treatment of ulcerative colitis in remission

The role is reviewed of sulphasalazine, 5-aminosalicylic acid (5-ASA), immunosuppressive agents and corticosteroids in the maintenance treatment of ulcerative colitis in remission. Sulphasalazine and oral 5-ASA are the drugs of first choice in preventing relapses for patients suffering from intermittent chronic ulcerative colitis. Rectally administered 5-ASA may be a valid alternative for treating patients with proctitis and left-sided ulcerative colitis. The optimal dosage of oral 5-ASA in the maintenance therapy of ulcerative colitis in remission is not clear. However, there is evidence that a higher dose of 5-ASA is more effective than low dosage in preventing relapses in patients in remission. For patients with chronically active or steroid-dependent ulcerative colitis who have achieved remission while taking immunosuppressants, continuing azathioprine or 6-mercaptopurine is indicated. Existing data cast doubts as to whether or not continuous maintenance is still necessary in patients suffering from intermittent chronic ulcerative colitis with prolonged endoscopic, clinical and histological remission.     

Management of recurrent Crohn's disease

After partial small bowel or colonic resection for Crohn's disease, recurrence frequently follows. Within half a year 60-73% of patients have endoscopic recurrence. This percentage increases substantially in as time passes. Symptoms will not always be present when endoscopic lesions are detected. The etiology of recurrent Crohn's disease is unknown. Some studies show that initial complications or extra-intestinal manifestations are more frequently seen in patients with a recurrence. The recurrent pattern of the lesions is also comparable to the pre-surgical state. The length of recurrent ileal inflammation after ileocolonic resection correlates with the pre-surgical extent of the disease. Some investigators have found electron-microscopic lesions in histologically unaffected resection margins demonstrating the presence of lesions. Luminal factors probably plays an important role as bypassing an anastomosis prevents an endoscopic recurrence. Some factors are considered to be important to increase the chance of a recurrence. A more aggressive disease may lead to earlier recurrence. Onset of disease at a younger age, a short pre-operative time, and localization, might play an important role. Smoking certainly influences the clinical, endoscopic and surgical recurrence. The number of daily cigarettes smoked and the duration of smoking, significantly increases the risk of recurrence. The type of surgery (kind of anastomosis, multiple anastomoses, length of resection) are not important. A longer macroscopic disease-free resection margin or presence of granuloma does not influence the recurrence rate. Also, the presence of microscopic disease at the margin is not important. Prevention of recurrent disease can be provided by administrating sulphasalazine, 5-aminosalicylic acid or metronidazole. For this reason, prophylactic medication after surgical resection seems appropriate.     

5-Aminosalicylic acid in the prevention of recurrences of Crohn's disease

AIM OF STUDY: To evaluate the efficacy of 5-aminosalicylic acid (5-ASA) in preventing recurrences of Crohn's disease. PATIENTS AND METHODS: Between January 1988 and December 1989 a total of 60 patients (37 men, 23 women, mean age 34.8 years) were selected in whom the diagnosis of Crohn's disease had been known for at least 2 years. A further criterion for inclusion was remission for at least one year in patients who had been operated or for one month in the nonoperated ones. Furthermore, the latter must have had at least one recurrence during the last year. They were in turn assigned to be treated with 5-ASA (2.4 g daily by mouth) or not treated (control). The activity and localization of Crohn's disease were defined according to the "Crohn's disease activity index" (CDAI) and the "laboratory index" (LI), as well as by endoscopy and (or) radiology. The patients were examined every 6 months for 4 years. A recurrence was diagnosed if the CDAI was more than 150 or had increased to at least 60 points above the initial value and the LI was above 100. RESULTS: 29 recurrences were noted, 72.4% within the first 2 years. 15 recurrences (46.9%) were in the treated patients and 14 (58.3%) among the untreated controls. The Kaplan-Meier curve (statistical comparison of the probability of recurrence) showed no significant difference between the two groups (P = 0.23): the recurrence rate was the same in the two groups, among the patients with or without previous operation and for different primary localizations. There were no notable side effects. CONCLUSION: Treatment with 5-ASA was not found to influence the likelihood of recurrence. Age, duration of the disease, primary localization and previous operation were not prognostic factors.     

Steady state disposition of 5-aminosalicyclic acid following oral dosing

In 18 healthy volunteers the steady state disposition of 5-aminosalicylic acid (5-ASA, mesalazine, CAS 89-57-6; 500 mg tid) was evaluated following the last oral dose in form of slow release tablets (Salofalk) either containing 500 mg or 250 mg 5-ASA. In none of the pharmacokinetic parameters of 5-ASA characterizing bioavailability (e.g. AUC approximately 6 ug/ml x h; Cmax approximately 1.7 micrograms/ml; tmax approximately 5 h; Cminss approximately 0.5 micrograms/ml; Cavss approximately 0.75 microgram/ml) differences between both forms were observed and the calculated 90% confidence intervals and point estimates indicated bioequivalence. Following the delayed absorption 5-ASA was rapidly eliminated (t1/2 = 1.4 +/- 0.5 h).     

Effects of smoking on the urine excretion of oral 51Cr EDTA in ulcerative colitis

BACKGROUND: Smokers have a reduced risk and ex-smokers an increased risk of ulcerative colitis (UC). Stopping smoking often precedes onset and relapses. Smoking reduces the 24 hour urine excretion of oral chromium-51 labelled EDTA in healthy individuals. AIMS: To estimate the effects of smoking on the urine excretion of oral 51Cr EDTA in well characterised patients with UC. SUBJECTS: Sixteen smoking and 16 non-smoking patients with UC in remission were studied. The non-smokers had never smoked. Most were taking 5-aminosalicylic acid. No patient took steroids or immunosuppressants. The control group comprised 25 smoking healthy volunteers and 25 who had never smoked. The median cigarette consumption was equal in the patients and volunteers. METHODS: The 24 hour urine excretion of oral 51Cr EDTA was measured and the results were correlated with smoking habits, number of cigarettes, and disease extent. RESULTS: Patients with UC had significantly higher 24 hour urine recoveries than healthy controls (p = 0.04). This difference was more pronounced when patients who smoked were compared with healthy smokers (p = 0.005) No significant differences were found when comparing non-smoking patients with non-smoking controls or when comparing smoking and non-smoking patients. Urine recoveries did not correlate with number of cigarettes or disease extent. Smoking was more prevalent in patients with a more limited disease extent (p = 0.033). CONCLUSIONS: Effects of smoking on the urine excretion of 51Cr EDTA in health were abolished by the presence of UC. The protective effects of smoking in established UC are not due to a moderating effect of smoking on intestinal permeability.     

Determination of tetracycline residues in animal tissues by liquid chromatography

BACKGROUND: Sufficient intraluminal concentrations of 5-aminosalicylic acid (ASA) within inflamed regions of the intestine are required for therapeutic efficacy in inflammatory bowel disease. Various oral delayed release preparations have been developed to ensure that 5-ASA is set free in those parts of the gut, which are most frequently affected. However, resulting intraluminal concentrations within the small bowel are unknown. Therefore, we determined and compared 5-ASA release within different segments of the small bowel from an Eudragit L coated 5-ASA preparation (Salofalk) and from an ethylcellulose coated microsphere preparation (Pentasa). METHODS: Twelve healthy subjects were intubated with an oro-ileal multilumen-tube for marker perfusion, duodenal, jejunal and ileal aspiration of chyme and intestinal manometry. Each subject received 500 mg 5-ASA (Salofalk, n = 6, or Pentasa, n = 6) together with a semiliquid test meal. Intestinal aspirates, blood and urine samples were obtained in regular intervals for 7 to 10 hours and were analysed for 5-ASA and its main metabolite acetyl-5-ASA by HPLC. RESULTS: With Salofalk, gastric emptying of 5-ASA did not take place in the digestive, but in the subsequent interdigestive period. Luminal delivery of 5-ASA and acetyl-5-ASA increased from the duodenum (3% of dose) to the ileum (30% of dose). 10% of the dose administered were excreted in urine and about 90% reached the colon unreleased or solubilised. By contrast, with Pentasa, 5-ASA was delivered to the duodenum together with the test meal and released continuously throughout the small intestine (about 20% of dose solubilised at each intestinal site). Only 3.5% of the dose administered were excreted in urine. Deliver of 5-ASA to the colon was equal to Salofalk. CONCLUSIONS: From both preparations, considerable amounts of 5-ASA are released during small intestinal transit thus explaining therapeutic efficacy in small intestinal Crohn's disease. Because of specific release patterns, Salofalk may be of use especially in terminal ileal disease, where as patients with extensive small intestinal disease including the proximal small intestine might benefit from Pentasa.     

Clinical status of ulcerative colitis in patients who smoke

OBJECTIVES: Ulcerative colitis (UC) is largely a disease of nonsmokers. There are few patients who are current smokers, but we have identified a group and reviewed their clinical status, disease activity, and nicotine exposure to examine whether they remain well controlled while smoking. METHODS: Fifty-one patients from three centers with verified UC were reviewed. RESULTS: Thirty of the group were men; mean age 50 yr, with a mean age of onset of 37 yr. Twenty-two patients had proctosigmoid disease, 12 involvement of left colon, and 17 total colitis. All were current smokers; 41 were cigarette smokers averaging 17 daily. At the onset of colitis 30 were nonsmokers, 25 of them were ex-smokers and 19 developed colitis within 2 yr of stopping smoking. Twenty-eight believed smoking improved disease activity and none felt smoking had a detrimental effect on their UC. Eleven were receiving no medication for UC, 40 were receiving 5-ASA (5-aminosalicylic acid) preparations, and only two took oral steroids. All were in clinical remission, with the exception of one patient; mean St. Marks score was 1.5, out of a possible total of 22. Sigmoidoscopic grades were inactive in all patients except three. Histological assessment showed significant activity in only five. Median serum nicotine was 8 ng/ml (range, 0.4-24.4), median serum cotinine 180 ng/ml (range, 20-453), with corresponding salivary cotinine of 255 ng/ml (range, 34-683). Median rise in nicotine 2 min after a cigarette in 35 patients was 12.1 ng/ml (range, 0.4-44). CONCLUSIONS: Because most current smokers with UC have inactive disease, smoking may contribute to the clinical remission in these patients.