Pharmacokinetics and retrograde colonic spread of budesonide enemas in patients with distal ulcerative colitis

METHODS: The retrograde spread of two budesonide enema formulations with different viscosities was investigated. The study design was open, randomized and two-period crossover. Three female and two male patients (age range: 35-45 years) with distal ulcerative colitis or proctitis participated. Both enema formulations contained a dose of 2 mg budesonide/100 mL. An unabsorbable radioactive marker (99mTc-labelled human serum albumin microcolloid) was added to the enema just before administration. All doses were given in the evening with the patients lying in a supine position during the whole investigation. The intestinal spread was followed for 8 h using scintigraphic imaging. Plasma samples for budesonide assay were taken during the 12 h after administration of the low viscosity enema. RESULTS: Budesonide plasma levels were measurable for up to 4-6 h. Cmax was 2.5 nmol/L (range: 0.9-4.5 nmol/L) and was attained in 1.5 h (range 1-3 h). The patients had no difficulty in retaining the enemas. There was a statistically significant difference in spread between the low and high viscosity enema. The low viscosity enema spread over an area situated between the rectum and the splenic flexure. The spread occurred mainly in the first 15 min after administration. In contrast, the high viscosity enema, in most cases, spread only over a minor part of this area and the rate and extent of spreading was also more variable with this formulation. CONCLUSION: The spread of a low viscosity enema appears to be well suited for the treatment of proctitis and distal colitis.     

A double-blind comparison of oral versus rectal mesalamine versus combination therapy in the treatment of distal ulcerative colitis

OBJECTIVES: The aim of this study was to compare the efficacy of mesalamine rectal suspension enema (Rowasa) alone, oral mesalamine tablets (Asacol) alone, and the combination of mesalamine enema and mesalamine tablets in patients with active mild-to-moderate distal ulcerative colitis. METHODS: Sixty outpatients with ulcerative colitis at least 5 cm above the anal verge and not more than 50 cm, inclusive, and a total disease activity index (DAI) score between 4 and 10, inclusive, were randomized to either mesalamine rectal enema (n = 18) once nightly, oral mesalamine 2.4 g/day (n = 22), or a combination of both treatments (n = 20). Placebo capsules and enemas were used to maintain a blind procedure. Total DAI scores and abbreviated DAI scores were evaluated at wk 3 and 6, and wk 1 and 2, respectively. Patients recorded the amount of blood in stools, urgency, straining at stools, and abdominal pain in daily diaries. Physicians and patients rated overall improvement at each visit. RESULTS: At wk 6, combination therapy produced a greater improvement (-5.2) in total DAI scores than did either mesalamine enema (-4.4) or mesalamine tablet (-3.9) therapy alone; similar treatment differences were observed at wk 3. Compared with patients given mesalamine enemas or mesalamine tablets, combination-therapy patients reported an absence of blood in stools significantly sooner and, at all visits, the combination therapy group had the highest percentage of patients who reported no blood in their stools. Physicians' and patients' ratings of improvement indicated that combination therapy significantly improved disease status, compared with mesalamine tablet therapy alone. All treatments were well tolerated. CONCLUSIONS: The combination of oral and rectal mesalamine therapy was well tolerated and produced earlier and more complete relief of rectal bleeding than oral or rectal therapy alone.     

Therapeutic effects of beclomethasone dipropionate enemas on colon damage of inflammatory bowel disease model rats]

The effects of beclomethasone dipropionate (BDP) enemas on ulcerative colitis were investigated by administrating BDP enemas to Fischer male rats with an inflammatory bowel disease induced by 2,4,6-trinitrobenzensulfonic acid (TNB). After administration of a TNB ethanol solution to rats, diarrhea and melena were found in all rats, and the wet tissue weights of the colons in the rats increased by erosion and thickness of epithelial mucous membranes with edema. BDP enemas were administered to the rats one time a day at a dose of 20 or 50 micrograms of BDP for 4 or 11 days from the day 3 after TNB treatment, respectively. After dosing of BDP, the rate of rats developing diarrhea and melena decreased more with time in comparison with that of BDP-free rats, and the symptoms of all rats developing the diseases were improved on the day 4 after administration of a dose of 50 micrograms of BDP. A dose dependent recovery in the wet tissue weights and scores of damages, and the myeloperoxidase (MPO) activity in the tissue were found at the early days (until the day 4). However, their measurements on the day 11 at each dose of BDP were not different from those of control rats significantly, as the damages in the colons of the control rats were recovered naturally with time. In conclusion, the clinical usefulness of BDP enemas was supported by elucidating the dose dependent effect of BDP at the early days in the model rats with an inflammatory bowel disease induced by TNB.     

Pharmacokinetics of nicotine carbomer enemas: a new treatment modality for ulcerative colitis

BACKGROUND: Ulcerative colitis is largely a disease of nonsmokers, and transdermal nicotine is of therapeutic value in the active disease. Because side effects are common, we developed a topical enema formulation of nicotine. OBJECTIVE: To study the pharmacokinetics of nicotine complexed with a polyacrylic carbomer and administered by enema to eight healthy volunteers and to eight patients with active ulcerative colitis, verified sigmoidoscopically. PATIENTS AND METHODS: All 16 subjects were nonsmokers. The mean age for normal subjects was 33 years; the mean for patients with ulcerative colitis was 60 years. Median stool frequency for patients with ulcerative colitis was four daily. Patients were taking 5-amino salicylic acid compounds and five were taking oral prednisolone (median dose, 12 mg daily). Nicotine, 6 mg, complexed with carbomer 974P, 400 mg, was administered in a 100 ml enema after an overnight fast, with serial blood measurements taken over 8 hours. Serum nicotine and cotinine were measured by gas liquid chromatography. Area under the concentration-time curves were calculated by the trapezoidal method, and the terminal elimination half-life was derived by extrapolation of the log-linear terminal phase. RESULTS: With the exception of nicotine time to reach peak concentration, which was longer in patients (median of 60 minutes compared with 45 minutes; p < 0.005), other comparisons between normal subjects and patients showed no statistically significant difference, although there was considerable inter-subject variation. Maximum concentration of nicotine, 8.1 +/- 3.5 ng/ml, in the 16 subjects occurred after a median of 60 minutes (range, 30 to 180 minutes); maximum cotinine concentrations of 60.4 +/- 11.5 ng/ml occurred after 4 hours. Side effects in five subjects were mild (four subjects) or moderate (one subject) and included lightheadedness, nausea, and headache; these five subjects were female lifelong nonsmokers of low body weight. CONCLUSION: Because most of the active ingredient of nicotine is converted to continine on the first pass through the liver, substantial concentrations can be achieved at the site of disease with only modest rises in serum nicotine, which are responsible for side effects; cotinine has low pharmacologic activity. Topical administration of nicotine may be useful treatment for distal ulcerative colitis.     

Comparison of mesalazine suppositories in proctitis and distal proctosigmoiditis

BACKGROUND: Mesalazine suppositories at 500 mg b.d. are a safe and effective treatment for patients with ulcerative proctitis or distal proctosigmoiditis. Recently a mesalazine 1 g suppository (Pentasa) has been developed. METHODS: Fifty patients with active ulcerative colitis extending not beyond 20 cm from the anus on sigmoidoscopy, participated in a randomized single-blind study comparing the efficacy, tolerance and acceptance of the new Pentasa mesalazine 1 g suppository, given once daily versus Claversal mesalazine 500 mg suppository b.d. RESULTS: After 2 weeks, clinical remission was observed in 16 of 25 (64%) in the Pentasa group and in 7 of 25 (28%) in the Claversal 500 mg b.d. treated group; sigmoidoscopic remission occurred in 13 of 25 (52%) in the Pentasa group and in six of 25 (24%) in the Claversal group (P < 0.01). After 4 weeks, clinical and sigmoidoscopic remission were observed, respectively, in 84 and 76% of patients treated with Pentasa suppositories, and in 80 and 72% of patients treated with Claversal suppositories 500 mg b.d. (P = N.S.). The patients' evaluation for tolerability and practicality showed that the Pentasa suppository was significantly superior to the Claversal suppository. CONCLUSIONS: Pentasa 1 g suppository once daily induces a quicker clinical and sigmoidoscopic remission, and was better tolerated, than the Claversal 500 mg suppository b.d., and it may represent an advance for the topical treatment of distal proctosigmoiditis.     

Malignant degeneration of experimental ulcerative colitis of the rat following s.c. injection of 1,2-dimethylhydrazine (author's transl)

Animal experiments were performed to answer the question whether ulcerative colitis is predisposed to malignant degeneration. Male Wistar rats were given aqueous solutions of degraded Carrageenan (4%; w/v). After induction of ulcerative colitis, 1,2-Dimethylhydrazine (DMH; 132 mg/kg body weight) was applicated during a period of 7 weeks. 17 of 18 rats developed multiple adenocarcinomas in the distal colon 15 weeks after the last injection of DMH. The Carrageenan induced colitis was localized predominantly in the distal part of the large bowel. Only 3 rats of a control group of 18 animals exposed to DMH only showed carcinomas of the colon. The difference is proven significant (P less than 0.01). Carrageenan for itself caused no malignancy. The results of the experiments demonstrate that, during ulcerative colitis, the colon of the rat is more susceptible to induction of cancer than the intact one.     

Lack of hypothalamic-pituitary-adrenal axis suppression with once-daily or twice-daily beclomethasone dipropionate aqueous nasal spray administered to patients with allergic rhinitis

The potential for a newly developed, double-strength (0.084%) beclomethasone dipropionate (BDP) aqueous (AQ) nasal suspension to produce effects associated with exposure to systemic corticosteroids was assessed by the plasma cortisol response to cosyntropin stimulation induced by a 6-hour intravenous infusion of 250 micrograms of cosyntropin in 500 mL of normal saline. Sixty-four patients with allergic rhinitis were enrolled in this study. Patients were randomly assigned to one of the following four treatment groups: (1) BDP AQ Forte (0.084%) nasal spray 336 micrograms once daily; (2) BDP AQ (0.042%) nasal spray 168 micrograms twice daily; (3) placebo nasal spray twice daily; or (4) oral prednisone 10 mg once daily in the morning. After 36 consecutive days of treatment, there was a significant (P < 0.01) difference in the plasma cortisol response to cosyntropin stimulation between the prednisone and placebo groups; however, there were no significant differences between the BDP AQ Forte or the BDP AQ groups compared with the placebo group. Secondary analyses comparing BDP AQ Forte administered as 336 micrograms once daily with BDP AQ administered as 168 micrograms twice daily showed no significant differences in plasma cortisol responses to cosyntropin stimulation. No serious adverse events were reported. Adverse events consisted of headache, pharyngitis, or nasal irritation, with headache being reported most frequently. These adverse events were similarly distributed among active treatment groups and were similar to placebo. No clinically relevant changes were observed in any treatment group in findings on clinical laboratory tests, physical examination, or electrocardiography. Vital signs, obtained daily, were consistent with values observed in healthy individuals. No patient exhibited signs of oral candidiasis. All patients met the plasma cortisol concentration criteria for discharge relative to expected hypothalamic-pituitary-adrenal axis function. In conclusion, there were no significant differences in plasma cortisol responses to cosyntropin stimulation between groups of patients with allergic rhinitis treated with either BDP AQ Forte (0.084%) nasal spray 336 micrograms once daily or BDP AQ (0.042%) nasal spray 168 micrograms twice daily compared with the placebo group. These results indicate that the dosing regimens of BDP AQ nasal suspensions used in this study lack systemic effects and are safe and well tolerated.     

Pneumatic lithotripsy applied through deflected working channel of miniureteroscope: results in 143 patients

OBJECTIVE: Transdermal nicotine appears to be of benefit in the short-term treatment of patients with ulcerative colitis. The aim of this study was to determine its long-term effects. DESIGN: A randomized, comparative study. PATIENTS AND METHODS: Patients with mild to moderate clinical relapses of left-sided ulcerative colitis during maintenance treatment with mesalamine 1 g b.i.d. were allocated to an additional treatment with either transdermal nicotine or prednisone for 5 weeks. The first consecutive 15 patients per group, with clinical and endoscopic signs of remission, were followed up for 6 months, while continuing mesalamine maintenance treatment. RESULTS: Relapses of active colitis were observed in 20% of patients formerly treated with nicotine and in 60% of patients in the prednisone group (P = 0.027). Relapses occurred earlier in the latter group. CONCLUSION: Our results confirm that nicotine is useful in cases of ulcerative colitis with mild or moderate activity and suggest that remissions induced by nicotine may last longer than those obtained with oral corticosteroids.     

Successive subcortical hemorrhages in the superior parietal lobule and postcentral gyrus in a 23-year-old female

BACKGROUND: To assess the role of contrast enemas for the evaluation of leaks in symptomatic and asymptomatic patients after the first stage of restorative proctocolectomy. METHODS: We reviewed the findings of 59 contrast enemas in 40 patients who underwent total proctocolectomy with creation of an ileoanal pouch and a proximal diverting ileostomy. Thirty-seven patients initially underwent routine contrast studies of the ileoanal pouch, and three underwent contrast studies because of suspected fistulas or obstruction. Medical records were also reviewed to determine the clinical presentation and course of these patients. RESULTS: Of 37 patients who underwent routine postoperative contrast enemas, 33 (89%) had normal studies, three (8%) had clinically silent leaks (including two blind-ending tracks from the ileoanal anastomosis and one from the pouch), and one (3%) had pouchitis. In all three patients with unsuspected leaks, ileostomy closure was delayed. In two other patients with abdominal pain and fever, contrast enemas revealed leaks from the ileoanal pouch and distal ileum, respectively. The remaining patient had a contrast enema because of abdominal pain and distention; this patient had a distal ileal obstruction due to adhesions. CONCLUSIONS: Routine postoperative contrast studies revealed clinically silent leaks from the ileal J pouch or ileoanal anastomosis in three of 37 patients (8%) after the first stage of restorative proctocolectomy. Our findings suggest that routine contrast enema can detect clinically silent leaks after this surgery.     

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.     

Cytokine production from colonic T cells in patients with ulcerative colitis with and without primary sclerosing cholangitis

PURPOSE: Only five percent of all patients with ulcerative colitis develop primary sclerosing cholangitis. T cells accumulate at the sites of the colonic and bile duct inflammation in both ulcerative colitis and primary sclerosing cholangitis. T helper cell populations comprise functionally distinct subsets characterized by the cytokines they produce. Several alterations in cytokine production have been described in patients with ulcerative colitis. The aim of this study was to investigate possible differences in T helper subsets and cytokine production in peripheral blood and colonic mucosa among ulcerative colitis patients with and without primary sclerosing cholangitis. METHODS: Eleven patients with primary sclerosing cholangitis and extensive ulcerative colitis, 11 patients with extensive ulcerative colitis and no liver disease, and 5 patients without any history of liver disease who underwent routine colonoscopy because of previous polypectomy were included in the study. Colonoscopy with multiple biopsies was performed on all patients. Lamina propria mononuclear cells and peripheral blood mononuclear cells were isolated. A modified version of solid-phase enzyme-linked immunospot assay was used for the separate counting of cells producing interferon-gamma, interleukin-2 (T helper 1), and interleukin-4 (T helper 2). RESULTS: No differences in spontaneous production of cytokines from peripheral blood mononuclear cells was found among the three groups. Patients with primary sclerosing cholangitis compared with patients with ulcerative colitis without liver disease showed a significant increase in the number of cells secreting interferon-gamma after purified protein derivative stimulation (P < 0.02). More cells secreting interferon-gamma were found in the two ulcerative colitis groups than in the cell populations from healthy controls (P < 0.03). The number of cells secreting interferon-gamma in the primary sclerosing cholangitis group was significantly lower than in the ulcerative colitis group without liver disease (P < 0.04). The number of cells secreting interleukin-4 was lower in the primary sclerosing cholangitis group than among the patients with ulcerative colitis only (P = 0.05). CONCLUSION: Isolated lymphocytes from colonic mucosa differ in cytokine production in patients with ulcerative colitis with and without primary sclerosing cholangitis.     

Treatment of ulcerative colitis with an engineered human anti-TNFalpha antibody CDP571

BACKGROUND: Tumour Necrosis Factor-alpha (TNFalpha) is a pro-inflammatory cytokine whose expression is increased in the colonic mucosa of patients with active ulcerative colitis. TNFalpha antibodies have been shown to be beneficial in animal models of bowel inflammation and in Crohn's disease but have not previously been studied in ulcerative colitis. METHODS: Patients with mild/moderate ulcerative colitis were treated openly with a single intravenous infusion of 5 mg/kg of an engineered human IgGgamma4 antibody CDP571 and monitored for 8 weeks. RESULTS: Fifteen patients entered the study, eight males and seven females, with a mean age of 44 years. Eleven had left-sided disease, four extensive disease and six patients were steroid-unresponsive. The treatment was well tolerated and plasma half-life of CDP571 was approximately 7 days. There was a significant reduction from 6.7 to 4.6 (P = 0.023) in the mean Powell-Tuck score by 1 week post-infusion and a reduction to 5.5 was seen at 2 weeks (P = 0.218). Significant but modest reductions also occurred in erythrocyte sedimentation rate and serum C reactive protein in the first 2 weeks. Mean Interleukin-6 plasma concentrations fell from 6.9 to 5.4 pg/mL by week 1, and to 6.1 pg/mL by week 2 (NS). Reductions in sigmoidoscopic score and number of liquid stools were noted but failed to reach statistical significance. CONCLUSION: A consistent improvement in disease activity was seen in the initial 2 weeks after infusion and the treatment was well tolerated. These promising results support the testing of CDP571 in a larger controlled trial.     

Gas enema for the reduction of intussusception: relationship between clinical signs and symptoms and outcome

OBJECTIVE: The aim of this study was to establish the extent to which the clinical features of intussusception can be used to predict successful outcome of gas enema and to determine whether the nonsurgical management of intussusception in children can be improved by refining the criteria used to select patients for gas enema. SUBJECTS AND METHODS: Clinical data on 282 consecutive episodes of intussusception (255 patients) were collected prospectively from January 1987 to July 1991. Gas enema was performed in 273 episodes, in which the clinical signs and symptoms were studied by using logistic regression. Nine patients had primary surgery. RESULTS: Gas enema was successful in 216 (79%) of 273 enemas attempted. Fifty-seven patients had surgery after unsuccessful enema. Univariate analysis showed significant associations between successful enema and duration of signs and symptoms less than 12 hr, no rectal bleeding, absence of small-bowel obstruction, presence of a palpable mass, and normal hydration. Multivariate analysis showed that dehydration, small-bowel obstruction, and duration of signs and symptoms longer than 12 hr were significant predictors of unsuccessful enema; yet, in these groups the rate of success still justified attempted enema. Even in severe dehydration, the successful enema reduction rate was 31%. CONCLUSION: Our data suggest that although the factors identified had some predictive value in determining the outcome of attempted enema reduction, they could not be used to indicate patients in whom enema reduction should not be attempted. All patients with intussusception should have a gas enema if the absolute contraindications to enema (i.e., peritonitis or perforation) are absent.     

Olsalazine versus mesalazine in the treatment of mild to moderate ulcerative colitis

AIM: To compare the efficacy and tolerability of olsalazine sodium with enteric-coated mesalazine in inducing endoscopic remission in patients with mild to moderate active ulcerative colitis. PATIENTS AND METHODS: Patients with mild to moderate active ulcerative colitis were randomized to receive either olsalazine sodium, 3 g/day (n = 88), or mesalazine, 3 g/day (n = 80), for up to 12 weeks. RESULTS: Of the patients treated with olsalazine sodium, 52.2% achieved endoscopic remission, compared with 48.8% of patients treated with mesalazine. This difference was not significant (P = 0.67). There was a nonsignificant trend for patients with left-sided colitis or a more severe endoscopic grade to achieve remission if they were treated with olsalazine sodium than if they were treated with mesalazine. Both treatments were comparable with respect to clinical activity index and an investigator's global assessment. Seventy patients reported one or more adverse events; adverse events were seen in 45% of olsalazine sodium-treated patients and in 36% of mesalazine-treated patients. Eleven patients treated with olsalazine sodium and nine patients treated with mesalazine withdrew from the study because of adverse events. One patient treated with olsalazine sodium compared with two treated with mesalazine stopped treatment because of diarrhoea. Serious adverse events occurred in three patients treated with olsalazine sodium and in four treated with mesalazine. CONCLUSION: Therapeutic effectiveness and tolerance to the treatment did not differ between olsalazine sodium, 3 g/day, and mesalazine, 3 g/day, in inducing endoscopic remission in patients with mild to moderate active ulcerative colitis within 12 weeks of treatment.     

Toxic megacolon of ulcerative colitis in infancy

A 12-week-old white male infant with ulcerative colitis and toxic megacolon is described. His diarrhea and rectal bleeding responded to prednisone. He subsequently developed toxic dilatation of the transverse colon while on salicylazosulfapyridine and one week after discontinuation of prednisone. His toxic megacolon disappeared during close medical observation, readministration of prednisone, and avoidance of repeated abdominal examinations. One year later sigmoidoscopy showed only friable mucosa and the barium enema showed the presence of ulcerative colitis but with improvement from the initial study. Currently he is taking 375 mg of salicylazosulfapyridine daily. Growth and development are normal and he is asymptomatic.     

Effects of high dose inhaled beclomethasone dipropionate, 750 micrograms and 1500 micrograms twice daily, and 40 mg per day oral prednisolone on lung function, symptoms, and bronchial hyperresponsiveness in patients with non-asthmatic chronic airflow obstruction

BACKGROUND: The effect of treatment with inhaled corticosteroids in patients with non-asthmatic chronic airflow obstruction is still disputed. Whether any physiological improvements seen are accompanied by changes in bronchial responsiveness and symptoms and quality of life is also still unclear. METHODS: A sequential placebo controlled, blinded parallel group study investigating the effect of three weeks of treatment with inhaled beclomethasone dipropionate (BDP), 750 micrograms or 1500 micrograms twice daily, and oral prednisolone, 40 mg per day, was carried out in 105 patients with severe non-asthmatic chronic airflow obstruction (mean age 66 years, mean forced expiratory volume in one second (FEV1) 1.05 litres [40% predicted], geometric mean PD20 0.52 mumol). End points assessed were FEV1, forced vital capacity (FVC), and peak expiratory flow (PEF), bronchial responsiveness to inhaled histamine, and quality of life as measured by a formal quality of life questionnaire. RESULTS: Both doses of BDP produced equivalent, small, but significant improvements in FEV1 (mean 48 ml), FVC (mean 120 ml), and PEF (mean 12.4 l/min). The addition of oral prednisolone to the treatment regime in two thirds of the patients did not produce any further improvement in these parameters. Inhaled BDP produced a treatment response in individual patients (defined as an improvement in FEV1, FVC, or mean PEF of at least 20% compared with baseline values) more commonly than placebo (34% v 15%). The two doses of BDP were equally effective in this respect and again no further benefit of treatment with oral prednisolone was noted. Treatment with BDP for up to six weeks did not affect bronchial responsiveness to histamine. Small but significant improvements were seen in dyspnoea during daily activities, and the feeling of mastery over the disease. CONCLUSIONS: High dose inhaled BDP is an effective treatment for patients with chronic airflow obstruction not caused by asthma. Both objective and subjective measures show improvement. Unlike asthma, no improvement in bronchial responsiveness was detected after six weeks of treatment.     

Correlation of a common mutation in the methylenetetrahydrofolate reductase gene with plasma homocysteine in patients with premature coronary artery disease

BACKGROUND: Recent clinical trials have demonstrated that methotrexate may have an important therapeutic role in the treatment of patients with inflammatory bowel disease, who are either refractory or intolerant to traditional medical therapy. The aim of this study was to evaluate the pharmacokinetics of low-dose oral methotrexate in patients with inflammatory bowel disease. METHODS: Methotrexate (12.5 mg) was given orally to nine patients with inflammatory bowel disease: five with Crohn's disease, and four with ulcerative colitis, and to six patients with rheumatoid arthritis who served as a control group. Blood samples were drawn at specific intervals to evaluate methotrexate plasma levels. RESULTS: Methotrexate was rapidly absorbed in all patients. Peak concentrations (Cmax) varied considerably, ranging from 0.25-0.87 micro M. The mean Cmax values were similar in all patient groups (0.59 +/- 0.12, 0.69 +/- 0.16 and 0.54 +/- 0.18 micro M, P not significant) for Crohn's disease, ulcerative colitis and rheumatoid arthritis, respectively. The mean area under curve in 120 min (AUC0-120) was also similar in all patient groups (32.9 + 11.3, 43.6 + 9.9 and 41.8 + 14.9 ng.min/mL, P not significant) for Crohn's disease, ulcerative colitis and rheumatoid arthritis, respectively. The mean time to reach Cmax, (tmax), varied between patient groups (84, 112 and 95 min, respectively, with a significant difference, P < 0.02, between the Crohn's disease and ulcerative colitis groups. A negative correlation was found between methotrexate dosage/kg and Cmax (r = -0.74) only in Crohn's disease patients but not in the other patient groups. CONCLUSIONS: Orally administered methotrexate is well absorbed in patients with inflammatory bowel disease including those with severe small bowel disease or resection. If methotrexate is proven to be effective in inflammatory bowel disease, it should be administered orally.     

The majority of myeloid-antigen-positive (My+) childhood B-cell precursor acute lymphoblastic leukaemias express TEL-AML1 fusion transcripts

BACKGROUND & AIMS: Crohn's disease and ulcerative colitis show a familial aggregation. In both diseases, anti-goblet cell autoantibodies (GABs) have been described. The aim of this study was to define the role of GABs in the pathogenesis of inflammatory bowel disease. METHODS: The study population comprised 61 patients with ulcerative colitis, 76 patients with Crohn's disease, 101 first-degree relatives of patients with ulcerative colitis, and 105 first-degree relatives of patients with Crohn's disease. Thirty-five patients with infectious enterocolitis and 56 healthy unrelated subjects served as controls. Autoantibodies were detected by indirect immunofluorescence. RESULTS: Thirty-nine percent of patients with ulcerative colitis (24 of 61) and 30% of patients with Crohn's disease (23 of 76) were positive for GABs. GABs were detected in 21% (21 of 101) of first-degree relatives of patients with ulcerative colitis and in 19% (20 of 105) of first-degree relatives of patients with Crohn's disease. In patients with infectious enterocolitis and in healthy controls, GABs were seen in 3% (1 of 35) and 2% (1 of 56), respectively. The differences between control groups and both groups of patients or their first-degree relatives were significant. CONCLUSIONS: The high prevalence in first-degree relatives suggests that GABs may represent a marker characterizing susceptibility to inflammatory bowel disease.     

Smooth-muscle hamartoma of the tunica dartos of the scrotum: report of a case

Corticosteroids are effective in bringing about a clinical remission in patients with ulcerative colitis. However, in severely relapsed cases, corticosteroids are not always effective even when a high dosage is administered. In addition, the long-term use of corticosteroids often causes serious side effects. Therefore, an alternative treatment for active ulcerative colitis is necessary in order to avoid these clinical problems. In the present pilot study, the efficacy of leukocytapheresis using a centrifugal procedure was evaluated for corticosteroid-resistant, active ulcerative colitis. Fourteen patients with corticosteroid-resistant severely active ulcerative colitis were treated by leukocytapheresis. Thirteen patients (92.9%) achieved clinical remission within 4 weeks after the apheresis, and remained in remission for 8 months on average without any additional corticosteroid therapy. In the remaining patient, in whom remission was not induced, a total colectomy was performed immediately after the fourth course of leukocytapheresis. No significant side effects were noticed throughout the therapy. Both colonoscopic and histological examinations confirmed the beneficial effect of this procedure in terms of the reduction of severe inflammation of the affected colon. We found that the expression of two adhesion molecules, L-selectin and VLA4a, on the surface of peripheral leukocytes was decreased after this new therapy.     

Predictors and the rate of medical treatment failure in ulcerative colitis

Eighty-nine admissions into Auckland Hospital with exacerbation of ulcerative colitis (between May 1985 and May 1991) were analyzed to determine the rate and any predictors of medical treatment failure. Twenty-five patients (28%) failed to respond to medical treatment and required surgery. Clinical information and laboratory indices available within 24 h of the admissions were compared between the patients requiring surgery and those who did not. There were no significant differences between the groups in sex distribution, age of onset of disease, duration of disease, hemoglobin concentration, or white cell count. However, "severe" diarrhea (chi 2 = 24.83, p = 0.0001), and lower albumin level (F1, 83 = 45.61, p = 0.0001) were noted in the surgical group. There was a tendency toward higher ESR (F1, 82 = 3.06, p = 0.08) and "extensive" colitis (chi 2 = 3.29, p = 0.07) in the patients requiring surgery. Univariate analysis confirmed albumin level and severity of diarrhea as significant discriminators. A discriminant function analysis showed that albumin level and severity of diarrhea would distinguish between surgical and nonsurgical outcome in 82% of cases. Distal colitis and mild to moderate diarrhea had negative predictive values of 80% and 91%, respectively, for nonsurgical outcome of acute ulcerative colitis. It is concluded that the above significant variables are good predictors of outcome of medical treatment for exacerbations of ulcerative colitis and that the proportion of patients needing surgery has not changed in the last 35 yr despite various management strategies.