Refractory IBD: medical management

Refractory inflammatory bowel disease (IBD) can be defined as persistent acute symptomatic disease despite anti-inflammatory therapy or as chronically active disease requiring continuous treatment for relief of symptoms. Treatment options include azathioprine (AZA), 6-mercaptopurine (6-MP), methotrexate (MTX), cyclosporine (CYA), and experimental therapies that are cytokines or cytokine antagonists. AZA and 6-MP have identical actions in IBD. 6-MP is effective in about 75% of patients with inflammatory Crohn's disease. The mean time until the onset of action is 3.1 months. AZA is effective in ulcerative colitis as a steroid-sparing agent. Side-effects occur in 10-15% of patients on AZA or 6-MP for IBD. MTX induces symptomatic remission in about 40% of patients with Crohn's disease. The potential for hepatic fibrosis from MTX is a concern. CYA appears effective in the acute management of severe ulcerative colitis. CYA has not proven useful in the long-term management of Crohn's disease. Potentially serious side-effects include hypertension and renal insufficiency. The cytokine antagonist, anti-tumor-necrosis-factor-alpha antibody, and the anti-inflammatory cytokine, interleukin 10, appear promising for the treatment of Crohn's disease.     

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.     

A role for TNF-alpha and mucosal T helper-1 cytokines in the pathogenesis of Crohn's disease

Recent clinical studies of Crohn's disease patients demonstrated dramatic clinical responses following one i.v. infusion of a chimeric mAb to TNF-alpha (cA2). To assess the role of TNF-alpha in mucosal cytokine regulation, the effects of TNF-alpha on lamina propria mononuclear cell (LPMC) Th1 production were determined. Increased IFN-gamma production was demonstrated in anti-CD2-stimulated LPMC cultured in TNF-alpha. To determine the effects of cA2 on cytokine production, TNF-alpha- and IFN-gamma-producing cells were quantitated in LPMC from five Crohn's disease patients treated with cA2. In all four patients who demonstrated clinical and endoscopic improvement, decreased numbers of LPMC producing IFN-gamma and TNF-alpha following CD2/CD28 activation paralleled improvement in disease activity over 8 wk. In one patient who did not improve, increased numbers of TNF-alpha- and IFN-gamma-secreting LPMC were observed. In three of four responding patients, CD2/CD28-activated PBMC demonstrated increased IFN-gamma production over 8 wk. These observations suggest that TNF-alpha may be a cofactor for mucosal Th1 responses, and improvement in clinical parameters and intestinal inflammation induced by cA2 in Crohn's disease may be mediated by down-regulation of mucosal Th1 cytokines.     

Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment

PURPOSE: To determine the toxicity, pharmacokinetics, response rate, and response duration of intravenous (i.v.) administration of recombinant, humanized anti-p185HER2 monoclonal antibody (rhuMAb HER2) plus cisplatin (CDDP) in a phase II, open-label, multicenter clinical trial for patients with HER2/neu-overexpressing metastatic breast cancer. PATIENTS AND METHODS: The study population consisted of extensively pretreated advanced breast cancer patients with HER2/neu overexpression and disease progression during standard chemotherapy. Patients received a loading dose of rhuMAb HER2 (250 mg i.v.) on day 0, followed by weekly doses of 100 mg i.v. for 9 weeks. Patients received CDDP (75 mg/m2) on days 1, 29, and 57. RESULTS: Of 37 patients assessable for response, nine (24.3%) achieved a PR, nine (24.3%) had a minor response or stable disease, and disease progression occurred in 19 (51.3%). The median response duration was 5.3 months (range, 1.6-18). Grade III or IV toxicity was observed in 22 of 39 patients (56%). The toxicity profile reflected that expected from CDDP alone with the most common toxicities being cytopenias (n = 10), nausea/vomiting (n = 9), and asthenia (n = 5). Mean pharmacokinetic parameters of rhuMAb HER2 were unaltered by coadministration of CDDP. CONCLUSION: The use of rhuMAb HER2 in combination with CDDP in patients with HER2/neu-overexpressing metastatic breast cancer results in objective clinical response rates higher than those reported previously for CDDP alone, or rhuMAb HER2 alone. In addition, the combination results in no apparent increase in toxicity. Finally, the pharmacology of rhuMAb HER2 was unaffected by coadministration with CDDP.     

Intravenous pulse cyclophosphamide in the treatment of interstitial lung disease due to collagen vascular diseases

OBJECTIVE: Substantial toxicity limits the use of daily oral cyclophosphamide (CYC) for the treatment of interstitial lung disease (ILD) due to collagen vascular diseases. We examined whether intravenous (i.v.) pulse CYC can be substituted for daily oral therapy. METHODS: Six patients with rapidly progressive ILD due to polymyositis, systemic sclerosis, systemic lupus erythematosus, or primary Sj?gren's syndrome received 6-9 cycles of i.v. pulse CYC (0.5 gm/m2 of body surface area), together with an initial course of 50 mg of prednisolone, which was tapered to a maintenance dosage of 5-7.5 mg/day, and their response was measured clinically, by high-resolution computed tomography (HRCT) and by assessment of the bronchoalveolar lavage (BAL) cell profile. RESULTS: All patients showed significant improvement in exercise tolerance and lung function. Elevated BAL neutrophils dropped substantially, whereas the response of BAL lymphocytes was inconsistent. Low-attenuation opacities in the HRCT regressed in 4 patients and remained unchanged in 2, but reticular infiltrates remained largely unaffected. Remission was maintained with hydroxychloroquine, azathioprine, or cyclosporin A. CONCLUSION: I.v. pulse CYC proved to be an effective and well-tolerated treatment in these patients. Since it appears to target mainly the inflammatory component of the disease, it should be reserved for progressive ILD featuring indices of high inflammatory activity.     

Mycophenolate mofetil, together with cyclosporin A, prevents anti-OKT3 antibody response in kidney transplant recipients

OKT3 monoclonal antibody, a murine IgG2a monoclonal antibody targeting the T cell CD3 antigen, elicits a neutralizing humoral response in 20 to 50% of kidney transplant recipients when the concomitant immunosuppression consists of CsA-Sandimmun (SAND) and azathioprine (AZA). In the present study, we investigated the impact of the newer agents, CsA-Neoral (NEO) and mycophenolate mofetil (MMF) on OKT3 sensitization. Sixty-two consecutive kidney transplant recipients received prophylactic OKT3 (5 mg/d) from days 0 to 13, together with steroids. Concomitant immunosuppression consisted of either AZA + SAND (n=20), AZA + NEO (n=31), or MMF + NEO (n=11). The following doses were used: AZA, 2 mg/kg per d from days 0 to 13, then 1 mg/kg per d; MMF, 2 g/d starting on day 1; and CsA, either SAND or NEO, 6 mg/kg per d from day 6. At least two serum samples per month were available during the initial 3 mo for each patient. IgG anti-OKT3 antibodies were first evaluated by enzyme-linked immunosorbent assay. Patients were considered sensitized if their serum scored positive at a dilution > or = 1/1000. Peak titers of IgG anti-OKT3 antibodies and the incidence of patients harboring neutralizing anti-idiotypic antibodies were also determined. A first reduction in OKT3 sensitization was seen in patients receiving Neoral instead of Sandimmun (AZA + SAND: 10 of 20 [50%] patients sensitized versus 6 of 31 [19%] in the AZA + NEO group; P=0.03). This was probably related to the achievement of higher mean CsA trough blood levels in the NEO group during the first month (253+/-44 versus 186+/-49 ng/ml in SAND patients). Peak antibody titers and the proportion of patients with anti-idiotypic antibodies were similar in the AZA + SAND and AZA + NEO groups. A further reduction in the sensitization rate was observed with the replacement of AZA by MMF (MMF + NEO: 0% sensitized patients; P=0.0013). It is concluded that the combination of CsA-Neoral and MMF efficiently prevents sensitization against OKT3.     

The sugar permeability test reflects disease activity in children and adolescents with inflammatory bowel disease

OBJECTIVES: To investigate the relationship of intestinal permeability in children and adolescents with inflammatory bowel disease (IBD) to disease activity, disease extent, and response to therapy. Study design: Patients with new and established diagnoses of IBD (12 Crohn's disease [CD] and 18 ulcerative colitis [UC]) were studied. Intestinal permeability was evaluated by measuring with high-performance liquid chromatography 5-hour urinary excretion ratio of lactulose/L-rhamnose (L/Rh). RESULTS: In 8 of 9 patients with active CD, the L/Rh ratio was higher than the reference range (0.006 to 0.074, n = 36). In inactive CD (n = 3) the L/Rh ratio was within the reference range. In 6 of 7 patients with active extensive UC, the L/Rh ratio was elevated. In inactive extensive UC (n = 6) the normal permeability ratio was shown. In both active CD and active extensive UC, the frequency of elevated intestinal permeability was significantly greater than values in both inactive forms. The permeability ratio was normal in 4 of 5 patients with active left-sided colitis. In 5 of 7 patients (3 CD, 4 UC), repeat permeability values entered the reference range after acute phase therapy. Two patients with persistently elevated intestinal permeability (1 CD, 1 UC) had a disease flare-up within 6 months. CONCLUSIONS: Intestinal permeability is a marker of disease activity in CD and extensive UC. Serial permeability test may be useful in monitoring disease activity.     

Safety of azathioprine and 6-mercaptopurine in pediatric patients with inflammatory bowel disease

BACKGROUND & AIMS: Azathioprine (AZA) and 6-mercaptopurine (6-MP) are used in pediatric patients with ulcerative colitis and Crohn's disease to reduce disease activity, maintain remission, prevent relapse, and lower corticosteroid dosage, but their long-term side effects remain to be studied. The aim of this study was to analyze the safety of AZA and 6-MP and steroid reduction in this age group. METHODS: The investigators' database identified 118 patients who received either drug; 23 were excluded (single visit, noncompliance, or therapy < 1 week), leaving 95 patients, with a mean (+/-SD) age of 14.2 +/- 4.4 years. Medical files were reviewed for adverse side effects: fever, pancreatitis, infections, gastrointestinal intolerance, aminotransferase level increase, leukopenia, and thrombocytopenia. Prednisone doses before and after immunomodulatory therapy were compared. RESULTS: AZA or 6-MP was tolerated in 51 of 95 patients (54%) without adverse reaction; 27 of 95 (28%) experienced side effects that responded to dose reduction (23 patients) or spontaneously (4 patients), most commonly increased aminotransferase level (13.7%). Cessation of therapy was needed in 17 of 95 patients (18%), including recurrent fever (4), pancreatitis (4), gastrointestinal intolerance (4), and recurrent infections (3). Mean prednisone dose decreased from 24.3 to 8.6 mg/day. CONCLUSIONS: AZA and 6-MP were well tolerated in 82% of patients; of these, prednisone reduction occurred in 87%. However, 18% required discontinuation because of hypersensitivity or infectious side effects.     

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.     

Influence of topically and systemically active steroids on circulating leukocytes in Crohn's disease

OBJECTIVE: Budesonide, although only topically active, is effective in the treatment of Crohn's disease. This study was performed to compare the clinical efficacies of budesonide and prednisolone in relation to the activation status of circulating leukocytes. METHODS: Twenty-four patients with active Crohn's disease were randomized to treatment with either budesonide or 6-methylprednisolone. Clinical response was monitored by the Crohn's disease activity index, C-reactive protein, and orosomucoid. Expression of CD25 and CD71 on T cells and CD64 on neutrophils was determined by flow cytometry. The release of TNF-alpha and IL-1beta by peripheral blood mononuclear cells was measured by ELISA. RESULTS: After 2 wk of treatment a clinical response was observed in both groups, but it was more accentuated in patients treated with prednisolone. At baseline an upregulation of CD71 and CD64, but not CD25, was found in active patients. Prednisolone significantly decreased the expression of CD64 and the release of TNF-alpha and IL-1beta, but did not alter the expression of CD25 and CD71. Budesonide treatment failed to exert any effect on circulating leukocytes. CONCLUSIONS: The inability of budesonide to downregulate activated circulating leukocytes may contribute to the somewhat lower clinical efficacy of this topical steroid in the treatment of active Crohn's disease.     

Percentage hypochromic red cells and the response to intravenous iron therapy in anaemic haemodialysis patients

INTRODUCTION: Iron deficiency is commonly encountered in haemodialysis (HD) patients and may be overcome by i.v. iron therapy. We have examined the percentage hypochromic red cells (%HRC) for predicting response to i.v. iron in subjects with a low serum ferritin. METHODS: Prospective study of i.v. iron saccharate (trivalent iron 200 mg/week for 8 weeks) in anaemic (Hb < 10 g/dl) HD patients with serum ferritin < 100 microg/l despite oral iron therapy. Response to i.v. iron was assessed by comparing Hb at 0 and 8 weeks according to %HRC at baseline (0-3%, 4-9%, > or = 10%). Results are mean+/-1 SD. RESULTS: For all subjects (n=82), Hb and ferritin increased between 0 and 8 weeks (8.9+/-1.0 to 10.1+/-1.4, P<0.0001; 55+/-24 to 288+/-126, P<0.0001). Patients were stratified into three groups according to %HRC at baseline (0-3%, 4-9%, > or = 10%). Hb increased significantly in all three groups. The mean increase in Hb was greater (0-3%, 0.6+/-1.2; 4-9%, 1.2+/-1.0; > or = 10%, 1.6+/-1.4; P=0.02) and the proportion of patients showing a > or = 1 g/dl increase in Hb was greater (0-3%, 27%; 4-9%, 57%; > or = 10%, 67%; P=0.02) in those with the largest %HRC pre-treatment. CONCLUSION: Intravenous iron therapy is effective in improving Hb in anaemic HD patients with a low ferritin. However, the magnitude of this response and the proportion of patients responding is related to the percentage hypochromic red cells prior to treatment.     

Risk indicators for inflammatory bowel disease

We investigated the association between different risk indicators and inflammatory bowel disease in a case-control study based on the population of Stockholm County during 1980-1984. Information on physical activity, oral contraceptives, some previous diseases and childhood characteristics was collected using a postal questionnaire for 152 cases of Crohn's disease, 145 cases of ulcerative colitis, and 305 controls. The relative risk (RR) of Crohn's disease was inversely related to regular physical activity and estimated at 0.6 (95% CI: 0.4-0.9) and 0.5 (95% CI: 0.3-0.9) for weekly and daily exercise, respectively. Having psoriasis prior to the inflammatory bowel disease was associated with an increased relative risk of Crohn's disease (RR = 2.9, 95% CI: 1.1-7.9). Use of oral contraceptives was associated with an increased RR of 1.7 for both Crohn's disease and ulcerative colitis. Crohn's disease confined to the colon and total ulcerative colitis at diagnosis were most strongly associated with oral contraceptives.     

Hepatitis G virus RNA and hepatitis G virus-E2 antibodies in Dutch hemophilia patients in relation to transfusion history

PURPOSE: Docetaxel is a highly active antineoplastic agent; however, grade IV leukopenia occurs in the large majority of patients treated with a dose of 100 mg/m2 every 3 weeks. Recent experience with weekly paclitaxel has demonstrated a bone marrow-sparing effect when a weekly administration schedule is used. We investigated a weekly schedule of docetaxel in an attempt to alter the toxicity profile and improve the therapeutic index. PATIENTS AND METHODS: Thirty-eight patients with advanced, refractory malignancy entered this phase I trial between October 1996 and June 1997. Docetaxel was administered weekly for 6 consecutive weeks, followed by 2 weeks without treatment. Sequential cohorts of patients were treated at the following dose levels: 20, 25, 30, 36, 43, and 52 mg/m2. Patients were reevaluated after one course (8 weeks); patients with objective response or stable disease continued treatment for a maximum of four courses or until disease progression. RESULTS: Thirty-five patients completed at least one course of therapy. Myelosuppression was not a dose-limiting toxicity (DLT) at any of the doses tested. Only five episodes of grade III leukopenia occurred (14% of patients, 2% of doses), and no grade IV leukopenia was produced. No grade III or IV thrombocytopenia or anemia was observed. Grade III fatigue and asthenia were observed in all three patients treated at 52 mg/m2/wk and in two of 10 at 43 mg/m2/wk. Other grade III toxicity included acral erythema (n = 1), neuropathy (n = 1), peripheral edema (n = 1), and diarrhea (n = 1). The DLTs of this docetaxel schedule are fatigue and asthenia. Although the maximum-tolerated dose by definition of this study was 43 mg/m2/wk, we selected 36 mg/m2/wk for ongoing phase II studies. CONCLUSION: The toxicity profile of docetaxel is markedly altered when the drug is administered by a weekly schedule. Myelosuppression is mild and uncommon. Fatigue and asthenia are the DLTs; other nonhematologic toxicities, which included peripheral edema and neuropathy, are uncommon, and the arthralgia/myalgia syndrome was not observed. Weekly administration of docetaxel may provide a better tolerated, efficacious use of this drug; further investigation of weekly docetaxel as a single agent and in combination regimens is warranted.     

Incidence of inflammatory bowel diseases in the department of Puy-de-D?me in 1993 and 1994. EPIMICI. Epidémiologie des Maladies Inflammatoires Cryptogenetiques de l'Intestin group

The aim of this prospective epidemiological study was to investigate the incidence of Inflammatory Bowel Disease in the Puy-de-D?me county using the same methodology as EPIMAD's registry. METHODS: From 01/01/93 to 31/12/94, each gastroenterologist (n = 22) collected patients consulting for the first time with clinical symptoms compatible with inflammatory bowel disease. Data were reported on a questionnaire by an interviewer practitioner. The final diagnosis of Crohn's disease and ulcerative colitis was made in a blind manner by two expert gastroenterologists and recorded according to the Calkin's criteria as definite, probable, or possible diagnosis, or unclassifiable chronic colitis or acute colitis. RESULTS: 167 new cases were identified: 112 (67.1%) inflammatory bowel disease for the combined group of definite and probable cases with 79 Crohn's disease (70.5%), 29 ulcerative colitis (25.9%) of which 11 ulcerative proctitis (37.9%), 4 unclassifiable chronic colitis (3.6%) and 55 acute colitis (32.9%). The crude and age-adjusted incidence (per 10(5)/year) was respectively 6.6 and 5.7 for Crohn's disease and 2.4 and 1.9 for ulcerative colitis. The highest age-specific incidence rate for Crohn's disease was between 40-49 years (14.1) and for ulcerative colitis between 80-89 years (6.8). The female/male ratio was 0.8 for Crohn's disease and 1.1 for ulcerative colitis. The median age at the time of diagnosis was 42.6 years for Crohn's disease and 35.3 years for ulcerative colitis. CONCLUSIONS: These preliminary findings revealed a high incidence of Crohn's disease and low of ulcerative colitis in this county. However, these results must be managed carefully because these data were recorded only on two years and the inflammatory bowel disease classified possible and acute colitis require a follow-up.     

Phase II trial of 96-hour paclitaxel plus oral estramustine phosphate in metastatic hormone-refractory prostate cancer

PURPOSE: To evaluate the antitumor activity of 96-hour paclitaxel and daily oral estramustine phosphate (EMP) in patients with metastatic hormone-refractory prostate cancer (HRPC). PATIENTS AND METHODS: Thirty-four patients with adenocarcinoma of the prostate that progressed after one or more hormonal therapies and a trial of antiandrogen withdrawal were enrolled onto this phase II trial. Patients received paclitaxel 120 mg/m2 by 96-hour intravenous (i.v.) infusion on days 1 through 4 of each 21-day cycle, together with daily oral EMP 600 mg/m2/d, continuously. RESULTS: Four of nine patients with measurable disease had objective responses (one complete response [CR] and three partial responses [PRs]) in liver (two patients) or nodes (two patients) of 2, 6, 8, and 20 months' duration. Of 25 assessable patients with metastases limited to bone, 14 had a > or = 50% decline in pretreatment prostate-specific antigen (PSA) level sustained for at least 6 weeks and seven had a > or = 80% decline. Overall, 17 of 32 patients (53.1%) with elevated pretreatment PSA levels had a > or = 50% decline of PSA and nine (28.1%) had a > or = 80% decrease. The main toxicities (> or = grade 2) were nausea, fluid retention, and fatigue, which occurred in 33%, 33%, and 24.2% of patients. Median time to progression, based on increasing PSA level and other clinical criteria, was 22.5 weeks. The estimated median overall survival time is 69 weeks. CONCLUSION: The combination of EMP and 96-hour paclitaxel is an active regimen for patients with HRPC. These results further support the therapeutic strategy of combining agents that impair microtubule function by complementary mechanisms.     

The role of Peyer's patches in the age-related incidence of Crohn's disease

Recently researchers have suggested that clinical subsets of Crohn's disease occur, which are variously described as inflammatory, fibrostenotic, and fistulizing. In addition, it has been observed that within families with multiple cases, often there is concordance of the site and type of disease. The lesions of Crohn's disease occur in segments that suggest that distribution of Peyer's patches. When the age-related incidence of Crohn's disease was plotted for all countries from which such data were available, the peaks of greatest case frequency occurred at ages 15 to 25 years and paralleled a similar peak representing the number of Peyer's patches as a function of age. This correlation suggests that Crohn's disease may develop as an inflammatory process specifically targeting these important lymphoid structures. Similar peaks of activity in the adolescent to early adult years occur for appendicitis and tonsillitis.     

A randomized, double-blind study of the effect of olestra on disease activity in patients with quiescent inflammatory bowel disease. Olestra in IBD Study Group

PURPOSE: To determine the effects of olestra, a zero-calorie fat substitute that is neither digested nor absorbed, on the well-being and disease state of persons with chronic inflammatory bowel disease (IBD) in remission. PATIENTS AND METHODS: Eighty-nine patients with mild to moderate ulcerative colitis (n = 43) or Crohn's disease (n = 46) in remission, with a history of disease of 2 years or longer, were enrolled in this prospective study from nine private practices, three university-based medical centers, and one Veterans Administration medical center in the United States. Forty-four patients were randomly assigned to receive olestra and 45 to receive triglycerides in chips or cookies daily for 4 weeks. At Week 4, patients were classified as in remission, worsened, or relapsed according to an investigator's global assessment based on sigmoidoscopy (for ulcerative colitis) or the Crohn's disease activity index, laboratory findings, and clinical course. RESULTS: At Week 4, the olestra and triglyceride groups did not differ significantly with respect to the percentages of patients who relapsed (P = 0.494; difference = 2.4%; upper 95% CL = 8.8%) or with respect to the percentages of patients who experienced any worsening of their symptoms (P = 0.630; difference = 0.2%; upper 95% CL = 13.3%). Of evaluable patients, 90% (37 of 41) given olestra remained in remission with no worsening, compared with 90% (38 of 42) given triglycerides. Gastrointestinal symptoms were comparable between the treatment groups, and there were no treatment-related laboratory abnormalities. Six patients were excluded from analysis for reasons unrelated to treatment. CONCLUSION: Olestra did not affect the activity of quiescent mild to moderate IBD.     

Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer

PURPOSE: To evaluate the efficacy and toxicity of paclitaxel administered as a 1-hour infusion on weekly basis, without interruption, to patients with metastatic breast cancer who had received prior therapy. PATIENTS AND METHODS: Thirty patients with metastatic breast cancer received sustained weekly paclitaxel therapy at an initial dose of 100 mg/m2 until disease progression. Prior therapy included adjuvant only (n=17), metastatic only (n=7), or both (n=6). Eighteen patients had received prior anthracycline therapy, 12 of whom had demonstrated progression of disease within 12 months of it. All patients were assessable for efficacy; 29 patients were assessable for toxicity. Pharmacokinetic studies of paclitaxel were also performed. RESULTS: A total of 469 weekly paclitaxel infusions were administered to 30 patients (median, 14 infusions/patient). The median delivered dose-intensity was 91 mg/m2/wk (range, 80 to 108). The overall response rate was 53% (95% confidence interval [CI], 34% to 72%), with 10% complete responses (CRs) and 43% partial responses (PRs). Median response duration was 7.5 months (range, 2 to 11+). Responses were observed in nine of 18 (50%) patients with prior anthracycline therapy, including six of 12 (50%) with disease progression on anthracycline within 1 year (three of four within 6 months). Therapy was well tolerated and remarkable for a lack of overall and cumulative myelosuppression. Grade 3/4 neutropenia occurred in four patients; febrile neutropenia was not observed. Peripheral neuropathy prohibited dose escalation above 100 mg/m2, and grade 3 neuropathy was observed in two of 21 patients at < or = 100 mg/m2. CONCLUSION: Weekly paclitaxel therapy is active and well tolerated in patients with metastatic breast cancer. Weekly therapy should be considered as a current clinical option for these patients and should be incorporated into future comparative clinical trials.     

Intravenous pulse administration of cyclophosphamide versus daily oral treatment in patients with antineutrophil cytoplasmic antibody-associated vasculitis and renal involvement: a prospective, randomized study

OBJECTIVE: There is growing concern about the toxic side effects of daily oral cyclophosphamide (CYC) treatment. Intravenous (i.v.) pulse administration of CYC has been shown to be effective in patients with systemic lupus erythematosus, but contradictory results have been reported in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. METHODS: The efficacy and toxicity of i.v. pulse administration of CYC (0.75 gm/m2) versus daily oral CYC treatment (2 mg/kg body weight) were investigated in a prospective, randomized, multicenter study in patients with ANCA-associated vasculitis and renal involvement. RESULTS: The cumulative CYC dose was reduced by 57% in patients with i.v. pulse treatment (n = 22) compared with patients treated with daily oral therapy (n = 25). Patient survival, remission rate, time of remission, relapse rate, and outcome of renal function were not different between the 2 treatment groups. However, the rate of leukopenia (P < 0.01) and severe infections (P < 0.05 by 1-tailed test) was significantly reduced in the i.v. pulse group compared with the group receiving daily oral treatment. Moreover, gonadal toxicity was reduced in the i.v. pulse group, as indicated by significantly lower levels of follicle-stimulating hormone. CONCLUSION: This randomized study shows that i.v. CYC administration is an effective therapeutic tool with low toxicity in patients with ANCA-associated vasculitis and renal involvement.     

Unexpected rhabdomyolysis with myoglobinuria in a patient in the supine position

BACKGROUND: The relapse rate after steroid induced remission in Crohn's disease is high. AIMS: To test whether oral pH modified release budesonide (3 x 1 mg/day) reduces the relapse rate and to identify patient subgroups with an increased risk of relapse. METHODS: In a multicentre, randomised, double blind study, 179 patients with steroid induced remission of Crohn's disease received either 3 x 1 mg budesonide (n = 84) or placebo (n = 95) for one year. The primary study aim was the maintenance of remission of Crohn's disease for one year. RESULTS: Patient characteristics at study entry were similar for both groups. The relapse rate was 67% (56/84) in the budesonide group and 65% (62/95) in the placebo group. The relapse curves in both groups were similar. The mean time to relapse was 93.5 days in the budesonide group and 67.0 days in the placebo group. No prognostic factors allowing prediction of an increased risk for relapse or definition of patient subgroups who derived benefit from low dose budesonide were found. Drug related side effects were mild and no different between the budesonide and the placebo group. CONCLUSION: Oral pH modified release budesonide at a dose of 3 x 1 mg/day is not effective for maintaining steroid induced remission in Crohn's disease.