Analysis of the therapeutic efficacy of different doses of budesonide in patients with active Crohn's ileocolitis depending on disease activity and localization.

BACKGROUND AND AIMS: The nonsystemic steroid budesonide has been used to treat active ileocecal and ileocolonic Crohn's disease (CD). This study investigated the optimal budesonide dose using a pH-dependent release formulation. The goal of treatment was the remission of CD (CDAI <150) within 6 weeks of treatment. PATIENTS AND METHODS: The study was of randomized, double-blind, dose-finding design. Patients with active CD ileocolitis without steroid pretreatment were treated with 3x2 mg ( n=39), 3x3 mg ( n=33), or 3x6 mg ( n=32) oral pH-modified released budesonide daily. RESULTS: The remission rates after 6 weeks were 36% with 3x2 mg, 55% with 3x3 mg, and 66% with 3x6 mg. Significantly more patients were in remission while treated with 3x6 mg than with 3x2 mg budesonide/day. Subgroup analyses revealed that patients with high disease activity (CDAI >/= 300) or ileocolonic disease with disease manifestation distal to the transverse colon responded better to the highest budesonide dose. CONCLUSION: Oral pH-modified released budesonide shows a dose-dependent effectiveness in patients with active ileocolonic CD. In the majority of patients 9 mg budesonide per day is sufficient. However, in patients with highly active disease or ileal disease with distal colonic manifestation higher doses of budesonide could increase the therapeutic response

Oral budesonide significantly improves water absorption in patients with ileostomy for Crohn disease.

BACKGROUND: In addition to their anti-inflammatory effects, steroids influence electrolyte and water transport systems in the intestinal mucosa. This study analysed the effect of the topically acting glucocorticoid budesonide on ileostomy output in patients with Crohn disease. METHODS: Oral budesonide (3 mg/three times daily for 8 days; n = 20) was compared to placebo (n = 20) in a double-blind design using matched-pair randomization according to ileal resection length in patients without detectable inflammatory activity. Under controlled hospital conditions, absolute output volumes were measured and response was defined as a reduction in intestinal output of > 25% compared to pretreatment conditions. RESULTS: In the treatment group, we observed an absolute decrease in median intestinal output from 1,240 ml to 865 ml (30.2%), compared to 0.3% under placebo (from 950 ml to 947.5 ml). Response was documented in 60% (12/20 patients) in the treatment group compared to no response under placebo (P < 0.0001). While both treatment groups showed similar absolute median reductions (400 ml with ileal resection < or = 20 cm and 405 ml with ileal resection > 20 cm), the relative reduction (response rate) was lower in the subgroup of an ileal resection > 20 cm (36%) due to the greater increase in output secondary to the loss of ileum. CONCLUSIONS: These data support the assumption that the absorptive capacity of the intestinal mucosa for water may be improved by topically acting steroids and suggest that this occurs independently of their anti-inflammatory effect.

Replacement of conventional glucocorticoids by oral pH-modified release budesonide in active and inactive Crohn's disease: results of an open, prospective, multicenter trial.

Glucocorticosteroids (GCS) are established in the treatment of active Crohn's ileitis and ileocolitis. Recently, the topical steroid budesonide was found to be effective in untreated patients with Crohn's disease (CD) causing less side effects than conventional GCS. No clinical data have been reported about the effects of switching from conventional GCS to budesonide in terms of side effects and disease activity. The primary aim of this study was to evaluate the development of side effects after switching from conventional GCS treatment to Eudragit L-coated budesonide (pH-modified release formulation) in patients taking 5-30 mg prednisolone equivalent per day for at least two weeks. In all, 178 patients with active CD (N = 88) or CD in remission during GCS treatment (N = 90) were included. Conventional GCS treatment was tapered down during a maximum of three weeks, with simultaneous intake of 3 x 3 mg budesonide. Thereafter, patients received 3 x 3 mg budesonide alone for six weeks. GCS-related side effects, disease activity and adverse events were documented at study entry and after 0, 2, 4, and 6 weeks of budesonide treatment. The percentage of patients with GCS-related side effects decreased from 65.2% (intention-to-treat-population) at entry to 43.3% (P < 0.0001) at the end of the trial. The total number of GCS-related side effects decreased significantly from 269 to 90. Of the patients who entered the study with active disease under conventional GCS therapy, 38.6% were in remission at the end of the study. Of the patients who entered the study with CD in remission, 78% stayed in remission after switching from conventinal GCS to budesonide. In conclusion, switching from conventional GCS treatment to budesonide leads to a significant reduction of GCS related side effects in patients with CD without causing rapid deterioration of the disease.

Association of HLA-DR genotypes and IL-1ra gene polymorphism with treatment failure of budesonide and disease patterns in Crohn's disease.

OBJECTIVE: Associations between HLA-DR genotypes and susceptibility to Crohn's disease (CD) have been reported. However, it is not known whether certain HLA-DR genotypes or IL-1ra gene polymorphism are associated with responsiveness to treatment or different clinical patterns of disease. DESIGN/SETTING: In a large, randomized, controlled multicentre trial, 318 patients with CD were treated with daily doses of 6, 9 or 18 mg budesonide. Patients were stratified into two groups: patients without steroid pretreatment and with active CD (CDAI > 150) and patients with conventional steroid pretreatment of < or= 30 mg prednisolone per day, which was replaced by oral budesonide within 3 weeks. MAIN OUTCOME MEASURES: The HLA-DRB1 genotypes 1-16 and the IL-1ra gene polymorphism were examined for an association with budesonide treatment failure. RESULTS: Only HLA-DR 8 was associated with treatment failure of budesonide. HLA-DR 8 is not very common. Only 17/243 patients who could be evaluated expressed this genotype, and 13 of these 17 patients did not respond to budesonide (P < 0.00067). Neither the other HLA-DR genotypes nor the IL-1ra gene polymorphism had an influence on treatment outcome of budesonide therapy. No significant association of fistulas, perianal disease, need for bowel resections, and disease localization with certain HLA-DRB1 genotypes or the IL-1ra gene polymorphism were found. CONCLUSIONS: This is the first description of an association of a certain HLA-DR genotype (HLA-DR 8) with treatment failure in inflammatory bowel disease (IBD).

Reoperations at the ileostomy in Crohn's disease reflect inflammatory activity rather than surgical stoma complications alone.

After ileostomy construction for Crohn's disease reoperations due to ileal recurrences are thought to be unusually rare, whereas reconstructions of the ileostomy due to stoma complications are considered to be unusually frequent. It remains unclear why the natural course of a disease as well as outstanding results of a standardized surgical procedure should be perverted. Therefore reconstructions of the ileostomy in 92 patients colectomized during a 12.5-year period and followed up for 5.4 years were analyzed concerning preoperative indication and postoperative histology. In 28 patients (30.4%) a total of 42 reoperations were necessary. The clinical indication was prestomal recurrence in 5 reoperations (11.9%) and stoma complications in 37 (88.1%). In contrast, ileal recurrence was demonstrated histologically in 28 specimens (66.7%) and healthy ileum in the rest. There was a statistically significant association between fibrotic recurrence and stoma stenosis/retraction and a trend for association between penetrating recurrence and peristomal ulceration. The cumulative risk for a first reoperation due to clinical recurrence was calculated at 3.3% and 14.0% at 5 and 10 years postoperatively, whereas the corresponding figures for stoma complications were 25.7% and 40.0%. In contrast, the cumulative risk that a recurrence was found histologically on the occasion of the reoperation was 23.0% and 35.0%, while the probability that the ileum was healthy in the case of a stoma complication remained low. In conclusion, most reoperations after ileostomy-construction in Crohn's disease are associated histologically with recurrent inflammation. The accentuation of the inflammatory recrudescence at the stoma itself or the prestomal ileum is decisive for the clinical presentation as stoma complication or intestinal complication. These findings reinforce both well known characteristics of the inflammatory disease and of established surgery.

Low dose oral pH modified release budesonide for maintenance of steroid induced remission in Crohn's disease. The Budesonide Study Group.

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.

Double-blind, placebo-controlled safety and efficacy trial with yohimbine hydrochloride in the treatment of nonorganic erectile dysfunction.

This double-blind, placebo-controlled clinical trial of yohimbine hydrochloride included 86 patients with erectile dysfunction and without clearly detectable organic or psychologic causes. The patient group fulfilled all entry criteria; 85 of these could be considered for the Safety-respectively 83 for the Intention-to-treat (ITT)-analysis. Yohimbine was administered orally in a dosage of 30 mg a day (two 5 mg tablets three times daily) for eight weeks. Patients were seen for follow-up after four weeks' treatment, and for a final visit after eight weeks. Efficacy evaluation was based on both subjective and objective criteria. Subjective criteria included improvement in sexual desire, sexual satisfaction, frequency of sexual contacts, and quality of erection (penile rigidity) during sexual contact/intercourse. Objective criteria of outcome were based on improvement in penile rigidity determined by use of polysomnography in the sleep laboratory. Overall Yohimbine was found significantly more effective than placebo in terms of response rate: 71 vs 45%. Yohimbine was well-tolerated: Only 7% of patients rated tolerability fair or poor, and most adverse experiences were mild. There was no serious adverse event.

Treatment of active and postactive ileal and colonic Crohn's disease with oral pH-modified-release budesonide. German Budesonide Study Group.

BACKGROUND/AIMS: Budesonide is a glucocorticoid with a high topical anti-inflammatory but low systemic activity due to its rapid hepatic inactivation. The aim of this open, multicenter study was to investigate efficacy and safety of oral pH-modified-release budesonide in patients with active Crohn's disease of the ileum and colon and in maintaining budesonide-induced remission in postactive Crohn's disease. MATERIALS AND METHODS: 81 patients (intention-to-treat) received 3 x 3 mg budesonide/day for 6 weeks, followed by 3 x 2 mg budesonide for another 6 weeks in case of response to initial treatment. Clinical and laboratory parameters were assessed at study entry as well as after 2, 4, 6 and 12 weeks of treatment. RESULTS: On an intention-to-treat basis remission was induced in 54.3% of 81 patients with active Crohn's disease, 71.4% of 35 patients stayed in remission after the acute-phase treatment until the end of the trial. Typical steroid-related side effects were observed during the acute-phase treatment in only 18% of the patients. Duration, severity and extent of disease at study entry played no significant role in the outcome of the trial, but there was a tendency towards better results during the acute-phase treatment in patients with moderate disease activity and affection of the terminal ileum and proximal colon. CONCLUSIONS: Budesonide could be an alternative to conventional steroid treatment in patients with active Crohn's disease.

Oral pH-modified release budesonide versus 6-methylprednisolone in active Crohn's disease. German/Austrian Budesonide Study Group.

OBJECTIVE: Corticosteroids are effective in acute Crohn's disease (CD). The present study assessed the effectiveness and safety of oral pH-modified release budesonide (BUD) in patients with active CD in comparison with 6-methylprednisolone (MPred). DESIGN: This was a prospective multicentre, randomized, double-blind, double-dummy study. METHODS: A total of 67 patients with active CD (CDAI > 150) were included. Patients were treated with 3 x 3 mg BUD (n = 34) or MPred (n = 33) according to a weekly tapering schedule (48-32-24-20-16-12-8 mg). The primary aim was remission of CD (CDAI < 150 and decrease by at least 60 points from baseline) after eight weeks. RESULTS: Baseline demographics, disease activity and localization of CD in the small bowel and the colon were similar in both treatment groups. On an intention-to-treat basis 19/34 patients in the BUD group (55.9%) and 24/33 patients in the MPred group (72.7%) were in remission after eight weeks (P = 0.237). Therapy failed in 15/34 patients (44.1%) of the BUD group and in 9/33 patients (27.3%) of the MPred group. The mean CDAI decreased from 262 +/- 50 to 118 +/- 69 in the BUD-group and from 262 +/- 81 to 95 +/- 61 in the Mored group (P = 0.183, final CDAI BUD vs. MPred). Steroid-related side effects appeared in 28.6% of the patients in the BUD group and in 69.7% of the patients in the Mored group (P = 0.0015). CONCLUSIONS: Oral pH-modified release budesonide (3 x 3 mg/day) is almost as effective as a conventional corticosteroid in patients with active CD but causes significantly less corticosteroid-related side effects.

Comparison between high dose 5-aminosalicylic acid and 6-methylprednisolone in active Crohn's ileocolitis. A multicenter randomized double-blind study. German 5-ASA Study Group.

BACKGROUND: The value of 5-aminosalicylic acid (5-ASA) in Crohn's disease (CD) is still under discussion. In a previous study 2 g 5-ASA per day were inferior to a standard glucocorticoid treatment with 6-methylprednisolone (6-MPred) (Can J Gastroenterol 1990; 4: 446-51). In the present study we tested whether in active CD response rates to 4.5 g 5-ASA/day were not different from those to 6-MPred. METHODS: Multicenter randomized double-blind double-dummy trial. 34 patients with active CD (CDAI > 150) were included. 17 patients were in the 5-ASA group (Salofalk, 4.5 g/day), 17 patients in the 6-MPred group (Urbason, initial dose 48 mg/day, weekly tapering). Duration of treatment was 8 weeks. Main outcome measure was remission of CD (CDAI < 150) and decrease of at least 60 points. RESULTS: Both groups were comparable with respect to demographic and clinical parameters. The median CDAI decrease in the 5-ASA group was 85, in the 6-MPred group 122 (p = 0.7437). The median AUC of the CDAI in the 5-ASA group was 1027, in the 6-MPred group 950 (p = 0.137). The median AUC of the CDAI per treatment day was 22.94 in the 5-ASA group, and 17.33 in the 6-MPred group (p = 0.0555). On an intention-to-treat basis remission rates after 8 weeks were 40.0% in the 5-ASA group and 56.3% in the 6-MPred group (p = 0.5867). CONCLUSIONS: Response rates to 5-ASA or 6-MPred were not significantly different although there was a trend towards a higher efficacy of 6-MPred. 5-ASA may be considered as alternative treatment in patients with activer CD who are intolerant to or refuse glucocorticoids.

Treatment of active Crohn's ileocolitis with oral pH-modified budesonide. Germany Budesonide Study Group.

Budesonide is a topical steroid which after intestinal absorption is rapidly degraded into inactive metabolites in the liver. Its systemic bioavailability is only 10-15%. In the present open trial the efficiency and safety of oral pH-modified release budesonide were assessed in patients with active Crohn's ileocolitis. This report describes the results of the first 30 of 78 patients. After 6 weeks of treatment with 3 x 3 mg budesonide/day 67% of the patients were in clinical remission. Typical steroid-related side effects were observed in only one patient. Budesonide therefore seems to be suited as an alternative for classical steroids in patients with Crohn's ileocolitis. Its clinical efficacy is comparable with classical steroids but it's rate of steroid-related side effects is lower.

Concentration/effect relationship and enantioselective analysis of verapamil in hypertensive patients.

The concentration/effect relationship of verapamil was analyzed in 9 hypertensive patients using concentrations of racemic verapamil and the corresponding decrease in mean arterial blood pressure (MBP) in a sigmoidal Emax model. Concentration/effect data were obtained after a first dose (240 mg sustained release preparation) and at steady state after stepwise dose adjustment to obtain satisfactory BP control (less than 90/150 mm Hg). Emax (MBP) ranged from 15 to 40 mm Hg, and EC50 averaged 81 +/- 40 ng/ml (mean +/- SD). The fraction of S-verapamil in the overall racemic verapamil concentrations was measured in two patients by chiral high-performance liquid chromatography (HPLC) and showed a slight increase at steady state from 12.2 +/- 1.5 to 14.4 +/- 1.4% and from 14.0 +/- 1.3 to 16.3 +/- 0.6%. Concentration/effect curves for S-verapamil concentrations were similar to those obtained with racemic verapamil concentrations.

Analgesic potency of a new anticonvulsant drug versus acetylsalicylic acid via laser somatosensory evoked potentials. Randomized placebo-controlled double-blind (5-way) crossover study.

A randomized, double-blind crossover study was performed with three different acute oral dosages of CM 40907 (3-(4-hydroxypiperidyl)-6-(2'-chlorophenyl)-pyridazine) (600, 900 and 1200 mg), a newly developed anticonvulsant drug, vs acetylsalicylic acid (ASA, 1000 mg) and placebo in 12 male healthy volunteers to check analgesic potency. Objective algesimetry was done by Laser Somatosensory Evoked Potentials (LSEP). Subjective pain intensities were measured by retrospective visual analog scale ratings (VAS). Effects on objective vigilance were checked by Auditory Evoked Potentials (AEP). For both types of evoked potentials there was a simultaneous control of alterations in vigilance by means of the adaptive pursuit tracking task (APTT). A vigilance-controlled EEG (V-EEG) and a resting (R-EEG), visual analog scales (VAS) on sedation, excitation and anxiety as well as vital parameters (blood pressure and heart rate under supine and upright conditions) and adverse event scales were included in this trial as well. CM 40907 showed distinct analgesic effects on objective and subjective algesimetric parameters, which for the highest dosage (1200 mg) were superior in ("central") P2-amplitude suppression of LSEPs to those of ASA in ("peripheral") N1-amplitudes suppression and ongoing for more than 6 h. Subjective sedation was decreased, however, AEP-findings indicated a decreased vigilance after CM 40907. Some EEG-patterns, specifically related with CM 40907--although being ambiguous in classification terms--resembled features of benzodiazepines. Blood pressure and heart rate were raised in a clinically irrelevant manner.

[Bioequivalence of non-retard verapamil. Realization of a draft monograph exemplified by Veramex 80]. / Untersuchung zur Bioäquivalenz von nichtretardiertem Verapamil. Umsetzung eines Monographieentwurfs am Beispiel Veramex 80.

The commercial preparation Veramex 80, containing 80 mg non-retarded Verapamil, was compared to the appropriate product being first on the market and containing the same amount of active substance according to the AMG 1976. This study was a randomized single-dose trial with a double cross-over-design and a one-week wash-out phase between the individual test periods. Equivalence of the most relevant pharmacokinetic parameters was checked in 18 volunteers according to the latest recommendations and regulations of the Zentrallaboratorium Deutscher Apotheker (ZL) and the APV-guidelines. The mean AUC (0-24) after application of Veramex 80, calculated with 217.2 micrograms X h/l +/- 65.6, was approximately 10% less than the mean AUC (0-24) after application of the reference substance, which reached 240.4 micrograms X h/l +/- 87.0. The difference was statistically not significant and the 90%-confidence interval could be estimated with 0.82 to 1.01 which is in accordance with the postulated limits (0.8 to 1.2). After application of the reference drug the mean maximal concentration (cmax) of Verapamil was 58.1 micrograms/l and thus approximately 10% higher than the appropriate value detected after application of Veramex 80, which was 51.8 micrograms/l. Again, this difference was statistically not significant and the 90%-confidence interval, calculated with 0.76 to 1.05, was located within the postulated limits (0.7 to 1.3). Mean value, median and the range for tmax after application of Veramex 80 resp. reference substance were comparable and differences were less than 30 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)

[Synovial tissue levels in comparison with synovial fluid and serum concentrations following a single daily administration of 20 mg piroxicam (Felden)]. / Synovialgewebsspiegel im Vergleich zu Synovia- und Serumkonzentrationen nach täglicher Einmalgabe von 20 mg Piroxicam (Felden).

Serum, synovial fluid and synovial tissue was taken from a total of 25 patients of both sexes on whom a synovectomy had been performed, after a 1, 3, 5, 6 or 7 day treatment with a daily administration of 20 mg Piroxicam (5 patients in each group) and the concentration of Piroxicam (Felden) determined. Parallel to this a part of the synovial tissue taken was histologically examined and classified. The analytical results presented here show that in the mean appr. 33% of the Piroxicam passed from the serum into the synovia, appr. 26% into the non or partially florid synovial tissue and appr. 32% into the florid or highly florid synovial tissue. Felden 20 (Piroxicam) thus fulfills the requirement of a good acting, non-steroidal, antiinflammatory substance (NSAID), namely of being available at the location of the inflammatory process.

Influence of immunosuppressive treatment of Borna Disease in rabbits.

A total of 72 Borna Disease virus infected rabbits were treated with different concentrations of cyclophosphamide, glucocorticoids or both in combination. Comparison with untreated, infected rabbits showed a drastic alteration in the clinical picture, a considerable prolongation of the survival time, and differences in weight and body temperature during the course of the disease. The immunosuppressed animals had no or low amounts of antibodies in the serum and cerebrospinal fluid, but they harbored infectious virus and high amounts of specific antigen in the brain. A quotient of the relative amount of antibodies and antigen never exceeded 0.20 and was significantly lower than in untreated rabbits. Immunohistologically, differences in location and distribution of antigen as compared to positive untreated animals could not be detected. In the immunosuppressed animals perivascular infiltrates were not observed in the different regions of the brain.