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Effect of food on budesonide pharmacokinetics in patients with active Crohn's disease
GASTROENTEROLOGY Vol. 114, No. 4
A1048 AGA ABSTRACTS • G4286
EFFECT OF FOOD ON BUDESONIDE PHARMACOKINETICS IN PATIENTS WITH ACTIVE CROHN'S DISEASE. T.H.J. Naber, J.B.M.J. Jansen, University Hospital, Nijmegen, The Netherlands; S.Cvetkovic; S.Edsb~icker, T. Persson, Astra Draco AB, Lund, Sweden. Budesonide Controlled Ileal Release (CIR) capsules (Entocort ®) were developed for the treatment of Crohn's disease of the ileum and proximal colon. Previous pharmacokinetic studies in patients with active Crohn's disease raised the question whether food affects budesonide's first pass metabolism and the purpose of this study was to further evaluate the pharmacokinetics of budesonide. Method: Eight patients (4 women) with active Crohn's disease (defined as Harvey-Bradshow Index score > 6) localised in the ileum or ileocaecal region and/or ascending colon participated in this open, crossover and randomised study. Each patient was given 9 mg budesonide CIR and 0.5 mg deuterium labelled (Ds) budesonide intravenously at 8 a.m., after overnight fasting, on two separate occasions: one during continuous fasting until noon, one immediately after a heavy breakfast. Plasma concentrations of budesonide and D8-budesonide were followed for 12 hours after administration. The two treatment periods were compared by two-way analysis of variance. Results: The absorption of budesonide given after a heavy breakfast was delayed compared with the administration in a fasting state; Traax was 6.2 hrs (95% CI 5.3 to 7.2 hrs) after a heavy breakfast and 3.8 hrs (95% CI 2.8 to 4.7 hrs) in a fasting state; p=0.005. Mean Cnaax was, however, similar on both treatment occasions (4.5 nmol/L (95% CI 3.3 to 5.7 nmol/L) after a heavy breakfast and 5.0 nmol/L (95% CI 3.8 to 6.1 nmol/L) in a fasting state). There was no statistically significant difference in bioavailability, 12% (95% CI 8 to 16%) in a fasting state vs. 15% (95% CI 11 to 20%) after a heavy breakfast (p=0.20). In addition, the intravenous kinetics did not differ between the two occasions. Conclusion: No statistically significant differences were found in systemic availability or Cmax of budesonide taken as CIR capsules after a heavy breakfast or on an empty stomach. However, absorption was delayed after food intake, probably due to delayed gastric emptying. This research was funded by Astra Draco AB, Land, Sweden. G4287
CHRONIC STRESS ATTENUATE A HEALING OF EXPERIMENTAL COLITIS IN RATS. H. Nagase, M. Sugisawa, A. Kokawa, T. Saitoh, S. Tominaga, H. Sekihara. Third Department of Internal Medicine, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan. Worsening of inflammatory bowel disease(IBD) due to some mental and physical stress is clinically often seen. However, there is little study about the mechanism of activating IBD caused by stress. In this study, we examined the effects of chronic mild stress on the experimental colitis induced by the intracolonic administration of trinitro benzene sulfonic acid(TNBS) in rats. Methods: Twelve weeks old male Sprague-Dawley rats were used in this study. Rats were divided into two groups. TNBS(300mg/kg) dissolved in 30% ethanol was injected into the colon in one group. Control group received saline intracolonically. In each group, half of rats suffered by mild stress were housed under 24hrs continuous lighting. Another half were housed under 12-12h light dark cycle. Fourteen days later, rats were sacrificed and the entire colon was excised. After measuring a wet weight and the area of ulcer, myeloperoxidase activity in the colonic tissue and histology were determined. Results: TNBS treated groups showed a higher colonic wet weight and MPO activity than control groups. In TNBS treated groups, chronic stress increased a colonic wet weight and MPO activity and exaggerated a neutrophil infiltration compared to non-stress group. Only in a TNBS treated group with chronic stress, colonic ulcer was observed. Conclusion: Although stress itself did not induce a colonic ulceration, stress attenuated a healing of TNBS-induced colitis in rats. Neutrophil infiltration should precipitate an attenuation of healing colitis by stress. G4288
VALIDITY OF THE COLONOSCOPY IN THE ASSESSMENT OF SEVERITY OF COLONIC CROHN'S DISEASE ATTACKS: CONFRONTATION WITH THE ANATOMICAL FINDINGS OF COLECTOMY SPECIMENS. S_, Nahon(1), Y. Bouhnik (1), A. LavergneSlove (2), A. Bitoun (1), Y, Panis (3), P. Valleur (3), C. Matuchansky (1), J.C. Rambaud (1). 1) Service de Gastroent~rologie, H6pital Saint Lazare, 2) Laboratoire d'Anatomie Pathologique, 3) Service de Chirurgie Vise&ale, H6pital Lariboisi~re, 75010 Pads, France. No clinico-biological and/or morphological severity criteria has been validated in the assessment of colonic Crohn's disease (CCD) attacks. The aim of this study was to evaluate the accuracy of the colonoscopy in the gravity diagnosis of CCD. Method: Colectomy specimens from 78 consecutive patients operated between 1982 and 1996 for CCD resistant to the medical treatment have been reviewed. Endoscopic criteria of gravity (ECG) were defined as following: a) deep ulcerations involving the circular muscle coat (El), b) deep ulcerations not extended into the circular muscle coat but covering more than 33% of the mucosal area of at least one colonic segment (E2) and c) mucosal detachment on the edge of ulcerations (E3). Pathological examination of colectomy specimens permitted to classify patients in 3 grades
among Buckell's classification defined for ulcerative colitis (Gastroenterology 1980; 79:19-25): Grade A, ulcerations confined to the mucosa; Grade B, extensive deep ulcerations confined to the submucosa; Grade C, deep ulcerations involving the circular muscle coat. Results: ECG E1 and/or E2+E3, ECG E2 and no ECG were found in 68, 2 and 8 patients, respectively. Anatomical grades A, B and C colitis were found in 10, 13 and 55 patients, respectively. Positive predictive value of ECGs El, E2 and E3 were 90, 98 and 92%, respectively. Negative predictive value of ECGs El, E2 and E3 were 28, 72 and 17%, respectively. The depth and the extent of ulcerations noted using colonoscopy were correlated to the results of pathological examination of colectomy specimens (r=0.69 and r=0.68, P<0,001 respectively). Taking into account only anatomical grades B and C colitis, 88% of ECGs have been disclosed below the splenic flexure. No complications related to colonoscopy were noted. Clinical and biological severity criteria were similar in the 3 anatomical groups (A, B and C). Conclusion: The colonoscopy, unless performed by senior endoscopist, is a safe and useful tool to appreciate the anatomical gravity of CCD lesions in colectomized patients, with a high positive but poor negative predictive values to detect ECG. Moreover, usual anatomical classification of lesions that take currently into account only the depth of lesions should also consider their extent in relation to the fact that patients with ECG classified E1 or E2+E3 share clinical and evolutionary similar criteria who led to perform a colectomy. G4289
THE EFFECT OF AMINOGUANIDINE, AN INOS-SELECTIVE NOs INHIBITOR, ON TNB COLITIS. H. Nakamura, H. Tsukada, M. Onomura, T. Saito, K. Fukuda, M. Kodama, M. Hosokawa, Y.Seino. The Department of Metabolism and Clinical Nutrition, Kyoto University, Kyoto 606-01 Japan. Nitric oxide (NO) derived from inducible NO synthase (iNOs) plays an important role in the pathogenesis of inflammatory bowel disease (IBD). Aminoguanidine (AG), an selective iNOs inhibitor, might be a new medicine for IBD. To determine the most effective of aminoguanidine, we studied the preventive effect of AG on TNB colitis. Materials and Methods: Male Wister rats, weighing 250g, divided into five groups. The rats of each groups were administrated 0.15uM/kg, 1.5uM/kg, 15uM/kg, 150uM/kg of AG and distill water as a control every day. Three days after the administration of these medicines, the rats were induced with colitis by the administration of 0.25 ml of 10 mg TNB / 50 % ethanol. Seven days after the induction of TNB colitis, all rats were killed and assessed the effect of aminoguanidine using macroscopic damage score (max=10), ulcer area(era2), MPO activities (units / g tissue). Results ulcer area i dose n i damage score i i 4.12 ± 1.84 i 7.5 ± 0.4 control 5 i 1.37+-0.47" i 2.2+_0.5** 0.15uM 5 ! i 0.97±0.48** i 1.6 +_0.5** 1.5uM 5 i i 0.99+-0.77"* i 2.6 ± 1.0"* 15uM 5 i i 2.37 ± 1.06 i 6.4 ± 0.7 150uM 5 i mean _+S.E.M) (compared with Control*: p<0.05,**:p<0.01)
MPO activity 59.84 ± 10.37 44.25±11.46 31.17±6.98" 42.73±2.16 89.20 ± 13.02
The 1.5 uM/kg of AG had the most preventive effect on the damage of TNB colitis. The 150 ug/kg of AG exacerbate the damage compared with 1.5 uM/kg of AG. Contusions: The proper inhibition of iNOs by aminoguanidine prevented the damage of TNB colitis. • G4290
THE EFFECT OF NOsINHIBITORS ON THE TNB COLITIS: A COMPARATIVE STUDY. H. Nakamura, H. Tsukada, M. Onomura, T. Saito, K. Fukuda, M. Kodama, M. Hosokawa, Y.Seino. The Department of Metabolism and Clinical Nutrition, Kyoto University, Kyoto 606-01 Japan. Amount of nitric oxide (NO), generated by NO synthase(NOs), is involved with the pathogenesis of inflammatory bowel disease. The inhibition of NO generation has been considered to be one of the new methods to repair the inflammation with IBD. We determined which NOs inhibitor prevent the damage of Trinitrobenzene sulfonic acid (TNB)-induced colitis using three kind of NOs inhibitors; aminoguanidine (AG), S-ethylthiourea (EIT) and N~-nitro-L-arginine methyl ester (L-NAME). Materials and Methods: Forty male Wister rats, weighing 250g, were divided into 4 groups and administrated AG (15uM/kg), EIT(M/kg), L-NAME (15uM/kg) every day. Three days after the administration, rats were induced with TNB colitis by the administration of 0.25 ml of 10 mg TNB / 50% ethanol with catheter (1.5 mm in diameter) 7 cm proximal to the anus. Three days after the induction of the colitis, five rats of each group were killed and NOs activity (nmol / rain / g tissue) measured. Seven days after, five rats of each group were killed and macroscopic damage score (max=10), ulcer area (cm2) and MPO activity (units / g tissue) measured.
A1048 AGA ABSTRACTS • G4286
EFFECT OF FOOD ON BUDESONIDE PHARMACOKINETICS IN PATIENTS WITH ACTIVE CROHN'S DISEASE. T.H.J. Naber, J.B.M.J. Jansen, University Hospital, Nijmegen, The Netherlands; S.Cvetkovic; S.Edsb~icker, T. Persson, Astra Draco AB, Lund, Sweden. Budesonide Controlled Ileal Release (CIR) capsules (Entocort ®) were developed for the treatment of Crohn's disease of the ileum and proximal colon. Previous pharmacokinetic studies in patients with active Crohn's disease raised the question whether food affects budesonide's first pass metabolism and the purpose of this study was to further evaluate the pharmacokinetics of budesonide. Method: Eight patients (4 women) with active Crohn's disease (defined as Harvey-Bradshow Index score > 6) localised in the ileum or ileocaecal region and/or ascending colon participated in this open, crossover and randomised study. Each patient was given 9 mg budesonide CIR and 0.5 mg deuterium labelled (Ds) budesonide intravenously at 8 a.m., after overnight fasting, on two separate occasions: one during continuous fasting until noon, one immediately after a heavy breakfast. Plasma concentrations of budesonide and D8-budesonide were followed for 12 hours after administration. The two treatment periods were compared by two-way analysis of variance. Results: The absorption of budesonide given after a heavy breakfast was delayed compared with the administration in a fasting state; Traax was 6.2 hrs (95% CI 5.3 to 7.2 hrs) after a heavy breakfast and 3.8 hrs (95% CI 2.8 to 4.7 hrs) in a fasting state; p=0.005. Mean Cnaax was, however, similar on both treatment occasions (4.5 nmol/L (95% CI 3.3 to 5.7 nmol/L) after a heavy breakfast and 5.0 nmol/L (95% CI 3.8 to 6.1 nmol/L) in a fasting state). There was no statistically significant difference in bioavailability, 12% (95% CI 8 to 16%) in a fasting state vs. 15% (95% CI 11 to 20%) after a heavy breakfast (p=0.20). In addition, the intravenous kinetics did not differ between the two occasions. Conclusion: No statistically significant differences were found in systemic availability or Cmax of budesonide taken as CIR capsules after a heavy breakfast or on an empty stomach. However, absorption was delayed after food intake, probably due to delayed gastric emptying. This research was funded by Astra Draco AB, Land, Sweden. G4287
CHRONIC STRESS ATTENUATE A HEALING OF EXPERIMENTAL COLITIS IN RATS. H. Nagase, M. Sugisawa, A. Kokawa, T. Saitoh, S. Tominaga, H. Sekihara. Third Department of Internal Medicine, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan. Worsening of inflammatory bowel disease(IBD) due to some mental and physical stress is clinically often seen. However, there is little study about the mechanism of activating IBD caused by stress. In this study, we examined the effects of chronic mild stress on the experimental colitis induced by the intracolonic administration of trinitro benzene sulfonic acid(TNBS) in rats. Methods: Twelve weeks old male Sprague-Dawley rats were used in this study. Rats were divided into two groups. TNBS(300mg/kg) dissolved in 30% ethanol was injected into the colon in one group. Control group received saline intracolonically. In each group, half of rats suffered by mild stress were housed under 24hrs continuous lighting. Another half were housed under 12-12h light dark cycle. Fourteen days later, rats were sacrificed and the entire colon was excised. After measuring a wet weight and the area of ulcer, myeloperoxidase activity in the colonic tissue and histology were determined. Results: TNBS treated groups showed a higher colonic wet weight and MPO activity than control groups. In TNBS treated groups, chronic stress increased a colonic wet weight and MPO activity and exaggerated a neutrophil infiltration compared to non-stress group. Only in a TNBS treated group with chronic stress, colonic ulcer was observed. Conclusion: Although stress itself did not induce a colonic ulceration, stress attenuated a healing of TNBS-induced colitis in rats. Neutrophil infiltration should precipitate an attenuation of healing colitis by stress. G4288
VALIDITY OF THE COLONOSCOPY IN THE ASSESSMENT OF SEVERITY OF COLONIC CROHN'S DISEASE ATTACKS: CONFRONTATION WITH THE ANATOMICAL FINDINGS OF COLECTOMY SPECIMENS. S_, Nahon(1), Y. Bouhnik (1), A. LavergneSlove (2), A. Bitoun (1), Y, Panis (3), P. Valleur (3), C. Matuchansky (1), J.C. Rambaud (1). 1) Service de Gastroent~rologie, H6pital Saint Lazare, 2) Laboratoire d'Anatomie Pathologique, 3) Service de Chirurgie Vise&ale, H6pital Lariboisi~re, 75010 Pads, France. No clinico-biological and/or morphological severity criteria has been validated in the assessment of colonic Crohn's disease (CCD) attacks. The aim of this study was to evaluate the accuracy of the colonoscopy in the gravity diagnosis of CCD. Method: Colectomy specimens from 78 consecutive patients operated between 1982 and 1996 for CCD resistant to the medical treatment have been reviewed. Endoscopic criteria of gravity (ECG) were defined as following: a) deep ulcerations involving the circular muscle coat (El), b) deep ulcerations not extended into the circular muscle coat but covering more than 33% of the mucosal area of at least one colonic segment (E2) and c) mucosal detachment on the edge of ulcerations (E3). Pathological examination of colectomy specimens permitted to classify patients in 3 grades
among Buckell's classification defined for ulcerative colitis (Gastroenterology 1980; 79:19-25): Grade A, ulcerations confined to the mucosa; Grade B, extensive deep ulcerations confined to the submucosa; Grade C, deep ulcerations involving the circular muscle coat. Results: ECG E1 and/or E2+E3, ECG E2 and no ECG were found in 68, 2 and 8 patients, respectively. Anatomical grades A, B and C colitis were found in 10, 13 and 55 patients, respectively. Positive predictive value of ECGs El, E2 and E3 were 90, 98 and 92%, respectively. Negative predictive value of ECGs El, E2 and E3 were 28, 72 and 17%, respectively. The depth and the extent of ulcerations noted using colonoscopy were correlated to the results of pathological examination of colectomy specimens (r=0.69 and r=0.68, P<0,001 respectively). Taking into account only anatomical grades B and C colitis, 88% of ECGs have been disclosed below the splenic flexure. No complications related to colonoscopy were noted. Clinical and biological severity criteria were similar in the 3 anatomical groups (A, B and C). Conclusion: The colonoscopy, unless performed by senior endoscopist, is a safe and useful tool to appreciate the anatomical gravity of CCD lesions in colectomized patients, with a high positive but poor negative predictive values to detect ECG. Moreover, usual anatomical classification of lesions that take currently into account only the depth of lesions should also consider their extent in relation to the fact that patients with ECG classified E1 or E2+E3 share clinical and evolutionary similar criteria who led to perform a colectomy. G4289
THE EFFECT OF AMINOGUANIDINE, AN INOS-SELECTIVE NOs INHIBITOR, ON TNB COLITIS. H. Nakamura, H. Tsukada, M. Onomura, T. Saito, K. Fukuda, M. Kodama, M. Hosokawa, Y.Seino. The Department of Metabolism and Clinical Nutrition, Kyoto University, Kyoto 606-01 Japan. Nitric oxide (NO) derived from inducible NO synthase (iNOs) plays an important role in the pathogenesis of inflammatory bowel disease (IBD). Aminoguanidine (AG), an selective iNOs inhibitor, might be a new medicine for IBD. To determine the most effective of aminoguanidine, we studied the preventive effect of AG on TNB colitis. Materials and Methods: Male Wister rats, weighing 250g, divided into five groups. The rats of each groups were administrated 0.15uM/kg, 1.5uM/kg, 15uM/kg, 150uM/kg of AG and distill water as a control every day. Three days after the administration of these medicines, the rats were induced with colitis by the administration of 0.25 ml of 10 mg TNB / 50 % ethanol. Seven days after the induction of TNB colitis, all rats were killed and assessed the effect of aminoguanidine using macroscopic damage score (max=10), ulcer area(era2), MPO activities (units / g tissue). Results ulcer area i dose n i damage score i i 4.12 ± 1.84 i 7.5 ± 0.4 control 5 i 1.37+-0.47" i 2.2+_0.5** 0.15uM 5 ! i 0.97±0.48** i 1.6 +_0.5** 1.5uM 5 i i 0.99+-0.77"* i 2.6 ± 1.0"* 15uM 5 i i 2.37 ± 1.06 i 6.4 ± 0.7 150uM 5 i mean _+S.E.M) (compared with Control*: p<0.05,**:p<0.01)
MPO activity 59.84 ± 10.37 44.25±11.46 31.17±6.98" 42.73±2.16 89.20 ± 13.02
The 1.5 uM/kg of AG had the most preventive effect on the damage of TNB colitis. The 150 ug/kg of AG exacerbate the damage compared with 1.5 uM/kg of AG. Contusions: The proper inhibition of iNOs by aminoguanidine prevented the damage of TNB colitis. • G4290
THE EFFECT OF NOsINHIBITORS ON THE TNB COLITIS: A COMPARATIVE STUDY. H. Nakamura, H. Tsukada, M. Onomura, T. Saito, K. Fukuda, M. Kodama, M. Hosokawa, Y.Seino. The Department of Metabolism and Clinical Nutrition, Kyoto University, Kyoto 606-01 Japan. Amount of nitric oxide (NO), generated by NO synthase(NOs), is involved with the pathogenesis of inflammatory bowel disease. The inhibition of NO generation has been considered to be one of the new methods to repair the inflammation with IBD. We determined which NOs inhibitor prevent the damage of Trinitrobenzene sulfonic acid (TNB)-induced colitis using three kind of NOs inhibitors; aminoguanidine (AG), S-ethylthiourea (EIT) and N~-nitro-L-arginine methyl ester (L-NAME). Materials and Methods: Forty male Wister rats, weighing 250g, were divided into 4 groups and administrated AG (15uM/kg), EIT(M/kg), L-NAME (15uM/kg) every day. Three days after the administration, rats were induced with TNB colitis by the administration of 0.25 ml of 10 mg TNB / 50% ethanol with catheter (1.5 mm in diameter) 7 cm proximal to the anus. Three days after the induction of the colitis, five rats of each group were killed and NOs activity (nmol / rain / g tissue) measured. Seven days after, five rats of each group were killed and macroscopic damage score (max=10), ulcer area (cm2) and MPO activity (units / g tissue) measured.