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Clarithromycin (CL) in combination with omeprazole (OM) for healing of duodenal ulcers (DU), prevention of DU recurrence, and eradication of H. pylori (HP) in two European studies
A184
AGA ABSTRACTS
GASTROENTEROLOGY, VoI. I O 8 , NO. 4
• CLARITHROMYCIN (CL) IN COMBINATION WITH OMEPRAZOLE (OM) FOR HEALING OF DUODENAL ULCERS (DU), PREVENTION OF DU RECURRENCE, AND ERADICATION OF H. PYLORI (HP) IN TWO EUROPEAN STUDIES. C. O'Moraln. R.P.H. Logan and the Clarlthromycln European H. pylori Study Group. Meath Hospital, Dub,n, Ire, BHURG study, St. Mary's Hospital, London, UK Patients with HP and DU were enrolled in two well-centrolled, randomized, double-blind, multi-center studies. Patientsreceived for two weeks either CL 500 mg TID and OM 40 mg QD or OM 40 mg QD alone; all patients received an additional two weeks of OM (40 mg QD in one study and 20 mg QD in the other). Patients were followed for 6 months. Ulcer status was assessed by endoscopy and HP status was assessed by culture, histology, and 13C-UBT at 4-6 weeks post-Rx. 356 patients with DU andHP pretreatment (mean age 47 yrs, mean DU size 10 ram) were enrolled. Treatment
DU Healing DOSI-Rx
CL+OM 99% (151/152) OM 97% (156/161)
Hp Eradication Ulcer Recurrence at 4-6 weekspost Rx at 6 monthsoost-Rx 78% (126/162) 3% (5/171)
8% 51%
(10/131) (77/150)
Tableincludesall patientswith both DU and HP pretreatmentwho had the appropriatepost-Rxvisit. 5% of Hp negative CL+OM patients and 13% of Hp positive CL+OM patients had recurrence of ulcer while 53% of Hp positive OM patients had recurrence of ulcer at the end of the 6 months follow-up. Both CL+OM and OM alone were well tolerated. Only 3% of CL+OM patients 2% of OM patients discontinued Rx due to adverse events. Dual therapy with CL+OM appears effective and safe as a treatment for eradication of HP and prevention DU recurrence. In addition, in patients with persistent Hp infection treatment with CL+OM may change the natural history of DU.
THE ROLE OF INTERLEUKIN-1 RECEPTOR ANTAGONIST IN THE EXPERIMENTAL GASTRIC ULCER MODEL. A. Oshima, G. Wakabayashi, M. Shimazu, A. Yoshida, K. Iwata, and M. Kitajima. Depts. of Surgery, Tokyo Adventist Hospital,Tokyo. Depts. of Surgery, Keio University, School of Medicine, Tokyo. The role of Interl ueki n-1 re cept or antagonist (IL- 1ra) on ischemia-reperfusion injury in r a t gastric ulcer model was investigated. (Materials and Methods) Male Wistar strain rats weighing 2 0 0 250g were heparinized and injected with either saline (control) or IL-1 ra at a do se of 50mg/kg. The celiac axis was t h e n occluded fo r 55 minute Swith a mi nicl ip. Me asurements of ulcer index, acid output, mucosal prostaglandin(PG)E2 content, and gastric mucosal blood f l o w (GMBF) were made prior to clamping and 30 minutes a f t e r its release. Gastric index by counting and measuring the lengths of each lesion in both groups were compared. Procedure f o r measuring gastric acid secretion was adopted f r o m the Japanese S o c i e t y o f Gastroente rology's modified method of Anson's assay of gastric juice. Measuring gastric mucosal PG E2 c o n t e n t was p e r f o r m e d by t h e method of Kleine et al. Multiple laser doppler system was used f o r d e t e r m i n i n g t h e GMBF. (Results)Ulcer index were 464-12 mm in control and 48-I-12 mm in I L - l r a group. There were no significant differences between t w o groups. Before occlusion, acid output in IL-1 ra group was significantly reduced to 10.O:F_D.71 mEcl/I compared with 32.4-1-1,.1 mEcl/I in control. A f t e r reperfusion, acid output in IL-1 ra group was also significanly reduced to 10.0-1-1.26 mECl/I compared with 16.4+__1.54 mECl/I in c o n t r o l Without occlusion mucosal release o f PGE2 in IL-1 ra group significantly increased to 11 7.5i9.62 pg/mg compared with 94.5-1-4.82 p g / m g in control. A f t e r release, PGE2 in IL-1 ra group also increased to 61.8+_.16.3 p g / m g co mpared with 48.6+_.7.62 pg/rn8 in control. Before occlusion, GMBF were 4.855:O.21 V in control and 4.38-1-0.07 V in IL-1 ragroup, A f t e r reperfusion, GM BF in IL-1 ra group slightly decreased to-3.27-t-0.29 V co mpared with 8.60+__0.18 V in control. (Conclusion) By injection of IL-1 re, acid output was significantly reduced and mucosal release of PGE2 significantly increased compared with control group. The results of this study suggest t h a t IL-1 ra may have its own biological activity or yet a n o t h e r f o r m of IL-1 may be present.
GASTROINTESTINAL MUCOSAL BLOOD FLOW (GMBF) BY REFLECTANCE SPECTROPHOTOMETRY (RS) IN PATIENTS WITH NORMAL ENDOSCOPIC FINDINGS AND DUODENAL ULCER DISEASE. ~ , C.K.Ching, S.K.Lam, J.K.S.Ko, C.H.Cho. Depts of Medicine & Pharmacology, University of Hong Kong, Hong Kong. We confirmed in the rat model that GMBF, using index of hemoglobin (IHb) and index of oxygen saturation (ISO2), measured by RS is highly reproducible. RS was employed to validate the results in normal human (N) and to assess changes in the GMBF in duodenal ulcer (DU) patients. RS was performed in 70 N and 14 DU patients who also had assessment at and around the ulcer. 30 N had repeat GMBF measurements 2 weeks later to assess intra-individual variation (reproducibility) by calculating the coefficient of variation [cv]. The mean IHb results in the normal regions were as follows: D2 DA** Dp** I A BLC Boc* DU (n=21) 74.9 86.0 92.4 72.9 75.7 81.9 103.0 N (n=70) 79.3 83.9 87.8 71.0 72.0 74.0 93.4 (D2, DA& Dp = 2rid & 1st part [anterior & posterior wall] of duodenum; I=incisura, A=antrum, BLC & BGc = lesser & greater curve the body) The mean IHb results at and around the ulcer were: Center Edge Margin DU (n=21) 77.0 101.0 104.5 The GC had significantly higher IHb* (p < 0.005) than other gastric sites in N & DU patients. N but not DU patients had significantly lower ISO2 (p<0.01) in the GC than other gastric sites. D(A)** and D(p)** had significantly higher IHb and ISO2 than D2 (p < 0.01). The mean cv for IHb & ISO2 were 17.8% & !3.9% respectively. The ulcer margin had significantly higher IHb (p < 0.005) and ISO2 (p <0.005) than the ulcer center. GMBF varies in different region of the stomach and the duodenum. Ischemia occurs in active ulcers but is compensated by increased GMBF in the periphery to help ulcer healing. RS is reproducible and probably a useful method for assessing GMBF changes in response to diseases and chemicals in the upper gastrointestinal tract.
INDUCTION OF SPERMIDINE/SPERMINE N ~-ACETYLTRANSFERASE IN RAT GASTRIC MUCOSA BY ADMINISTRATION OF HYPERTONIC NaCI SOLUTION. K. Otani. T. Arakawa, Y. Yano, T. Fukuda, A. Itani, K. Kobayashi, S. Otani. Third Department of Internal Medicine and Second Deparmaentof Biochemistry, Osaka City University Medical School, Osaka, Japan. Polyamines such as purrescine, spcrmidinc, and spcrmme are essentialin the regulation of cell growth. Ornithine dccarboxylase (ODC), which is the initialratc-limi~ng enzyme for polyamine biosynthesis, is induced by several kinds of celldamage. In the stomach, hypertonic NaCI can induce this enzyme. Spermidine/spcrminc N~-acetyltransferase (SAT) is acritical and. rate-limiting enzyme in the pathway for potyamine intcrconversion, in which spermine is converted back to spermidine and spermidine is converted back to putrescine. The physiological role of SAT, including that in the stomach, is not known. The aim of this study was tc find whether the administration of hypertonic NaC1 induced SAT in rat gastric mucosa. Male Wistar rats were starved and 1.0 ml of 20% NaCI was given by gastric tube. Thcratswcrekilled5 minor 1 3 , 5 , 6 , 7 , 9 , o r 12h(n=4-6) after administration and oxyntic gland mucesa of the stomach was collected. . . . . 14 S A T ac~vlty was assayed.by the incorporauon of the [i- C-']accty[momty -
•
.
•
.
.
•
.
was assessed by an RNase protection assay. The mean S A T aclJ.vity increased aft= t~atment and peaked at 5 h [166.6 - 51.8 (SD) pmol/10 rain per m g protein] and again at 7 h (180.5 ± 31.5) aftera decrease ~t 6 h (94.2 + 16.0). Both peaks were higher than in controls treatedwith saline(41.7 + 23.0). O D C activitypeaked at 6 h, when itwas higher than in the controls. Three hours aft= 2 0 % NaCI administration,the mean S A T m R N A level had increased twofold, which was less than the increase in enzyme acuwry, l--lypertonicNaCt administrationcaused a biphasic increase in S A T activity. The firstpeak appeared before O D C activityincreased, suggesting thatS A T acts in the initialphase of polyarnine accumulation aftergasmc damage. The S A T m R N A level controls S A T activity,but another mechanism(s) is involved, as well.
AGA ABSTRACTS
GASTROENTEROLOGY, VoI. I O 8 , NO. 4
• CLARITHROMYCIN (CL) IN COMBINATION WITH OMEPRAZOLE (OM) FOR HEALING OF DUODENAL ULCERS (DU), PREVENTION OF DU RECURRENCE, AND ERADICATION OF H. PYLORI (HP) IN TWO EUROPEAN STUDIES. C. O'Moraln. R.P.H. Logan and the Clarlthromycln European H. pylori Study Group. Meath Hospital, Dub,n, Ire, BHURG study, St. Mary's Hospital, London, UK Patients with HP and DU were enrolled in two well-centrolled, randomized, double-blind, multi-center studies. Patientsreceived for two weeks either CL 500 mg TID and OM 40 mg QD or OM 40 mg QD alone; all patients received an additional two weeks of OM (40 mg QD in one study and 20 mg QD in the other). Patients were followed for 6 months. Ulcer status was assessed by endoscopy and HP status was assessed by culture, histology, and 13C-UBT at 4-6 weeks post-Rx. 356 patients with DU andHP pretreatment (mean age 47 yrs, mean DU size 10 ram) were enrolled. Treatment
DU Healing DOSI-Rx
CL+OM 99% (151/152) OM 97% (156/161)
Hp Eradication Ulcer Recurrence at 4-6 weekspost Rx at 6 monthsoost-Rx 78% (126/162) 3% (5/171)
8% 51%
(10/131) (77/150)
Tableincludesall patientswith both DU and HP pretreatmentwho had the appropriatepost-Rxvisit. 5% of Hp negative CL+OM patients and 13% of Hp positive CL+OM patients had recurrence of ulcer while 53% of Hp positive OM patients had recurrence of ulcer at the end of the 6 months follow-up. Both CL+OM and OM alone were well tolerated. Only 3% of CL+OM patients 2% of OM patients discontinued Rx due to adverse events. Dual therapy with CL+OM appears effective and safe as a treatment for eradication of HP and prevention DU recurrence. In addition, in patients with persistent Hp infection treatment with CL+OM may change the natural history of DU.
THE ROLE OF INTERLEUKIN-1 RECEPTOR ANTAGONIST IN THE EXPERIMENTAL GASTRIC ULCER MODEL. A. Oshima, G. Wakabayashi, M. Shimazu, A. Yoshida, K. Iwata, and M. Kitajima. Depts. of Surgery, Tokyo Adventist Hospital,Tokyo. Depts. of Surgery, Keio University, School of Medicine, Tokyo. The role of Interl ueki n-1 re cept or antagonist (IL- 1ra) on ischemia-reperfusion injury in r a t gastric ulcer model was investigated. (Materials and Methods) Male Wistar strain rats weighing 2 0 0 250g were heparinized and injected with either saline (control) or IL-1 ra at a do se of 50mg/kg. The celiac axis was t h e n occluded fo r 55 minute Swith a mi nicl ip. Me asurements of ulcer index, acid output, mucosal prostaglandin(PG)E2 content, and gastric mucosal blood f l o w (GMBF) were made prior to clamping and 30 minutes a f t e r its release. Gastric index by counting and measuring the lengths of each lesion in both groups were compared. Procedure f o r measuring gastric acid secretion was adopted f r o m the Japanese S o c i e t y o f Gastroente rology's modified method of Anson's assay of gastric juice. Measuring gastric mucosal PG E2 c o n t e n t was p e r f o r m e d by t h e method of Kleine et al. Multiple laser doppler system was used f o r d e t e r m i n i n g t h e GMBF. (Results)Ulcer index were 464-12 mm in control and 48-I-12 mm in I L - l r a group. There were no significant differences between t w o groups. Before occlusion, acid output in IL-1 ra group was significantly reduced to 10.O:F_D.71 mEcl/I compared with 32.4-1-1,.1 mEcl/I in control. A f t e r reperfusion, acid output in IL-1 ra group was also significanly reduced to 10.0-1-1.26 mECl/I compared with 16.4+__1.54 mECl/I in c o n t r o l Without occlusion mucosal release o f PGE2 in IL-1 ra group significantly increased to 11 7.5i9.62 pg/mg compared with 94.5-1-4.82 p g / m g in control. A f t e r release, PGE2 in IL-1 ra group also increased to 61.8+_.16.3 p g / m g co mpared with 48.6+_.7.62 pg/rn8 in control. Before occlusion, GMBF were 4.855:O.21 V in control and 4.38-1-0.07 V in IL-1 ragroup, A f t e r reperfusion, GM BF in IL-1 ra group slightly decreased to-3.27-t-0.29 V co mpared with 8.60+__0.18 V in control. (Conclusion) By injection of IL-1 re, acid output was significantly reduced and mucosal release of PGE2 significantly increased compared with control group. The results of this study suggest t h a t IL-1 ra may have its own biological activity or yet a n o t h e r f o r m of IL-1 may be present.
GASTROINTESTINAL MUCOSAL BLOOD FLOW (GMBF) BY REFLECTANCE SPECTROPHOTOMETRY (RS) IN PATIENTS WITH NORMAL ENDOSCOPIC FINDINGS AND DUODENAL ULCER DISEASE. ~ , C.K.Ching, S.K.Lam, J.K.S.Ko, C.H.Cho. Depts of Medicine & Pharmacology, University of Hong Kong, Hong Kong. We confirmed in the rat model that GMBF, using index of hemoglobin (IHb) and index of oxygen saturation (ISO2), measured by RS is highly reproducible. RS was employed to validate the results in normal human (N) and to assess changes in the GMBF in duodenal ulcer (DU) patients. RS was performed in 70 N and 14 DU patients who also had assessment at and around the ulcer. 30 N had repeat GMBF measurements 2 weeks later to assess intra-individual variation (reproducibility) by calculating the coefficient of variation [cv]. The mean IHb results in the normal regions were as follows: D2 DA** Dp** I A BLC Boc* DU (n=21) 74.9 86.0 92.4 72.9 75.7 81.9 103.0 N (n=70) 79.3 83.9 87.8 71.0 72.0 74.0 93.4 (D2, DA& Dp = 2rid & 1st part [anterior & posterior wall] of duodenum; I=incisura, A=antrum, BLC & BGc = lesser & greater curve the body) The mean IHb results at and around the ulcer were: Center Edge Margin DU (n=21) 77.0 101.0 104.5 The GC had significantly higher IHb* (p < 0.005) than other gastric sites in N & DU patients. N but not DU patients had significantly lower ISO2 (p<0.01) in the GC than other gastric sites. D(A)** and D(p)** had significantly higher IHb and ISO2 than D2 (p < 0.01). The mean cv for IHb & ISO2 were 17.8% & !3.9% respectively. The ulcer margin had significantly higher IHb (p < 0.005) and ISO2 (p <0.005) than the ulcer center. GMBF varies in different region of the stomach and the duodenum. Ischemia occurs in active ulcers but is compensated by increased GMBF in the periphery to help ulcer healing. RS is reproducible and probably a useful method for assessing GMBF changes in response to diseases and chemicals in the upper gastrointestinal tract.
INDUCTION OF SPERMIDINE/SPERMINE N ~-ACETYLTRANSFERASE IN RAT GASTRIC MUCOSA BY ADMINISTRATION OF HYPERTONIC NaCI SOLUTION. K. Otani. T. Arakawa, Y. Yano, T. Fukuda, A. Itani, K. Kobayashi, S. Otani. Third Department of Internal Medicine and Second Deparmaentof Biochemistry, Osaka City University Medical School, Osaka, Japan. Polyamines such as purrescine, spcrmidinc, and spcrmme are essentialin the regulation of cell growth. Ornithine dccarboxylase (ODC), which is the initialratc-limi~ng enzyme for polyamine biosynthesis, is induced by several kinds of celldamage. In the stomach, hypertonic NaCI can induce this enzyme. Spermidine/spcrminc N~-acetyltransferase (SAT) is acritical and. rate-limiting enzyme in the pathway for potyamine intcrconversion, in which spermine is converted back to spermidine and spermidine is converted back to putrescine. The physiological role of SAT, including that in the stomach, is not known. The aim of this study was tc find whether the administration of hypertonic NaC1 induced SAT in rat gastric mucosa. Male Wistar rats were starved and 1.0 ml of 20% NaCI was given by gastric tube. Thcratswcrekilled5 minor 1 3 , 5 , 6 , 7 , 9 , o r 12h(n=4-6) after administration and oxyntic gland mucesa of the stomach was collected. . . . . 14 S A T ac~vlty was assayed.by the incorporauon of the [i- C-']accty[momty -
•
.
•
.
.
•
.
was assessed by an RNase protection assay. The mean S A T aclJ.vity increased aft= t~atment and peaked at 5 h [166.6 - 51.8 (SD) pmol/10 rain per m g protein] and again at 7 h (180.5 ± 31.5) aftera decrease ~t 6 h (94.2 + 16.0). Both peaks were higher than in controls treatedwith saline(41.7 + 23.0). O D C activitypeaked at 6 h, when itwas higher than in the controls. Three hours aft= 2 0 % NaCI administration,the mean S A T m R N A level had increased twofold, which was less than the increase in enzyme acuwry, l--lypertonicNaCt administrationcaused a biphasic increase in S A T activity. The firstpeak appeared before O D C activityincreased, suggesting thatS A T acts in the initialphase of polyarnine accumulation aftergasmc damage. The S A T m R N A level controls S A T activity,but another mechanism(s) is involved, as well.