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Platelet-derived growth factor (PDGF) accelerates the healing of experimental ulcerative colitis in rats
A208
AGA ABSTRACTS
GASTROENTEROLOGY, Vol. 108, No. 4
• CONTROLLEDTRIAL OF REVERSAL OF BARRETT'S ESOPHAGUSWITH ACID SUPPRESSIONAND MULTI-POLAR ELECTROCOAGULATION(MPEC). R.E. Samoliner. M.B~ Fennerty, HS. Garewal, Tucson VA Medical Center and Arizona Health Sciences Center, Department o f Medicine, Tucson, AZ. This study tests the hypothesis that reinjury o f Barretrs esophagus in an acid reduced environment will result in repopulation with normal squamous epithelium. Thirteen patients with documented Barretrs esophagus 2-9cm (mean 4.7cm) in length with intestinal metaplasia agreed to participate. Patients had 24-h pH performed while on omeprazole, 2080mg/dally (average 53rag). Thermal injury using MPEC was initially applied to a 2-3cm extent o f half the circumference o f Barrett's. The other halfoftha lesion served as an internal control for each patient: The treated half was identified with an India ink tattoo. One patient was lost to follow-up and one was dropped due to the development of metastatic lung cancer. In 10 of the remaining 11 patients, 24-h esophageal pH <4 ranged from 0-5.5%, a m e a n of 1.6%. Ten of these 11 patients had visual and biopsy elimination of the section of Berrett's subjected to MPEC therapy in an average of 3 sessions (range 2-4). At one point inthe course of therapy 2 patients demonstrated 1 and 4 residual glands of intestinal metaplasia underlying squamous epithelium. Nine patients agreed to treatment of the residual visible Barrett's and underwent 1-7 additional sessions resulting in a mean estimated reduction o f 83% of the initial Bat:rett's mueosa (range 33 - 100%). At the time o f analysis of this ongoing trial, 3 o f 11 patients have no endoscopic evidence of Barrett's esophagus or biopsy evidence o f intestinal metaplasia. Five patients had a complication of one MPEC session out of a total of 66 sessions: two odynophagia, one chest pain, one stricture requiring one dilatation, and one GI bleed two weeks post MPEC not requiring transfusion in an actively drinking patient. In summary, 10 of I 1 patients had elimination of Barrett%in the half circumference of the esophagus treated with MPEC. Subsequent therapy resulted in apparent elimination of Barrett's in 3 of 10 patients and a >65% reduction of Barrett's in six of the 7 remaining patients. Reversal in Barrett's esophagus is possible with control o f esophaguai acid exposure and MPEC Partially funded by ASGE Endoscopic Research Award.
•
MAINTENANCE TREATMENT VS. HELICOBACTER PYLORI ERADICATION THERAPY IN PREVENTING REBLEEDING OF THE PEPTIC ULCER DISEASE. A CLINICAL TRIAL AND FOLLOW-UP FOR TWO YEARS. C. S a n t a n d e r H.G. Gr~valos, A.G. Cedenilla y J.M. Pajares. Gastroenterology Department, Hospital Universitario de La Princesa, Madrid, Spain. H e l i c o b a c t e r Pylori (HP) e r a d i c a t i o n prevents peptic ulcer recurrence. Our a i m was to assess the effectiviness of HP e r a d i c a t i o n i n p r e v e n t i n g reble~ding in patients who initially p r e s e n t e d w i t h m a j o r upper gastrointestinal hemorrhage from peptic ulcer. Patients and methods: 125 consecutive patients (mean age:61,2 ; M/F: 8 3 / 4 2 ) p r e s e n t i n g w i t h a first episode of major upper gastrointestinal hemorrhage from H. Pylori-positive ulcer disease (22 gastric u l c e r s a n d 103 duodenal ulcers) were included. Patients who h a d p r e v i o u s l y had gastric surgery, or had taken corticosteroids, antiinflammatory drugs, or antibiotics in the eight weeks before entry w e r e e x c l u d e d . HP infection was d i a g n o s e d when at least two of the following tests were positive: h i s t o l o g i c e x a m i n a t i o n of antral b i o p s y specimens in frozen tissue sections on H-E and/or Giemsa, rapid urease test (Jatrox)on antral samples and/or 13C-urea b r e a t h test. After the acute phase of b l e e d i n g patients were randomly a l l o c a t e d into two treatment groups: ERADICATION THERAPY, 84 patients, in one of the f o l l o w i n g two regimes, l.Amoxicillin 500mg tid for 10 days + O m e p r a z o l e 20mg b i d for 30 days, or 2. A m Q x i c i l l i n 500 mg tid for' i0 days + M e t r o n i d a z o l e 500 mg tid for i0 days + Colloidal B i s m u t h Subcitrate 240mg bid for 30 days. If HP infection recurred, a s e c o n d course of e r a d i c a t i o n therapy was given. L O N G - T E R M M3%INTENANCE TREATMENT, 41 patients randomly allocatedto e i t h e r Omeprazole 20mg once a day or Ranitidine 150mg once a day for one year. Follow-up included b i m o n t h l y clinical a s s e s s m e n t and upper e n d o s c o p y every three months. Mean follow-up: 2.12 years. Statistical analysis: Chi-sqq/are test and Yates correction. Results: E R A D I C A T I O N T H E R A P y No__No e r a d i c a t i o n Ulcer relapse R e b l e e d i n q AMOXI-OME 74 15/74 6/74 2/74 AMOXI-METRO-CBS I0 3/10 0/I0 0/i0 TOTAL 84 18/84(21,4%) 6/84(7,14%)* 2/84(2,3%)* MAINTENANCE OMEPP~AZOLE R/uNITIDINE
TREATMENT TOTAL
NO~ 12 29 41
Ulcer
relapse 3/12 10/29 13/41(31,7%)*
Rebleedinq 1/12 4/29 5/41(12,1%) ÷
*p<0.001 *p<0.1 Conclusions:l.H Pylori eradication reduces peptic ulcer recurrence and r e b l e e d i n g in ulcer disease. 2 . H P e r a d i c a t i o n t h e r a p y is more e f f e c t i v e in p r e y e n t i n g recurrent bleeding from u l c e r disease than l o n g - t e r m maintenance therapy.
P L A T E L E T - D E R I V E D G R O W T H F A C T O R (PDGF) A C C E L E R A T E S THE H E A L I N G OF E X P E R I M E N T A L U L C E R A T I V E C O L I T I S IN RATS. ZS. Sander: D. Szeli, M. C h a r e t t e * and S. Szabo**, Dept. of M e d i c i n e , Seuunelweis Med. Univ., Budapest , Hungary; *Creative B i o m o l e c u l e s , Inc., H o p k i n t o n , MA, and **nepts. of P a t h o l o g y ~ B r i g h a m & W o m e n ' s Hosp., H a r v a r d Med. Sch., Boston, MA, USA. P D G F is a p o t e n t m i t o g e n for m e a e n c h y m a l a n d s m o o t h m u s c l e c e l l s and a c c e l e r a t e s the h e a l i n g of c h r o n i c d u o d e n a l ulcer and gastritis. The a i m of the s t u d y w a s to test the ulcer h e a l i n g e f f e c t of PDGP in our n e w u l c e r a t i v e c o l i t i s model, i n d u c e d by the s u l f h y d r y l (SH) a l k y l a t o r i o d o a c e t a m i d e (IA). G r o u p s of n o r m a l l y fed S p r a g u e - D a w l e y rats (170-200 g) w e r e g i v e n 0.1 ml of SS i o d c a c e t a m i d e (IA) in 1% m e t h y l c e l l u l o s e i n t r a c o l o n i c a l l y w i t h N e l a t o n c a t h e t e r 7 cm f r o m the a n u s o n c e in the first day of the e x p e r i m e n t . F r o m the s e c o n d day the rats w e r e g i v e n i00 or 800 n g / l O 0 g P D G F twice daily per rectum. The c o n t r o l a n i m a l s were g i v e n p h y s i o l o g i c a l saline. Rats w e r e k i l l e d on the 10th day w h e n the wet w e i g h t of the c o l o n (7 cm from the anus), th'e l e s i o n a r e a (mma), s e v e r i t y and e x t e n t Of c o l i t i s were r e c o r d e d , and s e c t i o n s f i x e d for h i a t o l o g l c evaluation. Colon Group Treatment wet w e i u h t ~u) L e s i o n a r e a |mm 2) 1 Controls ....2.2 ~ 0.4 167 ~ 33 2 PDGF, i ~ / 1 0 ~ 2"3 ! 0.3 158 ~ 25 3 PDGF, 500n~|~g 1.2 ~ 0.I* 33 ~ 9*
*p<0.05
Histoiogic e v a l u a t i o n of c o n t r o l rats r e v e a l e d m u l t i f o c a l c o l o n i c e r o s i o n s and s u p e r f i c i a l u l c e r s u r r o u n d e d by a c u t e and c h r o n i c inflant~atory cells. The l e s i o n s w e r e m i n i m a l and r e p l a c e d by r e - e p i t h e l i a l i z e d m u c o s a in m o s t of the rats treated with PDGF. Conclusions: I. Intracoloni~ administration of PDGF dose-dependently accelerated the h e a l i n g of e x p e r i m e n t a l c o l i t i s i n d u c e d by i o d o a c e t a m l d e . 2. The e f f e c t i n v o l v e d the r e d u c t i o n of u l c e r s and e r o s i o n s as well as diminishing or eliminating the accompanying inflammation. 3. Thus, PDGF m i g h t h a v e a role in the treatment ofulceratlvecolitis.
INDOMETHACIN INHIBITS NITRIC OXIDE SYNTHASE mRNA AND PROTEIN EXPRESSION IN THE GASTRIC MUCOSA. A KEY TO ITS INJURIOUS ACTION? A.M. Santos. I.J. Sarfeh, A. Tarnawsld, I 3 fold, p<0.001) preceding development of extensive mucosal necrosis at 4 and 18 hours. RT/PCR detected presence of NOS mRNA in normal gastric mucosa of placebo treated rats. INDO produced a significant, time dependent reduction of NOS mRNA expression levels (vs normal mucosa) 14%, 63%, 77% at 1, 4 and 18 hours, respectively. CONCLUSIONS: 1) INDO produces extensive gastric mucosal injury at 4 and 18 hours. 2) INDO reduces NOS mRNA level and NOS enzyme expression in gastric mucosa as early as 3 hours prior to development of extensive mncosal necrosis. 3) Since NO play important gastric mucosal defense, inhibition of NOS by INDO appears to be one of the major mechanisms of its mucosal damaging action.
AGA ABSTRACTS
GASTROENTEROLOGY, Vol. 108, No. 4
• CONTROLLEDTRIAL OF REVERSAL OF BARRETT'S ESOPHAGUSWITH ACID SUPPRESSIONAND MULTI-POLAR ELECTROCOAGULATION(MPEC). R.E. Samoliner. M.B~ Fennerty, HS. Garewal, Tucson VA Medical Center and Arizona Health Sciences Center, Department o f Medicine, Tucson, AZ. This study tests the hypothesis that reinjury o f Barretrs esophagus in an acid reduced environment will result in repopulation with normal squamous epithelium. Thirteen patients with documented Barretrs esophagus 2-9cm (mean 4.7cm) in length with intestinal metaplasia agreed to participate. Patients had 24-h pH performed while on omeprazole, 2080mg/dally (average 53rag). Thermal injury using MPEC was initially applied to a 2-3cm extent o f half the circumference o f Barrett's. The other halfoftha lesion served as an internal control for each patient: The treated half was identified with an India ink tattoo. One patient was lost to follow-up and one was dropped due to the development of metastatic lung cancer. In 10 of the remaining 11 patients, 24-h esophageal pH <4 ranged from 0-5.5%, a m e a n of 1.6%. Ten of these 11 patients had visual and biopsy elimination of the section of Berrett's subjected to MPEC therapy in an average of 3 sessions (range 2-4). At one point inthe course of therapy 2 patients demonstrated 1 and 4 residual glands of intestinal metaplasia underlying squamous epithelium. Nine patients agreed to treatment of the residual visible Barrett's and underwent 1-7 additional sessions resulting in a mean estimated reduction o f 83% of the initial Bat:rett's mueosa (range 33 - 100%). At the time o f analysis of this ongoing trial, 3 o f 11 patients have no endoscopic evidence of Barrett's esophagus or biopsy evidence o f intestinal metaplasia. Five patients had a complication of one MPEC session out of a total of 66 sessions: two odynophagia, one chest pain, one stricture requiring one dilatation, and one GI bleed two weeks post MPEC not requiring transfusion in an actively drinking patient. In summary, 10 of I 1 patients had elimination of Barrett%in the half circumference of the esophagus treated with MPEC. Subsequent therapy resulted in apparent elimination of Barrett's in 3 of 10 patients and a >65% reduction of Barrett's in six of the 7 remaining patients. Reversal in Barrett's esophagus is possible with control o f esophaguai acid exposure and MPEC Partially funded by ASGE Endoscopic Research Award.
•
MAINTENANCE TREATMENT VS. HELICOBACTER PYLORI ERADICATION THERAPY IN PREVENTING REBLEEDING OF THE PEPTIC ULCER DISEASE. A CLINICAL TRIAL AND FOLLOW-UP FOR TWO YEARS. C. S a n t a n d e r H.G. Gr~valos, A.G. Cedenilla y J.M. Pajares. Gastroenterology Department, Hospital Universitario de La Princesa, Madrid, Spain. H e l i c o b a c t e r Pylori (HP) e r a d i c a t i o n prevents peptic ulcer recurrence. Our a i m was to assess the effectiviness of HP e r a d i c a t i o n i n p r e v e n t i n g reble~ding in patients who initially p r e s e n t e d w i t h m a j o r upper gastrointestinal hemorrhage from peptic ulcer. Patients and methods: 125 consecutive patients (mean age:61,2 ; M/F: 8 3 / 4 2 ) p r e s e n t i n g w i t h a first episode of major upper gastrointestinal hemorrhage from H. Pylori-positive ulcer disease (22 gastric u l c e r s a n d 103 duodenal ulcers) were included. Patients who h a d p r e v i o u s l y had gastric surgery, or had taken corticosteroids, antiinflammatory drugs, or antibiotics in the eight weeks before entry w e r e e x c l u d e d . HP infection was d i a g n o s e d when at least two of the following tests were positive: h i s t o l o g i c e x a m i n a t i o n of antral b i o p s y specimens in frozen tissue sections on H-E and/or Giemsa, rapid urease test (Jatrox)on antral samples and/or 13C-urea b r e a t h test. After the acute phase of b l e e d i n g patients were randomly a l l o c a t e d into two treatment groups: ERADICATION THERAPY, 84 patients, in one of the f o l l o w i n g two regimes, l.Amoxicillin 500mg tid for 10 days + O m e p r a z o l e 20mg b i d for 30 days, or 2. A m Q x i c i l l i n 500 mg tid for' i0 days + M e t r o n i d a z o l e 500 mg tid for i0 days + Colloidal B i s m u t h Subcitrate 240mg bid for 30 days. If HP infection recurred, a s e c o n d course of e r a d i c a t i o n therapy was given. L O N G - T E R M M3%INTENANCE TREATMENT, 41 patients randomly allocatedto e i t h e r Omeprazole 20mg once a day or Ranitidine 150mg once a day for one year. Follow-up included b i m o n t h l y clinical a s s e s s m e n t and upper e n d o s c o p y every three months. Mean follow-up: 2.12 years. Statistical analysis: Chi-sqq/are test and Yates correction. Results: E R A D I C A T I O N T H E R A P y No__No e r a d i c a t i o n Ulcer relapse R e b l e e d i n q AMOXI-OME 74 15/74 6/74 2/74 AMOXI-METRO-CBS I0 3/10 0/I0 0/i0 TOTAL 84 18/84(21,4%) 6/84(7,14%)* 2/84(2,3%)* MAINTENANCE OMEPP~AZOLE R/uNITIDINE
TREATMENT TOTAL
NO~ 12 29 41
Ulcer
relapse 3/12 10/29 13/41(31,7%)*
Rebleedinq 1/12 4/29 5/41(12,1%) ÷
*p<0.001 *p<0.1 Conclusions:l.H Pylori eradication reduces peptic ulcer recurrence and r e b l e e d i n g in ulcer disease. 2 . H P e r a d i c a t i o n t h e r a p y is more e f f e c t i v e in p r e y e n t i n g recurrent bleeding from u l c e r disease than l o n g - t e r m maintenance therapy.
P L A T E L E T - D E R I V E D G R O W T H F A C T O R (PDGF) A C C E L E R A T E S THE H E A L I N G OF E X P E R I M E N T A L U L C E R A T I V E C O L I T I S IN RATS. ZS. Sander: D. Szeli, M. C h a r e t t e * and S. Szabo**, Dept. of M e d i c i n e , Seuunelweis Med. Univ., Budapest , Hungary; *Creative B i o m o l e c u l e s , Inc., H o p k i n t o n , MA, and **nepts. of P a t h o l o g y ~ B r i g h a m & W o m e n ' s Hosp., H a r v a r d Med. Sch., Boston, MA, USA. P D G F is a p o t e n t m i t o g e n for m e a e n c h y m a l a n d s m o o t h m u s c l e c e l l s and a c c e l e r a t e s the h e a l i n g of c h r o n i c d u o d e n a l ulcer and gastritis. The a i m of the s t u d y w a s to test the ulcer h e a l i n g e f f e c t of PDGP in our n e w u l c e r a t i v e c o l i t i s model, i n d u c e d by the s u l f h y d r y l (SH) a l k y l a t o r i o d o a c e t a m i d e (IA). G r o u p s of n o r m a l l y fed S p r a g u e - D a w l e y rats (170-200 g) w e r e g i v e n 0.1 ml of SS i o d c a c e t a m i d e (IA) in 1% m e t h y l c e l l u l o s e i n t r a c o l o n i c a l l y w i t h N e l a t o n c a t h e t e r 7 cm f r o m the a n u s o n c e in the first day of the e x p e r i m e n t . F r o m the s e c o n d day the rats w e r e g i v e n i00 or 800 n g / l O 0 g P D G F twice daily per rectum. The c o n t r o l a n i m a l s were g i v e n p h y s i o l o g i c a l saline. Rats w e r e k i l l e d on the 10th day w h e n the wet w e i g h t of the c o l o n (7 cm from the anus), th'e l e s i o n a r e a (mma), s e v e r i t y and e x t e n t Of c o l i t i s were r e c o r d e d , and s e c t i o n s f i x e d for h i a t o l o g l c evaluation. Colon Group Treatment wet w e i u h t ~u) L e s i o n a r e a |mm 2) 1 Controls ....2.2 ~ 0.4 167 ~ 33 2 PDGF, i ~ / 1 0 ~ 2"3 ! 0.3 158 ~ 25 3 PDGF, 500n~|~g 1.2 ~ 0.I* 33 ~ 9*
*p<0.05
Histoiogic e v a l u a t i o n of c o n t r o l rats r e v e a l e d m u l t i f o c a l c o l o n i c e r o s i o n s and s u p e r f i c i a l u l c e r s u r r o u n d e d by a c u t e and c h r o n i c inflant~atory cells. The l e s i o n s w e r e m i n i m a l and r e p l a c e d by r e - e p i t h e l i a l i z e d m u c o s a in m o s t of the rats treated with PDGF. Conclusions: I. Intracoloni~ administration of PDGF dose-dependently accelerated the h e a l i n g of e x p e r i m e n t a l c o l i t i s i n d u c e d by i o d o a c e t a m l d e . 2. The e f f e c t i n v o l v e d the r e d u c t i o n of u l c e r s and e r o s i o n s as well as diminishing or eliminating the accompanying inflammation. 3. Thus, PDGF m i g h t h a v e a role in the treatment ofulceratlvecolitis.
INDOMETHACIN INHIBITS NITRIC OXIDE SYNTHASE mRNA AND PROTEIN EXPRESSION IN THE GASTRIC MUCOSA. A KEY TO ITS INJURIOUS ACTION? A.M. Santos. I.J. Sarfeh, A. Tarnawsld, I 3 fold, p<0.001) preceding development of extensive mucosal necrosis at 4 and 18 hours. RT/PCR detected presence of NOS mRNA in normal gastric mucosa of placebo treated rats. INDO produced a significant, time dependent reduction of NOS mRNA expression levels (vs normal mucosa) 14%, 63%, 77% at 1, 4 and 18 hours, respectively. CONCLUSIONS: 1) INDO produces extensive gastric mucosal injury at 4 and 18 hours. 2) INDO reduces NOS mRNA level and NOS enzyme expression in gastric mucosa as early as 3 hours prior to development of extensive mncosal necrosis. 3) Since NO play important gastric mucosal defense, inhibition of NOS by INDO appears to be one of the major mechanisms of its mucosal damaging action.