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Type two of proteinase activated receptors (PAR-2) protects against colitis through a CGRP-dependent pathway
Abstracts
7
5 Endowopic Implantation of a biocompatible no-biodegmdabk polymer ENTERYX UCvbvlmc-Vinvl Akohon for the Trmtment of Gastmeaophq& l&h Di&e (GElUij. G fL%amaq A. Psstorelli, M. Cicsla’, S Ton&*, PVavsssori*, M. Mutigmni, V Peni. Uait$ di Esdoscopia Digestiva Uaiversitii Cattolics sad ‘Libera Usiversitl Campus Biomedico, Rams Italy. Background and sim: GEBD is primarily s motility disorder that fosters the sbnommsl exposure of the esophagus to gastric acid. Most cammoo abnormality is the incompetence of the lower ssophsgeal sphincter (LBS) due to inappropriate trsnsient relsxstioes, or to s fixed low pressure We evslusted the safety, sad effectiveness of ss endoscopicslly implaetsble biocompstlble polyps @llZRYX) in iscressisg the lower esophageal sphincter limction (LES) in patient with GBRD Patienta e Metbod8: five subjects (ZM 3F), mesa age 52 (rssgs 46-69) with a history of GERD sed responsive to PPI were enrolled All subjects were evalusted with, pre sad post-trestmset, gsstroscopy, standard mseomeby for LES pressure, 24h pHmsUy, barium esophsgrsm sad questioensries (SF36, GERLI index, Diary). The injsction catheter wss first flushed with s solvent, dimethyl sulfoxide (OMSO) and then filled with ENTERYX. The injedim needle (23 gauge) punchred the mucma at ihe “Z” line and was advanced into tbc muscle of the cardis. Four injections of 1 oc each were msde at the ssme level sad circumferestislly srousd the cardll. Implants were performed under fluoroscopy to cot&m intrsmuml implant location
f&J&:
Coadssioo: BNTBRYX implant is well tolerated and extremely promising for GERD trsatmset. Sigalficstive increase of LES pressers was demonstrsted with standard mssomeby Adverse events were limited to mild-moderste retrostemal discomfort and fever for 12-36 hours following trestmsnt in all the pstients
INFLIXIMAB THERAPY FOR CROHNS DISEASE FISTULAE. THE ITALIAN EXPERIENCE: PRELIMINARY RESULTS. Kohn A. Vscido A. Ardiuone S, Biancone L. Stumiolo GC, Vavasson P. Sostegni R. Pdncipi B, Papi C, Castiglione F, Zoli G, Caprilli R. Gruppo Italian0 Studio Infliximab. Background. Crohn’s Disease (CD) is characterized by segmental tiansmural inflammation with development of fistulae in approximately one third of patients. Spontaneous healing of Cstulae is rare and the result of diug treatments is deceivable lnfliximab has recently been developed as a treatment of CD and seems to be an efficacious traabnent for fistulae in patients with CD (1). Aim: To rawit the clinical outcome and side affects of 69 patients with tistulidng CD treated with lnfliximab at ten differenl Italian Centers of Gastmenterology. Methods: B&wean January 1999 and March 2000, 38 males and 31 females with intrabdominal and/or draining entenxutaneous fistulae from CD. mean age 36 year (*12.7). were treated with Inflixlmab. All patients had single or multiple Rstulae of at least three months duration; 137 fistulae, 83 c&anal (PA). 15 rectovaoinal fRVI. 15 entenxutaneous (EC). 24 intrabdo&ai’ (EE) ware ;denti&i.‘All patients received l&i&b (5 mglKgh.v.) at weeks 0. 2 and 6. Concurrent treatment with immune modllr agents and steroids was recorded. PA and EC fistulae ware considered closed when it no longer drained despite gentle finger compression. EE and RV fistulae were evaluated radiologically at the end of treatment. Results: Complete fistulae closure was observed in 33% (23/69l of oatients bv the end of the treatment regimen. Of 137 fistulae. i8% ‘were closed rifler the first infusion, 40% affer the second, 50% after the third. 62% of PA and 50% of EC fistulae closed in comparison with 15% of RV and 25% of EE fistulae. At follow up. 4.4 months (il.7) afler the last infusion, only 34% of fistulae were still closed. Twenty-six (38%) received concomitant treatment with immune modiLr agents, 21 (30%) were on steroids. Steroids withdrawal was possible in 86% patients. Infusion-related feactlons were observed in 81207 infusions (4%) in 7 patients. Conclusions: lofliximab .is an efficacious treatment for EC and PA fistulae complicating CD and healing is reported in l/3 of patients. The effect is temporary and 31% of responders will relapse within 4.4 months from their last dose. (1) Present DH. Rutgearts P. Targan S, at al. lnflllmab for the treatment of fistulae in patients with Cmhn’s Disease. N Engl J Med 1999; 340: 1398-1405.
6 TYPE TWO OF PROTEINASE ACTIVATED RECEPTORS (PAR-2) PROTECTS AGAINST COLlTlS THROUGH A CGRP-DEPENDENT PATHWAY. SFioruccL A.Mencarelli, B. Palazzett, G Cirino, E.Distrutti, JA Wallace, A. Morelli. GI Unit University of Perugia, Department of Pharmacology, University of Naples, Italy and University of Calgary CA. PAR receptors are a family of orphan receptors activated by trypsin. PAR-Z is expressed in the gastrointestinal tract although the physiological function is unknown. AIMS: to investigate whether PAR-2 modulates inflammation in a mouse model of colitis METHODS: Colitis was induced in mice bv intracolonic iniection of TNBS, 1 5 mglmouse. Animals ware then treated with placebo, PAR-2 agonist et the following doses 0.3, 1 and 1.4 mo/ka i.o alone or in combination wth the CGRP antaoonist (CGRP& br 7 days. Mice were then sacnficad and “&on segments harvested for histology and myeloperoxidase (MPO) assay. Colon expression of PAR-Z, IFNy, IL-10 and TNFa was assessed bv RT-PCR. The deoree of colon inflammation was graded on histologic sections frim 0 to 4.Colon content of IFNy, ILlp and TNFa was measured by specific ELISA Lamina propna T lymphocytes (LTL) were prepared from control and TNBSIPAR-2 treated mice and IFNy release in cell supernatants and cell proliferation in resting and CD3lCD20 stimulated calls measured. RESULTS PAR-2 administration resulted in a dose-dependent protection against colitis induced by TNBS. At the dose of 1.4 mg/kg the PAR-2 agonist completely protected against colitis as assessed bv measunna MPO acvtivitis. colitis scora and histoloav Cotreatina mice wth CGRPmt (10 pg/day) or eliminating caps&n sensitive fibers completely reverted the effect exerted by 1 4 mg/kg PAR-Z. Incubating LTL obtained from control animals and TNBS-treated mice with 10 @ml CD3iCD28 resulted in a concentrationdependent increase of IFNy release The stimulatory effect was completely lost in LPL prepared from TNBSIPAR-2 treated mice(P
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A60
LACTOEACILLUS GG IN THE PREVENTION OF POSTOPERATIVE RECURRENCE OF CROHN’S DISEASE: PRELIMINARY RESULTS OF A 12 MONTHS RANDOMIZED. DOUBLE-BLIND, PLACEBO CONTROLLED CLINICAL TRIAL. M.L. Scribano, G. Falasco and C. Prantera Division of Gastroenterology Azienda Ospedaliera “San Camille - Forlanini”. Rome, Italy. BACKGROUND: clinical and experimental observations have suggested that the intestinal flora may play a role in postsurgical recurrence of Crohn’s disease (CD). Conseauentlv. the ooerated patient represents the best condigon for studying the’influenck of the endoluminal bacteria on the recurrent lesions. AIMS: first aim of this trial has been to investigate the efficacy of a probiotic treatment with Lactobacillus GG (LGG) in reducing the severity of CD endoscopic recurrence afler surgery: secondary aim has been to assess whether LGG may influence the appearance and seventy of clinical symptoms. PATIENTS AND METHODS: 45 consecutive patients operated on for CD complications, have been randomized within 7-10 days after surgery to receive LGG, 6Xld u.f.c. bid, (n=23) or placebo (n=22) for 12 months. Clinical visits and laboratory tests were performed every 3 months. Endoscopic evaluation, following Rutgeetis scoring system (Gastroenteroloav 1990: 99: 956-63). was sheduled after 12 months br before in case of clinical recurrence. RESULTS: preliminary results are available on 26 of the 45 patients. Treatment characteristics and results are reported in the following table: LOG
Patients (male) Drop-outs Protocol violations Treatment failure Clinical remission (CDAI
14 2 3 2
:
(8) (14 %) (21 xj f22 %I
PLACEBO
12 (7) 1 (8%) 1 (8%j
2 (20 %l
7 +.sj
i iso%j
4 (50 %)
5 (62%)
CONCLUSIONS: preliminary results of this trial seem to suggest that LGG offers no benefit with respect to placebo in prevention of endoscopic and clinical recurrence after surgery for CD.
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5 Endowopic Implantation of a biocompatible no-biodegmdabk polymer ENTERYX UCvbvlmc-Vinvl Akohon for the Trmtment of Gastmeaophq& l&h Di&e (GElUij. G fL%amaq A. Psstorelli, M. Cicsla’, S Ton&*, PVavsssori*, M. Mutigmni, V Peni. Uait$ di Esdoscopia Digestiva Uaiversitii Cattolics sad ‘Libera Usiversitl Campus Biomedico, Rams Italy. Background and sim: GEBD is primarily s motility disorder that fosters the sbnommsl exposure of the esophagus to gastric acid. Most cammoo abnormality is the incompetence of the lower ssophsgeal sphincter (LBS) due to inappropriate trsnsient relsxstioes, or to s fixed low pressure We evslusted the safety, sad effectiveness of ss endoscopicslly implaetsble biocompstlble polyps @llZRYX) in iscressisg the lower esophageal sphincter limction (LES) in patient with GBRD Patienta e Metbod8: five subjects (ZM 3F), mesa age 52 (rssgs 46-69) with a history of GERD sed responsive to PPI were enrolled All subjects were evalusted with, pre sad post-trestmset, gsstroscopy, standard mseomeby for LES pressure, 24h pHmsUy, barium esophsgrsm sad questioensries (SF36, GERLI index, Diary). The injsction catheter wss first flushed with s solvent, dimethyl sulfoxide (OMSO) and then filled with ENTERYX. The injedim needle (23 gauge) punchred the mucma at ihe “Z” line and was advanced into tbc muscle of the cardis. Four injections of 1 oc each were msde at the ssme level sad circumferestislly srousd the cardll. Implants were performed under fluoroscopy to cot&m intrsmuml implant location
f&J&:
Coadssioo: BNTBRYX implant is well tolerated and extremely promising for GERD trsatmset. Sigalficstive increase of LES pressers was demonstrsted with standard mssomeby Adverse events were limited to mild-moderste retrostemal discomfort and fever for 12-36 hours following trestmsnt in all the pstients
INFLIXIMAB THERAPY FOR CROHNS DISEASE FISTULAE. THE ITALIAN EXPERIENCE: PRELIMINARY RESULTS. Kohn A. Vscido A. Ardiuone S, Biancone L. Stumiolo GC, Vavasson P. Sostegni R. Pdncipi B, Papi C, Castiglione F, Zoli G, Caprilli R. Gruppo Italian0 Studio Infliximab. Background. Crohn’s Disease (CD) is characterized by segmental tiansmural inflammation with development of fistulae in approximately one third of patients. Spontaneous healing of Cstulae is rare and the result of diug treatments is deceivable lnfliximab has recently been developed as a treatment of CD and seems to be an efficacious traabnent for fistulae in patients with CD (1). Aim: To rawit the clinical outcome and side affects of 69 patients with tistulidng CD treated with lnfliximab at ten differenl Italian Centers of Gastmenterology. Methods: B&wean January 1999 and March 2000, 38 males and 31 females with intrabdominal and/or draining entenxutaneous fistulae from CD. mean age 36 year (*12.7). were treated with Inflixlmab. All patients had single or multiple Rstulae of at least three months duration; 137 fistulae, 83 c&anal (PA). 15 rectovaoinal fRVI. 15 entenxutaneous (EC). 24 intrabdo&ai’ (EE) ware ;denti&i.‘All patients received l&i&b (5 mglKgh.v.) at weeks 0. 2 and 6. Concurrent treatment with immune modllr agents and steroids was recorded. PA and EC fistulae ware considered closed when it no longer drained despite gentle finger compression. EE and RV fistulae were evaluated radiologically at the end of treatment. Results: Complete fistulae closure was observed in 33% (23/69l of oatients bv the end of the treatment regimen. Of 137 fistulae. i8% ‘were closed rifler the first infusion, 40% affer the second, 50% after the third. 62% of PA and 50% of EC fistulae closed in comparison with 15% of RV and 25% of EE fistulae. At follow up. 4.4 months (il.7) afler the last infusion, only 34% of fistulae were still closed. Twenty-six (38%) received concomitant treatment with immune modiLr agents, 21 (30%) were on steroids. Steroids withdrawal was possible in 86% patients. Infusion-related feactlons were observed in 81207 infusions (4%) in 7 patients. Conclusions: lofliximab .is an efficacious treatment for EC and PA fistulae complicating CD and healing is reported in l/3 of patients. The effect is temporary and 31% of responders will relapse within 4.4 months from their last dose. (1) Present DH. Rutgearts P. Targan S, at al. lnflllmab for the treatment of fistulae in patients with Cmhn’s Disease. N Engl J Med 1999; 340: 1398-1405.
6 TYPE TWO OF PROTEINASE ACTIVATED RECEPTORS (PAR-2) PROTECTS AGAINST COLlTlS THROUGH A CGRP-DEPENDENT PATHWAY. SFioruccL A.Mencarelli, B. Palazzett, G Cirino, E.Distrutti, JA Wallace, A. Morelli. GI Unit University of Perugia, Department of Pharmacology, University of Naples, Italy and University of Calgary CA. PAR receptors are a family of orphan receptors activated by trypsin. PAR-Z is expressed in the gastrointestinal tract although the physiological function is unknown. AIMS: to investigate whether PAR-2 modulates inflammation in a mouse model of colitis METHODS: Colitis was induced in mice bv intracolonic iniection of TNBS, 1 5 mglmouse. Animals ware then treated with placebo, PAR-2 agonist et the following doses 0.3, 1 and 1.4 mo/ka i.o alone or in combination wth the CGRP antaoonist (CGRP& br 7 days. Mice were then sacnficad and “&on segments harvested for histology and myeloperoxidase (MPO) assay. Colon expression of PAR-Z, IFNy, IL-10 and TNFa was assessed bv RT-PCR. The deoree of colon inflammation was graded on histologic sections frim 0 to 4.Colon content of IFNy, ILlp and TNFa was measured by specific ELISA Lamina propna T lymphocytes (LTL) were prepared from control and TNBSIPAR-2 treated mice and IFNy release in cell supernatants and cell proliferation in resting and CD3lCD20 stimulated calls measured. RESULTS PAR-2 administration resulted in a dose-dependent protection against colitis induced by TNBS. At the dose of 1.4 mg/kg the PAR-2 agonist completely protected against colitis as assessed bv measunna MPO acvtivitis. colitis scora and histoloav Cotreatina mice wth CGRPmt (10 pg/day) or eliminating caps&n sensitive fibers completely reverted the effect exerted by 1 4 mg/kg PAR-Z. Incubating LTL obtained from control animals and TNBS-treated mice with 10 @ml CD3iCD28 resulted in a concentrationdependent increase of IFNy release The stimulatory effect was completely lost in LPL prepared from TNBSIPAR-2 treated mice(P
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A60
LACTOEACILLUS GG IN THE PREVENTION OF POSTOPERATIVE RECURRENCE OF CROHN’S DISEASE: PRELIMINARY RESULTS OF A 12 MONTHS RANDOMIZED. DOUBLE-BLIND, PLACEBO CONTROLLED CLINICAL TRIAL. M.L. Scribano, G. Falasco and C. Prantera Division of Gastroenterology Azienda Ospedaliera “San Camille - Forlanini”. Rome, Italy. BACKGROUND: clinical and experimental observations have suggested that the intestinal flora may play a role in postsurgical recurrence of Crohn’s disease (CD). Conseauentlv. the ooerated patient represents the best condigon for studying the’influenck of the endoluminal bacteria on the recurrent lesions. AIMS: first aim of this trial has been to investigate the efficacy of a probiotic treatment with Lactobacillus GG (LGG) in reducing the severity of CD endoscopic recurrence afler surgery: secondary aim has been to assess whether LGG may influence the appearance and seventy of clinical symptoms. PATIENTS AND METHODS: 45 consecutive patients operated on for CD complications, have been randomized within 7-10 days after surgery to receive LGG, 6Xld u.f.c. bid, (n=23) or placebo (n=22) for 12 months. Clinical visits and laboratory tests were performed every 3 months. Endoscopic evaluation, following Rutgeetis scoring system (Gastroenteroloav 1990: 99: 956-63). was sheduled after 12 months br before in case of clinical recurrence. RESULTS: preliminary results are available on 26 of the 45 patients. Treatment characteristics and results are reported in the following table: LOG
Patients (male) Drop-outs Protocol violations Treatment failure Clinical remission (CDAI
14 2 3 2
:
(8) (14 %) (21 xj f22 %I
PLACEBO
12 (7) 1 (8%) 1 (8%j
2 (20 %l
7 +.sj
i iso%j
4 (50 %)
5 (62%)
CONCLUSIONS: preliminary results of this trial seem to suggest that LGG offers no benefit with respect to placebo in prevention of endoscopic and clinical recurrence after surgery for CD.
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