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Morphine protection against ethanol-induced gastric damage - role of nitric oxide and neuropeptides
April 1995
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EVALUATION OF THE EFFICACY OF CLARITHROMYCIN ERADICATION OF HELICOBAC'rER PYLORI {Hp)
Esophageal, Gastric, and Duodenal Disorders
IN THE
C. Spiliadis1, S. Geor(]ooculos1. P. Stambolos1, A. Mentis2. L. Gianikaki2 Z. Manika3, N. Skandalis1 Department of GastroeneterologyI and Pathology3, General Hosp. of Athens Department of Bacteriology2, Hellenic Pasteur Institute, Athens The triple treatment regimen (metronidazole, tetracycline and Colloidal Bismuth Subeitratel s considered as the most effective in the eradication of Hp. although it is associated with undesirable events (such as glossitis, vertigo, diarrhea etc.). Recent studies have shown that clarithromycin (CL), aprticularly in combination with omprazole (OMP) has a similar efficacy in the eradication of Hp. The aim of this study was to evaluate the efficacy of CL alone and in combination with Colloidal Bismuth Subeitrate (CBS) comparatively with the triple treatment regimen for the eradication of Hp in patients with a healed duodenal ulcer (DU) after treatment with OMP. Patients-Methods: A hundred and two patients (73/29, men/women) with a documented Hp infection (by CIo-test. histology ano culture) had a 14 days treatment with OMP 20mgx2. Ninety seven (97) patients with encoscopically heale(~ DU were randomly assigneo to one of the three treatment groups: the group A received CL alone 250mgx4, the group B CL 250mgx4 in combination with CBS 30Omgx4 ano the group C metronidazole 500mgx3, tetracyclin 500mgx4 plus CBS 300mgx4. The eradication treatment was of 14 days duration in all the three groups. All the patients underwent a gastroscopy with biopsies 1 month after treatment completion in oraer to assess the presence or absence of Hp. Results: Group A: eradication of Hp in 22131 patients (71%) and the remaining 9 (29%) Hp positive patients, a (13%) had a recurrence of DU after the post treatment control. Group B: eradication of Hp in 29•32 patients [90,6%), and from the 3 (9,4%) Hp positive patients, 1 (3,1%) had a recurrence of DU. Group eradication of Hp in 29•32 patients (85,3%1 ana from the 5 (14,7%) Hp positive patients 2 (5,9%) had a recurrence of DU. The response of treatment was significantly increased in group B compared to group A (p<0.05). The therapeutic response was not statistically different between patients in group C and patients in the two other groups. Five (5) patients of group C pre~ented adverse events compared to no patient in groups A and B. Conclusions: 1. The combination therapy with CL and CBS has clear advantages over monotherapy with CL for the eradication of Hp in patients with healed DU after pre-treatment with OMP. 2. Compared to classical triple therapy, the therapeutic regimen including CL has an equal efficacy and a better tolerability.
Q PATH ANALYSIS MODELS FAIL TO LINK BALLOON-DISTENTION SENSITIVITY OR NONSPECIFIC MOTOR ABNORMALITIES WITH UNEXPLAINED CHEST PAIN. A. Stalano, K.E. Freedland, P.J, Lustman, R.E. Ctouse. Division of Gastroenterology and Department of Psychiatry, Washington University School of Medicine, St. Louis, MO Heightened sensitivity to intraluminal balloon distention (BD) and nonspecific motility abnormalities (NSM) are prevalent in patients with unexplained chest pain and other esophageal symptoms, but their importance remains unresolved: Coexistent psychologic disorders (e.g., anxiety, depression) or other clinical conditions may confound detecting a significant contribution by the physiologic markers to symptom production. Path analysis methods were used in 274 patients referred for evaluation ofunexplained esophageal symptoms to see ifNSM or BD hypersensitivity correlated with symptom production once potentially confounding variables were considered. Subjects completed a standardized clinical questionnaire (11 variables), the SCL-90 (4 psychologic scales), manometry (5 variables aimed at NSM), and BD testing using previously described techniques (0-12 ml/2 ml steps) with chest pain production as the endpoint. RESULTS: NSM was diagnosed in 121 (44.2%), organic motor disorder (OMD) in 29 (10.6%), normal motility in 124 (45.3%). BD hypersensitivity (pain at <8rnl) was present in 84 (30.1%). BD hypersensitivity was found in only 10.3% of subjects with OMD, but 33.1% of the remainder (p<0.05). Correlation matrices were established for all motility groups, NSM + normal motility, and individual groups using the 21 variables derived from the measures. Chest pain and global symptom ratings correlated most significantly (p<0.01) with all 4 SCL-90 scales (I=. 19-.26), abdominal pain, and other esophageal symptom measures, but not with BD sensitivity (r=-0.1, NS) nor any manometric indicator of NSM. BD sensitivity (continuous or categorical) correlated significantly (p<0.00l) only with gender (r=0.2 toward female) and younger age ([=0.2), but with no symptom or manometric variable. Path models created from literature associations interposing BD sensitivity and NSM as intermediaries to symptom production did not fit these data. CONCLUSIONS: Psychologic and certain other clinical factors are measurable contributors to symptom reporting in patients with unexplained chest pain and esophageal symptoms. Despite the prevalence of NSM and BD hypersensitivity, a relationship of these physiologic findings to chest symptoms is not apparent.
A225
EBROTIDINE VS RANITIDINE IN QUALITY HEALING OF DUODENAL ULCER (DU], J. Staohura S.J. Konttn'ek, N. Kwiecien, W. Dabros, E Sito. Inst. Physiol., Univ. Sch. Med. Krakow, Poland. The advent of H2-blockers greatly improved the rate of DU healing but ulcer frequently Feczu- due to poor quality of healing that has been attributed to Helicobacter pylorl {HID) infection. Ebrotidine (E} is a novel B2-antagonlst with unique c~rtoprotective activity and high inhibitory effects on protease and lipase activities of Hr. This study compared the quality of DU healing treated with E {800 mg nocte) or with ranitidine (R)(300 mg nocte). In 20 randomized DU endoscopy was performed prior and day after 4 wk therapy with E or R. Gastric blood flow (GBF) was measured by endoscopic laser Doppler technique and biopsy samples were taken from the ulcer bed, ulcer margin and distant duodenal mucosa. The antral mueosa was also biopsied to assess the HE' status. In addition routine histolo~, expression of EGF and cycIIDEPCNA (a proliferation marker) in mucosa adjacent to DU was studied hlstoohemlcally. At the beginning and the end of therapy all DO patients weFe'}~P positive. DU was endoscopioally healed in all patients after 4 wk therapy with E and R, By the end of therapy BOZ D U h e a l e d w i t h R showed poor quality of healing with flat red mucosal scar without villi formation oF only very short villi. This flat red scar was seen only in IOZ of DU healed with E while remaining showed formation of regular villi. There was no significant difference in ECF expression (present mostly at the ulcer margin) between E and R but PCNA expression was much stronger in flat mucosal scar that was common in patients treated with R but not with E. Initially, CBF was smaller (by about ISZ) at the ulcer bed than at ulcer margin in all DU but by the end the GBF was not different between the ulcer scar and ulcer rim both in E and R treated. We conclude that the quality of ulcer healing after therap~ with E ~ better than after R as assessed by histology and proliferation marker.
MORPHINE PROTECTION AGAINST ETHANOL-INDUCED GASTRIC DAMAGE - ROLE OF NITRIC OXIDE AND NEUROPEPTIDES. R. Stalnikowicz, F. Karmeli, D. Rachmilewitz, Department of Medicine, Hadassah University Hospital, Jerusalem, Israel. Nitric oxide (NO) contributes to the maintenance of mucosal integrity through its effects on mucosal blood flow, acid and alkali secretion. We tested whether the protection afforded by morphine (M) against ethanol (E) induced gastric damage is mediated by its effects on nitric oxide generation and whether it is mediated by neuropeptides. M (2.5 mg/kg) was injected s.c., with and without i.v. administration of L-NAME, 30 min before i.g. administration of 1 ml E (96%) to fasted rats. Other rats received capsaicin (CAPS) s.c. 20, 30 and 50 mg/kg, on three subsequent days, two weeks before i.g. E administration, with or without s.c. injection of M 30 min beforehand. Rats were sacrificed 30 min after E administration, the stomach removed, washed and hemorrhagic lesions measured (mm2/rat). Mucosal scrapings were taken for determination of NO synthase (NOS) activity (nmol/min/g). L-NAME and CAPS augmented E-induced gastric lesion formation by 59% and 39%, respectively, while pretreatment with M effectively decreased E and E + L-NAME or CAPS induced lesions by 49%, 41% and 66%, respectively. E and L-NAME or CAPS augmented damage was accompanied by significant decrease in NOS activity which was partially reversed by M. No~ Lesions NOS Control 33 5.1_+0.2 Ethanol 24 59_+8* 2.9_+0.3~* Ethanol + Morphine 8 30_+13"* 3:9_+0.2 Ethanol + L-NAME 10 1 5 1 + ~ 6 " 1.6_+0.2"** Ethanol + Morphine + L-NAME 10 62-+15"* 1.5-+0.02 Ethanol + Capsaicin 5 122_+18" 2.5+0.2~* Ethanol + Morphine + Capsaicin 6 28+16~ 2.5-+0.2 * significantly different from control and E; ~ from E, L-NAME + E or CAPS + E; ~ from control (p<0.05). Conclusions: 1) M effectively reduces E-induced gastric mucosal damage and its augmentation by L-NAME and CAPS. 2) The gastroprotective effect of M: a) is not neuropeptide-mediated since it was preserved despite ablation of afferent neurons by CAPS; b) is only partially related to the NO pathway since it was present, despite a significant decrease in NOS activity.
•
EVALUATION OF THE EFFICACY OF CLARITHROMYCIN ERADICATION OF HELICOBAC'rER PYLORI {Hp)
Esophageal, Gastric, and Duodenal Disorders
IN THE
C. Spiliadis1, S. Geor(]ooculos1. P. Stambolos1, A. Mentis2. L. Gianikaki2 Z. Manika3, N. Skandalis1 Department of GastroeneterologyI and Pathology3, General Hosp. of Athens Department of Bacteriology2, Hellenic Pasteur Institute, Athens The triple treatment regimen (metronidazole, tetracycline and Colloidal Bismuth Subeitratel s considered as the most effective in the eradication of Hp. although it is associated with undesirable events (such as glossitis, vertigo, diarrhea etc.). Recent studies have shown that clarithromycin (CL), aprticularly in combination with omprazole (OMP) has a similar efficacy in the eradication of Hp. The aim of this study was to evaluate the efficacy of CL alone and in combination with Colloidal Bismuth Subeitrate (CBS) comparatively with the triple treatment regimen for the eradication of Hp in patients with a healed duodenal ulcer (DU) after treatment with OMP. Patients-Methods: A hundred and two patients (73/29, men/women) with a documented Hp infection (by CIo-test. histology ano culture) had a 14 days treatment with OMP 20mgx2. Ninety seven (97) patients with encoscopically heale(~ DU were randomly assigneo to one of the three treatment groups: the group A received CL alone 250mgx4, the group B CL 250mgx4 in combination with CBS 30Omgx4 ano the group C metronidazole 500mgx3, tetracyclin 500mgx4 plus CBS 300mgx4. The eradication treatment was of 14 days duration in all the three groups. All the patients underwent a gastroscopy with biopsies 1 month after treatment completion in oraer to assess the presence or absence of Hp. Results: Group A: eradication of Hp in 22131 patients (71%) and the remaining 9 (29%) Hp positive patients, a (13%) had a recurrence of DU after the post treatment control. Group B: eradication of Hp in 29•32 patients [90,6%), and from the 3 (9,4%) Hp positive patients, 1 (3,1%) had a recurrence of DU. Group eradication of Hp in 29•32 patients (85,3%1 ana from the 5 (14,7%) Hp positive patients 2 (5,9%) had a recurrence of DU. The response of treatment was significantly increased in group B compared to group A (p<0.05). The therapeutic response was not statistically different between patients in group C and patients in the two other groups. Five (5) patients of group C pre~ented adverse events compared to no patient in groups A and B. Conclusions: 1. The combination therapy with CL and CBS has clear advantages over monotherapy with CL for the eradication of Hp in patients with healed DU after pre-treatment with OMP. 2. Compared to classical triple therapy, the therapeutic regimen including CL has an equal efficacy and a better tolerability.
Q PATH ANALYSIS MODELS FAIL TO LINK BALLOON-DISTENTION SENSITIVITY OR NONSPECIFIC MOTOR ABNORMALITIES WITH UNEXPLAINED CHEST PAIN. A. Stalano, K.E. Freedland, P.J, Lustman, R.E. Ctouse. Division of Gastroenterology and Department of Psychiatry, Washington University School of Medicine, St. Louis, MO Heightened sensitivity to intraluminal balloon distention (BD) and nonspecific motility abnormalities (NSM) are prevalent in patients with unexplained chest pain and other esophageal symptoms, but their importance remains unresolved: Coexistent psychologic disorders (e.g., anxiety, depression) or other clinical conditions may confound detecting a significant contribution by the physiologic markers to symptom production. Path analysis methods were used in 274 patients referred for evaluation ofunexplained esophageal symptoms to see ifNSM or BD hypersensitivity correlated with symptom production once potentially confounding variables were considered. Subjects completed a standardized clinical questionnaire (11 variables), the SCL-90 (4 psychologic scales), manometry (5 variables aimed at NSM), and BD testing using previously described techniques (0-12 ml/2 ml steps) with chest pain production as the endpoint. RESULTS: NSM was diagnosed in 121 (44.2%), organic motor disorder (OMD) in 29 (10.6%), normal motility in 124 (45.3%). BD hypersensitivity (pain at <8rnl) was present in 84 (30.1%). BD hypersensitivity was found in only 10.3% of subjects with OMD, but 33.1% of the remainder (p<0.05). Correlation matrices were established for all motility groups, NSM + normal motility, and individual groups using the 21 variables derived from the measures. Chest pain and global symptom ratings correlated most significantly (p<0.01) with all 4 SCL-90 scales (I=. 19-.26), abdominal pain, and other esophageal symptom measures, but not with BD sensitivity (r=-0.1, NS) nor any manometric indicator of NSM. BD sensitivity (continuous or categorical) correlated significantly (p<0.00l) only with gender (r=0.2 toward female) and younger age ([=0.2), but with no symptom or manometric variable. Path models created from literature associations interposing BD sensitivity and NSM as intermediaries to symptom production did not fit these data. CONCLUSIONS: Psychologic and certain other clinical factors are measurable contributors to symptom reporting in patients with unexplained chest pain and esophageal symptoms. Despite the prevalence of NSM and BD hypersensitivity, a relationship of these physiologic findings to chest symptoms is not apparent.
A225
EBROTIDINE VS RANITIDINE IN QUALITY HEALING OF DUODENAL ULCER (DU], J. Staohura S.J. Konttn'ek, N. Kwiecien, W. Dabros, E Sito. Inst. Physiol., Univ. Sch. Med. Krakow, Poland. The advent of H2-blockers greatly improved the rate of DU healing but ulcer frequently Feczu- due to poor quality of healing that has been attributed to Helicobacter pylorl {HID) infection. Ebrotidine (E} is a novel B2-antagonlst with unique c~rtoprotective activity and high inhibitory effects on protease and lipase activities of Hr. This study compared the quality of DU healing treated with E {800 mg nocte) or with ranitidine (R)(300 mg nocte). In 20 randomized DU endoscopy was performed prior and day after 4 wk therapy with E or R. Gastric blood flow (GBF) was measured by endoscopic laser Doppler technique and biopsy samples were taken from the ulcer bed, ulcer margin and distant duodenal mucosa. The antral mueosa was also biopsied to assess the HE' status. In addition routine histolo~, expression of EGF and cycIIDEPCNA (a proliferation marker) in mucosa adjacent to DU was studied hlstoohemlcally. At the beginning and the end of therapy all DO patients weFe'}~P positive. DU was endoscopioally healed in all patients after 4 wk therapy with E and R, By the end of therapy BOZ D U h e a l e d w i t h R showed poor quality of healing with flat red mucosal scar without villi formation oF only very short villi. This flat red scar was seen only in IOZ of DU healed with E while remaining showed formation of regular villi. There was no significant difference in ECF expression (present mostly at the ulcer margin) between E and R but PCNA expression was much stronger in flat mucosal scar that was common in patients treated with R but not with E. Initially, CBF was smaller (by about ISZ) at the ulcer bed than at ulcer margin in all DU but by the end the GBF was not different between the ulcer scar and ulcer rim both in E and R treated. We conclude that the quality of ulcer healing after therap~ with E ~ better than after R as assessed by histology and proliferation marker.
MORPHINE PROTECTION AGAINST ETHANOL-INDUCED GASTRIC DAMAGE - ROLE OF NITRIC OXIDE AND NEUROPEPTIDES. R. Stalnikowicz, F. Karmeli, D. Rachmilewitz, Department of Medicine, Hadassah University Hospital, Jerusalem, Israel. Nitric oxide (NO) contributes to the maintenance of mucosal integrity through its effects on mucosal blood flow, acid and alkali secretion. We tested whether the protection afforded by morphine (M) against ethanol (E) induced gastric damage is mediated by its effects on nitric oxide generation and whether it is mediated by neuropeptides. M (2.5 mg/kg) was injected s.c., with and without i.v. administration of L-NAME, 30 min before i.g. administration of 1 ml E (96%) to fasted rats. Other rats received capsaicin (CAPS) s.c. 20, 30 and 50 mg/kg, on three subsequent days, two weeks before i.g. E administration, with or without s.c. injection of M 30 min beforehand. Rats were sacrificed 30 min after E administration, the stomach removed, washed and hemorrhagic lesions measured (mm2/rat). Mucosal scrapings were taken for determination of NO synthase (NOS) activity (nmol/min/g). L-NAME and CAPS augmented E-induced gastric lesion formation by 59% and 39%, respectively, while pretreatment with M effectively decreased E and E + L-NAME or CAPS induced lesions by 49%, 41% and 66%, respectively. E and L-NAME or CAPS augmented damage was accompanied by significant decrease in NOS activity which was partially reversed by M. No~ Lesions NOS Control 33 5.1_+0.2 Ethanol 24 59_+8* 2.9_+0.3~* Ethanol + Morphine 8 30_+13"* 3:9_+0.2 Ethanol + L-NAME 10 1 5 1 + ~ 6 " 1.6_+0.2"** Ethanol + Morphine + L-NAME 10 62-+15"* 1.5-+0.02 Ethanol + Capsaicin 5 122_+18" 2.5+0.2~* Ethanol + Morphine + Capsaicin 6 28+16~ 2.5-+0.2 * significantly different from control and E; ~ from E, L-NAME + E or CAPS + E; ~ from control (p<0.05). Conclusions: 1) M effectively reduces E-induced gastric mucosal damage and its augmentation by L-NAME and CAPS. 2) The gastroprotective effect of M: a) is not neuropeptide-mediated since it was preserved despite ablation of afferent neurons by CAPS; b) is only partially related to the NO pathway since it was present, despite a significant decrease in NOS activity.