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Effect of high dose omeprazole on airway hyperresponsiveness and pulmonary function in patients with obstructive lung disease
April 1 9 9 5
RESoLuTIoN OF HELICOBACTER PYLORI-ASSOCIATED GASTRIC LYMPHOPROLIFERATIVE DISEASE DURING CHILDHOOD: A SEVEN YEAR FOLLOW-UP. U. Bleck@~*, T~W. MeKeithan +, J. Hart +, B.S. Kirschner*. Depts. of *Pediatrics and +Pathology, Pritzker School of Medicine, Wyler Children's Hospital, The University of Chicago, Chicago, IL.
Helicobacter pylori (H. pylori) has been found to be the major cause for gastroduodenal pathology, both in adults and children, a finding which resulted in a new understanding and approach of chronic active gastritis, duodenal ulcers, and, to a lesser degree, gastric ulcers. Very recently, H. p y l o r i has also been described in a s s o c i a t i o n with gastric lymphoproliferative disease, more specifically l o w - g r a d e B-cell lymphoma (MALToma) of the stomach, and even gastric non-Hodgkin lymphoma. We report the case of a 14-year-old girl presenting with severe cachexia, abdominal pain, and nausea, who was diagnosed with H. pylori chronic active gastritis and associated gastric lymphoproliferative disease of the low-grade MALT type (as defined by histology and typical gene rearrangements). The patient was treated only for the H. pylori infection (amoxicillin-bismuth-metronidazole t r i p l e therapy) without any adjuvant chemotherapy or surgery for her lymphoproliferative disease. The patient was subsequently followed for a period of 7 years with repeated esophago-gastroduodenoscopies with biopsies. There has been no histologic recurrence of H. pylori gastritis or lymphoproliferative disease. To our knowledge, this is the first report of an H. pylori associated gastric lymphoproliferative disorder in a pediatric patient who was exclusively treated for H. pylori infection and subsequently followed for a period of 7 years. Our observations suggest that H. pylori associated gastric lymphoproliferative disease can be completely cured by eradicating the organism. Therefore, this therapeutic approach, combined with close follow-up, should be the t r e a t m e n t of choice in children with this associated condition, before attempting more aggressive treatments, thus p o t e n t i a l l y avoiding chemotherapy and/or (partial) gastreetomy.
• EFFECT OF HIGH DOSE OMEPRAZOLE ON AIRWAY HYPERRESPONSIVENESS AND PULMONARY FUNCTION IN PATIENTS WITH OBSTRUCTIVE LUNG DISEASE. MJ Boeree, FTM Peters, DS P0stma, JH Kleibeuker. Depts Pulmonology and Gastroenterology, University Hospital, Groningen, The Netherlands.
The role of acid reflux in the pathogenesis of obstructive lung disease is an unsettled question. We studied the effect of high dose omeprazole on symptoms, airway hyperresponsiveness (AH) and pulmonary function in patients with obstructive lung disease and increased acid gastroesophageal reflux. Methods 36 pts, mean age 52 yrs, were included in this 3-month double-blind placebo-controlled study with omeprazole 40 mg b.i.d. Included were pts with airway obstruction, severe AH (PCzo methacholine < 2 mg/ml) despite maintenance treatment with _> 0.4 mg inhaled corticosteriod/day, and with increased acid reflux (pH < 4 more than 4%/24 h and/or more than 3% in supine position). Parameters tested were pulmonary and reflux symptoms, degree of acid reflux, AH (PC2o methacholine), spirometry (FEV1, VC), reversibility of FEVI, morning and evening peak flow and diurnal peak flow variability. Intention to treat analysis was performed. Results Omeprazole drastically reduced 24-h acid reflux (p=0.02 vs placebo) and improved heartburn (9=0.03 vs placebo). Also, nocturnal cough was better during omeprazole (9=0.03 vs placebo). However, effects on other pulmonary symptoms and on AH, spirometry, reversibility and peak flow parameters were not significantly different between omeprazole and placebo after 3 months treatment. Conclusion Despite its profound effect on acid reflux, treatment with high dose omeprazole did not improve airway hyperresponsiveness, pulmonary function and pulmonary symptoms, except for nocturnal cough. These results do not suggest a significant role of acid reflux in the pathogenesis of obstructive lung disease and thus do not support a role f~r acid inhibitory drugs in the treatment of this disorder. (Funded in part by Astra Pharmaceutica, Rijswijk, The Netherlands).
Esophageal, Gastric, and Duodenal Disorders
A61
PANTOPRAZOLE DOES NOT INTERACT WITH DICLOFENAC. H. Bliesath, R. Huber, .M. Hartmann, V.W. Steinijans, H.J. Koch, W. Wurst. Research Devision Byk Gulden, Konstanz, Germany Introduction: The treatment with non steroidal antiinflammatory drugs (NSAIDs) increases the risk of developing gastrointestinal ulcers. For prophylaxis or treatment of these lesions drugs are used which reduce gastric acidity. Therefore an interaction between a NSAID and concomitant medication is of interest. Pantoprazole, a new H*/K*-ATPase inhibitor with a low potential to interact with the cytochrome P450 system potently inhibits gastric acidity. We investigated the influence of pantoprazole on the pharmacokinetics of diclofenac as both drugs are metabolized by the liver. Methods: In a randomized crossover study 24 (13 m/11 f) healthy volunteers received orally: 100 mg diclofenac with 40 mg pantoprazole (Test), and 100 mg diclofenac alone (Reference). BP, HR, ECG and clinical laboratory were measured. The pharmacokinetic characteristics AUC and C_,x of diclofenac were determined after administration with and wi{~out pantoprazole. A possible pharmacokinetic interaction was calculated according to the bioequivalence procedure, i.e. no interaction was concluded if the 90% confidence intervals (CI) of the ratios Test/Reference were entirely within the range of 0,80 - 1.25. Results." Pantoprazole and diclofenac did not influence vital signs or clinical laboratory results. The following pharmacokinetic characteristics were calculated: Pharmacokinetic characteristic of diclofenac
AUC(o.=) (mgxh/L) Cmax (mg/L)
diclofenac alone geom. mean (68%-rankle)
diclofenac & pantoprazole geom. mean (68%-ran@e)
Teat:
Equivalence ratio
3.15
3.17 (2.44, 4.11 )
1.01 (0.95, 1.07)
Reference:
(2.51, 3.95) 2.32
(1.60, 3.37)
2.36
(1.79, 3.10)
(Test/Reference) Point estimate (90% CI)
1.01
(0.90, 1.15)
Conclusions: Both drugs were well tolerated. Lack of interaction
between pantoprazole and diclofenac was demonstrated and the two drugs can be administered concomitantly without dose adjustment.
ENDOSCOPIC GASTROESOPHAGEAL REFLUX DISEASE (GERD). RELATIONSHIP BETWEEN HISTOLOGY AND AGE AND EXTENT OF METAPLASTIC EPITHELIUM. L Bonelli, H. Aste, M. Conio and G.O.SPE.* National Institute for Cancer Research, Genova, Italy * (Gruppo Operativo per 1o Studio delle Precancerosi dell'Esofago)-Italy. The aim of the present study was to evaluate the characteristics of GERD at different ages. From November 1987, 661 pts (464 males and 197 females, median age 59 yrs, range 13-94 yrs) with endoscopic esophagitis grade 2-4, including Barrett's esophagus (BE) (Savary's classification) underwent multiple biopsies (at least 4) from the distal esophagus. Histologic examination showed esophagitis in 231 pts (34.9°/o), gastric type BE in 214 (32.4%) and specialized columnar epithelium (SCE), alone or associated with gastric types, in 216 (32.7%). The mean age at diagnosis in the three groups was 56.6~:14.3 yrs, 52.9±15.0 yrs and 60.2A:13.6 yrs respectively. The frequency of esophagitis was constant across age decades; gastric BE was more frequent among younger pts, as age increased a rising frequency of SCE was observed (l-way analysis of variance, p<0.0001). A correlation between age and extent of metaplastie epithelium (ME) w a s observed (r=0.12, p--0.01). The mean extent of ME was 2.73±1.88 for lmtieata with gastric type BE and 4.33:L2.96 for thos¢ with SCE (z=6.04, p<0.0001). The data suggest an association between age, extent of ME and detection of SCE. In order to avoid confounding effects~ data concerning gender, age and extent of metaplastic epitheliun were fitted to a multivariate logistic regressign analysis: increase in the age and in the extent of ME were independent eovariates significantly associated with the probability of detecting SCE at histology 0Lq=l.37, c.i. 1.19-1.58 and RR=l.90, c.i. 1.46-2.46, respectively). Dysplasia was observed only in SCE: 19 indefinite, 10 low grade, 2 high grade. Conclusions: as a result of the damage due to chronic gastroesoptmgeal reflux, pts can develop esophagitis or Barrett's esophagus. In the latter group, with advancing age an upward creep of ME and a progressive expansion of islands of SCE could be observed and dysplasia is usually confined to these islands. Therefore, SCE may represent a marker of disease chrnnicity in which dysplasia and neoplasia can develop. (Supported by Bracco S.p.A.-Milano, Italy)
RESoLuTIoN OF HELICOBACTER PYLORI-ASSOCIATED GASTRIC LYMPHOPROLIFERATIVE DISEASE DURING CHILDHOOD: A SEVEN YEAR FOLLOW-UP. U. Bleck@~*, T~W. MeKeithan +, J. Hart +, B.S. Kirschner*. Depts. of *Pediatrics and +Pathology, Pritzker School of Medicine, Wyler Children's Hospital, The University of Chicago, Chicago, IL.
Helicobacter pylori (H. pylori) has been found to be the major cause for gastroduodenal pathology, both in adults and children, a finding which resulted in a new understanding and approach of chronic active gastritis, duodenal ulcers, and, to a lesser degree, gastric ulcers. Very recently, H. p y l o r i has also been described in a s s o c i a t i o n with gastric lymphoproliferative disease, more specifically l o w - g r a d e B-cell lymphoma (MALToma) of the stomach, and even gastric non-Hodgkin lymphoma. We report the case of a 14-year-old girl presenting with severe cachexia, abdominal pain, and nausea, who was diagnosed with H. pylori chronic active gastritis and associated gastric lymphoproliferative disease of the low-grade MALT type (as defined by histology and typical gene rearrangements). The patient was treated only for the H. pylori infection (amoxicillin-bismuth-metronidazole t r i p l e therapy) without any adjuvant chemotherapy or surgery for her lymphoproliferative disease. The patient was subsequently followed for a period of 7 years with repeated esophago-gastroduodenoscopies with biopsies. There has been no histologic recurrence of H. pylori gastritis or lymphoproliferative disease. To our knowledge, this is the first report of an H. pylori associated gastric lymphoproliferative disorder in a pediatric patient who was exclusively treated for H. pylori infection and subsequently followed for a period of 7 years. Our observations suggest that H. pylori associated gastric lymphoproliferative disease can be completely cured by eradicating the organism. Therefore, this therapeutic approach, combined with close follow-up, should be the t r e a t m e n t of choice in children with this associated condition, before attempting more aggressive treatments, thus p o t e n t i a l l y avoiding chemotherapy and/or (partial) gastreetomy.
• EFFECT OF HIGH DOSE OMEPRAZOLE ON AIRWAY HYPERRESPONSIVENESS AND PULMONARY FUNCTION IN PATIENTS WITH OBSTRUCTIVE LUNG DISEASE. MJ Boeree, FTM Peters, DS P0stma, JH Kleibeuker. Depts Pulmonology and Gastroenterology, University Hospital, Groningen, The Netherlands.
The role of acid reflux in the pathogenesis of obstructive lung disease is an unsettled question. We studied the effect of high dose omeprazole on symptoms, airway hyperresponsiveness (AH) and pulmonary function in patients with obstructive lung disease and increased acid gastroesophageal reflux. Methods 36 pts, mean age 52 yrs, were included in this 3-month double-blind placebo-controlled study with omeprazole 40 mg b.i.d. Included were pts with airway obstruction, severe AH (PCzo methacholine < 2 mg/ml) despite maintenance treatment with _> 0.4 mg inhaled corticosteriod/day, and with increased acid reflux (pH < 4 more than 4%/24 h and/or more than 3% in supine position). Parameters tested were pulmonary and reflux symptoms, degree of acid reflux, AH (PC2o methacholine), spirometry (FEV1, VC), reversibility of FEVI, morning and evening peak flow and diurnal peak flow variability. Intention to treat analysis was performed. Results Omeprazole drastically reduced 24-h acid reflux (p=0.02 vs placebo) and improved heartburn (9=0.03 vs placebo). Also, nocturnal cough was better during omeprazole (9=0.03 vs placebo). However, effects on other pulmonary symptoms and on AH, spirometry, reversibility and peak flow parameters were not significantly different between omeprazole and placebo after 3 months treatment. Conclusion Despite its profound effect on acid reflux, treatment with high dose omeprazole did not improve airway hyperresponsiveness, pulmonary function and pulmonary symptoms, except for nocturnal cough. These results do not suggest a significant role of acid reflux in the pathogenesis of obstructive lung disease and thus do not support a role f~r acid inhibitory drugs in the treatment of this disorder. (Funded in part by Astra Pharmaceutica, Rijswijk, The Netherlands).
Esophageal, Gastric, and Duodenal Disorders
A61
PANTOPRAZOLE DOES NOT INTERACT WITH DICLOFENAC. H. Bliesath, R. Huber, .M. Hartmann, V.W. Steinijans, H.J. Koch, W. Wurst. Research Devision Byk Gulden, Konstanz, Germany Introduction: The treatment with non steroidal antiinflammatory drugs (NSAIDs) increases the risk of developing gastrointestinal ulcers. For prophylaxis or treatment of these lesions drugs are used which reduce gastric acidity. Therefore an interaction between a NSAID and concomitant medication is of interest. Pantoprazole, a new H*/K*-ATPase inhibitor with a low potential to interact with the cytochrome P450 system potently inhibits gastric acidity. We investigated the influence of pantoprazole on the pharmacokinetics of diclofenac as both drugs are metabolized by the liver. Methods: In a randomized crossover study 24 (13 m/11 f) healthy volunteers received orally: 100 mg diclofenac with 40 mg pantoprazole (Test), and 100 mg diclofenac alone (Reference). BP, HR, ECG and clinical laboratory were measured. The pharmacokinetic characteristics AUC and C_,x of diclofenac were determined after administration with and wi{~out pantoprazole. A possible pharmacokinetic interaction was calculated according to the bioequivalence procedure, i.e. no interaction was concluded if the 90% confidence intervals (CI) of the ratios Test/Reference were entirely within the range of 0,80 - 1.25. Results." Pantoprazole and diclofenac did not influence vital signs or clinical laboratory results. The following pharmacokinetic characteristics were calculated: Pharmacokinetic characteristic of diclofenac
AUC(o.=) (mgxh/L) Cmax (mg/L)
diclofenac alone geom. mean (68%-rankle)
diclofenac & pantoprazole geom. mean (68%-ran@e)
Teat:
Equivalence ratio
3.15
3.17 (2.44, 4.11 )
1.01 (0.95, 1.07)
Reference:
(2.51, 3.95) 2.32
(1.60, 3.37)
2.36
(1.79, 3.10)
(Test/Reference) Point estimate (90% CI)
1.01
(0.90, 1.15)
Conclusions: Both drugs were well tolerated. Lack of interaction
between pantoprazole and diclofenac was demonstrated and the two drugs can be administered concomitantly without dose adjustment.
ENDOSCOPIC GASTROESOPHAGEAL REFLUX DISEASE (GERD). RELATIONSHIP BETWEEN HISTOLOGY AND AGE AND EXTENT OF METAPLASTIC EPITHELIUM. L Bonelli, H. Aste, M. Conio and G.O.SPE.* National Institute for Cancer Research, Genova, Italy * (Gruppo Operativo per 1o Studio delle Precancerosi dell'Esofago)-Italy. The aim of the present study was to evaluate the characteristics of GERD at different ages. From November 1987, 661 pts (464 males and 197 females, median age 59 yrs, range 13-94 yrs) with endoscopic esophagitis grade 2-4, including Barrett's esophagus (BE) (Savary's classification) underwent multiple biopsies (at least 4) from the distal esophagus. Histologic examination showed esophagitis in 231 pts (34.9°/o), gastric type BE in 214 (32.4%) and specialized columnar epithelium (SCE), alone or associated with gastric types, in 216 (32.7%). The mean age at diagnosis in the three groups was 56.6~:14.3 yrs, 52.9±15.0 yrs and 60.2A:13.6 yrs respectively. The frequency of esophagitis was constant across age decades; gastric BE was more frequent among younger pts, as age increased a rising frequency of SCE was observed (l-way analysis of variance, p<0.0001). A correlation between age and extent of metaplastie epithelium (ME) w a s observed (r=0.12, p--0.01). The mean extent of ME was 2.73±1.88 for lmtieata with gastric type BE and 4.33:L2.96 for thos¢ with SCE (z=6.04, p<0.0001). The data suggest an association between age, extent of ME and detection of SCE. In order to avoid confounding effects~ data concerning gender, age and extent of metaplastic epitheliun were fitted to a multivariate logistic regressign analysis: increase in the age and in the extent of ME were independent eovariates significantly associated with the probability of detecting SCE at histology 0Lq=l.37, c.i. 1.19-1.58 and RR=l.90, c.i. 1.46-2.46, respectively). Dysplasia was observed only in SCE: 19 indefinite, 10 low grade, 2 high grade. Conclusions: as a result of the damage due to chronic gastroesoptmgeal reflux, pts can develop esophagitis or Barrett's esophagus. In the latter group, with advancing age an upward creep of ME and a progressive expansion of islands of SCE could be observed and dysplasia is usually confined to these islands. Therefore, SCE may represent a marker of disease chrnnicity in which dysplasia and neoplasia can develop. (Supported by Bracco S.p.A.-Milano, Italy)