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Ineffective esophageal motility is prevalent in gerd patients with or without respiratory symptoms
AGAA1241
Ap ril 2000
5680 INEFFECTIVE ESOPHAGEAL MOTILITY IS PREVALENT IN GERD P ATIENTS WITH OR WITHOUT RESPIRATORY SYMPT O MS. Antonio C. Gruber, Fernando Fornari, Antonio B. Lopes, Loreno Brentano, Rogerio G. Xavier, Sergio Gs de Barros, PPG-Gastroenterologia, Faculty de Mcdici na-UFRGS, Porto Alegre, Brazil.
Introduction: Gastroeso phagea l reflux disease (GERD) is assoc iated with respiratory symptoms. It has been shown that Ineffective Esophageal Motilit y OEM) is the most frequent motilit y abnormality in patients with GERD and when respiratory symptoms are present !EM would be even higher (Fouad et al., Am J Gastro-Jun e, 1999). Objective: The aim of this study was to determ ine the prevalence and associa tion between [EM and respiratory symptoms in GERD patient s. Methods: We re viewed manometry and pH studies of 138 consecutive patients referred to our laboratory . We found 9 1 with abnormal reflux and compared the prevalence and association of !EM in patient s with heartburn and no respiratory symptoms (n= 51) to patients with respiratory symptoms (asthma n= 10, chronic cough n = 25 and hoarsenessllaryngitis n= 22). Results: The mean age was 49 years and 54.3% were women and 45.7% men. In GERD- assoc iated respiratory symptoms IEM was found in 12/ 40 patient s (30%) while in subjec ts with heartburn and no respiratory symptoms IEM was present in 151 5 1 (29.6%). There was no statistical difference between the 2 group s (a = 5%. p = 0.8, OR= 1.03 C.I.=0.38-2.79). Conclusions: !EM was prev alent in subjec ts with GERD-symptoms with abnormal pH-metry. In this study we have found the same IEM prevalence in patient s with heartburn with and without respiratory symptoms.
5681 RISK FACTORS AND PREVALENCE OF CO RO NARY HEART DISEASE IN PATIENTS WITH BARRETT'S ESOPHAGUS. Sunna Gudlaugsdottir, Addy M. Remme, Jan Dees, John H. Wilson, Univ Hosp Digest, Rotterdam, Netherlands. In a previous follow-up study of patients with Barrett ' s eso phagus (BE)(Gut 1996; 39: 5-8), we found an exces s mortality of 50% in the BE population. mainly because of coronary heart disease (CHD). The aim of this study was to determine the prevalence of CHD and its risk factors in patients with BE. BE was defined as columnar mucosa 3 em or more in tubulair esophagus or histologica l proof of intestinal mateplasia. Sevent yeig ht patients with upper Gl complaints in who m BE was diagnosed at routine endoscopy were exa mined for risk facto rs for CHD using a standard questionnaire which included : age, sex, family history of CHD , personal history of CHD (myocardia l infarction. use of heart medication), smoking (active or past), history of hypertension. hyperlipidemia, diabetes mellitus or the use of medication for these diseases. Systolic and diastolic blood pressure, body mass index (kg/rrr' ), blood glucose, serum cholesterol. high-density-Iipoprote in- and low-density lipoprotein cholesterol were measured. Data from an epidemiological study of a cohort of 3105 men and 4878 women of the normal population of the same age range and living in the same area were used as control values. Results: CHD was found in the BE population in 47% of men and 32% of women, significantly more often than in the control group (2 1% and 14% respectively). Hyperten sion occ urred significantl y more freq uently in the BE patie nts than in the controls. The prevalen ces of diabetes mellitus, hypercholestero lemia and obesity were not significantly different. Conclusion: BE diagnosed in patie nts with upper GI complaints is associated with an increased preva lence of CHD and hypertension. This should be taken into account whe n designi ng or evaluating surveillance studie s.
PGEz and TxB 2 in the pouch exudate and in the stomach of the animals was measured by ELISA. Indomethacin dose-dependentl y caused a significant inhibitio n of synthesis of PGEz and TxB z both at the inflammatory site and in the stomach and induced formation of gastric erosi ons. On the co ntrary , celocox ib or darbufel one treated anima ls did not develop any gastric damage and inhibition of PGEz and TxB z synthesis was observed mainly in the pouch exudate. The degree of inhibition of PGEz and TxB z synthesis observed at a dose of 10 mg/kg for the three drugs tested is reported in the table below (Average :!: St. Err.)(n). In conclusion, our data suggest s that darbufelone has a celocox ib-like profile and the preferent ial inhibition of synthesis of arachidonic acid metabolit es at the inflammatory site but not in the stomach, could explain the low risk of de velopin g gastrointestinal damage. Compound
Control Indo Control Celo Control Darb
PGE, Pouch (ng/mll
TxB,
TxB,
Pouch (ng/mll
Stomach Inglmg prol)
3.6:l:.7(7) 04:l:.1(8)' 50±.8(8) O :l:.7 (10) 3 6:l:,5(10) 1.2±,3(9) ,
1.4±.1(9) 0.6±.09(13)' 2.0±.1 (10) 3.0±.5 (1 0) 1.0±.2(10) 1.3:l:.3(10)
PGE, Stomach (nglmg prot)
1.3±.2 (7) 7.5±14 (9) 0.3±.04 (8) , 2.3±.5(13) , 0.9±.2(9) 6.0±.7 (10) 0.3±.05(10)' 7.1±1.3 (9) 0 8±1 (10) 60±1 .1(10) 04± 06 (9)' 4 5±7 (10)
Frq('!o) of gastric damage
0 58.33 0 0 0 0
' =p <0.05
5683 PHARMACOKINETICS OF LANSOPRAZOLE IN ADOLESCENT PATIENTS WITH GASTROESOPHAGEAL REFLUX DISEASE (G ERD) . Thirumazhisai Gunasekaran, Wei-Jian Pan, Ramon Torres-Pinedo . Linda Book, David Gremse, Rita Steffen, Steven Czinn, Yi-Lin Chiu, Betsy L. Pilmer, Joseph Fitzgerald, Luthe ran Gen Acad Hosp, Park Ridge, IL; Abbott Lab, Abbott Park, IL; Digest Diseases Research Institute, Oklahoma City, OK; Prim ary Children's Med Ctr, Salt Lake City, UT; Univ of South Alabama, Mobile, AL; Cleve land Clin Fdn , Cleveland, OH; Rainbow Babies & Children's Hosp, Cleveland, OH; TAP Holdings, Inc, Deerfield, IL; Riley Hosp for Children, Indianapolis, IN. Purpose: To evalu ate the pharmacokinetics (PK) of 15 and 30 mg of lansoprazole (Ian) in adolesce nts with symptomatic GERD . Meth ods: This Phase I, double-blind. multicenter study was condu cted in 63 adolesc ents (12-17 yrs of age). Patients (pts) were randomized in a I: I ratio to receive once-a-day (morning), 5-day oral administratio n of 15 or 30 mg of Ian. Plasma samples were collecte d at the day 5 visit and analyzed using LCIMSIMS for the assessment of Ian PK. ANCOV A were performed to exa mine dose proportionality for both tx groups, and the effect of cova riates (weight, age & gender) on the PK of Ian. Result s: The data from 59 pts included in the final analyses are summarized belo w. Both C m " . and AUCo. z4 of Ian increased proport ionately with dose from 15 to 30 mg. None of the selected cov ariates had any statistically significant effect on Ian T m ax , C m a • or AUC o.24 ' While t l/Z increased slightly but significantly (p = 0.0358) with increasi ng age, this is not expected to have any clinical impact on the safety of the drug. Previous single- and multiple-dose studies showed that dose-normalized mean Ian C m a • and AUC in healthy adults were 27.5 ng/mL/mg and 71.1 ng . h/mL/mg, respectively. The range of Ian t 1/2 found in healthy adults was 0.39-8.50 hrs. Conclusion: The pharmacokinetic profile of lansoprazole in adolescents with GERD is similar to that of healthy adult s. The se data would suggest that adole scents be treated with dose s recommended for adults. This research was funded by TAP Holdings Inc., Deerfield. IL. SummaryofPharmacokinetic Data (mean e SO)
5682 EFFEC T OF DARBUFELONE O N ARA C HID O NIC ACID METABOLITES SYNT HESIS IN THE STO MAC H AND PERIPHERAL INFLAMMATORY SITES IN RATS. Antonio Guglietta, Charles A. Lesch, Brian Sanchez, Holly Van Vliet, Jean-L ouis Abitbol, Parke-D avis, Ann Arbor. MI. Darbufelone is an anti-inflammatory drug which carrie s a low risk of develop ing gastric damage. In this study, we eva luated the ability of indomethaci n, celocoxib and darbu felone to inhibit the synthesis of PGEz and TxB 2 in the stomach and at a peripheral inflammatory site. Rats were orally dosed with different doses of indometh aci n (Indo), celocoxib (Celo) or darbufelone (Darb). Sixty minutes later an inflammatory reaction was induced in rats by injecting 2 ml of PEG zoo in an air-pouch in the back of the animals. Six hours later. animals were sacrificed and the amount of
Pharmacokinetic Parameter (un~) Tm." (h)
em.. (nglmL) em.. (ng/mUmg)' AUC~" (ng'h/mL) AUC~" (ng'hlmUmg)'
I",' (hI
Lansoprazole Dose 15mgIN= 30)
Lansoprazole Dose 30mg(N= 29)
1.6±0.7 414.8 ± 215.5 27.7± 14.4 1017± 1737 67.8 ± 115.8 0.84+0.26
1.7± 0.7 1005± 604.9 335 ± 20.2 2490± 2522 83.0 ± 84.1 0.95+ 0.31
, Dose-normalized values. r Harmonic mean ± pseudo-standard deviation.
Ap ril 2000
5680 INEFFECTIVE ESOPHAGEAL MOTILITY IS PREVALENT IN GERD P ATIENTS WITH OR WITHOUT RESPIRATORY SYMPT O MS. Antonio C. Gruber, Fernando Fornari, Antonio B. Lopes, Loreno Brentano, Rogerio G. Xavier, Sergio Gs de Barros, PPG-Gastroenterologia, Faculty de Mcdici na-UFRGS, Porto Alegre, Brazil.
Introduction: Gastroeso phagea l reflux disease (GERD) is assoc iated with respiratory symptoms. It has been shown that Ineffective Esophageal Motilit y OEM) is the most frequent motilit y abnormality in patients with GERD and when respiratory symptoms are present !EM would be even higher (Fouad et al., Am J Gastro-Jun e, 1999). Objective: The aim of this study was to determ ine the prevalence and associa tion between [EM and respiratory symptoms in GERD patient s. Methods: We re viewed manometry and pH studies of 138 consecutive patients referred to our laboratory . We found 9 1 with abnormal reflux and compared the prevalence and association of !EM in patient s with heartburn and no respiratory symptoms (n= 51) to patients with respiratory symptoms (asthma n= 10, chronic cough n = 25 and hoarsenessllaryngitis n= 22). Results: The mean age was 49 years and 54.3% were women and 45.7% men. In GERD- assoc iated respiratory symptoms IEM was found in 12/ 40 patient s (30%) while in subjec ts with heartburn and no respiratory symptoms IEM was present in 151 5 1 (29.6%). There was no statistical difference between the 2 group s (a = 5%. p = 0.8, OR= 1.03 C.I.=0.38-2.79). Conclusions: !EM was prev alent in subjec ts with GERD-symptoms with abnormal pH-metry. In this study we have found the same IEM prevalence in patient s with heartburn with and without respiratory symptoms.
5681 RISK FACTORS AND PREVALENCE OF CO RO NARY HEART DISEASE IN PATIENTS WITH BARRETT'S ESOPHAGUS. Sunna Gudlaugsdottir, Addy M. Remme, Jan Dees, John H. Wilson, Univ Hosp Digest, Rotterdam, Netherlands. In a previous follow-up study of patients with Barrett ' s eso phagus (BE)(Gut 1996; 39: 5-8), we found an exces s mortality of 50% in the BE population. mainly because of coronary heart disease (CHD). The aim of this study was to determine the prevalence of CHD and its risk factors in patients with BE. BE was defined as columnar mucosa 3 em or more in tubulair esophagus or histologica l proof of intestinal mateplasia. Sevent yeig ht patients with upper Gl complaints in who m BE was diagnosed at routine endoscopy were exa mined for risk facto rs for CHD using a standard questionnaire which included : age, sex, family history of CHD , personal history of CHD (myocardia l infarction. use of heart medication), smoking (active or past), history of hypertension. hyperlipidemia, diabetes mellitus or the use of medication for these diseases. Systolic and diastolic blood pressure, body mass index (kg/rrr' ), blood glucose, serum cholesterol. high-density-Iipoprote in- and low-density lipoprotein cholesterol were measured. Data from an epidemiological study of a cohort of 3105 men and 4878 women of the normal population of the same age range and living in the same area were used as control values. Results: CHD was found in the BE population in 47% of men and 32% of women, significantly more often than in the control group (2 1% and 14% respectively). Hyperten sion occ urred significantl y more freq uently in the BE patie nts than in the controls. The prevalen ces of diabetes mellitus, hypercholestero lemia and obesity were not significantly different. Conclusion: BE diagnosed in patie nts with upper GI complaints is associated with an increased preva lence of CHD and hypertension. This should be taken into account whe n designi ng or evaluating surveillance studie s.
PGEz and TxB 2 in the pouch exudate and in the stomach of the animals was measured by ELISA. Indomethacin dose-dependentl y caused a significant inhibitio n of synthesis of PGEz and TxB z both at the inflammatory site and in the stomach and induced formation of gastric erosi ons. On the co ntrary , celocox ib or darbufel one treated anima ls did not develop any gastric damage and inhibition of PGEz and TxB z synthesis was observed mainly in the pouch exudate. The degree of inhibition of PGEz and TxB z synthesis observed at a dose of 10 mg/kg for the three drugs tested is reported in the table below (Average :!: St. Err.)(n). In conclusion, our data suggest s that darbufelone has a celocox ib-like profile and the preferent ial inhibition of synthesis of arachidonic acid metabolit es at the inflammatory site but not in the stomach, could explain the low risk of de velopin g gastrointestinal damage. Compound
Control Indo Control Celo Control Darb
PGE, Pouch (ng/mll
TxB,
TxB,
Pouch (ng/mll
Stomach Inglmg prol)
3.6:l:.7(7) 04:l:.1(8)' 50±.8(8) O :l:.7 (10) 3 6:l:,5(10) 1.2±,3(9) ,
1.4±.1(9) 0.6±.09(13)' 2.0±.1 (10) 3.0±.5 (1 0) 1.0±.2(10) 1.3:l:.3(10)
PGE, Stomach (nglmg prot)
1.3±.2 (7) 7.5±14 (9) 0.3±.04 (8) , 2.3±.5(13) , 0.9±.2(9) 6.0±.7 (10) 0.3±.05(10)' 7.1±1.3 (9) 0 8±1 (10) 60±1 .1(10) 04± 06 (9)' 4 5±7 (10)
Frq('!o) of gastric damage
0 58.33 0 0 0 0
' =p <0.05
5683 PHARMACOKINETICS OF LANSOPRAZOLE IN ADOLESCENT PATIENTS WITH GASTROESOPHAGEAL REFLUX DISEASE (G ERD) . Thirumazhisai Gunasekaran, Wei-Jian Pan, Ramon Torres-Pinedo . Linda Book, David Gremse, Rita Steffen, Steven Czinn, Yi-Lin Chiu, Betsy L. Pilmer, Joseph Fitzgerald, Luthe ran Gen Acad Hosp, Park Ridge, IL; Abbott Lab, Abbott Park, IL; Digest Diseases Research Institute, Oklahoma City, OK; Prim ary Children's Med Ctr, Salt Lake City, UT; Univ of South Alabama, Mobile, AL; Cleve land Clin Fdn , Cleveland, OH; Rainbow Babies & Children's Hosp, Cleveland, OH; TAP Holdings, Inc, Deerfield, IL; Riley Hosp for Children, Indianapolis, IN. Purpose: To evalu ate the pharmacokinetics (PK) of 15 and 30 mg of lansoprazole (Ian) in adolesce nts with symptomatic GERD . Meth ods: This Phase I, double-blind. multicenter study was condu cted in 63 adolesc ents (12-17 yrs of age). Patients (pts) were randomized in a I: I ratio to receive once-a-day (morning), 5-day oral administratio n of 15 or 30 mg of Ian. Plasma samples were collecte d at the day 5 visit and analyzed using LCIMSIMS for the assessment of Ian PK. ANCOV A were performed to exa mine dose proportionality for both tx groups, and the effect of cova riates (weight, age & gender) on the PK of Ian. Result s: The data from 59 pts included in the final analyses are summarized belo w. Both C m " . and AUCo. z4 of Ian increased proport ionately with dose from 15 to 30 mg. None of the selected cov ariates had any statistically significant effect on Ian T m ax , C m a • or AUC o.24 ' While t l/Z increased slightly but significantly (p = 0.0358) with increasi ng age, this is not expected to have any clinical impact on the safety of the drug. Previous single- and multiple-dose studies showed that dose-normalized mean Ian C m a • and AUC in healthy adults were 27.5 ng/mL/mg and 71.1 ng . h/mL/mg, respectively. The range of Ian t 1/2 found in healthy adults was 0.39-8.50 hrs. Conclusion: The pharmacokinetic profile of lansoprazole in adolescents with GERD is similar to that of healthy adult s. The se data would suggest that adole scents be treated with dose s recommended for adults. This research was funded by TAP Holdings Inc., Deerfield. IL. SummaryofPharmacokinetic Data (mean e SO)
5682 EFFEC T OF DARBUFELONE O N ARA C HID O NIC ACID METABOLITES SYNT HESIS IN THE STO MAC H AND PERIPHERAL INFLAMMATORY SITES IN RATS. Antonio Guglietta, Charles A. Lesch, Brian Sanchez, Holly Van Vliet, Jean-L ouis Abitbol, Parke-D avis, Ann Arbor. MI. Darbufelone is an anti-inflammatory drug which carrie s a low risk of develop ing gastric damage. In this study, we eva luated the ability of indomethaci n, celocoxib and darbu felone to inhibit the synthesis of PGEz and TxB 2 in the stomach and at a peripheral inflammatory site. Rats were orally dosed with different doses of indometh aci n (Indo), celocoxib (Celo) or darbufelone (Darb). Sixty minutes later an inflammatory reaction was induced in rats by injecting 2 ml of PEG zoo in an air-pouch in the back of the animals. Six hours later. animals were sacrificed and the amount of
Pharmacokinetic Parameter (un~) Tm." (h)
em.. (nglmL) em.. (ng/mUmg)' AUC~" (ng'h/mL) AUC~" (ng'hlmUmg)'
I",' (hI
Lansoprazole Dose 15mgIN= 30)
Lansoprazole Dose 30mg(N= 29)
1.6±0.7 414.8 ± 215.5 27.7± 14.4 1017± 1737 67.8 ± 115.8 0.84+0.26
1.7± 0.7 1005± 604.9 335 ± 20.2 2490± 2522 83.0 ± 84.1 0.95+ 0.31
, Dose-normalized values. r Harmonic mean ± pseudo-standard deviation.