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Does aging affect gastric myoelectrical activity in patients with functional dyspepsia?
AllGO AGA ABSTRACTS
GASTROENTEROLOGY Vol. 118, No.4
5339
5341
GASTRIC EMPTYING OF INDIGESTIBLE TABLETS IN RELA· TION TO THE MIGRATING MOTOR COMPLEX (MMC). Darius Apel, Baerbel Ueberschaer, Klaus Ewe, Clin Ludwigshafen, Ludwigshafen, Germany; Univ Mainz, Mainz, Germany.
A FOUR COMPONENT MODEL CAN QUANTITATIVELY PRO· FILE GASTRIC EMPTYING IN DIABETIC GASTROPATHY. Naeem Aslam, Hani M. Rashed, Jide Familoni, Thomas L. Abell, Univ of Tennessee, Dept of Medicine, Memphis, TN; UT Bowld Hosp Univ of Tennessee, Memphis, Memphis, TN; Univ of Memphis, Memphis, TN; Univ of Tennessee-Memphis, Memphis, TN.
Indigestible tablets leave the stomach during phase III of the MMC. The aim of the study was to measure the MMC manometrically and to demonstrate the gastric emptying by means of the enteric-coated tablet and of a metal detector. Material and methods: 20 (m/f= Ill) healthy volunteers aged 22-62 yr were investigated. The manometric probe included 8 sideholes and I central channel with the distal end connected to a latex balloon containing water for sonographic localization of the probe. For the measurement of gastric emptying we used the metal detector and a metal core tablet (6 mm in size). The position of tablet was documented in a system of coordination with the navel as the central point. The most important characteristics for gastric emptying of the tablet were a rapid movement over a distance of 6-10 em from the left of midline to the right as well as a decrease in intensity because of the retroperitonel localization and the changing location in the lower abdomen. After an overnight fast of at least 12 h the subjects ingested 100 ml of a liquid meal (420 kJ) with the tablet. Than the manometric probe was brought into position. Results: The table shows the gastric emptying of the indigestible particle in relation to the phases of the MMC. In one subject the tablet did not empty during the first MMC at all but during the phase III of the following MMC. The median time of gastric emptying of the tablet after the ingestion of a liquid meal was 150.0 [range 80-260] min. Discussion: The indigestible tablets empty the stomach not only during the phase III of the MMC as it was assumed till now. The gastric emptying of an acid resistent particle can occur in approximately 35% during the phase II of the MMC. One possible explanation for that could be the gaping pylorus. Whether this phenomenon was present in the study individuals with the emptying of the table during the phase II could not be anserwed by the design of this investigation.
Phase I Phase II Phase III noemptying during l.MMC
Gastric emptying
95%·confidence int.
7 (35%) 12(60%)
154-59.2 % 36.1-80.9 %
1(5%)
0.1-24.9 %
5340 SIMILAR PHARMACOKINETICS OF TEGASEROD (HTF 919) IN PATIENTS WITH CONSTIPATION· AND DIARRHEA·PREDOM· INANT IRRITABLE BOWEL SYNDROME. Silke Appel-Dingemanse, James Rawls, Joan Heggland, Joelle Campestrini, Romain Sechaud, Novartis Pharmaceuticals, Basel, Switzerland; Novartis Pharmaceuticals, East Hanover, NJ; Novartis Pharmaceuticals, Rueil Malmaison, France. Background: Tegaserod (T,HTF 919) is a selective partial agonist at the 5-HT4 receptor. T belongs to a new class of agents in development for the treatment of functional motility disorders of the gastrointestinal (GI) tract. In cI inical studies T has been shown to be effective and well tolerated in the treatment of IBS. Objective: Assessment of T pharmacokinetics (PK) in patients with constipation-predominant irritable bowel syndrome (C-IBS) and diarrhea-predominant IBS (D-IBS). Methods: The PK of T were characterized after 2 and 6 mg b.i.d. administrations for 4 weeks. Evaluations were performed in 54 C-IBS patients in a Phase III efficacy study and in 32 D-IBS patients in a Phase II safety study. Patients were instructed to take the drug within 30 minutes prior to a meal. Results: The table below displays the PK results of T for 6 mg b.i.d., the recommended therapeutic dosing regimen in C-IBS, together with those from patients with D-IBS and fasting healthy subjects (HS, study on dose proportional PK). AUC, and C n " " . " of T were similar between patients with C-IBS and D-IBS. Similar results were obtained for the 2 mg b.i.d. dosing regimen. To compare the multiple-dose PK of T between patients with IBS and HS (fasted administration) food effect must be taken into account. When administered with food, the systemic exposure of T was reduced by 40-65 % and the maximum plasma concentration by 20-40 %. Multiple-dose PK of T were comparable among IBS patients and HS when considering the food effect. Time to Cm"x was about I h after drug intake in all three populations. Conclusions: The PK of T are similar in patients with C-IBS and D-IBS indicating that the type of bowel function abnormality has no major impact on the PK of T. The PK of T were also comparable between IBS patients and HS. MUltiple-dose pharmacokinetics oftegaserod (mean ± SD and median for1m,,)
1m"." (h) Cm"."(nglmL) AUC, (h'ng/mL) a T intake
C·IBS patients' n=32
D·IBS patients' n=16
Healthy subjects' n=18
1.0 1.7±0.7 5.7 ± 2.5
1.0 1.9±14 48± 24
0.8 2.7± 1.2 8.9 ± 4.2
prior toa meai, b fasted T intake
Introduction. In diabetes mellitus(DM), abnormalities of Autonomic Function Testing (AFT) and Electrogastrography (EGG) are well documented. We have previously noted that Delayed and Very Delayed Gastric Emptying (GET) can be predicted by adrenergic and cholinergic AFT. In addition patients with very rapid GET can be predicted by AFT, EGG and Glycohemoglobin values (GE.110(4): A 35,1996). We investigated the hypothesis that GET in patients (pts) with diabetic gastropathy can be quantitatively profiled by a four component model, using Adrenergic, Cholinergic, Enteric, and Metabolic parameters. Methods. We analyzed 76 patients with DM presenting with signs and symptoms of Diabetic gastropathy (nausea, vomiting, early satiety, anorexia, bloating, and/or abdominal pain). Adrenergic autonomic tests were by vasoconstriction to cold (YC). Cholinergic AFT was measured by EKG R to R Interval (RRI). The Enteric Nervous System was measured by cutaneous electrogastrography (EGG). The Metabolic parameter Glycosylated hemoglobin (GH) was measured by radioenzymatic assay. Solid GET was by T 50 as: very rapid (VR), rapid (R), normal(N), delayed (D), or very delayed (YD). Results. The data, including comparisons by ANOV A, is summarized in the table below. VC is lowest in the VD group, and increases linearly with gastric emptying ( r= 0.99, p
GET
T50 Solid
VC
RRI
EGG
GH
V Delayed n=23 Delayed n=15 Normal n=15 Rapid n=7 V Rapid n=16 All patients
240±0· 183.4±4.6. 1381±25' 111.7±018 77.1±5.5' Linear Reg.
41±6' 54±7.4 60±6.8 63.9±75 65.8±5.97' r=-0.99 p<0.01
59±1.8 10412 15.3±307 1234±3.4 17.4±36 r=-083 p=0.08
31±0.1 3.47±0.09 322±01 3.43±0 17 365±022 r=-0.8 p=0.095
754±0.56 719±0.4 669±033 737±102 792±035 r=-0.15 p=0.8
·p<0.05 byANOVA
5342 DOES AGING AFFECT GASTRIC MYOELECTRICAL ACTIVITY IN PATIENTS WITH FUNCTIONAL DYSPEPSIA? Bashar M. Attar, Melchor Demetria, Srikiran Pothamsetty, Philip E. Donahue, Jiande Chen, Cook County Hosp, Chicago, IL; Univ of Texas Med Branch, Galveston, TX. Gastric dysrhythmia has been associated with functional dyspepsia. Gastric myoelectrical activity (GMA) is absent at birth, develops following the neonatal period and is similar in healthy children and adults. The aim of the study was to investigate the effect of age on gastric myoelectrical activity in patients with functional dyspepsia. Methods: We studied the gastric myoelectrical activity in 68 patients (40F, 28M), mean age 46 years (range of 21-78 years). Electrogastrography (EGG) was performed one hour prior to and one hour after a standard meal (turkey sandwich, 500 cal). Computerized spectral analysis (Polygram, Synectics) was utilized to compute: I) the number and percentage of normal slow waves (normal 2.4-3.6 cpm, bradygastria <2.4, tachygastria 3.7-9; a value below 60% was defined as abnormal); II) the ratio of pre-prandial and post-prandial EGG dominant power: III) the minute to minute variation of the dominant frequency (DFIC) and power (DPIC). To investigate the correlation between gastric myoelectrical activity and age, patients were divided into Group I: 2:50 years (n=40), and Group II: age <50 years (n=28). Results: The rhythmicity of the slow waves was abnormal in both groups in the fasting state (54% vs 74%) and in the fed state (540/c vs 22%). The older (Group I) patients had significantly lower prevalence of tachygastrialtachyarrhythmia (>4% in the fasting or fed recording) than in younger (Group II) patients (11.5% vs 46.7%, p=0.025) in the fasting state. This difference was, however, not significant in the fed state (30.1 % vs 42.9%, p=0.5l. The underlying mechanism is not known but a similar trend was seen in elderly healthy volunteers in previous studies. No difference was found in other EGG parameters between the two groups. Conclusion: I) Regular gastric slow waves in the fasting and fed state are substantially lower in patients with functional dyspepsia. 2) Younger patients with functional dyspepsia have a significantly higher prevalence of tachygastria/tachyarrhythmia in the fasting state. The exact mechanism is not known. 3) Bradygastria is the predominant abnormal slow wave during the fasting or fed state in both groups.
GASTROENTEROLOGY Vol. 118, No.4
5339
5341
GASTRIC EMPTYING OF INDIGESTIBLE TABLETS IN RELA· TION TO THE MIGRATING MOTOR COMPLEX (MMC). Darius Apel, Baerbel Ueberschaer, Klaus Ewe, Clin Ludwigshafen, Ludwigshafen, Germany; Univ Mainz, Mainz, Germany.
A FOUR COMPONENT MODEL CAN QUANTITATIVELY PRO· FILE GASTRIC EMPTYING IN DIABETIC GASTROPATHY. Naeem Aslam, Hani M. Rashed, Jide Familoni, Thomas L. Abell, Univ of Tennessee, Dept of Medicine, Memphis, TN; UT Bowld Hosp Univ of Tennessee, Memphis, Memphis, TN; Univ of Memphis, Memphis, TN; Univ of Tennessee-Memphis, Memphis, TN.
Indigestible tablets leave the stomach during phase III of the MMC. The aim of the study was to measure the MMC manometrically and to demonstrate the gastric emptying by means of the enteric-coated tablet and of a metal detector. Material and methods: 20 (m/f= Ill) healthy volunteers aged 22-62 yr were investigated. The manometric probe included 8 sideholes and I central channel with the distal end connected to a latex balloon containing water for sonographic localization of the probe. For the measurement of gastric emptying we used the metal detector and a metal core tablet (6 mm in size). The position of tablet was documented in a system of coordination with the navel as the central point. The most important characteristics for gastric emptying of the tablet were a rapid movement over a distance of 6-10 em from the left of midline to the right as well as a decrease in intensity because of the retroperitonel localization and the changing location in the lower abdomen. After an overnight fast of at least 12 h the subjects ingested 100 ml of a liquid meal (420 kJ) with the tablet. Than the manometric probe was brought into position. Results: The table shows the gastric emptying of the indigestible particle in relation to the phases of the MMC. In one subject the tablet did not empty during the first MMC at all but during the phase III of the following MMC. The median time of gastric emptying of the tablet after the ingestion of a liquid meal was 150.0 [range 80-260] min. Discussion: The indigestible tablets empty the stomach not only during the phase III of the MMC as it was assumed till now. The gastric emptying of an acid resistent particle can occur in approximately 35% during the phase II of the MMC. One possible explanation for that could be the gaping pylorus. Whether this phenomenon was present in the study individuals with the emptying of the table during the phase II could not be anserwed by the design of this investigation.
Phase I Phase II Phase III noemptying during l.MMC
Gastric emptying
95%·confidence int.
7 (35%) 12(60%)
154-59.2 % 36.1-80.9 %
1(5%)
0.1-24.9 %
5340 SIMILAR PHARMACOKINETICS OF TEGASEROD (HTF 919) IN PATIENTS WITH CONSTIPATION· AND DIARRHEA·PREDOM· INANT IRRITABLE BOWEL SYNDROME. Silke Appel-Dingemanse, James Rawls, Joan Heggland, Joelle Campestrini, Romain Sechaud, Novartis Pharmaceuticals, Basel, Switzerland; Novartis Pharmaceuticals, East Hanover, NJ; Novartis Pharmaceuticals, Rueil Malmaison, France. Background: Tegaserod (T,HTF 919) is a selective partial agonist at the 5-HT4 receptor. T belongs to a new class of agents in development for the treatment of functional motility disorders of the gastrointestinal (GI) tract. In cI inical studies T has been shown to be effective and well tolerated in the treatment of IBS. Objective: Assessment of T pharmacokinetics (PK) in patients with constipation-predominant irritable bowel syndrome (C-IBS) and diarrhea-predominant IBS (D-IBS). Methods: The PK of T were characterized after 2 and 6 mg b.i.d. administrations for 4 weeks. Evaluations were performed in 54 C-IBS patients in a Phase III efficacy study and in 32 D-IBS patients in a Phase II safety study. Patients were instructed to take the drug within 30 minutes prior to a meal. Results: The table below displays the PK results of T for 6 mg b.i.d., the recommended therapeutic dosing regimen in C-IBS, together with those from patients with D-IBS and fasting healthy subjects (HS, study on dose proportional PK). AUC, and C n " " . " of T were similar between patients with C-IBS and D-IBS. Similar results were obtained for the 2 mg b.i.d. dosing regimen. To compare the multiple-dose PK of T between patients with IBS and HS (fasted administration) food effect must be taken into account. When administered with food, the systemic exposure of T was reduced by 40-65 % and the maximum plasma concentration by 20-40 %. Multiple-dose PK of T were comparable among IBS patients and HS when considering the food effect. Time to Cm"x was about I h after drug intake in all three populations. Conclusions: The PK of T are similar in patients with C-IBS and D-IBS indicating that the type of bowel function abnormality has no major impact on the PK of T. The PK of T were also comparable between IBS patients and HS. MUltiple-dose pharmacokinetics oftegaserod (mean ± SD and median for1m,,)
1m"." (h) Cm"."(nglmL) AUC, (h'ng/mL) a T intake
C·IBS patients' n=32
D·IBS patients' n=16
Healthy subjects' n=18
1.0 1.7±0.7 5.7 ± 2.5
1.0 1.9±14 48± 24
0.8 2.7± 1.2 8.9 ± 4.2
prior toa meai, b fasted T intake
Introduction. In diabetes mellitus(DM), abnormalities of Autonomic Function Testing (AFT) and Electrogastrography (EGG) are well documented. We have previously noted that Delayed and Very Delayed Gastric Emptying (GET) can be predicted by adrenergic and cholinergic AFT. In addition patients with very rapid GET can be predicted by AFT, EGG and Glycohemoglobin values (GE.110(4): A 35,1996). We investigated the hypothesis that GET in patients (pts) with diabetic gastropathy can be quantitatively profiled by a four component model, using Adrenergic, Cholinergic, Enteric, and Metabolic parameters. Methods. We analyzed 76 patients with DM presenting with signs and symptoms of Diabetic gastropathy (nausea, vomiting, early satiety, anorexia, bloating, and/or abdominal pain). Adrenergic autonomic tests were by vasoconstriction to cold (YC). Cholinergic AFT was measured by EKG R to R Interval (RRI). The Enteric Nervous System was measured by cutaneous electrogastrography (EGG). The Metabolic parameter Glycosylated hemoglobin (GH) was measured by radioenzymatic assay. Solid GET was by T 50 as: very rapid (VR), rapid (R), normal(N), delayed (D), or very delayed (YD). Results. The data, including comparisons by ANOV A, is summarized in the table below. VC is lowest in the VD group, and increases linearly with gastric emptying ( r= 0.99, p
GET
T50 Solid
VC
RRI
EGG
GH
V Delayed n=23 Delayed n=15 Normal n=15 Rapid n=7 V Rapid n=16 All patients
240±0· 183.4±4.6. 1381±25' 111.7±018 77.1±5.5' Linear Reg.
41±6' 54±7.4 60±6.8 63.9±75 65.8±5.97' r=-0.99 p<0.01
59±1.8 10412 15.3±307 1234±3.4 17.4±36 r=-083 p=0.08
31±0.1 3.47±0.09 322±01 3.43±0 17 365±022 r=-0.8 p=0.095
754±0.56 719±0.4 669±033 737±102 792±035 r=-0.15 p=0.8
·p<0.05 byANOVA
5342 DOES AGING AFFECT GASTRIC MYOELECTRICAL ACTIVITY IN PATIENTS WITH FUNCTIONAL DYSPEPSIA? Bashar M. Attar, Melchor Demetria, Srikiran Pothamsetty, Philip E. Donahue, Jiande Chen, Cook County Hosp, Chicago, IL; Univ of Texas Med Branch, Galveston, TX. Gastric dysrhythmia has been associated with functional dyspepsia. Gastric myoelectrical activity (GMA) is absent at birth, develops following the neonatal period and is similar in healthy children and adults. The aim of the study was to investigate the effect of age on gastric myoelectrical activity in patients with functional dyspepsia. Methods: We studied the gastric myoelectrical activity in 68 patients (40F, 28M), mean age 46 years (range of 21-78 years). Electrogastrography (EGG) was performed one hour prior to and one hour after a standard meal (turkey sandwich, 500 cal). Computerized spectral analysis (Polygram, Synectics) was utilized to compute: I) the number and percentage of normal slow waves (normal 2.4-3.6 cpm, bradygastria <2.4, tachygastria 3.7-9; a value below 60% was defined as abnormal); II) the ratio of pre-prandial and post-prandial EGG dominant power: III) the minute to minute variation of the dominant frequency (DFIC) and power (DPIC). To investigate the correlation between gastric myoelectrical activity and age, patients were divided into Group I: 2:50 years (n=40), and Group II: age <50 years (n=28). Results: The rhythmicity of the slow waves was abnormal in both groups in the fasting state (54% vs 74%) and in the fed state (540/c vs 22%). The older (Group I) patients had significantly lower prevalence of tachygastrialtachyarrhythmia (>4% in the fasting or fed recording) than in younger (Group II) patients (11.5% vs 46.7%, p=0.025) in the fasting state. This difference was, however, not significant in the fed state (30.1 % vs 42.9%, p=0.5l. The underlying mechanism is not known but a similar trend was seen in elderly healthy volunteers in previous studies. No difference was found in other EGG parameters between the two groups. Conclusion: I) Regular gastric slow waves in the fasting and fed state are substantially lower in patients with functional dyspepsia. 2) Younger patients with functional dyspepsia have a significantly higher prevalence of tachygastria/tachyarrhythmia in the fasting state. The exact mechanism is not known. 3) Bradygastria is the predominant abnormal slow wave during the fasting or fed state in both groups.