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Rectal suppositories affect the parameters of the recto-anal reflex
AGAA1l79
April 2000
5420
5422
PSYCHOMETRICS OF TH E PHY SICAL SENSATIONS QUESTIONNAIRE: A MEAS URE OF DISEASE ATTRIBUTION IN IRRITABLE BOWEL SYNDROME PATIENTS. Kenneth R. Jones. Barbara Bradshaw, Chemise Overton, Douglas A. Drossman, William E. Whitehead, Univ of North Carolina. Chapel Hill,
TEGASEROD DOES NOT SIGNIFICANTLY AFFECT THE PHARMACOKINETICS OF DEXTROMETHORPHAN IN HEALTHY SUBJECTS. Jyoti Kalbag, Elizabeth Migoya, Stuart Osborne, Kenneth Lasseter, Manuel Pinto, James F. Mcleod, Novartis Pharmaceuticals, East Hanover, NJ; Clin Pharmacology Assoc, Miami, FL. Background: Tegaserod (HTF 9 19) is a 5-HT4 receptor partial agonist that enhances motility in the upper and lower gastrointestinal tract. Objective: This study was designed to determine the effects of multiple doses of tegaserod (TEG) on the pharmacokinetics (PK) of a prototype substrate for cytochrome P450-2D6 (CYP2D6), dextromethorphan (DMN), and its 2D6mediated metabolite, dextrorphan (DOR), in healthy subjects. Methods: In a randomized, open-label, 2-period crossover study, 18 healthy subjects who were extensive metabolizers of 2D6 were treated during each period with either a single dose of DMN (120 mg) after an overnight fast or BID doses of TEG (6 mg) on days I and 2, with a single dose of DMN (120 mg) I hour after the morning TEG dose on day 2. The 2 treatments were separated by 7 days. Blood samples were taken for 24 hours after DMN dosing and for 12 hours after the morning doses ofTEG. Results: Mean (:t SD) PK parameters and tmax (median) of DMN and DOR: The mean values for C max and AUCo_« of DMN were similar for both treatments with minimal differences between the treatment means of 4% and I %, respectively. The median values for Imax were the same for both treatments, indicating similar rates of absorption. The similarity in the estimated clearance (CIIF) of DMN suggests that TEG did not alter the metabolic elimination of DMN. The small differences in the C max and AUCo_ooof DOR (I I% and 9%, respectively) parallel the small reductions in DMN concentrations and also indicate that TEG did not alter the 2D6-mediated metabolism of DMN. TEG and DMN were safely administered and there were no discontinuations throughout the study due to adverse effects. Conclusions: TEG did not alter the 2D6-mediated metabolism of DMN. The lack of interaction between TEG and DMN suggests that it is unlikely that other CYP2D6 substrates, such as selective serotonin reuptake inhibitors, J3-adrenergic blocking agents, phenothiazines, and tricyclic antidepressants, will be affected by coadministration.
NC.
Whitehead and Pallson (Gastro. 1998:115:1263-71) have proposed a twofactor model to explain cognitive and psychological influences on pain perception in irritable bowel syndrome (IBS). The model proposes that IBS patients develop selective attention to GI sensations and demonstrate a cognitive disease attribution bias, interpreting GI sensations as signs of serious disease. The Physical Sensations Questionnaire (PSQ) was developed to assess disease attribution for GI and respiratory symptoms. Respondents rate the frequency and duration that a sensation would have to occur to be a sign of serious disease. The respondent' s actual experience with these sensations is also assessed. Before the instrument can be used with IBS patients, the psychometrics of the instrument must be determined. Aims: Examine the internal consistency and test-retest reliability of the PSQ. Methods: Through prior research, a pool of 68 respiratory and GI sensations have been developed and divided between two versions of the test. Fifty-two healty subjects were administered the PSQ (26 for each of two versions) and then returned two weeks later and were re-administered the same version. Cronbach ' s alpha was computed for the first administration to assess inter-item consistency. Spearman's rho was computed to assess test-retest reliability. Results: Inter-item and test-retest reliabilities are listed in Tables I and 2 below. Conclusions: The PSQ demonstrated excellent internal consistency and acceptable test-retest reliability. Future research will determine whether this measure differentiates IBS patients from normals (discriminant validity) and whether it correlates with other psychometric measures of disease attributon (construct validity). [Supported by grant RO I DK31369.]
Table I: Inter -Item Con sistency Versio n I Version 2 FreQ. Our . FreQ. E.xp Content Dis . A11rib. 0.935 0.925 0.89t 0.925 GI Experie nce 0.967 0.850 0.827 0.775 Resp . Dis. A11rib . 0.933 0.923 0 867 0.917 Experience 0.881 0.874 0.755 0.632 Neutral Dis . A11rib . 0.910 0.890 0.894 0.932 Experience 0.937 0.672 0.791 0.849
Table 2: Test-retest Reliabilities Version I Versio n 2 E.xp FreQ. Dur . Free . .621.... .585.... .539.... .564.... .586.... .577.... .715 d .567.... .638.... .484" .678.... .485" .536** .602.... .660· ... .548.... .640· · .557· " .780" · .719· ... .714' " .87S" · .. p<.05 .... p<.OI
.451" .720....
5421 EFFECTS OF CISAPRIDE ON ANTRAL AREA AND FULLNESS DURING INTRADUODENAL LIPID INFUSION. Karen L. Jones, Melanie K. Berry, Jane Andrews, Caroline Macint osh, Michael Horowitz, Royal Adelaide Hosp, Adelaide, SA, Australia. Recent studies suggest that the beneficial effects of cisapride on gastrointestinal symptoms may be related to changes in proximal stomach or antral tone. Intraduodenal (ID) lipid induces fullness and suppresses phasic antral pressure waves; effects on antral area have not been assessed. In 10 healthy subjects, aged 20-29yr, antral area and fullness was measured on two separate days before, during and after ID lipid infusion. Cisapride (I 0mg tid) or placebo was given for four days before each test, in random, double-blind, crossover fashion. On each day 0.9% saline was infused into the duodenum (2ml/min) for 30min, followed by 10% Intralipid (triglyceride emulsion) (2.2kcallmin) for 120min. Measurements of antral area (ultrasound) and perception of fullness (visual analog scale) were made at 15 min intervals, commencing 15min prior to the ID saline infusion. Fasting antral area tended to be less on cisapride when compared to placebo (2.98:t0.4cm2 vs 3.8:t0.4cm2 ; P= O.l l). ID lipid increased antral area with both cisapride and placebo (P< O.OI) , and the magnitude of this increase was greater (P<0.05) with cisapride (figure). ID lipid increased fullness (P< 0.05) with no difference between cisapride and placebo. We conclude that: (i) ID lipid increases antral area and (ii) cisapride accentuates this increase. Data are mean values :t SEM.
Ch a n ge ln
A n uel A re a
fro m b ••• llne (e m
J)
Tlmelmln)
_
placebo
_
cisapride
Treatment
DMN DMN+TEG
AUC.., (ngoh/ml) DMN DOR
158 (215) 145 (178)
162 (61) 177(68)
C..., (ng/mll DMN DOR
DMN
DOR
14.9(13.0) 30.5 (15.6) 15.1 (12.0) 345 (180l
2.9 2.9
2.3 1.8
t...,(hl
5423 RECTAL SUPPOSITORIES AFFECT THE PARAMETERS OF THE RECTO-ANAL REFLEX. Geetinder Kaur, Angela Gardiner, Peter W. Lee, John R. Monson, Graeme S. Duthie, Castle Hill Hosp, Cottingham. United Kingdom. Background: There has been no study of the effects of suppository insertion on the parameters of the recto-anal inhibitory reflex (RAIR). We analyzed this effect in patients with different anorectal disorders. Methods: Eleven constipated and II incontinent patients underwent manometry and rectal compliance studies before and after rectal suppository insertion. Parameters of the RAIR were analyzed; percentage sphincter relaxation calculated at each volume at which RAIR occurred. Changes in parameters were compared in both groups. Results: After suppository insertion, there was a significant decrease in the volume of rectal distension at which the RAIR was elicited (p = O.OOI). Both groups showed a consistent significant increase in percentage sphincter relaxation post suppository (p= O.OOO I). There was no significant difference in the volume of rectal distension at which sensation was first felt in either group. No difference was seen in the other pre and post-suppository compliance measurements in the incontinent group. In constipated patients, there was a significant decrease in the post-suppository volume of rectal distension at which flatus and urge sensation were felt as well as in MTV (p = O.04). Conclusions: Insertion of suppositories causes an increase in sphincter relaxation as well as significant differences in patients with different anorectal disorders. This has important clinical implications considering the frequency of suppository use in clinical practice.
April 2000
5420
5422
PSYCHOMETRICS OF TH E PHY SICAL SENSATIONS QUESTIONNAIRE: A MEAS URE OF DISEASE ATTRIBUTION IN IRRITABLE BOWEL SYNDROME PATIENTS. Kenneth R. Jones. Barbara Bradshaw, Chemise Overton, Douglas A. Drossman, William E. Whitehead, Univ of North Carolina. Chapel Hill,
TEGASEROD DOES NOT SIGNIFICANTLY AFFECT THE PHARMACOKINETICS OF DEXTROMETHORPHAN IN HEALTHY SUBJECTS. Jyoti Kalbag, Elizabeth Migoya, Stuart Osborne, Kenneth Lasseter, Manuel Pinto, James F. Mcleod, Novartis Pharmaceuticals, East Hanover, NJ; Clin Pharmacology Assoc, Miami, FL. Background: Tegaserod (HTF 9 19) is a 5-HT4 receptor partial agonist that enhances motility in the upper and lower gastrointestinal tract. Objective: This study was designed to determine the effects of multiple doses of tegaserod (TEG) on the pharmacokinetics (PK) of a prototype substrate for cytochrome P450-2D6 (CYP2D6), dextromethorphan (DMN), and its 2D6mediated metabolite, dextrorphan (DOR), in healthy subjects. Methods: In a randomized, open-label, 2-period crossover study, 18 healthy subjects who were extensive metabolizers of 2D6 were treated during each period with either a single dose of DMN (120 mg) after an overnight fast or BID doses of TEG (6 mg) on days I and 2, with a single dose of DMN (120 mg) I hour after the morning TEG dose on day 2. The 2 treatments were separated by 7 days. Blood samples were taken for 24 hours after DMN dosing and for 12 hours after the morning doses ofTEG. Results: Mean (:t SD) PK parameters and tmax (median) of DMN and DOR: The mean values for C max and AUCo_« of DMN were similar for both treatments with minimal differences between the treatment means of 4% and I %, respectively. The median values for Imax were the same for both treatments, indicating similar rates of absorption. The similarity in the estimated clearance (CIIF) of DMN suggests that TEG did not alter the metabolic elimination of DMN. The small differences in the C max and AUCo_ooof DOR (I I% and 9%, respectively) parallel the small reductions in DMN concentrations and also indicate that TEG did not alter the 2D6-mediated metabolism of DMN. TEG and DMN were safely administered and there were no discontinuations throughout the study due to adverse effects. Conclusions: TEG did not alter the 2D6-mediated metabolism of DMN. The lack of interaction between TEG and DMN suggests that it is unlikely that other CYP2D6 substrates, such as selective serotonin reuptake inhibitors, J3-adrenergic blocking agents, phenothiazines, and tricyclic antidepressants, will be affected by coadministration.
NC.
Whitehead and Pallson (Gastro. 1998:115:1263-71) have proposed a twofactor model to explain cognitive and psychological influences on pain perception in irritable bowel syndrome (IBS). The model proposes that IBS patients develop selective attention to GI sensations and demonstrate a cognitive disease attribution bias, interpreting GI sensations as signs of serious disease. The Physical Sensations Questionnaire (PSQ) was developed to assess disease attribution for GI and respiratory symptoms. Respondents rate the frequency and duration that a sensation would have to occur to be a sign of serious disease. The respondent' s actual experience with these sensations is also assessed. Before the instrument can be used with IBS patients, the psychometrics of the instrument must be determined. Aims: Examine the internal consistency and test-retest reliability of the PSQ. Methods: Through prior research, a pool of 68 respiratory and GI sensations have been developed and divided between two versions of the test. Fifty-two healty subjects were administered the PSQ (26 for each of two versions) and then returned two weeks later and were re-administered the same version. Cronbach ' s alpha was computed for the first administration to assess inter-item consistency. Spearman's rho was computed to assess test-retest reliability. Results: Inter-item and test-retest reliabilities are listed in Tables I and 2 below. Conclusions: The PSQ demonstrated excellent internal consistency and acceptable test-retest reliability. Future research will determine whether this measure differentiates IBS patients from normals (discriminant validity) and whether it correlates with other psychometric measures of disease attributon (construct validity). [Supported by grant RO I DK31369.]
Table I: Inter -Item Con sistency Versio n I Version 2 FreQ. Our . FreQ. E.xp Content Dis . A11rib. 0.935 0.925 0.89t 0.925 GI Experie nce 0.967 0.850 0.827 0.775 Resp . Dis. A11rib . 0.933 0.923 0 867 0.917 Experience 0.881 0.874 0.755 0.632 Neutral Dis . A11rib . 0.910 0.890 0.894 0.932 Experience 0.937 0.672 0.791 0.849
Table 2: Test-retest Reliabilities Version I Versio n 2 E.xp FreQ. Dur . Free . .621.... .585.... .539.... .564.... .586.... .577.... .715 d .567.... .638.... .484" .678.... .485" .536** .602.... .660· ... .548.... .640· · .557· " .780" · .719· ... .714' " .87S" · .. p<.05 .... p<.OI
.451" .720....
5421 EFFECTS OF CISAPRIDE ON ANTRAL AREA AND FULLNESS DURING INTRADUODENAL LIPID INFUSION. Karen L. Jones, Melanie K. Berry, Jane Andrews, Caroline Macint osh, Michael Horowitz, Royal Adelaide Hosp, Adelaide, SA, Australia. Recent studies suggest that the beneficial effects of cisapride on gastrointestinal symptoms may be related to changes in proximal stomach or antral tone. Intraduodenal (ID) lipid induces fullness and suppresses phasic antral pressure waves; effects on antral area have not been assessed. In 10 healthy subjects, aged 20-29yr, antral area and fullness was measured on two separate days before, during and after ID lipid infusion. Cisapride (I 0mg tid) or placebo was given for four days before each test, in random, double-blind, crossover fashion. On each day 0.9% saline was infused into the duodenum (2ml/min) for 30min, followed by 10% Intralipid (triglyceride emulsion) (2.2kcallmin) for 120min. Measurements of antral area (ultrasound) and perception of fullness (visual analog scale) were made at 15 min intervals, commencing 15min prior to the ID saline infusion. Fasting antral area tended to be less on cisapride when compared to placebo (2.98:t0.4cm2 vs 3.8:t0.4cm2 ; P= O.l l). ID lipid increased antral area with both cisapride and placebo (P< O.OI) , and the magnitude of this increase was greater (P<0.05) with cisapride (figure). ID lipid increased fullness (P< 0.05) with no difference between cisapride and placebo. We conclude that: (i) ID lipid increases antral area and (ii) cisapride accentuates this increase. Data are mean values :t SEM.
Ch a n ge ln
A n uel A re a
fro m b ••• llne (e m
J)
Tlmelmln)
_
placebo
_
cisapride
Treatment
DMN DMN+TEG
AUC.., (ngoh/ml) DMN DOR
158 (215) 145 (178)
162 (61) 177(68)
C..., (ng/mll DMN DOR
DMN
DOR
14.9(13.0) 30.5 (15.6) 15.1 (12.0) 345 (180l
2.9 2.9
2.3 1.8
t...,(hl
5423 RECTAL SUPPOSITORIES AFFECT THE PARAMETERS OF THE RECTO-ANAL REFLEX. Geetinder Kaur, Angela Gardiner, Peter W. Lee, John R. Monson, Graeme S. Duthie, Castle Hill Hosp, Cottingham. United Kingdom. Background: There has been no study of the effects of suppository insertion on the parameters of the recto-anal inhibitory reflex (RAIR). We analyzed this effect in patients with different anorectal disorders. Methods: Eleven constipated and II incontinent patients underwent manometry and rectal compliance studies before and after rectal suppository insertion. Parameters of the RAIR were analyzed; percentage sphincter relaxation calculated at each volume at which RAIR occurred. Changes in parameters were compared in both groups. Results: After suppository insertion, there was a significant decrease in the volume of rectal distension at which the RAIR was elicited (p = O.OOI). Both groups showed a consistent significant increase in percentage sphincter relaxation post suppository (p= O.OOO I). There was no significant difference in the volume of rectal distension at which sensation was first felt in either group. No difference was seen in the other pre and post-suppository compliance measurements in the incontinent group. In constipated patients, there was a significant decrease in the post-suppository volume of rectal distension at which flatus and urge sensation were felt as well as in MTV (p = O.04). Conclusions: Insertion of suppositories causes an increase in sphincter relaxation as well as significant differences in patients with different anorectal disorders. This has important clinical implications considering the frequency of suppository use in clinical practice.