1 Clinical Enteric Neuroscience Translational and Epidemiological Research Program and 2 Division of Biostatistics, Mayo Clinic, Rochester, Minnesota 55905; and 3 Merck KGaA, Darmstadt, Germany
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ABSTRACT |
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To
compare the effects of the -opioid agonist asimadoline and placebo
on visceral sensation and gastrointestinal (GI) motor functions in
humans, 91 healthy participants were randomized in a double-blind
fashion to 0.15, 0.5, or 1.5 mg of asimadoline or placebo orally twice
a day for 9 days. We assessed satiation (nutrient drink test), colonic
compliance, tone, perception of colonic distension (barostat), and
whole gut transit (scintigraphy). Treatment effect was assessed by
analysis of covariance. Asimadoline increased nutrient drink intake
(P = 0.03). Asimadoline decreased colonic tone during
fasting (P = 0.03) without affecting postprandial colonic contraction, compliance, or transit. Gas scores in response to
colonic distension were decreased with 0.5 mg of asimadoline at low
levels (8 mmHg above operating pressure) of distension (P = 0.04) but not at higher levels of distension.
Asimadoline at 1.5 mg increased gas scores at 16 mmHg of distension
(P = 0.03) and pain scores at distensions of 8 and 16 mmHg (P = 0.003 and 0.03, respectively) but not at
higher levels of distension. Further studies of this compound in
diseases with altered satiation or visceral sensation are warranted.
sensation; visceral; stomach; colon; barostat
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INTRODUCTION |
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VISCERAL PAIN AND DISCOMFORT are relevant clinical features of many medical processes, including functional gastrointestinal (GI) disorders (57). These are frequent and chronic-relapsing conditions with a great impact on quality of life (23), yet no satisfactory treatment is available for treatment of pain in these highly prevalent conditions.
The three major opioid receptors, µ, , and
, are distributed in
the peripheral and central nervous systems (45, 53) and
are known to modulate visceral nociception (16, 22, 29). Available opioid agonists relieve pain, but they usually result in many
adverse effects, such as constipation and central side effects
(13), including opioid dependence (51). Such
adverse effects preclude their general use in clinical practice. In
contrast, peripheral
-opioid receptor agonists seem to be devoid of
these side effects, and preliminary clinical evidence suggests that this class of compound can reduce visceral sensation in human studies
(14, 17, 20, 44).
Asimadoline (EMD-61753) is a compound with high affinity and
selectivity for the -opioid receptor (27) and does not
cross the blood-brain barrier (3, 4). Asimadoline has been
shown to reduce sensation responses to gastric and colonic distension (8, 41, 48) and to heat (54) in animal
models. In previous human phase I and phase IIa studies, asimadoline
has shown high oral bioavailability and a good safety profile with
single doses up to 10 mg and multiple doses up to 5 mg
(2). No withdrawal symptoms have been reported in animals
or humans (2).
The aims of this study were to determine the safety and effects of 9 days of treatment with three different doses of asimadoline compared
with placebo on visceral sensation and GI motor functions in healthy
volunteers. Such in-depth studies are essential for the translation of
basic physiological insights on -opioid receptor agonists to
potential therapies for patients with illnesses associated with altered
visceral sensation.
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MATERIALS AND METHODS |
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Study Population
The study was conducted between February 2001 and March 2002. Volunteers between 18 and 60 yr of age were recruited from the local community by public advertisement. Pregnant or breast-feeding women and those with child-bearing potential who were not using reliable methods of contraception were excluded. Other exclusion criteria included known hypersensitivity to asimadoline or opioid agonists; known substance abuse; significant affective or anxiety disorder (with the Hospital Anxiety and Depression Scale used for screening purposes), systemic disease, prior abdominal surgery other than appendectomy, laparoscopic cholecystectomy, or tubal ligation; present or previous chronic GI illness, including functional GI disorders (with the Bowel Disease Questionnaire used for this purpose); and use of medications that may alter GI motility or induce cytochrome P-3A4 and -2D6 or analgesic drugs, including opioids, nonsteroidal anti-inflammatory drugs, and cyclooxygenase-2 inhibitors. The protocol was approved by the Mayo Institutional Review Board, and written informed consent was obtained from all participants before enrollment in the study.Study Design
This was a randomized, double-blind, placebo-controlled study conducted in two parts. Part 2 was added to test a higher dose of asimadoline than those tested in part 1 and was planned and nested in the study before part 1 was finished. Eligible volunteers were randomized (using random permuted blocks stratified on age and gender) to receive a 9-day oral treatment with 0.15 or 0.5 mg of asimadoline (EMD-61753, Merck, Darmstadt, Germany) or identical-appearing placebo twice a day during part 1 and with 1.5 mg of asimadoline or placebo twice a day during part 2.Study Protocol
Satiation and postprandial symptoms were assessed at baseline (day 0) before initiation of the treatment period. On day 1, participants underwent colonic motor and sensory function measurements before the treatment and 1 h after the first dose of the assigned treatment. Satiation and postprandial symptoms were assessed on treatment day 6, and gastric emptying and small bowel and colonic transit were measured from day 7 to day 9 of treatment (Fig. 1).
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Medication was administered at the study site, except from day 2 to day 5 of treatment. Compliance with treatment was assessed by means of tablet counts and review of subjects' diaries.
Safety Monitoring
Adverse effects were monitored at the study site daily from day 6 to day 9, and patients were given a telephone number to contact study investigators to report any side effect. An electrocardiogram and routine laboratory tests were performed during the last 2 days of treatment and at the follow-up visit, scheduled within 1 wk of the end of active treatment, to follow any abnormality observed in the previous visit.Assessment of Satiation and Postprandial Symptoms: Nutrient Drink Test
To measure satiation [i.e., the final signal during ingestion that contributes to meal termination (37)] and postprandial symptoms, we used the nutrient drink test as described in the literature (19, 55). Briefly, after an overnight fast, participants drank a nutrient liquid meal (Ensure; 1 kcal/ml, 11% fat, 73% carbohydrate, and 16% protein) at a constant rate (30 ml/min). At 5-min intervals, participants scored their level of fullness or satiation using a scale from 0 (no symptoms) to 5 (maximum or unbearable fullness/satiation). Participants were asked to stop meal intake when they reached the score of 5, and the total volume ingested was recorded as the maximum tolerated volume (MTV). At 30 min after reaching the point of maximum satiation, participants used 100-mm visual analog scales (VAS), with the words "none" and "worst ever" anchored at the left and right ends of the lines, to score their symptoms of nausea, fullness, bloating, and pain.Assessment of GI Transit by Scintigraphy
We measured gastric emptying and small bowel and colonic transit of solids using scintigraphy as described in previous studies (5, 7, 9). Briefly, after an overnight fast, participants ingested an 111In-charcoal capsule coated with a pH-sensitive methacrylate that dissolves when it reaches the colon (9), allowing colonic transit measurement with a gamma camera. After the capsule was emptied from the stomach, participants ingested two scrambled eggs labeled with 99mTc-sulfur colloid with one slice of whole-wheat bread and one glass of whole milk (total 300 kcal) to measure gastric emptying and the colonic filling at 6 h after the meal as a measurement of small bowel transit. Subjects ingested standardized meals for lunch and dinner at 4 and 8 h after the radiolabeled meal. Anterior and posterior abdominal images of 2-min duration were obtained at 1-h intervals for the first 8 h and at 24, 32, and 48 h.Assessment of Colonic Motor and Sensory Function
To measure colonic tone and compliance and to perform colonic distensions, a barostat-balloon assembly was used as described in previous studies (52, 59). An "infinitely" compliant balloon, 10 cm long and with a maximum volume of 600 ml (Hefty Baggies, Mobil Chemical, Pittsford, NY), was placed into the descending colon using flexible colonoscopy and fluoroscopy.The balloon was linked to an electronic, rigid-piston barostat (Engineering Department, Mayo Clinic) by means of a double-lumen tube for balloon distension and intraballoon pressure measurement (56).
The operating pressure was set at 2 mmHg above the minimum distending pressure, defined as the pressure at which respiratory excursions during deep inspiration were accompanied by a noticeable deflection in the balloon volume. Intraballoon volumes were monitored throughout the study. A pneumobelt was applied to the abdominal wall at the level of the low costal margin to exclude artifact during movement and coughing.
After a conditioning distension (28) and an equilibration period at the operating pressure, we measured colonic compliance by increasing intraballoon pressure from 0 to 44 mmHg in 4-mmHg steps at 30-s intervals. During assessment of colonic compliance, participants were asked to report first perception of gas and pain. After compliance measurement, fasting colonic tone was assessed at the operating pressure and then at phasic balloon distensions of 8, 16, 24, and 32 mmHg above the operating pressure, performed in random order. During distensions, participants rated the intensity of gas and pain perception using a 100-mm VAS with the words "unnoticeable" and "unbearable" anchored at the left and right ends of the lines. This has been shown to be an adequate model of visceral sensation in humans (25, 40).
Colonic wall compliance and fasting tone, thresholds for first
perception of gas and pain, and the intensity of perception during
phasic distensions were measured before the subjects received the drug
and 1 h after the first dose of the drug. The timing of postdrug
measurements was based on the known pharmacokinetic profile of
asimadoline (2). After the drug was administered, we also
assessed postprandial colonic volume during 60 min after ingestion of a
750-ml milkshake containing 1,000 kcal (53% fat, 35% carbohydrate,
and 12% protein; Fig. 2).
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Data Analysis
MTV and postprandial symptoms. The total volume ingested (MTV) was recorded. The aggregate postprandial symptoms score (30 min after ingestion of Ensure) was calculated as the sum (0-400 mm) of VAS scores for each postprandial symptom (0-100 mm each).
GI transit. Gastric emptying was summarized as the proportion of 99mTc emptied from the stomach at 2 and 4 h and orocecal transit as the colonic filling with 99mTc at 6 h. Colonic transit was summarized by means of the geometric center (GC) at any given time, which is calculated by multiplying the proportion of 111In in each colonic region [ascending (AC), transverse (TC), descending (DC), rectosigmoid (RS), and stool] by its weighting factor as indicated in the following formula: GC = %AC × 1 + %TC × 2 + %DC × 3 + %RS × 4 + %stool × 5/100. A low GC, therefore, means slow transit, and a high GC indicates rapid colonic transit.
Colonic tone and compliance.
Colonic tone, i.e., intraballoon volume at the operating pressure, was
calculated by averaging the colonic volume throughout the period of
tone assessment during fasting and postprandially, as in previous
studies (5, 6, 58). Changes in colonic tone were
calculated as proportional changes during fasting [(fasting colonic
tone postdrug predrug) × 100/fasting colonic tone
predrug] and postprandially (postprandial colonic tone
fasting
colonic tone) (58). Because colonic pressure-volume
relations are not linear but sigmoidal, compliance was summarized by a
power exponential model by plotting observed volume at each pressure
divided by the maximum observed volume as a function of 1/pressure as
follows: Vol/Volmax = r + exp[
(
× 1/Pr)
], as in previous studies
(5, 6, 34, 58), where r represents the minimum
observed volume divided by the maximum observed volume (Volmax), Pr is pressure, and
and
are constants
that describe the compliance curve.
Perception of colonic distension. The pressures at which participants reported first perception for gas and pain, during stepwise distensions, were recorded as the pressure thresholds for gas and pain perception. Gas and pain VAS intensity scores at each distension pressure, during random phasic distensions, were also recorded.
Statistical Analysis
The primary outcomes for satiation and postprandial symptoms were the MTV and the aggregate postprandial symptoms score. These have been shown in previous studies to be the most robust end-point variables measured by the nutrient drink test (18). Primary outcomes for GI transit were the proportion emptied from the stomach at 4 h and colonic filling at 6 h. The primary outcomes for colonic motor function and transit were postprandial change in colonic tone and the colonic GC at 24 h. Primary outcomes for perception of colonic distension were the VAS scores for gas and pain at each distension pressure, because physiological evidence suggests that different neuronal populations respond to different ranges of colonic distension (35, 39, 40, 47).An analysis of covariance (ANCOVA) was used to assess treatment effects on the satiation, transit, tone, and compliance outcome responses. The covariates in these analyses included gender, body mass index, and baseline (pretreatment) response values for those outcomes measured before and after drug administration. Because the study was conducted in two parts, a main effect term for study phase (part 1 vs. part 2) was included in these ANCOVA models. The two-part study design resulted in the highest dose of drug only being used in part 2; thus the treatment effect was incorporated as a "nested factor" (within-study phase). Specific contrasts were then used to test for an overall drug effect (combined doses vs. respective placebos) and a treatment effect (simultaneous comparison of each dose vs. respective placebo). The results (P values) for this latter contrast are reported for each outcome variable. A multivariate ANCOVA model was used to assess treatment effects on the VAS perception scores at 8, 16, 24, and 32 mmHg. The results for the multivariate (4 pressure distension levels) version of the treatment effect contrast and the results for the individual pressure levels are reported below. The analysis of pressure thresholds for first perception of gas and pain was based on a proportional hazards regression model to account for censored values (i.e., maximum pressure level attained without specific type of sensation reported). The above specific contrast for treatment effect was also examined in these analyses.
Because treatment was nested within the separate study parts, data are displayed separately for parts 1 and 2. Values are means ± SE.
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RESULTS |
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Study Conduct and Participants
Sixty healthy subjects were randomized in part 1 of the study: 20 were assigned to receive placebo, 21 to receive 0.15 mg of asimadoline, and 19 to receive 0.5 mg of asimadoline. Thirty-one subjects were randomized in part 2: 10 were assigned to receive placebo and 21 to receive asimadoline at 1.5 mg. Participants' demographic characteristics are presented in Table 1. There was only one drop-out during part 2 of the study, in the group assigned to 1.5 mg of asimadoline; the participant withdrew because of severe abdominal pain after endoscopic tube placement before receiving the first dose of the assigned treatment. This participant was replaced as planned in the study protocol. Compliance was 100% for all participants, except for three subjects in the group that received 1.5 mg of asimadoline: two subjects missed 1 dose of a total of 18 (5%), and one subject did not take the last 9 doses (50%) and did not attend scheduled visits for transit measurements. None of the missed doses were due to adverse effects. Data on postprandial symptoms after maximum satiation were missing in three participants who departed from the study site without completing the VAS for symptoms. Data on transit were missing for the participant who did not attend the scheduled visits for transit measurement. The missing data for postdrug values of postprandial symptoms after maximum satiation (3 patients) were imputed on the basis of an overall patients regression of postdrug values on predrug data. Missing data for transit (only 1 patient) were imputed using an overall (patients) mean value of nonmissing values.
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Satiation and Postprandial Symptoms
Asimadoline significantly augmented the volume of Ensure that was ingested to reach satiation (P = 0.03). Figure 3 shows the change in ingested volume after treatment relative to before treatment.
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Treatment did not significantly affect aggregate (P = 0.18) or individual postprandial symptom scores. Table
2 shows data on individual postprandial
symptoms scores.
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GI and Colonic Transit
No significant treatment effect was observed for any of the primary or secondary outcomes for GI transit: gastric emptying at 2 h (P = 0.60), colonic filling at 6 h (P = 0.14), and GC at 24 h (P = 0.95; Table 2).Colonic Tone and Compliance
Asimadoline increased colonic volume (relaxation) during fasting (P = 0.03; Figure 4A). However, the colonic volume response (contraction) to the standard meal was preserved in all treatment groups (P = 0.32; Fig. 4B). No treatment effects were observed on colonic wall compliance (Fig. 5).
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Gas Perception of Phasic Colonic Distension
Significant treatment effects (overall multivariate test) were observed for gas scores (P = 0.002). Treatment effects were significant at the specific distension pressure of 8 mmHg (P = 0.04) but did not reach statistical significance at 16 mmHg (P = 0.09). When higher distension pressures were applied, no significant treatment effects were observed (P = 0.78 and 0.26 for 24 and 32 mmHg above operating pressure distensions, respectively; Fig. 6A).
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Post hoc analysis of pairwise comparisons between each specific dose and corresponding placebo suggested that 0.5 mg of asimadoline reduced gas perception related to placebo at 8 mmHg of distension (P = 0.04), whereas this comparison was not significant at 16 mmHg of distension (P = 0.23). Conversely, 1.5 mg of asimadoline tended (P = 0.11) to increase, rather than decrease, gas perception at 8 mmHg of distension, and a significant (P = 0.03) increase of gas perception was observed at 16 mmHg of distension.
Pain Perception of Phasic Colonic Distension
The simultaneous test (overall distension levels) indicated borderline statistically significant treatment effects (P = 0.096) for pain scores. The pain scores were also significantly affected by treatment at low distension pressures (P = 0.01 and 0.09 for 8 and 16 mmHg, respectively). This effect was not observed at higher distension pressures (P = 0.29 and 0.46 for 24 and 32 mmHg, respectively; Fig. 6B).Post hoc analysis of pairwise comparisons between each specific dose and corresponding placebo suggested that 1.5 mg of asimadoline was associated with increased pain perception at 8 and 16 mmHg of distension (P = 0.003 and 0.03, respectively).
Thresholds for Perception During Stepwise Distensions
We did not observe any significant effect of treatment on the thresholds for perception of gas (P = 0.36) or pain (P = 0.30). Figure 7 shows the Kaplan-Meier curves with the proportion of subjects reporting first perception for gas and pain at each distension pressure in each study group. The shift to the right in the curve of pain thresholds with 1.5 mg of asimadoline suggested a decrease in pain threshold for this group, but a post hoc pairwise comparison of 1.5 mg of asimadoline vs. placebo (log-rank test) did not detect a significant difference (P = 0.27).
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Adverse Events
Adverse events are described in Table 3. No serious adverse events were reported. The most commonly reported adverse events were those related to the central nervous system, such as dizziness and headache, and the GI system, such as abdominal complaints related to endoscopic tube placement, nausea, anorexia, or heartburn. All adverse events were equally prevalent in the placebo and active treatment groups.
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DISCUSSION |
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In this phase I study, oral administration of the selective
-opioid agonist asimadoline modulated nutrient liquid intake and
perception of colonic distension. This occurred without significant alteration of GI motor reflexes and transit.
Visceral pain is a common clinical problem for which there is no satisfactory or universally effective treatment. The role of the opiate system in the modulation of visceral pain has been long recognized, yet the widespread use of opioid receptor agonists to treat chronic visceral pain is avoided because of the associated high rate of central side effects (13). Side effects include tolerance and physical dependence (51) and the inhibition of GI motor reflexes (1) that result in transit delay (30) and severe constipation (13).
Asimadoline is a diarylacetamide -opioid receptor agonist that binds
preferentially to
-opioid receptors (27), which are involved in the perception of visceral pain (50). This
compound has a very low distribution to the brain (3, 4).
In animal studies, central nervous system-mediated adverse reactions
were seen at doses 50-600 times higher than analgesic doses, and
no opiate-like physical dependence has been observed after 8 wk of treatment with asimadoline in humans (2).
Asimadoline has been tested in animals and was shown to reduce sensation in response to gastric and colorectal distension (8, 41, 48). These properties suggest that asimadoline is a suitable medication to be tested for the treatment of visceral pain in humans.
In this study, we have also shown that oral administration of 0.15-1.5 mg of asimadoline twice a day over 9 days is well tolerated, with no serious adverse effects.
Our evaluation of gastric visceral nociception was not based on gastric distension stimuli. Instead, we tested the effects of the drug in a situation that mimics the common clinical presentation of early satiation and postprandial complaints, such as abdominal pain, nausea, fullness, and bloating. Asimadoline delayed the onset of satiation at constant rates of ingestion, allowing greater ingestion of a nutrient liquid meal than placebo without affecting postprandial symptoms. This is consistent with a specific effect of asimadoline on regulation of food intake, which is shared with other opioid agonists (21, 32). In all participants who received placebo, there was a decrease in the volume ingested during the nutrient drink test repeated after randomization. Interestingly, asimadoline appeared to prevent this decrease in MTV. Although we did not specifically question study participants about palatability or taste aversion of Ensure, these results suggest that asimadoline's effect on food intake may be, at least in part, related to its regulation of orosensory reward, perhaps increasing palatability of the ingested nutrient meal, as suggested with other opioid agonists (42, 61).
Asimadoline at 0.5 mg decreased perception of gas in response to low levels of colonic distension. This is in accordance with animal studies (8, 48). No effect was observed at higher levels of distension. At least two types of receptors in the colon encode nociception: intensity-encoding receptors, which have a low threshold to natural stimuli, and high-threshold receptors, which are evoked by stimuli within the noxious range (10, 26). Therefore, it is conceivable that oral asimadoline may act at the periphery, altering the function of the low-threshold receptor at the doses used in this study. This concurs with the different effects of asimadoline on pelvic afferent fibers stimulated by colorectal distension (54).
In contrast, the highest dose of asimadoline tested (1.5 mg) was
associated with increased gas and pain perception at low levels of
colonic distension. The hyperalgesia associated with high doses of
asimadoline has been previously observed in animals and humans
(36) and is consistent with the dual modulatory mechanisms of opioids proposed by Crain and Shen (15). Their proposed
dual modulatory mechanisms were based on electrophysiological studies on sensory dorsal root ganglion neurons that show that -opioid agonists can evoke prolongation (12, 49) or shortening
(11, 24, 38, 60) of the action potential of these cells
when applied at low and high concentrations, respectively.
Whether the hyperalgesic effects observed with the higher dose of
asimadoline in our study involve excitatory opioid receptors (15) or nonopioid receptors, such as the
N-methyl-D-aspartic acid receptor (31, 33,
46), is beyond the scope of this study. However, several lines
of evidence suggest that -opioid agonists exert hyperalgesia through
activation of the N-methyl-D-aspartic acid
receptor (31, 33, 46).
One of the significant deleterious effects associated with the use of opioid agonists is the inhibition of intestinal motor reflexes (1), which results in transit delay (30, 43) and severe constipation (13). At the doses used in this study, asimadoline modulates perception without altering compliance of the colon, the physiological postprandial colonic contraction, or GI or colonic transit.
In conclusion, in this phase I study, we have demonstrated that asimadoline appears to be safe and is capable of increasing acute nutrient intake and that low doses of asimadoline (0.5 mg) can decrease visceral perception in humans without deleterious effects on gut motor functions. Higher doses of asimadoline may increase visceral perception. Clinical studies of this compound in illnesses associated with altered satiation or visceral sensation are warranted.
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ACKNOWLEDGEMENTS |
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We thank Mary Lempke, George M. Thomforde, and Cindy Stanislav for pharmacy, technical, and secretarial support, respectively.
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FOOTNOTES |
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This study was supported by a grant from Merck (Darmstadt, Germany) and in part by National Institutes of Health General Clinical Research Center Grant RR-00585 (Physiology Core) and National Institute of Diabetes and Digestive and Kidney Diseases Grants R01-DK-54681 (M. Camilleri) and K24-DK-02638 (M. Camilleri).
Address for reprint requests and other correspondence: M. Camilleri, Mayo Clinic, Charlton 8-110, 200 First St. SW, Rochester, MN 55905 (E-mail: camilleri.michael{at}mayo.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpgi.00360.2002
Received 23 August 2002; accepted in final form 19 November 2002.
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