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CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2012;10:12391245Efficacy of Buspirone, a Fundus-Relaxing Drug, in Patients WithFunctional Dyspepsia

JAN TACK, PIETER JANSSEN, TATSUHIRO MASAOKA, RICARD FARR, and LUKAS VAN OUDENHOVETranslational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium

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BACKGROUND & AIMS: Impaired accommodation andhypersensitivity to gastric distention are believed to be involvedin the development of functional dyspepsia (FD). Buspirone, a5-hydroxytryptamine 1A receptor agonist, relaxes the proximalstomach in healthy individuals. We studied the effects of bu-spirone on symptoms and mechanisms of FD. METHODS:We performed a randomized, double-blind, placebo-controlled,crossover study of 17 patients (13 women; mean age, 38.5 2.4years). The study included 2 treatment periods of 4 weeks each,separated by a 2-week washout period. In the first period, 7participants were given buspirone (10 mg, 3 times daily for 4weeks) and 10 were given placebo 15 minutes before meals;patients switched groups for the second period. We assessedmeal-related symptoms and severity, along with gastric sensi-tivity, accommodation, and emptying (by using barostat andbreath tests) before and after 4 weeks of treatment. RESULTS:Buspirone significantly reduced the overall severity of symp-toms of dyspepsia (7.5 1.3 vs 11.5 1.2 for placebo; P .005)and individual symptoms of postprandial fullness, early satia-tion, and upper abdominal bloating, whereas placebo had nosignificant effect (all P .05). Buspirone did not alter the rateof gastric emptying of solids or sensitivity to gastric distention,but it significantly increased gastric accommodation, comparedwith placebo (229 28 vs 141 32 mL, respectively; P .05),and delayed gastric emptying of liquids (half-life 64 5 vs119 24 minutes, respectively). Adverse events were similarwhen patients were given buspirone or placebo. CONCLU-SIONS: In patients with FD, 4 weeks of administration of

uspirone significantly improved symptoms and gastric ac-ommodation, compared with placebo, whereas gastricmptying of liquids was delayed.

eywords: Gastric Barostat; Therapy; Clinical Trial; Mechano-eceptor.

Functional dyspepsia (FD), defined as the presence of symp-toms thought to originate in the gastroduodenal region inthe absence of organic, systemic, or metabolic disease that islikely to explain the symptoms, is one of the most commongastrointestinal disorders.1 According to the Rome III consen-us, typical FD symptoms are early satiation, postprandial full-ess, epigastric pain, and epigastric burning. Other symptomsuch as upper abdominal bloating, belching, and nausea oftenoexist, and a subset of patients may experience weight loss.1,2

At present, there is no treatment with established efficacy forFD. Proton pump inhibitors and prokinetic drugs are mostfrequently used, although the evidence to support their efficacyis limited.3 The rationales for the use of these classes of drugs

are the frequent overlap with gastroesophageal reflux diseaseand the hypothesis that delayed gastric emptying is an impor-tant underlying pathophysiological mechanism, respectively.4

However, it has become clear that delayed gastric emptying isonly present in a minority of FD patients.5

Several studies have reported impaired gastric accommoda-tion in FD, which may contribute to symptom generation.6 8

Gastric accommodation is a relaxation of the proximal stomachthat occurs during meal ingestion and provides the meal with areservoir, enabling a gastric volume increase without a rise inpressure.7,8 Impaired accommodation is present in approxi-

ately 40% of FD patients and is associated with more preva-ent symptoms of early satiation and weight loss.6 On the basis

of observations in healthy controls and in FD patients, resto-ration of accommodation is considered a valid therapeutictarget.6 8 Besides delayed gastric emptying and impaired ac-commodation, hypersensitivity to gastric distention is anotherprevalent pathophysiological abnormality in FD.9 Mechanisticstudies have established that tension-sensitive mechanorecep-tors are involved in symptom generation in FD patients withhypersensitivity to gastric distention and that drugs that relaxthe proximal stomach have a potential to improve symptoms inthese patients.10

Targeting impaired accommodation or visceral hypersensi-tivity in FD through enhanced relaxation of the proximal stom-ach is hampered by a lack of suitable pharmacologic tools forhuman use. Because nitric oxide is the major neurotransmittermediating gastric relaxation, nitric oxide donors have been usedto enhance gastric relaxation and to reduce dyspeptic symp-toms, but their effect was short-lasting and accompanied byvascular side effects.11,12 Animal studies identified a 5-hydroxy-ryptamine (5-HT)1p receptor on nitrergic enteric neurons as auitable target, and studies in humans confirmed the ability ofhe 5-HT1 receptor agonist sumatriptan to relax the proximal

stomach through a nitrergic pathway.6,1316 However, because ofits low bioavailability when taken orally and because of itspharmacologic profile, sumatriptan is less suitable for FD ther-apy.17 Activation of presynaptic 5-HT1A receptors on cholinergic

erve endings is another pathway that relaxes the proximaltomach in animal models.18 In healthy volunteers, buspirone,

5-HT1A receptor agonist used in the treatment of anxiety,ose-dependently relaxed the proximal stomach and delayedastric emptying of solids and liquids.19

Abbreviations used in this paper: DSS, dyspepsia symptom severity;FD, functional dyspepsia; 5-HT, 5-hydroxytryptamine; SCL-90R, Symp-tom Checklist-90-Revised.

2012 by the AGA Institute1542-3565/$36.00http://dx.doi.org/10.1016/j.cgh.2012.06.036

http://dx.doi.org/10.1016/j.cgh.2012.06.036

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1240 TACK ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 11Our aim was to study the influence of buspirone on symp-toms, gastric emptying rate, gastric accommodation, and sen-sitivity to gastric distention in FD patients.

MethodsPatient SelectionPatients aged 20 70 years with FD according to Rome

II criteria were eligible for the study.20 Organic or metabolicisease was excluded by routine biochemistry, upper abdominalltrasound, and upper gastrointestinal endoscopy. During en-oscopy, biopsies were taken to assess the presence of Helico-acter pylori. Exclusion criteria were the presence of esophagitis,astric atrophy, or erosive gastroduodenal lesions on endos-opy, heartburn as a predominant symptom, a history of pepticlcer, major abdominal surgery, and the use of nonsteroidalnti-inflammatory drugs, steroids, prokinetics, or drugs affect-ng gastric acid secretion.

All patients were seen by a psychiatrist for a structuredsychiatric interview.21 Patients with current anxiety or depres-ion and patients treated with antipsychotics or antidepressantsuring the last 6 weeks were not eligible for the study. Thesychiatrist also ruled out anorexia nervosa in patients witheight loss. Pregnant female patients or patients of childbear-

ng potential without effective contraception were also ex-luded. All drugs potentially affecting gastrointestinal motilityr sensitivity were discontinued at least 1 week before the startf the study and were forbidden for the entire course of thetudy. Informed consent was obtained from each participant.he protocol was approved by the Ethics Committee of theniversity Hospital.

Study DesignAfter a 2-week run-in period, the study consisted of two

4-week treatment periods, separated by a 2-week washout (Fig-ure 1). Treatment consisted of buspirone 10 mg or matchingplacebo 3 times daily 15 minutes before meals. Patients filledout a dyspepsia symptom severity (DSS) score at the end of therun-in period, at the end of the washout period, and at the endof each treatment period. In this questionnaire, whose repro-ducibility and sensitivity have previously been reported, pa-tients scored the intensity of 8 dyspeptic symptoms (epigastricpain, postprandial fullness, upper abdominal bloating, earlysatiation, nausea, vomiting, epigastric burning, belching) dur-ing the last week on a Likert scale (range, 0 3 [absent, mild,moderate, severe]).22,23 DSS is defined as the sum of all 8 items.At the beginning of the study, an extensive clinical psychiatricassessment was performed, and patients filled out the SymptomChecklist-90-Revised (SCL-90R) questionnaire.

At the end of the run-in period and at the end of eachtreatment period, all patients underwent a gastric barostatstudy and a gastric emptying study with registration of meal-related symptoms. The details of these measurements are out-lined below.

Gastric Emptying Breath Test andMeal-Related SymptomsGastric solid and liquid emptying rates were deter-

mined by the 14C-octanoic acid and 13C-glycin breath test,espectively.24,25 In the treatment phases, study medication wasingested 15 minutes before the meal. Breath samples were takenbefore the meal and at 15-minute intervals during 240 minutespostprandially and were analyzed as previously reported.24,25

At each breath sampling, the patient was asked to grade theintensity (0 3) of 6 epigastric symptoms (epigastric pain, bloat-ing, postprandial fullness, nausea, belching, and epigastricburning).26

Gastric Barostat StudiesGastric barostat studies to assess sensitivity to gastric

distention and meal-induced accommodation were performedas previously reported.6,8

Data AnalysisGastric half-emptying time was calculated from the

13CO2 and 14CO2 excretion curves as previously reported andalidated.24,25 For each symptom, a meal-related severity score

was obtained by adding scores at all time points. A cumulativemeal-related symptom score was obtained by adding individualsymptom severity scores.26

Gastric barostat studies were analyzed as previously re-ported.6,9 Hypersensitivity to gastric distention was defined as a

iscomfort threshold 6.6 mm Hg above intragastric pressure.mpaired accommodation to a meal was defined as a meal-nduced relaxation 64 mL.6,9

Statistical AnalysisData are presented as mean standard error of the

mean. The primary outcome variable was the improvement inDSS scores. DSS scores after 4 weeks of treatment were com-pared with the scores at the end of the preceding period offtherapy (run-in period or washout period, depending on treat-ment order allocation). To evaluate carryover effects, DSS

Figure 1. (A) Number of patients included and selected for random-ization. (B) Outline of the study protocol. AE, adverse event.scores at the end of run-in and the end of washout were also

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November 2012 BUSPIRONE IN FUNCTIONAL DYSPEPSIA 1241compared. The study was powered to detect a 30% difference insymptom scores with 85% sensitivity at P .05.

Secondary outcome variables were the effects of treatmenton meal-related symptom severity score, on solid and liquidgastric emptying rates, on gastric compliance, thresholds dur-ing gastric balloon distention, and meal-induced gastric accom-modation. Because gastric barostat and meal-related symptomassessment with gastric emptying were only performed at base-line and at the end of each treatment period, these analysescompared baseline with on-therapy measures.

The correlation between changes in DSS scores and thebaseline SCL-90R scores, changes in gastric emptying rate, andchanges in barostat parameters were assessed by Pearson corre-lation analysis. A similar correlation analysis was done forchanges in meal-related symptom scores.

Symptom scores and changes in measured variables of gas-tric sensorimotor function were compared by paired t test.Differences were considered significant, with P .05.

ResultsConduct of the StudyTwenty patients were recruited for the study. Three

were excluded during the run-in phase, one because of preg-nancy, one because the general practitioner started an antide-pressant, and one who was hospitalized with vomiting.

Seventeen FD patients (13 women; mean age, 38.5 2.4years) were randomized to the study drug or placebo. Table 1summarizes their symptom patterns at the end of the run-inperiod. Ten patients (58%) reported weight loss. All patientswere H pylori negative; 4 patients had a history of H pylorinfection, with eradication 6 months before the study. Ataseline, anxiety and depression levels, as assessed by the SCL-0R questionnaire, were 15.2 1.2 and 33.3 3.0, respectively,hich is below the Dutch norms for psychiatric outpatients (25nd 43, respectively). Seven patients were randomized to receiveuspirone first, and 10 patients received placebo first. Bothroups did not differ in mean age (35 5 vs 41 2.0 years; .18) and in sex distribution (2/7 vs 2/10 males; NS).Two patients (one female) stopped the study during the first

eek of treatment (one on buspirone, one on placebo) becausef nausea and abdominal discomfort. In one patient with poorolerance of the barostat, no repeat barostats were performed.ll other patients finished the protocol as planned.

Table 1. Symptom Profile in Patient Population at End ofRun-in Period (N 17)

Symptom Absent Mild Moderate Severe

Postprandial fullness 1 2 4 10Upper abdominal bloating 3 1 5 8Early satiation 6 2 3 6Nausea 4 2 6 5Belching 4 4 5 4Epigastric pain 8 3 2 4Vomiting 12 0 2 3Epigastric burning 8 4 5 0NOTE. Rows indicate number of patients for each symptom severity level.Dyspepsia Symptom SeverityDSS before placebo treatment was 10.8 1.0, and no

ignificant difference occurred after placebo (9.5 1.1; NS).efore buspirone treatment, DSS was 11.5 1.2, and this wasignificantly decreased after 4 weeks of buspirone therapy to.5 1.3 (P .005). The difference in DSS at the end oflacebo and buspirone treatment was borderline significant

P .05) (Figure 2A).Compared with the end of the pretreatment phase, the

individual symptoms of postprandial fullness (2.2 0.2 vs1.3 0.3; P .005), upper abdominal bloating (2.2 0.2 vs1.6 0.3; P .005), and early satiation (1.6 0.3 vs 0.5 0.3;

.005) were significantly improved by buspirone but not bylacebo treatment (Figure 2B). The severity of postprandialullness was significantly lower after 4 weeks of buspironeompared with placebo (1.3 0.3 vs 1.9 0.2; P .05).

Meal-Related Symptom Scores and GastricEmptying RatesTable 2 and Figure 3 summarize the meal-related symp-

tom scores and gastric emptying rates. No significant changesin solid emptying occurred, whereas liquid gastric emptying wassignificantly slower after buspirone compared with baseline

Figure 2. (A) Influence of buspirone and placebo on DSS. (B) Influenceof buspirone and placebo on severity scores of individual dyspepticsymptoms. *P .05 compared with baseline.(Table 2). Delayed gastric emptying was found in 2 patients at

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1242 TACK ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 11baseline, 3 during placebo treatment, and 5 during buspironetreatment (NS). Rapid gastric emptying, defined as half-empty-ing time below the 95% confidence interval in healthy volun-teers (44 minutes for solids, 35 minutes for liquids), wasound in only one patient at baseline (44 minutes for solids, 37

inutes for liquids).Total meal-related symptom severity scores were significantly

ower after buspirone compared with baseline (67 17 vs 119 24; P .005) or with placebo (67 17 vs 97 15; P .01),whereas baseline and placebo did not differ significantly (Figure3A).

Table 2. Influence of Placebo and Buspirone on Different Par

Test Variable

astric emptying rate Solid emptying half-emptying time (min)Liquid emptying half-emptying time (min)

Gastric barostat MDP (mm Hg)Fasting discomfort threshold (mm Hg abFasting discomfort volume (mL)Gastric accommodation (mL)Postprandial discomfort threshold (mm HPostprandial discomfort volume (mL)

MDP, minimal distending pressure.aP .05 compared with baseline.bP .05 compared with placebo.

Figure 3. (A) Influence of buspirone and placebo on gastric emptyingand total meal-related symptom severity. (B) Influence of buspirone andplacebo on individual meal-related symptom severity. *P .05 vs

un-in; **P .005 vs baseline; P .05 vs placebo.Compared with baseline, buspirone significantly improvedmeal-related symptom severities for postprandial fullness (27 6 vs 14 5; P .005), upper abdominal bloating (26 6 vs14 4; P .05), nausea (20 5 vs 12 4; P .01), andbelching (24 4 vs 12 3; P .005), whereas placebo onlyimproved belching (24 4 vs 16 3; P .05). Compared withplacebo, buspirone was associated with significantly lower meal-related symptom severity of postprandial fullness (23 5 vs14 5; P .05) and upper abdominal bloating (22 5 vs 14 4; P .05) (Figure 3B).

Gastric Barostat StudiesTable 2 summarizes the results of the gastric barostat

studies. No significant differences were found between baseline,placebo, and buspirone for minimal distending pressure, sensi-tivity to gastric distention in the fasting and postprandial state(Figure 4A), and gastric compliance. Hypersensitivity to fastinggastric distention was found in 13 patients at baseline, in 12during placebo, and in 10 during buspirone (NS).

Preprandial intraballoon volumes did not differ between the3 conditions. Postprandial intraballoon volumes tended to behigher after buspirone compared with placebo (367 35 vs

76 28; P .05). Gastric accommodation was significantlyigher after buspirone compared with placebo (229 28 vs41 32; P .05) (Figure 4B). Impaired accommodation toeal was found in 5 patients at baseline, in 6 during placebo

reatment (NS), and in 1 during buspirone treatment (P .09).

Correlates of Symptom EvolutionThe improvements in DSS and in meal-related symp-

toms were not significantly correlated to demographics, base-line severity scores, baseline anxiety and depression scores, andbaseline gastric emptying or barostat characteristics. Significantcorrelations were found between the improvement in DSS andchanges in solid and liquid gastric half-emptying times (R2 0.30 and R2 0.27, respectively; both P .04). Borderlinesignificant correlations were found between changes in gastricaccommodation and improvement in postprandial fullness andin upper abdominal bloating (R2, 0.26 and 0.24, respectively;

.05 and .06, respectively).

Carryover EffectIn crossover studies, symptom severity may fail to re-

turn to baseline after the first treatment period. In the present

ters of Gastric Sensorimotor Function Testing

Baseline Placebo Buspirone

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6.6 0.6 7.1 0.6 5.9 0.7DP) 5.5 0.3 5.3 0.5 5.9 0.4

406 21 367 47 380 25132 40 141 32 229 28a,b

ove MDP) 8.6 2.1 7.7 1.3 6.4 0.9523 84 457 54 593 49bame

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November 2012 BUSPIRONE IN FUNCTIONAL DYSPEPSIA 1243treatment period did not differ significantly from baseline11.4 1.2 vs 10.9 0.9; NS).

To further address the issue of a carryover effect, a separatenalysis of the first treatment period as a parallel group studyas performed, although numbers for this analysis are very low.ccording to this analysis, buspirone significantly decreasedSS (5.7 1.8 vs 9.7 0.9; P .01) compared with baseline,

nd the individual symptoms of postprandial fullness (1.0 .4 vs 2.2 0.3; P .05) and belching (0.8 0.3 vs 1.8 0.3;

P 0.05). In contrast, placebo had no significant effect onoverall (9.8 1.7 vs 11.5 1.4; NS) and individual symptomscores compared with baseline. No significant differences insymptom intensities were found at the end of the first treat-ment phase between placebo and buspirone in this parallelgroup analysis.

DiscussionFD is a highly prevalent condition for which no treat-

ment with well-established efficacy is presently available. Previ-ous approaches to improve FD symptoms through acid-sup-pressive or prokinetic drugs have failed to generate substantialsymptomatic benefit for the majority of patients.2 4 The use of

rokinetics was based on the assumption that delayed gastricmptying was a major pathophysiological mechanism, buttudies have identified impaired gastric accommodation andypersensitivity to gastric distention as potentially more rele-ant factors underlying FD symptom generation.2,59 In acute

Figure 4. (A) Influence of buspirone and placebo on gastric sensitivityto fasting and postprandial balloon distention. (B) Influence of buspironeand placebo on intraballoon volumes before and after a meal.tudies, relaxation of the proximal stomach has been identifieds a target to improve symptoms in FD patients with impairedccommodation and hypersensitivity to gastric distention, and-HT1A agonists have been identified as a class of agents that

nduce gastric relaxation.6 10,19,27

In the present proof-of-concept study evaluating symptomsand mechanisms, we demonstrated that the 5-HT1A agonist

uspirone was superior to placebo in alleviating FD symptoms,ore specifically early satiation, postprandial fullness, and up-

er abdominal bloating. Improvement was apparent both fromn FD symptom severity questionnaire28 and from the assess-

ment of postprandial symptoms after a standardized meal.26

Buspirone seemed most effective for the meal-related FD symp-toms of early satiation, upper abdominal bloating, and post-prandial fullness, whereas symptoms of epigastric pain andburning were not affected, suggesting that this treatment ap-proach may be most beneficial for the FD subgroup withpostprandial distress syndrome according to Rome III criteria.1

The observations are in agreement with a recent large placebo-controlled study from Japan, which showed significant benefitfrom a 4-week treatment with the 5-HT1A agonist tandospironeompared with placebo.29 Taken together, these studies support

a therapeutic benefit of 5-HT1A receptor agonists in FD. On theother hand, a smaller mechanistic study with R137696, another5-HT1A agonist, failed to demonstrate symptomatic benefit, butthere was a suggestion of lack of drug effect on repeatedadministration.30

The 5-HT1A agonists may improve FD symptom severityhrough a number of mechanisms. Both buspirone and tan-ospirone are clinically used as anxiolytic drugs. The comor-idity between functional gastrointestinal disorder and psychi-tric disorders, especially anxiety disorders, is high,31 and

experimentally induced anxiety in healthy volunteers is associ-ated with decreased gastric compliance and accommodationand increased epigastric symptom scores during a standardnutrient challenge.32 In hypersensitive FD patients, state anxietys significantly correlated with lower discomfort and painhresholds and decreased compliance during gastric balloonistention.33 These observations suggest a potential for anx-

iolytics to alter both FD symptoms and gastric sensorimotorfunction. In the present article, baseline anxiety scores were notcorrelated to symptom improvement, but because these scoreswere not repeated at the end of treatment, we are unable tocorrelate changes in anxiety levels with improvement in FDsymptoms. This, together with the relatively low number ofpatients studied, is the main limitation of the present proof-of-concept study. On the other hand, in the much larger tan-dospirone controlled trial, no correlation was found betweenanxiety scores and symptom improvement, arguing against ananxiolytic effect as a main mechanism underlying symptomimprovement with 5-HT1A agonists in FD.29

Symptom improvement in the present study was associatedwith a delay in liquid gastric emptying rate and an increase inmeal-induced gastric accommodation. These data suggest thatthe inhibitory effect of buspirone on proximal stomach tone isan important contributor to its therapeutic efficacy. The smallsample size of the current study does not allow comparisons ofsymptomatic benefit in specific subgroups such as patients withimpaired accommodation or visceral hypersensitivity. A signif-icant correlation was found between slowing of gastric empty-ing and symptom improvement by buspirone. However, with

only one patient with rapid gastric emptying at baseline, delay-

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1244 TACK ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 11ing gastric emptying rate per se is unlikely to mediate the effectsof buspirone. The increase in gastric accommodation was bor-derline significantly correlated to the improvement of symp-toms by buspirone treatment. Taking into account the preva-lence of impaired accommodation at baseline and duringbuspirone of 6 and 1 patients, respectively, it is conceivable thatenhancement of gastric accommodation underlies some of theobserved symptomatic benefit. Confirmation in a larger studywould strengthen this hypothesis, but measuring accommoda-tion with a barostat or with other techniques is technicallydifficult, which tends to preclude large-scale studies.7,8

The dose of buspirone, 10 mg 3 times daily, was based onprevious pharmacodynamic studies in healthy volunteers thatshowed that acute administration of this dose did cause a delayin solid gastric emptying; the latter is potentially undesirablefor FD symptom treatment.19 Buspirone was well tolerated inhe present study, with an adverse event and treatment inter-uption incidence similar to placebo. When used in large pa-ient samples for anxiolytic purposes, buspirone use has beenssociated with dizziness, lightheadedness, and nausea.34 Larg-

er-scale therapeutic studies with buspirone to further assess itsefficacy and tolerability profile in FD seem warranted on thebasis of our study.

In conclusion, in a placebo-controlled crossover trial, 4weeks of treatment with the 5-HT1A receptor agonist buspirone

0 mg 3 times daily significantly improved overall symptomeverity and the individual symptoms of early satiation, post-randial fullness, and upper abdominal bloating. The therapeu-ic effect was associated with a slowed liquid gastric emptyingnd enhanced gastric accommodation. Buspirone 10 mg 3imes daily was well tolerated in this proof-of-concept study,nd larger studies in FD seem warranted.

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Reprint requestsAddress requests for reprints to: Jan Tack, MD, PhD, Department of

Pathophysiology, Division of Gastroenterology, University HospitalsGasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. e-mail: [email protected]; fax: 32-16-34-44-19.

Conflicts of interestThe authors disclose no conflicts.

FundingSupported by a Methusalem grant from Leuven University to Prof J.Tack.

mailto:[email protected]:[email protected]

Efficacy of Buspirone, a Fundus-Relaxing Drug, in Patients With Functional DyspepsiaMethodsPatient SelectionStudy DesignGastric Emptying Breath Test and Meal-Related SymptomsGastric Barostat StudiesData AnalysisStatistical Analysis

ResultsConduct of the StudyDyspepsia Symptom SeverityMeal-Related Symptom Scores and Gastric Emptying RatesGastric Barostat StudiesCorrelates of Symptom EvolutionCarryover Effect

DiscussionReferences