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Biomedical subjects

M Camilleri

Publications and source records attributed to M Camilleri.

At least 19 recordsLinked to original sources
PubMed2007

Pharmacodynamic effects of a novel prokinetic 5-HT receptor agonist, ATI-7505, in humans.

ATI-7505, an investigational 5-HT(4) receptor agonist, was designed to have similar activity as cisapride without the cardiac adverse effects, i.e. without QT prolongation. In addition, ATI-7505 is not metabolized by CYP450. The aim of the study was to assess the effect of ATI-7505 on gastrointestinal (GI) and colonic transit in healthy humans. A randomized, parallel-group, double-blind, placebo-controlled study evaluated effects of 9-day treatment with ATI-7505 (3, 10 or 20 mg t.i.d.) on scintigraphic GI and colonic transit in healthy volunteers (12 per group). Primary endpoints were gastric-emptying (GE) T(1/2), colonic geometric centre (GC) at 24 h and ascending colon (AC) emptying T(1/2). Daily stool diaries were kept. Analysis of covariance assessed overall treatment group differences, followed by post hoc unadjusted pairwise comparisons. There were borderline overall treatment effects (decrease) on GE T(1/2) (P = 0.154); the 20 mg t.i.d. of ATI-7505-accelerated GE vs placebo (P = 0.038). ATI-7505 increased colonic transit (GC24, P = 0.031) with fastest transit at 10 mg t.i.d. vs placebo (P = 0.065). ATI-7505 accelerated AC emptying T(1/2) (overall P = 0.075) with 10 mg dose vs placebo (P = 0.042). There was looser stool (Bristol stool form scale, overall P = 0.056) with the 10 and 20 mg t.i.d. doses. No safety issues were identified. ATI-7505 accelerates overall colonic transit and tends to accelerate GE and AC emptying and loosen stool consistency.

Adolescent↗
PubMed2006

Effect of a proton pump inhibitor on postprandial gastric volume, emptying and symptoms in healthy human subjects: a pilot study.

BACKGROUND: In consensus guidelines, proton pump inhibitors (PPIs) are recommended for the treatment of functional dyspepsia. It is unclear whether PPIs change gastric volume or emptying. AIM: To assess the effect of a PPI, rabeprazole, on gastric volume and emptying and postprandial symptoms. METHODS: In a double-blind, parallel-group placebo-controlled trial, 13 healthy participants were randomized to rabeprazole, 20 mg b.d., or placebo. On day 3, fasting gastric volume was measured using intravenous (99m)Tc-pertechnate and single photon emission computed tomography (SPECT). After the last dose of study medication, an (111)In-chloride egg meal (300 kcal) was ingested, and postprandial gastric volume and emptying were measured by SPECT. Symptom ratings using a visual analogue scale (fullness, nausea, bloating, abdominal pain, aggregate score) were obtained at baseline and 15, 30, 45, 60 and 75 min postprandially. Group comparisons were performed using Mann-Whitney rank sum test. RESULTS: There were no statistically significant differences in gastric volume or emptying in the two groups. However, there was a borderline increase in gastric volume with rabeprazole compared with placebo. Rabeprazole treatment reduced aggregate postprandial symptoms, particularly fullness, 30 min after the meal (P = 0.01). CONCLUSIONS: In healthy participants, rabeprazole, 20 mg b.d., did not significantly change gastric emptying, but reduced symptoms and had a borderline effect on gastric volume postprandially. The mechanism of reduced postprandial symptoms with a PPI requires further study.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2006

Double-blind, randomized, placebo-controlled study to evaluate the effects of tegaserod on gastric motor, sensory and myoelectric function in healthy volunteers.

BACKGROUND: The effects of tegaserod on gastric accommodation and postprandial satiety remain unclear. AIM: To compare the effects of tegaserod 6 mg twice daily vs. placebo on gastric volumes, postprandial symptoms, gastric emptying, small bowel transit and the surface electrogastrogram in female and male healthy volunteers. METHODS: Randomized, double-blind, placebo-controlled study evaluated gastric function before and after 7 days of tegaserod 6 mg twice daily (n = 21) vs. placebo (n = 20) in healthy volunteers. Validated methods were used to study gastric emptying, myoelectrical activity, volumes and satiation postnutrient challenge. RESULTS: There were no significant effects of tegaserod on the primary endpoints assessing gastric function: emptying of solids or liquids, total gastric volumes or myoelectrical activity. Maximum tolerated volume and aggregate symptom score with nutrient challenge on placebo were 1,035 mL (+/-44) and 130 (+/-15) vs. 989 mL (+/-43) and 117 (+/-15) during tegaserod, respectively (all P = N.S.). Postprandial change in proximal gastric volume by single photon emission-computed tomography was decreased in females on tegaserod (246 +/- 30) vs. placebo (358 +/- 32) (P = 0.015). Proximal fasting volumes in females were increased on tegaserod (126 +/- 12) vs. placebo (92 +/- 13) (P = 0.066). CONCLUSIONS: While tegaserod decreased proximal gastric volume change after a meal, it does not appear to have significant effects on gastric motor and sensory function in healthy individuals. Further studies are required in patients with disturbances of gastric motor and sensory function.

Administration, Oral↗
PubMed2006

Effect of atilmotin on gastrointestinal transit in healthy subjects: a randomized, placebo-controlled study.

We studied effects of i.v. atilmotin (BAX-ACC-1638, a novel motilin agonist, circulating t(1/2) < 10 min) on gastrointestinal transit in humans using a randomized, parallel-group, dose-response double-blind study of i.v. atilmotin, 6, 30, 60 microg or vehicle (placebo) given 2 min after standardized breakfast, lunch and dinner. The breakfast meal contained (99m)Tc-eggs and (111)In-milk. Full gastrointestinal transit was measured by scintigraphy. Primary endpoints were % gastric emptying (GE) at 30 min, GE t(1/2), colonic filling (CF) at 6 h, and geometric centre of colonic transit at 24 h. Analysis included adjustment for age, gender and body mass index, with Bonferroni correction applied for multiple comparisons. A significant treatment effect of atilmotin was detected for GE (%) at 30 min for solids and liquids (P < 0.01 for both). There were no significant effects on CF or CT and no significant adverse clinical events. Thus, atilmotin accelerates GE of solids and liquids in healthy humans. These data suggest that, at the doses tested, atilmotin should be considered for treatment of stomach motility disorders.

Adolescent↗
PubMed2006

Management of patients with chronic abdominal pain in clinical practice.

A practical approach to the management of chronic abdominal pain is needed, given the high prevalence and impact of this problem. This article describes an approach that has evolved based on clinical experience and review of the literature: identifying predominant bloaters and abdominal wall pain; exclusion of organic disease, including consideration of laparoscopy for diagnosis; consideration of chronic functional abdominal pain and the first and second line pharmacotherapies; and seeking specialist care in a pain clinic, psychiatry, or behavioural therapy.

Abdominal Pain↗
PubMed2006

Is there a role of food allergy in irritable bowel syndrome and functional dyspepsia? A systematic review.

A significant proportion of adults believe they suffer from food allergy, and 20-65% of patients with irritable bowel syndrome (IBS) attribute their symptoms to something in food that activates an abnormal response. This systematic review evaluates the role of food allergy in aetiology and management of these disorders. Activation of gastrointestinal mucosal immune system may be one of the causative factors in the pathogenesis of functional dyspepsia and IBS. This activation may result from effects of bacterial infection or other luminal factors including commensal microbial flora and food antigens. Some studies have reported on the role of food allergy in IBS; only one epidemiological study on functional dyspepsia and food allergy has been published. The mechanism by which food activates mucosal immune system is uncertain, but food specific IgE and IgG4 appeared to mediate the hypersensitivity reaction in a subgroup of IBS patients. Exclusion diets based on skin prick test, RAST for IgE or IgG4, hypoallergic diet and clinical trials with oral disodium cromoglycate have been conducted, and some success has been reported in a subset of IBS patients. Further well-controlled studies are needed to establish whether food allergy plays a role in the pathophysiology of functional dyspepsia and IBS.

Adult↗
PubMed2006

Effects of an osmotically active agent on colonic transit.

It is unknown if sorbitol, a widely used laxative agent, accelerates colonic transit, and if these effects are modified by concomitant meal ingestion. Colonic transit was assessed by (111)In scintigraphy in 40 healthy subjects. After a 24-h scan, subjects received sorbitol (30 mL of 70% solution) or dextrose (30 mL of 70% solution), administered with or without a meal. Colonic transit, breath hydrogen excretion, and symptom scores were recorded for 4 h thereafter. VAS scores for flatulence, but not other symptoms increased (P = 0.004) by 13.1 +/- 6.3 mm (mean +/- SEM) on a 100 mm scale after sorbitol alone or sorbitol with a meal (by 18.9 +/- 7.2 mm), but not after dextrose. After adjusting for GC(24), sorbitol accelerated (P < 0.001) colonic transit (GC(28) = 3.0 +/- 0.3) compared with dextrose (GC(28) = 2.2 +/- 0.2), regardless of meal ingestion. Breath hydrogen excretion was correlated with the change in colonic transit (r = 0.52, P < 0.01) and with flatulence (r = 0.45, P = 0.003) after sugar ingestion. In healthy subjects, sorbitol accelerated colonic transit and increased flatulence but not other symptoms within 4 h, regardless of meal intake.

Adolescent↗
PubMed2006

Challenges in drug development for functional gastrointestinal disorders. Part I: functional dyspepsia.

There is a need to have predictive biomarkers to test novel experimental medicines in functional gastrointestinal disorders (FGID). The human pharmacodynamic models and biomarkers in functional dyspepsia (part I) and visceral pain (part II) are reviewed, including the general challenges of these two disorders (part I). Part II will also discuss the importance of drug pharmacokinetics and potential of pharmacogenomics, including the influence of CYP metabolism and potential drug interactions. The great heterogeneity of mechanisms potentially responsible for dyspeptic symptoms adds a significant complexity to this FGID. Strategies are needed to identify subgroups most likely to benefit from a specific pharmacological action targeted to one or more mechanisms. Thus, while there are significant challenges in drug development for functional dyspepsia, there is still an important role for pharmacodynamic studies. It remains to be demonstrated that identifying subgroups enhances the response to the pharmacological drug effect. This is feasible as the end points and performance of each test of gastric emptying, accommodation and sensitivity are well characterized. Of these, gastric emptying appears best validated at present, though responsiveness to this biomarker has not yet been translated into positive phase III trials. Eligibility criteria are proposed for selection of patients for functional dyspepsia trials.

Animals↗
PubMed2006

Challenges in drug development for functional gastrointestinal disorders. Part II: visceral pain.

There is a need to have predictive biomarkers to test novel experimental medicines in functional gastrointestinal disorders. The human pharmacodynamic models and biomarkers pertaining to two important conditions are reviewed in a two-part article: functional dyspepsia (part I) and visceral pain (part II). With visceral pain models, the large coefficient of variation in sensation end points in human studies precludes definitive conclusions such as go/no go decisions or dose selection for phase IIb or III studies, unless very large numbers of patients are evaluated in phase IIA pharmacodynamic studies. This renders such pharmacological studies ambitious, or unachievable in a timely fashion. Moreover, the results of tests and clinical trials should be interpreted with greater knowledge of the drug pharmacokinetics, including the influence of CYP metabolism and potential drug interactions. Thus, it is important to identify valid biomarkers of visceral pain for the assessment of treatment response in pharmacodynamic studies. In this second part of a two-part article, we shall discuss the special challenges in developing medications for visceral pain and the general importance of including pharmacokinetic and pharmacogenomic studies in drug development programmes.

Animals↗
PubMed2006

New imaging in neurogastroenterology: an overview.

Advances in imaging are being introduced initially as research tools and subsequently as clinical diagnostic tests. These investigations include modifications of the standard gastric emptying by scintigraphy to include application of intraluminal ultrasound to image sustained contractions and longitudinal shortening in the oesophagus, 2- and 4-h images, volumetric measurements to measure gastric volume, magnetic resonance (MR) imaging to appraise the structure and function of the rectal evacuation process, and brain imaging as a surrogate for the investigation of the brain's contribution to functional gastrointestinal disorders and chronic pain syndromes. There is a need for rigorous validation and measurement of the performance characteristics of these tests. Given the impact of gastric emptying at 4 h and single photon emission computerized tomography (SPECT) imaging for measuring gastric volumes on research and clinical practice, it is anticipated that, once validated, these different techniques are likely to have a significant impact on neurogastroenterology and, potentially, replace more invasive procedures.

Animals↗
PubMed2006

Effect of female sex hormone supplementation and withdrawal on gastrointestinal and colonic transit in postmenopausal women.

Females are disproportionately affected by constipation, which is often aggravated during pregnancy. Bowel function also changes during the luteal phase of the menstrual cycle. The aim was to compare the effects of acute administration of female sex steroids on gastric emptying, small bowel transit and colonic transit in healthy postmenopausal subjects. A second aim was to determine whether withdrawal of the hormones was associated with a change in transit. Forty-nine postmenopausal females were randomized to receive for 7 days 400 mg day(-1) micronized progesterone, 0.2 mg day(-1) oestradiol, combination of the two, or placebo. Treatment groups were balanced on age. Participants underwent whole gut transit measurement by scintigraphy using a 99m-labeled technetium-egg meal and 111-labeled indium-charcoal via a delayed-release capsule. Transit measurement was repeated after withdrawal of the study medications. The primary endpoints were ascending colon (AC) emptying half-life time (t1/2) and colonic geometric centre (GC) at 24 h. Secondary analysis variables were GC at 4 and 48 h, gastric emptying t1/2 and colonic filling at 6 h. There was a significant overall effect of progesterone on colonic transit with shorter AC emptying t1/2 and significantly greater colonic GC at 48 h. No transit endpoints were altered by oestradiol or combined hormonal treatment relative to placebo. Oestradiol and progesterone resulted in looser stool consistency. Withdrawal of the hormone supplement was not associated with significant alteration in transit. Micronized progesterone does not retard colonic transit in postmenopausal females.

Constipation↗
PubMed2006

Effect of a cannabinoid agonist on gastrointestinal transit and postprandial satiation in healthy human subjects: a randomized, placebo-controlled study.

Cannabinoid receptor (CBR) stimulation inhibits motility and increases food intake in rodents. Effects of CBR stimulation in human gastrointestinal (GI) tract are unclear. We compared effects of dronabinol (DRO) and placebo (PLA) on GI transit, gastric volume and satiation in humans. In a double-blind, randomized study, 30 healthy volunteers were randomly assigned to DRO 5 mg b.i.d. or PLA for three doses. We measured GI functions noninvasively: day 0, Ensure satiation test to measure maximum tolerated volume (MTV) and 30-min post-Ensure symptoms; day 1, scintigraphic transit ((111)In-egg meal) and fasting and postprandial gastric volume ((99Tcm)-SPECT); day 2, 24-h colonic transit and repeat satiation test. ancova was used to compare treatment groups with gender, age, and, for the satiation test, the baseline MTV, as covariates. A log-rank test was used to assess treatment effects on gastric emptying. Planned sample size had 80% power to detect 25-30% differences in primary end points. There was an overall retardation of gastric emptying with DRO (P = 0.018); this was more pronounced in females (P = 0.011), than in males (P = 0.184). No significant treatment differences were detected for gastric volumes, MTV, post-Ensure(R) symptoms, small bowel and colonic transit. Fasting gastric volume was greater in males receiving DRO compared with PLA (238 +/- 17 vs 185 +/- 16, P = 0.04). DRO retards gastric emptying in humans; effects are gender-related. Dronabinol also increases fasting gastric volumes in males.

Age Factors↗
PubMed2005

Does the nutrient drink test accurately predict postprandial gastric volume in health and community dyspepsia?

Nutrient drink tests have been proposed as a surrogate for measurement of gastric accommodation. To study the relationship of maximum tolerated volume (MTV) during nutrient drink test and gastric volumes measured by single-photon emission computed tomography (SPECT) in healthy controls and functional dyspepsia (FD) patients. We reviewed data from 85 healthy controls and 35 FD residents of south-eastern Minnesota. All underwent standardized nutrient drink and SPECT studies between August 2000 and June 2003. To test for associations between nutrient drink test and SPECT gastric volumes, we used multiple linear regression and partial regression analyses, assigning age, gender, dyspepsia status and postprandial symptoms as covariates in the model. In the combined group (healthy and FD), MTV was weakly associated with fasting gastric volume (r = 0.43, P = 0.0001) and with volume response to feeding (r = 0.25, P = 0.006). In the FD group, associations were similar (fasting r = 0.53, P = 0.001; postmeal r = 0.32, P = 0.06). After accounting for covariates, MTV only explained 13 and 3% of variations in fasting and postprandial volumes measured by SPECT. MTV during the nutrient drink test does not accurately reflect gastric volume measurements by SPECT in healthy controls and a sample of people in the community with FD.

Adolescent↗
PubMed2005

Alvimopan, a selective peripherally acting mu-opioid antagonist.

Alvimopan is a novel, peripherally acting mu-opioid antagonist that is being developed for the management of acute postoperative ileus and for the reversal of the delayed gastrointestinal and colonic transit that result in symptoms such as constipation, nausea and motility disorders in patients treated with opiate analgesics. There is a clinical need for effective medications for the treatment of postoperative ileus and opiate-induced constipation and other motility disorders. This review addresses the basic and applied pharmacology and current evidence for the use of the medication, alvimopan, in clinical gastroenterology.

Animals↗
PubMed2005

A randomized controlled trial of a probiotic combination VSL# 3 and placebo in irritable bowel syndrome with bloating.

AIM: To evaluate the effects of a combination probiotic on symptoms and colonic transit in patients with irritable bowel syndrome (IBS) and significant bloating. METHODS: Forty-eight patients with Rome II IBS were randomized in a parallel group, double-blind design to placebo or VSL# 3 twice daily (31 patients received 4 weeks and 17 patients 8 weeks of treatment). Pre- and post-treatment colonic transit measurements were performed using scintigraphy with (111)In charcoal. Symptoms were summarized as an average daily score for the entire period of treatment and separately for the first 4 weeks of treatment. Weekly satisfactory relief of abdominal bloating was assessed. RESULTS: Treatment with VSL# 3 was associated with reduced flatulence over the entire treatment period (placebo 39.5 +/- 2.6 vs VSL# 3 29.7 +/- 2.6, P = 0.011); similarly, during the first 4 weeks of treatment, flatulence scores were reduced (placebo 40.1 +/- 2.5 vs VSL# 3 30.8 +/- 2.5, P = 0.014). Proportions of responders for satisfactory relief of bloating, stool-related symptoms, abdominal pain and bloating scores were not different. Colonic transit was retarded with VSL# 3 relative to placebo (colon geometric center 2.27 +/- 0.20 vs 2.83 +/- 0.19, P = 0.05 respectively). CONCLUSION: VSL# 3 reduces flatulence scores and retards colonic transit without altering bowel function in patients with IBS and bloating.

Adult↗