Michael Camilleri

Temple University, Philadelphia, Pennsylvania, United States

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Publications (715)4749.82 Total impact

  • Madhusudan Grover, Michael Camilleri
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 01/2014; · 5.64 Impact Factor
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    ABSTRACT: Background & Aims: Acute hyperglycemia delays gastric emptying in patients with diabetes. However, it is not clear whether improved control of glycemia affects gastric emptying in these patients. We investigated whether overnight and short-term (6 months) improvements in control of glycemia affect gastric emptying. Methods We studied 30 patients with poorly controlled type 2 diabetes (levels of glycated hemoglobin >9%). We measured gastric emptying using the [13C]-spirulina platensis breath test on the patients’ first visit (visit 1), after overnight administration of insulin or saline, 1 week later (visit 2), and 6 months after intensive therapy for diabetes. We also measured fasting and post-prandial plasma levels of C-peptide, GLP1, and amylin, as well as autonomic functions. Results At visit 1, gastric emptying was normal in 10 patients, delayed in 14, and accelerated in 6; 6 patients had gastrointestinal symptoms; vagal dysfunction was associated with delayed gastric emptying (P<.05). Higher fasting blood levels of glucose were associated with shorter half-times of gastric emptying (thalf) at visits 1 (r= –0.46, P=.01) and 2 (r= –0.43, P=.02). Although blood levels of glucose were lower after administration of insulin (132±7 mg/dl) than saline (211±15 mg/dl; P=0.0002), gastric emptying thalf was not lower after administration of insulin, compared with saline. After 6 months of intensive therapy, levels of glycated hemoglobin decreased from 10.6%±0.3% to 9%±0.4% (P=.0003), but gastric emptying thalf did not change (92±8 min before, 92±7 min after). Gastric emptying did not correlate with plasma levels of GLP1 and amylin. Conclusions Two-thirds of patients with poorly-controlled type 2 diabetes have mostly asymptomatic yet abnormal gastric emptying. Higher fasting blood levels of glucose are associated with faster gastric emptying. Overnight and sustained (6 months) improvements in glycemic control do not affect gastric emptying.
    Clinical Gastroenterology and Hepatology. 01/2014;
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    ABSTRACT: Vagal interruption causes weight loss in humans and decreases endogenous glucose production in animals. However, it is unknown if this is due to a direct effect on glucose metabolism. We sought to determine if vagal blockade using electrical impulses alters glucose metabolism in humans.
    Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 01/2014; 7:305-12.
  • Michael Camilleri
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    ABSTRACT: Bile acids (BA) are actively reabsorbed in the terminal ileum by the apical Na(+)-dependent bile salt transporter. This review addresses the epidemiology, pathophysiology, diagnosis and treatment of BA diarrhea (BAD). BAD is typically caused by ileal resection or disease; 25-33% of patients with chronic functional diarrhea or irritable bowel syndrome-diarrhea (IBS-D) have BAD, possibly from deficiency in the ileal hormone, FGF-19, which normally provides feedback inhibition of BA synthesis. Diagnosis of BAD is typically based on reduced BA retention of radiolabeled BA ((75)SeHCAT), increased BA synthesis (serum C4) or increased fecal BA loss. In clinical practice, diagnosis is often based on response to BA sequestrants (e.g., cholestyramine or colesevelam). Diagnostic tests for BA malabsorption (BAM) need to be used more extensively in clinical practice. In the future, farnesoid X receptor agonists that stimulate ileal production of FGF-19 may be alternative treatments of BAD.
    Expert review of gastroenterology & hepatology 01/2014; 8(1):49-61.
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    ABSTRACT: Background & Aims: The allergic response associated with eosinophilic esophagitis (EoE) occurs when food antigens permeate tight junction-mediated epithelial dilated intercellular spaces. We assessed whether levels of tight junction proteins correlate with dilation of intercellular spaces (spongiosis) and the effects of topical steroids on these parameters. Methods We assessed esophageal biopsy samples from10 patients with active EoE treated with topical fluticasone, 10 untreated patients, and 10 patients without esophageal disease (controls) for degree of spongiosis Immunohistochemical assays were used to determine levels of the tight junction proteins filaggrin, ZO1, ZO2, ZO3, and claudin1 Histology and immunohistochemistry results were blindly assessed, with levels of tight junction proteins and degree of spongiosis rated on scales of 0 to 3. Results The mean degree of spongiosis in untreated and treated patients with EoE were 1.3 and 0.4, respectively (P=.016). Esophageal epithelia did not stain significantly for ZO1 or ZO2. Filaggrin was observed in a predominant cytoplasmic pattern, compared with the cytoplasmic and membranous patterns of ZO3 and claudin1. In biopsies from patients with active EoE, the mean staining intensities for filaggrin, ZO3, and claudin1 were 1.6, 1.4, and 0.7, respectively. In biopsies from patients treated with fluticasone, levels of filaggrin, ZO3, and claudin1 were 2.8 (P=.002 compared with untreated patients), 1.7 (P=.46 compared with untreated patients), and 1.3 (P=.25 compared with untreated patients), respectively. The correlation between level of filaggrin and degree of spongiosis was r=0.23, and between ZO3 staining and degree of spongiosis was r=.016, (P=.001 for filaggrin vs zo3 staining). Conclusions Filaggrin, ZO3, and claudin1 (but not ZO1 or ZO2) are detected in esophageal mucosa of patients with EoE treated with steroids and individuals without esophageal disease. Without treatment, spongiosis increases, corresponding with reduced levels of filaggrin, ZO3, and claudin1. Loss of tight junction regulators and dilation of intercellular spaces appear to be involved in pathophysiology of EoE and could be targets for treatment.
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 01/2014; · 5.64 Impact Factor
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    ABSTRACT: Background & Aims SCN5A encodes the α-subunit of the voltage-gated sodium channel NaV1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether patients with IBS have SCN5A variants that affect the function of Nav1.5. Methods We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without (controls). Mutant forms of SCN5A were expressed in HEK-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study (GWAS) was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls. Results Missense mutations were found in SCN5A in 13/584 patients (2.2%, probands). Diarrhea-predominant IBS (IBS-D) was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (IBS-C, 31%) than IBS-D (10%, P<.05). Electrophysiologic analysis showed that 10/13 detected mutations disrupted NaV1.5 function (9 reduced and 1 increased function); p.A997T-NaV1.5 had the greatest effect in reducing NaV1.5 function. Incubation of cells that expressed this variant with mexiletine restored their sodium current; administration of mexiletine to 1 carrier of this mutation (who had IBS-C) normalized their bowel habits. In the GWAS and 4 replicated studies, the SCN5A locus was strongly associated with IBS. Conclusions About 2% of patients with IBS carry mutations in SCN5A. Most of these are loss-of-function mutations that disrupt NaV1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.
    Gastroenterology 01/2014; · 12.82 Impact Factor
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    ABSTRACT: Highly selective 5-HT4 agonists have been suggested for the treatment of chronic constipation (CC). To assess the effects of highly selective 5-HT4 agonists (prucalopride, velusetrag or naronapride) on patient-important clinical efficacy outcomes and safety in adults with CC. We searched the medical literature in January 2013 using MEDLINE/Pubmed, Embase, Cochrane Library, and Web of Science/Scopus for randomised, controlled trials of highly selective 5-HT4 agonists in adults with CC, with no minimum duration of therapy (maximum 12 weeks) or date limitations. Data were extracted from intention-to-treat analyses, pooled using a random-effects model, and reported as relative risk (RR), mean differences, or standardised mean differences with 95% confidence intervals (CI). Main outcomes included stool frequency, Patient-Assessment of Constipation Quality of Life (PAC-QOL), PAC of symptoms (PAC-SYM) and adverse events. Thirteen eligible trials were identified: 11 prucalopride, 1 velusetrag, 1 naronapride. Relative to control, treatment with highly selective 5-HT4 agonists was superior for all outcomes: mean ≥3 spontaneous complete bowel movements (SCBM)/week (RR = 1.85; 95% CI 1.23-2.79); mean ≥1 SCBM over baseline (RR = 1.57; 95% CI 1.19, 2.06); ≥1 point improvement in PAC-QOL and PAC-SYM scores. The only active comparator trial of prucalopride and PEG3350 suggested PEG3350 is more efficacious for some end points. Adverse events were more common with highly selective 5-HT4 agonists, but were generally minor; headache was the most frequent. Most trials studied prucalopride. Demonstration of efficacy on patient-important outcomes and a favourable safety profile support the continued use and development of highly selective 5-HT4 agonists in the treatment of chronic constipation.
    Alimentary Pharmacology & Therapeutics 12/2013; · 4.55 Impact Factor
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    ABSTRACT: Study objectives were to: mine the complete exome to identify putative rare single nucleotide variants (SNVs) associated with irritable bowel syndrome-diarrhea (IBS D) phenotype; assess genes that regulate bile acids in IBS-D; explore univariate associations of SNVs with symptom phenotype and quantitative traits in independent IBS cohort. Using principal component analysis, we identified 2 groups of IBS-D (n=16) with increased fecal bile acids: rapid colonic transit or high bile acids synthesis. DNA was sequenced indepth, analyzing SNVs in bile acids genes (ASBT, FXR, OSTα/β, FGF19, FGFR4, KLB, SHP, CYP7A1, LRH-1, and FABP6). Exome findings were compared to 50 similar ethnicity controls. We assessed univariate associations of each SNV with quantitative traits and principal component analysis and associations between SNVs in KLB and FGFR4 and symptom phenotype in 405 IBS, 228 controls and colonic transit in 70 IBS-D, 71 IBS-C. Mining the complete exome did not reveal significant associations with IBS-D over controls. There were 54 SNVs in 10/11 bile acids-regulating genes, with no SNVs in FGF19; 15 non-synonymous SNVs were identified in similar proportions of IBS-D and controls. Variations in KLB (rs1015450, downstream) and FGFR4 (rs434434 [intronic], rs1966265, and rs351855 [non-synonymous]) were associated with colonic transit (rs1966265; P=.043), fecal bile acids (rs1015450; P=.064), and PCA groups (all 3 FGFR4 SNVs; P<.05). In the 633 person cohort, FGFR4 rs434434 was associated with symptom phenotype (P=.027) and rs1966265 with 24h colonic transit (P=.066). Thus, exome sequencing identified additional variants in KLB and FGFR4 associated with bile acids or colonic transit in IBS-D.
    AJP Gastrointestinal and Liver Physiology 11/2013; · 3.65 Impact Factor
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    M Camilleri, A Acosta
    Alimentary Pharmacology & Therapeutics 11/2013; 38(10):1320-1. · 4.55 Impact Factor
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    ABSTRACT: Nausea and vomiting are thought to result from upper gastrointestinal dysfunctions. Our clinical observations led to the hypothesis that colonic motor dysfunction is associated with nausea and vomiting. We reviewed electronic medical records (EMR) of 149 patients presenting with complaints of nausea and/or vomiting in a tertiary gastroenterology practice to investigate the association with disorders of colonic motor or evacuation disorders. We extracted demographics, gastric emptying (GE in 149) and colonic transit (CT in 138) of solids, ascending colon emptying half-time (AC t1/2 ), rectal evacuation by anorectal manometry (ARM) in 91 and balloon expulsion test (BE) in 55 patients. We estimated the proportions with delayed GE or CT, based on the 5th percentile of GE (in 319) and CT in 220 healthy volunteers using same method. Among 11 patients with nausea and/or vomiting with only GE measured, five had delayed and six normal GE. Among the 149 patients, 77 (52%) patients had evacuation disorders, confirmed by objective tests in 68 patients, and clinical examination in nine patients. In the 138 patients with both GE and CT measured, 106 (76%) had both normal GE and CT, 11 (8%) only delayed GE, 16 (11%) normal GE with delayed CT, and five (3%) delayed GE and CT. Among 21 patients (15%) with delayed CT, nine had slow AC t1/2 and 12 evacuation disorder. In patients with chronic nausea and/or vomiting in gastroenterology practice, evaluation of colonic motility and rectal evacuation should be considered, since about half the patients have abnormal functions that conceivably contribute to the presenting nausea and/or vomiting.
    Neurogastroenterology and Motility 10/2013; · 2.94 Impact Factor
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    ABSTRACT: In prior studies, pregabalin reduced rectal or colonic pain in patients with irritable bowel syndrome and healthy adults, suggesting reduction of afferent function. To assess effects of pregabalin on colonic compliance, sensory and motor functions in patients with constipation-predominant irritable bowel syndrome. In a pilot, double-blind, placebo-controlled, parallel-group study, we tested oral pregabalin, 200mg, in 18 patients with constipation-predominant irritable bowel syndrome. With a barostatically controlled polyethylene balloon in the left colon, we assessed sensation thresholds and colonic compliance using ascending method of limits, sensation ratings over 4 levels of distension, fasting and postprandial colonic tone and phasic motility. Analysis of covariance (adjusted for the corresponding pre-drug response) was used to compare placebo and pregabalin. After 45% participants completed studies, we conducted an interim analysis to assess the conditional power to detect pre-specified treatment effects given the observed variation and treatment group differences based on the planned sample size for the trial. Pregabalin did not significantly affect colonic compliance, sensation thresholds, sensation ratings, fasting or postprandial tone or motility index. The study was stopped for futility to detect an effect on visceral pain with the planned design and sample size. Pregabalin, 200mg, might not reduce distension-related colonic pain in constipation-predominant irritable bowel syndrome patients.
    Digestive and Liver Disease 10/2013; · 3.16 Impact Factor
  • Journal of Nuclear Medicine 10/2013; · 5.77 Impact Factor
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    ABSTRACT: The contribution of elevated Glucagon-Like Peptide-1 (GLP-1) to postprandial glucose metabolism after Roux-en-Y Gastric Bypass (RYGB) has been the subject of uncertainty. We utilized Exendin-9,39, a competitive antagonist of GLP-1 to examine glucose metabolism, islet hormone secretion and gastrointestinal transit in subjects after RYGB and in matched controls. Subjects were studied in the presence or absence of Exendin-9,39 infused at 300pmol/kg/min. Exendin-9,39 resulted in an increase in integrated postprandial glucose concentrations post-RYGB (3.6±0.5 vs. 2.0±0.4 Mol per 6hr, p=0.001). Exendin-9,39 decreased insulin concentrations (12.3±2.2 vs. 18.1±3.1 nmol per 6hr, p=0.002) and the β-cell response to glucose (Total - 13±1 vs. 11±1 10(-9)min(-1), p=0.01) but did not alter the Disposition Index. In control subjects, Exendin-9,39 also increased glucose (2.2±0.4 vs. 1.7±0.3 Mol per 6hr, p=0.03) without accompanying changes in insulin concentrations resulting in an impaired Disposition Index. Post-RYGB, acceleration of stomach emptying during the first 30 minutes by Exendin-9,39 did not alter meal appearance and similarly, suppression of glucose production and stimulation of glucose disappearance were unaltered in RYGB subjects. These data indicate that endogenous GLP-1 has effects on glucose metabolism and on gastrointestinal motility years after RYGB. However, it remains uncertain if this explains all the changes following RYGB.
    Diabetes 10/2013; · 7.90 Impact Factor
  • Michael Camilleri
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    ABSTRACT: Esophageal, gastrointestinal, and colonic diseases resulting from disorders of the motor and sensory functions represent almost half the patients presenting to gastroenterologists. There have been significant advances in understanding the mechanisms of these disorders, through basic and translational research, and in targeting the receptors or mediators involved, through clinical trials involving biomarkers and patient responses. These advances have led to relief of patients' symptoms and improved quality of life, although there are still significant unmet needs. This article reviews the pipeline of medications in development for esophageal sensorimotor disorders, gastroparesis, chronic diarrhea, chronic constipation (including opioid-induced constipation), and visceral pain.
    The Journal of clinical investigation 10/2013; 123(10):4111-4120. · 15.39 Impact Factor
  • M Camilleri, A Acosta
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    ABSTRACT: Ghrelin is the endogenous ligand for the growth hormone secretagogue-1a receptor and is a potential target for treatment of gastroparesis. This viewpoint assesses the potential role of ghrelin agonists in the treatment of gastroparesis through a review of the early phase, randomized, controlled trials of ghrelin agonists in patients with diabetes and, either, delayed gastric emptying at the time of the trial or symptoms at the time of the trial, and prior documentation of delayed gastric emptying of solids. Whereas recent experience with ghrelin agonists that have a macrocycle structure (TZP-101, TZP-102) has not confirmed earlier promising results, there is little evidence that ghrelin receptors downregulate with repeated treatment, in contrast to motilin receptors. Phase IIa clinical trials performed with a different agent (RM-131, which is a small molecule ghrelin agonist) suggest that, as a class, ghrelin agonists may be efficacious in stimulating gastric emptying. It is premature to dismiss ghrelin agonists as potential therapies for gastroparesis.
    Neurogastroenterology and Motility 09/2013; · 2.94 Impact Factor
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    Michael Camilleri, Henry Parkman
    The American Journal of Gastroenterology 09/2013; 108(9):1539-40. · 7.55 Impact Factor
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    Andrea S Shin, Michael Camilleri
    Diabetes 08/2013; 62(8):2667-73. · 7.90 Impact Factor
  • Article: Reply.
    Gastroenterology 07/2013; · 12.82 Impact Factor
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    ABSTRACT: Some women with urge-predominant fecal incontinence (FI) have diarrhea-predominant irritable bowel syndrome and a stiffer and hypersensitive rectum. We evaluated the effects of the α2-adrenergic agonist clonidine on symptoms and anorectal functions in women with FI in prospective, placebo-controlled trial. We assessed bowel symptoms and anorectal functions (anal pressures, rectal compliance, and sensation) in 43 women (58±2 y old) with urge-predominant FI randomly assigned to groups given oral clonidine (0.1 mg, twice daily) or placebo for 4 weeks. Before and after administration of the test article, anal pressures were evaluated by manometry, and rectal compliance and sensation were measured using a barostat. Anal sphincter injury was evaluated by endoanal magnetic resonance imaging. Bowel symptoms were recorded in daily and weekly diaries. The primary endpoint was the FI and Constipation Assessment symptom severity score. FI scores decreased from 9.1±0.3 to 7.6±0.5 among subjects given placebo and from 8.1±0.4 to 6.5±0.6 among patients given clonidine. Clonidine did not affect FI symptom severity, bowel symptoms (stool consistency or frequency), anal pressures, rectal compliance, or sensation, compared to placebo. However, when baseline data were used to categorize subjects as those with or without diarrhea, clonidine reduced the proportion of loose stools in patients with diarrhea only (P=.018). Clonidine also reduced the proportion of days with FI in patients with diarrhea (P=.0825). Overall, clonidine did not affect bowel symptoms, fecal continence, or anorectal functions, compared with placebo, in women with urge-predominant FI. Among patients with diarrhea, clonidine increased stool consistency, with a borderline significant improvement in fecal continence.
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 07/2013; · 5.64 Impact Factor
  • Priya Vijayvargiya, Michael Camilleri
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 06/2013; · 5.64 Impact Factor

Publication Stats

20k Citations
4,749.82 Total Impact Points

Institutions

  • 2013
    • Temple University
      Philadelphia, Pennsylvania, United States
  • 1989–2013
    • Mayo Foundation for Medical Education and Research
      • • Division of Gastroenterology and Hepatology
      • • College of Medicine
      • • Department of Medicine
      • • Mayo Medical School
      • • Department of Neurology
      Rochester, Michigan, United States
  • 1985–2013
    • Mayo Clinic - Rochester
      • • Department of Health Science Research
      • • Department of Hospital Internal Medicine
      Rochester, Minnesota, United States
  • 2012
    • Michigan State University
      East Lansing, Michigan, United States
    • The University of Western Ontario
      • Department of Clinical Neurological Sciences
      London, Ontario, Canada
  • 2011–2012
    • University of Michigan
      • • Division of Gastroenterology
      • • Medical School
      Ann Arbor, MI, United States
    • Karolinska Institutet
      • Institutionen för biovetenskaper och näringslära
      Solna, Stockholm, Sweden
  • 2010
    • Dartmouth–Hitchcock Medical Center
      Lebanon, New Hampshire, United States
  • 2009
    • Israelitisches Krankenhaus Hamburg
      Hamburg, Hamburg, Germany
    • Universidad de Extremadura
      Ara Pacis Augustalis, Extremadura, Spain
  • 2008–2009
    • University of Naples Federico II
      • Department of Pharmacy
      Napoli, Campania, Italy
    • University of Padova
      • Department of Information Engineering
      Padova, Veneto, Italy
  • 2005–2008
    • Rochester Clinical Research
      Rochester, New York, United States
  • 2007
    • St. Mary Medical Center
      Long Beach, California, United States
  • 2006
    • Kosin University
      • College of Medicine
      Pusan, Busan, South Korea
    • Yale-New Haven Hospital
      New Haven, Connecticut, United States
  • 2001–2006
    • University of Minnesota Rochester
      Rochester, Minnesota, United States
  • 2004
    • GlaxoSmithKline plc.
      • Neurology Centre of Excellence for Drug Discovery
      London, ENG, United Kingdom
    • Harvard University
      Cambridge, Massachusetts, United States
    • University of Bologna
      Bolonia, Emilia-Romagna, Italy
  • 2003
    • University of Illinois at Chicago
      Chicago, Illinois, United States
    • Beth Israel Deaconess Medical Center
      • Division of Gastroenterology
      Boston, MA, United States
  • 1997
    • University of North Carolina at Chapel Hill
      • Department of Medicine
      Chapel Hill, NC, United States