Archana S. Rao

Review article: metoclopramide and tardive dyskinesia

Background  Metoclopramide is a dopamine receptor antagonist which has been used for treatment of a variety of gastrointestinal symptoms over the last thirty years. In 2009, the FDA issued a black box warning regarding long‐term or high‐dose use of this medication because of the risk of developing tardive dyskinesia.

Chenodeoxycholate in Females With Irritable Bowel Syndrome-Constipation: A Pharmacodynamic and Pharmacogenetic Analysis

BACKGROUND & AIMS Sodium chenodeoxycholate (CDC) accelerates colonic transit in health. Our aim was to examine pharmacodynamics (colonic transit, bowel function) and pharmacogenetics of CDC in constipation-predominant irritable bowel syndrome (IBS-C). METHODS In a double-blind placebo-controlled study, 36 female patients with IBS-C were randomized to treatment with delayed-release oral formulations of placebo, 500 mg CDC, or 1000 mg CDC for 4 days. We assessed gastrointestinal and colonic transit, stool characteristics, and associations of transit with fasting serum 7αC4 (surrogate of bile acid synthesis) and FGF19 (negative regulator of bile acid synthesis) levels. Candidate genetic polymorphisms involved in regulation of bile acid synthesis were analyzed in the 36 patients with IBS-C and 57 healthy volunteers to assess genetic influence on effects of CDC on transit. RESULTS Overall colonic transit and ascending colon emptying (AC t(½)) were significantly accelerated in the CDC group compared with placebo (P = .005 and P = .028, respectively). Looser stool consistency (P = .003), increased stool frequency (P = .018), and greater ease of passage (P = .024) were noted with CDC compared with placebo. The most common side effect was lower abdominal cramping/pain (P = .01). Fasting serum 7αC4 (but not FGF19) was positively associated with colonic transit (r(s) = 0.749, P = .003, placebo group). Genetic variation in FGFR4 was associated with AC t(½) in response to CDC (uncorrected P = .015); αKlothoβ variant showed a gene-by-treatment interaction based on patient subgroup (uncorrected P = .0088). CONCLUSIONS CDC accelerates colonic transit and improves bowel function in female patients with IBS-C. The rate of bile acid synthesis influences colonic transit. Genetic variation in negative feedback inhibition of bile acid synthesis may affect CDC-mediated acceleration of colonic transit.

Urine sugars for in vivo gut permeability: validation and comparisons in irritable bowel syndrome-diarrhea and controls

Mucosal barrier dysfunction contributes to gastrointestinal diseases. Our aims were to validate urine sugar excretion as an in vivo test of small bowel (SB) and colonic permeability and to compare permeability in patients with irritable bowel syndrome-diarrhea (IBS-D) to positive and negative controls. Oral lactulose (L) and mannitol (M) were administered with (99m)Tc-oral solution, (111)In-oral delayed-release capsule, or directly into the ascending colon (only in healthy controls). We compared L and M excretion in urine collections at specific times in 12 patients with IBS-D, 12 healthy controls, and 10 patients with inactive or treated ulcerative or microscopic colitis (UC/MC). Sugars were measured by high-performance liquid chromatography-tandem mass spectrometry. Primary endpoints were cumulative 0-2-h, 2-8-h, and 8-24-h urinary sugars. Radioisotopes in the colon at 2 h and 8 h were measured by scintigraphy. Kruskal-Wallis and Wilcoxon tests were used to assess the overall and pairwise associations, respectively, between group and urinary sugars. The liquid in the colon at 2 h and 8 h was as follows: health, 62 ± 9% and 89 ± 3%; IBS-D, 56 ± 11% and 90 ± 3%; and UC/MC, 35 ± 8% and 78 ± 6%, respectively. Liquid formulation was associated with higher M excretion compared with capsule formulation at 0-2 h (health P = 0.049; IBS-D P < 0.001) but not during 8-24 h. UC/MC was associated with increased urine L and M excretion compared with health (but not to IBS-D) at 8-24 h, not at 0-2 h. There were significant differences between IBS-D and health in urine M excretion at 0-2 h and 2-8 h and L excretion at 8-24 h. Urine sugars at 0-2 h and 8-24 h reflect SB and colonic permeability, respectively. IBS-D is associated with increased SB and colonic mucosal permeability.

A Klothoβ variant mediates protein stability and associates with colon transit in irritable bowel syndrome with diarrhea.

BACKGROUND & AIMS Bile acid (BA) malabsorption of moderate severity is reported in 32% of patients with chronic unexplained diarrhea, including diarrhea-predominant irritable bowel syndrome (IBS-D). We hypothesized that variants of genes regulating hepatic BA synthesis play a role in IBS-D. METHODS In 435 IBS and 279 healthy subjects, we tested individual associations of 15 common single nucleotide polymorphisms (SNPs) from 7 genes critical to BA homeostasis with symptom-based subgroups using dominant genetic models. In a subset of 238 participants, we tested association with colonic transit. SNP-SNP interactions were investigated based on known protein interactions in BA homeostasis. The function of SNP rs17618244 in Klothoβ (KLB) was evaluated using a protein stability assay in HEK293 cells. RESULTS SNP rs17618244 (Arg728Gln in KLB) is associated with colonic transit at 24 hours. G allele (Arg728) compared with A allele (Gln728) is associated with accelerated colonic transit (P=.0007) in the overall cohort; this association was restricted to IBS-D (P=.0018). Interaction tests of KLB rs17618244 with 3 nonsynonymous SNPs of fibroblast growth factor receptor 4 (FGFR4) revealed that rs1966265 (Val10Ile) and rs351855 (Gly388Arg) modulate rs1768244s association with colonic transit in IBS-D (P=.0025 and P=.0023, respectively). KLB Arg728 significantly reduced protein stability compared with KLB Gln728, demonstrating KLB rs17618244s functional significance. No significant associations with symptom-based subgroups of IBS were detected. CONCLUSIONS A functional KLB gene variant mediating protein stability associates with colonic transit in IBS-D. This association is modulated by 2 genetic variants in FGFR4. The FGF19-FGFR4-KLB pathway links regulation of BA synthesis to colonic transit in IBS-D.

Effect of a glucagon-like peptide 1 analog, ROSE-010, on GI motor functions in female patients with constipation-predominant irritable bowel syndrome

The glucagon-like peptide 1 (GLP-1) analog ROSE-010 reduced pain during acute exacerbations of irritable bowel syndrome (IBS). Our objective was to assess effects of ROSE-010 on several gastrointestinal (GI) motor and bowel functions in constipation-predominant IBS (IBS-C). In a single-center, randomized, parallel-group, double-blind, placebo-controlled, dose-response study, we evaluated safety, pharmacodynamics, and pharmacokinetics in female patients with IBS-C. ROSE-010 (30, 100, or 300 μg sc) or matching placebo was administered once daily for 3 consecutive days and on 1 day 2-10 days later. We measured GI and colonic transit by validated scintigraphy and gastric volumes by single-photon emission computed tomography. The primary end points were half time of gastric emptying of solids, colonic transit geometric center at 24 h, and gastric accommodation volume. Analysis included intent-to-treat principle, analysis of covariance (with body mass index as covariate), and Dunnett-Hsu test for multiple comparisons. Exposure to ROSE-010 was approximately dose-proportional across the dose range tested. Demographic data in four treatment groups of female IBS-C patients (total 46) were not different. Gastric emptying was significantly retarded by 100 and 300 μg of ROSE-010. There were no significant effects of ROSE-010 on gastric volumes, small bowel or colonic transit at 24 h, or bowel functions. The 30- and 100-μg doses accelerated colonic transit at 48 h. Adverse effects were nausea (P < 0.001 vs. placebo) and vomiting (P = 0.008 vs. placebo). Laboratory safety results were not clinically significant. In IBS-C, ROSE-010 delayed gastric emptying of solids but did not retard colonic transit or alter gastric accommodation; the accelerated colonic transit at 48 h with 30 and 100 μg of ROSE-010 suggests potential for relief of constipation in IBS-C.

The effects of methylnaltrexone alone and in combination with acutely administered codeine on gastrointestinal and colonic transit in health.

Aliment Pharmacol Ther 2010; 32: 884–893

Emerging pharmacologic therapies for irritable bowel syndrome.

New therapies are being developed for irritable bowel syndrome (IBS). These advances are based on understanding pathophysiology or the development of medications with greater selectivity in classes of agents with known efficacy. Prucalopride, the newest European Medicines Agency-approved 5-hydroxytryptamine receptor 4 (5-HT4) agonist, is effective in the treatment of chronic constipation with improved cardiovascular safety relative to older 5-HT4 drugs; similarly, ramosetron, the 5-hydroxytryptamine receptor 3 (5-HT3) antagonist, appears efficacious in diarrhea-predominant IBS. Secretagogues with different mechanisms of action target apical domains in enterocytes that are involved in chloride secretion, such as chloride channels, the cystic fibrosis transmembrane regulator, and guanylate cyclase C. As a class, such secretagogues have high efficacy and safety for constipation. With more data obtained from phase 2 and 3 trials, we expect other classes of medications, including bile acid modulators, anti-inflammatory agents, visceral analgesics, and newer centrally acting agents to be efficacious and enter the armamentarium for the treatment of IBS in the future.

S1302 Dose-Related Effects of Chenodeoxycholate on Gastrointestinal and Colonic Transit and Bowel Function in Female Patients With Constipation-Predominant Irritable Bowel Syndrome

Background: A3309 modulates the enterohepatic circulation of bile acids (BA) by inhibiting the intestinal bile acid transporter (IBAT). This will result in an increased concentration of BA in the colon. The synthesis of bile acids in the liver can be measured indirectly by plasma concentrations of the intermediate 7-α-hydroxy-4-cholesten-3-one (C4). Methods: In Vitro part: A3309 potency was tested in transfected HEK293 cells. The cells expressing the various BA transporters were grown in Cytostar 96 w Scintillation Proximity Assay plates and the effect of increasing concentrations of A3309 on accumulation of 30 μM of radiolabelled glycocholic acid was monitored. In Vivo part: In dogs, constipation was induced by shifting the standard diet to ground beef dosed once daily until the faeces weight was <30 g/day. Vehicle or test compounds (A3309 or the active comparator tegaserod) were administered once daily for 3 days, and faeces was collected and weighed on a daily basis. The pharmacodynamic effect of A3309 was investigated in a 1-month study in 24 dogs by measuring the plasma concentration of C4. Results: A3309 was found to be highly potent and selective for IBAT with IC50 =0.53±0.17, 0.13±0.03 and 5.8±1.6 nM for the human, mouse and canine transporters, respectively, whereas the corresponding value for the human liver (basolateral) sodium/bile acid co-transporter was found to be 0.24±0.02 μM (400-fold higher than for IBAT inhibition). Furthermore, inhibition of amino acid uptake via the neutral amino acid transporter(s) in the HEK293 cells was at least 1000 times lower than that of BA transport via the human ileal bile acid transporter. In the constipated dog, A3309 increased faeces weight from 9.4+12.4 g/day (mean±SEM n=36) after vehicle to 25.8 g/day (1.5 μmol/kg, n=2), 34.4 g/day (5 μmol/kg, n=2), 31.3±4,5 g/day (15 μmol/kg, n=6) and for tegaserod 14 g/day (3.3 μmol/kg, n=1), 18.1±10,2g/day (3.3 μmol /kgx2, n=3), 23.9±7,1 g/day (10 μmol /kg, n=3) and 68.3 g/day (33 μmol /kgx2, n=2). In the dog, a dose dependant increase of C4 in plasma was observed already after single doses. After 26 days treatment with A3309 the plasma concentration of C4 increased 3 to 7 fold (43.0±8.43,150±48.8 ,190±47.0 and 350±49.0 nmol/L, pre-values, 5, 25, 200 μmol/kg, respectivly). Conclusion: A3309 was found to be highly potent and selective for IBAT and ameliorate meat-induced constipation in dogs. The increased BA synthesis effect last for at least 1 month. IBAT inhibitors have a potential clinical utility in the treatment of constipation.

T2084 Comparison of Small Bowel and Colonic Mucosal Permeability in Diarrhea-Predominant Irritable Bowel Syndrome and Health by Urinary Saccharide Excretion

Background: A significant proportion of patients with irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) suffer from psychological co-morbidities, i.e. depression. Recently, we identified 16 interferon (IFN)-responsive genes (ISGs) that were associated with IFN-α induced depression during therapy of chronic HCV infection as well as with severe endogenous depressive episodes. Based upon data that a large proportion of patients with chronic bowel disorders suffer from depressive disorders, we aimed to investigate, whether these “depression ISGs” may play a role in patients with IBS and IBD. Methods: 11 consecutive IBS (all constipation predominant) and 12 IBD patients (7 ulcerative colitis, 5 Crohns disease) as well as 14 healthy controls were included. Basal expression of ISGs and the internal expression of IFN-α, -β, and -γ was analyzed in whole blood (PAXgene blood RNA tubes) using quantitative real-time PCR. Additionally, PBMC were isolated from each patient by density gradient centrifugation and were stimulated In Vitro with IFN-α (0, 100, and 1000 IU/ mL for 16h). The upregulation of ISGs was analyzed by real-time PCR. HRQOL (SF-36, physical [PCS] and mental component score [MCS]) and affective disorders (Hospital Anxiety and Depression Scale) were also assessed. Results: We found highly significant differences in the basal expression of 11 out of 14 tested ISGs (p<0.001 for 10 genes) in IBS and IBD patients vs. healthy controls. Basal expression of ISGs associated with depression and of “classical” ISGs (IFIT1, ISG15, and MX1) was significantly lower in 13/ 14 genes in IBS and IBD patients compared to healthy controls. Basal expression of IFN-β was significantly upregulated in IBS and IBD patients (p<0.001), while there was no difference in basal expression of IFN-α and IFN-γ. Comparing IBS and IBD patients, no significant differences in basal gene expression were detected. PBMC of IBS and IBD patients were hyper-responsive to exogenous stimulation with IFN-α compared to healthy controls leading to significantly higher induction of selected ISGs. Summary: In patients with refractory IBS and chronic IBD a marked activation of the type I IFN system and a hyper-responsiveness to stimulation with type I IFNs can be observed. This is associated with a response pattern that is also found in patients with depressive disorders and may thus explain at least some of the psychopathological abnormalities in these patients.