Review article: A critical view on impaired accommodation as therapeutic target for functional dyspepsia

Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands.
Alimentary Pharmacology & Therapeutics (Impact Factor: 5.73). 07/2006; 23(11):1499-510. DOI: 10.1111/j.1365-2036.2006.02930.x
Source: PubMed


Several important pathophysiological mechanisms have been identified in functional dyspepsia, however a complete understanding of these mechanisms and beneficial therapeutic strategies are still lacking. Based on the currently available literature we aimed at providing a critical view on one of these pathophysiological mechanisms, impaired accommodation. Although impaired gastric accommodation is identified as a major pathophysiological mechanism, the clinical evidence supporting its role as an important therapeutic target is currently still lacking. Treatment with fundic relaxant drugs has shown conflicting results and has been rather disappointing in general. These negative findings could be explained by the fact that impaired fundic accommodation is part of a more complex disorder involving other regions of the proximal gut or by the increasing insight that central mechanisms may play an important role. Future studies of impaired accommodation should take these considerations into account.

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    • "These include delayed gastric emptying, impaired gastric accommodation to a meal, hypersensitivity to gastric distention, Helicobacter pylori infection, altered response to duodenal lipids or acid, abnormal duodenojejunal motility or central nervous system dysfunction.2 Delayed gastric emptying associated with the symptoms of postprandial fullness, nausea and vomiting, has been reported in approximately 30% of patients with FD.3,4 Impaired gastric accommodation associated with early satiety was present in 40% of patients with FD.5,6 "
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    ABSTRACT: Background/Aims DA-9701 significantly improved gastric accommodation by increasing the postprandial gastric volume. In this study, we investigated how DA-9701 affects the rat gastric fundus relaxation. Methods Gastric fundus muscle strips (9 longitudinal and 7 circular muscles) were obtained from rats. Electrical field stimulation (EFS) was performed at various frequencies (1, 5, 10 and 20 Hz) and train durations (1, 5, 10 and 20 seconds) to select optimal condition for experiments. Isometric force measurements were performed in response to EFS. Peak and nadir were observed during the first 1 minute after initiation of EFS in control state and after sequential addition of atropine (1 μM), DA-9701 (0.5, 5, 25 and 50 μg), N-nitro-L-arginine (L-NNA, 100 μM), MRS2500 (1 μM) and tetrodotoxin (TTX, 1 μM) to the organ bath. Results The optimal frequency and duration of EFS to evoke nerve-mediated relaxation was determined as 5 Hz for 10 seconds. Addition of L-NNA in the presence of atropine and DA-9701 (50 μg) decreased nadir by inhibiting relaxation from −0.054 ± 0.021 g to −0.022 ± 0.015 g (P = 0.026) in longitudinal muscles. However, subsequent application of MRS2500 in the presence of atropine, DA-9701 (50 μg) and L-NNA did not affect nadir. In circular muscles, subsequent addition of L-NNA and MRS2500 in the presence of atropine and DA-9701 (50 μg) did not show significant change of nadir. Conclusions Our data suggest that the effect of DA-9701 on the rat gastric fundus relaxation is mainly mediated by nitrergic rather than purinergic pathway.
    Journal of neurogastroenterology and motility 06/2014; 20(3). DOI:10.5056/jnm13098 · 2.30 Impact Factor
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    • "Functional dyspepsia is a very common chronic gastrointestinal disorder, with a prevalence of 40% using the more liberal criteria [1]. Although the etiology and pathogenesis of functional dyspepsia are poorly understood, pathophysiologic abnormalities such as delayed gastric emptying and impaired gastric accommodation have been reported in 30–40% of functional dyspepsia patients [2–5]. Medications used for the treatment of functional dyspepsia have been developed based on the pathophysiological mechanisms associated with functional dyspepsia; those medications include prokinetic agents, which are now restricted due to serious adverse effects and failure to confirm their efficacy. "
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    ABSTRACT: DA-9701 is a new botanical drug composed of the extracts of Corydalis tuber and Pharbitidis semen, and it is used as an oral therapy for the treatment of functional dyspepsia in Korea. The inhibitory potentials of DA-9701 and its component herbs, Corydalis tuber and Pharbitidis semen, on the activities of seven major human cytochrome P450 (CYP) enzymes and four UDP-glucuronosyltransferase (UGT) enzymes in human liver microsomes were investigated using liquid chromatography-tandem mass spectrometry. DA-9701 and Corydalis tuber extract slightly inhibited UGT1A1-mediated etoposide glucuronidation, with 50% inhibitory concentration (IC(50)) values of 188 and 290 μg/mL, respectively. DA-9701 inhibited CYP2D6-catalyzed bufuralol 1'-hydroxylation with an inhibition constant (K(i)) value of 6.3 μg/mL in a noncompetitive manner. Corydalis tuber extract competitively inhibited CYP2D6-mediated bufuralol 1'-hydroxylation, with a K(i) value of 3.7 μg/mL, whereas Pharbitidis semen extract showed no inhibition. The volume in which the dose could be diluted to generate an IC(50) equivalent concentration (volume per dose index) value of DA-9701 for inhibition of CYP2D6 activity was 1.16 L/dose, indicating that DA-9701 may not be a potent CYP2D6 inhibitor. Further clinical studies are warranted to evaluate the in vivo extent of the observed in vitro interactions.
    Evidence-based Complementary and Alternative Medicine 04/2012; 2012(2):650718. DOI:10.1155/2012/650718 · 1.88 Impact Factor
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    • "In smooth muscle cells, NO or NO donors increase cGMP levels, resulting in the activation of several downstream signalling cascades which ultimately result in Ca 2+ removal from the myoplasm, membrane hyperpolarization and relaxation (Petkov & Boev, 1996; Cohen et al. 1999; Yu et al. 2003). In gastric motility disorders where enteric neuropathies are implicated, such as impaired gastric accommodation, directly targeting smooth muscle cGMP levels with NO donors or phosphodiesterase inhibitors improves symptoms and gastric smooth muscle function (Tack et al. 2002; Sarnelli et al. 2004; van den Elzen & Boeckxstaens, 2006). We previously reported that SNP increased cGMP-dependent PLB phosphorylation, and relaxed murine gastric fundus and antrum smooth muscles (Kim et al. 2006; Kim & Perrino, 2007). "
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    ABSTRACT: We investigated intracellular Ca(2+) waves, spontaneous transient outward currents (STOCs), and membrane potentials of gastric antrum smooth muscle cells from wild-type and phospholamban-knockout mice. The NO donor sodium nitroprusside (SNP) increased intracellular Ca(2+) wave activity in wild-type antrum smooth muscle cells, but had no effect on the constitutively elevated intracellular Ca(2+) wave activity of phospholamban-knockout cells. STOC activity was also constitutively elevated in phospholamban-knockout antrum smooth muscle cells relative to wild-type cells. SNP or 8-bromo-cGMP increased the STOC activity of wild-type antrum smooth muscle cells, but had no effect on STOC activity of phospholamban-knockout cells. Iberiotoxin, but not apamin, inhibited STOC activity in wild-type and phospholamban-knockout antrum smooth muscle cells. In the presence of SNP, STOC activity in wild-type and phospholamban-knockout antrum smooth muscle cells was inhibited by ryanodine, but not 2-APB. The cGMP-dependent protein kinase inhibitor KT5823 reversed the increase in STOC activity evoked by SNP in wild-type antrum smooth muscle cells, but had no effect on STOC activity in phospholamban-knockout cells. The resting membrane potential of phospholamban-knockout antrum smooth muscle cells was hyperpolarized by approximately -6 mV compared to wild-type cells. SNP hyperpolarized the resting membrane potential of wild-type antrum smooth muscle cells to a greater extent than phospholamban-knockout antrum smooth muscles. Despite the hyperpolarized membrane potential, slow wave activity was significantly increased in phospholamban-knockout antrum smooth muscles compared to wild-type smooth muscles. These results suggest that phospholamban is an important component of the mechanisms regulating the electrical properties of gastric antrum smooth muscles.
    The Journal of Physiology 09/2008; 586(Pt 20):4977-91. DOI:10.1113/jphysiol.2008.156836 · 5.04 Impact Factor
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