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Extra-esophageal gastroesophageal reflux disease and asthma: understanding this interplay.
Naik RD, Vaezi MF
(2015) Expert Rev Gastroenterol Hepatol 9: 969-82
MeSH Terms: Asthma, Cough, Esophageal pH Monitoring, Gastroesophageal Reflux, Histamine H2 Antagonists, Humans, Laryngitis, Proton Pump Inhibitors, Sinusitis
Show Abstract · Added September 28, 2015
Gastroesophageal reflux disease (GERD) is a condition that develops when there is reflux of stomach contents, which typically manifests as heartburn and regurgitation. These esophageal symptoms are well recognized; however, there are extra-esophageal manifestations of GERD, which include asthma, chronic cough, laryngitis and sinusitis. With the rising incidence of asthma, there is increasing interest in identifying how GERD impacts asthma development and therapy. Due to the poor sensitivity of endoscopy and pH monitoring, empiric therapy with proton pump inhibitors (PPIs) is now considered the initial diagnostic step in patients suspected of having GERD-related symptoms. If unresponsive, diagnostic testing with pH monitoring off therapy and/or impedance/pH monitoring on therapy, may be reasonable in order to assess for baseline presence of reflux with the former and exclude continued acid or weakly acid reflux with the latter tests. PPI-unresponsive asthmatics, without overt regurgitation, usually have either no reflux or causes other than GERD. In this group, PPI therapy should be discontinued. In those with GERD as a contributing factor acid suppressive therapy should be continued as well as optimally treating other etiologies requiring concomitant treatment. Surgical fundoplication is rarely needed but in those with a large hiatal hernia, moderate-to-severe reflux by pH monitoring surgery might be helpful in eliminating the need for high-dose acid suppressive therapy.
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9 MeSH Terms
First-trimester antihistamine exposure and risk of spontaneous abortion or preterm birth.
Aldridge TD, Hartmann KE, Michels KA, Velez Edwards DR
(2014) Pharmacoepidemiol Drug Saf 23: 1043-50
MeSH Terms: Abortion, Spontaneous, Adolescent, Adult, Female, Histamine Antagonists, Humans, Maternal Exposure, Pregnancy, Pregnancy Trimester, First, Prospective Studies, Risk, United States, Young Adult
Show Abstract · Added June 27, 2014
PURPOSE - We tested whether antihistamine exposure during early pregnancy is associated with spontaneous abortion (SAB) or preterm birth (PTB).
METHODS - Women were enrolled in Right from the Start (2004-2010), a prospective pregnancy cohort. Data about first-trimester antihistamine use were obtained from screening and first-trimester interviews. Self-reported outcomes included SAB and PTB and were verified by medical records. Cox proportional hazards models were used to test for an association between antihistamine use and each outcome, both performed adjusting for confounders.
RESULTS - Among the 2685 pregnancies analyzed, 14% (n = 377) reported use of antihistamines. Among antihistamine users, 12% (n = 44) experienced SABs, and 6% (n = 21) had PTBs. Antihistamine exposure was not associated with SAB (adjusted hazard ratio [aHR] = 0.88, 95% confidence interval [CI] 0.64, 1.21) or PTB, which was modified by maternal race (aHR = 1.03, 95%CI 0.61, 1.72 among White women and aHR = 0.43, 95%CI 0.14, 1.34 among Black women).
CONCLUSIONS - Despite the biologic plausibility that antihistamine use may influence pregnancy outcomes, we did not detect evidence of an association with SAB or PTB. These data demonstrate the utility of large prospective cohorts for evaluating drug safety in pregnancy when concerns are raised from animal models.
Copyright © 2014 John Wiley & Sons, Ltd.
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13 MeSH Terms
Role of cyclic nucleotide-dependent actin cytoskeletal dynamics:Ca(2+)](i) and force suppression in forskolin-pretreated porcine coronary arteries.
Hocking KM, Baudenbacher FJ, Putumbaka G, Venkatraman S, Cheung-Flynn J, Brophy CM, Komalavilas P
(2013) PLoS One 8: e60986
MeSH Terms: Actin Cytoskeleton, Actin Depolymerizing Factors, Actins, Animals, Biomechanical Phenomena, Calcium, Cell Adhesion Molecules, Colforsin, Coronary Vessels, HSP20 Heat-Shock Proteins, Histamine, Intracellular Space, Microfilament Proteins, Muscle Contraction, Myosin Light Chains, Nucleotides, Cyclic, Paxillin, Phosphoproteins, Phosphorylation, Sus scrofa
Show Abstract · Added March 9, 2015
Initiation of force generation during vascular smooth muscle contraction involves a rise in intracellular calcium ([Ca(2+)]i) and phosphorylation of myosin light chains (MLC). However, reversal of these two processes alone does not account for the force inhibition that occurs during relaxation or inhibition of contraction, implicating that other mechanisms, such as actin cytoskeletal rearrangement, play a role in the suppression of force. In this study, we hypothesize that forskolin-induced force suppression is dependent upon changes in actin cytoskeletal dynamics. To focus on the actin cytoskeletal changes, a physiological model was developed in which forskolin treatment of intact porcine coronary arteries (PCA) prior to treatment with a contractile agonist resulted in complete suppression of force. Pretreatment of PCA with forskolin suppressed histamine-induced force generation but did not abolish [Ca(2+)]i rise or MLC phosphorylation. Additionally, forskolin pretreatment reduced filamentous actin in histamine-treated tissues, and prevented histamine-induced changes in the phosphorylation of the actin-regulatory proteins HSP20, VASP, cofilin, and paxillin. Taken together, these results suggest that forskolin-induced complete force suppression is dependent upon the actin cytoskeletal regulation initiated by the phosphorylation changes of the actin regulatory proteins and not on the MLC dephosphorylation. This model of complete force suppression can be employed to further elucidate the mechanisms responsible for smooth muscle tone, and may offer cues to pathological situations, such as hypertension and vasospasm.
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20 MeSH Terms
Cimetidine-associated patent ductus arteriosus is mediated via a cytochrome P450 mechanism independent of H2 receptor antagonism.
Cotton RB, Shah LP, Poole SD, Ehinger NJ, Brown N, Shelton EL, Slaughter JC, Baldwin HS, Paria BC, Reese J
(2013) J Mol Cell Cardiol 59: 86-94
MeSH Terms: Cimetidine, Cytochrome P-450 Enzyme System, Ductus Arteriosus, Patent, Histamine H2 Antagonists, Humans, Immunohistochemistry, Infant, Newborn, Ketoconazole, Polymerase Chain Reaction, Randomized Controlled Trials as Topic, Ranitidine, Receptors, Histamine, Retrospective Studies
Show Abstract · Added April 9, 2015
Persistent patency of the ductus arteriosus (PDA) is a common problem in preterm infants. The antacid cimetidine is a potent antagonist of the H2 histamine receptor but it also inhibits certain cytochrome P450 enzymes (CYPs), which may affect DA patency. We examined whether cimetidine contributes to PDA and is mediated by CYP inhibition rather than H2 blockade. Analysis of a clinical trial to prevent lung injury in premature infants revealed a significant association between cimetidine treatment and PDA. Cimetidine and ranitidine, both CYP inhibitors as well as H2 blockers, caused relaxation of the term and preterm mouse DA. CYP enzymes that are inhibited by cimetidine were expressed in DA subendothelial smooth muscle. The selective CYP3A inhibitor ketoconazole induced greater DA relaxation than cimetidine, whereas famotidine and other H2 antagonists with less CYP inhibitory effects caused less dilation. Histamine receptors were developmentally regulated and localized in DA smooth muscle. However, cimetidine caused DA relaxation in histamine-deficient mice, consistent with CYP inhibition, not H2 antagonism, as the mechanism for PDA. Oxygen-induced DA constriction was inhibited by both cimetidine and famotidine. These studies show that antacids and other compounds with CYP inhibitory properties pose a significant and previously unrecognized risk for PDA in critically ill newborn infants.
Copyright © 2013 Elsevier Ltd. All rights reserved.
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13 MeSH Terms
The International Serious Adverse Events Consortium (iSAEC) phenotype standardization project for drug-induced torsades de pointes.
Behr ER, January C, Schulze-Bahr E, Grace AA, Kääb S, Fiszman M, Gathers S, Buckman S, Youssef A, Pirmohamed M, Roden D
(2013) Eur Heart J 34: 1958-63
MeSH Terms: Adverse Drug Reaction Reporting Systems, Anti-Arrhythmia Agents, Anti-Infective Agents, Antipsychotic Agents, Consensus, Consensus Development Conferences as Topic, Drug-Related Side Effects and Adverse Reactions, Genetic Markers, Genetic Testing, Histamine Antagonists, Humans, Interprofessional Relations, Phenotype, Risk Factors, Sex Factors, Torsades de Pointes
Added June 26, 2014
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16 MeSH Terms
Functional selectivity induced by mGlu₄ receptor positive allosteric modulation and concomitant activation of Gq coupled receptors.
Yin S, Zamorano R, Conn PJ, Niswender CM
(2013) Neuropharmacology 66: 122-32
MeSH Terms: Adenylyl Cyclase Inhibitors, Adenylyl Cyclases, Allosteric Regulation, Animals, Benzopyrans, Calcium, Calcium Signaling, Cell Line, Excitatory Amino Acid Agonists, Excitatory Amino Acid Antagonists, GTP-Binding Protein alpha Subunits, Gq-G11, Glutamic Acid, Guinea Pigs, Histamine, Humans, Phosphatidylinositols, Rats, Receptors, Histamine H1, Receptors, Metabotropic Glutamate, Signal Transduction
Show Abstract · Added February 19, 2015
Metabotropic glutamate receptors (mGlus) are a group of Family C Seven Transmembrane Spanning Receptors (7TMRs) that play important roles in modulating signaling transduction, particularly within the central nervous system. mGlu(4) belongs to a subfamily of mGlus that is predominantly coupled to G(i/o) G proteins. We now report that the ubiquitous autacoid and neuromodulator, histamine, induces substantial glutamate-activated calcium mobilization in mGlu(4)-expressing cells, an effect which is observed in the absence of co-expressed chimeric G proteins. This strong induction of calcium signaling downstream of glutamate activation of mGlu(4) depends upon the presence of H(1) histamine receptors. Interestingly, the potentiating effect of histamine activation does not extend to other mGlu(4)-mediated signaling events downstream of G(i/o) G proteins, such as cAMP inhibition, suggesting that the presence of G(q) coupled receptors such as H(1) may bias normal mGlu(4)-mediated G(i/o) signaling events. When the activity induced by small molecule positive allosteric modulators of mGlu(4) is assessed, the potentiated signaling of mGlu(4) is further biased by histamine toward calcium-dependent pathways. These results suggest that G(i/o)-coupled mGlus may induce substantial, and potentially unexpected, calcium-mediated signaling events if stimulation occurs concomitantly with activation of G(q) receptors. Additionally, our results suggest that signaling induced by small molecule positive allosteric modulators may be substantially biased when G(q) receptors are co-activated. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.
Copyright © 2012 Elsevier Ltd. All rights reserved.
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20 MeSH Terms
Inadvertent relaxation of the ductus arteriosus by pharmacologic agents that are commonly used in the neonatal period.
Reese J, Veldman A, Shah L, Vucovich M, Cotton RB
(2010) Semin Perinatol 34: 222-30
MeSH Terms: Animals, Cimetidine, Ductus Arteriosus, Ductus Arteriosus, Patent, Gentamicins, Heparin, Histamine H2 Antagonists, Humans, Infant, Newborn, Infant, Premature, Infant, Premature, Diseases, Nitric Oxide, Prostaglandins, Risk Factors, Vasodilation, Vasodilator Agents
Show Abstract · Added April 9, 2015
Premature birth and disruption of the normal maturation process leave the immature ductus arteriosus unable to respond to postnatal cues for closure. Strategies that advocate conservative management of the patent ductus arteriosus (PDA) in premature infants are dependent on identification of the symptomatic PDA and understanding the risk factors that predispose to PDA. Exposure of premature infants to unintended vasodilatory stimuli may be one of the risk factors for PDA that is under recognized. In this article, we summarize the clinical factors that are associated with PDA and review commonly used neonatal drugs for their vasodilatory properties. Data demonstrating relaxation of the ductus arteriosus by gentamicin and other aminoglycoside antibiotics, by cimetidine and other H2 receptor antagonists, and by heparin are provided as examples of neonatal therapies that have unanticipated effects that may promote PDA.
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16 MeSH Terms
A novel class of H3 antagonists derived from the natural product guided synthesis of unnatural analogs of the marine bromopyrrole alkaloid dispyrin.
Kennedy JP, Conn PJ, Lindsley CW
(2009) Bioorg Med Chem Lett 19: 3204-8
MeSH Terms: Alkaloids, Animals, Biological Products, Bromine, Histamine H3 Antagonists, Humans, Inhibitory Concentration 50, Porifera, Pyrroles, Receptors, Histamine H3, Structure-Activity Relationship, Sympathomimetics, Tyramine
Show Abstract · Added March 5, 2014
This Letter describes the natural product guided synthesis of unnatural analogs of the marine bromopyrrole alkaloid dispyrin, and the resulting SAR of H(3) antagonism. Multiple rounds of iterative parallel synthesis improved human H(3) IC(50) approximately 33-fold, and afforded a new class of H(3) antagonists based on the novel bromotyramine core of dispyrin.
1 Communities
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13 MeSH Terms
Altered gastric chief cell lineage differentiation in histamine-deficient mice.
Nozaki K, Weis V, Wang TC, Falus A, Goldenring JR
(2009) Am J Physiol Gastrointest Liver Physiol 296: G1211-20
MeSH Terms: Age Factors, Animals, Azetidines, Basic Helix-Loop-Helix Transcription Factors, Cell Count, Cell Differentiation, Chief Cells, Gastric, Chromogranin A, Enterochromaffin-like Cells, Enzyme Inhibitors, Gastric Fundus, Gastric Mucosa, Gastrins, Histamine, Histidine Decarboxylase, Hyperplasia, Hypertrophy, Intrinsic Factor, Metaplasia, Mice, Mice, Inbred BALB C, Mice, Knockout, Mucins, Muscle Proteins, N-Acetylglucosaminyltransferases, Parietal Cells, Gastric, Peptides, Piperazines, Trefoil Factor-2
Show Abstract · Added October 7, 2013
The orderly differentiation of cell lineages within gastric glands is regulated by a complicated interplay of local mucosal growth factors and hormones. Histamine secreted from enterochromaffin-like cells plays an important role in not only stimulated gastric acid secretion but also coordination of intramucosal growth and lineage differentiation. We have examined histidine-decarboxylase (HDC)-deficient mice, which lack endogenous histamine synthesis, to evaluate the influence of histamine on differentiation of fundic mucosal lineages and the development of metaplasia following induction of acute oxyntic atrophy. Stomachs from HDC-deficient mice and wild-type mice were evaluated at 8 wk and 12 mo of age. DMP-777 was administrated orally to 6-wk-old mice for 1 to 14 days. Sections of gastric mucosa were stained with antibodies against Mist1, intrinsic factor, H/K-ATPase, trefoil factor 2 (TFF2), chromogranin A, and Ext1 and for the cell cycle marker phospho-histone H3. HDC-deficient mice at 8 wk of age demonstrated a prominent increase in chief cells expressing Mist1 and intrinsic factor. Importantly Mist1-positive mature chief cells were present in the midgland region as well as at the bases of fundic glands, indicating a premature differentiation of chief cells. Mice dually deficient for both HDC and gastrin showed a normal distribution of chief cells in fundic glands. Treatment of HDC-deficient mice with DMP-777 led to loss of parietal cells and an accelerated and exaggerated emergence of mucous cell metaplasia with the presence of dual intrinsic factor and TFF2-expressing cells throughout the gland length, indicative of the emergence of spasmolytic polypeptide-expressing metaplasia (SPEM) from chief cells. These findings indicate that histamine, in concert with gastrin, regulates the appropriate differentiation of chief cells from mucous neck cells as they migrate toward the bases of fundic glands. Nevertheless, histamine is not required for emergence of SPEM following acute oxyntic atrophy.
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29 MeSH Terms
Total synthesis and biological evaluation of the marine bromopyrrole alkaloid dispyrin: elucidation of discrete molecular targets with therapeutic potential.
Kennedy JP, Brogan JT, Lindsley CW
(2008) J Nat Prod 71: 1783-6
MeSH Terms: Adrenergic Agonists, Agelas, Alkaloids, Animals, Drug Screening Assays, Antitumor, Histamine Agents, Hydrocarbons, Brominated, Ligands, Marine Biology, Microbial Sensitivity Tests, Molecular Structure, Pyrroles, Receptors, G-Protein-Coupled
Show Abstract · Added March 5, 2014
The first total synthesis of dispyrin, a recently reported bromopyrrole alkaloid from Agelas dispar with an unprecedented bromopyrrole tyramine motif, was achieved in three steps on a gram scale (68.4% overall). No biological activity was reported for dispyrin, so we evaluated synthetic dispyrin against>200 discrete molecular targets in radioligand binding and functional assays. Unlike most marine natural products, dispyrin (1) possesses no antibacterial or anticancer activity, but was found to be a potent ligand and antagonist of several therapeutically relevant GPCRs, the alpha1D and alpha2A adrenergic receptors and the H2 and H3 histamine receptors.
1 Communities
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13 MeSH Terms