Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 10 of 153

Publication Record

Connections

PDA-TOLERATE Trial: An Exploratory Randomized Controlled Trial of Treatment of Moderate-to-Large Patent Ductus Arteriosus at 1 Week of Age.
Clyman RI, Liebowitz M, Kaempf J, Erdeve O, Bulbul A, Håkansson S, Lindqvist J, Farooqi A, Katheria A, Sauberan J, Singh J, Nelson K, Wickremasinghe A, Dong L, Hassinger DC, Aucott SW, Hayashi M, Heuchan AM, Carey WA, Derrick M, Fernandez E, Sankar M, Leone T, Perez J, Serize A, PDA-TOLERATE (PDA: TO LEave it alone or Respond And Treat Early) Trial Investigators
(2019) J Pediatr 205: 41-48.e6
MeSH Terms: Acetaminophen, Conservative Treatment, Continuous Positive Airway Pressure, Cyclooxygenase Inhibitors, Ductus Arteriosus, Patent, Female, Gestational Age, Humans, Ibuprofen, Indomethacin, Infant, Extremely Premature, Infant, Newborn, Male, Prospective Studies, Single-Blind Method, Treatment Outcome
Show Abstract · Added March 23, 2019
OBJECTIVE - To compare early routine pharmacologic treatment of moderate-to-large patent ductus arteriosus (PDA) at the end of week 1 with a conservative approach that requires prespecified respiratory and hemodynamic criteria before treatment can be given.
STUDY DESIGN - A total of 202 neonates of <28 weeks of gestation age (mean, 25.8 ± 1.1 weeks) with moderate-to-large PDA shunts were enrolled between age 6 and 14 days (mean, 8.1 ± 2.2 days) into an exploratory randomized controlled trial.
RESULTS - At enrollment, 49% of the patients were intubated and 48% required nasal ventilation or continuous positive airway pressure. There were no differences between the groups in either our primary outcome of ligation or presence of a PDA at discharge (early routine treatment [ERT], 32%; conservative treatment [CT], 39%) or any of our prespecified secondary outcomes of necrotizing enterocolitis (ERT, 16%; CT, 19%), bronchopulmonary dysplasia (BPD) (ERT, 49%; CT, 53%), BPD/death (ERT, 58%; CT, 57%), death (ERT,19%; CT, 10%), and weekly need for respiratory support. Fewer infants in the ERT group met the rescue criteria (ERT, 31%; CT, 62%). In secondary exploratory analyses, infants receiving ERT had significantly less need for inotropic support (ERT, 13%; CT, 25%). However, among infants who were ≥26 weeks gestational age, those receiving ERT took significantly longer to achieve enteral feeding of 120 mL/kg/day (median: ERT, 14 days [range, 4.5-19 days]; CT, 6 days [range, 3-14 days]), and had significantly higher incidences of late-onset non-coagulase-negative Staphylococcus bacteremia (ERT, 24%; CT,6%) and death (ERT, 16%; CT, 2%).
CONCLUSIONS - In preterm infants age <28 weeks with moderate-to-large PDAs who were receiving respiratory support after the first week, ERT did not reduce PDA ligations or the presence of a PDA at discharge and did not improve any of the prespecified secondary outcomes, but delayed full feeding and was associated with higher rates of late-onset sepsis and death in infants born at ≥26 weeks of gestation.
TRIAL REGISTRATION - ClinicalTrials.gov: NCT01958320.
Copyright © 2018 Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
16 MeSH Terms
Dual cyclooxygenase-fatty acid amide hydrolase inhibitor exploits novel binding interactions in the cyclooxygenase active site.
Goodman MC, Xu S, Rouzer CA, Banerjee S, Ghebreselasie K, Migliore M, Piomelli D, Marnett LJ
(2018) J Biol Chem 293: 3028-3038
MeSH Terms: Amidohydrolases, Catalytic Domain, Cyclooxygenase Inhibitors, Isoenzymes, Phenylcarbamates, Phenylpropionates, Prostaglandin-Endoperoxide Synthases, Protein Binding, Stereoisomerism, Substrate Specificity
Show Abstract · Added April 22, 2018
The cyclooxygenases COX-1 and COX-2 oxygenate arachidonic acid (AA) to prostaglandin H (PGH). COX-2 also oxygenates the endocannabinoids 2-arachidonoylglycerol (2-AG) and arachidonoylethanolamide (AEA) to the corresponding PGH analogs. Both enzymes are targets of nonsteroidal anti-inflammatory drugs (NSAIDs), but NSAID-mediated COX inhibition is associated with gastrointestinal toxicity. One potential strategy to counter this toxicity is to also inhibit fatty acid amide hydrolase (FAAH), which hydrolyzes bioactive fatty acid ethanolamides (FAEs) into fatty acids and ethanolamine. Here, we investigated the mechanism of COX inhibition by ARN2508, an NSAID that inhibits both COXs and FAAH with high potency, target selectivity, and decreased gastrointestinal toxicity in mouse models, presumably due to its ability to increase levels of FAEs. A 2.27-Å-resolution X-ray crystal structure of the COX-2·()-ARN2508 complex reveals that ARN2508 adopts a binding pose similar to that of its parent NSAID flurbiprofen. However, ARN2508's alkyl tail is inserted deep into the top channel, an active site region not exploited by any previously reported NSAID. As for flurbiprofen, ARN2508's potency is highly dependent on the configuration of the α-methyl group. Thus, ()-ARN2508 is more potent than ()-ARN2508 for inhibition of AA oxygenation by both COXs and 2-AG oxygenation by COX-2. Also, similarly to ()-flurbiprofen, ()-ARN2508 exhibits substrate selectivity for inhibition of 2-AG oxygenation. Site-directed mutagenesis confirms the importance of insertion of the alkyl tail into the top channel for ()-ARN2508's potency and suggests a role for Ser-530 as a determinant of the inhibitor's slow rate of inhibition compared with that of ()-flurbiprofen.
0 Communities
1 Members
0 Resources
10 MeSH Terms
Inhibition of the Biosynthesis of Prostaglandin E2 By Low-Dose Aspirin: Implications for Adenocarcinoma Metastasis.
Boutaud O, Sosa IR, Amin T, Oram D, Adler D, Hwang HS, Crews BC, Milne G, Harris BK, Hoeksema M, Knollmann BC, Lammers PE, Marnett LJ, Massion PP, Oates JA
(2016) Cancer Prev Res (Phila) 9: 855-865
MeSH Terms: Adenocarcinoma, Adult, Aspirin, Cell Line, Tumor, Cyclooxygenase 2, Cyclooxygenase Inhibitors, Dinoprostone, Female, Humans, Male, Neoplasm Invasiveness
Show Abstract · Added January 29, 2018
Meta-analyses have demonstrated that low-dose aspirin reduces the risk of developing adenocarcinoma metastasis, and when colon cancer is detected during aspirin treatment, there is a remarkable 83% reduction in risk of metastasis. As platelets participate in the metastatic process, the antiplatelet action of low-dose aspirin likely contributes to its antimetastatic effect. Cycloxooxygenase-2 (COX-2)-derived prostaglandin E (PGE) also contributes to metastasis, and we addressed the hypothesis that low-dose aspirin also inhibits PGE biosynthesis. We show that low-dose aspirin inhibits systemic PGE biosynthesis by 45% in healthy volunteers (P < 0.0001). Aspirin is found to be more potent in colon adenocarcinoma cells than in the platelet, and in lung adenocarcinoma cells, its inhibition is equivalent to that in the platelet. Inhibition of COX by aspirin in colon cancer cells is in the context of the metastasis of colon cancer primarily to the liver, the organ exposed to the same high concentrations of aspirin as the platelet. We find that the interaction of activated platelets with lung adenocarcinoma cells upregulates COX-2 expression and PGE biosynthesis, and inhibition of platelet COX-1 by aspirin inhibits PGE production by the platelet-tumor cell aggregates. In conclusion, low-dose aspirin has a significant effect on extraplatelet cyclooxygenase and potently inhibits COX-2 in lung and colon adenocarcinoma cells. This supports a hypothesis that the remarkable prevention of metastasis from adenocarcinomas, and particularly from colon adenocarcinomas, by low-dose aspirin results from its effect on platelet COX-1 combined with inhibition of PGE biosynthesis in metastasizing tumor cells. Cancer Prev Res; 9(11); 855-65. ©2016 AACR.
©2016 American Association for Cancer Research.
0 Communities
2 Members
0 Resources
11 MeSH Terms
Opposing roles of LTB4 and PGE2 in regulating the inflammasome-dependent scorpion venom-induced mortality.
Zoccal KF, Sorgi CA, Hori JI, Paula-Silva FW, Arantes EC, Serezani CH, Zamboni DS, Faccioli LH
(2016) Nat Commun 7: 10760
MeSH Terms: Animals, Arachidonate 5-Lipoxygenase, Blotting, Western, Carrier Proteins, Celecoxib, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Cyclooxygenase Inhibitors, Dinoprostone, In Vitro Techniques, Indoles, Indomethacin, Inflammasomes, Interleukin-1beta, Leukotriene B4, Lipoxygenase Inhibitors, Macrophages, Macrophages, Peritoneal, Mice, Mice, Knockout, NF-kappa B, NLR Family, Pyrin Domain-Containing 3 Protein, Phosphoproteins, Prostaglandin Antagonists, Receptors, Prostaglandin E, EP2 Subtype, Receptors, Prostaglandin E, EP4 Subtype, Reverse Transcriptase Polymerase Chain Reaction, Scorpion Stings, Scorpion Venoms, Scorpions, Xanthones
Show Abstract · Added May 4, 2017
Tityus serrulatus sting causes thousands of deaths annually worldwide. T. serrulatus-envenomed victims exhibit local or systemic reaction that culminates in pulmonary oedema, potentially leading to death. However, the molecular mechanisms underlying T. serrulatus venom (TsV) activity remain unknown. Here we show that TsV triggers NLRP3 inflammasome activation via K(+) efflux. Mechanistically, TsV triggers lung-resident cells to release PGE2, which induces IL-1β production via E prostanoid receptor 2/4-cAMP-PKA-NFκB-dependent mechanisms. IL-1β/IL-1R actions account for oedema and neutrophil recruitment to the lungs, leading to TsV-induced mortality. Inflammasome activation triggers LTB4 production and further PGE2 via IL-1β/IL-1R signalling. Activation of LTB4-BLT1/2 pathway decreases cAMP generation, controlling TsV-induced inflammation. Exogenous administration confirms LTB4 anti-inflammatory activity and abrogates TsV-induced mortality. These results suggest that the balance between LTB4 and PGE2 determines the amount of IL-1β inflammasome-dependent release and the outcome of envenomation. We suggest COX1/2 inhibition as an effective therapeutic intervention for scorpion envenomation.
0 Communities
1 Members
0 Resources
31 MeSH Terms
The role of prostaglandins in allergic lung inflammation and asthma.
Claar D, Hartert TV, Peebles RS
(2015) Expert Rev Respir Med 9: 55-72
MeSH Terms: Animals, Asthma, Cyclooxygenase Inhibitors, Disease Models, Animal, Humans, Lung, Pneumonia, Prostaglandin-Endoperoxide Synthases, Prostaglandins, Receptors, Prostaglandin, Respiratory Hypersensitivity, Signal Transduction
Show Abstract · Added January 20, 2015
Prostaglandins (PGs) are products of the COX pathway of arachidonic acid metabolism. There are five primary PGs, PGD₂, PGE₂, PGF₂, PGI₂ and thromboxane A₂, all of which signal through distinct seven transmembrane, G-protein coupled receptors. Some PGs may counteract the actions of others, or even the same PG may have opposing physiologic or immunologic effects, depending on the specific receptor through which it signals. In this review, we examine the effects of COX activity and the various PGs on allergic airway inflammation and physiology that is associated with asthma. We also highlight the potential therapeutic benefit of targeting PGs in allergic lung inflammation and asthma based on basic science, animal model and human studies.
0 Communities
2 Members
0 Resources
12 MeSH Terms
Conjugation of cisplatin analogues and cyclooxygenase inhibitors to overcome cisplatin resistance.
Neumann W, Crews BC, Sárosi MB, Daniel CM, Ghebreselasie K, Scholz MS, Marnett LJ, Hey-Hawkins E
(2015) ChemMedChem 10: 183-92
MeSH Terms: Antineoplastic Agents, Cell Line, Tumor, Cell Proliferation, Cisplatin, Cyclooxygenase 1, Cyclooxygenase 2, Cyclooxygenase Inhibitors, Drug Resistance, Neoplasm, HCT116 Cells, Humans
Show Abstract · Added February 22, 2016
Cyclooxygenase (COX) is an enzyme involved in tumorigenesis and is associated with tumor cell resistance against platinum-based antitumor drugs. Cisplatin analogues were conjugated with COX inhibitors (indomethacin, ibuprofen) to study the synergistic effects that were previously observed in combination treatments. The conjugates ensure concerted transport of both drugs into cells, and subsequent intracellular cleavage enables a dual-action mode. Whereas the platinum(II) complexes showed cytotoxicities similar to those of cisplatin, the platinum(IV) conjugates revealed highly increased cytotoxic activities and were able to completely overcome cisplatin-related resistance. Although some of the complexes are potent COX inhibitors, the conjugates appear to execute their cytotoxic action via COX-independent mechanisms. Instead, the increased lipophilicity and kinetic inertness of the conjugates seem to facilitate cellular accumulation of the platinum drugs and thus improve the efficacy of the antitumor agents. These conjugates are important tools for the elucidation of the direct influence of COX inhibitors on platinum-based anticancer drugs in tumor cells.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
0 Communities
1 Members
0 Resources
10 MeSH Terms
Efficacy of paracetamol on patent ductus arteriosus closure may be dose dependent: evidence from human and murine studies.
El-Khuffash A, Jain A, Corcoran D, Shah PS, Hooper CW, Brown N, Poole SD, Shelton EL, Milne GL, Reese J, McNamara PJ
(2014) Pediatr Res 76: 238-44
MeSH Terms: Acetaminophen, Administration, Intravenous, Administration, Oral, Animals, Blood Pressure, Cyclooxygenase Inhibitors, Dose-Response Relationship, Drug, Drug Administration Schedule, Ductus Arteriosus, Ductus Arteriosus, Patent, Humans, Indomethacin, Infant, Newborn, Ligation, Prostaglandin Antagonists, Retrospective Studies, Time Factors, Treatment Outcome, Vasoconstriction, Vasoconstrictor Agents
Show Abstract · Added April 9, 2015
BACKGROUND - We evaluated the clinical effectiveness of variable courses of paracetamol on patent ductus arteriosus (PDA) closure and examined its effect on the in vitro term and preterm murine ductus arteriosus (DA).
METHODS - Neonates received one of the following three paracetamol regimens: short course of oral paracetamol (SCOP), long course of oral paracetamol (LCOP), and intravenous paracetamol (IVP) for 2-6 d. Pressure myography was used to examine changes in vasomotor tone of the preterm and term mouse DA in response to paracetamol or indomethacin. Their effect on prostaglandin synthesis by DA explants was measured by mass spectroscopy.
RESULTS - Twenty-one preterm infants were included. No changes in PDA hemodynamics were seen in SCOP infants (n = 5). The PDA became less significant and eventually closed in six LCOP infants (n = 7). PDA closure was achieved in eight IVP infants (n = 9). On pressure myograph, paracetamol induced a concentration-dependent constriction of the term mouse DA, up to 30% of baseline (P < 0.01), but required >1 µmol/l. Indomethacin induced greater DA constriction and suppression of prostaglandin synthesis (P < 0.05).
CONCLUSION - The clinical efficacy of paracetamol on PDA closure may depend on the duration of treatment and the mode of administration. Paracetamol is less potent than indomethacin for constriction of the mouse DA in vitro.
0 Communities
1 Members
0 Resources
20 MeSH Terms
PET radiotracer [¹⁸F]-P6 selectively targeting COX-1 as a novel biomarker in ovarian cancer: preliminary investigation.
Perrone MG, Malerba P, Uddin J, Vitale P, Panella A, Crews BC, Daniel CK, Ghebreselasie K, Nickels M, Tantawy MN, Manning HC, Marnett LJ, Scilimati A
(2014) Eur J Med Chem 80: 562-568
MeSH Terms: Animals, Biomarkers, Tumor, Cell Line, Tumor, Cell Transformation, Neoplastic, Cyclooxygenase 1, Cyclooxygenase Inhibitors, Female, Fluorine Radioisotopes, Furans, Humans, Isoxazoles, Mice, Ovarian Neoplasms, Positron-Emission Tomography, Radioactive Tracers, Radiochemistry, Tomography, X-Ray Computed
Show Abstract · Added May 20, 2014
Cyclooxygenase-1 (COX-1), but not COX-2, is expressed at high levels in the early stages of human epithelial ovarian cancer where it seems to play a key role in cancer onset and progression. As a consequence, COX-1 is an ideal biomarker for early ovarian cancer detection. A series of novel fluorinated COX-1-targeted imaging agents derived from P6 was developed by using a highly selective COX-1 inhibitor as a lead compound. Among these new compounds, designed by structural modification of P6, 3-(5-chlorofuran-2-yl)-5-(fluoromethyl)-4-phenylisoxazole ([(18/19)F]-P6) is the most promising derivative [IC50 = 2.0 μM (purified oCOX-1) and 1.37 μM (hOVCAR-3 cell COX-1)]. Its tosylate precursor was also prepared and, a method for radio[(18)F]chemistry was developed and optimized. The radiochemistry was carried out using a carrier-free K(18)F/Kryptofix 2.2.2 complex, that afforded [(18)F]-P6 in good radiochemical yield (18%) and high purity (>95%). In vivo PET/CT imaging data showed that the radiotracer [(18)F]-P6 was selectively taken up by COX-1-expressing ovarian carcinoma (OVCAR 3) tumor xenografts as compared with the normal leg muscle. Our results suggest that [(18)F]-P6 might be an useful radiotracer in preclinical and clinical settings for in vivo PET-CT imaging of tissues that express elevated levels of COX-1.
Copyright © 2014 Elsevier Masson SAS. All rights reserved.
0 Communities
3 Members
0 Resources
17 MeSH Terms
Conjugates of cisplatin and cyclooxygenase inhibitors as potent antitumor agents overcoming cisplatin resistance.
Neumann W, Crews BC, Marnett LJ, Hey-Hawkins E
(2014) ChemMedChem 9: 1150-3
MeSH Terms: Antineoplastic Agents, Cell Line, Tumor, Cell Survival, Cisplatin, Cyclooxygenase Inhibitors, Drug Design, Drug Resistance, Neoplasm, HCT116 Cells, Humans, Neoplasms, Organoplatinum Compounds
Show Abstract · Added June 1, 2014
Cyclooxygenase-2 (COX-2) is an enzyme involved in tumorigenesis, and inhibitors of the enzyme are increasingly used as adjuvant modulators in anticancer therapies due to their synergistic effects with traditional chemotherapeutics. COX-2 is also reported to cause resistance towards antitumor agents, such as cisplatin. Here, the first covalently linked conjugates of cisplatin and COX inhibitors are reported. These conjugates exhibit concerted transport of both drugs into tumor cells and simultaneous action upon intracellular cleavage. These platinum(IV) complexes show highly increased cytotoxicity compared with cisplatin and are even able to overcome cisplatin-related resistance of tumor cells. While the results reported show that COX-2 inhibition is not directly responsible for the potent activities of these conjugates, they do represent useful tool compounds for the elucidation of the influence of COX inhibitors on the efficacy of antitumor agents.
© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
0 Communities
1 Members
0 Resources
11 MeSH Terms
Oxicams bind in a novel mode to the cyclooxygenase active site via a two-water-mediated H-bonding Network.
Xu S, Hermanson DJ, Banerjee S, Ghebreselasie K, Clayton GM, Garavito RM, Marnett LJ
(2014) J Biol Chem 289: 6799-808
MeSH Terms: Amino Acid Substitution, Animals, Anti-Inflammatory Agents, Non-Steroidal, Arginine, Binding Sites, Catalytic Domain, Cyclooxygenase 1, Cyclooxygenase 2, Cyclooxygenase Inhibitors, Hydrogen Bonding, Leucine, Meloxicam, Mice, Mutation, Piroxicam, Protein Structure, Secondary, Serine, Thiazines, Thiazoles, Tyrosine, Water
Show Abstract · Added March 27, 2014
Oxicams are widely used nonsteroidal anti-inflammatory drugs (NSAIDs), but little is known about the molecular basis of the interaction with their target enzymes, the cyclooxygenases (COX). Isoxicam is a nonselective inhibitor of COX-1 and COX-2 whereas meloxicam displays some selectivity for COX-2. Here we report crystal complexes of COX-2 with isoxicam and meloxicam at 2.0 and 2.45 angstroms, respectively, and a crystal complex of COX-1 with meloxicam at 2.4 angstroms. These structures reveal that the oxicams bind to the active site of COX-2 using a binding pose not seen with other NSAIDs through two highly coordinated water molecules. The 4-hydroxyl group on the thiazine ring partners with Ser-530 via hydrogen bonding, and the heteroatom of the carboxamide ring of the oxicam scaffold interacts with Tyr-385 and Ser-530 through a highly coordinated water molecule. The nitrogen atom of the thiazine and the oxygen atom of the carboxamide bind to Arg-120 and Tyr-355 via another highly ordered water molecule. The rotation of Leu-531 in the structure opens a novel binding pocket, which is not utilized for the binding of other NSAIDs. In addition, a detailed study of meloxicam·COX-2 interactions revealed that mutation of Val-434 to Ile significantly reduces inhibition by meloxicam due to subtle changes around Phe-518, giving rise to the preferential inhibition of COX-2 over COX-1.
0 Communities
2 Members
0 Resources
21 MeSH Terms