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  1. Article: Modulation of citric acid-induced cough following lipopolysaccharide-mediated neutrophilia in the guinea pig.

    Brown, Claire / Selig, William M / Ellis, James L

    Pulmonary pharmacology & therapeutics

    2007  Volume 20, Issue 1, Page(s) 90–97

    Abstract: This investigation examined a possible correlation between lipopolysaccharide (LPS)-induced pulmonary neutrophilia and cough. Conscious male guinea pigs were acutely exposed to aerosolized LPS and thereafter at various times challenged with citric acid ... ...

    Abstract This investigation examined a possible correlation between lipopolysaccharide (LPS)-induced pulmonary neutrophilia and cough. Conscious male guinea pigs were acutely exposed to aerosolized LPS and thereafter at various times challenged with citric acid aerosol (CA; 250mM) to induce cough followed by bronchoalveolar lavage (BAL) to quantitate inflammatory cell accumulation. LPS caused a hyporesponsive cough at 24h post-LPS with neutrophilia apparent from 2h post-LPS. By 96h post-LPS both cough and neutrophilia had returned towards normal. Dexamethasone (DEX, 2mgkg(-1)/day for 3 days prior) did not affect the cough hyporesponsiveness at 24h; however it attenuated LPS-induced BAL fluid neutrophilia. Since LPS can stimulate inducible nitric oxide synthase (iNOS) we hypothesized that the cough hyporesponsiveness may involve nitric oxide. To investigate this we treated animals with an aerosolized iNOS inhibitor 1400W (1mM) immediately prior to LPS. 1400W had no significant effect on either cough hyporesponsiveness or BAL fluid neutrophilia at 24h post-LPS. Despite differing effects on neutrophilia, these findings clearly indicate that neither DEX nor iNOS inhibition had any direct effect on LPS-induced cough hyporesponsiveness. The mechanism underlying the LPS-induced cough hyporesponsiveness does not appear to be directly linked to LPS-induced neutrophilic inflammation.
    MeSH term(s) Administration, Inhalation ; Aerosols ; Amidines/administration & dosage ; Amidines/therapeutic use ; Animals ; Anti-Inflammatory Agents/administration & dosage ; Anti-Inflammatory Agents/therapeutic use ; Benzylamines/administration & dosage ; Benzylamines/therapeutic use ; Bronchoalveolar Lavage Fluid/cytology ; Citric Acid/administration & dosage ; Citric Acid/toxicity ; Cough/chemically induced ; Cough/prevention & control ; Dexamethasone/administration & dosage ; Dexamethasone/therapeutic use ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/administration & dosage ; Enzyme Inhibitors/therapeutic use ; Guinea Pigs ; Injections, Intraperitoneal ; Lipopolysaccharides/administration & dosage ; Lipopolysaccharides/immunology ; Lipopolysaccharides/toxicity ; Lung Diseases/chemically induced ; Lung Diseases/immunology ; Lung Diseases/prevention & control ; Male ; Nebulizers and Vaporizers ; Neutrophil Infiltration/drug effects ; Neutrophils/drug effects ; Neutrophils/immunology ; Neutrophils/pathology ; Nitric Oxide Synthase Type II/antagonists & inhibitors ; Nitric Oxide Synthase Type II/genetics ; Nitric Oxide Synthase Type II/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Time Factors
    Chemical Substances Aerosols ; Amidines ; Anti-Inflammatory Agents ; Benzylamines ; Enzyme Inhibitors ; Lipopolysaccharides ; N-(3-(aminomethyl)benzyl)acetamidine ; Citric Acid (2968PHW8QP) ; Dexamethasone (7S5I7G3JQL) ; Nitric Oxide Synthase Type II (EC 1.14.13.39)
    Language English
    Publishing date 2007
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1399707-5
    ISSN 1522-9629 ; 1094-5539
    ISSN (online) 1522-9629
    ISSN 1094-5539
    DOI 10.1016/j.pupt.2005.12.009
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Antitussive activity of sigma-1 receptor agonists in the guinea-pig.

    Brown, Claire / Fezoui, Malika / Selig, William M / Schwartz, Carl E / Ellis, James L

    British journal of pharmacology

    2003  Volume 141, Issue 2, Page(s) 233–240

    Abstract: 1. Current antitussive medications have limited efficacy and often contain the opiate-like agent dextromethorphan (DEX). The mechanism whereby DEX inhibits cough is ill defined. DEX displays affinity at both NMDA and sigma receptors, suggesting that the ... ...

    Abstract 1. Current antitussive medications have limited efficacy and often contain the opiate-like agent dextromethorphan (DEX). The mechanism whereby DEX inhibits cough is ill defined. DEX displays affinity at both NMDA and sigma receptors, suggesting that the antitussive activity may involve central or peripheral activity at either of these receptors. This study examined and compared the antitussive activity of DEX and various putative sigma receptor agonists in the guinea-pig citric-acid cough model. 2. Intraperitoneal (i.p.) administration of DEX (30 mg kg(-1)) and the sigma-1 agonists SKF-10,047 (1-5 mg kg(-1)), Pre-084 (5 mg kg(-1)), and carbetapentane (1-5 mg kg(-1)) inhibited citric-acid-induced cough in guinea-pigs. Intraperitoneal administration of a sigma-1 antagonist, BD 1047 (1-5 mg kg(-1)), reversed the inhibition of cough elicited by SKF-10,047. In addition, two structurally dissimilar sigma agonists SKF-10,047 (1 mg ml(-1)) and Pre-084 (1 mg ml(-1)) inhibited cough when administered by aerosol. 3. Aerosolized BD 1047 (1 mg ml(-1), 30 min) prevented the antitussive action of SKF-10,047 (5 mg kg(-1)) or DEX (30 mg kg(-1)) given by i.p. administration and, likewise, i.p. administration of BD 1047 (5 mg kg(-1)) prevented the antitussive action of SKF-10,047 given by aerosol (1 mg ml(-1)). 4. These results therefore support the argument that antitussive effects of DEX may be mediated via sigma receptors, since both systemic and aerosol administration of sigma-1 receptor agonists inhibit citric-acid-induced cough in guinea-pigs. While significant systemic exposure is possible with aerosol administration, the very low doses administered (estimated <0.3 mg kg(-1)) suggest that there may be a peripheral component to the antitussive effect.
    MeSH term(s) Animals ; Antitussive Agents/pharmacology ; Antitussive Agents/therapeutic use ; Brain/drug effects ; Brain/metabolism ; Cough/drug therapy ; Cough/metabolism ; Dextromethorphan/pharmacology ; Dextromethorphan/therapeutic use ; Dose-Response Relationship, Drug ; Ethylenediamines/pharmacology ; Guinea Pigs ; Male ; Phenazocine/analogs & derivatives ; Phenazocine/pharmacology ; Phenazocine/therapeutic use ; Protein Binding/drug effects ; Protein Binding/physiology ; Receptors, sigma/agonists ; Receptors, sigma/metabolism ; Sigma-1 Receptor
    Chemical Substances Antitussive Agents ; Ethylenediamines ; Receptors, sigma ; N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin (1S3X75QGDO) ; Dextromethorphan (7355X3ROTS) ; SK&F 10047 (7619-35-4) ; Phenazocine (J0ND6N0AQC)
    Language English
    Publishing date 2003-12-22
    Publishing country England
    Document type Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80081-8
    ISSN 1476-5381 ; 0007-1188
    ISSN (online) 1476-5381
    ISSN 0007-1188
    DOI 10.1038/sj.bjp.0705605
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: UCB 62045: pharmacology of a novel, dual-function anti-inflammatory agent with histamine type 1 receptor antagonist and 5-lipoxygenase inhibitor activity.

    Selig, William M / Bayless, Lynn / Libertine, Lyn / Eckman, Joseph B / Wypij, Donna M / Wels, Bruce F / Eckert, Maria / Young, Michelle A / Nicolas, Jean M / Scannell, Ralph T / Ellis, James L

    Chest

    2002  Volume 123, Issue 3 Suppl, Page(s) 371S

    MeSH term(s) Animals ; Anti-Inflammatory Agents/pharmacology ; Arachidonate 5-Lipoxygenase/pharmacology ; Bronchoconstriction/drug effects ; Disease Models, Animal ; Guinea Pigs ; Histamine Antagonists/pharmacology ; Lipoxygenase Inhibitors
    Chemical Substances Anti-Inflammatory Agents ; Histamine Antagonists ; Lipoxygenase Inhibitors ; Arachidonate 5-Lipoxygenase (EC 1.13.11.34)
    Language English
    Publishing date 2002-10-21
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 1032552-9
    ISSN 1931-3543 ; 0012-3692
    ISSN (online) 1931-3543
    ISSN 0012-3692
    DOI 10.1378/chest.123.3_suppl.371s
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: A comparison of the cyclooxygenase inhibitor-NO donors (CINOD), NMI-1182 and AZD3582, using in vitro biochemical and pharmacological methods.

    Young, Delano V / Cochran, Edward D / Dhawan, Vijay / Earl, Richard A / Ellis, James L / Garvey, David S / Janero, David R / Khanapure, Subhash P / Letts, L Gordon / Melim, Terry L / Murty, Madhavi G / Shumway, Matthew J / Wey, Shiow-Jyi / Zemtseva, Irina S / Selig, William M

    Biochemical pharmacology

    2005  Volume 70, Issue 9, Page(s) 1343–1351

    Abstract: Cyclooxygenase (COX, EC 1.14.99.1) inhibitor-nitric oxide (NO) donor (CINOD) hybrid compounds represent an attractive alternative to NSAID and coxib therapy. This report compares two CINODs, NMI-1182 (naproxen-glyceryl dinitrate) and AZD3582 (naproxen-n- ... ...

    Abstract Cyclooxygenase (COX, EC 1.14.99.1) inhibitor-nitric oxide (NO) donor (CINOD) hybrid compounds represent an attractive alternative to NSAID and coxib therapy. This report compares two CINODs, NMI-1182 (naproxen-glyceryl dinitrate) and AZD3582 (naproxen-n-butyl nitrate), for their ability to inhibit COX-1 and -2, deliver bioavailable nitric oxide, and release naproxen, using in vitro biochemical and pharmacological methods. In human whole blood, both CINODs showed inhibition, comparable to naproxen, of both COX isozymes and slowly released naproxen. Both CINODs donated bioavailable NO, as detected by cGMP induction in the pig kidney transformed cell line, LLC-PK1, but NMI-1182 was more potent by 30-100 times than AZD3582, GTN, GDN, and ISDN and considerably faster in inducing cGMP synthesis than AZD3582. The nitrate groups of GTN, NMI-1182, and AZD3582 appeared to be bioactivated via a common pathway, since each compound desensitized LLC-PK1 cells to subsequent challenge with the other compounds. Similar cGMP induction also occurred in normal, untransformed cells (human renal proximal tubule epithelial cells and hepatocytes from man, rat, and monkey); again, NMI-1182 was superior to AZD3582. NMI-1182 was also the more metabolically labile compound, releasing more absolute nitrate and nitrite (total NO(x)) in human stomach (in which NO is salutary) and liver S9 homogenates. Naproxen was also more rapidly freed from NMI-1182 than AZD3582 in human stomach, although liver S9 hydrolyzed both CINODs with similar rates. These in vitro tests revealed that NMI-1182 may be a better CINOD than AZD3582 because of its superior NO donating and naproxen liberating properties.
    MeSH term(s) Cyclic GMP/biosynthesis ; Cyclooxygenase 1/drug effects ; Cyclooxygenase 2/drug effects ; Cyclooxygenase Inhibitors/pharmacology ; Humans ; Liver/metabolism ; Naphthalenes/pharmacokinetics ; Naphthalenes/pharmacology ; Naproxen/pharmacology ; Nitric Oxide/biosynthesis ; Nitric Oxide Donors/pharmacology
    Chemical Substances Cyclooxygenase Inhibitors ; NMI-1182 ; Naphthalenes ; Nitric Oxide Donors ; naproxen-n-butyl nitrate ; Nitric Oxide (31C4KY9ESH) ; Naproxen (57Y76R9ATQ) ; Cyclooxygenase 1 (EC 1.14.99.1) ; Cyclooxygenase 2 (EC 1.14.99.1) ; Cyclic GMP (H2D2X058MU)
    Language English
    Publishing date 2005-11-01
    Publishing country England
    Document type Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 208787-x
    ISSN 1873-2968 ; 0006-2952
    ISSN (online) 1873-2968
    ISSN 0006-2952
    DOI 10.1016/j.bcp.2005.08.004
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Structure-based design, synthesis, and biological evaluation of indomethacin derivatives as cyclooxygenase-2 inhibiting nitric oxide donors.

    Wey, Shiow-Jyi / Augustyniak, Michael E / Cochran, Edward D / Ellis, James L / Fang, Xinqin / Garvey, David S / Janero, David R / Letts, L Gordon / Martino, Allison M / Melim, Terry L / Murty, Madhavi G / Richardson, Steward K / Schroeder, Joseph D / Selig, William M / Trocha, A Mark / Wexler, Roseanne S / Young, Delano V / Zemtseva, Irina S / Zifcak, Brian M

    Journal of medicinal chemistry

    2007  Volume 50, Issue 25, Page(s) 6367–6382

    Abstract: Indomethacin, a nonselective cyclooxygenase (COX) inhibitor, was modified in three distinct regions in an attempt both to increase cyclooxygenase-2 (COX-2) selectivity and to enhance drug safety by covalent attachment of an organic nitrate moiety as a ... ...

    Abstract Indomethacin, a nonselective cyclooxygenase (COX) inhibitor, was modified in three distinct regions in an attempt both to increase cyclooxygenase-2 (COX-2) selectivity and to enhance drug safety by covalent attachment of an organic nitrate moiety as a nitric oxide donor. A human whole-blood COX assay shows the modifications on the 3-acetic acid part of the indomethacin yielding an amide-nitrate derivative 32 and a sulfonamide-nitrate derivative 61 conferred COX-2 selectivity. Along with their respective des-nitrate analogs, for example, 31 and 62, the nitrates 32 and 61 were effective antiinflammatory agents in the rat air-pouch model. After oral dosing, though, only 32 increased nitrate and nitrite levels in rat plasma, indicating that its nitrate tether served as a nitric oxide donor in vivo. In a rat gastric injury model, examples 31 and 32 both show a 98% reduction in gastric lesion score compared to that of indomethacin. In addition, the nitrated derivative 32 inducing 85% fewer gastric lesions when coadministered with aspirin as compared to the combination of aspirin and valdecoxib.
    MeSH term(s) Animals ; Aspirin/adverse effects ; Celecoxib ; Cyclooxygenase 2 Inhibitors/adverse effects ; Cyclooxygenase 2 Inhibitors/chemical synthesis ; Cyclooxygenase 2 Inhibitors/pharmacology ; Drug Design ; Drug Synergism ; Female ; Gastric Mucosa/pathology ; Humans ; Hydroxamic Acids/adverse effects ; Hydroxamic Acids/chemical synthesis ; Hydroxamic Acids/pharmacology ; Indomethacin/adverse effects ; Indomethacin/analogs & derivatives ; Indomethacin/chemical synthesis ; Indomethacin/pharmacology ; Male ; Nitric Oxide Donors/adverse effects ; Nitric Oxide Donors/chemical synthesis ; Nitric Oxide Donors/pharmacology ; Pyrazoles/pharmacology ; Rats ; Rats, Sprague-Dawley ; Stomach Ulcer/chemically induced ; Stomach Ulcer/pathology ; Structure-Activity Relationship ; Sulfonamides/pharmacology
    Chemical Substances Cyclooxygenase 2 Inhibitors ; Hydroxamic Acids ; Nitric Oxide Donors ; Pyrazoles ; Sulfonamides ; Celecoxib (JCX84Q7J1L) ; Aspirin (R16CO5Y76E) ; Indomethacin (XXE1CET956)
    Language English
    Publishing date 2007-12-13
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/jm0611861
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: NMI-1182, a gastro-protective cyclo-oxygenase-inhibiting nitric oxide donor.

    Ellis, James L / Augustyniak, Michael E / Cochran, Edward D / Earl, Richard A / Garvey, David S / Gordon, Laura J / Janero, David R / Khanapure, Subhash P / Letts, L Gordon / Melim, Terry L / Murty, Madhavi G / Schwalb, David J / Shumway, Matthew J / Selig, William M / Trocha, A Mark / Young, Delano V / Zemtseva, Irina S

    Inflammopharmacology

    2005  Volume 12, Issue 5-6, Page(s) 521–534

    Abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat inflammation and to provide pain relief but suffer from a major liability concerning their propensity to cause gastric damage. As nitric oxide (NO) is known to be gastro-protective ... ...

    Abstract Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat inflammation and to provide pain relief but suffer from a major liability concerning their propensity to cause gastric damage. As nitric oxide (NO) is known to be gastro-protective we have synthesized a NO-donating prodrug of naproxen named NMI-1182. We evaluated two cyclo-oxygenase (COX)-inhibiting nitric oxide donors (CINODs), NMI-1182 and AZD3582, for their ability to be gastro-protective compared to naproxen and for their anti-inflammatory activity. NMI-1182 and AZD3582 were found to produce similar inhibition of COX activity to that produced by naproxen. Both NMI-1182 and AZD3582 produced significantly less gastric lesions after oral administration than naproxen. All three compounds effectively inhibited paw swelling in the rat carrageenan paw edema model. In the carrageenan air pouch model all three compounds significantly reduced PGE2 levels in the pouch exudate but only NMI-1182 and naproxen inhibited leukocyte influx. These data demonstrate that NMI-1182 has comparable anti-inflammatory activity to naproxen but with a much reduced likelihood to cause gastric damage.
    MeSH term(s) Animals ; Anti-Inflammatory Agents/blood ; Anti-Inflammatory Agents/chemistry ; Anti-Inflammatory Agents/pharmacology ; Aorta, Abdominal/drug effects ; Aorta, Abdominal/physiology ; Carrageenan ; Cyclooxygenase 1/blood ; Cyclooxygenase 2/blood ; Cyclooxygenase Inhibitors/blood ; Cyclooxygenase Inhibitors/chemistry ; Cyclooxygenase Inhibitors/pharmacology ; Dinoprostone/antagonists & inhibitors ; Dinoprostone/metabolism ; Dose-Response Relationship, Drug ; Edema/chemically induced ; Edema/prevention & control ; Gastric Mucosa/drug effects ; Gastric Mucosa/metabolism ; Gastric Mucosa/pathology ; Humans ; In Vitro Techniques ; Inflammation/chemically induced ; Inflammation/prevention & control ; Male ; Molecular Structure ; Naphthalenes/blood ; Naphthalenes/chemistry ; Naphthalenes/pharmacology ; Naproxen/blood ; Naproxen/chemistry ; Naproxen/pharmacology ; Neutrophil Infiltration/drug effects ; Nitric Oxide Donors/blood ; Nitric Oxide Donors/chemistry ; Nitric Oxide Donors/pharmacology ; Protective Agents/chemistry ; Protective Agents/pharmacology ; Rats ; Rats, Sprague-Dawley ; Vasodilation/drug effects
    Chemical Substances Anti-Inflammatory Agents ; Cyclooxygenase Inhibitors ; NMI-1182 ; Naphthalenes ; Nitric Oxide Donors ; Protective Agents ; des-NO-NMI-1182 ; naproxen-n-butyl nitrate ; Naproxen (57Y76R9ATQ) ; Carrageenan (9000-07-1) ; Cyclooxygenase 1 (EC 1.14.99.1) ; Cyclooxygenase 2 (EC 1.14.99.1) ; Dinoprostone (K7Q1JQR04M)
    Language English
    Publishing date 2005
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 1080058-x
    ISSN 1568-5608 ; 0925-4692
    ISSN (online) 1568-5608
    ISSN 0925-4692
    DOI 10.1163/156856005774382661
    Database MEDical Literature Analysis and Retrieval System OnLINE

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