Skip to main content
SpringerLink
Log in

Druggable Prostanoid Pathway

  • Chapter
  • First Online:
Druggable Lipid Signaling Pathways

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1274))

Abstract

Prostanoids (prostaglandins, prostacyclin and thromboxane) belong to the oxylipin family of biologically active lipids generated from arachidonic acid (AA). Protanoids control numerous physiological and pathological processes. Cyclooxygenase (COX) is a rate-limiting enzyme involved in the conversion of AA into prostanoids. There are two COX isozymes: the constitutive COX-1 and the inducible COX-2. COX-1 and COX-2 have similar structures, catalytic activities, and subcellular localizations but differ in patterns of expression and biological functions. Non-selective COX-1/2 or traditional, non-steroidal anti-inflammatory drugs (tNSAIDs) target both COX isoforms and are widely used to relieve pain, fever and inflammation. However, the use of NSAIDs is associated with various side effects, particularly in the gastrointestinal tract. NSAIDs selective for COX-2 inhibition (coxibs) were purposefully designed to spare gastrointestinal toxicity, but predisposed patients to increased cardiovascular risks. These health complications from NSAIDs prompted interest in the downstream effectors of the COX enzymes as novel drug targets. This chapter describes various safety issues with tNSAIDs and coxibs, and discusses the current development of novel classes of drugs targeting the prostanoid pathway, including nitrogen oxide- and hydrogen sulfide-releasing NSAIDs, inhibitors of prostanoid synthases, dual inhibitors, and prostanoid receptor agonists and antagonists.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Smith WL, DeWitt DL, Garavito RM (2000) Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem 69:145–182

    Article  CAS  PubMed  Google Scholar 

  2. Kurzrok R, Lieb CC (1930) Biochemical studies of human semen. II. The action of semen on the human uterus. Proc Soc Exp Biol Med 28:268–272

    Article  Google Scholar 

  3. Goldblatt MW (1935) Properties of human seminal plasma. J Physiol 84:208–218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Von Euler US (1935) A depressor substance in the vesicular gland. J Physiolol (London) 84:21

    Article  Google Scholar 

  5. Bergström S, Sjövall J (1957) The isolation of prostaglandin. Acta Chem Scand 11:1086

    Article  Google Scholar 

  6. Bergstroem S, Ryhage R, Samuelsson B, Sjoevall J (1963) Prostaglandins and related factors. 15. The structures of prostaglandin E1, F1-alpha, and F1-Beta. J Biol Chem 238:3555–3564

    Article  CAS  PubMed  Google Scholar 

  7. Vane JR (1971) Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol 231:232–235

    Article  CAS  PubMed  Google Scholar 

  8. Moncada S, Gryglewski R, Bunting S, Vane JR (1976) An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature 263:663–665

    Article  CAS  PubMed  Google Scholar 

  9. Leslie CC (2015) Cytosolic phospholipase A(2): physiological function and role in disease. J Lipid Res 56:1386–1402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Samuelsson B, Morgenstern R, Jakobsson PJ (2007) Membrane prostaglandin E synthase-1: a novel therapeutic target. Pharmacol Rev 59:207–224

    Article  CAS  PubMed  Google Scholar 

  11. Song WL, Ricciotti E, Liang X, Grosser T, Grant GR, FitzGerald GA (2018) Lipocalin-like prostaglandin D synthase but not hemopoietic prostaglandin D synthase deletion causes hypertension and accelerates thrombogenesis in mice. J Pharmacol Exp Ther 367:425–432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ueno N, Takegoshi Y, Kamei D, Kudo I, Murakami M (2005) Coupling between cyclooxygenases and terminal prostanoid synthases. Biochem Biophys Res Commun 338:70–76

    Article  CAS  PubMed  Google Scholar 

  13. Song WL, Wang M, Ricciotti E, Fries S, Yu Y, Grosser T, Reilly M, Lawson JA, FitzGerald GA (2008) Tetranor PGDM, an abundant urinary metabolite reflects biosynthesis of prostaglandin D2 in mice and humans. J Biol Chem 283:1179–1188

    Article  CAS  PubMed  Google Scholar 

  14. Cheng Y, Wang M, Yu Y, Lawson J, Funk CD, Fitzgerald GA (2006) Cyclooxygenases, microsomal prostaglandin E synthase-1, and cardiovascular function. J Clin Invest 116:1391–1399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ricciotti E, FitzGerald GA (2011) Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol 31:986–1000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Daiyasu H, Toh H (2000) Molecular evolution of the myeloperoxidase family. J Mol Evol 51:433–445

    Article  CAS  PubMed  Google Scholar 

  17. Otto JC, DeWitt DL, Smith WL (1993) N-glycosylation of prostaglandin endoperoxide synthases-1 and -2 and their orientations in the endoplasmic reticulum. J Biol Chem 268:18234–18242

    Article  CAS  PubMed  Google Scholar 

  18. Chandrasekharan NV, Simmons DL (2004) The cyclooxygenases. Genome Biol 5:241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Smith WL, Malkowski MG (2019) Interactions of fatty acids, nonsteroidal anti-inflammatory drugs, and coxibs with the catalytic and allosteric subunits of cyclooxygenases-1 and -2. J Biol Chem 294:1697–1705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yu Y, Fan J, Chen XS, Wang D, Klein-Szanto AJ, Campbell RL, FitzGerald GA, Funk CD (2006) Genetic model of selective COX2 inhibition reveals novel heterodimer signaling. Nat Med 12:699–704

    Article  CAS  PubMed  Google Scholar 

  21. Tanabe T, Tohnai N (2002) Cyclooxygenase isozymes and their gene structures and expression. Prostaglandins Other Lipid Mediat 68–69:95–114

    Article  PubMed  Google Scholar 

  22. Kurumbail RG, Stevens AM, Gierse JK, McDonald JJ, Stegeman RA, Pak JY, Gildehaus D, Miyashiro JM, Penning TD, Seibert K, Isakson PC, Stallings WC (1996) Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature 384:644–648

    Article  CAS  PubMed  Google Scholar 

  23. Smyth EM, Grosser T, Wang M, Yu Y, FitzGerald GA (2009) Prostanoids in health and disease. J Lipid Res 50(Suppl):S423–S428

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Patrignani P, Tacconelli S, Bruno A, Sostres C, Lanas A (2011) Managing the adverse effects of nonsteroidal anti-inflammatory drugs. Expert Rev Clin Pharmacol 4:605–621

    Article  CAS  PubMed  Google Scholar 

  25. Bjarnason I, Scarpignato C, Holmgren E, Olszewski M, Rainsford KD, Lanas A (2018) Mechanisms of damage to the gastrointestinal tract from nonsteroidal anti-inflammatory drugs. Gastroenterology 154:500–514

    Article  CAS  PubMed  Google Scholar 

  26. Hao CM, Breyer MD (2008) Physiological regulation of prostaglandins in the kidney. Annu Rev Physiol 70:357–377

    Article  CAS  PubMed  Google Scholar 

  27. Topper JN, Cai J, Falb D, Gimbrone MA Jr (1996) Identification of vascular endothelial genes differentially responsive to fluid mechanical stimuli: cyclooxygenase-2, manganese superoxide dismutase, and endothelial cell nitric oxide synthase are selectively up-regulated by steady laminar shear stress. Proc Natl Acad Sci U S A 93:10417–10422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ricciotti E, Yu Y, Grosser T, Fitzgerald GA (2013) COX-2, the dominant source of prostacyclin. Proc Natl Acad Sci U S A 110:E183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Weksler BB (2015) Prostanoids and NSAIDs in cardiovascular biology and disease. Curr Atheroscler Rep 17:41

    Article  PubMed  CAS  Google Scholar 

  30. Braun M, Schror K (1992) Prostaglandin D2 relaxes bovine coronary arteries by endothelium-dependent nitric oxide-mediated cGMP formation. Circ Res 71:1305–1313

    Article  CAS  PubMed  Google Scholar 

  31. Narumiya S, Toda N (1985) Different responsiveness of prostaglandin D2-sensitive systems to prostaglandin D2 and its analogues. Br J Pharmacol 85:367–375

    Article  PubMed  PubMed Central  Google Scholar 

  32. Hall IP (2000) Second messengers, ion channels and pharmacology of airway smooth muscle. Eur Respir J 15:1120–1127

    Article  CAS  PubMed  Google Scholar 

  33. Song WL, Stubbe J, Ricciotti E, Alamuddin N, Ibrahim S, Crichton I, Prempeh M, Lawson JA, Wilensky RL, Rasmussen LM, Pure E, FitzGerald GA (2012) Niacin and biosynthesis of PGD(2)by platelet COX-1 in mice and humans. J Clin Invest 122:1459–1468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Patrono C (2016) Cardiovascular effects of cyclooxygenase-2 inhibitors: a mechanistic and clinical perspective. Br J Clin Pharmacol 82:957–964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. McAdam BF, Mardini IA, Habib A, Burke A, Lawson JA, Kapoor S, FitzGerald GA (2000) Effect of regulated expression of human cyclooxygenase isoforms on eicosanoid and isoeicosanoid production in inflammation. J Clin Invest 105:1473–1482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Engblom D, Saha S, Engstrom L, Westman M, Audoly LP, Jakobsson PJ, Blomqvist A (2003) Microsomal prostaglandin E synthase-1 is the central switch during immune-induced pyresis. Nat Neurosci 6:1137–1138

    Article  CAS  PubMed  Google Scholar 

  37. Basu S (2007) Novel cyclooxygenase-catalyzed bioactive prostaglandin F2alpha from physiology to new principles in inflammation. Med Res Rev 27:435–468

    Article  CAS  PubMed  Google Scholar 

  38. Sugimoto Y, Yamasaki A, Segi E, Tsuboi K, Aze Y, Nishimura T, Oida H, Yoshida N, Tanaka T, Katsuyama M, Hasumoto K, Murata T, Hirata M, Ushikubi F, Negishi M, Ichikawa A, Narumiya S (1997) Failure of parturition in mice lacking the prostaglandin F receptor. Science 277:681–683

    Article  CAS  PubMed  Google Scholar 

  39. Murakami Y, Akahoshi T, Hayashi I, Endo H, Hashimoto A, Kono S, Kondo H, Kawai S, Inoue M, Kitasato H (2003) Inhibition of monosodium urate monohydrate crystal-induced acute inflammation by retrovirally transfected prostaglandin D synthase. Arthritis Rheum 48:2931–2941

    Article  CAS  PubMed  Google Scholar 

  40. Zayed N, Afif H, Chabane N, Mfuna-Endam L, Benderdour M, Martel-Pelletier J, Pelletier JP, Motiani RK, Trebak M, Duval N, Fahmi H (2008) Inhibition of interleukin-1beta-induced matrix metalloproteinases 1 and 13 production in human osteoarthritic chondrocytes by prostaglandin D2. Arthritis Rheum 58:3530–3540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Rajakariar R, Hilliard M, Lawrence T, Trivedi S, Colville-Nash P, Bellingan G, Fitzgerald D, Yaqoob MM, Gilroy DW (2007) Hematopoietic prostaglandin D2 synthase controls the onset and resolution of acute inflammation through PGD2 and 15-deoxyDelta12 14 PGJ2. Proc Natl Acad Sci U S A 104:20979–20984

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Chen L, Yang G, Grosser T (2013) Prostanoids and inflammatory pain. Prostaglandins Other Lipid Mediat 104-105:58–66

    Article  CAS  PubMed  Google Scholar 

  43. Pettipher R, Hansel TT, Armer R (2007) Antagonism of the prostaglandin D2 receptors DP1 and CRTH2 as an approach to treat allergic diseases. Nat Rev Drug Discov 6:313–325

    Article  CAS  PubMed  Google Scholar 

  44. Grosser T, Theken KN, FitzGerald GA (2017) Cyclooxygenase inhibition: pain, inflammation, and the cardiovascular system. Clin Pharmacol Ther 102:611–622

    Article  PubMed  Google Scholar 

  45. Patrignani P, Patrono C (2015) Cyclooxygenase inhibitors: from pharmacology to clinical read-outs. Biochim Biophys Acta 1851:422–432

    Article  CAS  PubMed  Google Scholar 

  46. Brune K, Hinz B (2004) The discovery and development of antiinflammatory drugs. Arthritis Rheum 50:2391–2399

    Article  CAS  PubMed  Google Scholar 

  47. Kujubu DA, Fletcher BS, Varnum BC, Lim RW, Herschman HR (1991) TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue. J Biol Chem 266:12866–12872

    Article  CAS  PubMed  Google Scholar 

  48. FitzGerald GA, Patrono C (2001) The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 345:433–442

    Article  CAS  PubMed  Google Scholar 

  49. Patrono C, Ciabattoni G, Pinca E, Pugliese F, Castrucci G, De Salvo A, Satta MA, Peskar BA (1980) Low dose aspirin and inhibition of thromboxane B2 production in healthy subjects. Thromb Res 17:317–327

    Article  CAS  PubMed  Google Scholar 

  50. Patrignani P, Panara MR, Greco A, Fusco O, Natoli C, Iacobelli S, Cipollone F, Ganci A, Creminon C, Maclouf J et al (1994) Biochemical and pharmacological characterization of the cyclooxygenase activity of human blood prostaglandin endoperoxide synthases. J Pharmacol Exp Ther 271:1705–1712

    CAS  PubMed  Google Scholar 

  51. Tacconelli S, Bruno A, Grande R, Ballerini P, Patrignani P (2017) Nonsteroidal anti-inflammatory drugs and cardiovascular safety – translating pharmacological data into clinical readouts. Expert Opin Drug Saf 16:791–807

    Article  CAS  PubMed  Google Scholar 

  52. Patrono C, Baigent C (2014) Nonsteroidal anti-inflammatory drugs and the heart. Circulation 129:907–916

    Article  PubMed  Google Scholar 

  53. Grosser T, Ricciotti E, FitzGerald GA (2017) The cardiovascular pharmacology of nonsteroidal anti-inflammatory drugs. Trends Pharmacol Sci 38:733–748

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Grosser T, Fries S, FitzGerald GA (2006) Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Clin Invest 116:4–15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, Makuch R, Eisen G, Agrawal NM, Stenson WF, Burr AM, Zhao WW, Kent JD, Lefkowith JB, Verburg KM, Geis GS (2000) Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 284:1247–1255

    Article  CAS  PubMed  Google Scholar 

  56. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ, V. S. Group (2000) Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 343:1520–1528. 1522 p following 1528

    Article  CAS  PubMed  Google Scholar 

  57. Schnitzer TJ, Burmester GR, Mysler E, Hochberg MC, Doherty M, Ehrsam E, Gitton X, Krammer G, Mellein B, Matchaba P, Gimona A, Hawkey CJ, T. S. Group (2004) Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial. Lancet 364:665–674

    Article  CAS  PubMed  Google Scholar 

  58. Tacconelli S, Capone ML, Patrignani P (2004) Clinical pharmacology of novel selective COX-2 inhibitors. Curr Pharm Des 10:589–601

    Article  CAS  PubMed  Google Scholar 

  59. Baron JA, Sandler RS, Bresalier RS, Quan H, Riddell R, Lanas A, Bolognese JA, Oxenius B, Horgan K, Loftus S, Morton DG, Investigators APT (2006) A randomized trial of rofecoxib for the chemoprevention of colorectal adenomas. Gastroenterology 131:1674–1682

    Article  CAS  PubMed  Google Scholar 

  60. Bertagnolli MM, Eagle CJ, Zauber AG, Redston M, Solomon SD, Kim K, Tang J, Rosenstein RB, Wittes J, Corle D, Hess TM, Woloj GM, Boisserie F, Anderson WF, Viner JL, Bagheri D, Burn J, Chung DC, Dewar T, Foley TR, Hoffman N, Macrae F, Pruitt RE, Saltzman JR, Salzberg B, Sylwestrowicz T, Gordon GB, Hawk ET, Investigators APCS (2006) Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 355:873–884

    Article  CAS  PubMed  Google Scholar 

  61. Kuehn BM (2005) FDA panel: keep COX-2 drugs on market: black box for COX-2 labels, caution urged for all NSAIDs. JAMA 293:1571–1572

    Article  CAS  PubMed  Google Scholar 

  62. Grosser T, Yu Y, Fitzgerald GA (2010) Emotion recollected in tranquility: lessons learned from the COX-2 saga. Annu Rev Med 61:17–33

    Article  CAS  PubMed  Google Scholar 

  63. Coxib NTC, Traditional N, Bhala J, Emberson AM, Abramson S, Arber N, Baron JA, Bombardier C, Cannon C, Farkouh ME, FitzGerald GA, Goss P, Halls H, Hawk E, Hawkey C, Hennekens C, Hochberg M, Holland LE, Kearney PM, Laine L, Lanas A, Lance P, Laupacis A, Oates J, Patrono C, Schnitzer TJ, Solomon S, Tugwell P, Wilson K, Wittes J, Baigent C (2013) Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 382:769–779

    Article  CAS  Google Scholar 

  64. Capone ML, Tacconelli S, Di Francesco L, Sacchetti A, Sciulli MG, Patrignani P (2007) Pharmacodynamic of cyclooxygenase inhibitors in humans. Prostaglandins Other Lipid Mediat 82:85–94

    Article  CAS  PubMed  Google Scholar 

  65. Patrignani P, Panara MR, Sciulli MG, Santini G, Renda G, Patrono C (1997) Differential inhibition of human prostaglandin endoperoxide synthase-1 and -2 by nonsteroidal anti-inflammatory drugs. J Physiol Pharmacol 48:623–631

    CAS  PubMed  Google Scholar 

  66. Patrono C, Baigent C (2017) Coxibs, Traditional NSAIDs, and cardiovascular safety post-PRECISION: what we thought we knew then and what we think we know now. Clin Pharmacol Ther 102:238–245

    Article  CAS  PubMed  Google Scholar 

  67. FitzGerald GA (2017) Imprecision: limitations to interpretation of a large randomized clinical trial. Circulation 135:113–115

    Article  PubMed  Google Scholar 

  68. McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S, Lawson JA, FitzGerald GA (1999) Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci U S A 96:272–277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Capone ML, Tacconelli S, Sciulli MG, Anzellotti P, Di Francesco L, Merciaro G, Di Gregorio P, Patrignani P (2007) Human pharmacology of naproxen sodium. J Pharmacol Exp Ther 322:453–460

    Article  CAS  PubMed  Google Scholar 

  70. Wang D, Patel VV, Ricciotti E, Zhou R, Levin MD, Gao E, Yu Z, Ferrari VA, Lu MM, Xu J, Zhang H, Hui Y, Cheng Y, Petrenko N, Yu Y, FitzGerald GA (2009) Cardiomyocyte cyclooxygenase-2 influences cardiac rhythm and function. Proc Natl Acad Sci U S A 106:7548–7552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Yu Y, Ricciotti E, Scalia R, Tang SY, Grant G, Yu Z, Landesberg G, Crichton I, Wu W, Pure E, Funk CD, FitzGerald GA (2012) Vascular COX-2 modulates blood pressure and thrombosis in mice. Sci Transl Med 4:132ra154

    Article  Google Scholar 

  72. Chen MJ, Creinin MD (2015) Mifepristone with buccal misoprostol for medical abortion: a systematic review. Obstet Gynecol 126:12–21

    Article  CAS  PubMed  Google Scholar 

  73. Hanchanale V, Eardley I (2014) Alprostadil for the treatment of impotence. Expert Opin Pharmacother 15:421–428

    Article  CAS  PubMed  Google Scholar 

  74. Akkinapally S, Hundalani SG, Kulkarni M, Fernandes CJ, Cabrera AG, Shivanna B, Pammi M (2018) Prostaglandin E1 for maintaining ductal patency in neonates with ductal-dependent cardiac lesions. Cochrane Database Syst Rev 2:CD011417

    PubMed  Google Scholar 

  75. Kuwano K, Hashino A, Asaki T, Hamamoto T, Yamada T, Okubo K, Kuwabara K (2007) 2-[4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy]-N-(methylsulfonyl)acetam ide (NS-304), an orally available and long-acting prostacyclin receptor agonist prodrug. J Pharmacol Exp Ther 322:1181–1188

    Article  CAS  PubMed  Google Scholar 

  76. Honorato Perez J (2017) Selexipag, a selective prostacyclin receptor agonist in pulmonary arterial hypertension: a pharmacology review. Expert Rev Clin Pharmacol 10:753–762

    Article  CAS  PubMed  Google Scholar 

  77. Del Pozo R, Hernandez Gonzalez I, Escribano-Subias P (2017) The prostacyclin pathway in pulmonary arterial hypertension: a clinical review. Expert Rev Respir Med 11:491–503

    Article  PubMed  CAS  Google Scholar 

  78. Matsou A, Anastasopoulos E (2018) Investigational drugs targeting prostaglandin receptors for the treatment of glaucoma. Expert Opin Investig Drugs 27:777–785

    Article  CAS  PubMed  Google Scholar 

  79. Klimko PG, Sharif NA (2019) Discovery, characterization and clinical utility of prostaglandin agonists for the treatment of glaucoma. Br J Pharmacol 176:1051–1058

    Article  CAS  PubMed  Google Scholar 

  80. Mukhopadhyay P, Bian L, Yin H, Bhattacherjee P, Paterson C (2001) Localization of EP(1) and FP receptors in human ocular tissues by in situ hybridization. Invest Ophthalmol Vis Sci 42:424–428

    CAS  PubMed  Google Scholar 

  81. Takagi Y, Nakajima T, Shimazaki A, Kageyama M, Matsugi T, Matsumura Y, Gabelt BT, Kaufman PL, Hara H (2004) Pharmacological characteristics of AFP-168 (tafluprost), a new prostanoid FP receptor agonist, as an ocular hypotensive drug. Exp Eye Res 78:767–776

    Article  CAS  PubMed  Google Scholar 

  82. Ota T, Aihara M, Saeki T, Narumiya S, Araie M (2007) The IOP-lowering effects and mechanism of action of tafluprost in prostanoid receptor-deficient mice. Br J Ophthalmol 91:673–676

    Article  PubMed  PubMed Central  Google Scholar 

  83. Faulkner R, Sharif NA, Orr S, Sall K, Dubiner H, Whitson JT, Moster M, Craven ER, Curtis M, Pailliotet C, Martens K, Dahlin D (2010) Aqueous humor concentrations of bimatoprost free acid, bimatoprost and travoprost free acid in cataract surgical patients administered multiple topical ocular doses of LUMIGAN or TRAVATAN. J Ocul Pharmacol Ther 26:147–156

    Article  CAS  PubMed  Google Scholar 

  84. Woodward DF, Liang Y, Krauss AH (2008) Prostamides (prostaglandin-ethanolamides) and their pharmacology. Br J Pharmacol 153:410–419

    Article  CAS  PubMed  Google Scholar 

  85. Nakajima T, Matsugi T, Goto W, Kageyama M, Mori N, Matsumura Y, Hara H (2003) New fluoroprostaglandin F(2alpha) derivatives with prostanoid FP-receptor agonistic activity as potent ocular-hypotensive agents. Biol Pharm Bull 26:1691–1695

    Article  CAS  PubMed  Google Scholar 

  86. Scherer WJ (2002) A retrospective review of non-responders to latanoprost. J Ocul Pharmacol Ther 18:287–291

    Article  CAS  PubMed  Google Scholar 

  87. Sakurai M, Higashide T, Ohkubo S, Takeda H, Sugiyama K (2014) Association between genetic polymorphisms of the prostaglandin F2alpha receptor gene, and response to latanoprost in patients with glaucoma and ocular hypertension. Br J Ophthalmol 98:469–473

    Article  PubMed  Google Scholar 

  88. Krauss AH, Impagnatiello F, Toris CB, Gale DC, Prasanna G, Borghi V, Chiroli V, Chong WK, Carreiro ST, Ongini E (2011) Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating prostaglandin F2alpha agonist, in preclinical models. Exp Eye Res 93:250–255

    Article  CAS  PubMed  Google Scholar 

  89. Costa VP, Harris A, Anderson D, Stodtmeister R, Cremasco F, Kergoat H, Lovasik J, Stalmans I, Zeitz O, Lanzl I, Gugleta K, Schmetterer L (2014) Ocular perfusion pressure in glaucoma. Acta Ophthalmol 92:e252–e266

    Article  PubMed  Google Scholar 

  90. Resch H, Garhofer G, Fuchsjager-Mayrl G, Hommer A, Schmetterer L (2009) Endothelial dysfunction in glaucoma. Acta Ophthalmol 87:4–12

    Article  PubMed  Google Scholar 

  91. Impagnatiello F, Toris CB, Batugo M, Prasanna G, Borghi V, Bastia E, Ongini E, Krauss AH (2015) Intraocular pressure-lowering activity of NCX 470, a novel nitric oxide-donating bimatoprost in preclinical models. Invest Ophthalmol Vis Sci 56:6558–6564

    Article  CAS  PubMed  Google Scholar 

  92. Borhade N, Pathan AR, Halder S, Karwa M, Dhiman M, Pamidiboina V, Gund M, Deshattiwar JJ, Mali SV, Deshmukh NJ, Senthilkumar SP, Gaikwad P, Tipparam SG, Mudgal J, Dutta MC, Burhan AU, Thakre G, Sharma A, Deshpande S, Desai DC, Dubash NP, Jain AK, Sharma S, Nemmani KV, Satyam A (2012) NO-NSAIDs. Part 3: nitric oxide-releasing prodrugs of non-steroidal anti-inflammatory drugs. Chem Pharm Bull (Tokyo) 60:465–481

    Article  CAS  Google Scholar 

  93. Davies NM, Roseth AG, Appleyard CB, McKnight W, Del Soldato P, Calignano A, Cirino G, Wallace JL (1997) NO-naproxen vs. naproxen: ulcerogenic, analgesic and anti-inflammatory effects. Aliment Pharmacol Ther 11:69–79

    Article  CAS  PubMed  Google Scholar 

  94. Fiorucci S, Del Soldato P (2003) NO-aspirin: mechanism of action and gastrointestinal safety. Dig Liver Dis 35(Suppl 2):S9–S19

    Article  CAS  PubMed  Google Scholar 

  95. Fiorucci S, Distrutti E, Cirino G, Wallace JL (2006) The emerging roles of hydrogen sulfide in the gastrointestinal tract and liver. Gastroenterology 131:259–271

    Article  CAS  PubMed  Google Scholar 

  96. van Goor H, van den Born JC, Hillebrands JL, Joles JA (2016) Hydrogen sulfide in hypertension. Curr Opin Nephrol Hypertens 25:107–113

    Article  PubMed  CAS  Google Scholar 

  97. Trebino CE, Stock JL, Gibbons CP, Naiman BM, Wachtmann TS, Umland JP, Pandher K, Lapointe JM, Saha S, Roach ML, Carter D, Thomas NA, Durtschi BA, McNeish JD, Hambor JE, Jakobsson PJ, Carty TJ, Perez JR, Audoly LP (2003) Impaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase. Proc Natl Acad Sci U S A 100:9044–9049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Kamei D, Yamakawa K, Takegoshi Y, Mikami-Nakanishi M, Nakatani Y, Oh-Ishi S, Yasui H, Azuma Y, Hirasawa N, Ohuchi K, Kawaguchi H, Ishikawa Y, Ishii T, Uematsu S, Akira S, Murakami M, Kudo I (2004) Reduced pain hypersensitivity and inflammation in mice lacking microsomal prostaglandin e synthase-1. J Biol Chem 279:33684–33695

    Article  CAS  PubMed  Google Scholar 

  99. Ikeda-Matsuo Y, Ota A, Fukada T, Uematsu S, Akira S, Sasaki Y (2006) Microsomal prostaglandin E synthase-1 is a critical factor of stroke-reperfusion injury. Proc Natl Acad Sci U S A 103:11790–11795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Wang M, Zukas AM, Hui Y, Ricciotti E, Pure E, FitzGerald GA (2006) Deletion of microsomal prostaglandin E synthase-1 augments prostacyclin and retards atherogenesis. Proc Natl Acad Sci U S A 103:14507–14512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Wang M, Lee E, Song W, Ricciotti E, Rader DJ, Lawson JA, Pure E, FitzGerald GA (2008) Microsomal prostaglandin E synthase-1 deletion suppresses oxidative stress and angiotensin II-induced abdominal aortic aneurysm formation. Circulation 117:1302–1309

    Article  CAS  PubMed  Google Scholar 

  102. Wang M, Cooper PR, Jiang M, Zhao H, Hui Y, Yao Y, Tate JC, Damera G, Lawson JA, Jester WF Jr, Haczku A, Panettieri RA Jr, FitzGerald GA (2010) Deletion of microsomal prostaglandin E synthase-1 does not alter ozone-induced airway hyper-responsiveness. J Pharmacol Exp Ther 334:63–68

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Wang M, Ihida-Stansbury K, Kothapalli D, Tamby MC, Yu Z, Chen L, Grant G, Cheng Y, Lawson JA, Assoian RK, Jones PL, Fitzgerald GA (2011) Microsomal prostaglandin e2 synthase-1 modulates the response to vascular injury. Circulation 123:631–639

    Article  CAS  PubMed  Google Scholar 

  104. Xu D, Rowland SE, Clark P, Giroux A, Cote B, Guiral S, Salem M, Ducharme Y, Friesen RW, Methot N, Mancini J, Audoly L, Riendeau D (2008) MF63 [2-(6-chloro-1H-phenanthro[9,10-d]imidazol-2-yl)-isophthalonitrile], a selective microsomal prostaglandin E synthase-1 inhibitor, relieves pyresis and pain in preclinical models of inflammation. J Pharmacol Exp Ther 326:754–763

    Article  CAS  PubMed  Google Scholar 

  105. Facemire CS, Griffiths R, Audoly LP, Koller BH, Coffman TM (2010) The impact of microsomal prostaglandin e synthase 1 on blood pressure is determined by genetic background. Hypertensivon 55:531–538

    Google Scholar 

  106. Degousee N, Fazel S, Angoulvant D, Stefanski E, Pawelzik SC, Korotkova M, Arab S, Liu P, Lindsay TF, Zhuo S, Butany J, Li RK, Audoly L, Schmidt R, Angioni C, Geisslinger G, Jakobsson PJ, Rubin BB (2008) Microsomal prostaglandin E2 synthase-1 deletion leads to adverse left ventricular remodeling after myocardial infarction. Circulation 117:1701–1710

    Article  CAS  PubMed  Google Scholar 

  107. Degousee N, Simpson J, Fazel S, Scholich K, Angoulvant D, Angioni C, Schmidt H, Korotkova M, Stefanski E, Wang XH, Lindsay TF, Ofek E, Pierre S, Butany J, Jakobsson PJ, Keating A, Li RK, Nahrendorf M, Geisslinger G, Backx PH, Rubin BB (2012) Lack of microsomal prostaglandin e2 synthase-1 in bone marrow-derived myeloid cells impairs left ventricular function and increases mortality after acute myocardial infarction. Circulation 125:2904–2913

    Article  CAS  PubMed  Google Scholar 

  108. Zhu L, Xu C, Huo X, Hao H, Wan Q, Chen H, Zhang X, Breyer RM, Huang Y, Cao X, Liu DP, FitzGerald GA, Wang M (2019) The cyclooxygenase-1/mPGES-1/endothelial prostaglandin EP4 receptor pathway constrains myocardial ischemia-reperfusion injury. Nat Commun 10:1888

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Kawabata A (2011) Prostaglandin E2 and pain–an update. Biol Pharm Bull 34:1170–1173

    Article  CAS  PubMed  Google Scholar 

  110. Chen M, Boilard E, Nigrovic PA, Clark P, Xu D, Fitzgerald GA, Audoly LP, Lee DM (2008) Predominance of cyclooxygenase 1 over cyclooxygenase 2 in the generation of proinflammatory prostaglandins in autoantibody-driven K/BxN serum-transfer arthritis. Arthritis Rheum 58:1354–1365

    Article  CAS  PubMed  Google Scholar 

  111. Chen L, Yang G, Xu X, Grant G, Lawson JA, Bohlooly YM, FitzGerald GA (2013) Cell selective cardiovascular biology of microsomal prostaglandin E synthase-1. Circulation 127:233–243

    Article  CAS  PubMed  Google Scholar 

  112. Chen L, Yang G, Monslow J, Todd L, Cormode DP, Tang J, Grant GR, DeLong JH, Tang SY, Lawson JA, Pure E, Fitzgerald GA (2014) Myeloid cell microsomal prostaglandin E synthase-1 fosters atherogenesis in mice. Proc Natl Acad Sci U S A 111:6828–6833

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Cote B, Boulet L, Brideau C, Claveau D, Ethier D, Frenette R, Gagnon M, Giroux A, Guay J, Guiral S, Mancini J, Martins E, Masse F, Methot N, Riendeau D, Rubin J, Xu D, Yu H, Ducharme Y, Friesen RW (2007) Substituted phenanthrene imidazoles as potent, selective, and orally active mPGES-1 inhibitors. Bioorg Med Chem Lett 17:6816–6820

    Article  CAS  PubMed  Google Scholar 

  114. Giroux A, Boulet L, Brideau C, Chau A, Claveau D, Cote B, Ethier D, Frenette R, Gagnon M, Guay J, Guiral S, Mancini J, Martins E, Masse F, Methot N, Riendeau D, Rubin J, Xu D, Yu H, Ducharme Y, Friesen RW (2009) Discovery of disubstituted phenanthrene imidazoles as potent, selective and orally active mPGES-1 inhibitors. Bioorg Med Chem Lett 19:5837–5841

    Article  CAS  PubMed  Google Scholar 

  115. Pawelzik SC, Uda NR, Spahiu L, Jegerschold C, Stenberg P, Hebert H, Morgenstern R, Jakobsson PJ (2010) Identification of key residues determining species differences in inhibitor binding of microsomal prostaglandin E synthase-1. J Biol Chem 285:29254–29261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Gosselin F, Lau S, Nadeau C, Trinh T, O’Shea PD, Davies IW (2009) A practical synthesis of m-prostaglandin E synthase-1 inhibitor MK-7285. J Org Chem 74:7790–7797

    Article  CAS  PubMed  Google Scholar 

  117. Schiffler MA, Antonysamy S, Bhattachar SN, Campanale KM, Chandrasekhar S, Condon B, Desai PV, Fisher MJ, Groshong C, Harvey A, Hickey MJ, Hughes NE, Jones SA, Kim EJ, Kuklish SL, Luz JG, Norman BH, Rathmell RE, Rizzo JR, Seng TW, Thibodeaux SJ, Woods TA, York JS, Yu XP (2016) Discovery and characterization of 2-Acylaminoimidazole microsomal prostaglandin E synthase-1 inhibitors. J Med Chem 59:194–205

    Article  CAS  PubMed  Google Scholar 

  118. Jin Y, Smith CL, Hu L, Campanale KM, Stoltz R, Huffman LG Jr, McNearney TA, Yang XY, Ackermann BL, Dean R, Regev A, Landschulz W (2016) Pharmacodynamic comparison of LY3023703, a novel microsomal prostaglandin e synthase 1 inhibitor, with celecoxib. Clin Pharmacol Ther 99:274–284

    Article  CAS  PubMed  Google Scholar 

  119. Norman BH, Fisher MJ, Schiffler MA, Kuklish SL, Hughes NE, Czeskis BA, Cassidy KC, Abraham TL, Alberts JJ, Luffer-Atlas D (2018) Identification and mitigation of reactive metabolites of 2-aminoimidazole-containing microsomal prostaglandin E synthase-1 inhibitors terminated due to clinical drug-induced liver injury. J Med Chem 61:2041–2051

    Article  CAS  PubMed  Google Scholar 

  120. Jin Y, Regev A, Kam J, Phipps K, Smith C, Henck J, Campanale K, Hu L, Hall DG, Yang XY, Nakano M, McNearney TA, Uetrecht J, Landschulz W (2018) Dose-dependent acute liver injury with hypersensitivity features in humans due to a novel microsomal prostaglandin E synthase 1 inhibitor. Br J Clin Pharmacol 84:179–188

    Article  CAS  PubMed  Google Scholar 

  121. Banerjee A, Pawar MY, Patil S, Yadav PS, Kadam PA, Kattige VG, Deshpande DS, Pednekar PV, Pisat MK, Gharat LA (2014) Development of 2-aryl substituted quinazolin-4(3H)-one, pyrido[4,3-d]pyrimidin-4(3H)-one and pyrido[2,3-d]pyrimidin-4(3H)-one derivatives as microsomal prostaglandin E(2) synthase-1 inhibitors. Bioorg Med Chem Lett 24:4838–4844

    Article  CAS  PubMed  Google Scholar 

  122. Sant S, Tandon M, Menon V, Gudi G, Kattige V, Joshi NK, Korukonda K, Levine-Dolberg O (2018) GRC 27864, novel, microsomal prostaglandin E synthase-1 enzyme inhibitor: phase 1 study to evaluate safety, PK and biomarkers in healthy, adult subjects. Osteoarthr Cartil 26:S351–S352

    Article  Google Scholar 

  123. Glenmark pharmaceuticals provides update on clinical development of GRC 27864. Capital Market. January 15, 2018. www.businessstandard.com/article/news-cm/glenmark-pharmaceuticals-provides-update-on-clinical-development-of-grc-27864-118011500958_1.html Date of access May 24, 2019

    Google Scholar 

  124. Arima M, Fukuda T (2011) Prostaglandin D(2) and T(H)2 inflammation in the pathogenesis of bronchial asthma. Korean J Intern Med 26:8–18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Peebles RS Jr (2019) Prostaglandins in asthma and allergic diseases. Pharmacol Ther 193:1–19

    Article  CAS  PubMed  Google Scholar 

  126. Sulaiman I, Lim JC, Soo HL, Stanslas J (2016) Molecularly targeted therapies for asthma: current development, challenges and potential clinical translation. Pulm Pharmacol Ther 40:52–68

    Article  CAS  PubMed  Google Scholar 

  127. Stinson SE, Amrani Y, Brightling CE (2015) D prostanoid receptor 2 (chemoattractant receptor-homologous molecule expressed on TH2 cells) protein expression in asthmatic patients and its effects on bronchial epithelial cells. J Allergy Clin Immunol 135:395–406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Barnes N, Pavord I, Chuchalin A, Bell J, Hunter M, Lewis T, Parker D, Payton M, Collins LP, Pettipher R, Steiner J, Perkins CM (2012) A randomized, double-blind, placebo-controlled study of the CRTH2 antagonist OC000459 in moderate persistent asthma. Clin Exp Allergy 42:38–48

    Article  CAS  PubMed  Google Scholar 

  129. Singh D, Cadden P, Hunter M, Pearce Collins L, Perkins M, Pettipher R, Townsend E, Vinall S, O’Connor B (2013) Inhibition of the asthmatic allergen challenge response by the CRTH2 antagonist OC000459. Eur Respir J 41:46–52

    Article  CAS  PubMed  Google Scholar 

  130. Pettipher R, Hunter MG, Perkins CM, Collins LP, Lewis T, Baillet M, Steiner J, Bell J, Payton MA (2014) Heightened response of eosinophilic asthmatic patients to the CRTH2 antagonist OC000459. Allergy 69:1223–1232

    Article  CAS  PubMed  Google Scholar 

  131. Horak F, Zieglmayer P, Zieglmayer R, Lemell P, Collins LP, Hunter MG, Steiner J, Lewis T, Payton MA, Perkins CM, Pettipher R (2012) The CRTH2 antagonist OC000459 reduces nasal and ocular symptoms in allergic subjects exposed to grass pollen, a randomised, placebo-controlled, double-blind trial. Allergy 67:1572–1579

    CAS  PubMed  Google Scholar 

  132. Rittchen S, Heinemann A (2019) Therapeutic potential of hematopoietic prostaglandin D2 synthase in allergic inflammation. Cell 8:pii: E619

    Article  CAS  Google Scholar 

  133. Mohri I, Aritake K, Taniguchi H, Sato Y, Kamauchi S, Nagata N, Maruyama T, Taniike M, Urade Y (2009) Inhibition of prostaglandin D synthase suppresses muscular necrosis. Am J Pathol 174:1735–1744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Kamauchi S, Urade Y (2011) Hematopoietic prostaglandin D synthase inhibitors for the treatment of duchenne muscular dystrophy. Brain Nerve 63:1261–1269

    PubMed  Google Scholar 

  135. Thurairatnam S (2012) Hematopoietic prostaglandin D synthase inhibitors. Prog Med Chem 51:97–133

    Article  CAS  PubMed  Google Scholar 

  136. Takeshita E, Komaki H, Shimizu-Motohashi Y, Ishiyama A, Sasaki M, Takeda S (2018) A phase I study of TAS-205 in patients with Duchenne muscular dystrophy. Ann Clin Transl Neurol 5:1338–1349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Nakagawa T, Takeuchi A, Kakiuchi R, Lee T, Yagi M, Awano H, Iijima K, Takeshima Y, Urade Y, Matsuo M (2013) A prostaglandin D2 metabolite is elevated in the urine of Duchenne muscular dystrophy patients and increases further from 8 years old. Clin Chim Acta 423:10–14

    Article  CAS  PubMed  Google Scholar 

  138. Takeshita E, Komaki H, Tachimori H, Miyoshi K, Yamamiya I, Shimizu-Motohashi Y, Ishiyama A, Saito T, Nakagawa E, Sugai K, Sasaki M (2018) Urinary prostaglandin metabolites as Duchenne muscular dystrophy progression markers. Brain and Development 40:918–925

    Article  PubMed  Google Scholar 

  139. Tanaka K, Aritake K, Tayama M, Sasaki E, Utsugi T, Sasaoka T, Urade Y (2014) Novel inhibitor of hematopoietic prostaglandin D synthase improves the muscle disorder in an experimental model of Duchenne muscular dystrophy. Neuromuscul Disord 24:821

    Article  Google Scholar 

  140. Hernandez JM, Janssen LJ (2015) Revisiting the usefulness of thromboxane-A2 modulation in the treatment of bronchoconstriction in asthma. Can J Physiol Pharmacol 93:111–117

    Article  CAS  PubMed  Google Scholar 

  141. Kunitoh H, Watanabe K, Nagatomo A, Okamoto H, Nakagawa T (1998) A double-blind, placebo-controlled trial of the thromboxane synthetase blocker OKY-046 on bronchial hypersensitivity in bronchial asthma patients. J Asthma 35:355–360

    Article  CAS  PubMed  Google Scholar 

  142. Kurosawa M (1995) Role of thromboxane A2 synthetase inhibitors in the treatment of patients with bronchial asthma. Clin Ther 17:2–11; discussion 11

    Article  CAS  PubMed  Google Scholar 

  143. Gardiner PV, Young CL, Holmes K, Hendrick DJ, Walters EH (1993) Lack of short-term effect of the thromboxane synthetase inhibitor UK-38,485 on airway reactivity to methacholine in asthmatic subjects. Eur Respir J 6:1027–1030

    CAS  PubMed  Google Scholar 

  144. Manning PJ, Stevens WH, Cockcroft DW, O’Byrne PM (1991) The role of thromboxane in allergen-induced asthmatic responses. Eur Respir J 4:667–672

    CAS  PubMed  Google Scholar 

  145. Huang R, Southall N, Wang Y, Yasgar A, Shinn P, Jadhav A, Nguyen D-T, Austin CP (2011) The NCGC pharmaceutical collection: a comprehensive resource of clinically approved drugs enabling repurposing and chemical genomics. Sci Transl Med 3:80ps16

    Google Scholar 

  146. Charlier C, Michaux C (2003) Dual inhibition of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) as a new strategy to provide safer non-steroidal anti-inflammatory drugs. Eur J Med Chem 38:645–659

    Article  CAS  PubMed  Google Scholar 

  147. JJ P, Manju SL, Ethiraj KR, Elias G (2018) Safer anti-inflammatory therapy through dual COX-2/5-LOX inhibitors: a structure-based approach. Eur J Pharm Sci 121:356–381

    Article  CAS  Google Scholar 

  148. Alvaro-Gracia JM (2004) Licofelone–clinical update on a novel LOX/COX inhibitor for the treatment of osteoarthritis. Rheumatology (Oxford) 43(Suppl 1):i21–i25

    Article  CAS  Google Scholar 

  149. Bitto A, Squadrito F, Irrera N, Pizzino G, Pallio G, Mecchio A, Galfo F, Altavilla D (2014) Flavocoxid, a nutraceutical approach to blunt inflammatory conditions. Mediat Inflamm 2014:790851

    Article  CAS  Google Scholar 

  150. Burnett BP, Jia Q, Zhao Y, Levy RM (2007) A medicinal extract of Scutellaria baicalensis and Acacia catechu acts as a dual inhibitor of cyclooxygenase and 5-lipoxygenase to reduce inflammation. J Med Food 10:442–451

    Article  CAS  PubMed  Google Scholar 

  151. Levy RM, Khokhlov A, Kopenkin S, Bart B, Ermolova T, Kantemirova R, Mazurov V, Bell M, Caldron P, Pillai L, Burnett BP (2010) Efficacy and safety of flavocoxid, a novel therapeutic, compared with naproxen: a randomized multicenter controlled trial in subjects with osteoarthritis of the knee. Adv Ther 27:731–742

    Article  CAS  PubMed  Google Scholar 

  152. Levy R, Khokhlov A, Kopenkin S, Bart B, Ermolova T, Kantemirova R, Mazurov V, Bell M, Caldron P, Pillai L, Burnett B (2010) Efficacy and safety of flavocoxid compared with naproxen in subjects with osteoarthritis of the knee- a subset analysis. Adv Ther 27:953–962

    Article  CAS  PubMed  Google Scholar 

  153. Pillai L, Levy RM, Yimam M, Zhao Y, Jia Q, Burnett BP (2010) Flavocoxid, an anti-inflammatory agent of botanical origin, does not affect coagulation or interact with anticoagulation therapies. Adv Ther 27:400–411

    Article  CAS  PubMed  Google Scholar 

  154. Pillai L, Burnett BP, Levy RM, G. S. C. Group (2010) GOAL: multicenter, open-label, post-marketing study of flavocoxid, a novel dual pathway inhibitor anti-inflammatory agent of botanical origin. Curr Med Res Opin 26:1055–1063

    Article  CAS  PubMed  Google Scholar 

  155. Selg E, Buccellati C, Andersson M, Rovati GE, Ezinga M, Sala A, Larsson AK, Ambrosio M, Lastbom L, Capra V, Dahlen B, Ryrfeldt A, Folco GC, Dahlen SE (2007) Antagonism of thromboxane receptors by diclofenac and lumiracoxib. Br J Pharmacol 152:1185–1195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Bertinaria M, Shaikh MA, Buccellati C, Cena C, Rolando B, Lazzarato L, Fruttero R, Gasco A, Hoxha M, Capra V, Sala A, Rovati GE (2012) Designing multitarget anti-inflammatory agents: chemical modulation of the lumiracoxib structure toward dual thromboxane antagonists-COX-2 inhibitors. ChemMedChem 7:1647–1660

    Article  CAS  PubMed  Google Scholar 

  157. Carnevali S, Buccellati C, Bolego C, Bertinaria M, Rovati GE, Sala A (2017) Nonsteroidal anti-inflammatory drugs: exploiting bivalent COXIB/TP antagonists for the control of cardiovascular risk. Curr Med Chem 24:3218–3230

    Article  CAS  PubMed  Google Scholar 

  158. Elkady M, Niess R, Schaible AM, Bauer J, Luderer S, Ambrosi G, Werz O, Laufer SA (2012) Modified acidic nonsteroidal anti-inflammatory drugs as dual inhibitors of mPGES-1 and 5-LOX. J Med Chem 55:8958–8962

    Article  CAS  PubMed  Google Scholar 

  159. Shang E, Wu Y, Liu P, Liu Y, Zhu W, Deng X, He C, He S, Li C, Lai L (2014) Benzo[d]isothiazole 1,1-dioxide derivatives as dual functional inhibitors of 5-lipoxygenase and microsomal prostaglandin E(2) synthase-1. Bioorg Med Chem Lett 24:2764–2767

    Article  CAS  PubMed  Google Scholar 

  160. Devi NS, Paragi-Vedanthi P, Bender A, Doble M (2018) Common structural and pharmacophoric features of mPGES-1 and LTC4S. Future Med Chem 10:259–268

    Article  CAS  PubMed  Google Scholar 

  161. Kupczyk M, Kuna P (2017) Targeting the PGD2/CRTH2/DP1 signaling pathway in asthma and allergic disease: current status and future perspectives. Drugs 77:1281–1294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Krug N, Gupta A, Badorrek P, Koenen R, Mueller M, Pivovarova A, Hilbert J, Wetzel K, Hohlfeld JM, Wood C (2014) Efficacy of the oral chemoattractant receptor homologous molecule on TH2 cells antagonist BI 671800 in patients with seasonal allergic rhinitis. J Allergy Clin Immunol 133:414–419

    Article  CAS  PubMed  Google Scholar 

  163. Miller D, Wood C, Bateman E, LaForce C, Blatchford J, Hilbert J, Gupta A, Fowler A (2017) A randomized study of BI 671800, a CRTH2 antagonist, as add-on therapy in poorly controlled asthma. Allergy Asthma Proc 38:157–164

    Article  CAS  PubMed  Google Scholar 

  164. Hall IP, Fowler AV, Gupta A, Tetzlaff K, Nivens MC, Sarno M, Finnigan HA, Bateman ED, Rand Sutherland E (2015) Efficacy of BI 671800, an oral CRTH2 antagonist, in poorly controlled asthma as sole controller and in the presence of inhaled corticosteroid treatment. Pulm Pharmacol Ther 32:37–44

    Article  CAS  PubMed  Google Scholar 

  165. Fretz H, Valdenaire A, Pothier J, Hilpert K, Gnerre C, Peter O, Leroy X, Riederer MA (2013) Identification of 2-(2-(1-naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid (setipiprant/ACT-129968), a potent, selective, and orally bioavailable chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) antagonist. J Med Chem 56:4899–4911

    Article  CAS  PubMed  Google Scholar 

  166. Diamant Z, Sidharta PN, Singh D, O’Connor BJ, Zuiker R, Leaker BR, Silkey M, Dingemanse J (2014) Setipiprant, a selective CRTH2 antagonist, reduces allergen-induced airway responses in allergic asthmatics. Clin Exp Allergy 44:1044–1052

    Article  CAS  PubMed  Google Scholar 

  167. Ratner P, Andrews CP, Hampel FC, Martin B, Mohar DE, Bourrelly D, Danaietash P, Mangialaio S, Dingemanse J, Hmissi A, van Bavel J (2017) Efficacy and safety of setipiprant in seasonal allergic rhinitis: results from phase 2 and phase 3 randomized, double-blind, placebo- and active-referenced studies. Allergy Asthma Clin Immunol 13:18

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. Nilsson SF, Drecoll E, Lutjen-Drecoll E, Toris CB, Krauss AH, Kharlamb A, Nieves A, Guerra T, Woodward DF (2006) The prostanoid EP2 receptor agonist butaprost increases uveoscleral outflow in the cynomolgus monkey. Invest Ophthalmol Vis Sci 47:4042–4049

    Article  PubMed  Google Scholar 

  169. Prasanna G, Carreiro S, Anderson S, Gukasyan H, Sartnurak S, Younis H, Gale D, Xiang C, Wells P, Dinh D, Almaden C, Fortner J, Toris C, Niesman M, Lafontaine J, Krauss A (2011) Effect of PF-04217329 a prodrug of a selective prostaglandin EP(2) agonist on intraocular pressure in preclinical models of glaucoma. Exp Eye Res 93:256–264

    Article  CAS  PubMed  Google Scholar 

  170. Schachar RA, Raber S, Courtney R, Zhang M (2011) A phase 2, randomized, dose-response trial of taprenepag isopropyl (PF-04217329) versus latanoprost 0.005% in open-angle glaucoma and ocular hypertension. Curr Eye Res 36:809–817

    Article  CAS  PubMed  Google Scholar 

  171. Yanochko GM, Affolter T, Eighmy JJ, Evans MG, Khoh-Reiter S, Lee D, Miller PE, Shiue MH, Trajkovic D, Jessen BA (2014) Investigation of ocular events associated with Taprenepag isopropyl, a topical EP2 agonist in development for treatment of glaucoma. J Ocul Pharmacol Ther 30:429–439

    Article  CAS  PubMed  Google Scholar 

  172. Fuwa M, Toris CB, Fan S, Taniguchi T, Ichikawa M, Odani-Kawabata N, Iwamura R, Yoneda K, Matsugi T, Shams NK, Zhang JZ (2018) Effects of a novel selective EP2 receptor agonist, Omidenepag isopropyl, on aqueous humor dynamics in laser-induced ocular hypertensive monkeys. J Ocul Pharmacol Ther 34:531–537

    Article  CAS  PubMed  Google Scholar 

  173. Aihara M, Lu F, Kawata H, Iwata A, Liu K, Odani-Kawabata N, Shams NK (2019) Phase 2, randomized, dose-finding studies of Omidenepag isopropyl, a selective EP2 agonist, in patients with primary open-angle Glaucoma or ocular hypertension. J Glaucoma 28:375–385

    Article  PubMed  Google Scholar 

  174. Duggan S (2018) Omidenepag isopropyl ophthalmic solution 0.002%: first global approval. Drugs 78:1925–1929

    Article  PubMed  Google Scholar 

  175. Nitta M, Hirata I, Toshina K, Murano M, Maemura K, Hamamoto N, Sasaki S, Yamauchi H, Katsu K (2002) Expression of the EP4 prostaglandin E2 receptor subtype with rat dextran sodium sulphate colitis: colitis suppression by a selective agonist, ONO-AE1-329. Scand J Immunol 56:66–75

    Article  CAS  PubMed  Google Scholar 

  176. Kabashima K, Saji T, Murata T, Nagamachi M, Matsuoka T, Segi E, Tsuboi K, Sugimoto Y, Kobayashi T, Miyachi Y, Ichikawa A, Narumiya S (2002) The prostaglandin receptor EP4 suppresses colitis, mucosal damage and CD4 cell activation in the gut. J Clin Invest 109:883–893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Yoshida K, Oida H, Kobayashi T, Maruyama T, Tanaka M, Katayama T, Yamaguchi K, Segi E, Tsuboyama T, Matsushita M, Ito K, Ito Y, Sugimoto Y, Ushikubi F, Ohuchida S, Kondo K, Nakamura T, Narumiya S (2002) Stimulation of bone formation and prevention of bone loss by prostaglandin E EP4 receptor activation. Proc Natl Acad Sci U S A 99:4580–4585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Nakase H, Fujiyama Y, Oshitani N, Oga T, Nonomura K, Matsuoka T, Esaki Y, Murayama T, Teramukai S, Chiba T, Narumiya S (2010) Effect of EP4 agonist (ONO-4819CD) for patients with mild to moderate ulcerative colitis refractory to 5-aminosalicylates: a randomized phase II, placebo-controlled trial. Inflamm Bowel Dis 16:731–733

    Article  PubMed  Google Scholar 

  179. Watanabe Y, Murata T, Amakawa M, Miyake Y, Handa T, Konishi K, Matsumura Y, Tanaka T, Takeuchi K (2015) KAG-308, a newly-identified EP4-selective agonist shows efficacy for treating ulcerative colitis and can bring about lower risk of colorectal carcinogenesis by oral administration. Eur J Pharmacol 754:179–189

    Article  CAS  PubMed  Google Scholar 

  180. Markovic T, Jakopin Z, Dolenc MS, Mlinaric-Rascan I (2017) Structural features of subtype-selective EP receptor modulators. Drug Discov Today 22:57–71

    Article  CAS  PubMed  Google Scholar 

  181. Lin CR, Amaya F, Barrett L, Wang H, Takada J, Samad TA, Woolf CJ (2006) Prostaglandin E2 receptor EP4 contributes to inflammatory pain hypersensitivity. J Pharmacol Exp Ther 319:1096–1103

    Article  CAS  PubMed  Google Scholar 

  182. Nakao K, Murase A, Ohshiro H, Okumura T, Taniguchi K, Murata Y, Masuda M, Kato T, Okumura Y, Takada J (2007) CJ-023,423, a novel, potent and selective prostaglandin EP4 receptor antagonist with antihyperalgesic properties. J Pharmacol Exp Ther 322:686–694

    Article  CAS  PubMed  Google Scholar 

  183. Chen Q, Muramoto K, Masaaki N, Ding Y, Yang H, Mackey M, Li W, Inoue Y, Ackermann K, Shirota H, Matsumoto I, Spyvee M, Schiller S, Sumida T, Gusovsky F, Lamphier M (2010) A novel antagonist of the prostaglandin E(2) EP(4) receptor inhibits Th1 differentiation and Th17 expansion and is orally active in arthritis models. Br J Pharmacol 160:292–310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Boyd MJ, Berthelette C, Chiasson JF, Clark P, Colucci J, Denis D, Han Y, Levesque JF, Mathieu MC, Stocco R, Therien A, Rowland S, Wrona M, Xu D (2011) A novel series of potent and selective EP(4) receptor ligands: facile modulation of agonism and antagonism. Bioorg Med Chem Lett 21:484–487

    Article  CAS  PubMed  Google Scholar 

  185. McCoy JM, Wicks JR, Audoly LP (2002) The role of prostaglandin E2 receptors in the pathogenesis of rheumatoid arthritis. J Clin Invest 110:651–658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Colucci J, Boyd M, Berthelette C, Chiasson JF, Wang Z, Ducharme Y, Friesen R, Wrona M, Levesque JF, Denis D, Mathieu MC, Stocco R, Therien AG, Clarke P, Rowland S, Xu D, Han Y (2010) Discovery of 4-[1-[([1-[4-(trifluoromethyl)benzyl]-1H-indol-7-yl]carbonyl)amino]cyclopropyl]be nzoic acid (MF-766), a highly potent and selective EP4 antagonist for treating inflammatory pain. Bioorg Med Chem Lett 20:3760–3763

    Article  CAS  PubMed  Google Scholar 

  187. Chandrasekhar S, Yu XP, Harvey AK, Oskins JL, Lin C, Wang X, Blanco MJ, Fisher MJ, Kuklish SL, Schiffler MA, Vetman T, Warshawsky AM, York JS, Bendele AM, Chambers MG (2017) Analgesic and anti-inflammatory properties of novel, selective, and potent EP4 receptor antagonists. Pharmacol Res Perspect 5:e00316

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  188. Caselli G, Bonazzi A, Lanza M, Ferrari F, Maggioni D, Ferioli C, Giambelli R, Comi E, Zerbi S, Perrella M, Letari O, Di Luccio E, Colovic M, Persiani S, Zanelli T, Mennuni L, Piepoli T, Rovati LC (2018) Pharmacological characterisation of CR6086, a potent prostaglandin E2 receptor 4 antagonist, as a new potential disease-modifying anti-rheumatic drug. Arthritis Res Ther 20:39

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  189. Blanco MJ, Vetman T, Chandrasekhar S, Fisher MJ, Harvey A, Kuklish SL, Chambers M, Lin C, Mudra D, Oskins J, Wang XS, Yu XP, Warshawsky AM (2016) Identification and biological activity of 6-alkyl-substituted 3-methyl-pyridine-2-carbonyl amino dimethyl-benzoic acid EP4 antagonists. Bioorg Med Chem Lett 26:2303–2307

    Article  CAS  PubMed  Google Scholar 

  190. Lebkowska-Wieruszewska B, De Vito V, Owen H, Poapholatep A, Giorgi M (2017) Pharmacokinetics of grapiprant, a selective EP4 prostaglandin PGE2 receptor antagonist, after 2 mg/kg oral and i.v. administrations in cats. J Vet Pharmacol Ther 40:e11–e15

    Article  CAS  PubMed  Google Scholar 

  191. De Vito V, Salvadori M, Poapolathep A, Owen H, Rychshanova R, Giorgi M (2017) Pharmacokinetic/pharmacodynamic evaluation of grapiprant in a carrageenan-induced inflammatory pain model in the rabbit. J Vet Pharmacol Ther 40:468–475

    Article  PubMed  CAS  Google Scholar 

  192. Nagahisa A, Okumura T (2017) Pharmacology of grapiprant, a novel EP4 antagonist: receptor binding, efficacy in a rodent postoperative pain model, and a dose estimation for controlling pain in dogs. J Vet Pharmacol Ther 40:285–292

    Article  CAS  PubMed  Google Scholar 

  193. Knych HK, Seminoff K, McKemie DS (2018) Detection and pharmacokinetics of grapiprant following oral administration to exercised thoroughbred horses. Drug Test Anal 10(8):1237–1243

    Article  CAS  Google Scholar 

  194. Rausch-Derra LC, Huebner M, Rhodes L (2015) Evaluation of the safety of long-term, daily oral administration of grapiprant, a novel drug for treatment of osteoarthritic pain and inflammation, in healthy dogs. Am J Vet Res 76:853–859

    Article  CAS  PubMed  Google Scholar 

  195. Rausch-Derra L, Huebner M, Wofford J, Rhodes L (2016) A prospective, randomized, masked, placebo-controlled multisite clinical study of Grapiprant, an EP4 prostaglandin receptor antagonist (PRA), in dogs with osteoarthritis. J Vet Intern Med 30:756–763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Rausch-Derra LC, Rhodes L, Freshwater L, Hawks R (2016) Pharmacokinetic comparison of oral tablet and suspension formulations of grapiprant, a novel therapeutic for the pain and inflammation of osteoarthritis in dogs. J Vet Pharmacol Ther 39:566–571

    Article  CAS  PubMed  Google Scholar 

  197. Jin Y, Smith C, Hu L, Coutant DE, Whitehurst K, Phipps K, McNearney TA, Yang X, Ackermann B, Pottanat T, Landschulz W (2018) LY3127760, a selective prostaglandin E4 (EP4) receptor antagonist, and celecoxib: a comparison of pharmacological profiles. Clin Transl Sci 11:46–53

    Article  CAS  PubMed  Google Scholar 

  198. Sakata D, Yao C, Narumiya S (2010) Emerging roles of prostanoids in T cell-mediated immunity. IUBMB Life 62:591–596

    Article  CAS  PubMed  Google Scholar 

  199. Wherry EJ, Ha SJ, Kaech SM, Haining WN, Sarkar S, Kalia V, Subramaniam S, Blattman JN, Barber DL, Ahmed R (2007) Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27:670–684

    Article  CAS  PubMed  Google Scholar 

  200. Chen JH, Perry CJ, Tsui YC, Staron MM, Parish IA, Dominguez CX, Rosenberg DW, Kaech SM (2015) Prostaglandin E2 and programmed cell death 1 signaling coordinately impair CTL function and survival during chronic viral infection. Nat Med 21:327–334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Miao J, Lu X, Hu Y, Piao C, Wu X, Liu X, Huang C, Wang Y, Li D, Liu J (2017) Prostaglandin E2 and PD-1 mediated inhibition of antitumor CTL responses in the human tumor microenvironment. Oncotarget 8:89802–89810

    Article  PubMed  PubMed Central  Google Scholar 

  202. Dockens RC, Santone KS, Mitroka JG, Morrison RA, Jemal M, Greene DS, Barbhaiya RH (2000) Disposition of radiolabeled ifetroban in rats, dogs, monkeys, and humans. Drug Metab Dispos 28:973–980

    CAS  PubMed  Google Scholar 

  203. Ogletree ML, Harris DN, Schumacher WA, Webb ML, Misra RN (1993) Pharmacological profile of BMS 180,291: a potent, long-acting, orally active thromboxane A2/prostaglandin endoperoxide receptor antagonist. J Pharmacol Exp Ther 264:570–578

    CAS  PubMed  Google Scholar 

  204. Rosenfeld L, Grover GJ, Stier CT Jr (2001) Ifetroban sodium: an effective TxA2/PGH2 receptor antagonist. Cardiovasc Drug Rev 19:97–115

    Article  CAS  PubMed  Google Scholar 

  205. Webb ML, Liu EC, Monshizadegan H, Hedberg A, Misra RN, Goldenberg H, Harris DN (1993) Binding and function of a potent new thromboxane receptor antagonist, BMS 180,291, in human platelets. J Pharmacol Exp Ther 264:1387–1394

    CAS  PubMed  Google Scholar 

  206. Samara E, Cao G, Locke C, Granneman GR, Dean R, Killian A (1997) Population analysis of the pharmacokinetics and pharmacodynamics of seratrodast in patients with mild to moderate asthma. Clin Pharmacol Ther 62:426–435

    Article  CAS  PubMed  Google Scholar 

  207. Royer JF, Schratl P, Carrillo JJ, Jupp R, Barker J, Weyman-Jones C, Beri R, Sargent C, Schmidt JA, Lang-Loidolt D, Heinemann A (2008) A novel antagonist of prostaglandin D2 blocks the locomotion of eosinophils and basophils. Eur J Clin Investig 38:663–671

    Article  CAS  Google Scholar 

  208. Endo S, Akiyama K (1996) Thromboxane A2 receptor antagonist in asthma therapy. Nihon Rinsho 54:3045–3048

    CAS  PubMed  Google Scholar 

  209. Fiedler VB, Seuter F, Perzborn E (1990) Effects of the novel thromboxane antagonist bay U 3405 on experimental coronary artery disease. Stroke 21:IV149–IV151

    CAS  PubMed  Google Scholar 

  210. Chapple CR, Abrams P, Andersson KE, Radziszewski P, Masuda T, Small M, Kuwayama T, Deacon S (2014) Phase II study on the efficacy and safety of the EP1 receptor antagonist ONO-8539 for nonneurogenic overactive bladder syndrome. J Urol 191:253–260

    Article  CAS  PubMed  Google Scholar 

  211. Kondo T, Sei H, Yamasaki T, Tomita T, Ohda Y, Oshima T, Fukui H, Watari J, Miwa H (2017) A novel prostanoid EP1 receptor antagonist, ONO-8539, reduces acid-induced heartburn symptoms in healthy male volunteers: a randomized clinical trial. J Gastroenterol 52:1081–1089

    Article  CAS  PubMed  Google Scholar 

  212. Tilly P, Charles AL, Ludwig S, Slimani F, Gross S, Meilhac O, Geny B, Stefansson K, Gurney ME, Fabre JE (2014) Blocking the EP3 receptor for PGE2 with DG-041 decreases thrombosis without impairing haemostatic competence. Cardiovasc Res 101:482–491

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Liudmila L. Mazaleuskaya & Emanuela Ricciotti

  2. Institute for Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Liudmila L. Mazaleuskaya & Emanuela Ricciotti

Authors
  1. Liudmila L. Mazaleuskaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emanuela Ricciotti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Emanuela Ricciotti .

Editor information

Editors and Affiliations

  1. Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA

    Yasuyuki Kihara

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Mazaleuskaya, L.L., Ricciotti, E. (2020). Druggable Prostanoid Pathway. In: Kihara, Y. (eds) Druggable Lipid Signaling Pathways. Advances in Experimental Medicine and Biology, vol 1274. Springer, Cham. https://doi.org/10.1007/978-3-030-50621-6_3

Download citation

Publish with us

Policies and ethics

Search

Navigation