Advances in Therapy

, Volume 24, Issue 1, pp 189–222

Modulation of prostaglandin activity, part 1: Prostaglandin inhibition in the management of nonrheumatologic diseases: Immunologic and hematologic aspects

  • Noori S. Al-Waili
  • Khelod Y. Saloom
  • Thia Al-Waili
  • Ali Al-Waili
  • Hamza Al-Waili


Prostaglandins (PGs) are active biologic substances that are involved in a wide range of physiologic processes; when their production is out of balance, they are factors in the pathogenesis of illness. Modulation of PGs by inhibition or stimulation is promising for the management of various conditions. PG inhibitors are widely used to relieve pain and inflammation in patients with rheumatologic disease. Interest in the use of PG inhibitors to prevent cancer and cardiovascular events is growing. More than 27 y ago, investigators found that PG depresses antibody production in vivo; reduces serum iron, hemoglobin, and leukoid series in bone marrow during acute and chronic blood loss; reduces albumin during antigenic stimulation; suppresses hypercalcemia after bleeding; and reduces fasting blood sugar and hyperglycemia after ether anesthesia and bleeding. Chronic conditions that produce large quantities of PGs are associated with immunosuppression and secondary anemia. Investigators in the present study hypothesized (1) that the overproduction of PGs is responsible for immunosuppression and secondary anemia in conditions associated with increased PG synthesis, such as pathologic inflammation, malignancy, trauma, and injury, and (2) that PG inhibitors reverse immunosuppression and secondary anemia, thereby enhancing the immune response. This is supported by many reports that show the immunosuppressive effects of PGs and their role in the immunosuppression associated with pathologic inflammation, burns, trauma, and tumors. Inhibition of PGs can be achieved through the use of synthetic medicines and natural products. This article reviews the effects of PGs and inhibition of increased synthesis of PGs on the lymphoid system, hematologic indices, and bone marrow elements in trauma, injury, burns, and tumors. The Medline database (1966–2006) was used in this study. Investigators in the present study and others have provided evidence that shows the involvement of PGs in immunosuppression and secondary anemia, as well as the efficacy of inhibited overproduction of PGs in many pathologic conditions other than rheumatologic disease.


tumor free radicals NSAIDs anemia immunity inflammation trauma burn COX 


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  1. 1.
    Kam C, See AU. Cyclo-oxygenase isoenzymes: physiological and pharmacological role.Anaesthesia. 2000;55:442–449PubMedCrossRefGoogle Scholar
  2. 2.
    Samuelsson B, Dahlen S, Lindgren JA, Rouzer CA, Serhan CN. Leukotrienes and lipoxins: structure, biosynthesis, and biological effects.Science. 1987;237:1171–1176PubMedCrossRefGoogle Scholar
  3. 3.
    Stenson WF. Prostaglandins and epithelial response to injury.Curr Opin Gastroenterol. 2007;23:107–110PubMedCrossRefGoogle Scholar
  4. 4.
    Rajakariar R, Yaqoob MM, Gilroy DW. COX-2 in inflammation and resolution.Mol Interv. 2006;6:199–207PubMedCrossRefGoogle Scholar
  5. 5.
    Kim R, Emi M, Tanabe K. Cancer immunosuppression and autoimmune disease: beyond immunosuppressive networks for tumour immunity.Immunology. 2006;119:254–264PubMedCrossRefGoogle Scholar
  6. 6.
    Sohn HY, Krotz F. Cyclooxygenase inhibition and atherothrombosis.Curr Drug Targets. 2006;7:1275–1284PubMedCrossRefGoogle Scholar
  7. 7.
    Al-Waili N, Al-Azzawi H, Al-Obidi S. Hypoglycaemic effect of prostaglandin F2 alpha in normal rabbits.J F Med Bagh. 1981;25:247–249Google Scholar
  8. 8.
    Al-Waili N, Al-Azzawi H. The effects of prostaglandin E2 on hyperglycemia following hemorrhage and ether anesthesia.J F Med Bagh. 1981;23:405–407Google Scholar
  9. 9.
    Al-Azzawi H, Al-Dabbagh A, Al-Waili N. The effects of PGF2 on hyperglycemic response to ether anesthesia and bleeding, Fourth Scientific Congress. Baghdad, Iraq: College of Medicine, University of Baghdad; 1988:34.Google Scholar
  10. 10.
    Al-Azzawi H, Al-Waili N. Serum calcium, serum inorganic phosphorus and serum alkaline phosphates during hemorrhage and prostaglandin E2 treatment.J F Med Bagh. 1981;23:349–352Google Scholar
  11. 11.
    Al-Waili N, Al-Azzawi H. The effects of prostaglandin E2 on serum iron following acute and chronic blood loss.Clin Exp Pharm Physiol. 1985;12:443–446CrossRefGoogle Scholar
  12. 12.
    Al-Waili N, Al-Azzawi H, Al-Niami M. Bone marrow cellular elements and peripheral blood indices following acute hemorrhage and prostaglandin E2 treatment.Saudi Med J. 1983;4:236–242Google Scholar
  13. 13.
    Al-Azzawi H, Al-Waili N. Haemopoietic changes following chronic blood loss and PGE2 treatment, First Scientific Congress. Baghdad, Iraq: College of Medicine, University of Baghdad; 1984:109Google Scholar
  14. 14.
    Al-Azzawi H, Al-Waili N, Thewani A. The effects of PGAl on serum protein components during primary and secondary immune responses.J F Med Bagh. 1981;23:54–60Google Scholar
  15. 15.
    Al-Waili N. Three cases of nephrotic syndrome treated by indomethacin.J Pak Med Assoc. 1988;28:54–56Google Scholar
  16. 16.
    Al-Waili N. Oxidant stress: A common cause for diseases.ALSaha Wltab [in Arabic]. 2002;188:19–25Google Scholar
  17. 17.
    Smith C, Zhang Y, Koboldt C, Muhammad J, Zweifel B. Pharmacological analysis of cyclooxygenase-1 in inflammation.Pharmacology. 1998;95:13313–13318Google Scholar
  18. 18.
    Portanova P, Zhang Y, Andersson D, Hanser D. Selective neutralization of prostaglandin E2 blocks inflammation, hyperalgesia and interleukin 6 production in vivo.J Exp Med. 1996;186:883–891CrossRefGoogle Scholar
  19. 19.
    Basu S. Carbon tetrachloride-induced lipid peroxidation: eicosanoid formation and their regulation by antioxidant nutrients.Toxicology. 2003;189:113–127PubMedCrossRefGoogle Scholar
  20. 20.
    Chen L, Salafranca M, Mehat N. Cyclooxygenase inhibition decreases nitric oxide synthase activity in human platelets.Am J Physiol. 1997;273:H1854-H1859PubMedGoogle Scholar
  21. 21.
    DeGaetano C, Cerletti G, Dejana E, Latin R. Pharmacology of platelet inhibition in humans: implications of the salicylate-aspirin interaction.Circulation. 1985;72:1185–1193Google Scholar
  22. 22.
    Mehta J, Lawson L, Nichols W. Attenuated coronary relaxation after reperfusion: effects of superoxide dismutase and T×A2 inhibitor U-63557A.Am J Physiol. 1989;257:H1240-H1246PubMedGoogle Scholar
  23. 23.
    Schreiber J, Mason R, Eling T. Detection of glutathione free radical catalyzed by prostaglandin hydroperoxidase present in intact epidermal cells.Fed Proc Fed Am Soc Exp Biol. 1986;45:70–75Google Scholar
  24. 24.
    Montuschi P, Barnes PJ, Roberts LJ. Isoprostanes: markers and mediators of oxidative stress.FASEB J. 2004;18:1791–1800PubMedCrossRefGoogle Scholar
  25. 25.
    Mendelsohn J, Nordberg J. Adenylate cyclase in thymus-derived and bone marrow-derived lymphocytes from normal donors and patients with chronic lymphocytic leukemia.J Clin Invest. 1979;63:1124–1132PubMedCrossRefGoogle Scholar
  26. 26.
    Dunn CD. Prostaglandins and erythropoiesis: structure/action relationships and identification of the prostaglandin responsive cells.Blut. 1981;42:307–314PubMedCrossRefGoogle Scholar
  27. 27.
    Taniguchi S, Shibuya T, Harada M, Niho Y. Prostaglandin-mediated suppression of in vitro growth of erythroid progenitor cells.Kidney Int. 1989;36:712–718PubMedCrossRefGoogle Scholar
  28. 28.
    Fried W, Morley C, Barone-Varelas J, Bidani A, Prancan A. Effect of indomethacin and of prostaglandins on extrarenal erythropoietin production in rats.J Lab Clin Med. 1988;111:184–188PubMedGoogle Scholar
  29. 29.
    Gentile P, Byer D, Pelus L. In vivo modulation of murine myelopoiesis following intravenous administration of prostaglandin E2.Blood. 1983;62:1100–1107PubMedGoogle Scholar
  30. 30.
    Gentile P, Pelus L. In vivo modulation of myelopoiesis by prostaglandin E2. II. Inhibition of granulocyte-monocyte progenitor cell (CFU-GM) cell-cycle rate.Exp Hematol. 1987;15:119–126PubMedGoogle Scholar
  31. 31.
    Karim S, Raq B. Prostaglandins and tumors. In: Karim SMM, ed.Prostaglandins: Physiological, Pharmacological and Pathological Aspects. Lancaster: MTP Press; 1976:145–178Google Scholar
  32. 32.
    Bennett A, Berstock DA, Raja B. Survival time after surgery is inversely related to the amount of prostaglandin extracted from human breast.Br J Pharmacol. 1979;66:451–456Google Scholar
  33. 33.
    Bennett A, Charlier E, MacDonald A. Bone destruction by breast cancer.Prostaglandins. 1979;11:461–469CrossRefGoogle Scholar
  34. 34.
    Grinwich K, Plescia O. Tumor-mediated immunosuppression: prevention by inhibitors of prostaglandin synthesis.Prostaglandins. 1977;14:1175–1178PubMedCrossRefGoogle Scholar
  35. 35.
    Saito H, Tomioka H. Suppressive factor against macrophage phagocytosis produced by cultured sarcoma-180 cells.Gann. 1979;70:671–675PubMedGoogle Scholar
  36. 36.
    Ting CC, Rodrigues D, Ting RC, Wivel N, Collins MJ. Suppression of T cell-mediated immunity by tumor cells: immunogenicity versus immunosuppression and preliminary characterization of the suppressive factors.Int J Cancer. 1979;24:644–655PubMedCrossRefGoogle Scholar
  37. 37.
    Pelus L, Straussen H. Prostaglandins and the immune response.Life Sci. 1977;20:903–905PubMedCrossRefGoogle Scholar
  38. 38.
    Goodwin S, Webb D. Regulation of the immune response by prostaglandins.Clin Immunol Immunopathol. 1980;15:106–110PubMedCrossRefGoogle Scholar
  39. 39.
    Baker PE, Fahey JV, Munck A. Prostaglandin inhibition of T-cell proliferation is mediated at two levels.Cell Immunol. 1981;61:52–61PubMedCrossRefGoogle Scholar
  40. 40.
    Kato K, Askenase P. Reconstitution of an inactive antigen-specific T cell suppressor factor by incubation of the factor with prostaglandins.J Immunol. 1984;133:2025–2031PubMedGoogle Scholar
  41. 41.
    Goodwin S, Messner R, Peake G. Prostaglandin suppression of mitogen-stimulated lymphocytes in vitro.J Clin Invest. 1978;62:753–756PubMedCrossRefGoogle Scholar
  42. 42.
    Gordon D, Bray M, Morley J. Control of lymphokine secretion by prostaglandins.Nature. 1976;262:400–403CrossRefGoogle Scholar
  43. 43.
    Rappaport S, Dodge R. Prostaglandin E inhibits the production of human interleukin 2.J Exp Med. 1982;155:943–948PubMedCrossRefGoogle Scholar
  44. 44.
    Parhar R, Yagel S, Lala P. PGE2-mediated immunosuppression by first trimester human decidual cells blocks activation of maternal leukocytes in the decidua with potential anti-trophoblast activity.Cell Immunol. 1989;120:61–74PubMedCrossRefGoogle Scholar
  45. 45.
    Mannie MD, Prevost KD, Marinakis CA. Prostaglandin E2 promotes the induction of anergy during T helper cell recognition of myelin basic protein.Cell Immunol. 1995;160:132–138PubMedCrossRefGoogle Scholar
  46. 46.
    Thompson P, Jelinek D, Lipsky P. Regulation of human B cell proliferation by prostaglandin E2.J Immunol. 1984;133:2446–2453PubMedGoogle Scholar
  47. 47.
    Michelin M, Figueiredo F, Cunha F. Involvement of prostaglandins in the immunosuppression occurring during experimental infection by Paracoccidioides brasiliensis.Exp Parasitol. 2002;102:170–177PubMedGoogle Scholar
  48. 48.
    Webb D, Wieder K, Rogers T, Healy C, Nowowiejski-Wieder I. Chemical identification of a prostaglandin-induced T suppressor (PITS).Lymphokine Res. 1985;4:139–149PubMedGoogle Scholar
  49. 49.
    Brunda M, Herberman R, Holden H. Inhibition of murine natural killer cell activity by prostaglandins.J Immunol. 1980;124:2682–2687PubMedGoogle Scholar
  50. 50.
    Iberer F, Wasler A, Tscheliessnigg K, et al. Prostaglandin E1 reduces the frequency of rejection after heart transplantation.J Heart Lung Transplant. 1992;11(4 Pt 1):727–732PubMedGoogle Scholar
  51. 51.
    Alvarellos A, Lipsky P, Jasin H. Prostaglandin E2 modulation of rheumatoid factor synthesis.Arthritis Rheum. 1988;31:1473–1480PubMedCrossRefGoogle Scholar
  52. 52.
    Gualde N, Harizi H. Prostanoids and their receptors that modulate dendritic cell-mediated immunity.Immunol Cell Biol. 2004;82:353–360PubMedCrossRefGoogle Scholar
  53. 53.
    Hart P, Townley S, Grimbaldeston M, Khalil Z, Finlay-Jones J. Mast cells, neuropeptides, histamine, and prostaglandins in UV-induced systemic immunosuppression.Methods. 2002;28:79–89PubMedCrossRefGoogle Scholar
  54. 54.
    Josten C, Griga T, Muhr G. Immunostimulation with ibuprofen in chronic osteitis: an experimental study.Unfallchirurg. 1991;94:191–193PubMedGoogle Scholar
  55. 55.
    Kozlov V, Poveshchenko A, Gromykhina N. Some mechanisms involved in the prostaglandin E2 immunosuppressive effect in (CBA × C57BL) F1 mice in vivo.Cell Immunol. 1990;128:242–249PubMedCrossRefGoogle Scholar
  56. 56.
    Milch P, Salvatore W, Luft B, Baker D. Suppression of newborn natural killer cell activity by prostaglandin E2.Am J Obstet Gynecol. 1988;159:47–51Google Scholar
  57. 57.
    Moran M, Mozes M, Maddux M, et al. Prevention of acute graft rejection by the prostaglandin E1 analogue misoprostol in renal-transplant recipients treated with cyclosporine and prednisone.N Engl J Med. 1990;322:1183–1188PubMedCrossRefGoogle Scholar
  58. 58.
    Iyengar S, Contreras P, Mick S, Bremer M, McKearn J. Immune modifying effects of misoprostol and natural prostaglandins.Br J Rheumatol. 1991;30(suppl 2):71–74Google Scholar
  59. 59.
    Menger M, Vollmar B. Surgical trauma: hyperinflammation versus immunosuppression?Langenbecks Arch Surg. 2004;389:475–484PubMedCrossRefGoogle Scholar
  60. 60.
    Mackrell P, Daly J, Mestre J, et al. Elevated expression of cyclooxygenase-2 contributes to immune dysfunction in a murine model of trauma.Surgery. 2001;130:826–833PubMedCrossRefGoogle Scholar
  61. 61.
    Schaffer M, Barbul A. Lymphocyte function in wound healing and following injury.Br J Surg. 1998;85:444–460PubMedCrossRefGoogle Scholar
  62. 62.
    Ogawa K, Hirai M, Katsube T. Suppression of cellular immunity by surgical stress.Surgery. 2000;127:329–336PubMedCrossRefGoogle Scholar
  63. 63.
    Ben-Eliyahu S. The promotion of tumor metastasis by surgery and stress: immunological basis and implications for psychoneuroimmunology.Brain Behav Immun. 2003;17:S27-S36PubMedCrossRefGoogle Scholar
  64. 64.
    Ertel W, Morrison MH, Ayala A, Chaudry IH. Chloroquine attenuates hemorrhagic shock-induced immunosuppression and decreases susceptibility to sepsis.Arch Surg. 1992;127:70–75PubMedGoogle Scholar
  65. 65.
    Ross W, Leaver H, Yap P, et al. Macrophage prostaglandin E2 and oxidative responses to endotox-in during immunosuppression associated with anaesthesia and transfusion.Prostaglandins Leukot Essent Fatty Acids. 1993;49:945–953PubMedCrossRefGoogle Scholar
  66. 66.
    Shelby J, Hisatake G. Effect of ibuprofen and interleukin 2 on transfusion-induced suppression of cell-mediated immunity.Arch Surg. 1988;123:1397–1399PubMedGoogle Scholar
  67. 67.
    Asselin P, Benquet C, Krzystyniak K, Brousseau P, Savard R, Fournier M. In vivo indomethacin reverses exercise-induced immunosuppression in rats.Int J Immunopharmacol. 1996;18:491–497PubMedCrossRefGoogle Scholar
  68. 68.
    Shimazu S. Evaluation of immunosuppressive properties of fluid from healing wounds and influence of prostaglandins.Nippon Geka Gakkai Zasshi. 1987;88:1667–1675PubMedGoogle Scholar
  69. 69.
    Ozaki-Okayama Y, Matsumura K, Ibuki T, et al. Burn injury enhances brain prostaglandin E2 production through induction of cyclooxygenase-2 and microsomal prostaglandin E synthase in cerebral vascular endothelial cells in rats.Crit Care Med. 2004;32:795–800PubMedCrossRefGoogle Scholar
  70. 70.
    Schwacha MG, Chung CS, Ayala A, Bland KI, Chaudry IH. Cyclooxygenase 2-mediated suppression of macrophage interleukin-12 production after thermal injury.Am J Physiol Cell Physiol. 2002;282:C263-C270PubMedGoogle Scholar
  71. 71.
    Enkhbaatar P, Murakami K, Shimoda K, et al. Ketorolac attenuates cardiopulmonary derange-ments in sheep with combined burn and smoke inhalation injury.Clin Sci. 2003;105:621–628PubMedCrossRefGoogle Scholar
  72. 72.
    Santangelo S, Shoup M, Gamelli RL, Shankar R. Prostaglandin E2 receptor antagonist (SC-19220) treatment restores the balance to bone marrow myelopoiesis after burn sepsis.J Trauma. 2000;48:826–830PubMedGoogle Scholar
  73. 73.
    Shoup M, Weisenberger JM, Wang JL, Pyle JM, Gamelli RL, Shankar R. Mechanisms of neu-tropenia involving myeloid maturation arrest in burn sepsis.Ann Surg. 1998;228:112–122PubMedCrossRefGoogle Scholar
  74. 74.
    Gamelli RL, He LK, Liu H, Ricken JD. Burn wound infection-induced myeloid suppression: the role of prostaglandin E2, elevated adenylate cyclase, and cyclic adenosine monophosphate.J Trauma. 1998;44:469–474PubMedGoogle Scholar
  75. 75.
    Gamelli R, He L, Liu L. Macrophage mediated suppression of granulocyte and macrophage growth after burn wound infection reversal by means of anti-PGE2.J Burn Care Rehabil. 2000;21:64–69PubMedGoogle Scholar
  76. 76.
    Yamamoto H, Siltharm S, deSerres S, Hultman C, Meyer A. Effect of cyclo-oxygenase inhibition on in vitro B-cell function after burn injury.J Trauma. 1996;41:612–619PubMedGoogle Scholar
  77. 77.
    Latter D, Tchervenkov I, Nohr C, Christou N. The effect of indomethacin on burn-induced immunosuppression.J Surg Res. 1987;43:246–252PubMedCrossRefGoogle Scholar
  78. 78.
    Colacchio TA, Yeager P, Hildebrandt LW. Perioperative immunomodulation in cancer surgery.Am J Surg. 1994;167:174–179PubMedCrossRefGoogle Scholar
  79. 79.
    Knoferl MW, Diodato MD, Schwacha MG, Cioffi WG, Bland KI, Chaudry IH. Cyclooxygenase-2-mediated regulation of Kupffer cell interleukin-6 production following trauma—hemorrhage and subsequent sepsis.Shock. 2001;16:479–483PubMedGoogle Scholar
  80. 80.
    Gogos CA, Maroulis J, Zoumbos NC, Salsa B, Kalfarentzos F. The effect of parenteral indomethacin on T-lymphocyte subpopulations and cytokine production in patients under major surgical operations.Res Exp Med (Berl). 1995;195:85–92CrossRefGoogle Scholar
  81. 81.
    Hansbrough J, Zapata-Sirvent R, Shackford S, Hoyt D, Carter W. Immunomodulating drugs increase resistance against sepsis in traumatized mice.J Trauma. 1986;26:625–630PubMedGoogle Scholar
  82. 82.
    Al-Waili N, Butler G, Beale J, Hamilton R, Lee B, Lucas P. Hyperbaric oxygen and malignancies: a potential role in radiotherapy, chemotherapy, tumor surgery and phototherapy.Med Sci Monit. 2005;11:279–289Google Scholar
  83. 83.
    Al-Waili N. Medicine of balance and diseases triad: new concept and nomenclatures.FASEB J. 2003;17:453Google Scholar
  84. 84.
    Al-Waili N, Thewani A, Al-Azzawi H. The effects of PGA1 on antibody production: World Conference on Clinical Pharmacology and Therapeutics.London: XX; 1980:246Google Scholar
  85. 85.
    Al-Waili N, Thewani A, Al-Azzawi H. Prostaglandin A1 and antibody production.J F Med Bagh. 1981;23:32–35Google Scholar
  86. 86.
    Al-Waili N, Al-Azzawi H, Al-Rawi Z. Treatment of advanced chorionic carcinoma by indomethacin and steroids.Saudi Med J. 1984;5:81–86Google Scholar
  87. 87.
    Al-Waili N. Indomethacin in basal cell carcinoma.J Pak Med Assoc. 1989;39:134–136PubMedGoogle Scholar
  88. 88.
    Takit M, Inada M, Maruyama T, Miyaura C. Prostaglandin E receptor EP4 antagonist suppresses osteolysis due to bone metastasis of mouse malignant melanoma cells.FEBS Lett. 2007 Feb 6; 581(3):565–71CrossRefGoogle Scholar
  89. 89.
    Eisinger AL, Prescott SM, Jones DA, Stafforini DM. The role of cyclooxygenase-2 and prostaglandins in colon cancer.Prostaglandins Other Lipid Mediat. 2007;82:147–154PubMedCrossRefGoogle Scholar
  90. 90.
    Newman SJ, Mrkonjich L. Cyclooxygenase-2 expression in feline pancreatic adenocarcinomas.J Vet Diagn Invest. 2006 Nov;18(6):590–3PubMedGoogle Scholar
  91. 91.
    Piazuelo E, Jimenez P, Strunk M, Santander S, Garcia A, Esteva F, Lanas A. Effects of selective PGE2 receptor antagonists in esophageal adenocarcinoma cells derived from Barrett’s esophagus.Prostaglandins Other Lipid Mediat. 2006 Dec;81(3–4):150–61Google Scholar
  92. 92.
    Sandler A, Dubinett S. COX-2 inhibition and lung cancer.Semin Oncol. 2004;31(2 suppl 7):45–52CrossRefGoogle Scholar
  93. 93.
    Krishnan K, Brenner D. Prostaglandin inhibitors and the chemoprevention of noncolonic malignancy.Gastroenterol Clin North Am. 2001;30:981–1000PubMedCrossRefGoogle Scholar
  94. 94.
    Earnest DL, Hixson LJ, Alberts DS. Piroxicam and other cyclooxygenase inhibitors: potential for cancer chemoprevention.J Cell Biochem Suppl. 1992;161:156–166CrossRefGoogle Scholar
  95. 95.
    Arun B, Goss P. The role of COX-2 inhibition in breast cancer treatment and prevention.Semin Oncol. 2004;31(2 suppl 7):22–29.PubMedCrossRefGoogle Scholar
  96. 96.
    Ishihara S, Rumi MA, Okuyama T, Kinoshita Y. Effect of prostaglandins on the regulation of tumor growth.Curr Med Chem Anticancer Agents. 2004;4:379–387.PubMedCrossRefGoogle Scholar
  97. 97.
    Toshihiko K, Naoaki U, Seiichi N, et al. Chemopreventive effects of ONO-8711, a selective prostaglandin E receptor EP1 antagonist, on breast cancer development.Carcinogenesis. 2001;22:2001–2004.CrossRefGoogle Scholar
  98. 98.
    Ding X, Tong W, Adrian T. Cyclooxygenases and lipoxygenase as potential targets for treatment of pancreatic cancer.Pancreatology. 2001;1:291–299.PubMedCrossRefGoogle Scholar
  99. 99.
    Lieb J. Antidepressants, eicosanoids and the prevention and treatment of cancer: a review.Prostaglandins Leukot Essent Fatty Acids. 2001;65:233–239.PubMedCrossRefGoogle Scholar
  100. 100.
    Choy H, Milas L. Enhancing radiotherapy with cyclooxygenase-2 enzyme inhibitors: a rational advance?J Natl Cancer Inst. 2003;95:1440–1452.PubMedGoogle Scholar
  101. 101.
    Rodrigues S, Bruyneel E, Rodrigues CM, Shahin E, Gespach C. Cyclooxygenase 2 and carcinogenesis.Bull Cancer. 2004;91(suppl 2):S61-S76.Google Scholar
  102. 102.
    Pockaj B, Basu G, Pathangey L, et al. Reduced T-cell and dendritic cell function is related to cyclooxygenase-2 overexpression and prostaglandin E2 secretion in patients with breast cancer.Ann Surg Oncol. 2004;11:328–339.PubMedCrossRefGoogle Scholar
  103. 103.
    Pawelec G, Zeuthen J, Kiessling R. Escape from host-antitumor immunity.Crit Rev Oncog. 1997;8:111–141.PubMedGoogle Scholar
  104. 104.
    Hellstrom K, Hellstrom I. Novel approaches to therapeutic cancer vaccines.Expert Rev Vaccines. 2003;2:517–532.PubMedCrossRefGoogle Scholar
  105. 105.
    Foss F. Immunologic mechanisms of antitumor activity.Semin Oncol. 2002;29(3 suppl 7):5–11.CrossRefGoogle Scholar
  106. 106.
    Kim S, Iizuka K, Aguila H. In vivo natural killer cell activities revealed by natural killer cell-deficient mice.Proc Natl Acad Sci USA. 2000;97:2731–2736.PubMedCrossRefGoogle Scholar
  107. 107.
    Lanier L. On guard-activating NK cell receptors.Nat Immunol. 2001;2:23–27.PubMedCrossRefGoogle Scholar
  108. 108.
    Botti C, Seregni E, Ferrari L, Martinetti A, Bombardieri E. Immunosuppressive factors: role in cancer development and progression.Int J Biol Markers. 1998;13:51–69.PubMedGoogle Scholar
  109. 109.
    Paul S, Calmels B, Regulier E. Tumor-induced immunosuppression.Ann Biol Clin (Paris). 2002;60:143–512.Google Scholar
  110. 110.
    Garcia-Lora A, Algarra I, Garrido F. MHC class I antigens, immune surveillance, and tumor immune escape.J Cell Physiol. 2003;195:346–355.PubMedCrossRefGoogle Scholar
  111. 111.
    Ohm JE, Carbone DP. Immune dysfunction in cancer patients.Oncology (Williston Park). 2002;16(1 suppl 1):11–18.Google Scholar
  112. 112.
    al-Sarireh B, Eremin O. Tumor-associated macrophages (TAMS): disordered function, immune suppression and progressive tumor growth.J R Coll Surg Edinb. 2000;45:1–16.PubMedGoogle Scholar
  113. 113.
    Bronte V, Serafini P, Apolloni E, Zanovello P. Tumor-induced immune dysfunctions caused by myeloid suppressor cells.J Immunother. 2001;24:431–446.PubMedCrossRefGoogle Scholar
  114. 114.
    Alleva D, Burger C, Elgert K. Tumor growth causes suppression of autoreactive T-cell proliferation by disrupting macrophage responsiveness to interferon-gamma.Scand J Immunol. 1994;39:31–38.PubMedCrossRefGoogle Scholar
  115. 115.
    Loh JK, Hwang SL, Lieu AS, Huang TY, Howng SL. The alteration of prostaglandin E2 levels in patients with brain tumors before and after tumor removal.J Neurooncol. 2002;57:147–150.PubMedCrossRefGoogle Scholar
  116. 116.
    Dix A, Brooks W, Roszman T, Morford L. Immune defects observed in patients with primary malignant brain tumors.J Neuroimmunol. 1999;100:216–232.PubMedCrossRefGoogle Scholar
  117. 117.
    Yurochko A, Burger C, Elgert K. Tumor modulation of autoreactivity: decreased macrophage and autoreactive T cell interactions.Cell Immunol. 1990;127:105–119.PubMedCrossRefGoogle Scholar
  118. 118.
    Stanojevic-Bakic N, Vuckovic-Dekic L, Susnjar S, Spuzic I. In vitro effect of indomethacin on mitogen-induced lymphoproliferative response in lung cancer patients.Neoplasma. 1992;39:129–132.PubMedGoogle Scholar
  119. 119.
    Nakajima I, Chu T. Prostaglandin E2-mediated suppression of murine lymphokine-activated killer cell activity generated from tumor-bearing hosts by interferon-gamma.Mol Biother. 1990;2:228–232.PubMedGoogle Scholar
  120. 120.
    Sombroek C, Stam A, Masterson A, et al. Prostanoids play a major role in the primary tumor-induced inhibition of dendritic cell differentiation.J Immunol. 2002;168:4333–4343.PubMedGoogle Scholar
  121. 121.
    Kalmar L, Gyires K, Gergely P. Inhibitory effect of tumor cells on leukocyte motility.Immunol Lett. 1984;8:175–177.PubMedCrossRefGoogle Scholar
  122. 122.
    Tisdale M. Role of prostaglandins in metastatic dissemination of cancer: minireview on cancer research.Exp Cell Biol. 1983;51:250–256.Google Scholar
  123. 123.
    DeGowin R, Gibson DP, Knapp SA. Prostaglandin E and the erythropoietic and stromal insufficiency induced by extramedullary tumor.J Lab Clin Med. 1981;98:217–226.PubMedGoogle Scholar
  124. 124.
    Plescia OJ, Pontieri GM, Brown J, et al. Amplification by macrophages of prostaglandin-mediated immunosuppression in mice bearing syngeneic tumors.Prostaglandins Leukot Med. 1984;16:205–223.PubMedCrossRefGoogle Scholar
  125. 125.
    DeGowin R, Gibson D, Knapp S, Wathen L. Tumor-induced suppression of marrow stromal colonies.Exp Hematol. 1981;9:811–819.PubMedGoogle Scholar
  126. 126.
    Monnerat C, Leyvraz S. Tumor anemia: overview of the role of human recombinant erythropoietin (r-hu-EPO) in treatment of tumor anemia.Schweiz Rundsch Med Prax. 1999;88:178–188.PubMedGoogle Scholar
  127. 127.
    Manegold C. The causes and prognostic significance of low hemoglobin levels in tumor patients.Strahlenther Onkol. 1998;174(suppl 4):17–19.Google Scholar
  128. 128.
    Birgegard G, Aapro MS, Bokemeyer C, et al. Cancer-related anemia: pathogenesis, prevalence and treatment.Oncology. 2005;68(suppl 1):3–11.PubMedCrossRefGoogle Scholar
  129. 129.
    Bron D, Meuleman N, Mascaux C. Biological basis of anemia.Semin Oncol. 2001;28(2 suppl 8):1–6.PubMedCrossRefGoogle Scholar
  130. 130.
    Al-Waili N. Treatment of primary nocturnal enuresis by diclofenac sodium: double blind crossover study.Clin Exp Pharma Physiol. 1988;12:139–142.Google Scholar
  131. 131.
    Al-Waili N. Indomethacin suppositories: an alternative treatment for nocturnal frequency of micturition.IRCS Med Sci. 1986;14:322–323.Google Scholar
  132. 132.
    Al-Waili N. Indomethacin suppositories in the treatment of primary nocturnal enuresis: double-blind study.J Urol. 1988;142:1290–1292.Google Scholar
  133. 133.
    Al-Waili N. Increased urinary nitrite excretion in primary enuresis: effects of indomethacin treatment on urinary and serum osmolality and electrolytes, urinary volumes and nitrite excretion.BJU Int. 2002;90:295–301.CrossRefGoogle Scholar
  134. 134.
    Al-Waili N, Al-Waili T, Al-Waili A, Saloom K. Urinary nitrite excretion and urinary variables in patients with primary nocturnal frequency of micturition: effects of indomethacin.World J Urol. 2005;24:1–8.Google Scholar
  135. 135.
    Al-Waili N. Carbamazepine to treat primary nocturnal enuresis: double-blind study.Eur J Med Res. 2000;5:40–44.PubMedGoogle Scholar
  136. 136.
    Al-Waili NS, Al-Waili H, Saloom KY, et al. Effect of carbamazepine on urinary volume and osmolality, water clearance, and serum osmolality in patients with primary enuresis.Eur Urol. 2006;50:844–849.PubMedCrossRefGoogle Scholar
  137. 137.
    Al-Waili N. Prostaglandin synthesis inhibition with indomethacin rectal suppositories in the treatment of acute and chronic urinary calculus obstruction.Clin Exp Pharm Physiol. 1986;13:195–199.CrossRefGoogle Scholar
  138. 138.
    Al-Waili N. Clinical usefulness of nifedipine in the treatment of acute and chronic urinary colic.Med Sci Res. 1989;16:567–568.Google Scholar
  139. 139.
    Al-Waili NS. Intramuscular tenoxicam to treat acute renal colic.Br J Urol. 1996;77:15–16.PubMedGoogle Scholar
  140. 140.
    Al-Waili N., Saloom K. Intramuscular piroxicam to treat acute renal colic: comparison with intramuscular diclofenac sodium.Eur J Med Res. 1999;4:23–27.PubMedGoogle Scholar
  141. 141.
    Al-Waili N., Saloom K. Intravenous tenoxicam to treat acute renal colic: comparison with antispasmodics.J Pak Med Assoc. 1998;48:370–372.PubMedGoogle Scholar
  142. 142.
    Al-Waili N. Sublingual meloxicam for renal colic.Urol Int. 2001;67:119–120.CrossRefGoogle Scholar
  143. 143.
    Al-Waili N. Diclofenac sodium in intractable epilepsy.Acta Neurol Scand. 1987;73:507.Google Scholar
  144. 144.
    Al-Waili N. Two cases of psoriasis and high doses of indomethacin.Emir Med J. 1987;5:61–65.Google Scholar
  145. 145.
    Al-Waili N, Khalaf Z. Indomethacin suppositories in primary dymenorrhoea: double-blind crossover study.Ind J Med Res. 1990;92:298–301.Google Scholar
  146. 146.
    Al-Waili N. Intramuscular tenoxicam to treat primary dysmenorrhoea: double-blind study.Curr Opin Clin Exp Res. 2001;3:108–120.Google Scholar
  147. 147.
    Al-Waili N, Saloom K. The analgesic effects of intravenous tenoxicam in acute biliary colic: comparison with hyposcine N-butylbromide.Eur J Med Res. 1998;3:457–461.Google Scholar
  148. 148.
    Al-Waili N. Treatment of menstrual migraine with prostaglandin synthesis inhibitor mefenamic acid:double-blind study with placebo.Eur J Med Res. 2000;5:176–182.PubMedGoogle Scholar
  149. 149.
    Al-Waili N. Efficacy and safety of repeated intramuscular injection of diclofenac sodium in the treatment of postcaesarean section pain: double-blind study.Arch Med Res. 2001;32:148–154.PubMedCrossRefGoogle Scholar
  150. 150.
    Al-Waili N. Indomethacin suppositories for premature uterine contraction.FASEB J. 2001;15:235.Google Scholar
  151. 151.
    Saloom K, Al-Waili N. Intramuscular salicylate to treat acute migraine attacks: double-blind placebo controlled study.FASEB J. 2001;15:905.Google Scholar
  152. 152.
    Saloom K, Al-Waili N. Tenoxicam as an alternative to pethidine for postoperative pain.Pharmacol Toxicol. 2001;89(suppl 1):134.Google Scholar
  153. 153.
    Al-Waili N. Diclofenac to treat post-operative pain. Presented at: 30th Arab Medical Union Conference; July 15–17, 1997; Sanaa, Yemen.Google Scholar
  154. 154.
    Sharma S. An update on eicosanoids and inhibitors of cyclooxygenase enzyme system.Ind J Expl Biol. 1997;35:1025–1031.Google Scholar
  155. 155.
    Altman D. Neutrophil activation: an alternative to prostaglandin inhibition as the mechanism of action for NSAIDs.Semin Arthritis Rheum. 1990;19(4 suppl 2):1–5.Google Scholar
  156. 156.
    Ikeda Y, Matsumato K, Dohi K, Jimbo H, Sasaki K, Satoh K. Direct superoxide scavenging activity of nonsteroidal anti-inflammatory drugs: determination by electron spin resonance using spin trap method.Headache. 2001;41:138–144.PubMedCrossRefGoogle Scholar
  157. 157.
    Masue T, Dohi S, Asano T, Shimonatka H. Spinal antinociceptive effect of epidural nonsteroidal antiinflammatory drugs on nitric oxide-induced hyperalgesia in rat.Anesthesiology. 1999;91:198–206.PubMedCrossRefGoogle Scholar
  158. 158.
    Kankaanranta H, Moilanen E, Vapaatalo H. Effects of non-steroidal anti-inflammatory drugs on polymorphonuclear leukocyte function in vitro: focus on fenamates.Naunyn Schmiedebergs Arch Pharmacol. 1994;350:685–691.PubMedCrossRefGoogle Scholar
  159. 159.
    Gregorian S, Battisto J. Immunosuppression in murine renal cell carcinoma. II. Identification of responsible lymphoid cell phenotypes and examination of elimination of suppression.Cancer Immunol Immunother. 1990;31:335–341.PubMedCrossRefGoogle Scholar
  160. 160.
    Manning LS, Bowman RV, Davis MR, Musk AW, Robinson BW. Indomethacin augments lymphokine-activated killer cell generation by patients with malignant mesothelioma.Clin Immunol Immunopathol. 1989;53:68–77.PubMedCrossRefGoogle Scholar
  161. 161.
    Wasserman J, Blomgren H, Rotstein S, Petrini B, Hammarstrom S. Immunosuppression in irradiated breast cancer patients: in vitro effect of cyclooxygenase inhibitors.Bull N Y Acad Med 1989;65:36–44.PubMedGoogle Scholar
  162. 162.
    Wang Z, Chen Y, Zheng R, et al. In vitro effects of prostaglandin E2 or indomethacin on the proliferation of lymphokine-activated killer cells and their cytotoxicity against bladder tumor cells in patients with bladder cancer.Prostaglandins. 1997;54:769–779.PubMedCrossRefGoogle Scholar
  163. 163.
    Bennett A, Berstock D, Carrol M. Enhanced anticancer effects by combining cytotoxic drugs with the prostaglandin synthesis inhibitor flurbiprofen.Br J Pharmacol. 1981;74:208P-212P.Google Scholar
  164. 164.
    Brown J, DuBois R. COX-2: a molecular target for colorectal cancer prevention.J Clin Oncol. 2005;23:2840–2855.PubMedCrossRefGoogle Scholar
  165. 165.
    Kinoshita T. Growth stimulation and induction of epidermal growth factor receptor by overexpression of cyclooxygenases 1 and 2 in human colon carcinoma cells.Biochim Biophys Acta. 1999;1438:120–130.PubMedGoogle Scholar
  166. 166.
    Kawamura T. Prostaglandin E1 transported into cells blocks the apoptotic signals induced by nerve growth factor deprivation.J Neurochem. 1999;72:1907–1914.PubMedCrossRefGoogle Scholar
  167. 167.
    Liu X, Yao S, Kirschenbaum A, Levine A. NS398, a selective cyclooxygenase-2 inhibitor, induces apoptosis and down-regulates bcl-2 expression in LNCaP cells.Cancer Res. 1998;58:4245–4249.PubMedGoogle Scholar
  168. 168.
    Oshima M, Dinchuk JE, Kargman SL, et al. Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2).Cell. 1996;87:803–809.PubMedCrossRefGoogle Scholar
  169. 169.
    Steinbach G, Lynch PM, Phillips RK, et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis.N Engl J Med. 2000;342:1946–1952.PubMedCrossRefGoogle Scholar
  170. 170.
    Rahme E, Barkun AN, Toubouti Y, Bardou M. The cyclooxygenase-2-selective inhibitors rofecoxib and celecoxib prevent colorectal neoplasia occurrence and recurrence.Gastroenterology. 2003;125:404–412.PubMedCrossRefGoogle Scholar
  171. 171.
    Bardou M, Barkun AN, Ghosn J, Hudson M, Rahme E. Effect of chronic intake of NSAIDs and cyclooxygenase 2-selective inhibitors on esophageal cancer incidence.Clin Gastroenterol Hepatol. 2004;2:880–884.PubMedCrossRefGoogle Scholar
  172. 172.
    Morgan G, Vainio H. Barrett’s esophagus, esophageal cancer and colon cancer: an explanation of the association and cancer chemopreventive potential of non-steroidal anti-inflammatory drugs.Eur J Cancer Prev. 1998;7:195–199.PubMedCrossRefGoogle Scholar
  173. 173.
    Jiang X, Wong B. Cyclooxygenase-2 inhibition and gastric cancer.Curr Pharm Des. 2003;9:2281–2288.PubMedCrossRefGoogle Scholar
  174. 174.
    Piazuelo E, Jimenez P, Lanas A. COX-2 inhibition in esophagitis, Barrett’s esophagus and esophageal cancer.Curr Pharm Des. 2003;9:2267–2280.PubMedCrossRefGoogle Scholar
  175. 175.
    Ahnen D. Colon cancer prevention by NSAIDs: what is the mechanism of action.Eur J Surg Suppl. 1998;582:111–114.PubMedCrossRefGoogle Scholar
  176. 176.
    Terry MB, Gammon MD, Zhang FF, et al. Association of frequency and duration of aspirin use and hormone receptor status with breast cancer risk.JAMA. 2004;291:2433–2440.PubMedCrossRefGoogle Scholar
  177. 177.
    Rao C, Reddy B. NSAIDs and chemoprevention.Curr Cancer Drug Targets. 2004;4:29–42.PubMedCrossRefGoogle Scholar
  178. 178.
    Boorman GA, Luster MI, Dean JH, Luebke RW. Effect of indomethacin on the bone marrow and immune system of the mouse.J Clin Lab Immunol. 1982;7:119–126.PubMedGoogle Scholar
  179. 179.
    O’Reilly M, Gamelli RL. Indomethacin augments granulocyte-macrophage colony-stimulating factor-induced hematopoiesis following 5-FU treatment.Exp Hematol. 1990;18:974–978.PubMedGoogle Scholar
  180. 180.
    Pelus L. Blockade of prostaglandin biosynthesis in intact mice dramatically augments the expansion of committed myeloid progenitor cells (colony-forming units-granulocyte, macrophage) after acute administration of recombinant human IL-1 alpha.J Immunol. 1989;143:4171–4179.PubMedGoogle Scholar
  181. 181.
    Akarca US. Gastrointestinal effects of selective and non-selective non-steroidal anti-inflammatory drugs.Curr Pharm Des. 2005;11:1779–1793.PubMedCrossRefGoogle Scholar
  182. 182.
    Steen KS, Lems WF, Dijkmans BA. Effectiveness, safety, and costs of measures for prevention of gastropathy due to the use of nonsteroidal antiinflammatory drugs.Ned Tijdschr Geneeskd. 1999;143:1649–1652.PubMedGoogle Scholar
  183. 183.
    Davies NM. Toxicity of nonsteroidal anti-inflammatory drugs in the large intestine.Dis Colon Rectum. 1995;38:1311–1321.PubMedCrossRefGoogle Scholar
  184. 184.
    Sulowicz W, Stompor T, Tabor B. Nonsteroidal anti-inflammatory drugs—nephrotoxic mechanism of action.Przegl Lek. 1999;56:169–174.PubMedGoogle Scholar
  185. 185.
    Frishman W. Effects of nonsteroidal anti-inflammatory drug therapy on blood pressure and peripheral edema.Am J Cardiol. 2002;89:18D-25D.PubMedCrossRefGoogle Scholar
  186. 186.
    Ostensen ME, Skomsvoll JF. Anti-inflammatory pharmacotherapy during pregnancy.Expert Opin Pharmacother. 2004;5:571–580.PubMedCrossRefGoogle Scholar
  187. 187.
    Bannwarth B, Berenbaum F. New nonsteroidal anti-inflammatory agents: nitric oxide donors and selective cyclooxygenase-2 inhibitors.Rev Med Interne. 1999;20(suppl 3):341s-345s.CrossRefGoogle Scholar
  188. 188.
    Wong S, Mitsumasa F, Melnyk P, Rodger I, Giaid A. Induction of cyclooxygenase-2 and activation of nuclear factor-kB in myocardium of patients with congestive heart failure.Circulation. 1988;98:100–103.Google Scholar
  189. 189.
    Yang X, Ma N, Szabolcs MJ, et al. Upregulation of COX-2 during cardiac allograft rejection.Circulation. 2000;101:430–438.PubMedGoogle Scholar
  190. 190.
    Moncada S, Higgs J, Vane J. Human arterial and venous tissues generate prostacyclin (prostaglandin x), a potent inhibitor of platelet aggregation.Lancet. 1977;1:18–20.PubMedCrossRefGoogle Scholar
  191. 191.
    McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S, Lawson JA, Fitzgerald GA. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2.Proc Natl Acad Sci USA. 1999;96:272–277.PubMedCrossRefGoogle Scholar
  192. 192.
    Catella-Lawson F, McAdam B, Morrison BW, et al. Effects of specific inhibition of cyclooxygenase-2 on sodium balance, hemodynamics, and vasoactive eicosanoids.J Pharmacol Exp Ther. 1999;289:735–741.PubMedGoogle Scholar
  193. 193.
    Hennan JK, Huang J, Barrett TD, et al. Effects of selective cyclooxygenase-2 inhibition on vascu-lar responses and thrombosis in canine coronary arteries.Circulation. 2001;104:820–825.PubMedCrossRefGoogle Scholar
  194. 194.
    Pidgeon GP, Tamosiuniene R, Chen G, et al. Intravascular thrombosis after hypoxia-induced pulmonary hypertension: regulation by cyclooxygenase-2.Circulation. 2004;110:2701–2707.PubMedCrossRefGoogle Scholar
  195. 195.
    Bombardier C, Laine L, Reicin A. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis.N Engl J Med. 2000;343:1520–1528.PubMedCrossRefGoogle Scholar
  196. 196.
    Mukherjee D, Nissen SE, Topol RJ. Risk of cardiovascular events associated with selective COX-2 inhibitors.JAMA. 2001;286:954–959.PubMedCrossRefGoogle Scholar
  197. 197.
    Konstam MA, Weir MR, Reicin A. Cardiovascular thrombotic events in controlled, clinical trials of rofecoxib.Circulation. 2001;104:2280–2288.PubMedCrossRefGoogle Scholar
  198. 198.
    Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials.BMJ. 2006;332:1302–1308.PubMedCrossRefGoogle Scholar
  199. 199.
    Wong M, Chowienczyk P, Kirkham B. Cardiovascular issues of COX-2 inhibitors and NSAIDs.Aust Fam Physician. 2005;34:945–948.PubMedGoogle Scholar
  200. 200.
    Andersohn F, Suissa S, Garbe E. Use of first- and second-generation cyclooxygenase-2-selective nonsteroidal antiinflammatory drugs and risk of acute myocardial infarction.Circulation. 2006;113:1950–1957.PubMedCrossRefGoogle Scholar
  201. 201.
    Reikvam A, Hexeberg S, Kvien TK, et al. Clinical use of COX inhibitors—a consensus.Tidsskr Nor Laegeforen. 2006;126:591–595.PubMedGoogle Scholar
  202. 202.
    Caldwell B, Aldington S, Weatherall M, Shirtcliffe P, Beasley R. Risk of cardiovascular events and celecoxib: a systematic review and meta-analysis.J R Soc Med. 2006;99:132–140.PubMedCrossRefGoogle Scholar
  203. 203.
    Solomon SD, McMurray JJ, Pfeffer MA, Adenoma Prevention With Celecoxib (APC) Study Investigators. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention.N Engl J Med. 2005;352:1071–1080.PubMedCrossRefGoogle Scholar
  204. 204.
    Ott E, Nussmeier NA, Duke PCl. Efficacy and safety of the cyclooxygenase 2 inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery.J Thorac Cardiovasc Surg. 2003;125:1481–1492.PubMedCrossRefGoogle Scholar
  205. 205.
    Nussmeier NA, Whelton AA, Brown MT, et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery.N Engl J Med. 2005;352:1081–1091.PubMedCrossRefGoogle Scholar
  206. 206.
    Jüni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis.Lancet. 2004;364:2021–2029.PubMedCrossRefGoogle Scholar
  207. 207.
    Cheng Y, Austin SC, Rocca B, et al. Role of prostacyclin in the cardiovascular response to thromboxane A2.Science. 2002;296:539–541.PubMedCrossRefGoogle Scholar
  208. 208.
    Altman R, Luciardi HL, Muntaner J, et al. Efficacy assessment of meloxicam, a preferential cyclooxygenase-2 inhibitor, in acute coronary syndromes without ST-segment elevation: the Nonsteroidal Anti-inflammatory Drugs in Unstable Angina Treatment-2 (NUT-2) pilot study.Circulation. 2002;106:191–195.PubMedCrossRefGoogle Scholar
  209. 209.
    Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study:pp a randomized controlled trial.JAMA. 2000;284:1247–1255.PubMedCrossRefGoogle Scholar
  210. 210.
    Solomon DH, Glynn RJ, Levin R. Nonsteroidal anti-inflammatory drug use and acute myocardial infarction.Arch Intern Med. 2002;162:1099–1104.PubMedCrossRefGoogle Scholar
  211. 211.
    Rahme E, Pilote L, LeLorier J. Association between naproxen use and protection against acute myocardial infarction.Arch Intern Med. 2002;162:1111–1115.PubMedCrossRefGoogle Scholar
  212. 212.
    Hawkey CJ, Hawkey GM, Everitt S, Skelly MM, Stack WA, Gray D. Increased risk of myocardial infarction as first manifestation of ischemic heart disease and nonselective nonsteroidal anti-inflammatory drugs.Br J Clin Pharmacol. 2006;61:730–737.PubMedCrossRefGoogle Scholar
  213. 213.
    Fiorucci S, Antonelli E. NO-NSAIDs: from inflammatory mediators to clinical readouts.Inflamm Allergy Drug Targets. 2006;5:121–131.PubMedGoogle Scholar
  214. 214.
    Muscara MN, Wallace JL. COX-inhibiting nitric oxide donors (CINODs): potential benefits on cardiovascular and renal function.Cardiovasc Hematol Agents Med Chem. 2006;4:155–164.PubMedGoogle Scholar
  215. 215.
    Turnbull CM, Cena C, Fruttero R, Gasco A, Rossi AG, Megson IL. Mechanism of action of novel NO-releasing furoxan derivatives of aspirin in human platelets.Br J Pharmacol. 2006;148:517–526.PubMedCrossRefGoogle Scholar
  216. 216.
    Rigas B, Kalofonos H, Lebovics E, Vagenakis AG. NO-NSAIDs and cancer: promising novel agents.Dig Liver Dis. 2003;35(suppl 2):S27-S34.CrossRefGoogle Scholar
  217. 217.
    Ouyang N, Williams JL, Tsioulias GJ, et al. Nitric oxide-donating aspirin prevents pancreatic cancer in a hamster tumor model.Cancer Res. 2006;66:4503–4511.PubMedCrossRefGoogle Scholar
  218. 218.
    Rigas B, Kashfi K. Nitric-oxide-donating NSAIDs as agents for cancer prevention.Trends Mol Med. 2004;10:324–330.PubMedCrossRefGoogle Scholar
  219. 219.
    Al-Waili N. Oxidants and antioxidants in breast cancer: possible tumor marker.FASEB J. 2003;17:861.Google Scholar
  220. 220.
    Al-Waili N, Boni N. Natural honey lowers plasma prostaglandin concentrations in normal individuals.J Med Food. 2003;6:129–133.PubMedCrossRefGoogle Scholar
  221. 221.
    Al-Waili N. Effect of honey on urinary prostaglandin and total nitrite.Int Nephrol Urol. 2005;37:107–111.CrossRefGoogle Scholar
  222. 222.
    Al-Waili NS, Boni NS. Honey increased saliva, plasma, and urine content of total nitrite concentrations in normal individuals.J Med Food. 2004;7:377–380.PubMedCrossRefGoogle Scholar
  223. 223.
    Al-Waili N. Identification of nitric oxide metabolites in various honeys and effect of honey on plasma and urinary nitrite/nitrate concentrations.J Med Food. 2003;6:359–364.PubMedCrossRefGoogle Scholar
  224. 224.
    Al-Waili N, Boni N. Increased nitric oxide production in saliva by natural honey.FASEB J. 2003;17:546.Google Scholar
  225. 225.
    Al-Waili N. Topical honey application vs. acyclovir for the treatment of recurrent herpes simplex lesions.Med Sci Monit. 2004;10:94–98.Google Scholar
  226. 226.
    Al-Waili N, Saloom K. Honey to treat post-operative wound infections due to gram-positive and gram-negative bacteria following caesarian section and hysterectomies.Eur J Med Res. 1999;4:126–130.PubMedGoogle Scholar
  227. 227.
    Al-Waili NS. Therapeutic and prophylactic effects of crude honey on chronic seborrheic dermatitis and dandruff.Eur J Med Res. 2001;6:306–308.PubMedGoogle Scholar
  228. 228.
    Al-Waili N. Topical application of natural honey, beeswax and olive oil mixture to treat patients with atopic dermatitis or psoriasis.Compl Ther Med. 2003;11:226–234.CrossRefGoogle Scholar
  229. 229.
    Al-Waili N. Honey mixture with olive oil and beeswax for diaper dermatitis.Clin Microb Inf. 2005;11:160–163.CrossRefGoogle Scholar
  230. 230.
    Al-Waili NS, Haq A. Effect of honey on antibody production against thymus-dependent and thymus-independent antigens in primary and secondary immune responses.J Med Food. 2004;7:491–494.PubMedCrossRefGoogle Scholar
  231. 231.
    Al-Waili N. Investigating the antimicrobial activity of natural honey and its effects on the pathogenic bacterial infections of surgical wounds and conjunctiva.J Med Food. 2004;7:210–222.PubMedCrossRefGoogle Scholar
  232. 232.
    Al-Waili N. Effect of natural honey on chronic hepatitis B infection: case report.FASEB J. 2004;18:381.Google Scholar
  233. 233.
    Al-Waili S, Al-Waili T, Al-Waili A, Saloom K. Influence of natural honey on biochemical and hematological variables in AIDS: a case study.TSW Holistic Health Med. 2006;1:21–25.CrossRefGoogle Scholar
  234. 234.
    Al-Waili N, Saloom K, Al-Waili T, Al-Waili A. The safety and efficacy of a mixture of honey, olive oil and beeswax for the management of hemorrhoids and anal fissure: a pilot study.TSW Holistic Health Med. 2006;1:26–33.CrossRefGoogle Scholar
  235. 235.
    Al-Waili NS, Akmal M, Al-Waili FS, Saloom KY, Ali A. The antimicrobial potential of honey from United Arab Emirates on some microbial isolates.Med Sci Monit. 2005;11:433–438.Google Scholar
  236. 236.
    Al-Waili N, Saloom K, Al-Waili T, et al. Influence of various diet regimens on deterioration of hepatic function and hematological parameters following carbon tetrachloride: a potential protective role of natural honey.Nat Food Product. 2006;20):1258–64Google Scholar
  237. 237.
    Al-Waili N, Saloom K, Al-Waili T, et al. Honey ameliorates influences of hemorrhage and carbon tetrachloride administration on renal and hepatic functions, and hematological and biochemical variables.Int J Food Res Nutr. 2006;57:353–62CrossRefGoogle Scholar
  238. 238.
    Malone W, Kelloff G, Pierson H, Greenwald P. Chemoprevention of bladder cancer.Cancer. 1987;60(3 suppl):650–657.PubMedCrossRefGoogle Scholar
  239. 239.
    Garay CA, Engstrom PF. Chemoprevention of colorectal cancer: dietary and pharmacologic approaches.Oncology (Williston Park). 1999;13:89–97.Google Scholar
  240. 240.
    el-Attar TM, Lin HS. In vitro inhibition of prostaglandin biosynthesis in squamous cell carcinoma by retinoids.Eicosanoids. 1990;3:95–98.Google Scholar
  241. 241.
    Fylaktakidou KC, Hadjipavlou-Litina DJ, Litinas KE, Nicolaides DN. Natural and synthetic coumarin derivatives with anti-inflammatory/antioxidant activities.Curr Pharm Des. 2004;10:3813–3833.PubMedCrossRefGoogle Scholar
  242. 242.
    Nakahata N, Kyo R, Kutsuwa M, Ohizumi Y. Inhibition of mitogen-activated protein kinase cas-cade by baicalein, a flavonoid of natural origin.Nippon Yakurigaku Zasshi. 1999;114(suppl 1):215P-219P.PubMedGoogle Scholar
  243. 243.
    Park EJ, Min HY, Ahn YH, Bae CM, Pyee JH, Lee SK. Synthesis and inhibitory effects of pinosylvin derivatives on prostaglandin E2 production in lipopolysaccharide-induced mouse macrophage cells.Bioorg Med Chem Lett. 2004;14:5895–5898.PubMedCrossRefGoogle Scholar
  244. 244.
    Gerhauser C, Alt A, Heiss E, et al. Cancer chemopreventive activity of Xanthohumol, a natural product derived from hop.Mol Cancer Ther. 2002;1:959–969.PubMedGoogle Scholar
  245. 245.
    Cho H, Yun CW, Park WK, et al. Modulation of the activity of pro-inflammatory enzymes, COX-2 and iNOS, by chrysene derivatives.Pharmacol Res. 2004;49:37–43.PubMedCrossRefGoogle Scholar
  246. 246.
    Nam KW, Je KH, Lee JH, et al. Inhibition of COX-2 activity and proinflammatory cytokines (TNF-alpha and IL-1beta) production by water-soluble sub-fractionated parts from bee (Apis mellifera) venom.Arch Pharm Res. 2003;26:383–388.PubMedGoogle Scholar
  247. 247.
    Ganafa AA, Socci RR, Eatman D, Silvestrov N, Abukhalaf IK, Bayorh MA. Effect of palm oil on oxidative stress-induced hypertension in Sprague-Dawley rats.Am J Hypertens. 2002;15:725–731.PubMedCrossRefGoogle Scholar
  248. 248.
    Ringbom T, Huss U, Stenholm A, et al. COX-2 inhibitory effects of naturally occurring and modified fatty acids.J Nat Prod. 2001;64:745–749.PubMedCrossRefGoogle Scholar
  249. 249.
    Srivastava KC. Aqueous extracts of onion, garlic and ginger inhibit platelet aggregation and alter arachidonic acid metabolism.Biomed Biochim Acta. 1984;43:S335-S346.PubMedGoogle Scholar
  250. 250.
    Srivastava KC. Isolation and effects of some ginger components of platelet aggregation and eicosanoid biosynthesis.Prostaglandins Leukot Med. 1986;25:187–198.PubMedCrossRefGoogle Scholar
  251. 251.
    Srivastava KC. Onion exerts antiaggregatory effects by altering arachidonic acid metabolism in platelets.Prostaglandins Leukot Med. 1986;24:43–50.PubMedCrossRefGoogle Scholar
  252. 252.
    Bartoli R, Fernandez-Banares F, Navarro E, et al. Effect of olive oil on early and late events of colon carcinogenesis in rats: modulation of arachidonic acid metabolism and local prostaglandin E(2) synthesis.Gut. 2000;46:191–199.PubMedCrossRefGoogle Scholar
  253. 253.
    Bartram HP, Gostner A, Scheppach W, et al. Effects of fish oil on rectal cell proliferation, mucosal fatty acids, and prostaglandin E2 release in healthy subjects.Gastroenterology. 1993;105:1317–1322.PubMedGoogle Scholar
  254. 254.
    Sheng H, Shao J, Morrow JD. Modulation of apoptosis and Bcl-2 expression by prostaglandin E2 in human colon cancer cells.Cancer Res. 1998;58:362–366.PubMedGoogle Scholar
  255. 255.
    Minoura T, Takata T, Sakaguchi M. Effect of dietary eicosapentaenoic acid on azoxymethane-induced colon carcinogenesis in rats.Cancer Res. 1988;48:4790–4794.PubMedGoogle Scholar
  256. 256.
    Rao CV, Simi B, Wynn TT. Modulating effect of amount and types of dietary fat on colonic mucosal phospholipase A2, phosphatidylinositol-specific phospholipase C activities, and cyclooxygenase metabolite formation during different stages of colon tumour promotion in male F344 rats.Cancer Res. 1996;56:532–537.PubMedGoogle Scholar
  257. 257.
    Hillier K, Jewell R, Dorrell L, Smith CL. Incorporation of fatty acids from fish oil and olive oil into colonic mucosal lipids and effects upon eicosanoid synthesis in inflammatory bowel disease.Gut. 1991;32:1151–1155.PubMedCrossRefGoogle Scholar
  258. 258.
    al-Sereiti MR, Abu-Amer KM, Sen P. Pharmacology of rosemary (Rosmarinus officinalis Linn.) and its therapeutic potentials.Indian J Exp Biol. 1999;37:124–130.PubMedGoogle Scholar
  259. 259.
    Setty AR, Sigal LH. Herbal medications commonly used in the practice of rheumatology: mechanisms of action, efficacy, and side effects.Semin Arthritis Rheum. 2005;34:773–784.PubMedCrossRefGoogle Scholar
  260. 260.
    Wang SR, Guo ZQ, Liao JZ. Experimental study on effects of 18 kinds of Chinese herbal medicine for synthesis of thromboxane A2 and PGI2.Zhongguo Zhong Xi Yi Jie He Za Zhi. 1993;13:167–170.PubMedGoogle Scholar
  261. 261.
    Chou CT, Chang SC. The inhibitory effect of common traditional anti-rheumatic herb formulas on prostaglandin E and interleukin 2 in vitro: a comparative study with Tripterygium wilfordii.J Ethnopharmacol. 1998;62:167–171.PubMedCrossRefGoogle Scholar
  262. 262.
    Fukutake M, Miura N, Yamamoto M, et al. Suppressive effect of the herbal medicine Oren-gedoku-to on cyclooxygenase-2 activity and azoxymethane-induced aberrant crypt foci development in rats.Cancer Lett. 2000;157:9–14.PubMedCrossRefGoogle Scholar
  263. 263.
    Sengupta A, Ghosh S, Bhattacharjee S, Das S. Indian food ingredients and cancer prevention—an experimental evaluation of anticarcinogenic effects of garlic in rat colon.Asian Pac J Cancer Prev. 2004;5:126–132.PubMedGoogle Scholar
  264. 264.
    Sengupta A, Ghosh S, Das S. Modulatory influence of garlic and tomato on cyclooxygenase-2 activity, cell proliferation and apoptosis during azoxymethane induced colon carcinogenesis in rat.Cancer Lett. 2004;208:127–136.PubMedCrossRefGoogle Scholar

Copyright information

© Health Communications Inc 2007

Authors and Affiliations

  • Noori S. Al-Waili
    • 1
  • Khelod Y. Saloom
    • 1
  • Thia Al-Waili
    • 1
  • Ali Al-Waili
    • 1
  • Hamza Al-Waili
    • 1
  1. 1.Al-Waili’s Charitable Foundation for Science and TradingNew York City

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