PDF herunterladen
Semin Reprod Med 2008; 26(4): 341-348
DOI: 10.1055/s-0028-1082392
© Thieme Medical Publishers

Tranilast: A Pharmaceutical Candidate for Reduction of Adhesions Using a Novel Approach

Janel Petrilli1 , Scott Wadsworth1 , Kevin Cooper2 , Kathleen E. Rodgers3 , John Siekierka1 , Gere S. diZerega3
  • 1Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, New Jersey
  • 2Center for Biomaterials & Advanced Technologies, Medical Devices Group, A division of Ethicon, A Johnson & Johnson Company, Somerville, New Jersey
  • 3University of Southern California, Keck School of Medicine, Department of Obstetrics & Gynecology, Livingston Reproductive Biology Laboratories, Los Angeles, California
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
28. August 2008 (online)

    Lizenzen und Reprints

ABSTRACT

Postsurgical adhesion formation has numerous deleterious side effects in a wide variety of surgical settings. Physical barriers used together with laparoscopy were developed in hopes of reducing the tissue trauma seen with open procedures and separating tissues during the critical time of healing to reduce adhesion formation. Despite meticulous techniques by surgeons and the availability of barriers, adhesion formation remains a serious problem, with more than $1 billion spent annually on complications arising from adhesions. Our laboratories have combined a previously marketed drug, Tranilast, with a gel to provide a locally delivered medicated device that can reduce adhesion formation. This article will review the role of Tranilast in the key pathways involved in adhesion formation.

KEYWORDS

Transilast - adhesions - mast cells - gynecologic surgery - surgery

REFERENCES

  • 1 Ray T, Larson Jr J W, Stillman R J, Jacobs R J. Economic impact of hospitalizations for lower abdominal adhesiolysis in the United States in 1988.  Surg Gynecol Obstet. 1993;  176 271-276
    PubMedSuche in Google Scholar
  • 2 Diamond M P, DeCherney A H. Pathogenesis of adhesion formation/reformation: application to reproductive pelvic surgery.  Microsurgery. 1987;  8 103-107
    CrossrefPubMedSuche in Google Scholar
  • 3 Diamond M P, Daniell J F, Feste J et al.. Adhesion reformation and de novo adhesion formation following reproductive pelvic surgery.  Fertil Steril. 1987;  47 864-866
    PubMedSuche in Google Scholar
  • 4 Operative Laparoscopy Study Group . Postoperative adhesion development following operative laparoscopy: evaluation at early second-look procedures.  Fertil Steril. 1991;  55 700
    PubMedSuche in Google Scholar
  • 5 Diamond M P. Surgical aspects of infertility. In: Speroff L, Simpson JL, Sciarra JJ Obstetrics and Gynecology. Vol 5. Philadelphia, PA; JB Lippincott 1991: 1-23
    Suche in Google Scholar
  • 6 Ray N F, Denton W G, Thamer M, Henderson S C, Perry S. Abdominal adhesiolysis: inpatient care and expenditures in the United States in 1994.  J Am Coll Surg. 1998;  186 1-9
    CrossrefPubMedSuche in Google Scholar
  • 7 Ellis H, Moran B J, Thompson J N et al.. Adhesion-related hospital readmissions after abdominal and pelvic surgery: a retrospective cohort study.  Lancet. 1999;  353 1476-1480
    CrossrefPubMedSuche in Google Scholar
  • 8 Kamffer W J, Jooste E V, Nel J T, de Wet J I. Surgical glove powder and intraperitoneal adhesion formation. An appeal for the use of powder-free surgical gloves.  S Afr Med J. 1992;  81 158-159
    PubMedSuche in Google Scholar
  • 9 Weibel M A, Majno G. Peritoneal adhesions and their relation to abdominal surgery. A postmortem study.  Am J Surg. 1973;  126 345-353
    CrossrefPubMedSuche in Google Scholar
  • 10 Myllarniemi H, Frilander M, Turunen M, Saxen L. The effect of glove powders and their constituents on adhesion and granuloma formation in the abdominal cavity of rabbit.  Acta Chir Scand. 1966;  131 312-318
    PubMedSuche in Google Scholar
  • 11 Interceed (TC7) Adhesion Barrier Study Group . Prevention of postsurgical adhesions by Interceed (TC7), an absorbable adhesion barrier: a prospective, randomized multicenter clinical study.  Fertil Steril. 1989;  51 933-938
    PubMedSuche in Google Scholar
  • 12 Surrey M W, Friedman S. Second-look laparoscopy after reconstructive pelvic surgery for infertility.  J Reprod Med. 1982;  27 658-660
    PubMedSuche in Google Scholar
  • 13 diZerega G S. Contemporary adhesion prevention.  Fertil Steril. 1994;  61 219-235
    PubMedSuche in Google Scholar
  • 14 Galli S J, Gordon J R, Wershil B K. Mast cell cytokines in allergy and inflammation.  Agents Actions Suppl. 1993;  43 209-220
    PubMedSuche in Google Scholar
  • 15 Collins S M. The immunomodulation of gut motility: factors that determine the proliferation of mast cells in the sensitized gut.  Gastroenterology. 1988;  94 74
    PubMedSuche in Google Scholar
  • 16 Liebman S M, Langer J C, Marshall J S, Collins S M. Role of mast cells in peritoneal adhesion formation.  Am J Surg. 1993;  165 127-130
    CrossrefPubMedSuche in Google Scholar
  • 17 Langer J C, Liebman S M, Monk P K, Pelletier G J. Mast cell mediators and peritoneal adhesion formation in the rat.  J Surg Res. 1995;  59 344-348
    CrossrefPubMedSuche in Google Scholar
  • 18 Xu X, Pappo O, Garbuzenko E, Bischoff S C, Rivkind A, Levi-Schaffer F. Mast cell dynamics and involvement in the development of peritoneal adhesion in the rat.  Life Sci. 2002;  70 951-967
    CrossrefPubMedSuche in Google Scholar
  • 19 Levi-Schaffer F, Weg V B. Mast cells, eosinophils and fibrosis.  Clin Exp Allergy. 1997;  11 64-70
    PubMedSuche in Google Scholar
  • 20 Levi-Schaffer F, Kupietzky A. Mast cells enhance migration and proliferation of fibroblasts into an in vitro wound.  Exp Cell Res. 1990;  188 42-49
    CrossrefPubMedSuche in Google Scholar
  • 21 Kupietzky A, Levi-Schaffer F. The role of mast cells-derived histamine in the closure of an in vitro wound.  Inflamm Res. 1996;  45 176-180
    CrossrefPubMedSuche in Google Scholar
  • 22 Hatamochi A, Ueki H, Mauch C, Krieg T. Effect of histamine on collagen and non-collagen mRNA production in human skin fibroblasts. J Dermatol.  Sci. 1991;  2 407-412
    PubMedSuche in Google Scholar
  • 23 Claman H. Mast cells, T cells and abnormal fibrosis.  Immunol Today. 1985;  6 192
    CrossrefPubMedSuche in Google Scholar
  • 24 Adachi S, Maruyama T, Kondo T, Todoroki T, Fukao K. Prevention of postoperative intraperitoneal adhesions by tranilast: N-(3′,4′-dimethoxycinnamoyl)anthranilic acid.  Surg Today. 1999;  29 51-54
    CrossrefPubMedSuche in Google Scholar
  • 25 Holmdahl L. The role of fibrinolysis in adhesion formation.  Eur J Surg Suppl. 1997;  557 24-31
    PubMedSuche in Google Scholar
  • 26 Rubin J, Herrera G A, Collins D. An autopsy study of the peritoneal cavity from patients on continuous ambulatory peritoneal dialysis.  Am J Kidney Dis. 1991;  18 97-102
    PubMedSuche in Google Scholar
  • 27 Remick D G, Strieter M, Lynch III J P, Nguyen D, Eskandari M, Kunkel S L. In vivo dynamics of murine tumor necrosis factor-alpha gene expression.  Lab Invest. 1989;  60 766-771
    PubMedSuche in Google Scholar
  • 28 Scott-Coombs D M. Peritoneal cytokine response in surgery.  Br J Surg. 1994;  81 756
    PubMedSuche in Google Scholar
  • 29 Suzawa H, Kikuchi S, Ichikawa K, Koda A. Inhibitory action of tranilast, an anti-allergic drug, on the release of cytokines and PGE2 from human monocytes-macrophages.  Jpn J Pharmacol. 1992;  60 85-90
    CrossrefPubMedSuche in Google Scholar
  • 30 Chikaraishi A, Hirahashi J, Takase O et al.. Tranilast inhibits interleukin-1beta-induced monocyte chemoattractant protein-1 expression in rat mesangial cells.  Eur J Pharmacol. 2001;  427 151-158
    CrossrefPubMedSuche in Google Scholar
  • 31 Yanagi T, Watanabe M, Fukuda S, Tsuji Y. Suppressive effects of tranilast (TN) on human mononuclear cells.  Jpn J Inflammation. 1987;  7 169-176
    PubMedSuche in Google Scholar
  • 32 Mori H, Tanaka H, Kawada K, Nagai H, Koda A. Suppressive effects of tranilast on pulmonary fibrosis and activation of alveolar macrophages in mice treated with bleomycin: role of alveolar macrophages in the fibrosis.  Jpn J Pharmacol. 1995;  67 279-289
    CrossrefPubMedSuche in Google Scholar
  • 33 Ward M R, Agrotis A, Kanellakis P, Hall J, Jennings G, Bobik A. Tranilast prevents activation of transforming growth factor-b system, leukocyte accumulation, and neointimal growth in porcine coronary arteries after stenting.  Arterioscler Thromb Vasc Biol. 2002;  22 940-948
    CrossrefPubMedSuche in Google Scholar
  • 34 Raftery A T. Effect of peritoneal trauma on peritoneal fibrinolytic activity and intraperitoneal adhesion formation. An experimental study in the rat.  Eur Surg Res. 1981;  13 397-401
    CrossrefPubMedSuche in Google Scholar
  • 35 DiZerega G S, Campeau J D. Peritoneal repair and post-surgical adhesion formation.  Hum Reprod Update. 2001;  7 547-555
    CrossrefPubMedSuche in Google Scholar
  • 36 Koyama S, Takagi H, Otani A, Suzuma K, Nishimura K, Honda Y. Tranilast inhibits protein kinase C-dependent signaling pathway linked to angiogenic activities and gene expression of retinal microcapillary endothelial cells.  Br J Pharmacol. 1999;  127 537-545
    CrossrefPubMedSuche in Google Scholar
  • 37 Isaji M, Miyata H, Ajisawa Y, Yoshimura N. Tranilast inhibits the proliferation, chemotaxis and tube formation of human microvascular endothelial cells in vitro and angiogenesis in vivo.  Br J Pharmacol. 1997;  122 1061-1066
    CrossrefPubMedSuche in Google Scholar
  • 38 Squires C E, Escobar G P, Payne J F et al.. Altered fibroblast function following myocardial infarction.  J Mol Cell Cardiol. 2005;  39 699-707
    CrossrefPubMedSuche in Google Scholar
  • 39 Yasukawa T, Kimura H, Dong J et al.. Effect of Tranilast on proliferation, collagen gel contraction, and transforming growth factor beta secretion of retinal pigment epithelial cells and fibroblasts.  Ophthalmic Res. 2002;  34 206-212
    CrossrefPubMedSuche in Google Scholar
  • 40 Li Y, Foster W, Deasy B M et al.. Transforming growth factor-β1 induces the differentiation of myogenic cells into fibrotic cells in injured skeletal muscle: a key event in muscle fibrogenesis.  Am J Pathol. 2004;  164 1007-1019
    CrossrefPubMedSuche in Google Scholar
  • 41 Li Y, Huard J. Differentiation of muscle-derived cells into myofibroblasts in injured skeletal muscle.  Am J Pathol. 2002;  161 895-907
    CrossrefPubMedSuche in Google Scholar
  • 42 Huard J, Yong L, Ferddie H. Muscle injuries and repair: current trends in research.  J Bone Joint Surg Am. 2002;  84 822-832
    PubMedSuche in Google Scholar
  • 43 Border W A, Noble N A. Transforming growth factor-β in tissue fibrosis.  N Engl J Med. 1994;  10 1286-1292
    PubMedSuche in Google Scholar
  • 44 Branton M H, Kopp J B. TGF-beta and fibrosis.  Microbes Infect. 1999;  1 1349-1365
    CrossrefPubMedSuche in Google Scholar
  • 45 Bernasconi P, Torchiana E, Confalonieri P et al.. Expression of transforming growth factor-β1 in dystrophic patient muscles correlates with fibrosis. Pathogenic role of a fibrogenic cytokine.  J Clin Invest. 1995;  96 1137-1144
    CrossrefPubMedSuche in Google Scholar
  • 46 Lundberg I, Ulfgren A, Nyberg P, Andersson U, Klareskog L. Cytokine production in muscle tissue of patients with idiopathic inflammatory myopathies.  Arthritis Rheum. 1997;  40 865-874
    CrossrefPubMedSuche in Google Scholar
  • 47 Yamada H, Tajima S, Nishikawa T, Murad S, Pinnell S R. Tranilast, a selective inhibitor of collagen synthesis in human skin fibroblasts.  J Biochem (Tokyo). 1994;  116 892-897
    CrossrefPubMedSuche in Google Scholar
  • 48 Suzawa H, Kikuchi S, Arai N, Koda A. The mechanism involved in the inhibitory action of tranilast on collagen biosynthesis of keloid fibroblasts.  Jpn J Pharmacol. 1992;  60 91-96
    CrossrefPubMedSuche in Google Scholar
  • 49 Suzawa H, Kikuchi S, Ichikawa K et al.. Effect of tranilast, an antiallergic drug, on human keloid tissues.  Nippon Yakurigaku Zasshi. 1992;  99 231-239
    PubMedSuche in Google Scholar
  • 50 Ichikawa K, Suzawa H, Tsuchiya O et al.. Comparison of the effects of tranilast, triamcinolone, and a heparin-like substance on keloid and hypertrophic scar.  Oyo Yakur. 1992;  43 401
    PubMedSuche in Google Scholar
  • 51 Cohen I K, Keiser H R, Sjoerdsma A. Collagen synthesis in human keloid and hypertrophic scar.  Surg Forum. 1971;  22 488-489
    PubMedSuche in Google Scholar
  • 52 Shigeki S, Murakami T, Yata N, Ikuta Y. Treatment of keloid and hypertrophic scars by iontophoretic transdermal delivery of tranilast.  Scand J Plast Reconstr Surg Hand Surg. 1997;  31 151-158
    PubMedSuche in Google Scholar
  • 53 Taniguchi S, Yorifuji T, Hamada T. Treatment of linear localized scleroderma with the anti-allergic drug, Tranilast.  Clin Exp Dermatol. 1994;  19 391-393
    CrossrefPubMedSuche in Google Scholar
  • 54 Pinto Y M, Pinto-Sietsma S J, Philipp T et al.. Reduction in left ventricular messenger RNA from transforming growth factor beta (1) attenuates left ventricular fibrosis and improves survival without lowering blood pressure in the hypertensive TGR(mRen2)27 rat.  Hypertension. 2000;  36 747-754
    PubMedSuche in Google Scholar
  • 55 Mifsud S, Kelly D J, Qi W et al.. Intervention with tranilast attenuates renal pathology and alburminuria in advanced experimental diabetic neuropathy.  Nephron Physiol. 2003;  95 83-91
    CrossrefPubMedSuche in Google Scholar
  • 56 Martin J, Kelly D J, Mifsud S A et al.. Tranilast attenuates cardiac matrix deposition in experimental diabetes: role of transforming growth factor-β.  Cardiovasc Res. 2005;  65 691-694
    PubMedSuche in Google Scholar
  • 57 Guidry C. The role of Muller cells in fibrocontractive retinal disorders.  Prog Retin Eye Res. 2005;  24 75-86
    CrossrefPubMedSuche in Google Scholar
  • 58 Hocher B, Godes M, Olivier J et al.. Inhibition of left ventricular fibrosis by tranilast in rats with renovascular hypertension.  J Hypertens. 2002;  20 745-751
    CrossrefPubMedSuche in Google Scholar
  • 59 Ward M R, Agrotis A, Kanellakis P, Hall J, Jennings G, Bobik A. Tranilast prevents activation of transforming growth factor β system, leukocyte accumulation, and neointimal growth in porcine coronary arteries after stenting.  Arterioscler Thromb Vasc Biol. 2002;  22 940-948
    CrossrefPubMedSuche in Google Scholar
  • 60 Tamai H, Katoh O, Suzuki S et al.. Impact of tranilast on restenosis after coronary angioplasty: Tranilast Restenosis Following Angioplasty Trial (TREAT).  Am Heart J. 1999;  138 968-975
    CrossrefPubMedSuche in Google Scholar
  • 61 Holmes Jr D R, Savage M, LaBlanche J M et al.. Results of Prevention of REStenosis with Tranilast and its Outcomes (PRESTO) trial.  Circulation. 2002;  106 1243-1250
    CrossrefPubMedSuche in Google Scholar
  • 62 Kosuga K, Tamai H, Ueda K et al.. Effectiveness of tranilast on restenosis after directional coronary atherectomy.  Am Heart J. 1997;  134 712-718
    CrossrefPubMedSuche in Google Scholar
  • 63 Okada H, Kalluri R. Cellular and molecular pathyways that lead to progression and regression of renal fibrogenesis.  Curr Mol Med. 2005;  5 467-474
    CrossrefPubMedSuche in Google Scholar
  • 64 Kelly D J, Zhang Y, Gow R, Gilbert R E. Tranilast attenuates structural and functional aspects of renal injury in the remnant kidney model.  J Am Soc Nephrol. 2004;  15 2619-2629
    CrossrefPubMedSuche in Google Scholar
  • 65 Soma J, Sugawara T, Huang Y D, Nakajima J, Kawamura M. Tranilast slows the progression of advanced diabetic nephropathy.  Nephron. 2002;  92 693-698
    CrossrefPubMedSuche in Google Scholar
  • 66 Cooper K, Young J, Wadsworth S, Cui H, diZerega G S, Rodger K E. Reduction of post-surgical adhesion formation with Tranilast.  J Surg Res. 2007;  141(2) 153-161
    CrossrefPubMedSuche in Google Scholar
  • 67 Young J, Wadsworth S, Cooper K, Rosenblatt J, Cui H. Drug-enhanced adhesion prevention. United States Patent Application Publication. US 2005/0106229 A1 2005
    Suche in Google Scholar
  • 68 Dullerud R, Graver V, Haakonsen M, Haaland A K, Loeb M, Magnaes B. Influence of fibrinolytic factors on scar formation after lumbar discectomy. A magnetic resonance imaging follow-up study with clinical correlation performed 7 years after surgery.  Spine. 1998;  23 1464-1469
    CrossrefPubMedSuche in Google Scholar
  • 69 Rodgers K E, Robertson J T, Espinoza T et al.. Reduction of epidural fibrosis in lumbar surgery with Oxiplex adhesion barriers of carboxymethylcellulose and polyethylene oxide.  Spine J. 2003;  3 277-283
    CrossrefPubMedSuche in Google Scholar
  • 70 Jaibaji M, Brody G S, Rodgers K et al.. A new model for experimental tendon adhesions in the chicken.  Ann Plast Surg. 2000;  44 205-210
    CrossrefPubMedSuche in Google Scholar

Gere S diZeregaM.D. 

University of Southern California, Keck School of Medicine, Department of Obstetrics and Gynecology, Livingston Reproductive Biology Laboratories

1321 N. Mission Road, Los Angeles, CA 90033

eMail: GSD1270@aol.com