US005639468A United States Patent (19) 11 Patent Number: 5,639,468 Rodgers et al. 45 Date of Patent: Jun. 17, 1997 54 METHOD FOR REDUCING OR Glaser et al. (1987), "Inactivation of bee venom phospho PREVENTNG POSTSURGCALADHES ON lipase A by manoalide. A model based on the reactivity of FORMATION USING MANOALDE AND manoalide with amino acids and peptide sequences,” Bio ANALOGS THEREOF chem. Pharm, vol. 36(13), pp. 2079–2086. 75 Inventors: Kathleen Elizabeth Rodgers, Long Jacobson et al. (1990), "Inactivation of human synovial fluid Beach; Gere Stodder diZerega, phospholipase A by the marine natural product, Pasadena, both of Calif. manoalide,” Biochem, Pharm, vol.39, pp. 1557-1564. Mayer et al. (1988), "Regulation of eicosanoid biosynthesis (73) Assignee: University of Southern California, invitro and in vivo by the marine natural product manoalide: Los Angeles, Calif. A potent inactivator of venom phospholipases,” J. Pharm. and Exp. Therapeutics, vol. 244(3), pp. 871-878. 21 Appl. 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U.S. PATENT DOCUMENTS Locati et al. (1994), "Rapid induction of arachidonic acid 4,447,445 5/1984 Jacobs et al. ........................... 424/279 release by monocyte chemotactic protein-1 and related 4,616,089 10/1986 Jacobs et al. .. ... 549,323 chemokines. Role of Ca' influx, synergism with platele 4,786,651 11/1988 Wheeler .................................. 5147460 t-activating factor and significance for chemotaxis,” J. Bio 4,789,749 12/1988 Jacobs et al. ...... ... 549/33 logical Chemistry, vol. 269, pp. 4746-4753. 4,839,385 6/1989 Maullem et al. .. ... 514/473 4,935,530 6/1990 Lee ..................... ... 549/214 Lennartz et al. (1991), "Arachidonic acid is essential for IgG 4,937,254 6/1990 Sheffield et al. ... ... 514,420 Fe receptor-mediated phagocytosis by human monocytes,” J. 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Berghoff OTHER PUBLICATIONS 57 ABSTRACT diZerega, G.S. & Rodgers, K.E. (1992), "Prevention of Compositions and methods for minimizing or preventing Postoperative Adhesions.” in The Peritoneum, diZerega, G. post-Surgical adhesion formation between tissue, e.g., organ, S. & Rodgers, K.E., eds., Springer-Verlag, New York, pp. surfaces in body cavities, whereby an effective therapeutic 307-369. amount of manoaide or analog thereof is administered to the Elkins, T.E., (1990), "Can a Pro-Coagulant Substance Pre target injury site for a period of time sufficient to permit vent Adhesions?" in Treatment of Post-Surgical Adhesions, tissue repair. Manoalide or analog thereof is preferably diZerega, G.S. et al., eds., Wiley-Liss, New York, pp. administered in conjunction with a delivery vehicle (e.g., 103-112. microcapsules, microspheres, biodegradable polymer films, Rodgers, K.E. (1990), "Nonsteroidal anti-inflammatory lipid-based delivery systems such as liposomes and lipid drugs (NSAIDs) in the treatment of PostSurgical adhesion.” foams, crystalloid and viscous instillates and absorbable in Treatment of Post-Surgical Adhesions, diZerega, G.S. et mechanical barriers) useful for maintaining local concentra al., eds., Wiley-Liss, New York, pp. 119-129. tions of the inhibitor at the injury site at an effective level for Bennett et al. (1987), "Differential-effects of manoalide on a sustained period of time. secreted and intracellular phospholipases,” Biochem. Pharm, vol. 36(5), pp. 733–740. 21 Claims, No Drawings 5,639,468 Page 2 OTHER PUBLICATIONS Rodgers, K. etal. (1990), "Intraperitoneal Tolimetin Prevents Zhang and Dennis (1988), "Purification and characterization PostSurgical Adhesion Formation in Rabbits.” Int, J. Fertil, of a lysophospholipase from a macrophage-like cell line vol. 35, pp. 40-45. P388D1,” J. 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(1992), "Evidence that phospholipase A Abe, H. et al.(1990), "The Effect of intra-peritoneal Admin (PLA) inhibitors can selectively block PLA-mediated istration of Sodium Tolimetin-Hyaluronic Acid on the Post contractions of guinea pig lung pleural strips.” J. Pharm. Surgical Cell Infiltration in vivo.” J. Surg. Res., vol. 49, pp. and Exp. Therapeutics, vol. 262, pp. 1147-1153. 322-327. Glaser et al. (1989), "Manoalide: Structure activity studies and definition of the pharmacophore for phospholipase A Johnson and Johnson Medical, Inc., New Brunswick, New inactivation.” Molecular Pharmacology, vol. 36, pp. Jersey INTERCEED(TC7) Adhesion Barrier Study Group, 782-788. (1989), "Prevention of postsurgical adhesions by INTER Kobayahi et al. (1993), "Luffariolides F and G, new CEED(TC7), an absorbable adhesion barrier: a prospective, manoalide derivatives from the okinawan marine sponge randomized multicenter clinical study,” Fertility and Steril Lufarielle sp.," J. Natural Products, vol. 56, pp. 436-439. ity, vol. 51, pp. 933–938. Konig et al. (1992), "Four new antibacterial sesterterpenes from a marine sponge of the genus Lufariella, J. Natural Diamond, M.P. etal. (1991), "Synergistic effects of INTER Products," vol. 55, pp. 174-178. CEED(TC7) and heparin in reducing adhesion formation in Ortiz et al. (1993), "Molecular model of the interaction of the rabbit uterine horn model." Fertility and Sterility, vol. bee venon phospholipase A with manoalide,” J. Medicinal 55, pp. 389-394. Chemistry, vol. 36, pp. 1866-1879. Lewis, D.H. (1990), "Controlled Release of Bioactive Diamond, M.P. et al. (1991), "Adhesion reformation: reduc Agents from Lactide/Glycolide Polymers,” in Biodegrad tion by the use of INTERCEED(TC7) plus heparin.” J. Gyn. able Polymers as Drug Delivery Systems, Jason & Langer, Surg., vol. 7, pp. 1-6. eds., pp. 1-41. Nishimura, K. et al. (1984), "The Use of Ibuprofen for the Hockel, M. et al. (1987), "Prevention of Peritoneal Adhe Prevention of Postoperative Adhesions in Rabbits,” Am. J. sions in the Rat with Sustained Intraperitoneal Dexametha sone Delivered by a Novel Therapeutic System.” Annales Med, vol. 77, pp. 102-106. Chirurgiae et Gynaecologiae, vol. 76, pp. 306-313. Derwent Search Results dated May 24, 1995. 5,639,468 1. 2 METHOD FOR REDUCING OR Anti-inflammatory drugs have been evaluated for their PREVENTNG POSTSURGICAL ADHESION effects on postoperative adhesion formation, as they may FORMATION USNG MANOALDE AND limit the release of fibrinous exudate in response to inflam ANALOGS THEREOF mation at the surgical site. Two general classes of these drugs were tested: cortico-steroids and nonsteroidal anti FIELD OF THE INVENTION inflammatory drugs. The results of corticosteroid use in The present invention relates to manoalide and analogs animal studies have generally not been encouraging, and thereof and their use thereof in a method for reducing or clinical use of corticosteroids is limited by their other preventing post-operative adhesion formation between pharmacologic properties. While experimental