WO2002030446A2 - Procede visant a reduire ou a prevenir la formation d'adherences post-chirurgicales - Google Patents

Procede visant a reduire ou a prevenir la formation d'adherences post-chirurgicales Download PDF

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Publication number
WO2002030446A2
WO2002030446A2 PCT/US2001/032044 US0132044W WO0230446A2 WO 2002030446 A2 WO2002030446 A2 WO 2002030446A2 US 0132044 W US0132044 W US 0132044W WO 0230446 A2 WO0230446 A2 WO 0230446A2
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WO
WIPO (PCT)
Prior art keywords
fibrinogen
surgery
adhesions
solution
prevention
Prior art date
Application number
PCT/US2001/032044
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English (en)
Other versions
WO2002030446A3 (fr
Inventor
Heinz Redl
Reiner Spaethe
Manuela Simunek
Original Assignee
Baxter International Inc.
Baxter Healthcare S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Baxter International Inc., Baxter Healthcare S.A. filed Critical Baxter International Inc.
Priority to US10/399,223 priority Critical patent/US7198786B2/en
Priority to AU2002213195A priority patent/AU2002213195A1/en
Publication of WO2002030446A2 publication Critical patent/WO2002030446A2/fr
Publication of WO2002030446A3 publication Critical patent/WO2002030446A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/36—Blood coagulation or fibrinolysis factors
    • A61K38/363—Fibrinogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution

Definitions

  • Post-surgical adhesions are a major healthcare problem of significant clinical and medical economic relevance. Abdominal adhesions are not only the leading cause of small bowel obstruction but also major sources of infertility and of abdominal and pelvic pain. It could be shown that post-surgical adhesions cause at least 20% of cases of infertility and about 40% of cases of chronic pelvic pain.
  • fibrinogen preparations such as human cryoprecipitate (Toosie et al., The American Surgeon 66 (2000): 41-45; de Virgilio et al., Arch. Surg. Vol 125, Oct. 1990, p. 1378 ff.)
  • fibrinolytic inhibitors contained in all commercially available fibrin sealants significantly increased adhesion formation both to the parietal peritoneum and to the bowel compared with untreated control animals, whereas fibrinolytic activation with a recombinant tissue type plasminogen activator eliminated adhesion formation to the injured bowel and significantly reduced the number and extent of adhesions in the parietal peritoneum compared with untreated control animals.
  • the present invention provides a method for reducing or preventing the formation of adhesions which would form in a patient during or after surgery, said method comprising administering to the wound surface of said patient a fibrinogen preparation in an amount of about 0.025 ml/cm 2 to 0.25 ml/cm 2 of the surface being at risk for developing adhesions.
  • the present invention also provides a fibrinogen preparation comprising, when in liquid form, 20 to 80 mg/ml fibrinogen for the efficient administration of fibrinogen in amounts effective for reducing or preventing post-surgical adhesion formation.
  • Figure 1 Histological slide of mesothelium tissue repaired through use of the present invention. DETAILED DESCRIPTION OF THE INVENTION
  • the method according to the present invention is efficient in reducing or preventing adhesions in a patient by administering a fibrinogen solution in a specific amount, i.e. of about 0.025 ml/cm 2 to about 0.25 ml/cm 2 of a surface being at risk for developing adhesions.
  • a fibrinogen solution in a specific amount, i.e. of about 0.025 ml/cm 2 to about 0.25 ml/cm 2 of a surface being at risk for developing adhesions.
  • fibrinogen solution With amounts of fibrinogen solution lower than 0.025 ml per cm 2 surface the fibrin/fibrinogen layer provided seems to be too thin to provide an effective protection against adhesion formation. Amounts of fibrinogen higher than 0.25 ml/cm 2 surface yielded a layer with sufficient thickness but with very high clot persistance, i.e. the clot is not lysed within an appropriate time period. This high clot persistance leads to an inflammatory reaction on the surface which then leads to adhesion processes. Optimum amounts of fibrinogen solutions are around 0.1 ml/cm 2 , e.g. between 0.07 to 0.13, especially 0.085 to 0.115 ml/cm 2 . Optimally, a fibrinogen solution containing 35 - 55 mg/ml fibrinogen is used to administer these amounts to the wound surface.
  • the fibrinogen solution be applied in a uniform mode, i.e. with a constant thickness over the whole surface area to be treated. Therefore, it is preferred to use a spraying device for the present invention. Suitable spraying devices are known in the art; preferred spraying devices are those known for the application of classical tissue adhesives. The application with needles is - although possible for a very skilled person - not generally recommended for the present invention.
  • the fibrinogen preparation administered to the specific surface reacts with thrombin which is either added exogeneously together with the fibrinogen preparation (e.g. as a fibrin sealant kit) or with thrombin endogenously present in the patient at the administration site.
  • adhesions to be reduced or prevented with the method according to the present invention are those described in the prior art and may be adhesions to or between organs, parts of organs or tissues in a particular location.
  • adhesions may be defined as abnormal attachments between tissues and organs.
  • Such attachments may be developed in response to trauma to the peritoneum. These trauma may be inflammatory or surgical and may include: exposure to infection or to intestinal contents, ischemia, initation from exogeneous materials such as sutures, gauze particles or glove dusting powder, abrasion, desiccation or overheating by lamps or irrigation fluids.
  • adhesions may occur after injury to or deformation of the peritoneum during surgery which may be caused e.g. by abdominal surgery, reproductive surgery, spinal surgery, laparatomy or other surgery in cardiac or abdominal procedures or in the gynecological area.
  • the patient may be human or any animal having a risk for or having such adhesions.
  • the method according to the present invention may be useful for preventing and/or reducing newly formed adhesions as well as those adhesions which reform after adhesiolysis.
  • adhesions involving key organs and tissues, e g the small intestine or the uterus and adnexa, which are the most likely to be symptomatic, are treated or prevented
  • a thrombin preparation simultaneously with the fibrinogen preparation as known from the "classical" fibrinogen based tissue adhesives, as disclosed e g in the US patents 4,298,598, 4,362,567, 4,377,572 and 4,414,976 as well as all the patents or applications citing these patents or their corresponding counterparts in other countries, which are incorporated herein by reference
  • the thrombin preparation and the fibrinogen preparation may be provided as a set, preferably together with suitable administration devices, especially spraying devices, which are described in the EP 0
  • “Classical” tissue adhesives known in the art are provided in concentrations of at least 70 - 80 mg/ml fibrinogen
  • a physician of skill could practice the methods of the invention using fibrinogen preparations ranging from 20 to 150 mg fibrinogen/ml
  • a fibrinogen concentration of between 20 to 80 mg/ml, preferably 30 to 60 mg/ml, most preferably 35 to 55 mg/ml is preferred
  • fibrinogen preparations currently contain plasmin-acting fib ⁇ nolysis inhibitors such as aprotmin Plasmin-acting fib ⁇ nolysis inhibitors should be omitted from the fibrinogen preparation to be used in the present invention
  • Non-plasmin-acting fib ⁇ nolysis inhibitors such as elastase inhibitors (WO 99/11301) can be included in the fibrinogen preparation for the practice of the present invention.
  • fibrinolysis inhibitors can be omitted entirely from the fibrinogen preparation to be used in the present invention.
  • the adhesions which are reduced or prevented according to the present invention are adhesions which would form during surgery such as gynecological or reproductive surgery, laparoscopic surgery or spinal surgery.
  • a reduction or prevention of adhesions which would be newly formed can be achieved as well as reduction or prevention of those adhesions which would reform after adhesiolysis, if the present invention were not used.
  • the fibrinogen preparation may contain Factor XIII and other other proteins such as fibronectin, which are known to be present in most commercially available fibrinogen preparations.
  • the fibrinogen preparation may also contain additives such as antibiotics and cytokines.
  • the present invention provides an optimal preparation for administering fibrinogen to a wound site according to the method of the invention: the preparation of the invention comprises fibrinogen purified from a plasma pool, said fibrinogen, when in solution, being at a concentration of between 20 to 80 mg/ml, preferably 30 to 60 mg/ml, most preferably 35 to 55 mg/ml. Also provided is a set for the use in reducing or preventing post-surgical adhesions comprising the above described fibrinogen component together with a thrombin component.
  • the present invention also relates to a method of repairing mesothelium damages comprising administering about 0.025 ml/cm 2 to about 0.25 ml/cm 2 of a fibrinogen solution to a damaged mesothelium.
  • fibrinogen 5 may inhibit peritoneal inflammation (Jahoda et al., Surgery 125(1) (1999), pages 53-59) it was never shown or proposed that such solutions may have a cell repair capability which allows a reliable and quick repair of a mesothelium 0 being damaged in the course of surgical events.
  • the lateral abdominal wall associated with the cecum position is pressed through a fixation frame causing protrusion of a 4.5 x 3 cm area of the parietal peritoneum.
  • the externalized parietal wall is traumatized by removal of the peritoneum and the underlying transversal abdominal musculature.
  • test or control solutions in their predetermined volume are applied and the test solution is left to clot for 5 min.
  • the distance of the delivery device from the surface of the tissue is around 10 cm.
  • the surface is wetted with 5 ml saline to prevent the area from drying up.
  • the abdomen is closed.
  • the muscle and skin incisions are sutured separately using Synthofil® 2/0 or Steelex 0/4 as interrupted sutures in a three-level manner.
  • the animals are monitored daily for weight and clinical condition, at day 14. the animals are sacrificed and necropsies are performed to determine and quantify adhesion formation on the abdominal wall.
  • the adhesions are quantified by calibrated calipers.
  • the area of attachment to the abdominal wall is calculated in mm 2 by multiplying the length and width of the adhesion attachment.
  • the results of the present tests are depicted in the following table 1.
  • Control animals show a median of 1245 mm 2 .
  • the optimum amounts for the method according to the present invention are around 0.1 ml/cm 2 , i.e. from about 0.07 to 0.13, also slightly depending on the fibrinogen concentration and potentially present non-plasmin-acting inhibitors of lysis. Higher fibrinogen concentrations and presence of inhibitors may shift the optimum towards lower values.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Surgery (AREA)
  • Hematology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Materials For Medical Uses (AREA)

Abstract

L'invention concerne un procédé visant à réduire ou à prévenir chez un patient la formation d'adhérences pendant ou après une intervention chirurgicale, qui consiste à administrer à la surface de la plaie une solution de fibrinogène à raison d'environ 0,025-0,25 ml fibrinogène/cm2 de la surface présentant un risque de former des adhérences ; l'utilisation de fibrinogène dans une préparation renfermant du fibrinogène selon une concentration comprise entre 20 et 80 mg/ml, destinée à réduire ou à prévenir la formation d'adhérences post-chirurgicales.
PCT/US2001/032044 2000-10-13 2001-10-12 Procede visant a reduire ou a prevenir la formation d'adherences post-chirurgicales WO2002030446A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US10/399,223 US7198786B2 (en) 2001-10-12 2001-10-12 Method for the reduction or prevention of post-surgical adhesion formation
AU2002213195A AU2002213195A1 (en) 2000-10-13 2001-10-12 Reduction or prevention of post-surgical adhesion formation with fibrinogen

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US24020000P 2000-10-13 2000-10-13
US60/240,200 2000-10-13

Publications (2)

Publication Number Publication Date
WO2002030446A2 true WO2002030446A2 (fr) 2002-04-18
WO2002030446A3 WO2002030446A3 (fr) 2003-07-24

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AU (1) AU2002213195A1 (fr)
WO (1) WO2002030446A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006113249A2 (fr) * 2005-04-12 2006-10-26 Warsaw Orthopedic, Inc. Procedes et dispositifs de protection de la mobilite d'un disque prothetique articulaire
US20180093010A1 (en) * 2007-07-02 2018-04-05 Omrix Biopharmaceuticals Ltd. Kits, formulations and solutions having enzymatically- permissive amounts of visualization agents and uses thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992022312A1 (fr) * 1991-06-17 1992-12-23 Wadstroem Jonas Composition pour le traitement de tissus corporels, contenant de la fibrine ou du fibrogene et un polymere biodegradable et biocompatible
WO1999056797A1 (fr) * 1998-05-01 1999-11-11 Zymogenetics, Inc. Compositions d'adhesif tissulaire entierement recombinantes
WO2000071153A2 (fr) * 1999-05-19 2000-11-30 Bio & Bio Licensing Sa Medicament pour application locale, contenant du fibrinogene, de la thrombine, des transglutaminases et des inhibiteurs de protease
WO2000072852A1 (fr) * 1999-06-01 2000-12-07 Bristol-Myers Squibb Company Prevention d'adherences post-chirurgicales utilisant un scellement de monomere de fibrine
EP1157706A2 (fr) * 2000-05-22 2001-11-28 Aventis Behring GmbH Utilisation de colle tissulaire à base de fibrinogène pour la prévention d'adhérences de tissus

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992022312A1 (fr) * 1991-06-17 1992-12-23 Wadstroem Jonas Composition pour le traitement de tissus corporels, contenant de la fibrine ou du fibrogene et un polymere biodegradable et biocompatible
WO1999056797A1 (fr) * 1998-05-01 1999-11-11 Zymogenetics, Inc. Compositions d'adhesif tissulaire entierement recombinantes
WO2000071153A2 (fr) * 1999-05-19 2000-11-30 Bio & Bio Licensing Sa Medicament pour application locale, contenant du fibrinogene, de la thrombine, des transglutaminases et des inhibiteurs de protease
WO2000072852A1 (fr) * 1999-06-01 2000-12-07 Bristol-Myers Squibb Company Prevention d'adherences post-chirurgicales utilisant un scellement de monomere de fibrine
EP1157706A2 (fr) * 2000-05-22 2001-11-28 Aventis Behring GmbH Utilisation de colle tissulaire à base de fibrinogène pour la prévention d'adhérences de tissus

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ARNOLD P.B.: "Evaluation of resorbable barriers for preventing surgical adhesions" FERTILITY AND STERILITY, vol. 73, no. 1, January 2000 (2000-01), pages 157-161, XP001134965 *
BAXTER: "Tisseel, two component fibrin sealant human vapor heated" PACKAGE INSERT, [Online] November 1997 (1997-11), XP002230273 Retrieved from the Internet: <URL:http://www.baxter.ca/downloads/en/bio science/tisseel_insert_6208110ek11.pdf> [retrieved on 2003-02-06] *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006113249A2 (fr) * 2005-04-12 2006-10-26 Warsaw Orthopedic, Inc. Procedes et dispositifs de protection de la mobilite d'un disque prothetique articulaire
WO2006113249A3 (fr) * 2005-04-12 2007-08-02 Warsaw Orthopedic Inc Procedes et dispositifs de protection de la mobilite d'un disque prothetique articulaire
US8257438B2 (en) 2005-04-12 2012-09-04 Warsaw Orthopedic, Inc. Methods and devices for preserving motion in an articulating prosthetic disc
US20180093010A1 (en) * 2007-07-02 2018-04-05 Omrix Biopharmaceuticals Ltd. Kits, formulations and solutions having enzymatically- permissive amounts of visualization agents and uses thereof

Also Published As

Publication number Publication date
AU2002213195A1 (en) 2002-04-22
WO2002030446A3 (fr) 2003-07-24

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