AU2002360269A1 - Method for inhibiting the formation of seromas using factor XIII - Google Patents
Method for inhibiting the formation of seromas using factor XIIIInfo
- Publication number
- AU2002360269A1 AU2002360269A1 AU2002360269A AU2002360269A AU2002360269A1 AU 2002360269 A1 AU2002360269 A1 AU 2002360269A1 AU 2002360269 A AU2002360269 A AU 2002360269A AU 2002360269 A AU2002360269 A AU 2002360269A AU 2002360269 A1 AU2002360269 A1 AU 2002360269A1
- Authority
- AU
- Australia
- Prior art keywords
- factor
- formation
- seromas
- inhibiting
- administered
- Prior art date
- Legal status (The legal status 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 status listed.)
- Granted
Links
- 230000015572 biosynthetic process Effects 0.000 title claims description 10
- 238000000034 method Methods 0.000 title claims description 10
- 230000002401 inhibitory effect Effects 0.000 title claims description 4
- 206010040102 Seroma Diseases 0.000 title description 10
- 108010071289 Factor XIII Proteins 0.000 title description 4
- 229940012444 factor xiii Drugs 0.000 title description 3
- 238000001356 surgical procedure Methods 0.000 claims description 6
- 108090000190 Thrombin Proteins 0.000 claims description 5
- 229960004072 thrombin Drugs 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims 2
- 210000004911 serous fluid Anatomy 0.000 claims 1
- 239000012530 fluid Substances 0.000 description 10
- 241000700159 Rattus Species 0.000 description 9
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 4
- 239000004471 Glycine Substances 0.000 description 4
- 229930006000 Sucrose Natural products 0.000 description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
- 206010052428 Wound Diseases 0.000 description 4
- 208000027418 Wounds and injury Diseases 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 108010014173 Factor X Proteins 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 229940098773 bovine serum albumin Drugs 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000002224 dissection Methods 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 229960002725 isoflurane Drugs 0.000 description 2
- 210000002751 lymph Anatomy 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000008223 sterile water Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 108010088842 Fibrinolysin Proteins 0.000 description 1
- 206010025282 Lymphoedema Diseases 0.000 description 1
- 206010058046 Post procedural complication Diseases 0.000 description 1
- 208000035965 Postoperative Complications Diseases 0.000 description 1
- 206010042674 Swelling Diseases 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 208000009190 disseminated intravascular coagulation Diseases 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002642 gamma-glutamyl group Chemical group 0.000 description 1
- 210000004013 groin Anatomy 0.000 description 1
- 201000000079 gynecomastia Diseases 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 210000001365 lymphatic vessel Anatomy 0.000 description 1
- 208000002502 lymphedema Diseases 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 210000002976 pectoralis muscle Anatomy 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 238000007790 scraping Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Description
METHOD FOR INHIBITING THE FORMATION OF SEROMAS USING FACTOR xm
BACKGROUND OF THE INVENTION
Seromas are collections of lymph usually present as painless swellings within a wound or below flaps. These often develop in wounds involving dissection in lymph node-bearing areas, for example axillae, neck, groin etc., or in areas where significant dead space remains such as after abdominal-perineal resection, total mastectomy or in breast reduction procedures either for females or to treat gynecomastia in males. The seromas prevent adequate tissue approximation or may become secondarily infected.
The primary cause lies in the failure to identify and control lymphatic vessels during dissection. Though lymph is a protein-rich fluid, electrocauterization is ineffective to prevent seroma formation. Thus, there is a need to develop a treatment to prevent the formation of seromas.
DESCRIPTION OF THE INVENTION The present invention fills this need by administering factor XIH to patients who have undergone surgery to inhibit the build-up of fluids or seromas beneath the skin where the surgery took place or a wound has occurred. The factor XIH may be applied locally in solution beneath the skin or administered systemically. The factor XHI solution can be administered prior to surgery, prior to suturing of the surgical site or can be injected beneath the skin after surgery. If the factor XHI is administered locally, it may be activated or non-activated, or the non-activated factor Xm may be applied in conjunction with activated alpha-thrombin. The activated thrombin would then activate the factor XHI. Activated thrombin can be administered locally at a concentration of about 0.5 mg/mL of solution. A method for producing human recombinant thrombin can be found in U.S. Patent No. 5,502,034.
Factor Xm, also known as fibrin-stabilizing factor, circulates in the plasma at a concentration of 20 μg/ml. The protein exists in plasma as a tetramer comprised of two A subunits and two B subunits. Each subunit has a molecular weight of 83,000 Da, and the complete protein has a molecular weight of approximately 330,000 Da. Factor Xm catalyzes the cross-linkage between the γ-glutamyl and ε-lysyl groups of different fibrin strands. The catalytic activity of factor XH resides in the A subunits. The B subunits act as carriers for the A subunits in plasma factor Xm. Recombinant factor X can be produced according to the process described in European Patent No. 0 268 772 Bl. The level of factor XQI in the plasma can be increased by administering a factor Xm concentrate derived from human placenta called FIBROGAMMIN® (Aventis Corp.) or by administration of recombinant factor xm.
As stated above, administration of factor XM to a subject is may be administered locally at the site of the wound or systemically. If administered systemically, the factor Xm is generally administered intravenously. When administering therapeutic proteins by injection, the administration may be by continuous infusion or by single or multiple boluses. A pharmaceutical composition comprising factor Xm can be formulated according to known methods to prepare pharmaceutically useful compositions, whereby the therapeutic proteins are combined in a mixture with a pharmaceutically acceptable carrier. A composition is said to be a "pharmaceutically acceptable carrier" if its administration can be tolerated by a recipient patient. A suitable pharmaceutical composition of factor Xm will contain ImM EDTA, lOmM glycine, 2% sucrose in water. An alternative formulation will be a factor Xm composition containing 20 mM histidine, 3% wt/volume sucrose, 2 mM glycine and .01% wt/vol. polysorbate, pH 8.
Other suitable carriers are well known to those in the art. See, for example, Gennaro (ed.), Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company 1995).
Administration of Factor XIII
The levels of factor Xm in an individual can be determined by assays well known in the art such as the BERICHROM F Xm assay (Dade Behring Marburgh GmbH, Marburg, Germany). The normal adult has an average of about 45 ml of plasma per kg of body weight. Each liter of blood has 1000 units (U) of factor XE. The amount of factor XE administered should be enough to bring an individual's level of factor Xm in the plasma to 100% of normal plasma or slightly above to 1-5% above normal. A dose of .45 U/kg would raise the level of factor Xm by about 1% compared to normal. One unit of factor XM is about 10 μg of recombinant factor Xm, which contains only the dimerized A subunit. Thus, to raise the level of factor XHI by 1%, one would administer about 4.5 μg of the A2 subunit per kilogram weight of the individual. So to raise the level 30% of normal, one would administer 13.5 U/kg. For a 75 kg individual this would be about 1,012.5 U. Some patients may have consumptive coagulopathies that involve factor XHI losses. In such cases, a higher dosing (e.g., 1- 2U/kg-%) or multiple dosing of factor X (e.g., l-2U/kg-%-day) may be required.
Example 1
The Use of Factor XIII to Prevent Seroma Formation in a
Rat Seromal Mastectomy Model
Object of the Experiment
The object of the experiment was to determine if factor Xm when given systemically would influence seromal fluid formation using a rat mastectomy model.
Background Seromas are the most common postoperative complication for patients undergoing a mastectomy. The formation of these fluid collections is facilitated by the disruption of lymphatics and blood vessels as well as by the creation of large potential voids beneath the skin. Postoperative problems due to seroma formation include delayed wound healing, flap necrosis, lymph edema of the arm and infection.
Factor Xm PreparationFactor X was provided by ZymoGenetics, Inc., Seattle WA in bottles containing 13.2 mg of lyophilized factor XIH containing 0.3 mM ethylenediaminetetraacetic acid (EDTA), 31 mM glycine, and 6.2% sucrose. The lyophilized factor Xm was reconstituted with 3.3 mL of sterile water and pipetted into 0.5 mL aliquots and stored in a freezer at -20° C.
Vehicle Preparation
The vehicle preparation was a lyophilized powder comprised of 0.3 mM EDTA, 31 mM glycine and 6.2% sucrose. This was reconstituted with 3.3 ml of sterile water and pipetted into 0.5 mL aliquots and stored in a freezer at -20° C. After thawing, 0.5 mL of bovine serum albumin (BSA) was added to each vial.
Experimental Procedure
The rats were anesthetized with isoflurane (3% isoflurane, 1% oxygen) and a catheter was inserted into the jugular vein of each rat. Two to three days following catheter insertion, eleven rats received a single intravenous bolus injection through the catheter of the vehicle preparation (the control group) and 12 rats received a single bolus injection of 1 mg/kg of the factor Xm preparation (the experimental group) 30 minutes prior to a left side radical mastectomy. The mastectomy consisted of removal of the pectoralis muscle, lymphatic tissue including nodes (3 or more) and traumatization of subcutaneous lymphovasculature surface. The traumatization the lymphovasculature occurred by scraping 50 times the inner surface of the elevated skin flap with a No. 22 scalpel blade. Five days following mastectomy, the rats were anesthetized with urethane anesthesia. Blood samples were taken for analysis. Seromal fluid was aspirated and weighed from each rat to determine seromal fluid volume and factor X content.
Results
No significant differences were observed between the Control and Experimental rats for the following: hematology, clinical blood chemistry and factor Xm levels. A significant difference was observed in seromal fluid volume aspirate at time of sacrifice (day 5). The control group averaged 2.7 mL of seromal fluid and the group to whom factor XHI was administered averaged 1.4 mL of seromal fluid. Thus factor XE was effective in inhibiting the formation of seromal fluid.
Claims (5)
1. A method for inhibiting the formation of a seromal or serous fluid at the site of surgery or a wound in a mammal comprising administering to said mammal a therapeutically effective amount of factor XM.
2. The method of claim 1 wherein the factor Xm is administered systemically.
3. The method of claim 1 wherein the factor XM is administered locally at the site of the surgery or wound.
4. The method of claim 3 wherein the factor XM is activated.
5. The method of claim 3 wherein the factor XM is administered in conjunction with activated thrombin.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US32807001P | 2001-10-09 | 2001-10-09 | |
| US60/328,070 | 2001-10-09 | ||
| PCT/US2002/032450 WO2003037249A2 (en) | 2001-10-09 | 2002-10-09 | Method for inhibiting the formation of seromas using factor xiii |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2002360269A1 true AU2002360269A1 (en) | 2003-07-10 |
| AU2002360269B2 AU2002360269B2 (en) | 2007-03-22 |
Family
ID=23279383
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2002360269A Ceased AU2002360269B2 (en) | 2001-10-09 | 2002-10-09 | Method for inhibiting the formation of seromas using factor XIII |
Country Status (10)
| Country | Link |
|---|---|
| US (2) | US6890903B2 (en) |
| EP (1) | EP1434590B1 (en) |
| JP (1) | JP2005507926A (en) |
| AT (1) | ATE388715T1 (en) |
| AU (1) | AU2002360269B2 (en) |
| CA (1) | CA2463530A1 (en) |
| DE (1) | DE60225576T2 (en) |
| ES (1) | ES2303561T3 (en) |
| IL (2) | IL161189A0 (en) |
| WO (1) | WO2003037249A2 (en) |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3621371A1 (en) | 1986-03-12 | 1987-09-17 | Behringwerke Ag | GENETIC PRODUCTION OF FACTOR XIIIA |
| ATE121776T1 (en) | 1986-09-19 | 1995-05-15 | Zymogenetics Inc | EXPRESSION OF BIOLOGICALLY ACTIVE FACTOR XIII. |
| JPS63196520A (en) | 1987-02-09 | 1988-08-15 | Hoechst Japan Kk | Ulcerative colitis treatment agent |
| US5612456A (en) * | 1988-11-14 | 1997-03-18 | Zymogenetics, Inc. | Factor XIII compositions |
| US5318524A (en) * | 1990-01-03 | 1994-06-07 | Cryolife, Inc. | Fibrin sealant delivery kit |
| US6197325B1 (en) * | 1990-11-27 | 2001-03-06 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
| KR100302935B1 (en) | 1993-03-30 | 2001-11-30 | 바트 루디거 | Pharmaceutical composition comprising human blood coagulation factor XIII and aprotinin |
| WO2000051538A1 (en) * | 1999-03-01 | 2000-09-08 | Uab Research Foundation | Porous tissue scaffolding materials and uses thereof |
-
2002
- 2002-10-09 ES ES02795514T patent/ES2303561T3/en not_active Expired - Lifetime
- 2002-10-09 EP EP02795514A patent/EP1434590B1/en not_active Expired - Lifetime
- 2002-10-09 WO PCT/US2002/032450 patent/WO2003037249A2/en not_active Ceased
- 2002-10-09 JP JP2003539595A patent/JP2005507926A/en active Pending
- 2002-10-09 AU AU2002360269A patent/AU2002360269B2/en not_active Ceased
- 2002-10-09 IL IL16118902A patent/IL161189A0/en unknown
- 2002-10-09 AT AT02795514T patent/ATE388715T1/en not_active IP Right Cessation
- 2002-10-09 CA CA002463530A patent/CA2463530A1/en not_active Abandoned
- 2002-10-09 DE DE60225576T patent/DE60225576T2/en not_active Expired - Lifetime
- 2002-10-09 US US10/268,180 patent/US6890903B2/en not_active Expired - Fee Related
-
2004
- 2004-03-31 IL IL161189A patent/IL161189A/en not_active IP Right Cessation
-
2005
- 2005-03-16 US US11/081,322 patent/US7153830B2/en not_active Expired - Fee Related
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