WO1987006831A1 - Composition et procede de traitement d'un thrombus et d'un embolus - Google Patents

Composition et procede de traitement d'un thrombus et d'un embolus Download PDF

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Publication number
WO1987006831A1
WO1987006831A1 PCT/US1986/001747 US8601747W WO8706831A1 WO 1987006831 A1 WO1987006831 A1 WO 1987006831A1 US 8601747 W US8601747 W US 8601747W WO 8706831 A1 WO8706831 A1 WO 8706831A1
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WO
WIPO (PCT)
Prior art keywords
clot
composition
dissolving
solution
blood
Prior art date
Application number
PCT/US1986/001747
Other languages
English (en)
Inventor
Robert L. Hunter
Alexander Duncan
Original Assignee
Emory University
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 Emory University filed Critical Emory University
Publication of WO1987006831A1 publication Critical patent/WO1987006831A1/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
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/44—Oxidoreductases (1)
    • A61K38/446—Superoxide dismutase (1.15)
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/02—Preservation of living parts
    • A01N1/0205—Chemical aspects
    • A01N1/021—Preservation or perfusion media, liquids, solids or gases used in the preservation of cells, tissue, organs or bodily fluids
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/02—Preservation of living parts
    • A01N1/0205—Chemical aspects
    • A01N1/021—Preservation or perfusion media, liquids, solids or gases used in the preservation of cells, tissue, organs or bodily fluids
    • A01N1/0226—Physiologically active agents, i.e. substances affecting physiological processes of cells and tissue to be preserved, e.g. anti-oxidants or nutrients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • 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
    • A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • A61K38/166—Streptokinase
    • 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
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/49—Urokinase; Tissue plasminogen activator

Definitions

  • the present invention relates to a composition and method for treating a thrombus or embolus and, more particularly, to a composition comprising certain ethylene- oxide propylene oxide condensation products in combination with clot-dissolving enzymes.
  • the composition is effective in dissolving clots that occlude blood vessels, restoring the flow of blood through damaged tissue .and preventing new clots from forming.
  • copolymer -alone has little or no effect on a patient who has suffered a severe coronary infarction wherein a blood clot has formed in the coronary artery.
  • Large clots in which the fibrin has undergone crosslinking are not effected by presence of the ethylene oxide/propylene oxide copolymers.
  • SUBSTITUTE SHEET It has been found that certain enzymes are able to open clogged arteries.
  • the enzymes which have been used successfully include streptokinase, urokinase, tissue plasminogen activator produced from ceil cultures (tissue plasminogen activator) and tissue plasminogen activator produced by recombinant DNA technology (r-tissue plasminogen activator). These enzymes are most successful if administered shortly after the occlusion of the blood vessels before the heart tissue has sustained irreversible damage. In one study of 11,806 patients treated with intravenous streptokinase, an 18% improvement of survival was demonstrated.
  • Tissue plasminogen activator requires the addition of approximately 100 ⁇ l of Tween 80 per liter of solution to promote dispersion of the enzyme. (See Ko ninger, et al., Thrombos, Haemostas, (Stuttgart) Vol. 46(2), p 561-565
  • Fibrin is the protein produced by polymerization of fibrinogen. It forms a gel which holds the thrombus together.
  • the fibrin molecules which form clots gradually become cross-linked to make a more stable clot All three enzymes, urokinase, streptokinase and tissue plasminogen activator, have similar effects on fibrin; however, they have different toxicities. If the fribrinolysis mechanisms are activated in the vicinity of a clot, the clot is dissolved. If, however, they
  • IB is activated systemically throughout the circulation, the body's capacity to stop bleeding or hemorrhage is markedly reduced. Streptokinase and urokinase tend to activate systemic fibrinolysis. Consequently, they have been most effective when injected directly into the affected blood vessel. Tissue plasminogen activator, in contrast, becomes effective only when it is actually attached to fibrin. This means its activity is largely localized to the immediate area of a clot and does not produce systemic fibrinolysis. It can be injected intravenously into the general circulation.
  • Tissue plasminogen activator is able to lyse a clot which is extensively cross-linked. This means it is possible to lyse clots which have been present for many hours. Tissue plasminogen activator also produces less risk of hemorrhage than the other enzymes. Even more effective enzyme b.ased thrombolytic drugs are being developed.
  • Balloon angioplasty is a procedure whereby a catheter with a small balloon is inserted into the narrowed artery.
  • balloon is inflated, compresses the atherosclerotic plaque against the vesel wall and dilates the artery.
  • the effectiveness of this procedure is limited by the effects of ischemia produced by the balloon, by embolization of atheromatous material which lodges in distal vessels and by an increased tendency for immediate
  • SUBSTITUT tears the tissue exposing underlying collagen and lipid substances which induce formation of thrombi. What is needed is a means of rendering the surface of the dilated vessel less thrombogenic, improving the blood flow through the distal tissue and breaking the embolized material into smaller pieces which are less likely to produce embolic damage.
  • lipid material on the atherosclerotic wall contributes to the bulk of the plaque which narrows the lumen of the artery and produces a highly thrombogenic surface. What is needed is a method of extracting lipids from atherosclerotic plaques which leaves their surfaces less thrombogenic and reduces their bulk.
  • compositions that include a clot- dissolving activity and a substance or substances that will prevent a clot from reforming after the initial clot has been cleared. Such a composition would thereby protect the patient from a damage caused by the reformation of a clot
  • a composition that is effective in dissolving blood clots and reestablishing and maintaining blood flow through thrombosed coronary or other blood vessels.
  • the clot- dissolving composition of the present invention comprises an enzyme, such as streptokinase, urokinase, tissue plasminogen activator or other proteolytic enzyme, and a surface active copolymer.
  • the surface active copolymer can be an ethylene oxide-propylene oxide condensation product with the following general formula:
  • a is an integer such that the hydrophobe represented by (C3H6O) has a molecular weight of about 950 to 4000, preferably about 1750 to 3500, and b is an integer such that the hydrophile portion represented by (C2H4O) constitutes approximately 50% to 90% by weight of the compound.
  • the clot-dissolving composition of the present invention is usually administered by intravenous injection into a patient
  • the present invention provides a composition that can be administered to patients who have a blood clot occluding a blood vessel.
  • the combination of proteolytic enzyme and surface active copolymer according to the present invention increases blood flow around a clot, rapidly dissolves a clot, and provides further protection to the patient.by preventing a new clot from forming.
  • the clot-dissolving composition of the present invention stabilizes the patient to a greater extent than treatments in the prior art, the administration of more invasive procedures, such as balloon angioplasty, can be delayed thereby permitting selection of conditions for the invasive treatment that are most favorable to the patient
  • It another object of the present invention to provide a composition that will reduce the risk of rethrombosis and thereby allow delay in administering balloon angioplasty or other invasive procedures for treatment of the compromised vessels.
  • the present invention comprises a composition which provides a synergistic action in dissolving blood clots and reestablishing and maintaining blood flow through a thrombosed coronary vessel or other blood vessel.
  • the clot- dissolving composition of the present invention is a solution containing an effective concentration of a proteolytic enzyme and an effective concentration of a surface active copolymer. The combination of the two components is surprisingly effective in dissolving blood clots that are blocking blood vessels.
  • the clot-dissolving composition of the present invention is highly effective in preventing a blood clot from reforming and in maintaining blood flow through the blood vessel.
  • the clot-dissolving composition of the present invention improves the flow of blood through narrow passages around clots and increases the delivery of the proteolytic enzyme to the clot.
  • the present invention also speeds the rate of dissolution of the clot by the enzyme and increases the proportion of clots dissolved by promoting delivery of enzyme to clots which would not otherwise be exposed to sufficient enzyme for their dissolution.
  • the clot-dissolving composition of the present invention reduces the dose of enzyme required for particular applications and thereby reduces the incidence of complications due to side effects caused by the enzymes.
  • the clot-dissolving composition of the present invention reduces the risk of immediate rethrombosis by accelerating the dissolution of clots and freeing aggregated platelets and blocking further platelets from aggregating to the clot or clot site.
  • the clot-dissolving composition of the present invention will allow delay of balloon angioplasty or other invasive procedures for treatment of the compromised vessels which have become thrombosed. The delay will permit
  • isotonic or “isoosmotic” solution . are defined as solutions having the same osmotic pressure as blood. These terms are well know in the art Solutions which may be employed in the preparation of the clot-dissolving composition of the present invention include, but are not limited to, saline (a solution of sodium chloride, containing 8.5 to 9.5 grams of sodium chloride in 1000 cc of purified water), Ringer's solution, lactated Ringer's solution, Krebs-Ringer's solution, and various sugar solutions. All of these solutions are well known to one of ordinary skill in the art However, it is to be understood that the clot-dissolving composition of the present invention may be administered as a solution that is not isotonic.
  • saline a solution of sodium chloride, containing 8.5 to 9.5 grams of sodium chloride in 1000 cc of purified water
  • Ringer's solution containing 8.5 to 9.5 grams of sodium chloride in 1000 cc of purified water
  • the surface active copolymer is preferably an ethylene oxide-propylene oxide condensation product with the following general formula:
  • a is an integer such that the hydrophobe represented by (C3H6O) has a molecular weight of about 950 to 4000, preferably from 1750 to 3500, and b is an integer such that the hydrophile portion represented by (C2H4O) constitutes from about 50% to 90% by weight of the compound.
  • These copolymers are sold under the general trademark of Pluronic® polyols and are available from the BASF Corporation (Parsippany, NJ).
  • the polymer blocks are formed by condensation of ethylene oxide and propylene oxide at elevated temperature and pressure in the presence of a basic catalyst. There is some statistical variation in the number of monomer units which combine to form a polymer chain in each copolymer. The molecular weights given are approximations of the average weight of copolymer molecule in each preparation. It is to be understood that the blocks of propylene oxide and ethylene oxide do not have to be pure. Small amounts of other materials can be admixed so long as the overall physical chemical properties are not substantially changed. A more detailed discussion of the preparation of these products is found in U.S. Patent No. 2,674,619.
  • Illustrative ethylene oxide-propylene oxide condensation products which may be employed in the preparation of the clot-dissolving composition of the present invention include, but are not limited to, the following copolymers:
  • the preferred ethylene oxide-propylene oxide copolymer for use in the clot-dissolving composition of the present invention is a copolymer having the following formula
  • the concentration of copolymer in the clot- forming composition of the present invention can vary depending the total volume of solution needed in the particular circumstances.
  • the total amount of block copolymer employed in the present invention will also vary depending on the size and type of thrombus or embolus, the particular copolymer employed, the particul.ar proteolytic enzyme employed, and the size and weight of the patient
  • the copolymer can be used over a wide range of concentrations with no adverse side effects.
  • the copolymer is rapidly excreted intact; 90% of the copolymer administered is excreted within three hours. Because of the absence of toxicity and the rapid clearance from the body, the copolymer can be administered over a long period of time.
  • the the clot-dissolving composition of the present invention may be employed by admixing with blood in any standard manner.
  • the solutions are intravenously injected into the blood stream either as a bolus, slow drip or both.
  • the solutions are generally admixed with the blood in a manner so as to maintain a substantially steady venous pressure.
  • the proteolytic enzymes that can be used in the clot-dissolving composition of the present invention include, but are not limited to, streptokinase (available from Hoechst- Roussel under the trademark Streptase®), urokinase (available from Abbot Laboratories, North Chicago, II under the trademark Abbokinase®) and tissue plasminogen activator
  • proteolytic enzymes are only sparingly soluble in water and must therefore be emulsified with the surface active copolymer before administration to the patient
  • the clot-dissolving composition of the present invention is equally applicable to thrombosis in other parts of the body, such -as the brain, legs, lungs or gastrointestinal tract
  • urokinase (Abbokinase, Abbot Laboratories, North Chicago, 111) in 105 mis of sterile water.
  • urokinase solution add 90 ml of an 0.9% sodium chloride solution containing 6 grams of an ethylene oxide-propylene oxide copolymer with the following general formula:
  • a priming dose of the clot-dissolving composition of the present invention is administered at a rate of 90 ml/hour over a period of 10 minutes. This is followed by a continuous infusion of the present invention at a rate of 15 ml /hour for 12 hours. Since some of the present invention will remain in the tubing at the end of an infusion pump delivery cycle, the remaining solution is flushed out of the tube by administering a solution of 0.9% sodium chloride at a rate of 15 l/hour.
  • urokinase (Abbokinase, Abbot Laboratories, North Chicago, 111) in 15.6 mis of sterile water.
  • urokinase solution add 300 ml of 5% dextrose solution containing 15 grams of an ethylene oxide-propylene oxide copolymer with the following general formula:
  • the solution comprising the present invention is infused into the occluded artery at a rate of 4 ml per minute for - periods up to 2 hours.
  • periodic angiography is performed.
  • urokinase For treating a patient weighing about 180 lbs with a pulmonary embolism, reconstitute 500 mg of urokinase (Abbokinase, Abbot Laboratories, North Chicago, 111) in 105 1 ° mis of sterile water. To the urokinase solution add 90 ml of an urokinase (Abbokinase, Abbot Laboratories, North Chicago, 111) in 105 1 ° mis of sterile water. To the urokinase solution add 90 ml of an
  • the clot-dissolving composition of the present invention is then immediately administered by means of a constant infusion pump that is capable of delivering a total
  • a priming dose of the present invention is administered at a rate of 90 ml/hour over a period of 10 minutes. This is followed by a continuous infusion of the present invention at a rate of 15 ml /hour for 12 hours. Since some of the present invention will remain in the tubing at the end of an infusion pump delivery cycle, the remaining solution is flushed out of the tube by administering a solution of 0.9% sodium chloride containing 3.0% copolymer at a rate of 15 ml/hour.
  • a solution of the copolymer is administered by intravenous drip at a rate of about 25 mg/kg body weight hour to maintain a blood concentration of the copolymer of approximately 0.6 mg/ml.
  • the administration of the copolymer solution is continued for four days following the administration of the clot-dissolving composition of the present invention.

Abstract

La composition décrite a un effet synergique dans la dissolution de caillots sanguins et le rétablissement et le maintien de la circulation sanguine au travers d'un vaisseau coronaire ou autre vaisseau sanguin présentant un caillot sanguin. La composition de dissolution du caillot sanguin est une solution contenant une concentration efficace d'une enzyme protéolytique et une concentration efficace d'un copolymère tensio-actif. Le copolymère tensio-actif est de préférence un produit de condensation d'un oxyde d'éthylène et d'un oxyde de propylène ayant la formule générale suivante: HO(C2H4O)b(C3H6O)a(C2H4O)bH, dans laquelle a est un nombre entier tel que l'hydrophobe représenté par (C3H6O) possède un poids moléculaire compris entre 950 et 4000 environ et b est un nombre entier tel que la portion hydrophile représentée par (C2H4O) constitue environ entre 50 % et 90 % en poids du composé. Les enzymes protéolytiques pouvant être utilisées dans la composition de dissolution de caillots de la présente invention comprennent, sans caractère limitatif, la streptokinase, l'urokinase, et un activateur plasminogène tissulaire.
PCT/US1986/001747 1986-05-15 1986-08-25 Composition et procede de traitement d'un thrombus et d'un embolus WO1987006831A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US86358286A 1986-05-15 1986-05-15
US863,582 1986-05-15

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WO1987006831A1 true WO1987006831A1 (fr) 1987-11-19

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AU (1) AU6334586A (fr)
MX (2) MX9206335A (fr)
WO (1) WO1987006831A1 (fr)
ZA (1) ZA873512B (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0409940A1 (fr) * 1988-12-29 1991-01-30 Univ Emory Procedes et compositions servant au traitement des interactions hydrophobes pathologiques dans des fluides biologiques.
US5039520A (en) * 1986-05-15 1991-08-13 Emory University Plasma extender
WO1995010265A1 (fr) * 1993-10-15 1995-04-20 Cytrx Corporation Compositions d'apport therapeutique et leurs modes d'utilisation
US5470568A (en) * 1992-02-13 1995-11-28 Arch Development Corporation Methods and compositions of a polymer (poloxamer) for cell repair
US5605687A (en) * 1992-05-15 1997-02-25 Arch Development Corporation Methods and compositions of a polymer (poloxamer) for repair of electrical injury
US5648071A (en) * 1986-05-15 1997-07-15 Emory University Method of treating tumors
US5696298A (en) * 1991-03-19 1997-12-09 Cytrx Corporation Polyoxypropylene/polyoxyethylene copolymers with improved biological activity
US5811088A (en) * 1987-02-20 1998-09-22 Emory University Antiinfective compounds and methods of use
US5990241A (en) * 1991-03-19 1999-11-23 Cytrx, Corporation Polyoxypropylene/polyoxyethylene copolymers with improved biological activity
USRE38558E1 (en) 1991-03-19 2004-07-20 Cytrx Corporation Polyoxypropylene/polyoxyethylene copolymers with improved biological activity
US6933286B2 (en) 1991-03-19 2005-08-23 R. Martin Emanuele Therapeutic delivery compositions and methods of use thereof
US7202225B1 (en) 1993-10-15 2007-04-10 Emanuele R Martin Therapeutic delivery compositions and methods of use thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL8701113A (nl) * 1986-05-12 1987-12-01 Wellcome Found Nieuwe farmaceutische toepassing.

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US3541240A (en) * 1968-05-22 1970-11-17 Rca Corp Automatic beam current limiting using reference current sources
JPS545094B1 (fr) * 1969-06-27 1979-03-13
US4179337A (en) * 1973-07-20 1979-12-18 Davis Frank F Non-immunogenic polypeptides
US4305922A (en) * 1978-10-04 1981-12-15 University Patents, Inc. Labeling proteins with 99m-Tc by ligand exchange
SU1183112A1 (ru) * 1983-08-04 1985-10-07 Научно-Исследовательский Институт Экспериментальной И Клинической Терапии Министерства Здравоохранения Гсср Способ лечени острой ишемии миокарда
US4600652A (en) * 1985-04-01 1986-07-15 Warner-Lambert Company Permanently bonded antithrombogenic polyurethane surface
US4609546A (en) * 1982-06-24 1986-09-02 Japan Chemical Research Co., Ltd. Long-acting composition

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3541240A (en) * 1968-05-22 1970-11-17 Rca Corp Automatic beam current limiting using reference current sources
JPS545094B1 (fr) * 1969-06-27 1979-03-13
US4179337A (en) * 1973-07-20 1979-12-18 Davis Frank F Non-immunogenic polypeptides
US4305922A (en) * 1978-10-04 1981-12-15 University Patents, Inc. Labeling proteins with 99m-Tc by ligand exchange
US4609546A (en) * 1982-06-24 1986-09-02 Japan Chemical Research Co., Ltd. Long-acting composition
SU1183112A1 (ru) * 1983-08-04 1985-10-07 Научно-Исследовательский Институт Экспериментальной И Клинической Терапии Министерства Здравоохранения Гсср Способ лечени острой ишемии миокарда
US4600652A (en) * 1985-04-01 1986-07-15 Warner-Lambert Company Permanently bonded antithrombogenic polyurethane surface

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5039520A (en) * 1986-05-15 1991-08-13 Emory University Plasma extender
US5648071A (en) * 1986-05-15 1997-07-15 Emory University Method of treating tumors
US5811088A (en) * 1987-02-20 1998-09-22 Emory University Antiinfective compounds and methods of use
EP0409940B1 (fr) * 1988-12-29 1997-03-12 Emory University Procedes et compositions servant au traitement des interactions hydrophobes pathologiques dans des fluides biologiques
EP0409940A1 (fr) * 1988-12-29 1991-01-30 Univ Emory Procedes et compositions servant au traitement des interactions hydrophobes pathologiques dans des fluides biologiques.
US6359014B1 (en) 1991-03-19 2002-03-19 Cytrx Corporation Polyoxypropylene/polyoxyethylene copolymers with improved biological activity
US5696298A (en) * 1991-03-19 1997-12-09 Cytrx Corporation Polyoxypropylene/polyoxyethylene copolymers with improved biological activity
US5990241A (en) * 1991-03-19 1999-11-23 Cytrx, Corporation Polyoxypropylene/polyoxyethylene copolymers with improved biological activity
USRE36665E (en) * 1991-03-19 2000-04-18 Cytrx Corporation Polyoxypropylene/polyoxyethylene copolymers with improved biological activity
USRE37285E1 (en) 1991-03-19 2001-07-17 Cytrx Corporation Polyoxypropylene/polyoxyethylene copolmers with improved biological activity
US6747064B2 (en) 1991-03-19 2004-06-08 Cytrx Corporation Polyoxypropylene/polyoxyethylene copolymers with improved biological activity
USRE38558E1 (en) 1991-03-19 2004-07-20 Cytrx Corporation Polyoxypropylene/polyoxyethylene copolymers with improved biological activity
US6933286B2 (en) 1991-03-19 2005-08-23 R. Martin Emanuele Therapeutic delivery compositions and methods of use thereof
US5470568A (en) * 1992-02-13 1995-11-28 Arch Development Corporation Methods and compositions of a polymer (poloxamer) for cell repair
US5605687A (en) * 1992-05-15 1997-02-25 Arch Development Corporation Methods and compositions of a polymer (poloxamer) for repair of electrical injury
WO1995010265A1 (fr) * 1993-10-15 1995-04-20 Cytrx Corporation Compositions d'apport therapeutique et leurs modes d'utilisation
US7202225B1 (en) 1993-10-15 2007-04-10 Emanuele R Martin Therapeutic delivery compositions and methods of use thereof

Also Published As

Publication number Publication date
MX9206335A (es) 1994-05-31
MX9206336A (es) 1994-05-31
AU6334586A (en) 1987-12-01
ZA873512B (en) 1988-12-28

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