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WO1991015215A1 - Technique de reanimation par administration de fluide - Google Patents

Technique de reanimation par administration de fluide Download PDF

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Publication number
WO1991015215A1
WO1991015215A1 PCT/US1990/001768 US9001768W WO9115215A1 WO 1991015215 A1 WO1991015215 A1 WO 1991015215A1 US 9001768 W US9001768 W US 9001768W WO 9115215 A1 WO9115215 A1 WO 9115215A1
Authority
WO
WIPO (PCT)
Prior art keywords
biopolymer
dfo
fluid resuscitation
deferoxamine
dpo
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.)
Ceased
Application number
PCT/US1990/001768
Other languages
English (en)
Inventor
Bo Erik Hedlund
Philip E. Hallaway
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biomedical Frontiers Inc
Original Assignee
Biomedical Frontiers Inc
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 Biomedical Frontiers Inc filed Critical Biomedical Frontiers Inc
Priority to EP19900907852 priority Critical patent/EP0523037A4/en
Priority to CA002084073A priority patent/CA2084073A1/fr
Priority to US07/949,522 priority patent/US5416078A/en
Priority to AU56434/90A priority patent/AU654652B2/en
Priority to PCT/US1990/001768 priority patent/WO1991015215A1/fr
Priority to JP2507467A priority patent/JPH11514326A/ja
Priority claimed from CA002084073A external-priority patent/CA2084073A1/fr
Publication of WO1991015215A1 publication Critical patent/WO1991015215A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid

Definitions

  • the present invention relates to fluid resuscitation.
  • Such resuscitation is required or is desirable in treatment of burn injury, lung injury caused by inhalation of hot and/or toxic substances, such as smoke derived frcm combustion, and hei ⁇ iorrhagic shock.
  • Burn injury is often acco ⁇ panied by injury to the lungs caused by inhalation of hot and/or toxic substances, such as snroke, derived from combustion.
  • the critical period of initial resuscitation i.e. when fluid is administered, is the time when reperfusion injury occurs. During this period, which may be as short as a minute or as long as several hours, oxygen radical mediated injury appears to occur.
  • ej ⁇ anders crystalloids and colloids
  • Deferoxamine or desferrioxamine
  • Deferoxamine mesylate is commercially available and is used to treat severe iron intoxication, iron storage disease or iron overload resulting from hemolysis due to drugs, thalassemia, sickle-cell anemia, frequent blood transfusions and the like.
  • deferoxamine mesylate There are a number of problems with the clinical use of deferoxamine mesylate. Since the drug is not appreciably absorbed when orally administered, it generally must be given parenterally. Once administered, the drug is very rapidly excreted. For example, in humans the drug exhibits a vascular half-life of only about 5-10 min. Chelation therapy with the drug, as a result, involves continuous infusion or frequent intramuscular injections, which may cause pain and/or induration at the injection site. Further, the acute and chronic toxicities of deferoxamine are relatively high, making the substance less versatile for therapeutic uses.
  • DFO deferoxamine
  • DES diethylstilbesterol
  • EP-0 304 183A discloses pharmaceutically acceptable water-soluble biopolymers covalently bonded to deferoxamine. Such biopolymers covalently bonded to deferoxamine are herein referred to as conjugates.
  • Preferred conjugates consist of pharmaceutically acceptable water-soluble polysaccharides covalently bonded to deferoxamine, pharmaceutically acceptable water-soluble proteins covalently bonded to deferoxamine and water-soluble inulm-deferoxamine adducts. It has now been discovered that such conjugates of deferoxamine are useful in fluid resuscitation.
  • the present invention relates to the use of a pharmaceutically acceptable water-soluble biopolymer and deferoxamine (DFO) for use in fluid resuscitation.
  • DFO deferoxamine
  • the invention relates to the use of such biopolymer and DFO for the preparation or manufacture of a medicament for use in fluid resuscitation.
  • the biopolymer may be covalently bonded to the DFO. Conjugation of DFO as described above decreases the toxicity of the DFO whilst not reducing or not proportionally reducing its chelating ability.
  • the biopolymer may be a polysaccharide or a protein.
  • the DPO may be covalently bonded directly to aldehydde groups on the polysaccharide.
  • the DFO may be covalently bonded directly to one or more amino, carboxyl or thiol groups on the protein.
  • the polysaccharide may comprise dextran, hyaluronic acid, inulin, starch, e.g. hydroxyethyl starch or other modified form of starch.
  • the protein may co ⁇ prise serum albumin or other plasma protein fraction (human or animal) or hemoglobin.
  • hemoglobin may be used in resuscitation fluids. Such fluids will provide oxygen to ischemic tissue but may be toxic due to release of iron from the iron-containing protein. The presence of DPO, either bound to or mixed with the hemoglobin may decrease such toxicity.
  • the DFO-conjugate may be prepared by method as described in EP-E- 0 304 183A.
  • DPO and the biopolymer, whether or not conjugated together are preferably formulated as an aqueous solution suitable for parenteral administration e.g. by intramuscular, intraperitoneal or intravenous infusion.
  • the conjugates between, and the simple mixtures of, polysaccharides and DPO preferably contain from 5 to 25% chelator by weight. It is preferred that -solutions having conjugate cor ⁇ _ * entrations between 2 and 10% (w/v) , dissolved in saline or lactated Ringer's solution, are used for fluid resuscitation. Effective doses are generally in the range of from approximately 20 to 300 mg chelator/kg body weight, although higher doses of conjugated DPO can be given in certain circumstances, for example in the treatment of acute iron poisoning. Care should be taken when administering the chelator in a form not conjugated to the colloid, since adverse reactions can occur even at moderate doses. - 4A -
  • Fluid resuscitation using the biopolymer and the DPO ameliorates systemic oxidant injury occurring during ischemia and subsequent reperf sion.
  • the fluid resuscitation may be indicated in treatment of burn injury, lung injury caused by inhalation of hot and/or toxic substances, such as smoke, derived from combustion, - hemorrhagic shock and other types of trauma.
  • Oxygen derived radicals such as the hydroxyl radical
  • Oxygen derived radicals are cytotoxic and highly reactive molecules are thought to contribute to cellular death in hemorrhagic and thermal shock.
  • Production of hydroxyl radical is catalyzed by transition metal ions.
  • Chelation of transition metal ions with DPO prevents formation of hydroxyl radicals.
  • the burn was produced under halothane nitrous anesthesia.
  • the burn involved bilateral prefemoral areas over the distribution of bilateral flanks. Resuscitation was begun immediately post burn. The animals were then monitored for 6 hours, then sacrificed. Three groups of animals were studied.
  • Group 1 Ringers alone as resuscitation fluid Group 2 5% hydroxyethyl starch alone as resuscitation fluid; Group 3 5% deferoxamine chelator attached i.e. (covalently bonded) to hydroxyethyl starch alone as recuscitation fluid.
  • Aortic, . central venous, pulmonary arterial, and pulmonary wedge pressures as well as cardiac output were recorded. Hourly values for arterial and venous blood gases as well as ' co-oximetry were measured. Co-oximetry measurements include total hemoglobin, reduced hemoglobin, oxygen content, oxygen saturation, and oxygen capacity. Dynamic and static lung compliance was also measured. Urine output and specific gravity were recorded.
  • Malondialdehyde (MDA), a measure of lipid peroxidation, was measured in both lung and liver tissue.
  • Group 3 receiving iron chelator atached to hydroxyethyl starch, required significantly less fluid to maintain hemodynamic stability than either of the other two groups.
  • n number of sheep in group.
  • a porcine hemorrhagic shock model was used to evaluate the effects of 3 resuscitative fluids on survival and hepatic function. Fasted swine (14-16 kg) underwent splenectomy and placement cf arterial - 8 -
  • PS pentastarch (a form of hydroxyethyl starch)

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention se rapporte à une technique de réanimation de fluide chez l'homme ou chez un animal, le fluide administré étant composé de déferoxamine (DFO) et d'un biopolymère hydrosoluble. La DFO et le biopolymère sont de préférence agglomérés entre eux. Le biopolymère peut être un polysaccharide ou une protéine. La DFO et le biopolymère sont de préférence formulés sous la forme d'une solution aqueuse se prêtant à une administration par voie buccale. Cette technique de réanimation par administration de fluide peut être utlisée pour soigner des lésions oxydantes systémiques se produisant lors d'une ischémie et de la reperfusion qui s'ensuit. Cette technique de réanimation par administration de fluide peut être indiquée dans le traitement des lésions par brûlures, des lésions pulmonaires causées par l'inhalation de substances brûlantes et/ou toxiques, telles que de la fumée provenant d'une combustion, ainsi que dans le traitement d'accidents hémorragiques et d'autres types de trauma.
PCT/US1990/001768 1990-03-30 1990-03-30 Technique de reanimation par administration de fluide Ceased WO1991015215A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
EP19900907852 EP0523037A4 (en) 1990-03-30 1990-03-30 Fluid resuscitation
CA002084073A CA2084073A1 (fr) 1990-03-30 1990-03-30 Reanimation liquidienne
US07/949,522 US5416078A (en) 1990-03-30 1990-03-30 Fluid resuscitation
AU56434/90A AU654652B2 (en) 1990-03-30 1990-03-30 Fluid resuscitation
PCT/US1990/001768 WO1991015215A1 (fr) 1990-03-30 1990-03-30 Technique de reanimation par administration de fluide
JP2507467A JPH11514326A (ja) 1990-03-30 1990-03-30 液体蘇生用医薬物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CA002084073A CA2084073A1 (fr) 1990-03-30 1990-03-30 Reanimation liquidienne
PCT/US1990/001768 WO1991015215A1 (fr) 1990-03-30 1990-03-30 Technique de reanimation par administration de fluide

Publications (1)

Publication Number Publication Date
WO1991015215A1 true WO1991015215A1 (fr) 1991-10-17

Family

ID=25675695

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1990/001768 Ceased WO1991015215A1 (fr) 1990-03-30 1990-03-30 Technique de reanimation par administration de fluide

Country Status (2)

Country Link
EP (1) EP0523037A4 (fr)
WO (1) WO1991015215A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995014492A3 (fr) * 1993-11-29 1995-06-22 Access Pharma Inc Agents in vivo comprenant des chelates d'ions de metaux radioactifs avec des saccharides et glycosaminoglycanes acides, qui ameliorent la localisation selective des sites, le mecanisme de fixation, la sensibilite et les profils cinetiques dans l'espace
US5674857A (en) * 1992-02-20 1997-10-07 Hyal Pharmaceutical Corporation Use of hyaluronic acid to repair ischemia reperfusion damage
WO1999049897A1 (fr) * 1998-03-31 1999-10-07 Hemosol Inc. Conjugues d'hemoglobine-polysaccharide
US6406839B1 (en) * 1993-06-04 2002-06-18 Biotime, Inc. Methods for using a plasma-like solution
US7977383B2 (en) 2002-05-17 2011-07-12 Dr. Franz Koehler Chemie Gmbh Protective solutions for organs
EP2442641A4 (fr) * 2009-06-16 2016-03-09 Univ Columbia Procédés d'amélioration des effets indésirables associés à la transfusion de globules rouges âgés

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4684482A (en) * 1984-01-26 1987-08-04 Oral-D (L.P.) Orally effective ion chelators
US4863964A (en) * 1985-07-02 1989-09-05 Biomedical Frontiers, Inc. Method for the stabilization of deferoxamine to chelate free ions in physiological fluid

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4900780A (en) * 1988-05-25 1990-02-13 Masonic Medical Research Laboratory Acellular resuscitative fluid

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4684482A (en) * 1984-01-26 1987-08-04 Oral-D (L.P.) Orally effective ion chelators
US4863964A (en) * 1985-07-02 1989-09-05 Biomedical Frontiers, Inc. Method for the stabilization of deferoxamine to chelate free ions in physiological fluid

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0523037A4 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5674857A (en) * 1992-02-20 1997-10-07 Hyal Pharmaceutical Corporation Use of hyaluronic acid to repair ischemia reperfusion damage
US6406839B1 (en) * 1993-06-04 2002-06-18 Biotime, Inc. Methods for using a plasma-like solution
WO1995014492A3 (fr) * 1993-11-29 1995-06-22 Access Pharma Inc Agents in vivo comprenant des chelates d'ions de metaux radioactifs avec des saccharides et glycosaminoglycanes acides, qui ameliorent la localisation selective des sites, le mecanisme de fixation, la sensibilite et les profils cinetiques dans l'espace
WO1999049897A1 (fr) * 1998-03-31 1999-10-07 Hemosol Inc. Conjugues d'hemoglobine-polysaccharide
US6500930B2 (en) 1998-03-31 2002-12-31 Hemosol Inc. Hemoglobin-polysaccharide conjugates
US7977383B2 (en) 2002-05-17 2011-07-12 Dr. Franz Koehler Chemie Gmbh Protective solutions for organs
US9603354B2 (en) 2002-05-17 2017-03-28 Dr. Franz Koehler Chemie Gmbh Protective solutions for organs
EP2442641A4 (fr) * 2009-06-16 2016-03-09 Univ Columbia Procédés d'amélioration des effets indésirables associés à la transfusion de globules rouges âgés

Also Published As

Publication number Publication date
EP0523037A4 (en) 1993-07-28
EP0523037A1 (fr) 1993-01-20

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