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EP0523037A1 - Technique de reanimation par administration de fluide - Google Patents

Technique de reanimation par administration de fluide

Info

Publication number
EP0523037A1
EP0523037A1 EP90907852A EP90907852A EP0523037A1 EP 0523037 A1 EP0523037 A1 EP 0523037A1 EP 90907852 A EP90907852 A EP 90907852A EP 90907852 A EP90907852 A EP 90907852A EP 0523037 A1 EP0523037 A1 EP 0523037A1
Authority
EP
European Patent Office
Prior art keywords
biopolymer
dfo
fluid resuscitation
fluid
deferoxamine
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.)
Withdrawn
Application number
EP90907852A
Other languages
German (de)
English (en)
Other versions
EP0523037A4 (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 claimed from CA002084073A external-priority patent/CA2084073A1/fr
Publication of EP0523037A1 publication Critical patent/EP0523037A1/fr
Publication of EP0523037A4 publication Critical patent/EP0523037A4/en
Withdrawn legal-status Critical Current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)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (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.
EP19900907852 1990-03-30 1990-03-30 Fluid resuscitation Withdrawn EP0523037A4 (en)

Applications Claiming Priority (2)

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

Publications (2)

Publication Number Publication Date
EP0523037A1 true EP0523037A1 (fr) 1993-01-20
EP0523037A4 EP0523037A4 (en) 1993-07-28

Family

ID=25675695

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19900907852 Withdrawn EP0523037A4 (en) 1990-03-30 1990-03-30 Fluid resuscitation

Country Status (2)

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

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5672334A (en) * 1991-01-16 1997-09-30 Access Pharmaceuticals, Inc. Invivo agents comprising cationic metal chelators with acidic saccharides and glycosaminoglycans
CA2061567C (fr) * 1992-02-20 1998-02-03 Rudolf E. Falk Utilisation de l'acide hyaluronique pour reparer les dommages de reperfusion de l'ischemie
WO1994028950A1 (fr) * 1993-06-04 1994-12-22 Biotime, Inc. Solution semblable au plasma
CA2233725A1 (fr) * 1998-03-31 1999-09-30 Hemosol Inc. Complexes d'amidon hydroxyethyles d'hemoglobine
DE10222561B4 (de) 2002-05-17 2009-12-10 Dr. Franz Köhler Chemie GmbH Protektive Lösung zur Verhinderung von Ischämieschäden
JP2012530133A (ja) * 2009-06-16 2012-11-29 ザ トラスティーズ オブ コロンビア ユニバーシティ イン ザ シティ オブ ニューヨーク 時間の経った赤血球の輸血に伴う副作用を改善するための方法

Family Cites Families (3)

* 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
US4900780A (en) * 1988-05-25 1990-02-13 Masonic Medical Research Laboratory Acellular resuscitative fluid

Also Published As

Publication number Publication date
WO1991015215A1 (fr) 1991-10-17
EP0523037A4 (en) 1993-07-28

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