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WO2000069427A1 - Traitement de l'ischemie des membres et composition a cet effet - Google Patents

Traitement de l'ischemie des membres et composition a cet effet Download PDF

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Publication number
WO2000069427A1
WO2000069427A1 PCT/US1999/010867 US9910867W WO0069427A1 WO 2000069427 A1 WO2000069427 A1 WO 2000069427A1 US 9910867 W US9910867 W US 9910867W WO 0069427 A1 WO0069427 A1 WO 0069427A1
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composition
mixtures
group
acid
amount
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Scott Howell Davis
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WALKER PAUL MOORE
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WALKER PAUL MOORE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/01—Hydrocarbons
    • A61K31/015—Hydrocarbons carbocyclic
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7016—Disaccharides, e.g. lactose, lactulose
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
    • 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
    • A61K38/38—Albumins
    • 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
    • A61K38/41—Porphyrin- or corrin-ring-containing peptides
    • A61K38/42—Haemoglobins; Myoglobins

Definitions

  • This invention is directed to a composition and method for the treatment of circulatory occlusions, and specifically occlusions of the limbs.
  • vascular occlusions occur, the adequate flow of blood is presumptively prevented from reaching cellular systems. Because all living tissues require oxygen, nutrients, water, and other substances, this decreased flow of essential substances to the cells may cause cellular damage or cellular death.
  • Circulatory shock is a common life-threatening pathophysiological state that occurs secondary to trauma, hemorrhage, burns, sepsis, allergic reactions, and heart failure. These different types of circulatory shock are characterized by reduced blood pressure, cardiac output, and fluid volume flow. Furthermore, organ ischemia and inflammation (edema) are associated with certain procedures that can result in shock-like microcirculatory abnormalities. Both systemic shock and localized reactions cause a reduction in blood flow and oxygen delivery to vital organs and tissues. This low blood flow condition causes local hypoxia, interruption of nutrient delivery, and can lead to loss of cellular and organ function and even death. Accepted definitive treatment for some types of circulatory shock and useful therapy in all types of shock includes fluid volume infusions.
  • the electrolytes present to facilitate such treatment include the ions of sodium, potassium, calcium, and chloride in concentrations approximating that found in normal blood plasma.
  • magnesium ion is often used in excess of normal blood concentrations as a counter-measure to the cell membrane calcium channel transport mechanism.
  • One way of obtaining normal electrolyte concentrations is by using Ringer's lactate solution as the source of the needed electrolytes.
  • the desired concentration of electrolytes can be achieved directly by dissolving salts of the desired ions in water, preferably distilled water.
  • isotonic fluid replacement solutions have been used, including isotonic crystalloid solutions mixed with macromolecular solutions of plasma proteins or synthesized molecules with oncotic properties (colloids) similar to natural plasma proteins; including albumin, dextran, hetastarch, and polygelatin in 0.9% NaCl solution.
  • colloids oncotic properties
  • volume expanders that facilitate volume loading of the circulatory system without deleterious interstitial and tissue results.
  • whole blood may also be used, but is expensive, often unavailable, carries some risk of viral contamination, and cross matching may delay therapy and may not be entirely curative of the affliction.
  • Crystalloids and colloids have been used as volume expanders, but generally must be infused in large volumes so as to include other necessary metabolites. Such large volumes may, however, cause peripheral and pulmonary edema and thus the benefits of use are diminished. Additionally, the large volume requirements for infusion of isotonic fluids further requires time delays and logistic difficulties associated with vascular delivery of effective therapy. Hyperosmotic crystalloid and hyperosmotic/hyperoncotic
  • (crystalloid/colloid) formulations offer some physiological benefits for the treatment of circulatory shock, including improved efficacy for restoration of overall cardiovascular function in animals and man compared to conventional resuscitation. Normalization of circulatory function has been obtained with such solutions. Small volumes of salt and concentrated dextran formulations have been shown to rapidly restore and sustain normalization of circulatory function in situations involving hemorrhagic shock. However, there remain important limitations regarding the use of these formulations for reperfusion of ischemic limbs. One limitation involves the generation or liberation of metabolic toxins from the previously ischemic tissue.
  • Hypertonic saline infusions in shocked animals and patients have been shown to cause an initial acidosis and hypokalemia. Circulatory shock is often associated with an acidosis and thus increased acidotic insult may be deleterious. Treatment with hypertonic saline can also lead to a hyperchloremic acidosis, possibly due to excessive chloride ion load. Some isotonic Ringers solutions and mildly hypertonic formulations mimic sodium and chloride concentration ratios found in plasma and are thought to decrease the likelihood of acidosis.
  • 5,130,230 discloses a blood substitute that comprises an aqueous solution of electrolytes at physiological concentration, a macromolecular oncotic agent, a biological buffer having a buffering capacity in the range of physiological pH, simple nutritive sugar or sugars, magnesium ion in a concentration sufficient to substitute for the flux of calcium ion across cell membranes, and an anticoagulant.
  • the blood substitute also includes a cardioplegic agent, such as potassium ion, in a concentration sufficient to prevent or arrest cardiac fibrillation.
  • Limb ischemia as a consequence of local mural thrombus or distal embolus which occludes the arterial supply of the leg results in both local tissue injury and a systemic inflammatory response.
  • the local injury can result in muscle death with release of sequestered intramuscular products which are deleterious to the patient including hyperkalemia, lactic acidosis and myoglobinuria.
  • the hyperkalemia and lactic acidosis can result in cardiac arrythmias and cardiac arrest, while the myoglobinuria can cause acute tubular necrosis and renal failure.
  • the applicants have delineated the time course of muscle necrosis following ischemia and the relationship between intramuscular adenine nucleotide depletion and tissue survival. Harris, K., Walker, P., Mickle,
  • Petrasek P., Liauw, S., Romaschin, A., Walker, P., "Salvage of Post-Ischemia Skeletal Muscle by Monoclonal Antibody Blockade of Neutrophil Adhesion Molecule CD 18, " J. of Surgical Research 56: 5-12, 1994.
  • composition of matter comprising: (a) an amount of an oncotic agent sufficient to adjust colloid osmotic pressure of the composition to about 28 mm Hg;
  • the oncotic agent is a member selected from the group consisting of serum albumin and glucan polymers and mixtures thereof.
  • Preferred glucan polymers are selected from the group consisting of low molecular weight starches and waxy starches comprising hydroxyethyl ether groups introduced into alpha (1-4) linked glucose units and mixtures thereof.
  • a preferred amount of the oncotic agent is about 5-10% (w/v).
  • the easily oxidizable energy substrate is a member selected from the group consisting of simple sugars and amino acids and mixtures thereof.
  • Preferred simple sugars are selected from the group consisting of glucose, fructose, and sucrose and mixtures thereof, and preferred amino acids are selected from the group consisting of glutamate and aspartate and mixtures thereof.
  • a preferred free radical scavenger is a member selected from the group consisting of vitamin E, vitamin C, b-carotene, lipoic acid, and N-acetyl cysteine and mixtures thereof.
  • a method of use of a composition of matter for treating ischemia comprising:
  • composition comprises (i) an amount of an oncotic agent sufficient to adjust colloid osmotic pressure of the composition to about 28 mm Hg;
  • references to a composition containing "a buffer” includes a mixture of two or more of such buffers
  • reference to "an oncotic agent” includes reference to one or more of such oncotic agents
  • reference to "a free radical scavenger” includes reference to a mixture of two or more free radical scavengers.
  • a "biologically acceptable” or “biologically compatible” component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.
  • composition of the present invention is useful for treatment of different ischemic organs, including limbs.
  • the pH of the presently claimed composition or perfusate should be maintained in the range of physiological pH, generally between about pH 6.8 and 7.9. More preferably, the pH is maintained in the range of about pH 7.4 to 7.8, and most preferably about pH 7.6.
  • the pH is maintained by the use of biologically acceptable or compatible buffers. Such buffers have buffering capacities in the range of physiological pH between about 6.8 and 7.9, but may have also have a buffering capacity outside the range of physiological pH. Many such biologically compatible buffers are well known to a person of ordinary skill in the art.
  • One buffer suitable for use in the perfusate according to the invention is N-2-hydroxyethylpiperazine-N-2-hydroxypropanesulfonic acid (HEPES) buffer, which has a useful pH range between 6.8 and 8.2.
  • Other buffers such as 3-(N-morpholino) propanesulfonic acid (MOPS, pH range 6.5- 7.9); N-tris[hydroxymethyl]methyl-2-aminoethanesulfonic acid; 2-([2-hydroxyl- l,l-bis(hydroxymethyl)ethyl] amino) ethanesulfonic acid (TES, pH range 6.8 - 8.2); 3-[N-tris(hydroxy- methyl) methylamino]-2-hydroxypropanesulfonic acid (TAPSO, pH range 7.2 - 8.2); 4-[2-hydroxyethyl]-l-piperazinepropanesulfonic acid (EPPS, pH range 7.3 - 8.7); tris(hydroxymethyl)aminomethane (THAM®, T
  • Such buffers will generally be used in sufficient amounts to maintain the pH of the presently claimed composition or perfusate in the range of physiological pH.
  • Examplary concentrations of biologically compatible buffers may range from about 10 mM to 200 mM, and more preferably from 25 mM to 100 mM. Mixtures of buffers may also be used.
  • the perfusate also includes a concentration of divalent metal ions of a type and in an amount sufficient to displace or block the effects of calcium ion at the cellular membrane.
  • Magnesium ion is preferred in this regard, and it is preferable to supply the magnesium ion by the addition of a chloride salt of magnesium.
  • the additional magnesium ion in the perfusate is believed to displace calcium ion in the so- called cellular membrane calcium channel.
  • the magnesium ion preferably should be present in an amount in the range of about 0.1-10 mM.
  • the perfusate contains about 0.5-2.0 mM Mg " in the form of MgCl 2
  • the formulation contain additional electrolytes.
  • Examplary preferred formulations and ranges of such electrolytes approximately are as follows: 115-175 mM sodium; 0.5-4 mM potassium, and more preferably 2-3 mM potassium; 90-160 mM chloride; and 0.25-0.45 mM calcium.
  • Reasonable variations of the preferred ranges of electrolytes as understood by those skilled in the art are also within the scope of the present invention.
  • the perfusate should also contain an oncotic agent.
  • oncotic agent is meant substances, generally macromolecules, that are of a size that is unable to leave the circulation by traversing the fenestrations of the capillary bed.
  • oncotic agents are exemplified by blood plasma expanders, which are known in general as macromolecules having a size sufficient to prevent their escape from the blood plasma through the circulatory capillary bed into the interstitial spaces of the body.
  • Human serum albumin is one well known plasma protein that is used to expand plasma volume.
  • Other well known blood plasma expanders include dextran, hetastarch, and polygelatin.
  • Polysaccharide blood plasma expanders are generally characterized as glucan polymers. Pentastarch is an artificial colloid derived from a waxy starch composed almost entirely of hydroxyethyl ether groups introduced into the alpha (1-4) linked glucose units.
  • polysaccharide derivatives may be suitable as oncotic agents in the perfusate according to this invention.
  • other polysaccharide derivatives are cross linked hydroxy ethyl starch products.
  • the polysaccharide be sufficiently large such that it not escape from the capillary bed of the treated vasculature.
  • the concentration of the oncotic agent in the perfusate is sufficient to achieve, when taken together with electrolytes and simple sugar discussed below, a colloid osmotic pressure approximating that of normal human serum, about 28 mm Hg.
  • a colloid osmotic pressure approximating that of normal human serum, about 28 mm Hg.
  • Dextran 40 when used, about 6% dextran 40
  • oncotic agents are generally present in amounts ranging from about 5.0 to 10.0% (w/v).
  • the perfusate according to the invention also includes a readily oxidizable energy substrate, such as simple sugars, amino acids, and the like.
  • concentration of the readily oxidizable substrate will generally be in a range of from about 1 mM to about 100 mM.
  • Simple sugars include sucrose, fructose, and glucose or dextrose (alpha-D-glucose); most preferred is dextrose.
  • Glucose at a concentration of about 3.6 g per liter or about 20 mM dextrose is preferred.
  • the perfusate of the present invention may include organic compounds that are easily oxidizable under biological conditions. Such easily oxidizable organic compounds would be glycolized and simultaneously enter the mitochondria (such as glutamate and aspartate).
  • the concentration of the nutritive sugar may be further varied in a range between about 1 mM and 1 M.
  • concentration of dextrose about 10 to 20 mM is used.
  • an osmolality adjusting agent is mannitol. The inclusion of mannitol is beneficial for adjusting the final osmolality of the perfusate without the need to reduce or augment the concentrations of other components.
  • Osmolality of the perfusate according to the invention will be in a range of about 300 to 450 milliosmoles with an osmolality of about 405 to 415 being preferred.
  • certain specific antioxidants or free radical scavengers including b-carotene, vitamin E (d-alpha-tocopherol), N-acetyl cysteine, lipoic acid, and vitamin C (ascorbic acid).
  • lipophilic e.g. vitamin E
  • hydrophilic e.g.
  • N-acetyl cysteine, vitamin C) antioxidants or a mixture thereof can be used in the formulation. These substances provide a protective effect against free radicals and oxidative damage that can occur in an ischemic limb. These ingredients can be added in the following amounts: vitamin E, 0-100 mM; b-carotene, 0-100 mM; N-acetyl cysteine, 5-100 mM; vitamin C, 1-50 mM; lipoic acid, 0-50 mM.
  • the concentration of free radical scavengers in the formulation should generally be in the range of about 5-200 mM, and preferably about 20-100 mM.
  • Optional ingredients that can be added to the formulation include stroma free hemoglobin (e.g. "HEMASOL”), acetyl-carnitine, desferal (as an iron chelator), and SCR1 (a complement regulatory protein for preventing edema).
  • Carnitine (3-carboxy-2-hydroxypropyl)trimethylammonium hydroxide, inner salt; (CAR), one of the nutrients supplied mainly from meat and dairy products, is an essential cofactor for many metabolic interactions in the body.
  • CAR (3-carboxy-2-hydroxypropyl)trimethylammonium hydroxide, inner salt
  • the function of CAR to excrete an excess amount of organic acids upon their precipitation in the body has been clearly demonstrated in acidemia such as propionic acidemia and methylmalonic aciduria.
  • acyl-coenzyme A (CoA)
  • Carnitine accepts organic acid from the corresponding acyl CoA.
  • Carnitine facilitates the excretion of organic acids from the mitochondria by the reverse sequence of the reaction responsible for the influx of fatty acids into the mitochondria.
  • Each alternative additive could be included in a concentration commensurate with envisioned purpose in ranges of about 0 to 25 mM.
  • EXAMPLE 1 By way of example and not limitation, the following formulae represent specific embodiments of the invention. They may be prepared by dissolving solid ingredients in sterile distilled water and/or mixing solutions of such ingredients in proper proportions. Formulation I
  • Formulation IV 10% PENTASPAN 30 mM glucose 50 mM TES buffer, pH 7.5 120 mM sodium chloride 3.0 mM potassium chloride 5 mM aspartate
  • dextran 40 25 mM glucose 25 mM fructose 100 mM MOPS buffer, pH 7.6 150 mM sodium chloride 2.2 mM potassium chloride 0.25 mM calcium chloride 2 mM magnesium chloride 25 mM N-acetyl cysteine 10 mM ascorbic acid 10 mM acetyl carnitine
  • Formulation VII 7.5% (w/v) PENTASPAN 50 mM glucose 50 mM Tris buffer, pH 7.4 140 mM sodium chloride 2 mM potassium chloride 5 mM glutamate
  • 1 mM stroma free hemoglobin Formulation IX pH may be up to 8.0 at room temperature - for example, pH 7.6 at 37°
  • the perfusate of the present invention can be administered through the use of a specialized arterial cannula composed of two main segments.
  • This cannula provides simultaneous occlusion and perfusion capabilities in the arterial circulation vasculature.
  • the artery is first occluded by the occlusion segment thereby facilitating the incorporation of the pure perfusate into the vasculature.
  • the perfusate solution is next introduced into the circulatory system in the region to be treated through the same occlusion-perfusion cannula.
  • the perfusate infused into the muscle tissue is drained out through a retrograde venous cannula composed of an occlusive balloon at the distal end of the cannula and fenestrations proximal to the balloon through which the perfusate enters the cannula. In this manner the perfusate is introduced into the region of the limb in need thereof and subsequently drained from the limb.
  • the composition is infused at a pO 2 not to exceed about 150 mm Hg.
  • EXAMPLE 2 the ischemic lower extremity of a patient in need of treatment therefor is perfused with a composition according to the present invention to control edema, minimize free radical mediated injury, and provide a fluid that is hypocalcemic, alkalotic, and contains substrates that can be glycolized and simultaneously enter the mitochondria.
  • An arterial balloon catheter is inserted into the common femoral artery through an arteriotomy performed by standard anesthesia and vascular surgery procedures.
  • a venous balloon cannula is placed in the common femoral vein proximal to the deep femoral vein via a small venotomy using a purse string suture to secure the cannula.
  • a blood collection bag to collect venous perfusate is connected to the femoral venous balloon cannula.
  • the ischemic organ for example, limb such as an arm or a leg
  • a perfusate composition according to Example 1 at a rate of 100-200 ml/min at a pressure of 80-150 mmHg via a Sarns single chamber perfusion pump or rigid pressure bag attached to the femoral arterial balloon cannula.
  • the femoral venous effluent is collected at the same rate.

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Abstract

La présente invention concerne une formulation aqueuse et un procédé permettant la perfusion des membres ischémiques. Cette formulation contient un oncotique, des électrolytes, un substrat d'énergie facilement oxydable, un ion magnésium, un tampon maintenant le pH de la formulation à un niveau physiologique et un accepteur de radicaux libres.
PCT/US1999/010867 1999-05-17 1999-05-17 Traitement de l'ischemie des membres et composition a cet effet Ceased WO2000069427A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1256360A1 (fr) * 2001-05-10 2002-11-13 Université de Liège Composition médicamenteuse hypertonique et en particulier utilisation dans la fluidothérapie
EP2167132A4 (fr) * 2007-05-29 2012-08-15 Univ South Carolina Liquide de réanimation
GR20180100514A (el) * 2018-11-07 2020-06-15 Πανεπιστημιο Πατρων Φαρμακευτικοι συνδυασμοι και κιτ για την προληψη ή την θεραπεια του πονου και αλλων επιπλοκων της ορθοπαιδικης ή αγγειακης χειρουργικης και του πολλαπλου τραυματος

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5130230A (en) * 1988-05-02 1992-07-14 Cryomedical Sciences, Inc. Blood substitute
US5405742A (en) * 1993-07-16 1995-04-11 Cyromedical Sciences, Inc. Solutions for tissue preservation and bloodless surgery and methods using same

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5130230A (en) * 1988-05-02 1992-07-14 Cryomedical Sciences, Inc. Blood substitute
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EP1256360A1 (fr) * 2001-05-10 2002-11-13 Université de Liège Composition médicamenteuse hypertonique et en particulier utilisation dans la fluidothérapie
EP2167132A4 (fr) * 2007-05-29 2012-08-15 Univ South Carolina Liquide de réanimation
GR20180100514A (el) * 2018-11-07 2020-06-15 Πανεπιστημιο Πατρων Φαρμακευτικοι συνδυασμοι και κιτ για την προληψη ή την θεραπεια του πονου και αλλων επιπλοκων της ορθοπαιδικης ή αγγειακης χειρουργικης και του πολλαπλου τραυματος

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