WO1995003068A1 - Procede d'administration d'hemoglobine - Google Patents

Procede d'administration d'hemoglobine Download PDF

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Publication number
WO1995003068A1
WO1995003068A1 PCT/US1994/006030 US9406030W WO9503068A1 WO 1995003068 A1 WO1995003068 A1 WO 1995003068A1 US 9406030 W US9406030 W US 9406030W WO 9503068 A1 WO9503068 A1 WO 9503068A1
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WO
WIPO (PCT)
Prior art keywords
hemoglobin
patient
blood
administering
administered
Prior art date
Application number
PCT/US1994/006030
Other languages
English (en)
Inventor
George S. Hughes, Jr.
Original Assignee
The Upjohn Company
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 The Upjohn Company filed Critical The Upjohn Company
Priority to AU73121/94A priority Critical patent/AU7312194A/en
Priority to JP7505126A priority patent/JPH09500642A/ja
Priority to EP94923169A priority patent/EP0710115A1/fr
Publication of WO1995003068A1 publication Critical patent/WO1995003068A1/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
    • A61K38/41—Porphyrin- or corrin-ring-containing peptides
    • A61K38/42—Haemoglobins; Myoglobins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock

Definitions

  • the present invention is directed toward a novel approach for administering hemoglobin to patients in need of replacing, maintaining or elevating their hemoglobin levels.
  • the traditional techniques for administering blood components has been to give a continuous infusion.
  • a blood transfusion for elective or non-emergence indications involves administering one to two units of whole blood or packed red cells to a patient over a four hour period or longer.
  • the subject method utilizes pharmacokinetic principals to first administer a loading dose and then a continuous small dose infusion to maintain a desired hemoglobin level in the blood stream. This method is particularly useful in the infusion of blood substitutes where it is desirable to maintain a relatively low level of unnatural blood in the patient's blood stream to avoid toxicity or rejection while providing the necessary benefits of oxygen transport.
  • the present invention attempts to solve these problems by introducing a novel method for administration of blood components, especially blood substitutes. It has now been discovered that by employing pharmacokinetic principals instead of large scale transfusions one can minimize the amount of foreign bodies introduced into the patient but still replace, maintain or elevate a desired hemoglobin level to provide necessary oxygen transport in the patient.
  • the present invention is a method for administering hemoglobin to a patient in need thereof comprising the administration of a loading dose of a hemoglobin containing composition based upon the concentration of hemoglobin desired in a patient and the patient's apparent volume of distribution; and thereafter the administration of a maintenance dose of the hemoglobin containing composition calculated to maintain a steady-state hemoglobin level in the patient.
  • the maintenance dose can be administered as a continuous infusion or as single doses.
  • the hemoglobin containing composition can be a blood substitute comprising hemoglobin suspended in a pharmaceutically acceptable vehicle for administration such as modified regular donated or transfused blood, packed red blood cells, reconstituted human or other animal species blood synthesized for administration to the patient, a recombinant or other blood substitute.
  • a pharmaceutically acceptable vehicle for administration is any liquid or diluent suitable for admixing hemoglobin which does not interfere with its oxygen carrying role or have an adverse effect on the patient.
  • Such vehicles are well known in the art and include for example, normal saline or lactated Ringer's.
  • Preferred blood substitutes are crosslinked hemoglobin essentially free of 64,000 molecular weight or less hemoglobin components (i.e., tetramer free).
  • the present invention discloses the pharmacokinetic dosing of blood components, preferably hemoglobin to a patient in need of having their hemoglobin level replaced due to blood lose, maintained or modified for a therapeutic purpose, elevated or otherwise controlled.
  • a patient can be any mammal having a hemoglobin oxygen transportation mechanism for sustaining cell function. This administration procedure should be effective for all blood components such as white blood cells, red blood cells, platelets, plasma, Factor VIII, IX and XI.
  • Particularly useful in the subject method is the administration of blood substitutes such as blood or blood components not derived from the patient that is receiving such blood or blood component.
  • the present method is advantageously used for blood substitutes because it allows the practitioner to minimize the total exposure of the transfused blood to the patient over time, thus avoiding any dose related toxicity problems from the particular blood source utilized.
  • Typical blood substitutes are porcine derived blood components available from DNX, Princeton, NJ; recombinant derived blood components available from Somatogen, Inc., Boulder, CO (US Patent 5,028,588); processed human blood such as by purifying and crosslinking outdated human blood available from Northfield Labs Inc., Evanston, IL (US Patents 4,826,811, 5,194,590 and 5,194,270); and Baxter, Northfield, IL (US Patents 5,128,452, 4,861,867 and 4,831,012); bovine derived blood substitutes available from Enzon, S. Plainfield, NJ, and Biopure, Boston, MA (US Patent 5,084,558); and oxygen carrying fluorocarbons available through Alliance Pharm. Corp., San Diego, CA.
  • the hemoglobin is generally administered to a patient in need of such hemoglobin in a pharmaceutically acceptable vehicle.
  • a pharmaceutically acceptable vehicle for administration is any liquid or diluent suitable for admixing hemoglobin which does not interfere with its oxygen carrying role or have an adverse effect on the patient.
  • Such vehicles are well known in the art and include for example, normal saline or lactated Ringer's.
  • the subject method provides the distinct advantage of minimizing the amount of blood substitute needed to replace the oxygen carrying cat ty of the native hemoglobin lost from a patient.
  • the subject method allows the practitioner to elevate or maintain oxygen carrying capacity of the blood stream by administering controlled minimal amounts of a blood substitute.
  • large molecular weight hemoglobin substitutes blood substitutes
  • blood substitutes are administered because these have been found to have fewer side effects or adverse reactions.
  • High molecular weight, crosslinked hemoglobin are preferred because they result in the formation of high molecular weight oligomers of the hemoglobin tetramer which are extremely resistant to renal filtration and more stable to oxidation at physiological temperature than e ⁇ her unmodified hemoglobin or hemoglobin crosslinked to only the tetramer-dimer level.
  • the crosslinked, polymerized hemoglobin which are relatively free of tetramer or dimer components, i.e., having molecular weights greater than 64,000, but still possessing a P50 or oxygen affinity which is low enough to effectively transport oxygen and then release it to the cells of a living organism.
  • Hemoglobin compositions having less than 10% tetramer or dimer components are preferred with less than 6% being particularly preferred and essentially tetramer free compositions being most preferred. Examples of such tetramer free blood substitutes are disclosed in US Patent 5,194,590 to Northfield Laboratories, Inc., Evanston, ⁇ .
  • blood substitutes derived from various blood sources can also be filtered by molecular weight sieves or filters to eliminate essentially all tetramer and lower weight material to prepare this preferred material.
  • Methods to prepare high molecular weight blood substitutes can include a step where the purified, cross-linked hemoglobin is size excluded to remove low molecular weight hemoglobin (less than 64,000). Typically, this size exclusion is by low pressure size exclusion chromatography.
  • the blood substitutes have an oxygen affinity of the hemoglobin or P50 value which is low enough to effectively transport oxygen and then release it to the cells of a living organism more efficiently than native human hemoglobin.
  • the P50 is the partial pressure of oxygen at which 50% of the available sites have bound oxygen.
  • Pharmacokinetic dosing is a well understood method of dosing patients for intravenous drugs but has not been employed for transfusing blood. Pharmacokinetic dosing relies on calculating a loading dose usually based on the patient's weight and then a corresponding continuous infusion rate or maintenance dose, for maintaining a particular dosage level in the patient. The determination for the dose to use for the loading dose will be based on dosing in grams of hemoglobin per body weight or volume of fluid (mis of the blood substitute as based upon its content of hemoglobin) needed.
  • the continuous infusion rate or maintenance dosage regimen is to achieve a consistently desired concentration with a dose size and frequency that is practical without marked fluctuations in blood component, hemoglobin, concentrations. Consistency of concentrations is best maintained with continuous intravenous infusions or very frequent small doses. Particularly preferred with respect to the administration of a blood substitute is that the maintenance dose or continuous infusion is at a level to not produce toxicity and such that the concentration does not drop for long below the therapeutic range.
  • the maintenance dose is directed influenced by the clearance rate of the particular blood substitute employed and inversely related to changes in half life. These factors are known for the variously available blood substitutes and can be easily factored into any maintenance calculation formula.
  • the pharmacokinetics method of dosing is particular favorable for blood substitutes because it is easy to monitor not only hemoglobin level in a patient but also to monitor the individual species of the blood substitute itself. Thus, pharmacokinetic models for the particular blood substitute are easily prepared for proper administration. For example, if one desires a specific plasma hemoglobin concentration, one can calculate the amount (grams or milliliters) that are needed to raise the hemoglobin levels based on the patient's body weight. A loading dose given over a specified time to achieve these target concentrations.
  • a continuous infusion is started immediately after the loading dose is given.
  • the purpose of the loading dose is to be able to maintain steady-state plasma concentrations of hemoglobin.
  • the duration of administration of the continuous infusion will be up to 24 hours, but may exceed this, if clinically indicated. Furthermore, this dosing may be done anywhere in the preoperative period or during the operation itself. Small repeated bolus (or loading doses) may be necessary to maintain plasma hemoglobin levels, in the case of surgical blood loss, in excess of predicted amounts.
  • the procedure above should not be limited to a particular type of surgery, but globally to the patient who is in need of a transfusion .

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Un procédé pour administrer de l'hémoglobine à un patient à traiter consiste en une administration pharmacocinétique dans laquelle une composition renfermant de l'hémoglobine est tout d'abord administrée sous forme de dose d'attaque calculée sur la base de la concentration d'hémoglobine souhaitée chez ledit patient et de l'espace de diffusion apparent de ce dernier; et est ensuite administrée sous forme de dose d'entretien calculée pour maintenir chez le patient un taux d'hémoglobine stationnaire. La dose d'entretien peut être administrée sous forme d'injection continue ou de doses individuelles. Ce procédé est utile pour l'administration de tous les constituants sanguins et de toutes les sources sanguines, et peut être mis en ÷uvre dans des situations d'urgence, traumatiques, pré-chirurgicales, chirurgicales, ou postopératoires lorsqu'il est souhaitable de remplacer, réguler, augmenter ou maintenir chez un patient la concentration d'un constituant sanguin, notamment l'hémoglobine.
PCT/US1994/006030 1993-07-23 1994-06-02 Procede d'administration d'hemoglobine WO1995003068A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU73121/94A AU7312194A (en) 1993-07-23 1994-06-02 Method for administering hemoglobin
JP7505126A JPH09500642A (ja) 1993-07-23 1994-06-02 ヘモグロビンの投与方法
EP94923169A EP0710115A1 (fr) 1993-07-23 1994-06-02 Procede d'administration d'hemoglobine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US9725893A 1993-07-23 1993-07-23
US08/097,258 1993-07-23

Publications (1)

Publication Number Publication Date
WO1995003068A1 true WO1995003068A1 (fr) 1995-02-02

Family

ID=22262503

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1994/006030 WO1995003068A1 (fr) 1993-07-23 1994-06-02 Procede d'administration d'hemoglobine

Country Status (4)

Country Link
EP (1) EP0710115A1 (fr)
JP (1) JPH09500642A (fr)
AU (1) AU7312194A (fr)
WO (1) WO1995003068A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998020886A1 (fr) * 1996-11-12 1998-05-22 Baxter International Inc. Utilisation pre-traumatique d'hemoglobine
US5970985A (en) * 1996-11-12 1999-10-26 Baxter International, Inc. Use of hemoglobin to treat systemic inflammatory response syndrome
US6610702B2 (en) 2000-08-01 2003-08-26 Gmp Oxycell, Inc. Ammonium salts of inositol hexaphosphate, and uses thereof
US7618954B2 (en) 2002-04-29 2009-11-17 Normoxys, Inc. Inositol pyrophosphates, and methods of use thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1987007832A1 (fr) * 1986-06-20 1987-12-30 Northfield Laboratories, Inc. Substitut d'hematie acellulaire
US5194590A (en) * 1986-06-20 1993-03-16 Northfield Laboratories, Inc. Acellular red blood cell substitute

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1987007832A1 (fr) * 1986-06-20 1987-12-30 Northfield Laboratories, Inc. Substitut d'hematie acellulaire
US5194590A (en) * 1986-06-20 1993-03-16 Northfield Laboratories, Inc. Acellular red blood cell substitute

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
FILE SERVER STN KARLSRUHE,FILE MEDLINE ABSTRACT NO.77139496 & FORTSCHR MED, (1977 APR 7) 95 (13) 858-66 *
FILE SERVER STN KARLSRUHE,FILE MEDLINE ABSTRACT NO.84102558 & AM J VET RES, (1983 DEC) 44 (12) 2271-6 *
FILE SERVER STN KARLSRUHE,FILE MEDLINE ABSTRACT NO.86048841 & AM J VET RES, (1985 OCT) 46 (10) 2175-8 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998020886A1 (fr) * 1996-11-12 1998-05-22 Baxter International Inc. Utilisation pre-traumatique d'hemoglobine
US5804551A (en) * 1996-11-12 1998-09-08 Baxter International Inc. Pretraumatic use of hemoglobin
US5970985A (en) * 1996-11-12 1999-10-26 Baxter International, Inc. Use of hemoglobin to treat systemic inflammatory response syndrome
US6610702B2 (en) 2000-08-01 2003-08-26 Gmp Oxycell, Inc. Ammonium salts of inositol hexaphosphate, and uses thereof
US7618954B2 (en) 2002-04-29 2009-11-17 Normoxys, Inc. Inositol pyrophosphates, and methods of use thereof
US7648970B2 (en) 2002-04-29 2010-01-19 Normoxys, Inc. Inositol pyrophosphates, and methods of use thereof
US9078908B2 (en) 2002-04-29 2015-07-14 Normoxys, Inc. Inositol pyrophosphates, and methods of use thereof

Also Published As

Publication number Publication date
JPH09500642A (ja) 1997-01-21
EP0710115A1 (fr) 1996-05-08
AU7312194A (en) 1995-02-20

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