US3639213A - Streptokinase chemically bonded to a carbohydrate matrix - Google Patents

Streptokinase chemically bonded to a carbohydrate matrix Download PDF

Info

Publication number
US3639213A
US3639213A US881632A US3639213DA US3639213A US 3639213 A US3639213 A US 3639213A US 881632 A US881632 A US 881632A US 3639213D A US3639213D A US 3639213DA US 3639213 A US3639213 A US 3639213A
Authority
US
United States
Prior art keywords
streptokinase
weight
dextran
composition
support medium
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.)
Expired - Lifetime
Application number
US881632A
Other languages
English (en)
Inventor
Leonard George Ginger
Adaline Nicoles Mather
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.)
Baxter International Inc
Original Assignee
Baxter Laboratories 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 Baxter Laboratories Inc filed Critical Baxter Laboratories Inc
Application granted granted Critical
Publication of US3639213A publication Critical patent/US3639213A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

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
    • A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • A61K38/166—Streptokinase
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N11/00—Carrier-bound or immobilised enzymes; Carrier-bound or immobilised microbial cells; Preparation thereof
    • C12N11/02—Enzymes or microbial cells immobilised on or in an organic carrier
    • C12N11/10—Enzymes or microbial cells immobilised on or in an organic carrier the carrier being a carbohydrate

Definitions

  • the blood of each patient must be titrated to determine the proper initial dose of enzyme sufficient to nullify the antibodies present in the blood and to provide the proper level of streptokinase enzyme to function as desired, while avoiding the deleterious effects of an excessive dose of streptokinase.
  • a subsequent treatment with streptokinase at a later date may require an increased streptokinase dosage.
  • a subsequent dose may be dangerous since the patient can become sensitized to the enzyme, and may thus undergo a severe allergic reaction.
  • doses of the enzyme must be adequate in the first place in order to effectively dissolve blood clots, and they must be administered repeatedly or continuously, generally by intravenous drip, since the enzyme is metabolized by the body in a relatively short period of time.
  • composition of this application comprises 1 part by weight of streptokinase, chemically bonded to from 1 to 500 parts by weight of a carbohydrate support medium.
  • This material exhibits a streptokinaselike clot dissolving activity, yet it has improved stability in the blood stream, and is less subject to inactivation by blood antibodies than is free streptokinase. Because of this fact, it becomes frequently unnecessary to titrate the individual patients blood, so that a standardized dose can be more easily utilized to achieve the dissolution of blood clots, emboli and the like.
  • streptokinase is covalently bonded to the carbohydrate support medium with from l to 200 parts of the support medium being present for each part by weight of streptokinase. It is also preferred for the carbohydrate support medium used to be water dispersible or water soluble so that the chemically bonded product is able to form colloidal solutions having a particle size of less than about 2 microns. Such colloidal solutions of streptokinase chemically bonded to a carbohydrate can be directly injected, and can circulate freely in the blood without causing serious side effects due to blockage of capillaries and small blood vessels. In this manner, the chemically bonded streptokinase is brought into contact with the clot to act on it.
  • streptokinase is produced by many strains of hemolytic streptococci, including those of Group A and Lancefield Group C streptococci.
  • the selected streptococci can be conventionally cultured, and the crude streptokinase isolated in a conventional manner. Pyrogenic materials can be removed from the streptokinase preparation, for example, by utilizing the teachings of the Mather et al. US. Pat. No. 3,255,094.
  • the support media used herein may constitute carbohydrates such as cellulose, dextran, starch, dextrins, or other polysaccharides, preferably having a molecular weight of about 70,000 to about 500,000.
  • Carbohydrate derivatives are also included in the term carbohydrate, including alkali metal containing derivatives, carbohydrate-containing polymers such as copolymcrs of sucrose and epichlorohydrin,
  • carbohydrate support media are chemically modified to provide bonding sites for the streptokinase enzyme.
  • a carbohydrate support medium having pending carboxylic acid groups such as the carboxyalkylcarbohydrates, can be converted to an azide in the manner typified in example I below.
  • the azide is then reacted directly with streptokinase, generally at a low temperature between about 0 C.
  • R is the carbohydrate support medium having a bond on an oxygen atom thereof connected to the moiety within the brackets
  • R is said streptokinase having a bond connected to the moiety, typically on an amino nitrogen or a sulfhydryl sulfur atom of the streptokinase, referring to the condition of the atom of the streptokinase prior to reaction with the moiety
  • n is a positive integer, preferably 1 or 2.
  • Another technique for producing a chemical bond between a carbohydrate support medium having pendant carboxylic acid groups and streptokinase is to add a diorganocarbodiimide to a mixture of the support medium and streptokinase in the manner exemplified by examples 4, 5, and 6, to yield a product in which carbonyl groups of the support mediums carboxylic acid groups are directly bonded to the streptokinase, typically to amine nitrogen atoms thereof.
  • Carbohydrate support media can be covalently bonded to streptokinase as illustrated in example 3 by the use of a triazine of the formula to covalently bond streptokinase to a carbohydrate through a moiety of the formula shown within the brackets in which R and R are as defined above, and X is a halogen, hydrogen, or monovalent hydrocarbon radical of no more than about four carbon atoms. When X is a halogen, it also can be replaced with R or R' group.
  • carbohydrate support media can be chemically bonded to streptokinase by means of cyanogen bromide as shown in example 6.
  • the activation reaction is generally run under alkaline conditions, e.g., a pH of at least 7.5 and preferably above 1 I.
  • compositions of this invention can be used to dissolve blood clots and the like by direct administration of a colloidal solution to the clot site, or by passing blood, plasma, or the like through a bed of an insoluble composition of this invention. In this latter circumstance, it is generally preferred to use larger particle sizes, generally in the visible range.
  • An extracorporial circuit can be arranged by loosely packing a particulate composition of this invention into a cartridge, in which blood plasma, whole blood, or another solution passes through tubing into one end of the cartridge, through the par ticulate composition of the invention, and out of the particulate composition, generally past a filter and through an exit tubing. If desired, the blood or other fluid can be directly withdrawn from a subject and/or then administered to the subject after treatment.
  • reaction columns containing the material of this invention can be used, or the material of this invention can be impregnated in a matrix such as silicone rubber and incorporated in tubing through which the material to be treated passes.
  • EXAMPLE 1 Ten grams of the sodium salt of carboxymethyl dextran having a weight average molecular weight of about 100,000, 15 ml. of concentrated hydrochloric acid, and 250 ml. of methanol are heated at reflux for 4 hours. The solvent is removed by vacuum distillation, and the residue suspended in 50 ml. of methanol. A 20 percent solution of hydrazine in methanol is added and stirred until no more white precipitate is formed. The precipitate is then stirred for four hours, filtered and dried. Five grams of the precipitated product are then resuspended in 150 ml. of 2 percent hydrochloric acid, and cooled to between and 5 C. An excess of dilute nitrous acid solution is added slowly with constant stirring.
  • the resulting product is precipitated and washed with methanol.
  • the precipitate consists largely of dextran having units linked to oxygen atoms of the dextran, the material being informally called dextran azide.
  • the dextran azide is redissolved in a water solution of about 0.05 to 0.1M disodium phosphate and 0.9 weight percent sodium chloride, adjusted to about pH 7.0.
  • the concentration of dextran azide is adjusted to about 25 to 50 mg. per ml. of the phosphate-saline buffered solution.
  • Purified streptokinase is then dissolved in the above solution at a level of about 100,000 enzyme units per ml. of solution, and allowed to stand for about 12 hours (the enzyme units being as defined by the National Institutes of Health).
  • the resulting mixture is then passed through a molecular sieve comprising a material such as the cross-linked dextran sold under the name Sephadex 150 or Sephadex 200, or the commercially available material Biogel P, which is a crosslinked polyacrylamide.
  • a molecular sieve comprising a material such as the cross-linked dextran sold under the name Sephadex 150 or Sephadex 200, or the commercially available material Biogel P, which is a crosslinked polyacrylamide.
  • the resulting filtrate is a solution containing dextran which is covalently bonded to streptokinase by a linkage or moiety shown within the brackets of the formula 0 niomlig rn' in which R is dextran, bonded to the linkage through an oxygen atom of the dextran,and R is the streptokinase connected to the linkage. It is believed that the major portion of the linkages to the streptokinase are connected thereto through amine nitrogen atoms of the streptokinase. The free streptokinase is absorbed by the molecular sieve, and can be removed by further washing.
  • the resulting product exhibits the capability of dissolving blood clots and the like, while also showing growing greater stability at ambient and warm temperatures when compared with free streptokinase.
  • free streptokinase can be separated from the covalently bonded dextran-streptokinase composition by precipitation of thefree streptokinase with ammonium sulfate, and then removing of the precipitate by filtering or centrifuging. Excess salt and other ionic materials can be removed'from the dextrau-streptokinase solution by dialysis or in any other conventional manner.
  • EXAMPLE 3 A. Dextran having a molecular weight of about 200,000 is dissolved in a saturated solution of sodium bicarbonate. Cyanuric chloride is then added in such a concentration as to provide about one mole of cyanuric chloride for each mole ofON a group present upon the dextran. The mixture is then stirred for about 1 hour at room temperature, filtered to remove any insoluble material, and dialyzed against saturated sodium bicarbonate to remove any unreacted cyanuric chloride.
  • Purified streptokinase is added to provide about 100,000 enzyme units (as defined above) per ml. of solution containing the dissolved cyanuric chloride-dextran reaction product, and the mixture is allowed to react for about 14 hours at 5 C. Any remaining free streptokinase is separated from the resulting covalently bonded dextran-streptokinase by passing the material through a molecular sieve or by precipitation of the free streptokinase with ammonium sulfate.
  • the resulting material exhibits blood clot dissolving activity, and has increased stability with respect to free streptokinase.
  • EXAMPLE 6 Two grams of cyanogen bromide are dissolved in 50 ml. of distilled water adjusted to a pH of l 1.5 by addition of aqueous sodium hydroxide solution. Two grams of dextran having a weight average molecular weight of 500,000 are added, and the suspension is magnetically stirred for approximately 30 minutes. The dextran is precipitated by addition of 50 percent ethyl alcohol, centrifuged, and washed with absolute ethanol. Excess ethanol is removed under vacuum.
  • the resulting material comprises dextran chemically bonded to streptokinase, and has streptokinase clot dissolving activity.
  • a composition of matter which comprises one part by weight of streptokinase, covalently bonded to from l to 500 parts by weight of a dextran support medium having a molecular weight of about 70,000 to 500,000, said composition of matter being capable of forming colloidal solutions having a particular size ofless than about 2 microns.
  • composition of claim 1 in which said dextran support medium is modified with carboxyalkyl groups.
  • composition of claim 1 in which from 10 to 200 parts by weight of said dextran support medium are present per part by weight of streptokinase.
  • composition of claim 1 in which said streptokinase is bonded to a dextran support medium by at least one moiety shown within the brackets of the formula in which R is said dextran support medium having a bond on an oxygen atom thereof connected to said moiety, R is said streptokinase having a bond connected to said moiety on an atom thereof and n is a positive integer.
  • composition of claim 4 in which from l0 to 200 parts by weight of said support medium are present per part by weight of streptokinase.
  • composition of claim 1 in which said streptokinase is bonded to a dextran support medium by at least one moiety shown within the brackets of the formula I N- o R-C N in which R is said dextran support medium having a bond connected to said moiety on an oxygen atom thereof, R is said streptokinase having a bond connected to said moiety, and X is selected from the group consisting of monovalent hydrocarbon radicals of no more than 4 carbon atoms, hydrogen, halogen atoms, and R and R groups.
  • composition of claim 8 in which from 10 to 200 parts by weight of said dextran support medium are present per part by weight of streptokinase.
  • composition of claim 12 produced by contacting from 10 to 200 parts by weight of said reaction product with one part by weight of streptokinase.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Microbiology (AREA)
  • Epidemiology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Biotechnology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Immunology (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
US881632A 1969-12-02 1969-12-02 Streptokinase chemically bonded to a carbohydrate matrix Expired - Lifetime US3639213A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US88163269A 1969-12-02 1969-12-02

Publications (1)

Publication Number Publication Date
US3639213A true US3639213A (en) 1972-02-01

Family

ID=25378866

Family Applications (1)

Application Number Title Priority Date Filing Date
US881632A Expired - Lifetime US3639213A (en) 1969-12-02 1969-12-02 Streptokinase chemically bonded to a carbohydrate matrix

Country Status (11)

Country Link
US (1) US3639213A (fr)
BE (1) BE758425A (fr)
CA (1) CA976101A (fr)
DE (1) DE2059165A1 (fr)
DK (1) DK131471B (fr)
FR (1) FR2073443B1 (fr)
GB (1) GB1325912A (fr)
IL (1) IL35545A (fr)
IT (1) IT1050704B (fr)
NL (1) NL7017625A (fr)
ZA (1) ZA707355B (fr)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3865615A (en) * 1973-05-07 1975-02-11 Air Prod & Chem Non-thrombogenic plastics
US4055635A (en) * 1973-07-05 1977-10-25 Beecham Group Limited Fibrinolytic compositions
US4167446A (en) * 1973-03-15 1979-09-11 Bayer Aktiengesellschaft Water soluble carrier-bound penicillinacylase
US4179337A (en) * 1973-07-20 1979-12-18 Davis Frank F Non-immunogenic polypeptides
US4273873A (en) * 1977-10-25 1981-06-16 Unitika Ltd. Preparation of antithrombogenic polymeric materials
US4305926A (en) * 1979-09-13 1981-12-15 Johannes Everse Immobilization of Streptokinase
US4409138A (en) * 1980-07-01 1983-10-11 Etablissement Texcontor Non-absorbable compounds of mucolytic activity, the process for their preparation, and therapeutic compositions which contain them as active principle
US4474756A (en) * 1981-02-06 1984-10-02 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Process for the production of anti-human protein antibody
WO1990009798A1 (fr) * 1989-02-24 1990-09-07 Immunotherapeutics, Inc. Cytokines immobilisees
US5133968A (en) * 1990-08-20 1992-07-28 Kanebo, Ltd. Modified protease, method of producing the same and cosmetic products containing the modified protease
US5230891A (en) * 1990-08-20 1993-07-27 Kanebo Limited Modified protease, method of producing the same and cosmetic products containing the modified protease
WO1993020838A1 (fr) * 1992-04-20 1993-10-28 Rufeld, Inc. Procede et compositions pour le traitement de processus pyonecrotiques
US5382657A (en) * 1992-08-26 1995-01-17 Hoffmann-La Roche Inc. Peg-interferon conjugates
US5539063A (en) * 1991-03-25 1996-07-23 Hoffmann-La Roche Inc. Polymer for making poly(ethylene glycol)-protein conjugates
US20090130017A1 (en) * 2007-11-19 2009-05-21 Searete Llc Targeted short-lived drug delivery
US20110201077A1 (en) * 2008-06-04 2011-08-18 Talecris Biotherapeutics ,Inc. Composition, method, and kit for preparing plasmin
CN104758945A (zh) * 2015-02-26 2015-07-08 宁波大学 一种pH响应的溶栓药物靶向纳米凝胶及其合成方法和用途
US9206410B2 (en) 2009-03-03 2015-12-08 Grifols Therapeutics Inc. Compositions, methods and kits for preparing plasminogen and plasmin prepared therefrom

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3033029A1 (de) * 1979-09-28 1981-04-23 Vsesojuznyj kardiologičeskij naučnyj centr Akademii medicinskich Nauk SSSR,, Moskva Urokinasederivate und verfahren zu deren herstellung
US9791463B2 (en) 2013-03-15 2017-10-17 Lawrence Livermore National Security, Llc Methods for the selective detection of alkyne-presenting molecules and related compositions and systems

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3186920A (en) * 1962-10-17 1965-06-01 Behringwerke Ag Process for preparing a streptokinase
US3255094A (en) * 1963-01-10 1966-06-07 Baxter Laboratories Inc Method for purification of streptokinase
FR1577571A (fr) * 1967-07-14 1969-08-08

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1108533A (en) * 1965-03-20 1968-04-03 Kyowa Hakko Kogyo Kk Water-insoluble enzymes

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3186920A (en) * 1962-10-17 1965-06-01 Behringwerke Ag Process for preparing a streptokinase
US3255094A (en) * 1963-01-10 1966-06-07 Baxter Laboratories Inc Method for purification of streptokinase
FR1577571A (fr) * 1967-07-14 1969-08-08

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Axen et al., Nature, April 23, 1966 pages 367 369 *
Silman et al., Annual Review of Biochemistry Vol. 35 pages 873 907 (pages 873 886 relied on), 1966 Part II. *

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4167446A (en) * 1973-03-15 1979-09-11 Bayer Aktiengesellschaft Water soluble carrier-bound penicillinacylase
US3865615A (en) * 1973-05-07 1975-02-11 Air Prod & Chem Non-thrombogenic plastics
US4055635A (en) * 1973-07-05 1977-10-25 Beecham Group Limited Fibrinolytic compositions
US4179337A (en) * 1973-07-20 1979-12-18 Davis Frank F Non-immunogenic polypeptides
US4273873A (en) * 1977-10-25 1981-06-16 Unitika Ltd. Preparation of antithrombogenic polymeric materials
US4305926A (en) * 1979-09-13 1981-12-15 Johannes Everse Immobilization of Streptokinase
US4409138A (en) * 1980-07-01 1983-10-11 Etablissement Texcontor Non-absorbable compounds of mucolytic activity, the process for their preparation, and therapeutic compositions which contain them as active principle
US4559322A (en) * 1980-07-01 1985-12-17 Etablissement Texcontor Non-absorbable compounds of mucolytic activity, the process for their preparation, and therapeutic compositions which contain them as active principle
US4474756A (en) * 1981-02-06 1984-10-02 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Process for the production of anti-human protein antibody
WO1990009798A1 (fr) * 1989-02-24 1990-09-07 Immunotherapeutics, Inc. Cytokines immobilisees
US5133968A (en) * 1990-08-20 1992-07-28 Kanebo, Ltd. Modified protease, method of producing the same and cosmetic products containing the modified protease
US5230891A (en) * 1990-08-20 1993-07-27 Kanebo Limited Modified protease, method of producing the same and cosmetic products containing the modified protease
US5539063A (en) * 1991-03-25 1996-07-23 Hoffmann-La Roche Inc. Polymer for making poly(ethylene glycol)-protein conjugates
US5834594A (en) * 1991-03-25 1998-11-10 Hoffman-La Roche Inc. Polyethylene-protein conjugates
US5849860A (en) * 1991-03-25 1998-12-15 Hoffmann-La Roche Inc. Polyethylene-protein conjugates
US5559213A (en) * 1991-03-25 1996-09-24 Hoffmann-La Roche Inc. Polyethylene-protein conjugates
US5595732A (en) * 1991-03-25 1997-01-21 Hoffmann-La Roche Inc. Polyethylene-protein conjugates
US5747646A (en) * 1991-03-25 1998-05-05 Hoffmann-La Roche Inc. Polyethylene-protein conjugates
US5792834A (en) * 1991-03-25 1998-08-11 Hoffmann-La Roche Inc. Polyethylene-protein conjugates
WO1993020838A1 (fr) * 1992-04-20 1993-10-28 Rufeld, Inc. Procede et compositions pour le traitement de processus pyonecrotiques
US5382657A (en) * 1992-08-26 1995-01-17 Hoffmann-La Roche Inc. Peg-interferon conjugates
US20090130017A1 (en) * 2007-11-19 2009-05-21 Searete Llc Targeted short-lived drug delivery
US20090142413A1 (en) * 2007-11-19 2009-06-04 Searete Llc Targeted short-lived drug delivery
US20110201077A1 (en) * 2008-06-04 2011-08-18 Talecris Biotherapeutics ,Inc. Composition, method, and kit for preparing plasmin
US8617863B2 (en) 2008-06-04 2013-12-31 Grifols Therapeutics Inc. Composition, method, and kit for preparing plasmin
US9206410B2 (en) 2009-03-03 2015-12-08 Grifols Therapeutics Inc. Compositions, methods and kits for preparing plasminogen and plasmin prepared therefrom
CN104758945A (zh) * 2015-02-26 2015-07-08 宁波大学 一种pH响应的溶栓药物靶向纳米凝胶及其合成方法和用途
CN104758945B (zh) * 2015-02-26 2018-10-16 宁波大学 一种pH响应的溶栓药物靶向纳米凝胶及其合成方法和用途

Also Published As

Publication number Publication date
FR2073443A1 (fr) 1971-10-01
IL35545A (en) 1974-06-30
IT1050704B (it) 1981-03-20
GB1325912A (en) 1973-08-08
DK131471C (fr) 1975-12-08
DE2059165A1 (de) 1971-06-09
ZA707355B (en) 1971-07-28
FR2073443B1 (fr) 1975-04-18
CA976101A (en) 1975-10-14
NL7017625A (fr) 1971-06-04
DK131471B (da) 1975-07-21
BE758425A (fr) 1971-04-16
IL35545A0 (en) 1970-12-24

Similar Documents

Publication Publication Date Title
US3980772A (en) Methods of dissolving blood clots and the like with streptokinase chemically bonded to a carbohydrate matrix
US3639213A (en) Streptokinase chemically bonded to a carbohydrate matrix
Inman Thymus-independent antigens: the preparation of covalent, hapten-ficoll conjugates
US4913908A (en) Preparation of submicroscopic particles, particles thus obtained and pharmaceutical compositions containing them
KR870002161B1 (ko) 비루스 왁진의 제조방법
US5051408A (en) Inulin compositions in gamma polymorphic form
US4686288A (en) Process for preparing mucopolysaccharide compositions having high antithrombotic activity, the compositions obtained and their use as medicaments
US4808314A (en) Method for reducing bacterial endotoxin contamination in solutions of macromolecules
US2437518A (en) Manufacture of infusion and injection fluids
JPH037681B2 (fr)
US4372883A (en) Process for the production of vaccine
US5037649A (en) Method for treatment of HIV-infected patients
Enriquez et al. Conjugation of adenine arabinoside 5'-monophosphate to arabinogalactan: synthesis, characterization, and antiviral activity
US5284934A (en) Synthesis and utilization of carbohydrate-binding polymer-lectin conjugates
Watanabe et al. 6-O-Carboxymethyl-chitin (CM-chitin) as a drug carrier
Kent et al. Immunochemically-active cross-linked polystyrene preparations
Hofstee et al. Modifying factors in hydrophobic protein binding by substituted agaroses
US4415552A (en) Composition for establishing immunological tolerance
JPS6058927A (ja) 放射能標識血小板製剤
Van Arman et al. Experimental gouty synovitis caused by bacterial endotoxin adsorbed onto urate crystals
CA1117866A (fr) Vaccin contre haemophilus influenzae
US5314878A (en) Composition for removing or inactivating harmful components in blood or other extracellular body fluids
JP3157026B2 (ja) 血液浄化用吸着材
US3434927A (en) Highly purified intrinsic factor
AU589233B2 (en) Immunotherapeutic treatment