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US3730843A - Mass screening test for serum trypsin inhibitors - Google Patents

Mass screening test for serum trypsin inhibitors Download PDF

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US3730843A
US3730843A US00098213A US3730843DA US3730843A US 3730843 A US3730843 A US 3730843A US 00098213 A US00098213 A US 00098213A US 3730843D A US3730843D A US 3730843DA US 3730843 A US3730843 A US 3730843A
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trypsin
color film
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diagnostic
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US00098213A
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J Mckie
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Warner Lambert Co LLC
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Pfizer Corp Belgium
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
    • C12Q1/37—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase involving peptidase or proteinase
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B06—GENERATING OR TRANSMITTING MECHANICAL VIBRATIONS IN GENERAL
    • B06B—METHODS OR APPARATUS FOR GENERATING OR TRANSMITTING MECHANICAL VIBRATIONS OF INFRASONIC, SONIC, OR ULTRASONIC FREQUENCY, e.g. FOR PERFORMING MECHANICAL WORK IN GENERAL
    • B06B1/00—Methods or apparatus for generating mechanical vibrations of infrasonic, sonic, or ultrasonic frequency
    • B06B1/18—Methods or apparatus for generating mechanical vibrations of infrasonic, sonic, or ultrasonic frequency wherein the vibrator is actuated by pressure fluid
    • B06B1/183—Methods or apparatus for generating mechanical vibrations of infrasonic, sonic, or ultrasonic frequency wherein the vibrator is actuated by pressure fluid operating with reciprocating masses
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2337/00—N-linked chromogens for determinations of peptidases and proteinases
    • C12Q2337/10—Anilides
    • C12Q2337/12—Para-Nitroanilides p-NA
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/81—Protease inhibitors
    • G01N2333/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
    • G01N2333/811—Serine protease (E.C. 3.4.21) inhibitors
    • G01N2333/8121—Serpins
    • G01N2333/8125—Alpha-1-antitrypsin
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
    • G01N2333/976—Trypsin; Chymotrypsin

Definitions

  • the degree of clinical manifestation in al -antitrypsin deficiency is highly variable, ranging from complete absence of clinical symptoms to an early onset of severe emphysema with pronounced disability. But the homozygotes run greater risk of lung disease'than the heterozygotes. The high risk of developing emphysema is increased with the cigarette smokers in this population.
  • Methods currently available for estimating antitrypsin levels in serum include enzymologic procedures involving the inhibition of digestion of protein substrates such as casein, fibrinogen and hemoglobin, and inhibition of hydrolysis of synthetic substrates such as benzoyl-L-arginine p-nitroanalide and p-toluene sulfonyl-L-arginine methyl ester.
  • protein substrates such as casein, fibrinogen and hemoglobin
  • synthetic substrates such as benzoyl-L-arginine p-nitroanalide and p-toluene sulfonyl-L-arginine methyl ester.
  • a rapid and simple procedure is needed for the semi-quantitative measurement of antitryptic activity in human sera, a procedure which would make possible the screening of largepopulations for the genetically controlled u antitrypsin deficiency that is associated with an unusual familial variety of pulmonary emphysema.
  • Such inform ation would be a valuable guide for premarital testing and counseling that could prevent the unfortunate births of homozygotes with a high probability of future crippling emphysema. Such information would also serve as a precautionary screening in employment examinations in industries with high exposure to irritating fumes, dusts or excessive smog. A background would be available for medical advice on the dangers of cigarette smoking.
  • the object of this invention is to provide a rapid semi-quantitative procedure for determining antitrypsin levels in human sera in which one set of control sera serves as a reference for the mass screening of many individual human sera.
  • This invention is concerned with a diagnostic test package for use in an improved semi-quantitative method for estimating antitrypsin levels in human blood.
  • the diagnostic test package contains a strip of unexposed and developed color film, sample test vials (each containing a constant amount of freeze-dried trypsin for individual serum sample determinations when properly diluted with serum), and three reference vials (each containing a different amount of freezedried trypsin which serve as reference control sera when properly diluted with buffer).
  • Antitrypsin levels in human sera are determined by the color changes resulting from the hydrolysis of the gelatin substrate of color film by the serum trypsin reagent with side by side comparisons of the color changes produced by simulated normal, heterozygous and homozygous sera.
  • test method of this invention utilizes the depth of hydrolysis (with resultant color changes) into the trilayered/tri-colored gelatin sandwich of an unexposed and developed color film strip as the semi-quantitative measure of the trypsin inhibitory capacity of human sera. Side by side comparisons are made with simulated normal, heterozygous and homozygous antitrypsin sera.
  • test sera (0.2 ml.) are each added to individual vials containing 0.30 mg. of freeze-dried trypsin and mixed until all the trypsin has dissolved. After about 5 minutes incubation at room temperature, a drop (0.0l0.03 ml.) of each mixture is placed on the gelatin side of an unexposed and developed color film strip (any positive color film may be used, preferably Agfachrome). After approximately 5 minutes, the film strip is immersed in a pH 3 water rinse bath which stops the gelatin hydrolysis reaction. The film strip is gently rubbed or squeegeed until colored particles no longer are leached from the spotted area (approximately 30 seconds).
  • the film strip is then removed from the bath, dried and the colored spots compared with those obtained from the five minute hydrolysis action of a drop (0.01-0.03 ml.) of each of the simulated normal, heterozygous and homozygous sera (prepared inan identical manner as the test sera, i.e., 0.2 ml. of 0.05-0.10 M tris, 0005-002 M) CaCl,, pH 8 buffer solution added to each of three individual vials containing respectively 0.06 mg, 0.18 mg. and 0.26
  • a light aqua-blue colored spot is obtained with homozygous oi -antitrypsin human sera and the corresponding simulated homozygouscontrol.
  • a blue-violet spot results from the action of heterozygous (l -antitrypsin sera and the corresponding heterozygous control.
  • Normal a -antitrypsin sera and the simulated normal control react very little on the gelatin substrate of the color film under the conditions of the test, and the color of the spot on the film is black (film unchanged) to black-- violet.
  • the test sera are reported as normal,
  • the trypsin reagent vials (containing 0.30 mg.
  • freeze-dried trypsin are prepared by making up a 3.0
  • tyrpsin inhibitory capacity (I.l.().), expressed as mg. of trypsin capable of being inhibited by antitrypsin, taken from tho litm'atnrv for nornnil. hvtcrozygous and homozygous ai-antitrypsin deficiency.
  • the trypsin reagent has purposely been made more concentrated than the actual trypsin reagent concentration necessary to titratc exactly the mean normal I.l.0. of 1.2 lug/ml. This use of a slighly higher trypsin reagent concentration is used to reduce the possibility of false negatives.

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  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Analytical Chemistry (AREA)
  • Mechanical Engineering (AREA)
  • Immunology (AREA)
  • Microbiology (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Physics & Mathematics (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

A diagnostic test package for use in an improved semiquantitative method for estimating antitrypsin levels in human blood.

Description

United States Patent 1 McKie,Jr.
[4 1 May 1,1973
[ MASS SCREENING TEST FOR SERUM TRYPSIN INHIBITORS [75] Inventor: James E. McKie, Jr., Parsippany,
[73] Assignee: Pfizer Inc., New York, NY.
[22] Filed: Dec. 14, 1970 [21] Appl. No.: 98,213
[52] U.S. Cl ..l95/103.5 R, 23/230 B, 23/253 TP [51] Int. Cl. ..Cl2k 1/04 [58] Field of Search ..195/lO3.5 R
[56] References Cited OTHER PUBLICATIONS James et al., Journal of Lab and Clinical Medicine; Vol. 67, No. 1; pages 528532, publisher C. V. Moshy Primary ExaminerA. Louis Monacell Assistant Examiner-Robert J. Warden Attorney-Connolly and Hutz 5 7 ABSTRACT A diagnostic test package for use in an improved semiquantitative method for estimating antitrypsin levels in human blood.
11 Claims, N0 Drawings MASS SCREENING TEST FOR SERUM TRYPSIN INHIBITORS BACKGROUND OF THE INVENTION invariable presence of severe pulmonary emphysema in persons over 40 years of age who were homozygous for this inherited plasma protein defect. Individuals homozygous for the genetic defect possess approximately 10 percent of the normal level of serum a -antitrypsin; heterozygous individuals possess about 50 to 60 percent of the normal concentration of this protein.
As in other genetic entities, the degree of clinical manifestation in al -antitrypsin deficiency is highly variable, ranging from complete absence of clinical symptoms to an early onset of severe emphysema with pronounced disability. But the homozygotes run greater risk of lung disease'than the heterozygotes. The high risk of developing emphysema is increased with the cigarette smokers in this population.
Methods currently available for estimating antitrypsin levels in serum include enzymologic procedures involving the inhibition of digestion of protein substrates such as casein, fibrinogen and hemoglobin, and inhibition of hydrolysis of synthetic substrates such as benzoyl-L-arginine p-nitroanalide and p-toluene sulfonyl-L-arginine methyl ester. However, a rapid and simple procedure is needed for the semi-quantitative measurement of antitryptic activity in human sera, a procedure which would make possible the screening of largepopulations for the genetically controlled u antitrypsin deficiency that is associated with an unusual familial variety of pulmonary emphysema. Such inform ation would be a valuable guide for premarital testing and counseling that could prevent the unfortunate births of homozygotes with a high probability of future crippling emphysema. Such information would also serve as a precautionary screening in employment examinations in industries with high exposure to irritating fumes, dusts or excessive smog. A background would be available for medical advice on the dangers of cigarette smoking.
A semi-quantitative test reported by James, K., Collins, ML. and Fudenberg, I-I.I-I., J.Lab. and Clin. Med. 67, 528 (1966) measures the ability of antitrypsin containing serum to inhibit the capacity of reference trypsin standards to digest the gelatin surface of an unexposed and developed .(black) X-ray film. The titration procedure involves the use of three concentrations of trypsin for each serum sample.
The object of this invention is to provide a rapid semi-quantitative procedure for determining antitrypsin levels in human sera in which one set of control sera serves as a reference for the mass screening of many individual human sera.
SUMMARY OF THE INVENTION This invention is concerned with a diagnostic test package for use in an improved semi-quantitative method for estimating antitrypsin levels in human blood. The diagnostic test package contains a strip of unexposed and developed color film, sample test vials (each containing a constant amount of freeze-dried trypsin for individual serum sample determinations when properly diluted with serum), and three reference vials (each containing a different amount of freezedried trypsin which serve as reference control sera when properly diluted with buffer). Antitrypsin levels in human sera are determined by the color changes resulting from the hydrolysis of the gelatin substrate of color film by the serum trypsin reagent with side by side comparisons of the color changes produced by simulated normal, heterozygous and homozygous sera.
DETAILED DESCRIPTION OF THE INVENTION The test method of this invention utilizes the depth of hydrolysis (with resultant color changes) into the trilayered/tri-colored gelatin sandwich of an unexposed and developed color film strip as the semi-quantitative measure of the trypsin inhibitory capacity of human sera. Side by side comparisons are made with simulated normal, heterozygous and homozygous antitrypsin sera.
The test sera (0.2 ml.) are each added to individual vials containing 0.30 mg. of freeze-dried trypsin and mixed until all the trypsin has dissolved. After about 5 minutes incubation at room temperature, a drop (0.0l0.03 ml.) of each mixture is placed on the gelatin side of an unexposed and developed color film strip (any positive color film may be used, preferably Agfachrome). After approximately 5 minutes, the film strip is immersed in a pH 3 water rinse bath which stops the gelatin hydrolysis reaction. The film strip is gently rubbed or squeegeed until colored particles no longer are leached from the spotted area (approximately 30 seconds). The film strip is then removed from the bath, dried and the colored spots compared with those obtained from the five minute hydrolysis action of a drop (0.01-0.03 ml.) of each of the simulated normal, heterozygous and homozygous sera (prepared inan identical manner as the test sera, i.e., 0.2 ml. of 0.05-0.10 M tris, 0005-002 M) CaCl,, pH 8 buffer solution added to each of three individual vials containing respectively 0.06 mg, 0.18 mg. and 0.26
mg. of the samelot of freeze-driedtrypsin). A light aqua-blue colored spot is obtained with homozygous oi -antitrypsin human sera and the corresponding simulated homozygouscontrol. A blue-violet spot results from the action of heterozygous (l -antitrypsin sera and the corresponding heterozygous control. Normal a -antitrypsin sera and the simulated normal control react very little on the gelatin substrate of the color film under the conditions of the test, and the color of the spot on the film is black (film unchanged) to black-- violet. The test sera are reported as normal,
heterozygous or homozygous.
The trypsin reagent vials (containing 0.30 mg.
freeze-dried trypsin) are prepared by making up a 3.0
. mg/ml. stock solution of twice-crystallized trypsin (Worthington Biochemicals or other suitable supplier) 1. A vial containing 0.3 mg/ml (i trypsin [the normal reference control serum],
2. a vial containing 0.9 mg/ml (110%) trypsin [the heterozygous reference control serum],
3. a vial containing 1.3 mg/ml (i10%) trypsin [the homozygous reference control serum]and THREE CLASSES OI" I'IYPOTHETTCAL TES'I SERA Residual or Residual confree mass of centration of Mass of Mass of trypsin trypsin in trypsin in Mass of free trypsin reagent to the serumthe scrumtrypsin in 0.02 which 0.2 which 0.2 ml. trypsin try psin ml. of serum- Defieicnt Mean ml.of serum of serum is reaction reaction try psin mixture state I.l.C. can inhibit, added 3 mixture, mixture, applied to of serum ingJml. mg. mg. mg. ingJml. lilm, mg.
Normal 1. 2 0. 24 0.30 0. 06 0.3 0. 007 Heterozygous 0. 6 0.12 0.30 0.18 0. J 0. 018 .llomozygons 0. 2 0. 01 0.30 0. .26 l. 3 0. 020
The mean tyrpsin inhibitory capacity (I.l.().), expressed as mg. of trypsin capable of being inhibited by antitrypsin, taken from tho litm'atnrv for nornnil. hvtcrozygous and homozygous ai-antitrypsin deficiency.
The trypsin reagent has purposely been made more concentrated than the actual trypsin reagent concentration necessary to titratc exactly the mean normal I.l.0. of 1.2 lug/ml. This use of a slighly higher trypsin reagent concentration is used to reduce the possibility of false negatives.
THE THREE SIMULATED REFERENCE CONTROLS What is claimed is:
1. In a diagnostic test procedure for the-determination of a -antitrypsin levels in human blood by commingling test sera with'freeze-dried trypsin reagent and estimating the degree of hydrolysis of gelatin by the residual trypsin (free trypsin) into the surface of unexposed and developed photographic film, the improvement which comprises using unexposed and developed color film, producing color changes having colored end results into said surface by contacting said surface with sera-trypsin reaction mixtures and simulated normal, heterozygous and homozygous reference sera, and comparing the ultimate colors produced by said seratrypsin reaction mixtures with the ultimate colors produced by said simulated normal, heterozygous and homozygous reference sera. D
2. A lagnostic test procedure as set forth in claim 1,
B. freeze-dried trypsin test vials each containing 0.30
mg. of trypsin, and
C. 5.0 ml of (0.05-0.10 M) tris, (0.005-002 M) CaCl,, pH 8 buffer solution.
3. In a diagnostic test procedure as set forth in claim 2 wherein said strip of color film is a positive color film.
4. In a diagnostic test procedure as set forth in claim 1 wherein said color film includes three layers having different colorations and said color changes are produced as a result of the depth of hydrolysis by said residual trypsin.
5. In a diagnostic test procedure as set forth in claim 4 wherein said color film is a positive color film.
6. In a diagnostic procedure as set forth in claim 4 wherein a small amount of said mixture is applied to said color film and the time of contact being limited so that said colored end results occur.
7. In a diagnostic procedure as set forth in claim 6 wherein said color film to which said mixture is applied is washed after a predetermined time.
8. In a diagnostic procedure as set forth in claim 7 wherein said washed film strip is dried.
9. In a diagnostic procedure as set forth in claim 7 wherein said film strip is washed in a pI-I3 water rinse bath,
10. In a diagnostic procedure as set forth in claim 6 wherein said time of contact is about 5 minutes at about room temperature.
1 1. In a diagnostic procedure as set forth in claim 10 wherein a drop of said mixture is applied.

Claims (12)

  1. 2. A diagnostic test procedure as set forth in claim 1, wherein a strip of unexposed and developed color film and the following bottled reagent are utilized: A. freeze-dried trypsin of variable mass to provide on reconstitution with 0.2 ml. of pH 8 buffer:
  2. 2. a vial containing 0.9 mg/ml ( + or - 10%) trypsin (the heterozygous reference control serum),
  3. 3. a vial containing 1.3 mg/ml ( + or - 10%) trypsin (the homozygous reference control serum)and B. freeze-dried trypsin test vials each containing 0.30 mg. of trypsin, and C. 5.0 ml of (0.05-0.10 M) tris, (0.005-0.02 M) CaCl2, pH 8 buffer solution.
  4. 3. In a diagnostic test procedure as set forth in claim 2 wherein said strip of color film is a positive color film.
  5. 4. In a diagnostic test procedure as set forth in claim 1 wherein said color film includes three layers having different colorations and said color changes are produced as a result of the depth of hydrolysis by said residual trypsin.
  6. 5. In a diagnostic test procedure as set forth in claim 4 wherein said color film is a positive color film.
  7. 6. In a diagnostic procedure as set forth in claim 4 wherein a small amount of said mixture is applied to said color film and the time of contact being limited so that said colored end results occur.
  8. 7. In a diagnostic procedure as set forth in claim 6 wherein said color film to which said mixture is applied is washed after a predetermined time.
  9. 8. In a diagnostic procedure as set forth in claim 7 wherein said washed film strip is dried.
  10. 9. In a diagnostic procedure as set forth in claim 7 wherein said film strip is washed in a pH3 water rinse bath.
  11. 10. In a diagnostic procedure as set forth in claim 6 wherein said time of contact is about 5 minutes at about room temperature.
  12. 11. In a diagnostic procedure as set forth in claim 10 wherein a drop of said mixture is applied.
US00098213A 1970-12-14 1970-12-14 Mass screening test for serum trypsin inhibitors Expired - Lifetime US3730843A (en)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1979000045A1 (en) * 1977-07-14 1979-02-08 Hans Bjoerne Elwing Method for the determination of enzymes by diffusion in a porous matrix or by electrophoresis
DE2857015A1 (en) * 1977-07-14 1980-12-18 Elwing Hans Bjoerne METHOD FOR THE DETERMINATION OF ENZYMES BY DIFFUSION IN A POROUS MATRIX OR BY ELECTROPHORESIS
EP0048834A1 (en) * 1980-09-02 1982-04-07 Fuji Photo Film Co., Ltd. Method for measurement of trace enzymes
US4629694A (en) * 1983-07-12 1986-12-16 Cornell Research Foundation, Inc. Detecting and distinguishing between plasminogen activators
US4753875A (en) * 1981-11-02 1988-06-28 Ryan James W Method for assaying proteases with tagged proteinaceous inhibitors
US4931386A (en) * 1987-12-03 1990-06-05 Frederick H. Silver Method and collagen coated slide for assaying collagenase
US11604026B2 (en) 2019-03-14 2023-03-14 Terumo Bct Biotechnologies, Llc Lyophilization loading tray assembly and system
US11634257B2 (en) 2017-10-09 2023-04-25 Terumo Bct Biotechnologies, Llc Lyophilization container and method of using same

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Daughaday et al., Journal of Lab and Clinical Medicine; Vol. 67, No. 1; pgs. 528 532; publisher C. V. Moshy Co.; 1966 *
James et al., Journal of Lab and Clinical Medicine; Vol. 67, No. 1; pages 528 532, publisher C. V. Moshy Co.; 1966 *
Kenneth L. Burdon, Journal of Lab and Clinical Medicine; Vol. 37, No. 1; pages 494 498; publisher C. V. Moshy Co.; 1951 *
Umbriet et al., Advances In Applied Microbiology, Supplement 1, pages 21 22, Academic Press (1968) *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1979000045A1 (en) * 1977-07-14 1979-02-08 Hans Bjoerne Elwing Method for the determination of enzymes by diffusion in a porous matrix or by electrophoresis
DE2857015A1 (en) * 1977-07-14 1980-12-18 Elwing Hans Bjoerne METHOD FOR THE DETERMINATION OF ENZYMES BY DIFFUSION IN A POROUS MATRIX OR BY ELECTROPHORESIS
US4356260A (en) * 1977-07-14 1982-10-26 Elwing Hans B Enzymatic indicator system
EP0048834A1 (en) * 1980-09-02 1982-04-07 Fuji Photo Film Co., Ltd. Method for measurement of trace enzymes
US4753875A (en) * 1981-11-02 1988-06-28 Ryan James W Method for assaying proteases with tagged proteinaceous inhibitors
US4629694A (en) * 1983-07-12 1986-12-16 Cornell Research Foundation, Inc. Detecting and distinguishing between plasminogen activators
US4931386A (en) * 1987-12-03 1990-06-05 Frederick H. Silver Method and collagen coated slide for assaying collagenase
US11634257B2 (en) 2017-10-09 2023-04-25 Terumo Bct Biotechnologies, Llc Lyophilization container and method of using same
US11604026B2 (en) 2019-03-14 2023-03-14 Terumo Bct Biotechnologies, Llc Lyophilization loading tray assembly and system
US11609043B2 (en) 2019-03-14 2023-03-21 Terumo Bct Biotechnologies, Llc Lyophilization container fill fixture, system and method of use
US11609042B2 (en) 2019-03-14 2023-03-21 Terumo Bct Biotechnologies, Llc Multi-part lyophilization container and method of use
US11740019B2 (en) 2019-03-14 2023-08-29 Terumo Bct Biotechnologies, Llc Lyophilization loading tray assembly and system
US11747082B2 (en) 2019-03-14 2023-09-05 Terumo Bct Biotechnologies, Llc Multi-part lyophilization container and method of use
US11815311B2 (en) 2019-03-14 2023-11-14 Terumo Bct Biotechnologies, Llc Lyophilization container fill fixture, system and method of use
US11994343B2 (en) 2019-03-14 2024-05-28 Terumo Bct Biotechnologies, Llc Multi-part lyophilization container and method of use

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GB1297609A (en) 1972-11-29

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Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:PFIZER INC.;REEL/FRAME:003853/0905

Effective date: 19810409