AU620100B2 – Method of inhibiting the influx of leukocytes into organs during sepsis or other trauma
– Google Patents
AU620100B2 – Method of inhibiting the influx of leukocytes into organs during sepsis or other trauma
– Google Patents
Method of inhibiting the influx of leukocytes into organs during sepsis or other trauma
Download PDF
Info
Publication number
AU620100B2
AU620100B2
AU36084/89A
AU3608489A
AU620100B2
AU 620100 B2
AU620100 B2
AU 620100B2
AU 36084/89 A
AU36084/89 A
AU 36084/89A
AU 3608489 A
AU3608489 A
AU 3608489A
AU 620100 B2
AU620100 B2
AU 620100B2
Authority
AU
Australia
Prior art keywords
leukocytes
antibody
influx
infectious
administration
Prior art date
1988-06-07
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.)
Ceased
Application number
AU36084/89A
Other versions
AU3608489A
(en
Inventor
Elaine I. Toumanen
Samuel D. Wright
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.)
Rockefeller University
Original Assignee
Rockefeller University
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.)
1988-06-07
Filing date
1989-06-07
Publication date
1992-02-13
1989-06-07
Application filed by Rockefeller University
filed
Critical
Rockefeller University
1989-12-14
Publication of AU3608489A
publication
Critical
patent/AU3608489A/en
1992-02-13
Application granted
granted
Critical
1992-02-13
Publication of AU620100B2
publication
Critical
patent/AU620100B2/en
2009-06-07
Anticipated expiration
legal-status
Critical
Status
Ceased
legal-status
Critical
Current
Links
Espacenet
Global Dossier
Discuss
210000000265
leukocyte
Anatomy
0.000
title
claims
description
42
238000000034
method
Methods
0.000
title
claims
description
33
210000000056
organ
Anatomy
0.000
title
claims
description
19
230000004941
influx
Effects
0.000
title
claims
description
18
208000014674
injury
Diseases
0.000
title
claims
description
15
230000008733
trauma
Effects
0.000
title
claims
description
15
206010040047
Sepsis
Diseases
0.000
title
claims
description
14
230000002401
inhibitory effect
Effects
0.000
title
claims
description
8
208000015181
infectious disease
Diseases
0.000
claims
description
48
210000004072
lung
Anatomy
0.000
claims
description
37
206010061218
Inflammation
Diseases
0.000
claims
description
25
230000004054
inflammatory process
Effects
0.000
claims
description
25
229960005475
antiinfective agent
Drugs
0.000
claims
description
24
239000004599
antimicrobial
Substances
0.000
claims
description
24
230000002458
infectious effect
Effects
0.000
claims
description
23
239000012634
fragment
Substances
0.000
claims
description
22
239000000203
mixture
Substances
0.000
claims
description
19
206010001052
Acute respiratory distress syndrome
Diseases
0.000
claims
description
18
208000013616
Respiratory Distress Syndrome
Diseases
0.000
claims
description
18
208000011341
adult acute respiratory distress syndrome
Diseases
0.000
claims
description
16
201000000028
adult respiratory distress syndrome
Diseases
0.000
claims
description
16
206010040070
Septic Shock
Diseases
0.000
claims
description
11
238000001990
intravenous administration
Methods
0.000
claims
description
11
206010014824
Endotoxic shock
Diseases
0.000
claims
description
10
101000935040
Homo sapiens Integrin beta-2
Proteins
0.000
claims
description
10
102100025390
Integrin beta-2
Human genes
0.000
claims
description
10
201000010099
disease
Diseases
0.000
claims
description
9
208000037265
diseases, disorders, signs and symptoms
Diseases
0.000
claims
description
9
210000003038
endothelium
Anatomy
0.000
claims
description
9
239000003795
chemical substances by application
Substances
0.000
claims
description
8
238000009472
formulation
Methods
0.000
claims
description
8
239000003782
beta lactam antibiotic agent
Substances
0.000
claims
description
7
239000002132
β-lactam antibiotic
Substances
0.000
claims
description
7
229940124586
β-lactam antibiotics
Drugs
0.000
claims
description
7
201000009906
Meningitis
Diseases
0.000
claims
description
6
210000001519
tissue
Anatomy
0.000
claims
description
6
230000001154
acute effect
Effects
0.000
claims
description
4
238000003306
harvesting
Methods
0.000
claims
description
4
230000005764
inhibitory process
Effects
0.000
claims
description
4
230000000642
iatrogenic effect
Effects
0.000
claims
description
3
230000001524
infective effect
Effects
0.000
claims
description
3
239000000463
material
Substances
0.000
claims
description
3
230000001404
mediated effect
Effects
0.000
claims
description
3
208000011231
Crohn disease
Diseases
0.000
claims
description
2
208000006313
Delayed Hypersensitivity
Diseases
0.000
claims
description
2
201000004624
Dermatitis
Diseases
0.000
claims
description
2
206010051392
Diapedesis
Diseases
0.000
claims
description
2
208000022559
Inflammatory bowel disease
Diseases
0.000
claims
description
2
208000031845
Pernicious anaemia
Diseases
0.000
claims
description
2
201000004681
Psoriasis
Diseases
0.000
claims
description
2
206010052779
Transplant rejections
Diseases
0.000
claims
description
2
206010046851
Uveitis
Diseases
0.000
claims
description
2
206010003246
arthritis
Diseases
0.000
claims
description
2
238000002512
chemotherapy
Methods
0.000
claims
description
2
206010009887
colitis
Diseases
0.000
claims
description
2
206010014599
encephalitis
Diseases
0.000
claims
description
2
208000024908
graft versus host disease
Diseases
0.000
claims
description
2
208000026278
immune system disease
Diseases
0.000
claims
description
2
230000008816
organ damage
Effects
0.000
claims
description
2
229920001184
polypeptide
Polymers
0.000
claims
description
2
108090000765
processed proteins & peptides
Proteins
0.000
claims
description
2
102000004196
processed proteins & peptides
Human genes
0.000
claims
description
2
206010039073
rheumatoid arthritis
Diseases
0.000
claims
description
2
229940126585
therapeutic drug
Drugs
0.000
claims
description
2
239000008194
pharmaceutical composition
Substances
0.000
claims
5
238000002405
diagnostic procedure
Methods
0.000
claims
3
206010020751
Hypersensitivity
Diseases
0.000
claims
1
208000026935
allergic disease
Diseases
0.000
claims
1
206010012601
diabetes mellitus
Diseases
0.000
claims
1
239000003937
drug carrier
Substances
0.000
claims
1
230000009610
hypersensitivity
Effects
0.000
claims
1
239000003550
marker
Substances
0.000
claims
1
230000002265
prevention
Effects
0.000
claims
1
210000000440
neutrophil
Anatomy
0.000
description
25
239000002158
endotoxin
Substances
0.000
description
17
210000004369
blood
Anatomy
0.000
description
14
239000008280
blood
Substances
0.000
description
14
230000001225
therapeutic effect
Effects
0.000
description
14
241000283973
Oryctolagus cuniculus
Species
0.000
description
12
230000000694
effects
Effects
0.000
description
11
238000002560
therapeutic procedure
Methods
0.000
description
7
XLYOFNOQVPJJNP-UHFFFAOYSA-N
water
Chemical compound
O
XLYOFNOQVPJJNP-UHFFFAOYSA-N
0.000
description
6
208000035473
Communicable disease
Diseases
0.000
description
5
ZGTMUACCHSMWAC-UHFFFAOYSA-L
EDTA disodium salt (anhydrous)
Chemical compound
[Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O
ZGTMUACCHSMWAC-UHFFFAOYSA-L
0.000
description
5
DWAQJAXMDSEUJJ-UHFFFAOYSA-M
Sodium bisulfite
Chemical compound
[Na+].OS([O-])=O
DWAQJAXMDSEUJJ-UHFFFAOYSA-M
0.000
description
5
239000002552
dosage form
Substances
0.000
description
5
235000010267
sodium hydrogen sulphite
Nutrition
0.000
description
5
239000008215
water for injection
Substances
0.000
description
5
241001465754
Metazoa
Species
0.000
description
4
210000004027
cell
Anatomy
0.000
description
4
238000003384
imaging method
Methods
0.000
description
4
239000012678
infectious agent
Substances
0.000
description
4
230000002757
inflammatory effect
Effects
0.000
description
4
210000002381
plasma
Anatomy
0.000
description
4
241000894006
Bacteria
Species
0.000
description
3
241000588724
Escherichia coli
Species
0.000
description
3
CEAZRRDELHUEMR-URQXQFDESA-N
Gentamicin
Chemical compound
O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N
CEAZRRDELHUEMR-URQXQFDESA-N
0.000
description
3
229930182566
Gentamicin
Natural products
0.000
description
3
241000606768
Haemophilus influenzae
Species
0.000
description
3
241001529936
Murinae
Species
0.000
description
3
JGSARLDLIJGVTE-MBNYWOFBSA-N
Penicillin G
Chemical compound
N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1
JGSARLDLIJGVTE-MBNYWOFBSA-N
0.000
description
3
FAPWRFPIFSIZLT-UHFFFAOYSA-M
Sodium chloride
Chemical compound
[Na+].[Cl-]
FAPWRFPIFSIZLT-UHFFFAOYSA-M
0.000
description
3
230000001363
autoimmune
Effects
0.000
description
3
230000003115
biocidal effect
Effects
0.000
description
3
229960002518
gentamicin
Drugs
0.000
description
3
208000027866
inflammatory disease
Diseases
0.000
description
3
239000004615
ingredient
Substances
0.000
description
3
230000007246
mechanism
Effects
0.000
description
3
238000002360
preparation method
Methods
0.000
description
3
230000004044
response
Effects
0.000
description
3
230000009919
sequestration
Effects
0.000
description
3
241000283690
Bos taurus
Species
0.000
description
2
229930186147
Cephalosporin
Natural products
0.000
description
2
108010078015
Complement C3b
Proteins
0.000
description
2
WQZGKKKJIJFFOK-GASJEMHNSA-N
Glucose
Natural products
OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O
WQZGKKKJIJFFOK-GASJEMHNSA-N
0.000
description
2
108060003951
Immunoglobulin
Proteins
0.000
description
2
229930182555
Penicillin
Natural products
0.000
description
2
229930195708
Penicillin V
Natural products
0.000
description
2
241000589516
Pseudomonas
Species
0.000
description
2
241000295644
Staphylococcaceae
Species
0.000
description
2
241000193998
Streptococcus pneumoniae
Species
0.000
description
2
229940126575
aminoglycoside
Drugs
0.000
description
2
239000003242
anti bacterial agent
Substances
0.000
description
2
229960004261
cefotaxime
Drugs
0.000
description
2
GPRBEKHLDVQUJE-VINNURBNSA-N
cefotaxime
Chemical compound
N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C(O)=O)=O)C(=O)/C(=N/OC)C1=CSC(N)=N1
GPRBEKHLDVQUJE-VINNURBNSA-N
0.000
description
2
210000002421
cell wall
Anatomy
0.000
description
2
229940124587
cephalosporin
Drugs
0.000
description
2
150000001780
cephalosporins
Chemical class
0.000
description
2
230000035605
chemotaxis
Effects
0.000
description
2
230000009089
cytolysis
Effects
0.000
description
2
230000034994
death
Effects
0.000
description
2
230000002939
deleterious effect
Effects
0.000
description
2
239000008121
dextrose
Substances
0.000
description
2
229940124274
edetate disodium
Drugs
0.000
description
2
210000002889
endothelial cell
Anatomy
0.000
description
2
229940047650
haemophilus influenzae
Drugs
0.000
description
2
102000018358
immunoglobulin
Human genes
0.000
description
2
238000000338
in vitro
Methods
0.000
description
2
230000028709
inflammatory response
Effects
0.000
description
2
238000002347
injection
Methods
0.000
description
2
239000007924
injection
Substances
0.000
description
2
238000002955
isolation
Methods
0.000
description
2
238000002372
labelling
Methods
0.000
description
2
210000004185
liver
Anatomy
0.000
description
2
230000033001
locomotion
Effects
0.000
description
2
231100000516
lung damage
Toxicity
0.000
description
2
229940056367
penicillin v
Drugs
0.000
description
2
BPLBGHOLXOTWMN-MBNYWOFBSA-N
phenoxymethylpenicillin
Chemical compound
N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)COC1=CC=CC=C1
BPLBGHOLXOTWMN-MBNYWOFBSA-N
0.000
description
2
210000004623
platelet-rich plasma
Anatomy
0.000
description
2
102000004169
proteins and genes
Human genes
0.000
description
2
108090000623
proteins and genes
Proteins
0.000
description
2
102000005962
receptors
Human genes
0.000
description
2
108020003175
receptors
Proteins
0.000
description
2
238000011160
research
Methods
0.000
description
2
239000000243
solution
Substances
0.000
description
2
238000001228
spectrum
Methods
0.000
description
2
210000000952
spleen
Anatomy
0.000
description
2
229940031000
streptococcus pneumoniae
Drugs
0.000
description
2
239000000126
substance
Substances
0.000
description
2
231100000331
toxic
Toxicity
0.000
description
2
230000002588
toxic effect
Effects
0.000
description
2
MDYOLVRUBBJPFM-UHFFFAOYSA-N
tropolone
Chemical compound
OC1=CC=CC=CC1=O
MDYOLVRUBBJPFM-UHFFFAOYSA-N
0.000
description
2
206010003445
Ascites
Diseases
0.000
description
1
244000063299
Bacillus subtilis
Species
0.000
description
1
208000010392
Bone Fractures
Diseases
0.000
description
1
GXCRUTWHNMMJEK-WYUVZMMLSA-M
Cefacetrile sodium
Chemical compound
[Na+].S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H](NC(=O)CC#N)[C@@H]12
GXCRUTWHNMMJEK-WYUVZMMLSA-M
0.000
description
1
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Chloride anion
Chemical compound
[Cl-]
VEXZGXHMUGYJMC-UHFFFAOYSA-M
0.000
description
1
208000003322
Coinfection
Diseases
0.000
description
1
229920002307
Dextran
Polymers
0.000
description
1
241000233866
Fungi
Species
0.000
description
1
206010018364
Glomerulonephritis
Diseases
0.000
description
1
101001046686
Homo sapiens Integrin alpha-M
Proteins
0.000
description
1
206010062016
Immunosuppression
Diseases
0.000
description
1
102100022338
Integrin alpha-M
Human genes
0.000
description
1
241000239218
Limulus
Species
0.000
description
1
208000004852
Lung Injury
Diseases
0.000
description
1
241000124008
Mammalia
Species
0.000
description
1
206010027253
Meningitis pneumococcal
Diseases
0.000
description
1
206010027476
Metastases
Diseases
0.000
description
1
102000035195
Peptidases
Human genes
0.000
description
1
108091005804
Peptidases
Proteins
0.000
description
1
239000004365
Protease
Substances
0.000
description
1
206010063837
Reperfusion injury
Diseases
0.000
description
1
241000607142
Salmonella
Species
0.000
description
1
241000191940
Staphylococcus
Species
0.000
description
1
241000191967
Staphylococcus aureus
Species
0.000
description
1
241000193990
Streptococcus sp. ‘group B’
Species
0.000
description
1
238000000692
Student’s t-test
Methods
0.000
description
1
QAOWNCQODCNURD-UHFFFAOYSA-L
Sulfate
Chemical compound
[O-]S([O-])(=O)=O
QAOWNCQODCNURD-UHFFFAOYSA-L
0.000
description
1
210000001744
T-lymphocyte
Anatomy
0.000
description
1
WKDDRNSBRWANNC-UHFFFAOYSA-N
Thienamycin
Natural products
C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21
WKDDRNSBRWANNC-UHFFFAOYSA-N
0.000
description
1
206010044248
Toxic shock syndrome
Diseases
0.000
description
1
231100000650
Toxic shock syndrome
Toxicity
0.000
description
1
206010069363
Traumatic lung injury
Diseases
0.000
description
1
206010067584
Type 1 diabetes mellitus
Diseases
0.000
description
1
108010059993
Vancomycin
Proteins
0.000
description
1
241000700605
Viruses
Species
0.000
description
1
229920000392
Zymosan
Polymers
0.000
description
1
238000001042
affinity chromatography
Methods
0.000
description
1
230000004075
alteration
Effects
0.000
description
1
230000001668
ameliorated effect
Effects
0.000
description
1
229960000723
ampicillin
Drugs
0.000
description
1
AVKUERGKIZMTKX-NJBDSQKTSA-N
ampicillin
Chemical compound
C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1
AVKUERGKIZMTKX-NJBDSQKTSA-N
0.000
description
1
239000003708
ampul
Substances
0.000
description
1
238000000540
analysis of variance
Methods
0.000
description
1
230000002924
anti-infective effect
Effects
0.000
description
1
229940088710
antibiotic agent
Drugs
0.000
description
1
239000000427
antigen
Substances
0.000
description
1
102000036639
antigens
Human genes
0.000
description
1
108091007433
antigens
Proteins
0.000
description
1
210000001367
artery
Anatomy
0.000
description
1
238000003556
assay
Methods
0.000
description
1
QVGXLLKOCUKJST-UHFFFAOYSA-N
atomic oxygen
Chemical compound
[O]
QVGXLLKOCUKJST-UHFFFAOYSA-N
0.000
description
1
230000001580
bacterial effect
Effects
0.000
description
1
BVGLIYRKPOITBQ-ANPZCEIESA-N
benzylpenicillin benzathine
Chemical compound
C=1C=CC=CC=1C[NH2+]CC[NH2+]CC1=CC=CC=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)CC1=CC=CC=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)CC1=CC=CC=C1
BVGLIYRKPOITBQ-ANPZCEIESA-N
0.000
description
1
230000017531
blood circulation
Effects
0.000
description
1
229960003669
carbenicillin
Drugs
0.000
description
1
FPPNZSSZRUTDAP-UWFZAAFLSA-N
carbenicillin
Chemical compound
N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C(C(O)=O)C1=CC=CC=C1
FPPNZSSZRUTDAP-UWFZAAFLSA-N
0.000
description
1
238000012754
cardiac puncture
Methods
0.000
description
1
229960003866
cefaloridine
Drugs
0.000
description
1
CZTQZXZIADLWOZ-CRAIPNDOSA-N
cefaloridine
Chemical compound
O=C([C@@H](NC(=O)CC=1SC=CC=1)[C@H]1SC2)N1C(C(=O)[O-])=C2C[N+]1=CC=CC=C1
CZTQZXZIADLWOZ-CRAIPNDOSA-N
0.000
description
1
229960000603
cefalotin
Drugs
0.000
description
1
XIURVHNZVLADCM-IUODEOHRSA-N
cefalotin
Chemical compound
N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C(O)=O)C(=O)CC1=CC=CS1
XIURVHNZVLADCM-IUODEOHRSA-N
0.000
description
1
229960002588
cefradine
Drugs
0.000
description
1
-1
ceftriaxione
Chemical compound
0.000
description
1
210000003169
central nervous system
Anatomy
0.000
description
1
238000005119
centrifugation
Methods
0.000
description
1
229940106164
cephalexin
Drugs
0.000
description
1
ZAIPMKNFIOOWCQ-UEKVPHQBSA-N
cephalexin
Chemical compound
C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1
ZAIPMKNFIOOWCQ-UEKVPHQBSA-N
0.000
description
1
229940009063
cephapirin sodium
Drugs
0.000
description
1
VGEOUKPOQQEQSX-OALZAMAHSA-M
cephapirin sodium
Chemical compound
[Na+].N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C([O-])=O)C(=O)CSC1=CC=NC=C1
VGEOUKPOQQEQSX-OALZAMAHSA-M
0.000
description
1
RDLPVSKMFDYCOR-UEKVPHQBSA-N
cephradine
Chemical compound
C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CCC=CC1
RDLPVSKMFDYCOR-UEKVPHQBSA-N
0.000
description
1
239000003153
chemical reaction reagent
Substances
0.000
description
1
231100000481
chemical toxicant
Toxicity
0.000
description
1
229960005091
chloramphenicol
Drugs
0.000
description
1
WIIZWVCIJKGZOK-RKDXNWHRSA-N
chloramphenicol
Chemical compound
ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1
WIIZWVCIJKGZOK-RKDXNWHRSA-N
0.000
description
1
230000001684
chronic effect
Effects
0.000
description
1
230000004087
circulation
Effects
0.000
description
1
229960003326
cloxacillin
Drugs
0.000
description
1
LQOLIRLGBULYKD-JKIFEVAISA-N
cloxacillin
Chemical compound
N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl
LQOLIRLGBULYKD-JKIFEVAISA-N
0.000
description
1
230000000295
complement effect
Effects
0.000
description
1
238000011109
contamination
Methods
0.000
description
1
230000002596
correlated effect
Effects
0.000
description
1
230000000875
corresponding effect
Effects
0.000
description
1
230000006378
damage
Effects
0.000
description
1
238000007405
data analysis
Methods
0.000
description
1
230000002950
deficient
Effects
0.000
description
1
230000001419
dependent effect
Effects
0.000
description
1
230000008021
deposition
Effects
0.000
description
1
YFAGHNZHGGCZAX-JKIFEVAISA-N
dicloxacillin
Chemical compound
N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(Cl)C=CC=C1Cl
YFAGHNZHGGCZAX-JKIFEVAISA-N
0.000
description
1
229960001585
dicloxacillin
Drugs
0.000
description
1
239000012153
distilled water
Substances
0.000
description
1
210000005069
ears
Anatomy
0.000
description
1
230000008030
elimination
Effects
0.000
description
1
238000003379
elimination reaction
Methods
0.000
description
1
210000001174
endocardium
Anatomy
0.000
description
1
230000003511
endothelial effect
Effects
0.000
description
1
210000003989
endothelium vascular
Anatomy
0.000
description
1
239000003623
enhancer
Substances
0.000
description
1
210000003743
erythrocyte
Anatomy
0.000
description
1
210000001508
eye
Anatomy
0.000
description
1
239000012530
fluid
Substances
0.000
description
1
230000009395
genetic defect
Effects
0.000
description
1
238000010353
genetic engineering
Methods
0.000
description
1
210000000224
granular leucocyte
Anatomy
0.000
description
1
230000036541
health
Effects
0.000
description
1
210000004408
hybridoma
Anatomy
0.000
description
1
229960002182
imipenem
Drugs
0.000
description
1
ZSKVGTPCRGIANV-ZXFLCMHBSA-N
imipenem
Chemical compound
C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21
ZSKVGTPCRGIANV-ZXFLCMHBSA-N
0.000
description
1
230000028993
immune response
Effects
0.000
description
1
230000001506
immunosuppresive effect
Effects
0.000
description
1
208000037798
influenza B
Diseases
0.000
description
1
238000001802
infusion
Methods
0.000
description
1
239000000543
intermediate
Substances
0.000
description
1
239000006207
intravenous dosage form
Substances
0.000
description
1
210000001503
joint
Anatomy
0.000
description
1
229960000318
kanamycin
Drugs
0.000
description
1
229930027917
kanamycin
Natural products
0.000
description
1
SBUJHOSQTJFQJX-NOAMYHISSA-N
kanamycin
Chemical compound
O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N
SBUJHOSQTJFQJX-NOAMYHISSA-N
0.000
description
1
229930182823
kanamycin A
Natural products
0.000
description
1
210000003734
kidney
Anatomy
0.000
description
1
230000007774
longterm
Effects
0.000
description
1
231100000515
lung injury
Toxicity
0.000
description
1
239000006166
lysate
Substances
0.000
description
1
210000002540
macrophage
Anatomy
0.000
description
1
239000012528
membrane
Substances
0.000
description
1
230000009401
metastasis
Effects
0.000
description
1
MGFZNWDWOKASQZ-UMLIZJHQSA-M
methicillin sodium
Chemical compound
[Na+].COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21
MGFZNWDWOKASQZ-UMLIZJHQSA-M
0.000
description
1
229940019826
methicillin sodium
Drugs
0.000
description
1
210000000865
mononuclear phagocyte system
Anatomy
0.000
description
1
201000006417
multiple sclerosis
Diseases
0.000
description
1
229960001775
nafcillin sodium
Drugs
0.000
description
1
OCXSDHJRMYFTMA-KMFBOIRUSA-M
nafcillin sodium monohydrate
Chemical compound
O.[Na+].C1=CC=CC2=C(C(=O)N[C@@H]3C(N4[C@H](C(C)(C)S[C@@H]43)C([O-])=O)=O)C(OCC)=CC=C21
OCXSDHJRMYFTMA-KMFBOIRUSA-M
0.000
description
1
238000011587
new zealand white rabbit
Methods
0.000
description
1
UWYHMGVUTGAWSP-JKIFEVAISA-N
oxacillin
Chemical compound
N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1
UWYHMGVUTGAWSP-JKIFEVAISA-N
0.000
description
1
229960001019
oxacillin
Drugs
0.000
description
1
229910052760
oxygen
Inorganic materials
0.000
description
1
239000001301
oxygen
Substances
0.000
description
1
244000045947
parasite
Species
0.000
description
1
230000007170
pathology
Effects
0.000
description
1
239000008188
pellet
Substances
0.000
description
1
229940049954
penicillin
Drugs
0.000
description
1
235000019371
penicillin G benzathine
Nutrition
0.000
description
1
229940056360
penicillin g
Drugs
0.000
description
1
150000002960
penicillins
Chemical class
0.000
description
1
229960001412
pentobarbital
Drugs
0.000
description
1
WEXRUCMBJFQVBZ-UHFFFAOYSA-N
pentobarbital
Chemical compound
CCCC(C)C1(CC)C(=O)NC(=O)NC1=O
WEXRUCMBJFQVBZ-UHFFFAOYSA-N
0.000
description
1
PHEDXBVPIONUQT-RGYGYFBISA-N
phorbol 13-acetate 12-myristate
Chemical compound
C([C@]1(O)C(=O)C(C)=C[C@H]1[C@@]1(O)[C@H](C)[C@H]2OC(=O)CCCCCCCCCCCCC)C(CO)=C[C@H]1[C@H]1[C@]2(OC(C)=O)C1(C)C
PHEDXBVPIONUQT-RGYGYFBISA-N
0.000
description
1
208000004593
pneumococcal meningitis
Diseases
0.000
description
1
MFDFERRIHVXMIY-UHFFFAOYSA-N
procaine
Chemical compound
CCN(CC)CCOC(=O)C1=CC=C(N)C=C1
MFDFERRIHVXMIY-UHFFFAOYSA-N
0.000
description
1
229960004919
procaine
Drugs
0.000
description
1
230000009979
protective mechanism
Effects
0.000
description
1
210000001147
pulmonary artery
Anatomy
0.000
description
1
230000002685
pulmonary effect
Effects
0.000
description
1
239000000700
radioactive tracer
Substances
0.000
description
1
230000009467
reduction
Effects
0.000
description
1
230000002829
reductive effect
Effects
0.000
description
1
230000000452
restraining effect
Effects
0.000
description
1
230000000630
rising effect
Effects
0.000
description
1
239000013049
sediment
Substances
0.000
description
1
239000011780
sodium chloride
Substances
0.000
description
1
238000010561
standard procedure
Methods
0.000
description
1
238000001356
surgical procedure
Methods
0.000
description
1
230000000451
tissue damage
Effects
0.000
description
1
231100000827
tissue damage
Toxicity
0.000
description
1
239000003440
toxic substance
Substances
0.000
description
1
229960003165
vancomycin
Drugs
0.000
description
1
MYPYJXKWCTUITO-LYRMYLQWSA-N
vancomycin
Chemical compound
O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1
MYPYJXKWCTUITO-LYRMYLQWSA-N
0.000
description
1
MYPYJXKWCTUITO-UHFFFAOYSA-N
vancomycin
Natural products
O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1
MYPYJXKWCTUITO-UHFFFAOYSA-N
0.000
description
1
230000008728
vascular permeability
Effects
0.000
description
1
230000006442
vascular tone
Effects
0.000
description
1
210000003462
vein
Anatomy
0.000
description
1
Classifications
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
A61K39/00—Medicinal preparations containing antigens or antibodies
A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
C—CHEMISTRY; METALLURGY
C07—ORGANIC CHEMISTRY
C07K—PEPTIDES
C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
C07K16/2839—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily
C07K16/2845—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily against integrin beta2-subunit-containing molecules, e.g. CD11, CD18
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
A61P11/00—Drugs for disorders of the respiratory system
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
A61P17/00—Drugs for dermatological disorders
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
A61K38/00—Medicinal preparations containing peptides
Description
4| IYL~ i I Form COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-62 COMPLETE SPECIFICATION
(ORIGINAL)
620 100 FOR OFFICE USE: Application Number: Lodged: Class Int. Class Complete Specification Lodged: Accepted: Published: Prjotiy: RelalIe.Art: o 0 4 e* *e’<9 This document 'ontains the amendments Llowed under Section 83 b, the Superviaing Exa:.' r G.l and is fur i.r:nthig o TO BE COMPLETED BY APPLICANT Name of Applicant: THE ROCKEFELLER UNIVERSITY 90 0 @9 Address of Applicant: Actual Inventors 3 Address for Service: Complete Specification 1230 York Avenue, New York, New York, 10021-6399, United States of America Samuel D. WRIGHT v, and Elaine I. TUOMANEN R K Maddern Associates, 345 King William Street, Adelaide, South Australia, Australia, for the invention entitled: "METHOD OF INHIBITING THE INFLUX OF LEUKOCYTES INTO ORGANS DURING SEPSIS OR OTHER TRAUMA" The following statement is a full description of this invention, including the best method of performing it known to Ir us.
1 m~chanism bv which IB4 inhibits sequestration of PMN into A4$ 0 *000
C
0000 **00 o o 0* 0C @00 60 o 0 0 09 6000 0 cee o 5 so.
C
*0 @ha* la METHOD OF INHIBITING THE INFLUX OF LEUKOCYTES INTO ORGANS DURING SEPSIS OR OTHER TRAUMA The invention described herein was made, in part, in the course of work under Research Grants AI22003 and HL32418 from the National Institutes of Health, USPHS.
BACKGROUND OF THE INVENTION Leukocytes, and especially polymorphonuclear (PMN) leukocytes, circulate in the blood and do not adhere to the endothelium (the cells lining the vessels). Upon the introduction of an infectious agent, fragments that result from the death of an infectious agent, or another inflammatory substance into nearby tissues, leukocytes, especially PMN, are induced to bind to the endothelium and then migrate into the tissues. Since PMN can recognize and kill many infectious agents, this is a protective mechanism. However, in many disease 20 circumstances, such as sepsis and trauma, PMN react in an exaggerated and deleterious fashion. They may bind so avidly to endothelium as to occlude blood flow. Once in the tissues, they secrete proteases, reactive oxygen intermediates, and other toxic molecules which not only kill infectious agents, but also can result in extensive tissue damage. In addition, they release inflammatory mediators that alter vascular tone and permeability, and that recruit additional leukocytes to the site, thus perpetuating inflammation.
Two diseases in which PMN-mediated damage contributes to morbidity and mortality are endotoxic shock and adult respiratory distress syndrome. In both instances, the lung is a preferred organ for emigration of PMN, and lung damage can be severe enough to cause death.
Adult respiratory distress syndrome (ARDS) can result from both infectious and non-infectious causes; either r; _mark" I4 'cl i -1 ii: 1 iii i j j -i iir! it Intravenous Formulation IV 2 results in similar pathology as a consequence of PMN emigration. In endotoxic shock associated with infection, the use of antibiotics magnifies the deleterious effects of inflammation. This is due to the mechanism by which such agents exert their anti-infective effects. For example, following the administration of a beta-lactam antibiotic (or other cell-wall directed antibiotic), the bacteria disintegrate due to lysis by the anti-infective agents. The resulting fragments of bacteria initiate a dramatically enhanced inflammatory response. See Tuomanen et al., Am. Rev. Respir. Dis., 135, 869-874 (1987). Earlier research has indicated that inhibition of this antibiotic-induced inflammation correlates with improved morbidity and mortality in the 15 setting of meningitis; Tuomanen et al., J. Infect. Dis., So155, 985-990 (1985) and Kadurugamuwa, Program and ^o Abstracts of the 27th ICAA Meeting, p. 205 (1987). In pneumococcal meningitis, for instance, mortality can be directly correlated with the amount of meningeal 20 inflammation; McAllister et al., J. Infect. Dis., 132, 355-360 (1975). Thus, a method of dampening inflammation during the course of therapy with an antibiotic would be advantageous in treating infections, particularly o endotoxic shock and ARDS associated with infection.
t In a similar fashion, a method of dampening the inflammation associated with ARDS of noninfectious origin c would likewise be a useful therapeutic tool for physicians.
A molecule on the surface of PMN that mediates adhesion to endothelium has redentiy been defined. That molecule, CD18, is thought to mediate adhesion because (a) monoclonal antibodies against CD18 inhibit binding of PMN to endothelium in vitro, injection of monoclonal antibodies against CD18 into rabbits prevents normal emigration of PMN in response to an inflammatory c r 16 infection related auto-immune conditions such as Type I 3 stimulus, PMN from patients with a genetic defect in the expression of CD18 fail to bind to endothelial cells in vitro, and the deficient patients fail to recruit PMN to sites of infection.
CD18 has been previously described as a receptor for the third component of complement, C3bi (Wright et al., PNAS, 5699-5703 (1983). A single receptor thus functions in two capacities, to mediate the binding of polymorphonuclear leukocytes (PMN) to endothelial cells, and to C3bi-coated cells.
It is thus an object of the present invention to provide a method of inhibiting the influx of leukocytes and S.o: 15 particularly polymorphonuclear (PMN) leukocytes into the lung and other organs during sepsis or other infectious or non-infectious trauma which comprises the 0 administration of a therapeutic amount of an anti-CD18 monoclonal antibody or active fragment thereof to a 20 patient in need of such therapy.
o
S
It is a further object of this invention to treat inflammation in the lung and other organs in patients having an inflammation caused by sepsis or other infectious or non-infectious trauma by administration of e a therapeutic amount of an anti-CDl8 monoclonal antibody or active fragment thereof, to a patient in need of such therapy.
Another object of the present invention is to afford a method of treating a patient afflicted with endotoxic shock or adult respiratory distress syndrome by administering a therapeutic amount of an anti-CD18 monoclonal antibody, whereby the amount of the influx of i PMN into the lung is eliminated or greatly reduced.
1 1 1 1 1 1 1 1 1 1 1 1 5 1 4 It is a still further object of this invention to eliminate or reduce the influx of leukocytes, and particularly polymorphonuclear (PMN) leukocytes, into the lung and other organs of a patient wherein the patient is being administered an anti-infective agent for an infectious disease by administering a therapeutic amount of an anti-CD18 monoclonal antibody or an active fragment thereof prior to, concurrent with, or after, the administration of the anti-infective agent, thereby eliminating or reducing inflammation.
SUMMARY OF THE INVENTION The present invention concerns a method and associated agents and compositions for inhibiting the influx of :leukocytes into the lung and other organs during sepsis S"or other infectious or non-infectious trauma, the method comprising administering a therapeutic amount of an agent or composition comprising an anti-CD18 antibody or 20 fragment thereof. Highly preferred anti-CD18 antibodies o are monoclonal antibodies selected from the group consisting of anti-CD18 mAb IB4 (hereinafter designated 'as IB4) and anti-CD18 mAb 60.3 (hereinafter designated as 60.3) and/or active fragments thereof. Additionally, 25 this invention concerns a method and associated materials for inhibiting the ingress of leukocytes into the lung or other organs in patients having endotoxic shock or adult c respiratory distress syndrome of any cause by c c administration of a therapeutic amount of an anti-CD18 antibody or fragment thereof to a patient in need of such therapy. Highly preferred anti-CD18 antibodies are likewise selected from the group consisting of IB4 and 60.3 and active fragments thereof.
This invention also concerns a method and associated materials for eliminating or reducing inflammation in a ji patient wherein the patient is being administered an H 11 1 1 1 a s:: anti-infective agent for an infectious disease which comprises the administration prior to, along with or after the anti-infective agent of a therapeutic amount of an anti-CD18 antibody or fragment thereof. Preferred anti-CD18 antibodies are those selected from the group consisting of IB4, and 60.3 and frarments thereof.
Dosage forms combining an anti-infective agent and a therapeutic amount of the monoclonal antibody or fragment thereof are also described.
BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph showing the percentage of the injected neutrophil radioactivity in the lung versus S 15 time.
goa.
Figure 2 is a graph showing the neutrophil radioactivity in the blood versus time. The circulating radioactivity Figure 3 is a graph showing neutrophil radioactivity in I *in the blood versus time. The circulating radioactivity is S. is expressed as a ratiopere nt of the total injecte value.
20 radioactivity, SThis invention relates in a first aspect to inhibiting I the influx of leukocytes into the lung and other organs during sepsis or other non-infectious tauma by the administration of a therapeutic amount of an anti-CD18 antibody or active fragment thereof to a patient in need of such therapy.
The inflamed organ which is the target of the present invention may result from any of a variety of infective j |agents, including gram-positive and gram-negative l: 1 .lN 1 6 bacteria as well as viruses, parasites and fungi, or may arise from a non-infectious source such as trauma.
Particularly targeted infections are those which are susceptible to treatment with beta-lactam antibiotics, such as Haemophilus influenzae B; N. meninqitides b; pneumococci, Streptococcus pneumoniae; Escherichia coli; Staphylococcus epidermidus; Staphylococcus aureus; group B Streptococci; Salmonella; Bacillus subtillis; and Pseudomonas aeruqinosa.
The inflamed organ which is the target of the present invention can likewise be any body organ susceptible to inflammation by the above-described agents. The present invention is, however, particularly adaptable to the 15 treatment of the lung, central nervous system, kidney, joints, endocardium, eyes and ears, with the treatment of o 9 the lung being a highly preferred embodiment.
S The present invention has been found to be useful in 20 preventing the ingress of leukocytes into the lung of S" mammals afflicted with sepsis. Such activity enables their preferred route of administration to be intravenous, and their administration to be particularly useful in the treatment of such infections, including those arising from pneumococci, Haemophilus influenzae B, n"^t N. meningitides b and Escherichia coli, group B Streptococcus, Staphylococci and Pseudomonas.
Similarly, the present invention is also applicable to inflammation arising from causes other than infections, such as ARDS precipitated by burns, surgery, toxic chemicals, fracture of bones, or other trauma.
One of the characteristics of the antibodies useful in accordanc- with the present invention is the ability of such antibodies to recognize and bind a broad spectrum of polypeptides believed to comprise additional members of t:n -7the two-chain membrane leukocyte protein of which the chain bearing the receptor CD18 is but part. Thus, it is this broader spectrum of affinity possessed by the anti-CD18 antibodies of the present invention that is believed to promote their improved level and corresponding spectrum of performance and utility.
The particular anti-CD18 antibodies which can be utilized in the practice of the methods of the present invention are preparable by standard techniques. Preferred monoclonal antibody IB4 is described in Wright et al., Proc. Natl. A\ad.
Sci. USA, 80, 5699-5703 (1983). The IB4 hybridoma was deposited with the American Type C-lture Collection on 2nd June, 1989, and accorded ATCC designation number HB 10164.
Monoclonal antibody 60.3, another preferred embodiment, is described in Beatty, et al., J. Immunology, 131, 2913-2918 (1983).
099 a Other anti-CD18 monoclonal antibodies, as well as methods for their preparation, are described in "Leukocyte Typing III", Springer-Verlag, New York (1988).
In certain patients, a potential problem with the use of the o murine monoclonal antibody, such as IB4 or 60.3, may exist 25 since the patient may generate an immune response against a *a o murine monoclonal antibody. This effect may be ameliorated or a e.l obviated by using active fragments of the monoclonal antibody so as to minimize the amount of foreign protein injected.
Another alternative is to employ genetic engineering techniques '30 to make a chimeric antibody in which the binding region of the murine antibody IB4 or 60.3 is combined with the constant Sa regions of human immunoglobulin.
A further aspect of the present invention is that of reducing or eliminating the influx of leukocytes into the lung in endotoxic shock or adult respiratory distress syndrome associated with the administration of an anti-infective agent.
The method comprises the administration 4..C OF TH DIS. jOS 411 ABSTRACT OF THE DISCLOSURE 0 9 ;o 0 0 *0 *O 4 9 *i 9 .449 9 (C
C
CCC
C CC t C C prior to, along with, or after the anti-infective agent of a therapeutic amount of an anti-CD18 monoclonal antibody or an active fragment thereof to a patient in need of such therapy. Preferred anti-CD18 monoclonal antibodies are IB4 and 60.3. Due to the mechanism of their therapeutic activity, anti-infective agents, and particularly beta-lactam antibiotics, cause additional inflammation as a result of their therapeutic effect.
Although such anti-infective agents sterilize a given infection, they cause release of toxic products, for example, the cell wall and/or endotoxin of the infecting agent. Such bacterial components initiate an inflammatory response, often most acute in the lung. It is this inflammation which contributes significantly to 15 the lung damage that is the long-term consequence of many infections.
Reduction or elimination of inflammation in inflammatory diseases, particularly endotoxic shock and adult 20 respiratory distress syndrome, results in a diminution of the organ damage that usually accompanies such disease states. Since the monoclonal antibodies IB4 and 60.3 possess the unique ability to block movement of leukocytes into the lung and other organs, they are 25 uniquely suited to treat both non-infectious causes and infectious causes. Causative infective agents are those such as Haemophilus influenza B, N. meningitides b, E.
coli, Staphylococci, or a pneumococci such as Streptococcus pneumoniae. Such infections are generally treated with an aminoglycoside such as gentamicin or a beta-lactam antibiotic such as a penicillin or cephalosporin. Among the typically utilized aminoglycosides, penicillins and cephalosporins used in the treatment of such infections are cephalothin, cephaloridine, carbenicillin, ampicillin, nafcillin sodium, cloxacillin, dicloxacillin, oxacillin, methicillin sodium, phenoxymethyl penicillin, procaine i a4
I
i: 1
B
i i- l r penicillin G, benzathine penicillin G, penicillin G, cephacetrile sodium, cephalexin, cephapirin sodium, cephradine, penicillin V, gentamicin, kanamycin, chloramphenicol, cefotaxime, ceftriaxione, vancomycin, and imipenem.
Due to the ability of the anti-CD18 monoclonal antibodies to reduce or eliminate the influx of leukocytes into the lung and other organs in a infectious disease caused by the administration of an anti-infective agent, the anti- CD18 monoclonal antibody or active fragment thereof can be combined in a single unit dosage form with the antiinfective agent for convenience of administration. Such *o dosage form is most preferably an intravenous dosage form since most anti-infective agents, particularly the betalactam antibiotics, are available in a suitable chemical form omor administration via the intravenous route. This oe is also the preferred route of administration for the monoclonal antibodies, such as IB4 and 60.3. Typically, 20 the anti-infective agent and the monoclonal antibody can be combined in a single ampoule solution. Where this is possible, the anti-infective agent and the monoclonal o antibody can be packaged separately and mixed just prior Sto injection. Administration can likewise be via a S; 25 mixture with any standard intravenous solution, i.e., normal balije.
fr The amount of anti-infective agent in the dosage form is dependent upon the particular anti-infective agent being utilized and the particular infection being treated. The amount of the monoclonal antibody utilized in a dosage form can range from about 1 to about 1,000 mg, with 100 mg per dosage unit being highly preferred. Dosages can be administered one to four times daily, with continued therapy for as long as the infection persists.
17 a 2 mitur wih ay sandrdintaveoussoltio, If.
The method of administering the dosage unit may, of course, be varied by the treating physician due to patient condition and the severity of the infectious disease being treated.
The following examples illustrate the methods and preparations of the present invention.
EXAMPLE 1 Inhibition of Leukocytes in the Lung Rabbit Neutrophil Isolation New Zealand White Rabbits (2-3 kg) are given 60 mg/kg of 15 sodium Pentobarbital. Through a cardiac puncture, 60 ml r of blood is obtained into a heparinized syringe. The blood is centrifuged at 400 xg for 20 minutes and the platelet-rich plasma is removed. The platelet rich plasma co is centrifuged at 2500 xg for 15 minutes to provide a 20 source of autologous platelet-poor plasma. Eight ml of 6% dextran 500 in saline is added to the red cell pellet and normal saline is added to bring the volume up to ml. The red cell, are allowed to sediment for 30-60 minutes and the leukocyte-rich plasma is aspirated. The 25 neutrophils are separated from leukocytes by 'centrifugation over discontinuous Percoll-plasma gradients (43% over The neutrophils are pelleted and the remaining red blood cells are removed with distilled water lysis. All reagents used for neutrophil isolation procedure are tested for the presence of endotoxin using the limulus lysate assay and are not used if any contamination is found. Similarly, all laboratory ware that is used is endotoxin-free.
Preparation of IB4 Antibody: The antibody to the CD11b/CD18 receptor is prepared by the method described in Proc. Natl. Acad. Sci. USA, ii i
I
4 44 4 o 44 440 9: .4I *t 4
(I
11 5699-5703 (1983). The antibody is obtained from mouse ascites fluid and is purified by affinity chromatography to remove all non-immunoglobulin proteins.
Neutrophil-Labeling: Neutrophils are labelled with 1 "In. Tropolone (4 mM in normal saline) was added at equal volume to the 1 'In chloride (Amersham). The 'I-In-tropolone is added dropwise to neutrophils suspended in autologous plasma.
Neutrophils are allowed to incubate for 30 minutes at room temperature and are then washed with autologous plasma. Neutrophils are labelled with this technique generally with greater than 60% labelling efficiency.
Isolated and labelled neutrophils are tested for chemotaxis to opsonized zymosan and adherence into bovine pulmonary artery endothelial monolayers induced by phorbol myristate acetate. The neutrophils show normal chemotaxis and normal adherence. In addition, the PMAinduced adherence of rabbit neutrophils to bovine 20 pulmonary vascular endothelium could be inhibited by pretreatment with IB4.
Experimental Protocol: Rabbits are placed into a plastic restraining cage and 25 placed on a large field of view gamma-camera (Dymax, ElScint, Haifa, Israel). The camera is fitted with a medium energy, medium resolution parallel hole collimator. An intravenous line is placed into a marginal ear vein and an arterial line is placed into the central ear artery of the rabbit. The rabbit is infused with the labelled neutrophils and dynamic 5 minute gamma camera images are obtained for 4 hours. Arterial blood samples are obtained every 15 minutes through the 4-hour period. Control rabbits are not given any pretreatment.
One group of rabbits is treated 4 hours before imaging with E. Coli endotoxin (100 Mg). Another group is treated with endotoxin 24 hours prior to imaging and is
I:,
I~
.i:s i9i
I~
i i 1 i 1 12
I
given IB4 antibody (0.5 mg/kg) 20 minutes prior to imaging. Another group of animals received no endotoxin treatment, but are treated with IB4 antibody 20 minutes prior to imaging.
Data Analysis Regions of interest are drawn around the lungs, liver, spleen and the whole body of the rabbits. The counts within these regions of interest are summed to produce sum activity curves. The counts in the lung, liver and spleen are expressed as fractions of the activity within the entire rabbits' body. The activity in the blood samples is expressed as counts per minute/gm of blood and are also expressed as a fraction of circulating activity 15 relative to the total injected activity. The *o significance of differences between groups is determined 0.o by analysis of variance and student's T test where appropriate. The lung data are modeled to a two- 00 compartment exponential wash-out equation.
0° 0 Results eom;o The fraction of the injected neutrophil radioactivity in othe lung versus time is shown in Figure 1. Control a° animals show a rapid wash-out from the lung with tracer 25 activity in the lung reaching 13% by 90 minutes. The peak amount of activity in the lungs of the control rabbits is 31%. In animals treated with endotoxin 4 t hours prior to study, the peak amount of activity in the lungs is 41% and the wash-out from the lungs is slower, with 16% of the neutrophil radioactivity remaining in the lung at 90 minutes. With 24 hour pretreatment with endotoxin, an even greater response is seen with about 44% of the neutrophils initially localizing in the lung and with a 90-minute wash-out of 18%. When animals are given the e'dotoxin 24 hours before study and given IB4 minutes before study, the peak activity in the lung is less than both control and the 24-hour endotoxin i i .i 13 treatment group. The wash-out is faster and 6% of the neutrophil radioactivity remained in the lungs at minutes. These data indicate that IB4 prevents sequestration of PMN into the lung after endotoxininduced lung injury.
Blood Data The blood radioactivity is expressed as a fraction of the experimental value to the 15-minute baseline value (see Figure The control group shows a small rise in blood radioactivity over time, which likely represents wash-out from neutrophils sequestered in the lung. The 4-hour endotoxin group also shows a slight rise over time, very similar to the control group. The 24-hour endotoxin 15 group shows a large increase in the blood radioactivity 1 over time. The 24-hour endotoxin group, which was also o treated with IB4, showed the most rapid rise in blood o radioactivity which stabilizes at about 80 minutes and S0 then gradually falls. The rate of uptake in the 24-hour 3000 o. oo 20 endotoxin and IB4-treated group appears to be somewhat faster than that seen in the 24-hour endotoxin alone o0 treatment group.
0 The blood data expressed as a fraction of the infused .o 25 neutrophils that are in circulation are shown in Figure 3. Cuntol neutrophils show a slight rise over time with about 20-30% of neutrophils circulating after infusion.
0 The 4-hour endotoxin group also shows a stable amount but with about 3% of neutrophils circulating during this study. The 24-hour endotoxin group also shows a stable or gradually rising amount of radioactivity over time with about 8-12% of neutrophils circulating during the course of the study. The group treated with 24 hours of endotoxin and then IB4 shows a pattern that is similar to the 24-hour endotoxin treatment group with an initial rise and then a gradual plateau with circulating fractions between 3 and These data indicate that the *v y 4. t i 1 1 ii p -1- 4J I I 14 mechanism by which 1B4 inhibits sequestration of PMN into the lung is not due to clearance of the PMN by the reticuloendothel ial system.
EXAMPLE 2 Formulations 0000 0 0 00 0 0 0 0 0 0S 0000 0 0 0 0 0000 00 0 0 00 0 0000 QO OW 00 0 0 O 0 0000 0 00 00 0 0 00 00 0 *1 00 0 00 00 0 0000 0 00 00 0~4 Intravenous Formulation I Ingcredient cefotaxime monoclonal antibody 1B4 dextrose USP sodium bisulfite USP edetate disodium USP 15 water for injection q.s.a.d.
Intravenous Formulation II Ingredient amp ic ill in 20 monoclonal antibody 60.3 sodium bisulfite USP disodium edetate USP water for injection q.s.a.d.
25 Intravenous Formulation III IngrtediencL gentamicin (charged as sulfate) monoclonal antibody 1B4 sodium bisulfite USP disodium edetate USP water for injection q.s.a.d.
mgr/ml 250.0 10.0 45.0 3.2 0.10 1. 00 ml mq/m1 250.0 10.0 3.2 0.1 1. 00 ml mg/Ml 40.0 10. 0 3.2 1. 00 ml
C
4 Adult respiratory distress syndrome (ARDS) can result from both infectious and non-infectious causes; either i 11^: i 4 i; B T Intravenous Formulation IV Ingredient monoclonal antibody IB4 dextrose USP sodium bisulfite USP edetate disodium USP water for injection q.s.a.d.
Intravenous Formulation V Ingredient monoclonal antibody 60.3 sodium bisulfite USP disodium edetate USP water for injection q.s.a.d.
mI/mi 10.0 45.0 3.2 0.10 1.00 ml mg/mi 10.0 3.2 0.1 1.00 ml p 0s00 p~s 0*ee
OS
00 *s 0 0000 op 0 o o0 0s 0 0e 00 00 0 Puu 0 0r 0 Q0r~0 As indicated earlier, the present invention is applicable to the treatment of a variety of inflammatory disease states including infectious diseases where active infection exists at any body site, such as in the 20 instance of meningitis. Also included are conditions such as secondary inflammations whether acute or chronic, that may occur at a site of antigen deposition that is secondary to a primary infection at a distant body site, and exemplary specific conditions would also include 25 meningitis, as well as encephalitis, arthritis, uveitis, colitis, such as inflammatory bowel/Crohn's disease, glomerulonephritis, dermatitis, and psoriasis. Also included is the inflammation that results from alterations in leukocyte movement during infection such as adult respiratory distress syndrome associated with sepsis.
Other inflammatory disease states include immune disorders and conditions involving T-cell and/or macrophage attachment/recognition; such as, acute and delayed hypersensitivity, graft vs. host disease; primary auto-immune conditions such as pernicious anemia; *j 1 J antibodies against CD18 into rabbits prevents normal emigration of PMN in response to an inflammatory infection related auto-immune conditions such as Type I diabetes mellitis; flares during rheumatoid arthritis; diseases that involve leukocyte diapedesis, such as multiple sclerosis; antigen-antibody complex mediated diseases including certain of the secondary infection states listed above; immunosuppression; and transplant rejection. Inflammation due to toxic shock or trauma such as adult respiratory distress syndrome and reperfusion injury; and that which is due to tumorous conditions such as leukocyte dyscrasias and metastasis, is likewise included within the scope hereof.
In addition to the above, the present invention is applicable to the inhibition of leukocyte-endothelial attachment in the instances of non-disease states and in .o0 particular, for diagnostic and therapeutic purposes; such S as the iatrogenic opening of the endothelium to prevent o0 the ingress of leukocytes during the introduction of a 20* dye or image enhancer into tissue, or to allow the S, 20 selective entry of a therapeutic drug in the instance of chemotherapy; or to enhance the harvesting of leukocytes Oe 0 from patients.
0 0 This invention may be embodied in other forms or carried 0 25 out in other ways without departing from the spirit or essential characteristics thereof. The present disclosure is therefore to be considered as in all respects illustrative and not restrictive, the scope of the invention being indicated by the appended claims, and 30 all changes which come within the meaning and range of equivalency are intended to be embraced therein.
1 *i .T
Claims (15)
1. A pharmaceutical composition for eliminating or reducing inflammation in a patient being treated with an anti-infective agent, which pharmaceutical composition comprises a composition comprising an effective amount of an anti-CD18 antibody, or active fragment thereof, and a pharmaceutically acceptable carrier, or composition in combination with the anti-infective agent. I 2. The composition of Claim 1 wherein the anti-CD18 antibody is anti-CD18 mAb IB4. te S 3. The composition of Claim 1 wherein the anti-CD18 antibody is anti-CD18 mAb 60.3. o
4. The composition of Claim 1 wherein sa _i composition is prepared in suitable form for intravenous administration. S 5. A pharmaceutical composition for treating inflammation in the lung and other organs in patients having an inflammation S caused by sepsis or other infectious or non-infectious trauma comprising the composition of Claim 1. c fct6. The composition of any one of Claims 1 to 5 wherein the anti-infective agent is a beta-lactam antibiotic.
7. A method of using an anti-CD18 antibody or active fragment thereof to inhibit the influx of leukocytes into the lung and other organs during sepsis or other infectious or non- infectious trauma and/or to treat inflammation in the lung and other organs in patients having an inflammation caused by sepsis or other infectious or non-infectious trauma, and/or to eliminate or reduce inflammation in a patient wherein the patient is being administered an anti-infective agent; and/or to assist in the administration of a therapeutic drug to a patient during chemotherapy; which comprises administration of an effective amount of anti-CD18 monoclonal antibody. cssrsnV c CO'' opiigtecmoito fCam1 invention may result from any of a variety of infective agents, including gram-positive and gram-negative 18
8. The method according to Claim 7 wherein the anti-CD18 antibody is anti-CD18 mAb IB4.
9. The method according to Claim 7 wherein the anti'-CD18 antibody is anti-CD18 mAb 60.3. The method according to Claim 7 wherein the antibody or fragment thereof is administered i.travenously.
11. The method according to Claim 7 wherein the influx of leukocytes results from an infection. 0f
12. The method according to Claim 7 wherein the influx of leukocytes results from a non-infectious trauma.
13. The method according to Claim 7 wherein the influx of leukocytes results from endotoxic shock. S 14. The method according to Claim 7 wherein the influx of leukocytes results from adult respiratory distress syndrome.
15. The method according to Claim 11 wherein the infection is associated with a disease state selected from the group S" consisting of meningitis, encephalitis, arthritis, uveitis, colitis, inflammatory bowel/Crohn's disease, dermatitis, psoriasis, and adult respiratory distress syndrome.
16. The method according to Claim 7 wherein the influx of leukocytes results from an immune disorder selected from the group consisting of acute hypersensitivity, delayed hypersensitivity, graft vs. host disease, pernicious anemia, diabetes mellitus, flares during rheumatoid arthritis, diseases that involve leukocyte diapedesis, antigen-antibody complex mediated diseases, and transplant rejection.
17. The method according to Claim 7 wherein the influx of PL ~leukocytes results from an iatrogenic state. kmco1tci such antibodies to recognize and bind a broad spectrum of polypeptides believed to comprise additional members of
18. The method according to Claim 7 wherein said antibody or active fragment thereof is administered prior to, concurrent with, or after, the administration of the anti-infective agent.
19. The method-according to Claim 18 wherein the anti- infective agent.is a beta-lactam antibiotic. In a diagnostic method including the introduction of a marker material into tissue, the step of causing the iatrogenic c" opening of the endothelium to prevent leukocyte ingress into S'o said tissue by administering to said endothelium an inhibitory tc amount of an anti-CDl8 antibody or active fragment thereof.
21. In a diagnostic method including the harvesting of a quantity of leukocytes from a test subject, the step of administering to the endothelium of said test subject prior to the harvesting of said leukocytes of an amount of an anti-CD18 antibody, or active fragment thereof, effective to prevent the binding of a sufficient quantity of said leukocytes to provide fadequate harvest of said leukocytes for the successful practice of said diagnostic method. SC 22. A pharmaceutical composition substantially in accordance p with any one of the formulations of Example 2 herein described. tc C E cc 23. A pharmaceutical composition according to any one of Claims 1 to 6, substantially as herein described.
24. A method of using an anti-CD18 antibody or fragment thereof, substantially as herein described with reference to Example 1 or 2. Dated this 29th day of November 1991 THE ROCKEFELLER UNIVERSITY, SBy its Patent Attorneys, K. MADDE SSOCIATES I 1 j 11 1 1 v i O *AT E :1^C) endotoxic shock or adult respiratory distress syndrome associated with the administration of an anti-infective agent. The method comprises the administration 4 'v o I, rt'^iattadt.a-tttri.i. r ABSTRACT OF THE DISCLOSURE i The influx of leukocytes into the lung and other organs during sepsis or other infectious or non-infectious trauma can be inhibited by the administration of anti- CD18 monoclonal antibodies. Such inhibition results in a prevention and/or diminishment of organ damage in inflammations and especially in endotoxic shock and adult respiratory distress syndrome. 0 0 0 0 9a 6 0 0 0 o o a 0 a a *0 oo a a o e 0 0 0 0 0 0 0140~e C C C C I
AU36084/89A
1988-06-07
1989-06-07
Method of inhibiting the influx of leukocytes into organs during sepsis or other trauma
Ceased
AU620100B2
(en)
Applications Claiming Priority (4)
Application Number
Priority Date
Filing Date
Title
US20403788A
1988-06-07
1988-06-07
US204037
1988-06-07
US07/331,450
US5147637A
(en)
1988-06-07
1989-03-31
Method of inhibiting the influx of leukocytes into organs during sepsis or other trauma
US331450
1989-03-31
Publications (2)
Publication Number
Publication Date
AU3608489A
AU3608489A
(en)
1989-12-14
AU620100B2
true
AU620100B2
(en)
1992-02-13
Family
ID=26899117
Family Applications (1)
Application Number
Title
Priority Date
Filing Date
AU36084/89A
Ceased
AU620100B2
(en)
1988-06-07
1989-06-07
Method of inhibiting the influx of leukocytes into organs during sepsis or other trauma
Country Status (10)
Country
Link
US
(1)
US5147637A
(en)
EP
(1)
EP0346078A3
(en)
JP
(1)
JPH02104534A
(en)
KR
(1)
KR910000184A
(en)
AU
(1)
AU620100B2
(en)
DK
(1)
DK278589A
(en)
FI
(1)
FI892793A
(en)
IL
(1)
IL90529A
(en)
NO
(1)
NO892319L
(en)
PT
(1)
PT90775B
(en)
Cited By (1)
* Cited by examiner, † Cited by third party
Publication number
Priority date
Publication date
Assignee
Title
AU635996B2
(en)
*
1990-01-19
1993-04-08
Merck & Co., Inc.
Recombinant human anti-cd18 antibodies
Families Citing this family (50)
* Cited by examiner, † Cited by third party
Publication number
Priority date
Publication date
Assignee
Title
US5147637A
(en)
*
1988-06-07
1992-09-15
The Rockefeller University
Method of inhibiting the influx of leukocytes into organs during sepsis or other trauma
WO1990015076A2
(en)
1989-06-02
1990-12-13
The Johns Hopkins University School Of Medicine
MONOCLONAL ANTIBODIES AGAINST LEUKOCYTE ADHESION RECEPTOR β-CHAIN, METHODS OF PRODUCING THESE ANTIBODIES AND USE THEREFORE
DE4019024A1
(en)
*
1990-06-14
1991-12-19
Bayer Ag
USE OF EFOMYCINES A, E AND G AS DEHUMIDIFYING AGENTS
AU8631991A
(en)
*
1990-08-27
1992-03-17
Cetus Corporation
Cd18 peptide medicaments for the treatment of disease
ATE166230T1
(en)
*
1990-08-31
1998-06-15
Boehringer Ingelheim Pharma
USE OF ANTI-ICAM ANTIBODIES TO PRODUCE A PREPARATION FOR THE TREATMENT OF ENDOTOXIN SHOCK
EP0565642A1
(en)
*
1991-01-11
1993-10-20
Repligen Corporation
Method of preventing inflammatory damage
US5709859A
(en)
*
1991-01-24
1998-01-20
Bristol-Myers Squibb Company
Mixed specificity fusion proteins
DK0507187T3
(en)
*
1991-04-03
1997-04-07
Boehringer Ingelheim Pharma
Method for inhibiting pulmonary oxygen toxicity
US5932217A
(en)
*
1991-05-03
1999-08-03
The Rockefeller University
Peptides which inhibit adhesion between leukocytes and endothelial cells
GB9115364D0
(en)
*
1991-07-16
1991-08-28
Wellcome Found
Antibody
ATE180408T1
(en)
*
1991-10-04
1999-06-15
Us Health
PRODUCTION OF A MEDICINAL PRODUCT FOR THE TREATMENT OF EYE INFLAMMATION BY BLOCKING CELL ADHESION MOLECULES
GB9126918D0
(en)
*
1991-12-19
1992-02-19
Univ London
Members of specific binding pairs;methods of their making and using
US5932214A
(en)
1994-08-11
1999-08-03
Biogen, Inc.
Treatment for inflammatory bowel disease with VLA-4 blockers
DE69309906T2
(en)
*
1992-02-12
1997-11-06
Biogen Inc
TREATMENT FOR INFLAMMATORY DISEASES
US5714350A
(en)
*
1992-03-09
1998-02-03
Protein Design Labs, Inc.
Increasing antibody affinity by altering glycosylation in the immunoglobulin variable region
US5708141A
(en)
*
1992-05-11
1998-01-13
Corvas International, Inc.
Neutrophil inhibitors
JPH06511156A
(en)
*
1992-07-16
1994-12-15
イコス コーポレイション
Relief of symptoms associated with inflammatory disease conditions
DE69315847T2
(en)
*
1992-08-21
1998-06-25
Genentech Inc
METHOD FOR TREATING A FAULT BROUGHT BY LFA-1
AU5732694A
(en)
*
1992-12-01
1994-06-22
Protein Design Labs, Inc.
Humanized antibodies reactive with cd18
US6884590B1
(en)
1994-02-11
2005-04-26
Cedars-Sinai Medical Center
Methods of screening for ulcerative colitis and crohn's disease
US5681699A
(en)
*
1994-02-11
1997-10-28
Cedars-Sinai Medical Center
Methods of diagnosing ulcerative colitis and Crohn's disease
US6001356A
(en)
*
1995-09-29
1999-12-14
Rush-Presbyterian-St. Luke's Medical Center
Method of inhibiting tissue destruction in autoimmune disease using anti-CD44 antibodies
US20020081294A1
(en)
1996-01-23
2002-06-27
Genentech, Inc.
Co-administration of a thrombolytic and an anti-CD18 antibody in stroke
US5914112A
(en)
*
1996-01-23
1999-06-22
Genentech, Inc.
Anti-CD18 antibodies in stroke
US6171586B1
(en)
1997-06-13
2001-01-09
Genentech, Inc.
Antibody formulation
US6991790B1
(en)
1997-06-13
2006-01-31
Genentech, Inc.
Antibody formulation
US6582698B1
(en)
1999-03-19
2003-06-24
Genentech, Inc.
Treatment method
ES2331643T3
(en)
1999-03-19
2010-01-12
Genentech, Inc.
TREATMENT OF DISORDERS ASSOCIATED WITH LFA-1 WITH GROWING DOSE OF ANTIGONIST OF LFA-1.
WO2001002009A1
(en)
*
1999-07-06
2001-01-11
Johns Hopkins University
Method and composition for inhibition of vasospasm
WO2001070260A1
(en)
*
2000-03-17
2001-09-27
Millennium Pharmaceuticals, Inc.
Cd18-binding antibodies inhibit stenosis-related disorders
AU4574501A
(en)
2000-03-17
2001-10-03
Millennium Pharm Inc
Method of inhibiting stenosis and restenosis
US7396530B2
(en)
2004-06-09
2008-07-08
Genentech, Inc.
Method of treating granuloma annulare or sarcoid
WO2006063093A2
(en)
*
2004-12-08
2006-06-15
Cedars-Sinai Medical Center
Methods for diagnosis and treatment of crohn's disease
WO2010048415A1
(en)
*
2008-10-22
2010-04-29
Cedars-Sinai Medical Center
Methods of using jak3 genetic variants to diagnose and predict crohn's disease
US20100021917A1
(en)
*
2007-02-14
2010-01-28
Cedars-Sinai Medical Center
Methods of using genes and genetic variants to predict or diagnose inflammatory bowel disease
WO2008106451A2
(en)
*
2007-02-26
2008-09-04
Cedars-Sinai Medical Center
Methods of using single nucleotide polymorphisms in the tl1a gene to predict or diagnose inflammatory bowel disease
WO2010039931A2
(en)
*
2008-10-01
2010-04-08
Cedars-Sinai Medical Center
Methods of using il17rd and il23-il17 pathway genes to diagnose crohn's disease
WO2008116150A2
(en)
2007-03-21
2008-09-25
Cedars-Sinai Medical Center
Ileal pouch-anal anastomosis (ipaa) factors in the treatment of inflammatory bowel disease
WO2008134569A2
(en)
*
2007-04-26
2008-11-06
Cedars-Sinai Medical Center
Diagnosis and treatment of inflammatory bowel disease in the puerto rican population
US20100144903A1
(en)
*
2007-05-04
2010-06-10
Cedars-Sinai Medical Center
Methods of diagnosis and treatment of crohn's disease
US20110229471A1
(en)
*
2008-11-26
2011-09-22
Cedars-Sinai Medical Center
Methods of determining responsiveness to anti-tnf alpha therapy in inflammatory bowel disease
US9580752B2
(en)
2008-12-24
2017-02-28
Cedars-Sinai Medical Center
Methods of predicting medically refractive ulcerative colitis (MR-UC) requiring colectomy
CN107308161A
(en)
2010-06-16
2017-11-03
炎症反应研究股份有限公司
The purposes of levocetirizine and montelukast in treatment influenza, common cold and inflammation
CA2901410C
(en)
2013-03-13
2023-09-12
Bruce Chandler May
Use of levocetirizine and montelukast in the treatment of traumatic injury
CN105228700A
(en)
2013-03-13
2016-01-06
炎症反应研究公司
Levocetirizine and the purposes of montelukast in treatment autoimmune disease
KR20160125283A
(en)
2013-03-13
2016-10-31
인플래머토리 리스폰스 리서치, 아이엔씨.
Use of levocetirizine and montelukast in the treatment of autoimmune vasculitis
KR20210157418A
(en)
2013-03-27
2021-12-28
세다르스-신나이 메디칼 센터
Mitigation and reversal of fibrosis and inflammation by inhibition of tl1a function and related signaling pathways
US10316083B2
(en)
2013-07-19
2019-06-11
Cedars-Sinai Medical Center
Signature of TL1A (TNFSF15) signaling pathway
JP2017526728A
(en)
2014-09-15
2017-09-14
インフラマトリー・レスポンス・リサーチ・インコーポレイテッド
Levocetirizine and montelukast in the treatment of inflammation-mediated conditions
KR102464372B1
(en)
2016-03-17
2022-11-04
세다르스-신나이 메디칼 센터
Methods of diagnosing inflammatory bowel disease through rnaset2
Family Cites Families (6)
* Cited by examiner, † Cited by third party
Publication number
Priority date
Publication date
Assignee
Title
US4686100A
(en)
*
1985-04-02
1987-08-11
The Board Of Trustees Of The Leland Stanford Junior University
Method for the treatment of adult respiratory distress syndrome
EP0303692A4
(en)
*
1987-02-26
1990-12-05
Dana Farber Cancer Institute
Cloning of lfa-1
US4840793A
(en)
*
1987-06-11
1989-06-20
Dana-Farber Cancer Institute
Method of reducing tissue damage at an inflammatory site using a monoclonal antibody
US4935237A
(en)
*
1988-03-21
1990-06-19
Genentech, Inc.
Processes for the preparation of t-PA mutants
US4797277A
(en)
*
1987-09-22
1989-01-10
Pharmacia Ab
Method for reperfusion therapy
US5147637A
(en)
*
1988-06-07
1992-09-15
The Rockefeller University
Method of inhibiting the influx of leukocytes into organs during sepsis or other trauma
1989
1989-03-31
US
US07/331,450
patent/US5147637A/en
not_active
Expired - Fee Related
1989-06-05
IL
IL9052989A
patent/IL90529A/en
not_active
IP Right Cessation
1989-06-06
NO
NO89892319A
patent/NO892319L/en
unknown
1989-06-07
EP
EP19890305712
patent/EP0346078A3/en
not_active
Withdrawn
1989-06-07
AU
AU36084/89A
patent/AU620100B2/en
not_active
Ceased
1989-06-07
FI
FI892793A
patent/FI892793A/en
not_active
IP Right Cessation
1989-06-07
DK
DK278589A
patent/DK278589A/en
not_active
Application Discontinuation
1989-06-07
JP
JP1146552A
patent/JPH02104534A/en
active
Pending
1989-06-07
PT
PT90775A
patent/PT90775B/en
not_active
IP Right Cessation
1989-06-07
KR
KR1019890007897A
patent/KR910000184A/en
not_active
Application Discontinuation
Cited By (1)
* Cited by examiner, † Cited by third party
Publication number
Priority date
Publication date
Assignee
Title
AU635996B2
(en)
*
1990-01-19
1993-04-08
Merck & Co., Inc.
Recombinant human anti-cd18 antibodies
Also Published As
Publication number
Publication date
US5147637A
(en)
1992-09-15
DK278589A
(en)
1989-12-08
DK278589D0
(en)
1989-06-07
PT90775B
(en)
1994-11-30
NO892319L
(en)
1989-12-08
IL90529A
(en)
1994-01-25
FI892793A0
(en)
1989-06-07
JPH02104534A
(en)
1990-04-17
EP0346078A2
(en)
1989-12-13
EP0346078A3
(en)
1991-03-20
NO892319D0
(en)
1989-06-06
PT90775A
(en)
1989-12-29
IL90529A0
(en)
1990-01-18
FI892793A
(en)
1989-12-08
KR910000184A
(en)
1991-01-29
AU3608489A
(en)
1989-12-14
Similar Documents
Publication
Publication Date
Title
AU620100B2
(en)
1992-02-13
Method of inhibiting the influx of leukocytes into organs during sepsis or other trauma
Bajrami et al.
2016
G-CSF maintains controlled neutrophil mobilization during acute inflammation by negatively regulating CXCR2 signaling
Fei et al.
2011
The combination of a tumor necrosis factor inhibitor and antibiotic alleviates staphylococcal arthritis and sepsis in mice
Kielian et al.
2001
CXC chemokine receptor-2 ligands are required for neutrophil-mediated host defense in experimental brain abscesses
Kaizer et al.
1985
Autologous bone marrow transplantation in acute leukemia: A phase I study of in vitro treatment of marrow with 4-hydroperoxycyclophosphamide to purge tumor cells
Stegmayr et al.
1992
Septic shock induced by group A streptococcal infection: clinical and therapeutic aspects
Wade et al.
1981
Piperacillin or ticarcillin plus amikacin: a double-blind prospective comparison of empiric antibiotic therapy for febrile granulocytopenic cancer patients
US20080171054A1
(en)
2008-07-17
Treatment of micro-organism infection
Wong et al.
2000
Bacteremia due to Staphylococcus aureus with reduced susceptibility to vancomycin
JPH07501545A
(en)
1995-02-16
How to treat non-streptococcal bacterial infections
US5322699A
(en)
1994-06-21
Leukocyte-derived CR3 modulator, integrin modulating factor-1 (IMF-1)
Nunes et al.
2009
Lectin extracted from Canavalia grandiflora seeds presents potential anti-inflammatory and analgesic effects
Petito et al.
2017
The migration of platelets and their interaction with other migrating cells
NZ229434A
(en)
1992-03-26
Anti-cd18 antibodies, their use and compositions thereof for inhibiting leukocyte influx
WO2003041726A1
(en)
2003-05-22
Use of an extracellular adherence protein for the manufacture of an anti-inflammatory drug
Yousif et al.
1996
Induction of glomerulonephritis in rats with staphylococcal phosphatase: new aspects in post-infectious ICGN
Dang et al.
2010
Possible role of LECT2 as an intrinsic regulatory factor in SEA-induced toxicity in d-galactosamine-sensitized mice
EP0486609B1
(en)
1995-03-01
Pharmaceutical product for the treatment of sepsis
US6315999B1
(en)
2001-11-13
Pharmaceutical product for the treatment of sepsis
TUOMANEN et al.
1989
New antibodies as adjunctive therapies for gram-positive bacterial meningitis
Jenkinson et al.
1980
Cefotaxime in the treatment of pneumococcal pneumonia
Stephens
2020
ICU complications of hematopoietic stem cell transplant, including graft vs host disease
EP0584273B1
(en)
1998-12-30
Antibody recognizing endothelial cell ligand for leukocyte cr3
EP0675735A1
(en)
1995-10-11
Method for modulating transendothelial migration of cells promoting inflammation, and related methods of measurement thereof
EP4212168A1
(en)
2023-07-19
Novel composition for prevention or treatment of staphylococcus aureus infectious disease
Download PDF in English
