The effect of FUT-175 (nafamstat mesilate) on C3a, C4a and C5a generation in vitro and inflammatory reactions in vivo
Identifieur interne : 00DF91 ( Main/Exploration ); précédent : 00DF90; suivant : 00DF92The effect of FUT-175 (nafamstat mesilate) on C3a, C4a and C5a generation in vitro and inflammatory reactions in vivo
Auteurs : Andrew C. Issekutz [Canada] ; Dennis M. Roland [États-Unis] ; Richard A. Patrick [États-Unis]Source :
- International Journal of Immunopharmacology [ 0192-0561 ] ; 1990.
English descriptors
- Teeft :
- Activator, Acute inflammation, Additional observations, Additive effects, Alternative complement pathway, Alternative pathway, Antiinflammatory effects, Aoyama, Arthus, Arthus reaction, Arthus reactions, Baxter travenol, Broad effects, Chemotactic, Chemotactic factors, Cobra venom factor, Coli, Complement activation, Complement depletion, Complement system, Control animals, Endotoxin, Endotoxin inflammation, Exudation, Fujii hitomi, Human serum, Immune, Immune complexes, Indomethacin, Indomethacin treatment, Inflammation, Inflammatory, Inflammatory reaction, Inflammatory reactions, Inflammatory responses, Inflammatory stimulus, Infusion, Inhibitor, Issekutz, Issekutz bhimji, Issekutz movat, Leukocyte, Leukocyte accumulation, Leukocyte infiltration, Local indomethacin, Local indomethacin administration, Local pge2, Local pge2 administration, Ltb4, Megyeri issekutz, Movat, Movat cybulsky, Nafamstat mesilate, Nonsteroidal agents, Nova scotia, Passive arthus reaction, Passive arthus reactions, Pathway, Pge2, Plasma exudation, Pmnl, Polymorphonuclear leukocytes, Potent inhibitor, Protease, Same animal, Sigma chemical company, Skin lesions, Skin sites, Statistical significance, Striking contrast, Synthetic protease inhibitor, Systemic therapy, Tumor necrosis factor, Vascular permeability, Zymosan.
Abstract
Abstract: FUT-175 is a synthetic protease inhibitor and an inhibitor of the classical and alternate pathways of complement activation. In human serum, FUT-175 inhibited C3a, C4a and C5a generation induced by heat aggregated IgG, zymosan and Cobra venom factor with IC50 values in the range of 3–43 μM depending on the stimulus and the fragments. To assess in vivo anti-inflammatory activity, inflammatory reactions induced in the skin of rabbits were quantitated by using 125I-albumin extravasation, 51Cr-labelled leukocyte accumulation and 86RbCl accumulation as a measure of hyperemia. Infusion of FUT-175 at 2 mg/kg/h inhibited all three parameters by 50–80% in dermal reactions induced by killed E. coli, zymosan, immune complexes, the reversed Arthus reaction, zymosan activated plasma (ZAP), f-norleu-leu-phe (FNLP) and LTB4. In contrast, the response to endotoxin (0.1 μg) was not effected by FUT-175 treatment. The effect of FUT-175 was comparable to that of local or systemic therapy with indomethacin, but unlike indomethacin, the effect of FUT-175 was not reversed by local PGE2 administration. Furthermore, indomethacin and FUT-175 had additive anti-inflammatory effects. These results suggest that although FUT-175 is a potent inhibitor of C3a, C4a and C5a generation, it has novel and broad anti-inflammatory effects, possibly through actions in addition to complement inhibition as indicated by inhibition of FNLP-, LTB4- and ZAP-induced reactions.
Url:
DOI: 10.1016/0192-0561(90)90062-R
Affiliations:
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Patrick</name></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:D56CDB956E9EC9C76FED448F23FABDB50DBB3054</idno><date when="1989" year="1989">1989</date><idno type="doi">10.1016/0192-0561(90)90062-R</idno><idno type="url">https://api.istex.fr/ark:/67375/6H6-ZR3SJM0K-Z/fulltext.pdf</idno><idno type="wicri:Area/Istex/Corpus">003288</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">003288</idno><idno type="wicri:Area/Istex/Curation">003247</idno><idno type="wicri:Area/Istex/Checkpoint">003275</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Checkpoint">003275</idno><idno type="wicri:doubleKey">0192-0561:1989:Issekutz A:the:effect:of</idno><idno type="wicri:Area/Main/Merge">00E874</idno><idno type="wicri:Area/Main/Curation">00DF91</idno><idno type="wicri:Area/Main/Exploration">00DF91</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">The effect of FUT-175 (nafamstat mesilate) on C3a, C4a and C5a generation in vitro and inflammatory reactions in vivo</title><author><name sortKey="Issekutz, Andrew C" sort="Issekutz, Andrew C" uniqKey="Issekutz A" first="Andrew C." last="Issekutz">Andrew C. Issekutz</name><affiliation wicri:level="1"><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Pediatrics and Microbiology, Dalhousie University, Halifax, Nova Scotia</wicri:regionArea><wicri:noRegion>Nova Scotia</wicri:noRegion></affiliation></author><author><name sortKey="Roland, Dennis M" sort="Roland, Dennis M" uniqKey="Roland D" first="Dennis M." last="Roland">Dennis M. Roland</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Ciba Geigy Pharmaceuticals, Summit, New Jersey</wicri:regionArea><placeName><region type="state">New Jersey</region></placeName></affiliation></author><author><name sortKey="Patrick, Richard A" sort="Patrick, Richard A" uniqKey="Patrick R" first="Richard A." last="Patrick">Richard A. Patrick</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Ciba Geigy Pharmaceuticals, Summit, New Jersey</wicri:regionArea><placeName><region type="state">New Jersey</region></placeName></affiliation></author></analytic><monogr></monogr><series><title level="j">International Journal of Immunopharmacology</title><title level="j" type="abbrev">IMMP</title><idno type="ISSN">0192-0561</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1990">1990</date><biblScope unit="volume">12</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="1">1</biblScope><biblScope unit="page" to="9">9</biblScope></imprint><idno type="ISSN">0192-0561</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0192-0561</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="Teeft" xml:lang="en"><term>Activator</term><term>Acute inflammation</term><term>Additional observations</term><term>Additive effects</term><term>Alternative complement pathway</term><term>Alternative pathway</term><term>Antiinflammatory effects</term><term>Aoyama</term><term>Arthus</term><term>Arthus reaction</term><term>Arthus reactions</term><term>Baxter travenol</term><term>Broad effects</term><term>Chemotactic</term><term>Chemotactic factors</term><term>Cobra venom factor</term><term>Coli</term><term>Complement activation</term><term>Complement depletion</term><term>Complement system</term><term>Control animals</term><term>Endotoxin</term><term>Endotoxin inflammation</term><term>Exudation</term><term>Fujii hitomi</term><term>Human serum</term><term>Immune</term><term>Immune complexes</term><term>Indomethacin</term><term>Indomethacin treatment</term><term>Inflammation</term><term>Inflammatory</term><term>Inflammatory reaction</term><term>Inflammatory reactions</term><term>Inflammatory responses</term><term>Inflammatory stimulus</term><term>Infusion</term><term>Inhibitor</term><term>Issekutz</term><term>Issekutz bhimji</term><term>Issekutz movat</term><term>Leukocyte</term><term>Leukocyte accumulation</term><term>Leukocyte infiltration</term><term>Local indomethacin</term><term>Local indomethacin administration</term><term>Local pge2</term><term>Local pge2 administration</term><term>Ltb4</term><term>Megyeri issekutz</term><term>Movat</term><term>Movat cybulsky</term><term>Nafamstat mesilate</term><term>Nonsteroidal agents</term><term>Nova scotia</term><term>Passive arthus reaction</term><term>Passive arthus reactions</term><term>Pathway</term><term>Pge2</term><term>Plasma exudation</term><term>Pmnl</term><term>Polymorphonuclear leukocytes</term><term>Potent inhibitor</term><term>Protease</term><term>Same animal</term><term>Sigma chemical company</term><term>Skin lesions</term><term>Skin sites</term><term>Statistical significance</term><term>Striking contrast</term><term>Synthetic protease inhibitor</term><term>Systemic therapy</term><term>Tumor necrosis factor</term><term>Vascular permeability</term><term>Zymosan</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Abstract: FUT-175 is a synthetic protease inhibitor and an inhibitor of the classical and alternate pathways of complement activation. In human serum, FUT-175 inhibited C3a, C4a and C5a generation induced by heat aggregated IgG, zymosan and Cobra venom factor with IC50 values in the range of 3–43 μM depending on the stimulus and the fragments. To assess in vivo anti-inflammatory activity, inflammatory reactions induced in the skin of rabbits were quantitated by using 125I-albumin extravasation, 51Cr-labelled leukocyte accumulation and 86RbCl accumulation as a measure of hyperemia. Infusion of FUT-175 at 2 mg/kg/h inhibited all three parameters by 50–80% in dermal reactions induced by killed E. coli, zymosan, immune complexes, the reversed Arthus reaction, zymosan activated plasma (ZAP), f-norleu-leu-phe (FNLP) and LTB4. In contrast, the response to endotoxin (0.1 μg) was not effected by FUT-175 treatment. The effect of FUT-175 was comparable to that of local or systemic therapy with indomethacin, but unlike indomethacin, the effect of FUT-175 was not reversed by local PGE2 administration. Furthermore, indomethacin and FUT-175 had additive anti-inflammatory effects. These results suggest that although FUT-175 is a potent inhibitor of C3a, C4a and C5a generation, it has novel and broad anti-inflammatory effects, possibly through actions in addition to complement inhibition as indicated by inhibition of FNLP-, LTB4- and ZAP-induced reactions.</div></front></TEI><affiliations><list><country><li>Canada</li><li>États-Unis</li></country><region><li>New Jersey</li></region></list><tree><country name="Canada"><noRegion><name sortKey="Issekutz, Andrew C" sort="Issekutz, Andrew C" uniqKey="Issekutz A" first="Andrew C." last="Issekutz">Andrew C. Issekutz</name></noRegion></country><country name="États-Unis"><region name="New Jersey"><name sortKey="Roland, Dennis M" sort="Roland, Dennis M" uniqKey="Roland D" first="Dennis M." last="Roland">Dennis M. Roland</name></region><name sortKey="Patrick, Richard A" sort="Patrick, Richard A" uniqKey="Patrick R" first="Richard A." last="Patrick">Richard A. Patrick</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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