The effect of FUT-175 (nafamstat mesilate) on C3a, C4a and C5a generation in vitro and inflammatory reactions in vivo
Identifieur interne : 003288 ( Istex/Corpus ); précédent : 003287; suivant : 003289The effect of FUT-175 (nafamstat mesilate) on C3a, C4a and C5a generation in vitro and inflammatory reactions in vivo
Auteurs : Andrew C. Issekutz ; Dennis M. Roland ; Richard A. PatrickSource :
- 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
Links to Exploration step
ISTEX:D56CDB956E9EC9C76FED448F23FABDB50DBB3054Le document en format XML
<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title>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><mods:affiliation>Department of Pediatrics and Microbiology, Dalhousie University, Halifax, Nova Scotia, Canada</mods:affiliation></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><mods:affiliation>Ciba Geigy Pharmaceuticals, Summit, New Jersey, U.S.A.</mods:affiliation></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><mods:affiliation>Ciba Geigy Pharmaceuticals, Summit, New Jersey, U.S.A.</mods:affiliation></affiliation></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></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><mods:affiliation>Department of Pediatrics and Microbiology, Dalhousie University, Halifax, Nova Scotia, Canada</mods:affiliation></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><mods:affiliation>Ciba Geigy Pharmaceuticals, Summit, New Jersey, U.S.A.</mods:affiliation></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><mods:affiliation>Ciba Geigy Pharmaceuticals, Summit, New Jersey, U.S.A.</mods:affiliation></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><istex><corpusName>elsevier</corpusName><keywords><teeft><json:string>leukocyte</json:string><json:string>indomethacin</json:string><json:string>zymosan</json:string><json:string>issekutz</json:string><json:string>arthus</json:string><json:string>movat</json:string><json:string>exudation</json:string><json:string>pathway</json:string><json:string>leukocyte accumulation</json:string><json:string>plasma exudation</json:string><json:string>coli</json:string><json:string>pge2</json:string><json:string>endotoxin</json:string><json:string>inflammation</json:string><json:string>inflammatory</json:string><json:string>pmnl</json:string><json:string>chemotactic</json:string><json:string>immune</json:string><json:string>inflammatory reactions</json:string><json:string>aoyama</json:string><json:string>arthus reaction</json:string><json:string>ltb4</json:string><json:string>activator</json:string><json:string>human serum</json:string><json:string>complement activation</json:string><json:string>immune complexes</json:string><json:string>sigma chemical company</json:string><json:string>protease</json:string><json:string>infusion</json:string><json:string>nova scotia</json:string><json:string>complement system</json:string><json:string>nafamstat mesilate</json:string><json:string>acute inflammation</json:string><json:string>arthus reactions</json:string><json:string>issekutz bhimji</json:string><json:string>vascular permeability</json:string><json:string>skin lesions</json:string><json:string>inhibitor</json:string><json:string>leukocyte infiltration</json:string><json:string>movat cybulsky</json:string><json:string>cobra venom factor</json:string><json:string>local pge2 administration</json:string><json:string>passive arthus reaction</json:string><json:string>skin sites</json:string><json:string>control animals</json:string><json:string>broad effects</json:string><json:string>potent inhibitor</json:string><json:string>baxter travenol</json:string><json:string>polymorphonuclear leukocytes</json:string><json:string>additive effects</json:string><json:string>alternative complement pathway</json:string><json:string>systemic therapy</json:string><json:string>alternative pathway</json:string><json:string>synthetic protease inhibitor</json:string><json:string>statistical significance</json:string><json:string>striking contrast</json:string><json:string>fujii hitomi</json:string><json:string>indomethacin treatment</json:string><json:string>antiinflammatory effects</json:string><json:string>issekutz movat</json:string><json:string>local pge2</json:string><json:string>passive arthus reactions</json:string><json:string>same animal</json:string><json:string>inflammatory stimulus</json:string><json:string>local indomethacin administration</json:string><json:string>local indomethacin</json:string><json:string>inflammatory reaction</json:string><json:string>chemotactic factors</json:string><json:string>inflammatory responses</json:string><json:string>complement depletion</json:string><json:string>additional observations</json:string><json:string>endotoxin inflammation</json:string><json:string>megyeri issekutz</json:string><json:string>tumor necrosis factor</json:string><json:string>nonsteroidal agents</json:string></teeft></keywords><author><json:item><name>Andrew C. Issekutz</name><affiliations><json:string>Department of Pediatrics and Microbiology, Dalhousie University, Halifax, Nova Scotia, Canada</json:string></affiliations></json:item><json:item><name>Dennis M. Roland</name><affiliations><json:string>Ciba Geigy Pharmaceuticals, Summit, New Jersey, U.S.A.</json:string></affiliations></json:item><json:item><name>Richard A. Patrick</name><affiliations><json:string>Ciba Geigy Pharmaceuticals, Summit, New Jersey, U.S.A.</json:string></affiliations></json:item></author><arkIstex>ark:/67375/6H6-ZR3SJM0K-Z</arkIstex><language><json:string>eng</json:string></language><originalGenre><json:string>Full-length article</json:string></originalGenre><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.</abstract><qualityIndicators><score>9.556</score><pdfWordCount>5086</pdfWordCount><pdfCharCount>30806</pdfCharCount><pdfVersion>1.2</pdfVersion><pdfPageCount>9</pdfPageCount><pdfPageSize>519 x 699 pts</pdfPageSize><refBibsNative>true</refBibsNative><abstractWordCount>213</abstractWordCount><abstractCharCount>1463</abstractCharCount><keywordCount>0</keywordCount></qualityIndicators><title>The effect of FUT-175 (nafamstat mesilate) on C3a, C4a and C5a generation in vitro and inflammatory reactions in vivo</title><pmid><json:string>2303313</json:string></pmid><pii><json:string>0192-0561(90)90062-R</json:string></pii><genre><json:string>research-article</json:string></genre><serie><title>Proc. natn. Acad. Sci. U.S.A.</title><language><json:string>unknown</json:string></language><volume>82</volume><pages><first>8667</first><last>8671</last></pages></serie><host><title>International Journal of Immunopharmacology</title><language><json:string>unknown</json:string></language><publicationDate>1990</publicationDate><issn><json:string>0192-0561</json:string></issn><pii><json:string>S0192-0561(00)X0128-2</json:string></pii><volume>12</volume><issue>1</issue><pages><first>1</first><last>9</last></pages><genre><json:string>journal</json:string></genre></host><namedEntities><unitex><date><json:string>1989</json:string></date><geogName></geogName><orgName><json:string>Immunology Research Laboratory</json:string><json:string>Biomol Research Laboratory, Philadelphia, Pennsylvania</json:string><json:string>Sigma Chemical Company</json:string><json:string>Victoria General Hospital Pathology Laboratory</json:string><json:string>Medical Research Council of Canada</json:string><json:string>Dalhousie University</json:string><json:string>Difco Laboratories, Detroit</json:string><json:string>New Zealand White</json:string><json:string>Fluka Chemical Co.</json:string><json:string>Abbott Laboratories</json:string></orgName><orgName_funder></orgName_funder><orgName_provider></orgName_provider><persName><json:string>M. Gibner</json:string><json:string>Nova Scotia</json:string><json:string>Nancy Steel</json:string><json:string>Paul Peters</json:string><json:string>Laboratory</json:string></persName><placeName><json:string>Montreal</json:string><json:string>Canada</json:string><json:string>Halifax</json:string><json:string>N.Y.</json:string><json:string>Quebec</json:string><json:string>Havppauge</json:string></placeName><ref_url></ref_url><ref_bibl><json:string>Hospital for Children, 5850</json:string><json:string>Issekutz and Movat, 1980</json:string><json:string>Oda, Ogihara, Sato, Kurumi & Iwaki, 1986</json:string><json:string>Aoyama, 1984</json:string><json:string>Issekutz & Movat, 1980</json:string><json:string>Cochrane, Miiller-Eberhard & Aikin, 1970</json:string><json:string>Gamble, Harlan, Klebanoff & Vados, 1985</json:string><json:string>Movat & Cybulsky, 1987</json:string><json:string>Ikehara, Shimamura, Aoyama, Fujii & Hashima, 1985</json:string><json:string>Wankowicz, Megyeri & Issekutz, 1988</json:string><json:string>Issekutz et al., 1987</json:string><json:string>Hugli, 1981</json:string><json:string>Fujii & Hitomi, 1981</json:string><json:string>Issekutz & Bhimji, 1982a</json:string><json:string>Bevilacqua, Pober, Wheeler, Cotran & Gimbrone, 1985</json:string><json:string>reviewed by Henson & Johnston, 1987</json:string><json:string>Ikari et al., 1983</json:string><json:string>Issekutz et al., 1986</json:string><json:string>Tenner, Ziccardi & Cooper, 1984</json:string><json:string>Koyama, Inage, Sano, Narita, Jojo, Neild & Cameron, 1985</json:string><json:string>Aoyama et al., 1984</json:string><json:string>Crawford, Movat, Mintu & Opas, 1985</json:string><json:string>Kopaniak & Movat, 1983</json:string><json:string>Fernandez et al., 1978</json:string><json:string>Fernandez, Henson, Otani & Hugli, 1978</json:string><json:string>Issekutz, Megyeri & Issekutz, 1987</json:string><json:string>Issekutz, Szpejda & Ripley, 1986</json:string><json:string>Rother et al., 1985</json:string><json:string>Issekutz, Movat & Movat, 1980</json:string><json:string>Ikari, Sakai, Hitomi & Fujii, 1983</json:string><json:string>Udaka, Takeuchi & Movat, 1970</json:string></ref_bibl><bibl></bibl></unitex></namedEntities><ark><json:string>ark:/67375/6H6-ZR3SJM0K-Z</json:string></ark><categories><wos></wos><scienceMetrix><json:string>1 - health sciences</json:string><json:string>2 - clinical medicine</json:string><json:string>3 - immunology</json:string></scienceMetrix><scopus><json:string>1 - Life Sciences</json:string><json:string>2 - Pharmacology, Toxicology and Pharmaceutics</json:string><json:string>3 - Pharmacology</json:string><json:string>1 - Life Sciences</json:string><json:string>2 - Immunology and Microbiology</json:string><json:string>3 - Immunology</json:string></scopus><inist><json:string>1 - sciences appliquees, technologies et medecines</json:string><json:string>2 - sciences biologiques et medicales</json:string><json:string>3 - sciences medicales</json:string></inist></categories><publicationDate>1990</publicationDate><copyrightDate>1989</copyrightDate><doi><json:string>10.1016/0192-0561(90)90062-R</json:string></doi><id>D56CDB956E9EC9C76FED448F23FABDB50DBB3054</id><score>1</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/ark:/67375/6H6-ZR3SJM0K-Z/fulltext.pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/ark:/67375/6H6-ZR3SJM0K-Z/bundle.zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/ark:/67375/6H6-ZR3SJM0K-Z/fulltext.tei"><teiHeader><fileDesc><titleStmt><title level="a">The effect of FUT-175 (nafamstat mesilate) on C3a, C4a and C5a generation in vitro and inflammatory reactions in vivo</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher scheme="https://scientific-publisher.data.istex.fr">ELSEVIER</publisher><availability><licence><p>elsevier</p></licence></availability><p scheme="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-HKKZVM7B-M"></p><date>1989</date></publicationStmt><notesStmt><note type="research-article" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</note><note type="journal" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note></notesStmt><sourceDesc><biblStruct type="inbook"><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 xml:id="author-0000"><persName><forename type="first">Andrew C.</forename><surname>Issekutz</surname></persName><affiliation>Author to whom correspondence should be addressed, at: Infection and Immunology Research Laboratory, I.W.K. Hospital for Children, 5850 University Avenue, Halifax, Nova Scotia, B3J 3G9, Canada.</affiliation><affiliation>Department of Pediatrics and Microbiology, Dalhousie University, Halifax, Nova Scotia, Canada</affiliation></author><author xml:id="author-0001"><persName><forename type="first">Dennis M.</forename><surname>Roland</surname></persName><affiliation>Ciba Geigy Pharmaceuticals, Summit, New Jersey, U.S.A.</affiliation></author><author xml:id="author-0002"><persName><forename type="first">Richard A.</forename><surname>Patrick</surname></persName><affiliation>Ciba Geigy Pharmaceuticals, Summit, New Jersey, U.S.A.</affiliation></author><idno type="istex">D56CDB956E9EC9C76FED448F23FABDB50DBB3054</idno><idno type="ark">ark:/67375/6H6-ZR3SJM0K-Z</idno><idno type="DOI">10.1016/0192-0561(90)90062-R</idno><idno type="PII">0192-0561(90)90062-R</idno></analytic><monogr><title level="j">International Journal of Immunopharmacology</title><title level="j" type="abbrev">IMMP</title><idno type="pISSN">0192-0561</idno><idno type="PII">S0192-0561(00)X0128-2</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="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></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>1989</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>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.</p></abstract></profileDesc><revisionDesc><change when="1989-04-24">Modified</change><change when="1990">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/ark:/67375/6H6-ZR3SJM0K-Z/fulltext.txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Elsevier, elements deleted: tail"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//ES//DTD journal article DTD version 4.5.2//EN//XML" URI="art452.dtd" name="istex:docType"></istex:docType><istex:document><converted-article version="4.5.2" docsubtype="fla"><item-info><jid>IMMP</jid><aid>9090062R</aid><ce:pii>0192-0561(90)90062-R</ce:pii><ce:doi>10.1016/0192-0561(90)90062-R</ce:doi><ce:copyright type="unknown" year="1989"></ce:copyright></item-info><head><ce:title>The effect of FUT-175 (nafamstat mesilate) on C3<ce:inf>a</ce:inf>, C4<ce:inf>a</ce:inf> and C5<ce:inf>a</ce:inf> generation <ce:italic>in vitro</ce:italic> and inflammatory reactions <ce:italic>in vivo</ce:italic></ce:title><ce:author-group><ce:author><ce:given-name>Andrew C.</ce:given-name><ce:surname>Issekutz</ce:surname><ce:cross-ref refid="COR1"><ce:sup>∗</ce:sup></ce:cross-ref><ce:cross-ref refid="AFF1"><ce:sup>∗</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Dennis M.</ce:given-name><ce:surname>Roland</ce:surname><ce:cross-ref refid="AFF2"><ce:sup>†</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Richard A.</ce:given-name><ce:surname>Patrick</ce:surname><ce:cross-ref refid="AFF2"><ce:sup>†</ce:sup></ce:cross-ref></ce:author><ce:affiliation id="AFF1"><ce:label>∗</ce:label><ce:textfn>Department of Pediatrics and Microbiology, Dalhousie University, Halifax, Nova Scotia, Canada</ce:textfn></ce:affiliation><ce:affiliation id="AFF2"><ce:label>†</ce:label><ce:textfn>Ciba Geigy Pharmaceuticals, Summit, New Jersey, U.S.A.</ce:textfn></ce:affiliation><ce:correspondence id="COR1"><ce:label>∗</ce:label><ce:text>Author to whom correspondence should be addressed, at: Infection and Immunology Research Laboratory, I.W.K. Hospital for Children, 5850 University Avenue, Halifax, Nova Scotia, B3J 3G9, Canada.</ce:text></ce:correspondence></ce:author-group><ce:date-received day="23" month="11" year="1988"></ce:date-received><ce:date-revised day="24" month="4" year="1989"></ce:date-revised><ce:abstract><ce:section-title>Abstract</ce:section-title><ce:abstract-sec><ce:simple-para>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 C3<ce:inf>a</ce:inf>, C4<ce:inf>a</ce:inf> and C5<ce:inf>a</ce:inf> generation induced by heat aggregated IgG, zymosan and Cobra venom factor with <ce:small-caps>IC</ce:small-caps><ce:inf>50</ce:inf> values in the range of 3–43 μM depending on the stimulus and the fragments. To assess <ce:italic>in vivo</ce:italic> anti-inflammatory activity, inflammatory reactions induced in the skin of rabbits were quantitated by using <ce:sup loc="pre">125</ce:sup>I-albumin extravasation, <ce:sup loc="pre">51</ce:sup>Cr-labelled leukocyte accumulation and <ce:sup loc="pre">86</ce:sup>RbCl 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 <ce:italic>E. coli</ce:italic>, zymosan, immune complexes, the reversed Arthus reaction, zymosan activated plasma (ZAP), f-norleu-leu-phe (FNLP) and LTB<ce:inf>4</ce:inf>. 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 PGE<ce:inf>2</ce:inf> administration. Furthermore, indomethacin and FUT-175 had additive anti-inflammatory effects. These results suggest that although FUT-175 is a potent inhibitor of C3<ce:inf>a</ce:inf>, C4<ce:inf>a</ce:inf> and C5<ce:inf>a</ce:inf> generation, it has novel and broad anti-inflammatory effects, possibly through actions in addition to complement inhibition as indicated by inhibition of FNLP-, LTB<ce:inf>4</ce:inf>- and ZAP-induced reactions.</ce:simple-para></ce:abstract-sec></ce:abstract></head></converted-article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>The effect of FUT-175 (nafamstat mesilate) on C3a, C4a and C5a generation in vitro and inflammatory reactions in vivo</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>The effect of FUT-175 (nafamstat mesilate) on C3</title></titleInfo><name type="personal"><namePart type="given">Andrew C.</namePart><namePart type="family">Issekutz</namePart><affiliation>Department of Pediatrics and Microbiology, Dalhousie University, Halifax, Nova Scotia, Canada</affiliation><description>Author to whom correspondence should be addressed, at: Infection and Immunology Research Laboratory, I.W.K. Hospital for Children, 5850 University Avenue, Halifax, Nova Scotia, B3J 3G9, Canada.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Dennis M.</namePart><namePart type="family">Roland</namePart><affiliation>Ciba Geigy Pharmaceuticals, Summit, New Jersey, U.S.A.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Richard A.</namePart><namePart type="family">Patrick</namePart><affiliation>Ciba Geigy Pharmaceuticals, Summit, New Jersey, U.S.A.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="Full-length article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</genre><originInfo><publisher>ELSEVIER</publisher><dateIssued encoding="w3cdtf">1990</dateIssued><dateModified encoding="w3cdtf">1989-04-24</dateModified><copyrightDate encoding="w3cdtf">1989</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><abstract 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.</abstract><relatedItem type="host"><titleInfo><title>International Journal of Immunopharmacology</title></titleInfo><titleInfo type="abbreviated"><title>IMMP</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><originInfo><publisher>ELSEVIER</publisher><dateIssued encoding="w3cdtf">1990</dateIssued></originInfo><identifier type="ISSN">0192-0561</identifier><identifier type="PII">S0192-0561(00)X0128-2</identifier><part><date>1990</date><detail type="volume"><number>12</number><caption>vol.</caption></detail><detail type="issue"><number>1</number><caption>no.</caption></detail><extent unit="issue-pages"><start>1</start><end>143</end></extent><extent unit="pages"><start>1</start><end>9</end></extent></part></relatedItem><identifier type="istex">D56CDB956E9EC9C76FED448F23FABDB50DBB3054</identifier><identifier type="ark">ark:/67375/6H6-ZR3SJM0K-Z</identifier><identifier type="DOI">10.1016/0192-0561(90)90062-R</identifier><identifier type="PII">0192-0561(90)90062-R</identifier><recordInfo><recordContentSource authority="ISTEX" authorityURI="https://loaded-corpus.data.istex.fr" valueURI="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-HKKZVM7B-M">elsevier</recordContentSource></recordInfo></mods><json:item><extension>json</extension><original>false</original><mimetype>application/json</mimetype><uri>https://api.istex.fr/ark:/67375/6H6-ZR3SJM0K-Z/record.json</uri></json:item></metadata></istex></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Lorraine/explor/InforLorV4/Data/Istex/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 003288 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Istex/Corpus/biblio.hfd -nk 003288 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Lorraine
|area= InforLorV4
|flux= Istex
|étape= Corpus
|type= RBID
|clé= ISTEX:D56CDB956E9EC9C76FED448F23FABDB50DBB3054
|texte= The effect of FUT-175 (nafamstat mesilate) on C3a, C4a and C5a generation in vitro and inflammatory reactions in vivo
}}
| This area was generated with Dilib version V0.6.33. |  |