Potential therapeutic efficacy of inhibitors of human phospholipase A2 in septic shock
Identifieur interne : 003420 ( Main/Exploration ); précédent : 003419; suivant : 003421Potential therapeutic efficacy of inhibitors of human phospholipase A2 in septic shock
Auteurs : P. Vadas [Canada] ; E. Stefanski [Canada] ; W. Pruzanski [Canada]Source :
- Agents and Actions [ 0065-4299 ] ; 1986-11-01.
English descriptors
- Teeft :
- Acute hemorrhagic pancreatitis, Assay, Assay system, Bovine serum albumin, Calcium dependence, Chlorpromazine, Circulatory collapse, Coli, Coli phospholipids, Conventional therapy, Dexamethasone, Dexamethasone base, Dexamethasone sodium phosphate, Drug concentration, Drug concentrations, Effective inhibitor, Endotoxin shock, Enzyme activity, Enzyme concentration, Enzyme velocity, Experimental animals, Higher concentrations, Hyperbolic relationship, Incubation time, Inhibitor, Inhibitor studies, Inhibitory, Inhibitory effect, Membrane phospholipids, Micellar dispersion, Oleic acid, Palmitic acid, Phospholipase, Phospholipid, Phospholipid hydrolysis, Pla2, Pla2 activity, Pla2 hydrolysis, Pla2 inhibition, Plasma concentrations, Positional specificity, Promethazine, Pulmonary changes, Pulmonary dysfunction, Residual pla2 activity, Septic, Septic shock, Septic shock serum, Serum phospholipase, Serum pla2 levels, Shock serum, Shock serum phospholipase, Significant inhibition, Sodium phosphate salt, Soluble phospholipase, Soluble pla2, Substrate concentration, Substrate hydrolysis, Therapeutic agents, Therapeutic efficacy, Therapeutic range, Total volume, Vadas, Wellesley hospital.
Abstract
Abstract: Soluble phospholipase A2 has been implicated in the pathogenesis of local and systemic inflammatory reactions. Elevated levels of circulating phospholipase A2 (PLA2) correlate with the severity of circulatory collapse and pulmonary dysfunction in gram-negative septic shock. Characterization of septic shock serum PLA2 revealed a calcium-dependent enzyme with absolute 2-acyl specificity with a pH optimum of 7.5. We tested a number of therapeutic agents for their ability to inhibit PLA2 from human septic shock serum. Chloroquine, chlorpromazine, dexamethasone base, dexamethasone sodium phosphate, indomethacin, lidocaine, oleic acid, palmitic acid, promethazine, trans-retinoic acid, rutin and dl-α-tocopherol were all studied over the range of 10−2 to 10−7 M. All agents, with the sole exception of dexamethasone base, inhibited PLA2 activity at concentrations greater than 10−3M. PLA2 inhibition by dexamethasone sodium phosphate was factitious, due to the formation of calcium-phosphate complexes. Of the 11 agents studied, chlorpromazine was the most effective, with an IC50 of 7.5×10−5 M, a membrane concentration achievable within its therapeutic range. Inhibition was non-competitive, with an apparent Ki of 5 nM. Since serum PLA2 levels correlate with mortality in both experimental endotoxemia and clinical gram-negative septic shock, and chlorpromazine was previously shown to improve survival in these conditions, we postulate that its therapeutic efficacy resides at least in part in its PLA2-inhibitory activity.
Url:
DOI: 10.1007/BF01966206
Affiliations:
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Vadas</name><affiliation wicri:level="4"><country xml:lang="fr">Canada</country><wicri:regionArea>Immunology Diagnostic and Research Centre, Department of Medicine, The Wellesley Hospital, University of Toronto, 160 Wellesley St. East, M4Y 1J3, Toronto, Ontario</wicri:regionArea><orgName type="university">Université de Toronto</orgName><placeName><settlement type="city">Toronto</settlement><region type="state">Ontario</region></placeName></affiliation></author><author><name sortKey="Stefanski, E" sort="Stefanski, E" uniqKey="Stefanski E" first="E." last="Stefanski">E. 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Pruzanski</name><affiliation wicri:level="4"><country xml:lang="fr">Canada</country><wicri:regionArea>Immunology Diagnostic and Research Centre, Department of Medicine, The Wellesley Hospital, University of Toronto, 160 Wellesley St. East, M4Y 1J3, Toronto, Ontario</wicri:regionArea><orgName type="university">Université de Toronto</orgName><placeName><settlement type="city">Toronto</settlement><region type="state">Ontario</region></placeName></affiliation></author></analytic><monogr></monogr><series><title level="j">Agents and Actions</title><title level="j" type="abbrev">Agents and Actions</title><idno type="ISSN">0065-4299</idno><idno type="eISSN">1420-908X</idno><imprint><publisher>Birkhäuser-Verlag</publisher><pubPlace>Basel</pubPlace><date type="published" when="1986-11-01">1986-11-01</date><biblScope unit="volume">19</biblScope><biblScope unit="issue">3-4</biblScope><biblScope unit="page" from="194">194</biblScope><biblScope unit="page" to="202">202</biblScope></imprint><idno type="ISSN">0065-4299</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0065-4299</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="Teeft" xml:lang="en"><term>Acute hemorrhagic pancreatitis</term><term>Assay</term><term>Assay system</term><term>Bovine serum albumin</term><term>Calcium dependence</term><term>Chlorpromazine</term><term>Circulatory collapse</term><term>Coli</term><term>Coli phospholipids</term><term>Conventional therapy</term><term>Dexamethasone</term><term>Dexamethasone base</term><term>Dexamethasone sodium phosphate</term><term>Drug concentration</term><term>Drug concentrations</term><term>Effective inhibitor</term><term>Endotoxin shock</term><term>Enzyme activity</term><term>Enzyme concentration</term><term>Enzyme velocity</term><term>Experimental animals</term><term>Higher concentrations</term><term>Hyperbolic relationship</term><term>Incubation time</term><term>Inhibitor</term><term>Inhibitor studies</term><term>Inhibitory</term><term>Inhibitory effect</term><term>Membrane phospholipids</term><term>Micellar dispersion</term><term>Oleic acid</term><term>Palmitic acid</term><term>Phospholipase</term><term>Phospholipid</term><term>Phospholipid hydrolysis</term><term>Pla2</term><term>Pla2 activity</term><term>Pla2 hydrolysis</term><term>Pla2 inhibition</term><term>Plasma concentrations</term><term>Positional specificity</term><term>Promethazine</term><term>Pulmonary changes</term><term>Pulmonary dysfunction</term><term>Residual pla2 activity</term><term>Septic</term><term>Septic shock</term><term>Septic shock serum</term><term>Serum phospholipase</term><term>Serum pla2 levels</term><term>Shock serum</term><term>Shock serum phospholipase</term><term>Significant inhibition</term><term>Sodium phosphate salt</term><term>Soluble phospholipase</term><term>Soluble pla2</term><term>Substrate concentration</term><term>Substrate hydrolysis</term><term>Therapeutic agents</term><term>Therapeutic efficacy</term><term>Therapeutic range</term><term>Total volume</term><term>Vadas</term><term>Wellesley hospital</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Abstract: Soluble phospholipase A2 has been implicated in the pathogenesis of local and systemic inflammatory reactions. Elevated levels of circulating phospholipase A2 (PLA2) correlate with the severity of circulatory collapse and pulmonary dysfunction in gram-negative septic shock. Characterization of septic shock serum PLA2 revealed a calcium-dependent enzyme with absolute 2-acyl specificity with a pH optimum of 7.5. We tested a number of therapeutic agents for their ability to inhibit PLA2 from human septic shock serum. Chloroquine, chlorpromazine, dexamethasone base, dexamethasone sodium phosphate, indomethacin, lidocaine, oleic acid, palmitic acid, promethazine, trans-retinoic acid, rutin and dl-α-tocopherol were all studied over the range of 10−2 to 10−7 M. All agents, with the sole exception of dexamethasone base, inhibited PLA2 activity at concentrations greater than 10−3M. PLA2 inhibition by dexamethasone sodium phosphate was factitious, due to the formation of calcium-phosphate complexes. Of the 11 agents studied, chlorpromazine was the most effective, with an IC50 of 7.5×10−5 M, a membrane concentration achievable within its therapeutic range. Inhibition was non-competitive, with an apparent Ki of 5 nM. Since serum PLA2 levels correlate with mortality in both experimental endotoxemia and clinical gram-negative septic shock, and chlorpromazine was previously shown to improve survival in these conditions, we postulate that its therapeutic efficacy resides at least in part in its PLA2-inhibitory activity.</div></front></TEI><affiliations><list><country><li>Canada</li></country><region><li>Ontario</li></region><settlement><li>Toronto</li></settlement><orgName><li>Université de Toronto</li></orgName></list><tree><country name="Canada"><region name="Ontario"><name sortKey="Vadas, P" sort="Vadas, P" uniqKey="Vadas P" first="P." last="Vadas">P. Vadas</name></region><name sortKey="Pruzanski, W" sort="Pruzanski, W" uniqKey="Pruzanski W" first="W." last="Pruzanski">W. Pruzanski</name><name sortKey="Stefanski, E" sort="Stefanski, E" uniqKey="Stefanski E" first="E." last="Stefanski">E. Stefanski</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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