Effects of Carbidopa and Entacapone on the Metabolic Fate of the Norepinephrine Prodrug L‐DOPS
Identifieur interne : 001246 ( Main/Corpus ); précédent : 001245; suivant : 001247Effects of Carbidopa and Entacapone on the Metabolic Fate of the Norepinephrine Prodrug L‐DOPS
Auteurs : David S. Goldstein ; Courtney Holmes ; Latoya Sewell ; Sandra Pechnik ; Irwin J. KopinSource :
- The Journal of Clinical Pharmacology [ 0091-2700 ] ; 2011-01.
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- KwdEn :
Abstract
Background: L‐threo‐3,4‐dihydroxyphenylserine (L‐DOPS), a norepinephrine (NE) prodrug, is investigational for orthostatic hypotension, which occurs commonly in Parkinson's disease. Adjunctive anti‐parkinsonian drugs might interact with L‐DOPS. We tested whether L‐aromatic amino‐acid decarboxylase inhibition by carbidopa (CAR) attenuates L‐DOPS conversion to NE and blocks the pressor effect of L‐DOPS, whereas catechol‐O‐methyltransferase inhibition by entacapone (ENT) interferes with L‐DOPS metabolism and augments the pressor effect. Methods: Twelve patients with autonomic failure took 400 mg of L‐DOPS with 200 mg of placebo (PLA), CAR, or ENT on different days. Plasma L‐DOPS, NE, and deaminated NE metabolites (dihydroxyphenylglycol [DHPG], dihydroxymandelic acid [DHMA]) were measured. Results: L‐DOPS+PLA and L‐DOPS+ENT increased systolic pressure similarly (by 27 ± 8 and 24 ± 9 mm Hg at 3 hours). L‐DOPS+CAR did not increase pressure. The peak increase in plasma NE (0.57 ± 0.11 nmol/L) averaged less than 1/15000th that in L‐DOPS and less than 1/35th that in DHPG+DHMA. CAR prevented and ENT augmented responses of plasma DHPG and DHMA to L‐DOPS. Conclusions: After L‐DOPS administration plasma, NE levels do not increase sufficiently to increase blood pressure. Pressor responses to L‐DOPS seem to reflect NE produced extraneuronally that escapes extensive enzymatic deamination and O‐methylation and evokes vasoconstriction before reaching the systemic circulation.
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DOI: 10.1177/0091270010363476
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<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">Effects of Carbidopa and Entacapone on the Metabolic Fate of the Norepinephrine Prodrug L‐DOPS</title><author><name sortKey="Goldstein, David S" sort="Goldstein, David S" uniqKey="Goldstein D" first="David S." last="Goldstein">David S. Goldstein</name><affiliation><mods:affiliation>Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda Maryland.</mods:affiliation></affiliation></author><author><name sortKey="Holmes, Courtney" sort="Holmes, Courtney" uniqKey="Holmes C" first="Courtney" last="Holmes">Courtney Holmes</name><affiliation><mods:affiliation>Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda Maryland.</mods:affiliation></affiliation></author><author><name sortKey="Sewell, Latoya" sort="Sewell, Latoya" uniqKey="Sewell L" first="Latoya" last="Sewell">Latoya Sewell</name><affiliation><mods:affiliation>Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda Maryland.</mods:affiliation></affiliation></author><author><name sortKey="Pechnik, Sandra" sort="Pechnik, Sandra" uniqKey="Pechnik S" first="Sandra" last="Pechnik">Sandra Pechnik</name><affiliation><mods:affiliation>Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda Maryland.</mods:affiliation></affiliation></author><author><name sortKey="Kopin, Irwin J" sort="Kopin, Irwin J" uniqKey="Kopin I" first="Irwin J." last="Kopin">Irwin J. Kopin</name><affiliation><mods:affiliation>Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda Maryland.</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:0A9FFCB715E27F7295686042811237E6BB80A174</idno><date when="2011" year="2011">2011</date><idno type="doi">10.1177/0091270010363476</idno><idno type="url">https://api.istex.fr/document/0A9FFCB715E27F7295686042811237E6BB80A174/fulltext/pdf</idno><idno type="wicri:Area/Main/Corpus">001246</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Effects of Carbidopa and Entacapone on the Metabolic Fate of the Norepinephrine Prodrug L‐DOPS</title><author><name sortKey="Goldstein, David S" sort="Goldstein, David S" uniqKey="Goldstein D" first="David S." last="Goldstein">David S. Goldstein</name><affiliation><mods:affiliation>Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda Maryland.</mods:affiliation></affiliation></author><author><name sortKey="Holmes, Courtney" sort="Holmes, Courtney" uniqKey="Holmes C" first="Courtney" last="Holmes">Courtney Holmes</name><affiliation><mods:affiliation>Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda Maryland.</mods:affiliation></affiliation></author><author><name sortKey="Sewell, Latoya" sort="Sewell, Latoya" uniqKey="Sewell L" first="Latoya" last="Sewell">Latoya Sewell</name><affiliation><mods:affiliation>Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda Maryland.</mods:affiliation></affiliation></author><author><name sortKey="Pechnik, Sandra" sort="Pechnik, Sandra" uniqKey="Pechnik S" first="Sandra" last="Pechnik">Sandra Pechnik</name><affiliation><mods:affiliation>Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda Maryland.</mods:affiliation></affiliation></author><author><name sortKey="Kopin, Irwin J" sort="Kopin, Irwin J" uniqKey="Kopin I" first="Irwin J." last="Kopin">Irwin J. Kopin</name><affiliation><mods:affiliation>Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda Maryland.</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">The Journal of Clinical Pharmacology</title><idno type="ISSN">0091-2700</idno><idno type="eISSN">1552-4604</idno><imprint><publisher>Blackwell Publishing Ltd</publisher><pubPlace>Oxford, UK</pubPlace><date type="published" when="2011-01">2011-01</date><biblScope unit="volume">51</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="66">66</biblScope><biblScope unit="page" to="74">74</biblScope></imprint><idno type="ISSN">0091-2700</idno></series><idno type="istex">0A9FFCB715E27F7295686042811237E6BB80A174</idno><idno type="DOI">10.1177/0091270010363476</idno><idno type="ArticleID">JCPH2227</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0091-2700</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>DHPG</term><term>DOPS</term><term>Dihydroxyphenylserine</term><term>Parkinson's disease</term><term>autonomic failure</term><term>dihydroxymandelic acid</term><term>dihydroxyphenylglycol</term><term>norepinephrine</term><term>orthostatic hypotension</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Background: L‐threo‐3,4‐dihydroxyphenylserine (L‐DOPS), a norepinephrine (NE) prodrug, is investigational for orthostatic hypotension, which occurs commonly in Parkinson's disease. Adjunctive anti‐parkinsonian drugs might interact with L‐DOPS. We tested whether L‐aromatic amino‐acid decarboxylase inhibition by carbidopa (CAR) attenuates L‐DOPS conversion to NE and blocks the pressor effect of L‐DOPS, whereas catechol‐O‐methyltransferase inhibition by entacapone (ENT) interferes with L‐DOPS metabolism and augments the pressor effect. Methods: Twelve patients with autonomic failure took 400 mg of L‐DOPS with 200 mg of placebo (PLA), CAR, or ENT on different days. Plasma L‐DOPS, NE, and deaminated NE metabolites (dihydroxyphenylglycol [DHPG], dihydroxymandelic acid [DHMA]) were measured. Results: L‐DOPS+PLA and L‐DOPS+ENT increased systolic pressure similarly (by 27 ± 8 and 24 ± 9 mm Hg at 3 hours). L‐DOPS+CAR did not increase pressure. The peak increase in plasma NE (0.57 ± 0.11 nmol/L) averaged less than 1/15000th that in L‐DOPS and less than 1/35th that in DHPG+DHMA. CAR prevented and ENT augmented responses of plasma DHPG and DHMA to L‐DOPS. Conclusions: After L‐DOPS administration plasma, NE levels do not increase sufficiently to increase blood pressure. Pressor responses to L‐DOPS seem to reflect NE produced extraneuronally that escapes extensive enzymatic deamination and O‐methylation and evokes vasoconstriction before reaching the systemic circulation.</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>David S. Goldstein MD, PhD</name><affiliations><json:string>Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda Maryland.</json:string></affiliations></json:item><json:item><name>Courtney Holmes CMT</name><affiliations><json:string>Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda Maryland.</json:string></affiliations></json:item><json:item><name>LaToya Sewell CRNP</name><affiliations><json:string>Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda Maryland.</json:string></affiliations></json:item><json:item><name>Sandra Pechnik RN</name><affiliations><json:string>Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda Maryland.</json:string></affiliations></json:item><json:item><name>Irwin J. Kopin MD</name><affiliations><json:string>Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda Maryland.</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Dihydroxyphenylserine</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>norepinephrine</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>dihydroxyphenylglycol</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>dihydroxymandelic acid</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>orthostatic hypotension</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>autonomic failure</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Parkinson's disease</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>DHPG</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>DOPS</value></json:item></subject><articleId><json:string>JCPH2227</json:string></articleId><language><json:string>eng</json:string></language><abstract>Background: L‐threo‐3,4‐dihydroxyphenylserine (L‐DOPS), a norepinephrine (NE) prodrug, is investigational for orthostatic hypotension, which occurs commonly in Parkinson's disease. Adjunctive anti‐parkinsonian drugs might interact with L‐DOPS. We tested whether L‐aromatic amino‐acid decarboxylase inhibition by carbidopa (CAR) attenuates L‐DOPS conversion to NE and blocks the pressor effect of L‐DOPS, whereas catechol‐O‐methyltransferase inhibition by entacapone (ENT) interferes with L‐DOPS metabolism and augments the pressor effect. Methods: Twelve patients with autonomic failure took 400 mg of L‐DOPS with 200 mg of placebo (PLA), CAR, or ENT on different days. Plasma L‐DOPS, NE, and deaminated NE metabolites (dihydroxyphenylglycol [DHPG], dihydroxymandelic acid [DHMA]) were measured. Results: L‐DOPS+PLA and L‐DOPS+ENT increased systolic pressure similarly (by 27 ± 8 and 24 ± 9 mm Hg at 3 hours). L‐DOPS+CAR did not increase pressure. The peak increase in plasma NE (0.57 ± 0.11 nmol/L) averaged less than 1/15000th that in L‐DOPS and less than 1/35th that in DHPG+DHMA. CAR prevented and ENT augmented responses of plasma DHPG and DHMA to L‐DOPS. Conclusions: After L‐DOPS administration plasma, NE levels do not increase sufficiently to increase blood pressure. Pressor responses to L‐DOPS seem to reflect NE produced extraneuronally that escapes extensive enzymatic deamination and O‐methylation and evokes vasoconstriction before reaching the systemic circulation.</abstract><qualityIndicators><score>8.38</score><pdfVersion>1.7</pdfVersion><pdfPageSize>585 x 792 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>9</keywordCount><abstractCharCount>1481</abstractCharCount><pdfWordCount>3956</pdfWordCount><pdfCharCount>26019</pdfCharCount><pdfPageCount>9</pdfPageCount><abstractWordCount>202</abstractWordCount></qualityIndicators><title>Effects of Carbidopa and Entacapone on the Metabolic Fate of the Norepinephrine Prodrug L‐DOPS</title><genre><json:string>other</json:string></genre><host><volume>51</volume><publisherId><json:string>JCPH</json:string></publisherId><pages><total>9</total><last>74</last><first>66</first></pages><issn><json:string>0091-2700</json:string></issn><issue>1</issue><genre><json:string>Journal</json:string></genre><language><json:string>unknown</json:string></language><eissn><json:string>1552-4604</json:string></eissn><title>The Journal of Clinical Pharmacology</title><doi><json:string>10.1002/(ISSN)1552-4604</json:string></doi></host><publicationDate>2011</publicationDate><copyrightDate>2011</copyrightDate><doi><json:string>10.1177/0091270010363476</json:string></doi><id>0A9FFCB715E27F7295686042811237E6BB80A174</id><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/0A9FFCB715E27F7295686042811237E6BB80A174/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/0A9FFCB715E27F7295686042811237E6BB80A174/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/0A9FFCB715E27F7295686042811237E6BB80A174/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Effects of Carbidopa and Entacapone on the Metabolic Fate of the Norepinephrine Prodrug L‐DOPS</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Blackwell Publishing Ltd</publisher><pubPlace>Oxford, UK</pubPlace><availability><p>WILEY</p></availability><date>2011</date></publicationStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Effects of Carbidopa and Entacapone on the Metabolic Fate of the Norepinephrine Prodrug L‐DOPS</title><author><persName><forename type="first">David S.</forename><surname>Goldstein</surname></persName><roleName type="degree">MD, PhD</roleName><note type="correspondence"><p>Correspondence: Address for correspondence: David S. Goldstein, MD, PhD, NINDS, NIH, 10 Center Drive MSC‐1620, Building 10 Room 5N220, Bethesda, MD 20892‐1620; e‐mail: .</p></note><affiliation>Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda Maryland.</affiliation></author><author><persName><forename type="first">Courtney</forename><surname>Holmes</surname></persName><roleName type="degree">CMT</roleName><affiliation>Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda Maryland.</affiliation></author><author><persName><forename type="first">LaToya</forename><surname>Sewell</surname></persName><roleName type="degree">CRNP</roleName><affiliation>Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda Maryland.</affiliation></author><author><persName><forename type="first">Sandra</forename><surname>Pechnik</surname></persName><roleName type="degree">RN</roleName><affiliation>Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda Maryland.</affiliation></author><author><persName><forename type="first">Irwin J.</forename><surname>Kopin</surname></persName><roleName type="degree">MD</roleName><affiliation>Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda Maryland.</affiliation></author></analytic><monogr><title level="j">The Journal of Clinical Pharmacology</title><idno type="pISSN">0091-2700</idno><idno type="eISSN">1552-4604</idno><idno type="DOI">10.1002/(ISSN)1552-4604</idno><imprint><publisher>Blackwell Publishing Ltd</publisher><pubPlace>Oxford, UK</pubPlace><date type="published" when="2011-01"></date><biblScope unit="volume">51</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="66">66</biblScope><biblScope unit="page" to="74">74</biblScope></imprint></monogr><idno type="istex">0A9FFCB715E27F7295686042811237E6BB80A174</idno><idno type="DOI">10.1177/0091270010363476</idno><idno type="ArticleID">JCPH2227</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2011</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Background: L‐threo‐3,4‐dihydroxyphenylserine (L‐DOPS), a norepinephrine (NE) prodrug, is investigational for orthostatic hypotension, which occurs commonly in Parkinson's disease. Adjunctive anti‐parkinsonian drugs might interact with L‐DOPS. We tested whether L‐aromatic amino‐acid decarboxylase inhibition by carbidopa (CAR) attenuates L‐DOPS conversion to NE and blocks the pressor effect of L‐DOPS, whereas catechol‐O‐methyltransferase inhibition by entacapone (ENT) interferes with L‐DOPS metabolism and augments the pressor effect. Methods: Twelve patients with autonomic failure took 400 mg of L‐DOPS with 200 mg of placebo (PLA), CAR, or ENT on different days. Plasma L‐DOPS, NE, and deaminated NE metabolites (dihydroxyphenylglycol [DHPG], dihydroxymandelic acid [DHMA]) were measured. Results: L‐DOPS+PLA and L‐DOPS+ENT increased systolic pressure similarly (by 27 ± 8 and 24 ± 9 mm Hg at 3 hours). L‐DOPS+CAR did not increase pressure. The peak increase in plasma NE (0.57 ± 0.11 nmol/L) averaged less than 1/15000th that in L‐DOPS and less than 1/35th that in DHPG+DHMA. CAR prevented and ENT augmented responses of plasma DHPG and DHMA to L‐DOPS. Conclusions: After L‐DOPS administration plasma, NE levels do not increase sufficiently to increase blood pressure. Pressor responses to L‐DOPS seem to reflect NE produced extraneuronally that escapes extensive enzymatic deamination and O‐methylation and evokes vasoconstriction before reaching the systemic circulation.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>Keywords</head><item><term>Dihydroxyphenylserine</term></item><item><term>norepinephrine</term></item><item><term>dihydroxyphenylglycol</term></item><item><term>dihydroxymandelic acid</term></item><item><term>orthostatic hypotension</term></item><item><term>autonomic failure</term></item><item><term>Parkinson's disease</term></item><item><term>DHPG</term></item><item><term>DOPS</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2011-01">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/0A9FFCB715E27F7295686042811237E6BB80A174/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component version="2.0" type="serialArticle" xml:lang="en"><header><publicationMeta level="product"><publisherInfo><publisherName>Blackwell Publishing Ltd</publisherName><publisherLoc>Oxford, UK</publisherLoc></publisherInfo><doi origin="wiley" registered="yes">10.1002/(ISSN)1552-4604</doi><issn type="print">0091-2700</issn><issn type="electronic">1552-4604</issn><idGroup><id type="product" value="JCPH"></id><id type="publisherDivision" value="ST"></id></idGroup><titleGroup><title type="main" sort="JOURNAL OF CLINICAL PHARMACOLOGY">The Journal of Clinical Pharmacology</title></titleGroup></publicationMeta><publicationMeta level="part" position="01101"><doi origin="wiley">10.1002/jcph.2011.51.issue-1</doi><numberingGroup><numbering type="journalVolume" number="51">51</numbering><numbering type="journalIssue" number="1">1</numbering></numberingGroup><coverDate startDate="2011-01">January 2011</coverDate></publicationMeta><publicationMeta level="unit" type="miscellaneous" position="8" status="forIssue"><doi origin="wiley">10.1177/0091270010363476</doi><idGroup><id type="unit" value="JCPH2227"></id></idGroup><countGroup><count type="pageTotal" number="9"></count></countGroup><titleGroup><title type="tocHeading1">Pharmacodynamics</title></titleGroup><copyright>2011 American College of Clinical Pharmacology</copyright><eventGroup><event type="xmlConverted" agent="Converter:BPG_TO_WML3G version:3.2.0 mode:FullText" date="2013-03-08"></event><event type="publishedOnlineFinalForm" date="2013-03-08"></event><event type="firstOnline" date="2013-03-08"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:3.8.8" date="2014-01-30"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-11-04"></event></eventGroup><numberingGroup><numbering type="pageFirst" number="66">66</numbering><numbering type="pageLast" number="74">74</numbering></numberingGroup><correspondenceTo> Address for correspondence: David S. Goldstein, MD, PhD, NINDS, NIH, 10 Center Drive MSC‐1620, Building 10 Room 5N220, Bethesda, MD 20892‐1620; e‐mail: <email>goldsteind@ninds.nih.gov</email>.</correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:JCPH.JCPH2227.pdf"></link></linkGroup></publicationMeta><contentMeta><unparsedEditorialHistory>Revised version accepted January 17, 2010</unparsedEditorialHistory><countGroup><count type="figureTotal" number="5"></count><count type="tableTotal" number="1"></count><count type="formulaTotal" number="0"></count><count type="referenceTotal" number="19"></count><count type="linksCrossRef" number="40"></count></countGroup><titleGroup><title type="main">Effects of Carbidopa and Entacapone on the Metabolic Fate of the Norepinephrine Prodrug L‐DOPS</title></titleGroup><creators><creator creatorRole="author" xml:id="cr1" affiliationRef="#a1" corresponding="yes"><personName><givenNames>David S.</givenNames><familyName>Goldstein</familyName><degrees>MD, PhD</degrees></personName></creator><creator creatorRole="author" xml:id="cr2" affiliationRef="#a1"><personName><givenNames>Courtney</givenNames><familyName>Holmes</familyName><degrees>CMT</degrees></personName></creator><creator creatorRole="author" xml:id="cr3" affiliationRef="#a1"><personName><givenNames>LaToya</givenNames><familyName>Sewell</familyName><degrees>CRNP</degrees></personName></creator><creator creatorRole="author" xml:id="cr4" affiliationRef="#a1"><personName><givenNames>Sandra</givenNames><familyName>Pechnik</familyName><degrees>RN</degrees></personName></creator><creator creatorRole="author" xml:id="cr5" affiliationRef="#a1"><personName><givenNames>Irwin J.</givenNames><familyName>Kopin</familyName><degrees>MD</degrees></personName></creator></creators><affiliationGroup><affiliation xml:id="a1" countryCode="US"><unparsedAffiliation>Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda Maryland.</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en"><keyword xml:id="k1">Dihydroxyphenylserine</keyword><keyword xml:id="k2">norepinephrine</keyword><keyword xml:id="k3">dihydroxyphenylglycol</keyword><keyword xml:id="k4">dihydroxymandelic acid</keyword><keyword xml:id="k5">orthostatic hypotension</keyword><keyword xml:id="k6">autonomic failure</keyword><keyword xml:id="k7">Parkinson's disease</keyword><keyword xml:id="k8">DHPG</keyword><keyword xml:id="k9">DOPS</keyword></keywordGroup><abstractGroup><abstract type="main" xml:lang="en"><p><b>Background:</b> L‐threo‐3,4‐dihydroxyphenylserine (L‐DOPS), a norepinephrine (NE) prodrug, is investigational for orthostatic hypotension, which occurs commonly in Parkinson's disease. Adjunctive anti‐parkinsonian drugs might interact with L‐DOPS. We tested whether L‐aromatic amino‐acid decarboxylase inhibition by carbidopa (CAR) attenuates L‐DOPS conversion to NE and blocks the pressor effect of L‐DOPS, whereas catechol‐O‐methyltransferase inhibition by entacapone (ENT) interferes with L‐DOPS metabolism and augments the pressor effect. <b>Methods:</b> Twelve patients with autonomic failure took 400 mg of L‐DOPS with 200 mg of placebo (PLA), CAR, or ENT on different days. Plasma L‐DOPS, NE, and deaminated NE metabolites (dihydroxyphenylglycol [DHPG], dihydroxymandelic acid [DHMA]) were measured. <b>Results:</b> L‐DOPS+PLA and L‐DOPS+ENT increased systolic pressure similarly (by 27 ± 8 and 24 ± 9 mm Hg at 3 hours). L‐DOPS+CAR did not increase pressure. The peak increase in plasma NE (0.57 ± 0.11 nmol/L) averaged less than 1/15000th that in L‐DOPS and less than 1/35th that in DHPG+DHMA. CAR prevented and ENT augmented responses of plasma DHPG and DHMA to L‐DOPS. <b>Conclusions:</b> After L‐DOPS administration plasma, NE levels do not increase sufficiently to increase blood pressure. Pressor responses to L‐DOPS seem to reflect NE produced extraneuronally that escapes extensive enzymatic deamination and O‐methylation and evokes vasoconstriction before reaching the systemic circulation.</p></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Effects of Carbidopa and Entacapone on the Metabolic Fate of the Norepinephrine Prodrug L‐DOPS</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Effects of Carbidopa and Entacapone on the Metabolic Fate of the Norepinephrine Prodrug L‐DOPS</title></titleInfo><name type="personal"><namePart type="given">David S.</namePart><namePart type="family">Goldstein</namePart><namePart type="termsOfAddress">MD, PhD</namePart><affiliation>Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda Maryland.</affiliation><description>Correspondence: Address for correspondence: David S. Goldstein, MD, PhD, NINDS, NIH, 10 Center Drive MSC‐1620, Building 10 Room 5N220, Bethesda, MD 20892‐1620; e‐mail: .</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Courtney</namePart><namePart type="family">Holmes</namePart><namePart type="termsOfAddress">CMT</namePart><affiliation>Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda Maryland.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">LaToya</namePart><namePart type="family">Sewell</namePart><namePart type="termsOfAddress">CRNP</namePart><affiliation>Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda Maryland.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Sandra</namePart><namePart type="family">Pechnik</namePart><namePart type="termsOfAddress">RN</namePart><affiliation>Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda Maryland.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Irwin J.</namePart><namePart type="family">Kopin</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda Maryland.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="other" displayLabel="miscellaneous"></genre><originInfo><publisher>Blackwell Publishing Ltd</publisher><place><placeTerm type="text">Oxford, UK</placeTerm></place><dateIssued encoding="w3cdtf">2011-01</dateIssued><edition>Revised version accepted January 17, 2010</edition><copyrightDate encoding="w3cdtf">2011</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="figures">5</extent><extent unit="tables">1</extent><extent unit="references">19</extent></physicalDescription><abstract lang="en">Background: L‐threo‐3,4‐dihydroxyphenylserine (L‐DOPS), a norepinephrine (NE) prodrug, is investigational for orthostatic hypotension, which occurs commonly in Parkinson's disease. Adjunctive anti‐parkinsonian drugs might interact with L‐DOPS. We tested whether L‐aromatic amino‐acid decarboxylase inhibition by carbidopa (CAR) attenuates L‐DOPS conversion to NE and blocks the pressor effect of L‐DOPS, whereas catechol‐O‐methyltransferase inhibition by entacapone (ENT) interferes with L‐DOPS metabolism and augments the pressor effect. Methods: Twelve patients with autonomic failure took 400 mg of L‐DOPS with 200 mg of placebo (PLA), CAR, or ENT on different days. Plasma L‐DOPS, NE, and deaminated NE metabolites (dihydroxyphenylglycol [DHPG], dihydroxymandelic acid [DHMA]) were measured. Results: L‐DOPS+PLA and L‐DOPS+ENT increased systolic pressure similarly (by 27 ± 8 and 24 ± 9 mm Hg at 3 hours). L‐DOPS+CAR did not increase pressure. The peak increase in plasma NE (0.57 ± 0.11 nmol/L) averaged less than 1/15000th that in L‐DOPS and less than 1/35th that in DHPG+DHMA. CAR prevented and ENT augmented responses of plasma DHPG and DHMA to L‐DOPS. Conclusions: After L‐DOPS administration plasma, NE levels do not increase sufficiently to increase blood pressure. Pressor responses to L‐DOPS seem to reflect NE produced extraneuronally that escapes extensive enzymatic deamination and O‐methylation and evokes vasoconstriction before reaching the systemic circulation.</abstract><subject lang="en"><genre>Keywords</genre><topic>Dihydroxyphenylserine</topic><topic>norepinephrine</topic><topic>dihydroxyphenylglycol</topic><topic>dihydroxymandelic acid</topic><topic>orthostatic hypotension</topic><topic>autonomic failure</topic><topic>Parkinson's disease</topic><topic>DHPG</topic><topic>DOPS</topic></subject><relatedItem type="host"><titleInfo><title>The Journal of Clinical Pharmacology</title></titleInfo><genre type="Journal">journal</genre><identifier type="ISSN">0091-2700</identifier><identifier type="eISSN">1552-4604</identifier><identifier type="DOI">10.1002/(ISSN)1552-4604</identifier><identifier type="PublisherID">JCPH</identifier><part><date>2011</date><detail type="volume"><caption>vol.</caption><number>51</number></detail><detail type="issue"><caption>no.</caption><number>1</number></detail><extent unit="pages"><start>66</start><end>74</end><total>9</total></extent></part></relatedItem><identifier type="istex">0A9FFCB715E27F7295686042811237E6BB80A174</identifier><identifier type="DOI">10.1177/0091270010363476</identifier><identifier type="ArticleID">JCPH2227</identifier><accessCondition type="use and reproduction" contentType="copyright">2011 American College of Clinical Pharmacology</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>Blackwell Publishing Ltd</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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