The effect of multiple doses of ritonavir on the pharmacokinetics of rifabutin
Objective To investigate the effects of ritonavir on the pharmacokinetics of rifabutin. Methods In a multiple‐dose, randomized, parallel‐group, double‐blind study, subjects received 150 mg rifabutin daily for 24 days coadministered on days 15 to 24 with twice‐daily doses of either placebo or ritonav...
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| Veröffentlicht in: | Clinical pharmacology and therapeutics 1998-04, Vol.63 (4), p.414-421 |
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| creator | Cato, Allen Cavanaugh, John Shi, Harry Hsu, Ann Leonard, John Granneman, Richard |
| description | Objective
To investigate the effects of ritonavir on the pharmacokinetics of rifabutin.
Methods
In a multiple‐dose, randomized, parallel‐group, double‐blind study, subjects received 150 mg rifabutin daily for 24 days coadministered on days 15 to 24 with twice‐daily doses of either placebo or ritonavir (300 mg on day 15, 400 mg on day 16, and 500 mg on days 17 to 24). Plasma concentrations of rifabutin and 25‐O‐desacetylrifabutin were measured by HPLC, and the pharmacokinetics were determined after the rifabutin doses on days 14 and 24.
Results
For subjects receiving rifabutin and placebo who completed the study (n = 11), there were small but statistically significant differences (≤32%) in several rifabutin and 25‐O‐desacetylrifabutin pharmacokinetic parameters between the regimens of rifabutin alone and rifabutin with placebo. In contrast, the effect of ritonavir on rifabutin pharmacokinetics of subjects completing the study (n = 5) was substantial. Rifabutin mean minimum observed concentration (Cmin), maximum observed concentration (Cmax), and area under the concentration‐time curve [AUC(0–24)] increased by approximately sixfold, 2.5‐fold, and fourfold, respectively, and 25‐O‐desacetylrifabutin mean Cmin, Cmax, and AUC(0–24) increased by approximately 200‐, 16‐, and 35‐fold, respectively, when coadministered with ritonavir compared with rifabutin administered alone. The sum of the mean AUC(0–24) of rifabutin and 25‐O‐desacetylrifabutin increased nearly sevenfold when coadministered with ritonavir.
Conclusions
Ritonavir inhibited the metabolism of rifabutin and 25‐O‐desacetylrifabutin, suggesting that both are metabolized at least in part by CYP3A. Ritonavir may have enhanced rifabutin bioavailability by reducing either intestinal or hepatic metabolism or both. Clarithromycin is an alternative to rifabutin for antimycobacterial therapy that may be administered concurrently with ritonavir. Administration of ritonavir with a reduced rifabutin dosage regimen (150 mg every Monday, Wednesday, and Friday) is being investigated.
Clinical Pharmacology & Therapeutics (1998) 63, 414–421; doi: |
| doi_str_mv | 10.1016/S0009-9236(98)90036-4 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_79868584</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>79868584</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3902-c94ed8896eb0b1e4d18012caa48dac5822112bc5e1d50f78d8a392f9c9a86fcd3</originalsourceid><addsrcrecordid>eNqNkE1P3DAQhq2qFV1ofwJSDqgqh4A_4uzMrWjVAtKqILE9W44zFi752NpJEf-eDRvtmdNoZp6ZV3oYOxX8QnBRXj5wzjFHqcrvCOfIuSrz4gNbCK1kXmqlP7LFAfnMjlP6u2sLBDhiR6hBL1Ev2O_NI2XkPbkh633Wjs0Qtg1ldZ8oTZMYhr6z_0PM-i4bdvD20cbWuv4pdDQEN0PeVuMQui_sk7dNoq9zPWF_fv3crG7y9d317epqnTuFXOYOC6oBsKSKV4KKWgAX0llbQG2dBimFkJXTJGrN_RJqsAqlR4cWSu9qdcK-7f9uY_9vpDSYNiRHTWM76sdklgglaCh2oN6DLvYpRfJmG0Nr44sR3EwezZtHM0kyCObNo5nuTueAsWqpPlzN4nb7s3lvk7ONj7ZzIR0wKTXAcnrzY489h4Ze3pdtVveb1fp-IxBBSfUKf8SOJw</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>79868584</pqid></control><display><type>article</type><title>The effect of multiple doses of ritonavir on the pharmacokinetics of rifabutin</title><source>MEDLINE</source><source>Wiley Online Library Journals Frontfile Complete</source><creator>Cato, Allen ; Cavanaugh, John ; Shi, Harry ; Hsu, Ann ; Leonard, John ; Granneman, Richard</creator><creatorcontrib>Cato, Allen ; Cavanaugh, John ; Shi, Harry ; Hsu, Ann ; Leonard, John ; Granneman, Richard</creatorcontrib><description>Objective
To investigate the effects of ritonavir on the pharmacokinetics of rifabutin.
Methods
In a multiple‐dose, randomized, parallel‐group, double‐blind study, subjects received 150 mg rifabutin daily for 24 days coadministered on days 15 to 24 with twice‐daily doses of either placebo or ritonavir (300 mg on day 15, 400 mg on day 16, and 500 mg on days 17 to 24). Plasma concentrations of rifabutin and 25‐O‐desacetylrifabutin were measured by HPLC, and the pharmacokinetics were determined after the rifabutin doses on days 14 and 24.
Results
For subjects receiving rifabutin and placebo who completed the study (n = 11), there were small but statistically significant differences (≤32%) in several rifabutin and 25‐O‐desacetylrifabutin pharmacokinetic parameters between the regimens of rifabutin alone and rifabutin with placebo. In contrast, the effect of ritonavir on rifabutin pharmacokinetics of subjects completing the study (n = 5) was substantial. Rifabutin mean minimum observed concentration (Cmin), maximum observed concentration (Cmax), and area under the concentration‐time curve [AUC(0–24)] increased by approximately sixfold, 2.5‐fold, and fourfold, respectively, and 25‐O‐desacetylrifabutin mean Cmin, Cmax, and AUC(0–24) increased by approximately 200‐, 16‐, and 35‐fold, respectively, when coadministered with ritonavir compared with rifabutin administered alone. The sum of the mean AUC(0–24) of rifabutin and 25‐O‐desacetylrifabutin increased nearly sevenfold when coadministered with ritonavir.
Conclusions
Ritonavir inhibited the metabolism of rifabutin and 25‐O‐desacetylrifabutin, suggesting that both are metabolized at least in part by CYP3A. Ritonavir may have enhanced rifabutin bioavailability by reducing either intestinal or hepatic metabolism or both. Clarithromycin is an alternative to rifabutin for antimycobacterial therapy that may be administered concurrently with ritonavir. Administration of ritonavir with a reduced rifabutin dosage regimen (150 mg every Monday, Wednesday, and Friday) is being investigated.
Clinical Pharmacology & Therapeutics (1998) 63, 414–421; doi:</description><identifier>ISSN: 0009-9236</identifier><identifier>EISSN: 1532-6535</identifier><identifier>DOI: 10.1016/S0009-9236(98)90036-4</identifier><identifier>PMID: 9585795</identifier><identifier>CODEN: CLPTAT</identifier><language>eng</language><publisher>New York, NY: Nature Publishing</publisher><subject>Adult ; AIDS/HIV ; Anti-HIV Agents - administration & dosage ; Anti-HIV Agents - pharmacology ; Antibacterial agents ; Antibiotics, Antitubercular - administration & dosage ; Antibiotics, Antitubercular - pharmacokinetics ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Aryl Hydrocarbon Hydroxylases ; Biological and medical sciences ; Biological Availability ; Chromatography, High Pressure Liquid ; Cytochrome P-450 CYP3A ; Cytochrome P-450 Enzyme System - metabolism ; Double-Blind Method ; Drug Administration Schedule ; Female ; HIV Protease Inhibitors - administration & dosage ; HIV Protease Inhibitors - pharmacology ; Humans ; Male ; Medical sciences ; Oxidoreductases, N-Demethylating - metabolism ; Pharmacology. Drug treatments ; Reference Values ; Rifabutin - administration & dosage ; Rifabutin - pharmacokinetics ; Ritonavir - administration & dosage ; Ritonavir - pharmacology</subject><ispartof>Clinical pharmacology and therapeutics, 1998-04, Vol.63 (4), p.414-421</ispartof><rights>1998 American Society for Clinical Pharmacology and Therapeutics</rights><rights>1998 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3902-c94ed8896eb0b1e4d18012caa48dac5822112bc5e1d50f78d8a392f9c9a86fcd3</citedby><cites>FETCH-LOGICAL-c3902-c94ed8896eb0b1e4d18012caa48dac5822112bc5e1d50f78d8a392f9c9a86fcd3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1016%2FS0009-9236%2898%2990036-4$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1016%2FS0009-9236%2898%2990036-4$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27903,27904,45553,45554</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2258874$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9585795$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cato, Allen</creatorcontrib><creatorcontrib>Cavanaugh, John</creatorcontrib><creatorcontrib>Shi, Harry</creatorcontrib><creatorcontrib>Hsu, Ann</creatorcontrib><creatorcontrib>Leonard, John</creatorcontrib><creatorcontrib>Granneman, Richard</creatorcontrib><title>The effect of multiple doses of ritonavir on the pharmacokinetics of rifabutin</title><title>Clinical pharmacology and therapeutics</title><addtitle>Clin Pharmacol Ther</addtitle><description>Objective
To investigate the effects of ritonavir on the pharmacokinetics of rifabutin.
Methods
In a multiple‐dose, randomized, parallel‐group, double‐blind study, subjects received 150 mg rifabutin daily for 24 days coadministered on days 15 to 24 with twice‐daily doses of either placebo or ritonavir (300 mg on day 15, 400 mg on day 16, and 500 mg on days 17 to 24). Plasma concentrations of rifabutin and 25‐O‐desacetylrifabutin were measured by HPLC, and the pharmacokinetics were determined after the rifabutin doses on days 14 and 24.
Results
For subjects receiving rifabutin and placebo who completed the study (n = 11), there were small but statistically significant differences (≤32%) in several rifabutin and 25‐O‐desacetylrifabutin pharmacokinetic parameters between the regimens of rifabutin alone and rifabutin with placebo. In contrast, the effect of ritonavir on rifabutin pharmacokinetics of subjects completing the study (n = 5) was substantial. Rifabutin mean minimum observed concentration (Cmin), maximum observed concentration (Cmax), and area under the concentration‐time curve [AUC(0–24)] increased by approximately sixfold, 2.5‐fold, and fourfold, respectively, and 25‐O‐desacetylrifabutin mean Cmin, Cmax, and AUC(0–24) increased by approximately 200‐, 16‐, and 35‐fold, respectively, when coadministered with ritonavir compared with rifabutin administered alone. The sum of the mean AUC(0–24) of rifabutin and 25‐O‐desacetylrifabutin increased nearly sevenfold when coadministered with ritonavir.
Conclusions
Ritonavir inhibited the metabolism of rifabutin and 25‐O‐desacetylrifabutin, suggesting that both are metabolized at least in part by CYP3A. Ritonavir may have enhanced rifabutin bioavailability by reducing either intestinal or hepatic metabolism or both. Clarithromycin is an alternative to rifabutin for antimycobacterial therapy that may be administered concurrently with ritonavir. Administration of ritonavir with a reduced rifabutin dosage regimen (150 mg every Monday, Wednesday, and Friday) is being investigated.
Clinical Pharmacology & Therapeutics (1998) 63, 414–421; doi:</description><subject>Adult</subject><subject>AIDS/HIV</subject><subject>Anti-HIV Agents - administration & dosage</subject><subject>Anti-HIV Agents - pharmacology</subject><subject>Antibacterial agents</subject><subject>Antibiotics, Antitubercular - administration & dosage</subject><subject>Antibiotics, Antitubercular - pharmacokinetics</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Aryl Hydrocarbon Hydroxylases</subject><subject>Biological and medical sciences</subject><subject>Biological Availability</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Cytochrome P-450 CYP3A</subject><subject>Cytochrome P-450 Enzyme System - metabolism</subject><subject>Double-Blind Method</subject><subject>Drug Administration Schedule</subject><subject>Female</subject><subject>HIV Protease Inhibitors - administration & dosage</subject><subject>HIV Protease Inhibitors - pharmacology</subject><subject>Humans</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Oxidoreductases, N-Demethylating - metabolism</subject><subject>Pharmacology. Drug treatments</subject><subject>Reference Values</subject><subject>Rifabutin - administration & dosage</subject><subject>Rifabutin - pharmacokinetics</subject><subject>Ritonavir - administration & dosage</subject><subject>Ritonavir - pharmacology</subject><issn>0009-9236</issn><issn>1532-6535</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1998</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkE1P3DAQhq2qFV1ofwJSDqgqh4A_4uzMrWjVAtKqILE9W44zFi752NpJEf-eDRvtmdNoZp6ZV3oYOxX8QnBRXj5wzjFHqcrvCOfIuSrz4gNbCK1kXmqlP7LFAfnMjlP6u2sLBDhiR6hBL1Ev2O_NI2XkPbkh633Wjs0Qtg1ldZ8oTZMYhr6z_0PM-i4bdvD20cbWuv4pdDQEN0PeVuMQui_sk7dNoq9zPWF_fv3crG7y9d317epqnTuFXOYOC6oBsKSKV4KKWgAX0llbQG2dBimFkJXTJGrN_RJqsAqlR4cWSu9qdcK-7f9uY_9vpDSYNiRHTWM76sdklgglaCh2oN6DLvYpRfJmG0Nr44sR3EwezZtHM0kyCObNo5nuTueAsWqpPlzN4nb7s3lvk7ONj7ZzIR0wKTXAcnrzY489h4Ze3pdtVveb1fp-IxBBSfUKf8SOJw</recordid><startdate>199804</startdate><enddate>199804</enddate><creator>Cato, Allen</creator><creator>Cavanaugh, John</creator><creator>Shi, Harry</creator><creator>Hsu, Ann</creator><creator>Leonard, John</creator><creator>Granneman, Richard</creator><general>Nature Publishing</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>199804</creationdate><title>The effect of multiple doses of ritonavir on the pharmacokinetics of rifabutin</title><author>Cato, Allen ; Cavanaugh, John ; Shi, Harry ; Hsu, Ann ; Leonard, John ; Granneman, Richard</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3902-c94ed8896eb0b1e4d18012caa48dac5822112bc5e1d50f78d8a392f9c9a86fcd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1998</creationdate><topic>Adult</topic><topic>AIDS/HIV</topic><topic>Anti-HIV Agents - administration & dosage</topic><topic>Anti-HIV Agents - pharmacology</topic><topic>Antibacterial agents</topic><topic>Antibiotics, Antitubercular - administration & dosage</topic><topic>Antibiotics, Antitubercular - pharmacokinetics</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Aryl Hydrocarbon Hydroxylases</topic><topic>Biological and medical sciences</topic><topic>Biological Availability</topic><topic>Chromatography, High Pressure Liquid</topic><topic>Cytochrome P-450 CYP3A</topic><topic>Cytochrome P-450 Enzyme System - metabolism</topic><topic>Double-Blind Method</topic><topic>Drug Administration Schedule</topic><topic>Female</topic><topic>HIV Protease Inhibitors - administration & dosage</topic><topic>HIV Protease Inhibitors - pharmacology</topic><topic>Humans</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Oxidoreductases, N-Demethylating - metabolism</topic><topic>Pharmacology. Drug treatments</topic><topic>Reference Values</topic><topic>Rifabutin - administration & dosage</topic><topic>Rifabutin - pharmacokinetics</topic><topic>Ritonavir - administration & dosage</topic><topic>Ritonavir - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cato, Allen</creatorcontrib><creatorcontrib>Cavanaugh, John</creatorcontrib><creatorcontrib>Shi, Harry</creatorcontrib><creatorcontrib>Hsu, Ann</creatorcontrib><creatorcontrib>Leonard, John</creatorcontrib><creatorcontrib>Granneman, Richard</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Clinical pharmacology and therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cato, Allen</au><au>Cavanaugh, John</au><au>Shi, Harry</au><au>Hsu, Ann</au><au>Leonard, John</au><au>Granneman, Richard</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The effect of multiple doses of ritonavir on the pharmacokinetics of rifabutin</atitle><jtitle>Clinical pharmacology and therapeutics</jtitle><addtitle>Clin Pharmacol Ther</addtitle><date>1998-04</date><risdate>1998</risdate><volume>63</volume><issue>4</issue><spage>414</spage><epage>421</epage><pages>414-421</pages><issn>0009-9236</issn><eissn>1532-6535</eissn><coden>CLPTAT</coden><abstract>Objective
To investigate the effects of ritonavir on the pharmacokinetics of rifabutin.
Methods
In a multiple‐dose, randomized, parallel‐group, double‐blind study, subjects received 150 mg rifabutin daily for 24 days coadministered on days 15 to 24 with twice‐daily doses of either placebo or ritonavir (300 mg on day 15, 400 mg on day 16, and 500 mg on days 17 to 24). Plasma concentrations of rifabutin and 25‐O‐desacetylrifabutin were measured by HPLC, and the pharmacokinetics were determined after the rifabutin doses on days 14 and 24.
Results
For subjects receiving rifabutin and placebo who completed the study (n = 11), there were small but statistically significant differences (≤32%) in several rifabutin and 25‐O‐desacetylrifabutin pharmacokinetic parameters between the regimens of rifabutin alone and rifabutin with placebo. In contrast, the effect of ritonavir on rifabutin pharmacokinetics of subjects completing the study (n = 5) was substantial. Rifabutin mean minimum observed concentration (Cmin), maximum observed concentration (Cmax), and area under the concentration‐time curve [AUC(0–24)] increased by approximately sixfold, 2.5‐fold, and fourfold, respectively, and 25‐O‐desacetylrifabutin mean Cmin, Cmax, and AUC(0–24) increased by approximately 200‐, 16‐, and 35‐fold, respectively, when coadministered with ritonavir compared with rifabutin administered alone. The sum of the mean AUC(0–24) of rifabutin and 25‐O‐desacetylrifabutin increased nearly sevenfold when coadministered with ritonavir.
Conclusions
Ritonavir inhibited the metabolism of rifabutin and 25‐O‐desacetylrifabutin, suggesting that both are metabolized at least in part by CYP3A. Ritonavir may have enhanced rifabutin bioavailability by reducing either intestinal or hepatic metabolism or both. Clarithromycin is an alternative to rifabutin for antimycobacterial therapy that may be administered concurrently with ritonavir. Administration of ritonavir with a reduced rifabutin dosage regimen (150 mg every Monday, Wednesday, and Friday) is being investigated.
Clinical Pharmacology & Therapeutics (1998) 63, 414–421; doi:</abstract><cop>New York, NY</cop><pub>Nature Publishing</pub><pmid>9585795</pmid><doi>10.1016/S0009-9236(98)90036-4</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0009-9236 |
| ispartof | Clinical pharmacology and therapeutics, 1998-04, Vol.63 (4), p.414-421 |
| issn | 0009-9236 1532-6535 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_79868584 |
| source | MEDLINE; Wiley Online Library Journals Frontfile Complete |
| subjects | Adult AIDS/HIV Anti-HIV Agents - administration & dosage Anti-HIV Agents - pharmacology Antibacterial agents Antibiotics, Antitubercular - administration & dosage Antibiotics, Antitubercular - pharmacokinetics Antibiotics. Antiinfectious agents. Antiparasitic agents Aryl Hydrocarbon Hydroxylases Biological and medical sciences Biological Availability Chromatography, High Pressure Liquid Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme System - metabolism Double-Blind Method Drug Administration Schedule Female HIV Protease Inhibitors - administration & dosage HIV Protease Inhibitors - pharmacology Humans Male Medical sciences Oxidoreductases, N-Demethylating - metabolism Pharmacology. Drug treatments Reference Values Rifabutin - administration & dosage Rifabutin - pharmacokinetics Ritonavir - administration & dosage Ritonavir - pharmacology |
| title | The effect of multiple doses of ritonavir on the pharmacokinetics of rifabutin |
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