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Conference Paper: A randomized, double-blind, placebo-controlled, ascending dose trial of the pharmacokinetics and safety of intravenous infusion of recombinant human plasma gelsolin in acutely ill patients with decreased plasma gelsolin levels

TitleA randomized, double-blind, placebo-controlled, ascending dose trial of the pharmacokinetics and safety of intravenous infusion of recombinant human plasma gelsolin in acutely ill patients with decreased plasma gelsolin levels
Authors
KeywordsMedical sciences
Respiratory diseases
Issue Date2011
PublisherAmerican Thoracic Society. The Journal's web site is located at http://ajrccm.atsjournals.org
Citation
The 2011 International Conference of the American Thoracic Society (ATS 2011), Denver, CO., 13-18 May 2011. In American Journal of Respiratory and Critical Care Medicine, 2011, v. 183 meeting abstracts, A5601 How to Cite?
AbstractRATIONALE: Exposure of cellular actin by acute injury decreases concentrations of gelsolin (GSN), the fourth most abundant plasma protein below its normal levels of 250 ± 50 mg/L. GSN depletion below disease-specific critical levels strongly predicts adverse outcomes such as ARDS, prolonged hospitalization and death, consistent with GSN’s hypothesized physiological function to localize inflammation by binding and inactivating diverse inflammatory mediators. GSN repletion in animal models of acute injury prevents complications including death. METHODS: This is the first human study in which intravenous GSN is administered. Three cohorts of patients with early sepsis defined as a Multiple Organs System Failure (MOSF) Score of 3 or below admitted to or residing in an ICU with GSN levels below 100mg/L determined by ELISA assay were enrolled for a trial of GSN (or placebo) intravenous infusion. Cohort 1 received a 3mg/kg single dose cohort 2 a 6mg/kg single dose and cohort 3 6mg/kg daily for 3 days. A fourth cohort included patients with MOSF of 4 or above and received either placebo or the same dose as Cohort 3. Baseline demographic and clinical data and pre- and post-infusion cytokine profiles and GSN levels were measured. The primary objectives were to determine the safety and pharmacokinetics of GSN infusion in these patients. RESULTS: Twenty-one subjects, 24 male, 4 female, of mean age 70.3 years received GSN and 7 placebos. Whereas placebo had no effect, GSN infusion increased GSN levels above the critical level in all patients in cohorts 1 and 2 (Table 1) and in all but one in cohorts 3 and 4 for 4 -16 hours, depending on dose. Although not statistically significant, cytokine levels changed in a manner consistent with inflammation suppression. Although serious adverse events occurred, including 7 deaths occurring at a median of 16 days (Range 2-56 days) post infusion, the Safety Monitoring Committee determined that they were not related or unlikely to be related to GSN replacement. No subject developed antibodies against GSN measured at 1 and 3 months after infusion. CONCLUSIONS: Recombinant GSN can be safely given to patients with severe sepsis and increase levels above values associated with adverse outcomes. Further evaluation of the therapeutic effect of GSN replacement is warranted.
DescriptionSession - D17: Treatments for Sspsis: anything New? - Mini Symposium
Open Access Journal
Persistent Identifierhttp://hdl.handle.net/10722/165422
ISSN
2015 Impact Factor: 13.118
2015 SCImago Journal Rankings: 5.832

 

DC FieldValueLanguage
dc.contributor.authorChan, WMen_US
dc.contributor.authorLau, LSen_US
dc.contributor.authorKwok, KMen_US
dc.contributor.authorLaw, WLen_US
dc.contributor.authorHo, JCMen_US
dc.contributor.authorChu, KMen_US
dc.contributor.authorPoon, RTPen_US
dc.date.accessioned2012-09-20T08:18:10Z-
dc.date.available2012-09-20T08:18:10Z-
dc.date.issued2011en_US
dc.identifier.citationThe 2011 International Conference of the American Thoracic Society (ATS 2011), Denver, CO., 13-18 May 2011. In American Journal of Respiratory and Critical Care Medicine, 2011, v. 183 meeting abstracts, A5601en_US
dc.identifier.issn1073-449X-
dc.identifier.urihttp://hdl.handle.net/10722/165422-
dc.descriptionSession - D17: Treatments for Sspsis: anything New? - Mini Symposium-
dc.descriptionOpen Access Journal-
dc.description.abstractRATIONALE: Exposure of cellular actin by acute injury decreases concentrations of gelsolin (GSN), the fourth most abundant plasma protein below its normal levels of 250 ± 50 mg/L. GSN depletion below disease-specific critical levels strongly predicts adverse outcomes such as ARDS, prolonged hospitalization and death, consistent with GSN’s hypothesized physiological function to localize inflammation by binding and inactivating diverse inflammatory mediators. GSN repletion in animal models of acute injury prevents complications including death. METHODS: This is the first human study in which intravenous GSN is administered. Three cohorts of patients with early sepsis defined as a Multiple Organs System Failure (MOSF) Score of 3 or below admitted to or residing in an ICU with GSN levels below 100mg/L determined by ELISA assay were enrolled for a trial of GSN (or placebo) intravenous infusion. Cohort 1 received a 3mg/kg single dose cohort 2 a 6mg/kg single dose and cohort 3 6mg/kg daily for 3 days. A fourth cohort included patients with MOSF of 4 or above and received either placebo or the same dose as Cohort 3. Baseline demographic and clinical data and pre- and post-infusion cytokine profiles and GSN levels were measured. The primary objectives were to determine the safety and pharmacokinetics of GSN infusion in these patients. RESULTS: Twenty-one subjects, 24 male, 4 female, of mean age 70.3 years received GSN and 7 placebos. Whereas placebo had no effect, GSN infusion increased GSN levels above the critical level in all patients in cohorts 1 and 2 (Table 1) and in all but one in cohorts 3 and 4 for 4 -16 hours, depending on dose. Although not statistically significant, cytokine levels changed in a manner consistent with inflammation suppression. Although serious adverse events occurred, including 7 deaths occurring at a median of 16 days (Range 2-56 days) post infusion, the Safety Monitoring Committee determined that they were not related or unlikely to be related to GSN replacement. No subject developed antibodies against GSN measured at 1 and 3 months after infusion. CONCLUSIONS: Recombinant GSN can be safely given to patients with severe sepsis and increase levels above values associated with adverse outcomes. Further evaluation of the therapeutic effect of GSN replacement is warranted.-
dc.languageengen_US
dc.publisherAmerican Thoracic Society. The Journal's web site is located at http://ajrccm.atsjournals.org-
dc.relation.ispartofAmerican Journal of Respiratory and Critical Care Medicineen_US
dc.subjectMedical sciences-
dc.subjectRespiratory diseases-
dc.titleA randomized, double-blind, placebo-controlled, ascending dose trial of the pharmacokinetics and safety of intravenous infusion of recombinant human plasma gelsolin in acutely ill patients with decreased plasma gelsolin levelsen_US
dc.typeConference_Paperen_US
dc.identifier.emailChan, WM: drchanwm@hkucc.hku.hken_US
dc.identifier.emailLau, LS: milk820@hkusua.hku.hken_US
dc.identifier.emailKwok, KM: carmenk1@hku.hken_US
dc.identifier.emailLaw, WL: lawwl@hkucc.hku.hken_US
dc.identifier.emailHo, JCM: jhocm@hku.hken_US
dc.identifier.emailChu, KM: chukm@hkucc.hku.hken_US
dc.identifier.emailPoon, RTP: poontp@hku.hk-
dc.identifier.authorityLaw, WL=rp00436en_US
dc.identifier.authorityHo, JCM=rp00258en_US
dc.identifier.authorityChu, KM=rp00435en_US
dc.identifier.authorityPoon, RTP=rp00446en_US
dc.description.naturelink_to_OA_fulltext-
dc.identifier.hkuros190420en_US
dc.identifier.hkuros206186-
dc.identifier.volume183en_US
dc.identifier.issueMeeting abstracts-
dc.publisher.placeUnited States-
dc.description.otherThe 2011 International Conference of the American Thoracic Society (ATS 2011), Denver, CO., 13-18 May 2011. In American Journal of Respiratory and Critical Care Medicine, 2011, v. 183 meeting abstracts, A5601-

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