The combined administration of daniplestim and mpl ligand augments the hematopoietic reconstitution observed with single cytokine administration in a nonhuman primate model of myelosuppression
This study evaluated the ability of daniplestim, a high affinity interleukin 3 receptor agonist, to enhance the hematopoietic response of Mpl ligand (Mpl‐L) administration in nonhuman primates following severe, radiation‐induced myelosuppression. Rhesus monkeys were total body x‐irradiated (TBI) to...
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| creator | Farese, Ann M. Macvittie, Thomas J. Lind, Lisa B. Smith, Walter G. Mckearn, John P. |
| description | This study evaluated the ability of daniplestim, a high affinity interleukin 3 receptor agonist, to enhance the hematopoietic response of Mpl ligand (Mpl‐L) administration in nonhuman primates following severe, radiation‐induced myelosuppression. Rhesus monkeys were total body x‐irradiated (TBI) to 600 cGy, midline tissue dose. Beginning on day 1 post‐TBI, animals were s. c. administered daniplestim (100 μg/kg bid; n = 4), Mpl‐L (10 μg/kg qd; n = 3), daniplestim (100 μg/kg bid) plus Mpl‐L (10 μg/kg qd) (n = 4) or 0.1% autologous serum (AS) (n = 11) for 18 days. CBCs were monitored for 60 d after TBI. The duration of thrombocytopenia (platelet count; PLT |
| doi_str_mv | 10.1002/stem.5530160717 |
| format | Article |
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Rhesus monkeys were total body x‐irradiated (TBI) to 600 cGy, midline tissue dose. Beginning on day 1 post‐TBI, animals were s. c. administered daniplestim (100 μg/kg bid; n = 4), Mpl‐L (10 μg/kg qd; n = 3), daniplestim (100 μg/kg bid) plus Mpl‐L (10 μg/kg qd) (n = 4) or 0.1% autologous serum (AS) (n = 11) for 18 days. CBCs were monitored for 60 d after TBI. The duration of thrombocytopenia (platelet count; PLT <20,000/μl) was significantly decreased by the administration of daniplestim (6.5 d, p =.01), Mpl‐L (3.0 d, p =.003) and the coadministered daniplestim/Mpl‐L (1.3 d, p =.001) compared to controls (10.4 d). As monotherapy Mpl‐L but not daniplestim significantly improved the PLT nadir (21,000/μl, p =.023 and 5,000/μl, p =.266, respectively) compared to the control (3,000/μl). The combined administration of daniplestim and Mpl‐L significantly improved the PLT nadir (28,000/μl, p =.007) compared to both the control cohort (3,000/μl) and the daniplestim only cohort (5,000/μl, p =.043). Recovery of PLT to preirradiation values occurred earlier in the daniplestim only (d 21) or the daniplestim/Mpl‐L cohorts (d 18) than in the Mpl‐L only or control cohorts (d 28, d 29, respectively). The administration of daniplestim or Mpl‐L alone neither shortened the duration of neutropenia (ANC<500/μl) compared to the controls (15.8 d, 16.0 d versus 16.2 d, respectively), nor improved the recovery time of neutrophils to baseline values (d 22, d 25, and d 23, respectively). The ANC nadir was significantly improved by daniplestim alone but not Mpl‐L administration (76/μl, p =.001 and 50/μl, p =.093, respectively) compared to the controls (8/μl). Coadministration of daniplestim and Mpl‐L significantly improved the ANC nadir (196/μl, p =.001) compared to either the AS‐ or the monotherapy‐treated cohorts. Also the duration of neutropenia observed in the As‐controls (16.2 d) was significantly reduced in the daniplestim/Mpl‐L cohort (10.8 d, p =.002). The combined administration of daniplestim and Mpl‐L significantly improved hematopoietic recovery and further enhanced the stimulatory effect of cytokine monotherapy, as well as reducing clinical support requirements after radiation‐induced bone marrow myelosuppression.</description><identifier>ISSN: 1066-5099</identifier><identifier>EISSN: 1549-4918</identifier><identifier>DOI: 10.1002/stem.5530160717</identifier><identifier>PMID: 11012186</identifier><language>eng</language><publisher>Bristol: John Wiley & Sons, Ltd</publisher><subject>Animals ; Anti-Bacterial Agents - pharmacology ; Blood Transfusion ; Bone Marrow - drug effects ; Bone Marrow - metabolism ; Bone Marrow - radiation effects ; Cricetinae ; Cytokines - metabolism ; Cytokines - pharmacology ; Daniplestim ; Disease Models, Animal ; Drug Combinations ; Drug Interactions - physiology ; Hematopoiesis - drug effects ; Hematopoiesis - physiology ; Hematopoiesis - radiation effects ; Immunosuppression - methods ; Interleukin-3 ; Macaca mulatta ; Male ; Mpl‐L ; Myelosuppression ; Neutropenia - drug therapy ; Neutropenia - physiopathology ; Peptide Fragments ; Peptides - pharmacology ; Primate ; Radiation ; Recovery of Function - drug effects ; Recovery of Function - physiology ; Thrombocytopenia ; Thrombocytopenia - drug therapy ; Thrombocytopenia - physiopathology ; Thrombopoietin - metabolism ; Thrombopoietin - pharmacokinetics ; Time Factors</subject><ispartof>Stem cells (Dayton, Ohio), 1998, Vol.16 (S1), p.143-154</ispartof><rights>Copyright © 1998 AlphaMed Press</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3017-ccd2cd5c339552aaf44d75cb9ec3501cb31880dec1a67bed9559fbfd7aa5f2f23</citedby><cites>FETCH-LOGICAL-c3017-ccd2cd5c339552aaf44d75cb9ec3501cb31880dec1a67bed9559fbfd7aa5f2f23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,4010,27900,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11012186$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Farese, Ann M.</creatorcontrib><creatorcontrib>Macvittie, Thomas J.</creatorcontrib><creatorcontrib>Lind, Lisa B.</creatorcontrib><creatorcontrib>Smith, Walter G.</creatorcontrib><creatorcontrib>Mckearn, John P.</creatorcontrib><title>The combined administration of daniplestim and mpl ligand augments the hematopoietic reconstitution observed with single cytokine administration in a nonhuman primate model of myelosuppression</title><title>Stem cells (Dayton, Ohio)</title><addtitle>Stem Cells</addtitle><description>This study evaluated the ability of daniplestim, a high affinity interleukin 3 receptor agonist, to enhance the hematopoietic response of Mpl ligand (Mpl‐L) administration in nonhuman primates following severe, radiation‐induced myelosuppression. Rhesus monkeys were total body x‐irradiated (TBI) to 600 cGy, midline tissue dose. Beginning on day 1 post‐TBI, animals were s. c. administered daniplestim (100 μg/kg bid; n = 4), Mpl‐L (10 μg/kg qd; n = 3), daniplestim (100 μg/kg bid) plus Mpl‐L (10 μg/kg qd) (n = 4) or 0.1% autologous serum (AS) (n = 11) for 18 days. CBCs were monitored for 60 d after TBI. The duration of thrombocytopenia (platelet count; PLT <20,000/μl) was significantly decreased by the administration of daniplestim (6.5 d, p =.01), Mpl‐L (3.0 d, p =.003) and the coadministered daniplestim/Mpl‐L (1.3 d, p =.001) compared to controls (10.4 d). As monotherapy Mpl‐L but not daniplestim significantly improved the PLT nadir (21,000/μl, p =.023 and 5,000/μl, p =.266, respectively) compared to the control (3,000/μl). The combined administration of daniplestim and Mpl‐L significantly improved the PLT nadir (28,000/μl, p =.007) compared to both the control cohort (3,000/μl) and the daniplestim only cohort (5,000/μl, p =.043). Recovery of PLT to preirradiation values occurred earlier in the daniplestim only (d 21) or the daniplestim/Mpl‐L cohorts (d 18) than in the Mpl‐L only or control cohorts (d 28, d 29, respectively). The administration of daniplestim or Mpl‐L alone neither shortened the duration of neutropenia (ANC<500/μl) compared to the controls (15.8 d, 16.0 d versus 16.2 d, respectively), nor improved the recovery time of neutrophils to baseline values (d 22, d 25, and d 23, respectively). The ANC nadir was significantly improved by daniplestim alone but not Mpl‐L administration (76/μl, p =.001 and 50/μl, p =.093, respectively) compared to the controls (8/μl). Coadministration of daniplestim and Mpl‐L significantly improved the ANC nadir (196/μl, p =.001) compared to either the AS‐ or the monotherapy‐treated cohorts. Also the duration of neutropenia observed in the As‐controls (16.2 d) was significantly reduced in the daniplestim/Mpl‐L cohort (10.8 d, p =.002). The combined administration of daniplestim and Mpl‐L significantly improved hematopoietic recovery and further enhanced the stimulatory effect of cytokine monotherapy, as well as reducing clinical support requirements after radiation‐induced bone marrow myelosuppression.</description><subject>Animals</subject><subject>Anti-Bacterial Agents - pharmacology</subject><subject>Blood Transfusion</subject><subject>Bone Marrow - drug effects</subject><subject>Bone Marrow - metabolism</subject><subject>Bone Marrow - radiation effects</subject><subject>Cricetinae</subject><subject>Cytokines - metabolism</subject><subject>Cytokines - pharmacology</subject><subject>Daniplestim</subject><subject>Disease Models, Animal</subject><subject>Drug Combinations</subject><subject>Drug Interactions - physiology</subject><subject>Hematopoiesis - drug effects</subject><subject>Hematopoiesis - physiology</subject><subject>Hematopoiesis - radiation effects</subject><subject>Immunosuppression - methods</subject><subject>Interleukin-3</subject><subject>Macaca mulatta</subject><subject>Male</subject><subject>Mpl‐L</subject><subject>Myelosuppression</subject><subject>Neutropenia - drug therapy</subject><subject>Neutropenia - physiopathology</subject><subject>Peptide Fragments</subject><subject>Peptides - pharmacology</subject><subject>Primate</subject><subject>Radiation</subject><subject>Recovery of Function - drug effects</subject><subject>Recovery of Function - physiology</subject><subject>Thrombocytopenia</subject><subject>Thrombocytopenia - drug therapy</subject><subject>Thrombocytopenia - physiopathology</subject><subject>Thrombopoietin - metabolism</subject><subject>Thrombopoietin - pharmacokinetics</subject><subject>Time Factors</subject><issn>1066-5099</issn><issn>1549-4918</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1998</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1OwzAQhC0EolA4c0N-gbR2EudHnFDFn1TEgXKOHHvTGmI7ih2qvh2PhksrFXHhtHuY-Wa1g9AVJRNKSDx1HvSEsYTQjOQ0P0JnlKVllJa0OA47ybKIkbIcoXPn3gmhKSuKUzSilNCYFtkZ-lqsAAura2VAYi61Msr5nntlDbYNltyorgXnlcbcSKy7FrdquV35sNRgvMM-IFagubedVeCVwD0Ia4LHDztO7aD_DPy18ivslFm2IXTj7UdI_RuqDObYWLMaNDe461UAA9ZWQrs9SG-gtW7ouh6cC_oLdNLw1sHlfo7R2_3dYvYYzV8enma380iE5-SREDIWkokkKRmLOW_SVOZM1CWIhBEq6oQWBZEgKM_yGmRQlU3dyJxz1sRNnIzRdMcVvXWuh6b6Oa3fVJRU2y6qbRfVoYvguN45uqHWIA_6_fOD4GYnWKsWNv_xqtfF3fMv_DcZfJ-Z</recordid><startdate>1998</startdate><enddate>1998</enddate><creator>Farese, Ann M.</creator><creator>Macvittie, Thomas J.</creator><creator>Lind, Lisa B.</creator><creator>Smith, Walter G.</creator><creator>Mckearn, John P.</creator><general>John Wiley & Sons, Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>1998</creationdate><title>The combined administration of daniplestim and mpl ligand augments the hematopoietic reconstitution observed with single cytokine administration in a nonhuman primate model of myelosuppression</title><author>Farese, Ann M. ; Macvittie, Thomas J. ; Lind, Lisa B. ; Smith, Walter G. ; Mckearn, John P.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3017-ccd2cd5c339552aaf44d75cb9ec3501cb31880dec1a67bed9559fbfd7aa5f2f23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1998</creationdate><topic>Animals</topic><topic>Anti-Bacterial Agents - pharmacology</topic><topic>Blood Transfusion</topic><topic>Bone Marrow - drug effects</topic><topic>Bone Marrow - metabolism</topic><topic>Bone Marrow - radiation effects</topic><topic>Cricetinae</topic><topic>Cytokines - metabolism</topic><topic>Cytokines - pharmacology</topic><topic>Daniplestim</topic><topic>Disease Models, Animal</topic><topic>Drug Combinations</topic><topic>Drug Interactions - physiology</topic><topic>Hematopoiesis - drug effects</topic><topic>Hematopoiesis - physiology</topic><topic>Hematopoiesis - radiation effects</topic><topic>Immunosuppression - methods</topic><topic>Interleukin-3</topic><topic>Macaca mulatta</topic><topic>Male</topic><topic>Mpl‐L</topic><topic>Myelosuppression</topic><topic>Neutropenia - drug therapy</topic><topic>Neutropenia - physiopathology</topic><topic>Peptide Fragments</topic><topic>Peptides - pharmacology</topic><topic>Primate</topic><topic>Radiation</topic><topic>Recovery of Function - drug effects</topic><topic>Recovery of Function - physiology</topic><topic>Thrombocytopenia</topic><topic>Thrombocytopenia - drug therapy</topic><topic>Thrombocytopenia - physiopathology</topic><topic>Thrombopoietin - metabolism</topic><topic>Thrombopoietin - pharmacokinetics</topic><topic>Time Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Farese, Ann M.</creatorcontrib><creatorcontrib>Macvittie, Thomas J.</creatorcontrib><creatorcontrib>Lind, Lisa B.</creatorcontrib><creatorcontrib>Smith, Walter G.</creatorcontrib><creatorcontrib>Mckearn, John P.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Stem cells (Dayton, Ohio)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Farese, Ann M.</au><au>Macvittie, Thomas J.</au><au>Lind, Lisa B.</au><au>Smith, Walter G.</au><au>Mckearn, John P.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The combined administration of daniplestim and mpl ligand augments the hematopoietic reconstitution observed with single cytokine administration in a nonhuman primate model of myelosuppression</atitle><jtitle>Stem cells (Dayton, Ohio)</jtitle><addtitle>Stem Cells</addtitle><date>1998</date><risdate>1998</risdate><volume>16</volume><issue>S1</issue><spage>143</spage><epage>154</epage><pages>143-154</pages><issn>1066-5099</issn><eissn>1549-4918</eissn><abstract>This study evaluated the ability of daniplestim, a high affinity interleukin 3 receptor agonist, to enhance the hematopoietic response of Mpl ligand (Mpl‐L) administration in nonhuman primates following severe, radiation‐induced myelosuppression. Rhesus monkeys were total body x‐irradiated (TBI) to 600 cGy, midline tissue dose. Beginning on day 1 post‐TBI, animals were s. c. administered daniplestim (100 μg/kg bid; n = 4), Mpl‐L (10 μg/kg qd; n = 3), daniplestim (100 μg/kg bid) plus Mpl‐L (10 μg/kg qd) (n = 4) or 0.1% autologous serum (AS) (n = 11) for 18 days. CBCs were monitored for 60 d after TBI. The duration of thrombocytopenia (platelet count; PLT <20,000/μl) was significantly decreased by the administration of daniplestim (6.5 d, p =.01), Mpl‐L (3.0 d, p =.003) and the coadministered daniplestim/Mpl‐L (1.3 d, p =.001) compared to controls (10.4 d). As monotherapy Mpl‐L but not daniplestim significantly improved the PLT nadir (21,000/μl, p =.023 and 5,000/μl, p =.266, respectively) compared to the control (3,000/μl). The combined administration of daniplestim and Mpl‐L significantly improved the PLT nadir (28,000/μl, p =.007) compared to both the control cohort (3,000/μl) and the daniplestim only cohort (5,000/μl, p =.043). Recovery of PLT to preirradiation values occurred earlier in the daniplestim only (d 21) or the daniplestim/Mpl‐L cohorts (d 18) than in the Mpl‐L only or control cohorts (d 28, d 29, respectively). The administration of daniplestim or Mpl‐L alone neither shortened the duration of neutropenia (ANC<500/μl) compared to the controls (15.8 d, 16.0 d versus 16.2 d, respectively), nor improved the recovery time of neutrophils to baseline values (d 22, d 25, and d 23, respectively). The ANC nadir was significantly improved by daniplestim alone but not Mpl‐L administration (76/μl, p =.001 and 50/μl, p =.093, respectively) compared to the controls (8/μl). Coadministration of daniplestim and Mpl‐L significantly improved the ANC nadir (196/μl, p =.001) compared to either the AS‐ or the monotherapy‐treated cohorts. Also the duration of neutropenia observed in the As‐controls (16.2 d) was significantly reduced in the daniplestim/Mpl‐L cohort (10.8 d, p =.002). The combined administration of daniplestim and Mpl‐L significantly improved hematopoietic recovery and further enhanced the stimulatory effect of cytokine monotherapy, as well as reducing clinical support requirements after radiation‐induced bone marrow myelosuppression.</abstract><cop>Bristol</cop><pub>John Wiley & Sons, Ltd</pub><pmid>11012186</pmid><doi>10.1002/stem.5530160717</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1066-5099 |
| ispartof | Stem cells (Dayton, Ohio), 1998, Vol.16 (S1), p.143-154 |
| issn | 1066-5099 1549-4918 |
| language | eng |
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| source | MEDLINE; Alma/SFX Local Collection; EZB Electronic Journals Library; Oxford Journals |
| subjects | Animals Anti-Bacterial Agents - pharmacology Blood Transfusion Bone Marrow - drug effects Bone Marrow - metabolism Bone Marrow - radiation effects Cricetinae Cytokines - metabolism Cytokines - pharmacology Daniplestim Disease Models, Animal Drug Combinations Drug Interactions - physiology Hematopoiesis - drug effects Hematopoiesis - physiology Hematopoiesis - radiation effects Immunosuppression - methods Interleukin-3 Macaca mulatta Male Mpl‐L Myelosuppression Neutropenia - drug therapy Neutropenia - physiopathology Peptide Fragments Peptides - pharmacology Primate Radiation Recovery of Function - drug effects Recovery of Function - physiology Thrombocytopenia Thrombocytopenia - drug therapy Thrombocytopenia - physiopathology Thrombopoietin - metabolism Thrombopoietin - pharmacokinetics Time Factors |
| title | The combined administration of daniplestim and mpl ligand augments the hematopoietic reconstitution observed with single cytokine administration in a nonhuman primate model of myelosuppression |
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