Pharmacokinetics and Pharmacodynamics of 15-Deoxyspergualin in a Canine Renal Allograft Model of Local Immunosuppression

Local immunosuppression is based on the rationale that one can simultaneously prevent rejection and reduce systemic side effects by administering appropriately chosen immunosuppressive agents directly into the allograft. We utilized a mongrel canine renal transplant model with a programmable, implan...

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Veröffentlicht in:The Journal of surgical research 1997-08, Vol.71 (2), p.137-144
Hauptverfasser: Gruber, Scott A., Hughes, Stephen E., Xiao, Shengguang, Perera, Sardha, Jayasankar, Vasant, Rosario, Arthur Del, Singh, Jaswant
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container_end_page 144
container_issue 2
container_start_page 137
container_title The Journal of surgical research
container_volume 71
creator Gruber, Scott A.
Hughes, Stephen E.
Xiao, Shengguang
Perera, Sardha
Jayasankar, Vasant
Rosario, Arthur Del
Singh, Jaswant
description Local immunosuppression is based on the rationale that one can simultaneously prevent rejection and reduce systemic side effects by administering appropriately chosen immunosuppressive agents directly into the allograft. We utilized a mongrel canine renal transplant model with a programmable, implantable pump/catheter system to estimate the first-pass extraction of 15-deoxyspergualin (DSG) during renal artery infusion and to compare the efficacy and toxicity of continuous intraarterial (ia) versus intravenous (iv) DSG delivery. Six autotransplanted dogs were given DSG by both iv bolus (1 mg/kg) and ia infusion (1.0 mg/kg/d). DSG was administered to allograft recipients by continuous ia infusion at 0.5 (n= 11) and 0.75 (n= 8) mg/kg/day and by continuous iv infusion at 0.5 (n= 12) and 0.75 (n= 6) mg/kg/day. Mean ± SD elimination half-life was 0.6 ± 0.1 hr, and the transplanted kidney removed as much as 55–88% (mean 66%) of locally infused DSG. When compared with untreated controls [mean survival time (MST) = 8 days], low-dose (0.5 mg/kg/day) DSG produced a significant antirejection effect when given ia (MST = 12 days;P= 0.04) but not iv (MST = 9 days;P= 0.09), with equivalent overall mean drug levels during normal renal function. However, two of the four longest-surviving animals in the ia group died from severe systemic toxicity, manifested by anorexia, diarrhea, leukopenia, and sepsis. High-dose (0.75 mg/kg/day) DSG significantly prolonged survival via both local (MST = 12 days;P= 0.04) and systemic (MST = 11 days;P= 0.02) routes, but half of the iv-treated dogs died from, and four of the longer-surviving ia-treated animals manifested signs of, systemic toxicity, with significantly higher mean drug levels in the iv group. DSG significantly suppressed vascular rejection at both doses when administered locally and systemically, dose-dependently affected the severity of tubulointerstitial rejection and graft edema, and was not nephrotoxic. Our autotransplant pharmacokinetic data overestimated the allografted kidney's ability to extract DSG during local infusion of slightly lower, but immunosuppressive, doses, so that death from systemic toxicity was not prevented and a direct survival benefit of ia vs iv therapy was not realized. Local DSG administration might be combined with other immunosuppressants to therapeutic advantage.
doi_str_mv 10.1006/jsre.1997.5156
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We utilized a mongrel canine renal transplant model with a programmable, implantable pump/catheter system to estimate the first-pass extraction of 15-deoxyspergualin (DSG) during renal artery infusion and to compare the efficacy and toxicity of continuous intraarterial (ia) versus intravenous (iv) DSG delivery. Six autotransplanted dogs were given DSG by both iv bolus (1 mg/kg) and ia infusion (1.0 mg/kg/d). DSG was administered to allograft recipients by continuous ia infusion at 0.5 (n= 11) and 0.75 (n= 8) mg/kg/day and by continuous iv infusion at 0.5 (n= 12) and 0.75 (n= 6) mg/kg/day. Mean ± SD elimination half-life was 0.6 ± 0.1 hr, and the transplanted kidney removed as much as 55–88% (mean 66%) of locally infused DSG. When compared with untreated controls [mean survival time (MST) = 8 days], low-dose (0.5 mg/kg/day) DSG produced a significant antirejection effect when given ia (MST = 12 days;P= 0.04) but not iv (MST = 9 days;P= 0.09), with equivalent overall mean drug levels during normal renal function. However, two of the four longest-surviving animals in the ia group died from severe systemic toxicity, manifested by anorexia, diarrhea, leukopenia, and sepsis. High-dose (0.75 mg/kg/day) DSG significantly prolonged survival via both local (MST = 12 days;P= 0.04) and systemic (MST = 11 days;P= 0.02) routes, but half of the iv-treated dogs died from, and four of the longer-surviving ia-treated animals manifested signs of, systemic toxicity, with significantly higher mean drug levels in the iv group. 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We utilized a mongrel canine renal transplant model with a programmable, implantable pump/catheter system to estimate the first-pass extraction of 15-deoxyspergualin (DSG) during renal artery infusion and to compare the efficacy and toxicity of continuous intraarterial (ia) versus intravenous (iv) DSG delivery. Six autotransplanted dogs were given DSG by both iv bolus (1 mg/kg) and ia infusion (1.0 mg/kg/d). DSG was administered to allograft recipients by continuous ia infusion at 0.5 (n= 11) and 0.75 (n= 8) mg/kg/day and by continuous iv infusion at 0.5 (n= 12) and 0.75 (n= 6) mg/kg/day. Mean ± SD elimination half-life was 0.6 ± 0.1 hr, and the transplanted kidney removed as much as 55–88% (mean 66%) of locally infused DSG. When compared with untreated controls [mean survival time (MST) = 8 days], low-dose (0.5 mg/kg/day) DSG produced a significant antirejection effect when given ia (MST = 12 days;P= 0.04) but not iv (MST = 9 days;P= 0.09), with equivalent overall mean drug levels during normal renal function. However, two of the four longest-surviving animals in the ia group died from severe systemic toxicity, manifested by anorexia, diarrhea, leukopenia, and sepsis. High-dose (0.75 mg/kg/day) DSG significantly prolonged survival via both local (MST = 12 days;P= 0.04) and systemic (MST = 11 days;P= 0.02) routes, but half of the iv-treated dogs died from, and four of the longer-surviving ia-treated animals manifested signs of, systemic toxicity, with significantly higher mean drug levels in the iv group. 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Drug treatments</topic><topic>Transplantation, Autologous</topic><topic>Transplantation, Homologous</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gruber, Scott A.</creatorcontrib><creatorcontrib>Hughes, Stephen E.</creatorcontrib><creatorcontrib>Xiao, Shengguang</creatorcontrib><creatorcontrib>Perera, Sardha</creatorcontrib><creatorcontrib>Jayasankar, Vasant</creatorcontrib><creatorcontrib>Rosario, Arthur Del</creatorcontrib><creatorcontrib>Singh, Jaswant</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><jtitle>The Journal of surgical research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gruber, Scott A.</au><au>Hughes, Stephen E.</au><au>Xiao, Shengguang</au><au>Perera, Sardha</au><au>Jayasankar, Vasant</au><au>Rosario, Arthur Del</au><au>Singh, Jaswant</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pharmacokinetics and Pharmacodynamics of 15-Deoxyspergualin in a Canine Renal Allograft Model of Local Immunosuppression</atitle><jtitle>The Journal of surgical research</jtitle><addtitle>J Surg Res</addtitle><date>1997-08-01</date><risdate>1997</risdate><volume>71</volume><issue>2</issue><spage>137</spage><epage>144</epage><pages>137-144</pages><issn>0022-4804</issn><eissn>1095-8673</eissn><coden>JSGRA2</coden><abstract>Local immunosuppression is based on the rationale that one can simultaneously prevent rejection and reduce systemic side effects by administering appropriately chosen immunosuppressive agents directly into the allograft. We utilized a mongrel canine renal transplant model with a programmable, implantable pump/catheter system to estimate the first-pass extraction of 15-deoxyspergualin (DSG) during renal artery infusion and to compare the efficacy and toxicity of continuous intraarterial (ia) versus intravenous (iv) DSG delivery. Six autotransplanted dogs were given DSG by both iv bolus (1 mg/kg) and ia infusion (1.0 mg/kg/d). DSG was administered to allograft recipients by continuous ia infusion at 0.5 (n= 11) and 0.75 (n= 8) mg/kg/day and by continuous iv infusion at 0.5 (n= 12) and 0.75 (n= 6) mg/kg/day. Mean ± SD elimination half-life was 0.6 ± 0.1 hr, and the transplanted kidney removed as much as 55–88% (mean 66%) of locally infused DSG. When compared with untreated controls [mean survival time (MST) = 8 days], low-dose (0.5 mg/kg/day) DSG produced a significant antirejection effect when given ia (MST = 12 days;P= 0.04) but not iv (MST = 9 days;P= 0.09), with equivalent overall mean drug levels during normal renal function. However, two of the four longest-surviving animals in the ia group died from severe systemic toxicity, manifested by anorexia, diarrhea, leukopenia, and sepsis. High-dose (0.75 mg/kg/day) DSG significantly prolonged survival via both local (MST = 12 days;P= 0.04) and systemic (MST = 11 days;P= 0.02) routes, but half of the iv-treated dogs died from, and four of the longer-surviving ia-treated animals manifested signs of, systemic toxicity, with significantly higher mean drug levels in the iv group. DSG significantly suppressed vascular rejection at both doses when administered locally and systemically, dose-dependently affected the severity of tubulointerstitial rejection and graft edema, and was not nephrotoxic. Our autotransplant pharmacokinetic data overestimated the allografted kidney's ability to extract DSG during local infusion of slightly lower, but immunosuppressive, doses, so that death from systemic toxicity was not prevented and a direct survival benefit of ia vs iv therapy was not realized. Local DSG administration might be combined with other immunosuppressants to therapeutic advantage.</abstract><cop>New York, NY</cop><pub>Elsevier Inc</pub><pmid>9299281</pmid><doi>10.1006/jsre.1997.5156</doi><tpages>8</tpages></addata></record>
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subjects Animals
Biological and medical sciences
Dogs
Graft Rejection
Guanidines - pharmacokinetics
Guanidines - pharmacology
Immunomodulators
Immunosuppressive Agents - pharmacokinetics
Kidney - metabolism
Kidney Transplantation
Male
Medical sciences
Pharmacology. Drug treatments
Transplantation, Autologous
Transplantation, Homologous
title Pharmacokinetics and Pharmacodynamics of 15-Deoxyspergualin in a Canine Renal Allograft Model of Local Immunosuppression
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