title: Adenosine A1 receptor antagonist, L-97-1, improves survival and protects the kidney in a rat model of cecal ligation and puncture induced sepsis.
abstract: Previously it was reported that combining antibiotics with L-97-1, an adenosine A1 receptor antagonist, significantly improves survival and blocks acute lung injury induced by Yersinia pestis CO 99 in a rat model of pneumonic plague. In the current studies using a conscious rat model of cecal ligation and puncture (CLP) sepsis, L-97-1 was administered in daily intravenous infusions in combination with antibiotics to simulate the use of L-97-1 as an anti-sepsis therapeutic in the clinical setting. In these studies, when administered at 12 h following CLP, in combination with broad spectrum antibiotics, ceftriaxone and clindamycin, L-97-1 improves 7 day (d) survival [25%, 35%, and 75% for L-97-1 (10 mg/kg/h, 12.5 mg/kg/h, and 15 mg/kg/h, respectively) versus (vs.) 25% for antibiotics alone] in a dose-dependent manner. The addition of L-97-1, 15 mg/kg/h to antibiotics significantly increased 7 d survival following CLP compared to therapy with either antibiotics alone (P=0.002) or L-97-1 at 15 mg/kg/h alone (P<0.001) and was not significantly different than survival in sham CLP animals (Log-rank (Mantel-Cox) test with Bonferroni׳s correction for multiple comparisons). Moreover, in these studies, in combination with antibiotics L-97-1 dose-dependently protects the kidney, significantly improving renal function at 24 h post CLP at 10 mg/kg/h (P<0.001), 12.5 mg/kg/h (P<0.0001), and 15 mg/kg/h (P<0.0001) vs. antibiotics alone (ANOVA followed by Tukey׳s post-hoc test for pair-wise comparisons). The results of these studies support efficacy for L-97-1 as an anti-sepsis therapeutic.
authors.affiliation: Endacea Inc., 2 Davis Drive, P.O. Box 12076, Research Triangle Park, NC 27709-2076, United States. Electronic address: cwilson@endacea.com.
authors.forename: Constance N
authors.initials: CN
authors.lastname: Wilson
authors.affiliation: Endacea Inc., 2 Davis Drive, P.O. Box 12076, Research Triangle Park, NC 27709-2076, United States.
authors.forename: Constance O
authors.initials: CO
authors.lastname: Vance
authors.affiliation: Department of Medicine Brigham and Women׳s Hospital 75 Francis Street, Boston MA 02115, United States.
authors.forename: Melissa G
authors.initials: MG
authors.lastname: Lechner
authors.affiliation: Saint Louis University School of Medicine, St. Louis MO, United States.
authors.forename: George M
authors.initials: GM
authors.lastname: Matuschak
authors.affiliation: Saint Louis University School of Medicine, St. Louis MO, United States.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lechner
mesh_terms: D058916:Adenosine A1 Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001806:Blood Urea Nitrogen; D002432:Cecum / Q000601:surgery; D002443:Ceftriaxone / Q000627:therapeutic use; D002981:Clindamycin / Q000627:therapeutic use; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D007668:Kidney / Q000187:drug effects*; D008026:Ligation; D008297:Male; D010538:Peritonitis / Q000097:blood / Q000188:drug therapy*; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000097:blood / Q000188:drug therapy*
chemical_list: C505457:3-(2-(4-aminophenyl)ethyl)-8-benzyl-7-(2-ethyl(2-hydroxyethyl)aminoethyl)-1-propyl-3,7-dihydropurine-2,6-dione; D058916:Adenosine A1 Receptor Antagonists; D000900:Anti-Bacterial Agents; D016207:Cytokines; D020011:Protective Agents; D011687:Purines; D002981:Clindamycin; D002443:Ceftriaxone
keywords: Adenosine A1 receptor antagonists; Adenosine A1 receptors; Cecal ligation and puncture; L-97-1; Renal protection; Sepsis