title: Potential therapeutic role of histatin derivative P-113d in experimental rat models of Pseudomonas aeruginosa sepsis.
abstract: BACKGROUND
  Morbidity and mortality from Pseudomonas aeruginosa sepsis remain high despite the availability of antibiotics to which the microorganism is sensitive.
  
  
  METHODS
  The in vitro activity of histatin derivative P-113d was investigated against Pseudomonas aeruginosa. In addition, its in vivo efficacy was studied in 3 rat models of infection: intraperitoneal injection of 1 mg of P. aeruginosa 10 lipopolysachharide, intraperitoneal injection of 2 x 10(10) cfu of P. aeruginosa ATCC 27853, and intra-abdominal sepsis induced by cecal ligation and puncture. Rats received isotonic sodium chloride solution parenterally (control groups), 1 mg of P-113d/kg of body weight, 1 mg of polymyxin B/kg of body weight, or 20 mg of imipenem/kg of body weight. Main outcomes measured were abdominal exudate and plasma bacterial growth, plasma concentrations of endotoxin and tumor necrosis factor (TNF)- alpha, and lethality.
  
  
  RESULTS
  The in vivo studies showed that all compounds reduced lethality, when compared with results for the control group. Overall, P-113d exhibited a slightly lower antimicrobial activity than did imipenem, even though P-113d achieved a substantial decrease in plasma concentrations of endotoxin and TNF- alpha, compared with the imipenem. No statistically significant differences for antimicrobial and antiendotoxin activities were noted between P-113d and polymyxin B.
  
  
  CONCLUSIONS
  These results provide evidence for double antiendotoxin and antimicrobial activity for P-113d and point to its potential use for the treatment of severe infections.
authors.affiliation: Institute of Infectious Diseases and Public Health, National Institute for Research and Therapy in the Elderly, Universita Politecnica delle Marche, Ancona, Italy.
authors.forename: Oscar
authors.initials: O
authors.lastname: Cirioni
authors.forename: Andrea
authors.initials: A
authors.lastname: Giacometti
authors.forename: Roberto
authors.initials: R
authors.lastname: Ghiselli
authors.forename: Fiorenza
authors.initials: F
authors.lastname: Orlando
authors.forename: Wojciech
authors.initials: W
authors.lastname: Kamysz
authors.forename: Giuseppina
authors.initials: G
authors.lastname: D'Amato
authors.forename: Federico
authors.initials: F
authors.lastname: Mocchegiani
authors.forename: Jerzy
authors.initials: J
authors.lastname: Lukasiak
authors.forename: Carmela
authors.initials: C
authors.lastname: Silvestri
authors.forename: Vittorio
authors.initials: V
authors.lastname: Saba
authors.forename: Giorgio
authors.initials: G
authors.lastname: Scalise
mesh_terms: D034841:Abdominal Cavity / Q000473:pathology; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004731:Endotoxins / Q000097:blood; D054808:Histatins; D015378:Imipenem / Q000008:administration & dosage / Q000627:therapeutic use; D008297:Male; D008826:Microbial Sensitivity Tests; D010949:Plasma / Q000382:microbiology; D011113:Polymyxins / Q000008:administration & dosage / Q000627:therapeutic use; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000254:growth & development; D051381:Rats; D017208:Rats, Wistar; D012471:Salivary Proteins and Peptides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D018805:Sepsis / Q000188:drug therapy / Q000382:microbiology; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D023181:Antimicrobial Cationic Peptides; D004731:Endotoxins; C068075:HTN3 protein, human; D054808:Histatins; C488466:P-113D; D011113:Polymyxins; D012471:Salivary Proteins and Peptides; D014409:Tumor Necrosis Factor-alpha; D015378:Imipenem