title: Pharmacokinetic characterization of intravenous cyclosporine treatment for cardioprotection during resuscitation of asphyxiated newborn piglets.
abstract: OBJECTIVE
  Cyclosporine treatment, as a single intravenous bolus, during resuscitation has been shown to attenuate myocardial injury in asphyxiated newborn piglets. However, the pharmacokinetics of cyclosporine treatment for cardioprotection in newborns has not been studied. We aimed to assess the pharmacokinetics of a single intravenous cyclosporine treatment during resuscitation of asphyxiated newborn piglets and compare these parameters with healthy newborn piglets.
  
  
  METHODS
  Newborn piglets were acutely instrumented and normocapnic alveolar hypoxia was induced for 2 hours followed by 4 hours of reoxygenation. Piglets were block-randomized to receive a single intravenous bolus of cyclosporine (2.5-25 mg/kg) (n = 8 per group). Eight piglets underwent no hypoxia-reoxygenation and received 10 mg/kg cyclosporine at the corresponding time point. Plasma cyclosporine and troponin concentrations during reoxygenation period were determined by high-pressure liquid chromatography and enzyme-linked immunosorbent assay, respectively. Noncompartmental methods were used to calculate the pharmacokinetic parameters. Cyclosporine concentrations and pharmacokinetic parameters were analyzed by one-way analysis of variance.
  
  
  METHODS
  University animal laboratory.
  
  
  METHODS
  Piglets (1-4 days old, weighing 1.4-2.5 kg).
  
  
  METHODS
  Intravenous cyclosporine (2.5, 10, or 25 mg/kg) given during resuscitation.
  
  
  RESULTS
  In the hypoxic-reoxygenated piglets, the plasma AUC(0-4 hrs) and C(max) of cyclosporine at reoxygenation were in the following rank order: 25 > 10 > 2.5 mg/kg treatment (p < 0.001 between groups, analysis of variance). Plasma AUC(0-4 hrs) and C(max) in piglets treated with cyclosporine at 25 mg/kg was associated with increased plasma troponin levels, a marker of myocardial injury, relative to piglets treated with 2.5 and 10 mg/kg. Asphyxiated newborn piglets had higher clearance and lower AUC(0-∞), but similar AUC(0-4 hrs), steady-state volume of distribution, and mean residence time compared with those of healthy newborn piglets.
  
  
  CONCLUSIONS
  This is the first study to demonstrate the pharmacokinetics of intravenous cyclosporine treatment during resuscitation of asphyxiated newborn piglets, which did not appear to different from that of healthy piglets.
authors: Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
authors: Richdeep S
authors: RS
authors: Gill
authors: Dion R
authors: DR
authors: Brocks
authors: Thomas
authors: T
authors: Churchill
authors: Tze-Fun
authors: TF
authors: Lee
authors: David L
authors: DL
authors: Bigam
authors: Po-Yin
authors: PY
authors: Cheung
mesh_terms: D000818:Animals; D001237:Asphyxia / Q000628:therapy*; D015415:Biomarkers / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004797:Enzyme-Linked Immunosorbent Assay; D007275:Injections, Intravenous; D015428:Myocardial Reperfusion Injury / Q000097:blood / Q000175:diagnosis / Q000209:etiology / Q000517:prevention & control*; D020011:Protective Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011897:Random Allocation; D012151:Resuscitation / Q000009:adverse effects*; D016037:Single-Blind Method; D013552:Swine; D016896:Treatment Outcome; D014336:Troponin / Q000097:blood
chemical_list: D015415:Biomarkers; D020011:Protective Agents; D014336:Troponin; D016572:Cyclosporine