title: An evaluation of the utility of LVdP/dt40, QA interval, LVdP/dtminand Tau as indicators of drug-induced changes in contractility and lusitropy in dogs.
abstract: BACKGROUND
  The importance of drug-induced effects on the inotropic state of the heart is well known. Unlike hemodynamic and cardiac electrophysiological methods, which have been routinely used in drug safety testing for years, the non-clinical assessment of drug effects on myocardial contractility is used less frequently with no established translation to humans. The goal of these studies was to determine whether assessment of alternate measures of cardiac inotropy could detect drug-induced changes in the contractile state of the heart using drugs known to have clinically relevant positive and negative effects on myocardial contractility. This study also evaluated drug-induced effects on lusitropy (relaxation) parameters of the heart.
  
  
  METHODS
  A double 4×4 Latin square study design using Beagle dogs (n=8) was conducted. Drugs were administrated orally. Arterial blood pressure (BP), left ventricular pressure (LVP) and the electrocardiogram (ECG) were assessed across different laboratories using the same protocol. Each of the six laboratories studied at least 2 drugs (one positive inotrope (pimobendan or amrinone) and one negative inotrope (itraconazole or atenolol) at 3 doses selected to match clinical exposure data and a vehicle control). Animals were instrumented with an ITS telemetry system or DSI's D70-PCTP or PhysioTel™ Digital system. The data acquisition and analysis systems used were Ponemah, Notocord or EMKA.
  
  
  RESULTS
  The derived inotropic and lusitropic parameters evaluated included peak systolic and end diastolic LVP, LVdP/dtmax, LVdP/dt40, QA interval, LVdP/dtminand Tau. This study showed that LVdP/dt40provided essentially identical results to LVdP/dtmaxqualifying it as an index to assess drug effects on cardiac contractility. LVdP/dt40provided an essentially identical assessment to that of LVdP/dtmax. The QA interval did not react sensitively to the drugs tested in this study; however, it did detect large effects and could be useful in early cardiovascular safety studies. The lusitropic parameter, LVdP/dtmin, was modestly decreased, and Tau was increased, by atenolol and itraconazole. At the doses tested, amrinone and pimobendan produced no changes in LVdP/dtminwhile Tau was modestly increased. The drugs did not produce effects on BP, HR or the ECG at the doses tested. Blood samples were drawn to confirm drug exposures predicted from independent pharmacokinetic studies.
  
  
  CONCLUSIONS
  These findings indicate that this experimental model can accurately and consistently detect changes in cardiac contractility, across multiple sites and instrumentation systems. While LVdP/dt40produced responses similar to LVdP/dtmax, the QA interval and lusitropic parameters LVdP/dtminand Tau were not markedly changed at the dose of drugs tested. Further studies with drugs that affect early diastolic relaxation through calcium handling are needed to better evaluate drug-induced changes on lusitropic properties of the heart.
authors.affiliation: Purdue Pharma, LP, Cranbury, NJ, United States.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Pugsley
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: Brian
authors.initials: B
authors.lastname: Guth
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, United States.
authors.forename: Alan Y
authors.initials: AY
authors.lastname: Chiang
authors.affiliation: Data Sciences International, St. Paul, MN, United States.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Doyle
authors.affiliation: Amgen, Thousand Oaks, CA, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Engwall
authors.affiliation: Sanofi, Vitry sur Seine, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Guillon
authors.affiliation: Novartis, East Hanover, NJ, United States.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Hoffmann
authors.affiliation: FDA, Washington, DC, United States.
authors.forename: John E
authors.initials: JE
authors.lastname: Koerner
authors.affiliation: AbbVie, Abbott Park, IL, United States.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Mittelstadt
authors.affiliation: HESI, Washington, DC, United States.
authors.forename: Jennifer Beck
authors.initials: JB
authors.lastname: Pierson
authors.affiliation: GlaxoSmithKline, King of Prussia, PA, United States.
authors.forename: Eric I
authors.initials: EI
authors.lastname: Rossman
authors.affiliation: Independent, Rhinelander, WI, United States.
authors.forename: Dustan R
authors.initials: DR
authors.lastname: Sarazan
authors.affiliation: HESI, Washington, DC, United States. Electronic address: sparish@hesiglobal.org.
authors.forename: Stanley T
authors.initials: ST
authors.lastname: Parish
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology*; D006439:Hemodynamics / Q000502:physiology; D017964:Itraconazole / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology*; D016875:tau Proteins / Q000097:blood*
chemical_list: D002316:Cardiotonic Agents; D016875:tau Proteins; D017964:Itraconazole
keywords: Amrinone; Arterial blood pressure; Atenolol; Beagle dog; Cardiac Relaxation; Contractility; Heart rate; Itraconazole; Left ventricular dP/dt; Lusitropy; Myocardial; Pimobendan; QA interval; Super-interval; Tau