The Fentanyl/Etomidate‐Anesthetized Beagle (FEAB) Model in Safety Pharmacology Assessment

Henk J. van der Linde1, Bruno Van Deuren1, Yves Somers1, Ard Teisman1, David J. Gallacher1

1 Center of Excellence for Cardiovascular Safety Research & Mechanistic Pharmacology, Janssen Pharmaceutical Research & Development, A Division of Janssen Pharmaceutica NV, Pharmaceutical Companies of Johnson & Johnson, Beerse, Belgium
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 10.13
DOI:  10.1002/0471141755.ph1013s54
Online Posting Date:  September, 2011
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This unit describes a procedure for performing safety studies in the anesthetized beagle dog. Detailed are the anesthetic regime, the surgical procedure, and all materials needed to perform cardiovascular, central nervous system, and respiratory safety studies in these animals. An overview of all parameters that can be measured and calculated is provided, as are experimental protocols. Endpoints discussed include hemodynamic, electrocardiological, respiratory, arterial blood, and electroencephalogical parameters. Also presented are a formula to correct QT interval for changes in core body temperature and an overview of changes in ECG, MAP, and EEG traces that may occur during safety studies. The information provided yields a multiparametric model for performing reliable safety studies in anesthetized dogs. Curr. Protoc. Pharmacol. 54:10.13.1‐10.13.21. © 2011 by John Wiley & Sons, Inc.

Keywords: model; dog; anesthesia; safety pharmacology; fentanyl; etomidate; cardiovascular; respiratory; CNS

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Table of Contents

  • Commentary
  • Literature Cited
  • Figures
  • Tables
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Basic Protocol 1:

  • Anesthetics and solutions:
    • Fentanyl (0.25 mg/ml; Janssen Pharmaceuticals)
    • Lofentanil (0.3 mg/ml; Janssen Pharmaceuticals)
    • Etomidate (12.5 mg/ml; Janssen Pharmaceuticals)
    • Succinylcholine (50 mg/ml; Lysthenon 5%, Nycomed)
    • Scopolamine (0.063 mg/ml; Alcon Laboratories )
    • Heparin solution (250 IU/ml in saline; LEO Pharma)
    • Dextran 5%‐glucose 2.5% solution in saline 0.9% (prepared fresh; Acros Organics)
  • Beagle dogs, male and/or female, 10 to 15 kg (CEDS Les Souches)
  • Experimental room (Fig. )
  • 10‐ml syringes
  • Homeothermic blanket (circulating water mattress)
  • Laryngoscope (Medicon)
  • Intubation tube with internal diameter (i.d.) of 8.5 mm (FR34, Kruuse)
  • Respirator (Servo ventilator 900C, Siemens)
  • Electric shaver
  • Electro‐cutter‐coagulator (Erbotom ACC450, Erbe)
  • EEG module (Narcotrend, MonitorTechnik)
  • Surgical instruments including:
    • Scissors
    • Forceps
    • Clamps
  • Swan‐Ganz catheter with micro manometer tip (standard 131HF7, Edwards Life Sciences, adapted by Millar Instruments)
  • Blood sampling catheter: 7F open lumen (USCI)
  • Injection catheters: 8F and 7F open lumen catheters (USCI)
  • Micro manometer‐tip catheter (MTC800, Dräger or Gaeltec)
  • Micro manometer‐tip catheter with pig tail (Gaeltec)
  • Flow head (e.g., 4719 series; Hans Rudolph)
  • Steerable monophasic action potential catheter (Boston Scientific‐EP Technologies or Hugo Sachs Elektronik)
  • Fluoroscope (Siremobil2000, Siemens)
  • Syringe pump
  • Data acquisition software and hardware:
    • ECG module (EMKA)
    • Signal amplifiers (8 channel DBA18, Anerma)
    • Blood flow measurement equipment (T206, Transonic Systems)
    • Cardiac output module: in‐house developed thermodilution method; this module calculates cardiac output from the temperature measured in the pulmonary artery after a 5 ml injection of a glucose solution into the right atrium at ambient temperature (the cardiac output is calculated according to the Steward‐Hamilton formula; see Muir et al., )
    • Data acquisition software (HEM 3.5, Notocord)
    • Blood gas analyzer (ABL700; Radiometer)
    • Computer
    • Microsoft Excel
  • Temperature regulatory supplies:
    • Fan (Atlas200, Soler & Palau SA/NV)
    • Ice pack (CHD Götzl)
    • Heating plate (circulating water mattress)
    • Heating lamp for animals (Gebr. Schneider)
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Literature Cited

   Antzelevitch, C. 2001. Transmural dispersion of repolarization and the T wave. Cardiovasc. Res. 50:426–431.
   Champeroux, P., Ouillé, A., Martel, E., Sinclair, J., Fowler, L., Maurin, A., Jude, S., Lala, P., Le Guennec, J‐Y., and Richard, S. 2010. Interferences of the autonomic nervous system with drug induced QT prolongation: A point to consider in non‐clinical safety studies. J. Pharmacol. Toxicol. Methods 61:251‐263.
   Easter, A., Bell, M.E., Damewood, J.R., Redfern, W.S., Valentin, J‐P., Winter, M.J., Fonck, C., and Al Bialecki, R. 2009. Approaches to seizure risk assessment in preclinical drug discovery. Drug Disc. Today 14:876‐884.
   Franz, M.R. 1991. Method and theory of monophasic action potential recording. Progr. Cardiovasc. Dis. 6:347‐368.
   Gallacher, D.J., Van de Water, A., van der Linde, H.J., Hermans, A.N., Lu, H.R., Towart, R., and Volders, P.G.A. 2007. In vivo mechanisms precipitating torsade de pointes in canine model of drug‐induced long QT1 syndrome. Cardiovasc. Res. 76:247‐256.
   Ganz, W., Donoso, R., Marcus, H.S., Forrester, J.S., and Swan, H.J.C. 1971. A new technique for measurement of cardiac output by thermodilution in man. Am. J. Cardiol. 27:392‐396.
   Guth, B.D. 2007. Preclinical cardiovascular risk assessment in modern drug development. Toxicological Sci. 97:4‐20.
   King, A., Bailie, M., and Olivier, N.B. 2006. Magnitude of error introduced by application of heart rate correction formulas to the canine QT interval. Ann. Noninvasive Electrocardiol. 11:289‐298.
   Kreuer, S., Bruhn, J., Buchinger, H., Larsen, R., and Wilhelm, W. 2005. Dose‐response relationship between sevoflurane concentrations and Narcotrend index. Anesthesiology 103:A823.
   Kreuer, S. and Wilhelm, W. 2006. The Narcotrend monitor. Best Practice Res. Clin. Anaesthesiol. 20:111‐119.
   Kumar, S.S., Joshi, B., and Sharma, S.S. 2007. CNS safety pharmacology: International guidelines and methods. Curr. Res. Inform. Pharmaceut. Sci. 8:2‐5.
   Muir, W.W., Skarda, R.T., and Milne, D.W. 1976. Estimation of cardiac output in the horse by thermodilution techniques. Am. J. Vet. Res. 37:697‐703.
   Porsolt, R.D., Picard, S., and Lacroix, P. 2005. International safety pharmacology guidelines (ICH S7A and S7B): Where do we go from here? Drug Devel. 64:83‐89.
   Pugsley, M.K., Authier, S., and Curtis, M.J. 2008. Principles of safety pharmacology. Br. J. Pharmacol. 154:1382‐1399.
   Towart, R., Linders, J.T.M., Hermans, A.N., Rohrbacher, J., van der Linde, H.J., Ercken, M., Cik, M., Roevens, P., Teisman, A., and Gallacher, D.J., 2009. Blockade of the IKs potassium channel: An overlooked cardiovascular liability in drug safety screening? J. Pharmacol. Toxicol. Methods 60:1‐10.
   van der Linde, H.J., Van de Water, A., Loots, W., Van Deuren, B., Lu, H.R., Van Ammel, K., Peeters, M., and Gallacher, D.J. 2005. A new method to calculate the beat‐to‐beat instability of QT duration in drug‐induced long‐QT in anaesthetised dogs. J. Pharmacol. Toxicol. Methods 52:168‐177.
   van der Linde, H.J., Van Deuren, B., Teisman, A, Towart, R., and Gallacher, D.J. 2008. The effect of changes in core body temperature on the QT interval in beagle dogs: a previously ignored phenomenon, with a method for correction. Br. J. Pharmacol. 154:1474‐1481.
   van der Linde, H.J., Van Deuren, B., Somers, Y., Loenders, B., Towart, R., and Gallacher, D.J. 2010a. The Electro‐Mechanical window: A risk marker for Torsade de Pointes in a canine model of drug induced arrhythmias. Br. J. Pharmacol. 161:1444‐1454.
   van der Linde, H.J., Van Deuren, B., Somers, Y., Teisman, A., Drinkenburg, W.H., and Gallacher, D.J. 2010b. EEG in the FEAB model; measurement of electroencephalographical burst suppression and seizure liability in safety pharmacology. J. Pharmacol. Toxicol. Methods 63:96‐101.
Key References
   Van Deuren, B., Van Ammel, K., Somers, Y., Cools, F. Straetemans, R., van der Linde, H., and Gallacher, D. 2009. The fentanyl/etomidate‐anaesthetised beagle (FEAB) dog: A versatile in vivo model in cardiovascular safety research. J. Pharmacol. Toxicol. Methods 60:11‐23.
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