development of a conscious rabbit telemetry model for chronic monitoring of blood pressure, ecg and...

hyperthermia, increased respiratory rate, and decreased enhancedpause, was globally comparable at the beginning and at the end of the4-month period. In conclusion, when combined telemetry andWBP isused for repeated measurements of cardiovascular and respiratoryparameters, the study should be carefully designed to limit theinfluence of age or stress (inadequate conditioning to the WBPchamber) on the results.

doi:10.1016/j.vascn.2008.05.124

Assessment of cardiovascular parameters in teratology studies

N. Hébert, L. Pouliot, S. Mason (Charles River Laboratories PreclinicalServices, Montreal, Quebec, Canada)

The purpose of this study was to investigate the feasibility ofassessing cardiovascular function, by telemetry in teratology studies.DSI TA11PA-C40 transmitters were implanted subcutaneously in theflank, with catheter placed in the femoral vein, of female rats a weekprior to mating. Cardiovascular measurements of heart rate andsystolic, diastolic, mean and pulse pressures were obtained continu-ously from 2 days before mating through to gestation Day 21, whichincluded periods of continuous intravenous infusion of physiologicalsaline. Continuous monitoring of the heart rate, mean arterialpressure, systolic blood pressure, diastolic blood pressure and pulsepressure during the gestation period revealed apparent decreases insystolic, diastolic, mean and pulse pressures during the later part ofthe gestation period, with no related effects seen in the heart rate.There was no evidence of any adverse effects on the reproductivefunction secondary to the experimental procedures, i.e., surgicalimplantation of a transmitter oneweek before mating, presence of thetransmitter (implanted subcutaneously in the flank region) before andthroughout the gestation period. This study indicates that it is possibleto measure cardiovascular parameters during gestation and that thepresence of telemetry transmitters has no impact on gestation.

doi:10.1016/j.vascn.2008.05.125

Development of a conscious rabbit telemetry model for chronicmonitoring of blood pressure, ECG and temperature

Jan D'Aubioul, E. Van Eynde, F. Cools, J. Verrelst, Y. Somers, A.Vanlommel, S. Janssens, B. Loenders, J. D'Aubioul, D. Gallacher(Johnson & Johnson PRD, Center of Excellence for CardiovascularSafety Research, Turnhoutseweg 30, Beerse, Belgium)

Aim: To meet the demand for a long-term non-rodent, non dogmodel for cardiovascular safety studies, we assessed a new experi-mental model in conscious rabbits using radiotelemetry techniquesfor chronic cardiovascular safety studies on blood pressure and ECG.The rabbit is of particular interest as this species is sensitive to Ikr(hERG) blocking agents in a sex-dependent manner (femalesNmales).Indeed this is a species within which Torsades de Pointes can beinduced relatively easily with certain class III agents. Methods:Different surgical protocols were applied for the implantation of DSIChronic use TL11M2-C50-PXT transmitters in healthy female NewZealand White rabbits. For each method, recovery and survival wereevaluated, as well as the quality of the recordings of heart rate,systolic, diastolic and mean arterial blood pressure, ECG parametersand temperature. Key experimental findings: We optimized the sur-gical procedure to ensure a better recovery and to lengthen the usefullifespan of the instrumented animals. Cannulation of the carotidartery with total occlusion of the artery and positioning of thetransmitter subcutaneous in the neck was found to be the most

practical and least invasive method resulting in the best recovery,lifespan (i.e. reuse of animals for more than one year) and success. Thedevelopment of this model adds the rabbit to the species standardlyused in telemetry research (rat, dog and monkey) and as such addsrelevance to safety analysis on agents for therapeutic targetsexpressed in this species, as well as in man.

doi:10.1016/j.vascn.2008.05.126

Cardiovascular effects of D-sotalol and risperidone after oraladministration in conscious guinea-pigs using telemetry

Anne-Laure Leoni, M. Goubern, S. Hervouet, I. BarR, G. Lande, C.Bellocq, F. Charpentier (LaennecTek-INSERM, Faculte de Medecine,Nantes, Cedex, France)

The objective of this studywas to validate the conscious guinea-pig(GP) model for screening agents for their potential cardiac adverseeffects and improve QT correction formulae used in GP. Five maleHartley GP were implanted with telemetric devices. After a weekrecovery period, a 24-hour recording was performed in order to assessthe best formula to correct QT for the RR interval. The smallest slopesof the regression equation were obtained from the plots of QTc vs. RRinterval with a home-made (LTk) formula (QTcLTk=QT-260[exp(−1.32)−exp(−1.32(RR/250))], RR in ms) as compared to modifiedBazett's and Fridericia's formulae. With D-sotalol, HR was reduceddose-dependently with a maximum reached 60 min post-dose (with100 mg/kg, from 288'13 to 242'8 bpm). QTcLTk intervals increasedfrom 135'2 ms to 153'2 ms after 30 mg/kg and from 134'2 ms to162'5 ms after 100 mg/kg. Risperidone administration at both dosesinduced a severe hypotension. A transient increase in HR (+23%) wasobserved after risperidone at 30 mg/kg, whereas risperidone at100 mg/kg induced a slight HR reduction (−9%). PR interval wasprolonged by +12% (from 58'3 ms to 65'0 ms) after 100 mg/kg. QTcLTkinterval was significantly prolonged by +16% after the highest dose ofrisperidone (from 127'5 ms to 147'4 ms). This study demonstrates thesuitability of this model to assess both cardiac conduction andrepolarisation prolonging potential of a compound but also its abilityto alter blood pressure. In this study, the best-fit formula to correct QTfor RR interval was the LTk formula.

doi:10.1016/j.vascn.2008.05.127

Zebrafish: The future of in vivo safety pharmacology screening

S. Berghmans, T. Barros, Z. Golder, I.Gardner, P. Butler, A.Hill, A. Fleming,W. Alderton, A. Roach (VASTox, Cambridge, UK; VASTox, Abingdon, UK;Pfizer Global Research and Development, Sandwich, UK)

VASTox has developed a series of well validated high throughputautomated liability assays to assess drug safety in vivo at an early stageof drug discovery. The zebrafish is an establishedmodel system for thestudy of human diseases due to numerous advantages includinganatomical, physiological and genetic similarity to man. Zebrafishlarvae tolerate DMSO and require small compound amounts that areeasily absorbed and compounds are dosed in the water in which thelarvae swim. An outstanding issue is to establish compound uptakeand metabolism in zebrafish larvae. We have addressed this questionby undertaking a compound uptake study using 30 compoundscovering a range of physicochemical properties to correlate uptake,potency and adverse effects identified in zebrafish assays. Zebrafishare known to express drug metabolizing enzymes including CYPP450s. We have investigated metabolism by zebrafish larvae LC-MSidentification of metabolites of 3 compounds and showed that both

177Journal of Pharmacological and Toxicological Methods 58 (2008) 147–178