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doi:10.1016/j.toxlet.2012.03.447

Abstracts / Toxicology L

15: Safety Pharmacology

15-01redictive secondary pharmacology to identify off-targetffects in drug discovery

obias Noeske, Ola Engkvist, Scott Boyer

AstraZeneca, Sweden

Early identification of safety risks in drug discovery and theirolution is critical to avoid project closures at later stages and sec-ndary pharmacology prediction is important in the overall safetyssessment of a lead series. The concept of Predictive Secondaryharmacology (PSP) is a similarity search of a test compoundgainst AstraZenecaı̌s Chemistry Connect (CC) database1 to iden-ify similar compounds and their associated bioactivity data. Thisatabase incorporates standardized internal (AZ) and externalpublications/patents) pharmacology test results.

We assessed the performance of the underlying methods of ourSP implementation by subjecting the GOSTAR2 database, a subsetf CC, to a temporal test. New entries from Feb 2010 edition withultiple activity data served as query molecules and GOSTARı̌s Nov

009 edition comprised known active molecules. We investigatedhe probability of a query molecule to be active on the same tar-et as an active molecule as a function of Tanimoto similarity. Twoolecular fingerprints were tested: ECFI (connectivity fingerprint)

nd FOYFI (path-based fingerprint). ECFI achieved 50% correct pre-ictions in medium to high similarity ranges (random hit rates onselectivity panel of 100 targets do not exceed 5%).

This enables chemists and toxicologists to identify and addressafety risks in an interdisciplinary effort. A specific example includ-ng the identification of off-target pharmacology, identified by PSPnd confirmed through a cascade of in vitro tests will be presented.his study shows how PSP methods can be developed, validatednd put into practice in drug discovery.

oi:10.1016/j.toxlet.2012.03.445

15-02acketed external telemetry in the guinea-pig

bdel-Ilah El Amrani, Anne-Marie Bétat, Stéphane Loriot,ean-jacques Legrand, Roy Forster

CiToxLAB France, France

The guinea-pig is a well-established animal model for thevaluation of QT lengthening. The guinea-pig is routinely useds anesthetised model or as a conscious model using implantedelemetry. Implantation of telemetry devices in guinea-pigsequires surgical intervention that is time-consuming and expen-ive. Therefore, the purpose of the present study was to evaluate aewly established jacketed external telemetry approach in freelyoving guinea-pigs. Female guinea-pigs were equipped with

xternal jacketed telemetry using DSI transmitters and placed inlethysmography chambers allowing simultaneous recording of

CG and respiratory parameters. To evaluate the sensitivity ofhe model, effects of a low dose of sotalol (10 mg/kg) or vehicle0.5% methylcellulose) on ECG were investigated in freely moving

1 Drug Discovery Today 2011, 16, 1019.2 www.gvkbio.com.

211S (2012) S43–S216 S121

guinea-pigs (6 animals per group). In addition, effects of clonidine(5 mg/kg) on respiratory parameters were investigated. Drug treat-ments were performed by the oral route and all parameters wererecorded one hour before and for a minimum of four hours aftertreatment. Although the dose-level of Sotalol used in the presentstudy was low, significant increases in QT and QTb (Bazett’s cor-rection) were observed. When compared to the vehicle, clonidineproduced significant decreases in tidal volume and increases in res-piratory rate. The present study suggests that the jacketed externaltelemetry model in freely moving guinea-pigs can be a valuablescreening tool for the potential risk assessment of new chemicalentities or biologics on cardio-respiratory function during the earlydrug development process.

doi:10.1016/j.toxlet.2012.03.446

P15-03Integrative wireless monitoring for animal wellbeing in safetypharmacology

Didima De Groot 1, Roderick Slieker 2, Pascalle Van Loo 3, ElwinVerheij 3, Helle Lorentsen 4, Morton Laursen 5, Michael Markert 6,Fabien Masse 7, Frank Bouwens 7

1 TNO EELS, Netherlands, 2 Leiden University Medical Center, Leiden,Netherlands, 3 TNO EELS, Zeist, Netherlands, 4 Ellegaard GöttingenMinipigs A/S, Dalmose, Denmark, 5 Lundbeck A/S, Valby, Denmark,6 Boehringer Ingelheim Pharma GmbH & Co K, Germany, 7 HolstCentre/imec, Eindhoven, Netherlands

The applicability of Holst Centre wireless sensor node technol-ogy developed for use on humans is assessed for use on animalsin light of reduction and refinement of animal use for biomed-ical (preclinical) research. The ‘Holst Centre ECG Necklace’ with3D-accelerometer measuring non-invasively ECG, heart rate (HR)and motion/position was applied -for the first time- on minipigas new non-rodent model for safety pharmacology. Unlike pre-implanted devices, no surgery, anaesthesia or analgesia is requiredfor the Holst Centre ECG Necklace. Results were compared withresults of pre-implanted telemetry device (TSI technology). TheHolst Centre ECG Necklace proved to be an accurate and valuableasset for wireless monitoring of ECG/HR and motion/positioningsignals. The obtained results showed the reliability of the systemcompared to the existing technology, yet with a smaller form fac-tor. The ECG sensor node sampled a clear ECG signal and calculatedthe heart rate real-time, which was not influenced by motion arte-facts. In addition, the 3D accelerometer signals were successfullyused in combination with ECG/HR and could exclude ambiguoussignal changes. Its applicability to the minipig appeared very animalfriendly. The sensor node is a stable platform for future extensionand integration of more sensors. This warrants an integrative sys-tem for simultaneous assessment of multiple organ systems, withtime contributing in full extent to animal refinement and reduc-tion, and so, time and costs. Apart from different sensors, other