Abstracts / Toxicology Letters 189S (2009) S57–S273 S57

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Methods in Toxicology

M01Hepatoprotective effects of Polygonum bistorta and active prin-ciples on albino rats intoxicated with carbon tetrachloride andparacetamol

Deepak Mittal

Jiwaji University, Zoology, Gwalior, India

Herbal preparations have been recommended in alternative sys-tems of medicine for the treatment of hepatic disorders. Amongthe various studies involved in hepatotoxic effect of CCl4 (1.5 ml/kg,i.p.) and paracetamol (2 g/kg, p.o.) is oxidative damage through freeradical generation. Drug-induced hepatotoxicity is still a signifi-cant unresolved clinical problem as liver is the most common siteof damage. Polygonum bistorta is powerful astringent, demulcent,diuretic, febrifuge, laxative, strongly styptic and rich in tannins.No systematic study has been done on protective efficacy of P.bistorta (PB) and its active principles tannic acid (TA) and resver-atrol to treat hepatic diseases. The goal of the present work isto evaluate and compare the efficacy of root extract of P. bistorta(100 mg/kg), tannic acid (25 mg/kg, p.o.) and resveratrol (30 mg/kg,p.o.) against toxicants induced damage in liver and kidney. Theactivities of transaminases, alkaline phosphatase and protein wereincreased in serum after 48 h days of toxicants administration. Asignificant rise was observed in lipid peroxidation level, however,reduced glutathione content was decreased. A concomitant fall wasobserved in the enzymatic activities of adenosine triphosphatase,glucose-6-phosphatase. Administration of PB and TA and resvera-trol significantly brought the values of studied parameters towardsnormal and also reversed the histopathological alterations in liverand kidney. Thus, it may be concluded that P. bistorta and tannicacid can be used to reduce the hepatorenal damage and may serveas an alternative medicine. Thus it may be concluded that tannicacid (25 mg/kg) were found more effective values towards control.

Keywords: CCl4; Polygonum bistorta, Tannic acid; Serum transami-nases; Comet assay

doi:10.1016/j.toxlet.2009.06.291

M02Sensitivity of telemetry to predict QT interval prolongation indog toxicity studies: Assessment of effects of moxifloxacin byinvasive and non-invasive methods

Matthias Festag ∗, Andrea Greiter-Wilke, Georg Schmitt, HenryHolzgrefe, Alexander Breidenbach, Thomas Weiser

F. Hoffmann-La Roche, Non-Clinical Drug Safety, Basel, Switzerland

ECG assessment in repeat-dose toxicity studies offers impor-tant information that complements cardiovascular studies usinginvasive telemetry. However, the acquisition of conscious ECGsemploying physical restraint may transiently alter the fundamentalelectrophysiology of the subject, resulting in potentially misleadingresults.

Therefore, a variety of non-invasive jacketed telemetry systemsfor use in freely moving animals are available. The purpose ofthis study was to compare the sensitivity to detect moxifloxacin-

mediated (MOX) QT prolongation in two groups of dogs equippedwith either EMKA jacket (n = 5) or ITS invasive telemetric system(n = 6). QT was corrected for the effects of heart rate employing Vande Waters’ correction (QTcV for the EMKA system), or the proba-bilistic method (QTca for ITS data). All dogs received vehicle andMOX (30 mg/kg, p.o.) and continuous L-II ECGs were obtained. Tomimic the design of a toxicity study, ECGs were measured in EMKAdogs at pretest and for 6 h postdose. Dogs instrumented with ITStelemetry implants (Konigsberg) (three male, three female) weredosed in a crossover design (vehicle and MOX) and ECGs wereacquired for 20 h. Plasma MOX levels were measured 4 h postdoseto confirm exposure and were comparable in both studies (approx-imately 5.9 ± 0.6 �g/ml). MOX maximally increased QTcV by 28 ms(threshold for significance 18 ms; p ≤ 0.05) and QTca by 33 ms(threshold for significance 8 ms; p ≤ 0.05). These data demonstratethat while the sensitivity to detect significant QT prolongation wasslightly lower with the EMKA jacket system, both systems detecteda qualitatively similar response to MOX.

Thus, the EMKA jacket system is a sensitive method to detectQT prolongation which may provide high quality ECG signals inrepeat-dose toxicity studies while avoiding the confounding effectsof restraint.

doi:10.1016/j.toxlet.2009.06.292

M03Approach to predicting the human abuse liability using Condi-tioned Place Preference (CPP) method in rats

Izuru Miyawaki ∗, Juki Kimura, Hitoshi Funabashi, Takaki Seki

Dainippon Sumitomo Pharma Co., Ltd., Safety Research Laboratories,Osaka, Japan

The psycho-dependency of drugs is evaluated mostly using non-human primates in non-clinical safety studies. Recently, rodentsare being recommended for use in drug dependence studies fromthe standpoint of animal rights, and thereby the rodent study needsfurther improvement in prediction for human abuse liability. In thistime, we evaluated the abuse liability of addicted drugs using theCPP method by analyzing the data with new various aspects: I. opti-cal dose range, II. intensity, III. acquirement, IV. individual variation,V. duration, and VI. ambulation.

The drugs used in the study were morphine (MOR), metham-phetamine (MAP) and diazepam (DZP). The CPP apparatusconsisted of a shuttle-box that was divided into black/whitecompartments. For conditioning, rats were confined to any onecompartment following drug or vehicle injection alternately. Forthe test, rats were allowed for free access to both compartments,and time spent in each compartment was measured. CPP scoresrepresent the time difference between both compartments (drugand vehicle sides).

All the drugs used in this study showed an evident reward-ing effect. MOR and MAP widely abused for generations showedrobust rewarding effect and small individual differences commonly.On the other hand, DZP mostly abused in cases of long-term usefor patients or medical participants showed slow acquirement andweak rewarding effects.

Such that, the results obtained in this study mimicked someparts of abuse features in human, and thus suggested the CPPmethod could be useful to predict the abuse liability by examiningthe data carefully in various aspects.

doi:10.1016/j.toxlet.2009.06.293