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Corrected QT interval (QTc) prolongation in humans is usually predictable based on results from preclinical findings. This study confirms the signal from preclinical cardiac repolarization models (human ether-a-go-go-related gene, guinea pig monophasic action potential, and dog telemetry) on the clinical effects on the QTc interval. A thorough QT/QTc study is generally required for bioavailable pharmaceutical compounds to determine whether or not a drug shows a QTc effect above a threshold of regulatory interest. However, as demonstrated in this AZD3839 [(S)-1-(2-(difluoromethyl)pyridin-4-yl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine hemifumarate] single-ascending-dose (SAD) study, high-resolution digital electrocardiogram data, in combination with adequate efficacy biomarker and pharmacokinetic data and nonlinear mixed effects modeling, can provide the basis to safely explore the margins to allow for robust modeling of clinical effect versus the electrophysiological risk marker. We also conclude that a carefully conducted SAD study may provide reliable data for effective early strategic decision making ahead of the thorough QT/QTc study., (Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.)

Participants tasted two cups of coffee, decided which they preferred, and then rated each coffee. They were told (in lure) that one of the cups contained "eco-friendly" coffee while the other did not, although the two cups contained identical coffee. In Experiments 1 and 3, but not in Experiment 2, the participants were also told which cup contained which type of coffee before they tasted. The participants preferred the taste of, and were willing to pay more for, the "eco-friendly" coffee, at least those who scored high on a questionnaire on attitudes toward sustainable consumer behavior (Experiment 1). High sustainability consumers were also willing to pay more for "eco-friendly" coffee, even when they were told, after their decision, that they preferred the non-labeled alternative (Experiment 2). Moreover, the eco-label effect does not appear to be a consequence of social desirability, as participants were just as biased when reporting the taste estimates and willingness to pay anonymously (Experiment 3). Eco labels not only promote a willingness to pay more for the product but also lead to a more favorable perceptual experience of it.

Introduction: Anaesthetised guinea pigs are commonly used within Safety Pharmacology to evaluate drug effects on cardiac electrophysiology. However, anesthesia compromises the ability to thermoregulate, which can be further challenged when more invasive surgery is required. As anaesthetised animals are often used when screening for cardiotoxicity, thereby influencing go/no-go decisions, we wanted to quantify the impact of small temperature changes on the recorded electrophysiological parameters., Methods: Male guinea pigs were anaesthetised by pentobarbital, placed on a pre-heated table and a rectal thermistor inserted for monitoring of body temperature. After intubation animals were vagotomised and β-blocked, and lead II ECG needle electrodes attached. Following thoracotomy an atrial pacing electrode was attached and a suction MAP electrode positioned on the ventricular epicardium. In control animals temperature was kept constant (38.1±0.1°C) over the duration of the experiment. Animals in one group were slowly warmed to 41.9°C by a heating plate and a heating lamp, and in another group slowly cooled to 34.4°C by turning off all heating equipment. MAP duration at 90% repolarisation (MAPD90), AV conduction, ECG and body temperature were recorded during cardiac pacing every 5min up to 50min., Results: No time-dependent changes were seen in the control group. In contrast, a linear correlation was found between changes in body temperature and MAPD90, AV conduction, QTc and QRS intervals. For each degree temperature fell below 38°C MAPD90 was prolonged by 6.1ms, and for each degree above 38°C MAPD90 was shortened by 5.3ms. Corresponding changes were seen for QTc interval and AV conduction time, while effects on the QRS interval were smaller., Discussion: The data highlights the importance of carefully controlling body temperature when performing electrophysiological recordings in laboratory animals. A change by a single degree can affect electrophysiological parameters by 5-10%, thus increasing the risk for a false positive or negative interpretation of cardiotoxicity., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Introduction: While the dog in vivo model is commonly employed in the later phase of discovery for assessing drug-induced QT prolongation, an early screening assay is valuable when selecting compounds for further development and when compound availability usually is low. One such screening assay is the anaesthetised guinea pig monophasic action potential (MAP) model. The aim of the present study was to evaluate the ability of this model to detect proarrhythmic properties by testing a set of reference compounds with known clinical profile. Moreover, these results were compared to data previously obtained using in vivo canine QT assays (QT PRODACT study)., Methods: Anaesthetised and ventilated male guinea pigs were vagotomised and pretreated with propranolol. After thoracotomy, a pacing electrode was clipped to the left atrial appendage and a suction MAP electrode positioned on the left ventricular epicardium. The drug or corresponding vehicle was injected intravenously in cumulative doses and MAP duration at 90% repolarisation (MAPD90) was recorded during cardiac pacing., Results: The 8 drugs known to be proarrhythmic in the clinic all displayed dose-dependent prolongation of MAPD90, while the 4 drugs devoid of dysrhythmia in man had no effect. When comparing doses producing a 10% MAPD90 increase with doses reported to increase QTc by 10% in dogs a strong correlation was seen (R(2) 0.94 and 0.58 for anaesthetised and conscious dogs, respectively)., Discussion: The guinea pig MAP assay identified all clinically positive drugs while negative drugs were without effect on ventricular repolarisation. Furthermore, a good concurrence is shown between the guinea pig and dog models in identifying compounds with proarrhythmic properties. Overall, the study reinforces the anaesthetised guinea pig MAP model as a reliable assay predicting QT liability of new chemical entities and as a highly sensitive early screening model for cardiovascular risk.

Possible vasoactive effects on small diameter arteries from the rainbow trout gut of calcitonin gene-related peptide (CGRP-chicken) and different fish tachykinins; substance P (SP-trout), neurokinin A (NKA-trout), scyliorhinin I and II (SCY I and SCY II-dogfish), were investigated. CGRP relaxed precontracted arteries with a pD2 value of 8.3+/-0.2. Relaxation to CGRP 10(-8) M was reduced by 86.4+/-5.2% by the CGRP-1 receptor antagonist CGRP8-37 (10(-6) M), but unaffected by NG-nitro-L-arginine (10(-4) M), indomethacin (10(-6) M) and by removal of the endothelium, suggesting no involvement of nitric oxide, prostaglandins or endothelium-derived factors. A low number of CGRP immunoreactive fibers were present in the arterial wall. The tachykinins (10(-12)-10(-6) M) occasionally contracted the relaxed vessel. No synergistic action of SP on the CGRP-induced response was found. A dense plexus of tachykinin-containing fibers without coexisting CGRP innervated the arterial wall. Tachykinins or CGRP had no effect on small diameter veins, and no such immunoreactivity was found in these vessels. In conclusion, CGRP- and tachykinin-containing fibers innervate trout gut arteries. CGRP probably is vasodilatory, while the function of the tachykinin fibers is unknown.

Small arteries (internal diameter 376 +/- 69 microns) from the proximal intestine region of the rainbow trout were mounted in a myograph apparatus where changes in isometric tension could be recorded. VIP (vasoactive intestinal polypeptide) caused a concentration-dependent relaxation (10(-9)-3 x 10(-7) M) of vessels precontracted with the alpha-adrenoceptor agonist phenylephrine (10(-5) M). The nitric oxide synthase inhibitor L-NAME (10(-4) M) did not affect the VIP-relaxation, neither did the lipoxygenase inhibitor esculetin (10(-5) M). However, the cyclooxygenase inhibitor indomethacin (10(-6) M) shifted the concentration-response curve significantly to the right. The VIP-relaxation was still present after mechanical removal of the endothelium. Sodium nitroprusside (10(-9)-10(-6) M) caused a concentration-dependent relaxation of the precontracted vessel, indicating the presence of soluble guanylate cyclase in the vascular smooth muscle cells. VIP-immunoreactivity was found in varicose nerve fibers in these vessels, but nitric oxide synthase-immunoreactivity could not be demonstrated. These results suggest that in rainbow trout, as in mammals, VIP is an endogenous vasodilating neuropeptide. No endothelium-dependent mechanism seems to be involved, neither is production of nitric oxide. Instead the relaxation is mediated, at least in part, via prostaglandin synthesis.

The role of trout substance P (tSP) and neurokinin A (tNKA) in cardiovascular regulation was investigated in the rainbow trout, Oncorhynchus mykiss, in vivo and in vitro. In vivo, the coeliac arterial and ventral aortic relative blood flows were measured with Doppler flow probes, and blood pressure was measured via a cannula inserted into the dorsal aorta. tSP (0.1 and 1 nmol kg-1) and tNKA (1 nmol kg-1) increased both systemic and coeliac vascular resistances, leading to hypertension and bradycardia. In addition, cardiac output was decreased. The mammalian NK1 tachykinin receptor antagonist CP-96,345 did not affect the responses to tSP or tNKA. In vitro perfusions of the dorsal aortic and coeliacomesenteric vascular beds were performed using peristaltic pumps. The dorsal aortic vascular resistance was dose-dependently increased following infusion of the two peptides (pD2 values 7.6 +/- 0.1 and 7.3 +/- 0.1 for tSP and tNKA, respectively). Tetrodotoxin did not affect the tSP-induced hypertension. Increases in coeliac vascular resistance caused by tSP was correlated with stomach contractions when measurement of intragastric pressure was made using an inserted balloon. In conclusion, native SP and NKA are potent vasoconstrictors of rainbow trout vasculature, a property quite unusual to tachykinins compared with the vasodilation normally seen in mammals.