Furthermore, histological analysis, done at the end of treatment

Furthermore, histological analysis, done at the end of treatment with 1, revealed no evidence of lesions or morphological alterations in the organs and tissues examined. Nevertheless, just after 1 administration, a marked but reversible hypotension was observable, accompanied by a heart rate and cardiac output decrease in the treated compared to the control mice [18]. Several limitations exist in the use of mouse and rat models for the study of cardiotoxic effects in pharmacology, which regard differences in myocardial function compared to the human heart [26]. To better address the

question of cardiac toxicity of 1, more detailed study was conducted in anaesthetised guinea pigs, where application of an Capmatinib in vivo infusion pump Selleckchem Geneticin allowed for a constant rate of drug delivery over a period of up to 1 hour; this method also allowed for repeated administration of 1, with dose escalation, in the same animal over a 3 hour period. At escalating doses of 0.25, 0.5 and 1 mg/kg, each administered to the same guinea pig (n = 3) over a 5 minute period, and with each dose separated by a period of 1 hour (cumulative dose 1.75 mg/kg), there was a

dose-related decrease in heart rate during the course of the experiment (Figure  3a). Significantly, a marked and sustained decrease in the QTcB interval (QT interval corrected for heart rate) was observed at all doses (Figure  3b). Figure 3 Cardiovascular effects of 1. Effect of 1 on Heart Rate mTOR inhibitor (a) and QTcB Interval (b) in the Anaesthetized Guinea Pig Following Escalating Intravenous Doses of 0.25 mg/kg, 0.5 mg/kg and 1.0 mg/kg (Cumulative Dose: 1.75 mg/kg). Sequential doses of 0.25 mg/kg, 0.5 mg/kg and 1.0 mg/kg to each of three guinea pigs. Time interval between doses: 60 minutes. Plots represent mean data from three animals. To investigate the molecular bases of cardio

toxicity, Pregnenolone the agent was tested for its potential to interact with a panel of 54 pharmacological receptors, the majority being human recombinant receptors (Cerep ExpresSProfile screen) (http://​www.​cerep.​fr). At a concentration of 1 μM significant interaction (% inhibition of ligand binding >95%) was demonstrated with the β2 adrenergic receptor (Table  1), and M1, M2 and M3 muscarinic receptors (data not shown); of more concern, compound 1 was also classified as a highly potent inhibitor of the hERG (human Ether-a-go-go Related Gene) tail current when tested in a conventional patch clamp assay (100% inhibiton at 10 μM, Table  1), which can be predictive of possible cardiovascular complications in clinical development [27]. Table 1 On and off target profile of pentacyclic acridinium salts 1, 2 and 3 Compound Off-target effects: cardiac receptor inhibition On-target effects: ligand-quadruplex interaction hERG % inhib. (10 μM) B2 adrenergic % inhib.

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