Differential effects of thioridazine enantiomers on action potential duration in rabbit papillary muscle

Jensen, Ask Schou; Pennisi, Cristian Pablo; Sevcencu, Cristian; Christensen, Jørn B.; Kristiansen, Jette E.; Struijk, Johannes

doi:10.1016/j.ejphar.2014.11.015

Cited by 8 publications

(10 citation statements)

References 31 publications

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“…We have just recently published a study showing that the combined loading of DCX + TDZ into a polymer hybrid silicone catheter material increased the antibacterial efficiency, although release analyses revealed that this effect was caused by a change in loading kinetics and an enhanced loading capacity of DCX facilitated by the presence of TDZ [23]. Moreover, the purified (-) enantiomer of TDZ, also patented under the name JEK47, apparently exhibits a more favourable toxic profile than its racemate, while maintaining the same antibacterial activity [43]. JEK47 is a promising agent, although in vivo evidence of its combined activity with DCX is still lacking.…”

Section: Discussionmentioning

confidence: 99%

Systemic thioridazine in combination with dicloxacillin against early aortic graft infections caused by Staphylococcus aureus in a porcine model: In vivo results do not reproduce the in vitro synergistic activity

et al. 2017

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IntroductionConservative treatment solutions against aortic prosthetic vascular graft infection (APVGI) for inoperable patients are limited. The combination of antibiotics with antibacterial helper compounds, such as the neuroleptic drug thioridazine (TDZ), should be explored.AimTo investigate the efficacy of conservative systemic treatment with dicloxacillin (DCX) in combination with TDZ (DCX+TDZ), compared to DCX alone, against early APVGI caused by methicillin-sensitive Staphylococcus aureus (MSSA) in a porcine model.MethodsThe synergism of DCX+TDZ against MSSA was initially assessed in vitro by viability assay. Thereafter, thirty-two pigs had polyester grafts implanted in the infrarenal aorta, followed by inoculation with 106 CFU of MSSA, and were randomly administered oral systemic treatment with either 1) DCX or 2) DCX+TDZ. Treatment was initiated one week postoperatively and continued for a further 21 days. Weight, temperature, and blood samples were collected at predefined intervals. By termination, bacterial quantities from the graft surface, graft material, and perigraft tissue were obtained.ResultsDespite in vitro synergism, the porcine experiment revealed no statistical differences for bacteriological endpoints between the two treatment groups, and none of the treatments eradicated the APVGI. Accordingly, the mixed model analyses of weight, temperature, and blood samples revealed no statistical differences.ConclusionConservative systemic treatment with DCX+TDZ did not reproduce in vitro results against APVGI caused by MSSA in this porcine model. However, unexpected severe adverse effects related to the planned dose of TDZ required a considerable reduction to the administered dose of TDZ, which may have compromised the results.

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Section: Discussionmentioning

confidence: 99%

Systemic thioridazine in combination with dicloxacillin against early aortic graft infections caused by Staphylococcus aureus in a porcine model: In vivo results do not reproduce the in vitro synergistic activity

et al. 2017

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“…Data collection was previously described in detail [2]. APs were recorded in right ventricular papillary muscles isolated from 21 female New Zealand white rabbits.…”

Section: Methodsmentioning

confidence: 99%

Adaptation of rabbit ventricular cell model to reproduce action potentials in isolated papillary muscle

Jensen

Pennisi

Sevcencu

et al. 2015

2015 Computing in Cardiology Conference (CinC)

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IntroductionThe isolated papillary muscle is a standard preparation for investigation of drug induced effects on the ventricular AP. To facilitate model based analysis of mechanisms underlying drug effects in this preparation, we adapted the rabbit ventricular AP model published by Shannon et al.[1] to reproduce parameters of our baseline transmembrane AP recordings. The adapted model will be applied in future investigation of drug effects. Methods and materialsData collection was previously described in detail [2]. APs were recorded in right ventricular papillary muscles isolated from 21 female New Zealand white rabbits. For all rabbits, APs were recorded at baseline without any drugs at pacing rates of 0.5 and 2.0 Hz. Sequences of baseline recordings were obtained from approximately eight different cells from each rabbit, and a median AP was calculated for each cell. We used a current MatLab implementation of the Shannon rabbit ventricular AP model published online. Adaptation of the model was done by changes in the maximal current conductance of membrane currents. The major transmembrane currents investigated were: the fast inward sodium current (INa), the rapid and slow components of the delayed rectifier potassium current (I Kr , I Ks ), the fast and slow components of the transient outward potassium current (I tof , I tos ), the inward rectifier potassium current (I K1 ), the L-type calcium current (I CaL ), the sodium-potassium pump (I NaK ), and the sodium-calcium exchanger (I NaCa ). Baseline adaptationThe default model AP displayed longer APD 90 and greater amplitude compared to experiment. The mean and 95 % confidence interval of measured AP amplitude (defined as the maximal value of the upstroke) was 21.4 ± 2.5 mV and 23.8 ± 2.4 mV at 2.0 and 0.5 Hz pacing respectively. The default model AP amplitude was 42.7 mV and 43.7 mV. Before adaptation to APD, the model AP amplitude was reduced by reduction in INa current conductance determined by minimization of the error between model and measured AP amplitude.The mean and 95 % confidence interval of measured APD 90 was 113.9 ± 11.2 ms and 150.2 ± 13.1 ms at 2.0 and 0.5 Hz pacing respectively. The model APD 90 was 190 ms and 221.5 ms and was adapted to experiment by reduction of the I CaL , I NaK , and I NaCa currents by multiplication of the current conductances with an identical factor to minimize the error between model and measured APD 90 across both frequencies. This approach was based in part on the results of the sensitivity analysis as described in the discussion. ISSN 2325-8861Computing in Cardiology 2015; 42:429-432.

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“…Data collection was previously described in detail [1]. APs were recorded in right ventricular papillary muscles isolated from 21 female New Zealand white rabbits.…”

Section: Methodsmentioning

confidence: 99%

“…Investigation into the effects of the thioridazine (+)-and (-)-enantiomers on the isolated rabbit papillary APD showed that (+)-thioridazine and the racemate cause greater APD prolongation than (-)-thioridazine [1]. In order to further analyze possible mechanisms underlying the effects of these drugs, a mathematical model of the rabbit ventricular AP [2] was adapted to reproduce baseline APs [3].…”

Section: Introductionmentioning

confidence: 99%

Model-based analysis of the effects of thioridazine enantiomers on the rabbit papillary action potential

Jensen

Pennisi

Sevcencu

et al. 2015

2015 Computing in Cardiology Conference (CinC)

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Aims: We investigated mechanisms underlying the effects of the thioridazine enantiomers on the rabbit papillary action potential duration (AP, APD).Methods: An adapted computational model of the rabbit ventricular action potential was used to carry out a model-based analysis of transmembrane AP recordings from isolated right ventricular papillary muscles from 21 rabbits in four groups: control, (-)-thioridazine, (+)-thioridazine, and racemate. Drug effects were determined using an inverse method and a forward method. Effects were modeled by inhibition of the IKr and I CaL currents.Results: Simultaneous inhibition of I Kr and I CaL resulted in a more accurate description of the observed drug effects than could I Kr inhibition alone. The following values of I Kr inhibition at 10 mg L -1 were determined. Forward method: Racemate = 45%, (-)-thioridazine = 0%, and (+)-thioridazine = 85%. Inverse method: (-)-thioridazine = 35%, (+)-thioridazine = 80%.Conclusion: I Kr inhibition accurately described the observed APD prolongation, and the identified levels of I Kr inhibition were plausible when compared to literature. Both methods found (-)-thioridazine to cause less I Kr inhibition than (+)-thioridazine or the racemate. These results indicate that the prolonging effects observed in the experiment may be related to I Kr inhibition.

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Differential effects of thioridazine enantiomers on action potential duration in rabbit papillary muscle

Cited by 8 publications

References 31 publications

Systemic thioridazine in combination with dicloxacillin against early aortic graft infections caused by Staphylococcus aureus in a porcine model: In vivo results do not reproduce the in vitro synergistic activity

Systemic thioridazine in combination with dicloxacillin against early aortic graft infections caused by Staphylococcus aureus in a porcine model: In vivo results do not reproduce the in vitro synergistic activity

Adaptation of rabbit ventricular cell model to reproduce action potentials in isolated papillary muscle

Model-based analysis of the effects of thioridazine enantiomers on the rabbit papillary action potential

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