In vivo induction of interferon gamma expression in grey horses with metastatic melanoma resulting from direct injection of plasmid DNA coding for equine interleukin 12.

Whole blood pharmacokinetics of intratumourally injected naked plasmid DNA coding for equine Interleukin 12 (IL-12) was assessed as a means of in vivo gene transfer in the treatment of melanoma in grey horses. The expression of induced interferon gamma (IFN-g) was evaluated in order to determine the pharmacodynamic properties of in vivo gene transduction. Seven grey horses bearing melanoma were injected intratumourally with 250 µg naked plasmid DNA coding for IL-12. Peripheral blood and biopsies from the injection site were taken at 13 time points until day 14 post injection (p.i.). Samples were analysed using quantitative real-time PCR. Plasmid DNA was quantified in blood samples and mRNA expression for IFN-g in tissue samples. Plasmid DNA showed fast elimination kinetics with more than 99 % of the plasmid disappearing within 36 hours. IFN-g expression increased quickly after IL-12 plasmid injection, but varied between individual horses. Intratumoural injection of plasmid DNA is a feasible method for inducing transgene expression in vivo. Biological activity of the transgene IL-12 was confirmed by measuring expression of IFN-g.

[Effect of the class IA anti-arrhythmic agents ajmaline on end-systolic pressure-volume relations (conductance technique)]. / Einfluss des Klasse-IA-Antiarrhythmikums Ajmalin auf die endsystolische Druck-Volumen-Beziehung (Conductance-Technik).

To evaluate cardiodepressive risks of antiarrhythmic treatment with ajmaline, we monitored, in addition to conventional hemodynamic parameters, end systolic pressure-volume relations (ESPVR) to assess potential negative inotropic effects. Twelve patients (CAD without ischemia; EF = 60 +/- 3%) underwent hemodynamic analysis with and without the influence of ajmaline (1 mg/kg, i.v.) both 1) at rest (paced heart rate of 90 bpm) and 2) during tachycardia of 160 bpm. As a result, LV-pump function was found to have diminished moderately: EF by 23% vs 10%, respectively; stroke volume by 10% vs 0%; cardiac work by 5% vs 16%, and dP/dtmax by 14% vs 19%. While preload increased under the influence of ajmaline (LVEDP by 17% vs 30%), the LV-volumes increased (EDV by 18% vs 12%; ESV by 58% vs 21%), afterload remained unchanged. Ajmaline caused the loops of the ESPVR to move rightward and the slope k of the ESPVR to decrease, thus indicating loss of inotropy during the influence of the antiarrhythmic agent. Thus, ajmaline showed a tendency to generate cardiodepressive effects in patients with normal LV-function, and to depress contractility in single cases that clinically had no consequences. The conductance technique proved useful and safe in the assessment of inotropic drug effects by analyzing the ESPVR within the catheterization laboratory routine.

Enoximone: true inotropic effects? Do they cause ischemia? Analysis of end-systolic pressure-volume relations using the conductance (volume) catheter technique.

True positive inotropy of enoximone is hard to prove clinically. It could increase the risk of myocardial ischemia when used in coronary artery disease (CAD). The analysis of the end-systolic pressure-volume relationship (ESPVR) as a load-independent parameter of the contractile left ventricular function (LVF) allows for differentiation of enoximone's unloading effects. Therefore, we analyzed ESPVR and LVF in 12 of 18 CAD patients before and after enoximone, 0.75 mg/kg intravenously. The slope k increased (seven patients) and loops of the ESPVR (12 patients) moved leftward with the enoximone an average of 32% and downward 19%, in the diastolic portion. The delta percent changes in enoximone versus control (18 patients) indicated an improved LVF via load changes: LV filling pressure fell by 50% and end-systolic volume by 28%, while dp/dt max rose by 25%, LV work by 10%, and ejection fraction by 11%. Lastly, the pacing-induced myocardial ischemia threshold increased from an average of 58 +/- 18 sec to 89 +/- 12 sec after eximone, while ischemic postpacing LV filling pressure and ST-segment changes normalized under the drug's influence. Thus, enoximone improved LVF, both by unloading and by true positive inotropy. Lack of enoximone-induced angina and an increased anginal threshold indicate that the drug can be used safely in CAD patients as well.

Do class 1 antiarrhythmic drugs impair myocardial contractility? The class 1A example of ajmaline (conductance catheter technique).

Antiarrhythmic drug effects may include cardiodepression. This risk is theoretically well recognized but clinically rather poorly defined. To evaluate the risks of ajmaline treatment, we monitored hemodynamic parameters and end-systolic pressure-volume relations (ES-PVR) to evaluate potential negative inotropic effects. Twelve patients (nonischemic CAD) underwent hemodynamic analysis with and without the influence of ajmaline, 1 mg/kg i.v., both (a) at rest (paced constant heart rate of 90 beats/min) and (b) during tachycardia of 160 beats/min. With ajmaline, LV pump function was found to have diminished moderately; ejection fraction by 23 and 10%, stroke volume by 10 and 0%, cardiac work by 5 and 16%, and dP/dtmax by 14 and 19%, respectively. While preload increased under the influence of ajmaline (LVEDP by 17 and 30%, respectively), the LV volumes increased (EDV by 18 and 12%, and ESV by 58 and 21%, respectively), and afterload remained unchanged. Ajmaline caused the loops of the ESPVR to move rightward and the slope k to decrease, thus indicating loss of inotropy under the influence of the antiarrhythmic agent. In essence, ajmaline's negative inotropic components were defined by the conductance technique, but they failed to induce clinically relevant cardiodepression in the above NYHA class II patients. This technique proved to be sensitive, useful, and safe in the assessment of inotropic effects by analyzing the ESPVR within the routine of the catheterization laboratory.