M. Trojnar

Inflammatory activation following interruption of long-term cardiac resynchronization therapy

Previous observations suggest that cardiac resynchronization therapy (CRT) may exert an anti-inflammatory effect. The objective of this study was to evaluate the effect of temporary interruption of long-term CRT on plasma concentrations of proinflammatory cytokines and brain natriuretic peptide (BNP). The study group consisted of 54 patients (32 male and 22 female, mean age 64 years) with chronic heart failure (HF) treated with CRT. BNP, high-sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), and neopterin were measured three times: after 26–28 weeks of continuous CRT (CRT-on), 48 h after its cessation (CRT-off), and 48 h after switching the CRT-on again. CRT interruption resulted in a significant worsening of left ventricular systolic function: reduction of cardiac output (CO), dP/dt, and left ventricular ejection fraction (LVEF), as well as deterioration of mitral regurgitation in the CRT responder group. A significant increase in serum concentrations of hs-CRP, neopterin, IL-6, and BNP was noted in this subpopulation. In CRT nonresponders, no significant changes were observed. In responders the changes in serum concentrations of hs-CRP, IL-6, neopterin, and BNP, following CRT interruption, significantly correlated with the respective changes in thoracic fluid content (TFC) and inversely correlated with LVEF changes. Even short (48 h) interruption of long-term CRT led to a significant increase of proinflammatory cytokines and BNP concentrations in responders. The changes in hs-CRP, IL-6, neopterin, and BNP concentrations correlated with the change in TFC-marker of pulmonary congestion and inversely correlated with the change in LVEF.

Interactions of stiripentol with clobazam and valproate in the mouse maximal electroshock-induced seizure model.

The aim of this study was to characterize the anticonvulsant effects of stiripentol (STP) in combination with clobazam [CLB], and valproate [VPA]) in the mouse maximal electroshock (MES)-induced seizure model using the type I isobolographic analysis for parallel and non-parallel dose-response relationship curves (DRRCs). Potential adverse-effect profiles of interactions of STP with CLB and VPA at the fixed-ratio of 1:1 in the MES test with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain antiepileptic drug concentrations. In the mouse MES model, STP administered singly had its DRRC non-parallel to that for CLB and, simultaneously, parallel to that for VPA. With type I isobolography for parallel DRRCs, the combinations of STP with VPA at three fixed-ratios of 1:3, 1:1 and 3:1 exerted sub-additive (antagonistic) interaction. Isobolography for non-parallel DRRCs revealed that the combination of STP with CLB at the fixed-ratio of 1:1 produced additive interaction. For all combinations, neither motor coordination, long-term memory nor muscular strength was affected. Total brain antiepileptic drug concentrations revealed bi-direction changes with the most profound being an 18.6-fold increase in CLB by STP and a 2.3-fold increase in STP by VPA. In conclusion, the additive interaction between STP and CLB was associated with a concurrent pharmacokinetic interaction and these data may explain the clinical efficacy seen with this combination. In contrast, the antagonism between STP and VPA was surprising since synergism is observed clinically.

Effects of amlodipine, diltiazem, and verapamil on the anticonvulsant action of topiramate against maximal electroshock-induced seizures in mice.

To assess the effect of 3 calcium channel antagonists (amlodipine, diltiazem, and verapamil) on the anticonvulsant action of topiramate (a new generation antiepileptic drug) in the mouse maximal electroshock seizure (MES) model. Amlodipine (20 mg/kg) significantly enhanced the anticonvulsant activity of topiramate in the MES test in mice, reducing its ED50 value from 54.83 to 33.10 mg/kg (p < 0.05). Similarly, diltiazem (5 and 10 mg/kg) markedly potentiated the antiseizure action of topiramate against MES, lowering its ED50 value from 54.83 to 32.48 mg/kg (p < 0.05) and 28.68 mg/kg (p < 0.01), respectively. In contrast, lower doses of amlodipine (5 and 10 mg/kg) and diltiazem (2.5 mg/kg) and all doses of verapamil (5, 10, and 20 mg/kg) had no significant impact on the antiseizure action of topiramate. Pharmacokinetic verification of the interaction of topiramate with amlodipine and diltiazem revealed that neither amlodipine nor diltiazem affected total brain topiramate concentration in experimental animals, and thus, the observed interactions were concluded to be pharmacodynamic in nature. The favorable combinations of topiramate with amlodipine or diltiazem deserve more attention from a clinical viewpoint because the enhanced antiseizure action of topiramate was not associated with any pharmacokinetic changes in total brain topiramate concentration.

Stiripentol – characteristic of a new antiepileptic drug

Background: As 20 – 30% of patients are refractory to the presently available antiepileptic drugs, there is a strong need for the development of newer antiepileptics. Objective: A question arises whether stiripentol fulfills the criteria for a promising newer antiepileptic drug. Methods: A literature search, including experimental and clinical studies, with no time limit was performed. Results/conclusion: Stiripentol represents a group of drugs indirectly enhancing GABA-ergic neurotransmission and it exerts a protective activity in some experimental seizure models, including maximal electroshock (MES)-, pentylenetetrazol-, bicuculline-, strychnine-, and cocaine-induced convulsions. The drug potently inhibits metabolism of other antiepileptic drugs, significantly elevating their plasma and brain concentrations. This requires dosage adjustments of the concomitant antiepileptic drugs used in combination. In the form of an add-on therapy, stiripentol has proved to be effective in partial and atypical absence epilepsies. Considering its particular efficacy against severe myoclonic seizures in infancy (Dravets syndrome), stiripentol has been awarded an orphan drug status for an adjunctive therapy of this difficult-to-treat condition.

Double thrombolysis in early pregnancy can be safe

We describe the case of pregnant patient with diagnosed massive pulmonary embolism, who underwent successful double thrombolysis. A 23-year-old woman in the 7th week of her 3rd pregnancy was admitted to the Intensive Cardiac Care Unit 2 h after sudden onset of chest pain and dyspnoea. An immediate electrocardiography showed sinus tachycardia with typical S1Q3T3 pattern and rsr’ complex in lead V1. Transthoracic echocardiography on admission revealed right ventricular strain. We performed emergent computed tomography angiography of the chest, which showed significant thrombus in both pulmonary arteries, resulting in restricted blood flow. The patient was treated with unfractionated heparin infusion, monitored by activated partial thromboplastin time. Because of her deteriorating condition, we administered alteplase (10 mg bolus, then 90 mg over the next 2 h). Ultrasonography examination of her pelvis and lower extremities revealed spindle-shaped thrombus of the right common iliac and external iliac veins. On her 10th day of hospitalisation, during the patient’s mobilisation, she presented with symptoms of shock. She needed endotracheal intubation, mechanical ventilation and vasoconstrictor support. We treated her with a second round of full dose alteplase. No complications further developed for the mother or foetus in the subsequent days. She gave birth to a healthy son weighing 3580 g with Apgar score of 10 points in her 38th week of pregnancy by natural delivery. After delivery we switched low molecular weight heparin to warfarin according to her international normalised ratio. In conclusion, double thrombolysis in early pregnancy proved to be safe for both the mother and child, but additional studies need to be performed.

CRT47: WHAT FACTORS INFLUENCE HEMODYNAMIC IMPROVEMENT AFTER RIGHT VENTRICULAR TO BIVENTRICULAR PACING SYSTEM UPGRADE?

It is still hard to predict hemodynamic effects after biventricular pacing system (BiVp) implantation despite established inclusion criteria for CRT and left ventricular pacing (LVp) techniques. The aim of the study was to find the predictors of acute hemodynamic improvement after right ventricular (RVp) to biventricular pacing system upgrade. Methods: The study group consisted of 69 patients with permanently implanted BiV pacing system with standard CRT criteria. Hemodynamic effect was determined using impedance cardiography (BioZ.com; Cardiodynamics). Cardiac Index (CI) and other indirect parameters were determined during 3 min periods of RV and BiV pacing in turn. Correlations were searched among clinical, echocardiographic, ECG and initial hemodynamic parameters and multivariate analysis was performed as well. Results: Cardiac contractility was higher during BiVp than RVp and LVp: CI (l/min/m2): RVp 2,29* LVp 2,20∧ BiVp 2,56*∧ [*∧ANOVA-LSD p>0,05]. Increase of CI after RV to BiV reprogramming correlated with CI during RVp (r=−0,50 p>0,001), Thoracic Fluid Index (TFI) (r=−0,32 p>0,01) and with difference of CI between RVp vs LVp (r=0,57 p>0,001) and LVp vs BiVp (r= 0,30 p>0,05). Values of CI during LVp, BiVp, echocardiographic parameters, NYHA class, RVp-, LVp-, BiVp- QRS durations and axis, and their changes did not correlated with differences of CI during RVp and BiVp. Multivariate analysis showed that only CI during RVp and RVp vs LVp CI difference determined acute hemodynamic effect of BiVp in comparison to RVp. Conclusions: Increase of CI after RVp to BiVp upgrade depends mainly on cardiac performance during right ventricular pacing and its improvement caused by change from RVp to single site LVp.