Drug monitoring of a case of citalopram overdosage

Selective serotonin reuptake inhibitors are widely prescribed drugs without recognized cardiovascular risk. We report the case of a 54-year-old patient who developed QTc interval prolongation, followed by ventricular fibrillation episodes, 10 hours after admission to the ICU, in the setting of a citalopram overdose. Citalopram plasma values dropped from 5.88 to 0.34?mg/L at 9 days postadmission. The patient was treated by oral activated charcoal, and final outcome was favorable.     

The electro-mechanical window in anaesthetized guinea pigs: a new marker in screening for Torsade de Pointes risk

BACKGROUND AND PURPOSE

QT prolongation is commonly used as a surrogate marker for Torsade de Pointes (TdP) risk of non-cardiovascular drugs. However, use of this indirect marker often leads to misinterpretation of the realistic TdP risk, as tested compounds may cause QT prolongation without evoking TdP in humans. A negative electro-mechanical (E-M) window has recently been proposed as an alternative risk marker for TdP in a canine LQT1 model. Here, we evaluated the E-M window in anaesthetized guinea pigs as a screening marker for TdP in humans.

EXPERIMENTAL APPROACH

The effects of various reference drugs and changes in body temperature on the E-M window were assessed in instrumented guinea pigs. The E-M window was defined as the delay between the duration of the electrical (QT interval) and mechanical (QLVP_end) systole.

KEY RESULTS

Drugs with known TdP liability (quinidine, haloperidol, domperidone, terfenadine, thioridazine and dofetilide), but not those with no TdP risk in humans (salbutamol and diltiazem) consistently decreased the E-M window. Interestingly, drugs with known clinical QT prolongation, but with low risk for TdP (amiodarone, moxifloxacin and ciprofloxacin) did not decrease the E-M window. Furthermore, the E-M window was minimally affected by changes in heart rate or body temperature.

CONCLUSIONS AND IMPLICATIONS

A decreased E-M window was consistently observed with drugs already known to have high TdP risk, but not with drugs with low or no TdP risk. These results suggest that the E-M window in anaesthetized guinea pigs is a risk marker for TdP in humans.     

Modulation of the late sodium current by ATX-II and ranolazine affects the reverse use-dependence and proarrhythmic liability of IKr blockade

BACKGROUND AND PURPOSE

Drug-induced torsades de pointes (TdP) often occurs during bradycardia due to reverse use-dependence. We tested the hypothesis that inhibition or enhancement of late sodium current (I_Na,L) could modulate the drug-induced reverse use-dependence in QT and T_p-e (an index of dispersion of repolarization), and therefore the liability for TdP.

EXPERIMENTAL APPROACH

Arterially perfused rabbit left ventricular wedge preparations were used. Action potentials from the endocardium were recorded simultaneously with a transmural ECG. The effects of Anemonia sulcata toxin (ATX-II) (an I_Na,L enhancer), d,l-sotalol, clarithromycin and ranolazine (an I_Na,L blocker) on rate-dependent changes in QT, T_p-e and proarrhythmic events were tested, either alone or in combination. Rate-dependent QT and T_p-e slopes and TdP score (a combined index of TdP liability) were calculated at control and during drug infusion.

KEY RESULTS

ATX-II (30 nM) and sotalol (300 µM) caused a marked increase in QT and T_p-e intervals, steeper QT-basic cycle length (BCL) and T_p-e-BCL slopes (i.e. reverse use-dependence), and TdP. Addition of ranolazine (15 µM) to ATX-II or sotalol significantly attenuated QT-BCL, T_p-e-BCL slopes and the increased TdP scores. In contrast, clarithromycin (100 µM) moderately prolonged QT and T_p-e without causing R-on-T extrasystole or TdP, but addition of ATX-II (1 nM) to clarithromycin markedly amplified the QT-BCL and T_p-e-BCL slopes and further increased TdP score.

CONCLUSION AND IMPLICATIONS

Modulation of I_Na,L altered drug-induced reverse use-dependence related to QT as well as T_p-e, indicating that inhibition of I_Na,L can markedly reduce the TdP liability of agents that prolong QT intervals.