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Papers by Milou-daniel Drici

Thrombosis Research, 2015

No routine monitoring is required with factor Xa inhibitor rivaroxaban. Yet, its titration must b... more No routine monitoring is required with factor Xa inhibitor rivaroxaban. Yet, its titration must be adapted, and its misuse may lead to increased risk of bleeding; therefore, therapeutic rivaroxaban monitoring might help in specific situations. As asked by clinicians of our medical center, we measured rivaroxaban plasma concentrations in real conditions of use and checked their corresponding prescriptions. Measurement of 112 samples from 94 consecutive patients was performed with a Biophen LRT® anti-Xa chromogenic assay and compared blindly to the HPLC-MSMS "gold standard" method. Rivaroxaban was effectively given to 80 out of 94 patients but a mere 57% through an adequate prescription (within the scope of indications/titration). All chromogenic measurements were over the pre-specified 30ng/ml LOQ, whereas only 98 /114 samples had quantifiable rivaroxaban with HPLC-MSMS (LOQ 1ng/ml). Correlation between the two methods and linear regression were highly significant (p<0.0001). However, chromogenic values (mean 141.6ng/ml[96.6]) overestimated HPLC-MSMS values (119.7ng/ml[79.5]) by 22ng/ml according to Bland-Altman analysis (p<0.001). After re-assessing the chromogenic LOQ at 52ng/ml, 83 quantifiable samples had a mean concentration of 176.9ng/ml as compared to 158.5ng/ml with HPLC-MSMS, with no false positive anymore. In our medical center, rivaroxaban concentrations could be assessed by a rapid chromogenic method. Its pre-specified LOQ proved too high after being checked "on site" against HPLC-MSMS. Prescriptions for rivaroxaban were not optimal. An overestimated LOQ may impair observance monitoring or predispose patients to either risky thrombolysis or otherwise adjournable surgery in clinical practice.

Interactive Cardiovascular and Thoracic Surgery, 2000

A prospective case–control study was designed to confirm the higher plasma concentration of alumi... more A prospective case–control study was designed to confirm the higher plasma concentration of aluminium in primary spontaneous pneumothorax patients recently reported in literature. Ten consecutive patients with PSP entered the study. Comparison with the control group obtained from the database of the Pharmacology Department did not show any significant difference. The conclusion was that in patients with PSP from the

Archives of Cardiovascular Diseases, 2014

Drug and Alcohol Dependence, 2014

Background: Many drugs increase the duration of the QT interval of patients, potentially leading ... more Background: Many drugs increase the duration of the QT interval of patients, potentially leading to harmful effects such as polymorphic ventricular arrhythmias. Most of these drugs do so by inhibiting the rapid component IKr of the delayed rectifier potassium current IK. Methadone is the most prescribed heroin maintenance treatment and is known to inhibit the cardiac potassium channel hERG, which recapitulates IKr. In order to evaluate if any polymorphism of potassium channels' genes could explain some of the "idiosyncratic" QT prolongations observed in patients treated with methadone, we tested the association between KCNE1, KCNE2, and KCNH2 polymorphism and the QT interval prolongation in those patients, controlling for other variables associated with a decrease of the repolarizing reserve. Methods: A cohort of 82 patients treated with stable dosage of methadone (mean dosage 65 mg/d) for at least three months was genotyped for five polymorphisms in KCNE1, KCNE2 and KCNH2 genes and had their corrected QT (QTc) assessed. Results: The mean QTc interval was 415 ± 34 ms. In a linear regression model, longer QTc interval was associated with methadone dosage and with one genetic factor. Each copy of a Lys allele at codon 897 of KCNH2, the gene that encodes the cardiac potassium voltage-gated channel hERG, was associated with a 15.4 ms longer QTc (95% CI [4.6-26.2]; p = 0.001). Conclusion: KCNH2 genotyping may be relevant in the analysis of cumulative risk factors for QT prolongation in patients on methadone maintenance treatment.

Pharmacoepidemiology and Drug Safety, 2007

Atypical antipsychotics are the treatment of choice for patients with schizophrenia. They are gen... more Atypical antipsychotics are the treatment of choice for patients with schizophrenia. They are generally better tolerated than conventional antipsychotics since most do not cause debilitating extrapyramidal symptoms. They are associated though with an array of cardiovascular adverse events that may affect morbid-mortality of schizophrenic patients. Orthostatic hypotension, electrocardiographic changes and metabolic syndrome (MS) are the main cardiovascular effects of atypical antipsychotics. They contribute to the overall disease burden associated with schizophrenia even though the benefit risk of such treatments still is highly favourable.

Journal of Clinical Psychopharmacology, 1998

Some antipsychotic drugs have been found to prolong the QT interval on electrocardiographic (ECG)... more Some antipsychotic drugs have been found to prolong the QT interval on electrocardiographic (ECG) recordings, a phenomenon which, when severe, may facilitate the occurrence of complex ventricular arrhythmias such as torsade de pointes. However, the effects of these drugs on the cardiac repolarization process have not been evaluated extensively. This study was designed to examine the potency of five antipsychotic drugs in lengthening the QT interval of the perfused feline heart: haloperidol, risperidone, sertindole, clozapine, and olanzapine. The hearts were infused with increasing concentrations of drugs (0.1-20 micromol/L) for 40-minute intervals at each concentration. ECG recordings were made, with signals amplified and data recorded on a strip chart recorder. Four representative beats from each set of three signal recordings were chosen for QT interval measurement. Our data indicated that all tested drugs prolonged the QT interval in a concentration-dependent manner (p < 0.01). Haloperidol and risperidone were significantly more potent than sertindole, clozapine, and olanzapine (p < 0.001). At a concentration of 0.5 micromol/L over a 40-minute infusion interval, haloperidol lengthened the interval by 26.2+/-0.7%, risperidone by 19.4+/-2.2%, and sertindole by 8.9+/-3.5% (p < 0.05 compared with baseline); clozapine and olanzapine were less potent. Although species differences may limit extrapolation of our findings to humans, the cardiac potassium channels of felines clearly resemble those of humans. This model may serve as the basis for further studies of drug-induced prolongation of the QT interval and precipitation of ventricular arrhythmias.

Journal of Cardiovascular Electrophysiology, 2005

Females have a greater susceptibility to Torsade de Pointes in congenital and drug-induced long Q... more Females have a greater susceptibility to Torsade de Pointes in congenital and drug-induced long QT syndrome (LQTS) that has been attributed to the modulation of ion channel expression by sex hormones. However, little is known regarding sex differences in pre-puberty, that is, before the surge of sexual hormones. In patients with congenital LQTS types 1 and 2, male children tend to have a greater occurrence of adverse events, especially in 10-15 year olds, than their female counterpart. To evaluate whether the rabbit model of drug-acquired LQTS exhibits similar age dependences, hearts of prepubertal rabbits were perfused, mapped optically to record action potentials (APs) and treated with an I(Kr) blocker, E4031 to elicit LQTS2. As expected, AP durations (APD) were significantly longer in female (n = 18) than male hearts (n = 10), at long cycle length. Surprisingly, E4031 (50-250 nM) induced a greater prolongation of APDs in male than in female hearts, and in both genders reversed the direction of repolarization (apex --> base to base --> apex), enhancing dispersions of repolarization. Furthermore, in male hearts, E4031 (0.5 microM) elicited early afterdepolarizations (EADs) that progressed to polymorphic ventricular tachycardia (PVT) (n = 7/10) and were interrupted by isoproterenol (40 nM) and prevented by propranolol (0.5-2.5 microM). In female hearts, E4031 (0.5 microM) produced marked prolongations of APDs yet few EADs with no progression to PVT (n = 16/18). Thus, sex differences are opposite in prepubertal versus adult rabbits with respect to E4031-induced APD prolongation, EADs and PVT, underscoring the fact that APD prolongation alone is insufficient to predict arrhythmia susceptibility.

The Jervell and Lange-Nielsen (JLN) syndrome affects the human cardioauditory system, associating... more The Jervell and Lange-Nielsen (JLN) syndrome affects the human cardioauditory system, associating a profound bilateral deafness with an abnormally long QT interval on the ECG. It results from mutations in KVLQT1 and ISK genes that encode the 2 subunits forming the K ϩ channel responsible for the cardiac and inner ear slowly activating component of the delayed rectifier K ϩ current (I Ks ). A JLN mouse model that presents typical inner ear defects has been created by knocking out the isk gene (iskϪ/Ϫ). This study specifically reports on the cardiac phenotype counterpart, determined in the whole animal and at mRNAs and cellular levels. Surface ECG recordings of iskϪ/Ϫ mice showed a longer QT interval at slow heart rates, a paradoxical shorter QT interval at fast heart rates, and an overall exacerbated QT-heart rate adaptation compared with wild-type (WT) mice. A 300-ms increase in the heart rate cycle length induces a 309Ϯ21% increase in the QT duration of the WT mice versus a 500Ϯ50% in iskϪ/Ϫ mice (PϽ0.001). It is concluded that the isk gene product and/or I Ks , when present, blunts the QT adaptation to heart rate variations and that steeper QT-RR relationships reflect a greater susceptibility to arrhythmias in patients lacking I Ks . (Circ Res. 1998;83:95-102.)

Drug Safety, 2001

Drug-induced torsade de pointes is a rare life-threatening adverse drug reaction (ADR) which is s... more Drug-induced torsade de pointes is a rare life-threatening adverse drug reaction (ADR) which is strongly influenced by gender. Drugs that prolong cardiac repolarisation include antiarrhythmics, gastrokinetics, antipsychotics, antihistamines and antibacterials. Such drugs share the potential to block cardiac voltage-gated potassium channels, particularly the rapid component (I(Kr)) of the delayed rectifier potassium current (I(K)). By doing so, such drugs usually, but not always, prolong the QT interval. Even if the electrocardiographic signs are subdued, the underlying blockade of I(Kr) current may precipitate the occurrence of arrhythmia. Women are perceived to be more prone to ADRs than men. Such a propensity may result from gender-associated differences in drug exposure, in the number of drugs prescribed (polypharmacy), in drug pharmacology, as well as from possible differences in the way the adverse event is perceived. A prolonged QT interval on the electrocardiogram (time that elapses from the onset of the cardiac ventricular depolarisation to the completion of its repolarisation) is associated with the occurrence of torsade de pointes and related ventricular arrhythmias. The QT interval is influenced by heart rate, autonomic nervous system, electrolyte disturbances and above all, drugs that block potassium channels. Two-thirds of the cases of drug-induced torsade de pointes occur in women. Therefore, this adverse effect represents a perfect example of gender differences impairing women's health. Clinical and experimental studies show that female gender is associated with a longer corrected QT interval at baseline and a greater response to drugs that block I(Kr), both of which facilitate the emergence of arrhythmia. This results most likely from a specific regulation of ionic channel expression (potassium, calcium, etc) by sex steroids, even though nongenomic effects may play a role as well. Estrogens facilitate bradycardia-induced prolongation of the QT interval and the emergence of arrhythmia whereas androgens shorten the QT interval and blunt the QT response to drugs. Hence, underlying genetic defects of potassium channels that may be asymptomatic in normal conditions, may precipitate drug-induced arrhythmia in women more frequently than in men. Even in the presence of a drug that mildly blocks I(Kr) and seldom prolongs the QT interval, women are still more prone to drug-induced torsade de pointes, due to their reduced cardiac 'repolarisation reserve'. This is an important aspect of I(Kr) blockade to be aware of during the development of new drugs.

Proceedings of the National Academy of Sciences, 2001

The voltage-dependent K ؉ channel responsible for the slowly activating delayed K ؉ current IKs i... more The voltage-dependent K ؉ channel responsible for the slowly activating delayed K ؉ current IKs is composed of pore-forming KCNQ1 and regulatory KCNE1 subunits, which are mutated in familial forms of cardiac long QT syndrome. Because KCNQ1 and KCNE1 genes also are expressed in epithelial tissues, such as the kidneys and the intestine, we have investigated the adaptation of KCNE1-deficient mice to different K ؉ and Na ؉ intakes. On a normal K ؉ diet, homozygous kcne1 ؊/؊ mice exhibit signs of chronic volume depletion associated with fecal Na ؉ and K ؉ wasting and have lower plasma K ؉ concentration and higher levels of aldosterone than wild-type mice. Although plasma aldosterone can be suppressed by low K ؉ diets or stimulated by low Na ؉ diets, a high K ؉ diet provokes a tremendous increase of plasma aldosterone levels in kcne1 ؊/؊ mice as compared with wild-type mice (7.1-fold vs. 1.8-fold) despite lower plasma K ؉ in kcne1 ؊/؊ mice. This exacerbated aldosterone production in kcne1 ؊/؊ mice is accompanied by an abnormally high plasma renin concentration, which could partly explain the hyperaldosteronism. In addition, we found that KCNE1 and KCNQ1 mRNAs are expressed in the zona glomerulosa of adrenal glands where I Ks may directly participate in the control of aldosterone production by plasma K ؉ . These results, which show that KCNE1 and I Ks are involved in K ؉ homeostasis, might have important implications for patients with I Ks-related long QT syndrome, because hypokalemia is a well known risk factor for the occurrence of torsades de pointes ventricular arrhythmia.

Circulation, 2002

Molecularly engineered mice are extensively used as models of cardiovascular diseases, yet little... more Molecularly engineered mice are extensively used as models of cardiovascular diseases, yet little is known about sex differences in the electrophysiology of mouse hearts. This study investigated the influence of sex on drug-induced polymorphic ventricular tachycardia (PVT) in Langendorff-perfused male and female mice hearts (n=54) by injecting a bolus of halothane (1.75 mmol/L) in the perfusate while recording ECGs or optical action potentials (APs). There were no statistically significant differences between male and female hearts (n=54) with respect to mean RR (193+/-5 ms), PR (47+/-1 ms), QT intervals (101+/-3 ms), optical AP durations (APD(75)=23.11+/-4.2 ms), dispersion of refractory periods, and conduction velocities (n=5 male and 5 female). Halothane induced PVTs lasting a mean duration of 90 seconds; in female hearts, 55% of PVTs lasted longer than the median, whereas in male hearts 17% exceeded the mean (P<0.05). The total duration of PVTs exposed a marked sex difference, 378+/-144 seconds in female versus 27+/-10 seconds in male hearts (P<0.05). In optically mapped male hearts, halothane reduced APD(75) (17.61+/-1.6 ms) and then elicited VTs (n=6 of 6), but in female hearts, halothane elicited PVTs (n=1 of 6) or arrested the hearts (n=5 of 6). Except for KCNE1, Northern blots (KCNQ1, MERG, Kv1.5, connexins 40 and 43, TREK1, and TASK1) did not detect sex differences. This mouse model reveals sex difference in response to a pharmacological challenge yet does not display sex differences in standard electrophysiological parameters. Differences in KCNE1 may contribute to sex differences uncovered by halothane.

Circulation, 2002

Molecularly engineered mice are extensively used as models of cardiovascular diseases, yet little... more Molecularly engineered mice are extensively used as models of cardiovascular diseases, yet little is known about sex differences in the electrophysiology of mouse hearts. This study investigated the influence of sex on drug-induced polymorphic ventricular tachycardia (PVT) in Langendorff-perfused male and female mice hearts (n=54) by injecting a bolus of halothane (1.75 mmol/L) in the perfusate while recording ECGs or optical action potentials (APs). There were no statistically significant differences between male and female hearts (n=54) with respect to mean RR (193+/-5 ms), PR (47+/-1 ms), QT intervals (101+/-3 ms), optical AP durations (APD(75)=23.11+/-4.2 ms), dispersion of refractory periods, and conduction velocities (n=5 male and 5 female). Halothane induced PVTs lasting a mean duration of 90 seconds; in female hearts, 55% of PVTs lasted longer than the median, whereas in male hearts 17% exceeded the mean (P<0.05). The total duration of PVTs exposed a marked sex difference, 378+/-144 seconds in female versus 27+/-10 seconds in male hearts (P<0.05). In optically mapped male hearts, halothane reduced APD(75) (17.61+/-1.6 ms) and then elicited VTs (n=6 of 6), but in female hearts, halothane elicited PVTs (n=1 of 6) or arrested the hearts (n=5 of 6). Except for KCNE1, Northern blots (KCNQ1, MERG, Kv1.5, connexins 40 and 43, TREK1, and TASK1) did not detect sex differences. This mouse model reveals sex difference in response to a pharmacological challenge yet does not display sex differences in standard electrophysiological parameters. Differences in KCNE1 may contribute to sex differences uncovered by halothane.

British Journal of Pharmacology, 2000

1 Acetylcholine (ACh) is an important neuromodulator of cardiac function that is released upon st... more 1 Acetylcholine (ACh) is an important neuromodulator of cardiac function that is released upon stimulation of the vagus nerve. Despite numerous reports on activation of I KACh by acetylcholine in cardiomyocytes, it has yet to be demonstrated what role this channel plays in cardiac conduction. We studied the eect of tertiapin, a bee venom peptide blocking I KACh , to evaluate the role of I KACh in Langendor preparations challenged with ACh. 2 ACh (0.5 mM) reproducibly and reversibly induced complete atrioventricular (AV) blocks in retroperfused guinea-pig isolated hearts (n=12). 3 Tertiapin (10 to 300 nM) dose-dependently and reversibly prevented the AV conduction decrements and the complete blocks in unpaced hearts (n=8, P50.01). 4 Tertiapin dose-dependently blunted the ACh-induced negative chronotropic response from an ACh-induced decrease in heart rate of 39+16% in control conditions to 3+3% after 300 nM tertiapin (P=0.01). These eects were not accompanied by any signi®cant change in QT intervals. 5 Tertiapin blocked I KACh with an IC 50 of 30+4 nM with no signi®cant eect on the major currents classically associated with cardiac repolarisation process (I Kr , I Ks , I to1 , I sus , I K1 or I KATP ) or AV conduction (I Na and I Ca(L) ). 6 In summary, tertiapin prevents dose-dependently ACh-induced AV blocks in mammalian hearts by inhibiting I KACh .

British Journal of Pharmacology, 2000

1 Acetylcholine (ACh) is an important neuromodulator of cardiac function that is released upon st... more 1 Acetylcholine (ACh) is an important neuromodulator of cardiac function that is released upon stimulation of the vagus nerve. Despite numerous reports on activation of I KACh by acetylcholine in cardiomyocytes, it has yet to be demonstrated what role this channel plays in cardiac conduction. We studied the eect of tertiapin, a bee venom peptide blocking I KACh , to evaluate the role of I KACh in Langendor preparations challenged with ACh. 2 ACh (0.5 mM) reproducibly and reversibly induced complete atrioventricular (AV) blocks in retroperfused guinea-pig isolated hearts (n=12). 3 Tertiapin (10 to 300 nM) dose-dependently and reversibly prevented the AV conduction decrements and the complete blocks in unpaced hearts (n=8, P50.01). 4 Tertiapin dose-dependently blunted the ACh-induced negative chronotropic response from an ACh-induced decrease in heart rate of 39+16% in control conditions to 3+3% after 300 nM tertiapin (P=0.01). These eects were not accompanied by any signi®cant change in QT intervals. 5 Tertiapin blocked I KACh with an IC 50 of 30+4 nM with no signi®cant eect on the major currents classically associated with cardiac repolarisation process (I Kr , I Ks , I to1 , I sus , I K1 or I KATP ) or AV conduction (I Na and I Ca(L) ). 6 In summary, tertiapin prevents dose-dependently ACh-induced AV blocks in mammalian hearts by inhibiting I KACh .

British Journal of Pharmacology, 1999

1 In the present study, two new peptides, phrixotoxins PaTx1 and PaTx2 (29 ± 31 amino acids), whi... more 1 In the present study, two new peptides, phrixotoxins PaTx1 and PaTx2 (29 ± 31 amino acids), which potently block A-type potassium currents, have been puri®ed from the venom of the tarantula Phrixotrichus auratus. 2 Phrixotoxins speci®cally block Kv4.3 and Kv4.2 currents that underlie I to1 , with an 55IC 50 570 nM, by altering the gating properties of these channels. 3 Neither are the Shaker (Kv1), Shab (Kv2) and Shaw (Kv3) subfamilies of currents, nor HERG, KvLQT1/IsK, inhibited by phrixotoxins which appear speci®c of the Shal (Kv4) subfamily of currents and also block I to1 in isolated murine cardiomyocytes. 4 In order to evaluate the physiological consequences of the Ito1 inhibition, mice were injected intravenously with PaTx1, which resulted in numerous transient cardiac adverse reactions including the occurrence of premature ventricular beats, ventricular tachycardia and dierent degrees of atrioventricular block. 5 The analysis of the mouse electrocardiogram showed a dose-dependent prolongation of the QT interval, chosen as a surrogate marker for their ventricular repolarization, from 249+11 to 265+8 ms (P50.05). 6 It was concluded that phrixotoxins, are new and speci®c blockers of Kv4.3 and Kv4.2 potassium currents, and hence of I to1 that will enable further studies of Kv4.2 and Kv4.3 channel and/or I to1 expression.

Biochemical and Biophysical Research Communications, 2009

HIV-protease inhibitors (PIs) markedly decreased mortality of HIV-infected patients. However, the... more HIV-protease inhibitors (PIs) markedly decreased mortality of HIV-infected patients. However, their use has been associated with occurence of metabolic abnormalities the causes of which are not well understood. We report here that lopinavir, one of the most prescribed PI, dose-dependently co-induced insulin resistance and ER stress in human adipocytes obtained from differentiation of precursor cells. Insulin resistance was subsequent to IRS1 phosphorylation defects and resulted in a concentration-dependent decrease of glucose uptake. The major ER stress pathway involved was the phosphorylation of eIF2-alpha. Salubrinal, a selective eIF2-alpha dephosphorylation inhibitor, induced insulin resistance by targeting IRS1 phosphorylation at serine 312 and acted synergistically with LPV when both drugs were used in combination. This study points out the key role of eIF2-alpha phosphorylation in the development of PI-associated insulin resistance and ER stress. Thus, this protein represents a promising therapeutic target for development of new PIs devoid of adverse metabolic effects.

Thrombosis Research, 2015

No routine monitoring is required with factor Xa inhibitor rivaroxaban. Yet, its titration must b... more No routine monitoring is required with factor Xa inhibitor rivaroxaban. Yet, its titration must be adapted, and its misuse may lead to increased risk of bleeding; therefore, therapeutic rivaroxaban monitoring might help in specific situations. As asked by clinicians of our medical center, we measured rivaroxaban plasma concentrations in real conditions of use and checked their corresponding prescriptions. Measurement of 112 samples from 94 consecutive patients was performed with a Biophen LRT® anti-Xa chromogenic assay and compared blindly to the HPLC-MSMS "gold standard" method. Rivaroxaban was effectively given to 80 out of 94 patients but a mere 57% through an adequate prescription (within the scope of indications/titration). All chromogenic measurements were over the pre-specified 30ng/ml LOQ, whereas only 98 /114 samples had quantifiable rivaroxaban with HPLC-MSMS (LOQ 1ng/ml). Correlation between the two methods and linear regression were highly significant (p<0.0001). However, chromogenic values (mean 141.6ng/ml[96.6]) overestimated HPLC-MSMS values (119.7ng/ml[79.5]) by 22ng/ml according to Bland-Altman analysis (p<0.001). After re-assessing the chromogenic LOQ at 52ng/ml, 83 quantifiable samples had a mean concentration of 176.9ng/ml as compared to 158.5ng/ml with HPLC-MSMS, with no false positive anymore. In our medical center, rivaroxaban concentrations could be assessed by a rapid chromogenic method. Its pre-specified LOQ proved too high after being checked "on site" against HPLC-MSMS. Prescriptions for rivaroxaban were not optimal. An overestimated LOQ may impair observance monitoring or predispose patients to either risky thrombolysis or otherwise adjournable surgery in clinical practice.

Interactive Cardiovascular and Thoracic Surgery, 2000

A prospective case–control study was designed to confirm the higher plasma concentration of alumi... more A prospective case–control study was designed to confirm the higher plasma concentration of aluminium in primary spontaneous pneumothorax patients recently reported in literature. Ten consecutive patients with PSP entered the study. Comparison with the control group obtained from the database of the Pharmacology Department did not show any significant difference. The conclusion was that in patients with PSP from the

Archives of Cardiovascular Diseases, 2014

Drug and Alcohol Dependence, 2014

Background: Many drugs increase the duration of the QT interval of patients, potentially leading ... more Background: Many drugs increase the duration of the QT interval of patients, potentially leading to harmful effects such as polymorphic ventricular arrhythmias. Most of these drugs do so by inhibiting the rapid component IKr of the delayed rectifier potassium current IK. Methadone is the most prescribed heroin maintenance treatment and is known to inhibit the cardiac potassium channel hERG, which recapitulates IKr. In order to evaluate if any polymorphism of potassium channels' genes could explain some of the "idiosyncratic" QT prolongations observed in patients treated with methadone, we tested the association between KCNE1, KCNE2, and KCNH2 polymorphism and the QT interval prolongation in those patients, controlling for other variables associated with a decrease of the repolarizing reserve. Methods: A cohort of 82 patients treated with stable dosage of methadone (mean dosage 65 mg/d) for at least three months was genotyped for five polymorphisms in KCNE1, KCNE2 and KCNH2 genes and had their corrected QT (QTc) assessed. Results: The mean QTc interval was 415 ± 34 ms. In a linear regression model, longer QTc interval was associated with methadone dosage and with one genetic factor. Each copy of a Lys allele at codon 897 of KCNH2, the gene that encodes the cardiac potassium voltage-gated channel hERG, was associated with a 15.4 ms longer QTc (95% CI [4.6-26.2]; p = 0.001). Conclusion: KCNH2 genotyping may be relevant in the analysis of cumulative risk factors for QT prolongation in patients on methadone maintenance treatment.

Pharmacoepidemiology and Drug Safety, 2007

Atypical antipsychotics are the treatment of choice for patients with schizophrenia. They are gen... more Atypical antipsychotics are the treatment of choice for patients with schizophrenia. They are generally better tolerated than conventional antipsychotics since most do not cause debilitating extrapyramidal symptoms. They are associated though with an array of cardiovascular adverse events that may affect morbid-mortality of schizophrenic patients. Orthostatic hypotension, electrocardiographic changes and metabolic syndrome (MS) are the main cardiovascular effects of atypical antipsychotics. They contribute to the overall disease burden associated with schizophrenia even though the benefit risk of such treatments still is highly favourable.

Journal of Clinical Psychopharmacology, 1998

Some antipsychotic drugs have been found to prolong the QT interval on electrocardiographic (ECG)... more Some antipsychotic drugs have been found to prolong the QT interval on electrocardiographic (ECG) recordings, a phenomenon which, when severe, may facilitate the occurrence of complex ventricular arrhythmias such as torsade de pointes. However, the effects of these drugs on the cardiac repolarization process have not been evaluated extensively. This study was designed to examine the potency of five antipsychotic drugs in lengthening the QT interval of the perfused feline heart: haloperidol, risperidone, sertindole, clozapine, and olanzapine. The hearts were infused with increasing concentrations of drugs (0.1-20 micromol/L) for 40-minute intervals at each concentration. ECG recordings were made, with signals amplified and data recorded on a strip chart recorder. Four representative beats from each set of three signal recordings were chosen for QT interval measurement. Our data indicated that all tested drugs prolonged the QT interval in a concentration-dependent manner (p < 0.01). Haloperidol and risperidone were significantly more potent than sertindole, clozapine, and olanzapine (p < 0.001). At a concentration of 0.5 micromol/L over a 40-minute infusion interval, haloperidol lengthened the interval by 26.2+/-0.7%, risperidone by 19.4+/-2.2%, and sertindole by 8.9+/-3.5% (p < 0.05 compared with baseline); clozapine and olanzapine were less potent. Although species differences may limit extrapolation of our findings to humans, the cardiac potassium channels of felines clearly resemble those of humans. This model may serve as the basis for further studies of drug-induced prolongation of the QT interval and precipitation of ventricular arrhythmias.

Journal of Cardiovascular Electrophysiology, 2005

Females have a greater susceptibility to Torsade de Pointes in congenital and drug-induced long Q... more Females have a greater susceptibility to Torsade de Pointes in congenital and drug-induced long QT syndrome (LQTS) that has been attributed to the modulation of ion channel expression by sex hormones. However, little is known regarding sex differences in pre-puberty, that is, before the surge of sexual hormones. In patients with congenital LQTS types 1 and 2, male children tend to have a greater occurrence of adverse events, especially in 10-15 year olds, than their female counterpart. To evaluate whether the rabbit model of drug-acquired LQTS exhibits similar age dependences, hearts of prepubertal rabbits were perfused, mapped optically to record action potentials (APs) and treated with an I(Kr) blocker, E4031 to elicit LQTS2. As expected, AP durations (APD) were significantly longer in female (n = 18) than male hearts (n = 10), at long cycle length. Surprisingly, E4031 (50-250 nM) induced a greater prolongation of APDs in male than in female hearts, and in both genders reversed the direction of repolarization (apex --> base to base --> apex), enhancing dispersions of repolarization. Furthermore, in male hearts, E4031 (0.5 microM) elicited early afterdepolarizations (EADs) that progressed to polymorphic ventricular tachycardia (PVT) (n = 7/10) and were interrupted by isoproterenol (40 nM) and prevented by propranolol (0.5-2.5 microM). In female hearts, E4031 (0.5 microM) produced marked prolongations of APDs yet few EADs with no progression to PVT (n = 16/18). Thus, sex differences are opposite in prepubertal versus adult rabbits with respect to E4031-induced APD prolongation, EADs and PVT, underscoring the fact that APD prolongation alone is insufficient to predict arrhythmia susceptibility.

The Jervell and Lange-Nielsen (JLN) syndrome affects the human cardioauditory system, associating... more The Jervell and Lange-Nielsen (JLN) syndrome affects the human cardioauditory system, associating a profound bilateral deafness with an abnormally long QT interval on the ECG. It results from mutations in KVLQT1 and ISK genes that encode the 2 subunits forming the K ϩ channel responsible for the cardiac and inner ear slowly activating component of the delayed rectifier K ϩ current (I Ks ). A JLN mouse model that presents typical inner ear defects has been created by knocking out the isk gene (iskϪ/Ϫ). This study specifically reports on the cardiac phenotype counterpart, determined in the whole animal and at mRNAs and cellular levels. Surface ECG recordings of iskϪ/Ϫ mice showed a longer QT interval at slow heart rates, a paradoxical shorter QT interval at fast heart rates, and an overall exacerbated QT-heart rate adaptation compared with wild-type (WT) mice. A 300-ms increase in the heart rate cycle length induces a 309Ϯ21% increase in the QT duration of the WT mice versus a 500Ϯ50% in iskϪ/Ϫ mice (PϽ0.001). It is concluded that the isk gene product and/or I Ks , when present, blunts the QT adaptation to heart rate variations and that steeper QT-RR relationships reflect a greater susceptibility to arrhythmias in patients lacking I Ks . (Circ Res. 1998;83:95-102.)

Drug Safety, 2001

Drug-induced torsade de pointes is a rare life-threatening adverse drug reaction (ADR) which is s... more Drug-induced torsade de pointes is a rare life-threatening adverse drug reaction (ADR) which is strongly influenced by gender. Drugs that prolong cardiac repolarisation include antiarrhythmics, gastrokinetics, antipsychotics, antihistamines and antibacterials. Such drugs share the potential to block cardiac voltage-gated potassium channels, particularly the rapid component (I(Kr)) of the delayed rectifier potassium current (I(K)). By doing so, such drugs usually, but not always, prolong the QT interval. Even if the electrocardiographic signs are subdued, the underlying blockade of I(Kr) current may precipitate the occurrence of arrhythmia. Women are perceived to be more prone to ADRs than men. Such a propensity may result from gender-associated differences in drug exposure, in the number of drugs prescribed (polypharmacy), in drug pharmacology, as well as from possible differences in the way the adverse event is perceived. A prolonged QT interval on the electrocardiogram (time that elapses from the onset of the cardiac ventricular depolarisation to the completion of its repolarisation) is associated with the occurrence of torsade de pointes and related ventricular arrhythmias. The QT interval is influenced by heart rate, autonomic nervous system, electrolyte disturbances and above all, drugs that block potassium channels. Two-thirds of the cases of drug-induced torsade de pointes occur in women. Therefore, this adverse effect represents a perfect example of gender differences impairing women's health. Clinical and experimental studies show that female gender is associated with a longer corrected QT interval at baseline and a greater response to drugs that block I(Kr), both of which facilitate the emergence of arrhythmia. This results most likely from a specific regulation of ionic channel expression (potassium, calcium, etc) by sex steroids, even though nongenomic effects may play a role as well. Estrogens facilitate bradycardia-induced prolongation of the QT interval and the emergence of arrhythmia whereas androgens shorten the QT interval and blunt the QT response to drugs. Hence, underlying genetic defects of potassium channels that may be asymptomatic in normal conditions, may precipitate drug-induced arrhythmia in women more frequently than in men. Even in the presence of a drug that mildly blocks I(Kr) and seldom prolongs the QT interval, women are still more prone to drug-induced torsade de pointes, due to their reduced cardiac 'repolarisation reserve'. This is an important aspect of I(Kr) blockade to be aware of during the development of new drugs.

Proceedings of the National Academy of Sciences, 2001

The voltage-dependent K ؉ channel responsible for the slowly activating delayed K ؉ current IKs i... more The voltage-dependent K ؉ channel responsible for the slowly activating delayed K ؉ current IKs is composed of pore-forming KCNQ1 and regulatory KCNE1 subunits, which are mutated in familial forms of cardiac long QT syndrome. Because KCNQ1 and KCNE1 genes also are expressed in epithelial tissues, such as the kidneys and the intestine, we have investigated the adaptation of KCNE1-deficient mice to different K ؉ and Na ؉ intakes. On a normal K ؉ diet, homozygous kcne1 ؊/؊ mice exhibit signs of chronic volume depletion associated with fecal Na ؉ and K ؉ wasting and have lower plasma K ؉ concentration and higher levels of aldosterone than wild-type mice. Although plasma aldosterone can be suppressed by low K ؉ diets or stimulated by low Na ؉ diets, a high K ؉ diet provokes a tremendous increase of plasma aldosterone levels in kcne1 ؊/؊ mice as compared with wild-type mice (7.1-fold vs. 1.8-fold) despite lower plasma K ؉ in kcne1 ؊/؊ mice. This exacerbated aldosterone production in kcne1 ؊/؊ mice is accompanied by an abnormally high plasma renin concentration, which could partly explain the hyperaldosteronism. In addition, we found that KCNE1 and KCNQ1 mRNAs are expressed in the zona glomerulosa of adrenal glands where I Ks may directly participate in the control of aldosterone production by plasma K ؉ . These results, which show that KCNE1 and I Ks are involved in K ؉ homeostasis, might have important implications for patients with I Ks-related long QT syndrome, because hypokalemia is a well known risk factor for the occurrence of torsades de pointes ventricular arrhythmia.

Circulation, 2002

Molecularly engineered mice are extensively used as models of cardiovascular diseases, yet little... more Molecularly engineered mice are extensively used as models of cardiovascular diseases, yet little is known about sex differences in the electrophysiology of mouse hearts. This study investigated the influence of sex on drug-induced polymorphic ventricular tachycardia (PVT) in Langendorff-perfused male and female mice hearts (n=54) by injecting a bolus of halothane (1.75 mmol/L) in the perfusate while recording ECGs or optical action potentials (APs). There were no statistically significant differences between male and female hearts (n=54) with respect to mean RR (193+/-5 ms), PR (47+/-1 ms), QT intervals (101+/-3 ms), optical AP durations (APD(75)=23.11+/-4.2 ms), dispersion of refractory periods, and conduction velocities (n=5 male and 5 female). Halothane induced PVTs lasting a mean duration of 90 seconds; in female hearts, 55% of PVTs lasted longer than the median, whereas in male hearts 17% exceeded the mean (P<0.05). The total duration of PVTs exposed a marked sex difference, 378+/-144 seconds in female versus 27+/-10 seconds in male hearts (P<0.05). In optically mapped male hearts, halothane reduced APD(75) (17.61+/-1.6 ms) and then elicited VTs (n=6 of 6), but in female hearts, halothane elicited PVTs (n=1 of 6) or arrested the hearts (n=5 of 6). Except for KCNE1, Northern blots (KCNQ1, MERG, Kv1.5, connexins 40 and 43, TREK1, and TASK1) did not detect sex differences. This mouse model reveals sex difference in response to a pharmacological challenge yet does not display sex differences in standard electrophysiological parameters. Differences in KCNE1 may contribute to sex differences uncovered by halothane.

Circulation, 2002

Molecularly engineered mice are extensively used as models of cardiovascular diseases, yet little... more Molecularly engineered mice are extensively used as models of cardiovascular diseases, yet little is known about sex differences in the electrophysiology of mouse hearts. This study investigated the influence of sex on drug-induced polymorphic ventricular tachycardia (PVT) in Langendorff-perfused male and female mice hearts (n=54) by injecting a bolus of halothane (1.75 mmol/L) in the perfusate while recording ECGs or optical action potentials (APs). There were no statistically significant differences between male and female hearts (n=54) with respect to mean RR (193+/-5 ms), PR (47+/-1 ms), QT intervals (101+/-3 ms), optical AP durations (APD(75)=23.11+/-4.2 ms), dispersion of refractory periods, and conduction velocities (n=5 male and 5 female). Halothane induced PVTs lasting a mean duration of 90 seconds; in female hearts, 55% of PVTs lasted longer than the median, whereas in male hearts 17% exceeded the mean (P<0.05). The total duration of PVTs exposed a marked sex difference, 378+/-144 seconds in female versus 27+/-10 seconds in male hearts (P<0.05). In optically mapped male hearts, halothane reduced APD(75) (17.61+/-1.6 ms) and then elicited VTs (n=6 of 6), but in female hearts, halothane elicited PVTs (n=1 of 6) or arrested the hearts (n=5 of 6). Except for KCNE1, Northern blots (KCNQ1, MERG, Kv1.5, connexins 40 and 43, TREK1, and TASK1) did not detect sex differences. This mouse model reveals sex difference in response to a pharmacological challenge yet does not display sex differences in standard electrophysiological parameters. Differences in KCNE1 may contribute to sex differences uncovered by halothane.

British Journal of Pharmacology, 2000

1 Acetylcholine (ACh) is an important neuromodulator of cardiac function that is released upon st... more 1 Acetylcholine (ACh) is an important neuromodulator of cardiac function that is released upon stimulation of the vagus nerve. Despite numerous reports on activation of I KACh by acetylcholine in cardiomyocytes, it has yet to be demonstrated what role this channel plays in cardiac conduction. We studied the eect of tertiapin, a bee venom peptide blocking I KACh , to evaluate the role of I KACh in Langendor preparations challenged with ACh. 2 ACh (0.5 mM) reproducibly and reversibly induced complete atrioventricular (AV) blocks in retroperfused guinea-pig isolated hearts (n=12). 3 Tertiapin (10 to 300 nM) dose-dependently and reversibly prevented the AV conduction decrements and the complete blocks in unpaced hearts (n=8, P50.01). 4 Tertiapin dose-dependently blunted the ACh-induced negative chronotropic response from an ACh-induced decrease in heart rate of 39+16% in control conditions to 3+3% after 300 nM tertiapin (P=0.01). These eects were not accompanied by any signi®cant change in QT intervals. 5 Tertiapin blocked I KACh with an IC 50 of 30+4 nM with no signi®cant eect on the major currents classically associated with cardiac repolarisation process (I Kr , I Ks , I to1 , I sus , I K1 or I KATP ) or AV conduction (I Na and I Ca(L) ). 6 In summary, tertiapin prevents dose-dependently ACh-induced AV blocks in mammalian hearts by inhibiting I KACh .

British Journal of Pharmacology, 2000

1 Acetylcholine (ACh) is an important neuromodulator of cardiac function that is released upon st... more 1 Acetylcholine (ACh) is an important neuromodulator of cardiac function that is released upon stimulation of the vagus nerve. Despite numerous reports on activation of I KACh by acetylcholine in cardiomyocytes, it has yet to be demonstrated what role this channel plays in cardiac conduction. We studied the eect of tertiapin, a bee venom peptide blocking I KACh , to evaluate the role of I KACh in Langendor preparations challenged with ACh. 2 ACh (0.5 mM) reproducibly and reversibly induced complete atrioventricular (AV) blocks in retroperfused guinea-pig isolated hearts (n=12). 3 Tertiapin (10 to 300 nM) dose-dependently and reversibly prevented the AV conduction decrements and the complete blocks in unpaced hearts (n=8, P50.01). 4 Tertiapin dose-dependently blunted the ACh-induced negative chronotropic response from an ACh-induced decrease in heart rate of 39+16% in control conditions to 3+3% after 300 nM tertiapin (P=0.01). These eects were not accompanied by any signi®cant change in QT intervals. 5 Tertiapin blocked I KACh with an IC 50 of 30+4 nM with no signi®cant eect on the major currents classically associated with cardiac repolarisation process (I Kr , I Ks , I to1 , I sus , I K1 or I KATP ) or AV conduction (I Na and I Ca(L) ). 6 In summary, tertiapin prevents dose-dependently ACh-induced AV blocks in mammalian hearts by inhibiting I KACh .

British Journal of Pharmacology, 1999

1 In the present study, two new peptides, phrixotoxins PaTx1 and PaTx2 (29 ± 31 amino acids), whi... more 1 In the present study, two new peptides, phrixotoxins PaTx1 and PaTx2 (29 ± 31 amino acids), which potently block A-type potassium currents, have been puri®ed from the venom of the tarantula Phrixotrichus auratus. 2 Phrixotoxins speci®cally block Kv4.3 and Kv4.2 currents that underlie I to1 , with an 55IC 50 570 nM, by altering the gating properties of these channels. 3 Neither are the Shaker (Kv1), Shab (Kv2) and Shaw (Kv3) subfamilies of currents, nor HERG, KvLQT1/IsK, inhibited by phrixotoxins which appear speci®c of the Shal (Kv4) subfamily of currents and also block I to1 in isolated murine cardiomyocytes. 4 In order to evaluate the physiological consequences of the Ito1 inhibition, mice were injected intravenously with PaTx1, which resulted in numerous transient cardiac adverse reactions including the occurrence of premature ventricular beats, ventricular tachycardia and dierent degrees of atrioventricular block. 5 The analysis of the mouse electrocardiogram showed a dose-dependent prolongation of the QT interval, chosen as a surrogate marker for their ventricular repolarization, from 249+11 to 265+8 ms (P50.05). 6 It was concluded that phrixotoxins, are new and speci®c blockers of Kv4.3 and Kv4.2 potassium currents, and hence of I to1 that will enable further studies of Kv4.2 and Kv4.3 channel and/or I to1 expression.

Biochemical and Biophysical Research Communications, 2009

HIV-protease inhibitors (PIs) markedly decreased mortality of HIV-infected patients. However, the... more HIV-protease inhibitors (PIs) markedly decreased mortality of HIV-infected patients. However, their use has been associated with occurence of metabolic abnormalities the causes of which are not well understood. We report here that lopinavir, one of the most prescribed PI, dose-dependently co-induced insulin resistance and ER stress in human adipocytes obtained from differentiation of precursor cells. Insulin resistance was subsequent to IRS1 phosphorylation defects and resulted in a concentration-dependent decrease of glucose uptake. The major ER stress pathway involved was the phosphorylation of eIF2-alpha. Salubrinal, a selective eIF2-alpha dephosphorylation inhibitor, induced insulin resistance by targeting IRS1 phosphorylation at serine 312 and acted synergistically with LPV when both drugs were used in combination. This study points out the key role of eIF2-alpha phosphorylation in the development of PI-associated insulin resistance and ER stress. Thus, this protein represents a promising therapeutic target for development of new PIs devoid of adverse metabolic effects.