Postmortem PF4 antibodies confirm a rare case of thrombosis thrombocytopenia syndrome associated with ChAdOx1 nCoV-19 anti-COVID vaccination.

We report a case of cerebral venous sinus thrombosis, bilateral adrenal hemorrhage, and thrombocytopenia in a 70-year-old man found dead. He had previously received the ChAdOx1 nCoV-19 vaccine (Vaxzevria®, AstraZeneca) 18 days before, and had since developed unspecific and undiagnosed characteristics of what proved to be a rare case of vaccine-associated thrombocytopenia with thrombosis syndrome (TTS). He was found dead 1 week after the beginning of symptoms (day 25 post-vaccine). Autopsy yielded venous hemorrhagic infarction with the presence of thrombi within dural venous sinuses, and extensive hemorrhagic necrosis of the central part of the adrenal glands. Antibodies against platelet factor 4 (PF4) were strongly positive in postmortem fluids, as measured with an enzyme-linked immunosorbent assay (ELISA). This difficult diagnosis is usually made during the patient's lifetime. After eliminating differential diagnoses, we concluded on a fatal case of vaccine-induced immune TTS with positive anti-PF4 antibodies in cadaveric blood, 3 weeks after ChAdOx1 nCoV-19 vaccination. Specific search for anti-PF4 antibodies in cadaveric blood appears therefore paramount to assess postmortem cases of TTS associated with anti-COVID vaccines.

The cardiovascular safety of oral alitretinoin: a population-based cohort study involving 19 513 patients exposed to oral alitretinoin.

BACKGROUND: Oral alitretinoin is a retinoid used for severe chronic hand eczema. Although caution is recommended for patients with uncontrolled dyslipidaemia or cardiovascular risk factors, the actual atherothrombotic risk has not been investigated thus far. OBJECTIVES: To detect any excess of atherothrombotic events among patients exposed to alitretinoin, during treatment or in the 2 years following initiation. METHODS: Using the French Health Insurance database, we compared the number of patients who had an atherothrombotic event (coronary artery disease, ischaemic stroke or peripheral artery disease requiring revascularization) in the population exposed to oral alitretinoin vs. the general population of the same age, sex and baseline cardiovascular risk, using standardized morbidity ratios (SMRs). RESULTS: Between 2009 and 2017, 19 513 patients were exposed to oral alitretinoin in France. Sixty-four (0·3%) patients had an atherothrombotic event while on alitretinoin. Patients receiving alitretinoin experienced no more atherothrombotic events than the general population: patients without cardiovascular risk factors or previous atherothrombotic events had a SMR of 0·65 [95% confidence interval (CI) 0·26-1·34] during alitretinoin treatment, and 1·21 (95% CI 0·90-1·59) in the 2 years following initiation; patients with cardiovascular risk factors or previous atherothrombotic events had a SMR of 0·82 (95% CI 0·60-1·08) during alitretinoin treatment and 0·95 (95% CI 0·82-1·09) in the 2 years following initiation. Taken separately, SMRs for each outcome did not increase either. CONCLUSIONS: These data from an exhaustive nationwide population-based study do not support an increase in the incidence of atherothrombotic events with alitretinoin use, regardless of the baseline cardiovascular risk of the patient.

Chloroquine and hydroxychloroquine in the management of COVID-19: Much kerfuffle but little evidence.

Chloroquine and hydroxychloroquine are drugs that have shown in vitro activity on the replication of certain coronaviruses. In the context of the SARS-Cov-2 epidemic, the virus responsible for the novel coronavirus disease (COVID-19), these two drugs have been proposed as possible treatments. The results of the first clinical studies evaluating the effect of hydroxychloroquine do not support any efficacy of this drug in patients with COVID-19, due to major methodological weaknesses. Yet, these preliminary studies have aroused considerable media interest, raising fears of massive and uncontrolled use. In the absence of evidence of clinical benefits, the main risk is of exposing patients unnecessarily to the well-known adverse effects of hydroxychloroquine, with a possibly increased risk in the specific setting of COVID-19. In addition, widespread use outside of any recommendation risks compromising the completion of good quality clinical trials. The chloroquine hype, fueled by low-quality studies and media announcements, has yielded to the implementation of more than 150 studies worldwide. This represents a waste of resources and a loss of opportunity for other drugs to be properly evaluated. In the context of emergency, rigorous trials are more than ever needed in order to have, as soon as possible, reliable data on drugs that are possibly effective against the disease. Meanwhile, serious adverse drug reactions have been reported in patients with COVID-19 receiving hydroxychloroquine, justifying to limit its prescription, and to perform suitable cardiac and therapeutic drug monitoring.

Targeting cancer stem cells expressing an embryonic signature with anti-proteases to decrease their tumor potential.

Cancer stem cells (CSCs) are a specific subset of cancer cells that sustain tumor growth and dissemination. They might represent a significant treatment target to reduce malignant progression and prevent tumor recurrence. In solid tumors, several hierarchically organized CSC clones coexist, even within a single tumor. Among them, CSCs displaying an embryonic stem cell 'stemness' signature, based on the expression of Oct-4, Nanog and Sox2, are present in distinct high-grade tumor types associated with poor prognosis. We previously designed a model to isolate pure populations of these CSCs from distinct solid tumors and used it to screen for molecules showing selective toxicity for this type of CSC. Here we show that human immunodeficiency virus (HIV)-protease inhibitors (HIV-PIs) specifically target CSCs expressing an embryonic signature derived from tumors with distinct origins. They reduced proliferation in a dose-dependent manner with a higher specificity as compared with the total population of cancer cells and/or healthy stem cells, and they were efficient in inducing cell death. Lopinavir was the most effective HIV-PI among those tested. It reduced self-renewal and induced apoptosis of CSCs, subsequently impairing in vivo CSC-induced allograft formation. Two key pharmacophores in the LPV structure were also identified. They are responsible for the specificity of CSC targeting and also for the overall antitumoral activity. These results contribute to the identification of molecules presenting selective toxicity for CSCs expressing an embryonic stemness signature. This paves the way to promising therapeutic opportunities for patients suffering from solid cancer tumors of poor prognosis.

Safety of sertindole versus risperidone in schizophrenia: principal results of the sertindole cohort prospective study (SCoP).

OBJECTIVE: To explore whether sertindole increases all-cause mortality or cardiac events requiring hospitalization, compared with risperidone. METHOD: Multinational randomized, open-label, parallel-group study, with blinded classification of outcomes, in 9858 patients with schizophrenia. RESULTS: After 14147 person-years, there was no effect of treatment on overall mortality (sertindole 64, risperidone 61 deaths, Hazard Ratio (HR) = 1.12 (90% CI: 0.83, 1.50)) or cardiac events requiring hospitalization [sertindole 10, risperidone 6, HR = 1.73 (95% CI: 0.63, 4.78)]: Of these, four were considered arrhythmia-related (three sertindole, one risperidone). Cardiac mortality was higher with sertindole (Independent Safety Committee (ISC): 31 vs. 12, HR=2.84 (95% CI: 1.45, 5.55), P = 0.0022; Investigators 17 vs. 8, HR=2.13 (95% CI: 0.91, 4.98), P = 0.081). There was no significant difference in completed suicide, but fewer sertindole recipients attempted suicide (ISC: 68 vs. 78, HR=0.93 (95% CI: 0.66, 1.29), P = 0.65; Investigators: 43 vs. 65, HR=0.67 (95% CI: 0.45, 0.99), P = 0.044). CONCLUSION: Sertindole did not increase all-cause mortality, but cardiac mortality was higher and suicide attempts may be lower with sertindole.

[New antiarrhythmic drugs for atrial fibrillation]. / Les nouveaux médicaments antiarythmiques de la fibrillation auriculaire.

The development of new antiarrhythmic drugs is mainly aimed to treat atrial fibrillation, because of its prevalence and major consequences in terms cerebral vascular thrombosis. Specific blockade of I(Na) et I(K), even if efficacious, have previously shown to be proarrhythmogenic, with a global impairment of the cardiac patient's outcome. This lead to the development of new drugs, selectively targeting atrial currents such as I(Kur) ou I(KAch). The efficacy of amiodarone in treatment of atrial fibrillation has also yielded a whole array of new antiarrhythmic drugs targeting both these atrial currents but also sharing amiodarone pharmacodynamics properties. This renders the Vaughan-Williams classification ill-adapted for such drugs.

[The best of clinical pharmacology in 2006]. / L'essentiel de l'année 2006 en pharmacologie clinique cardiovasculaire.

The clinical pharmacological and therapeutic working group was particularly impressed by twelve recent publications relative to its various themes of interest. Two studies were made of the prognostic impact of non-observance of treatment which seems to be associated with an extra-mortality even when the treatment is placebo: the probable explanation is that the non-observance of drug therapy is also associated with the non observance of dietary/life style measures and with cognitive dysfunction associated with more severe cardiac disease. A recent study on n-acetyl-cysteine has rekindled the debate on this substance for preventing nephrotoxicity of radiological contrast used during angioplasty in high risk patients. The risks of AINS drug therapy has been reassessed. The increased risk of myocardial infarction is confirmed with celecoxib but not with "classical" AINS drugs if not prescribed for more than one year and without aspirin. With respect to lipid-lowering drugs, should statins be prescribed to attain a target value of LDL-cholesterol or to attain a given reduction in LDL-cholesterol? The death knell of fibrates has more or less been rung by the results of the FIELD study and the real value of OMEGA-3 drugs should be reassessed by good quality prospective studies. In the domain of hypertension, the recent arrival of aliskiren, the first of the antirenin drugs, is noteworthy although its role in the therapeutic strategy, remains to be defined. Finally, a comment is made on the results of the TROPHY study which suggest value in the possible prevention of hypertension with angiotensin II inhibitors in patients at risk of developing hypertension.

[The best of clinical cardiovascular pharmacology in 2005]. / L'essentiel de 2005 en pharmacologie clinique cardiovasculaire.

Although the year 2005 has reinforced the therapeutic advances of 2004, with confirmation of certain concepts, the 'coxib affair' has continued to provoke arguments between pharmaceutical companies, licensing agencies as well as patients, some of whom have amalgamated into consumer groups to reject en masse placing any responsibility on the prescribers in favour of an attack on the drug licensing process itself. Among the cardiovascular drugs that will soon be licensed, only ivabradine in stable angina, and remodulin in primary pulmonary arterial hypertension are new. The therapeutic advances in 2005 regarding platelet aggregation and blood coagulation have been significant, in the human, scientific and commercial context, while hypertension has not been ignored. Another new development is the ever more precise notion of the metabolic syndrome, a target of choice for the pharmaceutical industry. The potential range of applications has been widened to include obesity, hypertension, diabetes, HDL cholesterol... The licensing authorities find themselves facing a hurdle to overcome, with novel combinations of drugs (ACE inhibitors, calcium blockers/statins, statins/aspirin, ARA2/calcium blockers...).

[The best of clinical pharmacology in 2004]. / L'essentiel de 2004 en pharmacologie clinique cardiovasculaire.

The year 2004 was not marked by major pharmacological advances, but by confirmation of previous "evidence". Several innovative drugs for stable angina (ranolazine, ivabradine), some interesting results in acute coronary syndrome (PROVE IT study), some classic concepts (cannabinoid receptors and their antagonists such as rimonabant) applied to novel indications (treatment of obesity), hopes for the "sartans" revived in the light of new evidence (VALUE study), advances in the management of diabetes and hypertension (ASCOT and CARDS studies), nebivolol which is not just a betablocker but also produces the NO radical (is this why it decreased the mortality of heart failure in the elderly in the SENIOR study?). In contrast, although Chronadalate did not live up to expectations for coronary insufficiency, the year was marked above all by the much heralded withdrawal of Vioxx for increasing cardiovascular risk. The old adage: primum non nocere springs to mind.

Is gender a risk factor for adverse drug reactions? The example of drug-induced long QT syndrome.

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.

Altered potassium balance and aldosterone secretion in a mouse model of human congenital long QT syndrome.

The voltage-dependent K(+) channel responsible for the slowly activating delayed K(+) current I(Ks) 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.

The bee venom peptide tertiapin underlines the role of I(KACh) in acetylcholine-induced atrioventricular blocks.

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 effect of tertiapin, a bee venom peptide blocking I(KACh), to evaluate the role of I(KACh) in Langendorff preparations challenged with ACh. ACh (0.5 microM) reproducibly and reversibly induced complete atrioventricular (AV) blocks in retroperfused guinea-pig isolated hearts (n=12). Tertiapin (10 to 300 nM) dose-dependently and reversibly prevented the AV conduction decrements and the complete blocks in unpaced hearts (n=8, P<0.01). 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 effects were not accompanied by any significant change in QT intervals. Tertiapin blocked I(KACh) with an IC(50) of 30+/-4 nM with no significant effect 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))). In summary, tertiapin prevents dose-dependently ACh-induced AV blocks in mammalian hearts by inhibiting I(KACh).

Cardiac K+ channels and drug-acquired long QT syndrome.

The hallmark of long QT syndromes (LQTS) is an abnormal ventricular repolarization characterized by a prolonged QT interval on the electrocardiogram and a propensity to the occurrence of syncopes resulting from polymorphic ventricular tachycardia, called torsades de pointes. They may degenerate to ventricular fibrillation, possibly causing sudden death. Congenital LQTS, which implicates at least six chromosomal loci, LQT1 to LQT6, three of them corresponding to mutations concerning the coding of K+ channel proteins, give useful information about the mechanism underlying the arrhythmia. One of the potassium channel genes implicated in congenital LQTS is HERG, which encodes the IKr current channel protein. This current has provided a relevant insight into the occurrence of drug-acquired LQTS, since all drugs associated with torsades, such as erythromycin, terfenadine, haloperidol, or cisapride, also block IKr.

Effects of calcium channel blockers on cloned cardiac K+ channels IKr and IKs.

Cloned HERG and KvLQT1-IsK K+ channels have been expressed in mammalian cells and assayed as a target for calcium channel blockers. These channels generate the rapid and slow components of the cardiac delayed rectifier K+ current, and mutations can affect them that lead to long QT syndromes. HERG is blocked by bepridil (EC50 = 0.55 microM), verapamil (EC50 = 0.83 microM) and mibefradil (EC50 = 1.43 microM), whereas nitrendipine and diltiazem have negligible effects. Steady-state activation and inactivation parameters are shifted to more negative values in the presence of the blockers. Similarly, KvLQT1-IsK is inhibited by bepridil (EC50 = 10.0 microM) and mibefradil (EC50 = 11.8 microM), whilst being insensitive to nitrendipine, diltiazem or verapamil. This work may help to understand the mechanisms of action of verapamil in certain ventricular tachycardias as well as some of the deleterious adverse cardiac events associated with bepridil and mibefradil.

Studies on the mechanism of a fatal clarithromycin-pimozide interaction in a patient with Tourette syndrome.

The authors report in detail the case of a 27-year-old man who experienced sudden cardiac death 2 days after coprescription of the neuroleptic pimozide and the macrolide antibiotic clarithromycin after the documentation of a prolonged QT interval. To determine the prevalence of this interaction, the authors referred to the Spontaneous Reporting System of the Food and Drug Administration and identified one similar case in which clarithromycin was coprescribed with pimozide and sudden cardiac death occurred shortly thereafter. In addition, the search identified 39 cases of cardiac arrhythmia associated with pimozide, 11 with pimozide alone, and 6 with clarithromycin alone, 1 of which had a positive rechallenge. The mechanism of the interaction between clarithromycin and pimozide seems to involve the inhibition of the hepatic metabolism of pimozide by the macrolide. The authors demonstrated that clarithromycin is able to inhibit the metabolism of pimozide in human liver microsomal preparations (K(i) = 7.65 +/- 1.18 microM) and that pimozide, but not clarithromycin or its primary metabolite, is able to prolong the electrocardiac QT interval in a dose-dependent manner in the isolated perfused rabbit heart. The increase was 9.6 +/- 1.1% in male hearts (N = 5) and 13.4 +/- 1.2% in female hearts (N = 4) (p < 0.05).

Novel mutations in KvLQT1 that affect Iks activation through interactions with Isk.

OBJECTIVES: We report the functional expression of four KCNQ1 mutations affecting arginine residues and resulting in Romano-Ward (RW) and the Jervell and Lange-Nielsen (JLN) congenital long QT syndromes. RESULTS: The R539W and R190Q mutations were found in typical RW families with an autosomal dominant transmission. The R243H mutation was found in a compound heterozygous JLN patient who presents with deafness and cardiac symptoms. The fourth mutation, R533W, was a new case of recessive form of the RW syndrome since homozygous carriers experienced syncopes but showed no deafness, whereas the heterozygous carriers were asymptomatic. The R190Q mutation failed to produce functional homomeric channels. The R243H, R533W and R539W mutations induced a positive voltage shift of the channel activation but only when co-expressed with IsK, pointing out the critical role of these positively charged residues in the modulation of the gating properties of KvLQT1 by IsK. The positive shift induced by R533W was merely 15%. This small effect was compatible with the recessive character of the RW phenotype transmission. The average QTc was significantly longer (P < 0.01) in patients carrying mutations inducing a total loss of channel function and those patients were also prone to cardiac adverse symptoms (whether syncopes or sudden death) to a greater extent (62 vs. 21%, P < 0.001). CONCLUSIONS: Novel mutations are described that induce a voltage shift of the channel activation only in the presence of IsK. They appear associated with a milder cardiac phenotype.

Comparison of tegaserod (HTF 919) and its main human metabolite with cisapride and erythromycin on cardiac repolarization in the isolated rabbit heart.

Tegaserod (HTF 919) is a new drug being developed for gastrointestinal motility disorders. Because other gastrointestinal prokinetic agents, such as cisapride and erythromycin, cause slowing of cardiac repolarization and have been implicated in the development of the potentially fatal ventricular arrhythmia, torsades de pointes, a study was initiated to determine whether tegaserod and its main human metabolite adversely influence cardiac repolarization. By using isolated Langendorff-perfused rabbit hearts, we show that QT intervals remain unchanged at concentrations of tegaserod from 0.5 to 10 microM. It was not until the tegaserod concentration was increased to 50 microM (roughly 500-5,000 times more concentrated than those typically found in human plasma after administration of recommended clinical dosages), that a small, but significant increase in the QT interval (12+/-4%; p < 0.05; n = 4) was observed. No significant changes in QT occurred in the presence of the tegaserod metabolite at any of the concentrations tested (0.5-50 microM). In contrast, cisapride caused QT lengthening at concentrations as low as 0.1 microM, with significant QT increases occurring when 5-50 microM cisapride was used (22+/-4% to >70%, respectively; p < 0.01; n = 4). Erythromycin also caused significant lengthening of QT intervals (11+/-2%; p < 0.001; n = 4), although 100 microM concentrations of this drug were required to achieve this effect. These results demonstrate that both cisapride and erythromycin can slow cardiac repolarization at therapeutic doses and that tegaserod's lack of QT prolongation at therapeutic doses suggests that it has the potential to be a safer alternative to cisapride as a gastrointestinal prokinetic agent.

Effects of phrixotoxins on the Kv4 family of potassium channels and implications for the role of Ito1 in cardiac electrogenesis.

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 purified from the venom of the tarantula Phrixotrichus auratus. 2. Phrixotoxins specifically block Kv4.3 and Kv4.2 currents that underlie I(to1), with an 5 < IC50 < 70 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 specific 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 different 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 (P < 0.05). 6. It was concluded that phrixotoxins, are new and specific 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.

Prolongation of QT interval in isolated feline hearts by antipsychotic drugs.

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.

Cardiac actions of erythromycin: influence of female sex.

CONTEXT: Erythromycin is a widely used antibiotic that infrequently causes QT-prolongation and torsades de pointes cardiac arrhythmias. For antiarrhythmic drugs, women are at a higher risk for these cardiac arrhythmias, but few other classes of drugs have been studied. OBJECTIVES: To determine whether female sex is a risk factor for cardiac arrhythmias associated with erythromycin, and if this can be correlated with in vitro measurements of the QT-response to erythromycin in male and female rabbit hearts. DESIGN: Food and Drug Administration (FDA) MEDWATCH database analysis and in vitro experiment. MAIN OUTCOME MEASURES: Cardiac arrhythmia reports associated with erythromycin from 1970 until 1996 classified by patient sex and age, and effect of female sex on erythromycin-induced QT-prolongation in isolated perfused rabbit hearts. RESULTS: We observed a sex difference in cardiac arrhythmias associated with administration of erythromycin. A total of 346 cases were found in the FDA database: 201 females (58%), 110 males (32%), and 35 unspecified (10%). Forty-nine were life-threatening ventricular arrhythmias and deaths directly related to intravenous erythromycin lactobionate: 33 women (67%) and 16 men (33%) (P=.03). During the same period, no sex imbalance was present in the prescription pattern for intravenous erythromycin lacobionate (men 47%, women 49%, unspecified 4%). Perfusion with erythromycin caused significantly greater QT-prolongation in female rabbit hearts (mean [SD], 11.8% [2.3%]) than in male hearts (6.9% [2.1%]; P = .03). CONCLUSIONS: As has been shown in reports of antiarrhythmic drugs, we found a female predominance in the FDA reports of erythromycin-associated cardiac arrhythmias. Based on in vitro experiments, a sex difference in cardiac repolarization response to erythromycin is a potential contributing factor.