Prolongation of cardiac ventricular repolarization under paliperidone: how and how much?

INTRODUCTION: Paliperidone (9-hydroxyrisperidone) is a second-generation antipsychotic. As observed with risperidone, QT interval prolongation was reported with paliperidone. OBJECTIVE: The aim was to evaluate the effects of paliperidone on cardiac ventricular repolarization. METHODS: (1) Patch-clamp experiments: Human ether-a-go-go-related gene (HERG)- or KCNQ1 + KCNE1-transfected cells were exposed to 0.1-100 µmol/L paliperidone (N = 39 cells, total) to assess the drug effect on HERG and KCNQ1 + KCNE1 currents. (2) Langendorff perfusion experiments: Hearts isolated from male Hartley guinea pigs (N = 9) were exposed to 0.1 µmol/L paliperidone to assess drug-induced prolongation of monophasic action potential duration measured at 90% repolarization. (3) In vivo cardiac telemetry experiments: Guinea pigs (N = 8) implanted with transmitters were injected a single intraperitoneal dose of 1 mg/kg of paliperidone, and 24-hour electrocardiogram recordings were made. RESULTS: (1) The estimated concentration at which 50% of the maximal inhibitory effect is observed (IC(50)) for paliperidone on HERG current was 0.5276 µmol/L. In contrast, 1 µmol/L paliperidone had hardly any effect on KCNQ1 + KCNE1 current (4.0 ± 1.6% inhibition, N = 5 cells). (2) While pacing the hearts at cycle lengths of 150, 200, or 250 milliseconds, 0.1 µmol/L paliperidone prolonged monophasic action potential duration measured at 90% repolarization by, respectively, 6.1 ± 3.1, 9.8 ± 2.7, and 12.8 ± 2.7 milliseconds. (3) Paliperidone (1 mg/kg) intraperitoneal caused a maximal 15.7 ± 5.3-millisecond prolongation of QTc. CONCLUSIONS: Paliperidone prolongs the QT interval by blocking HERG current at clinically relevant concentrations and is potentially unsafe.

Cutaneous penetration of bisphenol A in pig skin.

Bisphenol A (BPA) is an endocrine disruptor with weak estrogenic activity, used in epoxy resin and polycarbonate plastic. Human exposure may occur by contamination from food or food-contact material and by occupational scenarios. Occupational health hazards may be associated with allergic contact dermatitis (ACD) secondary to BPA exposure. Most ACD occurs in workers handling BPA products, such as plastic-product workers, and those exposed to epoxy adhesive tapes, foams, and dental products. The present study examined in vitro cutaneous penetration of BPA through pig skin, using a Franz cell. After 2, 5, and 10 h of exposure, total BPA skin content was 3, 6.9, and 11.4% of the applied dose, respectively. BPA remained essentially on the skin surface and penetration mainly accumulated in the dermis. As the pig skin model is a reliable predictor of percutaneous penetration in humans, these findings may be reassuring for workers in contact with BPA-based products.

Evaluation of pyrethroid exposures in pregnant women from 10 Caribbean countries.

Pyrethroid pesticides are commonly used in tropical regions such as the Caribbean as household insecticides, pet sprays, and where malaria is endemic, impregnated into mosquito-repellent nets. Of particular concern is exposure during pregnancy, as these compounds have the potential to cross the placental barrier and interfere with fetal development, as was shown in limited animal studies. The objective of this study was to evaluate exposure to pyrethroids to pregnant women residing in 10 English-speaking Caribbean countries. Pyrethroid exposures were determined by analyzing five pyrethroid metabolites in urine samples from 295 pregnant women: cis-DBCA, cis-DCCA, trans-DCCA, 3-PBA, and 4-F-3-PBA. Pyrethroid metabolite concentrations in Caribbean pregnant women were generally higher in the 10 Caribbean countries than levels reported for Canadian and U.S. women. In Antigua & Barbuda and Jamaica participants the geometric mean concentrations of cis-DBCA was significantly higher than in the other nine countries together (p<0.0001 and <0.0012 respectively). For cis- and trans-DCCA, only Antigua & Barbuda women differed significantly from participants of the other nine Caribbean countries (p<0.0001). Urinary 4-F-3-PBA and 3-PBA levels were significantly higher in Antigua & Barbuda (p<0.0028 and p<0.0001 respectively) as well as in Grenada (p<0.0001 and p<0.007 respectively). These results indicate extensive use of pyrethroid compounds such as permethrin and cypermethrin in Caribbean households. In Antigua & Barbuda, the data reveals a greater use of deltamethrin. This study underscores the need for Caribbean public health authorities to encourage their populations, and in particular pregnant women, to utilize this class of pesticides more judiciously given the potentially adverse effects of exposure on fetuses and infants.

Tizanidine (Zanaflex): a muscle relaxant that may prolong the QT interval by blocking IKr.

BACKGROUND: Tizanidine (Zanaflex) is a centrally acting imidazoline muscle relaxant that is structurally similar to clonidine (α(2)-adrenergic agonist) but not to other myorelaxants such as baclofen or benzodiazepines. Interestingly, cardiac arrhythmias and QT interval prolongation have been reported with tizanidine. OBJECTIVE: To evaluate the effects of tizanidine on cardiac ventricular repolarization. METHODS: (1) Whole-cell patch-clamp experiments: HERG- or KCNQ1+KCNE1-transfected cells were exposed to tizanidine 0.1-100 µmol/L (n = 29 cells, total) to assess drug effect on the rapid (I(Kr)) and slow (I(Ks)) components of the delayed rectifier potassium current. (2) Langendorff retroperfusion experiments: isolated hearts from male Hartley guinea pigs (n = 6) were exposed to tizanidine 1 µmol/L to assess drug-induced prolongation of monophasic action potential duration measured at 90% repolarization (MAPD(90)). (3) In vivo wireless cardiac telemetry experiments: guinea pigs (n = 6) implanted with radio transmitters were injected a single intraperitoneal (ip) dose of tizanidine 0.25 mg/kg and 24 hours electrocardiography (ECG) recordings were made. RESULTS: (1) Patch-clamp experiments revealed an estimated IC(50) for tizanidine on I(Kr) above 100 µmol/L. Moreover, tizanidine 1 µmol/L had hardly any effect on I(Ks) (5.23% ± 4.54% inhibition, n = 5 cells). (2) While pacing the hearts at stimulation cycle lengths of 200 or 250 ms, tizanidine 1 µmol/L prolonged MAPD(90) by 8.22 ± 2.03 (6.7%) and 11.70 ± 3.08 ms (8.5%), respectively (both P < .05 vs baseline). (3) Tizanidine 0.25 mg/kg ip caused a maximal 11.93 ± 1.49 ms prolongation of corrected QT interval (QTc), 90 minutes after injection. CONCLUSION: Tizanidine prolongs the QT interval by blocking I(Kr). Patients could be at risk of cardiac proarrhythmia during impaired drug elimination, such as in case of CYP1A2 inhibition during drug interactions.

Galantamine (Reminyl) delays cardiac ventricular repolarization and prolongs the QT interval by blocking the HERG current.

Galantamine is a reversible inhibitor of acetylcholinesterase and an allosteric-potentiating ligand of the nicotinic acetylcholine receptors. It is used for treating mild-to-moderate Alzheimer's disease. Interestingly, QT interval prolongation on the electrocardiogram (ECG), malignant ventricular arrhythmias and syncope have been reported with galantamine. Our objective was to evaluate the effects of galantamine on cardiac ventricular repolarization. Three sets of experiments were undertaken: 1) Whole cell patch-clamp experiments: HERG- or KCNQ1+KCNE1-transfected cells were exposed to galantamine 0.1-1000 µmol/l (n=25 cells, total) to assess drug effect on HERG and KCNQ1+KCNE1 currents. 2) Langendorff perfusion experiments: Isolated hearts from male Hartley guinea pigs (n=9) were exposed to galantamine 1 µmol/l to assess drug-induced prolongation of monophasic action potential duration measured at 90% repolarization (MAPD(90)). 3) Cardiac telemetry experiments: Guinea pigs (n=7) implanted with wireless transmitters were injected a single intraperitoneal (i.p.) dose of galantamine 3mg/kg and 24h ECG recordings were made. 1) The estimated IC(50) for galantamine on HERG current was 760.2 µmol/l. Moreover, galantamine 10 µmol/l had a small inhibiting effect on KCNQ1+KCNE1 current (12.17 ± 2.19% inhibition, n=10 cells). 2) While pacing at cycle lengths of 150, 200 or 250 ms, galantamine 1 µmol/l prolonged MAPD(90) by respectively 5.1 ± 1.6 ms, 9.4 ± 1.9 ms and 12.1 ± 2.1 ms. 3) Galantamine 3 mg/kgi.p. caused a maximal 11.9 ± 2.7 ms prolongation of the corrected QT (QTc). Galantamine is a weak HERG blocker. This contributes to its mild QT-prolonging effect. Patients could be at risk of cardiac proarrhythmia during drug overdosage or interactions involving cytochrome 2D6 drug-metabolizing enzyme.

Development of a radioimmunoassay for the measurement of Bisphenol A in biological samples.

Bisphenol A (BPA) is widely used in the manufacturing of polycarbonate plastic food and drink packaging. Possessing a weak estrogenic activity, BPA is listed among a growing list of endocrine disrupting compounds. In this study, a polyclonal anti-BPA antibody was obtained by immunization with BPA-monocarboxymethylether covalently linked to BSA. The antibody demonstrates negligible cross-reactivity with most analogous BPA phenolic structures, and no cross-reactivity with endogenous steroids. An extraction step with ethyl acetate minimized matrix effects and allowed the BPA measurement in plasma and other biological samples. Recovery after loading test was 96 +/- 4% and dilution tests had a linear profile (r2 > 0.93). The limit of detection of the BPA RIA was 0.08 microg L(-1) with an IC50 of 1.25 microg L(-1). The intra- and inter-assay coefficients of variation were 5.6 and 8.6%, respectively at a BPA concentration of 0.7 microg L(-1) and 6.9 and 5.7% at a BPA concentration of 1.3 microg L(-1). A significant correlation was found between the values obtained by the RIA and HPLC-MS (r2 = 0.92) or HPLC coupled to a fluorescence detector (r2 = 0.80). In conclusion, we described a BPA-RIA that is a suitable tool for evaluating human exposure to BPA.