Guiding Chemically Synthesized Peptide Drug Lead Optimization by Derisking Mast Cell Degranulation-Related Toxicities of a NaV1.7 Peptide Inhibitor.

Studies have shown that some peptides and small molecules can induce non IgE-mediated anaphylactoid reactions through mast cell activation. Upon activation, mast cells degranulate and release vasoactive and proinflammatory mediators, from cytoplasmic granules into the extracellular environment which can induce a cascade of severe adverse reactions. This study describes a lead optimization strategy to select NaV1.7 inhibitor peptides that minimize acute mast cell degranulation (MCD) toxicities. Various in vitro, in vivo, and PKPD models were used to screen candidates and guide peptide chemical modifications to mitigate this risk. Anesthetized rats dosed with peptides demonstrated treatment-related decreases in blood pressure and increases in plasma histamine concentrations which were reversible with a mast cell stabilizer, supporting the MCD mechanism. In vitro testing in rat mast cells with NaV1.7 peptides demonstrated a concentration-dependent increase in histamine. Pharmacodynamic modeling facilitated establishing an in vitro to in vivo correlation for histamine as a biomarker for blood pressure decline via the MCD mechanism. These models enabled assessment of structure-activity relationship (SAR) to identify substructures that contribute to peptide-mediated MCD. Peptides with hydrophobic and cationic characteristics were determined to have an elevated risk for MCD, which could be reduced or avoided by incorporating anionic residues into the protoxin II scaffold. Our analyses support that in vitro MCD assessment in combination with PKPD modeling can guide SAR to improve peptide lead optimization and ensure an acceptable early in vivo tolerability profile with reduced resources, cycle time, and animal use.

Development of ProTx-II Analogues as Highly Selective Peptide Blockers of Nav1.7 for the Treatment of Pain.

Inhibitor cystine knot peptides, derived from venom, have evolved to block ion channel function but are often toxic when dosed at pharmacologically relevant levels in vivo. The article describes the design of analogues of ProTx-II that safely display systemic in vivo blocking of Nav1.7, resulting in a latency of response to thermal stimuli in rodents. The new designs achieve a better in vivo profile by improving ion channel selectivity and limiting the ability of the peptides to cause mast cell degranulation. The design rationale, structural modeling, in vitro profiles, and rat tail flick outcomes are disclosed and discussed.

Combining an in silico proarrhythmic risk assay with a tPKPD model to predict QTc interval prolongation in the anesthetized guinea pig assay.

Human-based in silico models are emerging as important tools to study the effects of integrating inward and outward ion channel currents to predict clinical proarrhythmic risk. The aims of this study were 2-fold: 1) Evaluate the capacity of an in silico model to predict QTc interval prolongation in the in vivo anesthetized cardiovascular guinea pig (CVGP) assay for new chemical entities (NCEs) and; 2) Determine if a translational pharmacokinetic/pharmacodynamic (tPKPD) model can improve the predictive capacity. In silico simulations for NCEs were performed using a population of human ventricular action potential (AP) models. PatchXpress® (PX) or high throughput screening (HTS) ion channel data from respectively n = 73 and n = 51 NCEs were used as inputs for the in silico population. These NCEs were also tested in the CVGP (n = 73). An M5 pruned decision tree-based regression tPKPD model was used to evaluate the concentration at which an NCE is liable to prolong the QTc interval in the CVGP. In silico results successfully predicted the QTc interval prolongation outcome observed in the CVGP with an accuracy/specificity of 85%/73% and 75%/77%, when using PX and HTS ion channel data, respectively. Considering the tPKPD predicted concentration resulting in QTc prolongation (EC5%) increased accuracy/specificity to 97%/95% using PX and 88%/97% when using HTS. Our results support that human-based in silico simulations in combination with tPKPD modeling can provide correlative results with a commonly used early in vivo safety assay, suggesting a path toward more rapid NCE assessment with reduced resources, cycle time, and animal use.

General Principles for the Validation of Proarrhythmia Risk Prediction Models: An Extension of the CiPA In Silico Strategy.

This white paper presents principles for validating proarrhythmia risk prediction models for regulatory use as discussed at the In Silico Breakout Session of a Cardiac Safety Research Consortium/Health and Environmental Sciences Institute/US Food and Drug Administration-sponsored Think Tank Meeting on May 22, 2018. The meeting was convened to evaluate the progress in the development of a new cardiac safety paradigm, the Comprehensive in Vitro Proarrhythmia Assay (CiPA). The opinions regarding these principles reflect the collective views of those who participated in the discussion of this topic both at and after the breakout session. Although primarily discussed in the context of in silico models, these principles describe the interface between experimental input and model-based interpretation and are intended to be general enough to be applied to other types of nonclinical models for proarrhythmia assessment. This document was developed with the intention of providing a foundation for more consistency and harmonization in developing and validating different models for proarrhythmia risk prediction using the example of the CiPA paradigm.

Drug-induced shortening of the electromechanical window is an effective biomarker for in silico prediction of clinical risk of arrhythmias.

BACKGROUND AND PURPOSE: Early identification of drug-induced cardiac adverse events is key in drug development. Human-based computer models are emerging as an effective approach, complementary to in vitro and animal models. Drug-induced shortening of the electromechanical window has been associated with increased risk of arrhythmias. This study investigates the potential of a cellular surrogate for the electromechanical window (EMw) for prediction of pro-arrhythmic cardiotoxicity, and its underlying ionic mechanisms, using human-based computer models. EXPERIMENTAL APPROACH: In silico drug trials for 40 reference compounds were performed, testing up to 100-fold the therapeutic concentrations (EFTPCmax ) and using a control population of human ventricular action potential (AP) models, optimised to capture pro-arrhythmic ionic profiles. EMw was calculated for each model in the population as the difference between AP and Ca2+ transient durations at 90%. Drug-induced changes in the EMw and occurrence of repolarisation abnormalities (RA) were quantified. KEY RESULTS: Drugs with clinical risk of Torsade de Pointes arrhythmias induced a concentration-dependent EMw shortening, while safe drugs lead to increase or small change in EMw. Risk predictions based on EMw shortening achieved 90% accuracy at 10× EFTPCmax , whereas RA-based predictions required 100× EFTPCmax to reach the same accuracy. As it is dependent on Ca2+ transient, the EMw was also more sensitive than AP prolongation in distinguishing between pure hERG blockers and multichannel compounds also blocking the calcium current. CONCLUSION AND IMPLICATIONS: The EMw is an effective biomarker for in silico predictions of drug-induced clinical pro-arrhythmic risk, particularly for compounds with multichannel blocking action.

Improvement of hERG-ROMK index of spirocyclic ROMK inhibitors through scaffold optimization and incorporation of novel pharmacophores.

SAR in the previously described spirocyclic ROMK inhibitor series was further evolved from lead 4 by modification of the spirocyclic core and identification of novel right-side pharmacophores. In this process, it was discovered that the spiropyrrolidinone core with the carbonyl group α to the spirocenter was preferred for potent ROMK activity. Efforts aimed at decreasing hERG affinity within the series led to the discovery of multiple novel right-hand pharmacophores including 3-methoxythiadiazole, 2-methoxypyrimidine, and pyridazinone. The most promising candidate is pyridazinone analog 32 that showed an improved functional hERG/ROMK potency ratio and preclinical PK profile. In vivo evaluation of 32 demonstrated blood pressure lowering effects in the spontaneously hypertensive rat model.

Cardiac drug-drug interaction between HCV-NS5B pronucleotide inhibitors and amiodarone is determined by their specific diastereochemistry.

Severe bradycardia/bradyarrhythmia following coadministration of the HCV-NS5B prodrug sofosbuvir with amiodarone was recently reported. Our previous preclinical in vivo experiments demonstrated that only certain HCV-NS5B prodrugs elicit bradycardia when combined with amiodarone. In this study, we evaluate the impact of HCV-NS5B prodrug phosphoramidate diastereochemistry (D-/L-alanine, R-/S-phosphoryl) in vitro and in vivo. Co-applied with amiodarone, L-ala,SP prodrugs increased beating rate and decreased beat amplitude in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), but D-ala,RP produgs, including MK-3682, did not. Stereochemical selectivity on emerging bradycardia was confirmed in vivo. Diastereomer pairs entered cells equally well, and there was no difference in intracellular accumulation of L-ala,SP metabolites ± amiodarone, but no D-ala,RP metabolites were detected. Cathepsin A (CatA) inhibitors attenuated L-ala,SP prodrug metabolite formation, yet exacerbated L-ala,SP + amiodarone effects, implicating the prodrugs in these effects. Experiments indicate that pharmacological effects and metabolic conversion to UTP analog are L-ala,SP prodrug-dependent in cardiomyocytes.

Satisfaction with civilian family medicine residency training: Perspectives from serving general duty medical officers in the Canadian Armed Forces.

OBJECTIVE: To evaluate satisfaction with civilian residency training programs among serving general duty medical officers within the Canadian Armed Forces. DESIGN: A 23-item, cross-sectional survey face-validated by the office of the Surgeon General of the Canadian Armed Forces. SETTING: Canada. PARTICIPANTS: General duty medical officers serving in the Canadian Armed Forces as of February 2014 identified through the Directorate of Health Services Personnel of the Canadian Forces Health Services Group Headquarters. MAIN OUTCOME MEASURES: Satisfaction with and time spent in 7 domains of training: trauma, critical care, emergency medicine, psychiatry, occupational health, sports medicine, and base clinic training. Overall preparedness for leading a health care team, caring for a military population, working in isolated and challenging environments, and being deployed were evaluated on a 5-point Likert scale. RESULTS: Among the survey respondents (n = 135, response rate 54%), 77% agreed or strongly agreed that their family medicine residency training was relevant to their role as a general duty medical officer. Most respondents were either satisfied or very satisfied with their emergency medicine training (77%) and psychiatry training (63%), while fewer were satisfied or very satisfied with their sports medicine (47%), base clinic (41%), and critical care (43%) training. Even fewer respondents were satisfied or very satisfied with their trauma (26%) and occupational health (12%) training. Regarding overall preparedness, 57% believed that they were adequately prepared to care for a military patient population, and 52% of respondents believed they were prepared for their first posting. Fewer respondents (38%) believed they were prepared to work in isolated, austere, or challenging environments, and even fewer (32%) believed that residency training prepared them to lead a health care team. CONCLUSION: General duty medical officers were satisfied with many aspects of their family medicine residency training; however, military-specific areas for improvement were identified. Many of these areas might be addressed within the context of a 2-year residency program without risking the generalist nature of family medicine training. These findings provide valuable data for residency programs that accept military trainees across the country.

Assessment of the clinical cardiac drug-drug interaction associated with the combination of hepatitis C virus nucleotide inhibitors and amiodarone in guinea pigs and rhesus monkeys.

In 2015, European and U.S. health agencies issued warning letters in response to 9 reported clinical cases of severe bradycardia/bradyarrhythmia in hepatitis C virus (HCV)-infected patients treated with sofosbuvir (SOF) in combination with other direct acting antivirals (DAAs) and the antiarrhythmic drug, amiodarone (AMIO). We utilized preclinical in vivo models to better understand this cardiac effect, the potential pharmacological mechanism(s), and to identify a clinically translatable model to assess the drug-drug interaction (DDI) cardiac risk of current and future HCV inhibitors. An anesthetized guinea pig model was used to elicit a SOF+AMIO-dependent bradycardia. Detailed cardiac electrophysiological studies in this species revealed SOF+AMIO-dependent selective nodal dysfunction, with initial, larger effects on the sinoatrial node. Further studies in conscious, rhesus monkeys revealed an emergent bradycardia and bradyarrhythmia in 3 of 4 monkeys administered SOF+AMIO, effects not observed with either agent alone. Morever, bradycardia and bradyarrhythmia were not observed in rhesus monkeys when intravenous infusion of MK-3682 was completed after AMIO pretreatment. CONCLUSIONS: These are the first preclinical in vivo experiments reported to replicate the severe clinical SOF+AMIO cardiac DDI and provide potential in vivo mechanism of action. As such, these data provide a preclinical risk assessment paradigm, including a clinically relevant nonhuman primate model, with which to better understand cardiovascular DDI risk for this therapeutic class. Furthermore, these studies suggest that not all HCV DAAs and, in particular, not all HCV nonstructural protein 5B inhibitors may exhibit this cardiac DDI with amiodarone. Given the selective in vivo cardiac electrophysiological effect, these data enable targeted cellular/molecular mechanistic studies to more precisely identify cell types, receptors, and/or ion channels responsible for the clinical DDI. (Hepatology 2016;64:1430-1441).

SAR exploration at the C-3 position of tetrahydro-ß-carboline sstr3 antagonists.

MK-4256, a tetrahydro-ß-carboline sstr3 antagonist, was discontinued due to a cardiovascular (CV) adverse effect observed in dogs. Additional investigations revealed that the CV liability (QTc prolongation) was caused by the hERG off-target activity of MK-4256 and was not due to sstr3 antagonism. In this Letter, we describe our extensive SAR effort at the C3 position of the tetrahydro-ß-carboline structure. This effort resulted in identification of 5-fluoro-pyridin-2-yl as the optimal substituent on the imidazole ring to balance sstr3 activity and the hERG off-target liability.

Application of a systems pharmacology model for translational prediction of hERG-mediated QTc prolongation.

Drug-induced QTc interval prolongation (Δ QTc) is a main surrogate for proarrhythmic risk assessment. A higher in vivo than in vitro potency for hERG-mediated QTc prolongation has been suggested. Also, in vivo between-species and patient populations' sensitivity to drug-induced QTc prolongation seems to differ. Here, a systems pharmacology model integrating preclinical in vitro (hERG binding) and in vivo (conscious dog Δ QTc) data of three hERG blockers (dofetilide, sotalol, moxifloxacin) was applied (1) to compare the operational efficacy of the three drugs in vivo and (2) to quantify dog-human differences in sensitivity to drug-induced QTc prolongation (for dofetilide only). Scaling parameters for translational in vivo extrapolation of drug effects were derived based on the assumption of system-specific myocardial ion channel densities and transduction of ion channel block: the operational efficacy (transduction of hERG block) in dogs was drug specific (1-19% hERG block corresponded to ≥10 msec Δ QTc). System-specific maximal achievable Δ QTc was estimated to 28% from baseline in both dog and human, while %hERG block leading to half-maximal effects was 58% lower in human, suggesting a higher contribution of hERG-mediated potassium current to cardiac repolarization. These results suggest that differences in sensitivity to drug-induced QTc prolongation may be well explained by drug- and system-specific differences in operational efficacy (transduction of hERG block), consistent with experimental reports. The proposed scaling approach may thus assist the translational risk assessment of QTc prolongation in different species and patient populations, if mediated by the hERG channel.

Discovery of MK-1421, a Potent, Selective sstr3 Antagonist, as a Development Candidate for Type 2 Diabetes.

The imidazolyl-tetrahydro-ß-carboline class of sstr3 antagonists have demonstrated efficacy in a murine model of glucose excursion and may have potential as a treatment for type 2 diabetes. The first candidate in this class caused unacceptable QTc interval prolongation in oral, telemetrized cardiovascular (CV) dogs. Herein, we describe our efforts to identify an acceptable candidate without CV effects. These efforts resulted in the identification of (1R,3R)-3-(4-(5-fluoropyridin-2-yl)-1H-imidazol-2-yl)-1-(1-ethyl-pyrazol-4-yl)-1-(3-methyl-1,3,4-oxadiazol-3H-2-one-5-yl)-2,3,4,9-tetrahydro-1H-ß-carboline (17e, MK-1421).

QT interval correction assessment in the anesthetized guinea pig.

INTRODUCTION: The anesthetized guinea pig (ANES GP) has proven to be an effective small animal model to evaluate cardiac electrophysiologic effects of drug-candidate molecules during lead optimization. While heart rate (HR) corrected QT interval (QTc) is a key variable to determine test article-dependent repolarization effects, ideal correction methods are an area of constant debate given the potential influence of anesthesia, autonomic tone, species, strain and gender on the QT/HR relationship. The aim of this study was to characterize the ability of common correction formulas to normalize rate-dependent effects on the QT interval in the ketamine/xylazine ANES GP. METHODS: Atrial pacing (n=10), ivabradine or ephedrine (n=6/group) infusions were used, respectively to evaluate the effects of a wide range of HRs on the QT/HR relationship. Correction formulas (Bazett [QTcb], Fridericia [QTcf] and Van de Water [QTcVdW]) were applied and the best fit formula was determined with the aid of the slope of their QT-HR linear relationship. RESULTS: From 100 to 220bpm, QTcb underestimated the change in QT interval duration (QT/HR slope=0.35 to 0.67). However, QTcVdW was more appropriate in this HR range (QT/HR slope=-0.07 and 0.09). At higher HRs (>220bpm), QTcb performed better (QT/HR slope=-0.02 and 0.07) as compared to QTcf (QT/HR slope=-0.18 to -0.1) and QTcVdW (QT/HR slope=-0.2 to -0.17) (p<0.01). All the correction formulas identified dofetilide- and sotalol-dependent repolarization delay (n=6/group) but QTcb and QTcf demonstrated reduced sensitivity as compared to fixed cardiac pacing (p<0.01). In contrast, QTcVdW resulted in an apparent underestimation of the QT interval duration at HR levels above the basal ketamine/xylazine ANES GP HRs (>220bpm) with ephedrine (n=6). DISCUSSION: The best fit correction formula in the ANES GP was highly dependent on the HR range. In the ketamine/xylazine model, QTcVdW performed best with HR <220bpm and QTcb performed best with HR >220bpm. The QTcVdW correction formula was thus selected in the ketamine/xylazine ANES GP since HRs in this model are generally within the optimal range for this correction formula.

Sensitivity of pharmacokinetic-pharmacodynamic analysis for detecting small magnitudes of QTc prolongation in preclinical safety testing.

INTRODUCTION: Preclinical concentration-effect (pharmacokinetic-pharmacodynamic, PKPD) modeling has successfully quantified QT effects of several drugs known for significant QT prolongation. This study investigated its sensitivity for detecting small magnitudes of QT-prolongation in a typical preclinical cardiovascular (CV) safety study in the conscious telemetered dog (crossover study in 4-8 animals receiving a vehicle and three dose levels). Results were compared with conventional statistical analysis (analysis of covariance, ANCOVA). METHODS: A PKPD model predicting individual QTc was first developed from vehicle arms of 28 typical CV studies and one positive control study (sotalol). The model quantified between-animal, inter-occasion and within-animal variability and described QTc over 24h as a function of circadian variation and drug concentration. This "true" model was used to repeatedly (n = 500) simulate studies with typical drug-induced QTc prolongation (∆QTc) of 1 to 12 ms at high-dose peak concentrations. Simulated studies were re-analyzed by both PKPD analysis (with varying complexity) and ANCOVA. Sensitivity (power) was calculated as the percentage of studies in which a significant (α = 0.05) drug effect was found. One simulation scenario did not include a concentration-effect relationship and served to investigate false-positive rates. Exposure-effect relationships were derived from both PKPD analysis (linear concentration-effect) and ANCOVA (linear trend test for dose) and compared. RESULTS: PKPD analysis/ANCOVA had a sensitivity of 80% to detect the effects of 7/13 ms (n = 4), 5/10 ms (n = 6) and 4.5/8 ms (n = 8), respectively. The false-positive rate was much higher using ANCOVA (40%) compared to PKPD analysis (1%). Typical drug effects were more precisely predicted using estimated concentration-effect slopes (± 1.5-2.8 ms) than dose-effect slopes (± 3.3-3.7 ms). DISCUSSION: Preclinical PKPD analysis can increase the confidence in the quantification of small QTc effects and potentially allow reducing the number of animals while maintaining the required study sensitivity. This underscores the value of PKPD modeling in preclinical safety testing.

Investigation of Cardiovascular Effects of Tetrahydro-ß-carboline sstr3 antagonists.

Antagonism of somatostatin subtype receptor 3 (sstr3) has emerged as a potential treatment of Type 2 diabetes. Unfortunately, the development of our first preclinical candidate, MK-4256, was discontinued due to a dose-dependent QTc (QT interval corrected for heart rate) prolongation observed in a conscious cardiovascular (CV) dog model. As the fate of the entire program rested on resolving this issue, it was imperative to determine whether the observed QTc prolongation was associated with hERG channel (the protein encoded by the human Ether-à-go-go-Related Gene) binding or was mechanism-based as a result of antagonizing sstr3. We investigated a structural series containing carboxylic acids to reduce the putative hERG off-target activity. A key tool compound, 3A, was identified from this SAR effort. As a potent sstr3 antagonist, 3A was shown to reduce glucose excursion in a mouse oGTT assay. Consistent with its minimal hERG activity from in vitro assays, 3A elicited little to no effect in an anesthetized, vagus-intact CV dog model at high plasma drug levels. These results afforded the critical conclusion that sstr3 antagonism is not responsible for the QTc effects and therefore cleared a path for the program to progress.

The anesthetized guinea pig: an effective early cardiovascular derisking and lead optimization model.

INTRODUCTION: In recent years, the anesthetized guinea pig has been used increasingly to evaluate the cardiovascular effects of drug-candidate molecules during lead optimization prior to conducting longer, more resource intensive safety pharmacology and toxicology studies. The aim of these studies was to evaluate the correlations between pharmacologically-induced ECG changes in the anesthetized cardiovascular guinea pig (CVGP) with ECG changes in conscious non-rodent telemetry models, human clinical studies and effects on key cardiac ion channels. METHODS: We compared the effects of 38 agents on ion channel inhibition to their ECG effects in the CVGP. 26 of these agents were also evaluated in non-rodent telemetry and compared to the results in the CVGP. RESULTS: The CVGP was highly sensitive for detecting QTc, PR and QRS interval prolongation mediated by inhibition of hERG, hCav1.2 and hNav1.5, respectively. There were robust correlations between ion channel inhibitory potencies and the free plasma concentrations (Cu) producing prolongation of the QTc, PR or QRS interval. Further evaluation showed that ECG changes in the CVGP were predictive of their effects on the QTc, PR and QRS intervals in non-rodent telemetry models with 92%, 92% and 100% accuracy, respectively. The CVGP proved to be 100% specific and 88%, 75% and 100% sensitive for QTc, PR and QRS interval prolongation, respectively. Similarly, the Cu that prolonged the QTc, PR and QRS in CVGP and humans correlated well. DISCUSSION: The CVGP is a sensitive model for assessing QTc, PR and QRS prolongation elicited by effects on hERG, hCav1.2 and hNav1.5, respectively. ECG changes in the CVGP are predictive of changes in non-rodent telemetry models and in humans (QTc). ECG parameters can be reliably evaluated with the CVGP model which increases the efficiency of CV derisking. Importantly, the design and implementation of this model is consistent with the "3Rs" for animal research.

Lengthening of cardiac repolarization in isolated guinea pigs hearts by sequential or concomitant administration of two IKr blockers.

Block of I(Kr) is of major concern in drug safety. The objective of this study was to assess prolongation of cardiac repolarization during the combined use of two I(Kr) blockers when administered concomitantly or sequentially. (1) When isolated hearts from male guinea pigs were perfused concomitantly with two I(Kr) blockers, prolongation of monophasic action potential duration measured at 90% (MAPD(90)) was less than the summation of effects observed for each drug perfused alone. (2) In sequential administration, when ketoconazole or erythromycin was perfused first, they antagonized MAPD(90)-prolonging effects of domperidone. This effect was absent when domperidone or dofetilide was perfused first. Patch-clamp experiments confirmed that the order of sequential perfusion impacts the decrease in HERG tail amplitude. In conclusion, this study does not support the concept that potentiation of drug effects is observed during the combined administration of two I(Kr) blockers. Furthermore, order of administration of two I(Kr) blockers together may be an important factor in drug-induced long QT syndrome.

Gender-related differences in drug-induced prolongation of cardiac repolarization in prepubertal guinea pigs.

Underlying mechanisms of drug-induced long QT syndrome are not fully understood. Our objective was to evaluate gender-related differences for block of the rapid (I(Kr) ) or/and the slow (I(Ks)) components of the delayed rectifier potassium current in prepubertal male and female guinea pigs (n = 120) treated with or without verapamil. Indapamide (I(Ks) blocker) prolonged the monophasic action potential duration at 90% repolarisation (MAPD( 90)) in females more than in males (15.1 + 0.5 vs 9.7 + 1.3 msec; P < .05) in verapamil treated animals. In contrast, MAPD(90) prolongation induced by domperidone or dofetilide (I(Kr) blockers) was not different between genders. Verapamil treatment augmented prolongation of MAPD( 90) caused by dofetilide or domperidone (P < .01). In conclusion, 1) females exhibited greater prolongation of MAPD(90) when exposed to indapamide, 2) no gender-related differences were observed for I( Kr) blockers, and 3) verapamil treatment did not uncover gender-related differences in I(Kr) or I(Ks) block, although it augmented prolongation of cardiac repolarization by I(Kr) blockers.

Drug-induced long QT syndrome in women: review of current evidence and remaining gaps.

BACKGROUND: Women are at an increased risk of drug-induced long QT syndrome (LQTS). This major cardiac adverse effect may lead to malignant polymorphic ventricular tachycardias, termed torsades de pointes, which may degenerate into ventricular fibrillation and cause sudden death. OBJECTIVE: This article reviews current evidence and remaining gaps in knowledge about drug-induced LQTS in women. METHODS: Using the search terms gender, sex, and sex differences in combination with cardiac electrophysiology, long QT syndrome, HERG, membrane transporters, and cytochromes, we conducted a systematic review of the available literature in the PubMed database. Relevant English- and French-language publications (to October 2007) on sex differences in LQTS were identified. RESULTS: Clinical and experimental studies have reported that gonadal hormones play a role in sex-related differences of QT interval prolongation. Androgens may diminish drug effects on heart repolarization, and estrogens may facilitate arrhythmias. Furthermore, sex-related differences in the density of ion channels may partially explain this phenomenon. However, the magnitude of hormone-dependent differences observed in these studies remains very small compared with the large differences observed in clinical settings. Therefore, many scientists agree that the mechanisms responsible for sex-related differences in the risk of proarrhythmia from drugs remain largely undefined. CONCLUSIONS: Other factors, such as sex-related modulation of drug disposition in situ, may fill the gaps in our understanding of the sex differences observed in drug-induced LQTS. We suggest that mechanisms such as the modulation of the pharmacokinetics of IKr (rapid component of the delayed rectifier potassium current) blockers, via modulation of intra- and extracellular concentrations, may be of major importance. Sex-specific changes in drug transport and metabolism will result in different plasma and intracellular levels acting along a dose-response effect on IKr block. Consequently, important hormone-dependent factors such as metabolic enzymes and membrane transporters need to be investigated in new basic research studies.