Cardiac Conduction Parameters Research Articles

A Phase 1 Study to Assess the Effect of Supratherapeutic Doses of Iptacopan on Cardiac Conduction Parameters and Safety

Introduction: Iptacopan is a first-in-class, oral, selective inhibitor of factor B, a key component of the complement system alternative pathway. Inhibition of the complement system represents a potential mechanism for treatment of several diseases including paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. The purpose of this randomized, participant-blinded, placebo-controlled phase 1 study was to assess the effect of supratherapeutic doses on the exposure-response relationship of iptacopan concentration and cardiac conduction, and to assess the cardiac safety and tolerability of ascending, supra-therapeutic single doses of iptacopan. Methods: Supratherapeutic doses of iptacopan 400, 800, and 1200 mg were included in this study, representing ≤6-fold higher dose than the planned clinical dose of 200 mg. The primary endpoints were change from baseline in Fridericia-corrected QT interval (QTcF) and safety endpoints. The analyses included data from this study pooled with part 1 data (single dose) from the first-in-human (CLNP023X2101) study (n=86). The study population included healthy men and women aged 18-55 years. The relationship between iptacopan plasma concentration and change from baseline in QTcF was estimated using a linear mixed effects model. Results: Thirty-two patients were randomized and received placebo (n=8) or iptacopan (n=24). The median age of participants in the 400-mg, 800-mg, 1200-mg, and placebo groups was 51.5, 35, 36, and 37 years, respectively. The upper bound of the 2-sided 90% CI for linear mixed effects model-derived placebo-adjusted change from baseline in QTcF at the geometric mean C max was 2.82 ms for 400-mg, 2.94 ms for 800-mg, and 3.22 ms for 1200-mg doses. Hence, there was no evidence of clinically meaningful QTc prolongation ( Table). The exposure-response analysis of PR and QRS intervals showed no iptacopan concentration-related effects. While the pre-specified and more simple exposure-response analysis of heart rate using change from day 1 baseline (0 hour) revealed an increase of 3 to 5 beats per minute, in a post hoc analysis using 24-hour, time-matched comparison for each participant at each time point before and after study treatment (the more common and gold-standard analysis), iptacopan had no effect on heart rate. No deaths, no moderate or severe treatment-emergent adverse events, and no treatment cohort discontinuations due to adverse events were reported. Conclusions: Three supratherapeutic doses were well tolerated and were not associated with any relevant change in QTcF. Iptacopan did not affect PR or QRS intervals and a time-matched post hoc analysis showed no effect on heart rate. These results indicate that the anticipated clinical dose of iptacopan (200 mg twice daily) has no adverse clinical effects on cardiac function.

Residential greenness alleviated the adverse associations of long-term exposure to ambient PM1 with cardiac conduction abnormalities in rural adults

Ambient air pollution was linked to elevated risks of adverse cardiovascular events, and alterations in electrophysiological properties of the heart might be potential pathways. However, there is still lacking research exploring the associations between PM1 exposure and cardiac conduction parameters. Additionally, the interactive effects of PM1 and residential greenness on cardiac conduction parameters in resource-limited areas remain unknown. A total of 27483 individuals were enrolled from Henan Rural Cohort study. Cardiac conduction parameters were tested by 12-lead electrocardiograms. Concentrations of PM1 were predicted by satellite-based spatiotemporal models. Levels of residential greenness were assessed using Enhanced Vegetation Index (EVI) and Normalized difference vegetation index (NDVI). Logistic regression models and restricted cubic splines were fitted to explore the associations of PM1 and residential greenness exposure with cardiac conduction abnormalities risk, interaction plot method was performed to visualize their interaction effects. The 3-year median concentration of PM1 was 56.47 (2.55) μg/m3, the adjusted odds rate (ORs) and 95% confidence intervals (CIs) for abnormal HR, PR, QRS, and QTc interval risk in response to 1 μg/m3 increase in PM1 were 1.064 (1.044, 1.085), 1.037 (1.002, 1.074), 1.061 (1.044, 1.077) and 1.046 (1.028, 1.065), respectively. Participants exposure to higher levels of PM1 had increased risks of abnormal HR (OR = 1.221, 95%CI: 1.144, 1.303), PR (OR = 1.061, 95%CI: 0.940, 1.196), QRS (OR = 1.225, 95%CI: 1.161, 1.294) and QTc interval (OR = 1.193, 95%CI: 1.121, 1.271) compared with lower levels of PM1. Negative interactive effects of exposure to PM1 and residential greenness on abnormal HR, QRS, and QTc intervals were observed (Pfor interaction < 0.05). Long-term PM1 exposure was associated with elevated cardiac conduction abnormalities risks, and this adverse association might be mitigated by residential greenness to some extent. These findings emphasize that controlling PM1 pollution and increasing greenness levels might be effective strategies to reduce cardiovascular disease burdens in resource-limited areas.

A Randomized Thorough QT Study of Apomorphine Sublingual Film in Patients With Parkinson's Disease.

A randomized thorough QT study was conducted to assess the effects of apomorphine sublingual film (SL‐APO) on corrected QT interval (QTc) and other cardiac conduction parameters in patients with Parkinson's disease (PD) and “OFF” episodes. Patients were titrated to an SL‐APO dose that resulted in FULL “ON,” followed by up to two additional doses (maximum 60 mg), then randomized at the highest tolerated dose to a treatment sequence of SL‐APO, placebo, and moxifloxacin (400 mg, positive control) in a three‐way crossover design. Changes from baseline in time‐matched, placebo‐adjusted Fridericia‐corrected QTc interval (ΔΔQTcF) and Bazett‐corrected QTc interval (ΔΔQTcB) were analyzed from postdose electrocardiograms. Forty patients were randomized and received single doses of study treatments. Upper limits of 90% confidence intervals (CIs) for ΔΔQTcF of SL‐APO were below the 10‐millisecond regulatory threshold at all prespecified timepoints, demonstrating no clinically significant effect on QTcF. Lower limits of 90% CIs for ΔΔQTcF of moxifloxacin exceeded the 5‐millisecond regulatory threshold at all timepoints up to 3 hours, confirming assay sensitivity. SL‐APO had no clinically meaningful effects on QTcB, PR/QRS intervals, heart rate, or electrocardiogram‐derived morphology (EudraCT identifier: 2016‐001762‐29; ClinicalTrials.gov identifier: NCT03187301).

Consortin: a potential modulator of ventricular conduction

Abstract Funding Acknowledgements Type of funding sources: None. Background Consortin, encoded by the CNST gene, is a ubiquitously expressed protein putatively involved in trafficking of connexins to the plasma membrane. In the heart, connexins form gap junctions, which are essential for cardiac conduction. Reduced levels and abnormal cellular distribution of connexins have been found in patients with heart failure, atrial fibrillation, arrhythmogenic cardiomyopathy and Brugada syndrome. Purpose To decipher the role of Consortin in cardiac electrophysiology. Methods Homozygous Cnst knockout mice (Cnst-/-) were generated using CRISPR-Cas9 technology. Consortin expression was assessed by Western blot analysis. Cardiac conduction parameters were recorded by electrocardiography in anesthetized wild-type (WT) and Cnst-/- male and female littermates aged 3-6 months. Conduction velocity (CV) was determined in Langendorff-perfused hearts by optical mapping of the right ventricle (RV) at a pacing cycle length of 120 ms. Data were analyzed by Student’s t­-test and P values &amp;lt; 0.05 were considered significant. Results Western blot analysis confirmed the presence of Consortin in WT mouse hearts, and its absence in Cnst-/- hearts. Heart rate, P-wave duration and PR-interval did not differ between groups, whereas QRS interval was significantly prolonged in Cnst-/- (mean±SEM 8.7±1.3 ms, n=13) compared to WT mice (7.9±1.1ms, n=13; (p=0.0009)). Hearts were structurally normal, and heart weight:body weight ratio was similar between groups. Preliminary optical mapping at the RV of Langendorff-perfused hearts demonstrated a lower, although not significantly different, transversal CV in Cnst-/- (56±4.3 cm/s, n=6) compared to WT (65±7.1 cm/s; n=3; p=0.31), whereas longitudinal CV was similar between groups (Cnst-/- 80±4.2 cm/s versus WT 83±9.1 cm/s; p=0.74). No differences were observed in RV effective refractory period (p=0.59). Conclusion These preliminary findings support a modulatory role of Consortin in ventricular conduction. Current efforts are aimed at elucidating the underlying electrophysiological and molecular mechanisms, including the impact of Consortin on cardiac connexins.

Cardiac Conduction Disorders as Markers of Cardiac Events in Myotonic Dystrophy Type 1.

BackgroundMyotonic dystrophy type 1 involves cardiac conduction disorders. Cardiac conduction disease can cause fatal arrhythmias or sudden death in patients with myotonic dystrophy type 1.Methods and ResultsThis study enrolled 506 patients with myotonic dystrophy type 1 (aged ≥15 years; >50 cytosine‐thymine‐guanine repeats) and was treated in 9 Japanese hospitals for neuromuscular diseases from January 2006 to August 2016. We investigated genetic and clinical backgrounds including health care, activities of daily living, dietary intake, cardiac involvement, and respiratory involvement during follow‐up. The cause of death or the occurrence of composite cardiac events (ie, ventricular arrhythmias, advanced atrioventricular blocks, and device implantations) were evaluated as significant outcomes. During a median follow‐up period of 87 months (Q1–Q3, 37–138 months), 71 patients expired. In the univariate analysis, pacemaker implantations (hazard ratio [HR], 4.35; 95% CI, 1.22–15.50) were associated with sudden death. In contrast, PQ interval ≥240 ms, QRS duration ≥120 ms, nutrition, or respiratory failure were not associated with the incidence of sudden death. The multivariable analysis revealed that a PQ interval ≥240 ms (HR, 2.79; 95% CI, 1.9–7.19, P<0.05) or QRS duration ≥120 ms (HR, 9.41; 95% CI, 2.62–33.77, P < 0.01) were independent factors associated with a higher occurrence of cardiac events than those observed with a PQ interval <240 ms or QRS duration <120 ms; these cardiac conduction parameters were not related to sudden death.ConclusionsCardiac conduction disorders are independent markers associated with cardiac events. Further investigation on the prediction of occurrence of sudden death is warranted.

Abstract 3945: CBT-102, an oral multi-kinase small molecule, demonstrates favorable activity in human hepatocellular carcinoma animal models and cardiac safety in rabbit Purkinje and beagle dogs compared to sorafenib

Abstract Background: Cancer is a complex disease involving disruption of more than one receptor or signaling pathway. Inhibiting multiple oncogenic targets have been shown to be an important strategy in managing relapse and resistance. CBT-102 is an oral mTKI inhibiting several key oncogenic drivers including angiogenesis via VEGFR and PDGFR, MAPK pathway via B-RAF and C-RAF, in addition to inhibiting RET, CSF1R, c-KIT, and FLT3. Antitumor activity of CBT-102 was compared to sorafenib in two human primary HCC carcinoma xenografts in nude mice (LIMsh050 and PLCPRF5) and cardiac safety was evaluated in rabbit heart Purkinje fibers and in conscious telemeterized beagle dogs. Methods: Female BALB/c nude mice were inoculated with LIMsh050 and PLCPRF5 tumors to establish the tumor models. In the LIMsh050 model, CBT-102 was administered orally QD x 21 days at 4, 10, and 25 mg/kg and sorafenib at 10 mg/kg (n=8/group). In the PLCPRF5 model, CBT-102 was administered orally QD x 14 days at 3, 8, and 20 mg/kg vs. 8 and 20 mg/kg sorafenib group (n=7/group). In both experiments, in addition to tumor volume, body weight and mortality were monitored. For the cardiac safety studies, rabbit Purkinje fibers were isolated from adult rabbit right heart perfused for 10 minutes with vehicle control, CBT-102 groups (1, 3, and 10 µM) or sorafenib and changes in action potentials were measured. In the second study, ECG parameters were measured after single oral administration of CBT-102 at 15, 45, and 67.5 mg/kg to beagle dogs (n=6/group) via telemetry for 24 h. Results: In both the LIMsh050 and PLCPRF5 models, CBT-102 and sorafenib doses were well tolerated with no suspension of dosing due to weight loss or deaths. CBT-102 demonstrated inhibition of tumor growth in both models, to a significantly greater extent than sorafenib at comparable doses. In the PLCPRF5 model, CBT-102 demonstrated an ED50 of 2.5 mg/kg vs. 16.8 mg/kg of sorafenib. Importantly, unlike sorafenib, CBT-102 did not show a cardiac liability: there were no changes in action potential duration in rabbit Purkinje fibers nor any changes in cardiac conduction parameters (HR, QTc, RR, PR, and QRS intervals) in beagle dogs. Conclusions: CBT-102 demonstrated improved efficacy in HCC xenografts models compared to sorafenib and does not appear to have the cardiac liability observed with sorafenib. CBT-102 will advance into GLP toxicology studies with a potential IND filing in 2H 2018. Citation Format: Sarath Kanekal, Xiquan Zhang, Yanrui Song, Tan Wenmiao, Juan Zhang, Deyi Zhang, Henry Li, Mamatha Reddy, Gavin Choy, Sanjeev Redkar. CBT-102, an oral multi-kinase small molecule, demonstrates favorable activity in human hepatocellular carcinoma animal models and cardiac safety in rabbit Purkinje and beagle dogs compared to sorafenib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3945.

Sudden cardiac death in J wave syndrome with short QT associated to a novel mutation in Nav 1.8 coding gene SCN10A: First case report for a possible pharmacogenomic role

IntroductionSudden cardiac death is an important cause of mortality in the general population. It represents an important challenge for clinicians, often being the only symptom of a broad spectrum of cardiac pathologies and inherited heart conditions. Early repolarization syndrome and Brugada syndrome are part of the wider “J-wave” syndrome, which may also include the short QT syndrome as a third factor of an ionic channel imbalance in the arrhythmogenic landscape. Case presentationWe describe the case of a woman struck down by sudden cardiac death, with short QT and early repolarization, in which we found an extremely rare and putatively pathogenic heterozygous variant in the SCN10A gene. Variants involving SCN10A, which encodes a voltage-gated sodium channel, were already associated with alterations of cardiac conduction parameters and the cardiac rhythm disorder, thereby influencing the cardiac physiology and predisposing to arrhythmia. ConclusionWe underline the role of genetic predisposition to sudden cardiac death and, for the first time, suggest a possible environmental effect, such as a pharmacological therapy in the setting of sudden death, with the purpose to increase awareness in clinical practice.

Effect of xylazine, medetomidine and dexmedetomidine on cardiac conduction in pigs

The majority of anaesthetics used in studies regarding heart arrhythmias may affect the cardiac conduction system, thus influencing the results. In veterinary medicine, xylazine, medetomidine and dexmedetomidine are commonly used for premedication in laboratory and companion animals. To date, there have been no studies assessing the effect of these substances on the cardiac conduction system. The aim of this study was to assess the effect of xylazine, medetomidine and dexmedetomidine on the parameters of the cardiac conduction system in pigs. The study was carried out on 18 Great White Polish male pigs weighing from 21 to 40 kg. The animals were divided into three equal groups. The animals from the first group received xylazine at a dose of 2 mg/kg i.v.; those from the second group received medetomidine at 40 mcg/kg i.v.; and those from the third group received dexmedetomidine at 10 mcg/kg i.v. The electrophysiological activity of the heart was analysed using an invasive electrophysiological study (EPS). During the EPS, a decrease in the heart rate after substance administration was observed in all animals, but there were no statistically significant differences in the cardiac conduction parameters. A pro-arrhythmic effect of xylazine was observed, but no statistically significant changes in the EPS parameters were noted. Our results indicate that medetomidine and dexmedetomidine may be used as standard premedication drugs in electrophysiological studies in pigs. Their use may facilitate animal preparation procedures without affecting study results..

No Apparent Cardiac Conduction Effects of Acute Treatment with Risperidone in Children with Autism Spectrum Disorder.

Risperidone is approved for the treatment of serious behavioral problems in children with autism spectrum disorder (ASD). This study examined the effects of risperidone on cardiac conduction in children with ASD. Data were collected from an 8-week, five-site trial conducted by the Research Units on Pediatric Psychopharmacology Autism Network. Children (age 5-17 years) were randomly assigned to risperidone (n = 49) or placebo (n = 52) under double-blind conditions. Risperidone was superior to placebo in reducing serious behavioral problems. A standard 12-lead, electrocardiogram (ECG) was obtained in most subjects at screening and week 8. A pediatric electrophysiologist blind to treatment assignment reviewed all available ECGs for readability, abnormalities, and cardiac conduction parameters, including QTc. The electrophysiologist measurements were compared to machine readings. A second blinded electrophysiologist examined all available ECGs for abnormalities and a 20% random sample for QTc. Of the 101 randomized subjects in the trial, complete pretreatment and week 8 data were available on 65 subjects (placebo n = 30; risperidone n = 35). The electrophysiologist did not identify any cardiac conduction adverse effects of risperidone and there was no difference in mean change on the QTc compared to placebo. The Bland-Altman plot showed a systematic bias in QTc measurements by the electrophysiologist and machine. Machine readings produced higher values than the electrophysiologist for shorter QTc intervals and machine scoring was lower than electrophysiologist readings for longer QTc values (p = 0.001). Two electrophysiologists had overall percent agreements of 82.9% (95% CI: 76.3 to 89.6) on qualitative assessment and 88.6% (95% CI: 79.3 to 98.0) on QTc interval. Using conventional doses during acute treatment in children with ASD and serious behavioral problems, there was no difference in the mean change in QTc between risperidone and placebo. Compared to the electrophysiologist, the machine readings may miss elevated QTc measurements.

Sleep-disordered breathing and daytime cardiac conduction abnormalities on 12-lead electrocardiogram in community-dwelling older men.

Nocturnal cardiac conduction abnormalities are commonly observed in patients with sleep-disordered breathing (SDB). However, few population-based studies have examined the association between SDB and daytime cardiac conduction abnormalities. We examined a random sample of 471 community-dwelling men, aged ≥67years, enrolled in the multi-center Outcomes of Sleep Disorders in Older Men (MrOS Sleep) study. SDB severity was categorized using percent of total sleep time with oxygen saturation <90% (%TST < 90) and apnea hypopnea index (AHI). Cardiac conduction parameters were assessed by resting 12-lead electrocardiography (ECG). All analyses were adjusted for age, site, β-blocker use, coronary heart disease, calcium channel blocker use, and use of antiarrhythmic medications. Mean age was 77 ± 6years, median %TST < 90 was 0.7 (IQR 0.00-3.40), and median AHI was 7.06 (IQR 2.55-15.32). Men with greater nocturnal hypoxemia (%TST < 90 ≥ 3.5%) compared with those without hypoxemia (%TST < 90 < 1.0%) had a lower odds of bradycardia (OR 0.55 [0.32-0.94]) and right bundle branch block (RBBB) (OR 0.24 [0.08-0.75]) but a higher odds of ventricular paced rhythm (OR 4.42 [1.29-15.19]). Heart rate (HR) increased in a graded manner with increasing %TST < 90 (p-trend 0.01) and increasing AHI (p-trend 0.006), but these gradients were small in absolute magnitude. There were no associations of SDB measures with other ECG conduction parameters. Greater nocturnal hypoxemia in older men was associated with a lower prevalence of daytime sinus bradycardia and RBBB, a higher prevalence of ventricular paced rhythm, and higher resting HR.

Effects of paediatric HIV infection on electrical conduction of the heart

ObjectiveTo investigate the effects of HIV infection in children on heart electrical conduction, particularly to delineate the effects of HIV infection from treatment.MethodsOn a 12-lead ECG, available for 37 antiretroviral...

Voltage-gated sodium channels in the mammalian heart.

Mammalian species express nine functional voltage-gated Na+ channels. Three of them, the cardiac-specific isoform Nav1.5 and the neuronal isoforms Nav1.8 and Nav1.9, are relatively resistant to the neurotoxin tetrodotoxin (TTX; IC50 ≥ 1 μM). The other six isoforms are highly sensitive to TTX with IC50 values in the nanomolar range. These isoforms are expressed in the central nervous system (Nav1.1, Nav1.2, Nav1.3, Nav1.6), in the skeletal muscle (Nav1.4), and in the peripheral nervous system (Nav1.6, Nav1.7). The isoform Nav1.5, encoded by the SCN5A gene, is responsible for the upstroke of the action potential in the heart. Mutations in SCN5A are associated with a variety of life-threatening arrhythmias, like long QT syndrome type 3 (LQT3), Brugada syndrome (BrS) or cardiac conduction disease (CCD). Previous immunohistochemical and electrophysiological assays demonstrated the cardiac expression of neuronal and skeletal muscle Na+ channels in the heart of various mammals, which led to far-reaching speculations on their function. However, when comparing the Na+ channel mRNA patterns in the heart of various mammalian species, only minute quantities of transcripts for TTX-sensitive Na+ channels were detectable in whole pig and human hearts, suggesting that these channels are not involved in cardiac excitation phenomena in higher mammals. This conclusion is strongly supported by the fact that mutations in TTX-sensitive Na+ channels were associated with epilepsy or skeletal muscle diseases, rather than with a pathological cardiac phenotype. Moreover, previous data from TTX-intoxicated animals and from cases of human tetrodotoxication showed that low TTX dosages caused at most little alterations of both the cardiac output and the electrocardiogram. Recently, genome-wide association studies identified SCN10A, the gene encoding Nav1.8, as a determinant of cardiac conduction parameters, and mutations in SCN10A have been associated with BrS. These novel findings opened a fascinating new research area in the cardiac ion channel field, and the on-going debate on how SCN10A/Nav1.8 affects cardiac conduction is very exciting.

A common genetic variant within SCN10A modulates cardiac SCN5A expression

Variants in SCN10A, which encodes a voltage-gated sodium channel, are associated with alterations of cardiac conduction parameters and the cardiac rhythm disorder Brugada syndrome; however, it is unclear how SCN10A variants promote dysfunctional cardiac conduction. Here we showed by high-resolution 4C-seq analysis of the Scn10a-Scn5a locus in murine heart tissue that a cardiac enhancer located in Scn10a, encompassing SCN10A functional variant rs6801957, interacts with the promoter of Scn5a, a sodium channel-encoding gene that is critical for cardiac conduction. We observed that SCN5A transcript levels were several orders of magnitude higher than SCN10A transcript levels in both adult human and mouse heart tissue. Analysis of BAC transgenic mouse strains harboring an engineered deletion of the enhancer within Scn10a revealed that the enhancer was essential for Scn5a expression in cardiac tissue. Furthermore, the common SCN10A variant rs6801957 modulated Scn5a expression in the heart. In humans, the SCN10A variant rs6801957, which correlated with slowed conduction, was associated with reduced SCN5A expression. These observations establish a genomic mechanism for how a common genetic variation at SCN10A influences cardiac physiology and predisposes to arrhythmia.

In Vivo Electrophysiologic Studies in Endothelial Nitric Oxide Synthase (eNOS)‐Deficient Mice

Endothelial nitric oxide synthase (eNOS) mediates attenuation of the L-type calcium channel and modulates myocyte contractility. Arrhythmogenic afterdepolarizations are seen in vitro in ouabain-treated isolated myocytes from eNOS-deficient mice. The aim of these studies was to characterize the baseline electrophysiologic (EP) phenotype of eNOS-deficient mice and their potential susceptibility to cardiac conduction abnormalities and inducible arrhythmias. Surface ECG and in vivo intracardiac EP studies were performed in 27 mice lacking the eNOS gene and 21 wild-type littermate control mice. Baseline studies were performed in 10 eNOS-deficient mice and 10 wild-type controls. Subsequently, 17 eNOS-deficient mice and 11 wild-type controls were pretreated with digoxin, and ECG and EP testing were repeated. Data analysis revealed no significant differences in ECG intervals or cardiac conduction parameters, except sinus cycle length was higher in eNOS-deficient mice than wild-type mice (P < 0.01). After digoxin pretreatment, 7 of 17 eNOS-deficient mice had inducible ventricular tachycardia and 2 others had frequent ventricular premature beats, compared with only 3 of 11 wild-type mice with inducible ventricular tachycardia. In addition, 2 digoxin-treated eNOS-deficient mice and 1 wild-type mouse had inducible nonsustained atrial fibrillation. Mice with a homozygous targeted disruption of the eNOS gene have slower heart rates but no other distinguishable EP characteristics under basal sedated conditions. Partial inhibition of the Na+/K+ ATPase pump with digoxin administration increases ventricular ectopic activity in eNOS-/- mice, a phenotype analogous to afterdepolarizations seen in vitro in this eNOS-deficient mouse model.

The pharmacologic profile of desloratadine: a review.

Desloratadine is a new agent for the treatment of diseases such as seasonal allergic rhinitis and chronic urticaria. The pharmacologic profile of desloratadine offers particular benefits in terms of histamine H1-receptor binding potency and H1 selectivity. Desloratadine has a half-life of 21-24 h, permitting once-daily dosing. No specific cautions are required with respect to administration in renal or hepatic failure, and food or grapefruit juice have no effect on the pharmacologic parameters. No clinically relevant racial or sex variations in the disposition of desloratadine have been noted. In combination with the cytochrome P450 inhibitors, ketoconazole and erythromycin, the AUC and Cmax of desloratadine were increased to a small extent, but no clinically relevant drug accumulation occurred. With high-dose treatment (45 mg/day for 10 days), no significant adverse events were observed, despite the sustained elevation of plasma desloratadine levels. Specifically, desloratadine had no effects on the corrected QT interval (QTc) when administered alone, at high dose, or in combination with ketoconazole or erythromycin. Preclinical studies also show that desloratadine does not interfere with HERG channels or cardiac conduction parameters even at high dose. Desloratadine is nonsedating and free of antimuscarinic/anticholinergic effects in preclinical and clinical studies. Novel antiallergic and anti-inflammatory effects have also been noted with desloratadine, a fact which may be relevant to its clinical efficacy.

Hyperbaric oxygen increases parasympathetic activity in professional divers

The role of autonomic nervous system in hyperoxic bradycardia was evaluated by using the power-spectral analysis of heart-rate variability (HRV). Ten professional divers went through two hyperbaric hyperoxic experiments: (1) hyperbaric oxygen (HBO), 100% oxygen at 2.5 ATA, (2) hyperbaric air (HBAIR), O(2) 21% at 2.5 ATA. Four-minute traces of ECG were registered and subjected to power-spectral analysis. Cardiac conduction parameters were evaluated by a diagnostic 12-lead ECG and arrhythmias by a continuous 3-lead ECG. Statistical analysis was made using analysis of variance for repeated measurements. Heart rate decreased (P < 0. 001), but the response was similar during both treatments (P=0.14). Total power increased significantly more during HBO than HBAIR (P=0.003). High-frequency (HF) power (P < 0.001), Hayano's index (P=0.001) and normalized units of HF power (P=0.002) increased and LF/HF index (P < 0.001) decreased more during HBO than HBAIR. There were no changes in cardiac conduction or incidence of arrhythmias. In conclusion, 100% oxygen at 2.5 ATA caused marked increase in parasympathetic tone compared with 21% oxygen at 2.5 ATA.

Clinical and electrophysiologic effects of intravenous dofetilide (UK-68,798), a new class III antiarrhythmic drug, in patients with angina pectoris

Dofetilide (UK-68,798) is a new class III antiarrhythmic agent. In animal experiments it selectively prolongs the refractory periods parallel to the action potential duration without any influence on upstroke velocity or conduction parameters. The present double-blind, placebo-controlled study was designed to show the effect of dofetilide on basic electrophysiologic parameters in patients with coronary artery disease. Eighteen patients (aged 31 to 64 years) with symptoms of stable angina pectoris admitted for routine coronary angiography were recruited. They were randomly allocated to receive either placebo or 1 of 2 dose levels of dofetilide intravenously with 6 patients in each group. Paired electrophysiologic variables were compared before and after administration of dofetilide. Both active dose levels produced significant prolongations (p < 0.05) of 10 to 23% in atrial effective refractory period, 6 to 16% in ventricular effective refractory period and 11 to 15% in ventricular functional refractory period. Atrial functional refractory period was prolonged by 14 to 22% at the high-dose level (p < 0.05). No effect was observed on conduction parameters (PA, AH, HV, PR or QRS intervals), sinus cycle length or sinus node recovery. The selective prolongation of the refractory periods in both atrium and ventricle, combined with a lack of effect on cardiac conduction parameters, indicates that this drug could be useful in the treatment of both atrial and ventricular reentrant tachyarrhythmias and fibrillation.