A Phase 1, Randomized, Open-Label, Safety, Tolerability, and Comparative Bioavailability Study of Intranasal Dihydroergotamine Powder (STS101), Intramuscular Dihydroergotamine Mesylate, and Intranasal DHE Mesylate Spray in Healthy Adult Subjects.

OBJECTIVE: To investigate and compare the safety and the pharmacokinetics of dihydroergotamine (DHE) after administration of intranasal DHE powder (STS101), intranasal DHE spray (Migranal® ), and intramuscular (IM) DHE injection in healthy subjects. METHODS: This was a 2-part, active-controlled, 3-period crossover study over 3 weeks, separated by 1-week washout periods. In part 1, 3 ascending dosage strengths of STS101 (1.3, 2.6, and 5.2 mg) were administered to 15 healthy subjects with no history of migraine. In part 2, 27 healthy subjects were administered 1 dose each of STS101 5.2 mg, Migranal DHE Mesylate Liquid Nasal Spray 2.0 mg, and IM DHE Mesylate 1.0 mg in a randomized order. Liquid chromatography, tandem mass spectrometry was used to determine plasma levels of DHE and its major metabolite, 8'OH-DHE. Pharmacokinetic parameters (Cmax , Tmax , AUC0-2 h , AUC0-48 h , AUC0-inf , and t1/2 ) for DHE and metabolite were calculated. Geometric means and 90% confidence intervals of log-transformed data were calculated and the ratio of means compared. Safety was evaluated by monitoring adverse events, vital signs, electrocardiograms, subjective and objective assessments of nasal signs and symptoms, and changes in laboratory parameters. The study is registered as NCT03874832. RESULTS: Forty-three subjects were enrolled and received study medication. Forty completed all study activities, 14 in part 1 and 26 in part 2. In part 1, DHE plasma levels showed a dose-dependent increase, with STS101 5.2 mg reaching a mean Cmax of 1870 pg/mL with a Tmax of 23 minutes. In part 2, STS101 5.2 mg showed rapid absorption, achieving mean DHE plasma concentrations of 1230 and 1850 pg/mL at 10 and 15 minutes after administration, respectively. In comparison to Migranal, STS101 5.2 mg showed approximately 2-fold higher Cmax (2175 vs 961 pg/mL), AUC0-2 h (2979 vs 1316 h × pg/mL), and AUC0-inf (12,030 vs 6498 h × pg/mL), respectively. The mean AUC0-inf of STS101 5.2 mg was comparable to IM DHE (12,030 vs 13,650 h × pg/mL). STS101 5.2 mg showed substantially lower variability compared to Migranal for Cmax (41% vs 76%), AUC0-2 h (39% vs 75%), and AUC0-inf (39% vs 55%). The incidence of treatment emergent AEs (TEAEs), all mild and transient, reported in parts 1 and 2 combined was 9/15 (60%), 5/15 (33%), and 16/41 (39%) of the subjects after 1.3, 2.6, and 5.2 mg STS101, respectively, and 4/26 (15%) and 5/27 (19%) of the subjects after IM DHE and Migranal, respectively. CONCLUSION: STS101 showed rapid absorption, achieving effective DHE plasma concentrations within 10 minutes. It achieved substantially higher Cmax , AUC0-2 h and AUC0-inf , compared to Migranal suggesting potentially better efficacy than Migranal. Its variability was better than Migranal, thus offering improved consistency of response. AUC0-inf was comparable to IM DHE, suggesting prolonged action and low recurrence. Additionally, the Cmax was sufficiently low to avoid any significant nausea reported with IV DHE. Thus, STS101 is an easy to administer, non-injected, acute treatment for migraine, with a favorable tolerability profile and is expected to provide rapid and consistent freedom from pain and associated migraine symptoms without recurrence.

Moxifloxacin-induced QTc interval prolongations in healthy male Japanese and Caucasian volunteers: a direct comparison in a thorough QT study.

AIM: We investigated whether moxifloxacin-induced QTc prolongations in Japanese and Caucasian healthy male volunteers were significantly different. METHODS: A two period, randomized, crossover, ICH-E14-compliant thorough QT (TQT) study compared placebo-corrected changes in QTc interval from baseline (ΔΔQTc F) and concentration-effect relationships following administration of placebo and 400 mg moxifloxacin to 40 healthy male volunteers from each ethnic population. The point estimates of ΔΔQTc F for each population, and the difference between the two, were calculated at a geometric mean Cmax of moxifloxacin using a linear mixed effects model. The concentration-effect slopes of the two populations were also compared. Equivalence was concluded if the two-sided 90% confidence interval of the difference in ΔΔQTc F was contained within -5 ms to +5 ms limits and the ratio of the slopes was between 0.5 and 2. RESULTS: There were no statistically significant differences between the two populations studied, Japanese vs. Caucasians, respectively, for moxifloxacin Cmax (3.27 ± 0.6 vs. 2.98 ± 0.7 µg ml(-1) ), ΔΔQTc F (9.63 ± 1.15 vs. 11.46 ± 1.19 ms at Cmax of 3.07 µg ml(-1) ) and concentration-response slopes (2.58 ± 0.62 vs. 2.34 ± 0.64 ms per µg ml(-1) ). The difference in the two ΔΔQTc F of -1.8 (90% CI -4.6, 0.9) and the ratio of the two slopes (1.1; 90% CI 0.63, 1.82) were within pre-specified equivalence limits. CONCLUSIONS: Moxifloxacin-induced QTc prolongations did not differ significantly between the Japanese and Caucasian subjects. However, before our findings are more widely generalized, further studies in other populations and with other QT-prolonging drugs are needed to clarify whether inter-ethnic differences in QT sensitivity exist and whether ethnicity of the study population may affect the outcome of a TQT study.

Relative Influence of Trans-Pacific and Regional Atmospheric Transport of PAHs in the Pacific Northwest, U.S.

The relative influences of trans-Pacific and regional atmospheric transport on measured concentrations of polycyclic aromatic hydrocarbons (PAHs), PAH derivatives (nitro- (NPAH) and oxy-(OPAH)), organic carbon (OC), and particulate matter (PM) less than 2.5 µm in diameter (PM2.5) were investigated in the Pacific Northwest, U.S. in 2010-2011. Ambient high volume PM2.5 air samples were collected at two sites in the Pacific Northwest: (1.) Mount Bachelor Observatory (MBO) in the Oregon Cascade Range (2763 m above sea level (asl)) and 2.) Confederated Tribes of the Umatilla Indian Reservation (CTUIR) in the Columbia River Gorge (CRG) (954 m asl). At MBO, the 1,8-dinitropyrene concentration was significantly positively correlated with the time a sampled air mass spent over Asia, suggesting that this NPAH may be a good marker for trans-Pacific atmospheric transport. At CTUIR, NOx, CO2, and SO2 emissions from a 585 MW coal fired power plant, in Boardman OR, were found to be significantly positively correlated with PAH, OPAH, NPAH, OC, and PM2.5 concentrations. By comparing the Boardman Plant operational time frames when the plant was operating to when it was shut down, the plant was found to contribute a large percentage of the measured PAH (67%), NPAH (91%), OPAH (54%), PM2.5 (39%), and OC (38%) concentrations at CTUIR and the CRG prior to Spring 2011 and likely masked trans-Pacific atmospheric transport events to the CRG. Upgrades installed to the Boardman Plant in the spring of 2011 dramatically reduced the plant's contribution to PAH and OPAH concentrations (by ∼72% and ∼40%, respectively) at CTUIR and the CRG, but not NPAH, PM2.5 or OC concentrations.

Withdrawal-related adverse events from clinical trials of clobazam in Lennox-Gastaut syndrome.

To assess withdrawal-related adverse event (AE) rates following abrupt clobazam discontinuation in Phase I trials and gradual clobazam tapering (2-3 weeks) following discontinuation from III trials met the criteria for potential/III trials, we evaluated AE data from four multiple-dosage Phase I trials (duration: 8-34 days). Therapeutic (20 and 40 mg/day) and supratherapeutic clobazam dosages (120 and 160 mg/day) were administered. Adverse events (AEs) were also assessed for patients with Lennox-Gastaut syndrome enrolled in Phase II (OV-1002) and Phase III (OV-1012) studies (duration ≤15 weeks) and in the open-label extension (OLE) trial OV-1004 (≤5 years). Potential withdrawal-related AEs were identified by preferred terms, provided that the AEs occurred ≥1 day following and ≤30 days after the last clobazam doses, or were deemed withdrawal symptoms by investigators. Clinical Institute Withdrawal Assessment for Benzodiazepines (CIWA-B) scale was used to evaluate withdrawal intensity in three of the four Phase I trials. A total of 207 participants in Phase I trials received steady-state clobazam dosages of 20-160 mg/day, 182 received clobazam dosages of ≥40 mg/day, and 94 received clobazam dosages of ≥120 mg/day. Abrupt clobazam discontinuation led to 193 withdrawal-related AEs for 68 Phase I participants. Nearly 50% of AEs occurred after discontinuation of clobazam dosages of ≥120 mg/day. Adverse events were mild or moderate and included headache (14% of Phase I participants), insomnia (12.6%), tremor (10.1%), and anxiety (8.7%). The CIWA-B scores varied (range: 0-59). Most scores were <30, indicating possible mild benzodiazepine withdrawal. III trials met the criteria for potential/III patients received clobazam dosages of ≤40 mg/day, and those in the OLE trial received clobazam dosages of ≤80 mg/day. Eighty-seven patients discontinued clobazam and were gradually tapered. No withdrawal-related AEs or incidences of status epilepticus were reported. Withdrawal-related AEs observed in Phase I studies following abrupt clobazam discontinuation at therapeutic and supratherapeutic dosages were generally mild. No withdrawal-related AEs occurred when dosages were tapered over 3 weeks, after short- or long-term clobazam use (≤5 years).

Cardiac safety of indacaterol in healthy subjects: a randomized, multidose, placebo- and positive-controlled, parallel-group thorough QT study.

BACKGROUND: Indacaterol is a novel once-daily ultra long-acting ß2-agonist for the treatment of chronic obstructive pulmonary disease. It is known that ß2-agonists, like other adrenergic compounds, can prolong the QT-interval. This thorough QT/QTc study (as per ICH E14 guideline) evaluated the effect of indacaterol on the QT interval in healthy subjects. METHODS: In this randomized, double-blind, parallel-group, placebo- and positive-controlled (open-label moxifloxacin) study, non-smoking healthy subjects (18-55 years, body mass index: 18.5-32.0 kg/m2) were randomized (4:4:2:4:1) to 14-day treatment with once-daily indacaterol (150 µg, 300 µg, or 600 µg), placebo, or placebo/moxifloxacin (double-blind 14-day treatment with placebo and a single open-label dose of 400 mg moxifloxacin on Day 14). The primary endpoint was the change from baseline on Day 14 in QTcF (QT interval corrected for heart rate using Fridericia's formula). RESULTS: In total, 404 subjects were randomized to receive indacaterol (150 [n = 108], 300 [n = 108], 600 µg [n = 54]), placebo (n = 107), or placebo/moxifloxacin (n = 27); 388 subjects completed the study. Maximal time-matched mean (90% confidence intervals) treatment differences from placebo in QTcF change from baseline on Day 14 were 2.66 (0.55, 4.77), 2.98 (1.02, 4.93) and 3.34 (0.86, 5.82) ms for indacaterol 150 µg, 300 µg and 600 µg, respectively. Study sensitivity was confirmed with moxifloxacin demonstrating a significant maximal time-matched QTcF prolongation of 13.90 (10.58, 17.22) ms compared to placebo. All indacaterol doses were well tolerated. CONCLUSION: Indacaterol, at doses up to 600 µg once daily (2-4 times the therapeutic dose) does not have any clinically relevant effect on the QT interval.

Ecological information needs for environmental justice.

The concept that all peoples should have their voices heard on matters that affect their well-being is at the core of environmental justice (EJ). The inability of some people of small towns, rural areas, minority, and low-income communities, to become involved in environmental decisions is sometimes due to a lack of information. We provide a template for the ecological information that is essential to examine environmental risks to EJ populations within average communities, using case studies from South Carolina (Savannah River, a DOE site with minority impacts), Washington (Hanford, a DOE site with Native American impacts), and New Jersey (nonpoint, urbanized community pollution). While the basic ecological and public health information needs for risk evaluations and assessments are well described, less attention has been focused on standardizing information about EJ communities or EJ populations within larger communities. We suggest that information needed about EJ communities and populations includes demographics, consumptive and nonconsumptive uses of their regional environment (for example, maintenance and cosmetic, medicinal/religious/cultural uses), eco-dependency webs, and eco-cultural attributes. A purely demographics approach might not even identify EJ populations or neighborhoods, much less their spatial relation to the impact source or to each other. Using information from three case studies, we illustrate that some information is readily available (e.g., consumption rates for standard items such as fish), but there is less information about medicinal, cultural, religious, eco-cultural dependency webs, and eco-cultural attributes, all of which depend in some way on intact, functioning, and healthy ecosystems.

PF-06881894, a Proposed Biosimilar to Pegfilgrastim, Versus US-Licensed and EU-Approved Pegfilgrastim Reference Products (Neulasta®): Pharmacodynamics, Pharmacokinetics, Immunogenicity, and Safety of Single or Multiple Subcutaneous Doses in Healthy Volunteers.

INTRODUCTION: PF-06881894 is a proposed biosimilar to pegfilgrastim (Neulasta®). This study evaluated the pharmacodynamic/pharmacokinetic (PD/PK) equivalence, immunogenicity, and safety of PF-06881894 vs pegfilgrastim reference products (US- and EU-Neulasta®) in healthy volunteers. METHODS: A phase 1, open-label, randomized, crossover study was conducted to assess the pharmacologic equivalence and safety of a single 6-mg dose of PF-06881894, pegfilgrastim-US, and pegfilgrastim-EU. The primary PD endpoints were area under the effect-versus-time curve for absolute neutrophil count (ANC) from dose administration to 288 h postdose, and maximum observed ANC value among subjects confirmed negative for anti-pegfilgrastim antibodies. Primary PK variables included area under the serum pegfilgrastim-versus-time curve from the time of dose administration to time infinity and maximum observed serum pegfilgrastim concentration. A second phase 1, open-label, randomized (1:1), parallel-group, non-inferiority study was conducted to assess the immunogenicity and safety of multiple 6-mg doses of PF-06881894 versus pegfilgrastim-US. The primary endpoint for the immunogenicity study was the proportion of subjects with both negative baseline and confirmed positive postdose anti-pegfilgrastim antibodies at any time during the study. RESULTS: Across the single- and multiple-dose studies (N = 153 and N = 420 treated subjects, respectively), demographics for age (18-65 years), male gender (n = 264/573), and white race (n = 423/573) were similar. Three-way PD/PK equivalence of PF-06881894, pegfilgrastim-US, and pegfilgrastim-EU was demonstrated with the primary PD endpoints and primary PK variables being completely contained within the predefined 90% confidence interval acceptance limits (80-125%). The non-inferiority of PF-06881894 versus pegfilgrastim-US in terms of immunogenicity was established according to the prespecified non-inferiority margin (≤10%). Overall, there were no clinically meaningful differences in safety profiles among or between study groups. CONCLUSIONS: Single-dose PF-06881894 demonstrated PD/PK equivalence and comparable safety with US- and EU-pegfilgrastim reference products. Multiple-dose PF-06881894 demonstrated immunogenicity non-inferiority to pegfilgrastim-US with comparable safety. Both studies contributed to the totality of evidence supporting biosimilarity. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02629289; NCT03273842 (C1221005).

A randomized-controlled trial comparing conventional with minimal catheter approaches for the mapping and ablation of regular supraventricular tachycardias.

AIMS: To compare the use of a minimal (MIN) with a conventional (CON) catheter approach for the mapping and ablation of regular supraventricular tachycardias (SVT) and typical atrial flutter (AFL) in the setting of a randomized-controlled trial. METHODS AND RESULTS: Two hundred patients (age 51.2 +/- 15.9 years, 99 male) were randomized to a MIN or CON group. The MIN approach involved using two catheters for AFL, one to three for other SVT (ablation catheter included), whereas the CON approach involved three and five catheters, respectively. Acute procedural success was similar between the two groups. There was no significant difference in overall procedure times, fluoroscopy times, or radiation doses. Procedure times were shorter for AFL ablation in MIN compared with CON [60 (30-150) vs. 85 (40-200) min, median (range), P = 0.03] from subgroup analysis. A median of three (one to six) catheters was used in MIN and five (three to seven) in CON (P < 0.0001). Catheter costs were significantly lower in MIN compared with CON [6.1 (2-61) vs. 8.5 (4.4-21.3) units, P < 0.0001, where one unit is equivalent to the cost of a diagnostic quadripolar catheter]. At 6-week follow-up, two patients in MIN (2.1%) and three patients in CON (3.2%) had documented recurrence of the index arrhythmia. CONCLUSION: The use of a MIN approach in the treatment of SVT and AFL is as effective, quick, and safe as using a CON approach and is therefore more cost-effective.

A randomized trial to compare atrial fibrillation ablation using a steerable vs. a non-steerable sheath.

AIMS: Catheter positioning and stability are recognized challenges in catheter ablation of atrial fibrillation (AF). This prospective randomized study assessed whether routinely using a steerable sheath affects procedure outcomes. METHODS AND RESULTS: Fifty-six AF patients were randomized to ablation using either an Agilis NXT (St Jude Medical, St Paul, MN, USA) steerable sheath or a fixed-curve Mullins sheath (Cook Medical Inc., Bloomington, IN, USA) for the ablation catheter. A mapping system with CT integration was used to isolate the pulmonary veins (PVs) in pairs and further ablation performed if AF persisted. There was no significant difference in time to gain trans-septal access, CT registration time, time to isolate PVs, fluoroscopy time for PV isolation, total procedure time, or total fluoroscopy time. A learning curve was seen for the steerable sheath, and after correcting for this, CT registration time and right PV isolation were quicker in this group. One patient crossed over from fixed-curve to steerable. Acute, 3-, and 6-month single procedure success were similar in both groups. CONCLUSION: Allowing for the usage learning curve, a steerable sheath reduced time for some elements of AF ablation. Although this did not result in improved success, it may be useful for inexperienced operators, but at increased procedure cost.

The impact of image integration on catheter ablation of atrial fibrillation using electroanatomic mapping: a prospective randomized study.

AIMS: A detailed appreciation of the left atrial/pulmonary venous (LA/PV) anatomy may be important in improving the safety and success of catheter ablation for AF. The aim of this randomized study was to determine the impact of computed tomographic (CT) integration into an electroanatomic mapping (EAM) system on clinical outcome in patients undergoing catheter ablation for atrial fibrillation (AF). METHODS AND RESULTS: Eighty patients with AF were randomized to undergo first-time wide encirclement of ipsilateral PV pairs using EAM alone (40 patients) or with CT (40 patients, Cartomerge). Wide encirclement of the pulmonary veins was performed using irrigated radiofrequency ablation with the electrophysiological endpoint of electrical isolation (EI). The primary endpoint was single-procedure success at 6 month follow up. Acute and long-term procedural outcomes were also determined. There was no significant difference in single procedure success between EAM (56%) and cavotricuspid isthmus image (CTI) (50%) groups (P = 0.9). Acute procedural outcomes (EI, PV reconnection, sinus rhythm restored by ablation in persistent AF), fluoroscopy, and procedure durations (EI of right PVs, EI of left PVs, total) did not differ significantly between EAM and CTI groups. CONCLUSION: Image integration to guide catheter ablation for AF did not significantly improve the clinical outcome. Achieving PV EI is the critical determinant of procedural success rather than the mapping tools used to achieve it.

PF-06881893 (Nivestym™), a Filgrastim Biosimilar, Versus US-Licensed Filgrastim Reference Product (US-Neupogen®): Pharmacokinetics, Pharmacodynamics, Immunogenicity, and Safety of Single or Multiple Subcutaneous Doses in Healthy Volunteers.

BACKGROUND: Three comparative clinical studies assessed the pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity and safety of PF-06881893 (filgrastim-aafi; Nivestym™), a filgrastim biosimilar, versus US-licensed reference product (filgrastim; US-Neupogen®) in healthy volunteers (HVs). METHODS: Two separate open-label, crossover-design PK/PD studies were conducted: a single-dose study (n = 24) and a multiple-dose study (n = 60). In each study, HVs were randomized to Nivestym followed by US-Neupogen, or vice versa. Study drug (5 µg/kg) was administered subcutaneously as a single injection or as five consecutive daily injections. Primary PK and PD endpoints were area under the filgrastim serum concentration-time curve, maximum observed concentration, area under the effect curve (AUEC) for absolute neutrophil count (ANC), maximum observed ANC, AUEC for cluster of differentiation (CD)-34+ count, and maximum observed CD34+ count. In an open-label, parallel-design, non-inferiority, comparative immunogenicity study, HVs were randomized (n = 128/treatment) to Nivestym or US-Neupogen. The primary endpoint was the proportion of subjects with a negative baseline antidrug antibody (ADA) test result and one or more confirmed post-dose positive ADA result. RESULTS: Overall demographics were as follows: female (n = 162/340); White (n = 274/340), Black (n = 58/340), and other (n = 8/340); age (18-65 years); and weight (50.8-96.5 kg). All primary PK and PD endpoints met the pre-specified criteria for PK and PD equivalence. The primary endpoint in the comparative immunogenicity study met pre-specified criteria for non-inferiority. CONCLUSIONS: Nivestym demonstrated PK and PD equivalence in single and multiple subcutaneous-dose settings and non-inferiority for immunogenicity to US-Neupogen, with a comparable safety profile, supporting the demonstration of biosimilarity. TRIAL REGISTRATION: ClinicalTrials.gov C1121002 (NCT02766647); C1121003 (NCT02766634); C1121012 (NCT02923791).

The use of a single chamber leadless pacemaker for the treatment of cardioinhibitory vasovagal syncope.

BACKGROUND: The use of pacemakers in the treatment of cardioinhibitory vasovagal syncope is controversial with a mixed message from the limited evidence base. Single chamber leadless pacemakers have been shown to be an effective alternative option to conventional pacemakers. OBJECTIVE: This study examines the use of leadless pacemakers in a cardioinhibitory vasovagal population in the United Kingdom. METHODS: Observational data on 32 patients implanted with the Micra Transcatheter Pacemaker System for vasovagal syncope are presented. Data was collected on implant indications, implant procedure and follow up data from 12 centres across the United Kingdom that had elected to use a Micra leadless pacemaker in this patient population. RESULTS: 32 patients aged 37 ±â€¯14 years (range 18 to 64 years) with 62% of the patients being female were recruited to the study. Vasovagal syncope was diagnosed clinically and with the support of Holter monitoring, tilt table testing and implantable loop recorders. The duration of symptoms was 8 ±â€¯8 yrs. with an average frequency of syncope being 4 ±â€¯6 times/year. The Micra pacemaker was successfully implanted in all patients with a major complication rate of 3.1%. Patients were followed up for 404 ±â€¯237 days (range 63-928 days). At follow up 28 (87%) patients were free from symptoms. CONCLUSIONS: This observational study suggests that the use of a single chamber leadless pacemaker in the treatment of cardioinhibitory vasovagal syncope might be a reasonable clinical option.

British Heart Rhythm Society Clinical Practice Guidelines on the Management of Patients Developing QT Prolongation on Antipsychotic Medication.

The British Heart Rhythm Society's Clinical Practice Guidelines on the Management of Patients Developing QT Prolongation on Antipsychotic Medication are written for heart rhythm consultants, primary care physicians, specialist registrars, nurses and physiologists who may be requested to review ECGs or advise on cases where antipsychotic-induced QT prolongation is suspected or proven. The guidance is adapted from the latest Maudsley Prescribing Guidelines in Psychiatry, published in 2018.

Validation of computed tomography image integration into the EnSite NavX mapping system to perform catheter ablation of atrial fibrillation.

INTRODUCTION: The complex anatomy of the left atrium (LA) makes location of ablation catheters difficult using fluoroscopy alone, and therefore 3D mapping systems are now routinely used. We describe the integration of a CT image into the EnSite NavX System with Fusion and its validation in patients undergoing atrial fibrillation (AF) or left atrial tachycardia (AT) catheter ablation. METHODS AND RESULTS: Twenty-three patients (61 +/- 9.2 years, 16 male) with paroxysmal (14) and persistent (8) AF and persistent (1) AT underwent ablation using CT image integration into the EnSite NavX mapping system with the EnSite Fusion Dynamic Registration software module. In all cases, segmentation of the CT data was accomplished using the EnSite Verismo segmentation tool, although repeat segmentation attempts were required in seven cases. The CT was registered with the NavX-created geometry using an average of 24 user-defined fiducial pairs (range 9 to 48). The average distance from NavX-measured lesion positions to the CT surface was 3.2 +/- 0.9 mm (median 2.4 mm). A large, automated, retrospective test using registrations with random subsets of each patient's fiducial pairs showed this average distance decreasing as the number of fiducial pairs increased, although the improvement ceased to be significant beyond 15 pairs. In confirmation, those studies which had used 16 or more pairs had a smaller average lesion-to-surface distance (2.9 +/- 0.7 mm) than those using 15 or fewer (4.3 +/- 0.8 mm, P < 0.02). Finally, for the 13 patients who underwent left atrial circumferential ablation (LACA), there was no significant difference between the circumference computed using NavX-measured positions and CT surface positions for either the left pulmonary veins (178 +/- 64 vs. 177 +/- 60 mm; P = 0.81) or the right pulmonary veins (218 +/- 86 vs. 207 +/- 81 mm; P = 0.08). CONCLUSION: CT image integration into the EnSite NavX Fusion system was successful in all patients undergoing catheter ablation. A learning curve exists for the Verismo segmentation tool; but once the 3D model was created, the registration process was easily accomplished, with a registration error that is comparable with registration errors using other mapping systems with CT image integration. All patients went on to have subsequent successful ablation procedures. Where LACA was performed (13 patients), only four patients required segmental ostial lesions to achieve electrical isolation.

Pharmacokinetics of [14C]-Benzo[a]pyrene (BaP) in humans: Impact of Co-Administration of smoked salmon and BaP dietary restriction.

Benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon (PAH), is a known human carcinogen. In non-smoking adults greater than 95% of BaP exposure is through diet. The carcinogenicity of BaP is utilized by the U.S. EPA to assess relative potency of complex PAH mixtures. PAH relative potency factors (RPFs, BaP = 1) are determined from high dose animal data. We employed accelerator mass spectrometry (AMS) to determine pharmacokinetics of [14C]-BaP in humans following dosing with 46 ng (an order of magnitude lower than human dietary daily exposure and million-fold lower than animal cancer models). To assess the impact of co-administration of food with a complex PAH mixture, humans were dosed with 46 ng of [14C]-BaP with or without smoked salmon. Subjects were asked to avoid high BaP-containing diets and a 3-day dietary questionnaire given to assess dietary exposure prior to dosing and three days post-dosing with [14C]-BaP. Co-administration of smoked salmon, containing a complex mixture of PAHs with an RPF of 460 ng BaPeq, reduced and delayed absorption. Administration of canned commercial salmon, containing very low amounts of PAHs, showed the impacts on pharmacokinetics were not due to high amounts of PAHs but rather a food matrix effect.

Electrophysiologic and anatomic characterization of sites resistant to electrical isolation during circumferential pulmonary vein ablation for atrial fibrillation: a prospective study.

BACKGROUND: Catheter ablation (CA) by wide encirclement of pulmonary veins (WEPV) restores sinus rhythm in up to 95%. Complex PV-left atrial (LA) connections make achieving electrical isolation (EI) challenging. We examined anatomical and technical features associated with resistance to EI during WEPV in a prospective study. METHODS: One hundred one consecutive patients with symptomatic AF underwent first-time CA guided by electroanatomic mapping and CT integration (Cartomerg). Following double-transseptal access, WEPV was performed. After completion of PV encirclement, the line was mapped and where no signal could be obtained, CA was performed inside the WE line at the site of earliest PV breakthrough on the circular mapping catheter. Sites of EI were tagged. Anatomic studies of corresponding regions of the venoatrial junction in 24 adult hearts were performed. RESULTS: Sites resistant to EI were located at the inferior quadrant (P < 0.001) for the RSPV, superior quadrant (P < 0.001) for the RIPV, and the inferior and anterior quadrants (P < 0.001) for the LSPV. EI was significantly less frequent at the posterior quadrant (P < 0.001) for the LIPV. To achieve EI, CA was necessary inside the WE on the intervenous ridge on the right in 51% and on the left in 41%. The LPV/LAA ridge was investigated by anatomic studies that demonstrated considerable variation in the narrowest width (3-23.7 mm) and transmural thickness (1-5 mm). CONCLUSION: Sites of EI after WEPV have a preferential distribution determined by anatomic features. CA on the intervenous ridge is required in a significant proportion of patients to achieve EI. Atrial folds and ridges increase myocardial thickness creating technical and anatomic challenges for achieving transmural lesions.

Current case mix and results of catheter ablation of regular supraventricular tachycardia: are we giving unrealistic expectations to patients?

AIMS: Catheter ablation (CA) has become the treatment of choice for regular supraventricular tachycardia (SVT). The purpose of this study was to investigate whether the current clinical results in a large single centre are as good as success rates quoted to patients from published trials and national cardiology society websites. METHODS AND RESULTS: We recorded and analysed prospectively the acute and follow-up (FU) results of all CA procedures performed for SVT at our institution over a 2-year period. We compared our results with the success rates of 90-98% for CA quoted in the literature. We performed a total of 547 CA at our institution over 2 years, of which 389 (71%) were for regular SVT. Of these, 71 procedures (18%) were redo procedures. The overall acute procedural success rate was 96.1% (374/389). Follow-up data were available for 367 of 389 (94.3%) procedures. The overall 6-week success rate varied between 74.7 and 91.3% depending on the SVT type (average 83.9%). The FU success rates were lower for redo procedures (47/66, 71.2%) when compared with first ablation (de novo) procedures (261/301, 86.7%), P = 0.003. CONCLUSION: Published success rates are much better than current success rates in a large single centre. It is possible that the information regarding outcome given to patients during the consent process is not accurate.

Vigabatrin Lacks Proarrhythmic Potential: Results from a Thorough QT/QTc Study in Healthy Volunteers.

PURPOSE: A thorough QT study was performed to assess the proarrhythmic potential of vigabatrin, an antiepileptic drug approved in the United States for the treatment of infantile spasms and refractory complex partial seizures. METHODS: In this Phase I, randomized, double-blind, placebo- and active-controlled (moxifloxacin), 4-sequence, crossover study conducted at a single center, healthy participants received 1 of 4 randomly assigned treatments: 3.0g vigabatrin solution (therapeutic dose) and 1 moxifloxacin placebo tablet; 6.0g vigabatrin solution (supratherapeutic dose) and 1 moxifloxacin placebo tablet; 400 mg moxifloxacin and vigabatrin placebo solution; moxifloxacin placebo tablet and vigabatrin placebo solution. FINDINGS: Mean changes from baseline in placebo-corrected QTcF, QTcB, and QTcI with vigabatrin 3.0 g and 6.0 g indicated no signal for any QTc effect relative to baseline. All 1-sided upper 95% confidence intervals for the differences between each vigabatrin dose and placebo were <10 ms at all time points. QTcF was unaffected by increasing plasma vigabatrin concentrations; no arrhythmias were observed in any treatment group. Low rates of first-degree atrioventricular block, sinus tachycardia, and sinus bradycardia occurred in all treatment groups. Most adverse events were mild. IMPLICATIONS: The findings from this thorough QT study are consistent with existing clinical data and confirm a lack of proarrhythmic potential of vigabatrin.

A Thorough QT/QTc Study of Clobazam in Healthy Volunteers.

PURPOSE: A thorough QT study was conducted to assess the proarrhythmic potential of clobazam and its active metabolite, N-desmethylclobazam (N-CLB). METHODS: In this Phase I, single-site, randomized, double-blind, double-dummy, parallel-group study, healthy participants were randomized to 1 of 4 treatment groups: clobazam 40 mg/d (maximum therapeutic dosage), clobazam 160 mg/d (supratherapeutic dosage), placebo, or moxifloxacin 400 mg (active control). FINDINGS: Of 280 enrolled participants (n = 70 per treatment arm), 250 (92%) completed the study; 194 were included in the pharmacokinetics population (clobazam 40 mg/d, n = 66; clobazam 160 mg/d, n = 62; and moxifloxacin, n = 66). Mean changes from baseline in QT interval placebo-corrected for heart rate using the Fridericia formula (primary end point), Bazett formula, and individual correction method (QTcF, QTcB, and QTcI, respectively) with clobazam 40 and 160 mg/d revealed no effect on QTc. No clinically relevant or treatment-related arrhythmias were observed, and there were no instances of second- or third-degree atrioventricular block. Given that clobazam is primarily demethylated to N-CLB by cytochrome P450 (CYP) enzyme, CYP3A4, the mean plasma time-concentration profile of clobazam was unchanged with the exclusion of CYP2C19 poor metabolizers. As N-CLB is metabolized by CYP2C19, the exclusion of CYP2C19 poor metabolizers resulted in slightly decreased mean plasma time-concentration profiles of N-CLB. Using a linear mixed-effects model, the effects of the clobazam and N-CLB Cmax values on the placebo-corrected changes from baseline in QTcF, QTcI, and QTcB were near zero or slightly negative, and are not considered clinically important. The incidence of treatment-emergent adverse events was greatest in the clobazam groups (number of moderate AEs experienced by patients: PBO, 3/70; MOXI, 5/70; CLB 40 mg/d, 18/70; CLB 160 mg/d, 21/70; severe AEs: PBO, MOXI, & CLB 160 mg/d, 0; CLB 40 mg/d, 2/70); there were no serious AEs in any treatment group. A total of 10% of participants experienced benzodiazepine-withdrawal symptoms (16%, 23%, and 3% in the clobazam 40 and 160 mg/d groups and the moxifloxacin group, respectively). IMPLICATIONS: The findings from this thorough QT study are consistent with existing clinical data and support the lack of proarrhythmic potential with clobazam.