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 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.

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.

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.

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).

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.

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.

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.

Communicating Results of a Dietary Exposure Study Following Consumption of Traditionally Smoked Salmon.

One expectation of community-based participatory research (CBPR) is participant access to study results. However, reporting experimental data produced by studies involving biological measurements in the absence of clinical relevance can be challenging to scientists and participants. We applied best practices in data sharing to report the results of a study designed to explore polycyclic aromatic hydrocarbons absorption, metabolism, and excretion following consumption of traditionally smoked salmon by members of the Confederated Tribes of the Umatilla Indian Reservation (CTUIR). A dietary exposure study was developed, in which nine Tribal members consumed 50 g of traditionally smoked salmon and provided repeated urine samples over 24 hours. During recruitment, participants requested access to their data following analysis. Disclosing data is an important element of CBPR and must be treated with the same rigor as that given to the data analysis. The field of data disclosure is relatively new, but when handled correctly can improve education within the community, reduce distrust, and enhance environmental health literacy. Using the results from this study, we suggest mechanisms for sharing data with a Tribal community.

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.

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.

Metabolism and excretion rates of parent and hydroxy-PAHs in urine collected after consumption of traditionally smoked salmon for Native American volunteers.

Few studies have been published on the excretion rates of parent polycyclic aromatic hydrocarbons (PAHs) and hydroxy-polycyclic aromatic hydrocarbons (OH-PAHs) following oral exposure. This study investigated the metabolism and excretion rates of 4 parent PAHs and 10 OH-PAHs after the consumption of smoked salmon. Nine members of the Confederated Tribes of the Umatilla Indian Reservation consumed 50 g of traditionally smoked salmon with breakfast and five urine samples were collected during the following 24 h. The concentrations of OH-PAHs increased from 43.9 µg/g creatinine for 2-OH-Nap to 349 ng/g creatinine for 1-OH-Pyr, 3 to 6 h post-consumption. Despite volunteers following a restricted diet, there appeared to be a secondary source of naphthalene and fluorene, which led to excretion efficiencies greater than 100%. For the parent PAHs that were detected in urine, the excretion efficiencies ranged from 13% for phenanthrene (and its metabolite) to 240% for naphthalene (and its metabolites). The half-lives for PAHs ranged from 1.4 h for retene to 3.3h for pyrene. The half-lives for OH-PAHs were higher and ranged from 1.7 h for 9-OH-fluorene to 7.0 h for 3-OH-fluorene. The concentrations of most parent PAHs, and their metabolites, returned to the background levels 24 h post-consumption.

Effects of age and sex on the single-dose pharmacokinetics and pharmacodynamics of apixaban.

BACKGROUND AND OBJECTIVES: The effects of age and sex on apixaban pharmacokinetics and pharmacodynamics were studied. METHODS: This was an open-label, single-dose, 2 × 2 factorial study. Healthy young (aged 18-40 years) and elderly (aged ≥ 65 years) male and female subjects received a single oral 20 mg dose of apixaban. Blood and urine samples were collected for pharmacokinetic and pharmacodynamic (blood only) analyses. Subjects were monitored for adverse events throughout the study. RESULTS: Seventy-nine subjects were enrolled into four groups: young males (n = 20), elderly males (n = 20), young females (n = 20) and elderly females (n = 19). Age did not affect the maximum observed plasma concentration (C max). The mean area under the concentration-time curve from time zero extrapolated to infinite time (AUC∞) was 32% greater in elderly subjects than in young subjects. The mean C max and AUC∞ values were 18 and 15% higher, respectively, in females than in males. The time course of the mean international normalized ratio (INR), modified prothrombin time (mPT) and anti-Xa activity tracked the apixaban concentration-time curve. All three pharmacodynamic measures exhibited a positive linear correlation with the plasma apixaban concentration. Differences in the mean INR, mPT and anti-Xa activity between age and sex groups were small (<15% at the maximum mean values) and were generally related to pharmacokinetic differences. However, anti-Xa activity demonstrated less variability than the INR or mPT, and may have utility as a bioassay for apixaban. Apixaban was well tolerated, with no serious adverse events. CONCLUSION: There were no clinically meaningful age- or sex-related differences in the pharmacokinetics and pharmacodynamics of apixaban that would require dose modification on the basis of age or sex alone.

Determination of parent and hydroxy PAHs in personal PM2.5 and urine samples collected during Native American fish smoking activities.

A method was developed for the measurement of 19 parent PAHs (PAHs) and 34 hydroxylated PAHs (OH-PAHs) in urine and personal air samples of particulate matter less than 2.5 µm in diameter (PM2.5) using GC-MS and validated using NIST SRM 3672 (Organic Contaminants in Smoker's Urine) and SRM 3673 (Organic Contaminants in Nonsmoker's Urine). The method was used to measure PAHs and OH-PAHs in urine and personal PM2.5 samples collected from the operators of two different fish smoking facilities (tipi and smoke shed) burning two different wood types (alder and apple) on the Confederated Tribes of Umatilla Indian Reservation (CTUIR) while they smoked salmon. Urine samples were spiked with ß-glucuronidase/arylsulfatase to hydrolyze the conjugates of OH-PAHs and the PAHs and OH-PAHs were extracted using Plexa and C18 solid phases, in series. The 34 OH-PAHs were derivatized using MTBSTFA, and the mixture was measured by GC-MS. The personal PM2.5 samples were extracted using pressurized liquid extraction, derivatized with MTBSTFA and analyzed by GC-MS for PAHs and OH-PAHs. Fourteen isotopically labeled surrogates were added to accurately quantify PAHs and OH-PAHs in the urine and PM2.5 samples and three isotopically labeled internal standards were used to calculate the recovery of the surrogates. Estimated detection limits in urine ranged from 6.0 to 181 pg/ml for OH-PAHs and from 3.0 to 90 pg/ml for PAHs, and, in PM2.5, they ranged from 5.2 to 155 pg/m(3) for OH-PAHs and from 2.5 to 77 pg/m(3) for PAHs. The results showed an increase in OH-PAH concentrations in urine after 6h of fish smoking and an increase in PAH concentrations in air within each smoking facility. In general, the PAH exposure in the smoke shed was higher than in the tipi and the PAH exposure from burning apple wood was higher than burning alder.

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).

Mass in the left atrial appendage: a therapeutic dilemma.

This is a case of a persistent mobile mass in the left atrial appendage in which 3-dimensional transesophageal echocardiography provided excellent definition of the contour of the mass and helped in comparison during follow-up. The mass was incidentally found before atrial fibrillation ablation and initially thought to be a thrombus. As it persisted almost unchanged despite adequate anticoagulation, a tumour such as a fibroelastoma became the leading possibility, presenting us with a management dilemma. Ablation was cancelled, and, because the mass was stable with no embolic sequelae, a conservative approach was adopted. The patient was discharged on long-term anticoagulation.

Effect of Vortioxetine on Cardiac Repolarization in Healthy Adult Male Subjects: Results of a Thorough QT/QTc Study.

This double-blind, randomized, placebo- and positive-controlled, parallel-group study evaluated the effect of vortioxetine (Lu AA21004), an investigational multimodal antidepressant, on QT interval in accordance with current guidelines of the International Conference on Harmonisation (ICH-E14). A total of 340 healthy men were randomized to receive 1 of 4 treatments for 14 days: (1) vortioxetine 10 mg once daily (QD), (2) vortioxetine 40 mg QD, (3) placebo QD, or (4) placebo QD on Days 1 through 13 followed by a single dose of moxifloxacin 400 mg (positive control). The primary endpoint was the largest time-matched, baseline-adjusted least-squares (LS) mean difference for the individual-corrected QT interval (QTcNi [linear]) between vortioxetine and placebo. Alternative QT correction formulas (i.e., Fredericia [QTcF], Bazett [QTcB], Framingham [QTcFm], and QTcNi [nonlinear]) were used as secondary endpoints. The upper bound of the 2-sided 90% confidence interval around the LS mean difference from placebo for baseline-adjusted QTcNi (linear), QTcF, QTcB, QTcFm, and QTcNi (nonlinear) did not exceed 10 ms at any time point after multiple doses of vortioxetine 10 mg (therapeutic) or 40 mg (supratherapeutic). Overall, the study results indicate that vortioxetine is unlikely to affect cardiac repolarization in healthy subjects.

Perceptions of the Environment and Health Among Members of the Confederated Tribes of the Umatilla Indian Reservation.

Indigenous cultures perceive the natural environment as an essential link between traditional cultural practices, social connectedness, identity, and health. Many tribal communities face substantial health disparities related to exposure to environmental hazards. Our study used qualitative methods to better understand the Confederated Tribes of the Umatilla Indian Reservation (CTUIR) members' perspectives about their environment and its connections with their health including views on environmental health hazards. Three 90-minute focus group sessions with a total of 27 participants were held to elicit opinions on meanings of health and how the environment interacts with health. A systematic text analysis was used to derive themes across focus groups. Participants expressed a holistic view of health that included environmental, physical, mental, spiritual, and social components. A healthy natural environment was identified as an essential component of a healthy individual and a healthy community. Participants also described many environmental health concerns including second-hand smoke, outdoor smoke, diesel exhaust, mold, pesticides, contaminated natural foods, and toxic wastes from the Hanford nuclear site and methamphetamine labs. Many believe the identified environmental hazards contribute to diseases in their community. The natural environment is an important resource to CTUIR members and plays an integral role in achieving and maintaining health. Knowledge about the values and concerns of the community are useful to the tribal and federal governments, health professionals, environmental health practitioners, and community members who seek to achieve sustainable and healthy rural Native communities.

Effect of Native American fish smoking methods on dietary exposure to polycyclic aromatic hydrocarbons and possible risks to human health.

Although it is known that polycyclic aromatic hydrocarbons (PAHs) can be found in smoked meats, little is known about their prevalence in Native American smoked fish. In this work, the effect of traditional Native American fish smoking methods on dietary exposure to PAHs and possible risks to human health has been assessed. Smoking methods considered smoking structure (tipi or shed) and wood type (apple or alder). Neither smoking structure nor wood type accounted for differences in smoked salmon content of 33 PAHs. Carcinogenic and noncarcinogenic PAH loads in traditionally smoked salmon were 40-430 times higher than those measured in commercial products. Dietary exposure to PAHs could result in excess lifetime cancer risks between 1 × 10(-5) and 1 × 10(-4) at a daily consumption rate of 5 g d(-1) and could approach 1 × 10(-2) at 300 g d(-1). Hazard indexes approached 0.005 at 5 g d(-1), or approximately 0.3 at 300 g d(-1). Levels of PAHs present in smoked salmon prepared using traditional Native American methods may pose elevated cancer risks if consumed at high consumption rates over many years.