Citizen science reveals waterfowl responses to extreme winter weather.

Global climate change is increasing the frequency and severity of extreme climatic events (ECEs) which may be especially detrimental during late-winter when many species are surviving on scarce resources. However, monitoring animal populations relative to ECEs is logistically challenging. Crowd-sourced datasets may provide opportunity to monitor species' responses to short-term chance phenomena such as ECEs. We used 14 years of eBird-a global citizen science initiative-to examine distribution changes for seven wintering waterfowl species across North America in response to recent extreme winter polar vortex disruptions. To validate inferences from eBird, we compared eBird distribution changes against locational data from 362 GPS-tagged Mallards (Anas platyrhynchos) in the Mississippi Flyway. Distributional shifts between eBird and GPS-tagged Mallards were similar following an ECE in February 2021. In general, the ECE affected continental waterfowl population distributions; however, responses were variable across species and flyways. Waterfowl distributions tended to stay near wintering latitudes or moved north at lesser distances compared with non-ECE years, suggesting preparedness for spring migration was a stronger "pull" than extreme weather was a "push" pressure. Surprisingly, larger-bodied waterfowl with grubbing foraging strategies (i.e., geese) delayed their northward range shift during ECE years, whereas smaller-bodied ducks were less affected. Lastly, wetland obligate species shifted southward during ECE years. Collectively, these results suggest specialized foraging strategies likely related to resource limitations, but not body size, necessitate movement from extreme late-winter weather in waterfowl. Our results demonstrate eBird's potential to monitor population-level effects of weather events, especially severe ECEs. eBird and other crowd-sourced datasets can be valuable to identify species which are adaptable or vulnerable to ECEs and thus, begin to inform conservation policy and management to combat negative effects of global climate change.

Assessment of the cardiac safety and pharmacokinetics of a short course, twice daily dose of orally-administered mifepristone in healthy male subjects.

BACKGROUND: Mifepristone is approved to control hyperglycemia in adults with endogenous Cushing's syndrome and is described as a mildly QTc prolonging drug, based on a TQT study. The aim of the present study was to assess the effect of mifepristone on the QTc interval at plasma mifepristone concentrations exceeding those observed in the TQT study. METHODS: Twenty healthy, male volunteers were given three doses of 1200 mg mifepristone every 12 h with a high-fat meal in a randomized, placebo-controlled 2-period crossover study. Holter ECG recordings were made on Day 1 and 2. RESULTS: Eighteen subjects completed the study. Mean peak plasma mifepristone concentrations were 4.01 µg/mL (CV: 31%) on the fi rst dose and 5.77 µg/mL (CV: 29%) on the third dose. Mifepristone did not have a meaningful QTc effect. The placebo-corrected, change-from- -baseline QTcF (ΔΔQTcF) was between -1.6 and 0.7 ms on the fi rst dose (upper bound of 90% CI 3.8 ms) and the largest ΔΔQTcF on the third dose was 4.9 ms (upper bound of 90% CI: 8.4 ms). Concentration effect modeling showed a slightly negative slope of -0.01 ms/ng/mL. CONCLUSIONS: Mifepristone did not cause a clinically meaningful QTc prolongation in healthy volunteers at plasma concent rations of mifepristone and its main metabolites that clearly exceeded those seen in a previous TQT study.

Assessment of the consistency of absorption of dihydroergotamine following oral inhalation: pooled results from four clinical studies.

BACKGROUND: MAP0004 is an investigational orally inhaled dihydroergotamine (DHE) delivered via a TEMPO(®) metered dose inhaler that was effective in the acute treatment of migraine in a large Phase 3 trial. Rapid and consistent absorption of DHE is important for efficacy in the acute treatment of migraine. METHODS: The pharmacokinetic parameters from four recent clinical studies, with doses including the proposed clinical dose of 1.0 mg nominal (0.65 mg emitted) MAP0004, were assessed for the consistency and speed of absorption of DHE. RESULTS: Across these studies, MAP0004 administration resulted in rapid DHE absorption, with a median time of maximum concentration (C(max)) of approximately 10 min. The C(max) and area under the curve from time zero to 2 hr associated with the MAP0004 1.0 mg nominal dose were also similar between the three studies with this dose. C(max) values after 1.0 mg MAP0004 administration were consistently lower than for 1.0 mg intravenous DHE administration, and C(max) appeared to correlate with incidence of nausea. In these studies, DHE absorption through the lung was fast, consistent, and not associated with any unique tolerability issues for this route of administration. CONCLUSIONS: These results provide evidence of the consistency of absorption that can be achieved with the use of an appropriate metered dose inhaler, which may translate into a predictable therapeutic response.

Tecarfarin, a novel vitamin K reductase antagonist, is not affected by CYP2C9 and CYP3A4 inhibition following concomitant administration of fluconazole in healthy participants.

Comparative pharmacokinetics of vitamin K epoxide reductase antagonists tecarfarin and warfarin were assessed before and after coadministration for 21 days of the CYP450 inhibitor fluconazole in a randomized, open-label, single-center drug interaction study. Twenty healthy adult participants were randomized 1:1 to receive approximately equipotent single oral doses of tecarfarin (50 mg) or warfarin (17.5 mg). Following 7 days of baseline serial blood level collections, each participant received oral fluconazole 400 mg daily for 21 days. A second identical single oral dose of tecarfarin or warfarin was given 14 days after starting fluconazole with serial pharmacokinetic sampling. Key pharmacokinetic parameters C(max), t(max), AUC(0-168), apparent clearance, and t(1/2) demonstrated no tecarfarin-fluconazole interaction but a strong warfarin-fluconazole interaction. The ratio of log-transformed mean AUC(0-168) with versus without fluconazole for tecarfarin was 91.2% (90% confidence interval [CI]: 83.3-99.8) and for racemic warfarin was 213% (90% CI: 202-226). The 90% CI was entirely within the standard 80% to 125% bioequivalence interval for tecarfarin but well outside the bioequivalence interval for warfarin, confirming a clinically significant pharmacokinetic interaction between warfarin and fluconazole. In contrast, tecarfarin pharmacokinetics were apparently unchanged by fluconazole.

A target-mediated model to describe the pharmacokinetics and hemodynamic effects of recombinant human vascular endothelial growth factor in humans.

BACKGROUND: The Vascular Endothelial Growth Factor (VEGF) in Ischemia for Vascular Angiogenesis (VIVA) trial was a double-blind, placebo-controlled, phase II clinical trial designed to evaluate the safety, efficacy, and pharmacokinetics of combined intracoronary and intravenous infusions of recombinant human vascular endothelial growth factor (rhVEGF(165)) for therapeutic angiogenesis. This study describes the use of a mechanism-based model to characterize the nonlinear kinetics observed after intravenous administration of rhVEGF(165). The model predicts that rhVEGF(165) distribution occurs through both saturable binding to high-affinity receptors and reversible interactions with low-affinity binding sites. METHODS: In this trial, rhVEGF(165) was administered to patients with coronary artery disease at a dose rate of 17 or 50 ng/kg/min by means of intracoronary infusion for 20 minutes, followed by three 4-hour intravenous infusions on days 3, 6, and 9. Pharmacokinetic samples and blood pressure measurements were collected at baseline, during infusion, and for 6 hours after infusion. RESULTS: The plasma clearance, steady-state volume of distribution, and terminal half-life after a 4-hour intravenous infusion of rhVEGF(165) at the high dose were 19.1 +/- 5.7 mL/min/kg, 960 +/- 260 mL/kg, and 33.7 +/- 13 minutes, respectively. The duration of hypotension that occurred after rhVEGF(165) administration appeared to be related to the model-predicted VEGF(165) concentration associated with the high-affinity receptor compartment. CONCLUSIONS: This mechanism-based model accurately predicted VEGF concentrations and allowed for the simulation of various rhVEGF(165) dose regimens that may aid in optimization of drug delivery for future clinical trials.