Safety of an intravenous formulation of lamotrigine

AbstractPurposeIntravenous (IV) formulations are useful when treating patients where oral administration is not possible and to study certain pharmacokinetic parameters such as bioavailability. We developed a stable-labeled IV formulation of lamotrigine (LTG) for studying pharmacokinetics in epilepsy patients.MethodsStable-labeled IV LTG was given to 20 persons with epilepsy (6 men; 14 women) with a mean age of 34.8 years (SD 11.7). A 50mg dose of LTG (stable labeled) was given intravenously and replaced 50mg of the regular morning oral dose of LTG (unlabeled, commercially available formulation).ResultsNo significant changes in blood pressure, heart rate, or adverse events including rash were attributed to administration of a 50-mg dose of the intravenous LTG formulation.ConclusionOur results show that LTG base that is complexed with 2-hydroxypropyl-β-cyclodextrin and stable-labeled can be given safely as a tracer replacement dose

Body size but not warning signal luminance influences predation risk in recently metamorphosed poison frogs.

During early development, many aposematic species have bright and conspicuous warning appearance, but have yet to acquire chemical defenses, a phenotypic state which presumably makes them vulnerable to predation. Body size and signal luminance in particular are known to be sensitive to variation in early nutrition. However, the relative importance of these traits as determinants of predation risk in juveniles is not known. To address this question, we utilized computer-assisted design (CAD) and information on putative predator visual sensitivities to produce artificial models of postmetamorphic froglets that varied in terms of body size and signal luminance. We then deployed the artificial models in the field and measured rates of attack by birds and unknown predators. Our results indicate that body size was a significant predictor of artificial prey survival. Rates of attack by bird predators were significantly higher on smaller models. However, predation by birds did not differ between artificial models of varying signal luminance. This suggests that at the completion of metamorphosis, smaller froglets may be at a selective disadvantage, potentially because predators can discern they have relatively low levels of chemical defense compared to larger froglets. There is likely to be a premium on efficient foraging, giving rise to rapid growth and the acquisition of toxins from dietary sources in juvenile poison frogs.This study was conducted in compliance with the scientific permit SE/A-19-11 provided by the Panamanian National Authority for the Environment (ANAM). This study was supported by a PhD scholarship (IFARHU-SENACYT program) and a research grant No. APY-NI-010-006B/SENACYT both awarded to EEF by the Government of Panama, and by a Royal Society University Research Fellowship to JDB. MS was supported by a Biotechnology and Biological Sciences Research Council David Phillips Research Fellowship (BB/G022887/1). HMR was supported by a Junior Research Fellowship from Churchill College, Cambridge. Special thanks to Rachel Page at STRI for supporting EEF with the grant application, Sistema Nacional de Investigacion de Panama (SNI), and the People of Santa Fe for their collaboration during the study. We are grateful to Leesther Vásquez, Joelbin De La Cruz, Georgia Croxford and field assistants from AMIPARQUE for assistance with the production of frog models.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/ece3.173

The effects of spatial legacies following shifting management practices and fire on boreal forest age structure

Forest age structure and its spatial arrangement are important elements of sustainable forestry because of their effects on biodiversity and timber availability. Forest management objectives that include specific forest age structure may not be easily attained due to constraints imposed by the legacies of historical management and natural disturbance. We used a spatially explicit stochastic model to explore the synergetic effects of forest management and fire on boreal forest age structure. Specifically, we examined (1) the duration of spatial legacies of different management practices in the boreal forest, (2) how multiple shifts in management practices affect legacy duration and the spatial trajectories of forest age structure, and (3) how fire influences legacy duration and pattern development in combination with harvesting. Results based on 30 replicates of 500 years for each scenario indicate that (1) spatial legacies persist over 200 years and the rate at which legacies are overcome depends on whether new management targets are in synchrony with existing spatial pattern; (2) age specific goals were met faster after multiple management shifts due to the similar spatial scale of the preceding management types; (3) because large fires can erase the spatial pattern created by smaller disturbances, scenarios with fire had shorter lags than scenarios without fire. These results suggest that forest management goals can be accelerated by applying management at a similar spatial scale as existing spatial patterns. Also, management planning should include careful consideration of historical management as well as current and likely future disturbances

Geographical trends in the yolk carotenoid composition of the pied flycatcher (Ficedula hypoleuca)

Carotenoids in the egg yolks of birds are considered to be important antioxidants and immune stimulants during the rapid growth of embryos. Yolk carotenoid composition is strongly affected by the carotenoid composition of the female’s diet at the time of egg formation. Spatial and temporal differences in carotenoid availability may thus be reflected in yolk concentrations. To assess whether yolk carotenoid concentrations or carotenoid profiles show any large-scale geographical trends or differences among habitats, we collected yolk samples from 16 European populations of the pied flycatcher, Ficedula hypoleuca. We found that the concentrations and proportions of lutein and some other xanthophylls in the egg yolks decreased from Central Europe northwards. The most southern population (which is also the one found at the highest altitude) also showed relatively low carotenoid levels. Concentrations of β-carotene and zeaxanthin did not show any obvious geographical gradients. Egg yolks also contained proportionally more lutein and other xanthophylls in deciduous than in mixed or coniferous habitats. We suggest that latitudinal gradients in lutein and xanthophylls reflect the lower availability of lutein-rich food items in the northern F. hypoleuca populations and in montane southern populations, which start egg-laying earlier relative to tree phenology than the Central European populations. Similarly, among-habitat variation is likely to reflect the better availability of lutein-rich food in deciduous forests. Our study is the first to indicate that the concentration and profile of yolk carotenoids may show large-scale spatial variation among populations in different parts of the species’ geographical range. Further studies are needed to test the fitness effects of this geographical variation

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)