Long-acting stimulants for treatment of attention-deficit/hyperactivity disorder: a focus on extended-release formulations and the prodrug lisdexamfetamine dimesylate to address continuing clinical challenges

Individuals with attention-deficit/hyperactivity disorder (ADHD) show pervasive impairments across family, peer, and school or work functioning that may extend throughout the day. Psychostimulants are highly effective medications for the treatment of ADHD, and the development of long-acting stimulant formulations has greatly expanded the treatment options for individuals with ADHD. Strategies for the formulation of long-acting stimulants include the combination of immediate-release and delayed-release beads, and an osmotic-release oral system. A recent development is the availability of the first prodrug stimulant, lisdexamfetamine dimesylate (LDX). LDX itself is inactive but is cleaved enzymatically, primarily in the bloodstream, to release d-amphetamine (d-AMP). Several clinical trials have demonstrated that long-acting stimulants are effective in reducing ADHD symptoms compared with placebo. Analog classroom and simulated adult workplace environment studies have shown that long-acting stimulants produce symptom reduction for at least 12 h. Long-acting stimulants exhibit similar tolerability and safety profiles to short-acting equivalents. While variations in gastric pH and motility can alter the availability and absorption of stimulants released from long-acting formulations, the systemic exposure to d-AMP following LDX administration is unlikely to be affected by gastrointestinal conditions. Long-acting formulations may also improve adherence and lower abuse potential compared with their short-acting counterparts. The development of long-acting stimulants provides physicians with an increased range of medication options to help tailor treatment for individuals with ADHD.     

Unifying sources and sinks in ecology and Earth sciences

The paired source and sink concepts are used increasingly in ecology and Earth sciences, but they have evolved in divergent directions, hampering communication across disciplines. We propose a conceptual framework that unifies existing definitions, and review their most significant consequences for the various disciplines. A general definition of the source and sink concepts that transcends disciplines is based on net flows between the components of a system: a source is a subsystem that is a net exporter of some living or non‐living entities of interest, and a sink is a net importer of these entities. Sources and sinks can further be classified as conditional and unconditional, depending on the intrinsic propensity of subsystems to either produce (source) or absorb (sink) a surplus of these entities under some (conditional) or all (unconditional) conditions. The distinction between conditional and unconditional sources and sinks, however, is strongly context dependent. Sources can turn into sinks, and vice versa, when the context is changed, when systems are subject to temporal fluctuations or evolution, or when they are considered at different spatial and temporal scales. The conservation of ecosystem services requires careful consideration of the source?sink dynamics of multiple ecosystem components. Our synthesis shows that source?sink dynamics has profound consequences for our ability to understand, predict, and manage species and ecosystems in heterogeneous landscapes.     

Inhibition of ethylene biosynthesis enhances embryogenesis of cultured microspores of Brassica napus

Procedures that induce microspore embryogenesis have been described for a range of Brassica species, but embryo yield remains low for a number of genotypes. We have carried out experiments with the microspores from a weakly responsive line of B. napus to determine the culture conditions that optimize their in vitro embryogenesis by treating them with effectors of ethylene synthesis and action. The results revealed that isolated microspores subjected to an initial heat stress in a medium supplemented with inhibitors of ethylene synthesis such as AVG and CoCl₂ exhibited significantly increased embryo yields. This suggested that regulatory effects are exerted by the ethylene produced by the isolated microspores on the early processes of gametogenesis. As a consequence, treatment of microspores with SAM, an ethylene synthesis precursor, or with the ethylene-releasing agent ethephon, led to decreases in embryo yield. A special response to ethylene during the early stages of microspore development was finally shown to occur through experiments where isolated microspores were treated for increasing periods of time with CoCl₂. Collectively, our data demonstrated that the induction of embryogenesis induced by heat stress can be enhanced by inhibitors of ethylene biosynthesis.