Viloxazine has a long history of clinical use in Europe as an antidepressant, and has recently been repurposed into an extended-release form for the treatment of attention-deficit/hyperactivity disorder in the USA. An immediate-release formulation was approved for the treatment of depression in the UK in 1974, and was subsequently marketed there and in several European countries for 30 years with no major safety concerns. In contrast to first-generation antidepressants (e.g., tricyclic antidepressants, monoamine oxidase inhibitors), viloxazine was associated with a relatively low risk for cardiotoxicity. Gastrointestinal symptoms were the most commonly reported side effects. The therapeutic effects of viloxazine are thought to be primarily the result of its action as a norepinephrine reuptake inhibitor, although in vitro and preclinical in vivo animal data suggest that viloxazine may also impact the serotoninergic system. This review summarizes the evolving knowledge of viloxazine based on information from previously published preclinical and clinical investigations, and acquired unpublished historical study reports from both open-label and blinded controlled clinical trials. We review the chemical properties, mechanism of action, safety, and tolerability across these studies, and discuss the contemporary rationale for the development of this agent as an extended-release oral formulation for the treatment of attention-deficit/hyperactivity disorder.

The pharmacokinetic parameters of ranitidine were studied following administration of a single intravenous dose in 9 critically ill infants. Ranitidine disposition was best described by a biphasic elimination curve. For 8 patients, the mean values for T 1/2, apparent volume of distribution, and total body clearance were 2.09 h, 1.61 l/kg, and 13.93 ml/min/kg, respectively. Based on simulated steady-state concentration profiles, a dose of 0.7 mg/kg administered intravenously every 6 h should maintain serum levels above 40 ng/ml for 4.7 h of the dosing interval with a wide degree of variability.

DISCLAIMERThie report wee prepared u an account of work tponeond by an agency of the UsJted SUM Government Netthw the Uaited Sutaa Oonmment swr any aneocy thereof, nor any of their iwHcyin, makae any warranty, txpreM or implied, or ajramei any legal liability or tatsontieiifcy for the aonracy, completeneM, or HHMMI of any infornation, appantw, product, or prooe* djedoeed, or reprmati that iti ma would not infringe privately owned rithu. Refer ence herein to any apeeiffc commercial product, proowi, or aervice by trade name, trademark, BtaMfactarer, or otherwiee doei not aeceewrily eonttitute or imply itt endonement, recommendatioe, or favoriat by the United Sutaa Oovernmaat or any agency thereof. Vx> viewi awl opinion* of authon eupmeed herein do not neceeserily Mate or reflect tboee of the United Statu Gwei-int or any anency thereof. LAWRENCE LIVERMORE NATIONAL LABORATORY Executive tUnder the direction of the Office of Civilian Radioactive Waste Management, the Department of Energy's (DOE) Nevada Nuclear Waste Storage Investigations (NNWSI) project is evaluating a candidate repository site at Yucca Mountain, Ne vada, for permanent disposal of high level nuclear waste. The Lawrence Livermore National Labora tory (LLNL), a participant in the NNWSI project, is developing waste package designs to meet NRC requirements. Included are designs for the refer ence waste form configurations of: (1) spent fuel (SF), which consists of both consolidated and un consolidated spent fuel rods from pressurizedwater-reactor (PWR) and boiling-water-reactor (BWR) assemblies, (2) commercial high level waste (CHLW), as a borosilicate glass containing commercial spent fuel reprocessing wastes, and (3) West Valley/defense high level waste (WV/ DHIW) immobilized in borosilicate glass. Refer ence and alternative package designs have been developed for each waste form for both vertical and horizontal emplacement configurations. All designs are for emplacement in a tuff repository located above the water table (in the vadose zone).Conceptual designs and analyses for waste packages in tuff below the water table were devel oped for the Office of Nuclear Waste Isolation Summary (ONWI) by Westinghouse Electric Corporation in 1981 -82 (Westinghouse, 1983. The candidate hori zon was changed by NNWSI to the vadose zone in late 1982 (Vieth, 1982;Dudley and Erdal, 1982). LLNL has made changes in and additions to the conceptual designs to reflect this change in the re pository location. Analyses have been performed to determine conformance of the selected design ensemble to NRC design requirements in the cur rently understood repository environment. Fig ure 1 shows the reference conceptual designs. The selected designs (Gregg and O'Neal, 1983) include reference and alternative designs that vary in com plexity, performance, and cost.From this ensemble, one set of designs (for SF, CHLW, and WV/DHIW) will be chosen which is expected to meet Nuclear Regulatory Commission (NRC)/Environmental Protection Agency (EPA) requirements when analyzed with accura...

Attention-deficit/hyperactivity disorder (ADHD), the single most common neuropsychiatric disorder with cognitive and behavioral manifestations, often starts in childhood and usually persists into adolescence and adulthood. Rarely seen alone, ADHD is most commonly complicated by other neuropsychiatric disorders that must be factored into any intervention plan to optimally address ADHD symptoms. With more than 30 classical Schedule II (CII) stimulant preparations available for ADHD treatment, only three nonstimulants (atomoxetine and extended-release formulations of clonidine and guanfacine) have been approved by the United States Food and Drug Administration (FDA), all of which focus on modulating the noradrenergic system. Given the heterogeneity and complex nature of ADHD in most patients, research efforts are identifying nonstimulants which modulate pathways beyond the noradrenergic system. New ADHD medications in clinical development include monoamine reuptake inhibitors, monoamine receptor modulators, and multimodal agents that combine receptor agonist/antagonist activity (receptor modulation) and monoamine transporter inhibition. Each of these “pipeline” ADHD medications has a unique chemical structure and differs in its pharmacologic profile in terms of molecular targets and mechanisms. The clinical role for each of these agents will need to be explored with regard to their potential to address the heterogeneity of individuals struggling with ADHD and ADHD-associated comorbidities. This review profiles alternatives to Schedule II (CII) stimulants that are in clinical stages of development (Phase 2 or 3). Particular attention is given to viloxazine extended-release, which has completed Phase 3 studies in children and adolescents with ADHD.

Objectives: Clinical trials in psychiatry frequently report results from lengthy, comprehensive assessments to characterize a subject emotionally, cognitively, and behaviorally before and after treatment. However, the potential treatment implications of these results and how they translate into clinical practice remain unclear. Conversely, the Clinical Global Impressions (CGI) scales are quick, intuitive assessments used to assess the functional impact of a treatment in clinically relevant terms. The objectives of the present analyses are to translate scores from comprehensive assessments of symptom severity and functional impairment into clinically meaningful CGI levels. Methods: These post-hoc analyses use data integrated from four pivotal Phase 3 trials in attention-deficit/hyperactivity disorder (ADHD) in children and adolescents treated with the novel nonstimulant SPN-812 (Viloxazine Extended-Release). In this study, we evaluated the ADHD Rating Scale-5 (ADHD-RS-5) and Weiss Functional Impairment Rating Scale-Parent (WFIRS-P), assessments of symptom severity and functional impairment, respectively, by linking these scales with the CGI scales at baseline and end of study. Results: For participants that improved, a one-level change on the CGI-Improvement (CGI-I) was associated with a 10–15-point change on the ADHD-RS-5, and a 0.2–0.5-point change on the WFIRS-P. On the CGI-I, ratings of much improved and very much improved were associated with a percent score decrease (i.e., improvement) of ∼55% and 80% on the ADHD-RS-5 and ∼40% and 70% on the WFIRS-P, respectively. Differences between children and adolescents were minor and are unlikely to be clinically meaningful. Conclusion: These post-hoc analyses provide clinically meaningful benchmarks for the interpretation of scores on the ADHD-RS-5 and WFIRS-P in terms of CGI evaluations in subjects with ADHD. These results may be useful for physicians seeking to understand a treatment's potential impact on their ADHD patients or for researchers looking to define their study results within a clinically relevant context. Data are from clinical trials NCT03247530, NCT03247543, NCT03247517, and NCT03247556.