Stimulant prodrugs: A pharmacological and clinical assessment of their role in treating ADHD and binge-eating disorder.

In this review, we critically evaluate the contribution of prodrugs to treating two related psychiatric disorders, attention-deficit hyperactivity disorder (ADHD) and binge-eating disorder (BED). ADHD is characterized by inattentiveness, distractibility, impulsiveness, and hyperactivity. BED is also an impulse-control disorder which leads to frequent, compulsive episodes of excessive eating (binges). Lisdexamfetamine (LDX; prodrug of d-amphetamine) is approved to treat both ADHD and BED. Serdexmethylphenidate (SDX; prodrug of d-threo-methylphenidate) is not clinically approved as monotherapy but, in a fixed-dose combination with immediate release d-threo-methylphenidate (Azstarys™), SDX is approved for managing ADHD in children/adolescents. The pharmacological actions of a stimulant mediate both its efficacy and side-effects. Therefore, daily management of ADHD or BED to maintain optimum efficacy and tolerability places highly restrictive requirements on the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of stimulant medications, especially prodrugs. Prodrugs must have good bioavailability and rapid metabolism to provide therapeutic efficacy soon after morning dosing combined with providing stimulant coverage throughout the day/evening. A wide selection of dosages and linear PK for the prodrug and its active metabolite are essential requirements for treatment of these conditions. The proposed neurobiological causes of ADHD and BED are described. The chemical, pharmacological and PK/PD properties responsible for the therapeutic actions of the prodrugs, LDX and SDX, are compared and contrasted. Finally, we critically assess their contribution as ADHD and BED medications, including advantages over their respective active metabolites, d-amphetamine and d-threo-methylphenidate, and also their potential for misuse and abuse.

Permafrost thaw induces short-term increase in vegetation productivity in northwestern Canada.

Over the past several decades, various trends in vegetation productivity, from increases to decreases, have been observed throughout Arctic-Boreal ecosystems. While some of this variation can be explained by recent climate warming and increased disturbance, very little is known about the impacts of permafrost thaw on productivity across diverse vegetation communities. Active layer thickness data from 135 permafrost monitoring sites along a 10° latitudinal transect of the Northwest Territories, Canada, paired with a Landsat time series of normalized difference vegetation index from 1984 to 2019, were used to quantify the impacts of changing permafrost conditions on vegetation productivity. We found that active layer thickness contributed to the observed variation in vegetation productivity in recent decades in the northwestern Arctic-Boreal, with the highest rates of greening occurring at sites where the near-surface permafrost recently had thawed. However, the greening associated with permafrost thaw was not sustained after prolonged periods of thaw and appeared to diminish after the thaw front extended outside the plants' rooting zone. Highest rates of greening were found at the mid-transect sites, between 62.4° N and 65.2° N, suggesting that more southernly sites may have already surpassed the period of beneficial permafrost thaw, while more northern sites may have yet to reach a level of thaw that supports enhanced vegetation productivity. These results indicate that the response of vegetation productivity to permafrost thaw is highly dependent on the extent of active layer thickening and that increases in productivity may not continue in the coming decades.

Psychedelic drug abuse potential assessment for new drug applications and controlled substance scheduling: A United States perspective.

BACKGROUND: Psychedelics are an increasingly active area of research and pharmaceutical development. This includes abuse potential assessment to better understand their pharmacological mechanisms and effects and guide controlled substance regulation. Psychedelics pose challenges to abuse assessments to ensure valid, reliable, and generalizable outcomes and safe study conduct. FINDINGS: Key nonclinical techniques, for example, receptor binding and functional assays in vitro, and nonclinical physical dependence determinations, are easily adaptable to psychedelics. However, the entactogens (weak reinforcers) and hallucinogens (non-reinforcers) require more flexible approaches than typically recommended by regulatory agencies. Phase 1 pharmacokinetic/pharmacodynamic safety studies and Phases 2/3 efficacy/safety trials with systematic monitoring of abuse-related adverse events are readily applicable to psychedelics. Human abuse trials require modification because supratherapeutic doses may not be safe and procedures, for example, personal monitors to manage serious adverse events, might bias outcomes. RECOMMENDATIONS: Abuse-related studies for psychedelics requiring approval by Food and Drug Administration and other agencies should take into consideration existing knowledge that will vary from extensive, for example, psilocybin, to zero for novel hallucinogens and entactogens. Many abuse assessments can be reasonably applied to animals and humans without compromising scientific integrity. Modification of existing techniques and incorporating a broader range of nonclinical tests should ensure generalizable outcomes. Human abuse studies merit reconsideration and possible modification to ensure safety and validity for psychedelic drug evaluation. Other nonclinical and clinical methods can provide evaluations of the pharmacological equivalence of test drugs to known drugs of abuse to provide context to the abuse assessment and guide drug scheduling.

New Drugs to Treat ADHD: Opportunities and Challenges in Research and Development.

Since the landmark MTA (Multimodal Treatment of ADHD) trial unequivocally demonstrated the efficacy of methylphenidate, catecholaminergic drugs, especially stimulants, have been the therapeutic mainstay in treatment of Attention-Deficit Hyperactivity Disorder (ADHD). We review the new drugs which have entered the ADHD formulary. The lessons learned from drug-candidates that have succeeded in clinical trials together with those that have not have also been considered. What emerges confirms and consolidates the hypothesis that clinically effective ADHD drugs indirectly or directly increase catecholaminergic neurotransmission in the prefrontal cortex (PFC). Attempts to enhance catecholaminergic signalling through modulatory neurotransmitter systems or cognitive-enhancing drugs have all failed. New drugs approved for ADHD are catecholaminergic reuptake inhibitors and releasing agents, or selective noradrenaline reuptake inhibitors. Triple reuptake inhibitors with preferential effects on dopamine have not been successful. The substantial number of failures probably accounts for a continued focus on developing novel catecholaminergic and noradrenergic drugs, and a dearth of drug-candidates with novel mechanisms entering clinical development. However, substantial improvements in ADHD pharmacotherapy have been achieved by the almost exclusive use of once-daily medications and prodrugs, e.g. lisdexamfetamine and Azstarys®, which improve compliance, deliver greater efficacy and reduce risks for diversion and abuse.

Prospects for new drugs to treat binge-eating disorder: Insights from psychopathology and neuropharmacology.

BACKGROUND: Binge-eating disorder (BED) is a common psychiatric condition with adverse psychological and metabolic consequences. Lisdexamfetamine (LDX) is the only approved BED drug treatment. New drugs to treat BED are urgently needed. METHODS: A comprehensive review of published psychopathological, pharmacological and clinical findings. RESULTS: The evidence supports the hypothesis that BED is an impulse control disorder with similarities to ADHD, including responsiveness to catecholaminergic drugs, for example LDX and dasotraline. The target product profile (TPP) of the ideal BED drug combines treating the psychopathological drivers of the disorder with an independent weight-loss effect. Drugs with proven efficacy in BED have a common pharmacology; they potentiate central noradrenergic and dopaminergic neurotransmission. Because of the overlap between pharmacotherapy in attention deficit hyperactivity disorder (ADHD) and BED, drug-candidates from diverse pharmacological classes, which have already failed in ADHD would also be predicted to fail if tested in BED. The failure in BED trials of drugs with diverse pharmacological mechanisms indicates many possible avenues for drug discovery can probably be discounted. CONCLUSIONS: (1) The efficacy of drugs for BED is dependent on reducing its core psychopathologies of impulsivity, compulsivity and perseveration and by increasing cognitive control of eating. (2) The analysis revealed a large number of pharmacological mechanisms are unlikely to be productive in the search for effective new BED drugs. (3) The most promising areas for new treatments for BED are drugs, which augment noradrenergic and dopaminergic neurotransmission and/or those which are effective in ADHD.

Contrasting effects of the α7 nicotinic receptor antagonist methyllycaconitine in different rat models of heroin reinstatement.

BACKGROUND: α7 Nicotinic acetylcholine receptors are implicated in the reinstatement of drug-seeking, an important component of relapse. We showed previously that the α7 nicotinic acetylcholine receptor antagonist, methyllycaconitine, specifically attenuated morphine-primed reinstatement of conditioned place preference in rodents and this effect was mediated in the ventral hippocampus. AIMS: The purpose of this study was to evaluate α7 nicotinic acetylcholine receptor antagonism in reinstatement of the conditioned place preference for the more widely abused opioid, heroin, and to compare the effect of α7 nicotinic acetylcholine receptor blockade on reinstatement of heroin-seeking and heroin self-administration in an intravenous self-administration model of addictive behaviour. METHODS: Rats were trained to acquire heroin conditioned place preference or heroin self-administration; both followed by extinction of responding. Methyllycaconitine or saline was given prior to reinstatement of drug-primed conditioned place preference, or drug-prime plus cue-induced reinstatement of intravenous self-administration, using two protocols: without delivery of heroin in response to lever pressing to model heroin-seeking, or with heroin self-administration, using fixed and progressive ratio reward schedules, to model relapse. RESULTS: Methyllycaconitine had no effect on acquisition of heroin conditioned place preference or lever-pressing for food rewards. Methyllycaconitine blocked reinstatement of heroin-primed conditioned place preference. Methyllycaconitine did not prevent drug-prime plus cue-induced reinstatement of heroin-seeking, reinstatement of heroin self-administration, or diminish the reinforcing effect of heroin. CONCLUSIONS: The α7 nicotinic acetylcholine receptor antagonist, methyllycaconitine, prevented reinstatement of the opioid conditioned place preference, consistent with a role for α7 nicotinic acetylcholine receptors in the retrieval of associative memories of drug liking. The lack of effect of methyllycaconitine in heroin-dependent rats in two intravenous self-administration models suggests that α7 nicotinic acetylcholine receptors do not play a role in later stages of heroin abuse.

Permafrost is warming at a global scale.

Permafrost warming has the potential to amplify global climate change, because when frozen sediments thaw it unlocks soil organic carbon. Yet to date, no globally consistent assessment of permafrost temperature change has been compiled. Here we use a global data set of permafrost temperature time series from the Global Terrestrial Network for Permafrost to evaluate temperature change across permafrost regions for the period since the International Polar Year (2007-2009). During the reference decade between 2007 and 2016, ground temperature near the depth of zero annual amplitude in the continuous permafrost zone increased by 0.39 ± 0.15 °C. Over the same period, discontinuous permafrost warmed by 0.20 ± 0.10 °C. Permafrost in mountains warmed by 0.19 ± 0.05 °C and in Antarctica by 0.37 ± 0.10 °C. Globally, permafrost temperature increased by 0.29 ± 0.12 °C. The observed trend follows the Arctic amplification of air temperature increase in the Northern Hemisphere. In the discontinuous zone, however, ground warming occurred due to increased snow thickness while air temperature remained statistically unchanged.

Investigation of the reinforcing potential of samidorphan and naltrexone by fixed and progressive ratio intravenous self-administration testing in heroin-maintained rats.

BACKGROUND: Samidorphan is a novel µ-opioid antagonist with low intrinsic activity at κ- and δ-opioid receptors. AIMS: Because samidorphan is central nervous system-active, we investigated whether samidorphan (13.6, 40.8, 68 µg/kg/injection) served as a positive reinforcer in rats trained to self-administer heroin on a fixed ratio-5 schedule. Samidorphan's relative reinforcing effect was evaluated by progressive ratio/break-point determination. Naltrexone (13.6, 40.8, 68 µg/kg/injection) and heroin (7.5, 15, 25 µg/kg/injection) were comparators. RESULTS: All heroin doses maintained self-administration on fixed ratio-5 and progressive ratio/break-points at levels significantly greater than saline. Samidorphan and naltrexone had similar profiles on fixed ratio-5 with one samidorphan dose serving as a positive reinforcer and one naltrexone dose showing a strong trend ( p=0.053) for positive reinforcement. The numbers of injections of every samidorphan and naltrexone dose were significantly lower than all heroin doses. The numbers of self-administered samidorphan and naltrexone injections/session on fixed ratio-5 were not significantly different from one another. The mean inter-injection intervals for heroin were significantly shorter than for saline, whereas those of samidorphan and naltrexone were not. Progressive ratio break-points for samidorphan and naltrexone were not different from saline except for the highest dose of samidorphan. In addition, the progressive ratio break-points for samidorphan were not significantly different from those of naltrexone and were significantly lower than heroin. The samidorphan unit-doses evaluated in self-administration yielded plasma concentrations ranging between 25-109% and 10-45% of the maximum concentration values in humans. CONCLUSIONS: Overall, the profiles of samidorphan and naltrexone, which has no abuse liability, were similar in this model.

Safe Patient Handling and Mobility: Development and Implementation of a Large-Scale Education Program.

This article addresses the development, implementation, and evaluation of an education program for safe patient handling and mobility at a large academic medical center. The ultimate goal of the program was to increase safety during patient mobility/transfer and reduce nursing staff injury from lifting/pulling. This comprehensive program was designed on the basis of the principles of prework, application, and support at the point of care. A combination of online learning, demonstration, skill evaluation, and coaching at the point of care was used to achieve the goal. Specific roles and responsibilities were developed to facilitate implementation. It took 17 master trainers, 88 certified trainers, 176 unit-based trainers, and 98 coaches to put 3706 nurses and nursing assistants through the program. Evaluations indicated both an increase in knowledge about safe patient handling and an increased ability to safely mobilize patients. The challenge now is sustainability of safe patient-handling practices and the growth and development of trainers and coaches.

Evaluating the abuse potential of psychedelic drugs as part of the safety pharmacology assessment for medical use in humans.

Psychedelics comprise drugs come from various pharmacological classes including 5-HT2A agonists, indirect 5-HT agonists, e.g., MDMA, NMDA antagonists and κ-opioid receptor agonists. There is resurgence in developing psychedelics to treat psychiatric disorders with high unmet clinical need. Many, but not all, psychedelics are schedule 1 controlled drugs (CDs), i.e., no approved medical use. For existing psychedelics in development, regulatory approval will require a move from schedule 1 to a CD schedule for drugs with medical use, i.e., schedules 2-5. Although abuse of the psychedelics is well documented, a systematic preclinical and clinical evaluation of the risks they pose in a medical-use setting does not exist. We describe the non-clinical tests required for a regulatory evaluation of abuse/dependence risks, i.e., drug-discrimination, intravenous self-administration and physical dependence liability. A synopsis of the existing data for the various types of psychedelics is provided and we describe our findings with psychedelic drugs in these models. FDA recently issued its guidance on abuse/dependence evaluation of drug-candidates (CDER/FDA, 2017). We critically review the guidance, discuss the impact this document will have on non-clinical abuse/dependence testing, and offer advice on how non-clinical abuse/dependence experiments can be designed to meet not only the expectations of FDA, but also other regulatory agencies. Finally, we offer views on how these non-clinical tests can be refined to provide more meaningful information to aid the assessment of the risks posed by CNS drug-candidates for abuse and physical dependence. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.

The National Trauma Research Repository: Ushering in a New ERA of trauma research (Commentary).

Despite being the leading cause of death in the United States for individuals 46 years and younger and the primary cause of death among military service members, trauma care research has been underfunded for the last 50 years. Sustained federal funding for a coordinated national trauma clinical research program is required to advance the science of caring for the injured. The Department of Defense is committed to funding studies with military relevance; therefore, it cannot fund pediatric or geriatric trauma clinical trials. Currently, trauma clinical trials are often performed within a single site or a small group of trauma hospitals, and research data are not available for secondary analysis or sharing across studies. Data-sharing platforms encourage transfer of research data and knowledge between civilian and military researchers, reduce redundancy, and maximize limited research funding. In collaboration with the Department of Defense, trauma researchers formed the Coalition for National Trauma Research (CNTR) in 2014 to advance trauma research in a coordinated effort. CNTR's member organizations are the American Association for the Surgery of Trauma (AAST), the American College of Surgeons Committee on Trauma (ACS COT), the Eastern Association for the Surgery of Trauma (EAST), the Western Trauma Association (WTA), and the National Trauma Institute (NTI). CNTR advocates for sustained federal funding for a multidisciplinary national trauma research program to be conducted through a large clinical trials network and a national trauma research repository. The initial advocacy and research activities underway to accomplish these goals are presented.

Vertical distribution of Eucalanoid copepods within the Costa Rica Dome area of the Eastern Tropical Pacific.

A variety of ecological strategies for tolerance of low-oxygen conditions within the Costa Rica Dome (CRD) area of the Eastern Tropical Pacific are documented for the copepod family Eucalanidae. During the summer of 2010, we compared the ecological strategies used by the Eucalanidae inside and outside the central CRD region. We compared the vertical and horizontal distributions of five species, Eucalanus inermis, Subeucalanus subtenuis, Subeucalanus subcrassus, Subeucalanus pileatus and Pareucalanus attenuatus together with Rhincalanus species, in the epipelagic (upper 200 m) among four locations, which we grouped into a section roughly crossing the core CRD area (inside-outside core CRD). The coastal area outside the CRD supported the most diverse assemblage, whereas overall abundance of Eucalanidae in the central CRD was 2-fold greater than outside and dominated by E. inermis (>60%). Eucalanidae in the central CRD had a shallow depth distribution, closely associated with the shallow thermocline (10-20 m). There was no evidence of daily vertical migration in the central CRD, but E. inermis demonstrated vertical migration outside the CRD. The vertical abundance patterns of Eucalanidae in the CRD region reflect complex interactions between subtle physical-chemical differences and food resources.

The National Trauma Institute: Lessons learned in the funding and conduct of 16 trauma research studies.

BACKGROUND: To increase trauma-related research and elevate trauma on the national research agenda, the National Trauma Institute (NTI) issued calls for proposals, selected funding recipients, and coordinated 16 federally funded (Department of Defense) trauma research awards over a 4-year period. We sought to collect and describe the lessons learned from this activity to inform future researchers of barriers and facilitators. METHODS: Fifteen principal investigators participated in semistructured interviews focused on study management issues such as securing institutional approvals, screening and enrollment, multisite trials management, project funding, staffing, and institutional support. NTI Science Committee meeting minutes and study management data were included in the analysis. Simple descriptive statistics were generated and textual data were analyzed for common themes. RESULTS: Principal investigators reported challenges in obtaining institutional approvals, delays in study initiation, screening and enrollment, multisite management, and study funding. Most were able to successfully resolve challenges and have been productive in terms of scholarly publications, securing additional research funding, and training future trauma investigators. CONCLUSION: Lessons learned in the conduct of the first two funding rounds managed by NTI are instructive in four key areas: regulatory processes, multisite coordination, adequate funding, and the importance of an established research infrastructure to ensure study success. Recommendations for addressing institution-related and investigator-related challenges are discussed along with ongoing advocacy efforts to secure sustained federal funding of a national trauma research program commensurate with the burden of injury.

Dopamine reuptake transporter (DAT) "inverse agonism"--a novel hypothesis to explain the enigmatic pharmacology of cocaine.

The long held view is cocaine's pharmacological effects are mediated by monoamine reuptake inhibition. However, drugs with rapid brain penetration like sibutramine, bupropion, mazindol and tesofensine, which are equal to or more potent than cocaine as dopamine reuptake inhibitors, produce no discernable subjective effects such as drug "highs" or euphoria in drug-experienced human volunteers. Moreover they are dysphoric and aversive when given at high doses. In vivo experiments in animals demonstrate that cocaine's monoaminergic pharmacology is profoundly different from that of other prescribed monoamine reuptake inhibitors, with the exception of methylphenidate. These findings led us to conclude that the highly unusual stimulant profile of cocaine and related compounds, eg methylphenidate, is not mediated by monoamine reuptake inhibition alone. We describe the experimental findings which suggest cocaine serves as a negative allosteric modulator to alter the function of the dopamine reuptake transporter (DAT) and reverse its direction of transport. This results in a firing-dependent, retro-transport of dopamine into the synaptic cleft. The proposed mechanism of cocaine is, therefore, different from other small molecule negative allostereric modulators of the monoamine reuptake transporters, eg SoRI-6238, which merely reduce the rate of inward transport. Because the physiological role of DAT is to remove dopamine from the synapse and the action of cocaine is the opposite of this, we have postulated that cocaine's effect is analogous to an inverse agonist. If this hypothesis is validated then cocaine is the prototypical compound that exemplifies a new class of monoaminergic drugs; DAT "inverse agonists". This article is part of the Special Issue entitled 'CNS Stimulants'.

Amphetamine, past and present--a pharmacological and clinical perspective.

Amphetamine was discovered over 100 years ago. Since then, it has transformed from a drug that was freely available without prescription as a panacea for a broad range of disorders into a highly restricted Controlled Drug with therapeutic applications restricted to attention deficit hyperactivity disorder (ADHD) and narcolepsy. This review describes the relationship between chemical structure and pharmacology of amphetamine and its congeners. Amphetamine's diverse pharmacological actions translate not only into therapeutic efficacy, but also into the production of adverse events and liability for recreational abuse. Accordingly, the balance of benefit/risk is the key challenge for its clinical use. The review charts advances in pharmaceutical development from the introduction of once-daily formulations of amphetamine through to lisdexamfetamine, which is the first d-amphetamine prodrug approved for the management of ADHD in children, adolescents and adults. The unusual metabolic route for lisdexamfetamine to deliver d-amphetamine makes an important contribution to its pharmacology. How lisdexamfetamine's distinctive pharmacokinetic/pharmacodynamic profile translates into sustained efficacy as a treatment for ADHD and its reduced potential for recreational abuse is also discussed.

Metabolic consequences of antipsychotic therapy: preclinical and clinical perspectives on diabetes, diabetic ketoacidosis, and obesity.

Antipsychotic drugs, particularly second-generation antipsychotics (SGAs), have reduced the burden to society of schizophrenia, but many still produce excessive weight gain. A significant number of SGAs also act directly to impair glycemic control causing insulin resistance, impaired glucose tolerance and type 2 diabetes, and also rarely diabetic ketoacidosis (DKA). Schizophrenia itself is almost certainly causal in many endocrine and metabolic disturbances, making this population especially vulnerable to the adverse metabolic consequences of treatment with SGAs. Hence, there is an urgent need for a new generation of antipsychotic drugs that provide efficacy equal to the best of the SGAs without their liability to cause weight gain or type 2 diabetes. In the absence of such safe and effective alternatives to the SGAs, there is a substantial clinical need for the introduction of new antipsychotics without adverse metabolic effects and new antiobesity drugs to combat these metabolic side effects. We discuss the adverse metabolic consequences of schizophrenia, its exacerbation by a lack of social care, and the additional burden placed on patients by their medication. A critical evaluation of the animal models of antipsychotic-induced metabolic disturbances is provided with observations on their strengths and limitations. Finally, we discuss novel antipsychotic drugs with a lower propensity to increase metabolic risk and adjunctive medications to mitigate the adverse metabolic actions of the current generation of antipsychotics.