Objective: Fasedienol (PH94B) is a pherine compound formulated as a nasal spray that is hypothesized to regulate olfactory-amygdala circuits of fear and anxiety. Fasedienol's effect on the local electrogram of nasal chemosensory neurons (EGNR) and autonomic nervous system (ANS) responses versus steroidal hormones and controls in healthy adults is reported.Methods: Eight males and 8 females randomly received aerosolized control (propylene glycol) and study drugs (fasedienol, 17 beta-estradiol, progesterone, cortisol, and testosterone, 0.4 mu g each in propylene glycol) onto the nasal septum mucosal lining at 30-min intervals over 2 sessions. EGNR was continuously monitored; autonomic parameters were recorded before and after administration.Results: Fasedienol significantly increased EGNR amplitude (males: 5.0 vs. 0.6 mV, p < 0.001; females:5.7 vs. 0.6 mV, p < 0.001), and rapidly reduced respiratory rate (p < 0.05), heart rate (p < 0.01), and electrodermal activity (p < 0.05) versus control. EGNR and ANS responses after steroidal hormone administration were similar to control. 81% reported feeling less tense/more relaxed after receiving fasedienol, but not after receiving either control or steroidal hormones.Conclusions: Intranasal fasedienol, but not control or steroidal hormones, activated EGNR and rapidly reduced ANS responses, consistent with sympatholytic effects. Combined with subjective reports, results suggest fasedienol may provide acute relief in anxiety conditions.

4-Chlorokynurenine (4-Cl-KYN, AV-101) is a prodrug of a NMDA receptor antagonist and is in clinical development for potential CNS indications. We sought to further understand the distribution and metabolism of 4-Cl-KYN, as this information might provide a strategy to enhance the clinical development of this drug. We used excretion studies in rats, in vitro transporter assays, and pharmacogenetic analysis of clinical trial data to determine how 4-Cl-KYN and metabolites are distributed. Our data indicated that a novel acetylated metabolite (N-acetyl-4-Cl-KYN) did not affect the uptake of 4-Cl-KYN across the blood-brain barrier via LAT1. 4-Cl-KYN and its metabolites were found to be renally excreted in rodents. In addition, we found that N-acetyl-4-Cl-KYN inhibited renal and hepatic transporters involved in excretion. Thus, this metabolite has the potential to limit the excretion of a range of compounds. Our pharmacogenetic analysis found that a SNP in N-acetyltransferase 8 (NAT8, rs13538) was linked to levels of N-acetyl-4-Cl-KYN relative to 4-Cl-KYN found in the plasma and that a SNP in SLC7A5 (rs28582913) was associated with the plasma levels of the active metabolite, 7-Cl-KYNA. Thus, we have a pharmacogenetics-based association for plasma drug level that could aid in the drug development of 4-Cl-KYN and have investigated the interaction of a novel metabolite with drug transporters.

4-chlorokynurenine (4-Cl-KYN) is in clinical development for potential CNS indications. We have sought to further understand the distribution and metabolism of 4-Cl-KYN as this information might provide a strategy to enhance the clinical development of this drug. We used excretion studies in rats, in vitro transporter assays and pharmacogenetic analysis of clinical trial data to determine how 4-Cl-KYN and metabolites are distributed. Our data indicated that a novel acetylated metabolite (N-acetyl-4-Cl-KYN) did not affect the uptake of 4-Cl-KYN across the blood-brain barrier via LAT1. 4-Cl-KYN and metabolites were found to be renally excreted in rodents. In addition, we found that N-acetyl-4-Cl-KYN inhibited renal and hepatic transporters involved in excretion. Thus, this metabolite had the potential to limit the excretion of a range of compounds. Our pharmacogenetic analysis found that a SNP in N-acetyltransferase 8 (NAT8, rs13538) was linked to levels of N-acetyl-4-Cl-KYN relative to 4-Cl-KYN found in the plasma and that a SNP in SLC7A5 (rs28582913) was associated with the plasma levels of the active metabolite, 7-Cl-KYNA. Thus, we have a pharmacogenetics-based association for plasma drug level that could aid in the drug development of 4-Cl-KYN and have investigated the interaction of a novel metabolite with drug transporters.

Mutations in the Leucine Rich Repeat Protein Kinase 2 gene (LRRK2) are genetic predispositions for Parkinson's Disease, of which the G2019S (GS) missense mutation is the most common. GS-LRRK2 has a hyperactive kinase, and although numerous drug discovery programs have targeted the LRRK2 kinase, few have reached clinical trials. We recently reported on the discovery of a novel LRRK2 kinase inhibitor chemotype, 1H-pyrazole biaryl sulfonamides. Although both potent and selective GS-LRRK2 inhibitors, 1H-pyrazole biaryl sulfonamides are incapable of crossing the blood-brain barrier. Retaining the core 1H-pyrazole and focusing our efforts on a phenylsulfonamide bioisosteric replacement, we report the discovery and preliminary development of azaspirocyclic 1H-3,4,5-trisubstituted pyrazoles as potent and selective (>2000-fold) GS-LRRK2 kinase inhibitors capable of entering rodent brain. The compounds disclosed here present an excellent starting point for the development of more brain penetrant compounds.

Future Medicinal ChemistryVol. 14, No. 16 EditorialOpen AccessTargeting LRRK2 mutations in Parkinson's diseaseRobert K Leśniak, Robert Jeremy Nichols, Mark Smith & Thomas J MontineRobert K Leśniak *Author for correspondence: Tel.: +1 415 917 0637; E-mail Address: r.k.lesniak@stanford.eduhttps://orcid.org/0000-0002-8712-9901Medicinal Chemistry Knowledge Center, Sarafan ChEM-H, Stanford University, Stanford, CA 94305, USADepartment of Pathology, 300 Pasteur Drive, Stanford University, Stanford, CA 94305, USA, Robert Jeremy NicholsDepartment of Pathology, 300 Pasteur Drive, Stanford University, Stanford, CA 94305, USA, Mark SmithMedicinal Chemistry Knowledge Center, Sarafan ChEM-H, Stanford University, Stanford, CA 94305, USA & Thomas J MontineDepartment of Pathology, 300 Pasteur Drive, Stanford University, Stanford, CA 94305, USAPublished Online:22 Jun 2022https://doi.org/10.4155/fmc-2022-0102AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: computational chemistry and molecular modelingdrug designdrug discoveryinflammation therapeuticsneurological therapeuticspharmacokinetics/pharmacodynamicsrare diseasesParkinson's disease (PD), originally named 'shaking palsy' [1], is a chronic neurodegenerative disorder manifesting hallmark symptoms of resting tremor and bradykinesia [2]. Since the first clinical characterization of PD in 1817, our understanding of this disease has expanded to recognize both motor and nonmotor symptoms. Modern treatments for PD remain largely symptomatic, meaning that they relieve symptoms but apparently do not target the underlying cause(s) of the disease, and are not without severe side effects in many cases. With an increasing global prevalence of PD (∼10 million), an urgent unmet medical need remains: to slow, prevent and perhaps even reverse the neuronal injury that underlies the debilitating symptoms of PD [3].PD is characterized neuropathologically by the degeneration of dopaminergic neurons in the substantia nigra compacta (SNpc) and by the appearance of intraneuronal Lewy bodies, which are formed in part by aggregated pathologic forms of α-synuclein, a presynaptic protein. Although originally thought to have minimal genetic influence, research over the last two decades has established numerous genetic causes and genetic risk loci for PD [4,5]. Of the genetic variants that have been associated with PD, by far the most common genetic cause of familial and sporadic PD are mutations in LRRK2 (PARK8) [6,7]. Transcription and translation of this gene yield a large (286 kDa) multidomain protein, LRRK2, a member of the ROCO superfamily of proteins. LRRK2 is composed of a tandem Ras of complex (Roc) G-domain linked to a kinase domain through a carboxy-terminal of Roc (COR) sequence. Outside of the characteristic ROCO family motifs, LRRK2 possesses protein–protein interaction (PPI)-associated domains, namely WD40, armadillo (ARM), ankyrin (ANK) and leucine-rich repeats (LRR). Although the precise physiological function of LRRK2 remains elusive, evidence suggests its primary functions are largely performed through its two enzymatic domains, kinase and ROC-GTPase, which catalyze phosphorylation and GTP-GDP hydrolysis, respectively. The roles of the multiple PPI domains of LRRK2 are also the subject of intensive research and the proposed cellular functions of LRRK2 are numerous. Indeed, LRRK2 has been implicated in neurite outgrowth, vesicle trafficking, cytoskeletal maintenance and autophagy, to name a few. While elucidation of the exact mechanisms of LRRK2 in the PD context is ongoing, one fact remains clear: modulating at least one of the critical functions of LRRK2 may provide a valid therapeutic target for medicinal chemistry efforts.To date, of the nearly 100 known mutations of LRRK2 [8], only a few are established as dominantly inherited causes of PD. Some notable examples are the G2019S, I2020T, R1441C/G/H, N1437H and Y1699C mutations occurring in catalytic domains of LRRK2; however, all increase the kinase activity of LRRK2 by varying amounts [9]. The G2019S mutation is the most prevalent in PD populations, accounting for around 6% of familial and 2% of sporadic PD, and has a high frequency in specific geographic populations. The G2019S mutation (and I2020T variant) occurs in the kinase domain of LRRK2, specifically in subdomain VII 'DFG' motif (DYG in LRRK2) and generates a hyperactive kinase, increasing Kcat but not Vmax (wildtype [WT]) LRRK2 kinase [9]. This hyperactive kinase activity thus is strongly supported by genetic evidence as a significant contributor to the pathogenesis of PD in G2019S LRRK2 mutation carriers. It is perhaps unsurprising then that modulation of the kinase domain of LRRK2 as a means to treat PD has motivated multiple medicinal chemistry campaigns over the last decade-plus, producing a wide variety of extremely efficacious LRRK2 kinase inhibitors, for example, MLi-2, GNE-7915 and PF-360 developed by Merck [10], Genentech [11] and Pfizer [12], respectively. These potent, brain-penetrant and highly kinome-selective LRRK2 inhibitors can be considered type I kinase inhibitors, binding to the kinase hinge region of the active site and competing with ATP, while the kinase is in the DYG-in configuration. To the best of our knowledge, published brain-penetrant LRRK2 kinase inhibitors are nonspecific toward pathogenic mutant LRRK2 variants over WT LRRK2. Interestingly, despite initial safety concerns raised with kinome-selective LRRK2 kinase inhibitors GNE-0877 and GNE-7915 [13], clinical trials are proceeding with likely structurally similar ATP-competitive inhibitors [14].Given that WT LRRK2 is proposed to be involved in many crucial cellular processes, it is expected that unwanted side effects may arise from the administration of inhibitors that do not discriminate between the WT and mutant LRRK2 variants. In this way, the development of kinase inhibitors that are selective toward G2019S LRRK2 while allowing the WT to maintain crucial cellular activities would be advantageous to heterozygous LRRK2 mutation carriers. Although a direct association between LRRK2 kinase inhibitor-associated side effects and lack of selectivity for G2019S LRRK2 has not been established, a more precise approach may be an attractive therapy for certain PD patients and may finally help elucidate the molecular and cellular mechanisms of LRRK2 kinase mutations in PD pathogenesis. The design of mutant-selective LRRK2 kinase inhibitors, however, poses a significant challenge. In the context of G2019S LRRK2, the presence of a single amino acid substitution resulting in a largely identical kinase active site and a lack of x-ray structural data has resulted in a heavy reliance on molecular docking and homology modeling in LRRK2 kinase medicinal chemistry programs. Indeed, recent single-particle cryoelectron microscopy (Cryo-EM) structures of G2019S and WT LRRK2 revealed both can adopt an almost identical kinase-inactive (DYG-out) conformation, leading the authors to suggest that G2019S LRRK2 hyperkinase activity may be a kinetic effect rather than a result of structural difference in the kinase active site [15,16]. This would suggest the generation of selective G2019S LRRK2 inhibitors is a fruitless endeavor. However, these findings are contrary to previous kinetic and computational studies involving type II kinase inhibitors (preferentially binding to and inhibiting kinases in their DYG-out conformation) showing the G2019S mutation (and also I2020T) may stabilize an active (DYG-in) conformation in solution compared with WT LRRK2 [15,16]. This stabilizing effect may be achieved through the contribution of Ser2019 to a hydrogen-bonding network with adjacent catalytic residues. WT LRRK2 was shown to readily access the active (DYG-in) and inactive (DYG-out) conformations, as many kinases do, thus a preference of type II kinase inhibitors for WT LRRK2 was observed over G2019S and I2020T LRRK2 variants. If true, unique binding sites may be present and thus exploited in the G2019S kinase domain by appropriately designed small molecules. Furthermore, an x-ray structure of various LRRK2 kinase inhibitors bound to a G2019S LRRK2 surrogate (mutated CHK1) revealed the kinase to be in an active (DYG-in) conformation, suggesting the presence of type I inhibitors may be required to stabilize this conformation [17,18]. Although such x-ray structural data using LRRK2 surrogates have yielded potent inhibitors, studies [19,20] have indeed shown that significant selectivity toward the G2019S LRRK2 mutant over WT can be obtained through systematic probing of the kinase active site using a combination of iterative synthesis of molecules, follow-up screening and molecular docking. Through such a process, it is possible to obtain a data-driven model of the G2019S LRRK2 active site, visualize potential structural differences between WT and G2019S LRRK2 kinase and design more selective inhibitors. From these recent medicinal chemistry efforts [19,20], it is clear that, as suggested in the aforementioned studies with type II inhibitors [15,16], the G2019S kinase may possess a unique binding site compared with WT. This structural difference provides opportunities for G2019S LRRK2-selective inhibitor design. Indeed, specific inhibitor modifications have resulted in significant selectivity toward the GS mutant, most likely through unique Van der Waals interactions with the highly mobile glycine-rich loop of the G2019S LRRK2 kinase active site. Such interactions may not be readily accessible to other LRRK2 kinase inhibitors.Although only differing by a single amino acid, the G2019S mutation clearly exerts a strong, ultimately pathogenic effect on the cellular functions of LRRK2. This may be through a structural effect on the kinase domain, which in turn affects global enzyme kinetics, architecture and substrate profile. In the absence of explicit x-ray structural data, selective inhibitor generation must rely on a data-driven approach to drive selective inhibitor design through the medium of computational modeling. Indeed, studies have shown that selective and efficacious mutant LRRK2 kinase inhibition is not only possible but also effective in animal models of mutant LRRK2-associated PD [19]. Alongside kinase inhibition of pathogenic LRRK2 variants, WT LRRK2 has itself also been suggested to play a role in PD pathogenesis, enabling LRRK2 inhibitors (nonselective for genetic variants) to progress through late-stage clinical trials. Time will tell if such compounds possess the ability to address the fundamental unmet need for effective but also safe PD treatments. While the advancement of these potential groundbreaking treatments for PD is highly encouraging, the progression of mutant-selective LRRK2 inhibitors provides an alternate and precise approach that may yield safer medicines. This approach would perhaps only benefit G2019S LRRK2 carriers in the first instance. However, a clinically useful mutant-selective LRRK2 inhibitor would provide unique insights into the molecular biology of LRRK2-associated PD, informing future drug discovery efforts for precision medicines for people with PD.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.Open accessThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/References1. Palacios-Sánchez L, Torres Nupan M, Botero-Meneses JS. James Parkinson and his essay on "shaking palsy", two hundred years later. Arq. Neuropsiquiatr. 75(9), 671–672 (2017).Crossref, Medline, Google Scholar2. Kalia LV, Lang AE. Parkinson's disease. Lancet 386(9996), 896–912 (2015).Crossref, Medline, CAS, Google Scholar3. Marras C, Beck JC, Bower JH et al. Prevalence of Parkinson's disease across North America. NPJ Parkinsons Dis. 4, 21 (2018).Crossref, Medline, CAS, Google Scholar4. Nalls MA, Plagnol V, Hernandez DG et al. Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies. Lancet 377(9766), 641–649 (2011).Crossref, Medline, Google Scholar5. Nalls MA, Blauwendraat C, Vallerga CL et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies. Lancet Neurol. 18(12), 1091–1102 (2019).Crossref, Medline, CAS, Google Scholar6. 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Type II kinase inhibitors show an unexpected inhibition mode against Parkinson's disease-linked LRRK2 mutant G2019S. Biochemistry 52(10), 1725–1736 (2013).Crossref, Medline, CAS, Google Scholar16. Ray S, Bender S, Kang S, Lin R, Glicksman MA, Liu M. The Parkinson disease-linked LRRK2 protein mutation I2020T stabilizes an active state conformation leading to increased kinase activity. J. Biol. Chem. 289(19), 13042–13053 (2014).Crossref, Medline, CAS, Google Scholar17. Williamson DS, Smith GP, Acheson-Dossang P et al. Design of leucine-rich repeat kinase 2 (LRRK2) inhibitors using a crystallographic surrogate derived from checkpoint kinase 1 (CHK1). J. Med. Chem. 60(21), 8945–8962 (2017).Crossref, Medline, CAS, Google Scholar18. Williamson DS, Smith GP, Mikkelsen GK et al. Design and synthesis of pyrrolo [2,3-d]pyrimidine-derived leucine-rich repeat kinase 2 (LRRK2) inhibitors using a checkpoint kinase 1 (CHK1)-derived crystallographic surrogate. J. Med. 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Chem. 63(23), 14821–14839 (2020).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetails Vol. 14, No. 16 Follow us on social media for the latest updates Metrics History Received 12 May 2022 Accepted 25 May 2022 Published online 22 June 2022 Published in print August 2022 Information© 2022 Stanford UniversityKeywordscomputational chemistry and molecular modelingdrug designdrug discoveryinflammation therapeuticsneurological therapeuticspharmacokinetics/pharmacodynamicsrare diseasesFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.Open accessThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/PDF download

Rapid antidepressant effects associated with ketamine have shifted the landscape for the development of therapeutics to treat major depressive disorder (MDD) from a monoaminergic to glutamatergic model. Treatment with ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, may be effective, but has many non-glutamatergic targets, and clinical and logistical problems are potential challenges. These factors underscore the importance of manipulations of binding mechanics to produce antidepressant effects without concomitant clinical side effects. This will require identification of efficient biomarkers to monitor target engagement. The mismatch negativity (MMN) is a widely used electrophysiological signature linked to the activity of NMDA receptors (NMDAR) in humans and animals and validated in pre-clinical and clinical studies of ketamine. In this review, we explore the flexibility of the MMN and its capabilities for reliable use in drug development for NMDAR antagonists in MDD. We supplement this with findings from our own research with three distinct NMDAR antagonists. The research described illustrates that there are important distinctions between the mechanisms of NMDAR antagonism, which are further crystallized when considering the paradigm used to study the MMN. We conclude that the lack of standardized methodology currently prevents MMN from being ready for common use in drug discovery. Clinical trial registration: This manuscript describes data collected from the following National Institutes of Health (NIH) and Veterans Affairs (VA) studies: AV-101, NCT03583554; lanicemine, NCT03166501; ketamine, NCT02556606.

BACKGROUND:Ketamine has rapid-acting antidepressant effects but is associated with psychotomimetic and other adverse effects. A 7-chlorokynurenic acid is a potent and specific glycine site N-methyl-d-aspartate receptor antagonist but crosses the blood-brain barrier inefficiently. Its prodrug, L-4-chlorokynurenine (4-Cl-KYN), exerts acute and sustained antidepressant-like effects in rodents and has no reported psychotomimetic effects in either rodents or healthy volunteers. This study examined whether 4-Cl-KYN has rapid antidepressant effects in individuals with treatment-resistant depression.METHODS:After a 2-week drug-free period, 19 participants with treatment-resistant depression were randomized to receive daily oral doses of 4-Cl-KYN monotherapy (1080 mg/d for 7 days, then 1440 mg/d for 7 days) or placebo for 14 days in a randomized, placebo-controlled, double-blind, crossover manner. The primary outcome measure was the Hamilton Depression Rating Scale score, assessed at several time points over a 2-week period; secondary outcome measures included additional rating scale scores. Pharmacokinetic measures of 7-chlorokynurenic acid and 4-Cl-KYN and pharmacodynamic assessments were obtained longitudinally and included 1H-magnetic resonance spectroscopy brain glutamate levels, resting-state functional magnetic resonance imaging, and plasma and cerebrospinal fluid measures of kynurenine metabolites and neurotrophic factors.RESULTS:Linear mixed models detected no treatment effects, as assessed by primary and secondary outcome measures. No difference was observed for any of the peripheral or central biological indices or for adverse effects at any time between groups. A 4-Cl-KYN was safe and well-tolerated, with generally minimal associated adverse events.CONCLUSIONS:In this small crossover trial, 4-Cl-KYN monotherapy exerted no antidepressant effects at the doses and treatment duration studied.ClinicalTrials.gov identifier: NCT02484456.

IBM Research in partnership with IBM Services developed an innovative set of tools that automatically and cognitively reads a request for proposal, extracts client requirements, and maps them to IBM offerings. It also performs accurate costing and recosting, pricing and repricing, and market benchmarking of the bid, and it predicts the status over time of the various deals being pursued to effectively manage IBM’s sales pipeline and align salesforce resources.

The kynurenine pathway (KP) is a strategic metabolic system that combines regulation of neuronal excitability via glutamate receptor function and neuroinflammation via other KP metabolites. This pathway has great promise in treatment of depression and suicidality. The KP modulator AV-101 (4-chlorokynurenine, 4-Cl-KYN), an oral prodrug of 7-chlorokynurenic acid (7-Cl-KYNA), an N-methyl-d-aspartate receptor (NMDAR) glycine site antagonist, and of 4-chloro-3-hydroxyanthranilic acid (4-Cl-3-HAA), a suppressor of NMDAR agonist quinolinic acid (QUIN), is a promising potential antidepressant that targets glutamate functioning via the KP. However, a recent placebo-controlled clinical trial of AV-101 in depression found negative results. This raises the question of whether AV-101 can penetrate the brain and engage the NMDAR and KP effectively. To address this problem, ten healthy US military veterans (mean age = 32.6 years ± 6.11; 1 female) completed a phase-1 randomized, double-blind, placebo-controlled, crossover study to examine dose-related effects of AV-101 (720 and 1440 mg) on NMDAR engagement measured by γ-frequency band auditory steady-state response (40 Hz ASSR) and resting EEG. Linear mixed models revealed that 1440 mg AV-101, but not 720 mg, increased 40 Hz ASSR and 40 Hz ASSR γ-inter-trial phase coherence relative to placebo. AV-101 also increased 4-Cl-KYN, 7-Cl-KYNA, 4-Cl-3-HAA, 3-HAA, and KYNA in a dose-dependent manner, without affecting KYN and QUIN. AV-101 was safe and well tolerated. These results corroborate brain target engagement of 1440 mg AV-101 in humans, consistent with blockade of interneuronal NMDAR blockade. Future studies should test higher doses of AV-101 in depression. Suicidal behavior, which has been associated with high QUIN and low KYNA, is also a potential target for AV-101.

PurposeSleep loss and fatigue, common in resident physicians, are related to increased medical errors and decreased physician wellbeing. Biomathematical modeling of fatigue can illuminate the relationship between surgical resident fatigue and work scheduling.MethodsGeneral surgery resident schedules were analyzed using the Sleep, Activity, Fatigue and Task Effectiveness model to predict resident performance during work hours. Hypothetical naps were built into the model to assess their effect on predicted performance and fatigue risk.Results12 months of duty-hours logged by 89 residents, ranging from post-graduate year (PGY) 1–5, were analyzed. Residents had moderate levels of fatigue risk over 12 month schedules, with at least an 8-h sleep debt during 24.36% of shifts. Performance scores decreased as shift lengths increased. The addition of hypothetical naps increased predicted performance and reduced shift time with fatigue risk.ConclusionsBiomathematical modeling of resident schedules and predicts a concerning level of fatigue and decreased effectiveness. Naps may improve performance without decreasing scheduled hours.

Recent advances in the understanding of depression have led to increasing interest in ketamine and the role that N-methyl-d-aspartate (NMDA) receptor inhibition plays in depression. l-4-Chlorokynurenine (4-Cl-KYN, AV-101), a prodrug, has shown promise as an antidepressant in preclinical studies, but this promise has not been realized in recent clinical trials. We sought to determine if transporters in the CNS could be playing a role in this clinical response. We used radiolabeled uptake assays and microdialysis studies to determine how 4-Cl-KYN and its active metabolite, 7-chlorokynurenic acid (7-Cl-KYNA), cross the blood-brain barrier (BBB) to access the brain and its extracellular fluid compartment. Our data indicates that 4-Cl-KYN crosses the blood-brain barrier via the amino acid transporter LAT1 (SLC7A5) after which the 7-Cl-KYNA metabolite leaves the brain extracellular fluid via probenecid-sensitive organic anion transporters OAT1/3 (SLC22A6 and SLC22A8) and MRP4 (ABCC4). Microdialysis studies further validated our in vitro data, indicating that probenecid may be used to boost the bioavailability of 7-Cl-KYNA. Indeed, we found that coadministration of 4-Cl-KYN with probenecid caused a dose-dependent increase by as much as an 885-fold increase in 7-Cl-KYNA concentration in the prefrontal cortex. In summary, our data show that 4-Cl-KYN crosses the BBB using LAT1, while its active metabolite, 7-Cl-KYNA, is rapidly transported out of the brain via OAT1/3 and MRP4. We also identify a hitherto unreported mechanism by which the brain extracellular concentration of 7-Cl-KYNA may be increased to produce significant boosting of the drug concentration at its site of action that could potentially lead to an increased therapeutic effect.

Medically severe suicide attempts are increasing amongst the civilian population, and persistently elevated in veterans. Suicidality has been linked with abnormal NMDA Receptor function stemming from dysfunction of the kynurenine pathway. In this Phase 1b trial, we investigated the dose-response relationship of the investigational drug AV-101 (L-4-chloro-kynurenine) and a known marker of NMDAR function: the 40 Hz auditory steady state gamma amplitude.

OBJECTIVE:To identify surgical resident and clinical rotation attributes which predict on-shift napping through objectively measured sleep patterns and work schedules over a 2-month period. DESIGN:In a cross-sectional study, participants provided schedules, completed the Epworth Sleepiness Scale (ESS), and wore sleep-tracking devices (Zulu watch) continuously for 8 weeks. Multiple linear regression predicted percent days with on-shift napping from resident and rotation characteristics. SETTING:Greater Washington, DC area hospitals. PARTICIPANTS:Twenty-two (n = 22) surgical residents rotating in at least 1 of 5 different clinical rotation categories. RESULTS:Residents slept 6 hours within a 24-hour period (370 ± 129 minutes) with normal sleep efficiency (sleep efficiency (SE): 87.13% ± 7.55%). Resident ESS scores indicated excessive daytime sleepiness (11.64 ± 4.03). Ninety-five percent (n = 21) of residents napped on-shift. Residents napped on-shift approximately 32% of their working days and were most likely to nap when working between 23:00 and 05:00 hours. Earlier shift start times predicted less on-shift napping (B = -0.08, SE = 0.04, β = -2.40, t = -2.09, p = 0.05) while working more night shifts (B = 1.55, SE = 0.44, β = 4.12, t = 3.52, p = 0.003) and shifts over 24 hours (B = 1.45, SE = 0.55, β = 1.96, t = 2.63, p = 0.01) predicted more frequent on-shift napping. CONCLUSIONS:Residents are taking advantage of opportunities to nap on-shift. Working at night seems to drive on-shift napping. However, residents still exhibit insufficient sleep and daytime sleepiness which could reduce competency and represent a safety risk to themselves and/or patients. These findings will help inform intervention strategies which are tailored to surgical residents using a biomathematical model of fatigue.

5-Hydroxytryptophan (5-HTP), a precursor of serotonin, is therapeutically used for several psychiatric disorders such as anxiety and depression in the clinic. However, severe side effects, including abnormal mental functions, behavioral disturbances and intolerance are associated with this treatment. 5-HTP-induced elevation of plasma and brain serotonin levels may affect blood-brain barrier (BBB) breakdown, edema formation and regional cerebral blood flow (CBF) disturbances. Breakdown of BBB to serum proteins leads to vasogenic brain edema formation and cellular injuries. However, 5-HTP-neurotoxicity is still not well known. In this investigations 5-HTP induced elevation of endogenous plasma and brain serotonin levels and its effect on BBB breakdown, edema formation neuronal injuries was examined in a rat model. Furthermore, potential role of oxidative stress and nitric oxide (NO) was evaluated. In addition, several neurochemical agents such as p-CPA (5-HT synthesis inhibitor) indomethacin (prostaglandin synthase inhibitor), diazepam (ant stress drug), cyproheptadine, ketanserin (5-HT2 receptor antagonists) and vinblastine (inhibitor of microtubule function) were examined on 5-HT neurotoxicity. Our observations suggest that 4h after 5-HTP administrations, the endogenous serotonin levels increased by fourfold (150mg/kg) in the plasma and brain associated with profound hyperthermia (+3.86±0.24°C, oxidative stress and NO upregulation. Breakdown of the BBB to Evans blue albumin (EBA) in 8 brain regions and to [131]Iodine in 14 brain regions was observed. The CBF exhibited marked reduction in all the brain regions examined. Brain edema and cellular injuries are present in the areas associated with BBB disruption. Drug treatments reduced the BBB breakdown, edema formation NO production and brain pathology. These observations are the first to point out that 5-HTP-neurotoxicity caused by BBB breakdown, edema formation and NO production is instrumental in causing adverse mental and behavioral abnormalities, not reported earlier.

BACKGROUND:Estrogen and hormone replacement therapies to reduce Alzheimer's disease (AD) have yielded conflicting results. However, this study proposes that the well-characterized increase in serum gonadotropins following menopause or andropause are accountable for the increased risk of developing AD among the elderly population.OBJECTIVE:To determine the role of gonadotropins in the development of AD and investigate gonadotropin-releasing hormone (GnRH) agonist therapy as a potential preventative and/or disease-modifying approach to AD management.METHODS:Male Medicare beneficiaries aged 67 to 75 and hospitalized with prostate cancer (n = 115,789) were compared to three control groups: men of the same demographics undergoing a cholecystectomy (n = 97,267), herniorrhaphy (n = 68,778), or transurethral prostatectomy (n = 267,691). A proportion of the patients hospitalized with prostate cancer were assumed to have low concentrations of serum gonadotropins and sex steroids as a result of GnRH agonist therapy, while those in the control groups were assumed to have elevated gonadotropin but lowered sex steroid levels that are associated with andropause in this age group.RESULTS:The rates of development of select diagnoses of dementia, including AD, over a twelve-year follow-up period following surgery. When compared to control patients, men hospitalized with prostate cancer have a protection against dementia after twelve years of follow-up, with relative risks ranging from 0.48 to 0.83.CONCLUSION:Patients with prostate cancer are treated with the GnRH analogue leuprolide acetate, our data suggest that leuprolide acetate may be therapeutic for AD via its downregulation of serum gonadotropins.

Highly valued Information technology (IT) service contracts involve the delivery of complex IT services, such as migrating the client's IT infrastructure to the Cloud, Mainframes, among others. IT service providers usually compete to win these IT service contracts. In order to bid on such deals, IT service providers need to price/quote the solution that they propose to the client, trying to convince him to use their services. A few analytical methods in the literature have been provided for pricing these deals. However, these methods ignore an important characteristic of these services; that is they are typically characterized by a decreasing cost profile in subsequent years to the first year. Typically, these methods require solutioners to manually input these annual cost reductions. In this paper, we present an analytical way for calculating this cost reduction, if applicable, via mining historical data. We show that using our methodology could achieve significant increase in the accuracy of estimating the costs and prices of IT service deals.

To test the efficacy and safety of leuprolide acetate (Lupron Depot) in the treatment of Alzheimer's disease (AD), we conducted a 48-week, double-blind, placebo-controlled, dose-ranging study in women aged 65 years or older with mild to moderate AD. A total of 109 women with mild to moderate AD and a Mini-Mental State Examination score between 12 and 24 inclusive were randomized to low dose Lupron Depot (11.25 mg leuprolide acetate), high dose Lupron Depot (22.5 mg leuprolide acetate), or placebo injections every 12 weeks. There were no statistically significant differences in primary efficacy parameters (ADAS-Cog and ADCS-CGIC), although there was a non-statistically significant trend in favor of the high dose Lupron group on the ADAS-Cog. There were no statistically significant differences in secondary efficacy parameters (NPI, ADCS-ADL, BI, and ADCS-Severity Rating). However, in the a priori designated subgroup analysis of patients taking an acetylcholinesterase inhibitor (AChEI), there was a statistically significant benefit in the high dose group compared to both the low dose and placebo groups as determined by ADAS-Cog (mean decline: 0.18, 4.21, and 3.30), ADCS-CGIC (% subjects experiencing decline: 38, 82, and 63), and ADCS-ADL (mean decline: -0.54, -8.00, and -6.85), respectively. No differences between treatment groups were seen on the NPI, ADCS-CGI Severity Rating, or the BI in the subgroup analysis. These data indicate that cognitive function is preserved in patients treated with high dose Lupron who were already using AChEIs. The positive interaction between Lupron and AChEIs warrants further investigation for the treatment of AD.

Shifting genres in late antiquity. Edited by Geoffrey Greatrex and Hugh Elton (with Lucas McMahon). Pp. xv + 341 incl. 24 figs. Farnham–Burlington, Vt: Ashgate, 2015. £75. 978 1 4724 4348 9 - Volume 66 Issue 4