569 results on '"Leander J"'
Search Results
252. SHOCK INTENSITY AND DURATION INTERACTIONS ON FREE-OPERANT AVOIDANCE BEHAVIOR1
- Author
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Leander, J. David, primary
- Published
- 1973
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253. EFFECTS OF FOOD DEPRIVATION ON FREE-OPERANT AVOIDANCE BEHAVIOR1
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Leander, J. David, primary
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- 1973
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254. Human Fixed Interval Performance as Related to Response Effortfulness and to Initial Point
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Lippman, Louis G., primary, Leander, J. David, additional, and Meyer, Merle E., additional
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- 1970
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255. Schedule control of the vocal behavior of Cebus monkeys: A progress report
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Leander, J. D., primary, Milan, M. A., additional, Heaton, K. B., additional, Jasper, K. B., additional, and Morris, A. S., additional
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- 1969
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256. Techniques for Measuring the Infrared Absorption Spectra of Fused Salts
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Jacob Greenberg and Leander J. Hallgren
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chemistry.chemical_classification ,Materials science ,business.industry ,Analytical chemistry ,chemistry.chemical_element ,Liquid phase ,Salt (chemistry) ,Infrared spectroscopy ,Reflectivity ,Spectral line ,Optics ,chemistry ,Platinum ,business ,Instrumentation - Abstract
The infrared absorption spectra of NaNO2 and LiNO3 in both the solid and liquid phase have been obtained by two methods. In one case the salt is supported in the interstices of a fine mesh platinum screen, and in the other case the measurements were made in a reflectance cell.
- Published
- 1960
257. THE BIBLE IN THE PUBLIC SCHOOLS.
- Author
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WOODARD, LEANDER J.
- Published
- 1875
258. Attention and Assimilation
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Leander J. Lohrenz and Riley W. Gardner
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Arts and Humanities (miscellaneous) ,Developmental and Educational Psychology ,Experimental and Cognitive Psychology ,Assimilation (biology) ,Psychology ,Cognitive psychology - Published
- 1961
259. ChemInform Abstract: Salvinorin C, a New Neoclerodane Diterpene from a Bioactive Fraction of the Hallucinogenic Mexican Mint Salvia divinorum.
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Valdes III, Leander J., Chang, Hui-Ming, Visger, Daniel C., and Koreeda, Masato
- Published
- 2002
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260. Effects of Mu- and kappa-opioid receptor agonists on urinary output in mice
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Rathbun, Robert C., Kattau, Richard W., and David Leander, J.
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- 1983
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261. Electric shock titration: Effects of meperidine, anileridine and alphaprodine
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Dykstra, Linda A. and David Leander, J.
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- 1978
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262. Attenuation of normeperidine's suppressing effect on schedule-controlled behavior
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David Leander, J. and Carter, Richard B.
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- 1982
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263. Novel phenylpiperidine opioid antagonists and partial agonists: Effects on fluid consumption
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Leander, J. David, Hart, John C., Lochner, Mary Ann, Hynes, Martin D., III, and Zimmerman, Dennis M.
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- 1982
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264. Salvinorin A is not your usual cup of tea.
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Valdes, Leander J. and Seymour, Richard B.
- Subjects
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SALVINORIN A , *HALLUCINOGENIC drugs - Abstract
Focuses on salvinorin A, an active hallucinogenic agent in the salvia divinorum plant. Indication that the drug has the characteristics of a powerful hallucinogen; Reference to an article in the `Journal of Psychoactive Drugs'; Where the plant can be found in the United States.
- Published
- 1998
265. ChemInform Abstract: Structure-Activity Studies of 6-(Tetrazolylalkyl)-Substituted Decahydroisoquinoline-3-carboxylic Acid AMPA Receptor Antagonists. Part 1. Effects of Stereochemistry, Chain Length, and Chain Substitution.
- Author
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ORNSTEIN, P. L., ARNOLD, M. B., ALLEN, N. K., BLEISCH, T., BORROMEO, P. S., LUGAR, C. W., LEANDER, J. D., LODGE, D., and SCHOEPP, D. D.
- Published
- 1996
- Full Text
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266. ChemInform Abstract: (3SR,4aRS,6SR,8aRS)-6-(1H-Tetrazol-5-yl)decahydroisoquinoline-3- carboxylic Acid, a Novel, Competitive, Systemically Active NMDA, and AMPA Receptor Antagonist.
- Author
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ORNSTEIN, P. L., ARNOLD, M. B., ALLEN, N. K., LEANDER, J. D., TIZZANO, J. P., LODGE, D., and SCHOEPP, D. D.
- Published
- 1996
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267. ChemInform Abstract: Anticonvulsant Properties of N-Substituted α,α-Diamino Acid Derivatives.
- Author
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KOHN, H., SAWHNEY, K. N., ROBERTSON, D. W., and LEANDER, J. D.
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- 1994
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268. ChemInform Abstract: Preparation and Anticonvulsant Activity of a Series of Functionalized . alpha.-Heteroatom-Substituted Amino Acids.
- Author
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KOHN, H., SAWHNEY, K. N., LEGALL, P., ROBERTSON, D. W., and LEANDER, J. D.
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- 1991
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269. STATE DELEGATE ELECTION RESULTS.
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Shaw, Leander J.
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BAR associations , *EMPLOYEES - Abstract
Reports the results of the American Bar Association's state delegation election in the U.S. in 1987. Candidates elected as state delegates; Specific terms of the elected delegates.
- Published
- 1988
270. Comparison of the Antiemetic Effects of a 5-HT~1~A Agonist, LY228729, and 5-HT~3 Antagonists in the Pigeon
- Author
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Wolff, M. C. and Leander, J. D.
- Published
- 1995
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271. Effects of viscosity and chemical relaxation on acoustic pulse propagation in seawater
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Leander, J
- Published
- 1989
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272. Tetrazole amino acids as competitive NMDA antagonists
- Author
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Ornstein, P. L., Arnold, M. B., Evrard, D., and Leander, J. D.
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- 1993
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273. NMDA receptor antagonists inhibit catalepsy induced by either dopamine D~1 or D~2 receptor antagonists
- Author
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Moore, N. A., Blackman, A., Awere, S., and Leander, J. D.
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- 1993
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274. Antiemetic effects of 5-HT~1~A agonists in the pigeon
- Author
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Wolff, M. C. and Leander, J. D.
- Published
- 1994
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275. In vitro and in vivo antagonism of AMPA receptor activation by (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid
- Author
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Schoepp, D. D., Lodge, D., Bleakman, D., and Leander, J. D.
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- 1995
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276. Waste Management and Resource Recovery
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Charles R. Rhyner, Leander J. Schwartz, Robert B. Wenger, Mary G. Kohrell, Charles R. Rhyner, Leander J. Schwartz, Robert B. Wenger, and Mary G. Kohrell
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- Sewage, Recycling (Waste, etc.), Refuse and refuse disposal, Compost, Water--Waste
- Abstract
This book provides a basic understanding of waste management problems and issues faced by modern society. Scientific, technical, and environmental principles are emphasized to illustrate the processes of municipal and industrial solid wastes and liquid wastes, and the nature of impacts resulting from waste dispersal and disposal in the environment. Economic, social, legal, and political aspects of waste management are also addressed.Environmental issues and concerns receive thorough coverage in discussing waste reduction, resource recovery, and efficient and practical waste disposal systems. Other specific topics include recycling, physical and chemical processing, the biological treatment of waste solids, incineration, pyrolysis, and energy recover, hazardous wastes, and landfill management.The role of government and other institutions in waste management and resource recovery matters is also detailed. Discussion questions, worked examples, and end-of-chapter problems reinforce important concepts.Waste Management and Resource Recovery is particularly suitable as a text in waste management courses in environmental science or engineering programs. It also works well as a reference for practitioners in the waste management field.
- Published
- 1995
277. GLYX-13, a NMDA Receptor Glycine-Site Functional Partial Agonist, Induces Antidepressant-Like Effects Without Ketamine-Like Side Effects.
- Author
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Burgdorf, Jeffrey, Zhang, Xiao-lei, Nicholson, Katherine L, Balster, Robert L, David Leander, J, Stanton, Patric K, Gross, Amanda L, Kroes, Roger A, and Moskal, Joseph R
- Subjects
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METHYL aspartate receptors , *GLYCINE , *KETAMINE , *PREFRONTAL cortex , *DRUG discrimination (Pharmacology) , *CLINICAL trials ,PHYSIOLOGICAL effects of antidepressants - Abstract
Recent human clinical studies with the NMDA receptor (NMDAR) antagonist ketamine have revealed profound and long-lasting antidepressant effects with rapid onset in several clinical trials, but antidepressant effects were preceded by dissociative side effects. Here we show that GLYX-13, a novel NMDAR glycine-site functional partial agonist, produces an antidepressant-like effect in the Porsolt, novelty induced hypophagia, and learned helplessness tests in rats without exhibiting substance abuse-related, gating, and sedative side effects of ketamine in the drug discrimination, conditioned place preference, pre-pulse inhibition and open-field tests. Like ketamine, the GLYX-13-induced antidepressant-like effects required AMPA/kainate receptor activation, as evidenced by the ability of NBQX to abolish the antidepressant-like effect. Both GLYX-13 and ketamine persistently (24 h) enhanced the induction of long-term potentiation of synaptic transmission and the magnitude of NMDAR-NR2B conductance at rat Schaffer collateral-CA1 synapses in vitro. Cell surface biotinylation studies showed that both GLYX-13 and ketamine led to increases in both NR2B and GluR1 protein levels, as measured by Western analysis, whereas no changes were seen in mRNA expression (microarray and qRT-PCR). GLYX-13, unlike ketamine, produced its antidepressant-like effect when injected directly into the medial prefrontal cortex (MPFC). These results suggest that GLYX-13 produces an antidepressant-like effect without the side effects seen with ketamine at least in part by directly modulating NR2B-containing NMDARs in the MPFC. Furthermore, the enhancement of 'metaplasticity' by both GLYX-13 and ketamine may help explain the long-lasting antidepressant effects of these NMDAR modulators. GLYX-13 is currently in a Phase II clinical development program for treatment-resistant depression. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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278. LETTERS TO THE EDITORS.
- Author
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Gallacher Jr., Thomas O'Rourke, Miller Jr., Ralph T., Friedrich, Alfred K., Purvis, J. B., Ewald, Dolores, Smith, Leander J., White, Alice, Norris, Kathleen D., Close, Perry, Durst, George, Bridges, Styles, Mosier Sr., M. L., Bennett, Girady, Gwinn, Ralph W., and Cheney, J. W.
- Subjects
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LETTERS to the editor , *HAZARDOUS occupations , *MILITARY missions , *MATE selection , *MARRIAGE - Abstract
Several letters to the editor are presented in response to articles in previous issues including "The Most Terrifying Job on Earth," by Bernard Peyton, Jr. in the February 23, 1952 issue, "The Mysterious Mission of Oro," by Herbert Yahraes in the February 23, 1952 issue, and "It's Tougher Than Ever to Get a Husband," by Rufus Jarman in the February 23, 1952 issue.
- Published
- 1952
279. Image-Based Concrete Crack Detection Method Using the Median Absolute Deviation.
- Author
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Avendaño JC, Leander J, and Karoumi R
- Abstract
This paper proposes an innovative approach for detecting and quantifying concrete cracks using an adaptive threshold method based on Median Absolute Deviation (MAD) in images. The technique applies limited pre-processing steps and then dynamically determines a threshold adapted for each sub-image depending on the greyscale distribution of the pixels, resulting in tailored crack segmentation. The edges of the crack are obtained using the Laplace edge detection method, and the width of the crack is obtained for each centreline point. The method's performance is measured using the Probability of Detection (POD) curves as a function of the actual crack size, revealing remarkable capabilities. It was found that the proposed method could detect cracks as narrow as 0.1 mm, with a probability of 94% and 100% for cracks with larger widths. It was also found that the method has higher accuracy, precision, and F2 score values than the Otsu and Niblack methods.
- Published
- 2024
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280. Dataset for damage detection retrieved from a monitored bridge pre and post verified damage.
- Author
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Leander J, Nyman J, Karoumi R, Rosengren P, and Johansson G
- Abstract
The Vänersborg Bridge in southwest Sweden is a single-leaf bascule bridge carrying railway traffic over a canal. The load consists of passing commuter trains, occasional freight trains and leaf openings to allow ships to pass on the canal. The bridge constructed from 1914 to 1916 was built by riveted truss members in steel. Over the years, several assessments and maintenance actions have been performed to keep the bridge in service. During autumn 2021, a long-term monitoring campaign was initiated with the installation of sensors to register the load effect and possible changes in the behaviour. In March 2023, the cloud-based service employed detected an abrupt change of behaviour. An emergency inspection revealed a large crack in one of the truss members in the counter-weight part. The published dataset contains sensor data from 64 registered bridge openings, comprising accelerations, strains, inclinations, and weather conditions. Data from before the fracture, during, and after are provided. During the bridge opening events, the data was recorded continuously with a sampling rate of 200 Hz. The evidence of damage in a real case scenario makes the dataset valuable for testing and evaluation of data-driven routines for infrastructure surveillance., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)
- Published
- 2023
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281. Pharmaceutical pollution disrupts the behavior and predator-prey interactions of two widespread aquatic insects.
- Author
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Bose APH, McCallum ES, Avramović M, Bertram MG, Blom EL, Cerveny D, Grønlund SN, Leander J, Lundberg P, Martin JM, Michelangeli M, Persson L, and Brodin T
- Abstract
Pharmaceutical pollution represents a rapidly growing threat to ecosystems worldwide. Drugs are now commonly detected in the tissues of wildlife and have the potential to alter the natural expression of behavior, though relatively little is known about how pharmaceuticals impact predator-prey interactions. We conducted parallel laboratory experiments using larval odonates (dragonfly and damselfly nymphs) to investigate the effects of exposure to two pharmaceuticals, cetirizine and citalopram, and their mixture on the outcomes of predator-prey interactions. We found that exposure to both compounds elevated dragonfly activity and impacted their predation success and efficiency in complex ways. While exposure to citalopram reduced predation efficiency, exposure to cetirizine showed varied effects, with predation success being enhanced in some contexts but impaired in others. Our findings underscore the importance of evaluating pharmaceutical effects under multiple contexts and indicate that these compounds can affect predator-prey outcomes at sublethal concentrations., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)
- Published
- 2022
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282. A stochastic mixed effects model to assess treatment effects and fluctuations in home-measured peak expiratory flow and the association with exacerbation risk in asthma.
- Author
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Leander J, Jirstrand M, Eriksson UG, and Palmér R
- Subjects
- Humans, Asthma drug therapy
- Abstract
Home-based measures of lung function, inflammation, symptoms, and medication use are frequently collected in respiratory clinical trials. However, new statistical approaches are needed to make better use of the information contained in these data-rich variables. In this work, we use data from two phase III asthma clinical trials demonstrating the benefit of benralizumab treatment to develop a novel longitudinal mixed effects model of peak expiratory flow (PEF), a lung function measure easily captured at home using a hand-held device. The model is based on an extension of the mixed effects modeling framework to incorporate stochastic differential equations and allows for quantification of several statistical properties of a patient's PEF data: the longitudinal trend, long-term fluctuations, and day-to-day variability. These properties are compared between treatment groups and related to a patient's exacerbation risk using a repeated time-to-event model. The mixed effects model adequately described the observed data from the two clinical trials, and model parameters were accurately estimated. Benralizumab treatment was shown to improve a patient's average PEF level and reduce long-term fluctuations. Both of these effects were shown to be associated with a lower exacerbation risk. The day-to-day variability was neither significantly affected by treatment nor associated with exacerbation risk. Our work shows the potential of a stochastic model-based analysis of home-based lung function measures to support better estimation and understanding of treatment effects and disease stability. The proposed analysis can serve as a complement to descriptive statistics of home-based measures in the reporting of respiratory clinical trials., (© 2021 Astrazeneca. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
- Published
- 2022
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283. A semi-mechanistic exposure-response model to assess the effects of verinurad, a potent URAT1 inhibitor, on serum and urine uric acid in patients with hyperuricemia-associated diseases.
- Author
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Leander J, Sunnåker M, Rekić D, Aksenov S, Eriksson UG, Johansson S, and Parkinson J
- Subjects
- Adult, Aged, Aged, 80 and over, Drug Therapy, Combination, Female, Humans, Hyperuricemia blood, Hyperuricemia urine, Kidney drug effects, Male, Middle Aged, Models, Statistical, Naphthalenes administration & dosage, Naphthalenes pharmacology, Propionates administration & dosage, Propionates pharmacology, Pyridines administration & dosage, Pyridines pharmacology, Uric Acid urine, Xanthine Oxidase antagonists & inhibitors, Young Adult, Hyperuricemia drug therapy, Naphthalenes therapeutic use, Organic Anion Transporters antagonists & inhibitors, Organic Cation Transport Proteins antagonists & inhibitors, Propionates therapeutic use, Pyridines therapeutic use, Uric Acid blood
- Abstract
Verinurad, a uric acid transporter 1 (URAT1) inhibitor, lowers serum uric acid by promoting its urinary excretion. Co-administration with a xanthine oxidase inhibitor (XOI) to simultaneously reduce uric acid production rate reduces the potential for renal tubular precipitation of uric acid, which can lead to acute kidney injury. The combination is currently in development for chronic kidney disease and heart failure. The aim of this work was to apply and extend a previously developed semi-mechanistic exposure-response model for uric acid kinetics to include between-subject variability to verinurad and its combinations with XOIs, and to provide predictions to support future treatment strategies. The model was developed using data from 12 clinical studies from a total of 434 individuals, including healthy volunteers, patients with hyperuricemia, and renally impaired subjects. The model described the data well, taking into account the impact of various patient characteristics such as renal function, baseline fractional excretion of uric acid, and race. The potencies (EC50s) of verinurad (reducing uric acid reuptake), febuxostat (reducing uric acid production), and oxypurinol (reducing uric acid production) were: 29, 128, and 13,030 ng/mL, respectively. For verinurad, symptomatic hyperuricemic (gout) subjects showed a higher EC50 compared with healthy volunteers (37 ng/mL versus 29 ng/mL); while no significant difference was found for asymptomatic hyperuricemic patients. Simulations based on the uric acid model were performed to assess dose-response of verinurad in combination with XOI, and to investigate the impact of covariates. The simulations demonstrated application of the model to support dose selection for verinurad.
- Published
- 2021
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284. Geriatric screening, fall characteristics and 3- and 12 months adverse outcomes in older patients visiting the emergency department with a fall.
- Author
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Blomaard LC, Mooijaart SP, van Meer LJ, Leander J, Lucke JA, de Gelder J, Anten S, Gussekloo J, and de Groot B
- Subjects
- Aged, Aged, 80 and over, Female, Humans, Male, Retrospective Studies, Risk Assessment, Accidental Falls, Emergency Service, Hospital, Geriatric Assessment, Outcome Assessment, Health Care
- Abstract
Background: Falls in older Emergency Department (ED) patients may indicate underlying frailty. Geriatric follow-up might help improve outcomes in addition to managing the direct cause and consequence of the fall. We aimed to study whether fall characteristics and the result of geriatric screening in the ED are independently related to adverse outcomes in older patients with fall-related ED visits., Methods: This was a secondary analysis of the observational multicenter Acutely Presenting Older Patient (APOP) study, of which a subset of patients aged ≥70 years with fall-related ED visits were prospectively included in EDs of two Dutch hospitals. Fall characteristics (cause and location) were retrospectively collected. The APOP-screener was used as a geriatric screening tool. The outcome was 3- and 12-months functional decline and mortality. We assessed to what extent fall characteristics and the geriatric screening result were independent predictors of the outcome, using multivariable logistic regression analysis., Results: We included 393 patients (median age 80 (IQR 76-86) years) of whom 23.0% were high risk according to screening. The cause of the fall was extrinsic (49.6%), intrinsic (29.3%), unexplained (6.4%) or missing (14.8%). A high risk geriatric screening result was related to increased risk of adverse outcomes (3-months adjusted odds ratio (AOR) 2.27 (1.29-3.98), 12-months AOR 2.20 (1.25-3.89)). Independent of geriatric screening result, an intrinsic cause of the fall increased the risk of 3-months adverse outcomes (AOR 1.92 (1.13-3.26)) and a fall indoors increased the risk of 3-months (AOR 2.14 (1.22-3.74)) and 12-months adverse outcomes (AOR 1.78 (1.03-3.10))., Conclusions: A high risk geriatric screening result and fall characteristics were both independently associated with adverse outcomes in older ED patients, suggesting that information on both should be evaluated to guide follow-up geriatric assessment and interventions in clinical care.
- Published
- 2021
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285. Higher Febuxostat Exposure Observed in Asian Compared with Caucasian Subjects Independent of Bodyweight.
- Author
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Rekić D, Johansson S, and Leander J
- Subjects
- Body Weight, Gout Suppressants therapeutic use, Humans, Male, Febuxostat therapeutic use, Gout drug therapy, Hyperuricemia drug therapy
- Abstract
Background and Objective: Febuxostat is a xanthine oxidase inhibitor indicated for gout and hyperuricemia. This work investigates potential clinically relevant covariates for febuxostat pharmacokinetics with a special focus on Asian race and bodyweight., Methods: Febuxostat plasma concentrations from 141 male subjects were obtained from two phase II studies in patients with hyperuricemia/gout (NCT02246673, NCT02317861) and one study in healthy volunteers (NCT01883167). Subjects were administered febuxostat oral doses from 10 to 80 mg. The pharmacokinetics of febuxostat was analyzed using non-linear mixed-effects modeling as implemented in NONMEM 7.3.0. The dataset consisted of racially diverse subjects, 40% being Japanese, 10% of unknown Asian origin, 39% Caucasian, and 10% Black. Most subjects (n = 92, 63%) had normal creatinine clearance (90 mL/min), while 52 subjects (36%) had mild renal impairment (creatinine clearance > 60 to < 90) at baseline. The effect of disease state, body weight, and creatinine clearance on febuxostat pharmacokinetics was investigated using stepwise covariate modeling., Results: Febuxostat pharmacokinetics was well described by a two-compartment disposition model. Asian race was the only covariate resulting in a potentially clinically important increase in febuxostat area under the curve (1.64-fold, 90% confidence interval 1.48-1.79) compared with Caucasian individuals. The difference in body weight between Asian and Caucasian subjects did not explain the difference in febuxostat exposure. Absorption was modeled as a sequential zero- to first-order process with lag-time., Conclusions: In this pooled analysis of three studies, we show that Asian individuals have a 1.64-fold higher febuxostat exposure than Caucasians, independent of bodyweight or other investigated covariates. These findings may be of importance when selecting starting febuxostat doses in Asian patients.
- Published
- 2021
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- View/download PDF
286. Estimation of Equipotent Doses for Anti-Inflammatory Effects of Prednisolone and AZD9567, an Oral Selective Nonsteroidal Glucocorticoid Receptor Modulator.
- Author
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Almquist J, Sadiq MW, Eriksson UG, Hegelund Myrbäck T, Prothon S, and Leander J
- Subjects
- Anti-Inflammatory Agents administration & dosage, Dose-Response Relationship, Drug, Humans, Indazoles administration & dosage, Lipopolysaccharides, Prednisolone administration & dosage, Pyridines administration & dosage, Randomized Controlled Trials as Topic, Receptors, Glucocorticoid drug effects, Receptors, Glucocorticoid metabolism, Tumor Necrosis Factor-alpha metabolism, Anti-Inflammatory Agents pharmacology, Indazoles pharmacology, Models, Biological, Prednisolone pharmacology, Pyridines pharmacology
- Abstract
AZD9567 is a potent and selective nonsteroidal oral glucocorticoid receptor modulator. It is developed as an anti-inflammatory drug with improved safety profile compared with steroids like prednisolone. Throughout the clinical development of AZD9567, dose selection and data interpretation require a method for determining doses with the same anti-inflammatory effect as prednisolone. Equipotent doses of AZD9567 and prednisolone were defined by the same average inhibition of TNFα release, a biomarker of anti-inflammatory effect, measured in a lipopolysaccharide-stimulated whole blood ex vivo assay. Based on pharmacokinetic-pharmacodynamic models, TNFα dose-response relationships for AZD9567 and prednisolone were established. A comparison of the dose-response curves enabled estimation of an equipotency relationship. Specifically, 20 mg prednisolone was estimated to be equipotent to 40 mg AZD9567 (95% confidence interval: 29-54 mg). Static concentration-response analyses showed that the relative potencies for inhibition of TNFα release of AZD9567 and prednisolone were well aligned with several other pro-inflammatory cytokines., (© 2020 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)
- Published
- 2020
- Full Text
- View/download PDF
287. Effects of a selective glucocorticoid receptor modulator (AZD9567) versus prednisolone in healthy volunteers: two phase 1, single-blind, randomised controlled trials.
- Author
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Hegelund Myrbäck T, Prothon S, Edman K, Leander J, Hashemi M, Dearman M, Edenro G, Svanberg P, Andersson EM, Almquist J, Ämmälä C, Hendrickx R, Taib Z, Johansson KA, Berggren AR, Keen CM, Eriksson UG, Fuhr R, and Carlsson BCL
- Abstract
Background: Glucocorticoids are highly effective and widely used anti-inflammatory drugs, but their use is limited by serious side-effects, including glucocorticoid-induced hyperglycaemia and diabetes. AZD9567 is a non-steroidal, selective glucocorticoid receptor modulator that aims to reduce side-effects. We aimed to assess the safety, tolerability, and pharmacokinetics of AZD9567 in healthy volunteers., Methods: Two phase 1 clinical studies were done. First, a randomised, placebo-controlled, single-blind, single-ascending dose study was done in healthy men who received single oral doses of AZD9567 2 mg, 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, 125 mg, or 155 mg, or prednisolone 60 mg (n=8 per dose group, randomly assigned [6:2] to receive active drug or placebo). Second, a randomised, active-controlled, single-blind, multiple-ascending dose study was done, in which men and women received oral AZD9567 or prednisolone once daily for 5 days. One cohort of volunteers with prediabetes received AZD9567 10 mg (n=7) or prednisolone 20 mg (n=2). All other cohorts comprised healthy volunteers, receiving AZD9567 20 mg, 40 mg, 80 mg, or 125 mg (n=7 per dose group), or prednisolone 5 mg (n=13), 20 mg (n=16), or 40 mg (n=13). Participants and study centre staff were masked to treatment assignment for each cohort, although data were unmasked for safety review between cohorts. The primary outcome of the single-ascending dose study was the safety, tolerability, and pharmacokinetics of single ascending doses of AZD9567; for the multiple-ascending dose study it was the safety and tolerability of AZD9567 following multiple ascending doses. As a secondary outcome, effects on glycaemic control were ascertained with oral glucose tolerance tests (OGTTs) done at baseline and on day 1 of the single-ascending dose study, and at baseline and on day 4 of the multiple-ascending dose study. These trials are registered at ClinicalTrials.gov, NCT02512575 and NCT02760316., Findings: In the single-ascending dose study, between Nov 18, 2015, and Sept 26, 2016, 72 healthy white men were enrolled, and all completed the study. In the multiple-ascending dose study, between May 2, 2016, and Sept 13, 2017, 77 predominantly white male volunteers (including nine individuals with prediabetes and eight women) were enrolled and 75 completed the study. All doses of AZD9567 and prednisolone were well tolerated, with no serious adverse events or events suggesting adrenal insufficiency. In the single-ascending dose study, nine adverse events of mild intensity were reported (five with AZD9567 and four with placebo); no adverse event was reported by more than one person. In the multiple-ascending dose study, 44 adverse events of mild or moderate intensity were reported (18 with AZD9567 and 26 with prednisolone). The most common were headache and micturition. Apparent clearance, volume of distribution, and half-life of AZD9567 were consistent across doses and for single versus repeated dosing. In the multiple-ascending dose study, OGTTs showed no significant difference with AZD9567 doses up to 80 mg compared with prednisolone 5 mg in glucose area under the curve from 0 h to 4 h post-OGTT (AUC
0-4h ) from baseline to day 4; the increase in glucose AUC0-4h from baseline to day 4 was significantly lower with all AZD9567 doses versus prednisolone 20 mg (AZD9567 20 mg p<0·0001, 40 mg p=0·0001, 80 mg p=0·0001, and 125 mg p=0·0237)., Interpretation: AZD9567 appears to be safe and well tolerated in healthy, predominantly white male volunteers and shows promising initial evidence for improved post-prandial glucose control. Studies of longer duration, with a greater proportion of women and other ethnic groups, and in patients requiring anti-inflammatory treatment are needed to characterise the clinical efficacy and safety profile of AZD9567., Funding: AstraZeneca., (Copyright © 2020 Elsevier Ltd. All rights reserved.)- Published
- 2020
- Full Text
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288. Less anxious salmon smolt become easy prey during downstream migration.
- Author
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Klaminder J, Jonsson M, Leander J, Fahlman J, Brodin T, Fick J, and Hellström G
- Subjects
- Animals, Anxiety, Animal Migration, Behavior, Animal, Salmo salar physiology
- Abstract
Hatchery-reared salmon smolt used for supplementary stocking often display poor migration behavior compared to wild smolt, which reduces the success of this management action. Oxazepam, an anxiolytic drug, has been shown to intensify salmon smolt migration in mesocosm experiments, and treatment with this drug has, therefore, been suggested as a management option to improve downstream smolt migration. In this study, we tested this by assessing migration performance of hatchery-reared Atlantic salmon (Salmo salar) smolt along a 21-km long natural river-to-sea migration route in a boreal river in Northern Sweden. Using acoustic telemetry, the migration rate and survival of smolt that had been exposed to oxazepam (200 μg L
-1 , N = 20) was monitored and compared with a control group (N = 20) of unexposed smolt. Exposed smolt took significantly longer time to initiate migration after release compared to the control fish, but after that we observed no significant difference in downstream migration speed. However, exposed smolt had considerably higher probability of being predated on compared to control smolt. We attribute these results to increased risk-taking and higher activity in oxazepam-exposed smolt, which in turn increased initial non-directional exploratory behavior and decreased predator vigilance. These results are discussed based on current concerns for ecological implications of behavioral modifications induced by pharmaceutical pollution and climate change. We conclude that exposure to oxazepam is an unsuitable management option to prime migration of reared salmon in natural systems., (Copyright © 2019 Elsevier B.V. All rights reserved.)- Published
- 2019
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289. Exact Gradients Improve Parameter Estimation in Nonlinear Mixed Effects Models with Stochastic Dynamics.
- Author
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Olafsdottir HK, Leander J, Almquist J, and Jirstrand M
- Subjects
- Algorithms, Computer Simulation, Humans, Uncertainty, Biological Variation, Population, Models, Biological, Nonlinear Dynamics, Pharmacokinetics, Stochastic Processes
- Abstract
Nonlinear mixed effects (NLME) modeling based on stochastic differential equations (SDEs) have evolved into a promising approach for analysis of PK/PD data. SDE-NLME models go beyond the realm of standard population modeling as they consider stochastic dynamics, thereby introducing a probabilistic perspective on the state variables. This article presents a summary of the main contributions to SDE-NLME models found in the literature. The aims of this work were to develop an exact gradient version of the first-order conditional estimation (FOCE) method for SDE-NLME models and to investigate whether it enabled faster estimation and better gradient precision/accuracy compared to the use of gradients approximated by finite differences. A simulation-estimation study was set up whereby finite difference approximations of the gradients of each level were interchanged with the exact gradients. Following previous work, the uncertainty of the state variables was accounted for using the extended Kalman filter (EKF). The exact gradient FOCE method was implemented in Mathematica 11 and evaluated on SDE versions of three common PK/PD models. When finite difference gradients were replaced by exact gradients at both FOCE levels, relative runtimes improved between 6- and 32-fold, depending on model complexity. Additionally, gradient precision/accuracy was significantly better in the exact gradient case. We conclude that parameter estimation using FOCE with exact gradients can successfully be applied to SDE-NLME models.
- Published
- 2018
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290. Behavioral Effects of a Novel Benzofuranyl-Piperazine Serotonin-2C Receptor Agonist Suggest a Potential Therapeutic Application in the Treatment of Obsessive-Compulsive Disorder.
- Author
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Rodriguez MM, Overshiner C, Leander JD, Li X, Morrow D, Conway RG, Nelson DL, Briner K, and Witkin JM
- Abstract
Selective serotonin reuptake inhibitors (SSRIs) are the only effective pharmacological treatments for obsessive-compulsive disorder (OCD). Nonetheless, their generally limited efficacy, side-effects, and delayed onset of action require improved medications for this highly prevalent disorder. Preclinical and clinical findings have suggested serotonin2C (5-HT
2C ) receptors as a potential drug target. Data in rats and mice are presented here on the effects of a novel 5-HT2C receptor agonist ((3S)-3-Methyl-1-[4-(trifluoromethyl)-7-benzofuranyl]-piperazine) (CPD 1) with high potency and full efficacy at 5-HT2C receptors and less potency and partial agonism at 5-HT2A and 5-HT2B receptors. Effects of CPD 1 on consummatory (schedule-induced polydipsia in rats) and non-consummatory behaviors (marble-burying and nestlet-shredding in mice) that are repetitive and non-habituating were studied. We also evaluated the effects of CPD 1 in rats with isoproterenol- and deprivation-induced drinking in rats to compare with the polydipsia studies. The SSRIs, fluoxetine, and chlomipramine decreased the high rates of drinking in rats engendered by a schedule of intermittent food delivery (schedule-induced polydipsia). The effects of fluoxetine, but not of d-amphetamine, were prevented by the selective 5-HT2C receptor antagonist SB242084. The 5-HT2C receptor agonists Ro 60-0175 and CPD 1 also decreased drinking, but unlike the SSRIs and Ro 60-0175, CPD 1 dose-dependently decreased excessive drinking without affecting lever press responses that produced food. The effects of CPD 1 were prevented by SB242084. CPD 1 also suppressed drinking induced by isoproterenol and by water deprivation without affecting normative drinking behavior. CPD 1, like fluoxetine, also suppressed marble-burying and nestlet-shredding in mice at doses that did not affect rotarod performance or locomotor activity. The behavioral specificity of effects of CPD 1 against repetitive and excessive behaviors suggests a potential therapeutic application in OCD.- Published
- 2017
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291. Using sensitivity equations for computing gradients of the FOCE and FOCEI approximations to the population likelihood.
- Author
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Almquist J, Leander J, and Jirstrand M
- Subjects
- Computer Simulation, Nonlinear Dynamics, Probability
- Abstract
The first order conditional estimation (FOCE) method is still one of the parameter estimation workhorses for nonlinear mixed effects (NLME) modeling used in population pharmacokinetics and pharmacodynamics. However, because this method involves two nested levels of optimizations, with respect to the empirical Bayes estimates and the population parameters, FOCE may be numerically unstable and have long run times, issues which are most apparent for models requiring numerical integration of differential equations. We propose an alternative implementation of the FOCE method, and the related FOCEI, for parameter estimation in NLME models. Instead of obtaining the gradients needed for the two levels of quasi-Newton optimizations from the standard finite difference approximation, gradients are computed using so called sensitivity equations. The advantages of this approach were demonstrated using different versions of a pharmacokinetic model defined by nonlinear differential equations. We show that both the accuracy and precision of gradients can be improved extensively, which will increase the chances of a successfully converging parameter estimation. We also show that the proposed approach can lead to markedly reduced computational times. The accumulated effect of the novel gradient computations ranged from a 10-fold decrease in run times for the least complex model when comparing to forward finite differences, to a substantial 100-fold decrease for the most complex model when comparing to central finite differences. Considering the use of finite differences in for instance NONMEM and Phoenix NLME, our results suggests that significant improvements in the execution of FOCE are possible and that the approach of sensitivity equations should be carefully considered for both levels of optimization.
- Published
- 2015
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292. Mixed Effects Modeling Using Stochastic Differential Equations: Illustrated by Pharmacokinetic Data of Nicotinic Acid in Obese Zucker Rats.
- Author
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Leander J, Almquist J, Ahlström C, Gabrielsson J, and Jirstrand M
- Subjects
- Animals, Computer Simulation, Nonlinear Dynamics, Rats, Rats, Zucker, Stochastic Processes, Models, Biological, Niacin pharmacokinetics, Obesity metabolism
- Abstract
Inclusion of stochastic differential equations in mixed effects models provides means to quantify and distinguish three sources of variability in data. In addition to the two commonly encountered sources, measurement error and interindividual variability, we also consider uncertainty in the dynamical model itself. To this end, we extend the ordinary differential equation setting used in nonlinear mixed effects models to include stochastic differential equations. The approximate population likelihood is derived using the first-order conditional estimation with interaction method and extended Kalman filtering. To illustrate the application of the stochastic differential mixed effects model, two pharmacokinetic models are considered. First, we use a stochastic one-compartmental model with first-order input and nonlinear elimination to generate synthetic data in a simulated study. We show that by using the proposed method, the three sources of variability can be successfully separated. If the stochastic part is neglected, the parameter estimates become biased, and the measurement error variance is significantly overestimated. Second, we consider an extension to a stochastic pharmacokinetic model in a preclinical study of nicotinic acid kinetics in obese Zucker rats. The parameter estimates are compared between a deterministic and a stochastic NiAc disposition model, respectively. Discrepancies between model predictions and observations, previously described as measurement noise only, are now separated into a comparatively lower level of measurement noise and a significant uncertainty in model dynamics. These examples demonstrate that stochastic differential mixed effects models are useful tools for identifying incomplete or inaccurate model dynamics and for reducing potential bias in parameter estimates due to such model deficiencies.
- Published
- 2015
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293. Joint feedback analysis modeling of nonesterified fatty acids in obese Zucker rats and normal Sprague-Dawley rats after different routes of administration of nicotinic acid.
- Author
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Tapani S, Almquist J, Leander J, Ahlström C, Peletier LA, Jirstrand M, and Gabrielsson J
- Subjects
- Animals, Drug Administration Routes, Fatty Acids, Nonesterified metabolism, Male, Models, Biological, Monte Carlo Method, Obesity metabolism, Rats, Sprague-Dawley, Rats, Zucker, Fatty Acids, Nonesterified blood, Hypolipidemic Agents administration & dosage, Hypolipidemic Agents pharmacology, Niacin administration & dosage, Niacin pharmacology, Obesity blood
- Abstract
Data were pooled from several studies on nicotinic acid (NiAc) intervention of fatty acid turnover in normal Sprague-Dawley and obese Zucker rats in order to perform a joint PKPD of data from more than 100 normal Sprague-Dawley and obese Zucker rats, exposed to several administration routes and rates. To describe the difference in pharmacodynamic parameters between obese and normal rats, we modified a previously published nonlinear mixed effects model describing tolerance and oscillatory rebound effects of NiAc on nonesterified fatty acids plasma concentrations. An important conclusion is that planning of experiments and dose scheduling cannot rely on pilot studies on normal animals alone. The obese rats have a less-pronounced concentration-response relationship and need higher doses to exhibit desired response. The relative level of fatty acid rebound after cessation of NiAc administration was also quantified in the two rat populations. Building joint normal-disease models with scaling parameter(s) to characterize the "degree of disease" can be a useful tool when designing informative experiments on diseased animals, particularly in the preclinical screen. Data were analyzed using nonlinear mixed effects modeling, for the optimization, we used an improved method for calculating the gradient than the usually adopted finite difference approximation., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)
- Published
- 2014
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294. Stochastic differential equations as a tool to regularize the parameter estimation problem for continuous time dynamical systems given discrete time measurements.
- Author
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Leander J, Lundh T, and Jirstrand M
- Subjects
- Animals, Computer Simulation, Ecosystem, Food Chain, Likelihood Functions, Mathematical Concepts, Membrane Potentials, Models, Neurological, Nonlinear Dynamics, Time Factors, Models, Biological, Models, Statistical, Stochastic Processes
- Abstract
In this paper we consider the problem of estimating parameters in ordinary differential equations given discrete time experimental data. The impact of going from an ordinary to a stochastic differential equation setting is investigated as a tool to overcome the problem of local minima in the objective function. Using two different models, it is demonstrated that by allowing noise in the underlying model itself, the objective functions to be minimized in the parameter estimation procedures are regularized in the sense that the number of local minima is reduced and better convergence is achieved. The advantage of using stochastic differential equations is that the actual states in the model are predicted from data and this will allow the prediction to stay close to data even when the parameters in the model is incorrect. The extended Kalman filter is used as a state estimator and sensitivity equations are provided to give an accurate calculation of the gradient of the objective function. The method is illustrated using in silico data from the FitzHugh-Nagumo model for excitable media and the Lotka-Volterra predator-prey system. The proposed method performs well on the models considered, and is able to regularize the objective function in both models. This leads to parameter estimation problems with fewer local minima which can be solved by efficient gradient-based methods., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
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295. GLYX-13, an NMDA receptor glycine site functional partial agonist enhances cognition and produces antidepressant effects without the psychotomimetic side effects of NMDA receptor antagonists.
- Author
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Moskal JR, Burch R, Burgdorf JS, Kroes RA, Stanton PK, Disterhoft JF, and Leander JD
- Subjects
- Animals, Antidepressive Agents pharmacokinetics, Antidepressive Agents pharmacology, Cognition drug effects, Excitatory Amino Acid Agonists pharmacokinetics, Excitatory Amino Acid Agonists pharmacology, Glycine metabolism, Humans, Oligopeptides pharmacokinetics, Oligopeptides pharmacology, Treatment Outcome, Antidepressive Agents therapeutic use, Depression drug therapy, Excitatory Amino Acid Agonists therapeutic use, Oligopeptides therapeutic use, Receptors, N-Methyl-D-Aspartate agonists
- Abstract
Introduction: The N-methyl-d-aspartate receptor-ionophore complex plays a key role in learning and memory and has efficacy in animals and humans with affective disorders. GLYX-13 is an N-methyl-d-aspartate receptor (NMDAR) glycine-site functional partial agonist and cognitive enhancer that also shows rapid antidepressant activity without psychotomimetic side effects., Areas Covered: The authors review the mechanism of action of GLYX-13 that was investigated in preclinical studies and evaluated in clinical studies. Specifically, the authors review its pharmacology, pharmacokinetics, and drug safety that were demonstrated in clinical studies., Expert Opinion: NMDAR full antagonists can produce rapid antidepressant effects in treatment-resistant subjects; however, they are often accompanied by psychotomimetic effects that make chronic use outside of a clinical trial inpatient setting problematic. GLYX-13 appears to exert its antidepressant effects in the frontal cortex via NMDAR-triggered synaptic plasticity. Understanding the mechanistic underpinning of GLYX-13's antidepressant action should provide both novel insights into the role of the glutamatergic system in depression and identify new targets for therapeutic development.
- Published
- 2014
- Full Text
- View/download PDF
296. Kappa-opioid receptor-mediated effects of the plant-derived hallucinogen, salvinorin A, on inverted screen performance in the mouse.
- Author
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Fantegrossi WE, Kugle KM, Valdes LJ 3rd, Koreeda M, and Woods JH
- Subjects
- Analgesics, Opioid pharmacology, Animals, Benzeneacetamides pharmacology, Diterpenes, Clerodane, Male, Mice, Naloxone pharmacology, Naltrexone analogs & derivatives, Naltrexone pharmacology, Narcotic Antagonists pharmacology, Piperidines pharmacology, Pyrrolidines pharmacology, Receptors, Opioid, delta antagonists & inhibitors, Receptors, Opioid, kappa antagonists & inhibitors, Receptors, Opioid, mu antagonists & inhibitors, Remifentanil, Behavior, Animal drug effects, Diterpenes pharmacology, Hallucinogens pharmacology, Psychotropic Drugs pharmacology, Receptors, Opioid, kappa agonists
- Abstract
Salvinorin A is a pharmacologically active diterpene that occurs naturally in the Mexican mint Ska Maria Pastora (Salvia divinorum) and represents the first naturally occurring kappa-opioid receptor agonist. The chemical structure of salvinorin A is novel among the opioids, and thus defines a new structural class of kappa-opioid-receptor selective drugs. Few studies have examined the effects of salvinorin A in vivo, and fewer still have attempted to assess the agonist actions of this compound at mu-opioid, delta-opioid, and kappa-opioid receptors using selective antagonists. In the mouse, salvinorin A disrupted climbing behavior on an inverted screen task, indicating a rapid, but short-lived induction of sedation/motor incoordination. Similar effects were observed with the mu-agonist remifentanil and the synthetic kappa-agonist U69,593. When behaviorally equivalent doses of all three opioids were challenged with antagonists at doses selective for mu-opioid, delta-opioid, or kappa-opioid receptors, results suggested that the motoric effects of remifentanil were mediated by mu-receptors, whereas those of salvinorin A and U69,593 were mediated via kappa-receptors. Despite similar potencies and degrees of effectiveness, salvinorin A and U69,593 differed with regard to their susceptibility to antagonism by the kappa-antagonist nor-binaltorphamine. This later finding, coupled with the novel chemical structure of the compound, is consistent with recent findings that the diterpene salvinorin A may bind to the kappa-receptor in a manner that is qualitatively different from that of more traditional kappa-agonists such as the benzeneacetamide U69,593. Such pharmacological differences among these kappa-opioids raise the possibility that the development of other diterpene-based opioids may yield important therapeutic compounds.
- Published
- 2005
- Full Text
- View/download PDF
297. SR141716A, a cannabinoid CB1 receptor antagonist, improves memory in a delayed radial maze task.
- Author
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Wolff MC and Leander JD
- Subjects
- Animals, Dose-Response Relationship, Drug, Injections, Intraperitoneal, Memory physiology, Mental Recall drug effects, Mental Recall physiology, Piperidines administration & dosage, Piperidines pharmacokinetics, Pyrazoles administration & dosage, Pyrazoles pharmacokinetics, Rats, Rats, Sprague-Dawley, Receptor, Cannabinoid, CB1 therapeutic use, Retention, Psychology drug effects, Retention, Psychology physiology, Rimonabant, Maze Learning drug effects, Memory drug effects, Piperidines therapeutic use, Pyrazoles therapeutic use, Receptor, Cannabinoid, CB1 antagonists & inhibitors
- Abstract
An endogenous cannabinoid system may play an important role in controlling memory processes. SR141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride), a selective cannabinoid CB(1) receptor antagonist, was studied in an eight-arm radial maze task in which either deficits or improvements in memory could be detected. This task required well-trained rats to recall after either a relatively short (3 h) or long (7 h) delay period where they had received rewards during an information phase in order to obtain the remaining rewards during a retention phase. SR141716A was administered intraperitoneally immediately after the information phase in order to determine the drug's effects on memory consolidation. Although SR141716A had no effect on the number of errors committed after a short interval, SR141716A significantly reduced the number of errors that occurred after 7 h. These results suggest that a cannabinoid CB(1) receptor antagonist can improve consolidation processes and thus may be useful in treating memory disorders.
- Published
- 2003
- Full Text
- View/download PDF
298. Comparison of the effects of antipsychotics on a delayed radial maze task in the rat.
- Author
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Wolff MC and Leander JD
- Subjects
- Administration, Oral, Animals, Benzodiazepines, Clozapine administration & dosage, Clozapine pharmacokinetics, Dose-Response Relationship, Drug, Food Deprivation, Haloperidol administration & dosage, Haloperidol pharmacokinetics, Male, Olanzapine, Piperazines administration & dosage, Piperazines pharmacokinetics, Pirenzepine administration & dosage, Pirenzepine pharmacokinetics, Rats, Rats, Sprague-Dawley, Risperidone administration & dosage, Risperidone pharmacokinetics, Thiazoles administration & dosage, Thiazoles pharmacokinetics, Antipsychotic Agents administration & dosage, Antipsychotic Agents pharmacokinetics, Cognition drug effects, Maze Learning drug effects, Memory drug effects, Pirenzepine analogs & derivatives
- Abstract
Rationale: The cognitive impairments evident in many schizophrenics are related to the severity of their negative symptoms and ability to function in society. Drugs that alleviate cognitive impairments, in addition to other psychotic symptoms, may have an important influence on treatment outcome and the course of the illness., Objectives: A delayed non-match to sample task conducted in an eight-arm radial maze was used to determine the influence of four atypical antipsychotics (olanzapine, ziprasidone, risperidone, and clozapine), as well as a typical neuroleptic (haloperidol) on consolidation processes in healthy rats., Method: Well-trained rats were required to recall after a 7-h delay where they had received food pellets during an information phase (first four arm choices) in order to obtain the remaining food pellets during a retention phase (second four arm choices)., Results: The total number of errors that occurred during the retention session increased with increasing delay periods from 0 to 7 h. When administered orally immediately after the information phase, olanzapine (3 and 5 mg/kg) and risperidone (0.1 mg/kg) significantly reduced the number of errors made during the retention phase. Under the same conditions, clozapine, ziprasidone and haloperidol failed to affect the total number of retention phase errors., Conclusion: Some atypical antipsychotics, such as olanzapine and risperidone, improve consolidation processes and may alleviate the cognitive impairments associated with schizophrenia.
- Published
- 2003
- Full Text
- View/download PDF
299. Selective serotonin reuptake inhibitors decrease impulsive behavior as measured by an adjusting delay procedure in the pigeon.
- Author
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Wolff MC and Leander JD
- Subjects
- 8-Hydroxy-2-(di-n-propylamino)tetralin pharmacology, Alprazolam pharmacology, Analysis of Variance, Animals, Anti-Anxiety Agents pharmacology, Chlordiazepoxide pharmacology, Columbidae, Cyclohexanes pharmacology, Dose-Response Relationship, Drug, Impulsive Behavior physiopathology, Impulsive Behavior psychology, Male, Piperazines pharmacology, Receptors, Serotonin drug effects, Receptors, Serotonin physiology, Receptors, Serotonin, 5-HT1, Reinforcement Schedule, Reward, Serotonin Receptor Agonists pharmacology, Time Factors, Fluoxetine pharmacology, Impulsive Behavior prevention & control, Selective Serotonin Reuptake Inhibitors pharmacology
- Abstract
The inability to delay gratification (reinforcement or reward) is one index of impulsive behavior. In order to measure the willingness of pigeons to delay reinforcement, an adjustable delay schedule was developed that allowed daily approximations of an indifference point between immediate brief access to reinforcer and delayed, longer access to reinforcer. Acute administration of the anxiolytic alprazolam (5 mg/kg) decreased the length of delay tolerated before a larger reinforcement. Likewise, acute administration of the anxiolytic chlordiazepoxide (10 mg/kg) produced a similar, although not significant, effect. Neither acute nor five daily injections of 8-OH-DPAT, a 5-HT(1A) agonist, or WAY100635, a 5-HT(1A) antagonist, affected the length of the delay period. Chronic (17 day), but not acute injections of the selective serotonin reuptake inhibitors (SSRIs) fluoxetine (10 mg/kg), citalopram (10 mg/kg) and paroxetine (3 mg/kg) increased the delay period. When given in addition to 1 mg/kg of 8-OH-DPAT, but not 1 mg/kg WAY100635, the effect of fluoxetine was accelerated in that the increase in delay was observed earlier in the treatment. These data support the use of SSRIs to decrease impulsive behavior. Addition of a 5-HT(1A) agonist, but not a 5-HT(1A) antagonist, to the SSRI may hasten the therapeutic activity of the SSRI in treating impulsivity.
- Published
- 2002
- Full Text
- View/download PDF
300. m-CPP hypolocomotion is selectively antagonized by compounds with high affinity for 5-HT(2C) receptors but not 5-HT(2A) or 5-HT(2B) receptors.
- Author
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Gleason SD, Lucaites VL, Shannon HE, Nelson DL, and Leander JD
- Subjects
- Amphetamines metabolism, Animals, Binding, Competitive drug effects, Cell Line, Cricetinae, Fluorobenzenes pharmacology, Humans, Kinetics, Male, Mice, Mice, Inbred Strains, Piperidines pharmacology, Radioligand Assay, Receptor, Serotonin, 5-HT2A, Receptor, Serotonin, 5-HT2B, Receptor, Serotonin, 5-HT2C, Serotonin Antagonists pharmacology, Motor Activity drug effects, Piperazines antagonists & inhibitors, Piperazines pharmacology, Receptors, Serotonin drug effects, Serotonin Agents pharmacology
- Abstract
The ability of m-CPP [1-(m-chlorophenyl)piperazine] to produce hypolocomotion is well documented. This effect has been postulated to be due to activation of the 5-HT(2C) receptor. It is only recently that the tools necessary to clearly delineate which serotonin receptors are involved in the mediation of m-CPP hypolocomotion have become available. We investigated the effects of the selective 5-HT(2A) antagonists, MDL 100,907 and ketanserin, the selective 5-HT(2B) antagonists, LY 202146 and LY 266097, the 5-HT(2B/2C) antagonist, SB 206553, and the selective 5-HT(2C) antagonist, SB 242084 on m-CPP-induced hypolocomotion and spontaneous locomotor activity in mice. Furthermore, we investigated the effects of the non-selective serotonin antagonists, ritanserin, LY 53857, mianserin and cyproheptadine on m-CPP hypolocomotion. Additionally, receptor-binding studies were employed as an in vitro assessment of relative affinities at the 5-HT(2A), 5-HT92B) and 5-HT(2C) receptors. Antagonists tested alone were without effect on spontaneous activity, with the sole exception of ketanserin, which decreased spontaneous activity at the high dose of 1 mg/kg. m-CPP-induced hypolocomotion was not significantly attenuated by various doses of MDL 100,907, ketanserin, LY 202146, LY 266097, ritanserin or cyproheptadine. In contrast, SB 206553, SB 242084, LY 53857 and mianserin were capable of reversing m-CPP-induced hypolocomotion. Consistent with previous suggestions, a detailed pharmacological evaluation with selective antagonists for the 5-HT2 family of receptors supports a primary role for the 5-HT(2C) receptor, and not 5-HT(2A) or 5-HT(2B) receptors, in mediating the hypolocomotion produced by m-CPP.
- Published
- 2001
- Full Text
- View/download PDF
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