83 results on '"de Visser, S. J."'
Search Results
2. The central nervous system effects, pharmacokinetics and safety of the NAALADase-inhibitor GPI 5693
- Author
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van der Post, J. P., de Visser, S. J., de Kam, M. L., Woelfler, M., Hilt, D. C., Vornov, J., Burak, E. S., Bortey, E., Slusher, B. S., Limsakun, T., Cohen, A. F., and van Gerven, J. M. A.
- Published
- 2005
3. Biomarkers for the effects of selective serotonin reuptake inhibitors (SSRIs) in healthy subjects
- Author
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Dumont, G. J. H., de Visser, S. J., Cohen, A. F., and van Gerven, J. M. A.
- Published
- 2005
4. Biomarkers for the effects of benzodiazepines in healthy volunteers
- Author
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de Visser, S. J., van der Post, J. P., de Waal, P. P., Cornet, F., Cohen, A. F., and van Gerven, J. M. A.
- Published
- 2003
5. Concentration-effect relationships of two infusion rates of the imidazoline antihypertensive agent rilmenidine for blood pressure and development of side-effects in healthy subjects
- Author
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de Visser, S. J., van Gerven, J. M. A., Schoemaker, R. C., and Cohen, A. F.
- Published
- 2001
6. Biomarkers for the effects of antipsychotic drugs in healthy volunteers
- Author
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de Visser, S. J., van der Post, J., Pieters, M. S. M., Cohen, A. F., and van Gerven, J. M. A.
- Published
- 2001
7. Pharmacodynamics and Pharmacokinetics of a Single Oral Dose of Nitrazepam in Healthy Volunteers: An Interethnic Comparative Study between Japanese and European Volunteers
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van Gerven, J. M. A., Uchida, E., Uchida, N., Pieters, M. S. M., Meinders, A. J., Schoemaker, R. C., Nanhekhan, L. V., Kroon, J. M., de Visser, S. J., Altorf, B., Yasuda, K., Yasuhara, H., and Cohen, A. F.
- Published
- 1998
8. Biomarkers for the effects of benzodiazepines in healthy volunteers
- Author
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de Visser, S J, van der Post, J P, de Waal, P P, Cornet, F, Cohen, A F, and van Gerven, J M A
- Subjects
Benzodiazepines ,Pharmacodynamics ,Dose-Response Relationship, Drug ,Eye Movements ,Motor Skills ,Humans ,Electroencephalography ,Proceedings of the Dutch Society for Clinical Pharmacology and Biopharmacy 19 April 2002 ,Biomarkers - Abstract
Studies of novel centrally acting drugs in healthy volunteers are traditionally concerned with kinetics and tolerability, but useful information may also be obtained from biomarkers of clinical endpoints. A useful biomarker should meet the following requirements: a consistent response across studies and drugs; a clear response of the biomarker to a therapeutic dose; a dose–response relationship; a plausible relationship between biomarker, pharmacology and pathogenesis. In the current review, all individual tests found in studies of benzodiazepine agonists registered for anxiety in healthy volunteers since 1966 were progressively evaluated for compliance with these requirements. A MedLine search yielded 56 different studies, investigating the effects of 16 different benzodiazepines on 73 different (variants of) neuropsychological tests, which could be clustered into seven neuropsychological domains. Subjective and objective measures of alertness were most sensitive to benzodiazepines. The most consistent effects were observed on saccadic peak velocity (SPV) and visual analogue scores ( VAS) of alertness, where 100% and 79% of all studies respectively showed statistically significant effects. A dose–response relationship could be constructed for temazepam and SPV, which was used to determine dose equivalencies relative to temazepam, for seven different benzodiazepines. These dose equivalencies correlated with the lowest recommended daily maintenance dose (r2 = 0.737, P < 0.05). This relationship between SPV reduction and clinical efficacy could reflect the clinical practice of aiming for maximum tolerated levels, or it could represent a common basis behind SPV reduction and anxiolytic activity for benzodiazepines (probably sedation). The number of tests used in human psychopharmacology appears to be excessive and their sensitivity and reproducibility low.
- Published
- 2002
9. Pharmacodynamic and pharmacokinetic effects of MK-0343, a GABA α2,3 subtype selective agonist, compared to lorazepam and placebo in healthy male volunteers.
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De Haas, S. L., De Visser, S. J., Van Der Post, J. P., Schoemaker, R. C., Van Dyck, K., Murphy, M. G., De Smet, M., Vessey, L. K., Ramakrishnan, R., Xue, L., Cohen, A. F., and Van Gerven, J. M. A.
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GABA agonists ,ANXIETY ,LORAZEPAM ,PLACEBOS ,TRANQUILIZING drugs ,MEMORY ,SACCADIC eye movements - Abstract
The use of non-selective γ-aminobutydc acid (GABA) enhancers, such as benzodiazepines in the treatment of anxiety disorders is still widespread but hampered by unfavourable side effects. Some of these may be associated with binding properties to certain subtypes of the GABA
A receptor that are unnecessary for therapeutic effects. MK-0343 was designed to be a less sedating anxiolytic, based on reduced efficacy at the α1 subtype and significant efficacy at α2 and α3 subtypes of the GABAA receptor. This paper is a double-blind, four-way cross-over (n = 12) study to investigate the effects of MK-0343 (0.25 and 0.75 rag) in comparison to placebo and an anxiolytic dose (2 mg) of the non-selective agonist lorazepam. Effects were measured by eye movements, body sway, Visual Analogue Scales (VAS) and memory tests. Lorazepam impaired saccadic peak velocity (SPV), VAS alertness scores, postural stability and memory and increased saccadic latency and inaccuracy. MK-0343 0.75 mg was equipotent with lorazepam as indicated by SPV (-42.4 deg/s), saccadic latency (0.02 s) and VAS alertness scores (1.50 ln mm), while effects on memory and postural stability were smaller. MK-0343 0.25 mg only affected postural stability to a similar extent as MK-0343 0.75 mg. The effect profile of MK-0343 0.75 mg is different from the full agonist lorazepam, which could reflect the selective actions of this compound. Although less effect on VAS alertness was expected, diminished effects on memory and postural stability were present. Clinical studies in anxiety patients should show whether this dose of MK-0343 is therapeutically effective with a different side-effect profile. [ABSTRACT FROM AUTHOR]- Published
- 2008
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10. Pharmacodynamic and pharmacokinetic effects of TPA023, a GABAA α2,3 subtype-selective agonist, compared to lorazepam and placebo in healthy volunteers.
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De Haas, S. L., De Visser, S. J., Van der Post, J. P., De Smet, M., Schoemaker, R. C., Rijnbeek, B., Cohen, A. F., Vega, J. M., Agrawal, N. G. B., Goel, T. V., Simpson, R. C., Pearson, L. K., Li, S., Hesney, M., Murphy, M. G., and Van Gerven, J. M. A.
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GABA agonists ,PHARMACODYNAMICS ,PHARMACOKINETICS ,LORAZEPAM ,PLACEBOS ,MEMORY ,SACCADIC eye movements ,BENZODIAZEPINES - Abstract
TPA023, a GABA
A α2,3 αsubtype-selective partial agonist, is expected to have comparable anxiolytic efficacy as benzodiazepines with reduced sedating effects. The compound lacks efficacy at the α1 subtype, which is believed to mediate these effects. This study investigated the effects of 0.5 and 1.5 mg TPA023 and compared them with placebo and lorazepam 2 mg (therapeutic anxiolytic dose). Twelve healthy male volunteers participated in this placebo-controlled, double-blind, double-dummy, four-way, cross-over study. Saccadic eye movements and visual analogue scales (VAS) were used to assess the sedative properties of TPA023. The effects on postural stability and cognition were assessed using body sway and a standardized battery of neurophysiological memory tests. Lorazepam caused a significant reduction in saccadic peak velocity, the VAS alertness score and impairment of memory and body sway. TPA023 had significant dose dependent effects on saccadic peak velocity (85 deg/sec maximum reduction at the higher dose) that approximated the effects of lorazepam. In contrast to lorazepam, TPA023 had no detectable effects on saccadic latency or inaccuracy. Also unlike lorazepam, TPA023 did not affect VAS alertness, memory or body sway. These results show that the effect profile of TPA023 differs markedly from that of lorazepam, at doses that were equipotent with regard to effects on saccadic peak velocity. Contrary to lorazepam, TPA023 caused no detectable memory impairment or postural imbalance. These differences reflect the selectivity of TPA023 for different GABAA receptor subtypes. [ABSTRACT FROM AUTHOR]- Published
- 2007
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11. Pharmacokinetic/pharmacodynamic assessment of tolerance to central nervous system effects of a 3 mg sustained release tablet of rilmenidine in hypertensive patients.
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Van der Post, J. P., De Visser, S. J., Schoemaker, R. C., Cohen, A. F., and Van Gerven, J. M. A.
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BLOOD pressure ,CENTRAL nervous system ,HYPERTENSION ,PHARMACOKINETICS ,PHARMACODYNAMICS - Abstract
Previous single-dose studies have shown clear blood pressure-lowering effects of a potential sustained release (SR) profile of rilmenidine, with concentration-dependent effects on the central nervous system. The aim of this study was to evaluate potential changes in concentration-effect-relationships for these central nervous system effects during a 4-week treatment period with an experimental SR formulation of rilmenidine 3 mg once daily in 15 mild-to-moderate hypertensive patients. The central nervous system effects of the treatment were evaluated using saccadic eye movements for sedative effects and visual analogue scales for subjective effects on alertness, mood and calmness. Measurements for pharmacokinetic and pharmacodynamic evaluations were performed on the first day of the treatment period and repeated after 1 week and 4 weeks of treatment. Drug concentrations increased during the study, whereas treatment related reductions in saccadic peak velocity (SPV) remained similar on all three study days. The slopes of the concentration-effect-curves for SPV remained unchanged throughout the study, while the intercepts tended to increase as a result of increased pre-dose values. Similar effects were observed for visual analogue scales for alertness: pre-dose values increased significantly during the study, while the size of the treatment responses (slopes) remained unaltered. The reasons for these adaptations cannot be determined but may include drug tolerance and habituations to study procedures. Blood pressure control remained stable and adequate throughout the study. [ABSTRACT FROM AUTHOR]
- Published
- 2004
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12. Psychomotor and cognitive effects of a single oral dose of talnetant (SB223412) in healthy volunteers compared with placebo or haloperidol.
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Liem-Moolenaar, M., Gray, F. A., de Visser, S. J., Franson, K. L., Schoemaker, R. C., Schmitt, J. A. J., Cohen, A. F., and van Gerven, J. M. A.
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ANTIPSYCHOTIC agents ,SCHIZOPHRENIA ,HALOPERIDOL ,PHARMACODYNAMICS ,PLACEBOS ,ELECTROENCEPHALOGRAPHY ,PHARMACOLOGY - Abstract
Central Nervous System (CNS) effects of talnetant, an NK-3 antagonist in development for schizophrenia, were compared to those of haloperidol and placebo. The study was randomised, double-blind, three-way crossover of talnetant 200 mg, haloperidol 3 mg or placebo. Twelve healthy males participated and EEG, saccadic and smooth pursuit eye movements, adaptive tracking, body sway, finger tapping, hormones, visual analogue scales (VAS) for alertness, mood and calmness and psychedelic effects, left/right distraction task, Tower of London and Visual and Verbal Learning Task were assessed. Haloperidol showed (difference to placebo; 95% CI; p-value) decreases in EEG a power (-0.87μV; -1.51/-0.22; p = 0.0110), saccadic inaccuracy (2.0%; 0.5/3.6; p = 0.0133), smooth pursuit eye movements (-7.5%; -12.0/-3.0; p = 0.0026), adaptive tracking (-3.5%; -5.4/-1.7; p = 0.0009), alertness (-6.8 mm; -11.1/-2.4; p = 0.0039), negative mood (-4.6 mm; -8.6/-0.6; p = 0.0266), the ability to control thoughts (1.2 mm; 0.2/2.3; p = 0.0214), and an increase of serum prolactin (ratio 4.1; 3.0/5.6; p < 0.0001). Talnetant showed decreased alpha power (-0.69 μV; -1.34/-0.04; p = 0.0390), improved adaptive tracking (1.9%; 0.1/3.7; p = 0.0370) and reduced calmness on VAS Bond and Lader (-4.5 mm; -8.0/-1.0; p = 0.0151). Haloperidol effects were predominantly CNS-depressant, while those of talnetant were slightly stimulatory. The results suggest that talnetant penetrates the brain, but it remains to be established whether this dose is sufficient and whether the observed effect profile is class-specific for NK3-antagonists. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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13. Sensitivity of cognitive function tests to acute hypoxia in healthy subjects: a systematic literature review.
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Post, Titiaan E., Heijn, Laurens G., Jordan, Jens, and van Gerven, Joop M. A.
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COGNITIVE testing ,EXECUTIVE function ,HYPOXEMIA ,STROOP effect ,OXYGEN saturation ,MOUNTAIN sickness ,RESPONSE inhibition - Abstract
Acute exposure to hypoxia can lead to cognitive impairment. Therefore, hypoxia may become a safety concern for occupational or recreational settings at altitude. Cognitive tests are used as a tool to assess the degree to which hypoxia affects cognitive performance. However, so many different cognitive tests are used that comparing studies is challenging. This structured literature evaluation provides an overview of the different cognitive tests used to assess the effects of acute hypoxia on cognitive performance in healthy volunteers. Less frequently used similar cognitive tests were clustered and classified into domains. Subsequently, the different cognitive test clusters were compared for sensitivity to different levels of oxygen saturation. A total of 38 articles complied with the selection criteria, covering 86 different cognitive tests. The tests and clusters showed that the most consistent effects of acute hypoxia were found with the Stroop test (where 42% of studies demonstrated significant abnormalities). The most sensitive clusters were auditory/verbal memory: delayed recognition (83%); evoked potentials (60%); visual/spatial delayed recognition (50%); and sustained attention (47%). Attention tasks were not particularly sensitive to acute hypoxia (impairments in 0%–47% of studies). A significant hypoxia level-response relationship was found for the Stroop test (p = 0.001), as well as three clusters in the executive domain: inhibition (p = 0.034), reasoning/association (p = 0.019), and working memory (p = 0.024). This relationship shows a higher test sensitivity at more severe levels of hypoxia, predominantly below 80% saturation. No significant influence of barometric pressure could be identified in the limited number of studies where this was varied. This review suggests that complex and executive functions are particularly sensitive to hypoxia. Moreover, this literature evaluation provides the first step towards standardization of cognitive testing, which is crucial for a better understanding of the effects of acute hypoxia on cognition. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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14. Combatting the rising costs of cancer drugs; interventions from a university hospital’s perspective.
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Dane, Aniek, van Leeuwen, Roelof, Hoedemakers, Maaike, van der Kuy, Hugo, and Sleijfer, Stefan
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ANTINEOPLASTIC agents ,UNIVERSITY hospitals ,DRUG prices ,COST control ,PATIENTS' rights - Abstract
Rapid increase in cost continues to have negative impact on patients’ accessibility to life-changing anticancer medications. Moreover, the rising cost does not equate to similar increase in medication effectiveness. We recognise our responsibility as a university hospital to tackle this imbalance and strive to provide high quality, sustainable, affordable and accessible care. An active approach in cost containment of expensive and innovative cancer drugs was adopted in our organisation to safeguard accessibility and improve quality of life for patients. In this article, we described four inverventions: 1) identify right patient and minimise overtreatment, 2) in-house medicine production for selected indications, 3) minimise medicine spillages and 4) effective procurement strategies. We call on other hospitals to take action and, favourably, to collaborate on a European level. Together, we will safeguard the current and future care of our patients. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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15. GABAergic Involvement in Selective Attention.
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Faßbender, Kaja, Baumert, Philine M., Wintergerst, Maximilian W. M., Terheyden, Jan H., Aslan, Behrem, M. Harmening, Wolf, and Ettinger, Ulrich
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GABA ,SELECTIVITY (Psychology) ,LORAZEPAM ,CATATONIA ,BENZODIAZEPINES - Abstract
Animals need to cope with abundant sensory information, and one strategy is to selectively direct attention to only the most relevant part of the environment. Although the cortical networks of selective attention have been studied extensively, its underlying neurotransmitter systems, especially the role of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), remain less well understood. Increased GABA
A receptor activity because of administration of benzodiazepines such as lorazepam is known to slow reactions in cognitive tasks. However, there is limited knowledge about GABAergic involvement in selective attention. Particularly, it is unknown whether increased GABAA receptor activity slows the build-up of selectivity or generally widens attentional focus. To address this question, participants (n = 29) received 1 mg lorazepam and placebo (within-subjects, double-blind) and performed an extended version of the flanker task. The spatial distribution of selective attention was studied by systematically manipulating number and position of incongruent flankers; the temporal build-up was characterized using delta plots. An online task version was presented to an independent, unmedicated sample (n = 25) to verify task effects. Under placebo and in the unmedicated sample, only the number of incongruent flankers, but not their position, influenced RTs. Incongruent flankers impaired RTs more strongly under lorazepam than placebo, especially when adjacent to the target. Delta plot analyses of RT showed that this effect persisted even when participants reacted slowly, indicating that lorazepam-induced impairments in selective attention do not result from simply slowed down build-up of selectivity. Instead, our data indicate that increased GABAA receptor activity widens the attentional focus. [ABSTRACT FROM AUTHOR]- Published
- 2023
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16. Fluoxetine degrades luminance perceptual thresholds while enhancing motivation and reward sensitivity.
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Gacoin, Maëva and Hamed, Suliann Ben
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REWARD (Psychology) ,BLINKING (Physiology) ,ANTIDEPRESSANTS ,PUPILLOMETRY ,SEROTONIN ,FLUOXETINE ,SEROTONIN uptake inhibitors ,CONTROL (Psychology) ,VISUAL perception - Abstract
Selective serotonin reuptake inhibitors (SSRIs) increase serotonin activity in the brain. While they are mostly known for their antidepressant properties, they have been shown to improve visual functions in amblyopia and impact cognitive functions ranging from attention to motivation and sensitivity to reward. Yet, a clear understanding of the specific action of serotonin to each of bottom-up sensory and top-down cognitive control components and their interaction is still missing. To address this question, we characterize, in two adult male macaques, the behavioral effects of fluoxetine, a specific SSRI, on visual perception under varying bottom-up (luminosity, distractors) and top-down (uncertainty, reward biases) constraints while they are performing three different visual tasks. We first manipulate target luminosity in a visual detection task, and we show that fluoxetine degrades luminance perceptual thresholds. We then use a target detection task in the presence of spatial distractors, and we show that under fluoxetine, monkeys display both more liberal responses as well as a degraded perceptual spatial resolution. In a last target selection task, involving free choice in the presence of reward biases, we show that monkeys display an increased sensitivity to reward outcome under fluoxetine. In addition, we report that monkeys produce, under fluoxetine, more trials and less aborts, increased pupil size, shorter blink durations, as well as task-dependent changes in reaction times. Overall, while low level vision appears to be degraded by fluoxetine, performances in the visual tasks are maintained under fluoxetine due to enhanced top-down control based on task outcome and reward maximization. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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17. Fit for purpose of on-the-road driving and simulated driving: A randomised crossover study using the effect of sleep deprivation.
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Koopmans, Ingrid, Doll, Robert-Jan, van der Wall, Hein, de Kam, Marieke, Groeneveld, Geert Jan, Cohen, Adam, and Zuiker, Rob
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SLEEP deprivation ,MOTOR vehicle driving ,TASK performance ,AUTOMOBILE driving simulators ,MOTOR ability testing ,AUTOMOBILE driving ,FATIGUE (Physiology) ,STANDARD deviations - Abstract
Introduction: Drivers should be aware of possible impairing effects of alcohol, medicinal substance, or fatigue on driving performance. Such effects are assessed in clinical trials, including a driving task or related psychomotor tasks. However, a choice between predicting tasks must be made. Here, we compare driving performance with on-the-road driving, simulator driving, and psychomotor tasks using the effect of sleep deprivation. Method: This two-way cross over study included 24 healthy men with a minimum driving experience of 3000km per year. Psychomotor tasks, simulated driving, and on-the-road driving were assessed in the morning and the afternoon after a well-rested night and in the morning after a sleep-deprived night. Driving behaviour was examined by calculating the Standard Deviation of Lateral Position (SDLP). Results: SDLP increased after sleep deprivation for simulated (10cm, 95%CI:6.7–13.3) and on-the-road driving (2.8cm, 95%CI:1.9–3.7). The psychomotor test battery detected effects of sleep deprivation in almost all tasks. Correlation between on-the-road tests and simulator SDLP after a well-rested night (0.63, p <.001) was not present after a night of sleep deprivation (0.31, p =.18). Regarding the effect of sleep deprivation on the psychomotor test battery, only adaptive tracking correlated with the SDLP of the driving simulator (-0.50, p =.02). Other significant correlations were related to subjective VAS scores. Discussion: The lack of apparent correlations and difference in sensitivity of performance of the psychomotor tasks, simulated driving and, on-the-road driving indicates that the tasks may not be interchangeable and may assess different aspects of driving behaviour. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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18. The sight of one's own body: Could qEEG help predict the treatment response in anorexia nervosa?
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Susta, Marek, Bizik, Gustav, Yamamotova, Anna, Petranek, Svojmil, Kadochova, Marie, and Papezova, Hana
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ANOREXIA nervosa ,BODY image ,PREFRONTAL cortex ,CEREBRAL hemispheres ,FUSIFORM gyrus ,PSYCHOTHERAPY - Abstract
Aims of the study: The study aims to identify the differences in brain activity between participants with anorexia nervosa and healthy control using visual stimulus conditions combined with the quantitative dense-array EEG recording analysis method called Brain Activation Sequences (BAS). Materials and methods: 23 participants with anorexia nervosa and 21 healthy controls were presented with visual stimuli, including the subject's facial expressions and body images. The 128-channel EEG data were processed using BAS and displayed as activity in up to 66 brain regions. Subsequent cluster analysis was used to identify groups of participants exhibiting area-specific activation patterns. Results: Cluster analysis identified three distinct groups: one including all healthy controls (HC) and two consisting of all participants with anorexia (ANI with 19 participants and AN-II with four participants). The AN-I and AN-II groups differed in their response to treatment. Comparisons of HC vs. AN confirmed the dominance of the right cerebral hemisphere in participants with anorexia nervosa in two of the three reported conditions. The facial expressions condition, specifically the facial reaction expressing disgust, indicates the existence of a social attentional bias toward faces, whereas emotions remained undetected in participants. High limbic activity, medial frontal gyrus involvement, low fusiform cortex activity, and milder visual cortex activity in healthy controls compared to participants indicate that the facial expression stimulus is perceived by healthy subjects primarily as an emotion, not as the face itself. In the body image condition, participants showed higher activity in the fusiform gyrus and right insula, indicating activation of the brain's "fear network." Conclusion: The study describes a specific pattern of brain activation in response to facial expression of disgust and body images that likely contributes to social-cognitive and behavioral impairments in anorexia. In addition, the substantial difference in the pattern of brain activation within the participants with AN and its association with treatment resistance deserves special attention because of its potential to develop a clinically useful prediction tool and identify potential targets for, for example, neuromodulatory treatments and/or individualized psychotherapy. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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19. Opportunities for growth in the growing field of psychobiotics.
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Wissel, E., Leon, L., and Tipton, L.
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- 2022
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20. Relation Between Gender and Concomitant Medications With Erythropoietin-Treatment on Wound Healing in Burn Patients. Post Hoc Subgroup-Analysis of the Randomized, Placebo-Controlled Clinical Trial "EPO in Burns".
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Günter, Christina Irene, Ilg, Felicitas Paula, Hapfelmeier, Alexander, Egert-Schwender, Silvia, Jelkmann, Wolfgang, Giri, Shibashish, Bader, Augustinus, and Machens, Hans-Günter
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ERYTHROPOIETIN ,WOUND healing ,BURN patients ,CLINICAL trials ,VASOCONSTRICTORS ,DRUGS ,HYPOGLYCEMIC agents ,ANTI-inflammatory agents - Abstract
Burns are leading causes of mortality and morbidity, Including prolonged hospitalization, disfigurement, and disability. Erythropoietin (EPO) is a well-known hormone causing erythropoiesis. However, EPO may play a role in healing acute and chronic wounds due to its anti-inflammatory and pro-regenerative effects. Therefore, the large, prospective, placebo-controlled, randomized, double-blind, multi-center clinical trial "EPO in Burns" was initiated to investigate the effects of EPO versus placebo treatment in severely burned patients. The primary endpoint of "EPO in Burns" was defined as the time elapsed until complete re-epithelialization of a defined split skin graft donor site. Additional analyses of post hoc defined subgroups were performed in view of the primary endpoint. The verum (n 45) and control (n 39) groups were compared with regard to the time it took for study wounds (a predefined split skin graft donor site) to reach the three stages of wound healing (re-epithelialization levels). In addition, the effects of gender (females n 18) and concomitant medications insulin (n 36), non-steroidal anti-inflammatory drugs (NSAIDs) (n 41), and vasopressor agents (n 43) were tested. Life tables were used to compare study groups (EPO vs. placebo) within subgroups. The Cox regression model was applied to evaluate interactions between the study drug (EPO) and concomitant medications for each re-epithelialization level. Using our post hoc defined subgroups, we observed a lower chance of wound healing for women compared to men (in terms of hazard ratio: hr
100% : 5.984 [95%-CI: (0.805-44.490), p = 0.080]) in our study population, regardless of the study medication. In addition, results indicated an earlier onset of re-epithelialization in the first days of EPO treatment (EPO: 10% vs. Placebo: 3%). Moreover, the interpretation of the hazard ratio suggested EPO might have a positive, synergistic effect on early stages of re-epithelialization when combined with insulin [hr50% : 1.307 (p = 0.568); hr75% : 1,199 (p = 0.715)], as well as a stabilizing effect on critically ill patients [reduced need for vasopressors in the EPO group (EPO: 44% vs. Placebo 59%)]. However, additional high-quality data from clinical trials designed to address these endpoints are required to gain further insight into these effects. [ABSTRACT FROM AUTHOR]- Published
- 2022
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21. Exploring Sex-Related Differences in Microglia May Be a Game-Changer in Precision Medicine.
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Lynch, Marina A.
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ALZHEIMER'S disease ,AGE distribution ,INDIVIDUALIZED medicine ,SEX distribution ,PARKINSON'S disease ,NEUROGLIA ,WOUNDS & injuries ,NEURODEGENERATION - Abstract
One area of microglial biology that has been relatively neglected until recently is sex differences and this is in spite of the fact that sex is a risk factor in several diseases that are characterized by neuroinflammation and, by extension, microglial activation. Why these sex differences exist is not known but the panoply of differences extend to microglial number, genotype and phenotype. Significantly, several of these sex-related differences are also evident in health and change during life emphasizing the dynamic and plastic nature of microglia. This review will consider how age impacts on sex-related differences in microglia and ask whether the advancement of personalized medicine demands that a greater focus is placed on studying sex-related differences in microglia in Alzheimer's disease, Parkinson's disease and models of inflammatory stress and trauma in order to make true progress in dealing with these conditions. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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22. Glutamate Carboxypeptidase II in Aging Rat Prefrontal Cortex Impairs Working Memory Performance.
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Datta, Dibyadeep, Leslie, Shannon N., Woo, Elizabeth, Amancharla, Nishita, Elmansy, Ayah, Lepe, Miguel, Mecca, Adam P., Slusher, Barbara S., Nairn, Angus C., and Arnsten, Amy F. T.
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SHORT-term memory ,PREFRONTAL cortex ,GLUTARIC acid ,COGNITION disorders ,AGING ,ASTROCYTES - Abstract
Glutamate carboxypeptidase II (GCPII) expression in brain is increased by inflammation, and reduces NAAG (N-acetyl aspartyl glutamate) stimulation of mGluR3 signaling. Genetic insults in this signaling cascade are increasingly linked to cognitive disorders in humans, where increased GCPII and or decreased NAAG-mGluR3 are associated with impaired prefrontal cortical (PFC) activation and cognitive impairment. As aging is associated with increased inflammation and PFC cognitive deficits, the current study examined GCPII and mGluR3 expression in the aging rat medial PFC, and tested whether GCPII inhibition with 2-(3-mercaptopropyl) pentanedioic acid (2-MPPA) would improve working memory performance. We found that GCPII protein was expressed on astrocytes and some microglia as expected from previous studies, but was also prominently expressed on neurons, and showed increased levels with advancing age. Systemic administration of the GCPII inhibitor, 2-MPPA, improved working memory performance in young and aged rats, and also improved performance after local infusion into the medial PFC. As GCPII inhibitors are well-tolerated, they may provide an important new direction for treatment of cognitive disorders associated with aging and/or inflammation. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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23. Drug Repurposing for Rare Diseases: A Role for Academia.
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van den Berg, Sibren, de Visser, Saco, Leufkens, Hubert G.M., and Hollak, Carla E.M.
- Subjects
DRUG repositioning ,RARE diseases ,MEDICAL personnel ,DRUG accessibility ,ORPHAN drugs - Abstract
Background: The European Commission highlights in its Pharmaceutical Strategy the role of academic researchers in drug repurposing, especially in the development of orphan medicinal products (OMPs). This study summarizes the contribution of academia over the last 5 years to registered repurposed OMPs and describes barriers to success, based upon three real world cases. Methods: OMPs granted marketing authorization between January 2016 and December 2020 were reviewed for repurposing and whether the idea originated from academia or industry. Three cases of drug repurposing were selected from different therapeutic areas and stages of development to identify obstacles to success. Results: Thirteen of the 68 OMPs were the result of drug repurposing. In three OMPs, there were two developments such as both a new indication and a modified application. In total, twelve developments originated from academia and four from industry. The three cases showed as barriers to success: lack of outlook for sufficient return of investments (abatacept), lack of regulatory alignment and timing of interaction between healthcare professionals and regulators (etidronate), failure to register an old drug for a fair price, resulting in commercialization as a high priced orphan drug (mexiletine). Conclusion: While the majority of repurposed OMPs originates in academia, a gap exists between healthcare professionals, regulators and industry. Future strategies should aim to overcome these hurdles leading to more patient benefit through sustainable access of repurposed drugs. Potential solutions include improved regulatory and reimbursement knowledge by academia and the right for regulators to integrate new effectiveness data into product labels. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
24. Judging the social value of controlled human infection studies.
- Author
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Rid, Annette and Roestenberg, Meta
- Subjects
CLINICAL trials ,DENGUE ,IMMUNIZATION ,INFECTION ,RESEARCH ethics ,RISK assessment ,SOCIAL values ,VIRUS diseases ,HUMAN research subjects - Abstract
In controlled human infection (CHI) studies, investigators deliberately infect healthy individuals with pathogens in order to study mechanisms of disease or obtain preliminary efficacy data on investigational vaccines and medicines. CHI studies offer a fast and cost‐effective way of generating new scientific insights, prioritizing investigational products for clinical testing, and reducing the risk that large numbers of people are exposed to ineffective or harmful substances in research or in practice. Yet depending on the pathogen, CHI studies can involve significant risks or burdens for participants, pose risks to individuals or communities not involved in the research, and lead to public controversy. It is therefore essential to ensure that the risks of CHI studies are justified by their social value—that is, their potential to generate benefits for society—and that public trust can be maintained. In this paper, we aim to clarify how research sponsors, research ethics committees and other reviewers should judge the social value of CHI studies. We develop a list of relevant considerations for making social value judgments based on the standard view of social value. We then use this list to discuss the example of potentially conducting dengue virus CHI studies in endemic settings. We argue that dengue virus CHI studies in endemic settings would fall on the higher end of the spectrum of social value, mostly because of their potential to redirect all fields of future dengue research. Drawing on this discussion, we derive several general recommendations for how reviewers should judge the social value of CHI studies. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
25. Ethical issues surrounding controlled human infection challenge studies in endemic low‐and middle‐income countries.
- Author
-
Jamrozik, Euzebiusz and Selgelid, Michael J.
- Subjects
BIOETHICS ,INFECTION ,INTERVIEWING ,RESEARCH ethics ,WORLD health ,MIDDLE-income countries ,LOW-income countries - Abstract
Controlled human infection challenge studies (CHIs) involve intentionally exposing research participants to, and/or thereby infecting them with, micro‐organisms. There have been increased calls for more CHIs to be conducted in low‐ and middle‐income countries (LMICs) where many relevant diseases are endemic. This article is based on a research project that identified and analyzed ethical and regulatory issues related to endemic LMIC CHIs via (a) a review of relevant literature and (b) qualitative interviews involving 45 scientists and ethicists with relevant expertise. In this article we argue that though there is an especially strong case for conducting CHIs in endemic (LMIC) settings, certain ethical issues related to the design and conduct of such studies (in such settings) nonetheless warrant particularly careful attention. We focus on ethical implications of endemic LMIC CHIs regarding (a) potential direct benefits for participants, (b) risks to participants, (c) third‐party risks, (d) informed consent, (e) payment of participants, and (f) community engagement. We conclude that there is a strong ethical rationale to conduct (well‐designed) CHIs in endemic LMICs, that certain ethical issues warrant particularly careful consideration, and that ethical analyses of endemic LMIC CHIs can inform current debates in research ethics more broadly. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
26. Stress-system activation in children with chronic pain: A focus for clinical intervention.
- Author
-
McInnis, Peter M, Braund, Taylor A, Chua, Zhi Kai, and Kozlowska, Kasia
- Subjects
C-reactive protein ,CHRONIC pain ,HEART beat ,MIND & body therapies ,QUESTIONNAIRES ,RESPIRATORY measurements ,PSYCHOLOGICAL stress - Abstract
Accumulating evidence indicates that psychological and neurophysiological processes interconnect and interact to activate the body's stress system and to trigger and maintain functional somatic symptoms. This study used the Early Life Stress Questionnaire, Depression Anxiety Stress Scales and biological markers (heart rate, heart rate variability, skin conductance, C-reactive protein (CRP) titre, respiratory rate, and accuracy and reaction time in an emotion-face identification task), to examine childhood adversity, psychological distress and stress-system activation in 35 children and adolescents (23 girls and 12 boys, 9–17 years old) disabled by chronic pain (vs two groups of age- and sex-matched healthy controls). Patients reported more early-life stress (U = 798.5, p =.026) and more psychological distress (U = 978, p <.001). They showed activation of the autonomic system: elevated heart rate (U = 862.5, p =.003), elevated electrodermal activity (U = 804.5, p =.024) and lower heart rate variability in the time domain (U = 380.5, p =.007) and frequency domain (U = 409.5, p =.017). The group showed an upward shift of CRP titres (with 75th and 90th CRP percentiles of 4.5 and 10.5 mg/L, respectively), suggesting the activation of the immune–inflammatory system. Elevated CRP titres were associated with elevated heart rate (p =.028). There were no differences in respiratory rate or in accuracy and reaction time in the emotion-face identification task. The results indicate that interventions for children and adolescents with chronic pain need a multidisciplinary mind–body approach that concurrently addresses psychological distress, physical impairment and stress-system dysregulation. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
27. Current Approaches to Group A Streptococcal Vaccine Development References
- Author
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Harbison-Price N, Rivera-Hernandez T, Osowicki J, Davies MR, Steer AC, Walker MJ, Dale JB, Ferretti JJ, Stevens DL, and Fischetti VA
- Published
- 2022
28. Increased Force Variability Is Associated with Altered Modulation of the Motorneuron Pool Activity in Autism Spectrum Disorder (ASD).
- Author
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Zheng Wang, Minhyuk Kwon, Mohanty, Suman, Schmitt, Lauren M., White, Stormi P., Christou, Evangelos A., and Mosconi, Matthew W.
- Subjects
AUTISM spectrum disorders ,ISOMETRIC exercise ,GAMMA distributions ,NEUROMUSCULAR diseases ,MUSCLE diseases - Abstract
Force control deficits have been repeatedly documented in autism spectrum disorder (ASD). They are associated with worse social and daily living skill impairments in patients suggesting that developing a more mechanistic understanding of the central and peripheral processes that cause them may help guide the development of treatments that improve multiple outcomes in ASD. The neuromuscular mechanisms underlying force control deficits are not yet understood. Seventeen individuals with ASD and 14 matched healthy controls completed an isometric index finger abduction test at 60% of their maximum voluntary contraction (MVC) during recording of the first dorsal interosseous (FDI) muscle to determine the neuromuscular processes associated with sustained force variability. Central modulation of the motorneuron pool activation of the FDI muscle was evaluated at delta (0–4 Hz), alpha (4–10 Hz), beta (10–35 Hz) and gamma (35–60 Hz) frequency bands. ASD patients showed greater force variability than controls when attempting to maintain a constant force. Relative to controls, patients also showed increased central modulation of the motorneuron pool at beta and gamma bands. For controls, reduced force variability was associated with reduced delta frequency modulation of the motorneuron pool activity of the FDI muscle and increased modulation at beta and gamma bands. In contrast, delta, beta, and gamma frequency oscillations were not associated with force variability in ASD. These findings suggest that alterations of central mechanisms that control motorneuron pool firing may underlie the common and often impairing symptoms of ASD. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
29. Emotion stimulus processing in narcolepsy with cataplexy.
- Author
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Susta, Marek, Nemcova, Veronika, Bizik, Gustav, and Sonka, Karel
- Subjects
BRAIN abnormalities ,NARCOLEPSY ,CATAPLEXY ,ELECTROENCEPHALOGRAPHY ,QUALITATIVE research - Abstract
Reported brain abnormalities in anatomy and function in patients with narcolepsy with cataplexy led to a project based on qualitative electroencephalography examination and analysis in an attempt to find a narcolepsy with cataplexy-specific brain-derived pattern, or a sequence of brain locations involved in processing humorous stimuli. Laughter is the trigger of cataplexy in these patients, and the difference between patients and healthy controls during the laughter should therefore be notable. Twenty-six adult patients (14 male, 12 female) suffering from narcolepsy with cataplexy and 10 healthy controls (five male, five female) were examined. The experiment was performed using a 256-channel electroencephalogram and then processed using specialized software built according to the scientific research team's specifications. The software utilizes electroencephalographic data recorded during elevated emotional states in participants to calculate the sequence of brain areas involved in emotion processing using non-linear and linear algorithms. Results show significant differences in activation (pre-laughter) patterns between the patients with narcolepsy and healthy controls, as well as significant similarities within the patients and the controls. Specifically, gyrus orbitalis, rectus and occipitalis inferior are active in healthy controls, while gyrus paracentralis, cingularis and cuneus are activated solely in the patients in response to humorous audio stimulus. There are qualitative electroencephalographic-based patterns clearly discriminating between patients with narcolepsy and healthy controls during laughter processing. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
30. DNA-linked Inhibitor Antibody Assay (DIANA) for sensitive and selective enzyme detection and inhibitor screening.
- Author
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Navrátil, Václav, Schimer, Jiří, Tykvart, Jan, Knedlík, Tomáš, Vik, Viktor, Majer, Pavel, Konvalinka, Jan, and Šácha, Pavel
- Published
- 2017
- Full Text
- View/download PDF
31. Photon noise from chaotic and coherent millimeter-wave sources measured with horn-coupled, aluminum lumped-element kinetic inductance detectors.
- Author
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Flanigan, D., McCarrick, H., Jones, G., Johnson, B. R., Abitbol, M. H., Ade, P., Araujo, D., Bradford, K., Cantor, R., Che, G., Day, P., Doyle, S., Kjellstrand, C. B., Leduc, H., Limon, M., Luu, V., Mauskopf, P., Miller, A., Mroczkowski, T., and Tucker, C.
- Subjects
PHOTONS ,SIGNAL-to-noise ratio ,ELECTRIC inductance ,WAVELENGTHS ,QUASIPARTICLES ,COSMIC background radiation - Abstract
We report photon-noise limited performance of horn-coupled, aluminum lumped-element kinetic inductance detectors at millimeter wavelengths. The detectors are illuminated by a millimeterwave source that uses an active multiplier chain to produce radiation between 140 and 160 GHz. We feed the multiplier with either amplified broadband noise or a continuous-wave tone from a microwave signal generator. We demonstrate that the detector response over a 40 dB range of source power is well-described by a simple model that considers the number of quasiparticles. The detector noise-equivalent power (NEP) is dominated by photon noise when the absorbed power is greater than approximately 1 pW, which corresponds to NEP ≈ 2 × 10
–17 WHz–1/2 , referenced to absorbed power. At higher source power levels, we observe the relationships between noise and power expected from the photon statistics of the source signal: NEP ∝ P for broadband (chaotic) illumination and NEP ∝ P1/2 for continuous-wave (coherent) illumination. [ABSTRACT FROM AUTHOR]- Published
- 2016
- Full Text
- View/download PDF
32. Medication Prediction with Electroencephalography Phenotypes and Biomarkers.
- Author
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Gunkelman, Jay
- Subjects
TREATMENT of attention-deficit hyperactivity disorder ,PREVENTION of drug side effects ,DECISION making in clinical medicine ,ANTICONVULSANTS ,ANTIPSYCHOTIC agents ,ATTENTION-deficit hyperactivity disorder ,BIOMARKERS ,DRUG therapy ,CHILDREN'S health ,COMBINED modality therapy ,DRUG withdrawal symptoms ,DOPAMINE uptake inhibitors ,ELECTROENCEPHALOGRAPHY ,CLASSIFICATION of mental disorders ,NEUROPHYSIOLOGY ,OXYTOCIN ,PRAZOSIN ,PSYCHOPHARMACOLOGY ,SEROTONIN uptake inhibitors ,PHENOTYPES ,CENTRAL nervous system stimulants ,INDIVIDUALIZED medicine - Abstract
This article reviews current medication practices for the Diagnostic and Statistical Manual of Mental Disorders, fifth edition, diagnostic category of attention-deficit hyperactivity disorder. A wide range of medication classes are in use clinically, based on divergent pharmacological mechanisms, from stimulants to anticonvulsants to antidepressants, and including even more esoteric medications such as oxytocin and the various channel blockers. The author proposes that quantitative electroencephalography (EEG) patterns can provide a more reliable basis for medication selection than diagnostic category. The EEG’s neurophysiological indicators for these medication classes are summarized and reviewed based not only on 41 years of experience in the field but also on outcomes from psychiatric practices, in an evidence-based approach to medication prediction. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
33. Glutamate carboxypeptidase II is not an amyloid peptide-degrading enzyme.
- Author
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Alt, Jesse, Stathis, Marigo, Rojas, Camilo, and Slusher, Barbara
- Subjects
GLUTAMIC acid ,CARBOXYPEPTIDASES ,HYDROLYSIS ,ASPARTATES ,ENDOPEPTIDASES - Abstract
Glutamate carboxypeptidase II (GCPII) is an exopeptidase that catalyzes the hydrolysis of N-acetylated aspartate-glutamate (NAAG) to N-acetyl aspartate (NAA) and glutamate. Consequently, GCPII inhibition has been of interest for the treatment of central and peripheral nervous system diseases associated with excess glutamate. Recently, it was reported that GCPII can also serve as an endopeptidase cleaving amyloid β (Aβ) peptides and that its inhibition could increase the risk of Alzheimer's disease by increasing brain Aβ levels. This study aimed to corroborate and extend these new findings. We incubated Aβ peptides (20 µM) with human recombinant GCPII (300 ng/ml) and monitored the appearance of degradation products by mass spectrometry. Aβ peptides remained intact after 18 h incubation with GCPII. Under the same experimental conditions, Aβ
1-40 (20 µM) was incubated with neprilysin (300 ng/ml), an endopeptidase known to hydrolyze Aβ1-40 and the expected cleavage products were observed. GCPII was confirmed active by catalyzing the complete hydrolysis of NAAG (100 µM). We also studied the hydrolysis of [³H]-NAAG (30 nM) catalyzed by GCPII (40 pM) in the presence of Aβ peptides (picomolar to micromolar range). The addition of Aβ peptides did not alter [³H]-NAAG hydrolysis. We conclude that GCPII is not an amyloid peptide-degrading enzyme. [ABSTRACT FROM AUTHOR]- Published
- 2013
- Full Text
- View/download PDF
34. Helping oxytocin deliver: considerations in the development of oxytocin-based therapeutics for brain disorders.
- Author
-
MacDonald, K. and Feifel, D.
- Subjects
OXYTOCIN ,BRAIN diseases ,PSYCHOPHARMACOLOGY ,DRUG development ,RANDOMIZED controlled trials - Abstract
Concerns regarding a drought in psychopharmacology have risen from many quarters. From one perspective, the wellspring of bedrock medications for anxiety disorders, depression, and schizophrenia was serendipitously discovered over 30 year ago, the swell of pharmaceutical investment in drug discovery has receded, and the pipeline's flow of medications with unique mechanisms of action (i.e., glutamatergic agents, CRF antagonists) has slowed to a trickle. Might oxytocin (OT)-based therapeutics be an oasis? Though a large basic science literature and a slowly increasing number of studies in human diseases support this hope, the bulk of extant OT studies in humans are single-dose studies on normals, and do not directly relate to improvements in human brain-based diseases. Instead, these studies have left us with a field pregnant with therapeutic possibilities, but barren of definitive treatments. In this clinically oriented review, we discuss the extant OT literature with an eye toward helping OT deliver on its promise as a therapeutic agent. To this end, we identify 10 key questions that we believe future OT research should address. From this overview, several conclusions are clear: (1) the OT system represents an extremely promising target for novel CNS drug development; (2) there is a pressing need for rigorous, randomized controlled clinical trials targeting actual patients; and (3) in order to inform the design and execution of these vital trials, we need further translational studies addressing the questions posed in this review. Looking forward, we extend a cautious hope that the next decade of OT research will birth OT-targeted treatments that can truly deliver on this system's therapeutic potential. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
35. Resting-State Oscillatory Activity in Autism Spectrum Disorders.
- Author
-
Cornew, Lauren, Roberts, Timothy, Blaskey, Lisa, and Edgar, J.
- Subjects
ANALYSIS of variance ,AUTISM ,ELECTROENCEPHALOGRAPHY ,MAGNETICS ,NERVOUS system ,NEUROBIOLOGY ,AUDIO-frequency oscillators ,QUESTIONNAIRES ,RESEARCH funding ,STATISTICS ,T-test (Statistics) ,DATA analysis ,REPEATED measures design ,DATA analysis software ,STATISTICAL models ,DESCRIPTIVE statistics - Abstract
Neural oscillatory anomalies in autism spectrum disorders (ASD) suggest an excitatory/inhibitory imbalance; however, the nature and clinical relevance of these anomalies are unclear. Whole-cortex magnetoencephalography data were collected while 50 children (27 with ASD, 23 controls) underwent an eyes-closed resting-state exam. A Fast Fourier Transform was applied and oscillatory activity examined from 1 to 120 Hz at 15 regional sources. Associations between oscillatory anomalies and symptom severity were probed. Children with ASD exhibited regionally specific elevations in delta (1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), and high frequency (20-120 Hz) power, supporting an imbalance of neural excitation/inhibition as a neurobiological feature of ASD. Increased temporal and parietal alpha power was associated with greater symptom severity and thus is of particular interest. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
36. Developing drug prototypes: pharmacology replaces safety and tolerability?
- Author
-
Cohen, Adam F.
- Subjects
DRUG development ,DRUG tolerance ,CLINICAL trials ,LINEAR statistical models ,ANIMALS ,DRUG design ,DRUG dosage ,DRUG side effects ,DRUG toxicity ,PHARMACOLOGY - Abstract
New medicines are designed to bind to receptors or enzymes and are tested in animal cells, tissues and whole organisms in a highly scientific process. Subsequently they are often administered to human subjects with tolerability as the primary objective. The process of development is considered to be linear and consecutive and passes through the famous four phases of development (Phase I-Phase IV). This is efficient for those projects for which the uncertainty about the development is low. There is, however, an increasing number of new prototypical compounds resulting from the increased biological knowledge with a high level of uncertainty. For these prototypical drugs development has to proceed in a much more adaptive manner, using tailor-made objectives, the development of special methodology and a cyclical rather than a linear type of project management. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
37. Role of Functional Magnetic Resonance Imaging in Drug Discovery.
- Author
-
Paulus, Martin P. and Stein, Murray B.
- Subjects
MAGNETIC resonance imaging ,DRUG development ,ANXIETY ,PSYCHIATRIC treatment ,BIOMARKERS ,PHARMACOLOGY - Abstract
In this review, we survey the state of the field of functional magnetic resonance imaging (fMRI) as it relates to drug discovery and drug development. We highlight the advantages and limitations of fMRI for this purpose and suggest ways to improve the use of fMRI for developing new therapeutics, with emphasis on treatments for anxiety disorders. Fundamentally, pharmacological studies with standard psychiatric treatments using standardized behavioral probes during fMRI will need to be carried out to determine characteristic brain signatures that could be used to predict whether novel compounds are likely to have specific therapeutic effects. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
38. Pharmacological models in healthy volunteers: their use in the clinical development of psychotropic drugs.
- Author
-
Gilles, Christian and Luthringer, Remy
- Subjects
ANIMAL models of pharmacogenomics ,DRUG development ,PSYCHOPHARMACOLOGY ,BIOMARKERS ,PANIC - Abstract
Animal models of diseases are widely used in the preclinical phase of drug development. They have a place in early human clinical psychopharmacology as well, in order to get early dues that contribute to establish the proof of concept (POC) already in healthy volunteers (HV). Different types of models are available (pharmacological or non-pharmacological provocation, models based on age-related characteristics). This review is focused on pharmacological models in HV, with the aim to identify the main issues raised by their use in pharmaceutical trials. The available models unevenly fulfil the requirements of face validity, sufficient response rate, test-retest consistence and responsiveness to reference drugs. Most of them have been developed in the purpose of pathophysiology studies, using rating instruments validated for clinical practice. Substantial progress could be made by adapting models to the specific requirements of pharmaceutical trials, including wider use of biomarkers. Characteristics that make models, as well as biomarkers, suitable for use in drug development are proposed. Despite obvious limitations, human models can significantly enhance the way phase I studies contribute to establish the POC, provided they are integrated into adapted phase I development plans. Their use as industrial tools for drug evaluation requires specific, dedicated development. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
39. PSMA-Targeting Radiopharmaceuticals for Prostate Cancer Therapy: Recent Developments and Future Perspectives.
- Author
-
El Fakiri, Mohamed, Geis, Nicolas M., Ayada, Nawal, Eder, Matthias, and Eder, Ann-Christin
- Subjects
PROSTATE tumors treatment ,RADIOISOTOPES ,METASTASIS ,MONOCLONAL antibodies ,RADIOPHARMACEUTICALS ,PROSTATE-specific membrane antigen ,MOLECULAR structure ,LIGANDS (Biochemistry) - Abstract
Simple Summary: One of the most frequently diagnosed cancer in men is adenocarcinoma of the prostate. Once the disease is metastatic, only very limited treatment options are available, resulting in a very short median survival time of 13 months; however, this reality is gradually changing due to the discovery of prostate-specific membrane antigen (PSMA), a protein that is present in cancerous prostate tissue. Researchers have developed pharmaceuticals specific for PSMA, ranging from antibodies (mAb) to low-molecular weight molecules coupled to beta minus and alpha-emitting radionuclides for their use in targeted radionuclide therapy (TRT). TRT offers the possibility of selectively removing cancer tissue via the emission of radiation or radioactive particles within the tumour. In this article, the major milestones in PSMA ligand research and the therapeutic developments are summarised, together with a future perspective on the enhancement of current therapeutic approaches. Prostate cancer (PC) is the second most common cancer among men, with 1.3 million yearly cases worldwide. Among those cancer-afflicted men, 30% will develop metastases and some will progress into metastatic castration-resistant prostate cancer (mCRPC), which is associated with a poor prognosis and median survival time that ranges from nine to 13 months. Nevertheless, the discovery of prostate specific membrane antigen (PSMA), a marker overexpressed in the majority of prostatic cancerous tissue, revolutionised PC care. Ever since, PSMA-targeted radionuclide therapy has gained remarkable international visibility in translational oncology. Furthermore, on first clinical application, it has shown significant influence on therapeutic management and patient care in metastatic and hormone-refractory prostate cancer, a disease that previously had remained immedicable. In this article, we provide a general overview of the main milestones in the development of ligands for PSMA-targeted radionuclide therapy, ranging from the firstly developed monoclonal antibodies to the current state-of-the-art low molecular weight entities conjugated with various radionuclides, as well as potential future efforts related to PSMA-targeted radionuclide therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
40. Targeting for Success: Demonstrating Proof-of-Concept with Mechanistic Early Phase Clinical Pharmacology Studies for Disease-Modification in Neurodegenerative Disorders.
- Author
-
Vissers, Maurits F. J. M., Heuberger, Jules A. A. C., and Groeneveld, Geert Jan
- Subjects
NEURODEGENERATION ,CLINICAL trials ,DISEASE progression ,BIOMARKERS ,SUCCESS ,PHARMACOLOGY - Abstract
The clinical failure rate for disease-modifying treatments (DMTs) that slow or stop disease progression has been nearly 100% for the major neurodegenerative disorders (NDDs), with many compounds failing in expensive and time-consuming phase 2 and 3 trials for lack of efficacy. Here, we critically review the use of pharmacological and mechanistic biomarkers in early phase clinical trials of DMTs in NDDs, and propose a roadmap for providing early proof-of-concept to increase R&D productivity in this field of high unmet medical need. A literature search was performed on published early phase clinical trials aimed at the evaluation of NDD DMT compounds using MESH terms in PubMed. Publications were selected that reported an early phase clinical trial with NDD DMT compounds between 2010 and November 2020. Attention was given to the reported use of pharmacodynamic (mechanistic and physiological response) biomarkers. A total of 121 early phase clinical trials were identified, of which 89 trials (74%) incorporated one or multiple pharmacodynamic biomarkers. However, only 65 trials (54%) used mechanistic (target occupancy or activation) biomarkers to demonstrate target engagement in humans. The most important categories of early phase mechanistic and response biomarkers are discussed and a roadmap for incorporation of a robust biomarker strategy for early phase NDD DMT clinical trials is proposed. As our understanding of NDDs is improving, there is a rise in potentially disease-modifying treatments being brought to the clinic. Further increasing the rational use of mechanistic biomarkers in early phase trials for these (targeted) therapies can increase R&D productivity with a quick win/fast fail approach in an area that has seen a nearly 100% failure rate to date. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
41. Cerebral blood flow modulations during antisaccade preparation in chronic hypotension.
- Author
-
Duschek, Stefan, Hoffmann, Alexandra, Montoro, Casandra I., Bair, Angela, Reyes del Paso, Gustavo A., and Ettinger, Ulrich
- Subjects
SACCADIC eye movements ,CEREBRAL circulation ,TRANSCRANIAL Doppler ultrasonography ,HYPOTENSION ,EYE tracking ,BLOOD flow - Abstract
In addition to symptoms including fatigue, dizziness, reduced drive, or mood disturbance, individuals with chronic low blood pressure (hypotension) frequently report cognitive complaints. While attentional deficits have been empirically confirmed, it is still unknown whether the impairments also encompass executive functions. This study investigated cerebral blood flow modulations in hypotension during a precued antisaccade/prosaccade task requiring the executive function of proactive inhibition in addition to preparatory attention. Using functional transcranial Doppler sonography, bilateral blood flow velocities in the middle cerebral arteries (MCA) were recorded in 39 hypotensive and 40 normotensive participants. In the task, a stimulus appeared left or right of a fixation point 5 s after a cuing stimulus; subjects had to move their gaze to the mirror image position of the stimulus (antisaccade) or toward it (prosaccade control condition). Video‐based eye tracking was used for ocular recording. A right dominant MCA blood flow increase arose during task preparation, which was smaller in hypotensive than normotensive participants. In addition, hypotensive participants exhibited lower peak velocity of the saccadic response. The extent of the reductions in blood flow and task performance in hypotension did not differ between antisaccade and prosaccade conditions. The smaller MCA flow increase may reflect reduced activity in the dorsolateral prefrontal and inferior parietal cortices during proactive inhibition and preparatory attention in hypotension. Given that group differences in blood flow and performance arose independent of task complexity and executive function load, hypotension may be characterized by basic attentional impairments rather than particular executive function deficits. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
42. Integrating sex and gender into biomedical research requires policy and culture change
- Author
-
Witt, Alice, Politis, Marina, Norton, Robyn, and Womersley, Kate
- Published
- 2024
- Full Text
- View/download PDF
43. Development of Gene Therapies : Strategic, Scientific, Regulatory, and Access Considerations
- Author
-
Avery McIntosh, Oleksandr Sverdlov, Avery McIntosh, and Oleksandr Sverdlov
- Subjects
- Drug development, Clinical trials--Statistical methods, Gene therapy
- Abstract
Cell and gene therapies have become the third major drug modality in pharmaceutical medicine of the 21st century after low molecular weight and antibody drugs. The gene therapy (GTx) field is rapidly advancing, and yet there are still fundamental scientific questions that remain to be answered. Development of GTx products poses unique challenges and opportunities for drug developers. However, there is lack of a systematic exposition of the GTx product development and the pivotal role of the biostatistician in this process. Development of Gene Therapies: Strategic, Scientific, and Regulatory, and Access Considerations attempts to summarize the current state-of-the-art strategic, scientific, statistical, and regulatory aspects of GTx development. Intended to provide an exposition to the GTx new product development through peer-reviewed papers written by subject matter experts in this emerging field, this book will be useful for researchers in gene therapy drug development, biostatisticians, regulators, patient advocates, graduate students, and the finance and business development community. Key Features: A collection of papers covering a wide spectrum of topics in gene therapies (GTx), written by leading subject matter experts An exposition of the core principles of GTx product development, emerging business models, industry standards, best practices, and regulatory pathways An exposition of statistical and innovative modeling tools for design and analysis of clinical trials of GTx Insights into commercial models, access hurdles, and health economics of gene therapies Case studies of successful GTx approvals from core team members that developed the first two FDA-approved AAV gene therapies: Luxturna and Zolgensma A discussion of potential benefits and hurdles to be overcome for GTx in coming years from a multi-stakeholder perspective
- Published
- 2024
44. Ethics in Social Science Research in Indonesia
- Author
-
Mayling Oey-Gardiner, Fandy Rahardi, Canyon Keanu Can, Mayling Oey-Gardiner, Fandy Rahardi, and Canyon Keanu Can
- Subjects
- Social sciences--Research--Indonesia, Social sciences--Research--Moral and ethical aspects
- Abstract
This textbook presents ethical guidelines for conducting research in the social sciences, focused on Indonesia. As a country with a fast-growing research environment, the real-life cases of ethical issues that arise in Indonesia can teach both aspiring and established researchers how to approach the complexity of research ethics and dilemmas. With technological advancement affecting how research is conducted, the necessary ethical guidelines for research are also evolving. The instantaneous nature of information movement has made confidentiality in research data more critical than before, and any negligence in protecting research participants has an unprecedented scope of damage. The methods book synthesises hundreds of worldwide ethical guidelines and past issues that social science researchers will find highly relevant. Arranged chronologically to represent each research stage—from research preparation to post-research—the book prepares researchers to mitigate ethical crises. Relevant to all social scientists, both emerging and established, conducting research in Indonesia, this co-published textbook between Springer and OBOR is also relevant to researchers beyond the archipelago. It is also an indispensable teaching resource for lecturers in research methods and ethics across social science disciplines.
- Published
- 2023
45. Discovering Psychology
- Author
-
John T. Cacioppo, Laura Freberg, Stephanie Cacioppo, John T. Cacioppo, Laura Freberg, and Stephanie Cacioppo
- Subjects
- Psychology
- Abstract
Psychology has insights relevant to all majors, all people. As a hub science, it also provides foundational material for many other scientific disciplines. Cacioppo/Freberg/Cacioppo's DISCOVERING PSYCHOLOGY: THE SCIENCE OF MIND, 4th edition, presents a cohesive understanding of the field, highlighting connections within psychology as well as between psychology and other disciplines. The fourth edition includes a new emphasis on social connectivity and loneliness, interpersonal relationships and myth busting, while author Dr. Stephanie Cacioppo brings additional insight as a licensed clinician. Smart and engaging writing, illuminating visuals and sound science illustrate the depth, breadth and diversity of this exciting field. Up-to-date coverage offers insight into the latest research, while hands-on activities help you sharpen your critical thinking skills. Also available: MindTap.
- Published
- 2022
46. Discovering Psychology
- Author
-
John T. Cacioppo, Laura Freberg, Stephanie Cacioppo, John T. Cacioppo, Laura Freberg, and Stephanie Cacioppo
- Abstract
Psychology has insights relevant to all majors, all people. As a hub science, it also provides foundational material for many other scientific disciplines. Cacioppo/Freberg/Cacioppo's DISCOVERING PSYCHOLOGY: THE SCIENCE OF MIND, 4th edition, presents a cohesive understanding of the field, highlighting connections within psychology as well as between psychology and other disciplines. The fourth edition includes a new emphasis on social connectivity and loneliness, interpersonal relationships and myth busting, while author Dr. Stephanie Cacioppo brings additional insight as a licensed clinician. Smart and engaging writing, illuminating visuals and sound science illustrate the depth, breadth and diversity of this exciting field. Up-to-date coverage offers insight into the latest research, while hands-on activities help you sharpen your critical thinking skills. Also available: MindTap.
- Published
- 2021
47. A Straight Talking Introduction to Psychiatric Drugs (second Edition)
- Author
-
Joanna Moncrieff and Joanna Moncrieff
- Abstract
In an era when more people are taking psychiatric drugs than ever before, Joanna Moncrieff's explosive book challenges the claims for their mythical powers. Drawing on extensive research, she demonstrates that psychiatric drugs do not'treat'or'cure'mental illness by acting on hypothesised chemical imbalances or other abnormalities in the brain. There is no evidence for any of these ideas. Moreover, any relief the drugs may offer from the distress and disturbance of a mental disorder can come at great cost to people's physical health and their ability to function in day-to-day life. And, once on these drugs, coming off them can be very difficult indeed. This book is a wake-up call to the potential damage we are doing to ourselves by relying on chemical cures for human distress. Its clear, concise explanations will enable people to make a fully informed decision about the benefits and harms of these drugs and whether and how to come off them if they so choose.
- Published
- 2020
48. Splitting : The Inside Story on Headaches
- Author
-
Amanda Ellison and Amanda Ellison
- Subjects
- Migraine--Popular works, Headache--Popular works
- Abstract
'From ice cream headaches to migraine, this fascinating and entertaining account of a common curse draws together modern science, ancient views and personal experience.'– Professor Roy Taylor, author of Life Without Diabetes'An insightful, entertaining book'– Daily MailWritten by a leading neuroscientist, Splitting tells the fascinating true story about headaches, and the secrets they reveal about your brain and overall health. Did you know...- chocolate doesn't give you a headache - and may in fact prevent one happening? - 30% of us sneeze at sunlight?- you can see off a headache with an orgasm? - that you shouldn't wear a striped top if your spouse gets migraines? From migraines to sinus pain to tension headaches – and everything in between – Splitting separates fact from fiction, putting you in control and helping you practise habits that will protect you from headache.
- Published
- 2020
49. Translational Medicine in CNS Drug Development
- Author
-
George G. Nomikos, Douglas E. Feltner, George G. Nomikos, and Douglas E. Feltner
- Subjects
- Drug development, Neuropsychopharmacology
- Abstract
Translational Medicine in CNS Drug Development, Volume 29, is the first book of its kind to offer a comprehensive overview of the latest developments in translational medicine and biomarker techniques. With extensive coverage on all aspects of biomarkers and personalized medicine, and numerous chapters devoted to the best strategies for developing drugs that target specific disorders, this book presents an essential reference for researchers in neuroscience and pharmacology who need the most up-to-date techniques for the successful development of drugs to treat central nervous system disorders. Despite increases in the number of individuals suffering from CNS-related disorders, the development and approval of drugs for their treatment have been hampered by inefficiencies in advancing compounds from preclinical discovery to the clinic. However, in the past decades, game-changing strides have been made in our understanding of the pathophysiology of CNS disorders and the relationship of drug exposure in plasma and CNS to pharmacodynamic measures in both animals and humans. - Includes comprehensive coverage of biomarker tools and the role of personalized medicine in CNS drug development - Discusses strategies for drug development for a full range of CNS indications, with particular attention to neuropsychiatric and neurocognitive disorders - Includes chapters written by international experts from industry and academia
- Published
- 2019
50. Discovering Psychology
- Author
-
John T. Cacioppo, Laura Freberg, John T. Cacioppo, and Laura Freberg
- Subjects
- Psychology
- Abstract
No matter your field of study, authors John Cacioppo and Laura Freberg believe that psychology has insights that are relevant to you. As a hub science, psychology is a discipline whose work provides foundational material for many other scientific fields. The authors present a cohesive understanding of the field, highlighting connections within psychology as well as between psychology and other disciplines. Through DISCOVERING PSYCHOLOGY's smart and engaging writing, illuminating visuals, and sound science, you'll discover that the field of psychology is larger, more diverse, more exciting, and more relevant than you may have realized. You'll also improve your critical thinking skills, gain an understanding of research, and get a glimpse of the current state of science about the mind.
- Published
- 2019
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