26 results on '"de Visser, S. J."'
Search Results
2. 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
3. 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
4. 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
5. 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
6. 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
7. Biomarkers for the effects of benzodiazepines in healthy volunteers
- Author
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De Visser, S. J., primary, Van Der Post, J. P., additional, De Waal, P. P., additional, Cornet, F., additional, Cohen, A. F., additional, and Van Gerven, J. M. A., additional
- Published
- 2002
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8. Sensitivity of cognitive function tests to acute hypoxia in healthy subjects: a systematic literature review.
- Author
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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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9. Combatting the rising costs of cancer drugs; interventions from a university hospital’s perspective.
- Author
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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
- Full Text
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10. 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
- Subjects
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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11. Fluoxetine degrades luminance perceptual thresholds while enhancing motivation and reward sensitivity.
- Author
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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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12. Fit for purpose of on-the-road driving and simulated driving: A randomised crossover study using the effect of sleep deprivation.
- Author
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Koopmans, Ingrid, Doll, Robert-Jan, van der Wall, Hein, de Kam, Marieke, Groeneveld, Geert Jan, Cohen, Adam, and Zuiker, Rob
- Subjects
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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13. The sight of one's own body: Could qEEG help predict the treatment response in anorexia nervosa?
- Author
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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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14. 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".
- Author
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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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15. Exploring Sex-Related Differences in Microglia May Be a Game-Changer in Precision Medicine.
- Author
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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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16. Glutamate Carboxypeptidase II in Aging Rat Prefrontal Cortex Impairs Working Memory Performance.
- Author
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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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17. Drug Repurposing for Rare Diseases: A Role for Academia.
- Author
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van den Berg, Sibren, de Visser, Saco, Leufkens, Hubert G.M., and Hollak, Carla E.M.
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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
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18. Judging the social value of controlled human infection studies.
- Author
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Rid, Annette and Roestenberg, Meta
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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
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19. Ethical issues surrounding controlled human infection challenge studies in endemic low‐and middle‐income countries.
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Jamrozik, Euzebiusz and Selgelid, Michael J.
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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
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20. 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.
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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
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21. 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
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22. Helping oxytocin deliver: considerations in the development of oxytocin-based therapeutics for brain disorders.
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MacDonald, K. and Feifel, D.
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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
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23. PSMA-Targeting Radiopharmaceuticals for Prostate Cancer Therapy: Recent Developments and Future Perspectives.
- Author
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El Fakiri, Mohamed, Geis, Nicolas M., Ayada, Nawal, Eder, Matthias, and Eder, Ann-Christin
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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
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24. Targeting for Success: Demonstrating Proof-of-Concept with Mechanistic Early Phase Clinical Pharmacology Studies for Disease-Modification in Neurodegenerative Disorders.
- Author
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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
25. Integrating sex and gender into biomedical research requires policy and culture change
- Author
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Witt, Alice, Politis, Marina, Norton, Robyn, and Womersley, Kate
- Published
- 2024
- Full Text
- View/download PDF
26. Effect of valproate and pregabalin on human anxiety-like behaviour in a randomised controlled trial
- Author
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Bach, Dominik R., Korn, Christoph W., Vunder, Johanna, and Bantel, Antonia
- Published
- 2018
- Full Text
- View/download PDF
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