Functional Measurements of Central Nervous System Drug Effects in Early Human Drug Development

Gerven, Joop van

doi:10.1016/b978-0-12-803161-2.00004-7

Cited by 2 publications

(5 citation statements)

References 76 publications

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Section: Methodsmentioning

confidence: 99%

“…The primary outcome of saccadic eye movement measurement is saccadic peak velocity (SPV) in degrees per second (deg/s), a sensitive parameter for numerous sedative compounds. 4,15,16 Tests were performed as described in previous publications. [15][16][17][18] Subjects were instructed to follow a dot jumping approximately 15 degrees to either side on a computer screen with their eyes, while head movements were restrained using a fixed head support at 58 cm from the computer screen.…”

Section: Saccadic Eye Movementmentioning

confidence: 99%

“…This allowed a comparison of the functional profile of this new pharmacologically heterogeneous compound to other known drug profiles, and consequently to obtain a better understanding of the underlying pharmacological effects. 3,4 What is already known about this subject The preclinical pharmacological profile of ALKS 7119, with relatively high affinity for different receptor types, required NeuroCart testing at dose levels with small increments, to be able to disentangle ALKS 7119's effects on distinct receptors with different affinities. Specific NeuroCart tests were selected based on ALKS 7119's pharmacological profile.…”

Section: Introductionmentioning

confidence: 99%

“…Several CNS‐active compounds, including compounds influencing serotonergic, opioid, GABA‐ergic and glutamatergic (via NMDA‐antagonism) networks, have been profiled using the NeuroCart. This allowed a comparison of the functional profile of this new pharmacologically heterogeneous compound to other known drug profiles, and consequently to obtain a better understanding of the underlying pharmacological effects 3,4 …”

Section: Introductionmentioning

confidence: 99%

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Pharmacological profile of ALKS 7119, an investigational compound evaluated for the treatment of neuropsychiatric disorders, in healthy volunteers

Dijkstra

Zuiker

Siebenga

et al. 2022

Brit J Clinical Pharma

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Methods: In 10 cohorts (n = 10 subjects each), PK, safety and PD (NeuroCart tests, measuring neurophysiologic effects [pupillometry, pharmaco-EEG (pEEG)], visuomotor coordination, alertness, [sustained] attention [saccadic peak velocity, adaptive tracking], subjective drug effects [VAS Bowdle and VAS Bond and Lader] and postural stability [body sway]) were evaluated. Neuroendocrine effects (cortisol, prolactin, growth hormone) were measured. Data were analysed over the 12-hour post-dose period using mixed-effects model for repeated measure (MMRM) with baseline as covariate.Results: ALKS 7119 demonstrated linear PK and was generally well tolerated. QTcF interval increases of 30-60 ms compared to baseline were observed with ALKS 7119 doses of ≥50 mg without related adverse events. Significant increases in left and right pupil/iris ratio were observed at dose levels ≥50 mg (estimate of difference [95% CI], P-value) (0.04 [0.01; 0.07], P < .01) and (0.06 [0.03; 0.09], P = .01), respectively. From dose levels ≥50 mg significant increases (% change) of serum cortisol (51.7 [8.4; 112.3], P = .02) and prolactin (77.9 [34.2; 135.8], P < .01) were observed. Conclusion:In line with ALKS 7119's in vitro pharmacological profile, the clinical profile observed in this study is most comparable to SERT inhibition.

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Section: Methodsmentioning

confidence: 99%

Section: Saccadic Eye Movementmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Pharmacological profile of ALKS 7119, an investigational compound evaluated for the treatment of neuropsychiatric disorders, in healthy volunteers

Dijkstra

Zuiker

Siebenga

et al. 2022

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…Previously, similar criteria were used to evaluate the usefulness of central nervous system (CNS)-tests for the effects of antipsychotic drugs ( De Visser et al, 2001 ), benzodiazepines ( De Visser et al, 2003 ), selective serotonin re-uptake inhibitors (SSRIs) ( Dumont et al, 2005 ), 3,4-methyleendioxymethamfetamine (MDMA) ( Dumont and Verkes, 2006 ), D9-tetrahydrocannabinol (THC) ( Zuurman et al, 2009 ) and alcohol ( Zoethout et al, 2011 ) in healthy subjects. In general, these systematic reviews showed that only a small number of tests actually display proper characteristics for a meaningful effect biomarker, and that these tests differ between drug classes ( Van Gerven et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Sensitivity of cognitive function tests to acute hypoxia in healthy subjects: a systematic literature review

Post,

Heijn,

Jordan

et al. 2023

Front. Physiol.

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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.

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Functional Measurements of Central Nervous System Drug Effects in Early Human Drug Development

Cited by 2 publications

References 76 publications

Pharmacological profile of ALKS 7119, an investigational compound evaluated for the treatment of neuropsychiatric disorders, in healthy volunteers

Pharmacological profile of ALKS 7119, an investigational compound evaluated for the treatment of neuropsychiatric disorders, in healthy volunteers

Sensitivity of cognitive function tests to acute hypoxia in healthy subjects: a systematic literature review

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