RESUMO
Dynamic balance assessments such as walking adaptability may yield a more realistic prediction of drug-induced falls compared with postural stability measurements, as falls often result from limited gait adjustments when walking. The Interactive Walkway (IWW) measures walking adaptability but sensitivity to medication effects is unknown. If proven sensitive and specific, IWW could serve as a biomarker for targeted fall-risk assessments in early clinical drug development. In this three-way crossover study, 18 healthy elderly (age: 65-80 years) subjects received 5 mg zolpidem, 10 mg suvorexant, or placebo in the morning. Assessments were performed pre-dose and approximately hourly until 9 h post-dose. IWW assessments included an 8-meter walking test, goal-directed stepping, obstacle-avoidance, and tandem-walking. Other pharmacodynamic measurements were the Timed-Up-and-Go (TUG) test at a comfortable and fast pace, adaptive tracking, and body sway. A decline in performance was observed for zolpidem compared with placebo for 3 h post-dose in IWW walking adaptability outcome measures, TUG, adaptive tracking, and body sway. For the IWW tasks, a decrease in walking speed (among others) was observed. IWW parameters were not affected by suvorexant compared with placebo at any timepoint. However, an increase of 9.8% (95%CI: 1.8%, 18.5%) in body sway was observed for suvorexant compared with placebo up to 3 h post-dose. The IWW successfully quantified drug effects of two hypnotic drugs and distinguished between zolpidem and suvorexant regarding their effects on walking. As a biomarker, the IWW demonstrated sensitivity in assessing dynamic balance and potential fall risk in early phase clinical drug development.
Assuntos
Acidentes por Quedas , Azepinas , Estudos Cross-Over , Equilíbrio Postural , Triazóis , Caminhada , Zolpidem , Humanos , Idoso , Zolpidem/administração & dosagem , Zolpidem/efeitos adversos , Triazóis/administração & dosagem , Triazóis/efeitos adversos , Masculino , Feminino , Idoso de 80 Anos ou mais , Acidentes por Quedas/prevenção & controle , Caminhada/fisiologia , Equilíbrio Postural/efeitos dos fármacos , Equilíbrio Postural/fisiologia , Azepinas/administração & dosagem , Azepinas/efeitos adversos , Biomarcadores , Medição de Risco/métodos , Método Duplo-Cego , Piridinas/administração & dosagem , Piridinas/efeitos adversosRESUMO
AIMS: To characterise the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending doses of oxathridine, a first-in-class histamine-3 receptor partialagonist, in healthy male volunteers. METHODS: A randomised, double-blind, placebo-controlled study including the NeuroCart, consisting of a battery of drug sensitive neurophysiological tests, was performed. Oxathridine was administered orally as an aqueous solution. After dosing, safety and NeuroCart tests (adaptive tracking [AT], body sway [BS], saccadic peak velocity [SPV], smooth pursuit [SP] eye movements, VAS according to Bond and Lader, VAS according to Bowdle [VAS B&L, Bowdle], pharmaco-electroencephalogram [pEEG], Sustained Attention to Response Task [SART]) were performed at set times. RESULTS: Forty volunteers completed the study. Given doses were: 0.5, 2.5, 5, 0.25 and 1.5 mg. At 5 mg, unacceptable and unanticipated adverse events (AEs) of (orthostatic) hypotension and pseudo-hallucinations were reported. Statistically significant effects ([CI]; p-value) of 2.5 mg and 5 mg oxathridine were observed on AT ([-8.28, -1.60]; p = 0.0048), ([-8.10, -1.51]; p = 0.00530), BS ([0.6, 80.2]; p = 0.0455), ([5.9, 93.1]; p = 0.0205) and SPV ([-59.0, -15.9]; p = 0.0011), ([-43.9, -1.09]; p = 0.0399), respectively. Oxathridine 5 mg significantly increased all three VAS Bowdle subscale scores; VAS external ([0.183, 0.476]; p = <.0001), VAS internal ([0.127, 0.370]; p = 0.0001) and VAS feeling high ([0.263, 0.887]; p = 0.0006). CONCLUSION: NeuroCart tests indicated central nervous system (CNS) depressant effects. Oxathridine also unexpectedly caused pseudohallucinations. Although this led to the decision to stop further development of oxathridine, these observations suggest that the H3R system could be an interesting new target for the development of novel antipsychotics.
Assuntos
Depressão , Histamina , Humanos , Masculino , Eletroencefalografia , Sistema Nervoso Central , Alucinações , Método Duplo-Cego , Voluntários Saudáveis , Relação Dose-Resposta a DrogaRESUMO
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.
Assuntos
Condução de Veículo , Privação do Sono , Masculino , Humanos , Estudos Cross-Over , Etanol/farmacologia , Conscientização , Fadiga , Desempenho PsicomotorRESUMO
AIM: We assessed whether total sleep deprivation (TSD) in combination with pain tests yields a reliable method to assess altered pain thresholds, which subsequently may be used to investigate (novel) analgesics in healthy subjects. METHODS: This was a two-part randomized crossover study in 24 healthy men and 24 women. Subjects were randomized 1:1 to first complete a day of nonsleep-deprived nociceptive threshold testing, followed directly by a TSD night and morning of sleep-deprived testing, or first complete the TSD night and morning sleep-deprived testing, returning 7 days later for a day of nonsleep-deprived testing. A validated pain test battery (heat, pressure, electrical burst and stair, cold pressor pain test and conditioned pain modulation [CPM] paradigm) and sleep questionnaires were performed. RESULTS: Subjects were significantly sleepier after TSD as measured using sleepiness questionnaires. Cold pressor pain tolerance (PTT, estimate of difference [ED] -10.8%, 95% CI -17.5 to -3.6%), CPM PTT (ED -0.69 mA, 95% CI -1.36 to -0.03 mA), pressure PTT (ED -11.2%, 95% CI -17.5% to -4.3%) and heat pain detection thresholds (ED -0.74 °C, 95% CI -1.34 to -0.14 °C) were significantly decreased after TSD compared to the baseline morning assessment in the combined analysis (men + women). Heat hyperalgesia was primarily driven by an effect of TSD in men, whereas cold and pressure hyperalgesia was primarily driven by the effects of TSD observed in women. CONCLUSIONS: TSD induced sex-dependent hyperalgesia on cold, heat and pressure pain, and CPM response. These results suggest that the TSD model may be suitable to evaluate (novel) analgesics in early-phase drug studies.
Assuntos
Hiperalgesia , Privação do Sono , Masculino , Humanos , Feminino , Estudos Cross-Over , Nociceptividade , Voluntários Saudáveis , Dor , Limiar da Dor , Analgésicos/farmacologiaRESUMO
TAK-653 is a novel AMPA receptor positive allosteric modulator in clinical development for the treatment of major depressive disorder (MDD). This study aimed to measure the functional pharmacodynamic central nervous system (CNS) effects of TAK-653. A randomised, double-blind, placebo-controlled, three-way crossover (placebo, TAK-653 0.5 mg and 6 mg) study with 24 healthy volunteers was performed. NeuroCart tests consisting of body sway (BS), saccadic peak velocity (SPV), smooth pursuit eye movements (SP), adaptive tracking (AT), Bowdle and Bond and Lader Visual Analogue Scales (B-VAS and BL-VAS) and Stroop test were performed pre-dose and 3.5 and 4 h post-dose. Data were analysed using a mixed model analysis of covariance with baseline as covariate. It was found that TAK-653 did not affect BS and subjective drug effects as measured by B-VAS and BL-VAS at either dose level. TAK-653 0.5 mg increased SPV (degrees/second) (19.49 [5.98, 32.99], P = 0.02) and affected Stroop difference in reaction time between correct congruent and correct incongruent answers and number of correct responses in incongruent trials (22.0 [4.0, 40.0], P = 0.05 and -0.3 [-0.5, -0.1], P = 0.02, respectively). TAK-653 6 mg improved AT (%) (1.68 [0.51, 2.84], P = 0.02) and increased SPV (degrees/s) (15.40 [1.91, 28.90], P = 0.06) and SP (%) (2.32 [0.37, 4.27], P = 0.05). Based on these findings it can be concluded that TAK-653 demonstrated a psychostimulant-like pharmacodynamic profile on the NeuroCart consistent with previously reported increase of cortical excitability following Transcranial Magnetic Stimulation (TMS) of the human motor cortex.
Assuntos
Transtorno Depressivo Maior , Isoxazóis , Sistema Nervoso Central , Transtorno Depressivo Maior/tratamento farmacológico , Método Duplo-Cego , Voluntários Saudáveis , Humanos , Isoxazóis/farmacologia , Receptores de AMPARESUMO
Use of hypnotics is often associated with next-morning residual effects and a higher risk of motor vehicle accidents. Measuring next-morning effects on driving performance is therefore advised by regulatory agencies. Here, we examined driving performance following administration of daridorexant, a new dual orexin receptor antagonist developed to treat insomnia. Sixty healthy male and female subjects (50-79 years of age) were randomized in a placebo- and active-controlled, four-way cross-over study. Each subject received evening administration of daridorexant 50 and 100 mg, zopiclone 7.5 mg, and placebo, in separate treatment phases of 4 days. Simulated driving performance was assessed after initial (day 2) and repeated dosing (day 5), 9 hours postdose. Standard deviation of the lateral position (SDLP) was the main outcome. On both days, with zopiclone, SDLP increased significantly compared with placebo, which confirmed sensitivity of the simulator. With daridorexant, on day 2, the placebo-corrected mean (97.5% confidence interval) SDLP increased by 2.19 cm (0.46-3.93) and 4.43 cm (2.72-6.15) for 50 and 100 mg, respectively. On day 5, SDLP values for both daridorexant doses were significantly below the prespecified threshold of impairment (2.6 cm) and statistically not different from placebo. Daridorexant showed a lower self-rated driving quality and higher effort compared to placebo on day 2 but not on day 5. In non-insomnia subjects, daridorexant impaired simulated driving after initial but not after repeated dosing. Subjects should be cautioned about driving until they know how daridorexant affects them.
Assuntos
Condução de Veículo , Antagonistas dos Receptores de Orexina , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Imidazóis , Masculino , Antagonistas dos Receptores de Orexina/efeitos adversos , Desempenho Psicomotor , PirrolidinasRESUMO
AIMS: ALKS 7119 is a novel compound with in vitro affinity highest for the SERT, and for µ receptor, α1A -adrenoceptor, α1B -adrenoceptor, NMDA receptor and sigma non-opioid intracellular receptor 1. This first-in-human study evaluated safety and PK/PD effects of single ascending doses (SAD) of ALKS 7119 in healthy males and compared effects with neurotransmitter modulators with partially overlapping targets. 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.
Assuntos
Hidrocortisona , Prolactina , Relação Dose-Resposta a Droga , Método Duplo-Cego , Voluntários Saudáveis , Humanos , Masculino , Receptores Adrenérgicos , Movimentos SacádicosRESUMO
Sleep deprivation has been shown to increase pain intensity and decrease pain thresholds in healthy subjects. In chronic pain patients, sleep impairment often worsens the perceived pain intensity. This increased pain perception is the result of altered nociceptive processing. We recently developed a method to quantify and monitor altered nociceptive processing by simultaneous tracking of psychophysical detection thresholds and recording of evoked cortical potentials during intra-epidermal electric stimulation. In this study, we assessed the sensitivity of nociceptive detection thresholds and evoked potentials to altered nociceptive processing after sleep deprivation in an exploratory study with 24 healthy male and 24 healthy female subjects. In each subject, we tracked nociceptive detection thresholds and recorded central evoked potentials in response to 180 single- and 180 double-pulse intra-epidermal electric stimuli. Results showed that the detection thresholds for single- and double-pulse stimuli and the average central evoked potential for single-pulse stimuli were significantly decreased after sleep deprivation. When analyzed separated by sex, these effects were only significant in the male population. Multivariate analysis showed that the decrease of central evoked potential was associated with a decrease of task-related evoked activity. Measurement repetition led to a decrease of the detection threshold to double-pulse stimuli in the mixed and the female population, but did not significantly affect any other outcome measures. These results suggest that simultaneous tracking of psychophysical detection thresholds and evoked potentials is a useful method to observe altered nociceptive processing after sleep deprivation, but is also sensitive to sex differences and measurement repetition.
Assuntos
Nociceptividade , Privação do Sono , Estimulação Elétrica/métodos , Potenciais Evocados , Feminino , Humanos , Masculino , Dor , Limiar da Dor/fisiologiaRESUMO
AIM: Traditional studies focusing on the relationship between pharmacokinetics (PK) and pharmacodynamics necessitate blood draws, which are too invasive for children or other vulnerable populations. A potential solution is to use noninvasive sampling matrices, such as saliva. The aim of this study was to develop a population PK model describing the relationship between plasma and saliva clonazepam kinetics and assess whether the model can be used to determine trough plasma concentrations based on saliva samples. METHODS: Twenty healthy subjects, aged 18-30, were recruited and administered 0.5 or 1 mg of clonazepam solution. Paired plasma and saliva samples were obtained until 48 hours post-dose. A population pharmacokinetic model was developed describing the PK of clonazepam in plasma and the relationship between plasma and saliva concentrations. Bayesian maximum a posteriori optimization was applied to estimate the predictive accuracy of the model. RESULTS: A two-compartment distribution model best characterized clonazepam plasma kinetics with a mixture component on the absorption rate constants. Oral administration of the clonazepam solution caused contamination of the saliva compartment during the first 4 hours post-dose, after which the concentrations were driven by the plasma concentrations. Simulations demonstrated that the lower and upper limits of agreements between true and predicted plasma concentrations were -28% to 36% with one saliva sample. Increasing the number of saliva samples improved these limits to -18% to 17%. CONCLUSION: The developed model described the salivary and plasma kinetics of clonazepam, and could predict steady-state trough plasma concentrations based on saliva concentrations with acceptable accuracy.
Assuntos
Clonazepam , Saliva , Teorema de Bayes , Criança , Clonazepam/farmacocinética , Humanos , Plasma , Populações VulneráveisRESUMO
Background: Digital technologies have the potential to provide objective and precise tools to detect depression-related symptoms. Deployment of digital technologies in clinical research can enable collection of large volumes of clinically relevant data that may not be captured using conventional psychometric questionnaires and patient-reported outcomes. Rigorous methodology studies to develop novel digital endpoints in depression are warranted. Objective: We conducted an exploratory, cross-sectional study to evaluate several digital technologies in subjects with major depressive disorder (MDD) and persistent depressive disorder (PDD), and healthy controls. The study aimed at assessing utility and accuracy of the digital technologies as potential diagnostic tools for unipolar depression, as well as correlating digital biomarkers to clinically validated psychometric questionnaires in depression. Methods: A cross-sectional, non-interventional study of 20 participants with unipolar depression (MDD and PDD/dysthymia) and 20 healthy controls was conducted at the Centre for Human Drug Research (CHDR), the Netherlands. Eligible participants attended three in-clinic visits (days 1, 7, and 14), at which they underwent a series of assessments, including conventional clinical psychometric questionnaires and digital technologies. Between the visits, there was at-home collection of data through mobile applications. In all, seven digital technologies were evaluated in this study. Three technologies were administered via mobile applications: an interactive tool for the self-assessment of mood, and a cognitive test; a passive behavioral monitor to assess social interactions and global mobility; and a platform to perform voice recordings and obtain vocal biomarkers. Four technologies were evaluated in the clinic: a neuropsychological test battery; an eye motor tracking system; a standard high-density electroencephalogram (EEG)-based technology to analyze the brain network activity during cognitive testing; and a task quantifying bias in emotion perception. Results: Our data analysis was organized by technology - to better understand individual features of various technologies. In many cases, we obtained simple, parsimonious models that have reasonably high diagnostic accuracy and potential to predict standard clinical outcome in depression. Conclusion: This study generated many useful insights for future methodology studies of digital technologies and proof-of-concept clinical trials in depression and possibly other indications.
RESUMO
TAK-653 is a novel α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-positive allosteric modulator being developed as a potential therapeutic for major depressive disorder (MDD). Currently, there are no translational biomarkers that evaluate physiological responses to the activation of glutamatergic brain circuits available. Here, we tested whether noninvasive neurostimulation, specifically single-pulse or paired-pulse motor cortex transcranial magnetic stimulation (spTMS and ppTMS, respectively), coupled with measures of evoked motor response captures the pharmacodynamic effects of TAK-653 in rats and healthy humans. In the rat study, five escalating TAK-653 doses (0.1-50 mg/kg) or vehicle were administered to 31 adult male rats, while measures of cortical excitability were obtained by spTMS coupled with mechanomyography. Twenty additional rats were used to measure brain and plasma TAK-653 concentrations. The human study was conducted in 24 healthy volunteers (23 males, 1 female) to assess the impact on cortical excitability of 0.5 and 6 mg TAK-653 compared with placebo, measured by spTMS and ppTMS coupled with electromyography in a double-blind crossover design. Plasma TAK-653 levels were also measured. TAK-653 increased both the mechanomyographic response to spTMS in rats and the amplitude of motor-evoked potentials in humans at doses yielding similar plasma concentrations. TAK-653 did not affect resting motor threshold or paired-pulse responses in humans. This is the first report of a translational functional biomarker for AMPA receptor potentiation and indicates that TMS may be a useful translational platform to assess the pharmacodynamic profile of glutamate receptor modulators.
Assuntos
Transtorno Depressivo Maior , Estimulação Magnética Transcraniana , Animais , Biomarcadores , Potencial Evocado Motor , Feminino , Masculino , Ratos , Receptores de AMPARESUMO
BACKGROUND: Daridorexant (ACT-541468) is a potent dual orexin receptor antagonist under development for the treatment of sleep disorders. Concomitant intake of ethanol and hypnotics has been shown to result in additive/supra-additive depression of the central nervous system, resulting in pronounced sedation. OBJECTIVE: The aim of this study was to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) interactions between ethanol and daridorexant. METHOD: This was a single-center, double-blind, placebo-controlled, randomized, four-way crossover study conducted in 19 healthy male/female subjects. Subjects received the following four treatments: ethanol with daridorexant, daridorexant alone, ethanol alone, and placebo. Daridorexant 50 mg and the matching placebo were administered as single oral tablets. Ethanol was infused intravenously and clamped at a level of 0.6 g/L for 5 h. The PK of ethanol and daridorexant were assessed and a battery of PD tests performed. RESULTS: Concomitant administration of ethanol prolonged the time to reach maximum plasma concentrations (tmax) of daridorexant (median difference 1.25 h). No other relevant PK interactions were observed. Coadministration with ethanol produced a numerically greater impairment on saccadic peak velocity, body sway, visual analog scale (VAS) alertness, VAS alcohol intoxication, smooth pursuit, and adaptive tracking compared with daridorexant alone. All treatments were generally well tolerated without serious adverse events (AEs). The most commonly reported treatment-emergent AEs following coadministration of daridorexant and ethanol included somnolence, headache, fatigue, sudden onset of sleep, and dizziness. CONCLUSIONS: Apart from a shift in tmax, no relevant changes in PK parameters were observed following coadministration of daridorexant and ethanol. The coadministration led to reinforced drug actions that were, at most, indicative of infra-additive effects on certain PD markers. Patients will be advised not to consume ethanol with daridorexant. CLINICAL TRIALS REGISTRATION NUMBER: NCT03609775 (ClinicalTrials.gov Identifier).
Assuntos
Etanol/farmacologia , Imidazóis/farmacologia , Antagonistas dos Receptores de Orexina/farmacologia , Pirrolidinas/farmacologia , Adulto , Estudos Cross-Over , Método Duplo-Cego , Interações Medicamentosas , Etanol/efeitos adversos , Feminino , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Masculino , Antagonistas dos Receptores de Orexina/efeitos adversos , Pirrolidinas/efeitos adversos , Pirrolidinas/farmacocinética , Adulto JovemRESUMO
Orexin neurons originating in the perifornical and lateral hypothalamic area project to anxiety- and panic-associated neural circuitry, and are highly reactive to anxiogenic stimuli. Preclinical evidence suggests that the orexin system, and particularly the orexin-1 receptor (OX1R), may be involved in the pathophysiology of panic and anxiety. Selective OX1R antagonists thus may constitute a potential new treatment strategy for panic- and anxiety-related disorders. Here, we characterized a novel selective OX1R antagonist, JNJ-61393215, and determined its affinity and potency for human and rat OX1R in vitro. We also evaluated the safety, pharmacokinetic, and pharmacodynamic properties of JNJ-61393215 in first-in-human single- and multiple-ascending dose studies conducted. Finally, the potential anxiolytic effects of JNJ-61393215 were evaluated both in rats and in healthy men using 35% CO2 inhalation challenge to induce panic symptoms. In the rat CO2 model of panic anxiety, JNJ-61393215 demonstrated dose-dependent attenuation of CO2-induced panic-like behavior without altering baseline locomotor or autonomic activity, and had minimal effect on spontaneous sleep. In phase-1 human studies, JNJ-61393215 at 90 mg demonstrated significant reduction (P < 0.02) in CO2-induced fear and anxiety symptoms that were comparable to those obtained using alprazolam. The most frequently reported adverse events were somnolence and headache, and all events were mild in severity. These results support the safety, tolerability, and anxiolytic effects of JNJ-61393215, and validate CO2 exposure as a translational cross-species experimental model to evaluate the therapeutic potential of novel anxiolytic drugs.
Assuntos
Antagonistas dos Receptores de Orexina , Pânico , Roedores , Animais , Humanos , Modelos Teóricos , Receptores de Orexina , RatosRESUMO
There is a lack of reliable, repeatable, and non-invasive clinical endpoints when investigating treatments for intellectual disability (ID). The aim of this study is to explore a novel approach towards developing new endpoints for neurodevelopmental disorders, in this case for ARID1B-related ID. In this study, twelve subjects with ARID1B-related ID and twelve age-matched controls were included in this observational case-control study. Subjects performed a battery of non-invasive neurobehavioral and neurophysiological assessments on two study days. Test domains included cognition, executive functioning, and eye tracking. Furthermore, several electrophysiological assessments were performed. Subjects wore a smartwatch (Withings® Steel HR) for 6 days. Tests were systematically assessed regarding tolerability, variability, repeatability, difference with control group, and correlation with traditional endpoints. Animal fluency, adaptive tracking, body sway, and smooth pursuit eye movements were assessed as fit-for-purpose regarding all criteria, while physical activity, heart rate, and sleep parameters show promise as well. The event-related potential waveform of the passive oddball and visual evoked potential tasks showed discriminatory ability, but EEG assessments were perceived as extremely burdensome. This approach successfully identified fit-for-purpose candidate endpoints for ARID1B-related ID and possibly for other neurodevelopmental disorders. Next, results could be replicated in different ID populations or the assessments could be included as exploratory endpoint in interventional trials in ARID1B-related ID.
Assuntos
Proteínas de Ligação a DNA/genética , Determinação de Ponto Final/métodos , Variação Genética/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Animais , Estudos de Casos e Controles , Criança , Pré-Escolar , Potenciais Evocados Visuais/genética , Função Executiva/fisiologia , Feminino , Humanos , Deficiência Intelectual/psicologia , Masculino , Estimulação Luminosa/métodos , Adulto JovemRESUMO
BACKGROUND: This is the first report of the pharmacodynamic (PD) effects of the selective, potent and brain-penetrant P2X7 receptor (P2X7R) antagonist JNJ-54175446. Activation of the P2X7R, an adenosine triphosphate-gated ion channel, leads to the production of pro-inflammatory cytokines, which have been linked to neuroinflammation and play a role in the pathogenesis of mood disorders. Previous clinical studies with JNJ-54175446 demonstrated peripheral target engagement of JNJ-54175446 by assessing ex vivo lipopolysaccharide (LPS)-stimulated cytokine production. Blood-brain barrier penetration and a clear dose-receptor occupancy relationship was demonstrated using positron emission tomography. AIMS: The objectives of this double-blind, placebo-controlled, translational study were to assess the safety and tolerability of administering multiple doses of JNJ-54175446 and to explore its PD effects using a dexamphetamine challenge. METHODS: Subjects (N = 64) were randomised to either JNJ-54175446 (50-450 mg; n = 48) or placebo (n = 16) and underwent a baseline oral 20 mg dexamphetamine challenge followed by 11 consecutive days q.d. dosing with JNJ-54175446/placebo and a randomised crossover dexamphetamine/placebo challenge. RESULTS: At all doses tested, JNJ-54175446 was well tolerated and suppressed the ex vivo LPS-induced release of cytokines. At doses ⩾100 mg, JNJ-54175446 attenuated dexamphetamine-induced increases in locomotion and enhanced the mood-elevating effects of dexamphetamine, suggesting that a dose that is approximately twice as high is needed to obtain a central PD response compared to the dose needed for maximum peripheral occupancy. CONCLUSION: Overall, the observed pharmacological profile of JNJ-54175446 in the dexamphetamine challenge paradigm is compatible with a potential mood-modulating effect.
Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Dextroanfetamina/farmacologia , Antagonistas do Receptor Purinérgico P2X/farmacologia , Piridinas/farmacologia , Triazóis/farmacologia , Adolescente , Adulto , Estimulantes do Sistema Nervoso Central/administração & dosagem , Transtorno Depressivo Maior/tratamento farmacológico , Dextroanfetamina/administração & dosagem , Método Duplo-Cego , Eletroencefalografia , Humanos , Inflamação/tratamento farmacológico , Masculino , Antagonistas do Receptor Purinérgico P2X/administração & dosagem , Antagonistas do Receptor Purinérgico P2X/efeitos adversos , Antagonistas do Receptor Purinérgico P2X/farmacocinética , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridinas/farmacocinética , Pesquisa Translacional Biomédica , Triazóis/administração & dosagem , Triazóis/efeitos adversos , Triazóis/farmacocinética , Adulto JovemRESUMO
PURPOSE/BACKGROUND: Daridorexant is a dual orexin receptor antagonist in development for the treatment of sleep disorders. Thus far, it has not yet been studied in Japanese subjects. Study objectives were to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and safety of single- and multiple-dose administration of daridorexant in healthy Caucasian and Japanese subjects. METHODS/PROCEDURES: This was a double-blind, placebo-controlled, randomized study. Subjects received once-daily doses of daridorexant (25 or 50 mg) or placebo for 5 days. Pharmacokinetics and safety were investigated using standard assessments. To assess PD effects, a battery of tests (saccadic peak velocity, body sway, adaptive tracking performance, and visual analog scales for alertness, mood, and calmness), known to be sensitive to sleep-promoting drugs was used. FINDINGS/RESULTS: On day 1, PK variables were similar between Caucasian and Japanese subjects. On day 5, slight accumulation occurred in Japanese but not in Caucasian subjects, resulting in a higher maximum concentration (1403 vs 1006 ng/mL) and area under the curve (8256 vs 6306 ng·h/mL) at a dose of 50 mg, whereas values for time to maximum concentration and half-life were similar. Daridorexant dose-dependently reduced vigilance, attention, visuomotor coordination, and postural stability. Pharmacokinetic effects were detectable within 1 hour after drug administration and returned to baseline 4 to 8 hours postdose. Overall, Japanese showed slightly larger PD effects and reported more adverse events than Caucasians. The most frequently reported were somnolence, fatigue, and headache. Changes in other safety assessments were unremarkable. IMPLICATIONS/CONCLUSIONS: The PK, PD, and safety profile of daridorexant were similar in Japanese and Caucasian subjects.
Assuntos
Povo Asiático , Antagonistas dos Receptores de Orexina/farmacologia , Antagonistas dos Receptores de Orexina/farmacocinética , População Branca , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas dos Receptores de Orexina/sangueRESUMO
Concentrations of drugs acting in the lungs are difficult to measure, resulting in relatively unknown local pharmacokinetics. The aim of this study is to assess the potential of exhaled breath condensate (EBC) as a matrix for pharmacokinetic analysis of inhaled and intravenous medication. A 4-way crossover study was conducted in 12 volunteers with tobramycin and salbutamol intravenously and via inhalation. EBC and plasma samples were collected postdose and analysed for drug concentrations. Sample dilution, calculated using urea concentrations, was used to estimate the epithelial lining fluid concentration. Salbutamol and tobramycin were largely undetectable in EBC after intravenous administration and were detectable after inhaled administration in all subjects in 50.8 and 51.5% of EBC samples, respectively. Correction of EBC concentrations for sample dilution did not explain the high variability. This high variability of EBC drug concentrations seems to preclude EBC as a matrix for pharmacokinetic analysis of tobramycin and salbutamol.
Assuntos
Albuterol , Tobramicina , Administração Intravenosa , Biomarcadores , Testes Respiratórios , Estudos Cross-Over , HumanosRESUMO
BACKGROUND: The dual orexin receptor antagonist ACT-541468 showed sedative pharmacodynamic effects during initial clinical testing in adult subjects. The present study explored pharmacokinetics, pharmacodynamics and tolerability in healthy elderly subjects. METHODS: Double-blind, placebo-controlled, randomised, single-ascending dose study in 24 male/female elderly (65-80 years, 5, 15 and 25 mg in the morning, 6/2 active/placebo per group). Additionally, 10 subjects (8/2 active/placebo) received 25 mg for 7 days in the evening. Pharmacokinetics, pharmacodynamics (saccadic peak velocity, adaptive tracking, body sway, visual analogue scales according to Bowdle and Bond and Lader, Karolinska Sleepiness Scale) and tolerability were assessed. In particular, pharmacodynamics results are to be interpreted exploratorily. RESULTS: Absorption was quick with a median time to maximum concentration of â¼ 1.0 h. The mean elimination half-life was 8.5-9.8 h, the area under the curve and the maximum plasma concentration increased proportionally with dose. Following repeated evening administration of 25 mg, minimal accumulation was observed. There were no pharmacodynamic effects at 5 mg. At 15 mg, saccadic peak velocity (degree/s; SD) was reduced (69; 38), while other variables showed no effects. At 25 mg, effects on all objective pharmacodynamic parameters were observed. At 8-12 h post-dose, there were no differences to placebo and no next-day effects on pharmacodynamic variables after evening administration. Elderly subjects reported fewer adverse events compared to adults in previous studies. CONCLUSION: ACT-541468 in elderly subjects was well tolerated and pharmacokinetics and pharmacodynamics are compatible with a drug for the treatment of insomnia. Clinicaltrials.gov: NCT02571855.
Assuntos
Imidazóis/efeitos adversos , Imidazóis/farmacologia , Imidazóis/farmacocinética , Pirrolidinas/efeitos adversos , Pirrolidinas/farmacologia , Pirrolidinas/farmacocinética , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Imidazóis/sangue , Masculino , Antagonistas dos Receptores de Orexina/efeitos adversos , Antagonistas dos Receptores de Orexina/farmacocinética , Antagonistas dos Receptores de Orexina/farmacologia , Satisfação do Paciente , Equilíbrio Postural/efeitos dos fármacos , Pirrolidinas/sangue , Movimentos Sacádicos/efeitos dos fármacosRESUMO
In the original Article, Tables two and three had formatting issues which affected their clarity. This has been corrected in the PDF and HTML versions of this Article.