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TAVO101 is a humanized anti‐human thymic stromal lymphopoietin (TSLP) monoclonal antibody under clinical development for the treatment of atopic dermatitis (AD) and other allergic inflammatory conditions. The crystallizable fragment region of the antibody was engineered for half‐life extension and attenuated effector functions. This Phase 1, double‐blinded, randomized, placebo‐controlled study assessed the safety, tolerability, pharmacokinetics, and immunogenicity of TAVO101 in healthy adult subjects in seven ascending dose cohorts. Subjects received a single intravenous administration of TAVO101 or placebo with a 195‐day follow‐up. TAVO101 was safe and well tolerated. The incidences and severities of treatment‐emergent adverse events were mostly mild and comparable between the active and placebo groups, with no trends of dose relationship. There were no severe adverse events, deaths, or treatment‐related withdrawals. TAVO101 exhibited a linear pharmacokinetic profile, low clearance, and a median elimination half‐life of 67 days in healthy subjects. All TAVO101‐treated subjects tested negative for anti‐drug antibodies. To support development in AD, TAVO101 was studied in an oxazolone‐induced AD model in hTSLP transgenic mice and demonstrated efficacy. This long‐acting anti‐TSLP antibody has the potential for stronger and sustained allergic inflammatory disease control. The results from this study warranted further clinical development of TAVO101 in patients. [ABSTRACT FROM AUTHOR]

Abstract Severe community-acquired pneumonia (SCAP) is a serious respiratory inflammation disease with high morbidity and mortality. This study aimed to evaluate the prognostic value of the platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), basophil-to-lymphocyte ratio (BLR) and eosinophil-to-lymphocyte ratio (ELR) in patients with SCAP. The study retrospectively included 554 patients with SCAP, and the clinical data were obtained from the electronic patient record (EMR) system. The primary outcome was in-hospital mortality, and the secondary outcomes included hospital length of stay (LOS), overall survival (OS), admission to ICU, ICU LOS, and ICU mortality. The results showed that both NLR and BLR were significant but not independent prognostic factors for in-hospital mortality; NLR was negatively correlated with hospital LOS while ELR was positively correlated with hospital LOS; both increased NLR and increased BLR were associated with reduced OS, while increased ELR was associated with improved OS; increased PLR, NLR, MLR, and BLR were all correlated with elevated ICU admission rates, while increased ELR was correlated with a reduced ICU admission rate; ELR was positively correlated with ICU LOS; both higher NLR and higher BLR were associated with increased ICU mortality. In summary, NLR and BLR were useful prognostic factors for clinical outcomes in patients with SCAP.

The study aimed to quantitatively clarify the effects of several weeks of static stretching on the flexibility of the rectus femoris muscle using shear wave elastography.

Background: Parenteral artesunate is the first-line therapy for severe malaria. Artesunate, in its current formulation, must be prepared immediately before administration by first dissolving in sodium bicarbonate solution and then diluting in saline. A novel solvent for rapid and stable single step reconstitution of artesunate was recently developed showing improved solubility and stability. This study aimed to compare the safety and pharmacokinetic properties of the currently available and newly developed parenteral formulation of artesunate in healthy Thai volunteers. Methods: This was an open-label, randomized, 4 periods, 4-treatments, 24-sequence, single-dose, cross-over study in 72 male and female healthy Thai volunteers. Frequent pharmacokinetic samples were collected in all volunteers at each dose occasion. Observed concentration–time profiles were analysed with a non-compartmental approach followed by a bioequivalence evaluation. Results: Both intramuscular and intravenous administrations of the new parenteral formulation of artesunate were safe and well-tolerated, with no additional safety signals compared to the currently used formulation. The pharmacokinetic properties of artesunate and its active metabolite, dihydroartemisinin, were well-characterized, and showed rapid conversion of artesunate into dihydroartemisinin. Intramuscular administration of the newly formulated artesunate resulted in almost complete bioavailability of dihydroartemisinin. The pharmacokinetic properties were similar between the old and new formulation. Conclusions: The new and more easily prepared formulation of artesunate was safe and well-tolerated, with similar pharmacokinetic properties compared to the currently used formulation. Dihydroartemisinin, the active metabolite responsible for the majority of the anti-malarial effect, showed equivalent exposure after both intravenous and intramuscular administration of artesunate, suggesting that both routes of administration should generate comparable therapeutic effects. Trial registration: The study was registered to clinicaltrials.gov (#TCTR20170907002). [ABSTRACT FROM AUTHOR]

Background: Nitrous oxide use is shifting from general anesthesia to sedation and pain control. Interest in novel uses of nitrous oxide in psychiatry is also growing. Thus, understanding the consequences of using nitrous oxide remains relevant. Previous quantitative research might not have fully captured the whole spectrum of nitrous oxide, whereas qualitative analysis can provide a more comprehensive description. This qualitative study aims to describe the subjective experiences of nitrous oxide use in healthy volunteers who have no prior history of recreational substance misuse. Methods: Twenty healthy male volunteers inhaled 50% nitrous oxide for 20 min. Females were excluded due to higher incidence of nausea with nitrous oxide. Afterwards, all participants answered an open‐ended question about their experiences during sedation. The answers were then analyzed with inductive qualitative content analysis to identify emergent subcategories, categories, and overarching themes. Results: We identified two themes: nitrous oxide is mind‐altering and produces sensory overload. The mind‐altering properties were represented by dreamlike states and heightened emotions. Dreamlike states comprised changes in consciousness and scary, bizarre, or transcendental dreams. Pleasant dreams were not reported. Heightened emotions included euphoria, anxiety, and fear of losing control. Sensory overload consists of distorted perception, bodily sensations, and a heightened sense of surroundings. Conclusions: Experiences under nitrous oxide sedation are extremely variable and not always pleasant. These findings can improve our understanding of the likes/dislikes of patients undergoing nitrous oxide sedation. Further qualitative studies should focus on the experiences of other groups, such as children or women in labor. [ABSTRACT FROM AUTHOR]

Aim: The study aimed to quantitatively clarify the effects of several weeks of static stretching on the flexibility of the rectus femoris muscle using shear wave elastography. Material and methods: Fifteen healthy men (age: 26.4 ± 2.2 years) were instructed to perform 5 min of voluntary static stretching of their right rectus femoris muscles five times a week for four weeks. The participants adjusted their stretching intensity to a point immediately before experiencing discomfort or pain. The Young's modulus of the rectus femoris muscle and the knee-flexion range of motion were measured as indicators of flexibility. The Young's modulus was measured using shear wave elastography. Measurements were performed at baseline, as well as at two and four weeks after the stretching program started. A generalized linear mixed model was used to assess the change in the Young's modulus after the stretching program and the effects of the Young's modulus on the knee-flexion range of motion. Results: The Young's modulus of the rectus femoris muscle decreased after two and four weeks of stretching compared with the baseline (p = 0.0004 and p <0.0001, respectively). The Young's modulus of the rectus femoris muscle and the four-week duration of stretching affected the knee-flexion range of motion (p = 0.0242 and 0.0016, respectively). Conclusions: Shear wave elastography quantitatively revealed that several weeks of static stretching increased the flexibility of the rectus femoris muscle in healthy men. A four-week static stretching regimen reduced the Young's modulus of the rectus femoris muscle and increased the knee-flexion range of motion. [ABSTRACT FROM AUTHOR]

Platelet aggregation is a complicated process mediated by different signaling pathways. As the process is highly complex and apparently redundant, the relationships between these pathways are not yet fully known. The aim of this project was to study the interconnections among seven different aggregation pathways in a group of 53 generally healthy volunteers aged 20 to 66 years. Platelet aggregation was induced with thrombin receptor activating peptide 6 (TRAP), arachidonic acid (AA), platelet activating factor 16 (PAF), ADP, collagen, thromboxane A2 analogue U46619 or ristocetin (platelet agglutination) ex vivo in fasting blood samples according to standardized timetable protocol. Additionally, some samples were pre-treated with known clinically used antiplatelet drugs (vorapaxar, ticagrelor or acetylsalicylic acid (ASA)). Significant correlations among all used inducers were detected (Pearson correlation coefficients (rP): 0.3 to 0.85). Of all the triggers, AA showed to be the best predictor of the response to other inducers with rP ranging from 0.66 to 0.85. Interestingly, the antiplatelet response to ticagrelor strongly predicted the response to unrelated drug vorapaxar (rP = 0.71). Our results indicate that a response to one inducer can predict the response for other triggers or even to an antiplatelet drug. These data are useful for future testing but should be also confirmed in patients.

Abstract Background The emergence of resistance to artemisinin-based combination therapy necessitates the search for new, more potent antiplasmodial compounds, including herbal remedies. The whole extract of Maytenus senegalensis has been scientifically investigated for potential biological activities both in vitro and in vivo, demonstrating strong antimalarial activity. However, there is a lack of data on the electrocardiographic effects of M. senegalensis in humans, which is a crucial aspect in the investigation of malaria treatment. Assessing the electrocardiographic effects of M. senegalensis is essential, as many anti-malarial drugs can inadvertently prolong the QT interval on electrocardiograms. Therefore, the study's objective was to evaluate the electrocardiographic effects of M. senegalensis in healthy adult volunteers. Methods This study is a secondary analysis of an open-label single-arm dose escalation. Twelve healthy eligible Tanzanian males, aged 18 to 45, were enrolled in four study dose groups. A single 12-lead electrocardiogram (ECG) was performed at baseline and on days 3, 7, 14, 28, and 56. Results No QTcF adverse events occurred with any drug dose. Only one volunteer who received the highest dose (800 mg) of M. senegalensis experienced a moderate transient change (△QTcF > 30 ms; specifically, the value was 37 ms) from baseline on day 28. There was no difference in maximum QTcF and maximum △QTcF between volunteers in all four study dose groups. Conclusions A four-day regimen of 800 mg every 8 h of M. senegalensis did not impact the electrocardiographic parameters in healthy volunteers. This study suggests that M. senegalensis could be a valuable addition to malaria treatment, providing a safer alternative and potentially aiding in the battle against artemisinin-resistant malaria. The results of this study support both the traditional use and the modern therapeutic potential of M. senegalensis. They also set the stage for future research involving larger and more diverse populations to explore the safety profile of M. senegalensis in different demographic groups. This is especially important considering the potential use of M. senegalensis as a therapeutic agent and its widespread utilization as traditional medicine. Trial registration ClinicalTrials.gov, NCT04944966. Registered 30 June 2021-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04944966?term=kamaka&draw=2&rank=1

Background: The emergence of resistance to artemisinin-based combination therapy necessitates the search for new, more potent antiplasmodial compounds, including herbal remedies. The whole extract of Maytenus senegalensis has been scientifically investigated for potential biological activities both in vitro and in vivo, demonstrating strong antimalarial activity. However, there is a lack of data on the electrocardiographic effects of M. senegalensis in humans, which is a crucial aspect in the investigation of malaria treatment. Assessing the electrocardiographic effects of M. senegalensis is essential, as many anti-malarial drugs can inadvertently prolong the QT interval on electrocardiograms. Therefore, the study's objective was to evaluate the electrocardiographic effects of M. senegalensis in healthy adult volunteers. Methods: This study is a secondary analysis of an open-label single-arm dose escalation. Twelve healthy eligible Tanzanian males, aged 18 to 45, were enrolled in four study dose groups. A single 12-lead electrocardiogram (ECG) was performed at baseline and on days 3, 7, 14, 28, and 56. Results: No QTcF adverse events occurred with any drug dose. Only one volunteer who received the highest dose (800 mg) of M. senegalensis experienced a moderate transient change (△QTcF > 30 ms; specifically, the value was 37 ms) from baseline on day 28. There was no difference in maximum QTcF and maximum △QTcF between volunteers in all four study dose groups. Conclusions: A four-day regimen of 800 mg every 8 h of M. senegalensis did not impact the electrocardiographic parameters in healthy volunteers. This study suggests that M. senegalensis could be a valuable addition to malaria treatment, providing a safer alternative and potentially aiding in the battle against artemisinin-resistant malaria. The results of this study support both the traditional use and the modern therapeutic potential of M. senegalensis. They also set the stage for future research involving larger and more diverse populations to explore the safety profile of M. senegalensis in different demographic groups. This is especially important considering the potential use of M. senegalensis as a therapeutic agent and its widespread utilization as traditional medicine. Trial registration ClinicalTrials.gov, NCT04944966. Registered 30 June 2021-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04944966?term=kamaka&draw=2&rank=1 [ABSTRACT FROM AUTHOR]

Platelet aggregation is a complicated process mediated by different signaling pathways. As the process is highly complex and apparently redundant, the relationships between these pathways are not yet fully known. The aim of this project was to study the interconnections among seven different aggregation pathways in a group of 53 generally healthy volunteers aged 20 to 66 years. Platelet aggregation was induced with thrombin receptor activating peptide 6 (TRAP), arachidonic acid (AA), platelet activating factor 16 (PAF), ADP, collagen, thromboxane A2 analogue U46619 or ristocetin (platelet agglutination) ex vivo in fasting blood samples according to standardized timetable protocol. Additionally, some samples were pre-treated with known clinically used antiplatelet drugs (vorapaxar, ticagrelor or acetylsalicylic acid (ASA)). Significant correlations among all used inducers were detected (Pearson correlation coefficients (rP): 0.3 to 0.85). Of all the triggers, AA showed to be the best predictor of the response to other inducers with rP ranging from 0.66 to 0.85. Interestingly, the antiplatelet response to ticagrelor strongly predicted the response to unrelated drug vorapaxar (rP = 0.71). Our results indicate that a response to one inducer can predict the response for other triggers or even to an antiplatelet drug. These data are useful for future testing but should be also confirmed in patients. [ABSTRACT FROM AUTHOR]

(1) Background: The inspiratory collapse of the inferior vena cava (IVC), a non-invasive surrogate for right atrial pressure, is often used to predict whether a patient will augment stroke volume (SV) in response to a preload challenge. There is a correlation between changing stroke volume (SV∆) and corrected flow time of the common carotid artery (ccFT∆). (2) Objective: We studied the relationship between IVC collapsibility and ccFT∆ in healthy volunteers during preload challenges. (3) Methods: A prospective, observational, pilot study in euvolemic, healthy volunteers with no cardiovascular history was undertaken in a local physiology lab. Using a tilt-table, we studied two degrees of preload augmentation from (a) supine to 30-degrees head-down and (b) fully-upright to 30-degrees head down. In the supine position, % of IVC collapse with respiration, sphericity index and portal vein pulsatility was calculated. The common carotid artery Doppler pulse was continuously captured using a wireless, wearable ultrasound system. (4) Results: Fourteen subjects were included. IVC % collapse with respiration ranged between 10% and 84% across all subjects. Preload responsiveness was defined as an increase in ccFT∆ of at least 7 milliseconds. A total of 79% (supine baseline) and 100% (head-up baseline) of subjects were preload-responsive. No supine venous measures (including IVC % collapse) were significantly related to ccFT∆. (5) Conclusions: From head-up baseline, 100% of healthy subjects were 'preload-responsive' as per the ccFT∆. Based on the 42% and 25% IVC collapse thresholds in the supine position, only 50% and 71% would have been labeled 'preload-responsive'. [ABSTRACT FROM AUTHOR]

The supply of branded 6‐mercaptopurine (6‐MP) is limited in China, necessitating the local production and clinical evaluation of generic alternatives. We evaluated the in vivo bioequivalence (BE) of a new generic mercaptopurine tablet (50 mg) formulation by comparing peak plasma concentration and area under the concentration–time curve (AUC) with a branded 6‐MP formulation as the reference in 36 healthy fasting Chinese adults. The in vivo BE was evaluated by the average BE test. The safety parameters of the test and reference formulations were also evaluated. The geometric mean ratios for AUC over the dosing interval and AUC from time zero to infinity were 104% and 104%, respectively, of the reference values, while the point estimate of the geometric mean ratio for peak plasma concentration was 104% of the reference value. The test and reference formulations in this study were both deemed safe as only 23 Grade 1 adverse events were observed in 13 of 36 subjects. The test and reference formulations of 6‐MP tablets meet the regulatory criteria for BE in healthy fasting Chinese adults. [ABSTRACT FROM AUTHOR]

Abstract Background The venous excess ultrasound (VExUS) score is a multi-organ Doppler approach to assess venous congestion. Despite growing use of VExUS in research and clinical practice, other veins can be visualized to assess for venous hypertension, which may overcome acquisition barriers of the VExUS exam. In this pilot, observational study, we used a wearable Doppler ultrasound to assess the relationship between jugular venous Doppler and the VExUS score under different preload conditions. We hypothesized that jugular Doppler morphology would accurately distinguish preload conditions, that it would most closely relate to the hepatic venous Doppler morphology in the fully supine position and that the VExUS score would be influenced by preload condition. Results We recruited 15 healthy volunteers with no cardiovascular history. Preload change was achieved using a tilt-table with three positions: supine, fully upright, and 30-degree head-down tilt. In each position, a VExUS score was performed; furthermore, inferior vena collapsibility and sphericity index were calculated. At the same time, jugular venous Doppler was captured by a novel, wireless, wearable ultrasound system. A continuous jugular venous Doppler morphology was 96% accurate for detecting the low preload condition. The jugular venous Doppler morphology was highly correlated with the hepatic vein, but only in the supine position. Gravitational position did not significantly affect the sphericity index or the VExUS score. Conclusions The jugular vein Doppler morphology was able to accurately distinguish low from high preload conditions in healthy volunteers. Comparisons between VExUS Doppler morphologies and other veins should occur in the supine position when gravitational pressure gradients are minimized; finally, different preload conditions in healthy subjects did not affect the VExUS score.

Ethical human subjects research requires participants to be treated safely and respectfully, yet much bioethical debate takes place without participants. We aim to address this gap in the context of controlled human infection model (CHIM) research. Based upon our own experience as study participants, and bolstered by a survey of 117 potential hepatitis C virus CHIM participants, we present ideas to inform efficient, ethical, and scientifically useful study design. We advocate for full protocol transparency, higher compensation, commitment to the rapid dissemination of study results, and proactive efforts to detail risk-minimization efforts as early as possible in the recruitment process, among other measures. We encourage researchers to proactively partner with volunteer advocacy organizations that promote collective representation of volunteers to maximize their agency, and guard against ethical issues arising from healthy human subjects research. [ABSTRACT FROM AUTHOR]

Imiquimod (IMQ) is a topical agent that induces local inflammation via the Toll-like receptor 7 pathway. Recently, an IMQ-driven skin inflammation model was developed in healthy volunteers for proof-of-pharmacology trials. The aim of this study was to profile the cellular, biochemical, and clinical effects of the marketed anti-inflammatory compound prednisolone in an IMQ model. This randomized, double-blind, placebo-controlled study was conducted in 24 healthy volunteers. Oral prednisolone (0.25 mg/kg/dose) or placebo (1:1) was administered twice daily for 6 consecutive days. Two days after treatment initiation with prednisolone or placebo, 5 mg imiquimod (IMQ) once daily for two following days was applied under occlusion on the tape-stripped skin of the back for 48 h in healthy volunteers. Non-invasive (imaging and biophysical) and invasive (skin punch biopsies and blister induction) assessments were performed, as well as IMQ ex vivo stimulation of whole blood. Prednisolone reduced blood perfusion and skin erythema following 48 h of IMQ application (95% CI [-26.4%, -4.3%], p = 0.0111 and 95% CI [-7.96, -2.13], p = 0.0016). Oral prednisolone suppressed the IMQ-elevated total cell count (95% CI [-79.7%, -16.3%], p = 0.0165), NK and dendritic cells (95% CI [-68.7%, -5.2%], p = 0.0333, 95% CI [-76.9%, -13.9%], p = 0.0184), and classical monocytes (95% CI [-76.7%, -26.6%], p = 0.0043) in blister fluid. Notably, TNF, IL-6, IL-8, and Mx-A responses in blister exudate were also reduced by prednisolone compared to placebo. Oral prednisolone suppresses IMQ-induced skin inflammation, which underlines the value of this cutaneous challenge model in clinical pharmacology studies of novel anti-inflammatory compounds. In these studies, prednisolone can be used as a benchmark. [ABSTRACT FROM AUTHOR]

Abstract Background To confirm the performance of the first hemispherical positron emission tomography (PET) for the brain (Vrain) that we developed to visualise the small nuclei in the deep brain area, we compared 18F-fluorodeoxyglucose (FDG) brain images with whole-body PET images. Methods Ten healthy male volunteers (aged 22–45 years) underwent a representative clinical whole-body PET, followed by Vrain each for 10 min. These two scans were initiated 30 min and 45 min after FDG injection (4.1 ± 0.5 MBq/kg), respectively. First, we visually identified the small nuclei and then compared their standardised uptake values (SUVs) with the participants’ age. Next, the SUVs of each brain region, which were determined by applying a volume-of-interest template for anatomically normalised PET images, were compared between the brain images with the Vrain and those with the whole-body PET images. Results Small nuclei, such as the inferior colliculus, red nucleus, and substantia nigra, were more clearly visualised in Vrain than in whole-body PET. The anterior nucleus and dorsomedial nucleus in the thalamus and raphe nucleus in the brainstem were identified in Vrain but not in whole-body PET. The SUVs of the inferior colliculus and dentate gyrus in the cerebellum positively correlated with age (Spearman’s correlation coefficient r = 0.811, p = 0.004; r = 0.738, p = 0.015, respectively). The SUVs of Vrain were slightly higher in the mesial temporal and medial parietal lobes than those in whole-body PET. Conclusions This was the first time that the raphe nuclei, anterior nuclei, and dorsomedial nuclei were successfully visualised using the first hemispherical brain PET. Trial registration Japan Registry of Clinical Trials, jRCTs032210086, Registered 13 May 2021, https://jrct.niph.go.jp/latest-detail/jRCTs032210086 .

Imiquimod (IMQ) is a topical agent that induces local inflammation via the Toll-like receptor 7 pathway. Recently, an IMQ-driven skin inflammation model was developed in healthy volunteers for proof-of-pharmacology trials. The aim of this study was to profile the cellular, biochemical, and clinical effects of the marketed anti-inflammatory compound prednisolone in an IMQ model. This randomized, double-blind, placebo-controlled study was conducted in 24 healthy volunteers. Oral prednisolone (0.25 mg/kg/dose) or placebo (1:1) was administered twice daily for 6 consecutive days. Two days after treatment initiation with prednisolone or placebo, 5 mg imiquimod (IMQ) once daily for two following days was applied under occlusion on the tape-stripped skin of the back for 48 h in healthy volunteers. Non-invasive (imaging and biophysical) and invasive (skin punch biopsies and blister induction) assessments were performed, as well as IMQ ex vivo stimulation of whole blood. Prednisolone reduced blood perfusion and skin erythema following 48 h of IMQ application (95% CI [−26.4%, −4.3%], p = 0.0111 and 95% CI [−7.96, −2.13], p = 0.0016). Oral prednisolone suppressed the IMQ-elevated total cell count (95% CI [−79.7%, −16.3%], p = 0.0165), NK and dendritic cells (95% CI [−68.7%, −5.2%], p = 0.0333, 95% CI [−76.9%, −13.9%], p = 0.0184), and classical monocytes (95% CI [−76.7%, −26.6%], p = 0.0043) in blister fluid. Notably, TNF, IL-6, IL-8, and Mx-A responses in blister exudate were also reduced by prednisolone compared to placebo. Oral prednisolone suppresses IMQ-induced skin inflammation, which underlines the value of this cutaneous challenge model in clinical pharmacology studies of novel anti-inflammatory compounds. In these studies, prednisolone can be used as a benchmark.

Excess visceral fat can accumulate owing to lack of exercise. The relationship between metabolic syndrome (MetS) and spinal range of motion (ROM) is not clear. The purpose of this study was to investigate the relationship between MetS and spinal alignment and ROM. Orthopedic evaluation was prospectively performed in 544 participants. The participants were classified into two groups on the basis of the Japanese-specific MetS criteria proposed by the Japanese Committee of the Criteria for MetS (JCCMS). Lower back pain (LBP), knee joint pain with the visual analog scale (VAS), Kellgren–Lawrence (K–L) grade for knee osteoarthritis, body mass index (BMI), and spinal alignment and ROM were evaluated. Forty-four (8.1%) were diagnosed as having MetS. The prevalence rate of K–L grade 4 in the MetS group was significantly higher than that in the non-MetS group (p < 0.05). When sex, age, and BMI were evaluated as covariates, there were significant differences in the VAS score for knee pain (non-MetS group vs MetS group: 13.7 vs 23.3, p < 0.05), L1–S1 flexion spinal ROM (44.1° vs 38.1°, p < 0.001), flexion spinal inclination angle (SIA) ROM (107.6° vs 99.3°, p < 0.01), and SIA ROM (135.4° vs 124.0°, p < 0.05). Knee pain increased and flexion spinal ROM decreased significantly in the MetS group as compared with non-MetS group. Systemic factors associated with MetS may have a specific impact on spinal ROM while promoting knee osteoarthrosis and increased knee pain. [ABSTRACT FROM AUTHOR]

Background: The venous excess ultrasound (VExUS) score is a multi-organ Doppler approach to assess venous congestion. Despite growing use of VExUS in research and clinical practice, other veins can be visualized to assess for venous hypertension, which may overcome acquisition barriers of the VExUS exam. In this pilot, observational study, we used a wearable Doppler ultrasound to assess the relationship between jugular venous Doppler and the VExUS score under different preload conditions. We hypothesized that jugular Doppler morphology would accurately distinguish preload conditions, that it would most closely relate to the hepatic venous Doppler morphology in the fully supine position and that the VExUS score would be influenced by preload condition. Results: We recruited 15 healthy volunteers with no cardiovascular history. Preload change was achieved using a tilt-table with three positions: supine, fully upright, and 30-degree head-down tilt. In each position, a VExUS score was performed; furthermore, inferior vena collapsibility and sphericity index were calculated. At the same time, jugular venous Doppler was captured by a novel, wireless, wearable ultrasound system. A continuous jugular venous Doppler morphology was 96% accurate for detecting the low preload condition. The jugular venous Doppler morphology was highly correlated with the hepatic vein, but only in the supine position. Gravitational position did not significantly affect the sphericity index or the VExUS score. Conclusions: The jugular vein Doppler morphology was able to accurately distinguish low from high preload conditions in healthy volunteers. Comparisons between VExUS Doppler morphologies and other veins should occur in the supine position when gravitational pressure gradients are minimized; finally, different preload conditions in healthy subjects did not affect the VExUS score. [ABSTRACT FROM AUTHOR]

Introduction: [18F]fluoroetoxybenzovesamicol ([18F]FEOBV) is a positron emission topography (PET) tracer for the vesicular acetylcholine transporter (VAChT), a protein located predominantly in synaptic vesicles in cholinergic nerve terminals. We aimed to use [18F]FEOBV PET to study the cholinergic topography of the healthy human brain. Materials and methods: [18F]FEOBV PET brain data volumes of healthy elderly humans were normalized to standard space and intensity-normalized to the white matter. Stereotactic atlases of regions of interest were superimposed to describe and quantify tracer distribution. The spatial distribution of [18F]FEOBV PET uptake was compared with histological and gene expression data. Results: Twenty participants of both sexes and a mean age of 73.9 ± 6.0 years, age-range [64; 86], were recruited. Highest tracer binding was present in the striatum, some thalamic nuclei, and the basal forebrain. Intermediate binding was found in most nuclei of the brainstem, thalamus, and hypothalamus; the vermis and flocculonodular lobe; and the hippocampus, amygdala, insula, cingulate, olfactory cortex, and Heschl's gyrus. Lowest binding was present in most areas of the cerebral cortex, and in the cerebellar nuclei and hemispheres. The spatial distribution of tracer correlated with immunohistochemical post-mortem data, as well as with regional expression levels of SLC18A3, the VAChT coding gene. Discussion: Our in vivo findings confirm the regional cholinergic distribution in specific brain structures as described post-mortem. A positive spatial correlation between tracer distribution and regional gene expression levels further corroborates [18F]FEOBV PET as a validated tool for in vivo cholinergic imaging. The study represents an advancement in the continued efforts to delineate the spatial topography of the human cholinergic system in vivo.

Albuvirtide (ABT) is a novel long-acting fusion inhibitor for human immunodeficiency virus type 1 (HIV-1), and may be co-administered with rifampicin (RIF) in patients concurrent with tubercle bacillus and HIV-1. This study was conducted to investigate the pharmacokinetic effect of co-administration of the two drugs. In the study, 24 healthy volunteers were randomized to receive ABT alone or with RIF. Plasma concentrations were measured using liquid chromatography-tandem mass spectrometry for RIF and competitive enzyme-linked immunosorbent assay for ABT. Co-administration with RIF increased the maximum concentration (C max ) of ABT by 6.93%, and the area under the plasma concentration-time curve (AUC) from time 0 to the last quantifiable concentration (AUC 0-t ) by 21.31%; the geometric mean ratio values (GMRs) for C max and AUC 0-t of ABT when co-administered with RIF, relative to administered alone, were 106.93% (90% confidence interval [CI] 97.53%-117.23%) and 121.31% (90% CI 108.68%-135.40%), respectively. Co-administration with ABT decreased the steady-state C max (C max,ss ) of RIF by 10.19%, and the steady-state AUC from time 0 to 24 h (AUC 0-24 h,ss ) by 19.93%; the GMRs for C max,ss and AUC 0-24 h,ss of RIF when co-administered with ABT, relative to administered alone, were 89.81% (90% CI, 79.97%-104.79%) and 80.07% (90% CI 75.68%-84.72%), respectively. The time to reach Cmax (Tmax) of both ABT and RIF demonstrated no statistically significant difference, whether administered alone or concurrently. The pharmacokinetics profiles of both RIF and ABT changed to some extent when co-administered, while no clinically significant impact on these two drugs was observed, indicating that ABT and RIF can be used together without necessitating dose adjustments., (© 2025, The American College of Clinical Pharmacology.)

BackgroundPrevious studies indicated the sedative effect of acupoint stimulation. However, its mechanism remains unclear. This study aimed to investigate the sedative effect of transcutaneous electrical acupoint stimulation (TEAS) and to explore the brain regions involved in this effect in healthy volunteers using functional magnetic resonance imaging (fMRI) techniques.MethodsIn this randomized trial, 26 healthy volunteers were randomly assigned to the TEAS group (receiving 30 min of acupoint stimulation at HT7/PC4) and the control group. fMRI was conducted before and after the intervention. The primary outcome was the BIS value during the intervention. Secondary outcomes included the amplitude of low-frequency fluctuation (ALFF) and region of interest (ROI)-based functional connectivity (FC) showed by fMRI.ResultsIn healthy volunteers, compared with the control group, ALFF values in the TEAS-treated volunteers decreased in the left thalamus, right putamen, and midbrain, while they increased in the left orbitofrontal cortex. More FC existed between the thalamus and the insula, middle cingulate cortex, somatosensory cortex, amygdala, and putamen in subjects after TEAS treatment compared with subjects that received non-stimulation. In addition, ALFF values of the thalamus positively correlated with BIS in both groups.ConclusionTranscutaneous electrical acupoint stimulation could induce a sedative effect in healthy volunteers, and inhibition of the thalamus was among its possible mechanisms.Clinical trial registrationwww.ClinicalTrials.gov; identifier: NCT01896063.

Background: To confirm the performance of the first hemispherical positron emission tomography (PET) for the brain (Vrain) that we developed to visualise the small nuclei in the deep brain area, we compared 18F-fluorodeoxyglucose (FDG) brain images with whole-body PET images. Methods: Ten healthy male volunteers (aged 22–45 years) underwent a representative clinical whole-body PET, followed by Vrain each for 10 min. These two scans were initiated 30 min and 45 min after FDG injection (4.1 ± 0.5 MBq/kg), respectively. First, we visually identified the small nuclei and then compared their standardised uptake values (SUVs) with the participants' age. Next, the SUVs of each brain region, which were determined by applying a volume-of-interest template for anatomically normalised PET images, were compared between the brain images with the Vrain and those with the whole-body PET images. Results: Small nuclei, such as the inferior colliculus, red nucleus, and substantia nigra, were more clearly visualised in Vrain than in whole-body PET. The anterior nucleus and dorsomedial nucleus in the thalamus and raphe nucleus in the brainstem were identified in Vrain but not in whole-body PET. The SUVs of the inferior colliculus and dentate gyrus in the cerebellum positively correlated with age (Spearman's correlation coefficient r = 0.811, p = 0.004; r = 0.738, p = 0.015, respectively). The SUVs of Vrain were slightly higher in the mesial temporal and medial parietal lobes than those in whole-body PET. Conclusions: This was the first time that the raphe nuclei, anterior nuclei, and dorsomedial nuclei were successfully visualised using the first hemispherical brain PET. Trial registration : Japan Registry of Clinical Trials, jRCTs032210086, Registered 13 May 2021, https://jrct.niph.go.jp/latest-detail/jRCTs032210086. [ABSTRACT FROM AUTHOR]

Patricia Muñoz-Villegas, Andrea A Navarro-Sánchez, Alejandra Sánchez-Ríos, Oscar Olvera-Montaño, Leopoldo M Baiza-Durán Medical Affairs Department, Laboratorios Sophia, S.A. de C.V., Zapopan, Jalisco, MéxicoCorrespondence: Patricia Muñoz-VillegasLaboratorios Sophia, S.A. de C.V., Paseo del Norte 5255, Guadalajara Technology Park, Zapopan, 45010, Jalisco, MéxicoTel +52 33 3001 4200, Ext: 1018Email patricia.munoz@sophia.com.mxPurpose: The purpose of this study was to evaluate the safety and tolerability profile of drugs used for treating common eye disorders when applied to normal healthy volunteers (NHVs) as explored in phase 1 trials.Subjects and Methods: A total of 166 NHVs were identified in six phase 1 trials, examined in a retrospective analysis. The primary endpoints were visual comfort (by ocular comfort index, OCI) and safety (laboratory evaluations, vital signs (VS), visual acuity (VA), intraocular pressure (IOP), lissamine green and fluorescein staining, conjunctival hyperemia, chemosis, and adverse events’ incidence (AE)).Results: Compared to baseline, 75.9%, 40.4% and 73.7% of NHV (for lubricant, hypotensive and antibiotic treatments, respectively) improved their OCI score by their final visit. Laboratory evaluations and VS were within normal ranges in 88% of NHV. Similar results were found for VA, corneal and conjunctival staining, and chemosis. IOP decreased significantly in the hypotensive agents’ group, trace to mild hyperemia was reported in 32.1%, 27.1%, and 6.8%, respectively. Additionally, lubricant and hypotensive investigational drugs (ID) had a lower risk of incidence of AE than approved drugs (OR 0.856, 95% CI [0.365, 1.999] and 0.636, 95% CI [0.096, 4.197], respectively). Meanwhile, on antibiotic drugs, the risk for ID-related AE was higher (OR 1.313, 95% CI [0.309, 5.583]).Conclusion: Phase 1 trials are important in order to ensure the safety and tolerability of ophthalmic medications. This study demonstrates that NHVs do not face a significant risk of harm in these studies, since 98% of the reported AE were mild, and all AE were resolved by the end of the study in which they appeared.Trial Registration: This is a retrospective study of six previously conducted clinical trials, registered on clinicaltrials.gov with the following registration IDs: NCT04081610, NCT03524157, NCT03520348, NCT03966365, NCT03965052 and, NCT03519516.Keywords: healthy volunteer, phase 1 trial, safety, tolerability, ophthalmic drug

Clinical development of Ebola virus vaccines (EVV) was accelerated by the West African Ebola virus epidemic which remains the deadliest in history. To compare and rank the EVV according to their immunogenicity and safety. A total of 21 randomized controlled trial, evaluating seven different vaccines with different doses, and 5,275 participants were analyzed. The rVSVΔG-ZEBOV-GP (2 × 10 7) vaccine was more immunogenic (P-score 0.80). For pain, rVSVΔG-ZEBOV-GP (≤10 5) had few events (P-score 0.90). For fatigue and headache, the DNA-EBOV (≤ 4 mg) was the best one with P-scores of 0.94 and 0.87, respectively. For myalgia, the ChAd3 (10 10) had a lower risk (P-score 0.94). For fever, the Ad5.ZEBOV (≤ 8 × 10 10) was the best one (P-score 0.80). The best vaccine to be used to stop future outbreak of Ebola is the rVSVDG-ZEBOV-GP vaccine at dose of 2 × 107 PFU.

Introduction: The six-minute walk test is a sub-maximal exercise test used in clinical populations to determine functional exercise capacity. It is a safe, simple, and inexpensive test. There are a number of reference equations described for estimating six-minute walk distance in healthy subjects in different countries. However, there is a lack of standard reference value for six minute walk distance in healthy Nepalese population. The aim of the study was to find the mean six minute walk distance of healthy healthcare workers of a tertiary care centre. Methods: A descriptive cross-sectional study was conducted among healthy health care workers of a tertiary care centre from 1 August 2021 to 30 November 2021 after taking ethical approval from Institutional Review Committee (Reference number: 1507202105). Convenience sampling was done. Point estimate and 95% Confidence Interval were calculated. Results: The mean six-minute walk distance of the 162 healthy health care workers was 486.74±74.73 (475.23–498.24, 95% Confidence Interval) m. Men walked 519.61±79.19 m and women walked 474.12±75.62 m. The mean age of the participants was 29.25±8.25 years. Conclusions: The mean six-minute walk distance was found to be lower when compared to similar studies conducted in similar settings.

Introduction: In this study, we aimed to investigate how the normal values of optic nerve sheath diameter are distributed in normal healthy volunteers in Turkish population. Materials and Methods: This prospective study was planned between November 15, 2019 and April 15, 2020. The study included 160 healthy volunteers who were over 18 years of age and didn’t have acute and chronic systemic disorders. The optic nerve sheath diameters (ONSD) of the subjects were measured from both eyes ultrasonographically. Results: ONSD means (median, IQR) of right and left eyes of the subjects were measured as 4.87 (0.41) mm and 4.86 (0.32) mm, respectively. Right and left eye ONSD measurements were detected lower in female gender than men, and this difference was statistically significant. (p = 0.017 and p = 0.031, respectively). Conclusion: Determination of ONSD optimal reference values in healthy individuals would benefit in predicting increase in intracranial pressure in clinical practice.

In an asymptomatic 19-year-old who regularly underwent cardiopulmonary fitness testing for national lifeguard-accreditation, 129Xe MRI unexpectedly revealed an abnormally augmented RBC signal and RBC-to-alveolar-capillary-tissue ratio with spatially homogeneous ventilation, tissue barrier, and RBC images. Pulmonary function was normal, but cardiopulmonary follow-up including transthoracic and transesophageal echocardiogram, heart catheterization, and contrast-enhanced cardiac CT imaging led to the diagnosis of a large (20 × 27 mm) secundum atrial septal defect (ASD) with a net right-to-left shunt (Qp:Qs = 0.5) and normal pulmonary pressures. This novel, unexpected case revealed that 129Xe RBC signal intensity likely reflected erythrocytosis, compensatory to the abnormal cardiovascular hemodynamics that resulted from a large congenital ASD. Unlike ASD cases that present with dyspnea and exercise limitation, this 129Xe MRI abnormality was detected in an asymptomatic teenager. This is the first report of asymptomatic adult congenital heart disease diagnosed subsequent to novel 129Xe MRI that led to early intervention, avoiding long-term complications of cyanosis, including ventricular fibrosis and thromboembolic and bleeding risks. [ABSTRACT FROM AUTHOR]

Fecal calprotectin (FC) is a marker used for the differential diagnosis of inflammatory bowel disease (IBD). FC is also used to determine the effects of treatment and recurrence prediction because of its non-decomposition by bacteria, relative week stability at room temperature, and its uniform distribution within feces. Healthy male and female adults between the age of 30 and 80 living in Jeju were selected for this study. The FC concentration in the healthy control group (N=45) was distributed widely as 0∼545.9 μg/g and showed a significant difference with age in healthy adults. The FC concentration in adults over 70 years old (80.6 years on average) was 160.3 μg/g. The result is approximately 10 times higher than in adults below 50 years (44 years on average), with FC concentrations at 15.88 μg/g. Moreover, adults over 50 years, with an average age of 59.6, had FC concentrations of 35.46 μg/g, which were two times higher than the below 50-year-old group, confirming the significant correlation between age and FC concentration. As the FC test is a non-invasive and cost-effective objective marker in IBD tests, a suitable cut-off value is required for different ages. This study provides the baseline data for differential diagnoses.

BackgroundSodium–glucose co-transport 2 inhibitors (SGLT2i) lower blood pressure (BP) in normotensive subjects and in hypertensive and normotensive diabetic and non-diabetic patients. However, the mechanisms of these BP changes are not fully understood. Therefore, we examined the clinical and biochemical determinants of the BP response to empagliflozin based on 24-h ambulatory BP monitoring.MethodsIn this post-hoc analysis of a double-blind, randomized, placebo-controlled study examining the renal effects of empagliflozin 10 mg vs. placebo in untreated normotensive non-diabetic subjects, the 1-month changes in 24 h ambulatory BP were analyzed in 39 subjects (13 placebo/26 empagliflozin) in regard to changes in biochemical and hormonal parameters.ResultsAt 1 month, empagliflozin 10 mg decreased 24-h systolic (SBP) and diastolic (DBP) BP significantly by −5 ± 7 mmHg (p < 0.001) and −2 ± 6 mmHg (p = 0.03). The effect on SBP and DBP was more pronounced during nighttime (resp. −6 ± 11 mmHg, p = 0.004; −4 ± 7 mmHg, p = 0.007). The main determinants of daytime and nighttime SBP and DBP responses were baseline BP levels (for daytime SBP: coefficient −0.5; adj. R2: 0.36; p = 0.0007; for night-time SBP: coefficient −0.6; adj. R2: 0.33; p = 0.001). Although empaglifozin induced significant biochemical changes, none correlated with blood pressure changes including urinary sodium, lithium, glucose and urate excretion and free water clearance. Plasma renin activity and plasma aldosterone levels increased significantly at 1 month suggesting plasma volume contraction, while plasma metanephrine and copeptin levels remained the same. Renal resistive indexes did not change with empagliflozin.ConclusionSGLT2 inhibition lowers daytime and nighttime ambulatory systolic and diastolic BP in normotensive non-diabetic subjects. Twenty-four jour changes are pronounced and comparable to those described in diabetic or hypertensive subjects. Baseline ambulatory BP was the only identified determinant of systolic and diastolic BP response. This suggests that still other factors than sustained glycosuria or proximal sodium excretion may contribute to the resetting to lower blood pressure levels with SGLT2 inhibition.Clinical Trial Registration:[https://www.clinicaltrials.gov], identifier [NCT03093103].

Aim: Hybrid mattresses are increasingly being used in UK healthcare due to their ability to be rapidly switched from a reactive mode to providing active alternating therapy. This study investigated a new hybrid mattress designed to automatically switch from its reactive to active mode where a person remains immobile for at least 60 minutes. Methods: Healthy volunteers rested upon the test mattress for 90 minutes remaining relatively immobile for the first hour. After 61 or 62 minutes of immobility the mattress switched to its active mode for each volunteer. Pressure measurements were performed using a pressure map during the 90-minute session. Results: We recruited 10 healthy volunteers. These data were heterogeneous, and in the absence of a control mattress surface challenging to interpret. The two volunteers with the highest body mass index (BMI) >30 both experienced malfunctions of the pressure map system. Conclusion: The link between BMI and the functioning of the pressure map requires further investigation. [ABSTRACT FROM AUTHOR]

Background: Dysphagia can result from shock, trauma, aging, head and neck neoplasms, and some cerebrovascular diseases or neuromotor degenerative disorders. Swallowing rehabilitation therapy combined with postural control of the neck, head, and body can be effective for patients with dysphagia. Though the lateral decubitus posture has been a favorable option for swallowing rehabilitation therapy, available clinical data pertaining to it are scarce. Methods: Twenty-seven healthy volunteers were enrolled in this study. The subjects underwent a repetitive saliva swallowing test, food swallowing test, and water swallowing test. The trials were performed in four different positions: upright sitting position, lateral decubitus position with the head raised to 60°, lateral decubitus position with the head raised to 30°, and complete lateral decubitus position. After each trial, the subjects were asked to declare the swallowing difficulty utilizing a visual analogue scale. Swallowing time and swallowing sound level were recorded simultaneously, as objective evaluation in each trial. We analyzed the visual analogue scale scores, swallowing time, and swallowing sound levels for all the four positions. Results: The results of the visual analogue scale of the water swallowing test in the sitting position were significantly lower than those of the complete lateral decubitus position (p < 0.01). However, statistical significance was not detected in swallowing time or the swallowing sound level among the four different positions. Although subjective discomfort in swallowing was identified, difficulty of swallowing was not objectively evident in the trials, irrespective of the position. Conclusions: A complete lateral decubitus position can be an effective and safe position in swallowing. [ABSTRACT FROM AUTHOR]

Aims: Dysregulation of histone methylation epigenetic marks may result in intellectual and developmental disability, as seen in Kabuki syndrome. Animal data suggest that increasing histone methylation by inhibiting lysine‐specific demethylase 1A (LSD1) may improve cognitive outcomes in a model of Kabuki syndrome. TAK‐418 is a novel LSD1 inhibitor, developed as a potential therapeutic agent for central nervous system disorders such as Kabuki syndrome. Here, we report safety, tolerability, pharmacokinetic and pharmacodynamic profiles of single and multiple doses of TAK‐418 (ClinicalTrials.gov: NCT03228433, NCT03501069). Methods: Two randomized, double‐blind, placebo‐controlled, phase 1 studies of oral TAK‐418 were performed, a first‐in‐human single‐rising‐dose (SRD) study (5–60 mg) in healthy adult male and female volunteers (placebo, n = 10; TAK‐418, n = 30), and an SRD (120–160 mg) and multiple‐rising‐dose (MRD) study (20–160 mg once daily for 10 days) in healthy female volunteers (placebo, n = 2 [SRD] and n = 6 [MRD]; TAK‐418, n = 6 [SRD] and n = 18 [MRD]). Results: TAK‐418 was well tolerated. No clinically significant changes in laboratory test results or vital signs were observed and no serious adverse events were reported. TAK‐418 had a nearly linear pharmacokinetic profile, with rapid absorption and short terminal half‐life across the evaluated dose range. No obvious accumulation was observed after daily administration for 10 days. Administration with food delayed peak plasma concentrations but overall exposure was unaffected. TAK‐418 rapidly crossed the blood–brain barrier and generally showed a dose‐dependent response in the peripheral pharmacodynamic biomarker formyl‐flavin adenine dinucleotide. Conclusion: The brain‐penetrant LSD1 inhibitor TAK‐418 was well tolerated, with pharmacokinetic and pharmacodynamic effects that support further investigation. [ABSTRACT FROM AUTHOR]

Background: Studies suggest that d-cycloserine (DCS) may have antidepressant potential through its interaction with the glycine site of the N-methyl-D-aspartate receptor; however, clinical evidence of DCS's efficacy as a treatment for depression is limited. Other evidence suggests that DCS affects emotional learning which may also be relevant for the treatment of depression and anxiety. The aim of the present investigation was to assess the effect of DCS on emotional processing in healthy volunteers and to further characterise its effects on emotional and autobiographical memory. Methods: Forty healthy volunteers were randomly allocated to a single dose of 250 mg DCS or placebo in a double-blind design. Three hours later, participants performed an Emotional Test Battery [including Facial Expression Recognition Task (FERT), Emotional Categorisation Task (ECAT), Emotional Recall Task (EREC), Facial Dot-Probe Task (FDOT) and Emotional Recognition Memory Task (EMEM)] and an Autobiographical Memory Test (AMT). Also, participants performed the FERT, EREC and AMT tasks again after 24 h in order to assess longer lasting effects of a single dose of DCS. Results: DCS did not significantly affect the FERT, EMEM and FDOT performance but significantly increased emotional memory and classification for positive words v. negative words. Also, DCS enhanced the retrieval of more specific autobiographical memories, and this effect persisted at 24 h. Conclusions: These findings support the suggestion that low-dose DCS increases specific autobiographical memory retrieval and positive emotional memory. Such effects make it an intriguing agent for further investigation in clinical depression, which is characterised by decreased autobiographical memory specificity and increased negative bias in memory recall. It also underscores the potential role of DCS as an adjunct to cognitive behavioural therapy in depression. [ABSTRACT FROM AUTHOR]

The roots of Eurycoma longifolia, Jack has a lot of beneficial activity on human health. The use of Eurycoma longifolia, Jack roots as a traditional medicine should be made in the form of a dosage that is more effective, safe, and had no side effects, especially on hematology. Easy preparations are capsule. This study aimed at identifying the effect of ethanol extract capsule of Eurycoma longifolia, Jack roots on hematology of healthy volunteers. Healthy volunteers were assigned in the study, each of which were 10 male and 10 female who met the inclusion criteria. Both groups were given ethanol extract capsule of Eurycoma longifolia, Jack roots for 14 days, with the dose of 300 mg extract once a day, after meal, at night. Hematology examination was performed on day 0; 14 and 42. Results were compared statistically using Repeated ANOVA and Friedman tests. The result of the study indicated that the average value of hematology at the examination day of 0; 14; and 42, there were significant differences in MCV and leukocyte parameters in healthy male volunteers (p

Background: Though Maytenus senegalensis is one of the medicinal plants widely used in traditional medicine to treat infectious and inflammatory diseases in Africa, there is a lack of safety data regarding its use. Therefore, the study aimed to asselss the safety and tolerability of the antimalarial herbal remedy M. senegalensis. Material and Methods: The study design was an open-label, single-arm, dose-escalation. Twelve eligible male healthy Tanzanians aged 18 to 45 years were enrolled in four study dose groups. Volunteers’ safety and tolerability post-investigational-product administration were monitored on days 0 to 7,14, and 56. Results: There were no deaths or serious adverse events in any of the study groups, nor any adverse events that resulted in premature discontinuation. The significant mean changes observed in WBC (p = 0.003), Neutrophils (p = 0.02), Lymphocytes (p = 0.001), Eosinophils (p = 0.009), Alanine aminotransferase (p = 0.002), Creatinine (p = 0.03) and Total bilirubin (p = 0.004) laboratory parameters were not associated with any signs of toxicity or clinical symptoms. Conclusions: M. senegalensis was demonstrated to be safe and tolerable when administered at a dose of 800 mg every eight hours a day for four days. This study design may be adapted to evaluate other herbal remedies.

Objective: Compressed sensing (CS) and parallel imaging (PI) are magnetic resonance (MR) imaging acceleration techniques. Image quality of two-dimensional fast spin echo imaging of the oral cavity using CS or combined CS and PI has not been evaluated. The aim of this study was to compare the acquisition time and image quality between T2-weighted imaging (T2WI) with CS and PI (CSPI-T2WI) and T2WI with PI (PI-T2WI) of the oral cavity. Materials and methods: Twenty healthy volunteers who underwent CSPI-T2WI and PI-T2WI of the oral cavity on a 3 T MR scanner were enrolled in the study. Contrast ratios of fat/muscle and bone/muscle on CSPI-T2WI and PI-T2WI were measured. Overall image quality, 4 kinds of artifacts, and visualization of 18 anatomical structures were independently evaluated by two radiologists with grading scales. The quantitative and qualitative measurements were compared between CSPI-T2WI and PI-T2WI by using the Wilcoxon signed-rank test. Results: Mean acquisition time of CSPI-T2WI and PI-T2WI was 72 s and 136 s, respectively (p <.001). CSPI-T2WI showed a significantly higher contrast ratio of fat/muscle than PI-T2WI (p <.01). There were no significant differences in the overall image quality, artifacts, and visualization of anatomical structures between CSPI-T2WI and PI-T2WI. Conclusions: CSPI-T2WI of the oral cavity in healthy volunteers can provide a reduction in acquisition time without impaired image quality compared to PI-T2WI. Key Points: • The acquisition time of T2WI with the combined CS and PI provided a 47% reduction in acquisition time compared with T2WI with PI. • T2WI with the combined CS and PI did not show impaired image quality compared with T2WI with PI. • Combined CS and PI can be a useful technology to evaluate the oral cavity with high-speed acquisition. [ABSTRACT FROM AUTHOR]

We determined normative data for plasma cytokines established from a cohort of 126 carefully screened healthy adults aged 18 to 64 years. Participants were enrolled to ensure an even age and sex distribution and to include at least 30% non-Caucasians. Plasma cytokines for 18 analytes were tested by multiplex immunoassay. The data are presented by age cohort (18–29 years, 30–39, 40–49, and 50–66), as well as by sex and racial background. This dataset complements published normative ranges of cellular subsets generated by comprehensive polychromatic flow cytometry analysis of the healthy human immune system [1]. These data are available to researchers and have value as a reference range for research involving peripheral cytokines.

Abstract Background With the exception of genotoxic oncology drugs, first-in-human, Phase 1 clinical studies of investigational drugs have traditionally been conducted in healthy volunteers (HVs). The primary goal of these studies is to investigate the pharmacokinetics and pharmacodynamics of a novel drug candidate, determine appropriate dosing, and document safety and tolerability. Main body When tailored to specific study objectives, HV studies are beneficial to manufacturers and patients alike and can be applied to both non-oncology and oncology drug development. Enrollment of HVs not only increases study accrual rates for dose-escalation studies but also alleviates the ethical concern of enrolling patients with disease in a short-term study at subtherapeutic doses when other studies (e.g. Phase 2 or Phase 3 studies) may be more appropriate for the patient. The use of HVs in non-oncology Phase 1 clinical trials is relatively safe but nonetheless poses ethical challenges because of the potential risks to which HVs are exposed. In general, most adverse events associated with non-oncology drugs are mild in severity, and serious adverse events are rare, but examples of severe toxicity have been reported. The use of HVs in the clinical development of oncology drugs is more limited but is nonetheless useful for evaluating clinical pharmacology and establishing an appropriate starting dose for studies in cancer patients. During the development of oncology drugs, clinical pharmacology studies in HVs have been used to assess pharmacokinetics, drug metabolism, food effects, potential drug–drug interactions, effects of hepatic and renal impairment, and other pharmacologic parameters vital for clinical decision-making in oncology. Studies in HVs are also being used to evaluate biosimilars versus established anticancer biologic agents. Conclusion A thorough assessment of toxicity and pharmacology throughout the drug development process is critical to ensure the safety of HVs. With the appropriate safeguards, HVs will continue to play an important role in future drug development.

Jie Huang,1,2,* Cheng-xiao Fu,1,2,* Xiao-yan Yang,1,2 Chan Cui,1,2 Shuang Yang,1,2 Yun Kuang,1,2 Cheng-xian Guo,1,2 Pei Hu,3 Qi Pei,2,4 Guo-ping Yang1,2 1Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, People’s Republic of China; 2Center for Clinical Drug Evaluation, Central South University, Changsha, Hunan 410013, People’s Republic of China; 3Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing 100032, People’s Republic of China; 4Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, People’s Republic of China *These authors contributed equally to this work Purpose: To determine the pharmacokinetic properties of the common tablet of roflumilast administered in single and multiple oral doses in Chinese subjects.Subjects and methods: Both the single- and multiple-dose studies included 12 adults (6 males and 6 females). In this single-center, open-label study, single doses of 0.25, 0.375, and 0.5 mg were administered using a randomized, three-way crossover design, and then, the 0.375 mg dose was continued for 11 days once daily. The pharmacokinetic parameters for roflumilast and roflumilast N-oxide were determined and the safety evaluation included adverse events assessed by monitoring, physical examination, vital sign tests, and clinical laboratory tests.Results: After every single dose, the time to the maximum concentration (Cmax) of roflumilast (Tmax) was 0.25–2.0 hours; thereafter, the concentration declined, with a mean half-life (t1/2) of 19.7–20.9 hours over the range of 0.25–0.50 mg. As for roflumilast N-oxide, the mean t1/2 was 23.2–26.2 hours. The area under curve from the beginning to 24 hours (AUC0–24 h), the AUC until infinity (AUCinf), and the Cmax of roflumilast and roflumilast N-oxide increased in a dose-proportional manner. After multiple doses, the accumulation index (Rac) on the 11th day of the steady state was ~1.63 for roflumilast and 3.20 for roflumilast N-oxide. No significant sex differences were observed in the pharmacokinetic parameters of roflumilast and roflumilast N-oxide. In addition, there were no serious adverse events across the trial.Conclusion: Roflumilast was safe and well-tolerated in healthy volunteers, and a linear increase in its Cmax and AUC values was observed at doses ranging from 0.25 to 0.50 mg. Keywords: pharmacokinetics, roflumilast, roflumilast N-oxide, healthy volunteer, phosphodiesterase 4 inhibitor

David A Brott,1 Michael J Goodman,1 Richard P Hermann,1 Michael Merz,2 Roser Calvo,1 Nadereh Poorkhalkali,3 Alexandre Kiazand1 1Patient Safety, Safety Science, AstraZeneca Pharmaceuticals, Gaithersburg, MD, USA; 2Patient Safety, Safety Science, AstraZeneca Pharmaceuticals, Webel, Germany; 3Patient Safety, Safety Science, AstraZeneca Pharmaceuticals, Gothenburg, Sweden Background: Liver biomarkers alanine aminotransferase (ALT) and bilirubin in patients with hepatitis are above the healthy volunteer reference range (HVRR) at baseline (prior to receiving the clinical trial medication). Discussions continue as how to best distinguish drug-induced liver injury in patients with abnormal baseline values participating in clinical trials. This study investigated if other baseline routine clinical safety biomarkers (lab parameters) are different from the HVRR. Materials and methods: Clinical trial data (TransCelerate dataset) from placebo and standard of care treated patients were compared to the HVRR using a 10% threshold above or below the HVRR to classify a lab parameter in a patient population as potentially different from the HVRR at baseline. The TransCelerate dataset, batch 4, contained data from patients with Alzheimer’s, asthma, COPD, cardiovascular disease, diabetes, hidradenitis, hypercholesterolemia, rheumatoid arthritis, schizophrenia, stroke, and ulcerative colitis. A subset of the 200 biomarkers in TransCelerate were evaluated in this pilot: glucose, platelet count, neutrophil count, ALT, aspartate aminotransferase (AST), and bilirubin. Results: Glucose was potentially higher than the HVRR in patients with diabetes, COPD, cardiovascular disease, hypercholesterolemia, and schizophrenia. At least one or more of the hematology and hepatic biomarkers were different from the HVRR in at least one patient population, except bilirubin. All the patient populations, except Alzheimer’s and asthma, had at least one biomarker that was higher than the HVRR. Summary: The routine biomarkers evaluated in this pilot study demonstrated that not all lab parameters in patient populations are similar to the HVRR. Further efforts are needed to determine which biomarkers are different from the HVRR and how to evaluate the biomarkers in patient populations for detecting drug-induced altered lab values in clinical trials. Keywords: patient populations, reference range, healthy volunteer, biomarkers

Rationale: Previous research suggests that sleep polysomnography and EEG endpoints can be used to assess GABAergic activity; however, the impact of GABAB receptor positive allosteric modulators on sleep endpoints remains unclear. Objectives: This phase 1 study compared a single dose of ASP8062 (35 mg or 70 mg), a GABAB receptor positive allosteric modulator, with placebo and paroxetine (40 mg). Methods: Healthy adult volunteers were randomized to four treatments (35 mg ASP8062, 70 mg ASP8062, paroxetine 40 mg, or matching placebo), each separated by a 14-day washout. Primary endpoints obtained by polysomnography were time in stage N3 or SWS and time in rapid eye movement (REM) sleep. Secondary endpoints included impact on sleep stages and electroencephalography parameters, pharmacokinetics, nighttime growth hormone (GH), and safety/tolerability. Results: In 20 randomized volunteers, ASP8062 led to a significant and seemingly dose-dependent increase in SWS over the entire night; this increase was mainly observed during the first third of the night. ASP8062 did not impact time in REM sleep. Paroxetine had no effect on SWS but produced a significant reduction in time spent in REM sleep. A dose-dependent trend in increased GH release was also observed with ASP8062. Headache and nausea were the most commonly reported treatment-emergent adverse events (TEAEs) for ASP8062; most TEAEs were mild in severity. Conclusions: Single-dose ASP8062 (35 and 70 mg) appeared to result in CNS penetration and enhanced GABAergic activity as measured by increases in slow-wave sleep and growth hormone release. [ABSTRACT FROM AUTHOR]

Introduction: Few studies have evaluated whether the pharmacokinetics of N-acetyl-cysteine (NAC) are different in Chinese and Caucasian individuals.Methods: This single- and multiple-dose, single-centre, open-label, phase I clinical study was conducted in healthy adult volunteers. All participants received oral NAC 600-mg uncoated tablets, which were administered first as a single dose and, following a 48-h wash-out period, twice daily for 3 days. Blood and urine were collected after single- and multiple-dose NAC administration. Adverse event (AE) data were collected throughout the study.Results: Fifteen Chinese and 15 Caucasian (mostly Italian) individuals (males 66.7%, mean age 36.8 years) participated in the study. Pharmacokinetic characteristics of NAC were similar in the two cohorts. Following both single- and multiple-dose administration, plasma concentration of NAC increased rapidly, reaching a peak at approximately 1.0 h. Maximum plasma concentration and extent of exposure were higher after multiple doses than after a single dose. The accumulation ratio was relatively consistent in both Chinese (mean ± standard deviation 1.5 ± 0.4) and Caucasian (1.4 ± 0.2) participants. The half-life was 15.4 h in Chinese and 18.7 h in Caucasian participants, and the fraction of NAC excreted in urine in the 36 h following administration was 3.7% in Chinese and 3.8% in Caucasian participants. Two Caucasian participants had a total of 3 AEs (headache, presyncope and dysmenorrhoea). No AEs occurred in Chinese participants.Conclusions: The pharmacokinetic characteristics of NAC are similar in healthy Chinese and Caucasian individuals after single and repeated administration. NAC has a favourable tolerability profile. [ABSTRACT FROM AUTHOR]