Biological variation of methylmalonic acid in urine in spanish population.

BACKGROUND-AIM: Methylmalonic acid (MMA) is currently the best biomarker of functional vitamin B12 deficiency. However, for a correct interpretation of the patient's results it is necessary to know its biological variation (BV). No BV data are available for urine MMA values, as measured by mass spectrometry. Hence, the aim of this study was to estimate the within- and between-person coefficients of variation (CVw, CVg) for MMA in a healthy population, and the associated index of individuality (II), as well as to define quality specifications based on BV and the reference change value (RCV). METHODS: Random urine samples from 34 healthy volunteers were collected over four consecutive weeks. Samples were stored at -80 °C until analysis in a single analytical run. MMA excretion was quantified by tandem liquid chromatography coupled to mass spectrometry (HPLC-MS/MS). Results were normalized to urine creatinine. The coefficients of variation were estimated by CV-ANOVA. Confidence intervals (95 %) were calculated. Quality specifications were defined according to international recommendations. RESULTS: A total of 128 samples were included. The coefficients of variation were CVw = 35.7 % (26.1-45.3) and CVg = 67.7 % (58.3-77.0). The associated II was 0.5 and the RCV was 88.1 %. CONCLUSION: Considering the II obtained, MMA in urine has high individuality, therefore, RCV is better to evaluate serial clinical results. Our results will contribute to a better clinical interpretation of this biomarker and will represent a great aid when defining analytical performance specifications for this magnitude.

Evaluation of low volume sampling devices for a pharmacodynamic biomarker analysis: Challenges and solutions.

Low volume sampling technologies have gained popularity as they are minimally invasive, reduce patient burden, enhance population diversity, and have the potential to facilitate decentralized clinical trials. Herein, we validated a Gyrolab assay to measure soluble Mucosal Addressin Cell Adhesion Molecule 1 (sMAdCAM-1) in dried blood samples collected using two low volume sampling devices, Mitra and Tasso-M20. This validated assay was implemented in a proof-of-concept study to compare three low volume sampling devices (Mitra, Tasso-M20 and TassoOne Plus) with serum collected via venipuncture from healthy volunteers receiving etrolizumab. We observed significantly higher concentration of sMAdCAM-1 in dried blood samples collected using Mitra and Tasso-M20 compared to serum in some paired samples, which was attributed to interference from the dried blood extraction buffer. To mitigate this interference, samples required substantial dilution into the appropriate buffer, which negatively impacted the detectability of sMAdCAM-1 with the Gyrolab assay. By employing the Quanterix single molecule array (Simoa), known for its superior assay sensitivity, the interference was minimized in the diluted samples. Both liquid blood collected in TassoOne Plus and dried blood collected using Mitra and Tasso-M20 demonstrated great concordance with serum for sMAdCAM-1 measurement. However, a bias was observed in Mitra dried blood samples, presumably due to the different sample collection sites in comparison with venipuncture and Tasso devices. Our study highlights the potential of low volume sampling technologies for biomarker analysis, and underscores the importance of understanding the challenges and limitations of these technologies before integrating them into clinical studies.

Randomized, placebo-controlled study on the effects of intravenous GSK3858279 (anti-CCL17) on a battery of evoked pain tests in healthy participants.

C-C Motif Chemokine Ligand 17 (CCL17) is a chemokine that binds and signals through the G-protein coupled CC-chemokine receptor 4 and has been implicated in the development of inflammatory and arthritic pain. GSK3858279 is a high-affinity, first-in-class, monoclonal antibody, binding specifically to CCL17 and inhibiting downstream signaling. In this phase I, randomized, single-center, double-blind, placebo-controlled, three-period, incomplete-block crossover study (NCT04114656), the analgesic effects and safety of intravenous GSK3858279 were assessed in a battery of evoked acute pain assessments on healthy, adult (aged ≥18 years), male participants. Participants were randomized 1:1 to receive either one placebo (0.9% w/v NaCl) dose followed by two GSK3858279 doses (PAA treatment sequence), or one GSK3858279 dose followed by two placebo doses (APP treatment sequence). The co-primary end points were ultraviolet B heat pain detection threshold (°C), cold pressor time to pain tolerance threshold (PTT, sec), and electrical PTT (mA, single stimulus). Twenty-one participants were enrolled (PAA = 11; APP = 10). Mean age (standard deviation) was 29.3 (7.9) years for PAA, 31.1 (7.7) years for APP. No significant differences were observed in the analgesic effect between GSK3858279 and placebo for any end point. Exposure to GSK3858279 was similar between Period 1 (APP sequence), and Periods 2 and 3 (PAA sequence), with some GSK3858279 carry-over. Changes in serum CCL17 levels were consistent with the expected GSK3858279 activity. All drug-related adverse events were mild in intensity and caused no discontinuations. The absence of an efficacy signal in this acute pain model does not preclude efficacy in chronic pain states.

Association between endothelial function and skin advanced glycation end-products (AGEs) accumulation in a sample of predominantly young and healthy adults.

BACKGROUND: In populations with chronic disease, skin autofluorescence (SAF), a measure of long-term fluorescent advanced glycation end-products (AGEs) accumulation in body tissues, has been associated with vascular endothelial function, measured using flow-mediated dilation (FMD). The primary aim of this study was to quantify the relationship between endothelial function and tissue accumulation of AGEs in adults from the general population to determine whether SAF could be used as a marker to predict early impairment of the endothelium. METHODS: A cross-sectional study was conducted with 125 participants (median age: 28.5 y, IQR: 24.4-36.0; 54% women). Endothelial function was measured by fasting FMD. Skin AGEs were measured as SAF using an AGE Reader. Participant anthropometry, blood pressure, and blood biomarkers were also measured. Associations were evaluated using multivariable regression analysis and were adjusted for significant covariates. RESULTS: FMD was inversely correlated with SAF (ρ = -0.50, P < 0.001) and chronological age (ρ = -0.51, P < 0.001). In the multivariable analysis, SAF, chronological age, and male sex were independently associated with reduced FMD (B [95% CI]; -2.60 [-4.40, -0.80]; -0.10 [-0.16, -0.03]; 1.40 [0.14, 2.67], respectively), with the multivariable model adjusted R2 = 0.31, P < 0.001. CONCLUSIONS: Higher skin AGE levels, as measured by SAF, were associated with lower FMD values, in a predominantly young, healthy population. Additionally, older age and male participants exhibited significantly lower FMD values, corresponding with compromised endothelial function. These results suggest that SAF, a simple and inexpensive marker, could be used to predict endothelial impairment before the emergence of any structural artery pathophysiology or classic cardiovascular disease risk markers. TRIAL REGISTRATION: The study was prospectively registered with the Australian New Zealand Clinical Trials Registry (ACTRN12621000821897) and concurrently entered into the WHO International Clinical Trials Registry Platform under the same ID number.

The Effect of Power Grip on Ulnar Variance A Computed Tomography Study of the Wrist and Elbow.

Although an increase in ulnar variance with power grip is well documented in the medical literature, there is a paucity of information concerning its mechanism. This concept was examined in five healthy individuals using computed tomography of their wrists and elbows. Images were obtained of both joints in the resting position and with maximum power grip. Ulnar variance at the wrist increased an average of 0.64 mm (range: 0.3 to 1.2 mm). While the ulnohumeral joint remained unchanged, the radiocapitellar distance shortened an average of 0.62 mm (range: 0.3 to 1.0 mm; p = 0.03), which correlated directly with the change at the wrist. Our study showed that the increase in ulnar variance with grip was due to proximal shift of the radius and not to any distal migration of the ulna, which may have clinical implications in reconstruction or arthroplasty of the elbow.

Characterizing Presumed Displaced Retinal Ganglion Cells in the Living Human Retina of Healthy and Glaucomatous Eyes.

Purpose: The purpose of this study was to investigate the large somas presumed to be displaced retinal ganglion cells (dRGCs) located in the inner nuclear layer (INL) of the living human retina. Whereas dRGCs have previously been studied in mammals and human donor tissue, they have never been investigated in the living human retina. Methods: Five young, healthy subjects and three subjects with varying types of glaucoma were imaged at multiple locations in the macula using adaptive optics optical coherence tomography. In the acquired volumes, bright large somas at the INL border with the inner plexiform layer were identified, and the morphometric biomarkers of soma density, en face diameter, and spatial distribution were measured at up to 13 degrees retinal eccentricity. Susceptibility to glaucoma was assessed. Results: In the young, healthy individuals, mean density of the bright, large somas was greatest foveally (550 and 543 cells/mm2 at 2 degrees temporal and nasal, respectively) and decreased with increasing retinal eccentricity (38 cells/mm2 at 13 degrees temporal, the farthest we measured). Soma size distribution showed the opposite trend with diameters and size variation increasing with retinal eccentricity, from 12.7 ± 1.8 µm at 2 degrees to 15.7 ± 3.5 µm at 13 degrees temporal, and showed evidence of a bimodal distribution in more peripheral locations. Within and adjacent to the arcuate defects of the subjects with glaucoma, density of the bright large somas was significantly lower than found in the young, healthy individuals. Conclusions: Our results suggest that the bright, large somas at the INL border are likely comprised of dRGCs but amacrine cells may contribute too. These somas appear highly susceptible to glaucomatous damage.

Distinct and additive effects of visual and vibratory feedback for motor rehabilitation: an EEG study in healthy subjects.

INTRODUCTION: The use of visual and proprioceptive feedback is a key property of motor rehabilitation techniques. This feedback can be used alone, for example, for vision in mirror or video therapy, for proprioception in focal tendon vibration therapy, or in combination, for example, in robot-assisted training. This Electroencephalographic (EEG) study in healthy subjects explored the distinct neurophysiological impact of adding visual (video therapy), proprioceptive (focal tendinous vibration), or combined feedback (video therapy and focal tendinous vibration) to a motor imagery task. METHODS: Sixteen healthy volunteers performed 20 mental imagery (MI) tasks involving right wrist extension and flexion under four conditions: MI alone (IA), MI + video feedback observation (IO), MI + vibratory feedback (IV), and MI + observation + vibratory feedback (IOV). Brain activity was monitored with EEG, and time-frequency neurophysiological markers of movement were computed. The emotions of the patients were also measured during the task. RESULTS: In the alpha band, we observed bilateral ERD in the visual feedback conditions (IO, IOV). In the beta band, the ERD was bilateral in the IA, IV and IOV but more lateralized in the IV and IOV. After movement, we observed strong ERS in the IO and IOV but not in the IA or IV. Embodiment was stronger in conditions with vibratory feedback (IOV > IV > IA and IO) CONCLUSION: Conditions with visual feedback (IO, IOV) recruit the mirror neurons system (alpha ERD) and provide more accurate feedback of the task than IA and IV, which triggers motor validation pathways (beta rebound analysis). Vibratory feedback enhances the recruitment of the left sensorimotor areas, with a synergistic effect in the IOV (beta ERD analysis), thus maximizing embodiment. Visual and vibratory feedback recruits the sensorimotor cortex during motor imagery in different ways and can be combined to maximize the benefits of both techniques TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT04449328 .

The Impact of Pinus koraiensis Leaf Extract Consumption on Postprandial ApoB100 and Lipid Metabolism: A Randomized, Double-Blind, Placebo-Controlled Trial in Healthy Participants Subjected to an Oral High-Fat Challenge.

Pinus koraiensis (PK) leaf extract, derived from Korean pine byproducts, holds promise for alleviating postprandial hyperlipidemia. In this study, we investigated the potential of PK leaf extract for modulating postprandial hyperlipidemia in adults with normal or borderline fasting triglyceride levels. In a randomized, double-blind, parallel design, 70 subjects were randomly assigned to either the placebo or PK group for 4 weeks. After 4 weeks of consuming PK leaf extract, the results indicated a trend toward decreased serum apolipoprotein B-100 (ApoB100) levels 2 h after a high-fat challenge. Furthermore, significant improvements were observed in the incremental area under the curve (iAUC) at 0-4 h and 2-4 h compared to baseline, particularly among individuals with a higher body weight (>61.35 kg) and daily caloric intake (>1276.5 kcal). Based on these findings, PK leaf extract may have beneficial effects on postprandial lipoprotein metabolism, especially among individuals with a relatively high body weight and caloric intake.

Nocturnal Gastroesophageal Reflux and Sleep Depth in Healthy Adults, as Measured by Portable High-Resolution Manometry, Esophageal pH, and Electroencephalography.

BACKGROUND: The primary mechanism of diurnal gastroesophageal reflux (GER) is transient lower esophageal sphincter relaxation (TLESR) in both healthy persons and patients with gastroesophageal reflux disease (GERD). However, few studies have examined nocturnal GER. Using portable high-resolution manometry (HRM), esophageal pH, and electroencephalography (EEG), we investigated the association of onset of nocturnal GER with sleep depth in healthy Japanese adults. METHODS: We recruited ten healthy men (mean age 33.5 ± 4.2 years) with no reflux symptoms, no history of surgery, and no current medication use. HRM and an esophageal pH catheter were inserted in the evening. The participants returned home after consuming a test meal, and EEG was placed at home before bedtime to measure sleep depth. RESULTS: The main mechanism underlying nocturnal GER was TLESR (15/17 episodes: 88.2%). The rate of TLESR with nocturnal GER during sleep was high (51.9%, 27/52 episodes). Sleep depth during TLESR was 44.2% (23/52 times) awake and 34.6% (18/52 times) shallow sleep (N1-2). Sleep depth during TLESR with nocturnal GER was 74.0% (20/27 time) awake and 18.5% (5/27 times) shallow sleep (N1-2). CONCLUSION: The primary mechanism underlying nocturnal GER was TLESR in healthy Japanese men. TLESR and TLESR with nocturnal GER were more frequent during awakenings and shallow sleep.

Differences in lung attenuation gradients between supine and standing positions in healthy participants on conventional/supine and upright computed tomography.

The effect of gravity on the lungs has been evaluated using computed tomography (CT) in the supine and prone positions but not the standing position. However, as humans spend most of the daytime in the standing position, we aimed to compare lung attenuation gradients between the supine and standing positions, and to assess the correlations between the lung attenuation gradients and participant characteristics, including pulmonary function test results. Overall, 100 healthy participants underwent conventional/supine and upright CT, and lung attenuation gradients were measured. Lung attenuation gradients in anteroposterior direction were greater in the supine position than in standing position (all p values < 0.0001) in both upper lobes at the level of the aortic arch (right: standing/supine, -0.02 ± 0.19/0.53 ± 0.21; left: standing/supine, -0.06 ± 0.20/0.51 ± 0.21); in the right middle (standing/supine, -0.26 ± 0.41/0.53 ± 0.39), left upper (standing/supine, -0.35 ± 0.50/0.66 ± 0.54), and lower lobes at the level of the inferior pulmonary vein (right: standing/supine, -0.22 ± 0.30/0.65 ± 0.41; left: standing/supine, -0.16 ± 0.25/0.73 ± 0.54); and in both lower lobes just above the diaphragm (right: standing/supine, -0.13 ± 0.22/0.52 ± 0.32; left: standing/supine, -0.30 ± 0.57/0.55 ± 0.37). Craniocaudal gradients were greater in the standing position (right: standing/supine, 0.41 ± 0.30/0.00 ± 0.16; left: standing/supine, 0.35 ± 0.30/-0.02 ± 0.16, all p values < 0.0001). No moderate to very high correlations were observed between age, sex, height, weight, body index mass, or pulmonary function test results and each lung attenuation gradient. Lung attenuation gradients in anteroposterior direction, which was observed in the supine position, disappeared in the standing position. However, the craniocaudal lung attenuation gradient, which was not present in the supine position, appeared in the standing position.

Comparison of facial skin ageing in healthy Asian and Caucasian females quantified by in vivo line-field confocal optical coherence tomography 3D imaging.

BACKGROUND: Quantitative biomarkers of facial skin aging were investigated in 109 healthy Asian female volunteers, aged 20 to 70 years. MATERIALS AND METHODS: In vivo 3D Line-field Confocal Optical Coherence Tomography (LC-OCT) imaging, enhanced by Artificial Intelligence (AI)-based quantification algorithms, was utilized to compute various metrics, including stratum corneum thickness (SC), viable epidermal (VE) thickness, and Dermal-Epidermal Junction (DEJ) undulation along with cellular metrics for the temple, cheekbone, and mandible. RESULTS: Comparison with data from a cohort of healthy Caucasian volunteers revealed similarities in the variations of stratum corneum and viable epidermis layers, as well as cellular shape and size with age in both ethnic groups. However, specific findings emerged, such as larger, more heterogeneous nuclei in both layers, demonstrated by an increase in nuclei volume and their standard deviation, and increased network atypia, all showing significant age-related variations. Caucasian females exhibited a flatter and more homogeneous epidermis, evidenced by a decreased standard deviation of the number of layers, and a less dense cellular network with fewer cells per layer, indicated by a decrease in cell surface density. CONCLUSION: Ethnicity-wise comparisons highlighted distinct biological features specific to each population. Asian individuals showed significantly higher DEJ undulation, higher compactness, and lower cell network atypia compared to their Caucasian counterparts across age groups. Differences in stratum corneum and viable epidermal thickness on the cheekbone were also significant. LC-OCT 3D imaging provides valuable insights into the aging process in different populations and underscores inherent biological differences between Caucasian and Asian female volunteers.

Analysis of anthropometric measurements taken from the periocular region in healthy young individuals with different somatotypes.

PURPOSE: Anthropometric parameters related with the periocular region (PR) have gained great importance with the optical technology used in the treatment of eye defects. They have also become important parameters that determine the limits of treatment in aesthetic surgery procedures in PR and the treatment of orbital diseases. The aim of this study was to examine the relationship of PR measurements with somatotype. METHODS: Somatotypes were determined by using the Heath-Carter method. Ten indirect anthropometric measurements, namely nasal root (mf-mf), outer chantal distance (ex-ex), inner chantal distance (en-en), interpupillary distance (p-p), right and left palpebral fissure width (ex-en), palpebral fissure height (ps-pi), and orbital height (os-oi), were taken from PR with Image J program. Kruskal-Wallis H test was used to compare data with each other. Post-hoc Mann-Whitney U test was used to find out which group caused statistically significant differences according to the results of the Kruskal-Wallis H test. RESULTS: A statistically significant difference was found between some indirect anthropometric measurements taken from PR and somatotypes (P < 0,05). This difference was found to result from central group somatotype, in which no somatotype component has different effects from another one, for both genders. In almost all of the indirect anthropometric measurements, it was found that balanced ectomorph somatotypes reached the highest median values, while central group somatotypes had the lowest median values. CONCLUSION: As a result of this study, somatotype affects the appearance of PR. It will be possible to obtain more accurate and reliable results in aesthetic surgery interventions and identification studies. Our study is the first and a pioneer in its field in the literature. It will inspire and guide future researchers, surgeons, anthropologists, and forensic doctors who will work in this field.

Agonist antibody to guanylate cyclase receptor NPR1 regulates vascular tone.

Heart failure is a leading cause of morbidity and mortality1,2. Elevated intracardiac pressures and myocyte stretch in heart failure trigger the release of counter-regulatory natriuretic peptides, which act through their receptor (NPR1) to affect vasodilation, diuresis and natriuresis, lowering venous pressures and relieving venous congestion3-8. Recombinant natriuretic peptide infusions were developed to treat heart failure but have been limited by a short duration of effect9,10. Here we report that in a human genetic analysis of over 700,000 individuals, lifelong exposure to coding variants of the NPR1 gene is associated with changes in blood pressure and risk of heart failure. We describe the development of REGN5381, an investigational monoclonal agonist antibody that targets the membrane-bound guanylate cyclase receptor NPR1. REGN5381, an allosteric agonist of NPR1, induces an active-like receptor conformation that results in haemodynamic effects preferentially on venous vasculature, including reductions in systolic blood pressure and venous pressure in animal models. In healthy human volunteers, REGN5381 produced the expected haemodynamic effects, reflecting reductions in venous pressures, without obvious changes in diuresis and natriuresis. These data support the development of REGN5381 for long-lasting and selective lowering of venous pressures that drive symptomatology in patients with heart failure.

Safety, tolerability and pharmacokinetics of the phosphodiesterase 2 inhibitor BI 474121: An overview of phase I randomized trials in healthy volunteers.

BACKGROUND: Cognitive impairment associated with schizophrenia predicts poor functional outcomes, but currently no efficacious pharmacotherapies are available. AIMS: Four phase I trials examined the safety, tolerability and pharmacokinetics of the phosphodiesterase 2 inhibitor BI 474121, along with potential drug-drug interactions. METHODS: Trial 1 evaluated single rising doses (SRDs) of BI 474121 versus placebo in healthy males. The influence of drug formulation and food on drug bioavailability was also examined. Trial 2 evaluated SRD of BI 474121 versus placebo in healthy Japanese males. Trial 3 evaluated multiple rising doses of BI 474121 in healthy young (with/without midazolam) and elderly (without midazolam) participants versus placebo. Trial 4 investigated interactions between itraconazole and single-dose BI 474121 in healthy males. RESULTS/OUTCOMES: No deaths, serious adverse events (AEs), severe AEs or protocol-specified AEs of special interest were observed. BI 474121 absorbed rapidly during fasting, achieved maximum concentration of analyte in plasma and dose proportionality via tablet formulation, and decreased in a multiphasic manner. BI 474121 steady state occurred within 11 days of multiple oral administration. Multiple doses increased BI 474121 plasma concentrations, but did not alter the time course of plasma concentrations. Urinary excretion of unchanged BI 474121 was negligible. No clinically relevant inhibition or induction of CYP3A4 by BI 474121 was observed. Itraconazole co-administration produced higher exposures of BI 474121 versus BI 474121 alone. CONCLUSIONS/INTERPRETATION: BI 474121 demonstrated favourable safety and pharmacokinetic profiles in healthy Caucasian and Japanese individuals, supporting further clinical development.

Dopamine has no direct causal role in the formation of treatment expectations and placebo analgesia in humans.

Dopamine-based reward and learning mechanisms have been suggested to contribute to placebo effects. However, the exact role of dopaminergic neurotransmission in their generation and maintenance is still unclear. This study aimed to shed light on the causal role of dopamine in establishing positive treatment expectations, as well as on the magnitude and duration of their effect on pain. To this end, we used an established placebo analgesia paradigm in combination with 2 opposing pharmacological modulations of dopaminergic tone, i.e., the dopamine antagonist sulpiride and the dopamine precursor L-dopa which were both applied in an experimental, double-blind, randomized, placebo-controlled trial with a between-subject design in N = 168 healthy volunteers. The study medication successfully altered dopaminergic tone during the conditioning procedure. Contrary to our hypotheses, the medication did not modulate the formation of positive treatment expectation and placebo analgesia tested 1 day later. Placebo analgesia was no longer detectable on day 8 after conditioning. Using a combined frequentist and Bayesian approach, our data provide strong evidence against a direct dopaminergic influence on the generation and maintenance of placebo effects. Further exploration of the neurochemical mechanisms underlying placebo analgesia remains paramount in the quest to exploit these effects for optimal treatment outcomes. Trial registration: ClinicalTrials.gov German Clinical Trials Register, ID: DRKS00029366, https://drks.de/search/en/trial/DRKS00029366.

Bioavailability of a novel sustained-release pellet formulation of 5-flucytosine in healthy-fed participants for use in patients with cryptococcal meningitis.

Cryptococcal meningoencephalitis (CM) is an opportunistic fungal infection and a major cause of death among people living with human immunodeficiency virus in sub-Saharan Africa. 5-flucytosine (5-FC) is a unique, brain-permeable antifungal agent used to reduce mortality from CM and to prevent disease in individuals carrying cryptococcal antigen. 5-FC has a short plasma half-life, requiring 6-hourly oral dosing with an immediate-release (IR) formulation, a significant challenge in hospital and outpatient settings, risking a lack of compliance. We recently reported the relative bioavailability in fasting conditions of a sustained release (SR) oral pellet formulation of 5-FC. In this phase I study, we assessed the safety and pharmacokinetic profiles of the new 5-FC SR formulation in a single dose (2 × 3000 mg), relative to 5-FC IR tablets (Ancotil®; 1500 mg b.i.d.) in healthy participants in fed conditions. This randomized, two-period crossover study was conducted in South Africa to confirm the dose of the identified 5-FC SR formulation for a twice-daily 5-FC regimen in patients. Thirty-six healthy participants were included. All treatments were well tolerated and no serious adverse event was reported. Cmax and AUC(0-t) for the SR formulation (49.2 ± 10.49 µg/mL and 640.4 ± 126.4 h.µg/mL, respectively) were significantly higher than for the IR formulation (36.8 ± 7.61 µg/mL and 456.6 ± 72.8 h.µg/mL, respectively). A physiological based pharmacokinetic model (PBPK) predicted that under fasting conditions, 6000 mg SR pellets would show a good overlap with the IR product (3000 mg b.i.d), thus 6000 mg SR 5-FC b.i.d. in fasting conditions is recommended.

Randomized, double-blind, phase 1a single-ascending dose and food effect studies assessing safety and pharmacokinetics of EC5026 in healthy volunteers.

Chronic pain represents a significant unmet medical need, affecting one-fifth of the U.S. population. EC5026 is a small molecule inhibitor of the enzyme soluble epoxide hydrolase (sEH) which is being developed as a novel non-opioid, non-NSAID analgesic. EC5026 prolongs the action of epoxy fatty acids, endogenous analgesic lipid mediators that are rapidly metabolized by sEH. We evaluated the safety and pharmacokinetic profile of EC5026 in two phase I trials, a single-ascending dose (SAD) study and a fed-fasted study. The SAD study evaluated EC5026 doses ranging from 0.5 to 24 mg in healthy volunteers. EC5026 was well tolerated. No treatment-emergent adverse events were considered related to EC5026. No apparent treatment- or dose-related trends in laboratory results, vital signs, physical examinations, or electrocardiograms were observed. A linear, near-dose-proportional increase in exposure was observed with progressive doses in the SAD study; plasma exposure was below or near the lower limit of quantification after 0.5-2 mg doses. Mean half-lives ranged from 41.8 to 59.1 h. for doses of 8-24 mg, supporting a once-daily dosing regimen. In the fed-fasted study using 8 mg EC5026 tablets, higher peak concentrations (66%) and total exposures (53%) were observed under the fed condition. Plasma concentrations declined in a monoexponential manner with mean half-lives of 59.5 h. in the fed state and 66.9 h. in the fasted state. Future clinical trials using EC5026 for the treatment of pain are justified based on the favorable outcomes from both clinical trials along with preclinical evidence of analgesic activity.

BWC0977, a broad-spectrum antibacterial clinical candidate to treat multidrug resistant infections.

The global crisis of antimicrobial resistance (AMR) necessitates the development of broad-spectrum antibacterial drugs effective against multi-drug resistant (MDR) pathogens. BWC0977, a Novel Bacterial Topoisomerase Inhibitor (NBTI) selectively inhibits bacterial DNA replication via inhibition of DNA gyrase and topoisomerase IV. BWC0977 exhibited a minimum inhibitory concentration (MIC90) of 0.03-2 µg/mL against a global panel of MDR Gram-negative bacteria including Enterobacterales and non-fermenters, Gram-positive bacteria, anaerobes and biothreat pathogens. BWC0977 retains activity against isolates resistant to fluoroquinolones (FQs), carbapenems and colistin and demonstrates efficacy against multiple pathogens in two rodent species with significantly higher drug levels in the epithelial lining fluid of infected lungs. In healthy volunteers, single-ascending doses of BWC0977 administered intravenously ( https://clinicaltrials.gov/study/NCT05088421 ) was found to be safe, well tolerated (primary endpoint) and achieved dose-proportional exposures (secondary endpoint) consistent with modelled data from preclinical studies. Here, we show that BWC0977 has the potential to treat a range of critical-care infections including MDR bacterial pneumonias.