Healthy Adult Volunteers Research Articles

Dermal and Systemic Pharmacokinetics of Oral DFD-29 (minocycline hydrochloride modified release capsules, 40 mg) vs Oral Doxycycline 40 mg in Healthy Subjects

Dermal and Systemic Pharmacokinetics of Oral DFD-29 (minocycline hydrochloride modified release capsules, 40 mg) vs Oral Doxycycline 40 mg in Healthy Subjects Adelaide A. Hebert, MD,1 Srinivas Sidgiddi, MD2 1UTHealth Houston McGovern Medical School, Houston, TX; 2Journey Medical Corporation, Scottsdale, AZ Introduction: A modified-release, low-dose formulation (DFD-29) of minocycline hydrochloride (HCl) is under investigation for the treatment of rosacea. This Phase 1 study compared the dermal and systemic pharmacokinetics of DFD-29 (minocycline HCl, 40 mg) and doxycycline 40 mg in healthy, adult subjects. Methods: This randomized, open-label, single-center, parallel-group study evaluated the systemic and dermal pharmacokinetics of once-daily administration of oral DFD-29 40 mg capsules or oral doxycycline 40 mg for 21 days in healthy adult volunteers. On Day 1, subjects received the assigned study drug under fasting conditions. Blood was sampled before drug administration, every 30 minutes for 4 hours, hourly for 4 hours, and 12 and 24 hours post dose. Dermal interstitial fluid (ISF) was sampled using three open-flow microperfusion probes before dosing, hourly for 8 hours, and at 11-12, 15-16, and 23-24 hours post dose. After discharge, subjects continued to take assigned study drug once daily through Day 21, when they returned to the center and underwent the same procedures as on Day 1. Safety was evaluated by monitoring adverse events (AEs), vital signs, and laboratory tests. Results: A total of 24 subjects were randomized and completed the study. On Day 1, mean plasma Cmax levels with DFD-29 (382.8 ng/mL) and doxycycline (405.9 ng/mL) were comparable (Pr > 0.716). By Day 21, mean plasma Cmax had nearly doubled with doxycycline but remained constant with DFD-29 (701.9 vs 337.7 ng/mL; Pr > 0.037). Mean plasma AUC was also significantly greater with doxycycline than with DFD-29 at Day 21 (6074.8 ng.hr/mL vs 3957.6 ng.hr/mL, Pr > 0.013). In contrast, mean dermal Cmax concentrations were numerically higher with DFD-29 (40 mg) than doxycycline at Day 1 (109.7 vs 81.5 ng/mL; Pr > 0.117) and Day 21 (125.7 vs 114.7 ng/mL; Pr > 0.681). The mean dermal AUC at Day 1 also was greater with DFD-29 than with doxycycline (1412.29 ng.hr/mL Vs 1088.55 ng.hr/mL, Pr > 0.213), and at Day 21 it was similar in the two groups (1604.77 ng.hr/mL for DFD-29 and 1573.63 ng.hr/mL for doxycycline, Pr > 0.954). Both DFD-29 and doxycycline 40 mg were well tolerated by the healthy volunteers. Conclusion: Minocycline from DFD-29 with its modified-release formulation provides higher dermal concentration than doxycycline from Day 1 onwards at a similar dose. The higher concentration from Day 1 at the site of action is expected to translate into a clinically meaningful impact in the treatment of patients with rosacea. This study and abstract are funded by Journey Medical Corporation.

Artificial gravity: an effective countermeasure for microgravity-induced headward fluid shift?

Long-duration spaceflight is associated with pathophysiological changes in the intracranial compartment hypothetically linked to microgravity-induced headward fluid shift. This study aimed to determine whether daily artificial gravity (AG) sessions can mitigate these effects, supporting its application as a countermeasure to spaceflight. Twenty-four healthy adult volunteers (16 men) were exposed to 60 days of 6° head-down tilt bed rest (HDTBR) as a ground-based analog of chronic headward fluid shift. Subjects were divided equally into three groups: no AG (control), daily 30-min intermittent AG (iAG), and daily 30-min continuous (cAG). Internal carotid artery (ICA) stroke volume (ICASV), ICA resistive index (ICARI), ICA flow rate (ICAFR), aqueductal cerebral spinal fluid flow velocity (CSFV), and intracranial volumetrics were quantified at 3 T. MRI was performed at baseline, 14 and 52 days into HDTBR, and 3 days after HDTBR (recovery). A mixed model approach was used with intervention and time as the fixed effect factors and the subject as the random effect factor. Compared with baseline, HDTBR was characterized by expansion of lateral ventricular, white matter, gray matter, and brain + total intracranial cerebral spinal fluid volumes, increased CSFv, decreased ICASV, and decreased ICAFR by 52 days into HBTBR (All Ps < 0.05). ICARI was only increased 14 days into HDTBR (P < 0.05). Neither iAG nor cAG significantly affected measurements compared with HDTBR alone, indicating that 30 min of daily exposure was insufficient to mitigate the intracranial effects of headward fluid shift. Greater AG session exposure time, gravitational force, or both are suggested for future countermeasure research.NEW & NOTEWORTHY Brief exposure to continuous or intermittent artificial gravity via short-arm centrifugation was insufficient in mitigating the intracranial pathophysiological effects of the headward fluid shift simulated during head-down tilt bed rest (HDTBR). Our results suggest that greater centrifugation session duration, gravitational force, or both may be required to prevent the development of spaceflight-associated neuro-ocular syndrome and should be considered in future ground-based countermeasure studies.

Assessment of Microcirculatory Dysfunction by Measuring Subcutaneous Tissue Oxygen Saturation Using Near-Infrared Spectroscopy in Patients with Circulatory Failure.

Patients with circulatory failure have high mortality rates and require prompt assessment of microcirculation. Despite the improvement in hemodynamic parameters, microcirculatory dysfunction persists. We measured subcutaneous regional tissue oxygen saturation (rSO2) with near-infrared spectroscopy (NIRS), which can assess microcirculation in patients with circulatory failure. A finger-worn oximeter with NIRS measured rSO2 in the forehead, thenar eminence, thumb, and knees. First, the rSO2 was measured in healthy adult volunteers (n = 10). Circulatory failure was defined as a systolic blood pressure ≤ 90 mmHg and lactate ≥ 2 mmol/L. The study included 35 patients without circulatory failure and SOFA score of 0 at ICU admission and 38 patients with circulatory failure at ICU admission. Both groups included a single-center prospective study of patients who were transported to the ICU of the Nihon University Hospital. The rSO2 was measured only on ICU admission in the non-circulatory failure group and later in the circulatory failure group. In the volunteer group, rSO2 at each site was approximately 58%. The rSO2 was significantly lower in the circulatory failure group than in the non-circulatory failure group (knee, p < 0.01). In the circulatory failure group, knee rSO2 showed a significant negative correlation with SOFA score (Day 0, ρ = -0.37, p = 0.02; Day 1, ρ = -0.53, p < 0.01; Day 2, ρ = -0.60, p < 0.01). Subcutaneous knee rSO2 was associated with SOFA score and was considered an indicator of microcirculatory dysfunction and organ damage.

Correlation of obesity indices with metabolic syndrome among Igbos in Enugu and their optimal cut-off points

Background: Metabolic syndrome also known as insulin resistance syndrome or Syndrome X, represents an association of risk factors for cardiovascular disease and type 2 diabetes mellitus. Its central diagnostic criteria include obesity, impaired fasting glucose, low HDL-cholesterol; elevated triglycerides levels and high blood pressure. Insulin resistance is believed to be the main cause of Metabolic Syndrome and is connected to the level of visceral or intra-abdominal adipose tissue, which could be assessed either by calculating body mass index or by measuring waist circumference. Objectives: This study aimed at determining the correlation of indices of obesity with metabolic syndrome among Igbos in Enugu and their optimal cut-off points. Method: This was a cross-sectional community-based descriptive survey carried out in Enugu Metropolis involving 469 apparently healthy adult volunteers age range 18-75 screened for metabolic syndrome using the Joint Interim Statement definition. Stratified random sampling technique was used in the selection of participants. The data obtained were coded and analyzed into percentages, mean and standard deviation using the Statistical Package for Social Sciences (SPSS), version 23. t-test was used to compare continuous variables for associations, while Youden index and Receiver Operating Characteristic analysis were used to determine optimal cut-off point of the obesity indices that best balances sensitivity and specificity of the obesity indices. Pearson correlation coefficient was used to examine correlation between obesity indices and cardiovascular risks. Statistical significance is set at p&lt; 0.05 and 95% confidence interval. Result: The study revealed that all indices of obesity showed positive correlation with metabolic syndrome. BMI showed the least strength of correlation while WC is the best discriminator for predicting Metabolic Syndrome however, the optimal cut-off point of the obesity indices differ from the standard cut-off points. Conclusion: All the obesity indices used in the study showed positive correlation with metabolic syndrome however, WC is to be preferred in screening for metabolic syndrome. The optimal cut-off point obtained can be applied specifically for Igbos in Enugu

Use of Laryngeal Ultrasound to Observe Laryngeal Movements During Noninvasive Ventilation in Healthy Volunteers.

Transnasal fiberoptic laryngoscopy (TFL) has revealed that laryngeal obstruction can hamper assisted ventilation. TFL may be considered invasive, and laryngeal ultrasound (US) could be a noninvasive alternative. The objective of this study was to investigate the feasibility of using laryngeal US to study laryngeal movements in healthy adult volunteers undergoing noninvasive ventilation (NIV) and to compare the observations with those of simultaneous TFL. In this cross-sectional study, 30 participants (19 females, age 22-65 y) underwent simultaneous video-recorded TFL and laryngeal US, breathing with and without NIV. Laryngeal US was repeated for anterior and both lateral approaches; the last 5 breaths from each assessment were analyzed. The participants rated discomfort using a numeric rating scale (NRS) from 0 (no discomfort)-10 (worst). Two blinded raters separately described and scored the TFL and laryngeal US recordings, and the findings were subsequently compared. The last 10 laryngeal US recordings were tested for interrater reliability. All participants were successfully assessed using the anterior and both lateral laryngeal US approaches during NIV. Both techniques were well tolerated; 5/30 scored 0 on NRS for TFL and 22/30 for laryngeal US. The visualization rate for all recorded breaths was 99.1% for TFL compared to 81.7% for laryngeal US; overall concordance rate was 84.6%. The discordance rate for the TFL versus laryngeal US observations was 11.1% for vocal fold movements and 11.7% for aryepiglottic fold movements. Interrater reliability showed substantial agreement (0.71). Laryngeal US emerged as a feasible method to describe laryngeal movements during NIV, providing high-quality observations and high concordance with TFL.

Safety, tolerability, and basic pharmacokinetic parameters of AUX-001, a once-daily extended release nicorandil in healthy volunteers under fasting and fed conditions

Abstract Introduction Chronic-stable angina pectoris (CSAP) is one of the most common cardiovascular conditions in the developed world with a rising prevalence in both Europe and North America. Mounting evidence from chronic angina outcomes studies, including COURAGE, BARI, ORBITA and recently ISCHEMIA, has reemphasized optimized medical therapy (OMT) as first-line treatment for most chronic-stable angina pectoris (CSAP) patients over coronary revascularization. Yet, there has been a lack of development of new antianginal medications since 2006. To lessen polypharmacy and enable better long-term compliance in CSAP patients, AUX-001, a once-daily (QD), extended-release (ER) nicorandil is in clinical development for treating CSAP as an innovative, novel version of the immediate-release (IR) antianginal. Objective To test the safety, tolerability, and basic pharmacokinetic (PK) parameters of AUX-001 QD in fasting and fed conditions in healthy volunteers during this first-in-human phase 1a study. Methods 16 healthy adult volunteers were enrolled. Vital signs (HR, BP, respiratory rate) and any adverse events were collected during screening, pre-dose, 1, 2, 6, 12, 24-h, and 48-h post-dose and at end-of-study for the two respective periods (fasting and fed). Results Evaluable information was available on 16 patients for fasting and 15 for fed conditions with one patient excluded due to protocol violation. No patient discontinued due to safety or tolerability. No severe AEs were recorded. AEs observed during period 1 included headaches (n=12), asymptomatic hypotension (n=3), palpitation (n=1) and nasal congestion (n=1). In period 2, leading AEs were headaches (n=11), neck pain (n=1) and decreased hemoglobin (n=1). Most AEs were mild and transitory and did not trigger medical intervention or discontinuation. AUX-001 pharmacokinetics exhibited a reduced Cmax, a right-hand shift in Tmax, and an extension of T1/2 beyond 9 hours compared to the historical data of the commercially available IR nicorandil. AUX-001 had a small, temporary effect on heart rate and systolic and diastolic blood pressure but within the normal compensatory haemodynamic steady-state stability. The peak effect with the current AUX-001 prototype was at 6 hours, independent of the food effect. Conclusion AUX-001 was safe and well tolerated. Initial vasodilator-induced headaches were manageable by using simple OTC NSAIDs and led to no dropouts. No patients discontinued due to AEs or tolerability issues. There were no lasting significant haemodynamic effects of AUX-001 beyond 24hours. PK parameters of AUX-001 are characteristic of an ER formulation. Observed pharmacokinetics indicates that the achieved T1/2 is substantially longer than with IR nicorandil (~1hour vs &amp;gt;9h) and shows promise for a potential once daily treatment of exercise induced chronic angina.AUX-001 Study Data ESC Abstract 2024

Free-breathing qRF-MRF with pilot tone respiratory motion navigator for T1, T2, T2*, and off-resonance mapping of the human body at 3T.

Standard quantitative abdominal MRI techniques are time consuming, require breath-holds, and are susceptible to patient motion artifacts. Magnetic resonance fingerprinting (MRF) is naturally multi-parametric and quantifies multiple tissue properties, including T1 and T2. This work includes T2* and off-resonance mapping into a free-breathing MRF framework utilizing a pilot tone navigator. The new acquisition and reconstruction are compared to current clinical standards. Prospective. Ten volunteers. 3T scanner, Quadratic-RF MRF, Balanced SSFP, Inversion recovery spin-echo, LiverLab. MRI ROIs were evaluated in the liver, spleen, pancreas, kidney (cortex and medulla), and paravertebral muscle by two abdominal imaging investigators for ten healthy adult volunteers for clinical standard, breath-Hold (BH) qRF-MRF, and free-breathing qRF-MRF with pilot-tone (PT) acquisitions. Bland-Altman analysis as well as Student's T tests were used to evaluate and compare the respective ROI analyses. Quantitative values between breath-Hold (BH) and free-breathing qRF-MRF with pilot-tone (PT) results show good agreement with clinical standard T1 and T2 quantitative mapping, and Dixon q-VIBE (acquired using the Siemens LiverLAB). In this work, we show free-breathing abdominal MRF (T1, T2) with T2* results that are quantitatively comparable to current breath-hold MRF and clinical techniques.

Cubosomes – A novel approach to taste masking using ibuprofen as a model drug

Taste masking of any pediatric oral formulation has always been a hurdle. Cubosomses, a type of lyotropic liquid crystal, have been used in this research to develop an oral formulation of ibuprofen. Ibuprofen cubosomes were prepared with glyceryl monooleate (GMO) and poloxamer 407 by high-pressure homogenization (HPH) technique. The formulation experiments were performed using a 2-level, 3-factor central composite design with drug loading, GMO concentration and HPH pressure as independent variables and vesicle size, entrapment efficiency and %drug content as the dependent variables. The most suitable ibuprofen cubosomes showed 94 nm vesicle size, −17.5 mV zeta potential, >75% drug content and >96% entrapment efficiency. The cubosomes released more than 80% of the drug within 2 hours. In vitro taste masking study showed significantly lower drug release than its bitterness threshold. An in vivo taste masking study in healthy adult volunteers showed significant taste masking compared to the marketed formulation and ibuprofen pure suspension. % of the volunteers observed cubosomes as not bitter. In contrast, 67% of the volunteers reported marketed suspension as very bitter. The developed cubosomes resulted in physical stability for three months of proper storage. The study has successfully achieved considerable taste-masking using cubosomes with GMO and Poloxmaer 407 formulation. This proof of concept can initiate a new field of research in taste-masked oral liquid formulation.

Reference Range of Quantitative MRI Metrics Corrected T1 and Liver Fat Content in Children and Young Adults: Pooled Participant Analysis.

Multiparametric MRI markers of liver health corrected T1 (cT1) and proton density fat fraction (PDFF) have shown utility in the management of various chronic liver diseases. We assessed the normal population reference range of both cT1 and PDFF in healthy child and adult volunteers without any known liver disease. A retrospective multi-centre pooled analysis of 102 child and young adult (9.1 years (6-18)) volunteers from three centres: Children's Memorial Health Institute (N = 21), University Hospital Southampton (N = 28) and Hospital Infantil de Mexico (N = 53). Sex and ethnic differences were investigated for both cT1 and PDFF. Age effects were investigated with comparison to a pooled adult cohort from the UK Biobank (N = 500) and CoverScan (N = 71), covering an age range of 21 to 81 years. cT1 values were normally distributed with a median of 748 ms (IQR: 725-768 ms; 2.5-97.5 percentiles: 683-820 ms). PDFF values followed a normal distribution with a median of 1.7% (IQR: 1.3-1.9%; 2.5-97.5 percentiles: 1-4.4%). There were no significant age and sex differences in cT1 and PDFF between children and young adults. No differences in cT1 and PDFF were found between ethnicities. Age comparisons showed statistically significant, but clinically negligible, cT1 (748 ms vs. 732 ms) and PDFF (2.4% vs. 1.9%) differences between paediatric and adult groups, respectively. Median healthy cT1 and PDFF reference ranges in children and young adults fall within the reported limits for normal of 800 ms and 5%, respectively.

Exploration of the Conditions for Occurrence of Photoplethysmographic Signal Inversion above the Dorsalis Pedis Artery.

Inversion of the photoplethysmographic (PPG) signal is a rarely reported case. This signal anomaly can have implications for PPG-based cardiovascular assessments. The conditions for PPG signal inversion in the vicinity of the dorsalis pedis (DPA) artery of the foot were investigated. Wireless multi-wavelength PPG sensing with skin-probe contact pressure and local skin temperature were studied at different sensor positions, and the occurrence of inversion (OOI) was investigated. Twelve healthy adult volunteers were studied over four LED wavelengths at three levels of contact pressure for 11 probe positions. A novel algorithm quantified the proportion of inverted samples with respect to the abovementioned variables. Our algorithm classifying inverted vs. non-inverted pulses achieved 98.3% accuracy. Ten of the participants had at least one inverted signal identified. The impact of interindividual variation on inversion prevalence was large, but different LEDs, relative position to the DPA and sensor contact pressure also affected OOI. Skin surface and room temperatures showed no impact on OOI. Lateral measurements showed 39.6% more inversion at maximum compared to minimum contact pressure. Mechanical capillary bed variations and arterial reflections during venous engorgement are considered viable explanations for our observations. These findings motivate an expanded study of the occurrence of PPG signal inversion.

An abnormal increase in CD26(-)CD28(-) cytotoxic effector CD4 and CD8 T cell populations in patients with systemic lupus erythematosus.

CD26 is a human T cell costimulatory molecule as well as a T cell subset marker, and increase of CD26+ T cells in inflamed tissues and peripheral blood has been reported in diverse autoimmune diseases. In contrast, our group has previously shown that levels of circulating CD26+ T cells are decreased in patients with systemic lupus erythematosus (SLE), although the role of reduced CD26 T cell surface expression in SLE pathology remains to be elucidated. In the present study, we conducted CD26-based T cell subset analyses utilizing peripheral blood mononuclear cells from 57 SLE patients and 31 healthy adult volunteers. We show that the increase in CD26(-) T cell population reflects the abnormal expansion of CD26(-)CD28(-) cytotoxic subsets of both CD8 T cells and CD4 T cells in SLE patients. Single cell RNA sequencing analysis of the CD26(-)CD28(-) CD4 and CD8 T cell populations reveals unique characteristics with similarities to natural killer T cells. In addition, the level of CD26(-)CD28(-) T cells is increased in some active stage SLE patients with renal manifestation. Meanwhile, effect of prednisolone treatment on these populations varies from patient to patient, with levels of these cytotoxic effector populations still being elevated in some inactive stage SLE patients. Taken together, our data suggest that analysis of these populations in SLE may be a useful tool to classify this markedly heterogeneous condition.

Factors Involved in the Development of Diabetic Kidney Disease in Patients With Slowly Progressive Type 1 Diabetes Mellitus: A Retrospective Cohort Study.

Introduction The duration of diabetes mellitus (DM), blood pro-inflammatory markers, and dipeptidyl peptidase 4 (DPP4) activity are known predictors of diabetic kidney disease (DKD) progression in acute-onset type 1 DM (AT1DM) and type 2 DM. However, predictors of DKD progression in slowly progressive type 1insulin-dependent DM (SPIDDM) have been less frequently studied. Patients and methods This retrospective cohort study included 60 patients with SPIDDM (definite) (26 men/34 women). We utilized Cox proportional hazard analyses to determine whether characteristics and laboratory findings at the time of the SPIDDM diagnosis were associated with subsequent DKD progression. The urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) at the last outpatient clinic visit served as indicators of renal function. Also, to compare blood markers in patients with SPIDDM, we included 21 patients diagnosed with AT1DM at the same department during the same period and 50 healthy adult volunteers. Results In patients with SPIDDM (definite), the multivariate Cox proportional hazard analysis revealed that the body mass index (BMI), high-sensitivity C-reactive protein (hs-CRP) levels at diagnosis, and the duration of DM prior to SPIDDM diagnosis were associated with the new onset of albuminuria and systolic blood pressure (SBP) at diagnosis, and the duration of DM prior to SPIDDM diagnosis was associated with a decline in eGFR to less than 60 ml/min/1.73 m². Additionally, serum hs-CRP levels were significantly higher in the SPIDDM (definite) group compared to both the AT1DM patients and healthy controls, suggesting a higher inflammatory state in patients with SPIDDM at the time of diagnosis. In patients with SPIDDM (definite) who were not treated with a DPP4 inhibitor, plasma DPP4 activity was associated with the new onset of albuminuria. Conclusions BMI, SBP, hs-CRP levels, DPP4 activity at SPIDDM diagnosis, and the duration of DM prior to SPIDDM diagnosis are associated with subsequent progression of DKD in SPIDDM. Also, we found that the patients with SPIDDM are often already being treated as DM for a long period of time at the time of diagnosis, which may be linked to their already high inflammatory status at the time of SPIDDM diagnosis and contribute to DKD progression. These findings underscore the importance of early diagnosis and management in preventing DKD progression in this population.

Comparative Bioequivalence Studies of doxysam and doxycycline (Pfizer) by reversed phase HPLC.

Isocratic high performance liquid chromatography on reversed phase a (150x 4.6 mm I.D), 5 ?m ?-Bondapak RP-8 column (with acidic mobile phase allow the separation of doxcycycline hydrochloride with low detection limit of 0.2 µg/ml detected by UV set at 226 nm. The method was validated for Doxycycline between 0.156- to 5 µg/ml. The concentration of doxycycline was assessed in two single dose randomized crossover studies with intervals of one week between two period. In sera of 20 adults healthy male volunteers with average age of (42 + 10) year, body weight 48-85 kg, body height of (160-185cm) after a single dose of doxycycline hydrochoride 100 mg in form of capsules were orally administrated for both formulations. The blood samples (2ml) were drawn concomitantly from 0.5 – 24 hours. µg The pharmacokinetics parameter were obtained from the mean serum concentration measured at various sampling times for both formulations. The maximum peak concentration (Cmax) of doxycycline reference drug from Pfizer In serum was (3.1 +0.094 µg /ml) attained in 2 hrs. While the maximum concentration (Cmax) of test drug doxysam (2.8 +0.098 µg /ml) attained in about 2 hrs, both drug have long elimination time with half time of approximately (13 hrs.) Both test and reference drug were show no significant difference in pharmacokinetics parameters, so they were considered to be bioequivalent.

Extracellular traps in peripheral blood mononuclear cell fraction in childhood-onset systemic lupus erythematosus.

Although the role of low-density granulocytes (LDGs), neutrophils in the peripheral blood mononuclear cell (PBMC) fraction, and neutrophil extracellular traps (NETs) in assessing lupus disease severity is acknowledged, data specific to childhood-onset lupus remains scarce. This study analyzed 46 patients with childhood-onset systemic lupus erythematosus (82.6% females, mean age 14.5 ± 0.3 years), including 26 cases with normal complement levels and 20 with low complement levels, along with 20 healthy adult volunteers. Key parameters that distinguished healthy volunteers from lupus patients and differentiated between lupus patients with low and normal complement were serum interferon (IFN)-α, serum citrullinated histone 3 (CitH3), and extracellular traps (ETs) in LDGs. However, NETs (assessed by nuclear staining morphology), LDG abundance, and other parameters (such as endotoxemia, cytokines, and double-stranded (ds) DNA) did not show such differentiation. When lipopolysaccharide (LPS) was administered to LDGs in the PBMC fraction, it induced ETs in both low and normal complement groups, indicating the inducible nature of ETs. In adult healthy volunteers, activation by recombinant IFN-α or dsDNA in isolated neutrophils induced LDGs and NETs (identified using immunofluorescent staining for CitH3, myeloperoxidase, and neutrophil elastase) at 45min and 3h post-stimulation, respectively. Additionally, approximately half of the LDGs underwent late apoptosis at 3h post-stimulation, as determined by flow cytometry analysis. Activation by IFN-α or dsDNA in LDGs also led to a more pronounced expression of CD66b, an adhesion molecule, compared to regular-density neutrophils, suggesting higher activity in LDGs. In conclusion, IFN-α and/or dsDNA in serum may transform regular-density neutrophils into LDGs before progressing to NETosis and apoptosis, potentially exacerbating lupus severity through cell death-induced self-antigens. Therefore, LDGs and ETs in LDGs could provide deeper insights into the pathophysiology of childhood-onset lupus.

In vitro comparison of low-power diode pumping solid-state laser radiation at 589 and 650 nm on red blood cells suspension viscosity, stability, and deformability.

To investigate the effect of diode-pumped solid-state laser irradiation with yellow 589nm and red 650nm wavelengths on rheological parameters in vitro. The comparative study was conducted between November 2021 and April 2022 at the at the Postgraduate Medical Physics Laboratory, Mustansiriyah University, Baghdad, Iraq, and comprised blood samples from healthy adult volunteers. The samples were divided into 4 aliquots. The first was preserved as a control sample, while the other 3 were exposed to a diode-pumped solid-state laser, delivering the beam for 589nm and 650nm wavelengths at radiation dose 15, 22.5, 33.5J/cm2 for 20, 30 and 45 minutes, and with each laser having a 50mW output power and a 4 mm2 spot diameter. Data was analysed using SPSS (version 24). There were 6 subjects aged 18-60 years. There was no significant difference in the viscosity values between laser wavelengths (p>0.05). Compared to the laser wavelength of 650nm, irradiation with a 589nm wavelength at the same dose resulted in a significant reduction (p<0.009) in deformability. The rigidity index of red blood cell suspension was reduced the most at a radiation dose of 22.5J/cm2 for both lasers compared to the control samples. No significant variations were found in suspended erythrocyte viscosity (p>0.05). The wavelength with 589nm lasers showed more effective influence than its 650nm counterpart in improving the rheological parameters of blood viscosity and erythrocytes deformability.

Investigating patellar motion using weight-bearing dynamic CT: normative values and morphological considerations for healthy volunteers

BackgroundPatellar instability is a well-known pathology in which kinematics can be investigated using metrics such as tibial tuberosity tracheal groove (TTTG), the bisect offset (BO), and the lateral patellar tilt (LPT). We used dynamic computed tomography (CT) to investigate the patellar motion of healthy subjects in weight-bearing conditions to provide normative values for TTTG, BO, and LPT, as well as to define whether BO and LPT are affected by the morphology of the trochlear groove.MethodsDynamic scanning was used to acquire images during weight-bearing in 21 adult healthy volunteers. TTTG, BO, and LPT metrics were computed between 0° and 30° of knee flexion. Sulcus angle, sulcus depth, and lateral trochlear inclination were calculated and used with the TTTG for simple linear regression models.ResultsAll metrics gradually decreased during eccentric movement (TTTG, -6.9 mm; BO, -12.6%; LPT, -4.3°). No significant differences were observed between eccentric and concentric phases at any flexion angle for all metrics. Linear regression between kinematic metrics towards full extension showed a moderate fit between BO and TTTG (R2 0.60, β 1.75) and BO and LPT (R2 0.59, β 1.49), and a low fit between TTTG and LPT (R2 0.38, β 0.53). A high impact of the TTTG distance over BO was shown in male participants (R2 0.71, β 1.89) and patella alta individuals (R2 0.55, β 1.91).ConclusionWe provided preliminary normative values of three common metrics during weight-bearing dynamic CT and showed the substantial impact of lateralisation of the patella tendon over patella displacement.Relevance statementThese normative values can be used by clinicians when evaluating knee patients using TTTG, BO, and LPT metrics. The lateralisation of the patellar tendon in subjects with patella alta or in males significantly impacts the lateral displacement of the patella.Key PointsTrochlear groove morphology had no substantial impact on motion prediction.The lateralisation of the patellar tendon seems a strong predictor of lateral displacement of the patella in male participants.Participants with patella alta displayed a strong fit between the patellar lateral displacement and tilt.TTTG, BO, and LPT decreased during concentric movement.Concentric and eccentric phases did not show differences for all metrics.Graphical

Interactive effect of air pollution and genetic risk of depression on processing speed by resting-state functional connectivity of occipitoparietal network

BackgroundAir pollution, a reversible environmental factor, was significantly associated with the cognitive domains that are impaired in major depressive disorder (MDD), notably processing speed. Limited evidence explores the interactive effect of air pollution and the genetic risk of depression on cognition. This cross-sectional study aims to extend the research by specifically examining how this interaction influences depression-related cognitive impairment and resting-state brain function.MethodsEligible participants were 497 healthy adult volunteers (48.7% males, mean age 24.5) living in Beijing for at least 1 year and exposed to relatively high air pollution from the local community controlling for socioeconomic and genomic. Six months’ ambient air pollution exposures were assessed based on residential addresses using monthly averages of fine particulate matter with a diameter of less than or equal to 2.5 μm (PM2.5). A cross-sectional analysis was conducted using functional magnetic resonance imaging (fMRI) and cognitive performance assessments. The polygenic risk score (PRS) of MDD was used to estimate genetic susceptibility.ResultsUsing a general linear model and partial least square regression, we observed a negative association between resting-state local connectivity in precuneus and PRS-by-PM2.5 interactive effect (PFWE = 0.028), indicating that PM2.5 exposure reduced the spontaneous activity in precuneus in individuals at high genetic risk for MDD. DNA methylation and gene expression of the SLC30A3 gene, responsible for maintaining zinc-glutamate homeostasis, was suggestively associated with this local connectivity. For the global functional connectivity, the polygenic risk for MDD augmented the neural impact of PM2.5 exposure, especially in the frontal-parietal and frontal-limbic regions of the default mode network (PFDR < 0.05). In those genetically predisposed to MDD, increased PM2.5 exposure positively correlated with resting-state functional connectivity between the left angular gyrus and left cuneus gyrus. This connectivity was negatively associated with processing speed.ConclusionsOur cross-sectional study suggests that air pollution may be associated with an increased likelihood of cognitive impairment in individuals genetically predisposed to depression, potentially through alterations in the resting-state function of the occipitoparietal and default mode network.

Effect of Food on the Pharmacokinetics, Safety, and Tolerability of Budesonide Oral Suspension in Healthy Adult Participants: A Randomized Phase 1 Study.

Budesonide oral suspension (BOS) is a swallowed corticosteroid indicated for 12-week therapy in eosinophilic esophagitis with minimal systemic exposure following administration. We aimed to assess the relative bioavailability of a single dose of BOS administered under fasting and fed (high-fat/high-calorie meal) conditions. Healthy adult volunteers (N = 20) were enrolled in an open-label, single-center, crossover study and were randomized (1:1) to receive a single oral dose of BOS 2.0 mg under fasting or fed conditions, with a 48-h washout period before crossover to the alternative conditions. Serial plasma samples were collected before and up to 24 h after dosing. Pharmacokinetic (PK) parameters were calculated from plasma budesonide concentration-time profiles by noncompartmental analysis. The mean peak budesonide concentration (Cmax) was ∼13% lower under fed than under fasting conditions (604.1 vs 692.9 pg/mL). Areas under the concentration-time curves from dosing to the last measurable budesonide concentration and from dosing to infinity were ∼26% higher and ∼27% higher under fed than fasting conditions (3529 vs 2811 pg h/mL and 3892 vs 3075 pg h/mL, respectively). The median time to peak plasma budesonide concentration was significantly longer (∼1 h) under fed than fasting conditions (2.516 vs 1.286 h, P <.001). Safety and tolerability were also assessed throughout the study; all adverse events were mild or moderate in severity. Despite slight differences in budesonide PK parameters between fed and fasting conditions, the effect of food on systemic exposure to budesonide (BOS formulation) is not expected to be clinically meaningful.

Comparative inhibition by oral bilastine, parenteral dexchlorpheniramine, and a new bilastine parenteral (i.v. and i.m.) formulation of histamine-induced wheal and flare response: A randomised phase I trial

BackgroundBilastine is a well-known non-sedating second-generation antihistamine authorised worldwide for the symptomatic treatment of allergic rhinoconjunctivitis (seasonal and perennial) and urticaria with proven efficacy and good safety and tolerability profile. When the oral route is not suitable or a rapid onset of action is preferred, parenteral formulations represent an effective treatment option. However, the parenteral formulations currently available are sedating antihistamines. The objective of this research was to compare the peripheral anti-H1 activity of different bilastine formulations (i.v., i.m. and oral) and dexchlorpheniramine among them also versus placebo. MethodsThis was a single-dose, randomized, crossover, double-blind, placebo-controlled, phase I clinical study performed on 25 adult healthy volunteers that compared the peripheral antihistaminic activity of a single dose of bilastine 12 mg i.v., bilastine 12 mg i.m., bilastine 20 mg oral tablets and dexchlorpheniramine 5 mg i.m. among them and versus placebo by inhibiting the histamine-induced wheal and flare (W&F) response. Pharmacokinetics, safety, and tolerability were also evaluated. ResultsAll bilastine formulations showed a rapid onset of action (15 min for parenteral and 30 min for the oral formulation), and the maximum effect in both wheal (i.v. 74.44 %; i.m.:74.29 %; oral 70,27 %) and flare area reduction (i.v. and i.m. 80.63 %; oral 77.67 %), was significantly larger compared to dexchlorpheniramine i.m. (25.85 % for wheal and 28.65 % for flare) and placebo (1.35 % for wheal and 4.02 % for flare). A more pronounced reduction in itching score was reached for bilastine oral, followed by i.m. and i.v. formulations. No serious adverse events (SAEs) were reported during the study, and 8 treatment-emergent adverse events (TEAEs) were reported by 5 subjects, all resolved without sequelae. For psychomotor assessments, dexchlorpheniramine i.m. showed a fast onset of drowsiness, as well as decreased attention and coordination when compared to all bilastine formulations and placebo. ConclusionsAll bilastine formulations showed a peripheral H1-blocking effect inducing a significantly greater inhibition of the wheal and flare response as compared to dexchlorpheniramine i.m. or placebo and provided a greater reduction of the itching sensation score. This study reconfirmed that bilastine has no sedative effect, even in a parenteral formulation. These results suggest that new bilastine parenteral formulation (i.v. or i.m.) may represent a suitable alternative for patients requiring immediate treatment of histamine-mediated type I hypersensitivity reactions, such as acute urticaria, or in those cases where oral administration is not possible.

Clinical Assessment of Breast Cancer Resistance Protein (BCRP)-Mediated Drug-Drug Interactions of Sepiapterin with Curcumin and Rosuvastatin in Healthy Volunteers.

Sepiapterin, also known as PTC923 and CNSA-001, is a synthetic form of endogenous sepiapterin being developed as a novel oral treatment for phenylketonuria. Sepiapterin is a natural precursor of tetrahydrobiopterin (BH4) and, when orally administered, is converted to BH4 via the pterin salvage pathway. In vitro studies have demonstrated that both sepiapterin and BH4 are both substrates and inhibitors of the breast cancer resistance protein (BCRP) transporter. This phase I study investigated BCRP-mediated drug-drug interactions of sepiapterin as a victim and as a perpetrator. An open-label, fixed-sequence, four-period, crossover, single-dose study was conducted in adult male and female healthy volunteers (18-55 years of age). In a given treatment period, subjects received a single oral dose of sepiapterin (20 mg/kg), sepiapterin (20 mg/kg) plus curcumin (2 g), rosuvastatin (10 mg), or rosuvastatin (10 mg) plus sepiapterin (60 mg/kg). The pharmacokinetics of sepiapterin, its metabolite BH4, and rosuvastatin were studied, and geometric mean ratios of exposures in the presence and absence of the BCRP inhibitor curcumin or sepiapterin were estimated. The presence of the BCRP c.421C>A polymorphism was evaluated in all subjects. A total of 29 subjects were enrolled and included in the safety analysis. Among them, 26 subjects were included in the pharmacokinetic and drug-drug interaction analyses. Following oral administration20 mg/kg sepiapterin, sepiapterin was rapidly and extensively converted to BH4, and BH4 maximum observed concentration (415.0 ng/mL) was observed 4.95 h (time to maximum observed concentration) post-dose. Sepiapterin maximum observed concentration and area under the concentration-time curve from time 0 to time of the last quantifiable measurement or the last sample collection time (AUClast) were <1% of BH4 values. Coadministration of the BCRP inhibitor curcumin (2 g) increased BH4 maximum observed concentration, AUClast, and area under the concentration-time curve from time 0 extrapolated to infinity by 24%, 21%, and 20%, respectively. When sepiapterin was coadministered with the BCRP substrate rosuvastatin, there was no effect on the pharmacokinetics of rosuvastatin. BCRP c.421C/A carriers (n = 4) had higher plasma exposures of BH4 (1.39 × for AUClast) and rosuvastatin (1.61 × for AUClast) than c.421C/C carriers (n = 22). Greater increases in BH4 exposures (1.33 vs 1.18 for AUClast) were observed in c.421C/A carriers compared with c.421C/C carriers when sepiapterin was coadministered with curcumin. All treatments were well tolerated during the study. Oral coadministration of the BCRP inhibitor curcumin slightly increased the plasma exposure of sepiapterin and its metabolite BH4 in healthy volunteers. This modest increase was deemed not clinically meaningful. Sepiapterin did not alter the pharmacokinetics of the BCRP substrate rosuvastatin.