Healthy Adult Male Volunteers Research Articles

Pharmacokinetics, Safety, Tolerability, and Immunogenicity of BP02 (Trastuzumab Biosimilar) Compared to EU- and US-Approved Trastuzumab in Healthy Adult Male Volunteers: A Phase 1, Randomized, Double-Blind Study.

This study evaluated the pharmacokinetic (PK) equivalence between BP02 (a proposed trastuzumab biosimilar) and the reference trastuzumab approved in the EU (EU-trastuzumab) and the US (US-trastuzumab). In this phase 1, double-blind, parallel-group trial, 111 healthy male volunteers were randomized 1:1:1 to receive a single 6-mg/kg intravenous infusion of BP02, EU-trastuzumab, or US-trastuzumab and were evaluated for 78days. Serum drug concentration-time data were analyzed by non-compartmental methods. The PK similarity of BP02 to the two reference products, and between EU-trastuzumab and US-trastuzumab, was determined using the standard 80-125% bioequivalence criteria. Baseline demographics for the 111 subjects with evaluable pharmacokinetics were similar across all treatment groups. PK profiles were similar for the three products. The 90% confidence intervals (CIs) for the ratios of area under the serum concentration-time curve (AUC) from the time of dosing to infinity (AUC0-inf), AUC from the time of dosing until the time of the last quantifiable concentration (AUC0-t), and peak serum concentration of trastuzumab (Cmax) were within 80% to 125% for all three pairwise comparisons. Adverse events (AEs) were similar across all arms, with treatment-related AEs reported by 73.0%, 73.0%, and 89.2% of the subjects in the BP02, EU-trastuzumab, and US-trastuzumab groups, respectively. The most common AEs were headache, infusion-related reactions, and upper-respiratory-tract infections. Four subjects-three in the US-trastuzumab group and one in the BP02 group-discontinued the study due to AEs. All post-dose samples except for two tested negative for anti-drug antibodies. This study demonstrates the PK similarity among BP02, EU-trastuzumab, and US-trastuzumab. The safety and immunogenicity profiles observed for the three products in this study are consistent with previous reports for trastuzumab. ANZCTR number: ACTRN12621000573853.

LSD increases sleep duration the night after microdosing

Microdosing psychedelic drugs at a level below the threshold to induce hallucinations is an increasingly common lifestyle practice. However, the effects of microdosing on sleep have not been previously reported. Here, we report results from a Phase 1 randomized controlled trial in which 80 healthy adult male volunteers received a 6-week course of either LSD (10 µg) or placebo with doses self-administered every third day. Participants used a commercially available sleep/activity tracker for the duration of the trial. Data from 3231 nights of sleep showed that on the night after microdosing, participants in the LSD group slept an extra 24.3 min per night (95% Confidence Interval 10.3–38.3 min) compared to placebo—with no reductions of sleep observed on the dosing day itself. There were no changes in the proportion of time spent in various sleep stages or in participant physical activity. These results show a clear modification of the physiological sleep requirements in healthy male volunteers who microdose LSD. The clear, clinically significant changes in objective measurements of sleep observed are difficult to explain as a placebo effect. Trial registration: Australian New Zealand Clinical Trials Registry: A randomized, double-blind, placebo-controlled trial of repeated microdoses of lysergic acid diethylamide (LSD) in healthy volunteers; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=381476; ACTRN12621000436875.

(031) Bioequivalence Studies of Sildenafil Citrate Orodispersible Film Administered With and Without Water versus Viagra Film-Coated Tablets in Healthy Adult Male Volunteers

Abstract Introduction Orodispersible film (ODF) formulation offers ease of use, convenience of administration, and other advantages, especially for patients who have difficulty in swallowing or are on liquid restriction compared with conventional oral formulations for the treatment of erectile dysfunction. Objective These studies compared the bioequivalence of 50 mg sildenafil citrate ODF formulation (test drug) with the marketed 50 mg sildenafil citrate film-coated tablet (FCT) (Viagra; Pfizer, New York, NY) (reference drug), with and without water in 2 randomized cross-over studies. Methods Two randomized cross-over studies were conducted. The first study explored the bioequivalence of test drug administered with and without water compared with the reference drug with water. The second study investigated the bioequivalence of test drug, without water, compared with the reference drug with water. 42 healthy adult male volunteers started the first study and only 40 completed. While 80 subjects who were enrolled completed the second study. All the 120 subjects from both the studies were included for pharmacokinetic and bioequivalence analysis. All volunteers fasted for 10 hours pre-dose. A 1-day washout period between doses was observed. Blood samples were collected at regular intervals both before (up to 120 minutes before dosing) and after dosing (at different intervals up to 14 hours) dosing stages. Statistical analyses on pharmacokinetic parameters were performed. Safety and tolerability for both the formulations were evaluated. Results In the first study, bioequivalence was demonstrated for sildenafil citrate ODF administered with water when compared with the Viagra FCT. The ratios of adjusted geometric means (90% confidence interval (CI)) were maximum plasma concentration: 1.02 (94.91–108.78) and area under the plasma concentration-time curve: 1.09 (104.49–113.21) for sildenafil citrate ODF administered with water vs Viagra FCT. These ratios were within the bioequivalence acceptance range of 80% to 125%, indicating that the bioequivalence criteria were met. The pharmacokinetic parameters for the second study also demonstrated bioequivalence for sildenafil citrate ODF when administered without water compared with Viagra FCT. The ratios of adjusted geometric means (90% CI) were maximum plasma concentration: 1.02 (95.47–109.36) and area under the plasma concentration-time curve: 1.06 (103.42–108.40) for sildenafil citrate ODF administered without water vs Viagra FCT. Adverse events in both the studies occurred at similar rates for the 2 formulations and were mild in intensity and were expected from the known safety profile. Conclusions Sildenafil citrate ODF administered with and without water met bioequivalence criteria compared with Viagra FCT administered with water under fasted conditions in healthy adult male volunteers. These results suggest that the new ODF formulation can be used interchangeably with the marketed FCT formulation. Therefore, the new ODF formulation can be used as a suitable alternative to the conventional oral solid dosage form for the treatment of ED. Disclosure Yes, this is sponsored by industry/sponsor: Viatris Inc. Clarification: Industry initiated, executed and funded study. Any of the authors act as a consultant, employee or shareholder of an industry for: Viatris Inc.

Investigation of the Validity and Reliability of Two Smart Bands Selected That Count Steps at Different Walking Speed

Whether activity monitor smart wristbands that have become widespread can accurately estimate the step count while walking is a matter of curiosity. The current study aims to analyze the validity and reliability of step count (SC) estimation at normal walking and fast walking pace under controlled conditions of two selected smart wristbands of the leading wearable device vendors, Xiaomi (Mi4) and Huawei (H4). Twenty healthy adult male and twenty healthy adult female were included in the study and analyzed separately. The mean age of male and female participants was 22.25 and 21.62 years, with BMI values of 24.22 kg/m2 and 21.42 kg/m2, respectively. The above-ground walking protocol consisted of four separate five-minute tests: Normal Walking Test, Normal Walking Retest, Fast Walking Test, and Fast Walking Retest. In the study, the analyses were performed by using activity monitor measurements and criterion measurements (the number of steps determined from video recordings), compatibility of test-retest measurement values, error indicators (MPE and MAPE), Intraclass Correlation Coefficients (ICC), and Bland-Altman limits of agreement. According to the current study results, it was revealed that the MAPE values recorded for Mi4 and H4 smart wristbands for both normal and fast walking pace in male and female participants were <5%, which was deemed excellent. According to all analyses, the H4 device was found to be valid and reliable, but according to ICC and Pearson Correlation analyses, the Mi4 device was not found to be valid and reliable at fast walking pace.

Finite element analysis and a pilot study of different fixation constructs for Danis-Weber A and B lateral malleolus fractures

BackgroundDisplaced lateral malleolus fractures are typically stabilised through open reduction and internal fixation. The biomechanically and clinically efficacy of locking plates and lag screws, particularly in Weber A and B distal fibular fractures remains a subject of contention. This study examines two locking plate designs for lateral malleolus fractures, evaluating their performance with and without interfragmentary screws using finite element models.MethodsUtilising CT images of a healthy adult male volunteer, a three-dimensional finite element model was constructed. The Fibula-specific Flank Multiaxial Locking Anatomic Plate (FMLP) and the Conventional Locking Plate (CLP) were subjected to stabilisation, both with and without an interfragmentary screw, mimicking the Danis-Weber A and B lateral malleolus oblique fracture fixation. Loads of 140 N and 70 N, equivalent to 20% of the body weight, were applied to simulate the single-leg and two-leg standing conditions in the axial direction. The von Mises stress (VMS) distributions and element displacements were subsequently analyzed.ResultsIn the Danis-Weber A fracture model group, the FMLP with an interfragmentary screw fixation exhibited the lowest peak VMS values: 51.9 MPa in the fibula, 89.0 MPa in the plate, and 61.3 MPa in the screws for simulating single-leg conditions. Under two-leg standing conditions, these peak VMS values decreased to 25.9 MPa in the fibula, 44.5 MPa in the plate, and 30.6 MPa in the screws, respectively. Furthermore, the overall structural peak displacements during single-leg standing for both Weber-A and B fractures with different implants ranged from 1.61 to 2.54 mm. While standing on two feet, the ranged was from 0.80 to 1.27 mm. An interfragmentary screw at the oblique fracture site resulted in reduced the peak value of VMS in the fibula, plate, screws, consequently decreased the overall structural displacement for FMLP and CLP fixation in lateral malleolus fractures.ConclusionsThe current finite element analysis (FEA) demonstrates that FMLP exhibits superior mechanical characteristics in Danis-Weber A and B lateral malleolus fractures compared to CLP. The inclusion of an interfragmentary screw, combined with locking plate design, enhances stability for simple oblique distal fibular fractures. The FMLP presents itself as potential as an alternative for lateral malleolus fractures from a biomechanical perspective. Nevertheless, further verification of these results is imperative through subsequent clinical studies.

Finite element analysis of artificial ankle elastic improved inserts

To discuss the influence of artificial ankle elastic improved inserts (hereinafter referred to as "improved inserts") in reducing prosthesis micromotion and improving joint surface contact mechanics by finite element analysis. Based on the original insert of INBONE Ⅱ implant system (model A), four kinds of improved inserts were constructed by adding arc or platform type flexible layer with thickness of 1.3 or 2.6 mm, respectively. They were Flying goose type_1.3 elastic improved insert (model B), Flying goose type_2.6 elastic improved insert (model C), Platform type_1.3 elastic improved insert (model D), Platform type_2.6 elastic improved insert (model E). Then, the CT data of right ankle at neutral position of a healthy adult male volunteer was collected, and finite element models of total ankle replacement (TAR) was constructed based on model A-E prostheses by software of Mimics 19.0, Geomagic wrap 2017, Creo 6.0, Hypermesh 14.0, and Abaqus 6.14. Finally, the differences of bone-metal prosthesis interface micromotion and articular surface contact behavior between different models were investigated under ISO gait load. The tibia/talus-metal prosthesis interfaces micromotion of the five TAR models gradually increased during the support phase, then gradually fell back after entering the swing phase. The improved models (models B-E) showed lower bone-metal prosthesis interface micromotion when compared with the original model (model A), but there was no significant difference among models A-E ( P>0.05). The maximum micromotion of tibia appeared at the dome of the tibial bone groove, and the ​​micromotion area was the largest in model A and the smallest in model E. The maximum micromotion of talus appeared at the posterior surface of the central bone groove, and there was no difference in the micromotion area among models A-E. The contact area of the articular surface of the insert/talus prosthesis in each group increased in the support phase and decreased in the swing phase during the gait cycle. Compared with model A, the articular surface contact area of models B-E increased, but there was no significant difference among models A-E ( P>0.05). The change trend of the maximum stress on the articular surface of the inserts/talus prosthesis was similar to that of the contact area. Only the maximum contact stress of the insert joint surface of models D and E was lower than that of model A, while the maximum contact stress of the talar prosthesis joint surface of models B-E was lower than that of model A, but there was no significant difference among models A-E ( P>0.05). The high stress area of the lateral articular surface of the improved inserts significantly reduced, and the articular surface stress distribution of the talus prosthesis was more uniform. Adding a flexible layer in the insert can improve the elasticity of the overall component, which is beneficial to absorb the impact force of the artificial ankle joint, thereby reducing interface micromotion and improving contact behavior. The mechanical properties of the inserts designed with the platform type and thicker flexible layer are better.

Finite element analysis of five internal fixation modes in treatment of Day type Ⅱcrescent fracture dislocation of pelvis

To compare the biomechanical differences among the five internal fixation modes in treatment of Day type Ⅱ crescent fracture dislocation of pelvis (CFDP), and find an internal fixation mode which was the most consistent with mechanical principles. Based on the pelvic CT data of a healthy adult male volunteer, a Day type Ⅱ CFDP finite element model was established by using Mimics 17.0, ANSYS 12.0-ICEM, Abaqus 2020, and SolidWorks 2012 softwares. After verifying the validity of the finite element model by comparing the anatomical parameters with the three-dimensional reconstruction model and the mechanical validity verification, the fracture and dislocated joint of models were fixed with S 1 sacroiliac screw combined with 1 LC-Ⅱ screw (S 1+LC-Ⅱ group), S 1 sacroiliac screw combined with 2 LC-Ⅱ screws (S 1+2LC-Ⅱ group), S 1 sacroiliac screw combined with 2 posterior iliac screws (S 1+2PIS group), S 1 and S 2 sacroiliac screws combined with 1 LC-Ⅱ screw (S 1+S 2+LC-Ⅱ group), S 2-alar-iliac (S 2AI) screw combined with 1 LC-Ⅱ screw (S 2AI+LC-Ⅱ group), respectively. After each internal fixation model was loaded with a force of 600 N in the standing position, the maximum displacement of the crescent fracture fragments, the maximum stress of the internal fixation (the maximum stress of the screw at the ilium fracture and the maximum stress of the screw at the sacroiliac joint), sacroiliac joint displacement, and bone stress distribution around internal fixation were observed in 5 groups. The finite element model in this study has been verified to be effective. After loading 600 N stress, there was a certain displacement of the crescent fracture of pelvis in each internal fixation model, among which the S 1+LC-Ⅱ group was the largest, the S 1+2LC-Ⅱ group and the S 1+2PIS group were the smallest. The maximum stress of the internal fixation mainly concentrated at the sacroiliac joint and the fracture line of crescent fracture. The maximum stress of the screw at the sacroiliac joint was the largest in the S 1+LC-Ⅱ group and the smallest in the S 2AI+LC-Ⅱ group. The maximum stress of the screw at the ilium fracture was the largest in the S 1+2PIS group and the smallest in the S 1+2LC-Ⅱ group. The displacement of the sacroiliac joint was the largest in the S 1+LC-Ⅱ group and the smallest in the S 1+S 2+LC-Ⅱ group. In each internal fixation model, the maximum stress around the sacroiliac screws concentrated on the contact surface between the screw and the cortical bone, the maximum stress around the screws at the iliac bone concentrated on the cancellous bone of the fracture line, and the maximum stress around the S 2AI screw concentrated on the cancellous bone on the iliac side. The maximum bone stress around the screws at the sacroiliac joint was the largest in the S 1+LC-Ⅱ group and the smallest in the S 2AI+LC-Ⅱ group. The maximum bone stress around the screws at the ilium was the largest in the S 1+2PIS group and the smallest in the S 1+LC-Ⅱ group. For the treatment of Day type Ⅱ CFDP, it is recommended to choose S 1 sacroiliac screw combined with 1 LC-Ⅱ screw for internal fixation, which can achieve a firm fixation effect without increasing the number of screws.

Body weight reduction by exercise increases the urinary 3-methylhistidine excretion level with relatively positive nitrogen, sodium, and potassium balances when compared to dietary restriction

BackgroundRegarding changes in muscle mass, differences due to types of exercise and/or nutritional interventions, and associations with nutrient balances are still unclear. MethodsTo estimate changes in muscle mass during a body weight loss program using either a diet or exercise regimen, we investigated levels of muscle mass-related indices, and body contents of nitrogen, sodium, and potassium as measured by the balance method. Six healthy young adult male volunteers participated in two 10-day crossover experiments (20 days total). The first 5 days comprised an adjustment period (energy intake, 2656 ± 367 kcal/day (mean ± standard deviation)). During the second 5-day period, the participants either reduced their energy intake to 1770 ± 244 kcal/day (diet regimen) or exercised on a bicycle ergometer to expend 886 ± 122 kcal/day (exercise regimen). ResultsThe nitrogen, sodium, and potassium balances were significantly more positive during the exercise regimen than during the diet regimen. The urinary excretion levels of creatinine, 3-methylhistidine (3-MH), aldosterone, and catecholamines, and the 3-MH/creatinine ratio were significantly increased only during the exercise regimen. ConclusionsThe exercise regimen suppresses the decrease in muscle mass-related indices during body weight loss compared to the diet regimen with a relatively positive state of whole-body protein, sodium, and potassium balances, accompanied by an increase in sympathetic/adrenal cortical functions.

The atherosclerosis index during body weight reduction is improved with exercise

IntroductionBody weight reduction is often used for addressing lifestyle-related diseases, and for slimming down or improving the competitiveness of athletes. It is known that high-density lipoprotein-cholesterol (HDL-C) levels can be increased by habitual exercise, while low-density lipoprotein-cholesterol (LDL-C) levels may not always be decreased by dietary restriction or exercise. We hypothesized that the levels of not only HDL-C, but also LDL-C improve more with body weight reduction by a combined diet-and-exercise regimen than that by a diet-only regimen. Summary of facts and resultsSix healthy young adult male volunteers participated in two 10-day crossover experiments (20 days total). The first 5 days comprised an adjustment period (energy intake, 2521±304kcal/day (mean±standard deviation)). During the second 5-day period, participants either reduced their energy intake to 1261±152kcal/day, or reduced their energy intake to 1891±228kcal/day and exercised on a bicycle ergometer to consume 630±76kcal/day. Decreases in the serum total cholesterol (TC), LDL-C, and apolipoprotein (apo) B levels were significantly larger, and decreases in the HDL-C and apo A1 levels were significantly smaller with the diet-and-exercise regimen than with the diet-only regimen. Consequently, the atherosclerosis index (AI: (TC–HDL-C)/HDL-C ratio) was significantly lower, and the degree of its reduction was significantly larger, after the diet-and-exercise regimen than after the diet-only regimen. ConclusionThese results suggest that reducing the body weight by a combination of diet and exercise has more beneficial effects on cholesterol metabolism, including changes in apo levels, than diet alone in healthy young adults.

The Left ventricular ejection fraction and left ventricular volumes assessed from 99mTC single photon emission tomography technique during stress and rest in relation to age in normal volunteer students.

The heart is subject to structural and functional changes with advancing age. Left ventricular compliance appears to decline with age, which could explain why the elderly have such a high rate of heart failure. Changes in heart function with age are associated with an increased risk of cardiovascular death and morbidity. Various techniques have been used to measure the impact of age on heart structure and function. Subject and methods: The study included 221 healthy adult male and female volunteers (160 females and 61 males, 20–80 years of age). All healthy subjects volunteered to participate in this study. They were classified according to their age. All healthy subjects enrolled in the study underwent myocardial perfusion imaging following the 2-day rest–stress 99mTc sestamibi (GSPECT) protocol. At rest and during stress, end-diastolic volume, end-systolic volume, and ejection fraction using the GSPECT software were assessed both at rest and during stress for comparison. The following parameters were measured: left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV), and left ventricular ejection fraction (LVEF). The results show that the change in left ventricular ejection fraction (LVEF) decreased during rest and stress in all age groups. In contrast, the change in left ventricular end-systolic volume (LVESV) increased during stress and rest compared with the left ventricular end-diastolic volume (LVEDV) for all ages. Results show a significant change in EDV, ESV, and EF% (16.49%, 30.35%, -7.49%) with p-value < 0.05 for the groups (20- 49). Also a significant change in EDV, ESV, and EF% (12.13%, 24.86%,-1.62%), respectively, with p-value <0.05. for age range (50-80) years. In conclusion, in people with no cardiac functional or structural problems, the aging process is linked to considerable alterations in left and right ventricular EF, ESV, and EDV. When assessing SPECT with 99mTc investigations, our findings highlight the need to adopt age-adapted data as a reference standard. Keywords: SPECT with 99mTC, Age, Hemodynamics, Rest and Stress

Mechanical analysis of the femoral neck dynamic intersection system with different nail angles and clinical applications.

The femoral neck dynamic intersection system (FNS) is mechanically more stable than other internal fixation techniques. Current studies have confirmed that the structural design of FNS has good biomechanical properties in European and American populations. However, whether the suitability of the FNS's 130° main nail angle design for Asian populations has been thoroughly investigated remains unclear. To compare the biomechanical stability differences among different main nail angles of the FNS in the treatment of femoral neck fractures in Asian populations. Computed tomography data of the femur of healthy adult male volunteers were imported into Mimics software to create a three-dimensional model of the femur. The model was adapted to the curve using Geomagic software and imported into Solidworks software to construct the Pauwels I femoral neck fracture model and design the FNS internal fixation model using different main nail angles. Afterward, the models were assembled with the FNS fracture model and meshed using the preprocessing Hypermesh software. Subsequently, they were imported into Abaqus software to analyze and evaluate the biomechanical effects of different angles of the FNS main nail on the treatment of femoral neck fractures. The peak displacement of the proximal femur under different angles of FNS fixation under stress was 7.446 millimeters in the 120° group and 7.416 millimeters in the 125° group; in the 130°, 135°, and 140° FNS fixation groups, the peak displacement was 7.324 millimeters, 8.138 millimeters, and 8.246 millimeters, respectively. In the 120° and 125° FNS fixation groups, the maximum stresses were concentrated at the main nail and the anti-rotation screw, which intersected the fracture line of the femur neck, resulting in peak stresses of 200.7 MPa and 138.8 MPa, respectively. Peak stresses of 208.8 MPa, 219.8 MPa, and 239.3 MPa were observed on the angular locking plate distal to the locking screw in the 130°, 135°, and 140° fixation groups. FNS has significant stress distribution properties, a minimal proximal femoral displacement, and an optimal stability for treating femoral neck fractures in Asian populations when performed with a 130° main nail angle.

Biomechanical effect of proximal multifidus injury on adjacent segments during posterior lumbar interbody fusion: a finite element study

BackgroundAdjacent segment degeneration (ASD) is a common complication of lumbar interbody fusion; the paraspinal muscles significantly maintain spinal biomechanical stability. This study aims to investigate the biomechanical effects of proximal multifidus injury on adjacent segments during posterior lumbar interbody fusion (PLIF).MethodsData from a lumbosacral vertebral computed tomography scan of a healthy adult male volunteer were used to establish a normal lumbosacral vertebral finite element model and load the muscle force of the multifidus. A normal model, an L4/5 PLIF model (PFM) based on a preserved proximal multifidus, a total laminectomy PLIF model (TLPFM), and a hemi-laminectomy PLIF model based on a severed proximal multifidus were established, respectively. The range of motion (ROM) and maximum von Mises stress of the upper and lower adjacent segments were analyzed along with the total work of the multifidus muscle force.ResultsThis model verified that the ROMs of all segments with four degrees of freedom were similar to those obtained in previous research data, which validated the model. PLIF resulted in an increased ROM and maximum von Mises stress in the upper and lower adjacent segments. The ROM and maximum von Mises stress in the TLPFM were most evident in the upper adjacent segment, except for lateral bending. The ROM of the lower adjacent segment increased most significantly in the PFM in flexion and extension and increased most significantly in the TLPFM in lateral bending and axial rotation, whereas the maximum von Mises stress of the lower adjacent segment increased the most in the TLPFM, except in flexion. The muscle force and work of the multifidus were the greatest in the TLPFM.ConclusionsPLIF increased the ROM and maximum von Mises stress in adjacent cranial segments. The preservation of the proximal multifidus muscle contributes to the maintenance of the physiological mechanical behavior of adjacent segments, thus preventing the occurrence and development of ASD.

Imaging evaluation of physical activity effect on knee articular cartilage

IntroductionHyaline cartilage is a complex tissue with great load absorbing-function. Studies showed that moderate exercise can have a positive effect on chondral matrix composition but excessive can be harmful to cartilage. ObjectivesEvaluate knee cartilage thickness before and after physical activity (running) in healthy young individuals. MethodsTen healthy young adult male volunteers aged between 18 and 21 years old were selected to undergo magnetic resonance imaging examination of the right knee to measure the cartilage thickness of the anterior, medial, and lateral compartments before and after 1 hour of continuous running. Cartilage thickness measurements were performed by a radiologist who did not know the identity of the volunteers or the moment of the evaluation (before or after the exercise). ResultsThe subjects' mean age, height, and weight were 19.5 years, 1.80 m, and 75.2 kg, respectively, with a mean body mass index of 23.14. There was a decrease in chondral thickness after running on all surfaces evaluated. The changes that were relevant (P < .05) were all the medial femoral condyle, the anterior portion of the lateral femoral condyle, the anterior portion of the lateral plateau, the entire surface of the patella and trochlea. The greatest difference in thickness between before and after exercise was observed in the lateral facet of the patella (−0.224 mm) followed by the anterior surface of the medial femoral condyle (−0.186 mm). In proportional values, the highest decrease occurred in the anterior portion of the medial femoral condyle (−11.42%). ConclusionThere was a decrease in knee chondral thickness after 60 minutes of running, being statistically significant in the medial femoral condyle, anterior surface of the lateral femoral condyle, and lateral plateau and patellofemoral joint (patella and trochlea). Level of evidenceIV (Case Series).

The Comparative Bioavailability of Fluticasone and Azelastine Delivered as a Single Fixed Dose Combination (MP-AzeFlu) in Comparison to Two Different Formulations of Azelastine and Fluticasone Propionate Following Intranasal Administration in Healthy Chinese Volunteers.

Two studies (Study I and Study II) were conducted in healthy Chinese volunteers to confirm that there was no pharmacokinetic drug interaction between AZE and FLU in MP-AzeFlu. The secondary objective was to evaluate the pharmacokinetic parameters of MP-AzeFlu compared with the commercially available mono-components. Both studies were a randomized, open-label, three-period, six-sequence, single-dose cross-over trial (William's design) conducted at Beijing Hospital (Beijing, China) in September and October of 2019 in 30 healthy adult male and female volunteers. The natural log transformed parameters: AUC0-tlast, AUC0-∞ and Cmax were analyzed. The comparison of PK parameters between MP-AzeFlu and Aze (commercially available) showed that the LS mean ratios (90% CI) values for, AUC0-tlast, AUC 0-∞ and Cmax were 100.29% (94.31-106.66%), 100.76% (94.60-107.32%) and 93.14% (81.47-106.48%). The comparison of PK parameters between MP-AzeFlu and Flu (commercially available) for the bioavailability evaluation showed that the LS mean ratios (90% CI) values for, AUC0-tlast, AUC 0-∞ and Cmax were 83.48% (69.81-99.82%), 100.19% (87.34-114.94%) and 81.91% (68.50-97.95%). The study results confirm that neither the FLU or the AZE component in the combination product (MP-AzeFlu), nor the existing qualitative and quantitative differences in the formulation between the currently marketed AZE and FLU mono-product, display significant potential to impact the systemic exposure of AZE or FLU in Chinese subjects.

A phase-I, open label clinical trial to assess the safety & tolerability of qHPV vaccine manufactured by Serum Institute of India Pvt. Ltd. in adults

BackgroundThis first in human study was designed as an open label clinical trial to assess safety and tolerability of Serum Institute of India Pvt. Ltd. (SIIPL) quadrivalent HPV (qHPV) vaccine. MethodsA total of 48 healthy male and female (24 each) adult volunteers were administered a 0.5 ml single dose of SIIPL qHPV vaccine intramuscularly, and were followed for one month for safety outcomes viz., immediate, solicited, unsolicited and serious adverse events. Results47 subjects completed the study in compliance with protocol. One subject had pain immediately after immunization which was recovered without treatment. None of the participants experienced any other local or systemic solicited AEs and serious AE. ConclusionqHPV vaccine manufactured by SIIPL was found to be safe and well tolerable in adults. Further clinical development should continue to assess safety and immunogenicity, in the target population following recommended 2 and 3-dose schedule.Clinical Trial Registration – CTRI/2017/02/007785.

Biomechanical evaluation of multiple pelvic screws and multirod construct for the augmentation of lumbosacral junction in long spinal fusion surgery.

Background: Posterior long spinal fusion was the common procedure for adult spinal deformity (ASD). Although the application of sacropelvic fixation (SPF), the incidence of pseudoarthrosis and implant failure is still high in long spinal fusion extending to lumbosacral junction (LSJ). To address these mechanical complications, advanced SPF technique by multiple pelvic screws or multirod construct has been recommended. This was the first study to compare the biomechanical performance of combining multiple pelvic screws and multirod construct to other advanced SPF constructs for the augmentation of LSJ in long spinal fusion surgery through finite element (FE) analysis. Methods: An intact lumbopelvic FE model based on computed tomography images of a healthy adult male volunteer was constructed and validated. The intact model was modified to develop five instrumented models, all of which had bilateral pedicle screw (PS) fixation from L1 to S1 with posterior lumbar interbody fusion and different SPF constructs, including No-SPF, bilateral single S2-alar-iliac (S2AI) screw and single rod (SS-SR), bilateral multiple S2AI screws and single rod (MS-SR), bilateral single S2AI screw and multiple rods (SS-MR), and bilateral multiple S2AI screws and multiple rods (MS-MR). The range of motion (ROM) and stress on instrumentation, cages, sacrum, and S1 superior endplate (SEP) in flexion (FL), extension (EX), lateral bending (LB), and axial rotation (AR) were compared among models. Results: Compared with intact model and No-SPF, the ROM of global lumbopelvis, LSJ, and sacroiliac joint (SIJ) was decreased in SS-SR, MS-SR, SS-MR, and MS-MR in all directions. Compared with SS-SR, the ROM of global lumbopelvis and LSJ of MS-SR, SS-MR, and MS-MR further decreased, while the ROM of SIJ was only decreased in MS-SR and MS-MR. The stress on instrumentation, cages, S1-SEP, and sacrum decreased in SS-SR, compared with no-SPF. Compared with SS-SR, the stress in EX and AR further decreased in SS-MR and MS-SR. The most significantly decreased ROM and stress were observed in MS-MR. Conclusion: Both multiple pelvic screws and multirod construct could increase the mechanical stability of LSJ and reduce stress on instrumentation, cages, S1-SEP, and sacrum. The MS-MR construct was the most adequate to reduce the risk of lumbosacral pseudarthrosis, implant failure, and sacrum fracture. This study may provide surgeons with important evidence for the application of MS-MR construct in the clinical settings.

Effect of Food on the Pharmacokinetics of Fluoxetine in Healthy Male Adult Volunteers(Conference Paper )#

Fluoxetine (FX) is an antidepressant drug administered only orally in humans. Despite the wide use of FX, until now, there is only limited literature concerning the pharmacokinetics (PK) of FX and the effect of food on its PK. Thus, the objective of this investigation was to study the PK of FX in Arabic healthy male adult volunteers under fasting and fed conditions. In the fasting study, FX 20 mg capsules (Prozac®, Eli Lilly, Canada) were administered to 41 volunteers after overnight fasting of 12 hours, followed by blood sampling from each volunteer immediately before dosing (zero time) and then at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 24, 36, 48, 60, 72, 96, 120, and eventually at 144 hours after FX dosing. The fed study was conducted after 90 days wash-out period following the completion of the fasting study. The same subjects who received FX in the fasting study were administered the drug directly after a fatty breakfast (fed study), followed by blood sampling intervals similar to the schedule mentioned above for the fasting study. The current investigation demonstrated no statistical differences in the FX pharmacokinetic parameters Cmax, AUC0–t, AUC0–∞, Kel, T1/2, MRT, Cl/F, and Vd/F after fasting compared to the fed conditions, whereas there was statistically significant elongation in the Tmax values after food intake. Therefore, this study concludes the absence of food effect on the PK of FX (except Tmax) in the Arabic population and confirms the method of administration mentioned in the product information but also concludes high interindividual variation in FX exposure (AUC), which suggest that therapeutic drug monitoring (TDM) might be advisable when feasible.

GLP-1 Receptor Agonists Induce Growth Hormone Secretion in Healthy Volunteers.

Growth hormone (GH) is an essential regulator of growth, body composition and fuel metabolism and, consequently, GH secretion is under the feedback control of numerous nutritional and endocrine mediators. Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have been shown to exert pleiotropic effects, including stimulation of the activity of the hypothalamic-pituitary-adrenal axis. As GLP-1RAs exert multiple metabolic effects, we hypothesised that they may also affect the secretion of GH and examined the effect of a short-acting and a long-acting GLP-1 RA on GH secretion. This is a post hoc analysis of data from clinical trials. Two separate single-group open-label clinical trials were carried out in the ambulatory care setting with a duration of 1 and 21days, respectively. Healthy adult male and female volunteers with no chronic illnesses or use of daily medicines were recruited for the study. The two interventions were: study 1, single dose of 10µg exenatide administered subcutaneously (s.c.); study 2, 0.6mg liraglutide administered s.c. once daily for 21days. Administration of a single dose of exenatide (study 1) caused a clear increase in GH levels, peaking between 60 and 120min post-administration. There was also a small but statistically significant decrease in luteinising hormone and testosterone levels 120min after exenatide dosing. Administration of the long-acting GLP-1RA liraglutide daily for 21 days (study 2) elicited an increase in GH levels with no change in insulin-like growth factor-1 (IGF-1) concentrations after 3weeks of treatment. The results show that the administration of GLP-1RAs may elicit an increase in growth hormone levels. GLP-1 signalling may be a novel mechanism of regulation of GH secretion. This finding needs to be replicated in the placebo-controlled trial. NCT02089256 and NCT03160261.

The Self-Rated Effects of Alcohol Are Related to Presystemic Metabolism of Alcohol.

A high number of alcohol units required to feel a subjective effect of alcohol predicts future alcohol use disorders (AUDs). The subjective response to alcohol can be measured using the validated retrospective self-rated effects of alcohol (SRE) questionnaire. Few studies have investigated the specific relationship between SRE and blood alcohol concentration (BAC) in an experimental setting. Twenty healthy young adult male volunteers who had experience with binge drinking, but did not have AUD, filled out the SRE-questionnaire and were served with a fixed amount of alcohol per body weight. BACs were measured throughout a 12-hour period, reaching a maximum BAC of ~0.13%. Median split of SRE-scores was utilized to compare BACs among participants with relatively high effects (low SRE) and relatively low effects (high SRE) of alcohol. Participants reporting a relatively low SRE-score had a statistically significant higher measured BAC at all time points until alcohol was eliminated. This was especially pronounced during the first 2 hours after alcohol (P = 0.015) without a significant difference in the alcohol elimination rate being detected. The study indicates that a self-ated SRE-score is related to BACs after the ingestion of a standardized amount of alcohol per body weight. Reporting a higher number of alcohol units before feeling an effect was related to a lower BAC. As the differences in BAC between relatively high and low self-rated effects appeared rapidly after intake, this could be interpreted as an effect of presystemic metabolism of alcohol.

Pharmacokinetic Study of Intranasal Dexamethasone and Methylprednisolone Compared with Intravenous Administration: Two Open-Label, Single-Dose, Two-Period, Two-Sequence, Cross-Over Study in Healthy Volunteers

Dexamethasone (DXM) and methylprednisolone (MEP) are potent glucocorticoids used to control several inflammatory conditions. Evidence of delayed DXM reaching the central nervous system (CNS) as well as tachyphylaxis and systemic, undesirable side effects are the main limitations of peripheral delivery. Intranasal administration offers direct access to the brain as it bypasses the blood-brain barrier. The Mucosal Atomization Device is an optimal tool that can achieve rapid absorption into the CNS and the bloodstream across mucosal membranes. This study was designed to evaluate and compare the bioavailability of DXM and MEP after intranasal versus intravenous administration. Two open-label, balanced, randomized, two-treatment, two-period, two-sequence, single-dose, crossover studies were conducted, which involved healthy male and female adult volunteers. After intranasal administration, DXM and MEP were detected in plasma after the first sampling time. Mean peak concentrations of DXM and MEP were 86.61 ng/mL at 60 min and 843.2 ng/mL at 1.5 h post-administration, respectively. DXM and MEP showed high absolute bioavailability, with values of 80% and 95%, respectively. No adverse effects were observed. DXM and MEP systemic bioavailability by intranasal administration was comparable with the intravenous one, suggesting that the intranasal route can be used as a non-invasive and appropriate alternative for systemic drug delivery.