Changes In Clearance Research Articles

Changes in Plasma Clearance of CYP450 Probe Drugs May Not be Specific for Altered In Vivo Enzyme Activity Under (Patho)Physiological Conditions: How to Interpret Findings of Probe Cocktail Studies.

CYP450 (CYP) phenotyping involves quantifying an individual's plasma clearance of CYP-specific probe drugs, as a proxy for in vivo CYP enzyme activity. It is increasingly applied to study alterations in CYP enzyme activity under various (patho)physiological conditions, such as inflammation, obesity, or pregnancy. The phenotyping approach assumes that changes in plasma clearance of probe drugs are driven by changes in CYP enzyme activity. However, plasma clearance is also influenced by protein binding, blood-to-plasma ratio, and hepatic blood flow, all of which may change under (patho)physiological conditions. Using a physiologically based pharmacokinetic (PBPK) workflow, we aimed to evaluate whether the plasma clearance of commonly used CYP probe drugs is indeed directly proportional to alterations in CYP enzyme activity (sensitivity), and to what extent alterations in protein binding, blood-to-plasma ratio, and hepatic blood flow observed under (patho)physiological conditions impact plasma clearance (specificity). Plasma clearance of CYP probe drugs is sensitive to alterations in CYP enzyme activity, since alterations in intrinsic clearance between - 90% and + 150% resulted in near-proportional changes in plasma clearance, except for midazolam in the case of > 50% CYP3A4 induction. However, plasma clearance also changed near-proportionally with alterations in the unbound drug fraction, diminishing probe specificity. This was particularly relevant for high protein-bound probe drugs, as alterations in plasma protein binding resulted in larger relative changes in the unbound drug fraction. Alterations in the blood-to-plasma ratio and hepatic blood flow of ± 50% resulted in plasma clearance changes of less than ± 16%, meaning they limitedly impacted plasma clearance of CYP probe drugs, except for midazolam. In order to correct for the impact of non-metabolic determinants on probe drug plasma clearance, an R script was developed to calculate how much the CYP enzyme activity is actually altered under (patho)physiological conditions, when alterations in the unbound drug fraction, blood-to-plasma ratio, and/or hepatic blood flow also impact probe drug plasma clearance. As plasma protein binding can change under (patho)physiological conditions, alterations in unbound drug fraction should be accounted for when using CYP probe drug plasma clearance as a proxy for CYP enzyme activity in patient populations. The tool developed in this study can support researchers in determining alterations in CYP enzyme activity in patients with (patho)physiological conditions.

Population pharmacokinetic modeling study and discovery of covariates for the antidepressant sertraline, a serotonin selective reuptake inhibitor

The purpose of this study was to discover effective covariates related to explanation of inter-individual pharmacokinetic (PK) variations through population pharmacokinetic (Pop-PK) modeling for sertraline and to provide insight into establishing scientific regimen. The bioequivalence results of sertraline performed on 24 healthy Korean men and the physiological and biochemical parameters derived from each individual were used as data to develop a Pop-PK model of sertraline for Koreans. And the relevant effectiveness of ∗10 allele polymorphisms of CYP2D6 in sertraline PK polymorphisms was further confirmed through a modeling approach. The Pop-PK profiles of sertraline were explained by the basic structure of sequential 2-absorption with 1-compartment, and in terms of inter-individual PK diversity, the volume of distribution could be significantly correlated with estimated glomerular filtration rate (eGFR) and clearance with total protein levels. CYP2D6∗10 allele was not significant in interpreting sertraline PK diversity. As a result of model simulation, the concentration of sertraline in serum significantly increased as total protein and eGFR levels became higher and lower, respectively. The mean serum concentrations of sertraline at steady-state differed by up to 2.12 times from 10.36 to 22.02 ng/mL depending on changes in total protein and eGFR levels, and the fluctuations between the maximum and minimum concentration values ranged from 2.02 to 29.51 to 4.31–63.78 ng/mL. The factor that significantly influenced change in mean serum concentration of sertraline at steady-state was the total protein level, which was interpreted to be closely related to the change in clearance due to the high serum protein binding of sertraline.

A Randomized-Controlled Trial Targeting Cognition in Early Alzheimer's Disease by Improving Sleep with Trazodone (REST).

Alzheimer's disease (AD) is a leading cause of mortality and morbidity among aging populations worldwide. Despite arduous research efforts, treatment options for this devastating neurodegenerative disease are limited. Sleep disturbances, through their link to changes in neural excitability and impaired clearance of interstitial abnormal protein aggregates, are a key risk factor for the development of AD. Research also suggests that the neuroprotective effects of sleep are particularly active during slow wave sleep. Given the strong link between sleep disturbance and AD, targeting sleep in the prodromal stages of AD, such as in mild cognitive impairment (MCI), represents a promising avenue for slowing the onset of AD-related cognitive decline. In efforts to improve sleep in older individuals, several pharmacologic approaches have been employed, but many pose safety risks, concern for worsening cognitive function, and fail to effectively target slow wave sleep. Trazodone, a safe and widely used drug in the older adult population, has shown promise in inducing slow wave sleep in older adults, but requires more rigorous research to understand its effects on sleep and cognition in the prodromal stages of AD. In this review, we present the rationale and study design for our randomized, double-bind, placebo-controlled, crossover trial (NCT05282550) investigating the effects of trazodone on sleep and cognition in 100 older adults with amnestic MCI and sleep complaints.

Analysis of relaxation characteristics of multi-bolted connections under the transverse cyclic load

A modeling method under lateral cyclic loading is proposed for the complex multi-bolt connection loosening problem. Firstly, the thread stress surface is divided into n small sectors, and the self-relaxation mechanical model of multi-bolt connection is established considering the interaction between bolts. Secondly, the self-relaxation model is solved by MATLAB software and compared with Nassar model to verify the correctness of the model. Finally, considering the influence of different bolt number, hole clearance and connection spacing, the relaxation characteristics of multi-bolt connection are studied. The results show that during the loosening process, the bolt head undergoes a bending-sliding-bending cycle process, and the bolt tension shows a wave downward trend. When multiple bolts are connected, the number of loosening cycles decreases linearly with the increase of hole clearance. With the equidistant increase of bolt connection spacing, the number of bolt loosening cycles shows a decreasing trend. Compared with the number of bolts, the change of bolt hole clearance and connection spacing is more likely to affect bolt loosening.

Are We Dosing Correctly? Population Pharmacokinetics of Cefepime in Critically Ill Pediatric Patients

Abstract Background Dosing guidelines of cefepime are well defined in healthy pediatric and adult populations but have not been extensively studied in critically ill pediatric patients. Patients who are critically ill may have significant alterations in antibiotic pharmacokinetics (PK) and pharmacodynamics (PD) due to many factors. Receipt of ECMO or CRRT may further alter PK/PD due to changes in clearance and volume of distribution and the depletion of plasma proteins. Since critically ill pediatric patients are likely to receive multiple courses of antimicrobials, optimization of drug dosing and delivery is critically important for individual patient outcomes. This study will test the hypothesis that the PK of cefepime is substantially altered in critically ill pediatric patients. Methods We prospectively enrolled patients in VUMC pediatric ICUs receiving cefepime, including those receiving ECMO or CRRT. Plasma samples were collected at opportune timepoints enriched for specific PK/PD metrics. Cefepime plasma concentrations were measured by LC-MS/MS. Weight, dose, interval, and administration time were extracted from the medical record. Monolix was used to fit population PK models using one and two-compartment models with a proportional error model. Covariate modeling was performed with a priori selected covariates: ECMO, CRRT, sex, race, ethnicity, gestational age, and creatinine clearance (CrCl). The final covariate model was used to perform probability of target attainment (PTA) analysis using Monte Carlo simulation. 6,000 subjects were simulated for each dosing regimen, with 3 weight categories (≤9 kg, 9-25 kg, and >25 kg) and 2 CrCl categories (≤90 mL/min and >90 mL/min). PTA was calculated over a grid of possible MIC values based on three targets, 65% fT>MIC, 100% fT>MIC, and 100% fT>4×MIC. Results Preliminary data from 84 pediatric participants receiving cefepime were analyzed. Of these, 9 received CRRT and 10 received ECMO. An average of 3 samples were collected per participant. A two compartment with proportional error model was selected as the base model. Population PK parameter estimates for the base model, base model with weight, and final covariate model were calculated. Inclusion of weight and CrCl significantly improved model fit. CRRT, ethnicity, and gestational age did significantly improve model fit, but their inclusion in the model did not provide evidence of being significantly better than the model with only weight and CrCl. The results from the PTA analysis are seen in Figure 1. We observed an overall ordering of PTA by dosing regimen across all three targets, with q8h 3-hour infusion having the highest PTA and q12h 30-minute infusion having the lowest PTA. Increased CrCl led to reduced PTA and as weight increased, PTA also increased. Conclusion This study will be among the first and largest to characterize cefepime PK in the critically ill pediatric population. Clinicians should incorporate local antibiograms with these population PK models to determine optimal dosing in critically ill pediatric patients. The use of extended infusions may be beneficial for PK/PD target achievement, particularly for resistant pathogens. Since clinical covariates affect PK parameters, this population may also benefit from therapeutic drug monitoring. Figure 1. Comparison of PTA among four dosing regimens of cefepime at targets of 65% fT>MIC, 100% fT>MIC, and 100% fT>4×MIC.

Evaluation of the effect of CYP2D6 and OCT1 polymorphisms on the pharmacokinetics of tramadol: Implications for clinical safety and dose rationale in paediatric chronic pain.

Our investigation aimed to assess the dose rationale of tramadol in paediatric patients considering the effect of CYP2D6/OCT1 polymorphisms on systemic exposure. Recommendations were made for the oral dose of tramadol to be used in a prospective study in children (3months to < 18 years old) with chronic pain. Intravenous pharmacokinetic and genotype data from neonatal patients (n = 46) were available for this analysis. The time course of tramadol and O-desmethyltramadol (M1) concentrations was characterized using a nonlinear mixed effects approach in conjunction with extrapolation principles. Clinical trial simulations were then implemented to explore the effects of polymorphism, maturation and developmental growth on the disposition of tramadol and M1. Reported efficacious exposure range in adult subjects were used as reference. The pharmacokinetics of tramadol and M1 was characterized by a two-compartment model. The total clearance of tramadol (CLPP) comprised CYP2D6-mediated metabolism (CLPM) and other pathways (CLPO). Age-related changes in CLPM, CLPO and M1 clearance (CLMO) were described by a sigmoid function, with CYP2D6 as a covariate on CLPP and CLPM, and OCT1 on CLMO. Simulation scenarios includingdifferent CYP2D6/OCT1 combinations revealed that steady-state concentrations are above the putative ranges for analgesia in >15% and >70% of subjects after doses of 3 and 8mg/kg, respectively. In the absence of genotyping, reference exposure ranges can be used to define the dose rationale for tramadol in paediatric chronic pain. However, a starting dose of 0.5mg/kg/day should be considered, followed by stepwise titration to the desired analgesic response.

Effectiveness of TheraPEP Versus Conventional Breathing Techniques in Managing Acute COPD Exacerbations

Background: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide, often complicated by acute exacerbations that impair lung function and quality of life. Effective airway clearance techniques are essential in managing exacerbations, but the comparative effectiveness of different methods remains unclear. This study aimed to evaluate the short-term effectiveness of TheraPEP, a positive expiratory pressure (PEP) device, versus the Active Cycle of Breathing Technique (ACBT) in managing acute COPD exacerbations. Methods: A randomized controlled trial (RCT) was conducted with 60 patients (≥40 years) admitted with acute exacerbations of COPD. Participants were randomly assigned to either the TheraPEP group (n=30) or the ACBT group (n=30). Each group received three daily sessions of their assigned therapy throughout their hospital stay. Primary outcomes included dyspnea, measured by the modified Borg Dyspnea Scale, and secondary outcomes included sputum clearance, lung function (FEV1, FVC, and FEV1/FVC ratio), oxygen saturation (SpO₂), and quality of life, measured by the Breathlessness, Cough, and Sputum Scale (BCSS). Data were collected at baseline, discharge, and 14-day follow-up. A two-way repeated-measures ANOVA was used to examine changes in dyspnea, lung function, sputum clearance, SpO₂, and BCSS scores over time (baseline, discharge, and 14-day follow-up) within and between groups. The main effects of time (within-subject factor) and group (between-subject factor) were assessed, along with the interaction effects (time × group). Results: Both groups demonstrated significant improvements in dyspnea, lung function, and quality of life from baseline to discharge and follow-up. However, the TheraPEP group showed significantly greater improvements in sputum clearance (p=0.01), oxygen saturation (p=0.03), and BCSS scores (p=0.03) compared to the ACBT group. No significant between-group differences were found for FEV1, FVC, or FEV1/FVC ratio (p &gt; 0.05). Conclusions: Both TheraPEP and ACBT are effective in managing acute COPD exacerbations, but TheraPEP offers additional benefits in terms of sputum clearance and oxygenation. These findings suggest that TheraPEP may be more suitable for patients with severe mucus hypersecretion. Further research is warranted to assess the long-term effects of these therapies on COPD progression and patient outcomes.

Cigarette smoking prolongs inflammation associated with influenza infection and delays its clearance in mice.

Epidemiological studies have shown that smoking is associated with increased incidence of severe viral infections leading to hospitalization. Moreover, studies in experimental models have identified impaired antiviral responses and altered inflammatory responses, yet it is unclear how the effects of smoke exposure and influenza A infection interact and how this varies over the course of infection. We hypothesized that smoking would exacerbate innate immune responses against influenza. To test this, female BALB/c mice were exposed to cigarette smoke or air twice a day for 24-28 days and (mock) infected with H3N2 influenza A on day 21 while smoking continued. Three and seven days after infection, changes in immune cell populations, the transcriptome, and viral clearance in lung tissue were analyzed. After influenza A infection, smoke-exposed mice lost significantly more weight than air-exposed controls, indicating that smoking resulted in more severe disease. Immune cell and lung tissue transcriptome analysis revealed that neutrophil infiltration was prolonged and macrophage activation dysregulated after infection of smoke-exposed mice compared to air-exposed controls. Expression of genes in IL-6 and interferon pathways was similarly longer active. In parallel, we observed lower clearance of influenza virus in smoke-exposed mice after infection compared to air-exposed controls, indicating ineffective antiviral responses. Altogether, the data from our mouse model indicate that cigarette smoke exposure prolongs innate immune responses against influenza A. The results from this study help to explain the susceptibility of current smokers to severe influenza A disease.

Abstract MP31: The effect of dual SGLT1/2 inhibition on the progression of salt-sensitive hypertension

The dual inhibition of sodium-glucose co-transporter 1 and 2 (SGLT1/SGLT2) presents a novel therapeutic approach to cardiovascular diseases. The FDA recently approved the dual SGLT1/2 inhibitor sotagliflozin (Sota) for treating heart failure regardless of ejection fraction. However, our understanding of the effects and mechanisms of SGLT2 and dual SGLT1/2 inhibitors in salt-sensitive hypertension (SS HTN) remains limited. Thus, additional studies are needed to reveal the role and mechanism(s) of SGLTi in SS hypertension. In our previous studies, we demonstrated the beneficial effect of SGLT2i dapagliflozin (Dapa) on SS HTN in male and female Dahl SS rats on blood pressure (MAP after 3 weeks on high salt diet were: Dapa vs. vehicle: 136 ± 3 vs. 156 ± 6 mmHg in males and 140 ± 5 vs. 160±9 mmHg in females). This study aims to define the effects and potential mechanisms of dual SGLT1/2 inhibition in managing SS HTN. Dual SGLT1/2 inhibition with Sota (30 mg/kg/day) prevented the development of SS HTN in Dahl SS in both sexes without changes in heart rate. By the 21 st day of the high-salt challenge, MAP was lower more than 30 mmHg in treated groups (Sota vs. vehicle: male rats 126 ± 2 vs 157 ± 5 mmHg (N=7, p=0.0002); female rats 126 ± 3 vs 167 ± 10 mmHg (N=6, p=0.0095). Under Sota treatment, rats had significantly increased diuresis (Sota vs. vehicle: males 69 ± 3 vs 35 ± 2 ml and females 48 ± 5 vs 31 ± 2 ml on day 21), glucose and sodium excretion. In both sexes, Sota treatment resulted in a lower heart-to-body weight ratio, and kidney weight was not changed. Also, Sota attenuated kidney fibrosis and protein cast formation (Sota vs. vehicle: cortex fibrosis in males 2.3 ± 0.4 vs 4.6 ± 0.5 % and females 2.0 ± 0.2 vs 4.0 ± 0.7 %, outer medullary protein casts in males 2.5 ± 0.2 vs 16.0 ± 2.6 % and 1.9 ± 0.3 vs 7.5 ± 0.9 % in females) without changes in albuminuria in both sexes. However, no changes in glomerular filtration rate or creatine clearance were detected. Based on our data, it can be inferred that dual SGLT1/2 inhibition prevents the development of SS HTN and kidney damage. Potential mechanisms underlying those beneficial effects of SGLT1/2 inhibition will be further explored.

Demodulation algorithm of low coherent heterodyne interference signal for axial clearance measurement of rotating machinery

The time-domain low coherent heterodyne interference axial clearance measurement method has the challenges of small range and low precision in the clearance measurement of rotating machinery. An axial clearance demodulation algorithm based on the windowed power spectrum density transform (WPSD) is proposed. Based on the characteristics of low coherent heterodyne interference signal, the relationship model between window width and rotating structure motion parameters (amplitude of axial clearance change, rotor speed) is constructed, and the optimal window width mathematical model is obtained. The axial clearance measurement experiments are completed under different axial clearance measurement distances based on an experimental clearance platform, different rotor speeds and different axial clearance variation amplitudes. The experimental results show that the absolute error of the axial clearance reconstruction signal is less than 17 μm and the relative error is less than 4.8 % when the axial clearance measurement distance is 2.1 mm ∼ 11.3 mm, the rotor speed is in the range of 6000 rad/min ∼ 12000 rad/min, and the variation of axial clearance is in the range of 150 μm ∼ 350 μm. The experimental and simulation results are basically consistent.

Multi-objective optimization design of aerothermal performance for turbine blade squealer tip with inclined suction-side rim

To optimize the inclined rim design, multi-objective optimization was numerically conducted on the suction-side rim of the squealer tip in the GE-E3 rotor blade. The RANS equations, incorporating with the standard k-ω model, were numerically solved. Through the implementation of a Kriging surrogate model coupled with the NSGA-II evolutionary optimization technique, six geometric parameters on the suction-side rim went through iterative optimization. This process yielded three optimized squealer tip geometries on the Pareto front: Structure 1 with minimum total pressure loss, Structure 2 with optimal comprehensive aerothermal performance, and Structure 3 with minimum tip heat load. Comparative analysis revealed that with the inner and external wall inclined toward the cavity and passage respectively, the optimization results in a 3 %–11 % reduction in tip heat load, accompanied by an 8.5 %–10.2 % reduction in aerodynamic loss, facilitated by an attenuated upper passage vortex (UPV) and strengthened tip leakage vortex (TLV). The critical inclined region of the external rim wall, spanning 7 %–80 %, influences the exit total pressure loss distribution. The inclined inner wall upstream of 50 % Cax obstructs coolant jets from exiting the cavity, reducing the heat load on the cavity bottom. However, the inclined external wall from 66 % to 90 % Cax amplifies the impingement of the scraping vortex (SV), increasing local heat transfer. The thermal behavior of Structure 1 is sensitive to changes in tip clearance, whereas Structure 2 and 3 show more robust advantages. As the clearance increased, the aerodynamic losses associated with the TLV rise for all three optimized tips, but losses from the UPV remain similar. This study provides a novel approach for designing efficient squealer tip geometries incorporating an inclined rim.

Elevations in plasma glucagon are associated with reduced insulin clearance after ingestion of a mixed-macronutrient meal in people with and without type 2 diabetes

Aims/hypothesisThe temporal suppression of insulin clearance after glucose ingestion is a key determinant of glucose tolerance for people without type 2 diabetes. Whether similar adaptations are observed after the ingestion of a mixed-macronutrient meal is unclear.MethodsIn a secondary analysis of data derived from two randomised, controlled trials, we studied the temporal responses of insulin clearance after the ingestion of a standardised breakfast meal consisting of cereal and milk in lean normoglycaemic individuals (n=12; Lean-NGT), normoglycaemic individuals with central obesity (n=11; Obese-NGT) and in people with type 2 diabetes (n=19). Pre-hepatic insulin secretion rates were determined by the deconvolution of C-peptide, and insulin clearance was calculated using a single-pool model. Insulin sensitivity was measured by an oral minimal model.ResultsThere were divergent time course changes in insulin clearance between groups. In the Lean-NGT group, there was an immediate post-meal increase in insulin clearance compared with pre-meal values (p<0.05), whereas insulin clearance remained stable at baseline values in Obese-NGT or declined slightly in the type 2 diabetes group (p<0.05). The mean AUC for insulin clearance during the test was ~40% lower in the Obese-NGT (1.3 ± 0.4 l min−1 m−2) and type 2 diabetes (1.4 ± 0.7 l min−1 m−2) groups compared with Lean-NGT (1.9 ± 0.5 l min−1 m−2; p<0.01), with no difference between the Obese-NGT and type 2 diabetes groups. HOMA-IR and glucagon AUC emerged as predictors of insulin clearance AUC, independent of BMI, age or insulin sensitivity (adjusted R2=0.670). Individuals with increased glucagon AUC had a 40% reduction in insulin clearance AUC (~ −0.75 l min−1 m−2; p<0.001).Conclusions/interpretationThe ingestion of a mixed-macronutrient meal augments differing temporal profiles in insulin clearance among individuals without type 2 diabetes, which is associated with HOMA-IR and the secretion of glucagon. Further research investigating the role of hepatic glucagon signalling in postprandial insulin kinetics is warranted.Trial registrationISRCTN17563146 and ISRCTN95281775Graphical

Dysregulation of Human Hepatic Drug Transporters by Proinflammatory Cytokines.

Proinflammatory cytokines, elevated during inflammation caused by infection and/or autoimmune disorders, result in reduced clearance of drugs eliminated primarily by cytochrome P450 enzymes (CYPs). However, the effect of cytokines on hepatic drug transporter expression or activity has not been well-studied. Here, using plated human hepatocytes (PHHs; n = 3 lots), we investigated the effect of interleukin (IL)-6, IL-1β, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ), on the mRNA expression and activity of hepatic drug transporters. PHHs were incubated for 72 hours at their pathophysiologically relevant plasma concentrations, both individually (0.01, 0.1, 1, 10 ng/ml) or as a cocktail (i.e., when each was combined at 0.1 or 1 ng/ml). Following cytokine cocktail exposure (1 ng/ml), significant downregulation of mRNA expression of organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, sodium/taurocholate cotransporting polypeptide (NTCP), breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), multidrug and toxin extrusion protein 1, multidrug resistance proteins (MRP) 2, 3, and 4 was observed. While the mRNA expression of organic anion transporter (OAT) 2 and organic cation transporter (OCT) 1 was downregulated in two lots, it was upregulated in one lot. In agreement (mostly), the 1 ng/ml cytokine cocktail reduced OATP1B1/3, OATP2B1, OAT2, OCT1, and NTCP activity by 75%, 44%, 82%, 47%, and 80%, respectively. Interestingly, upregulation of OAT2 and OCT1 mRNA in one donor did not translate into the same directional change in activity. Although significant interlot variability was observed, in general, the above effects, using individual cytokines, could be attributed to IL-1β, TNF-α, and IFN-γ. SIGNIFICANCE STATEMENT: To date, this is the first comprehensive study to investigate the effect of four major proinflammatory cytokines, both individually and as a cocktail, on the mRNA expression and activity of human hepatic drug transporters. The data obtained can be used in the future to predict transporter-mediated drug clearance changes during inflammation through physiologically based pharmacokinetic modeling and simulation.

Research on Spatial Developable Mechanism Considering Revolute Clearance Joints with Irregular Rough Surfaces

Due to assembling, manufacturing errors, and wear, irregular rough surfaces inevitably exist in joints, which will increase the contact stiffness nonlinearity at the joint of the spatial developable mechanism, and the traditional contact force model is difficult to accurately predict the contact force change of irregular rough surface clearance. Aiming at the difficulty of accurately predicting the dynamic behavior of the spatial developable mechanism caused by rough joint clearance, an improved clearance contact force modeling method based on an uncoordinated contact model is proposed in this paper. The influence of rough peak distribution on the contact area is analyzed. The stiffness of the traditional Hertz model is modified based on the probability distribution density function of the rough peak, and an improved contact force model based on dynamic contact stiffness is established. Based on the Lagrange multiplier method, the dynamics model of spatial developable mechanism is constructed. Based on the model, the dynamic analysis of the spatial expansion mechanism is carried out, and the influence of the roughness of the contact surface and the size of the clearance on the dynamic characteristics of the system are explored; as well, the influence of different clearance parameters on the dynamic characteristics of the development mechanism is revealed. Through the analysis, this paper provides a theoretical basis for predicting the effect of a spatial revolute clearance joint on the dynamic characteristics of the mechanism and lays a good foundation for the manufacture and application of the mechanism.

Effect of Axial Clearance Variation on Dual-Rotor Flowmeter Performance.

This study examines the impact of axial clearance variations on the performance characteristics of a dual-rotor flowmeter (DRT-FM) through numerical simulations, with the validity of the numerical results verified by calibration experiments. The results indicate that within the range of 200 L/h to 1600 L/h, the K factors of different groups increase as clearance increases. The K factor of the 0.80 mm group is the largest, showing an average increase of around 6% compared to that of the 0.50 mm group. Additionally, Linearity E also decreased, with a minimum of 1.07% in the 0.65 mm group, significantly lower than the 3.33% in the 0.50 mm group. Furthermore, the pressure loss increased slightly, with the 0.65 mm group having the largest pressure loss; however, at a flow rate of 1600 L/h, the pressure loss only increases by 0.186 kPa compared to that of the 0.50 mm group. Flow field analysis reveals that changes in axial clearance predominantly affect pressure distribution. Larger clearances reduce low-pressure regions on upstream and downstream transition surfaces, thereby reducing energy loss due to pressure changes. Entropy analysis further demonstrates that higher axial clearance decreases energy loss in the upstream and downstream stationary domains, optimizing the DRT-FM's energy characteristics.

Расчет и коррекция дозы цитостатических препаратов в режимах кондиционирования перед аллоТГСК у пациентов с избытком массы тела или ее дефицитом

In Russia, like in the rest of the world, the number of overweight people has been growing for the last 20 years. According to different studies, obesity and overweight incidence among adults is 20.5–54.0 %. Obesity incidence increased from 10.8 % in 1993 to 27.9 % in 2017 in men and from 26.4 to 31,8 % in women, respectively. Pharmacokinetics of drugs including cytostatic agents, differs in obese vs. normal-weight patients. This is accounted for by renal/hepatic clearance changes as well as by increased distribution of lipophilic drugs with their enhanced protein-binding ability. All these factors create a challenge for a correct calculation of drug doses for obese patients. This issue becomes particularly acute when such patients undergo allogeneic hematopoietic stem cell transplantation with preconditioning regimens using sublethal drug doses. This paper attempts to review current approaches to drug dose calculation to be used in preconditioning regimens for over- and underweight patients.

Dose rationale for the use of meropenem/vaborbactam combination in paediatric patients with Gram-negative bacterial infections.

Meropenem/vaborbactam combination is approved in adults by FDA and EMA for complicated urinary tract infections and by EMA also for other Gram-negative infections. We aimed to characterise the pharmacokinetics of both moieties in an ongoing study in children and use a model-based approach to inform adequate dosing regimens in paediatric patients. Over 4196 blood samples of meropenem and vaborbactam (n = 414 subjects) in adults, together with 114 blood samples (n = 39) in paediatric patients aged 3 months to 18 years were available for this analysis. Data were analysed using a population with prior information from a pharmacokinetic model in adults to inform parameter estimation in children. Simulations were performed to assess the suitability of different dosing regimens to achieve adequate probability of target attainment (PTA). Meropenem/vaborbactam PK was described with two-compartment models with first-order elimination. Body weight and CLcr were significant covariates on the disposition of both drugs. A maturation function was evaluated to explore changes in clearance in neonates. PTA ≥90% was derived for children aged ≥3 months after 3.5-h IV infusion of 40 mg/kg Q8h of both meropenem and vaborbactam and 2 g/2 g for those ≥50 kg. Extrapolation of disposition parameters suggest that adequate PTA is achieved after a 3.5-h IV infusion of 20 mg/kg for neonates and infants (3 months). An integrated analysis of adult and paediatric data allowed accurate description of sparsely sampled meropenem/vaborbactam PK in paediatric patients and provided recommendations for the dosing in neonates and infants (3 months).

Experimental Study and Influencing Factors Analysis of the Electric Gear Urea Pump Supply Performance

Abstract An experimental study on four electric gear urea pumps was carried out, and the variation rules of supply flow rate, speed, and volumetric efficiency of the urea pumps were obtained. Test results show that the volumetric efficiency will be affected by the coupling of multiple factors simultaneously, showing complex nonlinearity. A simulation model whose accuracy was verified by test data was established for analyzing the influencing factors of supply performance. With the increase in speed, the variation of volumetric efficiency has a linear relationship with the change of radial clearance and a quadratic parabola relationship with the change of axial clearance. In the range of working speed, the influence of radial clearance on volumetric efficiency is more significant, while the influence of axial clearance on volumetric efficiency will be gradually enhanced with increasing speed. The radial tolerance range should be as small as possible to ensure the consistency of the urea pump’s volumetric efficiency.

Research on the excitation force and vortex dynamics characteristics of pump-jet propulsor induced by shafting whirling vibration: Non-uniform blade tip clearance

The propulsion shafting whirling vibration causes non-uniform dynamic changes in the rotor tip clearance, which directly have a significant influence on the excitation force and vortex dynamic characteristics of the pump-jet propulsor. In the current study, based on improved delay detached eddy simulation, the influence of non-uniform blade tip clearance on the excitation force and vortex dynamics characteristics of the pump-jet propulsor is studied under design conditions. The results show that the application of propulsion shafting whirling vibration induces significant changes in the excitation force of the pump-jet propulsor. The rotor blades modulate the excitation forces of the stator blades and duct. The transverse and vertical excitation forces are more significant than the longitudinal excitation force. The magnitude change in the circular orbit shows a linear relationship with the excitation force magnitude. The characteristic frequency of the transverse and vertical excitation forces of each component is the shaft rotation frequency. In contrast, the characteristic frequency of the longitudinal excitation force is twice the shaft rotation frequency. In the elliptical orbit, the excitation force of each component is compressed or stretched in the time domain, and the dominant frequency is shifted in the frequency domain; there is no longer a linear relationship between the vibration magnitude change and the excitation force magnitude. Furthermore, an energy generation mechanism in the wake field of the pump-jet propulsor induces vortex frequency due to the whirling vibration of the propulsion shafting system.

Understanding the Liver’s Role in the Clearance of Aβ40

The clearance of peripheral beta amyloid (Aβ) is a potential target for the treatment of Alzheimer’s disease (AD). The liver has been implicated in the elimination of Aβ from the peripheral circulation. Here, the single-pass uptake of Aβ40 in perfused livers from young and old rats (6 to 10 rats per group) was investigated with the multiple indicator dilution technique. Aβ40 had volumes of distribution between those of the vascular marker Evans Blue and the extracellular marker sucrose. The hepatic extraction of Aβ40 was negligible, explained in part by the small permeability surface area products consistent with a high endothelial barrier to liver uptake. There were no substantial effects of age on any of these results. In vitro experiments with isolated hepatocytes and liver sinusoidal endothelial cells showed only very small amounts of Aβ uptake consistent with low intrinsic clearance. These results indicate that the hepatic clearance of Aβ is capacity-limited, explained by the low-permeability surface area products and hepatocyte uptake. However, this does not preclude an effect of aging in longer-term in vivo studies where age-related changes in liver blood flow and protein binding influence liver clearance.