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Blood Purification 2022Cytokine storm control is the main target for improving severe COVID-19 by using immunosuppressive treatment. Effective renal replacement therapy (RRT) could give us an... (Observational Study)
Observational Study
INTRODUCTION
Cytokine storm control is the main target for improving severe COVID-19 by using immunosuppressive treatment. Effective renal replacement therapy (RRT) could give us an advantage removing cytokines in patients with RRT requirements superimposed on COVID-19.
METHODS
This is a prospective observational study in COVID-19 patients who required hemodialysis (HD). Patients were assigned to online hemodiafiltration (OL-HDF) and expanded HD (HDx) according to Brescia group recommendations. We measured several cytokines, β2 microglobulin and albumin levels pre/post-dialysis and on 1st-2nd week. We compared levels among both techniques and control group (HD without COVID-19).
RESULTS
We included 26 patients: 18 with COVID-19 on RRT (5 of them had acute kidney injury [AKI]) and 8 controls. We confirm higher cytokine levels in COVID-19 patients than controls and even higher in patients with AKI than in those with chronic kidney disease. Most cytokines raised during HD session, except IL-10 and TNFα. IL-10 was eliminated by any dialysis technique, while clearance of TNFα was higher in the HDx group. HDx achieved a deeper normalization of cytokines and β2 microglobulin reduction. Mortality was higher in the OL-HDF group than the HDx group.
DISCUSSION
Not all cytokines behave equally along HD session. The following characteristics should be taken into account, such as intrinsic kinetic profile during a HD session. HDx seems to get better performance, probably due to the combination of different factors; however, we did not reach statistical significance due to the small sample size, dropout, and reduction of AKI incidence during the 2nd pandemic wave.
CONCLUSION
HDx appears to provide better clearance for TNFα and β2 microglobulin during HD session and associates lower mortality. We propose the HDx technique for COVID-19 patients with RRT requirements since it seems to be safe and more effective than OL-HDF. Further studies are still needed, but we hope that our preliminary data may help us in future pandemic waves of SARS-CoV-2 or other viruses still to come.
Topics: Acute Kidney Injury; Albumins; COVID-19; Hemodiafiltration; Humans; Interleukin-10; Kidney Failure, Chronic; Renal Dialysis; SARS-CoV-2; Tumor Necrosis Factor-alpha
PubMed: 35016172
DOI: 10.1159/000520891 -
Nature Nanotechnology Jun 2024Extracellular vesicles (EVs) derived from mesenchymal stem cells are promising nanotherapeutics in liver diseases due to their regenerative and immunomodulatory...
Extracellular vesicles (EVs) derived from mesenchymal stem cells are promising nanotherapeutics in liver diseases due to their regenerative and immunomodulatory properties. Nevertheless, a concern has been raised regarding the rapid clearance of exogenous EVs by phagocytic cells. Here we explore the impact of protein corona on EVs derived from two culturing conditions in which specific proteins acquired from media were simultaneously adsorbed on the EV surface. Additionally, by incubating EVs with serum, simulating protein corona formation upon systemic delivery, further resolved protein corona-EV complex patterns were investigated. Our findings reveal the potential influences of corona composition on EVs under in vitro conditions and their in vivo kinetics. Our data suggest that bound albumin creates an EV signature that can retarget EVs from hepatic macrophages. This results in markedly improved cellular uptake by hepatocytes, liver sinusoidal endothelial cells and hepatic stellate cells. This phenomenon can be applied as a camouflage strategy by precoating EVs with albumin to fabricate the albumin-enriched protein corona-EV complex, enhancing non-phagocytic uptake in the liver. This work addresses a critical challenge facing intravenously administered EVs for liver therapy by tailoring the protein corona-EV complex for liver cell targeting and immune evasion.
Topics: Extracellular Vesicles; Protein Corona; Mesenchymal Stem Cells; Animals; Humans; Mice; Hepatocytes; Liver; Macrophages
PubMed: 38366223
DOI: 10.1038/s41565-023-01585-y -
Heliyon Nov 2019Although Albumin (ALB) and alpha-1-acid glycoprotein (AGP) have distinctive structural and functional characteristics, they both play a key role in binding a large... (Review)
Review
Although Albumin (ALB) and alpha-1-acid glycoprotein (AGP) have distinctive structural and functional characteristics, they both play a key role in binding a large variety of endogenous and exogenous ligands. An extensive binding to these plasma proteins could have a potential impact on drugs disposition (e.g. bioavailability, distribution and clearance), on their innocuity and their efficacy. This review summarizes the common knowledge about the structural and molecular characteristics of both ALB and AGP in humans, and about the most involved amino acids in their high-affinity binding pockets. However, the variability in residues found in binding pockets, for the same species, allows each plasma protein to interact differently with the ligands. The protein-ligand interaction influences differently the disposition of drugs that bind to either of these plasma proteins. The content of this review is useful for the design of new drug entities with high-binding characteristics, in qualitative and quantitative modelling (e.g. extrapolations, 3D molecular docking, interspecies extrapolations), and for other interdisciplinary research.
PubMed: 31844752
DOI: 10.1016/j.heliyon.2019.e02879 -
Clinical Pharmacokinetics Oct 2023Dorzagliatin is a first-in-class small molecule glucokinase activator (GKA) that improves pancreatic insulin secretion behavior and regulates hepatic glucose conversion...
BACKGROUND AND OBJECTIVES
Dorzagliatin is a first-in-class small molecule glucokinase activator (GKA) that improves pancreatic insulin secretion behavior and regulates hepatic glucose conversion in a glucose concentration-dependent manner. The primary objective of this study was to develop a population pharmacokinetic model of dorzagliatin to evaluate the influence of covariates, such as demographic characteristics and liver and kidney function, on the pharmacokinetics of dorzagliatin and provide a basis for medication guidance.
METHOD
The pharmacokinetic data of dorzagliatin in this study came from six clinical trials. Based on the combined data, a population pharmacokinetic model of dorzagliatin was established using NONMEM software (ICON, MD, USA, version 7.4.3). The algorithm used was first-order conditional estimation with interaction (FOCEI). The dorzagliatin population pharmacokinetic modeling analysis included 1062 subjects and 7686 observable concentrations. Covariates, including age (AGE), sex (GEND), body weight (TBW), body mass index (BMI), body surface area (BSA), albumin (ALB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine (CR), creatinine clearance (CRCL), and total bilirubin (TBIL), were screened using the forward-backward method. Model evaluation was performed using goodness-of-fit plots, prediction corrected visual prediction check (pcVPC), and bootstrap.
RESULTS
Concentration data of dorzagliatin in the dose range were best characterized by a two-compartment model with sequential zero-order then first-order absorption and first-order elimination. The final model estimated dorzagliatin data for typical male subjects (69 kg body weight, 18 U/L AST and 55 years old); the apparent total clearance (CL/F) was 10.4 L/h, apparent volume of central compartment distribution (V/F) was 80.6 L, inter-compartmental clearance (Q/F) was 3.02 L/h, apparent volume of peripheral compartment distribution (V/F) was 26.5 L, absorption rate constant (K) was 3.29 h, and duration of zero-order absorption (D) was 0.418 h. The inter-individual variation of CL/F, V/F, V/F, and D was 22.5%, 14.9%, 48.8%, and 82.8%, respectively.
CONCLUSION
The two-compartment linear pharmacokinetic model with zero- and first-order sequential absorption adequately described the pharmacokinetic characteristics of dorzagliatin. Body weight, aspartate aminotransferase, and age had a statistically significant effect on the CL/F of dorzagliatin. Body weight and sex had a statistically significant effect on V/F. However, considering the clinically insignificant changes in the magnitude of steady-state exposure caused by these covariates, as well as the minimal changes in the steady-state exposure for individuals with mild and moderate impaired hepatic function and all stages of renal impairment, dose adjustments based on the tested covariates or for specific populations are deemed unnecessary.
Topics: Humans; Male; Diabetes Mellitus, Type 2; Healthy Volunteers; Body Weight; Aspartate Aminotransferases; Glucose; Models, Biological
PubMed: 37537410
DOI: 10.1007/s40262-023-01286-8 -
Frontiers in Pediatrics 2020To analyze the influence of perioperative complications in the management of biliary atresia (BA). A retrospective study was performed using a total of 422 BA patients...
To analyze the influence of perioperative complications in the management of biliary atresia (BA). A retrospective study was performed using a total of 422 BA patients who underwent Kasai portoenterostomy (KPE) in a single institution between February 2016 and May 2017. Data on patients' clinical characteristics, laboratory examinations, perioperative complications, and outcomes were collected. Unpaired two-tailed -test and χ test were employed for the comparison between BA patients with and without perioperative complications. Cox regression analysis was used to screen the risk factors for 2-years NLS in BA, and their influence on the 2-years NLS was analyzed using Kaplan-Meier survival analysis as well as the log-rank test. The incidence of perioperative complications, 6-months jaundice clearance (JC) and 2-years native liver survival (NLS) rate were 60.4, 59.5, and 56.6%, respectively. Patients with perioperative complications had lower serum albumin (ALB) level, but higher aspartate aminotransferase-to-platelet ratio index (APRI) and international normalized ratio (INR) levels when compared with those without perioperative complications (ALB, < 0.05; APRI, < 0.01; INR, < 0.05). Moreover, perioperative complications were correlated with glucocorticoid administration ( = 0.002). Univariate Cox regression analysis showed no relationship between perioperative complications and 2-years NLS ( > 0.05). However, multivariate Cox regression analysis indicated 6-months JC was an independent protective factor for 2-years NLS [ < 0.0001, hazard ratio (HR) = 0.074, 95% confidence interval = 0.05-0.11], and concordance index of this prediction model including age, weight, APRI, glucocorticoid, and 6-months JC was 0.811. Although perioperative complication is common during and after KPE, it had no influence on the prognosis of BA. However, assessment of the serum level of total bilirubin after KPE may serve as an important predictor for the outcome in BA.
PubMed: 33014917
DOI: 10.3389/fped.2020.00460 -
Respiratory Research Jun 2023Allergic asthma, one of the most common types of asthma, is thought to be highly susceptible to respiratory viral infections; however, its pathological mechanism needs...
BACKGROUND
Allergic asthma, one of the most common types of asthma, is thought to be highly susceptible to respiratory viral infections; however, its pathological mechanism needs to be elucidated. Recent studies have found impaired T-cell function in asthmatic mice. Therefore, we aimed to investigate the way by which asthma induction affects T-cell exhaustion in the lungs and assess the relationship between T-cell exhaustion and influenza viral infection.
METHODS
Chronic allergic asthma mice were induced by intranasal injection of ovalbumin for 6 weeks and asthmatic features and T cell populations in lung or airway were assessed. To determine the influenza virus susceptibility, control and asthma mice were challenged with the human influenza virus strain A/Puerto Rico/8/1934 H1N1 and evaluated the survival rate, lung damage, and virus titer.
RESULTS
Six weeks of OVA sensitization and challenge successfully induced chronic allergic asthma in a mouse model showing significant increase of sera IgE level and broncho-pathological features. A significant decrease in interferon-γ-producing T-cell populations and an increase in exhausted T-cell populations in the lungs of OVA-induced asthmatic mice were observed. Asthmatic mice were more susceptible to influenza virus infection than control mice showing lower survival rate and higher virus titer in lung, and a positive correlation existed between T-cell exhaustion in the lung and virus titer.
CONCLUSIONS
Asthma induction in mice results in the exhaustion of T-cell immunity, which may contribute to the defective capacity of viral protection. This study demonstrates a correlation between asthma conditions and viral susceptibility by investigating the functional characteristics of T-cells in asthma. Our results provide insights into the development of strategies to overcome the dangers of respiratory viral disease in patients with asthma.
Topics: Humans; Mice; Animals; Influenza, Human; Influenza A Virus, H1N1 Subtype; T-Cell Exhaustion; Asthma; Lung; Disease Models, Animal; Mice, Inbred BALB C; Ovalbumin; Bronchoalveolar Lavage Fluid
PubMed: 37424011
DOI: 10.1186/s12931-023-02448-9 -
Journal of Clinical Medicine Aug 2022We evaluated the prognostic value of C-reactive protein (CRP), albumin, CRP clearance (CRPc) and CRP/albumin ratio (CAR) in neurocritically ill patients with acute...
We evaluated the prognostic value of C-reactive protein (CRP), albumin, CRP clearance (CRPc) and CRP/albumin ratio (CAR) in neurocritically ill patients with acute stroke. This is a retrospective, observational study. We included acute stroke patients who were hospitalized in the neurosurgical ICU from January 2013 to September 2019. The primary outcome was in-hospital mortality. A total of 307 patients were enrolled in the study. Among them, 267 (87.0%) survived until discharge from the hospital. CRP and CAR were significantly higher in non-survivors than in survivors (both p < 0.001). Serum albumin levels were significantly lower in the non-survivors than in the survivors (p < 0.001). In receiver operating characteristic curve analysis for prediction of in-hospital mortality, the area under the curve of CRP (C-statistic: 0.820) and CAR (C-statistic: 0.824) were greater than that of CRPc (C-statistic: 0.650) and albumin (C-statistic: 0.734) (all p < 0.005). However, there was no significant difference in the predictive performance between CRP and CAR (p = 0.287). In this study, CRP and CAR were more important than CRPc and albumin in predicting mortality of neurocritically ill patients with stroke. Early CRP level and CAR determination may help to predict the in-hospital mortality of these patients.
PubMed: 36079002
DOI: 10.3390/jcm11175067 -
Therapeutics and Clinical Risk... 2019Renal dysfunction represents a dreadful complication of advanced liver cirrhosis. In addition to the traditional types of acute kidney injury (AKI) that can occur in the... (Review)
Review
Renal dysfunction represents a dreadful complication of advanced liver cirrhosis. In addition to the traditional types of acute kidney injury (AKI) that can occur in the general population, cirrhotics might experience a different kind of renal dysfunction, called hepatorenal syndrome (HRS). The exact definition of HRS is a functional renal dysfunction caused by overactivity of the endogenous vasoactive systems (in particular intrarenal circulation) which lead to reduced renal perfusion. Type I HRS (HRS-1) is characterized by an abrupt deterioration in renal function (in less than 2 weeks), defined by a doubling of baseline sCr to >2.5 mg/dL or a 50% reduction in the initial 24 hrs creatinine clearance to <20 mL/min. Frequent precipitating events leading to HRS-1 are bacterial infections, gastrointestinal hemorrhage, or large-volume paracentesis without adequate albumin administration as well as massive diuretic use. In 2015, the international club of ascites (ICA) revised the definitions and recommendations concerning HRS. The revised definition allows to adopt effective pharmacological therapy based on albumin and vasoconstrictors in an earlier stage thus not influenced anymore by a rigid sCr cut-off value as by the previous definition of HRS-1. The aim of this article was to provide an updated overview of the latest advancements in the field of hepatorenal syndrome and of the recent amendments of the previous definitions of kidney injury in cirrhotic patients.
PubMed: 31819465
DOI: 10.2147/TCRM.S205328 -
Drugs in R&D Dec 2021Intravenous (IV) belimumab is the first treatment approved for children ≥5 years of age with active autoantibody-positive systemic lupus erythematosus (SLE) in the...
BACKGROUND AND OBJECTIVE
Intravenous (IV) belimumab is the first treatment approved for children ≥5 years of age with active autoantibody-positive systemic lupus erythematosus (SLE) in the USA, Europe, and Japan. Pharmacokinetic data for belimumab were collected from several clinical trials in Chinese and non-Chinese adults and non-Chinese pediatric patients with SLE. This study aimed to predict the belimumab dose-exposure relationship to Chinese pediatric patients with SLE, as part of the belimumab registration process for this population in China, using a population PK modeling approach.
METHODS
An initial linear two-compartment population pharmacokinetic model was built using data from adults only, and considering and adjusting for the covariates age, body weight, body mass index, fat-free mass, race, baseline albumin and immunoglobulin G levels. The model was used to study possible ethnic differences between Chinese and non-Chinese adults and to predict pediatric pharmacokinetic data in a study of non-Chinese pediatric patients (PLUTO study; NCT01649765). The predicted data were compared with the observed data from PLUTO. The model was then updated with pediatric data from PLUTO to predict steady-state belimumab exposure in Chinese pediatric patients with SLE receiving belimumab 10 mg/kg IV every 4 weeks.
RESULTS
The dataset comprised 9650 sampled concentration values from 1783 patients. The pharmacokinetics of belimumab were adequately described by the final model using all adult and pediatric data with the estimated typical clearance of 238 ml/day in adult and pediatric patients and steady-state volume of distribution of 4915 ml in adults. Between-patient variability was modest (coefficients of variation: 26.1% for clearance; 8.9% and 28.5%, respectively, for volumes of distribution of the central and peripheral compartments). Six covariates were identified that influenced pharmacokinetics: age, fat-free mass, an indicator of North East Asian race, baseline albumin, immunoglobulin G, and an early study indicator (two early phase I and phase II belimumab studies: LBSL01 and LBSL02). The analysis showed no apparent difference in steady-state exposure between Chinese and non-Chinese populations and between pediatric and adult populations receiving belimumab 10 mg/kg IV.
CONCLUSIONS
In Chinese pediatric patients with SLE, belimumab 10 mg/kg IV every 4 weeks is expected to have exposure similar to that in Chinese adults and non-Chinese pediatric patients with SLE, supporting the use of this regimen in Chinese pediatric patients with SLE.
CLINICAL TRIAL REGISTRATION NUMBERS
NCT01649765, NCT00657007, NCT00071487, NCT01345253, NCT01516450, NCT00410384, NCT00424476, NCT02880852, NCT01583530.
Topics: Administration, Intravenous; Adult; Animals; Antibodies, Monoclonal, Humanized; Child; China; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Treatment Outcome
PubMed: 34628605
DOI: 10.1007/s40268-021-00363-2 -
International Journal of Molecular... Dec 2023Small molecule fluorophores often face challenges such as short blood half-life, limited physicochemical and optical stability, and poor pharmacokinetics. To overcome...
Small molecule fluorophores often face challenges such as short blood half-life, limited physicochemical and optical stability, and poor pharmacokinetics. To overcome these limitations, we conjugated the zwitterionic near-infrared fluorophore ZW800-PEG to human serum albumin (HSA), creating HSA-ZW800-PEG. This conjugation notably improves chemical, physical, and optical stability under physiological conditions, addressing issues commonly encountered with small molecules in biological applications. Additionally, the high molecular weight and extinction coefficient of HSA-ZW800-PEG enhances biodistribution and tumor targeting through the enhanced permeability and retention effect. The unique distribution and elimination dynamics, along with the significantly extended blood half-life of HSA-ZW800-PEG, contribute to improved tumor targetability in both subcutaneous and orthotopic xenograft tumor-bearing animal models. This modification not only influences the pharmacokinetic profile, affecting retention time and clearance patterns, but also enhances bioavailability for targeting tissues. Our study guides further development and optimization of targeted imaging agents and drug-delivery systems.
Topics: Animals; Humans; Serum Albumin, Human; Tissue Distribution; Neoplasms; Biological Availability; Drug Delivery Systems; Fluorescent Dyes; Ionophores
PubMed: 38203730
DOI: 10.3390/ijms25010559