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Kidney360 Jun 2023
Topics: Adult; Humans; Nephrosis, Lipoid; Chronic Disease; Recurrence; Albumins
PubMed: 37384885
DOI: 10.34067/KID.0000000000000169 -
Journal of Clinical Pharmacology Feb 2021Treatment of patients with biologics such as infliximab may trigger development of antidrug antibodies, which are associated with faster drug clearance, reduced... (Randomized Controlled Trial)
Randomized Controlled Trial
Treatment of patients with biologics such as infliximab may trigger development of antidrug antibodies, which are associated with faster drug clearance, reduced treatment efficacy, and increased risk of infusion-related reactions. The aim of this study was to identify predictors of baseline infliximab clearance and early antidrug antibody formation. Pharmacokinetic and pharmacokinetic/pharmacodynamic models for infliximab were developed using 21 178 observations from 859 patients from the PLANETRA (ClinicalTrials.gov identifier: NCT01217086) and PLANETAS (NCT01220518) studies in rheumatoid arthritis and ankylosing spondylitis, respectively, to address the specified aims. Infliximab pharmacokinetics were well described by a 2-compartment model with linear mean estimated baseline clearance of 0.26 L/day. Alongside increased body weight, serum C-reactive protein, and antidrug antibody concentrations and decreased serum albumin, elevated serum glucose levels predicted higher clearance. In patients with rheumatoid arthritis, baseline infliximab clearance and body weight were the only identified predictors of early antidrug antibody detection. The odds ratio for antidrug antibody detection for each 0.1 L/day increase in baseline infliximab clearance was 1.78 (95% confidence interval, 1.50-2.12); for each 10-kg increase in body weight, this was 1.19 (1.06-1.33). Here we describe increased serum glucose levels as a novel independent predictor of baseline infliximab clearance. Estimates of baseline infliximab clearance should be incorporated to guide dosing modifications and/or antidrug antibody prophylaxis in clinical practice.
Topics: Adolescent; Adult; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Blood Glucose; Body Weight; C-Reactive Protein; Double-Blind Method; Female; Humans; Infliximab; Male; Metabolic Clearance Rate; Middle Aged; Serum Albumin; Spondylitis, Ankylosing; Young Adult
PubMed: 32905628
DOI: 10.1002/jcph.1732 -
International Journal of Molecular... Jan 2023A hallmark of acute respiratory distress syndrome (ARDS) is an accumulation of protein-rich alveolar edema that impairs gas exchange and leads to worse outcomes. Thus,...
A hallmark of acute respiratory distress syndrome (ARDS) is an accumulation of protein-rich alveolar edema that impairs gas exchange and leads to worse outcomes. Thus, understanding the mechanisms of alveolar albumin clearance is of high clinical relevance. Here, we investigated the mechanisms of the cellular albumin uptake in a three-dimensional culture of precision-cut lung slices (PCLS). We found that up to 60% of PCLS cells incorporated labeled albumin in a time- and concentration-dependent manner, whereas virtually no uptake of labeled dextran was observed. Of note, at a low temperature (4 °C), saturating albumin receptors with unlabeled albumin and an inhibition of clathrin-mediated endocytosis markedly decreased the endocytic uptake of the labeled protein, implicating a receptor-driven internalization process. Importantly, uptake rates of albumin were comparable in alveolar epithelial type I (ATI) and type II (ATII) cells, as assessed in PCLS from a SftpcCre: tdTomato mouse strain (defined as EpCAMCD31CD45tdTomatoSPCT1α for ATI and EpCAMCD31CD45tdTomatoSPCT1α for ATII cells). Once internalized, albumin was found in the early and recycling endosomes of the alveolar epithelium as well as in endothelial, mesenchymal, and hematopoietic cell populations, which might indicate transcytosis of the protein. In summary, we characterize albumin uptake in alveolar epithelial cells in the complex setting of PCLS. These findings may open new possibilities for pulmonary drug delivery that may improve the outcomes for patients with respiratory failure.
Topics: Mice; Animals; Alveolar Epithelial Cells; Epithelial Cell Adhesion Molecule; Clathrin; Lung; Epithelial Cells; Serum Albumin; Pulmonary Alveoli
PubMed: 36768968
DOI: 10.3390/ijms24032644 -
European Heart Journal. Cardiovascular... Oct 2019Proprotein convertase subtilisin/kexin Type 9 (PCSK9) is now identified as an important and major player in hypercholesterolaemia and atherosclerosis pathophysiology.... (Review)
Review
Proprotein convertase subtilisin/kexin Type 9 (PCSK9) is now identified as an important and major player in hypercholesterolaemia and atherosclerosis pathophysiology. PCSK9, through promoting lysosomal degradation of hepatic low-density lipoprotein (LDL) receptor, can decrease the clearance of plasma LDLs, leading to hypercholesterolaemia and consequent atherosclerotic plaque formation. Hypercholesterolaemia has been found to promote systemic and vascular inflammation, which can cause atherosclerotic lesion formation and progression and subsequent incidence of cardiovascular disease. Recent studies have shown the involvement of PCSK9 in the inflammatory pathway of atherosclerosis. Although trials with PCSK9 inhibitors have not shown any alteration in plasma C-reactive protein levels, there is accumulating evidence showing lessened inflammatory response in the arterial wall that could attenuate atherosclerotic plaque development beyond the established LDL-lowering effect of PCSK9 inhibition. In this review, we represent mounting evidence indicating that PCSK9 can locally increase vascular inflammation and contribute to atherosclerotic plaque progression in patients with hypercholesterolaemia.
Topics: Animals; Anti-Inflammatory Agents; Anticholesteremic Agents; Atherosclerosis; C-Reactive Protein; Cytokines; Humans; Inflammation; Inflammation Mediators; PCSK9 Inhibitors; Plaque, Atherosclerotic; Proprotein Convertase 9; Serine Proteinase Inhibitors; Signal Transduction
PubMed: 31236571
DOI: 10.1093/ehjcvp/pvz022 -
Digestive Diseases and Sciences May 2023Children with Crohn's disease have lower response rates to infliximab, lower infliximab levels, and higher infliximab clearance on weight-based dosing than adults. We...
BACKGROUND AND AIMS
Children with Crohn's disease have lower response rates to infliximab, lower infliximab levels, and higher infliximab clearance on weight-based dosing than adults. We hypothesize infliximab clearance is a predictive of later outcomes on infliximab in children with Crohn's disease.
METHODS
In this single-center retrospective study, data were collected from charts on diagnosis, anthropometry, routine labs, infliximab therapeutic drug monitoring, infliximab dosing, disease activity, and other treatments. With these data we generated a population pharmacokinetic model using non-linear mixed effects modeling and calculated infliximab clearance for each patient over time. Patients were classified as in remission, responder-only or non-responder at 5, 10 and 16 months. Regression and ROC analyses were used to assess for early predictors of remission and response to infliximab.
RESULTS
Eighty-five subjects were included, with a median follow-up of 22.3 months (IQR 10.1-36.8). Our pharmacokinetic model showed infliximab clearance was positively associated with CRP and weight, while negatively associated with albumin. In regression analyses, early infliximab clearance was the only significant, consistent predictor of remission. A 0.1 L/day increase in infliximab clearance predicted remission with an OR between 0.179 and 0.426. Differences in dosing did not account for differences in outcome. Infliximab clearance alone had moderate predictive accuracy of remission, with an AUC between 0.682 and 0.738.
CONCLUSIONS
Early infliximab clearance is strongly associated with remission in children with Crohn's disease. It may be useful as a marker of response in proactive therapeutic drug monitoring to guide early dose optimization and/or changes in treatment for betterment of long-term outcomes.
Topics: Adult; Humans; Child; Infliximab; Crohn Disease; Immunosuppressive Agents; Azathioprine; Retrospective Studies; Gastrointestinal Agents; Remission Induction
PubMed: 36562887
DOI: 10.1007/s10620-022-07783-3 -
Balkan Medical Journal Oct 2023Identifying mortality risk in critically ill children is central to diagnostic and treatment practices. For this purpose, scoring systems, such as the Pediatric Index of...
BACKGROUND
Identifying mortality risk in critically ill children is central to diagnostic and treatment practices. For this purpose, scoring systems, such as the Pediatric Index of Mortality 3 (PIM 3), have been proposed; however, the role of biochemical markers, such as albumin-corrected anion gap (cAG) and lactate clearance (LC), in predicting mortality in pediatric intensive care unit (PICU) patients is yet to be explored.
AIMS
To evaluate the predictive value of the cAG and LC for mortality in pediatric patients admitted to a PICU.
STUDY DESIGN
Retrospective single-center cohort study.
METHODS
Clinical and laboratory data from the time of PICU admission were collected, and patients were classified into based on their 0- and 6-hour of admission lactate levels into an LC(+) group (patients with normal or decreasing lactate levels) or an LC(−) group (increasing lactate levels). LC and cAG levels were compared using the Mann-Whitney U test and Student’s t-test, respectively. Additionally, multiple logistic regression analysis was performed to evaluate the effect of LC and cAG on mortality.
RESULTS
We included 825 patients in the study; the mortality rate was 8.6%. The absence of LC [adjusted odds ratio (AOR) =4.735; 95% confidence interval (CI): 2.163-10.367; < 0.001], cAG (AOR =1.064; 95% CI: 1.010-1.122; = 0.019) and PIM 3 (AOR = 1.871; 95% CI: 1.553-2.254; < 0.001) were independent risk factors for mortality. Using the receiver operating characteristic curve analysis of PIM 3 as a predictor of mortality, area under the curve values of 0.832 (95% CI: 0.805-0.857; < 0.001) for the original score and 0.858 for a revised PIM 3 score (based on the β coefficients obtained for cAG and LC; 95% CI 0.832-0.881; < 0.001) were obtained, which was significantly different ( = 0.027).
CONCLUSION
A cAG value > 18 at the time of PICU admission high lactate levels which do not decrease within 6 hours of hospitalization are associated with an increased risk of mortality. The revised PIM 3 score, which includes cAG and LC, is a better predictor of mortality than the classical PIM 3 score.
Topics: Child; Humans; Acid-Base Equilibrium; Lactic Acid; Cohort Studies; Retrospective Studies; Hospital Mortality; Albumins; Critical Care
PubMed: 37815408
DOI: 10.4274/balkanmedj.galenos.2023.2023-7-87 -
Expert Opinion on Drug Metabolism &... Aug 2019: In quantitative modeling, the resolving of underpredictions and overpredictions of hepatic clearance (CLh) makes a top priority for pharmacokinetic modelers. Clearly,... (Review)
Review
The potential protein-mediated hepatic uptake: discussion on the molecular interactions between albumin and the hepatocyte cell surface and their implications for the in vitro-to-in vivo extrapolations of hepatic clearance of drugs.
: In quantitative modeling, the resolving of underpredictions and overpredictions of hepatic clearance (CLh) makes a top priority for pharmacokinetic modelers. Clearly, the 'protein-mediated hepatic uptake' is a violation of 'the free drug hypothesis', but the lack of its consideration in CLh-predictive approaches may be one of the reasons to explain the discrepancies between predicted and observed values. : We first review the two 'albumin-facilitated hepatic uptake' models that were recently challenged to improve the extrapolation (IVIVE) of CLh by reducing the underprediction bias, particularly in the absence of albumin (ALB) compared to the presence of ALB . Second, we identify three types of interactions related to the ALB-bound drug moiety (i.e., ALB-lipids, ALB-proteins, and ALB-ligand allosteric interactions) that may be behind the 'ALB-mediated hepatic uptake' mechanism(s) for highly bound drugs. Main keywords used in our search are IVIVE; albumin; allostery; protein-mediated uptake; hepatic clearance; polarized hepatocytes. : Understanding the implication of these interactions and the enzyme/transporter interplay for each drug would help selecting the appropriate IVIVE model. Therefore, we have proposed a tree of decision for guidance. The next step is to improve the 'ALB-facilitated hepatic uptake' models to cover the remaining uncertainties.
Topics: Albumins; Biological Transport; Hepatocytes; Humans; Lipids; Liver; Models, Biological; Pharmaceutical Preparations; Pharmacokinetics; Protein Binding; Proteins
PubMed: 31274340
DOI: 10.1080/17425255.2019.1640679 -
Seminars in Dialysis Jun 2023The key goals for dialysis treatments are to prevent the progressive accumulation of waste products of metabolism and volume overload. Traditionally uremic solutes have...
The key goals for dialysis treatments are to prevent the progressive accumulation of waste products of metabolism and volume overload. Traditionally uremic solutes have been classified according to molecular weight and termed small, middle sized, and large solutes. Solute clearance during dialysis sessions will potentially be by diffusion, convection and adsorption. Dialyzer membranes act as a semi-permeable membrane restricting solute removal predominantly by size. Small molecules move faster than large molecules, so small solutes are readily removed by diffusion. Increasing the size of the pores in the membrane will potentially allow middle and larger sized solutes to pass through the dialyzer membrane, although in practice there is a limit to increasing pore sizes to prevent the loss of albumin and other important proteins. Differences in membrane surface and charge will influence protein absorption. The removal of fluid during dialysis depends in part on the hydraulic permeability of the membrane. Combining higher hydraulic permeability and larger sized pores increases convective clearance with solutes moving across the membrane with the water movement. Depending upon dialyzer design, higher hydrostatic pressure as blood enters the dialyzer leads to a variable amount of internal diafiltration, so improving the clearance of middle sized solutes. Although the dialyzer membrane plays a key role in solute clearance, the design of the casing and header also play a role in directing the countercurrent blood and dialysate flows to maximize the surface area available for diffusive and convective clearances.
PubMed: 37278230
DOI: 10.1111/sdi.13161 -
Pharmacology & Therapeutics Jan 2022The accuracy in predicting in vivo hepatic clearance of drugs from in vitro data (often termed as in vitro-to-in vivo extrapolation, IVIVE) has improved in part by... (Review)
Review
The accuracy in predicting in vivo hepatic clearance of drugs from in vitro data (often termed as in vitro-to-in vivo extrapolation, IVIVE) has improved in part by applying the extended-clearance concept that considers the interplay between hepatic metabolism and uptake/efflux processes. However, the IVIVE-based prediction performs poorly in predicting the hepatic uptake clearance of highly albumin-bound anionic drugs. Their hepatic uptake clearances tend to be much higher than expected based on the free-drug theory. Such observation can be attributable to a phenomenon called albumin-mediated hepatic uptake, for which various models have been thus far proposed. Our group has been applying a facilitated-dissociation model, which assumes the enhanced dissociation of the drug-albumin complex upon interaction with the cell surface. By considering the albumin-mediated hepatic uptake (using the facilitated-dissociation model or alternative kinetic models), a number of investigations demonstrated the improvement in the prediction accuracy for the hepatic clearance of highly protein-bound anionic drugs that are substrates for hepatic uptake transporters. This review summarizes the reported kinetic analyses of the albumin-mediated hepatic uptake of highly albumin-bound drugs concerning the IVIVE and the clinical and physiological relevance.
Topics: Albumins; Hepatocytes; Humans; Liver; Metabolic Clearance Rate; Models, Biological; Organic Anion Transporters; Pharmaceutical Preparations
PubMed: 34171335
DOI: 10.1016/j.pharmthera.2021.107938 -
International Journal of Molecular... Dec 2022The care of systemic amyloidosis has improved dramatically due to improved awareness, accurate diagnostic tools, the development of powerful prognostic and companion... (Review)
Review
The care of systemic amyloidosis has improved dramatically due to improved awareness, accurate diagnostic tools, the development of powerful prognostic and companion biomarkers, and a continuous flow of innovative drugs, which translated into the blooming of phase 2/3 interventional studies for light chain (AL) and transthyretin (ATTR) amyloidosis. The unprecedented availability of effective drugs ignited great interest across various medical specialties, particularly among cardiologists who are now recognizing cardiac amyloidosis at an extraordinary pace. In all amyloidosis referral centers, we are observing a substantial increase in the prevalence of wild-type transthyretin (ATTRwt) cardiomyopathy, which is now becoming the most common form of cardiac amyloidosis. This review focuses on the oral drugs that have been recently introduced for the treatment of ATTR cardiac amyloidosis, for their ease of use in the clinic. They include both old repurposed drugs or fit-for-purpose designed compounds which bind and stabilize the TTR tetramer, thus reducing the formation of new amyloid fibrils, such as tafamidis, diflunisal, and acoramidis, as well as fibril disruptors which have the potential to promote the clearance of amyloid deposits, such as doxycycline. The development of novel therapies is based on the advances in the understanding of the molecular events underlying amyloid cardiomyopathy.
Topics: Humans; Amyloid Neuropathies, Familial; Prealbumin; Diflunisal; Cardiomyopathies; Amyloid
PubMed: 36555787
DOI: 10.3390/ijms232416145