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Gastroenterology Oct 2023Although transient bacteremia is common during dental and endoscopic procedures, infections developing during sterile diseases like acute pancreatitis (AP) can have...
BACKGROUND & AIMS
Although transient bacteremia is common during dental and endoscopic procedures, infections developing during sterile diseases like acute pancreatitis (AP) can have grave consequences. We examined how impaired bacterial clearance may cause this transition.
METHODS
Blood samples from patients with AP, normal controls, and rodents with pancreatitis or those administered different nonesterified fatty acids (NEFAs) were analyzed for albumin-unbound NEFAs, microbiome, and inflammatory cell injury. Macrophage uptake of unbound NEFAs using a novel coumarin tracer were done and the downstream effects-NEFA-membrane phospholipid (phosphatidylcholine) interactions-were studied on isothermal titration calorimetry.
RESULTS
Patients with infected AP had higher circulating unsaturated NEFAs; unbound NEFAs, including linoleic acid (LA) and oleic acid (OA); higher bacterial 16S DNA; mitochondrial DNA; altered β-diversity; enrichment in Pseudomonadales; and increased annexin V-positive myeloid (CD14) and CD3-positive T cells on admission. These, and increased circulating dead inflammatory cells, were also noted in rodents with unbound, unsaturated NEFAs. Isothermal titration calorimetry showed progressively stronger unbound LA interactions with aqueous media, phosphatidylcholine, cardiolipin, and albumin. Unbound NEFAs were taken into protein-free membranes, cells, and mitochondria, inducing voltage-dependent anion channel oligomerization, reducing ATP, and impairing phagocytosis. These were reversed by albumin. In vivo, unbound LA and OA increased bacterial loads and impaired phagocytosis, causing infection. LA and OA were more potent for these amphipathic interactions than the hydrophobic palmitic acid.
CONCLUSIONS
Release of stored LA and OA can increase their circulating unbound levels and cause amphipathic liponecrosis of immune cells via uptake by membrane phospholipids. This impairs bacterial clearance and causes infection during sterile inflammation.
Topics: Humans; Acute Disease; Pancreatitis; Fatty Acids, Nonesterified; Oleic Acid; Inflammation; Albumins; Phosphatidylcholines
PubMed: 37263302
DOI: 10.1053/j.gastro.2023.05.034 -
Journal of Clinical Medicine Nov 2023Biological therapy is very effective for treating patients with moderate to severe inflammatory bowel disease (IBD). However, up to 40% can have primary non-response,... (Review)
Review
Biological therapy is very effective for treating patients with moderate to severe inflammatory bowel disease (IBD). However, up to 40% can have primary non-response, and up to 50% of the patients can experience a loss of response to anti-tumor necrosis factor therapy. These undesirable outcomes can be attributed to either a mechanistic failure or pharmacokinetic (PK) issues characterized by an inadequate drug exposure and a high drug clearance. There are several factors associated with accelerated clearance of biologics including increased body weight, low serum albumin and immunogenicity. Drug clearance has gained a lot of attention recently as cumulative data suggest that there is an association between drug clearance and therapeutic outcomes in patients with IBD. Moreover, clearance is used by model informed precision dosing (MIDP) tools, or PK dashboards, to adjust the dosing for reaching a target drug concentration threshold towards a more personalized application of TDM. However, the role of drug clearance in clinical practice is yet to be determined. This comprehensive review aims to present data regarding the variables affecting the clearance of specific biologics, the association of clearance with therapeutic outcomes and the role of clearance monitoring and MIPD in patients with IBD.
PubMed: 38002743
DOI: 10.3390/jcm12227132 -
The Journal of Clinical Investigation Sep 2023Circadian rhythms govern glucose homeostasis, and their dysregulation leads to complex metabolic diseases. Gut microbes exhibit diurnal rhythms that influence host...
Circadian rhythms govern glucose homeostasis, and their dysregulation leads to complex metabolic diseases. Gut microbes exhibit diurnal rhythms that influence host circadian networks and metabolic processes, yet underlying mechanisms remain elusive. Here, we showed hierarchical, bidirectional communication among the liver circadian clock, gut microbes, and glucose homeostasis in mice. To assess this relationship, we utilized mice with liver-specific deletion of the core circadian clock gene Bmal1 via Albumin-cre maintained in either conventional or germ-free housing conditions. The liver clock, but not the forebrain clock, required gut microbes to drive glucose clearance and gluconeogenesis. Liver clock dysfunctionality expanded proportions and abundances of oscillating microbial features by 2-fold relative to that in controls. The liver clock was the primary driver of differential and rhythmic hepatic expression of glucose and fatty acid metabolic pathways. Absent the liver clock, gut microbes provided secondary cues that dampened these rhythms, resulting in reduced lipid fuel utilization relative to carbohydrates. All together, the liver clock transduced signals from gut microbes that were necessary for regulating glucose and lipid metabolism and meeting energy demands over 24 hours.
Topics: Animals; Mice; Glucose; Circadian Clocks; Lipid Metabolism; Gastrointestinal Microbiome; Liver
PubMed: 37712426
DOI: 10.1172/JCI162515 -
Frontiers in Immunology 2023Acute respiratory distress syndrome (ARDS) is a common complication of influenza virus (IV) infection. During ARDS, alveolar protein concentrations often reach 40-90% of...
INTRODUCTION
Acute respiratory distress syndrome (ARDS) is a common complication of influenza virus (IV) infection. During ARDS, alveolar protein concentrations often reach 40-90% of plasma levels, causing severe impairment of gas exchange and promoting deleterious alveolar remodeling. Protein clearance from the alveolar space is at least in part facilitated by the multi-ligand receptor megalin through clathrin-mediated endocytosis.
METHODS
To investigate whether IV infection impairs alveolar protein clearance, we examined albumin uptake and megalin expression in MLE-12 cells and alveolar epithelial cells (AEC) from murine precision-cut lung slices (PCLS) and in vivo, under IV infection conditions by flow cytometry and western blot. Transcriptional levels from AEC and broncho-alveolar lavage (BAL) cells were analyzed in an in-vivo mouse model by RNAseq.
RESULTS
IV significantly downregulated albumin uptake, independently of activation of the TGF-β1/GSK3β axis that has been previously implicated in the regulation of megalin function. Decreased plasma membrane abundance, total protein levels, and mRNA expression of megalin were associated with this phenotype. In IV-infected mice, we identified a significant upregulation of matrix metalloproteinase (MMP)-14 in BAL fluid cells. Furthermore, the inhibition of this protease partially recovered total megalin levels and albumin uptake.
DISCUSSION
Our results suggest that the previously described MMP-driven shedding mechanisms are potentially involved in downregulation of megalin cell surface abundance and clearance of excess alveolar protein. As lower alveolar edema protein concentrations are associated with better outcomes in respiratory failure, our findings highlight the therapeutic potential of a timely MMP inhibition in the treatment of IV-induced ARDS.
Topics: Animals; Mice; Alveolar Epithelial Cells; Low Density Lipoprotein Receptor-Related Protein-2; Biological Transport; Albumins; Orthomyxoviridae Infections; Orthomyxoviridae
PubMed: 37727782
DOI: 10.3389/fimmu.2023.1260973 -
Clinical and Experimental Medicine Mar 2024Cirrhosis is an advanced-stage liver disease that occurs due to persistent physiological insults such as excessive alcohol consumption, infections, or toxicity. It is... (Review)
Review
Cirrhosis is an advanced-stage liver disease that occurs due to persistent physiological insults such as excessive alcohol consumption, infections, or toxicity. It is characterised by scar tissue formation, portal hypertension, and ascites (accumulation of fluid in the abdominal cavity) in decompensated cirrhosis. This review evaluates how albumin infusion ameliorates cirrhosis-associated complications. Since albumin is an oncotic plasma protein, albumin infusion allows movement of water into the intravascular space, aids with fluid resuscitation, and thereby contributes to resolving cirrhosis-induced hypovolemia (loss of extracellular fluid) seen in ascites. Thus, albumin infusion helps prevent paracentesis-induced circulatory dysfunction, a complication that occurs when treating ascites. When cirrhosis advances, other complications such as spontaneous bacterial peritonitis and hepatorenal syndrome can manifest. Infused albumin helps mitigate these by exhibiting plasma expansion, antioxidant, and anti-inflammatory functions. In hepatic encephalopathy, albumin infusion is thought to improve cognitive function by reducing ammonia concentration in blood and thereby tackle cirrhosis-induced hepatocyte malfunction in ammonia clearance. Infused albumin can also exhibit protective effects by binding to the cirrhosis-induced proinflammatory cytokines TNFα and IL6. While albumin administration has shown to prolong overall survival of cirrhotic patients with ascites in the ANSWER trial, the ATTIRE and MACHT trials have shown either no effect or limitations such as development of pulmonary oedema and multiorgan failure. Thus, albumin infusion is not a generic treatment option for all cirrhosis patients. Interestingly, cirrhosis-induced structural alterations in native albumin (which lead to formation of different albumin isoforms) can be used as prognostic biomarkers because specific albumin isoforms indicate certain complications of decompensated cirrhosis.
Topics: Humans; Ascites; Ammonia; Liver Cirrhosis; Albumins; Protein Isoforms
PubMed: 38551716
DOI: 10.1007/s10238-024-01315-1 -
Cancer Biology & Medicine Nov 2023In oncolytic virus (OV) therapy, a critical component of tumor immunotherapy, viruses selectively infect, replicate within, and eventually destroy tumor cells.... (Review)
Review
In oncolytic virus (OV) therapy, a critical component of tumor immunotherapy, viruses selectively infect, replicate within, and eventually destroy tumor cells. Simultaneously, this therapy activates immune responses and mobilizes immune cells, thereby eliminating residual or distant cancer cells. However, because of OVs' high immunogenicity and immune clearance during circulation, their clinical applications are currently limited to intratumoral injections, and their use is severely restricted. In recent years, numerous studies have used nanomaterials to modify OVs to decrease virulence and increase safety for intravenous injection. The most commonly used nanomaterials for modifying OVs are liposomes, polymers, and albumin, because of their biosafety, practicability, and effectiveness. The aim of this review is to summarize progress in the use of these nanomaterials in preclinical experiments to modify OVs and to discuss the challenges encountered from basic research to clinical application.
Topics: Humans; Oncolytic Viruses; Neoplasms; Oncolytic Virotherapy; Immunotherapy
PubMed: 38009779
DOI: 10.20892/j.issn.2095-3941.2023.0275 -
Clinical Pharmacokinetics Oct 2023Mirikizumab is a humanized anti-interleukin-23-p19 monoclonal antibody being developed for ulcerative colitis and Crohn's disease. This analysis characterized...
BACKGROUND AND OBJECTIVE
Mirikizumab is a humanized anti-interleukin-23-p19 monoclonal antibody being developed for ulcerative colitis and Crohn's disease. This analysis characterized mirikizumab pharmacokinetics using phase II and III trial data from patients with moderately to severely active ulcerative colitis.
METHODS
Serum pharmacokinetic data in patients receiving mirikizumab 50-1000 mg intravenously every 4 weeks as induction treatment and mirikizumab 200 mg subcutaneously every 4 or 12 weeks as maintenance treatment across three trials (N = 1362) were analyzed using non-linear mixed-effects modeling. Covariate effects on mirikizumab exposure were evaluated using simulation-based estimations.
RESULTS
Mirikizumab pharmacokinetics was best described by a linear two-compartment model with first-order absorption. Clearance, volume of distribution for central and peripheral compartments, and half-life were estimated at approximately 0.022 L/h (linear), 3.11 L and 1.69 L, and 9.5 days, respectively. Statistically significant effects of body weight and serum albumin levels on clearance, body weight on central and peripheral volumes of distribution, and body mass index on bioavailability were observed but effects were small relative to random inter-individual variability (% coefficient of variation: 18-64%). The subcutaneous bioavailability of mirikizumab was 48%.
CONCLUSIONS
Mirikizumab displayed pharmacokinetic characteristics typical of a monoclonal antibody where clearance increased with body weight and decreased with the albumin level, and bioavailability decreased with body mass index. These effects were small relative to random variability, indicating that a dose adjustment for patient factors is not required.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov: NCT02589665 (28 October, 2015), NCT03518086 (8 May, 2018), NCT03524092 (14 May, 2018).
Topics: Humans; Colitis, Ulcerative; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Body Weight
PubMed: 37610533
DOI: 10.1007/s40262-023-01281-z -
Pharmaceutics Oct 2023Free drug concentrations are generally considered the pharmacologically active moiety and are important for cellular diffusion and distribution. Pregnancy-related...
Total and Free Blood and Plasma Concentration Changes in Pregnancy for Medicines Highly Bound to Plasma Proteins: Application of Physiologically Based Pharmacokinetic Modelling to Understand the Impact on Efficacy.
Free drug concentrations are generally considered the pharmacologically active moiety and are important for cellular diffusion and distribution. Pregnancy-related changes in plasma protein binding and blood partitioning are due to decreases in plasma albumin, alpha-1-acid glycoprotein, and haematocrit; this may lead to increased free concentrations, tissue distribution, and clearance during pregnancy. In this paper we highlight the importance and challenges of considering changes in total and free concentrations during pregnancy. For medicines highly bound to plasma proteins, such as tacrolimus, efavirenz, clindamycin, phenytoin, and carbamazepine, differential changes in concentrations of free drug during pregnancy may be clinically significant and have important implications for dose adjustment. Therapeutic drug monitoring usually relies on the measurement of total concentrations; this can result in dose adjustments that are not necessary when changes in free concentrations are considered. We explore the potential of physiologically based pharmacokinetic (PBPK) models to support the understanding of the changes in plasma proteins binding, using tacrolimus and efavirenz as example drug models. The exposure to either drug was predicted to be reduced during pregnancy; however, the decrease in the exposure to the total tacrolimus and efavirenz were significantly larger than the reduction in the exposure to the free drug. These data show that PBPK modelling can support the impact of the changes in plasma protein binding and may be used for the simulation of free concentrations in pregnancy to support dosing decisions.
PubMed: 37896215
DOI: 10.3390/pharmaceutics15102455