12,039 results match your criteria systemic clearance


Local antifungal immunity in the kidney in disseminated candidiasis.

Curr Opin Microbiol 2021 May 12;62:1-7. Epub 2021 May 12.

Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA. Electronic address:

Disseminated candidiasis is a hospital-acquired infection that results in high degree of mortality despite antifungal treatment. Autopsy studies revealed that kidneys are the major target organs in disseminated candidiasis and death due to kidney damage is a frequent outcome in these patients. Thus, the need for effective therapeutic strategies to mitigate kidney damage in disseminated candidiasis is compelling. Read More

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A physiologically-based pharmacokinetic model to describe antisense oligonucleotide distribution after intrathecal administration.

J Pharmacokinet Pharmacodyn 2021 May 15. Epub 2021 May 15.

Clinical Pharmacology and Pharmacometrics, Biogen Inc., 225 Binney Street, Cambridge, MA, 02142, USA.

Antisense oligonucleotides (ASOs) are promising therapeutic agents for a variety of neurodegenerative and neuromuscular disorders, e.g., Alzheimer's, Parkinson's and Huntington's diseases, spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), caused by genetic abnormalities or increased protein accumulation. Read More

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Senolytics and Senomorphics: natural and synthetic therapeutics in the treatment of aging and chronic diseases.

Free Radic Biol Med 2021 May 11. Epub 2021 May 11.

Institute of Chemical Biology, National Hellenic Research Foundation, 48 Vassileos Constantinou Ave., Athens 11635, Greece. Electronic address:

Cellular senescence is a heterogeneous process guided by genetic, epigenetic and environmental factors, characterizing many types of somatic cells. It has been suggested as an aging hallmark that is believed to contribute to aging and chronic diseases. Senescent cells (SC) exhibit a specific senescence-associated secretory phenotype (SASP), mainly characterized by the production of proinflammatory and matrix-degrading molecules. Read More

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Ceftriaxone as an Alternative Therapy for the Treatment of Methicillin-Susceptible Bacteremia after Initial Clearance of Bloodstream Infection.

Case Rep Infect Dis 2021 26;2021:8884685. Epub 2021 Apr 26.

University of Mississippi School of Pharmacy, Department of Pharmacy Practice, 2500 North State Street, Jackson, MS 39216, USA.

Introduction: spp. represent the leading cause of hospital-acquired infections and second-most frequent pathogen in bloodstream infections. Methicillin-susceptible (MSSA) comprise approximately half of all isolates. Read More

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Are body surface area (BSA) based estimates of liver volume applicable to children with overweight or obesity? An in-vivo validation study.

Clin Transl Sci 2021 May 13. Epub 2021 May 13.

Children's Mercy Kansas City, Kansas City.

The liver is the primary organ responsible for clearing most drugs from the body and thus determines systemic drug concentrations over time. Drug clearance by the liver appears to be directly related to organ size. In children, organ size changes as children age and grow. Read More

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There is Only One Valid Definition of Clearance: Critical Examination of Clearance Concepts Reveals the Potential for Errors in Clinical Drug Dosing Decisions.

AAPS J 2021 May 10;23(3):67. Epub 2021 May 10.

Department of Chemical and Biomolecular Engineering, University of California, Berkeley, California, 94720-1462, USA.

Drug dosing decisions in clinical medicine and in introducing a drug to market for the past 60 years are based on the pharmacokinetic/clinical pharmacology concept of clearance. We used chemical reaction engineering models to demonstrate the limitations of presently employed clearance measurements based upon systemic blood concentration in reflecting organ clearance. The belief for the last 49 years that in vivo clearance is independent of the mechanistic model for organ clearance is incorrect. Read More

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Mechanisms of Sound-Induced Opening of the Blood-Brain Barrier.

Adv Exp Med Biol 2021 ;1269:197-202

Saratov State University, Saratov, Russia.

The blood-brain barrier (BBB) poses a significant challenge for drug delivery to the brain. The limitations of our knowledge about the nature of BBB explain the slow progress in the therapy of brain diseases and absence of methods for drug delivery to the brain in clinical practice. Here, we show that the BBB opens for high-molecular-weight compounds after exposure to loud sound (100 dB 370 Hz) in rats. Read More

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Cellular Responses to the Efferocytosis of Apoptotic Cells.

Front Immunol 2021 20;12:631714. Epub 2021 Apr 20.

Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.

The rapid and efficient phagocytic clearance of apoptotic cells, termed efferocytosis, is a critical mechanism in the maintenance of tissue homeostasis. Removal of apoptotic cells through efferocytosis prevents secondary necrosis and the resultant inflammation caused by the release of intracellular contents. The importance of efferocytosis in homeostasis is underscored by the large number of inflammatory and autoimmune disorders, including atherosclerosis and systemic lupus erythematosus, that are characterized by defective apoptotic cell clearance. Read More

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A phase I, single and continuous dose administration study on the safety, tolerability, and pharmacokinetics of neorudin, a novel recombinant anticoagulant protein, in healthy subjects.

Pharmacol Res Perspect 2021 May;9(3):e00785

Beijing Institute of Radiation Medicine, Beijing, China.

The aim of this study was to evaluate the tolerability, safety, and pharmacokinetics of single and continuous dose administration of recombinant neorudin (EPR-hirudin, EH) by intravenous administration in healthy subjects, and to provide a safe dosage range for phase II clinical research. Forty-four subjects received EH as a single dose of between 0.2 and 2. Read More

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Dialyzer Performance During Hemodialysis Without Systemic Anticoagulation Using a Heparin-Grafted Dialyzer Combined With a Citrate-Enriched Dialysate: Results of the Randomized Crossover Noninferiority EVOCIT Study.

Am J Kidney Dis 2021 Apr 30. Epub 2021 Apr 30.

Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Division of Nephrology and Hypertension.

Rationale And Objective: The EVOCIT study was designed to evaluate dialyzer performance during hemodialysis with and without systemic anticoagulation.

Study Design: Randomized, crossover, non-inferiority trial. Noninferiority was defined as a difference of ≤10% for the primary outcome. Read More

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Circulating tumor DNA dynamics and recurrence risk in patients undergoing curative intent resection of colorectal cancer liver metastases: A prospective cohort study.

PLoS Med 2021 May 3;18(5):e1003620. Epub 2021 May 3.

The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.

Background: In patients with resectable colorectal liver metastases (CRLM), the role of pre- and postoperative systemic therapy continues to be debated. Previous studies have shown that circulating tumor DNA (ctDNA) analysis, as a marker of minimal residual disease, is a powerful prognostic factor in patients with nonmetastatic colorectal cancer (CRC). Serial analysis of ctDNA in patients with resectable CRLM could inform the optimal use of perioperative chemotherapy. Read More

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Deletion of the Gene in Blocks Its Escape From Macrophage Clearance.

Front Cell Infect Microbiol 2021 16;11:643121. Epub 2021 Apr 16.

Department of Dermatology, The First Affiliated Hospital of Jinan University, Guangzhou, China.

Macrophages provide the first-line defense against invasive fungal infections and, therefore, escape from macrophage becomes the basis for the establishment of invasive infection. Here, we found that deletion of (Δ/Δ) in resulted in a dramatic decrease from 69.2% (WT) to 1. Read More

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Factors associated with reduced infliximab exposure in the treatment of pediatric autoimmune disorders: a cross-sectional prospective convenience sampling study.

Pediatr Rheumatol Online J 2021 May 1;19(1):62. Epub 2021 May 1.

Department of Pediatrics, Duke University Hospital, Durham, NC, USA.

Background: Inadequate systemic exposure to infliximab (IFX) is associated with treatment failure. This work evaluated factors associated with reduced IFX exposure in children with autoimmune disorders requiring IFX therapy.

Methods: In this single-center cross-sectional prospective study IFX trough concentrations and anti-drug antibodies (ADAs) were measured in serum from children diagnosed with inflammatory bowel disease (IBD) (n = 73), juvenile idiopathic arthritis (JIA) (n = 16), or uveitis (n = 8) receiving maintenance IFX infusions at an outpatient infusion clinic in a tertiary academic pediatric hospital. Read More

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Systematic analysis of direct antiglobulin test results in post-artesunate delayed haemolysis.

Malar J 2021 Apr 29;20(1):206. Epub 2021 Apr 29.

Lazzaro Spallanzani, National Institute for Infectious Diseases-IRCCS, Via Portuense, 292, Cap 00149, Rome, Italy.

Background: Post-artesunate delayed haemolysis (PADH) is common after severe malaria episodes. PADH is related to the "pitting" phenomenon and the synchronous delayed clearance of once-infected erythrocytes, initially spared during treatment. However, direct antiglobulin test (DAT) positivity has been reported in several PADH cases, suggesting a contribution of immune-mediated erythrocyte clearance. Read More

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Role of Short Chain Fatty Acids and Apolipoproteins in the Regulation of Eosinophilia-Associated Diseases.

Int J Mol Sci 2021 Apr 22;22(9). Epub 2021 Apr 22.

Otto Loewi Research Center, Division of Pharmacology, Medical University of Graz, 8010 Graz, Austria.

Eosinophils are key components of our host defense and potent effectors in allergic and inflammatory diseases. Once recruited to the inflammatory site, eosinophils release their cytotoxic granule proteins as well as cytokines and lipid mediators, contributing to parasite clearance but also to exacerbation of inflammation and tissue damage. However, eosinophils have recently been shown to play an important homeostatic role in different tissues under steady state. Read More

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Pharmacokinetic-Pharmacodynamic Modelling of Systemic IL13 Blockade by Monoclonal Antibody Therapy: A Free Assay Disguised as Total.

Pharmaceutics 2021 Apr 9;13(4). Epub 2021 Apr 9.

Clinical Pharmacology and Quantitative Pharmacology, AstraZeneca, Cambridge CB21 6GH, UK.

A sequential pharmacokinetic (PK) and pharmacodynamic (PD) model was built with Nonlinear Mixed Effects Modelling based on data from a first-in-human trial of a novel biologic, MEDI7836. MEDI7836 is a human immunoglobulin G1 lambda (IgG1λ-YTE) monoclonal antibody, with an Fc modification to reduce metabolic clearance. MEDI7836 specifically binds to, and functionally neutralizes interleukin-13. Read More

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Successful Direct Acting Antiviral Therapy in Chronic Hepatitis C Normalizes IFNγ and IL2 Production in T Cells Together with TLR8 Expression and Functionality in Peripheral Blood Mononuclear Cells.

Viruses 2021 04 7;13(4). Epub 2021 Apr 7.

Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital, 39008 Santander, Spain.

Chronic hepatitis C infection (HCV) activates a systemic cell-mediated immune response characterized by the production of IFNγ and an innate immune response addressed by the activation of TLR signaling. We aimed to investigate whether HCV eradication by direct acting antivirals (DAA) leads to a recovery in cell-mediated immune response and TLR expression and functionality. Blood samples were obtained in HCV infected patients before DAA treatment and at week +48 after the end of treatment. Read More

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Relationship Between Apparent Systemic Clearance of Vemurafenib and Toxicity in Patients with Melanoma.

J Clin Pharmacol 2021 Apr 27. Epub 2021 Apr 27.

Flinders University, Flinders drive, Adelaide, South Australia, 5001, Australia.

Vemurafenib, a BRAF inhibitor, is commonly used in combination of cobimetinib for the treatment of melanoma. In the current study, we evaluated the relationship between vemurafenib exposure, as measured by the estimated apparent clearance (CL ) at steady state and any grade ≥ 3 toxicity, grade ≥ 3 skin rash or toxicity requiring dose modification using pooled data from 3 prospective clinical trials involving 898 patients. A total of 69% had any grade ≥ 3 toxicity; grade ≥ 3 skin rash in 15% and 47% had a dose reduction/interruption or cessation. Read More

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Mucosal immunity to severe acute respiratory syndrome coronavirus 2 infection.

Curr Opin Infect Dis 2021 06;34(3):181-186

Section Paediatric Infectious Diseases, Laboratory of Medical Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center.

Purpose Of Review: Despite its crucial role in protection against viral infections, mucosal immunity has been largely understudied in the context of coronavirus disease 2019 (COVID-19). This review outlines the current evidence about the role of mucosal immune responses in the clearance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as well as potential mucosal mechanisms of protection against (re-)infection.

Recent Findings: The angiotensin-converting enzyme 2 cellular entry receptor for SARS-CoV-2 is most highly expressed in the upper respiratory tract and most SARS-CoV-2 shedding occurs from the upper respiratory tract. Read More

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Which factors matter the most? Revisiting and dissecting antibody therapeutic doses.

Drug Discov Today 2021 Apr 22. Epub 2021 Apr 22.

Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address:

Factors such as antibody clearance and target affinity can influence antibodies' effective doses for specific indications. However, these factors vary considerably across antibody classes, precluding direct and quantitative comparisons. Here, we apply a dimensionless metric, the therapeutic exposure affinity ratio (TEAR), which normalizes the therapeutic doses by antibody bioavailability, systemic clearance and target-binding property to enable direct and quantitative comparisons of therapeutic doses. Read More

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Recombinant apoptosis inhibitor of macrophage protein reduces delayed graft function in a murine model of kidney transplantation.

PLoS One 2021 23;16(4):e0249838. Epub 2021 Apr 23.

Department of Microbiology and Immunology, Western University, London, Ontario, Canada.

Reperfusion injury following cold and warm ischemia (IRI) is unavoidable during kidney transplantation and contributes to delayed graft function (DGF) and premature graft loss. Death of tubular epithelial cells (TECs) by necrosis during IRI releases pro-inflammatory mediators (e.g. Read More

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ExoSTING, an extracellular vesicle loaded with STING agonists, promotes tumor immune surveillance.

Commun Biol 2021 Apr 22;4(1):497. Epub 2021 Apr 22.

Codiak BioSciences Inc., Cambridge, MA, USA.

Cyclic dinucleotide (CDN) agonists of the STimulator of InterferoN Genes (STING) pathway have shown immune activation and tumor clearance in pre-clinical models. However, CDNs administered intratumorally also promote STING activation leading to direct cytotoxicity of many cell types in the tumor microenvironment (TME), systemic inflammation due to rapid tumor extravasation of the CDN, and immune ablation in the TME. These result in a failure to establish immunological memory. Read More

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Vaccine-induced, but not natural immunity, against the Streptococcal inhibitor of complement protects against invasive disease.

NPJ Vaccines 2021 Apr 22;6(1):62. Epub 2021 Apr 22.

Section of Adult Infectious Disease, Department of Infectious Disease, Imperial College London, London, UK.

Highly pathogenic emm1 Streptococcus pyogenes strains secrete the multidomain Streptococcal inhibitor of complement (SIC) that binds and inactivates components of the innate immune response. We aimed to determine if naturally occurring or vaccine-induced antibodies to SIC are protective against invasive S. pyogenes infection. Read More

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Micelle-contained and PEGylated hybrid liposomes of combined gemcitabine and cisplatin delivery for enhancing antitumor activity.

Int J Pharm 2021 Apr 20;602:120619. Epub 2021 Apr 20.

Department of Pharmaceutics Science, Shenyang Pharmaceutical University, Shenyang 110116, China. Electronic address:

Combination, synergistic chemotherapy with gemcitabine (GEM) and cisplatin (CDDP) is a common strategy, and has been recommended for tumor treatment due to its promoted therapeutic effect and reduced systemic toxicity. However, this process involves the intravenous infusion of GEM prior to that of CDDP, which is inconvenient for patients and staff. Here, a novel hybrid nano-carrier system comprised of micelles encapsulated within PEGylated liposomes is proposed, in order to combine the unique strengths of each component. Read More

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COVID-19 Severity Is Associated with Differential Antibody Fc-Mediated Innate Immune Functions.

mBio 2021 04 20;12(2). Epub 2021 Apr 20.

The Wistar Institute, Philadelphia, Pennsylvania, USA

Beyond neutralization, antibodies binding to their Fc receptors elicit several innate immune functions including antibody-dependent complement deposition (ADCD), antibody-dependent cell-mediated phagocytosis (ADCP), and antibody-dependent cell-mediated cytotoxicity (ADCC). These functions are beneficial, as they contribute to pathogen clearance; however, they also can induce inflammation. We tested the possibility that qualitative differences in SARS-CoV-2-specific antibody-mediated innate immune functions contribute to coronavirus disease 2019 (COVID-19) severity. Read More

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Estimation of absolute oral bioavailability without performing an intravenous clinical study.

Drug Metab Pharmacokinet 2021 Mar 24;38:100392. Epub 2021 Mar 24.

Division of Clinical Pharmacokinetics, Keio University Faculty of Pharmacy, Shibakoen, Minato-ku, Tokyo, 105-8512, Japan.

The absolute oral bioavailability (BA) of drugs are yet to be determined, and intravenous pharmacokinetic studies are currently considered indispensable for determining the BA values of oral drugs. The aim of this study was to develop and validate a novel approach to estimating BA values without intravenous pharmacokinetic data. Based on the drug inclusion criteria, such as exhibiting a urinary recovery rate of (R) of ≥20% in a clinical study, 13 drugs were included in the present study, and pharmacokinetic data for them were collected from the literature. Read More

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Optimizing an Antioxidant TEMPO Copolymer for Reactive Oxygen Species Scavenging and Anti-Inflammatory Effects .

Bioconjug Chem 2021 Apr 19. Epub 2021 Apr 19.

Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee 37232, United States.

Oxidative stress is broadly implicated in chronic, inflammatory diseases because it causes protein and lipid damage, cell death, and stimulation of inflammatory signaling. Supplementation of innate antioxidant mechanisms with drugs such as the superoxide dismutase (SOD) mimetic compound 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) is a promising strategy for reducing oxidative stress-driven pathologies. TEMPO is inexpensive to produce and has strong antioxidant activity, but it is limited as a drug due to rapid clearance from the body. Read More

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NOX2 Deficiency Permits Sustained Survival of in Macrophages and Contributes to Severity of Infection.

Front Immunol 2021 22;12:633629. Epub 2021 Mar 22.

Paul-Ehrlich-Institut, Langen, Germany.

Although the crucial role of professional phagocytes for the clearance of infections is well-established, several studies indicate an adverse role of leukocytes in the dissemination of during infection. Since only little is known about macrophages in this context, we analyzed the role of macrophages, and in particular reactive oxygen species deficiency, for the seeding of metastases. Infection of bone marrow-derived macrophages (BMDM) with revealed that NADPH oxidase 2 (NOX2-) deficient, but not NOX1- or NOX4-deficient, BMDM failed to clear intracellular . Read More

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Renal clearable zwitterionic near-infrared fluorophores for potential clinical translation.

Angew Chem Int Ed Engl 2021 Apr 15. Epub 2021 Apr 15.

Massachusetts General Hospital, Radiology, 149 13th Street, 02129, Boston, UNITED STATES.

Near-infrared (NIR) fluorescence imaging has advanced medical imaging and image-guided interventions during the past three decades. However, despite major advances in imaging instrumentation, only a few dyes are currently available in the clinic. Previously, we reported two zwitterionic NIR fluorophores, ZW800-1A and ZW800-1C, which significantly improved the poor performance of the FDA-approved indocyanine green. Read More

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Safety and effectiveness of edoxaban in Japanese patients with nonvalvular atrial fibrillation: Final report of a two-year postmarketing surveillance study (ETNA-AF-Japan).

J Arrhythm 2021 Apr 24;37(2):370-383. Epub 2021 Feb 24.

Data Intelligence Department Daiichi Sankyo Co. Ltd Tokyo Japan.

Background: Direct oral anticoagulants (DOACs) are the recommended first-line therapy for ischemic stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). However, the safety and effectiveness of edoxaban for this indication requires monitoring over the long term in real-world settings.

Methods: ETNA-AF-Japan (trial no. Read More

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