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Current Research in Toxicology 2024Urinary cadmium excretion (E) rises with renal tissue content of the metal. Whereas glomerulopathies are sometimes associated with massive albuminuria, tubular...
BACKGROUND
Urinary cadmium excretion (E) rises with renal tissue content of the metal. Whereas glomerulopathies are sometimes associated with massive albuminuria, tubular accumulation of Cd typically causes modest albuminuria. Since β-microglobulinuria (E) is an established marker of proximal tubular dysfunction, we hypothesized that a comparison of albuminuria (E) to E in Cd-exposed subjects would provide evidence of similar mishandling of both proteins.
METHODS
To depict excretion rates per functional nephron, E, E, and E were normalized to creatinine clearance (C), a surrogate for the glomerular filtration rate (GFR). Estimation of GFR itself (eGFR) was accomplished with CKD-EPI formulas (2009). Linear and logistic regression analyses were performed to relate E/C, E/C, and eGFR to several independent variables. Simple linear regressions of eGFR, E/C, and E/C on E/C were examined before and after adjustment of dependent variables for age. All regressions were performed after log-transformation of ratios and standardization of all variables. Increments in E/C and E/C and decrements in eGFR were quantified through four quartiles of E/C.
RESULTS
As age or E/C rose, E/C and E/C also rose, and eGFR fell. In linear regressions, slopes relating E/C and E/C to E/C were similar. After adjustment of dependent variables for age, coefficients of determination (R) for all regressions rose by a multiple, and slopes approached unity. E/C and E/C were similarly associated with each other. Mean E/C and E/C rose and mean eGFR fell in stepwise fashion through quartiles of E/C. Whereas E/C did not vary with blood pressure, E/C rose in association with hypertension in two of the four quartiles.
CONCLUSIONS
Our data indicate that Cd in renal tissue affected tubular reabsorption of albumin and βM similarly in a large cohort of exposed subjects. The results suggest that Cd reduced receptor-mediated endocytosis and subsequent lysosomal degradation of each protein by a shared mechanism.
PubMed: 38116328
DOI: 10.1016/j.crtox.2023.100140 -
Stroke Apr 2023Recent evidence suggests that higher CRP (C-reactive protein) levels are associated with lower risk of Alzheimer disease, speculating that CRP might be involved in Aβ...
BACKGROUND
Recent evidence suggests that higher CRP (C-reactive protein) levels are associated with lower risk of Alzheimer disease, speculating that CRP might be involved in Aβ clearance mechanisms. Testing this hypothesis, we explored whether genetically proxied CRP levels are also associated with lobar intracerebral hemorrhage (ICH), commonly caused by cerebral amyloid angiopathy.
METHODS
We used 4 genetic variants within the gene that explain up to 64% of the variance of circulating CRP levels and explored in 2-sample Mendelian randomization analyses associations with risk of any, lobar, and deep ICH (1545 cases and 1481 controls).
RESULTS
Higher genetically proxied CRP levels were associated with lower odds of lobar ICH (odds ratio per SD increment in CRP, 0.45 [95% CI, 0.25-0.73]) but not deep ICH (odds ratio, 0.72 [95% CI, 0.45-1.14]). There was evidence of colocalization (posterior probability of association, 72.4%) in the signals for CRP and lobar ICH.
CONCLUSIONS
Our results provide supportive evidence that high CRP levels may have a protective role in amyloid-related pathology.
Topics: Humans; C-Reactive Protein; Cerebral Hemorrhage; Cerebral Amyloid Angiopathy; Magnetic Resonance Imaging
PubMed: 36891905
DOI: 10.1161/STROKEAHA.122.041889 -
International Journal of Molecular... Jan 2024Hepatitis C virus (HCV) infection alters lysophosphatidylcholine (LPC) metabolism, enhancing viral infectivity and replication. Direct-acting antivirals (DAAs)...
Hepatitis C virus (HCV) infection alters lysophosphatidylcholine (LPC) metabolism, enhancing viral infectivity and replication. Direct-acting antivirals (DAAs) effectively treat HCV and rapidly normalize serum cholesterol. In serum, LPC species are primarily albumin-bound but are also present in lipoprotein particles. This study aims to assess the impact of HCV eradication on serum LPC species levels in patients infected with HCV. Therefore, 12 different LPC species were measured by electrospray ionization tandem mass spectrometry (ESI-MS/MS) in the sera of 178 patients with chronic HCV infections at baseline, and in 176 of these patients after therapy with DAAs. All LPC species increased at 4 and 12 weeks post-initiation of DAA therapy. The serum profiles of the LPC species were similar before and after the viral cure. Patients with HCV and liver cirrhosis exhibited lower serum levels of all LPC species, except LPC 16:1, both before and after DAA treatment. Percentages of LPC 18:1 (relative to the total LPC level) were higher, and % LPC 22:5 and 22:6 were lower in cirrhotic compared to non-cirrhotic patients at baseline and at the end of therapy. LPC species levels inversely correlated with the model of end-stage liver disease score and directly with baseline and post-therapy albumin levels. Receiver operating characteristic curve analysis indicated an area under the curve of 0.773 and 0.720 for % LPC 18:1 (relative to total LPC levels) for classifying fibrosis at baseline and post-therapy, respectively. In summary, HCV elimination was found to increase all LPC species and elevated LPC 18:1 relative to total LPC levels may have pathological significance in HCV-related liver cirrhosis.
Topics: Humans; Hepacivirus; Antiviral Agents; Lysophosphatidylcholines; Tandem Mass Spectrometry; Hepatitis C, Chronic; Hepatitis C; Albumins; Liver Cirrhosis
PubMed: 38256273
DOI: 10.3390/ijms25021198 -
Antimicrobial Agents and Chemotherapy May 2022The effect of heart transplantation (HTx) on the pharmacokinetics (PK) of caspofungin is not well-characterized. The aim of this study was to investigate the population...
The effect of heart transplantation (HTx) on the pharmacokinetics (PK) of caspofungin is not well-characterized. The aim of this study was to investigate the population PK of caspofungin in HTx and non-HTx patients and to identify covariates that may affect the PK of caspofungin. Seven successive blood samples were collected before administration and at 1, 2, 6, 10, 16, and 24 h after the administration of caspofungin for at least 3 days. This study recruited 27 HTx recipients and 31 non-HTx patients with 414 plasma concentrations in total. A nonlinear mixed-effects model was used to describe the population PK of caspofungin. The PK of caspofungin was best described by a two-compartment model. The clearance (CL) and volume of the central compartment () of caspofungin were 0.385 liter/h and 4.27 liters, respectively. The intercompartmental clearance () and the volume of the peripheral compartment () were 2.85 liters/h and 6.01 liters, respectively. In the final model, we found that albumin (ALB) affected the CL of caspofungin with an adjustment factor of -1.01, and no other covariates were identified. In this study, HTx was not found to affect the PK of caspofungin. Based on the simulations, the dose of caspofungin should be proportionately increased in patients with decreased ALB levels.
Topics: Caspofungin; Heart Transplantation; Humans
PubMed: 35389237
DOI: 10.1128/aac.02249-21 -
JHEP Reports : Innovation in Hepatology Aug 2020Liver resection is one of the main curative options for early hepatocellular carcinoma (HCC) in patients with cirrhosis and is the treatment of choice in non-cirrhotic... (Review)
Review
Liver resection is one of the main curative options for early hepatocellular carcinoma (HCC) in patients with cirrhosis and is the treatment of choice in non-cirrhotic patients. However, careful patient selection is required to balance the risk of postoperative liver failure and the potential benefit on long-term outcomes. In the last decades, improved surgical techniques and perioperative management, as well as better patient selection, have enabled the indications for liver resection to be expanded. In this review, we aim to describe the main indications for liver resection in the management of HCC, its role compared to percutaneous ablation and liver transplantation in the therapeutic algorithm, as well as the recent advances in liver surgery that could be used to improve the prognosis of patients with HCC.
PubMed: 32695968
DOI: 10.1016/j.jhepr.2020.100134 -
Frontiers in Oncology 2022Over the last 20 years, granulocyte colony-stimulating factors (G-CSFs) have become the major therapeutic option for the treatment of patients with neutropenia. Most of... (Review)
Review
Over the last 20 years, granulocyte colony-stimulating factors (G-CSFs) have become the major therapeutic option for the treatment of patients with neutropenia. Most of the current G-CSFs require daily injections, which are inconvenient and expensive for patients. Increased understanding of G-CSFs' structure, expression, and mechanism of clearance has been very instrumental in the development of new generations of long-acting G-CSFs with improved efficacy. Several approaches to reducing G-CSF clearance conjugation techniques have been investigated. PEGylation, glycosylation, polysialylation, or conjugation with immunoglobulins or albumins have successfully increased G-CSFs' half-lives. Pegfilgrastim (Neulasta) has been successfully approved and marketed for the treatment of patients with neutropenia. The rapidly expanding market for G-CSFs has increased demand for G-CSF biosimilars. Therefore, the importance of this review is to highlight the principle, elimination's route, half-life, clearance, safety, benefits, and limitations of different strategies and techniques used to increase the half-life of biotherapeutic G-CSFs. Understanding these strategies will allow for a new treatment with more competitive manufacturing and lower unit costs compared with that of Neulasta.
PubMed: 36686781
DOI: 10.3389/fonc.2022.1026377 -
Pharmaceuticals (Basel, Switzerland) Jan 2023Zaltoprofen is a drug used for various pain and inflammatory diseases. Scientific and quantitative dosage regimen studies regarding its clinical application are scarce....
Zaltoprofen is a drug used for various pain and inflammatory diseases. Scientific and quantitative dosage regimen studies regarding its clinical application are scarce. This study aimed to discover effective covariates related to interindividual pharmacokinetic variability through population pharmacokinetic modeling for zaltoprofen and to explore dosage regimens. The bioequivalence results of healthy Korean males, biochemical analysis, and CYP2C9 genotyping information were utilized in modeling. The established model has been sufficiently verified through a bootstrap, goodness-of-fit, visual predictive check, and normalized prediction distribution error. External data sets derived from the literature were used for further model validation. The final model could be used to verify the dosage regimen through multiple exposure simulations according to the numerical change of the selected covariates. Zaltoprofen pharmacokinetics could be explained by a two-compartment with a first-order absorption model. Creatinine clearance (CrCL) and albumin were identified as effective covariates related to interindividual zaltoprofen pharmacokinetic variability, and they had positive and negative correlations with clearance (CL/F), respectively. The differences in pharmacokinetics between individuals according to CYP2C9 genetic polymorphisms (*1/*1 and *1/*3) were not significant or valid covariates. The model simulation confirmed that zaltoprofen pharmacokinetics could significantly differ as the CrCL and albumin levels changed within the normal range. Steady-state plasma exposure to zaltoprofen was significantly reduced in the group with CrCL and albumin levels of 130 mL/min and 3.5 g/dL, respectively, suggesting that dose adjustment may be necessary. This study is useful to guide precision medicine of zaltoprofen and provides scientific quantitative judgment data for its clinical applications.
PubMed: 37259312
DOI: 10.3390/ph16020161 -
Clinical Kidney Journal Apr 2022Dialyzers should be designed to efficiently eliminate uraemic toxins during dialysis treatment, given that the accumulation of small and middle molecular weight uraemic...
BACKGROUND
Dialyzers should be designed to efficiently eliminate uraemic toxins during dialysis treatment, given that the accumulation of small and middle molecular weight uraemic solutes is associated with increased mortality risk of patients with end-stage renal disease. In the present study we investigated the novel FX CorAL dialyzer with a modified membrane surface for performance during online hemodiafiltration (HDF) in a clinical setting.
METHODS
comPERFORM was a prospective, open, controlled, multicentric, interventional, crossover study with randomized treatment sequences. It randomized stable patients receiving regular post-dilution online HDF to FX CorAL 600 (Fresenius Medical Care Deutschland), xevonta Hi 15 (B. Braun) and ELISIO 150H (Nipro) each for 1 week. The primary outcome was β2-m removal rate (β2-m RR) during online HDF. Secondary endpoints were RR and/or clearance of β2-m and other molecules. Albumin removal over time was an exploratory endpoint. Non-inferiority and superiority of FX CorAL 600 versus comparators were tested.
RESULTS
Fifty-two patients were included and analysed. FX CorAL 600 showed the highest β2-m RR (75.47%), followed by xevonta Hi 15 (74.01%) and ELISIO 150H (72.70%). Superiority to its comparators was statistically significant (P = 0.0216 and P < 0.0001, respectively). Secondary endpoints related to middle molecules affirmed these results. FX CorAL 600 demonstrated the lowest albumin removal up to 60 minutes and its sieving properties changed less over time than with comparators.
CONCLUSIONS
FX CorAL 600 efficiently removed middle and small molecules and was superior to the two comparators in β2-m RR. Albumin sieving kinetics point to reduced formation of a secondary membrane.
PubMed: 35464193
DOI: 10.1093/ckj/sfab196 -
American Journal of Cancer Research 2021Paclitaxel is a widely used anti-tumor chemotherapeutic drug. Solvent-based paclitaxel causes bone marrow suppression, allergic reactions, neurotoxicity and systemic... (Review)
Review
Paclitaxel is a widely used anti-tumor chemotherapeutic drug. Solvent-based paclitaxel causes bone marrow suppression, allergic reactions, neurotoxicity and systemic toxicity, which are associated with non-specific cytotoxicity and side effects of fat-soluble solvents. Studies have explored various new nano-drug strategies of paclitaxel, including nanoparticle albumin-bound paclitaxel (nab-paclitaxel) to improve the water solubility and safety of paclitaxel. Nab-paclitaxel is a targeted solvent-free formulation that inhibits microtubule depolymerization to anticancer. It is easily taken up by tumor and immune cells owing to the nano-scaled size and superior biocompatibility. The internalized nab-paclitaxel exhibits significant immunostimulatory activities to promote cancer-immunity cycle. The aim of this study was to explore the synergistic effect of nab-paclitaxel in tumor antigen presentation, T cell activation, reversing the immunosuppressive pattern of tumor microenvironment (TME), and the synergistic effect with cytotoxic lymphocytes (CTLs) in clearance of tumor cells. The effects of nab-paclitaxel on modulation of cancer-immunity cycle, provides potential avenues for combined therapeutic rationale to improve efficacy of immunotherapy.
PubMed: 34354854
DOI: No ID Found -
Indian Journal of Nephrology 2021In advanced Chronic Kidney Disease, patients require renal replacement therapy (dialysis or transplantation) for clearance of toxins, electrolyte and acid-base balance... (Review)
Review
In advanced Chronic Kidney Disease, patients require renal replacement therapy (dialysis or transplantation) for clearance of toxins, electrolyte and acid-base balance and removal of excess fluid. Dialysis adequacy should be taken into consideration in the adjustment of the dialysis prescription. Kt/V is one method of measuring dialysis adequacy that is commonly used in clinical practice. Different formulae for calculating Kt/V are available. The appropriate Kt/V formula to be used depends on the clinical scenario, as well as parameters such as gender and size of patient, frequency of dialysis, mode of dialysis (ie hemodialysis vs, peritoneal dialysis), inter-dialysis weight gain, clinical symptoms, complications (fluid overload, hyperkalemia, intolerance to dialysis, etc), and residual kidney function. Nutrition parameters including serum protein and albumin levels, vitamin B12 and β2-microglobulin levels should be factored into the assessment of dialysis adequacy. In this review, we have described how Kt/V is calculated in hemodialysis and peritoneal dialysis with examples. We reviewed the available literature by searching for papers related to calculating Kt/V single pool Kt/V, double pool Kt/V, weekly Kt/V, standard Kt/V, surface area normalized Kt/V, and various equations commonly practiced in clinical practice. We found several original articles, some review articles along with detailed information from manufacturers of different dialyzers published on their websites or as package inserts. Understanding the different equations available for calculating Kt/V and the application of these results in the clinical setting is important for refining patient care and for designing clinical studies.
PubMed: 34267430
DOI: 10.4103/ijn.IJN_245_19