Intracellular iron uptake is favored in Hfe-KO mouse primary chondrocytes mimicking an osteoarthritis-related phenotype

HFE-hemochromatosis is a disease characterized by a systemic iron overload phenotype mainly associated with mutations in the HFE protein (HFE) gene. Osteoarthritis (OA) has been reported as one of the most prevalent complications in HFE-hemochromatosis patients, but the mechanisms associated with its onset and progression remain incompletely understood. In this study, we have characterized the response to high iron concentrations of a primary culture of articular chondrocytes isolated from newborn Hfe-KO mice and compared the results with that of a similar experiment developed in cells from C57BL/6 wild-type (wt) mice. Our data provide evidence that both wt- and Hfe-KO-derived chondrocytes, when exposed to 50 mu M iron, develop characteristics of an OA-related phenotype, such as an increased expression of metalloproteases, a decreased extracellular matrix production, and a lower expression level of aggrecan. In addition, Hfe-KO cells also showed an increased expression of iron metabolism markers and MMP3, indicating an increased susceptibility to intracellular iron accumulation and higher levels of chondrocyte catabolism. Accordingly, upon treatment with 50 mu M iron, these chondrocytes were found to preferentially differentiate toward hypertrophy with increased expression of collagen I and transferrin and downregulation of SRY (sex-determining region Y)-box containing gene 9 (Sox9). In conclusion, high iron exposure can compromise chondrocyte metabolism, which, when simultaneously affected by an Hfe loss of function, appears to be more susceptible to the establishment of an OA-related phenotype.European Regional Development FundEuropean Union (EU) [EMBRC.PT Alg-01-0145-FEDER-022121, Norte-01-0145-FEDER-000012]Fundacao para a Ciencia e a TecnologiaPortuguese Foundation for Science and Technology [SFRH/BD/77056/2011]Portuguese Foundation for Science and TechnologyPortuguese Foundation for Science and TechnologyPortuguese Science and Technology FoundationPortuguese Foundation for Science and Technologyinfo:eu-repo/semantics/publishedVersio

Pharmacokinetic and pharmacodynamic analysis comparing diverse effects of detomidine, medetomidine, and dexmedetomidine in the horse: a population analysis.

The present study characterizes the pharmacokinetic (PK) and pharmacodynamic (PD) relationships of the α2-adrenergic receptor agonists detomidine (DET), medetomidine (MED) and dexmedetomidine (DEX) in parallel groups of horses from in vivo data after single bolus doses. Head height (HH), heart rate (HR), and blood glucose concentrations were measured over 6 h. Compartmental PK and minimal physiologically based PK (mPBPK) models were applied and incorporated into basic and extended indirect response models (IRM). Population PK/PD analysis was conducted using the Monolix software implementing the stochastic approximation expectation maximization algorithm. Marked reductions in HH and HR were found. The drug concentrations required to obtain inhibition at half-maximal effect (IC50 ) were approximately four times larger for DET than MED and DEX for both HH and HR. These effects were not gender dependent. Medetomidine had a greater influence on the increase in glucose concentration than DEX. The developed models demonstrate the use of mechanistic and mPBPK/PD models for the analysis of clinically obtainable in vivo data

Peri-operative Medication Dosing in Adult Obese Elective Surgical Patients: A Systematic Review of Clinical Studies

Background: Despite the increasing numbers of obese patients undergoing elective surgery, there is a lack of evidence-based dosing guidelines for peri-operative medications in obesity. Objective: The objective was to systematically review the dosing and outcomes of peri-operative medications used in obese elective surgical patients. Methods: Medical subject headings and general keywords were used to systematically search multiple databases (PubMed, EMBASE, Cochrane Library and CINAHL). Studies of medications in obese surgical patients were included if they had a non-obese control or comparative dosing scalar group. The National Health and Medical Research Council GRADE tool was used to assess quality of evidence for each drug. Results: Thirty-three studies of six drug classes were identified: anaesthetics (n = 6), muscle relaxants (n = 10), neuromuscular reversal agents (n = 3), analgesics (n = 2), antibiotics (n = 5) and anticoagulants (n = 7). A variety of dose scalars and/or recommendations was observed for various medications. Lean body weight was proposed as a suitable weight scalar for induction of anaesthesia with propofol whereas total body weight for maintenance of anaesthesia with propofol and depolarizing muscle relaxants. Ideal body weight was reported as an appropriate dosing scalar for non-depolarizing muscle relaxants and neuromuscular reversal agents. Both corrected body weight 40% and ideal body weight were reported as suitable weight scalars for post-operative analgesia with morphine. The standard 2-g dose of cefazolin appeared effective in the prevention of surgical site infection. Body mass index stratified dosing of enoxaparin was effective for venous thromboembolism prevention. Conclusion: No drug recommendation achieved an “Excellent” quality of evidence. Limited data suggest that clinicians should consider each individual class of medication when selecting a dose for obese surgical patients. Routine use of fixed-dosing regimens is likely to under- or overdose obese patients thus predisposing them to adverse drug events or treatment failure leading to patient harm