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Antioxidant preconditioning attenuates liver ischemia/reperfusion injury after hepatectomy in swine.Journal of B.U.ON. : Official Journal... 2021The purpose of this study was to evaluate whether antioxidant preconditioning with Deferoxamine can attenuate liver ischemia reperfusion injury associated with extended...
PURPOSE
The purpose of this study was to evaluate whether antioxidant preconditioning with Deferoxamine can attenuate liver ischemia reperfusion injury associated with extended hepatectomy in swine.
METHODS
Eighteen swine were randomly assigned to two groups: Deferoxamine (DFO) and Surgery Only (SO). The animals in both groups were subjected to laparotomy, prolonged temporary occlusion of the right and middle hepatic pedicles and subsequent left hepatectomy. The DFO group received IV deferoxamine prior to induction of liver ischemia. Monitoring was performed for 6 h and samples (Protein carbonyls, Thiobarbituric acid reactive substances, Histology, ALT, AST, Lactic acid and WBC) were drawn at 0, 60 and 360 min.
RESULTS
Protein carbonyls and Thiobarbituric acid reactive substances had significantly lower concentration and higher reduction rates in serum and liver tissue of the DFO group. The histological examination of liver tissue showed less inflammation and necrosis in the DFO group. Hepatic enzymes and lactic acid measurements showed higher reduction rate in the DFO group by the end of the experiment.
CONCLUSIONS
This experimental study documents an early protective effect of deferoxamine administration in major hepatectomies against liver ischemia/reperfusion injury.
Topics: Animals; Antioxidants; Deferoxamine; Hepatectomy; Male; Postoperative Complications; Premedication; Random Allocation; Reperfusion Injury; Swine
PubMed: 34268984
DOI: No ID Found -
Revista Brasileira de Terapia Intensiva Mar 2020To examine the effectiveness of stratification to identify and target antioxidant therapy for animal models of lethal sepsis and in patients who develop sustained...
OBJECTIVE
To examine the effectiveness of stratification to identify and target antioxidant therapy for animal models of lethal sepsis and in patients who develop sustained hypotension.
METHODS
Rats were subjected to sepsis induced by cecal ligation and puncture. Animals were divided into two groups: those with high and low plasma levels of interleukin-6. Following stratification, N-acetylcysteine plus deferoxamine or saline was administered to animals starting 3 and 12 hours after surgery. N-Acetylcysteine plus deferoxamine or placebo was administered within 12 hours of meeting the inclusion criteria in hypotensive patients.
RESULTS
N-Acetylcysteine plus deferoxamine increased survival in the cecal ligation and puncture model when administered 3 and 12 hours after sepsis induction. When dividing animals that received antioxidants using plasma interleukin-6 levels, the protective effect was observed only in those animals with high IL-6 levels. The antioxidant effect of N-acetylcysteine + deferoxamine was similar in the two groups, but a significant decrease in plasma interleukin-6 levels was observed in the high-interleukin-6-level group. Compared with patients treated with antioxidants in the low-interleukin-6 subgroup, those in the high-interleukin-6 subgroup had a lower incidence of acute kidney injury but were not different in terms of acute kidney injury severity or intensive care unit mortality.
CONCLUSION
Targeting antioxidant therapy to a high inflammatory phenotype would select a responsive population.
Topics: Acetylcysteine; Adult; Aged; Animals; Antioxidants; Deferoxamine; Humans; Male; Middle Aged; Prognosis; Rats; Rats, Wistar; Retrospective Studies; Sepsis; Treatment Outcome
PubMed: 32401970
DOI: 10.5935/0103-507x.20200016 -
The Cochrane Database of Systematic... Mar 2023Regularly transfused people with sickle cell disease (SCD) and people with thalassaemia are at risk of iron overload. Iron overload can lead to iron toxicity in... (Review)
Review
BACKGROUND
Regularly transfused people with sickle cell disease (SCD) and people with thalassaemia are at risk of iron overload. Iron overload can lead to iron toxicity in vulnerable organs such as the heart, liver and endocrine glands, which can be prevented and treated with iron-chelating agents. The intensive demands and uncomfortable side effects of therapy can have a negative impact on daily activities and wellbeing, which may affect adherence.
OBJECTIVES
To identify and assess the effectiveness of different types of interventions (psychological and psychosocial, educational, medication interventions, or multi-component interventions) and interventions specific to different age groups, to improve adherence to iron chelation therapy compared to another listed intervention, or standard care in people with SCD or thalassaemia.
SEARCH METHODS
We searched CENTRAL (Cochrane Library), MEDLINE, PubMed, Embase, CINAHL, PsycINFO, ProQuest Dissertations & Global Theses, Web of Science & Social Sciences Conference Proceedings Indexes and ongoing trial databases (13 December 2021). We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register (1 August 2022).
SELECTION CRITERIA
For trials comparing medications or medication changes, only randomised controlled trials (RCTs) were eligible for inclusion. For studies including psychological and psychosocial interventions, educational interventions, or multi-component interventions, non-randomised studies of interventions (NRSIs), controlled before-after studies, and interrupted time series studies with adherence as a primary outcome were also eligible for inclusion.
DATA COLLECTION AND ANALYSIS
For this update, two authors independently assessed trial eligibility and risk of bias, and extracted data. We assessed the certainty of the evidence using GRADE.
MAIN RESULTS
We included 19 RCTs and one NRSI published between 1997 and 2021. One trial assessed medication management, one assessed an education intervention (NRSI) and 18 RCTs were of medication interventions. Medications assessed were subcutaneous deferoxamine, and two oral chelating agents, deferiprone and deferasirox. We rated the certainty of evidence as very low to low across all outcomes identified in this review. Four trials measured quality of life (QoL) with validated instruments, but provided no analysable data and reported no difference in QoL. We identified nine comparisons of interest. 1. Deferiprone versus deferoxamine We are uncertain whether or not deferiprone affects adherence to iron chelation therapy (four RCTs, unpooled, very low-certainty evidence), all-cause mortality (risk ratio (RR) 0.47, 95% confidence interval (CI) 0.18 to 1.21; 3 RCTs, 376 participants; very low-certainty evidence), or serious adverse events (SAEs) (RR 1.43, 95% CI 0.83 to 2.46; 1 RCT, 228 participants; very low-certainty evidence). Adherence was reported as "good", "high" or "excellent" by all seven trials, though the data could not be analysed formally: adherence ranged from 69% to 95% (deferiprone, mean 86.6%), and 71% to 93% (deferoxamine, mean 78.8%), based on five trials (474 participants) only. 2. Deferasirox versus deferoxamine We are uncertain whether or not deferasirox affects adherence to iron chelation therapy (three RCTs, unpooled, very low-certainty evidence), although medication adherence was high in all trials. We are uncertain whether or not there is any difference between the drug therapies in serious adverse events (SAEs) (SCD or thalassaemia) or all-cause mortality (thalassaemia). 3. Deferiprone versus deferasirox We are uncertain if there is a difference between oral deferiprone and deferasirox based on a single trial in children (average age 9 to 10 years) with any hereditary haemoglobinopathy in adherence, SAEs and all-cause mortality. 4. Deferasirox film-coated tablet (FCT) versus deferasirox dispersible tablet (DT) One RCT compared deferasirox in different tablet forms. There may be a preference for FCTs, shown through a trend for greater adherence (RR 1.10, 95% CI 0.99 to 1.22; 1 RCT, 88 participants), although medication adherence was high in both groups (FCT 92.9%; DT 85.3%). We are uncertain if there is a benefit in chelation-related AEs with FCTs. We are uncertain if there is a difference in the incidence of SAEs, all-cause mortality or sustained adherence. 5. Deferiprone and deferoxamine combined versus deferiprone alone We are uncertain if there is a difference in adherence, though reporting was usually narrative as triallists report it was "excellent" in both groups (three RCTs, unpooled). We are uncertain if there is a difference in the incidence of SAEs and all-cause mortality. 6. Deferiprone and deferoxamine combined versus deferoxamine alone We are uncertain if there is a difference in adherence (four RCTs), SAEs (none reported in the trial period) and all-cause mortality (no deaths reported in the trial period). There was high adherence in all trials. 7. Deferiprone and deferoxamine combined versus deferiprone and deferasirox combined There may be a difference in favour of deferiprone and deferasirox (combined) in rates of adherence (RR 0.84, 95% CI 0.72 to 0.99) (one RCT), although it was high (> 80%) in both groups. We are uncertain if there is a difference in SAEs, and no deaths were reported in the trial, so we cannot draw conclusions based on these data (one RCT). 8. Medication management versus standard care We are uncertain if there is a difference in QoL (one RCT), and we could not assess adherence due to a lack of reporting in the control group. 9. Education versus standard care One quasi-experimental (NRSI) study could not be analysed due to the severe baseline confounding.
AUTHORS' CONCLUSIONS
The medication comparisons included in this review had higher than average adherence rates not accounted for by differences in medication administration or side effects, though often follow-up was not good (high dropout over longer trials), with adherence based on a per protocol analysis. Participants may have been selected based on higher adherence to trial medications at baseline. Also, within the clinical trial context, there is increased attention and involvement of clinicians, thus high adherence rates may be an artefact of trial participation. Real-world, pragmatic trials in community and clinic settings are needed that examine both confirmed or unconfirmed adherence strategies that may increase adherence to iron chelation therapy. Due to lack of evidence this review cannot comment on intervention strategies for different age groups.
Topics: Child; Humans; Anemia, Sickle Cell; Chelating Agents; Chelation Therapy; Deferoxamine; Drug-Related Side Effects and Adverse Reactions; Iron; Thalassemia
PubMed: 36877640
DOI: 10.1002/14651858.CD012349.pub3 -
Drug and Chemical Toxicology Jan 2022We aimed to investigate the role of urinary kidney injury molecule-1 (KIM-1) in detection of subclinical nephrotoxicity in patients with Beta-thalassemia (β-TM) in...
We aimed to investigate the role of urinary kidney injury molecule-1 (KIM-1) in detection of subclinical nephrotoxicity in patients with Beta-thalassemia (β-TM) in relation to chelation therapy and to correlate the urinary KIM-1 level with other clinical and laboratory findings. We conducted a cross-sectional study on 66 thalassemic patients. Their ages range from 7 to 22 years. Routine kidney indices and novel urinary KIM/creatinine ratio (U) were measured. Estimated glomerular filtration rate (eGFR) was calculated. Results indicate that the level of serum creatinine was significantly higher in patients on deferasirox therapy than patients on deferoxamine and deferiprone therapy [median(IQR), 0.85(0.63-0.99), 0.50(0.34-0.58) and 0.44(0.36-0.45)] mg/dL, respectively, < 0.001]. The median(IQR) level of eGFR was significantly lower in patients on deferasirox therapy than patients on deferoxamine and deferiprone therapy [63.3(56.5-92.1), 117.3(91.9-162) and 136.7(109.4-157.6)] ml/min/1.73 m, respectively, < 0.001]. The mean level of U was significantly higher in patients on deferasirox therapy than patients on deferoxamine and deferiprone therapy (7.0 ± 1.9, 4.1 ± 1.7 and 4.2 ± 1.5) ng/mg creatinine, respectively, < 0.001). We concluded that urinary KIM-1 is an early predictive biomarker for decline in eGFR in patients with β-TM on deferasirox therapy. The appropriate chelation therapy and good monitoring of those patients are intensely needed for early detection of renal dysfunction and timely intervention.
Topics: Adolescent; Adult; Child; Cross-Sectional Studies; Deferasirox; Deferoxamine; Humans; Iron Chelating Agents; Iron Overload; Kidney; Young Adult; beta-Thalassemia
PubMed: 31905029
DOI: 10.1080/01480545.2019.1660362 -
Bioconjugate Chemistry Sep 2022The synthesis of radioimmunoconjugates via the stochastic attachment of bifunctional chelators to lysines can yield heterogeneous products with suboptimal and...
The synthesis of radioimmunoconjugates via the stochastic attachment of bifunctional chelators to lysines can yield heterogeneous products with suboptimal and behavior. In response to this, several site-selective approaches to bioconjugation have been developed, yet each has intrinsic drawbacks, such as the need for expensive reagents or the complexity of incorporating unnatural amino acids into IgGs. Herein, we describe the use of a simple and facile approach to lysine-directed site-selective bioconjugation for the generation of radioimmunoconjugates. This strategy relies upon on the selective modification of single lysine residues within each light chain of the monoclonal antibody (mAb) with a branched azide-bearing perfluorophenyl ester (PFP-bisN) followed by the ligation of dibenzocyclooctyne (DBCO)-bearing payloads to these bioorthogonal handles via the strain-promoted azide-alkyne cycloaddition. This methodology was used to create [Zr]Zr-DFO-pertuzumab, a radioimmunoconjugate of the HER2-targeting mAb pertuzumab labeled with desferrioxamine (DFO) and the positron-emitting radiometal zirconium-89 (Zr). [Zr]Zr-DFO-pertuzumab was compared to a pair of analogous probes: one synthesized via random lysine modification ([Zr]Zr-DFO-pertuzumab) and another via thiol-maleimide chemistry ([Zr]Zr-DFO-pertuzumab). The bioconjugation strategy was assessed using ESI mass spectrometry, SDS-PAGE, and autoradiography. All three immunoconjugates demonstrated comparable binding to HER2 via flow cytometry and surface plasmon resonance (SPR), and Zr-labeled variants of each were synthesized in >99% radiochemical yield and molar activities of up to ∼55.5 GBq/μmol (10 mCi/mg). Subsequently, the behavior of this trio of Zr-immunoPET probes was interrogated in athymic nude mice bearing subcutaneous HER2-expressing BT-474 human breast cancer xenografts. [Zr]Zr-DFO-pertuzumab, [Zr]Zr-DFO-pertuzumab, and [Zr]Zr-DFO-pertuzumab produced positron emission tomography (PET) images with high tumoral uptake and high tumor-to-healthy organ activity concentration ratios. A terminal biodistribution study complemented the PET results, revealing tumoral activity concentrations of 126.9 ± 50.3%ID/g, 86.9 ± 53.2%ID/g, and 92.5 ± 27.2%ID/g at 144 h post-injection for [Zr]Zr-DFO-pertuzumab, [Zr]Zr-DFO-pertuzumab, and [Zr]Zr-DFO-pertuzumab, respectively. Taken together, the data clearly illustrate that this highly modular and facile approach to site-selective bioconjugation produces radioimmunoconjugates that are better-defined and more homogeneous than stochastically modified constructs and also exhibit excellent and performance. Furthermore, we contend that this lysine-directed strategy holds several key advantages over extant approaches to site-selective bioconjugation, especially in the context of production for the clinic.
Topics: Alkynes; Animals; Antibodies, Monoclonal; Azides; Breast Neoplasms; Cell Line, Tumor; Chelating Agents; Deferoxamine; Esters; Female; Humans; Immunoconjugates; Lysine; Maleimides; Mice; Mice, Nude; Positron-Emission Tomography; Sulfhydryl Compounds; Tissue Distribution; Zirconium
PubMed: 35946495
DOI: 10.1021/acs.bioconjchem.2c00354 -
Frontiers in Bioscience (Landmark... Jan 2018Iron overload toxicity is the main cause of mortality and morbidity in thalassaemia patients. The complete elimination and prevention of iron overload is the main aim of...
Iron overload toxicity is the main cause of mortality and morbidity in thalassaemia patients. The complete elimination and prevention of iron overload is the main aim of chelation therapy, which can be achieved by chelation protocols that can effectively remove excess iron load and maintain body iron at normal levels. Deferiprone and selected combinations with deferoxamine can be designed, adjusted and used effectively for removing all excess stored iron and for maintaining normal iron stores (NIS) in different categories of thalassaemia patients. High doses of deferiprone (75-100 mg/kg/day) and deferoxamine (50-60 mg/kg, 1-7 days/week) combinations can be used for achieving and maintaining NIS in heavily iron loaded transfused patients. In contrast, deferiprone (75-100 mg/kg/day) can be used effectively and sometimes intermittently for maintaining NIS in non heavily transfused patients. Deferasirox can in particular be used in patients not tolerating deferoxamine and deferiprone. The design of tailored made personalised protocols using deferiprone and selected combinations with deferoxamine should be considered as optimum chelation therapies for the complete treatment and the prevention of iron overload in thalassaemia.
Topics: Benzoates; Chelation Therapy; Deferasirox; Deferiprone; Deferoxamine; Drug Therapy, Combination; Humans; Iron Chelating Agents; Iron Overload; Pyridones; Thalassemia; Triazoles
PubMed: 28930590
DOI: 10.2741/4634 -
Stroke May 2017CD163, a receptor for hemoglobin, is involved in hemoglobin clearance after intracerebral hemorrhage (ICH). In contrast to microglial/macrophage CD163, neuronal CD163...
BACKGROUND AND PURPOSE
CD163, a receptor for hemoglobin, is involved in hemoglobin clearance after intracerebral hemorrhage (ICH). In contrast to microglial/macrophage CD163, neuronal CD163 hemoglobin has not been well studied. This study examined the expression of neuronal CD163 in a pig model of ICH and in vitro rat cortical neurons and the impact of deferoxamine on that expression.
METHODS
There were 2 parts to this study. In the in vivo part, piglets had injection of autologous blood into the right frontal lobe. The time course of CD163 expression and the effect of deferoxamine on the expression of CD163 after ICH were determined in the grey matter. In the in vitro part, the levels of CD163 and neuronal death and the effect of deferoxamine were examined in rat cortical neurons culture treated with hemoglobin.
RESULTS
CD163-positive cells were found, and the CD163 protein levels were upregulated in the ipsilateral grey matter after ICH. The CD163 levels peaked at days 1 and 3. The CD163-positive cells were colocated with NeuN-positive, heme oxygenase-2-positive, and terminal deoxynucleatidyl transferase dUTP nick end labeling-positive cells. Deferoxamine treatment attenuated ICH-induced CD163 upregulation and significantly reduced both brain CD163 and hemoglobin levels at day 3. Treating neuronal cultures with hemoglobin for 24 hours resulted in CD163 upregulation and increased cell death. Deferoxamine significantly attenuated the hemoglobin-induced neuronal death and CD163 upregulation.
CONCLUSIONS
CD163 is expressed in neurons and upregulated after ICH. Deferoxamine reduced ICH-induced CD163 upregulation and brain cell death in vivo and hemoglobin-induced CD163 upregulation and neuronal death in vitro.
Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Brain; Cell Death; Cerebral Hemorrhage; Deferoxamine; Disease Models, Animal; Hemoglobins; Neurons; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Siderophores; Swine; Up-Regulation
PubMed: 28360115
DOI: 10.1161/STROKEAHA.117.016850 -
Antimicrobial Agents and Chemotherapy Nov 2022The opportunistic fungal infections are an increasing threat to humans due to the increasing number of patients with immunodeficiency, in which the most popular fungal...
The opportunistic fungal infections are an increasing threat to humans due to the increasing number of patients with immunodeficiency, in which the most popular fungal pathogen is Candida albicans. Fluconazole (FLC) is the common drug for treating C. albicans infections, but increasing drug resistance has limited its clinical use. Currently, combination therapy is being investigated as a treatment to overcome the resistance of C. albicans. This report investigated the synergistic properties of deferoxamine (DFO) and FLC combination therapy and against drug-resistant C. albicans. The results showed that the combination of DFO and FLC had a great synergistic antifungal effect against C. albicans, an FLC-resistant strain, with a fractional inhibition concentration index (FICI) of 0.25 by the broth microdilution checkerboard assay. Furthermore, the combination of DFO and FLC significantly inhibited the activity of C. glabrata cells (approximately 30% of C. glabrata cells are azole-resistant). The time-growth curves confirmed that the combination of DFO and FLC have a potent synergistic antifungal effect. Hyphal formation assays confirmed that DFO inhibited the hyphal induction of C. albicans. In addition, the combination of DFO and FLC significantly inhibited the expression of the adhesion gene (). experiments showed that the combination of DFO and FLC significantly reduced pustules, CFU counts and inflammatory cell infiltration in skin tissue. These results suggest that the combination of DFO and FLC inhibits yeast-hyphae transformation, reduces C. albicans infectivity and resistance and , and affects Cek1 MAPK signaling. This may offer a new option for the treatment of cutaneous candidiasis.
Topics: Humans; Fluconazole; Candida; Antifungal Agents; Deferoxamine; Drug Resistance, Fungal; Drug Synergism; Microbial Sensitivity Tests; Candida albicans; Candida glabrata
PubMed: 36286552
DOI: 10.1128/aac.00725-22 -
Internal Medicine (Tokyo, Japan) 2015
Topics: Aged; Anti-Inflammatory Agents; Deferoxamine; Humans; Male; Octreotide; Prednisolone; Sarcoidosis; Scalp; Tomography, Emission-Computed; Treatment Outcome
PubMed: 26521919
DOI: 10.2169/internalmedicine.54.5110 -
BioMed Research International 2015Deferoxamine mesylate (DFO) is the most commonly used iron-chelating agent to treat transfusion-related hemosiderosis. Despite the clear advantages for the use of DFO,... (Review)
Review
Deferoxamine mesylate (DFO) is the most commonly used iron-chelating agent to treat transfusion-related hemosiderosis. Despite the clear advantages for the use of DFO, numerous DFO-related systemic toxicities have been reported in the literature, as well as sight-threatening ocular toxicity involving the retinal pigment epithelium (RPE). The damage to the RPE can lead to visual field defects, color-vision defects, abnormal electrophysiological tests, and permanent visual deterioration. The purpose of this review is to provide an updated summary of the ocular findings, including both functional and structural abnormalities, in DFO-treated patients. In particular, we pay particular attention to analyzing results of multimodal technologies for retinal imaging, which help ophthalmologists in the early diagnosis and correct management of DFO retinopathy. Fundus autofluorescence, for example, is not only useful for screening patients at high-risk of DFO retinopathy, but is also a prerequisite for identify specific high-risk patterns of RPE changes that are relevant for the prognosis of the disease. In addition, optical coherence tomography may have a clinical usefulness in detecting extent and location of different retinal changes in DFO retinopathy. Finally, this review wants to underline the need for universally approved guidelines for screening and followup of this particular disease.
Topics: Deferoxamine; Hemosiderosis; Humans; Iron Chelating Agents; Retina; Retinal Diseases; Retinal Vessels
PubMed: 26167477
DOI: 10.1155/2015/249617