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Summary: Iron overload from repeated transfusions has a negative impact on cardiac function, and iron chelation therapy may help prevent cardiac dysfunction in transfusion‐dependent patients with myelodysplastic syndromes (MDS). TELESTO (NCT00940602) was a prospective, placebo‐controlled, randomised study to evaluate the iron chelator deferasirox in patients with low‐ or intermediate‐1–risk MDS and iron overload. Echocardiographic parameters were collected at screening and during treatment. Patients receiving deferasirox experienced a significant decrease in the composite risk of hospitalisation for congestive heart failure (CHF) or worsening of cardiac function (HR = 0.23; 95% CI: 0.05, 0.99; nominal p = 0.0322) versus placebo. No significant differences between the arms were found in left ventricular ejection fraction, ventricular diameter and mass or pulmonary artery pressure. The absolute number of events was low, but the enrolled patients were younger than average for patients with MDS, with no serious cardiac comorbidities and a modest cardiovascular risk profile. These results support the effectiveness of deferasirox in preventing cardiac damage caused by iron overload in this patient population. Identification of patients developing CHF is challenging due to the lack of distinctive echocardiographic features. The treatment of iron overload may be important to prevent cardiac dysfunction in these patients, even those with moderate CHF risk. [ABSTRACT FROM AUTHOR]

Hematoma, a risk factor of implant‐associated infections (IAIs), creates a Fe‐rich environment following implantation, which proliferates the growth of pathogenic bacteria. Fe metabolism is a major vulnerability for pathogens and is crucial for several fundamental physiological processes. Herein, a deferiprone (DFP)‐loaded layered double hydroxide (LDH)‐based nanomedicine (DFP@Ga‐LDH) that targets the Fe‐rich environments of IAIs is reported. In response to acidic changes at the infection site, DFP@Ga‐LDH systematically interferes with bacterial Fe metabolism via the substitution of Ga3+ and Fe scavenging by DFP. DFP@Ga‐LDH effectively reverses the Fe/Ga ratio in Pseudomonas aeruginosa, causing comprehensive interference in various Fe‐associated targets, including transcription and substance metabolism. In addition to its favorable antibacterial properties, DFP@Ga‐LDH functions as a nano‐adjuvant capable of delaying the emergence of antibiotic resistance. Accordingly, DFP@Ga‐LDH is loaded with a siderophore antibiotic (cefiderocol, Cefi) to achieve the antibacterial nanodrug DFP@Ga‐LDH‐Cefi. Antimicrobial and biosafety efficacies of DFP@Ga‐LDH‐Cefi are validated using ex vivo human skin and mouse IAI models. The pivotal role of the hematoma‐created Fe‐rich environment of IAIs is highlighted, and a nanoplatform that efficiently interferes with bacterial Fe metabolism is developed. The findings of the study provide promising guidance for future research on the exploration of nano‐adjuvants as antibacterial agents. [ABSTRACT FROM AUTHOR]

Administration of oral medicinal products as crushed tablets or open capsules is an important delivery option for patients suffering from dysphagia. To obtain full interchangeability of generics with the original products, demonstration of bioequivalence (BE) between both products administered as crushed tablets/open capsules was required for poorly soluble product by European Medicines Agency (EMA) at the time of development of our rivaroxaban and deferasirox generic products. We present the results of two BE studies with modified administration of these products, which compared relative bioavailability between generic and reference products. In the rivaroxaban study, the test product was administered as a capsule sprinkled on and mixed with applesauce, whereas the reference tablet was crushed and administered with applesauce under fed conditions. In the deferasirox study, both treatments were administered as crushed tablets under fasting conditions. Both studies applied a two‐way crossover design and were conducted after a single‐dose in healthy volunteers. The 90% confidence interval of the geometric mean ratio area under the analyte concentration versus time curve, from time zero to the time of the last measurable analyte concentration and maximum measured analyte concentration over the sampling period of the test to reference ratio were 103.36–110.37% and 97.98–108.45% for rivaroxaban, respectively, and 96.69–107.29% and 94.19–109.45% for deferasirox, respectively. Thus, the BE criteria (80.00–125.00%) were met in both studies which demonstrated that bioavailability was not affected when the test and reference products were administered in the form of crushed tablet/open capsule. These results support the argument of redundancy of crushed product studies for poorly soluble drugs, which is in line with the currently revised position of the EMA on this topic. [ABSTRACT FROM AUTHOR]

Combination chelation therapies are considered in transfusion‐dependent thalassemia patients for whom monotherapy regimens have failed to achieve iron balance or intensification of iron chelation therapy is required for the rapid reduction of excess iron to avoid permanent organ damage. Combination chelation may provide a more flexible approach for individualizing chelation therapy, thereby improving tolerability, adherence, and quality of life. In principle, iron chelators can be combined with an infinite number of dosing regimens; these involve simultaneous or sequential exposure to the chelators on the same day or alternating the drugs on different days. Clinical studies have established the safety and efficacy of chelation combinations. However, real‐life data with combination therapies indicate the significance of compliance for a meaningful reduction in iron overload compared to monotherapies. [ABSTRACT FROM AUTHOR]

A series of new conjugates comprised from a small synthetic antimicrobial peptide (AMP) and a siderophore‐type vector component was designed and tested for activity on P. aeruginosa PAO1 and several genetically modified strains. As AMP, the well‐established arginine‐tryptophane combination K(RW)3 (P1) was chosen with an added lysine for siderophore attachment. This peptide is easy to prepare, modify, and possesses good anti‐bacterial activity. On the vector part, we examined several moieties: (i) the natural siderophore deferoxamine (DFO); (ii) bidentate iron chelators based on the hydroxamate building block (4 a–c) ; (iii) the non‐siderophore chelators deferasirox (DFX) and deferiprone‐carboxylate (DFP‐COOH). All conjugates were prepared by solid phase synthesis techniques and fully characterized by HPLC and mass spectrometry (including HR‐MS). 55Fe uptake assays indicate a receptor‐mediated uptake for 4 a–c, DFP‐COOH and DFO, which is dependent on the outer membrane transporter FoxA in the case of DFO. All conjugates showed increased antibacterial activity against P. aeruginosa compared to the parent peptide P1 alone when investigated in iron‐depleted medium. MIC values were as low as 2 μM (for P1‐DFP) on wild type P. aeruginosa. The activity of P1‐DFO and P1‐DFP was even better on genetically mutated strains unable to produce siderophores (down to 0.5 μM). Although the DFX vector on its own was not able to transport iron inside the bacterial cell as shown by 55Fe uptake studies, the P1‐DFX conjugate had excellent antibacterial activity compared to P1 (2 μM, and as low as 0.25 μM on a receptor‐deficient strain unable to produce siderophores), suggesting that the conjugates were indeed recognized and internalized by an (unknown) transporter. Control experiments with an equimolar mixture of P1 and DFX confirm that the observed activity is intrinsic to vectorization. This work thus demonstrates the power of linking small AMPs covalently to siderophores for a new class of Trojan Horse antibiotics, with P1‐DFP and P1‐DFX being the most potent conjugates. [ABSTRACT FROM AUTHOR]

During the period of COVID‐19, the occurrences of mucormycosis in immunocompromised patients have increased significantly. Mucormycosis (black fungus) is a rare and rapidly progressing fungal infection associated with high mortality and morbidity in India as well as globally. The causative agents for this infection are collectively called mucoromycetes which are the members of the order Mucorales. The diagnosis of the infection needs to be performed as soon as the occurrence of clinical symptoms which differs with types of Mucorales infection. Imaging techniques magnetic resonance imaging or computed tomography scan, culture testing, and microscopy are the approaches for the diagnosis. After the diagnosis of the infection is confirmed, rapid action is needed for the treatment in the form of antifungal therapy or surgery depending upon the severity of the infection. Delaying in treatment declines the chances of survival. In antifungal therapy, there are two approaches first‐line therapy (monotherapy) and combination therapy. Amphotericin B (1) and isavuconazole (2) are the drugs of choice for first‐line therapy in the treatment of mucormycosis. Salvage therapy with posaconazole (3) and deferasirox (4) is another approach for patients who are not responsible for any other therapy. Adjunctive therapy is also used in the treatment of mucormycosis along with first‐line therapy, which involves hyperbaric oxygen and cytokine therapy. There are some drugs like VT‐1161 (5) and APX001A (6), Colistin, SCH 42427, and PC1244 that are under clinical trials. Despite all these approaches, none can be 100% successful in giving results. Therefore, new medications with favorable or little side effects are required for the treatment of mucormycosis. [ABSTRACT FROM AUTHOR]

Chronic red blood cell transfusion therapy (CRTT) prevents strokes and silent cerebral infarcts (SCIs) in children with sickle cell disease (SCD).[1] Deferasirox, a once-daily oral iron chelator, is used to manage transfusion-related iron overload. Deferasirox (Exjade, 25 mg/kg/day) was started in 2014 (ferritin 2232 ng/mL), held in 2015 (ferritin <500 ng/mL) and restarted in 2016 (ferritin 1050 ng/mL). Hyperammonemia and acute liver failure (ALF) have occurred in deferasirox-treated children with transfusion-dependent thalassaemia (TDT).[[2], [4]] We report two deferasirox-treated teens with SCD who developed hyperammonemia and ALF. [Extracted from the article]

In recent years, the experiments have revealed that plants raise the cytotoxicity and anticancer potentials of iron nanoparticles against several cell lines especially tumor cell lines. In the present study, we formulated a modern drug by iron nanoparticles (FeNPs) containing Glycyrrhiza glabra L leaf for the treatment of acute lymphoblastic leukemia. Characterization of FeNPs was done by TEM, FE‐SEM, UV–Vis, and FT‐IR. FE‐SEM and TEM images revealed an average diameter of 11–18 nm for the nanoparticles. UV–Vis revealed an absorption band at 298 nm that is related to the surface plasmon resonance of FeNPs. FT‐IR results offered antioxidant compounds in the nanoparticles were the sources of reducing power, reducing iron ions to FeNPs. MTT assay was used on normal (HUVEC) and acute lymphoblastic leukemia (MOLT‐3, CEM/C2, TALL‐104, and CCRF‐CEM) cell lines for comparing the anti‐acute lymphoblastic leukemia properties of FeCl3, G. glabra, and FeNPs. Iron nanoparticles had very low cell viability dose‐dependently against MOLT‐3, CEM/C2, TALL‐104, CCRF‐CEM cell lines without any cytotoxicity on the HUVEC cell line. The best result of cytotoxicity property of FeNPs against the above cell lines was seen in the case of CCRF‐CEM cell line. These nanoparticles can be administrated in humans for the treatment of acute lymphoblastic leukemia after confirming in the in vivo and clinical trials. [ABSTRACT FROM AUTHOR]

Summary: Regular transfusion and chelation therapy produces increased life expectancy in thalassaemic patients who may develop new complications. Since few data are available regarding hypercalciuria in β‐thalassaemia major (TM), the aim of our study was to evaluate its prevalence, risk factors and clinical consequences. We enrolled 176 adult TM patients followed at the Center of Thalassemia of Ferrara. Hypercalciuria was defined by a calciuria of 4 mg/kg/day or more in a 24‐h urine sample. Anamnestic, biochemical and radiological data were collected. Hypercalciuria prevalence was reported in 69.3% of patients (females 52.5%). Hypercalciuric (HC) patients used deferasirox (DFX) more often than normocalciuric (NC) patients (47.5% vs 29.6%; p < 0.05). In HC subjects plasma parathyroid hormone (PTH) (24.1 ± 10.4 vs 30.1 ± 13.2 pg/ml) and phosphate levels (3.6 ± 0.5 vs 3.8 ± 0.7 mg/dl) were lower, whereas serum calcium (9.6 ± 0.4 vs 9.4 ± 0.4 mg/dl) and urinary 24‐h phosphaturia (0.9 ± 0.4 vs 0.6 ± 0.3 g/day) were higher as compared to NC patients (p < 0.05 for all comparisons). Supplementation with oral calcium and cholecalciferol was similar between the groups. A higher rate of kidney stones was present in HC (14.8%) versus NC patients (3.7%) (p < 0.05). Hypercalciuria is a frequent complication in adequately treated adult TM patients. Hypercalciuria prevalence is increased in DFX users whereas haemoglobin level or calcium supplements play no role. A significant proportion of HC patients developed kidney stones. [ABSTRACT FROM AUTHOR]

Aims: To develop a drug–disease model describing iron overload and its effect on ferritin response in patients affected by transfusion‐dependent haemoglobinopathies and investigate the contribution of interindividual differences in demographic and clinical factors on chelation therapy with deferiprone or deferasirox. Methods: Individual and mean serum ferritin data were retrieved from 13 published studies in patients affected by haemoglobinopathies receiving deferiprone or deferasirox. A nonlinear mixed effects modelling approach was used to characterise iron homeostasis and serum ferritin production taking into account annual blood consumption, baseline demographic and clinical characteristics. The effect of chelation therapy was parameterised as an increase in the iron elimination rate. Internal and external validation procedures were used to assess model performance across different study populations. Results: An indirect response model was identified, including baseline ferritin concentrations and annual blood consumption as covariates. The effect of chelation on iron elimination rate was characterised by a linear function, with different slopes for each drug (0.0109 [90% CI: 0.0079–0.0131] vs. 0.0013 [90% CI: 0.0008–0.0018] L/mg mo). In addition to drug‐specific differences in the magnitude of the ferritin response, simulation scenarios indicate that ferritin elimination rates depend on ferritin concentrations at baseline. Conclusion: Modelling of serum ferritin following chronic blood transfusion enabled the evaluation of drug‐induced changes in iron elimination rate and ferritin production. The use of a semi‐mechanistic parameterisation allowed us to disentangle disease‐specific factors from drug‐specific properties. Despite comparable chelation mechanisms, deferiprone appears to have a significantly larger effect on the iron elimination rate than deferasirox. [ABSTRACT FROM AUTHOR]

Summary: Deferasirox (DFX) is used for the management of iron overload (IOL) in many haematological malignancies including myelofibrosis (MF). The 'RUX‐IOL' study retrospectively collected 69 MF patients treated with ruxolitinib (RUX) and DFX for IOL to assess: safety, efficacy in term of iron chelation response (ICR) and erythroid response (ER), and impact on overall survival of the combination therapy. The RUX–DFX therapy was administered for a median time of 12.4 months (interquartile range 3.1–71.2). During treatment, 36 (52.2%) and 34 (49.3%) patients required RUX and DFX dose reductions, while eight (11.6%) and nine (13.1%) patients discontinued due to RUX‐ or DFX‐related adverse events; no unexpected toxicity was reported. ICR and ER were achieved by 33 (47.8%) and 32 patients (46.4%) respectively. Thirteen (18.9%) patients became transfusion‐independent. Median time to ICR and ER was 6.2 and 2 months respectively. Patients achieving an ER were more likely to obtain an ICR also (p = 0.04). In multivariable analysis, the absence of leukocytosis at baseline (p = 0.02) and achievement of an ICR at any time (p = 0.02) predicted improved survival. In many MF patients, the RUX–DFX combination provided ICR and ER responses that correlated with improved outcome in the absence of unexpected toxicities. This strategy deserves further clinical investigation. [ABSTRACT FROM AUTHOR]

Aryloxyalkanoate dioxygenases are unique herbicide biodegrading nonheme iron enzymes found in plants and hence, from environmental and agricultural point of view they are important and valuable. However, they often are substrate specific and little is known on the details of the mechanism and the substrate scope. To this end, we created enzyme models and calculate the mechanism for 2,4‐dichlorophenoxyacetic acid biodegradation and 2‐methyl substituted analogues by density functional theory. The work shows that the substrate binding is tight and positions the aliphatic group close to the metal center to enable a chemoselective reaction mechanism to form the C2‐hydroxy products, whereas the aromatic hydroxylation barriers are well higher in energy. Subsequently, we investigated the metabolism of R‐ and S‐methyl substituted inhibitors and show that these do not react as efficiently as 2,4‐dichlorophenoxyacetic acid substrate due to stereochemical clashes in the active site and particularly for the R‐isomer give high rebound barriers. [ABSTRACT FROM AUTHOR]

A series of deferasirox derivatives of 1,2,4‐triazole (5 a–i,6 a–g) were designed and synthesized by the ring‐opening rearrangement reaction of phenyl hydrazine or its substituents and imines, compounds 5 d–i, 6 e–g are previously unknown. Obtained derivatives were characterized by IR, 1H NMR, 13C NMR, and Mass spectral. The antibacterial activities of all compounds against Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Candida albicans and Aspergillus niger were experimentally evaluated. Most of them exhibited potential antimicrobial activity and promising antifungal activity. Especially, 6 f and 6 g showed the best antimicrobial activity (MIC90=0.125–2.0 μg/mL) against Staphylococcus aureus, Staphylococcus epidermidis and Escherichia coli, while compounds 6 c, 6 e showed excellent antifungal activity (MIC90=0.5–2.0 μg/mL). The molecular docking analysis further revealed that all the synthesized derivatives have shown potential binding affinities. [ABSTRACT FROM AUTHOR]

Human ferritin has been heavily investigated as a protein‐based drug deliver agent, due to its unique hollow cage structure for drug loading and an intrinsic tumor targeting function. However, facile strategies for high‐level drug loading and controlled release have not been established, which hampered the use of ferritin as an in vivo delivery platform. We examined active drug uptake and release patterns of various flopped ferritin variants, which use fourfold channels as a route for drug uptake. A flopped channel pore structure was adjusted by diverse mutations around the helix‐connecting loop of the channel. Active loading and release of anti‐cancer drug doxorubicin for these ferritin variants were quantitatively monitored. Drug‐loading ability and spontaneous release degree were both enhanced by channel flopping and a pore size increase. The results could lay a stepping stone for further understanding of drug loading via fourfold ferritin channels. [ABSTRACT FROM AUTHOR]

A novel V(V) dimer complex [VO(DFX)(BuO)]2.BuOH, (DFX=deferasirox, BuOH=1‐butanol) was synthesized and fully characterized by elemental analysis, 1HNMR, 51V NMR, Fourier‐transform infrared spectroscopy (FTIR) and molar conductivity. The spectroscopically predicted structure of the synthesized Vanadium complex was also verified by single crystal X‐ray diffraction. The deferasirox ligand is coordinated to V(V) center in a tridentate fashion by two phenolate oxygen atoms and one triazole nitrogen atom, with one of the phenolates acting as bridging ligand in the dimer complex. The coordination sphere is completed by oxo group and butanolate anion. The antibacterial activities of deferasirox and its V(V) dimer complex were investigated using the zone of inhibition and the minimal inhibitory concentration of the dilution assays against Staphylococcus aureus, Bacillus cereus, Escherichia coli, and Pseudomonas aeruginosa bacteria strains. The antibiofilm potential of these compounds was also examined by evaluating their activity against biofilm formation of S. aureus and P. aeruginosa bacteria strains. Additionally, free‐radical‐scavenging ability of compounds was evaluated by their interaction with the stable free radical 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH). Generally, in all assays the V(V) synthesized complex, demonstrated a moderate and selective activity. [ABSTRACT FROM AUTHOR]

It is desirable for a simple and universal method to synthesize stimuli‐responsive nanocarriers to targeted delivery of pesticides. In this study, a novel pH‐value and laccase dual‐responsive nanopesticide system loaded with lambda‐cyhalothrin (LC) is established by iron mineralization after electrostatic self‐assembly between sodium lignosulphonate (SL) and dodecyl dimethyl benzyl ammonium chloride (DDBAC). These nanoparticles are core–shell structures in which iron mineralization plays a key role in stabilizing the nanoparticles. This synthesis strategy is suitable for encapsulating hydrophobic and low‐volatility compounds. The encapsulation of the nanocarriers prolongs the half‐life of the LC under UV irradiation by 4.4‐fold. After irradiation, the mortality of Agrotis ipsilon treated by the LC@SL/DDBAC/Fe is approximately 39% higher than that treated by emulsifiable concentrate (EC) at the concentration of 1 mg L−1. The dual‐responsive property of lignin‐based nanoplatform to alkalinity and laccase enable cargo release on demand. Although the toxicity of EC and LC@SL/DDBAC/Fe to A. ipsilon is similar, that of LC@SL/DDBAC/Fe to Brachydanio rerio is decreased by 11.57‐fold, and the toxicity selective pressure is enhanced by 11‐fold compared with EC. The SL/DDBAC/Fe nanocarriers represent a simple preparation procedure, excellent environmental safety, and dual‐responsive release profiles and can offer a promising nanoplatform for precise pesticide delivery. [ABSTRACT FROM AUTHOR]

Introduction: Early intervention in the devastating process of haemophilic arthropathy (HA) is highly desirable, but no disease‐modifying therapy is currently available. Considering the pivotal role of iron in the development of HA, iron chelation is considered a promising therapeutic approach. A previous study in haemophilic mice demonstrated that treatment with the iron chelator deferasirox (DFX) 8 weeks before joint bleed induction, attenuated cartilage damage upon blood exposure. However, in haemophilia patients this approach is not opportune given the unpredictable occurrence of hemarthroses. Aim: To evaluate the effectiveness of on‐demand DFX treatment, initiated immediately after joint bleed induction. Methods: A joint bleed was induced in 66 factor VIII‐deficient mice by infra‐patellar needle puncture. Mice were randomly assigned to treatment with either placebo (drinking water) or DFX (dissolved in drinking water) throughout the study. Five weeks after joint bleed induction, inflammation and cartilage damage were assessed histologically. Joints of ten bleed naive haemophilic mice served as controls. Results: A joint bleed resulted in significant inflammation and cartilage damage in the blood‐exposed joint compared with those of control animals, in both the placebo and DFX group (all p = <.05). No differences in tibiofemoral or patellar inflammation (p =.305 and p =.787, respectively) nor cartilage damage (p =.265 and p =.802, respectively) were found between the blood‐exposed joints of both treatment groups. Conclusion: On‐demand treatment with DFX does not prevent joint damage following blood exposure in haemophilic mice. DFX seems unable to reach the joint in time to exert its effect before the irreversible harmful process is initiated. [ABSTRACT FROM AUTHOR]

Background: Iron overload is a major complication of transfusion‐dependent thalassemia (TDT) and requires iron chelation (IC) therapy. However, a combination therapy may be required for patients responding poorly to monotherapy. Methods: Nine TDT patients previously treated with IC were enrolled; five patients were previously treated with deferasirox (DFX) twice daily. The dose of DFX was 20–40 mg/kg/day, while the dose of deferoxamine (DFO) was 18–40 mg/kg/day for 3–6 days/week. Results: At the 6‐ and 12‐month time points, six and eight patients demonstrated decreased serum ferritin levels, with median reductions of 707 ng/mL (range, 1,653–5,444 ng/mL) and 1,129 ng/mL (range, 1,781–7,725 ng/mL) compared to the baseline, respectively. Eight patients also had a reduced liver iron concentration (LIC), with a median reduction of 3.9 mg/g dry wt (range, 8.3–11.1 mg/g dry wt). Of the five patients treated with DFX twice daily, four responded to combination therapy. All responsive patients could finally stop DFO after the decline in LIC. Moreover, there were no treatment‐related complications. Conclusion: The combination of DFX and DFO proved to be effective and without significant toxicities for TDT patients who had been unresponsive to standard IC therapy. Further studies with a larger cohort size and long‐term follow‐up are warranted to elucidate the efficacy of the combination. [ABSTRACT FROM AUTHOR]

Summary: Mantle cell lymphoma (MCL) is a difficult‐to‐treat B‐cell malignancy characterized by cyclin D1 (CD1) overexpression. Targeting CD1 in MCL has been shown to be of therapeutic significance. However, treatment of MCL remains challenging since patients are still subject to early and frequent relapse of the disease. To ensure their high proliferation rate, tumour cells have increased iron needs, making them more susceptible to iron deprivation. Indeed, several iron chelators proved to be effective anti‐cancer agents. In this study, we demonstrate that the clinically approved iron chelator deferasirox (DFX) exerts an anti‐tumoural effect in MCL cell lines and patient cells. The exposure of MCL cells to clinically feasible concentrations of DFX resulted in growth inhibition, cell cycle arrest and induction of apoptosis. We show that DFX unfolds its cytotoxic effect by a rapid induction of reactive oxygen species (ROS) that leads to oxidative stress and severe DNA damage and by triggering CD1 proteolysis in a mechanism that requires its phosphorylation on T286 by glycogen synthase kinase‐3β (GSK3β). Moreover, we demonstrate that DFX mediates CD1 proteolysis by repressing the phosphatidylinositol 3‐kinase (PI3K)/AKT/GSK3β pathway via ROS generation. Our data suggest DFX as a potential therapeutic option for MCL and paves the way for more treatment options for these patients. [ABSTRACT FROM AUTHOR]

MDS are characterized by anemia and transfusion requirements. Transfused patients frequently show iron overload that negatively affects hematopoiesis. Iron chelation therapy can be effective in these MDS cases, but the molecular consequences of this treatment need to be further investigated. That is why we studied the molecular features of iron effect and Deferasirox therapy on PI‐PLCbeta1 inositide signaling, using hematopoietic cells and MDS samples. At baseline, MDS patients showing a positive response after iron chelation therapy displayed higher levels of PI‐PLCbeta1/Cyclin D3/PKCalpha expression. During treatment, these responder patients, as well as hematopoietic cells treated with FeCl3 and Deferasirox, showed a specific reduction of PI‐PLCbeta1/Cyclin D3/PKCalpha expression, indicating that this signaling pathway is targeted by Deferasirox. The treatment was also able to specifically decrease the production of ROS. This effect correlated with a reduction of IL‐1A and IL‐2, as well as Akt/mTOR phosphorylation. In contrast, cells exposed only to FeCl3 and cells from MDS patients refractory to Deferasirox showed a specific increase of ROS and PI‐PLCbeta1/Cyclin D3/PKCalpha expression. All in all, our data show that PI‐PLCbeta1 signaling is a target for iron‐induced oxidative stress and suggest that baseline PI‐PLCbeta1 quantification could predict iron chelation therapy response in MDS. [ABSTRACT FROM AUTHOR]

De-Iron: a phase 2 trial of the activity and safety of Deferasirox administered at early iron loading in patients with transfusion-dependent myelodysplastic syndromes Impact of treatment with iron chelation therapy in patients with lower-risk myelodysplastic syndromes participating in the European MDS registry. Delayed time from RBC transfusion dependence to first cardiac event in lower IPSS risk MDS patients receiving iron chelation therapy. [Extracted from the article]

Switching from dispersible to film coated tablet formulation of deferasirox improves hemoglobin levels and transfusional interval in patients with transfusion-dependent-thalassemia Keywords: transfusion-dependent thalassemia; iron chelation therapy; dispersible-tablet deferasirox; film-coated-tablet deferasirox; switch EN transfusion-dependent thalassemia iron chelation therapy dispersible-tablet deferasirox film-coated-tablet deferasirox switch e60 e63 4 04/15/20 20200415 NES 200415 Current treatment options for transfusion-dependent-thalassemia (TdT) are mostly limited to managing anaemia with regular red blood cell (RBC) transfusions and its complications, including iron overload (Taher & Saliba, [7]), with a life expectancy that in recent years extends beyond 40 years of age (Iolascon I et al. i , [3]). Transfusion-dependent thalassemia, iron chelation therapy, dispersible-tablet deferasirox, film-coated-tablet deferasirox, switch. [Extracted from the article]

Background: Ferroptosis, an iron-dependent form of regulated cell death, is a major cell death mode in myocardial ischemia reperfusion (I/R) injury, along with mitochondrial permeability transition-driven necrosis, which is inhibited by cyclosporine A (CsA). However, therapeutics targeting ferroptosis during myocardial I/R injury have not yet been developed. Hence, we aimed to investigate the therapeutic efficacy of deferasirox, an iron chelator, against hypoxia/reoxygenation-induced ferroptosis in cultured cardiomyocytes and myocardial I/R injury., Methods and Results: The effects of deferasirox on hypoxia/reoxygenation-induced iron overload in the endoplasmic reticulum, lipid peroxidation, and ferroptosis were examined in cultured cardiomyocytes. In a mouse model of I/R injury, the infarct size and adverse cardiac remodeling were examined after treatment with deferasirox, CsA, or both in combination. Deferasirox suppressed hypoxia- or hypoxia/reoxygenation-induced iron overload in the endoplasmic reticulum, lipid peroxidation, and ferroptosis in cultured cardiomyocytes. Deferasirox treatment reduced iron levels in the endoplasmic reticulum and prevented increases in lipid peroxidation and ferroptosis in the I/R-injured myocardium 24 hours after I/R. Deferasirox and CsA independently reduced the infarct size after I/R injury to a similar degree, and combination therapy with deferasirox and CsA synergistically reduced the infarct size (infarct area/area at risk; control treatment: 64±2%; deferasirox treatment: 48±3%; CsA treatment: 48±4%; deferasirox+CsA treatment: 37±3%), thereby ameliorating adverse cardiac remodeling on day 14 after I/R., Conclusions: Combination therapy with deferasirox and CsA may be a clinically feasible and effective therapeutic approach for limiting I/R injury and ameliorating adverse cardiac remodeling after myocardial infarction.

Summary: Patients with low‐risk myelodysplastic syndromes (MDS) usually develop iron overload. This leads to a high level of oxidative stress in the bone marrow (BM) and increases haematopoietic cell dysfunction. Our objective was to analyse whether chelation with deferasirox (DFX) alleviates the consequences of oxidative stress and improves BM cell functionality. We analysed 13 iron‐overloaded MDS patients' samples before and 4–10 months after treatment with DFX. Using multiparametric flow cytometry analysis, we measured intracellular reactive oxygen species (ROS), DNA oxidation and double strand breaks. Haematopoietic differentiation capacity was analysed by colony‐forming unit (CFU) assays. Compared to healthy donors, MDS showed a higher level of intracellular ROS and DNA oxidative damage in BM cells. DNA oxidative damage decreased following DFX treatment. Furthermore, the clonogenic assays carried out before treatment suggest an impaired haematopoietic differentiation. DFX seems to improve this capacity, as illustrated by a decreased cluster/CFU ratio, which reached values similar to controls. We conclude that BM cells from MDS are subject to higher oxidative stress conditions and show an impaired haematopoietic differentiation. These adverse features seem to be partially rectified after DFX treatment. [ABSTRACT FROM AUTHOR]

No disease modifying drugs have been approved for Alzheimer's disease despite recent major investments by industry and governments throughout the world. The burden of Alzheimer's disease is becoming increasingly unsustainable, and given the last decade of clinical trial failures, a renewed understanding of the disease mechanism is called for, and trialling of new therapeutic approaches to slow disease progression is warranted. Here, we review the evidence and rational for targeting brain iron in Alzheimer's disease. Although iron elevation in Alzheimer's disease was reported in the 1950s, renewed interest has been stimulated by the advancement of fluid and imaging biomarkers of brain iron that predict disease progression, and the recent discovery of the iron-dependent cell death pathway termed ferroptosis. We review these emerging clinical and biochemical findings and propose how this pathway may be targeted therapeutically to slow Alzheimer's disease progression. LINKED ARTICLES: This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc. [ABSTRACT FROM AUTHOR]

At present, very few data are available on the role of iron chelation therapy (ICT) with deferasirox (DFX) in MF (Elli I et al i , [3]; Latagliata I et al i , [5]). Patients received DFX after a median MF duration of 26-8 months [interquartile range (IQR) 2-6-208-7] with a TD latency of 12-5 months (IQR 1-2-146-1). Our preliminary data open new insights regarding the benefit of DFX in MF patients with TD anaemia. [Extracted from the article]

Deferasirox is an oral iron‐chelating agent having possible antileukemia and immune modulatory effects. Few reports have evaluated deferasirox in the setting of allogeneic hematopoietic stem cell transplantation (allo‐HSCT). We investigated the impact of deferasirox after allo‐HSCT in acute myeloid leukemia (AML). Of 326 consecutive patients undergoing allo‐HSCT in remission, analysis of 198 patients not receiving deferasirox revealed the negative prognostic effect of hyperferritinemia (≥1000 ng/mL) before and after allo‐HSCT on survival mainly due to increase in relapse. Of 276 patients with hyperferritinemia at 1 month after allo‐HSCT, 128 patients (46%) received deferasirox. Deferasirox induced a faster decline in serum ferritin level with a manageable safety profile, which significantly reduced relapse rather than nonrelapse mortality, resulting in better survival compared to patients not receiving deferasirox. Of note, the deferasirox group had a significantly higher incidence of chronic graft‐vs‐host disease, indicating improved graft‐vs‐leukemia (GVL) effects evidenced by the presence of suppressed regulatory T cells and sustained higher proportion of NK cells in peripheral blood. This study firstly demonstrates the improved survival and restoration of GVL effects of patients with AML by deferasirox, which also clarifies the detrimental effect of hyperferritinemia through after allo‐HSCT. Survival outcomes were improved according to iron chelation with deferasirox after allogeneic hematopoietic stem cell transplantation. [ABSTRACT FROM AUTHOR]

Summary: We prospectively assessed the efficacy of deferasirox versus deferiprone or desferrioxamine as monotherapy in thalassaemia major (TM) patients by magnetic resonance imaging (MRI). We selected the patients enrolled in the Myocardial Iron Overload in Thalassaemia network who received only one chelator between two MRIs (deferasirox = 235, deferiprone = 142, desferrioxamine = 162). Iron overload was measured by T2* technique and biventricular function by cine images. Among the patients with baseline myocardial iron, in all three groups there was a significant improvement in global heart T2* values. The deferiprone and desferrioxamine groups showed a significant improvement in left ventricular ejection fraction (LVEF). Only the deferiprone group showed a significant improvement in right ventricular ejection fraction (RVEF). The improvement in global heart T2* was significantly lower in the deferasirox versus the deferiprone group. The improvement in the LVEF was significantly higher in the deferiprone and desferrioxamine groups than in the deferasirox group and the improvement in the RVEF was significantly higher in the deferiprone than in deferasirox group. Among the patients with baseline hepatic iron, the changes in hepatic iron were comparable in deferasirox versus the other groups. Deferasirox monotherapy was less effective than deferiprone in improving myocardial siderosis and biventricular function and less effective than desferrioxamine in improving the LVEF. [ABSTRACT FROM AUTHOR]

In article number 2300092, Xuheng Chen, Runsheng Xu, and co-workers review the latest research progress on the preparation and application of iron coke in three dimensions: process, performance, and application. The evolution mechanism of iron coke strength and the catalytic mechanism of iron coke gasification are discussed in depth. [Extracted from the article]

Abstract: Background: Cutaneous manifestations can be found in many patients with hematologic disorders, including thalassemia. Methods: Patients with beta‐thalassemia major attending the pediatric department of Fayoum University Hospital from April 2016 to October 2016 (n = 100) were compared with controls (n = 100). Both groups underwent detailed history evaluation, clinical examination, and laboratory investigations, including complete blood count, liver and kidney function, serum ferritin, and thyroid profile. A single dermatologist conducted a clinical dermatologic examination for all participants. Results: Children with thalassemia had a greater prevalence of xerosis (72%), pruritus (52%), idiopathic guttate hypomelanosis (22%), urticaria (16%), ephelides (freckles; 13%), and scars (13%) than controls (P ≤ .001). We detected a significant relationship between serum ferritin and pruritus, xerosis, ephelides, idiopathic guttate hypomelanosis, urticaria, and age of patients with thalassemia (P < .05). Children without thyroid abnormalities were more likely to have xerosis, pruritus, idiopathic guttate hypomelanosis, urticaria, and ephelides (86%) than controls (P < .05). Although there was no significant difference in skin findings between patients who did and did not receive chelating agents (P > .05), a significant association was found between xerosis and the use of deferoxamine and deferiprone, whereas ephelides and urticaria were more common in patients receiving deferasirox. Conclusion: Because cutaneous manifestations are common in Egyptian patients with beta thalassemia major, regular dermatologic follow‐up is recommended for early management. [ABSTRACT FROM AUTHOR]

Abstract: Effective iron chelation therapy is an important part of treatment in patients with transfusion‐dependent thalassaemia and lower‐risk myelodysplastic syndromes (MDS). Key strategies for optimising iron chelation therapy include ensuring good adherence and preventing and managing adverse events (AEs). Good adherence to iron chelation therapy with deferoxamine and deferasirox has been linked to improved survival and/or reductions in complications related to iron overload; however, maintaining good adherence to iron chelators can be challenging. Patients with transfusion‐dependent thalassaemia or lower‐risk MDS showed better adherence to the deferasirox film‐coated tablet (FCT) formulation than to the deferasirox dispersible tablet formulation in the ECLIPSE trial, reflecting in part the improved palatability and convenience of deferasirox FCT. As well as affecting adherence, AEs may lead to dose reduction, interruption or discontinuation, resulting in suboptimal iron chelation therapy. Preventing and successfully managing AEs may help limit their impact on adherence, and following dosage and administration recommendations for iron chelators such as deferasirox may help minimise AEs and optimise treatment in patients with transfusion‐dependent thalassaemia and lower‐risk MDS. [ABSTRACT FROM AUTHOR]

Abstract: To ensure their high proliferation rate, tumor cells have an iron metabolic disorder causing them to have increased iron needs, making them more susceptible to iron deprivation. This vulnerability could be a therapeutic target. In breast cancers, the development of new therapeutic approaches is urgently needed for patients with triple‐negative tumors, which frequently relapse after chemotherapy and suffer from a lack of targeted therapies. In this study, we demonstrated that deferasirox (DFX) synergises with standard chemotherapeutic agents such as doxorubicin, cisplatin and carboplatin to inhibit cell proliferation and induce apoptosis and autophagy in triple‐negative breast cancer (TNBC) cells. Moreover, the combination of DFX with doxorubicin and cyclophosphamide delayed recurrences in breast cancer patient‐derived xenografts without increasing the side‐effects of chemotherapies alone or altering the global iron storage of mice. Antitumor synergy of DFX and doxorubicin seems to involve downregulation of the phosphoinositide 3‐kinase and nuclear factor‐κB pathways. Iron deprivation in combination with chemotherapy could thus help to improve the effectiveness of chemotherapy in TNBC patients without increasing toxicity. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objectives: Erythropoiesis-stimulating agents (ESAs) remain first-choice to treat symptomatic anemia and delay transfusion dependence in most patients with lower-risk myelodysplastic syndromes (MDS) without del(5q). Deferasirox increased erythroid responses in some lower-risk MDS patients in clinical trials, and adding low-dose deferasirox to ESA treatment may further improve erythroid response. Methods: KALLISTO (NCT01868477) was a randomized, open-l abel, multicenter, phase II study. Lower-risk MDS patients received deferasirox at 10 mg/kg/d (dispersible tablets) or 7 mg/kg/d (film-coated tablets) plus erythropoietin (n = 11), or erythropoietin alone (n = 12) for 24 weeks. The primary endpoint was the between-group difference in erythroid response within 12 weeks. Results: Erythroid response occurred in 27.3% of patients receiving deferasirox plus erythropoietin vs 41.7% of patients receiving erythropoietin alone within 12 weeks (difference 14.4%; 95% CI -24.0, 48.16). Within 24 weeks, the hematologic response rate was 27.3% with deferasirox plus erythropoietin vs 50% with erythropoietin alone, and hematologic improvement rates were 45.5% vs 100%. Deferasirox plus erythropoietin was generally well tolerated. Conclusions: In this small pilot study, combining low-dose deferasirox with erythropoietin did not improve erythroid response. It remains of interest to investigate early chelation approaches with even lower deferasirox doses plus erythropoietin in lower-risk MDS patients before the onset of transfusion dependence. [ABSTRACT FROM AUTHOR]

Objectives: To assess the reduction of transfusions rate in transfusion-dependent patients with low-risk myelodysplastic syndrome (MDS) with iron overload treated with deferasirox. Methods: Prospective observational study. Primary endpoint was reduction in transfusion requirements (RTR) at 3 months, (assessed on 8-week period). Secondary end-points were hematologic improvement according to International Working Group (IWG) 2006 criteria at 3, 6, and 12 months. Results: Fifty-seven patients were evaluable. After 3 months of chelation, no effect was seen on transfusion requirement (5.9 packed red blood cells (PRBC) vs 5.8 before chelation). According to the Kaplan-Meier analysis, the probability of RTR at 3, 6, and 12 months was assessed as 3.5%, 9.1%, and 18.7%, respectively. Median duration of RTR was 182 days. However, during the 12-month follow-up after deferasirox initiation, 17 patients (31.5%) achieved minor erythroid response [HI-E] according to IWG criteria, 10 of whom having achieved Hb improvement at month 12. Conclusion: After 3 months of treatment, deferasirox had no impact on transfusion requirement in regularly transfused patients with low-risk MDS. However, deferasirox could induce 31% of erythroid response during the 12-month follow-up period thus suggesting that iron chelation therapy with deferasirox may induce an effect on hematopoiesis in a subset of patients with MDS and iron overload. [ABSTRACT FROM AUTHOR]

Summary: We evaluated the role of deferasirox therapeutic drug monitoring in order to avoid toxicity or treatment failure. Plasma concentrations, measured between two consecutive liver iron determinations, were determined at the end of dosing interval. Fifty‐four β‐thalassemic adult patients were enrolled: 50% were males; median age was 32.3 years (IQR 19.1‐41.7 years) and median body mass index was 22.25 kg/m2 (IQR 20.24‐23.75 kg/m2). The mean deferasirox dose was 28.6 ± 6.3 mg/kg/d and mean plasma concentration was 17.3 ± 16.8 μg/mL. Drug levels showed lower results in males. Deferasirox concentration was significantly correlated with serum creatinine levels (P = .01) and serum ferritin (P < .0001). The assessment of deferasirox therapeutic drug monitoring could help clinicians to predict patient responses and to optimize the therapy. [ABSTRACT FROM AUTHOR]

Key Clinical Message This manuscript describes the case of a patient with sickle cell anemia who died of fulminant hepatitis after therapy with the iron chelator Deferasirox. The patient was homozygous for the −1774delG polymorphism in the Abcc2 gene, which raises the concern about the use of hepatotoxic drugs in this specific context. [ABSTRACT FROM AUTHOR]

Iron chelation is controversial in higher risk myelodysplastic syndromes ( HR- MDS), outside the allogeneic transplant setting. We conducted a retrospective, multicentre study in 51 patients with transfusion-dependent, intermediate-to-very high risk MDS, according to the revised international prognostic scoring system, treated with the oral iron chelating agent deferasirox ( DFX). Thirty-six patients (71%) received azacitidine concomitantly. DFX was given at a median dose of 1000 mg/day (range 375-2500 mg) for a median of 11 months (range 0·4-75). Eight patients (16%) showed grade 2-3 toxicities (renal or gastrointestinal), 4 of whom (8%) required drug interruption. Median ferritin levels decreased from 1709 μg/l at baseline to 1100 μg/l after 12 months of treatment ( P = 0·02). Seventeen patients showed abnormal transaminase levels at baseline, which improved or normalized under DFX treatment in eight cases. One patient showed a remarkable haematological improvement. At a median follow up of 35·3 months, median overall survival was 37·5 months. The results of this first survey of DFX in HR- MDS are comparable, in terms of safety and efficacy, with those observed in lower-risk MDS. Though larger, prospective studies are required to demonstrate real clinical benefits, our data suggest that DFX is feasible and might be considered in a selected cohort of HR- MDS patients. [ABSTRACT FROM AUTHOR]

Background In transfusion-dependent anaemias, while absolute serum ferritin levels broadly correlate with liver iron concentration ( LIC), relationships between trends in these variables are unclear. These relationships are important because serum ferritin changes are often used to adjust or switch chelation regimens when liver magnetic resonance imaging ( MRI) is unavailable. Objectives and methods This post hoc analysis of the EPIC study compared serum ferritin and LIC in 317 patients with transfusion-dependent thalassaemia before and after 1 yr of deferasirox. Results Serum ferritin responses (decreases) occurred in 73% of patients, 80% of whom also have decreased LIC. However, 52% of patients without a serum ferritin response did decrease LIC and by >1 mg Fe/g dw (median 3.9) in 77% of cases. Absolute serum ferritin and LIC values correlated significantly only when serum ferritin was <4000 ng/mL ( r = 0.59; P < 0.0001) and not at higher levels (≥4000 ng/mL; r = 0.19). Serum ferritin response was accompanied by decreased LIC in 89% and 70% of cases when serum ferritin was <4000 or ≥4000 ng/mL, respectively. Conclusions As serum ferritin non−response was associated with LIC decrease in over half of patients, use of liver MRI may be particularly useful for differentiating true from apparent non-responders to deferasirox based on serum ferritin trends alone. [ABSTRACT FROM AUTHOR]

Background This review describes the safety of deferoxamine ( DFO), deferiprone ( DFP), deferasirox ( DFX) and combined therapy in young patients less than 25 yr of age with haemoglobinopathies. Methods Searches in electronic literature databases were performed. Studies reporting adverse events associated with iron chelation therapy were included. Study and reporting quality was assessed using AHRQ Risk of Bias Assessment Tool and McMaster Quality Assessment Scale of Harms. Prospective clinical studies were pooled in a random-effects meta-analysis of proportions. Results Safety data of 2040 patients from 34 studies were included. Ninety-two case reports of 246 patients were identified. DFX (937 patients) and DFP (667 patients) possess the largest published safety evidence. Fewer studies on combination regimens are available. Increased transaminases were seen in all regimens (3.9-31.3%) and gastrointestinal disorders with DFP and DFX (3.7-18.4% and 5.8-18.8%, respectively). Therapy discontinuations due to adverse events were low (0-4.1%). Reporting quality was selective and poor in most of the studies. Conclusion Iron chelation therapy is generally safe in young patients, and published data correspond to summary of product characteristics. Each iron chelation regimen has its specific safety risks. DFO seems not to be associated with serious adverse effects in recommended doses. In DFP and DFX, rare, but serious, adverse reactions can occur. Data on combined therapy are scarce, but it seems equally safe compared to monotherapy. [ABSTRACT FROM AUTHOR]

Objectives To assess the effect of iron chelation therapy with deferasirox on cardiac iron and function in patients with transfusion-dependent thalassemia major, sickle cell disease ( SCD), and myelodysplastic syndromes ( MDS). Methods This phase IV, single-arm, open-label study over 53 wk evaluated the change in cardiac and liver iron load with deferasirox (up to 40 mg/kg/d), measured by magnetic resonance imaging ( MRI). Results Cardiac iron load (myocardial T2*) significantly improved ( P = 0.002) overall ( n = 46; n = 36 thalassemia major, n = 4 SCD, n = 6 MDS). Results were significant for patients with normal and moderate baseline cardiac iron ( P = 0.017 and P = 0.015, respectively), but not in the five patients with severe cardiac iron load. Liver iron concentration ( LIC) significantly decreased overall [mean LIC 10.4 to 8.2 mg Fe/g dry tissue (dw); P = 0.024], particularly in those with baseline LIC >7 mg Fe/g dw (19.9 to 15.6 mg Fe/g dw; P = 0.002). Furthermore, myocardial T2* significantly increased in patients with LIC <7 mg Fe/g dw, but not in those with a higher LIC. Safety was consistent with previous reports. Conclusions Once-daily deferasirox over 1 yr significantly increased myocardial T2* and reduced LIC. This confirms that single-agent deferasirox is effective in the management of cardiac iron, especially for patients with myocardial T2* >10 ms (Clinicaltrials.gov identifier: NCT00673608). [ABSTRACT FROM AUTHOR]

Iron-chelating agents, which are frequently prescribed to transfusion-dependent patients, have various useful biological effects in addition to chelation. Reactive oxygen species (ROS) produced by neutrophils can cause pulmonary endothelial cell damage, which can lead to acute lung injury (ALI). We previously reported that deferasirox (DFS), an iron-chelating agent, inhibits phorbol myristate acetate (PMA) or formyl-methionyl-leucyl-phenylalanine (fMLP)-induced ROS production in neutrophils, in vitro. Here, we investigate whether DFS inhibits vacuolization in neutrophils and neutrophil extracellular trap (NET) formation. Human neutrophils were incubated with DFS and stimulated with PMA or fMLP. Human neutrophils were separated from heparinized peripheral blood using density gradient centrifugation, and subsequently incubated with DFS. After 10 minutes, neutrophils were stimulated by PMA or fMLP. Vacuole formation was observed by electron microscopy. For observing NET formations using microscopes, immunohistological analyses using citrullinated histone H3 and myeloperoxidase antibodies, and SYTOX Green (an impermeable DNA detection dye) staining, were conducted. NET formation was measured as the quantity of double-stranded DNA (dsDNA), using the AccuBlue Broad Range dsDNA Quantitation Kit. DFS (50 μmol/L) inhibited vacuole formation in the cytoplasm and NET formation. Additionally, 5-100 μmol/L concentration of DFS inhibited the release of dsDNA in a dose-independent manner. We demonstrate that DFS inhibits not only ROS production but also vacuolization and NET formation in neutrophils. These results suggest the possibility of protective effects of DFS against NET-related adverse effects, including ALI and thrombosis. [ABSTRACT FROM AUTHOR]

Azole compounds have attracted commercial interest due to their high bactericidal and plant-growth-regulating activities. Uniconazole [or 1-(4-chlorophenyl)-4,4-dimethyl-2-(1 H-1,2,4-triazol-1-yl)pent-1-en-3-ol] is a highly active 1,2,4-triazole fungicide and plant-growth regulator with low toxicity. The pharmacological and toxicological properties of many drugs are modified by the formation of their metal complexes. Therefore, there is much interest in exploiting the coordination chemistry of triazole pesticides and their potential application in agriculture. However, reports of complexes of uniconazole are rare. A new cobalt(II) complex of uniconazole, namely dichloridotetrakis[1-(4-chlorophenyl)-4,4-dimethyl-2-(1 H-1,2,4-triazol-1-yl-κ N4)pent-1-en-3-ol]cobalt(II), [CoCl2(C15H18ClN3O)4], was synthesized and structurally characterized by element analysis, IR spectrometry and X-ray single-crystal diffraction. The crystal structural analysis shows that the CoII atom is located on the inversion centre and is coordinated by four uniconazole and two chloride ligands, forming a distorted octahedral geometry. The hydroxy groups of an uniconazole ligands of adjacent molecules form hydrogen bonds with the axial chloride ligands, resulting in one-dimensional chains parallel to the a axis. The complex was analysed for its antifungal activity by the mycelial growth rate method. It was revealed that the antifungal effect of the title complex is more pronounced than the effect of fungicide uniconazole for Botryosphaeria ribis, Wheat gibberellic and Grape anthracnose. [ABSTRACT FROM AUTHOR]

At present, very few data are available on deferasirox ( DFX) in the treatment of patients with Philadelphia-negative myeloproliferative neoplasms in fibrotic phase ( FP- MPN) and transfusion dependence. To address this issue, a retrospective analysis of 28 patients (22 male and 6 female) with FP- MPN and iron overload secondary to transfusion dependence was performed, based on patients enrolled in the database of our regional cooperative group who received treatment with DFX. DFX was started after a median interval from diagnosis of 12.8 months ( IR 7.1-43.1) with median ferritin values of 1415 ng/mL ( IR 1168-1768). Extra-hematological toxicity was reported in 16 of 28 patients (57.1%), but only two patients discontinued treatment due to toxicity. Among 26 patients evaluable for response (≥6 months of treatment), after a median treatment period of 15.4 months ( IR 8.1-22.3), 11 patients (42.3%) achieved a stable and consistent reduction in ferritin levels <1000 ng/mL. As for hematological improvement, 6 of 26 patients (23%) showed a persistent (>3 months) rise of Hb levels >1.5 g/dL, with disappearance of transfusion dependence in four cases. Treatment with DFX is feasible and effective in FP- MPN with iron overload. Moreover, in this setting, an erythroid response can occur in a significant proportion of patients. [ABSTRACT FROM AUTHOR]

Regular red cell transfusions used to treat thalassemia cause iron loading that must be treated with chelation therapy. Morbidity and mortality in thalassemia major are closely linked to the adequacy of chelation. Chelation therapy removes accumulated iron and detoxifies iron, which can prevent and reverse much of the iron-mediated organ injury. Currently, three chelators are commercially available--deferoxamine, deferasirox, and deferiprone--and each can be used as monotherapy or in combination. Close monitoring of hepatic and cardiac iron burden is central to tailoring chelation. Other factors, including properties of the individual chelators, ongoing transfusional iron burden, and patient preference, must be considered. Monotherapy generally is utilized if the iron burden is in an acceptable or near-acceptable range and the dose is adjusted accordingly. Combination chelation often is employed for patients with high iron burden, iron-related organ injury, or where adverse effects of chelators preclude administration of an appropriate chelator dose. The combination of deferoxamine and deferiprone is the best studied, but increasing data are available on the safety and efficacy of newer chelator combinations, including deferasirox with deferoxamine and the oral-only combination of deferasirox with deferiprone. The expanding chelation repertoire should enable better control of iron burden and improved outcomes. [ABSTRACT FROM AUTHOR]

Background Vitamin C, as antioxidant, increases the efficacy of deferoxamine (DFO). Aim To investigate the effects of vitamin C as an adjuvant therapy to the three used iron chelators in moderately iron-overloaded young vitamin C-deficient patients with β-thalassemia major (β-TM) in relation to tissue iron overload. Methods This randomized prospective trial that included 180 β-TM vitamin C-deficient patients were equally divided into three groups ( n = 60) and received DFO, deferiprone (DFP), and deferasirox (DFX). Patients in each group were further randomized either to receive vitamin C supplementation (100 mg daily) or not ( n = 30). All patients received vitamin C (group A) or no vitamin C (group B) were followed up for 1 yr with assessment of transfusion index, hemoglobin, iron profile, liver iron concentration (LIC) and cardiac magnetic resonance imaging (MRI) T2*. Results Baseline vitamin C was negatively correlated with transfusion index, serum ferritin (SF), and LIC. After vitamin C therapy, transfusion index, serum iron, SF, transferrin saturation (Tsat), and LIC were significantly decreased in group A patients, while hemoglobin and cardiac MRI T2* were elevated compared with baseline levels or those in group B without vitamin C. The same improvement was found among DFO-treated patients post-vitamin C compared with baseline data. DFO-treated patients had the highest hemoglobin with the lowest iron, SF, and Tsat compared with DFP or DFX subgroups. Conclusions Vitamin C as an adjuvant therapy possibly potentiates the efficacy of DFO more than DFP and DFX in reducing iron burden in the moderately iron-overloaded vitamin C-deficient patients with β-TM, with no adverse events. [ABSTRACT FROM AUTHOR]

Objectives: Plasma markers in addition to serum ferritin (SF) may be useful for the assessment of iron overload; however, predictive utility may differ depending on underlying, transfusion-dependent, anemias. Methods: Data were collected before and after 1 year of deferasirox treatment (end of study; EOS) from the large, 1-year EPIC (Evaluation of Patients' Iron Chelation with Exjade®) study. Trends were evaluated between liver iron concentration (LIC), transferrin saturation (TfSat), predose labile plasma iron (LPI) and their relationship to SF categories in 1530 patients: thalassemia major (TM; n = 1114), myelodysplastic syndromes (MDS, n = 336), and sickle-cell disease (SCD, n = 80). Results: Baseline and EOS SF values showed a clear and similar relationship to LIC for all disease groups. TfSat also showed a relationship to SF, most clearly in patients with SCD, where TfSat was lowest in the lowest relative SF category. Unlike SF or LIC, TfSat did not decrease at EOS in any disease group. Baseline LPI was raised in TM and MDS, but not in patients with SCD, decreasing at EOS in both patient groups. After 1 year of chelation therapy, there was a significant trend for greater LPI reduction in patients with TM achieving LIC <7 mg Fe/g dw (P = 0.0137). Conclusions: Despite limitations, SF showed the clearest relationship, of the plasma markers evaluated, to LIC before and after 1 year of deferasirox in patients with TM, MDS, and SCD. In patients with TM, changes in LPI with chelation show a significant relationship to EOS LIC and may provide an additional indicator of chelation response (clinicaltrials.gov identifier: NCT00171821). [ABSTRACT FROM AUTHOR]

Aim Deferasirox is a new oral iron chelating agent with several cases reporting renal adverse events in recent years. Our aim was to identify the incidence of deferasirox-related Fanconi syndrome ( FS) and its risk factors. Methods All transfusion-dependent thalassaemic patients who received deferasirox at the outpatient department of the National Taiwan University Hospital ( NTUH) from January 2006 to February 2014 were evaluated. Results This cohort study included 57 patients, and mean age of deferasirox initiation was 18.2 ± 7.7 years. After 6.9 ± 1.8 years of follow-up, 5 in 57 (8.8%) thalassaemic patients had FS. Age of starting deferasirox negatively correlated with incidence of FS (correlation coefficient −0.892, P = 0.008). Other factors were not significantly associated with FS. Serum creatinine level at the start of deferasirox compared to at the end of study or onset of FS did not show significant change ( P = 0.277). All the deferasirox-related FS manifested with proximal renal tubular acidosis and hypophosphataemia, which needed specific treatment or withdrawal of deferasirox use. Conclusions We recommend that children, especially of young age, who regularly use deferasirox should undergo routine urinalysis and blood testing for early detection of FS. [ABSTRACT FROM AUTHOR]