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An experimental investigation of a novel iron chelating protoporphyrin IX prodrug for the enhancement of photodynamic therapy.
Anayo, L, Magnussen, A, Perry, A, Wood, M, Curnow, A
Lasers in surgery and medicine. 2018;(5):552-565
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Abstract
OBJECTIVES Non-melanoma skin cancers are the most frequently occurring type of cancer worldwide. They can be effectively treated using topical dermatological photodynamic therapy (PDT) employing protoporphyrin IX (PpIX) as the active photosensitising agent as long as the disease remains superficial. Novel iron chelating agents are being investigated to enhance the effectiveness and extend the applications of this treatment modality, as limiting free iron increases the accumulation of PpIX available for light activation and thus cell kill. METHODS Human lung fibroblasts (MRC-5) and epithelial squamous carcinoma (A431) cells were treated with PpIX precursors (aminolaevulinic acid [ALA] or methyl-aminolevulinate [MAL]) with or without the separate hydroxypyridinone iron chelating agent (CP94) or alternatively, the new combined iron chelator and PpIX producing agent, AP2-18. PpIX fluorescence was monitored hourly for 6 hours prior to irradiation. PDT effectiveness was then assessed the following day using the lactate dehydrogenase and neutral red assays. RESULTS Generally, iron chelation achieved via CP94 or AP2-18 administration significantly increased PpIX fluorescence. ALA was more effective as a PpIX-prodrug than MAL in A431 cells, corresponding with the lower PpIX accumulation observed with the latter congener in this cell type. Addition of either iron chelating agent consistently increased PpIX accumulation but did not always convey an extra beneficial effect on PpIX-PDT cell kill when using the already highly effective higher dose of ALA. However, these adjuvants were highly beneficial in the skin cancer cells when compared with MAL administration alone. AP2-18 was also at least as effective as CP94 + ALA/MAL co-administration throughout and significantly better than CP94 supplementation at increasing PpIX fluorescence in MRC5 cells as well as at lower doses where PpIX accumulation was observed to be more limited. CONCLUSIONS PpIX fluorescence levels, as well as PDT cell kill effects on irradiation can be significantly increased by pyridinone iron chelation, either via the addition of CP94 to the administration of a PpIX precursor or alternatively via the newly synthesized combined PpIX prodrug and siderophore, AP2-18. The effect of the latter compound appears to be at least equivalent to, if not better than, the separate administration of its constituent parts, particularly when employing MAL to destroy skin cancer cells. AP2-18 therefore warrants further detailed analysis, as it may have the potential to improve dermatological PDT outcomes in applications currently requiring enhancement. Lasers Surg. Med. 50:552-565, 2018. © 2018 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.
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Reductive decolorization of azo dyes via in situ generation of green tea extract-iron chelate.
Yu, L, Qiu, Y, Yu, Y, Wang, S
Environmental science and pollution research international. 2018;(18):17300-17309
Abstract
In this study, rapid decolorization of azo dyes was achieved by in situ-generated green tea extract-iron (GTE-Fe) chelate for the first time. When changing reaction conditions from the aerobic condition to the anaerobic condition, the decolorization efficiencies of two azo dyes, i.e., acid orange 7 (AO7) and acid black 1 (AB1), increased from 46.38 and 83.17 to 90.13 and 95.37%, respectively. The recalcitrant AO7 was then selected as the targeting pollutant in subsequent optimization and mechanism studies. Experimental evidences showed that the initial concentrations of AO7, Fe(III), and GTE are the key factors to optimize the decolorization efficiency. Further characterization studies by spectroscopic analysis, including FESEM, FTIR, and XPS, suggested that the major mechanism of AO7 decolorization is the nucleophilic attack of the oxygen in green tea polyphenols (GTP), and this attack could be facilitated by the organometal chelation. This study provided an efficient and environmental friendly strategy to decolorize azo dyes via in situ generation of the GTE-Fe chelate, as well as its mechanistic insights, shedding lights on in situ remediation of azo dye pollution. Graphical abstract ᅟ.
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New targeted therapies and diagnostic methods for iron overload diseases.
Kolnagou, A, Kontoghiorghe, CN, Kontoghiorghes, GJ
Frontiers in bioscience (Scholar edition). 2018;(1):1-20
Abstract
Millions of people worldwide suffer from iron overload toxicity diseases such as transfusional iron overload in thalassaemia and hereditary haemochromatosis. The accumulation and presence of toxic focal iron deposits causing tissue damage can also be identified in Friedreich's ataxia, Alzheimer's, Parkinson's, renal and other diseases. Different diagnostic criteria of toxicity and therapeutic interventions apply to each disease of excess or misplaced iron. Magnetic resonance imaging relaxation times T2 and T2* for monitoring iron deposits in organs and iron biomarkers such as serum ferritin and transferrin iron saturation have contributed in the elucidation of iron toxicity mechanisms and pathways, and also the evaluation of the efficacy and mode of action of chelating drugs in the treatment of diseases related to iron overload, toxicity and metabolism. Similarly, histopathological and electron microscopy diagnostic methods have revealed mechanisms of iron overload toxicity at cellular and sub-cellular levels. These new diagnostic criteria and chelator dose adjustments could apply in different or special patient categories e.g. thalassaemia patients with normal iron stores, where iron deficiency and over-chelation toxicity should be avoided.
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Deferasirox for the treatment of iron overload after allogeneic hematopoietic cell transplantation: multicenter phase I study (KSGCT1302).
Tachibana, T, Kanda, J, Machida, S, Saito, T, Tanaka, M, Najima, Y, Koyama, S, Miyazaki, T, Yamamoto, E, Takeuchi, M, et al
International journal of hematology. 2018;(5):578-585
Abstract
UNLABELLED The aim of this study was to assess the safety and optimal dose of deferasirox for the treatment of iron overload after allogeneic hematopoietic cell transplantation (HCT). The primary endpoint was the maximum tolerated dose of deferasirox that was determined by the intrapatient dose escalation methods. A total of 16 patients with post-HCT iron overload were enrolled in the study. After excluding one case of early relapse, 15 remained evaluable. Their median age was 42 years (range 22-68). Median time from HCT to deferasirox administration was 9 months (range 6-84). Deferasirox was started at a dose of 5 mg/kg, and the dose was increased to 7.5 and 10 mg/kg every 4 weeks unless there were no grade ≥ 2 of adverse events. Achievement rates of planned medication were 80% in 5 mg/kg (12 of 15), 73% in 7.5 mg/kg (11 of 15), and 60% in 10 mg/kg (9 of 15), respectively. The reasons for discontinuation of the drug were grade 2 of adverse events (n = 4), late relapse (n = 1), and self-cessation (n = 1). None of the patients developed grade ≥ 3 of adverse events or exacerbation of GVHD. Among 11 evaluable cases, mean value of ferritin decreased from 1560 ng/ml pre-treatment to 1285 ng/ml post-treatment. These data suggested that 10 mg/kg of deferasirox may be maximum tolerated dose when given after HCT. Our dose escalating method of deferasirox is useful to identify the optimal dosage of the drug in each patient. TRIAL REGISTRATION UMIN000011251.
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Tolerability and efficacy of deferasirox in patients with transfusional iron overload: results from a German 2-year non-interventional study.
Nolte, F, Nückel, H, Schmidt, B, Geer, T, Rubanov, O, Hebart, H, Jarisch, A, Albrecht, S, Johr, C, Schumann, C, et al
Journal of cancer research and clinical oncology. 2018;(8):1531-1538
Abstract
BACKGROUND Iron overload (IOL) due to repetitive transfusions of packed red blood cells (pRBC) has a major impact on morbidity and mortality in patients with inherited bone marrow failure syndromes and hemoglobinopathies such as thalassemia and sickle cell disease. However, whether IOL influences the outcome of elderly patients with myeloid malignancies is not yet clear. Moreover, clinical trials have reported high drop-out rates during treatment with the oral iron chelator deferasirox (DFX). AIM: Here we report the results of a 2-year prospective observational study that aimed at describing the routine use of DFX in patients with hematological malignancies with regard to safety, efficacy and handling of the drug in a routine setting. RESULTS A total of 406 patients were included. 58% of the patients were male. Most of the patients had myelodysplastic syndromes (MDS) (68%) and myeloproliferative neoplasms (MPN) (14%). Median time from first transfusion to study enrollment was 1.1 years (0-25.5 years) and most patients were chelation naive (91%) at enrollment. With regard to transfusion burden, most of the patients were moderately or mildly transfusion-dependent with 53% receiving 2-4 and 27% receiving less than 2 units of pRBC per month. Serum ferritin decreased from a mean of 2305 μg/l (± 1449 μg/l) to a mean of 1910 μg/l (± 1529 μg/l) at 24 months. There was no substantial change in transfusion-dependence during the observation period. Dose adjustments were reported in 48% of the patients with dose-escalation strategies being the most frequent reason for dosage increases (49%). The median observation time was 355 days (5-1080 days). Median duration of exposure to DFX was 322 days (2-1078 days). Two-hundred and ninety (72%) patients discontinued the trial prematurely after a median time of 235 days (1-808 days). Death (29%) and adverse events (23%) were the main reasons for discontinuation. Eleven percent of the patients discontinued treatment due to sufficient decrease in serum ferritin. Most frequent adverse events were decrease in creatinine clearance (22%), increase in serum creatinine (18%) and diarrhea (16%). CONCLUSION This descriptive trial confirms the efficacy of DFX in decreasing the serum ferritin. Moreover, the high drop-out rates seen in prospective trials are recapitulated in this study, which can be attributed to adverse events in a substantial proportion of patients.
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Patient-reported outcomes from a randomized phase II study of the deferasirox film-coated tablet in patients with transfusion-dependent anemias.
Taher, AT, Origa, R, Perrotta, S, Kouraklis, A, Ruffo, GB, Kattamis, A, Goh, AS, Huang, V, Zia, A, Herranz, RM, et al
Health and quality of life outcomes. 2018;(1):216
Abstract
BACKGROUND Adherence to long-term chelation therapy in transfusion-dependent patients is critical to prevent iron overload-related complications. Once-daily deferasirox dispersible tablets (DT) have proven long-term efficacy and safety in patients ≥2 years old with chronic transfusional iron overload. However, barriers to optimal adherence remain, including palatability, preparation time, and requirements for fasting state. A new film-coated tablet (FCT) formulation was developed, swallowed once daily (whole/crushed) with/without a light meal. METHODS The open-label, Phase II ECLIPSE study evaluated patient-reported outcomes (PROs) in transfusion-dependent thalassemia or lower-risk myelodysplastic syndromes patients randomized 1:1 to receive deferasirox DT or FCT over 24 weeks as a secondary outcome of the study. Three PRO questionnaires were developed to evaluate both deferasirox formulations: 1) Modified Satisfaction with Iron Chelation Therapy Questionnaire; 2) Palatability Questionnaire; 3) Gastrointestinal (GI) Symptom Diary. RESULTS One hundred seventy three patients were enrolled; 87 received the FCT and 86 the DT formulation. FCT recipients consistently reported better adherence (easier to take medication, less bothered by time to prepare medication and waiting time before eating), greater satisfaction/preference (general satisfaction and with administration of medicine), and fewer concerns (less worry about not swallowing enough medication, fewer limitations in daily activities, less concern about side effects). FCT recipients reported no taste or aftertaste and could swallow all their medicine with an acceptable amount of liquid. GI summary scores were low for both formulations. CONCLUSIONS These findings suggest a preference in favor of the deferasirox FCT formulation regardless of underlying disease or age group. Better patient satisfaction and adherence to chelation therapy may reduce iron overload-related complications. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02125877; registered April 26, 2014.
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Interaction of Transfusion and Iron Chelation in Thalassemias.
Porter, JB, Garbowski, MW
Hematology/oncology clinics of North America. 2018;(2):247-259
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Abstract
The relationship between blood transfusion intensity, chelatable iron pools, and extrahepatic iron distribution is described in thalassemia. Risk factors for cardiosiderosis are discussed with particular reference to the balance of transfusional iron loading rate and transferrin-iron utilization rate as marked by plasma levels of soluble transferrin receptors. Low transfusion regimens increase residual erythropoiesis allowing for apotransferrin-dependent clearance of non-transferrin-bound iron species otherwise destined for myocardium. The impact of transfusion rates on chelation dosing required for iron balance is also shown.
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Iron overload cardiomyopathy: from diagnosis to management.
Díez-López, C, Comín-Colet, J, González-Costello, J
Current opinion in cardiology. 2018;(3):334-340
Abstract
PURPOSE OF REVIEW Iron overload cardiomyopathy (IOC) is an important predictor of prognosis in a significant number of patients with hereditary hemochromatosis and hematologic diseases. Its prevalence is increasing because of improved treatment strategies, which significantly improve life expectancy. We will review diagnosis, treatment, and recent findings in the field. RECENT FINDINGS The development of preclinical translational disease models during the last years have helped our understanding of specific disease pathophysiological pathways that might eventually change the outcomes of these patients. SUMMARY IOC is an overlooked disease because of the progressive silent disease pattern and the lack of physicians' expertise. It mainly affects patients with hemochromatosis and hematologic diseases and its prevalence is expected to increase with the improvement in life expectancy of hematologic disorders. Early diagnosis of IOC in patients at risk by means of biochemical parameters and cardiac imaging can lead to early treatment and improved prognosis. The mainstay of treatment of IOC is conventional heart failure treatment, combined with phlebotomies or iron chelation in the context of anemia. The development of preclinical models has provided a comprehensive look into specific pathophysiological pathways with potential treatment strategies that must be sustained by future randomized trials.
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Iron Chelation Therapy as a Modality of Management.
Aydinok, Y
Hematology/oncology clinics of North America. 2018;(2):261-275
Abstract
Introduction of MRI techniques for identifying and monitoring tissue iron overload and the current understanding of iron homeostasis in transfusion-dependent (TDT) and non-transfusion-dependent thalassemia have allowed for a more robust administration of iron chelation therapies. The development of safe and efficient oral iron chelators and the insights gained from large-scale prospective studies using these agents have improved iron overload management. A significant reduction in iron toxicity-induced morbidity and mortality and improvements in quality of life were observed in TDT. The appropriate management of tissue-specific iron loading in TDT has been portrayed using evidence-based data obtained from investigational studies.
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The effect of desferrioxamine chelation versus no therapy in patients with non transfusion-dependent thalassaemia: a multicenter prospective comparison from the MIOT network.
Ricchi, P, Meloni, A, Pistoia, L, Spasiano, A, Spiga, A, Allò, M, Gamberini, MR, Lisi, R, Campisi, S, Peluso, A, et al
Annals of hematology. 2018;(10):1925-1932
Abstract
We prospectively assessed by magnetic resonance imaging (MRI) the advantages of desferrioxamine (DFO) with respect to the absence of chelation therapy in non transfusion-dependent thalassaemia (NTDT) patients. We considered 18 patients non-chelated and 33 patients who received DFO alone between the two MRI scans. Iron overload was assessed by the T2* technique. Biventricular function parameters were quantified by cine sequences. No patient treated with DFO had cardiac iron. At baseline, only one non-chelated patient showed a pathological heart T2* value (< 20 ms) and he recovered at the follow-up. The percentage of patients who maintained a normal heart T2* value was 100% in both groups. A significant increase in the right ventricular ejection fraction was detected in DFO patients (3.48 ± 7.22%; P = 0.024). The changes in cardiac T2* values and in the biventricular function were comparable between the two groups. In patients with hepatic iron at baseline (MRI liver iron concentration (LIC) ≥ 3 mg/g/dw), the reduction in MRI LIC values was significant only in the DFO group (- 2.20 ± 4.84 mg/g/dw; P = 0.050). The decrease in MRI LIC was comparable between the groups. In conclusion, in NTDT patients, DFO therapy showed no advantage in terms of cardiac iron but its administration allowed an improvement in right ventricular function. Moreover, DFO reduced hepatic iron in patients with significant iron burden at baseline.