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International Journal of Molecular... Jul 2022Iron is a crucial element for mammalian cells, considering its intervention in several physiologic processes. Its homeostasis is finely regulated, and its alteration... (Review)
Review
Iron is a crucial element for mammalian cells, considering its intervention in several physiologic processes. Its homeostasis is finely regulated, and its alteration could be responsible for the onset of several disorders. Iron is closely related to inflammation; indeed, during inflammation high levels of interleukin-6 cause an increased production of hepcidin which induces a degradation of ferroportin. Ferroportin degradation leads to decreased iron efflux that culminates in elevated intracellular iron concentration and consequently iron toxicity in cells and tissues. Therefore, iron chelation could be considered a novel and useful therapeutic strategy in order to counteract the inflammation in several autoimmune and inflammatory diseases. Several iron chelators are already known to have anti-inflammatory effects, among them deferiprone, deferoxamine, deferasirox, and Dp44mT are noteworthy. Recently, eltrombopag has been reported to have an important role in reducing inflammation, acting both directly by chelating iron, and indirectly by modulating iron efflux. This review offers an overview of the possible novel biological effects of the iron chelators in inflammation, suggesting them as novel anti-inflammatory molecules.
Topics: Animals; Benzoates; Deferasirox; Deferiprone; Deferoxamine; Inflammation; Iron; Iron Chelating Agents; Iron Overload; Mammals; Pyridones
PubMed: 35887336
DOI: 10.3390/ijms23147977 -
Journal of Biochemical and Molecular... Sep 2023During the period of COVID-19, the occurrences of mucormycosis in immunocompromised patients have increased significantly. Mucormycosis (black fungus) is a rare and... (Review)
Review
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.
Topics: Humans; Antifungal Agents; Mucormycosis; COVID-19; Amphotericin B; Mucorales
PubMed: 37345721
DOI: 10.1002/jbt.23417 -
British Journal of Haematology Oct 2019
Topics: Bone Marrow Cells; DNA Damage; Deferasirox; Hematopoiesis; Humans; Iron; Iron Chelating Agents; Iron Overload; Oxidative Stress
PubMed: 31172507
DOI: 10.1111/bjh.16012 -
Cureus Nov 2023Despite the established efficacy of iron chelation therapy in transfusion-induced iron-overloaded patients, there is no universal agreement regarding the choice of an... (Review)
Review
Despite the established efficacy of iron chelation therapy in transfusion-induced iron-overloaded patients, there is no universal agreement regarding the choice of an optimal chelating regimen. Deferasirox (DFX) and deferiprone (DFP) are two oral iron chelators, and combination usage demonstrated effectiveness as an alternative to monotherapies in patients with a limited response to monotherapy. The present systematic review aimed to assess the evidence regarding the outcomes of combined DFP and DFX in iron-overloaded patients. An online search was conducted in PubMed, Scopus, Web of Science, and CENTRAL databases. Interventional and observational studies that assessed the outcomes of combined DFP and DFX in iron-overloaded patients were included. Eleven studies (12 reports) were considered in this meta-analysis. The studies included dual iron chelation strategies for a number of diagnoses. Single-arm studies (n =7) showed a reduction of serum ferritin, which reached the level of statistical significance in three studies. Likewise, most studies reported a numerical reduction in liver iron concentration (LIC) and increased cardiac MRI-T2* values after chelating therapy. Alternatively, comparative studies showed no significant difference in post-treatment serum ferritin between DFX plus DFP and DFX/DFP plus deferoxamine (DFO). The adherence to combination therapy was good to average in nearly 66.7-100% of the patients across four studies. One study reported a poor adherence rate. The combined regimen was generally tolerable, with no reported incidence of serious adverse events among the included studies. In conclusion, the DFP and DFX combination is a safe and feasible option for iron overload patients with a limited response to monotherapy.
PubMed: 38058350
DOI: 10.7759/cureus.48276 -
Vox Sanguinis Aug 2021Deferasirox is an oral chelator approved for iron overload, which has a potential side effect of renal Fanconi syndrome, with proximal tubular dysfunction and tubular... (Review)
Review
BACKGROUND AND OBJECTIVES
Deferasirox is an oral chelator approved for iron overload, which has a potential side effect of renal Fanconi syndrome, with proximal tubular dysfunction and tubular acidosis. Monitoring of renal function is recommended, though no standard for monitoring exists. We aim to describe cases of deferasirox-associated Fanconi syndrome in adults and the renal monitoring required to detect these findings.
MATERIALS AND METHODS
We present a review of the literature and six cases from our institution of deferasirox-associated partial Fanconi syndrome in adult patients with transfusional iron overload secondary to β-thalassemia or Diamond Blackfan Anaemia.
RESULTS
While prior cases in the literature occurred at high doses of deferasirox, our series included patients on doses as low as deferasirox 10 mg/kg who had been aggressively chelated. All patients had resolution of laboratory abnormalities with drug interruption.
CONCLUSION
Rather than chelating to normal iron levels, this series supports prior suggestions that deferasirox dose be reduced if ferritin <500-1000 ng/ml, and also supports dose reduction if liver iron content <3 mg iron per g dry weight or for those undergoing aggressive chelation with rapid decrease in iron. Monitoring with metabolic panel and urinalysis were sufficient to detect clinically significant proximal tubular dysfunction, but should be followed up with additional studies to confirm the diagnosis while deferasirox dose is decreased or held.
Topics: Adult; Benzoates; Deferasirox; Fanconi Syndrome; Humans; Iron Chelating Agents; Iron Overload; Triazoles
PubMed: 33529394
DOI: 10.1111/vox.13064 -
Mycoses Sep 2019Mucormycosis mostly affects immunocompromised patients and is associated with a high morbidity and mortality despite currently available treatments. In that context,... (Review)
Review
Mucormycosis mostly affects immunocompromised patients and is associated with a high morbidity and mortality despite currently available treatments. In that context, combination therapy might be the key to a better outcome for these patients. Purpose of this review is to summarise and to discuss the current combination data obtained in vitro, in vivo in animal models of mucormycosis, and in patients. In vitro combination studies showed that most of the interactions between antifungal drugs were indifferent, even though that some synergistic interactions were achieved for the combination of echinocandins with either azoles or amphotericin B. Importantly, antagonism was never observed. Animal models of mucormycosis focused on infections caused by Rhizopus arrhizus, neglecting most other species responsible for human disease. In these experimental animal models, no strong interactions have been demonstrated, although a certain degree of synergism has been reported in some instances. Combinations of antifungals with non-antifungal drugs have also been largely explored in vitro and in animal models and yielded interesting results. In patients with ketoacidosis and rhino-orbito-cerebral infection, combination of polyene with caspofungin was effective. In contrast, despite promising experimental data, adjunctive therapy with the iron chelator deferasirox was unfavourable and was associated with a higher mortality than monotherapy with liposomal amphotericin B. More combinations have to be tested in vitro and a much larger panel of Mucorales species has to be tested in vivo to give a valuable statement if antifungal combination therapy could be an effective treatment strategy in patients with mucormycosis.
Topics: Amphotericin B; Animals; Antifungal Agents; Azoles; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Humans; Immunocompromised Host; Lipopeptides; Mice; Microbial Sensitivity Tests; Mucorales; Mucormycosis
PubMed: 30830980
DOI: 10.1111/myc.12909 -
Frontiers in Bioengineering and... 2022Iron as an essential element, is involved in various cellular functions and maintaining cell viability, cancer cell is more dependent on iron than normal cell due to its...
Iron as an essential element, is involved in various cellular functions and maintaining cell viability, cancer cell is more dependent on iron than normal cell due to its chief characteristic of hyper-proliferation. Despite that some of the iron chelators exhibited potent and broad antitumor activity, severe systemic toxicities have limited their clinical application. Polyaminoacids, as both drug-delivery platform and therapeutic agents, have attracted great interests owing to their different medical applications and biocompatibility. Herein, we have developed a novel iron nanochelator PL-DFX, which composed of deferasirox and hyperbranched polylysine. PL-DFX has higher cytotoxicity than DFX and this effect can be partially reversed by Fe supplementation. PL-DFX also inhibited migration and invasion of cancer cells, interfere with iron metabolism, induce phase G1/S arrest and depolarize mitochondria membrane potential. Additionally, the anti-tumor potency of PL-DFX was also supported by organoids derived from clinical specimens. In this study, DFX-based iron nanochelator has provided a promising and prospective strategy for cancer therapy iron metabolism disruption.
PubMed: 36518196
DOI: 10.3389/fbioe.2022.1078137 -
Saudi Journal of Biological Sciences Apr 2022Ferritin, which includes twenty-four light and heavy chains in varying proportions in different tissues, is primarily responsible for maintaining the body's iron... (Review)
Review
Ferritin, which includes twenty-four light and heavy chains in varying proportions in different tissues, is primarily responsible for maintaining the body's iron metabolism. Its normal value is between 10 and 200 ngmL in men and between 30 and 300 ngmL in women. Iron is delivered to the tissue via them, and they act as immunomodulators, signaling molecules, and inflammatory markers. When ferritin level exceeds 1000 µgL, the patient is categorized as having hyperferritinemia. Iron chelators such as deferiprone, deferirox, and deferoxamine are currently FDA approved to treat iron overload. The inflammation cascade and poor prognosis of COVID-19 may be attributed to high ferritin levels. Critically ill patients can benefit from deferasirox, an iron chelator administered orally at 20-40 mgkg once daily, as well as intravenous deferoxamine at 1000 mg initially followed by 500 mg every 4 to 12 h. It can be combined with monoclonal antibodies, antioxidants, corticosteroids, and lactoferrin to make iron chelation therapy effective for COVID-19 victims. In this article, we analyze the antiviral and antifibrotic activity of iron chelators, thereby promoting iron depletion therapy as a potentially innovative treatment strategy for COVID-19.
PubMed: 34924800
DOI: 10.1016/j.sjbs.2021.11.061 -
Life Sciences Apr 2021Deferasirox (DFX) was formulated into oil-in-water microemulsions in the presence of pluronicto improve its oral bioavailability. The size of the...
Deferasirox (DFX) was formulated into oil-in-water microemulsions in the presence of pluronicto improve its oral bioavailability. The size of the DFX-loadedmicroemulsions system measured by dynamic light scattering (DLS) was about 9 nm. The anti-proliferative and anti-lipid peroxidation effects of DFX and DFX-loaded microemulsions were assessed on Human umbilical vein endothelial (HUVEC) cells. Our in vitro results showed that HUVEC cells are more susceptible to free DFX as compared to DFX-loaded microemulsions. Although both free and encapsulated DFX attenuated FeCl-induced lipid peroxidation, after 6 and 12 h treatment, DFX-loaded microemulsions did not appear a better ameliorator than DFX. To compare the in vivo efficacy of free DFX and DFX-loaded microemulsions in iron- intoxicated rats, the animals were orally administered with 25 mg/kg DFX, or 25 mg/kg DFX microemulsions, respectively. In vivo gavage handling of free DFX significantly increased serum biochemical parameters. There was also a significant increase in lipid peroxidation in rats who received free DFX compared to those in the control rats. Treatment with DFX-loaded microemulsions restored the elevated levels of serum AST, ALT, and creatinine levels and also reduced liver MDA content. Histopathological analysis of renal and hepatic tissues was in line with the biochemical results. In conclusion, DFX-loaded microemulsions induce less toxicity than free DFX and appear a more desirable and safer drug carrier in combating the iron-overload complications. Theoretical simulations are performed to get better insight regarding interactions between DFX and surfactant F127.
Topics: Animals; Deferasirox; Drug Delivery Systems; Emulsions; Human Umbilical Vein Endothelial Cells; Humans; Iron; Iron Chelating Agents; Iron Overload; Lipid Peroxidation; Liver; Male; Micelles; Rats; Rats, Wistar
PubMed: 33545199
DOI: 10.1016/j.lfs.2021.119146 -
BMJ Open Feb 2024Despite the improvement in medical management, many patients with transfusion-dependent β-thalassaemia die prematurely due to transfusion-related iron overload. As per...
Efficacy and safety of deferoxamine, deferasirox and deferiprone triple iron chelator combination therapy for transfusion-dependent β-thalassaemia with very high iron overload: a protocol for randomised controlled clinical trial.
INTRODUCTION
Despite the improvement in medical management, many patients with transfusion-dependent β-thalassaemia die prematurely due to transfusion-related iron overload. As per the current guidelines, the optimal chelation of iron cannot be achieved in many patients, even with two iron chelators at their maximum therapeutic doses. Here, we evaluate the efficacy and safety of triple combination treatment with deferoxamine, deferasirox and deferiprone over dual combination of deferoxamine and deferasirox on iron chelation in patients with transfusion-dependent β-thalassaemia with very high iron overload.
METHODS AND ANALYSIS
This is a single-centre, open-label, randomised, controlled clinical trial conducted at the Adult and Adolescent Thalassaemia Centre of Colombo North Teaching Hospital, Ragama, Sri Lanka. Patients with haematologically and genetically confirmed transfusion-dependent β-thalassaemia are enrolled and randomised into intervention or control groups. The intervention arm will receive a combination of oral deferasirox, oral deferiprone and subcutaneous deferoxamine for 6 months. The control arm will receive the combination of oral deferasirox and subcutaneous deferoxamine for 6 months. Reduction in iron overload, as measured by a reduction in the serum ferritin after completion of the treatment, will be the primary outcome measure. Reduction in liver and cardiac iron content as measured by T2* MRI and the side effect profile of trial medications are the secondary outcome measures.
ETHICS AND DISSEMINATION
Ethical approval for the study has been obtained from the Ethics Committee of the Faculty of Medicine, University of Kelaniya (Ref. P/06/02/2023). The trial results will be disseminated in scientific publications in reputed journals.
TRIAL REGISTRATION NUMBER
The trial is registered in the Sri Lanka Clinical Trials Registry (Ref: SLCTR/2023/010).
Topics: Adult; Adolescent; Humans; Deferasirox; Deferiprone; Deferoxamine; beta-Thalassemia; Benzoates; Triazoles; Pyridones; Iron Overload; Iron Chelating Agents; Iron; Randomized Controlled Trials as Topic
PubMed: 38331857
DOI: 10.1136/bmjopen-2023-077342