scholarly journals Renal clearable nanochelators for iron overload therapy

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Homan Kang ◽  
Murui Han ◽  
Jie Xue ◽  
Yoonji Baek ◽  
JuOae Chang ◽  
...  
Keyword(s):  
Iron Overload ◽  
Intravenous Injection ◽  
Renal Excretion ◽  
Fold Increase ◽  
Iron Chelators ◽  
Efficacy And Safety ◽  
Adverse Side Effects ◽  
Pharmacokinetic Properties ◽  
Secondary Iron Overload ◽  
Iron Excretion

Abstract Iron chelators have been widely used to remove excess toxic iron from patients with secondary iron overload. However, small molecule-based iron chelators can cause adverse side effects such as infection, gastrointestinal bleeding, kidney failure, and liver fibrosis. Here we report renal clearable nanochelators for iron overload disorders. First, after a singledose intravenous injection, the nanochelator shows favorable pharmacokinetic properties, such as kidney-specific biodistribution and rapid renal excretion (>80% injected dose in 4 h), compared to native deferoxamine (DFO). Second, subcutaneous (SC) administration of nanochelators improves pharmacodynamics, as evidenced by a 7-fold increase in efficiency of urinary iron excretion compared to intravenous injection. Third, daily SC injections of the nanochelator for 5 days to iron overload mice and rats decrease iron levels in serum and liver. Furthermore, the nanochelator significantly reduces kidney damage caused by iron overload without demonstrating DFO’s own nephrotoxicity. This renal clearable nanochelator provides enhanced efficacy and safety.

Iron Chelation by Deferoxamine Induces Autophagy

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 117-117 ◽  
Author(s):  
Ivana De Domenico ◽  
Diane McVey Ward ◽  
James P. Kushner ◽  
Jerry Kaplan
Keyword(s):  
Molecular Weight ◽  
Iron Overload ◽  
Iron Chelation ◽  
Iron Chelators ◽  
Immunochemical Analysis ◽  
Alternate Route ◽  
High Affinity ◽  
Secondary Iron Overload ◽  
Proteosomal Degradation ◽  
Permeable Iron

Abstract Deferoxamine (DFO) is a high affinity Fe (III) chelator produced by Streptomyces pilosus that is used clinically to remove systemic iron in secondary iron overload disorders. DFO cannot be absorbed through the intestine and must be injected. As shown previously, De Domenico et al. EMBO J (2006), expression of Ferroportin (Fpn), the only mammalian iron exporter, can deplete cells of ferritin by lowering cytosolic iron and by exporting iron from cells. Fpn-mediated iron loss induces ferritin degradation by the proteosome. In this study we show that permeable iron chelators, desferirax or deferriprone also induce the proteosomal degradation of ferritin. In contrast, DFO-mediated iron chelation at clinically useful concentrations, leads to ferritin degradation in lysosomes. Immunochemical analysis revealed that DFO-treated cells show increased levels of LC3B, a protein required for autophagy, suggesting that DFO induces autophagy. Treatment of cells with desferasirox or deferriprone did not lead to accumulation of LC3B. Studies using high molecular weight conjugates of DFO or inhibitors of endocytosis showed that the presence of DFO in lysosomes was responsible for the induction of autophagy. Incubation of DFO-treated cells with 3-methyladenine, an autophagy inhibitor, does not, however, prevent ferritin loss suggesting there may be an alternate route for ferritin degradation. This hypothesis was confirmed by examining the effect of the proteosome inhibitor, MG132, on DFOinduced autophagy in cells treated with DFO and 3-methyladenine. Addition of MG132 to 3-methyladenine treated cells prevents ferritin degradation. These results indicate that ferritin degradation occurs by two routes: a DFO-induced entry of ferritin into lysosomes and a cytosolic route in which iron is extracted from ferritin prior to degradation by the proteosome.

Analysis of efficacy and safety of two iron chelators in type 1 Gaucher disease patients with iron overload

2013 ◽  
Vol 108 (2) ◽  
pp. S64-S65 ◽  
Author(s):  
Blanca Medrano-Engay ◽  
María Pilar Irún ◽  
Luis Sarría ◽  
Pilar Alfonso ◽  
Miguel Pocoví ◽  
...  
Keyword(s):  
Iron Overload ◽  
Gaucher Disease ◽  
Iron Chelators ◽  
Efficacy And Safety ◽  
Type 1 Gaucher Disease

Secondary Iron Overload

Hematology ◽  
2001 ◽  
Vol 2001 (1) ◽  
pp. 47-61 ◽  
Author(s):  
James P. Kushner ◽  
John P. Porter ◽  
Nancy F. Olivieri
Keyword(s):  
Iron Overload ◽  
Chelating Agents ◽  
Chelation Therapy ◽  
Optimal Timing ◽  
Transfusion Therapy ◽  
Pharmacokinetic Properties ◽  
Clinical Consequences ◽  
Secondary Iron Overload ◽  
Iron Chelating Agents

Abstract Transfusion therapy for inherited anemias and acquired refractory anemias both improves the quality of life and prolongs survival. A consequence of chronic transfusion therapy is secondary iron overload, which adversely affects the function of the heart, the liver and other organs. This session will review the use of iron chelating agents in the management of transfusion-induced secondary iron overload. In Section I Dr. John Porter describes techniques for the administration of deferoxamine that exploit the pharmacokinetic properties of the drug and minimize potential toxic side effects. The experience with chelation therapy in patients with thalassemia and sickle cell disease will be reviewed and guidelines will be suggested for chelation therapy of chronically transfused adults with refractory anemias. In Section II Dr. Nancy Olivieri examines the clinical consequences of transfusion-induced secondary iron overload and suggests criteria useful in determining the optimal timing of the initiation of chelation therapy. Finally, Dr. Olivieri discusses the clinical trials evaluating orally administered iron chelators.

P-182 Analysis of efficacy and safety of two iron chelators in patients with iron overload (QueLaFer study)

2013 ◽  
Vol 37 ◽  
pp. S105 ◽  
Author(s):  
B. Medrano Engay ◽  
M.P. Irún ◽  
L. Sarría ◽  
M. Andrade ◽  
I. Murillo ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Chelators ◽  
Efficacy And Safety

Role of vitamin C as an adjuvant therapy to different iron chelators in young β-thalassemia major patients: efficacy and safety in relation to tissue iron overload

2015 ◽  
Vol 96 (3) ◽  
pp. 318-326 ◽  
Author(s):  
Mohsen S. Elalfy ◽  
Maha M. Saber ◽  
Amira Abdel Moneam Adly ◽  
Eman A. Ismail ◽  
Mohamed Tarif ◽  
...  
Keyword(s):  
Adjuvant Therapy ◽  
Vitamin C ◽  
Iron Overload ◽  
Thalassemia Major ◽  
Iron Chelators ◽  
Efficacy And Safety ◽  
Tissue Iron

MRi T2*-mapping for liver iron assessment in pediatric patients with secondary iron overload

2017 ◽  
Vol 16 (3) ◽  
pp. 23-27 ◽  
Author(s):  
E.E. Nazarova ◽  
◽  
G.V. Tereshchenko ◽  
M.A. Abakumov ◽  
V.A. Smantser ◽  
...  
Keyword(s):  
Iron Overload ◽  
Pediatric Patients ◽  
T2 Mapping ◽  
Liver Iron ◽  
Secondary Iron Overload

Therapeutic Macromolecular Iron Chelators

2019 ◽  
Vol 26 (2) ◽  
pp. 323-334 ◽  
Author(s):  
Upendra Bulbake ◽  
Alka Singh ◽  
Abraham J. Domb ◽  
Wahid Khan
Keyword(s):  
Iron Overload ◽  
Chelation Therapy ◽  
Iron Chelator ◽  
Therapeutic Agents ◽  
Iron Chelators ◽  
Low Molecular Weight ◽  
Research Findings ◽  
Pharmaceutical Properties ◽  
Single Living ◽  
Living Process

Iron is a key element for every single living process. On a fundamental level, targeting iron is a valuable approach for the treatment of disorders caused by iron overload. Utilizing iron chelators as therapeutic agents has received expanding consideration in chelation therapy. Approved low molecular weight (MW) iron chelators to treat iron overload may experience short half-lives and toxicities prompting moderately high adverse effects. In recent years, polymeric/macromolecular iron chelators have received attention as therapeutic agents. Polymeric iron chelators show unique pharmaceutical properties that are different to their conventional small molecule counterparts. These polymeric iron chelators possess longer plasma half-lives and reduced toxicities, thus exhibiting a significant supplement to currently using low MW iron chelator therapy. In this review, we have briefly discussed polymeric iron chelators and factors to be considered when designing clinically valuable iron chelators. We have also discussed applications of polymeric iron chelators in the diseases caused by iron overload associated with transfusional hemosiderosis, neurodegenerative disorders, malaria and cancer. With this, research findings for new polymeric iron chelators are also covered.

scholarly journals Treatment of iron overload syndrome: a general review

2019 ◽  
Vol 65 (9) ◽  
pp. 1216-1222 ◽  
Author(s):  
Tadeu Gonçalves de Lima ◽  
Fernanda Luna Neri Benevides ◽  
Flávio Lima Esmeraldo Filho ◽  
Igor Silva Farias ◽  
Diovana Ximenes Cavalcante Dourado ◽  
...  
Keyword(s):  
Life Expectancy ◽  
Oxidative Damage ◽  
Iron Overload ◽  
Hereditary Hemochromatosis ◽  
Treatment Strategies ◽  
Iron Chelators ◽  
Pharmacological Targets ◽  
Pubmed Database ◽  
Toxic Drugs ◽  
Oral Chelators

SUMMARY INTRODUCTION Iron overload is a broad syndrome with a large spectrum of causative etiologies that lead to iron deposition. When iron exceeds defenses, it causes oxidative damage and tissular disfunction. Treatment may prevent organ dysfunction, leading to greater life expectancy. METHODS Literature from the last five years was reviewed through the use of the PubMed database in search of treatment strategies. DISCUSSION Different pharmacological and non-pharmacological strategies are available for the treatment of iron overload and must be used according to etiology and patient compliance. Therapeutic phlebotomy is the basis for the treatment of hereditary hemochromatosis. Transfusional overload patients and those who cannot tolerate phlebotomy need iron chelators. CONCLUSION Advances in the understanding of iron overload have lead to great advances in therapies and new pharmacological targets. Research has lead to better compliance with the use of oral chelators and less toxic drugs.

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