Effect Of Iron Chelating Agents Research Articles

Long-Term Effects of Iron Chelating Agents on Ocular Function in Patients with Thalassemia Major.

BackgroundThe aim of this study is to evaluate eye structures and function in patients receiving iron chelating therapy and to assess whether a correlation exists between the onset of ocular alterations and the intake of iron chelating drugs.MethodsA prospective cohort study was performed. Eighty-eight patients, composed of children and adults with thalassemia major (TM) who are taking or had taken iron chelating drugs (deferoxamine, deferiprone or deferasirox), have been initially enrolled in the study. The final sample featured 80 patients, including 18 children and 62 adults. These subjects received an eye examination to evaluate intraocular pressure (IOP), best corrected visual acuity (BCVA), the presence of refractive defects, cornea, anterior chamber, lens, fundus oculi, visual field and mean retinal nerve fiber layer (RNFL) thickness. Logistic regression model analysis was performed in order to assess any correlation. In addition, a literature search regarding the relation between iron chelating drugs and ocular adverse events was carried out to compare the results obtained with the evidence in the literature.ResultsLogistic regression did not report a significant correlation between the intake of iron chelating drugs and the onset of anterior ocular segment alterations, lens opacities, retinal diseases, optical neuropathies, astigmatism, visual field and RNFL thickness defects. Logistic regression returned a statistically significant correlation between myopia and iron chelation therapy (p-value 0.04; OR 1.05) and also between presbyopia and total duration of therapy with deferoxamine (p-value 0.03; OR 1.21). Although intraocular pressure levels remained within the normal range, a significant correlation with the length of deferoxamine therapy has been found (p-value 0.002; association coefficient −0.12). A negative correlation between deferiprone and presbyopia has also been observed.ConclusionIron chelation therapy is not associated with severe visual function alterations. Limitation of deferoxamine treatment can help prevent ocular complications. Deferiprone and/or deferasirox may be preferable, especially in patients over age 40 years.

Mathematical calculations of iron complex stoichiometry by direct UV–Vis spectrophotometry

The effects of iron-chelating agents on miscellaneous pathologies are currently largely tested. Due to various indications, different properties for chelators are required. A stoichiometry of the complex in relation to pH is one of the crucial factors. Moreover, the published data on the stoichiometry, especially concerning flavonoids, are equivocal.In this study, a new complementary approach was employed for the determination of stoichiometry in 10 iron-chelating agents, including clinically used drugs, by UV–Vis spectrophotometry at relevant pH conditions and compared with the standard Job’s method.This study showed that the simple approach based on absorbance at the wavelength of complex absorption maximum was sufficient when the difference between absorption maximum of substance and complex was high. However, in majority of substances this difference was much lower (9–73nm). The novel complementary approach was able to determine the stoichiometry in all tested cases. The major benefit of this method compared to the standard Job’s approach seems to be its capability to reveal a reaction stoichiometry in chelators with moderate affinity to iron.In conclusion, using this complementary method may explain several previous contradictory data and lead to a better understanding of the underlying mechanisms of chelator’s action.

Erratum to: The effect of iron-chelating agents on Magnetospirillum magneticum strain AMB-1: stimulated growth and magnetosome production and improved magnetosome heating properties

Erratum to: The effect of iron-chelating agents on Magnetospirillum magneticum strain AMB-1: stimulated growth and magnetosome production and improved magnetosome heating properties

Deferasirox shows in vitro and in vivo antileukemic effects on murine leukemic cell lines regardless of iron status

Numerous studies have shown the antiproliferative effect of iron chelating agents (ICAs), which have been used traditionally in patients with secondary iron overload (SIO). Because the invivo model for these studies has been animals with normal iron status, the antileukemic effect of ICAs in the SIO condition has not been determined clearly. We investigated the invitro and invivo effects of ICAs in murine leukemic cell lines regarding the iron status. The viability of both EL4 cells and L1210 cells incubated with either deferoxamine (DFO) or deferasirox (DFX) decreased in a concentration-dependent manner. This effect was most prominent in L1210 cells treated with DFX. The viability of L1210 cells incubated with both ICAs did not change regardless of the presence of ferric chloride. The percentage of apoptosis in L1210 cells treated with DFO or DFX increased in a concentration-dependent manner; however, the expression of Fas showed no significant change. The non-SIO mice and SIO mice bearing L1210 cells showed longer survival than other groups when treated with DFX, whereas the SIO mice treated with DFO showed shorter survival than the control group. The tumor was significantly smaller in the SIO mice treated with DFX or DFO compared with the control group. The iron content of the liver or the tumor in SIO mice decreased after ICA treatment. This study indicates an antileukemic effect of DFX regardless of iron status and suggests that the use of DFX has a survival benefit for SIO leukemia murine model in terms of iron chelation and antileukemic therapy.

Iron Overload in Patients with Hematological Disorders Undergoing Allogeneic HSCT: Unrevealed Implication in Different Outcomes

AbstractAbstract 4527The main objective of this study was to determine the impact of serum ferritin level on the different allogeneic HSCT outcomes in adult patients with hematological disorders in addition to other disease and patient variables. We evaluated the implication of iron overload in the HSCT mortality causes and the potential role of iron chelation. We included 158 patients, 100 males and 58 females with a median age of 45 years (18–67) who underwent allo-HSCT between 2002 and 2010. There were 83 AML, 10 CML (3CP, 2AP, 5BC), 11 MDS (10 acute phase; 1 CMML), 7 myeloproliferative disorders, 19 MM, 9 NHL, 6 HDG, 5 aplastic anemia and 3 hemoglobinopathies. Sixty-seven (42%) patients were sex mismatched (F→M:37; M→F:30); for ABO compatibility, 61% were compatible, 18% had minor incompatibility and 21% had major incompatibility. For CMV status, 36% were sero-negative, 15% were D+R-, 18% were D-R+ and 31% were D+R+. Concerning the HSCT procedures, 60 patients (38%) received PBSC and 98 (62%) received BM from 97 (61%) HLA related donors [matched, n=76; mismatched, n=21], and 61 (39%) HLA unrelated donors [matched, n=36; mismatched, n=25] after MAC [n=64, (41%)] or RIC [n=94, (59%)]. At transplantation, 91 (58%) were in CR or CP [CR1: n=61 (67%); ≥CR2: n=30 (33%)] and the rest of patients were in less that CR or CP [n=67 (42%)]. The median serum ferritin level at HSCT was 1327 microg./l (26–14136); 31(20%) patients had a level 26–500, 33 (21%) had a level 500–2500, and 94 (59%) >2500. There were no significant correlation between the different ferritin levels, disease kind and status at HSCT. Twenty two patients received iron chelating agents (Exjade, n=19; Desferal, n=3). After allo-HSCT, the cumulative incidence of acute GVHD ≥ II at 3 months was 14% (11–16.5) with 10.5% (8–13) for grade III and 7% (5–9) for grade IV; the 1 year cumulative incidence of limited and extensive chronic GVHD were 4% (2–6) and 12.4% (9–16) respectively. After a median follow-up of 18 months (1–106), the median OS was 25 months (16-NR) with a 2 years probability of 50% (43–59). The median PFS was 13.5 months (9–25) with a 2 years probability of 43% (34–50). The cumulative incidence of relapse at 1 year was 31% (27–34), the TRM rate was 6.5% (4.5–8.5) and 20% (17–23.5) at 3 months and 1 year respectively. We performed a multivariate analysis taking into account the patient age, gender, diagnosis, disease status a allo-HSCT, matching variables (sex, ABO, HLA, CMV), conditioning/HSC source and the different serum ferritin levels; the different results are shown in table1. Interestingly, we found that ferritin level >500 has a significant impact on OS which is explained by a significant higher TRM for patients with level >2500 and a significant mortality after relapse in patients with level 500–2500 (figure).The analysis on effect of iron chelating agents is ongoing and results will be communicated later.Serum ferritin level has been previously shown to impact on allo-HSCT survival without a clear explanation of its implication and at which level; in our study, we demonstrated that this survival difference is caused in part by higher TRM and the other part by mortality after relapse.In conclusion, we should give a better attention to iron overload, confer an efficient follow-up of this parameter and provide a treatment strategy after allo-HSCT especially when its level reaches 500μg/l at transplantation. [Display omitted] Disclosures:Nicolini:Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

The effect of iron-chelating agents on Magnetospirillum magneticum strain AMB-1: stimulated growth and magnetosome production and improved magnetosome heating properties

The introduction of various iron-chelating agents to the Magnetospirillum magneticum strain AMB-1 bacterial growth medium stimulated the growth of M. magneticum strain AMB-1 magnetotactic bacteria and enhanced the production of magnetosomes. After 7days of growth, the number of bacteria and the production of magnetosomes were increased in the presence of iron-chelating agents by factors of up to ∼2 and ∼6, respectively. The presence of iron-chelating agents also produced an increase in magnetosome size and chain length and yielded improved magnetosome heating properties. The specific absorption rate of suspensions of magnetosome chains isolated from M. magneticum strain AMB-1 magnetotactic bacteria, measured under the application of an alternating magnetic field of average field strength ∼20mT and frequency 198kHz, increased from ∼222W/g(Fe) in the absence of iron-chelating agent up to ∼444W/g(Fe) in the presence of 4μM rhodamine B and to ∼723W/g(Fe) in the presence of 4μM EDTA. These observations were made at an iron concentration of 20μM and iron-chelating agent concentrations below 40μM.

A possible mechanism for initiation of lipid peroxidation by ascorbate in rat liver microsomes

The mechanism by which lipid peroxidation progresses has been known for years, but there is disagreement regarding the mode of its initiation. The aim of this study was to examine: (a) the role of endogenous iron in the initiation of ascorbate-induced lied peroxidation in microsomal and liposomal membranes; (b) the role of oxygen-free radicals in this process; and (c) the redox state of ascorbate during the course of lipid peroxidation. Asrorbate-induced lipid peroxidation was assessed by measuring hydroperoxide and thiobarbituric add reactive substances (MARS) formation in membranes after incubation in Tris-HO buffer (pH 7.4) for 15 min. To confirm the role of endogenous iron and oxygen-free radicals, the effect of iron chelating agents (EDTA and thiourea) and radical scavengers (benzoate, mannitol, catalase and SOD) on lipid peroxidation was examined. Spectrophotometric measurements and ESR spectra have made it possible to determine ascorbate concentration and its redox state. Ascorbate promoted lipid peroxidation in both rat liver micrsuomes and üposomes without addition of exogenous iron. Iron chelating agents such as EDTA and thiourea inhibited lipM peroxidation, while SOD, catalase, mannitol and benzoate had no effect. The addition of 5 μM Fe 2+ (or Fe 3+) to the incubation mixture did not significantly alter hydroperoxide production, but that of TBARS was increased. Lipid peroxidation significantly altered the fatty add profile in microsomes and liposomas, the. most affected being the C 20:4 and C 22:6 species. Ascorbate in Tris-HCI buffer (pH 7.4) autoxidized very slowly. Its oxidation was catalyzed by Fe 3+ ions at a rate determined by incubation time and iron concentration. In contrast, no ascorbate oxidation occurred in the presence of microsomes when lipid peroxidation was proceeding at a maximal rate. Under these conditions a typical ascorbyl radical ESR spectrum signal greater than that arising from ascorbate alone was obtained and the magnitude of this signal was unchanged by variations of microsome or ascorbate concentrations. A ferrous ion-ascorbyl radical complex was responsible for this signal. These results suggest that an asenrbate-microsomal iron complex is responsible for the initiation of lipid peroxidation, and that during this process ascorbate remains in its reduced form.

Studies on the differential mechanisms of inhibition of ribonucleotide reductase by specific inhibitors of the non-heme iron subunit

The data presented here show that while the non-heme iron subunit of ribonucleotide reductase is inhibited by IMPY, hydroxyurea and MAIQ, the mechanism of inhibition by hydroxyurea and IMPY is distinct from that for MAIQ. This difference in mechanisms is expressed not only in effects of iron-chelating agents on enzyme activity and of L1210 cell growth in culture, but also in differences in responses to catalase and peroxidase. Further, these data suggest that the inhibition of reductase activity by IMPY and IMPY/iron-chelator occurs through different pathways. The same conclusion can be drawn for the inhibition of reductase by hydroxyurea and hydroxyurea/iron-chelator. It is clear that additional studies will be required to understand the exact mechanism by which hydroxyurea or IMPY and the thiosemicarbazones inhibit the non-heme iron component of ribonucleotide reductase. It will also be necessary to better define the pathways of inhibition of reductase activity by IMPY and the IMPY/iron-chelator combination (or hydroxyurea and hydroxyurea/iron-chelator combination). From these studies may come information which will allow these antitumor agents to have greater utilization in the clinical management of neoplastic diseases.

Effect of iron-chelating agents on inhibitors of ribonucleotide reductase

Ribonucleotide reductase from Ehrlich tumor cells is inhibited by hydroxyurea (HU), guanazole (GZ), pyrazolo-imidazole (IMPY), 1-formylisoquinoline thiosemicarbazone (IQ), 4-methyl-5-aminoisoquinoline thiosemicarbazone (MAIQ). and the dialdehydes of inosine and 5′-deoxyinosine. In the presence of EDTA, desferal, or 8-hydroxyquinoline (8-HQ) at a concentration that did not affect reductase activity, HU, GZ and IMPY more effectively inhibited the reductase. EDTA, desferal, or 8-HQ in combination with the nucleoside dialdehyde derivatives did not affect the inhibition caused by these compounds. The combination of these iron-chelating agents with MAIQ and IQ, however, reversed the inhibition caused by MAIQ and IQ. These data indicate that the inhibitors of the nonheme iron-containing component of mammalian ribonucleotide reductase can be subclassified, based on their response to the presence of iron-chelating agents.