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Therapeutic Advances in Ophthalmology 2023Thalassemia major (TM) is an inherited anaemia caused by faulty haemoglobin synthesis. Reducing serum iron levels using iron chelating agents is an important step in the...
BACKGROUND
Thalassemia major (TM) is an inherited anaemia caused by faulty haemoglobin synthesis. Reducing serum iron levels using iron chelating agents is an important step in the treatment of TM, and the effects on the eye of both the disease and these agents can be determined by regular eye examination.
OBJECTIVES
We evaluated macular and optic nerve vascular densities in children with TM and compared the results with healthy controls using optical coherence tomography angiography (OCTA).
DESIGN
This is a prospective study.
METHODS
A total of 30 children with TM and 30 healthy controls were included in the study. The area of the foveal avascular zone (FAZ) and the vascular densities (VD) of the optic nerve head (ONH), radial peripapillary capillary (RPC) and deep and superficial retinal vascular networks were measured using OCTA.
RESULTS
A statistically significant decrease in VD was observed in the whole image and the parafovea, superior hemi, superior and inferior parts of the superficial capillary plexus and in the whole image and the superior regions of the deep capillary plexus in the TM patient group compared with the control group ( < 0.05). A significant decrease in VD was also observed in the whole image and the inside disc, peripapillary, nasal, inferonasal and temporal regions of the ONH and in the whole image and the inside disc, peripapillary and inferonasal regions of the RPC network in patients with TM ( < 0.05). A significant positive correlation was observed between both serum ferritin levels and deferasirox dosage, on one hand, and both the superficial ( = 0.023 and = 0.002, respectively) and deep FAZs ( = 0.015 and = 0.045, respectively), on the other hand. A negative correlation was also found between the deferasirox dosage and the VDs of the superficial ( = 0.010) and deep ( = 0.001) foveal plexuses.
CONCLUSION
Retinal VD and FAZ are affected in patients with TM. OCTA, which can noninvasively measure retinal VD in patients with TM, may be a useful tool for the early detection of retinal microvascular changes that may occur during the course of the disease.
PubMed: 37056915
DOI: 10.1177/25158414231162846 -
Toxicological Research Apr 2023The E3 ubiquitin ligase parkin plays neuroprotective functions in the brain and the deficits of parkin's ligase function in Parkinson's disease (PD) is associated with...
The E3 ubiquitin ligase parkin plays neuroprotective functions in the brain and the deficits of parkin's ligase function in Parkinson's disease (PD) is associated with reduced survival of dopaminergic neurons. Thus, compounds enhancing parkin expression have been developed as potential neuroprotective agents that prevent ongoing neurodegeneration in PD environments. Besides, iron chelators have been shown to have neuroprotective effects in diverse neurological disorders including PD. Although repression of iron accumulation and oxidative stress in brains has been implicated in their marked neuroprotective potential, molecular mechanisms of iron chelator's neuroprotective function are largely unexplored. Here, we show that the iron chelator deferasirox provides cytoprotection against oxidative stress through enhancing parkin expression under basal conditions. Parkin expression is required for cytoprotection against oxidative stress in SH-SY5Y cells with deferasirox treatment as confirmed by abolished deferasirox's cytoprotective effect after parkin knockdown by shRNA. Similar to the previously reported parkin inducing compound diaminodiphenyl sulfone, deferasirox-mediated parkin expression was induced by activation of the PERK-ATF4 pathway, which is associated with and stimulated by mild endoplasmic reticulum stress. The translational potential of deferasirox for PD treatment was further evaluated in cultured mouse dopaminergic neurons. There was a robust ATF4 activation and parkin expression in response to deferasirox treatment in dopaminergic neurons under basal conditions. Consequently, the enhanced parkin expression by deferasirox provided substantial neuroprotection against 6-hydroxydopamine-induced oxidative stress. Taken together, our study results revealed a novel mechanism through which an iron chelator, deferasirox induces neuroprotection. Since parkin function in the brain is compromised in PD and during aging, maintenance of parkin expression through the iron chelator treatment could be beneficial by increasing dopaminergic neuronal survival.
PubMed: 37008698
DOI: 10.1007/s43188-022-00157-x -
Cancers Mar 2023Latent infection of Epstein-Barr virus (EBV) is associated with lymphoid and epithelial cell cancers, including 10% of gastric carcinomas. We previously reported that...
Latent infection of Epstein-Barr virus (EBV) is associated with lymphoid and epithelial cell cancers, including 10% of gastric carcinomas. We previously reported that hypoxia inducible factor-1α (HIF-1α) induces EBV's latent-to-lytic switch and identified several HIF-1α-stabilizing drugs that induce this viral reactivation. Here, we tested three classes of these drugs for preferential killing of the EBV-positive gastric cancer AGS-Akata cell line compared to its matched EBV-negative AGS control. We observed preferential killing with iron chelators [Deferoxamine (DFO); Deferasirox (DFX)] and a prolyl hydroxylase inhibitor (BAY 85-3934 (Molidustat)), but not with a neddylation inhibitor [MLN4924 (Pevonedistat)]. DFO and DFX also induced preferential killing of the EBV-positive gastric cancer AGS-BDneo and SNU-719 cell lines. Preferential killing was enhanced when low-dose DFX (10 μM) was combined with the antiviral prodrug ganciclovir. DFO and DFX induced lytic EBV reactivation in approximately 10% of SNU-719 and 20-30% of AGS-Akata and AGS-BDneo cells. However, neither DFO nor DFX significantly induced synthesis of lytic EBV proteins in xenografts grown in NSG mice from AGS-Akata cells above the level observed in control-treated mice. Therefore, these FDA-approved iron chelators are less effective than gemcitabine at promoting EBV reactivation in vivo despite their high specificity and efficiency in vitro.
PubMed: 36980731
DOI: 10.3390/cancers15061846 -
The Cochrane Database of Systematic... Mar 2023Regularly transfused people with sickle cell disease (SCD) and people with thalassaemia are at risk of iron overload. Iron overload can lead to iron toxicity in... (Review)
Review
BACKGROUND
Regularly transfused people with sickle cell disease (SCD) and people with thalassaemia are at risk of iron overload. Iron overload can lead to iron toxicity in vulnerable organs such as the heart, liver and endocrine glands, which can be prevented and treated with iron-chelating agents. The intensive demands and uncomfortable side effects of therapy can have a negative impact on daily activities and wellbeing, which may affect adherence.
OBJECTIVES
To identify and assess the effectiveness of different types of interventions (psychological and psychosocial, educational, medication interventions, or multi-component interventions) and interventions specific to different age groups, to improve adherence to iron chelation therapy compared to another listed intervention, or standard care in people with SCD or thalassaemia.
SEARCH METHODS
We searched CENTRAL (Cochrane Library), MEDLINE, PubMed, Embase, CINAHL, PsycINFO, ProQuest Dissertations & Global Theses, Web of Science & Social Sciences Conference Proceedings Indexes and ongoing trial databases (13 December 2021). We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register (1 August 2022).
SELECTION CRITERIA
For trials comparing medications or medication changes, only randomised controlled trials (RCTs) were eligible for inclusion. For studies including psychological and psychosocial interventions, educational interventions, or multi-component interventions, non-randomised studies of interventions (NRSIs), controlled before-after studies, and interrupted time series studies with adherence as a primary outcome were also eligible for inclusion.
DATA COLLECTION AND ANALYSIS
For this update, two authors independently assessed trial eligibility and risk of bias, and extracted data. We assessed the certainty of the evidence using GRADE.
MAIN RESULTS
We included 19 RCTs and one NRSI published between 1997 and 2021. One trial assessed medication management, one assessed an education intervention (NRSI) and 18 RCTs were of medication interventions. Medications assessed were subcutaneous deferoxamine, and two oral chelating agents, deferiprone and deferasirox. We rated the certainty of evidence as very low to low across all outcomes identified in this review. Four trials measured quality of life (QoL) with validated instruments, but provided no analysable data and reported no difference in QoL. We identified nine comparisons of interest. 1. Deferiprone versus deferoxamine We are uncertain whether or not deferiprone affects adherence to iron chelation therapy (four RCTs, unpooled, very low-certainty evidence), all-cause mortality (risk ratio (RR) 0.47, 95% confidence interval (CI) 0.18 to 1.21; 3 RCTs, 376 participants; very low-certainty evidence), or serious adverse events (SAEs) (RR 1.43, 95% CI 0.83 to 2.46; 1 RCT, 228 participants; very low-certainty evidence). Adherence was reported as "good", "high" or "excellent" by all seven trials, though the data could not be analysed formally: adherence ranged from 69% to 95% (deferiprone, mean 86.6%), and 71% to 93% (deferoxamine, mean 78.8%), based on five trials (474 participants) only. 2. Deferasirox versus deferoxamine We are uncertain whether or not deferasirox affects adherence to iron chelation therapy (three RCTs, unpooled, very low-certainty evidence), although medication adherence was high in all trials. We are uncertain whether or not there is any difference between the drug therapies in serious adverse events (SAEs) (SCD or thalassaemia) or all-cause mortality (thalassaemia). 3. Deferiprone versus deferasirox We are uncertain if there is a difference between oral deferiprone and deferasirox based on a single trial in children (average age 9 to 10 years) with any hereditary haemoglobinopathy in adherence, SAEs and all-cause mortality. 4. Deferasirox film-coated tablet (FCT) versus deferasirox dispersible tablet (DT) One RCT compared deferasirox in different tablet forms. There may be a preference for FCTs, shown through a trend for greater adherence (RR 1.10, 95% CI 0.99 to 1.22; 1 RCT, 88 participants), although medication adherence was high in both groups (FCT 92.9%; DT 85.3%). We are uncertain if there is a benefit in chelation-related AEs with FCTs. We are uncertain if there is a difference in the incidence of SAEs, all-cause mortality or sustained adherence. 5. Deferiprone and deferoxamine combined versus deferiprone alone We are uncertain if there is a difference in adherence, though reporting was usually narrative as triallists report it was "excellent" in both groups (three RCTs, unpooled). We are uncertain if there is a difference in the incidence of SAEs and all-cause mortality. 6. Deferiprone and deferoxamine combined versus deferoxamine alone We are uncertain if there is a difference in adherence (four RCTs), SAEs (none reported in the trial period) and all-cause mortality (no deaths reported in the trial period). There was high adherence in all trials. 7. Deferiprone and deferoxamine combined versus deferiprone and deferasirox combined There may be a difference in favour of deferiprone and deferasirox (combined) in rates of adherence (RR 0.84, 95% CI 0.72 to 0.99) (one RCT), although it was high (> 80%) in both groups. We are uncertain if there is a difference in SAEs, and no deaths were reported in the trial, so we cannot draw conclusions based on these data (one RCT). 8. Medication management versus standard care We are uncertain if there is a difference in QoL (one RCT), and we could not assess adherence due to a lack of reporting in the control group. 9. Education versus standard care One quasi-experimental (NRSI) study could not be analysed due to the severe baseline confounding.
AUTHORS' CONCLUSIONS
The medication comparisons included in this review had higher than average adherence rates not accounted for by differences in medication administration or side effects, though often follow-up was not good (high dropout over longer trials), with adherence based on a per protocol analysis. Participants may have been selected based on higher adherence to trial medications at baseline. Also, within the clinical trial context, there is increased attention and involvement of clinicians, thus high adherence rates may be an artefact of trial participation. Real-world, pragmatic trials in community and clinic settings are needed that examine both confirmed or unconfirmed adherence strategies that may increase adherence to iron chelation therapy. Due to lack of evidence this review cannot comment on intervention strategies for different age groups.
Topics: Child; Humans; Anemia, Sickle Cell; Chelating Agents; Chelation Therapy; Deferoxamine; Drug-Related Side Effects and Adverse Reactions; Iron; Thalassemia
PubMed: 36877640
DOI: 10.1002/14651858.CD012349.pub3 -
Pharmacogenomics and Personalized... 2023Sickle cell disease (SCD) is a genetic disease influenced by ethnicity and regional differences in its clinical course. Recent advances in the management of SCD with... (Review)
Review
UNLABELLED
Sickle cell disease (SCD) is a genetic disease influenced by ethnicity and regional differences in its clinical course. Recent advances in the management of SCD with newer therapies are being introduced to the Western population. However, many of these treatments are yet to be used in the Arabic SCD population. Understanding the genetic variations of SCD regionally is essential to anticipate the utilization of new treatments. This systematic review's main objective is to pool the available data on the genetic composition of SCD in the Arabic population. Data for 44,034 patients was extracted from 184 studies (11 case reports, 8 case series, 56 retrospectives, 107 prospective observational studies, and 2 clinical trials) using PubMed, Scopus, and Google Scholar. Male (49%) and female (51%) patients were equally reported wherever gender was available (N=13105). Various SCD genotypes were reported in a total of 14,257 patients, including Hb SS (77%) Hb Sβ0 (9.9%), and Hb Sβ+ (7.2%), while the rest of the genotypes, including HbSC, HbSD, HbSE, HbSO Arab, Hb S/α-Thal, Hb Sβ0 + α-Thal, and HBS Oman were individually reported in <4% of the cases. Major SCD complications in the Arab population included pain crises (48.25%) followed by neurological complications (33.46%), hepatobiliary complications (25.53%), musculoskeletal complications (24.73%), and hemolytic anemia (23.57%). The treatments reported for SCD included hydroxyurea (20%), blood transfusion (14.32%), and Deferasirox (3.03%). We did not find the use of stem cell transplantation or newer treatments such as L-Glutamine, Voxelotor, Crizanlizumab, or gene therapy reported in any of the studies included in our review. This review highlights the genetic makeup of SCD in Arab countries and its common phenotypic manifestations and will help direct further research on SCD in this region, especially concerning genetic therapy.
SYSTEMATIC REVIEW REGISTRATION
The protocol has been registered in the International Prospective Register of Systematic Reviews(PROSPERO):CRD42020218,666. https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=218666.
PubMed: 36851992
DOI: 10.2147/PGPM.S391394 -
Expert Review of Hematology Feb 2023Regular blood transfusions in patients with thalassemia syndromes can cause iron overload resulting in complications including cirrhosis, heart problems, or endocrine...
INTRODUCTION
Regular blood transfusions in patients with thalassemia syndromes can cause iron overload resulting in complications including cirrhosis, heart problems, or endocrine abnormalities. To prevent iron overload toxicity in these patients, three iron chelators are currently FDA-approved for use: deferoxamine, deferasirox, and deferiprone. In the United States, deferiprone has been approved for three times daily dosing since 2011 and has recently gained approval for twice-daily administration.
AREAS COVERED
A PubMed literature search was performed with the keywords 'deferiprone' and 'thalassemia.' Relevant original research studying deferiprone's effects on transfusional iron overload in patients with thalassemia syndromes was included. Exclusion criteria included case reports and review papers. Deferiprone is effective at reducing serum ferritin levels in patients with iron overload. Twice-daily administration provides a similar level of iron chelation as three times daily dosing with a comparable side effect profile and increased patient acceptability.
EXPERT OPINION
New studies are highlighting deferiprone's potential for combination therapy with either deferoxamine or deferasirox to improve iron chelation. Deferiprone's ability to significantly decrease cardiac and liver iron content can be utilized in other transfusion-dependent hematologic conditions, as evidenced by its recent approval for use in the United States for sickle cell disease or other anemias.
Topics: Humans; Deferasirox; Deferoxamine; Syndrome; Iron Overload; Iron Chelating Agents; Thalassemia; Blood Transfusion; Pyridones; Benzoates
PubMed: 36755516
DOI: 10.1080/17474086.2023.2178409 -
Cancers Jan 2023Excess iron is known to be a risk factor of carcinogenesis. Although iron chelators show anti-cancer effects, they have not been used successfully to treat cancer...
Excess iron is known to be a risk factor of carcinogenesis. Although iron chelators show anti-cancer effects, they have not been used successfully to treat cancer patients. Triple-negative breast cancer (TNBC) is a disease with poor prognosis without effective treatments. Thus, we aimed to evaluate a possibility of iron chelators as a therapy for TNBC. Deferasirox (DFX), an iron chelator, suppressed the growth of 4T1 murine TNBC cell line cells in vitro and in vivo. Lung metastasis was further significantly reduced, leading to the hypothesis that iron metabolism between metastatic and non-metastatic cells may be different. An analysis of existing database demonstrated that the expression of iron-uptake genes was significantly suppressed in TNBC cells that metastasized to lymph nodes or lungs compared to those in primary tumors. A highly metastatic clone of the murine 4T1 TNBC cells (4T1-HM) did not proliferate well under iron-rich or iron-depleted conditions by iron chelators compared to a low-metastatic clone (4T1-LM). Bulk RNA-seq analysis of RNA from 4T1-HM and 4T1-LM cells suggested that the PI3K-AKT pathway might be responsible for this difference. Indeed, DFX suppressed the proliferation via the AKT-mTOR pathway in 4T1-HM and the human MDA-MB-231 cells, a human mesenchymal-like TNBC cell line. DFX also suppressed the growth of 4T1-HM tumors in comparison to 4T1-LM tumors, and reduced lung metastases after surgical resection of primary 4T1 tumors. These results indicated, for the first time, that highly metastatic TNBC cells have limited iron metabolism, and they can be more effectively targeted by iron chelators.
PubMed: 36672419
DOI: 10.3390/cancers15020468 -
Mediterranean Journal of Hematology and... 2023The primary aim of this study was to evaluate retrospectively the glucose homeostasis and surrogate indices of insulin sensitivity and resistance, during a 3-hour oral...
Glucose Homeostasis and Assessment of β-Cell Function by 3-hour Oral Glucose Tolerance (OGTT) in Patients with β-Thalassemia Major with Serum Ferritin below 1,000 ng/dL: Results from a Single ICET-A Centre.
AIMS
The primary aim of this study was to evaluate retrospectively the glucose homeostasis and surrogate indices of insulin sensitivity and resistance, during a 3-hour oral glucose tolerance test (OGTT), in β-thalassemia major patients (β-TM) with serum ferritin (SF) below 1,000 ng/mL.
PATIENTS AND METHODS
The retrospective cohort study evaluated the medical records of 24 β-TM patients from 2010 to 2022. At the year of study the mean age of patients was 31.0 ± 4.1 (20-37.11) years; 13 (54.1%) were females. The most commonly used iron chelator was deferoxamine (DFO: 75%), followed by deferiprone (DFP:12.5%) and deferasirox (DFX: 12.5%). Insulin sensitivity and resistance indices were derived from OGTT. A liver iron concentration (LIC) < 3 mg/g d.w. and a global heart T2* value > 20 ms were considered as conservative cut-off values for insignificant iron overload (IOL).
RESULTS
The mean SF levels in the whole study cohort population at the age of evaluation was 549.6 ± 232.3 ng/mL. Based on the SF levels, two groups were identified: Group A (N = 14) < 500 ng/mL and Group B (N=10) 500-1,000 ng/mL. Normal glucose tolerance (NGT) during OGTT was observed in 4 patients of Group A (28.5 %) and in 5 patients of Group B (50%) (P: 0.29). The remaining 15/24 patients (62.5%) had glucose dysregulation (GD). The mean age at starting iron chelation therapy (ICT) and the mean SF peak in Group A versus Group B were significantly higher in group A. The GD was associated with significantly attenuated IGI (first phase of insulin response) and impaired oral disposition index (oDI). Hypogonadotropic hypogonadism (HH) was the most common associated endocrine complication in both groups of patients.
CONCLUSIONS
This study showed that efficient iron chelation monotherapy in patients with β-TM and SF < 1,000 ng/ml did not entirely prevent glucose metabolism disorders, abnormalities of insulin secretion and sensitivity, and development of acquired hypogonadism.
PubMed: 36660350
DOI: 10.4084/MJHID.2023.006