-
Life Sciences Dec 2019We previously demonstrated that iron-overload in non-thalassemic rats induced neurotoxicity and cognitive decline. However, the effect of iron-overload on the brain of...
AIMS
We previously demonstrated that iron-overload in non-thalassemic rats induced neurotoxicity and cognitive decline. However, the effect of iron-overload on the brain of thalassemic condition has never been investigated. An iron chelator (deferiprone) provides neuroprotective effects against metal toxicity. Furthermore, a T-type calcium channels blocker (efonidipine) effectively attenuates cardiac dysfunction in thalassemic mice with iron-overload. However, the effects of both drugs on brain of iron-overload thalassemia has not been determined. We hypothesize that iron-overload induces neurotoxicity in Thalassemic and wild-type mice, and not only deferiprone, but also efonidipine, provides neuroprotection against iron-overload condition.
MAIN METHODS
Mice from both wild-type (WT) and β-thalassemic type (HT) groups were assigned to be fed with a standard-diet or high-iron diet containing 0.2% ferrocene/kg of diet (HFe) for 4 months consecutively. After three months of HFe, 75-mg/kg/d deferiprone or 4-mg/kg/d efonidipine were administered to the HFe-fed WT and HT mice for 1 month.
KEY FINDINGS
HFe consumption caused an equal impact on circulating iron-overload, oxidative stress, and inflammation in WT and HT mice. Brain iron-overload and iron-mediated neurotoxicity, such as oxidative stress, inflammation, glial activation, mitochondrial dysfunction, and Alzheimer's like pathologies, were observed to an equal degree in HFe fed WT and HT mice. These pathological conditions were mitigated by both deferiprone and efonidipine.
SIGNIFICANCE
These findings indicate that iron-overload itself caused neurotoxicity, and T-type calcium channels may play a role in this condition.
Topics: Animals; Calcium Channel Blockers; Calcium Channels, T-Type; Deferiprone; Dihydropyridines; Disease Models, Animal; Iron; Iron Chelating Agents; Iron Overload; Mice; Mice, Inbred C57BL; Neurotoxicity Syndromes; Nitrophenols; Organophosphorus Compounds; Thalassemia
PubMed: 31669736
DOI: 10.1016/j.lfs.2019.116878 -
Rheumatology (Oxford, England) Jan 2018Beta-thalassaemia, an autosomal recessive haemoglobinopathy, ranks among the most frequent monogenetic diseases globally. The severe form of the disease,... (Review)
Review
Beta-thalassaemia, an autosomal recessive haemoglobinopathy, ranks among the most frequent monogenetic diseases globally. The severe form of the disease, beta-thalassaemia major, is accompanied by progressive involvement of multiple organ systems as a result of the disease pathophysiology as well as iron overload from blood transfusions on a regular basis. Some of the manifestations might also be caused by medications used to manage iron overload. The purpose of this review is to highlight the rheumatological complications of beta-thalassaemia, which include musculoskeletal manifestations, such as arthritis and arthropathies, joint effusions, osteoporosis, bone fractures and myalgias, in addition to CTDs, such as pseudoxanthoma elasticum. Rheumatologists are strongly encouraged to take part in a multidisciplinary approach to the management of this debilitating disease.
Topics: Arthritis; Blood Transfusion; Connective Tissue Diseases; Deferiprone; Femur Head Necrosis; Fractures, Bone; Humans; Iron Chelating Agents; Iron Overload; Joint Diseases; Myalgia; Osteoporosis; Pseudoxanthoma Elasticum; Pyridones; Transfusion Reaction; beta-Thalassemia
PubMed: 28371817
DOI: 10.1093/rheumatology/kex058 -
Radiology Case Reports Nov 2022Superficial siderosis of the central nervous system is a chronic condition characterized by hemosiderin deposition in the brain and spinal cord. It's diagnosed by brain...
Superficial siderosis of the central nervous system is a chronic condition characterized by hemosiderin deposition in the brain and spinal cord. It's diagnosed by brain MRI. It can be caused by low-grade extravasation of blood into the subarachnoid space of the brain. There are 2 types of superficial siderosis cortical and infratentorial. Although asymptomatic in many cases; Cerebellar-predominant siderosis, a subtype of infratentorial, can affect hearing, gait, and even muscles. In this report, we present a case of a 51-year old female with complaints of hearing loss, unsteadiness in his lower limb, and spastic paresis. During MRI neuroimaging, we noticed findings of hypointensity areas within the brainstem and cerebellum, probably due to hemosiderin deposition. Based on the MRI findings, the patient was diagnosed with superficial siderosis. The patient was started on deferiprone and followed for the consecutive 18 months. Moderate improvement of the hearing loss and ataxia was noted while no change in muscle force. However, the repetitive MRI did not reveal any changes compared to the previous one.
PubMed: 36105843
DOI: 10.1016/j.radcr.2022.08.022 -
Hematology. American Society of... Dec 2017Thalassemic disorders lie on a phenotypic spectrum of clinical severity that depends on the severity of the globin gene mutation and coinheritance of other genetic... (Review)
Review
Thalassemic disorders lie on a phenotypic spectrum of clinical severity that depends on the severity of the globin gene mutation and coinheritance of other genetic determinants. Iron overload is associated with increased morbidity in both patients with transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT). The predominant mechanisms driving the process of iron loading include increased iron burden secondary to transfusion therapy in TDT and enhanced intestinal absorption secondary to ineffective erythropoiesis and hepcidin suppression in NTDT. Different organs are affected differently by iron overload in TDT and NTDT owing to the underlying iron loading mechanism and rate of iron accumulation. Serum ferritin measurement and noninvasive imaging techniques are available to diagnose iron overload, quantify its extent in different organs, and monitor clinical response to therapy. This chapter discusses the general approach to iron chelation therapy based on organ involvement using the available iron chelators: deferoxamine, deferiprone, and deferasirox. Other novel experimental options for treatment and prevention of complications associated with iron overload in thalassemia are briefly discussed.
Topics: Blood Transfusion; Erythropoiesis; Ferritins; Humans; Iron Chelating Agents; Iron Overload; Organ Specificity; Thalassemia
PubMed: 29222265
DOI: 10.1182/asheducation-2017.1.265 -
Methods in Molecular Biology (Clifton,... 2022Autophagy and autophagy-associated genes are implicated in a growing list of cellular, physiological, and pathophysiological processes and conditions. Therefore, it is...
Autophagy and autophagy-associated genes are implicated in a growing list of cellular, physiological, and pathophysiological processes and conditions. Therefore, it is ever more important to be able to reliably monitor and quantify autophagic activity. Whereas autophagic markers, such as LC3 can provide general indications about autophagy, specific and accurate detection of autophagic activity requires assessment of autophagic cargo flux. Here, we provide protocols on how to monitor bulk and selective autophagy by the use of inducible expression of exogenous probes based on the fluorescent coral protein Keima. To exemplify and demonstrate the power of this system, we provide data obtained by analyses of cytosolic and mitochondrially targeted Keima probes in human retinal epithelial cells treated with the mTOR-inhibitor Torin1 or with the iron chelator deferiprone (DFP). Our data indicate that Torin1 induces autophagic flux of cytosol and mitochondria to a similar degree, that is, compatible with induction of bulk autophagy, whereas DFP induces a highly selective form of mitophagy that efficiently excludes cytosol.
Topics: Autophagy; Microtubule-Associated Proteins; Mitochondria; Mitophagy
PubMed: 34972988
DOI: 10.1007/978-1-0716-2071-7_7 -
Drugs in Context 2022Hyperfunctional platelets play important roles in thromboembolism in patients with β-thalassaemia/ haemoglobin E (β-thal/HbE). Our previous study revealed ex vivo...
BACKGROUND
Hyperfunctional platelets play important roles in thromboembolism in patients with β-thalassaemia/ haemoglobin E (β-thal/HbE). Our previous study revealed ex vivo inhibitory effects of deferiprone on normal platelets. Herein, we aimed to investigate the in vivo effects on platelets in patients with β-thal/HbE.
METHODS
A prospective, self-controlled clinical study on 30 patients with β-thal/HbE who had received therapeutic deferiprone (20.8-94.5 mg/kg/day) was conducted. The study included a 4-week washout period followed by 4 and 12 weeks of deferiprone treatment. Platelet aggregation was performed by a turbidimetric method. Levels of deferiprone and soluble platelet (sP)-selectin in serum were measured by high-performance liquid chromatography (HPLC) and enzyme-linked immunosorbent assay (ELISA) kit, respectively.
RESULTS
The washout period significantly enhanced platelet hyperactivity both in patients who had undergone splenectomy and in those who had not. At 2 hours following the administration of a single dose of deferiprone, platelet sensitivity to ADP and arachidonic acid was significantly reduced. The inhibitory effects of deferiprone were gradually increased over the period of 4 and 12 weeks. Deferiprone also depressed sP-selectin levels, but the effect was stable over longer follow-up periods. Correlation analysis demonstrated the relationship between serum levels of deferiprone, sP-selectin, and platelet activities induced by ADP and arachidonic acid.
CONCLUSION
We first demonstrated the in vivo antiplatelet effect and benefit of short-term treatment of deferiprone in patients with β-thal/HbE. The impact on thrombotic outcomes deserves further study.
PubMed: 36544626
DOI: 10.7573/dic.2022-7-6 -
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 -
International Journal of Molecular... Mar 2023The historical insights and background of the discovery, development and clinical use of deferiprone (L1) and the maltol-iron complex, which were discovered over 40... (Review)
Review
The historical insights and background of the discovery, development and clinical use of deferiprone (L1) and the maltol-iron complex, which were discovered over 40 years ago, highlight the difficulties, complexities and efforts in general orphan drug development programs originating from academic centers. Deferiprone is widely used for the removal of excess iron in the treatment of iron overload diseases, but also in many other diseases associated with iron toxicity, as well as the modulation of iron metabolism pathways. The maltol-iron complex is a recently approved drug used for increasing iron intake in the treatment of iron deficiency anemia, a condition affecting one-third to one-quarter of the world's population. Detailed insights into different aspects of drug development associated with L1 and the maltol-iron complex are revealed, including theoretical concepts of invention; drug discovery; new chemical synthesis; in vitro, in vivo and clinical screening; toxicology; pharmacology; and the optimization of dose protocols. The prospects of the application of these two drugs in many other diseases are discussed under the light of competing drugs from other academic and commercial centers and also different regulatory authorities. The underlying scientific and other strategies, as well as the many limitations in the present global scene of pharmaceuticals, are also highlighted, with an emphasis on the priorities for orphan drug and emergency medicine development, including the roles of the academic scientific community, pharmaceutical companies and patient organizations.
Topics: Humans; Iron; Deferiprone; Iron Chelating Agents; Iron Overload; Drug Design; Pyridones
PubMed: 36902402
DOI: 10.3390/ijms24054970 -
Critical Reviews in Analytical Chemistry 2020Acute iron poisoning and chronic iron overload consequences in significant morbidity and mortality worldwide. Treatment of acute iron poisoning and chronic iron overload... (Review)
Review
Acute iron poisoning and chronic iron overload consequences in significant morbidity and mortality worldwide. Treatment of acute iron poisoning and chronic iron overload can be challenging and care providers are often tackled with management dilemmas. Iron chelating agents are commonly prescribed for patients with iron deficiency anemia. In this review article, different analytical techniques are reported used for qualitative and quantitative analysis of iron chelating agents like, deferiprone, deferoxamine, and deferasirox. Efforts are taken to collect all related articles published till October 2018. This review discusses all analytical methods, its advantages and disadvantages as well as its applications. This article will help you to know about basic analytical techniques as well as advanced hyphenated techniques practiced for determination of iron chelating agents in different matrices. The techniques discussed in this review follow the ICH guidelines for method validation.
Topics: Humans; Iron Chelating Agents
PubMed: 31140834
DOI: 10.1080/10408347.2019.1620095 -
Antioxidants (Basel, Switzerland) Apr 2022Iron progressively accumulates with age and can be further exacerbated by dietary iron intake, genetic factors, and repeated blood transfusions. While iron plays a vital...
Iron progressively accumulates with age and can be further exacerbated by dietary iron intake, genetic factors, and repeated blood transfusions. While iron plays a vital role in various physiological processes within the human body, its accumulation contributes to cellular aging in several species. In its free form, iron can initiate the formation of free radicals at a cellular level and contribute to systemic disorders. This is most evident in high iron conditions such as hereditary hemochromatosis, when accumulation of iron contributes to the development of arthritis, cirrhosis, or cardiomyopathy. A growing body of research has further identified iron's contributory effects in neurodegenerative diseases, ocular disorders, cancer, diabetes, endocrine dysfunction, and cardiovascular diseases. Reducing iron levels by repeated phlebotomy, iron chelation, and dietary restriction are the common therapeutic considerations to prevent iron toxicity. Chelators such as deferoxamine, deferiprone, and deferasirox have become the standard of care in managing iron overload conditions with other potential applications in cancer and cardiotoxicity. In certain animal models, drugs with iron chelating ability have been found to promote health and even extend lifespan. As we further explore the role of iron in the aging process, iron chelators will likely play an increasingly important role in our health.
PubMed: 35624729
DOI: 10.3390/antiox11050865