RESUMO
Increasing clinical data show that the imbalance of host metallome is closely associated with different kinds of disease, however, the intrinsic mechanisms of action of metals in immunity and pathogenesis of disease remain largely undefined. There is lack of multiplexed profiling system to integrate the metalloproteome-immunoproteome information at systemic level for exploring the roles of metals in immunity and disease pathogenesis. In this study, we build up a metal-coding assisted multiplexed proteome assay platform for serum metalloproteomic and immunoproteomic profiling. By taking COVID-19 as a showcase, we unbiasedly uncovered the most evident modulation of iron-related proteins, i.e., Ft and Tf, in serum of severe COVID-19 patients, and the value of Ft/Tf could work as a robust biomarker for COVID-19 severity stratification, which overtakes the well-established clinical risk factors (cytokines). We further uncovered a tight association of transferrin with inflammation mediator IL-10 in COVID-19 patients, which was proved to be mainly governed by the monocyte/macrophage of liver, shedding light on new pathophysiological and immune regulatory mechanisms of COVID-19 disease. We finally validated the beneficial effects of iron chelators as anti-viral agents in SARS-CoV-2-infected K18-hACE2 mice through modulation of iron dyshomeostasis and alleviating inflammation response. Our findings highlight the critical role of liver-mediated iron dysregulation in COVID-19 disease severity, providing solid evidence on the involvement of iron-related proteins in COVID-19 pathophysiology and immunity.
Assuntos
COVID-19 , Ferro , Proteoma , SARS-CoV-2 , COVID-19/imunologia , Humanos , Animais , SARS-CoV-2/imunologia , Camundongos , Ferro/metabolismo , Proteômica/métodos , Transferrina/metabolismo , Metaloproteínas/imunologia , Metaloproteínas/metabolismo , Masculino , Feminino , Biomarcadores/sangue , Biomarcadores/metabolismo , Quelantes de Ferro/uso terapêutico , Quelantes de Ferro/farmacologia , Interleucina-10/imunologia , Interleucina-10/metabolismo , Pessoa de Meia-IdadeRESUMO
Iron overload from repeated transfusions has a negative impact on cardiac function, and iron chelation therapy may help prevent cardiac dysfunction in transfusion-dependent patients with myelodysplastic syndromes (MDS). TELESTO (NCT00940602) was a prospective, placebo-controlled, randomised study to evaluate the iron chelator deferasirox in patients with low- or intermediate-1-risk MDS and iron overload. Echocardiographic parameters were collected at screening and during treatment. Patients receiving deferasirox experienced a significant decrease in the composite risk of hospitalisation for congestive heart failure (CHF) or worsening of cardiac function (HR = 0.23; 95% CI: 0.05, 0.99; nominal p = 0.0322) versus placebo. No significant differences between the arms were found in left ventricular ejection fraction, ventricular diameter and mass or pulmonary artery pressure. The absolute number of events was low, but the enrolled patients were younger than average for patients with MDS, with no serious cardiac comorbidities and a modest cardiovascular risk profile. These results support the effectiveness of deferasirox in preventing cardiac damage caused by iron overload in this patient population. Identification of patients developing CHF is challenging due to the lack of distinctive echocardiographic features. The treatment of iron overload may be important to prevent cardiac dysfunction in these patients, even those with moderate CHF risk.
Assuntos
Deferasirox , Quelantes de Ferro , Sobrecarga de Ferro , Síndromes Mielodisplásicas , Humanos , Deferasirox/uso terapêutico , Síndromes Mielodisplásicas/terapia , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/complicações , Masculino , Feminino , Quelantes de Ferro/uso terapêutico , Pessoa de Meia-Idade , Idoso , Sobrecarga de Ferro/etiologia , Sobrecarga de Ferro/tratamento farmacológico , Estudos Prospectivos , Benzoatos/uso terapêutico , Benzoatos/efeitos adversos , Insuficiência Cardíaca/etiologia , Reação Transfusional/etiologia , Ecocardiografia , Adulto , Idoso de 80 Anos ou mais , Triazóis/uso terapêutico , Triazóis/efeitos adversos , Transfusão de SangueRESUMO
We conducted a retrospective cohort study on 663 transfusion-dependent ß-thalassemia patients receiving the same iron chelation monotherapy with deferoxamine, deferiprone, or deferasirox for up to 10 years (median age 31.8 years, 49.9 % females). Patients on all three iron chelators had a steady and significant decline in serum ferritin over the 10 years (median deferoxamine: -170.7 ng/mL, P = 0.049, deferiprone: -236.7 ng/mL, P = 0.001; deferasirox: -323.7 ng/mL, P < 0.001) yet had no significant change in liver iron concentration or cardiac T2*; while noting that patients generally had low hepatic and cardiac iron levels at study start. Median absolute, relative, and normalized changes were generally comparable between the three iron chelators. Patients receiving deferasirox had the highest morbidity and mortality-free survival probability among the three chelators, although the difference was only statistically significant when compared with deferoxamine (P = 0.037). On multivariate Cox regression analysis, there was no significant association between iron chelator type and the composite outcome of morbidity or mortality. In a real-world setting, there is comparable long-term iron chelation effectiveness between the three available iron chelators for patients with mild-to-moderate iron overload.
Assuntos
Transfusão de Sangue , Deferasirox , Deferiprona , Desferroxamina , Quelantes de Ferro , Ferro , Piridonas , Talassemia beta , Humanos , Quelantes de Ferro/uso terapêutico , Talassemia beta/mortalidade , Talassemia beta/terapia , Talassemia beta/tratamento farmacológico , Talassemia beta/complicações , Feminino , Masculino , Adulto , Estudos Retrospectivos , Desferroxamina/uso terapêutico , Deferiprona/uso terapêutico , Ferro/metabolismo , Deferasirox/uso terapêutico , Piridonas/uso terapêutico , Sobrecarga de Ferro/etiologia , Sobrecarga de Ferro/tratamento farmacológico , Benzoatos/uso terapêutico , Ferritinas/sangue , Adolescente , Triazóis/uso terapêutico , Adulto Jovem , Criança , Resultado do Tratamento , Pessoa de Meia-Idade , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Estudos de CoortesRESUMO
BACKGROUND: Vascular calcification (VC) is an independent risk factor for cardiovascular diseases. Recently, ferroptosis has been recognised as a novel therapeutic target for cardiovascular diseases. Although an association between ferroptosis and vascular calcification has been reported, the role and mechanism of iron overload in vascular calcification are still poorly understood. Specifically, further in-depth research is required on whether metalloproteins SLC39a14 and SLC39a8 are involved in ferroptosis induced by iron overload. METHODS: R language was employed for the differential analysis of the dataset, revealing the correlation between ferroptosis and calcification. The experimental approaches encompassed both in vitro and in vivo studies, incorporating the use of iron chelators and models of iron overload. Additionally, gain- and loss-of-function experiments were conducted to investigate iron's effects on vascular calcification comprehensively. Electron microscopy, immunofluorescence, western blotting, and real-time polymerase chain reaction were used to elucidate how Slc39a14 and Slc39a8 mediate iron overload and promote calcification. RESULTS: Ferroptosis was observed in conjunction with vascular calcification (VC); the association was consistently confirmed by in vitro and in vivo studies. Our results showed a positive correlation between iron overload in VSMCs and calcification. Iron chelators are effective in reversing VC and iron overload exacerbates this process. The expression levels of the metal transport proteins Slc39a14 and Slc39a8 were significantly upregulated during calcification; the inhibition of their expression alleviated VC. Conversely, Slc39a14 overexpression exacerbates calcification and promotes intracellular iron accumulation in VSMCs. CONCLUSIONS: Our research demonstrates that iron overload occurs during VC, and that inhibition of Slc39a14 and Slc39a8 significantly relieves VC by intercepting iron overload-induced ferroptosis in VSMCs, providing new insights into the VC treatment.
Assuntos
Proteínas de Transporte de Cátions , Modelos Animais de Doenças , Ferroptose , Quelantes de Ferro , Camundongos Endogâmicos C57BL , Músculo Liso Vascular , Miócitos de Músculo Liso , Calcificação Vascular , Ferroptose/efeitos dos fármacos , Calcificação Vascular/metabolismo , Calcificação Vascular/patologia , Animais , Proteínas de Transporte de Cátions/metabolismo , Proteínas de Transporte de Cátions/genética , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Músculo Liso Vascular/patologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Quelantes de Ferro/farmacologia , Quelantes de Ferro/uso terapêutico , Transdução de Sinais , Masculino , Humanos , Ferro/metabolismo , Sobrecarga de Ferro/metabolismo , Sobrecarga de Ferro/patologiaRESUMO
Patients with sickle cell disease (SCD) and other anemias who receive blood transfusions are at risk of organ damage due to transfusional iron overload. Deferiprone is an iron chelator with a well-established safety and efficacy profile that is indicated for the treatment of transfusional iron overload. Here, we report safety data from the large-scale, retrospective Ferriprox® Total Care Registry, which involved all patients with SCD taking deferiprone following the 2011 approval of deferiprone in the United States through August 2020. A total of 634 patients who had initiated deferiprone treatment were included. The mean (SD) duration of deferiprone exposure in the registry was 1.6 (1.6) years (range 0 to 9.7 years). In the overall patient population (N = 634), 64.7% (n = 410) of patients reported a total of 1885 adverse events (AEs). In subgroup analyses, 54.6% (n = 71) of pediatric patients and 67.3% (n = 339) of adult patients reported AEs. The most common AEs reported in patients receiving deferiprone were sickle cell crisis (22.7%), nausea (12.1%), vomiting (8.7%), abdominal discomfort (5.4%), and fatigue (5.4%). Neutropenia was reported in four (0.6%) patients and severe neutropenia/agranulocytosis (defined as absolute neutrophil count <0.5 × 109/L) was reported in two (0.3%) patients. Of patients with evaluable data, all cases of neutropenia and severe neutropenia/agranulocytosis resolved with deferiprone discontinuation. Results from the nearly 10 years of real-world data collected in the Ferriprox® Total Care Registry demonstrate that deferiprone is safe and well tolerated in patients with SCD or other anemias who have transfusional iron overload.
Assuntos
Anemia Falciforme , Deferiprona , Quelantes de Ferro , Sistema de Registros , Humanos , Deferiprona/uso terapêutico , Deferiprona/efeitos adversos , Anemia Falciforme/tratamento farmacológico , Masculino , Criança , Adulto , Feminino , Adolescente , Quelantes de Ferro/uso terapêutico , Quelantes de Ferro/efeitos adversos , Quelantes de Ferro/administração & dosagem , Estudos Retrospectivos , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/etiologia , Pré-Escolar , Adulto Jovem , Pessoa de Meia-Idade , LactenteRESUMO
In this review, we provide a summary of evidence on iron overload in young children with transfusion-dependent ß-thalassemia (TDT) and explore the ideal timing for intervention. Key data from clinical trials and observational studies of the three available iron chelators deferoxamine, deferiprone, and deferasirox are also evaluated for inclusion of subsets of young children, especially those less than 6 years of age. Evidence on the efficacy and safety of iron chelation therapy for children ≥2 years of age with transfusional iron overload is widely available. New data exploring the risks and benefits of early-start iron chelation in younger patients with minimal iron overload are also emerging.
Assuntos
Transfusão de Sangue , Terapia por Quelação , Quelantes de Ferro , Sobrecarga de Ferro , Talassemia beta , Humanos , Talassemia beta/terapia , Talassemia beta/tratamento farmacológico , Talassemia beta/complicações , Quelantes de Ferro/uso terapêutico , Criança , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/etiologia , Terapia por Quelação/métodos , Pré-Escolar , Desferroxamina/uso terapêutico , Deferiprona/uso terapêutico , Piridonas/uso terapêutico , Piridonas/efeitos adversosRESUMO
BACKGROUND: Most patients with lower risk myelodysplastic neoplasms or syndromes (MDSs) become RBC transfusion-dependent, resulting in iron overload, which is associated with an increased oxidative stress state. Iron-chelation therapy is applied to attenuate the toxic effects of this state. Deferiprone (DFP) is an oral iron chelator, which is not commonly used in this patient population, due to safety concerns, mainly agranulocytosis. The purpose of this study was to assess the effect of DFP, on oxidative stress parameters in iron-overloaded RBC transfusion-dependent patients with lower risk MDSs. METHODS: Adult lower risk MDS patients with a cumulative transfusion burden of >20 red blood cell units and evidence of iron overload (serum ferritin >1,000 ng/mL) were included in this study. DFP was administered (100 mg/kg/day) for 4 months. Blood samples for oxidative stress parameters and iron overload parameters were done at baseline and monthly: reactive oxygen species (ROS), phosphatidylserine, reduced glutathione, membrane lipid peroxidation, serum ferritin, and cellular labile iron pool. The primary efficacy variable was ROS. Tolerability and side effects were recorded as well. A paired t test was applied for statistical analyses. RESULTS: Eighteen patients were treated with DFP. ROS significantly decreased in all cell lineages: median decrease of 58.6% in RBC, 33.3% in PMN, and 39.8% in platelets (p < 0.01 for all). Other oxidative stress markers improved: phosphatidylserine decreased by 57.95%, lipid peroxidase decreased by 141.3%, and reduced gluthathione increased by 72.8% (p < 0.01 for all). The iron-overload marker and cellular labile iron pool decreased by 35% in RBCs, 44.3% in PMN, and 46.3% in platelets (p < 0.01 for all). No significant changes were observed in SF levels. There were no events of agranulocytosis. All AEs were grades 1-2. CONCLUSIONS: Herein, we showed preliminary evidence that DFP decreases iron-induced oxidative stress in MDS patients with a good tolerability profile (albeit a short follow-up period). No cases of severe neutropenia or agranulocytosis were reported. The future challenge is to prove that reduction in iron toxicity will eventually be translated into a clinically meaningful improvement.
Assuntos
Deferiprona , Quelantes de Ferro , Sobrecarga de Ferro , Síndromes Mielodisplásicas , Estresse Oxidativo , Humanos , Deferiprona/uso terapêutico , Deferiprona/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Quelantes de Ferro/uso terapêutico , Quelantes de Ferro/farmacologia , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/etiologia , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/metabolismo , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Piridonas/uso terapêutico , Piridonas/efeitos adversos , Piridonas/administração & dosagem , Idoso de 80 Anos ou mais , Adulto , Israel , Administração Oral , Espécies Reativas de Oxigênio/metabolismo , Transfusão de Eritrócitos , Ferritinas/sangueRESUMO
Understanding consequences of poor chelation compliance is crucial given the enormous burden of post-transfusional iron overload complications. We systematically reviewed iron-chelation therapy (ICT) compliance, and the relationship between compliance with health outcome and health-related quality of life (HRQoL) in thalassaemia patients. Several reviewers performed systematic search strategy of literature through PubMed, Scopus, and EBSCOhost. The preferred reporting items of systematic reviews and meta-analyses (PRISMA) guidelines were followed. Of 4917 studies, 20 publications were included. The ICT compliance rate ranges from 20.93 to 75.3%. It also varied per agent, ranging from 48.84 to 85.1% for desferioxamine, 87.2-92.2% for deferiprone and 90-100% for deferasirox. Majority of studies (N = 10/11, 90.91%) demonstrated significantly negative correlation between compliance and serum ferritin, while numerous studies revealed poor ICT compliance linked with increased risk of liver disease (N = 4/7, 57.14%) and cardiac disease (N = 6/8, 75%), endocrinologic morbidity (N = 4/5, 90%), and lower HRQoL (N = 4/6, 66.67%). Inadequate compliance to ICT therapy is common. Higher compliance is correlated with lower serum ferritin, lower risk of complications, and higher HRQoL. These findings should be interpreted with caution given the few numbers of evidence.
Assuntos
Quelantes de Ferro , Talassemia , Humanos , Quelantes de Ferro/uso terapêutico , Deferasirox , Deferiprona , Desferroxamina/uso terapêutico , Qualidade de Vida , Piridonas/efeitos adversos , Benzoatos/efeitos adversos , Triazóis/efeitos adversos , Talassemia/tratamento farmacológico , Terapia por Quelação , Ferritinas , Avaliação de Resultados em Cuidados de SaúdeRESUMO
BACKGROUND: Hemoglobin disorders such as thalassemia major have created an economic burden on the health care system. Iron chelation therapy (ICT) is the most expensive cost component in patients with thalassemia. ICT was administered to reduce the toxic effects of iron overload. This study aims to compare the costs of iron chelators as monotherapy in patients with thalassemia major in Indonesia, specifically in Cipto Faculty of Medicine, Universit. METHODS: This is a retrospective analytical observational study. Data were collected from the thalassemia registry from 2016 to 2019. Patients' age, gender, type of thalassemia, and type of iron chelation were recorded. Complications and total annual costs were evaluated. All thalassemia patients aged ≥2 years who were only receiving monotherapy ICT and had no history of therapy switching were eligible. We excluded subjects who moved out to other facilities or lost to follow-up. RESULTS: From a total of 256 subjects, 249 subjects were included. The median age is 28 years old. Both sexes were represented equally. As many as 96.8% of subjects have thalassemia beta. Deferiprone was the most common iron chelator used (86.7%). Complications were observed in the subjects based on 4-year data collection; most of them were cardiomyopathy, diabetes mellitus, delayed puberty, and malnutrition ( P =0.422; P =0.867; P =0.004; and P =0.125, respectively). Deferiprone had a lower mean annual cost of USD 3581 than deferasirox, which had a cost of USD 6004. CONCLUSIONS: Cardiomyopathy, diabetes mellitus, delayed puberty, and malnutrition were the most common complications found in the study. This study showed that deferiprone should be taken as consideration as a drug of choice to treat iron overload in thalassemia provided by Indonesian national health insurance which is less costly despite the probability of complications found after the treatment was given. Further investigations are required to evaluate contributing factors of complications in thalassemia.
Assuntos
Deferasirox , Deferiprona , Quelantes de Ferro , Humanos , Deferiprona/uso terapêutico , Deferiprona/efeitos adversos , Masculino , Feminino , Deferasirox/efeitos adversos , Deferasirox/uso terapêutico , Deferasirox/economia , Estudos Retrospectivos , Quelantes de Ferro/economia , Quelantes de Ferro/uso terapêutico , Quelantes de Ferro/efeitos adversos , Adulto , Adolescente , Criança , Talassemia/economia , Talassemia/tratamento farmacológico , Adulto Jovem , Indonésia , Talassemia beta/tratamento farmacológico , Talassemia beta/economia , Talassemia beta/complicações , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/economia , Sobrecarga de Ferro/etiologia , Pré-Escolar , Terapia por Quelação/economia , Terapia por Quelação/efeitos adversosRESUMO
Iron accumulation in the brain is a common feature of many neurodegenerative diseases. Its involvement spans across the main proteinopathies involving tau, amyloid-beta, alpha-synuclein, and TDP-43. Accumulating evidence supports the contribution of iron in disease pathologies, but the delineation of its pathogenic role is yet challenged by the complex involvement of iron in multiple neurotoxicity mechanisms and evidence supporting a reciprocal influence between accumulation of iron and protein pathology. Here, we review the major proteinopathy-specific observations supporting four distinct hypotheses: (1) iron deposition is a consequence of protein pathology; (2) iron promotes protein pathology; (3) iron protects from or hinders protein pathology; and (4) deposition of iron and protein pathology contribute parallelly to pathogenesis. Iron is an essential element for physiological brain function, requiring a fine balance of its levels. Understanding of disease-related iron accumulation at a more intricate and systemic level is critical for advancements in iron chelation therapies.
Assuntos
Ferro , Doenças Neurodegenerativas , Humanos , Ferro/metabolismo , Doenças Neurodegenerativas/metabolismo , Animais , Proteínas tau/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , alfa-Sinucleína/metabolismo , Proteínas de Ligação a DNA/metabolismo , Quelantes de Ferro/uso terapêuticoRESUMO
The supply and control of iron is essential for all cells and vital for many physiological processes. All functions and activities of iron are expressed in conjunction with iron-binding molecules. For example, natural chelators such as transferrin and chelator-iron complexes such as haem play major roles in iron metabolism and human physiology. Similarly, the mainstay treatments of the most common diseases of iron metabolism, namely iron deficiency anaemia and iron overload, involve many iron-chelator complexes and the iron-chelating drugs deferiprone (L1), deferoxamine (DF) and deferasirox. Endogenous chelators such as citric acid and glutathione and exogenous chelators such as ascorbic acid also play important roles in iron metabolism and iron homeostasis. Recent advances in the treatment of iron deficiency anaemia with effective iron complexes such as the ferric iron tri-maltol complex (feraccru or accrufer) and the effective treatment of transfusional iron overload using L1 and L1/DF combinations have decreased associated mortality and morbidity and also improved the quality of life of millions of patients. Many other chelating drugs such as ciclopirox, dexrazoxane and EDTA are used daily by millions of patients in other diseases. Similarly, many other drugs or their metabolites with iron-chelation capacity such as hydroxyurea, tetracyclines, anthracyclines and aspirin, as well as dietary molecules such as gallic acid, caffeic acid, quercetin, ellagic acid, maltol and many other phytochelators, are known to interact with iron and affect iron metabolism and related diseases. Different interactions are also observed in the presence of essential, xenobiotic, diagnostic and theranostic metal ions competing with iron. Clinical trials using L1 in Parkinson's, Alzheimer's and other neurodegenerative diseases, as well as HIV and other infections, cancer, diabetic nephropathy and anaemia of inflammation, highlight the importance of chelation therapy in many other clinical conditions. The proposed use of iron chelators for modulating ferroptosis signifies a new era in the design of new therapeutic chelation strategies in many other diseases. The introduction of artificial intelligence guidance for optimal chelation therapeutic outcomes in personalised medicine is expected to increase further the impact of chelation in medicine, as well as the survival and quality of life of millions of patients with iron metabolic disorders and also other diseases.
Assuntos
Quelantes de Ferro , Sobrecarga de Ferro , Humanos , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/metabolismo , Quelantes de Ferro/uso terapêutico , Quelantes de Ferro/farmacologia , Anemia Ferropriva/tratamento farmacológico , Anemia Ferropriva/metabolismo , Ferro/metabolismo , Animais , Deferiprona/uso terapêutico , Deferiprona/farmacologiaRESUMO
In this short review we have presented and discussed studies on pharmacogenomics (also termed pharmacogenetics) of the drugs employed in the treatment of ß-thalassemia or Sickle-cell disease (SCD). This field of investigation is relevant, since it is expected to help clinicians select the appropriate drug and the correct dosage for each patient. We first discussed the search for DNA polymorphisms associated with a high expression of γ-globin genes and identified this using GWAS studies and CRISPR-based gene editing approaches. We then presented validated DNA polymorphisms associated with a high HbF production (including, but not limited to the HBG2 XmnI polymorphism and those related to the BCL11A, MYB, KLF-1, and LYAR genes). The expression of microRNAs involved in the regulation of γ-globin genes was also presented in the context of pharmacomiRNomics. Then, the pharmacogenomics of validated fetal hemoglobin inducers (hydroxyurea, butyrate and butyrate analogues, thalidomide, and sirolimus), of iron chelators, and of analgesics in the pain management of SCD patients were considered. Finally, we discuss current clinical trials, as well as international research networks focusing on clinical issues related to pharmacogenomics in hematological diseases.
Assuntos
Anemia Falciforme , Farmacogenética , Talassemia beta , Humanos , Anemia Falciforme/genética , Anemia Falciforme/tratamento farmacológico , Talassemia beta/genética , Talassemia beta/tratamento farmacológico , Farmacogenética/métodos , Hemoglobina Fetal/genética , gama-Globinas/genética , Quelantes de Ferro/uso terapêutico , Quelantes de Ferro/farmacologiaRESUMO
Acetylsalicylic acid or aspirin is the most commonly used drug in the world and is taken daily by millions of people. There is increasing evidence that chronic administration of low-dose aspirin of about 75-100 mg/day can cause iron deficiency anaemia (IDA) in the absence of major gastric bleeding; this is found in a large number of about 20% otherwise healthy elderly (>65 years) individuals. The mechanisms of the cause of IDA in this category of individuals are still largely unknown. Evidence is presented suggesting that a likely cause of IDA in this category of aspirin users is the chelation activity and increased excretion of iron caused by aspirin chelating metabolites (ACMs). It is estimated that 90% of oral aspirin is metabolized into about 70% of the ACMs salicyluric acid, salicylic acid, 2,5-dihydroxybenzoic acid, and 2,3-dihydroxybenzoic acid. All ACMs have a high affinity for binding iron and ability to mobilize iron from different iron pools, causing an overall net increase in iron excretion and altering iron balance. Interestingly, 2,3-dihydroxybenzoic acid has been previously tested in iron-loaded thalassaemia patients, leading to substantial increases in iron excretion. The daily administration of low-dose aspirin for long-term periods is likely to enhance the overall iron excretion in small increments each time due to the combined iron mobilization effect of the ACM. In particular, IDA is likely to occur mainly in populations such as elderly vegetarian adults with meals low in iron content. Furthermore, IDA may be exacerbated by the combinations of ACM with other dietary components, which can prevent iron absorption and enhance iron excretion. Overall, aspirin is acting as a chelating pro-drug similar to dexrazoxane, and the ACM as combination chelation therapy. Iron balance, pharmacological, and other studies on the interaction of iron and aspirin, as well as ACM, are likely to shed more light on the mechanism of IDA. Similar mechanisms of iron chelation through ACM may also be implicated in patient improvements observed in cancer, neurodegenerative, and other disease categories when treated long-term with daily aspirin. In particular, the role of aspirin and ACM in iron metabolism and free radical pathology includes ferroptosis, and may identify other missing links in the therapeutic effects of aspirin in many more diseases. It is suggested that aspirin is the first non-chelating drug described to cause IDA through its ACM metabolites. The therapeutic, pharmacological, toxicological and other implications of aspirin are incomplete without taking into consideration the iron binding and other effects of the ACM.
Assuntos
Anemia Ferropriva , Aspirina , Quelantes de Ferro , Ferro , Humanos , Aspirina/uso terapêutico , Aspirina/metabolismo , Anemia Ferropriva/metabolismo , Anemia Ferropriva/tratamento farmacológico , Ferro/metabolismo , Quelantes de Ferro/uso terapêutico , Quelantes de Ferro/metabolismo , Ácido Salicílico/metabolismo , Gentisatos/metabolismo , Hipuratos/metabolismo , HidroxibenzoatosRESUMO
Hemoglobinopathies are one of the most common single-gene genetic disorders globally, with approximately 1% to 5% of the global population carrying the mutated gene for thalassemia. Thalassemia are classified into transfusion-dependent thalassemia and non-transfusion-dependent thalassemia based on the need for blood transfusion. Traditional treatment modalities include blood transfusion, splenectomy, hydroxyurea therapy, and iron chelation therapy, which are now widely used for clinical treatment and constitute the main methods recommended in the ß-thalassemia treatment guidelines. However, there are multiple barriers and limitations to the application of these approaches, and there is an urgent need to explore new therapeutic approaches. With the in-depth study of the pathophysiological process of ß-thalassemia, a deeper understanding of the pathogenesis of the disease has been gained. It has been demonstrated that the pathogenesis of thalassemia is closely related to ineffective erythropoiesis (IE), imbalance in the ratio of α/ß-globin protein chains and iron overload. New therapeutic approaches are emerging for different pathogenic mechanisms. Among them, new drugs for the treatment of IE mainly include activin receptor II trap ligands, Janus kinase 2 inhibitors, pyruvate kinase activators, and glycine transporter protein 1 inhibitors. Correcting the imbalance in the hemoglobin chain is mainly due to emerging technologies such as bone marrow transplantation and gene editing. Measures in reducing iron overload are associated with inhibiting the activity of transferrin and hepcidin. These new approaches provide new ideas and options for the treatment and management of ß-thalassemia.
Assuntos
Terapia Genética , Talassemia beta , Talassemia beta/terapia , Talassemia beta/genética , Humanos , Terapia Genética/métodos , Transfusão de Sangue , Janus Quinase 2/genética , Receptores de Activinas Tipo II/genética , Esplenectomia , Edição de Genes , Quelantes de Ferro/uso terapêutico , Transplante de Medula Óssea/métodos , Sobrecarga de Ferro/terapia , Eritropoese , Fragmentos Fc das Imunoglobulinas , Proteínas Recombinantes de FusãoRESUMO
Accumulation of iron in vital organs is increasingly challenging in clinical settings during the lifespan of thalassemia patients. Iron overload hurdle these organs to redox imbalances. Commonly used iron-chelating agents in (deferasirox and, deferoxamine) could have a positive antioxidant role. Therefore, the aim of this study was designed to compare the effects of deferasirox and, deferoxamine, iron-chelating agents in oxidative stress in patients with ß-thalassemic major. In this case series comparative study, 60 known cases of ß-thalassemic patients receiving chelating agents therapy were divided into two groups of thirty, group one consisted of 30 patients 16 male and14 female, who received oral agent deferasirox tablets at dose 20-40mg/kg. Group two consisted of 30 patients, 16 male and 14 female, on intravenous therapy with Deferoxamine at a dose of 20-50mg/kg, Another thirty healthy individuals matched with age and gender, were kept as a control group. Total antioxidant capacity (TAOC) and Malondialdehyde (MDA) were measured in all studied groups. The three groups were similar in terms of age, and gender, A statistically non-significant difference in age (p>0.05) existed between the control and patient groups (10.9±2.93; 11.2±4.1*;11.6±3.6*) respectively. The number of patients in to control group and male-to-female numbers were matched since the ratios were similar. A statistically non-significant difference in BMI (p>0.05) existed between the control and patient groups (17±2, 17.2±2, 18±2.4*) respectively. TAOC is lower in-patient groups, when compared with the control group (27.8 ± 10.7; 32.5 ± 10.2; and 79.5 ± 7 u/ml) respectively, while the MDA value is higher when compared with the control group (7.2±4.6 and, 6.6±4.42; and 0.57±0.26; nmol/ml) respectively. The TAOC in patients group on Deferoxamine, is higher, while MDA is lower than in patients on Defrasirox. The TAOC in patients was reduced and Oxidative stress was enhanced in patients with thalassemia. Deferoxamine is more effective in modulating redox status.
Assuntos
Benzoatos , Deferasirox , Desferroxamina , Quelantes de Ferro , Malondialdeído , Estresse Oxidativo , Triazóis , Talassemia beta , Humanos , Deferasirox/uso terapêutico , Talassemia beta/tratamento farmacológico , Talassemia beta/complicações , Estresse Oxidativo/efeitos dos fármacos , Desferroxamina/uso terapêutico , Masculino , Feminino , Quelantes de Ferro/uso terapêutico , Benzoatos/uso terapêutico , Benzoatos/administração & dosagem , Triazóis/uso terapêutico , Malondialdeído/sangue , Malondialdeído/metabolismo , Adulto , Antioxidantes/uso terapêutico , Adolescente , Adulto Jovem , Sobrecarga de Ferro/tratamento farmacológicoRESUMO
BACKGROUND: Adherence to iron chelation therapy (ICT) remains an issue among thalassemia patients. This study aimed to determine the prevalence of non-adherence to ICT among children with beta thalassemia major in Malaysia and the factors associated with it. METHODS: This was a cross-sectional study conducted between November 2019 and November 2021 at seven tertiary hospitals in Malaysia. Participants registered with Malaysian Thalassemia Registry were recruited by convenience sampling. Adherence was measured via pill count and self-reported adherence. Knowledge about thalassemia and ICT was measured using a questionnaire from Modul Thalassemia by Ministry of Health of Malaysia. A decision tree was used to identify predictors of non-adherence. RESULTS: A total of 135 patients were recruited. The prevalence of non-adherence to ICT in those who took subcutaneous ± oral medications was 47.5% (95% CI: 31.5%, 63.9%) and the prevalence of non-adherence to ICT in those who took oral medications only was 21.1% (95% CI: 13.4%, 30.6%). The median knowledge score was 67.5% (IQR 15%). A decision tree has identified two factors associated with non-adherence. They were ICT's route of administration and knowledge score. Out of 100 patients who were on oral medications only, 79 were expected to adhere. Out of 100 patients who were on subcutaneous ± oral medications and scored less than 56.25% in knowledge questionnaire, 86 were expected to non-adhere. Based on the logistic regression, the odds of non-adherence in patients who took oral medications only was 71% lower than the odds of non-adherence in patients who took subcutaneous ± oral medications (OR = 0.29; 95% CI = 0.13, 0.65; p = .002). CONCLUSION: The prevalence of non-adherence to ICT among children with beta thalassemia major in Malaysia was 20/95 (21.1%) in those who took oral medications only and the prevalence of non-adherence was 19/40 (47.5%) in those who took subcutaneous ± oral medications. The factors associated with non-adherence were ICT's route of administration and knowledge score.
Assuntos
Sobrecarga de Ferro , Talassemia , Talassemia beta , Criança , Humanos , Terapia por Quelação , Talassemia beta/tratamento farmacológico , Talassemia beta/epidemiologia , Estudos Transversais , Talassemia/tratamento farmacológico , Ferro , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológicoRESUMO
Ferroptosis is a form of cell death that is distinguished from other types of death for its peculiar characteristics of death regulated by iron accumulation, increase in ROS, and lipid peroxidation. In the past few years, experimental evidence has correlated ferroptosis with various pathological processes including neurodegenerative and cardiovascular diseases. Ferroptosis also is involved in several types of cancer because it has been shown to induce tumor cell death. In particular, the pharmacological induction of ferroptosis, contributing to the inhibition of the proliferative process, provides new ideas for the pharmacological treatment of cancer. Emerging evidence suggests that certain mechanisms including the Xc- system, GPx4, and iron chelators play a key role in the regulation of ferroptosis and can be used to block the progression of many diseases. This review summarizes current knowledge on the mechanism of ferroptosis and the latest advances in its multiple regulatory pathways, underlining ferroptosis' involvement in the diseases. Finally, we focused on several types of ferroptosis inducers and inhibitors, evaluating their impact on the cell death principal targets to provide new perspectives in the treatment of the diseases and a potential pharmacological development of new clinical therapies.
Assuntos
Ferroptose , Neoplasias , Humanos , Ferro/metabolismo , Morte Celular/fisiologia , Quelantes de Ferro/farmacologia , Quelantes de Ferro/uso terapêutico , Neoplasias/metabolismo , Peroxidação de LipídeosAssuntos
Colite Ulcerativa , Deferasirox , Talassemia , Humanos , Deferasirox/uso terapêutico , Deferasirox/administração & dosagem , Deferasirox/efeitos adversos , Colite Ulcerativa/tratamento farmacológico , Talassemia/complicações , Talassemia/tratamento farmacológico , Feminino , Masculino , Adulto , Quelantes de Ferro/uso terapêutico , Quelantes de Ferro/efeitos adversos , ComprimidosAssuntos
Deferasirox , Quelantes de Ferro , Sistema de Registros , Talassemia , Humanos , Deferasirox/uso terapêutico , Deferasirox/administração & dosagem , Talassemia/terapia , Masculino , Feminino , Quelantes de Ferro/uso terapêutico , Quelantes de Ferro/administração & dosagem , Adolescente , França/epidemiologia , Criança , Transfusão de Sangue , Puberdade/efeitos dos fármacos , Administração Oral , Triazóis/administração & dosagem , Triazóis/uso terapêutico , Terapia por QuelaçãoRESUMO
Health-related quality of life (HRQOL) is a patient-reported outcome that assesses the impact of a disease or illness on different domains of a patient's life. Different general and disease-specific measures can be used to evaluate HRQOL. This article aimed to summarize the evidence for HRQOL among patients with transfusion-dependent (TDT) and non-transfusion-dependent thalassemia (NTDT). We included HRQOL data related to standard therapy with blood transfusions, iron chelation, and/or luspatercept in TDT and NTDT, as well as curative therapies for TDT, including hematopoietic stem cell transplant (HSCT) and gene therapy. Patients with thalassemia had worse HRQOL scores compared to the general population, and chronic pain was seen to increase in frequency and severity over time with age. NTDT patients reported worse physical health and functioning, mental health, general health, and vitality than TDT patients. However, TDT patients reported worse pain, change in health, and social support than NTDT. Most therapies improved overall HRQOL among thalassemia patients. Deferasirox, an oral iron chelator, was associated with more HRQOL benefits compared to deferoxamine, an intravenous iron chelator. Luspatercept showed clinically meaningful improvement in physical functioning among TDT and NTDT. Furthermore, HSCT and gene therapy were associated with better physical, emotional, and mental domains scores.