RESUMEN
Deferasirox (DFX) is the newest among three different chelators available to treat iron overload in iron-loading anaemias, firstly released as Dispersible Tablets (DT) and more recently replaced by Film-Coated Tablets (FCT). In this retrospective observational study, pharmacokinetics, pharmacodynamics, and safety features of DFX treatment were analyzed in 74 patients that took both formulations subsequently under clinical practice conditions. Bioavailability of DFX FCT compared to DT resulted higher than expected [Cmax: 99.5 (FCT) and 69.7 (DT) µMol/L; AUC: 1278 (FCT) and 846 (DT), P < 0.0001]. DFX FCT was also superior in scalability among doses. After one year of treatment for each formulation, no differences were observed between the treatments in the overall iron overload levels; however, DFX FCT but not DT showed a significant dose-response correlation [Spearman r (dose-serum ferritin variation): - 0.54, P < 0.0001]. Despite being administered at different dosages, the long-term safety profile was not different between formulations: a significant increase in renal impairment risk was observed for both treatments and it was reversible under strict monitoring (P < 0.002). Altogether, these data constitute a comprehensive comparison of DFX formulations in thalassaemia and other iron-loading anaemias, confirming the effectiveness and safety characteristics of DFX and its applicability for treatment tailoring.
Asunto(s)
Anemia/tratamiento farmacológico , Deferasirox/administración & dosificación , Sobrecarga de Hierro/tratamiento farmacológico , Talasemia/tratamiento farmacológico , Adulto , Anemia/sangre , Anemia/epidemiología , Anemia/patología , Terapia por Quelación/tendencias , Deferasirox/farmacocinética , Femenino , Ferritinas/sangre , Humanos , Hierro/sangre , Hierro/metabolismo , Quelantes del Hierro/administración & dosificación , Quelantes del Hierro/farmacocinética , Sobrecarga de Hierro/sangre , Sobrecarga de Hierro/epidemiología , Sobrecarga de Hierro/patología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Talasemia/sangre , Talasemia/epidemiología , Talasemia/patologíaRESUMEN
The consequence of regular blood transfusion in patients with thalassemia major (TM) is iron overload. Herein, we report the long-term impact of chelation on liver iron concentration (LIC) and cardiac T2* MR in patients with TM. This is a retrospective cohort study over 10 years of adolescents and adults with TM aged at least 10 years who had their first cardiac T2* MR between September 2006 and February 2007. One-year chelation therapy was considered the unit of analysis. A total of 99 patients were included in this study with a median age of 18 years. The median cardiac T2* MR and LIC at baseline were 19 ms and 11.6 mg/g dw, respectively. During follow-up, 18 patients died and six underwent successful bone marrow transplantation. Factors associated with decreased survival were older age (HR 1.12, p = 0.014) and high risk cardiac T2* (HR 8.04, p = 0.004). The median cardiac T2* and LIC significantly improved over the 10-year follow-up period (p = 0.000011 and 0.00072, respectively). In conclusion, this long-term "real-life" study confirms that low cardiac T2* adversely impacts the overall survival in patients with TM. Higher baseline LIC predicts a larger reduction in LIC, and lower baseline cardiac T2* predicts a larger improvement in T2*.
Asunto(s)
Terapia por Quelación/tendencias , Imagen por Resonancia Cinemagnética/métodos , Talasemia beta/diagnóstico por imagen , Talasemia beta/tratamiento farmacológico , Adolescente , Terapia por Quelación/métodos , Estudios de Cohortes , Deferasirox/uso terapéutico , Deferiprona/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Quelantes del Hierro/uso terapéutico , Sobrecarga de Hierro/diagnóstico por imagen , Sobrecarga de Hierro/tratamiento farmacológico , Sobrecarga de Hierro/mortalidad , Masculino , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Factores de Tiempo , Adulto Joven , Talasemia beta/mortalidadRESUMEN
A substantial proportion of patients with transfusion-dependent beta-thalassemia major suffer from chronic liver disease. Iron overload resulting from repeated transfusions and HCV infection has been implicated in the development of liver fibrosis. Hepatic siderosis and fibrosis were assessed in 99 transfusion-dependent thalassemia (TDT) patients using transient elastography (TE) and liver iron concentration (LIC) assessed by T2*MRI at baseline and after 4 years. Data were analyzed retrospectively. At baseline, the overall mean liver stiffness measurement (LSM) was 7.4 ± 3.2 kPa and the mean LIC was 4.81 ± 3.82 mg/g dw (n = 99). Data available at 4 ± 1.5 years showed a significant reduction in LSM (6.6 ± 3.2 kPa, p 0.017) and hepatic siderosis measured by LIC (3.65 ± 3.45 mg/g dw, p 0.001). This result was confirmed when considering patients with iron overload at the time of the first measurement (n = 41) and subjects treated with a stable dose of deferasirox over the entire period of observation (n = 39). A reduction of LSM, yet not statistically significant, was achieved in patients on combined deferoxamine + deferiprone, while the group on deferoxamine (n = 11) remained stable over time. HCV-RNA positivity was found in 33 patients at T0, 20 of which were treated during the observation period. Patients who underwent anti-HCV therapy showed a more evident reduction in LSM (9 ± 3 vs 7 ± 3.1 kPa, p 0.016). Adequate chelation therapy is mandatory in order to prevent liver disease progression in TDT. Patients could benefit from regular non-invasive assessment of liver fibrosis by TE to indirectly monitor treatment adequacy and therapeutic compliance.
Asunto(s)
Transfusión Sanguínea/tendencias , Quelantes del Hierro/uso terapéutico , Cirrosis Hepática/diagnóstico por imagen , Cirrosis Hepática/terapia , Talasemia/diagnóstico por imagen , Talasemia/terapia , Adulto , Terapia por Quelación/tendencias , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Humanos , Cirrosis Hepática/epidemiología , Imagen por Resonancia Magnética/tendencias , Masculino , Estudios Retrospectivos , Talasemia/epidemiologíaRESUMEN
This review outlines the effectiveness and safety of 10 different regimens for controlling iron overloading in thalassaemia major (TM). For each treatment, the strength of the evidence was documented according to the guidelines of the American College of Cardiology and the American Heart Association. Serum ferritin (SF), liver iron concentration (LIC), heart T2* signal, heart damage and survival were used to assess effectiveness. Five chelation regimens out of 10 showed Level A Evidence in controlling iron overloading, as determined by SF levels and LIC. Three out of 10 chelation regimens were able to control heart iron levels, as determined by T2* signals with Level A Evidence. Two chelation regimens were able to improve/reverse heart damage and four increased of survival with Level B Evidence. These advances mean that the current survival of TM patients is now similar to that of thalassaemia intermedia patients.
Asunto(s)
Terapia por Quelación/métodos , Quelantes del Hierro/uso terapéutico , Sobrecarga de Hierro/prevención & control , Talasemia beta/terapia , Terapia por Quelación/efectos adversos , Terapia por Quelación/tendencias , Quimioterapia Combinada , Humanos , Quelantes del Hierro/efectos adversos , Sobrecarga de Hierro/etiología , Reacción a la TransfusiónRESUMEN
Patients with thalassemia become iron overloaded from increased absorption of iron, ineffective erythropoiesis, and chronic transfusion. Before effective iron chelation became available, thalassemia major patients died of iron-related cardiac failure in the second decade of life. Initial treatment goals for chelation therapy were aimed at levels of ferritin and liver iron concentrations associated with prevention of adverse cardiac outcomes and avoidance of chelator toxicity. Cardiac deaths were greatly reduced and survival was much longer. Epidemiological data from the general population draw clear associations between increased transferrin saturation (and, by inference, labile iron) and early death, diabetes, and malignant transformation. The rate of cancers now seems to be significantly higher in thalassemia than in the general population. Reduction in iron can reverse many of these complications and reduce the risk of malignancy. As toxicity can result from prolonged exposure to even low levels of excess iron, and survival in thalassemia patients is now many decades, it would seem prudent to refocus attention on prevention of long-term complications of iron overload and to maintain labile iron and total body iron levels within a normal range, if expertise and resources are available to avoid complications of overtreatment.
Asunto(s)
Terapia por Quelación/métodos , Manejo de la Enfermedad , Hemoglobinopatías/sangre , Hemoglobinopatías/terapia , Sobrecarga de Hierro/sangre , Sobrecarga de Hierro/terapia , Animales , Terapia por Quelación/tendencias , Hemoglobinopatías/diagnóstico , Humanos , Hierro/sangre , Sobrecarga de Hierro/diagnósticoRESUMEN
Regular red cell transfusions used to treat thalassemia cause iron loading that must be treated with chelation therapy. Morbidity and mortality in thalassemia major are closely linked to the adequacy of chelation. Chelation therapy removes accumulated iron and detoxifies iron, which can prevent and reverse much of the iron-mediated organ injury. Currently, three chelators are commercially available--deferoxamine, deferasirox, and deferiprone--and each can be used as monotherapy or in combination. Close monitoring of hepatic and cardiac iron burden is central to tailoring chelation. Other factors, including properties of the individual chelators, ongoing transfusional iron burden, and patient preference, must be considered. Monotherapy generally is utilized if the iron burden is in an acceptable or near-acceptable range and the dose is adjusted accordingly. Combination chelation often is employed for patients with high iron burden, iron-related organ injury, or where adverse effects of chelators preclude administration of an appropriate chelator dose. The combination of deferoxamine and deferiprone is the best studied, but increasing data are available on the safety and efficacy of newer chelator combinations, including deferasirox with deferoxamine and the oral-only combination of deferasirox with deferiprone. The expanding chelation repertoire should enable better control of iron burden and improved outcomes.
Asunto(s)
Transfusión Sanguínea/métodos , Terapia por Quelación/métodos , Quelantes del Hierro/uso terapéutico , Talasemia/terapia , Animales , Transfusión Sanguínea/tendencias , Terapia por Quelación/tendencias , Ensayos Clínicos como Asunto/métodos , Humanos , Talasemia/sangre , Talasemia/diagnósticoRESUMEN
New developments on chelation have been discussed during the 20th International Conference on Chelation in Grand Rapids, MI, USA, which could affect the treatments of millions of patients worldwide. The complete treatment of transfusional iron overload in thalassaemia using the deferiprone (L1) and deferoxamine combination is a paradigm to be followed in the treatment of many other metal toxicity conditions. Encouraging results from clinical testing increased the prospects of the application of L1 as a pharmaceutical chelator antioxidant in renal, neurodegenerative and other conditions. The development of new chelators for the detoxification of heavy and radioactive metals is in the final stages of approval for clinical use. EDTA chelation for heavy metal detoxification has been used in millions of patients worldwide in the last 50 years and continues to attract many categories of patients because of low toxicity and therapeutic benefits. Major changes on chelation therapy policy have been introduced by the FDA in the USA in the last few years, including the approval of L1 in 2011, the release of reports with 2474 fatalities which include thalassaemia and sickle cell anaemia patients in the period 2007-2011 in the case of deferasirox and the reappraisal of EDTA chelation therapy by NIH for patients who have suffered myocardial infraction. Major controversies in the use of chelating drugs worldwide include the risk/benefit assessment of different chelation protocols for different conditions and the commercial conflicts between generic and patented drugs.
Asunto(s)
Quelantes/uso terapéutico , Terapia por Quelación/métodos , Terapia por Quelación/tendencias , Deferiprona , Deferoxamina/uso terapéutico , Ácido Edético/uso terapéutico , Humanos , Sobrecarga de Hierro/tratamiento farmacológico , Sobrecarga de Hierro/etiología , Metales/envenenamiento , Intoxicación/tratamiento farmacológico , Piridonas/uso terapéutico , Medición de Riesgo , Talasemia/complicaciones , Talasemia/tratamiento farmacológico , Resultado del Tratamiento , Estados UnidosRESUMEN
Major advances were presented at the 19th International Conference on Chelation (ICOC) in London, UK including changes in iron chelation therapy that led to the complete treatment of transfusional iron overload. The first oral iron chelation results in animals using deferiprone (L1) were published in 1985, and effective iron removal in thalassemia and myelodysplasia patients were reported 2 years later. The results of multicenter clinical trials of L1 were presented at the 1st ICOC in London, UK in 1989. Long-term use of L1 resulted in the reduction of the mortality rate in thalassemia patients due to the effective removal of all excess iron from the heart. In 2008, specific combinations of L1 and deferoxamine (DFO) were reported to cause the complete removal of excess iron load and the achievement of normal range body iron store levels (NRBISL) in thalassemia patients. Patients with NRBISL were identified to require lower doses of L1 for the maintenance of negative iron balance. The introduction of deferasirox (DFRA) may benefit patients not tolerating L1, DFO or their combination. A simple, inexpensive synthesis of L1 has encouraged its manufacture in developing countries for the benefit of patients who could not afford the expensive imported chelating drugs or formulations.
Asunto(s)
Terapia por Quelación/métodos , Quelantes del Hierro/uso terapéutico , Sobrecarga de Hierro/tratamiento farmacológico , Piridonas/uso terapéutico , Animales , Terapia por Quelación/tendencias , Deferiprona , Humanos , Londres , Resultado del TratamientoRESUMEN
Although blood transfusions are important for patients with hemoglobinopathies, chronic transfusions inevitably lead to iron overload as humans cannot actively remove excess iron. The cumulative effects of iron overload lead to significant morbidity and mortality, if untreated. Desferrioxamine (DFO) is the reference-standard iron chelator whose safety and efficacy profile has been established through many years of clinical use. DFO side effects are acceptable and manageable however the prolonged subcutaneous infusion regimen of 5-7 days per week is very demanding and results in poor adherence to therapy. Deferiprone (Ferriprox, L1) is a bidentate molecule, orally administrable three-times/day, licensed in Europe and in other regions but in the USA and Canada, for the treatment of iron overload in patients for whom DFO therapy is contraindicated or inadequate. Preliminary evidences suggest that Deferiprone may be more effective than DFO in chelating cardiac iron. The side effects include gastrointestinal symptoms, liver dysfunction, joint pain, neutropenia and agranulocytosis. A weekly assessment of white blood cell counts is recommended because of the risk of agranulocytosis. Deferasirox is a new, convenient, once-daily oral iron chelator that has demonstrated in various clinical trials good efficacy and acceptable safety profile in adult and pediatric patients affected by transfusion-dependent thalassemia major and by different chronic anemias (SCD, BDA, MDS). The long half-life of Deferasirox (16-18 hours) provides sustained 24 hr iron chelation coverage. The efficacy and safety profile have been evaluated in more than 1000 patients in clinical trials allowing FDA registration. Patient satisfaction with Deferasirox was superior than with DFO therapy.
Asunto(s)
Terapia por Quelación/tendencias , Hemoglobinopatías/tratamiento farmacológico , Quelantes del Hierro/uso terapéutico , Terapia por Quelación/economía , Humanos , Quelantes del Hierro/economía , Cooperación del PacienteRESUMEN
Chelates are used in cancer as cytotoxic agent, as radioactive agent in imaging studies and in radioimmunotherapy. Various chelates based on ruthenium, copper, zinc organocobalt, gold, platinum, palladium, cobalt, nickel and iron are reported as cytotoxic agent. Monoclonal antibodies labeled with radioactive metals such as yttrium-90, indium-111 and iodine-131 are used in radioimmunotherapy. This review is an attempt to compile the use of chelates as cytotoxic drugs and in radioimmunotherapy.
Asunto(s)
Terapia por Quelación/tendencias , Quimioterapia/tendencias , Neoplasias/tratamiento farmacológico , Neoplasias/radioterapia , Radioinmunoterapia/tendencias , Animales , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Procesos de Crecimiento Celular/efectos de los fármacos , Procesos de Crecimiento Celular/efectos de la radiación , Quelantes/uso terapéutico , Citotoxinas/uso terapéutico , Humanos , Ratones , Neoplasias/patología , Radioisótopos/uso terapéutico , Ratas , Resultado del TratamientoRESUMEN
Deferiprone (L1), and appropriate combinations with deferoxamine (DFO), can be used effectively for the treatment of thalassemia and other transfusional iron loading conditions. A number of experimental iron chelators such as deferasirox or ICL670 or Exjade (4-(3,5-bis (2-hydroxyphenyl)-1,2,4-triazol-1-yl)-benzoic acid), deferitrin (4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methylthiazole-4 (S)-carboxylic acid) or GT56-252, 1-allyl-2-methyl-3-hydroxypyrid-4-one or L1NAll and starch DFO polymers, are under clinical evaluation. ICL670 is the most advanced in development and appears to be effective in reducing liver iron in some patients but is overall ineffective in causing negative iron balance. It is also suspected that it is not effective in cardiac iron removal. Combination therapies using L1, DFO and new iron chelating drugs may cause higher efficacy and lower toxicity by comparison to monotherapies. However, several limitations including the high cost of the new chelating drugs may not facilitate the availability of these new treatments to the vast majority of thalassemia patients, most of whom live in developing countries.
Asunto(s)
Terapia por Quelación/tendencias , Quelantes del Hierro/uso terapéutico , Sobrecarga de Hierro/tratamiento farmacológico , Talasemia/tratamiento farmacológico , Benzoatos/uso terapéutico , Ácidos Carboxílicos/uso terapéutico , Terapia por Quelación/economía , Ensayos Clínicos como Asunto , Deferasirox , Deferiprona , Deferoxamina/uso terapéutico , Evaluación de Medicamentos , Quimioterapia Combinada , Predicción , Hemocromatosis/tratamiento farmacológico , Hemocromatosis/genética , Humanos , Derivados de Hidroxietil Almidón/uso terapéutico , Sobrecarga de Hierro/etiología , Estructura Molecular , Piridonas/uso terapéutico , Almidón/uso terapéutico , Talasemia/terapia , Tiazoles/uso terapéutico , Reacción a la Transfusión , Triazoles/uso terapéuticoRESUMEN
Levels of iron are increased in the brains of Parkinson's disease (PD) patients compared to age-matched controls. This has been postulated to contribute to progression of the disease via several mechanisms including exacerbation of oxidative stress, initiation of inflammatory responses and triggering of Lewy body formation. In this minireview, we examine the putative role of iron in PD and its pharmacological chelation as a prospective therapeutic for the disease.
Asunto(s)
Quelantes del Hierro/farmacología , Hierro/antagonistas & inhibidores , Hierro/metabolismo , Neuronas/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Sustancia Negra/metabolismo , Animales , Terapia por Quelación/métodos , Terapia por Quelación/tendencias , Encefalitis/tratamiento farmacológico , Encefalitis/metabolismo , Encefalitis/fisiopatología , Humanos , Quelantes del Hierro/uso terapéutico , Cuerpos de Lewy/efectos de los fármacos , Cuerpos de Lewy/metabolismo , Neuronas/efectos de los fármacos , Neuronas/patología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Sustancia Negra/patología , Sustancia Negra/fisiopatologíaRESUMEN
Iron chelators are used in clinical practice to protect patients from the complications of iron overload and iron toxicity because there is no physiologic way for excess iron to be actively excreted. Deferoxamine, the only iron-chelating agent available for clinical use in the United States, is administered as a prolonged (8 to 24 hours) infusion, leading to poor compliance in many patients. Although many compounds have been screened in tissue cultures and animals as iron chelators, few have reached the stage of phase I and II clinical trials. The search for new chelating agents, which includes the "slow-release" depot formulation of deferoxamine and the "long-acting" hydroxyethyl starch-deferoxamine, has been disappointing because clinical trials have not demonstrated the intended efficacy. A more promising compound, ICL 670A--an orally active representative of a new class of iron chelators designed by computer modeling-is a potent and selective iron chelator. Its ability to mobilize tissue iron and promote its excretion has been shown in several animal models. In phase I dose-finding trials, ICL 670A was well tolerated and had a good safety profile. This compound is currently undergoing further clinical evaluation.
Asunto(s)
Terapia por Quelación/métodos , Quelantes del Hierro/administración & dosificación , Animales , Terapia por Quelación/normas , Terapia por Quelación/tendencias , Vías de Administración de Medicamentos , Composición de Medicamentos , Humanos , Quelantes del Hierro/normas , Quelantes del Hierro/toxicidad , Sobrecarga de Hierro/tratamiento farmacológicoRESUMEN
Malaria is one of the major global health problems, and an urgent need for the development of new antimalarial agents faces the scientific community. A considerable number of iron(III) chelators, designed for purposes other than treating malaria, have antimalarial activity in vitro, apparently through the mechanism of withholding iron from vital metabolic pathways of the intra-erythrocytic parasite. Certain iron(II) chelators also have antimalarial activity, but the mechanism of action appears to be the formation of toxic complexes with iron rather than the withholding of iron. Several of the iron(III)-chelating compounds also have antimalarial activity in animal models of plasmodial infection. Iron chelation therapy with desferrioxamine, the only compound of this nature that is widely available for use in humans, has clinical activity in both uncomplicated and severe malaria in humans.
Asunto(s)
Terapia por Quelación/tendencias , Hierro , Malaria Falciparum/terapia , Animales , Humanos , Hierro/metabolismo , Plasmodium falciparum/metabolismoRESUMEN
La enfermedad de células falciformes (ECF) es definida como un grupo de desordenes genéticos caracterizados por la presencia de hemoglobina S (Hb S), anemia y daño tisular agudo y crónico. La anemia falciforme es el tipo más común de enfermedad de células falciformes, y es causada por la presencia del gen de blobina Bs en el estado hemocigoto. Por el momento no existe una cura para la anemia falciforme, con la excepción del transplante de médula ósea, que está disponible sólo para un número limitado de individuos. La falta de drogas o tratamientos para cura de la enfermedad de células falciformes es debida en parte a la ausencia de buenos modelos animales. Los modelos de ratones transgénicos para enfermedades falciformes brindan la oportunidad de experimentar con nuevos tratamientos, drogas y agentes anti-sickling para tratar estas enfermedades. Hasta que una cura sea hallada, el tratamiento continuará siendo para las complicaciones asociadas con la enfermedad. Ultimos avances sobre inmunizaciones, penicilina profiláctica, ácido fólico, trental, quelación y terapia de hierro, experimental y otras drogas para el tratamiento de la anemia falciforme son presentados en este artículo.