RESUMO
Background: Deferasirox is an active iron chelator, used in the treatment of iron overload such as hemochromatosis. Up to 28% may present adverse reactions to said drug. A desensitization protocol for this drug may be useful when there are no other therapeutic options. Case report: A 52-year-old female with a diagnosis of hemochromatosis who began treatment with phlebotomy, poor response and tolerance, so it was decided to treat with deferasirox 500 mg daily, presenting symptoms of urticaria and angioedema on the third dose. Hospitalization was decided for a desensitization protocol with an initial dose of 0.6mg with a gradual increase in the dose, reaching a maintenance dose of 500 mg per day on the third day. Conclusions: The rapid desensitization protocol for Deferasirox is useful when there is no response or therapeutic alternative.
Antecedentes: Deferasirox es un quelante de hierro activo, indicado en el tratamiento de pacientes con hemocromatosis; sin embargo, se ha informado que el 28% de los casos puede tener reacciones adversas al fármaco. El protocolo de desensibilización para deferasirox puede ser útil cuando no se dispone de opciones terapéuticas adicionales. Reporte de caso: Paciente femenina de 52 años, con diagnóstico de hemocromatosis, quien luego de practicarle una flebotomía se observó poca respuesta y tolerancia al tratamiento, por lo que se decidió indicar deferasirox (500 mg/día), manifestando un cuadro de urticaria y angioedema en la tercera toma. Se decidió hospitalizarla para implementar el protocolo de desensibilización con una dosis inicial de 0.6 mg, con incremento gradual hasta llegar, al tercer día, a una dosis de mantenimiento de 500 mg/día. Conclusiones: El protocolo de desensibilización rápida con deferasirox es útil cuando no se obtiene respuesta satisfactoria con la flebotomía o no se dispone opciones de tratamiento alternativas.
Assuntos
Deferasirox , Hemocromatose , Quelantes de Ferro , Feminino , Humanos , Pessoa de Meia-Idade , Deferasirox/uso terapêutico , Hemocromatose/tratamento farmacológico , Quelantes de Ferro/uso terapêuticoRESUMO
We evaluated the growth and the susceptibility to oxidative stress of Sporothrix spp., exposed to different iron concentrations in culture medium, and the susceptibility of Sporothrix spp. to itraconazole, alone and in combination with to the iron chelator deferasirox. The results showed that the growth of S. brasiliensis isolates was more affected by iron availability in comparison to S. schenckii, but both fungal species conidia became more prone to oxidative stress when iron was added to culture medium. Conversely, the combination of itraconazole and deferasirox only resulted in synergism against a minority of S. schenckii isolates.
Assuntos
Antifúngicos/farmacologia , Ferro/farmacologia , Itraconazol/farmacologia , Sporothrix/efeitos dos fármacos , Sporothrix/crescimento & desenvolvimento , Meios de Cultura/química , Deferasirox/farmacologia , Sinergismo Farmacológico , Ferro/metabolismo , Testes de Sensibilidade Microbiana , Esporos Fúngicos/efeitos dos fármacos , Sporothrix/metabolismo , Esporotricose/tratamento farmacológico , Esporotricose/microbiologiaRESUMO
Alterations in iron homeostasis are well described in obese patients. The effects of iron chelators on adipose tissue and other organs affected by obesity have been the interest of experimental studies, both in vivo and in vitro. The aim of this review was to update the available information indicating the potential of iron chelators as adjuvant drugs in the management of obesity and its comorbidities. The pharmacological actions of iron chelators, mainly deferoxamine, deferasirox, and deferiprone, on adipose tissue and liver alterations associated with obesity, were reviewed. Renal and other organ modifications observed in experimental obesity models (endotoxemia, ß-cell function, and systemic inflammation) were included, as well as data from clinical studies that were relevant to this review. The experimental results obtained with iron chelators showed their potential in the control of obesity-induced alterations in the adipose tissue and liver. However, knowledge about the possible systemic effects on endotoxemia and low-grade inflammation in obesity models is still lacking. In endotoxemia in humans, data obtained did not corroborate the anti-inflammatory effect described in experimental models. Clinical and experimental data reveal renal, ß-cell protection and inhibition of advanced glycation end products, which have long-term benefits in obesity. Experimental models of obesity demonstrated the beneficial effects of iron chelators on the adipose tissue, liver, kidneys, and ß-cells. Hence, clinical studies could be designed to evaluate the potential of iron chelators as a therapeutic option in the management of obesity.
Assuntos
Quelantes de Ferro/farmacologia , Obesidade/tratamento farmacológico , Animais , Homeostase/efeitos dos fármacos , Humanos , Ferro/metabolismo , Quelantes de Ferro/uso terapêutico , Obesidade/complicações , Obesidade/metabolismo , Obesidade/patologiaRESUMO
Using an iron overload mouse model, we explored the protective effect of deferasirox (DFX) and N-acetyl-L-cysteine (NAC) on injured bone marrow hematopoietic stem/progenitor cells (HSPC) induced by iron overload. Mice were intraperitoneally injected with 25 mg iron dextran every 3 days for 4 weeks to establish an iron overload (Fe) model. DFX or NAC were co-administered with iron dextran in two groups of mice (Fe+DFX and Fe+NAC), and the function of HSPCs was then examined. Iron overload markedly decreased the number of murine HSPCs in bone marrow. Subsequent colony-forming cell assays showed that iron overload also decreased the colony forming capacity of HSPCs, the effect of which could be reversed by DFX and NAC. The bone marrow hematopoiesis damage caused by iron overload could be alleviated by DFX and NAC.
Assuntos
Animais , Masculino , Acetilcisteína/farmacologia , Triazóis/farmacologia , Benzoatos/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Quelantes de Ferro/farmacologia , Sequestradores de Radicais Livres/farmacologia , Sobrecarga de Ferro/prevenção & controle , Substâncias Protetoras/farmacologia , Valores de Referência , Fatores de Tempo , Reprodutibilidade dos Testes , Resultado do Tratamento , Espécies Reativas de Oxigênio/análise , Ensaio de Unidades Formadoras de Colônias , Modelos Animais de Doenças , Citometria de Fluxo , Hematopoese/efeitos dos fármacos , Camundongos Endogâmicos C57BLRESUMO
Deferasirox (DFX), an orally active and clinically approved iron chelator, is being used extensively for the treatment of iron overload. However, its water insolubility makes it cumbersome for practical use. In addition to this, the low efficacy of DFX to remove brain iron prompted us to synthesize and evaluate a DFX-TAT(47-57) peptide conjugate for its iron chelation properties and permeability across RBE4 cell line, an in vitro model of the blood-brain barrier. The water-soluble conjugate was able to remove labile iron from buffered solution as well as from iron overloaded sera, and the permeability of DFX-TAT(47-57) conjugate into RBE4 cells was not affected compared to parent deferasirox. The iron bound conjugate was also able to translocate through the cell membrane.
Assuntos
Benzoatos/química , Quelantes de Ferro/química , Sobrecarga de Ferro/tratamento farmacológico , Fragmentos de Peptídeos/química , Triazóis/química , Produtos do Gene tat do Vírus da Imunodeficiência Humana/química , Animais , Benzoatos/administração & dosagem , Benzoatos/síntese química , Barreira Hematoencefálica/efeitos dos fármacos , Linhagem Celular , Membrana Celular/química , Membrana Celular/efeitos dos fármacos , Deferasirox , Humanos , Quelantes de Ferro/administração & dosagem , Quelantes de Ferro/síntese química , Sobrecarga de Ferro/patologia , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/síntese química , Ratos , Solubilidade , Triazóis/administração & dosagem , Triazóis/síntese química , Água/química , Produtos do Gene tat do Vírus da Imunodeficiência Humana/administração & dosagem , Produtos do Gene tat do Vírus da Imunodeficiência Humana/síntese químicaRESUMO
There has been a growing interest in the use of micelles with nanofiber geometry as nanocarriers for hydrophobic drugs. Here we show that the conjugate of penetratin, a cell-penetrating peptide (CPP) with blood-brain barrier (BBB) permeability, and deferasirox (DFX), a hydrophobic iron chelator, self-assembles to form micelles at a very low concentration (â¼15 mg/L). The critical micelle concentration (CMC) was determined, and the micelles were used for solubilizing curcumin, a hydrophobic anti-neurodegenerative drug, for successful delivery across RBE4 cells, a BBB model. Transmission Electron Microscope images of the curcumin-loaded micelles confirmed the formation of nanofibers. These results indicate the potential of CPP-drug conjugates for use as nanocarriers.
Assuntos
Benzoatos/química , Proteínas de Transporte/química , Linhagem Celular/química , Portadores de Fármacos , Micelas , Triazóis/química , Animais , Permeabilidade da Membrana Celular , Peptídeos Penetradores de Células , Cromatografia Líquida de Alta Pressão , Dicroísmo Circular , Curcumina/administração & dosagem , Deferasirox , Interações Hidrofóbicas e Hidrofílicas , Microscopia Eletrônica de Transmissão , Ratos , Espectrometria de Fluorescência , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
This open-label, prospective, phase 2 study evaluated the safety and efficacy of deferasirox (10 ± 5 mg/kg/d) in patients with hereditary hemochromatosis (HH) and iron overload refractory to or intolerant of phlebotomy. Ten patients were enrolled and all completed the 12-month treatment period. There were significant decreases from baseline to end of study (i.e., 12 months) in median serum ferritin (P < 0.001), mean transferrin saturation (P < 0.05), median liver iron concentration (P < 0.001), and mean alanine aminotransferase (P < 0.05). The median time to achieve serum ferritin reduction ≥50% compared to baseline was 7.53 months. The most common adverse events were mild, transient diarrhea (n = 5) and nausea (n = 2). No patient experienced an increase in serum creatinine that exceeded the upper limit of normal. These data confirm that deferasirox was well tolerated and effective in reducing iron burden in patients with hereditary hemochromatosis and could be a safe alternative to phlebotomy in selected patients.
Assuntos
Benzoatos/uso terapêutico , Hemocromatose/complicações , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/etiologia , Triazóis/uso terapêutico , Adulto , Idoso , Benzoatos/administração & dosagem , Benzoatos/efeitos adversos , Biomarcadores , Deferasirox , Índices de Eritrócitos , Feminino , Hemocromatose/diagnóstico , Hemocromatose/genética , Proteína da Hemocromatose , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Quelantes de Ferro/administração & dosagem , Quelantes de Ferro/efeitos adversos , Sobrecarga de Ferro/diagnóstico , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Mutação , Fatores de Tempo , Resultado do Tratamento , Triazóis/administração & dosagem , Triazóis/efeitos adversosRESUMO
In the absence of an iron chelating agent, patients with beta-thalassemia on regular transfusions present complications of transfusion-related iron overload. Without iron chelation therapy, heart disease is the major cause of death; however, hepatic and endocrine complications also occur. Currently there are three iron chelating agents available for continuous use in patients with thalassemia on regular transfusions (desferrioxamine, deferiprone, and deferasirox) providing good results in reducing cardiac, hepatic and endocrine toxicity. These practice guidelines, prepared by the Scientific Committee of Associação Brasileira de Thalassemia (ABRASTA), presents a review of the literature regarding iron overload assessment (by imaging and laboratory exams) and the role of T2* magnetic resonance imaging (MRI) to control iron overload and iron chelation therapy, with evidence-based recommendations for each clinical situation. Based on this review, the authors propose an iron chelation protocol for patients with thalassemia under regular transfusions.
RESUMO
In the absence of an iron chelating agent, patients with beta-thalassemia on regular transfusions present complications of transfusion-related iron overload. Without iron chelation therapy, heart disease is the major cause of death; however, hepatic and endocrine complications also occur. Currently there are three iron chelating agents available for continuous use in patients with thalassemia on regular transfusions (desferrioxamine, deferiprone, and deferasirox) providing good results in reducing cardiac, hepatic and endocrine toxicity. These practice guidelines, prepared by the Scientific Committee of Associação Brasileira de Thalassemia (ABRASTA), presents a review of the literature regarding iron overload assessment (by imaging and laboratory exams) and the role of T2* magnetic resonance imaging (MRI) to control iron overload and iron chelation therapy, with evidence-based recommendations for each clinical situation. Based on this review, the authors propose an iron chelation protocol for patients with thalassemia under regular transfusions.
Assuntos
Humanos , Talassemia beta , Transfusão de Sangue , Terapia por Quelação , Protocolos Clínicos , Quelantes de Ferro , Distúrbios do Metabolismo do Ferro , Imageamento por Ressonância MagnéticaRESUMO
Pacientes cronicamente transfundidos desenvolvem sobrecarga de ferro que ocasiona lesão orgânica e morte. Nos últimos trinta anos, pacientes com sobrecarga de ferro transfusional dependem de infusões noturnas de desferroxamina para quelação de ferro. Apesar da dramática melhora da expectativa de vida na era da desferroxamina para pacientes com anemias dependentes de transfusão, 50 por cento dos pacientes com talassemia maior morrem antes dos 30 anos de idade, predominantemente devido à insuficiência cardíaca induzida pelo ferro. A difícil natureza desse tratamento com infusão subcutânea prolongada por meio de aparelho infusor portátil motivou o desenvolvimento de formas alternativas de tratamento que facilitasse a aderência do paciente. Estratégias para reduzir a sobrecarga de ferro e suas conseqüências, através da melhora dos regimes de quelação, foram as prioridades mais importantes nos últimos anos. Nesta revisão, descrevemos os avanços mais importantes da terapia quelante de ferro. Em particular, analisamos os dois quelantes de ferro ativos por via oral: deferiprona e o novo quelante de ferro oral deferasirox.
Patients who are chronically dependent on transfusions will develop iron overload that leads to organ damage and eventually to death. For nearly 30 years, patients with transfusional iron overload have been subject to overnight deferoxamine infusions for iron chelation. Despite dramatic gains in terms of life expectancy in the deferoxamine era for patients with transfusion-dependent anemias, 50 percent of patients with thalassemia major die before the age of 35 years, predominantly due to iron-induced heart failure. The very demanding nature of this treatment with prolonged subcutaneous infusion via portable pump infusions has been the motivation for attempts to develop alternative forms of treatment that would facilitate the patients' compliance. Strategies to reduce iron overload and its consequences by improving chelation regimens have been of the highest priority in the last years.In this review, the most important advances in iron-chelating therapy are described, particularly the analysis of the two orally active iron chelators: deferiprone and the novel oral chelator deferasirox.