RESUMO
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: ß-Thalassemia major (BTM) is one of the most common hereditary anemias worldwide. Patients suffer from iron overload that results from repeated blood transfusion This in turn leads to multiple organ damage and endocrinopathies. This study aims to assess the prevalence of growth retardation, hypothyroidism, and diabetes mellitus in children and adolescents with BTM treated at Dubai Thalassemia Centre. METHODS: A total of 105 children and adolescents were included in this retrospective observational study. RESULTS: 39 children and 66 adolescents' data were analyzed. Females composed 51.3% (n = 20) of children and 53.0% (n = 35) of adolescents. Pretransfusion hemoglobin below 9 gm/dl was observed in 10.8% (n = 4) and 10.6% (n = 7) in children and adolescents, respectively. The mean age of menarche was 13.5 years. Among all study participants, 22.6% (n = 14) had normal height velocity whereas 37.1% (n = 23) had reduced height velocity in one year and 40.3% (n = 25) had reduced height velocity in two consecutive years. The proportion of children and adolescents showing reduced height velocity was significantly higher in females compared to the males (90.6% versus 63.3%, respectively, Chi-square = 6.597, p-value = 0.010). Although none of the study participants had diabetes mellitus, 26.1% (n = 12/46) had pre-diabetes. Elevated TSH was observed in 14.7% (n = 5) children and 8.1% (n = 5) adolescents while low FT4 was reported in one child and one adolescent. CONCLUSION: Of all endocrinopathies seen among children and adolescents with BTM, growth delay remains the main concern for this group of patients. Effective treatment is key to further reducing endocrinopathies. Although the sample size is limited, we postulate that the low percentage of endocrinopathies among children with BTM treated at Dubai thalassemia center and the low level of pretransfusion anemia reflect the effective transfusion and chelation at the center.
Assuntos
Diabetes Mellitus , Hipotireoidismo , Sobrecarga de Ferro , Talassemia beta , Masculino , Criança , Feminino , Adolescente , Humanos , Talassemia beta/complicações , Talassemia beta/epidemiologia , Talassemia beta/terapia , Quelantes de Ferro/efeitos adversos , Hipotireoidismo/epidemiologia , Hipotireoidismo/etiologiaRESUMO
BACKGROUND: Breast cancer (BC) stands as the second-leading cause of mortality among women worldwide. Many chemotherapeutic treatments for BC come with significant adverse effects. Additionally, BC is recognized as one of the most resistant forms of malignancy to treatment. Consequently, there exists a critical need for innovative therapeutic agents that are both highly effective and exhibit reduced toxicity and side effects for patients. Deferasirox (DFX), an iron-chelating drug approved by the FDA for oral use, emerges as a promising contender in the fight against BC proliferation. DFX, primarily administered orally, is utilized to address chronic iron excess resulting from blood transfusions, and it is the inaugural treatment for chronic iron overload syndrome. However, DFX encounters limitations due to its poor water solubility. AIM: This study aimed at incorporating DFX into lipid nanocapsules (DFX-LNCs) followed by investigating the anticancer effect of the DFX nanoform as compared to free DFX in-vitro and on an orthotopic BC mouse model in-vivo. METHODS: The DFX-LNCs was prepared and imaged using TEM and also characterized in terms of particle size (PS), zeta potential (ZP), and polydispersity index (PDI) using DLS. Moreover, drug release, cytotoxicity, and anticancer effect were assessed in-vitro, and in-vivo. RESULTS: The results revealed that DFX-LNCs are more cytotoxic than free DFX with IC50 of 4.417 µg/ml and 16.114 µg/ml, respectively, while the plain LNCs didn't show any cytotoxic effect on the 4T1 cell line (IC50 = 122.797 µg/ml). Besides, the apoptotic effect of DFX-LNCs was more pronounced than that of free DFX, as evidenced by Annexin V/PI staining, increased BAX expression, and decreased expression of BcL-2. Moreover, DFX-LNCs showed a superior antitumor effect in-vivo with potent antioxidant and anti-proliferative effects. CONCLUSION: The newly developed DFX nanoform demonstrated a high potential as a promising therapeutic agent for BC treatment.
Assuntos
Neoplasias da Mama , Sobrecarga de Ferro , Humanos , Feminino , Camundongos , Animais , Deferasirox/farmacologia , Deferasirox/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Quelantes de Ferro/efeitos adversos , Ferro/uso terapêutico , Sobrecarga de Ferro/induzido quimicamente , Sobrecarga de Ferro/tratamento farmacológicoRESUMO
The study aimed to determine efficacy and safety of generic deferasirox monotherapy. Deferasirox was administered in transfusion-induced iron overloaded thalassemia. Efficacy was defined as responders and nonresponders by ≤ 15 reduced serum ferritin from baseline. Adverse events were also monitored. Fifty-two patients with mainly Hb E/ß-thalassemia at the mean (SD) age of 8.7 (4.1) years, were enrolled. The mean (SD) daily transfusion iron load was 0.47 (0.1) mg/kg and maximum daily deferasirox was 35.0 (6.2) mg/kg. Altogether, 52, 40 and 18 patients completed the first, second and third years of study, respectively. The median baseline serum ferritin 2,383 ng/mL decreased to 1,478, 1,038 and 1,268 ng/mL at the end of first, second and third years, respectively, with overall response rate at 73.1% (38/52). Patients with baseline serum ferritin >2,500 ng/mL showed a change in serum ferritin higher than those ≤2,500 ng/mL starting from the 9th month of chelation. Adverse events were found in 5 of 52 patients (9.6%) including transaminitis (n = 2), one each of proteinuria, rash and proximal tubular dysfunction which resolved after transient stopping or decreasing the chelation dose. Generic deferasirox was effective and safe among pediatric patients with transfusion-induced iron overloaded thalassemia.
Assuntos
Sobrecarga de Ferro , Talassemia , Humanos , Criança , Deferasirox/efeitos adversos , Quelantes de Ferro/efeitos adversos , Benzoatos/efeitos adversos , Triazóis/efeitos adversos , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/etiologia , Talassemia/tratamento farmacológico , Ferro , FerritinasRESUMO
A series of new conjugates comprised from a small synthetic antimicrobial peptide (AMP) and a siderophore-type vector component was designed and tested for activity on P. aeruginosa PAO1 and several genetically modified strains. As AMP, the well-established arginine-tryptophane combination K(RW)3 (P1) was chosen with an added lysine for siderophore attachment. This peptide is easy to prepare, modify, and possesses good anti-bacterial activity. On the vector part, we examined several moieties: (i) the natural siderophore deferoxamine (DFO); (ii) bidentate iron chelators based on the hydroxamate building block (4 a-c) ; (iii) the non-siderophore chelators deferasirox (DFX) and deferiprone-carboxylate (DFP-COOH). All conjugates were prepared by solid phase synthesis techniques and fully characterized by HPLC and mass spectrometry (including HR-MS). 55 Fe uptake assays indicate a receptor-mediated uptake for 4 a-c, DFP-COOH and DFO, which is dependent on the outer membrane transporter FoxA in the case of DFO. All conjugates showed increased antibacterial activity against P. aeruginosa compared to the parent peptide P1 alone when investigated in iron-depleted medium. MIC values were as low as 2â µM (for P1-DFP) on wild type P. aeruginosa. The activity of P1-DFO and P1-DFP was even better on genetically mutated strains unable to produce siderophores (down to 0.5â µM). Although the DFX vector on its own was not able to transport iron inside the bacterial cell as shown by 55 Fe uptake studies, the P1-DFX conjugate had excellent antibacterial activity compared to P1 (2â µM, and as low as 0.25â µM on a receptor-deficient strain unable to produce siderophores), suggesting that the conjugates were indeed recognized and internalized by an (unknown) transporter. Control experiments with an equimolar mixture of P1 and DFX confirm that the observed activity is intrinsic to vectorization. This work thus demonstrates the power of linking small AMPs covalently to siderophores for a new class of Trojan Horse antibiotics, with P1-DFP and P1-DFX being the most potent conjugates.
Assuntos
Pseudomonas aeruginosa , Sideróforos , Sideróforos/química , Ferro/metabolismo , Antibacterianos/farmacologia , Antibacterianos/química , Proteínas de Membrana Transportadoras , Peptídeos , Proteínas de TransporteRESUMO
Iron chelation therapy (ICT) is the mainstay of treatment in patients with thalassemia requiring blood transfusions. This phase 2 JUPITER study evaluated patient preference between film-coated tablet (FCT) and dispersible tablet (DT) in transfusion-dependent thalassemia (TDT) or non-TDT (NTDT) patients treated with both formulations in a sequential manner. The primary endpoint was patient-reported preference for FCT over DT, while secondary outcomes included patient reported outcomes (PROs) evaluated by overall preference, and by age, thalassemia transfusion status, and previous ICT status. Out of 183 patients screened, 140 and 136 patients completed the treatment periods 1 and 2 of the core study, respectively. At week 48, the majority of patients preferred FCT over DT (90.3 vs. 7.5%; difference of percentage: 0.83 [95% confidence interval (CI), 0.75-0.89; P < 0.0001]). FCT scored better on secondary PROs and showed less severe gastrointestinal symptoms than DT, except in the change of modified Satisfaction with Iron Chelation Therapy (mSICT) preference scores, which were similar for both the formulations. Patients with TDT had stable ferritin levels, while it showed a downward trend up to week 48 in patients with NTDT on deferasirox treatment. Overall, 89.9% of patients reported ≥ 1 adverse event (AE), of which 20.3% experienced ≥ 1 serious AE. The most common treatment-emergent AEs were proteinuria, pyrexia, urine protein/creatinine ratio increase, diarrhea, upper respiratory tract infections, transaminase increase, and pharyngitis. Overall, this study reinforced the observations from the previous study by showing a distinct patient preference for FCT over DT formulation and further supported the potential benefits of life-long compliance with ICT.
Assuntos
Sobrecarga de Ferro , Talassemia , Humanos , Deferasirox , Sobrecarga de Ferro/complicações , Preferência do Paciente , Talassemia/tratamento farmacológico , Comprimidos , Ferro , Quelantes de Ferro/efeitos adversos , Benzoatos/efeitos adversosRESUMO
During the period of COVID-19, the occurrences of mucormycosis in immunocompromised patients have increased significantly. Mucormycosis (black fungus) is a rare and rapidly progressing fungal infection associated with high mortality and morbidity in India as well as globally. The causative agents for this infection are collectively called mucoromycetes which are the members of the order Mucorales. The diagnosis of the infection needs to be performed as soon as the occurrence of clinical symptoms which differs with types of Mucorales infection. Imaging techniques magnetic resonance imaging or computed tomography scan, culture testing, and microscopy are the approaches for the diagnosis. After the diagnosis of the infection is confirmed, rapid action is needed for the treatment in the form of antifungal therapy or surgery depending upon the severity of the infection. Delaying in treatment declines the chances of survival. In antifungal therapy, there are two approaches first-line therapy (monotherapy) and combination therapy. Amphotericin B (1) and isavuconazole (2) are the drugs of choice for first-line therapy in the treatment of mucormycosis. Salvage therapy with posaconazole (3) and deferasirox (4) is another approach for patients who are not responsible for any other therapy. Adjunctive therapy is also used in the treatment of mucormycosis along with first-line therapy, which involves hyperbaric oxygen and cytokine therapy. There are some drugs like VT-1161 (5) and APX001A (6), Colistin, SCH 42427, and PC1244 that are under clinical trials. Despite all these approaches, none can be 100% successful in giving results. Therefore, new medications with favorable or little side effects are required for the treatment of mucormycosis.
Assuntos
COVID-19 , Mucorales , Mucormicose , Humanos , Antifúngicos/uso terapêutico , Antifúngicos/farmacologia , Mucormicose/tratamento farmacológico , Mucormicose/diagnóstico , Mucormicose/microbiologia , Anfotericina B/uso terapêutico , Anfotericina B/farmacologiaRESUMO
Regular transfusion and chelation therapy produces increased life expectancy in thalassaemic patients who may develop new complications. Since few data are available regarding hypercalciuria in ß-thalassaemia major (TM), the aim of our study was to evaluate its prevalence, risk factors and clinical consequences. We enrolled 176 adult TM patients followed at the Center of Thalassemia of Ferrara. Hypercalciuria was defined by a calciuria of 4 mg/kg/day or more in a 24-h urine sample. Anamnestic, biochemical and radiological data were collected. Hypercalciuria prevalence was reported in 69.3% of patients (females 52.5%). Hypercalciuric (HC) patients used deferasirox (DFX) more often than normocalciuric (NC) patients (47.5% vs 29.6%; p < 0.05). In HC subjects plasma parathyroid hormone (PTH) (24.1 ± 10.4 vs 30.1 ± 13.2 pg/ml) and phosphate levels (3.6 ± 0.5 vs 3.8 ± 0.7 mg/dl) were lower, whereas serum calcium (9.6 ± 0.4 vs 9.4 ± 0.4 mg/dl) and urinary 24-h phosphaturia (0.9 ± 0.4 vs 0.6 ± 0.3 g/day) were higher as compared to NC patients (p < 0.05 for all comparisons). Supplementation with oral calcium and cholecalciferol was similar between the groups. A higher rate of kidney stones was present in HC (14.8%) versus NC patients (3.7%) (p < 0.05). Hypercalciuria is a frequent complication in adequately treated adult TM patients. Hypercalciuria prevalence is increased in DFX users whereas haemoglobin level or calcium supplements play no role. A significant proportion of HC patients developed kidney stones.
Assuntos
Cálculos Renais , Talassemia beta , Adulto , Cálcio , Feminino , Humanos , Hipercalciúria/epidemiologia , Hipercalciúria/etiologia , Hipercalciúria/urina , Cálculos Renais/urina , Prevalência , Fatores de Risco , Talassemia beta/complicações , Talassemia beta/tratamento farmacológicoRESUMO
Deferasirox (DFX) is used for the management of iron overload (IOL) in many haematological malignancies including myelofibrosis (MF). The 'RUX-IOL' study retrospectively collected 69 MF patients treated with ruxolitinib (RUX) and DFX for IOL to assess: safety, efficacy in term of iron chelation response (ICR) and erythroid response (ER), and impact on overall survival of the combination therapy. The RUX-DFX therapy was administered for a median time of 12.4 months (interquartile range 3.1-71.2). During treatment, 36 (52.2%) and 34 (49.3%) patients required RUX and DFX dose reductions, while eight (11.6%) and nine (13.1%) patients discontinued due to RUX- or DFX-related adverse events; no unexpected toxicity was reported. ICR and ER were achieved by 33 (47.8%) and 32 patients (46.4%) respectively. Thirteen (18.9%) patients became transfusion-independent. Median time to ICR and ER was 6.2 and 2 months respectively. Patients achieving an ER were more likely to obtain an ICR also (p = 0.04). In multivariable analysis, the absence of leukocytosis at baseline (p = 0.02) and achievement of an ICR at any time (p = 0.02) predicted improved survival. In many MF patients, the RUX-DFX combination provided ICR and ER responses that correlated with improved outcome in the absence of unexpected toxicities. This strategy deserves further clinical investigation.
Assuntos
Sobrecarga de Ferro , Mielofibrose Primária , Benzoatos/efeitos adversos , Deferasirox/uso terapêutico , Humanos , Quelantes de Ferro/efeitos adversos , Sobrecarga de Ferro/induzido quimicamente , Sobrecarga de Ferro/etiologia , Nitrilas , Mielofibrose Primária/tratamento farmacológico , Pirazóis , Pirimidinas , Estudos RetrospectivosRESUMO
OBJECTIVES: Reye Syndrome is an acute encephalopathy with increased liver enzymes and blood ammonia, without jaundice. The prevalence of an underlying inherited metabolic disorder (IMD) is unclear, nor the clinical or biological factors directing toward this diagnosis. Our aims were to define these clues in a large series of patients. PATIENTS AND METHODS: We retrospectively studied all patients with Reye admitted in our institution from 1995. We defined 3 groups: Group 1 with a confirmed IMD, Group 2 considered as free of IMD, Group 3 unclassified. Statistical analysis compared patients in Groups 1 and 2, to find criteria for a diagnosis of IMD. RESULTS: Fifty-eight children were included; 41 (71%) had a confirmed IMD, 12 (20%) were free of IMD, and 5 remained unclassified. IMDs included Urea Cycle Disorders (51%), Fatty-Acid Oxidation Disorders (24%), ketogenesis defects (5%), other mitochondrial energy metabolism defects (10%), NBAS mutation (7%), Glycosylation Disorders (2%). In Group 2, the trigger was a viral infection, or a drug, deferasirox in three children. Univariate analysis showed that onset before 2 years-old, recurrent Reye and the association with rhabdomyolysis were significantly associated with IMD. Blood ammonia was a poor discriminating marker. All children were admitted into the intensive care unit, 23% needed continuous venovenous hemodialysis and one died from brain oedema. CONCLUSION: Metabolic tests should be performed early in all cases of Reye, regardless of triggers. As they can be inconclusive, we suggest to systematically go to Next-Generation Sequencing study. These children should be transferred early to a specialized unit.
Assuntos
Acidose , Doenças Metabólicas , Síndrome de Reye , Amônia , Criança , Pré-Escolar , Humanos , Estudos Retrospectivos , Síndrome de Reye/metabolismoRESUMO
OBJECTIVE: Iron depletion may be a novel therapeutic strategy for cancer. This study aimed to assess the inhibition effects of deferasirox (DFX), an oral iron chelator, on cervical cancer. METHODS: In this study, we performed immunohistochemical analysis, enzyme-linked immunoassay, cell viability and invasive ability assay, cell cycle and apoptosis analysis, protein expression investigation, molecular mechanism investigation, and in vivo murine xenograft model to evaluate the impact of DFX on cervical cancer. RESULTS: The cervical cancer cell lines viability decreased and cell apoptosis was induced after DFX incubation. Additionally, DFX promoted cell cycle arrest by regulating the expression of cell cycle regulators cyclin D1, cyclin E and proliferating cell nuclear antigen (PCNA) in cervical cancer cell lines. DFX also decreased cell invasion by upregulating the expression of NDRG1 and downregulating c-Myc. The activation of Akt and the MEK/ERK signaling pathway was inhibited by DFX. DFX also significantly suppressed xenograft tumor growth, decreased the levels of ferritin in serum and tumor tissue, reduced iron deposits and reactive oxygen species (ROS) levels in xenografts of DFX-treated group compared with the control group, with no serious side effects. CONCLUSION: Present study demonstrated the inhibitory effect of DFX against cervical cancer, and provided a potential therapeutic agent for cervical cancer.
Assuntos
Quelantes de Ferro , Neoplasias do Colo do Útero , Animais , Benzoatos/farmacologia , Benzoatos/uso terapêutico , Deferasirox/farmacologia , Feminino , Humanos , Ferro , Quelantes de Ferro/farmacologia , Quelantes de Ferro/uso terapêutico , Camundongos , Triazóis/farmacologia , Triazóis/uso terapêutico , Neoplasias do Colo do Útero/tratamento farmacológicoRESUMO
Iron participates in myriad processes necessary to sustain life. During the past decades, great efforts have been made to understand iron regulation and function in health and disease. Indeed, iron is associated with both physiological (e.g., immune cell biology and function and hematopoiesis) and pathological (e.g., inflammatory and infectious diseases, ferroptosis and ferritinophagy) processes, yet few studies have addressed the potential functional link between iron, the aforementioned processes and extramedullary hematopoiesis, despite the obvious benefits that this could bring to clinical practice. Further investigation in this direction will shape the future development of individualized treatments for iron-linked diseases and chronic inflammatory disorders, including extramedullary hematopoiesis, metabolic syndrome, cardiovascular diseases and cancer.
Assuntos
Ferroptose , Hematopoese Extramedular , Distúrbios do Metabolismo do Ferro , Homeostase , Humanos , Ferro/metabolismoRESUMO
AIMS: To develop a drug-disease model describing iron overload and its effect on ferritin response in patients affected by transfusion-dependent haemoglobinopathies and investigate the contribution of interindividual differences in demographic and clinical factors on chelation therapy with deferiprone or deferasirox. METHODS: Individual and mean serum ferritin data were retrieved from 13 published studies in patients affected by haemoglobinopathies receiving deferiprone or deferasirox. A nonlinear mixed effects modelling approach was used to characterise iron homeostasis and serum ferritin production taking into account annual blood consumption, baseline demographic and clinical characteristics. The effect of chelation therapy was parameterised as an increase in the iron elimination rate. Internal and external validation procedures were used to assess model performance across different study populations. RESULTS: An indirect response model was identified, including baseline ferritin concentrations and annual blood consumption as covariates. The effect of chelation on iron elimination rate was characterised by a linear function, with different slopes for each drug (0.0109 [90% CI: 0.0079-0.0131] vs. 0.0013 [90% CI: 0.0008-0.0018] L/mg mo). In addition to drug-specific differences in the magnitude of the ferritin response, simulation scenarios indicate that ferritin elimination rates depend on ferritin concentrations at baseline. CONCLUSION: Modelling of serum ferritin following chronic blood transfusion enabled the evaluation of drug-induced changes in iron elimination rate and ferritin production. The use of a semi-mechanistic parameterisation allowed us to disentangle disease-specific factors from drug-specific properties. Despite comparable chelation mechanisms, deferiprone appears to have a significantly larger effect on the iron elimination rate than deferasirox.
Assuntos
Terapia por Quelação , Hemoglobinopatias , Benzoatos/uso terapêutico , Deferasirox , Deferiprona , Desferroxamina/uso terapêutico , Ferritinas , Hemoglobinopatias/induzido quimicamente , Hemoglobinopatias/tratamento farmacológico , Humanos , Ferro , Quelantes de Ferro/uso terapêutico , Piridonas/uso terapêutico , Triazóis/uso terapêuticoRESUMO
WHAT IS KNOWN AND OBJECTIVE: Patients with low-risk myelodysplastic syndrome (MDS) and aplastic anaemia (AA) often need transfusions, which may accelerate iron overload. The aim of this study was to evaluate the efficacy, safety and dose-effect relationships of deferasirox (DFX) in patients with low-risk MDS and AA who were refractory to regular treatment in a real-world setting. METHODS: Patient data were recorded, and dose-effect relationships of DFX were calculated after the first 6 months. Total annual exposure to DFX was calculated after 12 months and expressed as the accumulated exposure time at a dosage of 20 mg/kg/day. RESULTS AND DISCUSSION: Sixty-one patients with low-risk MDS and 51 with AA were enrolled. The minimum dosage of DFX needed for a significant serum ferritin (SF) decrease was 20 mg/kg/day at 6 months, and the minimum accumulation of DFX had to reach 9 months at 20 mg/kg/day by 12 months for patients with low-risk MDS. For patients with AA, the minimum dosage was 10 mg/kg/day at 6 months, and the minimum accumulation had to reach 3 months at 20 mg/kg/day by 12 months. With the same exposure, significant improvements in haematological parameters were also observed in AA. Lower liver enzymes compared with baseline were observed. Gastrointestinal disorders and elevated serum creatinine were the most common side effects. Higher exposure to DFX correlated with longer overall survival (OS). WHAT IS NEW AND CONCLUSION: A significant decrease in SF and an improvement in haematologic parameters, organ function and even OS can be achieved if the accumulated DFX dose reaches a certain level. Patients with low-risk MDS need a higher dose than those with AA.
Assuntos
Anemia Aplástica , Sobrecarga de Ferro , Síndromes Mielodisplásicas , Anemia Aplástica/tratamento farmacológico , Benzoatos/efeitos adversos , Creatinina , Deferasirox/uso terapêutico , Ferritinas/uso terapêutico , Humanos , Quelantes de Ferro/efeitos adversos , Sobrecarga de Ferro/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Triazóis/efeitos adversosRESUMO
We aimed to investigate the role of urinary kidney injury molecule-1 (KIM-1) in detection of subclinical nephrotoxicity in patients with Beta-thalassemia (ß-TM) in relation to chelation therapy and to correlate the urinary KIM-1 level with other clinical and laboratory findings. We conducted a cross-sectional study on 66 thalassemic patients. Their ages range from 7 to 22 years. Routine kidney indices and novel urinary KIM/creatinine ratio (UKIM-1/Cr) were measured. Estimated glomerular filtration rate (eGFR) was calculated. Results indicate that the level of serum creatinine was significantly higher in patients on deferasirox therapy than patients on deferoxamine and deferiprone therapy [median(IQR), 0.85(0.63-0.99), 0.50(0.34-0.58) and 0.44(0.36-0.45)] mg/dL, respectively, p < 0.001]. The median(IQR) level of eGFR was significantly lower in patients on deferasirox therapy than patients on deferoxamine and deferiprone therapy [63.3(56.5-92.1), 117.3(91.9-162) and 136.7(109.4-157.6)] ml/min/1.73 m2, respectively, p < 0.001]. The mean level of UKIM-1/Cr was significantly higher in patients on deferasirox therapy than patients on deferoxamine and deferiprone therapy (7.0 ± 1.9, 4.1 ± 1.7 and 4.2 ± 1.5) ng/mg creatinine, respectively, p < 0.001). We concluded that urinary KIM-1 is an early predictive biomarker for decline in eGFR in patients with ß-TM on deferasirox therapy. The appropriate chelation therapy and good monitoring of those patients are intensely needed for early detection of renal dysfunction and timely intervention.
Assuntos
Sobrecarga de Ferro , Talassemia beta , Adolescente , Adulto , Criança , Estudos Transversais , Deferasirox , Desferroxamina/efeitos adversos , Humanos , Quelantes de Ferro/efeitos adversos , Rim , Adulto Jovem , Talassemia beta/complicações , Talassemia beta/tratamento farmacológicoRESUMO
Iron is a crucial element for mammalian cells, considering its intervention in several physiologic processes. Its homeostasis is finely regulated, and its alteration could be responsible for the onset of several disorders. Iron is closely related to inflammation; indeed, during inflammation high levels of interleukin-6 cause an increased production of hepcidin which induces a degradation of ferroportin. Ferroportin degradation leads to decreased iron efflux that culminates in elevated intracellular iron concentration and consequently iron toxicity in cells and tissues. Therefore, iron chelation could be considered a novel and useful therapeutic strategy in order to counteract the inflammation in several autoimmune and inflammatory diseases. Several iron chelators are already known to have anti-inflammatory effects, among them deferiprone, deferoxamine, deferasirox, and Dp44mT are noteworthy. Recently, eltrombopag has been reported to have an important role in reducing inflammation, acting both directly by chelating iron, and indirectly by modulating iron efflux. This review offers an overview of the possible novel biological effects of the iron chelators in inflammation, suggesting them as novel anti-inflammatory molecules.
Assuntos
Sobrecarga de Ferro , Animais , Benzoatos/uso terapêutico , Deferasirox/uso terapêutico , Deferiprona , Desferroxamina/uso terapêutico , Inflamação/complicações , Inflamação/tratamento farmacológico , Ferro/uso terapêutico , Quelantes de Ferro/farmacologia , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/etiologia , Mamíferos , Piridonas/uso terapêuticoRESUMO
Mantle cell lymphoma (MCL) is a difficult-to-treat B-cell malignancy characterized by cyclin D1 (CD1) overexpression. Targeting CD1 in MCL has been shown to be of therapeutic significance. However, treatment of MCL remains challenging since patients are still subject to early and frequent relapse of the disease. To ensure their high proliferation rate, tumour cells have increased iron needs, making them more susceptible to iron deprivation. Indeed, several iron chelators proved to be effective anti-cancer agents. In this study, we demonstrate that the clinically approved iron chelator deferasirox (DFX) exerts an anti-tumoural effect in MCL cell lines and patient cells. The exposure of MCL cells to clinically feasible concentrations of DFX resulted in growth inhibition, cell cycle arrest and induction of apoptosis. We show that DFX unfolds its cytotoxic effect by a rapid induction of reactive oxygen species (ROS) that leads to oxidative stress and severe DNA damage and by triggering CD1 proteolysis in a mechanism that requires its phosphorylation on T286 by glycogen synthase kinase-3ß (GSK3ß). Moreover, we demonstrate that DFX mediates CD1 proteolysis by repressing the phosphatidylinositol 3-kinase (PI3K)/AKT/GSK3ß pathway via ROS generation. Our data suggest DFX as a potential therapeutic option for MCL and paves the way for more treatment options for these patients.
Assuntos
Apoptose/efeitos dos fármacos , Ciclina D1/metabolismo , Deferasirox/farmacologia , Quelantes de Ferro/farmacologia , Linfoma de Célula do Manto/tratamento farmacológico , Proteólise/efeitos dos fármacos , Linhagem Celular Tumoral , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Linfoma de Célula do Manto/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Células Tumorais CultivadasRESUMO
In the current study, the synthesis of a theranostic platform composed of superparamagnetic iron oxide nanoparticles (SPION)-deferasirox conjugates targeted with AS1411 DNA aptamer was reported. In this regard, SPION was amine-functionalized by (3-aminopropyl)trimethoxysilane (ATPMS), and then deferasirox was covalently conjugated onto its surface. Finally, to provide guided drug delivery to cancerous tissue, AS1411 aptamer was conjugated to the complex of SPION-deferasirox. The cellular toxicity assay on CHO, C-26 and AGS cell lines verified higher cellular toxicity of targeted complex in comparison with non-targeted one. The evaluation of in vivo tumor growth inhibitory effect in C26 tumor-bearing mice illustrated that the aptamer-targeted complex significantly enhanced the therapeutic outcome in comparison with both non-targeted complex and free drug. The diagnostic capability of the prepared platform was also evaluated implementing C26-tumor-bearing mice. Obtained data confirmed higher tumor accumulation and higher tumor residence time for targeted complex through MRI imaging due to the existence of SPION as a contrast agent in the core of the prepared complex. The prepared multimodal theranostic system provides a safe and effective platform for fighting against cancer.
Assuntos
Antineoplásicos/uso terapêutico , Meios de Contraste/uso terapêutico , Deferasirox/uso terapêutico , Quelantes de Ferro/uso terapêutico , Nanopartículas de Magnetita/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Aptâmeros de Nucleotídeos/química , Células CHO , Linhagem Celular Tumoral , Meios de Contraste/síntese química , Cricetulus , Deferasirox/química , Feminino , Humanos , Ácidos Nucleicos Imobilizados/química , Ácidos Nucleicos Imobilizados/uso terapêutico , Quelantes de Ferro/síntese química , Estimativa de Kaplan-Meier , Imageamento por Ressonância Magnética , Nanopartículas de Magnetita/química , Camundongos Endogâmicos BALB C , Medicina de Precisão , Propilaminas/química , Silanos/químicaRESUMO
MDS are characterized by anemia and transfusion requirements. Transfused patients frequently show iron overload that negatively affects hematopoiesis. Iron chelation therapy can be effective in these MDS cases, but the molecular consequences of this treatment need to be further investigated. That is why we studied the molecular features of iron effect and Deferasirox therapy on PI-PLCbeta1 inositide signaling, using hematopoietic cells and MDS samples. At baseline, MDS patients showing a positive response after iron chelation therapy displayed higher levels of PI-PLCbeta1/Cyclin D3/PKCalpha expression. During treatment, these responder patients, as well as hematopoietic cells treated with FeCl3 and Deferasirox, showed a specific reduction of PI-PLCbeta1/Cyclin D3/PKCalpha expression, indicating that this signaling pathway is targeted by Deferasirox. The treatment was also able to specifically decrease the production of ROS. This effect correlated with a reduction of IL-1A and IL-2, as well as Akt/mTOR phosphorylation. In contrast, cells exposed only to FeCl3 and cells from MDS patients refractory to Deferasirox showed a specific increase of ROS and PI-PLCbeta1/Cyclin D3/PKCalpha expression. All in all, our data show that PI-PLCbeta1 signaling is a target for iron-induced oxidative stress and suggest that baseline PI-PLCbeta1 quantification could predict iron chelation therapy response in MDS.