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1.
Br J Haematol ; 2024 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-38811201

RESUMEN

Pyruvate kinase (PK) is a key enzyme of anaerobic glycolysis. The genetic heterogeneity of PK deficiency (PKD) is high, and over 400 unique variants have been identified. Twenty-nine patients who had been diagnosed as PKD genetically in seven distinct paediatric haematology departments were evaluated. Fifteen of 23 patients (65.2%) had low PK levels. The PK:hexokinase ratio had 100% sensitivity for PKD diagnosis, superior to PK enzyme assay. Two novel intronic variants (c.695-1G>A and c.694+43C>T) have been described. PKD should be suspected in patients with chronic non-spherocytic haemolytic anaemia, even if enzyme levels are falsely normal. Total PKLR gene sequencing is necessary for the characterization of patients with PKD and for genetic counselling.

2.
Blood ; 139(17): 2642-2652, 2022 04 28.
Artículo en Inglés | MEDLINE | ID: mdl-35226723

RESUMEN

Excessive intravascular release of lysed cellular contents from damaged red blood cells (RBCs) in patients with sickle cell anemia (SCA) can activate the inflammasome, a multiprotein oligomer promoting maturation and secretion of proinflammatory cytokines, including interleukin-1ß (IL-1ß). We hypothesized that IL-1ß blockade by canakinumab in patients with SCA would reduce markers of inflammation and clinical disease activity. In this randomized, double-blind, multicenter phase 2a study, patients aged 8 to 20 years with SCA (HbSS or HbSß0-thalassemia), history of acute pain episodes, and elevated high-sensitivity C-reactive protein >1.0 mg/L at screening were randomized 1:1 to received 6 monthly treatments with 300 mg subcutaneous canakinumab or placebo. Measured outcomes at baseline and weeks 4, 8, 12, 16, 20, and 24 included electronic patient-reported outcomes, hospitalization rate, and adverse events (AEs) and serious AEs (SAEs). All but 1 of the 49 enrolled patients were receiving stable background hydroxyurea therapy. Although the primary objective (prespecified reduction of pain) was not met, compared with patients in the placebo arm, patients treated with canakinumab had reductions in markers of inflammation, occurrence of SCA-related AEs and SAEs, and number and duration of hospitalizations as well as trends for improvement in pain intensity, fatigue, and absences from school or work. Post hoc analysis revealed treatment effects on weight, restricted to pediatric patients. Canakinumab was well tolerated with no treatment-related SAEs and no new safety signal. These findings demonstrate that the inflammation associated with SCA can be reduced by selective IL-1ß blockade by canakinumab with potential for therapeutic benefits. This trial was registered at www.clinicaltrials.gov as #NCT02961218.


Asunto(s)
Anemia de Células Falciformes , Anticuerpos Monoclonales , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/tratamiento farmacológico , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Biomarcadores , Niño , Método Doble Ciego , Humanos , Inflamación/tratamiento farmacológico , Adulto Joven
3.
J Pediatr Hematol Oncol ; 44(1): e241-e242, 2022 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-33512868

RESUMEN

Allergic reactions from insect bites are mostly observed with bee stings. Bee sting reactions can be classified into 3 main headings: local, systemic, and rare reactions. Vascular thrombosis is considered both in rare and systemic reactions. The wild bee venom induces the secretion of many inflammatory mediators, including histamine, phospholipase A1, and thromboxane, leading to vasoconstriction and thrombosis. Inflammatory cytokines also cause endothelial injury and deterioration of the microcirculation. In the literature, rare reactions have been reported including various central and arterial vascular pathologies such as aortic thrombosis, cerebral infarction, and myocardial infarction; however, there is rare publication concerning peripheral deep vein thrombosis (DVT). Although DVT produces good results with effective and rapid treatment, it can be fatal because of causes such as pulmonary embolism in the absence of timely intervention. Herein, for the first time in the literature, we present a pediatric case of peripheral DVT after a wild bee sting.


Asunto(s)
Abejas , Mordeduras y Picaduras de Insectos , Trombosis de la Vena , Adolescente , Animales , Humanos , Mordeduras y Picaduras de Insectos/sangre , Mordeduras y Picaduras de Insectos/complicaciones , Masculino , Trombosis de la Vena/sangre , Trombosis de la Vena/etiología
4.
JAMA ; 325(15): 1513-1523, 2021 04 20.
Artículo en Inglés | MEDLINE | ID: mdl-33877274

RESUMEN

Importance: Although effective agents are available to prevent painful vaso-occlusive episodes of sickle cell disease (SCD), there are no disease-modifying therapies for ongoing painful vaso-occlusive episodes; treatment remains supportive. A previous phase 3 trial of poloxamer 188 reported shortened duration of painful vaso-occlusive episodes in SCD, particularly in children and participants treated with hydroxyurea. Objective: To reassess the efficacy of poloxamer 188 for vaso-occlusive episodes. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled, multicenter, international trial conducted from May 2013 to February 2016 that included 66 hospitals in 12 countries and 60 cities; 388 individuals with SCD (hemoglobin SS, SC, S-ß0 thalassemia, or S-ß+ thalassemia disease) aged 4 to 65 years with acute moderate to severe pain typical of painful vaso-occlusive episodes requiring hospitalization were included. Interventions: A 1-hour 100-mg/kg loading dose of poloxamer 188 intravenously followed by a 12-hour to 48-hour 30-mg/kg/h continuous infusion (n = 194) or placebo (n = 194). Main Outcomes and Measures: Time in hours from randomization to the last dose of parenteral opioids among all participants and among those younger than 16 years as a separate subgroup. Results: Of 437 participants assessed for eligibility, 388 were randomized (mean age, 15.2 years; 176 [45.4%] female), the primary outcome was available for 384 (99.0%), 15-day follow-up contacts were available for 357 (92.0%), and 30-day follow-up contacts were available for 368 (94.8%). There was no significant difference between the groups for the mean time to last dose of parenteral opioids (81.8 h for the poloxamer 188 group vs 77.8 h for the placebo group; difference, 4.0 h [95% CI, -7.8 to 15.7]; geometric mean ratio, 1.2 [95% CI, 1.0-1.5]; P = .09). Based on a significant interaction of age and treatment (P = .01), there was a treatment difference in time from randomization to last administration of parenteral opioids for participants younger than 16 years (88.7 h in the poloxamer 188 group vs 71.9 h in the placebo group; difference, 16.8 h [95% CI, 1.7-32.0]; geometric mean ratio, 1.4 [95% CI, 1.1-1.8]; P = .008). Adverse events that were more common in the poloxamer 188 group than the placebo group included hyperbilirubinemia (12.7% vs 5.2%); those more common in the placebo group included hypoxia (12.0% vs 5.3%). Conclusions and Relevance: Among children and adults with SCD, poloxamer 188 did not significantly shorten time to last dose of parenteral opioids during vaso-occlusive episodes. These findings do not support the use of poloxamer 188 for vaso-occlusive episodes. Trial Registration: ClinicalTrials.gov Identifier: NCT01737814.


Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Dolor/tratamiento farmacológico , Poloxámero/uso terapéutico , Vasodilatadores/uso terapéutico , Adolescente , Adulto , Analgésicos Opioides/uso terapéutico , Anemia de Células Falciformes/complicaciones , Niño , Método Doble Ciego , Femenino , Humanos , Masculino , Dolor/etiología , Placebos/efectos adversos , Placebos/uso terapéutico , Poloxámero/efectos adversos , Vasodilatadores/efectos adversos , Adulto Joven
5.
Turk J Med Sci ; 50(8): 1887-1893, 2020 12 17.
Artículo en Inglés | MEDLINE | ID: mdl-32599969

RESUMEN

Background/aim: Silent cerebral infarct (SCI) is an ischemic lesion seen before clinical signs of brain infarct and ischemic changes in brain tissue. This study aimed to detect SCI with noninvasive methods and to determine related risk factors in patients with sickle cell anemia (SCA). Materials and methods: Fifty-four SCA patients who had no history of cerebral infarct and whose neurological examinations were normal were included in this study. Brain magnetic resonance imaging (MRI) and diffusion MRI were taken and the acquired data was compared statistically. Results: SCI was detected in 11.1% (6/54) of the patients. No statistical differences in age, sex, physical examination findings, or treatments were detected between the 2 groups (with and without SCI). When examined in terms of HbS, the median (min­max) value in SCI-positive patients was 85.4 (80.5­92.1); the median value was 77.2 (49.0­96.7) in SCI-negative patients. The HbS values of the SCI group were statistically significantly higher than those of the group without SCI (P = 0.014). Patients with the HbSS or HbSß0 genotypes had a significantly higher prevalence of SCI when compared with other sickle cell syndromes (P = 0.038). Conclusion: SCI is not uncommon among SCA patients in Turkey. The presence of homozygote HbSS/Sß0 genotype, high MCV, and HbS are risk factors for SCI.


Asunto(s)
Anemia de Células Falciformes/complicaciones , Infarto Cerebral/complicaciones , Infarto Cerebral/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Adolescente , Encéfalo/diagnóstico por imagen , Niño , Femenino , Humanos , Masculino , Turquía
6.
Pediatr Blood Cancer ; 66(10): e27923, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31321910

RESUMEN

BACKGROUND: Severe congenital neutropenia is a rare disease, and autosomal dominantly inherited ELANE mutation is the most frequently observed genetic defect in the registries from North America and Western Europe. However, in eastern countries where consanguineous marriages are common, autosomal recessive forms might be more frequent. METHOD: Two hundred and sixteen patients with severe congenital neutropenia from 28 different pediatric centers in Turkey were registered. RESULTS: The most frequently observed mutation was HAX1 mutation (n = 78, 36.1%). A heterozygous ELANE mutation was detected in 29 patients (13.4%) in our cohort. Biallelic mutations of G6PC3 (n = 9, 4.3%), CSF3R (n = 6, 2.9%), and JAGN1 (n = 2, 1%) were also observed. Granulocyte colony-stimulating factor treatment was given to 174 patients (80.6%). Two patients died with infectious complications, and five patients developed myelodysplastic syndrome/acute myeloblastic leukemia. The mean (± mean standard error) follow-up period was 129.7 ± 76.3 months, and overall survival was 96.8% (CI, 94.4-99.1%) at the age of 15 years. In Turkey, severe congenital neutropenia mostly resulted from the p W44X mutation in the HAX1 gene. CONCLUSION: In Turkey, mutation analysis should be started with HAX1, and if this is negative, ELANE and G6PC3 should be checked. Because of the very high percentage of consanguineous marriage, rare mutations should be tested in patients with a negative mutation screen.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Síndromes Congénitos de Insuficiencia de la Médula Ósea/genética , Neutropenia/genética , Adolescente , Adulto , Niño , Preescolar , Consanguinidad , Análisis Mutacional de ADN , Femenino , Homocigoto , Humanos , Lactante , Masculino , Mutación , Sistema de Registros , Turquía , Adulto Joven
7.
Blood ; 125(25): 3868-77, 2015 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-25934475

RESUMEN

Deferasirox (DFX) monotherapy is effective for reducing myocardial and liver iron concentrations (LIC), although some patients may require intensive chelation for a limited duration. HYPERION, an open-label single-arm prospective phase 2 study, evaluated combination DFX-deferoxamine (DFO) in patients with severe transfusional myocardial siderosis (myocardial [m] T2* 5-<10 ms; left ventricular ejection fraction [LVEF] ≥56%) followed by optional switch to DFX monotherapy when achieving mT2* >10 ms. Mean dose was 30.5 mg/kg per day DFX and 36.3 mg/kg per day DFO on a 5-day regimen. Geometric mean mT2* ratios (Gmeanmonth12/24/Gmeanbaseline) were 1.09 and 1.30, respectively, increasing from 7.2 ms at baseline (n = 60) to 7.7 ms at 12 (n = 52) and 9.5 ms at 24 months (n = 36). Patients (17 of 60; 28.3%) achieved mT2* ≥10 ms and ≥10% increase from baseline at month 24; 15 switched to monotherapy during the study based on favorable mT2*. LIC decreased substantially from a baseline of 33.4 to 12.8 mg Fe/g dry weight at month 24 (-52%). LVEF remained stable with no new arrhythmias/cardiac failure. Five patients discontinued with mT2* <5 ms and 1 died (suspected central nervous system infection). Safety was consistent with established monotherapies. Results show clinically meaningful improvements in mT2* in about one-third of patients remaining on treatment at month 24, alongside rapid decreases in LIC in this heavily iron-overloaded, difficult-to-treat population. Combination therapy may be useful when rapid LIC reduction is required, regardless of myocardial iron overload. This trial was registered at www.clinicaltrials.gov as #NCT01254227.


Asunto(s)
Benzoatos/administración & dosificación , Deferoxamina/administración & dosificación , Quelantes del Hierro/administración & dosificación , Sobrecarga de Hierro/tratamiento farmacológico , Sideróforos/administración & dosificación , Triazoles/administración & dosificación , Adolescente , Adulto , Benzoatos/efectos adversos , Niño , Deferasirox , Deferoxamina/efectos adversos , Femenino , Corazón/efectos de los fármacos , Humanos , Quelantes del Hierro/efectos adversos , Sobrecarga de Hierro/etiología , Hígado/química , Hígado/efectos de los fármacos , Masculino , Miocardio/química , Sideróforos/efectos adversos , Reacción a la Transfusión , Triazoles/efectos adversos , Adulto Joven
8.
Blood ; 123(10): 1447-54, 2014 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-24385534

RESUMEN

Randomized comparison data on the efficacy and safety of deferasirox for myocardial iron removal in transfusion dependent patients are lacking. CORDELIA was a prospective, randomized comparison of deferasirox (target dose 40 mg/kg per day) vs subcutaneous deferoxamine (50-60 mg/kg per day for 5-7 days/week) for myocardial iron removal in 197 ß-thalassemia major patients with myocardial siderosis (T2* 6-20 milliseconds) and no signs of cardiac dysfunction (mean age, 19.8 years). Primary objective was to demonstrate noninferiority of deferasirox for myocardial iron removal, assessed by changes in myocardial T2* after 1 year using a per-protocol analysis. Geometric mean (Gmean) myocardial T2* improved with deferasirox from 11.2 milliseconds at baseline to 12.6 milliseconds at 1 year (Gmeans ratio, 1.12) and with deferoxamine (11.6 milliseconds to 12.3 milliseconds; Gmeans ratio, 1.07). The between-arm Gmeans ratio was 1.056 (95% confidence interval [CI], 0.998, 1.133). The lower 95% CI boundary was greater than the prespecified margin of 0.9, establishing noninferiority of deferasirox vs deferoxamine (P = .057 for superiority of deferasirox). Left ventricular ejection fraction remained stable in both arms. Frequency of drug-related adverse events was comparable between deferasirox (35.4%) and deferoxamine (30.8%). CORDELIA demonstrated the noninferiority of deferasirox compared with deferoxamine for myocardial iron removal. This trial is registered at www.clinicaltrials.gov as #NCT00600938.


Asunto(s)
Benzoatos/uso terapéutico , Deferoxamina/uso terapéutico , Quelantes del Hierro/uso terapéutico , Sobrecarga de Hierro/tratamiento farmacológico , Sobrecarga de Hierro/etiología , Miocardio/metabolismo , Miocardio/patología , Triazoles/uso terapéutico , Talasemia beta/complicaciones , Adolescente , Adulto , Benzoatos/administración & dosificación , Benzoatos/efectos adversos , Niño , Deferasirox , Deferoxamina/administración & dosificación , Deferoxamina/efectos adversos , Femenino , Ferritinas/sangre , Corazón/fisiopatología , Humanos , Hierro/administración & dosificación , Hierro/metabolismo , Quelantes del Hierro/administración & dosificación , Quelantes del Hierro/efectos adversos , Masculino , Cumplimiento de la Medicación , Resultado del Tratamiento , Triazoles/administración & dosificación , Triazoles/efectos adversos , Troponina T/metabolismo , Adulto Joven
9.
Eur J Haematol ; 95(3): 244-53, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25418187

RESUMEN

OBJECTIVES: The randomized comparison of deferasirox to deferoxamine for myocardial iron removal in patients with transfusion-dependent anemias (CORDELIA) gave the opportunity to assess relative prevalence and body distribution of iron overload in screened patients. METHODS: Patients aged ≥ 10 yr with transfusion-dependent anemias from 11 countries were screened. Data were summarized descriptively, overall and across regions. RESULTS: Among 925 patients (99.1% with ß-thalassemia major; 98.5% receiving prior chelation; mean age 19.2 yr), 36.7% had myocardial iron overload (myocardial T2* ≤ 20 ms), 12.1% had low left ventricular ejection fraction. Liver iron concentration (LIC) (mean 25.8 mg Fe/g dw) and serum ferritin (median 3702 ng/mL) were high. Fewer patients in the Middle East (ME; 28.5%) had myocardial T2* ≤ 20 ms vs. patients in the West (45.9%) and Far East (FE, 40.9%). Patients in the West had highest myocardial iron burden, but lowest LIC (26.9% with LIC < 7 mg Fe/g dw) and serum ferritin. Among patients with normal myocardial iron, a higher proportion of patients from the ME and FE had LIC ≥ 15 than < 7 mg Fe/g dw (ME, 56.7% vs. 17.2%; FE, 78.6% vs. 7.8%, respectively), a trend which was less evident in the West (44.6% vs. 33.9%, respectively). Transfusion and chelation practices differed between regions. CONCLUSIONS: Evidence of substantial myocardial and liver iron burden across regions revealed a need for optimization of effective, convenient iron chelation regimens. Significant regional variation exists in myocardial and liver iron loading that are not well explained; improved understanding of factors contributing to differences in body iron distribution may be of clinical benefit.


Asunto(s)
Anemia/complicaciones , Sobrecarga de Hierro/epidemiología , Sobrecarga de Hierro/etiología , Reacción a la Transfusión , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anemia/terapia , Niño , Deferoxamina/uso terapéutico , Femenino , Humanos , Hierro/metabolismo , Quelantes del Hierro/uso terapéutico , Sobrecarga de Hierro/tratamiento farmacológico , Sobrecarga de Hierro/metabolismo , Hígado/metabolismo , Hígado/patología , Masculino , Persona de Mediana Edad , Miocardio/metabolismo , Miocardio/patología , Prevalencia , Distribución Tisular , Adulto Joven
10.
Am J Hematol ; 90(2): 91-6, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25345697

RESUMEN

Long-term controlled studies are needed to inform on the clinical benefit of chelation therapy for myocardial iron removal in transfusion-dependent beta thalassemia patients. In a 1-year nonrandomized extension to the CORDELIA study, data collected from patients with myocardial siderosis provided additional information on deferasirox or deferoxamine (DFO) efficacy and safety. Myocardial (m)T2* increased from baseline 11.6 to 15.9 ms in patients receiving deferasirox for 24 months (n = 74; geometric mean [Gmean ] ratio of month 24/baseline 1.38 [95% confidence interval 1.28, 1.49]) and from 10.8 to 14.2 ms in those receiving DFO (n = 29; Gmean ratio 1.33 [1.13, 1.55]; P = 0.93 between groups). Improved mT2* with deferasirox was evident across all subgroups evaluated irrespective of baseline myocardial (mT2* < 10 vs. ≥ 10 ms) or liver (LIC <15 vs. ≥15 mg Fe/g dw) iron burden. Mean LVEF was stable and remained within normal limits with deferasirox or DFO. Liver iron concentration decreased from high baseline values of 30.6 ± 18.0 to 14.4 ± 16.6 mg Fe/g dw at month 24 in deferasirox patients and from 36.8 ± 15.6 to 11.0 ± 12.1 mg Fe/g dw in DFO patients. The long-term safety profile of deferasirox or DFO was consistent with previous reports; serious drug-related AEs were reported in 6.8% of deferasirox and 6.9% of DFO patients. Continued treatment of severely iron-overloaded beta thalassemia patients with deferasirox or DFO led to sustained improvements in myocardial iron irrespective of high or low baseline myocardial or liver iron burden, in parallel with substantial improvements in liver iron (Clinicaltrials.gov identifier: NCT00600938).


Asunto(s)
Benzoatos/uso terapéutico , Deferoxamina/uso terapéutico , Quelantes del Hierro/uso terapéutico , Sobrecarga de Hierro/tratamiento farmacológico , Hierro/metabolismo , Miocardio/metabolismo , Triazoles/uso terapéutico , Adolescente , Adulto , Benzoatos/efectos adversos , Terapia por Quelación , Niño , Deferasirox , Deferoxamina/efectos adversos , Femenino , Humanos , Quelantes del Hierro/efectos adversos , Sobrecarga de Hierro/etiología , Sobrecarga de Hierro/metabolismo , Sobrecarga de Hierro/patología , Hígado/metabolismo , Hígado/patología , Masculino , Miocardio/patología , Estudios Prospectivos , Reacción a la Transfusión , Resultado del Tratamiento , Triazoles/efectos adversos , Talasemia beta/metabolismo , Talasemia beta/patología , Talasemia beta/terapia
11.
Acta Haematol ; 134(4): 233-42, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26138856

RESUMEN

Iron overload in transfusion-dependent patients with rare anemias can be managed with chelation therapy. This study evaluated deferasirox efficacy and safety in patients with myelodysplastic syndromes (MDS), aplastic anemia (AA) or other rare anemias. A 1-year, open-label, multicenter, single-arm, phase II trial was performed with deferasirox (10­40 mg/kg/day, based on transfusion frequency and therapeutic goals), including an optional 1-year extension. The primary end point was a change in liver iron concentration (LIC) after 1 year. Secondary end points included changes in efficacy and safety parameters (including ophthalmologic assessments) overall as well as in a Japanese subpopulation. Overall, 102 patients (42 with MDS, 29 with AA and 31 with other rare anemias) were enrolled; 57 continued into the extension. Mean absolute change in LIC was ­10.9 mg Fe/g dry weight (d.w.) after 1 year (baseline: 24.5 mg Fe/g d.w.) and ­13.5 mg Fe/g d.w. after 2 years. The most common drug-related adverse event was increased serum creatinine (23.5%), predominantly in MDS patients. Four patients had suspected drug-related ophthalmologic abnormalities. Outcomes in Japanese patients were generally consistent with the overall population. Results confirm deferasirox efficacy in patients with rare anemias, including a Japanese subpopulation. The safety profile was consistent with previous studies and ophthalmologic parameters generally agreed with baseline values (EUDRACT 2006-003337-32).


Asunto(s)
Anemia Aplásica/tratamiento farmacológico , Benzoatos/administración & dosificación , Sobrecarga de Hierro/tratamiento farmacológico , Hígado/metabolismo , Síndromes Mielodisplásicos/tratamiento farmacológico , Triazoles/administración & dosificación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anemia Aplásica/metabolismo , Anemia Aplásica/patología , Benzoatos/efectos adversos , Niño , Preescolar , Deferasirox , Humanos , Sobrecarga de Hierro/metabolismo , Sobrecarga de Hierro/patología , Hígado/patología , Persona de Mediana Edad , Síndromes Mielodisplásicos/metabolismo , Síndromes Mielodisplásicos/patología , Triazoles/efectos adversos
12.
Pediatr Int ; 57(4): 711-3, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25711242

RESUMEN

Few data on the renal effects of thalassemia syndrome are available in the literature. Recent clinical studies identified proximal tubular damage and glomerular filtration abnormalities in thalassemia. Iron-chelating agents might be nephrotoxic as well, but proven glomerular injury, either due to anemia or chelating therapy, has not previously been demonstrated in thalassemia patients. Here, we report the first thalassemia patient presenting with nephrotic syndrome to be diagnosed with membranous nephropathy in the literature.


Asunto(s)
Glomerulonefritis Membranosa/complicaciones , Glomérulos Renales/patología , Síndrome Nefrótico/etiología , Talasemia beta/complicaciones , Biopsia , Niño , Diagnóstico Diferencial , Femenino , Tasa de Filtración Glomerular , Glomerulonefritis Membranosa/diagnóstico , Humanos , Microscopía Fluorescente , Síndrome Nefrótico/diagnóstico , Talasemia beta/diagnóstico
13.
Pediatr Blood Cancer ; 61(5): 879-84, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24376176

RESUMEN

BACKGROUND: A risk associated with the iron chelator deferiprone is the development of neutropenia or agranulocytosis. Accordingly, the product label recommends weekly blood monitoring and immediate interruption of treatment upon detection of an absolute neutrophil count (ANC) <1.5 × 10(9)/L, out of concern that continued therapy might lead to a more severe drop. However, it is uncertain how these recommendations are followed under real-life conditions and, if they are not followed, whether continuation of therapy results in increased incidence of agranulocytosis. PROCEDURE: This non-interventional surveillance program assessed the monitoring of deferiprone therapy in clinical practice. A total of 294 patients with transfusion-dependent anemias received deferiprone, as monotherapy or with another chelator, for up to 1 year. The participating physicians were not given any instructions about treatment and monitoring beyond being referred to the information in the package insert. RESULTS: ANC monitoring was conducted at an average interval of 5 ± 4 weeks, and deferiprone was not always interrupted upon detection of neutropenia. One patient (0.3%) experienced agranulocytosis, and nine others (3%) experienced a total of 11 episodes of neutropenia. All neutropenia episodes resolved; median time to resolution was similar whether or not treatment was interrupted; and no case of neutropenia progressed to agranulocytosis. CONCLUSIONS: These data indicate that less frequent ANC monitoring and continuation of deferiprone therapy during neutropenia are not associated with prolonged neutropenia or with progression to agranulocytosis.


Asunto(s)
Agranulocitosis/prevención & control , Quelantes del Hierro/uso terapéutico , Sobrecarga de Hierro/tratamiento farmacológico , Neutropenia/prevención & control , Guías de Práctica Clínica como Asunto , Pautas de la Práctica en Medicina , Piridonas/uso terapéutico , Adolescente , Adulto , Agranulocitosis/inducido químicamente , Transfusión Sanguínea , Niño , Preescolar , Deferiprona , Femenino , Estudios de Seguimiento , Humanos , Lactante , Sobrecarga de Hierro/complicaciones , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Neutrófilos , Estudios Prospectivos , Resultado del Tratamiento , Adulto Joven
14.
Turk J Haematol ; 31(1): 17-24, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24764725

RESUMEN

OBJECTIVE: A severe complication in the replacement therapy of hemophilia A (HA) patients is the development of alloantibodies (inhibitors) against factor VIII, which neutralizes the substituted factor. The primary genetic risk factors influencing the development of inhibitors are F8 gene mutations. Interleukins and cytokines that are involved in the regulation of B-lymphocyte development are other possible targets as genetic risk factors. This study assesses the possible involvement of 9 selected single nucleotide gene polymorphisms (SNPs) with interleukins (IL-4, IL-5, and IL-10), transforming growth factor beta 1 (TGF-ß1), and interferon gamma (IFN-γ) in inhibitor development in severely affected HA patients carrying a null mutation in the F8 gene. MATERIALS AND METHODS: A total of 173 HA patients were screened for intron 22 inversion and null mutations (nonsense and deletions). Genotyping of a total of 9 SNPs in genes IL-4, IL-5, IL-10, TGF-ß1, and IFN-γ in 103 patients and 100 healthy individuals was carried out. RESULTS: An association analysis between 42 inhibitor (+) and 61 inhibitor (-) patients showed a significant association with the T allele of rs2069812 in the IL-5 gene promoter and patients with inhibitors (p=0.0251). The TT genotype was also significantly associated with this group with a p-value of 0.0082, odds ratio of about 7, and confidence interval of over 90%, suggesting that it is the recessive susceptibility allele and that the C allele is the dominant protective allele. CONCLUSION: The lack of other variants in the IL-5 gene of patients and controls suggests that rs2069812 may be a regulatory SNP and may have a role in B-lymphocyte development, constituting a genetic risk factor in antibody development.

15.
Blood ; 118(4): 884-93, 2011 Jul 28.
Artículo en Inglés | MEDLINE | ID: mdl-21628399

RESUMEN

Patients with ß-thalassemia require lifelong iron chelation therapy from early childhood to prevent complications associated with transfusional iron overload. To evaluate long-term efficacy and safety of once-daily oral iron chelation with deferasirox, patients aged ≥ 2 years who completed a 1-year, phase 3, randomized trial entered a 4-year extension study, either continuing on deferasirox (deferasirox cohort) or switching from deferoxamine to deferasirox (crossover cohort). Of 555 patients who received ≥ 1 deferasirox dose, 66.8% completed the study; 43 patients (7.7%) discontinued because of adverse events. In patients with ≥ 4 years' deferasirox exposure who had liver biopsy, mean liver iron concentration significantly decreased by 7.8 ± 11.2 mg Fe/g dry weight (dw; n = 103; P < .001) and 3.1 ± 7.9 mg Fe/g dw (n = 68; P < .001) in the deferasirox and crossover cohorts, respectively. Median serum ferritin significantly decreased by 706 ng/mL (n = 196; P < .001) and 371 ng/mL (n = 147; P < .001), respectively, after ≥ 4 years' exposure. Investigator-assessed, drug-related adverse events, including increased blood creatinine (11.2%), abdominal pain (9.0%), and nausea (7.4%), were generally mild to moderate, transient, and reduced in frequency over time. No adverse effect was observed on pediatric growth or adolescent sexual development. This first prospective study of long-term deferasirox use in pediatric and adult patients with ß-thalassemia suggests treatment for ≤ 5 years is generally well tolerated and effectively reduces iron burden. This trial was registered at www.clinicaltrials.gov as #NCT00171210.


Asunto(s)
Benzoatos/uso terapéutico , Terapia por Quelación/métodos , Quelantes del Hierro/uso terapéutico , Triazoles/uso terapéutico , Talasemia beta/tratamiento farmacológico , Adolescente , Adulto , Benzoatos/administración & dosificación , Benzoatos/efectos adversos , Terapia por Quelación/efectos adversos , Niño , Preescolar , Estudios Cruzados , Deferasirox , Deferoxamina/uso terapéutico , Femenino , Estudios de Seguimiento , Crecimiento y Desarrollo/efectos de los fármacos , Humanos , Hierro/metabolismo , Quelantes del Hierro/administración & dosificación , Quelantes del Hierro/efectos adversos , Masculino , Persona de Mediana Edad , Triazoles/administración & dosificación , Triazoles/efectos adversos , Adulto Joven
16.
Pediatr Endocrinol Rev ; 11(2): 167-80, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24575552

RESUMEN

In recent years, the issue of osteopenia/osteoporosis in children, adolescents and young adults with thalassaemia major (TM) has attracted much attention because it is a prominent cause of morbidity despite adequate transfusion and iron chelation therapy. The reported frequency of osteoporosis, even in well treated TM patients varies from 13.6% to 50% with an additional 45% affected by osteopenia. The pathogenesis of TM-induced osteoporosis is multifactorial. Genetic and acquired factors play role in demineralization of bones in thalassemia. Osteoporosis is characterized by low bone mass and disruption of bone architecture, resulting in reduced bone strength and increased risk of fractures. The significant predictors of fracture prevalence include male gender, hypothyroidism, age, lack of spontaneous puberty in females, active hepatitis, heart disease and diabetes. The early identification of osteopenia and osteoporosis is of paramount importance. This is because delayed diagnosis and inadequate treatment have led to severe osteoporosis, skeletal abnormalities, fractures, spinal deformities, nerve compression and growth failure. dequate hormonal replacement, has been posponed, Effective iron chelation adequate hormonal replacement, improvement of hemoglobin levels, calcium and vitamin D administration and physical activity are currently the main measures for the management of the disease. The use of bisphosphonates in TM patients with osteoporosis is increasing and their positive effect in improving bone mineral density is encouraging. The recommendations of the International Network on Growth Disorders and Endocrine Complications in Thalassaemia (I-CET) for diagnosis and management of osteoporosis in TM are also briefly included in this review.


Asunto(s)
Monitoreo Fisiológico/métodos , Osteoporosis/etiología , Osteoporosis/terapia , Talasemia beta/complicaciones , Talasemia beta/terapia , Adolescente , Adulto , Densidad Ósea , Niño , Femenino , Fracturas Óseas/epidemiología , Fracturas Óseas/etiología , Fracturas Óseas/prevención & control , Humanos , Masculino , Osteoporosis/epidemiología , Factores de Riesgo , Adulto Joven , Talasemia beta/epidemiología
17.
Blood Adv ; 7(4): 611-619, 2023 02 28.
Artículo en Inglés | MEDLINE | ID: mdl-36018224

RESUMEN

Long-term safety and efficacy data on the iron chelator deferiprone in sickle cell disease (SCD) and other anemias are limited. FIRST-EXT was a 2-year extension study of FIRST (Ferriprox in Patients With Iron Overload in Sickle Cell Disease Trial), a 1-year, randomized noninferiority study of deferiprone vs deferoxamine in these populations. Patients who entered FIRST-EXT continued to receive, or were switched to, deferiprone. Altogether, 134 patients were enrolled in FIRST-EXT (mean age: 16.2 years), with mean (SD) exposure to deferiprone of 2.1 (0.8) years over the 2 studies. The primary end point was safety. Secondary end points were change in liver iron concentration (LIC), cardiac T2∗, serum ferritin (SF), and the proportion of responders (≥20% improvement in efficacy measure). The most common adverse events considered at least possibly related to deferiprone were neutropenia (9.0%) and abdominal pain (7.5%). LIC (mg/g dry weight) decreased over time, with mean (SD) changes from baseline at each time point (year 1, -2.64 [4.64]; year 2, -3.91 [6.38]; year 3, -6.64 [7.72], all P < .0001). Mean SF levels (µg/L) decreased significantly after year 2 (-771, P = .0008) and year 3 (-1016, P = .0420). Responder rates for LIC and SF increased each year (LIC: year 1, 46.5%; year 2, 57.1%; year 3, 66.1%; SF: year 1, 35.2%; year 2, 55.2%; year 3, 70.9%). Cardiac T2∗ remained normal in all patients. In conclusion, long-term therapy with deferiprone was not associated with new safety concerns and led to continued and progressive reduction in iron load in individuals with SCD or other anemias. The trial was registered at www.clinicaltrials.gov as #NCT02443545.


Asunto(s)
Anemia de Células Falciformes , Sobrecarga de Hierro , Adolescente , Humanos , Anemia de Células Falciformes/terapia , Ferritinas , Hierro/metabolismo , Quelantes del Hierro , Piridonas/efectos adversos
18.
Turk J Haematol ; 29(1): 48-54, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24744623

RESUMEN

OBJECTIVE: To retrospectively evaluate the clinical findings, laboratory data, management, and outcome in a group ofTurkish children diagnosed with rare coagulation deficiencies (RCDs) between January 1999 and June 2009. MATERIAL AND METHODS: The Turkish Society of Pediatric Hematology-Hemophilia-Thrombosis-Hemostasissubcommittee designed a Microsoft Excel-based questionnaire for standardized data collection and sent it to participatinginstitutions. RESULTS: In total, 156 patients from 12 pediatric referral centers were included in the study. The cost common RCDswere as follows: FVII (n = 53 [34%]), FV (n = 24 [15.4%]), and FX (n = 23 [14.7%]) deficiency. The most common initialfinding in the patients was epistaxis, followed by ecchymosis, and gingival bleeding. CONCLUSION: Initial symptoms were mucosal bleeding, and fresh frozen plasma (FFP) and tranexamic acid werethe most commonly used treatments. We think that prophylactic treatment used for hemophilia patients should beconsidered as an initial therapeutic option for patients with rare factor deficiencies and a severe clinical course, and forthose with a factor deficiency that can lead to severe bleeding.

19.
Blood Adv ; 6(4): 1243-1254, 2022 02 22.
Artículo en Inglés | MEDLINE | ID: mdl-34847228

RESUMEN

Many people with sickle cell disease (SCD) or other anemias require chronic blood transfusions, which often causes iron overload that requires chelation therapy. The iron chelator deferiprone is frequently used in individuals with thalassemia syndromes, but data in patients with SCD are limited. This open-label study assessed the efficacy and safety of deferiprone in patients with SCD or other anemias receiving chronic transfusion therapy. A total of 228 patients (mean age: 16.9 [range, 3-59] years; 46.9% female) were randomized to receive either oral deferiprone (n = 152) or subcutaneous deferoxamine (n = 76). The primary endpoint was change from baseline at 12 months in liver iron concentration (LIC), assessed by R2* magnetic resonance imaging (MRI). The least squares mean (standard error) change in LIC was -4.04 (0.48) mg/g dry weight for deferiprone vs -4.45 (0.57) mg/g dry weight for deferoxamine, with noninferiority of deferiprone to deferoxamine demonstrated by analysis of covariance (least squares mean difference 0.40 [0.56]; 96.01% confidence interval, -0.76 to 1.57). Noninferiority of deferiprone was also shown for both cardiac T2* MRI and serum ferritin. Rates of overall adverse events (AEs), treatment-related AEs, serious AEs, and AEs leading to withdrawal did not differ significantly between the groups. AEs related to deferiprone treatment included abdominal pain (17.1% of patients), vomiting (14.5%), pyrexia (9.2%), increased alanine transferase (9.2%) and aspartate transferase levels (9.2%), neutropenia (2.6%), and agranulocytosis (0.7%). The efficacy and safety profiles of deferiprone were acceptable and consistent with those seen in patients with transfusion-dependent thalassemia. This trial study was registered at www://clinicaltrials.gov as #NCT02041299.


Asunto(s)
Anemia de Células Falciformes , Sobrecarga de Hierro , Talasemia , Adolescente , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/tratamiento farmacológico , Transfusión Sanguínea , Deferiprona/uso terapéutico , Deferoxamina/efectos adversos , Femenino , Humanos , Quelantes del Hierro/efectos adversos , Sobrecarga de Hierro/tratamiento farmacológico , Sobrecarga de Hierro/etiología , Masculino , Piridonas/efectos adversos , Talasemia/complicaciones , Talasemia/tratamiento farmacológico , Transferasas
20.
Lancet Haematol ; 8(5): e334-e343, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33894169

RESUMEN

BACKGROUND: There are no approved treatments for vaso-occlusive crises in sickle cell disease. Sevuparin is a novel non-anticoagulant low molecular weight heparinoid, with anti-adhesive properties. In this study, we tested whether sevuparin could shorten vaso-occlusive crisis duration in hospitalised patients with sickle cell disease. METHODS: We did a multicentre, double-blinded, placebo-controlled, phase 2 study in 16 public access clinical hospitals in the Netherlands, Lebanon, Turkey, Bahrain, Oman, Saudi Arabia, and Jamaica. Patients aged 12-50 years with a diagnosis of sickle cell disease (types HbSS, HbSC, HbSß0-thalassaemia, or HbSß+-thalassaemia) on a stable dose of hydroxyurea, hospitalised with vaso-occlusive crisis for parenteral opioid analgesia with a projected stay of more than 48 h were included in the study. Patients were randomly assigned (1:1) using a computer-generated randomisation scheme to receive sevuparin (18 mg/kg per day) or placebo (NaCl, 0·9% solution) intravenously for 2-7 days until vaso-occlusive crisis resolution. All individuals involved in the trial were masked to treatment allocation. The analysis was done in the intention-to-treat population. The primary endpoint was time to vaso-occlusive crisis resolution defined as freedom from parenteral opioid use (in preceding 6-10 h); and readiness for discharge as judged by the patient or physician. The trial is registered with ClinicalTrials.gov, NCT02515838. FINDINGS: Between Oct 7, 2015, and Feb 10, 2019, 144 patients were randomly assigned and administered sevuparin (n=69) or placebo (n=75). The median age was 22·2 years (range 12·2-33·6), 104 (72%) 144 were adults (18 years or older), and 90 (63%) were male and 54 (37%) were female. The intention-to-treat analysis for the primary endpoint showed no significant difference in median time to vaso-occlusive crisis resolution between the sevuparin and placebo groups (100·4 h [95% CI 85·5-116·8]) vs 86·4 h [70·6-95·1]; hazard ratio 0·89 [0·6-1·3]; p=0·55). Serious adverse events occurred in 16 (22%) of 68 patients in the sevuparin group and in 21 (22%) of patients in the placebo group. The most frequent treatment-emergent adverse events were pyrexia (17 [25%] in the sevuparin group vs 17 [22%] in the placebo group), constipation (12 [18%] vs 17 [22%]), and decreased haemoglobin (18 [26%] vs 9 [12%]). There were no deaths in the sevuparin group and there was one (1%) death in the placebo group after a hyper-haemolytic episode due to alloimmunisation. INTERPRETATION: This result, as well as the results seen in other clinical studies of inhibitors of adhesion in sickle cell disease, suggest that selectin-mediated adhesion might be important in the initiation, but not maintenance of vaso-occlusion, indicating that strategies to treat vaso-occlusive crises differ from strategies to prevent this complication. FUNDING: Modus Therapeutics.


Asunto(s)
Dolor Agudo/tratamiento farmacológico , Anemia de Células Falciformes/patología , Heparina/análogos & derivados , Dolor Agudo/complicaciones , Adolescente , Adulto , Anemia de Células Falciformes/complicaciones , Niño , Femenino , Fiebre/etiología , Hemoglobinas/análisis , Heparina/efectos adversos , Heparina/uso terapéutico , Humanos , Masculino , Tiempo de Tromboplastina Parcial , Efecto Placebo , Modelos de Riesgos Proporcionales , Resultado del Tratamiento , Adulto Joven
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