Assessment of serum ferritin levels in transfusion dependent thalassemic children on oral deferiprone in a tertiary care centre

Background: Thalassemic patients require regular blood transfusions to maintain haemoglobin level around between 10gm/dl-15gm/dl, which would result in transfusional iron overload. The treatment of iron overload is carried out by using parenteral desferrioxamine (DFX) therapy or recently introduced oral Deferiprone (DFP,L1,Ferriprox,KELFER,CP20) an oral iron chelator, Oral deferiprone, DFP (3-hydroxy-1,2-dimethylpyridin-4-one) is a synthetic analogue of mimosine, an iron chelator isolated from the legume Mimosa paduca. Our study was undertaken to asses ferritin concentration in transfusion dependent thalassemic children on Deferiprone, attending thalassemia clinic in Anil Neerukonda hospital, Sanghivalasa, Visakhapatnam.Methods: The present study was a hospital based prospective study, 50 transfusion dependent thalassemic children on Deferiprone, attending thalassemia clinic in Anil Neerukonda hospital, Sanghivalasa, Visakhapatnam attached to NRI Medical College, Visakhapatnam were enrolled during the study period October 2017 and September 2018.Results: In our study authors found an increase in Serum ferritin concentration from 3067.99'1520.13 to 4281.10 '1760.42 ng/ml at the end of 12 months, which was quite significant.Conclusion: Authors concluded that oral Deferiprone is not an effective iron chelation agent and is associated with complications like GI symptoms, joint pains in significant number of children. So, search for an alternative iron chelator or combined chelation therapies which are safe and cost effective should be continued.

Clinical Profile and Outcome of Pediatric Sarcoidosis

Objectives: To document clinical features and outcome of children with sarcoidosis.Methods: Case records of 18 children (mean (SD) age 9 (2.2) years) diagnosed withsarcoidosis between 2006 and 2016 were reviewed. All children were followed up every 2-3months and monitored for clinical and laboratory parameters. Their treatment and outcomewere recorded. Results: Clinical features at the time of diagnosis were fever (83%), uveitis(50%), difficulty in breathing (44%), hepatosplenomegaly, weight loss, arthritis and peripheraladenopathy. Imaging findings included: hilar adenopathy (94%), abdominal nodes (50%) andpulmonary infiltrates (44%). All children were treated with steroids (range 6-12 months) andweekly low dose oral methotrexate. All patients showed significant improvement over a mean(SD) duration of follow-up of 3.1 (0.9) years, as assessed by resolution of clinical symptoms,and improvement in spirometry parameters, erythrocyte sedimentation rate, and serumangiotensin converting enzyme levels. Conclusions: Children with sarcoidosis seem torespond well to systemic steroids and low dose methotrexate. Delayed diagnosis and ocularinvolvement are probably associated with poor outcome.

A Patient with Beta-Propeller Protein-Associated Neurodegeneration: Treatment with Iron Chelation Therapy

We present a case of beta-propeller protein-associated neurodegeneration, a form of neurodegeneration with brain iron accumulation. The patient harbored a novel mutation in the WDR45 gene. A detailed video and description of her clinical condition are provided. Her movement disorder phenomenology was characterized primarily by limb stereotypies and gait dyspraxia. The patient's disability was advanced by the time iron-chelating therapy with deferiprone was initiated, and no clinical response in terms of cognitive function, behavior, speech, or movements were observed after one year of treatment.

Comparative Efficacy and Safety of Oral Iron Chelators and their Novel Combination in Children with Thalassemia.

Objective: To compare the efficacy and safety of oral iron chelators (Deferiprone and Deferasirox) when used singly and in combination in multi-transfused children with thalassemia. Design: Prospective comparative study. Setting: Thalassemia Center of a medical college affiliated hospital Participants and Intervention: 49 multi-transfused children with thalassemia with a mean (SD) age 11.6 (6.21) y received daily chelation therapy with either deferiprone alone (75 mg/kg/day in 3 divided doses), deferasirox alone (30 mg/kg/day single dose) or their daily combination (same dose as monotherapy) for 12 months. Outcome measures: Serum ferritin levels at the start of study, after 6 months and after 12 months. MRI T2* of liver and heart initially and after 6 months of follow up. 24-hour urinary iron excretion values at the outset and after 12 months of chelation therapy. At every visit for blood transfusion, all patients were clinically assessed for any adverse effects; liver and renal functions were monitored 6-monthly. Results: After 12 months of respective chelation therapy, serum ferritin values decreased from a mean of 3140.5 ng/mL to 2910.0 ng/mL in deferiprone alone group, 3859.2 ng/mL to 3417.4 ng/mL in deferasirox alone group and from 3696.5 ng/mL to 2572.1 ng/mL in the combination group. The combination therapy was more efficacious in causing fall in serum ferritin levels compared to deferiprone and deferasirox monotherapy (P=0.035 and 0.040, respectively). Results of MRI T2* were equivocal. Combined drug usage produced maximum negative iron balance in the body by maximally increasing the iron excretion in urine from 61.1 µmol/day to 343.3 µmol/day (P=0.002). No significant adverse reactions were noticed in either the monotherapy or the combination group. Conclusion: Oral combination therapy of deferiprone and deferasirox appears to be an efficacious and safe modality to reduce serum ferritin in multi-transfused children with thalassemia.

Iron chelation therapy in beta-thalassemia major: a systematic review with meta-analysis / 中国药学杂志

OBJECTIVE: The efficacy and safety of deferrioxamine (deferoxamine, DFO) and deferiprone(DFP) has been widely reported and researched so far, some scholars have reported the efficacy of the combination of the two drugs, but it is still lack of adequate research to prove the efficacy between combination therapy and single administration. This study is evaluate the efficacy of deferrioxamine, deferiprone and combination therapy in beta-thalassemia major patients. METHODS: The randomized controlled trials (RCT) were collected from the Cochrane library, PubMed, EMBASE, CBM, CNKI and VIP, etc. Serum ferritin(SF), liver iron concentration (LIC), urinary iron excretion(UIE), ejection fraction (EF) and myocardial iron concentration (MIC) were chosen as evaluation index to evaluate the efficacy. Studies were screened, data were extracted, and the methodological quality was assessed by two reviewers independently. Meta-analyses were conducted by using RevMan 5.0 software. RESULTS: Nine randomized controlled studies involving 654 patients were included. The results showed that compared with the group of single administration of either deferiprone or deferoxamine, the experimental group of deferiprone combined with deferoxamine was superior in the following aspects with significant differences: Serum ferritin levels [WMD = - 215.37, 95% CI (- 395.35, - 35.39), P = 0.02], liver iron concentration [SMD = - 1.06, 95%CI(- 1.54, - 0.58), P < 0.0001], urinary iron excretion [SMD = 1.04, 95% CI(0.61, 1.47), P < 0.00001], ejection fraction[WMD = 3.37, 95% CI (0.79, 5.95), P = 0.01]. But no statistically significant variation in myocardial iron concentration between deferoxamine combined with deferiprone and monotherapy [WMD = 1.70, 95%CI(- 2.78, 6.18), P = 0.46]. There was no statistically significant variation in serum ferritin[WMD = 133.45, 95% CI (- 48.92, 315.82), P = 0.15], ejection fraction [WMD = 0.96, 95%CI(- 2.74, 4.66), P = 0.40], myocardial iron concentration [WMD = 1.50, 95%CI(- 1.70, 4.70), P = 0.36] during deferoxamine versus deferiprone treatment. CONCLUSION: According to the domestic evidence, deferoxamine combined with deferiprone for treating beta-thalassemia major is superior to deferoxamine or deferiprone monotherapy. It provides a new and prospective therapeutic method for beta-thalassemia major. However, for the quality restrictions of the included studies, this conclusion has to be further verified by high quality, large scale and double blinded randomized controlled trials.

Brazilian Thalassemia Association protocol for iron chelation therapy in patients under regular transfusion

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.

A clinical audit of thalassaemia management at the Lady Ridgeway Hospital for Children, Colombo.

Objective: To assess the adherence of management of beta thalassaemia major patients at Lady Ridgeway Hospital to an established standard treatment protocol Method: A clinical audit was carried out in all six medical wards of Lady Ridgeway Hospital from 1st February 2008 to 31st March 2008 with retrospective data collected over the period 1st January 2005 to 31st December 2007. The study population comprised all beta thalassaemia major patients admitted to the wards during the study period. Patients who did not give consent and those having other transfusion dependant anaemias were excluded from the study. The study instrument used was a pretested structured data collection form. Data collection was done by referring the past medical records. Data on ‘compliance’ was based on recall by the parent. Data analysis was done on a Microsoft Excel worksheet. Results: During the study period data was collected from 61 patients. Age at time of diagnosis ranged from 2 months to 5 years. All patients had their diagnosis confirmed by haemoglobin electrophoresis, high performance liquid chromatography or both tests. Pre-transfusion haemoglobin levels ranged from 4.1 mg/dl to 11.2 mg/dl. Number of blood transfusions per year ranged from 4–18 per year. Almost 50% of the patients had serum ferritin levels above the potentially cardiotoxic level of 2500 µg/l. Conclusions: Compliance of the patients with the treatment protocol was unsatisfactory. A high proportion of patients had cardiotoxic levels of serum ferritin.

The anti-oxidative effect of deferiprone on ocular lens in diabetic rat / 中华实验眼科杂志

Background Oxidative stress is thought to be responsible to diabetes-complicated cataract.Our previous study demonstrated that as an iron chelator,deferiprone can protect lens from oxidative damage.Objective This further study aimed to investigate the role of deferiprone on the formation of diabetic-complicated cataract.Methods Forty 6-week-old Wistar rats were included in the study and randomized into 4 groups.Eight of them were used as the normal control group.Diabetes mellitus animal models were established in 22 rats by the carbonhydratediet and fat diet and the intraperitoneal injection of 40 mg/kg streptozocin (STZ).The deferiprone of 50 mg and 100 mg were intragastrically given in 8 model rats respectively after 3 days once a day for 8 weeks.The opacification of lenses was examined under the slit lamp weekly after treatment.The animals were sacrificed and the lenses were obtained at the eighth week of deferiprone injection.The concentrations of water-soluble protein ( WSP),urine-soluble protein (USP) and alkali-soluble protein (ASP) in rat lens suspension were detected by Bradford method.The super oxide dimutese (SOD),malondialdehyde (MDA) and glutathione (GSH) were determined spectrometically using xanthine oxidase,thiobarbituric acid,dithio bis-nitrobenzoic acid.Results No evidently differences were found in the content of the WSP,USP and ASP among the these groups( F=1.73,0.18,0.09,P＞0.05).The contents of MDA in 50 mg deferiprone group and 100 mg deferiprone group were ( 1.05 ± 0.10 ) mmol/g and ( 1.05 ± 0.22 ) mmol/g respectively,showing a significant decline in comparison with diabetic model group (P＜0.05).The SOD and GSH contents in lens were (321.29±16.57) U/mg,(322.07±22.16) U/mg and (7.83±0.65 ) mg/g,(7.70±0.77 ) mg/g respectively in 50 mg deferiprone group and 100 mg deferiprone group and were considerably elevated in comparison with ( 298.70± 14.69 ) U/mg and ( 5.47 ± 1.01 ) mg/g of diabetic model groups ( P＜0.05 ).No significant differences were found in the indexes mentioned above between 50 mg and 100 mg deferiprone groups(P＞0.05).Conclusions Deferiprone can reduce oxidative stress and improve the energy metabolism of the lens in diabetic rats.

Pharmacokinetics and tissue distribution of deferiprone in rats / 中国药理学与毒理学杂志

OBJECTIVE To study the pharmacokinetics and tissue distribution of deferiprone (DFP) in rats. METHODS Plasma and tissues were collected after male Wistar rats were ig given DFP 35, 70 and 140 mg·kg~(-1) at different time points. The DFP in plasma and tissues was determined by high performance liquid chromatography. The compartment model was fitted and pharmacokinetic parameters were calculated by DAS 2.0. RESULTS The results showed that the pharmacokinetic process of DFP in rats was two-compartment model after rats were ig given DFP 35, 70 and 140 mg·kg~(-1). The t_(1/2α) were 23.3, 22.2 and 20.9 min, respectively. The t_(1/2β) were 53.3, 50.9 and 46.3 min, respectively. The Cl were 0.017, 0.021 and 0.016 L·min~(-1)·kg~(-1), respectively. The content of DFP was high in stomach and liver tissues after rats were ig given DFP 70 mg·kg~(-1), and it was lower in the other tissues. The content of DFP in liver tissues was (359.22±31.16)μg·g~(-1), at 60 min after rats were ig given DFP 70 mg·kg~(-1). CONCLUSION The absorption and elimination of DFP are quick and the tissue distribution of DFP is wide in vivo.

Efficacy and safety of deferiprone (Ferriprox), an oral iron-chelating agent, in pediatric patients

BACKGROUND: Iron overload is a predictable and life-threatening complication in patients dependent on the regular transfusion of RBCs. The aims of this study were to investigate the efficacy and safety of deferiprone in a variety of pediatric hematologic and/or oncologic patients with a high iron overload. METHODS: Seventeen patients (age: 1.1-20.4 years; median: 10.6 years) from 7 hospitals who were treated with deferiprone from 2006 to 2009 were enrolled in this study. Medical records of enrolled patients were reviewed retrospectively. RESULTS: Serum ferritin levels were 4,677.8+/-1,130.9 microgram/L at baseline compared to 3,363.9+/-1,149.7 microgram/L at the end of deferiprone treatment (P=0.033). Only 1 patient developed neutropenia as a complication. CONCLUSION: Deferiprone treatment is relatively safe for pediatric patients suffering from various hematologic and oncologic diseases that require RBC transfusions as part of treatment. However, the potential development of critical complications such as agranulocytosis and/or neutropenia remains a concern.

Protective action of deferiprone and deferoxamine in erythrocytes isolated from patients with B-thalassemias / Ação protetora de deferiprona e desferoxamina nos eritrócitos isolados de pacientes com B-talassemias

One of the most deleterious consequences of iron overload in thalassemia is the presence of non-transferrin bound iron (NTBI), a free radical that acts as a catalyst for free oxygen radicals, in particular for hydroxyl free radicals (OH.). These radicals oxidize both membrane lipids and proteins causing irreversible damage to biologically important molecules and cellular structures. Treatment with iron chelators has been important to improve survival of these individuals. The aim of this work was the study on the effects of deferoxamine (DFO) and deferiprone (DFP) on erythrocytes under the pro-oxidative action of TBHP isolated from normal individuals and patients with β-thalassemia. The in vitro action of deferoxamine and deferiprone on the oxidative metabolism of erythrocytes from β-thalassemic patients treated at the Centro de Hematologia e Hemoterapia do Paraná (HEMEPAR), Brazil, under the pro-oxidative action of TBHP was studied. Methemoglobin concentrations, reduced glutathione (GSH), hemolysis indexes and the enzyme activities of G6-PD and GR were determined. The oxidation indexes were higher in erythrocytes of β-thalassemic individuals than those from normal individuals. Treatment of the normal and β-thalassemic erythrocytes with DFO and/or DFP protected against the formation of GSH promoted by TBHP.

Uma das maiores consequências da sobrecarga do ferro na β-talassemia é a presença de ferro não ligado à transferrina (NTBI), um radical livre que age como um catalisador do radical livre do oxigênio, particularmente radical hidroxil (OH.). Estes radicais oxidam os lipídeos e as proteínas da membrana causando danos irreversíveis às moléculas biologicamente importantes e às estruturas celulares. O tratamento com quelantes do ferro é importante para a melhoria da sobrevivência destes indivíduos. O objetivo deste trabalho foi o estudo sobre o efeito da desferoxamina (DFO) e da deferiprona (DFP) em eritrócitos isolados de indivíduos normais e de pacientes com β-talassemias, sob a ação pró-oxidativa de TBHP. Neste trabalho foi estudada a ação in vitro da desferoxamina e o deferiprona no metabolismo oxidativo dos eritrócitos de pacientes β-talassêmicos atendidos no Centro de Hematologia e Hemoterapia do Paraná (Hemepar), Brasil, sob a ação pró-oxidativa de TBHP. Concentrações de metahemoglobina glutationa reduzida, índices de hemólises, atividades das enzimas G6PD e GR foram determinadas. Os índices de oxidação analisados foram maiores nos eritrócitos de indivíduos β-talassêmicos do que nos normais. Tratamentos dos eritrócitos normais e β-talassêmicos com DFO e/ou DFP protegem contra a oxidação de GSH promovida por TBHP.

Effect of Iron-Chelator Deferiprone on the In Vitro Growth of Staphylococci

The standard iron-chelator deferoxamine is known to prevent the growth of coagulase-negative staphylococci (CoNS) which are major pathogens in iron-overloaded patients. However, we found that deferoxamine rather promotes the growth of coagulase-positive Staphylococcus aureus. Accordingly, we tested whether deferiprone, a new clinically-available iron-chelator, can prevent the growth of S. aureus strains as well as CoNS. Deferiprone did not at least promote the growth of all S. aureus strains (n=26) and CoNS (n=27) at relatively low doses; moreover, it could significantly inhibit the growth of all staphylococci on non-transferrin-bound-iron and the growth of all CoNS on transferrin-bound iron at relatively high doses. At the same doses, it did not at least promote the growth of all S. aureus strains on transferrin-bound-iron. These findings indicate that deferiprone can be useful to prevent staphylococcal infections, as well as to improve iron overload, in iron-overloaded patients.

Sobrecarga e quelação de ferro na anemia falciforme / Iron overload and iron chelation in sickle cell disease

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.