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Background: Medication burden and complexity have been longstanding problems in chronically ill patients. However, more data are needed on the extent and impact of medication burden and complexity in the transfusion-dependent thalassaemia population., Aim: The aim of this study was to determine the characteristics of medication complexity and polypharmacy and determine their relationship with drug-related problems (DRP) and control of iron overload in transfusion-dependent thalassaemia patients., Method: Data were derived from a cross-sectional observational study on characteristics of DRPs conducted at a Malaysian tertiary hospital. The medication regimen complexity index (MRCI) was determined using a validated tool, and polypharmacy was defined as the chronic use of five or more medications. The receiver operating characteristic curve analysis was used to determine the optimal cut-off value for MRCI, and logistic regression analysis was conducted., Results: The study enrolled 200 adult patients. The MRCI cut-off point was proposed to be 17.5 (Area Under Curve  =  0.722; sensitivity of 73.3% and specificity of 62.0%). Approximately 73% and 64.5% of the patients had polypharmacy and high MRCI, respectively. Findings indicated that DRP was a full mediator in the association between MRCI and iron overload., Conclusion: Transfusion-dependent thalassaemia patients have high MRCI and suboptimal control of iron overload conditions in the presence of DRPs. Thus, future interventions should consider MRCI and DRP as factors in serum iron control., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The thalassaemias are a group of genetic disorders of haemoglobin which are endemic in the tropics but are now found worldwide due to migration. Basic standard of care therapy includes regular transfusions to maintain a haemoglobin level of around 10 g/dL, together with iron chelation therapy to prevent iron overload. Novel therapies, bone marrow transplantation, and gene therapy are treatment options that are unavailable in many countries with stressed economies. This Wider Perspectives article presents the strategies for management of an adolescent refugee patient with beta thalassaemia, as it would be performed by expert haematologists in six countries: Italy, Lebanon, Oman, the Sudan, Thailand and the United States. The experienced clinicians in each country have adapted their practice according to the resources available, which vary greatly. Even in the current modern era, providing adequate transfusions and chelation is problematic in many countries. On the other hand, ensuring adherence to therapy, particularly during adolescence, is a similar challenge seen in all countries. The concluding section highlights the disparities in available therapies and puts the role of novel therapies into a societal context., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Introduction: Iron chelation therapy (ICT) is essential to prevent complications of iron overload in patients with transfusion-dependent thalassaemia. However, there is currently no standard for how to best measure adherence to ICT, nor what level of adherence necessitates concern for poor outcomes, especially in paediatric patients. The objectives of this review are to identify rates of adherence to ICT, predictors of adherence, methods of measurement, and adherence-related health outcomes in children and adolescents., Methods: This review covers the literature published between 1980 and 2020 on ICT in thalassaemia that assessed adherence or compliance. Included studies reflect original research. The preferred reporting items of systematic reviews and meta-analyses (PRISMA) guidelines were followed for reporting results, and the findings were critically appraised with the Oxford Centre for Evidence-based Medicine criteria., Results: Of the 543 articles, 37 met the inclusion criteria. The most common methods of assessing adherence included patient self-report ( n  = 15/36, 41.7%), and pill count ( n  = 15/36, 41.7%), followed by subcutaneous medication monitoring (5/36, 13.8%) and prescription refills ( n  = 4/36, 11.1%). Study sizes ranged from 7 to 1115 participants. Studies reported adherence either in "categories" with different levels of adherence ( n  = 29) or "quantitatively" as a percentage of medication taken out of those prescribed ( n  = 7). Quantitatively, the percentage of adherence varied from 57% to 98.4% with a median of 89.5%. Five studies focussed on interventions, four of which were designed to improve adherence. Studies varied in sample size and methods of assessment, which prohibited performing a meta-analysis., Conclusions: Due to a lack of clinical consensus on how adherence is defined, it is difficult to compare adherence to ICT in different studies. Future studies should be aimed at creating guidelines for assessing adherence and identifying suboptimal adherence. These future efforts will be crucial in informing evidence-based interventions to improve adherence and health outcomes in thalassaemia patients.Key messagesPredictive factors associated with ICT adherence in the paediatric population include age, social perception of ICT, social support, and side effects/discomfort.Increased adherence in the paediatric population is associated with decreased serum ferritin and improved cardiac, hepatic, and endocrine outcomes.Inadequate adherence to ICT is associated with increased lifetime health costs.There are few studies that focussed on interventions to increase adherence in the paediatric population, and the studies that do exist all focussed on different types of interventions; successful interventions focussed on consistent, long-term engagement with patients.

Although numerous patient-specific co-factors have been shown to be associated with worse outcomes in COVID-19, the prognostic value of thalassaemic syndromes in COVID-19 patients remains poorly understood. We studied the outcomes of 137 COVID-19 patients with a history of transfusion-dependent thalassaemia (TDT) and transfusion independent thalassaemia (TIT) extracted from a large international cohort and compared them with the outcomes from a matched cohort of COVID-19 patients with no history of thalassaemia. The mean age of thalassaemia patients included in our study was 41 ± 16 years (48.9% male). Almost 81% of these patients suffered from TDT requiring blood transfusions on a regular basis. 38.7% of patients were blood group O. Cardiac iron overload was documented in 6.8% of study patients, whereas liver iron overload was documented in 35% of study patients. 40% of thalassaemia patients had a history of splenectomy. 27.7% of study patients required hospitalization due to COVID-19 infection. Amongst the hospitalized patients, one patient died (0.7%) and one patient required intubation. Continuous positive airway pressure (CPAP) was required in almost 5% of study patients. After adjustment for age-, sex- and other known risk factors (cardiac disease, kidney disease and pulmonary disease), the rate of in-hospital complications (supplemental oxygen use, admission to an intensive care unit for CPAP therapy or intubation) and all-cause mortality was significantly lower in the thalassaemia group compared to the matched cohort with no history of thalassaemia. Amongst thalassaemia patients in general, the TIT group exhibited a higher rate of hospitalization compared to the TDT group (p = 0.001). In addition, the rate of complications such as acute kidney injury and need for supplemental oxygen was significantly higher in the TIT group compared to the TDT group. In the multivariable logistic regression analysis, age and history of heart or kidney disease were all found to be independent risk factors for increased in-hospital, all-cause mortality, whereas the presence of thalassaemia (either TDT or TIT) was found to be independently associated with reduced all-cause mortality. The presence of thalassaemia in COVID-19 patients was independently associated with lower in-hospital, all-cause mortality and few in-hospital complications in our study. The pathophysiology of this is unclear and needs to be studied in vitro and in animal models., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background and Objectives: Patients with thalassaemia experience complications related to iron overload. In Australia currently, the two main options for iron chelation are deferasirox and deferoxamine. Optimal iron chelation using monotherapy can be limited due to toxicity or tolerability. Dual chelation therapy (DCT) may provide more aggressive iron chelation., Material and Methods: A retrospective, observational study was performed on a state-wide referral centre for patients receiving red cell transfusions for haemoglobinopathies (Monash Health, Australia). All patients prescribed DCT were identified using a local pharmacy dispensing database and were included in the study. Pre-DCT initiation and post-DCT completion were correlated with serum ferritin, cardiac iron loading (based on MRI T2* measurements) and liver iron content (LIC) using Wilcoxon signed-rank test., Results: A total of 18 patients (12 adults, 6 children) were identified as receiving DCT. All patients received a combination of deferasirox and deferoxamine. The median duration of therapy was 23 months (range 2-73). Median serum ferritin reduced by 42% (p = 0.004) and there was a 76% reduction in LIC (p = 0.062). No significant changes were seen in cardiac iron loading., Conclusion: DCT over a prolonged period is effective at reducing serum ferritin and may contribute to improvement in liver iron loading., (© 2022 International Society of Blood Transfusion.)

Background and Objectives: Iron overload in thalassaemia is a crucial prognostic factor and a major cause of death due to heart failure or arrhythmia. Therefore, previous research has recommended amlodipine as an auxiliary treatment to current chelating agents for reducing iron overload in thalassaemia patients., Materials and Methods: A systematic review and meta-analysis of the results of three randomized clinical trials evaluating the use of amlodipine in thalassaemia patients through 12 databases were carried out., Results: Our final cohort included 130 patients. Insignificant difference in decreasing liver iron concentrations was found between amlodipine and control groups {weighted mean difference = -0·2, [95% confidence interval = (-0·55-0·15), P = 0·26]}. As regards serum ferritin, our analysis also showed no significant difference in serum ferritin between amlodipine and control groups {weighted mean difference [95% confidence interval = -0·16 (-0·51-0·19), P = 0·36]}. Similarly, there was insignificant difference in cardiac T2* between amlodipine and control groups {weighted mean difference [95% confidence interval = 0·34 (-0·01-0·69), P = 0·06]}., Conclusions: Despite the growing evidence supporting the role of amlodipine in reducing iron overload in thalassaemia patients, our meta-analysis did not find that evidence collectively significant. The results of our simulation suggest that when more data are available, a meta-analysis with more randomized clinical trials could provide more conclusive insights., (© 2021 International Society of Blood Transfusion.)

Effective iron chelation therapy is an important part of treatment in patients with transfusion-dependent thalassaemia and lower-risk myelodysplastic syndromes (MDS). Key strategies for optimising iron chelation therapy include ensuring good adherence and preventing and managing adverse events (AEs). Good adherence to iron chelation therapy with deferoxamine and deferasirox has been linked to improved survival and/or reductions in complications related to iron overload; however, maintaining good adherence to iron chelators can be challenging. Patients with transfusion-dependent thalassaemia or lower-risk MDS showed better adherence to the deferasirox film-coated tablet (FCT) formulation than to the deferasirox dispersible tablet formulation in the ECLIPSE trial, reflecting in part the improved palatability and convenience of deferasirox FCT. As well as affecting adherence, AEs may lead to dose reduction, interruption or discontinuation, resulting in suboptimal iron chelation therapy. Preventing and successfully managing AEs may help limit their impact on adherence, and following dosage and administration recommendations for iron chelators such as deferasirox may help minimise AEs and optimise treatment in patients with transfusion-dependent thalassaemia and lower-risk MDS., (© 2018 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd.)

Recent years have witnessed impressive advances in our understanding of iron metabolism. A number of studies of iron disorders and of their animal models have provided landmark insights into the mechanisms of iron trafficking, distribution and homeostatic regulation, the latter essential to prevent both iron deficiency and iron excess. Our perception of iron metabolism has been completely changed by an improved definition of cellular and systemic iron homeostasis, of the molecular pathogenesis of iron disorders, the fine tuning of the iron hormone hepcidin by activators and inhibitors and the dissection of the components of the hepcidin regulatory pathway. Important for haematology, the crosstalk of erythropoiesis, the most important iron consumer, and the hepcidin pathway has been at least partially clarified. Novel potential biomarkers are available and novel therapeutic targets for iron-related disorders have been tested in murine models. These preclinical studies provided proofs of principle and are laying the ground for clinical trials. Understanding iron control in tissues other than erythropoiesis remains a challenge for the future., (© 2018 John Wiley & Sons Ltd.)

Objective: The aim of this study was to analyse the value of diffusion-weighted magnetic resonance imaging (DWI) to determine the liver parenchyma iron concentration in β-thalassaemia major patients., Methods: Abdominal magnetic resonance (MR) imaging, including gradient echo sequences and DWI sequences, was undertaken of 55 β-thalassaemia major patients. The apparent diffusion coefficient (ADC) values of liver parenchyma were measured in seven regions at the level of the portal bifurcation and compared with liver iron concentration (LIC). Patients with normal and mild liver dry weight (LDW) results were classified as group 1, whereas patients with moderate and severe values were classified as group 2., Results: There was a dramatic decrease in ADC values as the severity of LIC increased. The median ADC values were 1.6-1.9 × 10 -3  mm 2 /sec in group 1 and 0.6-0.9 × 10 -3  mm 2 /sec in group 2. A negative correlation was observed between ADC and the LDW values in both groups. The ADC and LIC correlation in each subgroup was statistically significant with asymptotic 95% confidence intervals of 0.820-0.997., Conclusion: Diffusion-weighted imaging is sensitive to tissue changes as a result of iron accumulation and may be used to predict liver iron overload in β-thalassaemia major patients with a high sensitivity and specificity., (© 2017 The Royal Australian and New Zealand College of Radiologists.)

Beta-thalassaemia, an autosomal recessive haemoglobinopathy, ranks among the most frequent monogenetic diseases globally. The severe form of the disease, beta-thalassaemia major, is accompanied by progressive involvement of multiple organ systems as a result of the disease pathophysiology as well as iron overload from blood transfusions on a regular basis. Some of the manifestations might also be caused by medications used to manage iron overload. The purpose of this review is to highlight the rheumatological complications of beta-thalassaemia, which include musculoskeletal manifestations, such as arthritis and arthropathies, joint effusions, osteoporosis, bone fractures and myalgias, in addition to CTDs, such as pseudoxanthoma elasticum. Rheumatologists are strongly encouraged to take part in a multidisciplinary approach to the management of this debilitating disease., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

This review outlines the effectiveness and safety of 10 different regimens for controlling iron overloading in thalassaemia major (TM). For each treatment, the strength of the evidence was documented according to the guidelines of the American College of Cardiology and the American Heart Association. Serum ferritin (SF), liver iron concentration (LIC), heart T2* signal, heart damage and survival were used to assess effectiveness. Five chelation regimens out of 10 showed Level A Evidence in controlling iron overloading, as determined by SF levels and LIC. Three out of 10 chelation regimens were able to control heart iron levels, as determined by T2* signals with Level A Evidence. Two chelation regimens were able to improve/reverse heart damage and four increased of survival with Level B Evidence. These advances mean that the current survival of TM patients is now similar to that of thalassaemia intermedia patients., (© 2017 John Wiley & Sons Ltd.)

Hereditary haemoglobinopathies, mainly beta-thalassemia and sickle cell disease, constitute the most common monogenic disorders in humans, and although once geographically confined, they are currently globally distributed. They are demanding clinical entities that require multidisciplinary medical management. Despite their genotypic and phenotypic heterogeneity, the haemoglobinopathies share several similarities in pathophysiology, clinical manifestations, therapeutic requirements, and complications, among which heart failure (HF) represents a leading cause of mortality and morbidity. However, haemoglobinopathies have generally been addressed in a rather fragmentary manner. A unifying approach focusing on the underlying similarities of HF attributes in the two main entities might contribute to their better understanding, characterization, and management. In the present review, we attempt such an approach to the pathophysiology, clinical phenotypes, and management of HF in haemoglobinopathies., (© 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.)

Background: In transfusion-dependent anaemias, while absolute serum ferritin levels broadly correlate with liver iron concentration (LIC), relationships between trends in these variables are unclear. These relationships are important because serum ferritin changes are often used to adjust or switch chelation regimens when liver magnetic resonance imaging (MRI) is unavailable., Objectives and Methods: This post hoc analysis of the EPIC study compared serum ferritin and LIC in 317 patients with transfusion-dependent thalassaemia before and after 1 yr of deferasirox., Results: Serum ferritin responses (decreases) occurred in 73% of patients, 80% of whom also have decreased LIC. However, 52% of patients without a serum ferritin response did decrease LIC and by >1 mg Fe/g dw (median 3.9) in 77% of cases. Absolute serum ferritin and LIC values correlated significantly only when serum ferritin was <4000 ng/mL (r = 0.59; P < 0.0001) and not at higher levels (≥4000 ng/mL; r = 0.19). Serum ferritin response was accompanied by decreased LIC in 89% and 70% of cases when serum ferritin was <4000 or ≥4000 ng/mL, respectively., Conclusions: As serum ferritin non-response was associated with LIC decrease in over half of patients, use of liver MRI may be particularly useful for differentiating true from apparent non-responders to deferasirox based on serum ferritin trends alone., (© 2016 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd.)

Background: MRI imaging is an alternative to serum ferritin for assessing iron overload in patients with thalassaemia disease., Aims: To correlate liver iron concentration (LIC) determined by MRI and clinical and biochemical parameters., Methods: An MRI study using cardiovascular magnetic resonance (CMR) tools to determine cardiac and liver iron was undertaken in adolescents with thalassaemia disease., Results: Eighty-nine patients (48 males) with thalassaemia disease were enrolled. Seventy patients had been transfusion-dependent since a mean (SD) age of 3.8 (3.0) years, and 19 patients were not transfusiondependent. Mean (SD) haematocrit was 27.3 (2.9)%. Twenty-eight patients were splenectomized. Mean (SD) serum ferritin was 1673 (1506) μg/L. All transfusion-dependent patients received iron chelation at the mean (SD) age of 8.4 (3.5) years with either monotherapy of desferrioxamine, deferiprone, deferasirox or combined therapy of desferrioxamine and deferiprone, while only 5 of 19 patients who were not transfusion-dependent received oral chelation. The 89 patients underwent an MRI scan at the mean (SD) age of 14.8 (3.2) years. No patients had myocardial iron overload, but nine had severe liver iron overload, 27 had moderate liver iron overload, and 36 had mild liver iron overload. A significant correlation between liver T2* and serum ferritin was expressed as the equation: T2* (ms) = 28.080-7.629 log ferritin (μg/L) (r(2) 0.424, P = 0.0001). Patients with serum ferritin of >1000 to >2500 μg/L risked moderate and severe liver iron loading with the odds ratio ranging from 6.8 to 13.3 (95% CI 2.5-50.8)., Conclusion: In thalassaemia, MRI is an alternative means of assessing iron stores, but when it is not available serum ferritin can be used to estimate liver T2*.

Iron chelating drugs are primarily and widely used in the treatment of transfusional iron overload in thalassaemia and similar conditions. Recent in vivo and clinical studies have also shown that chelators, and in particular deferiprone, can be used effectively in many conditions involving free radical damage and pathology including neurodegenerative, renal, hepatic, cardiac conditions and cancer. Many classes of phytochelators (Greek: phyto (φυτό)-plant, chele (χηλή)-claw of the crab) with differing chelating properties, including plant polyphenols resembling chelating drugs, can be developed for clinical use. The phytochelators mimosine and tropolone have been identified to be orally active and effective in animal models for the treatment of iron overload and maltol for the treatment of iron deficiency anaemia. Many critical parameters are required for the development of phytochelators for clinical use including the characterization of the therapeutic targets, ADMET, identification of the therapeutic index and risk/benefit assessment by comparison to existing therapies. Phytochelators can be developed and used as main, alternative or adjuvant therapies including combination therapies with synthetic chelators for synergistic and or complimentary therapeutic effects. The development of phytochelators is a challenging area for the introduction of new pharmaceuticals which can be used in many diseases and also in ageing. The commercial and other considerations for such development have great advantages in comparison to synthetic drugs and could also benefit millions of patients in developing countries.

Iron overload is becoming an increasing problem as haemoglobinopathy patients gain greater access to good medical care and as therapies for myelodysplastic syndromes improve. Therapeutic options for iron chelation therapy have increased and many patients now receive combination therapies. However, optimal utilization of iron chelation therapy requires knowledge not only of the total body iron burden but the relative iron distribution among the different organs. The physiological basis for extrahepatic iron deposition is presented in order to help identify patients at highest risk for cardiac and endocrine complications. This manuscript reviews the current state of the art for monitoring global iron overload status as well as its compartmentalization. Plasma markers, computerized tomography, liver biopsy, magnetic susceptibility devices and magnetic resonance imaging (MRI) techniques are all discussed but MRI has come to dominate clinical practice. The potential impact of recent pancreatic and pituitary MRI studies on clinical practice are discussed as well as other works-in-progress. Clinical protocols are derived from experience in haemoglobinopathies but may provide useful guiding principles for other iron overload disorders, such as myelodysplastic syndromes., (© 2015 John Wiley & Sons Ltd.)

Purpose: We report the results of combining cardiac and hepatic MRI in the same examination to monitor 48 multi-transfused patients presenting iron overload secondary to their transfusions. This cardiac MRI technique uses acquisition sequences and calculation software that are readily available for 1.5 T systems, and it has been validated to screen for patients at risk of cardiac complications who present myocardial iron overload (T2*<20milliseconds)., Patients and Methods: A total of 176 combined MRI examinations were performed between May 2006 and January 2012 in 48 patients who had received transfusions due to thalassaemia. This monocentric retrospective study brings together all of the imaging examinations carried out., Results: There was a positive correlation between the cardiac T2* values and left ventricular ejection fraction, which were measured in the same examination. At the first assessment 23/48 patients had a T2*<20ms. These patients showed a significant improvement in cardiac T2* over time while their iron chelation therapy was being intensified., Conclusion: This study validates the application of the cardiac MRI technique used to monitor cardiac iron overload in patients who have undergone multiple transfusions., (Copyright © 2014. Published by Elsevier Masson SAS.)

Transfusion-dependent children, mostly with thalassaemia major, but also and occasionally to a more significant degree, with inherited bone marrow failures, can develop severe iron overload in early life. Moreover, chronic conditions associated with ineffective erythropoiesis, such as non-transfusion-dependent thalassaemia (NTDT), may lead to iron overload through increased gut absorption of iron starting in childhood. Currently, the goal of iron chelation has shifted from treating iron overload to preventing iron accumulation and iron-induced end-organ complications, in order to achieve a normal pattern of complication-free survival and of quality of life. New chelation options increase the likelihood of achieving these goals. Timely initiation, close monitoring and continuous adjustment are the cornerstones of optimal chelation therapy in children, who have a higher transfusional requirements compared to adults in order to reach haemoglobin levels adequate for normal growth and development. Despite increased knowledge, there are still uncertainties about the level of body iron at which iron chelation therapy should be started and about the appropriate degree of iron stores' depletion., (© 2014 John Wiley & Sons Ltd.)

Objectives: To compare the effectiveness of dark blood (DB) versus bright blood (BB) sequences. To assess the intra and inter-observer variability and inter-study reproducibility between BB versus DB. To evaluate image quality level in the two sequences., Methods: In a setting of 138 patients we performed CMR using cardiac gated Gradient-multiecho single breath-hold BB and DB sequences in the middle ventricular septum. Each acquisition was repeated during the same exam. Truncation method was used to account for background noise. Image quality (IQ) was assessed using a 5 point grading scale and image analysis was conducted by 2 experienced observers., Results: Compared with the conventional BB acquisition, the coefficient of correlation and significance of the DB technique was superior for intra-observer reproducibility (p<0.001), inter-observer reproducibility (p<0.001) and inter-study reproducibility (p<0.001). The variability is also lower for DB sequences for T2* values <14 ms. Assessment of artifacts showed a superior score for DB versus BB scans (4 versus 3, p<0.001)., Conclusions: Improvement in terms of inter observer and inter study variability using DB sequences was obtained. The greatest disparity between them was seen in inter-study reproducibility and higher IQ in DB was seen. Study demonstrates better performance of DB imaging compared to BB in presence of comparable effectiveness., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Summary Transfusion‐dependent β‐thalassaemia (TDβT) is a genetic disorder characterised by reduced or absent β‐globin chain synthesis, resulting in chronic anaemia. Treatment consists of regular blood transfusions and chelation therapy to limit iron overload and its negative effects on organs (e.g. heart, lungs and liver). Despite improved life expectancy with transfusions and chelation therapy, TDβT patients experience poor quality of life and impaired exercise capacity (mainly due to muscle deconditioning and reduced cardiac inotropism). The aims of this review are (i) to discuss the role of organ dysfunction in the impairment of exercise capacity and reduced quality of life of TDβT patients; and (ii) to discuss physical activity as a potential therapeutic strategy to alleviate the multifactorial impact of the disease. [ABSTRACT FROM AUTHOR]

Abstract Understanding consequences of poor chelation compliance is crucial given the enormous burden of post-transfusional iron overload complications. We systematically reviewed iron-chelation therapy (ICT) compliance, and the relationship between compliance with health outcome and health-related quality of life (HRQoL) in thalassaemia patients. Several reviewers performed systematic search strategy of literature through PubMed, Scopus, and EBSCOhost. The preferred reporting items of systematic reviews and meta-analyses (PRISMA) guidelines were followed. Of 4917 studies, 20 publications were included. The ICT compliance rate ranges from 20.93 to 75.3%. It also varied per agent, ranging from 48.84 to 85.1% for desferioxamine, 87.2–92.2% for deferiprone and 90–100% for deferasirox. Majority of studies (N = 10/11, 90.91%) demonstrated significantly negative correlation between compliance and serum ferritin, while numerous studies revealed poor ICT compliance linked with increased risk of liver disease (N = 4/7, 57.14%) and cardiac disease (N = 6/8, 75%), endocrinologic morbidity (N = 4/5, 90%), and lower HRQoL (N = 4/6, 66.67%). Inadequate compliance to ICT therapy is common. Higher compliance is correlated with lower serum ferritin, lower risk of complications, and higher HRQoL. These findings should be interpreted with caution given the few numbers of evidence.

Background: In the last few decades, the life expectancy of patients with transfusion‐dependent thalassaemia (TDT) and sickle cell disease (SCD) has improved significantly, in part because of improved iron chelation. Fertility challenges and pregnancy complications have historically limited reproductive options in this group; however, improved multi‐disciplinary care has made infertility a chronic disease complication requiring attention. Despite this, there are very few reports and no Australian data describing fertility and pregnancy outcomes in this population. Aims: To identify the rate of assisted reproductive technologies (ART) utilisation in our female transfusion‐dependent haemoglobinopathy patients and to establish the nature of maternal and neonatal complications in this cohort. Methods: A 20‐year retrospective analysis (1997–2017) at an Australian centre captured data on conception rates, use of assisted reproductive techniques (ART), and pregnancy and neonatal outcomes in female transfusion‐dependent haemoglobinopathy patients. Results: Conception was attempted in 14 women (11 TDT and three SCD) during the study period. A total of 28 pregnancies resulting in 25 live births were recorded. ART supported 13 conceptions. A positive association was not identified between elevated mean serum ferritin and ART use; however, all patients with an established diagnosis of hypogonadotropic hypogonadism (HH) required ART. Maternal complications included gestational diabetes mellitus and post‐partum haemorrhage. There were no cardiac complications. Two‐thirds of women underwent lower segment caesarean section, with prematurity complicating 20% of births. There were no neonatal or maternal deaths. Conclusion: Pregnancy is an achievable goal for women with transfusion‐dependent haemoglobinopathies, although the support of ART may be required in a subset of patients. [ABSTRACT FROM AUTHOR]

Understanding consequences of poor chelation compliance is crucial given the enormous burden of post-transfusional iron overload complications. We systematically reviewed iron-chelation therapy (ICT) compliance, and the relationship between compliance with health outcome and health-related quality of life (HRQoL) in thalassaemia patients. Several reviewers performed systematic search strategy of literature through PubMed, Scopus, and EBSCOhost. The preferred reporting items of systematic reviews and meta-analyses (PRISMA) guidelines were followed. Of 4917 studies, 20 publications were included. The ICT compliance rate ranges from 20.93 to 75.3%. It also varied per agent, ranging from 48.84 to 85.1% for desferioxamine, 87.2–92.2% for deferiprone and 90–100% for deferasirox. Majority of studies (N = 10/11, 90.91%) demonstrated significantly negative correlation between compliance and serum ferritin, while numerous studies revealed poor ICT compliance linked with increased risk of liver disease (N = 4/7, 57.14%) and cardiac disease (N = 6/8, 75%), endocrinologic morbidity (N = 4/5, 90%), and lower HRQoL (N = 4/6, 66.67%). Inadequate compliance to ICT therapy is common. Higher compliance is correlated with lower serum ferritin, lower risk of complications, and higher HRQoL. These findings should be interpreted with caution given the few numbers of evidence. [ABSTRACT FROM AUTHOR]

Thalassaemia is caused by genetic globin defects leading to anaemia, transfusion-dependence and comorbidities. Reduced survival and systemic organ disease affect transfusion-dependent thalassaemia major and thalassaemia intermedia. Recent improvements in clinical management have reduced thalassaemia mortality. The therapeutic landscape of thalassaemia may soon include gene therapies as functional cures. An analysis of the adult US thalassaemia population has not been performed since the Thalassemia Clinical Research Network cohort study from 2000 to 2006. The Centers for Disease Control and Prevention supported US thalassaemia treatment centres (TTCs) to compile longitudinal information on individuals with thalassaemia. This dataset provided an opportunity to evaluate iron balance, chelation, comorbidities and demographics of adults with thalassaemia receiving care at TTCs. Two adult cohorts were compared: those over 40 years old (n = 75) and younger adults ages 18-39 (n = 201). The older adult cohort was characterized by higher numbers of iron-related comorbidities and transfusion-related complications. By contrast, younger adults had excess hepatic and cardiac iron and were receiving combination chelation therapy. The ethnic composition of the younger cohort was predominantly of Asian origin, reflecting the demographics of immigration. These findings demonstrate that comprehensive care and periodic surveys are needed to ensure optimal health and access to emerging therapies.

Background: Hyperfunctional platelets play important roles in thromboembolism in patients with β-thalassaemia/ haemoglobin E (β-thal/HbE). Our previous study revealed ex vivo inhibitory effects of deferiprone on normal platelets. Herein, we aimed to investigate the in vivo effects on platelets in patients with β-thal/HbE. Methods: A prospective, self-controlled clinical study on 30 patients with β-thal/HbE who had received therapeutic deferiprone (20.8–94.5 mg/kg/day) was conducted. The study included a 4-week washout period followed by 4 and 12 weeks of deferiprone treatment. Platelet aggregation was performed by a turbidimetric method. Levels of deferiprone and soluble platelet (sP)-selectin in serum were measured by high-performance liquid chromatography (HPLC) and enzyme-linked immunosorbent assay (ELISA) kit, respectively. Results: The washout period significantly enhanced platelet hyperactivity both in patients who had undergone splenectomy and in those who had not. At 2 hours following the administration of a single dose of deferiprone, platelet sensitivity to ADP and arachidonic acid was significantly reduced. The inhibitory effects of deferiprone were gradually increased over the period of 4 and 12 weeks. Deferiprone also depressed sP-selectin levels, but the effect was stable over longer follow-up periods. Correlation analysis demonstrated the relationship between serum levels of deferiprone, sP-selectin, and platelet activities induced by ADP and arachidonic acid. Conclusion: We first demonstrated the in vivo antiplatelet effect and benefit of short-term treatment of deferiprone in patients with β-thal/HbE. The impact on thrombotic outcomes deserves further study.

Haemoglobinopathies, including thalassaemias and sickle-cell syndromes, are demanding, lifelong conditions that pose a significant burden to patients, families, and healthcare systems. Despite the therapeutic advances and the resulting improvements in prognosis accomplished in past decades, these patients still face important challenges, including suboptimal access to quality care in areas with developing economies, changing epidemiology due to massive migration flows, an evolving clinical spectrum due to ageing in well-treated patients, and limited access to novel high-cost therapies. We herein describe the organization of healthcare services for haemoglobinopathies in Cyprus—with particular focus on beta-thalassaemia, the most prevalent condition in this region—along with selected patient outcomes. This report aims at underscoring the fact that nationally funded and well-coordinated prevention and care programmes for chronic and complex conditions, such as haemoglobinopathies, with active involvement from patient organizations lead to effective disease control and excellent outcomes in survival, quality of life, social adaptation, and public health savings, and allow timely and effective responses to emerging crises, such as the COVID-19 pandemic. The Cyprus paradigm could therefore serve as a blueprint for the organization or adaptation of haemoglobinopathy programs in other countries since these disorders are still widely occurring.

The iron chelating orphan drug deferiprone (L1), discovered over 40 years ago, has been used daily by patients across the world at high doses (75–100 mg/kg) for more than 30 years with no serious toxicity. The level of safety and the simple, inexpensive synthesis are some of the many unique properties of L1, which played a major role in the contribution of the drug in the transition of thalassaemia from a fatal to a chronic disease. Other unique and valuable clinical properties of L1 in relation to pharmacology and metabolism include: oral effectiveness, which improved compliance compared to the prototype therapy with subcutaneous deferoxamine; highly effective iron removal from all iron-loaded organs, particularly the heart, which is the major target organ of iron toxicity and the cause of mortality in thalassaemic patients; an ability to achieve negative iron balance, completely remove all excess iron, and maintain normal iron stores in thalassaemic patients; rapid absorption from the stomach and rapid clearance from the body, allowing a greater frequency of repeated administration and overall increased efficacy of iron excretion, which is dependent on the dose used and also the concentration achieved at the site of drug action; and its ability to cross the blood–brain barrier and treat malignant, neurological, and microbial diseases affecting the brain. Some differential pharmacological activity by L1 among patients has been generally shown in relation to the absorption, distribution, metabolism, elimination, and toxicity (ADMET) of the drug. Unique properties exhibited by L1 in comparison to other drugs include specific protein interactions and antioxidant effects, such as iron removal from transferrin and lactoferrin; inhibition of iron and copper catalytic production of free radicals, ferroptosis, and cuproptosis; and inhibition of iron-containing proteins associated with different pathological conditions. The unique properties of L1 have attracted the interest of many investigators for drug repurposing and use in many pathological conditions, including cancer, neurodegenerative conditions, microbial conditions, renal conditions, free radical pathology, metal intoxication in relation to Fe, Cu, Al, Zn, Ga, In, U, and Pu, and other diseases. Similarly, the properties of L1 increase the prospects of its wider use in optimizing therapeutic efforts in many other fields of medicine, including synergies with other drugs. [ABSTRACT FROM AUTHOR]

Haemoglobinopathies, including thalassaemias and sickle-cell syndromes, are demanding, lifelong conditions that pose a significant burden to patients, families, and healthcare systems. Despite the therapeutic advances and the resulting improvements in prognosis accomplished in past decades, these patients still face important challenges, including suboptimal access to quality care in areas with developing economies, changing epidemiology due to massive migration flows, an evolving clinical spectrum due to ageing in well-treated patients, and limited access to novel high-cost therapies. We herein describe the organization of healthcare services for haemoglobinopathies in Cyprus--with particular focus on beta-thalassaemia, the most prevalent condition in this region--along with selected patient outcomes. This report aims at underscoring the fact that nationally funded and well-coordinated prevention and care programmes for chronic and complex conditions, such as haemoglobinopathies, with active involvement from patient organizations lead to effective disease control and excellent outcomes in survival, quality of life, social adaptation, and public health savings, and allow timely and effective responses to emerging crises, such as the COVID-19 pandemic. The Cyprus paradigm could therefore serve as a blueprint for the organization or adaptation of haemoglobinopathy programs in other countries since these disorders are still widely occurring. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Control haemoglobinopathy blood safety project Keywords: sickle cell disease; thalassaemia; vaccines; iron overload; hepatitis EN sickle cell disease thalassaemia vaccines iron overload hepatitis e160 e164 5 11/30/21 20211201 NES 211201 Non-concordance with preventive recommendations is common among patients with chronic conditions, including sickle cell disease (SCD) and transfusion-dependent thalassaemia (TDT).1,2 Iron overload is common among chronically transfused patients with SCD and TDT leading to increased morbidity, mortality and cost of care, especially as they live longer.3-5 The Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) recommendations support completion of hepatitis A (HepA) and hepatitis B (HepB) vaccinations, including SCD and TDT.6,7 Cardiac iron overload is the leading cause of mortality in TDT,8 while it is rare in SCD.9 Guidelines recommend liver iron overload assessment every 1-2 years for patients with SCD receiving chronic transfusions.10,11 The recommendation for TDT is annual assessment of liver and cardiac iron concentration.3,8 However, there are limited data on concordance with these recommendations. Child/adolescent patients with TDT who were concordant with HepA vaccination recommendations were concordant with the other two preventive service recommendations (Fig 1B). [Extracted from the article]

Haemoglobin H (HbH) disease is a type of non‐transfusion‐dependent thalassaemia. This cross‐sectional study aimed at determining the prevalence and severity of liver iron overload and liver fibrosis in patients with HbH disease. Risk factors for advanced liver fibrosis were also identified. A total of 80 patients were evaluated [median (range) age 53 (24–79) years, male 34%, non‐deletional HbH disease 24%]. Patients underwent 'observed' T2‐weighted magnetic resonance imaging examination for liver iron concentration (LIC) quantification, and transient elastography for liver stiffness measurement (LSM) and fibrosis staging. In all, 25 patients (31%) had moderate‐to‐severe liver iron overload (LIC ≥7 mg/g dry weight). The median LIC was higher in non‐deletional than in deletional HbH disease (7·8 vs. 2.9 mg/g dry weight, P = 0·002). In all, 16 patients (20%) had advanced liver fibrosis (LSM >7.9 kPa) and seven (9%) out of them had probable cirrhosis (LSM >11.9 kPa). LSM positively correlated with age (R = 0·24, P = 0·03), serum ferritin (R = 0·36, P = 0·001) and LIC (R = 0·28, P = 0·01). In multivariable regression, age ≥65 years [odds ratio (OR) 4·97, 95% confidence interval (CI) 1·52–17·50; P = 0·047] and moderate‐to‐severe liver iron overload (OR 3·47, 95% CI 1·01–12·14; P = 0·01) were independently associated with advanced liver fibrosis. The findings suggest that regular screening for liver complications should be considered in the management of HbH disease. [ABSTRACT FROM AUTHOR]

Summary: We longitudinally evaluated the effects of regular blood transfusions (BTs), in the real‐life context of the Myocardial Iron Overload in Thalassaemia network, in patients with thalassaemia intermedia (TI). We considered 88 patients with TI (52 females) who started regular BTs after the age of 18 years. Magnetic resonance imaging was used to quantify iron overload and biventricular function. For 56·8% of the patients there were more than two indications for the transition to regular BTs, with anaemia present in 94·0% of the cases. A significant decrease in nucleated red blood cells, platelets, lactate dehydrogenase, bilirubin, and uric acid levels was detected 6 months after starting regular BTs. After the transition to the regular BT regimen there was a significant increase only in the frequency of hypothyroidism and osteopenia, and a significant decrease in liver iron and cardiac index. The percentage of chelated patients increased significantly after starting regular BTs. The decision to regularly transfuse patients with TI may represent a way to prevent or slow down the natural progression of the disease, despite the more complex initial management. [ABSTRACT FROM AUTHOR]

Deferiprone (L1) was originally designed, synthesised and screened in vitro and in vivo in 1981 by Kontoghiorghes G. J. following his discovery of the novel alpha-ketohydroxypyridine class of iron chelators (1978-1981), which were intended for clinical use. The journey through the years for the treatment of thalassaemia with L1 has been a very difficult one with an intriguing turn of events, which continue until today. Despite many complications, such as the extensive use of L1 suboptimal dose protocols, the aim of chelation therapy-namely, the complete removal of excess iron in thalassaemia major patients, has been achieved in most cases following the introduction of specific L1 and L1/deferoxamine combinations. Many such patients continue to maintain normal iron stores. Thalassemia has changed from a fatal to chronic disease; also thanks to L1 therapy and thalassaemia patients are active professional members in all sectors of society, have their own families with children and grandchildren and their lifespan is approaching that of normal individuals. No changes in the low toxicity profile of L1 have been observed in more than 30 years of clinical use and prophylaxis against the low incidence of agranulocytosis is maintained using mandatory monitoring of weekly white blood cells' count. Thousands of thalassaemia patients are still denied the cardioprotective and other beneficial effects of L1 therapy. The safety of L1 in thalassaemia and other non-iron loaded diseases resulted in its selection as one of the leading therapeutics for the treatment of Friedreich's ataxia, pantothenate kinase-associated neurodegeneration and other similar cases. There are also increasing prospects for the application of L1 as a main, alternative or adjuvant therapy in many pathological conditions including cancer, infectious diseases and as a general antioxidant for diseases related to free radical pathology. [ABSTRACT FROM AUTHOR]

Background: Patients with thalassaemia who received regular transfusions had increased iron accumulation, leading to iron overload, which was associated with oxidative stress. Mitochondrial ferritin, encoded by the FTMT gene is an iron-storage protein in the mitochondria. The aim of this work was to investigate the expression levels of FTMT in the reticulocytes of patients with alpha-thalassaemia who were regularly transfused and rarely transfused compared with healthy controls and to evaluate the relationships of the levels of FTMT mRNA with malondialdehyde (MDA) and ferritin in these patients. Methods: The levels of FTMT mRNA in the reticulocytes of patients (30 regularly transfused and 30 rarely transfused) and 30 healthy individuals were assessed by quantitative reverse transcription-polymerase chain reaction. The levels of ferritin and MDA were analysed by ELISA and by a thiobarbituric acid reactive substance assay, respectively. Results: The levels of FTMT mRNA, ferritin and MDA in both groups of patients were significantly increased compared with those in the healthy controls. In addition, the levels of FTMT mRNA, ferritin and MDA in the regularly transfused patients were significantly higher than those in the rarely transfused patients. Furthermore, the relative expression levels of FTMT in patients correlated with those of MDA and ferritin. Conclusion: These results suggest that the elevation of expression levels of FTMT in the reticulocytes of patients with alpha-thalassaemia may be associated with iron loading and oxidative stress. [ABSTRACT FROM AUTHOR]

Beta-thalassaemia causes defective haemoglobin synthesis leading to ineffective erythropoiesis, chronic haemolytic anaemia, and subsequent clinical complications. Blood transfusion and iron chelation allow long-term disease control, and haematopoietic stem cell transplantation offers a potential cure for some patients. Nonetheless, there are still many challenges in the management of beta-thalassaemia. The main treatment option for most patients is supportive care; furthermore, the long-term efficacy and safety of current therapeutic strategies are limited and adherence is suboptimal. An increasing understanding of the underlying molecular and cellular disease mechanisms plus an awareness of limitations of current management strategies are driving research into novel therapeutic options. Here we provide an overview of the current pathophysiology, clinical manifestations, and global burden of beta-thalassaemia. We reflect on what has been achieved to date, describe the challenges associated with currently available therapy, and discuss how these issues might be addressed by novel therapeutic approaches in development. [ABSTRACT FROM AUTHOR]

Objectives Deferasirox adverse effects include the following: gastrointestinal disturbance, mild elevations in serum creatinine levels and intermittent proteinuria; these events are dose-dependent and reversible with drug discontinuation, but this solution can lead to an inadequate iron chelation. For these reasons, interindividual variability of drug plasma concentration could help the clinical management of deferasirox dosage. We sought to describe deferasirox plasma exposure in a cohort of 60 adult patients. Methods A fully validated chromatographic method was used to quantify deferasirox concentration in plasma collected from β-thalassaemia adult patients. Samples obtained before and after 2, 4, 6 and 24 h drug administration were evaluated. Associations between variables were tested using the Pearson test. Key findings Concerning pharmacokinetic parameters, a higher interindividual variability was shown. A positive correlation was found between deferasirox area under the concentration curve over 24 h and serum creatinine ( r = 0.314; P = 0.018) and between area and drug dose ( r = 0.311; P = 0.016). Moreover, a negative correlation resulted among area under the concentration curve over 24 h and serum ferritin ( r = −0.291; P = 0.026) and among drug half-life and its dose ( r = −0.319; P = 0.013). Conclusions Treatment decision based on the individual characteristics could strongly contribute to minimize toxicity and increase efficacy of deferasirox therapy. [ABSTRACT FROM AUTHOR]

Objectives A previous report revealed that thalassaemic patients with transfusional iron overload developed oxidative stress. The aims of this study were to investigate the FXN mRNA levels in the reticulocytes of patients with HbE-beta-thalassaemia who were treated with regular transfusions, to compare the results with those from normal controls and to evaluate the relationships of the levels of FXN mRNA with malondialdehyde (MDA) and iron parameters in these patients. Design and methods The levels of FXN mRNA in the reticulocytes of patients (30 non-splenectomized and 30 splenectomized) and 30 normal individuals were assessed by RT-PCR. The levels of MDA and the transferrin saturations (TSs) were analysed with thiobarbituric acid-reactive substance assay and spectrometry, respectively. The level of ferritin was determined by ELISA. Results The levels of FXN mRNA, MDA, ferritin, and TS in the patients were significantly higher than those in the controls. The levels of FXN mRNA, MDA, and ferritin in the non-splenectomized and splenectomized patients were significantly different, but the levels of TS in these two patient groups were comparable. The relative FXN expression in the patients was found to be correlated with the levels of MDA and ferritin but not correlated with TS. Conclusions The elevation of FXN expression in the reticulocytes of these patients seems to be linked to oxidative stress and iron status. [ABSTRACT FROM AUTHOR]

The definition 'iron loading anaemias' encompasses a group of inherited and acquired anaemias characterized by ineffective erythropoiesis, low hepcidin levels, excessive iron absorption and secondary iron overload. Non-transfusion-dependent β-thalassaemia is the paradigmatic example of these conditions that include dyserythropoietic and sideroblastic anaemias and some forms of myelodysplasia. Interrupting the vicious cycle between ineffective erythropoiesis and iron overload may be of therapeutic benefit in all these diseases. Induction of iron restriction by means of transferrin infusions, minihepcidins or manipulation of the hepcidin pathway prevents iron overload, redistributes iron from parenchymal cells to macrophage stores and partially controls anaemia in β-thalassaemic mice. Inhibition of ineffective erythropoiesis by activin ligand traps improves anaemia and iron overload in the same models. Targeting iron loading or ineffective erythropoiesis shows promise in preclinical studies; activin ligand traps are in clinical trials with promising results and may be useful in patients with ineffective erythropoiesis. [ABSTRACT FROM AUTHOR]

Thalassaemia, chelation, rare anaemia, diamond-blackfan, transfusion, sideroblastic anaemia Keywords: thalassaemia; chelation; rare anaemia; diamond-blackfan; transfusion; sideroblastic anaemia EN thalassaemia chelation rare anaemia diamond-blackfan transfusion sideroblastic anaemia 266 267 2 01/17/22 20220115 NES 220115 To sustain life with transfusions of blood For a small proportion of the UK population, life can only be sustained through regular transfusions of blood. [Extracted from the article]

Adherence to treatment is a great concern for patients who need long-life treatment. Thalassaemia is an inherited disease for whose treatment team-working is of a considerable importance. To logically face the problem of poor compliance patients, all members of the team ought to be aware of the causing factors and the ways to handle the problem. The factors which cause the lack of compliance among patients could be stratified into economic and structural facto. Furthermore, patient-related factors including ethnicity, gender, age, and regimen complexity such as dosing are also noteworthy. The supportive relationship between the health providers and the patients should be also established such as patients’ trust in their doctors. Last but not least, the pattern of health care delivery including the availability of health care requisites and operation of flexible hours and floating working hours. From the patients’ point of view, it is important to be aware of the significance of the adherence to treatment and the importance of providing prompt-routine reminders to patients to understand the consequence of incomplete treatment. Trained and motivated staffs play an effective role to enhance patients’ tendency to pursue the determined treatment. Health decision makers would be better to reinterpret the concept of health to “a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity”. The patients’ role in self-management should not be ignored and “medicalization” has to be altered by the patient centered care.

Today a patient born with thalassaemia major can expect to have a near normal life expectancy and remain free of complications of iron overload with good monitoring and excellent transfusion and chelation regimes. Unfortunately patients still develop complications as a consequence of iron overload including endocrinopathies and cardiac failure. The main reason behind this failure of effective treatment is inadequate treatment. This can be due to either clinician related factors, patient related factors or lack of adequate provision of medicines and services. In this short paper I will highlight where the challenges lie with regards adherence to treatment and suggest approaches to manage this.

High mobility group box -1 ( HMGB1) represents a common causal agent for various types of diseases, including infective pathologies. This study aimed to investigate the role of HMGB1 in β-thalassemia major ( TM) by evaluating its diagnostic and prognostic role. Fifty-one TM patients and 30 healthy subjects ( HS) were enrolled. Receiver operating characteristics ( ROC) analysis was employed to calculate the area under the curve ( AUC) for HMGB1 to determine the best cut-off values capable of identifying infectious episodes. Adjusted risk estimates for infective events were calculated using univariate followed by multivariate Cox proportional hazard regression analysis. Serum HMGB1 levels were higher in TM patients than in HS (14·6 ± 8·7 vs. 2·08 ± 0·9 ng/ml, P < 0·0001). Patients who underwent splenectomy were characterized by lower levels of HMGB1, when compared with patients with an intact spleen (10·2 ± 8 vs. 19·1 ± 7 ng/ml, P = 0·004). ROC analyses revealed an AUC for serum HMGB1 of 0·801, with a sensitivity and specificity of 92·3% and 68·2% to detect an infectious episode. Low HMGB1 levels predicted high risk of infective events ( HR: 0·81; P = 0·006). HMGB1 represents a prognostic marker for TM patients and a predictive factor for infectious events. [ABSTRACT FROM AUTHOR]

Iron chelators are increasingly combined clinically but the optimal conditions for cellular iron mobilization and mechanisms of interaction are unclear. Speciation plots for iron( III) binding of paired combinations of the licensed iron chelators desferrioxamine ( DFO), deferiprone ( DFP) and deferasirox ( DFX) suggest conditions under which chelators can combine as 'shuttle' and 'sink' molecules but this approach does not consider their relative access and interaction with cellular iron pools. To address this issue, a sensitive ferrozine-based detection system for intracellular iron removal from the human hepatocyte cell line (HuH-7) was developed. Antagonism, synergism or additivity with paired chelator combinations was distinguished using mathematical isobologram analysis over clinically relevant chelator concentrations. All combinations showed synergistic iron mobilization at 8 h with clinically achievable concentrations of sink and shuttle chelators. Greatest synergism was achieved by combining DFP with DFX, where about 60% of mobilized iron was attributable to synergistic interaction. These findings predict that the DFX dose required for a half-maximum effect can be reduced by 3·8-fold when only 1 μmol/l DFP is added. Mechanisms for the synergy are suggested by consideration of the iron-chelate speciation plots together with the size, charge and lipid solubilities for each chelator. Hydroxypyridinones with low lipid solubilities but otherwise similar properties to DFP were used to interrogate the mechanistic interactions of chelator pairs. These studies confirm that synergistic cellular iron mobilization requires one chelator to have the physicochemical properties to enter cells, chelate intracellular iron and subsequently donate iron to a second 'sink' chelator. [ABSTRACT FROM AUTHOR]

Thalassaemia is the commonest inherited anaemia world wide. There is wide spectrum of clinical severity spanning from insignificant to transfusion dependence. It is caused by abnormalities in the structure, manufacture or function of the globins that form the tetramers of normal adult haemoglobin A. The primary changes in erythropoiesis lead to the secondary changes of anaemia, splenomegaly, bone marrow expansion, extra medullary haemopoiesis, bone deformities and iron accumulation which in turn lead to long term organ damage. The anaemia itself results from a combination of ineffective erythropoiesis, peripheral haemolysis and an overall reduction in haemoglobin synthesis. Optimum management with early detection, appropriate transfusion, iron chelation and monitoring for complications can offer a good quality of life and a near normal lifespan. The major threats to this outcome in developed countries are serious infections and organ damage from iron overload. [ABSTRACT FROM AUTHOR]

Objectives Desferrioxamine ( DFO), deferiprone ( DFP) and deferasirox ( DFX) are iron chelators currently in clinical use for the treatment of iron overload. Due to difficulties with administration and associated side effects with these three molecules, the search continues for an efficient nontoxic orally active iron chelator. This communication describes the properties of one such candidate, 1-( N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one ( CM1). Methods Physicochemical characterisation techniques, including partition coefficient, p Ka values and log K values for iron( III). Iron scavenging assays, from iron citrate, nontransferrin bound iron and iron-loaded rats. Cytotoxicity studies using white cells, hepatocytes and cardiomyocytes. Key findings CM1 possesses high affinity and selectivity for iron( III) and a suitable partition coefficient to permeate membranes. CM1 forms a neutral 3 : 1 iron( III) complex under physiological conditions and so, it is predicted to be capable of entry into mammalian cells to scavenge excess intracellular iron and to efflux from cells as the neutral 3 : 1 complex. CM1 is demonstrated to be orally active and to possess a higher efficacy than DFP in rats. CM1 displays no toxicity to a range of cell types. Conclusion The above promising studies will be extended to monitor the pharmacokinetics and metabolism of CM1. CM1 is an excellent candidate for phase 1 clinical trials. [ABSTRACT FROM AUTHOR]