On improvement in ejection fraction with iron chelation in thalassemia major and the risk of future heart failure

<p>Abstract</p> <p>Background</p> <p>Trials of iron chelator regimens have increased the treatment options for cardiac siderosis in beta-thalassemia major (TM) patients. Treatment effects with improved left ventricular (LV) ejection fraction (EF) have been observed in patients without overt heart failure, but it is unclear whether these changes are clinically meaningful.</p> <p>Methods</p> <p>This retrospective study of a UK database of TM patients modelled the change in EF between serial scans measured by cardiovascular magnetic resonance (CMR) to the relative risk (RR) of future development of heart failure over 1 year. Patients were divided into 2 strata by baseline LVEF of 56-62% (below normal for TM) and 63-70% (lower half of the normal range for TM).</p> <p>Results</p> <p>A total of 315 patients with 754 CMR scans were analyzed. A 1% absolute increase in EF from baseline was associated with a statistically significant reduction in the risk of future development of heart failure for both the lower EF stratum (EF 56-62%, RR 0.818, p < 0.001) and the higher EF stratum (EF 63-70%, RR 0.893 p = 0.001).</p> <p>Conclusion</p> <p>These data show that during treatment with iron chelators for cardiac siderosis, small increases in LVEF in TM patients are associated with a significantly reduced risk of the development of heart failure. Thus the iron chelator induced improvements in LVEF of 2.6% to 3.1% that have been observed in randomized controlled trials, are associated with risk reductions of 25.5% to 46.4% for the development of heart failure over 12 months, which is clinically meaningful. In cardiac iron overload, heart mitochondrial dysfunction and its relief by iron chelation may underlie the changes in LV function.</p

Biological and pharmacokinetic studies on the oral iron chelator 1,2 dimethyl-3-hydroxypyrid-4-one

The iron chelator 1,2 dimethyl-3-hydroxypyrid-4-one (Deferiprone, L1) is currently the most promising orally active alternative to desferrioxamine (DFO) for the treatment of iron overload. The work contained in this thesis consists of a combination of in vivo and in vitro investigations into the pharmacology and toxicity of L1. in vivo experiments were performed in normal and iron-loaded rats. Parenchymal iron overload was achieved using 3,5,5-trimethylhexanoyl ferrocene. In normal rats, radiolabelled L1 (14C-L1) rapidly penetrated most tissues in the body. Upon intravenous administration, concentrations were highest in the liver, intermediate in the kidneys and gastrointestinal tract and lowest in other tissues examined (blood, bone marrow, heart, spleen, lungs, brain, testes, thyroid, thymus, salivary glands, muscle and pancreas). There was more radioactivity in the liver of iron-loaded animals compared to controls. L1 was effective in promoting faecal iron excretion in iron-loaded rats, presumably due to mobilization of hepatocellular iron stores. Pharmacokinetic experiments showed that parenchymal iron overload decreased the systemic exposure and mean residence time and increased the apparent clearance and volume of distribution of the drug. 14c-L1 was rapidly taken up by normal and sickle red blood cells and by the erythroleukaemia cell line K562, reaching equilibrium across the cell membrane within one minute of addition. 14C-L1 accumulated gradually in thalassaemic RBC which have high levels of intracellular iron, presumably due to the formation of the L1-iron(III) complex which is larger and more hydrophilic than L1 and therefore exits cells more slowly. Incubation of cultured rat hepatocytes with 14C-L1 showed saturable intracellular accumulation of radioactivity by an energy-requiring mechanism, which could be due to intracellular metabolism of L1 or to active transport of L1 into those cells. These findings demonstrate that L1 has excellent membrane permeation characteristics enabling it to access easily various cells and tissues. Complexing of L1 with iron decreases the cellular transport of the drug, leading to potential accumulation of L1 in sites of iron overload. The pharmacokinetic, clinical and possible toxicological implications of this are discussed. L1 and DFO were found to induce apoptosis in proliferating activated T-lymphocytes and in the promyelocytic cell line HL60 but not in resting peripheral blood lymphocytes or granulocytes. The cytotoxicity of both chelators to proliferating cells was mediated through intracellular iron depletion and concominant inhibition of proliferation and DNA synthesis. These results suggest that the intracellular chelation of iron in proliferating cells may be an important mechanism of L1 toxicity

Assessing Health Care Providers’ Knowledge and Practices of Nutrition during Pregnancy in Lebanon: A Cross-Sectional Study

Background and objectives: Health care professionals (HCPs) are well-positioned to discuss healthy behaviors during pregnancy, but the published research of prenatal healthcare providers’ knowledge about the significance of nutrition during pregnancy in Lebanon is scarce. The purpose of this study was to explore the knowledge, attitudes, and practices of Lebanese prenatal healthcare providers towards nutrition during pregnancy. Materials and Methods: A cross-sectional study using an online questionnaire was conducted. Health care providers were contacted by phone and email to participate in the online survey. A list of all clinics providing antenatal health services was obtained from the Order of Physicians and the Order of Midwives. A multistage random sample was selected. In the first stage, it was stratified per region (Beirut center or suburbs, and the southern region). In the second phase, it was stratified per clinic type (private, primary healthcare center, or hospital). Gynecologists and midwives who are members of the Order of Physicians and the Order of Midwives (n = 1333), were included. Results: Two-hundred and six responses (55% males) were obtained. Approximately 44% of the HCP were aged 50 and older, and 68.4% had more than 10 years of work experience. HCPs from Beirut represented 41.3% of the respondents. Eighty-eight percent of the HCPs were physicians, and 11% were midwives. The majority of the participants considered nutrition during pregnancy to be very important. Furthermore, half of these participants considered their position in delivering nutrition information as very significant. Most of the respondents reported that they provide nutrition advice to pregnant women, and they also received nutrition education during their profession. However, they perceived their nutrition knowledge as inadequate. Conclusion: Health care providers’ attitude towards the importance of maternal nutrition and their confidence in talking about nutrition-related topics with pregnant women were positive despite the lack of knowledge in several areas related to nutrition during pregnancy. Therefore, there is a need for continuing nutrition education for health care providers and the implementation of nutrition education programs to achieve better health outcomes

Weight gain in early infancy impacts appetite regulation in the first year of life. A prospective study of infants living in Cyprus

BACKGROUND: Eating behaviour is associated with weight gain in infancy and childhood. Few studies found a bi-directional association between weight gain and eating behaviour development in childhood but there is little data on the association in early infancy, a period critical for the programming of obesity risk. OBJECTIVE: We investigated the bi-directional association between appetite traits and weight gain during the first year of life. METHODS: Participants were part of a cohort of 432 infants born in Cyprus. Appetite traits were measured using the BEBQ or the CEBQ at age 2-4 weeks, 6 and 12 months. Weight and length were collected at birth, 4 weeks, 6 and 12 months. Multivariable linear regression was used to analyse associations between appetite traits at 2-4 weeks and 6 months and weight for age Z-score change (WFAZC) between 4 weeks-6 months and 6-12 months. Associations were also analysed in the opposite direction, between WFAZC from birth to 4 weeks, 4 weeks to 6 months, 6-12 months and appetite traits at 4 weeks, 6 months and 12 months. RESULTS: Satiety responsive (SR) at 2-4 weeks was associated with lower WFAZC from 4 weeks to 6 months (β=-0.17; 95%CI: -0.30, -0.04) and SR at age 6 months was associated with lower WFAZC from 6 to 12 months (β=-0.09; 95%CI: -0.17, -0.02). WFAZC from 4 weeks to 6 months was associated with higher EF at 12 months (β=0.11; 95%CI: 0.01, 0.20), higher FR at 12 months (β=0.17; 95%CI: 0.04, 0.30) and lower SR at both 6 (β=-0.11; 95%CI: -0.21, -0.01) and 12 months (β=-0.14; 95%CI: -0.24, -0.03) CONCLUSIONS: We found a bi-directional association between weight gain and appetite traits in infancy, suggesting that the effect of postnatal weight gain on obesity development is partly mediated by programming of appetite traits