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Abstract Context Functional hyperandrogenism may be associated with a mild increase in body iron stores. Iron depletion exerts a beneficial effect on metabolic endpoints in other iron overload states. Objectives (i) To determine the effect of iron depletion on the insulin sensitivity and frequency of abnormal glucose tolerance in patients with functional hyperandrogenism submitted to standard therapy with combined oral contraceptives (COC). ii) To assess the overall safety of this intervention. Design Randomized, parallel, open-label, clinical trial. Setting Academic hospital. Patients Adult women with polycystic ovary syndrome or idiopathic hyperandrogenism. Intervention After a 3-month run-in period of treatment with 35 μg ethinylestradiol plus 2 mg cyproterone acetate, participants were randomized (1:1) to 3 scheduled bloodlettings or observation for another 9 months. Main outcome measures Changes in insulin sensitivity index and frequency of prediabetes/diabetes, and percentage of women in whom bloodletting resulted in plasma hemoglobin <120 g/L and/or hematocrit <0.36. Results From 2015 to 2019, 33 women were included by intention-to-treat. During the follow-up, insulin sensitivity did not change in the whole group of women or between study arms [mean of the differences (MD): 0.0 (95%CI: −1.6 to 1.6)]. Women in the experimental arm showed a similar odds of having prediabetes/diabetes than women submitted to observation [odds ratio: 0.981 (95%CI: 0.712 to 1.351)]. After bloodletting, 4 (21.1%) and 2 women (10.5%) in the experimental arm had hemoglobin (Hb) levels <120 g/L and hematocrit (Hct) values <0.36, respectively, but none showed Hb <110 g/L or Hct <0.34. Conclusions Scheduled bloodletting does not improve insulin sensitivity in women with functional hyperandrogenism on COC.

Iron chelation therapy (ICT) is the mainstay of treatment in patients with thalassemia requiring blood transfusions. This phase 2 JUPITER study evaluated patient preference between film-coated tablet (FCT) and dispersible tablet (DT) in transfusion-dependent thalassemia (TDT) or non-TDT (NTDT) patients treated with both formulations in a sequential manner. The primary endpoint was patient-reported preference for FCT over DT, while secondary outcomes included patient reported outcomes (PROs) evaluated by overall preference, and by age, thalassemia transfusion status, and previous ICT status. Out of 183 patients screened, 140 and 136 patients completed the treatment periods 1 and 2 of the core study, respectively. At week 48, the majority of patients preferred FCT over DT (90.3 vs. 7.5%; difference of percentage: 0.83 [95% confidence interval (CI), 0.75–0.89; P < 0.0001]). FCT scored better on secondary PROs and showed less severe gastrointestinal symptoms than DT, except in the change of modified Satisfaction with Iron Chelation Therapy (mSICT) preference scores, which were similar for both the formulations. Patients with TDT had stable ferritin levels, while it showed a downward trend up to week 48 in patients with NTDT on deferasirox treatment. Overall, 89.9% of patients reported ≥ 1 adverse event (AE), of which 20.3% experienced ≥ 1 serious AE. The most common treatment-emergent AEs were proteinuria, pyrexia, urine protein/creatinine ratio increase, diarrhea, upper respiratory tract infections, transaminase increase, and pharyngitis. Overall, this study reinforced the observations from the previous study by showing a distinct patient preference for FCT over DT formulation and further supported the potential benefits of life-long compliance with ICT.

Experimental data suggest a role for iron in the course of tuberculosis (TB) infection, but there is limited evidence on the potential effects of iron deficiency or iron overload on the progression of TB disease in humans. The aim of the present analysis was to examine the association of iron status with the risk of TB progression and death. We analyzed plasma samples and data collected as part a randomized micronutrient supplementation trial (not including iron) among HIV-infected and HIV-uninfected TB patients in Dar es Salaam, Tanzania. We prospectively related baseline plasma ferritin concentrations from 705 subjects (362 HIV-infected and 343 HIV-uninfected) to the risk of treatment failure at one month after initiation, TB recurrence and death using binomial and Cox regression analyses. Overall, low (plasma ferritin<30 µg/L) and high (plasma ferritin>150 µg/L for women and>200 µg/L for men) iron status were seen in 9% and 48% of patients, respectively. Compared with normal levels, low plasma ferritin predicted an independent increased risk of treatment failure overall (adjusted RR = 1.95, 95% CI: 1.07 to 3.52) and of TB recurrence among HIV-infected patients (adjusted RR = 4.21, 95% CI: 1.22 to 14.55). High plasma ferritin, independent of C-reactive protein concentrations, was associated with an increased risk of overall mortality (adjusted RR = 3.02, 95% CI: 1.95 to 4.67). Both iron deficiency and overload exist in TB patients and may contribute to disease progression and poor clinical outcomes. Strategies to maintain normal iron status in TB patients could be helpful to reduce TB morbidity and mortality.

Transfusional iron overload is a potentially fatal complication of the treatment of thalassaemia. We aimed to investigate short-term efficacy, pharmacokinetic/pharma-codynamic (PK/PD) relations, and safety of ICL670, a novel, tridentate, orally active iron chelator. We enrolled 24 patients and divided them into three cohorts consisting of a minimum of seven individuals. Patients were admitted to a metabolic unit and consumed a diet with a defined content of iron. Two patients in each cohort were randomly allocated placebo. Five or more patients received one daily dose of ICL670 at 10, 20, or 40 mg kg−1 day−1, from day 1 to 12. Net iron excretion (NIE) was measured between days 1 and 12. Primary objectives included assessment of safety and tolerability (measured by adverse events and clinical laboratory monitoring), pharmacokinetics (measured as drug and drug-iron complex), and cumulative net iron excretion (measured by faecal and urine output minus food input). Analysis was for efficacy. ICL670 was absorbed promptly and was detectable in the blood for 24 h. Exposure (area under the curve of plasma concentration) to ICL670 at pharmacokinetic steady state was proportional to dose. All three doses resulted in positive NIE. The NIE achieved at 20 mg kg−1day−1 would prevent net iron accumulation in most patients transfused with 12–15 mL packed red-blood-cells kg−1 month−1, equivalent to 0·3–0·5 mg iron kg−1 day−1. A linear relation (PK/PD) was recorded between exposure to ICL670 and total iron excretion, by contrast with placebo (r2=0·54, p<0·0001). Skin rashes were noted in four patients treated at 20 and 40 mg kg−1 day−1, and one patient also developed grade 2 transaminitis. ICL670 given once daily at 20 mg/kg seems to be an effective orally active iron chelator and is reasonably well tolerated. Long-term studies are now necessary to establish the practical contribution of this drug.

Transfusions and iron-chelation therapy have dramatically improved the lives of patients with thalassemia major. 1 Transfusions can prevent death and promote normal development, but the iron in the transfused red cells accumulates and eventually damages the liver, heart, and other organs. Deferoxamine, the only iron-chelating agent approved for clinical use, prolongs survival and ameliorates iron-induced organ damage. 2 , 3 Unfortunately, to be effective, treatment with deferoxamine requires prolonged parenteral infusion, making compliance difficult. Considerable effort has been devoted to finding alternative treatments. 4 One candidate, deferiprone (1,2-dimethyl-3-hydroxypyridin-4-one, or L1), was initially evaluated with an indirect indicator of therapeutic effectiveness — the serum ferritin . . .

Objectives. We postulated the existence of a statin–iron nexus by which statins improve cardiovascular disease outcomes at least partially by countering proinflammatory effects of excess iron stores. Methods. Using data from a clinical trial of iron (ferritin) reduction in advanced peripheral arterial disease, the Iron and Atherosclerosis Study, we compared effects of ferritin levels versus high-density lipoprotein to low-density lipoprotein ratios (both were randomization variables) on clinical outcomes in participants receiving and not receiving statins. Results. Statins increased high-density lipoprotein to low-density lipoprotein ratios and reduced ferritin levels by noninteracting mechanisms. Improved clinical outcomes were associated with lower ferritin levels but not with improved lipid status. Conclusions. There are commonalities between the clinical benefits of statins and the maintenance of physiologic iron levels. Iron reduction may be a safe and low-cost alternative to statins.

Increased iron stores are associated with increased risk of type 2 diabetes, however, the mechanisms underlying these associations are poorly understood. Because a reduction of circulating osteocalcin levels after iron overload have been demonstrated in cell cultures, and osteocalcin is related to glucose and insulin metabolism, the iron-induced osteocalcin reductions could contribute to explain the role of iron metabolism in the development of type 2 diabetes mellitus. To analyzed the associations between serum total and uncarboxylated osteocalcin and adiponectin concentrations with serum ferritin and soluble transferrin receptor (sTfR) in elderly subjects. We evaluated a total of 423 subjects from the PREDIMED cohort in a population-based cross-sectional analysis. Extensive clinical, nutritional and laboratory measurements, including total and uncarboxylated osteocalcin, adiponectin, ferritin and sTfR were recorded. Serum ferritin was positively correlated with increased glucose and insulin circulating levels but also with HOMA-IR, and was inversely associated with total osteocalcin and adiponectin. A regression analysis revealed that serum ferritin and transferrin receptor levels were significantly associated with a decrease in total and uncarboxylated osteocalcin. Serum sTfR levels were associated with lower uncarboxylated osteocalcin levels in the whole-study subjects and remained significant only in the IFG (impaired fasting glucose) individuals. We described, for the first time, an inverse association between serum ferritin and sTfR with osteocalcin and extend previous results on adiponectin, thus supporting that factors related to iron metabolism could contribute to the insulin resistance and the development of type 2 diabetes mellitus. Controlled-Trials.com ISRCTN35739639 .

Introduction Sideroblastic cardiomyopathy secondary to repeated blood transfusions is a feared complication in thalassaemia. Control of myocardial iron is thus becoming the cornerstone of thalassaemia management. Recent evidence suggests a role for L-type Ca2+ channels in mediating iron uptake by the heart. Blocking the cellular iron uptake through these channels may add to the benefit of therapy to standard chelation in reducing myocardial iron. We aim to determine the efficacy of amlodipine (a calcium channel blocker) as an adjunct to standard aggressive chelation in retarding myocardial iron deposition in thalassaemics with or without cardiomyopathy. Outcomes The primary outcome is to compare the efficacy of amlodipine+chelation (intervention) versus standard chelation (control) in retarding myocardial iron deposition. Secondary outcomes include the effect of amlodipine therapy on systolic and diastolic function, strain and strain rate and liver iron content. Methods and analysis This is a single-centre, parallel-group, prospective randomised control trial. Twenty patients will be randomised in a 1:1 allocation ratio into the intervention and control arms. In addition to conventional echocardiography, MRI T2* values for assessment of cardiac and liver iron load will be obtained at baseline and at 6 and 12 months. Cardiac T2* will be reported as the geometric mean and per cent coefficient of variation, and an increase in cardiac T2* values from baseline will be used as an end point to compare the efficacy of therapy. A p Value of <0.05 will be considered significant. Study setting Department of Pediatric and Child Health, Aga Khan University Hospital, Karachi, Pakistan. Ethics and dissemination This study has been approved by the Ethics Review Committee and Clinical Trials Unit at The Aga Khan University with respect to scientific content and compliance with applicable research and human subjects regulations. Findings will be reported through scientific publications and research conferences and project summary papers for participants. Trial registration number ClinicalTrials.Gov. Registration no: NCT02065492.

We evaluated the risk factors for infection of 367 consecutive myeloma patients who underwent high-dose melphalan and autologous stem cell transplantation (ASCT). Examination of bone marrow iron stores (BMIS) prior to ASCT was used to evaluate body iron stores. Other variables included age, sex, active smoking, myeloma remission status, severity of mucositis and duration of severe neutropenia post-ASCT (<100 absolute neutrophils counts (ANC)/microl). Median age was 56 years; 61% of patients were males. 140 episodes of severe infections occurred in 116 patients, including bacteremia (73), pneumonia (40), severe colitis (25) and bacteremia with septic shock (two). The infection incidence per 1,000 days at risk was 45.2. Pre-ASCT risk factors for severe infection by univariate analysis were increased BMIS (OR=2.686; 95% CI 1.707-4.226; P<0.0001), smoking (OR=1.565; 95% CI 1.005-2.437; P=0.0474) and male gender (OR=1.624; 95% CI 1.019-2.589; P=0.0414). Increased BMIS (OR=2.716; 95% CI 1.720-4.287; P<0.0001) and smoking (OR=1.714; 95% CI 1.081-2.718; P=0.022) remained significant by multivariate analysis. Duration of ANC <100 micro/l (OR=1.129; 95% CI 1.039-1.226; P=0.0069 and OR=1.127; 95% CI 1.038-1.224; P=0.0045 by both univariate and multivariate analysis, respectively) was the only post-ASCT risk factor for infection. Increased pre-transplant BMIS and smoking are significant predictors of severe infection after myeloablative chemotherapy followed by ASCT in myeloma patients.

Iron is an essential trace metal for almost all organisms, including human; however, oxidative stress can easily be caused when iron is in excess, producing toxicity to the human body due to its capability to be both an electron donor and an electron acceptor. Although there is a strict regulation mechanism for iron homeostasis in the human body and brain, it is usually inevitably disturbed by genetic and environmental factors, or disordered with aging, which leads to iron metabolism diseases, including many neurodegenerative diseases such as Alzheimer’s disease (AD). AD is one of the most common degenerative diseases of the central nervous system (CNS) threatening human health. However, the precise pathogenesis of AD is still unclear, which seriously restricts the design of interventions and treatment drugs based on the pathogenesis of AD. Many studies have observed abnormal iron accumulation in different regions of the AD brain, resulting in cognitive, memory, motor and other nerve damages. Understanding the metabolic balance mechanism of iron in the brain is crucial for the treatment of AD, which would provide new cures for the disease. This paper reviews the recent progress in the relationship between iron and AD from the aspects of iron absorption in intestinal cells, storage and regulation of iron in cells and organs, especially for the regulation of iron homeostasis in the human brain and prospects the future directions for AD treatments.