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Study Objectives: The fractional concentration of exhaled nitric oxide (FENO) is a marker of asthmatic airway inflammation. We determined the dose response and the reproducibility of the FENO fall following inhaled beclomethasone dipropionate (iBDP) therapy in nonsteroid-treated asthmatic patients.Study Design: Study A: For four 1-week periods (period 1 to period 4), the following regimens were administered in sequential order to 15 nonsteroid-treated asthmatic patients: period 1, placebo; period 2, 100 microg/d of iBDP; period 3, 400 microg/D of iBDP; and period 4, 800 microg/d of iBDP. Spirometry, FENO, and provocative concentration of methacholine resulting in a 20% fall in FEV(1) (PC(20)) were measured at each of five visits (visit 1 to visit 5). Study B: During four periods, 12 nonsteroid-treated asthmatic patients received placebo treatment for 7 days (period 1), 200 microg/d of iBDP for 14 days (period 2), washout on placebo treatment until the FENO was within 15% of baseline (period 3), and 200 microg/d of iBDP for 14 days (period 4).Results: Study A: Mean FEV(1) rose progressively from 3.10 L (visit 1) to 3.41 L (visit 5; p = 0.001). All iBDP doses caused a significant FEV(1) rise compared to placebo treatment, but with no significant separation of doses using FEV(1). FENO geometric mean (95% confidence limits) fell progressively from 103.5 parts per billion (ppb) (78.5 to 136.7) to 37.4 ppb (29.1 to 48.0) from visit 1 to visit 5 (p = 0.001). All doses of iBDP resulted in a significant change in FENO from placebo treatment, but with significant separation of only the 100-microg and 800-microg doses by FENO. Geometric mean (95% confidence limits) PC(20) rose progressively from 0.01 mg/mL (0.00 to 0.19) to 0.48 mg/mL (0.01 to 8.1) from visit 1 to visit 5 (p = 0.002). All doses of iBDP resulted in a significant change in PC(20) from baseline or placebo treatment, but with no significant separation of active iBDP doses using PC(20). Study B: FENO fell from 111.56 ppb (80.3 to 155.1) to 66.3 ppb (49.2 to 89.5; p < 0.001) from period 1 to period 2, and from 110.2 ppb (79.3 to 153.1) to 61.7 ppb (42.9 to 88.8; p < 0.001) from period 3 to period 4. There were no significant differences between FENO in period 1 and period 3 (p = 0.83) or between period 2 and period 4 (p = 0.220).Conclusions: FENO was superior to FEV(1) and PC(20) in separating doses of iBDP. The fall in FENO after two identical administrations of iBDP separated by placebo washout was highly reproducible. [ABSTRACT FROM AUTHOR]

Importance: Interventions that substantially slow neurodegeneration are needed to address the growing burden of Alzheimer disease (AD) to societies worldwide. Elevated brain iron observed in AD has been associated with accelerated cognitive decline and may be a tractable drug target., Objective: To investigate whether the brain-permeable iron chelator deferiprone slows cognitive decline in people with AD., Design, Setting, and Participants: This phase 2, double-masked, placebo-controlled randomized clinical trial of 12-month duration was conducted at 9 sites in Australia between August 2, 2018, and April 1, 2023. Patients older than 54 years with amyloid-confirmed mild cognitive impairment or early AD (a Mini-Mental State Examination score of 20 or higher) were screened. Randomization was 2:1 and masked to participants and all study staff., Interventions: Deferiprone 15 mg/kg twice a day or placebo administered orally for 12 months., Main Outcomes and Measures: The primary outcome was a composite cognitive measure assessed at baseline, 6 months, and 12 months using a neuropsychological test battery (NTB) of memory, executive function, and attention tasks. Secondary outcomes included change in brain iron burden measured by quantitative susceptibility mapping (QSM) magnetic resonance imaging (target engagement), brain volume changes (secondary efficacy measure), and adverse events (safety analysis)., Results: Of 167 patients screened for eligibility, 81 were included, with 53 randomly assigned to the deferiprone group (mean [SD] age, 73.0 [8.0] years; 29 male [54.7%]) and 28 to the placebo group (mean [SD] age, 71.6 [7.2] years; 17 male [60.7%]); 54 participants completed the study (7 [25.0%] withdrew from the placebo group and 20 [37.7%] from the deferiprone group). In an intention-to-treat analysis, participants in the deferiprone group showed accelerated cognitive decline on the NTB primary outcome (β for interaction = -0.50; 95% CI, -0.80 to -0.20) compared with placebo (change in NTB composite z score for deferiprone, -0.80 [95% CI, -0.98 to -0.62]; for placebo, -0.30 [95% CI, -0.54 to -0.06]). Secondary analysis revealed that this result was driven by worsening performance on executive function tests. The QSM confirmed that deferiprone decreased iron in the hippocampus compared with placebo (change in hippocampal QSM for deferiprone, -0.36 ppb [95% CI, -0.76 to 0.04 ppb]; for placebo, 0.32 ppb [95% CI, -0.12 to 0.75 ppb]; β for interaction = -0.68 [95% CI, -1.27 to -0.09]). Longitudinal hippocampal volume loss was not affected by deferiprone, but exploratory analysis of other brain regions revealed increased volume loss with deferiprone in frontal areas. The frequency of the adverse effect of neutropenia (4 participants [7.5%] in the deferiprone group) was higher than in similar studies (1.6%-4.4%)., Conclusions: These trial findings show that deferiprone 15 mg/kg twice a day decreased hippocampal QSM and accelerated cognitive decline in patients with amyloid-confirmed early AD, suggesting that lowering iron with deferiprone is detrimental to patients with AD., Trial Registration: ClinicalTrials.gov Identifier: NCT03234686.

Background: Iron content is increased in the substantia nigra of persons with Parkinson's disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson's disease, but its effects on disease progression are unclear., Methods: We conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson's disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome., Results: A total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P<0.001). Nigrostriatal iron content decreased more in the deferiprone group than in the placebo group. The main serious adverse events with deferiprone were agranulocytosis in 2 participants and neutropenia in 3 participants., Conclusions: In participants with early Parkinson's disease who had never received levodopa and in whom treatment with dopaminergic medications was not planned, deferiprone was associated with worse scores in measures of parkinsonism than those with placebo over a period of 36 weeks. (Funded by the European Union Horizon 2020 program; FAIRPARK-II ClinicalTrials.gov number, NCT02655315.)., (Copyright © 2022 Massachusetts Medical Society.)

Pleomorphic xanthoastrocytoma (PXA) is a rare type of brain tumor that affects children and young adults. Molecular prognostic markers of PXAs remain poorly established. Similar to gangliogliomas, PXAs show prominent immune cell infiltrate, but its composition also remains unknown. In this study, we correlated DNA methylation and BRAF status with clinical outcome and explored the tumor microenvironment. We performed DNA methylation in 21 tumor samples from 18 subjects with a histological diagnosis of PXA. MethylCIBERSORT was used to deconvolute the PXA microenvironment by analyzing the associated immune cell-types. Median age at diagnosis was 16 years (range 7-32). At median follow-up of 30 months, 3-year and 5-year overall survival was 73% and 71%, respectively. Overall survival ranged from 1 to 139 months. Eleven out of 18 subjects (61%) showed disease progression. Progression-free survival ranged from 1 to 89 months. Trisomy 7 and CDKN2A/B (p16) homozygous deletion did not show any association with overall survival (p = 0.67 and p = 0.74, respectively). Decreased overall survival was observed for subjects with tumors lacking the BRAF V600E mutation (p = 0.02). PXAs had significantly increased CD8 T-cell epigenetic signatures compared with previously profiled gangliogliomas (p = 0.0019). The characterization of immune cell-types in PXAs may have implications for future development of immunotherapy., (© 2020 American Association of Neuropathologists, Inc. All rights reserved.)

Background: Transfusion-dependent haemoglobinopathies require lifelong iron chelation therapy with one of the three iron chelators (deferiprone, deferasirox, or deferoxamine). Deferasirox and deferiprone are the only two oral chelators used in adult patients with transfusion-dependent haemoglobinopathies. To our knowledge, there are no randomised clinical trials comparing deferiprone, a less expensive iron chelator, with deferasirox in paediatric patients. We aimed to show the non-inferiority of deferiprone versus deferasirox., Methods: DEEP-2 was a phase 3, multicentre, randomised trial in paediatric patients (aged 1 month to 18 years) with transfusion-dependent haemoglobinopathies. The study was done in 21 research hospitals and universities in Italy, Egypt, Greece, Albania, Cyprus, Tunisia, and the UK. Participants were receiving at least 150 mL/kg per year of red blood cells for the past 2 years at the time of enrolment, and were receiving deferoxamine (<100 mg/kg per day) or deferasirox (<40 mg/kg per day; deferasirox is not registered for use in children aged <2 years so only deferoxamine was being used in these patients). Any previous chelation treatment was permitted with a 7-day washout period. Patients were randomly assigned 1:1 to receive orally administered daily deferiprone (75-100 mg/kg per day) or daily deferasirox (20-40 mg/kg per day) administered as dispersible tablets, both with dose adjustment for 12 months, stratified by age (<10 years and ≥10 years) and balanced by country. The primary efficacy endpoint was based on predefined success criteria for changes in serum ferritin concentration (all patients) and cardiac MRI T2-star (T2*; patients aged >10 years) to show non-inferiority of deferiprone versus deferasirox in the per-protocol population, defined as all randomly assigned patients who received the study drugs and had available data for both variables at baseline and after 1 year of treatment, without major protocol violations. Non-inferiority was based on the two-sided 95% CI of the difference in the proportion of patients with treatment success between the two groups and was shown if the lower limit of the two-sided 95% CI was greater than -12·5%. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, 2012-000353-31, and ClinicalTrials.gov, NCT01825512., Findings: 435 patients were enrolled between March 17, 2014, and June 16, 2016, 393 of whom were randomly assigned to a treatment group (194 to the deferiprone group; 199 to the deferasirox group). 352 (90%) of 390 patients had β-thalassaemia major, 27 (7%) had sickle cell disease, five (1%) had thalassodrepanocytosis, and six (2%) had other haemoglobinopathies. Median follow-up was 379 days (IQR 294-392) for deferiprone and 381 days (350-392) for deferasirox. Non-inferiority of deferiprone versus deferasirox was established (treatment success in 69 [55·2%] of 125 patients assigned deferiprone with primary composite efficacy endpoint data available at baseline and 1 year vs 80 [54·8%] of 146 assigned deferasirox, difference 0·4%; 95% CI -11·9 to 12·6). No significant difference between the groups was shown in the occurrence of serious and drug-related adverse events. Three (2%) cases of reversible agranulocytosis occurred in the 193 patients in the safety analysis in the deferiprone group and two (1%) cases of reversible renal and urinary disorders (one case of each) occurred in the 197 patients in the deferasirox group. Compliance was similar between treatment groups: 183 (95%) of 193 patients in the deferiprone group versus 192 (97%) of 197 patients in the deferisirox group., Interpretation: In paediatric patients with transfusion-dependent haemoglobinopathies, deferiprone was effective and safe in inducing control of iron overload during 12 months of treatment. Considering the need for availability of more chelation treatments in paediatric populations, deferiprone offers a valuable treatment option for this age group., Funding: EU Seventh Framework Programme., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Intramyocardial hemorrhage is an independent predictor of adverse outcomes in ST-segment elevation myocardial infarction (STEMI). Iron deposition resulting from ischemia-reperfusion injury (I/R) is pro-inflammatory and has been associated with adverse remodeling. The role of iron chelation in hemorrhagic acute myocardial infarction (AMI) has never been explored. The purpose of this study was to investigate the cardioprotection offered by the iron-chelating agent deferiprone (DFP) in a porcine AMI model by evaluating hemorrhage neutralization and subsequent cardiac remodeling. Two groups of animals underwent a reperfused AMI procedure: control and DFP treated (N = 7 each). A comprehensive MRI examination was performed in healthy state and up to week 4 post-AMI, followed by histological assessment. Infarct size was not significantly different between the two groups; however, the DFP group demonstrated earlier resolution of hemorrhage (by T2* imaging) and edema (by T2 imaging). Additionally, ventricular enlargement and myocardial hypertrophy (wall thickness and mass) were significantly smaller with DFP, suggesting reduced adverse remodeling, compared to control. The histologic results were consistent with the MRI findings. To date, there is no effective targeted therapy for reperfusion hemorrhage. Our proof-of-concept study is the first to identify hemorrhage-derived iron as a therapeutic target in I/R and exploit the cardioprotective properties of an iron-chelating drug candidate in the setting of AMI. Iron chelation could potentially serve as an adjunctive therapy in hemorrhagic AMI.

Molecular studies have identified distinct genomic drivers providing insights in biology of brain tumors. Advances in genetic and epigenetic analysis, as well as development of mutation-specific antibodies enable more accurate classification of histologically indistinguishable tumors. Compared with histopathologic grading, molecular biomarkers are also superior in predicting natural behavior of tumors and therapeutic response. Diffuse gliomas can be separated in astrocytoma and oligodendroglioma based on IDH1/2, ATRX, and TP53 mutational status. Pediatric gliomas are molecularly distinct from adult tumors and molecular drivers include histone H3 genes and fusions involving the MAPK pathway. Using genetic and epigenetic profiling, ependymal tumors, medulloblastomas, and atypical teratoid/rhabdoid tumors can be separated in biologically and clinically distinct entities. Identification of novel gene fusions and matched DNA methylation signatures enable accurate diagnosis of primitive neuroectodermal tumors, which were previously misdiagnosed. Genomic classification of central nervous system tumors is being readily translated into the clinical practice and will enable molecularly based patient management and clinical trials.

Background: Pantothenate kinase-associated neurodegeneration (PKAN) is a rare genetic disorder characterised by progressive generalised dystonia and brain iron accumulation. We assessed whether the iron chelator deferiprone can reduce brain iron and slow disease progression., Methods: We did an 18-month, randomised, double-blind, placebo-controlled trial (TIRCON2012V1), followed by a pre-planned 18-month, open-label extension study, in patients with PKAN in four hospitals in Germany, Italy, England, and the USA. Patients aged 4 years or older with a genetically confirmed diagnosis of PKAN, a total score of at least 3 points on the Barry-Albright Dystonia (BAD) scale, and no evidence of iron deficiency, neutropenia, or abnormal hepatic or renal function, were randomly allocated (2:1) to receive an oral solution of either deferiprone (30 mg/kg per day divided into two equal doses) or placebo for 18 months. Randomisation was done with a centralised computer random number generator and with stratification based on age group at onset of symptoms. Patients were allocated to groups by a randomisation team not masked for study intervention that was independent of the study. Patients, caregivers, and investigators were masked to treatment allocation. Co-primary endpoints were the change from baseline to month 18 in the total score on the BAD scale (which measures severity of dystonia in eight body regions) and the score at month 18 on the Patient Global Impression of Improvement (PGI-I) scale, which is a patient-reported interpretation of symptom improvement. Efficacy analyses were done on all patients who received at least one dose of the study drug and who provided a baseline and at least one post-baseline efficacy assessment. Safety analyses were done for all patients who received at least one dose of the study drug. Patients who completed the randomised trial were eligible to enrol in a single-arm, open-label extension study of another 18 months, in which all participants received deferiprone with the same regimen as the main study. The trial was registered on ClinicalTrials.gov, number NCT01741532, and EudraCT, number 2012-000845-11., Findings: Following a screening of 100 prospective patients, 88 were randomly assigned to the deferiprone group (n=58) or placebo group (n=30) between Dec 13, 2012, and April 21, 2015. Of these, 76 patients completed the study (49 in the deferiprone group and 27 in the placebo group). After 18 months, the BAD score worsened by a mean of 2·48 points (SE 0·63) in patients in the deferiprone group versus 3·99 points (0·82) for patients in the control group (difference -1·51 points, 95% CI -3·19 to 0·16, p=0·076). No subjective change was detected as assessed by the PGI-I scale: mean scores at month 18 were 4·6 points (SE 0·3) for patients in the deferiprone group versus 4·7 points (0·4) for those in the placebo group (p=0·728). In the extension study, patients continuing deferiprone retained a similar rate of disease progression as assessed by the BAD scale (1·9 points [0·5] in the first 18 months vs 1·4 points [0·4] in the second 18 months, p=0·268), whereas progression in patients switching from placebo to deferiprone seemed to slow (4·4 points [1·1] vs 1·4 points [0·9], p=0·021). Patients did not detect a change in their condition after the additional 18 months of treatment as assessed by the PGI-I scale, with mean scores of 4·1 points [0·2] in the deferiprone-deferiprone group and of 4·7 points [0·3] in the placebo-deferiprone group. Deferiprone was well tolerated and adverse events were similar between the treatment groups, except for anaemia, which was seen in 12 (21%) of 58 patients in the deferiprone group, but was not seen in any patients in the placebo group. No patient discontinued therapy because of anaemia, and three discontinued because of moderate neutropenia. There was one death in each group of the extension study and both were secondary to aspiration. Neither of these events was considered related to deferiprone use., Interpretation: Deferiprone was well tolerated, achieved target engagement (lowering of iron in the basal ganglia), and seemed to somewhat slow disease progression at 18 months, although not significantly, as assessed by the BAD scale. These findings were corroborated by the results of an additional 18 months of treatment in the extension study. The subjective PGI-I scale was largely unchanged during both study periods, indicating that might not be an adequate tool for assessment of disease progression in patients with PKAN. Our trial provides the first indication of a decrease in disease progression in patients with neurodegeneration with brain iron accumulation. The extensive information collected and long follow-up of patients in the trial will improve the definition of appropriate endpoints, increase the understanding of the natural history, and thus help to shape the design of future trials in this ultra-orphan disease., Funding: European Commission, US Food and Drug Administration, and ApoPharma Inc., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: Isocitrate dehydrogenase ( IDH )-mutant glioma is a distinct glioma molecular subtype for which no effective molecularly directed therapy exists. Low-grade gliomas, which are 80%-90% IDH -mutant, have high RNA levels of the cell surface Notch ligand DLL3. We sought to determine DLL3 expression by IHC in glioma molecular subtypes and the potential efficacy of an anti-DLL3 antibody-drug conjugate (ADC), rovalpituzumab tesirine (Rova-T), in IDH -mutant glioma., Experimental Design: We evaluated DLL3 expression by RNA using TCGA data and by IHC in a discovery set of 63 gliomas and 20 nontumor brain tissues and a validation set of 62 known IDH wild-type and mutant gliomas using a monoclonal anti-DLL3 antibody. Genotype was determined using a DNA methylation array classifier or by sequencing. The effect of Rova-T on patient-derived endogenous IDH -mutant glioma tumorspheres was determined by cell viability assay., Results: Compared to IDH wild-type glioblastoma, IDH -mutant gliomas have significantly higher DLL3 RNA ( P < 1 × 10 -15 ) and protein by IHC ( P = 0.0014 and P < 4.3 × 10 -6 in the discovery and validation set, respectively). DLL3 immunostaining was intense and homogeneous in IDH -mutant gliomas, retained in all recurrent tumors, and detected in only 1 of 20 nontumor brains. Patient-derived IDH -mutant glioma tumorspheres overexpressed DLL3 and were potently sensitive to Rova-T in an antigen-dependent manner., Conclusions: DLL3 is selectively and homogeneously expressed in IDH -mutant gliomas and can be targeted with Rova-T in patient-derived IDH -mutant glioma tumorspheres. Our findings are potentially immediately translatable and have implications for therapeutic strategies that exploit cell surface tumor-associated antigens., (©2018 American Association for Cancer Research.)

While assessing the ability of mammalian lung tissue to metabolize theophylline, a new metabolite was isolated and characterized. The metabolite was produced by the microsomal fraction of lungs from several species, including rat, rabbit, dog, pig, sheep and human tissue. Metabolite production was blocked by boiling the microsomal tissue. This new metabolite, theophylline-7β-d-ribofuranoside (theonosine), was confirmed by several spectral methods and by comparison to an authentic synthetic compound. Tissue studies from rats, rabbits, dogs, and humans for cofactor involvement demonstrated an absolute requirement for NADP and enhanced metabolite production in the presence of magnesium ion. It remains to be demonstrated whether theonosine may contribute to the known pharmacological effects of theophylline., Competing Interests: The authors declare no conflicts of interest.

Parkinson's disease (PD) is associated with increased iron levels in the substantia nigra (SNc). This study evaluated whether the iron chelator, deferiprone, is well tolerated, able to chelate iron from various brain regions and improve PD symptomology. In a randomised double-blind, placebo controlled trial, 22 early onset PD patients, were administered deferiprone, 10 or 15 mg/kg BID or placebo, for 6 months. Patients were evaluated for PD severity, cognitive function, depression rating and quality of life. Iron concentrations were assessed in the substantia nigra (SNc), dentate and caudate nucleus, red nucleus, putamen and globus pallidus by T2* MRI at baseline and after 3 and 6 months of treatment. Deferiprone therapy was well tolerated and was associated with a reduced dentate and caudate nucleus iron content compared to placebo. Reductions in iron content of the SNc occurred in only 3 patients, with no changes being detected in the putamen or globus pallidus. Although 30 mg/kg deferiprone treated patients showed a trend for improvement in motor-UPDRS scores and quality of life, this did not reach significance. Cognitive function and mood were not adversely affected by deferiprone therapy. Such data supports more extensive clinical trials into the potential benefits of iron chelation in PD.

Aims: Despite long clinical experience with deferiprone, there is limited information on its pharmacokinetics in children aged <6 years. Here we assess the impact of developmental growth on the pharmacokinetics of deferiprone in this population using a population approach. Based on pharmacokinetic bridging concepts, we also evaluate whether the recommended doses yield appropriate systemic exposure in this group of patients., Methods: Data from a study in which 18 paediatric patients were enrolled were available for the purposes of this analysis. Patients were randomised to three deferiprone dose levels (8.3, 16.7 and 33.3 mg kg -1 ). Blood samples were collected according to an optimised sampling scheme in which each patient contributed to a maximum of five samples. A population pharmacokinetic model was developed using NONMEM v.7.2. Model selection criteria were based on graphical and statistical summaries., Results: A one-compartment model with first-order absorption and first-order elimination best described the pharmacokinetics of deferiprone. Drug disposition parameters were affected by body weight, with both clearance and volume increasing allometrically with size. Simulation scenarios show that comparable systemic exposure (AUC) is achieved in children and adults after similar dose levels in mg kg -1 , with median (5-95 th quantiles) AUC values, respectively, of 340.6 (223.2-520.0) μmol l -1  h and 318.5 (200.4-499.0) μmol l -1  h at 75 mg kg -1 day -1 , and 453.7 (297.3-693.0) μmol l -1  h and 424.2 (266.9-664.0) μmol l -1  h at 100 mg kg -1  day -1 given as three times daily (t.i.d.) doses., Conclusions: Based on the current findings, a dosing regimen of 25 mg kg -1  t.i.d. is recommended in children aged <6 years, with the possibility of titration up to 33.3 mg kg -1  t.i.d., (© 2016 The British Pharmacological Society.)

Use of the iron chelator deferiprone for treatment of iron overload in thalassemia patients is associated with concerns over agranulocytosis, which requires weekly absolute neutrophil counts (ANC). Here, we analyze all episodes of agranulocytosis (n = 161) and neutropenia (n = 250) during deferiprone use in clinical trials (CT) and postmarketing surveillance programs (PMSP). Rates of agranulocytosis and neutropenia in CT were 1.5% and 5.5%, respectively. Of the agranulocytosis cases, 61% occurred during the first 6 months of therapy and 78% during the first year. These events appeared to be independent of dose, and occurred three times more often in females than males. Their duration was not significantly shortened by use of G-CSF. No patient with baseline neutropenia (n = 12) developed agranulocytosis during treatment, which raises questions about the validity of prior neutropenia as a contraindication to use. Only 1/7 novel neutropenia cases in CT progressed to agranulocytosis with continued treatment, indicating that neutropenia does not necessarily lead to agranulocytosis. The agranulocytosis fatality rate was 0% in CT and 15/143 (11%) in PMSP. Rechallenge with deferiprone produced agranulocytosis in 75% of patients in whom the event had already occurred, and in 10% with previous neutropenia. Weekly ANC monitoring allows early detection and interruption of therapy, but does not prevent agranulocytosis from occurring. Its relevance appears to decrease after the first year of therapy, when agranulocytosis occurs less often. Based upon analysis of data collected over the past 20 years, it appears that patient education may be the key to minimizing agranulocytosis-associated risks during deferiprone therapy. Am. J. Hematol. 91:1026-1031, 2016. © 2016 The Authors. American Journal of Hematology Published by Wiley Periodicals, Inc., (© 2016 The Authors. American Journal of Hematology Published by Wiley Periodicals, Inc.)

Aims: In light of the growing recognition of renal disease in thalassemia, it is important to understand the impact of renal impairment on the pharmacokinetics of iron chelators. This study evaluated the pharmacokinetics and safety of the iron chelator deferiprone (DFP) in subjects with renal impairment in comparison with healthy volunteers (HVs)., Methods: Thirty-two subjects were categorized into four groups based on degree of renal impairment: none, mild, moderate or severe, as determined by estimated glomerular filtration rate (eGFR). All subjects received a single oral dose of 33 mg kg(-1) DFP, provided serum and urine samples for pharmacokinetic assessment over 24 h and were monitored for safety., Results: Renal clearance of DFP decreased as renal impairment increased. However, based on Cmax , AUC(0,t) and AUC(0,∞), there were no significant group differences in systemic exposure, because less than 4% of the drug was excreted unchanged in the urine. DFP is extensively metabolized to a renally excreted, pharmacologically inactive metabolite, deferiprone 3-O-glucuronide (DFP-G), which exhibited higher Cmax , AUC(0,t), AUC(0,∞) and longer tmax and t1/2 in the renally impaired groups compared with HVs. The Cmax and AUCs of DFP-G increased as eGFR decreased. Overall, 75%-95% of the dose was retrieved in urine, either as DFP or DFP-G, regardless of severity of renal impairment. With respect to safety, DFP was well tolerated., Conclusions: These data suggest that no adjustment of the DFP dosage regimen in patients with renal impairment is necessary, as there were no significant changes in the systemic exposure to the drug., (© 2016 The British Pharmacological Society.)

Unlabelled: Antiretrovirals suppress HIV-1 production yet spare the sites of HIV-1 production, the HIV-1 DNA-harboring cells that evade immune detection and enable viral resistance on-drug and viral rebound off-drug. Therapeutic ablation of pathogenic cells markedly improves the outcome of many diseases. We extend this strategy to HIV-1 infection. Using drug-based lead discovery, we report the concentration threshold-dependent antiretroviral action of the medicinal chelator deferiprone and validate preclinical findings by a proof-of-concept double-blind trial. In isolate-infected primary cultures, supra-threshold concentrations during deferiprone monotherapy caused decline of HIV-1 RNA and HIV-1 DNA; did not allow viral breakthrough for up to 35 days on-drug, indicating resiliency against viral resistance; and prevented, for at least 87 days off-drug, viral rebound. Displaying a steep dose-effect curve, deferiprone produced infection-independent deficiency of hydroxylated hypusyl-eIF5A. However, unhydroxylated deoxyhypusyl-eIF5A accumulated particularly in HIV-infected cells; they preferentially underwent apoptotic DNA fragmentation. Since the threshold, ascertained at about 150 μM, is achievable in deferiprone-treated patients, we proceeded from cell culture directly to an exploratory trial. HIV-1 RNA was measured after 7 days on-drug and after 28 and 56 days off-drug. Subjects who attained supra-threshold concentrations in serum and completed the protocol of 17 oral doses, experienced a zidovudine-like decline of HIV-1 RNA on-drug that was maintained off-drug without statistically significant rebound for 8 weeks, over 670 times the drug's half-life and thus clearance from circulation. The uniform deferiprone threshold is in agreement with mapping of, and crystallographic 3D-data on, the active site of deoxyhypusyl hydroxylase (DOHH), the eIF5A-hydroxylating enzyme. We propose that deficiency of hypusine-containing eIF5A impedes the translation of mRNAs encoding proline cluster ('polyproline')-containing proteins, exemplified by Gag/p24, and facilitated by the excess of deoxyhypusine-containing eIF5A, releases the innate apoptotic defense of HIV-infected cells from viral blockade, thus depleting the cellular reservoir of HIV-1 DNA that drives breakthrough and rebound., Trial Registration: ClinicalTrial.gov NCT02191657.

Brain iron accumulates in several neurodegenerative diseases and can cause oxidative damage, but mechanisms of brain iron homeostasis are incompletely understood. Patients with mutations in the cellular iron-exporting ferroxidase ceruloplasmin (Cp) have brain iron accumulation causing neurodegeneration. Here, we assessed the brains of mice with combined mutation of Cp and its homolog hephaestin. Compared to single mutants, brain iron accumulation was accelerated in double mutants in the cerebellum, substantia nigra, and hippocampus. Iron accumulated within glia, while neurons were iron deficient. There was loss of both neurons and glia. Mice developed ataxia and tremor, and most died by 9 months. Treatment with the oral iron chelator deferiprone diminished brain iron levels, protected against neuron loss, and extended lifespan. Ferroxidases play important, partially overlapping roles in brain iron homeostasis by facilitating iron export from glia, making iron available to neurons. Above: Iron (Fe) normally moves from capillaries to glia to neurons. It is exported from the glia by ferroportin (Fpn) with ferroxidases ceruloplasmin (Cp) and/or Hephaestin (Heph). Below: In mice with mutation of Cp and Heph, iron accumulates in glia, while neurons have low iron levels. Both neurons and glia degenerate and mice become ataxic unless given an iron chelator., (© 2015 International Society for Neurochemistry.)