457 results on '"John B. Porter"'
Search Results
2. P1497: MITAPIVAT IMPROVES IRON OVERLOAD IN PATIENTS WITH PYRUVATE KINASE DEFICIENCY WHO ARE REGULARLY TRANSFUSED
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Eduard van Beers, Hanny Al-Samkari, Rachael F. Grace, Wilma Barcellini, Andreas Glenthøj, Vanessa Beynon, Megan Wind-Rotolo, Rengyi Xu, Melissa Dibacco, Parija Patel, John B. Porter, and Kevin H.M. Kuo
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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3. P1493: DIAGNOSTIC ACCURACY OF AN AUTOMATED MAGNETIC RESONANCE IMAGE ANALYSIS SYSTEM FOR THE RAPID EVALUATION OF LIVER IRON CONCENTRATION IN PATIENTS WITH HFE RELATED HEMOCHROMATOSIS.
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John B. Porter, Perla Eleftheriou, Emma Drasar, Ryan Mullally, Deepak Suri, Kim Le, James Moon, Stephanie Muth, and Tim St Pierre
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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4. Effects of green tea extract treatment on erythropoiesis and iron parameters in iron-overloaded β-thalassemic mice
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Kornvipa Settakorn, Sarawut Kongkarnka, Anchan Chompupoung, Saovaros Svasti, Suthat Fucharoen, John B. Porter, Somdet Srichairatanakool, and Pimpisid Koonyosying
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green tea ,EGCG ,iron overload ,thalassemia ,erythropoiesis ,erythropoietin ,Physiology ,QP1-981 - Abstract
β-Thalassemia is characterized by ineffective erythropoiesis leading to chronic anemia. Thus, increased iron absorption from the duodenum and via blood transfusions is required to maintain normal blood hemoglobin (Hb) levels and iron chelators in the removal of excessive iron. Certain agents are also needed for the improvement of stress erythropoiesis and iron dysregulation. Green tea extract (GTE), which is rich in epigallocatechin-3-gallate (EGCG), is known to possess radical scavenging and iron-chelating activities. We aimed to assess the effects of green tea extract on erythroid regulators, iron mobilization and anti–lipid peroxidation in the liver, spleen, and kidneys of iron-loaded β-globin gene knockout thalassemic (BKO) mice. Our results indicate that treatments of green tea extract and/or deferiprone (DFP) diminished levels of plasma erythropoietin (EPO) and erythroferrone (ERFE), and consistently suppressed kidney Epo and spleen Erfe mRNA expressions (p < .05) in iron- loaded BKO mice when compared with untreated mice. Coincidently, the treatments decreased plasma ferritin (Ft) levels, iron content levels in the liver (p < .05), spleen (p < .05), and kidney tissues of iron–loaded BKO mice. Furthermore, lipid-peroxidation products in the tissues and plasma were also decreased when compared with untreated mice. This is the first evidence of the orchestral role of green tea extract abundant with epigallocatechin-3-gallate in improving ineffective erythropoiesis, iron dysregulation and oxidative stress in iron-overloaded β-thalassemic mice.
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- 2022
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5. Untreated Anemia in Nontransfusion-dependent β-thalassemia: Time to Sound the Alarm
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Khaled M. Musallam, Ali T. Taher, Maria Domenica Cappellini, Olivier Hermine, Kevin H. M. Kuo, Sujit Sheth, Vip Viprakasit, and John B. Porter
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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6. Intravenous iron preparations transiently generate non-transferrin-bound iron from two proposed pathways
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Maciej W. Garbowski, Sukhvinder Bansal, John B. Porter, Claudio Mori, Susanna Burckhardt, and Robert C. Hider
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Intravenous iron-carbohydrate complex preparations (IVIP) are noninterchangeable pro-drugs: their pharmacokinetics (PK) varies determined by semi-crystalline iron core and carbohydrate shell structures, influences pharmacodynamics (PD) and thus efficacy and safety. Examining PK/PD relationships of three IVIP we identify a two-pathway model of transient non-transferrin-bound iron (NTBI) generation following single dose administration. Twenty-eight hypoferremic non-anemic patients randomized to 200 mg iron as ferric carboxymaltose (Fe-carboxymaltose), iron sucrose (Fe-sucrose), iron isomaltoside 1000 (Fe-isomaltoside- 1000), n=8/arm, or placebo, n=4, on a 2-week PK/PD study, had samples analysed for total serum iron, IVIP-iron, transferrin-bound iron (TBI) by high-performance liquid chromatography in combination with inductively coupled plasma mass spectrometry (HPLC-ICP-MS), transferrin saturation (TSAT), serum ferritin (s-Ferritin) by standard methods, NTBI and hepcidin as published before. IVIP-dependent increases in these parameters returned to baseline in 48-150 hours (h), except for s-Ferritin and TSAT. NTBI was low with Fe-isomaltoside-1000 (0.13 μM at 8 h), rapidly increased with Fe-sucrose (0.8 μM at 2 h, 1.25 μM at 4 h), and delayed for Fe-carboxymaltose (0.57 μM at 24 h). NTBI area-under-curve (AUC) were 7-fold greater for Fe-carboxymaltose and Fe-sucrose than for Fe-isomaltoside-1000. Hepcidin peak time varied, but not AUC or mean levels. s-Ferritin levels and AUC were highest for Fe-carboxymaltose and greater than placebo for all IVIP. We propose two mechanisms for the observed NTBI kinetics: rapid and delayed NTBI appearance consistent with direct (circulating IVIP-to-plasma) and indirect (IVIP-to-macrophage-to-plasma) iron release based on IVIP plasma half-life and s-Ferritin dynamics. IVIP generate different, broadly stability- and PK-dependent, NTBI and s-Ferritin signatures, which may influence iron bioavailability, efficacy and safety. Longer-term studies should link NTBI exposure to subsequent safety and efficacy parameters and potential clinical consequences.
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- 2020
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7. Real-time national survey of COVID-19 in hemoglobinopathy and rare inherited anemia patients
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Paul Telfer, Josu de la Fuente, Mamta Sohal, Ralph Brown, Perla Eleftheriou, Noémi Roy, Frédéric B. Piel, Subarna Chakravorty, Kate Gardner, Mark Velangi, Emma Drasar, Farrukh Shah, John B. Porter, Sara Trompeter, Wale Atoyebi, Richard Szydlo, Kofi A. Anie, Kate Ryan, Joseph Sharif, Josh Wright, Emma Astwood, C. Sarah Nicolle, Amy Webster, David J. Roberts, Sanne Lugthart, Banu Kaya, Moji Awogbade, David C. Rees, Rob Hollingsworth, Baba Inusa, Jo Howard, and D. Mark Layton
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2020
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8. Patient-reported outcomes from a randomized phase II study of the deferasirox film-coated tablet in patients with transfusion-dependent anemias
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Ali T. Taher, Raffaella Origa, Silverio Perrotta, Alexandra Kouraklis, Giovan Battista Ruffo, Antonis Kattamis, Ai-Sim Goh, Vicky Huang, Aiesha Zia, Raquel Merino Herranz, and John B. Porter
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Iron chelation ,Iron overload ,Deferasirox ,Patient-reported outcomes ,Computer applications to medicine. Medical informatics ,R858-859.7 - Abstract
Abstract Background Adherence to long-term chelation therapy in transfusion-dependent patients is critical to prevent iron overload-related complications. Once-daily deferasirox dispersible tablets (DT) have proven long-term efficacy and safety in patients ≥2 years old with chronic transfusional iron overload. However, barriers to optimal adherence remain, including palatability, preparation time, and requirements for fasting state. A new film-coated tablet (FCT) formulation was developed, swallowed once daily (whole/crushed) with/without a light meal. Methods The open-label, Phase II ECLIPSE study evaluated patient-reported outcomes (PROs) in transfusion-dependent thalassemia or lower-risk myelodysplastic syndromes patients randomized 1:1 to receive deferasirox DT or FCT over 24 weeks as a secondary outcome of the study. Three PRO questionnaires were developed to evaluate both deferasirox formulations: 1) Modified Satisfaction with Iron Chelation Therapy Questionnaire; 2) Palatability Questionnaire; 3) Gastrointestinal (GI) Symptom Diary. Results One hundred seventy three patients were enrolled; 87 received the FCT and 86 the DT formulation. FCT recipients consistently reported better adherence (easier to take medication, less bothered by time to prepare medication and waiting time before eating), greater satisfaction/preference (general satisfaction and with administration of medicine), and fewer concerns (less worry about not swallowing enough medication, fewer limitations in daily activities, less concern about side effects). FCT recipients reported no taste or aftertaste and could swallow all their medicine with an acceptable amount of liquid. GI summary scores were low for both formulations. Conclusions These findings suggest a preference in favor of the deferasirox FCT formulation regardless of underlying disease or age group. Better patient satisfaction and adherence to chelation therapy may reduce iron overload-related complications. Trial registration ClinicalTrials.gov identifier: NCT02125877; registered April 26, 2014.
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- 2018
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9. Anti-Platelet Aggregation and Anti-Cyclooxygenase Activities for a Range of Coffee Extracts (Coffea arabica)
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Nuntouchaporn Hutachok, Pongsak Angkasith, Chaiwat Chumpun, Suthat Fucharoen, Ian J. Mackie, John B. Porter, and Somdet Srichairatanakool
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chlorogenic acid ,coffee ,cyclooxygenase ,espresso ,instant coffee ,platelet aggregation ,Organic chemistry ,QD241-441 - Abstract
Coffee is rich in caffeine (CF), chlorogenic acid (CGA) and phenolics. Differing types of coffee beverages and brewing procedures may result in differences in total phenolic contents (TPC) and biological activities. Inflammation and increases of platelet activation and aggregation can lead to thrombosis. We focused on determining the chemical composition, antioxidant activity and inhibitory effects on agonist-induced platelet aggregation and cyclooxygenase (COX) of coffee beverages in relation to their preparation method. We prepared instant coffee and brewed coffee beverages using drip, espresso, and boiling techniques. Coffee extracts were assayed for their CF and CGA contents using HPLC, TPC using colorimetry, platelet aggregation with an aggregometer, and COX activity using ELISA. The findings have shown all coffee extracts, except the decaffeinated types, contained nearly equal amounts of CF, CGA, and TPC. Inhibitory effects of coffee extracts on platelet aggregation differed depending on the activation pathways induced by different agonists. All espresso, drip and boiled coffee extracts caused dose dependent inhibition of platelet aggregation induced by ADP, collagen, epinephrine, and arachidonic acid (ARA). The most marked inhibition was seen at low doses of collagen or ARA. Espresso and drip extracts inhibited collagen-induced platelet aggregation more than purified caffeine or CGA. Espresso, boiled and drip coffee extracts were also a more potent inhibitors of COX-1 and COX-2 than purified caffeine or CGA. We conclude that inhibition of platelet aggregation and COX-1 and COX-2 may contribute to anti-platelet and anti-inflammatory effects of espresso and drip coffee extracts.
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- 2020
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10. Phytosterol, Lipid and Phenolic Composition, and Biological Activities of Guava Seed Oil
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Adchara Prommaban, Niramon Utama-ang, Anan Chaikitwattana, Chairat Uthaipibull, John B. Porter, and Somdet Srichairatanakool
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Psidium guajava ,seed ,hexane extract ,lipid ,phenolic compounds ,phytosterols ,Organic chemistry ,QD241-441 - Abstract
Plant seeds have been found to contain bioactive compounds that have potential nutraceutical benefits. Guava seeds (Psidium guajava) are by-products in the beverage and juice industry; however, they can be utilized for a variety of commercial purposes. This study was designed to analyze the phytochemicals of the n-hexane extract of guava seed oil (GSO), to study its free-radical scavenging activity, and to monitor the changes in serum lipids and fatty acid profiles in rats that were fed GSO. The GSO was analyzed for phytochemicals using chromatographic methods. It was also tested for free-radical scavenging activity in hepatoma and neuroblastoma cells, and analyzed in terms of serum lipids and fatty acids. GSO was found to contain phenolic compounds (e.g., chlorogenic acid and its derivatives) and phytosterols (e.g., stimasterol, β-sitosterol and campesterol), and exerted radical-scavenging activity in cell cultures in a concentration-dependent manner. Long-term consumption of GSO did not increase cholesterol and triglyceride levels in rat serum, but it tended to decrease serum fatty acid levels in a concentration-dependent manner. This is the first study to report on the lipid, phytosterol and phenolic compositions, antioxidant activity, and the hepato- and neuro-protection of hydrogen peroxide-induced oxidative stress levels in the GSO extract.
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- 2020
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11. Residual erythropoiesis protects against myocardial hemosiderosis in transfusion-dependent thalassemia by lowering labile plasma iron via transient generation of apotransferrin
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Maciej W. Garbowski, Patricia Evans, Evangelia Vlachodimitropoulou, Robert Hider, and John B. Porter
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Cardiosiderosis is a leading cause of mortality in transfusion-dependent thalassemias. Plasma non-transferrin-bound iron and its redox-active component, labile plasma iron, are key sources of iron loading in cardiosiderosis. Risk factors were identified in 73 patients with or without cardiosiderosis. Soluble transferrin receptor-1 levels were significantly lower in patients with cardiosiderosis (odds ratio 21). This risk increased when transfusion-iron loading rates exceeded the erythroid transferrin uptake rate (derived from soluble transferrin receptor-1) by >0.21 mg/kg/day (odds ratio 48). Labile plasma iron was >3-fold higher when this uptake rate threshold was exceeded, but non-transferrin-bound iron and transferrin saturation were comparable. The risk of cardiosiderosis was decreased in patients with low liver iron, ferritin and labile plasma iron, or high bilirubin, reticulocyte counts or hepcidin. We hypothesized that high erythroid transferrin uptake rate decreases cardiosiderosis through increased erythroid re-generation of apotransferrin. To test this, iron uptake and intracellular reactive oxygen species were examined in HL-1 cardiomyocytes under conditions modeling transferrin effects on non-transferrin-bound iron speciation with ferric citrate. Intracellular iron and reactive oxygen species increased with ferric citrate concentrations especially when iron-to-citrate ratios exceeded 1:100, i.e. conditions favoring kinetically labile monoferric rather than oligomer species. Excess iron-binding equivalents of apotransferrin inhibited iron uptake and decreased both intracellular reactive oxygen species and labile plasma iron under conditions favoring monoferric species. In conclusion, high transferrin iron utilization, relative to the transfusion-iron load rate, decreases the risk of cardiosiderosis. A putative mechanism is the transient re-generation of apotransferrin by an active erythron, rapidly binding labile plasma iron-detectable ferric monocitrate species.
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- 2017
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12. Second international round robin for the quantification of serum non-transferrin-bound iron and labile plasma iron in patients with iron-overload disorders
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Louise de Swart, Jan C.M. Hendriks, Lisa N. van der Vorm, Z. Ioav Cabantchik, Patricia J. Evans, Eldad A. Hod, Gary M. Brittenham, Yael Furman, Boguslaw Wojczyk, Mirian C.H. Janssen, John B. Porter, Vera E.J.M. Mattijssen, Bart J. Biemond, Marius A. MacKenzie, Raffaella Origa, Renzo Galanello, Robert C. Hider, and Dorine W. Swinkels
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Non-transferrin-bound iron and its labile (redox active) plasma iron component are thought to be potentially toxic forms of iron originally identified in the serum of patients with iron overload. We compared ten worldwide leading assays (6 for non-transferrin-bound iron and 4 for labile plasma iron) as part of an international inter-laboratory study. Serum samples from 60 patients with four different iron-overload disorders in various treatment phases were coded and sent in duplicate for analysis to five different laboratories worldwide. Some laboratories provided multiple assays. Overall, highest assay levels were observed for patients with untreated hereditary hemochromatosis and β-thalassemia intermedia, patients with transfusion-dependent myelodysplastic syndromes and patients with transfusion-dependent and chelated β-thalassemia major. Absolute levels differed considerably between assays and were lower for labile plasma iron than for non-transferrin-bound iron. Four assays also reported negative values. Assays were reproducible with high between-sample and low within-sample variation. Assays correlated and correlations were highest within the group of non-transferrin-bound iron assays and within that of labile plasma iron assays. Increased transferrin saturation, but not ferritin, was a good indicator of the presence of forms of circulating non-transferrin-bound iron. The possibility of using non-transferrin-bound iron and labile plasma iron measures as clinical indicators of overt iron overload and/or of treatment efficacy would largely depend on the rigorous validation and standardization of assays.
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- 2016
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13. Sildenafil therapy in thalassemia patients with Doppler-defined risk of pulmonary hypertension
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Claudia R. Morris, Hae-Young Kim, John Wood, John B. Porter, Elizabeth S. Klings, Felicia L. Trachtenberg, Nancy Sweeters, Nancy F. Olivieri, Janet L. Kwiatkowski, Lisa Virzi, Sylvia T. Singer, Ali Taher, Ellis J. Neufeld, Alexis A. Thompson, Vandana Sachdev, Sandra Larkin, Jung H. Suh, Frans A. Kuypers, and Elliott P. Vichinsky
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Pulmonary hypertension is a common but often overlooked complication associated with thalassemia syndromes. There are limited data on the safety and efficacy of selective pulmonary vasodilators in this at-risk population. We, therefore, designed a 12-week, open-label, phase 1/2, pilot-scale, proof-of-principle trial of sildenafil therapy in 10 patients with β-thalassemia and at increased risk of pulmonary hypertension based on an elevated tricuspid regurgitant jet velocity >2.5 m/s on Doppler-echocardiography. Variables compared at baseline and after 12 weeks of sildenafil treatment included Doppler-echocardiographic parameters, 6-minute walked distance, Borg Dyspnea Score, New York Heart Association functional class, pulmonary function, and laboratory parameters. Treatment with sildenafil resulted in a significant decrease in tricuspid regurgitant jet velocity by 13.3% (3.0±0.7 versus 2.6±0.5 m/s, P=0.04), improved left ventricular end systolic/diastolic volume, and a trend towards a improved New York Heart Association functional class. No significant change in 6-minute walked distance was noted. Sildenafil was well tolerated, although minor expected adverse events were commonly reported. The total dose of sildenafil (mg) was strongly correlated with percent change in nitric oxide metabolite concentration in the plasma (ρ=0.80, P=0.01). There were also significant increases in plasma and erythrocyte arginine concentrations. Our study suggests that sildenafil is safe and may improve pulmonary hemodynamics in patients at risk of pulmonary hypertension; however, it was not demonstrated to improve the distance walked in 6 minutes. Clinical trials are needed to identify the best treatment strategy for pulmonary hypertension in patients with β-thalassemia. (clinicaltrials.gov identifier: NCT00872170)
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- 2013
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14. Hematologic responses in patients with aplastic anemia treated with deferasirox: a post hoc analysis from the EPIC study
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Jong Wook Lee, Sung-Soo Yoon, Zhi Xiang Shen, Arnold Ganser, Hui-Chi Hsu, Ali El-Ali, Dany Habr, Nicolas Martin, and John B. Porter
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Reports are emerging of hematologic responses associated with iron chelation therapy; however, studies are limited in aplastic anemia patients. Deferasirox reduced iron overload in aplastic anemia patients enrolled in the EPIC (Evaluation of Patients’ Iron Chelation with Exjade®) study (n=116). A post hoc analysis of hematologic responses was conducted on 72 patients with evaluable hematologic parameters (according to UK guideline criteria), 24 of whom received deferasirox without concomitant immunosuppressive treatment. Partial hematologic responses were observed in 11 of 24 (45.8%) patients; all became transfusion-independent. One patient had an additional platelet response and one patient had an additional platelet and hemoglobin response. Mean serum ferritin levels at end of study were significantly reduced in partial hematologic responders (n=11; −3948±4998 ng/mL; baseline 6693±7014 ng/mL; percentage change from baseline −45.7%; P=0.0029). In non-responders, the reduction in serum ferritin was less pronounced (n=13; −2021±3242 ng/mL; baseline 4365±3063 ng/mL; % change from baseline −27.6%; P=0.0171). Alongside reduction in iron overload, deferasirox may, therefore, improve hematologic parameters in a subset of aplastic anemia patients. Further investigation is required to elucidate the mechanisms involved. (Clinicaltrials.gov identifier: NCT00171821)
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- 2013
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15. Timed non-transferrin bound iron determinations probe the origin of chelatable iron pools during deferiprone regimens and predict chelation response
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Yesim Aydinok, Patricia Evans, Chantal Y. Manz, and John B. Porter
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background Plasma non-transferrin bound iron refers to heterogeneous plasma iron species, not bound to transferrin, which appear in conditions of iron overload and ineffective erythropoiesis. The clinical utility of non-transferrin bound iron in predicting complications from iron overload, or response to chelation therapy remains unproven. We undertook carefully timed measurements of non-transferrin bound iron to explore the origin of chelatable iron and to predict clinical response to deferiprone.Design and Methods Non-transferrin bound iron levels were determined at baseline and after 1 week of chelation in 32 patients with thalassemia major receiving deferiprone alone, desferrioxamine alone, or a combination of the two chelators. Samples were taken at baseline, following a 2-week washout without chelation, and after 1 week of chelation, this last sample being taken 10 hours after the previous evening dose of deferiprone and, in those receiving desferrioxamine, 24 hours after cessation of the overnight subcutaneous infusion. Absolute or relative non-transferrin bound iron levels were related to transfusional iron loading rates, liver iron concentration, 24-hour urine iron and response to chelation therapy over the subsequent year.Results Changes in non-transferrin bound iron at week 1 were correlated positively with baseline liver iron, and inversely with transfusional iron loading rates, with deferiprone-containing regimens but not with desferrioxamine monotherapy. Changes in week 1 non-transferrin bound iron were also directly proportional to the plasma concentration of deferiprone-iron complexes and correlated significantly with urine iron excretion and with changes in liver iron concentration over the next 12 months.Conclusions The widely used assay chosen for this study detects both endogenous non-transferrin bound iron and the iron complexes of deferiprone. The week 1 increments reflect chelatable iron derived both from liver stores and from red cell catabolism. These increments correlate with urinary iron excretion and the change in liver iron concentration over the subsequent year thus predicting response to deferiprone-containing chelation regimes. This clinical study was registered at clinical.trials.gov with the number NCT00350662.
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- 2012
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16. Deferasirox for up to 3 years leads to continued improvement of myocardial T2* in patients with β-thalassemia major
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Dudley J. Pennell, John B. Porter, Maria Domenica Cappellini, Lee Lee Chan, Amal El-Beshlawy, Yesim Aydinok, Hishamshah Ibrahim, Chi-Kong Li, Vip Viprakasit, Mohsen S. Elalfy, Antonis Kattamis, Gillian Smith, Dany Habr, Gabor Domokos, Bernard Roubert, and Ali Taher
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background Prospective data on cardiac iron removal are limited beyond one year and longer-term studies are, therefore, important.Design and Methods Seventy-one patients in the EPIC cardiac substudy elected to continue into the 3rd year, allowing cardiac iron removal to be analyzed over three years.Results Mean deferasirox dose during year 3 was 33.6±9.8 mg/kg per day. Myocardial T2*, assessed by cardiovascular magnetic resonance, significantly increased from 12.0 ms ±39.1% at baseline to 17.1 ms ±62.0% at end of study (P
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- 2012
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17. A phase 1 dose-escalation study: safety, tolerability, and pharmacokinetics of FBS0701, a novel oral iron chelator for the treatment of transfusional iron overload
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Hugh Young Rienhoff, Vip Viprakasit, Lay Tay, Paul Harmatz, Elliott Vichinsky, Deborah Chirnomas, Janet L. Kwiatkowski, Amy Tapper, William Kramer, John B. Porter, and Ellis J. Neufeld
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background There is still a clinical need for a well-tolerated and safe iron chelator for the treatment of transfusional iron overload. We describe the pharmacokinetic properties and safety data after 7 days of dosing of FBS0701, a novel oral, once-daily iron chelator.Design and Methods This phase 1b dose-escalation study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of FBS0701, a novel oral iron chelator for the treatment of transfusional iron overload, was conducted in 16 adult patients with iron overloaded consequent to transfusions. FBS0701 was given daily for 7 days at doses up to 32 mg/kg and was well tolerated at all dose levels.Results Pharmacokinetics showed dose-proportionality. The maxium plasma concentration (Cmax) was reached within 60–90 minutes of dosing and the drug was rapidly distributed at the predicted therapeutic doses. The plasma elimination half-life (t1/2) was approximately 19 hours. There were no serious adverse events associated with the drug.Conclusions On the basis of these safety and pharmacokinetic data, FBS0701 warrants further clinical evaluation in patients with transfusional iron overload. (Clinicaltrials.gov identifier: NCT01186419)
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- 2011
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18. Continued improvement in myocardial T2* over two years of deferasirox therapy in β-thalassemia major patients with cardiac iron overload
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Dudley J. Pennell, John B. Porter, Maria Domenica Cappellini, Lee Lee Chan, Amal El-Beshlawy, Yesim Aydinok, Hishamshah Ibrahim, Chi-Kong Li, Vip Viprakasit, Mohsen Saleh Elalfy, Antonis Kattamis, Gillian Smith, Dany Habr, Gabor Domokos, Bernard Roubert, and Ali Taher
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background The efficacy of cardiac iron chelation in transfusion-dependent patients has been demonstrated in one-year prospective trials. Since normalization of cardiac T2* takes several years, the efficacy and safety of deferasirox was assessed for two years in patients with β-thalassemia major in the cardiac sub-study of the EPIC trial.Design and Methods Eligible patients with myocardial T2* greater than 5 to less than 20 ms received deferasirox, with the primary endpoint being the change in T2* from baseline to two years.Results Baseline myocardial T2* was severe (>5 to
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- 2011
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19. The clinical relevance of detectable plasma iron species in iron overload states and subsequent to intravenous iron‐carbohydrate administration
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Maciej W. Garbowski, Ioav Cabantchik, Chaim Hershko, Robert Hider, and John B. Porter
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Hematology - Abstract
Many disorders of iron homeostasis (e.g., iron overload) are associated with the dynamic kinetic profiles of multiple non-transferrin bound iron (NTBI) species, chronic exposure to which is associated with deleterious end-organ effects. Here we discuss the chemical nature of NTBI species, challenges with measuring NTBI in plasma, and the clinical relevance of NTBI exposure based on source (iron overload disorder vs. intravenous iron-carbohydrate complex administration). NTBI is not a single entity but consists of multiple, often poorly characterized species, some of which are kinetically non-exchangeable while others are relatively exchangeable. Prolonged presence of plasma NTBI is associated with excessive tissue iron accumulation in susceptible tissues, with consequences, such as endocrinopathy and heart failure. In contrast, intravenous iron-carbohydrate nanomedicines administration leads only to transient NTBI appearance and lacks evidence for association with adverse clinical outcomes. Assays to measure plasma NTBI are typically technically complex and remain chiefly a research tool. There have been two general approaches to estimating NTBI: capture assays and redox-activity assays. Early assays could not avoid capturing some iron from transferrin, thus overestimating NTBI. By contrast, some later assays may have promoted the donation of NTBI species to transferrin during the assay procedure, potentially underestimating NTBI levels. The levels of transferrin saturation at which NTBI species have been detectable have varied between different methodologies and between patient populations studied.
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- 2023
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20. Health‐related quality of life in patients with β‐thalassemia: Data from the phase 3 <scp>BELIEVE</scp> trial of luspatercept
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Maria Domenica Cappellini, Ali T. Taher, Antonio Piga, Farrukh Shah, Ersi Voskaridou, Vip Viprakasit, John B. Porter, Olivier Hermine, Ellis J. Neufeld, Alexis A. Thompson, Derek Tang, Aylin Yucel, Jennifer Lord‐Bessen, Peiwen Yu, Shien Guo, Jeevan K. Shetty, Dimana Miteva, Tatiana Zinger, Jay T. Backstrom, and Esther Natalie Oliva
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Hematology ,General Medicine - Published
- 2023
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21. Erythroid Response in Patients with Non-Transfusion-Dependent β-Thalassemia Treated with Luspatercept: Long-Term Data from the BEYOND Trial
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Ali T. Taher, Vip Viprakasit, Maria Domenica Domenica Cappellini, Antonio Piga, John B. Porter, Thomas D. Coates, Khaled M. Musallam, Gian Luca Forni, Jeevan K. Shetty, Marija Bosilkovska Weisskopf, Richard Wei, Wen-Ling Kuo, and Antonis Kattamis
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
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22. Effect of Luspatercept on Red Blood Cell (RBC) Transfusion Burden, Iron Chelation Therapy (ICT), and Iron Overload in Adults with Transfusion-Dependent β-Thalassemia (TDT) from the BELIEVE Trial: A Long-Term Analysis
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Olivier Hermine, Maria Domenica Domenica Cappellini, Ali T. Taher, Thomas D. Coates, Vip Viprakasit, Antonis Kattamis, Jeevan K. Shetty, Marija Bosilkovska Weisskopf, Natalia Holot, Sadanand Vodala, Wen-Ling Kuo, and John B. Porter
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
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23. Mitapivat Improves Iron Overload in Patients with Pyruvate Kinase Deficiency
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Eduard J. van Beers, Hanny Al-Samkari, Rachael F. Grace, Wilma Barcellini, Andreas Glenthøj, Melissa Dibacco, Penelope A. Kosinski, Emily Xu, Vanessa Beynon, Parija Patel, John B. Porter, and Kevin H.M. Kuo
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
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24. Long-Term Patient-Reported Outcomes Following Treatment with betibeglogene autotemcel in Patients with Transfusion-Dependent β-Thalassemia
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Franco Locatelli, Mark C. Walters, Janet L. Kwiatkowski, Marina Cavazzana, Suradej Hongeng, John B. Porter, Adrian J. Thrasher, Andreas E. Kulozik, Isabelle Thuret, John E.J. Rasko, Evangelia Yannaki, Martin G. Sauer, Shamshad Ali, Himal Thakar, Katiana Gruppioni, and Alexis A. Thompson
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
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25. Effect of Luspatercept in β-Thalassemia Patients with β0/β0 Genotype: A Subgroup Analysis of the BELIEVE Study
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Sujit Sheth, Olivier Hermine, Ali T. Taher, Kevin H.M. Kuo, John B. Porter, Antonio Piga, Thomas D. Coates, Antonis Kattamis, Loyse Felber Medlin, Wen-Ling Kuo, Natalia Holot, and Maria Domenica Domenica Cappellini
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
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26. Long Term Outcomes of 63 Patients with Transfusion-Dependent β-Thalassemia (TDT) Followed up to 7 Years Post-Treatment with betibeglogene autotemcel (beti-cel) Gene Therapy and Exploratory Analysis of Predictors of Successful Treatment Outcomes in Phase 3 Trials
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Mark C. Walters, Janet L. Kwiatkowski, John B. Porter, Jennifer Schneiderman, Suradej Hongeng, Andreas E. Kulozik, Marina Cavazzana, Martin G. Sauer, Adrian J. Thrasher, Isabelle Thuret, Ashutosh Lal, John E.J. Rasko, Evangelia Yannaki, Shamshad Ali, Ilya Shestopalov, Maeva Fincker, Richard A. Colvin, Dustin Whitney, Franco Locatelli, and Alexis A. Thompson
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
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27. Betibeglogene Autotemcel Gene Therapy for Non–β0/β0 Genotype β-Thalassemia
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Franco Locatelli, Alexis A. Thompson, Janet L. Kwiatkowski, John B. Porter, Adrian J. Thrasher, Suradej Hongeng, Martin G. Sauer, Isabelle Thuret, Ashutosh Lal, Mattia Algeri, Jennifer Schneiderman, Timothy S. Olson, Ben Carpenter, Persis J. Amrolia, Usanarat Anurathapan, Axel Schambach, Christian Chabannon, Manfred Schmidt, Ivan Labik, Heidi Elliot, Ruiting Guo, Mohammed Asmal, Richard A. Colvin, and Mark C. Walters
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thalassemia ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,General Medicine ,gene therapy - Published
- 2022
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28. Iron status influences the response of cord blood megakaryocyte progenitors to eltrombopag in vitro
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James B. Bussel, Henry A. Feldman, Haley E. Ramsey, E Vlachodimtropoulou Koumoutsea, Emoke Deschmann, Bethan Psaila, Nichola Cooper, Michael K. Georgieff, Liu Z-J., Martha Sola-Visner, and John B. Porter
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medicine.medical_specialty ,Iron ,Eltrombopag ,Stimulation ,Benzoates ,chemistry.chemical_compound ,Megakaryocyte ,Internal medicine ,medicine ,Progenitor cell ,Thrombopoietin ,Megakaryopoiesis ,Megakaryocyte Progenitor Cells ,Chemistry ,Cell Differentiation ,Hematology ,Iron deficiency ,medicine.disease ,Platelets and Thrombopoiesis ,Fetal Blood ,Endocrinology ,medicine.anatomical_structure ,Hydrazines ,Apoptosis ,Pyrazoles - Abstract
Key Points High concentrations of eltrombopag suppress cord blood MK differentiation and proliferation in vitro.These effects are mediated by the iron-chelating effects of eltrombopag and are modulated by the iron status of the MK progenitors., Visual Abstract, Eltrombopag (ELT) is a thrombopoietic agent approved for immune thrombocytopenia and also a potent iron chelator. Here we found that ELT exhibited dose-dependent opposing effects on in vitro megakaryopoiesis: low concentrations (≤6 µM, ELT6) stimulated megakaryopoiesis, but high concentrations (30 µM, ELT30) suppressed megakaryocyte (MK) differentiation and proliferation. The suppressive effects of ELT30 were reproduced by other iron chelators, supporting iron chelation as a likely mechanism. During MK differentiation, committed MK progenitors (CD34+/CD41+ and CD34−/CD41+ cells) were significantly more sensitive than undifferentiated progenitors (CD34+/CD41− cells) to the suppressive effects of ELT30, which resulted from both decreased proliferation and increased apoptosis. The antiproliferative effects of ELT30 were reversed by increased iron in the culture, as were the proapoptotic effects when exposure to ELT30 was short. Because committed MK progenitors exhibited the highest proliferative rate and the highest sensitivity to iron chelation, we tested whether their iron status influenced their response to ELT during rapid cell expansion. In these studies, iron deficiency reduced the proliferation of CD41+ cells in response to all ELT concentrations. Severe iron deficiency also reduced the number of MKs generated in response to high thrombopoietin concentrations by ∼50%, compared with iron-replete cultures. Our findings support the hypothesis that although iron deficiency can stimulate certain cells and steps in megakaryopoiesis, it can also limit the proliferation of committed MK progenitors, with severity of iron deficiency and degree of thrombopoietic stimulation influencing the ultimate output. Further studies are needed to clarify how megakaryopoiesis, iron deficiency, and ELT stimulation are clinically interrelated.
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- 2021
29. Early-onset reduced bone mineral density in patients with pyruvate kinase deficiency
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Hanny Al‐Samkari, Rachael F. Grace, Andreas Glenthøj, Oliver Andres, Wilma Barcellini, Frédéric Galactéros, Kevin H. M. Kuo, D. Mark Layton, Marta Morado Arias, Vip Viprakasit, Yan Dong, Feng Tai, Peter Hawkins, Sarah Gheuens, Jaime Morales‐Arias, Keely S. Gilroy, John B. Porter, and Eduard J. van Beers
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Hematology - Published
- 2022
30. Long-term Outcomes of 63 Patients with Transfusion-Dependent β-Thalassemia (TDT) Followed-up to 7 Years after Treatment with betibeglogene autotemcel (beti-cel) Gene Therapy (GT) and Factors Impacting Neutrophil and Platelet Engraftment
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Timothy S. Olson, Mark C. Walters, Janet L. Kwiatkowski, John B. Porter, Jennifer Schneiderman, Suradej Hongeng, Andreas E. Kulozik, Marina Cavazzana, Martin G. Sauer, Adrian J. Thrasher, Isabelle Thuret, Ashutosh Lal, John E.J. Rasko, Evangelia Yannaki, Shamshad Ali, Richard A. Colvin, Franco Locatelli, and Alexis A. Thompson
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Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Published
- 2023
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31. Investigations into the Mechanisms and Clinical Implications of Modulation of Hepcidin Levels By Luspatercept in TD MDS and TD b-Thalassemia
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Aarif Ahsan, Wei Fang, Manuel Ugidos, Danny V Jeyaraju, Pierre Fenaux, Uwe Platzbecker, Olivier Hermine, John B. Porter, Rajasekhar N.V.S. Suragani, Sadanand Vodala, and Anita K. Gandhi
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
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32. A Closer Look at Changes in Hemoglobin Levels in Patients with Non-Transfusion Dependent β-Thalassemia Treated with Luspatercept: Post Hoc Analysis of the Phase 2 BEYOND Trial
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Khaled M. Musallam, Ali T. Taher, John B. Porter, Antonis Kattamis, Mrudula B. Glassberg, Luciana Bueno, Jeevan K. Shetty, Frederik Lersch, Barbara Rosettani, and Maria Domenica Domenica Cappellini
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
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33. Protecting vulnerable patients with inherited anaemias from unnecessary death during the COVID‐19 pandemic
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Baba Inusa, Wale Atoyebi, Sara Trompeter, Sara Stuart-Smith, Josu de la Fuente, Farrukh Shah, Perla Eleftheriou, David J. Roberts, Sanne Lugthart, John B. Porter, Josh Wright, Subarna Chakravorty, Emma Drasar, Noémi B. A. Roy, D. Mark Layton, Jo Howard, and Paul Telfer
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medicine.medical_specialty ,Blood transfusion ,Isolation (health care) ,Anemia ,medicine.medical_treatment ,Fulminant ,Pneumonia, Viral ,Population ,Short Report ,Disease ,Betacoronavirus ,03 medical and health sciences ,0302 clinical medicine ,Short Reports ,COVID‐19 ,Pandemic ,Humans ,Medicine ,Blood Transfusion ,Intensive care medicine ,education ,Pandemics ,Stroke ,Bone Marrow Transplantation ,Cross Infection ,education.field_of_study ,SARS-CoV-2 ,business.industry ,COVID-19 ,Hematology ,medicine.disease ,030220 oncology & carcinogenesis ,Coronavirus Infections ,business ,030215 immunology - Abstract
Summary With the developing COVID‐19 pandemic, patients with inherited anaemias require specific advice regarding isolation and changes to usual treatment schedules. The National Haemoglobinopathy Panel (NHP) has issued guidance on the care of patients with sickle cell disease, thalassaemia, Diamond Blackfan anaemia (DBA), congenital dyserythropoietic anaemia (CDA), sideroblastic anaemia, pyruvate kinase deficiency and other red cell enzyme and membrane disorders. Cascading of accurate information for clinicians and patients is paramount to preventing adverse outcomes, such as patients who are at increased risk of fulminant bacterial infection due to their condition or its treatment erroneously self‐isolating if their fever is mistakenly attributed to a viral cause, delaying potentially life‐saving antibiotic therapy. Outpatient visits should be minimised for most patients, however some, such as first transcranial dopplers for children with sickle cell anaemia should not be delayed as known risk of stroke will outweigh the unknown risk from COVID‐19 infection. Blood transfusion programmes should be continued, but specific changes to usual clinical pathways can be instituted to reduce risk of patient exposure to COVID‐19, as well as contingency planning for possible reductions in blood available for transfusions. Bone marrow transplants for these disorders should be postponed until further notice. With the current lack of evidence on the risk and complications of COVID‐19 infection in these patients, national data collection is ongoing to record outcomes and eventually to identify predictors of disease severity, particularly important if further waves of infection travel through the population.
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- 2020
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34. Consumption of a green tea extract–curcumin drink decreases blood urea nitrogen and redox iron in β-thalassemia patients
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Somdet Srichairatanakool, John B. Porter, Niramon Utama-ang, Suthat Fucharoen, Pimpisid Koonyosying, Michael Cresswell, Sasinee Hantrakool, and Adisak Tantiworawit
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Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Curcumin ,Iron Overload ,Antioxidant ,Adolescent ,Thalassemia ,medicine.medical_treatment ,Renal function ,Green tea extract ,Iron Chelating Agents ,medicine.disease_cause ,Antioxidants ,Blood Urea Nitrogen ,Young Adult ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Chelation therapy ,Blood urea nitrogen ,Tea ,Chemistry ,beta-Thalassemia ,General Medicine ,Middle Aged ,medicine.disease ,Oxidative Stress ,030104 developmental biology ,Endocrinology ,030220 oncology & carcinogenesis ,Female ,Lipid Peroxidation ,Oxidative stress ,Food Science - Abstract
The most important cause of death in β-thalassemia major patients is organ dysfunction due to iron deposits. Non-transferrin bound iron (NTBI), labile plasma iron (LPI) and labile iron pool are redox-active forms of iron found in thalassemia. Iron chelation therapy is adopted to counteract the resulting iron overload. Extracts of green tea (GTE) and curcumin exhibit iron-chelating and antioxidant activities in iron-loaded cells and β-thalassemic mice. We have used our GTE-CUR drink to investigate the potential amelioration of iron overload and oxidative stress in transfusion-dependent β-thalassemia (TDT) patients. The patients were enrolled for a control group without and with GTE-CUR treatments (17.3 and 35.5 mg EGCG equivalent). Along with regular chelation therapy, they were daily administered the drink for 60 d. Blood samples were collected at the beginning of the study and after 30 d and 60 d for biochemical and hematological tests. Interestingly, we found a decrease of blood urea nitrogen levels (P < 0.05), along with a tendency for a decrease of NTBI and LPI, and a delay in increasing lipid-peroxidation product levels in the GTE-CUR groups. The findings suggest that GTE-CUR could increase kidney function and diminish redox-active iron in iron overloaded β-thalassemia patients.
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- 2020
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35. Luspatercept for the treatment of anaemia in non-transfusion-dependent β-thalassaemia (BEYOND): a phase 2, randomised, double-blind, multicentre, placebo-controlled trial
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Ali T Taher, Maria Domenica Cappellini, Antonis Kattamis, Ersi Voskaridou, Silverio Perrotta, Antonio G Piga, Aldo Filosa, John B Porter, Thomas D Coates, Gian Luca Forni, Alexis A Thompson, Immacolata Tartaglione, Khaled M Musallam, Jay T Backstrom, Oriana Esposito, Ana Carolina Giuseppi, Wen-Ling Kuo, Dimana Miteva, Jennifer Lord-Bessen, Aylin Yucel, Tatiana Zinger, Jeevan K Shetty, Vip Viprakasit, Jassada Buaboonnam, Supachai Ekwattanakit, Archrob Khunhapinant, Efthalia Loka, Maria Moraki, Pagona Flevari, Maria Dimopoulou, Vasiliki Bartzi, Hisham Daadaa, Georges El Hasbani, Suzanne Koussa, Federica Ammendola, Saverio Scianguetta, Marta Puglia, Ilaria Ferrara, Giovanni Ferrero, Carmen Gaglioti, Filomena Longo, Silvia Turrini, Vincenzo Voi, Elena Cassinerio, Anna De, Giovanna Graziadei, Alessia Marcon, Margherita Migone De Amicis, Irene Motta, Patrizia Cinque, Bruno Pannone, Paolo Ricchi, Manuela Balocco, Paola Carrara, Francesco Della Rovere, Martina Lamagna, Valeria Pinto, Sabrina Quintino, Perla Eleftheriou, Maciej Garbowski, Arne de Kreuk, Susan Carson, Christopher Denton, Tom Hofstra, Sayany Veluswamy, John Wood, Sherif Badawy, Rachel Bercovitz, Rukhmi Bhat, Diane Calamaras, Robert Liem, Astrid Mack, Taher, Ali T, Cappellini, Maria Domenica, Kattamis, Antoni, Voskaridou, Ersi, Perrotta, Silverio, Piga, Antonio G, Filosa, Aldo, Porter, John B, Coates, Thomas D, Forni, Gian Luca, Thompson, Alexis A, Tartaglione, Immacolata, Musallam, Khaled M, Backstrom, Jay T, Esposito, Oriana, Giuseppi, Ana Carolina, Kuo, Wen-Ling, Miteva, Dimana, Lord-Bessen, Jennifer, Yucel, Aylin, Zinger, Tatiana, Shetty, Jeevan K, and Viprakasit, Vip
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Adult ,Male ,Settore MED/09 - Medicina Interna ,Activin Receptors, Type II ,Hemoglobin E ,Recombinant Fusion Proteins ,beta-Thalassemia ,Hematology ,Immunoglobulin Fc Fragments ,Treatment Outcome ,Double-Blind Method ,alpha-Globins ,Quality of Life ,Unit ,Cardarelli Hospital ,Humans ,Thalassemia ,Female ,Settore MED/15 - Malattie del Sangue - Abstract
Background In patients with non-transfusion-dependent beta-thalassaemia, haemoglobin concentrations lower than 10 g/dL are associated with a higher risk of morbidity, mortality, and impaired quality of life. No drugs are specifically approved for anaemia management in patients with non-transfusion-dependent beta-thalassaemia, other than transfusion therapy administered infrequently in accordance with patients' needs. We assessed the efficacy and safety of luspatercept versus placebo in patients with non-transfusion-dependent beta-thalassaemia.Methods We did a phase 2, randomised, double-blind, multicentre, placebo-controlled trial in 12 centres in six countries (Thailand [n=1], Lebanon [n=1], Greece [n=2], Italy [n=5], the UK [n=1], and the USA [n=2]). Eligible patients were aged 18 years or older, had confirmed diagnosis of beta-thalassaemia or haemoglobin E/beta-thalassaemia (concomitant a-globin deletion, mutation, or duplication were allowed), and a baseline haemoglobin concentration of 10.0 g/dL or lower. All patients were non-transfusion-dependent. Patients were randomly assigned (2:1) to luspatercept or placebo using an interactive response technology system and stratified by baseline haemoglobin concentration (>= 8.5 g/dL vs = 3 vs
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- 2022
36. Betibeglogene Autotemcel Gene Therapy for Non-β
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Franco, Locatelli, Alexis A, Thompson, Janet L, Kwiatkowski, John B, Porter, Adrian J, Thrasher, Suradej, Hongeng, Martin G, Sauer, Isabelle, Thuret, Ashutosh, Lal, Mattia, Algeri, Jennifer, Schneiderman, Timothy S, Olson, Ben, Carpenter, Persis J, Amrolia, Usanarat, Anurathapan, Axel, Schambach, Christian, Chabannon, Manfred, Schmidt, Ivan, Labik, Heidi, Elliot, Ruiting, Guo, Mohammed, Asmal, Richard A, Colvin, and Mark C, Walters
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Adult ,Male ,Biological Products ,Iron Overload ,Adolescent ,Genotype ,Genetic Vectors ,Lentivirus ,beta-Thalassemia ,Genetic Therapy ,beta-Globins ,Middle Aged ,Myeloablative Agonists ,Hemoglobins ,Humans ,Erythropoiesis ,Female ,Child ,Erythrocyte Transfusion ,Busulfan - Abstract
Betibeglogene autotemcel (beti-cel) gene therapy for transfusion-dependent β-thalassemia contains autologous CD34+ hematopoietic stem cells and progenitor cells transduced with the BB305 lentiviral vector encoding the β-globin (βIn this open-label, phase 3 study, we evaluated the efficacy and safety of beti-cel in adult and pediatric patients with transfusion-dependent β-thalassemia and a non-βA total of 23 patients were enrolled and received treatment, with a median follow-up of 29.5 months (range, 13.0 to 48.2). Transfusion independence occurred in 20 of 22 patients who could be evaluated (91%), including 6 of 7 patients (86%) who were younger than 12 years of age. The average hemoglobin level during transfusion independence was 11.7 g per deciliter (range, 9.5 to 12.8). Twelve months after beti-cel infusion, the median level of gene therapy-derived adult hemoglobin (HbA) with a T87Q amino acid substitution (HbATreatment with beti-cel resulted in a sustained HbA
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- 2021
37. Response to Cabantchik and Hershko commentary 'Plasma nontransferrin bound iron-nontransferrin bound iron revisited: Implications for systemic iron overload and in iv iron supplementation'
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Robert C. Hider, Maciej W Garbowski, and John B. Porter
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2019-20 coronavirus outbreak ,Iron Overload ,Coronavirus disease 2019 (COVID-19) ,Chemistry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Iron ,Dietary Supplements ,Humans ,Hematology ,Microbiology - Published
- 2021
38. Oral ferroportin inhibitor vamifeport for improving iron homeostasis and erythropoiesis in β-thalassemia: current evidence and future clinical development
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Vip Viprakasit, Frank Richard, Vania Manolova, Franz Dürrenberger, John B. Porter, Thomas D. Coates, Ali T. Taher, Maciej W Garbowski, M. Domenica Cappellini, and Antonis Kattamis
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Ineffective erythropoiesis ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Iron Overload ,Thalassemia ,Iron ,Ferroportin ,medicine.disease_cause ,Iron homeostasis ,Hepcidins ,Hepcidin ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Homeostasis ,Humans ,Erythropoiesis ,Globin ,Cation Transport Proteins ,biology ,business.industry ,beta-Thalassemia ,Hematology ,medicine.disease ,Endocrinology ,biology.protein ,business ,Red blood cell survival - Abstract
In β-thalassemia, imbalanced globin synthesis causes reduced red blood cell survival and ineffective erythropoiesis. Suppressed hepcidin levels increase ferroportin-mediated iron transport in enterocytes, causing increased iron absorption and potentially iron overload. Low hepcidin also stimulates ferroportin-mediated iron release from macrophages, increasing transferrin saturation (TSAT), potentially forming non-transferrin-bound iron, which can be toxic. Modulating the hepcidin-ferroportin axis is an attractive strategy to improve ineffective erythropoiesis and limit the potential tissue damage resulting from iron overload. There are no oral β-thalassemia treatments that consistently ameliorate anemia and prevent iron overload.The preclinical and clinical development of vamifeport (VIT-2763), a novel ferroportin inhibitor, was reviewed. PubMed, EMBASE and ClinicalTrials.gov were searched using the search term 'VIT-2763'.Vamifeport is the first oral ferroportin inhibitor in clinical development. In healthy volunteers, vamifeport had comparable safety to placebo, was well tolerated and rapidly decreased iron levels and reduced TSAT, consistent with observations in preclinical models. Data from ongoing/planned Phase II studies are critical to define its potential in β-thalassemia and other conditions associated with iron overabsorption and/or ineffective erythropoiesis. If vamifeport potentially increases hemoglobin and reduces iron-related parameters, it could be a suitable treatment for non-transfusion-dependent and transfusion-dependent β-thalassemia.
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- 2021
39. Early-Onset Osteopenia and Osteoporosis in Patients with Pyruvate Kinase Deficiency
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Oliver Andres, Feng Tai, Vip Viprakasit, Wilma Barcellini, Sarah Gheuens, John B. Porter, Andreas Glenthoej, Chris Bowden, Yan Dong, Peter Hawkins, Kevin H.M. Kuo, Hanny Al-Samkari, D. Mark Layton, Rachael F. Grace, Eduard J. van Beers, Marta Morado, and Frédéric Galactéros
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medicine.medical_specialty ,business.industry ,Immunology ,Osteoporosis ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Osteopenia ,Clinical trial ,Family medicine ,Cohort ,Medicine ,Medical history ,In patient ,Current employment ,business ,health care economics and organizations ,Early onset - Abstract
Background: Hereditary pyruvate kinase (PK) deficiency results in lifelong hemolytic anemia and several significant comorbidities, the epidemiology of which are not well characterized. Among these is reduced bone mineral density (BMD), which can result in premature osteopenia, osteoporosis, and fractures. To better characterize the bone density abnormalities in patients with PK deficiency, this study evaluated pooled pre-treatment baseline data from 3 clinical trials involving patients with PK deficiency investigating mitapivat, an allosteric activator of PK: DRIVE-PK (NCT02476916), ACTIVATE (NCT03548220), and ACTIVATE-T (NCT03559699). This is the first large PK deficiency cohort in which dual-energy x-ray absorptiometry (DXA) scores were systematically and consistently assessed. Methods: DRIVE-PK is a completed phase 2, global, randomized, open-label study. ACTIVATE is an ongoing phase 3, global, randomized, double-blind, placebo-controlled study. ACTIVATE-T is an ongoing phase 3, global, open-label, single-arm study. In all 3 studies, patients ≥ 18 years of age with a confirmed diagnosis of PK deficiency were eligible to participate. Patients were eligible to participate in DRIVE-PK and in ACTIVATE if they were not regularly transfused (DRIVE-PK: ≤ 3 units of red blood cells in the prior 12 months; no transfusions in the prior 4 months; ACTIVATE: ≤ 4 transfusion episodes in the previous year; no transfusions in the prior 3 months) and in ACTIVATE-T if they were regularly transfused (≥ 6 transfusion episodes in the previous year). BMD was measured using DXA scans at baseline; scans were obtained locally for all 3 studies. Scans were interpreted locally for DRIVE-PK and centrally for ACTIVATE and ACTIVATE-T. Osteopenia and osteoporosis were identified on DXA scanning according to standard definitions, and the prevalence of each was compared to the prevalence ascertained via medical history. Results: Full demographics and characteristics of patients at baseline are shown in the Table. Of 159 patients evaluated (DRIVE-PK, n = 52; ACTIVATE, n = 80; ACTIVATE-T, n = 27), the median age was 34 years (range, 18-78) and the majority were female (n = 88; 55.3%). Of 155 patients who had baseline T-scores for total femur, spine, and femoral neck, 38 (24.5%) had a T-score of ≥ -1.0 at all locations, indicating normal BMD; 91 (58.7%) had a T-score of < -1.0 to > -2.5 at 1 or more locations, indicating osteopenia; and 26 (16.8%) had a T-score of ≤ -2.5 at 1 or more locations, indicating osteoporosis. The proportion of patients in each T-score range for each of the 3 locations is shown in the Figure. In contrast to the DXA scan findings, only 28 (17.6%) patients had a known medical history of osteopenia and 23 (14.5%) had a known medical history of osteoporosis. Taking together DXA scan results and medical history for all 159 patients, 85 patients (53.5%) had osteopenia and 33 patients (20.8%) had osteoporosis. The median age for patients with either osteopenia or osteoporosis (n = 118) was 36 years (range, 18-78). Of these, 20 patients (16.9%) were regularly transfused and 98 patients (83.1%) were not regularly transfused. Conclusions: In this large cohort, universal DXA scanning revealed that over three-quarters of adults with PK deficiency had osteopenia or osteoporosis, irrespective of transfusion requirements. Given the young median age of the cohort (34 years), these findings have considerable significance and implications for the screening and care of patients with PK deficiency throughout their adult lives. Early monitoring of these patients with DXA scans in order to ensure a prompt diagnosis of bone density abnormalities and indicated treatment may be warranted. Disclosures Al-Samkari: Argenx: Consultancy; Agios: Consultancy, Research Funding; Dova: Consultancy, Research Funding; Rigel: Consultancy; Amgen: Research Funding. Grace:Novartis: Research Funding; Agios: Research Funding; Dova: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding. Glenthoej:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bluebird: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexicon: Research Funding; Novo Nordisk: Honoraria. Barcellini:Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: invited speaker , Research Funding; Novartis: Honoraria, Other: invited speaker , Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Galactéros:Addmedica: Membership on an entity's Board of Directors or advisory committees. Kuo:Bluebird Bio: Consultancy; Novartis: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Apellis: Consultancy; Celgene: Consultancy; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Research Funding. Layton:Cerus: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Morado:Sanofi Genzyme: Honoraria, Other: Grants. Viprakasit:BMS, Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Agios Pharmaceuticals, Ionis Pharmaceuticals, La Jolla Pharmaceuticals, Protagonist Therapeutics, Vifor Pharma: Consultancy, Research Funding. Dong:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Tai:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Hawkins:Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company; Bristol-Myers Squibb: Current equity holder in publicly-traded company; Infinity Pharmaceuticals: Current equity holder in publicly-traded company; Jazz Pharmaceuticals: Current equity holder in publicly-traded company. Gheuens:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Bowden:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Porter:Silence Therapeutics: Honoraria; La Jolla Pharmaceuticals: Honoraria; Vifor Pharmaceuticals: Honoraria; Protagonist Therapeutics: Honoraria; Agios Pharmaceuticals: Consultancy, Honoraria; bluebird bio, Inc.: Consultancy, Honoraria; BMS: Consultancy, Honoraria. van Beers:Novartis: Research Funding; Pfizer: Research Funding; RR mechatronics: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees, Research Funding.
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- 2020
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40. Favorable Outcomes in Pediatric Patients in the Phase 3 Hgb-207 (Northstar-2) and Hgb-212 (Northstar-3) Studies of Betibeglogene Autotemcel Gene Therapy for the Treatment of Transfusion-Dependent β-Thalassemia
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Weijian Liu, Alexis A. Thompson, Janet L. Kwiatkowski, John B. Porter, Mark C. Walters, Ruiting Guo, Andreas E. Kulozik, Isabelle Thuret, Suradej Hongeng, Evangelia Yannaki, Franco Locatelli, Ashutosh Lal, Richard A. Colvin, Adrian J. Thrasher, and Martin Sauer
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medicine.medical_specialty ,Adult patients ,business.industry ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Transfusion volume ,Clinical trial ,Interim ,Family medicine ,Transfusion dependence ,Bluebird Bio ,Medicine ,Current employment ,business ,After treatment - Abstract
Introduction Betibeglogene autotemcel (beti-cel; LentiGlobin for β-thalassemia) gene therapy is being evaluated for the treatment of transfusion-dependent β-thalassemia (TDT). Initial positive results of beti-cel in the phase 3 studies, HGB-207 (NCT02906202; non-β0/β0 genotypes) and HGB-212 (NCT03207009; β0/β0, β0/β+ IVS-I-110 and β+ IVS-I-110/β+ IVS-I-110 genotypes), showed 10/12 adult patients achieved transfusion independence. The studies expanded enrollment to include adolescents and children. We present interim results from pediatric patients Methods After mobilization and apheresis, autologous CD34+ cells were transduced ex vivo with BB305 lentiviral vector, containing a modified human β-globin gene to produce beti-cel drug product (DP). Patients underwent busulfan myeloablation and infusion with beti-cel and were then followed longitudinally. Transfusion independence (TI; weighted average hemoglobin [Hb] ≥9 g/dL without transfusions for ≥12 mo) was the primary endpoint in HGB-207 and a secondary endpoint in HGB-212. Transfusion reduction (≥60% reduction in transfusion volume between Month 12 to 24 versus baseline) is the primary endpoint in HGB-212. Hb levels, TI characteristics, and quality of life were secondary endpoints. Assessments of ineffective erythropoiesis were exploratory. Data presented as median (min-max). Results Twenty-four pediatric patients were treated including 13 patients 3 mo follow-up achieved platelet engraftment and had platelets ≥100 x109/L by Month 12; one 17-yr old patient did not have platelets ≥100 x109/L until Month 15. In HGB-207, 6/7 (86%) patients 3 mo follow-up have stopped transfusions for ≥6 mo. TI was achieved in 3/4 (75%) evaluable patients In HGB-212, 3/5 (60%) patients 3mo follow-up have stopped transfusions for ≥6 mo. TI was achieved in 1/2 evaluable patients Post-infusion non-hematologic grade ≥3 adverse events (AEs) in ≥3 patients aged Summary Interim results in HGB-207 and HGB-212 show that after treatment with beti-cel, pediatric patients Disclosures Thompson: CRISPR/Vertex: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Baxalta: Research Funding; BMS: Consultancy, Research Funding; Biomarin: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding. Kwiatkowski:Novartis: Research Funding; Agios: Consultancy; Sangamo: Research Funding; bluebird bio,Inc.: Consultancy, Research Funding; Apopharma: Research Funding; Imara: Consultancy; BMS: Consultancy; Terumo Co: Research Funding; Celgene: Consultancy. Porter:Vifor Pharmaceuticals: Honoraria; bluebird bio, Inc.: Consultancy, Honoraria; Agios Pharmaceuticals: Consultancy, Honoraria; La Jolla Pharmaceuticals: Honoraria; Silence Therapeutics: Honoraria; Protagonist Therapeutics: Honoraria; BMS: Consultancy, Honoraria. Kulozik:Novartis: Consultancy, Honoraria; bluebird bio, Inc.: Consultancy, Honoraria. Thrasher:Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Generation bio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Equity ownership; Orchard Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Equity ownership; 4Bio Capital: Consultancy, Membership on an entity's Board of Directors or advisory committees. Thuret:Novartis pharma: Membership on an entity's Board of Directors or advisory committees, Other: Investigator in clinical trials; bluebird bio, Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Investigator in clinical trials; Apopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Investigator in clinical trials. Lal:Insight Magnetics: Research Funding; Celgene, BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Terumo Corporation: Research Funding; Agios Pharmaceuticals: Consultancy; Chiesi USA: Consultancy; La Jolla Pharmaceutical Company: Research Funding; bluebird bio, Inc.: Research Funding; Protagonist Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Guo:bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Liu:bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Colvin:bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Walters:Veevo Biomedicine: Consultancy; AllCells, Inc: Consultancy; Editas: Consultancy. Locatelli:Jazz Pharmaceeutical: Speakers Bureau; Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
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- 2020
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41. Response of Patients with Transfusion-Dependent β-Thalassemia (TDT) to Betibeglogene Autotemcel (beti-cel; LentiGlobin for β-Thalassemia) Gene Therapy Based on HBB Genotype and Disease Genetic Modifiers
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Janet L. Kwiatkowski, Franco Locatelli, Julia Yang, Isabelle Thuret, Alexis A. Thompson, John B. Porter, Richard A. Colvin, Evangelia Yannaki, Martin Sauer, Ashutosh Lal, Adrian J. Thrasher, Dustin Whitney, Suradej Hongeng, Mark C. Walters, Andreas E. Kulozik, John J. Farrell, David H.K. Chui, and Alexandria Petrusich
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business.industry ,Genetic enhancement ,Thalassemia ,Immunology ,Cell Biology ,Hematology ,Disease ,medicine.disease ,Biochemistry ,Genotype ,Transfusion dependence ,medicine ,business - Abstract
Introduction We investigated the impact of β-thalassemia genotypes and disease genetic modifiers including HBA and KLF1 genotype and sentinel single-nucleotide polymorphism (SNP) genotypes at 3 major HbF quantitative trait loci (QTL) on clinical outcomes of TDT patients treated with beti-cel gene therapy in two phase 3 studies, HGB-207 (NCT02906202) and HGB-212 (NCT03207009). Methods HBA deletions and triplications were determined by gap-polymerase chain reactions. HBG2 (including rs7482144, Xmn1 site) and HBG1 promoters, HBA2, HBA1, and KLF1 underwent individual nucleotide sequencing. Multiplex amplification refractory mutation system (ARMS) tests were used to identify HbF QTL SNPs (rs10128556 in HBBP1; rs766432, rs1427407, rs10189857 in BCL11A; rs9399137, rs66650371 in HMIP). Thalassemia severity score (TSS) was calculated as defined by Danjou et al, Haematologica, 2015, considering gender, HBB and HBA genotypes, and 4 SNPs in HbF QTL (HBG2, BCL11A, HMIP). Correlative analyses were performed to assess relationships between genotype, presence/absence of non-HBB mutations (HBA2, HBA1, KLF1), presence/absence of HbF QTL SNPs (HBG2, BCL11A, HMIP), and TSS with the achievement of transfusion independence (TI; weighted average hemoglobin [Hb] ≥9 g/dL without red blood cell [RBC] transfusions for ≥12 months). Correlation coefficients used percentage bend correlation. Statistical significance threshold was p ≤ 0.05. Results As of 3 March 2020, 38 patients were treated in HGB-207 and HGB-212 (β0/β0 genotype n=9; non-β0/β0 genotype n=29 [β+/β+ n=8; β0/β+ n=15; βE/β0 n=6]). All patients were heterozygous or homozygous for mutations or SNPs that may modulate disease severity; 20 patients were homozygous for ≥1 mutation or SNP. Patients had the following alleles associated with higher HbF synthesis: HBG2 rs7482144 C>T (Xmn1 site), C/T n=9, T/T n=1; BCL11A rs1427407 G>T, G/T n=8; BCL11A rs10189857 A>G, A/G n=16, G/G n=18; HMIP rs9399137 T>C, T/C n=9, C/C n=2. Three patients were heterozygous for single α-globin gene deletion (-α/αα) and 2 were heterozygous for α-globin gene triplication (αα/ααα). Median TSS was 3.65 (min - max 0.4 - 8.1). TI was achieved by 23/27 (85%) evaluable patients; 4 patients with ≥ 12 months follow-up have been transfusion free for > 10 months but were not yet evaluable for TI (Figure). β-thalassemia genotype did not strongly correlate with TI (two-sided Fisher's Exact Test, p-value = 0.78). Month 12 median (min - max) peripheral blood vector copy number (PB VCN) was 1.5 (0.2 - 5.0) c/dg in TI or transfusion-free patients (n=27) and 0.2 (0.2 - 0.4) c/dg in patients who did not achieve TI (n=4). The transfusion-free patient (β0/β0) with the lowest month 12 PB VCN was homozygous for T/T at rs7482144 (HBG2Xmn1 site) and G/G at rs10189857 (BCL11A), and heterozygous for single α-globin gene deletion. Endogenous Hb (5.9 g/dL HbF + 0.2 g/dL HbA2) and gene therapy-derived HbAT87Q (4.4 g/dL) at month 12 enabled this patient to stop transfusions. Tests of association of SNPs and mutations with TI were not significant; no p-value < 0.31 (chi-squared test). As only 4 patients did not achieve TI, the power to detect an association was limited. Larger sample sizes are needed to determine if individual SNPs and mutations may have an impact on TI. In TI or transfusion-free patients (n=27), TSS correlated strongly with month 12 endogenous unsupported Hb (HbA + HbA2 + HbF + HbE without RBC transfusions for 60 days) (correlation coeff. = -0.76, p < 0.0001), but not with HbAT87Q (correlation coeff. = 0.26, p = 0.19) or unsupported total Hb (correlation coeff. = 0.32, p = 0.10). Beti-cel-related adverse events (AE) in >1 patient were abdominal pain (n=2 non-β0/β0; n=1 β0/β0), thrombocytopenia (n=3 non-b0/b0). Serious AEs in ≥3 patients post-infusion were thrombocytopenia (n=2 non-β0/β0; n=1 β0/β0), pyrexia (n=1 non-b0/b0; n=2 β0/β0), veno-occlusive disease (n=3 non-β0/β0). Summary Genetic characterization of TDT patients treated with beti-cel revealed diverse HBB and non-HBB mutations and polymorphisms that may influence disease severity. Higher PB VCN and HbAT87Q levels were associated with increased likelihood of TI. In instances of lower HbAT87Q, higher endogenous HbF might be a determinant in whether TI is achieved. Despite genetic heterogeneity, beti-cel enabled patients to achieve TI regardless of β-thalassemia genotype, TSS, disease genetic modifiers including HBA, and HbF QTL SNP genotypes. Disclosures Walters: Veevo Biomedicine: Consultancy; AllCells, Inc: Consultancy; Editas: Consultancy. Chui:bluebird bio, Inc.: Other: Payment for lab use for the sequencing analyses done for the studies. Lal:bluebird bio, Inc.: Research Funding; Agios Pharmaceuticals: Consultancy; Celgene, BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; La Jolla Pharmaceutical Company: Research Funding; Novartis: Research Funding; Protagonist Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Terumo Corporation: Research Funding; Chiesi USA: Consultancy; Insight Magnetics: Research Funding. Locatelli:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Speakers Bureau; Medac: Speakers Bureau; Jazz Pharmaceeutical: Speakers Bureau. Kwiatkowski:bluebird bio, Inc.: Consultancy, Research Funding; Agios: Consultancy; Apopharma: Research Funding; Bristol Myers Squibb: Consultancy; Imara: Consultancy; Celgene: Consultancy; Sangamo: Research Funding; Terumo Corp: Research Funding; Novartis: Research Funding. Porter:bluebird bio, Inc.: Consultancy, Honoraria; Vifor Pharmaceuticals: Honoraria; La Jolla Pharmaceuticals: Honoraria; Protagonist Therapeutics: Honoraria; Agios Pharmaceuticals: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Silence Therapeutics: Honoraria. Thuret:Apopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis pharma: Membership on an entity's Board of Directors or advisory committees, Other: Investigator in clinical trials; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Investigator in clinical trials; bluebird bio, Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Investigator in clinical trials. Kulozik:Novartis: Consultancy, Honoraria; bluebird bio, Inc.: Consultancy, Honoraria. Thrasher:4Bio Capital: Consultancy, Membership on an entity's Board of Directors or advisory committees; Generation bio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Equity ownership; Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Equity ownership. Yannaki:bluebird bio, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Speakers Bureau; SANDOZ: Speakers Bureau; Gilead: Speakers Bureau. Yang:bluebird bio,Inc.: Current Employment, Current equity holder in publicly-traded company. Whitney:bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Petrusich:bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Colvin:bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Thompson:BMS: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; CRISPR/Vertex: Research Funding; Biomarin: Research Funding; Baxalta: Research Funding.
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- 2020
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42. Efficacy and Safety of Betibeglogene Autotemcel (beti-cel) Gene Therapy in 63 Patients with Transfusion-Dependent β-Thalassemia (TDT): 7-Year Post-Infusion Follow-up of Phase 1/2 and Phase 3 Studies
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Jennifer Schneiderman, Franco Locatelli, Alexis A. Thompson, Janet L. Kwiatkowski, John B. Porter, Suradej Hongeng, Andreas E. Kulozik, Marina Cavazzana, Martin G. Sauer, Adrian J. Thrasher, Isabelle Thuret, Ashutosh Lal, John E.J. Rasko, Evangelia Yannaki, Manfred Schmidt, Lin Du, Richard A. Colvin, and Mark C. Walters
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Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Published
- 2022
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43. Risks associated with oral deferiprone in the treatment of infratentorial superficial siderosis
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Simon F. Farmer, Yezen Sammaraiee, John B. Porter, Gargi Banerjee, David J. Werring, B. Hylton, P. Cowley, and Perla Eleftheriou
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0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Neurology ,Hemosiderosis ,Superficial siderosis ,Iron Chelating Agents ,Spinal Cord Diseases ,Sepsis ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Deferiprone ,Neuroradiology ,Aged ,Brain Diseases ,Original Communication ,business.industry ,Dural defects ,Middle Aged ,medicine.disease ,Discontinuation ,030104 developmental biology ,chemistry ,Tolerability ,Absolute neutrophil count ,Iron chelation ,Pia Mater ,Female ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Agranulocytosis ,Follow-Up Studies - Abstract
Objective Deferiprone is an iron chelator that has recently been used to treat patients with infratentorial superficial siderosis (iSS). It is considered to have a generally favourable safety profile but concerns have been raised due to the risk of agranulocytosis. We aimed to evaluate the safety and tolerability of oral deferiprone as a treatment for patients with iSS. Methods We present a case series of 10 consecutive patients presenting with classical iSS treated with deferiprone. Results Ten patients were followed up for a mean period of 2.3 years (range 0.5–5.5 years). Four patients (40%) were withdrawn from treatment because of treatment-related side effects. The reasons for treatment discontinuation were neutropenic sepsis (n = 3) and fatigue (n = 1). In 2 out of the 3 cases of neutropenic sepsis, patients initially developed neutropenia without sepsis. The mean time to neutropenic sepsis following deferiprone was 1.2 years (range 0.3–2.5) with mean neutrophil count of 0.4 (range 0.3–0.5). Six patients (60%) reported no change in neurological function while on treatment, and four patients (40%) reported that their condition deteriorated. Conclusions Deferiprone was poorly tolerated, with 40% of patients withdrawing from treatment, most commonly due to neutropenic sepsis, after an average of 2 years on treatment. This study increases the number of reported cases of agranulocytosis in patients with iSS treated with deferiprone. Clinicians treating iSS patients with deferiprone should be aware that this drug has a potentially life-threatening side effect of neutropenic sepsis, and should ensure that appropriate haematological monitoring is in place.
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- 2019
44. Decrement in Cellular Iron and Reactive Oxygen Species, and Improvement of Insulin Secretion in a Pancreatic Cell Line Using Green Tea Extract
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John B. Porter, Somdet Srichairatanakool, Evangelia Vlachodimitropoulou Koumoutsea, Suthat Fucharoen, Chairat Uthaipibull, and Pimpisid Koonyosying
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insulin ,Iron ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,green tea ,EGCG ,Green tea extract ,Pharmacology ,Redox ,Catechin ,Diabetes Complications ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Cell Line, Tumor ,Insulin-Secreting Cells ,Insulin Secretion ,Internal Medicine ,medicine ,Animals ,iron overload ,chemistry.chemical_classification ,Reactive oxygen species ,Tea ,Hepatology ,Plant Extracts ,Insulin ,beta-Thalassemia ,Rat Insulinoma ,food and beverages ,Original Articles ,Rats ,chemistry ,Cell culture ,030220 oncology & carcinogenesis ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,Ferric ,030211 gastroenterology & hepatology ,Reactive Oxygen Species ,pancreatic cell ,RINm5F ,Fetal bovine serum ,Phytotherapy ,medicine.drug - Abstract
Supplemental digital content is available in the text., Objectives We have investigated the efficacy of mono- and combined therapy with green tea extract (GTE) in mobilizing redox iron, scavenging reactive oxygen species (ROS), and improving insulin production in iron-loaded pancreatic cells. Methods Rat insulinoma pancreatic β-cells were iron-loaded using culture medium supplemented with either fetal bovine serum or ferric ammonium citrate and treated with various doses of GTE for epigallocatechin-3-gallate (EGCG) equivalence and in combination with iron chelators. Cellular iron, ROS, and secretory insulin were measured. Results The rat insulinoma pancreatic cells took up iron from fetal bovine serum more rapidly than ferric ammonium citrate. After treatment with GTE (0.23–2.29 μg EGCG equivalent), cellular levels of iron and ROS were dose dependently decreased. Importantly, secretory insulin levels were increased nearly 2.5-fold with 2.29 μg of EGCG equivalent GTE, indicating a recovery in insulin production. Conclusions Green tea EGCG ameliorated oxidative damage of iron-loaded β-cells by removing redox iron and free radicals and attenuating insulin production. The impact can result in the restoration of pancreatic functions and an increase in insulin production. Green tea extract exerts iron-chelating, free-radical scavenging, and pancreato-protective effects in the restoration of β-cell functions, all of which we believe can increase insulin production in diabetic β-thalassemia patients.
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- 2019
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45. A phase 1/2 ascending dose study and open-label extension study of voxelotor in patients with sickle cell disease
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Vincent Siu, Timothy Mant, Mira Patel, Noel Landsman, Joshua Lehrer-Graiwer, Moji Awogbade, Kobina Dufu, John B. Porter, Daniel D. Gretler, Athiwat Hutchaleelaha, Sandra V. Dixon, Claire Hemmaway, Paul Telfer, D. Mark Layton, Jo Howard, and Margaret Tonda
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Adult ,Male ,Hemolytic anemia ,medicine.medical_specialty ,Adolescent ,Maximum Tolerated Dose ,Anemia ,Immunology ,Anemia, Sickle Cell ,Placebo ,Biochemistry ,Gastroenterology ,Cohort Studies ,Young Adult ,Double-Blind Method ,Hematologic Agents ,Internal medicine ,medicine ,Humans ,Tissue Distribution ,Adverse effect ,business.industry ,Case-control study ,Cell Biology ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,Sickle cell anemia ,Tolerability ,Benzaldehydes ,Case-Control Studies ,Pyrazines ,Pyrazoles ,Female ,Hemoglobin ,business ,Follow-Up Studies - Abstract
New treatments directly targeting polymerization of sickle hemoglobin (HbS), the proximate event in the pathophysiology of sickle cell disease (SCD), are needed to address the severe morbidity and early mortality associated with the disease. Voxelotor (GBT440) is a first-in-class oral therapy specifically developed to treat SCD by modulating the affinity of hemoglobin (Hb) for oxygen, thus inhibiting HbS polymerization and downstream adverse effects of hemolytic anemia and vaso-occlusion. GBT440-001 was a phase 1/2 randomized, double-blind, placebo-controlled, single and multiple ascending dose study of voxelotor in adult healthy volunteers and patients with SCD, followed by a single-arm, open-label extension study. This report describes results of voxelotor (500-1000 mg per day) in patients with sickle cell anemia. The study evaluated the safety, tolerability, pharmacokinetic, and pharmacodynamic properties of voxelotor and established proof of concept by improving clinical measures of anemia, hemolysis, and sickling. Thirty-eight patients with SCD received 28 days of voxelotor 500, 700, or 1000 mg per day or placebo; 16 patients received 90 days of voxelotor 700 or 900 mg per day or placebo. Four patients from the 90-day cohort were subsequently enrolled in an extension study and treated with voxelotor 900 mg per day for 6 months. All patients who received multiple doses of voxelotor for ≥28 days experienced hematologic improvements including increased Hb and reduction in hemolysis and percentage of sickled red cells, supporting the potential of voxelotor to serve as a disease-modifying therapy for SCD. Voxelotor was well tolerated with no treatment-related serious adverse events and no evidence of tissue hypoxia. These trials were registered at www.clinicaltrials.gov as #NCT02285088 and #NCT03041909.
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- 2019
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46. Influence of patient‐reported outcomes on the treatment effect of deferasirox film‐coated and dispersible tablet formulations in the ECLIPSE trial: A post hoc mediation analysis
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Khawla Belhoul, Mei Sheng Duh, Vicky Huang, Raffaella Origa, John B. Porter, Silverio Perrotta, Alexandra Kouraklis, Jackie Han, Ali T. Taher, Andreas Bruederle, and Priyanka Bobbili
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Male ,medicine.medical_specialty ,Post hoc ,Medication adherence ,Iron Chelating Agents ,law.invention ,Medication Adherence ,Dispersible tablet ,Randomized controlled trial ,law ,Internal medicine ,Correspondence ,Medicine ,Humans ,Treatment effect ,Patient Reported Outcome Measures ,Eclipse ,business.industry ,Deferasirox ,E‐only Article ,Hematology ,Iron chelation therapy ,Myelodysplastic Syndromes ,Ferritins ,Thalassemia ,E‐only Articles ,Female ,business ,medicine.drug ,Tablets - Published
- 2019
47. Neuropsychological and neuroimaging characteristics of classical superficial siderosis
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Gargi Banerjee, Andreas Flores Martin, Parag Sayal, Lisa Cipolotti, Edgar Chan, Natasja van Harskamp, John B. Porter, Perla Eleftheriou, Yezen Sammaraiee, Natallia Kharytaniuk, David J. Werring, Peter Cowley, and Simon F. Farmer
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medicine.medical_specialty ,Pediatrics ,Neurology ,Ataxia ,Siderosis ,Neuroimaging ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,030212 general & internal medicine ,business.industry ,Neuropsychology ,Brain ,Middle Aged ,Executive functions ,medicine.disease ,Superficial siderosis ,Magnetic Resonance Imaging ,Hemosiderin ,Female ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Executive dysfunction ,Brain Stem - Abstract
To define the neuropsychological and neuroimaging characteristics of classical infratentorial superficial siderosis (iSS), a rare but disabling disorder defined by hemosiderin deposition affecting the superficial layers of the cerebellum, brainstem and spinal cord, usually associated with a slowly progressive neurological syndrome of deafness, ataxia and myelopathy. We present the detailed neuropsychological and neuroimaging findings in 16 patients with iSS (mean age 57 years; 6 female). Cognitive impairment was present in 8/16 (50%) of patients: executive dysfunction was the most prevalent (44%), followed by impairment of visual recognition memory (27%); other cognitive domains were largely spared. Disease symptom duration was significantly correlated with the number of cognitive domains impaired (r = 0.59, p = 0.011). Mood disorders were also common (anxiety 62%, depression 38%, both 69%) but not associated with disease symptom duration. MRI findings revealed siderosis was not only in infratentorial brain regions, but also in characteristic widespread symmetrical supratentorial brain regions, independent of disease duration and degree of cognitive impairment. The presence of small vessel disease markers was very low and did not account for the cognitive impairment observed. Neuropsychological disturbances are common in iSS and need to be routinely investigated. The lack of association between the anatomical extent of hemosiderin and cognitive impairment or disease duration suggests that hemosiderin itself is not directly neurotoxic. Additional biomarkers of iSS disease severity and progression are needed for future research and clinical trials.
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- 2021
48. Anti-Platelet Aggregation and Anti-Cyclooxygenase Activities for a Range of Coffee Extracts (Coffea arabica)
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IJ Mackie, Nuntouchaporn Hutachok, Suthat Fucharoen, Somdet Srichairatanakool, Pongsak Angkasith, John B. Porter, and Chaiwat Chumpun
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Antioxidant ,biology ,Coffea arabica ,medicine.medical_treatment ,Colorimetry (chemical method) ,chemistry.chemical_compound ,chemistry ,Chlorogenic acid ,medicine ,biology.protein ,Arachidonic acid ,Platelet activation ,Food science ,Cyclooxygenase ,Caffeine - Abstract
Coffee is rich in caffeine (CF), chlorogenic acid (CGA) and phenolics. Differing types of coffee beverages and brewing procedures may result in differences in total phenolic contents (TPC) and biological activities. Inflammation and increases of platelet activation and aggregation can lead to thrombosis. We focused on determining the chemical composition, antioxidant activity and inhibitory effects on agonist-induced platelet aggregation and cyclooxygenase (COX) of coffee beverages in relation to their preparation method. We prepared instant coffee and brewed coffee beverages using drip, espresso and boiling techniques. Coffee extracts were assayed for their CF and CGA contents using HPLC, TPC using colourimetry, platelet aggregation with an aggregometer and COX activity using ELISA. The findings have shown all coffee extracts, except the decaffeinated types, contained nearly equal amounts of CF, CGA and TPC. Inhibitory effects of coffee extracts on platelet aggregation differed depending on the activation pathways induced by different agonists. All espresso, drip and boiled coffee extracts caused dose dependent inhibition of platelet aggregation induced by ADP, collagen, epinephrine, and arachidonic acid (ARA). The most marked inhibition was seen at low doses of collagen or ARA. Espresso and drip extracts inhibited collagen-induced platelet aggregation more than purified caffeine or CGA. Espresso, boiled and drip coffee extracts were also a more potent inhibitors of COX-1 and COX-2 than purified caffeine or CGA. We conclude that inhibition of platelet aggregation and COX-1 and COX-2 may contribute to anti-platelet and anti-inflammatory effects of espresso and drip coffee extracts.
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- 2020
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49. Iron Through the Prism of Haematology
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John B, Porter
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Iron Overload ,Iron ,Disease Management ,Humans ,Disease Susceptibility ,Hemochromatosis ,Iron Chelating Agents ,Hematologic Diseases ,Biomarkers - Abstract
Since the inception of the British Society for Haematology (BSH) 60 years ago, our increased scientific understanding of iron metabolism, together with clinical developments, have changed the way we diagnose and treat its disorders. In the UK, perhaps the most notable contributions relate to iron overload, some of which I will outline from personal experience. Diagnostically, this began with the identification of serum ferritin as a marker of iron overload and continued later with the application of MRI-based imaging techniques for iron and its distribution. Therapeutically, the first trials of both parenteral and oral chelation, which have radically changed the outcomes of transfusional iron-overloaded patients, took place in the UK and are now part of standard clinical practice. During this time, our scientific understanding of iron metabolism at a cellular and systemic level have advanced the diagnosis and treatment of inherited disorders of iron metabolism. There are potential novel applications related to our recent understanding of hepcidin metabolism and manipulation.
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- 2020
50. Intravenous iron preparations transiently generate non-transferrin-bound iron from two proposed pathways
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John B. Porter, Claudio Mori, Maciej W Garbowski, Susanna Burckhardt, Sukhvinder S. Bansal, and Robert C. Hider
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Iron ,Pharmacology ,Iron sucrose ,Ferric Compounds ,Article ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Hepcidin ,Iron Isomaltoside 1000 ,medicine ,Humans ,chemistry.chemical_classification ,medicine.diagnostic_test ,biology ,Anemia, Iron-Deficiency ,Transferrin saturation ,Transferrin ,Hematology ,chemistry ,Pharmacodynamics ,Ferritins ,Serum iron ,biology.protein ,Hematinics ,030215 immunology ,medicine.drug - Abstract
Intravenous iron-carbohydrate complex preparations (IVIP) are noninterchangeable pro-drugs: their pharmacokinetics (PK) varies determined by semi-crystalline iron core and carbohydrate shell structures, influences pharmacodynamics (PD) and thus efficacy and safety. Examining PK/PD relationships of three IVIP we identify a two-pathway model of transient non-transferrin-bound iron (NTBI) generation following single dose administration. Twenty-eight hypoferremic non-anemic patients randomized to 200 mg iron as ferric carboxymaltose (Fe-carboxymaltose), iron sucrose (Fe-sucrose), iron isomaltoside 1000 (Fe-isomaltoside- 1000), n=8/arm, or placebo, n=4, on a 2-week PK/PD study, had samples analysed for total serum iron, IVIP-iron, transferrin-bound iron (TBI) by high-performance liquid chromatography in combination with inductively coupled plasma mass spectrometry (HPLC-ICP-MS), transferrin saturation (TSAT), serum ferritin (s-Ferritin) by standard methods, NTBI and hepcidin as published before. IVIP-dependent increases in these parameters returned to baseline in 48-150 hours (h), except for s-Ferritin and TSAT. NTBI was low with Fe-isomaltoside-1000 (0.13 μM at 8 h), rapidly increased with Fe-sucrose (0.8 μM at 2 h, 1.25 μM at 4 h), and delayed for Fe-carboxymaltose (0.57 μM at 24 h). NTBI area-under-curve (AUC) were 7-fold greater for Fe-carboxymaltose and Fe-sucrose than for Fe-isomaltoside-1000. Hepcidin peak time varied, but not AUC or mean levels. s-Ferritin levels and AUC were highest for Fe-carboxymaltose and greater than placebo for all IVIP. We propose two mechanisms for the observed NTBI kinetics: rapid and delayed NTBI appearance consistent with direct (circulating IVIP-to-plasma) and indirect (IVIP-to-macrophage-to-plasma) iron release based on IVIP plasma half-life and s-Ferritin dynamics. IVIP generate different, broadly stability- and PK-dependent, NTBI and s-Ferritin signatures, which may influence iron bioavailability, efficacy and safety. Longer-term studies should link NTBI exposure to subsequent safety and efficacy parameters and potential clinical consequences.
- Published
- 2020
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