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1
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Kaberi-Otarod J, Still CD, Wood GC, Benotti PN. Iron Treatment in Patients with Iron Deficiency Before and After Metabolic and Bariatric Surgery: A Narrative Review. Nutrients 2024; 16:3350. [PMID: 39408317 PMCID: PMC11478352 DOI: 10.3390/nu16193350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 09/27/2024] [Accepted: 09/30/2024] [Indexed: 10/20/2024] Open
Abstract
Iron is an essential nutrient in living organisms with multiple vital functions. Iron deficiency (ID) can cause long term health consequences beyond iron deficiency anemia (IDA). The high prevalence of ID and its long-term effects in patients with obesity and after metabolic and bariatric surgery (MBS) is recognized. Nevertheless, there is limited knowledge of the optimal route or dose for treatment of patients with obesity and post-MBS, and an evidence-based universal guideline for prevention and treatment of ID in short- and long-term post-MBS (PMBS) is not yet available. ID in the general population is currently treated with oral or parenteral iron, where oral iron treatment is considered the preferred option with parenteral iron as a second-line treatment in case there is intolerance or lack of response to oral iron. In patients with obesity with chronic low-grade inflammation and PMBS patients with altered gut anatomy and function, there are also alterations in the bioavailability and higher risks of side effects of available oral irons. The conclusions of current studies exploring effective treatment of iron deficiency in this population have been inconsistent and further well-planned randomized and prospective studies are needed. This is a narrative review of the literature on the available treatment options and strategies for treatment of ID in PMBS patients to recognize the knowledge gaps and provides topics of future research.
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Affiliation(s)
- Jila Kaberi-Otarod
- Department of Nutrition and Weight Management, Geisinger Health System Northeast, Scranton, PA 18503, USA
| | - Christopher D. Still
- The Center for Obesity and Metabolic Research, Geisinger Obesity Institute, Danville, PA 17821, USA; (C.D.S.); (G.C.W.); (P.N.B.)
| | - G. Craig Wood
- The Center for Obesity and Metabolic Research, Geisinger Obesity Institute, Danville, PA 17821, USA; (C.D.S.); (G.C.W.); (P.N.B.)
| | - Peter N. Benotti
- The Center for Obesity and Metabolic Research, Geisinger Obesity Institute, Danville, PA 17821, USA; (C.D.S.); (G.C.W.); (P.N.B.)
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2
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Stratmann K, Hentschel V, Zeuzem S, Blumenstein I, Klaus J. [Iron supplementation in patients with chronic inflammatory bowel disease: recommendations for a practical approach]. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:1389-1396. [PMID: 38657618 DOI: 10.1055/a-2274-1610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/26/2024]
Abstract
Iron deficiency is the predominant cause of anemia. Iron deficiency anemia plays a major role, especially in patients with inflammatory bowel disease (IBD), and is the most common extraintestinal manifestation and IBD-associated systemic complication. The presence of anemia leads to a reduction in quality of life in patients with IBD associated with limitations in physical, emotional, and cognitive function. In addition, it is associated with an increased hospitalization rate. For this reason, iron supplementation is of particular importance. Oral and intravenous iron supplements are used to treat iron deficiency. Due to the lack of absorption and gastrointestinal side effects of oral substitution, intravenous supplementation is becoming increasingly important. However, there are still certain concerns about intravenous administration.With the help of this review, we want to address the topic of iron substitution in patients with IBD, summarize current guideline recommendations, and provide a practical approach.
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Affiliation(s)
- Katharina Stratmann
- Universitätsklinikum, Medizinische Klinik 1, Goethe-Universität Frankfurt, Frankfurt am Main, Germany
| | | | - Stefan Zeuzem
- Universitätsklinikum, Medizinische Klinik 1, Goethe-Universität Frankfurt, Frankfurt am Main, Germany
| | - Irina Blumenstein
- Universitätsklinikum, Medizinische Klinik 1, Goethe-Universität Frankfurt, Frankfurt am Main, Germany
| | - Jochen Klaus
- Klinik für Innere Medizin 1, Universitätsklinikum Ulm, Ulm, Germany
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3
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Pantopoulos K. Oral iron supplementation: new formulations, old questions. Haematologica 2024; 109:2790-2801. [PMID: 38618666 PMCID: PMC11367235 DOI: 10.3324/haematol.2024.284967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Indexed: 04/16/2024] Open
Abstract
Iron-deficiency anemia and pre-anemic iron deficiency are the most frequent pathologies. The first line of treatment involves oral iron supplementation. The simplest, least expensive, and most commonly prescribed drug is ferrous sulfate, while other ferrous salts and ferric complexes with polysaccharides or succinylated milk proteins are also widely used. In recent years, novel iron formulations have been developed, such as the lipophilic iron donor ferric maltol, or nanoparticle encapsulated sucrosomial® iron. Oral iron supplementation is usually efficacious in correcting iron-deficiency anemia and replenishing iron stores but causes gastrointestinal side effects that reduce compliance. When oral iron supplementation is contraindicated, intravenous iron therapy can rapidly achieve therapeutic targets without gastrointestinal complications. Herein, we critically review literature on relative efficacy and tolerability of currently available oral iron supplements, and summarize recent data on optimal dosage and frequency.
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Affiliation(s)
- Kostas Pantopoulos
- Lady Davis Institute for Medical Research, Jewish General Hospital, and Department of Medicine, McGill University, Montreal, Quebec.
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4
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Kontoghiorghes GJ. The Importance and Essentiality of Natural and Synthetic Chelators in Medicine: Increased Prospects for the Effective Treatment of Iron Overload and Iron Deficiency. Int J Mol Sci 2024; 25:4654. [PMID: 38731873 PMCID: PMC11083551 DOI: 10.3390/ijms25094654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 04/19/2024] [Accepted: 04/22/2024] [Indexed: 05/13/2024] Open
Abstract
The supply and control of iron is essential for all cells and vital for many physiological processes. All functions and activities of iron are expressed in conjunction with iron-binding molecules. For example, natural chelators such as transferrin and chelator-iron complexes such as haem play major roles in iron metabolism and human physiology. Similarly, the mainstay treatments of the most common diseases of iron metabolism, namely iron deficiency anaemia and iron overload, involve many iron-chelator complexes and the iron-chelating drugs deferiprone (L1), deferoxamine (DF) and deferasirox. Endogenous chelators such as citric acid and glutathione and exogenous chelators such as ascorbic acid also play important roles in iron metabolism and iron homeostasis. Recent advances in the treatment of iron deficiency anaemia with effective iron complexes such as the ferric iron tri-maltol complex (feraccru or accrufer) and the effective treatment of transfusional iron overload using L1 and L1/DF combinations have decreased associated mortality and morbidity and also improved the quality of life of millions of patients. Many other chelating drugs such as ciclopirox, dexrazoxane and EDTA are used daily by millions of patients in other diseases. Similarly, many other drugs or their metabolites with iron-chelation capacity such as hydroxyurea, tetracyclines, anthracyclines and aspirin, as well as dietary molecules such as gallic acid, caffeic acid, quercetin, ellagic acid, maltol and many other phytochelators, are known to interact with iron and affect iron metabolism and related diseases. Different interactions are also observed in the presence of essential, xenobiotic, diagnostic and theranostic metal ions competing with iron. Clinical trials using L1 in Parkinson's, Alzheimer's and other neurodegenerative diseases, as well as HIV and other infections, cancer, diabetic nephropathy and anaemia of inflammation, highlight the importance of chelation therapy in many other clinical conditions. The proposed use of iron chelators for modulating ferroptosis signifies a new era in the design of new therapeutic chelation strategies in many other diseases. The introduction of artificial intelligence guidance for optimal chelation therapeutic outcomes in personalised medicine is expected to increase further the impact of chelation in medicine, as well as the survival and quality of life of millions of patients with iron metabolic disorders and also other diseases.
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Affiliation(s)
- George J Kontoghiorghes
- Postgraduate Research Institute of Science, Technology, Environment and Medicine, Limassol 3021, Cyprus
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5
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Zhang T, Luo L, He Q, Xiao S, Li Y, Chen J, Qin T, Xiao Z, Ge Q. Research advances on molecular mechanism and natural product therapy of iron metabolism in heart failure. Eur J Med Res 2024; 29:253. [PMID: 38659000 PMCID: PMC11044586 DOI: 10.1186/s40001-024-01809-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 03/22/2024] [Indexed: 04/26/2024] Open
Abstract
The progression of heart failure (HF) is complex and involves multiple regulatory pathways. Iron ions play a crucial supportive role as a cofactor for important proteins such as hemoglobin, myoglobin, oxidative respiratory chain, and DNA synthetase, in the myocardial energy metabolism process. In recent years, numerous studies have shown that HF is associated with iron dysmetabolism, and deficiencies in iron and overload of iron can both lead to the development of various myocarditis diseases, which ultimately progress to HF. Iron toxicity and iron metabolism may be key targets for the diagnosis, treatment, and prevention of HF. Some iron chelators (such as desferrioxamine), antioxidants (such as ascorbate), Fer-1, and molecules that regulate iron levels (such as lactoferrin) have been shown to be effective in treating HF and protecting the myocardium in multiple studies. Additionally, certain natural compounds can play a significant role by mediating the imbalance of iron-related signaling pathways and expression levels. Therefore, this review not only summarizes the basic processes of iron metabolism in the body and the mechanisms by which they play a role in HF, with the aim of providing new clues and considerations for the treatment of HF, but also summarizes recent studies on natural chemical components that involve ferroptosis and its role in HF pathology, as well as the mechanisms by which naturally occurring products regulate ferroptosis in HF, with the aim of providing reference information for the development of new ferroptosis inhibitors and lead compounds for the treatment of HF in the future.
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Affiliation(s)
- Tianqing Zhang
- Department of Cardiology, Changde Hospital, Xiangya School of Medicine, Central South University, Hunan, China
| | - Li Luo
- Department of Cardiology, Changde Hospital, Xiangya School of Medicine, Central South University, Hunan, China
| | - Qi He
- People's Hospital of Ningxiang City, Ningxiang City, China
| | - Sijie Xiao
- Department of Cardiology, Changde Hospital, Xiangya School of Medicine, Central South University, Hunan, China
| | - Yuwei Li
- Department of Cardiology, Changde Hospital, Xiangya School of Medicine, Central South University, Hunan, China
| | - Junpeng Chen
- Department of Cardiology, Changde Hospital, Xiangya School of Medicine, Central South University, Hunan, China
| | - Tao Qin
- Department of Cardiology, Changde Hospital, Xiangya School of Medicine, Central South University, Hunan, China
| | - Zhenni Xiao
- Department of Cardiology, Changde Hospital, Xiangya School of Medicine, Central South University, Hunan, China
| | - Qingliang Ge
- Department of Cardiology, Changde Hospital, Xiangya School of Medicine, Central South University, Hunan, China.
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6
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Su Z, Du T, Feng J, Wang J, Zhang W. Clinically Approved Ferric Maltol: A Potent Nanozyme with Added Effect for High-Efficient Catalytic Disinfection. ACS APPLIED MATERIALS & INTERFACES 2024; 16:11251-11262. [PMID: 38394459 DOI: 10.1021/acsami.3c17758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/25/2024]
Abstract
Nanozyme has been proven to be an attractive and promising candidate to alleviate the current pressing medical problems. However, the unknown clinical safety and limited function beyond the catalysis of the most reported nanozymes cannot promise an ideal therapeutic outcome in further clinical application. Herein, we find that ferric maltol (FM), a clinically approved iron supplement synthesized through a facile scalable method, exhibits excellent peroxidase-like activity than natural horseradish peroxidase-like (HRP) and commonly reported Fe-based nanozymes, and also shows high antibacterial performance for methicillin-resistant Staphylococcus aureus (MRSA) elimination (100%) and wound disinfection. In addition, with added effects inherited from contained maltol, FM can accelerate skin barrier recovery. Therefore, the exploration of FM as a safe and desired nanozyme provides a timely alternative to current antibiotic therapy against drug-resistant bacteria.
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Affiliation(s)
- Zehui Su
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Ting Du
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Jianxing Feng
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Jianlong Wang
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Wentao Zhang
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi 712100, China
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7
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Gordon H, Burisch J, Ellul P, Karmiris K, Katsanos K, Allocca M, Bamias G, Barreiro-de Acosta M, Braithwaite T, Greuter T, Harwood C, Juillerat P, Lobaton T, Müller-Ladner U, Noor N, Pellino G, Savarino E, Schramm C, Soriano A, Michael Stein J, Uzzan M, van Rheenen PF, Vavricka SR, Vecchi M, Zuily S, Kucharzik T. ECCO Guidelines on Extraintestinal Manifestations in Inflammatory Bowel Disease. J Crohns Colitis 2024; 18:1-37. [PMID: 37351850 DOI: 10.1093/ecco-jcc/jjad108] [Citation(s) in RCA: 45] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Indexed: 06/24/2023]
Affiliation(s)
- Hannah Gordon
- Department of Gastroenterology, Barts Health NHS Trust, London, Centre for Immunobiology, Blizard Institute, Faculty of Medicine, Barts & The London Medical School, Queen Mary University of London, UK
| | - Johan Burisch
- Gastrounit, medical division, Hvidovre Hospital, University of Copenhagen, Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults, Hvidovre Hospital, University of Copenhagen, Denmark
| | - Pierre Ellul
- Department of Medicine, Division of Gastroenterology, Mater Dei Hospital, Msida, Malta
| | | | - Konstantinos Katsanos
- Department of Gastroenterology and Hepatology, Division of Internal Medicine, University and Medical School of Ioannina, Ioannina, Greece
| | - Mariangela Allocca
- Department of Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Milan, Italy
| | - Giorgos Bamias
- GI Unit, 3rd Academic Department of Internal Medicine, National and Kapodistrian University of Athens, Sotiria Hospital, Athens, Greece
| | - Manuel Barreiro-de Acosta
- University Hospital Santiago De Compostela CHUS, Department of Gastroenterology - IBD Unit, Santiago De Compostela, Spain
| | - Tasanee Braithwaite
- School of Immunology and Microbiology, King's College London, The Medical Eye Unit, Guy's and St Thomas' Hospital NHS Foundation Trust, London, UK
| | - Thomas Greuter
- Division of Gastroenterology and Hepatology, GZO - Zurich Regional Health Center, Wetzikon, Division of Gastroenterology and Hepatology, University Hospital Lausanne - CHUV, Lausanne, Switzerland; Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Catherine Harwood
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London; Department of Dermatology, Royal London Hospital, Barts Health NHS Trust, London, UK
| | - Pascal Juillerat
- Gastroenterology, Clinic for Visceral Surgery and Medicine, Bern University Hospital, Bern, Switzerland; Crohn and Colitis Center, Gastro-entérologie Beaulieu SA, Lausanne, Switzerland
| | - Triana Lobaton
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent; Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium
| | - Ulf Müller-Ladner
- Department of Rheumatology and Clinical Immunology, Campus Kerckhoff, Justus Liebig University Giessen, Bad Nauheim, Germany
| | - Nurulamin Noor
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Gianluca Pellino
- Vall d'Hebron University Hospital, Universitat Autonoma de Barcelona UAB, Barcelona, Spain; Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania 'Luigi Vanvitelli', Naples, Italy
| | - Edoardo Savarino
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy; Gastroenterology Unit, Azienda Ospedale Università di Padova, Padua, Italy
| | - Christoph Schramm
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Alessandra Soriano
- Gastroenterology Division and IBD Center, Internal Medicine Department, Azienda Unità Sanitaria Locale - IRCCS, 42122 Reggio Emilia, Italy
| | - Jürgen Michael Stein
- Interdisciplinary Crohn Colitis Centre Rhein-Main, Frankfurt/Main, Department of Gastroenterology and Clinical Nutrition, DGD Clinics Sachsenhausen, Frankfurt/Main, Germany
| | - Mathieu Uzzan
- Department of Gastroenterology, Hôpital Henri Mondor, APHP, Créteil, France
| | - Patrick F van Rheenen
- Department of Paediatric Gastroenterology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Stephan R Vavricka
- Department of Gastroenterology and Hepatology, University Hospital, Zurich, Switzerland
| | - Maurizio Vecchi
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Stephane Zuily
- Vascular Medicine Division and French Referral Center for Rare Auto-Immune Diseases, Université de Lorraine, INSERM, DCAC and CHRU-Nancy, Nancy, France
| | - Torsten Kucharzik
- Department of Gastroenterology, Lüneburg Hospital, University of Münster, Lüneburg, Germany
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8
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Cai Z, Guo H, Zhou Q, Zhao S, Ding L. Simultaneous determination of maltol and maltol glucuronide in human plasma and urine by HPLC-MS/MS: Application in clinical study in patients with iron deficiency. J Chromatogr B Analyt Technol Biomed Life Sci 2023; 1225:123760. [PMID: 37270862 DOI: 10.1016/j.jchromb.2023.123760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 05/08/2023] [Accepted: 05/14/2023] [Indexed: 06/06/2023]
Abstract
Ferric maltol has been used as an oral drug for iron deficiency. This study developed and fully validated the novel HPLC-MS/MS methods to determine maltol and maltol glucuronide simultaneously in plasma and urine. The protein precipitation was performed by addition of acetonitrile in the plasma samples. The dilution was performed for the urine samples to reach the suitable concentrations for injection. The multiple reaction monitoring (MRM) with an electrospray ionization (ESI) positive ion detection mode was used for the quantification. The maltol concentration linear ranges were 6.00-150 ng/mL and 0.100-10.0 μg/mL for the plasma and urine samples, respectively. The maltol glucuronide concentration linear ranges were 50.0-15000 ng/mL and 2.00-2000 μg/mL for the plasma and urine samples, respectively. These methods were applied to a single dose clinical study at a dose of 60 mg ferric maltol capsule in the patients with iron deficiency. The half-lives of maltol and maltol glucuronide were 0.90 ± 0.40 h and 1.02 ± 0.25 h in the iron deficiency patients, respectively. 39.52 ± 7.11 % maltol were excreted in urine in the form of maltol glucuronide.
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Affiliation(s)
- Zhengwen Cai
- Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, China
| | - Haifang Guo
- Department of Clinical Pharmacology, Jiangsu Aosaikang Pharmaceutical Co. Ltd, Nanjing, China
| | - Qiaoyun Zhou
- Nanjing Clinical Tech. Laboratories Inc, Nanjing, China
| | - Shunbo Zhao
- Nanjing Clinical Tech. Laboratories Inc, Nanjing, China
| | - Li Ding
- Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, China; Nanjing Clinical Tech. Laboratories Inc, Nanjing, China.
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9
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Kontoghiorghes GJ. Deferiprone and Iron-Maltol: Forty Years since Their Discovery and Insights into Their Drug Design, Development, Clinical Use and Future Prospects. Int J Mol Sci 2023; 24:ijms24054970. [PMID: 36902402 PMCID: PMC10002863 DOI: 10.3390/ijms24054970] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 02/24/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023] Open
Abstract
The historical insights and background of the discovery, development and clinical use of deferiprone (L1) and the maltol-iron complex, which were discovered over 40 years ago, highlight the difficulties, complexities and efforts in general orphan drug development programs originating from academic centers. Deferiprone is widely used for the removal of excess iron in the treatment of iron overload diseases, but also in many other diseases associated with iron toxicity, as well as the modulation of iron metabolism pathways. The maltol-iron complex is a recently approved drug used for increasing iron intake in the treatment of iron deficiency anemia, a condition affecting one-third to one-quarter of the world's population. Detailed insights into different aspects of drug development associated with L1 and the maltol-iron complex are revealed, including theoretical concepts of invention; drug discovery; new chemical synthesis; in vitro, in vivo and clinical screening; toxicology; pharmacology; and the optimization of dose protocols. The prospects of the application of these two drugs in many other diseases are discussed under the light of competing drugs from other academic and commercial centers and also different regulatory authorities. The underlying scientific and other strategies, as well as the many limitations in the present global scene of pharmaceuticals, are also highlighted, with an emphasis on the priorities for orphan drug and emergency medicine development, including the roles of the academic scientific community, pharmaceutical companies and patient organizations.
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Affiliation(s)
- George J Kontoghiorghes
- Postgraduate Research Institute of Science, Technology, Environment and Medicine, Limassol 3021, Cyprus
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10
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Maas LA, Krishna M, Parian AM. Ironing It All Out: A Comprehensive Review of Iron Deficiency Anemia in Inflammatory Bowel Disease Patients. Dig Dis Sci 2023; 68:357-369. [PMID: 35930123 DOI: 10.1007/s10620-022-07599-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 06/10/2022] [Indexed: 12/09/2022]
Abstract
Iron deficiency anemia affects approximately 45% of patients with inflammatory bowel disease (IBD), negatively impacts the quality of life in this patient population, and significantly burdens our healthcare system. The pathogenesis of iron deficiency in IBD patients is multifactorial, including intestinal bleeding, malabsorption, and inadequate oral intake. Regular screening and diagnosis in these patients are imperative, and often patients have mixed iron deficiency anemia and anemia of chronic disease, especially in those with active inflammation. Iron may be replenished either orally or intravenously. While oral iron is safe, affordable, and easy to administer, patients often suffer from intolerable gastrointestinal side effects, and particularly in IBD patients, oral iron may increase inflammation and contribute to flares. Therefore, although it is substantially underused, intravenous (IV) iron is considered first-line treatment for patients with active disease, severe anemia, oral iron intolerance, and erythropoietin requirements. Several IV iron formulations are available, and iron sucrose and ferric carboxymaltose are the most frequently used and well studied in patients with IBD. However, iron isomaltoside could potentially become a popular choice among providers given its safety, efficacy, and convenience. Overall, screening, diagnosis, and treatment of iron deficiency anemia are important in patients with IBD. Individual patient characteristics, risks, and benefits, and advantages and disadvantages, should be considered when determining the best route and formulation for iron repletion.
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11
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Howaldt S, Domènech E, Martinez N, Schmidt C, Bokemeyer B. Long-Term Effectiveness of Oral Ferric Maltol vs Intravenous Ferric Carboxymaltose for the Treatment of Iron-Deficiency Anemia in Patients With Inflammatory Bowel Disease: A Randomized Controlled Noninferiority Trial. Inflamm Bowel Dis 2022; 28:373-384. [PMID: 33988236 PMCID: PMC8889281 DOI: 10.1093/ibd/izab073] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND Iron-deficiency anemia is common in inflammatory bowel disease, requiring oral or intravenous iron replacement therapy. Treatment with standard oral irons is limited by poor absorption and gastrointestinal toxicity. Ferric maltol is an oral iron designed for improved absorption and tolerability. METHODS In this open-label, phase 3b trial (EudraCT 2015-002496-26 and NCT02680756), adults with nonseverely active inflammatory bowel disease and iron-deficiency anemia (hemoglobin, 8.0-11.0/12.0 g/dL [women/men]; ferritin, <30 ng/mL/<100 ng/mL with transferrin saturation <20%) were randomized to oral ferric maltol 30 mg twice daily or intravenous ferric carboxymaltose given according to each center's standard practice. The primary endpoint was a hemoglobin responder rate (≥2 g/dL increase or normalization) at week 12, with a 20% noninferiority limit in the intent-to-treat and per-protocol populations. RESULTS For the intent-to-treat (ferric maltol, n = 125/ferric carboxymaltose, n = 125) and per-protocol (n = 78/88) analyses, week 12 responder rates were 67% and 68%, respectively, for ferric maltol vs 84% and 85%, respectively, for ferric carboxymaltose. As the confidence intervals crossed the noninferiority margin, the primary endpoint was not met. Mean hemoglobin increases at weeks 12, 24, and 52 were 2.5 vs 3.0 g/dL, 2.9 vs 2.8 g/dL, and 2.7 vs 2.8 g/dL with ferric maltol vs ferric carboxymaltose. Treatment-emergent adverse events occurred in 59% and 36% of patients, respectively, and resulted in treatment discontinuation in 10% and 3% of patients, respectively. CONCLUSIONS Ferric maltol achieved clinically relevant increases in hemoglobin but did not show noninferiority vs ferric carboxymaltose at week 12. Both treatments had comparable long-term effectiveness for hemoglobin and ferritin over 52 weeks and were well tolerated.
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Affiliation(s)
| | - Eugeni Domènech
- Gastroenterology and Hepatology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Catalonia, and Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | | | - Carsten Schmidt
- Department of Gastroenterology, Hepatology, Endocrinology, Diabetology, and Infectious Diseases, Klinikum Fulda, Fulda, Germany
| | - Bernd Bokemeyer
- Gastroenterology Practice Minden and University Hospital Schleswig-Holstein, Campus Kiel, Clinic for Internal Medicine I, Kiel, Germany
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12
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Kumar A, Sharma E, Marley A, Samaan MA, Brookes MJ. Iron deficiency anaemia: pathophysiology, assessment, practical management. BMJ Open Gastroenterol 2022; 9:e000759. [PMID: 34996762 PMCID: PMC8744124 DOI: 10.1136/bmjgast-2021-000759] [Citation(s) in RCA: 76] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 12/20/2021] [Indexed: 02/07/2023] Open
Abstract
The WHO has recognised iron deficiency anaemia (IDA) as the most common nutritional deficiency in the world, with 30% of the population being affected with this condition. Although the most common causes of IDA are gastrointestinal bleeding and menstruation in women, decreased dietary iron and decreased iron absorption are also culpable causes. Patients with IDA should be treated with the aim of replenishing iron stores and returning the haemoglobin to a normal level. This has shown to improve quality of life, morbidity, prognosis in chronic disease and outcomes in pregnancy. Iron deficiency occurs in many chronic inflammatory conditions, including congestive cardiac failure, chronic kidney disease and inflammatory bowel disease. This article will provide an updated overview on diagnosis and management of IDA in patients with chronic conditions, preoperative and in pregnancy. We will discuss the benefits and limitations of oral versus intravenous iron replacement in each cohort, with an overview on cost analysis between the different iron formulations currently on the market.
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Affiliation(s)
- Aditi Kumar
- Department of Gastroenterology, The Royal Wolverhampton NHS Trust, Wolverhampton, UK
| | - Esha Sharma
- Inflammatory Bowel Disease Unit, Guys and St Thomas' NHS Foundation Trust, London, UK
| | - Alexandra Marley
- Department of Gastroenterology, The Royal Wolverhampton NHS Trust, Wolverhampton, UK
| | - Mark A Samaan
- Inflammatory Bowel Disease Unit, Guys and St Thomas' NHS Foundation Trust, London, UK
| | - Matthew James Brookes
- Department of Gastroenterology, The Royal Wolverhampton NHS Trust, Wolverhampton, UK
- Research Institue, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton, UK
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Snook J, Bhala N, Beales ILP, Cannings D, Kightley C, Logan RP, Pritchard DM, Sidhu R, Surgenor S, Thomas W, Verma AM, Goddard AF. British Society of Gastroenterology guidelines for the management of iron deficiency anaemia in adults. Gut 2021; 70:2030-2051. [PMID: 34497146 PMCID: PMC8515119 DOI: 10.1136/gutjnl-2021-325210] [Citation(s) in RCA: 137] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 07/26/2021] [Indexed: 12/12/2022]
Abstract
Iron deficiency anaemia (IDA) is a major cause of morbidity and burden of disease worldwide. It can generally be diagnosed by blood testing and remedied by iron replacement therapy (IRT) using the oral or intravenous route. The many causes of iron deficiency include poor dietary intake and malabsorption of dietary iron, as well as a number of significant gastrointestinal (GI) pathologies. Because blood is iron-rich it can result from chronic blood loss, and this is a common mechanism underlying the development of IDA-for example, as a consequence of menstrual or GI blood loss.Approximately a third of men and postmenopausal women presenting with IDA have an underlying pathological abnormality, most commonly in the GI tract. Therefore optimal management of IDA requires IRT in combination with appropriate investigation to establish the underlying cause. Unexplained IDA in all at-risk individuals is an accepted indication for fast-track secondary care referral in the UK because GI malignancies can present in this way, often in the absence of specific symptoms. Bidirectional GI endoscopy is the standard diagnostic approach to examination of the upper and lower GI tract, though radiological scanning is an alternative in some situations for assessing the large bowel. In recurrent or refractory IDA, wireless capsule endoscopy plays an important role in assessment of the small bowel.IDA may present in primary care or across a range of specialties in secondary care, and because of this and the insidious nature of the condition it has not always been optimally managed despite the considerable burden of disease- with investigation sometimes being inappropriate, incorrectly timed or incomplete, and the role of IRT for symptom relief neglected. It is therefore important that contemporary guidelines for the management of IDA are available to all clinicians. This document is a revision of previous British Society of Gastroenterology guidelines, updated in the light of subsequent evidence and developments.
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Affiliation(s)
- Jonathon Snook
- Gastroenterology, University Hospitals Dorset NHS Foundation Trust, Poole, UK
| | - Neeraj Bhala
- Gastroenterology, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust and Institute of Applied Health Research, University of Birmingham, Birmingham, UK
| | - Ian L P Beales
- Gastroenterology, University of East Anglia, Norwich, UK
| | - David Cannings
- Gastroenterology, University Hospitals Dorset NHS Foundation Trust, Poole, UK
| | - Chris Kightley
- Digestive Diseases, Kettering General Hospital NHS Foundation Trust, Kettering, UK
| | | | - D Mark Pritchard
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool and Department of Gastroenterology, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK
| | - Reena Sidhu
- Gastroenterology, Royal Hallamshire Hospital, Sheffield, UK
| | - Sue Surgenor
- Gastroenterology, University Hospitals Dorset NHS Foundation Trust, Poole, UK
| | - Wayne Thomas
- Haematology, Plymouth Hospitals NHS Foundation Trust, Plymouth, Plymouth, UK
| | - Ajay M Verma
- Digestive Diseases, Kettering General Hospital NHS Foundation Trust, Kettering, UK
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Schmidt C, Allen S, Kopyt N, Pergola P. Iron Replacement Therapy with Oral Ferric Maltol: Review of the Evidence and Expert Opinion. J Clin Med 2021; 10:4448. [PMID: 34640466 PMCID: PMC8509126 DOI: 10.3390/jcm10194448] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/20/2021] [Accepted: 09/23/2021] [Indexed: 02/06/2023] Open
Abstract
Iron deficiency is the most common cause of anemia globally and is frequently reported in patients with underlying inflammatory conditions, such as inflammatory bowel disease (IBD) and chronic kidney disease (CKD). Ferric maltol is a new oral iron replacement therapy designed to optimize iron absorption while reducing the gastrointestinal adverse events associated with unabsorbed free iron. Ferric maltol has been studied in clinical trials involving almost 750 adults and adolescents with iron-deficiency anemia associated with IBD, CKD, and other underlying conditions, and it has been widely used in clinical practice. It is approved for the treatment of adults with iron deficiency with or without anemia, independent of the underlying condition, and is commercially available in Europe and the United States. We review the published evidence for ferric maltol, which demonstrates consistent and clinically meaningful improvements in hemoglobin and measures of iron availability (ferritin and transferrin saturation) and shows that it is well-tolerated over long-term treatment for up to 64 weeks-an important consideration in patients with chronic underlying conditions such as IBD and CKD. We believe that ferric maltol is an effective, convenient, and well-tolerated treatment option for iron deficiency and iron-deficiency anemia, especially when long-term management of chronic iron deficiency is required. Writing support was provided by Shield Therapeutics (Gateshead, UK).
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Affiliation(s)
- Carsten Schmidt
- Medical Clinic II, Department of Gastroenterology, Hepatology, Endocrinology, Diabetology and Infectious Diseases, Klinikum Fulda, Pacelliallee 4, 36043 Fulda, Germany
- Medical Faculty, Friedrich Schiller University, 07747 Jena, Germany
| | - Stephen Allen
- Department of Clinical Sciences, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK;
| | - Nelson Kopyt
- Department of Medicine, Division of Nephrology, Lehigh Valley Hospital, 1230 S Cedar Crest Boulevard, Suite 301, Allentown, PA 18103, USA;
| | - Pablo Pergola
- Renal Associates PA, 1123 N Main Av., Suite 120, San Antonio, TX 78212, USA;
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Allen S, Auth MKH, Kim JJ, Vadamalayan B. Safety, Tolerability, and Pharmacokinetics of Oral Ferric Maltol in Children With Iron Deficiency: Phase 1 Study. JPGN REPORTS 2021; 2:e090. [PMID: 37205968 PMCID: PMC10191551 DOI: 10.1097/pg9.0000000000000090] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Accepted: 04/20/2021] [Indexed: 05/21/2023]
Abstract
Iron deficiency is common in children and can have negative effects on behavior and function. Standard oral ferrous iron replacement is poorly absorbed and can cause treatment-limiting gastrointestinal adverse events (AEs). Ferric maltol is formulated to improve gastrointestinal absorption and tolerability versus oral ferrous compounds. In adult phase 3 trials, it increased hemoglobin and iron stores versus placebo, with a gastrointestinal AE profile similar to placebo. Here, we assess different doses of ferric maltol in children with iron deficiency. Methods This phase 1 trial involved children of age 10 to 17 years with ferritin <30 µg/L (or <50 µg/L with transferrin saturation [TSAT] <20%). Children were randomized 1:1:1 to oral ferric maltol 7.8 mg, 16.6 mg, or 30 mg twice daily for 9 days and once on day 10. The primary outcomes were iron uptake measures (serum iron and TSAT) and population pharmacokinetic analyses. Results The trial included 37 children (mean age 14.0 years; baseline mean ± standard deviation ferritin 16.3 ± 8.02 µg/L). Ferric maltol increased iron uptake nondose-proportionally: serum iron and TSAT plateaued between the 2 higher doses on day 1 and were comparable across all doses on day 10. Twenty children (54%) experienced AEs (all mild/moderate, gastrointestinal 32%), with similar frequencies in each group. Conclusions All 3 ferric maltol doses increased iron uptake in children with iron deficiency, even over the short study duration, and were well tolerated. Nondose-dependent changes in serum iron and TSAT indicate physiologic regulation of iron uptake to meet the body's needs.
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Affiliation(s)
- Stephen Allen
- From the Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK
- Department of Paediatric Gastroenterology, Hepatology and Nutrition, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK
| | - Marcus Karl-Heinz Auth
- Department of Paediatric Gastroenterology, Hepatology and Nutrition, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK
- Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK
| | - Jon Jin Kim
- Department of Paediatric Nephrology, Nottingham Children’s Hospital, Nottingham, UK
| | - Babu Vadamalayan
- Paediatric Gastroenterology and Nutrition Service, King’s College Hospital NHS Foundation Trust, London, UK
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Pergola PE, Kopyt NP. Oral Ferric Maltol for the Treatment of Iron-Deficiency Anemia in Patients With CKD: A Randomized Trial and Open-Label Extension. Am J Kidney Dis 2021; 78:846-856.e1. [PMID: 34029682 DOI: 10.1053/j.ajkd.2021.03.020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 03/05/2021] [Indexed: 02/08/2023]
Abstract
RATIONALE & OBJECTIVE Iron-deficiency anemia is common in patients with chronic kidney disease (CKD) not requiring kidney replacement therapy (KRT). We evaluated effects of oral iron replacement therapy with ferric maltol in these patients. STUDY DESIGN Phase 3, double-blind, randomized, placebo-controlled trial (AEGIS-CKD) and open-label extension. SETTING & PARTICIPANTS Adults with stage 3 or 4 CKD and iron-deficiency anemia at 30 US centers. INTERVENTION Oral ferric maltol at 30mg or placebo twice daily for 16 weeks (2:1 randomization) followed by ferric maltol at 30mg twice daily for up to 36 weeks (all patients). OUTCOME Change from baseline in hemoglobin (primary end point at week 16), ferritin, transferrin saturation, and serum iron; safety. RESULTS 167 patients were randomized (ferric maltol, n=111; placebo, n=56). At week 16, hemoglobin had increased significantly with ferric maltol versus placebo (least-squares mean difference: 0.5±0.2 [SE] g/dL; 95% CI, 0.1-0.9; P=0.01). Ferritin, transferrin saturation, and serum iron increased with ferric maltol but declined with placebo (all P<0.05). Hemoglobin levels were sustained up to week 52 in patients continuing ferric maltol and increased in patients switching from placebo to ferric maltol. The most frequent adverse events were gastrointestinal (randomized phase: 41% vs 30% [ferric maltol vs placebo]; open-label phase: 56% vs 46%, respectively). Adverse events led to treatment withdrawal in 7 patients (6%) receiving ferric maltol and 5 patients (9%) receiving placebo during double-blind treatment, and 11 patients (9%) during the open-label extension. LIMITATIONS Heterogeneity in baseline ferritin levels; high proportion of female participants; single-arm open-label extension. CONCLUSIONS Ferric maltol was associated with statistically significant (week 16) and sustained (up to week 52) increases in hemoglobin and iron indices in patients with CKD and iron deficiency, and was well tolerated during treatment for up to 52 weeks. FUNDING Funded by Shield Therapeutics (UK) Ltd. TRIAL REGISTRATION Registered at ClinicalTrials.gov with study number NCT02968368.
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Affiliation(s)
| | - Nelson P Kopyt
- Division of Nephrology, Department of Medicine, Lehigh Valley Hospital, Allentown, PA.
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Kontoghiorghes GJ, Kolnagou A, Demetriou T, Neocleous M, Kontoghiorghe CN. New Era in the Treatment of Iron Deficiency Anaemia Using Trimaltol Iron and Other Lipophilic Iron Chelator Complexes: Historical Perspectives of Discovery and Future Applications. Int J Mol Sci 2021; 22:ijms22115546. [PMID: 34074010 PMCID: PMC8197347 DOI: 10.3390/ijms22115546] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/08/2021] [Accepted: 05/18/2021] [Indexed: 12/11/2022] Open
Abstract
The trimaltol iron complex (International Non-proprietary Name: ferric maltol) was originally designed, synthesised, and screened in vitro and in vivo in 1980–1981 by Kontoghiorghes G.J. following his discovery of the novel alpha-ketohydroxyheteroaromatic (KHP) class of iron chelators (1978–1981), which were intended for clinical use, including the treatment of iron deficiency anaemia (IDA). Iron deficiency anaemia is a global health problem affecting about one-third of the world’s population. Many (and different) ferrous and ferric iron complex formulations are widely available and sold worldwide over the counter for the treatment of IDA. Almost all such complexes suffer from instability in the acidic environment of the stomach and competition from other dietary molecules or drugs. Natural and synthetic lipophilic KHP chelators, including maltol, have been shown in in vitro and in vivo studies to form stable iron complexes, to transfer iron across cell membranes, and to increase iron absorption in animals. Trimaltol iron, sold as Feraccru or Accrufer, was recently approved for clinical use in IDA patients in many countries, including the USA and in EU countries, and was shown to be effective and safe, with a better therapeutic index in comparison to other iron formulations. Similar properties of increased iron absorption were also shown by lipophilic iron complexes of 8-hydroxyquinoline, tropolone, 2-hydroxy-4-methoxypyridine-1-oxide, and related analogues. The interactions of the KHP iron complexes with natural chelators, drugs, metal ions, proteins, and other molecules appear to affect the pharmacological and metabolic effects of both iron and the KHP chelators. A new era in the treatment of IDA and other possible clinical applications, such as theranostic and anticancer formulations and metal radiotracers in diagnostic medicine, are envisaged from the introduction of maltol, KHP, and similar lipophilic chelators.
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18
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Cummings JF, Fraser A, Stansfield C, Beales I, Sebastian S, Hoque S. Ferric maltol Real-world Effectiveness Study in Hospital practice (FRESH): clinical characteristics and outcomes of patients with inflammatory bowel disease receiving ferric maltol for iron-deficiency anaemia in the UK. BMJ Open Gastroenterol 2021; 8:bmjgast-2020-000530. [PMID: 33622683 PMCID: PMC7907848 DOI: 10.1136/bmjgast-2020-000530] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 10/04/2020] [Indexed: 12/12/2022] Open
Abstract
Objective To assess outcomes in patients with iron-deficient inflammatory bowel disease (IBD) treated with ferric maltol in UK real-world practice. Design/Method This observational, multicentre, retrospective cohort study included adults with IBD and iron-deficiency anaemia (IDA; haemoglobin ≥95 to <120 g/L (women) or ≥95 to <130 g/L (men) plus serum ferritin <30 µg/L or transferrin saturation <20%) who received ferric maltol. Data were extracted from patient records. The primary analysis was the proportion of patients with normalised haemoglobin (≥120 g/L (women); ≥130 g/L (men)) over 12 weeks. Iron indices and safety were assessed. Results Thirty of 59 patients had data for the primary outcome, 19 of whom (63%) achieved haemoglobin normalisation at week 12. Mean±SD haemoglobin was 127±16 g/L at week 12 (increase of 14±17 g/L from baseline). Overall, 27 patients achieved haemoglobin normalisation by the end of the observation period; mean±SD time to normalisation was 49.5±25.6 days. Nine of 17 patients had normalised serum ferritin (30–300 µg/L) at week 12, and 16 patients had normalised ferritin at the end of the observation period; mean±SD time to normalisation was 71.3±27.6 days. Twenty-four adverse events occurred in 19 patients (32%); most frequent adverse events were abdominal pain or discomfort (n=9) and constipation (n=3). Conclusion Ferric maltol increases haemoglobin and iron indices and is generally well tolerated in patients with IBD and IDA treated in clinical practice. These real-world data support findings from randomised controlled trials.
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Affiliation(s)
- Jr Fraser Cummings
- Department of Gastroenterology, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Aileen Fraser
- Gastroenterology, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
| | | | - Ian Beales
- Department of Gastroenterology, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK
| | - Shaji Sebastian
- IBD Unit, Hull University Teaching Hospitals NHS Trust, Hull, UK
| | - Sami Hoque
- Department of Gastroenterology, Barts Health NHS Trust, London, UK
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Gordon M, Sinopoulou V, Iheozor-Ejiofor Z, Iqbal T, Allen P, Hoque S, Engineer J, Akobeng AK. Interventions for treating iron deficiency anaemia in inflammatory bowel disease. Cochrane Database Syst Rev 2021; 1:CD013529. [PMID: 33471939 PMCID: PMC8092475 DOI: 10.1002/14651858.cd013529.pub2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Inflammatory bowel disease affects approximately seven million people globally. Iron deficiency anaemia can occur as a common systemic manifestation, with a prevalence of up to 90%, which can significantly affect quality of life, both during periods of active disease or in remission. It is important that iron deficiency anaemia is treated effectively and not be assumed to be a normal finding of inflammatory bowel disease. The various routes of iron administration, doses and preparations present varying advantages and disadvantages, and a significant proportion of people experience adverse effects with current therapies. Currently, no consensus has been reached amongst physicians as to which treatment path is most beneficial. OBJECTIVES The primary objective was to evaluate the efficacy and safety of the interventions for the treatment of iron deficiency anaemia in people with inflammatory bowel disease. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, and two other databases on 21st November 2019. We also contacted experts in the field and searched references of trials for any additional trials. SELECTION CRITERIA Randomised controlled trials investigating the effectiveness and safety of iron administration interventions compared to other iron administration interventions or placebo in the treatment of iron deficiency anaemia in inflammatory bowel disease. We considered both adults and children, with studies reporting outcomes of clinical, endoscopic, histologic or surgical remission as defined by study authors. DATA COLLECTION AND ANALYSIS Two review authors independently conducted data extraction and 'Risk of bias' assessment of included studies. We expressed dichotomous and continuous outcomes as risk ratios and mean differences with 95% confidence intervals. We assessed the certainty of the evidence using the GRADE methodology. MAIN RESULTS We included 11 studies (1670 randomised participants) that met the inclusion criteria. The studies compared intravenous iron sucrose vs oral iron sulphate (2 studies); oral iron sulphate vs oral iron hydroxide polymaltose complex (1 study); oral iron fumarate vs intravenous iron sucrose (1 study); intravenous ferric carboxymaltose vs intravenous iron sucrose (1 study); erythropoietin injection + intravenous iron sucrose vs intravenous iron sucrose + injection placebo (1 study); oral ferric maltol vs oral placebo (1 study); oral ferric maltol vs intravenous ferric carboxymaltose (1 study); intravenous ferric carboxymaltose vs oral iron sulphate (1 study); intravenous iron isomaltoside vs oral iron sulphate (1 study); erythropoietin injection vs oral placebo (1 study). All studies compared participants with CD and UC together, as well as considering a range of disease activity states. The primary outcome of number of responders, when defined, was stated to be an increase in haemoglobin of 20 g/L in all but two studies in which an increase in 10g/L was used. In one study comparing intravenous ferric carboxymaltose and intravenous iron sucrose, moderate-certainty evidence was found that intravenous ferric carboxymaltose was probably superior to intravenous iron sucrose, although there were responders in both groups (150/244 versus 118/239, RR 1.25, 95% CI 1.06 to 1.46, number needed to treat for an additional beneficial outcome (NNTB) = 9). In one study comparing oral ferric maltol to placebo, there was low-certainty evidence of superiority of the iron (36/64 versus 0/64, RR 73.00, 95% CI 4.58 to 1164.36). There were no other direct comparisons that found any difference in the primary outcomes, although certainty was low and very low for all outcomes, due to imprecision from sparse data and risk of bias varying between moderate and high risk. The reporting of secondary outcomes was inconsistent. The most common was the occurrence of serious adverse events or those requiring withdrawal of therapy. In no comparisons was there a difference seen between any of the intervention agents being studied, although the certainty was very low for all comparisons made, due to risk of bias and significant imprecision due to the low numbers of events. Time to remission, histological and biochemical outcomes were sparsely reported in the studies. None of the other secondary outcomes were reported in any of the studies. An analysis of all intravenous iron preparations to all oral iron preparations showed that intravenous administration may lead to more responders (368/554 versus 205/373, RR 1.17, 95% CI 1.05 to 1.31, NNTB = 11, low-certainty due to risk of bias and inconsistency). Withdrawals due to adverse events may be greater in oral iron preparations vs intravenous (15/554 versus 31/373, RR 0.39, 95% CI 0.20 to 0.74, low-certainty due to risk of bias, inconsistency and imprecision). AUTHORS' CONCLUSIONS Intravenous ferric carboxymaltose probably leads to more people having resolution of IDA (iron deficiency anaemia) than intravenous iron sucrose. Oral ferric maltol may lead to more people having resolution of IDA than placebo. We are unable to draw conclusions on which of the other treatments is most effective in IDA with IBD (inflammatory bowel disease) due to low numbers of studies in each comparison area and clinical heterogeneity within the studies. Therefore, there are no other conclusions regarding the treatments that can be made and certainty of all findings are low or very low. Overall, intravenous iron delivery probably leads to greater response in patients compared with oral iron, with a NNTB (number needed to treat) of 11. Whilst no serious adverse events were specifically elicited with any of the treatments studied, the numbers of reported events were low and the certainty of these findings very low for all comparisons, so no conclusions can be drawn. There may be more withdrawals due to such events when oral is compared with intravenous iron delivery. Other outcomes were poorly reported and once again no conclusions can be made as to the impact of IDA on any of these outcomes. Given the widespread use of many of these treatments in practice and the only guideline that exists recommending the use of intravenous iron in favour of oral iron, research to investigate this key issue is clearly needed. Considering the current ongoing trials identified in this review, these are more focussed on the impact in specific patient groups (young people) or on other symptoms (such as fatigue). Therefore, there is a need for studies to be performed to fill this evidence gap.
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Affiliation(s)
- Morris Gordon
- School of Medicine, University of Central Lancashire, Preston, UK
| | | | - Zipporah Iheozor-Ejiofor
- Cochrane Bone Joint and Muscle Trauma Group, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, The University of Manchester, Manchester, UK
| | | | - Patrick Allen
- Department of Gastroenterology and Hepatology, Ulster Hospital, Belfast, Ireland
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New drug approvals for 2019: Synthesis and clinical applications. Eur J Med Chem 2020; 205:112667. [DOI: 10.1016/j.ejmech.2020.112667] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 07/13/2020] [Accepted: 07/13/2020] [Indexed: 12/17/2022]
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Anemia in Children With Inflammatory Bowel Disease: A Position Paper by the IBD Committee of the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2020; 71:563-582. [PMID: 32947565 DOI: 10.1097/mpg.0000000000002885] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Anemia is one of the most common extraintestinal manifestations of inflammatory bowel disease (IBD). It can be asymptomatic or associated with nonspecific symptoms, such as irritability, headaches, fatigue, dizziness, and anorexia. In IBD patients, the etiology of anemia is often multifactorial. Various causes include iron deficiency, anemia of inflammation and chronic disease, vitamin deficiencies, hemolysis, or myelosuppressive effect of drugs. Anemia and iron deficiency in these patients may be underestimated because of their insidious onset, lack of standardized screening practices, and possibly underappreciation that treatment of anemia is also required when treating IBD. Practitioners may hesitate to use oral preparations because of their intolerance whereas intravenous preparations are underutilized because of fear of adverse events, availability, and cost. Several publications in recent years have documented the safety and comparative efficacy of various intravenous preparations. This article reviews management of anemia in children with IBD, including diagnosis, etiopathogenesis, evaluation of a patient, protocol to screen and monitor patients for early detection and response to therapy, treatment including parenteral iron therapy, and newer approaches in management of anemia of chronic disease. This report has been compiled by a group of pediatric gastroenterologists serving on the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) IBD committee, in collaboration with a pediatric hematologist, pharmacist, and a registered dietician who specializes in pediatric IBD (IBD Anemia Working Group), after an extensive review of the current literature. The purpose of this review is to raise awareness of under-diagnosis of anemia in children with IBD and make recommendations for screening, testing, and treatment in this population.
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Khoury A, Pagan KA, Farland MZ. Ferric Maltol: A New Oral Iron Formulation for the Treatment of Iron Deficiency in Adults. Ann Pharmacother 2020; 55:222-229. [PMID: 32633548 DOI: 10.1177/1060028020941014] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVE To review the pharmacology, efficacy, and safety of ferric maltol (FM), an oral iron formulation, for iron deficiency anemia (IDA). DATA SOURCES A MEDLINE/PubMed and EMBASE (January 1, 1985, to June 19, 2020) literature search was performed using the terms ferric maltol, accrufer, feraccru, iron maltol, ferric trimaltol, iron deficiency, iron deficiency anemia, inflammatory bowel disease, and chronic kidney disease. Additional data sources included prescribing information, abstracts, and the National Institutes of Health Clinical Trials Registry. STUDY SELECTION/DATA EXTRACTION English language literature evaluating FM pharmacology, pharmacokinetics, efficacy, or safety in the treatment of IDA were reviewed. DATA SYNTHESIS FM is a ferric, non-salt-based oral iron formulation demonstrating improved tolerance in patients with previous intolerance to other iron formulations. Phase 3 trials demonstrated significant improvements in anemia and serum iron parameters in patients with inflammatory bowel disease (IBD) and chronic kidney disease (CKD). Common adverse effects were gastrointestinal intolerance. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE FM is an effective and well-tolerated alternative to oral iron salts for patients with IBD or CKD and IDA. Emerging data suggest that FM is noninferior to intravenous (IV) ferric carboxymaltose in patients with IBD and IDA. Prior to selecting FM over IV iron products, consideration should be given to time to normalization of Hb, ease of administration, cost, and tolerability. CONCLUSION FM is a relatively safe, effective oral iron therapy that may be better tolerated than other oral iron formulations. FM may be an effective alternative to IV iron in patients with IBD.
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Affiliation(s)
- Adonice Khoury
- University of Florida College of Pharmacy, Gainesville, FL, USA
| | - Kaley A Pagan
- University of Florida College of Pharmacy, Gainesville, FL, USA
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Lopes AI, Azevedo S, Cabral J, Ferreira MG, Sande-Lemos P, Ferreira R, Trindade E, Lima R, Antunes H. Portuguese Consensus on Diagnosis, Treatment, and Management of Anemia in Pediatric Inflammatory Bowel Disease. GE PORTUGUESE JOURNAL OF GASTROENTEROLOGY 2020; 27:244-254. [PMID: 32775546 DOI: 10.1159/000505071] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 11/26/2019] [Indexed: 12/11/2022]
Abstract
Anemia is a common extraintestinal manifestation of inflammatory bowel disease (IBD), both in pediatric and in adult patients. Iron deficiency is the main cause of anemia in patients with IBD. Anemia is a clinically relevant comorbidity, with impact on patients' quality of life and it should be timely diagnosed and adequately treated. Currently, an active treatment approach is the recommended strategy, with evidence showing efficacy and safety of intravenous iron formulations. However, evidence in pediatric age remains scarce and no clinical recommendations exist for the diagnosis and treatment of this particular age group. The present document represents the first national consensus on the management of anemia in pediatric IBD and is therefore particularly relevant. The authors anticipate that the proposed recommendations will be useful in daily clinical practice for diagnosing and managing iron deficiency and iron-deficiency anemia in the pediatric population with IBD.
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Affiliation(s)
- Ana Isabel Lopes
- Faculty of Medicine of the University of Lisbon, Lisbon Academic Medical Centre (CAML), Lisbon, Portugal.,Gastroenterology Unit, Pediatric Department, Hospital de Santa Maria, University Hospital Centre of North Lisbon, Lisbon, Portugal
| | - Sara Azevedo
- Gastroenterology Unit, Pediatric Department, Hospital de Santa Maria, University Hospital Centre of North Lisbon, Lisbon, Portugal
| | - José Cabral
- Pediatric Gastroenterology Unit, Dona Estefânia Hospital, University Hospital Centre of Central Lisbon, Lisbon, Portugal
| | | | - Piedade Sande-Lemos
- Pediatric Department, Hospital Prof. Doutor Fernando Fonseca EPE, Amadora, Portugal
| | - Ricardo Ferreira
- Pediatric Department, Pediatric Hospital, Coimbra Hospital and Universitary Centre (CHUC), Coimbra, Portugal
| | - Eunice Trindade
- Pediatric Gastroenterology Unit, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - Rosa Lima
- Pediatric Gastroenterology Unit, Centro Materno Infantil do Norte, Porto Hospital and Universitary Centre, Porto, Portugal
| | - Henedina Antunes
- Pediatric Gastroenterology, Hepatology and Nutrition Unit and Clinical Academic Center 2CA-Braga, Hospital de Braga, Braga, Portugal.,Life and Health Sciences Institute (ICVS), School of Medicine University of Minho, Braga, Portugal.,ICVS/3B's Associated Laboratory, Braga-Guimarães, Portugal
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D’Amico F, Peyrin-Biroulet L, Danese S. Oral Iron for IBD Patients: Lessons Learned at Time of COVID-19 Pandemic. J Clin Med 2020; 9:jcm9051536. [PMID: 32438763 PMCID: PMC7290728 DOI: 10.3390/jcm9051536] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 05/15/2020] [Accepted: 05/18/2020] [Indexed: 02/07/2023] Open
Abstract
Anemia is a frequent manifestation in patients with chronic inflammatory bowel disease (IBD) and requires tight monitoring and adequate supplementary therapy. Intravenous iron is the first-line treatment in subjects with moderate–severe anemia, active disease, or oral iron intolerance. On the other hand, oral iron is recommended in patients with mild anemia and inactive disease. However, during the current coronavirus pandemic, hospital activities have significantly changed, and all non-essential procedures, including non-urgent iron infusions, have been rescheduled. Oral iron, including both the traditional formulations with ferrous iron and the new ferric iron complexes, could constitute a valid alternative for anemia treatment. For this reason, we conducted a literature review, to summarize the scientific evidence on oral iron therapy in IBD patients with anemia.
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Affiliation(s)
- Ferdinando D’Amico
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy;
- Department of Gastroenterology and Inserm NGERE U1256, University Hospital of Nancy, University of Lorraine, 54500 Vandoeuvre-lès-Nancy, France;
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology and Inserm NGERE U1256, University Hospital of Nancy, University of Lorraine, 54500 Vandoeuvre-lès-Nancy, France;
| | - Silvio Danese
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy;
- IBD Center, Department of Gastroenterology, Humanitas Clinical and Research Center, IRCCS, Rozzano, 20089 Milan, Italy
- Correspondence: ; Tel.: +39-028-224-4771; Fax: +39-028-224-2591
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Treatment of iron deficiency anemia with liposomal iron in inflammatory bowel disease: efficacy and impact on quality of life. Int J Clin Pharm 2020; 42:895-902. [PMID: 32367457 DOI: 10.1007/s11096-020-01044-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Accepted: 04/22/2020] [Indexed: 12/17/2022]
Abstract
Background Anemia is a clinical condition frequently seen in patients with inflammatory bowel disease, which is responsible for a significant loss of quality of life. Objective To assess the efficacy and safety of using oral liposomal iron to treat iron deficiency anemia in inflammatory bowel disease patients, as well as assess the impact of this treatment on psychometric scores. Methods Patients with inactive/mildly active inflammatory bowel disease were screened for anemia in this interventional pilot study conducted from November 2016 to March 2018. Patients with mild anemia were treated with oral liposomal iron for 8 weeks. Main outcome measure The primary endpoint of the study was the response to liposomal oral iron therapy. Treatment response was defined as patients who achieved a hemoglobin increase of ≥ 1 g/dL and/or hemoglobin normalization by the 8th week of treatment. Results Out of 200 screened patients, 40 (20%) had anemia. Of the 21 patients who completed treatment, 13 (62%) responded to oral liposomal iron replacement therapy (mean increases of hemoglobin from 11.4 to 12.6 g/dL). The transferrin saturation index increased by an average of 10.2 (p = 0.006) and the quality of life by 26.3 (p < 0.0001). There was also a mean reduction of 9.2 in the perception of fatigue (p < 0.0001). Conclusion Treatment with oral liposomal iron is effective in improving mild iron deficiency anemia and quality of life, as well as in decreasing fatigue in patients with inactive or mildly active inflammatory bowel disease.
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Farrell D, Artom M, Czuber‐Dochan W, Jelsness‐Jørgensen LP, Norton C, Savage E. Interventions for fatigue in inflammatory bowel disease. Cochrane Database Syst Rev 2020; 4:CD012005. [PMID: 32297974 PMCID: PMC7161727 DOI: 10.1002/14651858.cd012005.pub2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is an umbrella term used to describe a group of chronic, progressive inflammatory disorders of the digestive tract. Crohn's disease and ulcerative colitis are the two main types. Fatigue is a common, debilitating and burdensome symptom experienced by individuals with IBD. The subjective, complex nature of fatigue can often hamper its management. The efficacy and safety of pharmacological or non-pharmacological treatments for fatigue in IBD is not yet established through systematic review of studies. OBJECTIVES To assess the efficacy and safety of pharmacological and non-pharmacological interventions for managing fatigue in IBD compared to no treatment, placebo or active comparator. SEARCH METHODS A systematic search of the databases Embase, MEDLINE, Cochrane Library, CINAHL, PsycINFO was undertaken from inception to July 2018. A top-up search was run in October 2019. We also searched the Cochrane IBD Group Specialized Register, the Cochrane Central Register of Controlled Trials, ongoing trials and research registers, conference abstracts and reference lists for potentially eligible studies. SELECTION CRITERIA Randomised controlled trials of pharmacological and non-pharmacological interventions in children or adults with IBD, where fatigue was assessed as a primary or secondary outcome using a generic or disease-specific fatigue measure, a subscale of a larger quality of life scale or as a single-item measure, were included. DATA COLLECTION AND ANALYSIS Two authors independently screened search results and four authors extracted and assessed bias independently using the Cochrane 'Risk of bias' tool. The primary outcome was fatigue and the secondary outcomes included quality of life, adverse events (AEs), serious AEs and withdrawal due to AEs. Standard methodological procedures were used. MAIN RESULTS We included 14 studies (3741 participants): nine trials of pharmacological interventions and five trials of non-pharmacological interventions. Thirty ongoing studies were identified, and five studies are awaiting classification. Data on fatigue were available from nine trials (1344 participants). In only four trials was managing fatigue the primary intention of the intervention (electroacupuncture, physical activity advice, cognitive behavioural therapy and solution-focused therapy). Electroacupuncture Fatigue was measured with Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) (scores range from 0 to 52). The FACIT-F score at week eight was 8.00 points higher (better) in participants receiving electroacupuncture compared with no treatment (mean difference (MD) 8.00, 95% CI 6.45 to 9.55; 1 RCT; 27 participants; low-certainty evidence). Results at week 16 could not be calculated. FACIT-F scores were also higher with electroacupuncture compared to sham electroacupuncture at week eight (MD 5.10, 95% CI 3.49 to 6.71; 1 RCT; 30 participants; low-certainty evidence) but not at week 16 (MD 2.60, 95% CI 0.74 to 4.46; 1 RCT; 30 participants; low-certainty evidence). No adverse events were reported, except for one adverse event in the sham electroacupuncture group. Cognitive behavioural therapy (CBT) and solution-focused therapy Compared with a fatigue information leaflet, the effects of CBT on fatigue are very uncertain (Inflammatory Bowel Disease-Fatigue (IBD-F) section I: MD -2.16, 95% CI -6.13 to 1.81; IBD-F section II: MD -21.62, 95% CI -45.02 to 1.78; 1 RCT, 18 participants, very low-certainty evidence). The efficacy of solution-focused therapy on fatigue is also very uncertain, because standard summary data were not reported (1 RCT, 98 participants). Physical activity advice One 2 x 2 factorial trial (45 participants) found physical activity advice may reduce fatigue but the evidence is very uncertain. At week 12, compared to a control group receiving no physical activity advice plus omega 3 capsules, FACIT-F scores were higher (better) in the physical activity advice plus omega 3 group (FACIT-F MD 6.40, 95% CI -1.80 to 14.60, very low-certainty evidence) and the physical activity advice plus placebo group (FACIT-F MD 9.00, 95% CI 1.64 to 16.36, very low-certainty evidence). Adverse events were predominantly gastrointestinal and similar across physical activity groups, although more adverse events were reported in the no physical activity advice plus omega 3 group. Pharmacological interventions Compared with placebo, adalimumab 40 mg, administered every other week ('eow') (only for those known to respond to adalimumab induction therapy), may reduce fatigue in patients with moderately-to-severely active Crohn's disease, but the evidence is very uncertain (FACIT-F MD 4.30, 95% CI 1.75 to 6.85; very low-certainty evidence). The adalimumab 40 mg eow group was less likely to experience serious adverse events (OR 0.56, 95% CI 0.33 to 0.96; 521 participants; moderate-certainty evidence) and withdrawal due to adverse events (OR 0.48, 95%CI 0.26 to 0.87; 521 participants; moderate-certainty evidence). Ferric maltol may result in a slight increase in fatigue, with better SF-36 vitality scores reported in the placebo group compared to the treatment group following 12 weeks of treatment (MD -9.31, 95% CI -17.15 to -1.47; 118 participants; low-certainty evidence). There may be little or no difference in adverse events (OR 0.55, 95% CI 0.26 to 1.18; 120 participants; low-certainty evidence) AUTHORS' CONCLUSIONS: The effects of interventions for the management of fatigue in IBD are uncertain. No firm conclusions regarding the efficacy and safety of interventions can be drawn. Further high-quality studies, with a larger number of participants, are required to assess the potential benefits and harms of therapies. Future studies should assess interventions specifically designed for fatigue management, targeted at selected IBD populations, and measure fatigue as the primary outcome.
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Affiliation(s)
- Dawn Farrell
- Institute of Technology TraleeDepartment of Nursing and Healthcare SciencesTraleeCounty KerryIreland
| | - Micol Artom
- King's College LondonFlorence Nightingale Faculty of Nursing, Midwifery and Palliative Care57 Waterloo RoadLondonUKSE1 8WA
| | - Wladyslawa Czuber‐Dochan
- King's College LondonFlorence Nightingale Faculty of Nursing, Midwifery and Palliative Care57 Waterloo RoadLondonUKSE1 8WA
| | | | - Christine Norton
- King's College LondonFlorence Nightingale Faculty of Nursing, Midwifery and Palliative Care57 Waterloo RoadLondonUKSE1 8WA
| | - Eileen Savage
- University College CorkSchool of Nursing and Midwifery, Brookfield Health Sciences ComplexCorkIreland
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The History of Deferiprone (L1) and the Paradigm of the Complete Treatment of Iron Overload in Thalassaemia. Mediterr J Hematol Infect Dis 2020; 12:e2020011. [PMID: 31934321 PMCID: PMC6951358 DOI: 10.4084/mjhid.2020.011] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Accepted: 12/18/2019] [Indexed: 01/19/2023] Open
Abstract
Deferiprone (L1) was originally designed, synthesised and screened in vitro and in vivo in 1981 by Kontoghiorghes G. J. following his discovery of the novel alpha-ketohydroxypyridine class of iron chelators (1978–1981), which were intended for clinical use. The journey through the years for the treatment of thalassaemia with L1 has been a very difficult one with an intriguing turn of events, which continue until today. Despite many complications, such as the extensive use of L1 suboptimal dose protocols, the aim of chelation therapy-namely, the complete removal of excess iron in thalassaemia major patients, has been achieved in most cases following the introduction of specific L1 and L1/deferoxamine combinations. Many such patients continue to maintain normal iron stores. Thalassemia has changed from a fatal to chronic disease; also thanks to L1 therapy and thalassaemia patients are active professional members in all sectors of society, have their own families with children and grandchildren and their lifespan is approaching that of normal individuals. No changes in the low toxicity profile of L1 have been observed in more than 30 years of clinical use and prophylaxis against the low incidence of agranulocytosis is maintained using mandatory monitoring of weekly white blood cells’ count. Thousands of thalassaemia patients are still denied the cardioprotective and other beneficial effects of L1 therapy. The safety of L1 in thalassaemia and other non-iron loaded diseases resulted in its selection as one of the leading therapeutics for the treatment of Friedreich’s ataxia, pantothenate kinase-associated neurodegeneration and other similar cases. There are also increasing prospects for the application of L1 as a main, alternative or adjuvant therapy in many pathological conditions including cancer, infectious diseases and as a general antioxidant for diseases related to free radical pathology.
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Abbati G, Incerti F, Boarini C, Pileri F, Bocchi D, Ventura P, Buzzetti E, Pietrangelo A. Safety and efficacy of sucrosomial iron in inflammatory bowel disease patients with iron deficiency anemia. Intern Emerg Med 2019; 14:423-431. [PMID: 30499070 DOI: 10.1007/s11739-018-1993-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 11/20/2018] [Indexed: 12/11/2022]
Abstract
Iron deficiency anemia (IDA) is one of the most common complications of inflammatory bowel disease (IBD). We planned a prospective study to address tolerability and efficacy of sucrosomial iron, a new oral formulation of ferric pyrophosphate, in IBD patients. Thirty patients with a confirmed diagnosis of Crohn's Disease (CD) or ulcerative colitis (UC) and mild IDA were enrolled. Patients with severe IBD were excluded. All patients underwent 12 weeks of oral treatment with 30 mg/day of sucrosomial iron. Treatment compliance and adverse events were investigated every 4 weeks. Iron status, hematological parameters and IBD activity scores were determined at baseline and at the end of treatment, as well as serum hepcidin and non-transferrin bound iron (NTBI) levels. Twenty-four (80%) patients took more than 90% of the prescribed regimen. Forty-four adverse events (AEs) were recorded, but none of them is considered certainly or probably related to the study treatment. Interestingly, only eleven gastrointestinal events were recorded in 9 (30%) patients. At the end of treatment, all iron parameters improved significantly and Hb increased in 86% of patients (from 11.67 to 12.37 g/dl, p = 0.001). Serum hepcidin showed a significant increase in 79% of patients and became positively correlated with C-reactive protein (CRP) at the end of the study, while NTBI remained below the detection threshold after iron supplementation. The IBD activity scores improved in both CD and UC. This pilot interventional study supports the therapeutic use of sucrosomial iron in IBD and paves the way for future studies in larger or more difficult IBD populations.
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Affiliation(s)
- Gianluca Abbati
- Division of Internal Medicine 2 and Center for Hemochromatosis, University of Modena and Reggio Emilia, Via DEL Pozzo 71, 41124, Modena, Italy.
| | - Federica Incerti
- Division of Internal Medicine 2 and Center for Hemochromatosis, University of Modena and Reggio Emilia, Via DEL Pozzo 71, 41124, Modena, Italy
| | - Chiara Boarini
- Division of Internal Medicine 2 and Center for Hemochromatosis, University of Modena and Reggio Emilia, Via DEL Pozzo 71, 41124, Modena, Italy
| | - Francesca Pileri
- Division of Internal Medicine 2 and Center for Hemochromatosis, University of Modena and Reggio Emilia, Via DEL Pozzo 71, 41124, Modena, Italy
| | - Davide Bocchi
- Division of Internal Medicine 2 and Center for Hemochromatosis, University of Modena and Reggio Emilia, Via DEL Pozzo 71, 41124, Modena, Italy
| | - Paolo Ventura
- Division of Internal Medicine 2 and Center for Hemochromatosis, University of Modena and Reggio Emilia, Via DEL Pozzo 71, 41124, Modena, Italy
| | - Elena Buzzetti
- Division of Internal Medicine 2 and Center for Hemochromatosis, University of Modena and Reggio Emilia, Via DEL Pozzo 71, 41124, Modena, Italy
| | - Antonello Pietrangelo
- Division of Internal Medicine 2 and Center for Hemochromatosis, University of Modena and Reggio Emilia, Via DEL Pozzo 71, 41124, Modena, Italy
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Aksan A, Farrag K, Stein J. An update on the evaluation and management of iron deficiency anemia in inflammatory bowel disease. Expert Rev Gastroenterol Hepatol 2019; 13:95-97. [PMID: 30791779 DOI: 10.1080/17474124.2019.1553618] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Affiliation(s)
- Ayşegül Aksan
- a Crohn Colitis Clinical Research Centre Rhein-Main , Frankfurt am Main , Germany.,b Faculty of Health Sciences , Hacettepe University , Ankara , Turkey
| | - Karima Farrag
- a Crohn Colitis Clinical Research Centre Rhein-Main , Frankfurt am Main , Germany.,c Gastroenterology and Clinical Nutrition , DGD Clinics Sachsenhausen , Frankfurt am Main , Germany
| | - Jürgen Stein
- a Crohn Colitis Clinical Research Centre Rhein-Main , Frankfurt am Main , Germany.,c Gastroenterology and Clinical Nutrition , DGD Clinics Sachsenhausen , Frankfurt am Main , Germany.,d Department of Pharmaceutical Chemistry , University of Frankfurt , Frankfurt am Main , Germany
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Bengi G, Keyvan H, Durmaz SB, Akpınar H. Frequency, types, and treatment of anemia in Turkish patients with inflammatory bowel disease. World J Gastroenterol 2018; 24:4186-4196. [PMID: 30271083 PMCID: PMC6158484 DOI: 10.3748/wjg.v24.i36.4186] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Revised: 07/30/2018] [Accepted: 08/24/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To specify the type and prevalence of anemia along with a treatment approach for inflammatory bowel disease (IBD).
METHODS We conducted a retrospective study on 465 patients who were diagnosed with IBD and followed up at our hospital from June 2015 to June 2016 [male: 254, female: 211; average age: 47 ± 14.4; Crohn’s disease (CD): 257, Ulcerative Colitis (UC): 208]. Epidemiological and clinical data, such as sex, age, age of diagnosis, type of IBD, disease extension, disease behavior and duration, treatments for IBD and anemia, and surgical history were obtained for each patient. Per World Health Organization guidelines, anemia was diagnosed for males if hemoglobin values were less than 13 g/dL and for females if hemoglobin values were less than 12 g/dL.
RESULTS We determined that 51.6% of the patients had anemia, which was more frequent in women then men (64% vs 41.3%, P < 0.001). Anemia frequency was higher in CD cases (57.6%) than in UC cases (44.2%) (P = 0.004). CD involvements were as follows: 48.2% in ileal involvement, 19% in colonic involvement, and 32.8% in ileocolonic involvement. Furthermore, 27.5% of UC patients had proctitis (E1) involvement, 41% of them had involvement in left colitis (E2), and 31.5% had pancolitis involvement. There was no significant relationship between anemia frequency and duration of disease (P = 0.55). Iron deficiency anemia (IDA) was the most common type of anemia in this cohort. Moreover, because anemia parameters have not been evaluated during follow-up of 15.3% of patients, the etiology of anemia has not been clarified. Fifty percent of patients with anemia received treatment. Twenty-three percent of IDA patients had oral iron intake and forty-one percent of IDA patients had parenteral iron treatment. Fifty-three percent of patients who were suffering from megaloblastic anemia received B12/folic acid treatment.
CONCLUSION We found out that almost half of all IBD patients (51.6%) had anemia, the most frequent of which was IDA. Almost half of these patients received treatment. We should increase the treatment rate in our IBD patients that have anemia.
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Affiliation(s)
- Göksel Bengi
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Dokuz Eylül University, İzmir 35360, Turkey
| | - Hatice Keyvan
- Department of Internal Medicine, Faculty of Medicine, Dokuz Eylül University, İzmir 35360, Turkey
| | - Seda Bayrak Durmaz
- Department of Internal Medicine, Faculty of Medicine, Dokuz Eylül University, İzmir 35360, Turkey
| | - Hale Akpınar
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Dokuz Eylül University, İzmir 35360, Turkey
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Current misconceptions in diagnosis and management of iron deficiency. BLOOD TRANSFUSION = TRASFUSIONE DEL SANGUE 2018; 15:422-437. [PMID: 28880842 DOI: 10.2450/2017.0113-17] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Accepted: 06/30/2017] [Indexed: 12/15/2022]
Abstract
The prevention and treatment of iron deficiency is a major public health goal. Challenges in the treatment of iron deficiency include finding and addressing the underlying cause and the selection of an iron replacement product which meets the needs of the patient. However, there are a number of non-evidence-based misconceptions regarding the diagnosis and management of iron deficiency, with or without anaemia, as well as inconsistency of terminology and lack of clear guidance on clinical pathways. In particular, the pathogenesis of iron deficiency is still frequently not addressed and iron not replaced, with indiscriminate red cell transfusion used as a default therapy. In our experience, this imprudent practice continues to be endorsed by non-evidence-based misconceptions. The intent of the authors is to provide a consensus that effectively challenges these misconceptions, and to highlight evidence-based alternatives for appropriate management (referred to as key points). We believe that this approach to the management of iron deficiency may be beneficial for both patients and healthcare systems. We stress that this paper solely presents the Authors' independent opinions. No pharmaceutical company funded or influenced the conception, development or writing of the manuscript.
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Patel D, Trivedi C, Khan N. Management of Anemia in Patients with Inflammatory Bowel Disease (IBD). ACTA ACUST UNITED AC 2018; 16:112-128. [PMID: 29404920 DOI: 10.1007/s11938-018-0174-2] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE OF REVIEW Anemia is the most common complication as well as an extra intestinal manifestation of inflammatory bowel disease (IBD). It is associated with a significant impact on patient's quality of life (QoL); as well it represents a common cause of frequent hospitalization, delay of hospital inpatient discharge and overall increased healthcare burden. In spite of all these, anemia is still often underdiagnosed and undertreated. Our aim in this review is to provide a pathway for physicians to help them achieve early diagnosis as well as timely and appropriate treatment of anemia which in turn would hopefully reduce the prevalence and subsequent complications of this condition among IBD patients. RECENT FINDINGS The etiology of anemia among IBD patients is most commonly due to iron deficiency anemia (IDA) followed by anemia of chronic disease. Despite this, more than a third of anemic ulcerative colitis (UC) patients are not tested for IDA and among those tested and diagnosed with IDA, a quarter are not treated with iron replacement therapy. A new algorithm has been validated to predict who will develop moderate to severe anemia at the time of UC diagnosis. While oral iron is effective for the treatment of mild iron deficiency-related anemia, the absorption of iron is influenced by chronic inflammatory states as a consequence of the presence of elevated levels of hepcidin. Also, it is important to recognize that ferritin is elevated in chronic inflammatory states and among patients with active IBD, ferritin levels less than 100 are considered to be diagnostic of iron deficiency. Newer formulations of intra-venous (IV) iron have a good safety profile and can be used for replenishment of iron stores and prevention of iron deficiency in the future. Routine screening for anemia is important among patients with IBD. The cornerstone for the accurate management of anemia in IBD patients lies in accurately diagnosing the type of anemia. All IBD patients with IDA should be considered appropriate for therapy with iron supplementation whereas IV administration of iron is recommended in patients with clinically active IBD, or for patients who are previously intolerant to oral iron, with hemoglobin levels below 10 g/dL, and in patients who need erythropoiesis-stimulating agents (ESAs). As the recurrence of anemia is common after resolution, the monitoring for recurrent anemia is equally important during the course of therapy.
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Affiliation(s)
- Dhruvan Patel
- Section of Gastroenterology, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Chinmay Trivedi
- Section of Gastroenterology, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA
| | - Nabeel Khan
- Section of Gastroenterology, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
- Section of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
- , 3900 Woodland Avenue, Philadelphia, PA, 19104, USA.
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Muñoz M, Gómez-Ramírez S, Bhandari S. The safety of available treatment options for iron-deficiency anemia. Expert Opin Drug Saf 2017; 17:149-159. [DOI: 10.1080/14740338.2018.1400009] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Affiliation(s)
- Manuel Muñoz
- Perioperative Transfusion Medicine, Department of Surgical Sciences, Biochemistry and Immunology, School of Medicine, University of Málaga, Málaga, Spain
| | - Susana Gómez-Ramírez
- Department of Internal Medicine, University Hospital “Virgen de la Victoria”, Málaga, Spain
| | - Sunil Bhandari
- Nephrology, Hull and East Yorkshire Hospitals NHS Trust, Hull York Medical School, Kingston upon Hull, UK
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Stein J, Aksan A, Farrag K, Dignass A, Radeke HH. Management of inflammatory bowel disease-related anemia and iron deficiency with specific reference to the role of intravenous iron in current practice. Expert Opin Pharmacother 2017; 18:1721-1737. [PMID: 29019427 DOI: 10.1080/14656566.2017.1391790] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Anemia is a common extraintestinal manifestation in patients with inflammatory bowel disease, impacting disease prognosis, morbidity, hospitalization rates and time lost from work. While iron deficiency anemia and anemia of chronic inflammation predominate, combinations of hematimetric and biochemical markers facilitate the diagnosis and targeted therapy of other etiologies according to their underlying pathophysiological causes. Intravenous iron replacement is currently recommended in IBD patients with moderate to severe anemia or intolerance to oral iron. Areas covered: This review examines the impact, pathophysiology and diagnostics of iron deficiency and anemia, compares the characteristics and safety profiles of available oral and intravenous iron preparations, and highlights issues which require consideration in decision making for therapy administration and monitoring. Expert opinion: Modern intravenous iron formulations have been shown to be safe and effective in IBD patients, allowing rapid anemia correction and repletion of iron stores. While traditional oral iron preparations are associated with increased inflammation, negative effects on the microbiome, and poor tolerance and compliance, first clinical trial data indicate that newer oral compounds such as ferric maltol and sucrosomial iron offer improved tolerability and may thus offer a viable alternative for the future.
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Affiliation(s)
- Jürgen Stein
- a Crohn Colitis Clinical Research Center Rhein-Main , Frankfurt/Main , Germany.,b Department of Pharmaceutical Chemistry , University of Frankfurt , Frankfurt/Main , Germany.,c Department of Gastroenterology and Clinical Nutrition , DGD Clinics Sachsenhausen , Frankfurt/Main , Germany
| | - Ayşegül Aksan
- a Crohn Colitis Clinical Research Center Rhein-Main , Frankfurt/Main , Germany.,d Faculty of Health Sciences , Hacettepe University , Ankara , Turkey
| | - Karima Farrag
- a Crohn Colitis Clinical Research Center Rhein-Main , Frankfurt/Main , Germany.,c Department of Gastroenterology and Clinical Nutrition , DGD Clinics Sachsenhausen , Frankfurt/Main , Germany
| | - Axel Dignass
- a Crohn Colitis Clinical Research Center Rhein-Main , Frankfurt/Main , Germany.,e Department of Medicine I , Agaplesion Markus Hospital , Frankfurt/Main , Germany
| | - Heinfried H Radeke
- a Crohn Colitis Clinical Research Center Rhein-Main , Frankfurt/Main , Germany.,b Department of Pharmaceutical Chemistry , University of Frankfurt , Frankfurt/Main , Germany
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Bou-Fakhredin R, Halawi R, Roumi J, Taher A. Insights into the diagnosis and management of iron deficiency in inflammatory bowel disease. Expert Rev Hematol 2017; 10:801-808. [PMID: 28701106 DOI: 10.1080/17474086.2017.1355233] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Iron deficiency is a frequent comorbidity of chronic diseases such as inflammatory bowel disease that can severely impact the health and quality of life of affected individuals. It can exist as a silent condition and manifest in non-specific symptoms even in the absence of anemia. Even though iron deficiency anemia is the most common complication and extra-intestinal manifestation of inflammatory bowel disease, the majority of inflammatory bowel disease patients who are diagnosed with iron deficiency anemia are not treated. Areas covered: In this review, we discuss iron deficiency and iron deficiency anemia in patients with inflammatory bowel disease, and review diagnostic and therapeutic options. Expert commentary: We invite international gastroenterological societies and associations to refine the practice guidelines and include iron deficiency as a potential morbidity associated with IBD in analogy to arthritis, uveitis or any other extra intestinal manifestations. There should a more unanimous agreement among different societies on the specific diagnostic cutoff values for C-reactive protein levels, serum ferritin, and transferrin saturation in order to differentiate iron deficiency anemia from anemia of chronic disease.
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Affiliation(s)
- Rayan Bou-Fakhredin
- a Department of Internal Medicine , American University of Beirut Medical Center , Beirut , Lebanon
| | - Racha Halawi
- b Division of General Medicine and Geriatrics , Emory University School of Medicine , Atlanta , GA , USA
| | - Joseph Roumi
- a Department of Internal Medicine , American University of Beirut Medical Center , Beirut , Lebanon
| | - Ali Taher
- a Department of Internal Medicine , American University of Beirut Medical Center , Beirut , Lebanon
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Barni S, Gascòn P, Petrelli F, García-Erce JA, Pedrazzoli P, Rosti G, Giordano G, Mafodda A, Múñoz M. Position paper on management of iron deficiency in adult cancer patients. Expert Rev Hematol 2017; 10:685-695. [PMID: 28656800 DOI: 10.1080/17474086.2017.1343140] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
INTRODUCTION Disorders of iron metabolism are commonly seen in onco-hematological clinical practice. Iron-deficiency anemia and cancer-associated anemia are usually treated with supportive therapies. Optimal management of these conditions are discussed in this perspective paper. Areas covered: A position paper discussing a number of hot topics on anemia in cancer patients is presented. The main areas covered by experts in the field are: definitions, prevalence and consequences of anemia and iron deficiency, incidence of anemia resulting from targeted therapies, importance of anemia diagnosis and monitoring, evaluation of iron status before and during treatment, role of transfusions and erythropoiesis-stimulating agents, management of iron deficiency with or without anemia, parenteral iron supplementation, role of new oral iron formulations, safety and cost issues regarding different iron compounds and administration routes. Expert commentary: Despite the availability of newer therapeutic options for its management, anemia still represents a major complication of treatment in cancer patients (surgery, chemotherapy, radiotherapy, targeted therapies), aggravating physical impairment, and negatively affecting general outcome. The view expressed by the panelists, attendees of the 4th Mediterranean Course on Iron Anemia, summarizes what they consider optimal clinical practice for screening, diagnosis, treatment and monitoring of iron deficiency and anemia in cancer patients.
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Affiliation(s)
- Sandro Barni
- a Oncology Department , Medical Oncology Unit , Treviglio , Italy
| | - Pere Gascòn
- b Division of Medical Oncology , Hospital Clinic, University of Barcelona , Barcelona , Spain
| | - Fausto Petrelli
- a Oncology Department , Medical Oncology Unit , Treviglio , Italy
| | | | - Paolo Pedrazzoli
- d Medical Oncology , Fondazione IRCCS Policlinico San Matteo , Pavia , Italy
| | - Giovanni Rosti
- d Medical Oncology , Fondazione IRCCS Policlinico San Matteo , Pavia , Italy
| | - Giulio Giordano
- e General Medicine and Hematology Department , General Medicine and Hematology Regional Hospital 'A. Cardarelli' , Campobasso , Italy
| | - Antonio Mafodda
- f Medical Oncology Unit , A.O. B.M.M , Reggio Calabria , Italy
| | - Manuel Múñoz
- g Peri-operative Transfusion Medicine , School of Medicine, University of Malaga , Malaga , Spain
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