铁过载概述及口服祛铁新药地拉罗司

规则输血是维持重度慢性贫血患者生命的重要治疗手段,患者长期依赖输血治疗不可避免地引起体内铁沉积增加。输血相关性铁过载可导致多脏器的损害,特别是沉积在肝脏或心脏,甚至可危及生命。作为传统的铁螯合剂,去铁酮和去铁胺因其不良反应或治疗依从性差等问题无法满足临床治疗需要。地拉罗司是一种新型的口服铁螯合剂,多个II期或III期试验证实其在输血依赖性患者中可获得与去铁胺相似的疗效。近期前瞻性、多中心EPIC研究也证实了其祛铁疗效,且有助于改善地中海贫血患者的心脏铁沉积。本文就铁过载的临床特征、危害性以及祛铁新药地拉罗司对比传统药物的优势做一综述。     

铁螯合剂治疗的新进展

长期输血患者的慢性铁超载是引起慢性心、肝、内分泌系统损害的严重并发症。慢性铁超载见于血色病患者、地中海贫血患者及其他需要长期输血以预防贫血的患者。铁螯合剂与体内铁离子结合能有效地提高铁的排泄,降低体内铁的含量及其在各器官的病理性沉积,其临床应用一直受到药学和临床研究者的广泛关注和重视。     

地中海贫血的临床用药

HLA相合同胞供体的造血干细胞移植是根治重症β地中海贫血(简称“地贫”)的有效方法。基因治疗仍在实验研究阶段，有些开启γ或β链合成的药物如羟基脲、丁酸盐等对某些D地贫基因突变型(如-28，-654—2)等重型或中间型地中海贫血有效，可提高血红蛋白水平20～40g／L，改善贫血症状。正规高量输血与去铁联合治疗是重症β地贫的基本辅助治疗，目前用于临床有效的去铁螯合剂有静脉／皮下输注的去铁胺，口服的去铁酮(L1)及ILC670(正进入Ⅲ期临床试验)。     

输血联合去铁胺治疗重型β地中海贫血

目的 观察输血联合去铁胺治疗重型β地中海贫血的临床疗效.方法 对我科25例重型β地中海贫血患儿采用输血联合去铁胺治疗,定期进行铁代谢的检测,观察其临床疗效.结果 经过治疗,患者相关症状得到不同程度缓解,输血后患者血红蛋白（Hb）恢复至＞ 100 g/L.血液中血清铁治疗前（35.08±1.41）μmol/L,治疗后（23.09±1.39）μmol/L;血清铁蛋白治疗前（2858.25±111.2）μg/L,治疗后（485.58±56.9） μg/L;经过治疗血清铁、血清铁蛋白均显著下降,差异有统计学意义（P＜0.05）.结论 输血加去铁胺治疗重型β地中海贫血可获得满意疗效,避免或减少因铁堆累导致的器官损害.     

去铁酮联合去铁胺治疗重型地中海贫血患儿血糖代谢及铁代谢的影响

目的:探讨使用去铁酮+去铁胺对重型地中海贫血患儿血糖、铁代谢的影响.方法:选取100例患儿随机分成观察组与对照组各50例,对照组单用去铁胺治疗,观察组则使用去铁酮联合去铁胺治疗,比较两组疗效.结果:治疗后两组血糖代谢正常率比治疗前高,观察组高于对照组(P<0.05)血清白蛋白水平治疗后比治疗前低,观察组低于对照组(P<0.05);临床疗效观察组96.00％明显高于对照组82.00％(P<0.05).结论:使用去铁酮联合去铁胺治疗重型地中海贫血患儿的效果满意,显著改善患儿血糖及铁代谢.     

Deferiprone获准用于治疗体内铁过量

美国FDA近日批准ApoPharma公司开发的deferiprone（商品名：Ferriprox）上市,用于治疗既往接受螯合剂治疗无效的地中海贫血患者因输血导致的铁过量。     

去铁酮片治疗广西重型β地中海贫血患儿的临床指标观察

目的:观察去铁酮片治疗广西重型β地中海贫血患儿的效果。方法:采用输血加去铁酮片治疗重型β地中海贫血患儿27例,比较用药前后患儿血清铁蛋白水平及肝、肾功能和血象指标变化。结果:口服去铁酮片可遏制输血后患儿的血清铁蛋白浓度升高,个别病例出现血象及肝功能异常变化。结论:给予患儿输血的同时,使用口服去铁酮片去铁是有效的,但应注意药物产生的不良反应。     

去铁酮与去铁胺对早期重型地中海贫血患儿血清铁蛋白水平及心功能的影响分析

目的比较去铁酮(DFP)与去铁胺(DFO)对早期重型地中海贫血患儿血清铁蛋白(SF)水平及心功能的影响。方法60例早期重型地中海贫血患儿,随机分为病例组和对照组,各30例。两组患儿均给予输血治疗和去铁治疗,病例组给予去铁酮进行去铁治疗,对照组给予去铁胺进行去铁治疗。比较两组患儿治疗前后血清铁蛋白、脑纳肽(BNP)水平及心输出量(CO)。结果治疗1年后,病例组和对照组血清铁蛋白水平分别为(714.4±251.4)、(797.4±218.3)μg/L,均低于治疗前的(1341.3±253.6)、(1387.3±227.7)μg/L,差异具有统计学意义(P<0.05);但两组治疗1年后血清铁蛋白水平比较差异无统计学意义(P>0.05)。两组治疗前后脑纳肽水平组间比较差异均无统计学意义(P>0.05);治疗1年后,两组脑纳肽水平均低于本组治疗前,但比较差异无统计学意义(P>0.05)。两组治疗前后心输出量组间比较差异均无统计学意义(P>0.05);治疗1年后,两组心输出量均略高于本组治疗前,但比较差异无统计学意义(P>0.05)。结论去铁酮和去铁胺在地中海贫血的早期治疗中疗效相当,均具有去铁和维持心功能的作用,因此需要结合患儿的实际情况来选择药物,如经济困难的儿童可以选择相对价格低廉的药物,经济条件好的儿童可以选择使用方便舒适的药物,但是两种药物均不能完全根治地中海贫血,需要长期治疗。     

去铁酮治疗高量输血的重型β-地中海贫血患儿临床观察

目的：探讨去铁酮治疗高量输血的重型β-地中海贫血患儿临床疗效。方法：选取我院2014年9月～2015年10月收治的31例需要高量输血的重型β-地中海贫血患儿为研究对象,采用去铁酮治疗,探讨临床疗效。结果：用药不超过1年的患儿有16例,与用药前相比,血清铁蛋白浓度变化不大,差异不显著,不具有统计学意义（P>0.05）,用药2年以上的患儿有15例,与用药前相比,患儿的血清铁蛋白逐渐下降,差异有统计学意义（P<0.05）;少数患儿用药后出现血象和肝功能异常变化。结论：采用去铁酮治疗重型β－地中海贫血患儿,坚持治疗,疗效显著,不良反应少,值得在临床上推广。     

地中海贫血伴铁缺乏临床分析

目的探讨铁缺乏在地中海贫血中的发生率及临床特点。方法作者在进修期间对本院近8年来确诊为地中海贫血的患者常规进行铁指标检查;对符合铁缺乏标准的30例患者进行总结,分析其性别、年龄、临床及实验室检查特点。结果铁缺乏占同期受检地中海贫血患儿的11.3%;男18例,女12例,年龄0.25~14岁;α型地中海贫血3例;β型地中海贫血27例;<3岁患儿(19例)铁缺乏多于>3岁患儿(11例),差异有统计学意义(P<0.05);两年龄组贫血程度分别为(71.58±8.55)g/L及(73.36±9.17)g/L,且差异无统计学意义(P>0.5);轻型及中间型β地中海贫血明显多于重型β地中海贫血(P<0.05)。20例患儿脾脏未扪及。结论地中海贫血患儿可能发生铁缺乏,尤其是婴幼儿及轻型β地中海贫血患儿以及脾脏无肿大的患儿。     

Advances in iron chelation: an update

INTRODUCTION: Oxidative stress (caused by excess iron) can result in tissue damage, organ failure and finally death, unless treated by iron chelators. The causative factor in the etiology of a variety of disease states is the presence of iron-generated reactive oxygen species (ROS), which can result in cell damage or which can affect the signaling pathways involved in cell necrosis-apoptosis or organ fibrosis, cancer, neurodegeneration and cardiovascular, hepatic or renal dysfunctions. Iron chelators can reduce oxidative stress by the removal of iron from target tissues. Equally as important, removal of iron from the active site of enzymes that play key roles in various diseases can be of considerable benefit to the patients. AREAS COVERED: This review focuses on iron chelators used as therapeutic agents. The importance of iron in oxidative damage is discussed, along with the three clinically approved iron chelators. EXPERT OPINION: A number of iron chelators are used as approved therapeutic agents in the treatment of thalassemia major, asthma, fungal infections and cancer. However, as our knowledge about the biochemistry of iron and its role in etiologies of seemingly unrelated diseases increases, new applications of the approved iron chelators, as well as the development of new iron chelators, present challenging opportunities in the areas of drug discovery and development.     

The role of iron chelation in cancer therapy

This review focuses on advances and strategies in the use of iron chelators as anti-tumor therapies. Although the development of iron chelators for human disease has focused primarily on their use in the treatment of secondary iron overload, chelators may also be useful anti-tumor agents. They can deplete iron or cause oxidative stress in the tumor due to redox perturbations in its environment. Iron chelators have been tested for their anti-tumor activity in cell culture experiments, animal models and human clinical trials. Largely for pragmatic reasons, clinical studies of the anti-tumor activity of iron chelators have generally focused on desferrioxamine (DFO), a drug approved for the treatment of iron overload. These studies have shown that DFO can retard tumor growth in many different experimental contexts. However, the activity of DFO is modest, and advances in the use of chelators as anti-cancer agents will require the development of new chelators based on new paradigms. Examples of iron chelators that have shown promising anti-tumor activity (in various stages of development) include heterocyclic carboxaldehyde thiosemicarbazones, analogs of pyridoxal isonicotinoyl hydrazone, tachpyridine, O-trensox, desferrithiocin, and other natural and synthetic chelators. Apart from their use as single agents, chelators may also synergize with other anti-cancer therapies. The development of chelators as anticancer agents is largely an unexplored field, but one with extraordinary potential to impact human cancer.     

Deferasirox: pharmacokinetics and clinical experience

INTRODUCTION: Iron overload is an inevitable consequence of transfusion therapy for a variety of underlying anemias. Iron overload, without effective chelation, will lead to significant morbidity and mortality. Deferasirox (Exjade?) is an oral tridentate iron chelator used for reducing iron overload. AREAS COVERED: In addition to the pharmacokinetic and pharmacodynamic profile of deferasirox, this review examines the efficacy and safety data from pivotal studies with deferasirox in iron-overloaded patients with various anemias, including thalassemia, sickle cell disease and myelodysplastic syndromes. A qualitative literature search for deferasirox was performed using PubMed and recent key congress publications (EHA and ASH); key search terms were deferasirox, pharmacokinetic, pharmacodynamic, efficacy and safety. EXPERT OPINION: Based on the current available data, deferasirox treatment is effective with a clinically manageable safety profile although appropriate dosing according to the severity of iron burden and iron intake, together with the careful monitoring of laboratory parameters and adverse events, is recommended. However, despite advances made in the treatment of iron overload, some patients still do not respond adequately to iron chelators, and increased awareness, understanding and further research are still needed.     

Iron chelator research: past,present, and future

The occurrence of in vivo iron toxicity in the human body can be categorized into iron overload and non-iron overload conditions. Iron overload conditions are common in beta-thalassemia and hereditary hemochromatosis patients, and anthracycline mediated cardiotoxicity is an example of a non-iron overload condition in cancer patients, in which the toxicity is iron-dependent. While hundreds of iron chelators have been evaluated in animal studies, only a few have been studied in humans. Examples of iron chelator drugs are desferrioxamine (DFO), deferiprone (L1), and dexrazoxane (ICRF 187). The compound ICL670 has completed phase II clinical trials and a phase III trial is planned in 2003. Triapine is currently in phase II clinical trial as an anticancer agent. CP502, GT56-252, NaHBED, and MPB0201 are examples of new chelators in preclinical/clinical development. In the past decade, many new viable utilities for iron chelators have been reported. This includes the use of iron chelators as antiviral, photoprotective, antiproliferative, and antifibrotic agents. This review will focus on the status of drug development for the treatment of iron overload in patients with beta-thalassemia and the potential use of iron chelators in the prevention and treatment of other diseases.     

The design and development of deferiprone (L1) and other iron chelators for clinical use: targeting methods and application prospects

Iron is essential for all human cells as well as neoplastic cells and invading microbes. Natural and synthetic iron chelators could affect biological processes involving iron and other metal ions in health and disease states. Iron overload is the most common metal toxicity condition worldwide. There are currently two iron chelating drugs, which are mostly used for the treatment of thalassaemia and other conditions of transfusional iron overload. Deferoxamine was until recently the only approved iron chelating drug, which is effective but very expensive and administered parenterally resulting in low compliance. Deferiprone (L1 or 1,2-dimethyl-3-hydroxypyrid-4-one) is the world's first and only orally active iron chelating drug, which is effective and inexpensive to synthesise thus increasing the prospects of making it available to most thalassaemia patients in third world countries who are not currently receiving any form of chelation therapy. Deferiprone has equivalent iron removal efficacy and comparable toxicity to deferoxamine. There are at least four other known iron chelators, which are currently being developed. Even if successful, these are not expected to become available for clinical use in the next five years and to be as inexpensive as deferiprone. The variation in the chemical, biological, pharmacological, toxicological and other properties of the chelating drugs and experimental chelators provide evidence of the difference in the mode of action of chelators and the need to identify and select molecular structures and substituents based on structure/activity correlations for specific pharmacological activity. Such information may increase the prospects of designing new chelating drugs, which could be targeted and act on different tissues, organs, proteins and iron pools that play important role not only in the treatment of iron overload but also in other diseases of iron and other metal imbalace and toxicity including free radical damage. Chelating drugs could also be designed, which could modify the enzymatic activity of iron and other metal containing enzymes, some of which play a key role in many diseases such as cancer, inflammation and atherosclerosis. Other applications of iron chelating drugs could involve the detoxification of toxic metals with similar metabolic pathways to iron such as Al, Cu, Ga, In, U and Pu.     

Iron chelation as therapy for HIV and Mycobacterium tuberculosis co-infection under conditions of iron overload

Iron chelators, as treatment for conditions of iron overload, have implications for AIDS and tuberculosis (TB) since excess iron in the system assists HIV and Mycobacterium tuberculosis (M.tb) multiplication. Excess iron, especially due to dietary habits, is almost as common in sub-Saharan Africa as infections by the two organisms. That HIV and M.tb influence each other's replication during co-infection is well established, but in vitro evaluations of concurrent infection of the two under conditions of iron overload and determining whether chelators reverse the effect, are limited. This review provides brief commentary on the possibility of iron chelators presently in clinical use influencing simultaneous HIV-M.tb infections during iron loading and the feasibility of evaluating this in vitro.     

An overview of iron metabolism: molecular and cellular criteria for the selection of iron chelators

Iron is a metal of capital importance in most living organisms. However, man differs from the rest of mammals by his incapacity to excrete significant amounts of iron. This means that both iron deficiency and iron overload are frequently encountered. We briefly review our current understanding of dietary iron absorption and then discuss iron transport and delivery to cells. The intracellular storage and utilisation of iron are then considered, with a particular emphasis on the transit iron pool. Cellular iron homeostasis appears principally to be regulated at the level of translation of key mRNA's involved in iron uptake, storage and utilisation, through iron regulatory proteins. The potential sites of iron chelation at the molecular level and cellular models which may be useful in the selection of potentially useful therapeutic iron chelators are briefly reviewed.     

Recent advances in the design of iron chelators against oxidative damage

Iron imbalance plays a pivotal role in oxidative damages associated with a wide range of pathological conditions. However, owing to the essential role of iron in biological processes, the beneficial effects of iron chelation therapy against oxidative damage have to be balanced against potential toxicity. The present review briefly introduces iron redox biochemistry and oxidative-stress associated pathologies, surveys recent advances in iron chelating strategies and summarizes some of our recent findings in this field, with a special emphasis on the chemical design constraints one must satisfy in order to synthesize iron chelators which could be beneficial against oxidative stress without inducing iron depletion of the body. The concept of oxidative stress activatable iron chelators is presented as a new paradigm for safe and efficient treatment of oxidative-stress associated conditions.     

铁过载对骨髓增生异常综合征患者的危害及地拉罗司祛铁疗效探讨

长期规律输血是骨髓增生异常综合征(MDS)最为重要的支持疗法,然而长期输血带来的铁过载会导致器官损害,严重影响患者的生存预后。祛铁治疗对于改善MDS患者造血机能、减少心脏事件、延长生存起着重要作用。地拉罗司是一种新型的口服铁螯合剂,能有效改善MDS患者的造血机能、促进血液学缓解并改善脏器功能,是MDS患者祛铁治疗的一线药物。本文就铁过载对MDS患者的危害、MDS祛铁治疗指南及地拉罗司在MDS铁过载治疗中的应用做一综述。     

Iron chelators for the treatment of cancer

The study of iron chelators as anti-tumor agents is still in its infancy. Iron is important for cellular proliferation and this is demonstrated by observations that iron-depletion results in cell cycle arrest and also apoptosis. In addition, many iron chelators are known to inhibit ribonucleotide reductase, the iron-containing enzyme that is the rate-limiting step for DNA synthesis. Desferrioxamine is a well known chelator used for the treatment of iron-overload disease, but it has also been shown to possess anti-cancer activity. Another class of chelators, namely the thiosemicarbazones, have been shown to possess anti-cancer activity since the 1950's, although their mechanism(s) of action have only recently been more comprehensively elucidated. In fact, the redox activity of thiosemicarbazone iron complexes is thought to be important in mediating their potent cytotoxicity. Moreover, unlike typical iron chelators which simply act to deplete tumors of iron, several thiosemicarbazones (i.e., Bp44mT and Dp44mT) do not induce this effect, their anti-cancer efficacy being due to other mechanisms e.g., redox activity. Other reports have also shown that some thiosemicarbazones inhibit topoisomerase IIα, demonstrating that this class of agents have multiple molecular targets and act by various mechanisms. The most well characterized thiosemicarbazone iron chelator in terms of its assessment in humans is 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP). Observations from these clinical trials highlight the less than optimal activity of this ligand and several side effects related to its use, including myelo-suppression, hypoxia and methemoglobinemia. The mechanisms responsible for these latter effects must be elucidated and the design of the ligand altered to minimize these problems and increase efficacy. This review discusses the development of chelators as unique agents for cancer treatment.