Drug Deferiprone Research Articles

Favipiravir vs. Deferiprone: Tautomeric, photophysical, in vitro biological studies, and binding interactions with SARS-Cov-2-MPro/ACE2

Coronavirus disease 2019 (COVID-19) still remains the most disastrous infection continuously affecting millions of people worldwide. Herein, we performed a comparative study between the anti-influenza drug favipiravir (FAV) and the anti-thalassemia drug deferiprone (DFP) in order to examine their potential as basic scaffolds for the generation of most effective and structurally novel antivirals. To conduct the initial molecular modelling and virtual screening steps, our recently proposed single crystal X-ray diffraction (SCXRD)/HYdrogen DEssolvation (HYDE) technology platform has been used. This platform allows molecular design, interactive prioritization and virtual evaluation of newly designed molecules, simultaneously affecting two COVID-related targets, including angiotensin-converting enzyme 2 (ACE2) as a host-cellular receptor (host-based approach) and the main protease (Mpro) enzyme of the spike glycoprotein of SARS-Cov-2 (virus-based approach). Based on the molecular docking results, DFP has shown higher binding affinity (Ki HYDE values) over FAV towards both biological targets. The tautomeric, physicochemical, and biological properties of FAV and DFP have been studied both experimentally and theoretically using molecular spectroscopy (UV–VIS absorption), parallel artificial membrane permeability assay, and cell biology (PAMPA and MTT assay), as well as DFT quantum chemical calculations. According to the obtained results, the enol tautomers of both compounds are considerably more stable in different organic solvents. However, the keto tautomer of FAV was estimated to be most preferable under physiological conditions, which is in good agreement with the molecular docking studies. The isolated crystal structure of DFP is in an excellent agreement with the computation in respect of the most stable tautomer. Combined single X-ray/molecular modeling studies including HYDE analyses provided not only insights into the protein–ligand interactions within the binding site of SARS-Cov-2-ACE2 and SARS-Cov-2-Mpro, but also a valuable information regarding the most stable enol tautomeric form of DFP that contributes to its estimated higher potency against these targets.

The Vital Role Played by Deferiprone in the Transition of Thalassaemia from a Fatal to a Chronic Disease and Challenges in Its Repurposing for Use in Non-Iron-Loaded Diseases.

The iron chelating orphan drug deferiprone (L1), discovered over 40 years ago, has been used daily by patients across the world at high doses (75-100 mg/kg) for more than 30 years with no serious toxicity. The level of safety and the simple, inexpensive synthesis are some of the many unique properties of L1, which played a major role in the contribution of the drug in the transition of thalassaemia from a fatal to a chronic disease. Other unique and valuable clinical properties of L1 in relation to pharmacology and metabolism include: oral effectiveness, which improved compliance compared to the prototype therapy with subcutaneous deferoxamine; highly effective iron removal from all iron-loaded organs, particularly the heart, which is the major target organ of iron toxicity and the cause of mortality in thalassaemic patients; an ability to achieve negative iron balance, completely remove all excess iron, and maintain normal iron stores in thalassaemic patients; rapid absorption from the stomach and rapid clearance from the body, allowing a greater frequency of repeated administration and overall increased efficacy of iron excretion, which is dependent on the dose used and also the concentration achieved at the site of drug action; and its ability to cross the blood-brain barrier and treat malignant, neurological, and microbial diseases affecting the brain. Some differential pharmacological activity by L1 among patients has been generally shown in relation to the absorption, distribution, metabolism, elimination, and toxicity (ADMET) of the drug. Unique properties exhibited by L1 in comparison to other drugs include specific protein interactions and antioxidant effects, such as iron removal from transferrin and lactoferrin; inhibition of iron and copper catalytic production of free radicals, ferroptosis, and cuproptosis; and inhibition of iron-containing proteins associated with different pathological conditions. The unique properties of L1 have attracted the interest of many investigators for drug repurposing and use in many pathological conditions, including cancer, neurodegenerative conditions, microbial conditions, renal conditions, free radical pathology, metal intoxication in relation to Fe, Cu, Al, Zn, Ga, In, U, and Pu, and other diseases. Similarly, the properties of L1 increase the prospects of its wider use in optimizing therapeutic efforts in many other fields of medicine, including synergies with other drugs.

Colorimetric detection of thalassaemia therapeutic drug deferiprone through tuning the peroxidase-like activity of MoS<sub>2</sub> quantum dots

Precisely regulating the catalytic activity of nanozymes is of great significance for their applications in sensing, biomedicine, etc . In this work, the peroxidase-like activity of MoS2 quantum dots (QDs) is controlled by regulating their aggregation or disaggregation in aqueous solution. Specifically, monodispersed MoS2 QDs show very weak peroxidase-like activity. Fe3+ ions can induce significant aggregation of MoS2 QDs in aqueous solution and thus greatly enhance their activity. However, the drug deferiprone that commonly used for thalassaemia treatment can selectively bind with Fe3+ via complexation, thus inhibiting the aggregation of MoS2 QDs and their enhancement of enzyme-like activity. Based on this mechanism, a new colorimetric method for the detection of deferiprone is developed and further successfully applied to the quality control of drug. Moreover, with the aid of photographing and chroma analysis by a smartphone, a smartphone-based analytical method for deferiprone is also established, which is expected to be extended to point-of-care testing and diagnosis.

Novel, immediately druggable targets in the ARK1 model of uterine serous papillary carcinoma (USPC): Proof-of-principle and clinical implications of blocking oncologically relevant posttranslational hydroxylations with a pioneer drug

Objective: The oxygenases that hydroxylate key proteins in cancer biology employ non-heme iron atoms for catalysis. Drugs targeting these atoms inhibit posttranslational hydroxylation (PTH) in preclinical tests and clinical trials. At clinical concentrations (≤150 μM), the drug deferiprone (DEF) blocks these non-heme iron atoms and thus every known PTH. The purpose of our study was to establish target expression response to DEF-blocked PTH activity in the ARK1 model of uterine serous papillary carcinoma (USPC).

Rational design, synthesis and biological evaluation of novel multitargeting anti-AD iron chelators with potent MAO-B inhibitory and antioxidant activity

A series of (3-hydroxypyridin-4-one)-coumarin hybrids were developed and investigated as potential multitargeting candidates for the treatment of Alzheimer's disease (AD) through the incorporation of iron-chelating and monoamine oxidase B (MAO-B) inhibition. This combination endowed the hybrids with good capacity to inhibit MAO-B as well as excellent iron-chelating effects. The pFe3+ values of the compounds were ranging from 16.91 to 20.16, comparable to more potent than the reference drug deferiprone (DFP). Among them, compound 18d exhibited the most promising activity against MAO-B, with an IC50 value of 87.9 nM. Moreover, compound 18d exerted favorable antioxidant activity, significantly reversed the amyloid-β1-42 (Aβ1-42) induced PC12 cell damage. More importantly, 18d remarkably ameliorated the cognitive dysfunction in a scopolamine-induced mice AD model. In brief, a series of hybrids with potential anti-AD effect were successfully obtained, indicating that the design of iron chelators with MAO-B inhibitory and antioxidant activities is an attractive strategy against AD progression.

Abstract 848: The Iron Chelator Deferiprone Clears Hemorrhagic Byproducts Following Acute Myocardial Infarction in a Swine Model of Ischemia-Reperfusion

Current treatments for myocardial infarction (MI) aim to remove the vascular occlusion and reperfuse the infarcted tissue. While reperfusion can salvage myocardium, it can also increase damage to the unsalvageable tissue, one mechanism of which is hemorrhage; the resulting blood and iron deposits increase edema and inflammation. We hypothesize that removing these iron deposits with the iron chelating drug deferiprone (DFP) will reduce inflammation and lead to faster healing post-MI. Using a swine model of ischemia-reperfusion, pigs were administered either DFP or saline for four weeks post-MI. Cardiac MRI tracked heart function, infarct progression (via late gadolinium enhancement), hemorrhage (via T2* imaging), and edema (via T2 imaging) at baseline and 1 day, 1 week, and 4 weeks post-MI. Animals were then sacrificed and hearts were processed for histology. Treatment with DFP decreased the presence of iron in the infarct compared to saline by one week post-MI, as shown by increased T2* values. DFP treatment also decreased end diastolic wall swelling, suggesting less inflammation post-MI. To support this, T2 values and histology both revealed trends toward less edema with DFP. Histology also showed trended increases in fibroblast proliferation and collagen deposition at four weeks post-MI in the treatment group, consistent with a faster resolution to scar. Ventricular remodeling (by ventricular volumes), infarct size (by MRI, histology and blood Troponin I levels), and infarct transmurality were all unaffected, but contractile function improved with DFP treatment: ejection fraction and wall thickening both improved faster. In conclusion, DFP treatment successfully reduced hemorrhagic iron within the infarct as compared to saline, indicating a clearing of the iron byproducts. Treatment also decreased wall swelling, suggesting reduced inflammation, and improved contractile function. In the infarct, reduced swelling could indicate faster remodeling and a faster resolution to scar, and histology confirms a more progressed scar structure with DFP treatment. Overall, iron chelation appears to be a promising therapy that could reduce the negative effects of hemorrhage and speed the functional recovery of patients post-MI.

A ratiometric fluorometric and colorimetric probe for the β-thalassemia drug deferiprone based on the use of gold nanoclusters and carbon dots.

A turn-on fluorometric probe is described for the β-thalassemia drug deferiprone (DFP). The probe is making use of carbon dots (C-dots) and gold nanoclusters (AuNCs) which, under 340-nm excitation, display dual emission with peaks at 445 and 592nm. The orange fluorescence of AuNCs is quenched after the addition of Fe(III), but recovered on addition of DFP. The blue fluorescence of the C-dots, in contrast, remains unchanged. The Fe(III)-DFP complex undergoes intermolecular electron transfer under UV excitation and displays only weak peaks in the UV region. The ratio of the two fluorescences is measured which makes the probe intrinsically self-calibrated. Colorimetry is best performed at a wavelength of 280nm. The ratio of fluorescences increases linearly in the 0.1-80μM DFP concentration range, and the detection limit is 0.1μM. The respective figures for colorimetry are 2.5-120μM and 0.3μM. The probe is highly selective for DFP. Thus, it possesses a large potential for detection of DFP in serum. Graphical abstract The orange fluorescence of gold nanoclusters (AuNCs) is quenched by Fe3+ ions but recovered on addition of deferiprone (DFP), while the change of blue fluorescence in carbon dots (C-dots) is minimal. Moreover, the Fe(III)-DFP complex undergoes intermolecular electron transfer under ultraviolet (UV) irradiation, and absorption spectra can be observed in the presence of Fe(III)-DFP detected by UV scanning. Thus, a ratiometric fluorometric and colorimetric assay is developed for DFP.

Bifunctional 3-hydroxy-4-pyridinones as effective aluminium chelators: synthesis, solution equilibrium studies and in vivo evaluation

This paper reports the results on the study of a set of synthesized bifunctional 3-hydroxy-4-pyridinones chelators as potential aluminium sequestering agents. They were N-functionalized with alkyl-amino, -carboxylic and –(amino-carboxylic) groups, envisaging the improvement of the Al3+ sequestering capacity, in comparison with the marketed chelating drug deferiprone. The main focus of this work was given to the assessment of their binding ability towards Al3+, which was studied by potentiometric and UV–Vis spectrophotometric measurements carried out at T = 298.15 K. The speciation models were characterized by AlpLqHr(3p+r−qz) species with different stoichiometry. Depending on ligand side-chain structures and on their thermodynamic properties, different trends of stability was found. Furthermore, the sequestering ability of the ligands towards Al3+ was investigated by the calculation of pL0.5 values at different experimental conditions. These results clearly indicate that the presence of amino-carboxylic groups in the ligands increases the sequestering ability towards Al3+. The in silico evaluation of pharmacokinetic descriptors indicated no violation to the Lipinski's rule and drug-likeness properties. Furthermore, the in vivo bioassays on a model of metal-overload mice showed for three investigated ligands a higher metal-sequestering capacity than for the chelating drug deferiprone, thus suggesting their potential interest as Al-chelating drug candidates.

Pyrophosphate functionalized silver nanoparticles for colorimetric determination of deferiprone via competitive binding to Fe(III)

The authors describe a colorimetric assay for the determination of the iron chelating drug deferiprone by using water dispersible silver nanoparticles functionalized with pyrophosphate groups (Pyro-AgNPs). The pyro-AgNPs are capable of cooperatively binding Fe3+ ions, and this results in a color change from yellow (peaking at 402 nm) to red (peaking at 520 nm) due to aggregation. However, this binding is competitively overruled, and hence aggregation is prevented in the presence of increasing concentrations of deferiprone. Consequently, the color (which is due to localized surface plasmon resonance) gradually changes from red to yellow, and this can be correlated to the concentration of the drug. The relative amounts of silver nanodispersion and pyrophosphate anions, of the pH values of the medium, and reaction times were optimized. Under the best conditions, the method exhibits a consistent optical response in the 6.0 to 100 μM deferiprone concentration range, with a 280 nM detection limit. The assay is selective over several amino acids, saccharides, and inorganic ions. The method was applied to the determination of deferiprone in pharmaceuticals and in spiked human plasma samples.

Characterization of the neuroprotective potential of derivatives of the iron chelating drug deferiprone.

There is growing evidence for alterations in iron homeostasis during aging that are exacerbated in neurodegenerative diseases such as Alzheimer's disease. However, since essentially all neurodegenerative diseases are multi-factorial in the sense that there are a large number of mechanisms that can be identified as contributing to nerve cell death, iron chelators that have additional activities might be the most useful for the treatment of age-related CNS diseases. We have described a series of cell culture-based assays that define molecular toxicity pathways relevant to neurodegenerative diseases and have used these assays to identify potential therapeutic compounds for the treatment of these diseases. Deferiprone is a blood brain barrier permeable, low molecular weight iron chelator that has been used for many years to treat systemic iron disease. In this study, we describe the use of our cell culture-based screening assays to identify deferiprone derivatives with the greatest therapeutic potential for the treatment of CNS diseases. We show that several derivatives are much more potent than deferiprone at reducing oxidative stress and preventing nerve cell death induced by multiple, age-related insults. In addition, we show that both deferiprone and the derivatives modulate several distinct signaling pathways associated with neuroprotection. All of the compounds were able to both inhibit the activation of p38 MAP kinase and JNK kinase and prevent the loss of PI3 kinase activity in response to a toxic stress. These results strongly suggest that these compounds have significant potential for the treatment of CNS diseases.

Bismuth coordination networks containing deferiprone: synthesis, characterisation, stability and antibacterial activity.

A series of bismuth-dicarboxylate-deferiprone coordination networks have been prepared and structurally characterised. The new compounds have been demonstrated to release the iron overload drug deferiprone on treatment with PBS and have also been shown to have antibacterial activity against H. pylori.

Inhibition of Fe2+- and Fe3+- induced hydroxyl radical production by the iron-chelating drug deferiprone

Deferiprone (L1) is an effective iron-chelating drug that is widely used for the treatment of iron-overload diseases. It is known that in aqueous solutions Fe2+ and Fe3+ ions can produce hydroxyl radicals via Fenton and photo-Fenton reactions. Although previous studies with Fe2+ have reported ferroxidase activity by L1 followed by the formation of Fe3+ chelate complexes and potential inhibition of Fenton reaction, no detailed data are available on the molecular antioxidant mechanisms involved. Similarly, in vitro studies have also shown that L1–Fe3+ complexes exhibit intense absorption bands up to 800nm and might be potential sources of phototoxicity. In this study we have applied an EPR spin trapping technique to answer two questions: (1) does L1 inhibit the Fenton reaction catalyzed by Fe2+ and Fe3+ ions and (2) does UV–Vis irradiation of the L1–Fe3+ complex result in the formation of reactive oxygen species. PBN and TMIO spin traps were used for detection of oxygen free radicals, and TEMP was used to trap singlet oxygen if it was formed via energy transfer from L1 in the triplet excited state. It was demonstrated that irradiation of Fe3+ aqua complexes by UV and visible light in the presence of spin traps results in the appearance of an EPR signal of the OH spin adduct (TMIO–OH, a(N)=14.15G, a(H)=16.25G; PBN–OH, a(N)=16.0G, a(H)=2.7G). The presence of L1 completely inhibited the OH radical production. The mechanism of OH spin adduct formation was confirmed by the detection of methyl radicals in the presence of dimethyl sulfoxide. No formation of singlet oxygen was detected under irradiation of L1 or its iron complexes. Furthermore, the interaction of L1 with Fe2+ ions completely inhibited hydroxyl radical production in the presence of hydrogen peroxide. These findings confirm an antioxidant targeting potential of L1 in diseases related to oxidative damage.

World health dilemmas: Orphan and rare diseases, orphan drugs and orphan patients.

According to global annual estimates hunger/malnutrition is the major cause of death (36 of 62 million). Cardiovascular diseases and cancer (5.44 of 13.43 million) are the major causes of death in developed countries, while lower respiratory tract infections, human immunodeficiency virus infection/acquired immunodeficiency syndrome, diarrhoeal disease, malaria and tuberculosis (10.88 of 27.12 million) are the major causes of death in developing countries with more than 70% of deaths occurring in children. The majority of approximately 800 million people with other rare diseases, including 100000 children born with thalassaemia annually receive no treatment. There are major ethical dilemmas in dealing with global health issues such as poverty and the treatment of orphan and rare diseases. Of approximately 50000 drugs about 10% are orphan drugs, with annual sales of the latter approaching 100 billion USD. In comparison, the annual revenue in 2009 from the top 12 pharmaceutical companies in Western countries was 445 billion USD and the top drug, atorvastatin, reached 100 billion USD. In the same year, the total government expenditure for health in the developing countries was 410 billion USD with only 6%-7% having been received as aid from developed countries. Drugs cost the National Health Service in the United Kingdom more than 20 billion USD or 10% of the annual health budget. Uncontrollable drug prices and marketing policies affect global health budgets, clinical practice, patient safety and survival. Fines of 5.3 billion USD were imposed on two pharmaceutical companies in the United States, the regulatory authority in France was replaced and clinicians were charged with bribery in order to overcome recent illegal practises affecting patient care. High expenditure for drug development is mainly related to marketing costs. However, only 2 million USD was spent developing the drug deferiprone (L1) for thalassaemia up to the stage of multicentre clinical trials. The criteria for drug development, price levels and use needs to be readdressed to improve drug safety and minimise costs. New global health policies based on cheaper drugs can help the treatment of many categories of orphan and rare diseases and millions of orphan patients in developing and developed countries.

Incorporation by coordination and release of the iron chelator drug deferiprone from zinc-based metal–organic frameworks

A series of new zinc-based metal-organic framework materials has been prepared in which deferiprone is incorporated as a chelating ligand on infinite or tri-zinc secondary building units following deprotonation. Deferiprone is immediately released from the MOFs on treatments with 1 N hydrochloric acid or buffer, but slow release is observed in ethanoic acid.

Treatment of Oxidative Stress With Chelation Therapy

mentosa. Hahn et al 1 have documented higher iron levels in eyes of patients with age-related macular degeneration than in eyes of age-matched controls (particularly chelatable iron deposition in the retinal pigment epithelium and Bruch membrane). Because iron catalyzes the Fenton reaction (which produces hydroxyl radical), these results may mean that ironmediated oxidative stress contributes to retinal degeneration in age-related macular degeneration. Furthermore, mice deficient in the ferroxidases ceruloplasmin and hephaestin accumulate iron in the retina and subsequently have retinal degeneration with features of age-related macular degeneration. 2,3 In these mice, iron chelation with the orally absorbed and cellpermeant iron chelator deferiprone (Ferriprox) ameliorated oxidative stress and protected against iron overload–induced retinal degeneration. 4 Because other investigators showed that the iron chelator deferoxamine can protect against retinal light damage and retinal ischemia reperfusion injury, Hadziahmetovicetal 5 decidedtotesttherecentlyUSFoodandDrug Administration–approved drug deferiprone because it is orally absorbed and has not been associated with retinal toxic effects in patients or mice. In the current issue of Translational Vision Science & Technology, Hadziahmetovic and colleagues report the ability of deferiprone to preventretinaldegenerationin2distinctpreclinicalmodels: sodium iodate (NaIO3)–induced retinal degeneration and the rd6 mouse. Sodium iodate is a retinotoxin, anditssystemicadministrationrelativelyselectivelydamagesretinalpigmentepitheliumandphotoreceptors.The rd6mutationaffectstheMfrpgene,afrizzled-relatedgene expressed in the retinal pigment epithelium. Mice homozygous for this mutation have an early-onset, slowly progressive loss of photoreceptors. Theinvestigatorsfoundthatsystemicpretreatmentand concomitant treatment with deferiprone modestly improved photoreceptor survival and markedly improved retinal pigment epithelium survival in the NaIO3model. Deferiprone also modestly improved photoreceptor survivalinrd6mice.Whatisthemechanismbywhichdeferiprone exerts these effects? The investigators found that deferiprone diminished NaIO3-induced upregulation of antioxidantandcomplementgenes(C3)causedbyNaIO3. Deferiprone also protected against NaIO3-induced reduction in the levels of visual cycle genesRhoandRpe65, consistent with retinal protection. These and other findings indicate that deferiprone reduces oxidative stress. The finding that deferiprone treatment ameliorated hereditary retinal degeneration due to the rd6 mutation in B6.C3Ga-Mfrprd6/J mutant mice is consistent with the previous work of Obolensky et al, 6 who found that deferoxamine provides functional and structural retina rescueintherd10mousemodelofretinitispigmentosa.Presumably, amelioration of oxidative stress also reduces photoreceptor damage in these models of human retinitis pigmentosa. 7 The dose of deferiprone used in this study is about 3-fold higher than that given to humans treated for systemic iron overload. In future studies, the investigators will examine both dose response and dosing frequency. The apparent lack of retinal toxic effects of deferiprone combined with the evidence that it can protect the retina against iron overload, NaIO3, the rd6 mutation, and light damage suggest that it merits further investigation for potential treatment of diverse retinal disorders. The results of these deferiprone experiments indicate that iron chelation may serve as a protective agent not only against iron overload–induced retinal degeneration but also against retinal disorders in which iron dysregulation is not the primary cause. In a Research Highlight in Translational Vision Science & Technology, Fliesler 8 notes that “drug repurposing” is a current buzz phrase in translational medicine. Deferiprone has been used for the treatment of thalassemia major and is currently being used in clinical trials in the United States for treatment of contrast-induced acute kidney disease and for slowing the progression of chronic kidney disease. The present article by Hadziahmetovic et al 5 may lead to such repurposing of deferiprone and thus represents yet another potential application of chelator-based therapeutics.

Effects on Mycobacterium avium Replication in Normal Human Macrophages by Deferiprone (L1) and Other Iron Chelators

Mycobacterium avium growth in cultured human macrophages is influenced by serum lipids, transferrin and iron levels. Iron-saturated transferrin enhances M. avium growth, whereas apotransferrin inhibits mycobacterial replication. The ability of iron chelators to mimic the effects of transferrin on intracellular and extracellular M. avium growth was examined. Smooth, transparent, AIDS patient derived M. avium 7497 scrovar 4 was used to infect 7-day cultured human macrophages. Growth was measured by determining the colony-forming units (CFU) after infected macrophages were lysed 0 to 7 days after infection. The new iron chelating drug deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one or L1, CAS 30652-11-0), 1-ethyl-2-methyl-3-hydroxypyrid-4-one (L1NEt), 1-propyl-2-methyl-3-hydroxypyrid-4-one (L1NPr), 1-allyl-2-methyl-3-hyproxypyrid-4-one (L1NAll), and 3,4-dihydroxycinnamic acid enhanced intracellular and extracellular mycobacterial replication at concentrations of 0.1-2.5 micrograms/ml. 2-Pyridinecarboxaldehyde-2-quinolylhydrazone (PCQH) inhibited intracellular replication from 0.1-1.0 microgram/ml. Most, but not all of the PCQH-induced intracellular inhibition could be eliminated using iron at concentrations greater than 1.0 microgram/ml. Iron also suppressed the effects of PCQH on extracellular M. avium replication. These results indicate that iron chelators may have variable effects at different concentrations and can significantly alter both intracellular and extracellular M. avium replication. It is suggested that at low concentrations deferiprone and other aketohydroxypyridine chelators could enhance the growth of M. avium but at high concentrations may function as adjunct therapy with other antimicrobials against infections with M. avium. These findings are important for therapeutic considerations and dose protocol design in relation to the new iron chelating drug deferiprone, which is currently used in thalassaemia and other iron loaded patients, some of whom are suffering from AIDS.

Interactions Of Hydroxycarbamide (Hydroxyurea) With Iron And Copper: Implications On Toxicity and Therapeutic Strategies

Presented at the 19th International Conference on Chelation, London, UK, 13-16 November 2009Preliminary spectrophotometric and potentiometric studies have shown that hydroxycarbamide or hydroxyurea (HU) can interact with copper(II) [Cu(II)], iron(II) [Fe(II)] and Fe(III) ions and form complexes, for example, a ratio of 1 HU:1 metal at pH 5. The affinity for Cu (log β1 = 3.1) and Fe (log β1 = 5) by HU is much lower than that of the Fe and Cu chelating drug deferiprone (L1), which is used for the treatment of iron overload. It is anticipated that under certain conditions of high concentrations of these metal ions such as in transfusional iron overload, the therapeutic, pharmacological and toxicological properties of HU could be affected. It is also suggested that excess chelatable and labile forms of Fe or Cu ions, such as non transferrin-bound iron (NTBI) or intracellular low molecular weight labile iron, are among the main factors that may cause variations in the therapeutic response to HU in cancer, sickle cell anemia, thalassemia intermedia and other groups of patients. Further studies are needed to clarify the interaction mechanisms of HU with metal ions in vitro, in vivo and in clinical conditions.

ChemInform Abstract: Design and Synthesis of Fluorine‐Substituted 3‐Hydroxypyridin‐4‐ones.

AbstractSeveral 2‐ and 5‐fluoro‐containing 3‐hydroxpyridin‐4‐ones such as (I)‐(IV) are prepared as modified analogues of the known drug deferiprone (V) in order to get substances with improved pharmaceutical profile.

Chelating Agents Used for Plutonium and Uranium Removal in Radiation Emergency Medicine

The prospects of using chelating agents for increasing the excretion of actinides are reviewed. The removal of plutonium by chelating agents is of great importance because plutonium is extremely dangerous and induces cancer due to radiation toxicity. Similarly, uranium is a radionuclide, which causes severe renal dysfunction within a short time period due to chemical toxicity. It may also induce cancers such as leukemia and osteosarcoma in cases of long-term internal radiation exposure. Investigations on chelating agents for the removal of plutonium were initiated in the 1960's and 1970's. Diethylenetriaminepentaacetic acid (DTPA) is recognized as a chelating agent that accelerates the excretion of plutonium in early treatment after an accident. Thereafter, there has long been an interest in finding new chelating agents with radionuclide removal properties for use in therapy, and many chelating agents such as 3,4,3-LIHOPO and CBMIDA have been studied for their ability to remove plutonium and uranium. Recently, the focus has turned to drugs that have been used successfully in the treatment of a variety of other diseases, for example the iron chelating drug deferiprone or 1,2-dimethyl-3-hydroxypyrid-4-one (L1), which is used in thalassaemia and ethane-1-hydroxy-1,1-bisphosphonate (EHBP), which is used in osteoporosis. Within this context, it is important to examine the clinical use of these two drugs as well as the properties of the experimental chelators 3,4,3-LIHOPO and CBMIDA in order to identify possible uses in the treatment of radiation workers contaminated with plutonium and uranium.

Clinical use, therapeutic aspects and future potential of deferiprone in thalassemia and other conditions of iron and other metal toxicity.

The therapeutic aspects and future prospects of the new iron chelating drug deferiprone are reviewed, with an emphasis on its clinical use in thalassemia and other conditions of iron overload, imbalance and toxicity, as well as its possible use in other metal toxicity conditions. Orally administered deferiprone appears to be as effective as subcutaneous deferoxamine in the removal of iron in transfused iron loaded patients, with an equivalent therapeutic index profile in both animals and humans. Only about 10% of patients requiring iron chelation therapy worldwide receive deferoxamine mainly because of its high cost, toxicity and low compliance with subcutaneous administration. Deferiprone has been used by over 6000 patients in 40 countries worldwide, in some cases daily for more than 10 years, with very promising results. Doses of 50-120 mg/kg/day are effective in bringing patients to negative iron balance. Deferiprone increases urinary iron excretion, decreases serum ferritin levels and reduces liver iron in the majority of chronically transfused iron loaded patients. All of the toxic side effects of deferiprone are considered reversible and manageable, and include agranulocytosis, musculoskeletal and joint pains, gastrointestinal complaints and zinc deficiency. In general, the incidence of toxic side effects could be reduced by using lower doses or combination therapy with deferoxamine. The suggestion that deferiprone therapy may cause liver fibrosis has not been confirmed. New therapeutic protocols for maximizing the efficacy and minimizing the toxicity of deferiprone are being considered based on new findings in relation to its metal chelation, pharmacological, toxicological and metabolic properties. (c) 2001 Prous Science. All rights reserved.