ABSTRACT
Fluorine-19 MRI is an emerging cellular imaging approach, enabling lucid, quantitative "hot-spot" imaging with no background signal. The utility of 19F-MRI to detect inflammation and cell therapy products in vivo could be expanded by improving the intrinsic sensitivity of the probe by molecular design. We describe a metal chelate based on a salicylidene-tris(aminomethyl)ethane core, with solubility in perfluorocarbon (PFC) oils, and a potent accelerator of the 19F longitudinal relaxation time ( T1). Shortening T1 can increase the 19F image sensitivity per time and decrease the minimum number of detectable cells. We used the condensation between the tripodal ligand tris-1,1,1-(aminomethyl)ethane and salicylaldehyde to form the salicylidene-tris(aminomethyl)ethane chelating agent (SALTAME). We purified four isomers of SALTAME, elucidated structures using X-ray scattering and NMR, and identified a single isomer with high PFC solubility. Mn4+, Fe3+, Co3+, and Ga3+ cations formed stable and separable chelates with SALTAME, but only Fe3+ yielded superior T1 shortening with modest line broadening at 3 and 9.4 T. We mixed Fe3+ chelate with perfluorooctyl bromide (PFOB) to formulate a stable paramagnetic nanoemulsion imaging probe and assessed its biocompatibility in macrophages in vitro using proliferation, cytotoxicity, and phenotypic cell assays. Signal-to-noise modeling of paramagnetic PFOB shows that sensitivity enhancement of nearly 4-fold is feasible at clinical magnetic field strengths using a 19F spin-density-weighted gradient-echo pulse sequence. We demonstrate the utility of this paramagnetic nanoemulsion as an in vivo MRI probe for detecting inflammation macrophages in mice. Overall, these paramagnetic PFC compounds represent a platform for the development of sensitive 19F probes.
Subject(s)
Fluorine/chemistry , Iron Chelating Agents/chemistry , Magnetic Resonance Imaging/methods , Animals , Cobalt/chemistry , Contrast Media/chemistry , Emulsions/chemistry , Ethylenediamines/chemistry , Fluorocarbons/chemistry , Gallium/chemistry , Iron Chelating Agents/adverse effects , Iron Chelating Agents/standards , Macrophages/drug effects , Manganese/chemistry , Metals/chemistry , MiceSubject(s)
Genetic Testing/standards , Molecular Diagnostic Techniques/standards , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/therapy , Practice Guidelines as Topic , Combined Modality Therapy/standards , Diagnosis, Differential , Evidence-Based Medicine , Germany , Hematinics/standards , Hematinics/therapeutic use , Hematology/standards , Humans , Iron Chelating Agents/standards , Iron Chelating Agents/therapeutic use , Molecular Targeted Therapy/standards , Myelodysplastic Syndromes/blood , Stem Cell Transplantation/standards , Treatment OutcomeABSTRACT
Zinc oxide nanocrystals-methylene blue nanocomposites were developed by electrodeposition of methylene blue onto the thin films of zinc oxide nanocrystals deposited onto SnO2/F coated glass substrates for in vitro sensing of anti-thalassemic drug i.e. deferiprone. Detailed morphological, electrochemical, structural and optical characterizations of ZnONC-MB/FTO electrode were done using XRD, SEM, EIS, FTIR, LSV, and CV and show quick response time (within 5 s), linearity as 1 × 10(-3) to 10(3) µM and shelf life of about 10 weeks under refrigerated conditions. Attempts have been made to utilize this electrode for estimation of deferiprone in urine samples. The developed sensor exhibited high reproducibility and good storage stability.
Subject(s)
Electrochemical Techniques , Iron Chelating Agents/analysis , Metal Nanoparticles/chemistry , Methylene Blue/chemistry , Zinc Oxide/chemistry , Calibration , Deferiprone , Electrochemical Techniques/standards , Electrodes , Electroplating , Fluorine/chemistry , Iron Chelating Agents/standards , Limit of Detection , Microscopy, Electron, Scanning , Pyridones/analysis , Pyridones/standards , Spectroscopy, Fourier Transform Infrared , Tin Compounds/chemistry , X-Ray DiffractionABSTRACT
INTRODUCTION: The Satisfaction with Iron Chelation Therapy (SICT) instrument was developed based on a literature review, in-depth patient and clinician interviews, and cognitive debriefing interviews. An, open-label, single arm, multicenter trial evaluating the efficacy and safety of deferasirox in patients diagnosed with transfusion-dependent iron overload, provided an opportunity to assess the psychometric measurement properties of the instrument. METHODS: Psychometric analyses were performed using data at baseline from 273 patients with a range of transfusion-dependent iron overload conditions who were participating in a multinational study. Responsiveness was further evaluated for all patients who also had subsequent satisfaction domain scores collected at week 4. RESULTS: Baseline SICT domain scores had acceptable floor and ceiling effects and internal consistency reliability (Cronbach's alpha: 0.75-0.85). Item discriminant and item convergent validity were both excellent although one item in each analysis did not meet the specified criterion. Small to moderate correlations were observed between SICT and Short Form 36 Health Survey (SF-36) domain scores. Patients with the highest levels of serum ferritin at baseline (>3100 ng/mL) were the least satisfied about the Perceived Effectiveness of ICT and vice versa. Satisfaction improved in all patients, although there were no clear differences observed between groups of patients defined according to changes in serum ferritin levels from baseline to week 4 (stable, improved, or worsened). CONCLUSIONS: The SICT domains are reliable and valid. Further testing using a more specific criterion (such as assessing patient global ratings of change in satisfaction domains that correspond to the SICT domains) could help to establish with greater confidence the responsiveness of the instrument.
Subject(s)
Iron Chelating Agents , Iron Overload/psychology , Psychometrics , Surveys and Questionnaires , Adult , Ferritins/blood , Humans , Iron Chelating Agents/standards , Iron Chelating Agents/therapeutic use , Iron Overload/blood , Iron Overload/etiology , Iron Overload/therapy , Middle Aged , Patient Satisfaction/statistics & numerical data , Reference Standards , Surveys and Questionnaires/standards , Transfusion Reaction , Treatment Outcome , Young AdultABSTRACT
Iron chelators are used in clinical practice to protect patients from the complications of iron overload and iron toxicity because there is no physiologic way for excess iron to be actively excreted. Deferoxamine, the only iron-chelating agent available for clinical use in the United States, is administered as a prolonged (8 to 24 hours) infusion, leading to poor compliance in many patients. Although many compounds have been screened in tissue cultures and animals as iron chelators, few have reached the stage of phase I and II clinical trials. The search for new chelating agents, which includes the "slow-release" depot formulation of deferoxamine and the "long-acting" hydroxyethyl starch-deferoxamine, has been disappointing because clinical trials have not demonstrated the intended efficacy. A more promising compound, ICL 670A--an orally active representative of a new class of iron chelators designed by computer modeling-is a potent and selective iron chelator. Its ability to mobilize tissue iron and promote its excretion has been shown in several animal models. In phase I dose-finding trials, ICL 670A was well tolerated and had a good safety profile. This compound is currently undergoing further clinical evaluation.
Subject(s)
Chelation Therapy/methods , Iron Chelating Agents/administration & dosage , Animals , Chelation Therapy/standards , Chelation Therapy/trends , Drug Administration Routes , Drug Compounding , Humans , Iron Chelating Agents/standards , Iron Chelating Agents/toxicity , Iron Overload/drug therapyABSTRACT
Iron chelation therapy with deferoxamine enhances iron excretion and removes excessive tissue iron in regularly transfused patients with sickle cell disease. Long-term studies of deferoxamine in other hemoglobinopathies demonstrate that regular chelation therapy also reduces iron-related organ damage and mortality. Careful design of chelation regimens and attention to compliance are critical elements of successful therapy. The role of new chelators in sickle cell disease is currently under Investigation.
Subject(s)
Anemia, Sickle Cell/drug therapy , Chelation Therapy/methods , Iron Chelating Agents/administration & dosage , Anemia, Sickle Cell/blood , Follow-Up Studies , Humans , Iron/metabolism , Iron Chelating Agents/standardsABSTRACT
A reversed-phase HPLC separation of iron(III) chelates of 16 representative fungal siderophores including ferrichromes, coprogens and triacetylfusarinine C was established in order to investigate siderophore production of fungi. For comparison purposes, the widely used bacterial siderophore ferrioxamine B was included. Culture filtrates of the fungi Penicillium resticulosum, Fusarium dimerum, Aspergillus fumigatus and Neurospora crassa were quantitatively analyzed for the presence of known and unknown siderophores after growth in low-iron culture media and adsorption on XAD-2 columns using this HPLC separation system. Photodiode array detection allowed the distinction between siderophores and non-siderophores. According to their ultraviolet/visible spectra, a further classification of the siderophores into four types due to the number of anhydromevalonic acid residues per molecule (0-3) was possible.