RESUMO
Antibacterial drug resistance of gram-negative bacteria (GNB) results in high morbidity and mortality of GNB infection, seriously threaten human health globally. Developing new antibiotics has become the critical need for dealing with drug-resistant bacterial infections. Cefiderocol is an iron carrier cephalosporin that achieves drug accumulation through a unique "Trojan horse" strategy into the bacterial periplasm. It shows high antibacterial activity against multidrug-resistant (MDR) Enterobacteriaceae and MDR non-fermentative bacteria. The application of cefiderocol offers new hope for treating clinical drug-resistant bacterial infections. However, limited clinical data and uncertainties about its resistance mechanisms constrain the choice of its therapeutic use. This review aimed to summarize the clinical applications, drug resistance mechanisms, and co-administration of cefiderocol.
Assuntos
Cefiderocol , Infecções por Bactérias Gram-Negativas , Humanos , Sideróforos/farmacologia , Sideróforos/uso terapêutico , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Cefalosporinas/farmacologia , Cefalosporinas/uso terapêutico , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/microbiologia , Bactérias Gram-Negativas , Farmacorresistência Bacteriana Múltipla , Testes de Sensibilidade MicrobianaRESUMO
Fungal diseases have become a major public health issue worldwide. Increasing drug resistance and the limited number of available antifungals result in high morbidity and mortality. Metal-based drugs have been reported to be therapeutic agents against major protozoan diseases, but knowledge of their ability to function as antifungals is limited. In this study, we found that calcium supplementation combined with iron deficiency causes dramatic growth inhibition of the human fungal pathogens Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans. Calcium induces the downregulation of iron uptake-related genes and, in particular, causes a decrease in the expression of the transcription factor HapX, which tends to transcriptionally activate siderophore-mediated iron acquisition under iron-deficient conditions. Iron deficiency causes calcium overload and the overproduction of intracellular reactive oxygen species (ROS), and perturbed ion homeostasis suppresses fungal growth. These phenomena are consistently identified in azole-resistant A. fumigatus isolates. The findings here imply that low iron availability lets cells mistakenly absorb calcium as a substitute, causing calcium abnormalities. Thus, there is a mutual effect between iron and calcium in fungal pathogens, and the combination of calcium with an iron chelator could serve to improve antifungal therapy. IMPORTANCE Millions of immunocompromised people are at a higher risk of developing different types of severe fungal diseases. The limited number of antifungals and the emergence of antimicrobial resistance highlight an urgent need for new strategies against invasive fungal infections. Here, we report that calcium can interfere with iron absorption of fungal pathogens, especially in iron-limited environments. Thus, a combination of calcium supplementation with an iron chelator inhibits the growth of human fungal pathogens, including Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans. Moreover, we demonstrate that iron deficiency induces a nonspecific calcium uptake response, which results in toxic levels of metal. Findings in this study suggest that a microenvironment with excess calcium and limited iron is an efficient strategy to curb the growth of fungal pathogens, especially for drug-resistant isolates.
Assuntos
Criptococose , Cryptococcus neoformans , Deficiências de Ferro , Micoses , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Aspergillus fumigatus , Cálcio/metabolismo , Cálcio/farmacologia , Cálcio/uso terapêutico , Candida albicans/metabolismo , Cryptococcus neoformans/metabolismo , Suplementos Nutricionais , Farmacorresistência Fúngica , Humanos , Ferro/metabolismo , Micoses/microbiologia , Sideróforos/metabolismo , Sideróforos/farmacologia , Sideróforos/uso terapêuticoRESUMO
We report a case of resistance development toward cefiderocol in a patient with intra-abdominal and bloodstream infections caused by carbapenemase-producing Enterobacter cloacae within 21 days of cefiderocol therapy. Whole genome sequencing revealed heterogeneous mutations in the cirA gene, encoding a catecholate siderophore receptor, conferring phenotypic resistance to cefiderocol.
Assuntos
Enterobacter cloacae , Sideróforos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Proteínas de Bactérias/genética , Carbapenêmicos/farmacologia , Carbapenêmicos/uso terapêutico , Cefalosporinas , Enterobacter cloacae/genética , Humanos , Testes de Sensibilidade Microbiana , Mutação , Sideróforos/uso terapêutico , beta-Lactamases/genética , CefiderocolRESUMO
ABSTRACT A 10-year-old Malay girl with underlying HbE/beta-thalassemia, on regular blood transfusion and deferoxamine iron chelation therapy, presented with two-month history of bilateral blurring of vision. On examination, her vision was 6/36 both eyes. Other optic nerve functions were normal. Anterior segment examination of both eyes was unremarkable. Fundus examination of both eyes revealed dull foveal reflex. Optical coherence tomography of both maculae showed increased central subfield thickness. Fundus fluorescence angiography showed patchy hypofluorescence over macular region for both eyes and late staining, indicating retinal pigment epithelium anomalies. A diagnosis of iron-chelation-therapy-related bilateral maculopathy was made. Patient was co-managed with pediatric hematology team to adjust the dose of deferoxamine, and was given three monthly appointments to monitor the progression of maculopathy at the ophthalmology clinic. However patient defaulted ophthalmology follow-up after the first visit.
RESUMO Uma menina malaia de 10 anos de idade com doença de base- B/beta-talassemia, em transfusão de sangue regular e terapia quelante de ferro deferoxamina, apresentou história de dois meses de visão turva bilateral. Ao exame, sua visão era de 6/36 em ambos os olhos. Outras funções do nervo óptico estavam normais. O exame do segmento anterior de ambos os olhos foi normal. Exame do fundo de ambos os olhos revelou reflexo foveal opaco. A tomografia de coerência óptica de ambas as máculas mostrou aumento da espessura do subcampo central. A angiografia de fluorescência do fundo mostrou hipofluorescência irregular sobre a região macular de ambos os olhos e coloração tardia, indicando anomalias de epitélio pigmentar da retina. Um diagnóstico de maculopatia bilateral relacionada à terapia quelante de ferro foi feito. A paciente foi avaliada em conjunto com a equipe de hematologia pediátrica para ajustar a dose de deferoxamina, e foram oferecidas três consultas mensais na clínica oftalmológica, para monitorar a progressão da maculopatia. No entanto, ela não compareceu para acompanhamento oftalmológico após a primeira visita.
Assuntos
Humanos , Feminino , Criança , Sideróforos/efeitos adversos , Talassemia beta/tratamento farmacológico , Desferroxamina/efeitos adversos , Reação Transfusional , Degeneração Macular/complicações , Transfusão de Sangue , Sideróforos/uso terapêutico , Talassemia beta/diagnóstico , Desferroxamina/uso terapêuticoRESUMO
Cefiderocol is a newly approved siderophore cephalosporin that demonstrates expanded in vitro activity against multidrug-resistant Gram-negative bacteria. In two challenging cases reported here, cefiderocol shows potential utility as salvage therapy against difficult-to-treat pathogens with limited or no treatment options; however, two multicenter, randomized clinical trials have yielded mixed results among cefiderocol-treated patients. Taken together, clinicians must balance a clear need for cefiderocol in clinical practice with the uncertainties that have stemmed from the available data.
Assuntos
Antibacterianos/uso terapêutico , Cefalosporinas/uso terapêutico , Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae/efeitos dos fármacos , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Adolescente , Compostos Azabicíclicos/uso terapêutico , Bacteriemia/tratamento farmacológico , Bacteriemia/microbiologia , Ceftazidima/uso terapêutico , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla/fisiologia , Humanos , Masculino , Testes de Sensibilidade Microbiana , Osteomielite/tratamento farmacológico , Osteomielite/microbiologia , Polimixina B/uso terapêutico , Sideróforos/uso terapêutico , beta-Lactamases/metabolismo , CefiderocolRESUMO
The pharmacokinetic (PK) and pharmacodynamic (PD) parameters which correlated with the in vivo efficacy of cefiderocol were evaluated using neutropenic murine thigh and lung infection models in which the infections were caused by a variety of Gram-negative bacilli. The dose fractionation study using the thigh infection model in which the infection was caused by Pseudomonas aeruginosa showed that the cumulative percentage of a 24-h period that the free drug concentration in plasma exceeds the MIC (%fT>MIC) rather than the free peak level divided by the MIC (fCmax/MIC) and the area under the free concentration-time curve over 24 h divided by the MIC (fAUC/MIC) was the PK/PD parameter that best correlated with efficacy. The study with multiple carbapenem-resistant strains revealed that the %fT>MIC determined in iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) better reflected the in vivo efficacy of cefiderocol than the %fT>MIC determined in cation-adjusted Mueller-Hinton broth (CAMHB). The mean %fT>MIC of cefiderocol required for a 1-log10 reduction against 10 strains of Enterobacteriaceae and 3 strains of Pseudomonas aeruginosa in the thigh infection models were 73.3% and 77.2%, respectively. The mean %fT>MIC for Enterobacteriaceae, P. aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia in the lung infection model were 64.4%, 70.3%, 88.1%, and 53.9%, respectively. These results indicate that cefiderocol has potent efficacy against Gram-negative bacilli, including carbapenem-resistant strains, irrespective of the bacterial species, in neutropenic thigh and lung infection models and that the in vivo efficacy correlated with the in vitro MIC under iron-deficient conditions.
Assuntos
Cefalosporinas/farmacocinética , Cefalosporinas/uso terapêutico , Pulmão/microbiologia , Sideróforos/uso terapêutico , Coxa da Perna/microbiologia , Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/patogenicidade , Animais , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Carbapenêmicos/farmacocinética , Carbapenêmicos/uso terapêutico , Farmacorresistência Bacteriana Múltipla , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/patogenicidade , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/patogenicidade , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Ligação Proteica , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/patogenicidade , Sideróforos/farmacocinética , Stenotrophomonas maltophilia/efeitos dos fármacos , Stenotrophomonas maltophilia/patogenicidade , CefiderocolRESUMO
OBJECTIVE: Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder accompanied with hyperalgesia, edema and pain. At least 30% of the patients failed to respond to the available treatments and medications, which yet have a lot of serious adverse effects on patients. So, using novel technologies to produce more efficient medications is needed. According to the role of iron manipulation in inflammatory process, we have synthetized RAc1 nano particle, which contains zinc and has iron chelating property. In the present study, we evaluated RAc1 nano particle effects on hyperalgesia and liver hepcidin and serum IL-1ß and TNF-α expression levels during acute and chronic phases of adjuvant-induced inflammation in male rats and compared its effects with Deferoxamine. METHODS AND MATERIALS: Complete Freund's adjuvant (CFA)-induced arthritis was caused by single subcutaneous injection of CFA into the rat's hind paw on day zero. RAc1 with 100, 200 and 400â¯ng/kg doses and deferoxamin with doses of 200â¯mg/kg after diluting in vehicles were administered daily (i.p.) during the 21â¯days of the study after CFA injection. Hyperalgesia, Edema, liver hepcidin and serum IL-1ß and TNF-α expression levels were assessed on days 0, 7, 14 and 21 of the study. RESULTS: The results of this study indicated the role of RAc1 nano particle administration in reducing paw edema, thermal hyperalgesia, and liver hepcidin and serum IL-1ß and TNF-α expression even in comparison with Deferoxamine during different phases of inflammation caused by CFA. CONCLUSION: It seems that RAc1 nano particle exerts its immune modulatory effects by decreasing liver hepcidin expression and serum IL-1ß and TNF-α levels.
Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Inflamação/tratamento farmacológico , Quelantes de Ferro/uso terapêutico , Nanopartículas/uso terapêutico , Animais , Desferroxamina/uso terapêutico , Hepcidinas/metabolismo , Humanos , Interleucina-1beta/sangue , Irã (Geográfico) , Fígado/metabolismo , Masculino , Ratos , Ratos Wistar , Sideróforos/uso terapêutico , Fator de Necrose Tumoral alfa/sangueRESUMO
PURPOSE: To compare contrast sensitivity (CS) in multi-transfused ß-thalassemia patients who received deferoxamine with those who received Osveral. METHODS: In this cross sectional study a total of 60 ß-thalassemia patients (30 used deferoxamine and 30 used deferasirox) were regarded as case group and 30 age and sex matched healthy subjects were selected as control group. All subjects had a set of examinations including refraction, visual acuity, Biomicroscopy, ophthalmoscopy and CS. Contrast threshold was assessed with the use of Freiberg visual acuity and contrast test under the mesopic light condition for three frequencies; 1, 5, 15cpd. All data analysis was performed using SPSS, version 17. RESULTS: In visual acuity tests, thalassemic patients did not have any problem. Contrast threshold was higher in thalassemic patients who infuse deferoxamine (1.87±0.63, 1.46±0.81, and 2.96±1.68 in 1, 5, and 15cpd, respectively) than that of those who intake deferasirox (1.74±0.80 (P=0.743), 0.99±0.74 (P=0.047), and 2.42±1.36 (P=0.321) for 1, 5, and 15cpd, respectively), and also than healthy patients (1.33±0.58 (P=0.009), 0.95±0.68 (P=0.022), and 2.24±1.23 (P=0.135) for 1, 5, and 15cpd, respectively). Comparing those who used deferasirox with healthy subjects, contrast threshold was higher in deferasirox group at all special frequencies (P>0.05). No significant relationship was observed between CS values and duration of transfusion, serum ferritin concentration and dose of chelation therapy (P>0.05). CONCLUSIONS: CS tests can detect visual disturbance in thalassemic patients before the impairment of visual acuity. It is suggested that CS tests be included in their regular eye examination.
Assuntos
Sensibilidades de Contraste/fisiologia , Deferasirox/uso terapêutico , Desferroxamina/uso terapêutico , Sideróforos/uso terapêutico , Transtornos da Visão/fisiopatologia , Talassemia beta/tratamento farmacológico , Adulto , Análise de Variância , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Masculino , Acuidade Visual/fisiologia , Adulto Jovem , Talassemia beta/fisiopatologiaRESUMO
Excess iron deposition in the brain often causes oxidative stress-related damage and necrosis of dopaminergic neurons in the substantia nigra and has been reported to be one of the major vulnerability factors in Parkinson's disease (PD). Iron chelation therapy using deferoxamine (DFO) may inhibit this nigrostriatal degeneration and prevent the progress of PD. However, DFO shows very short half-life in vivo and hardly penetrates the blood brain barrier (BBB). Hence, it is of great interest to develop DFO formulations for safe and efficient intracerebral drug delivery. Herein, we report a polymeric nanoparticle system modified with brain-targeting peptide rabies virus glycoprotein (RVG) 29 that can intracerebrally deliver DFO. The nanoparticle system penetrates the BBB possibly through specific receptor-mediated endocytosis triggered by the RVG29 peptide. Administration of these nanoparticles significantly decreased iron content and oxidative stress levels in the substantia nigra and striatum of PD mice and effectively reduced their dopaminergic neuron damage and as reversed their neurobehavioral deficits, without causing any overt adverse effects in the brain or other organs. This DFO-based nanoformulation holds great promise for delivery of DFO into the brain and for realizing iron chelation therapy in PD treatment.
Assuntos
Encéfalo/metabolismo , Desferroxamina/administração & dosagem , Sistemas de Liberação de Medicamentos , Glicoproteínas/química , Nanopartículas/administração & dosagem , Nanopartículas/metabolismo , Doença de Parkinson/tratamento farmacológico , Fragmentos de Peptídeos/química , Proteínas Virais/química , Animais , Encéfalo/efeitos dos fármacos , Desferroxamina/farmacocinética , Desferroxamina/farmacologia , Desferroxamina/uso terapêutico , Glicoproteínas/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doença de Parkinson/metabolismo , Fragmentos de Peptídeos/administração & dosagem , Sideróforos/administração & dosagem , Sideróforos/farmacocinética , Sideróforos/farmacologia , Sideróforos/uso terapêutico , Proteínas Virais/administração & dosagemRESUMO
Iron overload (IOL) due to increased intestinal iron absorption constitutes a major clinical problem in patients with non-transfusion-dependent thalassemia (NTDT), which is a cumulative process with advancing age. Current models for iron metabolism in patients with NTDT suggest that suppression of serum hepcidin leads to an increase in iron absorption and subsequent release of iron from the reticuloendothelial system, leading to depletion of macrophage iron, relatively low levels of serum ferritin, and liver iron loading. The consequences of IOL in patients with NTDT are multiple and multifactorial. Accurate and reliable methods of diagnosis and monitoring of body iron levels are essential, and the method of choice for measuring iron accumulation will depend on the patient's needs and on the available facilities. Iron chelation therapy (ICT) remains the backbone of NTDT management and is one of the most effective and practical ways of decreasing morbidity and mortality. The aim of this review is to describe the mechanism of IOL in NTDT, and the clinical complications that can develop as a result, in addition to the current and future therapeutic options available for the management of IOL in NTDT.
Assuntos
Sobrecarga de Ferro/tratamento farmacológico , Sideróforos/uso terapêutico , Talassemia/tratamento farmacológico , Ensaios Clínicos como Assunto , Humanos , Ferro/metabolismo , Sobrecarga de Ferro/diagnóstico , Sobrecarga de Ferro/etiologia , Sideróforos/administração & dosagem , Sideróforos/efeitos adversos , Sideróforos/farmacologia , Talassemia/complicaçõesRESUMO
Our phase I, open-label, multi-center, dose-escalation study evaluated the pharmacokinetics (PK) of SP-420, a tridentate oral iron chelating agent of the desferrithiocin class, in patients with transfusion dependent ß-thalassemia. SP-420 was administered as a single dose of 1.5 (n = 3), 3 (n = 3), 6 (n = 3), 12 (n = 3), and 24 (n = 6) mg/kg or as a twice-daily dose of 9 mg/kg (n = 6) over 14-28 days. There was a near dose-linear increase in the mean plasma SP-420 concentrations and in the mean values for Cmax and AUC0-τ over the dose range evaluated. The median tmax ranged from 0.5 to 2.25 h and was not dose dependent. The study was prematurely terminated by the sponsor due to renal adverse events (AE) including proteinuria, increase in serum creatinine, and one case of Fanconi syndrome. Other adverse effects included hypersensitivity reactions and gastrointestinal disturbances. Based on current dose administration, the renal AE observed outweighed the possible benefits from chelation therapy. However, additional studies assessing efficacy and safety of lower doses or less frequent dosing of SP-420 over longer durations with close monitoring would be necessary to better explain the findings of our study and characterize the safety of the study drug.
Assuntos
Cicloexanonas/farmacocinética , Di-Hidropiridinas/efeitos adversos , Quelantes de Ferro/efeitos adversos , Quelantes de Ferro/farmacocinética , Tiazóis/efeitos adversos , Tiazóis/farmacocinética , Talassemia beta/terapia , Adolescente , Adulto , Transfusão de Sangue , Cicloexanonas/efeitos adversos , Cicloexanonas/uso terapêutico , Di-Hidropiridinas/uso terapêutico , Relação Dose-Resposta a Droga , Humanos , Quelantes de Ferro/administração & dosagem , Nefropatias/induzido quimicamente , Pessoa de Meia-Idade , Sideróforos/uso terapêutico , Sideróforos/toxicidade , Tiazóis/uso terapêutico , Adulto Jovem , Talassemia beta/complicações , Talassemia beta/tratamento farmacológicoRESUMO
AIM OF THE STUDY: To investigate the pulmonary oxidative stress and possible protective effect of N-Acetylcysteine (NAC) and Desferoxamine (DFX)in a porcine model subjected to hemorrhagic shock. MATERIALS AND METHODS: Twenty-one pigs were randomly allocated to Group-A (sham, n = 5), Group-B (fluid resuscitation, n = 8) and Group-C (fluid, NAC and DFX resuscitation, n = 8). Groups B and C were subjected to a 40-min shock period induced by liver trauma, followed by a 60-min resuscitation period. During shock, the mean arterial pressure (MAP) was maintained at 30-40 mmHg. Resuscitation consisted of crystalloids (35 mL/kg) and colloids (18 mL/kg) targeting to MAP normalization (baseline values ± 10%). In addition, Group-C received pretreatment with NAC 200 mg/kg plus DFX 2 g as intravenous infusions. Thiobarbituric Acid Reactive Substances (TBARS), protein carbonyls and glutathione peroxidase (GPx) activity were determined in lung tissue homogenates. Also, histological examination of pulmonary tissue specimens was performed. RESULTS: TBARS were higher in Group-B than in Group-A or Group-C: 2.90 ± 0.47, 0.57 ± 0.10, 1.78 ± 0.47 pmol/µg protein, respectively (p < 0.05). Protein carbonyls content was higher in Group-B than in Group-A or Group-C: 3.22 ± 0.68, 0.89 ± 0.30, 1.95 ± 0.54 nmol/mg protein, respectively (p > 0.05). GPx activity did not differ significantly between the three groups (p > 0.05). Lung histology was improved in Group-C versus Group-B, with less alveolar collapse, interstitial edema and inflammation. CONCLUSION: NAC plus DFX prevented the increase of pulmonary oxidative stress markers and protein damage after resuscitated hemorrhagic shock and had beneficial effect on lung histology. NAC/DFX combination may be used in the multimodal treatment of hemorrhagic shock, since it may significantly prevent free radical injury in the lung.
Assuntos
Acetilcisteína/uso terapêutico , Desferroxamina/uso terapêutico , Sequestradores de Radicais Livres/uso terapêutico , Pulmão/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Choque Hemorrágico/tratamento farmacológico , Sideróforos/uso terapêutico , Acetilcisteína/administração & dosagem , Animais , Biomarcadores/análise , Coloides , Soluções Cristaloides , Desferroxamina/administração & dosagem , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Hidratação/métodos , Glutationa Peroxidase/análise , Humanos , Infusões Intravenosas , Soluções Isotônicas/administração & dosagem , Pulmão/enzimologia , Pulmão/patologia , Masculino , Carbonilação Proteica/efeitos dos fármacos , Distribuição Aleatória , Soluções para Reidratação/administração & dosagem , Choque Hemorrágico/complicações , Suínos , Substâncias Reativas com Ácido Tiobarbitúrico/análiseRESUMO
PURPOSE: To assess the impact of two iron chelation modalities in thalassemic patients on foveal and subfoveal choroidal thickness. METHODS: The study included 60 ß-thalassemia major patients. They included 30 patients on oral deferasirox after a period of subcutaneous deferoxamine (Group 2) and 30 patients on subcutaneous deferoxamine (Group 3). Thirty age- and sex-matched healthy children were included as a control group (Group 1). All participants underwent a complete ophthalmologic evaluation and Spectral Domain Optical Coherence Tomography. RESULTS: Age, gender, intraocular pressure, best-corrected visual acuity, and refraction were not statistically different between the three studied groups. Ferritin level, pretransfusion hemoglobin, serum iron, and duration of thalassemia were not statistically different between the two thalassemic groups. Foveal thickness in Group 1 (225.15 ± 17.35 µm) was statistically higher than in Group 2 (210.53 ± 21.73 µm) (P < 0.001) and Group 3 (200.15 ± 7.34 µm) (P < 0.001). It was statistically higher in Group 2 than in Group 3 (P = 0.001). Subfoveal choroidal thickness in Group 1 (279.70 ± 32.54 µm) was statistically higher than in Group 2 (255.80 ± 19.20 µm) (P < 0.001) and Group 3 (248.28 ± 20.43 µm) (P < 0.001). It was statistically higher in Group 2 than in Group 3 (P < 0.05). CONCLUSION: Thalassemic patients can develop a significant decrease in foveal thickness because of the inevitable use of chelation therapy. Deferoxamine as a chelating agent can affect foveal thickness more than the oral form (deferasirox).
Assuntos
Corioide/patologia , Fóvea Central/patologia , Talassemia beta/complicações , Administração Oral , Adolescente , Criança , Corioide/diagnóstico por imagem , Estudos Transversais , Desferroxamina/uso terapêutico , Feminino , Ferritinas/sangue , Fóvea Central/diagnóstico por imagem , Humanos , Infusões Subcutâneas , Pressão Intraocular/fisiologia , Masculino , Sideróforos/uso terapêutico , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Talassemia beta/diagnóstico por imagem , Talassemia beta/tratamento farmacológicoRESUMO
PURPOSE: Here we show how a model-based approach may be used to provide further insight into the role of clinical and demographic covariates on the progression of iron overload. The therapeutic effect of deferoxamine is used to illustrate the application of disease modelling as a means to characterising treatment response in individual patients. METHODS: Serum ferritin, demographic characteristics and individual treatment data from clinical routine practice on 27 patients affected by ß-thalassaemia major were used for the purposes of this analysis. The time course of serum ferritin was described by a hierarchical nonlinear mixed effects model, in which compliance was parameterised as a covariate factor. Modelling and simulation procedures were implemented in NONMEM (7.2.0). RESULTS: A turnover model best described serum ferritin changes over time, with the effect of blood transfusions introduced on the ferritin conversion rate and the effect of deferoxamine on the elimination parameter (Kout) in a proportional manner. The results of the simulations showed that poor quality of execution is preferable over drug holidays; and that independently of the compliance pattern, the therapeutic intervention is not effective if >60% of the doses are missed. CONCLUSIONS: Modelling of ferritin response enables characterisation of the dynamics of iron overload due to chronic transfusion. The approach can be used to support decision making in clinical practice, including personalisation of the dose for existing and novel chelating agents.
Assuntos
Terapia por Quelação/métodos , Desferroxamina/uso terapêutico , Ferritinas/sangue , Sobrecarga de Ferro/tratamento farmacológico , Sideróforos/uso terapêutico , Talassemia beta/terapia , Adolescente , Adulto , Criança , Simulação por Computador , Desferroxamina/sangue , Desferroxamina/farmacologia , Relação Dose-Resposta a Droga , Transfusão de Eritrócitos/efeitos adversos , Humanos , Sobrecarga de Ferro/sangue , Sobrecarga de Ferro/etiologia , Modelos Biológicos , Sideróforos/sangue , Sideróforos/farmacologia , Adulto Jovem , Talassemia beta/sangue , Talassemia beta/complicaçõesRESUMO
Iron-overload is a well-known factor of hepatotoxicity and liver fibrosis, which found to be a common finding among hepatitis C virus patients and related to interferon resistance. We aimed to elucidate the potential antifibrotic effect of deferoxamine; the main iron chelator, and its additional usefulness to interferon-based therapy in concanavalin A-induced immunological model of liver fibrosis. Rats were treated with deferoxamine and/or pegylated interferon-α for 6 weeks. Hepatotoxicity indices, oxidative stress, inflammatory and liver fibrosis markers were assessed. Concanavalin A induced a significant increase in hepatotoxicity indices and lipid peroxidation accompanied with a significant depletion of total antioxidant capacity, glutathione level and superoxide dismutase activity. Besides, it increased CD4(+) T-cells content and the downstream inflammatory cascades, including NF-κB, TNF-α, iNOS, COX-2, IL-6 and IFN-γ. Furthermore, α-SMA, TGF-ß1 and hydroxyproline were increased markedly, which confirmed by histopathology. Treatment with either deferoxamine or pegylated interferon-α alone reduced liver fibrosis markers significantly and improved liver histology. However, some of the hepatotoxicity indices and oxidative stress markers did not improve upon pegylated interferon-α treatment alone, besides the remarkable increase in IL-6. Combination therapy of deferoxamine with pegylated interferon-α further improved all previous markers, ameliorated IL-6 elevation, as well as increased hepcidin expression. In conclusion, our study provides evidences for the potent antifibrotic effects of deferoxamine and the underlying mechanisms that involved attenuating oxidative stress and subsequent inflammatory cascade, as well as the production of profibrogenic factors. Addition of deferoxamine to interferon regimen for HCV patients may offer a promising adjuvant modality to enhance therapeutic response.
Assuntos
Concanavalina A/toxicidade , Desferroxamina/uso terapêutico , Interferon-alfa/uso terapêutico , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Animais , Antivirais/uso terapêutico , Interferon alfa-2 , Ferro/metabolismo , Fígado/metabolismo , Mitógenos/toxicidade , Estresse Oxidativo , Ratos , Ratos Wistar , Proteínas Recombinantes/uso terapêutico , Sideróforos/uso terapêuticoRESUMO
Thalassemias are genetic disorders characterized by decreased synthesis of one of the globin chains. Beta-thalassemia is caused by impairment in the production of beta-globin chains leaving the excess alpha chains unstable. With better treatment approaches and improvement in chelation therapy, thalassemic patients are living longer. As a consequence, new complications and associations with other conditions including malignancy have emerged. The occurrence of malignancies in thalassemia has rarely been reported, and our review of the literature revealed only few cases. We report the first case of a thalassemic patient developing breast cancer and discuss the possibility of a link between the two disease entities. This case is intended to alert physicians of the possibility of a malignancy in thalassemia patients.
Assuntos
Neoplasias da Mama/complicações , Carcinoma Intraductal não Infiltrante/complicações , Hipogonadismo/complicações , Talassemia beta/complicações , Adulto , Transfusão de Sangue , Neoplasias da Mama/diagnóstico por imagem , Carcinoma Intraductal não Infiltrante/diagnóstico por imagem , Desferroxamina/uso terapêutico , Estradiol/uso terapêutico , Terapia de Reposição de Estrogênios , Estrogênios/uso terapêutico , Feminino , Humanos , Hipogonadismo/tratamento farmacológico , Mamografia , Sideróforos/uso terapêutico , Talassemia beta/terapiaRESUMO
SIGNIFICANCE: Exochelins are lipid- and water-soluble siderophores of Mycobacterium tuberculosis with unique properties that endow them with exceptional pharmacologic utility. Exochelins can be utilized as probes to decipher the role of iron in normal and pathological states, and, since they rapidly cross cell membranes and chelate intracellular iron with little or no toxicity, exochelins are potentially useful for the treatment of a number of iron-dependent pathological phenomena. RECENT ADVANCES: In animal models, exochelins have been demonstrated to have promise for the treatment of transfusion-related iron overload, restenosis after coronary artery angioplasty, cancer, and oxidative injury associated with acute myocardial infarction and transplantation. CRITICAL ISSUES: To be clinically effective, iron chelators should be able to rapidly enter cells and chelate iron at key intracellular sites. Desferri-exochelins, and other lipid-soluble chelators, can readily cross cell membranes and remove intracellular free iron; whereas deferoxamine, which is lipid insoluble, cannot do so. Clinical utility also requires that the chelators be nontoxic, which, we hypothesize, includes the capability to prevent iron from catalyzing free radical reactions which produce â¢OH or other reactive oxygen species. Lipid-soluble iron chelators currently available for clinical application are bidentate (deferiprone) or tridentate (desferasirox) molecules that do not block all six sites on the iron molecule capable of catalyzing free radical reactions. In contrast, desferri-exochelins are hexadentate molecules, and by forming a one-to-one binding relationship with iron, they prevent free radical reactions. FUTURE DIRECTIONS: Clinical studies are needed to assess the utility of desferri-exochelins in the treatment of iron-dependent pathological disorders.
Assuntos
Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Mycobacterium tuberculosis/metabolismo , Peptídeos Cíclicos/uso terapêutico , Sideróforos/uso terapêutico , Humanos , Mycobacterium/metabolismo , Peptídeos Cíclicos/metabolismo , Sideróforos/metabolismoRESUMO
Relatar um caso de sobrecarga de ferro secundária à xerocitose, uma doença rara, em uma adolescente, diagnosticada por meio de ressonância magnética em T2*. Relatamos o caso de uma paciente sintomática com xerocitose, nível de ferritina de 350ng/mL e sobrecarga de ferro cardíaca significativa. Ela foi diagnosticada por ressonância magnética em T2* e recebeu terapia de quelação. Análise por ectacitometria confirmou o diagnóstico de xerocitose hereditária. Na sequência, a ressonância magnética em T2* demonstrou resolução completa da sobrecarga de ferro em vários órgãos e novo ecocardiograma revelou resolução completa das alterações cardíacas anteriores. A paciente permanece em terapia de quelação. Xerocitose é uma desordem genética autossômica dominante rara, caracterizada por estomatocitose desidratada. O paciente pode apresentar fadiga intensa e sobrecarga de ferro. Sugerimos o uso regular de ressonância magnética em T2* para o diagnóstico e controle da resposta à quelação de ferro em xerocitose e acreditamos que o exame pode ser útil também em outras anemias hemolíticas que necessitam de transfusões.
To report a case of iron overload secondary to xerocytosis, a rare disease in a teenager, diagnosed, by T2* magnetic resonance imaging. We report the case of a symptomatic patient with xerocytosis, a ferritin level of 350ng/mL and a significant cardiac iron overload. She was diagnosed by T2* magnetic resonance imaging and received chelation therapy Ektacytometric analysis confirmed the diagnosis of hereditary xerocytosis. Subsequent T2* magnetic resonance imaging demonstrated complete resolution of the iron overload in various organs, as a new echocardiography revealed a complete resolution of previous cardiac alterations. The patient remains in chelation therapy. Xerocytosis is a rare autosomal dominant genetic disorder characterized by dehydrated stomatocytosis. The patient may present with intense fatigue and iron overload. We suggest the regular use of T2* magnetic resonance imaging for the diagnosis and control of the response to iron chelation in xerocytosis, and we believe it can be used also in other hemolytic anemia requiring transfusions.
Assuntos
Adolescente , Feminino , Humanos , Anemia Hemolítica Congênita/diagnóstico , Hidropisia Fetal/diagnóstico , Sobrecarga de Ferro/diagnóstico , Anemia Hemolítica Congênita/complicações , Anemia Hemolítica Congênita/tratamento farmacológico , Terapia por Quelação , Desferroxamina/uso terapêutico , Hidropisia Fetal/tratamento farmacológico , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/etiologia , Imageamento por Ressonância Magnética , Sideróforos/uso terapêuticoRESUMO
In this case presentation, a woman with high serum levels of aluminum was treated with chelation therapy with deferoxamine and ascorbic acid. This patient was initially bedridden and the clinical situation was complicated by epileptic seizures. After the chelation therapy, the clinical condition was ameliorated and the therapy continued without the correlation to aluminum serum levels. The role of metals in neurodegenerative disorders and the correlation between iron metabolism and amyloid beta peptide are described. This case suggests chelation therapy could represent a promising therapeutic option for this dramatic disease.
Assuntos
Alumínio/sangue , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Terapia por Quelação/métodos , Ferro/sangue , Idoso , Antioxidantes/uso terapêutico , Ácido Ascórbico/uso terapêutico , Desferroxamina/uso terapêutico , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Evolução Fatal , Feminino , Humanos , Sideróforos/uso terapêuticoRESUMO
To report a case of iron overload secondary to xerocytosis, a rare disease in a teenager, diagnosed, by T2* magnetic resonance imaging. We report the case of a symptomatic patient with xerocytosis, a ferritin level of 350ng/mL and a significant cardiac iron overload. She was diagnosed by T2* magnetic resonance imaging and received chelation therapy Ektacytometric analysis confirmed the diagnosis of hereditary xerocytosis. Subsequent T2* magnetic resonance imaging demonstrated complete resolution of the iron overload in various organs, as a new echocardiography revealed a complete resolution of previous cardiac alterations. The patient remains in chelation therapy. Xerocytosis is a rare autosomal dominant genetic disorder characterized by dehydrated stomatocytosis. The patient may present with intense fatigue and iron overload. We suggest the regular use of T2* magnetic resonance imaging for the diagnosis and control of the response to iron chelation in xerocytosis, and we believe it can be used also in other hemolytic anemia requiring transfusions.