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1.
Ann Hematol ; 99(10): 2289-2294, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32737633

RESUMO

Iron overload-induced cardiomyopathy is the leading cause of death in patients with transfusion-dependent thalassemia (TDT). The mortality is extremely high in these patients with severe cardiac complications, and how to rescue them remains a challenge. It is reasonable to use combined chelation with deferiprone (L1) and deferoxamine (DFO) because of their shuttle and synergistic effects on iron chelation. Here, seven consecutive patients with TDT who had severe cardiac complications between 2002 and 2019 and received combined chelation therapy with oral high-dose L1 (100 mg/kg/day) and continuous 24-h DFO infusion (50 mg/kg/day) in our hospital were reported. Survival for eight consecutive patients receiving DFO monotherapy for their severe cardiac complications between 1984 and 2001 was compared. We found that combined chelation therapy with high-dose L1 and DFO was efficient to improve survival and cardiac function in patients with TDT presenting severe cardiac complications. Reversal of arrhythmia to sinus rhythm was noted in all patients. Their 1-month follow-up left ventricular ejection fraction increased significantly (P < 0.001). There were no deaths, and all patients were discharged from hospital with good quality of life. In contrast, all the eight patients receiving DFO monotherapy died (P < 0.001). Accordingly, combined chelation therapy with high-dose L1 and DFO should be considered in patients with TDT presenting cardiac complications.


Assuntos
Arritmias Cardíacas/tratamento farmacológico , Terapia por Quelação/métodos , Deferiprona/uso terapêutico , Desferroxamina/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Talassemia/terapia , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/fisiopatologia , Transfusão de Sangue , Deferiprona/administração & dosagem , Desferroxamina/administração & dosagem , Avaliação de Medicamentos , Quimioterapia Combinada , Feminino , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Quelantes de Ferro/administração & dosagem , Sobrecarga de Ferro/etiologia , Masculino , Qualidade de Vida , Estudos Retrospectivos , Talassemia/complicações , Reação Transfusional , Resultado do Tratamento , Função Ventricular Esquerda
2.
Arq. bras. med. vet. zootec. (Online) ; 72(4): 1321-1328, July-Aug. 2020. ilus
Artigo em Inglês | LILACS, VETINDEX | ID: biblio-1131480

RESUMO

Fifteen New Zealand adult rabbits were randomly allocated into three groups: Sham-operated (group A), Ischemia and Reperfusion (group B) and Carolina Rinse Solution (CRS) (group C). Groups B and C were subjected to one hour of ischemia and two hours of reperfusion. In group C, ten minutes before reperfusion, the bowel lumen was filled with CRS, and the segment immersed in CRS. Necrosis and loss of integrity of the villi were visible in groups B and C. Edema of the submucosa and circular muscle was observed in all groups. Hemorrhage was observed in different layers for groups B and C, but group C showed more severe hemorrhage in different layers during reperfusion. All groups showed polymorphonuclear leukocyte infiltration on the base of the mucosa, submucosa, and longitudinal muscle, in addition to polymorphonuclear leukocytes margination in the mucosal and submucosal vessels. Necrosis of enterocytes, muscles, crypts of Lieberkühn and myenteric plexus was observed in groups B and C during reperfusion. Topical and intraluminal Carolina Rinse Solution did not attenuate the effects of ischemia and reperfusion in the small intestine of rabbits.(AU)


Quinze coelhos da raça Nova Zelândia foram alocados em três grupos: instrumentado (grupo A), isquemia e reperfusão (grupo B) e solução de Carolina rinse (CRS) (grupo C). Os grupos B e C foram submetidos a uma hora de isquemia e a duas horas de reperfusão. No grupo C, 10 minutos antes da reperfusão, o segmento isolado foi imerso e teve seu lúmen preenchido com CRS. Os grupos B e C apresentaram necrose e perda progressiva da integridade das vilosidades. Foi observado edema na submucosa e na camada muscular circular em todos os grupos. Nos grupos B e C, foi observada hemorragia em diferentes camadas, mas, no grupo C, a hemorragia foi mais intensa durante a reperfusão. Todos os grupos apresentaram infiltrado de PMN na base da mucosa, na submucosa e na camada muscular longitudinal e marginação de PMN nos vasos da mucosa e da submucosa. Durante a reperfusão, foi observada necrose dos enterócitos, das camadas musculares, das criptas de Lieberkühn e do plexo mioentérico nos grupos B e C. O uso tópico e intraluminal de CRS não atenuou os efeitos da isquemia e da reperfusão no intestino delgado de coelhos.(AU)


Assuntos
Animais , Coelhos , Reperfusão/veterinária , Alopurinol/administração & dosagem , Desferroxamina/administração & dosagem , Glutationa/administração & dosagem , Isquemia/veterinária , Jejuno/cirurgia
3.
Medicine (Baltimore) ; 99(28): e20949, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664096

RESUMO

OBJECTIVES: Thalassemia is a hereditary disease, which caused economic burden in developing countries. This study evaluated the cost utility of new formulation of deferasirox (Jadenu) vs deferoxamine (Desferal) among B-Thalassemia-major patients from payer perspective in Iran. METHODS: An economic-evaluation through Markov model was performed. A systematic review was conducted in order to evaluate the clinical effectiveness of comparators. Because of chelating therapy is weight-dependent, patients were assumed to be 2 years-old at initiation in first and 18 years-old in second scenario, and model was estimated lifetime costs and utilities. Costs were calculated to the Iran healthcare system through payer perspective and measured effectiveness using quality-adjusted life years (QALYs). One-way sensitivity analysis and budget impact analysis was also employed. RESULTS: The 381 studies were retrieved from systematic searching through databases. After eliminating duplicate and irrelevant studies, 2 studies selected for evaluating the effectiveness. Jadenu was associated with an incremental cost-effectiveness ratio (ICER) of 1470.6 and 2544.7 US$ vs Desferal in first and second scenario respectively. The estimated ICER for Jadenu compared to generic deferoxamine was 2837.0 and 6924.1 US$ for first and second scenario respectively. For all scenarios Jadenu is presumed as cost-effective option based on calculated ICER which was lower than 1 gross domestic product per capita in Iran. Sensitivity analysis showed that different parameters except discount rate and indirect cost did not have impact on results. Based on budget impact analysis the estimated cost for patients using Desferal (based on the market share of brand) was 44,021,478 US$ in 3 years vs 42,452,606 US$ in replacing 33% of brand market share with Jadenu. This replacement corresponded to the cost saving of almost 1,568,872 US$ for the payers in 3 years. The calculated cost of using generic deferoxamine in all patients was 68,948,392 US$. The increase in the cost of using Jadenu for 10% of all patients in this scenario would be 934,427 US$ (1.36%) US$ at the first year. CONCLUSIONS: Based on this analysis, film-coated deferasirox appeared to be cost-effective treatment in comparison with Desferal for managing child and adult chronic iron overload in B-thalassemia major patients of Iran.


Assuntos
Análise Custo-Benefício , Deferasirox/administração & dosagem , Deferasirox/economia , Desferroxamina/administração & dosagem , Desferroxamina/economia , Quelantes de Ferro/administração & dosagem , Talassemia beta/tratamento farmacológico , Humanos , Irã (Geográfico) , Comprimidos/economia
4.
Taiwan J Obstet Gynecol ; 59(1): 120-122, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32039778

RESUMO

OBJECTIVE: To report cases of use of chelation therapy during pregnancy which resulted in favorable outcomes for the babies. MATERIALS AND METHODS: In this retrospective cohort study, we described the evolution and outcome of 9 pregnancies in Italian thalassemic women who received deferoxamine (DFO) inadvertently during early pregnancy. RESULTS: The use of deferoxamine during first trimester did not lead to adverse effects on the fetus or cause major complications for the gestation, although an increase in iron burden was observed after suspending chelation therapy. CONCLUSION: In our experience, iron-chelation therapy might be administrated in pregnancy where the benefits to the mother outweigh the potential risks to the baby.


Assuntos
Terapia por Quelação/efeitos adversos , Desferroxamina/efeitos adversos , Exposição Materna/efeitos adversos , Complicações Hematológicas na Gravidez/tratamento farmacológico , Sideróforos/efeitos adversos , Talassemia beta/tratamento farmacológico , Adulto , Desferroxamina/administração & dosagem , Feminino , Humanos , Nascimento Vivo , Troca Materno-Fetal/efeitos dos fármacos , Gravidez , Primeiro Trimestre da Gravidez , Estudos Retrospectivos , Sideróforos/administração & dosagem
5.
ACS Chem Neurosci ; 10(11): 4571-4578, 2019 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-31573798

RESUMO

Deferoxamine, a metal chelator, has been shown to be neuroprotective in animal models of ischemic stroke, traumatic brain injury and both subarachnoid and intracerebral hemorrhage. Intranasal deferoxamine (IN DFO) has also shown promise as a potential treatment for multiple neurodegenerative diseases, including Parkinson's and Alzheimer's. However, there have been no attempts to thoroughly understand the dynamics and pharmacokinetics of IN DFO. We developed a new high-performance liquid-chromatography electrospray-tandem mass spectrometry (HPLC/ESI-MS2) method to quantify the combined total levels of DFO, ferrioxamine (FO; DFO bound to iron), and aluminoxamine (AO; aluminum-bound DFO) in brain tissue using a custom-synthesized deuterated analogue (DFO-d7, Medical Isotopes Inc., Pelham NH) as an internal standard. We applied our method toward understanding the pharmacokinetics of IN DFO delivery to the brain and blood of rats from 15 min to 4 h after delivery. We found that IN delivery successfully targets DFO to the brain to achieve concentrations of 0.5-15 µM in various brain regions within 15 min, and decreasing though still detectable after 4 h. Systemic exposure was minimized as assessed by concentration in blood serum. Serum concentrations were 0.02 µM at 15 min and no more than 0.1 µM at later time points. Compared to blood serum, brain region-specific drug exposure (as measured by area under the curve) ranged from slightly under 10 times exposure in the hippocampus to almost 200 times exposure in the olfactory bulb with IN DFO delivery. These findings represent a major step toward future method development, pharmacokinetic studies, and clinical trials for this promising therapeutic.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Desferroxamina/administração & dosagem , Desferroxamina/metabolismo , Sideróforos/administração & dosagem , Sideróforos/metabolismo , Administração Intranasal , Animais , Química Encefálica/efeitos dos fármacos , Química Encefálica/fisiologia , Desferroxamina/análise , Espectrometria de Massas/métodos , Ratos , Ratos Sprague-Dawley , Sideróforos/análise
6.
Invest Ophthalmol Vis Sci ; 60(12): 3887-3896, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31529120

RESUMO

Purpose: To investigate foveal avascular zone (FAZ) changes in the superficial (SCP) and deep (DCP) capillary plexuses in beta-thalassemia major (BTM) patients, as shown in optical coherence tomography angiography. Methods: Nonrandomized, comparative case series of 54 eyes of 27 BTM patients and 46 eyes of 23 healthy controls, utilizing an automated FAZ detection algorithm. Measurements included FAZ area and FAZ shape descriptors (convexity, circularity, and contour temperature). Results were compared between the two groups, and correlated to iron load and chelation therapy parameters. Results: SCP and DCP FAZ area were not significantly different between the control and BTM groups (P = 0.778 and P = 0.408, respectively). The same was true regarding SCP FAZ convexity (P = 0.946), circularity (P = 0.838), and contour temperature (P = 0.907). In contrast, a statistically significant difference was detected between controls and BTM group regarding DCP FAZ convexity (P = 0.013), circularity (P = 0.010), and contour temperature (P = 0.014). Desferrioxamine dosage was strongly correlated to the DCP area (r = 0.650, P = 0.05) and liver magnetic resonance imaging/T2-star to DCP circularity (r = -0.492, P = 0.038). Correlations were also revealed between urine Fe excretion and DCP convexity (r = 0.531, P = 0.019), circularity (r = 0.661, P = 0.002), and contour temperature (r = -0.591, P = 0.008). Conclusions: Retinal capillary plexuses and especially DCP seem to present unique morphologic changes in BTM patients, not in the FAZ area, but in specific shape descriptors, indicating minor but detectable FAZ changes. These changes correlate well with iron load and chelation therapy parameters. Their clinical importance and pathophysiologic implications remain to be elucidated through further studies.


Assuntos
Fóvea Central/irrigação sanguínea , Vasos Retinianos/patologia , Talassemia beta/diagnóstico , Adulto , Capilares/patologia , Desferroxamina/administração & dosagem , Feminino , Ferritinas/sangue , Angiofluoresceinografia/métodos , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Vasos Retinianos/diagnóstico por imagem , Sideróforos/administração & dosagem , Tomografia de Coerência Óptica/métodos , Talassemia beta/sangue , Talassemia beta/tratamento farmacológico
7.
J Control Release ; 308: 232-239, 2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31299261

RESUMO

Chronic wounds remain a significant burden to both the healthcare system and individual patients, indicating an urgent need for new interventions. Deferoxamine (DFO), an iron-chelating agent clinically used to treat iron toxicity, has been shown to reduce oxidative stress and increase hypoxia-inducible factor-1 alpha (HIF-1α) activation, thereby promoting neovascularization and enhancing regeneration in chronic wounds. However due to its short half-life and adverse side effects associated with systemic absorption, there is a pressing need for targeted DFO delivery. We recently published a preclinical proof of concept drug delivery system (TDDS) which showed that transdermally applied DFO is effective in improving chronic wound healing. Here we present an enhanced TDDS (eTDDS) comprised exclusively of FDA-compliant constituents to optimize drug release and expedite clinical translation. We evaluate the eTDDS to the original TDDS and compare this with other commonly used delivery methods including DFO drip-on and polymer spray applications. The eTDDS displayed excellent physicochemical characteristics and markedly improved DFO delivery into human skin when compared to other topical application techniques. We demonstrate an accelerated wound healing response with the eTDDS treatment resulting in significantly increased wound vascularity, dermal thickness, collagen deposition and tensile strength. Together, these findings highlight the immediate clinical potential of DFO eTDDS to treating diabetic wounds. Further, the topical drug delivery platform has important implications for targeted pharmacologic therapy of a wide range of cutaneous diseases.


Assuntos
Desferroxamina/administração & dosagem , Sistemas de Liberação de Medicamentos , Sideróforos/administração & dosagem , Cicatrização/efeitos dos fármacos , Administração Cutânea , Animais , Colágeno/metabolismo , Desferroxamina/farmacologia , Liberação Controlada de Fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Fisiológica/efeitos dos fármacos , Sideróforos/farmacologia , Pele/efeitos dos fármacos , Pele/patologia
8.
Tissue Eng Part B Rev ; 25(6): 461-470, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31184273

RESUMO

Deferoxamine (DFO) has been in use for half a century as a Food and Drug Administration-approved iron chelator, but recent studies indicate a variety of properties that could expand this drug's application into the fields of tissue and regenerative engineering. DFO has been implicated as an angiogenic agent in studies on ischemia, wound healing, and bone regeneration because of its ability to upregulate hypoxia-inducible factor-1 alpha (HIF-1α) and other key downstream angiogenic factors. DFO has also demonstrated antioxidant capabilities unrelated to its iron-chelating properties, making it a potential modulator of the oxidative stress involved in the inflammation response. Together, these properties make DFO a potential bioactive molecule to promote wound healing and enhance tissue integration of biomaterials in vivo. Impact Statement Deferoxamine (DFO) is approved by the Food and Drug Administration as an iron chelator and is been used to treat iron overload. Recent studies indicate that DFO may have important applications in the growing field of tissue regeneration because of its unique properties of downregulating inflammation while promoting vascularization, thereby enhancing wound healing in vivo.


Assuntos
Indutores da Angiogênese/administração & dosagem , Antioxidantes/administração & dosagem , Desferroxamina/administração & dosagem , Neovascularização Fisiológica/efeitos dos fármacos , Regeneração , Cicatrização , Animais , Humanos
9.
Int J Pharm ; 566: 342-351, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31158456

RESUMO

In situ keratin hydrogel offer a promising strategy to relieve the brain injury after intracerebral hemorrhage (ICH) by delivering the iron chelator directly to the stroke site. However, the injectable property of traditional keratin hydrogel is unsatisfactory, which can't provide adaptable filling of lesion defects with irregular shapes. Herein, the thermo sensitive keratin-g-PNIPAM polymers with different graft ratios were synthesized, and deferoxamine mesylate (DFO) loaded thermo sensitive keratin hydrogels (TKGs) were prepared using the oxidative crosslinking method. The lower critical solution temperature of TKGs can be tailored from 28.5 to 31.8 °C by varying the graft ratios of keratin to NIPAM, and TKG can fill up the complex shapes of lesion cavities easily due to the characteristic of sol-gel transition. In addition, TKGs exhibit stronger adsorption and clearance capacities for the Fe2+ than keratin gel. Meanwhile, in situ injection of TKG with different DFO loadings (0.1, 1.0, and 10 mg/mL) into the hematoma region after ICH surgery showed a stronger effect on the reduction of ICH-induced iron deposits, brain non-heme iron content, brain edema and ROS level compared to the DFO treatment by intraperitoneal administration. Thus, the developed TKG can be potentially exploited for iron-induced brain injury after ICH.


Assuntos
Resinas Acrílicas/administração & dosagem , Lesões Encefálicas/tratamento farmacológico , Desferroxamina/administração & dosagem , Hidrogéis/administração & dosagem , Ferro , Queratinas/administração & dosagem , Sideróforos/administração & dosagem , Resinas Acrílicas/química , Adsorção , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Lesões Encefálicas/induzido quimicamente , Hemorragia Cerebral/tratamento farmacológico , Desferroxamina/química , Modelos Animais de Doenças , Liberação Controlada de Fármacos , Hidrogéis/química , Ferro/química , Queratinas/química , Masculino , Ratos Sprague-Dawley , Sideróforos/química , Temperatura
10.
Transfus Apher Sci ; 58(4): 429-433, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31229401

RESUMO

AIM: Iron chelators are extensively used to reduce iron overload. Our purpose was to compare effects of deferasirox versus deferasirox and deferoxamine in patients with thalassemia major. METHODS: This randomized and double blind trial was performed on 62 patients. Patients were assigned 1:1 to oral 30 mg/kg deferasirox daily or oral 30 mg/kg deferasirox daily plus SC 50 mg/kg deferoxamine for 5 days a week. Treatment continued for 12 months in both groups. RESULTS: Fifty-five patients completed the 1 year of treatment. Mean age was 24.5 years with an excess of females. Combined therapy caused a significant increase in myocardial T2* from 23.1 ± 7.5 ms at baseline to 27.1 ± 7.0 ms at 12 months (P < 0.05). This difference was statistically significant between 2 groups at 12 months (P = 0.01). Combined therapy and monotherapy had no significant effect on liver T2*. At 12 months, serum ferritin levels were reduced in two groups; however, the difference was significant (737 ± 459 µg/ml vs 1085 ± 919 µg/ml, P < 0.01). CONCLUSION: Our study indicates that combined treatment with deferasirox and deferoxmaine is more effective than deferasirox for reduction of iron over load in patients with thalassemia major.


Assuntos
Deferasirox/administração & dosagem , Desferroxamina/administração & dosagem , Sobrecarga de Ferro/tratamento farmacológico , Talassemia beta/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Ferritinas/sangue , Humanos , Sobrecarga de Ferro/sangue , Masculino , Fatores de Tempo , Talassemia beta/sangue
11.
Expert Rev Hematol ; 12(4): 265-272, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30920854

RESUMO

OBJECTIVES: Three iron chelators are used to treat transfusion-dependent beta-thalassemia: desferrioxamine (DFO), deferasirox (DFX), and deferiprone (DFP). Compliance is low for DFO as it cannot be administered orally. Combined administration of DFP and DFX is orally available, however, the therapeutic mechanism is unknown. This pilot study investigated the iron removal mechanisms of DFX and DFP treatment in patients with transfusion-dependent thalassemia major. METHODS: Each patient received three treatments sequentially: (1) DFX monotherapy, (2) DFP monotherapy, and (3) DFX/DFP combination therapy with a four-day washout period between each treatment. Urine and stool specimens were collected to determine the primary outcome of iron excretion volumes. RESULTS: The mean iron excretion was seven times higher after combination therapy with DFX and DFP. Monotherapies also increased excretions volumes, though to a significantly lesser degree. Combined administration of DFX and DFP achieves maximum iron removal in transfusion-dependent thalassemia major compared to monotherapy with either drug. CONCLUSIONS: We suggest combination therapy in chronic severe iron overload cases, especially for patients in poor compliance with DFO/DFP combination therapy or those exhibiting poor iron removal from DFX or DFP monotherapy.


Assuntos
Deferasirox/uso terapêutico , Deferiprona/uso terapêutico , Desferroxamina/uso terapêutico , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Talassemia beta/tratamento farmacológico , Administração Oral , Adulto , Transfusão de Sangue , Terapia por Quelação , Deferasirox/administração & dosagem , Deferiprona/administração & dosagem , Desferroxamina/administração & dosagem , Quimioterapia Combinada , Feminino , Humanos , Ferro/isolamento & purificação , Ferro/urina , Quelantes de Ferro/administração & dosagem , Sobrecarga de Ferro/complicações , Sobrecarga de Ferro/urina , Masculino , Projetos Piloto , Adulto Jovem , Talassemia beta/complicações , Talassemia beta/urina
12.
J Biomater Appl ; 33(9): 1277-1284, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30760093

RESUMO

Thixotropic clays have favorable properties for tissue regeneration. Hypoxia mimetic agents showed promising results in pre-clinical models for hard and soft tissue regeneration. It is unclear if clays can be used as carrier for hypoxia mimetic agent in a periodontal regenerative setting. Here, we tested the response of human fibroblasts of the periodontal soft tissue to synthetic clay hydrogels and assessed hypoxia mimetic agent release. Cells were cultured on synthetic clay hydrogels (5.00%-0.15%). We assessed viability and differentiation capacity with resazurin-based toxicity assays, MTT staining, Live-Dead staining, and alkaline phosphatase staining. To reveal the response of fibroblasts to hypoxia mimetic agent-loaded clay hydrogels, cells were exposed to clay supplemented with dimethyloxalylglycine, deferoxamine, l-mimosine, and CoCl2. Supernatants from hypoxia mimetic agent-loaded clay hydrogels were harvested and replaced with medium at hour 1, 3, 6, 24, 48, and 72. To reveal the hypoxia mimetic capacity of supernatants, vascular endothelial growth factor production in the fibroblasts was assessed in the culture medium. Our data show that clay did not induce relevant toxic effects in the fibroblasts which remained capable to differentiate into alkaline phosphatase-positive cells at the relevant concentrations. Fibroblasts cultured on clay hydrogel loaded with dimethyloxalylglycine, deferoxamine, l-mimosine, and CoCl2 remained vital, however, no significant increase in vascular endothelial growth factor levels was found in the culture medium. Only dimethyloxalylglycine-loaded clay supernatants taken in the first hours stimulated vascular endothelial growth factor production in fibroblasts. In conclusion no pronounced toxic effects of synthetic clay were observed. Supplementation with dimethyloxalylglycine leads to hypoxia mimetic activity. This pilot study provides first insights into the impact of synthetic clay on periodontal tissue.


Assuntos
Hipóxia Celular/efeitos dos fármacos , Argila/química , Fibroblastos/efeitos dos fármacos , Hidrogéis/química , Periodonto/citologia , Aminoácidos Dicarboxílicos/administração & dosagem , Aminoácidos Dicarboxílicos/farmacologia , Materiais Biocompatíveis/química , Células Cultivadas , Cobalto/administração & dosagem , Cobalto/farmacologia , Desferroxamina/administração & dosagem , Desferroxamina/farmacologia , Sistemas de Liberação de Medicamentos , Fibroblastos/citologia , Humanos , Mimosina/administração & dosagem , Mimosina/farmacologia , Periodonto/efeitos dos fármacos , Tecidos Suporte/química
13.
Therapie ; 74(5): 507-512, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30704764

RESUMO

AIM: Complications due to iron overload exert a problematic situation in patients with thalassemia. Proton pump inhibitors (PPIs) like pantoprazole are effective agents to reduce acid gastric acid secretion and perhaps to interrupt iron absorption in conditions with increased iron absorption. Our purpose was to study effects of pantoprazole addition to chelators on iron levels in patients with thalassemia major and intermedia. METHODS: This randomized, controlled, and single center trial was performed on 60 patients with thalassemia major and intermedia in Amir Kabir hospital, Iran. Patients were randomized 1:1 to pantoprazole group (iron chelator plus pantoprazole) or control group (iron chelator) for 6 months. Serum ferritin was measured by ELISA. Iron content was measured by magnetic resonance imaging; heart T2*, and liver T2*. RESULTS: After 6 months of treatment, a significant reduction was seen in serum ferritin levels in the pantoprazole group (1444±613µg/mL to 1197±956µg/mL; P<0.001). A further reduction was seen in patients with thalassmeia intermedia. There were no significant changes in myocardial T2* values in pantoprazole group compared to control group (23.6±7.3ms to 24.1±6.4ms). Compared to the control group, pantoprazole therapy had no effect on hepatic T2* value (9.7±2.3ms to 9.8±2.6ms). However, between-group difference was significant (P<0.05). CONCLUSION: Pantoprazole therapy for 6 months has benefits for reducing serum ferritin in patients with thalassemia major and intermedia. Pantoprazole addition to iron chelators seems safe.


Assuntos
Ferritinas/sangue , Quelantes de Ferro/administração & dosagem , Pantoprazol/farmacologia , Inibidores da Bomba de Prótons/farmacologia , Talassemia beta/sangue , Adolescente , Adulto , Criança , Deferasirox/administração & dosagem , Deferiprona/administração & dosagem , Desferroxamina/administração & dosagem , Feminino , Ferritinas/análise , Humanos , Irã (Geográfico) , Fígado/química , Masculino , Pessoa de Meia-Idade , Miocárdio/química , Pantoprazol/efeitos adversos , Inibidores da Bomba de Prótons/efeitos adversos , Método Simples-Cego , Fatores de Tempo , Adulto Jovem
14.
ACS Nano ; 13(2): 2176-2189, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30676731

RESUMO

Rapidly growing cancer cells exhibit a strong dependence on iron for their survival. Thus, iron-removing drugs, iron chelators, have potential applications in cancer treatment. Deferoxamine (DFO) is an efficient iron chelator, but its short circulation half-life and ability to induce hypoxia-inducible factor 1α (HIF1α) overexpression restricts its use as an antitumor agent. In the present study, we first found that a pattern of iron-related protein expression favoring higher intracellular iron closely correlates with shorter overall and relapse-free survival in pancreatic cancer patients. We subsequently found that a combination of DFO and the HIF1α inhibitor, lificiguat (also named YC1), significantly enhanced the antitumor efficacy of DFO in vitro. We then employed transferrin receptor 1 (TFR1) targeting liposomes to codeliver DFO and YC1 to pancreatic tumors in a mouse model. The encapsulation of DFO prolonged its circulation time, improved its accumulation in tumor tissues via the enhanced permeability and retention (EPR) effect, and facilitated efficient uptake by cancer cells, which express high level of TFR1. After entering the tumor cells, the encapsulated DFO and YC1 were released to elicit a synergistic antitumor effect in subcutaneous and orthotopic pancreatic cancer xenografts. In summary, our work overcame two major obstacles in DFO-based cancer treatment through a simple liposome-based drug delivery system. This nanoencapsulation and targeting paradigm lays the foundation for future application of iron chelation in cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Desferroxamina/farmacologia , Sistemas de Liberação de Medicamentos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Quelantes de Ferro/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Administração Oral , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desferroxamina/administração & dosagem , Desferroxamina/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Quelantes de Ferro/administração & dosagem , Quelantes de Ferro/química , Nanopartículas/administração & dosagem , Nanopartículas/química , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia
15.
Ann Plast Surg ; 82(1): 104-109, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30531453

RESUMO

PURPOSE: Postmastectomy radiation therapy is an important component of the multimodality approach to later-stage breast cancers. Unfortunately, despite its proven survival benefits, postmastectomy radiation therapy is deleterious to the skin and soft tissue, causing increased complications and worse aesthetic outcomes after breast reconstruction.There is currently no effective pharmaceutical agent to mitigate the soft tissue fibrosis and hypovascularity associated with soft tissue radiation. We hypothesized that a novel topical formulation of deferoxamine (DFX) will result in improved cutaneous vascularity and soft tissue pliability in an animal model of irradiated tissue expander-based breast reconstruction. METHODS: This study consisted of 16 hairless rats divided into 4 equal groups: a control group (expander only), a tissue expanded and irradiated group, a tissue expanded + DFX group, and a tissue expanded/irradiated/DFX group. A novel topical formulation of DFX consisted of reconstituted drug dissolved in agents designed to enhance dermal penetrance. Vessels per high-power field (vHPF) were quantified histologically; micro-computed tomography angiography was used to assess vessel volume fraction (VVF) and vessel length density. RESULTS: Irradiated skin had less vascularity compared with control (3.81 vHPF vs 8.25 vHPF, P = 0.03; 0.79% VVF vs 1.53% VVF, P = 0.06). Treatment of irradiated skin with topical DFX reversed these effects, resulting in vascular findings similar to the control group histologically (7.94 vHPF vs 8.25 HPF, P = 0.985) and via micro-computed tomography angiography (1.05% VVF vs 1.53% VVF, P = 0.272). Similarly, radiation resulted in less volume expansion compared with controls (0.72 vs 0.8 mL, P = 0.04), whereas treatment with topical DFX reversed this effect, allowing for an expansion volume similar to the control group (0.81 vs 0.80 mL, P = 0.999). CONCLUSIONS: In an animal model of irradiated tissue expander-based breast reconstruction, treatment with topical DFX improved the cutaneous vascularity and tissue pliability, resulting in vascular density and final tissue expansion volumes similar to those found in the nonirradiated control group. Topical DFX may be an effective agent for the treatment of soft tissue radiation injury; future studies are indicated to further characterize this novel drug formulation.


Assuntos
Neoplasias da Mama/radioterapia , Neoplasias da Mama/cirurgia , Desferroxamina/administração & dosagem , Mamoplastia/métodos , Pele/irrigação sanguínea , Expansão de Tecido/instrumentação , Administração Tópica , Animais , Modelos Animais de Doenças , Feminino , Lesões por Radiação/tratamento farmacológico , Distribuição Aleatória , Ratos , Fluxo Sanguíneo Regional/efeitos dos fármacos , Medição de Risco , Pele/efeitos dos fármacos , Expansão de Tecido/métodos , Cicatrização/efeitos dos fármacos , Microtomografia por Raio-X/métodos
16.
J Pediatr Hematol Oncol ; 41(3): 210-214, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30585946

RESUMO

The researcher assessed the beliefs and adherence associated with both oral deferasirox and deferoxamine infusion chelation therapies among Jordanian children with thalassemia major, and compared the adherence levels between the recipients of each. In this descriptive cross-sectional study, 120 participants were recruited from 3 major thalassemia treatment clinics in Jordan using convenience sampling. Data were collected through questionnaires on demographic- and disease-related information, the beliefs about medicines, and a medication adherence report scale. Most participants showed a high adherence to deferoxamine infusion and oral deferasirox (87.20% and 89.08%, respectively), and believed in the necessity of deferoxamine for maintaining health (89.34%). However, 41.32% of the participants had strong concerns about deferoxamine use. While most participants believed in the need for oral deferasirox (89.84%), about 40.7% had strong concerns about its use. An independent samples t test showed no statistically significant difference in the adherence between the oral deferasirox and infusion deferoxamine recipients (t=1.048, DF=118, P=0.075). Jordanian children with thalassemia have positive beliefs and adherence to both oral and infusion chelation therapies. Health care providers should pay attention to patients' beliefs and discuss the major concerns pertaining to iron chelation therapy with them to enhance the continuity of adherence therapy.


Assuntos
Terapia por Quelação/métodos , Adesão à Medicação/psicologia , Talassemia beta/terapia , Adolescente , Terapia por Quelação/psicologia , Criança , Estudos Transversais , Cultura , Deferasirox/administração & dosagem , Deferasirox/uso terapêutico , Desferroxamina/administração & dosagem , Desferroxamina/uso terapêutico , Feminino , Humanos , Jordânia , Masculino , Inquéritos e Questionários
17.
Biomaterials ; 190-191: 97-110, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30415019

RESUMO

3D printed scaffolds hold promising perspective for bone tissue regeneration. Inspired by process of bone development stage, 3D printed scaffolds with rapid internal vascularization ability and robust osteoinduction bioactivity will be an ideal bone substitute for clinical use. Here, we fabricated a 3D printed biodegradable scaffold that can control release deferoxamine, via surface aminolysis and layer-by-layer assembly technique, which is essential for angiogenesis and osteogenesis and match to bone development and reconstruction. Our in vitro studies show that the scaffold significantly accelerates the vascular pattern formation of human umbilical endothelial cells, boosts the mineralized matrix production, and the expression of osteogenesis-related genes during osteogenic differentiation of mesenchymal stem cells. In vivo results show that deferoxamine promotes the vascular ingrowth and enhances the bone regeneration at the defect site in a rat large bone defect model. Moreover, this 3D-printed scaffold has excellent biocompatibility that is suitable for mesenchymal stem cells grow and differentiate and possess the appropriate mechanical property that is similar to natural cancellous bone. In summary, this 3D-printed scaffold holds huge potential for clinical translation in the treatment of segmental bone defect, due to its flexibility, economical friendly and practicality.


Assuntos
Regeneração Óssea , Impressão Tridimensional , Tecidos Suporte/química , Animais , Materiais Biocompatíveis/química , Regeneração Óssea/efeitos dos fármacos , Células Cultivadas , Desferroxamina/administração & dosagem , Desferroxamina/farmacologia , Preparações de Ação Retardada/química , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Ratos Sprague-Dawley
18.
Drug Deliv ; 25(1): 1779-1789, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30338719

RESUMO

Nonhealing chronic wounds on foot induced by diabetes is a complicated pathologic process. They are mainly caused by impaired neovascularization, neuropathy, and excessive inflammation. A strategy, which can accelerate the vessel network formation as well as inhibit inflammatory response at the same time, makes it possible for effective diabetic ulcers treatment. Co-delivery of multiple drugs with complementary bioactivity offers a strategy to properly treat diabetic wound. We previously demonstrated that hydroxysafflor yellow A (HSYA) could accelerate diabetic wound healing through promoting angiogenesis and reducing inflammatory response. In order to further enhance blood vessel formation, a pro-angiogenic molecular called deferoxamine (DFO) was topically co-administrated with HSYA. The in vitro results showed that the combination of DFO and HSYA exerted synergistic effect on enhancing angiogenesis by upregulation of hypoxia inducible factor-1 alpha (HIF-1α) expression. The interpenetrating polymer networks hydrogels, characterized by good breathability and water absorption, were designed for co-loading of DFO and HSYA aiming to recruit angiogenesis relative cells and upgrade wound healing in vivo. Both DFO and HSYA in hydrogel have achieved sustained release. The in vivo studies indicated that HSYA/DFO hydrogel could accelerate diabetic wound healing. With a high expression of Hif-1α which is similar to that of normal tissue. The noninvasive US/PA imaging revealed that the wound could be recovered completely with abundant blood perfusion in dermis after given HSYA/DFO hydrogel for 28 days. In conclusion, combination of pro-angiogenic small molecule DFO and HSYA in hydrogel provides a promising strategy to productively promote diabetic wound healing as well as better the repair quality.


Assuntos
Chalcona/análogos & derivados , Desferroxamina/administração & dosagem , Sistemas de Liberação de Medicamentos , Neovascularização Fisiológica/efeitos dos fármacos , Quinonas/administração & dosagem , Sideróforos/administração & dosagem , Cicatrização/efeitos dos fármacos , Administração Tópica , Animais , Chalcona/administração & dosagem , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Quimioterapia Combinada , Humanos , Masculino , Ratos Sprague-Dawley
19.
BMC Ophthalmol ; 18(1): 246, 2018 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-30208862

RESUMO

BACKGROUND: Deferoxamine (DFO) is one of the most commonly used chelation treatments for transfusional hemosiderosis. Pattern dystrophies constitute a distinct entity of retinal disorders that has been occasionally identified in association with deferoxamine. CASE PRESENTATION: We report two cases of bilateral macular pattern dystrophy in transfusion dependent patients undergoing chronic chelation therapy with deferoxamine due to thalassemias. Our patients were evaluated with multimodal imaging and the results are presented. Both patients had normal cone and rod responses in the full-field electroretinogram and continued the prescribed chelation therapy, after hematology consult. The patients were followed up every 3 months for 2 and 4 years respectively for possible deterioration. Their best corrected visual acuity remained stable with no anatomic change on Optical Coherence Tomography findings. CONCLUSION: Multimodal imaging of our patients allowed a better evaluation and possibly earlier detection of the DFO-related changes. Screening and close follow up of patients under chronic chelating therapy is important in order to promptly diagnose and manage possible toxicity either with discontinuation of the offending agent or dose modification.


Assuntos
Desferroxamina/efeitos adversos , Retina/diagnóstico por imagem , Degeneração Retiniana/induzido quimicamente , Talassemia/tratamento farmacológico , Desferroxamina/administração & dosagem , Eletrorretinografia , Feminino , Humanos , Infusões Subcutâneas/efeitos adversos , Pessoa de Meia-Idade , Degeneração Retiniana/diagnóstico , Sideróforos/administração & dosagem , Sideróforos/efeitos adversos , Tomografia de Coerência Óptica
20.
Ann Plast Surg ; 81(5): 604-608, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30113984

RESUMO

BACKGROUND: Breast cancer is most commonly managed with a combination of tumor ablation, radiation, and/or chemotherapy. Despite the oncologic benefit of these treatments, the detrimental effect of radiation on surrounding tissue challenges the attainment of ideal breast reconstruction outcomes. The purpose of this study was to determine the ability of topical deferoxamine (DFO) to reduce cutaneous ulceration and collagen disorganization following radiotherapy in a murine model of expander-based breast reconstruction. METHODS: Female Sprague-Dawley rats (n = 15) were divided into 3 groups: control (expander), XRT (expander + radiation), and DFO (expander + radiation + deferoxamine [DFO]). Expanders were placed in a submusculocutaneous plane in the right upper back and ultimately filled to 15 mL. Radiation was administered via a fractionated dose of 28 Gy. Deferoxamine was delivered topically for 10 days following radiation. After a 20-day recovery period, skin ulceration and dermal type I collagen organization were analyzed. RESULTS: Compared with control, the XRT group demonstrated a significant increase in skin ulceration (3.7% vs 43.3%, P = 0.00) and collagen fibril disorganization (26.3% vs 81.8%, P = 0.00). Compared with the XRT group, treatment with topical DFO resulted in a significant reduction in ulceration (43.3% vs 7.0%, P = 0.00) and fibril disorganization (81.8% vs 15.3%, P = 0.00). There were no statistical differences between the control and DFO groups in skin ulceration or collagen disorganization. CONCLUSIONS: This study suggests topical DFO is capable of reducing skin ulceration and type I collagen fibril disorganization following radiotherapy. This novel application of DFO has potential to enhance expander-based breast reconstruction outcomes and improve quality of life for women suffering the devastating effects of breast cancer.


Assuntos
Dorso/cirurgia , Desferroxamina/administração & dosagem , Desferroxamina/farmacologia , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Administração Tópica , Animais , Modelos Animais de Doenças , Feminino , Microscopia de Força Atômica , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Dispositivos para Expansão de Tecidos
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