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1.
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
2.
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
3.
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
4.
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
5.
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
6.
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
7.
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
8.
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
9.
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
10.
Wound Repair Regen ; 26(3): 300-305, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-30152571

RESUMO

Chronic wounds are a significant medical and economic problem worldwide. Individuals over the age of 65 are particularly vulnerable to pressure ulcers and impaired wound healing. With this demographic growing rapidly, there is a need for effective treatments. We have previously demonstrated that defective hypoxia signaling through destabilization of the master hypoxia-inducible factor 1α (HIF-1α) underlies impairments in both aging and diabetic wound healing. To stabilize HIF-1α, we developed a transdermal delivery system of the Food and Drug Administration-approved small molecule deferoxamine (DFO) and found that transdermal DFO could both prevent and treat ulcers in diabetic mice. Here, we demonstrate that transdermal DFO can similarly prevent pressure ulcers and normalize aged wound healing. Enhanced wound healing by DFO is brought about by stabilization of HIF-1α and improvements in neovascularization. Transdermal DFO can be rapidly translated into the clinic and may represent a new approach to prevent and treat pressure ulcers in aged patients.


Assuntos
Desferroxamina/farmacologia , Lesão por Pressão/prevenção & controle , Sideróforos/farmacologia , Cicatrização/efeitos dos fármacos , Administração Cutânea , Animais , Desferroxamina/administração & dosagem , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/fisiologia , Lesão por Pressão/fisiopatologia , Sideróforos/administração & dosagem , Cicatrização/fisiologia
11.
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
12.
J Wound Care ; 27(Sup6): S26-S32, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29883292

RESUMO

OBJECTIVE: Angiogenesis, formation of new vessels from pre-existing vessels, is an essential part of wound healing. We aimed to compare amniotic membrane extract with deferoxamine in angiogenesis and to assess any synergistic effect. METHOD: We examined four groups of rats (five per group): control, deferoxamine, amniotic membrane extract, and deferocxamine and amniotic membrane extract in combination. A distal-based skin flap was created. Deferoxamine (100mg/kg), amniotic membrane extract (0.1mg/ml), and the combination of both were injected subcutaneously every other day in 10 separate points (0.1 ml at each point) in the skin flap. On day 11, the animals were euthanised for histopathological evaluation. RESULTS: Results indicated that the amniotic membrane extract raised the angiogenic markers, particularly new vessel numbers (p<0.008) and CD31+ compared with controls (p <0.003), and deferoxamine increased new vessel numbers and Von Willebrand factor (vWF) significantly compared with controls (p<0.008). There was an increase in angiogenic factors in the combined group, however, this was not statistically significant difference was observed. There was no difference between amniotic membrane extract and deferoxamine. CONCLUSION: Amniotic membrane extract or deferoxamine could be used interchangeably in angiogenesis within wound healing due to their high safety and availability.


Assuntos
Âmnio , Desferroxamina/administração & dosagem , Úlcera Cutânea/terapia , Indutores da Angiogênese , Animais , Desferroxamina/farmacologia , Modelos Animais de Doenças , Sinergismo Farmacológico , Técnicas In Vitro , Masculino , Ratos , Ratos Wistar , Retalhos Cirúrgicos , Cicatrização/efeitos dos fármacos
13.
J Control Release ; 283: 84-93, 2018 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-29792889

RESUMO

Iron-mediated generation of highly toxic Reactive Oxygen Species (ROS) plays a major role in the process leading to iron overload-related diseases. The long-term subcutaneous administration of Deferoxamine (DFO) is currently clinically-approved to improve patient symptoms and survival. However, non-specific toxicity and short circulation times of the drug in humans often leads to poor patient compliance. Herein, thioketal-based ROS-responsive polymeric nanogels containing DFO moieties (rNG-DFO) were designed to chelate iron and to degrade under oxidative stimuli into fragments <10 nm to enhance excretion of iron-bound chelates. Serum ferritin levels and iron concentrations in major organs of IO mice decreased following treatment with rNG-DFO, and fecal elimination of iron-bound chelates increased compared to free DFO. Furthermore, rNG-DFO decreased iron mediated oxidative stress levels in vitro and reduced iron-mediated inflammation in the liver of IO mice. The study confirms that ROS-responsive nanogels may serve as a promising alternative to DFO for safer and more efficient iron chelation therapy.


Assuntos
Desferroxamina/administração & dosagem , Quelantes de Ferro/administração & dosagem , Sobrecarga de Ferro/tratamento farmacológico , Ferro/metabolismo , Nanopartículas/administração & dosagem , Espécies Reativas de Oxigênio/metabolismo , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Terapia por Quelação , Feminino , Géis , Sobrecarga de Ferro/metabolismo , Sobrecarga de Ferro/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Camundongos Endogâmicos BALB C , Polímeros/administração & dosagem
14.
Drug Des Devel Ther ; 12: 1081-1091, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29760547

RESUMO

Background and aim: Iron overload is commonly observed during the course of aplastic anemia (AA), which is believed to aggravate hematopoiesis, cause multiple organ dysfunction, lead to disease progression, and impair quality of life. Deferasirox (DFX) and deferoxamine (DFO) are among the most common iron chelation agents available in the clinical setting. The aim of this study was to investigate if the combination therapy with DFX and DFO is superior in hematopoietic recovery and iron chelation. Methods: Briefly, we developed a composite mouse model with AA and iron overload that was consequently treated with DFX, DFO, or with a combination of both agents. The changes in peripheral hemogram, marrow apoptosis, and its related protein expressions were compared during the process of iron chelation, while the iron depositions in liver and bone marrow and its regulator were also detected. Results: The obtained results showed that compared to DFX, DFO has a better effect in protecting the bone marrow from apoptosis-induced failure. The combination of DFO and DFX accelerated the chelation of iron, while their efficiency on further hemogram improvement appeared limited. Conclusion: To sum up, our data suggest that single treatment with DFO may be a better choice for improving the hematopoiesis during the gradual chelation treatment irrespective of the convenience of oral DFX, while the combination treatment should be considered for urgent reduction of the iron burden.


Assuntos
Anemia Aplástica/tratamento farmacológico , Benzoatos/uso terapêutico , Desferroxamina/uso terapêutico , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Triazóis/uso terapêutico , Animais , Benzoatos/administração & dosagem , Deferasirox , Desferroxamina/administração & dosagem , Modelos Animais de Doenças , Quimioterapia Combinada , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Triazóis/administração & dosagem
15.
J Control Release ; 281: 139-177, 2018 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-29772289

RESUMO

According to the Alzheimer Association Report (2017), Alzheimer's disease (AD) is the 6th primary cause of death in the USA, which affects nearly 5.5 million people. In the year 2017 itself, the cost of AD treatment in the USA has been reported to rise to $259 billion. This statistic shows the severity of the disease in the USA which is very much similar across the globe. On the other hand, the treatment remains limited to a few conventional oral medications (approved by FDA). These are mainly acting superficially from mild to the moderate AD. The therapeutic efficacy of the drug is not only affected by its reduced concentration in the brain owing to the existence of blood-brain-barrier (BBB) but also due to its low brain permeability. In this context, the intranasal (IN) route of drug administration has emerged as an alternative route over the systemic (oral and parenteral) drug delivery to the brain. The delivery of the drug via an IN route offers various advantages over systemic drug delivery system, as it directly delivers the drug into the brain via olfactory route. Presence of drug in the olfactory bulb, in turn, increases the drug bioavailability in the brain and reduces the drug degradation as well as wastage of the drug through` systemic clearance. However, there is also some limitation associated with IN like poor drug permeation through the nasal mucosa and mucociliary clearance. The delivery system various through novel strategies (nano drug carrier system, colloidal carriers, mucoadhesive devices, controlled delivery system, pro-drug, etc.) are adapted to overcome the above-stated limitations. Although, after all, such successful research claims, very few of the nose-to-brain drug delivery of anti-AD drugs have gained market approval due to lack of sufficient clinical evidence. Onzetra Xsail® is one such marketed preparations approved for IN delivery used for the treatment of a brain disorder; migraine. In the field of patents also, no work is found which could present sufficient experimental findings to support its clinical safety profile. It also underlines the fact that majority of work related to the nose-to-brain delivery of anti-AD drugs is limited only up to preclinical studies. In this review article, we have discussed the latest works on various novel formulations loaded with various anti-Alzheimer agents. These agents include galantamine, deferoxamine, tacrine, tarenflurbil, rivastigmine, risperidone, curcumin, quercetin, piperine, insulin, etc. and various peptides towards the development of a promising IN drug delivery system for the treatment of AD. Through this review article, we want to drag the attention of the researchers working in this field towards the challenges and hurdles of practical applicability IN delivery of anti-AD drugs. Moreover, the attention towards the clinical studies will ease the approval process for the administration of anti-Alzheimer drugs via IN route.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Barreira Hematoencefálica/metabolismo , Encéfalo , Portadores de Fármacos/farmacocinética , Nanopartículas/química , Nariz , Administração Intranasal , Animais , Disponibilidade Biológica , Desferroxamina/administração & dosagem , Desferroxamina/farmacocinética , Desferroxamina/uso terapêutico , Donepezila/administração & dosagem , Donepezila/farmacocinética , Donepezila/uso terapêutico , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/uso terapêutico , Liberação Controlada de Fármacos , Galantamina/administração & dosagem , Galantamina/farmacocinética , Galantamina/uso terapêutico , Humanos , Depuração Mucociliar , Mucosa Nasal/metabolismo , Bulbo Olfatório/metabolismo , Risperidona/administração & dosagem , Risperidona/farmacocinética , Risperidona/uso terapêutico , Distribuição Tecidual
16.
Expert Rev Clin Pharmacol ; 11(6): 641-650, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29727586

RESUMO

BACKGROUND: To compare the efficacy and safety of desferrioxamine (DFO), deferiprone (DFP), deferasirox (DFX) and silymarin in patients with either thalassemia or sickle cell disorder through network meta-analysis. METHODS: Electronic databases were searched for appropriate randomized clinical trials comparing iron chelators in patients with iron overload. Random effects model was used to generate direct, indirect and mixed treatment comparison pooled estimates for the following outcomes: serum ferritin, liver iron concentration (LIC), changes in serum ferritin, mortality, urine iron excretion, adverse events, neutropenia, agranulocytosis and number of patients withdrawing the chelating therapy. RESULTS: Thirty-two clinical trials were included in the meta-analysis. DFX/DFO was associated with better serum ferritin levels compared to DFO, DFX, DFO/Silymarin and DFP/DFO. DFX/DFO also lower LIC significantly compared to DFO. DFP/DFO was associated with higher LVEF, low risk of adverse events and reduced end of serum ferritin compared to DFO. Combination of silymarin with either DFP or DFX was observed with reduced end of treatment serum ferritin compared to using either of the drugs alone. DFP was observed with better effects in sickle cell disease. The strength of evidence was very low for most of the comparisons. CONCLUSION: Relative estimates between the individual iron chelators have been established. However, this evidence should be considered preliminary and may change with the results of future head-to-head clinical trials.


Assuntos
Anemia Falciforme/tratamento farmacológico , Quelantes de Ferro/uso terapêutico , Talassemia/tratamento farmacológico , Benzoatos/administração & dosagem , Benzoatos/efeitos adversos , Benzoatos/uso terapêutico , Deferasirox , Deferiprona , Desferroxamina/administração & dosagem , Desferroxamina/efeitos adversos , Desferroxamina/uso terapêutico , Quimioterapia Combinada , Humanos , Quelantes de Ferro/administração & dosagem , Quelantes de Ferro/efeitos adversos , Sobrecarga de Ferro , Metanálise em Rede , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Piridonas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Silimarina/administração & dosagem , Silimarina/efeitos adversos , Silimarina/uso terapêutico , Triazóis/administração & dosagem , Triazóis/efeitos adversos , Triazóis/uso terapêutico
17.
ACS Nano ; 12(5): 4123-4139, 2018 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-29617109

RESUMO

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 & dosagem
18.
J Control Release ; 279: 69-78, 2018 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-29649529

RESUMO

Controlled delivery systems play a critical role in the success of bone morphogenetic proteins (i.e., BMP2 and BMP7) for challenged bone repair. Instead of single-drug release that is currently and commonly prevalent, dual-drug delivery strategies are highly desired to achieve effective bone regeneration because natural bone repair process is driven by multiple factors. Particularly, angiogenesis is essential for osteogenesis and requires more than just one factor (e.g., Vascular Endothelial Growth Factor, VEGF). Therefore, we developed a novel mesoporous silicate nanoparticles (MSNs) incorporated-3D nanofibrous gelatin (GF) scaffold for dual-delivery of BMP2 and deferoxamine (DFO). DFO is a hypoxia-mimetic drug that can activate hypoxia-inducible factor-1 alpha (HIF-1α), and trigger subsequent angiogenesis. Sustained BMP2 release system was achieved through encapsulation into large-pored MSNs, while the relative short-term release of DFO was engineered through covalent conjugation with chitosan to reduce its cytotoxicity and elongate its half-life. Both MSNs and DFO were incorporated onto a porous 3D GF scaffold to serve as a biomimetic osteogenic microenvironment. Our data indicated that DFO and BMP2 were released from a scaffold at different release rates (10 vs 28 days) yet maintained their angiogenic and osteogenic ability, respectively. Importantly, our data indicated that the released DFO significantly improved BMP2-induced osteogenic differentiation where the dose/duration was important for its effects in both mouse and human stem cell models. Thus, we developed a novel and tunable MSNs/GF 3D scaffold-mediated dual-drug delivery system and studied the potential application of the both FDA-approved DFO and BMP2 for bone tissue engineering.


Assuntos
Proteína Morfogenética Óssea 2/administração & dosagem , Desferroxamina/administração & dosagem , Sistemas de Liberação de Medicamentos , Engenharia Tecidual/métodos , Animais , Osso e Ossos/metabolismo , Diferenciação Celular , Quitosana/química , Liberação Controlada de Fármacos , Gelatina/química , Humanos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Nanofibras , Nanopartículas , Osteogênese/fisiologia , Porosidade , Silicatos/química , Fatores de Tempo
19.
Stem Cells ; 36(8): 1226-1236, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29577517

RESUMO

Mesenchymal stem cells (MSCs) are commonly used in regenerative medicine, but their therapeutic effects vary depending on the culture environment. Hypoxic culturing can be used to maintain stem cells in an undifferentiated state, but is expensive and difficult to perform. The aim of this study was to determine the effectiveness of desferrioxamine (DFO), a hypoxia-mimetic reagent, as an alternative to hypoxic culturing by analyzing metabolic changes in MSCs under hypoxic conditions compared with changes induced by DFO. Low concentrations of DFO reduced mitochondrial activity and apoptosis. Therefore, low concentrations of DFO may be useful for MSC preconditioning. Metabolome analysis showed that both hypoxic treatment and DFO administration exhibited similar metabolite patterns except purine, pyrimidine, and tricarboxylic acid cycle (TCA) cycle related metabolites. Therefore, the use of DFO at low concentrations is a potential substitute for hypoxic culturing. These findings may form the foundation for the development of future regenerative therapies using MSCs. Stem Cells 2018;36:1226-1236.


Assuntos
Desferroxamina/farmacologia , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Metabolômica , Trifosfato de Adenosina/biossíntese , Adulto , Apoptose/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Desferroxamina/administração & dosagem , Doxorrubicina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glutamina/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Ácidos Nucleicos/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Análise de Componente Principal , Regulação para Cima/efeitos dos fármacos
20.
Int J Pharm ; 538(1-2): 79-86, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29341909

RESUMO

Deferoxamine (DFO) to treat iron overload (IO) has been limited by toxicity issues and short circulation times and it would be desirable to prolong circulation to improve non-transferrin bound iron (NTBI) chelation. In addition, DFO is currently unable to efficiently target the large pool of iron in the liver and spleen. Nanogel-Deferoxamine conjugates (NG-DFO) can prove useful as a model to investigate the pharmacokinetic (PK) properties and biodistribution (BD) behavior of iron-chelating macromolecules and their overall effect on serum ferritin levels. NG-DFO reduced the cytotoxicity of DFO and significantly reduced cellular ferritin levels in IO macrophages in vitro. PK/BD studies in normal rats revealed that NG-DFO displayed prolonged circulation and preferential accumulation into the liver and spleen. IO mice treated with NG1-DFO presented significantly lower levels of serum ferritin compared to DFO. Total renal and fecal elimination data point to the need to balance prolonged circulation with controlled degradation to accelerate clearance of iron-chelating macromolecules.


Assuntos
Desferroxamina/administração & dosagem , Quelantes de Ferro/administração & dosagem , Sobrecarga de Ferro/tratamento farmacológico , Modelos Biológicos , Animais , Desferroxamina/farmacocinética , Desferroxamina/farmacologia , Modelos Animais de Doenças , Feminino , Ferritinas/sangue , Células Endoteliais da Veia Umbilical Humana , Humanos , Quelantes de Ferro/farmacocinética , Quelantes de Ferro/farmacologia , Fígado/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas , Ratos , Baço/metabolismo , Distribuição Tecidual
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