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1.
Oncology ; 98(2): 61-80, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31846959

RESUMO

BACKGROUND: Radiation therapy is a cornerstone of the therapeutic modalities used in modern oncology. However, it is sometimes limited in its ability to achieve optimal tumor control by radiation-induced normal tissue toxicity. In delivering radiation therapy, a balance must be achieved between maximizing the dose to the tumor and minimizing any injury to the normal tissues. Amifostine was the first Food and Drug Administration (FDA)-approved clinical radiation protector intended to reduce the impact of radiation on normal tissue, lessening its toxicity and potentially allowing for increased tumor dose/control. Despite being FDA-approved almost 20 years ago, Amifostine has yet to achieve widespread clinical use. SUMMARY: A thorough review of Amifostine's development, mechanism of action, and current clinical status were conducted. A brief history of Amifostine is given, from its development at Walter Reid Institute of Research to its approval for clinical use. The mechanism of action of Amifostine is explored. The results of a complete literature review of all prospective randomized trials to date involving the use of Amifostine in radiation therapy are presented. The results are arranged by treatment site and salient findings discussed. Side effects and complications to consider in using Amifostine are reviewed. Key Messages: Amifostine has been explored as a radiation protectant in most radiation treatment sites. Studies have demonstrated efficacy of Amifostine in all treatment sites reviewed, but results are heterogeneous. The heterogeneity of studies looking at Amifostine as a clinical radiation protectant has precluded a definitive answer on its efficacy. Complicating its clinical use is its toxicity and delivery requirements. Amifostine has largely fallen out of use with the advent of intensity modulated radiation therapy (IMRT). However, side effects with IMRT remain a challenge and concern. The use of Amifostine in the IMRT era has been poorly explored and is worthy of future study.


Assuntos
Amifostina/uso terapêutico , Citoproteção/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Protetores contra Radiação/uso terapêutico , Amifostina/administração & dosagem , Amifostina/efeitos adversos , Ensaios Clínicos como Assunto , Gerenciamento Clínico , Humanos , Especificidade de Órgãos , Protetores contra Radiação/administração & dosagem , Protetores contra Radiação/efeitos adversos , Resultado do Tratamento
2.
J Surg Oncol ; 120(7): 1220-1226, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31602673

RESUMO

BACKGROUND AND OBJECTIVES: Hyperthermic intrathoracic chemotherapy (HITOC) is used for the treatment of malignant pleural tumors. Although HITOC proved to be safe, postoperative renal failure due to nephrotoxicity of intrapleural cisplatin remains a concern. METHODS: This single-center study was performed retrospectively in patients who underwent pleural tumor resection and HITOC between September 2008 and December 2018. RESULTS: A total of 84 patients (female n = 33; 39.3%) with malignant pleural tumors underwent surgical cytoreduction with subsequent HITOC (60 minutes; 42°C). During the study period, we gradually increased the dosage of cisplatin (100-150 mg/m2 BSA n = 36; 175 mg/m2 BSA n = 2) and finally added doxorubicin (cisplatin 175 mg/m2 BSA/doxorubicin 65 mg; n = 46). All patients had perioperative fluid balancing. The last 54 (64.3%) patients also received perioperative cytoprotection. Overall 29 patients (34.5%) experienced renal insufficiency. Despite higher cisplatin concentrations, patients with cytoprotection showed significantly lower postoperative serum creatinine levels after 1 week (P = .006) and at discharge (P = .020). Also, they showed less intermediate and severe renal insufficiencies (5.6% vs 13.3%). CONCLUSIONS: Adequate perioperative fluid management and cytoprotection seem to be effective in protecting renal function. This allows the administration of higher intracavitary cisplatin doses without raising the rate of renal insufficiencies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia do Câncer por Perfusão Regional/efeitos adversos , Hipertermia Induzida/efeitos adversos , Mesotelioma/terapia , Néfrons/efeitos dos fármacos , Neoplasias Pleurais/terapia , Substâncias Protetoras/administração & dosagem , Insuficiência Renal Crônica/tratamento farmacológico , Amifostina/administração & dosagem , Cisplatino/administração & dosagem , Terapia Combinada , Creatinina/sangue , Citoproteção , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Humanos , Masculino , Mesotelioma/patologia , Pessoa de Meia-Idade , Neoplasias Pleurais/patologia , Cuidados Pós-Operatórios , Prognóstico , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/patologia , Estudos Retrospectivos , Taxa de Sobrevida , Tiossulfatos/administração & dosagem , Cavidade Torácica/cirurgia
3.
Expert Opin Drug Saf ; 18(11): 1077-1090, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31526195

RESUMO

Introduction: A radiation countermeasure that can be used prior to radiation exposure to protect the population from the harmful effects of radiation exposure remains a major unmet medical need and is recognized as an important area for research. Despite substantial advances in the research and development for finding nontoxic, safe, and effective prophylactic countermeasures for the acute radiation syndrome (ARS), no such agent has been approved by the United States Food and Drug Administration (FDA). Area covered: Despite the progress made to improve the effectiveness of amifostine as a radioprotector for ARS, none of the strategies have resolved the issue of its toxicity/side effects. Thus, the FDA has approved amifostine for limited clinical indications, but not for non-clinical uses. This article reviews recent strategies and progress that have been made to move forward this potentially useful countermeasure for ARS. Expert opinion: Although the recent investigations have been promising for fielding safe and effective radiation countermeasures, additional work is needed to improve and advance drug design and delivery strategies to get FDA approval for broadened, non-clinical use of amifostine during a radiological/nuclear scenario.


Assuntos
Síndrome Aguda da Radiação/tratamento farmacológico , Amifostina/administração & dosagem , Protetores contra Radiação/administração & dosagem , Amifostina/efeitos adversos , Animais , Aprovação de Drogas , Desenho de Drogas , Humanos , Protetores contra Radiação/efeitos adversos , Estados Unidos , United States Food and Drug Administration
4.
Int J Radiat Oncol Biol Phys ; 104(5): 1141-1152, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31063799

RESUMO

PURPOSE: Despite the development of high-precision radiation therapy, ionizing radiation inevitably damages healthy tissues. Radiodermatitis and radioinduced oral mucositis are frequent and significant side effects among patients with breast and head and neck cancer, respectively. These radiation-related injuries negatively affect patient quality of life and can lead to unplanned therapeutic breaks and compromise treatment outcomes. Currently, no preventive or mitigating agent has emerged to address these issues. Although amifostine, a well-known free radical scavenger, has proven efficacy against specific radio- and chemo-induced toxicities, severe adverse side effects (reversible hypotension, nausea, emesis, etc) combined with logistical hurdles are associated with its recommended intravenous route of administration, limiting its use. METHODS AND MATERIALS: We developed a thermogel containing the active thiol metabolite of amifostine (CPh-1014) that polymerizes at body temperature and serves as a matrix for topical application onto the skin or mucosa. RESULTS: Applied before irradiation, CPh-1014 greatly reduced the severity of oral mucositis and dermatitis induced by either a single dose or fractionated irradiation regimens in in vivo mouse models. The cytoprotective effect of CPh-1014 was confirmed by the decrease in DNA double-strand breaks in the irradiated epithelium. Noticeably, CPh-1014 did not affect radiation therapy efficacy against tumors grafted at submucosal and subcutaneous sites. In contrast to the intravenous administration of amifostine, CPh-1014 oral application did not induce hypotension in dogs. CONCLUSIONS: CPh-1014 confers radioprotective effects in healthy tissues with reduced systemic side effects without compromising radiation therapy efficacy. We propose CPh-1014 as an easy-to-implement therapeutic approach to alleviate radiation therapy toxicity in patients with breast and head and neck cancer.


Assuntos
Amifostina/administração & dosagem , Géis/administração & dosagem , Lesões Experimentais por Radiação/prevenção & controle , Protetores contra Radiação/administração & dosagem , Radiodermatite/prevenção & controle , Estomatite/prevenção & controle , Amifostina/efeitos adversos , Animais , Pressão Sanguínea/efeitos dos fármacos , Neoplasias da Mama/radioterapia , Dano ao DNA , Modelos Animais de Doenças , Cães , Portadores de Fármacos , Feminino , Neoplasias de Cabeça e Pescoço/radioterapia , Hipotensão Ortostática/induzido quimicamente , Camundongos , Camundongos Endogâmicos C57BL , Lesões Experimentais por Radiação/tratamento farmacológico , Protetores contra Radiação/efeitos adversos , Radiodermatite/tratamento farmacológico , Distribuição Aleatória , Neoplasias Cutâneas/radioterapia , Estomatite/tratamento farmacológico , Estomatite/etiologia
5.
Bone Marrow Transplant ; 54(2): 293-299, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29907806

RESUMO

The most common preparative regimen for autologous transplantation (ASCT) in myeloma (MM) consists of melphalan 200 mg/m2 (MEL 200). Higher doses of melphalan 220-260 mg/m2, although relatively well tolerated, have not shown significant improvement in clinical outcomes. Several approaches have been pursued in the past to improve CR rates, including poly-chemotherapy preparative regimens, tandem ASCT, consolidation, and/or maintenance therapy. Since there is a steep dose-response effect for intravenous melphalan, we evaluated an alternative single ASCT strategy using higher-dose melphalan at 280 mg/m2 (MEL 280) with amifostine as a cytoprotectant as the maximum tolerated dose determined in an earlier phase I dose escalation trial. We report the final long-term outcomes of MM patients who underwent conditioning with MEL 280 with amifostine cytoprotection followed by ASCT. Although the complete response rate was quite high in the era pre-dating the routine use of novel therapies (proteasome inhibitors, immunomodulatory agents) (49%), the progression-free survival was a disappointing 22 months. The implications of this dichotomy between the excellent depth of ASCT response and progression-free survival are discussed.


Assuntos
Amifostina/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/métodos , Melfalan/administração & dosagem , Mieloma Múltiplo/terapia , Adulto , Idoso , Citoproteção/efeitos dos fármacos , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Estudos Prospectivos , Indução de Remissão , Condicionamento Pré-Transplante/métodos , Condicionamento Pré-Transplante/mortalidade , Transplante Autólogo , Resultado do Tratamento
6.
J Dent Res ; 97(11): 1252-1259, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29634396

RESUMO

Radiotherapy for head and neck cancers commonly causes damage to salivary gland tissue, resulting in xerostomia (dry mouth) and numerous adverse medical and quality-of-life issues. Amifostine is the only Food and Drug Administration-approved radioprotective drug used clinically to prevent xerostomia. However, systemic administration of amifostine is limited by severe side effects, including rapid decrease in blood pressure (hypotension), nausea, and a narrow therapeutic window. In this study, we demonstrate that retroductal delivery of amifostine and its active metabolite, WR-1065, to murine submandibular glands prior to a single radiation dose of 15 Gy maintained gland function and significantly increased acinar cell survival. Furthermore, in vivo stimulated saliva secretion was maintained in retrograde-treated groups at levels significantly higher than irradiated-only and systemically treated groups. In contrast to intravenous injections, retroductal delivery of WR-1065 or amifostine significantly attenuated hypotension. We conclude that localized delivery to salivary glands markedly improves radioprotection at the cellular level, as well as mitigates the adverse side effects associated with systemic administration. These results support the further development of a localized delivery system that would be compatible with the fractionated dose regimen used clinically.


Assuntos
Amifostina/administração & dosagem , Protetores contra Radiação/administração & dosagem , Glândulas Salivares/efeitos da radiação , Células Acinares/efeitos dos fármacos , Células Acinares/efeitos da radiação , Amifostina/uso terapêutico , Animais , Feminino , Imunofluorescência , Injeções , Mercaptoetilaminas/administração & dosagem , Mercaptoetilaminas/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/prevenção & controle , Protetores contra Radiação/uso terapêutico , Glândulas Salivares/efeitos dos fármacos , Glândulas Salivares/patologia , Glândula Submandibular/efeitos dos fármacos , Glândula Submandibular/efeitos da radiação
7.
Pharm Res ; 35(5): 99, 2018 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-29556791

RESUMO

PURPOSE: Amifostine (AMF), a radioprotectant, is FDA-approved for intravenous administration in cancer patients receiving radiation therapy (XRT). Unfortunately, it remains clinically underutilized due to adverse side effects. The purpose of this study is to define the pharmacokinetic profile of an oral AMF formulation potentially capable of reducing side effects and increasing clinical feasibility. METHODS: Calvarial osteoblasts were radiated under three conditions: no drug, AMF, and WR-1065 (active metabolite). Osteogenic potential of cells was measured using alkaline phosphatase staining. Next, rats were given AMF intravenously or directly into the jejunum, and pharmacokinetic profiles were evaluated. Finally, rats were given AMF orally or subcutaneously, and blood samples were analyzed for pharmacokinetics. RESULTS: WR-1065 preserved osteogenic potential of calvarial osteoblasts after XRT to a greater degree than AMF. Direct jejunal AMF administration incurred a systemic bioavailability of 61.5%. Subcutaneously administrated AMF yielded higher systemic levels, a more rapid peak exposure (0.438 vs. 0.875 h), and greater total systemic exposure of WR-1065 (116,756 vs. 16,874 ng*hr/ml) compared to orally administered AMF. CONCLUSIONS: Orally administered AMF achieves a similar systemic bioavailability and decreased peak plasma level of WR-1065 compared to intravenously administered AMF, suggesting oral AMF formulations maintain radioprotective efficacy without causing onerous side effects, and are clinically feasible.


Assuntos
Amifostina/farmacocinética , Mercaptoetilaminas/farmacocinética , Osteogênese/efeitos dos fármacos , Lesões Experimentais por Radiação/prevenção & controle , Protetores contra Radiação/farmacocinética , Administração Intravenosa , Administração Oral , Amifostina/administração & dosagem , Animais , Disponibilidade Biológica , Linhagem Celular , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Injeções Subcutâneas , Jejuno/efeitos dos fármacos , Jejuno/metabolismo , Jejuno/efeitos da radiação , Masculino , Mercaptoetilaminas/administração & dosagem , Osteoblastos/efeitos dos fármacos , Osteoblastos/efeitos da radiação , Osteogênese/efeitos da radiação , Lesões Experimentais por Radiação/etiologia , Protetores contra Radiação/administração & dosagem , Ratos , Crânio/citologia , Resultado do Tratamento
8.
Leuk Lymphoma ; 59(8): 1905-1912, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29295650

RESUMO

High-dose melphalan (HDM) followed by autologous hematopoietic cell transplantation (auto-HCT) remains the standard-of-care therapy for multiple myeloma (MM) even with the availability of proteasome inhibitors and immunomodulatory drugs. Gastrointestinal (GI) toxicity is the main cause of morbidity after HDM. Amifostine, a cytoprotective agent, may reduce HDM-associated GI toxicity. We conducted a case control study comparing HDM + auto-HCT with or without amifostine for MM patients. One hundred and seven patients treated at University Hospitals Cleveland Medical Center who received pre-transplant amifostine were compared to 114 patients treated at MD Anderson Cancer Center without use of this agent. Amifostine 740 mg/m2 was administered as a bolus infusion at 24 h and 15 min before HDM. Patients' characteristics were similar in both the groups. Amifostine therapy was well tolerated without any significant adverse effects. Grade II or greater oral mucositis (27.1% vs 47.4%; p = .002), nausea (31.8% vs. 86.0%; p = .0001), vomiting (18.7% vs. 52.6%; p = .0001) and diarrhea (56.1% vs. 72.7%; p = .006) occurred less frequently in the amifostine-treated group. There was no discernable effect of amifostine on engraftment, progression-free or overall survival. Our results indicate that amifostine decreases GI toxicity while preserving anti-myeloma efficacy of HDM and auto-HCT.


Assuntos
Amifostina/administração & dosagem , Gastroenteropatias/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Melfalan/administração & dosagem , Mieloma Múltiplo/terapia , Adulto , Idoso , Estudos de Casos e Controles , Terapia Combinada , Diarreia/etiologia , Diarreia/prevenção & controle , Intervalo Livre de Doença , Feminino , Gastroenteropatias/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Náusea/etiologia , Náusea/prevenção & controle , Transplante Autólogo , Vômito/etiologia , Vômito/prevenção & controle
9.
Acta bioquím. clín. latinoam ; 50(4): 733-744, dic. 2016. ilus, graf, tab
Artigo em Espanhol | LILACS | ID: biblio-837647

RESUMO

Entre los radioprotectores con uso clínico se destaca la amifostina (WR- 2721), eficaz pero con efectos secundarios que impiden su uso repetitivo. Es interés de los autores desarrollar radioprotectores menos tóxicos, por sí mismos o como coadyuvantes de amifostina. Ratas machos o hembras se expusieron a una dosis de rayos X de 2 Gy. Se ensayó el piruvato de etilo, solo o conjuntamente con amifostina. Cuarenta y ocho horas después de la exposición a la radiación, se realizó el recuento de eritrocitos, de leucocitos y la fórmula leucocitaria. Los efectos genotóxicos se evaluaron en leucocitos de sangre mediante el ensayo Cometa. Se realizaron también estudios de supervivencia a 60 días post-irradiación. En los animales irradiados disminuyeron los eritrocitos, y el recuento de leucocitos se redujo drásticamente respecto al control, presentando además una fórmula alterada. El tratamiento con piruvato de etilo resultó en una protección de los eritrocitos en ambos sexos. El daño genético disminuyó significativamente por el tratamiento con piruvato de etilo solo o combinado con amifostina, y en hembras se observó una mayor supervivencia solo con el tratamiento combinado. El piruvato de etilo mostró una acción radioprotectora significativa, que podría mejorarse aumentando la dosis o el tiempo de tratamiento, ya que tiene muy baja toxicidad.


Among the currently available radioprotectors, only amifostine (WR-2721) has shown in clinical trials to reduce radiation-induced toxicity. This compound is an efficient radioprotector but it exhibits some undesirable side effects which prevent its repetitive use. Efforts are directed to develop radioprotective agents with lower toxicity, with their own protective potential or suitable as coadyuvants of amifostine. The present study describes the results obtained by repetitive oral administration of ethyl pyruvate. Male or female rats were exposed to an X-ray dose of 2 Gy. Forty-eight hours after exposure to radiation, erythrocyte count, leukocyte and differential count were performed. Genotoxic effects were assessed in blood leukocytes by the Comet assay. Survival studies were also performed at 60 days post-irradiation. Eritrocyte and leukocyte were reduced in animals exposed to radiation compared to the control, also presenting an altered formula. Treatment with ethyl pyruvate resulted in a protection on erythrocytes of both sexes. Genetic damage was significantly decreased by ethyl pyruvate alone or combined with amifostine, and in females, higher survival was observed only with combined administration. Ethyl pyruvate showed a significant radioprotective action, which could be improved by increasing the dose or time of treatment because it has low toxicity.


Entre os radioprotetores com uso clínico destaca-se a amifostina (WR-2721) eficaz mas com efeitos secundários que impedem seu uso repetitivo. O interesse dos autores é desenvolver radioprotetores menos tóxicos, por si mesmos ou como coadjuvantes de amistofina. Ratos machos ou fêmeas foram expostos a doses de raios X de 2Gy. Ensaiou-se o piruvato de etila, só ou junto com amifostina. Quarenta e oito horas após a exposição à radiação foi realizada a contagem de eritrócitos, de leucócitos e da fórmula leucocitária. Efeitos genotóxicos foram avaliados em leucócitos do sangue pelo Ensaio Cometa. Estudos de sobrevivência foram também realizados a 60 dias pós-irradiação. Nos animais irradiados diminuíram os eritrócitos, e a contagem de leucócitos se reduziu drasticamente em comparação com o controle, apresentando também uma fórmula alterada. O tratamento com piruvato de etila resultou numa proteção dos eritrócitos em ambos os sexos. O dano genético diminuiu significativamente pelo tratamento com piruvato de etila sozinho ou combinado com amifostina, e nas fêmeas se observou maior sobrevivência só com o tratamento combinado. O piruvato de etila mostrou uma ação radioprotetora significativa, que poderia ser melhorada pelo aumento da dose ou do tempo de tratamento, visto que tem baixa toxicidade.


Assuntos
Ratos , Amifostina/toxicidade , Radiação , Protetores contra Radiação/uso terapêutico , Amifostina/administração & dosagem , Terapêutica/estatística & dados numéricos
10.
Drug Deliv ; 23(9): 3704-3711, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27855533

RESUMO

A biweekly administration of sustained-release microsphere dosage form of amifostine, a radioprotective drug used in radiotherapy, was performed to examine the feasibility to minimize injection frequency and blood concentration-associated side effects. Model animal trials indicated that this subcutaneously injecting microspheres, 50-100 µm in diameter, achieved bi-weekly prolonged radio-protective efficacy and, at the same time, significantly reduced skin irritation than the solution form of amifostine given by the same administration route. In addition, the hypertension associated with blood concentration of amifostine was not observed in the drug-treated rats. The animals given the amifostine microspheres and amifostine showed significantly differences in white blood cell, red blood cell, hematocrit, hemoglobin and spleen tissue histopathology after exposed under a cobalt-60 γ-radiation at a dose rate of 1.0 Gy/min for 6 min. The in vitro release profile of amifostine from the micropsheres showed a minor initial burst (less than 20% of total drug loading in the first day of administration), consisting with the side effects observations. The results suggest that amifostine encapsulated in sustained-release microspheres may be an ideal dosage form for prolonged radio-protective efficacy and improved patient compliance.


Assuntos
Amifostina/administração & dosagem , Amifostina/efeitos adversos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/efeitos adversos , Protetores contra Radiação/administração & dosagem , Protetores contra Radiação/efeitos adversos , Amifostina/química , Animais , Preparações de Ação Retardada/química , Humanos , Injeções Subcutâneas/métodos , Masculino , Camundongos , Microesferas , Tamanho da Partícula , Cooperação do Paciente , Protetores contra Radiação/química , Radioterapia/efeitos adversos , Ratos , Ratos Sprague-Dawley
11.
Int J Radiat Biol ; 92(12): 837-848, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27585945

RESUMO

PURPOSE: To investigate the effects of whole body ionizing radiation at a sublethal dose on rat brain homogenate membranes and the protective effects of amifostine on these systems at molecular level. MATERIALS AND METHODS: Sprague-Dawley rats, in the absence and presence of amifostine, were whole-body irradiated at a single dose of 8 Gy and decapitated after 24 h. The brain homogenate membranes of these rats were analyzed using Fourier Transform Infrared (FTIR) spectroscopy. RESULTS: Ionizing radiation caused a significant increase in the lipid to protein ratio and significant decreases in the ratios of olefinic = CH/lipid, CH2/lipid, carbonyl ester/lipid and CH3/lipid suggesting, respectively, a more excessive decrease in the protein content and the degradation of lipids as a result of lipid peroxidation. In addition, radiation changed the secondary structure of proteins and the status of packing of membrane lipid head groups. Furthermore, it caused a decrease in lipid order and an increase in membrane fluidity. The administration of amifostine before ionizing radiation inhibited all the radiation-induced alterations in brain homogenate membranes. CONCLUSIONS: The results revealed that whole body ionizing radiation at a sublethal dose causes significant alterations in the structure, composition and dynamics of brain homogenate membranes and amifostine has a protective effect on these membranes.


Assuntos
Amifostina/administração & dosagem , Lesões Encefálicas/metabolismo , Lesões Encefálicas/prevenção & controle , Lipídeos de Membrana/metabolismo , Proteínas de Membrana/metabolismo , Lesões por Radiação/metabolismo , Lesões por Radiação/prevenção & controle , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/efeitos da radiação , Lesões Encefálicas/etiologia , Masculino , Fluidez de Membrana/efeitos dos fármacos , Fluidez de Membrana/efeitos da radiação , Doses de Radiação , Lesões por Radiação/etiologia , Protetores contra Radiação/administração & dosagem , Ratos , Ratos Sprague-Dawley , Irradiação Corporal Total/efeitos adversos
12.
Radiat Prot Dosimetry ; 172(1-3): 302-310, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27542813

RESUMO

This study was designed to evaluate the possible potentiation of survival protection afforded by relatively low-dose amifostine prophylaxis against total body irradiation in combination with a protective, less toxic agent, gamma-tocotrienol (GT3). Mice were administered amifostine and/or GT3, then exposed to 9.2 Gy 60Co γ-irradiation and monitored for survival for 30 days. To investigate cytokine stimulation, mice were administered amifostine or GT3; serum samples were collected and analyzed for cytokines. Survival studies show single treatments of GT3 or amifostine significantly improved survival, compared to the vehicle, and combination treatments resulted in significantly higher survival compared to single treatments. In vivo studies with GT3 confirmed prior work indicating GT3 induces granulocyte colony-stimulating factor (G-CSF). This approach, the prophylactic combination of amifostine and GT3, which act through different mechanisms, shows promise and should be investigated further as a potential countermeasure for acute radiation syndrome.


Assuntos
Amifostina/administração & dosagem , Cromanos/administração & dosagem , Lesões Experimentais por Radiação/tratamento farmacológico , Lesões Experimentais por Radiação/prevenção & controle , Protetores contra Radiação/administração & dosagem , Taxa de Sobrevida , Vitamina E/análogos & derivados , Animais , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Combinação de Medicamentos , Masculino , Camundongos , Doses de Radiação , Resultado do Tratamento , Vitamina E/administração & dosagem , Irradiação Corporal Total
13.
Ann Plast Surg ; 77(2): 164-8, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27070667

RESUMO

According to the American Society of Clinical Oncology, in 2012, more than 53,000 new cases of head and neck cancers (HNCs) were reported in the United States alone and nearly 12,000 deaths occurred relating to HNC. Although radiotherapy (XRT) has increased survival, the adverse effects can be unrelenting and their management is rarely remedial. Current treatment dictates surgical mandibular reconstruction using free tissue transfer. These complex operations entail extended hospitalizations and attendant complications often lead to delays in initiation of adjuvant therapy, jeopardizing prognosis as well as quality of life. The creation of new bone by distraction osteogenesis (DO) generates a replacement of deficient tissue from local substrate and could have immense potential therapeutic ramifications. Radiotherapy drastically impairs bone healing, precluding its use as a reconstructive method for HNC. We posit that the deleterious effects of XRT on bone formation could be pharmacologically mitigated. To test this hypothesis, we used a rodent model of DO and treated with amifostine, a radioprotectant, to assuage the XRT-induced injury on new bone formation. Amifostine had a profound salutary effect on bone regeneration, allowing the successful implementation of DO as a reconstructive technique. The optimization of bone regeneration in the irradiated mandible has immense potential for translation from the bench to the bedside, providing improved therapeutic options for patients subjected to XRT.


Assuntos
Amifostina/farmacologia , Regeneração Óssea/efeitos dos fármacos , Mandíbula/efeitos dos fármacos , Osteogênese por Distração , Lesões por Radiação/tratamento farmacológico , Protetores contra Radiação/farmacologia , Radioterapia/efeitos adversos , Amifostina/administração & dosagem , Amifostina/uso terapêutico , Animais , Regeneração Óssea/efeitos da radiação , Masculino , Mandíbula/efeitos da radiação , Mandíbula/cirurgia , Protetores contra Radiação/administração & dosagem , Protetores contra Radiação/uso terapêutico , Distribuição Aleatória , Ratos Sprague-Dawley
14.
Radiat Res ; 185(1): 77-86, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26789847

RESUMO

There are few safe and effective drugs available that protect healthy tissue against radiation-induced damage, highlighting the need to develop such radioprotective agents. We investigated the mechanism underlying the protective effects of the novel, recombinant, flagellin-like protein FlaA N/C against radiation-induced tissue damage in female BALB/c mice. FlaA N/C treatment increased the levels of several pro-proliferative cytokines while inhibiting apoptosis and reducing inflammation. These effects were accompanied by activation of the nuclear factor κB signaling pathway via direct interaction of FlaA N/C with Toll-like receptor 5, as well as enhanced survival of mice after total-body irradiation compared to that observed with treatment with amifostine, a radioprotective agent that is currently being used in clinical practice. These results indicate that FlaA N/C could be further explored as a possible protector of damage to healthy tissue during radiotherapy.


Assuntos
Flagelina/administração & dosagem , NF-kappa B/imunologia , Lesões por Radiação/imunologia , Lesões por Radiação/prevenção & controle , Protetores contra Radiação/administração & dosagem , Transdução de Sinais/imunologia , Amifostina/administração & dosagem , Animais , Citocinas/imunologia , Relação Dose-Resposta à Radiação , Feminino , Flagelina/genética , Camundongos , Camundongos Endogâmicos C57BL , Doses de Radiação , Lesões por Radiação/etiologia , Tolerância a Radiação/efeitos dos fármacos , Tolerância a Radiação/imunologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/genética , Transdução de Sinais/efeitos da radiação , Taxa de Sobrevida , Resultado do Tratamento , Irradiação Corporal Total/efeitos adversos
15.
Drug Chem Toxicol ; 39(2): 182-9, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26247826

RESUMO

OBJECTIVE: The present study was planned to investigate the prophylactic efficacy of S-2(2-aminoethylamino)ethyl phenyl sulfide (DRDE-07), against topically applied SM induced pulmonary toxicity in mouse. MATERIALS AND METHODS: Animals were pretreated with S-2(2-aminoethylamino)ethyl phenyl sulfide (DRDE-07) (249.4 mg/kg by oral gavage) 30 minutes before SM exposure. The SM (6.48 mg/kg) was applied on hair clipped dorsocaudal region (percutaneous) of the animal. The animals were sacrificed on day 1, 3, 5 and 7. The biochemical changes those were observed in the bronchoalveolar lavage (BAL) fluid and lung tissue included protein, LDH, MPO, ß-glucuronidase, MMP-2, MMP-9, activated macrophages, reduced glutathione and lipid peroxidation level. RESULTS AND DISCUSSION: Pretreatment with DRDE-07 (0.2 LD50) attenuated SM-induced changes at all time point tested. BAL fluid biochemical endpoints indicated epithelial and endothelial cell damages as evidenced by increase in BAL protein, LDH level and increased number of activated macrophages. The increased myeloperoxidase activity and ß-glucuronidase level exhibited the degranulation of neutrophils due to SM toxicity in lung. The zymogrphy analysis of BAL fluid showed a significant increase in matrix metalloproteases (MMP) activity due to inflammatory cells accumulation. CONCLUSION: Thirty minutes pretreatment with DRDE-07 decreased vascular permeability reduced the inflammation and oxidative stress, hence may be recommended as a potential prophylactic agent for SM intoxication.


Assuntos
Amifostina/análogos & derivados , Substâncias para a Guerra Química/toxicidade , Lesão Pulmonar/prevenção & controle , Pulmão/efeitos dos fármacos , Gás de Mostarda/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Administração Cutânea , Administração Oral , Amifostina/administração & dosagem , Amifostina/farmacologia , Amifostina/uso terapêutico , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Feminino , Citometria de Fluxo , Glucuronidase/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/patologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/imunologia , Camundongos , Infiltração de Neutrófilos/efeitos dos fármacos , Peroxidase/metabolismo
16.
J Plast Reconstr Aesthet Surg ; 69(2): 234-40, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26631290

RESUMO

BACKGROUND: Although expander-based breast reconstruction is the most commonly used method of reconstruction worldwide, it continues to be plagued with complication rates as high as 60% when radiotherapy is implemented. We hypothesized that quantitative measures of radiotherapy-induced vascular injury can be mitigated by utilizing amifostine in a murine model of expander-based breast reconstruction. METHODS: 30 rats were divided into three groups: expander placement (Control), expander placement followed by radiotherapy (XRT), and expander placement followed by radiotherapy with amifostine (AMF/XRT). All groups underwent placement of a sub-latissimus tissue expander. After a 45 day recovery period, all groups underwent vascular perfusion and micro-CT analysis. RESULTS: Micro-CT analysis was used to calculate vessel volume fraction (VVF), vessel number (VN), and vessel separation (VSp). A significant increase in VN was seen in the XRT group as compared to the Control (p = 0.021) and the AMF/XRT (p = 0.027). There was no difference between Control and AMF/XRT (p = 0.862). VVF was significantly higher in XRT than either Control (p = 0.043) and AMF/XRT (p = 0.040), however no difference was seen between Control and AMF/XRT (p = 0.980). VSp of XRT was smaller when compared to both Control and AMF/XRT specimens (p = 0.05 and p = 0.048, respectively), and no difference was seen between Control and AMF/XRT (p = 0.339). CONCLUSIONS: Amifostine administered prior to radiotherapy preserved vascular metrics similar to those of non-radiated specimens. Elevated vascularity demonstrated within the XRT group was not seen in either the Control or AMF/XRT groups. These results indicate that amifostine protects soft tissue in our model from a radiotherapy-induced pathologic vascular response.


Assuntos
Amifostina/administração & dosagem , Neoplasias da Mama/radioterapia , Mamoplastia/métodos , Artéria Torácica Interna/patologia , Neoplasias Experimentais , Lesões Experimentais por Radiação/prevenção & controle , Dispositivos para Expansão de Tecidos , Angiografia , Animais , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/cirurgia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Imagem Tridimensional , Masculino , Artéria Torácica Interna/efeitos dos fármacos , Artéria Torácica Interna/efeitos da radiação , Lesões Experimentais por Radiação/diagnóstico , Protetores contra Radiação/administração & dosagem , Ratos , Ratos Sprague-Dawley
17.
Health Phys ; 109(3): 242-8, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26222219

RESUMO

Acute radiation syndrome results from radiation exposure, such as in accidental nuclear disasters. Safe and effective radioprotectants, mitigators, and treatment drugs must be developed as medical countermeasures against radiation exposure. Here, the authors evaluated CCM-Ami, a novel polyethylene glycol micelle encapsulated with amifostine, for its radioprotective properties after total-body irradiation from a 60Co source. Male C57BL/6 mice (6-8 wk old) were intravenously injected with 45 mg kg(-1) of CCM-Ami 90 min before exposure to 7.2 and 8.5 Gy irradiation at a dose rate of 0.04 Gy min(-1). Both survival benefit and hematopoietic protection were observed after prophylactic CCM-Ami administration when compared with the effects measured in excipient control and amifostine groups. Pharmacokinetic results showed that after the intravenous injection, the plasma concentration of WR-1065, the active form of amifostine, was higher in CCM-Ami-treated mice than in amifostine-treated mice. These findings suggest that CCM-Ami-mediated hematopoietic protection plays a key role in enhancing survival of mice exposed to radiation toxicity and thus indicate that CCM-Ami is a radioprotectant that can be used safely and effectively in nuclear disasters.


Assuntos
Síndrome Aguda da Radiação/prevenção & controle , Amifostina/administração & dosagem , Protetores contra Radiação/administração & dosagem , Síndrome Aguda da Radiação/sangue , Amifostina/farmacocinética , Animais , Modelos Animais de Doenças , Relação Dose-Resposta à Radiação , Masculino , Mercaptoetilaminas/sangue , Camundongos , Camundongos Endogâmicos C57BL , Micelas , Polietilenoglicóis , Protetores contra Radiação/farmacocinética , Irradiação Corporal Total
18.
Anticancer Res ; 35(5): 2817-22, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25964561

RESUMO

BACKGROUND/AIM: The aim of this study was to evaluate the expression of FASL, FAS and FADD and caspase-3 in oesophagus, stomach and colonic tissues of mice irradiated in vivo by immunohistochemistry. MATERIALS AND METHODS: A total of 48 adult male C57BL mice were distributed into four groups: Ami(-)/Rad(-): Mice received 0.5 ml of 0.9% physiological saline solution (PPS) intraperitioneally (i.p.); Ami(+)/Rad(-): mice received amifostine (400mg/kg i.p.) freshly dissolved in double-distilled water; Ami(-)/Rad(+): mice received 0.5 ml of PSS i.p. 30 min before a single whole-body radiation dose of 7 Gy; Ami(+)/Rad(+): mice received 0.5 ml of an aqueous solution of 400 mg/kg amifostine i.p.30 min prior to irradiation. All groups were assigned into subgroups sacrificed at 0.5 h, 1 h, 2 h and 4 h after irradiation. RESULTS: In oesophagus and stomach tissues, we did not observe any difference between Ami(-)/ad(-), Ami(+)/Rad(-), Ami(-)/Rad(+) and Ami(+)/Rad(+) groups in the expression of FASL, FAS and FADD. The colonic tissue was the only to exhibit any difference in the expression of FAS and caspase-3 protein in the Ami(-)/Rad(+)group at 1 and 2 h. Amifostine increased FAS and caspase-3 immunoexpression when compared to the control. Immunoexpression for FASL and FADD was not remarkably different in colonic tissue. CONCLUSION: Taken together, our results demonstrate that amifostine increases FAS and caspase-3 expression in colonic tissue of irradiated mice.


Assuntos
Amifostina/administração & dosagem , Caspase 3/biossíntese , Colo/metabolismo , Animais , Colo/patologia , Colo/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Camundongos , Protetores contra Radiação/administração & dosagem , Irradiação Corporal Total
19.
J Radiat Res ; 56(3): 515-22, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25852150

RESUMO

This study investigated the radioprotective effect of Sipunculus nudus L. polysaccharide (SNP) in combination with WR-2721, rhIL-11 and rhG-CSF on irradiated mice. A total of 70 Imprinting Control Region (ICR) mice were divided into seven groups: the control group, the model group and five administration groups. All groups, except the control group, were exposed to a 5 Gy (60)Co γ-ray beam. Blood parameters [including white blood cell (WBC), red blood cell (RBC) and platelet counts and hemoglobin level] were assessed three days before irradiation, and the on the 3rd, 7th and 14th days after irradiation. Spleen, thymus and testicular indices, DNA contents of bone marrow cells, bone marrow nucleated cells, sperm counts, superoxide dismutase (SOD), malondialdehyde (MDA), testosterone and estradiol levels in the serum were assessed on the 14th day after irradiation. The combined administration of SNP, WR-2721, rhIL-11 and rhG-CSF exerted synergistic recovery effects on peripheral blood WBC, RBC and platelet counts and hemoglobin levels in irradiated mice, and synergistic promotion effects on spleen, thymus, testicle, bone marrow nucleated cells and sperm counts in irradiated mice. The synergistic administration increased the serum SOD activities and serum testosterone content of irradiated mice, but synergy decreased the content of serum MDA and estradiol in irradiated mice. These results suggest that the combined administration of SNP, WR-2721, rhIL-11 and rhG-CSF should increase the efficacy of these drugs for acute radiation sickness, protect immunity, hematopoiesis and the reproductive organs of irradiated-damaged mice, and improve oxidation resistance in the body.


Assuntos
Amifostina/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Interleucina-11/administração & dosagem , Nematoides/química , Polissacarídeos/administração & dosagem , Lesões por Radiação/prevenção & controle , Animais , Quimioterapia Combinada/métodos , Fator Estimulador de Colônias de Granulócitos/genética , Interleucina-11/genética , Masculino , Camundongos , Camundongos Endogâmicos ICR , Lesões por Radiação/diagnóstico , Lesões por Radiação/fisiopatologia , Protetores contra Radiação/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Resultado do Tratamento
20.
Indian J Pharmacol ; 47(2): 185-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25878379

RESUMO

OBJECTIVES: Amifostine is a drug which can eliminate free oxygen radicals that appear in the body after radiation or chemotherapeutic agent exposure. It is used to decrease the renal toxicity of cisplatin. The aim of this study was to determine the role of amifostine in warm ischemia kidney model for prevention of ischemia/reperfusion injury and also to find out the mechanism for prevention from ischemia/reperfusion injury if such an effect does exist. MATERIALS AND METHODS: Adult female rats (n = 40) that used in our study were divided into three groups. Group 1: Control (n = 8), group 2: Ischemia-control (n = 16), group 3: Amifostine treated (n = 16). The effect of amifostine on ischemia/reperfusion injury investigated in rat kidneys. RESULTS: At the 7(th) day, blood urea nitrogen level was statistically significantly higher in ischemia-control group than all groups (P = 0.001) and mean serum creatinine levels were found to be the highest in ischemia-control group (P = 0.091). Mean malondialdehyde levels in left kidneys removed on the 7(th) day were not significantly different (P = 0.105) at all three groups. Between ischemia-control group and amifostine group, there was a significant difference in reduced glutathione (GSH) levels (P = 0.001). In amifostine group, grade 4 necrosis was not detected neither on 7(th) day nor day 0. CONCLUSION: Amifostine could decrease the degree and severity of necrosis after reperfusion. Amifostine could not prevent membrane lipid peroxidation caused by superoxide anion radicals in kidney but they could protect tissues from the harmful effects of ischemia/reperfusion injury by increasing the level of reduced GSH which is a well-known oxygen radical eliminator.


Assuntos
Amifostina/uso terapêutico , Antioxidantes/uso terapêutico , Rim/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle , Amifostina/administração & dosagem , Animais , Antioxidantes/administração & dosagem , Modelos Animais de Doenças , Feminino , Glutationa/metabolismo , Rim/irrigação sanguínea , Rim/metabolismo , Rim/patologia , Testes de Função Renal , Peroxidação de Lipídeos/efeitos dos fármacos , Necrose , Ratos , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Resultado do Tratamento , Isquemia Quente
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