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2.
Rio de Janeiro; s.n; 2018. 91 f p. il.
Tese em Português | LILACS | ID: biblio-904966

RESUMO

Com o objetivo de contribuir para a tomada de decisão do processo de gestão de tecnologias no âmbito do SUS, foi desenvolvida neste trabalho, uma avaliação de custo efetividade que compare o uso do dexrazoxano em diferentes populações e o uso do acelerador de prótons com o de fótons para tratar crianças com meduloblastoma. O horizonte temporal de toda a vida do paciente e a perspectiva de análise do SUS, foram usados em ambos os estudos. Uma análise de impacto orçamentário para cada tecnologia também foi construída. Após uma busca na literatura, foi desenvolvido um modelo de Markov capaz de comparar o uso do dexrazoxano em 6 perfis de pacientes com risco de desenvolver cardiotoxicidade. Usar o medicamento nas crianças menores de 5 anos de idade se mostrou a alternativa mais custo-efetiva (ICER de R$6.156,96), seguido de usar em todos os pacientes (ICER de R$ 58.968,7). Caso o preço diminua a um valor menor que R$250,00 por frasco, a alternativa de usar em todas as crianças se torna a mais custo-efetiva. O impacto orçamentário ao final de 5 anos foi de R$30.622.404,81 para uso apenas nas crianças menores de 5 anos. Usar a tecnologia em todas as crianças, produziria um impacto incremental de R$ 94.352.898,77. Para avaliar o custo-efetividade do acelerador de prótons, foi desenvolvido um modelo de microssimulação comparando cenários de vida útil dos equipamentos e número de pacientes tratados. Como cenário base foi adotado os parâmetros de 50 pacientes com vida útil dos equipamentos de 20 anos. Para esse cenário, o ganho em QALY foi de 2,71 e o ICER médio de R$171.012,51/QALY. Para o limiar de disposição a pagar de 1 PIB percapita foi observado que a incorporação da tecnologia seria custo-efetiva, se fosse tratar a partir de 150 pacientes. A vida útil dos equipamentos e as outras variáveis tiveram participação limitada ao serem variadas na análise de sensibilidade, sem alterar significativamente as respostas do modelo. Ao final de 20 anos, o impacto orçamentário foi de R$ 345.598.440,91. O estudo recomenda a incorporação do dexrazoxano para crianças menores de 5 anos e não recomenda a incorporação do acelerador de prótons no tratamento do meduloblastoma em crianças


Assuntos
Humanos , Criança , Criança , Análise Custo-Benefício/economia , Dexrazoxano/uso terapêutico , Efetividade , Avaliação em Saúde/economia , Meduloblastoma/terapia , Aceleradores de Partículas , Avaliação da Tecnologia Biomédica/economia
3.
Expert Opin Drug Metab Toxicol ; 13(8): 817-832, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28679288

RESUMO

INTRODUCTION: With advances in clinical oncology, the burden of morbidity and mortality for cancer survivors due to the cardiac side effects of the chemotherapy is steadily increasing. Treatment-related cardiac damage is progressive and often irreversible. Primary prevention of cardiotoxicity during treatment is possible with strategies like limiting the cumulative anthracycline dose, the use of anthracycline structural analogs, and especially cardioprotective agents. Areas covered: This review covers the various cardiotoxic chemotherapeutic agents, the pathophysiology of cardiotoxicity due to anthracyclines, and the clinical and subclinical presentations and progression of childhood anthracycline cardiotoxicity. We also discuss preventive measures and strategies, especially the cardioprotectant agent dexrazoxane where there is strong evidence-based support for its use with anthracycline chemotherapy. However, there is a paucity of evidence-based recommendations for diagnosing and treating cancer therapy-induced cardiovascular complications. Finally, we discuss the potential of cardio-oncology. Expert opinion: There is no 'safe' anthracycline dose if the goal is normal long-term cardiovascular status but higher lifetime cumulative doses of anthracyclines, higher dose rates, female sex, longer follow-up, younger age at anthracycline treatment, pre-existing cardiovascular disease, and cardiac irradiation are associated with more severe cardiotoxicity. With deeper understanding of the mechanisms of the adverse cardiac effects and identification of driver mutations causing these effects, personalized cancer therapy to limit cardiotoxic effects can be achieved, such as with the cardioprotectant dexrazoxane.


Assuntos
Antraciclinas/efeitos adversos , Antineoplásicos/efeitos adversos , Cardiotoxicidade/etiologia , Animais , Antraciclinas/administração & dosagem , Antineoplásicos/administração & dosagem , Cardiotônicos/uso terapêutico , Cardiotoxicidade/prevenção & controle , Criança , Dexrazoxano/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Neoplasias/tratamento farmacológico , Prevenção Primária/métodos , Fatores de Risco
4.
Am Soc Clin Oncol Educ Book ; 37: 799-806, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28561655

RESUMO

The combination of cisplatin, doxorubicin, and methotrexate was established as the standard backbone of contemporary osteosarcoma therapy in 1986. Since then, however, further improving the survival of patients with osteosarcoma has been challenging-30% to 40% of patients with osteosarcoma still die of this disease. In addition, these patients often experience loss of fertility at a young age, short- and long-term treatment-related cardiotoxicity, and adverse orthopedic effects from surgical resection of the tumor or endoprosthetic reconstructions. Cancer treatment often markedly increases the risk of infertility later in life, causing many patients substantial distress and regret. Sperm banking and oocyte cryopreservation are standard of care and should be available to all at-risk patients. Newer techniques, such as autologous gonadal tissue transplant for prepubertal children, are being developed, and newer systemic agents have infertility risk profiles that remain undefined and warrant further study. Cost and access remain barriers to these options. The late effects of anthracycline-induced cardiotoxicity are also increasingly a problem for these patients. These effects are often progressive and can be disabling. Adding dexrazoxane to doxorubicin therapy significantly reduces the risk for most adverse cardiac outcomes without compromising the efficacy of induction chemotherapy. Limb salvage surgery remains the standard of care for treatment in the majority of patients with extremity sarcomas. Modular metal prostheses and allograft reconstructions comprised the majority of surgical procedures for limb salvage surgery. The most common mechanism of failure of these implants is infection and mechanical failure of the implant.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Cardiotoxicidade/fisiopatologia , Infertilidade/fisiopatologia , Osteossarcoma/tratamento farmacológico , Adolescente , Adulto , Neoplasias Ósseas/complicações , Neoplasias Ósseas/fisiopatologia , Sobreviventes de Câncer , Cardiotoxicidade/etiologia , Cardiotoxicidade/prevenção & controle , Criança , Cisplatino/efeitos adversos , Dexrazoxano/uso terapêutico , Doxorrubicina/efeitos adversos , Feminino , Humanos , Infertilidade/induzido quimicamente , Infertilidade/prevenção & controle , Masculino , Metotrexato/efeitos adversos , Osteossarcoma/complicações , Osteossarcoma/fisiopatologia
5.
Thorac Cancer ; 8(4): 363-364, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28371390

RESUMO

The extravasation of cytotoxic agents into subcutaneous tissue is a serious complication of chemotherapy. Unfortunately, if such extravasation occurs into the pleural space, limited data is available to guide appropriate management. We present the first report in the literature of video-assisted thoracoscopy combined with a topoisomerase II inhibitor and iron chelator, dexrazoxane, in the successful management of this complication.


Assuntos
Dexrazoxano/administração & dosagem , Extravasamento de Materiais Terapêuticos e Diagnósticos/terapia , Toracoscopia/métodos , Neoplasias da Mama/tratamento farmacológico , Terapia Combinada , Dexrazoxano/uso terapêutico , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Extravasamento de Materiais Terapêuticos e Diagnósticos/etiologia , Feminino , Humanos , Doença Iatrogênica , Pessoa de Meia-Idade , Cirurgia Torácica Vídeoassistida , Resultado do Tratamento
6.
Ann Oncol ; 28(3): 628-633, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28028033

RESUMO

Background: The relative efficacy of interventions for primary prevention of anthracycline-associated cardiotoxicity is unknown. Methods: We conducted a systematic review of randomized controlled trials for primary prevention of anthracycline-associated cardiotoxicity in adult cancer patients. We used hierarchal outcome definitions in the following order of priority: (1) composite of heart failure or decline in left ventricular ejection fraction, (2) decline in ejection fraction, or (3) heart failure. Data were analyzed using a Bayesian network meta-analysis with random effects. Results: A total of 16 trials reported cardiotoxicity as a dichotomous outcome among 1918 patients, evaluating dexrazoxane, angiotensin antagonists, beta-blockers, combination angiotensin antagonists and beta-blockers, statins, Co-enzyme Q-10, prenylamine, and N-acetylcysteine. Compared with control, dexrazoxane reduced cardiotoxicity with a pooled odds ratio (OR) of 0.26 (95% credible interval [CrI] 0.11-0.74) and had the highest probability (33%) of being most effective. No other agent was demonstrably better than placebo. Angiotensin antagonists had an 84% probability of being most effective in a sensitivity analysis excluding one outlying study (OR 0.06 [95% CrI 0.01- 0.24]). When the outcome was restricted to heart failure, dexrazoxane was associated with an OR of 0.12 (95% CrI 0.06-0.23) relative to control and had 58% probability of being most effective, while angiotensin antagonists had an OR of 0.18 (95% CrI 0.05-0.55). Available data suggested that dexrazoxane and angiotensin antagonists did not affect malignancy response rate or risk of death. Conclusion: Moderate quality data suggest that dexrazoxane, and low quality data suggest angiotensin antagonists, are likely to be effective for cardiotoxicity prevention.


Assuntos
Antraciclinas/efeitos adversos , Cardiomiopatias/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Neoplasias/complicações , Disfunção Ventricular Esquerda/tratamento farmacológico , Acetilcisteína/uso terapêutico , Antagonistas Adrenérgicos beta/uso terapêutico , Angiotensinas/antagonistas & inibidores , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/mortalidade , Cardiomiopatias/patologia , Ensaios Clínicos como Assunto , Dexrazoxano/uso terapêutico , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/patologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Neoplasias/tratamento farmacológico , Meta-Análise em Rede , Prenilamina/uso terapêutico , Disfunção Ventricular Esquerda/induzido quimicamente , Disfunção Ventricular Esquerda/mortalidade , Disfunção Ventricular Esquerda/patologia
7.
Br J Clin Pharmacol ; 83(3): 455-465, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27591829

RESUMO

LINKED ARTICLES: This article is part of a joint Themed section with the British Journal of Pharmacology on Cardiotoxicity. The rest of the Themed section will appear in a future issue of BJP and will be available at http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1476-5381 The number of survivors of childhood cancers has increased exponentially over the past few decades. However, these survivors are also at substantially increased long-term risk of morbidity and mortality, especially from treatment-related cardiotoxicity. Preventing these risks is now a priority when treating children and adolescents with cancer. Dexrazoxane reduces the risk of anthracycline-induced cardiotoxicity among adults and children with cancer without reducing its antineoplastic effects or event-free survival. Thus, it should be strongly considered as a part of therapy for children and adolescents treated with anthracyclines.


Assuntos
Antraciclinas/efeitos adversos , Sobreviventes de Câncer , Cardiotoxicidade/prevenção & controle , Dexrazoxano/uso terapêutico , Antibióticos Antineoplásicos/efeitos adversos , Cardiotônicos/uso terapêutico , Humanos , Modelos Cardiovasculares
8.
Am J Physiol Heart Circ Physiol ; 312(2): H213-H222, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-27923793

RESUMO

Cancer and cardiovascular disease are major causes of morbidity and mortality worldwide. Older cancer patients often wrestle with underlying heart disease during cancer therapy, whereas childhood cancer survivors are living long enough to face long-term unintended cardiac consequences of cancer therapies, including anthracyclines. Although effective and widely used, particularly in the pediatric population, anthracycline-related side effects including dose-dependent association with cardiac dysfunction limit their usage. Currently, there is only one United States Food and Drug Administration-approved drug, dexrazoxane, available for the prevention and mitigation of cardiotoxicity related to anthracycline therapy. While aerobic exercise has been shown to reduce cardiovascular complications in multiple diseases, its role as a therapeutic approach to mitigate cardiovascular consequences of cancer therapy is in its infancy. This systematic review aims to summarize how aerobic exercise can help to alleviate unintended cardiotoxic side effects and identify gaps in need of further research. While published work supports the benefits of aerobic exercise, additional clinical investigations are warranted to determine the effects of different exercise modalities, timing, and duration to identify optimal aerobic training regimens for reducing cardiovascular complications, particularly late cardiac effects, in cancer survivors exposed to anthracyclines.


Assuntos
Antraciclinas/efeitos adversos , Cardiotoxicidade/prevenção & controle , Terapia por Exercício/métodos , Exercício , Cardiopatias/prevenção & controle , Neoplasias/tratamento farmacológico , Cardiotônicos/uso terapêutico , Cardiotoxicidade/etiologia , Dexrazoxano/uso terapêutico , Humanos , Sobreviventes
9.
Gan To Kagaku Ryoho ; 43(13): 2517-2521, 2016 Dec.
Artigo em Japonês | MEDLINE | ID: mdl-28028257

RESUMO

Dexrazoxane(DXZ)is a drug used for treating extravasation(EV)of anthracycline antitumor antibiotics based on 2 of its mechanisms of action through Topo II. In Japan, it has been used in approximately 150 patients as of January 2016, but there is no detailed report. Three DXZ treatments were carried out for 2 cases in our facilities. One case involved a patient's right forearm while 2 cases occurred involved the left and right forearms of each of the patients, and both were Grade 2(CTCAE v4.0). The EV healed in all cases, and surgical procedures were not needed. Moreover, chemotherapy was performed without extending the treatment period. One year 8 months after administration there was no recurrence in both cases, and skin disorders did not develop. In our hospital, DXZ is managed based on the regimen as well as the anticancer agents, and administration within 6 hours from extravasation was made possible by the cooperation of pharmaceutical wholesalers. Nurses and pharmacists who engage in chemotherapy are encouraged to participate in the study sessions of the hospital, it has been the effort to learn the day-to-day knowledge and technology. DXZ is effective in treating the EV of anthracycline antitumor antibiotics and may be well tolerated. To properly use DXZ by integrating these cases, it is necessary to verify its effectiveness and safety.


Assuntos
Antraciclinas/efeitos adversos , Antibióticos Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Dexrazoxano/uso terapêutico , Extravasamento de Materiais Terapêuticos e Diagnósticos/tratamento farmacológico , Neoplasias/tratamento farmacológico , Antraciclinas/uso terapêutico , Antibióticos Antineoplásicos/uso terapêutico , Feminino , Hospitais , Humanos , Pessoa de Meia-Idade
10.
PLoS One ; 11(12): e0168541, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28002439

RESUMO

Calcium and iron overload participate in the mechanisms of ischemia/reperfusion (I/R) injury during myocardial infarction (MI). Calcium overload induces cardiomyocyte death by hypercontraction, while iron catalyses generation of reactive oxygen species (ROS). We therefore hypothesized that dexrazoxane, an intracellular metal chelator, would attenuate I/R injury. MI was induced in pigs by occlusion of the left anterior descending artery for 1 hour followed by 2 hours reperfusion. Thirty minutes before reperfusion either 5 mg/ml dexrazoxane (n = 5) or saline (n = 5) was infused intravenously. Myocardial necrosis as percentage of the area at ischemic risk was found to be similar in both groups (77.2 ± 18% for dexrazoxane and 76.4 ± 14% for saline group) as determined by triphenyl tetrazolium chloride staining of the ischemic myocardium. Also, serum levels of troponin-I were similar in both groups. A conductance catheter was used to measure left ventricular pressure and volume at all times. Markers for tissue damage due to ROS (HNE), endothelial cell activation (CD31) and inflammation (IgG, C3b/c, C5b9, MCP-1) were assessed on tissue and/or in serum. No significant differences were observed between the groups for the parameters analyzed. To conclude, in this clinically relevant model of early reperfusion after acute myocardial ischemia, dexrazoxane lacked attenuating effects on I/R injury as shown by the measured parameters.


Assuntos
Dexrazoxano/uso terapêutico , Infarto do Miocárdio/etiologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Doença Aguda , Administração Intravenosa , Animais , Quimiocina CCL2/metabolismo , Complemento C3c/metabolismo , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Dexrazoxano/farmacologia , Modelos Animais de Doenças , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/complicações , Miocárdio/patologia , Necrose , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fatores de Risco , Suínos , Troponina I/sangue , Função Ventricular Esquerda/efeitos dos fármacos
11.
Medicine (Baltimore) ; 95(44): e5228, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27858873

RESUMO

OBJECTIVE: The study objective was to investigate the protective effects of dexrazoxane (DRZ) on the cardiac autonomic nervous system (ANS) activity in anthracycline-treated breast cancer patients with diabetes. METHODS: A total of 110 early stage breast cancer patients with type 2 diabetes were divided randomly into 2 even groups: chemotherapy alone (Chemo) and chemotherapy + DRZ (Chemo + DRZ). All patients underwent adjuvant chemotherapy (80 mg/m epirubicin and 500 mg/m cyclophosphamide) for a total of 6 cycles with 21 days/cycle. The Chemo + DRZ group patients were treated intravenously with 800 mg/m DRZ 30 minutes prior to the administration of epirubicin, while the Chemo group patients were given saline. The cardiac ANS function was evaluated for each patient before and after 6 cycles of chemotherapy by resting heart rate (RHR) and heart rate variability (HRV), which was evaluated by both time and frequency domains. RESULTS: Before and after chemotherapy, patients in both groups showed significant decreases in HRV indices and increases in RHR and the low-frequency/high-frequency ratio. There were no significant differences between Chemo and Chemo + DRZ groups in terms of RHR and HRV indices before chemotherapy; however, after chemotherapy, patients in the Chemo group had a higher average RHR and lower HRV indices compared with patients in the Chemo + DRZ group. CONCLUSION: DRZ protects the cardiac ANS in epirubicin-treated early stage breast cancer patients with diabetes.


Assuntos
Antineoplásicos/uso terapêutico , Sistema Nervoso Autônomo/efeitos dos fármacos , Sistema Nervoso Autônomo/fisiopatologia , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Dexrazoxano/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Epirubicina/uso terapêutico , Coração/efeitos dos fármacos , Coração/fisiopatologia , Antineoplásicos/farmacologia , Dexrazoxano/farmacologia , Feminino , Coração/inervação , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos
12.
Indian J Pharmacol ; 48(5): 490-497, 2016 Sep-Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27721532

RESUMO

Advances in oncologic therapies have allowed many patients with breast cancer to achieve better outcomes and longer survival. However, this progress has been tempered by cardiotoxicity, associated with anticancer therapies, ranging from subclinical abnormalities to irreversible life-threatening complications, such as congestive heart failure or cardiomyopathy. In particular, exposure to chemotherapy (CHT), including anthracyclines and trastuzumab, can lead to cardiac dysfunction with short- or long-term consequences, among patients with breast cancer. The aim of this study is to highlight the potential role of commonly used cardiac medications in the prevention of anthracycline- and trastuzumab-mediated cardiotoxicity, in women with breast cancer, based on evidence from recent clinical trials. This overview is focused on the use of antihypertensive medications, such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, outlining their cardioprotective effects in this patient population. In addition, the importance of biomarkers and modern imaging tests, as potential tools for detection and monitoring of cardiac dysfunction, induced by CHT, as well as some practical preventive and therapeutic strategies for cardio-oncology treatment teams, involved in the management of a growing number of women with breast cancer have been outlined. The content of this overview is based on a literature search of PubMed, within the last 5 years, mostly in relevance to the human epidermal growth factor receptor 2-positive patients with breast cancer, treated with anthracycline or trastuzumab therapy (in addition to surgery and/or radiation therapy [RT] regimen).


Assuntos
Anti-Hipertensivos/uso terapêutico , Antineoplásicos/efeitos adversos , Cardiotônicos/uso terapêutico , Cardiotoxicidade/tratamento farmacológico , Antraciclinas/efeitos adversos , Biomarcadores/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Doenças Cardiovasculares/metabolismo , Dexrazoxano/uso terapêutico , Feminino , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Trastuzumab/efeitos adversos
13.
Brasília; CONITEC; jun. 2016. tab, ilus.
Monografia em Português | LILACS, BRISA/RedTESA | ID: biblio-837309

RESUMO

Contexto: O tratamento do câncer com medicamentos da classe das antraciclinas está frequentemente associado ao aparecimento de cardiotoxicidade. Esse grupo de medicamentos faz parte de aproximadamente 60% dos protocolos terapêuticos em oncologia pediátrica. No SUS, não existem protocolos que pautem a prevenção de cardiotoxicidade no uso de antraciclinas. Dentre as estratégias existentes, o dexrazoxano obteve resultados favoráveis pautados em desfechos intermediários (marcadores bioquímicos e medidas ecocardiográficas). Desfechos clínicos finalísticos (internações evitadas) não foram avaliados. Pergunta: O uso de dexrazoxano associado à antraciclinas para o tratamento do câncer em pacientes pediátricos é eficaz, seguro e custo-efetivo na prevenção de cardiotoxicidade geradora de insuficiência cardíaca e outras doenças do coração quando comparado à quimioterapia isolada? Evidências científicas: Dentre as melhores evidências recuperadas, encontram-se 5 estudos que avaliaram eficácia e segurança, dentre eles ensaios clínicos e estudos de coorte nos Estados Unidos e Coréia do Sul respectivamente. Os grupos de pacientes em sua maioria tinham idade inferior a 18 anos, com leucemia linfoblástica aguda e linfoma de Hodking, e em tratamento com antraciclinas, em doses que variaram de 110 a 410mg/m2. Os desfechos analisados pelos estudos são bastante heterogêneos. Em sua maioria, os estudos usaram marcadores bioquímicos e medidas ecocardiográficas para prever cardiotoxicidade tardia, mortalidade, e sobrevida livre de eventos. Como resultado, o dexrazoxano se mostrou eficaz na prevenção da alteração de marcadores bioquímicos e medidas ecocardiográficas preditoras de cardiotoxicidade tardia. No que diz respeito à mortalidade e ao surgimento de neoplasias secundárias, não houve diferença estatisticamente significativa entre os braços de análise dos estudos. No âmbito da segurança do medicamento, medidas de toxicidade hematológica se apresentaram desfavoráveis ao uso do dexrazoxano. Discussão: As interpretações dos resultados dos estudos devem ser observadas com cautela, pois nenhum deles, com os tempos de acompanhamento propostos, foram capazes de avaliar desfechos clínicos importantes e conclusivos como insuficiência cardíaca ou internação. Apesar disso, são algumas evidências apontam que desfechos intermediários (marcadores bioquímicos) podem ser bons preditores de problemas cardíacos sintomáticos no futuro. Decisão: Não incorporar o dexrazoxano para prevenção de cardiotoxicidade causada por antraciclinas em crianças, como procedimento específico, no âmbito do Sistema Único de Saúde ­ SUS, dada pela Portaria SCTIE-MS nº 25 publicada no Diário Oficial da União (D.O.U.) nº 110, de 10 de junho de 2016.


Assuntos
Humanos , Criança , Antraciclinas/efeitos adversos , Cardiotoxicidade/prevenção & controle , Dexrazoxano/uso terapêutico , Brasil , Análise Custo-Benefício , Dexrazoxano , Avaliação da Tecnologia Biomédica , Sistema Único de Saúde
14.
Toxicol Mech Methods ; 26(3): 189-95, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26899300

RESUMO

Carfilzomib (CFZ) is an inhibitor of proteasome that is generally used in the treatment of multiple myeloma but due to its cardiotoxicity clinical use may be limited. Dexrazoxane (DZR), an inhibitor of topoisomerase-II, prevents cardiac damage by reducing the formation of reactive oxygen species and hypertrophic gene expression. This study evaluated the protective effect of DZR on CFZ-induced cardiotoxicity. Thirty-two male Albino rats were randomly divided into four groups (n = 8). Group I received DMSO, Group II received CFZ (4 mg/kg, intraperitoneally [i.p.]) twice weekly up to day 16, Group III received DZR (20 mg/kg, i.p.) for 16 days and CFZ twice weekly for 16, Group IV received DZR (40 mg/kg, i.p.) for 16 days and CFZ twice weekly for 16. CFZ-induced cardiotoxicity was assessed by hematological, biochemical, mRNA expression, oxidative stress and histopathological studies. CFZ-induced significant changes have been observed in blood parameters including red blood cells, white blood cells, hemoglobin and hematocrit concentrations which were associated with increase in cardiac enzymes markers like creatine kinase (CK), CK-MB and lactate dehydrogenase. Treatment with DZR reversed the hematological statistics and the biochemical markers of CFZ-induced cardiotoxicity. Furthermore, DZR also attenuated the effects of CFZ-induced toxic effect on redox markers such as malondialdehyde and reduced glutathione. Above findings were further confirmed by beta-myosin heavy chain (ß-MHC) and alpha-MHC (α-MHC) gene expression. Histopathological reports suggested that DZR ameliorates CFZ-induced changes in cardiac cellular architecture in rats. These results confirm that DZR protects heart from CFZ-induced cardiotoxicity.


Assuntos
Cardiomiopatias/prevenção & controle , Cardiotônicos/uso terapêutico , Dexrazoxano/uso terapêutico , Expressão Gênica/efeitos dos fármacos , Oligopeptídeos/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Animais , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/genética , Cardiomiopatias/patologia , Cardiotônicos/administração & dosagem , Cardiotoxicidade , Dexrazoxano/administração & dosagem , Masculino , Ratos Wistar , Miosinas Ventriculares/genética
15.
Cancer ; 122(6): 946-53, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26762648

RESUMO

BACKGROUND: Impaired cardiac function in doxorubicin-treated childhood cancer survivors is partly mediated by the disruption of mitochondrial energy production. Doxorubicin intercalates into mitochondrial DNA (mtDNA) and disrupts genes encoding for polypeptides that make adenosine triphosphate. METHODS: This cross-sectional study examined mtDNA copy numbers per cell and oxidative phosphorylation (OXPHOS) in peripheral blood mononuclear cells (PBMCs) in 64 childhood survivors of high-risk acute lymphoblastic leukemia (ALL) who had been treated on Dana-Farber Cancer Institute childhood ALL protocols and had received doxorubicin alone (42%) or doxorubicin with the cardioprotectant dexrazoxane (58%). The number of mtDNA copies per cell and the OXPHOS enzyme activity of nicotinamide adenine dinucleotide dehydrogenase (complex I [CI]) and cytochrome c oxidase (complex IV [CIV]) were measured with quantitative real-time polymerase chain reaction immunoassays and thin-layer chromatography, respectively. RESULTS: At a median follow-up of 7.8 years after treatment, the median number of mtDNA copies per cell for patients treated with doxorubicin alone (1106.3) was significantly higher than the median number for those who had also received dexrazoxane (310.5; P = .001). No significant differences were detected between the groups for CI or CIV activity. CONCLUSIONS: Doxorubicin-treated survivors had an increased number of PBMC mtDNA copies per cell, and concomitant use of dexrazoxane was associated with a lower number of mtDNA copies per cell. Because of a possible compensatory increase in mtDNA copies per cell to maintain mitochondrial function in the setting of mitochondrial dysfunction, overall OXPHOS activity was not different between the groups. The long-term sustainability of this compensatory response in these survivors at risk for cardiac dysfunction over their lifespan is concerning.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cardiotônicos/uso terapêutico , Variações do Número de Cópias de DNA/efeitos dos fármacos , DNA Mitocondrial/efeitos dos fármacos , Dexrazoxano/uso terapêutico , Doxorrubicina/efeitos adversos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Mitocôndrias Cardíacas/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Antibióticos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Cromatografia em Camada Delgada , Estudos Transversais , Doxorrubicina/administração & dosagem , Complexo I de Transporte de Elétrons/efeitos dos fármacos , Complexo I de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/efeitos dos fármacos , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Seguimentos , Humanos , Lactente , Leucócitos Mononucleares/enzimologia , Masculino , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/genética , Oxirredução , Fosforilação , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Reação em Cadeia da Polimerase em Tempo Real , Fatores Sexuais , Sobreviventes
16.
Pharmacogenomics J ; 16(6): 530-535, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-26345518

RESUMO

Anthracyclines are efficient chemotherapy agents. However, their use is limited by anthracycline-induced cardiotoxicity (CT). We investigated the influence of polymorphisms in doxorubicin metabolic and functional pathways on late-onset CT as estimated by echocardiography in 251 childhood acute lymphoblastic leukemia (cALL) patients. Association analyses revealed a modulating effect of two variants: A-1629 T in ABCC5, an ATP-binding cassette transporter, and G894T in the NOS3 endothelial nitric oxide synthase gene. Individuals with the ABCC5 TT-1629 genotype had an average of 8-12% reduction of ejection (EF) and shortening fractions (SF; EF: P<0.0001, and SF: P=0.001, respectively). A protective effect of the NOS3 TT894 genotype on EF was seen in high-risk patients (P=0.02), especially in those who did not receive dexrazoxane (P=0.002). Analysis of an additional cohort of 44 cALL patients replicated the ABCC5 association but was underpowered for NOS3. In summary, we identified two biomarkers that may contribute to cALL anthracycline CT risk stratification.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Doxorrubicina/efeitos adversos , Cardiopatias/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Óxido Nítrico Sintase Tipo III/genética , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Adulto , Cardiotônicos/uso terapêutico , Cardiotoxicidade , Criança , Pré-Escolar , Dexrazoxano/uso terapêutico , Feminino , Predisposição Genética para Doença , Cardiopatias/induzido quimicamente , Cardiopatias/enzimologia , Cardiopatias/prevenção & controle , Heterozigoto , Homozigoto , Humanos , Lactente , Masculino , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Contração Miocárdica , Óxido Nítrico Sintase Tipo III/metabolismo , Farmacogenética , Fenótipo , Fatores de Proteção , Medição de Risco , Fatores de Risco , Volume Sistólico , Fatores de Tempo , Resultado do Tratamento , Função Ventricular Esquerda , Adulto Jovem
17.
PLoS One ; 10(11): e0142588, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26544188

RESUMO

Advances in cancer treatment utilizing multiple chemotherapies have dramatically increased cancer survivorship. Female cancer survivors treated with doxorubicin (DXR) chemotherapy often suffer from an acute impairment of ovarian function, which can persist as long-term, permanent ovarian insufficiency. Dexrazoxane (Dexra) pretreatment reduces DXR-induced insult in the heart, and protects in vitro cultured murine and non-human primate ovaries, demonstrating a drug-based shield to prevent DXR insult. The present study tested the ability of Dexra pretreatment to mitigate acute DXR chemotherapy ovarian toxicity in mice through the first 24 hours post-treatment, and improve subsequent long-term fertility throughout the reproductive lifespan. Adolescent CD-1 mice were treated with Dexra 1 hour prior to DXR treatment in a 1:1 mg or 10:1 mg Dexra:DXR ratio. During the acute injury period (2-24 hours post-injection), Dexra pretreatment at a 1:1 mg ratio decreased the extent of double strand DNA breaks, diminished γH2FAX activation, and reduced subsequent follicular cellular demise caused by DXR. In fertility and fecundity studies, dams pretreated with either Dexra:DXR dose ratio exhibited litter sizes larger than DXR-treated dams, and mice treated with a 1:1 mg Dexra:DXR ratio delivered pups with birth weights greater than DXR-treated females. While DXR significantly increased the "infertility index" (quantifying the percentage of dams failing to achieve pregnancy) through 6 gestations following treatment, Dexra pretreatment significantly reduced the infertility index following DXR treatment, improving fecundity. Low dose Dexra not only protected the ovaries, but also bestowed a considerable survival advantage following exposure to DXR chemotherapy. Mouse survivorship increased from 25% post-DXR treatment to over 80% with Dexra pretreatment. These data demonstrate that Dexra provides acute ovarian protection from DXR toxicity, improving reproductive health in a mouse model, suggesting this clinically available drug may provide ovarian protection for cancer patients.


Assuntos
Antineoplásicos/efeitos adversos , Dexrazoxano/uso terapêutico , Doxorrubicina/efeitos adversos , Ovário/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Ensaio Cometa , Dano ao DNA , Avaliação Pré-Clínica de Medicamentos , Feminino , Fertilidade/efeitos dos fármacos , Tamanho da Ninhada de Vivíparos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos , Ovário/fisiologia , Fosforilação
18.
Cardiol Young ; 25 Suppl 2: 107-16, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26377717

RESUMO

Cardiovascular complications are among the leading causes of morbidity and mortality among survivors of childhood cancer, after cancer relapse and secondary malignancies. Although advances in cancer treatment have improved the 5-year survival rates, the same treatments, such as anthracyclines, that cure cancer also increase the risk for adverse cardiovascular effects. Anthracycline-related cardiotoxicity in survivors of childhood cancer is progressive and can take years to develop, initially presenting as sub-clinical cardiac abnormalities that, if left undetected or untreated, can lead to heart failure, myocardial infarction, or other clinical cardiac dysfunction. A higher cumulative dose of anthracycline is associated with cardiotoxicity in children; however, sub-clinical cardiac abnormalities are evident at lower doses with longer follow-up, suggesting that there is no "safe" dose of anthracycline. Other risk factors include female sex, younger age at diagnosis, black race, trisomy 21, longer time since treatment, and the presence of pre-existing cardiovascular disease and co-morbidities. Cardioprotective strategies during treatment are limited in children. Enalapril provides only temporary cardioprotection, whereas continuous anthracycline infusion extends none. On the other hand, dexrazoxane successfully prevents or reduces anthracycline-related cardiotoxicity in children with cancer, without increased risks for recurrence of primary or second malignancies or reductions in anti-tumour efficacy. With more childhood cancer survivors now reaching adulthood, it is vital to understand the adverse effects of cancer treatment on the cardiovascular system and their long-term consequences to identify and establish optimal prevention and management strategies that balance oncologic efficacy with long-term safety.


Assuntos
Antraciclinas/efeitos adversos , Antineoplásicos/efeitos adversos , Cardiotoxicidade/tratamento farmacológico , Dexrazoxano/uso terapêutico , Insuficiência Cardíaca/induzido quimicamente , Neoplasias/complicações , Antraciclinas/uso terapêutico , Antineoplásicos/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Pediatria , Fatores de Risco , Sobreviventes
19.
Support Care Cancer ; 23(5): 1459-71, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25711653

RESUMO

BACKGROUND: Extravasation is a potentially severe complication that can occur during the administration of chemotherapy. The scarcity of evidence available makes it difficult to develop an optimal management scheme. The purpose of this guideline is to review the relevant scientific literature on the prevention, management, and treatment of extravasation occurring during the administration of chemotherapy to cancer patients. METHOD: A scientific literature review was conducted using the PubMed search tool. The period covered was from database inception to April 2014, inclusively. Since the literature on extravasation treatment is often empirical, anecdotal, and controversial, the review also identified clinical practice guidelines and expert consensuses published by relevant international organizations and cancer agencies. RESULTS: Identification of potential risk factors and preventive measures can reduce the risk of extravasation. Recognition and management of symptoms are crucial in patients with this complication. Provision of adequate instruction to personnel responsible for administering chemotherapy and to patients on recognizing symptoms, preventing, and managing extravasation is essential. Extravasation can be treated with dry warm or cold compresses and various antidotes such as dimethyl sulfoxide, dexrazoxane, hyaluronidase, or sodium thiosulfate, depending on the agent that has caused extravasation. Patient monitoring to assess the progression or regression of symptoms and to thus take the appropriate measures is necessary. CONCLUSION: Several strategies must be established to ensure that extravasation is recognized and properly managed. Given the evidence available at this time, the Comité de l'évolution des pratiques en oncologie (CEPO) has made recommendations for clinical practice in Quebec.


Assuntos
Antineoplásicos/efeitos adversos , Cateterismo Venoso Central/efeitos adversos , Cateterismo Periférico/efeitos adversos , Extravasamento de Materiais Terapêuticos e Diagnósticos/diagnóstico , Extravasamento de Materiais Terapêuticos e Diagnósticos/terapia , Neoplasias/tratamento farmacológico , Antineoplásicos/uso terapêutico , Dexrazoxano/uso terapêutico , Dimetil Sulfóxido/uso terapêutico , Extravasamento de Materiais Terapêuticos e Diagnósticos/prevenção & controle , Humanos , Hialuronoglucosaminidase/uso terapêutico , Quebeque , Fatores de Risco , Tiossulfatos/uso terapêutico
20.
Annu Rev Med ; 66: 161-76, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25587648

RESUMO

Treatment advances have increased survival in children with cancer, but subclinical, progressive, irreversible, and sometimes fatal treatment-related cardiovascular effects may appear years later. Cardio-oncologists have identified promising preventive and treatment strategies. Dexrazoxane provides long-term cardioprotection from doxorubicin-associated cardiotoxicity without compromising the efficacy of anticancer treatment. Continuous infusion of doxorubicin is as effective as bolus administration in leukemia treatment, but no evidence has indicated that it provides long-term cardioprotection; continuous infusions should be eliminated from pediatric cancer treatment. Angiotensin-converting enzyme inhibitors can delay the progression of subclinical and clinical cardiotoxicity. All survivors, regardless of whether they were treated with anthracyclines or radiation, should be monitored for systemic inflammation and the risk of premature cardiovascular disease. Echocardiographic screening must be supplemented with screening for biomarkers of cardiotoxicity and perhaps by identification of genetic susceptibilities to cardiovascular diseases; optimal strategies need to be identified. The health burden related to cancer treatment will increase as this population expands and ages.


Assuntos
Antineoplásicos/efeitos adversos , Cardiotônicos/uso terapêutico , Cardiotoxicidade/prevenção & controle , Doenças Cardiovasculares/prevenção & controle , Neoplasias/tratamento farmacológico , Sobreviventes , Adulto , Doenças Cardiovasculares/induzido quimicamente , Criança , Dexrazoxano/uso terapêutico , Doxorrubicina/efeitos adversos , Humanos
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