RESUMO
Cabozantinib (XL184) is an oral multiple receptor tyrosine kinase inhibitor manufactured by Exelixis Inc., CA, USA. It mainly inhibits three tyrosine kinase receptors: MET, VEGFR2 and RET. In both preclinical and clinical studies it has been shown to inhibit tumor angiogenesis, invasiveness and metastases. The most frequent side effects are fatigue, diarrhea, decreased appetite, nausea, weight loss and palmar-plantar erythrodysesthesia. A Phase III clinical trial (EXAM study) of XL184 versus placebo in advanced and progressive medullary thyroid cancer showed a 28 versus 0% overall response rate and a progression-free survival of 11.2 versus 4.0 months (hazard ratio: 0.28; 95% CI: 0.19-0.40; p < 0.0001) in patients treated with cabozantinib and placebo, respectively. The drug has been approved by the US FDA for the treatment of advanced/progressive metastatic medullary thyroid cancer in the USA. The EMA is now evaluating its approval in Europe.
Assuntos
Anilidas/administração & dosagem , Metástase Neoplásica/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Piridinas/administração & dosagem , Neoplasias da Glândula Tireoide/tratamento farmacológico , Anilidas/efeitos adversos , Anilidas/farmacocinética , Carcinoma Neuroendócrino , Ensaios Clínicos Fase III como Assunto , Aprovação de Drogas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/induzido quimicamente , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Humanos , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , Metástase Neoplásica/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Neovascularização Patológica/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/efeitos adversos , Piridinas/farmacocinética , Neoplasias da Glândula Tireoide/patologiaRESUMO
In recent years, targeted agents have rapidly evolved as effective tools in the clinical management of a broad range of malignant diseases. These agents disrupt molecular mechanisms and signaling modules that drive the malignant phenotype in defined subsets of malignancies. Beyond the intended cellular targets crucial to tumor growth and progression, these agents also affect signal transduction in normal cells and tissues. The resulting adverse events and their clinical management continue to change, as newer agents with an ever-increasing target spectrum are developed. We provide a succinct overview of dermatologic toxicities arising from the targeting of receptor tyrosine kinases and downstream effectors. Emergent insights into the pathomechanisms involved and the use of this knowledge base to alleviate cutaneous adverse events are discussed.
Assuntos
Terapia de Alvo Molecular/efeitos adversos , Neoplasias/genética , Inibidores de Proteínas Quinases/efeitos adversos , Anormalidades da Pele/metabolismo , Anormalidades da Pele/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/induzido quimicamente , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Humanos , Neoplasias/metabolismo , Neoplasias/terapia , Inibidores de Proteínas Quinases/administração & dosagem , Receptores Proteína Tirosina Quinases/efeitos dos fármacos , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Anormalidades da Pele/induzido quimicamente , Anormalidades da Pele/classificaçãoRESUMO
AIM: The treatment of pediatric low-grade gliomas with current treatment modalities still remains ineffective among a subset of patients; hence, justifying the need to further investigate more effective therapies. Dipotassium bisperoxo (picolinato) oxovanadate V (Bpv[pic]), is a derivative of the trace metal vanadium and a potent inhibitor of protein tyrosine phosphatases, which are important mediators of oncogenic and tumor suppressive activities in cancers. In this study, we undertook a preclinical evaluation of the antineoplastic functions of Bpv(pic) in the treatment of pediatric low-grade gliomas. MATERIALS & METHODS: We utilized pediatric low-grade glioma cell lines (Res186, Res259 and R286) in a wide variety of cancer assays to determine whether Bpv(pic) can abrogate the neoplastic properties of these cells. RESULTS: Our preclinical evaluation of the antineoplastic properties of Bpv(pic) in pediatric low-grade gliomas reveals a significant dose-dependent decrease in cell viability as a consequence of decreased proliferation and sustained induction of growth arrest and apoptosis. Bpv(pic) significantly decreases cell migration/invasion and anchorage-independent growth in soft agarose. Within cells, Bpv(pic) functions by attenuating CDC25A activity, and by decreasing the expression of multiple protein tyrosine phosphatases, DNA repair genes, microtubule-associated genes, such as PLK1, AURKA and HDAC6, and conversely augmenting the expression of proapoptotic mediators such as BAK, AIFM and CTSL1. CONCLUSION: Collectively, our data strongly suggest novel evidence of Bpv(pic) being a potent antineoplastic drug and a suitable alternative for the treatment of pediatric low-grade gliomas.
Assuntos
Antineoplásicos/administração & dosagem , Sobrevivência Celular/efeitos dos fármacos , Glioma/tratamento farmacológico , Compostos Organometálicos/administração & dosagem , Antineoplásicos/efeitos adversos , Apoptose/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/induzido quimicamente , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/genética , Glioma/patologia , Humanos , Estadiamento de Neoplasias , Compostos Organometálicos/efeitos adversos , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Pediatria/métodos , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Fosfatases cdc25/metabolismoAssuntos
Ensaios Clínicos como Assunto/ética , Ensaios Clínicos como Assunto/enfermagem , Indústria Farmacêutica/ética , Indústria Farmacêutica/legislação & jurisprudência , Ética em Pesquisa , Experimentação Humana/ética , Experimentação Humana/legislação & jurisprudência , Programas Nacionais de Saúde/ética , Programas Nacionais de Saúde/legislação & jurisprudência , Adulto , Criança , Ensaios Clínicos como Assunto/legislação & jurisprudência , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/induzido quimicamente , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/enfermagem , Europa (Continente) , Alemanha , Fidelidade a Diretrizes/ética , Fidelidade a Diretrizes/legislação & jurisprudência , Humanos , Política , Ensaios Clínicos Controlados Aleatórios como Assunto/ética , Ensaios Clínicos Controlados Aleatórios como Assunto/legislação & jurisprudência , Ensaios Clínicos Controlados Aleatórios como Assunto/enfermagem , Medição de Risco/ética , Medição de Risco/legislação & jurisprudência , Estados UnidosRESUMO
AIMS AND BACKGROUND: For advanced cancers of the bile duct, gallbladder and ampulla of Vater, there are only a few treatment options. We explored the efficacy of the combination of gemcitabine, 5-fluorouracil and cisplatin for advanced biliary cancers. METHODS: From September 2003 to April 2010, 28 patients with recurrent or metastatic biliary tract cancer were enrolled. A treatment regimen consisting of gemcitabine (800 mg/m² at a fixed dose rate on days 1 and 8), 5-fluorouracil (1 g/m²/day continuous infusion for 4 days) and cisplatin (60 mg/m² on day 2) was repeated every 3 weeks. RESULTS: One (3.6%) patient showed complete response, 8 (28.6%) partial response, 14 (50%) stable disease and 5 (17.9%) disease progression. Overall, the objective response rate was 32.1% (95% CI, 17.9-50.6%) and the disease control rate was 82.1% (95% CI, 64.4-92.1%). Median progression-free survival and overall survival were 7.6 months (95% CI, 5.5-9.7) and 11.2 months (95% CI, 6.8-15.5), respectively. G3/4 neutropenia was observed in 44 (24.3%) of 181 cycles and G3/4 thrombocytopenia in 48 (26.5%) of 181 cycles. There was no treatment-related mortality. CONCLUSIONS: The combined regimen of gemcitabine, 5-fluorouracil and cisplatin has comparable activity for patients with advanced cancer of the bile duct, gallbladder and ampulla of Vater. Toxicity was tolerable but substantial.
Assuntos
Adenocarcinoma/tratamento farmacológico , Ampola Hepatopancreática , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias dos Ductos Biliares/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/induzido quimicamente , Neoplasias da Vesícula Biliar/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adenocarcinoma/secundário , Adulto , Idoso , Anemia/induzido quimicamente , Neoplasias dos Ductos Biliares/patologia , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Neoplasias do Ducto Colédoco/tratamento farmacológico , Creatinina/sangue , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Esquema de Medicação , Sinergismo Farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Neoplasias da Vesícula Biliar/patologia , Hospitais Universitários , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Estadiamento de Neoplasias , Neutropenia/induzido quimicamente , Doenças do Sistema Nervoso Periférico/induzido quimicamente , República da Coreia/epidemiologia , Índice de Gravidade de Doença , Estomatite/induzido quimicamente , Trombocitopenia/induzido quimicamente , Vômito/induzido quimicamente , GencitabinaRESUMO
BACKGROUND: Cytotoxic chemotherapy is the basic treatment for metastatic gastric cancer. The "docetaxel, cisplatin, 5-day infusion of 5-FU (DCF5)" regimen is regarded as an effective therapy. However, the poor toxicity profile of this regimen and administration by 5-day infusion are major drawbacks of this method. METHODS: Patients with measurable metastatic gastric carcinoma, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, normal hematological and renal function, adequate hepatic function, and not pretreated for advanced disease with chemotherapy, received docetaxel on day 1, cisplatin on day 1, and 5-FU peripheral IV on day 1 (DCF1) every 3 weeks. The patients undergoing the DCF1 regimen could not receive the infusion regimen. This was a retrospective study about the use of DCF in 1 day in not previously treated metastatic gastric cancer. RESULTS: In total, 95 patients were treated with a median of 5 cycles per patient. Those not previously treated for advanced disease received docetaxel 75 mg/m² on day 1, cisplatin 75 mg/m² on day 1, and 5-FU peripheral IV 750 mg/m²/day on day 1, plus filgrastim or lenograstim between days 3 and 7. Grade ≥3 toxicities were neutropenia (12%), anemia (11%), thrombocytopenia (3%), fatigue (18%), mucositis (10%), diarrhea (3%), nausea/vomiting (6%), neurological (3%), and palmar-plantar (2%). Two nonfatal febrile neutropenia episodes were recorded. There were no treatment-related deaths. In all patients with measurable disease, we observed an overall response rate of 46% (40 partial responses, 4 complete responses). Thirty-one patients (33%) had stable disease. The median overall survival was 9.0 months (95% CI 7.34-10.6). CONCLUSIONS: Use of the DCF1 regimen in metastatic gastric cancer is feasible, with comparable activity to previous results achieved with epirubicin-based chemotherapy and infusion DCF in terms of overall survival. However, randomized and prospective studies need to be carried out with this regimen.
Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/secundário , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/induzido quimicamente , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Adulto , Idoso , Anemia/induzido quimicamente , Carcinoma de Células em Anel de Sinete/tratamento farmacológico , Carcinoma de Células em Anel de Sinete/secundário , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Diarreia/induzido quimicamente , Docetaxel , Esquema de Medicação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Estudos de Viabilidade , Feminino , Filgrastim , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Infusões Intravenosas , Lenograstim , Masculino , Pessoa de Meia-Idade , Mucosite/induzido quimicamente , Estadiamento de Neoplasias , Neutropenia/induzido quimicamente , Substâncias Protetoras/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Índice de Gravidade de Doença , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Trombocitopenia/induzido quimicamente , Resultado do Tratamento , Vômito/induzido quimicamenteRESUMO
Tyrosine kinase inhibitors (TKIs) represent important therapeutic alternatives to, or combinations with, traditional cytotoxic chemotherapy. Despite their selective molecular targeting and demonstrated clinical benefit, TKIs produce a range of serious adverse events, including drug-induced liver injury, that require careful patient management to maintain treatment benefit without harm. Genetic characterization of serious adverse events can identify mechanisms of injury and improve safety risk management. This review presents pharmacogenetic comparisons of two approved TKIs, lapatinib and pazopanib, which reveal different mechanisms of injury and inform the characteristics and risk of serious liver injury in treated patients. The data presented demonstrate the utility of genetic studies to investigate drug-induced liver injury and potentially support its management in patients.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Glucuronosiltransferase/genética , Inibidores de Proteínas Quinases/toxicidade , Biomarcadores Farmacológicos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/induzido quimicamente , Doença de Gilbert/tratamento farmacológico , Doença de Gilbert/genética , Humanos , Indazóis , Lapatinib , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Pirimidinas/toxicidade , Quinazolinas/administração & dosagem , Quinazolinas/toxicidade , Sulfonamidas/administração & dosagem , Sulfonamidas/toxicidadeRESUMO
PURPOSE: Few data are available on the occurrence of renal failure during continuous infusion of vancomycin in critically ill patients. METHODS: We reviewed the data of all patients admitted to the intensive care unit (ICU) between January 2008 and December 2009 in whom vancomycin was given as a continuous infusion for more than 48 h in the absence of renal replacement therapy. We collected data on the doses of vancomycin and blood concentrations during therapy. Acute kidney injury (AKI) was defined as a daily urine output <0.5 ml/kg/h and/or an increase in the serum creatinine of ≥0.3 mg/dl from baseline levels during vancomycin therapy or within 72 h after its discontinuation. Multivariable logistic regression analysis was performed to identify predictors of AKI. RESULTS: Of 207 patients who met the inclusion criteria, 50 (24 %) developed AKI. These patients were more severely ill, had lower creatinine clearance at admission, were more frequently exposed to other nephrotoxic agents, had a longer duration of therapy, and had higher concentrations of vancomycin during the first 3 days of treatment (C(mean)). The C(mean) was independently associated with early AKI (within 48 h from the onset of therapy) and the duration of vancomycin administration with late AKI. CONCLUSIONS: AKI occurred in almost 25 % of critically ill patients treated with a continuous infusion of vancomycin. Vancomycin concentrations and duration of therapy were the strongest variables associated with the development of early and late AKI during therapy, respectively.
Assuntos
Injúria Renal Aguda/induzido quimicamente , Antibacterianos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/induzido quimicamente , Sepse/complicações , Sepse/tratamento farmacológico , Vancomicina/efeitos adversos , Injúria Renal Aguda/epidemiologia , Adulto , Idoso , Antibacterianos/administração & dosagem , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Humanos , Infusões Intravenosas/métodos , Masculino , Pessoa de Meia-Idade , Plasma/química , Prevalência , Vancomicina/administração & dosagemRESUMO
Perioperative intravesical chemotherapy has a well-established role in the treatment of non-muscle invasive bladder cancer. There are multiple agents that can be used in this fashion with varying properties. Although chemical cystitis is the most common side effect and is usually self-limiting, significant toxicity can occur with intravesical chemotherapy. It is imperative that the urologist is aware of the acute and delayed side effects of intravesical chemotherapy and how to manage potential complications. Both local and systemic toxicities are discussed, as well as strategies to minimize and manage them.
Assuntos
Antineoplásicos/efeitos adversos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Administração Intravesical , Antineoplásicos/administração & dosagem , Terapia Combinada , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/induzido quimicamente , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/terapia , Humanos , Assistência Perioperatória , Neoplasias da Bexiga Urinária/cirurgiaRESUMO
PURPOSE: Treating cancer often involves the use of chemotherapeutic agents. Due to the growing incidence of cancer worldwide and the expanding number of treatment options, it is important to understand the risks of adverse events associated with these treatments. In this study, we monitored the occurrence of acute infusion reactions in an outpatient chemotherapy center from April 2011 to April 2012. METHODS: For patients who developed infusion reactions, the causative drug, the dose and number of treatments received, the onset time of the reaction, the duration of the reaction, blood pressure, pulse, level of oxygen saturation during the reaction, and other symptoms were recorded. The severity of reactions was determined in accordance with NCI toxicity criteria. A reaction was considered as grade 1-2 (mild-moderate) if the patient experienced flushing, rash, fever, tremor, dyspnea, rigor, and mild hypotension. Symptoms such as severe hypotension, bronchospasm, cardiac dysfunction and anaphylaxis, requiring therapeutic intervention, were classified as severe, grade 3-4 reactions. RESULTS: Of the 2213 patients receiving chemotherapy during the study period, 138 (62%) developed an infusion reaction to the treatment. Among 138 patients most commonly treated types of carcinoma included breast (39.2%), lung (17.8%), colorectal (10%), and ovarian (8.5%) cancers. Docetaxel administration resulted in the largest number of infusion reactions, though most reactions were mild to moderate and did not require the cessation of treatment. Patients with mild to moderate reactions (89.2%) were able to continue treatment, while those who developed severe reactions (10.8%) could not continue treatment with the same agent. CONCLUSION: Although severe reactions are rare, the incidence of mild to moderate reactions against taxanes, platinum compounds, and monoclonal antibodies is quite high. Clinical symptoms do not vary widely among the agents, though the onset time of symptoms does vary. While reactions against platinum agents were of type 1 anaphylactic reactions, reactions against taxanes and monoclonal antibodies during the first infusion and in the following minutes suggest the activation of different mechanisms.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Hipersensibilidade a Drogas/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/induzido quimicamente , Doença Aguda , Adulto , Idoso , Assistência Ambulatorial , Hipersensibilidade a Drogas/diagnóstico , Hipersensibilidade a Drogas/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Humanos , Incidência , Infusões Parenterais , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Índice de Gravidade de Doença , Fatores de Tempo , Turquia/epidemiologiaRESUMO
CONTEXT: The use of kinase inhibitors (KIs) in the treatment of cancer has become increasingly common, and practitioners must be familiar with endocrine-related side effects associated with these agents. This review provides an update to the clinician regarding the management of potential endocrinological effects of KIs. EVIDENCE ACQUISITION: PubMed was employed to identify relevant manuscripts. A review of the literature was conducted, and data were summarized and incorporated. EVIDENCE SYNTHESIS: KIs, including small molecule KIs and monoclonal antibodies directed against kinases, have emerged over the past decade as an important class of anticancer agents. KIs specifically interfere with signaling pathways that are dysregulated in certain types of cancers and also target common mechanisms of growth, invasion, metastasis, and angiogenesis. Currently, at least 20 KIs are approved as cancer therapeutics. However, KIs may affect a broad spectrum of targets and may have additional, unidentified mechanisms of action at the cellular level due to overlap between signaling pathways in the tumor cell and endocrine system. Recent reports in the literature have identified side effects associated with KIs, including alterations in thyroid function, bone metabolism, linear growth, gonadal function, fetal development, adrenal function, and glucose metabolism. CONCLUSIONS: Clinicians need to monitor the thyroid functions of patients on KIs. In addition, bone density and vitamin D status should be assessed. Special care should be taken to follow linear growth and development in children taking these agents. Clinicians should counsel patients appropriately on the potential adverse effects of KIs on fetal development.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/terapia , Doenças do Sistema Endócrino/induzido quimicamente , Doenças do Sistema Endócrino/terapia , Sistema Endócrino/efeitos dos fármacos , Inibidores de Proteínas Quinases/efeitos adversos , Antineoplásicos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/induzido quimicamente , Sistema Endócrino/fisiologia , Feminino , Fertilidade/efeitos dos fármacos , Fertilidade/fisiologia , Humanos , Doenças Maxilomandibulares/induzido quimicamente , Doenças Maxilomandibulares/epidemiologia , Doenças Maxilomandibulares/terapia , Osteonecrose/induzido quimicamente , Osteonecrose/epidemiologia , Osteonecrose/terapia , Gravidez , Inibidores de Proteínas Quinases/uso terapêutico , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/fisiologiaRESUMO
Idiosyncratic drug reactions are a significant cause of morbidity and mortality for patients; they also markedly increase the uncertainty of drug development. The major targets are skin, liver, and bone marrow. Clinical characteristics suggest that IDRs are immune mediated, and there is substantive evidence that most, but not all, IDRs are caused by chemically reactive species. However, rigorous mechanistic studies are very difficult to perform, especially in the absence of valid animal models. Models to explain how drugs or reactive metabolites interact with the MHC/T-cell receptor complex include the hapten and P-I models, and most recently it was found that abacavir can interact reversibly with MHC to alter the endogenous peptides that are presented to T cells. The discovery of HLA molecules as important risk factors for some IDRs has also significantly contributed to our understanding of these adverse reactions, but it is not yet clear what fraction of IDRs have a strong HLA dependence. In addition, with the exception of abacavir, most patients who have the HLA that confers a higher IDR risk with a specific drug will not have an IDR when treated with that drug. Interindividual differences in T-cell receptors and other factors also presumably play a role in determining which patients will have an IDR. The immune response represents a delicate balance, and immune tolerance may be the dominant response to a drug that can cause IDRs.
Assuntos
Antibacterianos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Sulfonamidas/efeitos adversos , beta-Lactamas/efeitos adversos , Animais , Citocinas/imunologia , Modelos Animais de Doenças , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/induzido quimicamente , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/imunologia , Humanos , Ativação Linfocitária/efeitos dos fármacos , Fatores de Risco , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Viroses/complicaçõesRESUMO
CONTEXT: In recent years, progress has been made in cancer immunotherapy by the development of drugs acting as modulators of immune checkpoint proteins, such as the cytotoxic T-lymphocyte antigen-4 (CTLA4) and programmed death-1 (PD-1), two co-inhibitory receptors that are expressed on T cells upon activation. These molecules play crucial roles in maintaining immune homeostasis by down-regulating T-cell signaling, thereby preventing unbridled T-cell proliferation while maintaining tolerance to self-antigens, such as tumor-associated antigens. CTLA4 blockade through systemic administration of the CTLA4-blocking antibody ipilimumab was shown to confer significant survival benefit and prolonged stable disease in patients affected by advanced cutaneous melanoma. Other immune checkpoint inhibitors are under clinical evaluation. However, immune checkpoint blockade can lead to the breaking of immune self-tolerance, thereby inducing a novel syndrome of autoimmune/autoinflammatory side effects, designated as "immune-related adverse events," mainly including rash, colitis, hepatitis, and endocrinopathies. DATA ACQUISITION: We searched the medical literature using the words "hypophysitis," "hypopituitarism," "thyroid," "adrenal insufficiency," and "endocrine adverse events" in association with "immune checkpoint inhibitors," "ipilimumab," "tremelimumab," "PD-1," and "PD-1-L." EVIDENCE SYNTHESIS: The spectrum of endocrine disease experienced by patients treated with ipilimumab includes most commonly hypophysitis, more rarely thyroid disease or abnormalities in thyroid function tests, and occasionally primary adrenal insufficiency. Hypophysitis has emerged as a distinctive side effect of CTLA4-blocking antibodies, establishing a new form of autoimmune pituitary disease. This condition, if not promptly recognized, may be life-threatening (due to secondary hypoadrenalism). Hypopituitarism caused by these agents is rarely reversible, and prolonged or lifelong substitutive hormonal treatment is often required. The precise mechanism of injury to the endocrine system triggered by these drugs is yet to be fully elucidated. CONCLUSIONS: Although reports of endocrine side effects caused by cancer immune therapy are abundant, their exact prevalence and mechanism are unclear. Well-designed correlative studies oriented to finding and validating predictive factors of autoimmune toxicity are urgently needed.
Assuntos
Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Pontos de Checagem do Ciclo Celular/imunologia , Doenças do Sistema Endócrino/induzido quimicamente , Sistema Endócrino/efeitos dos fármacos , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/induzido quimicamente , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Doenças do Sistema Endócrino/epidemiologia , Humanos , Imunoterapia/efeitos adversos , Neoplasias/terapiaRESUMO
OBJECTIVE: To analyze the efficacy and safety of entecavir (ETV) treatment for up to 5 years in nucleos(t)ide-naïve chronic hepatitis B patients in real life. METHODS: We retrospectively analyzed 230 nucleos(t)ide naïve chronic hepatitis B patients who received ETV 0.5 mg/day monotherapy for at least 3 months, of whom 113 were HBeAg positive and 117 were HBeAg negative. The primary endpoints was cumulative probability of achieving a virological response (undetectable serum HBV DNA, <100IU/mL). Secondary endpoints were rates of ALT normalization (ALT < upper limit of normal), HBeAg seroconversion, resistance, and safety. RESULTS: The median follow-up duration was 27.5 months (3-73 months) and mean age was 42 years. With 230, 214, 180, 142, 88, 42 and 11 patients followed-up for at least 3 months,6 months, 1, 2, 3, 4 and 5 years, respectively. In all, Incremental increases were observed in the rates of undetectable HBV DNA. 67.0%, 85.0%, 89.4%, 94.4%, 95.5%, 97.6%, 100% had undetectable HBV DNA at month 3, month 6, 1 year, 2 years, 3 years, 4 years and 5 years. Proportions of patients achieving normal ALT were 73.9%, 85.5%, 82.8%, 89.4%, 80.7%, 85.7%, 100%, respectively. The rate of HBeAg seroconversion reached 21.4% and 15.4% at year2, 3, respectively. One patient achieved HBsAg seroclearance after 1 year, and achieved anti-HBs seroconversion at year 3. Of 180 patients, HBV DNA was detectable (partial virological response, PVR) in 19 patients at year 1 of follow-up, twelve of 14 (85.7%) patients with PVR need more than 1 year of continuous ETV therapy to achieved VR. At baseline, no ETV-resistance was detected in 25 ETV-naïve patients. One patient developed ETV-resistance mutations due to noncompliance. No serious adverse event was reported. CONCLUSION: Long-term ETV treatment of nucleos(t)ide-naïve was effective and safe in real life. Adjustment of ETV monotherapy in nucleos(t)ide-naïve patients with a partial virological response at 1 year may be unnecessary.
Assuntos
Antivirais/administração & dosagem , Guanina/análogos & derivados , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/tratamento farmacológico , Adolescente , Adulto , Idoso , Antivirais/efeitos adversos , Farmacorresistência Viral/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/induzido quimicamente , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Seguimentos , Guanina/administração & dosagem , Guanina/efeitos adversos , Guanina/metabolismo , Antígenos E da Hepatite B/genética , Hepatite B Crônica/sangue , Hepatite B Crônica/patologia , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Resultado do TratamentoRESUMO
BACKGROUND AND AIMS: Ankaferd Blood Stopper (ABS) is a herbal extract obtained from five different plants. It has a therapeutic potential for the management of external hemorrhage and controlling gastrointestinal bleeding. However, ABS's effects are not unknown on gastrointestinal systems. The aim of this study was to assess the effect of short- and long-term systemic exposure and gastrointestinal safety following the oral administration of high-dose ABS in rats. METHODS: Eighteen healthy adult male rats were included into the study. The rats were divided into 4 groups: group A was fed with high dose ABS (2ml/Kg) for one week, group B for one month, group C for three months and group D's diet did not contain any ABS. On termination of the ABS treatment, the gastrointestinal system from the esophagus to the anus and the liver were surgically removed and histological investigated. RESULTS: During the study period, there was no mortality; signs of intoxication in any of the studied groups. No gastrointestinal tissue fibrosis, dysplasia, or metaplasia was detectable in any of the groups. The stomach had a normal morphology in all groups. However, the other gastrointestinal tract sections showed mucosal inflammation, goblet cell decrements, and intra-epithelial lymphocyte infiltration. The most common changes were mucosal inflammation in all rats in group B and C. Frequency of inflammation was greater in groups B and C in comparison to group A (P= 0.001). Loss of goblet cell and intra-epithelial lymphocyte infiltration were not significantly different between groups A and B (P=0.308 and P=0.189, respectively). However, there was significantly higher intra-epithelial lymphocyte infiltration in group C than in group A (P=0.04). Histopathological examination of the liver showed no inflammation, fibrosis, bile duct destruction or proliferation in any of the groups. However, each groups revealed vascular dilatation and erythrocyte accumulation at the sinusoidal structures of the liver. CONCLUSIONS: ABS seems to be a safe agent and it can be used for hemorrhage originated from gastric lesions. Further work needs to be done to establish whether ABS leads to be used to stop gastrointestinal bleeding.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Trato Gastrointestinal/patologia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/efeitos adversos , Administração Oral , Animais , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/induzido quimicamente , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Esôfago/efeitos dos fármacos , Hemorragia Gastrointestinal/tratamento farmacológico , Trato Gastrointestinal/efeitos dos fármacos , Humanos , Masculino , RatosRESUMO
OBJECTIVES: This analysis was conducted to clarify risk factors for severe adverse effects and treatment-related deaths reported during a postmarketing survey of irinotecan. METHODS: The survey covered all patients treated with irinotecan in Japan between April 1995 and January 2000. The patient background data and adverse drug reactions were collected through case report forms. Univariate and multivariate logistic regression analyses including 14 explanatory variables were performed to determine the risk factors for grade 3-4 leukopenia, thrombocytopenia and diarrhea for all patients and subgroups with five major cancers. Treatment-related deaths were also analyzed. RESULTS: Case report forms of 13 935 patients (94.1% of 14 802 patients registered) treated with irinotecan-based chemotherapy were collected. Major grade 3-4 adverse drug reactions were leukopenia (34.8%), thrombocytopenia (12.4%) and diarrhea (10.1%). Multivariate analysis revealed that the risk factors (odds ratio ≥1.5) common for all these three adverse drug reactions were performance status (≥3), infection and renal dysfunction before starting irinotecan therapy. Additionally, the risk factors for leukopenia were being female and prior radiotherapy, those for thrombocytopenia were age (≥65 years), while those for diarrhea were pleural effusion and watery stool. The risk factors in each cancer were also identified. The incidence of treatment-related death was 1.3% (176). Myelosuppression-related deaths accounted for 70% and interstitial lung disease for 11% of all treatment-related deaths. Being male, age, performance status ≥3, massive ascites and infection and renal dysfunction were identified as risk factors for treatment-related death. CONCLUSIONS: To ensure the safety of irinotecan therapy, it is important to select appropriate patients by considering the risk factors.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/análogos & derivados , Morte , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/induzido quimicamente , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Neoplasias/tratamento farmacológico , Idoso , Análise de Variância , Antineoplásicos Fitogênicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Povo Asiático/estatística & dados numéricos , Neoplasias da Mama/tratamento farmacológico , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Diarreia/induzido quimicamente , Diarreia/epidemiologia , Esquema de Medicação , Feminino , Humanos , Irinotecano , Japão/epidemiologia , Leucopenia/induzido quimicamente , Leucopenia/epidemiologia , Modelos Logísticos , Neoplasias Pulmonares/tratamento farmacológico , Linfoma/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Vigilância de Produtos Comercializados , Medição de Risco , Fatores de Risco , Fatores Sexuais , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Trombocitopenia/induzido quimicamente , Trombocitopenia/epidemiologiaRESUMO
CLINICAL/METHODOLOGICAL ISSUE: In antineoplastic chemotherapy classical cytostatic drugs are increasingly being supplemented by antibodies and so-called targeted therapies. In addition to the antineoplastic effect and general intolerance quite characteristic morphological changes can often be found and identified by the radiologist. The distinction between findings indicating side effects versus tumor progression or an infectious etiology is essential. FACTS AND CIRCUMSTANCES: Classical antineoplastic chemotherapy interacts with DNA and RNA synthesis, DNA repair or the mitosis process. In contrast modern targeted anticancer therapies act at the level of signal transduction pathways.Localized, organ-related changes are related to the metabolic characteristics of organs or anatomical features such as the properties of the local blood-tissue barrier. Toxicity associated findings often resemble fulminant tumor progression. EVALUATION: In new targeted anti-cancer therapies toxicity often occurs in a non-cumulative way; therefore, morphological changes are often precursors of the manifestation of clinical toxicity. PRACTICAL RECOMMENDATIONS: Oncological radiology requires increasingly active interdisciplinary dialogue in order to delineate morphological correlates of organ toxicity against tumor progression and initiate appropriate therapeutic measures.
Assuntos
Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Diagnóstico por Imagem/tendências , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/induzido quimicamente , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Humanos , Oncologia/tendências , Avaliação de Resultados em Cuidados de Saúde/tendências , Radiologia/tendências , Resultado do TratamentoRESUMO
BACKGROUND: Preclinical studies have shown synergistic antitumour activity by inhibition of insulin-like growth factor-1 receptor (IGF-1R) and mTOR. The expression of IGF-1R seems to be crucial for this effect. We investigated the safety and efficacy of the combination of the IGF-1R antibody cixutumumab and the mTOR inhibitor temsirolimus in patients with chemotherapy-refractory bone and soft-tissue sarcomas according to IGF-1R expression by immunohistochemistry. METHODS: We undertook a multicentre, open-label, phase 2 study in 19 cancer centres in the USA. Patients aged at least 16 years with a histologically confirmed diagnosis of bone or soft-tissue sarcoma were allocated on the basis of IGF-1R expression by immunohistochemistry to one of three treatment groups: IGF-1R-positive soft-tissue sarcoma (group A), IGF-1R-positive bone sarcomas (group B), or IGF-1R-negative bone and soft-tissue sarcoma (group C). Patients received weekly treatment with cixutumumab (6 mg/kg, intravenous) and temsirolimus (25 mg, intravenous flat dose) in 6-week cycles. A Simon optimal two-stage design was used for every arm. The primary endpoint was progression-free survival (PFS) at 12 weeks by intention-to-treat analysis in the first 54 patients assigned to every treatment arm. Although patients still remain on treatment, this trial has completed enrolment and this represents the final analysis. This study is registered with ClinicalTrials.gov, number NCT01016015. FINDINGS: Between Nov 18, 2009, and April 11, 2012, 388 patients were screened for IGF-1R expression and 54 were assigned to each arm. 17 of 54 patients in the IGF-1R-positive soft-tissue sarcoma group (31%; one-sided 95% CI lower bound 21%; two-sided 90% CI 21-43), 19 of 54 in IGF-1R-positive bone sarcoma group (35%; one-sided 95% CI lower bound 24%; two-sided 90% CI 24-47), and 21 of 54 in the IGF-1R-negative group (39%, one-sided 95% CI lower bound 28%; two-sided 90% CI 28-51) were progression free at 12 weeks. On April 6, 2011, the protocol was amended to include three additional patients in the IGF-1R-positive soft-tissue sarcoma group (total of 57 patients) and nine more in the IGF-1R-negative group (total of 63 patients). There were 2546 adverse events reported during the study, 214 (8%) of which were grade 3-4. The most common grade 3-4 toxicities in the 174 treated patients were anaemia in 16 (9%) patients, hyperglycaemia in 18 (10%), hypophosphataemia in 16 (9%), lymphopenia in 25 (14%), oral mucositis in 19 (11%), and thrombocytopenia in 19 (11%). INTERPRETATION: The combination of cixutumumab and temsirolimus shows clinical activity in patients with sarcoma and forms a basis for future trials. However, IGF-1R expression by immunohistochemistry is not predictive of clinical outcome after treatment with this combination. FUNDING: National Cancer Institute and CycleforSurvival Fund, Memorial Sloan-Kettering Cancer Center.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Ósseas , Sarcoma , Sirolimo/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/induzido quimicamente , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/imunologia , Receptor IGF Tipo 1/metabolismo , Sarcoma/tratamento farmacológico , Sarcoma/mortalidade , Sarcoma/patologia , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismoRESUMO
BACKGROUND: Adding patients to the range of potential reporters of adverse drug reactions (ADRs) may increase spontaneous reporting and contribute to the detection of signals, one of the primary aims of spontaneous reporting systems. Community pharmacies could have an important role in this context as a service for promoting patient reporting of ADRs. OBJECTIVES: The main objectives of the present study were to assess the potential impact of an intervention to promote patient reporting in community pharmacies in the Veneto region of Italy, and to compare the characteristics of patients' and general practitioners' (GPs) reports of ADRs. METHODS: The study was conducted in the Veneto region of Italy and involved 211 pharmacists working in 118 community pharmacies. Each pharmacist was asked to select, during the study period, about 250 customers who had received at least one drug, and then to present the spontaneous reporting form to those who had experienced a suspected ADR. Patients were asked to complete the ADR report form and either give it back to the pharmacist, or send it by fax or mail, or else to fill in the form online. RESULTS: In a 4-month period, 52,495 customers were interviewed by the pharmacists and 4,949 of them (9.4 %) referred a suspected ADR. The Pharmacovigilance Centre of the Veneto region received 2,311 citizen's ADR reporting forms related to the study (from 46.7 % of all patients interviewed who had experienced suspected ADRs). After quality control 1,794 of these reports were entered into the Italian Pharmacovigilance Database and were compared with the reports (226) sent by GPs in the Veneto region in the same period. Patients reported a higher percentage of known and non-serious reactions than did GPs. Drugs widely used in the community setting, and over-the-counter products, were the drugs most frequently reported by patients. In contrast, few reports involving reactions to antineoplastic agents or contrast media-drugs mostly used in a hospital setting-were sent by patients. CONCLUSIONS: Our study shows that patient reporting has the potential to add value to the pharmacovigilance system. The overall quality of the information provided in patients' reports was good. The differences between reports by patients and by GPs indicate different points of view that can enrich spontaneous reporting.