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2.
Xenobiotica ; 50(1): 101-109, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31682552

RESUMO

The thiopurine drugs azathioprine and mercaptopurine are effective in the treatment of disorders of immune regulation and acute lymphoblastic leukaemia. Although developed in the 1950s, thiopurines remained relevant in the anti-tumour necrosis factor biologic era, finding widespread use as a co-immunomodulator. Step changes in the management of patients treated with thiopurines have reduced the incidence of severe, sometimes life-threatening toxicity. Testing for thiopurine methyltransferase (TPMT) deficiency directs a safe initial dose for therapy. The introduction of red cell thioguanine nucleotide (TGN) monitoring provides a basis for dose adjustment and the identification of patients with high levels of red cell methylmercaptopurine (MMP) and an increase in the MMP:TGN ratio. These patients are at risk for hepatotoxicity and where TGN levels are sub-therapeutic, non-response to therapy. Switching thiopurine hypermethylators to low-dose thiopurine and allopurinol combination therapy resolves hepatoxicity and increases sub-therapeutic TGN levels to regain clinical response. NUDT15 variants are a common cause of severe myelotoxicity in Asian populations where the frequency of TPMT deficiency is low. There is increasing evidence that testing for NUDT15 and TPMT deficiency in all populations prior to the start of thiopurine therapy is clinically useful and should be the first step in personalising thiopurine therapy.


Assuntos
Hipersensibilidade a Drogas/genética , Erros Inatos do Metabolismo da Purina-Pirimidina/genética , Purinas/uso terapêutico , Azatioprina/efeitos adversos , Azatioprina/uso terapêutico , Eritrócitos , Feminino , Genótipo , Humanos , Masculino , Mercaptopurina/efeitos adversos , Mercaptopurina/análogos & derivados , Mercaptopurina/uso terapêutico , Metiltransferases , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Purinas/efeitos adversos
3.
N Engl J Med ; 382(6): 514-524, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-31826360

RESUMO

BACKGROUND: In an earlier analysis of this phase 3 trial, ribociclib plus fulvestrant showed a greater benefit with regard to progression-free survival than fulvestrant alone in postmenopausal patients with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Here we report the results of a protocol-specified second interim analysis of overall survival. METHODS: Patients were randomly assigned in a 2:1 ratio to receive either ribociclib or placebo in addition to fulvestrant as first-line or second-line treatment. Survival was evaluated by means of a stratified log-rank test and summarized with the use of Kaplan-Meier methods. RESULTS: This analysis was based on 275 deaths: 167 among 484 patients (34.5%) receiving ribociclib and 108 among 242 (44.6%) receiving placebo. Ribociclib plus fulvestrant showed a significant overall survival benefit over placebo plus fulvestrant. The estimated overall survival at 42 months was 57.8% (95% confidence interval [CI], 52.0 to 63.2) in the ribociclib group and 45.9% (95% CI, 36.9 to 54.5) in the placebo group, for a 28% difference in the relative risk of death (hazard ratio, 0.72; 95% CI, 0.57 to 0.92; P = 0.00455). The benefit was consistent across most subgroups. In a descriptive update, median progression-free survival among patients receiving first-line treatment was 33.6 months (95% CI, 27.1 to 41.3) in the ribociclib group and 19.2 months (95% CI, 14.9 to 23.6) in the placebo group. No new safety signals were observed. CONCLUSIONS: Ribociclib plus fulvestrant showed a significant overall survival benefit over placebo plus fulvestrant in patients with hormone-receptor-positive, HER2-negative advanced breast cancer. (Funded by Novartis; MONALEESA-3 ClinicalTrials.gov number, NCT02422615.).


Assuntos
Aminopiridinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Fulvestranto/administração & dosagem , Purinas/administração & dosagem , Idoso , Aminopiridinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/mortalidade , Esquema de Medicação , Feminino , Fulvestranto/efeitos adversos , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Pós-Menopausa , Intervalo Livre de Progressão , Purinas/efeitos adversos , Receptor ErbB-2 , Receptores Estrogênicos , Receptores de Progesterona
4.
PLoS Genet ; 15(8): e1008318, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31415568

RESUMO

Elevated uric acid (UA) is a key risk factor for many disorders, including metabolic syndrome, gout and kidney stones. Despite frequent occurrence of these disorders, the genetic pathways influencing UA metabolism and the association with disease remain poorly understood. In humans, elevated UA levels resulted from the loss of the of the urate oxidase (Uro) gene around 15 million years ago. Therefore, we established a Drosophila melanogaster model with reduced expression of the orthologous Uro gene to study the pathogenesis arising from elevated UA. Reduced Uro expression in Drosophila resulted in elevated UA levels, accumulation of concretions in the excretory system, and shortening of lifespan when reared on diets containing high levels of yeast extract. Furthermore, high levels of dietary purines, but not protein or sugar, were sufficient to produce the same effects of shortened lifespan and concretion formation in the Drosophila model. The insulin-like signaling (ILS) pathway has been shown to respond to changes in nutrient status in several species. We observed that genetic suppression of ILS genes reduced both UA levels and concretion load in flies fed high levels of yeast extract. Further support for the role of the ILS pathway in modulating UA metabolism stems from a human candidate gene study identifying SNPs in the ILS genes AKT2 and FOXO3 being associated with serum UA levels or gout. Additionally, inhibition of the NADPH oxidase (NOX) gene rescued the reduced lifespan and concretion phenotypes in Uro knockdown flies. Thus, components of the ILS pathway and the downstream protein NOX represent potential therapeutic targets for treating UA associated pathologies, including gout and kidney stones, as well as extending human healthspan.


Assuntos
Gota/etiologia , Cálculos Renais/etiologia , Redes e Vias Metabólicas/genética , Transdução de Sinais/genética , Ácido Úrico/metabolismo , Animais , Animais Geneticamente Modificados , Estudos de Coortes , Modelos Animais de Doenças , Drosophila melanogaster , Comportamento Alimentar , Feminino , Técnicas de Silenciamento de Genes , Gota/metabolismo , Humanos , Insulina/metabolismo , Cálculos Renais/metabolismo , Longevidade/genética , Masculino , Pessoa de Meia-Idade , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Polimorfismo de Nucleotídeo Único , Purinas/administração & dosagem , Purinas/efeitos adversos , Urato Oxidase/genética , Urato Oxidase/metabolismo
5.
N Engl J Med ; 381(4): 307-316, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31166679

RESUMO

BACKGROUND: An earlier analysis of this phase 3 trial showed that the addition of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor to endocrine therapy provided a greater benefit with regard to progression-free survival than endocrine therapy alone in premenopausal or perimenopausal patients with advanced hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Here we report the results of a protocol-specified interim analysis of the key secondary end point of overall survival. METHODS: We randomly assigned patients to receive either ribociclib or placebo in addition to endocrine therapy (goserelin and either a nonsteroidal aromatase inhibitor or tamoxifen). Overall survival was evaluated with the use of a stratified log-rank test and summarized with the use of Kaplan-Meier methods. RESULTS: A total of 672 patients were included in the intention-to-treat population. There were 83 deaths among 335 patients (24.8%) in the ribociclib group and 109 deaths among 337 patients (32.3%) in the placebo group. The addition of ribociclib to endocrine therapy resulted in significantly longer overall survival than endocrine therapy alone. The estimated overall survival at 42 months was 70.2% (95% confidence interval [CI], 63.5 to 76.0) in the ribociclib group and 46.0% (95% CI, 32.0 to 58.9) in the placebo group (hazard ratio for death, 0.71; 95% CI, 0.54 to 0.95; P = 0.00973 by log-rank test). The survival benefit seen in the subgroup of 495 patients who received an aromatase inhibitor was consistent with that in the overall intention-to-treat population (hazard ratio for death, 0.70; 95% CI, 0.50 to 0.98). The percentage of patients who received subsequent antineoplastic therapy was balanced between the groups (68.9% in the ribociclib group and 73.2% in the placebo group). The time from randomization to disease progression during receipt of second-line therapy or to death was also longer in the ribociclib group than in the placebo group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.55 to 0.87). CONCLUSIONS: This trial showed significantly longer overall survival with a CDK4/6 inhibitor plus endocrine therapy than with endocrine therapy alone among patients with advanced hormone-receptor-positive, HER2-negative breast cancer. No new concerns regarding toxic effects emerged with longer follow-up. (Funded by Novartis; MONALEESA-7 ClinicalTrials.gov number, NCT02278120.).


Assuntos
Aminopiridinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Quinases Ciclina-Dependentes/antagonistas & inibidores , Inibidores de Proteínas Quinases/administração & dosagem , Purinas/administração & dosagem , Adulto , Aminopiridinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/mortalidade , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Análise de Intenção de Tratamento , Pessoa de Meia-Idade , Perimenopausa , Pré-Menopausa , Inibidores de Proteínas Quinases/efeitos adversos , Purinas/efeitos adversos , Receptor ErbB-2 , Receptores Estrogênicos , Receptores de Progesterona , Análise de Sobrevida , Tamoxifeno/administração & dosagem
6.
Expert Opin Pharmacother ; 20(11): 1405-1411, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31039621

RESUMO

Background: Gait disorders are common in Parkinson's disease patients who respond poorly to dopaminergic treatment. Blockade of adenosine A2A receptors is expected to improve gait disorders. Istradefylline is a first-in-class selective adenosine A2A receptor antagonist with benefits for motor complications associated with Parkinson's disease. Research design and methods: This multicenter, open-label, single-group, prospective interventional study evaluated changes in total gait-related scores of the Part II/III Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and Freezing of Gait Questionnaire (FOG-Q) in 31 Parkinson's disease patients treated with istradefylline. Gait analysis by portable gait rhythmogram was performed. Results: MDS-UPDRS Part III gait-related total scores significantly decreased at Weeks 4-12 from baseline with significant improvements in gait, freezing of gait, and postural stability. Significant decreases in MDS-UPDRS Part II total scores and individual item scores at Week 12 indicated improved daily living activities. At Week 12, there were significant improvements in FOG-Q, new FOG-Q, and overall movement per 48 h measured by portable gait rhythmogram. Adverse events occurred in 7/31 patients. Conclusions: Istradefylline improved gait disorders in Parkinson's disease patients complicated with freezing of gait, improving their quality of life. No unexpected adverse drug reactions were identified. Trial registration: UMIN-CTR (UMIN000020288).


Assuntos
Antagonistas do Receptor A2 de Adenosina/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Purinas/uso terapêutico , Antagonistas do Receptor A2 de Adenosina/efeitos adversos , Administração Oral , Idoso , Esquema de Medicação , Discinesias/etiologia , Feminino , Marcha/fisiologia , Transtornos Neurológicos da Marcha/complicações , Transtornos Neurológicos da Marcha/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Estudos Prospectivos , Purinas/efeitos adversos , Qualidade de Vida , Resultado do Tratamento
7.
Future Oncol ; 15(19): 2227-2239, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31137964

RESUMO

P110-γ and -δ act in lymphocytes chemotaxis, presenting distinct, nonredundant roles in B- and T-cell migration and adhesion to stromal cells. Moreover, phosphoinositide-3-kinase-γ inhibition contributes to regulate macrophage polarization inhibiting cancer growth. Duvelisib (IPI-145) is an oral first-in-class, dual phosphoinositide-3-kinase inhibitor targeting p110-δ/γ exerting its activity in preclinical studies across different prognostic groups. In a large Phase III study, duvelisib showed superior progression-free survival and overall response rate compared with ofatumumab, thus leading to its approval for relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Immune-related effects are the main reason for treatment suspension, thus affecting survival benefit. Nevertheless, the correct management of adverse events, eventually including dose modification, allows patients to remain on treatment. In conclusion, duvelisib represents a promising treatment in chronic lymphocytic leukemia and a salvage therapy after ibrutinib.


Assuntos
Isoquinolinas/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Purinas/administração & dosagem , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/genética , Avaliação de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Isoquinolinas/efeitos adversos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/genética , Prognóstico , Purinas/efeitos adversos , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Terapia de Salvação/efeitos adversos
9.
BioDrugs ; 33(2): 125-135, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30847853

RESUMO

The majority of patients with metastatic breast cancer (MBC) have hormone receptor-positive HER2-negative disease. For this subgroup, endocrine therapy is the key therapeutic option. Recently, therapeutic options have been expanded by introduction of the inhibitors of cyclin-dependent kinases 4/6 (CDK4/6i). Three compounds, palbociclib, ribociclib, and abemaciclib, have already been approved by the FDA for use together with endocrine therapy such as aromatase inhibitors (AIs) or fulvestrant; abemaciclib is also approved as a single agent. In the first-line setting, all three agents-together with an AI-substantially prolonged progression-free survival with a consistent hazard ratio of around 0.5 in all phase III trials. The data for second-line settings and beyond is also quite consistent, with again a substantial prolongation of progression-free survival demonstrated for fulvestrant together with palbociclib, ribociclib, or abemaciclib. Treatment with CDK4/6i is well tolerated and side effects are manageable. With palbociclib and ribociclib, hematological toxicities are most frequent. Abemaciclib has a lower incidence of neutropenia and a much greater incidence of all grades of diarrhea compared with other CDK4/6i, making diarrhea the key toxicity for abemaciclib. Patient quality of life is maintained under therapy and, particularly in later line settings, deterioration of quality of life is slowed down and symptoms such as pain are better controlled by CDK4/6i. Their consistent and clinically relevant efficacy makes these drugs an important improvement in our armamentarium against MBC and, potentially, ideal candidates in early breast cancer (EBC). This review summarizes the available clinical data for CDK4/6i and current research activities, particularly in EBC.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/administração & dosagem , Aminopiridinas/administração & dosagem , Aminopiridinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Neoplasias da Mama/enzimologia , Ensaios Clínicos como Assunto , Feminino , Humanos , Terapia de Alvo Molecular , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Purinas/administração & dosagem , Purinas/efeitos adversos , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto
10.
J Clin Oncol ; 37(11): 912-922, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30742566

RESUMO

PURPOSE: Indolent non-Hodgkin lymphoma (iNHL) remains largely incurable and often requires multiple lines of treatment after becoming refractory to standard therapies. Duvelisib was approved by the Food and Drug Administration for relapsed or refractory (RR) chronic lymphocytic leukemia or small lymphocytic lymphoma (SLL) and RR follicular lymphoma (FL) after two or more prior systemic therapies. On the basis of the activity of duvelisib, a first-in-class oral dual inhibitor of phosphoinositide 3-kinase-δ,-γ, in RR iNHL in a phase I study, the safety and efficacy of duvelisib monotherapy was evaluated in iNHL refractory to rituximab and either chemotherapy or radioimmunotherapy. PATIENTS AND METHODS: Eligible patients had measurable iNHL (FL, SLL, or marginal zone B-cell lymphoma) double refractory to rituximab (monotherapy or in combination) and to either chemotherapy or radioimmunotherapy. All were treated with duvelisib 25 mg orally twice daily in 28-day cycles until progression, unacceptable toxicity, or death. The primary end point was overall response rate (ORR) using the revised International Working Group criteria for malignant lymphoma. RESULTS: This open-label, global phase II trial enrolled 129 patients (median age, 65 years; median of three prior lines of therapy) with an ORR of 47.3% (SLL, 67.9%; FL, 42.2%; MZL, 38.9%). The estimated median duration of response was 10 months, and the estimated median progression-free survival was 9.5 months. The most frequent any-grade treatment-emergent adverse events (TEAEs) were diarrhea (48.8%), nausea (29.5%), neutropenia (28.7%), fatigue (27.9%), and cough (27.1%). Among the 88.4% of patients with at least one grade 3 or greater TEAE, the most common TEAEs were neutropenia (24.8%), diarrhea (14.7%), anemia (14.7%), and thrombocytopenia (11.6%). CONCLUSION: In the DYNAMO study, oral duvelisib monotherapy demonstrated clinically meaningful activity and a manageable safety profile in heavily pretreated, double-refractory iNHL, consistent with previous observations. Duvelisib may provide a new oral treatment option for this patient population of which many are elderly and in need of additional therapies.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores Enzimáticos/uso terapêutico , Isoquinolinas/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Purinas/uso terapêutico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Diarreia/induzido quimicamente , Esquema de Medicação , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Feminino , Humanos , Isoquinolinas/administração & dosagem , Isoquinolinas/efeitos adversos , Estimativa de Kaplan-Meier , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Fosfatidilinositol 3-Quinases/metabolismo , Purinas/administração & dosagem , Purinas/efeitos adversos , Rituximab/administração & dosagem
11.
Drug Saf ; 42(2): 247-262, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30649751

RESUMO

Activation of phosphatidylinositol-3-kinase (PI3K) and downstream signalling by AKT/mammalian target of rapamycin (mTOR) modulates cellular processes such as increased cell growth, cell proliferation and increased cell migration as well as deregulated apoptosis and oncogenesis. The PI3K/AKT/mTOR pathway (particularly Class I PI3K isoforms) is frequently activated in a variety of solid tumours and haematological malignancies, making PI3K an attractive therapeutic target in oncology. Inhibitors of PI3K also have the potential to restore sensitivity to other modalities of treatments when administered as part of combination regimens. Although many PI3K inhibitors have reached different stages of clinical development, only two (idelalisib and copanlisib) have been currently approved for use in the treatment of B cell lymphoma and leukaemias. While these two agents are effective clinically, their use is associated with a number of serious class-related as well as drug-specific adverse effects. Some of these are immune-mediated and include cutaneous reactions, severe diarrhoea with or without colitis, hepatotoxicity and pneumonitis. They also induce various metabolic abnormalities such as hyperglycaemia and hypertriglyceridaemia. Not surprisingly, therefore, many new PI3K inhibitors with a varying degree of target selectivity have been synthesised in expectations of improved safety and efficacy, and are currently under clinical investigations for use in a variety of solid tumours as well as haematological malignancies. However, evidence from early clinical trials, reviewed herein, suggests that these newer agents are also associated not only with class-related but also other serious and unexpected adverse effects. Their risk/benefit evaluations have resulted in a number of them being discontinued from further development. Cumulative experience with the use of PI3K inhibitors under development suggests that, compared with their use as monotherapy, combining them with other anticancer therapies may be a more effective strategy in improving current standard-of-care and clinical outcomes in cancers beyond haematological cancers. For example, combination of alpelisib with fulvestrant has recently demonstrated unexpectedly superior efficacy compared to fulvestrant alone. Furthermore, the immunomodulatory activity of PI3Kδ and PI3Kγ inhibitors also provides unexpected opportunities for their use in cancer immunotherapy, as is currently being tested in several clinical trials.


Assuntos
Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Diarreia/induzido quimicamente , Diarreia/metabolismo , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacologia , Humanos , Neoplasias/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Pneumonia/induzido quimicamente , Pneumonia/metabolismo , Purinas/efeitos adversos , Purinas/farmacologia , Purinas/uso terapêutico , Quinazolinonas/efeitos adversos , Quinazolinonas/farmacologia , Quinazolinonas/uso terapêutico
12.
Breast Cancer Res Treat ; 174(3): 597-604, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30659432

RESUMO

BACKGROUND: Several trials have demonstrated the benefit of anti-CDK4/6 inhibitors plus endocrine therapy in estrogen receptor-positive (ER+) advanced breast cancer (BC), in first or subsequent lines of therapy. However, due to the lack of direct/indirect comparisons, there are no data demonstrating the superiority of one drug over the other. We compared the effectiveness of palbociclib, ribociclib, and abemaciclib in advanced ER + BC via an indirect adjusted analysis. METHODS: We performed electronic searches in the PubMed, EMBASE, and Cochrane databases for prospective phase 3 randomized trials evaluating anti-CDK4/6 inhibitors plus endocrine agents. We compared the results with an adjusted indirect analysis of randomized-controlled trials. Outcomes of interest were progression-free survival (PFS), overall response rate (ORR) and G3-4 toxicities occurring in ≥ 5% of patients. RESULTS: Six trials and six treatment arms including a total of 3743 participants, were included. For PFS and ORR analysis, the three agents were similar in both first- and second-line studies. All G3-4 toxicities were similar, with reduced risk of diarrhea for palbociclib versus abemaciclib (relative risk [RR] 0.13, 95% CI 0.02-0.92; P = 0.04) and of QTc prolongation for palbociclib versus ribociclib (RR 0.02, 95% CI 0-0.83; P = 0.03). Despite different inclusion criteria and length of follow-up, similar features were noticed among second-line studies with the exception of increased risk of anemia G3-4 and diarrhea G3-4 for abemaciclib. CONCLUSIONS: Based on PFS and ORR results of this indirect meta-analysis, palbociclib, ribociclib, and abemaciclib are equally effective in either first- or second-line therapy for advanced ER + BC. They, however, ported different toxicity profiles.


Assuntos
Aminopiridinas/uso terapêutico , Benzimidazóis/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Piperazinas/uso terapêutico , Purinas/uso terapêutico , Piridinas/uso terapêutico , Aminopiridinas/efeitos adversos , Benzimidazóis/efeitos adversos , Neoplasias da Mama/metabolismo , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Piperazinas/efeitos adversos , Estudos Prospectivos , Purinas/efeitos adversos , Piridinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores Estrogênicos/metabolismo , Análise de Sobrevida , Resultado do Tratamento
13.
J Cardiovasc Magn Reson ; 21(1): 9, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30674318

RESUMO

BACKGROUND: There is a critical need for non-invasive methods to detect coronary allograft vasculopathy and to risk stratify heart transplant recipients. Vasodilator stress testing using cardiovascular magnetic resonance imaging (CMR) is a promising technique for this purpose. We aimed to evaluate the safety and the prognostic value of regadenoson stress CMR in heart transplant recipients. METHODS: To evaluate the safety, we assessed adverse effects in a retrospective matched cohort study of consecutive heart transplant recipients who underwent regadenoson stress CMR matched in a 2:1 ratio to age- and gender-matched non-heart transplant patients. To evaluate the prognostic value, we compared the outcomes of patients with abnormal vs. normal regadenoson stress CMRs using a composite endpoint of myocardial infarction, percutaneous intervention, cardiac hospitalization, retransplantation or death. RESULTS: For the safety analysis, 234 regadenoson stress CMR studies were included - 78 performed in 57 heart transplant recipients and 156 performed in non-heart transplant patients. Those in heart transplant recipients were performed at a median of 2.74 years after transplantation. Thirty-four (44%) CMR studies were performed in the first two years after heart transplantation. There were no differences in the rates of adverse effects between heart transplant recipients and non-heart transplant patients. To study the prognostic value of regadenoson stress CMRs, 20 heart transplant recipients with abnormal regadenoson stress CMRs were compared to 37 with normal regadenoson stress CMRs. An abnormal regadenoson stress CMR was associated with a significantly higher incidence of the composite endpoint compared with a normal regadenoson stress CMR (3-year cumulative incidence estimates of 32.1% vs. 12.7%, p = 0.034). CONCLUSIONS: Regadenoson stress CMR is safe and well tolerated in heart transplant recipients, with no incidence of sinus node dysfunction or high-degree atrioventricular block, including in the first two years after heart transplantation. An abnormal regadenoson stress CMR identifies heart transplant recipients at a higher risk for major adverse cardiovascular events.


Assuntos
Doença da Artéria Coronariana/diagnóstico por imagem , Transplante de Coração/efeitos adversos , Imagem por Ressonância Magnética , Infarto do Miocárdio/diagnóstico por imagem , Purinas/administração & dosagem , Pirazóis/administração & dosagem , Vasodilatadores/administração & dosagem , Adulto , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/mortalidade , Doença da Artéria Coronariana/terapia , Feminino , Transplante de Coração/mortalidade , Humanos , Imagem por Ressonância Magnética/efeitos adversos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/terapia , Intervenção Coronária Percutânea , Valor Preditivo dos Testes , Purinas/efeitos adversos , Pirazóis/efeitos adversos , Reoperação , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Vasodilatadores/efeitos adversos
15.
Gastroenterology ; 156(1): 36-42, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30195449

RESUMO

Thiopurines (azathioprine, mercaptopurine, thioguanine) and methotrexate are widely used in a variety of clinical management scenarios for ulcerative colitis and Crohn's disease. With the introduction of biologic therapies over the last 2 decades, controversies have emerged as to how these immunomodulators should be used in clinical practice, either alone as monotherapies or in combination with biologic therapies. Here, we provide a summary of evidence and our interpretations regarding how physicians can or should incorporate these agents into clinical practice. We have organized the review into sections regarding their utility as monotherapy or as combination therapy with biologics and safety considerations. Clinical pharmacologic considerations are important regarding both efficacy and safety.


Assuntos
Anti-Inflamatórios/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Purinas/uso terapêutico , Anti-Inflamatórios/efeitos adversos , Azatioprina/uso terapêutico , Produtos Biológicos/uso terapêutico , Tomada de Decisão Clínica , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/imunologia , Doença de Crohn/diagnóstico , Doença de Crohn/imunologia , Quimioterapia Combinada , Fármacos Gastrointestinais/efeitos adversos , Humanos , Mercaptopurina/uso terapêutico , Metotrexato/uso terapêutico , Purinas/efeitos adversos , Fatores de Risco , Tioguanina/uso terapêutico , Resultado do Tratamento
16.
Hematol Oncol ; 37(1): 3-14, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30187496

RESUMO

The introduction of new therapeutic agents in chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL), including the new kinase inhibitor idelalisib, has changed the therapeutic landscape of these diseases. However, the use of idelalisib is associated with a peculiar profile of side effects, which require an optimization of the current approach to prophylaxis and supportive treatment. Moving from the recognition that the abovementioned issue represents an unmet need in CLL and FL, a multidisciplinary panel of experts was convened to produce a consensus document aiming to provide practical recommendations for the management of the side effects during idelalisib therapy for CLL and FL. The present publication represents a consensus document from a series of meetings held during 2017. The Panel generated clinical key questions using the criterion of clinical relevance through a Delphi process and explored 4 domains, ie, diarrhea/colitis, transaminitis, pneumonitis, and infectious complications. Using the consensus method, the Panel was able to shape recommendations which may assist hematologist to minimize adverse events and guarantee adherence to treatment in patients with CLL and FL candidate to receive idelalisib.


Assuntos
Antineoplásicos/efeitos adversos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma Folicular/tratamento farmacológico , Purinas/efeitos adversos , Quinazolinonas/efeitos adversos , Aldeído Oxidase/metabolismo , Algoritmos , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Colite/diagnóstico , Colite/etiologia , Citocromo P-450 CYP3A/metabolismo , Diarreia/diagnóstico , Diarreia/etiologia , Gerenciamento Clínico , Interações de Medicamentos , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/metabolismo , Linfoma Folicular/diagnóstico , Linfoma Folicular/metabolismo , Purinas/farmacocinética , Purinas/uso terapêutico , Quinazolinonas/farmacocinética , Quinazolinonas/uso terapêutico
17.
Acta Oncol ; 58(2): 147-153, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30375908

RESUMO

INTRODUCTION: Recently, new targeted agents have been developed, which can prolong the effect of endocrine treatment (ET) by targeting resistance pathways in HR+/HER2- advanced breast cancer. This review examines available studies of everolimus, an mTOR inhibitor, and the CDK 4/6 inhibitors ribociclib, palbociclib and abemaciclib in terms of efficacy, tolerability and safety. MATERIAL AND METHODS: A systematic literature search was performed in Pubmed. Evaluation of the quality of the identified studies was based on selected elements from the GRADE guidelines. RESULTS: The literature search yielded eight randomized trials that all presented a significant increase in the progression free survival (PFS)/time to progression (TTP) for the targeted agents plus ET vs ET only. The improvement was evident as first-line therapy with an increase in PFS of 10-11 months when adding a CDK4/6 inhibitor to ET, as well as in patients previously treated for metastatic disease, with an increase of 5-6 months. The common adverse events (AEs) of the CDK 4/6 inhibitors were due to myelosuppression. In addition, abemaciclib was associated with liver toxicity and diarrhea, and ribociclib with liver toxicity and QTcF prolongation. The most common grade 3/4 AE of everolimus was stomatitis. The majority (five) of the trials had no serious limitations, and thus the quality of evidence was high. DISCUSSION: The new targeted agents are all associated with an improvement of the PFS with an acceptable tolerability, and they should be offered to women with advanced HR+/HER2- breast cancer both as first-line therapy as well as among patients previously treated in metastatic regimens. However, further data regarding the impact on overall survival are required to evaluate the full benefit for patients. Price and differences in AEs could become substantial arguments for the choice of therapy for the individual patient.


Assuntos
Antineoplásicos Hormonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Aminopiridinas/administração & dosagem , Aminopiridinas/efeitos adversos , Antineoplásicos Hormonais/efeitos adversos , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Progressão da Doença , Drogas em Investigação/uso terapêutico , Everolimo/administração & dosagem , Everolimo/efeitos adversos , Feminino , Humanos , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Purinas/administração & dosagem , Purinas/efeitos adversos , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Receptor ErbB-2/genética , Receptores Citoplasmáticos e Nucleares/genética , Resultado do Tratamento
18.
Breast Cancer Res Treat ; 174(1): 271-278, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30465154

RESUMO

PURPOSE: Adding cyclin-dependent kinase (CDK) 4/6 inhibitor to endocrine therapy improves progression-free survival (PFS) in advanced breast cancer but the impact of ethnicity on efficacy and toxicity is unclear. We aimed to estimate the relative treatment efficacy and toxicity of endocrine therapy with and without CDK4/6 inhibitors, and compare between Asian/non-Asian subgroups. METHOD: This meta-analysis included published first-line randomized trials comparing CDK4/6 inhibitor-endocrine therapy versus endocrine monotherapy. Hazard ratios (HR) and 95% confidence intervals (CI) for the overall population and Asian/non-Asian subgroups were extracted. The inverse-variance-weighted method was used to pool treatment estimates of PFS. RESULTS: Four trials (N = 2499) were included. Patients received combination CDK4/6 inhibitor-endocrine therapy (N = 1441; ribociclib, [46.4%]; palbociclib, [30.8%]; or abemaciclib, [22.8%]) versus endocrine monotherapy (N = 1058). CDK4/6 inhibitor-endocrine therapy was associated with prolonged PFS compared with endocrine monotherapy (HR 0.56; 95% CI 0.50-0.62). In Asians (N = 492), PFS HR was 0.39 (95% CI 0.29-0.51, P < 0.0001). In non-Asians (N = 2007), PFS HR was 0.62 (95% CI 0.54-0.71, P < 0.0001). There was a significant treatment-by-ethnicity interaction (P = 0.002). Toxicity data by ethnic subgroup were only available from two trials (n = 1334) with no convincing evidence that the risk of toxicity between CDK4/6 inhibitor-endocrine therapy and endocrine monotherapy varied by ethnicity. CONCLUSION: Adding CDK4/6 inhibitor to endocrine therapy prolongs PFS compared to endocrine therapy alone as first-line treatment in advanced breast cancer. The magnitude of PFS benefit is ethnicity-dependent but there is no interethnic differences in relative treatment-related toxicities. These findings may assist in the design and interpretation of trials, inform economic analyses, and stimulate pharmacogenomic research.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/etnologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Aminopiridinas/administração & dosagem , Aminopiridinas/efeitos adversos , Antineoplásicos Hormonais/uso terapêutico , Grupo com Ancestrais do Continente Asiático , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Neoplasias da Mama/mortalidade , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Feminino , Humanos , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Intervalo Livre de Progressão , Purinas/administração & dosagem , Purinas/efeitos adversos , Piridinas/administração & dosagem , Piridinas/efeitos adversos
19.
Mol Cancer Ther ; 18(2): 257-266, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30401694

RESUMO

Recently three different cyclin-dependent kinase 4 and 6 (CDK4/6) dual inhibitors were approved for the treatment of breast cancer (palbociclib, ribociclib, and abemaciclib), all of which offer comparable therapeutic benefits. Their safety profiles, however, are different. For example, neutropenia is observed at varying incidences in patients treated with these drugs; however, it is the most common adverse event for palbociclib and ribociclib, whereas diarrhea is the most common adverse event observed in patients treated with abemaciclib. To understand the mechanism of diarrhea observed with these drugs and in an effort to guide the development of safer drugs, we compared the effects of oral administration of palbociclib, ribociclib, and abemaciclib on the gastrointestinal tract of rats using doses intended to produce comparable CDK4/6 inhibition. Rats administered abemaciclib, but not palbociclib or ribociclib, had fecal alterations, unique histopathologic findings, and distinctive changes in intestinal gene expression. Morphologic changes in the intestine were characterized by proliferation of crypt cells, loss of goblet cells, poorly differentiated and degenerating enterocytes with loss of microvilli, and mucosal inflammation. In the jejunum of abemaciclib-treated rats, downregulation of enterocyte membrane transporters and upregulation of genes associated with cell proliferation were observed, consistent with activation of the Wnt pathway and downstream transcriptional regulation. Among these CDK4/6 inhibitors, intestinal toxicity was unique to rats treated with abemaciclib, suggesting a mechanism of toxicity not due to primary pharmacology (CDK4/6 inhibition), but to activity at secondary pharmacologic targets.


Assuntos
Aminopiridinas/administração & dosagem , Benzimidazóis/administração & dosagem , Diarreia/induzido quimicamente , Piperazinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Purinas/administração & dosagem , Piridinas/administração & dosagem , Aminopiridinas/efeitos adversos , Animais , Benzimidazóis/efeitos adversos , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Diarreia/genética , Diarreia/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Piperazinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Purinas/efeitos adversos , Piridinas/efeitos adversos , Ratos , Ratos Sprague-Dawley
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