Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 5.144
Filtrar
1.
J Cancer Res Clin Oncol ; 146(2): 503-514, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31745703

RESUMO

PURPOSE: Fusion genes can be therapeutically relevant if they result in constitutive activation of oncogenes or repression of tumor suppressors. However, the prevalence and role of fusion genes in female cancers remain largely unexplored. Here, we investigate the fusion gene landscape in triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC), two subtypes of female cancers with high molecular similarity but limited treatment options at present. METHODS: RNA-seq was utilized to identify fusion genes in a cohort of 18 TNBC and HGSOC patients treated with the PI3K inhibitor buparlisib and the PARP inhibitor olaparib in a phase I clinical trial (NCT01623349). Differential gene expression analysis was performed to assess the function of fusion genes in silico. Finally, these findings were correlated with the reported clinical outcomes. RESULTS: A total of 156 fusion genes was detected, whereof 44/156 (28%) events occurred in more than one patient. Low recurrence across samples indicated that the majority of fusion genes were private passenger events. The long non-coding RNA MALAT1 was involved in 97/156 (62%) fusion genes, followed in prevalence by MUC16, FOXP1, WWOX and XIST. Gene expression of FOXP1 was significantly elevated in patients with vs. without FOXP1 fusion (P= 0.02). From a clinical perspective, FOXP1 fusions were associated with a favorable overall survival. CONCLUSIONS: In summary, this study provides the first characterization of fusion genes in a cohort of TNBC and HGSOC patients. An improved mechanistic understanding of fusion genes will support the future identification of innovative therapeutic approaches for these challenging diseases.


Assuntos
Cistadenocarcinoma Seroso/genética , Fusão Gênica , Neoplasias Ovarianas/genética , Neoplasias de Mama Triplo Negativas/genética , Adulto , Idoso , Aminopiridinas/administração & dosagem , Aminopiridinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ensaios Clínicos Fase I como Assunto , Cistadenocarcinoma Seroso/tratamento farmacológico , Feminino , Fatores de Transcrição Forkhead/genética , Perfilação da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Morfolinas/administração & dosagem , Morfolinas/efeitos adversos , Neoplasias Ovarianas/tratamento farmacológico , Ftalazinas/administração & dosagem , Ftalazinas/efeitos adversos , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Proteínas Repressoras/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
2.
N Engl J Med ; 381(25): 2416-2428, 2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31851799

RESUMO

BACKGROUND: Olaparib has shown significant clinical benefit as maintenance therapy in women with newly diagnosed advanced ovarian cancer with a BRCA mutation. The effect of combining maintenance olaparib and bevacizumab in patients regardless of BRCA mutation status is unknown. METHODS: We conducted a randomized, double-blind, international phase 3 trial. Eligible patients had newly diagnosed, advanced, high-grade ovarian cancer and were having a response after first-line platinum-taxane chemotherapy plus bevacizumab. Patients were eligible regardless of surgical outcome or BRCA mutation status. Patients were randomly assigned in a 2:1 ratio to receive olaparib tablets (300 mg twice daily) or placebo for up to 24 months; all the patients received bevacizumab at a dose of 15 mg per kilogram of body weight every 3 weeks for up to 15 months in total. The primary end point was the time from randomization until investigator-assessed disease progression or death. RESULTS: Of the 806 patients who underwent randomization, 537 were assigned to receive olaparib and 269 to receive placebo. After a median follow-up of 22.9 months, the median progression-free survival was 22.1 months with olaparib plus bevacizumab and 16.6 months with placebo plus bevacizumab (hazard ratio for disease progression or death, 0.59; 95% confidence interval [CI], 0.49 to 0.72; P<0.001). The hazard ratio (olaparib group vs. placebo group) for disease progression or death was 0.33 (95% CI, 0.25 to 0.45) in patients with tumors positive for homologous-recombination deficiency (HRD), including tumors that had BRCA mutations (median progression-free survival, 37.2 vs. 17.7 months), and 0.43 (95% CI, 0.28 to 0.66) in patients with HRD-positive tumors that did not have BRCA mutations (median progression-free survival, 28.1 vs. 16.6 months). Adverse events were consistent with the established safety profiles of olaparib and bevacizumab. CONCLUSIONS: In patients with advanced ovarian cancer receiving first-line standard therapy including bevacizumab, the addition of maintenance olaparib provided a significant progression-free survival benefit, which was substantial in patients with HRD-positive tumors, including those without a BRCA mutation. (Funded by ARCAGY Research and others; PAOLA-1 ClinicalTrials.gov number, NCT02477644.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Ftalazinas/administração & dosagem , Piperazinas/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Terapia Combinada , Método Duplo-Cego , Feminino , Humanos , Quimioterapia de Manutenção , Pessoa de Meia-Idade , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/cirurgia , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Intervalo Livre de Progressão , Qualidade de Vida
3.
Lancet Psychiatry ; 6(11): 935-950, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31588045

RESUMO

BACKGROUND: Antidepressants, opioids for non-cancer pain, gabapentinoids (gabapentin and pregabalin), benzodiazepines, and Z-drugs (zopiclone, zaleplon, and zolpidem) are commonly prescribed medicine classes associated with a risk of dependence or withdrawal. We aimed to review the evidence for these harms and estimate the prevalence of dispensed prescriptions, their geographical distribution, and duration of continuous receipt using all patient-linked prescription data in England. METHODS: This was a mixed-methods public health review, comprising a rapid evidence assessment of articles (Jan 1, 2008, to Oct 3, 2018; with searches of MEDLINE, Embase, and PsycINFO, and the Cochrane and King's Fund libraries), an open call-for-evidence on patient experience and service evaluations, and a retrospective, patient-linked analysis of the National Health Service (NHS) Business Services Authority prescription database (April 1, 2015, to March 30, 2018) for all adults aged 18 years and over. Indirectly (sex and age) standardised rates (ISRs) were computed for all 195 NHS Clinical Commissioning Groups in England, containing 7821 general practices for the geographical analysis. We used publicly available mid-year (June 30) data on the resident adult population and investigated deprivation using the English Indices of Multiple Deprivation (IMD) quintiles (quintile 1 least deprived, quintile 5 most deprived), with each patient assigned to the IMD quintile score of their general practitioner's practice for each year. Statistical modelling (adjusted incident rate ratios [IRRs]) of the number of patients who had a prescription dispensed for each medicine class, and the number of patients in receipt of a prescription for at least 12 months, was done by sex, age group, and IMD quintile. FINDINGS: 77 articles on the five medicine classes were identified from the literature search and call-for-evidence. 17 randomised placebo-controlled trials (6729 participants) reported antidepressant-associated withdrawal symptoms. Almost all studies were rated of very low, low, or moderate quality. The focus of qualitative and other reports was on patients' experiences of long-term antidepressant use, and typically sudden onset, severe, and protracted withdrawal symptoms when medication was stopped. Between April 1, 2017, and March 31, 2018, 11·53 million individuals (26·3% of residents in England) had a prescription dispensed for at least one medicine class: antidepressants (7·26 million [16·6%]), opioids (5·61 million [12·8%]), gabapentinoids (1·46 million [3·3%]), benzodiazepines (1·35 million [3·1%]), and Z-drugs (0·99 million [2·3%]). For three of these medicine classes, more people had a prescription dispensed in areas of higher deprivation, with adjusted IRRs (referenced to quintile 1) ranging from 1·10 to 1·24 for antidepressants, 1·20 to 1·85 for opioids, and 1·21 to 1·85 for gabapentinoids across quintiles, and higher ISRs generally concentrated in the north and east of England. In contrast, the highest ISRs for benzodiazepines and Z-drugs were generally in the southwest, southeast, and east of England, with low ISRs in the north. Z-drugs were associated with increased deprivation, but only at the highest quintile (adjusted IRR 1·11 [95% CI 1·01-1·22]). For benzodiazepines, prescribing was reduced for people in quintiles 4 (0·90 [0·85-0·96]) and 5 (0·89 [0·82-0·97]). In March, 2018, for each of medicine class, about 50% of patients who had a prescription dispensed had done so continuously for at least 12 months, with the highest ISRs in the north and east. Long-term prescribing was associated with a gradient of increased deprivation. INTERPRETATION: In 1 year over a quarter of the adult population in England had a prescription dispensed for antidepressants, opioids (for non-cancer pain), gabapentinoids, benzodiazepines, or Z-drugs. Long-term (>12 months) prescribing is common, despite being either not recommended by clinical guidelines or of doubtful efficacy in many cases. Enhanced national and local monitoring, better guidance for personalised care, and better doctor-patient decision making are needed. FUNDING: Public Health England.


Assuntos
Analgésicos Opioides/efeitos adversos , Analgésicos/efeitos adversos , Antidepressivos/efeitos adversos , Benzodiazepinas/efeitos adversos , Hipnóticos e Sedativos/efeitos adversos , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Acetamidas/efeitos adversos , Adolescente , Adulto , Idoso , Compostos Azabicíclicos/efeitos adversos , Bases de Dados Factuais/estatística & dados numéricos , Inglaterra/epidemiologia , Feminino , Gabapentina/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Piperazinas/efeitos adversos , Pregabalina/efeitos adversos , Saúde Pública , Pirimidinas/efeitos adversos , Síndrome de Abstinência a Substâncias/epidemiologia , Adulto Jovem , Zolpidem/efeitos adversos
4.
BMC Neurol ; 19(1): 247, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640597

RESUMO

BACKGROUND: Palbociclib is a selective well-tolerated antineoplastic drug used in the treatment of advanced HER2-negative, estrogen-receptor positive breast cancer that has shown significant improvement in progression-free survival. We present a patient that developed severe rhabdomyolysis with tetra-affection and loss of gait after initiating the first cycle of Palbociclib concomitantly with Simvastatin 40 mg treatment. CASE PRESENTATION: A 71-year-old woman with metastatic breast cancer developed tetraparesis and near fatal rhabdomyolysis after initiation of first cycle Palbociclib. For 10 years prior to this treatment, the patient had been treated with Simvastatin without myalgia or other neuromuscular complaints prior to the first cycle of Palbociclib. The patient was admitted at the neurology department, where Palbociclib and Simvastatin were discontinued. The patient was aggressively hydrated and treated with intravenous immunoglobulin therapy with slowly remission and finally regaining independent gait function. Evaluation showed a negative myositis antibody work-up. Muscle magnetic resonance imaging showed edema in multiple foci, but skeletal muscle biopsy did not show necrosis. Post discharge genetic analysis showed single heterozygosity for nucleotide polymorphism rs4149056. CONCLUSION: We present a patient who developed severe rhabdomyolysis induced by a combination of Palbociclib and Simvastatin treatment. Rhabdomyolysis was most likely induced by toxic plasma concentrations of Simvastatin due to Palbociclibs inhibition of the CYP3A4 enzyme in combination with a decreased hepatic uptake of Simvastatin due to single nucleotide polymorphism rs4149056. The study underscores that combining Simvastatin and Palbociclib should be done cautiously and genetic testing of the rs4149056 SNP is warranted. If present, Simvastatin should be discontinued or replaced with a lesser myopathic statin in regard to patients risk of cardiovascular events.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Piperazinas/efeitos adversos , Piridinas/efeitos adversos , Rabdomiólise/induzido quimicamente , Sinvastatina/efeitos adversos , Idoso , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos
5.
Expert Opin Pharmacother ; 20(17): 2063-2072, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31644326

RESUMO

Introduction: Cariprazine, a D3-preferring, dopamine D2/D3 partial agonist, has efficacy in treating both acute phases of bipolar I disorder (BD-I). It has been approved by the FDA for treatment of acute manic, mixed and depressive episodes associated with BD-I.Areas covered: In this review, the authors discuss the unique pharmacological properties and clinical efficacy profile of cariprazine, and their relevance in the context of routine clinical decision-making for BD-I. For the purpose of this review, the authors searched for clinical trials in BD published in the PubMed, Web of Science, Embase and PsychInfo databases as well as for studies registered in the ClinicalTrials.gov database.Expert opinion: Based on evidence from RCTs in manic and mixed episodes, cariprazine in a dose-range of 3-12 mg is effective for treating acute mania and mixed states associated with BD-I. Importantly, evidence from placebo-controlled trials in bipolar depression suggests that cariprazine is also effective as a monotherapy in treating acute bipolar depression in doses of 1.5-3 mg/day. It is overall well tolerated; however, clinicians need to monitor patients for akathisia.


Assuntos
Antipsicóticos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Piperazinas/uso terapêutico , Antipsicóticos/efeitos adversos , Antipsicóticos/farmacocinética , Ensaios Clínicos como Assunto , Bases de Dados Factuais , Agonistas de Dopamina/efeitos adversos , Meia-Vida , Humanos , Piperazinas/efeitos adversos , Piperazinas/farmacocinética , Resultado do Tratamento
6.
N Engl J Med ; 381(10): 933-944, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31483964

RESUMO

BACKGROUND: Pyruvate kinase deficiency is caused by mutations in PKLR and leads to congenital hemolytic anemia. Mitapivat is an oral, small-molecule allosteric activator of pyruvate kinase in red cells. METHODS: In this uncontrolled, phase 2 study, we evaluated the safety and efficacy of mitapivat in 52 adults with pyruvate kinase deficiency who were not receiving red-cell transfusions. The patients were randomly assigned to receive either 50 mg or 300 mg of mitapivat twice daily for a 24-week core period; eligible patients could continue treatment in an ongoing extension phase. RESULTS: Common adverse events, including headache and insomnia, occurred at the time of drug initiation and were transient; 92% of the episodes of headache and 47% of the episodes of insomnia resolved within 7 days. The most common serious adverse events, hemolytic anemia and pharyngitis, each occurred in 2 patients (4%). A total of 26 patients (50%) had an increase of more than 1.0 g per deciliter in the hemoglobin level. Among these patients, the mean maximum increase was 3.4 g per deciliter (range, 1.1 to 5.8), and the median time until the first increase of more than 1.0 g per deciliter was 10 days (range, 7 to 187); 20 patients (77%) had an increase of more than 1.0 g per deciliter in the hemoglobin level at more than 50% of visits during the core study period, with improvement in markers of hemolysis. The response was sustained in all 19 patients remaining in the extension phase, with a median follow-up of 29 months (range, 22 to 35). Hemoglobin responses were observed only in patients who had at least one missense PKLR mutation and were associated with the red-cell pyruvate kinase protein level at baseline. CONCLUSIONS: The administration of mitapivat was associated with a rapid increase in the hemoglobin level in 50% of adults with pyruvate kinase deficiency, with a sustained response during a median follow-up of 29 months during the extension phase. Adverse effects were mainly low-grade and transient. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02476916.).


Assuntos
Anemia Hemolítica Congênita não Esferocítica/tratamento farmacológico , Hemoglobinas/metabolismo , Piperazinas/administração & dosagem , Piruvato Quinase/deficiência , Erros Inatos do Metabolismo dos Piruvatos/tratamento farmacológico , Quinolinas/administração & dosagem , Administração Oral , Adolescente , Adulto , Anemia Hemolítica Congênita não Esferocítica/sangue , Anemia Hemolítica Congênita não Esferocítica/genética , Catecóis , Esquema de Medicação , Feminino , Seguimentos , Cefaleia/induzido quimicamente , Humanos , Masculino , Mutação , Piperazinas/efeitos adversos , Piruvato Quinase/sangue , Piruvato Quinase/genética , Erros Inatos do Metabolismo dos Piruvatos/sangue , Erros Inatos do Metabolismo dos Piruvatos/genética , Quinolinas/efeitos adversos , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente , Tirfostinas , Adulto Jovem
7.
Nucleic Acids Res ; 47(17): 9132-9143, 2019 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-31329989

RESUMO

Poly(ADP-ribose) polymerases (PARPs) facilitate the repair of DNA single-strand breaks (SSBs). When PARPs are inhibited, unrepaired SSBs colliding with replication forks give rise to cytotoxic double-strand breaks. These are normally rescued by homologous recombination (HR), but, in cells with suboptimal HR, PARP inhibition leads to genomic instability and cell death, a phenomenon currently exploited in the therapy of ovarian cancers in BRCA1/2 mutation carriers. In spite of their promise, resistance to PARP inhibitors (PARPis) has already emerged. In order to identify the possible underlying causes of the resistance, we set out to identify the endogenous source of DNA damage that activates PARPs. We argued that if the toxicity of PARPis is indeed caused by unrepaired SSBs, these breaks must arise spontaneously, because PARPis are used as single agents. We now show that a significant contributor to PARPi toxicity is oxygen metabolism. While BRCA1-depleted or -mutated cells were hypersensitive to the clinically approved PARPi olaparib, its toxicity was significantly attenuated by depletion of OGG1 or MYH DNA glycosylases, as well as by treatment with reactive oxygen species scavengers, growth under hypoxic conditions or chemical OGG1 inhibition. Thus, clinical resistance to PARPi therapy may emerge simply through reduced efficiency of oxidative damage repair.


Assuntos
Proteína BRCA1/genética , DNA Glicosilases/genética , Neoplasias Ovarianas/tratamento farmacológico , Poli(ADP-Ribose) Polimerases/genética , Linhagem Celular Tumoral , Quebras de DNA de Cadeia Simples/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , DNA Glicosilases/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Recombinação Homóloga/efeitos dos fármacos , Recombinação Homóloga/genética , Humanos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Oxirredução/efeitos dos fármacos , Ftalazinas/efeitos adversos , Ftalazinas/farmacologia , Piperazinas/efeitos adversos , Piperazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Mutações Sintéticas Letais/genética
8.
Gan To Kagaku Ryoho ; 46(7): 1137-1140, 2019 Jul.
Artigo em Japonês | MEDLINE | ID: mdl-31296819

RESUMO

We aimed to examine palbociclib toxicity in patients aged 70 years and older with metastatic breast cancer(MBC). From December 2017 to August 2018, 32 patients with estrogen receptor(ER)-positive, human epidermal growth factor receptor 2(HER2)-negative MBC were included in this study. The most common adverse event(AE)observed was neutropenia, and comparative rates of grade 3 or 4 AE were identified in the groups of patients aged ≥70 years(n=11)and <70 years(n=21) (91% vs 81%). Febrile neutropenia occurred in one patient. Although dose interruption rate was higher in the older group (≥70 years of age)than in the younger group(<70 years of age)(100% vs 86%, respectively), reduction rates were similar between the two groups(64% vs 62%, respectively). Palbociclib was well-tolerated in Japanese older(≥70 years of age) MBC patients.


Assuntos
Neoplasias da Mama , Piperazinas/efeitos adversos , Piridinas/efeitos adversos , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama/tratamento farmacológico , Humanos
9.
N Engl J Med ; 381(4): 317-327, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31157963

RESUMO

BACKGROUND: Patients with a germline BRCA1 or BRCA2 mutation make up a small subgroup of those with metastatic pancreatic cancer. The poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor olaparib has had antitumor activity in this population. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy of olaparib as maintenance therapy in patients who had a germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer and disease that had not progressed during first-line platinum-based chemotherapy. Patients were randomly assigned, in a 3:2 ratio, to receive maintenance olaparib tablets (300 mg twice daily) or placebo. The primary end point was progression-free survival, which was assessed by blinded independent central review. RESULTS: Of the 3315 patients who underwent screening, 154 underwent randomization and were assigned to a trial intervention (92 to receive olaparib and 62 to receive placebo). The median progression-free survival was significantly longer in the olaparib group than in the placebo group (7.4 months vs. 3.8 months; hazard ratio for disease progression or death, 0.53; 95% confidence interval [CI], 0.35 to 0.82; P = 0.004). An interim analysis of overall survival, at a data maturity of 46%, showed no difference between the olaparib and placebo groups (median, 18.9 months vs. 18.1 months; hazard ratio for death, 0.91; 95% CI, 0.56 to 1.46; P = 0.68). There was no significant between-group difference in health-related quality of life, as indicated by the overall change from baseline in the global quality-of-life score (on a 100-point scale, with higher scores indicating better quality of life) based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (between-group difference, -2.47 points; 95% CI, -7.27 to 2.33). The incidence of grade 3 or higher adverse events was 40% in the olaparib group and 23% in the placebo group (between-group difference, 16 percentage points; 95% CI, -0.02 to 31); 5% and 2% of the patients, respectively, discontinued the trial intervention because of an adverse event. CONCLUSIONS: Among patients with a germline BRCA mutation and metastatic pancreatic cancer, progression-free survival was longer with maintenance olaparib than with placebo. (Funded by AstraZeneca and others; POLO ClinicalTrials.gov number, NCT02184195.).


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa , Quimioterapia de Manutenção , Neoplasias Pancreáticas/tratamento farmacológico , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Estimativa de Kaplan-Meier , Quimioterapia de Manutenção/efeitos adversos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Intervalo Livre de Progressão
10.
Breast Cancer Res ; 21(1): 71, 2019 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-31142370

RESUMO

Currently, there is limited data regarding the effectiveness of standard subsequent line therapies such as endocrine therapy, chemotherapy, or targeted agents after progression on CDK4/6 inhibitor-based regimens. This paper describes time-to-treatment failure beyond progression on palbociclib or palbociclib+endocrine therapy in patients enrolled in the phase II, multicenter TREnd trial. Our results indicate that there is limited benefit from post-palbociclib treatment, regardless of the type of therapy received. A small population of long responders were identified who demonstrated ongoing benefit from a subsequent line of endocrine therapy after progression to palbociclib-based regimens. A translational research program is ongoing on this population of outliers.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Piperazinas/uso terapêutico , Piridinas/uso terapêutico , Antineoplásicos Hormonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Pós-Menopausa , Prognóstico , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Resultado do Tratamento
11.
Basic Clin Pharmacol Toxicol ; 125(4): 370-381, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31125491

RESUMO

The main objective of this phase I trial was to investigate pharmacokinetics (PKs) of olmutinib in three racial subjects. We also evaluate safety/tolerability and a population PK and pharmacogenomic analysis were performed for explorative purposes. A dose escalation study was conducted in 56 Korean, Japanese and Caucasian subjects. The food effect was assessed in the 300 mg Korean group. Individual PK parameters were calculated by non-compartmental methods and presented by dose and race. Genotype analysis was performed using DMET® plus to identify genotypes which affect PK characteristics. A population PK model was developed to explore inter-individual variability and to evaluate the influence of possible covariates using NONMEM® . Tmax was 2-3 hour, regardless of race. The mean terminal half-life ranged from 4.8 to 7.4 hour, with no significant differences between dose or racial groups. Dose-normalized Cmax and AUClast were not significantly different between race groups. PK parameters were similar between the fasting and fed conditions. A single-nucleotide polymorphism in the GSTM3 gene (rs4783) and a copy number variation in the GSTM1 gene were significantly related to AUC. A one-compartment model with first-order absorption adequately described the observed olmutinib data. Thirty adverse events were observed in 15 subjects, of which 26 events, all mild, were possibly related to olmutinib. A single oral dose of olmutinib 100-300 mg was safe and well tolerated. PK parameters were dose-proportional and did not differ by race. Food intake did not affect olmutinib absorption. Pharmacogenomic analysis indicated that glutathione S-transferase might be involved in olmutinib metabolism.


Assuntos
Glutationa Transferase/genética , Piperazinas/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/farmacocinética , Administração Oral , Adulto , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático , Variações do Número de Cópias de DNA , Relação Dose-Resposta a Droga , Receptores ErbB , Grupo com Ancestrais do Continente Europeu , Interações Alimento-Droga , Glutationa Transferase/metabolismo , Meia-Vida , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Polimorfismo de Nucleotídeo Único , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Adulto Jovem
12.
Future Oncol ; 15(16): 1845-1853, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31037967

RESUMO

Maintenance therapy with PARP inhibitors has heralded a new era in the management of recurrent epithelial ovarian cancer. The greatest effect is seen in women with BRCA1/2 tumors but those without this mutation also benefit. However, in most patients, the drugs eventually fail to prevent progression, so alternative strategies are needed. The SOLO1 trial randomized women with BRCA1/2-mutated advanced ovarian cancer to olaparib or placebo maintenance after first-line chemotherapy. Olaparib significantly improved progression-free survival to a degree that has not been seen in other first-line trials in ovarian cancer. This landmark trial is likely to change practice for this group of women. Here, we focus on the SOLO1 results in the context of the current management of advanced ovarian cancer.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Biomarcadores Tumorais , Ensaios Clínicos Fase III como Assunto , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Quimioterapia de Manutenção , Terapia de Alvo Molecular , Estudos Multicêntricos como Assunto , Mutação , Estadiamento de Neoplasias , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Ftalazinas/administração & dosagem , Ftalazinas/efeitos adversos , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Padrão de Cuidado , Resultado do Tratamento
13.
BMC Cancer ; 19(1): 186, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30819142

RESUMO

BACKGROUND: Pneumatosis intestinalis is a rare adverse event that occurs in patients with lung cancer, especially those undergoing treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI). Osimertinib is the most recently approved EGFR-TKI, and its usage is increasing in clinical practice for lung cancer patients who have mutations in the EGFR gene. CASE PRESENTATION: A 74-year-old woman with clinical stage IV (T2aN2M1b) lung adenocarcinoma was determined to have EGFR gene mutations, namely a deletion in exon 19 and a point mutation (T790 M) in exon 20. Osimertinib was started as seventh-line therapy. Follow-up computed tomography on the 97th day after osimertinib administration incidentally demonstrated intra-mural air in the transverse colon, as well as intrahepatic portal vein gas. Pneumatosis intestinalis and portal vein gas improved by fasting and temporary interruption of osimertinib. Osimertinib was then restarted and continued without recurrence of pneumatosis intestinalis. Overall, following progression-free survival of 12.2 months, with an overall duration of administration of 19.4 months (581 days), osimertinib was continued during beyond-progressive disease status, until a few days before the patient died of lung cancer. CONCLUSIONS: Pneumatosis intestinalis should be noted as an important adverse event that can occur with administration of osimertinib; thus far, such an event has never been reported. This was a valuable case in which osimertinib was successfully restarted after complete recovery from pneumatosis intestinalis, such that further extended administration of osimertinib was achieved.


Assuntos
Adenocarcinoma de Pulmão/complicações , Adenocarcinoma de Pulmão/genética , Mutação , Piperazinas/efeitos adversos , Pneumatose Cistoide Intestinal/etiologia , Inibidores de Proteínas Quinases/efeitos adversos , Acrilamidas , Adenocarcinoma de Pulmão/tratamento farmacológico , Idoso , Compostos de Anilina , Receptores ErbB/genética , Éxons , Evolução Fatal , Feminino , Humanos , Piperazinas/uso terapêutico , Pneumatose Cistoide Intestinal/diagnóstico , Mutação Puntual , Inibidores de Proteínas Quinases/uso terapêutico , Radiografia Torácica , Deleção de Sequência , Tomografia Computadorizada por Raios X
14.
Cancer Chemother Pharmacol ; 83(5): 963-974, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30887180

RESUMO

PURPOSE: Chinese patients have been enrolled in multiple Phase III trials of the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib (Lynparza); however, the pharmacokinetic (PK) profile of olaparib has not been investigated in this population. This two-part, open-label Phase I study was, therefore, carried out to determine the PK and safety profile of olaparib (tablet formulation) in Chinese patients with advanced solid tumours as monotherapy and in combination with paclitaxel (NCT02430311). METHODS: The PK profile of olaparib 300 mg (twice daily [bid]; Cohort 1) as monotherapy after a single dose and at steady state, and 100 mg (bid; Cohort 2) as monotherapy (single dose and at steady state) and in combination (at steady state) with weekly paclitaxel (80 mg/m2) was assessed during Part A. Patients could continue to receive treatment (monotherapy, Cohort 1; combination therapy, Cohort 2) in Part B, which assessed safety and tolerability. RESULTS: Twenty and 16 patients were enrolled into Cohorts 1 and 2, respectively. Steady-state olaparib exposure increased slightly less than proportionally with increasing monotherapy dose and inter-patient variability was high. A statistically significant decrease in olaparib exposure was seen when given in combination with paclitaxel. Discontinuation due to adverse events (AEs) was rare and haematological AEs were more common in patients receiving combination treatment. CONCLUSIONS: The PK and safety profile of olaparib monotherapy in Chinese patients is consistent with that seen previously in Western and Japanese patients, and the recommended Phase III monotherapy tablet dose (300 mg bid) is suitable for use in this population.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias/tratamento farmacológico , Ftalazinas/administração & dosagem , Piperazinas/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Ftalazinas/efeitos adversos , Ftalazinas/farmacocinética , Piperazinas/efeitos adversos , Piperazinas/farmacocinética , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacocinética , Comprimidos
15.
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
16.
Bioorg Med Chem ; 27(8): 1619-1628, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30852078

RESUMO

Gastrotoxicity continues to be a major issue in therapy with nonsteroidal anti-inflammatory drugs (NSAIDs). Medicine is yet to develop absolutely safe analgesics. Numerous strategies are employed to discover new, safer NSAIDs, for example selective inhibition of cyclooxygenase-2, new molecular targets (e.g. microsomal prostaglandin E2 synthase-1), incorporation of cytoprotective compounds in the drug molecule or modification of the classic NSAIDs currently available on the market. The research presented in this paper is indicative of a current worldwide trend in this area of science, and is an example of the fourth strategy noted above. Two series of new arylpiperazine derivatives of the classic NSAID - piroxicam, were developed by conventional synthesis. The full range of compounds obtained proved to be between two and five times analgesically more potent than the reference drug and, most importantly, they did not show any ulcerogenic activity.


Assuntos
Analgésicos/química , Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Piperazinas/química , Piperazinas/farmacologia , Analgésicos/efeitos adversos , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Masculino , Camundongos , Modelos Moleculares , Piperazinas/efeitos adversos , Piroxicam/efeitos adversos , Piroxicam/análogos & derivados , Piroxicam/farmacologia , Ratos Wistar , Úlcera/induzido quimicamente
17.
Breast Cancer Res Treat ; 175(3): 667-674, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30835017

RESUMO

PURPOSE: Over 40% of newly diagnosed metastatic breast cancer patients are ≥ 70 years old; however, this population is less likely to be represented in clinical trials. The objective of this study was to analyze PFS, dose reductions, dose delays, and toxicity in a geriatric population receiving palbociclib in a non-trial setting. METHODS: Patients with metastatic breast cancer receiving palbociclib in any line of therapy were identified from a cohort of 845 patients at a large academic institution. Dose delays, dose reductions, and toxicities were retrospectively extracted from the medical record. Data were analyzed using Fischer's exact test for categorized variables and T test/Wilcoxon rank-sum test for continuous variables. PFS and OS were analyzed using the Kaplan-Meier method. RESULTS: 605 patients who met eligibility criteria were included. 160 patients were ≥ 65 years old and 92 patients were ≥ 70 years old. Patients ≥ 70 had a significantly increased number of dose reductions (p = 0.03) and dose delays (p = 0.02) compared to the younger patients. There was no significant increase in toxicities, including neutropenic fever, infections, or hospitalizations, in the ≥ 70 cohort (p = 0.3). The ≥ 70 cohort had a significantly improved PFS as compared to the younger cohort (p = 0.02); however, age was no longer a significant variable in the multivariate analysis. CONCLUSIONS: Palbociclib was well tolerated in the geriatric population and there was no difference in PFS between older and younger patients. These results are reassuring as palbociclib becomes the frontline standard of care therapy for patients.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Piperazinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Piridinas/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-Idade , Piperazinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Piridinas/efeitos adversos , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
18.
Breast Cancer Res Treat ; 176(2): 429-434, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30895534

RESUMO

PURPOSE: Real-world data are critical to demonstrate the reproducibility of evidence and external generalizability of randomized clinical trials. Palbociclib is an oral small-molecule inhibitor of cyclin-dependent kinases 4 and 6 that has been shown to improve progression-free survival (PFS) when combined with letrozole or fulvestrant in phase 3 clinical trials. We evaluated real-world outcomes in metastatic breast cancer patients who received palbociclib in combination with endocrine therapy in routine clinical practice. METHODS: Records of patients with advanced hormone receptor (HR)-positive breast cancer treated with palbociclib at the Cleveland Clinic health system from February, 2015 to December, 2017 were retrospectively reviewed. The primary end point was PFS. RESULTS: In this cohort, 411 women were included. The median age and follow-up times were 53.5 years and 10.2 months, respectively. The median PFS for palbociclib plus letrozole was 15.1 months for patients treated in first line, 10.5 months in second line, and 4.2 months in third line and beyond. For patients who received fulvestrant plus palbociclib, the median PFS in first, second, and third line and beyond were 11.6, 12.3, and 6.4 months, respectively. The most common adverse events were hematologic, with grade 3-4 neutropenia occurring in 58% of patients. Thirty-one (8%) patients permanently discontinued palbociclib due to adverse events. CONCLUSIONS: Among patients with HR-positive advanced breast cancer, the estimated PFS in patients treated with fulvestrant and palbociclib was comparable to a previously reported phase 3 trial. However, the median PFS with letrozole and palbociclib was shorter than previously reported data from phase 2 and 3 trials. Palbociclib toxicity was very manageable, with a low drug discontinuation rate.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Fulvestranto/administração & dosagem , Letrozol/administração & dosagem , Piperazinas/administração & dosagem , Piridinas/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos como Assunto , Terapia Combinada , Intervalo Livre de Doença , Feminino , Fulvestranto/efeitos adversos , Humanos , Letrozol/efeitos adversos , Pessoa de Meia-Idade , Metástase Neoplásica , Piperazinas/efeitos adversos , Piridinas/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
19.
Int J Neuropsychopharmacol ; 22(4): 270-277, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30722037

RESUMO

BACKGROUND: Although originally marketed as safe alternatives to the habit-forming benzodiazepines, growing numbers of zaleplon, zolpidem, and zopiclone ("Z-drugs") clinical concerns relating to their potential of abuse, dependence, and withdrawal have been reported over time. We aimed here at assessing these issues analyzing datasets of adverse drug reactions provided by the European Medicines Agency through the EudraVigilance system. METHODS: Analyzing the adverse drug reactions databases of each Z-drug, descriptive analyses have been performed on cases and proportional reporting ratios (PRRs) computed. RESULTS: An overall number of 33 240 (e.g., 23 420 zolpidem; 9283 zopiclone; and 537 zaleplon) misuse-, abuse-, dependence-, and withdrawal-related adverse drug reactions, corresponding to some 6246 unique patients given Z-drugs, were here identified. Cases were studied and described, including demographic characteristics and clinical data such as concomitant drugs, doses, routes of administration, and outcomes of the reactions (being fatalities recorded). Considering PRR values and in comparison with zopiclone, zolpidem was more frequently involved in both misuse/abuse and withdrawal issues. Zolpidem and zopiclone presented with the same dependence risk, but zopiclone was most involved in overdose adverse drug reactions. Compared with zaleplon, zopiclone presented higher dependence and overdose-related issues but slightly lower misuse/abuse and withdrawal PRR values. CONCLUSION: Current data may only represent a gross underestimate of the real prevalence of Z-drug misuse. Caution should be exercised when prescribing those molecules, especially for patients with psychiatric illnesses and/or history of drug abuse. We recommend the need to invest in proactive pharmacovigilance activities to better and promptly detect, understand, and prevent any possible misuse potential of prescribed medications.


Assuntos
Acetamidas/efeitos adversos , Compostos Azabicíclicos/efeitos adversos , Uso Indevido de Medicamentos/estatística & dados numéricos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Hipnóticos e Sedativos/efeitos adversos , Farmacovigilância , Piperazinas/efeitos adversos , Pirimidinas/efeitos adversos , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Zolpidem/efeitos adversos , Adolescente , Adulto , Bases de Dados Factuais , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
20.
J Clin Psychopharmacol ; 39(2): 100-107, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30707117

RESUMO

PURPOSE/BACKGROUND: Prolonged ventricular repolarization, measured by heart rate-corrected QT interval (QTc) prolongation, might be a biomarker for risk of torsade de pointes (TdP) and sudden cardiac death. However, the predictive value of QTc has been challenged, and a component of QTc, peak-to-end of the T-wave (Tpe), and a high Tpe/QT ratio might be superior biomarkers because they better reflect increased transmural dispersion of ventricular myocyte repolarization, which can lead to TDP. The purpose of this pilot study was to provide the first measurements of heart rate, QTc, Tpe, Tpe/QTc, and their variability over 24 hours in medication-free patients with schizophrenia, during treatment with ziprasidone or other antipsychotic drugs, and healthy controls. METHODS: Subjects included 12 patients treated with ziprasidone, 30 treated with other antipsychotic drugs, 3 unmedicated patients, and 15 normal controls. Subjects underwent 24-hour analog Holter recording, and the recordings were digitized. A cardiologist blind to treatment selected multiple 10-cycle segments throughout each recording and measured the electrocardiogram metrics. RESULTS: Variability in QTc, Tpe, and Tpe/QTc over the 24 hours was present in all groups; 91.1% of patients and 100% of controls had 1 or more QTc values of 450 milliseconds or greater. Mean QTc length was significantly greater in the ziprasidone-treated than the non-ziprasidone-treated patients (P = 0.02). Mean Tpe was not elevated in the ziprasidone patients, whereas mean Tpe/QTc was lower (P < 0.01). CONCLUSIONS: The large variability in QTc, Tpe, and Tpe/QTc observed supports the need for 24-hour electrocardiogram recordings to provide an accurate assessment of risk of TdP. Heart rate-corrected QT interval alone does not capture the risk of TdP.


Assuntos
Antipsicóticos/efeitos adversos , Frequência Cardíaca/efeitos dos fármacos , Piperazinas/efeitos adversos , Tiazóis/efeitos adversos , Torsades de Pointes/induzido quimicamente , Adulto , Antipsicóticos/administração & dosagem , Estudos de Casos e Controles , Eletrocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Piperazinas/administração & dosagem , Tiazóis/administração & dosagem , Torsades de Pointes/diagnóstico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA