Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.171
Filtrar
1.
Lancet Oncol ; 21(6): 763-775, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32353342

RESUMO

BACKGROUND: Patients with HER2-positive breast cancer who have received two or more previous therapies for advanced disease have few effective treatment options. The monarcHER trial aimed to compare the efficacy of abemaciclib plus trastuzumab with or without fulvestrant with standard-of-care chemotherapy of physician's choice plus trastuzumab in women with advanced breast cancer. METHODS: This phase 2, three-group, open-label trial was done across 75 hospitals, clinics, and medical centres in 14 countries. Eligible patients were women aged 18 years or older, who had hormone receptor-positive, HER2-positive advanced breast cancer with unresectable, locally advanced, recurrent or metastatic disease, Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received at least two HER2-targeted therapies for advanced disease. Patients were randomly assigned 1:1:1 to the abemaciclib, trastuzumab, and fulvestrant (group A), abemaciclib and trastuzumab (group B), or standard-of-care chemotherapy and trastuzumab (group C). Oral abemaciclib 150 mg 12 hourly was administered on days 1-21 of a 21-day cycle, intravenous trastuzumab 8 mg/kg on cycle 1 day 1, followed by 6 mg/kg on day 1 of each subsequent 21-day cycle, and intramuscular fulvestrant 500 mg on days 1, 15, and 29 and once every 4 weeks thereafter. Standard-of-care chemotherapy was administered as specified by the product label. Randomisation was by a computer-generated random sequence by means of an interactive web-response system and stratified by number of previous systemic therapies for advanced breast cancer and measurable versus non-measurable disease. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, first testing group A versus group C and, if this result was significant, then group B versus group C. Safety was assessed in all patients who had received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov (NCT02675231) and is ongoing for long-term survival follow-up. FINDINGS: Between May 31, 2016, and Feb 28, 2018, 325 patients were screened, of whom 237 eligible patients were enrolled and randomly assigned to groups A (n=79), B (n=79), and C (n=79). Median follow-up was 19·0 months (IQR 14·7-25·1). The study met its primary endpoint, showing a significant difference at the prespecified two-sided α of 0·2 in median progression-free survival between group A (8·3 months, 95% CI 5·9-12·6) and group C (5·7 months, 5·4-7·0; HR 0·67 [95% CI 0·45-1·00]; p=0·051). No difference was observed between median progression-free survival in group B (5·7 months, 95% CI 4·2-7·2) and group C (HR 0·94 [0·64-1·38]; p=0·77). The most common grade 3-4 treatment-emergent adverse event in groups A, B, and C was neutropenia (21 [27%] of 78 patients, 17 [22%] of 77, and 19 [26%] of 72). The most common serious adverse events were: in group A, pyrexia (three [4%]), diarrhoea (two [3%]), urinary tract infection (two [3%]), and acute kidney injury (two [3%]); in group B, diarrhoea (two [3%]) and pneumonitis (two [3%]); and in group C, neutropenia (four [6%]) and pleural effusion (two [3%]). Two deaths were attributed to treatment: one due to pulmonary fibrosis in group B and one due to febrile neutropenia in group C. INTERPRETATION: The combination of abemaciclib, fulvestrant, and trastuzumab significantly improved progression-free survival versus standard-of-care chemotherapy plus trastuzumab while showing a tolerable safety profile. Our results suggest that a chemotherapy-free regimen might potentially be an alternative treatment option for patients with hormone receptor-positive, HER2-positive advanced breast cancer. FUNDING: Eli Lilly and Company.


Assuntos
Aminopiridinas/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Antagonistas do Receptor de Estrogênio/administração & dosagem , Fulvestranto/administração & dosagem , Receptor ErbB-2/antagonistas & inibidores , Receptores Estrogênicos/efeitos dos fármacos , Trastuzumab/administração & dosagem , Idoso , Aminopiridinas/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Argentina , Austrália , Benzimidazóis/efeitos adversos , Brasil , Neoplasias da Mama/enzimologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Progressão da Doença , Antagonistas do Receptor de Estrogênio/efeitos adversos , Europa (Continente) , Feminino , Fulvestranto/efeitos adversos , Humanos , Pessoa de Meia-Idade , América do Norte , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , República da Coreia , Transdução de Sinais , Fatores de Tempo , Trastuzumab/efeitos adversos
2.
N Engl J Med ; 382(15): 1430-1442, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32187457

RESUMO

BACKGROUND: No approved therapies exist for inoperable plexiform neurofibromas in patients with neurofibromatosis type 1. METHODS: We conducted an open-label, phase 2 trial of selumetinib to determine the objective response rate among patients with plexiform neurofibromas and to assess clinical benefit. Children with neurofibromatosis type 1 and symptomatic inoperable plexiform neurofibromas received oral selumetinib twice daily at a dose of 25 mg per square meter of body-surface area on a continuous dosing schedule (28-day cycles). Volumetric magnetic resonance imaging and clinical outcome assessments (pain, quality of life, disfigurement, and function) were performed at least every four cycles. Children rated tumor pain intensity on a scale from 0 (no pain) to 10 (worst pain imaginable). RESULTS: A total of 50 children (median age, 10.2 years; range, 3.5 to 17.4) were enrolled from August 2015 through August 2016. The most frequent neurofibroma-related symptoms were disfigurement (44 patients), motor dysfunction (33), and pain (26). A total of 35 patients (70%) had a confirmed partial response as of March 29, 2019, and 28 of these patients had a durable response (lasting ≥1 year). After 1 year of treatment, the mean decrease in child-reported tumor pain-intensity scores was 2 points, considered a clinically meaningful improvement. In addition, clinically meaningful improvements were seen in child-reported and parent-reported interference of pain in daily functioning (38% and 50%, respectively) and overall health-related quality of life (48% and 58%, respectively) as well as in functional outcomes of strength (56% of patients) and range of motion (38% of patients). Five patients discontinued treatment because of toxic effects possibly related to selumetinib, and 6 patients had disease progression. The most frequent toxic effects were nausea, vomiting, or diarrhea; an asymptomatic increase in the creatine phosphokinase level; acneiform rash; and paronychia. CONCLUSIONS: In this phase 2 trial, most children with neurofibromatosis type 1 and inoperable plexiform neurofibromas had durable tumor shrinkage and clinical benefit from selumetinib. (Funded by the Intramural Research Program of the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803.).


Assuntos
Benzimidazóis/uso terapêutico , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Neurofibroma Plexiforme/tratamento farmacológico , Neurofibromatose 1/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adolescente , Benzimidazóis/efeitos adversos , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Náusea/induzido quimicamente , Neurofibroma Plexiforme/complicações , Neurofibroma Plexiforme/patologia , Neurofibromatose 1/complicações , Neurofibromatose 1/patologia , Dor/etiologia , Medidas de Resultados Relatados pelo Paciente , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Carga Tumoral/efeitos dos fármacos
3.
Expert Opin Pharmacother ; 21(5): 523-530, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32027196

RESUMO

Introduction: Despite recent advances in the treatment of adult acute myelogenous leukemia (AML), the overall outcome remains dismal especially in high-risk AML patients, including the elderly and the relapsed/refractory populations. In this setting, various clinical trials have recently explored novel therapeutic agents either used alone or in combination with intensive chemotherapy or low-intensity treatments.Areas covered: The current paper reviews the clinical development of glasdegib, a selective inhibitor of the Hedgehog signaling pathway through binding to its target SMO, for the treatment of AML.Expert opinion: Glasdegib confirmed its efficacy and showed an acceptable tolerability, especially when used in combination either with '3 + 7' chemotherapy or with low-intensity therapies. In 2018, glasdegib was approved by the Food and Drug Administration (FDA) in combination with low-dose cytarabine for the treatment of newly diagnosed AML in patients older than 75 years or presenting with severe comorbidities.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/uso terapêutico , Citarabina/uso terapêutico , Proteínas Hedgehog/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Humanos , Leucemia Mieloide Aguda/metabolismo , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Transdução de Sinais , Estados Unidos , United States Food and Drug Administration
4.
PLoS One ; 15(2): e0229517, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32106270

RESUMO

AIMS: To analyze the efficacy and safety of sofosbuvir (SOF)-based regimens in Thai patients with chronic hepatitis C virus infection who had pre-existing significant liver fibrosis. PATIENTS AND METHODS: This was a retrospective cohort study, conducted between 1 June 2018 and 31 May 2019 at Rajavithi Hospital, Bangkok, Thailand. All patients completed 12 weeks of SOF-based regimens and had follow-up for at least 12 weeks after therapy discontinuation. The primary outcome was sustained virological response (SVR) 12 weeks after the end of therapy. RESULT: A total of 185 patients were included, with 52, 63 and 70 taking SOF+Ledipasvir (SOF+LDV), SOF+LDV+ribavirin (RBV) and SOF+Pegylated interferon (Peg-IFN)+RBV (SOF+Peg-IFN+RBV) respectively. Genotype (GT) 1 was predominant at 40.0%, followed by GT3 at 37.8%, and GT6 at 22.2%. Overall 95.1% of patients in this study achieved SVR (n = 176/185), and the only factor associated with SVR was HCV genotype (p = 0.001). GT6 patients had lower SVR rates compared to GT1 and GT3 patients (82.9%, 98.6%, and 98.6% respectively) while there was no association between SVR and other factors (p >0.05) such as gender, age, BMI, underlying cirrhosis, baseline HCV viral load, or prior treatment history. No serious adverse events were reported in the present study. CONCLUSION: Sofosbuvir-based regimens in the treatment of patients with chronic HCV infection were highly efficacious with excellent safety and tolerability profiles in a real-world setting; however, further research is required to establish whether or not such a regimen is an adequate treatment for all genotype 6 patients.


Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Sofosbuvir/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Estudos de Coortes , Quimioterapia Combinada , Feminino , Fluorenos/administração & dosagem , Fluorenos/efeitos adversos , Genótipo , Hepacivirus/genética , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Humanos , Interferon alfa-2/administração & dosagem , Interferon alfa-2/efeitos adversos , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Estudos Retrospectivos , Ribavirina/administração & dosagem , Ribavirina/efeitos adversos , Sofosbuvir/administração & dosagem , Sofosbuvir/efeitos adversos , Resposta Viral Sustentada , Tailândia , Fatores de Tempo , Resultado do Tratamento , Uridina Monofosfato/administração & dosagem , Uridina Monofosfato/efeitos adversos , Uridina Monofosfato/análogos & derivados
5.
Expert Opin Pharmacother ; 21(7): 747-754, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32100585

RESUMO

INTRODUCTION: Approximately 50% of patients with metastatic melanoma have mutations in BRAF. Based on the results of prior phase III trials, the combination of a BRAF inhibitor (BRAFi) and a MEK inhibitor (MEKi) is the standard of care in patients with BRAF-mutant metastatic melanoma. AREAS COVERED: The author summarizes the available data on binimetinib, a reversible inhibitor of the kinase activity of MEK1 and MEK2, in BRAF- and NRAS-mutated melanoma. EXPERT OPINION: With the advent of binimetinib and encorafenib, clinicians can choose between three BRAFi/MEKi combinations. Indirect comparison and a network meta-analysis suggest that binimetinib plus encorafenib is at least as active as the other two BRAFi/MEKi combinations and that safety is similar. The choice should be guided by the slightly different toxicity profile, local availability, and product experience. The optimal sequence of immunotherapy and BRAFi/MEKi in patients with BRAF-mutated tumors is unclear. As the response to BRAF/MEK inhibition is usually prompt and response to immunotherapy can be delayed, clinicians often choose a BRAFi/MEKi combination as first-line therapy in patients with rapidly evolving and threatening disease. Single-agent binimetinib almost doubled median progression-free survival when compared to dacarbazine in patients with NRAS-mutated melanoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/uso terapêutico , Carbamatos/uso terapêutico , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Sulfonamidas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Carbamatos/administração & dosagem , Carbamatos/efeitos adversos , Ensaios Clínicos como Assunto , GTP Fosfo-Hidrolases/genética , Humanos , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 2/metabolismo , Melanoma/enzimologia , Melanoma/genética , Proteínas de Membrana/genética , Terapia de Alvo Molecular , Mutação , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/genética , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos
7.
Gynecol Oncol ; 156(1): 13-22, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31708167

RESUMO

BACKGROUND: Improvements in disease free survival for epithelial ovarian, peritoneal or fallopian tube cancer (EOC) will only come with improved primary therapy. Incorporation of poly-ADP-ribose inhibitors (PARPi) in the frontline setting may represent one strategy. This study sought to determine the maximum tolerated and feasible doses of the PARPi veliparib in combination with chemotherapy for EOC. METHODS: A phase I, 3 + 3 dose escalation evaluated dose-limiting toxicities (DLTs) in cycles 1-2. Once <2/6 patients experienced a DLT, that dose level expanded to evaluate feasibility over 4 cycles. This study opened 10/2009 and closed 8/2016. Eligible patients had untreated, stage II-IV EOC. Veliparib was added either continuous (day 1-21) or intermittent (day - 2 to 5) during 6 cycles of chemotherapy. Three chemotherapy backbones were evaluated (2 intravenous (q3week and weekly) and 1 intraperitoneal (IP)) all inclusive of bevacizumab with and as maintenance to 22 cycles. FINDINGS: Dose evaluations for 424 treated patients were available. Regimen 1 (q3 week), continuous (Reg1c) the maximum tolerated dose (MTD) was 250 mg veliparib BID and feasible dose was 150 mg BID. For regimen 1, intermittent (Reg1i) the MTD and feasible dose were 400 and 250 mg BID. For Reg2c (weekly paclitaxel) the MTD and feasible dose were 150 mg BID. For Reg2i the MTD and feasible dose were 250 and 150 mg BID. For Reg3c (IP) the MTD and feasible dose were 150 mg BID and for Reg3i (IP), the MTD and feasible dose were 400 mg and 300 mg BID. INTERPRETATION: The feasible dose for Reg1c, 2c, 2i and 3c was 150 mg po BID. For Reg1i and 3i the dose was pushed to 250 and 300 mg po BID respectively. There is no apparent difference in efficacy between continuous and intermittent dosing indicating that the higher doses achieved in intermittent dosing may not be needed. (NCT00989651). FUNDING: National Cancer Institute.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Epitelial do Ovário/tratamento farmacológico , Neoplasias das Tubas Uterinas/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carcinoma Epitelial do Ovário/patologia , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Estudos de Coortes , Relação Dose-Resposta a Droga , Neoplasias das Tubas Uterinas/patologia , Feminino , Humanos , Injeções Intraperitoneais , Injeções Intravenosas , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Neoplasias Peritoneais/patologia , Intervalo Livre de Progressão
8.
J Dermatolog Treat ; 31(3): 270-278, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-30835579

RESUMO

Purpose: To evaluate the efficacy/safety of bilastine in pruritus relief in patients with chronic spontaneous urticaria (CSU) or other pruritic skin diseases.Methods: In this multicenter, open-label, exploratory study (EudraCT No.: 2016-001505-17), 115 adults with CSU (n = 34), eczema/dermatitis (n = 30), prurigo (n = 25) or cutaneous pruritus (n = 26), received bilastine 20 mg once daily for 8 weeks, or in non-responder patients (<30% improvement in pruritus score at week 2), 40 mg/day from week 2.Results: The mean change in weekly pruritus severity score from baseline to week 8 (primary endpoint) was reduced with bilastine (overall and by disease group); overall, percentage and absolute reductions were 71.16% and 1.63 points, respectively (p < .001). Updosed non-responders (n = 31) had improved weekly pruritus severity scores from baseline to week 8; percentage and absolute reductions were 49.08% and 1.13 points, respectively (p < .001). Bilastine improved the Dermatology Life Quality Index at weeks 4 and 8 (p < .001) in all disease groups, and the 7-day Urticaria Activity Score in CSU patients (p < .001). Bilastine was well tolerated.Conclusions: Bilastine relieved pruritus associated with urticaria and other skin diseases, with a very good safety profile.


Assuntos
Benzimidazóis/uso terapêutico , Urticária Crônica/tratamento farmacológico , Piperidinas/uso terapêutico , Prurido/tratamento farmacológico , Adolescente , Adulto , Idoso , Benzimidazóis/efeitos adversos , Urticária Crônica/patologia , Dermatite/tratamento farmacológico , Dermatite/patologia , Esquema de Medicação , Feminino , Cefaleia/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Prurigo/tratamento farmacológico , Prurigo/patologia , Prurido/patologia , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
9.
Expert Opin Drug Saf ; 19(1): 1-8, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31855607

RESUMO

Introduction: Hypoactive sexual desire disorder (HSDD) is the most prevalent sexual dysfunction in women, previously managed with off-label therapies. Indicated for premenopausal women, flibanserin is the first FDA-approved medication to treat HSDD.Areas covered: This review summarizes flibanserin's pharmacokinetics, proposed mechanism of action, and safety data in clinical trials with a focus on sedation- and hypotension-related adverse events, and drug interactions with alcohol and antidepressants. Sources included peer-reviewed publications and internal data from the manufacturer.Expert opinion: Flibanserin is a well-tolerated and effective treatment that decreases distress and restores sexual desire to a level that is normative for the individual patient with HSDD. Simplification of a risk mitigation program for flibanserin in the US is likely to increase the number of prescribing clinicians if accompanied with educational efforts to clarify flibanserin's risk-benefit profile. As flibanserin is dosed daily and may be used for a decade or more in the typical premenopausal patient, long-term pharmacovigilance data will be essential. Over time, HSDD will be treated by more nonspecialist health care professionals and flibanserin will likely become established as a significant treatment option along with other medications approved for this indication in the context of a holistic biopsychosocial treatment paradigm.


Assuntos
Benzimidazóis/administração & dosagem , Pré-Menopausa , Disfunções Sexuais Psicogênicas/tratamento farmacológico , Benzimidazóis/efeitos adversos , Interações Medicamentosas , Humanos , Hipotensão/induzido quimicamente , Hipotensão/epidemiologia
10.
Future Oncol ; 15(34): 3935-3944, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31660764

RESUMO

Aim: To examine the effectiveness of eribulin mesylate for metastatic breast cancer post cyclin-dependent kinase inhibitor (CDKi) 4/6 therapy. Materials & methods: US community oncologists reviewed charts of patients who had received eribulin from 3 February 2015 to 31 December 2017 after prior CDKi 4/6 therapy and detailed their clinical/treatment history, clinical outcomes (lesion measurements, progression, death) and toxicity. Results: Four patient cohorts were created according to eribulin line of therapy: second line, third line, per US label and fourth line with objective response rates/clinical benefit rates of 42.2%/58.7%, 26.1%/42.3%, 26.7%/54.1% and 17.9%/46.4%, respectively. Median progression-free survival/6-month progression-free survival (79.5% of all patients censored) by cohort was: 9.7 months/77.3%, 10.3 months/71.3%, not reached/70.4% and 4.0 months/0.0%, respectively. Overall occurrence of neutropenia = 23.5%, febrile neutropenia = 1.3%, peripheral neuropathy = 10.1% and diarrhea = 11.1%. Conclusion: Clinical outcome and adverse event rates were similar to those in clinical trials and other observational studies. Longer follow-up is required to confirm these findings.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/terapia , Furanos/administração & dosagem , Cetonas/administração & dosagem , Cuidados Paliativos/métodos , Inibidores de Proteínas Quinases/administração & dosagem , Adulto , Idoso , Aminopiridinas/administração & dosagem , Aminopiridinas/efeitos adversos , Antineoplásicos/efeitos adversos , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Quimioterapia Adjuvante/métodos , Neutropenia Febril Induzida por Quimioterapia/epidemiologia , Neutropenia Febril Induzida por Quimioterapia/etiologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Diarreia/induzido quimicamente , Diarreia/epidemiologia , Progressão da Doença , Feminino , Seguimentos , Furanos/efeitos adversos , Humanos , Cetonas/efeitos adversos , Mastectomia , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Cuidados Paliativos/tendências , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/epidemiologia , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Purinas/administração & dosagem , Purinas/efeitos adversos , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Resultado do Tratamento , Estados Unidos/epidemiologia , Adulto Jovem
11.
West Afr J Med ; 36(3): 280-282, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31622492

RESUMO

The advent of direct-acting anti-virals revolutionized the treatment and prognosis of patients infected with hepatitis C. The interest of this presentation is to draw attention to the issue of therapeutic management posed by the hepatitis C virus in a kidney graft in Côte d'Ivoire, a resource-limited country where all the direct-acting anti-virals are not yet available. We report the case of a kidney transplant of 52 years old, chronic carrier of viral hepatitis C who presented after his kidney transplant in decompensated active cirrhosis. A treatment based on Sofosbuvir 400 mg/Ledipasvir 90 mg in this patient with genotype 2 for 12 weeks was initiated. Sustained virologic response 12 weeks and 24 weeks off therapy was observed. This is the first documented case of successful treatment of a genotype 2 viral C infection based on Sofosbuvir/Ledipasvir in a black African cirrhotic kidney transplant patient undergoing immunosuppressive therapy.


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Fluorenos/uso terapêutico , Hepacivirus/isolamento & purificação , Hepatite C Crônica/tratamento farmacológico , Transplante de Rim , Sofosbuvir/uso terapêutico , Antivirais/efeitos adversos , Benzimidazóis/efeitos adversos , Quimioterapia Combinada , Fluorenos/efeitos adversos , Genótipo , Hepacivirus/genética , Hepatite C Crônica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Sofosbuvir/efeitos adversos , Resultado do Tratamento
13.
Medicine (Baltimore) ; 98(39): e17343, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574875

RESUMO

RATIONALE: Glecaprevir/pibrentasvir, a pan-genotypic and ribavirin-free direct acting antiviral agent regimen, has shown significant efficacy and very few serious complications. However, as the drug metabolizes in the liver, it is not recommended in patients with decompensated liver cirrhosis. Herein, we report the case of a patient with compensated liver cirrhosis who developed severe jaundice after glecaprevir/pibrentasvir medication. PATIENT CONCERNS: A 77-year-old man diagnosed with chronic hepatitis C-related compensated liver cirrhosis visited hospital due to severe jaundice after 12 weeks of glecaprevir/pibrentasvir medication. DIAGNOSES: On the laboratory work-up, the total/direct bilirubin level was markedly elevated to 21.56/11.68 from 1.81 mg/dL; the alanine aminotransferase and aspartate aminotransferase levels were within the normal range. We checked the plasma drug concentration level of glecaprevir, and 18,500 ng/mL was detected, which was more than 15 times higher than the drug concentration level verified in normal healthy adults. INTERVENTIONS: Glecaprevir/pibrentasvir was abruptly stopped and after 6 days, the drug concentration level decreased to 35 ng/mL and the serum total/direct bilirubin decreased to 7.49/4.06 mg/dL. OUTCOMES: Three months after drug cessation, the serum total bilirubin level normalized to 1.21 mg/dL and HCV RNA was not detected. LESSONS: We report what is likely the first known case of severe jaundice after medication with glecaprevir/pibrentasvir in a patient with compensated liver cirrhosis. Clinicians should bear potential hyperbilirubinemia in mind when treating chronic hepatitis C with this regimen and should monitor the patient closely during follow-up laboratory exams, especially in elderly cirrhotic patients.


Assuntos
Antivirais/efeitos adversos , Benzimidazóis/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Hepatite C Crônica/tratamento farmacológico , Hiperbilirrubinemia/induzido quimicamente , Cirrose Hepática/induzido quimicamente , Pirrolidinas/efeitos adversos , Quinoxalinas/efeitos adversos , Sulfonamidas/efeitos adversos , Idoso , Doença Hepática Induzida por Substâncias e Drogas/virologia , Combinação de Medicamentos , Humanos , Hiperbilirrubinemia/virologia , Fígado/efeitos dos fármacos , Fígado/virologia , Cirrose Hepática/virologia , Masculino
14.
J Aquat Anim Health ; 31(4): 371-379, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31519048

RESUMO

Carbendazim (CBZ) is a widely used, systemic, broad-spectrum benzimidazole fungicide. It is used worldwide against fungal diseases on a wide range of agricultural products and in domestic gardens. The activities of brain oxidative stress biomarkers and acetylcholinesterase (AChE) in juvenile African Catfish Clarias gariepinus exposed to CBZ were investigated. Juveniles were exposed to sublethal concentrations of 0.22, 0.43, and 0.64 mg/L CBZ, which corresponded to 5, 10, and 15% of the 96-h LC50 (the concentration that was lethal to 50% of the test organisms over the first 96 h) of CBZ fungicide for 21 d. Individuals were allowed an extra 7-d recovery period. The brain tissues were sampled and analyzed on days 1, 7, 14, 21, and 28 (including the 7-d recovery period). The results indicated significant concentration-dependent inhibition of the brain AChE activities in all exposed groups. The lipid peroxidation was significantly elevated while the antioxidant enzymes and protein values were significantly inhibited by CBZ exposure. However, the values of catalase on days 7, 14, and 21 were significantly higher than day 1 values. Overall, CBZ altered brain oxidative stress parameters and led to the inhibition of AChE. This fungicide should be used with utmost caution to protect and safeguard fish, ensuring that fish production and survival in the environment remain unaffected.


Assuntos
Acetilcolinesterase/metabolismo , Benzimidazóis/efeitos adversos , Carbamatos/efeitos adversos , Peixes-Gato/metabolismo , Fungicidas Industriais/efeitos adversos , Estresse Oxidativo/fisiologia , Poluentes Químicos da Água/efeitos adversos , Animais , Biomarcadores/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo
15.
N Engl J Med ; 381(12): 1136-1147, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31532960

RESUMO

BACKGROUND: Maribavir is a benzimidazole riboside with activity against cytomegalovirus (CMV). The safety and efficacy of maribavir for preemptive treatment of CMV infection in transplant recipients is not known. METHODS: In a phase 2, open-label, maribavir dose-blinded trial, recipients of hematopoietic-cell or solid-organ transplants (≥18 years of age, with CMV reactivation [1000 to 100,000 DNA copies per milliliter]) were randomly assigned to receive maribavir at a dose of 400, 800, or 1200 mg twice daily or the standard dose of valganciclovir for no more than 12 weeks. The primary efficacy end point was the percentage of patients with a response to treatment, defined as confirmed undetectable CMV DNA in plasma, within 3 weeks and 6 weeks after the start of treatment. The primary safety end point was the incidence of adverse events that occurred or worsened during treatment. RESULTS: Of the 161 patients who underwent randomization, 159 received treatment, and 156 had postbaseline data available - 117 in the maribavir group and 39 in the valganciclovir group. The percentage of patients with postbaseline data available who had a response to treatment within 3 weeks was 62% among those who received maribavir and 56% among those who received valganciclovir. Within 6 weeks, 79% and 67% of patients, respectively, had a response (risk ratio, 1.20; 95% confidence interval, 0.95 to 1.51). The percentages of patients with a response to treatment were similar among the maribavir dose groups. Two patients who had a response to treatment had a recurrence of CMV infection within 6 weeks after starting maribavir at a dose of 800 mg twice daily; T409M resistance mutations in CMV UL97 protein kinase developed in both patients. The incidence of serious adverse events that occurred or worsened during treatment was higher in the maribavir group than in the valganciclovir group (52 of 119 patients [44%] vs. 13 of 40 [32%]). A greater percentage of patients in the maribavir group discontinued the trial medication because of an adverse event (27 of 119 [23%] vs. 5 of 40 [12%]). A higher incidence of gastrointestinal adverse events was reported with maribavir, and a higher incidence of neutropenia was reported with valganciclovir. CONCLUSIONS: Maribavir at a dose of at least 400 mg twice daily had efficacy similar to that of valganciclovir for clearing CMV viremia among recipients of hematopoietic-cell or solid-organ transplants. A higher incidence of gastrointestinal adverse events - notably dysgeusia - and a lower incidence of neutropenia were found in the maribavir group. (Funded by ViroPharma/Shire Development; EudraCT number, 2010-024247-32.).


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Infecções por Citomegalovirus/tratamento farmacológico , Citomegalovirus/fisiologia , Ribonucleosídeos/uso terapêutico , Valganciclovir/uso terapêutico , Viremia/tratamento farmacológico , Adulto , Idoso , Aloenxertos , Antivirais/efeitos adversos , Antivirais/farmacologia , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacologia , Citomegalovirus/efeitos dos fármacos , Infecções por Citomegalovirus/virologia , Disgeusia/induzido quimicamente , Feminino , Gastroenteropatias/induzido quimicamente , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Transplante de Órgãos/efeitos adversos , Ribonucleosídeos/efeitos adversos , Ribonucleosídeos/farmacologia , Valganciclovir/efeitos adversos , Valganciclovir/farmacologia , Ativação Viral/efeitos dos fármacos
16.
N Engl J Med ; 381(25): 2403-2415, 2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31562800

RESUMO

BACKGROUND: Data are limited regarding the use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors, such as veliparib, in combination with chemotherapy followed by maintenance as initial treatment in patients with high-grade serous ovarian carcinoma. METHODS: In an international, phase 3, placebo-controlled trial, we assessed the efficacy of veliparib added to first-line induction chemotherapy with carboplatin and paclitaxel and continued as maintenance monotherapy in patients with previously untreated stage III or IV high-grade serous ovarian carcinoma. Patients were randomly assigned in a 1:1:1 ratio to receive chemotherapy plus placebo followed by placebo maintenance (control), chemotherapy plus veliparib followed by placebo maintenance (veliparib combination only), or chemotherapy plus veliparib followed by veliparib maintenance (veliparib throughout). Cytoreductive surgery could be performed before initiation or after 3 cycles of trial treatment. Combination chemotherapy was 6 cycles, and maintenance therapy was 30 additional cycles. The primary end point was investigator-assessed progression-free survival in the veliparib-throughout group as compared with the control group, analyzed sequentially in the BRCA-mutation cohort, the cohort with homologous-recombination deficiency (HRD) (which included the BRCA-mutation cohort), and the intention-to-treat population. RESULTS: A total of 1140 patients underwent randomization. In the BRCA-mutation cohort, the median progression-free survival was 34.7 months in the veliparib-throughout group and 22.0 months in the control group (hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.28 to 0.68; P<0.001); in the HRD cohort, it was 31.9 months and 20.5 months, respectively (hazard ratio, 0.57; 95 CI, 0.43 to 0.76; P<0.001); and in the intention-to-treat population, it was 23.5 months and 17.3 months (hazard ratio, 0.68; 95% CI, 0.56 to 0.83; P<0.001). Veliparib led to a higher incidence of anemia and thrombocytopenia when combined with chemotherapy as well as of nausea and fatigue overall. CONCLUSIONS: Across all trial populations, a regimen of carboplatin, paclitaxel, and veliparib induction therapy followed by veliparib maintenance therapy led to significantly longer progression-free survival than carboplatin plus paclitaxel induction therapy alone. The independent value of adding veliparib during induction therapy without veliparib maintenance was less clear. (Funded by AbbVie; VELIA/GOG-3005 ClinicalTrials.gov number, NCT02470585.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/uso terapêutico , Cistadenocarcinoma Seroso/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/efeitos adversos , Carboplatina/administração & dosagem , Terapia Combinada , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/cirurgia , Método Duplo-Cego , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Análise de Intenção de Tratamento , Quimioterapia de Manutenção , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/cirurgia , Paclitaxel/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Intervalo Livre de Progressão , Qualidade de Vida
17.
Br J Cancer ; 121(4): 332-339, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31312030

RESUMO

BACKGROUND: A phase Ib study of binimetinib and capecitabine for gemcitabine-pretreated biliary tract cancer (BTC) patients was conducted. METHODS: Binimetinib and capecitabine were dosed twice daily on days 1-14, in 3-week cycles. In the dose-escalation (DE) part, three dose levels (DL) were tested (DL1: binimetinib/capecitabine, 15 mg/1000 mg/m2; DL2: 30 mg/1000 mg/m2; DL3: 30 mg/1250 mg/m2). RESULTS: In the DE part, nine patients were recruited and no dose-limiting toxicity was noted. Therefore, the recommended phase 2 dose was determined as DL3. In the expansion part, 25 patients were enrolled. In total, 34 patients, 25 (73.5%) and 9 patients (26.5%) were second-line and third-line settings, respectively. The 3-month progression-free survival (PFS) rate was 64.0%, and the median PFS and overall survival (OS) were 4.1 and 7.8 months. The objective response rate and disease control rate were 20.6% and 76.5%. In total, 68.4% of stable diseases were durable (> 12 weeks). Furthermore, patients with RAS/RAF/MEK/ERK pathway mutations (38.5%) showed significantly better tumour response (p = 0.028), PFS (5.4 vs. 3.5 months, p = 0.010) and OS (10.8 vs. 5.9 months, p = 0.160) than wild type. Most of the adverse events were grade 1/2 and manageable. CONCLUSIONS: A combination of binimetinib and capecitabine shows acceptable tolerability and promising antitumor efficacy for gemcitabine-pretreated BTC, especially in patients with RAS/RAF/MEK/ERK pathway mutations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT02773459).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , MAP Quinases Reguladas por Sinal Extracelular/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Mutação , Quinases raf/genética , Proteínas ras/genética , Idoso , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Neoplasias do Sistema Biliar/genética , Neoplasias do Sistema Biliar/mortalidade , Neoplasias do Sistema Biliar/psicologia , Capecitabina/administração & dosagem , Capecitabina/efeitos adversos , Linhagem Celular Tumoral , MAP Quinases Reguladas por Sinal Extracelular/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno/fisiologia , Qualidade de Vida , Transdução de Sinais , Quinases raf/fisiologia , Proteínas ras/fisiologia
18.
Biomed Res Int ; 2019: 9584748, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31360729

RESUMO

Background: The effect of ramosetron on the analgesic action of tramadol is not well known when ramosetron is added to intravenous-tramadol patient-controlled analgesia (PCA) and infused continuously. The aim of this randomized noninferiority study was to evaluate the effects of ramosetron on the analgesic action of tramadol when it is administered simultaneously in women undergoing laparoscopic gynecology who are receiving tramadol via IV PCA. Method: This study used a prospective, randomized, controlled, noninferiority clinical trial design and compared the analgesic effect of tramadol plus ramosetron with that of tramadol only. A total of 110 postoperative patients, who were using IV PCA tramadol, were randomly assigned either to a group receiving ramosetron (group R, n=49) or to a group that received the same volume of normal saline continuously (group N, n=51). Observation time points for cumulative tramadol consumption were the first hour, and every 4 h up to 12 h and then 24 h after surgery. Pain intensity at rest and during movement, coughing, and nausea scores, the analgesic and antiemetic doses used, side effects, and patient satisfaction were evaluated 1 and 24 h after surgery. Results: Groups R and N received, respectively, 88 ± 55 vs. 79 ± 42 mg tramadol (P=0.511) after 1 h, 211 ± 122 vs. 198 ± 109 mg cumulative tramadol (P=0.610) after 4 h, 244 ± 150 vs. 231 ± 134 mg cumulative tramadol (P= 0.793) after 8 h, 250 ± 156 vs. 247 ± 153 mg cumulative tramadol (P=0.972) after 12 h, and 294 ± 190 vs. 284 ± 178 mg cumulative tramadol (P=0.791) after 24 h, postsurgery. Tramadol plus ramosetron was shown to be not significantly inferior to tramadol alone in alleviating the postoperative pain. Conclusions: The analgesic effect of tramadol combined with ramosetron was found to be noninferior to tramadol alone for postoperative PCA after laparoscopic gynecologic surgery.


Assuntos
Benzimidazóis/administração & dosagem , Procedimentos Cirúrgicos em Ginecologia/efeitos adversos , Dor Pós-Operatória/tratamento farmacológico , Tramadol/administração & dosagem , Administração Intravenosa , Adulto , Benzimidazóis/efeitos adversos , Combinação de Medicamentos , Feminino , Humanos , Laparoscopia/efeitos adversos , Masculino , Pessoa de Meia-Idade , Medição da Dor/métodos , Dor Pós-Operatória/patologia , Tramadol/efeitos adversos
19.
J Formos Med Assoc ; 118(8): 1187-1192, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31279502

RESUMO

BACKGROUND: Glecaprevir/pibrentasvir (GLE/PIB) is a pangenotypic direct-acting antiviral agent for the treatment of chronic hepatitis C virus (HCV) infection. Real-world data of GLE/PIB in Asian patients other than Japanese are limited. We thus investigated the effectiveness and safety profile of GLE/PIB in Taiwanese patients with chronic hepatitis C (CHC). METHODS: CHC patients who received 8, 12, or 16 weeks of GLE/PIB between August and October of 2018 were consecutively enrolled. The treatment duration was determined according to drug label. The hepatic fibrosis was staged according to liver histology, transient elastography, fibrosis index based on 4 factors (FIB-4), or findings of ultrasonography/endoscopy. The primary endpoint was sustained virological response at week 12 off therapy (SVR12). The safety profiles were also assessed. RESULTS: A total of 110 CHC patients with 51% of males were enrolled. The median age was 70 years. A majority (82%) of patients were infected with HCV genotype 2. Forty-six (42%) and 64 (58%) patients had advanced hepatic fibrosis and compensated cirrhosis, respectively. Forty-five (41%) non-cirrhotic patients were treated for 8 weeks. The overall SVR12 rates were 100%, regardless of baseline clinical characteristics. The common adverse events (AEs) were pruritus (12%), anorexia (6%), and fatigue (5%). Nine (8%) serious AEs unrelated to GLE/PIB occurred. Three (2%) patients had Grade 3 elevation of total bilirubin level. None had premature treatment termination, hepatic decompensation, or death. CONCLUSION: Interferon-free GLE/PIB regimen is highly effective and safe for Asian chronic hepatitis C patients with advanced hepatic fibrosis or compensated cirrhosis.


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Cirrose Hepática/virologia , Quinoxalinas/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/efeitos adversos , Benzimidazóis/efeitos adversos , Quimioterapia Combinada , Feminino , Hepacivirus/efeitos dos fármacos , Humanos , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Quinoxalinas/efeitos adversos , Estudos Retrospectivos , Sulfonamidas/efeitos adversos , Resposta Viral Sustentada , Taiwan
20.
Int J Antimicrob Agents ; 54(6): 780-789, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31284039

RESUMO

This systematic review and meta-analysis investigated the efficacy and safety of glecaprevir and pibrentasvir (G/P) for chronic hepatitis C virus (HCV) infection. Pubmed, Embase, Cochrane Library and Scopus were searched to identify relevant studies through August 2018. Data from eligible studies were pooled and sustained virological response rates at 12 weeks' post-treatment (SVR12) were calculated. Thirteen studies with 3082 patients were included and the overall SVR12 rate was 97.8%. The SVR12 rates of subgroups were: G/P 300 mg/120 mg and 200 mg/120 mg: 97.9% and 98.3%; HCV genotype (GT)1, GT2, GT3 and GT4-6: 99.8%, 99.2%, 96.1% and 100%; G/P and G/P plus ribavirin (RBV): 97.9% and 98.2%; G/P (300 mg/120 mg) for 8 weeks, 12 weeks and 16 weeks: 98.8%, 98.5% and 95.6%; treatment-naïve and treatment-experienced patients: 96.7% and 98.3%; patients without and with compensated cirrhosis: 99.4% and 98.8%; patients without and with human immunodeficiency virus (HIV) co-infection: 97.8% and 99.4%; and patients without and with severe renal impairment (SRI): 97.8% and 99.4%. Virological failure and relapse and serious drug-related adverse events were rare. These results indicate that 8- or 12-week G/P treatment achieved high SVR12 rates in HCV GTs 1-6 patients without or with compensated cirrhosis, with good safety profiles, irrespective of dose, RBV use, treatment-experience, HIV co-infection and renal impairment. Due to the limited number of evaluated patients with GT3 infection, further studies are needed to define optimal treatment duration for GT3 cirrhosis patients and patients with prior treatment experience of direct-acting antivirals.


Assuntos
Antivirais/efeitos adversos , Antivirais/uso terapêutico , Benzimidazóis/efeitos adversos , Benzimidazóis/uso terapêutico , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Pirrolidinas/efeitos adversos , Pirrolidinas/uso terapêutico , Quinoxalinas/efeitos adversos , Quinoxalinas/uso terapêutico , Sulfonamidas/efeitos adversos , Sulfonamidas/uso terapêutico , Combinação de Medicamentos , Quimioterapia Combinada , Genótipo , Humanos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA