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1.
Breast Cancer Res ; 20(1): 109, 2018 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-30185228

RESUMO

BACKGROUND: This phase Ib study (NCT00960960) evaluated pictilisib (GDC-0941; pan-phosphatidylinositol 3-kinase inhibitor) plus paclitaxel, with and without bevacizumab or trastuzumab, or in combination with letrozole, in patients with locally recurrent or metastatic breast cancer. METHODS: This was a three-part multischedule study. Patients in parts 1 and 2, which comprised 3 + 3 dose escalation and cohort expansion stages, received pictilisib (60-330 mg) plus paclitaxel (90 mg/m2) with and without bevacizumab (10 mg/kg) or trastuzumab (2-4 mg/kg). In part 3, patients received pictilisib (260 mg) plus letrozole (2.5 mg). Primary objectives were evaluation of safety and tolerability, identification of dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of pictilisib, and recommendation of a phase II dosing regimen. Secondary endpoints included pharmacokinetics and preliminary antitumor activity. RESULTS: Sixty-nine patients were enrolled; all experienced at least one adverse event (AE). Grade ≥ 3 AEs, serious AEs, and AEs leading to death were reported in 50 (72.5%), 21 (30.4%), and 2 (2.9%) patients, respectively. Six (8.7%) patients reported a DLT, and the MTD and recommended phase II pictilisib doses were established where possible. There was no pictilisib-paclitaxel drug-drug interaction. Two (3.4%) patients experienced complete responses, and 17 (29.3%) patients had partial responses. CONCLUSIONS: Combining pictilisib with paclitaxel, with and without bevacizumab or trastuzumab, or letrozole, had a manageable safety profile in patients with locally recurrent or metastatic breast cancer. The combination had antitumor activity, and the additive effect of pictilisib supported further investigation in a randomized study. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00960960 . Registered on August 13, 2009.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Neoplasias da Mama/patologia , Estudos de Coortes , Diarreia/induzido quimicamente , Relação Dose-Resposta a Droga , Feminino , Humanos , Indazóis/administração & dosagem , Indazóis/efeitos adversos , Letrozol/administração & dosagem , Letrozol/efeitos adversos , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Trastuzumab/administração & dosagem , Trastuzumab/efeitos adversos
2.
Sci Adv ; 9(44): eadi4777, 2023 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-37922358

RESUMO

Early-onset preeclampsia (EOPE) is a severe pregnancy complication associated with defective trophoblast differentiation and functions at implantation, but manifestation of its phenotypes is in late pregnancy. There is no reliable method for early prediction and treatment of EOPE. Adrenomedullin (ADM) is an abundant placental peptide in early pregnancy. Integrated single-cell sequencing and spatial transcriptomics confirm a high ADM expression in the human villous cytotrophoblast and syncytiotrophoblast. The levels of ADM in chorionic villi and serum were lower in first-trimester pregnant women who later developed EOPE than those with normotensive pregnancy. ADM stimulates differentiation of trophoblast stem cells and trophoblast organoids in vitro. In pregnant mice, placenta-specific ADM suppression led to EOPE-like phenotypes. The EOPE-like phenotypes in a mouse PE model were reduced by a placenta-specific nanoparticle-based forced expression of ADM. Our study reveals the roles of trophoblastic ADM in placental development, EOPE pathogenesis, and its potential clinical uses.


Assuntos
Pré-Eclâmpsia , Gravidez , Feminino , Camundongos , Humanos , Animais , Pré-Eclâmpsia/terapia , Pré-Eclâmpsia/metabolismo , Trofoblastos/metabolismo , Adrenomedulina/metabolismo , Placenta/metabolismo , Diferenciação Celular
3.
Cureus ; 14(7): e27165, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36017286

RESUMO

Uterine fibroid causes heavy menstrual bleeding and can be difficult to manage particularly in patients with complicated medical history. We present a woman with Eisenmenger syndrome, who presented with heavy menses due to fibroid uterus. She was advised against having hormonal therapy or major surgery under general anesthesia. We successfully controlled her heavy menses and avoided surgery using high-intensity focused ultrasound ablation of her fibroid.

5.
Cancer Chemother Pharmacol ; 73(4): 737-47, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24519752

RESUMO

PURPOSE: The aim of this study was to characterize trastuzumab population pharmacokinetics (PKs) in patients with human epidermal growth factor receptor 2-positive advanced gastric or gastroesophageal junction cancer and the relationship of trastuzumab PK with patient response. METHODS: A nonlinear mixed effects PK model was built using data from the ToGA study. Patients were randomized to intravenous trastuzumab plus chemotherapy or chemotherapy alone. The influence of demographic, laboratory, and disease characteristics on PK parameters was assessed. An exploratory exposure-response analysis compared various PK parameters at steady state with best overall tumor response and overall survival (OS). RESULTS: Trastuzumab PK was best described by a two-compartment model with parallel linear and nonlinear (Michaelis-Menten) elimination from the central compartment. Total clearance (and half-life) of trastuzumab was concentration-dependent. Body weight, prior gastrectomy, and serum albumin had the greatest influence on trastuzumab PK; increasing weight and decreasing albumin levels were associated with increased clearance, while prior gastrectomy correlated with decreased clearance. Median values for AUC, Cmax, and Cmin were lower in patients with progressive disease (PD) than other response categories, although the 1.5 interquartile ranges overlapped. Patients with the lowest Cmin had the highest PD rate and a shorter OS. CONCLUSIONS: In the advanced gastric cancer population, trastuzumab PK was best described by a two-compartment model with parallel linear and nonlinear elimination. Predicted PK exposure was lower than previously reported for breast cancer. Patients with the lowest Cmin had a shorter OS and the highest PD rate, but a distinct correlation was not observed for tumor response.


Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/metabolismo , Junção Esofagogástrica/patologia , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Neoplasias Esofágicas/sangue , Neoplasias Esofágicas/patologia , Junção Esofagogástrica/metabolismo , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/análogos & derivados , Humanos , Masculino , Pessoa de Meia-Idade , Receptor ErbB-2/genética , Neoplasias Gástricas/sangue , Neoplasias Gástricas/patologia , Análise de Sobrevida , Trastuzumab , Adulto Jovem
6.
BMJ Open ; 4(2): e003505, 2014 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-24500611

RESUMO

OBJECTIVE: Low-carbohydrate diets may be useful for weight loss. Diets high in vegetable proteins and oils may reduce the risk of coronary heart disease. The main objective was to determine the longer term effect of a diet that was both low-carbohydrate and plant-based on weight loss and low-density lipoprotein cholesterol (LDL-C). DESIGN, SETTING, PARTICIPANTS: A parallel design study of 39 overweight hyperlipidaemic men and postmenopausal women conducted at a Canadian university-affiliated hospital nutrition research centre from April 2005 to November 2006. INTERVENTION: Participants were advised to consume either a low-carbohydrate vegan diet or a high-carbohydrate lacto-ovo vegetarian diet for 6 months after completing 1-month metabolic (all foods provided) versions of these diets. The prescribed macronutrient intakes for the low-carbohydrate and high-carbohydrate diets were: 26% and 58% of energy from carbohydrate, 31% and 16% from protein and 43% and 25% from fat, respectively. PRIMARY OUTCOME: Change in body weight. RESULTS: 23 participants (50% test, 68% control) completed the 6-month ad libitum study. The approximate 4 kg weight loss on the metabolic study was increased to -6.9 kg on low-carbohydrate and -5.8 kg on high-carbohydrate 6-month ad libitum treatments (treatment difference (95% CI) -1.1 kg (-2.1 to 0.0), p=0.047). The relative LDL-C and triglyceride reductions were also greater on the low-carbohydrate treatment (treatment difference (95% CI) -0.49 mmol/L (-0.70 to -0.28), p<0.001 and -0.34 mmol/L (-0.57 to -0.11), p=0.005, respectively), as were the total cholesterol:HDL-C and apolipoprotein B:A1 ratios (-0.57 (-0.83, -0.32), p<0.001 and -0.05 (-0.09, -0.02), p=0.003, respectively). CONCLUSIONS: A self-selected low-carbohydrate vegan diet, containing increased protein and fat from gluten and soy products, nuts and vegetable oils, had lipid lowering advantages over a high-carbohydrate, low-fat weight loss diet, thus improving heart disease risk factors. TRIAL REGISTRATION: clinicaltrials.gov (http://www.clinicaltrials.gov/), #NCT00256516.


Assuntos
Peso Corporal , Doenças Cardiovasculares/prevenção & controle , Dieta com Restrição de Carboidratos , Hiperlipidemias/prevenção & controle , Veganos , Adulto , Feminino , Humanos , Masculino , Fatores de Risco , Resultado do Tratamento
7.
Arch Intern Med ; 169(11): 1046-54, 2009 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-19506174

RESUMO

BACKGROUND: Low-carbohydrate, high-animal protein diets, which are advocated for weight loss, may not promote the desired reduction in low-density lipoprotein cholesterol (LDL-C) concentration. The effect of exchanging the animal proteins and fats for those of vegetable origin has not been tested. Our objective was to determine the effect on weight loss and LDL-C concentration of a low-carbohydrate diet high in vegetable proteins from gluten, soy, nuts, fruits, vegetables, cereals, and vegetable oils compared with a high-carbohydrate diet based on low-fat dairy and whole grain products. METHODS: A total of 47 overweight hyperlipidemic men and women consumed either (1) a low-carbohydrate (26% of total calories), high-vegetable protein (31% from gluten, soy, nuts, fruit, vegetables, and cereals), and vegetable oil (43%) plant-based diet or (2) a high-carbohydrate lacto-ovo vegetarian diet (58% carbohydrate, 16% protein, and 25% fat) for 4 weeks each in a parallel study design. The study food was provided at 60% of calorie requirements. RESULTS: Of the 47 subjects, 44 (94%) (test, n = 22 [92%]; control, n = 22 [96%]) completed the study. Weight loss was similar for both diets (approximately 4.0 kg). However, reductions in LDL-C concentration and total cholesterol-HDL-C and apolipoprotein B-apolipoprotein AI ratios were greater for the low-carbohydrate compared with the high-carbohydrate diet (-8.1% [P = .002], -8.7% [P = .004], and -9.6% [P = .001], respectively). Reductions in systolic and diastolic blood pressure were also seen (-1.9% [P = .052] and -2.4% [P = .02], respectively). CONCLUSION: A low-carbohydrate plant-based diet has lipid-lowering advantages over a high-carbohydrate, low-fat weight-loss diet in improving heart disease risk factors not seen with conventional low-fat diets with animal products.


Assuntos
Dieta com Restrição de Carboidratos , Hiperlipidemias/sangue , Lipídeos/sangue , Redução de Peso , Glicemia/análise , Pressão Sanguínea , Proteína C-Reativa/análise , Restrição Calórica , LDL-Colesterol/sangue , Carboidratos da Dieta/administração & dosagem , Proteínas Alimentares/administração & dosagem , Feminino , Humanos , Insulina/sangue , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Sobrepeso/complicações , Sobrepeso/dietoterapia , Proteínas de Vegetais Comestíveis/administração & dosagem
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