RESUMO
AIMS: Increasing evidence indicates that the ATP-generating enzyme creatine kinase (CK) is involved in hypertension. CK rapidly regenerates ATP from creatine phosphate and ADP. Recently, it has been shown that beta-guanidinopropionic acid (GPA), a kidney-synthesized creatine analogue and competitive CK inhibitor, reduced blood pressure in spontaneously hypertensive rats. To further develop the substance as a potential blood pressure-lowering agent, we assessed the tolerability of a sub-therapeutic GPA dose in healthy men. METHODS: In this active and placebo-controlled, triple-blind, single-centre trial, we recruited 24 healthy men (18-50 years old, BMI 18.5-29.9 kg m-2 ) in the Netherlands. Participants were randomized (1:1:1) to one week daily oral administration of GPA 100 mg, creatine 5 g, or matching placebo. The primary outcome was the tolerability of GPA, in an intent-to-treat analysis. RESULTS: Twenty-four randomized participants received the allocated intervention and 23 completed the study. One participant in the placebo arm dropped out for personal reasons. GPA was well tolerated, without serious or severe adverse events. No abnormalities were reported with GPA use in clinical safety parameters, including physical examination, laboratory studies, or 12-Lead ECG. At day 8, mean plasma GPA was 213.88 (SE 0.07) in the GPA arm vs. 32.75 (0.00) nmol l-1 in the placebo arm, a mean difference of 181.13 (95% CI 26.53-335.72). CONCLUSION: In this first-in-human trial, low-dose GPA was safe and well-tolerated when used during 1 week in healthy men. Subsequent studies should focus on human pharmacokinetic and pharmacodynamic assessments with different doses.
Assuntos
Anti-Hipertensivos/administração & dosagem , Creatina/administração & dosagem , Guanidinas/administração & dosagem , Propionatos/administração & dosagem , Administração Oral , Adolescente , Adulto , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/sangue , Creatina/efeitos adversos , Esquema de Medicação , Guanidinas/efeitos adversos , Guanidinas/sangue , Voluntários Saudáveis , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Países Baixos , Propionatos/efeitos adversos , Propionatos/sangue , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: Chemoradiotherapy (CRT) is the standard of care in inoperable non-small-cell lung cancer (NSCLC) patients, favoring concurrent (cCRT) over sequential CRT (seqCRT), with adjuvant immunotherapy in responders. Elderly and frail NSCLC patients have generally been excluded from trials in the past. In elderly patients however, the higher treatment related morbidity of cCRT, may outweigh the possible lower tumor control of seqCRT. For elderly patients with locally advanced NSCLC real-world data is essential to be able to balance treatment toxicity and treatment outcome. The aim of this study is to analyze acute toxicity and 3-month mortality of curative chemoradiation (CRT) in patients with stage III NSCLC and to analyze whether cCRT for elderly stage III NSCLC patients is safe. METHODS: The Dutch Lung Cancer Audit-Radiotherapy (DLCA-R) is a national lung cancer audit that started in 2013 for patients treated with curative intent radiotherapy. All Dutch patients treated for stage III NSCLC between 2015 and 2018 with seqCRT or cCRT for (primary or recurrent) stage III lung cancer are included in this population-based study. Information was collected on patient, tumor- and treatment characteristics and the incidence and severity of acute non-hematological toxicity (CTCAE-4 version 4.03) and mortality within 3 months after the end of radiotherapy. To evaluate the association between prognostic factors and outcome (acute toxicity and mortality within 3 months), an univariable and multivariable analysis was performed. The definition of cCRT was:radiotherapy started within 30 days after the start of chemotherapy. RESULTS: Out of all 20 Dutch departments of radiation oncology, 19 centers participated in the registry. A total of 2942 NSCLC stage III patients were treated with CRT. Of these 67.2% (n = 1977) were treated with cCRT (median age 66 years) and 32.8% (n = 965) were treated with seqCRT (median age 69 years). Good performance status (WHO 0-1) was scored in 88.6% for patients treated with cCRT and in 71.0% in the patients treated with seqCRT. Acute nonhematological 3-month toxicity (CTCAE grade ≥3 or radiation pneumonitis grade ≥2) was scored in 21.9% of the patients treated with cCRT and in 17.7% of the patients treated with seqCRT. The univariable analysis for acute toxicity showed significantly increased toxicity for cCRT (P = .008), WHO ≥2 (P = .006), and TNM IIIC (P = .031). The multivariable analysis for acute toxicity was significant for cCRT (P = .015), WHO ≥2 (P = .001) and TNM IIIC (P = .016). The univariable analysis for 3-month mortality showed significance for seqCRT (P = .025), WHO ≥2 (P < .001), higher cumulative radiotherapy dose (P < .001), higher gross tumor volume total (P = .020) and male patients (p < .001). None of these variables reached significance in the multivariable analysis for 3-month mortality. CONCLUSION: In this national lung cancer audit of inoperable NSCLC patients, 3-month toxicity was significantly higher in patients treated with cCRT (21.9% vs. 17.7% for seqCRT) higher TNM stage IIIC, and poor performance (WHO≥2) patients.The 3-months mortality was not significantly different for tested parameters. Age was not a risk factor for acute toxicity, nor 3 months mortality.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Radioterapia (Especialidade) , Humanos , Masculino , Idoso , Lactente , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Estadiamento de Neoplasias , Quimiorradioterapia/efeitos adversosRESUMO
OBJECTIVE: In patients with NSCLC, lymph node metastases are an important prognostic factor. Despite an accurate pre-operative work up, for optimal staging an intrapulmonary- and mediastinal lymph node dissection (LND) as part of the operation is mandatory. The aim of this study is to assess the completeness of LND in patients undergoing an intended curative resection for NSCLC in the Netherlands and to compare performance between open surgery and minimally invasive surgery (MIS). MATERIALS AND METHODS: The intraoperative LND was evaluated in 7460 patients who had undergone a lobectomy for clinically staged N0-1 NSCLC (2013-2018). The LND was considered complete, when three mediastinal (N2) lymph node stations, including station 7, were sampled or dissected, in addition to the lymph nodes from station 10 and 11. A comparison was made between open surgery and MIS. RESULTS: Of 5154 patients, who had MIS, a sufficient intrapulmonary LND was performed in 47.9% and a sufficient mediastinal LND in 58.6%. A complete LND was performed in 31.6%. For 2306 patients who had an open resection, these numbers were 45.0%, 59.0%, and 30.6%, respectively. The overall between-hospital variation in a complete LND ranged between 0 and 72.5%. CONCLUSION: In the Netherlands, a complete LND of both intrapulmonary- and mediastinal lymph nodes is performed only in a minority of patients with clinically staged N0-1 NSCLC, with substantial between-hospital variation. No differences were seen between open surgery and MIS. Because of poor performance, completeness of lymph node dissection will be recorded as a mandatory performance indicator in our national audit, to improve the quality of resection.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/cirurgia , Neoplasias Pulmonares/cirurgia , Excisão de Linfonodo , Procedimentos Cirúrgicos Minimamente Invasivos , Pneumonectomia , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/patologia , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Países Baixos , PrognósticoRESUMO
Women with fibroids have a notably high hypertension risk. However, adjusted data regarding other cardiovascular disease (CVD) risk factors are scarce. In this cross-sectional study, CVD risk factors, hemodynamic parameters, and asymptomatic organ damage were analyzed between women with uterine fibroids and controls in a multi-ethnic population. In total, 104 women with self-reported fibroids and 624 controls were included. Women with fibroids had significantly higher odds to have hypertension (OR 3.4; 95% CI 2.2-5.2), diabetes (1.7; 1.0-2.9), and hypercholesterolemia (1.8; 1.1-3.2). After adjustment for confounders, only the odds ratio for hypertension was significant (1.8; 1.1-3.1). Asymptomatic organ damage occurred significantly more often in women with fibroids (66.7%; 95% CI 55.8%-77.6% vs 42.9%; 38.0-47.8 in controls), especially in the younger age group (respectively 48.5%; 31.1%-65.9% vs 22.1%; 17.0-27.2). In this study, women with fibroids had a remarkably high hypertension risk compared to controls, with more asymptomatic organ damage, in particular young women.
Assuntos
Doenças Cardiovasculares/epidemiologia , Hipertensão/epidemiologia , Leiomioma/complicações , Adulto , Idoso , Doenças Cardiovasculares/etiologia , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Hipertensão/etiologia , Leiomioma/epidemiologia , Pessoa de Meia-Idade , Prevalência , Medição de Risco , Autorrelato , Adulto JovemRESUMO
BACKGROUND: Despite adequate treatment, up to 30% of treated antihypertensive patients with primary, uncomplicated hypertension remain uncontrolled. We proposed that high intracellular activity of the ATP regenerating enzyme creatine kinase (CK) increases pressor responses and hypertension risk. In line with this, we found that plasma CK activity after rest, a surrogate measure of tissue activity, is the main predictor of blood pressure levels and failure of antihypertensive therapy in the general population. In addition, the creatine analog and competitive oral creatine kinase inhibitor beta-guanidinopropionic acid effectively and safely reduced blood pressure in the spontaneously hypertensive rat. However, to our knowledge there are no human data on the safety of oral supplementation with this substance. Therefore, we will assess the tolerability of beta-guanidinopropionic acid in men, compared to creatine and placebo. METHODS/DESIGN: This is a randomized, active and placebo controlled, triple blind, double dummy, single center clinical intervention trial in 24 healthy male volunteers, 18 to 50 years old, recruited in the Netherlands. The intervention consists of one week of daily oral administration of beta-guanidinopropionic acid 100 mg, creatine 5 gram, or placebo. The primary outcome is the tolerability of beta-guanidinopropionic acid as a descriptive measure, in an intent-to-treat analysis. Other outcomes include the placebo-adjusted differences with baseline in biochemical and hemodynamic parameters, including plasma markers of muscle tissue damage, urine sodium excretion, resting sitting systolic and diastolic brachial blood pressure, supine systolic and diastolic central blood pressure, pulse wave velocity and augmentation index, heart rate, cardiac contractility, cardiac output, and total peripheral resistance. DISCUSSION: There is an unfulfilled need for new conservative options to treat resistant hypertension. This study will provide first-in-men data on creatine kinase inhibition as a potential new class of antihypertensive drugs. TRIAL REGISTRATION: The Netherlands National Trial Register Trialregister.nl (identifier NTR 4444) , registered 9 March 2014.