RESUMEN
BACKGROUND AND PURPOSE: The duration of antibiotic coverage in hand tissues during surgery is unknown. We investigated the time the free concentration of cefuroxime was above the minimal inhibitory concentration (fT>MIC) of 4 µg/mL in hand tissues after single and repeated administration. METHODS: In a prospective, unblinded randomized study 16 patients (13 female, age range 51-80 years) underwent trapeziectomy. Microdialysis catheters were placed in the metacarpal bone (primary effect parameter), synovial sheath, and subcutaneous tissue. Patients were randomized to postoperative administration of either intravenous single administration of cefuroxime (1,500 mg) (Group 1, n = 8) or repeated dosing (2 x 1,500 mg) with a 4 h interval (Group 2, n = 8). Samples were taken over 8 h. RESULTS: The fT>MIC of 4 µg/mL was found to be significantly longer in the metacarpal bone in Group 2 compared with Group 1 with a mean difference of 199 min (95% confidence interval 158-239). The same trend was evident in the remaining compartments. A concentration of 4 µg/mL was reached in all compartments in both groups within a mean time of 6 min (range 0-27 min). In Group 1, the mean concentrations decreased below 4 µg/mL between 3 h 59 min and 5 h 38 min. CONCLUSION: The fT>MIC was longer after repeated administration compared with single administration in all compartments. A single administration of cefuroxime 1,500 mg provided antimicrobial hand tissue coverage for a minimum of 3 h 59 min. Cefuroxime administration in hand surgeries should be done minimum 27 min prior to incision to achieve sufficient coverage in all individuals. Cefuroxime readministration should be considered in hand surgeries lasting longer than 4 h from time of administration.
Asunto(s)
Antibacterianos , Cefuroxima , Hueso Trapecio , Humanos , Cefuroxima/administración & dosificación , Cefuroxima/farmacocinética , Femenino , Persona de Mediana Edad , Anciano , Masculino , Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Estudios Prospectivos , Anciano de 80 o más Años , Hueso Trapecio/cirugía , Mano/cirugía , Huesos del Metacarpo/cirugía , Esquema de MedicaciónRESUMEN
BACKGROUND: The purpose of the study is to examine if prolonged thromboprophylaxis decreases the risk of thrombosis after intended curative surgery for oesophageal cancer. Study results are expected to inform a guideline for thromboprophylaxis after oesophageal cancer surgery. The perspective is to reduce morbidity and mortality in this critically ill patient group. Thrombosis is the second-most common cause of cancer death after the cancer itself. The risk of thrombosis depends on the cancer type, and upper gastrointestinal cancers are considered high risk. This risk is further increased when patients undergo surgery. However, only few studies have investigated the peri- and postoperative coagulation profile in oesophageal cancer patients. Due to this lack of knowledge, prophylaxis is currently restricted to 5000 IU (international units) low-molecular weight heparin daily from surgery until discharge from hospital (approximately 10 days), whereas patients with gastric cancer receive 30 days of treatment. The present study examines whether a 30-day treatment is superior and safe, compared with the current standard treatment. METHODS: The study is a randomised controlled trial. Inclusion is ongoing, and we aim to include 100 patients. Blood samples are drawn before and after surgery, and the coagulation is extensively examined. The primary endpoint is the difference in plasma levels of prothrombin fragment 1 + 2 (F1 + 2) 30 days after surgery between the intervention and the standard group. Furthermore, patients are examined with ultrasound to screen for asymptomatic venous thrombotic events (VTE). Secondary endpoints are incidence of bleeding, symptomatic and asymptomatic VTE and mortality 30 days 1 one year after surgery. DISCUSSION: The study will provide valuable information on the perioperative coagulation profile and VTE risk of oesophageal cancer patients. The study seeks to aid in optimising the postoperative thromboprophylaxis, and the perspective is to reduce morbidity and mortality in this at-risk patient population. TRIALS REGISTRATION: The trial was prospectively registered at the EU Clinical Trials Register with ID 2021-001335-24 on 30 June 2021 and at ClinicalTrials.gov with study identifier NCT05067153.
Asunto(s)
Anticoagulantes , Neoplasias Esofágicas , Protrombina , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Neoplasias Esofágicas/cirugía , Neoplasias Esofágicas/mortalidad , Anticoagulantes/uso terapéutico , Anticoagulantes/administración & dosificación , Anticoagulantes/efectos adversos , Esofagectomía/efectos adversos , Factores de Tiempo , Heparina de Bajo-Peso-Molecular/uso terapéutico , Heparina de Bajo-Peso-Molecular/administración & dosificación , Fragmentos de Péptidos/sangre , Resultado del Tratamiento , Tromboembolia Venosa/prevención & control , Tromboembolia Venosa/etiología , Coagulación Sanguínea/efectos de los fármacos , Factores de Riesgo , Esquema de MedicaciónRESUMEN
SOURCE CITATION: Abdul-Aziz MH, Hammond NE, Brett SJ, et al. Prolonged vs intermittent infusions of ß-lactam antibiotics in adults with sepsis or septic shock: a systematic review and meta-analysis. JAMA. 12 June 2024. [Epub ahead of print.] 38864162.
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Antibacterianos , Sepsis , Choque Séptico , beta-Lactamas , Humanos , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Choque Séptico/tratamiento farmacológico , Choque Séptico/mortalidad , beta-Lactamas/administración & dosificación , beta-Lactamas/uso terapéutico , Sepsis/tratamiento farmacológico , Sepsis/mortalidad , Infusiones Intravenosas , Esquema de Medicación , Antibióticos BetalactámicosRESUMEN
SOURCE CITATION: Dulhunty JM, Brett SJ, De Waele JJ, et al; BLING III Study Investigators. Continuous vs intermittent ß-lactam antibiotic infusions in critically ill patients with sepsis: the BLING III randomized clinical trial. JAMA. 12 June 2024. [Epub ahead of print.] 38864155.
Asunto(s)
Antibacterianos , Sepsis , beta-Lactamas , Humanos , Sepsis/tratamiento farmacológico , Sepsis/mortalidad , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , beta-Lactamas/administración & dosificación , beta-Lactamas/uso terapéutico , Infusiones Intravenosas , Enfermedad Crítica/mortalidad , Esquema de Medicación , Persona de Mediana Edad , Masculino , Antibióticos BetalactámicosAsunto(s)
Esquema de Medicación , Hipoglucemiantes , Insulina , Humanos , Hipoglucemiantes/administración & dosificación , Insulina/administración & dosificación , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/sangre , Resultado del TratamientoRESUMEN
BACKGROUND: F-627 (efbemalenograstim alfa) is a novel long acting granulocyte colony-stimulating factor (G-CSF) that contains two human G-CSF fused to a human immunoglobulin G2 (hIgG2) -Fc fragment with a peptide linker. This studyevaluated the efficacy and safety of F-627, also known as efbemalenograstim alfa (Ryzneuta®) in reducing neutropenia compared with filgrastim (GRAN®). METHODS: This was a multicenter, randomized, open-label, active-controlled non-inferiority study. Two hundred thirty nine (239) patients were enrolled in thirteen centers and received the chemotherapy with epirubicin (100 mg/m2) and cyclophosphamide (600 mg/m2) on day 1 of each cycle for a maximum of four cycles. Patients were randomized to receive either a single 20 mg subcutaneous (s.c.) injection of F-627 on day 3 of each cycle or daily s.c. injection of filgrastim 5 µg/kg/d starting from day 3 of each cycle. The primary endpoint was the duration of grade 3 or 4 neutropenia in cycle 1. The safety profile was also evaluated. RESULTS: The mean (SD) duration of grade 3 or 4 neutropenia in cycle 1 was 0.68 (1.10) and 0.71 (0.95) days for the F-627 and the filgrastim groups, respectively. The Hodges-Lehmann estimate of the between-group median difference (F-627 vs filgrastim) in the duration of grade 3 or 4 neutropenia in cycle 1 was 0 day and the upper limit of the one-sided 97.5% CI was 0 day, which was within the prespecified non-inferiority margin of 1-day. Results for all efficacy endpoints in cycles 2 - 4 were consistent with the results in cycle 1, however a trend towards a lower incidence and a shorter duration of grade 3 or 4 neutropenia and grade 4 neutropenia was observed in the F-627 group compared with the filgrastim group. The ANC nadir in the F-627 group was significantly higher than that in the filgrastim group in each cycle. A single fixed dose of F-627 was well tolerated and as safe as standard daily filgrastim. CONCLUSIONS: A single fixed dose of 20 mg of F-627 in each cycle was as safe and effective as a daily dose of filgrastim 5 µg/kg/d in reducing neutropenia and its complications in patients who received four cycles of EC. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04174599, on 22/11/2019.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama , Factor Estimulante de Colonias de Granulocitos , Neutropenia , Humanos , Femenino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Neutropenia/prevención & control , Adulto , Neoplasias de la Mama/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Filgrastim/administración & dosificación , Filgrastim/efectos adversos , Filgrastim/uso terapéutico , Ciclofosfamida/efectos adversos , Ciclofosfamida/administración & dosificación , Epirrubicina/efectos adversos , Epirrubicina/administración & dosificación , Esquema de MedicaciónRESUMEN
PURPOSE: This study aims to prospectively analyze the effects of anticholinergic therapy using imidafenacin on detrusor overactivity occurring after robot-assisted radical prostatectomy (RARP). MATERIALS AND METHODS: Patients were followed-up at outpatient visits 2-4 weeks post-surgery (visit 2) to confirm the presence of urinary incontinence. Those confirmed with urinary incontinence were randomly assigned in a 1:1 ratio to the anticholinergic medication group (imidafenacin 0.1 mg twice daily) or the control group. Patients were followed-up at 1, 3, and 6 months post-surgery for observational assessments, including the International Prostate Symptom Score (IPSS) and Overactive Bladder Symptom Score (OABSS). RESULTS: A total of 49 patients (25 in the treatment group and 24 in the control group) were randomized for the study. There were no differences observed between the groups in terms of age, comorbidities, prostate size, or pathological staging. According to the IPSS questionnaire results, there was no statistically significant difference between the medication and control groups (p=0.161). However, when comparing storage and voiding symptoms separately, there was a statistically significant improvement in storage symptom scores (p=0.012). OABSS also revealed statistically significant improvement in symptoms from 3 months post-surgery (p=0.005), which persisted until 6 months post-surgery (IPSS storage: p=0.023, OABSS: p=0.013). CONCLUSIONS: In the case of urinary incontinence that occurs after RARP, even if the function of the intrinsic sphincter is sufficiently preserved, if urinary incontinence persists due to changes in the bladder, pharmacological therapy using imidafenacin can be beneficial in managing urinary incontinence.
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Imidazoles , Prostatectomía , Neoplasias de la Próstata , Incontinencia Urinaria , Humanos , Masculino , Prostatectomía/efectos adversos , Prostatectomía/métodos , Imidazoles/uso terapéutico , Imidazoles/administración & dosificación , Imidazoles/efectos adversos , Incontinencia Urinaria/etiología , Estudios Prospectivos , Anciano , Neoplasias de la Próstata/cirugía , Persona de Mediana Edad , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Vejiga Urinaria Hiperactiva/etiología , Recuperación de la Función , Complicaciones Posoperatorias/tratamiento farmacológico , Resultado del Tratamiento , Esquema de Medicación , Antagonistas Colinérgicos/uso terapéutico , Antagonistas Colinérgicos/administración & dosificación , Antagonistas Colinérgicos/efectos adversos , Agentes Urológicos/uso terapéutico , Agentes Urológicos/administración & dosificación , Procedimientos Quirúrgicos Robotizados/efectos adversosRESUMEN
OBJECTIVES: This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the safety and effectiveness of shorter versus longer duration antibiotic regimens for the treatment of suspected neonatal sepsis.
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Antibacterianos , Esquema de Medicación , Sepsis Neonatal , Humanos , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Recién Nacido , Sepsis Neonatal/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto , Sepsis/tratamiento farmacológicoRESUMEN
BACKGROUND: The optimal timing of tocilizumab treatment during the disease course of COVID-19 has yet to be adequately defined in the context of randomised controlled trials and the effect of tocilizumab on real-world populations remains unclear. We examined the effect of different timing of tocilizumab, on mortality, in a cohort of adults with COVID-19. METHODS: All adults (≥18 years old) with confirmed COVID-19 admitted to four hospitals in the West of Scotland between 8 January 2021 and 31 March 2021 and who received tocilizumab were included in a retrospective observational cohort study. Patients were assigned to either an early (day of admission or first day after admission) or late (days 2-7 of admission) cohort based on tocilizumab initiation. The primary outcome was 90-day all-cause mortality in early versus late cohorts. Secondary outcomes were 28 and 180-day all-cause mortality. RESULTS: 203 patients were included in the analysis (138 in the early cohort, 65 in the late cohort). Mortality in 90 days in the early cohort was 22% (n=30) compared with 45% (n=29) in the late cohort (p<0.001). The adjusted mortality was significantly higher in the late cohort compared with the early cohort (adjusted OR: 3.33; 95% CI: 1.29 to 8.54; p=0.012). The secondary outcomes demonstrated the same effect with higher rates of death in 28 days (late cohort adjusted OR: 3.28; 95% CI: 1.23 to 8.75; p=0.018) and 180 days (late cohort adjusted OR: 3.70; 95% CI: 1.45 to 9.45; p=0.006). The effect was seen whether the outcome was adjusted or unadjusted. CONCLUSION: Early administration of tocilizumab within the first 2 days of hospitalisation was associated with a significant survival benefit compared with late exposure. Late administration was associated with particularly high mortality. The observed association may be a result of residual confounders and further research is needed.
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Anticuerpos Monoclonales Humanizados , Tratamiento Farmacológico de COVID-19 , COVID-19 , Humanos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , COVID-19/mortalidad , Escocia/epidemiología , SARS-CoV-2 , Factores de Tiempo , Adulto , Resultado del Tratamiento , Anciano de 80 o más Años , Esquema de MedicaciónRESUMEN
Importance: The standard adjuvant treatment for patients with ERRB2-positive breast cancer is chemotherapy plus 1 year of trastuzumab. Shorter durations of trastuzumab administration improve cardiac safety, but more information is needed about their effect on survival. Objective: To compare survival outcomes after 9-week vs 1-year administration of trastuzumab with the same adjuvant chemotherapy. Design, Setting, and Participants: This post hoc secondary analysis of an open-label, multicenter, noninferiority-design randomized clinical trial included women aged 18 years or older with early ERBB2-positive, axillary node-negative or axillary node-positive breast cancer who were enrolled from January 3, 2008, to December 16, 2014, at 65 centers in 7 European countries. The current exploratory analysis was conducted after achieving the maximum attainable follow-up data when the last patient enrolled had completed the last scheduled visit in December 2022. Intervention: Chemotherapy consisted of 3 cycles of docetaxel administered at 3-week intervals followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide at 3-week intervals. Trastuzumab was administered in both groups for 9 weeks concomitantly with docetaxel. In the 9-week group, no further trastuzumab was administered after chemotherapy, whereas in the 1-year group, trastuzumab was continued after chemotherapy to complete 1 year of administration. Main Outcomes and Measures: The primary objective was disease-free survival (DFS). Distant DFS and OS were secondary objectives. Survival between groups was compared using the Kaplan-Meier method and log-rank test or univariable Cox proportional hazards regression. Results: Among the 2174 women analyzed, median age was 56 years (IQR, 48-64 years). The median follow-up time was 8.1 years (IQR, 8.0-8.9 years); 357 DFS events and 176 deaths occurred. Trastuzumab for 9 weeks was associated with shorter DFS compared with trastuzumab for 1 year (hazard ratio [HR], 1.36; 90% CI, 1.14-1.62); 10-year DFS was 80.3% in the 1-year group vs 78.6% in the 9-week group. The 5-year and 10-year OS rates were comparable between the 9-week and 1-year groups (95.0% vs 95.9% and 89.1% vs 88.2%, respectively; HR for all time points, 1.20; 90% CI, 0.94-1.54). In multivariable analyses, 9-week treatment was associated with shorter DFS compared with 1-year treatment (HR for recurrence or death, 1.36; 95% CI, 1.10-1.68; P = .005), but there was no between-group difference in OS (HR, 1.22; 95% CI, 0.90-1.64; P = .20). Only 4 patients (0.2%) died of a cardiac cause. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, 1-year vs 9-week adjuvant trastuzumab was associated with improved DFS among patients with ERRB2-positive breast cancer receiving chemotherapy, but there was no significant difference in OS between the groups. Trial Registration: ClinicalTrials.gov Identifier: NCT00593697.
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Neoplasias de la Mama , Receptor ErbB-2 , Trastuzumab , Humanos , Trastuzumab/uso terapéutico , Trastuzumab/administración & dosificación , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Persona de Mediana Edad , Quimioterapia Adyuvante/métodos , Receptor ErbB-2/metabolismo , Adulto , Ciclofosfamida/uso terapéutico , Ciclofosfamida/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Docetaxel/uso terapéutico , Epirrubicina/uso terapéutico , Epirrubicina/administración & dosificación , Antineoplásicos Inmunológicos/uso terapéutico , Anciano , Esquema de Medicación , Resultado del Tratamiento , Supervivencia sin Enfermedad , Fluorouracilo/uso terapéutico , Fluorouracilo/administración & dosificaciónRESUMEN
Weekly paclitaxel (WP) is a chemotherapeutic cornerstone in the management of patients with platinum-resistant ovarian carcinoma. Multiple WP dosing regimens have been used clinically and studied individually. However, no formal comparison of these regimens is available to provide objective guidance in clinical decision making. The primary objective of this study was to compare the cumulative dose of paclitaxel delivered using 80 mg/m2/week, administered using either a 3 weeks out of 4 (WP3) or a 4 weeks out of 4 (WP4) regimen. The secondary objective was to evaluate the clinical outcomes associated with both regimens, including efficacy and toxicity parameters. Our retrospective cohort comprised 149 patients harboring platinum-resistant ovarian cancer treated at the CHU de Québec from January 2012 to January 2023. WP3 and WP4 reached a similar cumulative dose (1353.7 vs. 1404.2 mg/m2; p = 0.29). No significant differences in the clinical outcomes were observed. The frequency of dose reduction was significantly higher for WP4 than WP3 (44.7% vs. 4.9%; p < 0.01), mainly due to treatment intolerance from toxicity (34.0% vs. 3.9%; p < 0.01). Our data suggest that a WP3 regimen delivers a similar cumulative dose to WP4, hence offering a better efficacy profile without compromising efficacy.
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Resistencia a Antineoplásicos , Neoplasias Ováricas , Paclitaxel , Humanos , Femenino , Paclitaxel/uso terapéutico , Paclitaxel/administración & dosificación , Estudios Retrospectivos , Neoplasias Ováricas/tratamiento farmacológico , Persona de Mediana Edad , Anciano , Adulto , Recurrencia Local de Neoplasia/tratamiento farmacológico , Esquema de Medicación , Antineoplásicos Fitogénicos/uso terapéutico , Anciano de 80 o más AñosRESUMEN
This review summarises the current and possible future insulin treatment of type 2 diabetes. The type 2 diabetes treatment guidelines prioritise a person-centred approach with various options before insulin addressing cardiorenal protection. Long-acting daily insulin injections are warranted in severe hyperglycaemia or when glycaemic targets are not met. Insulin, when possible, should be combined with other agents to lower insulin dosage, weight gain and hypoglycaemia. Once-weekly insulin offers a promising treatment, reducing injection burden, enhancing treatment satisfaction, and lowering the risk of severe hypoglycaemia, potentially improving type 2 diabetes management.
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Diabetes Mellitus Tipo 2 , Hipoglucemiantes , Insulina , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/administración & dosificación , Insulina/administración & dosificación , Insulina/uso terapéutico , Hipoglucemia/inducido químicamente , Hipoglucemia/prevención & control , Esquema de MedicaciónRESUMEN
We investigate an efficient computational tool to suggest useful treatment regimens for people infected with the human immunodeficiency virus (HIV). Structured treatment interruption (STI) is a regimen in which therapeutic drugs are periodically administered and withdrawn to give patients relief from an arduous drug therapy. Numerous studies have been conducted to find better STI treatment strategies using various computational tools with mathematical models of HIV infection. In this paper, we leverage a modified version of the double deep Q network with prioritized experience replay to improve the performance of classic deep learning algorithms. Numerical simulation results show that our methodology produces significantly more optimal cost values for shorter treatment periods compared to other recent studies. Furthermore, our proposed algorithm performs well in one-day segment scenarios, whereas previous studies only reported results for five-day segment scenarios.
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Aprendizaje Profundo , Infecciones por VIH , Humanos , Infecciones por VIH/tratamiento farmacológico , Algoritmos , Fármacos Anti-VIH/uso terapéutico , Simulación por Computador , Esquema de MedicaciónRESUMEN
BACKGROUND: The long-term impact of tyrosine kinase inhibitor (TKI) discontinuation on resistance and survival in patients with advanced gastrointestinal stromal tumours (GIST) is unclear. We report the exploratory long-term outcomes of patients with advanced GIST stopping imatinib in the BFR14 trial. METHODS: BFR14, an open-label, randomised, phase 3 trial, was done in 17 comprehensive cancer centres or hospitals across France. Patients with advanced GIST aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-3, no previous treatment with imatinib, and no previous malignancy were eligible. Patients were treated with oral imatinib 400 mg daily. Patients with a complete or partial response, or stable disease, according to Response Evaluation Criteria in Solid Tumours (1.0) at 1 year, 3 years, and 5 years from the start of treatment were randomly assigned (1:1) to treatment discontinuation until progression (interruption group) or treatment continuation until progression (continuation group). Randomisation was done centrally with computer-generated permuted blocks of two and six patients stratified by participating centre and presence or absence of residual disease on CT scan. The primary endpoint was progression-free survival. Secondary endpoints included time to imatinib resistance and overall survival. Analyses were conducted on an intention-to-treat basis in all randomly assigned patients who were not lost to follow-up. This trial is registered with ClinicalTrial.gov, NCT00367861. FINDINGS: Between May 12, 2003, and March 16, 2004, after 1 year of imatinib, 32 patients were randomly assigned to the interruption group and 26 to the continuation group. Between June 13, 2005, and May 30, 2007, after 3 years of imatinib, 25 patients were randomly assigned to the interruption group and 25 to the continuation group. Between Nov 9, 2007, and July 12, 2010, after 5 years of imatinib, 14 patients were randomly assigned to the interruption group and 13 to the continuation group. Median follow-up was 235·2 months (IQR 128·8-236·6) after the 1-year randomisation, 200·9 months (190·2-208·4) after the 3-year randomisation, and 164·5 months (134·4-176·4) after the 5-year randomisation. Median progression-free survival in the interruption group versus the continuation group after 1 year of imatinib was 6·1 months (95% CI 2·5-10·1) versus 27·8 months (19·5-37·9; hazard ratio [HR] 0·36 [95% CI 0·20-0·64], log-rank p=0·0003), after 3 years of imatinib was 7·0 months (3·5-11·7) versus 67·0 months (48·8-85·6; 0·15 [0·07-0·32], log-rank p<0·0001), and after 5 years of imatinib was 12·0 months (9·0-16·6) versus not reached (NR; NR-NR; 0·13 [0·03-0·58], log-rank p=0·0016). The median time to imatinib resistance after 1 year of imatinib was 28·7 months (95% CI 18·1-39·1) versus 90·6 months (25·3-156·1; HR 0·93 [95% CI 0·51-1·71], log-rank p=0·82), after 3 years was 66·2 months (43·0-89·6) versus 127·3 months (15·0-239·7; 0·35 [0·17-0·72, log-rank p=0·0028), and after 5 years was 58·6 months (0·0-167·4) versus NR (NR-NR; 0·24 [0·05-1·12], log-rank p=0·049). Median overall survival after 1 year of imatinib was 56·0 months (95% CI 30·3-82·9) versus 105·0 months (20·6-189·6; HR 0·84 [95% CI 0·46-1·54], log-rank p=0·57), after 3 years was 104·0 months (90·7-118·7) versus 134·0 months (89·7-178·3; 0·40 [0·20-0·82], log-rank p=0·0096), and after 5 years was NR (NR-NR) versus 110·4 months (82·7-154·1; 1·28 [0·41-3·99]; log-rank p=0·67), INTERPRETATION: Imatinib interruption in patients with GIST without progressive disease is not recommended. Imatinib interruption in non-progressing patients with GIST was associated with rapid progression, faster resistance to imatinib, and shorter overall survival in the long-term follow-up when compared with imatinib continuation in patients after 3 years and 5 years of imatinib. FUNDING: Centre Léon Bérard, INCa, CONTICANET, Ligue Contre le Cancer, and Novartis.
Asunto(s)
Tumores del Estroma Gastrointestinal , Mesilato de Imatinib , Inhibidores de Proteínas Quinasas , Humanos , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/patología , Tumores del Estroma Gastrointestinal/mortalidad , Mesilato de Imatinib/administración & dosificación , Mesilato de Imatinib/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Estudios de Seguimiento , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Francia , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/patología , Neoplasias Gastrointestinales/mortalidad , Supervivencia sin Progresión , Adulto , Factores de Tiempo , Resistencia a Antineoplásicos , Privación de Tratamiento/estadística & datos numéricos , Esquema de MedicaciónRESUMEN
BACKGROUND: A standardised dose-reduction strategy has not been established for the widely used gemcitabine plus nab-paclitaxel regimen in patients with metastatic pancreatic ductal adenocarcinoma. We aimed to investigate the efficacy and tolerability of alternating treatment cycles of nab-paclitaxel-gemcitabine combination therapy and gemcitabine alone versus continuous treatment with the nab-paclitaxel-gemcitabine combination. METHODS: ALPACA was a randomised, open-label, phase 2 trial conducted at 29 study centres across Germany. Patients aged 18 years or older with a histologically or cytologically confirmed diagnosis of metastatic pancreatic ductal adenocarcinoma who had not been previously treated for advanced disease were enrolled. After an induction phase with three cycles of nab-paclitaxel-gemcitabine combination therapy (nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 administered intravenously on days 1, 8, and 15 of each 28-day cycle), patients were randomly assigned (1:1) by stratified permuted block randomisation either to continue treatment with standard nab-paclitaxel-gemcitabine or to receive alternating cycles of nab-paclitaxel-gemcitabine and gemcitabine alone. Patients and investigators were not masked to treatment allocation. Randomisation was done centrally by the study statistician using a computer-generated randomisation list, and was stratified by Karnofsky Performance Status and presence of liver metastases. The primary endpoint was the derivation of an unbiased point estimate and an associated confidence interval with a confidence coefficient of 80% for the hazard ratio (HR) for overall survival after randomisation, without testing a specific hypothesis, analysed by intention to treat in all patients who started randomised treatment. Safety was analysed according to treatment received. This trial is registered with ClinicalTrials.gov, NCT02564146, and is completed. FINDINGS: Between May 27, 2016, and May 27, 2021, 325 patients were enrolled. Following three cycles of induction treatment, 174 patients were randomly assigned: 85 to continue receiving standard nab-paclitaxel-gemcitabine, of whom 79 started treatment, and 89 to the alternating treatment schedule, of whom 88 started treatment. Of the 167 patients who started randomised treatment, 88 (53%) were female and 79 (47%) were male. Median overall survival after randomisation was 10·4 months (80% CI 9·2-12·0) in the group that received standard treatment and 10·5 months (10·2-11·1) in the group that received alternating treatment (HR 0·90, 80% CI 0·72-1·13; p=0·56). The most common adverse events of any grade were peripheral neuropathy (59 [74%] of 80 patients in the continuous treatment group vs 53 [62%] of 85 patients in the alternating treatment group) and fatigue (43 [54%] vs 44 [52%]). Treatment-emergent serious adverse events after randomisation occurred in 40 (50%) patients in the continuous treatment group and in 28 (33%) in the alternating treatment group. Fewer treatment-emergent adverse events of grade 3 or higher occurred in patients treated with alternating cycles compared with those receiving standard therapy, especially for peripheral neuropathy (17 [21%] patients in the continuous treatment group vs 12 [14%] in the alternating treatment group) and infections (16 [20%] vs nine [11%]). There were two treatment-related deaths after randomisation, both in the continuous treatment group (one multiple organ dysfunction syndrome, not treated after randomisation, and one interstitial lung disease). INTERPRETATION: Our findings suggest that a dose-reduced regimen with alternating cycles of nab-paclitaxel-gemcitabine and gemcitabine alone after three induction cycles is associated with similar overall survival to that for standard treatment with nab-paclitaxel-gemcitabine, but with improved tolerability. We therefore propose that a switch to the alternating schedule could be considered in a clinical setting for patients with metastatic pancreatic cancer who have at least stable disease after three cycles of nab-paclitaxel-gemcitabine treatment. FUNDING: Celgene/Bristol Myers Squibb.
Asunto(s)
Albúminas , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Ductal Pancreático , Desoxicitidina , Gemcitabina , Paclitaxel , Neoplasias Pancreáticas , Humanos , Desoxicitidina/análogos & derivados , Desoxicitidina/administración & dosificación , Desoxicitidina/uso terapéutico , Desoxicitidina/efectos adversos , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Paclitaxel/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Albúminas/administración & dosificación , Albúminas/efectos adversos , Albúminas/uso terapéutico , Femenino , Masculino , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Anciano , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/patología , Quimioterapia de Inducción/métodos , Esquema de MedicaciónRESUMEN
SOURCE CITATION: Park DY, Hu JR, Jamil Y, et al. Shorter dual antiplatelet therapy for older adults after percutaneous coronary intervention: a systematic review and network meta-analysis. JAMA Netw Open. 2024;7:e244000. 38546647.
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Intervención Coronaria Percutánea , Inhibidores de Agregación Plaquetaria , Humanos , Anciano , Inhibidores de Agregación Plaquetaria/uso terapéutico , Inhibidores de Agregación Plaquetaria/administración & dosificación , Terapia Antiplaquetaria Doble , Hemorragia/inducido químicamente , Esquema de MedicaciónRESUMEN
Thrombopoietin receptor agonists (TPO-Ras; romiplostim/eltrombopag/avatrombopag) have demonstrated high efficacy rates (59-88%) and a good safety profile in clinical trials with adult patients with immune thrombocytopenia (ITP). Similar efficacy and safety results have been observed with romiplostim and eltrombopag in paediatric cohorts. Continuous treatment with TPO-RAs has shown durable responses with long-term use, up to 3 years. The effect of TPO-RAs was generally considered transient, as platelet counts tended to drop to baseline values after a short period of time (about 2 weeks), unless treatment was maintained. Several groups have reported successful discontinuation of TPO-RAs without the need for concomitant treatments. This is referred to as sustained remission off treatment (SROT). Both short- and medium-term treatment with TPO-RAs may reduce costs to our healthcare systems and, more importantly, may reduce the potential side effects that may be associated with continuous TPO-RA treatment. The issue of tapering and discontinuation of TPO-RAs in paediatric patients with ITP has received little attention to date. Given that paediatric ITP has much higher rates of spontaneous remission than ITP in adults, we consider that the possibility of SROT of TPO-RAs in paediatric patients with ITP is a neglected but very relevant issue in this subtype of the disease.
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Benzoatos , Hidrazinas , Púrpura Trombocitopénica Idiopática , Pirazoles , Receptores Fc , Receptores de Trombopoyetina , Proteínas Recombinantes de Fusión , Inducción de Remisión , Trombopoyetina , Humanos , Receptores de Trombopoyetina/agonistas , Proteínas Recombinantes de Fusión/uso terapéutico , Proteínas Recombinantes de Fusión/administración & dosificación , Trombopoyetina/uso terapéutico , Receptores Fc/uso terapéutico , Niño , Benzoatos/uso terapéutico , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Pirazoles/uso terapéutico , Hidrazinas/uso terapéutico , Esquema de Medicación , Recuento de Plaquetas , Resultado del Tratamiento , Tiazoles , TiofenosRESUMEN
Antiretroviral therapy has substantially reduced morbidity, mortality, and disease transmission in people living with HIV. Islatravir is a nucleoside reverse transcriptase translocation inhibitor that inhibits HIV-1 replication by multiple mechanisms of action, and it is in development for the treatment of HIV-1 infection. In preclinical and clinical studies, islatravir had a long half-life (t½) of 3.0 and 8.7 days (72 and 209 hours, respectively); therefore, islatravir is being investigated as a long-acting oral antiretroviral agent. A study was conducted to definitively elucidate the terminal t½ of islatravir and its active form islatravir-triphosphate (islatravir-TP). A single-site, open-label, non-randomized, single-dose phase 1 study was performed to evaluate the pharmacokinetics and safety of islatravir in plasma and the pharmacokinetics of islatravir-TP in peripheral blood mononuclear cells after administration of a single oral dose of islatravir 30 mg. Eligible participants were healthy adult males without HIV infection between the ages of 18 and 65 years. Fourteen participants were enrolled. The median time to maximum plasma islatravir concentration was 1 hour. Plasma islatravir concentrations decreased in a biphasic manner, with a t½ of 73 hours. The t½ (percentage geometric coefficient of variation) of islatravir-TP in peripheral blood mononuclear cells through 6 weeks (~1008 hours) after dosing was 8.1 days or 195 hours (25.6%). Islatravir was generally well tolerated with no drug-related adverse events observed. Islatravir-TP has a long intracellular t½, supporting further clinical investigation of islatravir administered at an extended dosing interval.
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Fármacos Anti-VIH , Leucocitos Mononucleares , Humanos , Masculino , Adulto , Semivida , Persona de Mediana Edad , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/administración & dosificación , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Adulto Joven , Desoxiadenosinas/farmacocinética , Desoxiadenosinas/administración & dosificación , Desoxiadenosinas/uso terapéutico , Inhibidores de la Transcriptasa Inversa/farmacocinética , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Adolescente , VIH-1/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , Anciano , Esquema de Medicación , PolifosfatosRESUMEN
Daily vitamin D supplementation using higher than normal dosing (up to the upper limit value) and intermittent (once or twice per week) dosing were studied in patients with increased risk of vitamin D deficiency. Using a PubMed database, a thorough search for published randomized controlled trials and other studies was conducted, and the results were analyzed. This review provides an overview of the use of 7000 IU daily, 30,000 IU per week or twice weekly, and 50,000 IU weekly of vitamin D for obtaining and maintaining 25(OH)D concentrations of at least 30 ng/mL in patients at high risk of vitamin D deficiency. The abovementioned dosages should be considered in adults with obesity, liver disease or malabsorption syndromes, or multi-diseased patients, mainly seniors requiring multi-drug treatment, including drugs affecting vitamin D metabolism. The simple schedules of 7000 IU/day, 30,000 IU/week or twice weekly, and 50,000 IU/week for use by patients with an increased risk of vitamin D deficiency were provided for consideration. Without monitoring of 25(OH)D, daily doses of 7000 IU or intermittent doses of 30,000 IU/week should be considered for a prolonged time as prophylactic or maintenance doses, mainly in obese patients, patients with liver disease and patients with malabsorption syndromes. For the treatment of possible vitamin D deficiency without assessment of 25(OH)D in these groups, intermittent doses of 30,000 IU twice weekly or 50,000 IU per week should be considered for a 6-8-week period only. The higher daily doses or the intermittent doses suggested above are effective, safe and responsive based on patient's preferences.
Asunto(s)
Colecalciferol , Suplementos Dietéticos , Obesidad , Deficiencia de Vitamina D , Humanos , Deficiencia de Vitamina D/tratamiento farmacológico , Deficiencia de Vitamina D/sangre , Obesidad/tratamiento farmacológico , Colecalciferol/administración & dosificación , Colecalciferol/uso terapéutico , Vitamina D/administración & dosificación , Vitamina D/sangre , Vitamina D/análogos & derivados , Esquema de Medicación , Femenino , Masculino , Polifarmacia , Adulto , AncianoRESUMEN
Although, in randomized clinical trials, once-weekly subcutaneous semaglutide (OW s.c.) has demonstrated superior efficacy in comparison with placebo and active controls in terms of glycemic control and body weight reduction in patients with type 2 diabetes mellitus (T2DM), these results need to be confirmed in a real-world (RW) setting. An RW ambispective study (6 months retrospective and 6 months prospective) was conducted in 10 tertiary hospitals in Spain. We evaluated changes in HbA1c and body weight in patients with T2DM treated with semaglutide OW s.c. Additionally, we analyzed different subgroups of patients treated with semaglutide OW s.c. as an add-on to glucose-lowering therapy. A total of 752 patients with a mean age of 60.2 years, a mean HbA1c level of 8.5%, a mean body weight of 101.6 kg, and a mean T2DM duration of 10 years were included. At 12 months, compared with baseline, there was a mean difference of -2.1% in HbA1c levels (p < 0.001) and a mean difference of 9.2 kg in body weight (p < 0.001). Moreover, there were statistically significant differences (p < 0.001) between baseline and month 12 in both HbA1c and body weight in the four subgroups receiving semaglutide OW s.c. as an add-on to glucose-lowering therapy. Semaglutide OW s.c. was well tolerated, with gastrointestinal disorders being the most commonly reported side effects. In this RW study, 12 months of treatment with semaglutide OW s.c. in patients with T2DM was associated with significant and clinically relevant improvements in glycemic control and weight loss, regardless of the glucose-lowering therapy received, and the overall safety profile was positive.