Assuntos
Anticoagulantes , Fibrilação Atrial , Cirrose Hepática , Pirazóis , Piridonas , Rivaroxabana , Varfarina , Humanos , Rivaroxabana/uso terapêutico , Rivaroxabana/administração & dosagem , Varfarina/uso terapêutico , Varfarina/administração & dosagem , Piridonas/uso terapêutico , Piridonas/administração & dosagem , Anticoagulantes/uso terapêutico , Anticoagulantes/administração & dosagem , Cirrose Hepática/complicações , Cirrose Hepática/tratamento farmacológico , Pirazóis/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/complicações , Inibidores do Fator Xa/uso terapêuticoAssuntos
Fármacos Anti-HIV , Farmacorresistência Viral , Infecções por HIV , Adulto , Humanos , Adenina/análogos & derivados , Adenina/uso terapêutico , Fármacos Anti-HIV/uso terapêutico , Negro ou Afro-Americano , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Combinação de Medicamentos , Emtricitabina/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Adesão à Medicação/estatística & dados numéricos , Piperazinas/uso terapêutico , Piridonas/uso terapêutico , Tenofovir/uso terapêutico , Tenofovir/análogos & derivados , Resultado do Tratamento , Estados UnidosRESUMO
BACKGROUND: Preclinical models of pancreatic cancer (PDAC) suggest a synergistic role for combined MEK and autophagy signaling inhibition, as well as MEK and CDK4/6 pathway targeting. Several case reports implicate clinical activity of the combination of either trametinib and hydroxychloroquine (HCQ) in patients with KRAS-mutant PDAC or trametinib with CDK4/6 inhibitors in patients with KRAS and CDKN2A/B alterations. However, prospective data from clinical trials is lacking. Here, we aim to provide clinical evidence regarding the use of these experimental regimens in the setting of dedicated precision oncology programs. METHODS: In this retrospective case series, PDAC patients who received either trametinib/HCQ (THCQ) or trametinib/palbociclib (TP) were retrospectively identified across 11 participating cancer centers in Germany. RESULTS: Overall, 34 patients were identified. 19 patients received THCQ, and 15 received TP, respectively. In patients treated with THCQ, the median duration of treatment was 46 days, median progression-free survival (PFS) was 52 days and median overall survival (OS) was 68 days. In the THCQ subgroup, all patients evaluable for response (13/19) had progressive disease (PD) within 100 days. In the TP subgroup, the median duration of treatment was 60 days, median PFS was 56 days and median OS was 195 days. In the TP subgroup, 9/15 patients were evaluable for response, of which 1/9 showed a partial response (PR) while 8/9 had PD. One patient achieved a clinical benefit despite progression under TP. CONCLUSION: THCQ and TP are not effective in patients with advanced PDAC harboring KRAS mutations or alterations in MAPK/CDKN2A/B.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Hidroxicloroquina , Neoplasias Pancreáticas , Piperazinas , Piridinas , Piridonas , Pirimidinonas , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Feminino , Idoso , Piridonas/administração & dosagem , Piridonas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pirimidinonas/administração & dosagem , Pirimidinonas/uso terapêutico , Piridinas/uso terapêutico , Piridinas/administração & dosagem , Hidroxicloroquina/uso terapêutico , Hidroxicloroquina/administração & dosagem , Piperazinas/uso terapêutico , Piperazinas/administração & dosagem , Adulto , Idoso de 80 Anos ou maisRESUMO
Juvenile myelomonocytic leukemia (JMML) is a rare pediatric hematologic malignancy with a high relapse rate and a poor prognosis hallmarked by RAS pathway mutations. Stieglitz and colleagues conducted a phase II clinical trial using the MEK inhibitor trametinib to treat patients with relapsed and refractory juvenile myelomonocytic leukemia and observed an objective response rate of 50% and an overall survival of 80% after 4 years. See related article by Stieglitz et al., p. 1590 (4) .
Assuntos
Leucemia Mielomonocítica Juvenil , Piridonas , Pirimidinonas , Humanos , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Leucemia Mielomonocítica Juvenil/tratamento farmacológico , Leucemia Mielomonocítica Juvenil/genética , Inibidores de Proteínas Quinases/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Recidiva Local de Neoplasia/tratamento farmacológico , Antineoplásicos/uso terapêutico , Resultado do Tratamento , Doenças Raras/tratamento farmacológico , Ensaios Clínicos como AssuntoRESUMO
This systematic review and meta-analysis evaluates the effects of dabrafenib and/or trametinib in treating BRAF V600-mutant gliomas. The study analyzed eight trials involving both high-grade and low-grade glioma patients, assessing outcomes such as progression-free survival (PFS), overall survival (OS), adverse events (AEs), and disease response. The pooled results showed a median PFS of 6.10 months and OS of 22.73 months, with notable improvement in disease response rates when using combination therapy. However, the high incidence of AEs (50%) and death events (43%) necessitates caution in interpreting these results. The study's limitations include a lack of randomized controlled trials and high heterogeneity in AE data. Future research should focus on larger, controlled studies, standardized AE assessments, and exploration of neurocognitive outcomes to better understand and optimize treatment strategies for BRAF V600-mutant gliomas.
Assuntos
Neoplasias Encefálicas , Glioma , Imidazóis , Mutação , Oximas , Proteínas Proto-Oncogênicas B-raf , Piridonas , Pirimidinonas , Humanos , Oximas/uso terapêutico , Pirimidinonas/uso terapêutico , Glioma/tratamento farmacológico , Glioma/genética , Piridonas/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Imidazóis/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Resultado do TratamentoRESUMO
BACKGROUND: An increase in the prevalence of HIV drug resistance (HIVDR) has been reported in recent years, especially in persons on non-nucleoside reverse transcriptase inhibitors (NNRTIs) due to their low genetic barrier to mutations. However, there is a paucity of epidemiological data quantifying HIVDR in the era of new drugs like dolutegravir (DTG) in sub-Saharan Africa. We, therefore, sought to determine the prevalence and correlates of viral load (VL) suppression in adult people with HIV (PWH) on a fixed-dose combination of tenofovir disoproxil fumarate/lamivudine/dolutegravir (TLD) or tenofovir alafenamide/emtricitabine/dolutegravir (TAFED) and describe patterns of mutations in individuals failing treatment. METHODS: We conducted a cross-sectional study among 384 adults living with HIV aged ≥15 years between 5th June 2023 and 10th August 2023. Demographic, laboratory and clinical data were collected from electronic health records using a data collection form. Viral load suppression was defined as plasma HIV-1 RNA VL of <1000 copies/ml after being on ART for ≥ 6 months. SPSS version 22 to analyze the data. Descriptive statistics and logistic regression were the statistical methods used. RESULTS: The median (interquartile range (IQR)) age was 22 (IQR 18, 38) years, and 66.1% (n = 254) were females. VL suppression was 90.4% (n = 347); (95% confidence interval (CI) 87.6%-93.6%) after switching to TLD/TAFED. Among the virally suppressed, the majority (67.1%, n = 233) were female. Those who missed ≥2 doses in the last 30 days prior to the most recent review were less likely to attain viral suppression compared to those who did not miss any dose (adjusted odds ratio (AOR) 0.047; 95% CI 0.016-0.136; p<0.001). Four participants had resistance mutations to lamivudine and tenofovir. The most common NRTI mutations were M184MV and K65R while K101E was the most common NNRTI mutation. CONCLUSION: Our findings show that viral suppression was high after switching to TLD/TAFED; but lower than the last 95% target of the UNAIDS. Adherence to antiretroviral therapy was a significant correlate of VL suppression. We, therefore, recommend prompt switching of PWH to TLD/TAFED regimen and close monitoring to enhance adherence to therapy.
Assuntos
Fármacos Anti-HIV , Farmacorresistência Viral , Infecções por HIV , HIV-1 , Lamivudina , Mutação , Piperazinas , Piridonas , Tenofovir , Carga Viral , Humanos , Feminino , Adulto , HIV-1/genética , HIV-1/efeitos dos fármacos , Masculino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Farmacorresistência Viral/genética , Carga Viral/efeitos dos fármacos , Zâmbia/epidemiologia , Estudos Transversais , Tenofovir/uso terapêutico , Tenofovir/farmacologia , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/farmacologia , Piperazinas/uso terapêutico , Lamivudina/uso terapêutico , Lamivudina/farmacologia , Piridonas/uso terapêutico , Oxazinas/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/farmacologia , Emtricitabina/uso terapêutico , Pessoa de Meia-Idade , Adulto Jovem , Adolescente , Combinação de MedicamentosRESUMO
The systematic review and meta-analysis titled "The Effects of Dabrafenib and/or Trametinib Treatment in BRAF V600-Mutant Glioma" provides a critical evaluation of these targeted therapies for a challenging subset of gliomas. This review is notable for its comprehensive data integration, offering a robust assessment of the efficacy and safety of dabrafenib and trametinib. By focusing on BRAF V600 mutations, it contributes valuable insights into personalized treatment strategies. However, limitations include study heterogeneity and a lack of long-term follow-up data, which hinder the generalizability and complete understanding of treatment effects. Additionally, while the review emphasizes therapeutic potential, it requires a thorough evaluation of adverse effects. Future research should address these limitations by providing more consistent data, longer follow-up, and a balanced view of treatment risks and benefits.
Assuntos
Neoplasias Encefálicas , Glioma , Imidazóis , Oximas , Piridonas , Pirimidinonas , Humanos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Glioma/tratamento farmacológico , Glioma/genética , Imidazóis/uso terapêutico , Mutação , Oximas/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Metanálise como Assunto , Revisões Sistemáticas como AssuntoRESUMO
BACKGROUND AND OBJECTIVE: Prospective sequential analyses after a new drug approval allow proactive surveillance of new drugs. In the current study, we demonstrate feasibility of frailty-specific sequential analyses for dabigatran, rivaroxaban, and apixaban versus warfarin. METHODS: We partitioned Medicare data from 2011 to 2020 into datasets based on calendar year following the date of drug approval. Each calendar year of data was added sequentially for analysis. We used a new-user, active comparative design by comparing the initiators of dabigatran versus warfarin, rivaroxaban versus warfarin, and apixaban versus warfarin. Patients aged ≥ 65 years with atrial fibrillation without contraindication to the anticoagulants were included. Claims-based frailty index ≥ 0.25 was used to define frailty. The initiators of each direct oral anticoagulant were propensity-score matched to the initiators of warfarin within each frailty status. The effectiveness outcome was ischemic stroke or systemic thromboembolism, and the safety outcome was major bleeding. For each calendar year, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) from Cox proportional hazards models using all data available up to that year. RESULTS: As an example of the results, in the 2020 dataset, compared with warfarin, apixaban was associated with a reduced risk of ischemic stroke or systemic thromboembolism (frail: HR 0.73, 95% CI 0.63-0.85; non-frail: HR 0.65, 95% CI 0.59-0.72) and major bleeding (frail: HR 0.63, 95% CI 0.57-0.69; non-frail: HR 0.59, 95% CI 0.56-0.63) in both frail and non-frail patients. We found evidence for apixaban's effectiveness and safety within 1-2 years after the drug approval in frail older patients. CONCLUSION: Our frailty-specific sequential analyses can be applied to future near-real-time monitoring of newly approved drugs.
Assuntos
Anticoagulantes , Fragilidade , Medicare , Humanos , Idoso , Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Anticoagulantes/administração & dosagem , Estados Unidos , Masculino , Feminino , Medicare/estatística & dados numéricos , Idoso de 80 Anos ou mais , Administração Oral , Estudos Prospectivos , Fragilidade/tratamento farmacológico , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Varfarina/uso terapêutico , Varfarina/efeitos adversos , Rivaroxabana/uso terapêutico , Rivaroxabana/efeitos adversos , Rivaroxabana/administração & dosagem , Dabigatrana/uso terapêutico , Dabigatrana/efeitos adversos , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/complicações , Piridonas/uso terapêutico , Piridonas/efeitos adversos , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Idoso FragilizadoRESUMO
BACKGROUND: Vitamin-K antagonists (VKAs) have widely been replaced by non-VKA oral anticoagulants (NOACs). This includes Austria, Germany and Switzerland, where as VKA, instead of warfarin, the much longer-acting phenprocoumon is used, which was not compared to NOACs in clinical trials. METHODS: Using administrative data from a large German health insurance, we included all anticoagulation-naïve patients with a first prescription of a NOAC or VKA between 2012 and 2020. We analysed overall survival, major adverse cardiac and cerebrovascular events, major thromboembolic events and major bleeding. RESULTS: Overall, 570,137 patients were included (apixaban: 26.9%, dabigatran: 4.6%, edoxaban: 8.8%, rivaroxaban: 39.1% and VKA: 20.7% of these 99.4% phenprocoumon). In the primary analysis using a 1:1 propensity score matching-cohort (PSM-cohort), a significantly higher overall mortality was found for apixaban, edoxaban and rivaroxaban (all p < 0.001) but not for dabigatran (p = 0.13) compared to VKA. In this PSM-cohort, 5-year mortality was 22.7% for apixaban versus 12.7% for VKA, 19.5% for edoxaban versus 11.4% for VKA, 16.0% for rivaroxaban versus 12.3% for VKA (all p < 0.001) and 13.0% for dabigatran versus 12.8% for VKA (p = 0.06). The observed effect was confirmed in sensitivity analyses using un-weighted and three different weighted Fine-Gray regression models on the basis of the entire cohort. CONCLUSIONS: In this large real-world analysis, apixaban, edoxaban and rivaroxaban, but not dabigatran, were associated with worse survival compared to VKA. These findings, consistent with a few other studies including phenprocoumon, cast profound doubts on the unreflected, general use of NOACs. Randomized trials should assess whether phenprocoumon might actually be superior to NOACs.
Assuntos
Anticoagulantes , Dabigatrana , Pirazóis , Piridinas , Piridonas , Rivaroxabana , Tiazóis , Vitamina K , Humanos , Rivaroxabana/uso terapêutico , Rivaroxabana/efeitos adversos , Feminino , Dabigatrana/uso terapêutico , Dabigatrana/efeitos adversos , Masculino , Alemanha/epidemiologia , Piridonas/uso terapêutico , Piridonas/efeitos adversos , Idoso , Estudos Retrospectivos , Anticoagulantes/uso terapêutico , Anticoagulantes/efeitos adversos , Tiazóis/uso terapêutico , Tiazóis/efeitos adversos , Piridinas/uso terapêutico , Pirazóis/uso terapêutico , Vitamina K/antagonistas & inibidores , Hemorragia/induzido quimicamente , Hemorragia/mortalidade , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Inibidores do Fator Xa/uso terapêutico , Inibidores do Fator Xa/efeitos adversos , Pontuação de Propensão , Tromboembolia/prevenção & controle , Tromboembolia/mortalidadeAssuntos
Anticoagulantes , Transplante de Rim , Pirazóis , Piridonas , Humanos , Pirazóis/uso terapêutico , Piridonas/uso terapêutico , Anticoagulantes/uso terapêutico , Falência Renal Crônica/cirurgia , Masculino , Prognóstico , Pessoa de Meia-Idade , Feminino , Inibidores do Fator Xa/uso terapêuticoRESUMO
Our study assessed the CD4+/CD8+ ratio in people with HIV (PWH) switching from a second-generation integrase inhibitor regimen to long-acting cabotegravir (CAB) and rilpivirine (RPV). Over one year, we observed a significant improvement in the CD4+/CD8+ ratio; In addition, our data showed that time spent in CAB+RPV was significantly associated with an increased CD4+/CD8+ ratio. These findings suggest that long-acting therapy may enhance immune recovery, also in treatment-experienced PWH.
Assuntos
Relação CD4-CD8 , Infecções por HIV , Piridonas , Rilpivirina , Humanos , Rilpivirina/uso terapêutico , Rilpivirina/administração & dosagem , Infecções por HIV/tratamento farmacológico , Masculino , Piridonas/uso terapêutico , Feminino , Pessoa de Meia-Idade , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/administração & dosagem , Adulto , Inibidores de Integrase de HIV/uso terapêutico , Inibidores de Integrase de HIV/administração & dosagem , Resultado do Tratamento , Substituição de Medicamentos , DicetopiperazinasRESUMO
BACKGROUND: To assess the characteristics of patients enrolled in the ILD-PRO Registry. METHODS: The ILD-PRO Registry is a multicentre US registry of patients with progressive pulmonary fibrosis. This registry is enrolling patients with an interstitial lung disease (ILD) other than idiopathic pulmonary fibrosis who have reticular abnormality and traction bronchiectasis on HRCT, and who meet criteria for ILD progression within the prior 24 months. Patient characteristics were analysed based on the number of patients with available data. RESULTS: Of the first 491 patients enrolled, the majority were white (75.4%) and female (60.6%); 47.4% had a history of smoking. Reported ILDs were autoimmune disease-associated ILDs (47.2%), hypersensitivity pneumonitis (17.5%), idiopathic non-specific interstitial pneumonia (9.1%), interstitial pneumonia with autoimmune features (8.9%), unclassifiable ILD (7.6%), other ILDs (9.7%). At enrolment, median (Q1, Q3) FVC % predicted was 62.2 (49.4, 72.4) and DLco % predicted was 39.2 (30.2, 49.2). Median (Q1, Q3) total score on the St. George's Respiratory Questionnaire was 50.8 (35.9, 64.7). The most common comorbidities were gastroesophageal reflux disease (61.1%) and sleep apnoea (29.6%). Overall, 64.5% of patients were receiving immunosuppressive or cytotoxic therapy, 61.1% proton-pump inhibitors, 53.2% oral steroids, 19.8% nintedanib and 3.6% pirfenidone. CONCLUSIONS: Patients enrolled into the ILD-PRO Registry have a variety of ILD diagnoses, marked impairment in lung function and health-related quality of life, and high medication use. Longitudinal data from this registry will further our knowledge of the course of progressive pulmonary fibrosis. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01915511; registered August 5, 2013.
Assuntos
Progressão da Doença , Doenças Pulmonares Intersticiais , Sistema de Registros , Humanos , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Doenças Pulmonares Intersticiais/epidemiologia , Doenças Pulmonares Intersticiais/tratamento farmacológico , Piridonas/uso terapêutico , Qualidade de Vida , Fibrose Pulmonar/epidemiologia , Fibrose Pulmonar/complicações , Indóis/uso terapêutico , Estados Unidos/epidemiologia , Capacidade Vital , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/epidemiologia , Fibrose Pulmonar Idiopática/fisiopatologia , Tomografia Computadorizada por Raios XRESUMO
INTRODUCTION: CARISEL is an implementation-effectiveness "hybrid" study examining the perspectives of people living with HIV-1 (patient study participants [PSPs]) on cabotegravir (CAB) plus rilpivirine (RPV) long-acting (LA) dosed every 2 months (Q2M) across 5 European countries. METHODS: PSPs completed questionnaires on acceptability (Acceptability of Intervention Measure), appropriateness (Intervention Appropriateness Measure), and feasibility (Feasibility of Intervention Measure) at their first (Month [M] 1), third (M4), and seventh (M12) injection visits. Semistructured qualitative interviews were also conducted. RESULTS: Overall, 437 PSPs were enrolled, of whom 430 received treatment. Median (interquartile range) age was 44 (37-51) years, 25.3% (n = 109/430) were female (sex at birth), and 21.9% (n = 94/430) were persons of color. Across time points, PSPs found CAB + RPV LA highly acceptable, appropriate, and feasible (mean scores ≥4.47/5). Qualitative data supported these observations. CONCLUSIONS: PSPs found CAB + RPV LA Q2M to be an acceptable, appropriate, and feasible treatment option.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Piridonas , Rilpivirina , Humanos , Rilpivirina/uso terapêutico , Rilpivirina/administração & dosagem , Feminino , Masculino , Adulto , Infecções por HIV/tratamento farmacológico , Pessoa de Meia-Idade , Europa (Continente) , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/administração & dosagem , Piridonas/uso terapêutico , Piridonas/administração & dosagem , HIV-1/efeitos dos fármacos , Inquéritos e Questionários , DicetopiperazinasAssuntos
Fármacos Anti-HIV , Farmacorresistência Viral , Emtricitabina , Infecções por HIV , HIV-1 , Compostos Heterocíclicos com 3 Anéis , Oxazinas , Piperazinas , Piridonas , Tenofovir , Humanos , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , HIV-1/genética , Emtricitabina/uso terapêutico , Piridonas/uso terapêutico , Piperazinas/uso terapêutico , Tenofovir/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Fármacos Anti-HIV/uso terapêutico , Oxazinas/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Hepatite B/tratamento farmacológico , Adenina/análogos & derivados , Adenina/uso terapêutico , Masculino , Feminino , AmidasRESUMO
OBJECTIVE: This study examined the prevalence, severity and risk factors of anaemia among adult people living with HIV attending an antiretroviral therapy centre in Woreta Primary Hospital, Woreta town, Ethiopia. DESIGN: Hospital-based retrospective cross-sectional study. SETTING: Public health facility that provides HIV care in Woreta town. PARTICIPANTS: A total of 289 medical records of adults living with HIV/AIDS on highly active antiretroviral therapy from February 2019 to September 2023 at government hospital were reviewed using a systematic sampling method. The data were entered using Epi-info V.7 and exported to SPSS V.23 for data analysis. The data were analysed using bivariate and then multivariate logistic regression models in order to identify variables associated with anaemia. At the 95% CI level, variables having a p value of <0.05 were deemed to be statistically significant predictors. PRIMARY OUTCOME: Prevalence and severity of anaemia and its predictors among adult patients living with HIV on antiretroviral therapy in Woreta Primary Hospital. RESULTS: The total prevalence of anaemia was 31.5% (95% CI 28.9 to 33.8). The prevalence of mild, moderate and severe anaemia was 20.42%, 10.38% and 0.70%, respectively. Predictors independently linked with anaemia were female sex (adjusted OR (AOR) 1.08), age ≥40 years (AOR 1.21), lived with HIV >10 years (AOR 2.31), CD4 counts <200 cells/µL (AOR 3.81), non-suppressed viral load (AOR 1.28), history of opportunistic infections (AOR 1.54), WHO clinical stages III and IV (AOR 1.37 and 2.23, respectively) and history of parasitic infestation (AOR 2.81). CONCLUSIONS: A sizeable proportion of participants were found anaemic. Female sex, older age, longer periods lived with the virus, lower CD4 count, non-suppressed viral load, history of opportunistic infections, WHO clinical stages III and IV and history of parasitic infestation were the contributing factors. Therefore, to improve the anaemic status and living circumstances of patients living with HIV, immediate action on the linked factors is needed, such as monitoring for maintenance of CD4 counts >200 cells/µL and avoiding progression of HIV to the advanced WHO clinical stages, suppressed viral load, preventing opportunistic infections and parasitic infestation.
Assuntos
Anemia , Terapia Antirretroviral de Alta Atividade , Infecções por HIV , Compostos Heterocíclicos com 3 Anéis , Oxazinas , Piridonas , Humanos , Feminino , Masculino , Adulto , Estudos Transversais , Estudos Retrospectivos , Anemia/epidemiologia , Etiópia/epidemiologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Prevalência , Pessoa de Meia-Idade , Fatores de Risco , Piridonas/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Contagem de Linfócito CD4 , Adulto Jovem , Inibidores de Integrase de HIV/uso terapêutico , Índice de Gravidade de Doença , PiperazinasRESUMO
INTRODUCTION: Several randomised controlled trials have demonstrated that novel oral anticoagulants are safer compared with vitamin K antagonists for the management of non-valvular atrial fibrillation (NVAF) to prevent thromboembolic events in the general population. There is a growing interest in the use of apixaban in patients with end-stage renal disease (ESRD) undergoing peritoneal dialysis (PD) but there is a lack of randomised data in this population. METHODS AND ANALYSIS: APIDP2 is a prospective parallel, randomised, open-label, blinded endpoint trial involving patients with ESRD undergoing chronic PD who have NVAF. A total of 178 participants will be recruited from 20 French PD centres. Eligible patients will be randomly assigned to receive either apixaban at a reduced dose of 2.5 mg two times per day (dose determined with the previous pharmacokinetic study APIDP1) or dose-adjusted to international normalised ratio (INR) target (2-3) coumadin therapy. Anticoagulation to prevent thromboembolic events will be initiated or changed according to the randomisation for a duration of 1 year. The primary outcome is a major or clinically relevant non-major bleeding from randomisation up to month 12, assessed according to the International Society on Thrombosis and Haemostasis Score. Secondary outcomes encompass an efficacy composite criterion combining stroke or transient ischaemic attack (TIA), cardiovascular death and thrombosis including myocardial infarction cumulated at 12 months. Bleeding events will be also classified according to Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) and Thrombolysis In Myocardial Infarction (TIMI) criteria and pharmacodynamics outcomes will evaluate the time within the INR target range of 2-3 in the warfarin arm over 1 year, and anti-Xa apixaban activity in case of bleeding events and at 1 month, 6 months and 12 months of follow-up in the apixaban arm. To demonstrate that apixaban is safer than warfarin at 1 year, assuming two interim analyses after 60 and 118 patients, a bilateral alpha risk of 5% and a power of 80%, 178 patients are needed in this randomised trial (effect size found from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Study among patients with creatinine clearance 25-30 ml/min), that is, 89 patients per group. ETHICS AND DISSEMINATION: The study has been approved by the ethics committee Comité de Protection des Personnes Sud Est III - Lyon - FRANCE, CT number 2023-507544-37-00. Written informed consent is required for each participant. Findings will be presented at scientific meetings and published in peer-reviewed journals. TRIAL REGISTRATION: ClinicalTrials.gov, NCT06045858; European Clinical Trial System, CT number 2023-507544-37-00.
Assuntos
Anticoagulantes , Fibrilação Atrial , Falência Renal Crônica , Diálise Peritoneal , Pirazóis , Piridonas , Varfarina , Humanos , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Piridonas/uso terapêutico , Piridonas/efeitos adversos , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/complicações , Varfarina/uso terapêutico , Varfarina/efeitos adversos , Anticoagulantes/uso terapêutico , Anticoagulantes/efeitos adversos , Falência Renal Crônica/terapia , Falência Renal Crônica/complicações , Estudos Prospectivos , Inibidores do Fator Xa/uso terapêutico , Inibidores do Fator Xa/efeitos adversos , Hemorragia/induzido quimicamente , Tromboembolia/prevenção & controle , Tromboembolia/etiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Acidente Vascular Cerebral/prevenção & controle , Acidente Vascular Cerebral/etiologia , Feminino , França , MasculinoRESUMO
Patients with thrombotic antiphospholipid syndrome (APS) are at high risk for recurrent thrombosis, and indefinite anticoagulation is recommended. Patients with APS merit indefinite anticoagulation, and vitamin K antagonists (VKAs) have historically been the standard treatment. Direct oral anticoagulants (DOACs) present an appealing alternative to VKAs. Due to their pharmacokinetic and pharmacodynamic characteristics, DOACs offer advantages over VKAs, namely the lack of need for laboratory monitoring, the usage of a fixed dosage, and the absence of significant interaction with dietary components and drugs. The efficacy and safety of DOACs in patients with APS have been studied in four phase II/III clinical trials (three with rivaroxaban and one with apixaban). These studies showed DOACs' inferiority compared to VKAs in preventing recurrent thrombosis. Recurrence was significantly greater in patients with arterial thrombotic events and a triple positivity for antiphospholipid antibodies. No differences were observed in the incidence of venous thromboembolism between both groups. Major bleeding was similar in patients treated with DOACs or VKAs. Several observational studies have reported similar results. This review aims to analyse the existing evidence on the efficacy and safety of DOACs for secondary prevention in patients with APS.
Assuntos
Anticoagulantes , Síndrome Antifosfolipídica , Prevenção Secundária , Trombose , Humanos , Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/tratamento farmacológico , Administração Oral , Anticoagulantes/uso terapêutico , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Prevenção Secundária/métodos , Trombose/prevenção & controle , Trombose/etiologia , Rivaroxabana/uso terapêutico , Rivaroxabana/administração & dosagem , Rivaroxabana/efeitos adversos , Pirazóis/uso terapêutico , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Piridonas/uso terapêutico , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Inibidores do Fator Xa/uso terapêutico , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/efeitos adversos , Hemorragia/induzido quimicamente , Tromboembolia Venosa/prevenção & controle , Tromboembolia Venosa/etiologiaRESUMO
Acute respiratory distress syndrome (ARDS) occurs as an acute onset condition, and patients present with diffuse alveolar damage, refractory hypoxemia, and non-cardiac pulmonary edema. ARDS progresses through an initial exudative phase, an inflammatory phase, and a final fibrotic phase. Pirfenidone, a powerful anti-fibrotic agent, is known as an agent that inhibits the progression of fibrosis in idiopathic pulmonary fibrosis. In this study, we studied the treatment efficiency of pirfenidone on lipopolysaccharide (LPS) and bleomycin-induced ARDS using rats. The ARDS rat model was created by the intratracheal administration of 3 mg/kg LPS of and 3 mg/kg of bleomycin dissolved in 0.2 mL of normal saline. The pirfenidone treatment group was administered 100 or 200 mg/kg of pirfenidone dissolved in 0.5 mL distilled water orally 10 times every 2 days for 20 days. The administration of LPS and bleomycin intratracheally increased lung injury scores and significantly produced pro-inflammatory cytokines. ARDS induction increased the expressions of transforming growth factor (TGF)-ß1/Smad-2 signaling factors. Additionally, matrix metalloproteinase (MMP)-9/tissue inhibitor of metalloproteinase (TIMP)-1 imbalance occurred, resulting in enhanced fibrosis-related factors. Treatment with pirfenidone strongly suppressed the expressions of TGF-ß1/Smad-2 signaling factors and improved the imbalance of MMP-9/TIMP-1 compared to the untreated group. These effects led to a decrease in fibrosis factors and pro-inflammatory cytokines, promoting the recovery of damaged lung tissue. These results of this study showed that pirfenidone administration suppressed inflammation and fibrosis in the ARDS animal model. Therefore, pirfenidone can be considered a new early treatment for ARDS.
Assuntos
Bleomicina , Lipopolissacarídeos , Piridonas , Síndrome do Desconforto Respiratório , Transdução de Sinais , Animais , Piridonas/farmacologia , Piridonas/uso terapêutico , Síndrome do Desconforto Respiratório/tratamento farmacológico , Síndrome do Desconforto Respiratório/metabolismo , Síndrome do Desconforto Respiratório/patologia , Síndrome do Desconforto Respiratório/induzido quimicamente , Transdução de Sinais/efeitos dos fármacos , Ratos , Masculino , Bleomicina/efeitos adversos , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Proteína Smad2/metabolismo , Ratos Sprague-Dawley , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Modelos Animais de Doenças , Metaloproteinase 9 da Matriz/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Pulmão/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Proteínas Smad/metabolismoRESUMO
Langerhans cell histiocytosis (LCH) is a histiocytic disorder that predominantly affects young children, with congenital manifestations being exceedingly rare. Here, we report a male infant with congenital LCH harboring a driving mutation within the mitogen-activated protein kinase pathway, specifically MAP2K1 Q56P. First-line use of targeted therapy with oral MEK inhibitor trametinib led to rapid and complete resolution of the infant's widespread cutaneous disease. This patient remains clinically well with normal growth and development and no sign of progressive disease or medication intolerance. This case demonstrates the impact that targeted therapy can have as an alternative to systemic chemotherapy in an age group known to experience more extensive disease.
Assuntos
Histiocitose de Células de Langerhans , MAP Quinase Quinase 1 , Inibidores de Proteínas Quinases , Piridonas , Pirimidinonas , Humanos , Histiocitose de Células de Langerhans/tratamento farmacológico , Histiocitose de Células de Langerhans/congênito , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/patologia , Masculino , Pirimidinonas/uso terapêutico , Piridonas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 1/genética , LactenteRESUMO
OBJECTIVE: Targeted therapy (TT) with BRAF/MEK inhibitors has emerged as a potential treatment in papillary craniopharyngiomas (PCPs). However, standardized data on large cohorts are lacking. Our study aimed to assess real-life efficacy and safety of BRAF/MEK inhibition in patients with PCPs. DESIGN: Retrospective French multicenter study involving BRAF V600E-mutated PCP patients, treated with BRAF/MEK inhibitor combination dabrafenib and trametinib, from April 2019 to July 2023. METHODS: Objective response and clinical and safety outcomes were assessed after 3 months and at the last available follow-up during TT. RESULTS: Sixteen patients (8 females, mean age 50.5 ± 15.75 years), receiving either neoadjuvant therapy (NEO) for non-resectable tumors (n = 6), post-surgical adjuvant therapy (ADJ; n = 8), or palliative therapy (PAL) following failure of multimodal treatment (n = 2), were included.At the last follow-up (mean 7.6 ± 5.3 months), 12 patients showed subtotal response, 3 exhibited partial response, and 1 maintained stable disease. Mean volume reduction was 88.9 ± 4.4%, 73.3 ± 23.4%, and 91.8 ± 4.3% in the NEO, ADJ, and PAL groups, respectively.Targeted therapy resolved headaches in 5/5 patients and visual impairment in 6/9; 2/3 patients had improved neurological symptoms, 1/4 presented weight loss, and 2/14 recovered endocrine function.Targeted therapy was well-tolerated in 62.5% of cases; adverse events led to treatment discontinuation in 5 patients and definitive discontinuation in 3 cases. CONCLUSIONS: In this study, 94% of patients showed partial response or better to TT. Adverse events were acceptable. Further research is needed to establish standardized protocols; however, these results advocate for a NEO approach in invasive PCPs.