RESUMO
The role of astroglial and microglial cells in the pathogenesis of epilepsy is currently under active investigation. It has been proposed that the activity of these cells may be regulated by the agonists of peroxisome proliferator-activated nuclear receptors (PPARs). This study investigated the effects of a seven-day treatment with the PPAR ß/δ agonist GW0742 (Fitorine, 5 mg/kg/day) on the behavior and gene expression of the astroglial and microglial proteins involved in the regulation of epileptogenesis in the rat brain within a lithium-pilocarpine model of temporal lobe epilepsy (TLE). TLE resulted in decreased social and increased locomotor activity in the rats, increased expression of astro- and microglial activation marker genes (Gfap, Aif1), pro- and anti-inflammatory cytokine genes (Tnfa, Il1b, Il1rn), and altered expression of other microglial (Nlrp3, Arg1) and astroglial (Lcn2, S100a10) genes in the dorsal hippocampus and cerebral cortex. GW0742 attenuated, but did not completely block, some of these impairments. Specifically, the treatment affected Gfap gene expression in the dorsal hippocampus and Aif1 gene expression in the cortex. The GW0742 injections attenuated the TLE-specific enhancement of Nlrp3 and Il1rn gene expression in the cortex. These results suggest that GW0742 may affect the expression of some genes involved in the regulation of epileptogenesis.
Assuntos
Astrócitos , Modelos Animais de Doenças , Epilepsia do Lobo Temporal , Microglia , PPAR delta , PPAR beta , Tiazóis , Animais , Microglia/efeitos dos fármacos , Microglia/metabolismo , Epilepsia do Lobo Temporal/tratamento farmacológico , Epilepsia do Lobo Temporal/genética , Epilepsia do Lobo Temporal/metabolismo , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Ratos , PPAR delta/agonistas , PPAR delta/genética , PPAR delta/metabolismo , Masculino , Tiazóis/farmacologia , Tiazóis/uso terapêutico , PPAR beta/agonistas , PPAR beta/genética , PPAR beta/metabolismo , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Pilocarpina/farmacologia , Citocinas/metabolismo , Citocinas/genética , Fenóis , Compostos de SulfidrilaRESUMO
BACKGROUND: Vitamin-K antagonists (VKAs) have widely been replaced by non-VKA oral anticoagulants (NOACs).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/mortalidadeRESUMO
BACKGROUND: Treatment with different antipsychotics can lead to various metabolic side effects in patients with psychosis, impacting long-term prognosis. This study aimed to compare the changes and clinical efficacy of insulin resistance in patients treated with olanzapine and ziprasidone. METHOD: A retrospective analysis was conducted on the clinical data of 80 patients with schizophrenia. The patients were divided into olanzapine treatment group and ziprasidone treatment group. Parameters including body weight, body mass index (BMI), fasting plasma glucose (FPG), fasting plasma insulin (FPI), cholesterol (CHO), triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), insulin resistance index, and Positive and Negative Syndrome Scale (PANSS) scores were recorded and compared before and after treatment. RESULTS: BMI, FPG, FPI, homeostatic model assessment of insulin resistance (HOMA-IR), CHO, TG and LDL in both groups were significantly higher than before treatment (p < 0.05). These parameters were significantly higher in the olanzapine group than in the ziprasidone group (p < 0.05). The level of HDL in both groups was significantly decreased after treatment, and the level of HDL in the olanzapine group was significantly lower than that in the ziprasidone group after treatment (p < 0.05). After treatment, the total score and score of PANSS in both groups were significantly lower than before treatment (p < 0.05). After treatment, there was no significant difference in total score and PANSS score between both groups (p > 0.05). The incidence of insulin resistance (IR) was significantly higher in the olanzapine group compared to the ziprasidone group (χ2 = 4.021, p < 0.05). In the IR group, BMI, FPG, FPI, TG, and LDL levels were higher than in the non-IR group (p < 0.05). Multivariate analysis indicated that BMI, FPG, FPI, TG, and LDL were independent risk factors for IR (odd ratio (OR) >1, p < 0.05). CONCLUSIONS: Treatment with olanzapine and ziprasidone improves clinical symptoms in patients with schizophrenia, but increases the risk of insulin resistance. The metabolic side effects of olanzapine are more pronounced.
Assuntos
Antipsicóticos , Resistência à Insulina , Olanzapina , Esquizofrenia , Humanos , Antipsicóticos/uso terapêutico , Antipsicóticos/efeitos adversos , Antipsicóticos/administração & dosagem , Esquizofrenia/tratamento farmacológico , Esquizofrenia/sangue , Masculino , Feminino , Olanzapina/uso terapêutico , Olanzapina/efeitos adversos , Estudos Retrospectivos , Adulto , Pessoa de Meia-Idade , Tiazóis/uso terapêutico , Tiazóis/efeitos adversos , Tiazóis/administração & dosagem , Piperazinas/uso terapêutico , Piperazinas/efeitos adversos , Piperazinas/administração & dosagem , Benzodiazepinas/uso terapêutico , Benzodiazepinas/efeitos adversosRESUMO
Although the adverse effects of long-term use of vitamin K oral anticoagulant (OAC), warfarin, on the coronary vasculature are well-established, it remains unknown whether nonvitamin K oral anticoagulants play a role in the attenuation of plaque progression and coronary calcification. This study aimed to compare the changes in atherosclerotic plaques and calcification of the coronary arteries in patients with atrial fibrillation (AF) treated with edoxaban and warfarin. A total of 150 OAC-naïve patients with AF and atherosclerotic lesions on coronary computed tomography angiography (CCTA) were enrolled and randomly assigned to the edoxaban or warfarin treatment groups. All enrolled patients received rosuvastatin 10 mg and 119 patients completed the entire study protocol. A total of 12 months after the assigned OAC treatment, follow-up CCTA was performed and changes in plaque and calcium volumes of the coronary arteries were analyzed. The baseline characteristics of the 2 groups were well-balanced. The percentage of time in therapeutic range in the warfarin group was 61.1%. Compared with the baseline CCTA, there was a significant reduction in plaque volume after 12 months of OAC and rosuvastatin administration in both groups, and the extent of regression did not differ significantly between the groups. The increase in calcium volume was greater in the warfarin group than in the edoxaban group; however, the difference was not significant. In OAC-naïve patients with AF and atherosclerotic coronary lesions who were treated with moderate-intensity statin, edoxaban use did not have a positive effect on atherosclerotic plaques and coronary calcification compared with warfarin use over a 12-month follow-up period.
Assuntos
Anticoagulantes , Fibrilação Atrial , Doença da Artéria Coronariana , Progressão da Doença , Inibidores do Fator Xa , Placa Aterosclerótica , Piridinas , Tiazóis , Calcificação Vascular , Varfarina , Humanos , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/complicações , Masculino , Feminino , Tiazóis/uso terapêutico , Varfarina/uso terapêutico , Placa Aterosclerótica/complicações , Placa Aterosclerótica/diagnóstico por imagem , Idoso , Piridinas/uso terapêutico , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/complicações , Inibidores do Fator Xa/uso terapêutico , Anticoagulantes/uso terapêutico , Calcificação Vascular/diagnóstico por imagem , Angiografia por Tomografia Computadorizada , Angiografia Coronária , Pessoa de Meia-Idade , Vasos Coronários/diagnóstico por imagem , SeguimentosRESUMO
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.
Assuntos
Benzoatos , Hidrazinas , Púrpura Trombocitopênica Idiopática , Pirazóis , Receptores de Trombopoetina , Proteínas Recombinantes de Fusão , Tiazóis , Trombopoetina , Criança , Humanos , Benzoatos/uso terapêutico , Esquema de Medicação , Hidrazinas/uso terapêutico , Contagem de Plaquetas , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis/uso terapêutico , Receptores Fc/uso terapêutico , Receptores de Trombopoetina/agonistas , Proteínas Recombinantes de Fusão/uso terapêutico , Proteínas Recombinantes de Fusão/administração & dosagem , Indução de Remissão , Tiazóis/uso terapêutico , Tiofenos , Trombopoetina/uso terapêutico , Resultado do TratamentoRESUMO
What is this summary about? This is a plain language summary of a research study called ALPINE. The study involved people who had been diagnosed with, and previously treated at least once for, relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).Lymphocytes help to find and fight off viruses and infections in the body, but when someone has CLL or SLL, the body creates abnormal lymphocytes, leaving the patient with a weakened immune system and susceptible to illness. In CLL, these lymphocytes are in the bone marrow and bloodstream, whereas for SLL, they are mostly found in the lymph nodes, such as those in the neck.How was the research done? The ALPINE study was designed to directly compare the cancer-fighting effects and side effects of zanubrutinib and ibrutinib as treatment for patients with relapsed or refractory CLL/SLL.What were the results? After 30 months, zanubrutinib was more effective than ibrutinib at reducing and keeping the cancer from coming back. Clinical Trial Registration: NCT03734016 (ClinicalTrials.gov).
Assuntos
Adenina , Resistencia a Medicamentos Antineoplásicos , Leucemia Linfocítica Crônica de Células B , Piperidinas , Inibidores de Proteínas Quinases , Pirazóis , Pirimidinas , Humanos , Piperidinas/uso terapêutico , Adenina/análogos & derivados , Adenina/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pirimidinas/uso terapêutico , Pirazóis/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Antineoplásicos/uso terapêutico , Pirazinas/uso terapêutico , Tiazóis/uso terapêutico , Resultado do TratamentoAssuntos
Crise Blástica , Dasatinibe , Leucemia Mielogênica Crônica BCR-ABL Positiva , Pirimidinas , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Pirimidinas/administração & dosagem , Dasatinibe/administração & dosagem , Masculino , Tiazóis/uso terapêutico , Tiazóis/administração & dosagem , Linfócitos T , Pessoa de Meia-Idade , FemininoRESUMO
BACKGROUND: Clinical evidence surrounding edoxaban use in patients weighing <50 kg and >120 kg is lacking. The International Society of Thrombosis and Haemostasis Scientific and Standardisation Committee suggests avoiding edoxaban in patients >120 kg. Additionally, concerns exist regarding decreased efficacy in patients prescribed edoxaban for atrial fibrillation with a creatinine clearance (CrCl) >95 ml/min, a finding of the ENGAGE AF-TIMI 48 trial when edoxaban was compared to warfarin. OBJECTIVE: To derive a population pharmacokinetic (PopPK) model using clinical practice data, to understand the impact of bodyweight and renal function on edoxaban pharmacokinetics. METHOD: Edoxaban plasma concentrations and patient characteristics were collated from King's College Hospital anticoagulation clinics between 11/2016 and 08/2022. A PopPK model was developed using non-linear mixed effects modelling and used to simulate edoxaban concentrations at the extremes of bodyweight and with varying renal function. RESULTS: Data from 409 patients (46 < 50 kg, 34 > 120 kg and 123 with a CrCl > 95 ml/min) provided 455 edoxaban plasma concentrations. A one-compartment model with between-subject variability on clearance with a proportional error model best described the data. The most significant covariates impacting on edoxaban exposure were CrCl and bodyweight. Our work suggests that edoxaban exposure in patients weighing up to 140 kg is comparable to those weighing 75 kg. Edoxaban exposure is reduced in patients weighing <50 kg due to the recommended dose reductions. There is also a reduction in AUCss when CrCl > 95 ml/min compared to CrCl 80 ml/min. CONCLUSIONS: Our population PK model for edoxaban suggests that renal function is a key driver for overall edoxaban exposure. Further clinical outcome data is required to understand clinical effectiveness and adverse outcomes.
Assuntos
Peso Corporal , Creatinina , Inibidores do Fator Xa , Piridinas , Tiazóis , Humanos , Piridinas/farmacocinética , Piridinas/uso terapêutico , Tiazóis/farmacocinética , Tiazóis/uso terapêutico , Tiazóis/sangue , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Inibidores do Fator Xa/farmacocinética , Inibidores do Fator Xa/uso terapêutico , Creatinina/sangue , Idoso de 80 Anos ou mais , AdultoRESUMO
INTRODUCTION AND HYPOTHESIS: To compare change in urgency urinary incontinence episodes (UUIEs) in women undergoing posterior tibial nerve stimulation (PTNS) plus mirabegron versus PTNS plus placebo for the treatment of refractory urgency urinary incontinence (UUI). The primary hypothesis was that combination therapy is superior to monotherapy. METHODS: A randomized controlled trial was performed in individuals identifying as female aged ≥ 18 years with UUI symptoms refractory to second-line treatment or who could not tolerate antimuscarinic medications. Both participants and providers were blinded to medication treatment allocation. Participants were randomized (1:1) to PTNS plus mirabegron or PTNS plus placebo. Participants completed a 3-day bladder diary prior to and after 12-week treatment. Validated symptom distress and impact questionnaires were obtained pre- and post-treatment. The primary outcome was change in mean number of UUIEs on a 3-day bladder diary pre- versus post-treatment between arms. Primary and secondary outcomes were analyzed via sample t tests. RESULTS: Fifty-four subjects were randomized, mean ± SD baseline age 56.2±15.6 years and body mass index 35.0±9.4 (kg/m2); no differences were noted in any clinical-demographic characteristics. There was a significant difference between arms in mean pre- to post-treatment UUIEs, 9.4±3.9, mirabegron versus 5.3±5.5, placebo (p=0.007). Significant differences were found pre- compared with post-treatment in urinary frequency, Overactive Bladder Questionnaire Short Form Symptom Bother and Symptom Health-Related Quality of Life scores. CONCLUSIONS: In subjects undergoing PTNS treatment for refractory UUI and OAB-wet symptoms, the addition of a ß-3 agonist produced significant improvement in both objective and subjective overactive bladder symptom outcomes compared with PTNS plus placebo.
Assuntos
Acetanilidas , Tiazóis , Nervo Tibial , Humanos , Feminino , Tiazóis/uso terapêutico , Tiazóis/administração & dosagem , Acetanilidas/uso terapêutico , Pessoa de Meia-Idade , Idoso , Adulto , Resultado do Tratamento , Incontinência Urinária de Urgência/terapia , Incontinência Urinária de Urgência/tratamento farmacológico , Terapia Combinada , Método Duplo-CegoRESUMO
OBJECTIVE: To describe the prevalence of frailty among Medicare beneficiaries with overactive bladder (OAB), analyze oral therapy patterns, and examine potential disparities in treatment. METHODS: This retrospective cohort study utilized the 20% Research Identifiable File Medicare Part D prescription claims dataset (2013-2018). Using the Claims-Based Frailty Index (CFI), Medicare beneficiaries ≥65 years old with OAB were categorized as not frail (CFI <0.15), prefrail (0.15 ≤CFI<0.25), and frail (CFI >0.25). Logistic regression models assessed associations between frailty and pharmacotherapy utilization. RESULTS: Among 111,761 patients (15.8% of the OAB cohort) receiving oral pharmacotherapy (anticholinergic oral medications or mirabegron), 71% were women, 83% were White, and 11.9% were frail. After controlling for age, copayments and dual eligibility status, frail status (OR 1.16; 95% CI [1.09-1.24]), urology (OR 2.05; 95% CI [1.94-2.16]) or gynecology (OR 1.74; 95% CI [1.6-1.9]) prescribers and residing in the Southern United States (OR 1.53; CI [1.49-1.61]) were associated with higher likelihood of mirabegron utilization. Black (OR 0.79; 95% CI [0.74-0.85]) and American Indian/Alaska Native (OR 0.54; 95% CI [0.39-0.74]) patients were less likely to utilize Mirabegron than White beneficiaries. CONCLUSION: Frail beneficiaries and those with urology and gynecology prescribers showed higher likelihoods of beta-3 agonist utilization. Despite adjustments, Black and American Indian/Alaskan Native patients were less likely to fill mirabegron prescriptions, suggesting disparities in treatment. Our findings highlight the need for policies, interventions, and initiatives to promote equitable OAB oral therapy utilization in vulnerable populations.
Assuntos
Acetanilidas , Disparidades em Assistência à Saúde , Medicare Part D , Bexiga Urinária Hiperativa , Humanos , Bexiga Urinária Hiperativa/tratamento farmacológico , Estados Unidos , Feminino , Idoso , Masculino , Estudos Retrospectivos , Medicare Part D/estatística & dados numéricos , Disparidades em Assistência à Saúde/estatística & dados numéricos , Administração Oral , Idoso de 80 Anos ou mais , Acetanilidas/uso terapêutico , Tiazóis/uso terapêutico , Antagonistas Colinérgicos/uso terapêutico , Fragilidade , Fatores Sociodemográficos , Estudos de CoortesRESUMO
Importance: In older patients with atrial fibrillation who take anticoagulants for stroke prevention, bleeding is increased compared with younger patients, thus, clinicians frequently prescribe lower than recommended doses in older patients despite limited randomized data. Objective: To evaluate ischemic and bleeding outcomes in patients 80 years and older with atrial fibrillation receiving edoxaban, 60 mg vs 30 mg, and edoxaban, 30 mg vs warfarin. Design, Setting, and Participants: The ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a parallel-design, double-blind, global clinical trial that randomized patients with atrial fibrillation to either one of 2 edoxaban dosing regimens or warfarin. This secondary analysis focused on patients 80 years or older without dose-reduction criteria receiving edoxaban, 60 mg vs 30 mg, as well as patients with or without dose-reduction criteria receiving edoxaban, 30 mg, vs warfarin. Study data were analyzed between October 2022 and December 2023. Interventions: Oral edoxaban, 30 mg once daily; edoxaban, 60 mg once daily; or warfarin. Main Outcomes and Measures: Primary net clinical outcome of death, stroke or systemic embolism, and major bleeding and each individual component. Results: The current analysis included 2966 patients 80 years and older (mean [SD] age, 83 [2.7] years; 1671 male [56%]). Among 1138 patients 80 years and older without dose-reduction criteria, those receiving edoxaban, 60 mg vs 30 mg, had more major bleeding events (hazard ratio [HR], 1.57; 95% CI, 1.04-2.38; P = .03), particularly gastrointestinal hemorrhage (HR, 2.24; 95% CI, 1.29-3.90; P = .004), with no significant difference in efficacy end points. Findings were supported by analyses of endogenous factor Xa inhibition, a marker of anticoagulant effect, which was comparable between younger patients receiving edoxaban, 60 mg, and older patients receiving edoxaban, 30 mg. In 2406 patients 80 years and older with or without dose-reduction criteria, patients receiving edoxaban, 30 mg, vs warfarin had lower rates of the primary net clinical outcome (HR, 0.78; 95% CI, 0.68-0.91; P = .001), major bleeding (HR, 0.59; 95% CI, 0.45-0.77; P < .001), and death (HR, 0.83; 95% CI, 0.70-1.00; P = .046), whereas rates of stroke or systemic embolism were comparable. Conclusions and Relevance: In this post hoc analysis of the ENGAGE AF-TIMI 48 randomized clinical trial, in patients 80 years and older with atrial fibrillation, major bleeding events were lower in patients randomized to receive edoxaban, 30 mg per day, compared with either edoxaban, 60 mg per day (in patients without dose-reduction criteria), or warfarin (irrespective of dose-reduction status), without an offsetting increase in ischemic events. These data support the concept that lower-dose anticoagulants, such as edoxaban, 30 mg, may be considered in older patients with atrial fibrillation even in the absence of dose-reduction criteria. Trial Registration: ClinicalTrials.gov Identifier: NCT00781391.
Assuntos
Fibrilação Atrial , Inibidores do Fator Xa , Piridinas , Tiazóis , Varfarina , Humanos , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/complicações , Masculino , Tiazóis/administração & dosagem , Tiazóis/uso terapêutico , Feminino , Inibidores do Fator Xa/uso terapêutico , Inibidores do Fator Xa/administração & dosagem , Idoso de 80 Anos ou mais , Piridinas/uso terapêutico , Piridinas/administração & dosagem , Método Duplo-Cego , Varfarina/uso terapêutico , Varfarina/administração & dosagem , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Anticoagulantes/administração & dosagem , Anticoagulantes/uso terapêutico , Acidente Vascular Cerebral/prevenção & controle , Relação Dose-Resposta a Droga , Redução da MedicaçãoRESUMO
In patients with prevalent or incident atrial fibrillation (AF) after successful transcatheter aortic valve implantation (TAVI) enrolled in the EdoxabaN Versus standard of care and theIr effectS on clinical outcomes in pAtients havinG undergonE Transcatheter Aortic Valve Implantation - in Atrial Fibrillation (ENVISAGE-TAVI AF) trial, the incidence of ischemic stroke (IS) and any stroke was numerically less in the edoxaban group than in the vitamin K antagonist (VKA) group. The present study aimed to identify risk factors associated with IS in an on-treatment subanalysis in patients from ENVISAGE-TAVI AF who received ≥1 dose of edoxaban or VKA. Baseline patient characteristics were compared in patients with and those without IS. Numerical variables were compared using a 1-way analysis of variance; categorical variables were compared using Fisher's exact test. Stepwise Cox regression determined patient characteristics associated with the first IS event. Of 1,377 patients, 41 (3.0%) experienced an IS, and 1,336 (97.0%) did not; baseline demographics and clinical characteristics were well balanced between groups. Most ISs occurred within 180 days of TAVI for edoxaban (57.9%) and VKA (68.2%). The rate of IS was 2.0/100 person-years for edoxaban versus 2.7/100 person-years for VKA. Independently associated with IS were history of systemic embolic events (hazard ratio 2.96, 95% confidence interval 1.26 to 7.00, pâ¯=â¯0.01) and pre-TAVI use of VKAs (hazard ratio 2.17, 95% confidence interval 1.12 to 4.20, pâ¯=â¯0.02). In conclusion, although the overall incidence of IS was small for patients with AF on edoxaban or VKA after successful TAVI, patients with a history of systemic embolic events or pre-TAVI use of VKAs may be at greater risk of IS after TAVI.
Assuntos
Estenose da Valva Aórtica , Fibrilação Atrial , Inibidores do Fator Xa , AVC Isquêmico , Piridinas , Substituição da Valva Aórtica Transcateter , Humanos , Substituição da Valva Aórtica Transcateter/efeitos adversos , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/complicações , Masculino , Feminino , AVC Isquêmico/epidemiologia , AVC Isquêmico/prevenção & controle , AVC Isquêmico/etiologia , Fatores de Risco , Idoso de 80 Anos ou mais , Estenose da Valva Aórtica/cirurgia , Estenose da Valva Aórtica/complicações , Inibidores do Fator Xa/uso terapêutico , Incidência , Piridinas/uso terapêutico , Tiazóis/uso terapêutico , Idoso , Complicações Pós-Operatórias/epidemiologia , Vitamina K/antagonistas & inibidoresAssuntos
Bexaroteno , Proteínas Proto-Oncogênicas c-ret , Humanos , Bexaroteno/uso terapêutico , Bexaroteno/farmacologia , Proteínas Proto-Oncogênicas c-ret/genética , Pirazóis/uso terapêutico , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/genética , Antineoplásicos/uso terapêutico , Tetra-Hidronaftalenos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Mutação , Piridinas/uso terapêutico , Proteínas Proto-Oncogênicas c-met/genética , Aprovação de Drogas , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Leucemia-Linfoma de Células T do Adulto/genética , Leucemia-Linfoma de Células T do Adulto/patologia , Pirimidinas/uso terapêutico , Morfolinas/uso terapêutico , Tiazóis/uso terapêutico , Tiazóis/farmacologia , Éxons , BenzamidasAssuntos
Fibrilação Atrial , Piridinas , Sistema de Registros , Acidente Vascular Cerebral , Tiazóis , Humanos , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/complicações , Alemanha , Piridinas/uso terapêutico , Piridinas/administração & dosagem , Acidente Vascular Cerebral/prevenção & controle , Tiazóis/uso terapêutico , Tiazóis/administração & dosagem , Áustria , Idoso , Masculino , Feminino , Suíça , Anticoagulantes/uso terapêutico , Anticoagulantes/administração & dosagem , Administração Oral , Seguimentos , Inibidores do Fator Xa/uso terapêutico , Inibidores do Fator Xa/administração & dosagem , Idoso de 80 Anos ou mais , Resultado do Tratamento , Pessoa de Meia-IdadeAssuntos
Antibacterianos , Cefepima , Cefalosporinas , Infecções Urinárias , Humanos , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia , Cefalosporinas/efeitos adversos , Cefalosporinas/uso terapêutico , Cefepima/administração & dosagem , Cefepima/efeitos adversos , Cefepima/uso terapêutico , Antibacterianos/efeitos adversos , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Combinação de Medicamentos , Tiazóis/efeitos adversos , Tiazóis/uso terapêutico , Tiazóis/administração & dosagemRESUMO
OBJECTIVES: Multiple sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative progressive disease of central nervous system that mostly affects young adults. (1) Because of involvement of spinal cord and brain, lower urinary dysfunction symptoms are commonly encountered. MS patients mostly show overactive bladder symptoms like urgency, frequent daytime urination, and urgency incontinence. Among MS patients, antimuscarinic therapy is the first-line treatment with overactive bladder symptoms as well as in general population yet 30% of the patients show insufficient improvement or intolerance to the treatment (2). In our study, our aim is to evaluate the efficacy and safety of mirabegron add-on treatment in MS patients after inadequate response to antimuscarinic monotherapy. METHODS: University of Kyrenia and Dr Burhan Nalbantoglu State hospital's databases were screened for the study. Seventy patients who were residents diagnosed with MS according to McDonald criteria were questioned. Among these patients, a total of 22 of them were included in the study. Inclusion criteria was at least 3 years of MS diagnosis, score of <6 at Expanded Disability Status Scale, and a score of ≥3 at Overactive Bladder Symptom Score Scale. RESULTS: Among selected patients, 10 mg solifenacin treatment was daily started and followed for 4 weeks. Mirabegron add-on treatment was initiated to the 11 patient who had inadequate improvement in overactive bladder symptom score. After mirabegron add-on treatment among 11 patient, there was a sufficient improvement in overactive bladder symptom score ( P < 0.008). CONCLUSIONS: In our study, we have found that antimuscarinic and mirabegron combination causes improved efficacy for overactive bladder in MS population.
Assuntos
Acetanilidas , Quimioterapia Combinada , Esclerose Múltipla , Antagonistas Muscarínicos , Succinato de Solifenacina , Tiazóis , Bexiga Urinária Hiperativa , Humanos , Acetanilidas/uso terapêutico , Acetanilidas/efeitos adversos , Bexiga Urinária Hiperativa/tratamento farmacológico , Bexiga Urinária Hiperativa/etiologia , Tiazóis/uso terapêutico , Tiazóis/efeitos adversos , Succinato de Solifenacina/uso terapêutico , Projetos Piloto , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Antagonistas Muscarínicos/uso terapêutico , Antagonistas Muscarínicos/efeitos adversos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/complicações , Resultado do Tratamento , Agentes Urológicos/uso terapêutico , Agentes Urológicos/efeitos adversosRESUMO
EDOSURE is a trial program of the direct oral anticoagulant drug edoxaban, comprising ten randomized clinical trials of which eight are currently published. They evaluate the use of edoxaban in the treatment of nonvalvular atrial fibrillation and acute venous thromboembolism, including in special circumstances such as patients undergoing cardiac procedures, cancer-associated venous thromboembolism, and elderly patients whose bleeding risk precludes conventional anticoagulation strategies. As a result of the collective evidence generated by EDOSURE, edoxaban is now recommended as a treatment option by numerous international guidelines. This review summarizes the context, rationale, and key findings of the studies.
EDOSURE is a collection of clinical trials of the medication edoxaban a blood thinner used to treat or prevent clotting. It encompasses ten trials, eight of which are complete and two are ongoing. Edoxaban's main uses are in patients with atrial fibrillation, or venous clots (e.g., deep vein thrombosis). Trials of blood thinners need to assess the balance of effectiveness (how well the drug treats or prevents clotting) against risk (causing bleeding). These trials collectively demonstrate first that edoxaban is an effective treatment in these conditions and is at least as safe as traditional options like warfarin. Second, in patients with atrial fibrillation who are undergoing procedures like cardiac stenting or ablations, edoxaban is as effective as the previous standard treatments. Finally, in higher-risk populations, such as frail and/or elderly patients, edoxaban can represent a relatively safe option at lower doses. This article is a review of the individual trials, their important findings, and potential limiting factors.
Assuntos
Fibrilação Atrial , Piridinas , Tiazóis , Tromboembolia Venosa , Humanos , Piridinas/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/complicações , Tromboembolia Venosa/prevenção & controle , Tiazóis/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Anticoagulantes/uso terapêutico , Inibidores do Fator Xa/uso terapêuticoRESUMO
Epithelial ovarian cancer is one of the most lethal gynecologic malignancies and poses a considerable threat to women's health. Although the progression-free survival of patients has been prolonged with the application of anti-angiogenesis drugs and Poly (ADP-ribose) polymerases (PARP) inhibitors, overall survival has not substantially improved. Thus, new therapeutic strategies are essential for the treatment of ovarian cancer. Nitazoxanide (NTZ), an FDA-approved anti-parasitic drug, has garnered attention for its potential anti-cancer activity. However, the anti-tumor effects and possible underlying mechanisms of NTZ on ovarian cancer remain unclear. In this study, we investigated the anti-tumor effects and the mechanism of NTZ on ovarian cancer in vitro and in vivo. We found that NTZ inhibited the proliferation of A2780 and SKOV3 epithelial ovarian cancer cells in a time- and concentration-dependent manner; Furthermore, NTZ suppressed the metastasis and invasion of A2780 and SKOV3 cells in vitro, correlating with the inhibition of epithelial-mesenchymal transition; Additionally, NTZ suppressed the Hippo/YAP/TAZ signaling pathway both in vitro and in vivo and demonstrated a good binding activity with core genes of Hippo pathway, including Hippo, YAP, TAZ, LATS1, and LATS2. Oral administration of NTZ inhibited tumor growth in xenograft ovarian cancer mice models without causing considerable damage to major organs. Overall, these data suggest that NTZ has therapeutic potential for treating epithelial ovarian cancer.
Assuntos
Antineoplásicos , Carcinoma Epitelial do Ovário , Proliferação de Células , Transição Epitelial-Mesenquimal , Camundongos Nus , Nitrocompostos , Neoplasias Ovarianas , Tiazóis , Feminino , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Nitrocompostos/farmacologia , Animais , Humanos , Tiazóis/farmacologia , Tiazóis/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Camundongos , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Movimento Celular/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: Among cases of breast cancer, estrogen receptor-positive (ER +), PIK3CA-mutant, HER2- advanced breast cancer stands as a particularly complex clinical indication where approximately 40% of ER + /HER2- breast carcinomas present mutations in the PIK3CA gene. A significant hurdle in treating ER + breast cancer lies in surmounting the challenges of endocrine resistance. In the clinical setting, a multifaceted approach is essential for this indication, one that not only explores the effectiveness of individual treatments but also delves into the potential gains in therapeutic outcome from combination therapies. METHODS: In the current study, longitudinal tumor growth inhibition (TGI) models were developed to characterize tumor response over time in postmenopausal women with ER + /HER2- advanced or metastatic breast cancer undergoing treatment with fulvestrant alone or in combination with the PI3K inhibitor, taselisib. Impact of clinically relevant covariates on TGI metrics was assessed to identify patient subsets most likely to benefit from treatment with fulvestrant monotherapy or combination with taselisib. RESULTS: Tumor growth rate constant (Kg) was found to increase with increasing baseline tumor size and in the absence of baseline endocrine sensitivity. Further, Kg decreased in the absence of baseline liver metastases both in fulvestrant monotherapy and combination therapy with taselisib. Overall, additive/potentially synergistic anti-tumor effects were observed in patients treated with the taselisib-fulvestrant combination. CONCLUSION: These results have important implications for understanding the therapeutic impact of combination treatment approaches and individualized responses to these treatments. Finally, this work, emphasizes the importance of model informed drug development for targeted cancer therapy. CLINICAL TRIAL REGISTRATION: NCT02340221 Registered January 16, 2015, NCT01296555 Registered February 14, 2011.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama , Classe I de Fosfatidilinositol 3-Quinases , Fulvestranto , Mutação , Inibidores de Fosfoinositídeo-3 Quinase , Receptor ErbB-2 , Receptores de Estrogênio , Tiazóis , Humanos , Fulvestranto/administração & dosagem , Fulvestranto/uso terapêutico , Feminino , Classe I de Fosfatidilinositol 3-Quinases/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Receptores de Estrogênio/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Receptor ErbB-2/genética , Tiazóis/administração & dosagem , Tiazóis/uso terapêutico , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/administração & dosagem , Imidazóis/administração & dosagem , Imidazóis/uso terapêutico , Oxazepinas/administração & dosagem , Oxazepinas/farmacologia , Oxazepinas/uso terapêutico , Metástase Neoplásica , Pessoa de Meia-Idade , Estradiol/análogos & derivados , Estradiol/administração & dosagem , Estradiol/farmacologia , Idoso , Estudos LongitudinaisRESUMO
BACKGROUND: In patients with atrial fibrillation (AF), direct oral anticoagulants (DOACs) have been utilized as an alternative to warfarin, which is known to have several limitations. This study aimed to clarify the selection criteria for anticoagulants, considering both individual patient factors and the differences between various drugs. METHODS: This study conducted a web-based questionnaire from September 20, 2023 to October 3, 2023, among physicians who were members of a cardiology-specific website. RESULTS: In total, 172 respondents were enrolled in this study. Edoxaban was the most frequently selected anticoagulant (39.1%), followed by apixaban (32.7%) and rivaroxaban (16.8%). Logistic regression analysis revealed that increased concern for adherence enhanced the frequency of selecting edoxaban (odds ratio [OR] = 2.42; p = 0.047), with the opposite trend observed for dabigatran (OR = 0.404; p = 0.029). The selection of apixaban is related to whether the patient is able to maintain a regular lifestyle, including adherence to medication schedules (OR = 1.874; p = 0.031). Furthermore, detailing activities from a medical representative, especially regarding a new indication, were found to influence drug selection for rivaroxaban (OR = 2.422; p = 0.047). CONCLUSION: This study revealed that edoxaban is the most frequently selected anticoagulant. Although prescribing cardiologists select drugs based on background factors, adherence to medication and information from medical representatives were also crucial factors in the selection process.