RESUMEN

BACKGROUND: Early neurological deterioration (END) occurs in many patients with acute ischemic stroke due to a variety of causes. Although pharmacologically induced hypertension (PIH) and anticoagulants have been investigated in several clinical trials for the treatment of END, the efficacy and safety of these treatments remain unclear. Here, we investigated whether PIH or anticoagulation is better as a rescue therapy for the progression of END in patients with lacunar stroke. METHODS: This study included patients with lacunar stroke who received rescue therapy with END within 3 days of symptom onset between April 2014 and August 2021. In the PIH group, phenylephrine was administered intravenously for 24 h and slowly tapered when symptoms improved or after 5 days of PIH. In the anticoagulation group, argatroban was administered continuously intravenously for 2 days and twice daily for next 5 days. We compared END recovery, defined as improvement in NIHSS from baseline, excellent outcomes (0 or 1 mRS at 3 months), and safety profile. RESULTS: Among the 4818 patients with the lacunar stroke, END occurred in 147 patients. Seventy-nine patients with END received PIH (46.9%) and 68 patients (46.3%) received anticoagulation therapy. There was no significant difference in age (P = 0.82) and sex (P = 0.87) between the two groups. Compared to the anticoagulation group, the PIH group had a higher incidence of END recovery (77.2% vs. 51.5%, P < 0.01) and excellent outcomes (34.2% vs. 16.2%, P = 0.04). PIH was associated with END (HR 2.49; 95% CI 1.06-5.81, P = 0.04). PIH remained associated with END recovery (adjusted HR 3.91; 95% CI 1.19-12.90, P = 0.02). Safety outcomes, like hemorrhagic conversion and mortality, were not significantly different between the two groups. CONCLUSIONS: As a rescue therapy for the progression of END in lacunar stroke patients, PIH with phenylephrine was more effective with similar safety compared to anticoagulation with argatroban.

Asunto(s)

Anticoagulantes , Accidente Vascular Cerebral Lacunar , Humanos , Masculino , Femenino , Accidente Vascular Cerebral Lacunar/tratamiento farmacológico , Anciano , Persona de Mediana Edad , Anticoagulantes/uso terapéutico , Anticoagulantes/administración & dosificación , Hipertensión/tratamiento farmacológico , Hipertensión/complicaciones , Anciano de 80 o más Años , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificación , Arginina/análogos & derivados , Arginina/uso terapéutico , Arginina/administración & dosificación , Resultado del Tratamiento , Antihipertensivos/uso terapéutico , Antihipertensivos/administración & dosificación , Estudios Retrospectivos , Progresión de la Enfermedad , Ácidos Pipecólicos

RESUMEN

BACKGROUND: We compared efficacy of vonoprazan-dual or triple therapies and bismuth-quadruple therapy for treatment-naive Helicobacter pylori (HP) infection in Southern China, where primary resistance rates of clarithromycin and levofloxacin are >30%. METHODS: This was an investigator-initiated, three-arm, randomized clinical trial in Southern China. Between March 2022 and August 2023, treatment-naïve HP-infected adults were randomly assigned to receive one of three 14-day regimens (1:1:1 ratio): vonoprazan-dual (VA-dual; vonoprazan 20 mg twice daily and amoxicillin 1 g thrice daily), vonoprazan-triple (VAC-triple; vonoprazan 20 mg/amoxicillin 1 g/clarithromycin 500 mg twice daily), or bismuth-quadruple therapy containing bismuth, esomeprazole, tetracycline, and metronidazole. Primary outcome was noninferiority in HP eradication, evaluated by UBT 4-6 weeks post-treatment by intention-to-treat (ITT) and per-protocol (PP) analysis (based on subjects who completed 14-day treatment and rechecked UBT). Bonferroni-adjusted p-value of <0.017 was used to determine statistical significance. RESULTS: A total of 298 subjects (mean age: 35.7 ± 8.4 years; male: 134 [45.0%]; VC-dual: 100, VAC-triple: 98, bismuth-quadruple: 100) were enrolled, and 292 (98.0%) had UBT rechecked. ITT analysis showed that both VA-dual (eradication rate of 96.0%) and VAC-triple therapies (95.9%) were noninferior to bismuth-quadruple therapy (92.0%) (difference: 4.0%, 95% CI: -2.9% to 11.5%, p < 0.001; and 3.9%, 95% CI: -3.1% to 11.5%, p < 0.001, respectively). PP analysis also revealed noninferiority (96.7% or 96.7% vs. 97.4%, with difference: -2.9% and -2.9%, p = 0.009 and 0.010, respectively). The frequency of adverse events was 39.0%, 56.1%, and 71.0% in VA-dual, VAC-triple, and bismuth-quadruple therapies, respectively. CONCLUSIONS: VA-dual and VA-triple therapies are highly effective and noninferior to bismuth-quadruple therapy in Southern China. Given the lower adverse effects and fewer antibiotic use, VA-dual therapy is the preferred first-line treatment for HP infection. TRIAL REGISTRATION: Chinese Clinical Trial Registry (No. ChiCTR2200056375). Registered on February 4, 2022, https://www.chictr.org.cn/showproj.aspx?proj=14131.

Asunto(s)

Antibacterianos , Bismuto , Quimioterapia Combinada , Infecciones por Helicobacter , Helicobacter pylori , Pirroles , Sulfonamidas , Humanos , Infecciones por Helicobacter/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificación , Masculino , Femenino , Persona de Mediana Edad , Adulto , Helicobacter pylori/efectos de los fármacos , Bismuto/uso terapéutico , Pirroles/uso terapéutico , Pirroles/administración & dosificación , Antibacterianos/uso terapéutico , Antibacterianos/administración & dosificación , China , Resultado del Tratamiento , Claritromicina/uso terapéutico , Amoxicilina/uso terapéutico , Amoxicilina/administración & dosificación , Metronidazol/uso terapéutico , Inhibidores de la Bomba de Protones/uso terapéutico , Adulto Joven , Esomeprazol/uso terapéutico , Esomeprazol/administración & dosificación

RESUMEN

BACKGROUND: Head-to-head data for bictegravir/emtricitabine/tenofovir alafenamide (BIC/F/TAF; B) and darunavir/cobicistat/emtricitabine/tenofovir alafenamide (DRV/c/F/TAF; D) are lacking in the context of rapid antiretroviral therapy (ART) initiation. This study, BIC-T&T, evaluates the efficacy and tolerability of B vs D in a UK test-and-treat setting. SETTING: BIC-T&T was a randomised, open-label, multi-centre, study in which participants initiated ART within 14 days after confirmed HIV-1 diagnosis before baseline laboratory. METHODS: The primary endpoint is the virological response (HIV RNA < 50copies/mL) at week 12 by time-weighted average change in log10 HIV RNA recorded in viral load assays from treatment initiation to week 12, using two-sample Wilcoxon rank-sum test. RESULTS: 36 participants were randomised: 94% were male, 53% white; mean (SD) age was 35 years (11.8). Baseline mean (±SD) log10 HIV-RNA was 4.79 (± 0.87) log10 copies/mL and CD4 505 (±253) cells/mm3. The mean (±SD) time from confirmed HIV diagnosis to ART initiation was 7.9 (± 3.7) days. The time-weighted mean decrease in log10 HIV RNA from treatment initiation to week 12 was significantly greater in B in comparison to D (3.1 vs. 2.6 log10 copies/mL, p < 0.001). Both regimens demonstrated good tolerability with infrequent laboratory abnormalities and no grade 3 or 4 adverse events. CONCLUSION: In this first head-to-head study in the context of ART initiation, HIV RNA decline from baseline to week 12 was significantly more rapid for BIC/F/TAF compared with DRV/c/F/TAF.

Asunto(s)

Fármacos Anti-VIH , Emtricitabina , Infecciones por VIH , Tenofovir , Carga Viral , Humanos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Masculino , Femenino , Adulto , Tenofovir/uso terapéutico , Tenofovir/análogos & derivados , Fármacos Anti-VIH/uso terapéutico , Carga Viral/efectos de los fármacos , Emtricitabina/uso terapéutico , VIH-1/efectos de los fármacos , VIH-1/genética , Adenina/análogos & derivados , Adenina/uso terapéutico , Piperazinas/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Darunavir/uso terapéutico , Alanina/uso terapéutico , Alanina/análogos & derivados , Resultado del Tratamiento , ARN Viral , Sulfonamidas/uso terapéutico , Persona de Mediana Edad , Cobicistat/uso terapéutico , Reino Unido , Combinación de Medicamentos , Amidas , Piridonas

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica , Compuestos Bicíclicos Heterocíclicos con Puentes , Leucemia Linfocítica Crónica de Células B , Sulfonamidas , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/administración & dosificación , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Resultado del Tratamiento

RESUMEN

OBJECTIVE: The aim of this study was to evaluate the effectiveness and safety of the nine most widely studied Vonoprazan (VPZ)-based treatment regimens along with traditional Proton pump inhibitor (PPI)-based treatment regimens in eradicating Helicobacter pylori (H. pylori) infection. DESIGN: Through searching PubMed, Embase, Cochrane Library, Web of Science, we exclusively included randomized controlled trials (RCTs) to investigate the efficacy of VPZ-based and PPI-based therapies for H. pylori infection. The included studies were evaluated for methodological quality using the Cochrane bias risk assessment tool, and the data analysis software was used to analyze the data accordingly. RESULTS: The RCTs were collected from the earliest available date up to August 2023. Twenty-one RCTs were included, with a total sample size of 5481. The results of the network meta-analysis showed that the eradication rate of the VPZ-based quadruple 14-day (VPZ-Q14) treatment regimen in Intention-to-treat (ITT) analysis was the highest (SUCRA: 0.874); The eradication rate of the VPZ-based quadruple 10-day (VPZ-Q10) treatment plan in Per-protocol (PP) analysis was the highest (SUCRA: 0.849). All regimens were well tolerated without significant differences. According to the probability ranking of safety, high-dose VPZ-based dual 14-day therapy (H-VPZ-D14) ranked first in SUCRA, reaching 0.952. This indicates that H-VPZ-D14 treatment is the safest with a relatively low incidence of adverse effect. Therefore, VPZ-based therapies not only have a higher eradication rate, but also possess satisfactory safety. CONCLUSION: Compared with traditional PPI-based therapies, VPZ-based therapies have shown superior eradication effects. Based on the Ranking Plot of the Network, the VPZ-Q14 or VPZ-Q10 treatment regimen for H. pylori has a higher eradication rate and acceptable differences compared to other treatment regimens. In addition, for regions with high antibiotic resistance rates, we recommend a 14-day quadruple therapy with bismuth based on VPZ.

Asunto(s)

Quimioterapia Combinada , Infecciones por Helicobacter , Helicobacter pylori , Metaanálisis en Red , Inhibidores de la Bomba de Protones , Pirroles , Sulfonamidas , Humanos , Infecciones por Helicobacter/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Pirroles/uso terapéutico , Pirroles/efectos adversos , Pirroles/administración & dosificación , Inhibidores de la Bomba de Protones/uso terapéutico , Inhibidores de la Bomba de Protones/administración & dosificación , Inhibidores de la Bomba de Protones/efectos adversos , Helicobacter pylori/efectos de los fármacos , Antibacterianos/uso terapéutico , Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Resultado del Tratamiento , Ensayos Clínicos Controlados Aleatorios como Asunto

RESUMEN

INTRODUCTION: Acute promyelocytic leukemia (APL) is mainly due to the chromosome translocation t(15; 17) (q22; q12), leading to the formation of PML-RARα fusion protein. However, some patients carried rare translocation involving RARα gene, and they were referred to as variant APL caused by the RAR family (RARα, RARB, and RARG) and partner genes. PLZF-RARα was a rare type of molecular genetic abnormality with unfavorable prognosis that has been reported in few cases in variant APL. Knowledge of PLZF-RARα (+) APL treatment remains limited understood. CASE REPORT: We presented a case of variant APL in a 47-year-old female, who was PLZF-RARα positive detected by reverse transcription polymerase chain reaction (RT-PCR). The patient did not respond to all-trans retinoic acid (ATRA), idarubicin, and arsenic trioxide (As2O3) combined induction chemotherapy. Then, the patient was treated with Venetoclax combining with decitabine as the salvage therapy and achieved morphological remission and PLZF/RARα gene negative. CONCLUSION: Venetoclax combining with decitabine can be used as an effective therapy in the PLZF-RARα positive APL.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica , Compuestos Bicíclicos Heterocíclicos con Puentes , Decitabina , Leucemia Promielocítica Aguda , Proteínas de Fusión Oncogénica , Sulfonamidas , Humanos , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/genética , Femenino , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/genética , Decitabina/uso terapéutico , Decitabina/administración & dosificación , Sulfonamidas/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Azacitidina/uso terapéutico

Asunto(s)

Compuestos Bicíclicos Heterocíclicos con Puentes , Leucemia Mieloide Aguda , Sulfonamidas , Humanos , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Sulfonamidas/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Adulto , Infecciones/mortalidad , Infecciones/etiología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Pronóstico , Neoplasias Primarias Secundarias/mortalidad , Neoplasias Primarias Secundarias/tratamiento farmacológico , Tasa de Supervivencia , Anciano de 80 o más Años

Asunto(s)

Antivirales , Tratamiento Farmacológico de COVID-19 , Combinación de Medicamentos , Hospitalización , Huésped Inmunocomprometido , Ritonavir , Humanos , Ritonavir/uso terapéutico , Ritonavir/administración & dosificación , Hospitalización/estadística & datos numéricos , Antivirales/uso terapéutico , Antivirales/administración & dosificación , Citidina/análogos & derivados , Citidina/uso terapéutico , Hidroxilaminas/uso terapéutico , Leucina/análogos & derivados , Leucina/uso terapéutico , Prolina/análogos & derivados , Prolina/uso terapéutico , Sulfonamidas/administración & dosificación , Sulfonamidas/uso terapéutico , COVID-19/prevención & control , Lactamas , Nitrilos

RESUMEN

BACKGROUND: We previously optimized the duration and dose of vonoprazan and amoxicillin dual therapy in China. The efficacy of vonoprazan with b.i.d. amoxicillin in comparison with vonoprazan-containing quadruple therapy as the first-line treatment of Helicobacter pylori infection has not been adequately evaluated. METHODS: In a non-inferiority, randomized clinical trial, H. pylori infected and treatment-naïve patients were randomly assigned to receive 14 days of either vonoprazan dual (vonoprazan 20 mg and amoxicillin 1 g twice daily) or quadruple therapy (vonoprazan 20 mg + amoxicillin 1 g + furazolidone 100 mg + bismuth potassium citrate 600 mg twice daily). H. pylori status was confirmed using 13C-urea breath tests or fecal antigen test. The primary outcome was the H. pylori eradication rate following vonoprazan dual and quadruple therapy at 4-12 weeks. We also compared drug compliance to either regimen and documented their side effect. RESULTS: A total of 190 subjects were randomized. The eradication rate of vonoprazan dual and quadruple therapy were 87.4% and 92.6% (p = 0.23) by intention-to-treat analysis, respectively, and 96.5% and 97.7% (p = 0.63) by per-protocol analysis, respectively. The efficacy of vonoprazan dual therapy was non-inferior to vonoprazan-containing quadruple therapy in per-protocol analysis (p < 0.001; difference: -1.2%; 90% confidence interval: -5.4% to 3.0%). CONCLUSION: Vonoprazan with b.i.d. amoxicillin for 14 days provided similar satisfactory efficacy with vonoprazan-containing quadruple therapy as a first-line H. pylori treatment in China.

Asunto(s)

Amoxicilina , Antibacterianos , Quimioterapia Combinada , Infecciones por Helicobacter , Helicobacter pylori , Pirroles , Sulfonamidas , Humanos , Infecciones por Helicobacter/tratamiento farmacológico , Pirroles/uso terapéutico , Pirroles/administración & dosificación , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificación , Amoxicilina/uso terapéutico , Amoxicilina/administración & dosificación , Femenino , Persona de Mediana Edad , Masculino , Helicobacter pylori/efectos de los fármacos , Antibacterianos/uso terapéutico , Antibacterianos/administración & dosificación , Adulto , Resultado del Tratamiento , China , Anciano , Inhibidores de la Bomba de Protones/uso terapéutico , Inhibidores de la Bomba de Protones/administración & dosificación

Asunto(s)

Adalimumab , Proteínas Proto-Oncogénicas B-raf , Síndrome Uveomeningoencefálico , Humanos , Adalimumab/uso terapéutico , Adalimumab/efectos adversos , Síndrome Uveomeningoencefálico/tratamiento farmacológico , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Resistencia a Medicamentos , Femenino , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Masculino , Antiinflamatorios/uso terapéutico , Antiinflamatorios/efectos adversos , Persona de Mediana Edad , Sulfonamidas/uso terapéutico , Sulfonamidas/efectos adversos

RESUMEN

Cardiac fibrosis is characterized by the over-proliferation, over-transdifferentiation and over-deposition of extracellular matrix (ECM) of cardiac fibroblasts (CFs). Cardiac sympathetic activation is one of the leading causes of myocardial fibrosis. Meanwhile, cardiac fibrosis is often together with cardiac inflammation, which accelerates fibrosis by mediating inflammatory cytokines secretion. Recently, the Janus kinase/signal transducer and activator of transcription (JAK/STAT3) signaling pathway has been confirmed by its vital role during the progression of cardiac fibrosis. Thus, JAK/STAT3 signaling pathway is thought to be a potential therapeutic target for cardiac fibrosis. Baricitinib (BR), a novel JAK1/2 inhibitor, has been reported excellent effects of anti-fibrosis in multiple fibrotic diseases. However, little is known about whether and how BR ameliorates cardiac fibrosis caused by chronic sympathetic activation. Isoproterenol (ISO), a ß-Adrenergic receptor (ß-AR) nonselective agonist, was used to modulate chronic sympathetic activation in mice. As expected, our results proved that BR ameliorated ISO-induced cardiac dysfunction. Meanwhile, BR attenuated ISO-induced cardiac fibrosis and cardiac inflammation in mice. Moreover, BR also inhibited ISO-induced cardiac fibroblasts activation and macrophages pro-inflammatory secretion. As for mechanism studies, BR reduced ISO-induced cardiac fibroblasts by JAK2/STAT3 and PI3K/Akt signaling, while reduced ISO-induced macrophages pro-inflammatory secretion by JAK1/STAT3 and NF-κB signaling. In summary, BR alleviates cardiac fibrosis and inflammation caused by chronic sympathetic activation. The underlying mechanism involves BR-mediated suppression of JAK1/2/STAT3, PI3K/Akt and NF-κB signaling.

Asunto(s)

Azetidinas , Fibroblastos , Fibrosis , Ratones Endogámicos C57BL , Purinas , Pirazoles , Sulfonamidas , Animales , Fibrosis/tratamiento farmacológico , Azetidinas/farmacología , Azetidinas/uso terapéutico , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Masculino , Fibroblastos/efectos de los fármacos , Purinas/farmacología , Purinas/uso terapéutico , Pirazoles/farmacología , Pirazoles/uso terapéutico , Ratones , Transducción de Señal/efectos de los fármacos , Factor de Transcripción STAT3/metabolismo , Miocardio/patología , Isoproterenol , Células Cultivadas , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , FN-kappa B/metabolismo , Inflamación/tratamiento farmacológico , Citocinas/metabolismo , Humanos , Sistema Nervioso Simpático/efectos de los fármacos

RESUMEN

This study aimed to examine the relationship between blood pressure (BP) and blood pressure variability (BPV) during the first 24 hours from admission with 90-day functional outcomes in acute ischemic stroke (AIS) patients whose onset within 24 hours and receiving early argatroban treatment. The study recruited 214 AIS patients. BP was monitored using a cuff at 1-hour fixed intervals, and BP/BPV parameters [standard deviation (SD), coefficient of variation (CV), successive variation (SV), and average real variability (ARV)] were collected. Age, the National Institutes of Health Stroke Scale (NIHSS) score at admission, previous history of diabetes mellitus (DM), and infarction site (located in anterior circulation) were identified as independent factors affecting 90-day outcomes in multiple logistic regression. After adjusting for confounding variables, association between BP/BPV and 90-day modified Rankin Scale (mRS) was assessed using logistic regression models. In model 1 (adjusted for age and NIHSS score at admission), mean-systolic blood pressure (SBP) showed association with 90-day outcomes [1.068 (1.008, 1.131), P = .025]. In model 2 (adjusted for age, NIHSS score at admission, previous history of DM), mean-SBP [1.061 (1.001, 1.123), P = .045] and max-SBP [0.951 (0.906, 0.998), P = .040] showed relatively weak association with outcomes. In model 3 [adjusted for age, NIHSS score at admission, previous history of DM, infarct site (located in anterior circulation)], all BP values were not related with outcomes, meanwhile, none of the BPV parameters calculated from SBP, diastolic blood pressure and mean arterial pressure showed association with 90-day outcomes. Future prospective studies are required to assess the relationship between early BP/BPV parameters with 90-day outcomes and further clarify the reference values for BP parameters. This is important for effective BP/BPV management and improved patient prognosis.

Asunto(s)

Presión Sanguínea , Accidente Cerebrovascular Isquémico , Humanos , Femenino , Masculino , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Anciano , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/fisiopatología , Persona de Mediana Edad , Anticoagulantes/uso terapéutico , Anticoagulantes/administración & dosificación , Resultado del Tratamiento , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificación , Arginina/análogos & derivados , Ácidos Pipecólicos

RESUMEN

INTRODUCTION: Pharmacotherapy against hepatitis C virus (HCV) infection has tremendously improved since the advent of interferon (IFN)-free direct-acting antivirals (DAAs). Additionally, fixed-dose pangenotypic DAAs, which are safe, potent, easy for use, and can cover a wide spectrum of patients, have been recommended by professional guidelines for DAA-naïve and DAA-experienced patients with HCV. AREAS COVERED: We review the pharmacokinetics, pharmacodynamics, and potential drug-drug interactions (DDIs) of fixed-dose pangenotypic DAA regimens, including glecaprevir/pibrentasvir (GLE/PIB), sofosbuvir/velpatasvir (SOF/VEL), and sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX). Additionally, we summarize the efficacy and safety of these regimens in clinical trials as well as real-world studies for treating different populations. Lastly, we discuss unmet medical needs in managing HCV in the era of fixed-dose pangenotypic DAAs. EXPERT OPINION: Protease inhibitors (PIs), including GLE and VOX, are prone to have more frequent DDIs, compared to the non-structural (NS) 5A and 5B inhibitors. These regimens are generally well tolerated and can be applied to different populations, except for the contraindicated use of PI-containing DAA regimens in decompensated cirrhosis. Using the first-line GLE/PIB and SOF/VEL can eradicate HCV in more than 95% of DAA-naïve patients across different populations. The viral cure usually exceeds 95% when using the rescue SOF/VEL/VOX regimen for prior DAA failures.

Asunto(s)

Antivirales , Interacciones Farmacológicas , Humanos , Antivirales/uso terapéutico , Antivirales/efectos adversos , Antivirales/farmacocinética , Antivirales/farmacología , Antivirales/administración & dosificación , Hepatitis C/tratamiento farmacológico , Hepatitis C/virología , Combinación de Medicamentos , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Bencimidazoles/uso terapéutico , Bencimidazoles/farmacología , Sulfonamidas/uso terapéutico , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Pirrolidinas/uso terapéutico

RESUMEN

PURPOSE OF REVIEW: To analyze the efficacy and safety of Janus kinase inhibitors (JAKi) in the treatment of pediatric AD. RECENT FINDINGS: Adolescents with moderate and severe atopic dermatitis (AD) need systemic therapies, as stated several recent practice guidelines. (JAKi) have shown their efficacy in the treatment of adult AD, however, there is a lack of information concerning efficacy and safety of their use in pediatric AD. We found that the JAKi's abrocitinib (ABRO), baricitinib (BARI), and upadacitinib (UPA), are all an effective treatment option with a very fast onset of action for adolescents with moderate-to-severe AD. BARI was not effective in children between 2 and 10 years with moderate-to-severe AD. Fortunately, major safety issues with JAKi in adolescents with AD have not been documented in the trials, so far, contrasting with the reports in adults with AD, where these events have very rarely occurred. There are some reports of herpes zoster (HZ) infection in adolescents on JAKi, but it is not a major safety concern. Acne is a relatively common AE with UPA in adolescents; however, it is responsive to standard treatment. This review will help the clinician to choose among the JAKi according to the needs and clinical features of patients with moderate and severe AD. In the following years, with the advent of new biologicals and JAKi, these therapies will fall into place in each phase of the evolution of patients with AD.

Asunto(s)

Dermatitis Atópica , Inhibidores de las Cinasas Janus , Humanos , Dermatitis Atópica/tratamiento farmacológico , Inhibidores de las Cinasas Janus/uso terapéutico , Inhibidores de las Cinasas Janus/efectos adversos , Inhibidores de las Cinasas Janus/administración & dosificación , Niño , Adolescente , Purinas/uso terapéutico , Administración Oral , Azetidinas/uso terapéutico , Azetidinas/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Pirazoles/uso terapéutico , Pirazoles/administración & dosificación , Pirimidinas/uso terapéutico , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificación , Resultado del Tratamiento

Asunto(s)

Adenina , Protocolos de Quimioterapia Combinada Antineoplásica , Compuestos Bicíclicos Heterocíclicos con Puentes , Linfoma de Células del Manto , Piperidinas , Sulfonamidas , Humanos , Adenina/análogos & derivados , Piperidinas/uso terapéutico , Piperidinas/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/patología , Pirimidinas/uso terapéutico , Pirimidinas/administración & dosificación , Pirazoles/uso terapéutico , Pirazoles/administración & dosificación

RESUMEN

INTRODUCTION: Primary pulmonary angiosarcoma (PPA) is a highly aggressive and rare malignancy originating from the endothelial cells of blood vessels in the lungs. PPA is an extremely rare subtype, with less than 30 cases reported to date. PPA is not only challenging to diagnose but also has a poor prognosis, often resulting in a high mortality rate within a year of diagnosis, regardless of the treatment approach. METHOD: We present the case of a 33-year-old woman with no significant past medical history who presented with abdominal pain and was incidentally found to have a right hilar mass with pleural effusion and empyema. After undergoing surgery for a perforated gastric ulcer, her pulmonary lesions were further worked up. Despite an extensive diagnostic evaluation, including imaging, bronchoscopy, and thoracotomy, establishing a diagnosis was challenging. Ultimately, PPA was diagnosed on surgical lung biopsy, and the patient was started on pazopanib and paclitaxel chemotherapy but expired after 1 month due to multiple complications. CONCLUSION: This case highlights the difficulty in diagnosing this rare tumor and its poor prognosis regardless of therapy. Greater awareness of PPA and more research are needed to improve early detection and treatment options for this deadly disease.

Asunto(s)

Hemangiosarcoma , Hallazgos Incidentales , Neoplasias Pulmonares , Humanos , Hemangiosarcoma/diagnóstico , Hemangiosarcoma/complicaciones , Hemangiosarcoma/patología , Femenino , Adulto , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patología , Resultado Fatal , Tomografía Computarizada por Rayos X/métodos , Broncoscopía/métodos , Pirimidinas/uso terapéutico , Indazoles , Biopsia , Sulfonamidas/uso terapéutico , Paclitaxel/uso terapéutico , Paclitaxel/administración & dosificación

RESUMEN

BACKGROUND: Genetic variants of UGT1A1, involved in glucuronidation and clearance of bilirubin, are associated with reduced bilirubin metabolization and drug-induced isolated hyperbilirubinemia. We studied the impact of the UGT1A1*28 polymorphism on drug-induced isolated hyperbilirubinemia in metastatic renal cell carcinoma patients treated with pazopanib, cabozantinib, and axitinib. METHODS: We genotyped the UGT1A1*28 TA6/TA6-TA6/TA7-TA7/TA7 polymorphism and correlated with median baseline, on-treatment and peak bilirubin levels during therapy, incidence of grade-1- or -2 (G1/2)-hyperbilirubinemia and time-to-G1-hyperbilirubinemia. RESULTS: Of the 66 patients treated with pazopanib, 29 received axitinib and 28 cabozantinib upon progression. Median baseline bilirubin was higher in TA7/TA7-carriers versus TA6/TA6+TA6/TA7-carriers at start of pazopanib (P < .0001), cabozantinib (P < .0001), and axitinib (P = .007). During pazopanib therapy, median bilirubin increased 1.4-fold in TA7/TA7+TA6/TA7-carriers but not in TA6/TA6-carriers. On cabozantinib, bilirubin increased 1.5-fold in TA7/TA7-carriers but not in TA6/TA6+TA6/TA7-carriers. Axitinib did not increase bilirubin in any genotype. Peak bilirubin in TA7/TA7- versus TA6/TA6+TA6/TA7-carriers was higher on pazopanib (P < .0001) or cabozantinib (P < .0001). With pazopanib, G1-hyperbilirubinemia occurred in 57% of TA7/TA7- and 12% of TA6/TA6+TA6/TA7-carriers (P = .0009) and G2-hyperbilirubinemia in 36% and 6% of the patients, respectively (P = .004). On cabozantinib, G1-hyperbilirubinemia occurred in 100% of TA7/TA7- and 5% of TA6/TA6+TA6/TA7-carriers (P < .0001) and G2-hyperbilirubinemia in 33% and 0% of the patients, respectively (P = .04). On axitinib, no correlation between the genotypes and G1/2-hyperbilirubinemia was observed. CONCLUSION: We validate the previously described impact of the UGT1A1*28 polymorphism on isolated bilirubin increase on pazopanib. We report for the first time that cabozantinib also interferes with UGT1A1 and causes isolated bilirubin increase.

Asunto(s)

Anilidas , Carcinoma de Células Renales , Glucuronosiltransferasa , Hiperbilirrubinemia , Indazoles , Neoplasias Renales , Piridinas , Pirimidinas , Sulfonamidas , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Glucuronosiltransferasa/genética , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Neoplasias Renales/patología , Masculino , Femenino , Persona de Mediana Edad , Hiperbilirrubinemia/inducido químicamente , Hiperbilirrubinemia/genética , Piridinas/uso terapéutico , Piridinas/efectos adversos , Anilidas/uso terapéutico , Anilidas/efectos adversos , Sulfonamidas/efectos adversos , Sulfonamidas/uso terapéutico , Indazoles/uso terapéutico , Anciano , Pirimidinas/uso terapéutico , Pirimidinas/efectos adversos , Axitinib/uso terapéutico , Axitinib/efectos adversos , Axitinib/administración & dosificación , Bilirrubina/sangre , Genotipo , Adulto , Polimorfismo Genético , Anciano de 80 o más Años

RESUMEN

The FMS-related tyrosine kinase 3 (FLT3) inhibitor gilteritinib is standard therapy for relapsed/refractory (R/R) FLT3-mutated (FLT3mut) acute myeloid leukemia (AML) but the overall survival (OS) is only approximately 20 % and few patients achieve deep and/ or durable response. We retrospectively analyzed 29 R/R FLT3mut AML patients treated on triplet regimens (gilteritinib+ venetoclaxï¼»VEN] +azacitidineï¼»AZA]). Nineteen patients (65.5 %) had received prior FLT3 inhibitor therapy. The modified composite complete remission (mCRc) rate was 62.1 % (n = 18; CR, 4/29,13.8 %; CRi, 6/29, 20.7 %; MLFS, 8/29, 27.6 %). Among 18 patients achieved mCRc, FLT3-PCR negativity was 94.4 % (n=17), and flow-cytometry negativity was 77.7 % (n=14). The mCRc rate was 70 % (n=7) in 10 patients without prior FLT3 TKI exposure and 57.8 % (n=11) in 19 patients with prior FLT3 TKI exposure (P=0.52). At the end of the first cycle, the median time to ANC > 0.5× 109/L was 38 days and platelet > 50× 109/L was 31 days among responders, but 60-day mortality was 0 %. The estimated 2-year OS was 60.9 % for all R/R FLT3mut patients. The 1-year OS was 80 % and 58.8 % in patients without and with prior FLT3 TKI exposure, respectively (P=0.79). The estimated 2-year OS was 62 % in 19 (65.5 %) patients who received allo-HSCT after triplet therapy and 37 % in 10 patients who did not receive allo-HSCT (P=0.03). In conclusion, triplet therapy with gilteritinib, VEN, and AZA is effective and safe and an excellent frontline option for R/R FLT3mut AML.

Asunto(s)

Compuestos de Anilina , Protocolos de Quimioterapia Combinada Antineoplásica , Azacitidina , Compuestos Bicíclicos Heterocíclicos con Puentes , Leucemia Mieloide Aguda , Pirazinas , Sulfonamidas , Tirosina Quinasa 3 Similar a fms , Humanos , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Masculino , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/genética , Femenino , Persona de Mediana Edad , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificación , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Estudios Retrospectivos , Compuestos de Anilina/uso terapéutico , Adulto , Pirazinas/uso terapéutico , Pirazinas/administración & dosificación , Azacitidina/uso terapéutico , Azacitidina/administración & dosificación , Mutación , Tiofenos/uso terapéutico , Tiofenos/administración & dosificación , Resistencia a Antineoplásicos

RESUMEN

This mini-review presents our current understanding of serotonin type 7 receptor research focusing on the possible network mechanisms underlying the behavioral action of receptor antagonists. The serotonin type 7 receptor is expressed widely throughout the nervous system and known to be involved in various cognitive and physiological mechanisms. It became a clinically significant target after the discovery that its selective antagonist SB 269970 can exert rapid-onset antidepressant effects either alone or in combination with lower doses of conventional antidepressant drugs. Further research has shown that administration of SB 269970 can effectively counteract negative neurobiological outcomes in various chronic stress paradigms. The authors hope they can introduce a wider scientific audience to this promising pharmacological target which, if successful, could in time lead to more discoveries and a better understanding of the underlying serotonin receptor biology as well as its clinical potential. HIGHLIGHTS.

Asunto(s)

Antagonistas de la Serotonina , Estrés Psicológico , Animales , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/metabolismo , Antagonistas de la Serotonina/uso terapéutico , Antagonistas de la Serotonina/farmacología , Humanos , Antidepresivos/uso terapéutico , Antidepresivos/farmacología , Enfermedad Crónica , Sulfonamidas/uso terapéutico , Sulfonamidas/farmacología , Modelos Animales de Enfermedad

RESUMEN

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by the accumulation of malignant myeloid progenitor hematopoietic cells in the bone marrow and peripheral blood. Recent studies have shown promising results with the use of small molecule inhibitors and targeted therapy in the treatment of patients with AML. One such molecule is venetoclax, which has been approved in AML by the FDA in combination with hypomethylating agents or low-dose cytarabine. We thoroughly searched electronic literature related to venetoclax and its role in AML, using databases such as MEDLINE, PubMed, Google Scholar, and PsychInfo, through April 2024. We applied population, intervention, comparison, and outcome criteria, specifically focusing on studies with a population using venetoclax from review articles and clinical trials. All selected studies were required to be in English, and any study that did not involve the use of venetoclax was excluded. A meticulous literature review was conducted to consolidate the current knowledge and new combination therapies on AML. In our review article, we focused on the latest advances in the treatment of patients with AML. Based on the literature, we recommend that physicians prioritize the use of venetoclax in the management of this deadly disease because it has been shown to significantly impact the course of the disease.

Asunto(s)

Compuestos Bicíclicos Heterocíclicos con Puentes , Leucemia Mieloide Aguda , Sulfonamidas , Humanos , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Sulfonamidas/uso terapéutico