Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.568
Filtrar
Más filtros

Intervalo de año de publicación
1.
Ann Oncol ; 35(8): 718-727, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38729566

RESUMEN

BACKGROUND: In MONARCH 2, the addition of abemaciclib to fulvestrant significantly improved both progression-free survival (PFS) and overall survival (OS) in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) with disease progression on prior endocrine therapy. In MONARCH 3, the addition of abemaciclib to a nonsteroidal aromatase inhibitor (NSAI) as initial therapy for HR+, HER2- ABC significantly improved PFS. Here, we present the prespecified final OS results for MONARCH 3. PATIENTS AND METHODS: MONARCH 3 is a randomized, double-blind, phase III study of abemaciclib plus NSAI (anastrozole or letrozole) versus placebo plus NSAI in postmenopausal women with HR+, HER2- ABC without prior systemic therapy in the advanced setting. The primary objective was investigator-assessed PFS; OS was a gated secondary endpoint, and chemotherapy-free survival was an exploratory endpoint. RESULTS: A total of 493 women were randomized 2 : 1 to receive abemaciclib plus NSAI (n = 328) or placebo plus NSAI (n = 165). After a median follow-up of 8.1 years, there were 198 OS events (60.4%) in the abemaciclib arm and 116 (70.3%) in the placebo arm (hazard ratio, 0.804; 95% confidence interval 0.637-1.015; P = 0.0664, non-significant). Median OS was 66.8 versus 53.7 months for abemaciclib versus placebo. In the subgroup with visceral disease, there were 113 OS events (65.3%) in the abemaciclib arm and 65 (72.2%) in the placebo arm (hazard ratio, 0.758; 95% confidence interval 0.558-1.030; P = 0.0757, non-significant). Median OS was 63.7 months versus 48.8 months for abemaciclib versus placebo. The previously demonstrated PFS benefit was sustained, and chemotherapy-free survival numerically improved with the addition of abemaciclib. No new safety signals were observed. CONCLUSIONS: Abemaciclib combined with an NSAI resulted in clinically meaningful improvement in median OS (intent-to-treat population: 13.1 months; subgroup with visceral disease: 14.9 months) in patients with HR+ HER2- ABC; however, statistical significance was not reached.


Asunto(s)
Aminopiridinas , Protocolos de Quimioterapia Combinada Antineoplásica , Inhibidores de la Aromatasa , Bencimidazoles , Neoplasias de la Mama , Letrozol , Receptor ErbB-2 , Receptores de Estrógenos , Receptores de Progesterona , Humanos , Femenino , Aminopiridinas/administración & dosificación , Aminopiridinas/uso terapéutico , Bencimidazoles/administración & dosificación , Bencimidazoles/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/mortalidad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Receptor ErbB-2/metabolismo , Receptor ErbB-2/antagonistas & inhibidores , Método Doble Ciego , Letrozol/administración & dosificación , Letrozol/uso terapéutico , Inhibidores de la Aromatasa/uso terapéutico , Inhibidores de la Aromatasa/administración & dosificación , Persona de Mediana Edad , Anciano , Receptores de Progesterona/metabolismo , Receptores de Estrógenos/metabolismo , Anastrozol/uso terapéutico , Anastrozol/administración & dosificación , Adulto , Anciano de 80 o más Años , Supervivencia sin Progresión
2.
J Viral Hepat ; 31(7): 409-415, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38654438

RESUMEN

Glecaprevir/pibrentasvir (GLE/PIB) is an approved guideline-recommended chronic hepatitis C virus infection treatment. GLE/PIB coadministration with ethinyl oestradiol (EE) is not recommended in current labels owing to a Phase 1 study observing Grade ≥2 alanine aminotransferase (ALT) elevation in 2 out of 12 healthy women cotreated for 11 days with GLE/PIB and oral contraceptive (OC) containing 35 µg/250 µg EE/norgestimate. No Grade ≥2 elevation was observed with low-dose (20 µg) EE (n = 14). This Phase 1 study examined safety/tolerability of GLE/PIB coadministered with an OC containing low-dose EE using a larger sample size and longer treatment duration. Healthy premenopausal women were treated with EE/levonorgestrel alone (20/100 µg, Cycles 1-2), followed by coadministration with GLE/PIB (300/120 mg; Cycles 3-4). A safety criterion of special interest was a confirmed Grade ≥2 ALT elevation (>3× upper normal limit). Adverse events (AEs) and study drugs concentrations were examined. Of 85 enrolled women, 72 initiated combined GLE/PIB + EE/levonorgestrel treatment, 66 completed the study and 19 discontinued prematurely (non-safety reason, n = 16; AE [deemed unelated to GLE/PIB], n = 3). No participant met the safety criterion of special interest of confirmed Grade ≥2 ALT elevation. No serious/Grade ≥3 AEs were reported. Study drug concentrations were within the expected ranges. GLE/PIB in combination with an OC containing low-dose EE was generally well tolerated with no confirmed Grade ≥2 ALT elevation and no evidence of drug-induced liver injury. No pattern to the reported AEs and no new safety issues were identified. This was a Phase 1 study of healthy volunteers, not a registered clinical trial.


Asunto(s)
Antivirales , Bencimidazoles , Etinilestradiol , Voluntarios Sanos , Premenopausia , Pirrolidinas , Quinoxalinas , Sulfonamidas , Humanos , Femenino , Adulto , Bencimidazoles/efectos adversos , Bencimidazoles/administración & dosificación , Quinoxalinas/efectos adversos , Quinoxalinas/administración & dosificación , Etinilestradiol/efectos adversos , Etinilestradiol/administración & dosificación , Sulfonamidas/efectos adversos , Sulfonamidas/administración & dosificación , Antivirales/efectos adversos , Antivirales/administración & dosificación , Antivirales/uso terapéutico , Adulto Joven , Pirrolidinas/efectos adversos , Pirrolidinas/administración & dosificación , Persona de Mediana Edad , Anticonceptivos Orales/efectos adversos , Anticonceptivos Orales/administración & dosificación , Alanina Transaminasa/sangre , Ácidos Aminoisobutíricos , Leucina/análogos & derivados , Leucina/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Combinación de Medicamentos
3.
Rheumatology (Oxford) ; 63(9): 2372-2378, 2024 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-38796688

RESUMEN

OBJECTIVE: This study aimed to assess the efficacy and safety of intravenous ramosetron for pain relief in patients with fibromyalgia (FM) unresponsive to conventional treatments. METHODS: In this prospective, double-blind, placebo-controlled trial, 80 FM patients were randomly allocated to receive either placebo (n = 40) or ramosetron (n = 40) at a dosage of 0.3 mg/day intravenously for five consecutive days. The primary outcome was the reduction in pain intensity at the end of the treatment period, evaluated using a visual analogue scale (VAS). Secondary outcome measures included the FM Impact Questionnaire, Beck Depression Inventory (BDI), Multi-Dimensional Health Assessment Questionnaire (MDHAQ), EQ-5D and State-Trait Anxiety Inventory on days 5 (end of treatment), 7, 10 and 28. Safety was continuously monitored throughout the study. RESULTS: At the end of the treatment phase, the ramosetron group demonstrated a significantly greater reduction in VAS pain scores compared with the placebo group (1.18 ± 1.60 vs 0.54 ± 1.59, P < 0.05). Additionally, the ramosetron group exhibited significant improvements in BDI (4.42 ± 5.18 vs 1.33 ± 4.87, P < 0.05) and MDHAQ pain scale (0.37 ± 0.74 vs 0.04 ± 0.52, P < 0.05) scores. However, these improvements in pain VAS and BDI scores were not sustained through day 28. The safety profile of ramosetron was favorable, with gastrointestinal symptoms, particularly constipation, being the most commonly reported adverse events. CONCLUSIONS: Intravenous administration of ramosetron provided safe and effective short-term relief of pain intensity in FM patients with inadequate response to standard treatments.


Asunto(s)
Bencimidazoles , Fibromialgia , Dimensión del Dolor , Humanos , Método Doble Ciego , Femenino , Fibromialgia/tratamiento farmacológico , Bencimidazoles/uso terapéutico , Bencimidazoles/administración & dosificación , Bencimidazoles/efectos adversos , Persona de Mediana Edad , Adulto , Masculino , Resultado del Tratamiento , Estudios Prospectivos
4.
Invest New Drugs ; 42(3): 241-251, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38483782

RESUMEN

MEK inhibitors have immunomodulatory activity and potential for synergistic activity when combined with PD-1 inhibitors. We evaluated selumetinib (inhibitor of MEK1/2) plus pembrolizumab (anti‒PD-1 antibody) in patients with advanced/metastatic solid tumors. In this phase 1b study, adults with previously treated advanced/metastatic solid tumors received pembrolizumab 200 mg intravenously every 3 weeks plus selumetinib on days 1‒14 per 3-week cycle (2 weeks on/1 week off); selumetinib dosing began at 50 mg orally twice daily with escalation in 25 mg increments for ≤ 35 cycles. Primary endpoints were dose-limiting toxicities (DLTs), adverse events (AEs), and treatment discontinuations due to AEs. Thirty-two patients were enrolled. Dose escalation was completed up to selumetinib 125 mg twice daily. The target DLT rate of 30% was not reached at any dose level. In the selumetinib 100 mg group, 2/11 patients (18.2%) experienced DLTs (n = 1 grade 3 diarrhea, n = 1 grade 3 fatigue). In the selumetinib 125 mg group, 3/14 (21.4%) experienced DLTs (n = 1 grade 2 retinal detachment, n = 1 grade 3 retinopathy, n = 1 grade 3 stomatitis). Dose-related changes in pharmacokinetic exposures were observed for selumetinib and N-desmethyl selumetinib up to 100 mg (saturation at 125 mg). Two patients achieved partial responses (1 each with selumetinib 75 mg and 125 mg) for an objective response rate of 6%. The study was stopped early because of insufficient efficacy. Although the target DLT rate was not reached at any dose level and no new safety signals were identified, selumetinib plus pembrolizumab had limited antitumor activity in this population. Trial registration: ClinicalTrials.gov , NCT03833427.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Bencimidazoles , Neoplasias , Humanos , Bencimidazoles/administración & dosificación , Bencimidazoles/farmacocinética , Bencimidazoles/uso terapéutico , Bencimidazoles/efectos adversos , Femenino , Masculino , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Monoclonales Humanizados/uso terapéutico , Persona de Mediana Edad , Anciano , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Adulto , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Dosis Máxima Tolerada , Relación Dosis-Respuesta a Droga , Anciano de 80 o más Años
5.
Future Oncol ; 20(29): 2179-2188, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38861285

RESUMEN

Aim: To understand the real-world use of abemaciclib in Japanese patients with early breast cancer (EBC).Methods: This retrospective observational study was conducted using a Japanese administrative claims database in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative EBC who received abemaciclib adjuvant therapy from December 2021-March 2023. Patient characteristics and treatment patterns were summarized.Results: Among 374 patients, 38.2, 51.6 and 63.4% patients received neoadjuvant chemotherapy, adjuvant chemotherapy and radiotherapy, respectively; 13.1% were chemotherapy naive. Tamoxifen (37.7%), letrozole (35.6%), anastrozole (24.3%) were the commonly prescribed concomitant adjuvant endocrine therapies. Abemaciclib dose reductions were observed in 42.0% patients.Conclusion: Use of abemaciclib for treatment of high-risk EBC was described, which could help inform patient selection and treatment patterns.


Abemaciclib (150 mg twice daily) is prescribed with hormonal therapy for the treatment of early breast cancer (EBC) with high risk of recurrence. We used a big database from Japan that has anonymized information about 44 million patients from 480 hospitals. We aim to describe the characteristics of patients with EBC who receive abemaciclib and their treatment patterns in Japan.We included 374 patients with EBC who had breast cancer surgery and were prescribed abemaciclib with hormonal therapy between December 2021 and March 2023. The median age of patients is 54 years, almost all (99.2%) are female. The most commonly prescribed hormonal therapy with abemaciclib is tamoxifen (37.7%), letrozole (35.6%) and anastrozole (24.3%).Of the 374 patients who were prescribed abemaciclib, 38.2% patients received chemotherapy before surgery, 51.6% received chemotherapy after surgery and 63.4% received radiation therapy after surgery; whereas, 13.1% received no perioperative chemotherapy before abemaciclib therapy. Around 42% of patients reduced their dose from starting dose of abemaciclib. Higher proportion of older patients and patients with low body weight, had dose reduction. Majority of the patients are prescribed either an antidiarrheal agent or probiotic within a day of starting abemaciclib.This is the first study describing patient characteristics and treatment patterns of Japanese patients who are prescribed abemaciclib in the clinical practice. The results will help understand who can benefit from abemaciclib, and to choose the most appropriate patients to receive abemaciclib for the treatment of EBC.


Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Quimioterapia Adyuvante/métodos , Quimioterapia Adyuvante/estadística & datos numéricos , Estudios Retrospectivos , Persona de Mediana Edad , Japón , Anciano , Bencimidazoles/uso terapéutico , Bencimidazoles/administración & dosificación , Adulto , Aminopiridinas/uso terapéutico , Aminopiridinas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Tamoxifeno/uso terapéutico , Tamoxifeno/administración & dosificación , Anastrozol/uso terapéutico , Anastrozol/administración & dosificación , Receptor ErbB-2/metabolismo
6.
Future Oncol ; 20(28): 2037-2048, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39023253

RESUMEN

WHAT IS THIS SUMMARY ABOUT?: This article summarizes the most recent results of the monarchE study. This study was completed in participants with a type of breast cancer called HR+, HER2-, node-positive, high-risk early breast cancer. In this study, abemaciclib, a non-chemotherapy treatment, was administered with standard of care endocrine therapy after curative surgery. Most participants had received prior chemotherapy and/or radiotherapy. The study investigated if abemaciclib helped participants live longer without their cancer returning compared with participants who only received standard of care endocrine therapy. The study participants were assigned to 1 of 2 treatment groups. Participants in Group A were assigned to receive standard of care endocrine therapy with abemaciclib for 2 years, followed by endocrine therapy for a total of at least 5 years. Participants in Group B were assigned to receive standard of care endocrine therapy only for at least 5 years. The effect of treatment was compared between these 2 groups. WHAT WERE THE RESULTS?: Overall, the results showed that the cancer was 34% less likely to come back after surgery in the participants in Group A (abemaciclib plus endocrine therapy) compared with those in Group B (endocrine therapy only). At 4 years since the start of the study treatment, more participants who received the combination of abemaciclib plus endocrine therapy remained free of cancer compared with participants who received endocrine therapy alone (86% versus 79%). Participants who received abemaciclib plus endocrine therapy had more side effects than those who received endocrine therapy alone, but most of these effects were mild to moderate and reversible upon the end of therapy. The most common side effects in the abemaciclib group were diarrhea, infections, low number of white blood cells, and tiredness. WHAT DO THE RESULTS MEAN?: This study found that administering abemaciclib in combination with standard endocrine therapy after curative breast surgery helped lower the risk of cancer returning in people with HR+, HER2-, node-positive, high-risk early breast cancer. Abemaciclib is a new treatment option for people with this diagnosis. People with high-risk early breast cancer should always talk to their doctors and nurses before making any decisions about their treatment.Clinical Trial Registration: NCT03155997 (monarchE study).


Asunto(s)
Aminopiridinas , Protocolos de Quimioterapia Combinada Antineoplásica , Bencimidazoles , Neoplasias de la Mama , Receptor ErbB-2 , Humanos , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/terapia , Femenino , Bencimidazoles/administración & dosificación , Bencimidazoles/uso terapéutico , Aminopiridinas/administración & dosificación , Aminopiridinas/uso terapéutico , Receptor ErbB-2/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Receptores de Estrógenos/metabolismo , Antineoplásicos Hormonales/uso terapéutico , Antineoplásicos Hormonales/administración & dosificación , Persona de Mediana Edad , Receptores de Progesterona/metabolismo , Adulto , Resultado del Tratamiento , Anciano , Estadificación de Neoplasias
7.
Future Oncol ; 20(16): 1047-1055, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38357801

RESUMEN

WHAT IS THIS SUMMARY ABOUT?: This is a summary of the results of a study called PHAROS. This study looked at combination treatment with encorafenib (BRAFTOVI®) and binimetinib (MEKTOVI®). This combination of medicines was studied in people with metastatic non-small-cell lung cancer (NSCLC). NSCLC is the most common type of lung cancer. Metastatic means that the cancer has spread to other parts of the body. All people in this study had a type of NSCLC that has a change in a gene called BRAF termed a BRAF V600E mutation. A gene is a part of the DNA that has instructions for making things that your body needs to work, and the BRAF V600E mutation contributes to the growth of the lung cancer. WHAT WERE THE RESULTS?: In this study, 98 people with BRAF V600E-mutant metastatic NSCLC were treated with the combination of encorafenib and binimetinib (called encorafenib plus binimetinib in this summary). Before starting the study, 59 people had not received any treatment for their metastatic NSCLC, and 39 people had received previous anticancer treatment. At the time of this analysis, 44 (75%) out of 59 people who did not receive any treatment before taking encorafenib plus binimetinib had their tumors shrink or disappear. Eighteen (46%) out of 39 people who had received treatment before starting encorafenib plus binimetinib also had their tumors shrink or disappear. The most common side effects of encorafenib plus binimetinib were nausea, diarrhea, fatigue, and vomiting. WHAT DO THE RESULTS MEAN?: These results support the use of encorafenib plus binimetinib combination treatment as a new treatment option in people with BRAF V600E-mutant metastatic NSCLC. The side effects of encorafenib plus binimetinib in this study were similar to the side effects seen with encorafenib plus binimetinib in people with a type of skin cancer called metastatic melanoma.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Bencimidazoles , Carbamatos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Proteínas Proto-Oncogénicas B-raf , Sulfonamidas , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bencimidazoles/administración & dosificación , Bencimidazoles/efectos adversos , Bencimidazoles/uso terapéutico , Carbamatos/administración & dosificación , Carbamatos/efectos adversos , Carbamatos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Metástasis de la Neoplasia , Proteínas Proto-Oncogénicas B-raf/genética , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Sulfonamidas/uso terapéutico , Resultado del Tratamiento
8.
Nature ; 564(7736): 439-443, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30405246

RESUMEN

Stimulator of interferon genes (STING) is a receptor in the endoplasmic reticulum that propagates innate immune sensing of cytosolic pathogen-derived and self DNA1. The development of compounds that modulate STING has recently been the focus of intense research for the treatment of cancer and infectious diseases and as vaccine adjuvants2. To our knowledge, current efforts are focused on the development of modified cyclic dinucleotides that mimic the endogenous STING ligand cGAMP; these have progressed into clinical trials in patients with solid accessible tumours amenable to intratumoral delivery3. Here we report the discovery of a small molecule STING agonist that is not a cyclic dinucleotide and is systemically efficacious for treating tumours in mice. We developed a linking strategy to synergize the effect of two symmetry-related amidobenzimidazole (ABZI)-based compounds to create linked ABZIs (diABZIs) with enhanced binding to STING and cellular function. Intravenous administration of a diABZI STING agonist to immunocompetent mice with established syngeneic colon tumours elicited strong anti-tumour activity, with complete and lasting regression of tumours. Our findings represent a milestone in the rapidly growing field of immune-modifying cancer therapies.


Asunto(s)
Bencimidazoles/química , Bencimidazoles/farmacología , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/inmunología , Diseño de Fármacos , Proteínas de la Membrana/agonistas , Animales , Bencimidazoles/administración & dosificación , Bencimidazoles/uso terapéutico , Humanos , Ligandos , Proteínas de la Membrana/inmunología , Ratones , Modelos Moleculares , Nucleótidos Cíclicos/metabolismo
9.
Exp Parasitol ; 266: 108830, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-39260814

RESUMEN

Two controlled efficacy studies were conducted to determine the effective dose of fosfatriclaben (FTCB) and compare its fasciolicidal efficacy with that of three commercial products against eggs and adult stages of Fasciola hepatica in artificially infected cattle. In study 1, 20 trematode-free Holstein Friesian steers were infected on day 0 with 500 F. hepatica metacercariae. Ten weeks after infection and the steers were confirmed to be positive for trematode eggs through a modified sedimentation method. On day 75, they were divided into five groups of four animals each for treatment. Group 1 (G1) served as the untreated control; G2, G3, and G4 received FTCB at 4, 6, and 8 mg/kg/intramuscularly (IM), respectively. G5 received a combined treatment of triclabendazole (TCBZ) (12 mg/kg IM + ivermectin (0.2 mg/kg IM). Individual faecal analyses were performed on days -8, 0, 70, 75, and 105 to evaluate the reduction in trematode eggs. Four weeks after treatment, the steers were humanely slaughtered to harvest the livers and remove the parasites present in the bile ducts. Efficacy was evaluated by the reduction in fecal egg counts or in number of adult parasites, compared to the untreated control. The effective FTCB dose was 6 mg/kg. Once the effective dose was determined, study 2 was conducted on another 20 steers infected with 500 F. hepatica metacercariae, to compare the effectiveness of FTCB with three commercials fasciolicides. All procedures were performed as described in study 1, and treatments were as follows: Group 1 (G1), closantel (5 mg/kg subcutaneously (SC)); G2, TCBZ (12 mg/kg IM) + ivermectin (0.2 mg/kg IM); G3, FTCB (6 mg/kg IM); G4, triclabendazole (12 mg/kg) + albendazole (5 mg/kg/PO (orally); and G5 served as an untreated control. The results indicated that all tested compounds were highly effective in the reduction of faecal egg excretion (99.7-100%) and adult parasites (98.9-100%), except closantel, which exhibited low efficacy (74.4%) when tested against adult trematodes. We concluded that the effective dose of FTCB for cattle was 6 mg/kg IM, which is half the recommended clinical dose of the commercial combination of TCBZ and ivermectin. The fasciolicidal efficacy of FTCB was like the other three flukicides in reducing adult F. hepatica and Fasciola eggs; however, closantel was not sufficiently efficient against adult flukes.


Asunto(s)
Albendazol , Antihelmínticos , Bencimidazoles , Enfermedades de los Bovinos , Fasciola hepatica , Fascioliasis , Heces , Ivermectina , Recuento de Huevos de Parásitos , Salicilanilidas , Triclabendazol , Animales , Bovinos , Fascioliasis/tratamiento farmacológico , Fascioliasis/veterinaria , Triclabendazol/uso terapéutico , Triclabendazol/administración & dosificación , Heces/parasitología , Ivermectina/farmacología , Ivermectina/uso terapéutico , Ivermectina/administración & dosificación , Fasciola hepatica/efectos de los fármacos , Masculino , Enfermedades de los Bovinos/tratamiento farmacológico , Enfermedades de los Bovinos/parasitología , Salicilanilidas/farmacología , Salicilanilidas/administración & dosificación , Salicilanilidas/uso terapéutico , Recuento de Huevos de Parásitos/veterinaria , Antihelmínticos/uso terapéutico , Antihelmínticos/farmacología , Antihelmínticos/administración & dosificación , Bencimidazoles/farmacología , Bencimidazoles/uso terapéutico , Bencimidazoles/administración & dosificación , Albendazol/farmacología , Albendazol/uso terapéutico , Albendazol/administración & dosificación , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada
10.
Arch Gynecol Obstet ; 309(6): 2811-2819, 2024 06.
Artículo en Inglés | MEDLINE | ID: mdl-38472501

RESUMEN

BACKGROUND: Following the positive iDFS and OS results of the phase III clinical trials monarchE, NATALEE and OlympiA, new oral anticancer agents (the CDK4/6 inhibitors abemaciclib, ribociclib as well as the PARP inhibitor olaparib) have recently been introduced into the treatment of high-risk early breast cancer (eBC). However, only few male patients were included in these trials (0.4%, 0.6% and 0.3%, respectively). The objective of this real-world analysis was to determine the proportion of male patients with eBC fulfilling the clinical high-risk criteria of above-mentioned trials. PATIENTS AND METHODS: We conducted a data inquiry and analysis with the Cancer Registry of Baden-Württemberg of men with breast cancer diagnosed between January 1, 2015 and December 31, 2021. Men with eBC were identified and the number of patients at clinical high-risk according to the inclusion criteria of monarchE, NATALEE and OlympiA was assessed. RESULTS: Of 397 men with eBC, 354 (89.1%) had a HR + /Her2- and 4 (1.0%) a triple-negative subtype. 84 patients (21.2%) met the clinical high-risk criteria according to the monarchE, 189 (47.6%) those according to the NATALEE and 50 (12.6%) those according to the OlympiA trial. CONCLUSION: In a large real-world sample, more men with eBC are at clinical high risk according to the inclusion criteria of monarchE, NATALEE and OlympiA than would be expected in women. This is most likely due to more advanced stages at initial diagnosis in men. To evaluate whether CDK4/6 and PARP inhibitors improve prognosis also in men should be the topic of future real- world analyses.


Asunto(s)
Neoplasias de la Mama Masculina , Estudios de Factibilidad , Sistema de Registros , Humanos , Masculino , Neoplasias de la Mama Masculina/tratamiento farmacológico , Persona de Mediana Edad , Anciano , Quimioterapia Adyuvante , Adulto , Terapia Molecular Dirigida/métodos , Aminopiridinas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Bencimidazoles/uso terapéutico , Bencimidazoles/administración & dosificación , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Purinas
11.
Int J Mol Sci ; 25(13)2024 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-39000513

RESUMEN

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, including abemaciclib, have been approved for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced, and metastatic breast cancer. Despite the high therapeutic efficacy of CDK4/6 inhibitors, they are associated with various adverse effects, including potentially fatal interstitial lung disease. Therefore, a combination of CDK4/6 inhibitors with letrozole or fulvestrant has been attempted but has demonstrated limitations in reducing adverse effects, highlighting the need to develop new combination therapies. This study proposes a combination strategy using CDK4/6 inhibitors and tricyclic antidepressants to enhance the therapeutic outcomes of these inhibitors while reducing their side effects. The therapeutic efficacies of abemaciclib and desipramine were tested in different cancer cell lines (H460, MCF7, and HCT-116). The antitumor effects of the combined abemaciclib and desipramine treatment were evaluated in a xenograft colon tumor model. In vitro cell studies have shown the synergistic anticancer effects of combination therapy in the HCT-116 cell line. The combination treatment significantly reduced tumor size compared with control or single treatment without causing apparent toxicity to normal tissues. Although additional in vivo studies are necessary, this study suggests that the combination therapy of abemaciclib and desipramine may represent a novel therapeutic approach for treating solid tumors.


Asunto(s)
Aminopiridinas , Bencimidazoles , Desipramina , Sinergismo Farmacológico , Ensayos Antitumor por Modelo de Xenoinjerto , Humanos , Bencimidazoles/farmacología , Bencimidazoles/administración & dosificación , Aminopiridinas/farmacología , Aminopiridinas/administración & dosificación , Animales , Ratones , Desipramina/farmacología , Línea Celular Tumoral , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/metabolismo , Proliferación Celular/efectos de los fármacos , Ratones Desnudos , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/metabolismo , Células MCF-7 , Células HCT116 , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/administración & dosificación , Ratones Endogámicos BALB C
12.
Pharm Dev Technol ; 29(8): 855-861, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39286857

RESUMEN

Understanding drug behavior within the skin, especially for photosensitive compounds, is crucial for developing effective and safe topical therapies. This study employs Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging (MALDI-MSI) and Liquid Chromatography-Mass Spectrometry (LC-MS/MS) to investigate the skin permeation and photostability of selumetinib, a MEK inhibitor used in treating type 1 neurofibromatosis (NF1). The highest amounts of selumetinib in the skin sections were obtained when using the gel formulation, suggesting that it is to be preferred to cream formulations to achieve higher permeation of the drug. Our study also revealed that selumetinib is amenable to photodegradation in ex vivo skin explants, and yields one main degradation product, whose degradation is likely triggered by hydrogen abstraction. MALDI-MSI results showed selumetinib and its degradation product concentrate in skin appendages, indicating these structures might serve as drug reservoirs, potentially prolonging retention and efficacy. This study demonstrates that combining MALDI-MSI with LC/MS-MS can highly contribute to the characterization of the fate of photosensitive compounds in the skin, an essential prerequisite to the development of compound-specific photoprotective measures. It will also pave the way for innovative topical delivery strategies for NF1 treatment.


Asunto(s)
Bencimidazoles , Fotólisis , Absorción Cutánea , Piel , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Espectrometría de Masas en Tándem , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Piel/metabolismo , Espectrometría de Masas en Tándem/métodos , Animales , Bencimidazoles/administración & dosificación , Bencimidazoles/farmacocinética , Bencimidazoles/química , Absorción Cutánea/efectos de los fármacos , Cromatografía Liquida/métodos , Administración Cutánea , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacología , Cromatografía Líquida con Espectrometría de Masas
13.
Pharm Dev Technol ; 29(7): 751-761, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39138563

RESUMEN

Chemotherapeutic drug delivery systems are commonly limited by their short half-lives, poor bioavailability, and unsuccessful targetability. Herein, pH-responsive hybrid NPs consist of benzimidazole-coated mesoporous silica nanoparticles (BZ-MSN) loaded with naturally occurring flavonoid quercetin (QUE-BZ-MSN). The NPs were further capped with beta-cyclodextrin (BCD) to obtain our desired BCD-QUE-BZMSN, with a zeta potential around 7.05 ± 2.37 mV and diameter about 115.2 ± 19.02 nm. The abundance of BZ onto the nanoparticles facilitates targeted quercetin chemotherapy against model lung and liver cancer cell lines. FTIR, EDX, and NMR analyses revealed evidence of possible surface functionalizations. Powder XRD analysis showed that our designed BCD-QUE-BZMSN formulation is amorphous in nature. The UV and SEM showed that our designed BCD-QUE-BZMSN has high drug entrapment efficiency and a nearly spherical morphology. In vitro, drug release assessments show controlled pH-dependent release profiles that could enhance the targeted chemotherapeutic response against mildly acidic regions in cancer cell lines. The obtained BCD-QUE-BZMSN nanovalve achieved significantly higher cytotoxic efficacy as compared to QUE alone, which was evaluated by in vitro cellular uptake against liver and lung cancer cell lines, and the cellular morphological ablation was further confirmed via inverted microscopy. The outcomes of the study imply that our designed BCD-QUE-BZMSN nanovalve is a potential carrier for cancer chemotherapeutics.


Asunto(s)
Antineoplásicos , Liberación de Fármacos , Nanopartículas , Quercetina , Dióxido de Silicio , beta-Ciclodextrinas , Humanos , Concentración de Iones de Hidrógeno , Quercetina/administración & dosificación , Quercetina/farmacología , Quercetina/química , Quercetina/farmacocinética , Nanopartículas/química , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , beta-Ciclodextrinas/química , Dióxido de Silicio/química , Línea Celular Tumoral , Bencimidazoles/química , Bencimidazoles/administración & dosificación , Bencimidazoles/farmacología , Bencimidazoles/farmacocinética , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/métodos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Supervivencia Celular/efectos de los fármacos
14.
Gan To Kagaku Ryoho ; 51(5): 557-559, 2024 May.
Artículo en Japonés | MEDLINE | ID: mdl-38881068

RESUMEN

A Japanese woman in her early 70's presented to our hospital with abdominal pain and nausea. Abdominal computed tomography showed irregular wall thickening of the ileocecal region and small intestine dilatation. Colonoscopy revealed a tumor lesion at the ileocecal valve and adenocarcinoma was detected in the biopsy specimen. Accordingly, the diagnosis was cecal cancer and bowel obstruction. Right hemicolectomy was performed as palliative surgery, and laparotomy findings revealed peritoneal dissemination. The final staging was pT4a, pN2b, pM1c, pStage Ⅳc, harboring a BRAFV600E mutation. Rapid postoperative tumor progression occurred, leading to multiple liver metastases and ascites. Encorafenib, binimetinib, and cetuximab triple therapy was started as a second line regimen. The therapy was extremely effective. CA19-9 level decreased to within normal range, and the liver tumor size was visibly diminished. After receiving treatment for 2 months in outpatient care, she had to discontinue the treatment due to carcinomatous peritonitis. Unfortunately, she died 6 months after initial diagnosis. BRAF-mutated colon cancer is associated with poor prognosis. In Japan, encorafenib, binimetinib, and cetuximab triple therapy is a new BRAF targeting regimen approved in 2020. We report this clinical course in hopes of eventually achieving better outcomes for patients with this aggressive disease.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Bencimidazoles , Carbamatos , Neoplasias del Ciego , Cetuximab , Mutación , Proteínas Proto-Oncogénicas B-raf , Sulfonamidas , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carbamatos/administración & dosificación , Proteínas Proto-Oncogénicas B-raf/genética , Cetuximab/administración & dosificación , Femenino , Sulfonamidas/administración & dosificación , Bencimidazoles/administración & dosificación , Anciano , Neoplasias del Ciego/tratamiento farmacológico , Neoplasias del Ciego/patología , Neoplasias del Ciego/genética , Neoplasias del Ciego/cirugía , Resultado Fatal
15.
Gan To Kagaku Ryoho ; 51(9): 935-938, 2024 Sep.
Artículo en Japonés | MEDLINE | ID: mdl-39462630

RESUMEN

A 74-year-old woman was diagnosed with invasive breast ductal carcinoma, cT2N0M1 (PUL), stage Ⅳ, and treated with abemaciclib and letrozole. The day after drug administration, the patient developed a fever of 38℃ and dyspnea upon exertion, and was diagnosed with drug-induced pneumonia. Steroid pulse therapy was administered during hospitalization, and the patient was discharged after the dose of prednisolone was gradually reduced. This case shows that, when abemaciclib is administered, drug-induced lung injury can occur within 1 week.


Asunto(s)
Aminopiridinas , Bencimidazoles , Neoplasias de la Mama , Lesión Pulmonar , Humanos , Femenino , Anciano , Neoplasias de la Mama/tratamiento farmacológico , Aminopiridinas/administración & dosificación , Aminopiridinas/efectos adversos , Aminopiridinas/uso terapéutico , Bencimidazoles/efectos adversos , Bencimidazoles/administración & dosificación , Bencimidazoles/uso terapéutico , Lesión Pulmonar/inducido químicamente , Letrozol/administración & dosificación , Letrozol/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma Ductal de Mama/tratamiento farmacológico
16.
Kardiologiia ; 64(7): 48-55, 2024 Jul 31.
Artículo en Ruso, Inglés | MEDLINE | ID: mdl-39102573

RESUMEN

AIM: To evaluate the efficacy and safety of azilsartan medoxomil for preoperative preparation and improving the long-term prognosis of elective percutaneous coronary intervention (PCI) in patients with ischemic heart disease (IHD), arterial hypertension (AH), and type 2 diabetes mellitus (DM). MATERIAL AND METHODS: The study sample included patients with type 2 DM referred for elective PCI who had poor blood pressure (BP) control according to 24-hour BP monitoring (24-BPM) (mean daily systolic BP ≥130 mmHg, mean daily diastolic BP ≥80 mmHg). The data were collected from 2018 through 2020. A total of 75 patients was included and distributed by simple randomization into two groups: group 1 (main, n=37) received azilsartan medoxomil as an antihypertensive drug at a dose of 40 mg/day (previously prescribed angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (ARB) were discontinued); group 2 (control, n=38) continued on their previous antihypertensive therapy. The follow-up period was 6 months. During each of 5 consecutive follow-up visits, the patient was examined, 24-BPM was recorded, and urinary markers of renal dysfunction (glomerular filtration rate, GFR; neutrophil gelatinase-associated lipocalin, NGAL; urine albumin-creatinine ratio, UACR; kidney injury molecule, KIM-1; and interleukin-18, IL-18) were measured. RESULTS: During the azilsartan treatment, GFR decreased by 7.4%, while in the control group, it decreased by 18.9% (p<0.001). For 6 months of follow-up, no changes in the NGAL concentration were found in the main group, while the NGAL concentration in the control group increased by 12.9%. With azilsartan, there was a decrease in the urinary concentration of IL-18 (16.9%), while in patients of the control group, IL-18 increased (7.14%). Proteinuria progressed in both groups, which was expectable given the presence of DM; however, in patients receiving azilsartan, the UACR value increased by 37.5%, while in patients of the control group, it increased by 96.15%. These differences were statistically significant. No statistically significant differences were found in the concentrations of cystatin C and KIM-1. CONCLUSION: This study demonstrated two important facts: the possibility for diagnosing contrast-induced acute kidney injury (CI-AKI) using new, more sensitive markers of kidney damage, which is important for assessing the effectiveness of prevention, and the possibility of using ARBs, in particular azilsartan, for the prevention of CI-AKI in patients with IHD in combination with AH and DM.


Asunto(s)
Bencimidazoles , Diabetes Mellitus Tipo 2 , Hipertensión , Oxadiazoles , Intervención Coronaria Percutánea , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Masculino , Femenino , Oxadiazoles/efectos adversos , Oxadiazoles/administración & dosificación , Persona de Mediana Edad , Bencimidazoles/efectos adversos , Bencimidazoles/administración & dosificación , Intervención Coronaria Percutánea/métodos , Anciano , Antihipertensivos/uso terapéutico , Cuidados Preoperatorios/métodos , Isquemia Miocárdica
17.
Proc Natl Acad Sci U S A ; 117(22): 11987-11994, 2020 06 02.
Artículo en Inglés | MEDLINE | ID: mdl-32424082

RESUMEN

Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis worldwide and kills more Americans than 59 other infections, including HIV and tuberculosis, combined. While direct-acting antiviral (DAA) treatments are effective, limited uptake of therapy, particularly in high-risk groups, remains a substantial barrier to eliminating HCV. We developed a long-acting DAA system (LA-DAAS) capable of prolonged dosing and explored its cost-effectiveness. We designed a retrievable coil-shaped LA-DAAS compatible with nasogastric tube administration and the capacity to encapsulate and release gram levels of drugs while resident in the stomach. We formulated DAAs in drug-polymer pills and studied the release kinetics for 1 mo in vitro and in vivo in a swine model. The LA-DAAS was equipped with ethanol and temperature sensors linked via Bluetooth to a phone application to provide patient engagement. We then performed a cost-effectiveness analysis comparing LA-DAAS to DAA alone in various patient groups, including people who inject drugs. Tunable release kinetics of DAAs was enabled for 1 mo with drug-polymer pills in vitro, and the LA-DAAS safely and successfully provided at least month-long release of sofosbuvir in vivo. Temperature and alcohol sensors could interface with external sources for at least 1 mo. The LA-DAAS was cost-effective compared to DAA therapy alone in all groups considered (base case incremental cost-effectiveness ratio $39,800). We believe that the LA-DAA system can provide a cost-effective and patient-centric method for HCV treatment, including in high-risk populations who are currently undertreated.


Asunto(s)
Antivirales/administración & dosificación , Sistemas de Liberación de Medicamentos , Hepatitis C Crónica/tratamiento farmacológico , Animales , Antivirales/farmacocinética , Bencimidazoles/administración & dosificación , Bencimidazoles/farmacocinética , Carbamatos , Análisis Costo-Beneficio , Modelos Animales de Enfermedad , Portadores de Fármacos/farmacocinética , Sistemas de Liberación de Medicamentos/economía , Sistemas de Liberación de Medicamentos/instrumentación , Sistemas de Liberación de Medicamentos/métodos , Fluorenos/administración & dosificación , Fluorenos/farmacocinética , Hepacivirus/efectos de los fármacos , Imidazoles/administración & dosificación , Imidazoles/farmacocinética , Cirrosis Hepática/tratamiento farmacológico , Modelos Animales , Pirrolidinas , Ribavirina/administración & dosificación , Ribavirina/farmacocinética , Sofosbuvir/administración & dosificación , Sofosbuvir/farmacocinética , Porcinos , Valina/análogos & derivados
18.
J Assoc Physicians India ; 71(12): 56-61, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38736055

RESUMEN

INTRODUCTION: Hypertension (HTN) remains one of the most important risk factors for cardiovascular (CV) diseases and a leading cause of mortality worldwide. Despite improvement in detection and treatment, poor blood pressure (BP) control rates are observed globally. The situation in India is alarming with only 22.5% of patients maintaining their BP under control. Initiating early and effective treatment for HTN helps control BP within normal limits and reduces associated health risks. In India, currently, there are no guidelines on the choice of dual combination treatment that can be considered an initial treatment for newly diagnosed HTN patients to achieve effective BP control and reduce CV risks. OBJECTIVE: To provide consensus recommendations for preferred initial combinations in newly diagnosed Indian patients with HTN. METHODOLOGY: A core group of 100 experts with HTN expertise conceptualized and formulated the four key questions based on answerability, effectiveness, potential for translation to clinical practice, novelty, and potential impact on the healthcare burden. A mix of Delphi and Child Health and Nutrition Research Initiative (CHNRI) methods was adopted for acceptance or refusal of recommendations. Likert scale 1-9 was used for scoring. A score of ≥7 was considered "statement accepted," >6.50 "near to acceptance" and <6.50 "not accepted." A vote of ≥7 by at least two-thirds of the experts (66.66%) was mandatory for acceptance of the recommendation. CONCLUSION: Combination therapy could be necessary for a majority of newly diagnosed Indian patients for effective BP control. It can manage HTN with better clinical outcomes. Based on mean rating scores from experts, telmisartan plus amlodipine can be considered the preferred initial combination in the management of newly diagnosed Indian patients with HTN to achieve better BP control and improve CV outcomes.


Asunto(s)
Amlodipino , Antihipertensivos , Hipertensión , Telmisartán , Humanos , Hipertensión/tratamiento farmacológico , Amlodipino/administración & dosificación , Amlodipino/uso terapéutico , India , Telmisartán/administración & dosificación , Antihipertensivos/uso terapéutico , Antihipertensivos/administración & dosificación , Consenso , Combinación de Medicamentos , Bencimidazoles/administración & dosificación , Bencimidazoles/uso terapéutico , Quimioterapia Combinada , Benzoatos/administración & dosificación , Benzoatos/uso terapéutico
19.
J Neurosci ; 41(12): 2566-2580, 2021 03 24.
Artículo en Inglés | MEDLINE | ID: mdl-33536197

RESUMEN

We show for the first time that the neuropeptide orexin modulates pupillary light response, a non-image-forming visual function, in mice of either sex. Intravitreal injection of the orexin receptor (OXR) antagonist TCS1102 and orexin-A reduced and enhanced pupillary constriction in response to light, respectively. Orexin-A activated OX1Rs on M2-type intrinsically photosensitive retinal ganglion cells (M2 cells), and caused membrane depolarization of these cells by modulating inward rectifier potassium channels and nonselective cation channels, thus resulting in an increase in intrinsic excitability. The increased intrinsic excitability could account for the orexin-A-evoked increase in spontaneous discharges and light-induced spiking rates of M2 cells, leading to an intensification of pupillary constriction. Orexin-A did not alter the light response of M1 cells, which could be because of no or weak expression of OX1Rs on them, as revealed by RNAscope in situ hybridization. In sum, orexin-A is likely to decrease the pupil size of mice by influencing M2 cells, thereby improving visual performance in awake mice via enhancing the focal depth of the eye's refractive system.SIGNIFICANCE STATEMENT This study reveals the role of the neuropeptide orexin in mouse pupillary light response, a non-image-forming visual function. Intravitreal orexin-A administration intensifies light-induced pupillary constriction via increasing the excitability of M2 intrinsically photosensitive retinal ganglion cells by activating the orexin receptor subtype OX1R. Modulation of inward rectifier potassium channels and nonselective cation channels were both involved in the ionic mechanisms underlying such intensification. Orexin could improve visual performance in awake mice by reducing the pupil size and thereby enhancing the focal depth of the eye's refractive system.


Asunto(s)
Orexinas/administración & dosificación , Estimulación Luminosa/métodos , Pupila/efectos de los fármacos , Reflejo Pupilar/efectos de los fármacos , Células Ganglionares de la Retina/citología , Células Ganglionares de la Retina/efectos de los fármacos , Animales , Bencimidazoles/administración & dosificación , Femenino , Inyecciones Intravítreas , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Orexina/agonistas , Receptores de Orexina/metabolismo , Orexinas/antagonistas & inhibidores , Pupila/fisiología , Pirrolidinas/administración & dosificación , Reflejo Pupilar/fisiología , Células Ganglionares de la Retina/metabolismo
20.
N Engl J Med ; 381(17): 1632-1643, 2019 10 24.
Artículo en Inglés | MEDLINE | ID: mdl-31566309

RESUMEN

BACKGROUND: Patients with metastatic colorectal cancer with the BRAF V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling. METHODS: In this open-label, phase 3 trial, we enrolled 665 patients with BRAF V600E-mutated metastatic colorectal cancer who had had disease progression after one or two previous regimens. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators' choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan) (control group). The primary end points were overall survival and objective response rate in the triplet-therapy group as compared with the control group. A secondary end point was overall survival in the doublet-therapy group as compared with the control group. We report here the results of a prespecified interim analysis. RESULTS: The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group. CONCLUSIONS: A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35.).


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencimidazoles/administración & dosificación , Carbamatos/administración & dosificación , Cetuximab/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Sulfonamidas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Progresión de la Enfermedad , Electrocorticografía , Femenino , Humanos , Análisis de Intención de Tratar , Irinotecán/uso terapéutico , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis de Supervivencia
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA