RESUMEN

This retrospective cohort study analyzed data from a Japanese health insurance database to assess the effectiveness of baloxavir (n = 4822) for preventing severe events compared with oseltamivir (n = 10,523) in patients with influenza B. The primary endpoint was hospitalization incidence (Days 2-14). The secondary endpoints included intravenous antibacterial drug use, pneumonia hospitalization, heart failure hospitalization, inhalational oxygen requirement, and use of other anti-influenza drugs. The hospitalization incidence was significantly lower with baloxavir (0.15% vs. 0.37%; risk ratio: 2.48, 95% confidence interval: 1.13-5.43). Pneumonia and additional anti-influenza therapy were also less frequent with baloxavir, thus supporting its use. Trial Registration: UMIN Clinical Trials Registry Study ID: UMIN000051382.

Asunto(s)

Antivirales , Dibenzotiepinas , Virus de la Influenza B , Gripe Humana , Morfolinas , Oseltamivir , Pacientes Ambulatorios , Piridonas , Triazinas , Humanos , Gripe Humana/tratamiento farmacológico , Dibenzotiepinas/uso terapéutico , Oseltamivir/uso terapéutico , Antivirales/uso terapéutico , Masculino , Estudios Retrospectivos , Femenino , Persona de Mediana Edad , Adulto , Piridonas/uso terapéutico , Morfolinas/uso terapéutico , Triazinas/uso terapéutico , Anciano , Virus de la Influenza B/efectos de los fármacos , Adulto Joven , Adolescente , Hospitalización/estadística & datos numéricos , Niño , Piridinas/uso terapéutico , Japón/epidemiología , Preescolar , Resultado del Tratamiento , Lactante , Anciano de 80 o más Años

RESUMEN

PURPOSE: The purpose of this study was to evaluate the effect of UGT1A4 and UGT2B7 polymorphisms on the plasma concentration of lamotrigine in Chinese patients with bipolar disorder. METHODS: A total of 104 patients were included in this study. Steady-state plasma lamotrigine concentrations were determined in each patient after at least 21 days of continuous treatment with a set dose of the drug. Lamotrigine plasma concentrations were ascertained using ultra-performance liquid chromatography. Simultaneously, plasma samples were used for patient genotyping. RESULTS: The age, sex, BMI, daily lamotrigine dose, plasma lamotrigine concentration, and lamotrigine concentration/dose ratio of patients exhibited significant differences, and these were associated with differences in the genotype [ UGT1A4 -142T>G and UGT2B7 -161C>T ( P  < 0.05)]. Patients with the GG and GT genotypes in UGT1A4 -142T>G had significantly higher lamotrigine concentration/dose values (1.6 ±â€…1.1 and 1.7 ±â€…0.5 µg/ml per mg/kg) than those with the TT genotype (1.4 ±â€…1.1 µg/ml per mg/kg). Likewise, patients with the UGT2B7 -161C>T TT genotype had significantly higher lamotrigine concentration/dose values (1.6 ±â€…1.1 µg/ml per mg/kg) than those with the CC genotype (1.3 ±â€…1.3 µg/ml per mg/kg). Multiple linear regression analysis showed that sex, lamotrigine dose, UGT1A4 -142T>G, and UGT2B7 -161C>T were the most important factors influencing lamotrigine pharmacokinetics ( P  < 0.001). CONCLUSION: The study results suggest that the UGT1A4 -142T>G and UGT2B7 -161C>T polymorphisms affect lamotrigine plasma concentrations in patients with bipolar disorder.

Asunto(s)

Trastorno Bipolar , Glucuronosiltransferasa , Lamotrigina , Triazinas , Humanos , Lamotrigina/sangre , Lamotrigina/farmacocinética , Lamotrigina/administración & dosificación , Lamotrigina/uso terapéutico , Glucuronosiltransferasa/genética , Masculino , Femenino , Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/genética , Trastorno Bipolar/sangre , Adulto , Triazinas/farmacocinética , Triazinas/sangre , Triazinas/administración & dosificación , Triazinas/uso terapéutico , Persona de Mediana Edad , Genotipo , Polimorfismo de Nucleótido Simple/genética , Pueblo Asiatico/genética

RESUMEN

eEF2K, an atypical alpha-kinase, is responsible for regulating protein synthesis and energy homeostasis. Aberrant eEF2K function has been linked to various human cancers, including triple-negative breast cancer (TNBC). However, limited cellular activity of current eEF2K modulators impedes their clinical application. Based on the 2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione scaffold of our hits I4 and C1, structure-activity relationship analysis led to the discovery of several more active derivatives (e.g., 19, 34, and 36) in inhibiting the viability of TNBC cell line MDA-MB-231. Moreover, the most potent compound 36 significantly suppresses the viability, proliferation, and migration of both MDA-MB-231 and HCC1806 cell lines. Mechanistically, compound 36 has a high binding affinity for the eEF2K protein and effectively induces its degradation. Additionally, 36 exerts a comparable tumor-suppressive effect to paclitaxel in an MDA-MB-231 cell xenograft mouse model with no obvious toxicity, demonstrating that compound 36 could be developed as a potential novel therapeutic for TNBC treatment.

Asunto(s)

Antineoplásicos , Proliferación Celular , Quinasa del Factor 2 de Elongación , Triazinas , Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Relación Estructura-Actividad , Animales , Quinasa del Factor 2 de Elongación/metabolismo , Quinasa del Factor 2 de Elongación/antagonistas & inhibidores , Triazinas/farmacología , Triazinas/química , Triazinas/síntesis química , Triazinas/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Femenino , Ratones , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ratones Desnudos , Ensayos Antitumor por Modelo de Xenoinjerto , Movimiento Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Supervivencia Celular/efectos de los fármacos

RESUMEN

Traditionally, the D1228 E/G/H/N mutation has been thought to cause Type I MET-TKI resistance. We reported a 75-year-old female with non-small cell lung cancer harboring MET exon 14 skipping mutation, who developed acquired MET D1228H mutation induced by capmatinib treatment. Interestingly, the patient demonstrated marked response to second-line savolitinib treatment with the duration of response of 19 months and several additional metastatic lesions appeared. Pathological assessment of rebiopsy sample showed adenocarcinoma and targeted next-generation sequencing revealed the loss of MET D1228H mutation and presence of MET p.Y1230N mutation. In response, the treatment regimen was amended to include a daily administration of 60 mg of cabozantinib, which resulted in moderate size reduction of the tumours. The switch of resistance mutations indicated that different type Ib MET inhibitors may exhibit distinct mechanisms of resistance. We call for futher studies on resistance based on patient-derived pre-clinical models including patient-derived tumor-like cell clusters, patient-derived organoids, and patient-derived xenografts.

Asunto(s)

Adenocarcinoma del Pulmón , Resistencia a Antineoplásicos , Exones , Neoplasias Pulmonares , Mutación , Proteínas Proto-Oncogénicas c-met , Humanos , Proteínas Proto-Oncogénicas c-met/genética , Femenino , Anciano , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Resistencia a Antineoplásicos/genética , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Benzamidas , Acrilamidas/uso terapéutico , Triazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/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 , Imidazoles , Pirazinas

RESUMEN

Baloxavir marboxil (baloxavir), approved as an anti-influenza drug in Japan in March 2018, can induce reduced therapeutic effectiveness due to PA protein substitutions. We assessed PA substitutions in clinical samples from influenza-infected children and adults pre- and post-baloxavir treatment, examining their impact on fever and symptom duration. During the 2022-2023 influenza season, the predominant circulating influenza subtype detected by cycling-probe RT-PCR was A(H3N2) (n = 234), with a minor circulation of A(H1N1)pdm09 (n = 10). Of the 234 influenza A(H3N2) viruses collected prior to baloxavir treatment, 2 (0.8%) viruses carry PA/I38T substitution. One virus was collected from a toddler and one from an adult, indicating the presence of viruses with reduced susceptibility to baloxavir, without prior exposure to the drug. Of the 54 paired influenza A(H3N2) viruses collected following baloxavir treatment, 8 (14.8%) viruses carried E23 K/G, or I38 M/T substitutions in PA. Variant calling through next-generation sequencing (NGS) showed varying proportions (6-100 %), a polymorphism and a mixture of PA/E23 K/G, and I38 M/T substitutions in the clinical samples. These eight viruses were obtained from children aged 7-14 years, with a median fever duration of 16.7 h and a median symptom duration of 93.7 h, which were similar to those of the wild type. However, the delayed viral clearance associated with the emergence of PA substitutions was observed. No substitutions conferring resistance to neuraminidase inhibitors were detected in 37 paired samples collected before and following oseltamivir treatment. These findings underscore the need for ongoing antiviral surveillance, informing public health strategies and clinical antiviral recommendations for seasonal influenza.

Asunto(s)

Sustitución de Aminoácidos , Antivirales , Dibenzotiepinas , Farmacorresistencia Viral , Subtipo H3N2 del Virus de la Influenza A , Gripe Humana , Morfolinas , Piridonas , Triazinas , Proteínas Virales , Humanos , Dibenzotiepinas/uso terapéutico , Dibenzotiepinas/farmacología , Gripe Humana/tratamiento farmacológico , Gripe Humana/virología , Subtipo H3N2 del Virus de la Influenza A/genética , Subtipo H3N2 del Virus de la Influenza A/efectos de los fármacos , Subtipo H3N2 del Virus de la Influenza A/enzimología , Triazinas/uso terapéutico , Triazinas/farmacología , Japón , Antivirales/farmacología , Antivirales/uso terapéutico , Morfolinas/uso terapéutico , Farmacorresistencia Viral/genética , Niño , Adulto , Preescolar , Adolescente , Proteínas Virales/genética , ARN Polimerasa Dependiente del ARN/genética , Femenino , Masculino , Tiepinas/uso terapéutico , Tiepinas/farmacología , Lactante , Persona de Mediana Edad , Estaciones del Año , Piridinas/uso terapéutico , Piridinas/farmacología , Adulto Joven , Subtipo H1N1 del Virus de la Influenza A/genética , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Anciano

RESUMEN

PURPOSE: This phase 1b/2 trial evaluated the efficacy and safety of capmatinib plus nazartinib in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). METHODS: In phase 1b, patients with progression on first-/second-generation EGFR-TKIs received escalating doses of capmatinib 200-400 mg bid plus nazartinib 50-150 mg qd. Once the MTD/RP2D was declared, phase 2 commenced with patient enrollment into groups according to mutation status and prior lines of treatment: group 1 (fasted; EGFR-TKI resistant; 1-3 prior lines; EGFRL858R/ex19del; any T790M/MET); group 2 (fasted; EGFR-TKI naïve; 0-2 prior lines; de novo T790M+; any MET); group 3 (fasted; treatment-naïve; EGFRL858R/ex19del; T790M-; any MET); group 4 (with food; 0-2 prior lines; EGFRL858R/ex19del; any T790M/MET). Primary endpoints in phase 2 were investigator-assessed overall response rate (ORR) per RECIST v1.1 (groups 1-3), safety, and tolerability of the combination with food (group 4). Efficacy was assessed by T790M and MET status for a subgroup of patients. RESULTS: The RP2D was capmatinib 400 mg bid plus nazartinib 100 mg qd. In phase 2 (n = 144), the ORR was 28.8 %, 33.3 %, 61.7 %, and 42.9 % in groups 1 (n = 52), 2 (n = 3), 3 (n = 47), and 4 (n = 42), respectively. In group 1 +phase 1b RP2D, the ORR was 45.8 %, 26.2 %, 37.9 %, and 32.4 % in MET+ (n = 24), MET- (n = 42), T790M+ (n = 29), and T790M- (n = 34) patients. Most common any-grade treatment-related adverse events (≥25 %; n = 144) were peripheral edema (54.9 %), nausea (41.7 %), diarrhea (34.0 %), and maculopapular rash (25.0 %). CONCLUSION: Capmatinib plus nazartinib showed antitumor activity in patients with EGFR-TKI-resistant, EGFR-mutated NSCLC. The overall safety profile was acceptable. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02335944.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Pulmón de Células no Pequeñas , Receptores ErbB , Neoplasias Pulmonares , Mutación , Triazinas , Humanos , 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 , Masculino , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Femenino , Receptores ErbB/genética , Receptores ErbB/antagonistas & inhibidores , Persona de Mediana Edad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Triazinas/administración & dosificación , Triazinas/uso terapéutico , Triazinas/efectos adversos , Adulto , Benzamidas/administración & dosificación , Benzamidas/efectos adversos , Benzamidas/uso terapéutico , Anciano de 80 o más Años , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Imidazoles

RESUMEN

BACKGROUND: Pandemic influenza poses a recurring threat to public health. Antiviral drugs are vital in combating influenza pandemics. Baloxavir marboxil (BXM) is a novel agent that provides clinical and public health benefits in influenza treatment. METHODS: We constructed a linked dynamic transmission-economic evaluation model combining a modified susceptible-exposed-infected-recovered (SEIR) model and a decision tree model to evaluate the cost-effectiveness of adding BXM to oseltamivir in China's influenza pandemic scenario. The cost-effectiveness was evaluated for the general population from the Chinese healthcare system perspective, although the users of BXM and oseltamivir were influenza-infected persons. The SEIR model simulated the transmission dynamics, dividing the population into four compartments: susceptible, exposed, infected, and recovered, while the decision tree model assessed disease severity and costs. We utilized data from clinical trials and observational studies in the literature to parameterize the models. Costs were based on 2021 CN¥ and not discounted due to a short time-frame of one year in the model. One-way, two-way, and probabilistic sensitivity analyses were also conducted. RESULTS: The integrated model demonstrated that adding BXM to treatment choices reduced the cumulative incidence of infection from 49.49% to 43.26% and increased quality-adjusted life years (QALYs) by 0.00021 per person compared with oseltamivir alone in the base-case scenario. The intervention also amounted to a positive net monetary benefit of CN¥77.85 per person at the willingness to pay of CN¥80,976 per QALY. Sensitivity analysis confirmed the robustness of these findings, with consistent results across varied key parameters and assumptions. CONCLUSIONS: Adding BXM to treatment choices instead of only treating with oseltamivir for influenza pandemic control in China appears to be cost-effective compared with oseltamivir alone. The dual-agent strategy not only enhances population health outcomes and conserves resources, but also mitigates influenza transmission and alleviates healthcare burden.

Asunto(s)

Antivirales , Análisis Costo-Beneficio , Dibenzotiepinas , Gripe Humana , Modelos Económicos , Morfolinas , Oseltamivir , Pandemias , Piridonas , Triazinas , Humanos , Oseltamivir/economía , Oseltamivir/uso terapéutico , Gripe Humana/economía , Gripe Humana/prevención & control , Gripe Humana/tratamiento farmacológico , Gripe Humana/epidemiología , Antivirales/economía , Antivirales/uso terapéutico , China/epidemiología , Piridonas/economía , Piridonas/uso terapéutico , Triazinas/economía , Triazinas/uso terapéutico , Dibenzotiepinas/uso terapéutico , Dibenzotiepinas/economía , Morfolinas/economía , Morfolinas/uso terapéutico , Años de Vida Ajustados por Calidad de Vida , Salud Pública/economía , Árboles de Decisión , Tiepinas/uso terapéutico , Tiepinas/economía , Análisis de Costo-Efectividad

RESUMEN

OBJECTIVES: Immunocompromised patients may experience prolonged shedding of influenza virus potentially leading to severe infections. Alternatives to monotherapy with neuraminidase inhibitors should be evaluated to entirely suppress viral replication and prevent drug-resistant mutations. METHODS: We investigated the clinical and virological evolution in a case of persistent influenza A and human coronavirus OC43 (HCoV-OC43) coinfection in a hematopoietic stem cell transplant recipient after different therapeutic strategies. RESULTS: Successive oseltamivir and zanamivir monotherapies failed to control both infections, with positive results persisting for over 110 days each. This led to the emergence of highly resistant oseltamivir strains due to neuraminidase mutations (E119V and R292K) followed by a deletion (del245-248), while maintaining sensitivity to zanamivir. The intra-host viral diversity data showed that the treatments impacted viral diversity of influenza virus, but not of HCoV-OC43. Considering the patient's underlying condition and the impact of prolonged viral shedding on pulmonary function, eradicating the influenza virus was necessary. A 10-day regimen combining zanamivir and baloxavir-marboxil effectively controlled influenza virus replication and was associated with the clearance of HCoV-OC43, finally resulting in comprehensive respiratory recovery. CONCLUSION: These observations underscore the importance of further investigating combination treatments as the primary approach to achieve influenza eradication in immunocompromised patients.

Asunto(s)

Antivirales , Dibenzotiepinas , Trasplante de Células Madre Hematopoyéticas , Gripe Humana , Morfolinas , Piridonas , Triazinas , Zanamivir , Humanos , Zanamivir/uso terapéutico , Zanamivir/farmacología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Antivirales/uso terapéutico , Antivirales/farmacología , Gripe Humana/tratamiento farmacológico , Gripe Humana/virología , Piridonas/uso terapéutico , Dibenzotiepinas/uso terapéutico , Morfolinas/uso terapéutico , Triazinas/uso terapéutico , Triazinas/farmacología , Coronavirus Humano OC43/efectos de los fármacos , Coronavirus Humano OC43/genética , Farmacorresistencia Viral/genética , Virus de la Influenza A/efectos de los fármacos , Virus de la Influenza A/genética , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/virología , Huésped Inmunocomprometido , Masculino , Quimioterapia Combinada , Persona de Mediana Edad , Esparcimiento de Virus/efectos de los fármacos , Replicación Viral/efectos de los fármacos , Femenino

Asunto(s)

Anticonvulsivantes , Lamotrigina , Topiramato , Ácido Valproico , Humanos , Lamotrigina/uso terapéutico , Lamotrigina/efectos adversos , Topiramato/uso terapéutico , Topiramato/efectos adversos , Ácido Valproico/uso terapéutico , Ácido Valproico/efectos adversos , Anticonvulsivantes/uso terapéutico , Anticonvulsivantes/efectos adversos , Femenino , Trastorno Autístico/tratamiento farmacológico , Masculino , Niño , Fructosa/análogos & derivados , Fructosa/efectos adversos , Fructosa/uso terapéutico , Triazinas/uso terapéutico , Triazinas/efectos adversos , Preescolar

RESUMEN

mTORC1/2 dual inhibitors may be more effective than mTORC1 inhibitor rapamycin. However, their metabolic impacts on colon cancer cells remain unexplored. We conducted a comparative analysis of the anti-proliferative effects of rapamycin and the novel OSI-027 in colon cancer cells HCT-116, evaluating their metabolic influences through ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS/MS). Our results demonstrate that OSI-027 more effectively inhibits colon cancer cell proliferation than rapamycin. Additionally, we identified nearly 600 metabolites from the spectra, revealing significant differences in metabolic patterns between cells treated with OSI-027 and rapamycin. Through VIP value screening, we pinpointed crucial metabolites contributing to these distinctions. For inhibiting glycolysis and reducing glucose consumption, OSI-027 was likely to be more potent than rapamycin. For amino acids metabolism, although OSI-027 has a broad effect as rapamycin, their effects in degrees were not exactly the same. These findings address the knowledge gap regarding mTORC1/2 dual inhibitors and lay a foundation for their further development and research.

Asunto(s)

Neoplasias del Colon , Imidazoles , Diana Mecanicista del Complejo 1 de la Rapamicina , Diana Mecanicista del Complejo 2 de la Rapamicina , Metabolómica , Sirolimus , Triazinas , Humanos , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismo , Células HCT116 , Imidazoles/farmacología , Imidazoles/uso terapéutico , Cromatografía Líquida con Espectrometría de Masas , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Diana Mecanicista del Complejo 2 de la Rapamicina/antagonistas & inhibidores , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Metabolómica/métodos , Sirolimus/farmacología , Sirolimus/uso terapéutico , Espectrometría de Masas en Tándem , Triazinas/farmacología , Triazinas/uso terapéutico

RESUMEN

Comprehensive genomic profiling is highly recommended for treatment decision in nonsquamous, non-small cell lung cancer (NSCLC). However, rare genomic alterations are still being unveiled, with scarce data to guide therapy. Herein, we describe the treatment journey of a 56-year-old, never-smoker Caucasian woman with a metastatic NSCLC harboring a CD47-MET fusion, initially classified as a variant of unknown significance. She had undergone 3 lines of therapy over the course of 3 years, including chemotherapy, immunotherapy, and anti-angiogenic therapy. After reanalysis of her next-generation sequencing data in our service, the fusion was reclassified as likely oncogenic. The patient was started with fourth-line capmatinib, with a good tolerance so far and a complete metabolic response in the active sites of disease, currently ongoing for 18 months. In conclusion, we highlight the sensitivity of a novel MET fusion to capmatinib and emphasize the need for comprehensive panels in NSCLC and molecular tumor board discussions with specialized centers when rare findings arise.

Asunto(s)

Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Proteínas Proto-Oncogénicas c-met , Humanos , Femenino , Persona de Mediana Edad , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Proteínas Proto-Oncogénicas c-met/genética , Acrilamidas/uso terapéutico , Benzamidas/uso terapéutico , Proteínas de Fusión Oncogénica/genética , Triazinas/uso terapéutico , Imidazoles

RESUMEN

BACKGROUND: This study provides comparative evidence of the selective MET inhibitor capmatinib versus standard of care (SOC) in first-line (1 L) and second-line (2 L) non-small cell lung cancer (NSCLC) patients with METex14 mutations in German routine care. METHODS: SOC data were collected from German routine care via retrospective chart review. Analyses were conducted as naive and propensity score adjusted (PSA) comparisons to capmatinib-treated patients within the GEOMETRY mono-1 trial. Effectiveness endpoints included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), time to CNS progression (CNSprog), and exploratory safety endpoints. RESULTS: The SOC arm included 119 patients in 1 L and 46 in 2 L versus 60 patients in 1 L and 81 in 2 L treated with capmatinib, with balanced baseline characteristics after PSA. In 1 L, the naive comparison showed a significant benefit of capmatinib versus SOC for OS (median: 25.49 vs 14.59 months; HR 0.58; 95 % CI 0.39-0.87; P = 0.011), PFS (median: 12.45 vs 5.03 months; HR: 0.44; 95 % CI: 0.31-0.63; P < 0.001), and ORR (event rate: 68.3 vs 26.9 %; RR 2.54; 95 % CI 1.80-3.58; P < 0.001). In 2 L, OS, PFS, and ORR showed positive trends favoring capmatinib over SOC. Capmatinib treatment in the 1 L and 2 L led to significant benefit in CNSprog. PSA analyses showed consistent results to naive analysis. Exploratory safety endpoints indicated a manageable safety profile for capmatinib. CONCLUSIONS: The present study demonstrates the important role of capmatinib in providing robust clinically meaningful benefit to patients with NSCLC harboring METex14 mutations and its significant role in preventing the development of brain metastases.

Asunto(s)

Benzamidas , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Mutación , Proteínas Proto-Oncogénicas c-met , Triazinas , Humanos , 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 , Masculino , Femenino , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Persona de Mediana Edad , Anciano , Benzamidas/uso terapéutico , Alemania , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Triazinas/uso terapéutico , Triazinas/efectos adversos , Estudios Retrospectivos , Adulto , Anciano de 80 o más Años , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Imidazoles

RESUMEN

BACKGROUND: KRAS-mutant non-small cell lung cancer (NSCLC) shows a relatively low response rate to chemotherapy, immunotherapy and KRAS-G12C selective inhibitors, leading to short median progression-free survival, and overall survival. The MET receptor tyrosine kinase (c-MET), the cognate receptor of hepatocyte growth factor (HGF), was reported to be overexpressed in KRAS-mutant lung cancer cells leading to tumor-growth in anchorage-independent conditions. METHODS: Cell viability assay and synergy analysis were carried out in native, sotorasib and trametinib-resistant KRAS-mutant NSCLC cell lines. Colony formation assays and Western blot analysis were also performed. RNA isolation from tumors of KRAS-mutant NSCLC patients was performed and KRAS and MET mRNA expression was determined by real-time RT-qPCR. In vivo studies were conducted in NSCLC (NCI-H358) cell-derived tumor xenograft model. RESULTS: Our research has shown promising activity of omeprazole, a V-ATPase-driven proton pump inhibitor with potential anti-cancer properties, in combination with the MET inhibitor tepotinib in KRAS-mutant G12C and non-G12C NSCLC cell lines, as well as in G12C inhibitor (AMG510, sotorasib) and MEK inhibitor (trametinib)-resistant cell lines. Moreover, in a xenograft mouse model, combination of omeprazole plus tepotinib caused tumor growth regression. We observed that the combination of these two drugs downregulates phosphorylation of the glycolytic enzyme enolase 1 (ENO1) and the low-density lipoprotein receptor-related protein (LRP) 5/6 in the H358 KRAS G12C cell line, but not in the H358 sotorasib resistant, indicating that the effect of the combination could be independent of ENO1. In addition, we examined the probability of recurrence-free survival and overall survival in 40 early lung adenocarcinoma patients with KRAS G12C mutation stratified by KRAS and MET mRNA levels. Significant differences were observed in recurrence-free survival according to high levels of KRAS mRNA expression. Hazard ratio (HR) of recurrence-free survival was 7.291 (p = 0.014) for high levels of KRAS mRNA expression and 3.742 (p = 0.052) for high MET mRNA expression. CONCLUSIONS: We posit that the combination of the V-ATPase inhibitor omeprazole plus tepotinib warrants further assessment in KRAS-mutant G12C and non G12C cell lines, including those resistant to the covalent KRAS G12C inhibitors.

Asunto(s)

Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Mutación , Omeprazol , Proteínas Proto-Oncogénicas c-met , Proteínas Proto-Oncogénicas p21(ras) , 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 , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , Línea Celular Tumoral , Animales , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas c-met/metabolismo , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Omeprazol/farmacología , Omeprazol/uso terapéutico , Ratones , Piridinas/farmacología , Piridinas/uso terapéutico , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones Desnudos , Pirimidinonas/farmacología , Pirimidinonas/uso terapéutico , Femenino , Triazinas/farmacología , Triazinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Piperazinas , Piperidinas , Piridazinas , Piridonas

RESUMEN

We compared the duration of fever in children infected with A(H1N1)pdm09, A(H3N2), or influenza B viruses following treatment with baloxavir marboxil (baloxavir) or neuraminidase inhibitors (NAIs) (oseltamivir, zanamivir, or laninamivir). This observational study was conducted at 10 outpatient clinics across 9 prefectures in Japan during the 2012-2013 and 2019-2020 influenza seasons. Patients with influenza rapid antigen test positive were treated with one of four anti-influenza drugs. The type/subtype of influenza viruses were identified from MDCK or MDCK SIAT1 cell-grown samples using two-step real-time PCR. Daily self-reported body temperature after treatment were used to evaluate the duration of fever by treatment group and various underlying factors. Among 1742 patients <19 years old analyzed, 452 (26.0%) were A(H1N1)pdm09, 827 (48.0%) A(H3N2), and 463 (26.0%) influenza B virus infections. Among fours treatment groups, baloxavir showed a shorter median duration of fever compared to oseltamivir in univariate analysis for A(H1N1)pdm09 virus infections (baloxavir, 22.0 h versus oseltamivir, 26.7 h, P < 0.05; laninamivir, 25.5 h, and zanamivir, 25.0 h). However, this difference was not significant in multivariable analyses. For A(H3N2) virus infections, there were no statistically significant differences observed (20.3, 21.0, 22.0, and 19.0 h) uni- and multivariable analyses. For influenza B, baloxavir shortened the fever duration by approximately 15 h than NAIs (20.3, 35.0, 34.3, and 34.1 h), as supported by uni- and multivariable analyses. Baloxavir seems to have comparable clinical effectiveness with NAIs on influenza A but can be more effective for treating pediatric influenza B virus infections than NAIs.

Asunto(s)

Antivirales , Dibenzotiepinas , Fiebre , Guanidinas , Subtipo H1N1 del Virus de la Influenza A , Subtipo H3N2 del Virus de la Influenza A , Virus de la Influenza B , Gripe Humana , Morfolinas , Oseltamivir , Piranos , Piridonas , Ácidos Siálicos , Triazinas , Zanamivir , Humanos , Gripe Humana/tratamiento farmacológico , Gripe Humana/virología , Antivirales/uso terapéutico , Antivirales/farmacología , Virus de la Influenza B/efectos de los fármacos , Virus de la Influenza B/genética , Niño , Zanamivir/uso terapéutico , Zanamivir/análogos & derivados , Zanamivir/farmacología , Triazinas/uso terapéutico , Triazinas/farmacología , Guanidinas/uso terapéutico , Subtipo H3N2 del Virus de la Influenza A/efectos de los fármacos , Subtipo H3N2 del Virus de la Influenza A/genética , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Piridonas/uso terapéutico , Dibenzotiepinas/uso terapéutico , Japón , Femenino , Masculino , Preescolar , Oseltamivir/uso terapéutico , Fiebre/tratamiento farmacológico , Fiebre/virología , Adolescente , Morfolinas/uso terapéutico , Lactante , Estaciones del Año , Tiepinas/uso terapéutico , Tiepinas/farmacología , Oxazinas/uso terapéutico , Factores de Tiempo , Benzoxazinas/uso terapéutico

RESUMEN

OBJECTIVE: To provide up-to-date clinical guidance on the efficacy of lamotrigine in bipolar disorder (BD). METHODS: Eligible studies were identified during a systematic literature search according to PRISMA-guidelines. We included randomized controlled trials (RCTs) and cohort studies that quantitatively assessed lamotrigine's efficacy in BD. We divided the included studies into three groups: 1. acute treatment of depression, 2. acute treatment of mania and hypomania, and 3. maintenance treatment. Analyses were stratified by control group (placebo vs active comparator) and treatment strategy (monotherapy vs add-on treatment). RESULTS: We included 20 RCTs (n = 1166 lamotrigine users) and 20 cohort studies (n = 11,141 lamotrigine users). Twenty-four of these studies were included in meta-analyses. During depressive episodes, greater decreases in depressive symptomatology were associated with initiation of lamotrigine as add-on treatment than with placebo (SMD -0.30 [95% CI = -0.51, -0.10], df = 3, p = 0.004). Decreases in depressive symptomatology did not differ significantly between lamotrigine and the active comparator (SMD -0.28 [95% CI = -1.06, 0.50], df = 3, p = 0.488). As a maintenance treatment, lamotrigine was associated with a significantly lower relapse/recurrence rate than placebo (risk ratio (RR) 0.84 [95% CI = 0.71, 0.99], df = 2, p = 0.037). Relapse/recurrence rates did not differ significantly between lamotrigine and lithium (RR 1.06 [95% CI = 0.89, 1.25], df = 2, p = 0.513). A qualitative assessment of high-quality register-based studies found that lamotrigine was associated with lower hospital admission rates than other commonly used treatment regimes. CONCLUSIONS: There is substantial evidence for the efficacy of lamotrigine in BD, specifically as add-on treatment during acute depressive episodes and as maintenance treatment for preventing relapse and recurrence.

Asunto(s)

Trastorno Bipolar , Lamotrigina , Triazinas , Lamotrigina/uso terapéutico , Humanos , Trastorno Bipolar/tratamiento farmacológico , Triazinas/uso terapéutico , Antimaníacos/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento , Anticonvulsivantes/uso terapéutico

RESUMEN

It is imperative to optimize chemotherapy for heightened anti-tumor therapeutic efficacy. Unrestrained tumor cell proliferation and sustained angiogenesis are pivotal for cancer progression. Plinabulin, a vascular disrupting agent, selectively destroys tumor blood vessels. Tirapazamine (TPZ), a hypoxia-activated prodrug, intensifies cytotoxicity in diminishing oxygen levels within tumor cells. Despite completing Phase III clinical trials, both agents exhibited modest treatment efficiency due to dose-limiting toxicity. In this study, we employed methoxy poly(ethylene glycol)-b-poly(D,L-lactide) (mPEG-b-PDLLA) to co-deliver Plinabulin and TPZ to the tumor site, concurrently disrupting blood vessels and eliminating tumor cells, addressing both symptoms and the root cause of tumor progression. Plinabulin was converted into a prodrug with esterase response (PSM), and TPZ was synthesized into a hexyl chain-containing derivative (TPZHex) for effective co-delivery. PSM and TPZHex were co-encapsulated with mPEG-b-PDLLA, forming nanodrugs (PT-NPs). At the tumor site, PT-NPs responded to esterase overexpression, releasing Plinabulin, disrupting blood vessels, and causing nutritional and oxygen deficiency. TPZHex was activated in response to increased hypoxia, killing tumor cells. In treating 4T1 tumors, PT-NPs demonstrated enhanced therapeutic efficacy, achieving a 92.9 % tumor suppression rate and a 20 % cure rate. This research presented an innovative strategy to enhance synergistic efficacy and reduce toxicity in combination chemotherapy.

Asunto(s)

Polietilenglicoles , Tirapazamina , Tirapazamina/farmacología , Animales , Línea Celular Tumoral , Humanos , Polietilenglicoles/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Femenino , Ratones , Ratones Endogámicos BALB C , Neovascularización Patológica/tratamiento farmacológico , Triazinas/farmacología , Triazinas/química , Triazinas/uso terapéutico , Dicetopiperazinas

RESUMEN

BACKGROUND: The transmission of influenza virus in households, especially by children, is a major route of infection. Prior studies suggest that timely antiviral treatment of ill cases may reduce infection in household contacts. The aim of the study was to compare the effects of oseltamivir (OTV) and baloxavir marboxil (BXM) treatment of index cases on the secondary attack rate (SAR) of influenza within household. METHODS: A post hoc analysis was done in BLOCKSTONE trial-a placebo-controlled, double-blinded post-exposure prophylaxis of BXM. Data were derived from the laboratory-confirmed index cases' household contacts who received placebo in the trial and also from household members who did not participate in the trial but completed illness questionnaires. To assess the SAR of household members, multivariate analyses adjusted for factors including age, vaccination status, and household size were performed and compared between contacts of index cases treated with BXM or OTV. RESULTS: In total, 185 index cases (116 treated with BXM and 69 treated with OTV) and 410 household contacts (201 from trial, 209 by questionnaire) were included. The Poisson regression modeling showed that the SAR in household contacts of index cases treated with BXM and OTV was 10.8% and 18.5%, respectively; the adjusted relative reduction in SAR was 41.8% (95% confidence interval: 1.0%-65.7%, p = 0.0456) greater with BXM than OTV. Similar reductions were found in contacts from the trial and those included by questionnaire. CONCLUSION: BXM treatment of index cases appeared to result in a greater reduction in secondary household transmission than OTV treatment.

Asunto(s)

Antivirales , Dibenzotiepinas , Composición Familiar , Gripe Humana , Morfolinas , Oseltamivir , Profilaxis Posexposición , Piridonas , Triazinas , Humanos , Gripe Humana/tratamiento farmacológico , Gripe Humana/prevención & control , Gripe Humana/transmisión , Piridonas/uso terapéutico , Antivirales/uso terapéutico , Triazinas/uso terapéutico , Dibenzotiepinas/uso terapéutico , Femenino , Masculino , Oseltamivir/uso terapéutico , Adulto , Adolescente , Niño , Persona de Mediana Edad , Adulto Joven , Profilaxis Posexposición/métodos , Preescolar , Morfolinas/uso terapéutico , Tiepinas/uso terapéutico , Método Doble Ciego , Lactante , Piridinas/uso terapéutico , Anciano , Oxazinas/uso terapéutico

RESUMEN

With the increasing prevalence of type 2 diabetes mellitus (T2DM), it has become critical to identify effective treatment strategies. In recent years, the novel oral hypoglycaemic drug Imeglimin has attracted much attention in the field of diabetes treatment. The mechanisms of its therapeutic action are complex and are not yet fully understood by current research. Current evidence suggests that pancreatic ß-cells, liver, and skeletal muscle are the main organs in which Imeglimin lowers blood glucose levels and that it acts mainly by targeting mitochondrial function, thereby inhibiting hepatic gluconeogenesis, enhancing insulin sensitivity, promoting pancreatic ß-cell function, and regulating energy metabolism. There is growing evidence that the drug also has a potentially volatile role in the treatment of diabetic complications, including metabolic cardiomyopathy, diabetic vasculopathy, and diabetic neuroinflammation. According to available clinical studies, its efficacy and safety profile are more evident than other hypoglycaemic agents, and it has synergistic effects when combined with other antidiabetic drugs, and also has potential in the treatment of T2DM-related complications. This review aims to shed light on the latest research progress in the treatment of T2DM with Imeglimin, thereby providing clinicians and researchers with the latest insights into Imeglimin as a viable option for the treatment of T2DM.

Asunto(s)

Diabetes Mellitus Tipo 2 , Hipoglucemiantes , Mitocondrias , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Animales , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Triazinas/uso terapéutico , Triazinas/farmacología

RESUMEN

MET exon14 skipping mutations (METex14s) are rarely reported as a potential resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs). The efficacy of targeted therapy against METex14s emerging after osimertinib resistance is uncertain. Herein, we report a case of EGFR-mutated metastatic lung adenocarcinoma in which METex14 was detected in a re-biopsy upon first-line osimertinib resistance. The patient received capmatinib monotherapy as third-line therapy, which was ineffective, followed by an exceptional response to salvage therapy with afatinib. This report highlights the heterogeneity of EGFR-TKI resistance and that targeting rare resistance mechanisms remains challenging.

Asunto(s)

Acrilamidas , Adenocarcinoma del Pulmón , Compuestos de Anilina , Resistencia a Antineoplásicos , Receptores ErbB , Neoplasias Pulmonares , Proteínas Proto-Oncogénicas c-met , Humanos , Masculino , Acrilamidas/uso terapéutico , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Afatinib/uso terapéutico , Afatinib/administración & dosificación , Compuestos de Anilina/uso terapéutico , Antineoplásicos/uso terapéutico , Benzamidas/uso terapéutico , Resistencia a Antineoplásicos/genética , Receptores ErbB/genética , Exones/genética , Imidazoles , Indoles , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-met/genética , Pirimidinas , Terapia Recuperativa , Triazinas/uso terapéutico , Triazinas/administración & dosificación

RESUMEN

INTRODUCTION: ZSP1601 is a novel pan-phosphodiesterase inhibitor developed in China specifically for the treatment of nonalcoholic fatty liver disease (NAFLD). AIM: The aim is to develop a population pharmacokinetic (pop PK) model for ZSP1601 by integrating data from two clinical studies. This undertaking aims to deepen our understanding of the clinical factors that influence ZSP1601 exposure while simultaneously investigating exposure-response (ER) relationships related to efficacy and safety. The goal is to guide formulating optimal dosage strategies in the subsequent phases of clinical trials. METHODS: Analysis of pooled concentration-time data from 95 subjects, with 2647 observations from two clinical trials involving healthy volunteers and NAFLD patients, employed a nonlinear mixed-effects modeling approach to characterize ZSP1601 pharmacokinetics. Covariate impact on ZSP1601 pharmacokinetics was investigated, and relationships between ZSP1601 exposure, efficacy and safety endpoints were explored. RESULTS: A two-compartment model featuring sequential zero-order then first-order absorption and first-order elimination effectively described ZSP1601's pharmacokinetic profile. Covariate analyses identified body weight as a statistically significant factor affecting drug central volume, while FED (food consumption) influenced absorption rate constant and duration. The Sigmoid Emax model aptly captured exposure-response relationships for ALT (alanine aminotransferase), AST (aspartate aminotransferase), and LFC (liver fat content) percentage changes relative to baseline and ZSP1601 exposure levels (AUCss) on the 29th day. ZSP1601 exposure levels (Cmax1) exhibited a significant exposure-response relationship with headaches (p < 0.001). CONCLUSION: The PopPK model and ER analysis, based on available data, comprehensively characterizes ZSP1601's pharmacokinetic, safety and efficacy profile, aiding informed decisions regarding dosage selection for the drug's complete developmental trajectory. The exposure-response (ER) analysis yields quantitative insights into the optimal balance of efficacy and safety within different dosage regimens for patient administration. In light of these findings, the dose regimen of 100 mg administered twice daily is proposed for subsequent clinical investigations.

Asunto(s)

Relación Dosis-Respuesta a Droga , Modelos Biológicos , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Masculino , Adulto , Persona de Mediana Edad , Femenino , Triazinas/farmacocinética , Triazinas/administración & dosificación , Triazinas/uso terapéutico , Adulto Joven , Inhibidores de Fosfodiesterasa/farmacocinética , Inhibidores de Fosfodiesterasa/administración & dosificación