RESUMEN
PURPOSE: This retrospective real-world study compared overall survival (OS) between patients with BRCA wild-type (BRCAwt) recurrent epithelial ovarian cancer (OC) who received niraparib second-line maintenance (2LM) versus active surveillance (AS) using target trial emulation, cloning, inverse probability of censoring weighting (IPCW) methodology to minimize immortal time bias. METHODS: Eligible patients from a United States-based, deidentified, electronic health record-derived database were diagnosed with epithelial OC (January 1, 2011-May 31, 2021), were BRCAwt, and completed second-line (2L) therapy (January 1, 2017-March 2, 2022). Patient data were cloned at index (2L last treatment date), assigned to niraparib 2LM and AS cohorts, and censored when treatment deviated from clone assignment. Follow-up was measured from index to earliest of study end (May 31, 2022), last activity, or death. Median OS (mOS) and hazard ratios were estimated from stabilized IPCW Kaplan-Meier curves and Cox regression models. RESULTS: Overall, 199 patients received niraparib 2LM, and 707 had their care managed with AS. Key characteristics were balanced across cohorts after cloning and stabilized IPCW. Median follow-up was 15.6- and 9.3-months pre-cloning. IPCW mOS was 24.1 months (95% CI: 20.9-29.5) and 18.4 months (95% CI: 15.1-22.8) in niraparib 2LM and AS cohorts, respectively (hazard ratio, 0.77; 95% CI: 0.66-0.89). CONCLUSIONS: This real-world study provides supportive evidence of an OS benefit for patients with BRCAwt recurrent OC who received 2LM niraparib monotherapy compared with those whose care was managed with AS. The analytic strategies implemented were useful in minimizing immortal time bias and measured confounding.
Asunto(s)
Indazoles , Recurrencia Local de Neoplasia , Neoplasias Ováricas , Piperidinas , Humanos , Femenino , Piperidinas/uso terapéutico , Piperidinas/administración & dosificación , Indazoles/uso terapéutico , Indazoles/administración & dosificación , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/mortalidad , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/mortalidad , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Adulto , Espera Vigilante , Estados Unidos/epidemiología , Quimioterapia de Mantención/métodos , Bases de Datos FactualesRESUMEN
Donepezil (DPZ), a piperidine-based reversible cholinesterase inhibitor, finds extensive use in treating Alzheimer's disease (AD). Originally designed as an oral formulation, DPZ encounters drawbacks such as a brief duration of action and reduced treatment effectiveness in elderly patients with memory impairment or difficulty swallowing medications. To address these issues and improve patient compliance, researchers are actively exploring alternative DPZ formulations. Consequently, reliable methods are necessary to quantitate DPZ in biological samples for in vivo assessment. Therefore, we propose an efficient, sensitive, wide-dynamic, and cost-effective method for quantitating DPZ in rat plasma. Our method employs liquid-liquid extraction (LLE) followed by liquid chromatography and tandem mass spectrometry, enabling in vivo evaluation of novel DPZ formulations. Notably, our method requires only 20 µL of rat plasma and employs icopezil as the internal standard-a cost-effective compound with chemical similarity to DPZ. We meticulously optimized LLE conditions, taking into account factor interactions through design of experiments (DOE). Our rapid and straightforward extraction and purification involved using 500 µL of pure methyl tert-butyl ether to extract DPZ from the sample within five minutes. The dynamic range of the method extends from 0.5 ng/mL to 1,000 ng/mL, demonstrating excellent sensitivity and suitability for pharmacokinetic studies across diverse DPZ formulations. Following the FDA guidelines, we rigorously validated the developed method, evaluating selectivity, linearity (with a coefficient of determination ≥0.9999), accuracy (ranging from 96.0% to 109.6%), precision (≤13.9%), matrix effect (92.2% to 103.8%), recovery (98.5% to 106.8%), the lower limit of quantitation (0.5 ng/mL), and stability. Finally, we effectively employed the validated method for the long-term pharmacokinetic assessment of a DPZ formulation. We expect that this approach will make a substantial contribution to the advancement of new DPZ formulations, ultimately benefiting individuals afflicted by AD.
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Donepezilo , Extracción Líquido-Líquido , Piperidinas , Espectrometría de Masas en Tándem , Donepezilo/sangre , Donepezilo/farmacocinética , Animales , Espectrometría de Masas en Tándem/métodos , Extracción Líquido-Líquido/métodos , Ratas , Cromatografía Liquida/métodos , Piperidinas/sangre , Piperidinas/farmacocinética , Piperidinas/química , Inhibidores de la Colinesterasa/sangre , Inhibidores de la Colinesterasa/farmacocinética , Indanos/sangre , Indanos/farmacocinética , Masculino , Reproducibilidad de los Resultados , Ratas Sprague-Dawley , Cromatografía Líquida con Espectrometría de MasasRESUMEN
Patients on B cell immunosuppressive treatments have been shown to have persistent infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this report, a woman treated with ibrutinib for chronic lymphocytic leukemia experienced more than 40 days of coronavirus disease 2019 (COVID-19) infection. Unexpectedly, her peripheral blood experiments showed a normal SARS-CoV-2-specific antibody level and a relatively elevated percentage of CD19 + B cells, while an obvious decrease in the percentages of NK cells, CD4 + T cells and CD8 + T cells. Further SARS-CoV-2-specific T cell analysis in this patient indicated a significant decrease in the percentage of SARS-CoV-2-specific IFN-γ, TNF-α or IL-2 producing CD4 + T or CD8 + T cells. Most notably, ten days after the cease of ibrutinib, the PCR for SARS-CoV-2 turned negative and the reduced proportions of peripheral CD4 + T cells and CD8 + T cells recovered. Our research predicted that the depleted B-cell function therapies may play considerable role in the development of long COVID-19 and the abnormal T-cell subset distribution might be the underlying mechanism.
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Adenina , COVID-19 , Leucemia Linfocítica Crónica de Células B , Piperidinas , SARS-CoV-2 , Esparcimiento de Virus , Humanos , Adenina/análogos & derivados , Adenina/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Piperidinas/uso terapéutico , Femenino , COVID-19/virología , Linfocitos T CD8-positivos/inmunología , Pirimidinas/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Anciano , Pirazoles/uso terapéutico , Persona de Mediana EdadRESUMEN
Tepotinib is approved for the treatment of patients with non-small-cell lung cancer harboring MET exon 14 skipping alterations. While edema is the most prevalent adverse event (AE) and a known class effect of MET inhibitors including tepotinib, there is still limited understanding about the factors contributing to its occurrence. Herein, we apply machine learning (ML)-based approaches to predict the likelihood of occurrence of edema in patients undergoing tepotinib treatment, and to identify factors influencing its development over time. Data from 612 patients receiving tepotinib in five Phase I/II studies were modeled with two ML algorithms, Random Forest, and Gradient Boosting Trees, to predict edema AE incidence and severity. Probability calibration was applied to give a realistic estimation of the likelihood of edema AE. Best model was tested on follow-up data and on data from clinical studies unused while training. Results showed high performances across all the tested settings, with F1 scores up to 0.961 when retraining the model with the most relevant covariates. The use of ML explainability methods identified serum albumin as the most informative longitudinal covariate, and higher age as associated with higher probabilities of more severe edema. The developed methodological framework enables the use of ML algorithms for analyzing clinical safety data and exploiting longitudinal information through various covariate engineering approaches. Probability calibration ensures the accurate estimation of the likelihood of the AE occurrence, while explainability tools can identify factors contributing to model predictions, hence supporting population and individual patient-level interpretation.
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Carcinoma de Pulmón de Células no Pequeñas , Edema , Aprendizaje Automático , Humanos , Edema/inducido químicamente , Femenino , Masculino , Persona de Mediana Edad , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Anciano , Neoplasias Pulmonares/tratamiento farmacológico , Ensayos Clínicos Fase II como Asunto , Pirimidinas/efectos adversos , Pirimidinas/administración & dosificación , Ensayos Clínicos Fase I como Asunto , Adulto , Antineoplásicos/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Piperidinas , PiridazinasRESUMEN
Objective: To observe the effects of targeting and blocking cannabinoid receptor 1 (CB1R) on mouse spleen immune function and inflammatory response under chronic intermittent hypoxia (CIH) conditions, and to explore its regulatory effort. Methods: Forty SPF male C57BL/6 mice aged 4 to 5 weeks,from May 2021 to August 2021 in Experimental Animal Center of the Second Hospital of Shanxi Medical University, were randomly divided into normal oxygen control group (NC), 6-week CIH group (6w CIH), 10-week CIH group (10w CIH), 6-week CIH+CB1R group (6w CIH+AM251) and 10-week CIH+CB1R group (10w CIH+AM251) according to the method of random number table. The advanced programmable intermittent low oxygen chamber was used to prepare the CIH mouse model. The morphological structure of spleen tissue of CIH mice was stained by hematoxylin-eosin (HE) staining. The expression levels of M1 and M2 macrophage surface markers CD86, CD206 were determined by immunofluorescence. The mRNA expression levels of CB1R, CD86, CD206 and the relative expression levels of RORγt and Foxp3,which are characteristic transcriptional regulators of T helper 17(Th17) and Treg cells were detected by quantitative reverse transcriptase PCR(qRT-PCR). The expression of inflammatory factors IL-6 and IL-10 was determined by ELISA. SPSS 26.0 and Graphpad prism 8.3 were used to analyze the data. Results: (1) Compared with NC group, spleen tissue structure was disordered, fibrous tissue hyperplasia, lymphocyte proliferation and disordered arrangement in periarteriole lymphatic sheath in CIH group. The expression of CB1R in CIH group was higher than that in NC group (P<0.05), and with the prolongation of CIH time, the expression of 10w CIH group was higher than that in 6w CIH group(P<0.05). The expression of CB1R in CIH+AM251 group was lower than that in the corresponding CIH group(all P<0.05). (2) Compared with NC group, the expression level of CD86 in macrophages in CIH group was higher than that in NC group(all P<0.05). The relative expression of RORγt in 6w and 10w CIH groups was 0.76±0.03 and 0.91±0.04, respectively, which was higher than that in NC group (0.65±0.06)(all P<0.05). The relative expression levels of inflammatory factor IL-6 were 10.80±1.73 and 14.86±0.01, respectively, which were higher than 6.69±0.23 in the NC group (all P<0.05). The expression level of CD206 in macrophages in the CIH+AM251 group was higher than that in the CIH group(all P<0.05). The relative expression levels of Foxp3 in 6w and 10w CIH+AM251 groups were 0.62±0.05 and 0.32±0.21, respectively, which were higher than those in 6w CIH group (0.28±0.02) and 10w CIH group (0.02±0.01)(P<0.05). The relative expression levels of anti-inflammatory factor IL-10 were 668.45±15.71 and 379.15±56.84, respectively, which were higher than those in CIH group (all P<0.05). Conclusion: Targeted sealing of CB1R may alleviate inflammatory response of mouse spleen under CIH conditions by regulating macrophage polarization and the expression of inflammatory factors, and may have some protective effect.
Asunto(s)
Hipoxia , Inflamación , Receptor Cannabinoide CB1 , Bazo , Animales , Masculino , Ratones , Modelos Animales de Enfermedad , Hipoxia/metabolismo , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Ratones Endogámicos C57BL , Piperidinas/farmacología , Pirazoles/farmacología , Receptor Cannabinoide CB1/metabolismo , Bazo/metabolismo , Linfocitos T Reguladores/inmunologíaRESUMEN
Introduction: Bruton's tyrosine kinase (BTK) and interleukin (IL)-2 Inducible T-cell Kinase (ITK) inhibitors have anti-inflammatory properties. We investigated the therapeutic effect of ibrutinib, an orally bioavailable BTK/ITK inhibitor, in a mouse model of Graves' orbitopathy (GO). Methods: Genetic immunization was performed through intramuscular administration of the recombinant plasmid, pCMV6-hTSHR cDNA, to 8-week-old female BALB/c mice. Serum levels of T3, T4, and thyroid-stimulating hormone receptor (TSHR) antibodies (TRAbs) were quantified using enzyme-linked immunosorbent assay. Histopathological changes in orbital tissues were examined using immunohistochemistry (IHC) staining for TSHR and various inflammatory markers. Following successful genetic immunization, ibrutinib was orally administered daily for 2 weeks in the GO model mice. After treatment, the mRNA and protein expression levels of BTK, ITK, IL-1ß, and IL-6 in orbital tissues were evaluated using real-time PCR and Western blotting. Results: In total, 20 mice were sacrificed to confirm successful genetic immunization. The GO mouse group exhibited significantly increased serum T3, T4, and TRAb levels. IHC revealed increased expression of TSHR, IL-1ß, IL-6, transforming growth factor-ß1, interferon-γ, CD40, CD4, BTK, and ITK in the GO mouse model. The orbital inflammation was significantly attenuated in ibrutinib-treated mice. The mRNA and protein expression levels of BTK, ITK, IL-1ß, and IL-6 in orbital tissue were lower in ibrutinib-treated GO mouse group compared to the phosphate-buffered saline-treated GO mouse group. Conclusion: The GO mouse model demonstrated enhanced BTK and ITK expression. Ibrutinib, a BTK/ITK inhibitor, suppressed the inflammatory cytokine production. These findings highlight the potential involvement of BTK/ITK in the inflammatory pathogenesis of GO, suggesting its role as a novel therapeutic target.
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Adenina , Agammaglobulinemia Tirosina Quinasa , Modelos Animales de Enfermedad , Oftalmopatía de Graves , Inflamación , Ratones Endogámicos BALB C , Piperidinas , Pirimidinas , Animales , Oftalmopatía de Graves/tratamiento farmacológico , Oftalmopatía de Graves/metabolismo , Oftalmopatía de Graves/patología , Adenina/análogos & derivados , Piperidinas/uso terapéutico , Ratones , Femenino , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Agammaglobulinemia Tirosina Quinasa/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/patología , Pirimidinas/uso terapéutico , Pirazoles/uso terapéutico , Pirazoles/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Receptores de Tirotropina/metabolismo , Receptores de Tirotropina/genética , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and STAT3 has emerged as an effective drug target for TNBC treatment. Herein, we employed a scaffold-hopping strategy of natural products to develop a series of naphthoquinone-furopiperidine derivatives as novel STAT3 inhibitors. The in vitro assay showed that compound 10g possessed higher antiproliferative activity than Cryptotanshinone and Napabucasin against TNBC cell lines, along with lower toxicity and potent antitumor activity in a TNBC xenograft model. Mechanistically, 10g could inhibit the phosphorylation of STAT3 and the binding affinity was determined by the SPR assay (KD = 8.30 µM). Molecule docking studies suggested a plausible binding mode between 10g and the SH2 domain, in which the piperidine fragment and the terminal hydroxy group of 10g played an important role in demonstrating the success of this evolution strategy. These findings provide a natural product-inspired novel STAT3 inhibitor for TNBC treatment.
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Antineoplásicos , Productos Biológicos , Proliferación Celular , Simulación del Acoplamiento Molecular , Naftoquinonas , Piperidinas , Factor de Transcripción STAT3 , Neoplasias de la Mama Triple Negativas , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/metabolismo , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Naftoquinonas/farmacología , Naftoquinonas/química , Naftoquinonas/síntesis química , Naftoquinonas/uso terapéutico , Productos Biológicos/farmacología , Productos Biológicos/química , Productos Biológicos/síntesis química , Piperidinas/farmacología , Piperidinas/química , Piperidinas/síntesis química , Piperidinas/uso terapéutico , Animales , Femenino , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ratones , Relación Estructura-Actividad , Ratones Desnudos , Ensayos Antitumor por Modelo de Xenoinjerto , Descubrimiento de Drogas , Ratones Endogámicos BALB C , Ensayos de Selección de Medicamentos AntitumoralesRESUMEN
Chronic lymphocytic leukemia (CLL) is a B-cell-derived hematologic malignancy whose progression depends on active B-cell receptor (BCR) signaling. Despite the spectacular efficacy of Ibrutinib, an irreversible inhibitor of Bruton tyrosine kinase (BTK), resistance can develop in CLL patients, and alternative therapeutic strategies are therefore required. Cancer immunotherapy has revolutionized cancer care and may be an attractive approach in this context. We speculated that characterizing the immune responses of CLL patients may highlight putative immunotherapeutic targets. Here, we used high-dimensional spectral flow cytometry to compare the distribution and phenotype of non-B-cell immune populations in the circulating blood of CLL patients treated with Ibrutinib displaying a complete response or secondary progression. Although no drastic changes were observed in the composition of their immune subsets, the Ibrutinib-resistant group showed increased cycling of CD8+ T cells, leading to their overabundance at the expense of dendritic cells. In addition, the expression of 11 different surface checkpoints was similar regardless of response status. Together, this suggests that CLL relapse upon Ibrutinib treatment may not lead to major alterations in the peripheral immune response.
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Adenina , Inmunofenotipificación , Leucemia Linfocítica Crónica de Células B , Piperidinas , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/sangre , Leucemia Linfocítica Crónica de Células B/inmunología , Adenina/análogos & derivados , Adenina/uso terapéutico , Adenina/farmacología , Piperidinas/uso terapéutico , Piperidinas/farmacología , Masculino , Femenino , Anciano , Persona de Mediana Edad , Anciano de 80 o más Años , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Células Sanguíneas/efectos de los fármacos , Células Sanguíneas/metabolismo , Pirimidinas/uso terapéutico , Pirimidinas/farmacología , Resistencia a Antineoplásicos/efectos de los fármacosRESUMEN
Intrahepatic cholangiocarcinoma (ICC) is a universally lethal malignancy with increasing incidence. However, ICC patients receive limited benefits from current drugs; therefore, we must urgently explore new drugs for treating ICC. Quinolizidine alkaloids, as essential active ingredients extracted from Sophora alopecuroides Linn, can suppress cancer cell growth via numerous mechanisms and have therapeutic effects on liver-related diseases. However, the impact of quinolizidine alkaloids on intrahepatic cholangiocarcinoma has not been fully studied. In this article, the in vitro anti-ICC activities of six natural quinolizidine alkaloids were explored. Aloperine was the most potent antitumor compound among the tested quinolizidine alkaloids, and it preferentially inhibited RBE cells rather than HCCC-9810 cells. Mechanistically, aloperine can potentially decrease glutamate content by inhibiting the hydrolysis of glutamine, reducing D-2-hydroxyglutarate levels and, consequently, leading to preferential growth inhibition in isocitrate dehydrogenase (IDH)-mutant ICC cells. In addition, aloperine preferentially resensitizes RBE cells to 5-fluorouracil, AGI-5198 and olaparib. This article demonstrates that aloperine shows preferential antitumor effects in intrahepatic cholangiocarcinoma cells harboring the mutant IDH1 by decreasing D-2-hydroxyglutarate, suggesting that aloperine could be used as a lead compound or adjuvant chemotherapy drug to treat ICC harboring the mutant IDH.
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Antineoplásicos , Neoplasias de los Conductos Biliares , Colangiocarcinoma , Isocitrato Deshidrogenasa , Mutación , Piperidinas , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patología , Humanos , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/metabolismo , Neoplasias de los Conductos Biliares/patología , Línea Celular Tumoral , Piperidinas/farmacología , Antineoplásicos/farmacología , Quinolizidinas/farmacología , Proliferación Celular/efectos de los fármacosRESUMEN
A series of novel piperidamide-3-carboxamide derivatives were synthesized and evaluated for their inhibitory activities against cathepsin K. Among these derivatives, compound H-9 exhibited the most potent inhibition, with an IC50 value of 0.08 µM. Molecular docking studies revealed that H-9 formed several hydrogen bonds and hydrophobic interactions with key active-site residues of cathepsin K. In vitro, H-9 demonstrated anti-bone resorption effects that were comparable to those of MIV-711, a cathepsin K inhibitor currently in phase 2a clinical trials for the treatment of bone metabolic disease. Western blot analysis confirmed that H-9 effectively downregulated cathepsin K expression in RANKL-reduced RAW264.7 cells. Moreover, in vivo experiments showed that H-9 increased the bone mineral density of OVX-induced osteoporosis mice. These results suggest that H-9 is a potent anti-bone resorption agent targeting cathepsin K and warrants further investigation for its potential anti-osteoporosis values.
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Catepsina K , Simulación del Acoplamiento Molecular , Osteoporosis , Piperidinas , Catepsina K/antagonistas & inhibidores , Catepsina K/metabolismo , Animales , Ratones , Osteoporosis/tratamiento farmacológico , Osteoporosis/metabolismo , Piperidinas/farmacología , Piperidinas/química , Piperidinas/síntesis química , Células RAW 264.7 , Resorción Ósea/tratamiento farmacológico , Femenino , Densidad Ósea/efectos de los fármacos , Ligando RANK/metabolismo , Relación Estructura-Actividad , Humanos , Estructura MolecularRESUMEN
Alzheimer's disease is associated with a progressive loss of neurons and synaptic connections in the cholinergic system. Oxidative stress contributes to neuronal damages and to the development of amyloid plaques and neurofibrillary tangles. Therefore, antioxidants have been widely studied to mitigate the progression of Alzheimer's disease, and among these, lipoic acid has demonstrated a neuroprotective effect. Here, we present the synthesis, the molecular modelling, and the evaluation of lipoic acid-donepezil hybrids based on O-desmethyldonepezil. As compounds 5 and 6 display a high inhibition of acetylcholinesterase (IC50 = 7.6 nM and 9.1 nM, respectively), selective against butyrylcholinesterase, and a notable neuroprotective effect, slightly better than that of lipoic acid, the present study suggests that O-desmethyldonepezil could serve as a platform for the straightforward design of donepezil hybrids.
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Acetilcolinesterasa , Enfermedad de Alzheimer , Butirilcolinesterasa , Inhibidores de la Colinesterasa , Donepezilo , Indanos , Fármacos Neuroprotectores , Piperidinas , Ácido Tióctico , Ácido Tióctico/química , Ácido Tióctico/farmacología , Ácido Tióctico/síntesis química , Donepezilo/farmacología , Donepezilo/química , Donepezilo/síntesis química , Enfermedad de Alzheimer/tratamiento farmacológico , Piperidinas/química , Piperidinas/farmacología , Piperidinas/síntesis química , Indanos/química , Indanos/farmacología , Indanos/síntesis química , Humanos , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/química , Acetilcolinesterasa/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Butirilcolinesterasa/metabolismo , Relación Estructura-Actividad , Estructura Molecular , Relación Dosis-Respuesta a Droga , Modelos MolecularesRESUMEN
A novel series of 3-amino-piperidin-2-one-based calcitonin gene-related peptide (CGRP) receptor antagonists was invented based upon the discovery of unexpected structure-activity observations. Initial exploration of the structure-activity relationships enabled the generation of a moderately potent lead structure (4). A series of modifications, including ring contraction and inversion of stereocenters, led to surprising improvements in CGRP receptor affinity. These studies identified compound 23, a structurally novel potent, orally bioavailable CGRP receptor antagonist.
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Piperidinas , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/farmacología , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/química , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/síntesis química , Relación Estructura-Actividad , Humanos , Piperidinas/química , Piperidinas/farmacología , Piperidinas/síntesis química , Animales , Ratas , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Estructura MolecularRESUMEN
OBJECTIVE: To evaluate the long-term efficacy and safety of niraparib in Japanese women with heavily pretreated ovarian cancer. METHODS: This was the follow-up analysis of a phase 2, multicenter, open-label, single-arm study in Japanese women with homologous recombination-deficient, platinum-sensitive, relapsed, high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who had completed 3-4 lines of chemotherapy and were poly(ADP-ribose) polymerase inhibitor naïve. Participants received niraparib (starting dose, 300 mg) once daily in continuous 28-day cycles until objective disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was confirmed objective response rate (ORR), as assessed using Response Evaluation Criteria in Solid Tumors version 1.1. Safety evaluations included treatment-emergent adverse events (TEAEs). RESULTS: 20 patients were enrolled in the study and included in both efficacy and safety analyses. Median total study duration was 759.5 days. Median dose intensity was 201.3 mg/day. Confirmed ORR was 60.0% (90% confidence interval [CI]=39.4-78.3); 2 patients had complete response and 10 patients had partial response. Median duration of response was 9.9 months (95% CI=3.9-26.9) and the disease control rate was 90.0% (95% CI=68.3-98.8). The most common TEAEs were anemia (n=15), nausea (n=12), and decreased platelet count (n=11). TEAEs leading to study drug dose reduction, interruption, or discontinuation were reported in 16 (80.0%), 15 (75.0%), and 2 patients (10.0%), respectively. CONCLUSION: The long-term efficacy and safety profile of niraparib was consistent with previous findings in the equivalent population in non-Japanese patients. No new safety signals were identified. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03759600.
Asunto(s)
Indazoles , Neoplasias Ováricas , Piperidinas , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Humanos , Femenino , Persona de Mediana Edad , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Anciano , Indazoles/efectos adversos , Indazoles/administración & dosificación , Indazoles/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Piperidinas/efectos adversos , Piperidinas/administración & dosificación , Piperidinas/uso terapéutico , Adulto , Japón , Ftalazinas/efectos adversos , Ftalazinas/administración & dosificación , Ftalazinas/uso terapéutico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Neoplasias de las Trompas Uterinas/tratamiento farmacológico , Recombinación Homóloga , Neoplasias Peritoneales/tratamiento farmacológico , Pueblos del Este de AsiaRESUMEN
BACKGROUND: Glioblastoma is a highly malignant disease with limited treatment options. Ibrutinib, a covalent Bruton tyrosine kinase inhibitor, is an oral agent with manageable side effects used for hematological diseases including Waldenström macroglobulinemia. We present the case of a 69-year-old Caucasian male patient treated with ibrutinib for suspected Bing-Neel syndrome (BNS), which following a biopsy, was reclassified as glioblastoma. CASE PRESENTATION: In December 2018, a 69-year-old Caucasian male patient was diagnosed with Waldenström macroglobulinemia. As the patient was asymptomatic, without bone marrow failure or high M-component count, watchful waiting was initiated. Due to increasing neurological symptoms, the patient, based on magnetic resonance imaging, was diagnosed with Bing-Neel syndrome in May 2019. The patient received different treatments before starting ibrutinib monotherapy in August 2019 due to disease progression, both on magnetic resonance imaging and clinically. The patient remained clinically stable for 7 months. In March 2020, the patient developed headaches, and both magnetic resonance imaging and a biopsy revealed glioblastoma IDH-wildtype. Treatment was changed in line with the new diagnosis, but the patient died at the end of 2020. CONCLUSION: We present a case in which a patient with glioblastoma IDH-wildtype remained clinically stable for 7 months when treated with ibrutinib monotherapy, which is similar to what would be expected for the standard treatment for glioblastoma. To our knowledge, this is the first patient receiving ibrutinib for a glioblastoma IDH-wildtype with a meaningful clinical outcome. Our case may therefore support previous nonclinical findings, indicating a therapeutic value of ibrutinib in patients with glioblastoma and support for further investigation of ibrutinib as a possible treatment for glioblastoma.
Asunto(s)
Adenina , Glioblastoma , Imagen por Resonancia Magnética , Piperidinas , Macroglobulinemia de Waldenström , Humanos , Adenina/análogos & derivados , Adenina/uso terapéutico , Masculino , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Anciano , Piperidinas/uso terapéutico , Macroglobulinemia de Waldenström/tratamiento farmacológico , Resultado Fatal , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/secundario , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
Epithelial-to-mesenchymal transition (EMT) plays a major role in breast cancer progression and the development of drug resistance. We have previously demonstrated a trans-differentiation therapeutic approach targeting invasive dedifferentiated cancer cells. Using a combination of PPARγ agonists and MEK inhibitors, we forced the differentiation of disseminating breast cancer cells into post-mitotic adipocytes. Utilizing murine breast cancer cells, we demonstrated a broad class effect of PPARγ agonists and MEK inhibitors in inducing cancer cell trans-differentiation into adipocytes. Both Rosiglitazone and Pioglitazone effectively induced adipogenesis in cancer cells, marked by PPARγ and C/EBPα upregulation, cytoskeleton rearrangement, and lipid droplet accumulation. All tested MEK inhibitors promoted adipogenesis in the presence of TGFß, with Cobimetinib showing the most prominent effects. A metastasis ex vivo culture from a patient diagnosed with triple-negative breast cancer demonstrated a synergistic upregulation of PPARγ with the combination of Pioglitazone and Cobimetinib. Our results highlight the potential for new therapeutic strategies targeting cancer cell plasticity and the dedifferentiation phenotype in aggressive breast cancer subtypes. Combining differentiation treatments with standard therapeutic approaches may offer a strategy to overcome drug resistance.
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Diferenciación Celular , PPAR gamma , Pioglitazona , PPAR gamma/metabolismo , PPAR gamma/agonistas , Humanos , Animales , Ratones , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Femenino , Pioglitazona/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Adipogénesis/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Rosiglitazona/farmacología , Azetidinas/farmacología , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Piperidinas/farmacologíaRESUMEN
BACKGROUND: We report the final results of treatment with aripiprazole, blonanserin, and paliperidone from the Japan Useful Medication Program for Schizophrenia (JUMPs), a 104-week naturalistic study. METHODS: JUMPs was an open-label, three-arm, randomized, parallel-group, 104-week study. Patients aged ≥ 20 years with schizophrenia requiring antipsychotic treatment or a switch from previous therapy were enrolled. The primary endpoint was treatment discontinuation rate over 104 weeks. Secondary endpoints included remission rate, Personal and Social Performance (PSP), safety, Positive and Negative Syndrome Scale (PANSS), and quality of life (QOL; EuroQol-5 dimension). RESULTS: In total, 251 patients received aripiprazole (n = 82), blonanserin (n = 85), or paliperidone (n = 84). Treatment discontinuation rates (aripiprazole, 80.5%; blonanserin, 81.2%; paliperidone, 71.4%) were not significantly different (p = 0.2385) among the treatment groups at 104 weeks; comparable outcomes were observed for endpoints, including remission (42.9%, 46.7%, and 45.8%), PANSS, and safety. In the overall cohort, while the improvement in the PSP total score at Week 104 was not significantly different from baseline, a significant improvement (p < 0.05) in QOL and total PANSS scores (including all subscales) was observed at Week 104 compared with baseline. Multivariable analysis identified a shorter disease duration and a higher chlorpromazine-equivalent antipsychotic dosage level (≥ 1000 mg) before switching to monotherapy as predictors of treatment discontinuation. CONCLUSIONS: The 104-week treatment outcomes were comparable between groups; the overall trend of improvement in remission rate, safety, and QOL suggests the importance of continued treatment. CLINICAL TRIAL REGISTRATION: UMIN-Clinical Trials Registry UMIN000007942 (public release date: 14/05/2012).
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Antipsicóticos , Aripiprazol , Palmitato de Paliperidona , Calidad de Vida , Esquizofrenia , Humanos , Esquizofrenia/tratamiento farmacológico , Antipsicóticos/uso terapéutico , Masculino , Femenino , Adulto , Aripiprazol/uso terapéutico , Palmitato de Paliperidona/uso terapéutico , Palmitato de Paliperidona/administración & dosificación , Persona de Mediana Edad , Piperazinas/uso terapéutico , Piperidinas/uso terapéutico , Resultado del Tratamiento , Inducción de Remisión , Japón , Escalas de Valoración Psiquiátrica , Psicología del EsquizofrénicoRESUMEN
ß-site amyloid precursor protein cleaving enzyme (BACE1) represents a key target for Alzheimer's disease (AD) therapy because it is essential for producing the toxic amyloid ß (Aß) peptide that plays a crucial role in the disease's development. BACE1 inhibitors are a promising approach to reducing Aß levels in the brain and preventing AD progression. However, systemic delivery of such inhibitors to the brain demonstrates limited efficacy because of the presence of the blood-brain barrier (BBB). Nose-to-brain (NtB) delivery has the potential to overcome this obstacle. Liposomal drug delivery systems offer several advantages over traditional methods for delivering drugs and nucleic acids from the nose to the brain. The current study aims to prepare, characterize, and evaluate in vitro liposomal forms of donepezil, memantine, BACE-1 siRNA, and their combination for possible treatment of AD via NtB delivery. All the liposomal formulations were prepared using the rotary evaporation method. Their cellular internalization, cytotoxicity, and the suppression of beta-amyloid plaque and other pro-inflammatory cytokine expressions were studied. The Calu-3 Transwell model was used as an in vitro system for mimicking the anatomical and physiological conditions of the nasal epithelium and studying the suitability of the proposed formulations for possible NtB delivery. The investigation results show that liposomes provided the effective intracellular delivery of therapeutics, the potential to overcome tight junctions in BBB, reduced beta-amyloid plaque accumulation and pro-inflammatory cytokine expression, supporting the therapeutic potential of our approach.
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Administración Intranasal , Enfermedad de Alzheimer , Secretasas de la Proteína Precursora del Amiloide , Ácido Aspártico Endopeptidasas , Donepezilo , Liposomas , ARN Interferente Pequeño , Enfermedad de Alzheimer/tratamiento farmacológico , Humanos , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , ARN Interferente Pequeño/administración & dosificación , Donepezilo/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Piperidinas/administración & dosificación , Piperidinas/farmacocinética , Piperidinas/farmacología , Mucosa Nasal/metabolismo , Mucosa Nasal/efectos de los fármacos , Indanos/administración & dosificación , Indanos/farmacocinética , Péptidos beta-Amiloides/metabolismoRESUMEN
BACKGROUND: Postoperative ileus (POI) is a common complication following abdominal surgery, often leading to extended hospital stays and a higher risk of post-operative complications, leading to poorer patient outcomes. Alvimopan, a peripherally acting µ-opioid receptor antagonist, has been shown to aid in the recovery of normal bowel function after surgery. While its benefits are well-established in open abdominal surgeries, its efficacy in laparoscopic procedures had not been conclusively determined. However, recent clinical trials involving laparoscopic surgeries have since been conducted. This review aims to reassess the efficacy of Alvimopan by incorporating findings from these new studies, potentially providing further insight into its clinical benefits. METHODS: A comprehensive search of PubMed, Google Scholar, EMBASE, and the Cochrane Library was conducted. Studies were included based on the PICO framework, focusing on Alvimopan's impact on postoperative gastrointestinal recovery. Primary outcomes were time to gastrointestinal function recovery (GI-3) and hospital stay duration. RESULTS: Ten studies met the inclusion criteria, with seven focusing on the use of Alvimopan in open abdominal surgeries and three in laparoscopic procedures. Collectively, these studies involved 18,822 patients undergoing various types of abdominal Administration of Alvimopan 6 mg accelerated gastrointestinal function recovery by an average of 14 h (Hazard ratio: 1.62, p = 0.002) and reduced hospital stays by 5.2 h (Hazard ratio: 1.52, p = 0.04) compared to placebo. Similarly, Alvimopan 12 mg reduced GI-3 recovery time by 13.5 h (Hazard ratio: 1.58, p = 0.02) and hospital stay duration by 6.2 h (Hazard ratio: 1.46, p = 0.018). CONCLUSION: Alvimopan shows promise in reducing POI and hospital stay durations following abdominal surgeries. The incorporation of the recent studies in laparoscopic abdominal procedures further supports these findings. Integrating Alvimopan into perioperative care protocols may enhance patient outcomes and help lower healthcare costs.
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Abdomen , Ileus , Piperidinas , Complicaciones Posoperatorias , Humanos , Piperidinas/uso terapéutico , Ileus/etiología , Abdomen/cirugía , Fármacos Gastrointestinales/uso terapéutico , Laparoscopía/efectos adversos , Tiempo de InternaciónAsunto(s)
Inhibidores de la Colinesterasa , Delirio , Donepezilo , Humanos , Donepezilo/efectos adversos , Donepezilo/administración & dosificación , Delirio/inducido químicamente , Delirio/tratamiento farmacológico , Inhibidores de la Colinesterasa/efectos adversos , Inhibidores de la Colinesterasa/administración & dosificación , Quimioterapia Combinada , Masculino , Anciano , Femenino , Piperidinas/efectos adversos , Piperidinas/administración & dosificación , Indanos/efectos adversos , Indanos/administración & dosificaciónRESUMEN
Sepsis, a life-threatening condition, involves complex interactions among metabolic alterations, inflammatory mediators, and host responses. This study utilized a bidirectional Mendelian randomization approach to investigate the causal relationships between 1400 metabolites and sepsis, and the mediating role of inflammatory factors. We identified 36 metabolites significantly associated with sepsis (p < 0.05), with AXIN1, FGF-19, FGF-23, IL-4, and OSM showing an inverse association, suggesting a protective role, while IL-2 exhibited a positive correlation, indicating a potential risk factor. Among these metabolites, Piperine and 9-Hydroxystearate demonstrated particularly interesting protective effects against sepsis. Piperine's protective effect was mediated through its interaction with AXIN1, contributing to a 16.296% reduction in sepsis risk. This suggests a potential pathway where Piperine influences sepsis outcomes by modulating AXIN1 levels. 9-Hydroxystearate also exhibited a protective role against sepsis, mediated through its positive association with FGF-19 and negative association with IL-2, contributing 9.436% and 12.565%, respectively, to its protective effect. Experimental validation confirmed significantly elevated IL-2 levels and reduced FGF-19, AXIN1, piperine, and 9-hydroxyoctadecanoic acid levels in sepsis patients compared to healthy controls. Piperine levels positively correlated with AXIN1, while 9-hydroxyoctadecanoic acid levels negatively correlated with IL-2 and positively correlated with FGF-19, supporting the Mendelian randomization findings. Our findings provide insights into the molecular mechanisms of sepsis, highlighting the unique roles and contributions of specific metabolites and their interactions with inflammatory mediators. This study enhances our understanding of sepsis pathophysiology and opens avenues for targeted therapeutic interventions and biomarker development for sepsis management. However, further research is essential to validate these pathways across diverse populations and fully explore the roles of these metabolites in sepsis.