Asunto(s)
Fármacos Anti-VIH , Farmacorresistencia Viral , Emtricitabina , Infecciones por VIH , VIH-1 , Compuestos Heterocíclicos con 3 Anillos , Oxazinas , Piperazinas , Piridonas , Tenofovir , Humanos , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , VIH-1/genética , Emtricitabina/uso terapéutico , Piridonas/uso terapéutico , Piperazinas/uso terapéutico , Tenofovir/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Fármacos Anti-VIH/uso terapéutico , Oxazinas/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Hepatitis B/tratamiento farmacológico , Adenina/análogos & derivados , Adenina/uso terapéutico , Masculino , Femenino , AmidasRESUMEN
BACKGROUND: Head-to-head data for bictegravir/emtricitabine/tenofovir alafenamide (BIC/F/TAF; B) and darunavir/cobicistat/emtricitabine/tenofovir alafenamide (DRV/c/F/TAF; D) are lacking in the context of rapid antiretroviral therapy (ART) initiation. This study, BIC-T&T, evaluates the efficacy and tolerability of B vs D in a UK test-and-treat setting. SETTING: BIC-T&T was a randomised, open-label, multi-centre, study in which participants initiated ART within 14 days after confirmed HIV-1 diagnosis before baseline laboratory. METHODS: The primary endpoint is the virological response (HIV RNA < 50copies/mL) at week 12 by time-weighted average change in log10 HIV RNA recorded in viral load assays from treatment initiation to week 12, using two-sample Wilcoxon rank-sum test. RESULTS: 36 participants were randomised: 94% were male, 53% white; mean (SD) age was 35 years (11.8). Baseline mean (±SD) log10 HIV-RNA was 4.79 (± 0.87) log10 copies/mL and CD4 505 (±253) cells/mm3. The mean (±SD) time from confirmed HIV diagnosis to ART initiation was 7.9 (± 3.7) days. The time-weighted mean decrease in log10 HIV RNA from treatment initiation to week 12 was significantly greater in B in comparison to D (3.1 vs. 2.6 log10 copies/mL, p < 0.001). Both regimens demonstrated good tolerability with infrequent laboratory abnormalities and no grade 3 or 4 adverse events. CONCLUSION: In this first head-to-head study in the context of ART initiation, HIV RNA decline from baseline to week 12 was significantly more rapid for BIC/F/TAF compared with DRV/c/F/TAF.
Asunto(s)
Fármacos Anti-VIH , Emtricitabina , Infecciones por VIH , Tenofovir , Carga Viral , Humanos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Masculino , Femenino , Adulto , Tenofovir/uso terapéutico , Tenofovir/análogos & derivados , Fármacos Anti-VIH/uso terapéutico , Carga Viral/efectos de los fármacos , Emtricitabina/uso terapéutico , VIH-1/efectos de los fármacos , VIH-1/genética , Adenina/análogos & derivados , Adenina/uso terapéutico , Piperazinas/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Darunavir/uso terapéutico , Alanina/uso terapéutico , Alanina/análogos & derivados , Resultado del Tratamiento , ARN Viral , Sulfonamidas/uso terapéutico , Persona de Mediana Edad , Cobicistat/uso terapéutico , Reino Unido , Combinación de Medicamentos , Amidas , PiridonasRESUMEN
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
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
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
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
BACKGROUND/AIM: Tenofovir amibufenamide (TMF) employs innovative ProTide technology and a methylation strategy to enhance the lipid solubility and plasma stability of the amide bond, providing advantages over tenofovir alafenamide (TAF). Despite promising Phase III clinical trial results demonstrating its antiviral efficacy, real-world data on TMF remains scarce. This study evaluates the antiviral efficacy and safety of TMF compared to TAF as the initial treatment in patients with high viral loads of chronic hepatitis B (CHB). METHODS: We retrospectively collected clinical data from March 1 2022 to June 30 2022 for highly viremic CHB patients who received either TMF (n = 58) or TAF (n = 32) as their initial monotherapy at Beijing YouAn Hospital. To understand the efficacy and safety of TMF over 48 weeks, we compared the virological response rates and HBeAg/HBsAg serological clearance rates between TMF and TAF groups. Also, the changes in serum creatinine, eGFR and serum lipid levels were assessed. RESULTS: Baseline median HBV DNA levels were 7.85 (6.89, 8.36) IgIU/ml for TMF and 7.44 (6.89, 8.03) IgIU/ml for TAF. Median ALT levels were 102.0 (56.0, 210.0) U/L for TMF and 195.0 (73.5, 371.0) U/L for TAF, with HBeAg positivity rates of 70.7% and 75.0%, respectively. At 48 weeks, virological response rates (HBV DNA <10 IU/ml) were 43.5% (20/46) for TMF and 42.9% (12/28) for TAF (p = 1.000). ALT normalization rates were 87.9% for TMF and 90.6% for TAF (p = .969), and HBeAg serological clearance rates were 21.1% and 18.2%, respectively (p = 1.000). No patients achieved HBsAg clearance. Compared with the baseline, LDL-C levels increased, while eGFR decreased, with no significant differences in serum creatinine, triglycerides and total cholesterol levels noted at week 48 for both TMF and TAF groups. CONCLUSION: TMF demonstrates comparable antiviral efficacy to TAF when used as initial therapy in highly viremic CHB patients, with similar impacts on renal function and lipid profiles.
Asunto(s)
Antivirales , Hepatitis B Crónica , Tenofovir , Carga Viral , Humanos , Tenofovir/uso terapéutico , Tenofovir/análogos & derivados , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/virología , Hepatitis B Crónica/sangre , Masculino , Femenino , Carga Viral/efectos de los fármacos , Estudios Retrospectivos , Antivirales/uso terapéutico , Antivirales/efectos adversos , Antivirales/farmacología , Adulto , Persona de Mediana Edad , Resultado del Tratamiento , Virus de la Hepatitis B/efectos de los fármacos , Virus de la Hepatitis B/genética , Alanina/análogos & derivados , Alanina/uso terapéutico , Adenina/análogos & derivados , Adenina/uso terapéutico , Adenina/efectos adversos , ADN Viral/sangreRESUMEN
PURPOSE OF REVIEW: Adherence-concentration-efficacy benchmarks have not been fully characterized for cisgender women using emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) oral daily pre-exposure prophylaxis (PrEP) for HIV prevention. RECENT FINDINGS: We conducted a systematic review to investigate current evidence on the adherence-concentration-efficacy relationship of tenofovir-diphosphate (TFV-DP) derived from FTC/TDF PrEP in dried blood spots (DBS) and peripheral mononuclear cells (PBMC) in cisgender women without HIV, including during pregnancy. We searched for completed and ongoing studies published before May 2024 in PubMed, Embase, Cochrane Library, CINAHL, and clinicaltrial.gov. Overall, 11 studies assessing adherence benchmarks focusing on (n = 5) or involving (n = 6) cisgender women were included. Women-specific median steady-state TFV-DP concentration for daily dosing ranged from 17 to 51 fmol/106 in PBMC and 1389 to 1685 fmol/punch in DBS in non-pregnant women; 50 to 71 fmol/106 in PBMC and 583 to 965 fmol/punch in DBS in pregnant women; and 618 to 1406 fmol/punch in DBS in postpartum women. DBS TFV-DP levels were 14-43% lower in pregnancy versus postpartum or non-pregnant periods, but PBMC TFV-DP levels appear to be comparable. Clinical and modeling studies demonstrate effective HIV protection for women taking at least four doses/week of oral TDF-based PrEP, and emerging evidence suggests that systemic drug levels are more likely to be predictive of efficacy than local tissue levels at the site of exposure. The preponderance of emerging evidence points to comparable efficacy and similar adherence requirement for women as men among those with detectable drug levels, although there was an indication that the highest achievable efficacy may be reached at a lower adherence level in men than women. In this review, we found evidence that women-specific TFV-DP adherence benchmarks in DBS and PBMC are within range of US-based historical thresholds derived from healthy men and women. Emerging evidence suggests that imperfect but adequate adherence to oral FTC/TDF PrEP with at least four doses/week provides sufficient HIV protection in cisgender women as it does in MSM, but more data are still needed to refine intrinsic achievable efficacy estimates for cisgender women.
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Fármacos Anti-VIH , Infecciones por VIH , Cumplimiento de la Medicación , Profilaxis Pre-Exposición , Tenofovir , Humanos , Profilaxis Pre-Exposición/métodos , Femenino , Infecciones por VIH/prevención & control , Infecciones por VIH/tratamiento farmacológico , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/administración & dosificación , Cumplimiento de la Medicación/estadística & datos numéricos , Tenofovir/uso terapéutico , Tenofovir/administración & dosificación , Emtricitabina/uso terapéutico , Emtricitabina/administración & dosificación , Embarazo , Combinación Emtricitabina y Fumarato de Tenofovir Disoproxil/uso terapéutico , Combinación Emtricitabina y Fumarato de Tenofovir Disoproxil/administración & dosificación , Leucocitos Mononucleares , Adenina/análogos & derivados , OrganofosfatosRESUMEN
Ibrutinib (IB) is a tyrosine kinase inhibitor (TKI) that has immunomodulatory action and can be used as second-line therapy for steroid-refractory or steroid-resistant chronic Graft versus Host Disease (cGVHD). Mesenchymal stromal cells (MSCs) are distributed throughout the body and their infusion has also been explored as a second-line therapeutic alternative for the treatment of cGVHD. Considering the currently unknown effects of IB on endogenous MSCs, as well as the possible combined use of IB and MSCs for cGVHD, we investigated whether adipose tissue-derived MSCs present IB-targets, as well as the consequences of treating MSCs with this drug, regarding cell viability, proliferation, phenotype, and anti-inflammatory potential. Interestingly, we show for the first time that MSCs express several IB target genes. Also of note, the treatment of such cells with this TKI elevated the levels of CD90 and CD105 surface proteins, as well as VCAM-1. Furthermore, IB-treated MSCs presented increased mRNA expression of the anti-inflammatory genes PD-L1, TSG-6, and IL-10. However, continued exposure to IB, even at low doses, compromised the viability of MSCs. These data indicate that the use of IB can stimulate an anti-inflammatory profile in MSCs, but also that a continued exposure to IB can compromise MSC viability over time.
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Adenina , Tejido Adiposo , Proliferación Celular , Supervivencia Celular , Células Madre Mesenquimatosas , Piperidinas , Pirazoles , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Adenina/análogos & derivados , Adenina/farmacología , Proliferación Celular/efectos de los fármacos , Humanos , Piperidinas/farmacología , Supervivencia Celular/efectos de los fármacos , Tejido Adiposo/citología , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Pirazoles/farmacología , Fenotipo , Pirimidinas/farmacología , Antiinflamatorios/farmacología , Células CultivadasRESUMEN
A high throughput screen performed to identify catalytic inhibitors of the oncogenic fusion form of cAMP-dependent protein kinase A catalytic subunit alpha (J-PKAcα) found an individual fraction from an organic extract of the marine soft coral Acrozoanthus australiae as active. Bioassay-guided isolation led to the identification of a 2-amino adenine alkaloid acroamine A (1), the first secondary metabolite discovered from this genus and previously reported as a synthetic product. As a naturally occurring protein kinase inhibitor, to unambiguously assign its chemical structure using modern spectroscopic and spectrometric techniques, five N-methylated derivatives acroamines A1-A5 (2-6) were semisynthesized. Three additional brominated congeners A6-A8 (7-9) were also semisynthesized to investigate the structure-activity relationship of the nine compounds as J-PKAcα inhibitors. Compounds 1-9 were tested for J-PKAcα and wild-type PKA inhibitory activities, which were observed exclusively in acroamine A (1) and its brominated analogs (7-9) achieving moderate potency (IC50 2-50 µM) while none of the N-methylated analogs exhibited kinase inhibition.
Asunto(s)
Alcaloides , Antozoos , Proteínas Quinasas Dependientes de AMP Cíclico , Animales , Antozoos/química , Estructura Molecular , Alcaloides/farmacología , Alcaloides/química , Alcaloides/aislamiento & purificación , Relación Estructura-Actividad , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Adenina/farmacología , Adenina/análogos & derivados , Adenina/química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Dominio CatalíticoRESUMEN
What is this summary about? This is a plain language summary of a research study called ALPINE. The study involved people who had been diagnosed with, and previously treated at least once for, relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).Lymphocytes help to find and fight off viruses and infections in the body, but when someone has CLL or SLL, the body creates abnormal lymphocytes, leaving the patient with a weakened immune system and susceptible to illness. In CLL, these lymphocytes are in the bone marrow and bloodstream, whereas for SLL, they are mostly found in the lymph nodes, such as those in the neck.How was the research done? The ALPINE study was designed to directly compare the cancer-fighting effects and side effects of zanubrutinib and ibrutinib as treatment for patients with relapsed or refractory CLL/SLL.What were the results? After 30 months, zanubrutinib was more effective than ibrutinib at reducing and keeping the cancer from coming back. Clinical Trial Registration: NCT03734016 (ClinicalTrials.gov).
Asunto(s)
Adenina , Resistencia a Antineoplásicos , Leucemia Linfocítica Crónica de Células B , Piperidinas , Inhibidores de Proteínas Quinasas , Pirazoles , Pirimidinas , Humanos , Piperidinas/uso terapéutico , Adenina/análogos & derivados , Adenina/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Pirimidinas/uso terapéutico , Pirazoles/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Antineoplásicos/uso terapéutico , Pirazinas/uso terapéutico , Tiazoles/uso terapéutico , Resultado del TratamientoAsunto(s)
Adenina , Protocolos de Quimioterapia Combinada Antineoplásica , Compuestos Bicíclicos Heterocíclicos con Puentes , Linfoma de Células del Manto , Piperidinas , Sulfonamidas , Humanos , Adenina/análogos & derivados , Piperidinas/uso terapéutico , Piperidinas/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/patología , Pirimidinas/uso terapéutico , Pirimidinas/administración & dosificación , Pirazoles/uso terapéutico , Pirazoles/administración & dosificaciónRESUMEN
Targeted covalent inhibitors (TCIs) directing cysteine have historically relied on a narrow set of electrophilic "warheads". While Michael acceptors remain at the forefront of TCI design strategies, they show variable stability and selectivity under physiological conditions. Here, we show that the 2-sulfonylpyrimidine motif is an effective replacement for the acrylamide warhead of Ibrutinib, for the inhibition of Bruton's tyrosine kinase. In a few iterations, we discovered new derivatives, which inhibit BTK both in vitro and in cellulo at low nanomolar concentrations, on par with Ibrutinib. Several derivatives also displayed good plasma stability and reduced off-target binding in vitro across 135 tyrosine kinases. This proof-of-concept study on a well-studied kinase/TCI system highlights the 2-sulfonylpyrimidine group as a useful acrylamide replacement. In the future, it will be interesting to investigate its wider potential for developing TCIs with improved pharmacologies and selectivity profiles across structurally related protein families.
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Acrilamida , Agammaglobulinemia Tirosina Quinasa , Inhibidores de Proteínas Quinasas , Pirimidinas , Humanos , Acrilamida/química , Acrilamida/farmacología , Adenina/química , Adenina/análogos & derivados , Adenina/farmacología , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Agammaglobulinemia Tirosina Quinasa/metabolismo , Piperidinas/química , Piperidinas/farmacología , Piperidinas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Pirazoles/química , Pirazoles/farmacología , Pirazoles/síntesis química , Pirimidinas/química , Pirimidinas/farmacología , Pirimidinas/síntesis química , Relación Estructura-ActividadRESUMEN
The integrated stress response (ISR) is a vital signaling pathway initiated by four kinases, PERK, GCN2, HRI and PKR, that ensure cellular resilience and protect cells from challenges. Here, we investigated whether increasing ISR signaling could rescue diabetes-like phenotypes in a mouse model of diet-induced obesity (DIO). We show that the orally available and clinically approved GCN2 activator halofuginone (HF) can activate the ISR in mouse tissues. We found that daily oral administration of HF increases glucose tolerance whilst reducing weight gain, insulin resistance, and serum insulin in DIO mice. Conversely, the ISR inhibitor GSK2656157, used at low doses to optimize its selectivity, aggravates glucose intolerance in DIO mice. Whilst loss of function mutations in mice and humans have revealed that PERK is the essential ISR kinase that protects from diabetes, our work demonstrates the therapeutic value of increasing ISR signaling by activating the related kinase GCN2 to reduce diabetes phenotypes in a DIO mouse model.
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Obesidad , Fenotipo , Piperidinas , Proteínas Serina-Treonina Quinasas , Quinazolinonas , Transducción de Señal , eIF-2 Quinasa , Animales , Quinazolinonas/farmacología , Piperidinas/farmacología , Ratones , eIF-2 Quinasa/metabolismo , eIF-2 Quinasa/genética , Obesidad/patología , Obesidad/metabolismo , Obesidad/prevención & control , Obesidad/genética , Transducción de Señal/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Ratones Endogámicos C57BL , Masculino , Resistencia a la Insulina , Insulina/metabolismo , Insulina/sangre , Estrés Fisiológico/efectos de los fármacos , Modelos Animales de Enfermedad , Dieta Alta en Grasa/efectos adversos , Diabetes Mellitus/patología , Diabetes Mellitus/metabolismo , Diabetes Mellitus/genética , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/prevención & control , Intolerancia a la Glucosa/tratamiento farmacológico , Adenina/análogos & derivados , IndolesRESUMEN
Bleeding diathesis is an uncommon side effect of ibrutinib use and is seen in less than 5% of the population. We describe a case of an elderly woman with ibrutinib-induced spontaneous major extradural haematoma presenting as acute compressive myelopathy. She is a known case of splenic marginal zone lymphoma with multiple extramedullary relapses and presented to the emergency department with acute-onset low backache, followed by urinary retention. MRI revealed extradural haemorrhage. After possible evaluation, she was diagnosed with ibrutinib-induced extradural haematoma.
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Adenina , Linfoma de Células B de la Zona Marginal , Piperidinas , Pirazoles , Humanos , Femenino , Piperidinas/efectos adversos , Adenina/análogos & derivados , Adenina/efectos adversos , Linfoma de Células B de la Zona Marginal/tratamiento farmacológico , Pirazoles/efectos adversos , Imagen por Resonancia Magnética , Pirimidinas/efectos adversos , Pirimidinas/uso terapéutico , Compresión de la Médula Espinal/inducido químicamente , Compresión de la Médula Espinal/diagnóstico por imagen , Anciano , Hematoma Espinal Epidural/inducido químicamente , Hematoma Espinal Epidural/diagnóstico por imagenRESUMEN
Lipid-based formulations (LbFs) have demonstrated success in pharmaceutical applications; however, challenges persist in dissolving entire doses of the drug into defined liquid volumes. In this study, the temperature-induced supersaturation method was employed in LbF to address drug loading and pill burden issues. Supersaturated LbFs (super-LbF) were prepared using the temperature-induced supersaturation method, where the drug load is above its equilibrium solubility. Further, the influence of the drug's physicochemical and thermal characteristics on drug loading and their relevance with an apparent degree of supersaturation (aDS) was studied using two model drugs, ibrutinib and enzalutamide. All the prepared LbFs were evaluated in terms of physical stability, dispersion, and solubilization capacity, as well as pharmacokinetic assessments. Drug re-crystallization was observed in the lipid solution on long-term storage at higher aDS values of 2-2.5. Furthermore, high-throughput lipolysis studies demonstrated a significant decrease in drug concentration across all LbFs (regardless of drug loading) due to a decline in the formulation solvation capacity and subsequent generation of in-situ supersaturation. Further, the in vivo results demonstrated comparable pharmacokinetic parameters between conventional LbF and super-LbF. The short duration of the thermodynamic metastable state limits the potential absorption benefits. However, super-LbFs of Ibr and Enz showed superior profiles, with 1.7-fold and 5.2-fold increased drug exposure compared to their respective crystalline suspensions. In summary, this study emphasizes the potential of temperature-induced supersaturation in LbF for enhancing drug loading and highlights the intricate interplay between drug properties, formulation characteristics, and in vivo performance.
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Adenina , Benzamidas , Química Farmacéutica , Lípidos , Nitrilos , Feniltiohidantoína , Piperidinas , Solubilidad , Temperatura , Nitrilos/química , Nitrilos/administración & dosificación , Piperidinas/química , Piperidinas/administración & dosificación , Piperidinas/farmacocinética , Benzamidas/química , Benzamidas/farmacocinética , Adenina/análogos & derivados , Adenina/química , Adenina/administración & dosificación , Feniltiohidantoína/farmacocinética , Feniltiohidantoína/administración & dosificación , Lípidos/química , Animales , Química Farmacéutica/métodos , Composición de Medicamentos/métodos , Masculino , Pirimidinas/farmacocinética , Pirimidinas/química , Pirimidinas/administración & dosificación , Estabilidad de Medicamentos , Cristalización/métodos , Pirazoles/química , Pirazoles/farmacocinética , Pirazoles/administración & dosificación , Lipólisis/efectos de los fármacos , RatasRESUMEN
Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, plays a remarkable role in the transmission and amplification of extracellular signals to intracellular signaling pathways. Various types of cells use the BTK pathway to communicate, including hematopoietic cells particularly B cells and T cells. The BTK pathway plays a role in controlling the proliferation, survival, and functions of B cells as well as other myeloid cells. First, second, and third-generation BTK inhibitors are currently being evaluated for the treatment of immune-mediated diseases in addition to B cell malignancies. In this article, the available evidence on the action mechanisms of BTK inhibitors is reviewed. Then, the most recent data obtained from preclinical studies and ongoing clinical trials for the treatment of autoimmune diseases, such as pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, systemic lupus erythematosus, Sjögren's disease, rheumatoid arthritis, systemic sclerosis, multiple sclerosis, myasthenia gravis, and inflammatory diseases such as psoriasis, chronic spontaneous urticaria, atopic dermatitis, and asthma are discussed. In addition, adverse effects and complications associated with BTK inhibitors as well as factors predisposing patients to BTK inhibitors complications are discussed.
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Agammaglobulinemia Tirosina Quinasa , Enfermedades Autoinmunes , Pénfigo , Inhibidores de Proteínas Quinasas , Transducción de Señal , Humanos , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Enfermedades Autoinmunes/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pénfigo/tratamiento farmacológico , Pénfigo/inmunología , Pirimidinas/uso terapéutico , Piperidinas/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inmunología , Miastenia Gravis/tratamiento farmacológico , Esclerosis Múltiple/tratamiento farmacológico , Pirazoles/uso terapéutico , Pirazoles/farmacología , Nitrilos/uso terapéutico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/inmunología , Adenina/análogos & derivados , Adenina/uso terapéutico , Asma/tratamiento farmacológico , Linfocitos B/inmunología , Síndrome de Sjögren/tratamiento farmacológico , Psoriasis/tratamiento farmacológico , Psoriasis/inmunología , Esclerodermia Sistémica/tratamiento farmacológico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Benzamidas , Imidazoles , PirazinasRESUMEN
This letter to the editor relates to the study entitled "Tenofovir amibufenamide vs tenofovir alafenamide for treating chronic hepatitis B: A real-world study", which was recently published by Peng et al. Hepatitis B virus infection represents a significant health burden worldwide and can lead to cirrhosis and even liver cancer. The antiviral drugs currently used to treat patients with chronic hepatitis B infection still have many side effects, so it is crucial to identify safe and effective drugs to inhibit viral replication.
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Antivirales , Virus de la Hepatitis B , Hepatitis B Crónica , Tenofovir , Humanos , Antivirales/uso terapéutico , Antivirales/efectos adversos , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/virología , Tenofovir/uso terapéutico , Tenofovir/análogos & derivados , Tenofovir/efectos adversos , Virus de la Hepatitis B/efectos de los fármacos , Resultado del Tratamiento , Replicación Viral/efectos de los fármacos , Adenina/análogos & derivados , Adenina/uso terapéutico , Adenina/efectos adversos , Alanina/análogos & derivados , Alanina/uso terapéutico , Alanina/efectos adversosRESUMEN
BACKGROUND: Ferroptosis is a newly recognized form of regulatory cell death characterized by severe lipid peroxidation triggered by iron overload and the production of reactive oxygen species (ROS). However, the role of ferroptosis in severe acute pancreatitis(SAP) has not been fully elucidated. METHODS: We established four severe acute pancreatitis models of rats including the sham control group, the SAP group, the Fer -1-treated SAP (SAP + Fer-1) group, the 3-MA-treated SAP (SAP + 3-MA) group. The SAP group was induced by retrograde injection of sodium taurocholate into the pancreatic duct. The other two groups were intraperitoneally injected with ferroptosis inhibitor (Fer-1) and autophagy inhibitor (3-MA), respectively. The model of severe acute pancreatitis with amylase crest-related inflammatory factors was successfully established. Then we detected ferroptosis (GPX4, SLC7A1 etc.) and autophagy-related factors (LC3II, p62 ect.) to further clarify the relationship between ferroptosis and autophagy. RESULTS: Our study found that ferroptosis occurs during the development of SAP, such as iron and lipid peroxidation in pancreatic tissues, decreased levels of reduced glutathione peroxidase 4 (GPX 4) and glutathione (GSH), and increased malondialdehyde(MDA) and significant mitochondrial damage. In addition, ferroptosis related proteins such as GPX4, solute carrier family 7 member 11(SLC7A11) and ferritin heavy chain 1(FTH1) were significantly decreased. Next, the pathogenesis of ferroptosis in SAP was studied. First, treatment with the ferroptosis inhibitor ferrostatin-1(Fer-1) significantly alleviated ferroptosis in SAP. Interestingly, autophagy occurs during the pathogenesis of SAP, and autophagy promotes the occurrence of ferroptosis in SAP. Moreover, 3-methyladenine (3-MA) inhibition of autophagy can significantly reduce iron overload and ferroptosis in SAP. CONCLUSIONS: Our results suggest that ferroptosis is a novel pathogenesis of SAP and is dependent on autophagy. This study provides a new theoretical basis for the study of SAP.
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Autofagia , Modelos Animales de Enfermedad , Ferroptosis , Peroxidación de Lípido , Pancreatitis , Ratas Sprague-Dawley , Animales , Pancreatitis/metabolismo , Pancreatitis/patología , Ratas , Masculino , Adenina/análogos & derivados , Adenina/farmacología , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Ácido Taurocólico , Ciclohexilaminas/farmacología , Páncreas/patología , Páncreas/metabolismo , Fenilendiaminas/farmacología , Malondialdehído/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Enfermedad Aguda , Glutatión/metabolismo , Hierro/metabolismoRESUMEN
Obesity is associated with metabolic inflammation, which can contribute to insulin resistance, higher blood glucose, and higher insulin indicative of prediabetes progression. The nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a metabolic danger sensor implicated in metabolic inflammation. Many features of metabolic disease can activate the NLRP3 inflammasome; however, it is not yet clear which upstream triggers to target, and there are no clinically approved NLRP3 inflammasome inhibitors for metabolic disease. Bruton's tyrosine kinase (BTK) mediates activation of the NLRP3 inflammasome. Ibrutinib is the most-studied pharmacological inhibitor of BTK, and it can improve blood glucose control in obese mice. However, inhibitors of tyrosine kinases are permissive, and it is unknown if BTK inhibitors require BTK to alter endocrine control of metabolism or metabolic inflammation. We tested whether ibrutinib and acalabrutinib, a new generation BTK inhibitor with higher selectivity, require BTK to inhibit the NLRP3 inflammasome, metabolic inflammation, and blood glucose in obese mice. Chronic ibrutinib administration lowered fasting blood glucose and improved glycemia, whereas acalabrutinib increased fasting insulin levels and increased markers of insulin resistance in high-fat diet-fed CBA/J mice with intact Btk. These metabolic effects of BTK inhibitors were absent in CBA/CaHN-Btkxid/J mice with mutant Btk. However, ibrutinib and acalabrutinib reduced NF-κB activity, proinflammatory gene expression, and NLRP3 inflammasome activation in macrophages with and without functional BTK. These data highlight that the BTK inhibitors can have divergent effects on metabolism and separate effects on metabolic inflammation that can occur independently of actions on BTK.NEW & NOTEWORTHY Bruton's tyrosine kinase (BTK) is involved in immune function. It was thought that BTK inhibitors improve characteristics of obesity-related metabolic disease by lowering metabolic inflammation. However, tyrosine kinase inhibitors are permissive, and it was not known if different BTK inhibitors alter host metabolism or immunity through actions on BTK. We found that two BTK inhibitors had divergent effects on blood glucose and insulin via BTK, but inhibition of metabolic inflammation occurred independently of BTK in obese mice.