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2.
Am J Physiol Heart Circ Physiol ; 318(4): H985-H993, 2020 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-32167781

RESUMEN

The roles of ACE-independent ANG II production via chymase and therapeutic potential of epoxyeicosatrienoic acids (EETs) in fructose-induced metabolic syndrome (MetS) in the adolescent population remain elusive. Thus we tested the hypothesis that a high-fructose diet (HFD) in young rats elicits chymase-dependent increases in ANG II production and oxidative stress, responses that are reversible by 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), an inhibitor of soluble epoxide hydrolase (sEH) that metabolizes EETs. Three groups of weanling rats (21-day-old) were fed a normal diet, 60% HFD, and HFD with TPPU, respectively, for 30 days. HFD rats developed MetS, characterized by hyperglycemia, hyperinsulinemia, and hypertension and associated with decreases in cardiac output and stroke volume and loss of nitric oxide (NO) modulation of myocardial oxygen consumption; all impairments were normalized by TPPU that significantly elevated circulating 11,12-EET, a major cardiac EET isoform. In the presence of comparable cardiac angiotensin-converting enzyme (ACE) expression/activity among the three groups, HFD rats exhibited significantly greater chymase-dependent ANG II formation in hearts, as indicated by an augmented cardiac chymase content as a function of enhanced mast cell degranulation. The enhanced chymase-dependent ANG II production was paralleled with increases in ANG II type 1 receptor (AT1R) expression and NADPH oxidase (Nox)-induced superoxide, alterations that were significantly reversed by TPPU. Conversely, HFD-induced downregulation of cardiac ACE2, followed by a lower Ang-(1-7) level displayed in an TPPU-irreversible manner. In conclusion, HFD-driven adverse chymase/ANG II/Nox/superoxide signaling in young rats was prevented by inhibition of sEH via, at least in part, an EET-mediated stabilization of mast cells, highlighting chymase and sEH as therapeutic targets during treatment of MetS.NEW & NOTEWORTHY As the highest fructose consumers, the adolescent population is highly susceptible to the metabolic syndrome, where increases in mast cell chymase-dependent formation of ANG II, ensued by cardiometabolic dysfunction, are reversible in response to inhibition of soluble epoxide hydrolase (sEH). This study highlights chymase and sEH as therapeutic targets and unravels novel avenues for the development of optimal strategies for young patients with fructose-induced metabolic syndrome.


Asunto(s)
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Angiotensina II/metabolismo , Quimasas/metabolismo , Fructosa/efectos adversos , Cardiopatías/metabolismo , Síndrome Metabólico/complicaciones , Ácido 8,11,14-Eicosatrienoico/metabolismo , Animales , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Gasto Cardíaco , Células Cultivadas , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Epóxido Hidrolasas/antagonistas & inhibidores , Corazón/efectos de los fármacos , Corazón/fisiopatología , Cardiopatías/tratamiento farmacológico , Cardiopatías/etiología , Frecuencia Cardíaca , Masculino , Síndrome Metabólico/etiología , Miocardio/metabolismo , Estrés Oxidativo , Compuestos de Fenilurea/farmacología , Compuestos de Fenilurea/uso terapéutico , Piperidinas/farmacología , Piperidinas/uso terapéutico , Ratas , Ratas Sprague-Dawley
3.
Life Sci ; 250: 117551, 2020 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-32179075

RESUMEN

AIMS: Increasing evidence indicates that FK866, a specific noncompetitive nicotinamide phosphoribosyl transferase inhibitor, exhibits a protective effect on acute lung injury (ALI). Autophagy plays a pivotal role in sepsis-induced ALI. However, the contribution of autophagy and the underlying mechanism by which FK866-confered lung protection remains elusive. Herein, we aimed to study whether FK866 could alleviate sepsis-induced ALI via the JNK-dependent autophagy. MAIN METHODS: Male C57BL/6 mice were subjected to cecal ligation and puncture (CLP) to establish the polymicrobial sepsis mice model, and treated with FK866 (10 mg/kg) at 24, 12 and 0.5 h before the CLP procedure. The lung protective effects were measured by lung histopathology, tissue edema, vascular leakage, inflammation infiltration, autophagy-related protein expression and JNK activity. A549 cells were stimulated with LPS (1000 ng/ml) to generate the ALI cell model, and pretreated with FK866 or SP600125 for 30 min to measure the autophagy-related protein expression and JNK activity. KEY FINDINGS: Our results demonstrated that FK866 reduced lung injury score, tissue edema, vascular leakage, and inflammatory infiltration, and upregulated autophagy. The protective effect of autophagy conferred by FK866 on ALI was further clarified by using 3-methyladenine (3MA) and rapamycin. Additionally, the activity of JNK was suppressed by FK866, and inhibition of JNK promoted autophagy and showed a benefit effect. SIGNIFICANCE: Our study indicates that FK866 protects against sepsis-induced ALI by induction of JNK-dependent autophagy. This may provide new insights into the functional mechanism of NAMPT inhibition in sepsis-induced ALI.


Asunto(s)
Acrilamidas/uso terapéutico , Lesión Pulmonar Aguda/tratamiento farmacológico , Autofagia , MAP Quinasa Quinasa 4/metabolismo , Piperidinas/uso terapéutico , Sepsis/tratamiento farmacológico , Células A549 , Lesión Pulmonar Aguda/complicaciones , Animales , Líquido del Lavado Bronquioalveolar , Permeabilidad Capilar , Modelos Animales de Enfermedad , Humanos , Pulmón/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Sepsis/complicaciones , Transducción de Señal , Regulación hacia Arriba
4.
Nursing ; 50(2): 31-38, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31895198
6.
Cochrane Database Syst Rev ; 1: CD012381, 2020 Jan 27.
Artículo en Inglés | MEDLINE | ID: mdl-31984480

RESUMEN

BACKGROUND: Tofacitinib is an oral Janus kinase (JAK) inhibitor which blocks cytokine signaling involved in the pathogenesis of autoimmune diseases including ulcerative colitis (UC). The etiology of UC is poorly understood, however research suggests the development and progression of the disease is due to a dysregulated immune response leading to inflammation of the colonic mucosa in genetically predisposed individuals. Additional medications are currently required since some patients do not respond to the available medications and some medications are associated with serious adverse events (SAEs). JAK inhibitors have been widely studied in diseases including rheumatoid arthritis and Crohn's disease and may represent a promising and novel therapeutic option for the treatment of UC. OBJECTIVES: The primary objective was to assess the efficacy and safety of oral JAK inhibitors for the maintenance of remission in participants with quiescent UC. SEARCH METHODS: We searched the following databases from inception to 20 September 2019: MEDLINE, Embase, CENTRAL, and the Cochrane IBD Group Specialized Register, WHO trials registry and clinicaltrials.gov. References and conference abstracts were searched to identify additional studies. SELECTION CRITERIA: Randomized control trial (RCTs) in which an oral JAK inhibitor was compared with placebo or active comparator in the treatment of quiescent UC were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently screened studies for inclusion and extraction. Bias was assessed using the Cochrane 'Risk of bias' tool. The primary outcome was the proportion of participants who failed to maintain remission as defined by any included studies. Secondary outcomes included failure to maintain clinical response, failure to maintain endoscopic remission, failure to maintain endoscopic response, disease-specific quality of life, adverse events (AEs), withdrawal due to AEs and SAEs. We calculated the risk ratio (RR) and 95% confidence intervals (95% CI) for each dichotomous outcome. Data were analyzed on an intention-to-treat basis. The overall certainty of the evidence supporting the outcomes was evaluated using the GRADE criteria. MAIN RESULTS: One RCT (593 participants) including patients with moderately to severely active UC met the inclusion criteria. Patients were randomly assigned in a 1:1:1 ratio to receive maintenance therapy with tofacitinib at 5 mg twice daily, 10 mg twice daily or placebo for 52 weeks. The primary endpoint was remission at 52 weeks and the secondary endpoints included mucosal healing at 52 weeks, sustained remission at 24 and 52 weeks and glucocorticosteroid-free remission. This study was rated as low risk of bias. The study reported on most of the pre-specified primary and secondary outcomes for this review including clinical remission, clinical response, endoscopic remission, AEs, SAEs and withdrawal due to AEs. However, the included study did not report on endoscopic response or disease-specific quality of life. Sixty-three per cent (247/395) of tofacitinib participants failed to maintain clinical remission at 52 weeks compared to 89% (176/198) of placebo participants (RR 0.70, 95% CI 0.64 to 0.77; high-certainty evidence). Forty-three per cent (171/395) of tofacitinib participants failed to maintain clinical response at 52 weeks compared to 80% (158/198) of placebo participants (RR 0.54, 95% CI 0.48 to 0.62; high-certainty evidence). Eighty-four per cent (333/395) of tofacitinib participants failed to maintain endoscopic remission at 52 weeks compared to 96% (190/198) of placebo participants (RR 0.88, 95% CI 0.83 to 0.92; high-certainty evidence). AEs were reported in 76% (299/394) of tofacitinib participants compared with 75% (149/198) of placebo participants (RR 1.01, 95% CI 0.92 to 1.11; high-certainty evidence). Commonly reported AEs included worsening UC, nasopharyngitis, arthralgia (joint pain)and headache. SAEs were reported in 5% (21/394) of tofacitinib participants compared with 7% (13/198) of placebo participants (RR 0.81, 95% CI 0.42 to 1.59; low-certainty evidence). SAEs included non-melanoma skin cancers, cardiovascular events, cancer other than non-melanoma skin cancer, Bowen's disease, skin papilloma and uterine leiomyoma (a tumour in the uterus). There was a higher proportion of participants who withdrew due to an AE in the placebo group compared to the tofacitinib group. Nine per cent (37/394) of participants taking tofacitinib withdrew due to an AE compared to 19% (37/198) of participants taking placebo (RR 0.50, 95% CI 0.33 to 0.77; moderate-certainty evidence). The most common reason for withdrawal due to an AE was worsening UC. The included study did not report on endoscopic response or on mean disease-specific quality of life scores. AUTHORS' CONCLUSIONS: High-certainty evidence suggests that tofacitinib is superior to placebo for maintenance of clinical and endoscopic remission at 52 weeks in participants with moderate-to-severe UC in remission. The optimal dose of tofacitinib for maintenance therapy is unknown. High-certainty evidence suggests that there is no increased risk of AEs with tofacitinib compared to placebo. However, we are uncertain about the effect of tofacitinib on SAEs due to the low number of events. Further studies are required to look at the long-term effectiveness and safety of using tofacitinib and other oral JAK inhibitors as maintenance therapy in participants with moderate-to-severe UC in remission.


Asunto(s)
Colitis Ulcerosa/tratamiento farmacológico , Inhibidores de las Cinasas Janus/uso terapéutico , Piperidinas/uso terapéutico , Pirimidinas/uso terapéutico , Pirroles/uso terapéutico , Humanos , Quimioterapia de Mantención , Inhibidores de Proteínas Quinasas , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto
7.
Nat Med ; 26(2): 236-243, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31959990

RESUMEN

Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DiHS/DRESS) is a potentially fatal multiorgan inflammatory disease associated with herpesvirus reactivation and subsequent onset of autoimmune diseases1-4. Pathophysiology remains elusive and therapeutic options are limited. Cases refractory to corticosteroid therapy pose a clinical challenge1,5 and approximately 30% of patients with DiHS/DRESS develop complications, including infections and inflammatory and autoimmune diseases1,2,5. Progress in single-cell RNA sequencing (scRNA-seq) provides an opportunity to dissect human disease pathophysiology at unprecedented resolutions6, particularly in diseases lacking animal models, such as DiHS/DRESS. We performed scRNA-seq on skin and blood from a patient with refractory DiHS/DRESS, identifying the JAK-STAT signaling pathway as a potential target. We further showed that central memory CD4+ T cells were enriched with DNA from human herpesvirus 6b. Intervention via tofacitinib enabled disease control and tapering of other immunosuppressive agents. Tofacitinib, as well as antiviral agents, suppressed culprit-induced T cell proliferation in vitro, further supporting the roles of the JAK-STAT pathway and herpesviruses in mediating the adverse drug reaction. Thus, scRNA-seq analyses guided successful therapeutic intervention in the patient with refractory DiHS/DRESS. scRNA-seq may improve our understanding of complicated human disease pathophysiology and provide an alternative approach in personalized medicine.


Asunto(s)
Síndrome de Hipersensibilidad a Medicamentos/terapia , Análisis de la Célula Individual , Transcriptoma , Corticoesteroides/uso terapéutico , Adulto , Antivirales/uso terapéutico , Enfermedades Autoinmunes/complicaciones , Linfocitos T CD4-Positivos/citología , Proliferación Celular , Separación Celular , Citometría de Flujo , Herpesvirus Humano 6/inmunología , Humanos , Inmunosupresores/uso terapéutico , Leucocitos Mononucleares/citología , Linfocitos/citología , Masculino , Piperidinas/uso terapéutico , Pirimidinas/uso terapéutico , Pirroles/uso terapéutico , RNA-Seq , Transducción de Señal , Linfocitos T Reguladores/citología , VDJ Recombinasas/metabolismo
8.
Cancer Sci ; 111(3): 932-939, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31961053

RESUMEN

The treatment for anaplastic lymphoma kinase (ALK)-positive lung cancer has been rapidly evolving since the introduction of several ALK tyrosine kinase inhibitors (ALK-TKI) in clinical practice. However, the acquired resistance to these drugs has become an important issue. In this study, we collected a total of 112 serial biopsy samples from 32 patients with ALK-positive lung cancer during multiple ALK-TKI treatments to reveal the resistance mechanisms to ALK-TKI. Among 32 patients, 24 patients received more than two ALK-TKI. Secondary mutations were observed in 8 of 12 specimens after crizotinib failure (G1202R, G1269A, I1171T, L1196M, C1156Y and F1245V). After alectinib failure, G1202R and I1171N mutations were detected in 7 of 15 specimens. G1202R, F1174V and G1202R, and P-gp overexpression were observed in 3 of 7 samples after ceritinib treatment. L1196M + G1202R, a compound mutation, was detected in 1 specimen after lorlatinib treatment. ALK-TKI treatment duration was longer in the on-target treatment group than that in the off-target group (13.0 vs 1.2 months). In conclusion, resistance to ALK-TKI based on secondary mutation in this study was similar to that in previous reports, except for crizotinib resistance. Understanding the appropriate treatment matching resistance mechanisms contributes to the efficacy of multiple ALK-TKI treatment strategies.


Asunto(s)
Quinasa de Linfoma Anaplásico/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Resistencia a Antineoplásicos/genética , Neoplasias Pulmonares/genética , Grupo de Ascendencia Continental Asiática , Carbazoles/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Crizotinib/uso terapéutico , Humanos , Lactamas Macrocíclicas/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Mutación/genética , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Proteínas Recombinantes/genética , Sulfonas/uso terapéutico
9.
N Engl J Med ; 381(25): 2391-2402, 2019 12 19.
Artículo en Inglés | MEDLINE | ID: mdl-31562799

RESUMEN

BACKGROUND: Niraparib, an inhibitor of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP), has been associated with significantly increased progression-free survival among patients with recurrent ovarian cancer after platinum-based chemotherapy, regardless of the presence or absence of BRCA mutations. The efficacy of niraparib in patients with newly diagnosed advanced ovarian cancer after a response to first-line platinum-based chemotherapy is unknown. METHODS: In this randomized, double-blind, phase 3 trial, we randomly assigned patients with newly diagnosed advanced ovarian cancer in a 2:1 ratio to receive niraparib or placebo once daily after a response to platinum-based chemotherapy. The primary end point was progression-free survival in patients who had tumors with homologous-recombination deficiency and in those in the overall population, as determined on hierarchical testing. A prespecified interim analysis for overall survival was conducted at the time of the primary analysis of progression-free survival. RESULTS: Of the 733 patients who underwent randomization, 373 (50.9%) had tumors with homologous-recombination deficiency. Among the patients in this category, the median progression-free survival was significantly longer in the niraparib group than in the placebo group (21.9 months vs. 10.4 months; hazard ratio for disease progression or death, 0.43; 95% confidence interval [CI], 0.31 to 0.59; P<0.001). In the overall population, the corresponding progression-free survival was 13.8 months and 8.2 months (hazard ratio, 0.62; 95% CI, 0.50 to 0.76; P<0.001). At the 24-month interim analysis, the rate of overall survival was 84% in the niraparib group and 77% in the placebo group (hazard ratio, 0.70; 95% CI, 0.44 to 1.11). The most common adverse events of grade 3 or higher were anemia (in 31.0% of the patients), thrombocytopenia (in 28.7%), and neutropenia (in 12.8%). No treatment-related deaths occurred. CONCLUSIONS: Among patients with newly diagnosed advanced ovarian cancer who had a response to platinum-based chemotherapy, those who received niraparib had significantly longer progression-free survival than those who received placebo, regardless of the presence or absence of homologous-recombination deficiency. (Funded by GlaxoSmithKline; PRIMA/ENGOT-OV26/GOG-3012 ClinicalTrials.gov number, NCT02655016.).


Asunto(s)
Indazoles/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Piperidinas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Terapia Combinada , Método Doble Ciego , Femenino , Humanos , Indazoles/efectos adversos , Quimioterapia de Mantención , Persona de Mediana Edad , Náusea/inducido químicamente , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/cirugía , Piperidinas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Supervivencia sin Progresión , Calidad de Vida , Análisis de Supervivencia
10.
Internist (Berl) ; 60(11): 1215-1220, 2019 Nov.
Artículo en Alemán | MEDLINE | ID: mdl-31486859

RESUMEN

Janus kinases inhibitors (JAKI) are new orally administrable disease-modifying antirheumatic drugs (DMARD) for the treatment of rheumatoid arthritis (RA) and psoriatic arthritis (PsA), representing a treatment alternative equally effective as biological DMARD that is also classified equivalent in the guidelines. JAKI reversibly inhibit intracellular signal transduction from the cytokine receptor to the nucleus. Tofacitinib and baricitinib, two JAKI already approved for RA treatment, are taken once or twice a day, respectively, and two more are expected to receive approval next year. Tofacitinib is also approved for PsA. Generally, JAKI are initially used in combination with methotrexate (MTX) but are equally effective as monotherapeutic treatment if MTX is contraindicated. In terms of therapy safety, JAKI and bDMARD are generally comparable with one exception: JAKI are associated with an increased risk of herpes zoster infection. JAKI treatment requires laboratory blood tests, especially blood count, transaminases and creatinine. Due to hepatic metabolization, tofacitinib is associated with certain drug interactions. Altogether JAKI enhance treatment possibilities for diseases such as RA and PsA combining the same effectiveness and safety as bDMARD with the option of oral administration.


Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Psoriásica/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Inhibidores de las Cinasas Janus/uso terapéutico , Metotrexato/uso terapéutico , Azetidinas/uso terapéutico , Quimioterapia Combinada , Humanos , Piperidinas/uso terapéutico , Pirimidinas/uso terapéutico , Pirroles/uso terapéutico , Sulfonamidas/uso terapéutico , Resultado del Tratamiento
11.
World J Gastroenterol ; 25(32): 4580-4597, 2019 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-31528088

RESUMEN

Chronic delta hepatitis is the most severe form of viral hepatitis affecting nearly 65 million people worldwide. Individuals with this devastating illness are at higher risk for developing cirrhosis and hepatocellular carcinoma. Delta virus is a defective RNA virus that requires hepatitis B surface antigen for propagation in humans. Infection can occur in the form of a co-infection with hepatitis B, which can be self-limiting, vs superinfection in a patient with established hepatitis B infection, which often leads to chronicity in majority of cases. Current noninvasive tools to assess for advanced liver disease have limited utility in delta hepatitis. Guidelines recommend treatment with pegylated interferon, but this is limited to patients with compensated disease and is efficacious in about 30% of those treated. Due to limited treatment options, novel agents are being investigated and include entry, assembly and export inhibitors of viral particles in addition to stimulators of the host immune response. Future clinical trials should take into consideration the interaction of hepatitis B and hepatitis D as suppression of one virus can lead to the activation of the other. Also, surrogate markers of treatment efficacy have been proposed.


Asunto(s)
Antivirales/uso terapéutico , Coinfección/tratamiento farmacológico , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis D Crónica/tratamiento farmacológico , Sobreinfección/tratamiento farmacológico , Terapias en Investigación/métodos , Antivirales/farmacología , Coinfección/epidemiología , Coinfección/virología , Quimioterapia Combinada/métodos , Carga Global de Enfermedades , Antígenos de Superficie de la Hepatitis B/inmunología , Antígenos de Superficie de la Hepatitis B/metabolismo , Virus de la Hepatitis B/inmunología , Virus de la Hepatitis B/patogenicidad , Hepatitis B Crónica/epidemiología , Hepatitis B Crónica/virología , Hepatitis D Crónica/epidemiología , Hepatitis D Crónica/virología , Virus de la Hepatitis Delta/inmunología , Virus de la Hepatitis Delta/patogenicidad , Humanos , Interferón-alfa/farmacología , Interferón-alfa/uso terapéutico , Lipopéptidos/farmacología , Lipopéptidos/uso terapéutico , Transportadores de Anión Orgánico Sodio-Dependiente/antagonistas & inhibidores , Transportadores de Anión Orgánico Sodio-Dependiente/metabolismo , Piperidinas/farmacología , Piperidinas/uso terapéutico , Piridinas/farmacología , Piridinas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Literatura de Revisión como Asunto , Sobreinfección/epidemiología , Sobreinfección/virología , Simportadores/antagonistas & inhibidores , Simportadores/metabolismo , Resultado del Tratamiento , Ensamble de Virus/efectos de los fármacos , Internalización del Virus/efectos de los fármacos
12.
Mol Med Rep ; 20(4): 3709-3718, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31485676

RESUMEN

Chronic pancreatitis (CP) is characterized by recurrent pancreatic injury, resulting in inflammation and fibrosis. Currently, there are no drugs for the treatment of pancreatic fibrosis associated with CP. Piperine, a natural alkaloid found in black pepper, has been reported to show anti­inflammatory, anti­oxidative, and antitumor activities. Although piperine exhibits numerous properties in regards to the regulation of diverse diseases, the effects of piperine on CP have not been established. To investigate the effects of piperine on CP in vivo, we induced CP in mice through the repetitive administration of cerulein (50 µg/kg) six times at 1­h intervals, 5 times per week, for a total of 3 weeks. In the pre­treatment groups, piperine (1, 5, or 10 mg/kg) or corn oil were administrated orally at 1 h before the first cerulein injection, once a day, 5 times a week, for a total of 3 weeks. In the post­treatment groups, piperine (10 mg/kg) or corn oil was administered orally at 1 or 2 week after the first cerulein injection. Pancreases were collected for histological analysis. In addition, pancreatic stellate cells (PSCs) were isolated to examine the anti­fibrogenic effects and regulatory mechanisms of piperine. Piperine treatment significantly inhibited histological damage in the pancreas, increased the pancreatic acinar cell survival, reduced collagen deposition and reduced pro­inflammatory cytokines and chemokines. In addition, piperine treatment reduced the expression of fibrotic mediators, such as α­smooth muscle actin (α­SMA), collagen, and fibronectin 1 in the pancreas and PSCs. Moreover, piperine treatment reduced the production of transforming growth factor (TGF)­ß in the pancreas and PSCs. Furthermore, piperine treatment inhibited TGF­ß­induced pSMAD2/3 activation but not pSMAD1/5 in the PSCs. These findings suggest that piperine treatment ameliorates pancreatic fibrosis by inhibiting TGF­ß/SMAD2/3 signaling during CP.


Asunto(s)
Alcaloides/uso terapéutico , Antiinflamatorios/uso terapéutico , Benzodioxoles/uso terapéutico , Pancreatitis Crónica/tratamiento farmacológico , Piperidinas/uso terapéutico , Alcamidas Poliinsaturadas/uso terapéutico , Proteínas Smad/inmunología , Factor de Crecimiento Transformador beta/inmunología , Animales , Modelos Animales de Enfermedad , Femenino , Fibrosis , Ratones , Ratones Endogámicos C57BL , Páncreas/efectos de los fármacos , Páncreas/inmunología , Páncreas/patología , Pancreatitis Crónica/inmunología , Pancreatitis Crónica/patología , Transducción de Señal/efectos de los fármacos
13.
Hematol Oncol ; 37(4): 392-400, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31420873

RESUMEN

Ibrutinib, a first-generation Bruton's tyrosine kinase (BTK) inhibitor, could improve immunity of relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) patients. Whether zanubrutinib, a second-generation selective BTK inhibitor, has similar effects as ibrutinib remains to be determined. Dynamics of number and immunophenotype of immune cells during zanubrutinib treatment in 25 R/R CLL/SLL patients were examined by flow cytometry and blood routine tests. The expression intensity of programmed death-1 (PD-1) on total CD4+ (P < .01), total CD8+ (P < .01), and T helper cells (P < .05) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) on total CD4+ (P = .010) and regulatory T cells (P < .05) reduced after treatment. There were significant differences in expression intensity of CD19 (P < .01), C-X-C chemokine receptor type 5 (CXCR5) (P < .01), and CD49d (P < .05) on B cells before and after treatment. Downregulation of PD-1 on T cells and CXCR5 and CD19 on B cells were observed in nearly all patients after zanubrutinib treatment. Programmed death-ligand 1 expression downregulated, especially in the female, CLL, normal spleen, normal ß2-macroglobulin (ß2-MG) and abnormal lactate dehydrogenase (LDH) subgroups, and CTLA-4 expression on CD4+ T cells tended to decrease in the male, old, CLL, splenomegaly, abnormal ß2-MG, normal LDH, IGHV-mutated and wild-type tumor protein 53 subgroups after zanubrutinib treatment. These findings suggest that zanubrutinib can regulate immunity primarily by improving T cell exhaustion, inhibiting suppressor cells and disrupting CLL cells migration through downregulation of adhesion/homing receptors. Furthermore, favorable changes in cell number and immunophenotype were preferably observed in patients without adverse prognostic factors.


Asunto(s)
Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Antineoplásicos/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Proteínas de Neoplasias/antagonistas & inhibidores , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Adulto , Anciano , Antineoplásicos/farmacología , Subgrupos de Linfocitos B/efectos de los fármacos , Femenino , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Humanos , Inmunofenotipificación , Células Asesinas Naturales/efectos de los fármacos , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Pirimidinas/farmacología , Receptores de Antígenos de Linfocitos B/inmunología , Subgrupos de Linfocitos T/efectos de los fármacos
14.
Sleep Med Clin ; 14(3): 333-350, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31375202

RESUMEN

Idiopathic hypersomnia (IH) is characterized by excessive daytime sleepiness despite normal or prolonged sleep. IH is distinguished from narcolepsy by the female predominance, severe morning inertia, continuous drowsiness (rather than sleep attacks), unrefreshing naps, absence of cataplexy, sleep onset in REM periods, and hypocretin deficiency. In IH, the multiple sleep latency test demonstrates low sensitivity, specificity, and reproducibility, compared with prolonged sleep monitoring. In some IH cases, an endogenous hypnotic peptide stimulating GABA receptors during wakefulness is suspected, which are improved by anti-GABA drugs. The benefits of modafinil, sodium oxybate, mazindol, and pitolisant were found in mostly retrospective studies.


Asunto(s)
Moduladores del GABA/uso terapéutico , Promotores de la Vigilia/uso terapéutico , Estimulantes del Sistema Nervioso Central/uso terapéutico , Claritromicina/uso terapéutico , Flumazenil/uso terapéutico , Humanos , /fisiopatología , Mazindol/uso terapéutico , Modafinilo/uso terapéutico , Orexinas/metabolismo , Piperidinas/uso terapéutico , Polisomnografía , Medicina de Precisión , Sueño , Oxibato de Sodio/uso terapéutico , Vigilia
15.
Arthritis Rheumatol ; 71(9): 1450-1459, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31385441

RESUMEN

OBJECTIVE: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). This study was undertaken to evaluate the risk of major adverse cardiovascular events (MACE) in patients with RA receiving tofacitinib. METHODS: Data were pooled from patients with moderately to severely active RA receiving ≥1 tofacitinib dose in 6 phase III and 2 long-term extension studies over 7 years. MACE (myocardial infarction, stroke, cardiovascular death) were independently adjudicated. Cox regression models were used to evaluate associations between baseline variables and time to first MACE. Following 24 weeks of tofacitinib, changes in variables and time to future MACE were evaluated after adjusment for age, baseline values, and time-varying tofacitinib dose. Hazard ratios and 95% confidence intervals were calculated. RESULTS: Fifty-two MACE occurred in 4,076 patients over 12,873 patient-years of exposure (incidence rate 0.4 patients with events per 100 patient-years). In univariable analyses of baseline variables, traditional cardiovascular risk factors and glucocorticoid and statin use were associated with MACE risk; disease activity and inflammation measures were not. In subsequent multivariable analyses, baseline age, hypertension, and the total cholesterol to high-density lipoprotein (HDL) cholesterol ratio remained significantly associated with risk of MACE. After 24 weeks of treatment, an increase in HDL cholesterol and a decrease in the total to HDL cholesterol were associated with decreased MACE risk; changes in total cholesterol, low-density lipoprotein (LDL) cholesterol, and disease activity measures were not. Increased erythrocyte sedimentation rates trended with increased future MACE risk. CONCLUSION: In this post hoc analysis, after 24 weeks of tofacitinib treatment, increased HDL cholesterol, but not increased LDL cholesterol or total cholesterol, appeared to be associated with lower future MACE risk. Further data are needed to test the cardiovascular safety of tofacitinib.


Asunto(s)
Artritis Reumatoide/complicaciones , Artritis Reumatoide/tratamiento farmacológico , Enfermedades Cardiovasculares/etiología , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Pirroles/uso terapéutico , Anciano , Artritis Reumatoide/sangre , Sedimentación Sanguínea , Enfermedades Cardiovasculares/epidemiología , Colesterol/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Ensayos Clínicos Fase III como Asunto , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Infarto del Miocardio/epidemiología , Infarto del Miocardio/etiología , Modelos de Riesgos Proporcionales , Factores de Riesgo , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiología , Resultado del Tratamiento
16.
Medicine (Baltimore) ; 98(31): e16392, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31374006

RESUMEN

RATIONALE: Vandetanib is effective for treating symptomatic or progressive medullary thyroid cancer (MTC) in patients with unresectable locally advanced or metastatic disease, but its toxicity such as photosensitivity reactions should be considered. It is a rare adverse effect of this drug but might cause severe morbidity and even mortality. PATIENT CONCERNS: A 26-year man with MTC developed phototoxic rashes on the sun-exposed areas of his shin after 15 days from the initiation of vandetanib treatment. Grade II skin toxicity was evaluated based on the Common Terminology Criteria for Adverse Events standard. DIAGNOSES: Drug-induced phototoxic rash. INTERVENTIONS: The vandetanib dose was reduced by 30%, and the application of topical steroids and sunscreen was adopted. OUTCOMES: After dose reduction of vandetanib, the symptoms of vandetanib-induced phototoxic rash resolved, although residual pigmentation was observed. LESSONS: Close attention should be paid to the adverse effect of vandetanib, phototoxic rash, and patients should be advised on the prevention and treatment measures.


Asunto(s)
Dermatitis Fototóxica/etiología , Piperidinas/efectos adversos , Quinazolinas/efectos adversos , Neoplasias de la Tiroides/tratamiento farmacológico , Adulto , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Masculino , Piperidinas/uso terapéutico , Quinazolinas/uso terapéutico
17.
Arthritis Rheumatol ; 71(10): 1599-1613, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31436036

RESUMEN

OBJECTIVE: To update evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). METHODS: We conducted updated systematic literature reviews for 20 clinical questions on pharmacologic treatment addressed in the 2015 guidelines, and for 26 new questions on pharmacologic treatment, treat-to-target strategy, and use of imaging. New questions addressed the use of secukinumab, ixekizumab, tofacitinib, tumor necrosis factor inhibitor (TNFi) biosimilars, and biologic tapering/discontinuation, among others. We used the Grading of Recommendations, Assessment, Development and Evaluation methodology to assess the quality of evidence and formulate recommendations and required at least 70% agreement among the voting panel. RESULTS: Recommendations for AS and nonradiographic axial SpA are similar. TNFi are recommended over secukinumab or ixekizumab as the first biologic to be used. Secukinumab or ixekizumab is recommended over the use of a second TNFi in patients with primary nonresponse to the first TNFi. TNFi, secukinumab, and ixekizumab are favored over tofacitinib. Co-administration of low-dose methotrexate with TNFi is not recommended, nor is a strict treat-to-target strategy or discontinuation or tapering of biologics in patients with stable disease. Sulfasalazine is recommended only for persistent peripheral arthritis when TNFi are contraindicated. For patients with unclear disease activity, spine or pelvis magnetic resonance imaging could aid assessment. Routine monitoring of radiographic changes with serial spine radiographs is not recommended. CONCLUSION: These recommendations provide updated guidance regarding use of new medications and imaging of the axial skeleton in the management of AS and nonradiographic axial SpA.


Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Antirreumáticos/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Espondilitis Anquilosante/tratamiento farmacológico , /uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Productos Biológicos/uso terapéutico , Biosimilares Farmacéuticos/uso terapéutico , Deprescripciones , Humanos , Imagen por Resonancia Magnética , Piperidinas/uso terapéutico , Pirimidinas/uso terapéutico , Pirroles/uso terapéutico , Radiografía , Sociedades Médicas , Espondiloartropatías/diagnóstico por imagen , Espondiloartropatías/tratamiento farmacológico , Espondilitis Anquilosante/diagnóstico por imagen
18.
BMJ Case Rep ; 12(8)2019 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-31466953

RESUMEN

Ovarian cancer is the second the most common gynaecological malignancy in developed countries. 70% of patients relapse in the first 3 years following debulking surgery and first-line chemotherapy. Niraparib is a poly adenosine diphosphate ribose polymerase inhibitor which uses the concept of synthetic lethality in the presence of a mutation in the breast cancer susceptibility gene (BRCA), and is now recommended as maintenance treatment in patients with platinum-sensitive relapse of ovarian cancer. It has been shown to increase progression-free survival. We present a case of a 68-year-old woman with brain metastases from high-grade serous ovarian cancer who has remained free of disease progression for longer than 17 months with niraparib use as maintenance treatment after second-line chemotherapy.


Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/secundario , Cistadenocarcinoma Seroso/tratamiento farmacológico , Indazoles/administración & dosificación , Neoplasias Ováricas/tratamiento farmacológico , Piperidinas/administración & dosificación , Anciano , Cistadenocarcinoma Seroso/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Indazoles/uso terapéutico , Quimioterapia de Mantención , Clasificación del Tumor , Neoplasias Ováricas/patología , Piperidinas/uso terapéutico , Resultado del Tratamiento
19.
Expert Opin Pharmacother ; 20(16): 1953-1960, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31456440

RESUMEN

Introduction: Psoriatic arthritis (PsA) is a chronic inflammatory condition that is associated with progressive joint destruction and reduced quality of life. Despite the common use of disease-modifying anti-rheumatic drugs (DMARDs) in PsA, their influence has been investigated in a number of studies with conflicting results. There is also concern about their safety and tolerability. Tofacitinib is an orally administered Janus kinase (JAK) inhibitor that has recently been approved for the treatment of PsA by various international regulatory authorities, including the FDA, EMA, and NICE. Areas covered: In this review, the mechanism of action and the pharmacokinetic properties of tofacitinib are discussed. The data from two large phase III clinical studies evaluating the use of tofacitinib in PsA is also discussed in addition to the findings from other relevant studies. Expert opinion: The clinical data demonstrate significant improvement in disease activity in PsA patients using tofacitinib. There is also an acceptable clinical safety profile for the drug. Tofacitinib has various advantages over several existing drug treatments for PsA including an oral route of administration, a short half-life and a fast onset of action. Consequently, we anticipate that tofacitinib will become an increasingly used targeted synthetic DMARD (tsDMARD) for active PsA over the coming years.


Asunto(s)
Artritis Psoriásica/tratamiento farmacológico , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Pirroles/uso terapéutico , Ensayos Clínicos como Asunto , Relación Dosis-Respuesta a Droga , Semivida , Humanos , Quinasas Janus/antagonistas & inhibidores , Quinasas Janus/metabolismo , Piperidinas/efectos adversos , Piperidinas/farmacocinética , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Pirimidinas/efectos adversos , Pirimidinas/farmacocinética , Pirroles/efectos adversos , Pirroles/farmacocinética
20.
J Headache Pain ; 20(1): 90, 2019 Aug 29.
Artículo en Inglés | MEDLINE | ID: mdl-31464581

RESUMEN

BACKGROUND: In addition to the increased risk for cardiovascular (CV) disease and CV events associated with migraine, patients with migraine can also present with a number of CV risk factors (CVRFs). Existing treatment options can be limited due to contraindications, increased burden associated with monitoring, or patient avoidance of side effects. Safe and effective migraine treatment options are needed for patients with migraine and a history of CV or cerebrovascular disease or with increased risk for CV events. This analysis was designed to evaluate the safety and efficacy of oral lasmiditan, a selective serotonin 5-hydroxytryptamine 1F receptor agonist, in acute treatment of migraine attacks in patients with CVRFs. METHODS: SAMURAI and SPARTAN were similarly designed, Phase 3, randomized, double-blind, placebo-controlled trials in adults treating a single migraine attack with lasmiditan 50, 100, or 200 mg. Both studies included patients with CVRFs, and SPARTAN allowed patients with coronary artery disease, clinically significant arrhythmia, or uncontrolled hypertension. Efficacy and safety of lasmiditan in subgroups of patients with differing levels of CVRFs are reported. For efficacy analyses, logistic regression was used to assess treatment-by-subgroup interactions. For safety analyses, Cochran-Mantel-Haenszel test of general association evaluated treatment comparisons; Mantel-Haenszel odds ratio assessed significant treatment effects. RESULTS: In this pooled analysis, a total of 4439 patients received ≥1 dose of study drug. A total of 3500 patients (78.8%) had ≥1 CVRF, and 1833 patients (41.3%) had ≥2 CVRFs at baseline. Both trials met the primary endpoints of headache pain freedom and most bothersome symptom freedom at 2 h. The presence of CVRFs did not affect efficacy results. There was a low frequency of likely CV treatment-emergent adverse events (TEAEs) overall (lasmiditan, 30 [0.9%]; placebo, 5 [0.4%]). There was no statistical difference in the frequency of likely CV TEAEs in either the absence or presence of any CVRFs. The only likely CV TEAE seen across patients with ≥1, ≥ 2, ≥ 3, or ≥ 4 CVRFs was palpitations. CONCLUSIONS: When analyzed by the presence of CVRFs, there was no statistical difference in lasmiditan efficacy or the frequency of likely CV TEAEs. Despite the analysis being limited by a single-migraine-attack design, the lack of differences in efficacy and safety with increasing numbers of CVRFs indicates that lasmiditan might be considered in the treatment algorithm for patients with CVRFs. Future studies are needed to assess long-term efficacy and safety. TRIAL REGISTRATION: ClinicalTrials.gov NCT02439320 (SAMURAI), registered 18 March 2015 and ClinicalTrials.gov NCT02605174 (SPARTAN), registered 11 November 2015.


Asunto(s)
Benzamidas/uso terapéutico , Enfermedades Cardiovasculares/fisiopatología , Trastornos Migrañosos/tratamiento farmacológico , Piperidinas/uso terapéutico , Piridinas/uso terapéutico , Agonistas de Receptores de Serotonina/uso terapéutico , Adulto , Método Doble Ciego , Femenino , Cefalea , Humanos , Masculino , Persona de Mediana Edad , Receptores de Serotonina , Resultado del Tratamiento
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