Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 82
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
PLoS Biol ; 18(5): e3000660, 2020 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-32453744

RESUMO

Increased life expectancy of patients diagnosed with HIV in the current era of antiretroviral therapy is unfortunately accompanied with the prevalence of HIV-associated neurocognitive disorders (HANDs) and risk of comorbidities such as Alzheimer-like pathology. HIV-1 transactivator of transcription (Tat) protein has been shown to induce the production of toxic neuronal amyloid protein and also enhance neurotoxicity. The contribution of astrocytes in Tat-mediated amyloidosis remains an enigma. We report here, in simian immunodeficiency virus (SIV)+ rhesus macaques and patients diagnosed with HIV, brain region-specific up-regulation of amyloid precursor protein (APP) and Aß (40 and 42) in astrocytes. In addition, we find increased expression of ß-site cleaving enzyme (BACE1), APP, and Aß in human primary astrocytes (HPAs) exposed to Tat. Mechanisms involved up-regulation of hypoxia-inducible factor (HIF-1α), its translocation and binding to the long noncoding RNA (lncRNA) BACE1-antisense transcript (BACE1-AS), resulting, in turn, in the formation of the BACE1-AS/BACE1 RNA complex, subsequently leading to increased BACE1 protein, and activity and generation of Aß-42. Gene silencing approaches confirmed the regulatory role of HIF-1α in BACE1-AS/BACE1 in Tat-mediated amyloidosis. This is the first report implicating the role of the HIF-1α/lncRNABACE1-AS/BACE1 axis in Tat-mediated induction of astrocytic amyloidosis, which could be targeted as adjunctive therapies for HAND-associated Alzheimer-like comorbidity.

2.
BioDrugs ; 34(3): 405, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32253718

RESUMO

The article Effectiveness of Switching from Reference Product Infliximab to Infliximab-Dyyb in Patients with Inflammatory Bowel Disease in an Integrated Healthcare System in the United States: A Retrospective, Propensity Score-Matched, Non-Inferiority Cohort Study, written by Stephanie L. Ho, Fang Niu, Suresh Pola, Fernando S. Velayos, Xian Ning and Rita L. Hui, was originally published electronically on 26 February 2020 without open access.

3.
Tissue Barriers ; : 1748983, 2020 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-32299282

RESUMO

The blood-brain barrier (BBB) is a tight barrier that is critical for preventing the entry of pathogens and small molecules into the brain. HIV protein Tat (Tat) is known to disrupt the tight junctions of the BBB. Autophagy is an intracellular process that involves degradation and recycling of damaged organelles to the lysosome and has recently been implicated in the BBB disruption. The role of autophagy in Tat-mediated BBB disruption, however, remains elusive. Herein we hypothesized that Tat induces endothelial autophagy resulting in decreased expression of the tight junction protein ZO-1 leading to breach of the BBB. In this study, we demonstrated that exposure of human brain microvessel endothelial cells (HBMECs) to Tat resulted in induction of autophagy in a dose- and time-dependent manner, with upregulation of BECN1/Beclin 1, ATG5 and MAP1LC3B proteins and a concomitant downregulation of the tight junction protein ZO-1 ultimately leading to increased endothelial cell monolayer paracellular permeability in an in vitro BBB model. Pharmacological and genetic inhibition of autophagy resulted in the abrogation of Tat-mediated induction of MAP1LC3B with a concomitant restoration of tight junction proteins, thereby underscoring the role of autophagy in Tat-mediated breach of the BBB. Additionally, our data also demonstrated that Tat-mediated induction of autophagy involved PELI1/K63-linked ubiquitination of BECN1. Increased autophagy and decreased ZO-1 was further recapitulated in microvessels isolated from the brains of HIV Tg26 mice as well as the frontal cortex of HIV-infected autopsied brains. Overall, our findings identify autophagy as an important mechanism underlying Tat-mediated disruption of the BBB.

4.
J Manag Care Spec Pharm ; 26(2): 197-202, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32011964

RESUMO

BACKGROUND: Few studies have examined factors that determine bisphosphonate (BP) continuation beyond 5 years in clinical practice. OBJECTIVE: To investigate factors associated with BP continuation among women who completed 5 years of BP therapy. METHODS: Women who received 5 consecutive years of oral BP treatment entered the cohort during 2002-2014 and were followed up to 5 additional years. Multivariable logistic regression was used to evaluate the association of demographic and clinical factors with adherent treatment continuation. RESULTS: The cohort included 19,091 women with a median age of 72 years. Baseline and time-varying factors associated with increased odds of BP continuation after 5 years were (a) most recent bone mineral density (BMD) T-score -2 to -2.4 (OR = 1.31, 95% CI = 1.25-1.38), T-score -2.5 to -2.9 (OR = 1.48, 95% CI = 1.39-1.57), and T-score ≤ -3.0 (OR = 1.57, 95% CI = 1.47-1.68) versus T-scores above -2.0; (b) index date before 2008 (OR =1.35, 95% CI = 1.29-1.41); and (c) diabetes mellitus (OR = 1.08, 95% CI = 1.01-1.16). In contrast, factors associated with decreased odds of BP continuation were (a) recent hip (OR = 0.61, 95% CI = 0.52-0.71) or humerus (OR = 0.79, 95% CI = 0.66-0.94) fracture or fracture other than hip, wrist, spine, or humerus (OR = 0.90, 95% CI = 0.84-0.97); (b) Charlson Comorbidity Index score > 2 (OR = 0.91, 95% CI = 0.84-0.98); (c) history of rheumatoid arthritis (OR = 0.89, 95% CI = 0.80-0.99); (d) Hispanic (OR = 0.89, 95% CI=0.85-0.94) or Asian (OR = 0.90, 95% CI = 0.85-0.94) race/ethnicity; and (e) use of proton pump inhibitors (OR = 0.65, 95% CI = 0.59-0.71). Patient age and fracture before BP initiation were not associated with treatment continuation. CONCLUSIONS: Clinical factors predicting continued BP treatment beyond 5 years include low BMD T-score, absence of recent fracture, and earlier era of treatment. Use of proton pump inhibitors was associated with lower likelihood of BP continuation. Other clinical and demographic factors were also noted to have variable effects on BP treatment continuation. DISCLOSURES: This study was supported by a grant from the National Institute on Aging and National Institute of Arthritis, Musculoskeletal and Skin Diseases at the National Institutes of Health (NIH; R01AG047230, S1). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or Kaiser Permanente. Lo has received previous research funding from Amgen and Sanofi, unrelated to the current study. Adams has received previous research funding from Merck, Amgen, Otsuka, and Radius Health, unrelated to the current study. Ettinger has served as an expert witness for Teva Pharmaceuticals, unrelated to the current study. Ott previously attended a scientific advisory meeting for Amgen but declined the honorarium. The other authors have nothing to disclose. These data were presented at the 2018 Annual Meeting of the American Society of Bone and Mineral Research (ASBMR), September 28-October 1, 2018, Montreal, Quebec, Canada.

5.
BioDrugs ; 34(3): 395-404, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32103457

RESUMO

PURPOSE: The aim was to compare outcomes in adult patients with inflammatory bowel disease (IBD) who switched to infliximab-dyyb with those who remained on reference product (RP) infliximab in the United States (US) in a retrospective, propensity score-matched, non-inferiority cohort trial. METHODS: This study was a retrospective, non-inferiority study conducted within a US integrated healthcare system and included adult patients with a confirmed diagnosis of Crohn's disease or ulcerative colitis. A 1:1 propensity score matching was utilized to match patients who switched to infliximab-dyyb during the period April 2016-March 2018 to patients who remained on RP infliximab. The non-inferiority margin was set at + 10% of the upper limit. The primary outcome was a composite measure of disease worsening requiring acute care after the index date of switching to infliximab-dyyb or continuing RP infliximab. Disease worsening requiring acute care was defined as any IBD-related emergency room visit, hospitalization, or surgery. The secondary outcome was the composite measure of disease worsening requiring acute care or treatment failure. A switch to another biologic or tofacitinib was a proxy for treatment failure. All patients were followed for up to 9 months. RESULTS: After propensity score matching, the matched cohort included 1409 patients in the infliximab-dyyb group and 1409 patients in the RP infliximab group. The overall mean age (± standard deviation) was 47.7 ± 17.0 years, 50.9% of patients were of male gender, and 51.8% of patients had Crohn's disease, while the remainder of the cohort had ulcerative colitis. There were 144 patients (10.2%) in the infliximab-dyyb group and 245 patients (17.4%) in the RP infliximab group who experienced disease worsening requiring acute care (P < 0.01 for non-inferiority). There were 347 patients (24.6%) in the infliximab-dyyb group who experienced disease worsening requiring acute care or treatment failure compared to 375 patients (26.6%) who remained on RP infliximab (P < 0.01 for non-inferiority). CONCLUSION: There was no increased risk of (1) disease worsening requiring acute care or (2) disease worsening requiring acute care or treatment failure in patients with IBD who switched from RP infliximab to infliximab-dyyb when compared to patients who remained on RP infliximab in this US population. Infliximab-dyyb is an option for patients with IBD who need to use RP infliximab.

6.
J Gen Intern Med ; 35(3): 696-703, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31919729

RESUMO

BACKGROUND: Concurrent use of benzodiazepines in opioid users has been linked to a higher risk of an emergency room visit or inpatient admission for opioid overdose and death from drug overdose. Further research is needed to confirm the findings and analyze contributing risk factors for opioid overdoses in a large commercially insured population. OBJECTIVES: To estimate the risk of opioid overdose associated with opioid users exposed to various combinations of opioid, benzodiazepine, and non-benzodiazepine sedative-hypnotic therapy. To identify other factors that are associated with increased risk for opioid overdose. DESIGN: Retrospective cohort study. PATIENTS: New start adult users of opioids, defined as naïve to opioids for 6 months, in Kaiser Permanente California regions from January 2013 through September 2017. MAIN MEASURES: Inpatient or emergency department admissions due to opioid-related overdose. KEY RESULTS: A total of 2,241,530 patients were included in this study. Patients exposed to opioids, benzodiazepines, and non-benzodiazepine sedative-hypnotics at any point during their follow-up were 60% more likely to overdose than those who were only exposed to opioids (p < 0.0001). Those exposed to opioids and benzodiazepines were 20% more likely to have an opioid-related overdose than those exposed to opioids only (p < 0.0001). Significant risk factors for opioid overdose included exposure to all three medication classes, higher opioid dosage strengths, elderly age (age ≥ 65 years), history of previous overdose, and substance use disorder. CONCLUSIONS: Results from this study demonstrate a significant increase in risk of opioid overdose in patients exposed to combinations of sedative-hypnotics with opioids compared to those only taking opioids. Findings from this study provide evidence that opioids should be avoided in combination with benzodiazepines and non-benzodiazepine sedative-hypnotics, used at the lowest dose possible, and used with caution in the elderly, those with previous history of overdose, and those with substance use disorder at baseline.

7.
Wideochir Inne Tech Maloinwazyjne ; 14(3): 394-400, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31534569

RESUMO

Introduction: The number of elderly patients with biliary and pancreatic diseases has increased significantly. The characteristics of biliary and pancreatic diseases in the elderly increase the risk of treatment. Aim: To study the safety and efficacy of therapeutic endoscopic retrograde cholangiopancreatography (ERCP) in elderly patients with biliary and pancreatic diseases with the concept of enhanced recovery after surgery (ERAS). Material and methods: Patients receiving ERCP under ERAS were grouped into an elderly group (group A, n = 58, aged 75 years or above) and a young and middle-aged group (group B, n = 202, aged less than 60 years). The clinical parameters before, during and after the operation of the two groups were compared. Results: Before the operation, the incidences of cholangiocarcinoma and complications, nutritional screening score ≥ 3, ASA degree III and Child-Pugh grade A in group A were significantly higher than those in group B (p < 0.05), while the incidences of nausea and vomiting, abdominal pain, nutritional screening < 3 and ASA grade I in group A were significantly lower than those in group B (p < 0.05). Intraoperatively, the incidence of juxta-ampullary duodenal diverticulum (JAD) in internal or bottom papilla in the elder patients with difficult selective biliary cannulation (DSBC) was significantly higher than that in the young and middle-aged group (p < 0.05). In addition, the continuous ECG monitoring duration and the first exhaust time in group A were significantly longer than those in group B (p < 0.05). Conclusions: Endoscopic retrograde cholangiopancreatography under ERAS in elderly patients is as safe and effective as in young patients.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31401755

RESUMO

Although combination antiretroviral therapy (cART) has improved the health of millions of those living with HIV-1 (Human Immunodeficiency Virus, Type 1), the penetration into the central nervous system (CNS) of many such therapies is limited, thereby resulting in residual neurocognitive impairment commonly referred to as NeuroHIV. Additionally, while cART has successfully suppressed peripheral viremia, cytotoxicity associated with the presence of viral Transactivator of transcription (Tat) protein in tissues such as the brain, remains a significant concern. Our previous study has demonstrated that both HIV-1 Tat as well as opiates such as morphine, can directly induce synaptic alterations via independent pathways. Herein, we demonstrate that exposure of astrocytes to HIV-1 protein Tat mediates the induction and release of extracellular vesicle (EV) microRNA-7 (miR-7) that is taken up by neurons, leading in turn, to downregulation of neuronal neuroligin 2 (NLGN2) and ultimately to synaptic alterations. More importantly, we report that these impairments could be reversed by pretreatment of neurons with a neurotrophic factor platelet-derived growth factor-CC (PDGF-CC). Graphical Abstract.

9.
Mol Genet Genomic Med ; 7(9): e890, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31359629

RESUMO

BACKGROUND: Lumbar disc herniation (LDH) is a common spinal disease in clinical practice. Once lumbar disc herniation occurs, it seriously reduces patient's quality of life. The EYS (eyes shut homolog) was discovered in recent years and it may be related to lumbar disc herniation. So we conducted a case-control study to explore the relationship between EYS polymorphism and lumbar disc herniation risk. METHODS: We selected 5 single-nucleotide polymorphisms (SNPs) of EYS gene in a case-control study with 508 cases and 508 healthy controls to evaluate the relatedness by using genetic model, haplotype, and stratification analysis. RESULTS: We found that the minor alleles of rs62413038 (OR = 1.21, 95%CI: 1.01-1.43, p = .036) and rs9450607 (OR = 1.26, 95% CI: 1.05-1.53, p = .016) were associated with an increased risk of lumbar disc herniation in the allelic model analysis. In the genotypic model analysis, rs62413038 displayed a significantly increased risk of lumbar disc herniation in log-additive models (OR = 1.20, 95% CI: 1.01-1.43, p = .039). While the rs9450607 was also obviously associated with an increased lumbar disc herniation risk in recessive (OR = 1.98, 95% CI: 1.24-3.13, p = .004) and log-additive models (OR = 1.27, 95% CI: 1.05-1.55, p = .014). In addition, in the haplotype analyses of the SNPs, we found that the "CGGA" haplotype of rs1482456, rs9342097, rs9450607, and rs7757884 was associated with lumbar disc herniation. (OR = 0.52, 95% CI: 0.30-0.89, p = .017). CONCLUSION: These results suggest that EYS polymorphism may be associated with lumbar disc herniation among Han Chinese population. It also opens up a new exploration direction for the etiology of lumbar disc herniation.

10.
J Manag Care Spec Pharm ; 25(8): 927-934, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31347983

RESUMO

BACKGROUND: In the elderly, use of medications may increase the propensity for adverse drug events due to alterations in pharmacokinetic and pharmacodynamic profiles from normal aging processes. Deprescribing is the planned and supervised process of dose reduction or discontinuation of medications that may lead to harm or are no longer beneficial. While there are studies detailing strategies to deprescribe medications such as benzodiazepines and antipsychotics in nursing homes or for patients with dementia, there is a lack of guidance to safely deprescribe chronic medications, such as antidiabetics, for older patients in the community setting. OBJECTIVE: To evaluate the risk of hypoglycemia and other outcomes of pharmacist-managed deprescribing on selected antidiabetic medications under the guidance of a standardized program compared with usual care within an integrated health care system. METHODS: This was a retrospective propensity score-matched cohort study. The pharmacist-managed deprescribing group included patients who were enrolled in the deprescribing program between July 1, 2016, and June 30, 2017. The usual care group included eligible patients who did not receive the deprescribing intervention and were matched to the deprescribing group using propensity score matching (PSM). Baseline demographics and clinical variables were used for matching. Patients were followed for 6 months or the end of membership or death, whichever occurred first. Primary outcome was the risk of hypoglycemia. Secondary outcomes included risk of hyperglycemia, proportion of patients at goal (A1c), change in A1c, change in monthly antidiabetic drug cost, and all-cause mortality. Outcomes were analyzed using descriptive statistics and multivariant regression or Cox proportional hazard models when appropriate. RESULTS: After PSM, 685 patients in the deprescribing group and 2,055 patients in the usual care group were similar in age, gender, weight, and comorbidity burden (mean [SD] age 82.4 [5.4] years, 48% female, mean [SD] weight 81.7 [19.2] kg, mean [SD] Charlson Comorbidity Index score 3.2 [1.6]). Compared with the usual care group, the deprescribing group had a lower risk of hypoglycemia (1.5% vs. 3.1%, P < 0.02; adjusted odds ratio 0.42, P < 0.01). As for the secondary outcomes, the deprescribing group had a greater change (SD) in A1c (0.3 [0.6] vs. 0.2 [0.7] P < 0.01) and lower all-cause mortality (2.3% vs 5.6%, P < 0.01; adjusted hazard ratio 0.35, P < 0.01). There were no differences observed in the risk of hyperglycemia, proportion of patients at goal A1c < 7%, and change in monthly antidiabetic drug costs between the 2 groups. CONCLUSIONS: There are currently no studies to our knowledge that evaluate the outcomes of a pharmacist-managed deprescribing program targeting antidiabetic medications. The results of our study showed that deprescribing of selected antidiabetics reduced the risk of hypoglycemia and may have mortality benefit in elderly patients with well-controlled type 2 diabetes, who are taking medications that can cause hypoglycemia. Further and longer studies are needed to validate these benefits. DISCLOSURES: No outside funding was provided to support this research study. The authors of this study have no actual or potential conflicts of interest to report. Parts of this study were presented in a nonreviewed resident poster at the Academy of Managed Care Pharmacy Managed Care and Specialty Pharmacy Annual Meeting; April 23-26, 2018; Boston, MA.


Assuntos
Prestação Integrada de Cuidados de Saúde/organização & administração , Assistência à Saúde/organização & administração , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Programas de Assistência Gerenciada/organização & administração , Farmacêuticos/organização & administração , Idoso de 80 Anos ou mais , Desprescrições , Feminino , Humanos , Hipoglicemia/etiologia , Masculino , Assistência Farmacêutica , Pontuação de Propensão , Estudos Retrospectivos , Risco
11.
Artigo em Inglês | MEDLINE | ID: mdl-31325121

RESUMO

Long non-coding RNAs (lncRNAs), including long intergenic non-coding RNAs (lincRNAs), play an important regulatory role in controlling various biological processes. Both in vitro and in vivo studies have demonstrated that lincRNA-Cox2 plays a global regulatory role in regulating the expression of immune genes. Extracellular vesicles (EVs) are cell-derived nanosized membrane vesicles that have gained increasing attention in recent years due to their ability to efficiently deliver therapeutics to specific target organs or cell types. In this study, we found that lincRNA-Cox2 controls the expression of a set of cell cycle genes in lipopolysaccharide (LPS)-stimulated microglial cells. Our in vitro study suggested that knocking down lincRNA-Cox2 reversed LPS-induced microglial proliferation. In addition, our in vivo study demonstrated that intranasally delivered lincRNA-Cox2-siRNA loaded EVs could reach the brain resulting in a significant decrease in the expression of lincRNA-Cox2 in the microglia. Importantly, lincRNA-Cox2-siRNA loaded EVs also decreased LPS-induced microglial proliferation in mice. These findings indicate that intranasal delivery of EV-loaded small RNA could be developed as therapeutics for treatment of a multitude of CNS disorders.

12.
Int Immunopharmacol ; 75: 105731, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31344555

RESUMO

BACKGROUND: Sepsis is a systemic inflammatory response that can lead to organ dysfunction and/or circulatory disorders in severe cases. The dysregulated inflammatory response plays a pivotal role in sepsis-induced liver injury. A variety of microRNAs and lncRNAs have been shown to be involved in the inflammatory response. However, their role in regulating sepsis-induced liver injury remains to be revealed. METHODS: Human hepatic tissue and healthy tissue were used for in vivo level detection. And Raw264.7 cells and Kupffer cells were used for in vitro modelling. The relative mRNA expression and the protein levels of TNF-α, IL-6 and IL-1ß were detected by q-PCR or by enzyme-linked immunosorbent assay (ELISA), respectively. The binding of lncRNA NEAT1/Let-7a and Let-7a/TLR4 was detected by dual-luciferase reporter assay. RNA Immunoprecipitation (RIP) was used to detect the targeting relationship between lncRNA NEAT1 and Let-7a. Western blotting (WB) was used to detect TLR4 expression in different cell models. RESULTS: The overexpression of lncRNA NEAT1 accompanied by Let-7a inhibition and TLR4 activation was found in sepsis-induced liver injury patients. Similarly, LPS stimulation upregulated lncRNA NEAT1 expression, and lncRNA NEAT1 inhibition decreased the levels of inflammatory cytokines in vitro. Let-7a inhibitor treatment as well as TLR4 overexpression rescued the expression of inflammatory cytokines in lncRNA NEAT1-knockdown cells. Moreover, Let-7a interacted with both lncRNA NEAT1 and TLR4. CONCLUSION: We demonstrate that lncRNA NEAT1 interacts with Let-7a, targeting TLR4 to contribute to the LPS-induced inflammatory response. Our assay can provide a potential therapeutic target for sepsis-induced liver injury.

13.
Environ Sci Pollut Res Int ; 26(21): 21629-21640, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31129896

RESUMO

Pesticides are capable of increasing risks to the early development of nontarget organisms through oxidative stress. The supplementation of antioxidants could help to modulate the toxic effects of pesticides, but much remains to be understood in the interactions between pesticides and antioxidants in amphibians. In the present study, the embryotoxicity of a widely used pyrethroid, lambda-cyhalothrin (LCT), and the potential effect of α-tocopherol (TOC) on embryos of Xenopus tropicalis were evaluated. Exposure to LCT did not affect the hatch rate, survival, or body length of the embryos. However, environmentally relevant concentrations of LCT could induce significant malformations on the larvae. Exposure to LCT led to a concentration-dependent induction of oxidative stress and cytotoxicity that subsequently resulted in embryotoxicity. During the early developmental stages, vitamin E could work as a powerful protective antioxidant. The LCT-induced overproduction of reactive oxygen species and increased enzymatic activities were fully inhibited by treatment with 1 µg/L TOC. However, only supplementation with 100 µg/L TOC provided partial protection against the morphological changes caused by LCT. The results from the present study suggest that antioxidant vitamin E possesses protective potential against pyrethroid-induced embryotoxicity in amphibian embryos through the prevention of oxidative stress.


Assuntos
Antioxidantes/metabolismo , Inseticidas/toxicidade , Nitrilos/toxicidade , Piretrinas/toxicidade , Vitamina E/metabolismo , Xenopus/embriologia , Animais , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Praguicidas/toxicidade
14.
J Manag Care Spec Pharm ; 25(6): 719-723, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31134854

RESUMO

BACKGROUND: Assigning drug exposure is a necessary first step in examining bisphosphonate (BP) treatment in observational studies using pharmacy data. OBJECTIVE: To determine whether the choice of adherence level using the proportion of days covered (PDC) affected BP exposure assignment. METHODS: 10,381 female health plan members who initiated oral BP therapy between 2002 and 2010 and had received 5 consecutive years of treatment were identified and subsequently followed up to 5 additional years. In each 90-day interval of follow-up, a woman was considered "on treatment" if she received the drug for more than a predetermined PDC based on pharmacy days supply and "off treatment" if she received the drug for less than that PDC. Women who continued on therapy above the PDC threshold during follow-up were considered continuously on therapy. Women who were off treatment during the first 90-days of follow-up were classified as off therapy and were followed to determine if they remained continuously off treatment. This study evaluated the extent to which varying the PDC threshold (≥ 0.5, ≥ 0.6, and ≥ 0.7) affected the proportion of women classified as "continuously on" or "continuously off" BP during follow-up. RESULTS: Under PDC thresholds of 0.5, 0.6, and 0.7, 48%, 43%, and 36% of women who remained on follow-up were categorized as continuously on treatment at year 2 of follow-up, and 18%, 14%, and 12% were categorized as continuously on treatment by the end of follow-up. Using these same PDC thresholds, 9%, 12%, and 15% of women were categorized as off therapy during the first quarter of follow-up and were highly likely to remain off therapy: 4%, 5%, and 5% were classified as continuously off therapy at year 2, and 4% of women were classified as such by the end of follow-up for all 3 thresholds. CONCLUSIONS: A PDC of 0.6 was chosen as a practical threshold for drug adherence. Varying the PDC to 0.5 or 0.7 resulted in modest changes in the proportions of women considered continuously on BP therapy. DISCLOSURES: This study was supported by a grant from the National Institute of Aging and National Institute of Arthritis, Musculoskeletal and Skin Diseases at the National Institutes of Health (R01AG047230, S1). Lo has received previous research funding from Amgen and Sanofi, outside of the current study. Chandra has received previous research funding from Amgen outside of the current study. Adams has received previous research funding from Merck, Amgen, Otsuka, and Radius Health, outside of the current study. Ott previously attended a scientific advisory meeting for Amgen but declined the honorarium. Ettinger previously served as an expert witness for Teva Pharmaceuticals.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/uso terapêutico , Adesão à Medicação/estatística & dados numéricos , Fraturas por Osteoporose/prevenção & controle , Assistência Farmacêutica/estatística & dados numéricos , Idoso , Prescrições de Medicamentos/estatística & dados numéricos , Feminino , Seguimentos , Humanos , Osteoporose/complicações , Fraturas por Osteoporose/etiologia , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Estados Unidos
15.
Microb Pathog ; 131: 227-233, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30943433

RESUMO

Baicalein, an isolate of secutellaria baicalensis is known for its anti-inflammatory activity. In the present study, 12-triazole derivatives of baicalein were synthesized and evaluated against RSV infected BEAS-2B cells in vitro and in mice model in vivo. The preventive effect of most active compound 5f against RSV infection was studied in detail. The compound 5f treatment increased IFN-ß1 expression in BEAS-2B cells infected with RSV. In BEAS-2B cells treatment with compound 5f inhibited RSV-induced secretion of interleukin-6 and -8 cytokines. It decreased RSV-induced nitric oxide & malondialdehyde production and inhibited the RSV-mediated activation of NF-κB, COX-2, Stat3 and MAPK. The p38 phosphorylation was enhanced significantly in RSV infected cells by compound 5f pre-treatment. RT-qPCR showed that compound 5f treatment of the RSV-infected mice significantly (P < 0.05) decreased viral load through reduction in the viral replication. In the mice model of RSV-infection compound 5f treatment decreased interleukin-6, -8 and tumor necrosis factor-α expression. The level of MPO, nitric oxide and malondialdehyde was also decreased significantly by compound 5f in the RSV infected mice BALF. It also reduced the infiltration of neutrophils and lymphocytes in the BALF of RVS-infected mice. In summary, compound 5f inhibits RSV-infection and prevents pulmonary airway inflammation through the activation of IFN signalling pathway.


Assuntos
Flavanonas/farmacologia , Estresse Oxidativo , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Infecções Respiratórias/prevenção & controle , Triazóis/farmacologia , Animais , Citocinas/metabolismo , Feminino , Flavanonas/síntese química , Interferon beta/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Linfócitos , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Neutrófilos/metabolismo , Pneumonia/prevenção & controle , Pneumonia/virologia , Infecções Respiratórias/virologia , Ribavirina/farmacologia , Fator de Transcrição STAT3/metabolismo , Triazóis/síntese química , Fator de Necrose Tumoral alfa/metabolismo , Replicação Viral/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
16.
J Manag Care Spec Pharm ; 25(3): 350-356, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30816819

RESUMO

BACKGROUND: Type 2 diabetes (T2D) is characterized by chronic hyper-glycemia and can lead to life-threatening complications if not treated. A stepwise and patient-centered approach is recommended when managing patients with T2D. Metformin is the preferred first-line agent, while sulfonylureas (SU) are often chosen as second-line agents. If a patient's hemoglobin A1c (A1c) goal is not achieved despite 3 months of treatment with dual therapy, then triple therapy is recommended. However, due to the lack of head-to-head trials for different triple antidiabetic regimens, the recommendations are unclear for selection of an optimal third-line agent. OBJECTIVE: To evaluate the comparative effectiveness of a glucagon-like peptide-1 receptor agonist (GLP-1 RA) compared with a thiazolidinedione (TZD) or insulin as a third-line add-on therapy in patients who have not achieved A1c goals while receiving metformin and SU dual therapy in the real-world setting within an integrated health care system. METHODS: This is a retrospective cohort study of adult patients with T2D who were not at goal A1c while on dual therapy with metformin and an SU and initiated triple antidiabetic therapy. The primary outcome was the proportion of patients who achieved goal A1c within 3-7 months after starting triple therapy with a GLP-1 RA compared with a TZD or insulin. Goal A1c was defined as an A1c of < 7% for patients aged less than 65 years and A1c of < 8% for patients aged 65 years or older. Secondary outcomes included mean change in A1c, mean change in weight, and the proportion of patients with an emergent health care encounter due to a hypoglycemic event. Propensity score matching was used to select comparison groups from the insulin and TZD groups with similar baseline characteristics to the GLP-1 RA group in a 4:1 ratio. RESULTS: 274 patients initiated a GLP-1 RA in addition to dual therapy with metformin and an SU. A propensity matched group of 1,096 patients who initiated insulin and 1,096 patients who initiated a TZD were selected as the control groups. Addition of a GLP-1 RA resulted in a significantly lower proportion of patients achieving goal A1c (23.0%) compared with the addition of a TZD (30.8%, P = 0.011). There was no significant difference with the addition of a GLP-1 RA when compared with insulin (24.1%, P = 0.704). CONCLUSIONS: This study reflects data from real-world practice in a large integrated health care system. Significantly less patients achieved goal A1c with the addition of a GLP-1 RA as a third-line add-on option to dual therapy with metformin and an SU compared with the addition of a TZD. Providers and patients should carefully weigh the risks and benefits of different antidiabetic agents when choosing triple therapy regimens. DISCLOSURES: No outside funding supported this study. The authors have nothing to disclose. Part of this study was presented as a nonreviewed resident poster at the Academy of Managed Care & Specialty Pharmacy Annual Meeting 2017 in Denver, CO, on March 27-29, 2017.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hemoglobina A Glicada/metabolismo , Hipoglicemiantes/administração & dosagem , Metformina/administração & dosagem , Adulto , Idoso , Estudos de Coortes , Prestação Integrada de Cuidados de Saúde , Quimioterapia Combinada , Feminino , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Hipoglicemiantes/farmacologia , Insulina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Compostos de Sulfonilureia/administração & dosagem , Tiazolidinedionas/administração & dosagem , Resultado do Tratamento
17.
J Colloid Interface Sci ; 539: 646-653, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30616195

RESUMO

Transition-metal cobalt-based chalcogenides have wide application in the fields of energy conversion and storage. Suitable morphologies can effectively improve the surface area and performance of the materials. Herein, we reported a simple and controlled strategy to fabricate the CoSe2 with various shapes and applied these in water splitting. We successfully synthesized the spheres, wires and rods of CoSe2 via facile hydrothermal process through regulating the addition of NH4F to alter the morphologies of samples. Among these samples, the as-prepared CoSe2 spheres have urchin-like morphology with highly hollow structure, leading to large specific surface area and a great number of channels for promoting mass transfer efficiency. Therefore, the CoSe2 spheres as electrocatalyst exhibits excellent oxygen evolution reaction and hydrogen evolution reaction performance in alkaline and acidic conditions, respectively. Electrochemical measurement illustrated that the CoSe2 spheres as electrocatalyst shown small overpotential and superior stability, which could be a promising candidate of effective electrocatalyst.

18.
J Cell Biol ; 218(2): 700-721, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30626719

RESUMO

Cocaine is known to facilitate the transmigration of inflammatory leukocytes into the brain, an important mechanism underlying neuroinflammation. Pericytes are well-recognized as important constituents of the blood-brain barrier (BBB), playing a key role in maintaining barrier integrity. In the present study, we demonstrate for the first time that exposure of human brain vascular pericytes to cocaine results in enhanced secretion of CXCL10, leading, in turn, to increased monocyte transmigration across the BBB both in vitro and in vivo. This process involved translocation of σ-1 receptor (σ-1R) and interaction of σ-1R with c-Src kinase, leading to activation of the Src-PDGFR-ß-NF-κB pathway. These findings imply a novel role for pericytes as a source of CXCL10 in the pericyte-monocyte cross talk in cocaine-mediated neuroinflammation, underpinning their role as active components of the innate immune responses.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/toxicidade , Quimiocina CXCL10/metabolismo , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Cocaína/toxicidade , Monócitos/efeitos dos fármacos , Comunicação Parácrina/efeitos dos fármacos , Pericitos/efeitos dos fármacos , Migração Transendotelial e Transepitelial/efeitos dos fármacos , Animais , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/metabolismo , Receptor 1 de Quimiocina CX3C/genética , Receptor 1 de Quimiocina CX3C/metabolismo , Estudos de Casos e Controles , Transtornos Relacionados ao Uso de Cocaína/imunologia , Técnicas de Cocultura , Células HEK293 , Humanos , Imunidade Inata/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Monócitos/imunologia , Monócitos/metabolismo , NF-kappa B/metabolismo , Pericitos/imunologia , Pericitos/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores sigma/metabolismo , Transdução de Sinais
19.
Mol Neurobiol ; 56(5): 3576-3590, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30151726

RESUMO

Cocaine, a known psychostimulant, results in oxidative stress and inflammation. Recent studies from our group have shown that cocaine induces inflammation in glial cells. Our current study was aimed at investigating whether cocaine exposure could also induce inflammation in non-glial cells such as the pericytes with a focus on the endoplasmic reticulum (ER) stress/autophagy axis. Our in vitro findings demonstrated that exposure of pericytes to cocaine resulted in upregulation of the pro-inflammatory cytokines (TNF-α, IL-1ß, and IL-6) in both the intracellular as well as extracellular compartments, thus underpinning pericytes as yet another source of neuroinflammation. Cocaine exposure of pericytes resulted in increased formation of autophagosomes as demonstrated by a time-dependent increase of autophagy markers, with a concomitant defect in the fusion of the autophagosome with the lysosomes. Pharmacological blocking of the sigma 1 receptor underscored its role in cocaine-mediated activation of pericytes. Furthermore, it was also demonstrated that cocaine-mediated dysregulation of autophagy involved upstream activation of the ER stress pathways, with a subsequent downstream production of pro-inflammatory cytokines in pericytes. These findings were also validated in an in vivo model wherein pericytes in the isolated brain microvessels of cocaine injected mice (7 days) exhibited increased expression of both the autophagy marker-LC3 as well as the pro-inflammatory cytokine, IL-6. This is the first report describing the role of pericytes in cocaine-mediated neuroinflammation. Interventions aimed at blocking either the sigma-1 receptor or the upstream ER stress mediators could likely be envisioned as promising therapeutic targets for abrogating cocaine-mediated inflammation in pericytes.


Assuntos
Autofagia/efeitos dos fármacos , Cocaína/toxicidade , Inflamação/patologia , Pericitos/patologia , Animais , Encéfalo/irrigação sanguínea , Células Cultivadas , Citocinas/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Microvasos/efeitos dos fármacos , Microvasos/patologia , Modelos Biológicos , Pericitos/efeitos dos fármacos , Pericitos/metabolismo , Receptores sigma/metabolismo
20.
Mol Ther Nucleic Acids ; 13: 450-463, 2018 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-30388619

RESUMO

Impairment of microglial functions, such as phagocytosis and/or dysregulation of immune responses, has been implicated as an underlying factor involved in the pathogenesis of various neurodegenerative disorders. Our previous studies have demonstrated that long intergenic noncoding RNA (lincRNA)-Cox2 expression is influenced by nuclear factor κB (NF-κB) signaling and serves as a coactivator of transcriptional factors to regulate the expression of a vast array of immune-related genes in microglia. Extracellular vesicles (EVs) have been recognized as primary facilitators of cell-to-cell communication and cellular regulation. Herein, we show that EVs derived from astrocytes exposed to morphine can be taken up by microglial endosomes, leading, in turn, to activation of Toll-like receptor 7 (TLR7) with a subsequent upregulation of lincRNA-Cox2 expression, ultimately resulting in impaired microglial phagocytosis. This was further validated in vivo, wherein inhibition of microglial phagocytic activity was also observed in brain slices isolated from morphine-administrated mice compared with control mice. Additionally, we also showed that intranasal delivery of EVs containing lincRNA-Cox2 siRNA (small interfering RNA) was able to restore microglial phagocytic activity in mice administered morphine. These findings have ramifications for the development of EV-loaded RNA-based therapeutics for the treatment of various disorders involving functional impairment of microglia.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA