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1.
Infect Dis (Lond) ; : 1-4, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33645461

RESUMEN

BACKGROUND: Several cases of invasive fungal diseases in patients with COVID-19 have been reported, mostly due to Aspergillus spp., with anecdotic reports of Pneumocystis jirovecii pneumonia (PJP) as co-infections in immunocompromised patients. We describe the first case of PJP in an immunocompetent patient who recovered from COVID-19 pneumonia. CASE DESCRIPTION: Our patient was hospitalized for 18 d for respiratory failure due to Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) pneumonia and successfully treated with continuous positive airway pressure (CPAP) respiratory support, enoxaparin, ceftaroline and intravenous 6 mg of dexamethasone for 10 d, then with oral prednisone tapering. Despite his improved radiological and clinical conditions at discharge, he was admitted again after 18 d for worsening of respiratory conditions. Upon the second admission, a high-resolution CT-scan of the chest showed the development of new ground-glass opacities and P. jirovecii was detected on bronchoalveolar lavage fluid. A therapy with trimethoprim-sulphamethoxazole 20 mg/kg and methylprednisolone 40 mg i.v. bis in die (BID) was started, with improvement of clinical, biochemical and radiological conditions. CONCLUSIONS: COVID-19 patients may have multiple risk factors for development of PJP, in particular lymphopaenia and use of steroids. PJP must be ruled out with direct microbiological methods in patients presenting with radiologic and clinical features of possible or probable PJP, even in immunocompetent hosts.

2.
Invest New Drugs ; 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33646489

RESUMEN

Background Sorafenib (Sor) remains a first-line option for hepatocellular carcinoma (HCC) or refractory renal cell carcinomas (RCC). PLC/PRF/5 HCC model showed upregulation of hypoxia with enhanced efficacy when Sor is combined with hypoxia-activated prodrug evofosfamide (Evo). Methods This phase IB 3 + 3 design investigated 3 Evo dose levels (240, 340, 480 mg/m2 on days 8, 15, 22), combined with Sor 200 mg orally twice daily (po bid) on days 1-28 of a 28-day cycle. Primary objectives included determining maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of Sor + Evo. Results Eighteen patients were enrolled (median age 62.5 years; 17 male /1 female; 12 HCC/6 RCC) across three dose levels (DL0: Sor 200 mg bid/Evo 240 mg/m2 [n = 6], DL1:Sor 200 mg bid/Evo 480 mg/m2 [n = 5], DL1a: Sor 200 mg bid/Evo 340 mg/m2 [n = 7]). Two dose-limiting toxicities (DLTs) were reported with Evo 480 mg/m2 (grade 3 mucositis, grade 4 hepatic failure). Grade 3 rash DLT was observed in one patient at Evo 240 mg/m2. No DLTs were observed at Evo 340 mg/m2. MTD and RP2D were established as Sor 200 mg/Evo 340 mg/m2 and Sor 200/Evo 240 mg/m2, respectively. The most common treatment-related adverse events included fatigue, hand-foot syndrome, hypertension, and nausea/vomiting. Two partial responses were observed, one each at DL0 and DL1a.; disease control rate was 55%. Conclusions RP2D was established as sorafenib 200 mg bid + Evo 240 mg/m2. While preliminary anti-tumor activity was observed, future development must account for advances in immunotherapy in HCC/RCC.

3.
Allergol. immunopatol ; 49(1): 50-57, ene.-feb. 2021. tab
Artículo en Inglés | IBECS-Express | IBECS | ID: ibc-ET5-2685

RESUMEN

INTRODUCTION AND OBJECTIVES: To determine the quality of life (QoL) in Caucasian children with atopic dermatitis (AD) and their families and possible factors that might impact their QoL. MATERIALS AND METHODS: In this cross-sectional study, 83 children aged 2-7 with AD and their families were enrolled as the study group, and 83 age-matched healthy children were included as controls. All patients in the AD and control groups were sorted into two age-based groups: (1) 2-4 and (2) 5-7 years of age. The parents of all children completed the Turkish version of the Pediatric Quality of Life Inventory (PedsQL). The Family Impact Scale for Dermatological Diseases (FIS-DD) was administered to the study group. Disease severity was evaluated with the Patient-Oriented Scoring Atopic Dermatitis (PO-SCORAD) scale. RESULTS: In both age groups, a negative correlation between the PedsQL and the FIS-DD scores (p < 0.001) was found. A positive correlation was found between the PO-SCORAD and FIS- DD scores among the second age group (p = 0.011). In the first age group, AD patients with comor­bid allergic diseases had higher FIS-DD scores than those without any other allergic problems (p = 0.007). CONCLUSIONS: We suggest that considering family QoL may positively contribute to the treat­ment of pre-school age AD children


No disponible

4.
Preprint | bioRxiv | ID: ppbiorxiv-429108

RESUMEN

In response to the ongoing COVID-19 pandemic, repurposing of drugs for the treatment of SARS-CoV-2 infections is being explored. The FDA-approved HIV protease inhibitor Nelfinavir is one of the drugs that has been reported to inhibit in vitro SARS-CoV2 replication. We here report on the effect of Nelfinavir in the Syrian hamster SARS-CoV-2 infection model. Although treatment of infected hamsters with either 15 mg/kg BID or 50 mg/kg BID Nelfinavir [for four consecutive days, initiated on the day of infection] did not reduce viral RNA loads nor infectious virus titres in the lungs (as compared to the vehicle control at the end of treatment) the drug markedly improved virus-induced lung pathology at doses that were well tolerated. Yet, a massive interstitial infiltration of neutrophils was observed in the lungs of treated (infected and uninfected) animals. The protective effect of Nelfinavir on SARS-CoV-2-induced lung pathology that is unrelated to an antiviral effect warrants further exploration in the context of the treatment of COVID-19.

5.
Medicine (Baltimore) ; 100(5): e24461, 2021 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-33592899

RESUMEN

RATIONALE: Adenomyoepithelioma (AME) is a rare biphasic tumor consisting of epithelial and Myoepithelial cell. Most of the AME is benign, and only a few will progress to malignancy, Here, we report a case of low-grade malignant adenomyoepithelioma, and review the related literature, in a bid to investigate its clinical and pathological features and thus, enhance our understanding of this tumor. PATIENT CONCERNS: A 64-year-old woman visited our hospital with a 1-year history of a painless mass in her left breast. Physical examination revealed a palpable painless mass, measuring approximately 4.5 cm, in the left breast. DIAGNOSIS: Histological examination confirmed the diagnosis of malignant adenomyoepithelioma. INTERVENTIONS: The patient underwent local excision of the mass, with frozen section analysis revealing ductal carcinoma in situ. Mastectomy and sentinel lymph node biopsy were then performed. OUTCOMES: We conducted a one-year follow-up, and relapse was not observed. LESSONS: Treatment of AME remains controversial owing to the lack of high volume data and absence of prospective studies. Simple mastectomy is an acceptable treatment of this tumor.

6.
Oncogene ; 2021 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-33603166

RESUMEN

Use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with reduced risk of colorectal cancer (CRC). However, the mechanism by which NSAIDs suppress colorectal tumorigenesis remains unclear. We previously showed that NSAIDs selectively kill emerging tumor cells via death receptor (DR) signaling and a synthetic lethal interaction mediated by the proapoptotic Bcl-2 family protein BID. In this study, we found NSAIDs induce endoplasmic reticulum (ER) stress to activate DR signaling and BID in tumor suppression. Importantly, our results unveiled an ER stress- and BID-dependent immunogenic effect of NSAIDs, which may be critical for tumor suppression. NSAID treatment induced hallmarks of immunogenic cell death (ICD) in CRC cells and colonic epithelial cells upon loss of APC tumor suppressor, and elevated tumor-infiltrating lymphocytes (TILs) in the polyps of APCMin/+ mice. ER stress inhibition or BID deletion abrogated the antitumor and immunogenic effects of NSAIDs. Furthermore, increased ER stress and TILs were detected in human advanced adenomas from NSAID-treated patients. Together, our results suggest that NSAIDs induce ER stress- and BID-mediated ICD to restore immunosurveillance and suppress colorectal tumor formation.

7.
Sci Rep ; 11(1): 4244, 2021 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-33608599

RESUMEN

The application of machine learning (ML) techniques in materials science has attracted significant attention in recent years, due to their impressive ability to efficiently extract data-driven linkages from various input materials representations to their output properties. While the application of traditional ML techniques has become quite ubiquitous, there have been limited applications of more advanced deep learning (DL) techniques, primarily because big materials datasets are relatively rare. Given the demonstrated potential and advantages of DL and the increasing availability of big materials datasets, it is attractive to go for deeper neural networks in a bid to boost model performance, but in reality, it leads to performance degradation due to the vanishing gradient problem. In this paper, we address the question of how to enable deeper learning for cases where big materials data is available. Here, we present a general deep learning framework based on Individual Residual learning (IRNet) composed of very deep neural networks that can work with any vector-based materials representation as input to build accurate property prediction models. We find that the proposed IRNet models can not only successfully alleviate the vanishing gradient problem and enable deeper learning, but also lead to significantly (up to 47%) better model accuracy as compared to plain deep neural networks and traditional ML techniques for a given input materials representation in the presence of big data.

8.
Curr Med Res Opin ; : 1-21, 2021 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-33534617

RESUMEN

OBJECTIVES: To evaluate the efficacy and safety of oral sitafloxacin versus oral moxifloxacin in the treatment of Chinese adults with community-acquired pneumonia (CAP). PATIENTS AND METHODS: This is a multicenter, randomized, open-label, positive-controlled clinical trial (chinadrugtrials.org.cn identifier: CTR20130046). CAP patients received sitafloxacin tablets 100 mg once daily (qd) or 100 mg twice daily (bid) to compare with moxifloxacin tablets 400 mg qd, for 7-10 days. The primary outcome was non-inferiority of sitafloxacin to moxifloxacin in clinical cure rate at test of cure (TOC) visit in per-protocol set (PPS). RESULTS: A total of 343 patients were randomized (sitafloxacin 100 mg qd, n = 117; sitafloxacin 100 mg bid, n = 116; moxifloxacin, n = 110), 291 patients were included in the PPS (sitafloxacin 100 mg qd, n = 96; sitafloxacin 100 mg bid, n = 94; moxifloxacin, n = 101). The clinical cure rate was 94.8% in the sitafloxacin 100 mg qd group, 96.8% in the sitafloxacin 100 mg bid group and 95.0% in the moxifloxacin group. At the TOC visit, the microbiological success rate was 97.0% (32/33) in the sitafloxacin 100 mg qd group, 97.1% (34/35) in the sitafloxacin 100 mg bid group and 94.9% (37/39) in the moxifloxacin group in the microbiological evaluable set (MES). The incidence of study-drug-related adverse events (AEs) was 23.3% (27/116) in the sitafloxacin 100 mg qd group, 29.8% (34/114) in the sitafloxacin 100 mg bid group and 28.2% (31/110) in the moxifloxacin group (p > .05). The common AEs related to study drug were dizziness, nausea, diarrhea, increased platelet count and alanine transaminase (ALT) elevation. All the AEs resolved completely after discontinuation of study drug. CONCLUSION: Sitafloxacin 100 mg qd or 100 mg bid for 7-10 days is not inferior to moxifloxacin 400 mg qd for 7-10 days in clinical efficacy for adult CAP patients. Sitafloxacin provides a safety profile comparable to moxifloxacin.

9.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1866(5): 158902, 2021 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-33578050

RESUMEN

Endothelial cells, which help to maintain vascular homeostasis, can be functionally modulated by polyunsaturated fatty acids. Previously, we reported that docosahexaenoic acid (DHA) reduced the viability of confluent EA.hy926 endothelial cells with caspase-3 activation. This study therefore examined the molecular mechanism by which DHA affects the viability of confluent cells, with a focus on the interaction between caspase-9, caspase-8, caspase-3, p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) by Western blotting. Our results revealed that DHA induces apoptosis of confluent cells through both intrinsic and extrinsic pathways, which requires activation of p38 MAPK, and involves activation of JNK, caspase-9, caspase-8 and caspase-3 with the exception that cleavage of caspase-8 was incomplete and truncated BID was not detected at the maximum time (8 h) examined. Apoptosis induced by high levels of DHA in healthy endothelial cells is achieved through positive feedback loops linking these MAPKs to multiple caspases, as well as negative feedback from p38 MAPK to JNK. However, only p38 MAPK is crucial in apoptosis induction in comparison with JNK or any other caspase examined. This study has expanded the knowledge on the molecular mechanism of DHA-induced apoptosis in human endothelial cells and has also implied the differential roles of MAP kinases and caspases in apoptosis.

10.
Stroke ; 52(3): 1069-1073, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33588594

RESUMEN

BACKGROUND AND PURPOSE: We assessed the outcomes of dabigatran versus aspirin in a prespecified subgroup analysis of East Asian patients with embolic stroke of undetermined source in the RE-SPECT ESUS trial (Randomized, Double-Blind, Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate Versus Acetylsalicylic Acid in Patients With Embolic Stroke of Undetermined Source). METHODS: Patients with a recent embolic stroke of undetermined source were randomized to dabigatran (150 or 110 mg BID) or aspirin (100 mg QD). The primary efficacy outcome was recurrent stroke; the primary safety outcome was major bleeding. The East Asia cohort was compared with patients from all other countries (non-East Asia cohort). RESULTS: Overall, 988 of 5390 patients (18%) were randomized in East Asia. During a median follow-up of 18.8 months, there was no statistically significant difference in recurrent stroke (hazard ratio, 0.65 [95% CI, 0.41-1.03]) or major bleeding (hazard ratio, 1.04 [95% CI, 0.57-1.91]) in East Asian patients receiving dabigatran versus aspirin. Death from any cause occurred more often in the dabigatran versus the aspirin group (hazard ratio, 3.98 [95% CI, 1.32-12.01]). CONCLUSIONS: The treatment effect of dabigatran versus aspirin was consistent between cohorts, with no apparent superiority for dabigatran over aspirin in preventing recurrent stroke in patients with embolic stroke of undetermined source. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02239120.

11.
Int Braz J Urol ; 47(3): 596-609, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33621009

RESUMEN

BACKGROUND: Many medical therapies have been tested to deal with urinary stent-related symptoms (USRS). Several preventive and pharmaceutical methods have been already used for better compatibility of stents. However, the existing evidence for pharmacological treatment is still controversial. This study aims to evaluate the effects of pregabalin, solifenacin, and combination therapy on ureteral double-J stent-related symptoms following ureteroscopy and transureteral lithotripsy (TUL). MATERIALS AND METHODS: In a randomized controlled clinical trial, from November 2017 to March 2019, 256 patients who underwent ureteroscopy were enrolled. Patients were randomly divided into four groups including: group A received pregabalin 75mg BID (twice daily), group B received solifenacin 5mg orally once daily, group C received combination of pregabalin and solifenacin and the group D (control) given no drugs. RESULTS: One hundred and fifty-one (58.9%) males and 101 (41.1%) females were enrolled in this study with a mean age of 43.47±7 (p=0.32, p=0.67). USSQ domains score such as urinary symptoms, pain, general condition, work performance, sexual matters and additional problems were significantly differenced during second and fourth week of follow-up among study groups (p <0.0001). In Tukey's multiple comparison test, urinary symptoms (p=0.735), pain (p=0.954) and sexual matters (p=0.080) in second week and work performance in forth week in group B was not significantly better than group D. Only group C in all indexes of USSQ showed significantly beneficial effects over group D (p <0.0001). CONCLUSION: Combination therapy of pregabalin and solifenacin has a significant effect on stent-related symptoms and is preferred over monotherapy of the respected medications.

12.
Trials ; 22(1): 159, 2021 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-33622382

RESUMEN

BACKGROUND: Atypical antipsychotic medications, which are effective for the treatment of schizophrenia and bipolar disorder, are associated with features of metabolic syndrome, such as weight gain, hyperglycemia, dyslipidemia, and insulin resistance. Although there are a few studies on the effects of dietary fiber or probiotics on weight loss in obese people, no published trials have reported the efficacy of dietary fiber and probiotics on reducing atypical antipsychotic-induced weight gain. METHODS: For this 12-week randomized, double-blind, placebo-controlled study, 100 patients with a weight gain of more than 10% after taking atypical antipsychotic medications were recruited. Participants were randomized to four groups as follows: probiotics (840 mg twice daily (bid)) plus dietary fiber (30 g bid), probiotics (840 mg bid) plus placebo, placebo plus dietary fiber (30 g bid), or placebo group. The primary outcome was the change in body weight. Secondary outcomes included changes in metabolic syndrome parameters, appetite score, biomarkers associated with a change in weight, and gut microbiota composition and function. DISCUSSION: To date, this is the first randomized, placebo-controlled, double-blinded trial investigating the efficacy of dietary fiber and probiotics alone and in combination to reduce metabolic side effects induced by atypical antipsychotic medications. If effective, it is possible to conclude that dietary fiber and probiotics can reduce atypical antipsychotic-induced metabolic side effects. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT03379597 . Registered on 19 November 2017.

13.
Clin Cancer Res ; 2021 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-33622704

RESUMEN

PURPOSE: BAY1436032, an inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), was active against multiple IDH1-R132X solid tumors in preclinical models. This first-in-human study was designed to determine the safety and pharmacokinetics (PK) of BAY1436032, and to evaluate its potential pharmacodynamic and antitumor effects. EXPERIMENTAL DESIGN: The study comprised dose escalation and dose expansion cohorts. BAY1436032 tablets were orally administered twice daily (BID) on a continuous basis in subjects with mIDH1 solid tumors. RESULTS: In dose escalation, 29 subjects with various tumor types were administered BAY1436032 across 5 doses (150-1500 mg BID). BAY1432032 exhibited a relatively short half-life. Most evaluable subjects experienced target inhibition as indicated by a median maximal reduction of plasma R-2HG levels of 76%. BAY1436032 was well-tolerated and a maximum-tolerated dose was not identified. A dose of 1500 mg BID was selected for dose expansion, where 52 subjects were treated in cohorts representing 4 different tumor types (lower-grade glioma [LGG], glioblastoma, intrahepatic cholangiocarcinoma and a basket cohort of other tumor types). The best clinical outcomes were in subjects with LGG (n=35), with an objective response rate of 11% (1 CR, 3 PR) and stable disease in 43%. As of August 2020, 4 of these subjects were in treatment for >2 years and still ongoing. Objective responses were observed only in LGG. CONCLUSIONS: BAY1436032 was well-tolerated and showed evidence of target inhibition and durable objective responses in a small subset of subjects with LGG.

14.
Neurotherapeutics ; 2021 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-33624184

RESUMEN

This phase 2, double-blind, placebo-controlled, hypothesis-generating study evaluated the effects of oral reldesemtiv, a fast skeletal muscle troponin activator, in patients with spinal muscular atrophy (SMA). Patients ≥ 12 years of age with type II, III, or IV SMA were randomized into 2 sequential, ascending reldesemtiv dosing cohorts (cohort 1: 150 mg bid or placebo [2:1]; cohort 2: 450 mg bid or placebo [2:1]). The primary objective was to determine potential pharmacodynamic effects of reldesemtiv on 8 outcome measures in SMA, including 6-minute walk distance (6MWD) and maximum expiratory pressure (MEP). Changes from baseline to weeks 4 and 8 were determined. Pharmacokinetics and safety were also evaluated. Patients were randomized to reldesemtiv 150 mg, 450 mg, or placebo (24, 20, and 26, respectively). The change from baseline in 6MWD was greater for reldesemtiv 450 mg than for placebo at weeks 4 and 8 (least squares [LS] mean difference, 35.6 m [p = 0.0037] and 24.9 m [p = 0.058], respectively). Changes from baseline in MEP at week 8 on reldesemtiv 150 and 450 mg were significantly greater than those on placebo (LS mean differences, 11.7 [p = 0.038] and 13.2 cm H2O [p = 0.03], respectively). For 6MWD and MEP, significant changes from placebo were seen in the highest reldesemtiv peak plasma concentration quartile (Cmax > 3.29 µg/mL; LS mean differences, 43.3 m [p = 0.010] and 28.8 cm H2O [p = 0.0002], respectively). Both dose levels of reldesemtiv were well tolerated. Results suggest reldesemtiv may offer clinical benefit and support evaluation in larger SMA patient populations.

15.
Life Sci ; 271: 119151, 2021 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-33539912

RESUMEN

AIMS: Limited cutaneous systemic sclerosis-associated pulmonary arterial hypertension (lcSSc-PAH) is a complex multi-system disease with high morbidity and mortality. The purpose of this study is to identify the hub genes and immune characteristics of limited cutaneous systemic sclerosis (lcSSc) and lcSSc-PAH through bioinformatics. MAIN METHODS: LcSSc-PAH raw data were obtained from the GEO database (GSE19617). Weighted gene Co-expression Network analysis (WGCNA) was used to evaluate key modules. Then, we performed Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis with R software and verified the diagnostic value of the hub genes. Finally, Immune Cell Abundance Identifier (ImmuCellAI) was used to analyze the immune characteristics of the normal subjects, lcSSc and lcSSc-PAH patients, the results were displayed graphically. KEY FINDINGS: Enrichment of two important modules by GO and KEGG identified key biological processes and pathways related to pathogen infection and immune function. Three hub genes (BID, IFNGR1, ZAP70) related to immune function were identified. The analysis of immune characteristics showed that the correlation and abundance of immune cells such as inducible regulatory T (iTreg) cells, B cells, macrophages, natural killer (NK) cells, CD8T cells, mucosal-associated invariant T(MAIT) cells and dendritic cells(DCs) were significantly different in the normal subjects, lcSSc and lcSSc-PAH patients. SIGNIFICANCE: Pathogen infection, changes in the number and function of immune cells, and interactions among immune cells may preliminarily reveal the pathological mechanism of lcSSc-PAH. The hub genes, pathways and immune characteristics identified in this research remains to be further studied.

16.
Artículo en Inglés | MEDLINE | ID: mdl-33616643

RESUMEN

CONTEXT: Post-bariatric hypoglycemia (PBH), characterized by enteroinsular axis overstimulation and hyperinsulinemic hypoglycemia, is a complication of bariatric surgery for which there is no approved therapy. OBJECTIVE: To evaluate efficacy and safety of avexitide [exendin(9-39)], a GLP-1 antagonist, for treatment of PBH. DESIGN: Phase II, randomized, placebo-controlled crossover study (PREVENT). SETTING: Multicenter. PARTICIPANTS: Eighteen female patients with PBH. INTERVENTION: Placebo for 14 days followed by avexitide 30 mg BID and 60 mg QD, each for 14 days in random order. MAIN OUTCOME MEASURES: Glucose nadir and insulin peak during mixed-meal tolerance testing (MMTT) and hypoglycemic events captured by self-monitoring of blood glucose (SMBG), electronic diary, and blinded continuous glucose monitor (CGM). RESULTS: Compared to placebo, avexitide 30 mg BID and 60 mg QD raised the glucose nadir by 21% (p=0.001) and 26% (p=0.0002) and lowered the insulin peak by 23% (p=0.029) and 21% (p=0.042), corresponding to 50% and 75% fewer participants requiring rescue during MMTT, respectively. Significant reductions in rates of Levels 1-3 hypoglycemia were observed, defined, respectively, as SMBG<70 mg/dL, SMBG<54 mg/dL, and a severe event characterized by altered mental and/or physical function requiring assistance. CGM demonstrated reductions in hypoglycemia without induction of clinically-relevant hyperglycemia. Avexitide was well-tolerated, with no increase in adverse events. CONCLUSIONS: Avexitide administered for 28 days was well-tolerated and resulted in robust and consistent improvements across multiple clinical and metabolic parameters, reinforcing the targeted therapeutic approach and demonstrating durability of effect. Avexitide may represent a first promising treatment for patients with severe PBH.

17.
Artículo en Inglés | MEDLINE | ID: mdl-33527141

RESUMEN

BACKGROUND: An open-label phase 1 study was conducted to evaluate the effect of voclosporin on blood levels of mycophenolic acid (MPA, active moiety) and mycophenolic acid glucuronide (MPAG, pharmacologically inactive metabolite) following dosing with mycophenolate mofetil (MMF) in subjects with systemic lupus erythematosus (SLE) and to assess the safety and tolerability of the combination. METHODS: MMF was orally administered at a dose of 1 g BID for at least 28 days prior to the study and continued at the same dose throughout the study. Voclosporin was orally administered at a dose of 23.7 mg BID for seven consecutive days (Day 1 to Day 7), starting in the evening of Day 1 and ending with the morning dose on Day 7. Dense PK blood samplings were collected pre-dose in the morning and from 0.25 to 12 hours post-morning doses. Analyses were derived by non-compartmental methods. RESULTS: In 24 patients, MPA exposure (Cmax and AUC0-12) was similar in the presence and absence of voclosporin, with treatment ratios of 0.94 and 1.09, respectively (Cmax: 16.5 µg/mL [Day 1] vs.15.8 µg/mL [Day 7], AUC0-12: 39.1 µg.h/mL [Day 1] vs. 40.8 µg.h/mL [Day 7]. MPAG exposure showed a small increase in the presence of voclosporin (12% for Cmax and 27% for AUC0-12). Combination therapy was well tolerated. CONCLUSIONS: There is no clinically meaningful interaction between voclosporin and MMF. As changes in exposure to MPA may affect efficacy and safety, these data confirm that voclosporin and MMF can be given concomitantly without the need for dose adjustment.

18.
J Ethnopharmacol ; : 113888, 2021 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-33529638

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: The coronavirus disease 2019 (COVID-19) has formed a global pandemic since late 2019. Benefit from the application experience of Chinese Medicine (CM) for influenza and SARS, CM has been used to save patients at the early stage of COVID-19 outbreak in China. AIM OF THE STUDY: In order to evaluate the efficacy and safety of CM, and comparing with that of Western Medicine (WM) for COVID-19, we conducted a retrospective case series study based on the patients in Wuhan Jinyintan Hospital, Wuhan, China. METHODS: The inclusion and exclusion criteria of data extraction was set for this retrospective study. All patients who were admitted by the Wuhan Jinyintan Hospital between January 17 and February 25, 2020 were considered. In addition, patients enrolled met the severe defined by the guidelines released by the National Health Commission of the People's Republic of China. In these cases included in the study, CM or WM treatment was selected according to the wishes of the patients at the beginning of hospitalization. The patients in CM group was treated with Huashi Baidu granule (137 g po, bid) combined with the injections of Xiyanping (100 mg iv, bid), Xuebijing (100 ml iv, bid,) and Shenmai (60 ml iv, qd) according to the syndrome of epidemic toxin blocking the lung in the theory of Traditional Chinese Medicine. The WM group received antiviral therapy (including abidor capsule 0.2 g po, tid; Lopinavir-Ritonavir tablets, 500 mg po, bid), antibiotics (such as cefoperazone, 2 g iv, bid; moxifloxacin hydrochloride tablets, 0.4 g po, qd) or corticosteroid therapy (such as methylprednisolone succinate sodium, 40mg, iv, 40 mg, qd; prednisone, 30 mg po, qd). In addition, patients in both groups received routine supportive treatment, including oxygen inhalation, symptomatic therapy, and/or human intravenous immunoglobulin, and/or serum albumin, and therapy for underlying diseases. The clinical outcomes were evaluated based on changes before and after the treatment related with clinical manifestations, computer tomography (CT) scan images, and laboratory examinations. RESULTS: 55 severe COVID-19 patients, with 23 in CM group and 32 in WM group, were included for analyzed. There was no case of death, transferred to ICU, or received invasive mechanical ventilation in two groups during hospitalization. The median time of SARS-CoV-2 RNA clearance in CM and WM group were 12 days and 15.5 days (P=0.018). Further, the chest CT imaging showed more widely lung lesion opacity absorbed in the CM group (P<0.05). The C-reactive protein level, erythrocyte sedimentation rate, serum ferritin, and myoglobin decreased significantly in the CM group (P<0.05). There was no significant difference in adverse events in terms of liver function and renal function between the two groups. CONCLUSION: Based on this retrospective analysis from Wuhan Jinyintan Hospital, CM has better effects in SARS-CoV-2 RNA clearance, lung lesion opacity absorbed and reduced inflammation in severe COVID-19 patients, is effective and safe therapy for treating severe COVID-19 and reducing mortality.

19.
Wien Klin Wochenschr ; 2021 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-33534047

RESUMEN

PURPOSE: To determine whether a 6-day course of methylprednisolone (MP) improves outcome in patients with severe SARS-CoV­2 (Corona Virus Disease 2019 [COVID-19]). METHODS: The study was a multicentric open-label trial of COVID-19 patients who were aged ≥ 18 years, receiving oxygen without mechanical ventilation, and with evidence of systemic inflammatory response who were assigned to standard of care (SOC) or SOC plus intravenous MP (40 mg bid for 3 days followed by 20 mg bid for 3 days). The primary outcome was a composite of death, admission to the intensive care unit, or requirement for noninvasive ventilation. Both intention-to-treat (ITT) and per protocol (PP) analyses were performed. RESULTS: A total of 91 patients were screened, and 64 were randomized (mean age70 ± 12 years). In the ITT analysis, 14 of 29 patients (48%) in the SOC group and 14 of 35 (40%) in the MP group suffered the composite endpoint (40% versus 20% in patients under 72 years and 67% versus 48% in those over 72 years; p = 0.25). In the PP analysis, patients on MP had a significantly lower risk of experiencing the composite endpoint (age-adjusted risk ratio 0.42; 95% confidence interval, CI 0.20-0.89; p = 0.043). CONCLUSION: The planned sample size was not achieved, and our results should therefore be interpreted with caution. The use of MP had no significant effect on the primary endpoint in ITT analysis; however, the PP analysis showed a beneficial effect due to MP, which consistent with other published trials support the use of glucocorticoids in severe cases of COVID-19.

20.
Neuro Oncol ; 2021 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-33631016

RESUMEN

BACKGROUND: Pediatric low-grade gliomas (pLGGs) are the most common childhood brain tumor. Progression-free survival (PFS) is much lower than overall survival, emphasizing the need for alternative treatments. Sporadic (without neurofibromatosis type-1) optic pathway and hypothalamic glioma (OPHGs) are often multiply recurrent and cause significant visual deficits. Recently, there has been a prioritization of functional outcomes. METHODS: We present results from children with recurrent/progressive OPHGs treated on a PBTC phase 2 trial evaluating efficacy of selumetinib, (AZD6244, ARRY-142886) a MEK-1/2 inhibitor. Stratum 4 of PBTC-029 included patients with sporadic recurrent/progressive OPHGs treated with selumetinib at the recommended phase 2 dose (25mg/m 2 /dose BID) for a maximum of 26 courses. RESULTS: Twenty-five eligible and evaluable patients were enrolled with a median of 4 (1-11) previous therapies. Six of 25 (24%) had partial response, 14/25 (56%) had stable disease and 5 (20%) had progressive disease while on treatment. The median treatment courses were 26 (2-26); 14/25 patients completed all 26 courses. Two-year PFS was 78 ± 8.5%. Nineteen of 25 patients were evaluable for visual acuity which improved in 4/19 patients (21%), was stable in 13/19 (68%) and worsened in 2/19 (11%). Five of 19 patients (26%) had improved visual fields and 14/19 (74%) were stable. The most common toxicities were grade 1/2 CPK elevation, anemia, diarrhea, headache, nausea/emesis, fatigue, AST and ALT increase, hypoalbuminemia and rash. CONCLUSIONS: Selumetinib was tolerable and led to responses and prolonged disease stability in children with recurrent/progressive OPHGs based upon radiographic response, PFS and visual outcomes.

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