Silencing of the long non-coding RNA LINC00265 triggers autophagy and apoptosis in lung cancer by reducing protein stability of SIN3A oncogene.

Background: Long non-coding RNAs are important regulators in cancer biology and function either as tumor suppressors or as oncogenes. Their dysregulation has been closely associated with tumorigenesis. LINC00265 is upregulated in lung adenocarcinoma and is a prognostic biomarker of this cancer. However, the mechanism underlying its function in cancer progression remains poorly understood. Methods: Here, the regulatory role of LINC00265 in lung adenocarcinoma was examined using lung cancer cell lines, clinical samples, and xenografts. Results: We found that high levels of LINC00265 expression were associated with shorter overall survival rate of patients, whereas knockdown of LINC00265 inhibited proliferation of cancer cell lines and tumor growth in xenografts. Western blot and flow cytometry analyses indicated that silencing of LINC00265 induced autophagy and apoptosis. Moreover, we showed that LINC00265 interacted with and stabilized the transcriptional co-repressor Switch-independent 3a (SIN3A), which is a scaffold protein functioning either as a tumor repressor or as an oncogene in a context-dependent manner. Silencing of SIN3A also reduced proliferation of lung cancer cells, which was correlated with the induction of autophagy. These observations raise the possibility that LINC00265 functions to promote the oncogenic activity of SIN3A in lung adenocarcinoma. Conclusions: Our findings thus identify SIN3A as a LINC00265-associated protein and should help to understand the mechanism underlying LINC00265-mediated oncogenesis.

Association of congenital heart disease and neurodevelopmental disorders: an observational and Mendelian randomization study.

BACKGROUND: This study aims to thoroughly study the connection between congenital heart disease (CHD) and neurodevelopmental disorders (NDDs) through observational and Mendelian randomization (MR) designs. METHODS: This observational study uses data from the National Survey of Children's Health (2020-2021). Multivariable logistic regression and propensity score matching (PSM) were performed to analyze the association. PSM was used to minimize bias for covariates such as age, race, gender, maternal age, birth weight, concussion or brain injury, preterm birth, cerebral palsy, Down syndrome, and other inherited conditions. In MR analyses, inverse variance-weighted measures, weighted median, and MR-Egger were employed to calculate causal effects. RESULTS: A total of 85,314 children aged 0-17 were analyzed in this study. In regression analysis, CHD (p = 0.04), the current heart condition (p = 0.03), and the severity of current heart condition (p < 0.05) had a suggestive association with speech or language disorders. The severity of current heart condition (p = 0.08) has a potential statistically significant association with attention deficit hyperactivity disorder(ADHD). In PSM samples, ADHD(p = 0.003), intellectual disability(p = 0.012), and speech or language disorders(p < 0.001) were all significantly associated with CHD. The severity of current heart condition (p < 0.001) also had a significant association with autism. MR analysis did not find causality between genetically proxied congenital cardiac malformations and the risk of NDDs. CONCLUSIONS: Our study shows that children with CHD have an increased risk of developing NDDs. Heart conditions currently and severity of current heart conditions were also significantly associated with these NDDs. In the future, we need to try more methods to clarify the causal relationship between CHD and NDDs.

Suppression of the long non-coding RNA LINC01279 triggers autophagy and apoptosis in lung cancer by regulating FAK and SIN3A.

Long non-coding RNAs play critical roles in the development of lung cancer by functioning as tumor suppressors or oncogenes. Changes in the expression of LINC01279 have been associated with cell differentiation and human diseases. However, the mechanism underlying LINC01279 activity in tumorigenesis is not clear. Here, we analyzed the function of LINC01279 in lung adenocarcinoma using clinical samples, xenografts, and non-small-cell lung cancer cell lines. We found that LINC01279 is highly expressed in lung adenocarcinoma and may be considered as a predictive factor for this cancer. Knockdown of LINC01279 prevents tumor growth in xenografts and in cancer cell lines by activating autophagy and apoptosis. Molecularly, we revealed that LINC01279 regulates the expression of focal adhesion kinase and extracellular-regulated kinase signaling. In addition, it complexes with and stabilizes the transcriptional co-repressor SIN3A protein. Suppression of focal adhesion kinase and SIN3A also induces apoptosis and prevents tumor progression, suggesting that they may at least in part mediate the oncogenic activity of LINC01279. These results identify LINC01279 as a possible oncogene that plays an important role in the development of lung cancer. Our findings provide insights into the mechanism underlying LINC01279-mediated oncogenesis of lung adenocarcinoma. They may help to discover potential therapeutic targets for cancer diagnosis and prognosis.

Serum amyloid A as a biomarker for immunoglobulin resistance in Kawasaki disease.

BACKGROUND: Intravenous immunoglobulin (IVIG) resistance is of prime importance in Kawasaki disease (KD). In this study, we examined the value and mechanism of serum amyloid A (SAA) level in predicting IVIG resistance in patients with KD. METHODS: SAA levels were measured in 497 consecutive patients with KD before IVIG therapy in the training set. The patients were divided into two groups (IVIG-responsive and IVIG-resistant) according to the American Heart Association (AHA) definition of IVIG resistance. Demographic, echocardiographic, and laboratory data were also retrospectively analyzed and tabulated to predict IVIG resistance. The predictive value of SAA was validated on test sets of prospective data. Cytokine microarrays were analyzed from 4 patients with resistant to IVIG, 4 patients with responsive to IVIG and 4 healthy volunteers. RESULTS: During the training set, 409 patients with KD were enrolled, of whom 43 (10.5%) were resistant to initial IVIG treatment and 47 (11.49%) had coronary artery lesions (CALs). Serum levels of SAA were higher in the IVIG resistant group compared to the IVIG responsive group, (380.00 [204.40-547.25] vs 230.85 [105.40-490.00] mg/L; p = .008). The values of total bilirubin, C-reactive protein, neutrophils, alanine aminotransferase, aspartate aminotransferase, interleukin-6(IL-6), and procalcitonin were significantly higher in the IVIG-resistant group than in the IVIG-responsive group (p < .05); however, the lymphocytes, platelets, serum sodium levels, and duration of fever before IVIG therapy were significantly lower (p < .05). There was no significant difference in SAA levels between patients with KD with and without CALs. Binary logistic regression analysis showed that SAA (p = .008), neutrophils (p < .001), total bilirubin (p = .001), platelet count (p = .004), and serum sodium level (p = .019) were independent factors influencing IVIG resistance. The optimal cutoff value of SAA for IVIG resistance prediction was 252.45 mg/L, with a corresponding clinical sensitivity of 69.8% and specificity of 54.4%. Based on receiver operating characteristic (ROC) curve analyses, the area under the curve (AUC) of combined detection with these five indicators was 0.800, clinical sensitivity was 69.8%, and specificity was 76.2%. In the prospective data, the sensitivity, specificity, and accuracy of SAA for identifying IVIG resistance KD were 77.8%,69.0%, and 70.0%, respectively. Compared with IVIG- responsive group and healthy children, the levels of IL-6 was upregulated significantly in IVIG-resistant group through cytokine microarrays. CONCLUSIONS: SAA may be a potential biomarker for predicting IVIG responsiveness to KD, Combined detection of SAA levels, total bilirubin, neutrophil count, platelet count, and serum sodium levels is superior to that of any other single indicator for predicting IVIG resistance in KD. And elevated SAA may accompany with IL-6 in KD patients, its use in clinical practice may be helpful for treatment management.

Circular RNA-mediated ceRNA network was identified in human lung adenocarcinoma by high-throughput sequencing.

OBJECTIVES: Aberrantly expressed circular RNAs (circRNAs) have been detected in many types of tumors. Hence, they are currently investigated as candidate biomarkers for diagnostic and potential targets for therapy in cancers. The objective of this study was to assess the expression profile of circRNA in lung adenocarcinoma (LUAD). METHODS: This study included 14 pairs of postoperative lung adenocarcinoma specimens, including cancer tissues and matched adjacent tissues. Second-generation sequencing was applied to the specimens to determine the circRNA expression in them among the 5242 distinct circRNAs detected. RESULTS: We identified a total of 18 significantly dysregulated circRNAs in the LUAD tissues: upregulation in four and downregulation in 14. ROC (The receiver operating characteristic curve) further suggested that hsa_circ_0120106, has_circ_0007342, has_circ_0005937, and circRNA_0000826 could potentially be used as biomarkers in the diagnosis of LUAD. Furthermore, study of the circRNA-microRNA (miRNA)-messenger RNA (mRNA) revealed interactions between the 18 dysregulated circRNA and several cancer-related miRNAs. Finally, a further Kyoto Encyclopedia of Genes and Genomes analysis showed that the cell cycle phase transition, p53 signaling pathway, AMP-activated protein kinase (AMPK) relative signaling pathway, and so on were key putative pathways in the process of LUAD. CONCLUSIONS: These findings demonstrated the correlation between abnormality in circRNA expression and LUAD, which lays the foundation of making CircRNAs candidate biomarkers in the diagnosis of LUAD.

Development of Henoch-Schoenlein purpura in a child with idiopathic hypereosinophilia syndrome with multiple thrombotic onset: A case report.

BACKGROUND: The incidence of pulmonary embolism (PE) in children is low, but its mortality is high. Hypereosinophilic syndrome (HES) is a group of diseases caused by an abnormal increase in eosinophilic granulocytes resulting in multiple-organ dysfunction. The urgent event of thromboembolism in the pulmonary region provoked by eosinophils in idiopathic HES (IHES) is relatively unusual. This article reports a case of IHES with multiple PEs and left leg venous thrombosis as the first manifestation. One month later, the patient developed Henoch-Schonlein purpura (HSP), which is very rare. CASE SUMMARY: We report the case of a 12-year-old boy who was admitted to the hospital with dyspnea, left leg pain, and aggravation. He had bilateral PE and left leg venous embolism with mild eosinophilia. Low-molecular-weight heparin and urokinase were given. At the same time, the interventional department was contacted about filter implantation, followed by urokinase thrombolysis. The left leg thrombus was aspirated under ultrasound guidance. He was discharged from the hospital on rivaroxaban. One month later, he developed a rash on both legs and ankle pain consistent with HSP, with severe eosinophilia and motor and sensory disturbances. The patient was diagnosed with IHES with multiple embolisms complicated by HSP after excluding other causes of the eosinophil elevation. After glucocorticoid treatment, the symptoms were relieved, but the patient later developed purpura nephritis. CONCLUSION: We report a rare and life-threatening case of IHES with multiple embolisms associated with HSP. A mild elevation of eosinophils early in the disease leads to difficulties in diagnosis and delayed treatment.

Trial of Anti-BDCA2 Antibody Litifilimab for Systemic Lupus Erythematosus.

BACKGROUND: Antibody-binding of blood dendritic cell antigen 2 (BDCA2), which is expressed exclusively on plasmacytoid dendritic cells, suppresses the production of type I interferon that is involved in the pathogenesis of systemic lupus erythematosus (SLE). The safety and efficacy of subcutaneous litifilimab, a humanized monoclonal antibody that binds to BDCA2, in patients with SLE have not been extensively studied. METHODS: We conducted a phase 2 trial of litifilimab involving participants with SLE. The initial trial design called for randomly assigning participants to receive litifilimab (at a dose of 50, 150, or 450 mg) or placebo administered subcutaneously at weeks 0, 2, 4, 8, 12, 16, and 20, with the primary end point of evaluating cutaneous lupus activity. The trial design was subsequently modified; adults with SLE, arthritis, and active skin disease were randomly assigned to receive either litifilimab at a dose of 450 mg or placebo. The revised primary end point was the change from baseline in the total number of active joints (defined as the sum of the swollen joints and the tender joints) at week 24. Secondary end points were changes in cutaneous and global disease activity. Safety was also assessed. RESULTS: A total of 334 adults were assessed for eligibility, and 132 underwent randomization (64 were assigned to receive 450-mg litifilimab, 6 to receive 150-mg litifilimab, 6 to receive 50-mg litifilimab, and 56 to receive placebo). The primary analysis was conducted in the 102 participants who had received 450-mg litifilimab or placebo and had at least four tender and at least four swollen joints. The mean (±SD) baseline number of active joints was 19.0±8.4 in the litifilimab group and 21.6±8.5 in the placebo group. The least-squares mean (±SE) change from baseline to week 24 in the total number of active joints was -15.0±1.2 with litifilimab and -11.6±1.3 with placebo (mean difference, -3.4; 95% confidence interval, -6.7 to -0.2; P = 0.04). Most of the secondary end points did not support the results of the analysis of the primary end point. Receipt of litifilimab was associated with adverse events, including two cases of herpes zoster and one case of herpes keratitis. CONCLUSIONS: In a phase 2 trial involving participants with SLE, litifilimab was associated with a greater reduction from baseline in the number of swollen and tender joints than placebo over a period of 24 weeks. Longer and larger trials are required to determine the safety and efficacy of litifilimab for the treatment of SLE. (Funded by Biogen; LILAC ClinicalTrials.gov number, NCT02847598.).

Trial of Anti-BDCA2 Antibody Litifilimab for Cutaneous Lupus Erythematosus.

BACKGROUND: Blood dendritic cell antigen 2 (BDCA2) is a receptor that is exclusively expressed on plasmacytoid dendritic cells, which are implicated in the pathogenesis of lupus erythematosus. Whether treatment with litifilimab, a humanized monoclonal antibody against BDCA2, would be efficacious in reducing disease activity in patients with cutaneous lupus erythematosus has not been extensively studied. METHODS: In this phase 2 trial, we randomly assigned adults with histologically confirmed cutaneous lupus erythematosus with or without systemic manifestations in a 1:1:1:1 ratio to receive subcutaneous litifilimab (at a dose of 50, 150, or 450 mg) or placebo at weeks 0, 2, 4, 8, and 12. We used a dose-response model to assess whether there was a response across the four groups on the basis of the primary end point, which was the percent change from baseline to 16 weeks in the Cutaneous Lupus Erythematosus Disease Area and Severity Index-Activity score (CLASI-A; scores range from 0 to 70, with higher scores indicating more widespread or severe skin involvement). Safety was also assessed. RESULTS: A total of 132 participants were enrolled; 26 were assigned to the 50-mg litifilimab group, 25 to the 150-mg litifilimab group, 48 to the 450-mg litifilimab group, and 33 to the placebo group. Mean CLASI-A scores for the groups at baseline were 15.2, 18.4, 16.5, and 16.5, respectively. The difference from placebo in the change from baseline in CLASI-A score at week 16 was -24.3 percentage points (95% confidence interval [CI] -43.7 to -4.9) in the 50-mg litifilimab group, -33.4 percentage points (95% CI, -52.7 to -14.1) in the 150-mg group, and -28.0 percentage points (95% CI, -44.6 to -11.4) in the 450-mg group. The least squares mean changes were used in the primary analysis of a best-fitting dose-response model across the three drug-dose levels and placebo, which showed a significant effect. Most of the secondary end points did not support the results of the primary analysis. Litifilimab was associated with three cases each of hypersensitivity and oral herpes infection and one case of herpes zoster infection. One case of herpes zoster meningitis occurred 4 months after the participant received the last dose of litifilimab. CONCLUSIONS: In a phase 2 trial involving participants with cutaneous lupus erythematosus, treatment with litifilimab was superior to placebo with regard to a measure of skin disease activity over a period of 16 weeks. Larger and longer trials are needed to determine the effect and safety of litifilimab for the treatment of cutaneous lupus erythematosus. (Funded by Biogen; LILAC ClinicalTrials.gov number, NCT02847598.).

Development and Validation of a Diagnostic Nomogram to Predict the Anthracycline-Induced Early Cardiotoxicity in Children with Hematological Tumors.

This study aimed to establish and validate an effective nomogram to predict the risk of cardiotoxicity in children after each anthracycline treatment. According to the inclusion and exclusion criteria, the eligible children were randomly divided into the training cohort (75%) and the validation cohort (25%). Least absolute shrinkage and selection operator (LASSO) regression was used to select the predictors and a nomogram was developed. Then, concordance index (C-index), the area under the curve (AUC), Hosmer-Lemeshow (H-L) test, and decision curve analysis (DCA) were employed to evaluate the performance and clinical utility of nomogram. Internal validation was processed to inspect the stability of the model. A total of 796 eligible children were included in this study and divided into a training set (n = 597) and a validation set (n = 199). LASSO regression analysis revealed that cumulative anthracycline dose, ejection fractions, NT-proBNP, and diastolic dysfunction were effective predictors of cardiotoxicity. The nomogram was established based on these variables. The C-index and the AUC of the predicting nomogram were 0.818 in the training cohort and 0.773 in the validation cohort, suggesting that the nomogram had good discrimination. The calibration curve of the nomogram presented no significant deviation from the reference line, and the P-value of the H-L test was 0.283, implying a preferable degree of calibration. The threshold of DCA also reflects that the nomogram is clinically useful. A nomogram was developed to predict anthracycline chemotherapy-induced cardiotoxicity in children with hematological tumors. The nomogram has a good prediction effect and can provide a reference for clinicians' diagnosis and treatment.

Efficacy and safety of alemtuzumab over 6 years: final results of the 4-year CARE-MS extension trial.

BACKGROUND: In the 2-year CARE-MS I and II trials, alemtuzumab 12 mg administered on 5 consecutive days at core study baseline and on 3 consecutive days 12 months later significantly improved outcomes versus subcutaneous interferon beta-1a (SC IFNB-1a) in relapsing-remitting multiple sclerosis patients. Here, we present the final 6-year CARE-MS extension trial results (CAMMS03409), and compare outcomes over 6 years in patients randomized to both treatment groups at core study baseline. METHODS: Over a 4-year extension, alemtuzumab patients (alemtuzumab-only) received as-needed additional alemtuzumab (⩾12 months apart) for disease activity after course 2. SC IFNB-1a patients who entered the extension discontinued SC IFNB-1a and received 2 alemtuzumab 12 mg courses (IFN-alemtuzumab), followed by additional, as-needed, alemtuzumab. RESULTS: Through year 6, 63% of CARE-MS I and 50% of CARE-MS II alemtuzumab-only patients received neither additional alemtuzumab nor other disease-modifying therapy, with lasting suppression of disease activity, improved disability, and slowing of brain volume loss (BVL). In CARE-MS I patients (treatment-naive; less disability; shorter disease duration), disease activity and BVL were significantly reduced in IFN-alemtuzumab patients, similar to alemtuzumab-only patients at year 6. Among CARE-MS II patients (inadequate response to prior treatment; more disability; longer disease duration), alemtuzumab significantly improved clinical and magnetic resonance imaging outcomes, including BVL, in IFN-alemtuzumab patients; however, disability outcomes were less favorable versus alemtuzumab-only patients. Safety profiles, including infections and autoimmunities, following alemtuzumab were similar between treatment groups. CONCLUSION: This study demonstrates the high efficacy of alemtuzumab over 6 years, with a similar safety profile between treatment groups. CLINICALTRIALSGOV IDENTIFIERS: NCT00530348; NCT00548405; NCT00930553.

The Clinical Characteristics and Prognosis of Different Age Patients with Lung Cancer.

OBJECTIVE: Cancer is closely related to age, and the incidence of cancer increases with age. However, there are few studies on the relationship between age and clinical characteristics of lung cancer. PATIENTS AND METHODS: We collected all the consecutive lung cancer cases from 2012 to 2017 in our hospital and divided them into 6 groups according to their ages: ≤40 y/o, 41~50 y/o, 51~60 y/o, 61~70 y/o, 71~80 y/o and >80 y/o. The clinical characteristics and prognosis of these patients were evaluated. RESULTS: There were 1143 cases diagnosed in our hospital from 2012 to 2017. There were more non-smokers (p<0.01), stage IV (p<0.01) and anaplastic lymphoma kinase (ALK) fusion (p<0.01) patients but less stage I patients in ≤40 y/o group compared with other age groups. It seemed that older patients were more likely had co-exist driver gene mutations (p=0.04). There was no significant difference in overall survival (OS) among these 6 age groups. However, the age may be an independent prognostic factor compared with the patients in ≤40 y/o group, the patients in >80 y/o group were associated with a higher mortality risk, while the patients in other groups had the similar mortality risk. CONCLUSION: There are some differences in clinical characteristics and prognosis among different age groups. The reasons behind the phenomenon are largely unclear. The age should be taken into account when we develop clinical trials.

LncRNA MIR22HG abrogation inhibits proliferation and induces apoptosis in esophageal adenocarcinoma cells via activation of the STAT3/c-Myc/FAK signaling.

Long non-coding RNAs (lncRNAs) have involved in human malignancies and played an important role in gene regulations. The dysregulation of lncRNA MIR22HG has been reported in several cancers. However, the role of MIR22HG in esophageal adenocarcinoma (EAC) is poorly understood. Loss of function approaches were used to investigate the biological role of MIR22HG in EAC cells. The effects of MIR22HG on cell proliferation were evaluated by WST-1 and colony formation assays. The effects of MIR22HG on cell migration and invasion were examined using transwell assays. QRT-PCR and Western blot were used to evaluate the mRNA and protein expression of related genes. In this study, abrogation of MIR22HG inhibited cell proliferation, colony formation, invasion and migration in EAC 3 cell lines (OE33, OE19 and FLO-1). Mechanistically, MIR22HG silencing decreased the expression of STAT3/c-Myc/p-FAK proteins and induced apoptosis in EAC cell lines. These results delineate a novel mechanism of MIR22HG in EAC, and may provide potential targets by developing lncRNA-based therapies for EAC.

Assessment of Drug Interaction Potential Between the Hepatitis C Virus Direct-Acting Antiviral Agents Elbasvir/Grazoprevir and the Nucleotide Analog Reverse-Transcriptase Inhibitor Tenofovir Disoproxil Fumarate.

Treatment of individuals coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) requires careful consideration of potential drug-drug interactions. We evaluated the pharmacokinetic interaction of the direct-acting antiviral agents elbasvir and grazoprevir coadministered with the nucleotide reverse transcriptase inhibitor tenofovir disoproxil fumarate (TDF). Three open-label, multidose studies in healthy adults were conducted. In the first study (N = 10), participants received TDF 300 mg once daily, elbasvir 50 mg once daily, and elbasvir coadministered with TDF. In the second study (N = 12), participants received TDF 300 mg once daily, grazoprevir 200 mg once daily, and grazoprevir coadministered with TDF. In the third study (N = 14), participants received TDF 300 mg once daily and TDF 300 mg coadministered with coformulated elbasvir/grazoprevir 50 mg/100 mg once daily. Pharmacokinetics and safety were evaluated. Following coadministration, the tenofovir area under the plasma concentration-time curve to 24 hours and maximum plasma concentration geometric mean ratios (90% confidence intervals) for tenofovir and coadministered drug(s) versus tenofovir were 1.3 (1.2, 1.5) and 1.5 (1.3, 1.6), respectively, when coadministered with elbasvir; 1.2 (1.1, 1.3) and 1.1 (1.0, 1.2), respectively, when coadministered with grazoprevir; and 1.3 (1.2, 1.4) and 1.1 (1.0, 1.4), respectively, when coadministered with the elbasvir/grazoprevir coformulation. TDF had minimal effect on elbasvir and grazoprevir pharmacokinetics. Elbasvir and/or grazoprevir coadministered with TDF resulted in no clinically meaningful tenofovir exposure increases and was generally well tolerated, with no deaths, serious adverse events (AEs), discontinuations due to AEs, or laboratory AEs reported. No dose adjustments for elbasvir/grazoprevir or TDF are needed for coadministration in HCV/HIV-coinfected people.

Pharmacokinetic Interactions between the Hepatitis C Virus Inhibitors Elbasvir and Grazoprevir and HIV Protease Inhibitors Ritonavir, Atazanavir, Lopinavir, and Darunavir in Healthy Volunteers.

The combination of the hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor elbasvir and the NS3/4A protease inhibitor grazoprevir is a potent, once-daily therapy indicated for the treatment of chronic HCV infection in individuals coinfected with human immunodeficiency virus (HIV). We explored the pharmacokinetic interactions of elbasvir and grazoprevir with ritonavir and ritonavir-boosted HIV protease inhibitors in three phase 1 trials. Drug-drug interaction trials with healthy participants were conducted to evaluate the effect of ritonavir on the pharmacokinetics of grazoprevir (n = 10) and the potential two-way pharmacokinetic interactions of elbasvir (n = 30) or grazoprevir (n = 39) when coadministered with ritonavir-boosted atazanavir, lopinavir, or darunavir. Coadministration of ritonavir with grazoprevir increased grazoprevir exposure; the geometric mean ratio (GMR) for grazoprevir plus ritonavir versus grazoprevir alone area under the concentration-time curve from 0 to 24 h (AUC0-24) was 1.91 (90% confidence interval [CI]; 1.31 to 2.79). Grazoprevir exposure was markedly increased with coadministration of atazanavir-ritonavir, lopinavir-ritonavir, and darunavir-ritonavir, with GMRs for grazoprevir AUC0-24 of 10.58 (90% CI, 7.78 to 14.39), 12.86 (90% CI, 10.25 to 16.13), and 7.50 (90% CI, 5.92 to 9.51), respectively. Elbasvir exposure was increased with coadministration of atazanavir-ritonavir, lopinavir-ritonavir, and darunavir-ritonavir, with GMRs for elbasvir AUC0-24 of 4.76 (90% CI, 4.07 to 5.56), 3.71 (90% CI, 3.05 to 4.53), and 1.66 (90% CI, 1.35 to 2.05), respectively. Grazoprevir and elbasvir had little effect on atazanavir, lopinavir, and darunavir pharmacokinetics. Coadministration of elbasvir-grazoprevir with atazanavir-ritonavir, lopinavir-ritonavir, or darunavir-ritonavir is contraindicated, owing to an increase in grazoprevir exposure. Therefore, HIV treatment regimens without HIV protease inhibitors should be considered for HCV/HIV-coinfected individuals who are being treated with elbasvir-grazoprevir.

Assessment of drug interaction potential between the HCV direct-acting antiviral agents elbasvir/grazoprevir and the HIV integrase inhibitors raltegravir and dolutegravir.

BACKGROUND: Elbasvir/grazoprevir is a once-daily fixed-dose combination therapy for the treatment of chronic HCV infection, including HCV/HIV coinfection. OBJECTIVES: To evaluate the pharmacokinetic interaction of elbasvir and grazoprevir with raltegravir or dolutegravir. METHODS: Three open-label trials in healthy adult participants were conducted. In the raltegravir trials, participants received a single dose of raltegravir 400 mg, a single dose of elbasvir 50 mg or grazoprevir 200 mg, and raltegravir with either elbasvir or grazoprevir. In the dolutegravir trial, participants received a single dose of dolutegravir 50 mg alone or co-administered with once-daily elbasvir 50 mg and grazoprevir 200 mg. RESULTS: The raltegravir AUC0-∞ geometric mean ratio (GMR) (90% CI) was 1.02 (0.81-1.27) with elbasvir and 1.43 (0.89-2.30) with grazoprevir. Dolutegravir AUC0-∞ GMR (90% CI) was 1.16 (1.00-1.34) with elbasvir and grazoprevir. The elbasvir AUC0-∞ GMR (90% CI) was 0.81 (0.57-1.17) with raltegravir and 0.98 (0.93-1.04) with dolutegravir. The grazoprevir AUC0-24 GMR (90% CI) was 0.89 (0.72-1.09) with raltegravir and 0.81 (0.67-0.97) with dolutegravir. CONCLUSIONS: Elbasvir or grazoprevir co-administered with raltegravir or dolutegravir resulted in no clinically meaningful drug-drug interactions and was generally well tolerated. These results support the assertion that no dose adjustments for elbasvir, grazoprevir, raltegravir or dolutegravir are needed for co-administration in HCV/HIV-coinfected people.

Antiviral Activity, Safety, and Tolerability of Multiple Ascending Doses of Elbasvir or Grazoprevir in Participants Infected With Hepatitis C Virus Genotype-1 or -3.

PURPOSE: Elbasvir (MK-8742) and grazoprevir (MK-5172; Merck & Co, Inc, Kenilworth, New Jersey) are hepatitis C virus (HCV)-specific inhibitors of the nonstructural protein 5A phosphoprotein and the nonstructural protein 3/4A protease, respectively. The aims of these studies were to evaluate the antiviral activity and safety of different doses of elbasvir or grazoprevir each administered as monotherapy to participants infected with either HCV genotype (GT) 1 or GT3. METHODS: These 2 double-blind, randomized, placebo-controlled, sequential-panel, multiple ascending dose studies were conducted to assess the safety and pharmacodynamics of 5 days of once-daily elbasvir or 7 days of once-daily grazoprevir in adult male participants chronically infected with either HCV GT1 or GT3. FINDINGS: Oral administration of elbasvir or grazoprevir once daily exhibited potent antiviral activity in participants with chronic GT1 or GT3 HCV infections. HCV RNA levels declined rapidly (within 1 day for elbasvir and 2 days for grazoprevir). At 50 mg of elbasvir once daily, the mean maximum reductions in HCV RNA from baseline were 5.21, 4.17, and 3.12 log10 IU/mL for GT1b-, GT1a-, and GT3-infected participants, respectively. At 100 mg of grazoprevir once daily, the mean maximum reductions in HCV RNA from baseline were 4.74 and 2.64 log10 IU/mL for GT1- and GT3-infected participants. IMPLICATIONS: The results in the elbasvir monotherapy study showed that 10 to 50 mg of elbasvir was associated with a rapid decline in HCV viral load; the results in the grazoprevir monotherapy study suggest that doses of 50 mg of grazoprevir and higher are on the maximum response plateau of the dose-response curve for GT1-infected participants. The results of these proof-of-concept studies provided preliminary data for the selection of the dosages of elbasvir and grazoprevir to test in Phase II and III clinical studies. ClinicalTrials.gov identifiers: NCT00998985 (Protocol 5172-004) and NCT01532973 (Protocol 8742-002).

Pharmacokinetics, Safety, and Tolerability of Single-Dose Elbasvir in Participants with Hepatic Impairment.

BACKGROUND: The combination of elbasvir and grazoprevir is approved for the treatment of hepatitis C virus genotype 1 or 4 infection. OBJECTIVE: To evaluate the pharmacokinetics and safety of single-dose elbasvir 50 mg in participants with hepatic impairment. METHODS: Participants with mild, moderate, or severe hepatic impairment and age-, sex-, and weight-matched healthy controls were enrolled in a 3-part, open-label, sequential-panel, single-dose pharmacokinetic study. Blood samples were collected to assess pharmacokinetics. Safety and tolerability were assessed throughout the study. RESULTS: Thirty-four participants were enrolled: eight with mild hepatic impairment, 11 with moderate hepatic impairment, seven with severe hepatic impairment, and eight healthy matched controls. Participants with mild, moderate, and severe hepatic impairment demonstrated a numeric, but not statistically significant, decrease in elbasvir exposure compared with controls, with a mean 39, 28, and 12% decrease in area under the concentration-time curve from time 0 extrapolated to infinity, as well as a 42, 31, and 42% decrease in maximum plasma concentration (C max), respectively. The observed median time to C max was similar in participants with hepatic impairment and controls. Single-dose administration of elbasvir was well tolerated. CONCLUSIONS: The pharmacokinetics of elbasvir after a single, oral 50-mg dose were not clinically meaningfully altered in non-HCV-infected participants with mild, moderate, or severe hepatic dysfunction. However, since elbasvir is currently available only as part of a fixed-dose combination with grazoprevir, the fixed-dose combination should not be administered to patients with moderate or severe hepatic impairment, due to the significantly increased plasma grazoprevir exposures in those populations.

No clinically meaningful pharmacokinetic interaction between the hepatitis C virus inhibitors elbasvir and grazoprevir and the oral contraceptives ethinyl estradiol and levonorgestrel.

PURPOSE: Oral contraceptive pills (OCPs) are an important element of hepatitis C virus (HCV) treatment in women of childbearing potential. These studies evaluated the safety and pharmacokinetic interactions between elbasvir (EBR) and grazoprevir (GZR) and ethinyl estradiol/levonorgestrel (EE/LNG). METHODS: Both studies were open-label, single-site, two-period, fixed-sequence, one-way interaction studies. In period 1, subjects received one tablet of EE/LNG (0.03 mg/0.15 mg). In period 2, subjects received EBR (50 mg once daily) for 13 days or GZR (200 mg once daily) for 10 days, with one tablet of EE/LNG on day 7 (GZR group) or 10 (EBR group). Each study enrolled 20 healthy, nonsmoking adult females. RESULTS: There was no clinically meaningful effect of multiple doses of EBR or GZR on the pharmacokinetics of EE or LNG. Geometric mean ratios (GMRs) for AUC0-∞ and Cmax in the presence and absence of EBR were 1.01 and 1.10 for EE and 1.14 and 1.02 for LNG, with 90% confidence intervals (CIs) that were contained in the interval [0.80, 1.25]. Similarly, the AUC0-∞ and Cmax GMRs in the presence and absence of GZR were 1.10 and 1.05 for EE and 1.23 and 0.93 for LNG, respectively. The 90% CIs for EE AUC0-∞ and for EE and LNG Cmax were contained in the interval [0.80, 1.25]; however, the 90% CI for the LNG AUC0-∞ [1.15, 1.32] slightly exceeded the upper bound. CONCLUSIONS: These results suggest that EBR/GZR can be co-administered to female patients with HCV of childbearing potential who are on OCPs to prevent pregnancy.

[Comparison of tubeless-percutaneous nephrolithotomy and ureteroscopic lithotripsy in treatment of upper-ureteral calculi sized ≥ 1.5 cm].

OBJECTIVE: To compare the efficacy and safety of tubeless percutaneous nephrolithotomy (tubeless-PCNL) and ureteroscopic lithotripsy (URL) in treatment of impacted upper-ureteral calculi ≥ 1.5 cm in size. METHODS: Patients with ureteral stones sized ≥ 1.5 cm and lodged above the fourth lumbar vertebra who were treated between September 2009 and July 2013 in Peking University People's Hospital were retrospectively analyzed. In the study, 182 patients underwent tubeless-PCNL or URL treatment respectively, and the operation success rates were compared. The duration of operation, intraoperative blood loss(average hemoglobin decrease), complications, mean hospital stay and residual stone rates were also compared. RESULTS: Fifty-four patients underwent tubeless-PCNL treatment,the average stone size was (1.9 ± 0.4) cm,nephrostomy tubes were placed in two patients,and the operation success rate was 96.3%(52/54). In the rest of the 52 patients,and the mean operation time was (30.1 ± 14.8) minutes with an average postoperative hemoglobin decrease of (10.2 ± 6.1) g/L, and the mean hospital stay was (3.0 ± 1.4) days. Only one of the patients had residual fragments (2%). The main complications included minor perirenal hematoma in 1 patient, fever in 2 patients,elevated blood WBC in 11 patients,and analgesics requirement in 3 patients. In the study, 128 patients were treated with URL,the average stone size was (1.7 ± 0.3) cm. 19 procedures failed,and 10 patients were converted to PCNL,extracorporeal shock wave lithotripsy was executed subsequently after double-J stent placement in 5 patients,and migration of calculi or stone fragments happened in 4 patients. The mean operative time was (51.3 ± 25.5) minutes for the remaining 109 patients with a hemoglobin reduction of (5.2 ± 7.2) g/L. The mean hospital stay was (2.9 ± 1.3) days, and residual stones were found in 13 of the 109 patients (11.9%). The main complications included fever in 3 patients, elevated blood WBC in 42 patients, analgesics requirement in 13 patients because of pain in the urethra or flank. The size of the stones between the two group didn't show significant difference,but the success rate of the tubeless-PCNL procedure was significantly higher. Except that hemoglobin decrease was slightly higher in the tubeless-PCNL group,the mean operative time, the rate of residual stones and rate of complications of the tubeless-PCNL group were lower significantly. CONCLUSION: Treating stones above 4th lumbar vertebra larger than 1.5 cm were challenging. It is difficult to treat these stones with URL because of a high probability to fail, but on the contrary, tubeless-PCNL was more likely to be performed successfully. For surgeons experienced with the PCNL technology, treating stones ≥ 1.5 cm with tubeless-PCNL procedure may turn out to be more efficient and with a higher operation success rate, and the risk of complications was lower without lengthening the postoperative hospital stay.