Long noncoding RNA ANRIL regulates endothelial cell activities associated with coronary artery disease by up-regulating CLIP1, EZR, and LYVE1 genes.

Coronary artery disease (CAD) is the leading cause of death worldwide. Long noncoding RNAs (lncRNAs) are a class of noncoding transcripts of > 200 nucleotides and are increasingly recognized as playing functional roles in physiology and disease. ANRIL is an lncRNA gene mapped to the chromosome 9p21 genetic locus for CAD identified by the first series of genome-wide association studies (GWAS). However, ANRIL's role in CAD and the underlying molecular mechanism are unknown. Here, we show that the major ANRIL transcript in endothelial cells (ECs) is DQ485454 with a much higher expression level in ECs than in THP-1 monocytes. Of note, DQ485454 expression was down-regulated in CAD coronary arteries compared with non-CAD arteries. DQ485454 overexpression significantly reduced monocyte adhesion to ECs, transendothelial monocyte migration (TEM), and EC migration, which are critical cellular processes involved in CAD initiation, whereas siRNA-mediated ANRIL knockdown (KD) had the opposite effect. Microarray and follow-up quantitative RT-PCR analyses revealed that the ANRIL KD down-regulated expression of AHNAK2, CLIP1, CXCL11, ENC1, EZR, LYVE1, WASL, and TNFSF10 genes and up-regulated TMEM100 and TMEM106B genes. Mechanistic studies disclosed that overexpression of CLIP1, EZR, and LYVE1 reversed the effects of ANRIL KD on monocyte adhesion to ECs, TEM, and EC migration. These findings indicate that ANRIL regulates EC functions directly related to CAD, supporting the hypothesis that ANRIL is involved in CAD pathogenesis at the 9p21 genetic locus and identifying a molecular mechanism underlying lncRNA-mediated regulation of EC function and CAD development.

Drug-Drug Interaction Studies Between Hepatitis C Virus Antivirals Sofosbuvir/Velpatasvir and Boosted and Unboosted Human Immunodeficiency Virus Antiretroviral Regimens in Healthy Volunteers.

Background: Combining antiviral regimens in the hepatitis C virus (HCV)/human immunodeficiency virus (HIV)-coinfected population can be complex as they share overlapping mechanisms for elimination that may result in drug interactions. The pharmacokinetics, safety, and tolerability of sofosbuvir/velpatasvir (SOF/VEL) with multiple antiretroviral (ARV) regimens were evaluated. Methods: Healthy volunteers were enrolled into 2 phase 1, open-label, randomized, multiple-dose, cross-over studies. SOF/VEL and ARV regimens were administered alone and in combination; ARVs (and pharmacokinetic enhancers) included atazanavir (ATV), cobicistat (COBI), darunavir (DRV), dolutegravir (DTG), efavirenz (EFV), elvitegravir (EVG), emtricitabine (FTC), lopinavir (LPV), raltegravir (RAL), rilpivirine (RPV), ritonavir (RTV), tenofovir alafenamide (TAF), and tenofovir disoproxil fumarate (TDF). Geometric least squares means ratios (coadministration:alone) and 90% confidence intervals were constructed for area under the plasma concentration-time curve over the dosing interval, maximum concentration, and trough, for all analytes. Safety and tolerability were also evaluated. Results: In total, 237 participants were enrolled. No clinically relevant differences in the pharmacokinetics (PK) of SOF, SOF metabolite GS-331007, or VEL were observed other than an approximate 50% decrease in VEL exposure when administered with EFV/FTC/TDF. No clinically relevant differences in the PK of ARVs were observed when administered with SOF/VEL. Study treatments were well tolerated, including no observed creatinine clearance changes during evaluation of TDF-containing regimens. Conclusions: SOF/VEL and ARV regimens including ATV, COBI, DRV, DTG, EVG, FTC, LPV, RAL, RPV, RTV, TAF, or TDF may be coadministered without dose adjustment. Use of SOF/VEL with EFV-containing regimens is not recommended due to an approximate 50% reduction in VEL exposure.

Pharmacokinetics and safety of boosted elvitegravir in subjects with hepatic impairment.

Elvitegravir (EVG), an HIV strand transfer integrase inhibitor, is metabolized primarily via cytochrome P450 3A4 (CYP3A) and secondarily via glucuronidation. The pharmacokinetics (PK) and safety of cobicistat (COBI)-boosted EVG (EVG/co) were evaluated in subjects with impaired liver function. The enrolled subjects had stable moderate liver impairment (n = 10; Child-Pugh-Turcotte [CPT] class B) or were healthy controls (n = 10) matched for age (±5 years), gender, and body mass index (±15%). EVG/co (150/150 mg) was administered once daily for 10 days, followed by pharmacokinetic (PK) sampling. Safety was assessed throughout the study. EVG and COBI exposures were compared between the impairment and control groups, with a ≥100% increase considered clinically relevant. EVG and COBI protein binding was also measured. All enrolled subjects completed the study. The treatment-emergent adverse event (AE) incidences were comparable between the groups; all study drug-related AEs were mild. The geometric mean ratio (90% confidence interval [CI]) for EVG area under the concentration-time curve over the dosing interval (AUCtau) and maximum observed plasma concentration (Cmax) were 135% (103%, 177%) and 141% (109%, 183%), respectively. The corresponding values for COBI were 99.8% (76.0%, 131%) and 86.1% (65.4%, 113%), respectively, indicating no clinically relevant change in exposure. No correlations were observed between the EVG and COBI exposures versus CPT score. The EVG- and COBI-free fractions were similar between groups. EVG and COBI do not require dose adjustment in moderate or mild liver impairment, as no clinically relevant PK changes were observed for EVG or COBI in this special population. No PK or safety data are available for EVG or COBI in subjects with severe hepatic impairment.

The Effects of Hydroxypropyl Methyl Cellulose and Metakaolin on the Properties of Self-Compacting Solidified Soil Based on Abandoned Slurry.

As a new type of backfill material, Self-compacting solidified soil (SCSS) takes the abandoned slurry of cast-in-place piles after dewatering and reduction as the main raw material, which brings a problem of coordinating the working performance with the mechanical property under the condition of high mobility. In this paper, hydroxypropyl methyl cellulose (HPMC) and metakaolin were introduced as additives to solve this problem. First, the workability and mechanical properties of SCSS were regulated and optimized by means of the water seepage rate test, the flowability test, and the unconfined compressive strength test. Second, this study also used X-ray diffraction (XRD) and scanning electron microscopy (SEM) to investigate the effects of HPMC and metakaolin on the physical phase and microstructure of SCSS. In this way, the results showed that there was a significant impact on the flowability of SCSS, that is, when the dosage reached 0.3%, the water seepage rate of SCSS was reduced to less than 1%, and the compressive strength at 7 days reached its peak. At the same time, HPMC weakened the strength growth of SCSS in the age period of 7 days to 14 days. However, the addition of metakaolin promoted its compressive strength. XRD analysis showed that the additives had no significant effects on the physical phases. And, from the SEM results, it can be seen that although the water-retaining effect of HPMC makes hydration of cement more exhaustive, more ettringite (AFt) can be observed in the microstructure. In addition, it can be observed that the addition of metakaolin can generate more hydrated calcium silicate (C-S-H) due to the strong surface energy possessed by metakaolin. As a result of the above factors, SCSS filled the voids between particles and improved the interface structure between particles, thus enhanced the compressive strength.

Bending Fatigue Properties of Ultra-High Toughness Cementitious Composite (UHTCC).

Ultra-High Toughness Cementitious Composite (UHTCC) represents a composite material meticulously engineered on the foundation of micromechanical principles. The multi-crack cracking and strain-hardening characteristics of UHTCC enable it to be applied to orthotropic steel decks to control the crack width. Different from most studies which only focus on hybrid fiber or fatigue characteristics, this paper studies the influence of hybrid fiber content on static mechanical properties, flexural toughness, and flexural fatigue characteristics of UHTCC under different stress levels. The compressive and flexural strength, bending toughness, and fatigue damage of UHTCC under different fiber ratios were compared, and the fatigue properties of hybrid fiber UHTCC were verified. The results reveal that hybrid fiber exerts a more pronounced effect on toughness, augmenting the maximum folding ratio by 23.7%. Single-doped steel fiber UHTCC exhibits a characteristic strain-softening phenomenon attributable to inadequate fiber content, whereas the bending toughness index of hybrid fiber UHTCC surpasses that of SF1.5P0 by 18.6%. Under low-stress conditions, UHTCC demonstrates a nearly threefold increase in bending fatigue life with a mere 1% steel fiber content, while the influence of polyvinyl alcohol (PVA) fiber on fatigue life is more significant: with an increase of only 1/5 volume content, the fatigue life increased by 29.8%, reaching a maximum increase of 43.2% at 1/4 volume content. Furthermore, the fatigue damage accumulation curve of UHTCC follows a three-stage inverted S-shaped trajectory. The inclusion of PVA fiber facilitates early initiation of stable cracking during the fatigue failure process, thereby advancing the entire strain stability development stage and mitigating external load forces through the proliferation of micro-cracks. Consequently, compared to SF1P0, the ε0 of SF1P5 experiences a significant increase, reaching 143.43%.

Pharmacokinetics and Safety of Cilofexor and Firsocostat in Healthy Japanese and Non-Japanese Participants.

Cilofexor, an oral farnesoid X receptor agonist, and firsocostat, an oral, liver-targeted inhibitor of acetyl-coenzyme A carboxylase, are being investigated in combination with semaglutide for the treatment of metabolic dysfunction-associated steatohepatitis (previously known as nonalcoholic steatohepatitis; NCT04971785). The pharmacokinetics and safety profiles of cilofexor (100 mg) and firsocostat (20 mg) were separately investigated in two phase 1 studies, each of which included healthy Japanese participants (n = 20 in the cilofexor study and n = 21 in the firsocostat study) and non-Japanese participants (n = 20 in the cilofexor study and n = 21 in the firsocostat study). Intensive pharmacokinetic sampling was performed over 96 h following a single-dose administration of the study drug. Safety was monitored throughout the study. In total, 39 participants completed each study. The plasma exposures of cilofexor and firsocostat (area under the concentration-time curve [AUC] calculated from time 0 to infinity [AUCinf]) in Japanese participants were 1.24-fold and 1.98-fold, respectively, of those in non-Japanese participants. Both study drugs were well tolerated with no clear differences in adverse events or laboratory abnormalities between Japanese and non-Japanese participants. The approximate 2-fold exposure difference of firsocostat between Japanese and non-Japanese participants at the 20 mg dose does not warrant dose reduction given the previously established safety and tolerability of once-daily doses of firsocostat up to 200 mg.

Pharmacokinetics, Disposition, and Biotransformation of [14C]Lenacapavir, a Novel, First-in-Class, Selective Inhibitor of HIV-1 Capsid Function, in Healthy Participants Following a Single Intravenous Infusion.

BACKGROUND AND OBJECTIVE: Lenacapavir (LEN) is a novel, first-in-class, multistage, selective inhibitor of human immunodeficiency virus type 1 (HIV-1) capsid function recently approved for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection. The purpose of this multicohort study was to evaluate the pharmacokinetics, metabolism, excretion, safety, and tolerability of LEN following a single intravenous (IV) infusion of 10 mg LEN or 20 mg [14C]LEN in healthy participants. METHODS: Twenty-one healthy adult participants were enrolled into the study and received either a single IV dose of 10 mg LEN (n = 8 active, n = 3 placebo; cohort 1) or a single IV dose of 20 mg [14C]LEN containing 200 µCi (n = 10; cohort 2). Blood, urine, and feces samples (when applicable) were collected after dosing, and radioactivity (cohort 2) was assessed using liquid scintillation counting in both plasma and excreta. LEN in plasma was quantified by liquid chromatography (LC) tandem mass spectroscopy (MS/MS) method bioanalysis. Metabolite profiling in plasma and excreta were performed using LC-fraction collect (FC)-high-resolution MS and LC-FC-accelerator mass spectrometry in plasma. RESULTS: Between the 10 mg and 20 mg doses of LEN, the observed plasma exposure of LEN doubled, while the elimination half-life was similar. Following administration of 20 mg [14C]LEN (200 µCi), the mean cumulative recovery of [14C] radioactivity was 75.9% and 0.24% from feces and urine, respectively. The mean whole [14C] blood-to-plasma concentration ratio was 0.5-0.7, which showed a low distribution of LEN to red blood cells. Intact LEN was the predominant circulating species in plasma (representing 68.8% of circulating radioactivity), and no single metabolite contributed to > 10% of total radioactivity exposure through 1176 h postdose. Similarly, intact LEN was the most abundant component (32.9% of administered dose; 75.9% of recovered dose) measured in feces, with metabolites accounting for trace amounts. These results suggest metabolism of LEN is not a primary pathway of elimination. Of the metabolites observed in the feces, the three most abundant metabolites were direct phase 2 conjugates (glucuronide, hexose, and pentose conjugates), with additional metabolites formed to a lesser extent via other pathways. The administered LEN IV doses were generally safe and well-tolerated across participants in this study. CONCLUSIONS: The results of this mass balance study indicated that LEN was majorly eliminated as intact LEN via the feces. The renal pathway played a minor role in LEN elimination (0.24%). In addition, no major circulating metabolites in plasma or feces were found, indicating minimal metabolism of LEN.

Pharmacokinetics, Mass Balance, Safety, and Tolerability of Obeldesivir in Healthy Participants.

There is an unmet need for safe and efficacious oral therapies for COVID-19 with low potential for drug-drug interactions. Obeldesivir is an orally administered nucleoside prodrug that has shown antiviral potency in nonclinical studies against SARS-CoV-2 and its circulating variants. Obeldesivir is metabolized to the active nucleoside triphosphate (GS-443902), which acts as an inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase, thereby inhibiting viral RNA synthesis. Here, we report the safety, tolerability, and pharmacokinetics from a first-in-human, randomized, placebo-controlled, phase I study following oral administration of obeldesivir and a phase I, open-label absorption, distribution, metabolism, and excretion study following oral administration of [14C]-obeldesivir. Overall, obeldesivir was safe and well tolerated at single and multiple doses between 100 and 1,600 mg, with low potential for QT prolongation as assessed by QT-concentration analysis. The exposures to GS-441524 increased dose proportionally in the 100-900-mg dose range. GS-441524 accumulated by 35% after twice-daily and 12% after once-daily dosing for 5 days. Dose-proportional increases in the intracellular concentration of GS-443902 were also observed in peripheral blood mononuclar cells. Plasma exposure of GS-441524 was not significantly altered by food intake. Following oral administration of [14C]-obeldesivir (500 mg; 100 µCi), the mean cumulative [14C]-dose recovery was 90.7% with 58.5% in urine and 32.2% in feces. GS-441524 was the predominant plasma component (90% of 14C-area under the concentration-time curve) and was primarily eliminated via renal excretion. Collectively, data from these studies support selection of the obeldesivir 350 mg twice-daily dosing regimen for further evaluation in phase III studies for COVID-19.

Evaluation of the Potential for Cytochrome P450 and Transporter-Mediated Drug-Drug Interactions for Cilofexor, a Selective Nonsteroidal Farnesoid X Receptor (FXR) Agonist.

BACKGROUND AND OBJECTIVE: Cilofexor is a selective farnesoid X receptor (FXR) agonist in development for the treatment of nonalcoholic steatohepatitis and primary sclerosing cholangitis. Our objective was to evaluate potential drug-drug interactions of cilofexor as a victim and as a perpetrator. METHODS: In this Phase 1 study, healthy adult participants (n = 18-24 per each of the 6 cohorts) were administered cilofexor in combination with either perpetrators or substrates of cytochrome P-450 (CYP) enzymes and drug transporters. RESULTS: In total, 131 participants completed the study. As a victim, cilofexor area under the curve (AUC) was 651%, 795%, and 175% when administered following single-dose cyclosporine (600 mg; organic anion transporting polypeptide [OATP]/P-glycoprotein [P-gp]/CYP3A inhibitor), single-dose rifampin (600 mg; OATP1B1/1B3 inhibitor), and multiple-dose gemfibrozil (600 mg twice daily [BID]; CYP2C8 inhibitor), respectively, compared with the administration of cilofexor alone. Cilofexor AUC was 33% when administered following multiple-dose rifampin (600 mg; OATP/CYP/P-gp inducer). Multiple-dose voriconazole (200 mg BID; CYP3A4 inhibitor) and grapefruit juice (16 ounces; intestinal OATP inhibitor) did not affect cilofexor exposure. As a perpetrator, multiple-dose cilofexor did not affect the exposure of midazolam (2 mg; CYP3A substrate), pravastatin (40 mg; OATP substrate), or dabigatran etexilate (75 mg; intestinal P-gp substrate), but atorvastatin (10 mg; OATP/CYP3A4 substrate) AUC was 139% compared with atorvastatin administered alone. CONCLUSION: Cilofexor may be coadministered with inhibitors of P-gp, CYP3A4, or CYP2C8 without the need for dose modification. Cilofexor may be coadministered with OATP, BCRP, P-gp, and/or CYP3A4 substrates-including statins-without dose modification. However, coadministration of cilofexor with strong hepatic OATP inhibitors, or with strong or moderate inducers of OATP/CYP2C8, is not recommended.

Genetic variant R952Q in LRP8 is associated with increased plasma triglyceride levels in patients with early-onset CAD and MI.

We previously identified a novel locus for plasma triglyceride (TG) levels on chromosome 1p31-32 by genome-wide linkage analysis in the GeneQuest population with familial and premature coronary artery disease (CAD). Here we tested a hypothesis that variants in LRP8, a gene that is under the 1p31-32 linkage peak and associated with risk of familial and premature CAD and increased platelet activation, are associated with TG levels. Seven tagSNPs that cover the entire LRP8 gene were characterized in 358 GeneQuest Caucasian probands. Only SNP R952Q (rs5174) was associated with TG levels (P-adj = 0.0016), and this finding was replicated in one other independent population of 134 patients with early-onset myocardial infarction (males <45; females <55; P-adj = 0.0098). TG levels were higher in the group with higher body mass index (BMI ≥ 25) than in the group with lower BMI (BMI < 25). The association was significant in the overweight group (P-adj = 0.0029) or in the smoking group (P-adj = 0.0004), but not in the group with normal BMI or without smoking history. These results suggest that genetic variant R952Q of LRP8 is associated with increased plasma TG levels in patients who are overweight and have premature CAD/MI and history of smoking.

Evaluation of the potential drug interactions mediated through P-gp, OCT2, and MATE1/2K with filgotinib in healthy subjects.

Filgotinib, a preferential Janus Kinase-1 inhibitor, is approved in Europe and Japan for treatment of rheumatoid arthritis and is being developed for treatment of other chronic inflammatory diseases. Three drug-drug interactions studies were conducted in healthy subjects to evaluate the effect of P-glycoprotein (P-gp) modulation (study 1: P-gp inhibition by itraconazole and study 2: P-gp induction by rifampin) on filgotinib pharmacokinetics and the potential of filgotinib to impact exposure of metformin, an organic cation transporter (OCT) 2 and multidrug and toxin extrusion (MATE) 1/2K substrate (study 3). Co-administration of filgotinib with itraconazole increased filgotinib exposure (maximum concentration [Cmax ] by 64% and area under the curve to infinity [AUCinf ] by 45%) but had no effect on the exposure of GS-829845, filgotinib's primary metabolite. Rifampin moderately reduced exposures of filgotinib and GS-829845 (Cmax by 26% and AUCinf by 27% for filgotinib; Cmax by 19% and AUCinf by 38% for GS-829845). The data confirmed that filgotinib is a P-gp substrate. However, the magnitude of change in filgotinib/GS-829845 exposure by P-gp modulators is not deemed to be clinically relevant based on filgotinib exposure-response analyses in subjects with rheumatoid arthritis. Filgotinib did not alter metformin exposures, indicating that filgotinib and GS-829845 do not inhibit OCT2 and MATE1/2K at the clinical doses. Filgotinib was generally well-tolerated when administered alone or with the co-administered drugs in the studies. Results from these studies were the basis to enable the use of P-gp modulators and substrates of OCT2, MATE1, and MATE2K with filgotinib without the need for dose modifications in the current approved rheumatoid arthritis population.

Association of SNP rs17465637 on chromosome 1q41 and rs599839 on 1p13.3 with myocardial infarction in an American caucasian population.

Recent genome-wide single nucleotide polymorphism (SNP) association studies (GWAS) have identified a number of SNPs that were significantly associated with coronary artery disease and myocardial infarction (MI). However, many independent replication studies in other populations are needed to unequivocally confirm the GWAS association. To assess GWAS association, we have established a case-control cohort consisting of 1231 well-characterised MI patients and 560 controls without detectable coronary stenosis, all selected from the Cleveland Genebank population. The Genebank cohort has sufficient power to detect the association between MI and four GWAS SNPs, including rs17465637 within the MIA3 gene, rs2943634 (intergenic), rs6922269 in MTHFD1L, and rs599839 near SORT1. SNPs were genotyped by TaqMan assays and follow-up multivariate logistic regression analysis with incorporation of significant covariates showed significant association with MI for MIA3 SNP rs17465637 (P-adj= 0.0034) and SORT1 SNP rs599839 (P-adj= 0.009). The minor allele G of rs599839 was also associated with a decreased LDL-C level of 5-9 mg/dL per allele, but not with HDL-C or triglyceride levels. No association for MI or lipid levels was found for SNPs rs2943634 and rs6922269 (P-adj > 0.05). Our results establish two SNPs, rs17465637 in MIA3 and rs599839 near SORT1 as significant risk factors for MI in the American Genebank Caucasian population.

Family-based and population-based association studies validate PTPRD as a risk factor for restless legs syndrome.

OBJECTIVE: We previously mapped a genetic locus for restless legs syndrome (RLS) to chromosome 9p22-24 (RLS3) and a later genome-wide association study (GWAS) implicated the PTPRD gene at the RLS3 locus as a susceptibility gene for RLS. However, from the standpoint of genetics, the GWAS association needs to be validated by independent studies. In this study, we used both family-based and population-based association studies to assess the association between PTPRD and RLS in an American Caucasian population. METHODS: We genotyped two intronic SNPs rs1975197 and rs4626664 in PTPRD in 144 family members from 15 families and a case control cohort of 189 patients and 560 controls. Direct DNA sequence analysis was used to screen coding exons and exon-intron boundaries of PTPRD for rare mutations. RESULTS: A family-based sibling transmission disequilibrium test showed association of RLS with SNP rs1975197 (P = 0.015), but not with rs4626664 (P = 0.622). The association with rs1975197 was significantly replicated by a population-based case control association study (allelic P = 0.0004, odds ratio = 1.68; genotypic P = 0.0013 and 0.0003 for an additive and dominant model, respectively). One rare p.E1639D variant was identified in exon 39 in kindred RLS40005. The rare D1639 allele did not co-segregate with RLS in the family, suggesting that p.E1639D variant is not a causative mutation. CONCLUSIONS: This represents the first independent study to validate the association between PTPRD variants and RLS. Both family-based and population-based association studies suggest that PTPRD variant rs1975197 confers risk of RLS.

A genome-wide linkage scan identifies multiple quantitative trait loci for HDL-cholesterol levels in families with premature CAD and MI.

Plasma HDL cholesterol levels (HDL-C) are an independent predictor of coronary artery disease (CAD). We have completed a genome-wide linkage scan for HDL-C in a US cohort consisting of 388 multiplex families with premature CAD (GeneQuest). The heritability of HDL-C in GeneQuest was 0.37 with gender and age as covariates (P = 5.1 x 10(-4)). Two major quantitative trait loci (QTL) for log-transformed HDL-C adjusted for age and gender were identified onto chromosomes 7p22 and 15q25 with maximum multipoint logarithm of odds (LOD) scores of 3.76 and 6.69, respectively. Fine mapping decreased the 7p22 LOD score to a nonsignificant level of 3.09 and split the 15q25 QTL into two loci, one minor QTL on 15q22 (LOD = 2.73) that spanned the LIPC gene, and the other at 15q25 (LOD = 5.63). A family-based quantitative transmission disequilibrium test (QTDT) revealed significant association between variant rs1800588 in LIPC and HDL-C in the GeneQuest population (P = 0.0067), which may account for the minor QTL on 15q22. The 15q25 QTL is the most significant locus identified for HDL-C to date, and these results provide a framework for the ultimate identification of the underlying HDL-C variant and gene on chromosomes 15q25, which will provide insights into novel regulatory mechanisms of HDL-C metabolism.

Synthesis and biological evaluation of azobicyclo[3.3.0] octane derivatives as dipeptidyl peptidase 4 inhibitors for the treatment of type 2 diabetes.

A series of novel azobicyclo[3.3.0]octane derivatives were synthesized and evaluated as dipeptidyl peptidase 4 (DPP-4) inhibitors. The effort resulted in the discovery of inhibitor 2a, which exhibited excellent efficacies in an oral glucose tolerance test. Introduction of methyl group (2j) could prolong the inhibition of serum DPP-4 activity.

Pharmacokinetics, Safety, and Tolerability of Ledipasvir/Sofosbuvir and Sofosbuvir/Velpatasvir in Healthy Chinese Subjects.

PURPOSE: Ledipasvir/sofosbuvir and sofosbuvir/velpatasvir have been approved worldwide for the treatment of chronic hepatitis C virus (HCV) infection. Although both have been approved in China, there are currently no data on their pharmacokinetic profiles in Chinese individuals. Two studies investigated the pharmacokinetic properties, safety, and tolerability of ledipasvir/sofosbuvir and sofosbuvir/velpatasvir, respectively, in healthy Chinese subjects. METHODS: Two Phase I, open-label, single- and multiple-dose studies were conducted in healthy Chinese subjects. Ledipasvir/sofosbuvir (90/400 mg) or sofosbuvir/velpatasvir (400/100 mg), respectively, was administered orally once daily under fasted conditions. Subjects received a single dose (day 1) and multiple doses (days 8-17 [ledipasvir/sofosbuvir]; days 8-14 [sofosbuvir/velpatasvir]). Plasma pharmacokinetic parameters were estimated by using noncompartmental models, and safety was assessed through clinical evaluation and monitoring of adverse events. FINDINGS: Fourteen subjects were enrolled in each study (7 men, 7 women each; mean age, 30 years [ledipasvir/sofosbuvir] and 29 years [sofosbuvir/velpatasvir]). The pharmacokinetic parameters for sofosbuvir, GS-566500, GS-331007, and ledipasvir or velpatasvir were similar to historical values in non-Chinese subjects. Consistent with the t1/2 of ledipasvir relative to 24-h dosing, accumulation of 177% (AUC) and 107% (Cmax) was observed. There was no significant accumulation of velpatasvir, sofosbuvir, GS-566500, or GS-331007. Both drugs were generally well tolerated; no serious adverse events or discontinuations due to adverse events were reported. IMPLICATIONS: Overall, ledipasvir/sofosbuvir and sofosbuvir/velpatasvir exhibited pharmacokinetic and safety profiles in healthy Chinese subjects similar to those in non-Chinese subjects in historical studies, supporting their use in the Chinese population with HCV infection. ChinaDrugTrials.org.cn identifiers: CTR20160149 (ledipasvir/sofosbuvir); CTR20160602 (sofosbuvir/velpatasvir).

Safety, Tolerability, and Pharmacokinetics of Remdesivir, An Antiviral for Treatment of COVID-19, in Healthy Subjects.

Remdesivir (RDV), a single diastereomeric monophosphoramidate prodrug that inhibits viral RNA polymerases, has potent in vitro antiviral activity against severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). RDV received the US Food and Drug Administration (FDA)'s emergency use authorization in the United States and approval in Japan for treatment of patients with severe coronavirus disease 2019 (COVID-19). This report describes two phase I studies that evaluated the safety and pharmacokinetics (PKs) of single escalating and multiple i.v. doses of RDV (solution or lyophilized formulation) in healthy subjects. Lyophilized formulation was evaluated for potential future use in clinical trials due to its storage stability in resource-limited settings. All adverse events were grade 1 or 2 in severity. Overall, RDV exhibited a linear profile following single-dose i.v. administration over 2 hours of RDV solution formulation across the dose range of 3-225 mg. Both lyophilized and solution formulations provided comparable PK parameters. High intracellular concentrations of the active triphosphate (~ 220-fold to 370-fold higher than the in vitro half-maximal effective concentration against SARS-CoV-2 clinical isolate) were achieved following infusion of 75 mg or 150 mg lyophilized formulation over 30 minutes or 2 hours. Following multiple-doses of RDV 150 mg once daily for 7 or 14 days, RDV exhibited a PK profile similar to single-dose administration. Metabolite GS-441524 accumulated ~ 1.9-fold after daily dosing. Overall, RDV exhibited favorable safety and PK profiles that supported once-daily dosing.

Additive effect of LRP8/APOER2 R952Q variant to APOE epsilon2/epsilon3/epsilon4 genotype in modulating apolipoprotein E concentration and the risk of myocardial infarction: a case-control study.

BACKGROUND: The R952Q variant in the low density lipoprotein receptor-related protein 8 (LRP8)/apolipoprotein E receptor 2 (ApoER2) gene has been recently associated with familial and premature myocardial infarction (MI) by means of genome-wide linkage scan/association studies. We were interested in the possible interaction of the R952Q variant with another established cardiovascular genetic risk factor belonging to the same pathway, namely apolipoprotein E (APOE) epsilon2/epsilon3/epsilon4 genotype, in modulating apolipoprotein E (ApoE) plasma levels and risk of MI. METHODS: In the Italian cohort used to confirm the association of the R952Q variant with MI, we assessed lipid profile, apolipoprotein concentrations, and APOE epsilon2/epsilon3/epsilon4 genotype. Complete data were available for a total of 681 subjects in a case-control setting (287 controls and 394 patients with MI). RESULTS: Plasma ApoE levels decreased progressively across R952Q genotypes (mean levels +/- SD = RR: 0.045 +/- 0.020, RQ: 0.044 +/- 0.014, QQ: 0.040 +/- 0.008 g/l; P for trend = 0.047). Combination with APOE genotypes revealed an additive effect on ApoE levels, with the highest level observed in RR/non-carriers of the E4 allele (0.046 +/- 0.021 g/l), and the lowest level in QQ/E4 carriers (0.035 +/- 0.009 g/l; P for trend = 0.010). QQ/E4 was also the combined genotype with the most significant association with MI (OR 3.88 with 95%CI 1.08-13.9 as compared with RR/non-carriers E4). CONCLUSION: Our data suggest that LRP8 R952Q variant may have an additive effect to APOE epsilon2/epsilon3/epsilon4 genotype in determining ApoE concentrations and risk of MI in an Italian population.

Four SNPs on chromosome 9p21 in a South Korean population implicate a genetic locus that confers high cross-race risk for development of coronary artery disease.

OBJECTIVE: Recent genome-wide association studies have identified 4 SNPs on chromosome 9p21 associated with CAD (rs10757274 and rs2383206) and myocardial infarction (MI: rs2383207 and rs10757278) in White populations in Northern Europe and North America. We aimed to determine whether this locus confers significant susceptibility to CAD in a South Korean population, and thus cross-race susceptibility to CAD. METHODS AND RESULTS: We performed a case-control association study with 611 unrelated CAD patients and 294 normal controls from South Korea. Allelic associations of SNPs and SNP haplotypes with CAD were evaluated. Multivariate logistic regression analysis was used to adjust effects of clinical covariates. We found that 4 SNPs on chromosome 9p21 were associated with susceptibility to CAD in a South Korean population. The association remained significant after adjusting for significant clinical covariates (P=0.001 to 0.024). We identified one risk haplotype (GGGG; P=0.017) and one protective haplotype (AAAA; P=0.007) for development of CAD. Further analysis suggested that the SNPs probably confer susceptibility to CAD in a dominance model (covariates-adjusted P=0.001 to 0.024; OR=2.37 to 1.54). This represents the first study that expands association of these 9p21 SNPs with CAD beyond White populations. CONCLUSIONS: Chromosome 9p21 is an important susceptibility locus that confers high cross-race risk for development of CAD.