Metabolism, toxicity and management of fruquintinib: a novel drug for metastatic colorectal cancer.

INTRODUCTION: Colorectal cancer (CRC) is the third most diagnosed cancer globally and despite therapeutic strides, the prognosis for patients with metastatic disease (mCRC) remains poor. Fruquintinib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) targeting VEGFR -1, -2, and -3, and has recently received approval by the U.S. Food and Drug Administration for treatment of mCRC refractory to standard chemotherapy, anti-VEGF therapy, and anti-epidermal growth factor receptor (EGFR) therapy. AREAS COVERED: This article provides an overview of the pre-clinical data, pharmacokinetics, clinical efficacy, and safety profile of fruquintinib, as well as the management of clinical toxicities associated with fruquintinib. EXPERT OPINION: Fruquintinib is a valuable additional treatment option for patients with refractory mCRC. The pivotal role of vigilant toxicity management cannot be understated. While fruquintinib offers a convenient and overall, well-tolerated treatment option, ongoing research is essential to determine its efficacy in different patient subsets, evaluate it in combination with chemotherapy and immunotherapy, and determine its role in earlier lines of therapy.

Senkyunolide A inhibits the progression of osteoarthritis by inhibiting the NLRP3 signalling pathway.

CONTEXT: Osteoarthritis (OA) is a degenerative disease. Senkyunolide A (SenA) is an important phthalide from Ligusticum chuanxiong Hort (Umbelliferae) with anti-spasmodic and neuroprotective effects. OBJECTIVE: We explored the effect of SenA on IL-1ß-stimulated chondrocytes and OA mice. MATERIALS AND METHODS: Chondrocytes were stimulated by IL-1ß (10 ng/mL) to establish an OA model in vitro. Cells were treated with SenA (20, 40, 80 and 160 µg/mL) for 48 h. The in vivo OA model was established by cutting off the medial meniscus tibial ligament (MMTL) at right knee incision of male C57BL/6 mice. One week after surgery, mice were injected with SenA (intraperitoneally one week) and divided into four groups (n = 6 per group): Sham, OA, OA + SenA 20 mg/kg and OA + SenA 40 mg/kg. The OA progression was examined by haematoxylin and eosin (H&E) staining. RESULTS: SenA treatment increased cell viability (33%), proliferation (71%), inhibited apoptosis (21%), decreased levels of catabolic marker proteins (MMP13, 23%; ADAMTS4, 31%; ADAMTS5, 19%), increased levels of anabolic marker proteins (IGF-1, 57%; aggrecan, 75%; Col2a1, 48%), reduced levels of inflammation cytokines (TNF-α, 31%; IL-6, 19%; IL-18, 20%) and decreased levels of NLRP3 (21%), ASC (20%) and caspase-1 (29%) of chondrocytes. However, NLRP3 agonist nigericin increased levels of MMP13 (55%), ADAMTS4 (70%), ADAMTS5 (53%), decreased levels of IGF-1 (36%), aggrecan (26%), Col2a1 (25%), inhibited proliferation (61%) and promoted apoptosis (76%). DISCUSSION AND CONCLUSIONS: SenA alleviates OA progression by inhibiting NLRP3 signalling pathways. These findings provide an experimental basis for the clinical application of drugs in the treatment of OA.

Mitigative Effects of PFF-A Isolated from Ecklonia cava on Pigmentation in a Zebrafish Model and Melanogenesis in B16F10 Cells.

Melanin synthesis is a defense mechanism that prevents skin damage, but excessive accumulation of melanin occurs in the skin in various reactions such as pigmentation, lentigines, and freckles. Although anti-melanogenic effects have been demonstrated for various naturally occurring marine products that inhibit and control tyrosinase activity, most studies have not been extended to in vivo applications. Phlorofucofuroeckol-A (PFF-A, 12.5-100 µM) isolated from Ecklonia cava has previously been shown to have tyrosinase-mitigative effects in B16F10 cells, but it has not been evaluated in an in vivo model, and its underlying mechanism for anti-melanogenic effects has not been studied. In the present study, we evaluated the safety and efficacy of PFF-A for anti-melanogenic effects in an in vivo model. We selected low doses of PFF-A (1.5-15 nM) and investigated their mitigative effects on pigmentation stimulated by α-MSH in vivo and their related-mechanism in an in vitro model. The findings suggest that low-dose PFF-A derived from E. cava suppresses pigmentation in vivo and melanogenesis in vitro. Therefore, this study presents the possibility that PFF-A could be utilized as a new anti-melanogenic agent in the cosmeceutical industries.

Dissection of the potential anti-diabetes mechanism of salvianolic acid B by metabolite profiling and network pharmacology.

RATIONALE: Salvianolic acid B (Sal B), the Q-marker in Salvia miltiorrhiza, was proved to present an obvious anti-diabetes effect when treated as a food intake. Until now, the metabolism feature, tissue distribution and anti-diabetes mechanism of Sal B have not been fully elucidated. METHODS: The metabolites of Sal B in rats were profiled using ultrahigh-performance liquid chromatography coupled with time-of-flight mass spectrometry. The potential anti-diabetes mechanism of Sal B was predicted by network pharmacology. RESULTS: A total of 31 metabolites were characterized in rats after ingestion of Sal B at a dosage of 40 mg/kg, including 1 in plasma, 19 in urine, 31 in feces, 0 in heart, 0 in liver, 0 in spleen, 1 in lung, 1 in kidney and 0 in brain. Among them, 18 metabolites were reported for the first time. Phase I reactions of hydrolysis, hydrogenation, dehydroxylation, hydroxylation, decarboxylation and isomerization, and phase II reactions of methylation were found in Sal B. Notably, decarboxylation and dehydroxylation were revealed in Sal B for the first time. The pharmacology network results showed that Sal B and its metabolites could regulate ALB, PLG, ACE, CASP3, MMP9, MMP2, MTOR, etc. The above targets were involved in insulin signaling pathway, PI3K-Akt signaling pathway, HIF-1 signaling pathway, TNF signaling pathway, etc. CONCLUSIONS: The metabolism feature of Sal B in vivo was systematically revealed, and its anti-diabetes mechanism for further pharmacological validations was predicted based on metabolite profiling and network pharmacology for the first time.

Salvianolic acid B and ferulic acid synergistically promote angiogenesis in HUVECs and zebrafish via regulating VEGF signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Induced vascular growth in the myocardium has been widely acknowledged as a promising intervention strategy for patients with ischemic coronary artery disease. Yet despite long-term efforts on gene, protein or cell-based pro-angiogenic therapies, the clinical translation remains challenging. Noticeably, multiple medicinal herbs have long-term documented effects in promoting blood circulation. Salvia miltiorrhiza and Ligusticum stratum are two representative traditional Chinese medicine herbs with suggested roles in enhancing organ blood supply, and Guanxinning Tablet (GXNT), a botanical drug which is formulated with these two herbs, exhibited significant efficacy against angina pectoris in clinical practices. AIM OF THE STUDY: This study aimed to examine the pro-angiogenic activity of GXNT and its major components, as well as to explore their pharmacological mechanism in promoting angiogenesis. MATERIALS AND METHODS: In vitro, the pro-angiogenic effects of GXNT and its major components were examined on human umbilical vein endothelial cells by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), scratch assay, and endothelial cell tube formation assay. In vivo, the pro-angiogenic effects were examined on the ponatinib-induced angiogenesis defective zebrafish model. The active compounds were identified through phenotype-based screening in zebrafish, and their pharmacological mechanism was explored in both in vitro and in vivo models by immunofluorescent staining, cell cycle analysis, quantitative PCR and whole embryo in-situ hybridization. RESULTS: We demonstrated strong pro-angiogenic effects of GXNT in both human umbilical vein endothelial cells and zebrafish model. Moreover, through phenotype-based screening in zebrafish for active compounds, pro-angiogenic effects was discovered for salvianolic acid B (Sal B), a major component of Salvia miltiorrhiza, and its activity was further enhanced when co-administered with ferulic acid (FA), which is contained in Ligusticum stratum. On the cellular level, Sal B and FA cotreatment increased endothelial cell proliferation of sprouting arterial intersomitic vessels in zebrafish, as well as largely restored G1-S cell cycle progression and cyclin D1 expression in angiogenic defective HUVECs. Through quantitative transcriptional analysis, increased expression of vegfr2 (kdr, kdrl) and vegfr1 was detected after GXNT or SalB/FA treatment, together with upregulated transcription of their ligands including vegf-a, vegf-b, and pgfb. Bevacizumab, an anti-human VEGF-A monoclonal antibody, was able to significantly, but not completely, block the pro-angiogenic effects of GXNT or SalB/FA, suggesting their multi-targeting properties. CONCLUSIONS: In conclusion, from a traditional Chinese medicine with effects in enhancing blood circulation, we demonstrated the synergistic pro-angiogenic effects of Sal B and FA via both in vitro and in vivo models, which function at least partially through regulating the expression of VEGF receptors and ligands. Future studies are warranted to further elaborate the molecular interaction between these two compounds and the key regulators in the process of neovascularization.

Trans-ε-Viniferin Encapsulation in Multi-Lamellar Liposomes: Consequences on Pharmacokinetic Parameters, Biodistribution and Glucuronide Formation in Rats.

Trans-ε-viniferin (εVin) is a resveratrol dimer exhibiting promising biological activities for human health. Its bioavailability being low, the development of encapsulation methods would be used to overcome this issue. The aim of this study was to measure the consequences of the encapsulation of εVin in multilamellar liposomes on its pharmacokinetic parameters, metabolism and tissue distribution in rats. After oral administration of εVin (20 mg/kg body weight), either as free or encapsulated forms, plasmas were sequentially collected (from 0 to 4 h) as well as liver, kidneys and adipose tissues (4 h after administration) and analyzed by LC-HRMS. The glucuronide metabolites (εVG) were also produced by hemisynthesis for their quantification in plasma and tissues. The encapsulation process did not significantly modify the pharmacokinetic parameters of εVin itself. However, a significant increase of the T1/2 was noticed for εVG after administration of the encapsulated form as compared to the free form. An accumulation of εVin and εVG in adipose tissues was noticed, and interestingly a significant increase of the latter in the mesenteric one after administration of the encapsulated form was highlighted. Since adipose tissues could represent storage depots, and encapsulation allows for prolonging the exposure time of glucuronide metabolites in the organism, this could be of interest to promote their potential biological activities.

Rapid and improved oral absorption of N-butylphthalide by sodium cholate-appended liposomes for efficient ischemic stroke therapy.

As a multi-target drug to treat ischemic stroke, N-butylphthalide (NBP) is extremely water-insoluble and exhibits limited oral bioavailability, impeding its wide oral application. Effective treatment of ischemic stroke by NBP requires timely and efficient drug exposure, necessitating the development of new oral formulations. Herein, liposomes containing biosurfactant sodium cholate (CA-liposomes) were systemically investigated as an oral NBP delivery platform because of its high biocompatibility and great potential for clinical applications. The optimized liposomes have a uniform hydrodynamic size of 104.30 ± 1.60 nm and excellent encapsulation efficiency (93.91 ± 1.10%). Intriguingly, NBP-loaded CA-liposomes produced rapid drug release and the cumulative release was up to 88.09 ± 4.04% during 12 h while that for NBP group was only 6.79 ± 0.99%. Caco-2 cell monolayer assay demonstrated the superior cell uptake and transport efficiency of NBP-loaded CA-liposomes than free NBP, which was mediated by passive diffusion via transcellular and paracellular routes. After oral administration to rats, NBP-loaded CA-liposomes exhibited rapid and almost complete drug absorption, with a tmax of 0.70 ± 0.14 h and an absolute bioavailability of 92.65% while NBP suspension demonstrated relatively low bioavailability (21.7%). Meanwhile, NBP-loaded CA-liposomes produced 18.30-fold drug concentration in the brain at 5 min compared with NBP suspension, and the brain bioavailability increased by 2.48-fold. As expected, NBP-loaded CA-liposomes demonstrated significant therapeutic efficacy in a middle cerebral artery occlusion rat model. Our study provides new insights for engineering oral formulations of NBP with fast and sufficient drug exposure against ischemic stroke in the clinic.

Synthetic Aurones: New Features for Schistosoma mansoni Therapy.

In this work, two synthetic aurones revealed moderate schistosomicidal potential in in vitro and in vivo assays. Aurones (1) and (2) promoted changes in tegument integrity and motor activity, leading to death of adult Schistosoma mansoni worms in in vitro assays. When administered orally (two doses of 50 mg/kg) in experimentally infected animals, synthetic aurones (1) and (2) promoted reductions of 56.20 % and 57.61 % of the parasite load and stimulated the displacement towards the liver of the remaining adult worms. The oogram analysis revealed that the treatment with both aurones interferes with the egg development kinetics in the intestinal tissue. Seeking an action target for compounds (1) and (2), the connection with NTPDases enzymes, recognized as important therapeutic targets for S. mansoni, was evaluated. Molecular docking studies have shown promising results. The dataset reveals the anthelmintic character of these compounds, which can be used in the development of new therapies for schistosomiasis.

Rational formulation engineering of fraxinellone utilizing 6-O-α-D-maltosyl-ß-cyclodextrin for enhanced oral bioavailability and hepatic fibrosis therapy.

Although Fraxinellone (Frax) isolated from Dictamnus albus L. possessed excellent anti-hepatic fibrosis activity, oral administration of Frax suffered from the inefficient therapeutic outcome in vivo due to negligible oral absorption. At present, the oral formulation of Frax is rarely exploited. For rational formulation design, we evaluated preabsorption risks of Frax and found that Frax was rather stable while poorly dissolved in the gastrointestinal tract (78.88 µg/mL), which predominantly limited its oral absorption. Further solubility test revealed the outstanding capacity of cyclodextrin derivatives (CDs) to solubilize Frax (6.8-12.8 mg/mL). This led us to study the inclusion complexes of Frax with a series of CDs and holistically explore their drug delivery performance. Characterization techniques involving 1H-NMR, FT-IR, DSC, PXRD, and molecular docking confirmed the most stable binding interactions when Frax complexed with 6-O-α-D-maltosyl-ß-cyclodextrin (G2-ß-CD-Frax). Notably, G2-ß-CD-Frax exhibited the highest solubilizing capacity, fast dissolution rate, and superior Caco-2 cell internalization with no obvious toxicity. Pharmacokinetic studies demonstrated markedly higher oral bioavailability of G2-ß-CD-Frax (5.8-fold that of free drug) than other Frax-CDs. Further, long-term administration of G2-ß-CD-Frax (5 mg/kg) efficiently inhibited CCl4-induced hepatic fibrosis in the mouse without inducing any toxicity. Our results will inspire the continued advancement of optimal oral Frax formulations for anti-fibrotic therapy.

Combination of tetrandrine and 3-n-butylphthalide protects against cerebral ischemia-reperfusion injury via ATF2/TLR4 pathway.

OBJECTIVE: Cerebral infarction (CI) is the mayor reason of death in China. Reperfusion is the only immediate treatment for acute cerebral infarction. However, blood reperfusion recovery may cause ischemia-reperfusion (I/R) injuries. The purpose of this study was to investigate the effects of Tetrandrine (TTD) and 3-n-Butylphthalide (NBP) on cerebral I/R injury. MATERIALS AND METHODS: I/R was used to establish CI model in vivo. TTD was performed to analyze cerebral infarction volume. OGD was applied to establish CI model in vitro. Flow cytometry and TUNEL assays were utilized to determine the cell death. ELISA was conducted to determine the release of cytokines. mRNA and protein expressions were detected using qRT-PCR and western blot. RESULTS: We found that NBP + TTD treatment significantly reduced cerebral infarction volume and inhibited the death of neurons in vivo. Moreover, NBP + TTD treatment suppressed the apoptosis and inflammatory response of neurons in vitro. Additionally, NBP + TTD suppressed the expression of activator transcription factor 2 (ATF2). However, overexpression of ATF2 contributed to the degeneration of neurons. Moreover, ATF2 transcriptionally activated Toll-like receptor 4 (TLR4). NBP + TTD inactivated ATF2/TLR4 signaling. CONCLUSIONS: Taken together, TTD combined with NBP protected against cerebral infarction by inhibiting the inflammatory response and neuronal cell apoptosis via inactivating ATF2/TLR4 signaling pathways. This may provide an alternative for I/R injury.

Absorption, distribution, metabolism, and excretion of [14C]NBP (3-n-butylphthalide) in rats.

3-n-Butylphthalide (NBP) has a considerable neuroprotective effect and is currently used for the treatment of ischemic stroke. NBP was launched on the market in 2004. However, information on its metabolism in humans and preclinical animal models is insufficient. Although the metabolism of unradiolabeled NBP in humans has been reported, the quantitative metabolite profile, blood-to-plasma radioactivity concentration ratio (B/P), and tissue distribution of this drug remain unclear. We evaluated the pharmacokinetics, tissue distribution, mass balance, and metabolism of NBP in rats after a single oral dose of 60 mg/kg (100 µCi/kg) [14C]NBP to understand the biotransformation of NBP comprehensively and to provide preclinical drug metabolism data prior to human mass balance studies with [14C]NBP in the near future. NBP absorption was rapid (Tmax = 0.75 h) and declined with a terminal half-life of 9.73 h. In rats, the B/P was 0.63 during the 48 h postdose period, indicating that drug-related substances did not tend to be distributed into blood cells. Tissue distribution was determined by using the oxidative combustion method. NBP-related components were widely distributed throughout the body, and high concentrations were detected in the stomach, small intestine, fat, bladder, kidney, liver and ovary. At 168 h after oral administration, the mean cumulative recovered radioactivity was 99.85% of the original dose, and was 85.12% in urine and 14.73% in feces. Metabolite profiles were detected via radiochromatography. A total of 49 metabolites were identified in rat plasma, urine, and feces. The main metabolic pathways were oxidation, glucuronidation, and sulfation. Overall, NBP was absorbed rapidly, distributed throughout the body, and excreted in the form of metabolites. Urine was the main excretion route, and the absorption, distribution, metabolism and excretion of NBP showed no significant gender difference between male and female rats.

Dieckol Decreases Caloric Intake and Attenuates Nonalcoholic Fatty Liver Disease and Hepatic Lymphatic Vessel Dysfunction in High-Fat-Diet-Fed Mice.

Increased inflammation is the main pathophysiology of nonalcoholic fatty liver disease (NAFLD). Inflammation affects lymphatic vessel function that contributes to the removal of immune cells or macromolecules. Dysfunctional lymphatic vessels with decreased permeability are present in NAFLD. High-fat diet (HFD) is known to increase body weight, food intake, and inflammation in the liver. Previously, it was reported that Ecklonia cava extracts (ECE) decreased food intake or weight gain, and low-calorie diet and weight loss is known as a treatment for NAFLD. In this study, the effects of ECE and dieckol (DK)-which is one component of ECE that decreases inflammation and increases lymphangiogenesis and lymphatic drainage by controlling lymphatic permeability in high-fat diet (HFD)-fed mice-on weight gain and food intake were investigated. ECE and DK decreased weight gain and food intake in the HFD-fed mice. NAFLD activities such as steatosis, lobular inflammation, and ballooning were increased by HFD and attenuated by ECE and DK. The expression of inflammatory cytokines such as IL-6 and TNF-α and infiltration of M1 macrophages were increased by HFD, and they were decreased by ECE or DK. The signaling pathways of lymphangiogenesis, VEGFR-3, PI3K/pAKT, and pERK were decreased by HFD, and they were restored by either ECE or DK. The expression of VE-cadherin (which represents lymphatic junctional function) was increased by HFD, although it was restored by either ECE or DK. In conclusion, ECE and DK attenuated NAFLD by decreasing weight gain and food intake, decreasing inflammation, and increasing lymphangiogenesis, as well as modulating lymphatic vessel permeability.

A Pragmatic, Randomized Controlled Trial of Oral Antivirals for the Treatment of Chronic Hepatitis C: The PRIORITIZE Study.

BACKGROUND AND AIMS: Multiple direct-acting antiviral (DAA) regimens are available to treat HCV genotype 1 infection. However, comparative effectiveness from randomized controlled trials of DAA regimens is unavailable. APPROACH AND RESULTS: We conducted a pragmatic randomized controlled trial (NCT02786537) to compare the effectiveness of DAAs for HCV genotype 1a or 1b on viral response, safety, tolerability, and medication nonadherence. Adults with compensated liver disease, HCV genotype 1, not pregnant or breastfeeding, and with health insurance likely to cover ledipasvir/sofosbuvir (LDV/SOF) were recruited from 34 US viral hepatitis clinics. Participants were randomized (± ribavirin) to LDV/SOF, elbasvir/grazoprevir (EBR/GZR), and paritaprevir/ritonavir/ombitasvir+dasabuvir (PrOD; treatment arm stopped early). Primary outcomes included sustained viral response at 12 weeks (SVR12), clinician-recorded adverse events, patient-reported symptoms, and medication nonadherence. Between June 2016 and March 2018, 1,609 participants were randomized. Among 1,128 participants who received ≥1 dose of EBR/GZR or LDV/SOF (± ribavirin), SVR12 was 95.2% (95% CI, 92.8%-97.6%) and 97.4% (95% CI, 95.5%-99.2%), respectively, with a difference estimate of 2.2% (-0.5% to 4.7%), falling within the "equivalence" interval (-5% to 5%). While most (56%) participants experienced adverse events, few were serious (4.2%) or severe (1.8%). In the absence of ribavirin, discontinuations due to adverse events were rare. Patient-reported symptoms and medication nonadherence were similar. Study limitations were dropout due to insurance denial and loss to follow-up after treatment, limiting the ability to measure SVR12. CONCLUSIONS: This pragmatic trial demonstrated high SVR12 for participants treated with EBR/GZR and LDV/SOF with few adverse effects. Overall, the two regimens were equivalent in effectiveness. The results support current HCV guidelines that do not distinguish between ribavirin-free EBR/GZR and LDV/SOF.

Pharmacokinetics, Tolerability and Pharmacogenetics of DA-8031 After Multiple Ascending Doses in Healthy Male Subjects.

PURPOSE: DA-8031 is a novel selective serotonin reuptake inhibitor for the treatment of premature ejaculation. This study investigated the pharmacokinetics, safety and tolerability of multiple oral doses of DA-8031. In addition, a genetic analysis was explored to evaluate the effect of genetic polymorphisms on the pharmacokinetics of DA-8031. SUBJECTS AND METHODS: A dose block-randomized, double-blind, placebo-controlled study was conducted in 3 dose groups with 20, 30 and 40 mg of DA-8031. Healthy male subjects were randomized to DA-8031 or placebo at a 4:1 ratio in each dose group of 10 subjects by oral administration once daily for 7 consecutive days. Serial blood and urine samples were collected for the pharmacokinetic evaluation, and the pharmacokinetic-related genes were analyzed by DMETTM plus. A safety evaluation was conducted including adverse events (AEs) monitoring and 12-lead electrocardiogram (ECG). RESULTS: The plasma DA-8031 concentration reached the maximum concentration (Cmax) in 2.2 to 3.0 h and was eliminated with a mean half-life of 25.5 to 26.7 h at steady state. The accumulation index of DA-8031 ranged 2.3 to 2.8. The systemic exposure of DA-8031 of the CYP2D6 intermediate metabolizer (IM) was significantly higher compared to the CYP2D6 poor metabolizer (PM). There were no clinically significant QTc interval changes, and all the adverse events were mild. CONCLUSION: After multiple oral doses of DA-8031 20, 30, and 40 mg in this study, the systemic exposure of DA-8031 increased in a more than dose-proportional manner with the increasing doses, and DA-8031 was generally well tolerated. In addition, the genetic polymorphisms of CYP2D6 have an impact on the pharmacokinetics of DA-8031.

L-3-n-butylphthalide promotes restoration after an experimental animal model of intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is a devastating type of stroke with high morbidity and mortality, and the effective therapies for ICH remain to be explored. L-3-n-butylphthalide (NBP) is widely used in the treatment of ischemic stroke. However, few studies evaluated the therapeutic effects of NBP on ICH. Therefore, the present study aims to evaluate the effects of NBP on ICH and its potential mechanism. The rats were randomly divided into sham-operated group, saline-treated (ICH + saline) group, and NBP-treated (ICH + NBP) group. The ICH model of SD rats induced by IV collagenase was established. The modified Garcia JH score was used to detect the neurological deficit in rats. Western Blot and immunohistochemistry analysis was applied to test the levels of UBIAD1 and caspase-3 expressions in the perihematomal region. The rates of apoptotic cells were detected by TUNEL staining. The results showed that NBP up-regulated the expression of UBIAD1, reduced the apoptotic cells in the perihematomal region, and improved the neurological deficit. Taken together, our study added some new evidence to the application of NBP in ICH treatment.

Napabucasin Drug-Drug Interaction Potential, Safety, Tolerability, and Pharmacokinetics Following Oral Dosing in Healthy Adult Volunteers.

Napabucasin is an orally administered reactive oxygen species generator that is bioactivated by the intracellular antioxidant nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1. Napabucasin induces cell death in cancer cells, including cancer stem cells. This phase 1 study (NCT03411122) evaluated napabucasin drug-drug interaction potential for 7 cytochrome P450 (CYP) enzymes and the breast cancer resistance protein transporter/organic anion transporter 3. Healthy volunteers who tolerated napabucasin during period 1 received probe drugs during period 2, and in period 3 received napabucasin (240 mg twice daily; days 1-11) plus a phenotyping cocktail containing omeprazole (CYP2C19), caffeine (CYP1A2), flurbiprofen (CYP2C9), bupropion (CYP2B6), dextromethorphan (CYP2D6), midazolam (CYP3A) (all oral; day 6), intravenous midazolam (day 7), repaglinide (CYP2C8; day 8), and rosuvastatin (breast cancer resistance protein/organic anion transporter 3; day 9). Drug-drug interaction potential was evaluated in 17 of 30 enrolled volunteers. Napabucasin coadministration increased the area under the plasma concentration-time curve from time 0 extrapolated to infinity (geometric mean ratio [90% confidence interval]) of caffeine (124% [109.0%-141.4%]), intravenous midazolam (118% [94.4%-147.3%]), repaglinide (127% [104.7%-153.3%]), and rosuvastatin (213% [42.5%-1068.3%]) and decreased the area under the plasma concentration-time curve from time 0 extrapolated to infinity of dextromethorphan (71% [47.1%-108.3%]), bupropion (79% [64.6%-97.0%]), and hydroxybupropion (45% [15.7%-129.6%]). No serious adverse events/deaths were reported. Generally, napabucasin is not expected to induce/inhibit drug clearance to a clinically meaningful degree.

Gene Expression Signature Correlates with Outcomes in Metastatic Renal Cell Carcinoma Patients Treated with Everolimus Alone or with a Vascular Disrupting Agent.

Everolimus monotherapy use for metastatic renal cell carcinoma (mRCC) has diminished due to recent approvals of immune checkpoint and VEGF inhibitors. We hypothesized that gene expression associated with everolimus benefit may provide rationale to select appropriate patients. To address this hypothesis, tumors from a phase I/II trial that compared everolimus alone or with BNC105P, a vascular disrupting agent, were profiled using Nanostring as a discovery cohort. A phase III trial (CheckMate 025) was used for validation. Clinical benefit (CB) was defined as response or stable disease for ≥6 months. A propensity score covariate adjustment was used, and model discrimination performance was assessed using the area under the ROC curve (AUC). In a discovery cohort of 82 patients, 35 (43%) were treated with everolimus alone and 47 (57%) received everolimus + BNC105P. Median PFS (mPFS) was 4.9 (95% CI, 2.8-6.2) months. A four-gene signature (ASXL1, DUSP6, ERCC2, and HSPA6) correlated with CB with everolimus ± BNC105P [AUC, 86.9% (95% CI, 79.2-94.7)]. This was validated in 130 patients from CheckMate 025 treated with everolimus [AUC, 60.2% (95% CI, 49.7-70.7)]. Among 43 patients (52.4%) with low expression of an 18-gene signature, everolimus + BNC105P was associated with significantly longer mPFS compared with everolimus alone (10.4 vs. 6.9 months; HR, 0.49; 95% CI, 0.24-1.002; P = 0.047). These signatures warrant further validation to select patients who may benefit from everolimus alone or with a vascular disrupting agent.

Senkyunolide I attenuates hepatic ischemia/reperfusion injury in mice via anti-oxidative, anti-inflammatory and anti-apoptotic pathways.

BACKGROUND: Senkyunolide I (SEI)exerts considerable protective effects in various disease models, but its effect on hepatic ischemia-reperfusion (I/R) injury remains unknown. This research aimed to investigate the effect of SEI in a murine model of hepatic I/R injury. METHODS: With modified liver I/R murine model, low, medium and high doses of SEI were injected intraperitoneally after operation. After 6 h of reperfusion, the blood and liver were collected. Serum ALT and AST were detected by automatic analyzer, while liver injury was evaluated by HE staining. High-dose SEI was selected to further explore its impacts on oxidative stress, inflammatory responses and apoptosis induced by hepatic I/R. The pharmacological effect of SEI was also compared with a positive control, glutathione (GSH). We used ELISA to detect serum TNF-α, IL-1 ß and IL-6, special kit to explore activities of SOD and GSH-Px, and the content of MDA, and western blotting to detect HO-1, Bax and Bcl-2 levels, and to perceive expressions and phosphorylations of NF- κB p65 and p38/ERK/JNK in liver tissues. Apoptosis in liver tissue was evaluated by TUNEL. The antioxidative effect of SEI was further investigated using the HuCCT1 cells stimulated with H2O2 and the role of SEI on regulation of Nrf-2/HO-1 was determined. RESULTS: 200 mg/kg of SEI was optimal dose for treating liver I/R injury. Elevated ALT, AST and histopathological injury in I/R liver was attenuated by SEI administration, similarly to GSH. Serum TNF-α, IL-1ß, and IL-6 were reduced in liver I/R mice treated with SEI, and in liver tissues, phosphorylation of p65 NF-κB and MAPK kinases (p38, ERK, JNK), were inhibited. SEI reduced the MDA content, but increased HO-1 level and enhanced SOD and GSH-Px activities. Apoptosis of liver tissues was decreased, while SEI inhibited Bax and elevated Bcl-2 expression. In in vitro experiments, H2O2 reduced the survival rate of HuCCT1 cells, which was protected by SEI administration. SEI reduced the ROS and MDA content. The transportation of Nrf-2 into the nucleus was enhanced and HO-1 expression was upregulated. CONCLUSIONS: SEI attenuates hepatic I/R injury in mice via anti-oxidative, anti-inflammatory and anti-apoptotic pathways.

Elbasvir/grazoprevir administered for 12 weeks via percutaneous endoscopic gastrostomy tube achieves sustained virologic response: A case report and a review of the literature.

Enteral tubes are necessary for certain patients; however, medication absorption can be affected by this route of administration potentially resulting in decreased efficacy. All first-line treatments for Hepatitis C Virus (HCV) infection are only available as tablets and may have decreased absorption if administered via an enteral tube. This report describes the first case of a pegylated interferon and ribavirin treatment-experienced patient who successfully achieved HCV cure after 12 weeks of elbasvir/grazoprevir administered via percutaneous gastrostomy tube. We further review the available pharmacokinetic and clinical literature regarding administration via enteral feeding tubes for all first-line direct-acting antivirals (DAAs). The literature suggests that crushed administration can be considered for DAAs in patients with gastric access. However, caution should be exercised in patients with extragastric enteral tubes and in those with altered gastrointestinal tract anatomy.

Synthesis and biological evaluation of novel 18F-labeled phenylbenzofuran-2-carboxamide derivative for detection of orexin 1 receptor in the brain.

Although the orexin 1 receptor (OX1R) in the brain is considered to regulate reward and feeding, the in vivo function of OX1R has not been fully elucidated. In vivo imaging of OX1R with positron emission tomography (PET) may be useful to further understand the molecular details of OX1R. In this study, we newly designed and synthesized a phenylbenzofuran-2-carboxamide (PBC) derivative ([18F]PBC-1) and evaluated its utility as a PET probe targeting OX1R in the brain. The results of cell binding assays suggested that [18F]PBC-1 has affinity for OX1R. In an in vitro competitive inhibition assay, PBC-1 showed selective binding affinity for OX1R (IC50 = 19.5 nM) over orexin 2 receptor (IC50 = 456.7 nM). Furthermore, [18F]PBC-1 displayed sufficient brain uptake for in vivo imaging with PET in a biodistribution study using normal mice, but in vivo instability was observed. These results suggest that further modifications for improvement of the pharmacokinetics are needed, but the PBC scaffold has potential for the development of useful PET probes targeting OX1R in the brain.