Polyethlyene Glycol 200 Can Protect Rats Against Drug-Induced Kidney Toxicity Through Inhibition of the Renal Organic Anion Transporter 3.

MK-7680, a cyclic nucleotide prodrug, caused significant kidney tubule injury in female rats when administered orally at 1000 mg/kg/day for 2 weeks using 10% Polysorbate 80 as vehicle. However, kidney injury was absent when MK-7680 was administered at the same dose regimen using 100% Polyethylene Glycol 200 (PEG 200) as the vehicle. Subsequent investigations revealed that MK-7680 triphosphate concentrations in kidney were much lower in rats treated with MK-7680 using PEG 200 compared with 10% Polysorbate 80 vehicle, whereas plasma exposures of MK-7680 prodrug were similar. In vitro studies demonstrated that PEG 200 is an inhibitor of human renal uptake transporter organic anion transporter 3 (OAT3), of which MK-7680 is a substrate. Furthermore, PEG 200 and PEG 400 were found to interfere in vitro with human renal transporters OAT3, organic cation transporter (OCT) 2, multidrug resistance-associated protein (MRP) 2 and 4, and multidrug and toxin extrusion protein (MATE) 1 and 2K, but not OAT1. These results support a conclusion that PEG 200 may prevent MK-7680-induced kidney injury by inhibiting its active uptake into proximal tubular cells by OAT3. Caution should be exercised therefore when using PEGs as vehicles for toxicity assessment for compounds that are substrates of renal transporters.

Role of transporters in the disposition of a novel ß-lactamase inhibitor: relebactam (MK-7655).

OBJECTIVES: To identify the transporters involved in renal elimination of relebactam, and to assess the potential of relebactam as a perpetrator or victim of drug-drug interactions (DDIs) for major drug transporters. METHODS: A series of bidirectional transport, uptake and inhibition studies were conducted in vitro using transfected cell lines and membrane vesicles. The inhibitory effects of relebactam on major drug transporters, as well as the inhibitory effects of commonly used antibiotics/antifungals on organic anion transporter (OAT) 3-mediated uptake of relebactam, were assessed. RESULTS: Relebactam was shown to be a substrate of OAT3, OAT4, and multidrug and toxin extrusion (MATE) proteins MATE1 and MATE2K. Relebactam did not show profound inhibition across a panel of transporters, including organic anion-transporting polypeptides 1B1 and 1B3, OAT1, OAT3, organic cation transporter 2, MATE1, MATE2K, breast cancer resistance protein, multidrug resistance protein 1 and the bile salt export pump. Among the antibiotics/antifungals assessed for potential DDIs, probenecid demonstrated the most potent in vitro inhibition of relebactam uptake; however, such in vitro data did not translate into clinically relevant DDIs, suggesting that relebactam can be co-administered with OAT inhibitors, such as probenecid. CONCLUSIONS: Overall, relebactam has low potential to be a victim or perpetrator of DDIs with major drug transporters.

Use of Emotional Intelligence to Enhance Advanced Practice Registered Nursing Competencies.

BACKGROUND: Interpersonal relationships are fundamental to competent delivery of health care. Nursing practice is grounded in interpersonal relationships, making advanced practice registered nurses (APRNs) well prepared to ensure the delivery of safe, effective care. Research demonstrates interpersonal dynamics can be enhanced. Emotional intelligence (EI) is the ability to perceive, understand, manage, and use emotions in self and others, and it comprises a key factor in interpersonal relationships. METHOD: APRN education is grounded in the Quality and Safety Education for Nurses and master's Essentials competencies. This analysis provides a framework to align APRN professional competencies with EI competencies to enhance leadership, communication, and teamwork in health care teams. RESULTS: By using the matrix of EI and APRN competencies provided, nurse educators may implement learning strategies to improve EI and support APRN competencies. CONCLUSION: Well-educated and emotionally intelligent APRNs can enhance cooperation in multidisciplinary teams, promote better communication, and demonstrate APRN leadership to improve patient outcomes. [J Nurs Educ. 2018;57(11):648-654.].

Overcoming Time-Dependent Inhibition (TDI) of Cytochrome P450 3A4 (CYP3A4) Resulting from Bioactivation of a Fluoropyrimidine Moiety.

Herein we describe structure-activity relationship (SAR) and metabolite identification (Met-ID) studies that provided insight into the origin of time-dependent inhibition (TDI) of cytochrome P450 3A4 (CYP3A4) by compound 1. Collectively, these efforts revealed that bioactivation of the fluoropyrimidine moiety of 1 led to reactive metabolite formation via oxidative defluorination and was responsible for the observed TDI. We discovered that substitution at both the 4- and 6-positions of the 5-fluoropyrimidine of 1 was necessary to ameliorate this TDI as exemplified by compound 19.

MK-8353: Discovery of an Orally Bioavailable Dual Mechanism ERK Inhibitor for Oncology.

The emergence and evolution of new immunological cancer therapies has sparked a rapidly growing interest in discovering novel pathways to treat cancer. Toward this aim, a novel series of pyrrolidine derivatives (compound 5) were identified as potent inhibitors of ERK1/2 with excellent kinase selectivity and dual mechanism of action but suffered from poor pharmacokinetics (PK). The challenge of PK was overcome by the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 7. Lead optimization through focused structure-activity relationship led to the discovery of a clinical candidate MK-8353 suitable for twice daily oral dosing as a potential new cancer therapeutic.

Ionic solutions of two-dimensional materials.

Strategies for forming liquid dispersions of nanomaterials typically focus on retarding reaggregation, for example via surface modification, as opposed to promoting the thermodynamically driven dissolution common for molecule-sized species. Here we demonstrate the true dissolution of a wide range of important 2D nanomaterials by forming layered material salts that spontaneously dissolve in polar solvents yielding ionic solutions. The benign dissolution advantageously maintains the morphology of the starting material, is stable against reaggregation and can achieve solutions containing exclusively individualized monolayers. Importantly, the charge on the anionic nanosheet solutes is reversible, enables targeted deposition over large areas via electroplating and can initiate novel self-assembly upon drying. Our findings thus reveal a unique solution-like behaviour for 2D materials that enables their scalable production and controlled manipulation.

Discovery of the 3-Imino-1,2,4-thiadiazinane 1,1-Dioxide Derivative Verubecestat (MK-8931)-A ß-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor for the Treatment of Alzheimer's Disease.

Verubecestat 3 (MK-8931), a diaryl amide-substituted 3-imino-1,2,4-thiadiazinane 1,1-dioxide derivative, is a high-affinity ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor currently undergoing Phase 3 clinical evaluation for the treatment of mild to moderate and prodromal Alzheimer's disease. Although not selective over the closely related aspartyl protease BACE2, verubecestat has high selectivity for BACE1 over other key aspartyl proteases, notably cathepsin D, and profoundly lowers CSF and brain Aß levels in rats and nonhuman primates and CSF Aß levels in humans. In this annotation, we describe the discovery of 3, including design, validation, and selected SAR around the novel iminothiadiazinane dioxide core as well as aspects of its preclinical and Phase 1 clinical characterization.

The BACE1 inhibitor verubecestat (MK-8931) reduces CNS ß-amyloid in animal models and in Alzheimer's disease patients.

ß-Amyloid (Aß) peptides are thought to be critically involved in the etiology of Alzheimer's disease (AD). The aspartyl protease ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of Aß, and BACE1 inhibition is thus an attractive target for the treatment of AD. We show that verubecestat (MK-8931) is a potent, selective, structurally unique BACE1 inhibitor that reduced plasma, cerebrospinal fluid (CSF), and brain concentrations of Aß40, Aß42, and sAPPß (a direct product of BACE1 enzymatic activity) after acute and chronic administration to rats and monkeys. Chronic treatment of rats and monkeys with verubecestat achieved exposures >40-fold higher than those being tested in clinical trials in AD patients yet did not elicit many of the adverse effects previously attributed to BACE inhibition, such as reduced nerve myelination, neurodegeneration, altered glucose homeostasis, or hepatotoxicity. Fur hypopigmentation was observed in rabbits and mice but not in monkeys. Single and multiple doses were generally well tolerated and produced reductions in Aß40, Aß42, and sAPPß in the CSF of both healthy human subjects and AD patients. The human data were fit to an amyloid pathway model that provided insight into the Aß pools affected by BACE1 inhibition and guided the choice of doses for subsequent clinical trials.

Structure-Based Design of an Iminoheterocyclic ß-Site Amyloid Precursor Protein Cleaving Enzyme (BACE) Inhibitor that Lowers Central Aß in Nonhuman Primates.

We describe successful efforts to optimize the in vivo profile and address off-target liabilities of a series of BACE1 inhibitors represented by 6 that embodies the recently validated fused pyrrolidine iminopyrimidinone scaffold. Employing structure-based design, truncation of the cyanophenyl group of 6 that binds in the S3 pocket of BACE1 followed by modification of the thienyl group in S1 was pursued. Optimization of the pyrimidine substituent that binds in the S2'-S2″ pocket of BACE1 remediated time-dependent CYP3A4 inhibition of earlier analogues in this series and imparted high BACE1 affinity. These efforts resulted in the discovery of difluorophenyl analogue 9 (MBi-4), which robustly lowered CSF and cortex Aß40 in both rats and cynomolgus monkeys following a single oral dose. Compound 9 represents a unique molecular shape among BACE inhibitors reported to potently lower central Aß in nonrodent preclinical species.

A model to develop nurse leaders for rural practice.

Rural health disparities are due in part to access barriers to health care providers. Nursing education has been extended into rural areas, yet a limited rural research and practice literature informs the content and delivery of these educational programs. The University Of Virginia School of Nursing through a grant from the Health Resources and Services Administration developed the Nursing Leadership in Rural Health Care (NLRHC) Program. The transformational nursing leadership in rural health care (TNLRHC) model guided the development of NLRHC program content and teaching methods. This article describes the TNLRHC model and how it has steered the integration of rural content into advanced practice nursing (APN) education. The capacity of the TNLRHC model for promoting innovation in APN education is described. Recommendations regarding the future development of APN education are presented.

The new Intragroup Conflict Scale: testing and psychometric properties.

BACKGROUND AND PURPOSE: The importance of healthy work environments has received attention. Health care organizations are plagued with conflict which is detrimental to work environments. Thus, conflict must be studied. The purpose of this article is to describe the testing of a measure of conflict. METHODS: A survey was used to evaluate the psychometric properties. The sample consisted of 430 nurses at an academic medical center. RESULTS: Using principal component analysis (PCA) with varimax rotation, a six-factor solution (30 items) that explained 74.3% of variance emerged. Coefficient alpha ranged from .95 to .81. Correlations with existing scales supported construct validity (r = -.32(-)-.58). CONCLUSIONS: The results are encouraging. Use of the scale may provide insight into the impact of conflict on patient, staff, and organizational outcomes.

The discovery of N-((2H-tetrazol-5-yl)methyl)-4-((R)-1-((5r,8R)-8-(tert-butyl)-3-(3,5-dichlorophenyl)-2-oxo-1,4-diazaspiro[4.5]dec-3-en-1-yl)-4,4-dimethylpentyl)benzamide (SCH 900822): a potent and selective glucagon receptor antagonist.

A novel series of spiroimidazolone-based antagonists of the human glucagon receptor (hGCGR) has been developed. Our efforts have led to compound 1, N-((2H-tetrazol-5-yl)methyl)-4-((R)-1-((5r,8R)-8-(tert-butyl)-3-(3,5-dichlorophenyl)-2-oxo-1,4-diazaspiro[4.5]dec-3-en-1-yl)-4,4-dimethylpentyl)benzamide (SCH 900822), a potent hGCGR antagonist with exceptional selectivity over the human glucagon-like peptide-1 receptor. Oral administration of 1 lowered 24 h nonfasting glucose levels in imprinting control region mice on a high fat diet with diet-induced obesity following single oral doses of 3 and 10 mg/kg. Furthermore, compound 1, when dosed orally, was found to decrease fasting blood glucose at 30 mg/kg in a streptozotocin-treated, diet-induced obesity mouse pharmacodynamic assay and blunt exogenous glucagon-stimulated glucose excursion in prediabetic mice.

Successful treatment of recurrent primary sclerosing cholangitis after orthotopic liver transplantation with oral vancomycin.

Primary sclerosing cholangitis (PSC) is a progressive, cholestatic disease of the liver that is marked by inflammation of the bile ducts and damage to the hepatic biliary tree. Approximately 60-70% of patients also have inflammatory bowel disease and progression of PSC can lead to ulcerative colitis and cirrhosis of the liver. Due to limited understanding of the etiology and mechanism of PSC, the only existing treatment option is orthotopic liver transplantation (OLT); however, recurrence of PSC, after OLT is estimated to be between 5% and 35%. We discuss the successful treatment of a pediatric patient, with recurrent PSC, after OLT with oral Vancomycin.

Immunomodulatory effect of vancomycin on Treg in pediatric inflammatory bowel disease and primary sclerosing cholangitis.

Vancomycin has been shown to affect tumor necrosis factor-alpha (TNF-α) pathways as an immunomodulator; this is thought to be separate from its function as an antibiotic [1]. Previous studies have shown that oral vancomycin (OV) is an effective treatment for concomitant primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) in children [2, 3]. Since both diseases are associated with immune dysfunction, we hypothesized that vancomycin's therapeutic effect in IBD and PSC occurs through immunomodulation. Therefore, we examined the in vivo immunological changes that occur during OV treatment of 14 children with PSC and IBD. Within 3 months of OV administration, peripheral gamma-glutamyl transpeptidase (GGT) and alanine aminotransferase (ALT) concentrations, white blood cell (WBC) counts, and neutrophil counts normalized from elevated levels before treatment. Patients also demonstrated improved biliary imaging studies, liver biopsies and IBD symptoms and biopsies. Additionally, plasma transforming growth factor beta (TGF-ß) levels were increased without concurrent shifts in Th1-or Th2-associated cytokine production. Peripheral levels of CD4 + CD25hiCD127lo and CD4 + FoxP3+ regulatory T (Treg) cells also increased in OV-treated PSC + IBD patients compared to pretreatment levels. A unique case study shows that the therapeutic effects of OV in the treatment of PSC + IBD do not always endure after OV discontinuation, with relapse of PSC associated with a decrease in blood Treg levels; subsequent OV retreatment was then associated with a rise in blood Treg levels and normalization of liver function tests (LFTs). Taken together, these studies support immune-related pathophysiology of PSC with IBD, which is responsive to OV.

Participant anxiety and presence of hyperfunction in stroboscopy.

OBJECTIVE: Excessive supraglottic and abnormal fine vibratory characteristics associated with vocal hyperfunction are identified even in individuals with normal laryngeal structure, function and vocal quality when they undergo stroboscopy, possibly due to anxiety. The purpose of this study is to (a) test for vocal hyperfunction in individuals with normal laryngeal structure and function and if present, (b) to track changes in vocal hyperfunction associated with anxiety when stroboscopy is repeated within 24-48 h. PARTICIPANTS AND METHODS: Thirty participants, naïve to stroboscopy, underwent the procedure and completed the State-Trait Anxiety Inventory 3 times over 24-48 h. RESULTS: 41.4% of participants demonstrated vocal hyperfunction in supraglottic and fine vibratory characteristics after the first trial. Vocal hyperfunction decreased to 27.6% after the third trial. RESULTS showed a significant main effect of time indicating that vocal hyperfunction decreased as participants repeated stroboscopy. Although the average anxiety score decreased across trials, state (anxiety) had no significant effect on change in vocal hyperfunction. CONCLUSIONS: In the real world, true representation of vocal function can be achieved by getting a patient acquainted to the presence of strobe in the oral cavity and practice the tasks that will be attempted during the procedure without introducing vocal hyperfunction and most importantly, without the use of a topical anesthetic.

Pathways involved in the synergistic activation of macrophages by lipoteichoic acid and hemoglobin.

Lipoteichoic acid (LTA) is a Gram-positive cell surface molecule that is found in both a cell-bound form and cell-free form in the host during an infection. Hemoglobin (Hb) can synergize with LTA, a TLR2 ligand, to potently activate macrophage innate immune responses in a TLR2- and TLR4-dependent way. At low levels of LTA, the presence of Hb can result in a 200-fold increase in the secretion of IL-6 following macrophage activation. Six hours after activation, the macrophage genes that are most highly up-regulated by LTA plus Hb activation compared to LTA alone are cytokines, chemokines, receptors and interferon-regulated genes. Several of these genes exhibit a unique TLR4-dependent increase in mRNA levels that continued to rise more than eight hours after stimulation. This prolonged increase in mRNA levels could be the result of an extended period of NF-κB nuclear localization and the concurrent absence of the NF-κB inhibitor, IκBα, after stimulation with LTA plus Hb. Dynasore inhibition experiments indicate that an endocytosis-dependent pathway is required for the TLR4-dependent up-regulation of IL-6 secretion following activation with LTA plus Hb. In addition, interferon-ß mRNA is present after activation with LTA plus Hb, suggesting that the TRIF/TRAM-dependent pathway may be involved. Hb alone can elicit the TLR4-dependent secretion of TNF-α from macrophages, so it may be the TLR4 ligand. Hb also led to secretion of high mobility group box 1 protein (HMGB1), which synergized with LTA to increase secretion of IL-6. The activation of both the TLR2 and TLR4 pathways by LTA plus Hb leads to an enhanced innate immune response.

Design and validation of bicyclic iminopyrimidinones as beta amyloid cleaving enzyme-1 (BACE1) inhibitors: conformational constraint to favor a bioactive conformation.

On the basis of our observation that the biaryl substituent of iminopyrimidinone 7 must be in a pseudoaxial conformation to occupy the contiguous S1-S3 subsites of BACE1, we have designed a novel fused bicyclic iminopyrimidinone scaffold intended to favor this bioactive conformation. Strategic incorporation of a nitrogen atom in the new constrained ring allowed us to develop SAR around the S2' binding pocket and ultimately resulted in analogues with low nanomolar potency for BACE1. In particular, optimization of the prime side substituent led to major improvements in potency by displacement of two conserved water molecules from a region near S2'. Further optimization of the pharmacokinetic properties of this fused pyrrolidine series, in conjunction with facile access to a rat pharmacodynamic model, led to identification of compound 43, which is an orally active, brain penetrant inhibitor that reduces Aß(40) in the plasma, CSF, and cortex of rats in a dose-dependent manner.

Structure based design of iminohydantoin BACE1 inhibitors: identification of an orally available, centrally active BACE1 inhibitor.

From an initial lead 1, a structure-based design approach led to identification of a novel, high-affinity iminohydantoin BACE1 inhibitor that lowers CNS-derived Aß following oral administration to rats. Herein we report SAR development in the S3 and F' subsites of BACE1 for this series, the synthetic approaches employed in this effort, and in vivo data for the optimized compound.

Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor that Affords Robust CNS Aß Reduction.

Inhibition of BACE1 to prevent brain Aß peptide formation is a potential disease-modifying approach to the treatment of Alzheimer's disease. Despite over a decade of drug discovery efforts, the identification of brain-penetrant BACE1 inhibitors that substantially lower CNS Aß levels following systemic administration remains challenging. In this report we describe structure-based optimization of a series of brain-penetrant BACE1 inhibitors derived from an iminopyrimidinone scaffold. Application of structure-based design in tandem with control of physicochemical properties culminated in the discovery of compound 16, which potently reduced cortex and CSF Aß40 levels when administered orally to rats.

Evaluating the effectiveness of intercultural teachers.

With globalization and major immigration flows, intercultural teaching encounters are likely to increase, along with the need to assure intercultural teaching effectiveness.Thus, the purpose of this article is to present a conceptual framework for nurse educators to consider when anticipating an intercultural teaching experience. Kirkpatrick's and Bushnell's models provide a basis for the conceptual framework. Major concepts of the model include input, process, output, and outcome.The model may possibly be used to guide future research to determine which variables are most influential in explaining intercultural teaching effectiveness.