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Modulation of estrogen-related receptors subtype selectivity: Conversion of an ERRβ/γ selective agonist to ERRα/β/γ pan agonists
No full textEstrogen Related Receptors (ERRs) are key regulators of energy homeostasis and play important role in the etiology of metabolic disorders, skeletal muscle related disorders, and neurodegenerative diseases. Among the three ERR isoforms, ERRα emerged as a potential drug target for metabolic and neurodegenerative diseases. Although ERRβ/γ selective agonist chemical tools have been identified, there are no chemical tools that effectively target ERRα agonism. We successfully engineered high affinity ERRα agonism into a chemical scaffold that displays selective ERRβ/γ agonist activity (GSK4716), providing novel ERRα/β/γ pan agonists that can be used as tools to probe the physiological roles of these nuclear receptors. We identified the structural requirements to enhance selectivity toward ERRα. Molecular modeling shows that our novel modulators have favorable binding modes in the LBP of ERRα and can induce conformational changes where Phe328 that originally occupies the pocket is dislocated to accommodate the ligands in a rather small cavity. The best agonists up-regulated the expression of target genes PGC-1α and PGC-1β, which are necessary to achieve maximal mitochondrial biogenesis. Moreover, they increased the mRNA levels of PDK4, which play an important role in energy homeostasis
The Orphan Nuclear Receptor TLX Is a Receptor for Synthetic and Natural Retinoids
No full textTLX is an orphan nuclear receptor that plays a critical role in both embryonic and adult neurogenesis, as well in the pathogenesis of glioblastomas. TLX functions predominately as a transcriptional repressor, but no natural ligands or high-affinity synthetic ligands have been identified. Here, we describe the identification of natural and synthetic retinoids as functional ligands for TLX. We identified potent synthetic retinoids that directly bind to TLX and either activate or inhibit its transcriptional repressor activity. Furthermore, we identified all-trans and 11-cis retinaldehyde (retinal), retinoids that play an essential role in the visual cycle, as the preferential natural retinoids that bind to and modulate the function of TLX. Molecular dynamics simulations followed by mutational analysis provided insight into the molecular basis of retinoid binding to TLX. Our data support the validity of TLX as a target for development of therapeutics to treat cognitive disorders and/or glioblastomas
Perceptions and experiences of promotoras and pharmacists in an academic-community partnership providing telephonic MTM services to a Spanish-speaking, rural population: A focus group study
No full textBACKGROUND: The literature is limited concerning the collaboration between pharmacists and promotoras in the delivery of medication therapy management (MTM) services. Yet, this information could help address a practice gap while improving MTM collaborative care approaches. OBJECTIVE: To identify the knowledge, attitudes, and barriers of clinical call center health professionals (pharmacists, nurses, pharmacy interns) and promotoras towards MTM collaborative care in implementing the Rural Arizona Medication Therapy Management (RAzMTM) program. METHODS: A descriptive, qualitative study using semistructured focus groups was conducted with call center health professionals and promotoras who participated in the RAzMTM program to improve pharmaceutical care for patients with diabetes and/or hypertension in rural Arizona. Recruitment and consent letters, a demographic questionnaire, and a focus group guide were designed specifically for this project. Three facilitators participated in each focus group-one guided the discussion while the others took notes. Focus groups were audio recorded to verify all responses and transcribed verbatim with omission of participant identifiers. Thematic analysis was conducted by 2 independent researchers who reviewed the transcripts to identify codes, seek consensus, and agree on themes, with negotiation from a third independent researcher. RESULTS: Nine participants took part in 2 focus groups. Participants were predominantly female (89%), college graduates and/or had postgraduate/professional degrees (78%), and were Hispanic or Latino (89%). Five themes were identified: (1) roles and responsibilities of RAzMTM participants; (2) benefits unique to the RAzMTM program; (3) interprofessional experience of RAzMTM participants; (4) professional growth for RAzMTM participants; and (5) opportunities for future improvement. Perceptions of the participants in the RAzMTM program were consistent-experiences of health professionals and promotoras were positive; they recognized the benefit of each other\u27s involvement in the program; and they learned how to work together to improve patient care. Future recommended program improvements include improving ease of scheduling (e.g., extending pharmacist availability to provide MTM services). CONCLUSIONS: These focus group results suggest that provision of telephonic MTM services, using an academic-community partnership, was positively received by participating pharmacists and promotoras. However, future work is needed for continued improvement of strategies to enhance interprofessional relationships in patient chronic disease management
Impact of Baseline Characteristics on Future Episodes of Bloodstream Infections: Multistate Model in Septic Patients with Bloodstream Infections
No full textBackground: Looking only at the index infection, studies have described risk factors for infections caused by resistant bacteria. We hypothesized that septic patients with bloodstream infections may transition across states characterized by different microbiology and that their trajectory is not uniform. We also hypothesized that baseline risk factors may influence subsequent blood culture results. Methods: All adult septic patients with positive blood cultures over a 7-year period were included in the study. Baseline risk factors were recorded. We followed all survivors longitudinally and recorded subsequent blood culture results. We separated states into bacteremia caused by gram-positive cocci, susceptible gram-negative bacilli (sGNB), resistant GNB (rGNB), and Candida spp. Detrimental transitions were considered when transitioning to a culture with a higher mortality risk (rGNB and Candida spp.). A multistate Markov-like model was used to determine risk factors associated with detrimental transitions. Results: A total of 990 patients survived and experienced at least 1 transition, with a total of 4282 transitions. Inappropriate antibiotics, previous antibiotic exposure, and index bloodstream infection caused by either rGNB or Candida spp. were associated with detrimental transitions. Double antibiotic therapy (beta-lactam plus either an aminoglycoside or a fluoroquinolone) protected against detrimental transitions. Conclusion: Baseline characteristics that include prescribed antibiotics can identify patients at risk for subsequent bloodstream infections caused by resistant bacteria. By altering the initial treatment, we could potentially influence future bacteremic states
Tumor microenvironment-targeted nanoparticles loaded with bortezomib and ROCK inhibitor improve efficacy in multiple myeloma
No full textDrug resistance and dose-limiting toxicities are significant barriers for treatment of multiple myeloma (MM). Bone marrow microenvironment (BMME) plays a major role in drug resistance in MM. Drug delivery with targeted nanoparticles have been shown to improve specificity and efficacy and reduce toxicity. We aim to improve treatments for MM by (1) using nanoparticle delivery to enhance efficacy and reduce toxicity; (2) targeting the tumor-associated endothelium for specific delivery of the cargo to the tumor area, and (3) synchronizing the delivery of chemotherapy (bortezomib; BTZ) and BMME-disrupting agents (ROCK inhibitor) to overcome BMME-induced drug resistance. We find that targeting the BMME with P-selectin glycoprotein ligand-1 (PSGL-1)-targeted BTZ and ROCK inhibitor-loaded liposomes is more effective than free drugs, non-targeted liposomes, and single-agent controls and reduces severe BTZ-associated side effects. These results support the use of PSGL-1-targeted multi-drug and even non-targeted liposomal BTZ formulations for the enhancement of patient outcome in MM
2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines
No full textEvaluation of a ceiling effect on the association of new resistance development to antipseudomonal beta-lactam exposure in the critically ill
No full textA Systematic Literature Review of the Prognostic and Predictive Value of PIK3CA Mutations in HR\u3csup\u3e+\u3c/sup\u3e/HER2\u3csup\u3e−\u3c/sup\u3e Metastatic Breast Cancer
No full textPIK3CA mutations may have prognostic value for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer, representing an important potential target for systemic therapy. Prognostic and predictive values associated with PIK3CA mutations are not well understood. A comprehensive search of PubMed/MEDLINE, EMBASE, Cochrane Central, and conference abstracts was performed for English-language articles published January 1993 through April 2019. Articles were categorized by treatment arms based on experimental and treatment drug classes. Information on progression-free survival (PFS), hazard ratios, overall survival, response rate, and clinical benefit rate was obtained. A total of 17 studies were included. Among those evaluating non-PI3Ki based therapies, 91% showed numerically shorter median PFS, ranging from 1.5 to 19.2 months and 1.8 to 29.6 months for the mutant versus non-mutant subgroups, respectively. Where reported (n = 13 studies), PFS was shorter between those arms offering endocrine monotherapy (range, 1.6-14.7 months) compared with a corresponding targeted therapy + endocrine monotherapy (range, 3.9-29.6 months). Of 5 PI3Ki-based arms comparing PFS, higher median PFS in PIK3CA mutant versus non-mutant cases was demonstrated. PFS was shorter for patients with PIK3CA mutant (range, 1.6-19.2 months) compared with PIK3CA wild-type (range, 1.8-29.6 months) in 10 (71%) of 14 treatment arms reporting PFS. Studies (n = 4) not reporting PFS reported response rate, but there were no clear directional trends. The presence of PIK3CA mutations may be associated with worse clinical outcomes in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. Clinical outcomes such as PFS may be improved using a combination of PI3Ki-based therapies and endocrine therapies among this population. However, more research is warranted to fully elucidate this association
Vancomycin Dosing Practices among Critical Care Pharmacists: A Survey of Society of Critical Care Medicine Pharmacists
No full textINTRODUCTION: Critically ill patients and their pharmacokinetics present complexities often not considered by consensus guidelines from the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Prior surveys have suggested discordance between certain guideline recommendations and reported infectious disease pharmacist practice. Vancomycin dosing practices, including institutional considerations, have not previously been well described in the critically ill patient population. OBJECTIVES: To evaluate critical care pharmacists\u27 self-reported vancomycin practices in comparison to the 2009 guideline recommendations and other best practices identified by the study investigators. METHODS: An online survey developed by the Research and Scholarship Committee of the Clinical Pharmacy and Pharmacology (CPP) Section of the Society of Critical Care Medicine (SCCM) was sent to pharmacist members of the SCCM CPP Section practicing in adult intensive care units in the spring of 2017. This survey queried pharmacists\u27 self-reported practices regarding vancomycin dosing and monitoring in critically ill adults. RESULTS: Three-hundred and sixty-four responses were received for an estimated response rate of 26%. Critical care pharmacists self-reported largely following the 2009 vancomycin dosing and monitoring guidelines. The largest deviations in guideline recommendation compliance involve consistent use of a loading dose, dosing weight in obese patients, and quality improvement efforts related to systematically monitoring vancomycin-associated nephrotoxicity. Variation exists regarding pharmacist protocols and other practices of vancomycin use in critically ill patients. CONCLUSION: Among critical care pharmacists, reported vancomycin practices are largely consistent with the 2009 guideline recommendations. Variations in vancomycin dosing and monitoring protocols are identified, and rationale for guideline non-adherence with loading doses elucidated