UHSP Collections (University of Health Sciences and Pharmacy)
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Mitochondrial pyruvate carrier inhibitors improve metabolic parameters in diet-induced obese mice
No full textThe mitochondrial pyruvate carrier (MPC) is an inner mitochondrial membrane complex that plays a critical role in intermediary metabolism. Inhibition of the MPC, especially in liver, may have efficacy for treating type 2 diabetes mellitus. Herein, we examined the antidiabetic effects of zaprinast and 7ACC2, small molecules which have been reported to act as MPC inhibitors. Both compounds activated a bioluminescence resonance energy transfer–based MPC reporter assay (reporter sensitive to pyruvate) and potently inhibited pyruvate-mediated respiration in isolated mitochondria. Furthermore, zaprinast and 7ACC2 acutely improved glucose tolerance in diet-induced obese mice in vivo. Although some findings were suggestive of improved insulin sensitivity, hyperinsulinemic–euglycemic clamp studies did not detect enhanced insulin action in response to 7ACC2 treatment. Rather, our data suggest acute glucose-lowering effects of MPC inhibition may be due to suppressed hepatic gluconeogenesis. Finally, we used reporter sensitive to pyruvate to screen a chemical library of drugs and identified 35 potentially novel MPC modulators. Using available evidence, we generated a pharmacophore model to prioritize which hits to pursue. Our analysis revealed carsalam and six quinolone antibiotics, as well as 7ACC1, share a common pharmacophore with 7ACC2. We validated that these compounds are novel inhibitors of the MPC and suppress hepatocyte glucose production and demonstrated that one quinolone (nalidixic acid) improved glucose tolerance in obese mice. In conclusion, these data demonstrate the feasibility of therapeutic targeting of the MPC for treating diabetes and provide scaffolds that can be used to develop potent and novel classes of MPC inhibitors
Examination of the Effectiveness of Direct Oral Anticoagulants in Comparison to Warfarin in an Obese Population
No full textBackground: While commonly prescribed today, direct oral anticoagulants (DOACs) have historically been avoided in patients with class III obesity or a weight \u3e120 kg due to limited literature regarding the efficacy and safety in this population. Objective: The overall objective was to examine the effectiveness of DOACs compared to warfarin in a population with obesity. Methods: Patients with a diagnosis of venous thromboembolism (VTE) or atrial fibrillation and a body mass index (BMI) ≥35 kg/m2 from August 1, 2015, to August 1, 2020, were included in this retrospective cohort study. Patients receiving a DOAC were matched in a 1:2 ratio to warfarin. The primary outcome was a composite of stroke or recurrent VTE. Secondary outcomes included the individual components of the primary outcome, hospitalization for bleed, and the primary outcome in patients with a BMI ≥40 kg/m2. Results: A total of 162 patients were included, with 54 and 108 in the DOAC and warfarin groups, respectively. Baseline BMI was similar between groups (45.7 kg/m2 for DOACs vs 43.8 kg/m2 for warfarin), with approximately 70% of patients having a BMI ≥40 kg/m2. The primary outcome occurred in 1 patient (1.9%) in the DOAC group and 2 patients (1.9%) in the warfarin group. The DOAC group had a higher, nonsignificant incidence of bleeding (5.6% vs 0.9%, P = 0.11). There was no difference between groups in incidence of deep vein thrombosis (DVT), pulmonary embolism (PE), or stroke in patients with a BMI ≥40 kg/m2. Conclusion: DOACs may be as efficacious as warfarin in the prevention of stroke or recurrent VTE in patients with a BMI of ≥35 kg/m2. Prospective, randomized trials are warranted to further assess the efficacy and safety of DOACs in this population
The role of inflammation in the pathogenesis and treatment of arrhythmias
No full textThe pathogenesis of arrhythmias is complex and multifactorial. The role of inflammation in the pathogenesis of both atrial and ventricular arrhythmias (VA) has been explored. However, developing successful pharmacotherapy regimens based on those pathways has proven more of a challenge. This narrative review provides an overview of five common arrhythmias impacted by inflammation, including atrial fibrillation (AF), myocardial infarction, arrhythmogenic cardiomyopathy, cardiac sarcoidosis, and QT prolongation, and the potential role for anti-inflammatory therapy in their management. We identified arrhythmias and arrhythmogenic disease states with the most evidence linking pathogenesis to inflammation and conducted comprehensive searches of United States National Library of Medicine MEDLINE® and PubMed databases. Although a variety of agents have been studied for the management of AF, primarily in an effort to reduce postoperative AF following cardiac surgery, no standard anti-inflammatory agents are used in clinical practice at this time. Although inflammation following myocardial infarction may contribute to the development of VA, there is no clear benefit with the use of anti-inflammatory agents at this time. Similarly, although inflammation is clearly linked to the development of arrhythmias in arrhythmogenic cardiomyopathy, data demonstrating a benefit with anti-inflammatory agents are limited. Cardiac sarcoidosis, an infiltrative disease eliciting an immune response, is primarily treated by immunosuppressive therapy and steroids, despite a lack of primary literature to support such regimens. In this case, anti-inflammatory agents are frequently used in clinical practice. The pathophysiology of arrhythmias is complex, and inflammation likely plays a role in both onset and duration, however, for most arrhythmias the role of pharmacotherapy targeting inflammation remains unclear
An Academic-Community Collaboration to Deliver Medication Therapy Management (MTM) Services to Patients Living in Rural Counties of a Southwestern State in the United States
No full textBackground: Patients living in rural communities often experience pronounced health disparities, have a higher prevalence of diabetes and hypertension, and poorer access to care compared to urban areas. To address these unmet healthcare service needs, an established, academic-based MTM provider created a novel, collaborative program to provide comprehensive, telephonic services to patients living in rural Arizona counties. Objective: This study assessed the program effectiveness and described differences in health process and outcome measures (e.g., clinical outcomes, gaps in care for prescribed medications, medication-related problems) between individuals residing in different rural-urban commuting area (RUCA) groups (urban, micropolitan, and small town) in rural Arizona counties. Methods: Subjects eligible for inclusion were 18 years or older with diabetes and/or hypertension, living in rural Arizona counties. Data were collected on: demographic characteristics, medical conditions, clinical values, gaps in care, medication-related problems (MRPs), and health promotion guidance. Subjects were analyzed using 3 intra-county RUCA levels (i.e., urban, micropolitan, and small town). Results: A total of 384 patients were included from: urban (36.7%), micropolitan (19.3%) and small town (44.0%) areas. Positive trends were observed for clinical values, gaps in care, and MRPs between initial and follow-up consultations. Urban dwellers had significantly lower average SBP values at follow-up than those from small towns (p \u3c 0.05). A total of 192 MRPs were identified; 75.0% were resolved immediately or referred to providers and 16.7% were accepted by prescribers. Conclusion: This academic-community partnership highlights the benefits of innovative collaborative programs, such as this, for individuals living in underserved, rural areas
Nature-inspired engineering of an artificial ligase enzyme by domain fusion
No full textThe function of most proteins is accomplished through the interplay of two or more protein domains and fine-tuned by natural evolution. In contrast, artificial enzymes have often been engineered from a single domain scaffold and frequently have lower catalytic activity than natural enzymes. We previously generated an artificial enzyme that catalyzed an RNA ligation by \u3e2 million-fold but was likely limited in its activity by low substrate affinity. Inspired by nature\u27s concept of domain fusion, we fused the artificial enzyme to a series of protein domains known to bind nucleic acids with the goal of improving its catalytic activity. The effect of the fused domains on catalytic activity varied greatly, yielding severalfold increases but also reductions caused by domains that previously enhanced nucleic acid binding in other protein engineering projects. The combination of the two better performing binding domains improved the activity of the parental ligase by more than an order of magnitude. These results demonstrate for the first time that nature\u27s successful evolutionary mechanism of domain fusion can also improve an unevolved primordial-like protein whose structure and function had just been created in the test tube. The generation of multi-domain proteins might therefore be an ancient evolutionary process
“I changed, I had to realize that I was wrong”: Identity gap management amidst evolving illness uncertainty
No full textDoubt that a family member’s health issues are real, severe, or even possible entwines some of the most challenging aspects of medical, personal, and social uncertainty. Although several studies have examined doubt, this investigation focuses on how doubt evolves and foregrounds the identity implications of uncertainty. Guided by Communication Theory of Identity (CTI), the purpose of this study was to explore the identity gaps people experience as they navigate evolving doubt about a family member’s health and how they manage those identity gaps. We interviewed 33 individuals in the U.S. about a family member’s health issues that they doubted but began to believe. Our analysis uncovered three identity gaps among personal, relational, and enacted layers of identity: personal-enacted, relational-enacted, and personal-relational-enacted identity gaps. Participants managed identity gaps in two primary ways: (a) closing gaps by altering personal, relational, or enacted layers of their own identity; and (b) maintaining identity gaps by putting the locus of responsibility for identity change within their family member’s relational identities. This study offers theoretical implications for CTI as well as practical implications for individuals navigating doubt and evolving illness uncertainty in their family relationships
A workshop to co-design messages that may increase uptake of vaccines: A case study
No full textThe present case study describes a co-produced and theoretically informed workshop wherein messages were co-designed to increase the uptake of future COVID-19 vaccines in the United Kingdom. Co-design can enhance the legitimacy and effectiveness of public interventions, but many researchers, service providers, and policymakers may be uncertain where to start. This demonstrative example applies behavioural science and design thinking theory, illustrating how others can integrate theoretically informed co-design into similar and more complex projects efficiently. The workshop brought together members of the public, immunisers, and public health specialists. A narrative analysis was conducted to identify themes related to vaccine hesitancy. The workshop\u27s supporting materials are made available as supplemental materials, which can be modified for future workshops. The discussion encourages additional workshops to be conducted, including diverse members of the public, to co-design novel solutions to improve public health more generally
Pharmacist beliefs about antimicrobial resistance and impacts on antibiotic supply: A multinational survey
No full textBackground: Pharmacists have important antimicrobial stewardship (AMS) roles yet limited literature exists on pharmacists\u27 knowledge and beliefs about antimicrobial resistance (AMR) and antimicrobials and how these beliefs influence antimicrobial supply in different countries. Methods: A cross-sectional survey was disseminated to pharmacists around the world via the Commonwealth Pharmacists\u27 Association and related networks. Data were collected on demographics, antibiotic supply practices, and knowledge and beliefs about AMR. Results: A total of 546 pharmacists responded from 59 countries, most commonly from Africa (41%) followed by Asia (26%) and Oceania (22%). Respondents supplied a mean of 46±81 antibiotic prescriptions/week, 73%±35% of which were given in response to a prescription. Overall, 60.2% dispensed antibiotics at least once without a prescription. Respondents had good knowledge (mean 9.6±1.3 (out of 12), and held positive beliefs about AMR [mean 3.9±0.6 (out of 5)]. Knowledge about antibiotics and beliefs about AMR were positively correlated. The odds of supplying antibiotics without a prescription were 7.4 times higher among respondents from lower income countries [adjusted odds ratio (AOR)=7.42, 95% CI 4.16-13.24]. Conversely, more positive AMR beliefs were associated with a lower odds of supplying antibiotics without a prescription (AOR=0.91, 95% CI 0.86-0.95). Conclusions: Most pharmacists had the good knowledge about antibiotics and positive beliefs about AMR. These beliefs were influenced by knowledge, work setting, and country income. A proportion of respondents provided antibiotics without a prescription; the likelihood of this occurring was higher in those who held more negative beliefs about AMR
Structural basis of synthetic agonist activation of the nuclear receptor REV-ERB
No full textThe nuclear receptor REV-ERB plays an important role in a range of physiological processes. REV-ERB behaves as a ligand-dependent transcriptional repressor and heme has been identified as a physiological agonist. Our current understanding of how ligands bind to and regulate transcriptional repression by REV-ERB is based on the structure of heme bound to REV-ERB. However, porphyrin (heme) analogues have been avoided as a source of synthetic agonists due to the wide range of heme binding proteins and potential pleotropic effects. How non-porphyrin synthetic agonists bind to and regulate REV-ERB has not yet been defined. Here, we characterize a high affinity synthetic REV-ERB agonist, STL1267, and describe its mechanism of binding to REV-ERB as well as the method by which it recruits transcriptional corepressor both of which are unique and distinct from that of heme-bound REV-ERB
