A nonthrombotic pulmonary embolus caused by polyalkylimide dermal filler: A case report and literature review of medication management.

BACKGROUND: This report presents the case of a patient who developed a nonthrombotic embolus attributed to a polyalkylimide dermal filler, and it also charts pharmacotherapeutic strategies for polyalkylimide complications reported in the literature. CASE SUMMARY: A 31-year-old female presented to a community teaching hospital with dyspnea, hemoptysis, and fever. A thorough history revealed that the patient received intragluteal injections of a polyalkylimide dermal filler (Bio-Alcamid) 4 days before hospitalization, although it was initially and incorrectly diagnosed as silicone embolism syndrome. High-dose intravenous steroids and antibiotics were ineffective, and the patient was transferred to a higher level of care for surgical management. Therein, the patient developed additional complications, including multiple thromboembolic events and the need for long-term enteral nutrition. After a 63-day stay in the intensive care unit and a 13-day stay in an inpatient postacute facility, the patient's postdischarge care transitions included 3 subsequent emergency department visits related to enteral feeding tube malfunction. PRACTICE IMPLICATIONS: Polyalkylimide is a hydrogel polymer derived from acrylic acid that is used as a dermal filler. Postinjection complications include dermal filler migration and abscess formation. Surgical resection of the filler and prophylactic antibiotics have, anecdotally, been used with success. Comparatively, silicone dermal filler complications may be treated with high-dose intravenous corticosteroids. Although silicone and polyalkylimide are both classified as permanent dermal fillers, the management of their complications differs, especially with regard to medications. This case underscores the necessity for clinicians to accurately identify the type of dermal filler used in order to recommend effective medication management to treat complications. Unlike silicone dermal filler treatment, corticosteroids may actually exacerbate polyalkylimide dermal filler complications. Beta-lactam antibiotics for at least 14 days may be reasonable to treat the cutaneous infectious complications arising from polyalkylimide dermal filler use.

Development and Implementation of Interprofessional Relations Between a College of Pharmacy and Osteopathic Residency Programs in a Community Teaching Hospital.

Background: Team-based health care optimizes patient outcomes, and therefore, both interprofessional education (IPE) and interprofessional relations (IPR) are required in health professions education, postgraduate training, and real-world clinical practice. Existing literature describes progressive developments and assessments of IPE in colleges of pharmacy and medicine; however, there are fewer reports describing processes or projects that foster physician-pharmacist IPR in clinical practices without established interprofessional collaborations. Objectives: The primary objective was to establish IPR between pharmacists and osteopathic residents in a community teaching hospital. The secondary objective was to innovate the delivery of pharmacotherapeutic content delivered to the residents during their didactic lecture series by providing active learning strategies. Methods: This report describes a project wherein college of pharmacy faculty developed IPR with osteopathic residents in a community teaching hospital that previously did not have any established physician-pharmacist IPR. Osteopathic medical residents completed a post-implementation survey after they attended a 12-month series of didactic lectures that incorporated active learning delivered by pharmacist faculty. Results: Sixty-six residents were eligible to complete the survey; 20 residents completed the survey. Eighteen residents believed that both physicians and pharmacists should be educated to establish IPR and that it should be included in professional, graduate, and continuing education settings for both professions. Sixteen residents believed that the active learning techniques employed by college of pharmacy faculty were useful for IPR. Conclusions: Physician-pharmacist IPR may be achievable in settings where IPR was previously sparse. Shared interests, adherence, and innovations in IPR frameworks are essential for developing physician-pharmacist IPR.

Novel inhibitors of Staphylococcus aureus RnpA that synergize with mupirocin.

We recently discovered RnpA as a promising new drug discovery target for methicillin-resistant S. aureus (MRSA). RnpA is an essential protein that is thought to perform two required cellular processes. As part of the RNA degrasome Rnpa mediates RNA degradation. In combination with rnpB it forms RNase P haloenzymes which are required for tRNA maturation. A high throughput screen identified RNPA2000 as an inhibitor of both RnpA-associated activities that displayed antibacterial activity against clinically relevant strains of S. aureus, including MRSA. Structure-activity studies aimed at improving potency and replacing the potentially metabotoxic furan moiety led to the identification of a number of more potent analogs. Many of these new analogs possessed overt cellular toxicity that precluded their use as antibiotics but two derivatives, including compound 5o, displayed an impressive synergy with mupirocin, an antibiotic used for decolonizing MSRA whose effectiveness has recently been jeopardized by bacterial resistance. Based on our results, compounds like 5o may ultimately find use in resensitizing mupirocin-resistant bacteria to mupirocin.

Small-molecule inhibitors of Staphylococcus aureus RnpA-mediated RNA turnover and tRNA processing.

New agents are urgently needed for the therapeutic treatment of Staphylococcus aureus infections. In that regard, S. aureus RNase RnpA may represent a promising novel dual-function antimicrobial target that participates in two essential cellular processes, RNA degradation and tRNA maturation. Accordingly, we previously used a high-throughput screen to identify small-molecule inhibitors of the RNA-degrading activity of the enzyme and showed that the RnpA inhibitor RNPA1000 is an attractive antimicrobial development candidate. In this study, we used a series of in vitro and cellular assays to characterize a second RnpA inhibitor, RNPA2000, which was identified in our initial screening campaign and is structurally distinct from RNPA1000. In doing so, it was found that S. aureus RnpA does indeed participate in 5'-precursor tRNA processing, as was previously hypothesized. Further, we show that RNPA2000 is a bactericidal agent that inhibits both RnpA-associated RNA degradation and tRNA maturation activities both in vitro and within S. aureus. The compound appears to display specificity for RnpA, as it did not significantly affect the in vitro activities of unrelated bacterial or eukaryotic ribonucleases and did not display measurable human cytotoxicity. Finally, we show that RNPA2000 exhibits antimicrobial activity and inhibits tRNA processing in efflux-deficient Gram-negative pathogens. Taken together, these data support the targeting of RnpA for antimicrobial development purposes, establish that small-molecule inhibitors of both of the functions of the enzyme can be identified, and lend evidence that RnpA inhibitors may have broad-spectrum antimicrobial activities.

Heterocyclic chalcone activators of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) with improved in vivo efficacy.

Nrf2 activators represent a good drug target for designing agents to treat diseases associated with oxidative stress. Building upon previous work, we designed and prepared a series of heterocyclic chalcone-based Nrf2 activators with reduced lipophilicity and, in some cases, greater in vitro potency compared to the respective carbocyclic scaffold. These changes resulted in enhanced oral bioavailability and a superior pharmacodynamic effect in vivo.

The effect of socioeconomic disadvantage for on-time graduation in an accelerated doctor of pharmacy program.

INTRODUCTION: The purpose of this study was to determine if there is a relationship between socioeconomic disadvantage and student progression in an accelerated, three-year, doctor of pharmacy (PharmD) program. METHODS: The percentage of socioeconomically disadvantaged students in Larkin University's applicant and accepted pool was compared to national data using an N-1 Chi-square. The on-time graduation rate for three classes of PharmD students were compared based on the economic or environmental disadvantage questions posed by Pharmacy College Application Service (PharmCAS). On-time graduation rates were also analyzed by sex, race/ethnicity, and geographical area using a Pearson's Chi-square. Student academic admissions profiles were compared by race/ethnicity using analysis of variance. RESULTS: Larkin University had a higher percentage of applicants and accepted candidates from certain underrepresented groups. There was no significant difference in on-time graduation for students who answered yes to any of the economic or environmental disadvantage questions as opposed to those who answered no, nor was there a significant difference in on-time graduation by sex or geographical area. For race, there was a significantly lower rate of on-time graduation for students who were Black or African American, even though their admissions criteria were comparable to that of students of other races. CONCLUSIONS: Students who had an economic or environmental disadvantage graduated on-time at the same rate as students who did not have such disadvantages. Black or African American students had lower on-time rates than other ethnic groups, but the reason for lower on-time graduation was unclear.

Creation and implementation of a drug discovery and development game.

BACKGROUND AND PURPOSE: Gamification is a commonly employed active-learning technique to increase student engagement and learning. Few games teaching the drug discovery and development process exist. EDUCATIONAL ACTIVITY AND SETTING: A six hour component of the elective course Non-traditional Pharmacy Career Routes focused on drug development. Four of the six hours were devoted to a game designed to mimic the drug discovery and development process. The 17 enrolled students were split into smaller groups designated to represent large pharmaceutical, start-up, or generic companies. The number of resources each group began with varied depending on the type of company they were assigned. Students worked to develop and bring to market the most drugs and gain the most money. To reinforce the reflective and innovative learning process, students created "failure" cards before the game started that had reasons for failures during the drug development process. FINDINGS: Two questions about the drug discovery and development process were on a pre-/post-assessment. The first question was answered correctly by 12 of 16 students on the pre-assessment, while 15 of 17 students answered correctly on the post-assessment. The second question was answered correctly by 13 of 16 students on the pre-assessment and all students on the post-assessment. The students enjoyed playing the game and felt that it helped them to understand the drug development process. SUMMARY: A novel, role-play game that allows students to learn the drug discovery and development process has the potential to be implemented in similar courses.

Advances in CXCR7 Modulators.

CXC chemokine receptor 7 (CXCR7) is a G-protein-coupled receptor that signals through the ß-arrestin pathway. Its ligands include interferon-inducible T cell α chemoattractant (CXCL11) and stromal cell-derived factor-1 (CXCL12). It interacts with CXCR4, and the two are associated with various cancers, as well as other disease states such as coronary artery disease, stroke, inflammation and human immunodeficiency virus (HIV). Antibodies and small interfering RNA (siRNA) have shown the utility of antagonists of CXCR7 in these disease states. Although some small molecules were initially reported as antagonists due to their displayed activity, many function as agonists while still producing the desired pharmacologic effects. A potential reason for this contradiction is that effects may be due to elevated extracellular CXCL12 levels.

A Mini-Review on Ceftaroline in Bacteremia Patients with Methicillin-Resistant Staphylococcus aureus (MRSA) Infections.

OBJECTIVE: The objective of this review is to describe the outcomes of patients treated with ceftaroline in the non-Food and Drug Administration (FDA) approved indication of methicillin-resistant Staphylococcus aureus (MRSA) infections in both pediatric and adult populations. DATA SOURCES: A systematic overview was conducted by searching PubMed, Medline, and The Cochrane Library up to January 2019. STUDY SELECTION AND DATA EXTRACTION: All English-language clinical trials and case reports related to the efficacy of ceftaroline in new, not-yet-approved FDA indications in MRSA infections in pediatric or adult populations. DATA SYNTHESIS: In the case of MRSA bacteremia (MRSAB) infections, three different randomized studies in pediatric patients showed effectiveness of ceftaroline. When used in the case of adult populations with MRSA bacteremia, a small trial of 16 patients showed 50% clinical success in patients with acute bacterial skin and skin structure infections versus 63% clinical success in patients with community-acquired bacterial pneumonia. Another case series of six refractory case reports showed 50% clinical success of ceftaroline in patients with MRSA. CONCLUSIONS: Although there are few case reports and limited data to date, ceftaroline fosamil should continue to be studied as an alternative therapy in MRSA infections in both pediatric and adult populations. Clinical success rates of ceftaroline were, in most cases, considered high when treating patients with MRSA infection. More clinical trials need to be studied. In the specific case of MRSA bacteremia, the treatment options remain few and ceftaroline should be extensively studied for the salvage treatment of MRSAB.

Resistance to BET Bromodomain Inhibitors Is Mediated by Kinome Reprogramming in Ovarian Cancer.

Small-molecule BET bromodomain inhibitors (BETis) are actively being pursued in clinical trials for the treatment of a variety of cancers, but the mechanisms of resistance to BETis remain poorly understood. Using a mass spectrometry approach that globally measures kinase signaling at the proteomic level, we evaluated the response of the kinome to targeted BETi treatment in a panel of BRD4-dependent ovarian carcinoma (OC) cell lines. Despite initial inhibitory effects of BETi, OC cells acquired resistance following sustained treatment with the BETi JQ1. Through application of multiplexed inhibitor beads (MIBs) and mass spectrometry, we demonstrate that BETi resistance is mediated by adaptive kinome reprogramming, where activation of compensatory pro-survival kinase networks overcomes BET protein inhibition. Furthermore, drug combinations blocking these kinases may prevent or delay the development of drug resistance and enhance the efficacy of BETi therapy.