Development of a Medication-Use Evaluation Template for Andexanet Alfa in the Reversal of Anticoagulation With Factor Xa Inhibitors.

Medication-use evaluations are meant to ensure that medication-use processes are consistent with prevailing standards of care, assure optimal use of therapy, and reduce the risk of medication-related problems. Reversal agents for direct oral anticoagulants are a worthy focus for medication-use evaluations for reasons of efficacy, safety, and cost. A multidisciplinary team of experts developed 2 medication-use evaluation templates illustrating the application of professional society guidelines to the appropriate use of andexanet alfa.

Presentation, management, and outcomes of norovirus in adult and pediatric solid organ and hematopoietic stem cell transplant recipients: A multicenter, retrospective study.

Background: Norovirus (NoV) can cause chronic relapsing and remitting diarrhea in immunocompromised patients.  Few multicenter studies have described the clinical course, outcomes, and complications of chronic NoV in transplant recipients.

Methods: A multicenter retrospective study of adult and pediatric SOT and HSCT recipients diagnosed with NoV between November 1, 2017, and February 28, 2021.

Improving inpatient discharge workflows through pharmacist pending discharge medication orders.

Purpose: Hospital discharge represents a difficult care transition for patients, with the potential for medication-related problems (MRPs) and adverse events. Medication reconciliation is widely accepted as a best practice to minimize MRPs at the time of discharge. Pharmacists can play a key role in identification and resolution of MRPs, although pharmacist reconciliation usually occurs after provider medication reconciliation.

Clinical investigation and management of Brucella suis seropositive dogs: A longitudinal case series.

Background: Brucellosis in dogs caused by Brucella suis is an emerging zoonotic disease.

Objectives: To document clinical characteristics, serology, microbiology, and clinical response to treatment in B. suis-seropositive dogs.

Reengaging patients with forgotten filters through an institutional multidisciplinary approach.

Objective: The aim of the present study was to evaluate the outcomes of a hospital-wide multidisciplinary initiative to reengage and manage patients with unretrieved chronic indwelling inferior vena cava (IVC) filters placed at a large tertiary care center, who had been lost to follow-up.

Methods: We performed a retrospective review of outcomes from a completed multidisciplinary quality improvement project. The quality improvement project identified and contacted (via letter) patients with chronic indwelling IVC filters placed at a single tertiary care center from 2008 to 2016 who were alive and without evidence of filter retrieval in the medical records.

Emergent Reversal of Antithrombotics and Treatment of Life-Threatening Bleeding from Coagulopathies: A Clinical Review.

Background: Reversal of antithrombotic agents and treatment of life-threatening bleeding episodes from coagulopathies can be a stressful scenario for clinicians, especially when the selection of treatment options should occur quickly. Understanding the options available for these agents requires emergency physicians to be familiar with the current data surrounding new therapies and dosing strategies for the treatment of bleeding from reversible and nonreversible antithrombotics and coagulopathic conditions.

Objective: To provide quick resource guides for the reversal of major or life-threatening bleeding caused by antithrombotic agents or in the setting of coagulopathies.

Development of a Pharmacist-Led Opt-Out Cessation Treatment Protocol for Combustible Tobacco Smoking Within Inpatient Settings.

Although people who smoke cigarettes are overrepresented among hospital inpatients, few are connected with smoking cessation treatment during their hospitalization. Training, accountability for medication use, and monitoring of all patients position pharmacists well to deliver cessation interventions to all hospitalized patients who smoke. A large Midwestern University hospital implemented a pharmacist-led smoking cessation intervention.

BMS-813160: A Potent CCR2 and CCR5 Dual Antagonist Selected as a Clinical Candidate.

BMS-813160 (compound ) was identified as a potent and selective CCR2/5 dual antagonist. Compound displayed good permeability at pH = 7.4 in PAMPA experiments and demonstrated excellent human liver microsome stability.

Discovery of BMS-753426: A Potent Orally Bioavailable Antagonist of CC Chemokine Receptor 2.

To improve the metabolic stability profile of BMS-741672 (), we undertook a structure-activity relationship study in our trisubstituted cyclohexylamine series. This ultimately led to the identification of (BMS-753426) as a potent and orally bioavailable antagonist of CCR2. Compared to previous clinical candidate , the -butyl amine showed significant improvements in pharmacokinetic properties, with lower clearance and higher oral bioavailability.

Solvent-Casted Films to Assist Polymer Selection for Amorphous Solid Dispersions During Preclinical Studies: In-vitro and In-vivo Exploration.

Purpose: The use of two solvent-casted film methods to select optimal polymer compositions for amorphous solid dispersions prepared to support preclinical pharmacokinetic and toxicology studies is described.

Methods: Evaporation of solvent from cover slips by using nitrogen flow, and solvent removal from vials by using rotary evaporation were employed. The films prepared on cover slips were evaluated under the microscope to determine crystallinity.

Thoracic Lymph Duct Catheterization with a Venous Shunt in the Nonhuman Primate.

Biologic therapeutics constitute up to 30% of all drugs approved from 2010 to 2018 and represent a continuous growing market. In contrast to small molecules, biologic therapeutics (>1 kDa MW) are administered parenterally or intravenously due to poor bioavailability when administered orally. The absorption and disposition of biologics that are administered subcutaneously may be absorbed via lymphatic or blood capillaries.

Evaluation of a Fixed-Dose Regimen of 4-Factor Prothrombin Complex Concentrate for Warfarin Reversal.

Background: Fixed-dose (FD) regimens of 4-factor prothrombin complex concentrate (4F-PCC) may be effective for the emergent reversal of warfarin; however, the optimal dosing is unknown. Our institution transitioned to a FD regimen of 1000 or 2000 units of 4F-PCC based on indication.

Objective: The purpose of this study is to report our experience with FD 4F-PCC compared with a historical weight-based dosing cohort for warfarin reversal.

Antithrombotic selection in patients undergoing transcatheter aortic valve replacement.

Purpose: Clinical controversy regarding the most appropriate antithrombotic regimen after transcatheter aortic valve replacement remains. Current evidence, guidelines, and recommendations are discussed.

Summary: Antithrombotic selection following transcatheter aortic valve replacement depends on a variety of patient-specific factors.

Discovery of a phenylpyrazole amide ROCK inhibitor as a tool molecule for in vivo studies.

Structure-activity relationship optimization on a series of phenylpyrazole amides led to the identification of a dual ROCK1 and ROCK2 inhibitor (25) which demonstrated good potency, kinome selectivity and favorable pharmacokinetic profiles. Compound 25 was selected as a tool molecule for in vivo studies including evaluating hemodynamic effects in telemeterized mice, from which moderate decreases in blood pressure were observed.

Lymphatic Distribution of Etanercept Following Intravenous and Subcutaneous Delivery to Rats.

Purpose: The purpose of this work was to investigate the role of the lymphatic system in the pharmacokinetics of etanercept, a fusion protein.

Methods: Etanercept 1 mg/kg was administered intravenously (IV) and subcutaneously (SC) to thoracic lymph duct-cannulated and sham-operated control rats. Blood and lymph samples were obtained for up to 6 days.

Electronic clinical decision support to facilitate a change in clinical practice: Small details can make or break success.

Background: The use of electronic clinical decision support (CDS) is becoming common to change historically common clinical practices considered outdated by current guidelines. Preimplementation design of CDS tools is key to their success in changing clinical behaviors. Unfortunately, there are no established protocols for CDS tool development, and CDS failure can result from even small design flaws.

Discovery and SAR of aryl hydroxy pyrimidinones as potent small molecule agonists of the GPCR APJ.

This article describes the discovery of aryl hydroxy pyrimidinones and the medicinal chemistry efforts to optimize this chemotype for potent APJ agonism. APJ is a G-protein coupled receptor whose natural agonist peptide, apelin, displays hemodynamic improvement in the cardiac function of heart failure patients. A high throughput screen was undertaken to identify small molecule hits that could be optimized to mimic the apelin in vitro response.

Pharmacist involvement in clinical assessment and laboratory testing for heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a rare adverse drug reaction. The anti-PF4 antibody assay (ELISA) is utilized to assist in the clinical evaluation of HIT due to its high negative predictability and wide-spread availability. However, it also associated with false positive results.

Use of a Conformational-Switching Mechanism to Modulate Exposed Polarity: Discovery of CCR2 Antagonist BMS-741672.

We encountered a dilemma in the course of studying a series of antagonists of the G-protein coupled receptor CC chemokine receptor-2 (CCR2): compounds with polar C3 side chains exhibited good ion channel selectivity but poor oral bioavailability, whereas compounds with lipophilic C3 side chains exhibited good oral bioavailability in preclinical species but poor ion channel selectivity. Attempts to solve this through the direct modulation of physicochemical properties failed. However, the installation of a protonation-dependent conformational switching mechanism resolved the problem because it enabled a highly selective and relatively polar molecule to access a small population of a conformer with lower polar surface area and higher membrane permeability.

Sulfonylated Benzothiazoles as Inhibitors of Endothelial Lipase.

Endothelial lipase (EL) selectively metabolizes high density lipoprotein (HDL) particles. Inhibition of EL has been shown to increase HDL concentration in preclinical animal models and was targeted as a potential treatment of atherosclerosis. We describe the introduction of an α-sulfone moiety to a benzothiazole series of EL inhibitors resulting in increased potency versus EL.

Linking (Pyr)apelin-13 pharmacokinetics to efficacy: Stabilization and measurement of a high clearance peptide in rodents.

Apelin, the endogenous ligand for the APJ receptor, has generated interest due to its beneficial effects on the cardiovascular system. Synthesized as a 77 amino acid preproprotein, apelin is post-translationally cleaved to a series of shorter peptides. Though (Pyr)apelin-13 represents the major circulating form in plasma, it is highly susceptible to proteolytic degradation and has an extremely short half-life, making it challenging to quantify.

Discovery of 4-Azaindole Inhibitors of TGFβRI as Immuno-oncology Agents.

The multifunctional cytokine TGFβ plays a central role in regulating antitumor immunity. It has been postulated that inhibition of TGFβ signaling in concert with checkpoint blockade will provide improved and durable immune response against tumors. Herein, we describe a novel series of 4-azaindole TGFβ receptor kinase inhibitors with excellent selectivity for TGFβ receptor 1 kinase.

Interdisciplinary Diagnosis, Therapy and Follow-up of Patients with Endometrial Cancer. Guideline (S3-Level, AWMF Registry Nummer 032/034-OL, April 2018) - Part 1 with Recommendations on the Epidemiology, Screening, Diagnosis and Hereditary Factors of Endometrial Cancer.

The first German interdisciplinary S3-guideline on the diagnosis, therapy and follow-up of patients with endometrial cancer was published in April 2018. Funded by German Cancer Aid as part of an Oncology Guidelines Program, the lead coordinators of the guideline were the German Society of Gynecology and Obstetrics (DGGG) and the Gynecological Oncology Working Group (AGO) of the German Cancer Society (DKG). The use of evidence-based, risk-adapted therapy to treat low-risk women with endometrial cancer avoids unnecessarily radical surgery and non-useful adjuvant radiotherapy and/or chemotherapy.

The effect of recumbency position on the ultrasound measurement of the canine adrenal gland in non-adrenal gland illness.

Abdominal ultrasound is frequently used to assess the canine adrenal gland (AG) and subjective and objective features of normal AGs have been described. The effect of the dogs' recumbency position on the accuracy of AG measurement acquisition is not known. This prospective study, performed in dogs with non-adrenal illness, compared ultrasonographic AG measurements made in dogs placed in dorsal recumbency with those made in left or right lateral recumbency.