Acute kidney injury (AKI) is a potentially fatal syndrome characterized by a rapid decline in kidney function caused by ischemic or toxic injury to renal tubular cells. The widely used chemotherapy drug cisplatin accumulates preferentially in the renal tubular cells and is a frequent cause of drug-induced AKI. During the development of AKI the quiescent tubular cells reenter the cell cycle. Strategies that block cell-cycle progression ameliorate kidney injury, possibly by averting cell division in the presence of extensive DNA damage. However, the early signaling events that lead to cell-cycle activation during AKI are not known. In the current study, using mouse models of cisplatin nephrotoxicity, we show that the G1/S-regulating cyclin-dependent kinase 4/6 (CDK4/6) pathway is activated in parallel with renal cell-cycle entry but before the development of AKI. Targeted inhibition of CDK4/6 pathway by small-molecule inhibitors palbociclib (PD-0332991) and ribociclib (LEE011) resulted in inhibition of cell-cycle progression, amelioration of kidney injury, and improved overall survival. Of additional significance, these compounds were found to be potent inhibitors of organic cation transporter 2 (OCT2), which contributes to the cellular accumulation of cisplatin and subsequent kidney injury. The unique cell-cycle and OCT2-targeting activities of palbociclib and LEE011, combined with their potential for clinical translation, support their further exploration as therapeutic candidates for prevention of AKI.

Purpose With the rapid spread of COVID-19 in New York City since early March 2020, innovative measures were needed for clinical pharmacy specialists to provide direct clinical care safely to cancer patients. Allocating the workforce was necessary to meet the surging needs of the inpatient services due to the COVID-19 outbreak, which had the potential to compromise outpatient services. We present here our approach of restructuring clinical pharmacy services and providing direct patient care in outpatient clinics during the pandemic. Data sources We conducted a retrospective review of electronic clinical documentation involving clinical pharmacy specialist patient encounters in 9 outpatient clinics from March 1, 2020 to May 31, 2020. The analysis of the clinical pharmacy specialist interventions and the impact of the interventions was descriptive. Data summary As hospital services were modified to handle the surge due to COVID-19, select clinical pharmacy specialists were redeployed from the outpatient clinics or research blocks to COVID-19 inpatient teams. During these 3 months, clinical pharmacy specialists were involved in 2535 patient visits from 9 outpatient clinics and contributed a total of 4022 interventions, the majority of which utilized telemedicine. The interventions provided critical clinical pharmacy care during the pandemic and omitted 199 in-person visits for medical care. Conclusion The swift transition to telemedicine allowed the provision of direct clinical pharmacy services to patients with cancer during the COVID-19 pandemic.

Solithromycin is a novel ketolide antibiotic with activity against a broad spectrum of intracellular organisms, including those displaying macrolide resistance. While demonstrating noninferiority to a current first-line agent in the treatment of CABP, concerns for drug-induced liver injury and infusion-site reactions have placed its regulatory future in doubt.

Acute myeloid leukemia (AML) is a debilitating and life-threatening condition, especially for elderly patients who account for over 50% of diagnoses. For over four decades, standard induction therapy with intensive cytotoxic chemotherapy for AML had remained unchanged. However, for most patients, standard therapy continues to have its shortcomings, especially for elderly patients who may not be able to tolerate the complications from intensive cytotoxic chemotherapy. New research into the development of targeted and alternative therapies has led to a new era in AML therapy. For the nearly 20% of diagnoses harboring a mutation in isocitrate dehydrogenase 1 or 2 (IDH1/2), potential treatment options have undergone a paradigm shift away from intensive cytotoxic chemotherapy and towards targeted therapy alone or in combination with lower intensity chemotherapy. The first FDA approved IDH2 inhibitor was enasidenib in 2017. In addition, IDH1 inhibitors are in ongoing clinical studies, and the oral BCL-2 inhibitor venetoclax shows preliminary efficacy in this subset of patients. These new tools aim to improve outcomes and change the treatment paradigm for elderly patients with IDH mutant AML. However, the challenge of how to best incorporate these agents into standard practice remains.

Objective: To review the pharmacology, pharmacokinetics, efficacy, and safety of selinexor for management of relapsed multiple myeloma (MM). Data Sources: A literature search was performed of PubMed and MEDLINE databases (January 1, 2000, to November 14, 2019), abstracts from the American Society of Hematology and the American Society of Clinical Oncology, and ongoing studies from US National Institutes of Health ClinicalTrials.gov. Queries were performed using key words selinexor, SINE, XPO1, and Xpovio. Study Selection/Data Extraction: Human and animal studies related to the pharmacology, pharmacokinetics, efficacy, and safety of selinexor were identified. Data Synthesis: Although numerous advances have been made in MM management, there remains an unmet need for treatment of heavily relapsed/refractory disease. Selinexor is a first-in-class selective inhibitor of nuclear export, which, through inhibition of exportin-1, causes accumulation of tumor suppressor proteins, reduction in oncoproteins, and apoptosis of plasma cells. Selinexor exhibited an overall response in 26% of patients with multiply relapsed MM. Median progression-free survival was 3.7 months, and overall survival was 8.6 months. Common adverse effects include thrombocytopenia, neutropenia, fatigue, and nausea. Ongoing studies are investigating combination therapies utilizing selinexor. Relevance to Patient Care and Clinical Practice: This review describes the efficacy, safety, and clinical applicability of selinexor, a novel agent with potential to meet an unmet need in refractory MM. Conclusion: Selinexor has demonstrated activity in a heavily refractory patient population. Given the adverse effect profile and associated costs, additional studies are needed to further elucidate the appropriate clinical scenario and combinations for selinexor use.

Innovative catheter systems with lower-profile sheaths and a dynamic expansion mechanism (DEM) were recently introduced for transcatheter aortic valve replacement (TAVR). However, the labeling of 14 F and 16 F eSheaths denote the inner nominal diameter. Exact changes of the clinically relevant outer diameters during usage are not available. eSheaths were measured every 30 mm using a digital caliper. Unused 14 F and 16 F eSheaths served as controls. Maximum eSheath diameters were measured after insertion of the Edwards Commander Delivery System (ECDS) into 14 F and 16 F eSheaths.Finally, eSheaths were retrieved and measured after TAVR. Outer diameters of control 14 F eSheaths were 5.8 mm and 6.50 mm for the 16 F eSheath. Introduction of the 23 mm and 26 mm ECDS into 14 F eSheaths showed a maximum diameter of 7.65 mm and 7.64 mm (P = NS). Introduction of the 29 mm ECDS into the 16 F eSheath showed the greatest diameter of 8.18 mm (P = 0.03). After TAVR, diameters of the 14 F eSheaths were 7.14 mm (23 mm valve) and 7.26 mm (26 mm valve) (P = NS), while 16 F eSheaths were 8.10 mm (29 mm valve) (P ≤ 0.03). Nominal 14 F and 16 F eSheaths showed a significant increase of the outer diameter during advancement of the ECDS and after TAVR implantation.

Poly(ADP-Ribose) Polymerase (PARP) is a family of enzymes involved in DNA repair, genome stability, cellular energy metabolism and cell division. Inhibition of PARP-1, the well characterized member of this family, has been explored as a strategy for enhancing anti-cancer activity of existing drugs and for developing new drugs. Recently unique enzymatic properties and biological functions of PARP-2 and PARP-3 have been discovered, further expanding the utility of PARP as a target for cancer pharmacotherapy. We compare and contrast the structural and enzymatic properties of these three members of the PARP family. Interactions of these enzymes with proteins specific to different DNA repair pathways are summarized. Further, we evaluate progress on development of PARP inhibitors as anticancer agents. Results of Phase I and Phase II clinical trials of seven PARP inhibitors, used alone or in combination with known anticancer agents are reviewed highlighting common observations regarding the maximum tolerable dose, adverse reactions profile, PARP inhibition and anticancer effects. While further clinical studies are warranted, based on current data, Olaparib (Ola), Veliparib (Veli) and Rucaparib (Ruca) offer considerable potential. Prolonged exposure to Ola and Veli leads to resistant cancer cells, primarily through restoration of the HR pathway, overexpression of the P-glycoprotein efflux pump or modulation of PARP expression. Some resistant cancer cells continue to respond to platinum based drugs, encouraging further development of PARP inhibitors for cancer treatment. Future course of this research, specifically focusing on use of PARP inhibition as a strategy for personalized cancer therapy, is discussed.

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