Olanzapine for Non-Chemotherapy Related Nausea and Emesis in Patients with a Palliative Care Consult.

CONTEXT: Current palliative care guidelines lack a specific treatment algorithm for nausea and emesis. Olanzapine is an atypical antipsychotic with antiemetic activity that's recommended in the guidelines for the treatment of chemotherapy induced nausea and vomiting, but outside of oncologic indications there is a lack of research. OBJECTIVES: To describe the safety and efficacy of olanzapine for nausea and emesis in the palliative care domain, excluding patients actively undergoing chemotherapy or radiation. METHODS: This retrospective chart review encompassed hospitalized adult patients from six hospitals across a large health system admitted from August 2020 through August 2021, with a palliative care consult, and being treated with olanzapine for nausea or emesis. Data was collected on antiemetic therapy affordability, the ability for patients to tolerate medications by mouth, and safety outcomes such as QTc prolongation and increased liver function tests. RESULTS: A total of 78 patients were included in the study. Olanzapine decreased the number of doses required of antiemetic medications, the median doses of antiemetic medications pre-olanzapine was 1.6 (IQR 0.8-2.8) and post-olanzapine was 0.6 (IQR 0-2.4) (P = 0.0006). After olanzapine was initiated, appetite was improved (P < 0.001), cost of antiemetic therapy was reduced by 65 cents per day (P = 0.059) and olanzapine was prescribed at discharge in 69% of patients. QTc prolongation was observed in 19% of patients, and increased ALT and AST were observed in 4.3% and 0%, respectively. CONCLUSION: This retrospective review demonstrated benefit to utilizing olanzapine for nausea and emesis in palliative care patients and should be considered to aid in symptom management.

Improving the efficiency of integrated cancer screening delivery across multiple cancers: case studies from Idaho, Rhode Island, and Nebraska.

BACKGROUND: Three current and former awardees of the Centers for Disease Control and Prevention's Colorectal Cancer Control Program launched integrated cancer screening strategies to better coordinate multiple cancer screenings (e.g., breast, cervical, colorectal). By integrating the strategies, efficiencies of administration and provision of screenings can be increased and costs can be reduced. This paper shares findings from these strategies and describes their effects. METHODS: The Idaho Department of Health and Welfare developed a Baseline Assessment Checklist for six health systems to assess the current state of policies regarding cancer screening. We analyzed the checklist and reported the percentage of checklist components completed. In Rhode Island, we collaborated with a nurse-patient navigator, who promoted cancer screening, to collect details on patient navigation activities and program costs. We then described the program and reported total costs and cost per activity. In Nebraska, we described the experience of the state in administering an integrated contracts payment model across colorectal, breast, and cervical cancer screening and reported cost per person screened. Across all awardees, we interviewed key stakeholders. RESULTS: In Idaho, results from the checklist offered guidance on areas for enhancement before integrated cancer screening strategies, but identified challenges, including lack of capacity, limited staff availability, and staff turnover. In Rhode Island, 76.1% of 1023 patient navigation activities were for colorectal cancer screening only, with a much smaller proportion devoted to breast and cervical cancer screening. Although the patient navigator found the discussions around multiple cancer screening efficient, patients were not always willing to discuss all cancer screenings. Nebraska changed its payment system from fee-for-service to fixed cost subawards with its local health departments, which integrated cancer screening funding. Screening uptake improved for breast and cervical cancer but was mixed for colorectal cancer screening. CONCLUSIONS: The results from the case studies show that there are barriers and facilitators to integrating approaches to increasing cancer screening among primary care facilities. However, more research could further elucidate the viability and practicality of integrated cancer screening programs.

Evaluation of functional and binding assays in cells expressing either recombinant or endogenous hERG channel.

INTRODUCTION: The hERG (human ether-a-go-go related gene) potassium channel is required for normal cardiac repolarization, is susceptible to inhibition by a wide variety of compounds, and its blockage can lead to cardiac QT interval prolongation and life threatening arrhythmias. The present report examines the ability of hERG binding and functional assays to identify compounds with potential cardiovascular liabilities at the earliest stages of drug discovery. METHODS: Competitive binding assays were developed using (3)H-dofetilide and membranes from HEK293EBNA cells stably expressing recombinant hERG (HEK293-hERG) and IMR-32 cells expressing hERG endogenously. hERG functional assays were also developed using membrane potential indicator dye and rubidium efflux. The ability of these assays to identify compounds with potential adverse cardiac effects was examined using drugs with known cardiac effects ranging from those with no known adverse effects to drugs that were withdrawn from the market due to increased risk of sudden death associated with Torsades de Points. RESULTS: Binding assays using HEK293-hERG membranes and (3)H-dofetilide were robust (Z'=0.69+/-0.015, mean+/-S.E.M.), highly reproducible (test-retest slope=1.04, r(2)=0.98), and correlated well with IC(50) values obtained by patch clamp (slope=0.98, r(2)=0.89). Binding assays using IMR-32 membranes were less sensitive (Z'=0.4+/-0.03, mean+/-S.E.M., false negative rate=0.4) but still correlated well with patch clamp data (slope=1.06, r(2)=0.83). The hERG membrane potential assay could detect potent hERG inhibitors (defined by hERG patch clamp IC(50)<0.1 muM) using HEK293-hERG cells, but were prone to generate false-negative results with less potent inhibitors (false negative rate=0.5). Finally, the rubidium efflux assay gave highly reproducible results (Z'=0.80+/-0.02, mean+/-S.E.M.) that correlated with patch clamp IC(50) values (slope=0.87, r(2)=0.73). DISCUSSION: The hERG binding and rubidium efflux assays are robust, predictive of patch clamp results, and can be used at the earliest stages of drug discovery.

Identification of a novel extracellular cation-sensing G-protein-coupled receptor.

The C family G-protein-coupled receptors contain members that sense amino acid and extracellular cations, of which calcium-sensing receptor (CASR) is the prototypic extracellular calcium-sensing receptor. Some cells, such as osteoblasts in bone, retain responsiveness to extracellular calcium in CASR-deficient mice, consistent with the existence of another calcium-sensing receptor. We examined the calcium-sensing properties of GPRC6A, a newly identified member of this family. Alignment of GPRC6A with CASR revealed conservation of both calcium and calcimimetic binding sites. In addition, calcium, magnesium, strontium, aluminum, gadolinium, and the calcimimetic NPS 568 resulted in a dose-dependent stimulation of GPRC6A overexpressed in human embryonic kidney cells 293 cells. Also, osteocalcin, a calcium-binding protein highly expressed in bone, dose-dependently stimulated GPRC6A activity in the presence of calcium but inhibited the calcium-dependent activation of CASR. Coexpression of beta-arrestins 1 and 2, regulators of G-protein signaling RGS2 or RGS4, the RhoA inhibitor C3 toxin, the dominant negative Galpha(q)-(305-359) minigene, and pretreatment with pertussis toxin inhibited activation of GPRC6A by extracellular cations. Reverse transcription-PCR analyses showed that mouse GPRC6A is widely expressed in mouse tissues, including bone, calvaria, and the osteoblastic cell line MC3T3-E1. These data suggest that in addition to sensing amino acids, GPRC6A is a cation-, calcimimetic-, and osteocalcin-sensing receptor and a candidate for mediating extracellular calcium-sensing responses in osteoblasts and possibly other tissues.