Medication use evaluation of programmed death-1 inhibitors in a veteran population.

OBJECTIVES: To evaluate the safety and efficacy of programmed death-1 immune checkpoint inhibitors in a clinical practice setting. METHODS: Chart reviews were conducted on a total of 21 Veterans with advanced or metastatic cancers treated with programmed death-1 checkpoint inhibitors between 1 January 2015 and 31 July 2017. Among them, 16 patients were treated with nivolumab, including 12 with non-small cell lung cancer, 2 with melanoma, and 2 with bladder cancer. Pembrolizumab was used in 5 patients, including 4 with melanoma and 1 with head and neck cancer. The clinical outcomes were assessed based on overall disease control rates, objective response rates, median progression free survival, and median overall survival. The safety of programmed death-1 checkpoint inhibitors was evaluated based on the incidence and the severity of immune-related adverse events as defined by National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. RESULTS: For nivolumab, the overall disease control rate was 63%, including 67% in non-small cell lung cancer and 100% in melanoma patients. The objective response rate was 31%, with partial response 25% and complete response 6%. The overall disease control rate was 100% for pembrolizumab, with objective response rate 100%, partial response 40%, and complete response 60%. The median progression free survival was 4.5 months with nivolumab, with 4.5 months in non-small cell lung cancer and 6 months in melanoma. Nivolumab showed median overall survival of 14 months across all patients and 13 months for non-small cell lung cancer. The median progression free survival and overall survival for pembrolizumab have not yet been reached, but 6-month progression free survival and overall survival rates were 80% and 100%, respectively. With nivolumab, 6-month and 12-month overall survival rates were 81% and 69%, respectively. The rate of overall toxicities (grades 2-4) was 90% for programmed death-1 checkpoint inhibitors, including 88% with nivolumab and 100% with pembrolizumab. The overall incidences of grade ≥ 3 immune-related adverse events was 24% (n = 5), occurring 25% (n = 4) with nivolumab and 20% (n = 1) with pembrolizumab. The major toxicities were endocrine and gastrointestinal related, occurring 71% and 33%, respectively. Most adverse events were clinically manageable. CONCLUSION: The clinical outcomes and the incidence of adverse events for programmed death-1 checkpoint inhibitors in our clinic patients are different from the data that have been published. This difference should be further investigated with a large real-world patient population.

Docetaxel-induced cardiac-respiratory arrest in a patient with chronic atrial fibrillation.

Docetaxel has been approved by the Food and Drug Administration for the treatment of many cancer types, including breast cancer, head and neck cancer, lung cancer, and prostate cancer. Many severe to life-threatening side effects (Grades 3-5) of docetaxel have been reported in clinical trials, case reports, and Food and Drug Administration Adverse Events Reporting System. These include anaphylactic reactions, febrile neutropenia, fluid retention, acute respiratory distress, pleural effusion, pneumonia, and peripheral neuropathy. There were fewer cardiac toxicities reported for docetaxel as compared to paclitaxel, which were less severe. In this report, we present a clinical case of docetaxel-induced cardiac-respiratory arrest in a 62-year-old Hispanic male patient with stable chronic atrial fibrillation, who has been recently diagnosed with metastatic prostate cancer. The cardiac event developed within 15 min of docetaxel infusion during the second cycle of chemotherapy despite using recommended premedication with corticosteroids.

The impacts of a pharmacist-managed outpatient clinic and chemotherapy-directed electronic order sets for monitoring oral chemotherapy.

Objectives Patients treated with oral chemotherapy appear to have less contact with the treating providers. As a result, safety, adherence, medication therapy monitoring, and timely follow-up may be compromised. The trend of treating cancer with oral chemotherapy agents is on the rise. However, standard clinical guidance is still lacking for prescribing, monitoring, patient education, and follow-up of patients on oral chemotherapy across the healthcare settings. The purpose of this project is to establish an oral chemotherapy monitoring clinic, to create drug and lab specific provider order sets for prescribing and lab monitoring, and ultimately to ensure safe and effective treatment of the veterans we serve. Methods A collaborative agreement was reached among oncology pharmacists, a pharmacy resident, two oncologists, and a physician assistant to establish a pharmacist-managed oral chemotherapy monitoring clinic at the VA Sierra Nevada Healthcare System. Drug-specific electronic order sets for prescribing and lab monitoring were created for initiating new drug therapy and prescription renewal. The order sets were created to be provider-centric, minimizing clicks needed to order necessary medications and lab monitoring. A standard progress note template was developed for documenting interventions made by the clinic. Patients new to an oral chemotherapy regimen were first counseled by an oncology pharmacist. The patients were then enrolled into the oral chemotherapy monitoring clinic for subsequent follow up and pharmacist interventions. Further, patients lacking monitoring or missing provider appointments were captured through a Clinical Dashboard developed by the US Department of Veterans Affairs (VA) Regional Office (VISN21) using SQL Server Reporting Services. Between September 2014 and April 2015, a total of 68 patients on different oral chemotherapy agents were enrolled into the clinic. Results Out of the 68 patients enrolled into the oral chemotherapy monitoring clinic, 31 patients (45%) were identified as having a therapy-related problem with their oral chemotherapy regimen on a gross measure for safety and appropriateness of medication management during the course of eight months follow-up between September 2014 and April 2015. In addition, the clinic helped to reestablish care for three patients (4.4%) who were lost to follow-up. The clinic identified 12 patients (17.6%) non-adherent to their prescribed regimen in some degree, where patients were suspected to miss doses due to delay in refilling prescriptions at least three days later than the expected date. However, these patients denied non-adherence. Among them, six patients (8.8%) were truly non-adherent. These patients stated that they had missed at least one day of therapy or were not taking the medication as prescribed. Medication regimen errors were discovered for five patients, accounting for a 7.3% medication-related error rate. Finally, seven patients (10.3%) were found to have an adverse reaction attributed to their oral chemotherapy. Two of them (2.9%) developed severe adverse reactions (Grade 3 and 4), which required hospitalization or immediate dose de-escalation. Conclusions The pilot clinic was able to identify current deficiencies and gaps in our practice settings for managing oral chemotherapy in a Veterans population. The oral chemotherapy monitoring clinic played a proactive role to identify preventable medication errors, monitor medication therapy, improve adherence, manage adverse drug reactions and re-establish care for patients who were lost to follow-up. The results suggest that close monitoring and follow-up of patients on oral chemotherapy is crucial to achieve therapeutic goals, improve patient safety and adherence, and to reduce drug adverse events and health care cost.

Activation of testicular orphan receptor 4 by fatty acids.

Nuclear receptors can be activated by chemicals, metabolites, hormones or environmental compounds to regulate gene expression. Bioassay-guided screening of mouse tissue extracts found that natural fatty acids of a certain carbon length and level of unsaturation could activate the mouse orphan nuclear receptor, testicular orphan receptor 4 (TR4). Subsequent experiments focused on gamma-linoleic acid, a compound identified during screening of mouse tissues that exerts regulatory activity in TR4 transactivation assays. gamma-linoleic acid positively modulates TR4 activity to promote the expression of downstream genes such as apolipoprotein E (ApoE) and phosphoenolpyruvate carboxykinase, and to activate a reporter carrying direct repeat 1 from the ApoE promoter. It also induced the interaction of TR4 with transcription coregulators such as RIP140 and PCAF. Comparisons of transactivation by TR4 and the metabolism-related peroxisome proliferator-activated nuclear receptors indicate that gamma-linoleic acid regulation is specific to TR4. The data suggest that TR4 might exert its physiological function by sensing certain lipids. Identifying these compounds could be useful for examining the physiological pathways in which TR4 and its target genes are involved.

Modulation of lysine acetylation-stimulated repressive activity by Erk2-mediated phosphorylation of RIP140 in adipocyte differentiation.

Receptor-interacting protein 140 is a co-regulator for many transcription factors. Previous mass spectrometry studies showed that either phosphorylation or lysine acetylation of RIP140 directly enhanced its trans-repressive activity. In this study, we first identified p300 as a specific lysine acetyltransferase, and extracellular-signal-related kinase 2 (Erk2) as a specific kinase for threonine phosphorylation, of RIP140 in vivo. We further determined two specific acetylated lysine residues (Lys(158)/Lys(287)) and phosphorylated threonine residues (Thr(202)/Thr(207)) that were critical for its gene-repressive activity. We then delineated signal transduction from Erk2-mediated phosphorylation of RIP140 that enhanced its recruiting p300 for subsequent lysine acetylation, and demonstrated the kinetics of activation of this signal transduction pathway in differentiating adipocytes. Finally, the physiological significance of this cell signal transduction pathway was illustrated in rescuing experiments where the defect in fat accumulation of RIP140-null cultures was rescued by re-expressing the wild type RIP140 or its phospho-mimetic mutant, but not its acetylation deficient mutant. These results demonstrate the signal transduction pathway, initiated from Erk2 activation for specific threonine phosphorylation, followed by p300 recruitment for lysine acetylation, which ultimately enhances the gene-repressive activity of RIP140 and its functional role in fat accumulation in differentiated adipocytes.

Utilizing Clinical Pharmacist Specialist to Manage Hepatitis C Virus Patients on Direct-Acting Antiviral Therapy.

OBJECTIVES: To evaluate outcomes of a clinical pharmacist specialist (CPS)-managed hepatitis C virus (HCV) treatment clinic (HCVTC) in treating HCV-infected veterans with direct-acting antivirals (DAAs). METHODS: We established a CPS-managed HCVTC under a collaborative practice agreement with our infectious disease physician (IDP). A total of 132 veterans were treated between November 1, 2014, and November 30, 2015. The CPS engaged in pretreatment screening, drug selection, patient education, medication counseling, drug therapy monitoring, drug utilization review, addressing issues on drug adherence, and routine and posttreatment follow-up of patients to assess sustained virologic response (SVR) after 12 weeks of treatment. RESULTS: Of 132 patients managed by the CPS, 87 (66%) were treated with ledipasvir/sofosbuvir (LDV/SOF), 29 (22%) with paritaprevir/ritonavir/ombitasvir + dasabuvir (PrOD), and 16 (12%) with sofosbuvir (SOF)-based regimen. The corresponding regimens demonstrated a SVR rate of 92% (n = 80), 100% (n = 29), and 93.8% (n = 15), respectively. We achieved an SVR rate of 94% against HCV genotype 1 (GT-1) and 100% against GT-2 to GT-4. The overall SVR rate was 94% across regimens, showing 93% in treatment-naive patients and 96% in treatment-experienced patients, and 93% in noncirrhotic and 94% in compensated cirrhotic patients. The results were comparable to SVR data reported in pivotal trials for DAAs. CONCLUSION: The results suggest that CPS could be effectively utilized in drug therapy management of HCV-infected patients treated with DAAs.

Kola acuminata proanthocyanidins: a class of anti-trypanosomal compounds effective against Trypanosoma brucei.

Human African trypanosomiasis is undergoing an alarming rate of recrudescence in many parts of sub-Saharan Africa. Yet, there is no successful chemotherapy for the disease due to a limited number of useful drugs, side effects and drawbacks of the existing medication, as well as the development of drug resistance by the parasite. Here we describe a new lead anti-trypanosomal compound isolated from Kola acuminata (Makasu). We purified a proanthocyanidin by chromatographic procedures and confirmed its homogeneity and structure by Nuclear Magnetic Resonance and Matrix-Assisted Laser Desorption Ionisation Time-of-Flight mass spectrometry, respectively. In vitro, this compound potently induced growth arrest and lysis of bloodstream form trypanosomes in a dose- and time-dependent manner. In a mouse model, it exhibited a trypanostatic effect that extended the life of infected, treated animals up to 8 days post-infection against the 4 days for infected, untreated animals. The proanthocyanidin showed a low cytotoxicity against mammalian cells, whereas treated-BF showed massive enlargement of their flagellar pocket and lysosome-like structures caused by an intense formation of multivesicular bodies and vesicles within these organelles. The observed ultrastructural alterations caused rupture of plasma membranes and the release of cell contents, indicative of a necrotic process rather than a programmed cell death. Interestingly, the proanthocyanidin acted against BF but not procyclic form trypanosomes. This new anti-trypanosomal compound should be further studied to determine its efficacy and suitability as an anti-trypanosomal drug and may be used as a tool to define novel specific drug targets in BF trypanosomes.

Protein kinase C-mediated phosphorylation of orphan nuclear receptor TR2: effects on receptor stability and activity.

In vivo metabolic labeling showed that orphan nuclear receptor TR2 could be phosphorylated. Systematic studies were conducted using specific kinases/phosphatase inhibitors to determine the enzymes responsible for TR2 phosphorylation and the effects of TR2 phosphorylation on its protein stability and activation of its target gene. The data showed that protein kinase C (PKC)-mediated phosphorylation enhanced the activating ability of TR2 on target gene RARbeta as well as its stability through protection from proteosome-mediated degradation. Several PKC-mediated potential serine/threonine phosphorylation sites on TR2 protein were predicted from the computer analysis using NetPhos software (http://us.expasy.org) and were commensurate by in vitro phosphorylation of purified TR2 protein using PKC enzyme. Two phosphorylation sites at Ser-461 and Ser-568 were identified by LC-ESI-MS/MS. Point mutations at Ser-568 or Ser-461 were prepared and evaluated for their biological activity. Ser-568, but not Ser-461, mutation significantly reduced PKC-mediated TR2 protein stability and its transcriptional activity.