Comparing the safety and efficacy of intravenous naloxone administration in opioid-naive and opioid-tolerant hospitalized oncology patients.

OBJECTIVE: To compare naloxone doses and clinical outcomes after emergency opioid reversal in opioid-naïve and opi-oid-tolerant inpatients. DESIGN: Cross-sectional, retrospective chart review. SETTING: Comprehensive cancer center. PATIENTS: In-patients who received ≥1 dose of intravenous naloxone for emergency opioid reversal between 2014 and 2018. METHODS: Patients were classified as opioid-tolerant based on opioid dosing history ≥60 morphine milligram equivalents/day for ≥7 consecutive days prior to naloxone administration. Response to naloxone was based on documentation of improvement in respiratory rate to >10 breaths/min or improved response to stimuli. OUTCOMES: Naloxone doses and clinical outcomes after naloxone administration. RESULTS: Ninety-three naloxone episodes (58 opioid-naive and 35 opioid-tolerant) in 80 unique patients were included. No differences between opioid-naïve and opioid-tolerant groups were found for naloxone mean starting doses (0.14 mg vs 0.19 mg, p = 0.35), total doses (0.50 mg vs 0.32 mg, p = 0.07), and response rates (74.1 percent vs 77.1 percent, p = 0.81). Naloxone adverse reactions were more frequent in the opioid-tolerant group than the opioid-naïve group (opioid withdrawal symptoms (OWSs): 14.3 percent vs 0 percent; increase in pain: 20 percent vs 8.6 percent, p = 0.002). CONCLUSIONS: In opioid-tolerant patients, naloxone total doses required and response rates were similar to opioid-naïve patients. Use of opioid dosing history to identify potentially opioid-dependent patients should be considered prior to naloxone administration to guide dosing and reduce the risk for precipitating OWSs.

A Longitudinal Integrative Course Series to Prepare Students for Advanced Pharmacy Practice Experiences.

Background: This paper describes a series of integrative courses intentionally designed to prepare students for Advanced Pharmacy Practice Experiences (APPEs) in a block system curriculum. Innovation: Three integration blocks are interspersed throughout the didactic curriculum to serve as checkpoints to ensure competency as students progress in the curriculum, rather than waiting until the end to determine competency. Complex patient case discussions and a series of high-stakes assessments are used to reinforce and evaluate cumulative retention of knowledge, skills, and attitudes. Findings: Class of 2022 exam results showed that in the cohort of students who failed the high-stakes comprehensive knowledge assessment (CKA) and pharmacy calculations exams during the first integration block (IB), failure rates decreased in subsequent IBs, indicating early detection of knowledge deficiencies and either exam performance improvement in each IB or failure to progress to the next IB. A survey of the same cohort indicated that the final integration block prior to advanced pharmacy practice experiences (APPEs) helped improve confidence in applying key knowledge and skills into practice. Conclusion: The series of integration blocks designed and implemented at WesternU provides opportunities to reinforce knowledge and skills while requiring students to demonstrate maintenance of core competency as they progress through the curriculum.

Biological predictors of chemotherapy-induced peripheral neuropathy (CIPN): MASCC neurological complications working group overview.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating condition associated with a number of chemotherapeutic agents. Drugs commonly implicated in the development of CIPN include platinum agents, taxanes, vinca alkaloids, bortezomib, and thalidomide analogues. As a drug response can vary between individuals, it is hypothesized that an individual's specific genetic variants could impact the regulation of genes involved in drug pharmacokinetics, ion channel functioning, neurotoxicity, and DNA repair, which in turn affect CIPN development and severity. Variations of other molecular markers may also affect the incidence and severity of CIPN. Hence, the objective of this review was to summarize the known biological (molecular and genomic) predictors of CIPN and discuss the means to facilitate progress in this field.

Effect of isavuconazole on tacrolimus and sirolimus serum concentrations in allogeneic hematopoietic stem cell transplant patients: A drug-drug interaction study.

INTRODUCTION: Isavuconazole, a triazole antifungal, is an inhibitor of cytochrome P450 3A4, which also metabolizes tacrolimus and sirolimus. In previous studies, isavuconazole administration increased tacrolimus and sirolimus area under the curve values by 2.3-fold and 1.8-fold, respectively, in healthy adults and tacrolimus concentration/dose (C/D) ratio by 1.3-fold in solid organ transplant patients. We aimed to determine the magnitude of effect of isavuconazole administration on tacrolimus and sirolimus C/D ratios in allogeneic hematopoietic stem cell transplant (alloHSCT) patients. METHODS: A retrospective, single-center, single-arm study in adult alloHSCT patients who received at least 10 days of combination therapy with isavuconazole and tacrolimus and/or sirolimus as inpatients or outpatients was conducted. Tacrolimus and sirolimus trough serum concentrations were measured up to twice weekly for up to 4 weeks. RESULTS: Twenty-two patients receiving tacrolimus and twenty patients receiving sirolimus met the inclusion criteria. The mean C/D ratio increased from baseline by 1.42-fold for tacrolimus during week 1 (P = 0.002) and up to 1.56-fold for sirolimus during week 2 (P = 0.02). For the remaining timepoints, tacrolimus and sirolimus C/D ratios were not statistically significantly different from baseline. CONCLUSION: In alloHSCT patients, modest increases in tacrolimus and sirolimus C/D ratios from baseline were observed within the first 2 weeks after initiation of isavuconazole.

Improving Pharmacy Calculations Using an Instructional Design Model.

Objective. To describe an evidence-based instructional design to improve performance and foster retention of pharmacy students' calculation skills longitudinally across the curriculum. Methods. Gagne's nine events of instructional design were employed in a longitudinal pharmacy calculations curriculum. Mean pharmacy calculation examination scores from four courses spanning the didactic curriculum for four different academic years (before and after the redesign) were compared. Results. Students demonstrated more stable outcomes with consistently higher means after the redesign, which may indicate improved retention. Additionally, the post-redesign classes have experienced fewer failures (score of <80%). Conclusion. Using an instructional design model to optimize immediate instructional outcomes is an effective method of enhancing retention of calculation skills over time.

Off-Label Use of Dexmedetomidine for the Treatment of Delirium in the Intensive Care Unit.

OBJECTIVE: Evaluate recent clinical studies involving the use of dexmedetomidine (DEX) infusion for the treatment of delirium in the intensive care unit (ICU). METHODS: A literature search was conducted to identify peer-reviewed articles in MEDLINE (1966-June 2016) using the terms sedation, analgesic, dexmedetomidine, delirium, and critically ill adult patients. RESULTS: Two studies in the ICU setting reported the potential benefits of DEX for managing agitation during weaning from mechanical ventilation. One pilot study and a clinical trial reported the use of DEX in the treatment of ICU delirium. CONCLUSION: Further studies are required to evaluate the use of DEX treatment in critically ill patients presenting with delirium.

Decreased responsiveness to oxycodone: A case of a pharmacokinetic drug interaction?

Concurrent administration of oxycodone and phenytoin may cause, through induction of CYP3A4 enzymes, decreased analgesic effects of oxycodone. However, no descriptions of this interaction exist. A patient who was on oxycodone for chronic back pain was admitted to the hospital. Five days after initiating fosphenytoin, the patient experienced a dramatic escalation in his pain and lack of response to oxycodone breakthrough doses. Changing oxycodone to hydromorphone resulted in significantly improved analgesia. Concurrent use of fosphenytoin and oxycodone may increase the conversion of oxycodone to inactive metabolites, resulting in decreased analgesia. This may be avoided using hydromorphone, morphine, or oxymorphone.

Management of drug interaction between posaconazole and sirolimus in patients who undergo hematopoietic stem cell transplant.

STUDY OBJECTIVE: To determine an appropriate empiric oral sirolimus dose adjustment when given concurrently with posaconazole oral suspension in patients who undergo hematopoietic stem cell transplant (HSCT). DESIGN: Retrospective cohort study. SETTING: Comprehensive cancer center in the United States. SUBJECTS: Seventy five allogeneic HSCT patients who received posaconazole oral suspension and oral sirolimus concurrently between 2009 and 2011. MEASUREMENTS AND MAIN RESULTS: Sirolimus concentrations were recorded at baseline and for up to 28 days after posaconazole initiation. The sirolimus concentration/dose (C/D) ratio was determined for each sirolimus concentration obtained. Following analysis of patient data and based on the initial empiric sirolimus dose reduction, patients were stratified into two groups: ≥50% sirolimus dose reduction (Group 1) and <50% sirolimus dose reduction (Group 2). The mean sirolimus C/D ratio was 2.29 ng/mL/mg prior to posaconzole initiation. Coadministration of posaconazole and sirolimus resulted in an increase in the steady state sirolimus C/D ratio to 6.24 ng/mL/mg, which occurred approximately 17-20 days after initiation of posaconazole. The mean maximum sirolimus concentration was significantly higher in Group 2 compared to Group 1 (12.64 ng/mL vs. 9.24 ng/mL, p=0.001). Significantly more patients in Group 2 than Group 1 experienced at least one sirolimus concentration >15 ng/mL (27% vs. 2.6%, p=0.003). CONCLUSION: Coadministration of posaconazole oral suspension with oral sirolimus increases the sirolimus C/D ratio by approximately 2.7-fold in HSCT patients. An initial empiric oral sirolimus dose reduction between 50% and 65% may be recommended for most clinically stable patients with close sirolimus concentration monitoring for at least 3 weeks following posaconazole initiation.

Molecular signatures in the prevention of radiation damage by the synergistic effect of N-acetyl cysteine and qingre liyan decoction, a traditional chinese medicine, using a 3-dimensional cell culture model of oral mucositis.

Qingre Liyan decoction (QYD), a Traditional Chinese medicine, and N-acetyl cysteine (NAC) have been used to prevent radiation induced mucositis. This work evaluates the protective mechanisms of QYD, NAC, and their combination (NAC-QYD) at the cellular and transcriptional level. A validated organotypic model of oral mucosal consisting of a three-dimensional (3D) cell tissue-culture of primary human keratinocytes exposed to X-ray irradiation was used. Six hours after the irradiation, the tissues were evaluated by hematoxylin and eosin (H and E) and a TUNEL assay to assess histopathology and apoptosis, respectively. Total RNA was extracted and used for microarray gene expression profiling. The tissue-cultures treated with NAC-QYD preserved their integrity and showed no apoptosis. Microarray results revealed that the NAC-QYD caused the upregulation of genes encoding metallothioneins, HMOX1, and other components of the Nrf2 pathway, which protects against oxidative stress. DNA repair genes (XCP, GADD45G, RAD9, and XRCC1), protective genes (EGFR and PPARD), and genes of the NFκB pathway were upregulated. Finally, tissue-cultures treated prophylactically with NAC-QYD showed significant downregulation of apoptosis, cytokines and chemokines genes, and constrained damage-associated molecular patterns (DAMPs). NAC-QYD treatment involves the protective effect of Nrf2, NFκB, and DNA repair factors.

Combating an Epidemic of Prescription Opioid Abuse.

The past decade has witnessed an alarming increase in the number of deaths due to prescription opioids that has paralleled the rise in the number of opioid prescriptions dispensed. Prescription drug monitoring programs, abuse-deterrent formulations and proper disposal of opioids have been promoted to help combat the opioid epidemic. We discuss changes that dentists, the third most frequent prescribers of opioids, can implement to help reduce the risk of prescription opioid abuse in their communities.

A review of statin use and prostate cancer.

Prostate cancer is the second most common cause of cancer and, when it metastasizes, has a high mortality rate. Statins may affect prostate cancer progression through cholesterol- and pleiotropic-mediated effects. The data on statin effects on prostate cancer has been mixed with benefit most likely occurring in reducing prostate cancer recurrence after radiation therapy and reduced mortality due to prostate cancer. More research is needed in this area to better characterize potential statin-mediated mechanisms that affect cancer. Also, future studies should report patients' anatomic/prognostic stage based on the updated staging system of the American Joint Committee on Cancer, which is a more effective predictor of recurrence and mortality than anatomic stage alone.

Nutraceuticals for prostate cancer chemoprevention: from molecular mechanisms to clinical application.

INTRODUCTION: Nutraceutical is a food, or part of a food, used for the prevention and/or treatment of diseases. A number of nutraceuticals serve as candidates for development of prostate cancer chemopreventive agents because of promising epidemiological, preclinical and pilot clinical findings. Their mechanisms of action may involve an ability to target multiple molecular pathways in carcinogenesis without eliciting toxic side effects. AREAS COVERED: This review provides an overview of several nutraceuticals, including green tea polyphenol, omega-3 fatty acids, vitamin D, lycopene, genistein, quercetin, resveratrol and sulforaphane, for the clinical relevance to chemoprevention of prostate cancer. Their mechanisms of action on regulating key processes of carcinogenesis are also discussed. For each of these agents, a brief summary of completed or currently ongoing clinical trials related to the chemopreventive efficacy on prostate cancer is given. EXPERT OPINION: Even though a few clinical trials have been conducted, review of these results indicate that further studies are required to confirm the clinical efficacy and safety, and to provide a guidance on how to use nutraceuticals for optimal effect. Future cancer prevention clinical trials for the nutraceuticals should recruit men with an increased risk of prostate cancer.

Identifying cell and molecular stress after radiation in a three-dimensional (3-D) model of oral mucositis.

Mucositis is a debilitating adverse effect of chemotherapy and radiation treatment. It is important to develop a simple and reliable in vitro model, which can routinely be used to screen new drugs for prevention and treatment of mucositis. Furthermore, identifying cell and molecular stresses especially in the initiation phase of mucositis in this model will help towards this end. We evaluated a three-dimensional (3-D) human oral cell culture that consisted of oral keratinocytes and fibroblasts as a model of oral mucositis. The 3-D cell culture model was irradiated with 12 or 2 Gy. Six hours after the irradiation we evaluated microscopic sections of the cell culture for evidence of morphologic changes including apoptosis. We used microarrays to compare the expression of several genes from the irradiated tissue with identical genes from tissue that was not irradiated. We found that irradiation with 12 Gy induced significant histopathologic effects including cellular apoptosis. Irradiation significantly affected the expression of several genes of the NF-kB pathway and several inflammatory cytokines, such as IL-1B, 1L-8, NF-kB1, and FOS compared to tissue that was not irradiated. We identified significant upregulation of several genes that belong to damage-associated molecular patterns (DAMPs) such as HMB1, S100A13, SA10014, and SA10016 in the 3-D tissues that received 12 Gy but not in tissues that received 2 Gy. In conclusion, this model quantifies radiation damage and this is an important first step towards the development 3-D tissue as a screening tool.

Harnessing traditional Chinese medicine to improve cancer therapy: issues for future development.

Traditional Chinese medicine (TCM) has recently yielded a number of chemical compounds with clinically significant anticancer activity. The theory of TCM formulas, however, unlike Western medicine, is based on the interactions of the various Chinese medicinal materials in the body, rather than the activity of a single purified chemical compound. Mechanisms for the possible synergistic anticancer effects of components in TCM formulas have recently been postulated. Advanced research on the clinical effects of TCM formulas, however, has been hampered by inconsistent dosage formulations and unreliable quality control. Scientific challenges in dosage formulation and methods for ensuring quality control of TCM products will be discussed.