Search

Objective: To compare naloxone doses and clinical outcomes after emergency opioid reversal in opioid-naïve and opioid-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.

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.

Background Patients (pts) with newly diagnosed acute myeloid leukemia (AML) undergoing induction chemotherapy are at increased risk for invasive fungal infections (IFI). Guidelines recommend posaconazole prophylaxis (ppx), but use is precluded by interactions and adverse effects. Micafungin (MCF) is an alternative, but data is limited by small prospective and retrospective studies. Primary objective: describe incidence of probable/proven IFI until neutrophil recovery (ANC ≥ 500 cells/µL) or 28 days after induction start date, whichever occurred first, in pts receiving MCF ppx. Secondary objective: describe incidence of clinical failure to MCF prophylaxis. Methods Retrospective review (January 2017 to January 2020) of newly diagnosed AML adult pts undergoing 7 + 3 using idarubicin (7 + 3-ida), 7 + 3 using daunorubicin (7 + 3-dau), venetoclax/decitabine (VEN/DEC), or venetoclax/azacitadine (VEN/AZA) receiving MCF ppx for at least 7 days included. Diagnosis of IFI < 30 days prior to induction, liver function tests (LFT) 5x ULN at start of induction, or evidence of refractory disease after induction excluded. Probable/proven IFI defined by EORTC criteria. Clinical failure: changing to a different antifungal class for any reason until ANC recovery or 28 days after induction start date. Results Ninety-five pts included. Baseline characteristics: mean (±SD) age 57.8 (±13.0) years; 53.6% males. 62% (59/95) 7 + 3-ida, 13.7% (13/95) 7 + 3-dau, 15.8% (15/95) VEN/DEC, 8.4% (8/95) VEN/AZA. Mean (±SD): 32.5% (±26) blasts, WBC 13.2 (±23.8), ANC 2.4 (±4.6), ALC 1.9 (±1.6), platelets 92.6 (±123.2). Incidence of probable IFI 2/95 (2.1%). No proven IFI cases identified. Clinical failure occurred in 37/95 (39%): 8 persistent febrile neutropenia, 29 due to suspected IFI. No MCF discontinuation due to adverse events. Conclusion Our findings suggest that prophylactic MCF is safe and effective in pts with newly diagnosed AML undergoing induction chemotherapy. Outcomes were similar to those of prophylactic posaconazole studies, indicating MCF may be considered as an alternative when interactions and adverse effects preclude use of posaconazole. Our study was limited by small numbers, retrospective, single-center design. Future opportunities include prospective trials of prophylactic MCF in this setting. Disclosures All Authors: No reported disclosures

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, andXRCC1), protective genes (EGFRandPPARD), 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.

Chronic myeloid leukemia (CML) is a haematopoietic neoplasm with clinically distinct phases and BCR⁄ABL1 oncogene. Imatinib mesylate, a potent inhibitor of BCR-ABL was highly effective in CML but later in-vitro derived cell line with resistance namely BCR-ABL duplication point mutation, P loop mutation, T315I mutation, C helix, SH2 domain, activation loop, C terminal lobe, SRC family kinase activation led to development of Nilotinib. Although it has potential drug targets as BCR-ABL kinase, KIT, PDGFR but has no role in overcoming in Src family kinase. It prompted strategic rational drug design of Dual Src Family Kinase/Abl Inhibitor Dasatinib, active against 15 clinically significant Imatinib resistant BCR-ABL mutations but inactive against T315I mutation. The propensity of Ph+ CML to develop novel mechanism of resistance led designing of rational therapeutic approaches to eradicate minutest residual diseases along with long term resistance risk. DOI: http://dx.doi.org/10.3126/ajms.v6i1.10454 Asian Journal of Medical Sciences Vol.6(1) 2015 8-15

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.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.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.

Evaluate recent clinical studies involving the use of dexmedetomidine (DEX) infusion for the treatment of delirium in the intensive care unit (ICU).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.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.Further studies are required to evaluate the use of DEX treatment in critically ill patients presenting with delirium.

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.

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.

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

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.

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.

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).Retrospective cohort study.Comprehensive cancer center in the United States.Seventy five allogeneic HSCT patients who received posaconazole oral suspension and oral sirolimus concurrently between 2009 and 2011.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) and50% 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 concentration15 ng/mL (27% vs. 2.6%, p=0.003).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.

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.

Objective:To identify risk factors associated with an unexpected outbreak of pyrogenic reactions (PR) following intravenous gentamicin.Design:We conducted two cohort studies. PRs were defined as chills, rigors, or shaking within 3 hours after initiating the gentamicin infusion during the preepidemic (December 1, 1997-January 15,1998) or epidemic (May 1-June 15,1998) periods. We tested gentamicin vials for endotoxin using the limulus amebocyte lysate assay.Setting:Inpatient services of a large community hospital in Los Angeles, California.Results:During the epidemic period, 22 (15%) of 152 patients developed documented PRs following intravenous gentamicin. PRs were more likely among patients receiving single daily dosing (SDD) than multiple daily dosing gentamicin (20/73 [27%] vs 2/79 [3%]; relative risk, 10.8; 95% confidence interval, 2.644.7). Laboratory analysis of gentamicin vials found endotoxin levels that were higher among Fujisawa-brand gentamicin (implicated brand) than gentamicin used after the outbreak terminated (non-implicated brand). Although endotoxin levels in the vials did not exceed US Pharmacopeia limits (1.7 endotoxin units/mg gentamicin), the use of SDD gentamicin may place patients at greater risk of receiving doses of endotoxin above the threshold for PRs in humans.Conclusions:Reassessment of the acceptable amounts of endotoxin in gentamicin and other parenteral products should be considered when dosing intervals used in clinical practice change.

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.