Optimizing Symptoms and Management of Febrile Neutropenia among Cancer Patients: Current Status and Future Directions.

Curr Oncol Rep. 2017 Mar;19(3):20

Authors: Wang XJ, Chan A

Abstract
Febrile neutropenia (FN) is a common and serious complication among cancer patients undergoing myelosuppressive chemotherapy. FN should be treated as a medical emergency because it can lead to life-threatening complications if appropriate treatment is not initiated immediately. This study provides a critical review on the current management of FN and identifies possible directions to optimize FN management.

PMID: 28271398 [PubMed - indexed for MEDLINE]

Safety and Immunogenicity of the Recombinant Mycobacterium bovis BCG Vaccine VPM1002 in HIV-Unexposed Newborn Infants in South Africa.

Clin Vaccine Immunol. 2017 02;24(2):

Authors: Loxton AG, Knaul JK, Grode L, Gutschmidt A, Meller C, Eisele B, Johnstone H, van der Spuy G, Maertzdorf J, Kaufmann SH, Hesseling AC, Walzl G, Cotton MF, VPM Study Group

Abstract
Tuberculosis is a global threat to which infants are especially vulnerable. Effective vaccines are required to protect infants from this devastating disease. VPM1002, a novel recombinant Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccine previously shown to be safe and immunogenic in adults, was evaluated for safety in its intended target population, namely, newborn infants in a region with high prevalence of tuberculosis. A total of 48 newborns were vaccinated intradermally with VPM1002 (n = 36) or BCG Danish strain (n = 12) in a phase II open-labeled, randomized trial with a 6-month follow-up period. Clinical and laboratory measures of safety were evaluated during this time. In addition, vaccine-induced immune responses to mycobacteria were analyzed in whole-blood stimulation and proliferation assays. The safety parameters and immunogenicity were comparable in the two groups. Both vaccines induced interleukin-17 (IL-17) responses; however, VPM1002 vaccination led to an increase of CD8(+) IL-17(+) T cells at the week 16 and month 6 time points. The incidence of abscess formation was lower for VPM1002 than for BCG. We conclude that VPM1002 is a safe, well-tolerated, and immunogenic vaccine in newborn infants, confirming results from previous trials in adults. These results strongly support further evaluation of the safety and efficacy of this vaccination in larger studies. (This study has been registered at ClinicalTrials.gov under registration no. NCT01479972.).

PMID: 27974398 [PubMed - indexed for MEDLINE]

Non-cytochrome P450-mediated bioactivation and its toxicological relevance.

Drug Metab Rev. 2016 Nov;48(4):473-501

Authors: Gan J, Ma S, Zhang D

Abstract
The bioactivation of drugs is often associated with toxicological outcomes; however, for most cases, the causal relationship between bioactivation and toxicity is not well established despite extensive research that attempts to elucidate the mechanisms leading to the formation of chemically reactive species, presumably the initial step towards adverse reactions. Due to rapid advancement in the research of cytochrome P450s (CYPs) and the prevalence of CYP involvement in the metabolic clearance of pharmaceuticals, CYP-mediated bioactivation is widely investigated and reviewed, while non-CYP-mediated bioactivation has not been emphasized. The widespread use of metabolic stability screening in drug discovery, however, has led to the identification of new chemical entities that rely on non-CYP enzymes for clearance, and the number of drugs that undergo metabolism via these enzymes has increased. Non-CYP enzymes can be divided into four general categories according to their enzymatic function, namely, oxidative, reductive, conjugative and hydrolytic. The aim of this review is to complement the existing literature on CYP-mediated metabolism by focusing on bioactivation mediated non-CYP enzymes and provide representative examples in each category.

PMID: 27533622 [PubMed - indexed for MEDLINE]

Safety of Recombinant Fusion Protein ESAT6-CFP10 as a Skin Test Reagent for Tuberculosis Diagnosis: an Open-Label, Randomized, Single-Center Phase I Clinical Trial.

Clin Vaccine Immunol. 2016 Sep;23(9):767-73

Authors: Li F, Xu M, Zhou L, Xiong Y, Xia L, Fan X, Gu J, Pu J, Lu S, Wang G

Abstract
This trial was conducted to explore the safety of recombinant fusion protein ESAT6-CFP10 as a skin test reagent for the diagnosis of Mycobacterium tuberculosis infection. Twenty-four healthy adult volunteers were recruited and randomized into four groups (groups A to D) to study four increasing doses of ESAT6-CFP10. All subjects in each dose group received an intradermal injection of reagent (0.1 ml) via the Mantoux technique. Then, the vital signs of all subjects were monitored, and skin reactions around injection sites and adverse events were recorded at different detection time points after the skin test. No serious adverse events were observed in this study. A total of 3 subjects had unexpected events. One subject in group A developed subcutaneous hemorrhage 24 h after the skin test, one subject in group B was found with red spots 15 min after the skin test, and another subject in group A showed abnormity during a chest X-ray after the skin test without affecting her health. One of three adverse events (red spots) was probably related to the recombinant ESAT6-CFP10 reagent. A single dose of 1, 5, 10, or 20 μg/ml of recombinant ESAT6-CFP10 as a skin test reagent for M. tuberculosis infection diagnosis is well tolerated and safe in China. (This study has been registered at ClinicalTrials.gov under registration no. NCT01999231.).

PMID: 27413070 [PubMed - indexed for MEDLINE]

Pharmacokinetics of Co-Formulated Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate After Switch From Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate in Healthy Subjects.

J Acquir Immune Defic Syndr. 2016 Jul 01;72(3):281-8

Authors: Ramanathan S, Custodio JM, Wei X, Wang H, Fordyce M, Dave A, Ling KH, Szwarcberg J, Kearney BP

Abstract
BACKGROUND: Elvitegravir (EVG), a HIV integrase inhibitor, is metabolized primarily by CYP3A, and secondarily by UGT1A1/3; Efavirenz (EFV), a HIV non-nucleoside reverse transcriptase inhibitor, is metabolized by Cytochrome P450 (CYP) 2B6 and induces CYP3A and uridine diphosphate glucuronosyltransferase (UGT) with residual effects post discontinuation because of long T1/2 (40-55 hours). This study evaluated the pharmacokinetics after switching from efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) to elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF).
METHODS: Healthy subjects (n = 32 including n = 8 CYP2B6 poor metabolizers) received EVG/COBI/FTC/TDF (150/150/200/300 mg) on days 1-7, and after a washout, received EFV/FTC/TDF (600/200/300 mg) on days 15-28 and switched to EVG/COBI/FTC/TDF (150/150/200/300 mg) for 5 weeks (days 29-62). Pharmacokinetic assessments occurred on days 7, 28, 35, and 42; trough samples (Ctrough) were collected periodically until day 63. Safety was assessed throughout the study.
RESULTS: Twenty-nine subjects completed with 3 adverse events leading to discontinuation; no grade ≥3 adverse events were reported. Post-EFV/FTC/TDF, mean EVG area under concentration (AUCtau) was 37% and 29% lower and mean Ctrough ∼3- and ∼5-fold above IC95, respectively, on days 35 and 42, and 7-8-fold above IC95 by 5 weeks. COBI AUCtau returned to normal by day 42. EVG glucuronide, GS-9200, AUCtau was higher (46% and 32% on days 35 and 42, respectively) postswitch. CYP2B6 poor metabolizers displayed higher EFV AUCtau and Cmax (125% and 91%, respectively) versus non-poor metabolizers, and lower EVG and COBI exposures. EFV Ctrough was >IC90 (10 ng/mL) in all subjects postswitch. FTC and tenofovir (TFV) exposures were unaffected.
CONCLUSIONS: After EFV/FTC/TDF to EVG/COBI/FTC/TDF switch, EVG and/or EFV exposures were in an active range. These findings support further evaluation of switching regimens in HIV-1 patients.

PMID: 26885802 [PubMed - indexed for MEDLINE]

Depletion of enteric bacteria diminishes leukocyte infiltration following doxorubicin-induced small intestinal damage in mice.

PLoS One. 2017;12(3):e0173429

Authors: Carr JS, King S, Dekaney CM

Abstract
BACKGROUND & AIMS: While enteric bacteria have been shown to play a critical role in other forms of intestinal damage, their role in mediating the response to the chemotherapeutic drug Doxorubicin (Doxo) is unclear. In this study, we used a mouse model of intestinal bacterial depletion to evaluate the role enteric bacteria play in mediating Doxo-induced small intestinal damage and, more specifically, in mediating chemokine expression and leukocyte infiltration following Doxo treatment. An understanding of this pathway may allow for development of intervention strategies to reduce chemotherapy-induced small intestinal damage.
METHODS: Mice were treated with (Abx) or without (NoAbx) oral antibiotics in drinking water for four weeks and then with Doxo. Jejunal tissues were collected at various time points following Doxo treatment and stained and analyzed for apoptosis, crypt damage and restitution, and macrophage and neutrophil number. In addition, RNA expression of inflammatory markers (TNFα, IL1-β, IL-10) and cytokines (CCL2, CC7, KC) was assessed by qRT-PCR.
RESULTS: In NoAbx mice Doxo-induced damage was associated with rapid induction of apoptosis in jejunal crypt epithelium and an increase weight loss and crypt loss. In addition, we observed an increase in immune-modulating chemokines CCL2, CCL7 and KC and infiltration of macrophages and neutrophils. In contrast, while still positive for induction of apoptosis following Doxo treatment, Abx mice showed neither the overall weight loss nor crypt loss seen in NoAbx mice nor the increased chemokine expression and leukocyte infiltration.
CONCLUSION: Enteric bacteria play a critical role in Doxo-induced small intestinal damage and are associated with an increase in immune-modulating chemokines and cells. Manipulation of enteric bacteria or the damage pathway may allow for prevention or treatment of chemotherapy-induced small intestinal damage.

PMID: 28257503 [PubMed - indexed for MEDLINE]

Safety of measles-containing vaccines in post-marketing surveillance in Anhui, China.

PLoS One. 2017;12(2):e0172108

Authors: Meng FY, Sun Y, Shen YG, Pan HF, Tang JH, Wang BB, Wu CH, Ye DQ

Abstract
The safety of measles vaccination is of great interest and importance to public health practice and the general society. We have analyzed the adverse events following immunization (AEFIs) of currently used measles-containing vaccines (including live attenuated measles vaccine, live attenuated measles and rubella combined vaccine, live attenuated measles and mumps combined vaccine, live attenuated Measles, Mumps and Rubella Combined Vaccine) in Anhui Province, China. From 2009 to 2014, 9.9 million doses of measles-containing vaccines were administrated and 1893 AEFIs were found (191.4 per million doses), of which, 33 serious AEFIs (3.3 per million vaccine doses) were reported. 59.4% (1124 cases) were male cases, and 85.1% (1611 cases) occurred in persons aged < 1 year. 93.3% (1766 cases) occurred at the first dose of vaccination and 95.9% (1815 cases) were found within 3 days after vaccination. This study presents up-to-date data and suggests that the measles-containing vaccines used in Anhui Province of China are safe.

PMID: 28192490 [PubMed - indexed for MEDLINE]

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Utilization of iPSC-derived human neurons for high-throughput drug-induced peripheral neuropathy screening.

Toxicol In Vitro. 2017 Aug 23;:

Authors: Rana P, Luerman G, Hess D, Rubitski E, Adkins K, Somps C

Abstract
As the number of cancer survivors continues to grow, awareness of long-term toxicities and impact on quality of life after chemotherapy treatment in cancer survivors has intensified. Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common side effects of modern chemotherapy. Animal models are used to study peripheral neuropathy and predict human risk; however, such models are labor-intensive and limited translatability between species has become a major challenge. Moreover, the mechanisms underlying CIPN have not been precisely determined and few human neuronal models to study CIPN exist. Here, we have developed a high-throughput drug-induced neurotoxicity screening model using human iPSC-derived peripheral-like neurons to study the effect of chemotherapy agents on neuronal health and morphology using high content imaging measurements (neurite length and neuronal cell viability). We utilized this model to test various classes of chemotherapeutic agents with known clinical liability to cause peripheral neuropathy such as platinum agents, taxanes, vinca alkaloids, proteasome inhibitors, and anti-angiogenic compounds. The model was sensitive to compounds that cause interference in microtubule dynamics, especially the taxane, epothilone, and vinca alkaloids. Conversely, the model was not sensitive to platinum and anti-angiogenic chemotherapeutics; compounds that are not reported to act directly on neuronal processes. In summary, we believe this model has utility for high-throughput screening and prediction of human risk for CIPN for novel chemotherapeutics.

PMID: 28843493 [PubMed - as supplied by publisher]

A pilot trial of nivolumab treatment for advanced non-small cell lung cancer patients with mild idiopathic interstitial pneumonia.

Lung Cancer. 2017 Sep;111:1-5

Authors: Fujimoto D, Morimoto T, Ito J, Sato Y, Ito M, Teraoka S, Otsuka K, Nagata K, Nakagawa A, Tomii K

Abstract
INTRODUCTION: Nivolumab has demonstrated efficacy against metastatic non-small cell lung cancer (NSCLC). However, immune-related adverse events can occur, among which pneumonitis is relatively common. Lung cancer patients with idiopathic interstitial pneumonia (IIP) have a higher risk of pneumonitis associated with anticancer therapy. We hypothesized that the benefit of nivolumab may outweigh the risks of pneumonitis in patients with NSCLC who have mild IIP. We performed a pilot trial to evaluate the safety of nivolumab in NSCLC patients with mild IIP.
METHODS: Previously treated, inoperable NSCLC patients with mild IIP were enrolled. Mild IIP was defined as having a predicted vital capacity ≥80% and a possible usual interstitial pneumonia (UIP) or inconsistent with UIP pattern on chest high-resolution computed tomography. Patients received nivolumab at a dose of 3mg/kg biweekly.
RESULTS: Six patients were enrolled in this trial between April 2016 and December 2016. None experienced drug-related nonhematologic grade 3/4 or hematologic grade 4 adverse events in the 12 weeks following the initiation of nivolumab treatment. Furthermore, none of the patients had pneumonitis of any grade. At the time of analysis, all patients were alive, and 3 had experienced a partial response.
CONCLUSIONS: Nivolumab therapy may be feasible in NSCLC patients with mild IIP. (Trial registration number: UMIN000022037).

PMID: 28838377 [PubMed - in process]

[Arterial Hyper- and Hypotension associated with psychiatric medications: a risk assessment based on the summaries of product characteristics (SmPCs)].

Dtsch Med Wochenschr. 2017 Aug;142(16):e100-e107

Authors: Freudenmann RW, Freudenmann N, Zurowski B, Schönfeldt-Lecuona C, Maier L, Schmieder RE, Lange-Asschenfeldt C, Gahr M

Abstract
Introduction Psychiatric medications are well-known triggers of clinically relevant blood pressure changes. Therefore, we aimed at creating ranking lists for their risk of causing arterial hyper- or hypotension. Methods We analyzed 784 Summaries of Product characteristics (SmPCs, available online from "Rote Liste" or "Gelbe Liste" websites) from 105 psychiatric medications registered in adult psychiatry in Germany and extracted the standardized reported risks of increasing or decreasing arterial blood pressure. Results According to the SmPCs, atomoxetine had the highest risk of arterial hypertension ("very frequent", > 10 %), and another 15 substances followed in the category "frequent" (> 1 %): duloxetine, milnacipran, venlafaxine, bupropion, citalopram, tranylcypromine (particularly with certain diets), reboxetine, methylphenidate, clozapine, paliperidone, risperidone, buprenorphine+naloxone, memantine, galantamine, and rivastigmine. Conversely, 7 substances, namely amitriptyline, tranylcypromine, chlorprothixen, flupentixol, levomepromazine, olanzapine and trimipramine had the highest reported risk of low blood pressure ("very frequent"), and another 25 substances had the risk "frequent". No risk of hypertension or hypotension was documented for many other substances. Incidentally, we observed that the reported effects on blood pressure for single substances (e. g. citalopram) markedly differed between the SmPCs from different manufacturers, rendering a clear risk assessment impossible for many medications. Discussion According to the German SmPc, many psychiatric medications are associated with the risk of arterial hypertension and, even more so, hypotension. We hardly observed substance group effects, such as high blood pressure with noradrenergic antidepressants. Commonly used tables summarising secondary causes of arterial hypertension should be revised in terms of psychiatric medications. Our rank orders of risk may aid choosing the best psychiatric medications in patients with known hypertension or at risk for syncope, as well as when blood pressure changes occur under psychiatric pharmacotherapy. A definitive risk assessment however requires controlled studies.

PMID: 28645134 [PubMed - indexed for MEDLINE]

Nicotine Withdrawal, Relapse of Mental Illness, or Medication Side-Effect? Implementing a Monitoring Tool for People With Mental Illness Into Quitline Counseling.

J Dual Diagn. 2017 Jan-Mar;13(1):60-66

Authors: Segan CJ, Baker AL, Turner A, Williams JM

Abstract
BACKGROUND: Smokers with mental illness and their health care providers are often concerned that smoking cessation will worsen mental health. Smokers with mental illness tend to be more nicotine-dependent and experience more severe symptoms of nicotine withdrawal, some of which are difficult to distinguish from psychiatric symptoms. In addition, smoking cessation can increase the blood levels and hence side effects of some psychotropic medications. Improved monitoring of nicotine withdrawal and medication side effects may help distinguish temporary withdrawal symptoms from psychiatric symptoms and facilitate targeted treatment to help smokers with mental illness manage the acute phase of nicotine withdrawal.
OBJECTIVE: The aim of this research was to examine the acceptability and feasibility to quitline counselors of implementing structured assessments of nicotine withdrawal and common medication side effects in people with mental illness who are quitting smoking using a telephone smoking cessation service.
METHODS: Monitoring involves administering (once pre-cessation and at each contact post-cessation) (1) the Minnesota Nicotine Withdrawal Scale, assessing eight symptoms: anger, anxiety, depression, cravings, difficulty concentrating, increased appetite, insomnia, and restlessness and (2) an adverse side effects checklist of 5 to 10 symptoms, for example, dry mouth and increased thirst. Following a 1-day update training in mental health, quitline counselors were asked to offer these assessments to callers disclosing mental illness in addition to usual counseling. Group interviews with counselors were conducted 2 months later to examine implementation barriers and benefits.
RESULTS: Barriers included awkwardness in integrating a new structured practice into counseling, difficulty in limiting some callers to only the content of new items, and initial anxieties about how to respond to changes in some symptoms. Benefits included the ability to provide objective feedback on changes in symptoms, as this identified early benefits of quitting, provided reassurance for clients, and provided an opportunity for early intervention where symptoms worsened.
CONCLUSIONS: Structured monitoring of withdrawal symptoms and medication side effects was able to be integrated into the quitline's counseling and was valued by counselors and clients. Given evidence of its benefits in this limited pilot study, we recommend it be considered for larger-scale adoption by quitlines.

PMID: 28067594 [PubMed - indexed for MEDLINE]

A Systematic Review and Network Meta-Analysis to Evaluate the Comparative Efficacy of Interventions for Unfit Patients with Chronic Lymphocytic Leukemia.

Adv Ther. 2016 Oct;33(10):1814-1830

Authors: Städler N, Shang A, Bosch F, Briggs A, Goede V, Berthier A, Renaudin C, Leblond V

Abstract
INTRODUCTION: Rituximab plus fludarabine and cyclophosphamide (RFC) is the standard of care for fit patients with untreated chronic lymphocytic leukemia (CLL); however, its use is limited in 'unfit' (co-morbid and/or full-dose F-ineligible) patients due to its toxicity profile. We conducted a systematic review and Bayesian network meta-analysis (NMA) to determine the relative efficacy of commercially available interventions for the first-line treatment of unfit CLL patients.
METHODS: For inclusion in the NMA, studies had to be linked via common treatment comparators, report progression-free survival (PFS), and/or overall survival (OS), and meet at least one of the five inclusion criteria: median cumulative illness score >6, median creatinine clearance ≤70 mL/min, existing co-morbidities, median age ≥70 years, and no full-dose F in the comparator arm. A manual review, validated by external experts, of all studies that met at least one of these criteria was also performed to confirm that they evaluated first-line therapeutic options for unfit patients with CLL.
RESULTS: In unfit patients, the main NMA (five studies for PFS and four for OS) demonstrated clear preference in terms of PFS for obinutuzumab + chlorambucil (G-Clb) versus rituximab + chlorambucil (R-Clb), ofatumumab + chlorambucil (O-Clb), fludarabine and chlorambucil (median hazard ratios [HRs] 0.43, 0.33, 0.20, and 0.19, respectively), and a trend for better efficacy versus rituximab + bendamustine (R-Benda) and RFC-Lite (median HR 0.81 and 0.88, respectively). OS results were generally consistent with PFS data, (median HR 0.48, 0.53, and 0.81, respectively) for G-Clb versus Clb, O-Clb, and R-Clb 0.35 and 0.81 versus F and R-Benda, respectively); however, the OS findings were associated with higher uncertainty. Treatment ranking reflected improved PFS and OS with G-Clb over other treatment strategies (median rank of one for both endpoints).
CONCLUSION: G-Clb is likely to show superior efficacy to other treatment options selected in our NMA for unfit treatment-naïve patients with CLL.
FUNDING: F. Hoffmann-La Roche Ltd.

PMID: 27535291 [PubMed - indexed for MEDLINE]

The Role of the Pharmacist in the Treatment of Patients with Infantile Hemangioma Using Propranolol.

Adv Ther. 2016 Oct;33(10):1831-1839

Authors: Castaneda S, Melendez-Lopez S, Garcia E, De la Cruz H, Sanchez-Palacio J

Abstract
INTRODUCTION: Infantile hemangiomas (IH) are the most common benign vascular tumors of childhood, with an incidence of 5-10% during the first year of age. Propranolol is considered the first-line treatment for this condition. Potentially there is a high probability of negative results to therapy, because in many countries there are no treatment protocols or propranolol formulations appropriate for the pediatric population. The objective of the present study was to evaluate the impact of pharmacist interventions such as detecting, analyzing, and solving problems presented during treatment with propranolol in patients with IH.
METHODS: An open observational prospective study was performed over 25 months in a group of pediatric patients diagnosed with infantile hemangioma treated with propranolol. Pharmacist participation consisted of development of an extemporaneous formulation and counseling the child's parents. At each visit to the pharmacy service, family members were interviewed, detecting and classifying problems related to treatment.
RESULTS: Sixty-three children with IH were treated during the period under review. Patient ages ranged from 3 to 11 months old; 64% were female and 36% were male. Forty-nine problems in 30 patients were detected, principally inadequate dose (18.4%), non-adherence to treatment (16.3%), side effects (14.3%), and wrong administration (14.3%). Of the problems detected, 81.6% were resolved. Interventions by the pharmacist in 27 patients were intensive counseling on adherence to therapy (20%), detection of adverse effects (11.4%), and adjustment of the dose (22.9%). In 95.2% of patients a good response to treatment was obtained compared with 77.2% reported in European studies without pharmacist intervention.
CONCLUSION: It seems that pharmacist participation increases adherence to treatment and reduces the likelihood of adverse effects, allowing for safe and effective therapy in patients with IH.

PMID: 27461120 [PubMed - indexed for MEDLINE]

Safety and Antitumor Activity of Pembrolizumab in Patients With Programmed Death-Ligand 1-Positive Nasopharyngeal Carcinoma: Results of the KEYNOTE-028 Study.

J Clin Oncol. 2017 Aug 24;:JCO2017733675

Authors: Hsu C, Lee SH, Ejadi S, Even C, Cohen RB, Le Tourneau C, Mehnert JM, Algazi A, van Brummelen EMJ, Saraf S, Thanigaimani P, Cheng JD, Hansen AR

Abstract
Purpose To establish the safety profile and antitumor activity of the anti-programmed death 1 receptor monoclonal antibody, pembrolizumab, in patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) that expressed programmed death-ligand 1 (PD-L1). Patients and Methods KEYNOTE-028 (NCT02054806) is a nonrandomized, multicohort, phase Ib trial of pembrolizumab in patients with PD-L1-positive advanced solid tumors. Key eligibility criteria for the NPC cohort included unresectable or metastatic disease, failure on prior standard therapy, and PD-L1 expression in 1% or more of tumor cells or tumor-infiltrating lymphocytes. Patients received pembrolizumab 10 mg/kg every 2 weeks up to 2 years or until disease progression or unacceptable toxicity. Primary end point was objective response rate (ORR) per investigator review. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) every 8 weeks for the first 6 months and every 12 weeks thereafter. Results Twenty-seven patients received pembrolizumab. Median age was 52.0 years (range, 18 to 68 years); 92.6% received prior therapies for RM-NPC; 70.4% had received three or more therapies. Partial response and stable disease were observed in seven and 14 patients, respectively, for an ORR of 25.9% (95% CI, 11.1 to 46.3) over a median follow-up of 20 months. ORR by central review was similar (26.3%). Drug-related adverse events that occurred in 15% or more of patients included rash (25.9%), pruritus (25.9%), pain (22.2%), hypothyroidism (18.5%), and fatigue (18.5%). Grade ≥ 3 drug-related adverse events occurred in eight patients (29.6%), and there was one drug-related death (sepsis). As of the data cutoff (June 20, 2016), two patients remained on pembrolizumab treatment. Conclusion Pembrolizumab demonstrated antitumor activity and a manageable safety profile in patients with RM-NPC.

PMID: 28837405 [PubMed - as supplied by publisher]

Keratitis in association with herpes zoster and varicella vaccines.

Drugs Today (Barc). 2017 Jul;53(7):393-397

Authors: Grillo AP, Fraunfelder FW

Abstract
The objective of this review was to collect reports of keratitis in association with herpes zoster virus (HZV) or varicella zoster virus (VZV) vaccines. HZV vaccination is intended for at-risk adult populations and VZV vaccination is intended for all pediatric patients. We reviewed the literature and reports of keratitis in association with herpes zoster or varicella vaccine from the National Registry of Drug-Induced Ocular Side Effects and the World Health Organization. Twenty-four cases of unilateral keratitis in association with VZV vaccines were collected from the adverse reaction databases and literature. In most cases, the onset of keratitis occurred within days of vaccination and resolved with topical steroid eye drops and oral acyclovir. Data suggest that keratitis in association with herpes zoster or varicella vaccine is rare, is usually self-limited or resolves with treatment. The mechanism may be the persistence of viral antigens in the cornea after VZV vaccination or herpes zoster ophthalmicus. This reaction is probable, given the plausible biological mechanism, the temporal relationship between vaccination and keratitis, and overall patterns of presentation after vaccination.

PMID: 28837183 [PubMed - in process]

Regulatory T-Cell Augmentation or Interleukin-17 Inhibition Prevents Calcineurin Inhibitor-Induced Hypertension in Mice.

Hypertension. 2017 Jul;70(1):183-191

Authors: Chiasson VL, Pakanati AR, Hernandez M, Young KJ, Bounds KR, Mitchell BM

Abstract
The immunosuppressive calcineurin inhibitors cyclosporine A and tacrolimus alter T-cell subsets and can cause hypertension, vascular dysfunction, and renal toxicity. We and others have reported that cyclosporine A and tacrolimus decrease anti-inflammatory regulatory T cells and increase proinflammatory interleukin-17-producing T cells; therefore, we hypothesized that inhibition of these effects using noncellular therapies would prevent the hypertension, endothelial dysfunction, and renal glomerular injury induced by calcineurin inhibitor therapy. Daily treatment of mice with cyclosporine A or tacrolimus for 1 week significantly decreased CD4(+)/FoxP3(+) regulatory T cells in the spleen and lymph nodes, as well as induced hypertension, vascular injury and dysfunction, and glomerular mesangial expansion in mice. Daily cotreatment with all-trans retinoic acid reported to increase regulatory T cells and decrease interleukin-17-producing T cells, prevented all of the detrimental effects of cyclosporine A and tacrolimus. All-trans retinoic acid also increased regulatory T cells and prevented the hypertension, endothelial dysfunction, and glomerular injury in genetically modified mice that phenocopy calcineurin inhibitor-treated mice (FKBP12-Tie2 knockout). Treatment with an interleukin-17-neutralizing antibody also increased regulatory T-cell levels and prevented the hypertension, endothelial dysfunction, and glomerular injury in cyclosporine A-treated and tacrolimus-treated mice and FKBP12-Tie2 knockout mice, whereas an isotype control had no effect. Augmenting regulatory T cells and inhibiting interleukin-17 signaling using noncellular therapies prevents the cardiovascular and renal toxicity of calcineurin inhibitors in mice.

PMID: 28584011 [PubMed - indexed for MEDLINE]

Medication Regimen Complexity in Long-Term Care Facilities and Adverse Drug Events-Related Hospitalizations.

Consult Pharm. 2017 May 01;32(5):281-284

Authors: Tam SHY, Hirsch JD, Watanabe JH

Abstract
Adverse drug events (ADE) are a leading cause of mortality in the United States. Recent studies have demonstrated a high level of complex medication regimens in institutionalized residents. Evidence of the relationship between medication regimen complexity (MRC) and ADE-related rehospitalizations or emergency department (ED) visits is evolving. Therefore, there is a demand for better characterization and study of MRC as an objective identifier to quickly screen and prioritize high-risk patients for follow-up medication management therapy. This manuscript will serve as a brief summary review of the current findings regarding the relationship between MRC and hospital readmission and ED usage and provide strategies for pharmacists to more efficiently evaluate complex medication regimens and optimize therapies.

PMID: 28483008 [PubMed - indexed for MEDLINE]

Dangers of Nonprescription Medicines: Educating and Counseling Older Adults.

Consult Pharm. 2017 May 01;32(5):269-280

Authors: Kinsey JD, Nykamp D

Abstract
OBJECTIVE: To provide a review for health care providers regarding appropriate education and counseling for older adults involving commonly used nonprescription medicines with potential for adverse effects, drug-drug interactions, or toxicity when incorrectly selected or overused.
DATA SOURCES: A literature search was performed using MEDLINE and PUBMED to locate relevant articles. DAILYMED was used for manufacturer dosage recommendations. Additionally, peer-reviewed textbooks were consulted for evidence-based standards of care.
STUDY SELECTION/DATA EXTRACTION: Articles were reviewed and selected for inclusion based on relevance to the subject and accuracy of information provided. Articles chosen were published between March 2008 and December 2016. Additionally, several textbook chapters providing information for nonprescription medicines chosen for evaluation in this review were used.
DATA SYNTHESIS: Nonprescription medicines are accessible and widely used by older adults. Polypharmacy and drug duplication are concerns because of negative outcomes. Given the accessibility and knowledge of pharmacists, they are often asked questions regarding nonprescription medicines.
CONCLUSION: Pharmacists have a duty and responsibility to commit to lifelong learning and to provide appropriate education and counseling on the use of nonprescription medicines. This will help decrease overall health care costs and potential negative problems associated with polypharmacy among older adults that include adverse effects, toxicity, and drug-drug interactions.

PMID: 28483007 [PubMed - indexed for MEDLINE]

Neda Leonard: Filling a Void.

Consult Pharm. 2017 May 01;32(5):256-257

Authors:

PMID: 28483005 [PubMed - indexed for MEDLINE]