Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.

Ann Oncol. 2017 Jul 01;28(suppl_4):iv119-iv142

Authors: Haanen JBAG, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, Jordan K, ESMO Guidelines Committee

PMID: 28881921 [PubMed - indexed for MEDLINE]

Management of infusion reactions to systemic anticancer therapy: ESMO Clinical Practice Guidelines.

Ann Oncol. 2017 Jul 01;28(suppl_4):iv100-iv118

Authors: Roselló S, Blasco I, García Fabregat L, Cervantes A, Jordan K, ESMO Guidelines Committee

PMID: 28881914 [PubMed - indexed for MEDLINE]

Predictors on admission of functional decline among older patients hospitalised for acute care: A prospective observational study.

Australas J Ageing. 2017 Dec;36(4):E57-E63

Authors: Basic D, Ní Chróinín D, Conforti D, Shanley C

Abstract
OBJECTIVE: We sought to investigate the incidence of, and factors associated with, in-hospital functional decline among older acute hospital patients.
METHODS: We conducted a prospective observational study of consecutive patients admitted under geriatric medicine over 5 years. The primary outcome measure was functional decline between admission and discharge, representing deterioration in any of the following: Modified Barthel Index (MBI), independence in Timed Up and Go test or walking, and/or need for walking aid.
RESULTS: Overall, 56% (950/1693) patients (mean age 81.9 years) exhibited in-hospital functional decline. Premorbid MBI (odds ratio (OR) 1.05 per unit increase, P < 0.001), adverse drug reaction (OR 1.50, P = 0.001) and in-hospital consultation as the referral source (OR 1.57, P = 0.001) were independently associated with functional decline, adjusting for age, dementia and nursing home residence.
CONCLUSION: These factors may aid identification of vulnerable patients who might particularly benefit from targeted multidisciplinary intervention. Further studies validating this, and exploring the impact of focussed management, are needed.

PMID: 28856791 [PubMed - indexed for MEDLINE]

The Interplay between Pharmacokinetics and Pharmacodynamics.

Pediatr Rev. 2017 May;38(5):195-206

Authors: Sandritter TL, McLaughlin M, Artman M, Lowry J

PMID: 28461611 [PubMed - indexed for MEDLINE]

Common and Rare Ocular Side-effects of the Dexamethasone Implant.

Ocul Immunol Inflamm. 2017 Dec;25(6):834-840

Authors: Fassbender Adeniran JM, Jusufbegovic D, Schaal S

Abstract
PURPOSE: Expanding indications for use, and overall increased use of the slow-release dexamethasone (DEX) implant yields an opportunity to study the reported ocular side-effects and adverse events associated with this drug.
METHODS: A PubMed.gov (US National Library of Medicine, National Institutes of Health) review of literature for the search terms, "Ozurdex and complication," through December 2015.
RESULTS: Ocular hypertension and cataract are the main long-term sequelae identified in large, randomized clinical trials. Case reports have emerged regarding implant migration, complications with implantation, infection, and posterior segment sequelae, including vitreomacular traction.
CONCLUSION: DEX implant overall is well-tolerated and, with careful monitoring, can be a useful adjunct to treating macular edema associated with diabetes, retinal vein occlusion, and chronic uveitis.

PMID: 27379861 [PubMed - indexed for MEDLINE]

The affinity of antipsychotic drugs to dopamine and serotonin 5-HT2 receptors determines their effects on prefrontal-striatal functional connectivity.

Eur Neuropsychopharmacol. 2018 Jul 10;:

Authors: Tollens F, Gass N, Becker R, Schwarz AJ, Risterucci C, Künnecke B, Lebhardt P, Reinwald J, Sack M, Weber-Fahr W, Meyer-Lindenberg A, Sartorius A

Abstract
One of the major challenges of cross-species translation in psychiatry is the identification of quantifiable brain phenotypes linked to drug efficacy and/or side effects. A measure that has received increasing interest is the effect of antipsychotic drugs on resting-state functional connectivity (FC) in magnetic resonance imaging. However, quantitative comparisons of antipsychotic drug-induced alterations of FC patterns are missing. Consideration of receptor binding affinities provides a means for the effects of antipsychotic drugs on extended brain networks to be related directly to their molecular mechanism of action. Therefore, we examined the relationship between the affinities of three second-generation antipsychotics (amisulpride, risperidone and olanzapine) to dopamine and serotonin receptors and FC patterns related to the prefrontal cortex (PFC) and striatum in Sprague-Dawley rats. FC of the relevant regions was quantified by correlation coefficients and local network properties. Each drug group (32 animals per group) was subdivided into three dose groups and a vehicle control group. A linear relationship was discovered for the mid-dose of antipsychotic compounds, with stronger affinity to serotonin 5-HT2A, 5-HT2C and 5-HT1A receptors and decreased affinity to D3 receptors associated with increased prefrontal-striatal FC (p = 0.0004, r² = 0.46; p = 0.004, r² = 0.33; p = 0.002, r² = 0.37; p = 0.02, r² = 0.22, respectively). Interestingly, no correlation was observed for the low and high dose groups, and for D2 receptors. Our results indicate that drug-induced FC patterns may be linked to antipsychotic mechanism of action on the molecular level and suggest the technique's value for drug development, especially if our results are extended to a larger number of antipsychotics.

PMID: 30006253 [PubMed - as supplied by publisher]

12 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2018/07/14

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

12 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2018/07/14

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

16 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2018/07/13

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

16 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2018/07/13

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

The use of carbon dioxide insufflation to facilitate identification of intestinal injuries in patients undergoing cytoreductive surgery and intraperitoneal chemotherapy.

Tech Coloproctol. 2017 06;21(6):479-480

Authors: Kozman MA, Fisher OM, Valle SJ, Alzahrani N, Morris DL

PMID: 28616792 [PubMed - indexed for MEDLINE]

State-of-the-Art Metabolic Toxicity Screening and Pathway Evaluation.

Anal Chem. 2016 05 03;88(9):4584-99

Authors: Hvastkovs EG, Rusling JF

Abstract
Routine in vitro bioassays and animal toxicity studies of drug and environmental chemical candidates fail to reveal toxicity in ∼30% of cases. This Feature article addresses research on new approaches to in vitro toxicity testing as well as our own efforts to produce high-throughput genotoxicity arrays and LC-MS/MS approaches to reveal possible chemical pathways of toxicity.

PMID: 27043322 [PubMed - indexed for MEDLINE]

Possible associations of personality traits representing harm avoidance and self-directedness with medication adherence in Japanese patients with type 2 diabetes.

J Pharm Health Care Sci. 2018;4:16

Authors: Tominaga Y, Aomori T, Hayakawa T, Kijima N, Morisky DE, Takahashi K, Mochizuki M

Abstract
Background: Insufficient medication adherence in diabetes patients, of which numbers continue to increase globally, remains a critical issue. Medication adherence is multifactorial and determined by interactions among factors including socioeconomic status, health care team and system, condition, therapy, and patient-specific factors. On the other hand, personality traits have been studied in adherence other than to medication. Using the instruments of Temperament and Character Inventory (TCI), Harm Avoidance (TCI-HA) and Self-directedness (TCI-SD) showed distinguishing associations with adherence of health-related programs. However, few studies have been performed to elucidate psychometric properties related to medication adherence. We investigated how TCI-HA and TCI-SD of patients with diabetes are related to medication adherence.
Method: A cross-sectional survey was conducted among type 2 diabetes patients recruited at medical institutions or via an online research company. Medication adherence was measured using the 8-item Morisky Medication Adherence Scale (MMAS-8). Personality traits were assessed using the established scales of TCI-HA and TCI-SD. Univariate and multivariate regression analyses of the MMAS-8 scores were performed in addition to assessing demographic and disease characteristics and TCI-HA and TCI-SD.
Results: A total of 358 responses were analyzed. Multivariate regression analysis of MMAS-8 scores revealed that higher TCI-SD was related to better adherence and experiencing drug-related side effects was related to poor adherence. Aging was significantly associated with better medication adherence in univariate regression analysis but became insignificant in multivariate regression.
Conclusions: In diabetes patients, the anxiety reflected in TCI-HA tends to lower and the self-control reflected in TCI-SD tends to promote medication adherence. TCI-SD has a greater effect than TCI-HA.

PMID: 29988655 [PubMed]

A phase I study of panobinostat in pediatric patients with refractory solid tumors, including CNS tumors.

Cancer Chemother Pharmacol. 2018 Jul 09;:

Authors: Wood PJ, Strong R, McArthur GA, Michael M, Algar E, Muscat A, Rigby L, Ferguson M, Ashley DM

Abstract
PURPOSE: This was an open label, phase I (3 + 3 design), multi-centre study evaluating panobinostat in pediatric patients with refractory solid tumors.
METHODS: Primary endpoints were to establish MTD, define and describe associated toxicities, including dose limiting toxicities (DLT) and to characterize its pharmacokinetics (PK). Secondary endpoints included assessing the anti-tumour activity of panobinostat, and its biologic activity, by measuring acetylation of histones in peripheral blood mononuclear cells.
RESULTS: Nine patients were enrolled and treated with intravenous panobinostat at a dosing level of 15 mg/m2 which was tolerated. Six were evaluable for adverse events. Two (33%) patients experienced Grade 3-4 thrombocytopenia, 1 (17%) experienced Grade 3 anemia, and 2 (33%) experienced Grade 3 neutropenia. Grade 4 drug related pain occurred in 2 (33%) of the patients studied. Two (33%) patients experienced a Grade 2 QTcF change (0.478 ± 0.006 ms). One cardiac DLT (T wave changes) was reported. PK values for 15 mg/m2 (n = 9) dosing were: Tmax 0.8 h, Cmax 235.2 ng/mL, AUC0-t 346.8 h ng/mL and t1/2 7.3 h. Panobinostat significantly induced acetylation of histone H3 and H4 at all time points measured when compared to pre-treatment samples (p < 0.05). Pooled quantitative Western blot data confirmed that panobinostat significantly induced acetylation of histone H4 at 6 h (p < 0.01), 24 h (p < 0.01) and 28-70 h (p < 0.01) post dose.
CONCLUSION: A significant biological effect of panobinostat, measured by acetylation status of histone H3 and H4, was achieved at a dose of 15 mg/m2. PK data and drug tolerability at 15 mg/m2 was similar to that previously published.

PMID: 29987369 [PubMed - as supplied by publisher]

Malaria Prophylaxis Using Naphthoquine-Azithromycin Combination: Randomized, Double-Blind, Placebo-Controlled Studies to Assess Safety and Protective Efficacy in Southeast Asia.

Antimicrob Agents Chemother. 2018 Jul 09;:

Authors: Yang H, Wang J, Liu H, Li X, Nie R, Li C, Wang H, Wang Q, Cao Y, Cui L

Abstract
New prophylactic drugs against malaria infections are urgently needed. We conducted randomized, double-blind, placebo-controlled, phase 2 trials of a new antimalarial drug combination, naphthoquine-azithromycin (NQAZ), to determine its safety and protective efficacy in a low-endemicity area of Southeast Asia. In the first trial, 127 healthy volunteers were randomized to receive two single-doses of either 400 mg of NQAZ (200 mg of each drug), 800 mg of NQAZ (400 mg of each drug), or placebo on day 0 and day 30. Weekly follow-ups were performed for two months, and physical and clinical laboratory exams were done during the second and eighth week. Both drug regimens were well tolerated without any serious adverse events. Four adverse events (transient and slight elevation of serum transaminase concentrations) were found only in the two drug-treated groups and thus might be drug-related. In the second trial, 353 volunteer villagers were randomized into the same three groups as in the first trial, and malaria infections were followed for a month. For the intention-to-treat analysis, both regimens offered greater than 90% prophylactic efficacies against all malaria infections. When the analysis was done according to parasite species, 400 mg and 800 mg NQAZ provided 81.63 and 90.59% prophylactic efficacies, respectively, against Plasmodium falciparum infections, whereas both offered 100% prophylactic efficacy against Plasmodium vivax and Plasmodium ovale These trials showed that NQAZ had a good safety profile and monthly single doses of 400 mg or 800 mg for adults offered excellent prophylaxis against malaria infections, especially the two relapsing species.

PMID: 29987144 [PubMed - as supplied by publisher]

Use of a trigger tool to detect adverse drug reactions in an emergency department.

BMC Pharmacol Toxicol. 2017 Nov 15;18(1):71

Authors: de Almeida SM, Romualdo A, de Abreu Ferraresi A, Zelezoglo GR, Marra AR, Edmond MB

Abstract
BACKGROUND: Although there are systems for reporting adverse drug reactions (ADR), these safety events remain under reported. The low-cost, low-tech trigger tool method is based on the detection of events through clues, and it seems to increase the detection of adverse events compared to traditional methodologies. This study seeks to estimate the prevalence of adverse reactions to drugs in patients seeking care in the emergency department.
METHODS: Retrospective study from January to December, 2014, applying the Institute for Healthcare Improvement (IHI) trigger tool methodology for patients treated at the emergency room of a tertiary care hospital.
RESULTS: The estimated prevalence of adverse reactions in patients presenting to the emergency department was 2.3% [CI95 1.3% to 3.3%]; 28.6% of cases required hospitalization at an average cost of US$ 5698.44. The most common triggers were hydrocortisone (57% of the cases), diphenhydramine (14%) and fexofenadine (14%). Anti-infectives (19%), cardiovascular agents (14%), and musculoskeletal drugs (14%) were the most common causes of adverse reactions. According to the Naranjo Scale, 71% were classified as possible and 29% as probable. There was no association between adverse reactions and age and sex in the present study.
CONCLUSIONS: The use of the trigger tool to identify adverse reactions in the emergency department was possible to identify a prevalence of 2.3%. It showed to be a viable method that can provide a better understanding of adverse drug reactions in this patient population.

PMID: 29141696 [PubMed - indexed for MEDLINE]

Surface-modified mucoadhesive microgels as a controlled release system for miconazole nitrate to improve localized treatment of vulvovaginal candidiasis.

Eur J Pharm Sci. 2018 Jan 01;111:358-375

Authors: Kenechukwu FC, Attama AA, Ibezim EC, Nnamani PO, Umeyor CE, Uronnachi EM, Gugu TH, Momoh MA, Ofokansi KC, Akpa PA

Abstract
The use of conventional vaginal formulations of miconazole nitrate (MN) in the treatment of deep-seated VVC (vulvovaginal candidiasis) is limited by poor penetration capacity and low solubility of MN, short residence time and irritation at the application site. Surface-modified mucoadhesive microgels were developed to minimize local irritation, enhance penetration capacity and solubility and prolong localized vaginal delivery of MN for effective treatment of deep-seated VVC. Solid lipid microparticles (SLMs) were prepared from matrices consisting of hydrogenated palm oil (Softisan® 154, SF) and super-refined sunseed oil (SO) with or without polyethylene glycol (PEG)-4000, characterized for physicochemical performance and used to prepare mucoadhesive microgels (MMs) encapsulating MN, employing Polycarbophil as bioadhesive polymer. The MMs were evaluated for physicochemical performance and in vitro drug release in simulated vaginal fluid (pH=4.2), whereas mucoadhesive, rheological and stability tests, anticandidal efficacy in immunosuppressed estrogen-dependent female rats and vaginal tolerance test in rabbits were performed with optimized formulation. The amorphicity of 1:9 phytolipid blend (SO:SF) was increased in the presence of PEG-4000. The physicochemical properties of the SLMs and MMs indicated their suitability for vaginal drug delivery. Overall, MN-loaded PEGylated MMs exhibited significantly (p<0.05) more prolonged drug release than non-PEGylated MMs. Additionally, optimized PEGylated MMs was stable at 40±2°C over a period of 6months, viscoelastic, mucoadhesive, non-sensitizing, histopathologically safe and gave remarkably (p<0.05) higher reduction in Candida albicans load (86.06%) than Daktarin® (75.0%) and MN-loaded polymeric-hydrogel (47.74%) in treated rats in 12days. Thus, PEGylated MMs is promising for effective and convenient treatment of VVC.

PMID: 28986195 [PubMed - indexed for MEDLINE]

Pharmacovigilance in Israel - tools, processes, and actions.

Isr J Health Policy Res. 2017 Aug 01;6(1):29

Authors: Schwartzberg E, Berkovitch M, Dil Nahlieli D, Nathan J, Gorelik E

Abstract
BACKGROUND: Due to the limited safety data available at the time that a new medication is first marketed, it is essential to continue the collection and monitoring of safety data about adverse drug reactions (ADRs) during the medication's life cycle. This activity, known as pharmacovigilance (PV), is performed worldwide by the pharmaceutical industry as well as by regulatory agencies. In 2012, the Israeli Ministry of Health (MOH) established a Pharmacovigilance and Drug Information Department. The Department is tasked with identifying, monitoring, and initiating activities aimed at minimizing risks associated with medication utilization. To enable this, the MOH has devised procedures for PV and promoted extensive legislation in this area that require marketing authorization holders (MAHs) and medical institutions in Israel to report ADRs and new safety information to the MOH. A computerized database was created to support the reporting process. The objective of this article is to characterize the PV tools and activities implemented in Israel.
METHODS: Since September 2014, The Israeli Pharmacovigilance and Drug Information Department receives ICSRs at a central computerized database developed for this purpose. The data were analyzed by Department personnel and ICSRs were characterized according to their seriousness, source, categories of drugs involved, and the reporting format. Additionally, the Department reviewed signals detected from ADR reports and from other sources and assessed the resulting regulatory actions.
RESULTS: An analysis of the Individual Case Safety Reports (ICSRs) submitted to the MOH's ADRs central database reveals that during the review period, a total of 16,409 ICSRs were received by the Department and 850 signals were identified, resulting in the following PV activities: inquiry and enhanced follow-up (430, 50.6%), prescriber's and patient's leaflets updates (204, 24%), recall of products/batches (6, 0.7%), alerts for health care professionals (63, 7.4%). Eighty five (10%) of the signals required a comprehensive investigation involving external specialist and 1 (0.1%) resulted in initiation of epidemiologic study. Additionally, in 2015 the Department incorporated comprehensive framework for risk minimization of marketed medicinal products, also known as risk management plans (RMPs).
CONCLUSIONS: As practiced by other health authorities, the Israeli MOH effectively implemented various PV tools to ensure the safety of the Israeli health consumer.

PMID: 28760141 [PubMed - indexed for MEDLINE]

A Multicentre Study on the Efficacy, Safety and Pharmacokinetics of IqYmune®, a Highly Purified 10% Liquid Intravenous Immunoglobulin, in Patients with Primary Immune Deficiency.

J Clin Immunol. 2017 Aug;37(6):539-547

Authors: Krivan G, Chernyshova L, Kostyuchenko L, Lange A, Nyul Z, Derfalvi B, Musial J, Bellon A, Kappler M, Sadoun A, Bernatowska E

Abstract
This multicentre, open-label, prospective, single-arm study was designed to evaluate the efficacy, pharmacokinetics, and safety of IqYmune®, a highly purified 10% polyvalent immunoglobulin preparation for intravenous administration in patients with primary immunodeficiency. IqYmune® was administered to 62 patients (aged 2-61 years) with X-linked agammaglobulinemia or common variable immune deficiency at a dose from 0.22 to 0.97 g/kg every 3 to 4 weeks for 12 months with an infusion rate up to 8 mL/kg/h. A pharmacokinetic study was performed at steady state between the 8th and the 9th infusion. A single case of serious bacterial infection was observed, leading to an annualized rate of serious bacterial infections/patient (primary endpoint) of 0.017 (98% CI: 0.000, 0.115). Overall, 228 infections were reported, most frequently bronchitis, chronic sinusitis, nasopharyngitis and upper respiratory tract infection. The mean annualized rate of infections was 3.79/patient. A lower risk of infections was associated with an IgG trough level > 8 g/L (p = 0.01). The mean annualized durations of absence from work or school and of hospitalization due to infections were 1.01 and 0.89 days/patient, respectively. The mean serum IgG trough level before the 6th infusion was 7.73 g/L after a mean dose of IqYmune® of 0.57 g/kg. The pharmacokinetic profile of IqYmune® was consistent with that of other intravenous immunoglobulins. Overall, 15.5% of infusions were associated with an adverse event occurring within 72 h post infusion. Headache was the most common adverse event. In conclusion, IqYmune® was shown to be effective and well tolerated in patients with primary immunodeficiency.

PMID: 28711959 [PubMed - indexed for MEDLINE]

Week 96 results of the randomized, multicentre Maraviroc Switch (MARCH) study.

HIV Med. 2018 Jan;19(1):65-71

Authors: Pett SL, Amin J, Horban A, Andrade-Villanueva J, Losso M, Porteiro N, Madero JS, Belloso W, Tu E, Silk D, Kelleher A, Harrigan R, Clark A, Sugiura W, Wolff M, Gill J, Gatell J, Clarke A, Ruxrungtham K, Prazuck T, Kaiser R, Woolley I, Alberto Arnaiz J, Cooper D, Rockstroh JK, Mallon P, Emery S, MARCH study group

Abstract
OBJECTIVES: The Maraviroc Switch (MARCH) study week 48 data demonstrated that maraviroc, a chemokine receptor-5 (CCR5) inhibitor, was a safe and effective switch for the ritonavir-boosted protease inhibitor (PI/r) component of a two nucleos(t)ide reverse transcriptase inhibitor [N(t)RTI] plus PI/r-based antiretroviral regimen in patients with R5-tropic virus. Here we report the durability of this finding.
METHODS: MARCH, an international, multicentre, randomized, 96-week open-label switch study, enrolled HIV-1-infected adults with R5-tropic virus who were stable (> 24 weeks) and virologically suppressed [plasma viral load (pVL) < 50 HIV-1 RNA copies/mL]. Participants were randomized to continue their current PI/r-based regimen (PI/r) or to switch to MVC plus two N(t)RTIs (MVC) (1:2 randomization). The primary endpoint was the difference in the proportion with pVL < 200 copies/mL at 96 weeks. The switch arm was defined as noninferior if the lower limit of the 95% confidence interval (CI) for the difference was < -12% in the intention-to-treat (ITT) population. Safety endpoints (the difference in the mean change from baseline or a comparison of proportions) were analysed as key secondary endpoints.
RESULTS: Eighty-two (PI/r) and 156 (MVC) participants were randomized and included in the ITT analysis; 71 (87%) and 130 (83%) were in follow-up and on therapy at week 96. At week 96, 89.0% and 90.4% in the PI/r and MVC arms, respectively, had pVL < 50 copies/mL (95% CI -6.6, 10.2). Moreover, in those switching away from PI/r, there were significant reductions in mean total cholesterol (differences 0.31 mmol/L; P = 0.02) and triglycerides (difference 0.44 mmol/L; P < 0.001). Changes in CD4 T-cell count, renal function, and serious and nonserious adverse events were similar in the two arms.
CONCLUSIONS: MVC as a switch for a PI/r is safe and effective at maintaining virological suppression while having significant lipid benefits over 96 weeks.

PMID: 28703491 [PubMed - indexed for MEDLINE]