Normalizing Spontaneous Reports Into MedDRA: Some Experiments With MagiCoder.

IEEE J Biomed Health Inform. 2019 01;23(1):95-102

Authors: Combi C, Zorzi M, Pozzani G, Arzenton E, Moretti U

Abstract
Text normalization into medical dictionaries is useful to support clinical tasks. A typical setting is pharmacovigilance (PV). The manual detection of suspected adverse drug reactions (ADRs) in narrative reports is time consuming and natural language processing (NLP) provides a concrete help to PV experts. In this paper, we carry out experiments for testing performances of MagiCoder, an NLP application designed to extract MedDRA terms from narrative clinical text. Given a narrative description, MagiCoder proposes an automatic encoding. The pharmacologist reviews, (possibly) corrects, and then, validates the solution. This drastically reduces the time needed for the validation of reports with respect to a completely manual encoding. In previous work, we mainly tested MagiCoder performances on Italian written spontaneous reports. In this paper, we include some new features, change the experiment design, and carry on more tests about MagiCoder. Moreover, we do a change of language, moving to English documents. In particular, we tested MagiCoder on the CADEC dataset, a corpus of manually annotated posts about ADRs collected from the social media.

PMID: 30059326 [PubMed - in process]

Burden of Exposure to Potential Interactions Between Antiretroviral and Non-Antiretroviral Medications in a Population of HIV-Positive Patients Aged 50 Years or Older.

J Acquir Immune Defic Syndr. 2018 06 01;78(2):193-201

Authors: Ranzani A, Oreni L, Agrò M, van den Bogaart L, Milazzo L, Giacomelli A, Cattaneo D, Gervasoni C, Ridolfo AL

Abstract
BACKGROUND: As HIV-infected patients aged 50 years or older are at increased risk of comorbidities and multidrug treatments, we examined their exposure to the potential drug-drug interactions (PDDIs) of antiretroviral (ARV) and other medications.
METHODS: This cross-sectional study involved the patients aged 50 years or older receiving ARV and non-ARV medications at our clinic. PDDIs were identified using the University of Liverpool HIV Drug Interaction Checker. Logistic regression models were used to assess risk factors for PDDIs. The American Geriatrics Society Beers Criteria were used to identify potentially inappropriate medications (PIMs).
RESULTS: A total of 395 (53.9%) of 744 patients showed ≥1 PDDI: 47.4% ≥ 1 amber-PDDI (comedications requiring appropriate management) and 5.6% ≥ 1 red-PDDI (contraindicated comedications). A higher risk of PDDIs was associated with the use of ≥5 medications (P < 0.001), of antiosteoporotics (P < 0.001), calcium channel blockers (P < 0.001), anti-benign prostatic hypertrophy agents (P < 0.001), hypnotics/sedatives (P = 0.022), and anticoagulants (P = 0.006). A higher risk of red-PDDIs was associated with the use of antacids (P < 0.001), anti-benign prostatic hypertrophy agents (P < 0.001) and antipsychotics (P = 0.023). The use of nucleoside reverse transcriptase inhibitor + nonnucleoside reverse transcriptase inhibitor and nucleoside reverse transcriptase inhibitor + integrase strand transfer inhibitor rather than protease inhibitor-based regimens was associated with a reduced risk of PDDIs (P < 0.001). Overall, 119 (16.0%) patients were receiving PIMs (mainly hypnotics/sedatives) and 49 (41.2%) of them had PDDIs able to increase the blood levels of these medications.
CONCLUSIONS: Older patients with HIV are highly exposed to PDDIs between ARVs and comedications. The knowledge of their complete medication regimens and the screening for PDDIs and PIMs is therefore crucial to prevent drug-related adverse outcomes in this population.

PMID: 29767640 [PubMed - in process]

Network-Based Assessment of Adverse Drug Reaction Risk in Polypharmacy Using High-Throughput Screening Data.

Int J Mol Sci. 2019 Jan 17;20(2):

Authors: de Anda-Jáuregui G, Guo K, Hur J

Abstract
The risk of adverse drug reactions increases in a polypharmacology setting. High-throughput drug screening with transcriptomics applied to human cells has shown that drugs have effects on several molecular pathways, and these affected pathways may be predictive proxy for adverse drug reactions. Depending on the way that different drugs may contribute to adverse drug reactions, different options may exist in the clinical setting. Here, we formulate a network framework to integrate the relationships between drugs, biological functions, and adverse drug reactions based on the high-throughput drug perturbation data from the Library of Integrated Network-Based Cellular Signatures (LINCS) project. We present network-based parameters that indicate whether a given reaction may be related to the effect of a single drug or to the combination of several drugs, as well as the relative risk of adverse drug reaction manifestation given a certain drug combination.

PMID: 30658437 [PubMed - indexed for MEDLINE]

Panproteome-wide analysis of antibody responses to whole cell pneumococcal vaccination.

Elife. 2018 12 28;7:

Authors: Campo JJ, Le TQ, Pablo JV, Hung C, Teng AA, Tettelin H, Tate A, Hanage WP, Alderson MR, Liang X, Malley R, Lipsitch M, Croucher NJ

Abstract
Pneumococcal whole cell vaccines (WCVs) could cost-effectively protect against a greater strain diversity than current capsule-based vaccines. Immunoglobulin G (IgG) responses to a WCV were characterised by applying longitudinally-sampled sera, available from 35 adult placebo-controlled phase I trial participants, to a panproteome microarray. Despite individuals maintaining distinctive antibody 'fingerprints', responses were consistent across vaccinated cohorts. Seventy-two functionally distinct proteins were associated with WCV-induced increases in IgG binding. These shared characteristics with naturally immunogenic proteins, being enriched for transporters and cell wall metabolism enzymes, likely unusually exposed on the unencapsulated WCV's surface. Vaccine-induced responses were specific to variants of the diverse PclA, PspC and ZmpB proteins, whereas PspA- and ZmpA-induced antibodies recognised a broader set of alleles. Temporal variation in IgG levels suggested a mixture of anamnestic and novel responses. These reproducible increases in IgG binding to a limited, but functionally diverse, set of conserved proteins indicate WCV could provide species-wide immunity.
Clinical trial registration: The trial was registered with ClinicalTrials.gov with Identifier NCT01537185; the results are available from https://clinicaltrials.gov/ct2/show/results/NCT01537185.

PMID: 30592459 [PubMed - indexed for MEDLINE]

Interactions of organophosphorus pesticides with solute carrier (SLC) drug transporters.

Xenobiotica. 2019 Mar;49(3):363-374

Authors: Chedik L, Bruyere A, Fardel O

Abstract
1. Organophosphorus pesticides (OPs) are known to interact with human ATP-binding cassette drug efflux pumps. The present study was designed to determine whether they can also target activities of human solute carrier (SLC) drug transporters. 2. The interactions of 13 OPs with SLC transporters involved in drug disposition, such as organic cation transporters (OCTs), multidrug and toxin extrusion proteins (MATEs), organic anion transporters (OATs) and organic anion transporting polypeptides (OATPs), were mainly investigated using transporter-overexpressing cell clones and fluorescent or radiolabeled reference substrates. 3. With a cut-off value of at least 50% modulation of transporter activity by 100 µM OPs, OAT1 and MATE2-K were not impacted, whereas OATP1B1 and MATE1 were inhibited by two and three OPs, respectively. OAT3 activity was similarly blocked by three OPs, and was additionally stimulated by one OP. Five OPs cis-stimulated OATP2B1 activity. Both OCT1 and OCT2 were inhibited by the same eight OPs, including fenamiphos and phosmet, with IC50 values however in the 3-30 µM range, likely not relevant to environmental exposure. 4. These data demonstrated that various OPs inhibit SLC drug transporter activities, especially those of OCT1 and OCT2, but only when used at high concentrations not expected to occur in environmentally-exposed humans.

PMID: 29448871 [PubMed - indexed for MEDLINE]

[Fecal microbiota transplantation for the treatment of ulcerative colitis: a Meta-analysis].

Zhonghua Nei Ke Za Zhi. 2019 Mar 01;58(3):202-208

Authors: Mo R, Ren RR, Zhang XW, Yang YS

Abstract
Objective: We aimed to evaluate the efficacy and safety of fecal microbiota transplantation (FMT) for the treatment of ulcerative colitis (UC) in this Meta-analysis. Methods: Literature related to FMT for the treatment of UC from PubMed, Embase, Cochrane databases, CNKI, VIP and Wanfang Data were searched and screened with update study in May 2018. Two independent investigators extracted information according to inclusion and exclusion criteria. The Meta-analysis was conducted by Stata 12.0 software. Results: A total of 4 randomized controlled trials (RCTs) and 19 non-randomized controlled trials (non-RCTs) including 536 participants met the inclusion criteria. Meta-analysis of RCTs showed that FMT significantly increased the clinical remission rate (OR=2.47, 95%CI 1.40-4.33, P=0.02) and clinical response rate (OR=1.86, 95%CI 1.15-3.02, P=0.01) in UC patients without increasing the incidence of severe adverse effects (OR=1.40, 95%CI 0.51-3.79, P=0.51). The results from 19 non-RCTs showed that clinical remission rate in UC patients with FMT treatment was 20%(95%CI 13%-28%) and the clinical response rate was 50%(95%CI 36%-65%). All adverse events were graded as mild and self-resolving. No FMT-related severe adverse effects were reported. Conclusions: Our analysis suggests that FMT is a safe and effective method for the treatment of UC. Considering several limitations of this Meta-analysis and previous clinical trials, further large-scale multicenter RCTs are still required to further verify the conclusion.

PMID: 30803179 [PubMed - indexed for MEDLINE]

Exogenous steroid-induced hypoadrenalism in a person living with HIV caused by a drug-drug interaction between cobicistat and intrabursal triamcinolone.

BMJ Case Rep. 2018 Dec 14;11(1):

Authors: Makaram N, Russell CD, Roberts SB, Stevens J, Macpherson G

Abstract
We report a diagnosis of exogenous steroid-induced hypoadrenalism in a person living with HIV caused by a drug-drug interaction (DDI) between intrabursal triamcinolone and the pharmacokinetic booster cobicistat. A 53-year-old woman living with HIV, managed with dolutegravir and cobicistat-boosted darunavir, presented to the orthopaedic clinic with worsening hip pain. She was diagnosed with greater trochanteric pain syndrome (GTPS) of the hip and was treated with intrabursal injection of bupivacaine and triamcinolone. Seven days following this injection, she presented with Cushingoid features, an undetectable cortisol and was diagnosed with exogenous steroid-induced hypoadrenalism. Cobicistat is a cytochrome P450 3A inhibitor and in this case inhibited clearance of intrabursal triamcinolone, leading to exogenous glucocorticoid excess and adrenal suppression. This is the first report to describe this predictable DDI with cobicistat following intrabursal glucocorticoid injection. This case highlights the complexities in managing non-HIV-related chronic morbidities in people living with HIV.

PMID: 30567264 [PubMed - indexed for MEDLINE]

Chemical hazard prediction and hypothesis testing using quantitative adverse outcome pathways.

ALTEX. 2019;36(1):91-102

Authors: Perkins EJ, Gayen K, Shoemaker JE, Antczak P, Burgoon L, Falciani F, Gutsell S, Hodges G, Kienzler A, Knapen D, McBride M, Willett C, Doyle FJ, Garcia-Reyero N

Abstract
Current efforts in chemical safety are focused on utilizing human in vitro or alternative animal data in biological pathway context. However, it remains unclear how biological pathways, and toxicology data developed in that context, can be used to quantitatively facilitate decision-making.  The objective of this work is to determine if hypothesis testing using Adverse Outcome Pathways (AOPs) can provide quantitative chemical hazard predictions.  Current methods for predicting hazards of chemicals in a biological pathway context were extensively reviewed, specific case studies examined and computational modeling used to demonstrate quantitative hazard prediction based on an AOP. Since AOPs are chemically agnostic, we propose that AOPs function as hypotheses for how specific chemicals may cause adverse effects via specific pathways. Three broad approaches were identified for testing the hypothesis with AOPs, semi-quantitative weight of evidence, probabilistic, and mechanistic modeling. We then demonstrate how these approaches could be used to test hypotheses using high throughput in vitro data and alternative animal data. Finally, we discuss standards in development and documentation that would facilitate use in a regulatory context. We conclude that quantitative AOPs provide a flexible hypothesis framework for predicting chemical hazards. It accommodates a wide range of approaches that are useful at many stages and build upon one another to become increasingly quantitative.

PMID: 30332685 [PubMed - indexed for MEDLINE]

Contractility of the epididymal duct: function, regulation and potential drug effects

Reproduction. 2018 10 01;156(4):R125–R141

Authors: Elfgen V, Mietens A, Mewe M, Hau T, Middendorff R

Abstract
During their transit through the epididymis, spermatozoa mature and acquire motility and fertilizing capacity. The smooth muscle cells (SMCs) of the epididymal duct are thought to be responsible for the adequate transport of spermatozoa. Thus, precise regulation of SMC function also represents a prerequisite for sperm maturation thereby contributing to male fertility. In this review, we would like to highlight various aspects of epididymal SMC function and discuss several angles with respect to regulation of contraction and relaxation. Different to the vas deferens, where disturbed SMC pathways resulting in male infertility could be defined, comparable information is missing in the epididymis. We therefore include some vas deferens data which could also be useful for a better understanding of epididymal SMC function. Furthermore, we would like to draw attention to drugs used in clinical practice and their potential (side) effects on contractions in the epididymis.

PMID: 30304934 [PubMed - indexed for MEDLINE]

Investigating cell type specific mechanisms contributing to acute oral toxicity.

ALTEX. 2019;36(1):39-64

Authors: Prieto P, Graepel R, Gerloff K, Lamon L, Sachana M, Pistollato F, Gribaldo L, Bal-Price A, Worth A

Abstract
The replacement of animals in acute systemic toxicity testing remains a considerable challenge. Only animal data are currently accepted by regulators, including data generated by reduction and refinement methods. The development of Integrated Approaches to Testing and Assessment (IATA) is hampered by an insufficient understanding of the numerous toxicity pathways that lead to acute systemic toxicity. Therefore, central to our work has been the collection and evaluation of the mechanistic information on eight organs identified as relevant for acute systemic toxicity (nervous system, cardiovascular system, liver, kidney, lung, blood, gastrointestinal system and immune system). While the nervous and cardiovascular systems are the most frequent targets, no clear relationship emerged between specific mechanisms of target organ toxicity and the level (category) of toxicity. From a list of 114 chemicals with acute oral in vivo and in vitro data, 98 were identified with target organ specific effects, of which 93% were predicted as acutely toxic by the 3T3 neutral red uptake cytotoxicity assay and 6% as non-toxic. This analysis will help to prioritise the development of adverse outcome pathways for acute oral toxicity, which will support the assessment of chemicals using mechanistically informed IATA.

PMID: 30015985 [PubMed - indexed for MEDLINE]

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Radiation dosimetry and biodistribution of 18F-PSMA-11 for PET imaging of prostate cancer.

J Nucl Med. 2019 Apr 26;:

Authors: Piron S, De Man K, Van Laeken N, D'Asseler Y, Bacher K, Kersemans K, Ost P, Decaestecker K, Deseyne P, Fonteyne V, Lumen N, Achten E, Brans B, De Vos F

Abstract
Prostate specific membrane antigen (PSMA) is highly overexpressed in prostate cancer. Many PSMA analogue radiotracers for PET/CT imaging of prostate cancer staging have been developed such as 68Ga-PSMA-11. This radiotracer has achieved good results in multiple clinical trials, but because of superior imaging characteristics of 18F-fluoride, 18F-PSMA-11 was developed. The aim of this study was to evaluate the safety of administration and the radiation dosimetry of 18F-PSMA-11. METHODS: Six patients (age 62-68y, mean 66 ± 2y) with suspected prostate cancer recurrence after previous treatment were administered 2 MBq/kg bodyweight 18F-PSMA-11 followed by PET/CTlow-dose imaging at 0, 20, 50, 90 and 300 min post injection (p.i.). To evaluate the safety of administration, vital parameters were monitored. To assess toxicity, full blood count and biochemical parameters were determined. According to the latest ICRP recommendations, radiation dosimetry analysis was performed using IDAC-Dose 2.1. For blood activity measurement, small samples of venous blood were collected at various timepoints p.i. The unbound 18F-fluoride fraction was determined in plasma 20, 50 and 90 min after administration to evaluate the defluorination rate of 18F-PSMA-11. RESULTS: After injection, 18F-PSMA-11 was rapidly cleared from the blood. 29.0 ± 5.9% of the activity was excreted in urine at 5h p.i. The free 18F fraction in plasma increased from 9.7 ± 1.0% 20 min p.i. to 22.2 ± 1.5% 90 min p.i. The highest tracer uptake was observed in kidneys, bladder, spleen and liver. No study drug related adverse events were observed. The calculated mean effective dose was 12.8 ± 0.6 µSv/MBq. CONCLUSION: 18F-PSMA-11 can be safely administered and results in a mean effective dose of 12.8 ± 0.6 µSv/MBq. Therefore, the total radiation dose is lower compared to other PSMA PET agents and in the same range of 18F-DCFPyL.

PMID: 31028165 [PubMed - as supplied by publisher]

Metronomic Capecitabine With Cyclophosphamide Regimen in Unresectable or Relapsed Pseudomyxoma Peritonei.

Clin Colorectal Cancer. 2019 Apr 01;:

Authors: Raimondi A, Corallo S, Niger M, Antista M, Randon G, Morano F, Milione M, Kusamura S, Baratti D, Guaglio M, Cremolini C, Marmorino F, Di Bartolomeo M, Deraco M, De Braud F, Pietrantonio F

Abstract
BACKGROUND: No standard treatment for advanced unresectable pseudomyxoma peritonei (PMP) has been defined so far. PMP is traditionally considered chemoresistant but nonrandomized series showed promising results with regimens for gastrointestinal tumors.
PATIENTS AND METHODS: We conducted a single-center prospective single-arm trial. Inclusion criteria were histologically confirmed PMP, unresectable or progressive to surgery/previous treatments. Patients received a continuous metronomic regimen with capecitabine (625 mg/m2 twice per day) with cyclophosphamide (50 mg/d) until progression, unacceptable toxicity, or consent withdrawal. The primary end point was progression-free survival (PFS); secondary end points were disease control rate (DCR), overall survival (OS), and safety. Exploratory analyses were the variation of circulating tumor biomarkers and neutrophil to lymphocyte ratio (NLR).
RESULTS: Twenty-three consecutive patients were enrolled from April 2015 to October 2017. At a median follow up of 22.4 months, median PFS was 9.5 months and 1-year OS rate was 73.7%. Overall, DCR was 87% and 6 (27%) patients achieved disease control ≥12 months. The safety profile was manageable: 26% of patients reported Grade 3 drug-related adverse events and none Grade 4/5. NLR baseline < 3 versus ≥ 3 was associated with prolonged PFS (12.6 vs. 3.4 months; P = .0001).
CONCLUSION: Metronomic capecitabine with cyclophosphamide is a well tolerated regimen in unresectable/recurrent PMP, and its safety profile favorably compares with previously investigated regimens.

PMID: 31023524 [PubMed - as supplied by publisher]

Impact of AferBio® on quality of life and chemotherapy toxicity in advanced lung cancer patients (AFERBIO study): protocol study for a phase II randomized controlled trial.

BMC Cancer. 2019 Apr 25;19(1):382

Authors: D'Almeida Preto D, Baston MT, Geraige CC, Augusto SB, de Oliveira MA, Mamere AE, Pinto GDJ, Dias JM, De Marchi PRM, Paiva BSR, Paiva CE

Abstract
BACKGROUND: Lung cancer patients undergoing palliative chemotherapy exhibit many symptoms related to the disease, such as adverse events and infectious complications during treatment, which impacts directly their health-related quality of life (HRQOL). Nutritional status is a relevant aspect among advanced cancer patients under palliative care and food supplementation has the potential to reduce treatment-related adverse effects and improve the nutritional status. The product named AferBio® is a fermented supplement that has been described as able to provide some benefits, including the capacity to potentiate the effects of anticancer drugs, by promoting the reduction of side effects and ultimately improving HRQOL.
METHODS/DESIGN: A Phase II double-blind placebo-controlled randomized clinical trial to assess the use of food supplementation with AferBio® in Stage IIIB or IV non-small cell lung cancer (NSCLC) patients beginning a second-line palliative mono-chemotherapy. The primary goal is to compare HRQOL scores between the arms of the study over time. The ten first patients included in the present study will undergo an AferBio®toxicity-testing (non-randomized phase). If no significant toxicity is found, the study will move on to the randomized phase. All patients will be randomized in blocks at a 1:1 ratio using the online tool REDCap. ECOG-PS (0-1 versus 2) criteria will be used for stratification. All patients included in the trial will be evaluated at baseline and at each chemotherapy cycle. Each evaluation will include the following: HRQOL (EORTC QLQ-C30, LC13 and IQualiV-Lung), ECOG-PS, anthropometric measurements, clinical and laboratory toxicity assessment and response evaluation.
DISCUSSION: During palliative systemic therapy in advanced cancer patients, one of the main goals is the improvement and maintenance of HRQOL, which can be negatively affected by cancer symptoms, cancer- or treatment-related psychosocial difficulties, and chemotherapy toxicity. Thus, much research has been dedicated to the development of new and more effective and/or less toxic cancer therapies. The present study is justified by the testing of a novel food supplement that may reduce some toxicities, thus, having a potential positive impact on the HRQOL of lung cancer patients. The product in question (AferBio®) is already available for sale in Brazil, but has not yet been fully tested in cancer patients.
TRIAL REGISTRATION: This Trial was registered on March 19, 2018 with ClinicalTrials.gov , NCT03469063. Protocol version: 2.0 from March 26, 2018. Trial status: Patient enrollment in the study began in April, 2018.

PMID: 31023257 [PubMed - in process]

Tracking pressure injuries as adverse events: National use of the Global Trigger Tool over a 4-year period.

J Eval Clin Pract. 2019 Feb;25(1):21-27

Authors: Gunningberg L, Sving E, Hommel A, Ålenius C, Wiger P, Bååth C

Abstract
AIM: To examine the frequency, preventability, and consequences of hospital acquired pressure injuries in acute care hospitals over a 4-year period.
METHOD: A retrospective record review was performed using the Swedish version of the Global Trigger Tool (GTT). A total of 64 917 hospital admissions were reviewed. Data were collected between 2013 and 2016 from all 63 Swedish acute care hospitals.
RESULTS: The prevalence of pressure injuries (category 2-4) was 1%. Older patients, "satellite patients", and patients with acute admissions had more pressure injuries. Most pressure injuries (91%) were determined to be preventable. The mean extended length of hospital stay was 15.8 days for patients who developed pressure injuries during hospitalization.
CONCLUSION: The GTT provides a useful and complementary national perspective on hospital acquired pressure injuries across hospitals, informing health care providers on safety priorities to reduce patient harm. Clinical leaders can use information on the preventability and the consequences of pressure injuries, as well as evidence-based arguments for improving the health care organization.

PMID: 30027549 [PubMed - indexed for MEDLINE]

Phase Ib study of the MEK inhibitor cobimetinib (GDC-0973) in combination with the PI3K inhibitor pictilisib (GDC-0941) in patients with advanced solid tumors.

Invest New Drugs. 2019 Apr 24;:

Authors: Shapiro GI, LoRusso P, Kwak E, Pandya S, Rudin CM, Kurkjian C, Cleary JM, Pilat MJ, Jones S, de Crespigny A, Fredrickson J, Musib L, Yan Y, Wongchenko M, Hsieh HJ, Gates MR, Chan IT, Bendell J

Abstract
Purpose We investigated the combination of the MEK inhibitor, cobimetinib, and the pan-PI3K inhibitor, pictilisib, in an open-label, phase Ib study. Experimental Design Patients with advanced solid tumors were enrolled in 3 dose escalation schedules: (1) both agents once-daily for 21-days-on 7-days-off ("21/7"); (2) intermittent cobimetinib and 21/7 pictilisib ("intermittent"); or (3) both agents once-daily for 7-days-on 7-days-off ("7/7"). Starting doses for the 21/7, intermittent, and 7/7 schedules were 20/80, 100/130, and 40/130 mg of cobimetinib/pictilisib, respectively. Nine indication-specific expansion cohorts interrogated the recommended phase II dose and schedule. Results Of 178 enrollees (dose escalation: n = 98), 177 patients were dosed. The maximum tolerated doses for cobimetinib/pictilisib (mg) were 40/100, 125/180, and not reached, for the 21/7, intermittent, and 7/7 schedules, respectively. Six dose-limiting toxicities included grade 3 (G3) elevated lipase, G4 elevated creatine phosphokinase, and G3 events including fatigue concurrent with a serious adverse event (SAE) of diarrhea, decreased appetite, and SAEs of hypersensitivity and dehydration. Common drug-related adverse events included nausea, fatigue, vomiting, decreased appetite, dysgeusia, rash, and stomatitis. Pharmacokinetic parameters of the drugs used in combination were unaltered compared to monotherapy exposures. Confirmed partial responses were observed in patients with BRAF-mutant melanoma (n = 1) and KRAS-mutant endometrioid adenocarcinoma (n = 1). Eighteen patients remained on study ≥6 months. Biomarker data established successful blockade of MAP kinase (MAPK) and PI3K pathways. The metabolic response rate documented by FDG-PET was similar to that observed with cobimetinib monotherapy. Conclusions Cobimetinib and pictilisib combination therapy in patients with solid tumors had limited tolerability and efficacy.

PMID: 31020608 [PubMed - as supplied by publisher]

New-onset cutaneous sarcoidosis under tocilizumab treatment for giant cell arteritis: a quasi-paradoxical adverse drug reaction. Case report and literature review.

Ther Adv Musculoskelet Dis. 2019;11:1759720X19841796

Authors: Del Giorno R, Iodice A, Mangas C, Gabutti L

Abstract
Background: New-onset sarcoidosis has been previously described in three case reports in patients affected by rheumatoid arthritis treated with tocilizumab (TCZ). The existence of a cause-effect mechanism between the biological treatment and the onset of the illness is still being debated.
Patient concerns: A 74-year-old woman was diagnosed with giant cell arteritis (GCA). The first-line treatment with glucocorticoids; and the second-line with methotrexate and low-dose glucocorticoids were stopped due to multiple pathological vertebral fractures and insufficient biological and clinical response. The cytotoxic agent, cyclophosphamide, was then introduced and in turn stopped, because of gastrointestinal side effects. Thereafter a treatment with TCZ was begun. The patient experienced good clinical response; however, 8 months later she developed painful hyper-pigmented reddish cutaneous micronodular lesions localized to the abdomen and thorax. A cutaneous biopsy was performed, and histological analysis showed noncaseating epithelioid granulomas in the hypodermis. The diagnosis of cutaneous sarcoidosis was made.
Interventions: Topical corticosteroids were administered and, as requested by the patient, TCZ was discontinued with slow but complete resolution of the skin lesions. After TCZ discontinuation however, the GCA flared and the patient's symptoms and biological abnormalities reappeared. Thus, after a 6-month suspension, TCZ was re-administered. At 2 months later the skin lesions compatible with cutaneous sarcoidosis reappeared. Topical corticosteroids were once again prescribed and as suggested by the patient the TCZ posology was reduced. The patient's symptoms disappeared, and the cutaneous lesions resolved.
Lessons: The time elapsed from TCZ treatment start and the onset of cutaneous sarcoidosis, as well as its recurrence after TCZ suspension and rechallenge supported the diagnosis of a drug-induced reaction. To the best of our knowledge, this case report represents the first instance of cutaneous sarcoidosis most likely induced by TCZ in patients affected by GCA. In addition, our case emphasizes that although TCZ in monotherapy confirms to be an effective treatment for GCA, further immunological disorders could be unmasked, and the discussed side effect of the drug could be dose-dependent.

PMID: 31019572 [PubMed]

Economic Outcomes Associated with Safety Interventions by a Pharmacist-Adjudicated Prior Authorization Consult Service.

J Manag Care Spec Pharm. 2019 Mar;25(3):411-416

Authors: Jacob S, Britt RB, Bryan WE, Hashem MG, Hale JC, Brown JN

Abstract
BACKGROUND: The establishment of a formulary management system ensures that health care professionals work together in an integrated patient care process to promote clinically sound, safe, and cost-effective medication therapy. Pharmacists have a foundational role within this system. A pharmacist-adjudicated prior authorization drug request (PADR) consult service has the potential to optimize drug therapy by decreasing medication misuse, minimizing adverse drug events (ADEs), and preventing medication errors.
OBJECTIVES: To (a) determine cost avoidance associated with pharmacist-adjudicated PADR safety interventions within the Durham Veterans Affairs Health Care System and (b) evaluate cost savings associated with pharmacist-adjudicated PADRs not approved due to a safety intervention, evaluate cost avoidance and direct cost savings based on clinical specialty of pharmacist adjudicating PADR, and characterize severity of avoided ADEs.
METHODS: Pharmacist-adjudicated PADRs not approved between July 1, 2016, and June 30, 2017, because of safety interventions were retrospectively reviewed. Cost avoidance was determined by multiplying the probability of ADE occurrence in the absence of PADR safety intervention by the estimated cost avoided based on the type of intervention. Direct cost savings was calculated by totaling the cost of requested medications not approved for each PADR and subtracting the cost of recommended alternative therapies and cost of pharmacist PADR review. All potential ADEs avoided were reviewed by a panel of 3 clinical pharmacists to validate ADE classification and ADE probability and severity scores. Descriptive statistics were used for all analyses.
RESULTS: Of the 910 PADRs that were not approved during the study period, 96 met inclusion criteria. Pharmacist-adjudicated PADR safety interventions resulted in a total cost avoidance of $24,485.34 (mean = $255.06) and a direct cost savings of $288,695.63 (mean = $3,007.25). The practice settings of anticoagulation and infectious diseases PADRs resulted in the largest contribution to cost avoidance and direct cost savings, respectively. Prevented ADEs were classified as major for 64.6% of the PADRs.
CONCLUSIONS: Pharmacist-adjudicated PADR safety reviews resulted in substantial economic benefit and prevention of major ADEs. This analysis supports the pharmacist's role in a formulary management system to optimize medication therapy.
DISCLOSURES: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for profit sectors. The authors have nothing to disclose.

PMID: 30816815 [PubMed - indexed for MEDLINE]

Use of Medicare Administrative Claims to Identify a Population at High Risk for Adverse Drug Events and Hospital Use for Quality Improvement.

J Manag Care Spec Pharm. 2019 Mar;25(3):402-410

Authors: Digmann R, Thomas A, Peppercorn S, Ryan A, Zhang L, Irby K, Brock J

Abstract
BACKGROUND: A system using administrative claims to monitor medication use patterns and associated adverse events is not currently available. Establishment of a standardized method to identify Medicare beneficiaries at high risk for adverse events, by assessing Medicare Part D medication claim patterns and associated outcomes, including outpatient adverse drug events (ADEs) and hospital use, enhances prevention efforts and monitoring for quality improvement efforts.
OBJECTIVES: To (a) demonstrate that Medicare claims data can be used to identify a population of beneficiaries at high risk for adverse events for quality improvement and (b) define trends associated with adverse health outcomes in identified high-risk beneficiaries for quality improvement opportunities.
METHODS: We used Medicare fee-for-service Part D claims data to identify a population at high risk for adverse events by evaluating medication use patterns. This population was taking at least 3 medications, 1 of which was an anticoagulant, an opioid, or an antidiabetic agent. Next, we used associated Part A claims to calculate rates of outpatient ADEs, looking for specific ICD-9-CM or ICD-10-CM codes in the principal diagnosis code position. Rates of hospital use (inpatient hospitalization, observation stays, emergency department visits, and 30-day rehospitalizations) were also evaluated for the identified high-risk population. The data were then shared for targeted quality improvement.
RESULTS: We identified 8,178,753 beneficiaries at high risk for adverse events, or 20.7% of the total eligible fee-for-service population (time frame of October 2016-September 2017). The overall rate of outpatient ADEs for beneficiaries at high risk was 46.28 per 1,000, with anticoagulant users demonstrating the highest rate of ADEs (68.52/1,000), followed by opioid users (42.11/1,000) and diabetic medication users (20.72/1,000). As expected, the primary setting for beneficiaries at high risk to seek care for outpatient ADEs was the emergency department, followed by inpatient hospitalizations and observation stays.
CONCLUSIONS: Medicare claims are an accessible source of data, which can be used to establish for quality improvement a population at high risk for ADEs and increased hospital use. Using medication use patterns to attribute risk and associated outcomes, such as outpatient ADEs and hospital use, is a simple process that can be readily implemented. The described method has the potential to be further validated and used as a foundation to monitor population-based quality improvement efforts for medication safety.
DISCLOSURES: This work was performed under contract HHSM-500-2014-QINNCC, Modification No. 000004, funded by Centers for Medicare & Medicaid Services (CMS), an agency of the U.S. Department of Health and Human Services. CMS did not have a role in the analysis. At the time of this analysis, Digmann, Peppercorn, Zhang, Irby, and Brock were employees of Telligen, which was awarded the National Coordinating Center-Quality Improvement Organization contract from CMS, which supported the work. Ryan was an employee at Qsource, which was awarded the Quality Innovation Network-Quality Improvement Organization contract from CMS, which supported the work. Thomas was employed by CMS. The content is solely the responsibility of the authors and does not necessarily represent the official views or policies of the CMS. This work is posted on the QIOprogram.org website, as recommended in the Common Rule ( https://www.hhs.gov/ohrp/regulations-and-policy/regulations/common-rule/index.html ).

PMID: 30816813 [PubMed - indexed for MEDLINE]

Incidence and predictors of acute akathisia in severely ill patients with first-episode schizophrenia treated with aripiprazole or risperidone: secondary analysis of an observational study.

Psychopharmacology (Berl). 2019 Feb;236(2):723-730

Authors: Yoshimura B, Sato K, Sakamoto S, Tsukahara M, Yoshimura Y, So R

Abstract
RATIONALE: In the antipsychotic treatment of schizophrenia with little medication history, especially in drug-naïve cases, predictors of side effects are important. However, predictors of antipsychotic-induced akathisia remain unclear.
OBJECTIVES: This study aimed to investigate the incidence and predictors of acute akathisia in severely ill patients with first-episode schizophrenia spectrum disorders (FES).
METHODS: This is a secondary analysis of our retrospective observational study. Data were obtained from 129 consecutive patients with FES involuntarily hospitalized in a tertiary psychiatric public hospital and treated with aripiprazole or risperidone. The primary outcome was the presence of acute akathisia during the first 1 month. A Cox proportional hazard model was used to examine significant predictors of the onset of akathisia.
RESULTS: Acute akathisia was diagnosed in 54 patients (42%). Neither antipsychotics (aripiprazole or risperidone), duration of untreated psychosis, iron deficiency, sex, age nor baseline symptomatic severity was identified as an independent predictor of akathisia. Rapid risperidone initiation significantly increased the onset of akathisia (adjusted hazard ratio [HR], 6.47; 95%; 95% confidence interval [CI], 1.94-21.65; p = 0.002), but rapid aripiprazole initiation did not (adjusted HR, 1.08; 95% CI, 0.50-2.31; p = 0.84). A significant interaction was found between rapid antipsychotic initiation and the risk of akathisia with aripiprazole versus risperidone (p = 0.027).
CONCLUSIONS: Severely ill patients with FES initiating aripiprazole or risperidone could have a high risk for akathisia. Rapid risperidone initiation should be avoided because of the risk for akathisia, and careful monitoring of akathisia may be necessary for all patients initiating aripiprazole.

PMID: 30443794 [PubMed - indexed for MEDLINE]