Developing a Multi-Dose Computational Model for Drug-Induced Hepatotoxicity Prediction Based on Toxicogenomics Data.

IEEE/ACM Trans Comput Biol Bioinform. 2019 Jul-Aug;16(4):1231-1239

Authors: Su R, Wu H, Xu B, Liu X, Wei L

Abstract
Drug-induced hepatotoxicity may cause acute and chronic liver disease, leading to great concern for patient safety. It is also one of the main reasons for drug withdrawal from the market. Toxicogenomics data has been widely used in hepatotoxicity prediction. In our study, we proposed a multi-dose computational model to predict the drug-induced hepatotoxicity based on gene expression and toxicity data. The dose/concentration information after drug treatment is fully utilized in our study based on the dose-response curve, thus a more informative representative of the dose-response relationship is considered. We also proposed a new feature selection method, named MEMO, which is also one important aspect of our multi-dose model in our study, to deal with the high-dimensional toxicogenomics data. We validated the proposed model using the TG-GATEs, which is a large database recording toxicogenomics data from multiple views. The experimental results show that the drug-induced hepatotoxicity can be predicted with high accuracy and efficiency using the proposed predictive model.

PMID: 30040651 [PubMed - indexed for MEDLINE]

Randomised clinical trial to determine the safety of quercetin supplementation in patients with chronic obstructive pulmonary disease.

BMJ Open Respir Res. 2020 Feb;7(1):

Authors: Han MK, Barreto TA, Martinez FJ, Comstock AT, Sajjan US

Abstract
INTRODUCTION: Quercetin is a plant flavonoid and has potent antioxidant and anti-inflammatory properties. In a preclinical model of chronic obstructive pulmonary disease (COPD), quercetin reduced markers of both oxidative stress and lung inflammation and also reduced rhinovirus-induced progression of lung disease. Although quercetin appears to be an attractive natural alternative to manage COPD, the safety of quercetin supplementation in this population is unknown.
METHODS: We recruited COPD patients with mild-to-severe lung disease with FVE1 ranging between >35% and <80% and supplemented with either placebo or quercetin at 500, 1000 or 2000 mg/day in a dose-escalation manner. The duration of quercetin supplementation was 1 week.
RESULTS: Patients had no study drug-related severe adverse events based on blood tests, which included both complete blood counts and evaluation of comprehensive metabolic panel. One of the patients reported mild adverse events included gastro-oesophageal reflux disease, which was observed in both placebo and quercetin groups.
CONCLUSIONS: Quercetin was safely tolerated up to 2000 mg/day as assessed by lung function, blood profile and COPD assessment test questionnaire.
TRIAL REGISTRATION NUMBER: NCT01708278.

PMID: 32071149 [PubMed - in process]

Physician and pharmacist satisfaction and clinical needs for the real-time medication surveillance program in South Korea.

BMC Health Serv Res. 2019 Nov 06;19(1):805

Authors: Shin SM, Kim HA, Song I, Jeon HL, Shin JY

Abstract
BACKGROUND: Since December 2010, a nationwide real-time medication surveillance program has been implemented in Korea to prevent potential adverse drug reactions. Our goal was to evaluate physicians' and pharmacists' satisfaction and clinical needs for the medication surveillance program in Korea.
METHODS: Both web- and paper-based surveys were conducted using a structured questionnaire among 1164 physicians and pharmacists from May 23, 2014 to August 11, 2014. The survey consisted of questions about the participant's satisfaction with the medication surveillance program, clinical usefulness, clinical need for the medication surveillance program, and sociodemographic characteristics. Multivariate ordinal logistic regression was performed to investigate the factors influencing satisfaction levels with the medication surveillance program.
RESULTS: We analyzed data from 1120 respondents, including 503 physicians and 617 pharmacists. Overall, 63.1% of the respondents were satisfied with the medication surveillance program. Pharmacists were more satisfied with the program than were physicians (69.1% vs. 55.6%; adjusted odds ratio, 2.13; 95% confidence interval, 1.65-2.76). Among the respondents, 77.8% cited a decrease in therapeutic duplication to be a major improvement resulting from the medication surveillance program, 82.6% considered the drug-drug interaction information useful, and 48.7% suggested that the program should include information on liver or kidney disease-drug interaction.
CONCLUSIONS: Overall, 63.0% of physicians and pharmacists were satisfied, and a decrease in therapeutic duplication was regarded as the most beneficial component. Further improvements by considering clinical needs of physicians and pharmacists will be needed to increase satisfaction.

PMID: 31694628 [PubMed - indexed for MEDLINE]

Process, impact and outcomes of medication review in Australian residential aged care facilities: A systematic review.

Australas J Ageing. 2019 Sep;38 Suppl 2:9-25

Authors: Chen EYH, Wang KN, Sluggett JK, Ilomäki J, Hilmer SN, Corlis M, Bell JS

Abstract
OBJECTIVE: To systematically review literature reporting processes, impact and outcomes of medication review and reconciliation in Australian residential aged care facilities (RACFs).
METHODS: PubMed/MEDLINE, EMBASE, CINAHL, Informit Health and grey literature were searched from 1995 to July 2018. Studies reporting outcomes of a stand-alone medication review or reconciliation interventions in Australian RACFs were included.
RESULTS: Thirteen studies investigated medication review, eight of which studied Residential Medication Management Reviews (RMMRs). Five studies reported that medication reviews identified an average of 2.7-3.9 medication-related problems (MRPs) per resident. One study reported medication reviews had no impact on quality of life, hospitalisation or mortality, but was not powered to assess these. Three studies reported general practitioners' acceptance of pharmacists' recommendations to resolve MRPs, ranging between 45 and 84%.
CONCLUSIONS: Medication review may be a useful strategy to identify and prompt resolution of MRPs. However, the impact on clinical and resident-centred outcomes remains unclear.

PMID: 31496065 [PubMed - indexed for MEDLINE]

Mental health professionals' views and experiences of antipsychotic reduction and discontinuation.

PLoS One. 2019;14(6):e0218711

Authors: Cooper RE, Hanratty É, Morant N, Moncrieff J

Abstract
BACKGROUND: The widely established treatment for psychosis is long-term antipsychotic medication. However, many people stop taking this treatment, and request other options. There are also growing concerns about adverse effects, but currently no professional guidelines to support reducing or stopping these drugs. The views and experiences of individual mental health professionals around reducing and stopping antipsychotics are therefore crucial in treatment decisions.
METHODS: We conducted 7 focus groups with prescribing psychiatrists and other members of community-based statutory mental health services in London. Participants discussed their views about, experiences, and processes of antipsychotic reduction and discontinuation. Data were analysed using thematic analysis.
RESULTS: Participants acknowledged that antipsychotics can have severe adverse effects. They were generally supportive of trying to reduce these drugs to the lowest effective dose, although stopping antipsychotics was less acceptable. Prior experiences of adverse events after reduction or discontinuation meant that both were approached with caution. Reduction was also reported to be hampered by organisational and knowledge barriers. Lack of resources, pressure to discharge, and poor continuity of care were seen as organisational barriers. Knowledge barriers included inadequate evidence about who might be best suited to reduction, and lack of guidance about how this could be done safely. This meant that reduction was often prompted by patients, and sometimes actively discouraged, and stability with maintenance treatment was often favoured.
CONCLUSIONS: Concerns about risk and other barriers means that clinicians are often reluctant to implement reduction or discontinuation of antipsychotic medication. In order to increase the treatment options available to service users, more research and guidance on how to minimise the risks of antipsychotic reduction and discontinuation is required to enable clinicians to engage more constructively with service users requests, offering people more choice and control in managing their mental health condition.

PMID: 31220160 [PubMed - indexed for MEDLINE]

Long term time trends in use of medications associated with risk of developing osteoporosis: Nationwide data for Denmark from 1999 to 2016.

Bone. 2019 03;120:94-100

Authors: Skjødt MK, Ostadahmadli Y, Abrahamsen B

Abstract
PURPOSE: To evaluate the development in the use of medications associated with an increased risk of developing osteoporosis over the time period from 1999 to 2016.
METHODS: We extracted data on total sale, sales rate and usage rate for the medications of interest from www.medstat.dk, which is an online, open-source database reporting the monthly sale of both over-the-counter and prescription-based medications in Denmark. The dataset covers both the primary and secondary health sectors.
RESULTS: Most medications exhibited an increasing use from 1999 to 2016, though some had stable (e.g. glucocorticoids) or declining use. Notably, some medications showed widespread and increasing use, including proton pump inhibitors (PPI), selective serotonine reuptake inhibitors (SSRI) and venlafaxine. For PPI, sales rates increased by 461% from 1999 to 2016, with 9% of men and 11.4% of women filling at least one prescription in 2016. The use of SSRI and venlafaxine increased by 114% and 613%, respectively. This was more pronounced in women and for SSRI also in the elderly (80+ years). The sale of aromatase inhibitors was moderate (1-10 DDD per 1000 capita per day) in 2016, yet grew by 2400% from 1999, almost exclusively in women aged 80 years or older.
CONCLUSION: We found a trend of increasing use from 1999 to 2016 of most medications with a potential for causing osteoporosis, often most pronounced in fracture risk groups (postmenopausal women and/or in the elderly). This may play a clinically relevant role in both current and future causality of osteoporosis.

PMID: 30172013 [PubMed - indexed for MEDLINE]

The impact of drug interactions on adverse effects of oral oxycodone in male geriatric patients.

J Clin Pharm Ther. 2020 Feb 18;:

Authors: Kim JH, Kim JY, Lee N, Yee J, Gwak HS

Abstract
WHAT IS KNOWN AND OBJECTIVE: With increased opioid use, drug-drug interactions (DDIs) and associated adverse events are growing among geriatric patients. However, the clinical significance of potential metabolic DDIs associated with opioid use has not been fully evaluated among geriatric patients. Particularly, cytochrome (CYP) P450 enzymes are important in drug metabolism of oxycodone and a black box warning for oxycodone reveals serious risks associated with drug-oxycodone interactions. This study focused on the use of oxycodone in geriatric patients to evaluate its adverse drug reactions (ADRs) and DDIs associated with CYP P450 enzymes.
METHODS: A retrospective cohort study using patients treated at Korea Veterans Hospital was performed. Data from male patients aged 65 years and older who received oxycodone were analysed. Binomial variables describing patient-related characteristics, drug-related characteristics and CYP-mediating drugs were constructed. Associations between these variables and the frequency of ADRs were determined. The odds ratio (OR) and adjusted odds ratio (AOR) were calculated from univariable and multivariable analyses, respectively.
RESULTS AND DISCUSSION: Among 111 patients, 32.4% experienced at least one ADR. The most common ADR was gastrointestinal-related (n = 21), followed by dizziness and drowsiness (n = 8). Use of either CYP2D6 inhibitors or CYP3A4 inhibitors increased the rate of ADRs by 20.4 and 25.4 times, respectively. In the case of patients taking both inhibitors, the adjusted OR was 48.6, and the attributable risk was 97.9%.
WHAT IS NEW AND CONCLUSION: This study suggests that inappropriate combinations of oxycodone with CYP2D6 inhibitors and/or CYP3A4 inhibitors may warrant treatment modification to avoid ADRs in geriatric patients. Clinicians should monitor any signs of ADRs that may reflect DDIs while a geriatric patient is taking oxycodone.

PMID: 32068910 [PubMed - as supplied by publisher]

Effects of Elamipretide on Left Ventricular Function in Patients with Heart Failure with Reduced Ejection Fraction: The PROGRESS-HF Phase 2 Trial.

J Card Fail. 2020 Feb 14;:

Authors: Butler J, Khan MS, Anker SD, Fonarow GC, Kim RJ, Nodari S, O'Connor CM, Pieske B, Pieske-Kraigher E, Sabbah HN, Senni M, Voors AA, Udelson JE, Carr J, Gheorghiade M, Filippatos G

Abstract
BACKGROUND: Elamipretide, a novel mitochondrial modulating agent, improves myocardial energetics, however, it is unknown whether this mechanistic benefit translates into improved cardiac structure and function in HF with reduced ejection fraction (HFrEF). The objective of this study was to evaluate the effects of multiple subcutaneous doses of elamipretide on left ventricular end systolic volume (LVESV) assessed by cardiac magnetic resonance imaging (MRI).
METHODS: Seventy-one HFrEF (LVEF ≤ 40%) patients were randomized in a double-blind, placebo-controlled trial in a 1:1:1 ratio to receive either placebo, 4 mg or 40 mg elamipretide once daily for 28 consecutive days.
RESULTS: Mean age (SD) of the study population was 65±10 years, 24% were females, and mean EF was 31±7%. The change in LVESV from baseline to week 4 was not significantly different between elamipretide 4mg (89.4 ml to 85 ml; difference, -4.4 ml) or 40 mg (77.9 ml to 76.6 ml; difference, -1.2 ml) compared with placebo (77.7 ml to 74.6 ml; difference, -3.8 ml) [4mg versus placebo: difference of means, -0.3; 95% CI, -4.6 to 4.0; P = 0.90; and 40mg versus placebo: difference of means, 2.3; 95% CI, -1.9 to 6.5; P = 0.28]. Also, no significant differences in change in left ventricular end diastolic volume and left ventricular ejection fraction were observed between placebo and either of the elamipretide group. Rates of any study drug related adverse events were similar among the three groups.
CONCLUSIONS: Elamipretide was well tolerated but did not improve LVESV at 4 weeks in stable HFrEF patients compared with placebo.

PMID: 32068002 [PubMed - as supplied by publisher]

Feasibility of Mapping Austrian Health Claims Data to the OMOP Common Data Model.

J Med Syst. 2019 Sep 07;43(10):314

Authors: Haberson A, Rinner C, Schöberl A, Gall W

Abstract
The Main Association of Austrian Social Security Institutions collects pseudonymized claims data from Austrian social security institutions and information about hospital stays in a database for research purposes. For new studies the same data are repeatedly reprocessed and it is difficult to compare different study results even though the data is already preprocessed and prepared in a proprietary data model. Based on a study on adverse drug events in relation to inappropriate medication in geriatric patients the suitability of the Observational Medical Outcomes Partnership (OMOP) common data model (CDM) is analyzed and data is transformed into the OMOP CDM. 1,023 (99.7%) of drug codes and 3,812 (99.2%) of diagnoses codes coincide with the OMOP vocabularies. The biggest obstacles are missing mappings for the Local Vocabularies like the Austrian pharmaceutical registration numbers and the Socio-Economic Index to the OMOP vocabularies. OMOP CDM is a promising approach for the standardization of Austrian claims data. In the long run, the benefits of standardization and reproducibility of research should outweigh this initial drawback.

PMID: 31494719 [PubMed - indexed for MEDLINE]

Exposure assessments in reproductive and developmental toxicity testing: An IQ-DruSafe industry survey on current practices and experiences in support of exposure-based high dose selection.

Regul Toxicol Pharmacol. 2019 Oct;107:104413

Authors: Andrews PA, McNerney ME, DeGeorge JJ

Abstract
The draft ICH S5(R3) guideline includes an exposure-based endpoint as an option for selecting the high dose in developmental and reproductive toxicity (DART) studies. In 2016, IQ DruSafe conducted an anonymous survey to identify industry practices and experiences related to pharmacokinetic assessments in DART studies in order to facilitate a pragmatic data-driven approach to development of an acceptable multiple of the clinical exposure to be proposed for dose selection in the guideline. Questions in the survey were designed to explore pharmacokinetic differences in pregnant versus non-pregnant animals, and to assess exposure levels attained in the absence of maternal toxicity as well as DART outcomes in animal studies associated with those exposures. Small molecule and therapeutic proteins were analyzed separately. The key findings for small molecules were: a) differences in exposures between pregnant and non-pregnant animals were generally ≤3-fold, b) Cmax or AUC exposures ≥25-fold the clinical exposure were achieved in the absence of maternal toxicity for 31% and 23% of rat and rabbit developmental toxicity studies, respectively, and c) only 3.3% (5/153) and 1.6% (2/128) of the developmental toxicity studies were positive for malformations or embryofetal lethality in rats and rabbits, respectively, that were not observed until exposure margins were ≥25-fold.

PMID: 31229519 [PubMed - indexed for MEDLINE]

Fluoxetine and Risk of Bleeding in Patients Aged 60 Years and Older Using the Korea Adverse Event Reporting System Database: A Case/Noncase Study.

J Clin Psychopharmacol. 2019 Jul/Aug;39(4):362-366

Authors: Kim S, Ko YJ, Park K, Yang BR, Kim MS, Park BJ

Abstract
BACKGROUND: Depression, the leading cause of nonfatal disease burden, has a strong correlation with suicide and affects approximately 7% of the general elderly population. Adverse drug reactions in older patients are particularly important because of reduced drug metabolism, polypharmacy, drug-drug interactions, and drug-disease interactions. Fluoxetine is the first representative selective serotonin reuptake inhibitor but is associated with the possibility of hemorrhage based on its mechanism of action. Serious cases of gastrointestinal bleeding and cerebral hemorrhage have been reported, raising concerns about the safety of this drug.
METHODS: We detected signals of bleeding risk associated with fluoxetine in an elderly population using the Korea Adverse Event Reporting System database. Reporting odds ratios and 95% confidence intervals (CIs) were calculated.
RESULTS: A total of 16,517 adverse events related to antidepressants were reported. The reporting odds ratios for fluoxetine were 2.34 (95% CI, 1.03-5.34) for total bleeding, 4.41 (95% CI, 1.60-12.15) for major bleeding, 2.06 (95% CI, 0.28-15.03) for gastrointestinal bleeding, and 6.12 (95% CI, 2.14-22.60) for brain hemorrhage compared with those of all other antidepressants.
CONCLUSIONS: We detected safety signals with total bleeding, major bleeding, and brain hemorrhage related to fluoxetine. For patients with a high risk of bleeding, such as the elderly population, prescribing antidepressants other than fluoxetine can be considered. The results of this study provide preliminary evidence of a relationship between fluoxetine and hemorrhage but have wide 95% CIs. Further pharmacoepidemiological studies will be needed to confirm the risk of bleeding associated with fluoxetine.

PMID: 31206390 [PubMed - indexed for MEDLINE]

Identification of potential biomarkers of vaccine inflammation in mice.

Elife. 2019 05 14;8:

Authors: McKay PF, Cizmeci D, Aldon Y, Maertzdorf J, Weiner J, Kaufmann SH, Lewis DJ, van den Berg RA, Del Giudice G, Shattock RJ

Abstract
Systems vaccinology approaches have been used successfully to define early signatures of the vaccine-induced immune response. However, the possibility that transcriptomics can also identify a correlate or surrogate for vaccine inflammation has not been fully explored. We have compared four licensed vaccines with known safety profiles, as well as three agonists of Toll-like receptors (TLRs) with known inflammatory potential, to elucidate the transcriptomic profile of an acceptable response to vaccination versus that of an inflammatory reaction. In mice, we looked at the transcriptomic changes in muscle at the injection site, the lymph node that drained the muscle, and the peripheral blood mononuclear cells (PBMCs)isolated from the circulating blood from 4 hr after injection and over the next week. A detailed examination and comparative analysis of these transcriptomes revealed a set of novel biomarkers that are reflective of inflammation after vaccination. These biomarkers are readily measurable in the peripheral blood, providing useful surrogates of inflammation, and provide a way to select candidates with acceptable safety profiles.

PMID: 31084714 [PubMed - indexed for MEDLINE]

The effectiveness of pharmacist- led discharge medication counselling in the emergency department (ExPLAIN): A pilot quasi-experimental study.

Patient Educ Couns. 2019 06;102(6):1157-1163

Authors: Cabilan CJ, Boyde M, Currey E

Abstract
OBJECTIVE: To evaluate the effectiveness of pharmacist-led discharge medication counselling using a structured, multimodal educational strategy with teach-back (intervention) against standard care.
METHODS: This was a quasi-experimental study in a public, metropolitan ED. Participants discharged home with new medications were allocated to receive the intervention or standard care using convenience sampling. Participant characteristics (i.e. age, sex, socio-economic status, medications) and health literacy were collected. The outcomes measured were satisfaction with information, ED re-presentation and length of stay.
RESULTS: There were 51 participants: 14 received intervention, 37 had standard care. Overall, 12% had inadequate health literacy. Group characteristics and health literacy were similar. Participants who received the intervention were significantly reported higher satisfaction with information about their new medications compared to standard care (p = 0.009). Specifically, the intervention was associated with a 98% increase in satisfaction with information relating to side-effects. There were no differences in re-presentation and length of stay.
CONCLUSION: Pharmacist-led discharge medication counselling incorporating a structured, multimodal educational strategy and teach-back was effective in improving patient satisfaction with medication information in the ED.
PRACTICE IMPLICATIONS: A similar intervention could be trialled in other EDs, but outcomes other beyond satisfaction should be considered.

PMID: 30712945 [PubMed - indexed for MEDLINE]

Long-term safety and tolerability of cariprazine as adjunctive therapy in major depressive disorder.

Int Clin Psychopharmacol. 2019 03;34(2):76-83

Authors: Vieta E, Earley WR, Burgess MV, Durgam S, Chen C, Zhong Y, Barabássy Á, Németh G

Abstract
Lack of treatment response is a critical problem in major depressive disorder (MDD). Cariprazine is a D3-preferring dopamine D3/D2 receptor partial agonist and 5-HT1A partial agonist. This phase 3, multicenter, open-label, long-term (26-week), flexible-dose (1.5-4.5 mg/day) study assessed the long-term safety and tolerability of cariprazine used adjunctively with antidepressant therapy in adult patients with MDD who had either completed a lead-in study (n=311) or had been newly recruited (n=131). A higher percentage of continuing patients (66.2%) than new patients (35.9%) completed the study. The most common reason for discontinuation was adverse events (AEs; 13.9%); 79% of patients experienced a treatment-emergent AE [most common: akathisia (15.9%,) headache (11.6%)]. Serious AEs occurred in 2% of patients; two deaths occurred (one traffic accident, one completed suicide, both considered unrelated to treatment). The mean changes in clinical laboratory, cardiovascular, and ophthalmologic parameters were generally not clinically relevant. The mean (SD) changes from the open-label baseline in Montgomery-Åsberg Depression Rating Scale total score and Clinical Global Impression-Severity score at week 26 were -7.3 (9.5) and -1.0 (1.2), respectively. By week 26, 53.3% of patients were in remission (Montgomery-Åsberg Depression Rating Scale total score≤10). The results suggest that cariprazine was generally safe and well tolerated as adjunctive therapy to treat MDD.

PMID: 30531358 [PubMed - indexed for MEDLINE]

15 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 2020/02/18

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.

13 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 2020/02/15

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.

13 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 2020/02/15

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.

Towards defining the safer use of opioids in rheumatology.

Nat Rev Rheumatol. 2020 Feb;16(2):71-72

Authors: Kim SC, Solomon DH

PMID: 31889161 [PubMed - indexed for MEDLINE]

A retrospective analysis of reporting of adverse drug reactions over 4 years in a primary care health clinic in Malaysia.

Pharmacoepidemiol Drug Saf. 2019 12;28(12):1560-1561

Authors: Kua KP, Jamil MFB, Liew MH, Si JY, Lee SWH

PMID: 31736190 [PubMed - indexed for MEDLINE]

Pharmacy-led pharmacovigilance: Ready for use or missed opportunity?

Pharmacoepidemiol Drug Saf. 2019 12;28(12):1562

Authors: Leufkens HG

PMID: 31714644 [PubMed - indexed for MEDLINE]