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Preexposure Prophylaxis for HIV Prevention in a Large Integrated Health Care System: Adherence, Renal Safety, and Discontinuation.

J Acquir Immune Defic Syndr. 2016 Dec 15;73(5):540-546

Authors: Marcus JL, Hurley LB, Hare CB, Nguyen DP, Phengrasamy T, Silverberg MJ, Stoltey JE, Volk JE

Abstract
BACKGROUND: Placebo-controlled and open-label studies have demonstrated the safety and efficacy of daily oral preexposure prophylaxis (PrEP) in preventing HIV infection, but data are limited on real-world PrEP use.
METHODS: We conducted a cohort study from July 2012 through June 2015 of Kaiser Permanente Northern California members initiating PrEP. We assessed pharmacy refill adherence and discontinuation, decreases in estimated glomerular filtration rate (eGFR), and sexually transmitted infection (STI)/HIV incidence.
RESULTS: Overall, 972 individuals initiated PrEP, accumulating 850 person-years of PrEP use. Mean adherence was 92% overall. Black race/ethnicity [adjusted risk ratio (aRR) 3.0; 95% confidence interval: 1.7 to 5.1, P < 0.001], higher copayments (aRR 2.0; 1.2 to 3.3, P = 0.005), and smoking (aRR 1.6; 1.1 to 2.3, P = 0.025) were associated with <80% adherence. PrEP was discontinued by 219 (22.5%); female sex (aRR 2.6; 1.5 to 4.6, P < 0.001) and drug/alcohol abuse (aRR 1.8; 1.3 to 2.6, P = 0.002) were associated with discontinuation. Among 909 with follow-up creatinine testing, 141 (15.5%) had an eGFR <70 mL·min·1.73 m and 5 (0.6%) stopped PrEP because of low eGFR. Quarterly STI positivity was high and increased over time for rectal chlamydia (P < 0.001) and urethral gonorrhea (P = 0.012). No HIV seroconversions occurred during PrEP use; however, 2 occurred in individuals who discontinued PrEP after losing insurance coverage.
CONCLUSIONS: PrEP adherence was high in clinical practice, consistent with the lack of HIV seroconversions during PrEP use. Discontinuation because of renal toxicity was rare. STI screening every 6 months, as recommended by current guidelines, may be inadequate. Strategies are needed to increase PrEP access during gaps in insurance coverage.

PMID: 27851714 [PubMed - indexed for MEDLINE]

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Searching for Positive Side Effects of Common Drugs.

Trends Pharmacol Sci. 2017 02;38(2):111

Authors: Cvek B

PMID: 27823801 [PubMed - indexed for MEDLINE]

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Incidence of Exposure of Patients in the United States to Multiple Drugs for Which Pharmacogenomic Guidelines Are Available.

PLoS One. 2016;11(10):e0164972

Authors: Samwald M, Xu H, Blagec K, Empey PE, Malone DC, Ahmed SM, Ryan P, Hofer S, Boyce RD

Abstract
Pre-emptive pharmacogenomic (PGx) testing of a panel of genes may be easier to implement and more cost-effective than reactive pharmacogenomic testing if a sufficient number of medications are covered by a single test and future medication exposure can be anticipated. We analysed the incidence of exposure of individual patients in the United States to multiple drugs for which pharmacogenomic guidelines are available (PGx drugs) within a selected four-year period (2009-2012) in order to identify and quantify the incidence of pharmacotherapy in a nation-wide patient population that could be impacted by pre-emptive PGx testing based on currently available clinical guidelines. In total, 73 024 095 patient records from private insurance, Medicare Supplemental and Medicaid were included. Patients enrolled in Medicare Supplemental age > = 65 or Medicaid age 40-64 had the highest incidence of PGx drug use, with approximately half of the patients receiving at least one PGx drug during the 4 year period and one fourth to one third of patients receiving two or more PGx drugs. These data suggest that exposure to multiple PGx drugs is common and that it may be beneficial to implement wide-scale pre-emptive genomic testing. Future work should therefore concentrate on investigating the cost-effectiveness of multiplexed pre-emptive testing strategies.

PMID: 27764192 [PubMed - indexed for MEDLINE]

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Reporting of Adverse Events in Published and Unpublished Studies of Health Care Interventions: A Systematic Review.

PLoS Med. 2016 Sep;13(9):e1002127

Authors: Golder S, Loke YK, Wright K, Norman G

Abstract
BACKGROUND: We performed a systematic review to assess whether we can quantify the underreporting of adverse events (AEs) in the published medical literature documenting the results of clinical trials as compared with other nonpublished sources, and whether we can measure the impact this underreporting has on systematic reviews of adverse events.
METHODS AND FINDINGS: Studies were identified from 15 databases (including MEDLINE and Embase) and by handsearching, reference checking, internet searches, and contacting experts. The last database searches were conducted in July 2016. There were 28 methodological evaluations that met the inclusion criteria. Of these, 9 studies compared the proportion of trials reporting adverse events by publication status. The median percentage of published documents with adverse events information was 46% compared to 95% in the corresponding unpublished documents. There was a similar pattern with unmatched studies, for which 43% of published studies contained adverse events information compared to 83% of unpublished studies. A total of 11 studies compared the numbers of adverse events in matched published and unpublished documents. The percentage of adverse events that would have been missed had each analysis relied only on the published versions varied between 43% and 100%, with a median of 64%. Within these 11 studies, 24 comparisons of named adverse events such as death, suicide, or respiratory adverse events were undertaken. In 18 of the 24 comparisons, the number of named adverse events was higher in unpublished than published documents. Additionally, 2 other studies demonstrated that there are substantially more types of adverse events reported in matched unpublished than published documents. There were 20 meta-analyses that reported the odds ratios (ORs) and/or risk ratios (RRs) for adverse events with and without unpublished data. Inclusion of unpublished data increased the precision of the pooled estimates (narrower 95% confidence intervals) in 15 of the 20 pooled analyses, but did not markedly change the direction or statistical significance of the risk in most cases. The main limitations of this review are that the included case examples represent only a small number amongst thousands of meta-analyses of harms and that the included studies may suffer from publication bias, whereby substantial differences between published and unpublished data are more likely to be published.
CONCLUSIONS: There is strong evidence that much of the information on adverse events remains unpublished and that the number and range of adverse events is higher in unpublished than in published versions of the same study. The inclusion of unpublished data can also reduce the imprecision of pooled effect estimates during meta-analysis of adverse events.

PMID: 27649528 [PubMed - indexed for MEDLINE]

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Predicting the Unpredictable: Drug-Induced QT Prolongation and Torsades de Pointes.

J Am Coll Cardiol. 2016 Apr 05;67(13):1639-50

Authors: Schwartz PJ, Woosley RL

Abstract
Drug-induced long QT syndrome (diLQTS) and congenital LQTS (cLQTS) share many features, and both syndromes can result in life-threatening torsades de pointes (TdP). Our understanding of their mechanistic and genetic similarities has led to their improved clinical management. However, our inability to prevent diLQTS has resulted in removal of many medicines from the market and from development. Genetic and clinical risk factors for diLQTS and TdP are well known and raise the possibility of TdP prevention. Clinical decision support systems (CDSS) can scan the patient's electronic health records for clinical risk factors predictive of diLQTS and warn when a drug that can cause TdP is prescribed. CDSS have reduced prescriptions of QT-prolonging drugs, but these relatively small changes lack the power to reduce TdP. The growing genetic evidence linking diLQTS to cLQTS suggests that prevention of TdP in the future may require inclusion of both genetic and clinical predictors into CDSS.

PMID: 27150690 [PubMed - indexed for MEDLINE]

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Hydroxyurea in Pediatric Patients With Sickle Cell Disease: What Nurses Need to Know.

J Pediatr Oncol Nurs. 2016 Sep;33(5):339-44

Authors: Rees AL

Abstract
Sickle cell disease (SCD) is an inherited disorder in which sickled red blood cells occlude the small vessels of the body, reducing oxygen delivery to tissues and ultimately negatively affecting many of the body's major organs. Hydroxyurea has proven beneficial in the treatment of SCD and prevention of disease-related complications. The 2014 guidelines put forth by the National Heart, Lung, and Blood Institute recommend hydroxyurea treatment in infants 9 months and older, children, and adolescents with SCD-SS or SCD-Sβ(0) thalassemia regardless of clinical severity. This is a change from the 2002 guidelines in which hydroxyurea was recommended for adolescents and children with SCD-SS or SCD-Sβ(0) thalassemia with frequent episodes of pain, a history of acute chest syndrome, severe and symptomatic anemia or other severe vaso-occlusive events. Nurses play a critical role in working with patients and families to provide education, guidance, and support to improve compliance to mitigate the long-term effects of SCD.

PMID: 26611755 [PubMed - indexed for MEDLINE]

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

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2017/06/07

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

"systems biology"

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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.

Notice NOT-FD-17-011 from the NIH Guide for Grants and Contracts

Funding Opportunity PA-17-307 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) announces the availability of administrative supplements to support research in which the supplemental funding would investigate the role of dietary supplements and/or their ingredients in health maintenance and disease prevention. Parent awards need not be focused on dietary supplements; this FOA may provide support to include dietary supplements within the scope of relevant research projects. Research interests of ODS are not limited to specific health conditions, organ systems or population groups. ODS supports all types of research, including pre-clinical, clinical, behavioral, and epidemiological. Additionally, ODS supports research and training programs that build future research capacity for studying the role of dietary supplements in health and disease prevention. Primary consideration for support will be given to applications that stimulate dietary supplement research where it is lacking or lagging, clarify gaps, opportunities and balance between benefits and risks where data are in conflict, target special population groups where additional science on dietary supplements is needed, and focus on the use of dietary supplements in improving or maintaining health and reducing the risk of chronic disease. This FOA will not support new clinical trials.

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

"Rare Diseases"[Mesh] OR "orphan disease"

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pharmacogenomics

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"systems biology"

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

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Related Articles

MyoD reprogramming requires Six1 and Six4 homeoproteins: genome-wide cis-regulatory module analysis.

Nucleic Acids Res. 2016 Oct 14;44(18):8621-8640

Authors: Santolini M, Sakakibara I, Gauthier M, Ribas-Aulinas F, Takahashi H, Sawasaki T, Mouly V, Concordet JP, Defossez PA, Hakim V, Maire P

Abstract
Myogenic regulatory factors of the MyoD family have the ability to reprogram differentiated cells toward a myogenic fate. In this study, we demonstrate that Six1 or Six4 are required for the reprogramming by MyoD of mouse embryonic fibroblasts (MEFs). Using microarray experiments, we found 761 genes under the control of both Six and MyoD. Using MyoD ChIPseq data and a genome-wide search for Six1/4 MEF3 binding sites, we found significant co-localization of binding sites for MyoD and Six proteins on over a thousand mouse genomic DNA regions. The combination of both datasets yielded 82 genes which are synergistically activated by Six and MyoD, with 96 associated MyoD+MEF3 putative cis-regulatory modules (CRMs). Fourteen out of 19 of the CRMs that we tested demonstrated in Luciferase assays a synergistic action also observed for their cognate gene. We searched putative binding sites on these CRMs using available databases and de novo search of conserved motifs and demonstrated that the Six/MyoD synergistic activation takes place in a feedforward way. It involves the recruitment of these two families of transcription factors to their targets, together with partner transcription factors, encoded by genes that are themselves activated by Six and MyoD, including Mef2, Pbx-Meis and EBF.

PMID: 27302134 [PubMed - indexed for MEDLINE]

Literature-based prediction of novel drug indications considering relationships between entities.

Mol Biosyst. 2017 Jun 05;:

Authors: Jang G, Lee T, Lee BM, Yoon Y

Abstract
There have been many attempts to identify and develop new uses for existing drugs, which is known as drug repositioning. Among these efforts, text mining is an effective means of discovering novel knowledge from a large amount of literature data. We identify a gene regulation by a drug and a phenotype based on the biomedical literature. Drugs or phenotypes can activate or inhibit gene regulation. We calculate the therapeutic possibility that a drug acts on a phenotype by means of these two types of regulation. We assume that a drug treats a phenotype if the genes regulated by the phenotype are inversely correlated with the genes regulated by the drug. Based on this hypothesis, we identify drug-phenotype associations with therapeutic possibility. To validate the drug-phenotype associations predicted by our method, we make an enrichment comparison with known drug-phenotype associations. We also identify candidate drugs for drug repositioning from novel associations and thus reveal that our method is a novel approach to drug repositioning.

PMID: 28581007 [PubMed - as supplied by publisher]

Anti-obesogenic and hypolipidemic effects of a glucagon-like peptide-1 receptor agonist derived from the saliva of the Gila monster.

Toxicon. 2017 Jun 01;:

Authors: Alves PL, Abdalla FMF, Alponti RF, Silveira PF

Abstract
INTRODUCTION: Glucagon-like peptide-1 (GLP-1) receptor (R) agonists are a class of incretin mimetic drugs that have been used for the treatment of type 2 diabetes mellitus and also considered strong candidates for the treatment of obesity. The original prototypical drug in this class is the exenatide, a synthetic peptide with the same structure as the native molecule, exendin-4, found in the saliva of the Gila monster (Heloderma suspectum suspectum lizard).
OBJECTIVES: To identify and compare the anti-obesogenic, antidyslipidemic and antidiabetogenic effects of agonism in GLP-1R by exenatide on two distinct models of obesity: induced by hypothalamic injury (MSG) or high-calorie diet (DIO).
METHODS: To obtain MSG, neonatal rats were daily subcutaneously injected with 4 g monosodium glutamate/kg, for 10 consecutive days. To obtain DIO, 72-75 days old rats received hyperlipid food and 30% sucrose for drinking up to 142-145 days old. Untreated healthy rats with the same age were used as control. General biometric and metabolic parameters were measured.
RESULTS: MSG was characterized by decreased naso-anal length, food and fluid intake, plasma protein and glucose decay rate per minute after insulin administration (KITT), as well as increased Lee index (body mass(0.33)/naso-anal length), mass of retroperitoneal and periepididymal fat pads, glycemia, triglycerides (TG), LDL and VLDL. Exenatide ameliorated KITT and food and fluid intake, and it also restored glycemia in MSG. DIO was characterized by glucose intolerance, increased body mass, Lee index, fluid intake, mass of retroperitoneal and periepididymal fat pads, glycemia, glycated hemoglobin (HbA1c), TG, VLDL and total cholesterol, as well as decreased food intake and KITT. Exenatide restored glycemia, HbA1c, TG, VLDL, total cholesterol and body mass, and it also ameliorated food and fluid intake, KITT and mass of retroperitoneal fat pad in DIO.
CONCLUSIONS: The hypothalamic injury and the high-calorie diet induce dyslipidemia and glycemic dysregulation in addition to obesity in rats. The usual therapeutic dose of exenatide in humans is antidiabetogenic in both these obesity models, but is anti-obesogenic and hypolipidemic only in diet-induced obesity. Agonists of GLP-1R are promising anti-obesogenic and antidyslipidemic drugs in the early stages of the obesity, in which the integrity of the nervous system was unaffected.

PMID: 28579479 [PubMed - as supplied by publisher]

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Macromolecular target prediction by self-organizing feature maps.

Expert Opin Drug Discov. 2017 Mar;12(3):271-277

Authors: Schneider G, Schneider P

Abstract
INTRODUCTION: Rational drug discovery would greatly benefit from a more nuanced appreciation of the activity of pharmacologically active compounds against a diverse panel of macromolecular targets. Already, computational target-prediction models assist medicinal chemists in library screening, de novo molecular design, optimization of active chemical agents, drug re-purposing, in the spotting of potential undesired off-target activities, and in the 'de-orphaning' of phenotypic screening hits. The self-organizing map (SOM) algorithm has been employed successfully for these and other purposes. Areas covered: The authors recapitulate contemporary artificial neural network methods for macromolecular target prediction, and present the basic SOM algorithm at a conceptual level. Specifically, they highlight consensus target-scoring by the employment of multiple SOMs, and discuss the opportunities and limitations of this technique. Expert opinion: Self-organizing feature maps represent a straightforward approach to ligand clustering and classification. Some of the appeal lies in their conceptual simplicity and broad applicability domain. Despite known algorithmic shortcomings, this computational target prediction concept has been proven to work in prospective settings with high success rates. It represents a prototypic technique for future advances in the in silico identification of the modes of action and macromolecular targets of bioactive molecules.

PMID: 27997811 [PubMed - indexed for MEDLINE]

The role of Nrf1 and Nrf2 in the regulation of glutathione and redox dynamics in the developing zebrafish embryo.

Redox Biol. 2017 May 30;13:207-218

Authors: Sant KE, Hansen JM, Williams LM, Tran NL, Goldstone JV, Stegeman JJ, Hahn ME, Timme-Laragy A

Abstract
Redox signaling is important for embryogenesis, guiding pathways that govern processes crucial for embryo patterning, including cell polarization, proliferation, and apoptosis. Exposure to pro-oxidants during this period can be deleterious, resulting in altered physiology, teratogenesis, later-life diseases, or lethality. We previously reported that the glutathione antioxidant defense system becomes increasingly robust, including a doubling of total glutathione and dynamic shifts in the glutathione redox potential at specific stages during embryonic development in the zebrafish, Danio rerio. However, the mechanisms underlying these changes are unclear, as is the effectiveness of the glutathione system in ameliorating oxidative insults to the embryo at different stages. Here, we examine how the glutathione system responds to the model pro-oxidants tert-butylhydroperoxide and tert-butylhydroquinone at different developmental stages, and the role of Nuclear factor erythroid 2-related factor (Nrf) proteins in regulating developmental glutathione redox status. Embryos became increasingly sensitive to pro-oxidants after 72h post-fertilization (hpf), after which the duration of the recovery period for the glutathione redox potential was increased. To determine whether the doubling of glutathione or the dynamic changes in glutathione redox potential are mediated by zebrafish paralogs of Nrf transcription factors, morpholino oligonucleotides were used to knock down translation of Nrf1 and Nrf2 (nrf1a, nrf1b, nrf2a, nrf2b). Knockdown of Nrf1a or Nrf1b perturbed glutathione redox state until 72 hpf. Knockdown of Nrf2 paralogs also perturbed glutathione redox state but did not significantly affect the response of glutathione to pro-oxidants. Nrf1b morphants had decreased gene expression of glutathione synthesis enzymes, while hsp70 increased in Nrf2b morphants. This work demonstrates that despite having a more robust glutathione system, embryos become more sensitive to oxidative stress later in development, and that neither Nrf1 nor Nrf2 alone appear to be essential for the response and recovery of glutathione to oxidative insults.

PMID: 28582729 [PubMed - as supplied by publisher]

Omalizumab effectively protects against early- and late allergic responses in asthma after 4 weeks.

Allergy. 2017 Jun 05;:

Authors: Trischler J, Lieb A, Arnold M, Schulze J, Rosewich M, Schubert R, Bottoli I, Zielen S

Abstract
Omalizumab is licensed for therapy in severe allergic asthma with an effect demonstrated after 8 weeks or longer treatment. Since new applications for omalizumab demand precise knowledge of the onset of effects, the objective of this study was to determine the time course of the early (EAR) and late allergic reaction (LAR). Ten patients (IgE >300 IU/mL and <700 IU/mL) with a significant response to allergen challenge were treated with omalizumab according to the approved dosing table. Bronchial allergen provocations (BAP) were repeated at week 1, 2, 4 and 8. EAR was significantly reduced after 4 weeks (ΔFEV1 28 vs. 11%; p<0.001), eNO (86 vs. 53ppb; p<0.05) and basophil activation after 2 weeks (CD63 expression 79 vs. 32%, p<0.05) and LAR already after 1 week (ΔFEV1 26 vs. 13%, p<0.05). These results demonstrate the onset of protective effects earlier than previously determined, potentially improving seasonal utilization and combination with immunotherapy. This article is protected by copyright. All rights reserved.

PMID: 28581121 [PubMed - as supplied by publisher]