Attempted replication of SNPs in RANKL and OPG with musculoskeletal adverse events during aromatase inhibitor treatment for breast cancer.

Physiol Genomics. 2017 Dec 06;:physiolgenomics.00085.2017

Authors: Dempsey JM, Xi J, Henry NL, Rae JM, Hertz DL

Abstract
Aromatase inhibitor (AI) therapy is highly efficacious in the treatment of estrogen receptor-positive breast cancer, however in a subset of patients AI use is discontinued due to drug-induced musculoskeletal adverse events (MS-AE). Several studies have investigated the role of germline single nucleotide polymorphisms on patients' risk of MS-AE's, however no associations have yet to be validated for translation into clinical practice. This study attempted to replicate SNPs in RANKL (rs7984870) and OPG (rs2073618) on the risk of AI-induced MS-AEs, and screen for secondary associations with MS-AE related treatment discontinuation and serum and urine markers of bone health. Previously reported associations were not replicated with our primary hypothesis, change in MS-AE from baseline to three months, however, patients homozygous for the G allele of rs7984870 in RANKL had lower risk of MS-AE-associated treatment discontinuation in analyses of secondary phenotypes without statistical correction.

PMID: 29212847 [PubMed - as supplied by publisher]

Leukocytoclastic vasculitis complicating cisplatin + radiation treatment for laryngeal cancer: a case report.

BMC Cancer. 2017 Dec 06;17(1):831

Authors: Quintanilha JCF, Visacri MB, Amaral LS, Lima CSP, Cintra ML, Moriel P

Abstract
BACKGROUND: Leukocytoclastic vasculitis is typically mediated by deposition of immune complexes and is related to many causes, including medication. To the best of our knowledge, leukocytoclastic vasculitis related to cisplatin has not yet been described in the scientific literature.
CASE PRESENTATION: We report a rare case of leukocytoclastic vasculitis after the first cycle of high-dose cisplatin chemotherapy in a patient with larynx carcinoma. A 48-year-old Caucasian man with larynx carcinoma received a high-dose of cisplatin monochemotherapy (100 mg/m2 every 21 days), along with 70 Gy of radiotherapy divided into 35 sessions, as a therapeutic schedule. Twelve days after the first chemotherapy administration and after 8 sessions of radiotherapy (total of 16 Gy), the patient presented with acute onset of palpable purpura in the lower limbs. The patient was hospitalized for 10 days, and during this period, he underwent several examinations to rule out infectious, autoimmune, and neoplastic disorders. A skin biopsy showed leukocytoclastic vasculitis with a positive pattern for IgM and C3, as detected through direct immunofluorescence. Twenty-five days after cisplatin administration, the chemotherapy regimen was changed to carboplatin AUC 5, and the episodes of purpura ceased, reinforcing the hypothesis of an adverse reaction to cisplatin.
CONCLUSIONS: Cisplatin can induce leukocytoclastic vasculitis and clinicians should be aware of this potential effect for better case management and diagnosis.

PMID: 29212535 [PubMed - in process]

[NEPHROTOXIC DRUGS].

Acta Med Croatica. 2016 12;70(4-5):309-14

Authors: Popović B, Šutić I, Marković NB

Abstract
Renal tissue is sensitive to the effect of potentially nephrotoxic drugs and other substances that are available over-the-counter or can be purchased at healthy food stores or elsewhere, and harmful substances from the environment. The harmful effects of these substances lead to the development of recognizable clinical syndromes, including acute or chronic renal failure, tubulopathy, and proteinuria. Risk factors that influence the development of kidney disease induced by drugs are divided into those related to patient characteristics, drug characteristics, and renal function. Drugs that commonly exhibit nephrotoxic effects are analgesics, antimicrobials, chemotherapeutics, contrast agents, immunosuppressants, herbal preparations and substances containing heavy metals. Family physician must carefully observe their patients, nurturing individual approach to drug selection and determining the dose. Renal function can quickly return to normal if the damage is recognized on time. Recent research yields insights into the identification of new biomarkers that will contribute to early detection of drug induced kidney damage.

PMID: 29087164 [PubMed - indexed for MEDLINE]

Legacy data sharing to improve drug safety assessment: the eTOX project.

Nat Rev Drug Discov. 2017 Dec;16(12):811-812

Authors: Sanz F, Pognan F, Steger-Hartmann T, Díaz C, eTOX, Cases M, Pastor M, Marc P, Wichard J, Briggs K, Watson DK, Kleinöder T, Yang C, Amberg A, Beaumont M, Brookes AJ, Brunak S, Cronin MTD, Ecker GF, Escher S, Greene N, Guzmán A, Hersey A, Jacques P, Lammens L, Mestres J, Muster W, Northeved H, Pinches M, Saiz J, Sajot N, Valencia A, van der Lei J, Vermeulen NPE, Vock E, Wolber G, Zamora I

Abstract
The sharing of legacy preclinical safety data among pharmaceutical companies and its integration with other information sources offers unprecedented opportunities to improve the early assessment of drug safety. Here, we discuss the experience of the eTOX project, which was established through the Innovative Medicines Initiative to explore this possibility.

PMID: 29026211 [PubMed - indexed for MEDLINE]

Mitochondrial disease patients' perception of dietary supplements' use.

Mol Genet Metab. 2016 Sep;119(1-2):100-8

Authors: Karaa A, Kriger J, Grier J, Holbert A, Thompson JL, Parikh S, Hirano M

Abstract
Surveys of mitochondrial disease physicians conducted through the Mitochondrial Medicine Society have shown that virtually all providers recommend a variety of dietary supplements as treatments to their patients in an effort to enhance energy production and reduce oxidative stress. In this survey, we asked patients and their parents about their experiences taking these dietary supplements for mitochondrial disease. The survey was disseminated through the North American Mitochondrial Disease Consortium (NAMDC) and the Rare Disease Clinical Research Network (RDCRN) registries and gathered 162 responses. The study ascertained each patient's mitochondrial disease diagnosis, dietary supplements used, adjunct therapy, and effects of the supplements on symptoms and health. Regardless of the specific underlying mitochondrial disease, the majority of the survey respondents stated they are or have been on dietary supplements. Most patients take more than four supplements primarily coenzyme Q10, l-carnitine, and riboflavin. The majority of patients taking supplements reported health benefits from the supplements. The onset of perceived benefits was between 2weeks to 3months of initiating intake. Supplements seem to be safe, with only 28% of patients experiencing mild side-effects and only 5.6% discontinuing their intake due to intolerance. Only 9% of patients had insurance coverage for their supplements and when paying out of pocket, 95% of them spend up to $500/month. Despite the use of concomitant therapies (prescribed medications, physical therapy, diet changes and other), 45.5% of patients think that dietary supplements are the only intervention improving their symptoms. Some limitations of this study include the retrospective collection of data probably associated with substantial recall bias, lack of longitudinal follow up to document pre- and post-supplement clinical status and second hand reports by parents for children which may reflect parents' subjective interpretation of symptoms severity and supplements effect rather than real patients' experience. More extensive prospective studies will help further elucidate this topic.

PMID: 27444792 [PubMed - indexed for MEDLINE]

Small cell lung cancer: Time to revisit DNA-damaging chemotherapy.

Sci Transl Med. 2016 Jul 06;8(346):346fs12

Authors: Thomas A, Pommier Y

Abstract
Rational use of DNA-damaging chemotherapy, with new combinations to heighten DNA replication stress, could improve outcomes in small cell lung cancer.

PMID: 27384345 [PubMed - indexed for MEDLINE]

Content, Consistency, and Quality of Black Box Warnings.

Ann Intern Med. 2016 07 05;165(1):74-5

Authors: Elraiyah T, Murad MH

PMID: 27380161 [PubMed - indexed for MEDLINE]

Incidence of adverse events in paediatric procedural sedation in the emergency department: a systematic review and meta-analysis.

BMJ Open. 2016 Jun 15;6(6):e011384

Authors: Bellolio MF, Puls HA, Anderson JL, Gilani WI, Murad MH, Barrionuevo P, Erwin PJ, Wang Z, Hess EP

Abstract
OBJECTIVE AND DESIGN: We conducted a systematic review and meta-analysis to evaluate the incidence of adverse events in the emergency department (ED) during procedural sedation in the paediatric population. Randomised controlled trials and observational studies from the past 10 years were included. We adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.
SETTING: ED.
PARTICIPANTS: Children.
INTERVENTIONS: Procedural sedation.
OUTCOMES: Adverse events like vomiting, agitation, hypoxia and apnoea. Meta-analysis was performed with random-effects model and reported as incidence rates with 95% CIs.
RESULTS: A total of 1177 studies were retrieved for screening and 258 were selected for full-text review. 41 studies reporting on 13 883 procedural sedations in 13 876 children (≤18 years) were included. The most common adverse events (all reported per 1000 sedations) were: vomiting 55.5 (CI 45.2 to 65.8), agitation 17.9 (CI 12.2 to 23.7), hypoxia 14.8 (CI 10.2 to 19.3) and apnoea 7.1 (CI 3.2 to 11.0). The need to intervene with either bag valve mask, oral airway or positive pressure ventilation occurred in 5.0 per 1000 sedations (CI 2.3 to 7.6). The incidences of severe respiratory events were: 34 cases of laryngospasm among 8687 sedations (2.9 per 1000 sedations, CI 1.1 to 4.7; absolute rate 3.9 per 1000 sedations), 4 intubations among 9136 sedations and 0 cases of aspiration among 3326 sedations. 33 of the 34 cases of laryngospasm occurred in patients who received ketamine.
CONCLUSIONS: Serious adverse respiratory events are very rare in paediatric procedural sedation in the ED. Emesis and agitation are the most frequent adverse events. Hypoxia, a late indicator of respiratory depression, occurs in 1.5% of sedations. Laryngospasm, though rare, happens most frequently with ketamine. The results of this study provide quantitative risk estimates to facilitate shared decision-making, risk communication, informed consent and resource allocation in children undergoing procedural sedation in the ED.

PMID: 27311910 [PubMed - indexed for MEDLINE]

Updates on drug-target network; facilitating polypharmacology and data integration by growth of DrugBank database.

Brief Bioinform. 2016 Nov;17(6):1070-1080

Authors: Barneh F, Jafari M, Mirzaie M

Abstract
Network pharmacology elucidates the relationship between drugs and targets. As the identified targets for each drug increases, the corresponding drug-target network (DTN) evolves from solely reflection of the pharmaceutical industry trend to a portrait of polypharmacology. The aim of this study was to evaluate the potentials of DrugBank database in advancing systems pharmacology. We constructed and analyzed DTN from drugs and targets associations in the DrugBank 4.0 database. Our results showed that in bipartite DTN, increased ratio of identified targets for drugs augmented density and connectivity of drugs and targets and decreased modular structure. To clear up the details in the network structure, the DTNs were projected into two networks namely, drug similarity network (DSN) and target similarity network (TSN). In DSN, various classes of Food and Drug Administration-approved drugs with distinct therapeutic categories were linked together based on shared targets. Projected TSN also showed complexity because of promiscuity of the drugs. By including investigational drugs that are currently being tested in clinical trials, the networks manifested more connectivity and pictured the upcoming pharmacological space in the future years. Diverse biological processes and protein-protein interactions were manipulated by new drugs, which can extend possible target combinations. We conclude that network-based organization of DrugBank 4.0 data not only reveals the potential for repurposing of existing drugs, also allows generating novel predictions about drugs off-targets, drug-drug interactions and their side effects. Our results also encourage further effort for high-throughput identification of targets to build networks that can be integrated into disease networks.

PMID: 26490381 [PubMed - indexed for MEDLINE]

Molecular Mechanisms of Antipsychotic Drug-Induced Diabetes.

Front Neurosci. 2017;11:643

Authors: Chen J, Huang XF, Shao R, Chen C, Deng C

Abstract
Antipsychotic drugs (APDs) are widely prescribed to control various mental disorders. As mental disorders are chronic diseases, these drugs are often used over a life-time. However, APDs can cause serious glucometabolic side-effects including type 2 diabetes and hyperglycaemic emergency, leading to medication non-compliance. At present, there is no effective approach to overcome these side-effects. Understanding the mechanisms for APD-induced diabetes should be helpful in prevention and treatment of these side-effects of APDs and thus improve the clinical outcomes of APDs. In this review, the potential mechanisms for APD-induced diabetes are summarized so that novel approaches can be considered to relieve APD-induced diabetes. APD-induced diabetes could be mediated by multiple mechanisms: (1) APDs can inhibit the insulin signaling pathway in the target cells such as muscle cells, hepatocytes and adipocytes to cause insulin resistance; (2) APD-induced obesity can result in high levels of free fatty acids (FFA) and inflammation, which can also cause insulin resistance. (3) APDs can cause direct damage to β-cells, leading to dysfunction and apoptosis of β-cells. A recent theory considers that both β-cell damage and insulin resistance are necessary factors for the development of diabetes. In high-fat diet-induced diabetes, the compensatory ability of β-cells is gradually damaged, while APDs cause direct β-cell damage, accounting for the severe form of APD-induced diabetes. Based on these mechanisms, effective prevention of APD-induced diabetes may need an integrated approach to combat various effects of APDs on multiple pathways.

PMID: 29209160 [PubMed]

The electronic medication complete communication (EMC2) study: Rationale and methods for a randomized controlled trial of a strategy to promote medication safety in ambulatory care.

Contemp Clin Trials. 2016 Nov;51:72-77

Authors: Bailey SC, Paasche-Orlow MK, Adams WG, Brokenshire SA, Hickson RP, Oramasionwu CU, Curtis LM, Kwasny MJ, Wolf MS

Abstract
BACKGROUND: Adverse drug events (ADEs) affect millions of patients annually and place a significant burden on the healthcare system. The Food and Drug Administration (FDA) has developed patient safety information for high-risk medications that pose serious public health concerns. However, there are currently few assurances that patients receive this information or are able to identify or respond correctly to ADEs.
OBJECTIVE: To evaluate the effectiveness of the Electronic Medication Complete Communication (EMC2) Strategy to promote safe medication use and reporting of ADEs in comparison to usual care.
METHODS: The automated EMC2 Strategy consists of: 1) provider alerts to counsel patients on medication risks, 2) the delivery of patient-friendly medication information via the electronic health record, and 3) an automated telephone assessment to identify potential medication concerns or ADEs. The study will take place in two community health centers in Chicago, IL. Adult, English or Spanish-speaking patients (N=1200) who have been prescribed a high-risk medication will be enrolled and randomized to the intervention arm or usual care based upon practice location. The primary outcomes of the study are medication knowledge, proper medication use, and reporting of ADEs; these will be measured at baseline, 4weeks, and three months. Intervention fidelity as well as barriers and costs of implementation will be evaluated.
CONCLUSIONS: The EMC2 Strategy automates a patient-friendly risk communication and surveillance process to promote safe medication use while minimizing clinic burden. This trial seeks to evaluate the effectiveness and feasibility of this strategy in comparison to usual care.

PMID: 27777127 [PubMed - indexed for MEDLINE]

A comparison of the CARG tool, the VES-13, and oncologist judgment in predicting grade 3+ toxicities in men undergoing chemotherapy for metastatic prostate cancer.

J Geriatr Oncol. 2017 Jan;8(1):31-36

Authors: Alibhai SM, Aziz S, Manokumar T, Timilshina N, Breunis H

Abstract
OBJECTIVE: Since the benefits of chemotherapy in treating older men with metastatic castration-resistant prostate cancer (mCRPC) are modest, validated tools that predict the risk of treatment toxicity may aid clinical decision-making. Whether these tools are better than oncologist judgment remains unclear. We compared the Cancer and Aging Research Group (CARG) tool, the Vulnerable Elders Survey-13 (VES-13), and oncologist judgment in predicting toxicity in men with mCRPC undergoing chemotherapy.
MATERIALS AND METHODS: Men aged 65+ with mCRPC starting first-line or second-line chemotherapy were enrolled in this prospective observational study. At baseline, VES-13 and CARG risk scores were calculated and treating oncologists were asked to rate toxicity risk on a 10-point scale. Toxicity was captured using the Common Terminology Criteria for Adverse Events version 4. Logistic regression was performed to examine relationships between risk prediction tools and the development of grade 3+ toxicity.
RESULTS: 46 patients (mean age 75) were accrued, with most receiving Docetaxel 75mg/m2 q3weekly. A total of 9 patients (20%, 95% confidence interval (CI) 9-34%) developed grade 3+ toxicity. Using the CARG tool, 0% (95% CI 0-84%), 17% (95% CI 6-36%), and 27% (95% CI 18-55%) of patients in the low, intermediate, and high risk groups developed grade 3+ toxicity, respectively (p=0.65). Although the CARG tool, the VES-13, and oncologist judgment appeared to perform similarly, comparisons were limited by the small sample size.
CONCLUSION: Chemotherapy for mCRPC was associated with lower than predicted rates of severe toxicity across all predicted risk groups. Further disease-specific validation studies are warranted.

PMID: 27756545 [PubMed - indexed for MEDLINE]

Ten Medication-Related Tips in Outpatient Practice.

Am J Med. 2017 Feb;130(2):146-147

Authors: Greenberg J

PMID: 27746292 [PubMed - indexed for MEDLINE]

Safety profile of the varicella vaccine (Oka vaccine strain) based on reported cases from 2005 to 2015 in Japan.

Vaccine. 2016 Sep 22;34(41):4943-4947

Authors: Yoshikawa T, Ando Y, Nakagawa T, Gomi Y

Abstract
BACKGROUND: As of 2014, routine vaccination strategies in Japan have included the varicella vaccine. Given the widespread use of the vaccine, it is important to investigate the safety profile of the vaccine strain, Oka/Biken varicella, in Japanese patients.
METHODS: Reports of adverse events associated with varicella vaccination between 2005 and 2015 were retrospectively reviewed. Virological analysis was performed on clinical specimens collected from some of the reported cases to determine whether the etiological agent was the wild-type or Oka vaccine-strains.
RESULTS: There were 351 reports (3.71/100,000 doses) of adverse events during the observation period. Among the 351 reports, there were 88 reports (0.93/100,000 doses) of varicella-like and 66 reports (0.70/100,000 doses) of zoster-like skin rashes. The wild-type strain induced varicella-like skin rashes earlier than the Oka vaccine strain. The Oka vaccine strain induced zoster-like skin rashes in younger patients compared to the wild-type strain. The onset of zoster-like skin rashes after vaccination was earlier in patients vaccinated with the Oka vaccine-type strain.
CONCLUSION: The Oka/Biken vaccine is generally safe and well tolerated in Japan. Clinical aspects of adverse reactions caused by the Oka vaccine strain were consistent with previous reports from the United States and Europe.

PMID: 27591104 [PubMed - indexed for MEDLINE]

Safety and Tolerability of Stribild in the Southeast United States.

J Int Assoc Provid AIDS Care. 2016 Sep;15(5):432-9

Authors: Derrick CB, Lu ZK, Caulder CR, Hester EK, Wagner TD, Bookstaver PB

Abstract
PURPOSE: The purpose of this study is to assess postmarketing safety and tolerability of Stribild (elvitegravir [EVG]/cobicistat [COBI]/tenofovir disoproxil fumarate [TDF]/emtricitabine [FTC]).
METHODS: A retrospective, pharmacoepidemiologic study in 2 outpatient HIV clinics in the Southeast United States was conducted among adults receiving EVG/COBI/TDF/FTC. We evaluated incidence and treatment-related adverse events, including change in serum creatinine (SCr).
RESULTS: Patients were primarily treatment experienced (n = 173, 60%), African American (n = 210, 73%), and males (n = 187, 65%). One hundred ninety-five (68%) patients had any increase in SCr, and 65 (23%) had an increase of ≥0.3 mg/dL. Mean SCr change from baseline to peak was 0.2 mg/dL. Being treatment experienced (odds ratio [OR] = 2.21, 95% confidence interval [CI]: 1.12-4.38) was associated with SCr ≥0.3 mg/dL, while body mass index ≥30 kg/m(2) (OR = 0.41, 95% CI: 0.18-0.93) was protective. Twenty (7%) patients discontinued therapy, 3 due to acute kidney injury.
CONCLUSION: Our results demonstrate limited adverse events and low discontinuation rates associated with EVG/COBI/TDF/FTC.

PMID: 27225853 [PubMed - indexed for MEDLINE]

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 2017/12/06

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 2017/12/06

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 2017/12/05

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.

Pharmacogenetics: A strategy for personalized medicine for autoimmune diseases.

Clin Genet. 2017 Nov 30;:

Authors: Tavakolpour S, Darvishi M, Ghasemiadl M

Abstract
For many years, a considerable number of patients with autoimmune diseases (ADs) have suffered from a lack of drug response and drug-related toxicity. Despite the emergence of new therapeutic options such as biological agents, patients continue to struggle with these problems. Unfortunately, new challenges, including the paradoxical effects of biological drugs, have complicated the situation. In recent decades, efforts have been made to predict drug response as well as drug-related side-effects. Thanks to the many advances in genetics, evaluation of markers to predict drug response/toxicity before the initiation of treatment may be an avenue toward personalizing treatments. Implementing pharmacogenetics and pharmacogenomics in the clinic could improve clinical care; however, obstacles remain to effective personalized medicine for ADs. The present study attempted to clarify the concept of pharmacogenetics/pharmacogenomics for ADs. After an overview on the pathogenesis of the most common types of treatments, this paper focuses on pharmacogenetic studies related to the selected ADs. Bridging the gap between pharmacogenetics and personalized medicine is also discussed. Moreover, the advantages, disadvantages and recommendations related to making personalized medicine practical for ADs have been addressed.

PMID: 29194620 [PubMed - as supplied by publisher]

Longitudinal Study of Short-term Corticosteroid Use by Working-Age Adults with Diabetes Mellitus: Risks and Mitigating Factors.

J Diabetes. 2017 Nov 28;:

Authors: Rogers MAM, Lin P, Nallamothu BK, Kim C, Waljee AK

Abstract
BACKGROUND: We assessed the frequency of short-term oral corticosteroid use in adults with diabetes, and examined the incidence of fractures, venous thromboembolism (VTE) and hospitalization for sepsis after corticosteroid use. We also evaluated whether preventative medications mitigated adverse events.
METHODS: We conducted a longitudinal study of 1,548,945 adults (ages 18-64 years) who received healthcare coverage through a large national health insurer, years 2012-2014. Incidence rate ratios (IRR) were calculated using conditional Poisson regression.
RESULTS: Short-term oral corticosteroids were used by 23.9% of adults with type 2 diabetes, 20.8% with type 1, and 20.9% without diabetes during the 3-year period (p<0.001). Baseline risks of fracture, VTE, and sepsis were greater for individuals with diabetes than those without (p<0.001). The combined effect of having diabetes and using corticosteroids was greater than the sum of the individual effects (synergy indices of 1.17, 1.23, 1.30 for fracture, VTE and sepsis, respectively). The IRR for venous thromboembolism was 3.62 (95% CI, 2.41-5.45) in the 5-30 days after corticosteroid use. Fractures increased in the 5-30 days after corticosteroid use (IRR=2.06, 95% CI: 1.52, 2.80), but concomitant use of ergocalciferol mitigated this risk (IRR=1.13; 95% CI: 0.12, 11.07). The risk of hospitalization for sepsis was elevated with corticosteroid use (IRR=3.79; 95% CI: 2.05, 7.01) but was mitigated by the concomitant use of statins.
CONCLUSIONS: Short-term oral corticosteroid use is common in adults with diabetes and is associated with an elevated, but low, risk of adverse events. Our findings suggest that preventative medications may mitigate risk.

PMID: 29193668 [PubMed - as supplied by publisher]