Drug-induced Shortening of the Electromechanical Window is an Effective Biomarker for in Silico Prediction of Clinical Risk of Arrhythmias.

Br J Pharmacol. 2019 Jul 04;:

Authors: Passini E, Trovato C, Morissette P, Sannajust F, Bueno-Orovio A, Rodriguez B

Abstract
BACKGROUND AND PURPOSE: Early identification of drug-induced cardiac adverse events is key in drug development. Human-based computer models are emerging as an effective approach, complementary to in vitro and animal models. Drug-induced shortening of the electromechanical window has been associated with increased risk of arrhythmias. This study investigates the potential of a cellular surrogate for the electromechanical window (EMw) for prediction of pro-arrhythmic cardiotoxicity, and its underlying ionic mechanisms, using human-based computer models.
EXPERIMENTAL APPROACH: In silico drug trials for 40 reference compounds were performed, testing up to 100-fold the therapeutic concentrations (EFTPCmax ) and using a control population of human ventricular action potential (AP) models, optimised to capture pro-arrhythmic ionic profiles. EMw was calculated for each model in the population as the difference between AP and Ca2+ -transient durations at 90%. Drug-induced changes in the EMw and occurrence of repolarisation abnormalities (RA) were quantified.
KEY RESULTS: Drugs with clinical risk of Torsade de Pointes arrhythmias induced a concentration-dependent EMw shortening, while safe drugs lead to increase or small change in EMw. Risk predictions based on EMw shortening achieved 90% accuracy at 10x EFTPCmax , whereas RA-based predictions required 100x EFTPCmax to reach the same accuracy. Due to its dependence on Ca2+ -transient, the EMw was also shown to be more sensitive than AP prolongation in distinguishing between pure hERG blockers and multichannel compounds also blocking the calcium current.
CONCLUSION AND IMPLICATIONS: The EMw is an effective biomarker for in silico predictions of drug-induced clinical pro-arrhythmic risk, particularly for compounds with multichannel blocking action.

PMID: 31271649 [PubMed - as supplied by publisher]

Effect of supplementation with omega-3 fatty acids on hypertriglyceridemia in pediatric patients with obesity.

J Pediatr Endocrinol Metab. 2019 Jul 04;:

Authors: Del-Río-Navarro BE, Miranda-Lora AL, Huang F, Hall-Mondragon MS, Leija-Martínez JJ

Abstract
Background The beneficial effects of treating hypertriglyceridemic adults with omega-3 fatty acids have been reported. However, information regarding omega-3 treatment of pediatric patients is limited. Objective To evaluate the efficacy and safety of administering omega-3 fatty acids (3 g/day for 12 weeks) to children/adolescents with obesity and hypertriglyceridemia. Methods A randomized, double-blind, placebo-controlled, parallel study involving pediatric patients (10-16 years old) with obesity and hypertriglyceridemia was conducted. The National Center for Health Statistics (CDC) defines obesity as a body mass index (BMI) ≥95th percentile. Subjects with triglyceride concentrations ranging from 150 to 1000 mg/dL were randomized into two groups: those receiving omega-3 fatty acids (eicosapentaenoic and docosahexaenoic acids) (n = 65) and those receiving a placebo (n = 65) for 12 weeks. Serum triglyceride concentrations were always measured from 8 to 9 am after a 12-h fast. Results By the end of treatment, triglyceride concentrations had decreased by 39.1% in the omega-3 group and 14.6% in the placebo group (p < 0.01). The incidence of adverse gastrointestinal events (e.g. flatulence, belching) was 41.2% and 6.2% in the omega-3 and placebo groups, respectively (p < 0.01). There were no serious drug-related adverse events. Conclusions Supplementation with 3 g/day of omega-3 fatty acids is a safe and effective option for treating hypertriglyceridemia in children and adolescents with obesity.

PMID: 31271554 [PubMed - as supplied by publisher]

Literature review of the evidence regarding intravenous lipid administration in drug-induced cardiotoxicity.

Expert Rev Clin Pharmacol. 2019 Jul;12(7):591-602

Authors: Paneta M, Waring WS

Abstract
Introduction: Intravenous lipid emulsion (ILE) administration is capable of reversing the acute cardiac and neurological toxicity caused by local anesthetic agents. In recent years, ILE has also been explored as a potential antidote for cardiotoxicity caused by non-anesthetic agents too. Areas covered: The potential mechanisms, safety, and efficacy of this approach are considered. Data were sought from published reports listed in PubMed and EMBASE, and abstracts of meetings of the North American Congress of Clinical Toxicology and European Association of Poisons Centres and Clinical Toxicologists. There were reports involving 298 patients where ILE has been administered for severe drug toxicity. Clinical improvement was observed in 57 of 59 patients with local anesthetic toxicity (96.6%); there were 239 patients where toxicity was due to non-anesthetic agents, and ILE apparently improved clinical outcome in 215 (72.1%). Expert opinion: Response rates were similar between ILE treated toxicity caused by lipid soluble and non-lipid soluble drugs. Potential adverse effects of ILE include interference with laboratory assays, acute pancreatitis, and adult respiratory distress syndrome, although the rate of occurrence is difficult to ascertain.

PMID: 31106655 [PubMed - indexed for MEDLINE]

An Open Letter to Health Canada.

J Cutan Med Surg. 2017 May/Jun;21(3):195-196

Authors: Papp K, Albrecht L, Barber K, Bourcier M, Dion PL, Freiman A, Gooderham M, Guenther L, Gulliver W, Hong CH, Lynde C, Poulin Y, Siddha S, Toole J, Toth D, Vender R, Wasel N, Wiseman M

PMID: 28903599 [PubMed - indexed for MEDLINE]

The TREAT Registry: Evolution of Knowledge From 1999 to 2017: Lessons Learned.

Clin Gastroenterol Hepatol. 2017 09;15(9):1319-1321

Authors: Lichtenstein GR

PMID: 28554680 [PubMed - indexed for MEDLINE]

The Right Idea for the Wrong Patient: Results of a National Survey on Stopping PPIs.

Clin Gastroenterol Hepatol. 2017 09;15(9):1475-1476

Authors: Kurlander JE, Kolbe M, Scheiman JM, Weissman A, Piette JD, Rubenstein JH, Waljee AK, Saini SD

PMID: 28392438 [PubMed - indexed for MEDLINE]

Development and implementation of "Check of Medication Appropriateness" (CMA): advanced pharmacotherapy-related clinical rules to support medication surveillance.

BMC Med Inform Decis Mak. 2019 02 11;19(1):29

Authors: Quintens C, De Rijdt T, Van Nieuwenhuyse T, Simoens S, Peetermans WE, Van den Bosch B, Casteels M, Spriet I

Abstract
BACKGROUND: To improve medication surveillance and provide pharmacotherapeutic support in University Hospitals Leuven, a back-office clinical service, called "Check of Medication Appropriateness" (CMA), was developed, consisting of clinical rule based screening for medication inappropriateness. The aim of this study is twofold: 1) describing the development of CMA and 2) evaluating the preliminary results, more specifically the number of clinical rule alerts, number of actions on the alerts and acceptance rate by physicians.
METHODS: CMA focuses on patients at risk for potentially inappropriate medication and involves the daily checking by a pharmacist of high-risk prescriptions generated by advanced clinical rules integrating patient specific characteristics with details on medication. Pharmacists' actions are performed by adding an electronic note in the patients' medical record or by contacting the physician by phone. A retrospective observational study was performed to evaluate the primary outcomes during an 18-month study period.
RESULTS: 39,481 clinical rule alerts were checked by pharmacists for which 2568 (7%) electronic notes were sent and 637 (1.6%) phone calls were performed. 37,782 (96%) alerts were checked within four pharmacotherapeutic categories: drug use in renal insufficiency (25%), QTc interval prolonging drugs (11%), drugs with a restricted indication or dosing (14%) and overruled very severe drug-drug interactions (50%). The emergency department was a frequently involved ward and anticoagulants are the drug class for which actions are most frequently carried out. From the 458 actions performed for the four abovementioned categories, 69% were accepted by physicians.
CONCLUSIONS: These results demonstrate the added value of CMA to support medication surveillance in synergy with already integrated basic clinical decision support and bedside clinical pharmacy. Otherwise, the study also highlighted a number of limitations, allowing improvement of the service.

PMID: 30744674 [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:

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

These pubmed results were generated on 2019/07/03

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.

Berberine coated mannosylated liposomes curtail RANKL stimulated osteoclastogenesis through the modulation of GSK3β pathway via upregulating miR-23a.

Int Immunopharmacol. 2019 Jun 28;74:105703

Authors: Sujitha S, Rasool M

Abstract
Drug-induced microRNAs manifest significant therapeutic approaches; however, such progress in the treatment of osteopathic disorders including osteoporosis and rheumatoid arthritis still remains obscure. Contrarily, non-specific drug delivery, at high doses, increases the risk of side effects and reduces drug therapeutic efficacy. Accordingly, the present study was designed to examine the therapeutic effect of berberine coated mannosylated liposomes (ML-BBR) on RANKL (100 ng/ml) stimulated bone marrow-derived monocytes/macrophages (BMMs) via altering miR-23a expression. Initial studies using confocal microscopy showed successful internalization of ML-BBR in RANKL stimulated BMMs. Treatment with ML-BBR abrogated the increased osteoclast formation in BMM cells via inhibiting phosphorylated glutathione synthase kinase beta (p-GSK3β) mediated NFATc1 activation. Consequently, ML-BBR also attenuated the expression of bone-degrading enzymes (TRAP, cathepsin K and MMP-9) thereby inhibiting the bone resorptive activity of osteoclasts. Moreover, ML-BBR induced the expression levels of miR-23a at the gene level, which in turn attenuated GSK3β/p-GSK3β expression as confirmed via blotting analysis. Further miR-23a inhibition of the GSK3β phosphorylation was confirmed using luciferase reporter assay. Comparatively, LY2090314 (GSK3β inhibitor) treatment inhibited the protein level expression of GSK3β/p-GSK3β. However, LY2090314 treatment induced a basal level expression of miR-23a owing to the suggestion that ML-BBR has an influential role in upregulating miR-23a level to inhibit GSK-3β phosphorylation. Cumulatively, our findings endorsed that preferential internalization of ML-BBR by BMMs effectively modulated the RANKL/p-GSK3β pathway and curtailed the osteoclast-mediated bone erosion possibly through post-transcriptional gene silencing via miR-23a.

PMID: 31261037 [PubMed - as supplied by publisher]

Systemic effects of fluoroscopically guided epidural steroid injection with dexamethasone.

Korean J Pain. 2019 Jul 01;32(3):178-186

Authors: Kang WY, Lee JW, Lee E, Kang Y, Ahn JM, Kang HS

Abstract
Background: Epidural steroid injections (ESIs) have been widely used in managing spinal pain. Dexamethasone has recently emerged as a useful drug in this setting, relative to particulate steroids, although the associated systemic effects have not been fully elucidated. This study aimed to investigate the incidences and types of systemic effects after fluoroscopically guided ESI with dexamethasone.
Methods: This retrospective study included 888 ESIs with dexamethasone (fluoroscopically guided at the cervical and lumbosacral levels) performed on 825 patients during January to June 2017. Data regarding systemic effects were collected via telephone interviews using a standardized questionnaire at 2 weeks after the procedure. Data on patient demographic, clinical, and procedural characteristics were collected and analyzed to identify factors that were associated with systemic effects. All statistical analyses were performed using the chi-squared test.
Results: Among the 825 patients, 40 patients (4.8%) experienced systemic effects during the 2-week follow-up period. The most common systemic effect was facial flushing (12 patients, 1.5%), which was followed by urticaria (7 patients, 0.8%) and insomnia (7 patients, 0.8%). A history of spine surgery was significantly associated with the occurrence of systemic effects (P = 0.036). Systemic effects were significantly more common for injections at the cervical level than at the lumbar level (P = 0.019).
Conclusions: Approximately 4.8% of the patients who underwent ESI with dexamethasone experienced minor and transient systemic effects. These effects were more common in patients who had undergone a previous spine surgery or received a cervical ESI.

PMID: 31257826 [PubMed]

Insights into mechanisms and severity of drug-induced liver injury via computational systems toxicology approach.

Toxicol Lett. 2019 Sep 15;312:22-33

Authors: Peng Y, Wu Z, Yang H, Cai Y, Liu G, Li W, Tang Y

Abstract
Liver is the central place for drug metabolism. Drug-induced liver injury (DILI) is hence inevitable, and has become one of the leading causes for drug failure in development and drug withdrawal from the market. Due to lack of reliable preclinical and in vivo toxicology test conditions, it is time-consuming, laborious and costly to interpret the mechanisms of DILI through bioassays. In this paper, we developed a computational systems toxicology approach to investigate the molecular mechanisms of DILI. Totally 1478 DILI compounds were collected, together with 1067 known targets for 896 DILI compounds. Then, 173 new potential targets of these compounds were predicted by our bSDTNBI (balanced substructure-drug-target network-based inference) method. After network analysis, 145 primary genes were found to relate with hepatotoxicity and have higher expression in liver, among which 26 genes were predicted by our method, such as CYP2E1, GSTA1, EPHX1, ADH1B, ADH1C, ALDH2, F7, and IL2. A scoring function, DILI-Score, was further proposed to assess the hepatotoxic severity of a given compound. Finally, as case studies, we analyzed the mechanisms of DILI from the perspective of off-targets, and found out the pivotal genes for liver injuries induced by tyrosine kinase inhibitors and TAK-875. This work would be helpful for better understanding mechanisms of DILI and provide clues for reducing risk of DILI.

PMID: 31063831 [PubMed - indexed for MEDLINE]

Tolmetin sodium-loaded thermosensitive mucoadhesive liquid suppositories for rectal delivery; strategy to overcome oral delivery drawbacks.

Drug Dev Ind Pharm. 2019 Feb;45(2):252-264

Authors: Akl MA, Ismael HR, Abd Allah FI, Kassem AA, Samy AM

Abstract
Tolmetin sodium (TS) is a nonsteroidal anti-inflammatory drug (NSAID) indicated for treatment of musculoskeletal issues. As other NSAID, TS displays a marked side effects on the gastro-intestinal (GI) tract after oral administration. Traditional solid suppositories can cause pain and discomfort for patients, may reach the end of the colon; consequently, the drug can undergo the first-pass effect. TS liquid suppository (TS-LS) was developed to enhance patient compliance and rectal mucosal safety in high-risk patients receiving highly NSAID therapy. This work was conducted to optimize and evaluate Poloxamer P407/P188-based thermoresponsive TS-LS by using mucoadhesive polymers such as methylcellulose (MC). TS-LS was prepared by cold method and characterized their in vitro physicochemical properties as gelation temperature (GT), gel strength, bioadhesive properties, and in vitro release. The safety of the prepared suppository on rectum, stomach, and liver was evaluated histologically. Pharmacokinetic analyses were performed to compare rectal TS-LS to orally Rhumtol® capsules. The results showed that the optimized TS-LS; composed of P407/P188/MC (21/9/0.5% w/w) displayed gelation at rectum temperature ∼32.90 °C, gel strength of 21.35 s and rectal retention force at the administration site of 24.25 × 102 dyne/cm2. Moreover, TS-LS did not cause any morphological damage to the rectal tissues. Pharmacokinetic parameters of optimized TS-LS formulation revealed 4.6 fold increase in bioavailability as compared to Rhumtol® capsules. Taken together, the results demonstrated that liquid suppository is a potential and physically safe rectal delivery carrier for improvement rectal bioavailability and in vivo safety of TS.

PMID: 30303407 [PubMed - indexed for MEDLINE]

ACVR2B/Fc counteracts chemotherapy-induced loss of muscle and bone mass.

Sci Rep. 2017 10 31;7(1):14470

Authors: Barreto R, Kitase Y, Matsumoto T, Pin F, Colston KC, Couch KE, O'Connell TM, Couch ME, Bonewald LF, Bonetto A

Abstract
Chemotherapy promotes the development of cachexia, a debilitating condition characterized by muscle and fat loss. ACVR2B/Fc, an inhibitor of the Activin Receptor 2B signaling, has been shown to preserve muscle mass and prolong survival in tumor hosts, and to increase bone mass in models of osteogenesis imperfecta and muscular dystrophy. We compared the effects of ACVR2B/Fc on muscle and bone mass in mice exposed to Folfiri. In addition to impairing muscle mass and function, Folfiri had severe negative effects on bone, as shown by reduced trabecular bone volume fraction (BV/TV), thickness (Tb.Th), number (Tb.N), connectivity density (Conn.Dn), and by increased separation (Tb.Sp) in trabecular bone of the femur and vertebra. ACVR2B/Fc prevented the loss of muscle mass and strength, and the loss of trabecular bone in femurs and vertebrae following Folfiri administration. Neither Folfiri nor ACVR2B/Fc had effects on femoral cortical bone, as shown by unchanged cortical bone volume fraction (Ct.BV/TV), thickness (Ct.Th) and porosity. Our results suggest that Folfiri is responsible for concomitant muscle and bone degeneration, and that ACVR2B/Fc prevents these derangements. Future studies are required to determine if the same protective effects are observed in combination with other anticancer regimens or in the presence of cancer.

PMID: 29089584 [PubMed - indexed for MEDLINE]

Perceived adverse effects from handling systemic anti-cancer therapy agents.

Br J Nurs. 2017 Sep 07;26(16):S38-S44

Authors: Simons A, Toland S

Abstract
This article explores the immediate adverse effects experienced by nurses during the administration of systemic anti-cancer therapy (SACT), specifically cytotoxic chemotherapy, and whether closed systems are being used to minimise exposure risk. Many SACT agents are known to be carcinogenic, teratogenic and mutagenic and this has led to concerns relating to the increased number of healthcare workers potentially exposed to these agents. An anonymous online survey was designed, made up of four questions, to elicit whether adverse effects were experienced by nurses during preparation, administration or following administration of chemotherapy. A total of 46% of respondents stated that they experienced some form of adverse effect either during preparation, administration or following administration of SACT. More formal research is required in this area to explore the relationship between exposure to SACT and perceived adverse effects in healthcare workers administering SACT.

PMID: 28880622 [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 2019/06/30

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.

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 2019/06/30

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.

Successful Treatment of Hepatocellular Carcinoma with Regorafenib after Sorafenib-induced Hypersensitivity.

Intern Med. 2019 Jun 27;:

Authors: Yoshioka N, Kuzuya T, Ito T, Ishizu Y, Honda T, Ishikawa T, Ishigami M, Fujishiro M

Abstract
Sorafenib and regorafenib are tyrosine kinase inhibitors that are used in the treatment of hepatocellular carcinoma and which have similar chemical structures and toxicity profiles. We herein report a case in which with regorafenib treatment could be continued for 10 months and stable disease could be maintained for a long period despite the discontinuation of sorafenib due to grade 4 liver injury and grade 3 fever. The severe adverse events could be attributed to drug hypersensitivity, since a drug-induced lymphocyte stimulation test (DLST) indicated sensitivity to sorafenib. A DLST for regorafenib was negative. This is the first report showing that regorafenib could be safely administered after the discontinuation of sorafenib due to hypersensitivity.

PMID: 31243207 [PubMed - as supplied by publisher]

Long-term mood/antidepressant effects of quetiapine extended-release formulation: an open-label, non-controlled extension study in Japanese patients with bipolar depression.

BMC Psychiatry. 2019 Jun 26;19(1):198

Authors: Kanba S, Murasaki M, Koyama T, Takeuchi M, Shimizu Y, Arita E, Kuroishi K, Takeuchi M, Kamei S

Abstract
BACKGROUND: In an 8-week, randomized, placebo-controlled, double-blind study, an extended-release formulation of quetiapine, quetiapine XR, demonstrated efficacy and safety in Japanese patients with bipolar depression. Bipolar disorder is a chronic disease requiring continuous treatment.
METHODS: This was a long-term (52-week), open-label, non-controlled extension study to evaluate the long-term safety and efficacy of quetiapine XR in Japanese patients with bipolar depression who had previously completed the initial 8-week double-blind study. Efficacy was determined by the Montgomery-Åsberg Depression Rating Scale (MADRS), Hamilton Depression Scale 17-item (HAM-D17), and Clinical Global Impressions-Bipolar scale (CGI-BP). Safety evaluations included analysis of adverse events, clinical laboratory measures, vital signs, Drug-induced Extrapyramidal Symptoms Scale, Young Mania Rating Scale, and the Columbia Suicide Severity Rating Scale.
RESULTS: The mean (SD) MADRS total score decreased from 30.9 (6.9) at baseline to 16.1 (10.6) at week 8, and eventually to 9.1 (8.7) at week 52. The sustained efficacy of quetiapine XR treatment was also shown using HAM-D17 total scores, CGI-BP-Severity and Change evaluations. The most common adverse events were somnolence, nasopharyngitis, and thirst. Long-term treatment with quetiapine XR caused no substantial changes in the safety profiles, including clinical laboratory parameters, and no new safety concerns were identified.
CONCLUSIONS: The efficacy of quetiapine XR was sustained long-term and no new safety concerns were identified in Japanese patients with bipolar depression.
TRIAL REGISTRATION: ClinicalTrials.gov Registration: NCT01725308. Date of registration; 12th November 2012 (retrospectively registered).

PMID: 31242884 [PubMed - in process]

43 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 2019/06/27

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.

42 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 2019/06/27

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.