Phase I clinical trial of an intranodally administered mRNA-based therapeutic vaccine against HIV-1 infection.

AIDS. 2018 11 13;32(17):2533-2545

Authors: Leal L, Guardo AC, Morón-López S, Salgado M, Mothe B, Heirman C, Pannus P, Vanham G, van den Ham HJ, Gruters R, Andeweg A, Van Meirvenne S, Pich J, Arnaiz JA, Gatell JM, Brander C, Thielemans K, Martínez-Picado J, Plana M, García F, iHIVARNA consortium

Abstract
OBJECTIVE: The efficacy of therapeutic vaccines against HIV-1 infection has been modest. New inerts to redirect responses to vulnerable sites are urgently needed to improve these results.
DESIGN: We performed the first-in-human clinical trial with naked mRNA (iHIVARNA) combining a dendritic cell activation strategy (TriMix:CD40L+CD70+caTLR4 RNA) with a novel HIV immunogen sequences (HTI immunogen).
METHODS: A dose escalation, phase I clinical trial was performed in 21 chronic HIV-1-infected patients under ART who received three intranodal doses of mRNA (weeks 0, 2 and 4) as follow: TriMix-100 g, TriMix-300 g, TriMix-300 g with HTI-300 g, TriMix-300 g with HTI-600 g, TriMix-300 g with HTI-900 g. Primary end-point was safety and secondary-exploratory end-points were immunogenicity, changes in viral reservoir and transcriptome.
RESULTS: Overall, the vaccine was secure and well tolerated. There were 31 grade 1/2 and 1 grade 3 adverse events, mostly unrelated to the vaccination. Patients who received the highest dose showed a moderate increase in T-cell responses spanning HTI sequence at week 8. In addition, the proportion of responders receiving any dose of HTI increased from 31% at w0 to 80% postvaccination. The intervention had no impact on caHIV-DNA levels, however, caHIV-RNA expression and usVL were transiently increased at weeks 5 and 6 in the highest dose of iHIVARNA, and these changes were positively correlated with HIV-1-specific-induced immune responses.
CONCLUSION: This phase I dose-escalating trial showed that iHIVARNA administration was safe and well tolerated, induced moderate HIV-specific T-cell responses and transiently increased different viral replication readouts. These data support further exploration of iHIVARNA in a phase II study. CLINICALTRIALS.
GOV IDENTIFIER: NCT02413645.

PMID: 30289805 [PubMed - indexed for MEDLINE]

Daily or on-demand oral tenofovir disoproxil fumarate/emtricitabine for HIV pre-exposure prophylaxis: experience from a hospital-based clinic in France.

AIDS. 2018 09 24;32(15):2161-2169

Authors: Noret M, Balavoine S, Pintado C, Siguier M, Brun A, Bauer R, Loze B, Leplatois A, Aslan A, Moudachirou K, Delaugerre C, Rozenbaum W, Molina JM

Abstract
BACKGROUND: On-demand oral tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) has been approved for pre-exposure prophylaxis (PrEP) in MSM in France following the results of clinical studies, but data are limited on real-world experience.
DESIGN: A single-center, open-label, prospective cohort study that recruited people at high risk of HIV infection in Paris.
METHODS: Participants were enrolled in a single hospital-based outpatient clinic and were proposed to start PrEP with daily or on demand TDF/FTC. At baseline and every 3 months thereafter, patients were tested for HIV and creatinine plasma levels, and data on sexual behavior, other sexually transmitted infections (STIs), and tolerability were collected.
RESULTS: From 10 November 2015 to 30 April 2017, 1069 patients were screened and 1049 (98.1%) started PrEP. Median age was 36 years, 99.4% were MSM with a median number of partners of 10, and 793 (75.6%) opted for on demand PrEP. Over 486 person-years of follow-up, four HIV-infections were diagnosed in poorly or nonadherent patients (incidence 0.82/100 person-years). Rate of condomless sex at last intercourse increased from 53.3% at baseline to 79% at month 12 (P < 10), but increase in bacterial STI rates was modest (14.6% at baseline vs. 19.2% at month 12; P < 10). Most adverse events were gastrointestinal and did not lead to PrEP discontinuation.
CONCLUSIONS: Most PrEP users were high-risk MSM and opted for on-demand PrEP. PrEP use was associated with a low HIV incidence and a high rate of condomless sex with a modest increase in bacterial STIs.

PMID: 30212403 [PubMed - indexed for MEDLINE]

Evaluation of Natural Language Processing (NLP) systems to annotate drug product labeling with MedDRA terminology.

J Biomed Inform. 2018 07;83:73-86

Authors: Ly T, Pamer C, Dang O, Brajovic S, Haider S, Botsis T, Milward D, Winter A, Lu S, Ball R

Abstract
INTRODUCTION: The FDA Adverse Event Reporting System (FAERS) is a primary data source for identifying unlabeled adverse events (AEs) in a drug or biologic drug product's postmarketing phase. Many AE reports must be reviewed by drug safety experts to identify unlabeled AEs, even if the reported AEs are previously identified, labeled AEs. Integrating the labeling status of drug product AEs into FAERS could increase report triage and review efficiency. Medical Dictionary for Regulatory Activities (MedDRA) is the standard for coding AE terms in FAERS cases. However, drug manufacturers are not required to use MedDRA to describe AEs in product labels. We hypothesized that natural language processing (NLP) tools could assist in automating the extraction and MedDRA mapping of AE terms in drug product labels.
MATERIALS AND METHODS: We evaluated the performance of three NLP systems, (ETHER, I2E, MetaMap) for their ability to extract AE terms from drug labels and translate the terms to MedDRA Preferred Terms (PTs). Pharmacovigilance-based annotation guidelines for extracting AE terms from drug labels were developed for this study. We compared each system's output to MedDRA PT AE lists, manually mapped by FDA pharmacovigilance experts using the guidelines, for ten drug product labels known as the "gold standard AE list" (GSL) dataset. Strict time and configuration conditions were imposed in order to test each system's capabilities under conditions of no human intervention and minimal system configuration. Each NLP system's output was evaluated for precision, recall and F measure in comparison to the GSL. A qualitative error analysis (QEA) was conducted to categorize a random sample of each NLP system's false positive and false negative errors.
RESULTS: A total of 417, 278, and 250 false positive errors occurred in the ETHER, I2E, and MetaMap outputs, respectively. A total of 100, 80, and 187 false negative errors occurred in ETHER, I2E, and MetaMap outputs, respectively. Precision ranged from 64% to 77%, recall from 64% to 83% and F measure from 67% to 79%. I2E had the highest precision (77%), recall (83%) and F measure (79%). ETHER had the lowest precision (64%). MetaMap had the lowest recall (64%). The QEA found that the most prevalent false positive errors were context errors such as "Context error/General term", "Context error/Instructions or monitoring parameters", "Context error/Medical history preexisting condition underlying condition risk factor or contraindication", and "Context error/AE manifestations or secondary complication". The most prevalent false negative errors were in the "Incomplete or missed extraction" error category. Missing AE terms were typically due to long terms, or terms containing non-contiguous words which do not correspond exactly to MedDRA synonyms. MedDRA mapping errors were a minority of errors for ETHER and I2E but were the most prevalent false positive errors for MetaMap.
CONCLUSIONS: The results demonstrate that it may be feasible to use NLP tools to extract and map AE terms to MedDRA PTs. However, the NLP tools we tested would need to be modified or reconfigured to lower the error rates to support their use in a regulatory setting. Tools specific for extracting AE terms from drug labels and mapping the terms to MedDRA PTs may need to be developed to support pharmacovigilance. Conducting research using additional NLP systems on a larger, diverse GSL would also be informative.

PMID: 29860093 [PubMed - indexed for MEDLINE]

The Evidence for Laboratory Test-Based Computer Clinical Decision Support Tools on Medication Errors and Adverse Drug Events.

J Appl Lab Med. 2019 05;3(6):922-924

Authors: Kavsak PA

PMID: 31639683 [PubMed - indexed for MEDLINE]

[Adverse events with oral anticoagulants].

Ugeskr Laeger. 2018 Aug 06;180(32):

Authors: Bovin A, Knudsen P, Hellfritzsch M, Grove EL

Abstract
Anticoagulant therapy is widely used for prevention and treatment of cardiovascular disease and is frequently prescribed both in primary and secondary care. In comparison to other drugs, the frequency of medication errors is high for anticoagulant therapy. In Denmark, 4,383 adverse events with vitamin K antagonists and 3,234 adverse events with non-vitamin K antagonist oral anticoagulants were reported to the Danish Patient Safety Authority in 2014-2017. In this review, we provide an overview of medication errors and discuss frequent adverse events and pitfalls.

PMID: 30070627 [PubMed - indexed for MEDLINE]

The Changing Landscape of Parkinson Epidemiologic Research.

J Parkinsons Dis. 2018;8(1):1-12

Authors: Chen H

Abstract
Despite recent successes in understanding the genetics of Parkinson's disease (PD), the causes of late-onset sporadic PD remain elusive. Many of the epidemiologic findings on PD etiology have been challenged by alternative explanations such as reverse causation. This is mainly because PD often takes decades to develop before it can be diagnosed late in life. Convincing evidence shows that this prodromal stage of PD is characterized by various prodromal symptoms such as olfactory impairment and rapid-eye-movement sleep behavior disorder (RBD). As they likely reflect PD pathogenesis years, if not decades, before nigrostriatal involvement, research on these symptoms may represent an unprecedented opportunity to dissect the etiology of PD. Using PD prodromal symptoms as intermediate phenotypes, we may be able to identify factors that contribute to the development of these symptoms and factors that modify their progression to clinical PD. Further, this line of research will also enable examinations of novel etiological hypotheses of PD development such as the microbiome and prion hypotheses. In this article, the author used olfactory impairment and RBD as examples to illustrate the promises and challenges of epidemiologic research on prodromal symptoms to understand PD etiology.

PMID: 29154293 [PubMed - indexed for MEDLINE]

20 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 2019/10/29

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 2019/10/28

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.

A Phase 1 Study of LY3009120, a Pan-RAF Inhibitor, in Patients with Advanced or Metastatic Cancer.

Mol Cancer Ther. 2019 Oct 23;:

Authors: Sullivan RJ, Hollebecque A, Flaherty KT, Shapiro GI, Rodon Ahnert J, Millward MJ, Zhang W, Gao L, Sykes A, Willard MD, Yu D, Schade AE, Crowe KJ, Flynn DL, Kaufman MD, Henry JR, Peng SB, Benhadji KA, Conti I, Gordon MS, Tiu RV, Hong DS

Abstract
Mutations in extracellular signal regulated kinase signaling drive a significant percentage of malignancies. LY3009120, a pan-RAF and dimer inhibitor, has preclinical activity in RAS- and BRAF-mutated cell lines including BRAF-mutant melanoma resistant to BRAF inhibitors. This multicenter, open-label, Phase 1 clinical trial (NCT02014116) consisted of Part A (dose escalation) and Part B (dose confirmation) in patients with advanced/metastatic cancer. In Part A, oral LY3009120 was dose escalated from 50 to 700 mg twice daily (BID) on a 28-day cycle. In Part B, 300 mg LY3009120 was given BID. The primary objective was to identify a recommended Phase 2 dose (RP2D). Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary efficacy. Identification of pharmacodynamic biomarkers was exploratory. In Parts A and B, 35 and sixteen patients were treated, respectively (N=51). In Part A, six patients experienced eight dose-limiting toxicities. The RP2D was 300 mg BID. Common (>10%) any-grade drug-related treatment-emergent adverse events were fatigue (n=15), nausea (n=12), dermatitis acneiform (n=10), decreased appetite (n=7), and maculopapular rash (n=7). The median duration of treatment was four weeks; 84% of patients completed one or two cycles of treatment. Exposures observed at 300 mg BID were above the preclinical concentration associated with tumor regression. Eight patients had a best overall response of stable disease; there were no complete or partial clinical responses. Despite adequate plasma exposure levels, predicted pharmacodynamic effects were not observed.

PMID: 31645440 [PubMed - as supplied by publisher]

The Emperor's New Clothes: What Randomized Controlled Trials Don't Cover.

J Bone Miner Res. 2018 08;33(8):1394-1396

Authors: Eisman JA, Geusens P, van den Bergh J

PMID: 29953664 [PubMed - indexed for MEDLINE]

Parametric modeling and optimal experimental designs for estimating isobolograms for drug interactions in toxicology.

J Biopharm Stat. 2018;28(4):763-777

Authors: Holland-Letz T, Gunkel N, Amtmann E, Kopp-Schneider A

Abstract
In toxicology and related areas, interaction effects between two substances are commonly expressed through a combination index [Formula: see text] evaluated separately at different effect levels and mixture ratios. Often, these indices are combined into a graphical representation, the isobologram. Instead of estimating the combination indices at the experimental mixture ratios only, we propose a simple parametric model for estimating the underlying interaction function. We integrate this approach into a joint model where both the parameters of the dose-response functions of the singular substances and the interaction parameters can be estimated simultaneously. As an additional benefit, this concept allows to determine optimal statistical designs for combination studies optimizing the estimation of the interaction function as a whole. From an optimal design perspective, finding the interaction parameters generally corresponds to a [Formula: see text]-optimality resp. [Formula: see text]-optimality design problem, while estimation of all underlying dose response parameters corresponds to a [Formula: see text]-optimality design problem. We show how optimal designs can be obtained in either case as well as how combination designs providing reasonable performance in regard to both criteria can be determined by putting a constraint on the efficiency in regard to one of the criteria and optimizing for the other. As all designs require prior information about model parameter values, which may be unreliable in practice, the effect of misspecifications is investigated as well.

PMID: 29173022 [PubMed - indexed for MEDLINE]

Assessing performance of sequential analysis methods for active drug safety surveillance using observational data.

J Biopharm Stat. 2018;28(4):668-681

Authors: Zhou X, Bao W, Gaffney M, Shen R, Young S, Bate A

Abstract
The routine use of sequential methods is well established in clinical studies. Recently, there has been increasing interest in applying these methods to prospectively monitor the safety of newly approved drugs through accrual of real-world data. However, the application to marketed drugs using real-world data has been limited and work is needed to determine which sequential approaches are most suited to such data. In this study, the conditional sequential sampling procedure (CSSP), a group sequential method, was compared with a log-linear model with Poisson distribution (LLMP) through a SAS procedure (PROC GENMOD) combined with an alpha-spending function on two large longitudinal US administrative health claims databases. Relative performance in identifying known drug-outcome associations was examined using a set of 50 well-studied drug-outcome pairs. The study finds that neither method correctly identified all pairs but that LLMP often provides better ability and shorter time for identifying the known drug-outcome associations with superior computational performance when compared with CSSP, albeit with more false positives. With the features of flexible confounding control and ease of implementation, LLMP may be a good alternative or complement to CSSP.

PMID: 29157113 [PubMed - indexed for MEDLINE]

76 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 2019/10/24

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.

Glucocorticosteroid induced cataract – drug-induced damage of vision organ which is worth paying attention in the treatment of inflammatory bowel diseases

Postepy Biochem. 2019 10 01;65(3):227-230

Authors: Caban M

Abstract
Inflammatory bowel diseases (IBD) are a group of diseases which concern an increasing number of patients and are more and more often recognized at a young age. Because of unknown etiology, IBD treatment involves mainly non-specific suppression of inflammatory condition and is based among others on steroids. Glucocorticosteroids display anti-inflammatory action by affecting the course of immune responses, but they also possess several side effects which manifest predominantly during a long-term therapy. These concern, among others the eye and manifest by impaired vision; if left untreated, can lead to blindness. The glucocorticosteroid induced cataract is one of the most common complications of treatment with glucocorticosteroids. In the absence of pharmacological options which have a protective effect, the glucocor­ticosteroid induced cataract is a major problem not only for patients but also clinicians and needs immediate solutions.

PMID: 31643171 [PubMed - in process]

Hepatitis C virus infection: a challenge in the complex management of two cases of multidrug-resistant tuberculosis.

BMC Infect Dis. 2019 Oct 22;19(1):882

Authors: Musso M, Mosti S, Gualano G, Mencarini P, Urso R, Ghirga P, Rianda A, Del Nonno F, Goletti D, Palmieri F

Abstract
BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) requires lengthy use of second-line drugs, burdened by many side effects. Hepatitis C virus (HCV) chronic infection increases risk of drug-induced liver injury (DILI) in these patients. Data on MDR-TB patients with concurrent HCV chronic infection treated at the same time with second-line antitubercular drugs and new direct-acting antivirals (DAAs) are lacking. We evaluate if treating at the same time HCV infection and pulmonary MDR-TB is feasible and effective.
CASES PRESENTATION: In this study, we described two cases of patients with pulmonary MDR-TB and concurrent HCV chronic infection cured with DAAs at a Tertiary Infectious Diseases Hospital in Italy. During antitubercular treatment, both patients experienced a DILI before treating HCV infection. After DAAs liver enzymes normalized and HCV RNA was undetectable. Then antitubercular regimen was started according to the institutional protocol, drawn up following WHO MDR-TB guidelines. It was completed without further liver side effects and patients were declared cured from both HCV infection and MDR-TB.
CONCLUSIONS: We suggest to consider treatment of chronic hepatitis C with DAAs as a useful intervention for reintroduction of second-line antitubercular agents in those patients who developed DILI, reducing the risk of treatment interruption when re-exposed to these drugs.

PMID: 31640579 [PubMed - in process]

Toxicological pitfalls in ICU practice.

Anaesthesiol Intensive Ther. 2018;50(5):378-383

Authors: Janus T, Pabisiak K

Abstract
Either analgosedation or central nervous system dysfunction may be a side effect of implemented pharmacological treatment, as well as a consequence of intentional or unintentional poisoning. In traumatic lesions or anoxia of the central nervous system, a question arises after a recommended follow-up period about the effects of xenobiotics on nervous system function. Although therapeutic drug monitoring is the gold standard in such cases, usually a single toxicological estimation of "a neurodepressive compound" is performed after treatment discontinuation in order to determine the type and amount of exogenous substances, or their metabolites, in a patient's bodily fluids, which allows for an assessment of its actual effects on central nervous system functions. The aim of this paper was to describe the aspects of diagnostic toxicology which are essential for improved determination of the type and amount of exogenous substances present in biological fluids of intensive care patients. We present examples of clinical cases in order to discuss the most common discrepancies in interpretation related to the ordering of toxicology tests.

PMID: 30615797 [PubMed - indexed for MEDLINE]

A 10-year review of single medication double-dose ingestions in the nation's largest poison control system.

Clin Toxicol (Phila). 2019 01;57(1):31-35

Authors: Correia MS, Whitehead E, Cantrell FL, Lasoff DR, Minns AB

Abstract
BACKGROUND: Most Americans take at least one medication on a daily basis. Inadvertently ingesting a double-dose of a medication with a narrow therapeutic index may lead to adverse effects. When a patient or medical professional contacts the local poison center after an overdose, a poison specialist fields the incoming information and, depending on the caller, provides specific recommendations. We sought to determine which medication classes were most likely to lead to significant adverse outcomes when an extra dose was ingested.
METHODS: This was a retrospective review of all double-dose medication ingestions reported to the California Poison Control System (CPCS) between January 2006 and December 2015. Inclusion criteria were single-instance, single-medication ingestions where the dose was known. All ages and both sexes were included. We evaluated generalized outcomes per AAPCC criteria stratified as no effect, minor, moderate, major or death. We also documented specific symptoms and interventions noted by the poison control specialists.
RESULTS: Out of 1286 cases, 876 ingestions met the inclusion criteria. Medications with antihypertensive and behavior modulating effects each accounted for over a third of all moderate and major effects. The medications/medication classes implicated in the 12 major outcomes included propafenone, beta blockers (βBs), calcium channel blockers (CCBs), bupropion, and tramadol. Of these, vasoactive medications were associated with the most severe effects requiring cardiac pacing and vasopressor drips. Analgesics, antimicrobials, and anti-allergy medications were well tolerated. There were no deaths.
CONCLUSIONS: Major adverse outcomes after a double dose ingestion were rare. Most double dose medication ingestions can be safely monitored at home, albeit with a few exceptions. Vigilance is warranted in cases of βB and CCB ingestion due to the risk of hemodynamic collapse or seizures with tramadol and bupropion.

PMID: 30484705 [PubMed - indexed for MEDLINE]

Relevance of the incubation period in cytotoxicity testing with primary human hepatocytes.

Arch Toxicol. 2018 12;92(12):3505-3515

Authors: Gu X, Albrecht W, Edlund K, Kappenberg F, Rahnenführer J, Leist M, Moritz W, Godoy P, Cadenas C, Marchan R, Brecklinghaus T, Pardo LT, Castell JV, Gardner I, Han B, Hengstler JG, Stoeber R

Abstract
Primary human hepatocytes (PHHs) remain the gold standard for in vitro testing in the field of pharmacology and toxicology. One crucial parameter influencing the results of in vitro tests is the incubation period with test compounds. It has been suggested that longer incubation periods may be critical for the prediction of repeated dose toxicity. However, a study that systematically analyzes the relationship between incubation period and cytotoxicity in PHHs is not available. To close this gap, 30 compounds were tested in a concentration-dependent manner for cytotoxicity in cultivated cryopreserved PHHs (three donors per compound) for 1, 2 and 7 days. The median of the EC50 values of all compounds decreased 1.78-fold on day 2 compared to day 1, and 1.89-fold on day 7 compared to day 1. Median values of EC50 ratios of all compounds at day 2 and day 7 were close to one but for individual compounds the ratio increased up to almost six. Strong correlations were obtained for EC50 on day 1 and day 7 (R = 0.985; 95% CI 0.960-0.994), day 1 and day 2 (R = 0.964; 95% CI 0.910-0.986), as well as day 2 and day 7 (R = 0.981; 95% CI 0.955-0.992). However, compound specific differences also occurred. Whereas, for example, busulfan showed a relatively strong increase on day 7 compared to day 1, cytotoxicity of acetaminophen did not increase during longer incubation periods. To validate the observed correlations, a publicly available data set, containing data on the cytotoxicity of human hepatocytes cultivated as spheroids for incubation periods of 5 and 14 days, was analyzed. A high correlation coefficient of EC50 values at day 5 and day 14 was obtained (R = 0.894; 95% CI 0.798-0.945). In conclusion, the median cytotoxicity of the test compounds increased between 1 and 2 days of incubation, with no or only a minimal further increase until day 7. It remains to be studied whether the different results obtained for some individual compounds after longer exposure periods would correspond better to human-repeated dose toxicity.

PMID: 30317417 [PubMed - indexed for MEDLINE]

Mechanisms of toxic cardiomyopathy.

Clin Toxicol (Phila). 2019 01;57(1):1-9

Authors: Hantson P

Abstract
BACKGROUND: Dilated cardiomyopathy is a frequent disease responsible for 40-50% of cases of heart failure. Idiopathic cardiomyopathy is a primary disorder often related to familial/genetic predisposition. Before the diagnosis of idiopathic cardiomyopathy is made, clinicians must not only rule out viral and immune causes, but also toxic causes such as drugs, environmental agents, illicit substances and natural toxins.
OBJECTIVE: The objective of this review is to present recent data on the mechanisms underlying toxic cardiomyopathy.
METHODS: The US National Library of Medicine Pubmed database was searched from 1980 to December 2017 utilizing the combinations of the search terms "toxic cardiomyopathy", "drugs", "anticancer drugs", "azidothymidine", "rosiglitazone", "carbon monoxide", "alcohol", "illicit drugs", "cocaine", "metamfetamine", "metals", "venom". A total of 339 articles were screened and papers that dealt with the pathophysiology of toxic cardiomyopathy, either in animal models or in clinical practice were selected, with preference being given to more recently published papers, which left 92 articles. Anticancer drugs: The mechanisms of anthracycline-induced cardiotoxicity are primarily related to their mechanisms of action as anticancer drugs, mainly the inhibition of topoisomerase II β and DNA cleavage. Additional metabolic or oxidative stress factors may play a part, together with interference with iron metabolism. The more recent drugs, trastuzumab and imatinib, also influence stress pathways. Antiretroviral agents: Azidothymidine is cardiotoxic as a result of mitochondrial toxicity. In addition to energy depletion, azidothymidine also increases the production of mitochondrial reactive oxygen species (ROS). Antidiabetic drugs: The cardiotoxicity of thiazolidinedione antidiabetic drugs is still under investigation, though interference with mitochondrial respiration or oxidative stress is suspected. Cocaine: Among the multiple mechanisms involved in cocaine-related cardiotoxicity, excessive sympathetic stimulation with increased myocardial oxygen consumption is well documented in the acute form of left ventricular dysfunction. As for cocaine-related cardiomyopathy, the role of apoptosis and ROS is under investigation. Ethanol: The aetiology of ethanol-related cardiotoxicity is multifactorial, with individual susceptibility being important. It involves apoptosis, alterations of the excitation-contraction coupling in cardiac myocytes, structural and functional alterations of the mitochondria and sarcoplasmic reticulum, changes in cytosolic calcium flows, changes in calcium sensitivity of myofilaments, alterations of mitochondrial oxidation, deregulation of protein synthesis, decrease of contractile proteins and disproportion between the different types of myofibrils, changes in the regulation of myosin ATPase, up-regulation of the L-type calcium channels, increase of oxidative stress, and induction of ANP and p21 mRNA expression in ventricular myocardium. Metamfetamines: Catecholamine-mediated toxicity is the probable cause, with a possible role for genetic susceptibility. Carbon monoxide: In addition to hypoxic injury, carbon monoxide is also directly toxic to the mitochondria, with impairment of mitochondrial respiratory chain at the cytochrome c oxidase level, decrease of glutathione concentrations and of ATP production. There is no evidence for a delayed dilated cardiomyopathy in survivors of an acute exposure. Metals: Cobalt-related cardiomyopathy probably results from interference with energy production and contractile mechanisms, but additional factors (nutrition, hypothyroidism) are often required. Antimony may cause lethal oxidative stress and cell death mediated by elevation in intra-cellular calcium. Proposed mechanisms for mercury toxicity include glutathione depletion, production of ROS, and interruption in selenium-dependent endogenous enzymatic reactions. The existence of a lithium-induced cardiomyopathy is still debated. Scorpion venom: Catecholamine release is the probable cause of acute cardiomyopathy following scorpion envenomation.
CONCLUSIONS: The mechanisms behind toxic cardiomyopathy are complex and multifactorial but include interference with myocardial cell bioenergetics and intracellular calcium handling, the generation of ROS, neurohormonal stress, and induction of apoptosis.

PMID: 30260248 [PubMed - indexed for MEDLINE]

Acute poisoning in Shenyang, China: a retrospective and descriptive study from 2012 to 2016.

BMJ Open. 2018 08 29;8(8):e021881

Authors: Zhang Y, Yu B, Wang N, Li T

Abstract
OBJECTIVES: Up-to-date information on the patterns of acute poisoning is crucial for the proper management of poisoning events. The objectives of this study were to analyse the characteristics of patients suffering from acute poisoning admitted to the emergency department (ED) in a tertiary medical centre in Northeast China and to compare these characteristics with those of a previous comparable study.
DESIGN: Retrospective and descriptive study.
SETTING: Data were collected from the hospital information system in Shengjing Hospital, China, from January 2012 to December 2016.
PARTICIPANTS: All cases aged ≥11 years old with a diagnosis of acute poisoning.
RESULTS: In total, 5009 patients aged ≥11 years presented to the ED with acute poisoning during the study period. The average age of the patients was 36.0±15.1 years and over half (52.7%) were in the 20-39age group. The female to male ratio was 1.2:1. Patients with acute poisoning mainly lived in rural areas rather than in urban areas. The majority of patients consumed poison as suicide attempts (56.7%). Men were more commonly poisoned by drug abuse than women, but women outnumbered men in suicidal poisoning. The most common form of poison intake was ingestion (oral intake; 86.2%). The five most common toxic agent groups, in descending order, were therapeutic drugs (32.6%), pesticides (26.9%), alcohol (20.7%), fumes/gases/vapours (11.4%) and chemicals (3.6%). Sedatives/hypnotics in the therapeutic drugs group and paraquat in the pesticides group were the most common toxic agents, respectively. The mortality rate of study participants was 1.3%, with 64 deaths.
CONCLUSIONS: The results of this study indicate the need to strengthen education on the rational and safe use of drugs in Shenyang.

PMID: 30158226 [PubMed - indexed for MEDLINE]