W. Stephen Waring

Earlier recognition of nephrotoxicity using novel biomarkers of acute kidney injury

Context. A broad range of drugs and chemicals are capable of evoking acute kidney injury, which is conventionally determined by rising serum creatinine concentrations. However there are important limitations to this approach, and there has been interest in alternative biomarkers that might provide a more sensitive and rapid means of detecting acute kidney injury. Most of the available clinical data have thus far been ascertained in patients requiring critical care or with acute sepsis. However, if a sensitive indicator of acute kidney injury were developed, then this could provide a significantly improved means of detecting the effects of acute drug or toxin exposure. Objective. To review the available data concerning potential biomarkers of acute kidney injury and to assess their relative strengths and weaknesses in comparison to existing methods based on serum creatinine concentrations. A large number of possible biomarkers have been proposed. Evidence for individual biomarkers is reviewed with a particular emphasis on those with potential application in clinical toxicology. Where available, comparative data are presented. Methods. There were 236 papers identified using Medline, Embase, and Google Scholar databases, of which 52 were considered directly relevant. Creatinine. Creatinine is subject to glomerular filtration and, to a lesser extent tubular secretion. Serum concentrations are an insensitive marker of acute kidney injury, and the speed of an increase from baseline depends on the magnitude of the acute injury and pre-existing kidney functional reserve. A wide range of inter-individual concentrations means that single time-point determinations are difficult to interpret, and acute kidney injury may not manifest as a detectable increase in serum creatinine concentrations until at least 24–48 h after the primary insult. Kidney enzymes. Enzymes are often localised to specific anatomical locations, and acute injury may cause a detectable increase in urinary activity due to up-regulated activity or leakage due to cell membrane disruption. Key examples include gamma-glutamyl transpeptidase (GGT), glutathione-S-transferase (GST), and N-acetyl-glucosaminidase (NAG), which are found predominantly in the proximal tubule and urinary enzyme activity increases after acute exposure to heavy metals and other nephrotoxins .Neutrophil gelatinase-associated lipocalin. Neutrophil gelatinase-associated lipocalin (NGAL) is expressed by renal tubular epithelium, and a rise in urinary concentrations may provide an indicator of acute renal injury caused by any one of a broad range of provoking factors that is detectable before a rise in serum creatinine concentrations. Cystatin C. Serum and urinary cystatin C concentrations are closely related to kidney function and, for example, in acute tubular necrosis allow better prediction of the need for renal replacement therapy than serum creatinine concentrations. Kidney injury molecule 1. Kidney injury molecule 1 (KIM-1) is expressed in the proximal tubule in the setting of acute ischaemia. For example, urinary KIM-1 concentrations becomes detectable within 24 h of acute tubular necrosis. Urinary KIM-1 expression may be detected after exposure to a variety of nephrotoxic agents, even when serum creatinine concentrations do not increase, and this has been accepted by regulatory authorities as a sensitive biomarker of acute kidney injury during early drug development. Conclusions. Novel biomarkers appear capable of offering a more sensitive means of detecting acute kidney injury than existing approaches. Certain of these allow discrimination between the various mechanisms and anatomical site of acute injury. Ultimately, clinical assessment might incorporate a panel of different biomarkers, each informing on the integrated aspects of glomerular, tubular and interstitial function. Presence of biomarkers may in some cases detect mild or transient renal dysfunction that is presently undetected, and the clinical relevance needs further exploration. Whilst many potentially useful biomarkers have been proposed, comparatively few clinical data exist to support their validity in routine practice. Further prospective clinical studies are required to examine the validity of biomarkers after acute drug or toxin exposure, and to establish whether they might offer improved clinical outcomes in the setting of clinical toxicology.

Bibliometric profile of the global scientific research on methanol poisoning (1902–2012)

BackgroundMethanol poisoning is on the rise and has been associated with high morbidity and mortality; it has resulted in growing research in the field of toxicology. The aim of this study was to reveal underlying patterns in scientific outputs related to methanol poisoning at the global level by evaluating different bibliometric indices.MethodsWe searched for publications that contained specific words regarding methanol poisoning in Scopus database.ResultsA total of 912 articles, with 8,317 citations and with an average of 9.1 citations per document, were retrieved on methanol poisoning, and the bulk of the articles were published from the USA (20.9%), followed by Spain (4.4%), Canada (4.3%), India (3.1%), and France (3.0%). The articles were published belonging to 57 countries. No data related to methanol poisoning were published from 155 (73.1%) out of 212 countries. Twenty-one documents (2.3%) were published in Clinical Toxicology, whereas 18 (2.0%) were published in The Lancet.ConclusionsScientific production related to methanol poisoning is increasing. articles have been published in a wide range of journals with a variety of subject areas, most notably clinical toxicology; and the country with the greatest production was the USA.

Clinical toxicology and drug regulation: A United Kingdom perspective

The Medicines and Healthcare products Regulatory Authority (MHRA) is the government body with responsibility for regulating new and existing medicines and medical devices in the United Kingdom. The Yellow Card scheme is a well-established pharmacovigilance system that collects voluntary reports of adverse effects associated with therapeutic drug use. In contrast, data concerning clinical toxicological effects are more poorly characterised. No comparable surveillance processes exist in the United Kingdom or elsewhere in Europe that might allow systematic collection of clinical data and outcomes after drug overdose. Toxicological effects are normally ascertained from individual patient reports or small case series from a few specialised poisons units, so that these data are generally under-represented in post-marketing consideration of risks and benefits. Safety concerns may lead to withdrawal of the Marketing Authorisation or restricted prescribing conditions, which are conveyed to health care professionals by means of safety warnings. These may have a variable impact, and three selected examples are presented to illustrate the complex interaction between drug regulation and clinical toxicology. First, the effects of the withdrawal of rofecoxib in 2004 shows that regulatory responses may reduce the prescribing of drugs across a particular class, and this has resulted in fewer enquiries to Poisons Control Centres regarding all cyclooxygenase-2 selective inhibitors. Secondly, data concerning the impact of safety warnings about antipsychotic medications illustrate that regulatory decisions may have a variable impact due to other factors that influence prescribing, including clinical guidelines, marketing pressures, and lack of alternative safe medications. Finally, the recent withdrawal of co-proxamol serves as an example of how clinical toxicology data can inform the drug regulation process and improve safety by minimising the risk of death associated with overdose. Greater reliance on clinical toxicology data could better inform the drug regulation process, perhaps through coordinated data collection systems that already exist in certain national poisons centres. Routine collection of high quality data concerning the effects of drug overdose could allow a more comprehensive review of risk and benefit by the regulatory authorities.

Intravenous lipid emulsion as an antidote for the treatment of acute poisoning: a bibliometric analysis of human and animal studies

In recent years, there has been increasing interest in the role of intravenous lipid formulations as potential antidotes in patients with severe cardiotoxicity caused by drug toxicity. The aim of this study was to conduct a comprehensive bibliometric analysis of all human and animal studies featuring lipid emulsion as an antidote for the treatment of acute poisoning. The Scopus database search was performed on 5 February 2016 to analyse the research output related to intravenous lipid emulsion as an antidote for the treatment of acute poisoning. Research indicators used for analysis included total number of articles, date (year) of publication, total citations, value of the h‐index, document types, countries of publication, journal names, collaboration patterns and institutions. A total of 594 articles were retrieved from Scopus database for the period of 1955–2015. The percentage share of global intravenous lipid emulsion research output showed that research output was 85.86% in 2006–2015 with yearly average growth in this field of 51 articles per year. The USA, United Kingdom (UK), France, Canada, New Zealand, Germany, Australia, China, Turkey and Japan accounted for 449 (75.6%) of all the publications. The total number of citations for all documents was 9,333, with an average of 15.7 citations per document. The h‐index of the retrieved documents for lipid emulsion research as antidote for the treatment of acute poisoning was 49. The USA and the UK achieved the highest h‐indices, 34 and 14, respectively. New Zealand produced the greatest number of documents with international collaboration (51.9%) followed by Australia (50%) and Canada (41.4%) out of the total number of publications for each country. In summary, we found an increase in the number of publications in the field of lipid emulsion after 2006. The results of this study demonstrate that the majority of publications in the field of lipid emulsion were published by high‐income countries. Researchers from institutions in the USA led scientific production on lipid emulsion research. There is an obvious need to promote a deeper engagement through international collaborative research projects and funding mechanisms.

Criteria for acetylcysteine treatment and clinical outcomes after paracetamol poisoning.

Acetylcysteine is an effective antidote for paracetamol (acetaminophen) poisoning, but different treatment criteria exist internationally. In the UK, acetylcysteine is indicated by paracetamol concentrations higher than the Prescott nomogram or higher than 50% of the nomogram in patients with increased susceptibility to liver toxicity. In the USA, a single ‘150-line’ nomogram has been used that removes the need for additional clinical risk assessment. The latter approach has recently been adopted in Australia, New Zealand and elsewhere. Few data exist to allow direct comparison of these different international approaches. An existing database of 1191 patients admitted to hospital after paracetamol overdose identified that the 4-h equivalent paracetamol concentration was: ≥200 mg/l in 163 patients (15.6%; 95% CI: 13.3–18.2%), ≥150 mg/l in 264 (24.3%; 95% CI: 21.5–27.5%) and ≥100 mg/l in 426 patients (39.3%; 95% CI: 35.6–43.2%), and acute liver injury occurred in 3.7% (95% CI: 1.4–8.0%), 2.3% (95% CI: 0.8–5.0%) and 1.9% (95% CI: 0.8–3.7%), respectively. The different indications for acetylcysteine used by the UK and USA would result in similar numbers of patients treated, although the criteria would define patients with different characteristics and patterns of overdose. The relative merit of these different international approaches to acetylcysteine administration is considered in this article.

Global cocaine intoxication research trends during 1975–2015: a bibliometric analysis of Web of Science publications

BackgroundCocaine is subject to recreational abuse as a stimulant and psychoactive agent, which poses a major worldwide health problem. The aim of the present study was to perform a bibliometric analysis of publication related to cocaine intoxication an insight of the research trends at a global level to enable recommendations for future research strategies in this field.MethodsPublications about cocaine intoxication were retrieved from the Web of Science (WoS) Core Collection database on December 28, 2016, and analysed regarding the following bibliometric indicators: research trends, document types, languages, countries/territories with their h-index, collaboration patterns, journals with their impact factors (IF), and institutions.ResultsIn total, 2,902 scientific publications from 1975 to 2015 were retrieved from the WoS database. The annual number of publications related to cocaine toxicity increased slightly after 1990 and reached a peak of 148 in 1992, with an average of 103 publications per year. The USA outranked other countries/territories with 2,089 publications, of which 1,927 arose exclusively from the USA and 162 involved international collaborations. The h-index for all publications related to cocaine was 212, and the h-index for all publications related to cocaine intoxication was 99. Moreover, the USA had the highest h-index of 95, followed by Spain with h-index of 24, and Canada with h-index of 24. The main research topics were consistently reproductive toxicity, clinical management of acute cocaine exposure, laboratory methods for detection of exposure to cocaine, cocaine metabolism, and cocaine toxicity in animals.ConclusionsThis is the first bibliometric approach to examining research related to cocaine toxicity and shows that research activity has become more global and extensive since 1990. The USA remains the leading country regarding published literature, the highest h-index, and greatest role in international collaborations.

Comparative Drug Dose and Drug Combinations in Patients that Present to Hospital Due to Self-Poisoning

Self‐poisoning is a common reason for acute presentation to hospital. Commonly involved drugs have been reported, but few data exist concerning the different combinations of agents or comparative doses ingested. The present study sought to better characterise the typical patterns of drug overdose that may present via the emergency department. Consecutive adults ≥16 years of age that presented to York Hospital owing to self‐poisoning were studied for 2010–2011 inclusive. The primary outcome measure was reported dose, expressed as a multiple of the defined daily dose (DDD) to allow comparison between different agents. There were 1024 patients, including 622 women (60.7%), and median age was 32 years (range, 16 to 92 years). Overdose in men was associated with a higher overall quantity of drugs: arithmetic mean of 20 DDD multiples (95% CI, 15–26) versus 13 (11–15), p = 0.001. Overdose involved a single agent only in 538 patients (52.5%). The mean paracetamol dose was 4.0 (95% CI, 3.7–4.3) DDD multiples; the doses of antidepressants (19.4, 17.0–21.7, p < 0.0001) and benzodiazepines (18.0, 12.8–23.2, p < 0.0001) were comparatively higher. The types of agents involved in self‐poisoning and common combinations of agents are characterised. Psychotropic medications were ingested in comparatively larger quantities than analgesic agents and had worse clinical outcome. Further work is required to understand the factors that determine the quantity of drug ingested in patients at risk of drug overdose so as to minimise the risk of significant toxicity.

Global Research Trends in Lithium Toxicity from 1913 to 2015: A Bibliometric Analysis.

Lithium salts have been used to treat psychiatric disorders since the 1940s and are currently used in prophylaxis and treatment of depression and bipolar disorder. Therefore, we conducted this study to assess lithium toxicity‐related publications using bibliometric approaches from a health point of view to assess global research trends in the lithium toxicity field to offer guidance to future research in this field. The data were retrieved from the online version of Scopus database on 6 August 2016. All records with the term ‘lithium’ in the title were retrieved, and those related to lithium toxicity were evaluated. There were a total of 1241 publications related to lithium toxicity published from 1913 to 2016. Articles (971 or 78.2%) were the most common type, followed by letters (179 or 14.4%) and reviews (61 or 4.9%). The annual publication of articles increased slightly after 1950 and the total number of publications related to lithium toxicity fluctuated with three peaks occurred in 1978, 1985 and 2014. The USA was the predominant country (25.38%), followed by the UK (7.82%), France (6.85%) and Canada (3.55%). Denmark had the highest productivity of publication after standardization by gross domestic product and population size. The average number of citations per article was 9.24, and the h‐index for all publications in the field of lithium toxicity was 46. The highest h‐index value was achieved by the USA (31) followed by the UK (21) and Canada (13). The Lancet was the highest ranked journal with 27 articles, followed by American Journal of Psychiatry with 23 articles. This study provides a bibliometric analysis on the global research trends in lithium toxicity studies during 1913–2015. There has been a progressive increase in the number of publications related to lithium toxicity published in the last decade, and most of the studies related to lithium toxicity arose from the USA and the UK.

Reported dose as a measure of drug exposure after paracetamol overdose in children.

The decision to administer antidote after paracetamol overdose is based on the extent of drug exposure, and this often relies on the reported dose. Few data exist concerning the validity of this approach in children. The present observational study sought to examine the relationship between the reported dose and paracetamol concentrations in patients aged ≤18 years admitted to York Hospital between October 2008 and November 2010 inclusive. There were 77 cases and casenotes were evaluable in 61, with median age 14 years (IQR 3-15 years), and weight 54.0 kg (18.2-63.5 kg), including 47 females (71%). Paracetamol dose was 83 mg/kg (57-148 mg/kg), and interval between ingestion and serum concentration was 4.5 hours (4.0-5.4 hours). There was a positive correlation between dose and equivalent 4-hour paracetamol concentration: Spearmans rho=0.57, 95% CI 0.36-0.73, P< 0.0001. These findings support the importance of reported dose as part of initial risk assessment, especially in situations where laboratory determination is unhelpful, such as after a staggered ingestion.

Dermal toxicity associated with epibatidine exposure

Epibatidine is an alkaloid similar to nicotine, which was originally discovered in the skin of the Ecuadorian poisonous frog. A number of synthetic preparations are available, and it is subject to medical research for a variety of disorders. This article describes a previously healthy 25-year-old researcher who developed an itchy, vesicular rash after working for around 2 h in a laboratory environment with epibatidine hydrochloride (Tocris Bioscience, Ellisville, MO, USA). An urticarial rash developed on the extensor surfaces of forearms, calves, axillae, and upper torso. Mucous membranes were spared, and there was no lymphadenopathy. The patient had a history of asthma, but no documented allergy or skin disorder, and no family history of atopy. He underwent treatment with oral prednisolone 40 mg, and regular oral chlorpheniramine 4 mg three times daily, and the rash had fully resolved in 1 week.