Calls made to the Poisons Information Centre reveal need for improved risk management of cleaning agents in the workplace.

Purpose. This study aimed to investigate chemical injuries caused by cleaning agents and disinfectants by reviewing poison control data. Methods. We performed a 5-year retrospective analysis of calls to the Swedish Poisons Information Centre (PIC) concerning occupational use of cleaning agents and disinfectants. In addition, callers for 17 new cases were interviewed. Results. Out of 8240 occupationally related cases handled by the PIC during 2010-2014, 24% concerned cleaning agents and disinfectants (N = 1983). Of these, one-third were classified as major risk cases, generally due to potential for corrosive eye and skin injuries. The most frequent type of workplace was restaurants and caterers. However, information about occupation was only identifiable for 30% of the cases. Follow-up interviews exemplify how limited awareness of safety data sheets and disregard of protective equipment may contribute to health-related outcomes such as absence at work. Conclusions. Management and prevention strategies for cleaning agents should be improved. PIC records hold relevant information both for designing interventions and for future research on occupational health and safety management. We suggest that systematic collection by the PIC of information on occupation and age would further improve the usefulness for occupational injury surveillance purposes.

Potential pharmacobezoar formation of large size extended-release tablets and their dissolution - an in vitro study.

OBJECTIVE: Extended release (ER) tablets/capsules in massive ingestion overdoses are prone to form pharmacobezoars potentially increasing the risk of late-appearing toxic effects and prolonged symptoms. Oral activated charcoal is often sufficient to prevent drug absorption, but in a recent massive ingestion of highly toxic substances, prior orogastric lavage might be considered. The disintegration characteristics of ER preparations in overdose situations is valuable to understand if the time line and course of the intoxication might be prolonged, but information on these characteristics are unavailable. Slow disintegration and/or pharmacobezoar formation, and the large size makes ER preparation impossible to evacuate using a 30F orogastric lavage tube. This study evaluates the disintegration and pharmacobezoar formation of a simulated massive ER tablet ingestion in an in vitro model, using a selection of extended release tablets, with different disintegrating characteristics when present in therapeutic numbers. Furthermore, the sizes of the formed pharmacobezoars were compared with the dimensions of a 30F orogastric lavage tube. METHOD: A standardized model mimicking the physical effects on pharmaceutical preparations in simulated gastric fluid (SGF) was developed and tested on three mono-depot ER tablets (quetiapine/Seroquel®XR 50 mg, paracetamol/Pinex®Retard 500 mg, verapamil/Isoptin®Retard 240 mg), one poly-depot ER tablet (carbamazepine/Tegretol®Retard 200 mg), and one immediate-release tablet (paracetamol/Panodil® 500mg). Thirty tablets were placed in polyamide mesh bags, either together in one bag or in separate bags, immersed in 1 L SGF, and incubated at 37 °C for 48 h. Released drugs were quantified at 0.5-48 h. RESULTS: Visual inspection showed that Seroquel®XR, Pinex®Retard, and Isoptin®Retard tablets formed firm pharmacobezoars stable for more than 4 h and intact fractions remained for up to 24 h. Drug releases were reduced by 53%, 40%, and 31%, respectively, for up to 8 h compared to separated tablets. Light microscopy showed that contact with SGF transformed the coating of Seroquel®XR and Pinex®Retard to a diffusion-controlled swelled gel-layer, and the Isoptin®Retard tablets into a rigid and slow-releasing matrix. Tegretol®Retard disintegrated into microspheres within 30 min, and Panodil® disintegrated within minutes. DISCUSSION: The developed pharmacobezoars of mono-depot ER tablets demonstrated prolonged drug release. Neither the formed pharmacobezoars, nor the single tablets of the tested mono-depot ER preparations, would pass through the lumen of a standard orogastric lavage tube, rendering this modality ineffective for tablet removal in gastrointestinal decontamination.

Characteristics and outcomes of e-cigarette exposure incidents reported to 10 European Poison Centers: a retrospective data analysis.

BACKGROUND: The use of e-cigarettes has increased during the past few years. Exposure to e-cigarette liquids, whether intentional or accidental, may lead to adverse events our aim was to assess factors associated with e-cigarette exposures across European Union Member States (EU MS). METHODS: A retrospective analysis of exposures associated with e-cigarettes reported to national poison centers was performed covering incidents from 2012 to March 2015 from 10 EU MS. De-identified and anonymous raw data was acquired. RESULTS: In total, 277 incidents were reported. Unintentional exposure was the most frequently cited type of exposure (71.3%), while e-cigarette refill vials were responsible for the majority of the reported incidents (87.3%). Two-thirds of all exposures (67.5%) occurred as ingestion of e-liquids, which was more frequent among children (≤ 5 years, 6-18 years) compared to adults (87.0% vs. 59.3% vs. 57.6%, p < 0.001 respectively), exposure via the respiratory (5.4% vs. 22.2% vs. 22.2%, p < 0.001) were more frequent among paediatric patients while ocular routes (2.2% vs. 3.7% vs. 11.4%, p = 0.021) were more frequent among adults. Logistic regression analyses indicated that paediatric incidents (≤ 5 years) were more likely to be through ingestion (adjusted Odds Ratio [aOR] = 4.36, 95% Confidence Interval [C.I.]: 1.87-10.18), but less likely to have a reported clinical effect (aOR = 0.41, 95% C.I.: 0.21-0.82). CONCLUSIONS: Our study highlighted parameters related to e-cigarette exposure incidents in 10 EU MS, the results of which indicate that consideration should be given to the design features which may mitigate risks, thereby protecting users, non-users and especially children.

Towards Development of a Dermal Pain Model: In Vitro Activation of Rat and Human Transient Receptor Potential Ankyrin Repeat 1 and Safe Dermal Injection of o-Chlorobenzylidene Malononitrile to Rat.

During clinical development of analgesics, it is important to have access to pharmacologically specific human pain models. o-Chlorobenzylidene malononitrile (CS) is a selective and potent agonist of the transient receptor potential ankyrin repeat 1 (TRPA1), which is a transducer molecule in nociceptors sensing reactive chemical species. While CS has been subject to extensive toxicological investigations in animals and human beings, its effects on intradermal or subcutaneous injection have not previously been reported. We have investigated the potential of CS to be used as an agonist on TRPA1 in human experimental pain studies. A calcium influx assay was used to confirm the capacity of CS to activate TRPA1 with >100,000 times the selectivity over the transient receptor potential vanilloid receptor 1. CS dose-dependently (EC50 0.9 µM) released calcitonin gene-related peptide in rat dorsal root ganglion cultures, supporting involvement in pain signalling. In a local tolerance study, injection of a single intradermal dose of 20 mM CS to rats resulted in superficial, circular crusts at the injection sites after approximately 4 days. The histopathology evaluation revealed a mild, acute inflammatory reaction in the epidermis and dermis at the intradermal CS injection site 1 day after administration. After 14 days, the epidermal epithelium was fully restored. The symptoms were not considered to be adverse, and it is suggested that doses up to 20 µL of 20 mM CS can be safely administered to human beings. In conclusion, our data support development of a CS human dermal pain model.

Strategic focus on 3R principles reveals major reductions in the use of animals in pharmaceutical toxicity testing.

The principles of the 3Rs, Replacement, Reduction and Refinement, are being increasingly incorporated into legislations, guidelines and practice of animal experiments in order to safeguard animal welfare. In the present study we have studied the systematic application of 3R principles to toxicological research in the pharmaceutical industry, with particular focus on achieving reductions in animal numbers used in regulatory and investigatory in vivo studies. The work also details major factors influencing these reductions including the conception of ideas, cross-departmental working and acceptance into the work process. Data from 36 reduction projects were collected retrospectively from work between 2006 and 2010. Substantial reduction in animal use was achieved by different strategies, including improved study design, method development and project coordination. Major animal savings were shown in both regulatory and investigative safety studies. If a similar (i.e. 53%) reduction had been achieved simultaneously within the twelve largest pharmaceutical companies, the equivalent reduction world-wide would be about 150,000 rats annually. The results point at the importance of a strong 3R culture, with scientific engagement, collaboration and a responsive management being vital components. A strong commitment in leadership for the 3R is recommended to be translated into cross-department and inter-profession involvement in projects for innovation, validation and implementation. Synergies between all the three Rs are observed and conclude that in silico-, in vitro- and in vivo-methods all hold the potential for applying the reduction R and should be consequently coordinated at a strategic level.

Comparative effects of sodium channel blockers in short term rat whole embryo culture.

This study was undertaken to examine the effect on the rat embryonic heart of two experimental drugs (AZA and AZB) which are known to block the sodium channel Nav1.5, the hERG potassium channel and the l-type calcium channel. The sodium channel blockers bupivacaine, lidocaine, and the l-type calcium channel blocker nifedipine were used as reference substances. The experimental model was the gestational day (GD) 13 rat embryo cultured in vitro. In this model the embryonic heart activity can be directly observed, recorded and analyzed using computer assisted image analysis as it responds to the addition of test drugs. The effect on the heart was studied for a range of concentrations and for a duration up to 3h. The results showed that AZA and AZB caused a concentration-dependent bradycardia of the embryonic heart and at high concentrations heart block. These effects were reversible on washout. In terms of potency to cause bradycardia the compounds were ranked AZB>bupivacaine>AZA>lidocaine>nifedipine. Comparison with results from previous studies with more specific ion channel blockers suggests that the primary effect of AZA and AZB was sodium channel blockage. The study shows that the short-term rat whole embryo culture (WEC) is a suitable system to detect substances hazardous to the embryonic heart.

Amide hydrolysis of a novel chemical series of microsomal prostaglandin E synthase-1 inhibitors induces kidney toxicity in the rat.

A novel microsomal prostaglandin E synthase 1 (mPGES-1) inhibitor induced kidney injury at exposures representing less than 4 times the anticipated efficacious exposure in man during a 7-day toxicity study in rats. The findings consisted mainly of tubular lesions and the presence of crystalline material and increases in plasma urea and creatinine. In vitro and in vivo metabolic profiling generated a working hypothesis that a bis-sulfonamide metabolite (determined M1) formed by amide hydrolysis caused this toxicity. To test this hypothesis, rats were subjected to a 7-day study and were administered the suspected metabolite and two low-potency mPGES-1 inhibitor analogs, where amide hydrolysis was undetectable in rat hepatocyte experiments. The results suggested that compounds with a reduced propensity to undergo amide hydrolysis, thus having less ability to form M1, reduced the risk of inducing kidney toxicity. Rats treated with M1 alone showed no histopathologic change in the kidney, which was likely related to underexposure to M1. To circumvent rat kidney toxicity, we identified a potent mPGES-1 inhibitor with a low propensity for amide hydrolysis and superior rat pharmacokinetic properties. A subsequent 14-day rat toxicity study showed that this compound was associated with kidney toxicity at 42, but not 21, times the anticipated efficacious exposure in humans. In conclusion, by including metabolic profiling and exploratory rat toxicity studies, a new and active mPGES-1 inhibitor with improved margins to chemically induced kidney toxicity in rats has been identified.

In situ mass spectrometry imaging and ex vivo characterization of renal crystalline deposits induced in multiple preclinical drug toxicology studies.

Drug toxicity observed in animal studies during drug development accounts for the discontinuation of many drug candidates, with the kidney being a major site of tissue damage. Extensive investigations are often required to reveal the mechanisms underlying such toxicological events and in the case of crystalline deposits the chemical composition can be problematic to determine. In the present study, we have used mass spectrometry imaging combined with a set of advanced analytical techniques to characterize such crystalline deposits in situ. Two potential microsomal prostaglandin E synthase 1 inhibitors, with similar chemical structure, were administered to rats over a seven day period. This resulted in kidney damage with marked tubular degeneration/regeneration and crystal deposits within the tissue that was detected by histopathology. Results from direct tissue section analysis by matrix-assisted laser desorption ionization mass spectrometry imaging were combined with data obtained following manual crystal dissection analyzed by liquid chromatography mass spectrometry and nuclear magnetic resonance spectroscopy. The chemical composition of the crystal deposits was successfully identified as a common metabolite, bisulphonamide, of the two drug candidates. In addition, an un-targeted analysis revealed molecular changes in the kidney that were specifically associated with the area of the tissue defined as pathologically damaged. In the presented study, we show the usefulness of combining mass spectrometry imaging with an array of powerful analytical tools to solve complex toxicological problems occurring during drug development.

The effect of ketoconazole and diltiazem on oestrogen metabolism in postmenopausal women after single dose oestradiol treatment.

AIMS: The effect of the CYP3A4 inhibitors ketoconazole and diltiazem on the pharmacokinetics of oestrone was studied in six healthy postmenopausal women after treatment with a single oral dose of oestradiol. METHODS: Plasma oestrone concentrations were measured following the administration of 1) oestradiol, 2) oestradiol and ketoconazole and 3) oestradiol and diltiazem. RESULTS: Treatment with ketoconazole increased the AUC of oestrone (+ 4029 nmol l-1 h; 95% CI on the difference: 1588, 6471) and its Cmax (+ 306 nmol l-1; 95% CI on the difference: 117, 496). The AUC and Cmax of oestrone tended to increase on treatment with diltiazem although this did not reach the level of statistical significance. CONCLUSIONS: The small increase in the plasma concentrations of oestrone formed from 17beta-oestradiol during co-administration with ketoconazole is unlikely to be clinically significant.

Effect of ketoconazole on venlafaxine plasma concentrations in extensive and poor metabolisers of debrisoquine.

OBJECTIVE: To study the influence of CYP3A4 inhibition by ketoconazole on the disposition of venlafaxine in individuals with different CYP2D6 pheno- and genotypes. METHODS: In an open two-phase study, 21 healthy volunteers with known CYP2D6 pheno- and genotype [14 extensive metabolisers (EMs), 7 poor metabolisers (PMs)] were given a single oral dose of venlafaxine (50 mg to EMs and 25 mg to PMs). Plasma and urine levels of venlafaxine and its three metabolites were measured and the pharmacokinetics of venlafaxine were determined. After a 2-week washout period, subjects were treated for 2 days with ketoconazole (100 mg twice daily) starting 1 day before the administration of venlafaxine; and the same parameters as for the administration of venlafaxine only were measured. RESULTS: Data were evaluated from 20 subjects (14 EMs and 6 PMs) who completed the study. The dose-corrected AUC of venlafaxine was on average 2.3 times higher ( P<0.01) and that of its active metabolite O-desmethylvenlafaxine 3.4 times lower ( P<0.0001) in PMs than EMs. There was a good correlation between the debrisoquine metabolic ratio and the ratio between the AUC of venlafaxine and that of O-desmethylvenlafaxine ( Rs=0.93, P<0.002). The majority of subjects showed higher plasma levels of venlafaxine and O-desmethylvenlafaxine upon co-administration of ketoconazole. AUC of venlafaxine significantly increased by 36% and that of O-desmethylvenlafaxine by 26% ( P<0.01). C(max) values increased by 32% and 18%, respectively. The elimination half-life of venlafaxine was unaltered. Three of the PMs displayed marked increases in AUC (81, 126 and 206%) and C(max) (60, 72, 119%) of venlafaxine while the other three showed small or no changes. CONCLUSIONS: Ketoconazole consistently affected the disposition of venlafaxine in EMs of debrisoquine while the response in PMs was erratic. The precise mechanisms underlying this interaction remain to be elucidated.