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A thorough understanding of which of the effects assessed in the in vivo Draize eye test are responsible for driving UN GHS/EU CLP classification is critical for an adequate selection of chemicals to be used in the development and/or evaluation of alternative methods/strategies and for properly assessing their predictive capacity and limitations. For this reason, Cosmetics Europe has compiled a database of Draize data (Draize eye test Reference Database, DRD) from external lists that were created to support past validation activities. This database contains 681 independent in vivo studies on 634 individual chemicals representing a wide range of chemical classes. A description of all the ocular effects observed in vivo, i.e. degree of severity and persistence of corneal opacity (CO), iritis, and/or conjunctiva effects, was added for each individual study in the database, and the studies were categorised according to their UN GHS/EU CLP classification and the main effect driving the classification. An evaluation of the various in vivo drivers of classification compiled in the database was performed to establish which of these are most important from a regulatory point of view. These analyses established that the most important drivers for Cat 1 Classification are (1) CO mean ≥ 3 (days 1-3) (severity) and (2) CO persistence on day 21 in the absence of severity, and those for Cat 2 classification are (3) CO mean ≥ 1 and (4) conjunctival redness mean ≥ 2. Moreover, it is shown that all classifiable effects (including persistence and CO = 4) should be present in ≥60 % of the animals to drive a classification. As a consequence, our analyses suggest the need for a critical revision of the UN GHS/EU CLP decision criteria for the Cat 1 classification of chemicals. Finally, a number of key criteria are identified that should be taken into consideration when selecting reference chemicals for the development, evaluation and/or validation of alternative methods and/or strategies for serious eye damage/eye irritation testing. Most important, the DRD is an invaluable tool for any future activity involving the selection of reference chemicals.
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Cosméticos/efeitos adversos , Cosméticos/classificação , Avaliação Pré-Clínica de Medicamentos/métodos , Olho/efeitos dos fármacos , Testes de Toxicidade/métodos , Animais , Cosméticos/toxicidade , Bases de Dados Factuais , Europa (Continente) , Humanos , Irritantes/classificação , Irritantes/toxicidade , Coelhos , Reprodutibilidade dos TestesRESUMO
AIMS AND BACKGROUND: We compared the bone mineral density (BMD) of adult Wilson disease (WD) patients (n = 148), with an age- and gender-matched healthy control population (n = 148). Within the WD cohort, correlations of BMD with WD disease parameters, lab results, type of treatment and known osteoporosis risk factors were analysed. METHODS: Hip and lumbar spine absolute BMD and T-score were measured by dual-energy X-ray absorptiometry. Osteoporosis and osteopenia were defined as a T-score ≤ -2.5, and between -1 and -2.5, respectively. RESULTS: There were significantly more subjects with abnormal T-scores in the WD population (58.8%) than in the control population (45.3%) (χ(2) = 6.65, df = 2, p = 0.036), as there were 50.0% osteopenic and 8.8% osteoporotic WD patients, vs. 41.2% and 4.1%, respectively, in the controls. Especially L2-L4 spine BMD measurements (BMD and T-scores) differed significantly between the WD population and matched controls. L2-L4 spine BMD for WD patients was on average 0.054 g/cm(2) (5.1%) lower than in matched normal controls (0.995 ± 0.156 vs 1.050 ± 0.135; p = 0.002). We found no significant correlation between BMD values and any of the WD disease parameters (e.g. the severity of liver disease), lab results, type of treatment or known osteoporosis risk factors. Duration of D-penicillamine treatment was negatively correlated with femoral BMD value, but in a clinically irrelevant manner, compared to age and gender. Importantly, BMD remained significantly lower in WD patients (n = 89) vs. controls after excluding WD patients with cirrhosis (p = 0.009). CONCLUSIONS: Our study suggests that WD is intrinsically associated with bone demineralisation.
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Desmineralização Patológica Óssea/etiologia , Degeneração Hepatolenticular/complicações , Absorciometria de Fóton/métodos , Adolescente , Adulto , Idoso , Desmineralização Patológica Óssea/diagnóstico por imagem , Desmineralização Patológica Óssea/epidemiologia , Densidade Óssea , Doenças Ósseas Metabólicas/diagnóstico por imagem , Doenças Ósseas Metabólicas/epidemiologia , Estudos de Coortes , Feminino , Colo do Fêmur , Degeneração Hepatolenticular/diagnóstico por imagem , Degeneração Hepatolenticular/epidemiologia , Humanos , Vértebras Lombares , Masculino , Pessoa de Meia-Idade , Osteoporose/diagnóstico por imagem , Osteoporose/epidemiologia , Fatores de Risco , Adulto JovemRESUMO
AIMS: Few well-designed randomized controlled trials have been conducted regarding the impact of community pharmacist interventions on pharmacotherapeutic monitoring of patients with chronic obstructive pulmonary disease (COPD). We assessed the effectiveness of a pharmaceutical care programme for patients with COPD. METHODS: The pharmaceutical care for patients with COPD (PHARMACOP) trial is a single-blind 3 month randomized controlled trial, conducted in 170 community pharmacies in Belgium, enrolling patients prescribed daily COPD medication, aged ≥ 50 years and with a smoking history of ≥ 10 pack-years. A computer-generated randomization sequence allocated patients to an intervention group (n = 371), receiving protocol-defined pharmacist care, or a control group (n = 363), receiving usual pharmacist care (1:1 ratio, stratified by centre). Interventions focusing on inhalation technique and adherence to maintenance therapy were carried out at start of the trial and at 1 month follow-up. Primary outcomes were inhalation technique and medication adherence. Secondary outcomes were exacerbation rate, dyspnoea, COPD-specific and generic health status and smoking behaviour. RESULTS: From December 2010 to April 2011, 734 patients were enrolled. Forty-two patients (5.7%) were lost to follow-up. At the end of the trial, inhalation score [mean estimated difference (Δ),13.5%; 95% confidence interval (CI), 10.8-16.1; P < 0.0001] and medication adherence (Δ, 8.51%; 95% CI, 4.63-12.4; P < 0.0001) were significantly higher in the intervention group compared with the control group. In the intervention group, a significantly lower hospitalization rate was observed (9 vs. 35; rate ratio, 0.28; 95% CI, 0.12-0.64; P = 0.003). No other significant between-group differences were observed. CONCLUSIONS: Pragmatic pharmacist care programmes improve the pharmacotherapeutic regimen in patients with COPD and could reduce hospitalization rates.
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Serviços Comunitários de Farmácia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Idoso , Feminino , Nível de Saúde , Humanos , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/complicações , Método Simples-CegoRESUMO
For more than two decades, scientists have been trying to replace the regulatory in vivo Draize eye test by in vitro methods, but so far only partial replacement has been achieved. In order to better understand the reasons for this, historical in vivo rabbit data were analysed in detail and resampled with the purpose of (1) revealing which of the in vivo endpoints are most important in driving United Nations Globally Harmonized System/European Union Regulation on Classification, Labelling and Packaging (UN GHS/EU CLP) classification for serious eye damage/eye irritation and (2) evaluating the method's within-test variability for proposing acceptable and justifiable target values of sensitivity and specificity for alternative methods and their combinations in testing strategies. Among the Cat 1 chemicals evaluated, 36-65 % (depending on the database) were classified based only on persistence of effects, with the remaining being classified mostly based on severe corneal effects. Iritis was found to rarely drive the classification (<4 % of both Cat 1 and Cat 2 chemicals). The two most important endpoints driving Cat 2 classification are conjunctiva redness (75-81 %) and corneal opacity (54-75 %). The resampling analyses demonstrated an overall probability of at least 11 % that chemicals classified as Cat 1 by the Draize eye test could be equally identified as Cat 2 and of about 12 % for Cat 2 chemicals to be equally identified as No Cat. On the other hand, the over-classification error for No Cat and Cat 2 was negligible (<1 %), which strongly suggests a high over-predictive power of the Draize eye test. Moreover, our analyses of the classification drivers suggest a critical revision of the UN GHS/EU CLP decision criteria for the classification of chemicals based on Draize eye test data, in particular Cat 1 based only on persistence of conjunctiva effects or corneal opacity scores of 4. In order to successfully replace the regulatory in vivo Draize eye test, it will be important to recognise these uncertainties and to have in vitro tools to address the most important in vivo endpoints identified in this paper.
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Olho/efeitos dos fármacos , Irritantes/classificação , Irritantes/toxicidade , Testes de Toxicidade/métodos , Animais , Túnica Conjuntiva/efeitos dos fármacos , Córnea/efeitos dos fármacos , Bases de Dados Factuais , Avaliação Pré-Clínica de Medicamentos/métodos , União Europeia , Probabilidade , Coelhos , Estudos Retrospectivos , Testes de Toxicidade/normas , Nações UnidasRESUMO
Flatworms possess adult pluripotent stem cells, which make them extraordinary experimental model organisms to assess in vivo the undesirable effects of substances on stem cells. Currently, quality practices, implying evaluation of the stability of the test compound under the proposed experimental conditions, are uncommon in this research field. Nevertheless, performing a stability study during the rational design of in vivo assay protocols will result in more reliable assay results. To illustrate the influence of the stability of the test substance on the final experimental outcome, we performed a short-term International Conference on Harmonization (ICH)-based stability study of cyclophosphamide in the culture medium, to which a marine flatworm model Macrostomum lignano is exposed. Using a validated U(H)PLC method, it was demonstrated that the cyclophosphamide concentration in the culture medium at 20°C is lowered to 80% of the initial concentration after 21days. The multiwell plates, flatworms and diatoms, as well as light exposure, did not influence significantly the cyclophosphamide concentration in the medium. The results of the stability study have practical implications on the experimental set-up of the carcinogenicity assay like the frequency of medium renewal. This case study demonstrates the benefits of applying appropriate quality guidelines already during fundamental research increasing the credibility of the results.
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Cromatografia Líquida de Alta Pressão/métodos , Ciclofosfamida/química , Modelos Animais , Platelmintos , Animais , Ciclofosfamida/análise , Estabilidade de Medicamentos , Células-Tronco Pluripotentes/metabolismo , Fatores de TempoRESUMO
Currently there are two OECD-adopted defined approaches (DA) for eye hazard identification of non-surfactant liquids (OECD TG 467). The current study aimed to develop a DA for eye hazard identification of solid chemicals according to the three UN GHS categories (Cat.1, Cat. 2, No Cat.): the DAS. The DAS combines two test methods described in OECD TG 437 and TG 492. The DAS was developed based on in-depth statistical analysis of a database on solids containing in vitro and historically curated in vivo Draize eye test data. The performance of the DAS was assessed by comparing the predictions with the classification based on in vivo Draize eye test data, on the one hand, and with the performance criteria established by the OECD expert group, on the other hand. In a first tier of the DAS, the SkinEthic™ HCE EIT method (TG 492) is used to distinguish No Cat. from classified substances. For classified substances, the BCOP LLBO method (TG 437) is used to identify Cat. 1, and the remaining solids are predicted Cat. 2. In summary, 77.4% Cat. 1 (N=31), 52.3% Cat. 2 (N=18), and 70.0% of No Cat. (N=60) solids were correctly identified compared to the classification based on the Draize eye test. The percentage of correct predictions met the minimum OECD performance values of 75% Cat. 1, 50% Cat. 2, and 70% No Cat., and the percentage of mispredictions was below the established maximum values. Therefore, inclusion of the DAS in OECD TG 467 has been achieved.
Defined approaches combine information from different non-animal testing methods in a specific way and interpret the results according to a fixed procedure. Such defined approaches are already available as full replacements of animal testing to assess the eye hazard of liquid chemicals (OECD Test Guideline 467). This study used two OECD-adopted in vitro methods, based on human cells and corneas from cattle, to create a defined approach that can be used for solid chemicals. The performance of the procedure was assessed against data from previous animal tests for 109 solid chemicals. The results have already led to this defined approach being adopted by the OECD TGs programme for inclusion in TG 467. With the adoption of the new defined approach, non-animal human relevant strategies are now available for eye hazard assessment of liquids and solids, reducing the need for animal testing.
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Alternativas aos Testes com Animais , Substâncias Perigosas , Alternativas aos Testes com Animais/métodos , Substâncias Perigosas/toxicidade , Testes de Toxicidade/métodos , Humanos , Olho/efeitos dos fármacos , Nações Unidas , AnimaisRESUMO
Currently, the OECD has adopted three defined approaches (DAs) for eye hazard identification of non-surfactant liquids and solids (TG467) according to the three UN GHS categories (Cat.1, Cat.2, No Cat.). We are now expanding the applicability domain with a new DA for chemicals having surfactant (SF) properties (DASF). It is based on a combination of RhCE test methods (OECD TG492: EpiOcular™ EIT or SkinEthic™ HCE EIT) and a modification of the Short Time Exposure (STE, TG491) method. The aim of the current study was to compare the performance of the DASF with the performance of other NAMs currently included in the OECD TGs and with the classification based on the Draize eye test to identify potential additional DAs. The minimum performance criteria (75% Cat.1, 50% Cat.2, 70% No Cat.) used for the adoption of the DAs currently included in OECD TG467 were used for this purpose. The DASF identified 90.9% of Cat. 1 (N=23), 77.8% of Cat. 2 (N=9) and 76.0% of No Cat. (N=17) surfactants, meeting the minimum performance criteria. Some of the NAMs that are currently included in the OECD TGs seem promising methods to be part of a DA to identify Cat. 1 or No Cat. for eye hazard assessment of surfactants. However, the number of surfactants that have been tested to evaluate reliability and relevance was often too small. To date, the DASF is the only DA that has evaluated a sufficiently large number of surfactants and whose performance met the OECD acceptance criteria.
Three non-animal-based defined approaches (DAs) for eye hazard assessment of non-surfactant liquid and solid chemicals were adopted as full replacements as OECD Test Guideline (TG 467). We now extend the applicability domain to surfactants with a new DA (DASF), which combines OECD-adopted test systems based on human 3D eye models and rabbit 2D corneal cells. The DASF has been shown to provide reliable results in predicting the eye irritation potential of 50 surfactants. The aim of the current study was to compare the performance of the DASF with the performance of other OECD TG new approach methodologies and compare it with the classification based on historical animal test data. Based on this analysis no additional DAs could be derived. Until today, the DASF is the best predicting, human-relevant DA that covers the whole range of eye irritation responses across the different surfactant classes.
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ToxTracker is a mammalian cell reporter assay that predicts the genotoxic properties of compounds with high accuracy. By evaluating induction of various reporter genes that play a key role in relevant cellular pathways, it provides insight into chemical mode-of-action (MoA), thereby supporting discrimination of direct-acting genotoxicants and cytotoxic chemicals. A comprehensive interlaboratory validation trial was conducted, in which the principles outlined in OECD Guidance Document 34 were followed, with the primary objectives of establishing transferability and reproducibility of the assay and confirming the ability of ToxTracker to correctly classify genotoxic and non-genotoxic compounds. Reproducibility of the assay to predict genotoxic MoA was confirmed across participating laboratories and data were evaluated in terms of concordance with in vivo genotoxicity outcomes. Seven laboratories tested a total of 64 genotoxic and non-genotoxic chemicals that together cover a broad chemical space. The within-laboratory reproducibility (WLR) was up to 98% (73%-98% across participants) and the overall between-laboratory reproducibility (BLR) was 83%. This trial confirmed the accuracy of ToxTracker to predict in vivo genotoxicants with a sensitivity of 84.4% and a specificity of 91.2%. We concluded that ToxTracker is a robust in vitro assay for the accurate prediction of in vivo genotoxicity. Considering ToxTracker's robust standalone accuracy and that it can provide important information on the MoA of chemicals, it is seen as a valuable addition to the regulatory in vitro genotoxicity battery that may even have the potential to replace certain currently used in vitro battery assays.
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Dano ao DNA , Mamíferos , Animais , Humanos , Testes de Mutagenicidade , Reprodutibilidade dos Testes , Genes ReporterRESUMO
BACKGROUND: Joint discomfort is a widespread and growing problem in active adults. The rising interest in preventative nutrition has increased the demand for supplements reducing joint discomfort. Protocols assessing the effect of a nutritional intervention on health commonly involve a series of face-to-face meetings between participants and study staff that can weigh on resources, participant availabilities, and even increase dropout rates. Digital tools are increasingly added to protocols to facilitate study conduct, but fully digitally run studies are still scarce. With the increasing interest in real-world studies, the development of health apps for mobile devices to monitor study outcomes is of great importance. OBJECTIVE: The purpose of this real-world study was to develop a specific mobile app, Ingredients for Life, to conduct a 100% digital study testing the effectiveness of a hydrolyzed cartilage matrix (HCM) supplement on joint discomfort in a heterogeneous group of healthy, active consumers. METHODS: The Ingredients for Life mobile app using a visual analog scale was specifically developed to monitor the variation in joint pain after exercise by the study participants. A total of 201 healthy and physically active women and men (18-72 years old) with joint pain completed the study over a period of 16 weeks. Participants were randomly allocated to the study groups and did not receive any dietary or lifestyle advice. Each participant indicated one area of joint pain and logged the type and duration of their weekly activities. They received blinded study supplements and took a daily regimen of 1 g of HCM (HCM group) or 1 g of maltodextrin (placebo group) for 12 weeks while weekly logging joint pain scores in the app. This was followed by a 4-week washout period during which participants continued reporting their joint pain scores (until the end of week 16). RESULTS: Joint pain was reduced within 3 weeks of taking a low dosage of HCM (1 g/day), regardless of gender, age group, and activity intensity when compared with the placebo group. After stopping supplementation, joint pain scores gradually increased but still remained significantly lower than those of the placebo group after 4 weeks of washout. The low dropout rate (<6% of participants, mainly in the placebo group) demonstrates that the digital study was well received by the study population. CONCLUSIONS: The digital tool allowed us to measure a heterogeneous group of active adults in a real-world setting (without any lifestyle intervention), thus promoting inclusivity and diversity. With low dropout rates, it demonstrates that mobile apps can generate qualitative, quantifiable, real-world data showcasing supplement effectiveness. The study confirmed that the oral intake of a low dose (1 g/day) of HCM led to a significant reduction of joint pain from 3 weeks after starting supplementation.
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The use of Integrated Testing Strategies (ITS) permits the combination of diverse types of chemical and toxicological data for the purposes of hazard identification and characterisation. In November 2008, the European Partnership for Alternative Approaches to Animal Testing (EPAA), together with the European Centre for the Validation of Alternative Methods (ECVAM), held a workshop on Overcoming Barriers to Validation of Non-animal Partial Replacement Methods/Integrated Testing Strategies, in Ispra, Italy, to discuss the extent to which current ECVAM approaches to validation can be used to evaluate partial replacement in vitro test methods (i.e. as potential ITS components) and ITS themselves. The main conclusions of these discussions were that formal validation was only considered necessary for regulatory purposes (e.g. the replacement of a test guideline), and that current ECVAM approaches to validation should be adapted to accommodate such test methods. With these conclusions in mind, a follow-up EPAA-ECVAM workshop was held in October 2009, to discuss the extent to which existing validation principles are applicable to the validation of ITS test methods, and to develop a draft approach for the validation of such test methods and/or overall ITS for regulatory purposes. This report summarises the workshop discussions that started with a review of the current validation methodologies and the presentation of two case studies (skin sensitisation and acute toxicity), before covering the definition of ITS and their components, including their validation and regulatory acceptance. The following main conclusions/recommendations were made: that the validation of a partial replacement test method (for application as part of a testing strategy) should be differentiated from the validation of an in vitro test method for application as a stand-alone replacement, especially with regard to its predictive capacity; that, in the former case, the predictive capacity of the whole testing strategy (rather than of the individual test methods) would be more important, especially if the individual test methods had a high biological relevance; that ITS allowing for flexible and ad hoc approaches cannot be validated, whereas the validation of clearly defined ITS would be feasible, although practically quite difficult; and that test method developers should be encouraged to develop and submit to ECVAM not only full replacement test methods, but also partial replacement methods to be placed as parts of testing strategies. The added value from the formal validation of testing strategies, and the requirements needed in view of regulatory acceptance of the data, require further informed discussion within the EPAA forum on the basis of case studies provided by industry.
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Alternativas aos Testes com Animais , Testes de Toxicidade/métodos , Estudos de Validação como Assunto , AnimaisRESUMO
Stinging, itching and/or burning (SIB) sensations cannot be detected by animal tests or in vitro models. In the past, the Slug Mucosal Irritation (SMI) assay demonstrated a relation between an increased mucus production in slugs and an elevated incidence of SIB sensations in humans. A new 1-day SMI test procedure was developed focusing on the prediction of these short-term sensations. The objective of this study was to verify whether this new procedure is capable predicting mucosal tolerance of several marketed nasal formulations using the slug Arion lusitanicus. Irritation and tissue damage were quantified with a 5-day repeated exposure study by means of the mucus produced and proteins and enzymes released. The new protocol predicted SIB sensations by means of mucus production. The effects of six liquid nasal formulations were tested with both protocols, while five physiologic saline solutions were only tested with the new protocol to optimize it. None of the tested liquid nasal formulations resulted in tissue damage; however, exposure to the different formulations had a clear effect on the mucus production of the slugs and moderate discomfort was observed in some cases. These effects were due to the active ingredient, the presence of benzalkonium chloride as a preservative or the hyperosmolality of the formulation. For the most part results agreed with clinical data found in literature. It was concluded that the SMI assay, and the new 1-day protocol in particular, is a good tool to predict nasal clinical discomfort.
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Gastrópodes/efeitos dos fármacos , Mucosa/efeitos dos fármacos , Parestesia/induzido quimicamente , Prurido/induzido quimicamente , Testes de Toxicidade/métodos , Animais , Compostos de Benzalcônio/farmacologia , Concentração de Íons de Hidrogênio , Irritantes/farmacologia , Mucosa/metabolismo , Muco/efeitos dos fármacos , Muco/metabolismo , Conservantes Farmacêuticos/farmacologiaRESUMO
INTRODUCTION: Cryotherapy is an efficient method to treat various cutaneous lesions. In the current clinical evaluation, the efficacy of the Pixie® Skin Tag cryogenic pen as a home treatment for benign skin tags was evaluated against a marketed comparator device. In addition, the safety, tolerability, and expected visual effects of the treatment were assessed. METHODS: Fifty-six healthy volunteers presenting with skin tags were included and randomized in a prospective, single-blinded, parallel, single-center, comparative trial and subjected to treatment with either Pixie® Skin Tag or a comparator device, Wortie® skin tag remover. Selected skin tags located on the neck, breast, and under the armpits were topically treated according to device prescriptions for maximally three times with a 15-day interval between treatments. RESULTS: Of the skin tags treated with Pixie® Skin Tag, 64.3% completely disappeared during the study, of which half of the skin tags were cleared after one treatment, compared with 7.1% of the study population treated with Wortie® skin tag remover (p < 0.001). Both medical devices were safe to use, painless, and very well tolerated by 64.3% in the Pixie® Skin Tag and 96.4% in the Wortie® skin tag remover group. In addition, 72% of the subjects using Pixie® Skin Tag were satisfied with the results, and two-thirds of this study group would buy and use the device for the treatment of other skin tags. For the comparator device, only 11.0% were satisfied and 7.0% would buy the device. CONCLUSION: Treatment of skin tags with Pixie® Skin Tag showed superior clinical performance when compared to Wortie® skin tag remover. Both treatments were safe and well tolerated, with the majority of skin response serving as a predictor for clinical performance in the Pixie® Skin Tag treated group. TRIAL REGISTRATION NUMBER: ANSL Registration: 2018-A01804-51.
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Historically, performance of in vitro toxicology test methods has been evaluated and considered for regulatory purposes based on sensitivity & specificity values derived from validation studies. Other indicators are however useful to evaluate in vitro tests such as positive & negative predictive values (PPV & NPV), likelihood ratios (LRs) or odds ratio (OR). These indicators, which are routinely used in diagnostic tests, if adapted and adequately applied to in vitro tests would help determine their realistic predictive power in real world-like situation and help risk assessors know how they can rely on in vitro tests used for their safety assessments. This paper performs a series of simulations considering the actual distribution in ECHA C&L inventory of skin corrosive chemicals to calculate several of these indicators of performance (PPV, NPV, LRs, OR). It shows applied examples of predictive power on EpiSkin™ and SkinEthic™ RHE two validated in vitro skin corrosive tests, explains how to build testing strategies based on these examples, compares so called 'bottom-up' and 'top-down' approaches, and demonstrates the number of tests required, and how risk assessors can practically take advantage of this.
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Cáusticos/toxicidade , Técnicas In Vitro , Testes de Irritação da Pele , Humanos , Pele/efeitos dos fármacos , ToxicologiaRESUMO
This study describes the development of a Time-to-Toxicity approach for solids (TTS) based on the SkinEthic™ HCE tissue construct, capable to distinguish chemicals that do not require classification for serious eye damage/eye irritation (No Cat.) from chemicals that require classification for eye irritation (Cat. 2), and serious eye damage (Cat. 1). Briefly, the time-to-toxicity of 69 solids was evaluated by exposing SkinEthic™ HCE tissue constructs to the test chemical for two different time periods (30-min, and 120-min). Based on the viability observed for the different exposure periods, a classification was assigned. The within laboratory reproducibility in terms of concordance in classifications (3 UN GHS categories), based on a set of 48 solids, was 93.7%. Furthermore, 73.6% Cat. 1 (N = 24), 55.6% Cat. 2 (N = 15) and 72.2% No Cat. (N = 30) were correctly identified with the SkinEthic™ HCE TTS test method. This study provides evidence that the SkinEthic™ HCE Time-to-Toxicity method (multiple exposure times) can distinguish Cat. 2 solids from Cat. 1 solids. This is an added value compared to the SkinEthic™ HCE EITS method (single exposure time) that can distinguish No Cat. chemicals from chemicals that do require classification and labelling for eye irritation/serious eye damage (Cat. 2/Cat. 1).
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Epitélio Corneano/efeitos dos fármacos , Traumatismos Oculares/induzido quimicamente , Irritantes/classificação , Irritantes/toxicidade , Alternativas aos Testes com Animais , Sobrevivência Celular , Humanos , Técnicas In Vitro , Rotulagem de Produtos , Reprodutibilidade dos Testes , Testes de Toxicidade/métodosRESUMO
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a prevalent disease that is frequently treated in primary care. However, data regarding the primary care management of COPD are scarce. Such observational data are necessary to detect problem areas and to develop targeted interventions for improvement of COPD management. OBJECTIVE: To provide a detailed description of (1) drug therapy, (2) drug adherence, (3) inhalation technique, and (4) health status of patients with COPD recruited via community pharmacies. METHODS: A cross-sectional, observational study was conducted in 93 pharmacies in Belgium. Participants (N = 555) completed a questionnaire collecting information on personal characteristics, smoking history, influenza vaccination, COPD medication, and adverse effects. Adherence to COPD maintenance medication was analyzed 1 year retrospectively through prescription refill rates. Inhalation technique was scored using a checklist. Health status was evaluated with the St. George's Respiratory Questionnaire, the Clinical COPD Questionnaire, and the Modified Medical Research Council dyspnea scale. RESULTS: The mean age of the patients was 68.6 years; 73.7% were men and 37.2% were current smokers. The influenza vaccination status was significantly lower in patients aged less than 65 years (65.7%) than in patients aged 65 years or more (86.2%) (p < 0.001). Fixed combinations of inhaled corticosteroids and long-acting beta(2)-agonists were the most frequently used COPD medications (75.4%). About 48% of patients were underadherent (<80% adherence), 47% were adherent (80-120% adherence) and 5% were overadherent (>120% adherence). Predictors for underadherence were age and number of drugs. Twenty-one percent of patients made major inhalation technique errors with rescue medication; these were all errors in handling pressurized metered-dose inhalers (pMDIs). CONCLUSIONS: This observational study on COPD management in primary care highlights 4 main aspects that could be improved: (1) drug adherence, (2) inhalation technique with pMDIs, (3) influenza vaccination in COPD patients younger than 65 years, and (4) smoking cessation.
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Adesão à Medicação , Preparações Farmacêuticas/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração por Inalação , Aerossóis , Idoso , Idoso de 80 Anos ou mais , Bélgica , Serviços Comunitários de Farmácia , Estudos Transversais , Feminino , Humanos , Vacinas contra Influenza/administração & dosagem , Masculino , Erros de Medicação , Inaladores Dosimetrados , Pessoa de Meia-Idade , Atenção Primária à Saúde , Estudos Retrospectivos , Fumar/epidemiologia , Inquéritos e QuestionáriosRESUMO
The "Peira LLBO 180" is a Laser Light-Based Opacitometer that can be used as an alternative for the standard OP-KIT device in the Bovine Corneal Opacity and Permeability (BCOP) test Organisation for Economic Co-operation and Development (OECD) Test Guideline (TG) 437 to identify chemicals inducing serious eye damage as defined by United Nations Globally Harmonized System of Classification and Labelling of Chemicals (UN GHS), i.e. chemicals to be classified as UN GHS Category 1 and chemicals not requiring classification for eye irritation or serious eye damage under the UN GHS classification system (No Category). ⢠The Peira LLBO 180 offers the advantage of analysing the complete corneal surface and is therefore able to detect more efficiently opaque spots located around the periphery of the excised corneas. ⢠This new device will allow not only a more accurate definition of the eye irritating potential of compounds, but also a more precise ranking of moderate to mild and non-irritating compounds. ⢠The value of Peira LLBO 180 is confirmed during in-house and multi-laboratory evaluation studies and is now included in the updated OECD TG 437, dated 26th of June 2020. The results demonstrate that the presented methodology is an improved new approach methodology (NAM) for ocular irritation testing of liquids and solids.
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This study describes the development of a Time-to-Toxicity approach for liquids (TTL) based on the SkinEthic™ HCE tissue construct, capable to distinguish chemicals that do not require classification for serious eye damage/eye irritation (No Cat.) from chemicals that require classification for eye irritation (Cat. 2), and serious eye damage (Cat. 1). Briefly, the Time-to-Toxicity of 56 liquids was evaluated by exposing SkinEthic™ HCE tissue constructs to the test chemical for three different time periods (5-min, 16-min, and 120-min). Based on the viability observed for the different exposure periods, a classification was assigned. The within laboratory reproducibility in terms of concordance in classifications (3 UN GHS categories), based on a set of 50 liquids, was 80.0%. Furthermore, 84.3% Cat. 1 (Nâ¯=â¯17), 79.4% Cat. 2 (Nâ¯=â¯21) and 72.2% No Cat. (Nâ¯=â¯18) were correctly identified with the SkinEthic™ HCE TTL test method. This study provides evidence that the SkinEthic™ HCE Time-to-Toxicity method (multiple exposure times) is capable of distinguishing Cat. 2 liquids from Cat. 1 liquids. This is an advantage compared to the SkinEthic™ HCE EITL method (single exposure time) that can distinguish No Cat. chemicals from chemicals that do require classification and labelling for eye irritation/serious eye damage (Cat. 2/Cat. 1).
Assuntos
Epitélio Corneano/efeitos dos fármacos , Irritantes/classificação , Irritantes/toxicidade , Testes de Toxicidade/métodos , Alternativas aos Testes com Animais , Rotulagem de Produtos , Reprodutibilidade dos TestesRESUMO
INTRODUCTION: Silicones (e.g., dimethicone) are effective and safe alternatives to insecticides for the treatment of head lice. However, silicones are lipophilic substances and do not only leave the hair greasy but they are also difficult to wash out. We have evaluated the efficacy and safety of a potential solution to this problem: an aqueous dispersion of a novel silylated polyol that has the same mode of action as dimethicone (suffocation) without its negative impact on hair characteristics. METHODS: This was a randomized, controlled, investigator-blinded, bicentric study that was conducted at two locations in the state of Florida (USA) to compare the test product (medical device) to a pyrethrum-based pediculicide that is a first-line, prescription-free treatment against head lice in the USA. The subjects (n = 70) were randomly divided into two groups of 35 persons (test product group and reference product group), with each participant receiving two applications (day 0 and 7) of the product to be tested, according to the instructions for use. Efficacy and safety was evaluated at distinct time points. The primary objective was to establish a cure rate for the test product that was better than 70% at study end (day 10). Esthetic effects of the test product versus dimethicone were evaluated in a blinded, cross-over consumer study (n = 100). RESULTS: At study end, the cure rate (corrected for re-infestation) of 88.2% with the test product significantly surpassed the pre-defined target of 70%, and thus the superiority of the test product versus the reference product was confirmed. The number of subjects cured (free of head lice) after the first treatment was remarkably higher with the test product than with the reference product (57.1 vs. 2.9%, respectively). Both products were safe and well tolerated and both showed beneficial esthetical effects. The consumer test demonstrated that the test product had better washing-out properties than dimethicone, as reflected by a significantly lower average rinsing time and number of washings required to restore the visual aspect of the hair, especially in terms of greasiness. CONCLUSION: Aqueous dispersions of silylated polyols are a promising new class of pediculicides that combine high cure rates with optimal user convenience (short treatment period, easy wash-out with positive effect on hair quality). TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03617926. FUNDING: Oystershell Laboratories.
RESUMO
Assessment of ocular irritation risk is an international regulatory requirement in the safety evaluation of products. In response to this need, L'Oréal developed the SkinEthic™ Human Corneal Epithelium (HCE) Eye Irritation Test (EIT) that has been included in OECD Test Guideline 492. SkinEthic™ HCE EIT is able to correctly and reliably identify chemicals not requiring classification versus labelling for eye irritation or serious eye damage according to UN GHS. In an effort to promote its global use, the performance of the method was evaluated after long-distance shipment and compared to European shipment conditions. Results obtained by Cosmos Technical Center (Japan) after extended tissues transit were compared to results obtained in L'Oréal (France). Thirty-nine out of 40 blinded chemicals, representing different functional chemical classes, were consistently classified in both laboratories. The SkinEthic™ HCE EIT test method was also evaluated for its performance after extended storage of the tissues. The performance was in agreement with the values reported in OECD TG 492, with an overall accuracy of 87.1% (based on 119 chemicals), sensitivity of 95.5% and specificity of 73.5%. The reliability and relevance of SkinEthic™ HCE EIT test method after long-distance shipment and extended storage remain in agreement with regulatory validation criteria.
Assuntos
Epitélio Corneano/efeitos dos fármacos , Irritantes/toxicidade , Testes de Toxicidade/normas , Humanos , Reprodutibilidade dos TestesRESUMO
Pain is a common reason for self-medication with over-the-counter (OTC) analgesics. However, this self-treating population has remained largely uncharacterized. This cross-sectional observational study investigated individuals who self-medicate their pain with OTC analgesics to elucidate their pain characteristics and medication use. In addition, presence of and risk factors for concerns about pain medication were examined. The clinical profile of the participants (nâ¯=â¯1,889) was worse than expected with long-standing pain complaints (median pain duration of 9 years), pain located at multiple body sites (median of 4, and 13% with ≥10 painful body areas), about one-third suffering from daily pain and about 40% experiencing substantial pain-related disability. Head (58.6% of sample), low back (43.6%), and neck (30.7%) were the most common pain locations. About 73% had a physician diagnosis, mainly migraine and osteoarthritis. Paracetamol (used by 68.6% of patients) and nonsteroidal anti-inflammatory drugs (46.8%) were the most frequently used pain medications. About 40% of our sample showed substantial concern about the perceived need for pain medication and the perceived potential for harmful effects (eg, fear for addiction). These findings highlight the importance for health professionals to systematically probe pain patients about their self-medication practices and explore attitudes about pain medication. Perspective: This study found that the clinical picture of people who self-medicate their pain with OTC analgesics looked worse than expected. We also identified substantial concerns about pain medication. Therefore, we recommend that health professionals systematically probe pain patients about their self-medication practices and explore concerns about pain medication.