An Integrated Decision-tree Testing Strategy for Repeat Dose Toxicity with Respect to the Requirements of the EU REACH Legislation

This paper presents some results of a joint research project conducted by FRAME and Liverpool John Moores University, and sponsored by Defra, on the status of alternatives to animal testing with regard to the European Union REACH (Registration, Evaluation and Authorisation of Chemicals) system for the safety testing and risk assessment of chemicals. The project covered all the main toxicity end-points associated with REACH. This paper focuses on the use of alternative (non-animal) methods (both in vitro and in silico) for repeat dose (sub-acute, sub-chronic and chronic) toxicity testing. It reviews the limited number of in silico and in vitro tests available for this endpoint, and outlines new technologies which could be used in the future, e.g. the use of biomarkers and the ‘omics’ technologies. An integrated testing strategy is proposed, which makes use of as much non-animal data as possible, before any essential in vivo studies are performed. Although none of the non-animal tests are currently undergoing validation, their results could help to reduce the number of animals required for testing for repeat dose toxicity.

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An Integrated Decision-tree Testing Strategy for Eye Irritation with Respect to the Requirements of the EU REACH Legislation

Alternatives to Laboratory Animals ◽

10.1177/026119290803600109 ◽

2008 ◽

Vol 36 (1) ◽

pp. 81-92 ◽

Cited By ~ 5

Author(s):

Christina Grindon ◽

Robert Combes ◽

Mark T.D. Cronin ◽

David W. Roberts ◽

John F. Garrod

Keyword(s):

In Silico ◽

In Vitro Tests ◽

The European Union ◽

Testing Strategy ◽

Animal Testing ◽

Joint Research ◽

Eye Irritation ◽

Joint Research Project

This paper presents some results of a joint research project, sponsored by Defra and conducted by FRAME and Liverpool John Moores University, on the status of alternatives to animal testing with regard to the European Union REACH (Registration, Evaluation and Authorisation of Chemicals) system for the safety testing and risk assessment of chemicals. The project covered all the main toxicity endpoints associated with REACH. This paper focuses on the use of alternative (non-animal) methods (both in vitro and in silico) for eye irritation testing. The manuscript reviews numerous in vitro tests and their possible collation into test batteries, in silico models and a refined in vivo method (the low volume eye test), before combining the use of all these methods into an integrated testing strategy. The aim of this strategy is a reduction in the number of animal tests which would need to be performed in the process of fulfilling the REACH system criteria; this would also lead to a lowering of the number of animals required in compliance with the REACH system requirements.

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An Integrated Decision-tree Testing Strategy for Eye Irritation with Respect to the Requirements of the EU REACH Legislation

Alternatives to Laboratory Animals ◽

10.1177/026119290803601s09 ◽

2008 ◽

Vol 36 (1_suppl) ◽

pp. 111-122 ◽

Cited By ~ 2

Author(s):

Christina Grindon ◽

Robert Combes ◽

Mark T.D. Cronin ◽

David W. Roberts ◽

John F. Garrod

Keyword(s):

In Silico ◽

In Vitro Tests ◽

The European Union ◽

Testing Strategy ◽

Animal Testing ◽

Joint Research ◽

Eye Irritation ◽

Joint Research Project

This paper presents some results of a joint research project, sponsored by Defra and conducted by FRAME and Liverpool John Moores University, on the status of alternatives to animal testing with regard to the European Union REACH (Registration, Evaluation and Authorisation of Chemicals) system for the safety testing and risk assessment of chemicals. The project covered all the main toxicity endpoints associated with REACH. This paper focuses on the use of alternative (non-animal) methods (both in vitro and in silico) for eye irritation testing. The manuscript reviews numerous in vitro tests and their possible collation into test batteries, in silico models and a refined in vivo method (the low volume eye test), before combining the use of all these methods into an integrated testing strategy. The aim of this strategy is a reduction in the number of animal tests which would need to be performed in the process of fulfilling the REACH system criteria; this would also lead to a lowering of the number of animals required in compliance with the REACH system requirements.

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An Integrated Decision-tree Testing Strategy for Skin Sensitisation with Respect to the Requirements of the EU REACH Legislation

Alternatives to Laboratory Animals ◽

10.1177/026119290803601s07 ◽

2008 ◽

Vol 36 (1_suppl) ◽

pp. 75-89 ◽

Cited By ~ 7

Author(s):

Christina Grindon ◽

Robert Combes ◽

Mark T.D. Cronin ◽

David W. Roberts ◽

John F. Garrod

Keyword(s):

Decision Tree ◽

In Vitro Tests ◽

The European Union ◽

Testing Strategy ◽

Animal Testing ◽

Joint Research ◽

Skin Sensitisation ◽

Joint Research Project ◽

The Eu

This report presents some of the results of a joint research project, sponsored by Defra and conducted by FRAME and Liverpool John Moores University, on the status of alternatives to animal testing with regard to the European Union REACH (Registration, Evaluation and Authorisation of Chemicals) system for the safety testing and risk assessment of chemicals. The project covered all the main toxicity end-points associated with the REACH system. This report focuses on the use of alternative (non-animal) methods (both in vitro and in silico) for skin sensitisation testing. The manuscript reviews in vitro tests based on protein-ligand binding, dendritic/Langerhans cells and T-lymphocyte activation, and also the QSAR models and expert systems available for this endpoint. These tests are then incorporated into an integrated, decision-tree testing strategy, which also includes the Local Lymph Node Assay (in its original and new reduced protocols) and the traditional guinea-pig tests (which should only be used as a last resort). The aim of the strategy is to minimise the use of animals in testing for skin sensitisation, while satisfying the scientific and logistical demands of the EU REACH legislation.

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Integrated Decision-tree Testing Strategies for Acute Systemic Toxicity and Toxicokinetics with Respect to the Requirements of the EU REACH Legislation

Alternatives to Laboratory Animals ◽

10.1177/026119290803601s08 ◽

2008 ◽

Vol 36 (1_suppl) ◽

pp. 91-109 ◽

Cited By ~ 4

Author(s):

Robert Combes ◽

Christina Grindon ◽

Mark T.D. Cronin ◽

David W. Roberts ◽

John F. Garrod

Keyword(s):

Decision Tree ◽

Systemic Toxicity ◽

Toxicity Tests ◽

In Vitro Tests ◽

The European Union ◽

Animal Testing ◽

Pbpk Modelling ◽

Joint Research Project ◽

The Eu

Liverpool John Moores University and FRAME conducted a joint research project, sponsored by Defra, on the status of alternatives to animal testing with regard to the European Union REACH (Registration, Evaluation and Authorisation of Chemicals) system for the safety testing and risk assessment of chemicals. The project covered all the main toxicity endpoints associated with REACH. This paper focuses on the use of alternative (non-animal) methods (both in vitro and in silico) for acute systemic toxicity and toxicokinetic testing. The paper reviews in vitro tests based on basal cytotoxicity and target organ toxicity, along with QSAR models and expert systems available for this endpoint. The use of PBPK modelling for the prediction of ADME properties is also discussed. These tests are then incorporated into a decision-tree style, integrated testing strategy, which also includes the use of refined in vivo acute toxicity tests, as a last resort. The implementation of the strategy is intended to minimise the use of animals in the testing of acute systemic toxicity and toxicokinetics, whilst satisfying the scientific and logistical demands of the EU REACH legislation.

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Integrated Decision-tree Testing Strategies for Acute Systemic Toxicity and Toxicokinetics with Respect to the Requirements of the EU REACH Legislation

Alternatives to Laboratory Animals ◽

10.1177/026119290803600107 ◽

2008 ◽

Vol 36 (1) ◽

pp. 45-63 ◽

Cited By ~ 12

Author(s):

Robert Combes ◽

Christina Grindon ◽

Mark T.D. Cronin ◽

David W. Roberts ◽

John F. Garrod

Keyword(s):

Decision Tree ◽

Systemic Toxicity ◽

Toxicity Tests ◽

In Vitro Tests ◽

The European Union ◽

Animal Testing ◽

Pbpk Modelling ◽

Joint Research Project ◽

The Eu

Liverpool John Moores University and FRAME conducted a joint research project, sponsored by Defra, on the status of alternatives to animal testing with regard to the European Union REACH (Registration, Evaluation and Authorisation of Chemicals) system for the safety testing and risk assessment of chemicals. The project covered all the main toxicity endpoints associated with REACH. This paper focuses on the use of alternative (non-animal) methods (both in vitro and in silico) for acute systemic toxicity and toxicokinetic testing. The paper reviews in vitro tests based on basal cytotoxicity and target organ toxicity, along with QSAR models and expert systems available for this endpoint. The use of PBPK modelling for the prediction of ADME properties is also discussed. These tests are then incorporated into a decision-tree style, integrated testing strategy, which also includes the use of refined in vivo acute toxicity tests, as a last resort. The implementation of the strategy is intended to minimise the use of animals in the testing of acute systemic toxicity and toxicokinetics, whilst satisfying the scientific and logistical demands of the EU REACH legislation.

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Insight into Gentisic Acid Antidiabetic Potential Using In Vitro and In Silico Approaches

Molecules ◽

10.3390/molecules26071932 ◽

2021 ◽

Vol 26 (7) ◽

pp. 1932

Author(s):

Hamza Mechchate ◽

Imane Es-safi ◽

Omkulthom Mohamed Al kamaly ◽

Dalila Bousta

Keyword(s):

In Silico ◽

Tyrosine Phosphatase ◽

Health Benefit ◽

In Vivo Studies ◽

In Vitro Tests ◽

Therapeutic Effects ◽

Peroxisome Proliferator ◽

Gentisic Acid

Numerous scientific studies have confirmed the beneficial therapeutic effects of phenolic acids. Among them gentisic acid (GA), a phenolic acid extensively found in many fruit and vegetables has been associated with an enormous confirmed health benefit. The present study aims to evaluate the antidiabetic potential of gentisic acid and highlight its mechanisms of action following in silico and in vitro approaches. The in silico study was intended to predict the interaction of GA with eight different receptors highly involved in the management and complications of diabetes (dipeptidyl-peptidase 4 (DPP4), protein tyrosine phosphatase 1B (PTP1B), free fatty acid receptor 1 (FFAR1), aldose reductase (AldR), glycogen phosphorylase (GP), α-amylase, peroxisome proliferator-activated receptor gamma (PPAR-γ) and α-glucosidase), while the in vitro study studied the potential inhibitory effect of GA against α-amylase and α-glucosidase. The results indicate that GA interacted moderately with most of the receptors and had a moderate inhibitory activity during the in vitro tests. The study therefore encourages further in vivo studies to confirm the given results.

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Recent In Vitro and In Silico Advances in the Understanding of Intranasal Drug Delivery

Current Pharmaceutical Design ◽

10.2174/1381612826666201112143230 ◽

2020 ◽

Vol 26 ◽

Author(s):

John Chen ◽

Andrew Martin ◽

Warren H. Finlay

Keyword(s):

Drug Delivery ◽

In Silico ◽

Local Drug Delivery ◽

In Vivo Studies ◽

Intranasal Drug Delivery ◽

Nasal Sprays ◽

In Silico Studies ◽

Drug Delivery Devices

Background: Many drugs are delivered intranasally for local or systemic effect, typically in the form of droplets or aerosols. Because of the high cost of in vivo studies, drug developers and researchers often turn to in vitro or in silico testing when first evaluating the behavior and properties of intranasal drug delivery devices and formulations. Recent advances in manufacturing and computer technologies have allowed for increasingly realistic and sophisticated in vitro and in silico reconstructions of the human nasal airways. Objective: To perform a summary of advances in understanding of intranasal drug delivery based on recent in vitro and in silico studies. Conclusion: The turbinates are a common target for local drug delivery applications, and while nasal sprays are able to reach this region, there is currently no broad consensus across the in vitro and in silico literature concerning optimal parameters for device design, formulation properties and patient technique which would maximize turbinate deposition. Nebulizers are able to more easily target the turbinates, but come with the disadvantage of significant lung deposition. Targeting of the olfactory region of the nasal cavity has been explored for potential treatment of central nervous system conditions. Conventional intranasal devices, such as nasal sprays and nebulizers, deliver very little dose to the olfactory region. Recent progress in our understanding of intranasal delivery will be useful in the development of the next generation of intranasal drug delivery devices.

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In-silico Studies of Isolated Phytoalkaloid Against Lipoxygenase: Study Based on Possible Correlation

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207321666180220125406 ◽

2018 ◽

Vol 21 (3) ◽

pp. 215-221

Author(s):

Haroon Khan ◽

Muhammad Zafar ◽

Helena Den-Haan ◽

Horacio Perez-Sanchez ◽

Mohammad Amjad Kamal

Keyword(s):

In Silico ◽

Docking Studies ◽

In Vivo Studies ◽

In Vitro Assays ◽

Chronic Obstructive ◽

Lipoxygenase Inhibitors ◽

Lipoxygenase Inhibition ◽

In Silico Studies

Aim and Objective: Lipoxygenase (LOX) enzymes play an important role in the pathophysiology of several inflammatory and allergic diseases including bronchial asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, rheumatoid arthritis and chronic obstructive pulmonary disease. Inhibitors of the LOX are believed to be an ideal approach in the treatment of diseases caused by its over-expression. In this regard, several synthetic and natural agents are under investigation worldwide. Alkaloids are the most thoroughly investigated class of natural compounds with outstanding past in clinically useful drugs. In this article, we have discussed various alkaloids of plant origin that have already shown lipoxygenase inhibition in-vitro with possible correlation in in silico studies. Materials and Methods: Molecular docking studies were performed using MOE (Molecular Operating Environment) software. Among the ten reported LOX alkaloids inhibitors, derived from plant, compounds 4, 2, 3 and 1 showed excellent docking scores and receptor sensitivity. Result and Conclusion: These compounds already exhibited in vitro lipoxygenase inhibition and the MOE results strongly correlated with the experimental results. On the basis of these in vitro assays and computer aided results, we suggest that these compounds need further detail in vivo studies and clinical trial for the discovery of new more effective and safe lipoxygenase inhibitors. In conclusion, these results might be useful in the design of new and potential lipoxygenase (LOX) inhibitors.

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