Human-based Systems in Drug and Chemical Safety Testing — toward <i>Replacement</i>, the ‘Single R’

Coleman, Robert A.

doi:10.1177/026119291404200605

Cited by 3 publications

(3 citation statements)

References 54 publications

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Section: Discussionmentioning

confidence: 99%

“…It can be used for specific tissue tests when induced for differentiation, and it contributes to a precise evaluation of methods and compounds that promote cellular alterations according to the period of exposure and concentration. [54][55][56][57] Cancer treatments include surgical removal, chemotherapy and radiotherapy. However, relapsing tumors are often resistant to conventional approaches.…”

Section: Discussionmentioning

confidence: 99%

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In-Vitro Growth Kinetics of Mesenchymal Stem Cells in Cytotoxicity Tests Using Low-Diluted Viscum Album

Valle

Brunel²,

Dallago³

et al. 2022

Homeopathy

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Introduction The use of mesenchymal stem cells (MSC) in cytotoxicity tests is an in-vitro alternative model for predicting initial doses. Homeopathic medicines may stimulate the immune system to combat a pathology effectively and have been used for over two centuries. Viscum album (VA) extracts are widely used in the treatment of cancer, due to their immunomodulatory, cytotoxic and pro-apoptotic properties. Objective This study aimed to evaluate the in-vitro growth kinetics of canine MSC in relation to cytotoxicity, cell differentiation and expression of pluripotentiality markers, using a VA preparation at the D1D2 (1×10−1, 1×10−2 potency (VAD1D2). Methods MSC were obtained from adipose tissue sampled from a healthy dog that was undergoing an elective veterinary procedure and with its owner's permission. The experiments were performed in three groups: MSC treated with VAD1D2 or diluent or untreated (control). The cytotoxicity was evaluated by MTT assay. The differentiation was induced in three lineages, and apoptotic cell labeling was performed by an Annexin-V test. Results At the concentration of 10 μL/mL of VA, the number of cells after in-vitro culture was maintained when compared with the control (untreated) group. A significant and gradual decrease in cell viability was recorded as VA concentrations increased. The apoptosis analysis showed that VA at 20 μL/mL presented absolute percentages of initial apoptosis twice as high as at 10 μL/mL, which was similar to the control (untreated group). Conclusion The results suggest that the use of efficient methods to assess the in-vitro cytotoxicity of VA-based homeopathic medicines using MSC lineages may predict the potential action at different concentrations. These findings demonstrated that VAD1D2 interferes with canine MSC growth kinetics.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

In-Vitro Growth Kinetics of Mesenchymal Stem Cells in Cytotoxicity Tests Using Low-Diluted Viscum Album

Valle

Brunel²,

Dallago³

et al. 2022

Homeopathy

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show abstract

“…Industry and regulators are inherently conservative, so will naturally opt for the least challenging of the Three Rs -Reduction and Refinement -at the expense of the considerably more challenging, but infinitely more valuable, Replacement. The two more conservative Rs may be ethically desirable, but they do not address the issue of species relevance (23,24).…”

Section: The Challenge Of Humanising the Processmentioning

confidence: 99%

Barriers to the Uptake of Human-based Test Methods, and how to Overcome Them

Archibald

Drake²,

Coleman

2015

Altern Lab Anim

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Although there is growing concern as to the questionable value of animal-based methods for determining the safety and efficacy of new medicines, which has in turn led to many groups developing innovative human-based methods, there are many barriers to their adoption for regulatory submissions. The reasons for this are various, and include a lack of confidence that the available human-based methods, be they in vivo, in silico or in vitro, can be sufficiently predictive of clinical outcomes. However, this is not the only problem: the issue of validation presents a serious impediment to progress, a particularly frustrating situation, in view of the fact that the existing animal-based methods have never themselves been formally validated. Superimposed upon this is the issue of regulatory requirements, where, although regulators may be willing to accept non-animal approaches in place of particular animal tests, nowhere is this explicitly stated in their guidelines. Such problems are far from trivial, and represent major hurdles to be overcome. In addition, there are a range of other barriers, real or self-imposed, that are hindering a more-predictive approach to establishing a new drug's clinical safety and efficacy profiles. Some of these barriers are identified, and ways forward are suggested.

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Development of a drug screening system using three-dimensional cardiac tissues containing multiple cell types

Takeda

Miyagawa

Ito

et al. 2021

Sci Rep

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We hypothesized that an appropriate ratio of cardiomyocytes, fibroblasts, endothelial cells, and extracellular matrix (ECM) factors would be required for the development of three-dimensional cardiac tissues (3D-CTs) as drug screening systems. To verify this hypothesis, ECM-coated human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), ECM-coated cardiac fibroblasts (CFs), and uncoated cardiac endothelial cells (CEs) were mixed in the following ratios: 10:0:0 (10CT), 7:2:1 (7CT), 5:4:1 (5CT), and 2:7:1 (2CT). The expression of cardiac-, fibroblasts-, and endothelial-specific markers was assessed by FACS, qPCR, and immunostaining while that of ECM-, cell adhesion-, and ion channel-related genes was examined by qPCR. Finally, the contractile properties of the tissues were evaluated in the absence or presence of E-4031 and isoproterenol. The expression of ECM- and adhesion-related genes significantly increased, while that of ion channel-related genes significantly decreased with the CF proportion. Notably, 7CT showed the greatest contractility of all 3D-CTs. When exposed to E-4031 (hERG K channel blocker), 7CT and 5CT showed significantly decreased contractility and increased QT prolongation. Moreover, 10CT and 7CT exhibited a stronger response to isoproterenol than did the other 3D-CTs. Finally, 7CT showed the highest drug sensitivity among all 3D-CTs. In conclusion, 3D-CTs with an appropriate amount of fibroblasts/endothelial cells (7CT in this study) are suitable drug screening systems, e.g. for the detection of drug-induced arrhythmia.

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Human-based Systems in Drug and Chemical Safety Testing — toward Replacement, the ‘Single R’

Cited by 3 publications

References 54 publications

In-Vitro Growth Kinetics of Mesenchymal Stem Cells in Cytotoxicity Tests Using Low-Diluted Viscum Album

In-Vitro Growth Kinetics of Mesenchymal Stem Cells in Cytotoxicity Tests Using Low-Diluted Viscum Album

Barriers to the Uptake of Human-based Test Methods, and how to Overcome Them

Development of a drug screening system using three-dimensional cardiac tissues containing multiple cell types

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