human tissues

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Haematotoxicology: Scientific Basis and Regulatory Aspects

Laura Gribaldo

Haematopoietic tissues are the targets of numerous xenobiotics. The purpose of in vitro haematotoxicology is the prediction of adverse haematological effects from toxicants on human haematopoietic targets under controlled experimental conditions in the laboratory. Building on its foundations in experimental haematology and the wealth of haematotoxicological data found in experimental oncology, this field of alternatives toxicology has developed rapidly during the past decade. Preclinical and clinical drug development for anti-cancer drugs differs from that for other pharmaceuticals, because of the life-threatening nature of the disease. Treatment with anti-cancer drugs at clinically efficacious doses usually induces serious side-effects. The design of preclinical toxicology studies for anti-cancer drugs is intended to identify a safe clinical starting dose, characterise toxicities that could be encountered in human clinical trials, and determine whether these toxicities are reversible, manageable, and predictable. Although the myeloid colony-forming unit (CFU-GM) progenitor is most frequently evaluated, other defined progenitors and stem cells, as well as cell types found in the bone-marrow stroma, can now be evaluated in vitro. Genetic damage to haematopoietic cells can occur in the absence of any overt haematological signs. The development of tissue-specific screening systems that are able to give information about the toxic effects of chemicals, drugs and environmental hazards on target genes is needed, in order to make preliminary decisions or to set priorities for selection among large groups of chemicals and possible drugs.
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The Use of Human Tissues and Cells in Biomedical Research: The Unusual Suspects

Andrew Bennett

There are compelling reasons to search for alternatives to the use of animals in medical and pharmaceutical research. Aside from the obvious animal welfare issues, both the well-established differences between animal models and humans, and the inherent inter-individual variability in human biological responses, indicate that human-based alternatives are urgently required. However, any such alternative must out-perform the animal-based alternative, otherwise there will be little or no uptake and adoption by end-users. Data obtained from inbred animal models is often highly reproducible, and is therefore attractive to researchers in the fields of biomedical and pharmaceutical research. The inter-individual variability observed during human volunteer and human tissue-based studies is often considered to be problematic, and has been highlighted further with the advent of the ‘omics’ technologies, which generate large biological datasets. However, the variability in both baseline data and response to pharmacological or toxicological challenge observed in human tissues potentially contains a veritable gold mine of information, which may be critical for the advancement of drug discovery.
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A Human Approach to Drug Development: Opportunities and Limitations

Robert A. Coleman

The pharmaceutical industry is failing in its primary function, with increasing expenditure and decreased output in terms of new medicines brought to market. It cannot carry on as it is, without sliding into a terminal decline. It must, therefore, take some positive steps toward addressing its problems. We do not have to look far to see one very obvious problem, namely, the industry’s continuing reliance on nonhuman biology as the basis of its evaluation of potential safety and efficacy. The time has come to focus on the relevant, and to realise that more human-based testing is essential, if the industry is to survive as a source of innovation in drug therapy. This can incorporate earlier clinical testing, in the form of microdosing, and promotion of the development of more-powerful computational approaches based on human information. Fortunately, headway is being made in both approaches. However, a problem remains in the lack of functional evaluation of human tissues, where the lack of commitment, and the inadequacy of the tissue resource itself, are hampering any serious developments. An outline of a collaborative scheme is proposed, that will address this issue, central to which is improved access to research tissues from heart-beating organ donors.
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The Use of Functional Human Tissues in Drug Development

David Bunton

Drug development currently depends on animal models to provide an accurate prediction of human physiology and pathophysiology. However, as is clear from clinical trial failures during phases II and III, such in vivo models do not always predict the effects that a drug can elicit in humans. Tests with human tissues, which are obviously considered to be the closest model of human in vivo function, could fill the gap between animal-based tests and trials in patients. Despite clear advantages, logistical and ethical barriers prevent fresh human tissues from being widely used during drug development. Biopta is aiming to make human tissue testing a regular element of drug development, and works to lower the barriers surrounding the availability of tissue and practicalities of experimental work.
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