Unexpected adverse preclinical findings (APFs) are not infrequently encountered during drug development. Such APFs can be functional disturbances such as QT prolongation, morphological toxicity or carcinogenicity. The latter is of particular concern in conjunction with equivocal genotoxicity results. The toxicologic pathologist plays an important role in recognizing these effects, in helping to characterize them, to evaluate their risk for man, and in proposing measures to mitigate the risk particularly in early clinical trials. A careful scientific evaluation is crucial while termination of the development of a potentially useful drug must be avoided. This first part of the review discusses processes to address unexpected APFs and provides an overview over typical APFs in particular classes of drugs. If the mode of action (MoA) by which a drug candidate produces an APF is known, this supports evaluation of its relevance for humans. Tailor-made mechanistic studies, when needed, must be planned carefully to test one or several hypotheses regarding the potential MoA and to provide further data for risk evaluation. Safety considerations are based on exposure at no-observed-adverse-effect levels (NOAEL) of the most sensitive and relevant animal species and guide dose escalation in clinical trials. The availability of early markers of toxicity for monitoring of humans adds further safety to clinical studies. Risk evaluation is concluded by a weight of evidence analysis (WoE) with an array of parameters including drug use, medical need and alternatives on the market. In the second part of this review relevant examples of APFs will be discussed in more detail. 相似文献
This investigation aims to classify, describe and evaluate the sustainability of dairy goat production systems (GPS) in South Spain Sierra de Cadiz. The research took place throughout 25 goat farms during the 2001–2002 campaigns, with the method posed by Masera et al. (1999) [Masera, O., Astier, M., S., López-Ridaura. 1999. Sustentabilidad y manejo de recursos naturales. El marco de evaluación MESMIS (Sustainability and natural resource management. The MESMIS evaluation framework). Mundi-Prensa, S.A., Gira, IE-UNAM, México. 109 pp.] and adapted to animal production systems, as the guideline and framework to evaluate sustainability.
The principal component, namely energy input from grazing (eigenvalue 1.329) which comprises the indicators total area per goat (factorial value 0.664) together with net energy obtained from grazing (factorial value 0.903) allowed to differentiate significantly between semi extensive (SES), semi intensive (SIS) and intensive (IS) goat production systems.
Intensification of the GPS tends to be inefficient, especially in terms of net margin per litre of milk produced (p < 0.05). A higher degree of adaptability of IS (64.8%) derives from a higher investment on new production strategies. Likewise, higher self-management capacity of SES (60.9%) fosters standards of productivity (76.0%) and stability (42.9%). The SIS presented the highest equity values (67.8%).
On the whole, sustainability of GPS tends to decrease as the degree of intensification increases: SES = 57.3%; SIS = 55.7% and IS = 53.1%. The reduction of the dependency on external input alongside with the optimization of natural resources management would surely improve the standard of sustainability. 相似文献
