Animal testing, preclinical

True zwitterionic compounds are rare among drugs. The oral absorption of truly zwitterionic compounds is poor unless the compound is a substrate for an absorptive biological transporter as in an a-amino acid which is a substrate for the PepTl nutrient transporter. The aqueous solubility of a true zwitterionic compound will be at a minimum at the isoelectric point which unfortunately for many compounds happens close to the neutral pH at which oral absorphon occurs. Species extrapolation predicting oral absorphon and pk/pD from preclinical animal tests to man are difficult for zwitterions. 

Preclinical drug development also involves animal testing [61]. Data from one rodent species and one nonrodent species are usually collected to determine the absorption, metabolism, and toxicity characteristics of the compound. Both short-term (2 weeks to 3 months) and long-term (up to several years) studies are done. The long-term studies are particularly useful for... 

The costs of drug development increase as a drug progresses through the development pipeline. Preclinical development is the time when chemical compounds are tested in the laboratory to learn as much as possible about how medicines work "in a test tube." These types of experiments can be done with many compounds in a relatively short time and with relatively low cost. This is also the time that animal testing begins to see whether the chemical compounds are safe. These studies help scientists to determine how medicines will be dosed in humans. They are also important to understand whether any toxicity is related to the medicines. Toxicological tests are time... 

Oligomers of perfluorohexyl-ethene fulfilled these expectations in all preclinical studies, in vitro tests as well in animal tests. A radical polymerisation, followed by ultra-purification steps, created a crystal clear gel-like substance. The behaviours of the mixture of dimeric, trimeric and tetrameric star-shaped species with an inner core of hydrocarbon bonds and an outer layer of perfluoro-alkyl chains could be adjusted by the ratio of the dimeric, trimeric and tetrameric species, using a thin layer distillation. In dependence on this ratio, the viscosity could be adjusted in the range between 90 mPas and 1700 mPas, the specific density between 1.60 g/ml and 1.66 g/ml and the interfacial tension against water between... 

Preclinical and clinical process laboratories serve a critical function in the development and organization of toxicology data, animal testing results, and ultimately of human test results. Again, the GLPs provide guidance and assure both minimization of misinterpretation and control of both the potential risks to human subjects and the suffering of test animals. 

The trials described so far have commonly shown a lack of usefulness of NKi receptor antagonists in the treatment of pain. But we do not know whether the failure of the selected compounds is a matter of pharmacodynamics (e.g. poor penetration of the blood brain barrier) or a genuine discrepancy between animal and human pain pathophysiology (Urban and Fox, 2000). Hence, animal tests should carefully be chosen whether they are predictive or not, and it would be helpful if a wider range of conditions could be examined (Hill, 2000a). Therefore, new preclinical analysis methods should be developed for a more effective judgement of likely clinical outcomes. 

Before a drug may be tested on humans, it must first be tested on animals. Tests on humans are called clinical trials, and animal trials are often referred to as preclinical trials. Preclinical trials differ from the animal tests mentioned earlier in this chapter. The previously discussed animal tests help the drug discovery team determine and optimize the pharmacodynamic and pharmacokinetic behavior of a hit or lead. Preclinical trials, in contrast, are standardized, industrywide tests. The preclinical tests have technical names such as Segment II Reproductive Study in Rabbits or 6-Month Toxicity Study in Rats. The specific names suggest the exact nature of each study. Each trial seeks to answer predefined safety questions concerning a drug candidate. Preclinical trials do not address the therapeutic effectiveness of the drug candidate in any way. Preclinical trials examine exclusively safety issues. 

Review preclinical/animal testing and plan for Approve to test the drug candidate in humans... 

Attempts are underway to harmonize guidelines for preclinical test procedures in the EEC, Japan and USA in order to avoid the unnecessary duplication of animal tests due to different formal requirements. Other countries will adopt such common... 

Carcinogenesis see also Preclinical testing (p. 45). Mechanisms of carcinogenesis are complex prediction from animal tests is imcertain and causal... 

Current clinical and preclinical biomarkers suffer from lack of target organ specificity, sensitivity issues, and poor mechanistic insight. There is therefore a lot of interest in the field of biomarker discovery to overcome these issues, for both clinical and preclinical applications. In this chapter we set out to demonstrate how in vitro techniques are an indispensable tool in the development and discovery of novel mechanistically based biomarkers. We provide examples of several novel biomarkers which have been either discovered in vitro or where such systems have been used to elucidate key mechanistic information. Many of these biomarkers are more than innocent bystanders leaked into the surrounding tissue, with most highly implicated in cell and tissue survival as well as tissue differentiation. These new biomarkers will be not only useful for current preclinical and clinical applications but also advantageous in the development of better in vitro systems in order to reduce or replace animal testing. 

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