Animal models principles

Since the pioneering work of Kleymann et al. (2002), Betz et al. (2002), Baumeister et al. (2007), and Crute et al. (2002), who showed that compounds identified as inhibitors of the helicase-primase enzyme complex could alleviate herpesvirus-induced disease in animal models, the attention of researchers developing antiviral compounds has been drawn more and more towards the virus-encoded helicases, particularly those of Herpes viruses and of RNA viruses such as Hepatitis C Virus (HCV) and SAKS coronavirus (SARS-CoV). Enzyme activity is usually assayed by measuring NTPase activity in the presence of an appropriate nucleic acid co-substrate although, more recently, novel fiuorimetric and luminescence principles have been applied to the measurement of strand unwinding and/or translocation of the protein along the nucleic acid (Frick 2003, 2006). 

Alarie, Y., Kane, L. and Barrow, C. (1980). Sensory irritation The use of an animal model to establish acceptable exposure to airborne chemical irritants. In Toxicology Principles and Practice 1 (Reeves, A.L., Ed.). Wiley, New York. 

Different formulation principles, dosage forms, and DDSs are commonly evaluated in animal models, and attempts are made to predict human absorption on the basis of such studies.80 Human studies are also conducted in some cases to confirm predictions from animal models. Chiou et a 1.81,82 demonstrated that there is a highly significant correlation of absorption (r2 = 0.97) between humans and rats with a slope near unity. In comparison, the correlation of absorption between dog and human was poor (r2 = 0.512) as compared to that between rat and human (r2 = 0.97). Therefore, although dog has been commonly employed as an animal model for studying oral absorption in drug discovery and development, one may need to exercise caution in the interpretation of data obtained. 

Although the individual inhibition of either MAO or COMT may be comparatively minor in isolation, their combined inhibition along with other monoamine or nonmonoamine actions could have additive if not synergistic effects. For example, a fraction with combined hypericin and flavonoids had antidepressant effects in an animal model (Butterweck et al. 1997). Hypericum is a particular case wherein a single isolated principle may be sufficient for the desired effect, but less effective than the entire plant extract. 

Based on the view that the transition to external feeding is a critical step to independence, and that the stages before this step constitute an extension of embryonic development after hatching (the eleutheroembryo) [37], zebraflsh assays during the initial endotrophic nutritional period (0-120 hpf) are considered nonanimal based assays by Directive 86/609/EEC and 2010/63/EU. In the principle of 3Rs (reduce, refine, replace), it is important to have an animal model that meets these requirements to a maximum level and the zebraflsh eleutheroembryo is for all the aforementioned reasons an ideal candidate to study toxicology. 

High dilutions of drugs have been used on human patients for a couple of centuries, and animal experimentation has been done only to confirm their therapeutic effects and study their mode of action. High dilutions have been found to produce effects on such animals as rats, mice, birds, toads and fishes. The basic principle is to create a disease in the animals and test appropriate remedies on them. Some models like catalepsy and righting reflex ones are non-sacrifice animal models which can be easily used to test the biological effects of potentized drugs. Potentized Nux vomica significantly reduced alcohol intake in rats and reversed to some extent... 

Early reports with rAd vectors may provide the proof of principle for transient expression of a number of potentially therapeutic proteins. For instance the Na+/K+-ATPase was found to promote reabsorption of alveolar fluid in an ARDS model (Factor et al., 1999 Sartori and Matthay, 2002). Anti-inflammatory cytokines and antioxidants have also been used with some success in a similar context in animal models of sepsis and ARDS (Van Laethem et al., 1998 Dumasius et al., 2002). 

With respect to studies in animal models which dissect the mechanisms of formation, localization, and fate of immune complexes, the mechanisms by which they elicit an inflammatory response, and their biologic activities, we provide little more than summary information required to understand the concept of immune complex disease and the principles of the tests. For more detailed information, the reader is referred to several excellent reviews (C14, H2, Til, Ul, W12). 

The principle animal model of psychosis has for many years been the hyperactivity and stereotypies induced by stimulant drugs. In animals... 

The principle of estimating a therapeutic index prior to clinical trials typically involves determining the no observable adverse effect level (NOAEL) and comparing that to the projected human dose. In providing the estimate, the efficacious dose is typically obtained from in vitro data with human cells or tissues and in vivo preclinical pharmacology studies that involve animal disease models. Not infrequently the species used to estimate the toxic level is different from the species used to estimate an efficacious level. Thus the therapeutic index is not a true ratio as the units (species and/or conditions) are often different. On the other hand, if one were to obtain information relating to toxicity as well as efficacy from studies employing animal models of disease, a direct estimate of therapeutic index could be made provided that appropriate models had been characterized or validated in the relevant species. 

However evaluation of safety in animal models of disease may be difficult to conduct with strict adhere to current good laboratory practices (cGLPs) due to novel routes of administration, limited animal numbers, uniqueness of the animal model of disease, and/or novel surgical procedures. In such cases the principles of the regulation can still be followed, and where deviations occur, they should be evaluated for their impact on the expected clinical application and discussed. An in-depth discussion should be provided to support a regulatory submission. 

For assessment of degenerative joint disorders as potential side effects of drugs under investigation, a multitude of animal models for osteoarthritis is available, and their respective suitability for the pleiotropic disease aspects have been recently described and discussed by Oegema and Visco (1999), van den Berg (2001), and Brandt (2002). However, novel therapeutic principles, like e.g. the matrix metalloproteinases, have revealed their musculoskeletal side effects as late as in clinical studies only, which then retraced the focus of drug developmental steps back to scrutinize and refine existent models for different applications (Jacobson et al. 1999 Renkiewicz et al. 2003 Peterson 2004). 

The components of preclinical drug development can be divided into four general areas that include (1) in vitro studies to define a new agent s pharmacologic properties (2) drug supply and manufacturing, (3) drug formulation, and, finally, (4) in vivo studies in animal models to provide an initial proof of therapeutic principle and demonstrate the potential for clinical efficacy. 

Regimbeau, J.M., Mallet, V.O., Bralet, M.P., Gilgenkrantz, H., Hous-sin, D., Soubrane, O. Transplantation of isolated hepatocytes. Principles, mechanisms, animal models, chnical results. Gastroenterol. Clin. Biol. 2002 26 591-601... 

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