Animal models for

Toxicity Amelioration. Cancer researchers traditionally have not focused their attention on the question of toxicity amehoration. This is partiy attributed to the lack of predictive animal models for human toxicities. For example, the preclinical rat model, used as a predictor of myelosuppression, has failed to predict myelosuppression in humans in clinical trials. In addition, reduction of one toxicity may result in the emergence of another, more serious problem. Research efforts to address the problem of toxicity amelioration has progressed in several directions. The three most prominent areas are analogue synthesis, chemoprotection, and dmg targeting. 

Several other antigens with good immunocontraceptive potential have been identified and investigated in laboratory animals. In most studies, the rate and duration of the immunocontraceptive effect are less than acceptable. A potential problem in immunological approaches to antifertUity research is the need for a safe, effective adjuvant and suitable animal models for evaluating the efficacy and safety of methods (111). Newer and more effective adjuvants are required for contraceptive vaccines and vaccines in general. 

Kraeling, M. E. K., Reddy, K., and Bronaugh, R, T. (1998). Percuraneous absorption of trim rrobenzene animal models for human skin. /. Appl. Toxicol. 18, 387-392. 

The development of tolerance for GHB has been repeatedly described in clinical vignettes and demonstrated in animal models. For example, with repeated... 

Anderson C, Sundberg K, Groth O. 1986. Animal model for assessment of skin irritancy. Contact Dermatitis 15 143-151. 

The use of animal models for depression has two main objectives. One is to provide a behavioural model that can be used to screen potential antidepressant treatments. For this, the behaviour does not have to be an animal analogue of depression all that is needed is for it to be consistently prevented by established antidepressant agents (i.e. no false negatives) but not by drugs which have no antidepressant effect in humans (i.e. no false positives). 

Table 20.3 Procedures that have been used as animal models for depression or as a preclinical...

Kita, T., Nagano, X., Yokode, M., Ishii, K., Kume, N., Ooshima, A., Yoshida, H. and Kawai, C. (1987). Probucol prevents the progression of atherosclerosis in Watanabe heritable hyperlipidaemic rabbits an animal model for hyper-cholesterolaemic. Proc. Natl Acad. Sci. USA 84, 5928-5931. 

Ho NFH, JY Park, PF Ni, WI Higuchi. (1983). Advancing quantitative and mechanistic approaches in interfacing gastrointestinal drug absorption studies in animals and man. In WG Crouthamel, A Sarapu, eds. Animal Models for Oral Drug Delivery in Man In Situ and In Vivo Approaches. Washington, DC APh/APS, pp 27-106. 

Sanz, MM, Johnson, LE, Ahuja, S, Ekstrom, PA, Romero, J, and van Veen, T, 2007. Significant photoreceptor rescue by treatment with a combination of antioxidants in an animal model for retinal degeneration. Neuroscience 145, 1120-1129. 

The yellow coloration in the Monarch as well as the larva of three other species of butterfly from South Florida is exclusively due to the specific accumulation of exceptionally high levels of lutein producing a pigmented epidermis. This active accumulation, reminiscent of the specific accumulation that occurs in the primate macula, indicates that butterfly larva is an excellent animal model for the study of carotenoid transport and binding. As such, elucidation of the mechanism of transport and binding of lutein in the epidermis and other tissues of these butterfly larvae may provide insight into xanthophyll uptake within the human eye (Bhosale et al. 2004). 

Although many animal models for iron overload exist, some mimicking certain aspects of HH, the 32-microglobulin knockout mouse is of special interest as it revealed for the first time crucial aspects of the pathogenesis of human HH in an animal model, and also because it underlines the important links between iron metabolism and the immune system. Hepatic iron overload in 32-microglobulin ( 32m)-deficient mice appeared to be similar to that found in HH, with pathological iron depositions occurring predominantly in liver parenchymal cells (de Sousa et ah,... 

Although the usual animal model for i.t. studies is the rat [45, 47, 48, 54], studies on dogs [50, 54], rabbits [49] and guinea pigs [55] have also been reported. 

Hofmann,W., and F. Daschil, The Relevance of Animal Models for Radionuclide Inhalation in Man, in Current Concepts in Lung Dosimetry, Proc. of the 30th Annual Meeting of the Radiation Research Society at Salt Lake City 1982 (D.R. Fisher, ed) pp 95-102, Utah... 

Singh K, Masuda K, An H (2008) Animal models for human disc degeneration. In Yue J, Bertagnoli R, McAfee P, An H (eds) Motion preservation surgery of the spine advanced techniques and controversies. Elsevier, Philadelphia, pp 639-648... 

During product development, many of the initial non-clinical studies were undertaken in GAA knockout mice (i.e. mice devoid of a functional GAA gene), which serves as an animal model for Pompe s disease. The mice proved useful in assessing the pharmacodynamic effect of Myozyme on glycogen depletion and helped establish appropriate dosage regimens. The mice were also used to evaluate pharmacokinetics and biodistribution of GAA following its administration at clinically relevant doses. 

Two allelic trembler mutations, which affect only the PNS, result from different point mutations in transmembrane domains of peripheral myelin protein-22 (PMP-22) [1,45] (Table 4-2). The trembler phenotypes are characterized by hypomyelination, continued Schwann cell proliferation and partial paralysis of the limbs. These murine mutants are animal models for some of the inherited human neuropathies caused by abnormalities of the... 

Animal models for OTC deficiency include the sparse fur (spf) mouse (15% control enzyme activity) and the sparse fur-abnormal skin and hair (spf-ash) mouse (5% of control). Both kinds of mutant mouse manifest hyperammonemia, orotic aciduria, growth failure and sparse fur. 

There are three generally accepted criteria for validating animal models for human psychiatric disorders face validity, construct validity, and predictive validity. Face validity refers to the outward appearance of the model, i.e. does the animal s behavior adequately reflect the human behavior being modeled In this dimension, anxiety models have a clear advantage over other psychiatric models it is usually quite apparent if an animal is frightened, whereas it is a much more difficult to assess whether an animal is displaying psychotic-like or depressive-like behavior, for example. 

Predictive validity is the ability of a model to predict the effect that pharmacological or other manipulations will have on the condition being modeled. This criterion can present a real difficulty, in that drug development is often dictated by animal models. For example, if a given model only detects a subset of effective compounds (i.e. those belonging to a specific chemical class), then useful candidates will be discarded long before clinical trials, and the flaw in the model s predictive validity will not be discovered. Thus, the possibility that a model will yield false negatives cannot be ruled out. 

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