Animal models for human

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. 

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. 

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... 

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. 

R. L. Bronaugh, R. E Stewart, and E. R. Congdon. Methods for in vitro percutaneous absorption studies. II. Animal models for human skin. Toxicol. Appl. Pharmacol. 62 481 188 (1982). 

Offspring are tran enic New gene inserted is a transgene Design animal model for human disease this way... 

Toxicological studies have suggested that the species specificity for induction of ovarian tumors (produced in mice but not rats) occurs because the blood level of the ovotoxic VCH metabolite VCH-1,2-epoxide is dramatically higher in VCH-treated female mice compared with rats. VCH has been shown to be metabolized by the liver of mice to the ovotoxic metabolite (VCH-1,2-epoxide), which circulates in blood and is delivered to the ovary, where it destroys small oocytes. This destruction of small oocytes is considered to be an early event in carcinogenesis. Species difference in epoxidation of VCH by hepatic micro-somes correlates well with the differences observed in the blood concentration of VCH-1,2-epoxide and VCH ovarian toxicity. Further in vitro studies have found that the rate of VCH epoxidation in humans by human hepatic microsomes was 13- and 2-fold lower than epoxidation by mouse and rat systems respec-tively. Therefore, if the rate of hepatic VCH epoxidation is the main factor that determines the ovotoxicity of VCH, rats may be a more appropriate animal model for humans. 

A number of limitations related to PK/PD modeling are also a reality in situations where predictability of the animal model to man is questionable, where the time course of the pharmacodynamic effect cannot be assessed for drug candidates and when, for example, no accessible/ valid pharmacodynamic endpoint for PK/PD is available. The relevance of the animal model for human could be addressed to some extent at least by measuring relative potency in animal versus man in vitro. In situations where no relevant PD endpoint is available (e.g., for CNS efficacy models), effects at target level (i.e., enzyme inhibition, receptor occupancy) might represent a valuable alternative. In this context however the level and duration of target effect required for clinical efficacy requires careful considerations. 

Beach FA (1979) Animal models for human sexuality. In Sex, hormones, and behavior. London, Elsevier/North-Holland, pp 113-143 (Ciba Foundation Symposium No. 62). 

A sufficient animal model for human Alzheimer s disease has not been developed. Although animals, particularly rabbits, exposed to aluminum develop neurofibrillary tangles (Crapper-McLachlan and... 

Lundgren K, Andries M, Thompson C, et al. 1986. Dioxin treatment of rats results in increased in vitro induction of sister chromatid exchanges by -naphthoflavone An animal model for human exposure to halogenated aromatics. Toxicol Appl Pharmacol 85 189-195. 

The use of nonrelevant animal species is discouraged as the results of such studies may be misleading (per ICH S6). Therefore the next option, when available, is to substitute a relevant transgenic animal model for a pharmacologically relevant species. Transgenic animal models for human EpCAM have been developed, but they either have a different tissue expression pattern from that seen in humans [41,43] or the model has not been validated [40], making them unsuitable for the evaluation of the safety of anti-EpCAM immunotherapeutics. 

Generation of metabolic profiles especially by use of radiolabeled test compounds in preclinical development makes sure that the animal model allows a qualitative and/or quantitative prediction to human. This is crucial for proof of validity of pharmacological and toxicological data obtained in animal models for humans. 

Falconer, I.R., Burch, M.D., Steffensen, D.A., Choice, M., Coverdale, O.R. (1994). Toxicity of the blue-green alga (cyanobacterium) Microcystis aeruginosa in drinking water to growing pigs, as an animal model for human injury and risk assessment. Environ. Toxicol. Water Qual. 9 131-9. 

A number of animal model systems have been developed to provide tumor microenvironments that mimic the clinical situation. However, there are no perfect animal models for drug development. The adequacy of any specific animal model depends on its validity, selectivity, predictability, and reproducibility (22). In cancer chemotherapy, animal models are selected to simultaneously demonstrate antitumor efficacy and evaluate systemic toxicities in an intact organism. Ideally, the tumor system under study in the animal model should be genetically stable over time, with homogeneous characteristics that mimic human tumor biology. In oncology, a variety of diverse animal models for human tumors have been developed. These models can be broadly categorized in to three... 

Lairmore MD, Silverman L, Ratner L (2005) Animal models for human T-lymphotropic virus type 1 (HTLV-1) infection and transformation. Oncogene 24 6005-6015. 

Regional variations in percutaneous absorption contribute to differences in the systemic availability of a drug depending on the site of topical application. The Rhesus monkey Macaca mulatta) could probably serve as an animal model for human skin regional variation.f ° ... 

Taneja V, David CS. Lessons from animal models for human autoimmune diseases. Nat Immunol. 2001 2(9),781-784. 

Additional studies to better define the threshold region for intermediate-duration inhalation, oral, and dermal exposure would be useful, but the animal data currently available suggest that tested species may not be suitable models for human response to this chemical. Studies to identify a suitable animal model may be worthwhile. Further studies on the cataractogenesis of 2,4-DNP in immature rabbits may provide a useful animal model for humans. 

Turpeinen M, Ghiciuc C, Orpitoui M et al (2007) Predictive value of animal models for human cytochrome P450 (CYP)-mediated enzymes a comparative study in vitro. Xenobiotica 37 1367-1377... 

Gonzalez, F. J. (2007) Animal models for human risk assessment the peroxisome proliferator-activated receptor alpha-humanized mouse. Nutt Rev. 65, S2-S6. 

Reisner Y, Dagan S. The Trimera mouse generating human monoclonal antibodies and an animal model for human diseases. Trends Bio-technol. 1998 16 242-246. 

Unfortunately, it is more difficult to choose an animal model for human aldehyde oxidase because of the different substrate variation for each species. Table 3.3 compares the in vivo and in vitro activity of the enzyme from some... 

While rodents probably serve as the most utilized safety testing animal model for human health protection, there are limitations that are important to recognize. Beyond fundamental xenogenic differences with humans that can result in species differences in pharmacokinetics and actions of certain chemicals, rodent and human immune development does not proceed on an identical timeline. Landreth (2002) and Landreth and Dodson (2005) have shown that some events that occur gestationally in humans happen postnatally in rodents. This may be a consideration if limited exposure windows are utilized or if the maternally transferred exposure in rodents could not simulate the appropriate human fetal exposure. Therefore, knowledge of drug metabolism and the... 

---