Animal model

Whole-animal test models are commonly used to determine the potential carcinogenicity of an agent (see Chapter 14). Animal models provide a platform to evaluate cancer outcomes after long-term exposure to the agent at various doses, as well as to identify possible modes of action. Although epidemiologic studies are favored 

Based on a series of experimental studies on classical animal models (Table 9.5), the lARC Working Group on the Evaluation of the Carcinogenic Risk of Chemicals to 

Humans concluded that there was sufficient evidence for the carcinogenicity of soluble calcium chromate and several relatively insoluble hexavalent chromium compounds in laboratory animals. Tumors were mainly induced at the administration site. In addition, experimental exposure to Be, Cd, Ni, and Sb has caused lung tumors in rats, while various beryllium compounds produced osteosarcomas in rabbits by implantation or injection (Hayes 1997). Rossman et al. (2001) could show a co-carcinogenic action of arsenic with solar UV radiation on mouse skin. Apparently strain as well as species differences of the susceptibility to the action of metals may cause variable outcome of carcinogenicity tests for example, in mice this is caused by higher metallo-thionein levels (Oberdorster et al. 1994, Waalkes and Rehm 1994). 

From an epidemiologic view, the potential carcinogenic consequences due to occupa- 

Induction of mutations in cancer- In-vitro cell Carcinogenic action on classi- Epidemiologic data 

4 to 11.9 Hayes 1997), beryllium (more than 10000 exposed estimated risk 1.3 to 2.3 Hayes 1997), and also to cadmium (about 15000 exposed, estimated risks 1.3 to 3.7 Hayes 1997). 

The toxicokinetics of sulfur mustard have been studied in various animal models, e.g., the rat, hairless guinea pig, small pig and marmoset monkey. 

The rat is a generally accepted model for toxicokinetic studies. Maisonneuve et al (1993) do not provide a rationale for choosing this rodent as an animal model for sulfur mustard intoxication. The authors only studied the intravenous (iv) toxicokinetics. 

Zhang and Wu (1987) chose the small pig (male and female, black, 4.2-13.0 kg) because of the aforementioned resemblance of its skin to that of humans. They chose this model to study the percutaneous toxicokinetics of occluded liquid sulfur mustard, and studied the iv route in this species as the reference route, as well as the toxicokinetics after subcutaneous (sc) exposure. 

While there is no specific scientific reason to select the rat for evaluating renal safety, three factors should be kept in mind  

When comparing GFR and RPF between rats of different strains, it is appropriate to correct these parameters for body weight because they are genetically correlated but for high within-strain variation of kidney weight not correlated with renal function, don t correct GFR for kidney weight. 

Another example Dehydration greatly enhances the sensitivity of rats to the nephrotoxicity of aminoglycosides. 

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Historically, drug absorption, distribution, metabolism, excretion, and toxicity ADMET) studies in animal models were performed after the identification of a lead compound. In order to avoid costs, nowadays pharmaceutical companies evaluate the ADMET profiles of potential leads at an earlier stage of the development... 

Yohimbine (104), also from the bark of C.johimbe K Schum. and from the roots of R. serpentina (1. ) Benth. has a folk history (unsubstantiated) of use as an aphrodisiac. Its use has been confirmed experimentally as a local anesthetic, with occasional employment for rehef ia angiaa pectoris and arteriosclerosis, but is frequently contraindicated by its undesired renal effects. Yohimbine and some of its derivatives have been reported as hahuciaogenic (70). In addition, its pattern of pharmacological activities ia a variety of animal models is so broad that its general use is avoided. All ten carbon atoms of secologanin (102) as well as the entire skeleton of tryptamine (98, R = H) are clearly seen as iatact portions of this alkaloid. 

The principal organs involved in the peripheral clearance of hGH from the plasma are the kidney and fiver. hGH is cleared via glomerular filtration at the kidney and by a receptor-mediated mechanism at the fiver (58,59). In animal models, derivatives of hGH such as the 20,000 mol wt variant, oligomeric forms, and hGH complexed with GH-binding protein have been shown to be cleared from the semm at significandy lower rates than 22,000 mol wt hGH (60—62). The prolonged plasma half-life of these derivatives probably reflects a combination of decreased receptor affinity and size constraints on glomerular filtration. 

A novel approach to the problem of amiaoglycoside nephrotoxicity has been to search for compounds that can inhibit toxicity without compromising efficacy. A number of agents have been reported to reduce amiaoglycoside toxicity ia animal models the most extensively studied of these is sodium polyaspartate (103—107). 

Argatroban [74863-84-6] ((2R,4R)-4-methyl-l-[A/ -)(3 methyl l,2,3,4-tetrahydto-8-quiaoIiaesulfonyl)-L-atgiayl]-2-piperidiaecatboxyhc acid monohydrate) is a potent inhibitor of thrombin formation and activity (49). This agent has been studied in vitro and ia a few animal models. Its toxicity and activity ia humans ate unknown. 

Amine boranes have been examined by a variety of spectroscopic methods (24—29). The boron-substituted alpha-amino acids have been utilized in animal model studies. These compounds along with their precursors and selected derivatives have been shown to possess antineoplastic, antiarthritic, and hypolipidemic activity (30—32). The boron amino acid analogues are also being evaluated for possible utility in boron neutron capture therapy (BNCT) (33). 

Probucol. Probucol is an antioxidant that is effective in lowering LDL cholesterol. Whereas probucol was known to lower cholesterol after relatively simple clinical trials (160), its mechanism of action as an antioxidant in the treatment of atherosclerosis is quite novel. Probucol has been shown to have the abiUty to produce regression of atherosclerotic lesions in animal models (161). Probucol therefore represents a novel class of pharmaceutical agent for the treatment of atherosclerosis. This effect occurs mechanistically, in part, by preventing oxidation of LDL, a necessary step in foam cell formation. This antioxidant activity has been shown in laboratory experiments and its activity in lowering LDL cholesterol in human studies is well documented (162). 

In animal models, renin inhibitors after iv adrninistration have been shown to be equally efficacious as compared to ACE inhibitors in lowering blood pressure, and to have similar effects on the cardiovascular and renal parameters. Some of the renin inhibitors tested are enalkiren (A-64662), CGP 38 560A, CP 71362, KRI-1230, U-71039, ES6864, and PD-134672. The stmctures of enalkiren and the formula for PD-134672 are shown in Figure 4. 

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. 

Studies of the pharmacokinetics of this deHvery system in two animal models have been reported in the Hterature. After iajection of these microspheres at three doses, leuproHde concentrations were sustained for over four weeks foUowing an initial burst (116). The results iadicated that linear pharmacokinetic profiles in absorption, distribution, metaboHsm, and excretion were achieved at doses of 3 to 15 mg/kg using the dmg loaded microspheres in once-a-month repeated injections. 

Erythrocyte Entrapment of Enzymes. Erythrocytes have been used as carriers for therapeutic enzymes in the treatment of inborn errors (249). Exogenous enzymes encapsulated in erythrocytes may be useful both for dehvery of a given enzyme to the site of its intended function and for the degradation of pathologically elevated, diffusible substances in the plasma. In the use of this approach, it is important to determine that the enzyme is completely internalized without adsorption to the erythrocyte membrane. Since exposed protein on the erythrocyte surface may ehcit an immune response following repeated sensitization with enzyme loaded erythrocytes, an immunologic assessment of each potential system in animal models is required prior to human trials (250). 

Modifications of the morphine skeleton have produced butorphanol [42408-82-2] (35) and drotebanol [3176-03-2] (36), which in animal models have demonstrated antitussive activity much greater than that of codeine (51,52). Butorphanol is also a potent analgetic of the narcotic antagonist type (51). Both compounds possess a unique 14-hydroxyl group. 

A number of 4-pyrazolylpyridinium salts (687) have been found to have hypoglycemic activity in several animal models (68JMC981). The possibility that the corresponding 4-pyrazolylpyridine I-oxides might also exhibit this type of activity was investigated without success (69JMC945). 

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. 

Pentylenetetrazol (188) is a drug with profound stimulatory activity on the central nervous system. As such, the agent was at one time used in shock therapy for treatment of mental disease. Although it has since been supplanted by safer methods, the agents still occupy an important role in various experimental animal models in pharmacology. Addition of hydrazine to the imino ether (186) obtained from caprolactam affords 187. Treat-... 

While the obvious value of in vivo animal models is clear, there also are instances—especially in cases of inflammatory arthritis, behavior, and tumor growth—where they have failed to be predictive of useful clinical activity in humans [51], For example, leukotriene (LTB4) antagonists showed activity in animal models of inflammatory arthritis yet failed to be useful in rheumatoid arthritis [52]. Similarly, dopamine D4 antagonists showed activity in animal behavior models previously predictive of dopamine D2 antagonists in schizophrenia. However, testing of dopamine D4 antagonists showed no efficacy in humans [53]. 

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