Supporting Evidence from Animal Models

Of relevance to clinical studies of eosinophil esophagatis, which are discussed in the next section, both CCR3 and CCLll appear to be important in the constitutive homing of mouse eosinophils to the gut and the subsequent homeostasis of this organ. Mice deficient in either ligand or receptor exhibit reduced numbers of eosinophils in the gut [36, 40]. This is in contrast to CCL24-deficient mice, which have been reported to have comparable numbers of eosinophils within in the gastrointestinal tract to their wildtype littermates [44]. 

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During the last 10 years it has been attempted to develop in vitro methods as alternative methods in the study of effects where animal models have previously been necessary. Such effects include skin and eye irritation and specific organ damage. Validation programs have been launched, and some of the above-mentioned methods have been sufficiently validated for use in regulatory risk assessment of chemical substances and may now for certain purposes be used as stand-alone evidence. Results from nonvahdated methods can in some cases be used as supportive evidence to human and animal data. 

Clearly, a single neurotransmitter theory does not suffice to explain all known evidence. As a result, models that include two or more systems have been developed to encompass their modulatory interactions. One of the most cogent is the permissive hypothesis, which proposes that a decreased function in central serotonin transmission sets the stage for either a depressive or manic phase ( 60). This circumstance itself is not sufficient to produce the mood disturbance, however, with superimposed aberrations in NE function required to determine the phase of an affective episode (i.e., decreased 5-HT and decreased NE subserves depression decreased 5-HT and increased NE subserves mania). Data from animal studies to support this theory include the following ... 

Another source of evidence supporting the neurotrophic hypothesis of depression comes from studies of the direct effects of BDNF on emotional regulation. Direct infusion of BDNF into the midbrain, hippocampus, and lateral ventricles of rodents has an antidepressant-like effect in animal models. Moreover, all known classes of antidepressants are associated with an increase in BDNF levels in animal models with chronic (but not acute) administration. This increase in BDNF levels is consistently associated with increased neurogenesis in the hippocampus in these animal models. Other interventions thought to be effective in the treatment of major depression, including electroconvulsive therapy, also appear to robustly stimulate BDNF levels and hippocampus neurogenesis in animal models. 

Although there are preliminary data supporting the antitumoral activity of quercetin, the most common flavonoid, in humans in the course of a Phase I clinical trial [189], direct evidence of the anticancer effect of flavonoids is derived almost exclusively from studies performed in animal models as well as studies performed on cultured cell lines, Fig. (2). Most animal studies on gastrointestinal cancer have focused on colon cancer using the azoxymethane (AOM) model in rats or mice [190-197]. There are also available reports on models of cancer of the stomach (induced by benzo[a]pyrene [198] or N-methyl-N-nitro-N-nitro so guanidine [199]), oesophagus (N-methyl-N-amylnitrosamine [200]), and the tongue/oral cavity (methyl-(acetoxymethyl)-nitrosamine [198], 7,12-dimethyl-... 

The demonstration of a renal protective effect of salt loading on AmB-induced nephrotoxicity in animal models has provided a rational basis to evaluate this simple intervention in patients. Clinical evidence supporting the ability of sodium loading to attenuate AmB-induced nephrotoxicity is derived from three sources case reports, retrospective studies and prospective studies. 

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