Main study animals

Blood Collection. In rodent studies, large numbers of satellite animals (often close to the number used in the main study phase) are usually needed for pharmacokinetic blood sampling, whereas with most nonrodent species, blood samples can be collected from the main study animals without compromising their health status. 

Groups of animals included in the design and conduct of a toxicity study treated and housed under conditions identical to those of the main study animals, but used primarily for toxicokinetics. 

Week 4—full necropsy in all main study animals... 

Examples of suitable methods for application to main study animals in repeat-dose toxicity studies are given in Table 3. 

This parallel determination consists of measuring plasma levels of the administered agent and its major metabolites either in animals that are part of the main study or in a separate set of animals (in parallel with the main study) that are dosed and evaluated to determine just these endpoints. The purpose of these determinations is both to allow a better interpretation of the findings of the study and to encourage the... 

After one or more lead compounds have been selected for further development, more preclinical investigations are needed before it is possible to start studies in humans. The main studies during this phase are toxicity studies in animals. It is important to note that the goal of these studies is not so much to find safe compounds and rejecf unsafe ones, but rather to learn under which conditions a potentially beneficial compound can be harmful, and to find out how it can be used safely in humans, if at all. Details on the type, duration and extent of toxicity studies needed can be found in various regulatory guidelines issued by ICH, FDA and EMEA and are easily accessible via the internet sites of these bodies. Although there are still differences in the requirements... 

For most substances, however, a preliminary study is advisable to avoid the use of inappropriate (i.e., either too high or too low) dose levels. The design would be as described below for a main study but with typically five or six animals per dose level and fetal evaluation restricted to an external examination and weight. Sexing of fetuses is not needed, although many laboratories will sex fetuses as routine. 

A dose-range finding study in pregnant animals is recommended to aid in dose selection for the main study. Typically, six mated animals per group are used for dose-range finding investigations. 

Hematology, coagulation, and clinical chemistry at termination Pilot study (week 4) or main study (week 26)—full necropsy in all surviving animals See Appendix B See Appendix D... 

There are several approaches to the study of metabolism. First, isolation of steroid metabolites from various steroid-forming tissues (testes, ovaries, placentae, adrenal glands) makes it possible to evaluate the usefulness of a particular endocrine gland in the production of steroids. Secondly, in vitro experiments are conducted by incubation with tissue preparations followed by isolation of the metabolities of steroids. Thirdly, in vivo experiments are carried out by isolation of steroids from biological fluids, mainly from animal and human blood and urine. This last method includes evaluation of the rates of secretion and metabolism of... 

Glycofurol is used as a solvent in parenteral products for intravenous or intramuscular injection in concentrations up to 50% v/v. It has also been investigated, mainly in animal studies, for use as a penetration enhancer and solvent in topicah and intranasal formulations.Glycofurol has also been used at 20% v/v concentration in a rectal formulation. ... 

Groups of female animals are exposed for at least 4 h to graduated concentrations of the test substance, one concentration being used per group. A sighting study is included in the proposed Guideline 433 in order to choose an appropriate starting concentration for a main study and to minimize the number of animals used (see Table 2). Prespecified fixed... 

The test substance is administered to single animals in a sequential manner following the flowcharts in Table 2 for a period of at least 4 h. The sighting study is completed when a decision on the starting concentration for the main study can be made, based on... 

More subjects are necessary for sensitization studies in humans than in animal studies because of the larger variation in immune responses and the need to use lower concentrations of the test material in human exposure. Usually, the sensitization of a material is assessed in a preliminary study with 20-25 subjects, and then expanded to a main study with up to 200 subjects. The sample size of test subjects in the main study must be large enough so that the results are valid for the population for which the preparation is intended. It may be of interest to use a particular component at a level 10 times the concentration in the finished product for induction. For the challenge dose, a nonirritating concentration should be used. In addition, the test conditions should reproduce the actual use of the final product, that is, the materials tested should contain all of the ingredients. In general, sensitization procedures are similar to the procedures described above ... 

More than 15 additional trace elements are considered by some investigators to have a potentially important role in human medicine. A review by Nielsen considers these in detail and discusses emerging concepts of essentiality. For some such as lead, cadmium, arsenic, aluminum, and nickel, the clinical laboratory will primarily consider them as toxic elements (see Chapter 35). Others, such as lithium and fluoride, are classified as pharmacologically beneficial and monitoring of dosage may be required. Some elements can be considered nutritionally beneficial and are reported to produce restorative health effects at lower dosages. Evidence comes mainly from animal studies when dietary depletion of the element is combined with other metabohc, hormonal, or physiological stressors. ... 

Several pharmacogenomic studies, mainly in animal models, have characterized the molecular mechanisms contributing to the lipidlowering effect of fibrates. Hepatic transcription profiling of clofibrate or gemfibrozil-treated WT rats demonstrated increased expression of many genes involved in beta-oxidation, as well as FFA and cholesterol synthesis, including fatty acyl-Coenzyme A oxidase [45, 191, 192], acetyl-Coenzyme A acetyltransferase... 

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