Animals preclinics

Studies on tissues and whole animal (preclinical studies)... 

Preclinical pharmacokinetic (PK) studies provide information useful for supporting efficacy and safety evaluation studies in animals, preclinical and clinical study designs, dosing regimen development, and interpretation of toxicity data. These studies provide PK data that may be useful in dose escalation in healthy volunteers and patients. Toxicokinetics is a major component of toxicology studies. It enables the investigation of the relationship between drug dose and measured concentration, primarily the establishment of the dose proportionahty and hnearity or nonlinearity in pharmacokinetics. 

It has become accepted that the main pharmaceutical areas where metabonomics is impacting include validation of animal models of disease, including genetically modified animals preclinical evaluation of drug safety studies allowing ranking of candidate compounds assessment of safety in humans in clinical trials after product launch, quantitation, or ranking of the beneficial effects of pharmaceuticals. 

As mentioned earlier, biotextile retrieval studies can be carried out in animals (preclinical trials) as well as in human subjects (clinical trials). Retrieval studies using animal models are usually planned studies where the device to be tested is implanted in the animal for a fixed duration after which it is harvested and studied for the desired characteristics. 

The preclinical trials are performed in in vitro and animal studies to assess the biological activity of the new compound. In phase 1 of the clinical trials the safety of a new drug is examined and the dosage is determined by administering the compound to about 20 to 100 healthy volunteers. The focus in phase II is directed onto the issues of safety, evaluation of efficacy, and investigation of side effects in 100 to 300 patient volimteers. More than 1000 patient volunteers are treated with the new drug in phase 111 to prove its efficacy and safety over long-term use. 

Japan. In Japan, registration of dmgs for aquatic species requires the same data as those required for dmgs on other animals. The Ministry of Agriculture, Eorests, and Eisheries and the Ministry of Welfare control the use of chemicals in aquaculture in Japan (17). The preclinical data requirements include product chemistry, toxicity (acute, subacute, special) using rats and mice, safety to target animals, and metaboHsm. The requirements for clinical data include avadabiHty and residues. As of July 1990, more chemicals were registered for aquacultural use in Japan than in any other country (Table 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 glutamate antagonists have been or are in the process of being evaluated both preclinically and clinically as neuroprotective agents. For example, MK-801, an NMDA antagonist, reduces the detrimental effects of excess glutamate (as well as other insults to neurons) in a variety of animal models. Unfortunately the... 

Toxicology studies must be performed in at least two animal species. If the toxicity profile of the compound is acceptable, then it joins the hit or lead list of compounds to proceed. The metabolism of the compound must be understood and pharmacokinetic studies must be performed in small and large animals. Efficacy studies must be performed in relevant animal models, especially in chimpanzees when more than one candidate is identified and a choice has to be made before proceeding to studies in humans. The ultimate preclinical steps include various studies testing drug combinations in vitro and in vivo, selection of resistant viruses, viral fitness, pyrophosphorolysis, and others. 

Figure 11.1 shows different kinds of decisions important to preclinical research. Clearly, IT and simulation support are completely accepted at the lowest level of this diagram as ways of predicting molecular, cellular, organ, animal, or human properties, interactions, and responses (covered elsewhere in this volume). Therefore, scientists moving into leadership roles will very often be familiar with the strengths and weaknesses of such methods. 

All preclinical animal models of anxiety involve exposing animals (usually rats or mice) to environmental stimuli that disrupt their normal pattern of behaviour (Table 19.2). Obviously, it can never be confirmed that animals are actually experiencing the equivalent of human anxiety and so the validity of all preclinical models rests largely on confirming that the change in behaviour is prevented by drugs that have established anti-anxiety effects in humans. 

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

MASAO s, SAiTO H and TAKEO T (1994) Irritation test of skin and eye mucosa on oolong tea water-soluhle extracts , Preclinical Rep of the Central Inst for Exp Animals, 19 (3), 199-203. 

True zwitterionic compounds are rare among drugs. The oral absorption of truly zwitterionic compounds is poor unless the compound is a substrate for an absorptive biological transporter as in an a-amino acid which is a substrate for the PepTl nutrient transporter. The aqueous solubility of a true zwitterionic compound will be at a minimum at the isoelectric point which unfortunately for many compounds happens close to the neutral pH at which oral absorphon occurs. Species extrapolation predicting oral absorphon and pk/pD from preclinical animal tests to man are difficult for zwitterions. 

To determine whether human testing for a new drug or new drug product is reasonable, it is first necessary to conduct preclinical studies and to submit the IND. The necessary information needed to prepare the IND is outlined in Table 1. The IND is to contain information on appropriate prior animal studies for safety evaluation, any available clinical data, adequate drug identification and manufacturing instructions, and a detailed outline of the proposed clinical study, routs of administration, approximate number of patients to be used, and an estimate of the length of treatment and an environmental impact statement. 

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