Toxicity studies animal models

Today, the overwhelming majority of animal ocular toxicity studies are performed in the rabbit model, and the study of SM is no exception. New Zealand white rabbits have been used extensively with both liquid SM and vapor exposures (Amir et al, 2000, 2003 Bossone et al, 2002 Vidan et al, 2002 Babin et al, 2004). Other animal models have been employed, including those using bovine and rat corneas. Many articles appear on these in the Bulletin of Johns Hopkins Hospital, Vol. 82, 1948. Individual articles from this volume are cited in the mechanism of action section. 

The use of in vitro systems such as cell cultures, tissue slices, and cell lines has become of major importance for several reasons. First of all, the common practice of the use of experimental animal models for studying toxicity of chemicals meets serious and growing criticism for ethical and economic reasons. Toxicity studies aiming at performing a hazard or a risk assessment inevitably will include adverse effects and thus discomfort for the animals involved. Moreover, the cost of running an animal facility and performing toxicity studies is an increasingly important limitation. 

Despite first results demonstrating that polyplexes can mediate gene therapeutic effects in animal models, these studies also demonstrated clear limitations. The systemic targeting efficiencies are by far not perfect polyplex formulations often have significant toxic properties, and low in vivo gene transfer activity. 

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... 

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. 

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. 

The development of nucleic acid-based therapeutics is not as straightforward as researchers had initially anticipated. Stability, toxicity, specificity, and delivery of the compounds continue to be challenging issues that need further optimization. In recent years, researchers have come up with intricate solutions that have greatly improved the efficacy of potential antisense, ribozyme, as well as RNAi-based therapeutics. Clinical trials for all these types of nucleic acid-based therapeutics are underway. So far, data from several trials and studies in animal models look promising, in particular, the therapies that trigger the RNAi pathway. However, history has shown that compounds that do well in phase I or phase II clinical trials may still fail in phase III. A striking example is the nonspecific suppression of angiogenesis by siRNA via toII-Iike receptor 3 (Kleinman et al. 2008). It will become clear in the near future which compounds will make it as a new class of antiviral therapeutics. 

For a number of liposome preparations—both injectables and locally administered products—the therapeutic advantages over existing formulations have been proven in animal models clinical trials with liposome preparations are now under way. So far, clinical studies showed no significant toxic effects which could be ascribed to the lipid components of the liposomes used. 

Studies in animals have provided abundant support for the plausibility of the neurodevelopmental effects of lead that have been associated with lead exposure in children, and researchers have begun to identify potential mechanisms (i.e., Cory-Slechta 1995a). However, mechanistic connections between behavioral deficits, or changes observed in animals, and those that have been associated with lead exposure in children have not been completely elucidated. Understanding of such connections would be valuable for developing better and more relevant animal models of lead toxicity. 

During the 1970 s and early 1980 s a large number of test methods were developed to measure the toxic potency of the smoke produced from burning materials. The ones most widely used are in refs. 29-32. These tests differ in several respects the conditions under which the material is burnt, the characteristics of the air flow (i.e. static or dynamic), the type of method used to evaluate smoke toxicity (i.e. analytical or bioassay), the animal model used for bioassay tests, and the end point determined. As a consequence of all these differences the tests result in a tremendous variation of ranking for the smoke of various materials. A case in point was made in a study of the toxic potency of 14 materials by two methods [33]. It showed (Table I) that the material ranked most toxic by one of the protocols used was ranked least toxic by the other protocol Although neither of these protocols is in common use in the late 1980 s, it illustrates some of the shortcomings associated with small scale toxic potency of smoke tests. 

Detailed studies have also been made on the toxicity of HC1, an irritant gas often present in fires. It does not cause baboon or rat incapacitation up to very high exposure doses which are sufficient (or very close) to cause eventual death [12]. Furthermore, a recent study has shown that the effects of irritants are heavily dependent on the animal model used [13]. 

---