Preclinical animal models

Compound Preclinical Animal Model Preclinical Results Reference Clinical Indication Clinical Result Reference... 

Gambogic acid derivatives Activators of caspase-3 Induce apoptosis by activating caspase-3 in syngeneic prostate animal model Preclinical 101... 

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. 

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...

Much of the preclinical data generated with regard to these vaccines entailed the use of one of two animal model systems simian immunodeficiency virus infection of macaque monkeys and HIV infection of chimpanzees. Most of the positive results observed in such systems have been in association with the chimp-HI V model. However, no such system can replace actual testing in humans. 

During preclinical assessment of an enantiometric mixture, it may be important to determine to which of these three classes it belongs. The pharmacological and toxicological properties of the individual isomers should be characterized. The pharmacokinetic profile of each isomer should be characterized in animal models with regard to disposition and interconversion. It is not at all unusual for each enantiomer to have a completely different pharmacokinetic behavior. 

The appropriate animal model is also important when performing follow-up testing or additional mechanistic tests to further investigate findings observed as part of the routine preclinical safety tests. When possible, these studies should employ the same animals or animal model in which the change was initially observed for several reasons, as outlined by Bloom et al. (1987), including ... 

An autoimmune response is rarely detected during preclinical drug development because of the lack of good predictive animal models for the human immune system. Owing to their low incidence and idiosyncratic nature, autoimmune diseases quite often appear as a serious issue only after product launch [2,22]. 

As the drug discovery process increased in intensity in the mid- to late 20th century, primarily as a result of the major screening and chemical synthetic efforts in the pharmaceutical industry in industrialized countries worldwide, but also as a result of the biotechnology revolution, the need for increased sophistication and efficacy in (1) how to discover new drugs, (2) how to reproducibly prepare bulk chemicals, (3) how to determine the activity and safety of new drug candidates in preclinical animal models prior to their... 

Another creative trial design was performed for the pivotal trial for approval of the monoclonal antibody cetuzimab (Erbitux). The clinical trial was based on the preclinical evidence. Erbitux was synergistic in animal model systems. 

Undertake preclinical studies (Preclinical Development) this involves many different important steps, of which the most critical is safety evaluation of the efficacious drug candidate in animal models. Before introduction of any new drug in humans it must be shown to be safe in animals. 

Antithrombotic prophylactic in Europe, for interstitial cystitis in the United States Animal models to treat osteoarthritis, preclinical studies as anticancer agent, inhibits metastasis and angiogenesis 1, 32-37... 

Hydroxyurea is an oral agent that inhibits ribonucleotide diphosphate reductase and interferes with the synthesis of DNA, specifically the S phase of the cell cycle. Sinclair et al. have demonstrated in preclinical animal models that hydroxyurea may inhibit cells from leaving the Gj radiosensitive phase and entering the radioresistant S phase (9). Early studies have demonstrated little or no efficacy associated with the use of single-agent hydroxyurea (10). It has received FDA approval in the use of head and neck cancer when administered concomitantly with radiotherapy based upon promising results from earlier studies (11). 

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