Animals lead compounds

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... 

The last step of the drug discovery process involves the testing of lead compounds to address issues such as efficacy, bioavailability, and safety. Testing may include in vitro assays but ultimately would require a suitable disease model and studies in animals. Many compounds may need to be designed and synthesized to identify the one compound with all the desired properties. Such a compound can be advanced to preclinical studies and eventually to the clinic. 

The International Agency for Research on Cancer (IARC 1987) concluded that the evidence for carcinogenicity of lead and inorganic lead compounds was inadequate in humans and sufficient in animals. IARC (1987) classified lead and inorganic lead compounds in IARC Group 2B, possible human carcinogen. The Department of Health and Human Services (DHHS) has determined that lead acetate and phosphate may reasonably be anticipated to be carcinogens based on sufficient evidence from animal studies, but inadequate evidence from human studies (NTP 1994). 

Drug Development Tests are performed on the lead compounds in test tubes (laboratory, in vitro) and on animals (in vivo) to check how they affect the biological systems. The tests, often called preclinical research activities. 

Traditionally, lead compounds have been discovered in one of two ways. The hrst is one of trial and error. This is the way many plant and animal products and minerals have been found to be effective in the treatment of some medical disorder. For example, no one knows when the hrst person learned that chewing on the bark of the willow tree [Salix alba) helped relieve pain and reduce fever, but willow bark has been used in many cultures for untold centuries for just that purpose. Today we know that the active ingredient in willow bark is a derivative of salicylic acid (CgH4(OH)COOH), which today is sold commercially as aspirin or one of its analogs. Drug researchers continue to rely heavily on the study of folk medicines—a science known as ethnopharmacology—for the discovery of new plant and animal products that may have medical applications in the modern world. Indeed, scientists have discovered that the medical... 

There are several reports that certain lead compounds, including lead acetate and lead phosphate, administered to animals in high doses are carcinogenic, primarily producing renal tumors.(Note Those salts demonstrating carcinogenicity in animals are soluble, whereas human beings are primarily exposed to insoluble metallic lead and lead oxide.)... 

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... 

In section 3.2.3, the utility of namrally occurring molecules, which are endogenous to the human body, was discussed as a source of bioactive lead compounds. An alternative is to exploit molecules that are endogenous to other life forms (animal or plant) but do not naturally occur within humans. Such molecules would be classed as exogenous from the perspective of drug design for humans. 

By far the most useful assay is the in vivo assay. Regrettably but understandably, this assay is the most labor-intensive and costly. In vivo assays give the highest quality information about the efficacy of a lead compound. In vivo models are accurate animal models of a human disease. Ideally, a candidate drug molecule should not be advanced in the development process unless it demonstrates good to excellent efficacy in an appropriate in vivo model. 

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