Animal trials

A pharmaceutical company must be profitable to stay in business, and protecting its work through patents is part of the process. When a compound is protected by a patent, the patent holder may legally exclude others from using that compound for the lifetime of the patent. Patents on compounds are generally filed early in the lead optimization stage. 

Before a drug may be tested on humans, it must first be tested on animals. Tests on humans are called clinical trials, and animal trials are often referred to as preclinical trials. Preclinical trials differ from the animal tests mentioned earlier in this chapter. The previously discussed animal tests help the drug discovery team determine and optimize the pharmacodynamic and pharmacokinetic behavior of a hit or lead. Preclinical trials, in contrast, are standardized, industrywide tests. The preclinical tests have technical names such as Segment II Reproductive Study in Rabbits or 6-Month Toxicity Study in Rats. The specific names suggest the exact nature of each study. Each trial seeks to answer predefined safety questions concerning a drug candidate. Preclinical trials do not address the therapeutic effectiveness of the drug candidate in any way. Preclinical trials examine exclusively safety issues. 

Animal trials continue to be performed after clinical trials in humans have begun. The later studies focus on long-term (chronic) side effects that require extended drug exposure to appear. The long-term animal trials can last up to two years and often overlap with phase I and II trials in humans. Reproductive studies on pregnant rats and rabbits are normally not complete when the drug is first tested on humans. For this reason, subjects involved in early clinical trials are almost always male. 

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Several pure hemoglobin solutions were later produced on a large scale for experimental use. A procedure was described for crystallization of hemoglobin and the product was evaluated in a series of animal trials (38—41). A 6 g/dL hemoglobin solution that had a P q of about 2.4—2.7 kPa (18—20... 

The US regulates animal trials mainly through the requirement to inform the authorities before non-approved veterinary pharmaceuticals are shipped to trial sites. Depending on whether it is classified as a drug or a biologic, information must be submitted to either the FDA Center for Veterinary Medicines (CVM) or the United States Department of Agriculture (USDA) Center for Veterinary Biologies (CVB). 

A number of additional methods have been proposed to target CH4 emissions such as the use of bacteriophages and bacteriocins (McAllister and Newbold, 2008), defaunation, and reductive acetogenesis (Martin et ah, 2010 McAllister and Newbold, 2008). Additional research is needed as well as animal trials for potential use on dairy farms. 

In summary, available scientific evidence on the effects of tamoxifen on human bone seems to parallel data collected in animal trials. Tamoxifen, acting as a partial estrogen agonist, seems to have beneficial effects on the preservation of bone mass in postmenopausal women, while in premenopausal women it might act as an estrogen antagonist. An alternative explanation could be that... 

Interest in dendritic polymers (dendrimers) has grown steadily over the past decade due to use of these molecules in numerous industrial and biomedical applications. One particular class of dendrimers, Starburst polyamidoamine (PAMAM) polymers, a new class of nanoscopic, spherical polymers that appears safe and nonimmunogenic for potential use in a variety of therapeutic applications for human diseases. This chapter will focus on investigations into PAMAM dendrimers for in vitro and in vivo nonviral gene delivery as these studies have progressed from initial discoveries to recent animal trials. In addition, we will review other applications of dendrimers where the polymers are surface modified. This allows the opportunity to target-deliver therapeutics or act as competitive inhibitors of viral or toxin attachment to cells. 

Table 5.8. Some potential clinical applications of IL-12. While animal trials and in vitro studies have yielded encouraging results, clinical trials in humans must be undertaken to assess the real therapeutic potential of this cytokine...

The most advanced technology is the extracorporeal hollow fiber reactor. It is currently in Phase III trial and achieved a good Phase II record to support it. Other techniques including a polyurethane system devised in Japan and encapsulated hepatocytes from UCLA are or were in large animal trials. Whether a device is extracorporeal or is intended for implantation, clinical significance requires a suitable scaffold to support a sufficiently large colony of hepatic cells. For both extracorporeal and implant use, the physical structure of the scaffold must meet certain requirements of strength, void volume, biocompatibility, and other parameters. 

While these devices represent the leading edge in extracorporeal liver-assist devices, two other projects currently in animal trials deserve some attention as they represent other scaffold types. 

Drugs are typically tested in animals initially, often using several different species. Initial information on the basic pharmacokinetic and pharmacodynamic properties of the compound is obtained. Information on dosage and toxicity is also obtained from these animal trials. 

If the results from animal trials are favorable, the drug sponsor files an investigational new drug (IND) application with the FDA. If approved as an IND, the sponsor may begin testing the drug in humans. Human, or clinical testing, is divided into three primary phases. 

Therapeutic index (ABBR TI) A ratio used to represent the relative safety of a particular drug the larger the therapeutic index, the safer the drug. It is calculated as the median toxic dose divided by the median effective dose. (In animal trials, the median lethal dose is often substituted for the median toxic dose.)... 

Once a hit is elevated to the status of a lead compound, the activity of the lead must be increased. This is accomplished by making structural modifications to the lead compound. The link between modification of a lead s structure and changes in activity is called a structure-activity relationship (SAR). As it becomes better understood, the SAR of a lead guides the medicinal chemistry team as it seeks the best methods of increasing the lead s activity. Once the lead has been adequately optimized and shows desirable properties, the lead then graduates to candidate status. Standardized safety testing in animals, called animal trials, is the next step. A more detailed discussion of the lead optimization process may be found in Chapters 11 and 12. 

Toward the end of a phase II trial, the sponsoring company often meets with the FDA to present clinical and late animal data collected. Plans for moving forward into phase III trials are also covered. Depending on the data, the FDA may recommend specific clinical tests or additional animal trials to clarify any questions. 

MPPP is a street drug and not approved by the FDA. If MPPP were to be submitted for regulatory approval, the Parkinson s-related issues of MPPP would likely have been discovered early in animal trials. Regardless, the story of MPPP demonstrates the complexity of anticipating the possible metabolic pathways of drugs. 

Animal Efficacy Rule—The animal efficacy rule permits the FDA to rely on animal evidence when (1) the agent s mechanism of toxicity is well understood (2) the end points in the animal trials are clearly related to benefit in humans (3) the drug s effect is demonstrated in a species expected to react similarly to humans and (4) data allow selection of an effective human dose. 

Although it is essential to test promising compounds in mice and other animal models prior to human trials, it is economically, ethically and often scientifically preferable to use cell-based and in vitro approaches to eliminate inactive compounds before commencing animal trials. Clearly, animal models are not an appropriate screen for combinatorial libraries of platinum complexes they should be used to study further the promising leads identified by high-throughput methods. 

Perfused organs Phase I and II present, whole metabolic profile observed, best correlation to in vivo expensive, ex vivo animal trial, complex methodology, high technical effort, batch variability, more complicated than enzyme-only system, quality control, limited use for multiple compounds... 

For its part, the TB Alliance interviewed outside research organizations that Big Pharma might hire to conduct the early-stage animal trials. Its data on human trials came partly from the experience of staffers who used to work in the industry and partly from government institutions that run trials in the developing world. But the group s 76 million-... 

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