Pre-clinical trials

In infectious disease compounds such as ANA975 (phase I trials) and Resiquimod (phase II trails) have been developed to target Hepatitis C and genital herpes, respectively. DRS954 is a TLR-7 and 9 antagonist in pre-clinical trials for Systemic Lupus Erythematosus (SLE). 

Other photosensitisers in clinical or pre-clinical trials include zinc phthalocya-nine, aluminium sulphonated phthalocyanines, benzoporphyrins, benzochlorins and purpurin-lS-iV-alkylamides, all of which absorb strongly in the 675-700 nm region. An alternative approach to the photosensitisation in PDT involves the use of 5-aminolaevulinic acid (ALA). This compound itself is not a sensitiser but in human cells it is the key metabolic precursor in the biosynthesis of protoporphyrin IX, which can act as a photosensitiser. Normally the biosynthetic process would continue beyond protoporphyrin IX to the iron containing haem. However, by adding extra ALA and iron chelators, the ferrochelatase action is inhibited and the normal feedback mechanism by-passed resulting in a build up of protoporphyrin IX in the cell. The mechanism is illustrated in Figure 4.24. ... 

If an interesting activity is described, larger quantities (10-100 kg) of the plant material are collected, from which chemists purify and characterize the active principle. The active principle is known as a lead compound . Chemists will then usually attempt to modify the lead compound in order to render it more therapeutically useful (e.g. make it more potent, or perhaps increase its hydrophobicity so that it can pass through biological membranes). This is then subjected to further pre-clinical trials, and chemists determine whether an economically feasible method, allowing the drug s chemical synthesis, can be developed. 

Table 2.4. The range of major tests undertaken on a potential new drug during pre-clinical trials. The emphasis at this stage of the drug development process is upon assessing safety. Satisfactory pharmacological, and particularly toxicological, results must be obtained before any regulatory authority will permit commencement of human trials...

In addition, tests for mutagenicity and carcinogenicity are probably not required for most biopharmaceutical substances. The regulatory guidelines and industrial practices relating to biopharmaceutical pre-clinical trials thus remain in an evolutionary mode. 

Both pre-clinical and clinical trials are underpinned by a necessity to produce sufficient quantities of the prospective drug for its evaluation. Depending on the biopharmaceutical product, this could require from several hundred grams to over a kilo of active ingredient. Typical production protocols for biopharmaceutical products are outlined in detail in Chapter 3. It is important that a suitable production process be designed prior to commencement of pre-clinical trials, that the process be amenable to scale-up and, as far as is practicable, that it is optimized (Figure 2.9). The material used for pre-clinical and clinical trials should be produced using the same process by which it is intended to undertake final commercial-scale manufacture. 

Some cytokines have already gained approval for medical use. Many more are currently undergoing clinical or pre-clinical trials. Over the next few chapters, the biology and potential medical applications of these cytokines will be discussed in detail. The remainder of this chapter concerns itself with the prototypic cytokine family — the interferons. 

Pre-clinical trials (as well as phase I and II clinical trials) utilizing CNTF yielded promising results, but the neurotrophic factor then failed phase III clinical trials on the basis of insufficient efficacy. However, myotrophin (IGF-1, produced by Cephalon Inc.) has proved more successful. A 266 patient phase III clinical study found that IGF-1 administration to ALS sufferers resulted in reduced severity of symptoms, and slower disease progression, although this or no related product has yet been approved for medical use. The potential world market for an ALS therapeutic agent approaches 1 billion. 

In addition to artemisinin, other synthetic trioxanes and endoperoxides (fenozan BO-7 4 and arteflene 5 " ) have enjoyed some success arteflene reached Phase II pre-clinical trials. More recently, Vennerstrom and coworkers have reported on the outstanding antimalarial properties of several 1,2,4-trioxolanes, one of which, OZ 277 (6), has entered clinical trials in man . These exciting, easily prepared drugs will be discussed in detail later in this chapter. In order to determine the parasiticidal action of this class of antimalarial, many research groups have focused their efforts on artemisinin and its semi-synthetic derivatives (artemether, arteether and artesunate Ic, Id and le), and this is the point where our discussion will begin. 

There is a high level of expression of P-gp in the epithelial cells of the small intestine. Compounds that have been found to be substrates exhibit a wide range of chemical structures. However, they tend to be lipophilic and, for some, cationic, such as anthracyclines, vinca alkaloids, cyclosporin, etoposide, and celiprolol. It has been shown that taxol, an anti-microtubule anticancer drag, was not absorbed after oral administration in pre-clinical trials. This can probably be attributed to P-gp, since the flux from the... 

Phase I Clinical Trials Studies in this phase include initial introduction of an investigational drug into humans. These studies are closely monitored and are usually conducted in healthy volunteers. Phase I trials are conducted after the completion of extensive nonclinical or pre-clinical trials not involving humans. Phase I studies include the determination of clinical pharmacology, bioavailability, drug interactions and side effects associated with increasing doses of the drug. 

Angiogenesis for cardiovascular disease. Angiogenesis represents an excellent therapeutic target for the treatment of cardiovascular disease, namely the production of new collateral vessels to overcome the ischaemic insult. However, despite the large number of pre-clinical trials in animal models of cardiac ischaemia, no therapy designed to stimulate angiogenesis in underperfused tissue has yet become viable in man. 

Airway administration of liposome complexes was used for the treatment of pulmonary diseases including cystic fibrosis. Cationic liposome/DNA complex showed no adverse effect towards airway epithelial integrity (190) therefore, the cationic lipid-based delivery system proved to be appropriate for use in human trials for cystic fibrosis (CF). A series of pre-clinical trials were done in CF patients with intranasal instillation to evaluate the risk factors associated with the treatment (191-193). Because there was no apparent toxicity associated with lipoplexes as was seen from these trials, progress had been made in delivering the complexes to the entire lung by aerosol in CF patients (192,194,195). By nebulization, the DNA-liposome complex was delivered into the airways of mutant mice to obtain human cystic fibrosis transmem-... 

In view of the large number of bioactive oxadiazoles, this section is limited to a discussion of two molecules that are widely in use, either in clinical and pre-clinical trials or in clinical use. These are 5-(4-phenyl-5-(trifluoromethyl)-2-thienyl)-3-(3-(trifluoromethyl)phenyl)-l,2,4-oxadiazole (SEW2871) and... 

Saudek, C. D., Fishell, R. E., and Swindle, M. M., 1990, The programmable implantable medication systems (PIMS) Design features and pre-clinical trials. Norm. Metab. Res. 22 201-206. 

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