Pre-clinical studies

Safety (S) relating to in-vitro and in-vivo pre-clinical studies. 

Clinical trials must be conducted to establish safety in each target animal species which, in the majority of cases, will include food-producing species. Although the same types of animal may be involved in both pre-clinical and clinical trials, dear distinctions can be drawn between each type of study. Pre-clinical studies are only conducted in animals that are kept for the purposes of laboratory research, and that are usually maintained in a very controlled environment. Clinical trials, on the other hand, are conducted in animals that are representative of the normal conditions (field conditions) and purposes for which they are maintained. 

Kopf-Maier, P., Kopf H. Transition and Main-Group Metal Cyclopentadienyl Complexes Pre-clinical Studies on a Series of Antitumor Agents of Different Structural Type. Vol. 70, pp. 103-185. 

Although prediction of ADME/PK in man may be the primary purpose for the pre-clinical studies, it is also important that potential new drugs have acceptable properties in toxicology species. Without these it can be very difficult to generate adequate safety margins to allow studies in man to start. It is also likely that the development safety assessment program will be difficult and hence slow. 

Development and validation of PD assays to confirm drug effect on molecular target in pre-clinical studies and clinical trials conducted under an exploratory INDA, or in a traditional Phase I/II setting... 

Calu-3 cells have shown the ability to perform fatty acid esterification of budes-onide [132], In pre-clinical studies, this esterification results in a prolonged local tissue binding and efficacy, which is not found when the esterification is inhibited [133]. The precise mechanism remains undefined in that the identity of specific enzyme(s) responsible for this metabolic reaction is unclear [134], Assessment of the potential toxicity and metabolism of pharmaceuticals and other xenobiotics using in vitro respiratory models is still at its infancy. The development of robust in vitro human models (i.e., cell lines from human pulmonary origin) has the potential to contribute significantly to better understanding the role of biotransformation enzymes in the bioactivation/detoxication processes in the lung. 

My own practice was to refer to agents such as BZ or other related glycolates as similar to belladonna or atropine - belladonnoids if you will. Since the terms atropine and belladonna were also unfamiliar to many volunteers, I said that the effects would vary from person to person, but generally, they would include dryness of the mouth, sleepiness, difficulty in solving problems, and altered perceptions. I assured them that both the nursing staff and I would monitor them closely. I explained that extensive pre-clinical studies in several animal species had revealed no permanent ill effects. I told them we believed the drug to be safe, and would discuss the effects in detail after the test was over. Very few volunteers chose to withdraw after this orientation. 

The limitation of pre-clinical studies on the development of novel psychotropic drugs... 

A problem with toxicity produced by an extension of the pharmacology of a compound, is that the conventional use of no-effect doses based on pre-clinical animal studies may not apply. Moreover pre-clinical studies may be complicated by the often understated ranges of response seen across species due to species differences in the receptors, enzymes and ion channels that comprise drug targets. Table 8.1 lists some of these known variations and the consequences range from an exaggerated response, to an absence of a response. 

Peripheral neuropathy (degeneration of peripheral sensory and/or motor neurons) represents another target for neurotrophic intervention. It often occurs as a complication of diabetes or in cancer patients receiving chemotherapy. In severe cases, amputation of limbs affected by neuronal loss is warranted. Pre-clinical studies have clearly shown that sensory and sympathetic neurons depleted in peripheral neuropathy respond to NGF. Indeed, NGF, along with IGF-1, can prevent the occurrence of drug-induced peripheral neuropathy in animals. Human clinical trials continue. 

The use of a combination of neurotrophic factors in the treatment of neurodegenerative disease may well prove an avenue worthy of consideration. For example, pre-clinical studies reveal that administration of a combination of CNTF and BDNF to Wobbler mice (an animal model of motor neuron disease), prevented progression of motor neuron dysfuction, whereas administration of either factor on its own only slowed progression of the disease. 

Chinese hamster ovary (CHO) cells and baby hamster kidney (BHK) cell lines have been most commonly used, in addition to other cell lines, such as various mouse carcinoma cell lines. The recombinant factor VIII product generally contains only VIILC (i.e. is devoid of vWF). However, both clinical and pre-clinical studies have shown that administration of this product to patients suffering from haemophilia A is equally as effective as administering blood-derived factor VIII complex. The recombinant VIILC product appears to bind plasma vWF with equal affinity to native VIILC, upon its injection into the patient s circulatory system. Animal and human pharmacokinetic data reveal no significant difference between the properties of recombinant and native products. 

Determination of brinzolamide and its 3 principal metabolites (the N-desethyl, A -desmethoxypropyl and O-desmethyl analogs) in whole blood and plasma from clinical and pre-clinical studies was performed using high performance liquid chromatography (HPLC) with UV detection. After addition of a known amount of internal standard (AL-5138, the 4-methoxybutyl analog of brinzolamide), the sample was acidified with 50 mM sodium phosphate buffer, pH 3.0 and extracted with ethyl acetate. 

---