Preliminary animal studies

During 1962-1972, 123 irritant chemicals were tested. Further details on the chemicals are available from the NRC repository of Edgewood data. The substances were classified as irritants on the basis of the preliminary animal studies. Except where noted below, exposures were for 1 min or less in an aerosol chamber each subject was exposed to a chemical only once. 

Preliminary animal studies have demonstrated the possibility that scullcap may improve the tolerability and efficacy of some chemotherapeutic agents. Scutellaria baicalensis Georgi was found to decrease tumor cell viability and ameliorate myelosuppression when used with cyclophosphamide and 5-fluorouracil in both mice and rats (Razina et al., 1987). 

Collins, R.L., Christiansen, D., Zazanis, G.A., and Silver, EH. 1991. Use of collagen film as a dural substitute Preliminary animal studies. J. Biomed. Mater. Res. 25 267-276. 

In response to the rapid adoption of Embospheres for UFE, many companies have introduced the spherical PVA (sPVA) [16, 17]. Preliminary animal studies demonstrate that sPVA is safe, and the FDA has approved its clinical usage in UFE patients. An animal study has recently demonstrated a different... 

In preliminary animal studies that sought to treat surgically induced carotid side-wall aneurysms in a porcine model, polyurethane SMP scaffolds proved to be highly advantageous materials to create long-term, stable occlusion without recanalization (Rodriguez et al., 2014). The histology performed in this study 90 days postimplantation... 

Extended biological studies of this candidate require a substantial amount of the agent. At this stage the scale-up laboratory takes over and an initial quantity of several grams is made that is used for preliminary animal studies by biologists, pharmacologists, and pharmacists. 

GCNU (3-(TETRAACETAR GLUCOPYRANNUA-2-YL)-l-(2-CHLOROETHYL)-l-NITROSOUREA) This is an aminoglycose chloroethyl nitrosourea, structurally related to the non-myelosuppressive but diabetogenic antitumour agent streptozotocin. Preliminary animal studies are reported (75). 

In-vitro models can provide preliminary insights into some pharmacodynamic aspects. For example, cultured Caco 2 cell lines (derived from a human colorectal carcinoma) may be used to simulate intestinal absorption behaviour, while cultured hepatic cell lines are available for metabolic studies. However, a comprehensive understanding of the pharmacokinetic effects vfill require the use of in-vivo animal studies, where the drug levels in various tissues can be measured after different dosages and time intervals. Radioactively labelled drugs (carbon-14) may be used to facilitate detection. Animal model studies of human biopharmaceutical products may be compromised by immune responses that would not be expected when actually treating human subjects. 

Compound 34 (BCZ-1812, RWJ-270201, peramivir) showed selective inhibition of influenza virus sialidases over bacterial and mammalian sialidases (Babu et al. 2000 Bantia et al. 2001 Sidwell and Smee 2002). Successful inhibition of influenza virus infectivity in vitro (Smee et al. 2001) and upon oral administration in vivo [mice (Bantia et al. 2001) and ferrets, reviewed in Sidwell and Smee 2002] led to human clinical trials of orally administered peramivir (Barroso et al. 2005). While orally administrated peramivir successfully completed animal studies and Phase I and Phase II clinical trials, in which the compound was showing neither major side effects nor toxicity (Sidwell and Smee 2002), preliminary results of the Phase III trials (June 2002) demonstrated no statistically significant difference in the primary efficacy endpoint, possibly due to low bioavailability (Barroso et al. 2005). 

Depletion of the antioxidant capacity of LDL is an early event in the oxidation process. The main antioxidant in LDL is a-tocopherol, with smaller quantities of 0-carotene and 7-tocopherol also present. The importance of antioxidants in inhibiting the oxidative modification of LDL is su ested by human and animal studies on the prevention of atherosclerosis. Preliminary reports... 

Approved clinical investigations follow three phases. In Phase 1, about 100 to 200 people are exposed to the drug to determine the tolerance, absorption, excretion, half-life, and other pharmacologic reactions the preferred route of administration and the safe dosage. In Phase 2, initial trials are conducted on 500 to 1000 patients to assess the treatment or prevention of the specific disease. Additional animal studies to indicate safety may be conducted concurrently. If these preliminary studies demonstrate sufficient promise. Phase 3 clinical trials are performed with several thousand patients. 

In a preliminary in vivo animal study, DCE gel, without pharmaceutical active, reduced pregnancy rates to the same degree as a leading commercial product containing 4% N9. The addition of 2% N9 to DCE gel induced a significantly lower embryo implantation rate than the commercial product containing 4% N9. 

Preliminary in vitro and animal studies of the effects of silymarin and silybinin have been carried out with several cancer cell lines. In murine models of skin cancer, silybinin and silymarin were said to reduce tumor initiation and promotion. Induction of apoptosis has also been reported using silymarin in a variety of malignant human cell lines (eg, melanoma, prostate, leukemia cells, bladder transitional-cell papilloma cells, and hepatoma cells). Inhibition of cell growth and proliferation by inducing a Gx cell cycle arrest has also been claimed in cultured human breast and prostate cancer cell lines. The use of milk thistle in the clinical treatment of cancer has not yet been adequately studied but preliminary trials are under way. 

The compounds were also tested in sheep experimentally infected with Haemonchus contortus. The treatments were given orally in propylene glycol/glycerol formal (60 40 v v) vehicle on day 35 post-inoculation. Animals were necropsied 7 days post-treatment and examined for worm burdens. Approximate ED95 for the marcfortine compounds, PHA and PNU-141962 are shown in Table 2. Against H. contortus, the approximate 95% effective dose for PNU-141962 was 0.5-1.0 mg/kg ED95 for the marcfortines ranged from 1-12.5 mg/kg and for PHA 1-2 mg/kg. It should be noted that formulation has not been optimized for ruminants, and subsequent preliminary pharmacokinetic studies have shown that the bioavailability of PNU-141962 in sheep is low (10-15%) in the vehicle used, when dosed orally or subcutaneously (unpublished observations). 

There is some evidence, mostly from animal studies, to suggest that high dietary levels of phosphorus, especially if dietary levels of calcium are low, may adversely affect bone mass and calcium metabolism (Greger and Krystofiak 1982). However, in humans there is little direct evidence to indicate that large variations in dietary phosphorus or in the Ca P ratio have any significant influence on calcium utilization or balance (Heaney et al. 1982). Some preliminary findings, however, suggest that the form of phosphorus may influence calcium absorption (Zemel et al. 1982). Hexametaphosphate, as compared with orthophos-... 

Although there are preliminary data supporting the antitumoral activity of quercetin, the most common flavonoid, in humans in the course of a Phase I clinical trial [189], direct evidence of the anticancer effect of flavonoids is derived almost exclusively from studies performed in animal models as well as studies performed on cultured cell lines, Fig. (2). Most animal studies on gastrointestinal cancer have focused on colon cancer using the azoxymethane (AOM) model in rats or mice [190-197]. There are also available reports on models of cancer of the stomach (induced by benzo[a]pyrene [198] or N-methyl-N-nitro-N-nitro so guanidine [199]), oesophagus (N-methyl-N-amylnitrosamine [200]), and the tongue/oral cavity (methyl-(acetoxymethyl)-nitrosamine [198], 7,12-dimethyl-... 

In dmg discovery, preliminary PK studies are usually conducted in rodents to evaluate the extent of dmg exposure in vivo. This is commonly followed by PK studies in larger animals such as dog or monkey to better characterize the PK profile of the compound and to support safety studies. Pharmacokinetic scaling (also called allometry) is a discipline that is used to predict human PK profiles using preclinical data and is widely used in predicting the dmg human half-life, dose, and extent of absorption. Accurate prediction of a human PK profile is imperative to minimize dmg failure in development due to poor PK attributes. A detailed description of methods in predicting human PK is beyond the scope of this chapter but can be found in many excellent reviews (Obach et al., 1997 Miners et al., 2004 Poggesi, 2004 Raunio et al., 2004 Thomas et al., 2006 Hurst et al., 2007). A more in-depth discussion of various PK concepts and their applications can be found in various references (Gibaldi and Perrier, 1982 Rowland and Tozer, 1995 Hurst et al., 2007). 

Owing to thalidomide s serious toxicity profile, considerable effort has been expended in the development of analogs. Immunomodulatory derivatives of thalidomide are termed IMiDs. Some IMiDs are much more potent than thalidomide in regulating cytokines and affecting T cell proliferation. CC-5013 (Revimid) is an IMiD that in in vitro and animal studies has been shown to be similar to thalidomide in action but without the sedative effects or teratogenicity. CC-5013 is currently in phase I and II clinical trials for the treatment of myeloma, some myelodysplastic syndromes, and melanoma. Preliminary results show efficacy with decreased toxicity compared with thalidomide. 

---