Biomedical subjects

J S Kerr

Publications and source records attributed to J S Kerr.

77 records · Page 5Linked to original sources

PubMedDate not supplied

Comparison of five anxiolytic benzodiazepines on measures of psychomotor performance and sleep.

The behavioural toxicity of five anxiolytic benzodiazepines was examined in 28 volunteers who were studied in two groups of 14 subjects each. Each drug was taken nocte for 7 days, with a 4-week washout period between drugs. Assessments of psychomotor performance and sleep were made the morning following the first administration and the morning following the last administration. Comparisons of drug effect magnitudes using Cohen's d scores suggest that effects on psychological function should be considered as central to the selection and use of such compounds.

Adult↗

PubMedDate not supplied

Psychopharmacological effects of pyritinol in normal volunteers.

Twelve healthy male volunteers received pyritinol 600 or 1,200 mg or placebo for 3 days according to a randomised, double-blind crossover design. On the 1st and 3rd days of each of the three treatment periods subjects completed a battery of psychological tests including Critical Flicker Fusion (CFFT), Choice Reaction Time (CRT), tests of memory and subjective drug effects at 1, 2, 4 and 6 h after dosing. Significant improvements in CFFT and CRT were found after pyritinol. There were no significant differences on the other tests, however, the observed enhancement in performance could be attributed to the effect of the drug.

Adult↗

PubMedDate not supplied

Novel small molecule alpha v integrin antagonists: comparative anti-cancer efficacy with known angiogenesis inhibitors.

Recent evidence supports the involvement of integrins in angiogenesis: blockade of alpha v beta 3 and alpha v beta 5 integrins disrupts angiogenesis leading to decreased blood vessel formation and hence decreased tumor growth. We hypothesized that av antagonists could inhibit tumor growth in tumor cells devoid of alpha v beta 3 integrins. We evaluated SM256 and SD983, novel small molecules that are specific av antagonists in mouse models of angiogenesis and tumorigenesis, and compared them with standards: TNP470, a fumagillin analog in the clinic, and flavopiridol, a cell cycle kinase inhibitor. In vitro SM256 was a selective alpha v beta 3 inhibitor with an IC50 = 4nM, and the affinity of SD983 against the mouse endothelial alpha v beta 3 integrin yielded an IC50 = 2nM and an IC50 = 54nM against alpha v beta 5. In the mouse Matrigel model of angiogenesis SM256 decreased blood vessel formation (hemoglobin content) with an ED50 = 0.055 ug/kg/day, tenfold more potent than TNP470. SG545, an ester of SD983, decreased blood vessel formation with an ED50 = 6 ug/kg/day, while flavopiridol ED50 = 18 ug/kg/day. In the mouse xenograft model, using human colon carcinoma RKO cells that do not express alpha v beta 3 but express alpha v beta 5, tumor growth was inhibited by SG545 (10 mg/kg/day) and flavopiridol (5 mg/kg/every other day) 40% and 70%, respectively (p < 0.05). Although the proliferative index (measured by BrdU incorporation) was not significantly changed with SM256, SG545 or flavopiridol (29-32%), the apoptotic index increased significantly (p < 0.05) in the SM256 and SG545-treated groups (2.3-2.7%) compared with controls (1.1%), suggesting increased cell death contributed to decreased tumor volumes. Neovascularization decreased with SM256 and SG545 treatment. The data demonstrate that potent selective av antagonist can target endothelial cells, tumor cells, inhibit angiogenesis and inhibit tumor growth.

Animals↗

PubMedDate not supplied

The hollow fiber assay: continued characterization with novel approaches.

The hollow fiber assay, a unique in vivo model, permits the simultaneous evaluation of compound efficacy against multiple cell lines in two physiological compartments. This assay has been used to characterize in vivo activity of cytotoxic compounds. The purpose of the present study was to characterize and optimize this assay for compounds with a defined mechanism of action, specifically cell cycle inhibition. Two human tumor cell lines and one normal human cell line were loaded into polyvinylidene fluoride hollow fibers at two or more cell concentrations and grown in mice for 3-10 days. The data demonstrate the importance of characterizing the initial loading density of various cell lines in the evaluation of compounds. All studies were performed with cells in the linear part of the cell growth curves. Initial loading densities of 1-2 x 10(4) cells/fiber gave the greatest opportunity for growth in the three human cell lines tested (HCT116 colon carcinoma, NCI-H460 non-small cell carcinoma, and AG 1523 normal fibroblast). Utilizing the MTT assay, standard curves were constructed to correlate the final number of cells with optical density (OD) readings at 540 nm in order to calculate cell numbers in the fibers. Insights into the mechanism of action of cisplatin have been gained using Western blot analysis of the cell cycle markers PCNA (a protein present throughout the cell cycle) and Rb (a protein that acts as a tumor suppressor gene product) from the hollow fiber cells. In cisplatin-treated NCI-H460 cells both PCNA and Rb phosphorylation decreased, suggesting the arrest of the cells prior to the S phase. Standard therapeutic agents, cisplatin, racemic flavopiridol, cyclophosphamide and mitomycin C, were evaluated independently in the hollow fiber assay and the xenograft model. The data demonstrate that compounds active in the hollow fiber assay are also active in the xenograft.

Animals↗

PubMedDate not supplied

Regulation of gene expression and cell growth in vivo by tetracycline using the hollow fiber assay.

The hollow fiber assay presents a potentially unique tool to study the effects of regulated gene expression in cell lines that do not form tumors in vivo. The hollow fibers allow small molecules to pass freely through while keeping the cells within the fibers and segregated from host cells. OSp16.1 cells, derived from the U24 clone of the U2-OS osteogenic sarcoma tumor line, express the p16INK4a tumor suppressor under the regulation of tetracycline (tet) (Mitra J et al. Mol Cell Bio 19:3916, 1999). The in vitro induction of p16 in the OSp16.1 cell line is regulated by tet. The hollow fiber assay was used to determine whether the regulation of the p16 gene could be achieved in vivo, since these cells did not grow in the xenograft model. There were no differences in the in vivo growth pattern of U24 cells loaded into the hollow fibers with and without tet: 807% and 839% net growth, respectively. OSp16.1 cells in fibers in mice receiving 3.33 mg/kg/day tet had a 644% net growth after 21 days. There was a 194% net growth without tet. Immunoblotting of extracts prepared from the hollow fibers confirmed that p16 was induced in the absence of tet. These data demonstrate this assay is a useful tool for studying the effects of regulated gene expression in vivo.

Animals↗