In vivo study

3 In vivo studies. - Many natural compounds and therapeutic drugs form glycosides during transport through the gastrointestinal tract. Mortenson et al have used directly coupled LC- H NMR to various acylated isomers of the glucuronide of S-naproxen in human urine samples. This technique has also been used to study the metabolic variation in rats to identify metabolic populations in urine. 

Vongvanich, P. Kittakoop, J. Kramyu, M. Tanticharoen and Y. Thebt-aranonth, J. Org. Chem., 2000,65, 5420-5423. 

Simmen, J. Heilmann, I. Calis, B. Meier and O. Stitcher, Phytochemistry, 2000,55, 941-947. 

Schettino, T. Simioli and A. Dini, J. Agric. Food Chem., 2001, 49, 741-746. 

Haraguchi, Y. Mimaki, M. Motidome, H. Morita, K. Takeya, H. Itokawa, A. Yokosuka and Y. Sashida, Phytochemistry, 2000,55, 715-720. 

Shvedova et al. [59] demonstrated that inhalation of SWNTs resulted in mutations of the k-ras gene locus in the lung of mice. Among the mutated genes implicated in pulmonary tumorigenesis, the k-ras oncogene is relevant in lung tumors of mice exposed to chemicals. 

Zhu et al. [57,58] applied PB-PK modelling to radiolabeUed tumour-targeted monoclonal antibodies for radioimmunodetection and radioimmunotherapy. 

Sakaeda et cd. [59] described an example of physiologically-based modelling for a lung-specific pro-drug of the antibiotic drug ceftazidime. 

Appropriately designed pharmaeokinetie drug interaetion studies can provide important information about metabolic pathways and their eontribution to overall elimination. Together with information from in vitro studies, these in vivo studies can be a primary basis of labehng statements and often can help avoid the need for further unneeessary investigations. 

FIGURE 7.4 AUC fold increase of 5 mg vardenafil after coadministration of various CYP3A4 inhibitors. 

TABLE 7.8 Pharmacokinetic parameters of fluticasone nasal spray (200 xg once daily) +7 days with ritonavir (100 mg twice daily). 

PK parameter Fluticasone alone Fluticasone + ritonavir Ratio 

3 Cocktail Approaches Simultaneous administration of a mixture of two or more probe substrates of CYP enzymes in one study in human volunteers is referred to as a cocktail approach.  

The cost and duration of the combined chronic/cancer bioassay has limited its conduct to small numbers of selected chemicals. As a result, several short-term methods aimed at increasing predictive accuracy to enable testing of larger numbers of chemicals have been developed in attempts to successfully correlate Iheir results with evidence of carcinogenicity (or lack of carcinogenicity). This includes investigation of potential to promote tumor development, several model systems in Irans-genic and knockout models, and consideration of the predictive potential of traditional toxicity endpoints in shorter-term studies. 

Short- and medium-term assays in transgenic models as a basis to provide essential information about the predisposing factors to specific genetic alterations in carcinogenesis include the rat liver foci model, the XPA—/— and the p53+/— knockout mouse models, the Tg.AC and Tg.rasH2 transgenic mouse models, and Ihe neonatal 

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Cagle D W, Kennel S J, Mirzadeh S, Alford J M and Wilson L J 1999 In vivo studies of fullerene-based materials using endohedral metallofullerene radiotraoers Proc. Natl Acad. Sc/. USA 96 5182-7... 

In experimental animals and in vitro, DHBs show a variety of biological effects including binding of metaboHtes to various proteins. Clastogenic effects have been observed in vitro and in some in vivo studies with the three compounds. No reproductive effects have been shown by conventional studies with either hydroquinone, catechol, or resorcinol (122). Hydroquinone has been shown to induce nephrotoxicity and kidney tumors at very high doses in some strains of rat (123) catechol induces glandular stomach tumors at very high dose (124). Repeated dermal appHcation of resorcinol did not induce cancer formation (125). 

Investigations are carried out using a variety of biological systems, including observations on exposed whole animals in vivo studies) or on appropriately treated isolated tissues and cells, homogenates of tissues, or cultured lower organisms in vitro studies). 

Syrett and Davis conducted in-vivo studies wherein they implanted crevice corrosion specimens of Co-Cr-Mo in dogs and rhesus monkeys for up to two years. Their results indicated the alloy was not susceptible to crevice corrosion. Galante and Rostoker implanted crevice-type specimens of Co-Cr-Mo and Ti-6A1-4V in the back of rabbits for 12 months. Although no evidence of severe corrosion was found in any of the specimens, several of the titanium and cobalt specimens did show signs of single pits in the crevice regions. 

Syrett, B. C. and Davis, E. E., Crevice Corrosion of Implant Alloys —A comparison of In-Vitro and In-Vivo Studies , Presented at Spring meeting of the ASTM, Kansas City, MO. (1978)... 

Green, P.B., Erickson, R.O. Buggy, J. (1971). Metabolic and physical control cell elongation rate in vivo studies in Nitella. Plant Physiology, 47, 423-30. 

Various in vivo studies have been performed to assess the biocompatibility of PEG/PBT copolymers upon implantation in soft and hard tissues." ... 

Sakkers RJB, Dalmeyer RAJ, Wijn JR, and Blitterswijk CA. Use of bone-bonding hydrogel copolymers in bone An in vitro and in vivo study of expanding PEO-PBT copolymers in goat femora. J Biomed Mater Res, 2000, 49, 312-318. 

In vivo studies in animals suggest that endosulfan may disrupt normal reproductive hormone levels in male animals, but that it is not an endocrine disrupter in females. Persistent depressed testicular testosterone was seen in male rats after intermediate duration oral exposures to endosulfan. In ovariectomized female rats, orally administered endosulfan did not induce normal development of female reproductive tissues, and in female mice and immature female rats, acute parenteral exposure to endosulfan did not affect several endocrine-related end points. In vitro studies have evaluated endosulfan for estrogen receptor (ER) and cytosolic protein binding affinity, ER-mediated reporter gene expression, estrogenic induction of cell proliferation, and alteration of relative abundance of active estradiol metabolites. Overall, in vitro evidence in favor of endosulfan estrogenicity indicates relatively weak potency compared to 17[3-estradiol. Apparently contradictory results were reported in different... 

A few ex vivo and in vivo studies have been published claiming an antigene (and antisense) effect of mixed purine/pyrimidine sequence PNA [48, 49, 78-80]. However, as pointed out by us in recent reviews [81, 82] these studies lack fundamental controls such as the inclusion of relevant internal standards as a control for sequence-specific non-antigene/antisense effects, thus confirmatory studies are warranted. The in vivo antigene studies from Richelsoris group [79, 83] completely lack a rational basis for the claimed effects. First of all there is no evidence that... 

Kristensen E. In vitro and in vivo studies on pharmacokinetics and metabolism of PNA constructs in rodents. In Peptide Nucleic Acids Methods and Protocols, Nielsen P. E. (Ed.). 2002, Humana Press (To-towa, N.J., United States) Copenhagen, pp. 259-269. 

Recently, Tsakala et al. (90) formulated pyrimethamine systems based on several lactide/glycolide polymers. These studies were conducted with both microspheres (solvent evaporation process) and implants (melt extrusion process). In vitro studies indicated that pyrimethamine-loaded implants exhibited apparent zero-order release kinetics in aqueous buffer whereas the microspheres showed an initial high burst and considerably more rapid drug release. In vivo studies in berghi infected mice confirmed that the microspheres did not have adequate duration of release for practical application. However, the implants offer promise for future clinical work as more than 3 months protection was observed in animals. 

M., McConnell, R., Lange, N., and Langer, R., Poly(anhy-dride) administration in high doses in vivo Studies of biocompatibility and toxicology, J. Biomed. Mat. Res., In Press. 

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