In vivo assessments

Vasilik DG, Aikin IC, Coop KL, et al. 1984. In vivo assessment of lung burdens at the Los Alamos National Laboratory. GRAI 18 26p. 

A direct in vivo assessment of the quantitative importance of gut wall metabolism and transport of drugs and metabolites in humans is difficult and consequently has been attempted only rarely [3, 6, 11, 12, 15, 16, 23, 25-32, 34, 35, 81]. The most direct in vivo approach to investigating these processes in drugs with variable and incomplete bioavailability was intestinal perfusion by single-pass per-... 

A direct in vivo assessment was carried out with the single-pass perfusion approach in the human jejunum by using the Loc-I-Gut technique with R/S-verapamil (log D6 5 2.7, octanol/water pH 7.4 MW 455 Da) as the model compound for CYP 3A4 and P-gp-mediated local intestinal kinetics [2, 34, 35, 122] (see Figs. 7.7 and 7.9). The Peff for both enantiomers at each of the concentrations (4.0, 40, 120, and 400 mg L-1) was 2.5 x 10 4, 4.7 x 105.5 x 104 and 6.7 x 104 cm s-1, respectively (Fig. 7.15) [34, 35], A luminal concentration of 400 mg L 1 is expected to be achieved in the upper part of the small intestine after oral administration of a 100-mg dose of verapamil in an immediate-release dosage form [1, 34, 35], The three other perfusate concentrations represent fractions of the dose when 30%, 10%, and 1%, respectively are left to be absorbed [34, 35], The increased in vivo jejunal Peff of R/S-vcrapamil, along with its increased luminal perfusate concentration, is in accordance with a saturable efflux mechanism mediated by... 

In vitro estimates of risk for Q-T prolongation and in vivo assessments of hemodynamic interactions with cocaine and methamphetamine... 

Cirrito, J. R., May, P. C., O Dell, M. A. et al. In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-beta metabolism and half-life. /. Neurosci. 23 8844-8853, 2003. 

For the present, the utilization of in vivo toxicological models is imperative for responsible risk assessment of new chemical entities. At the same time, the use of the many in vitro models currently available can serve as valuable adjuncts to these in vivo assessments, not only reducing the number of animals used in risk assessment, but providing unique information and possibilities for scientists involved in the drug discovery and development process. 

Takeuchi, Y. and Koike, Y. (1985). Electrophysiological methods for the in vivo assessment of neurotoxicology. In Neurotoxicology. Edited by (Blum, K. and Manzo, L., (Eds.) Marcel Dekker, New York, pp. 613-629. 

Flow cytometry (FCM) is widely used for exploring mechanism of action of compounds that compromise proliferation since it is rapid, accurate and usable for any cellular context [5], In this chapter we want to point out technical and strategic aspects of use of FCM for cell cycle studies of a putative anticancer agent. As an example we used Edotecarin, a topi inhibitor, firstly evaluating proliferation outcome and classical DNA content analysis by propidium iodide, and then since the compound treatment produced cell cycle perturbation difficult to interprete, a two-parametric analysis by 5-bromo-deoxyuridine (BrdU) was applied for separating cell cycle phases. Moreover we put our efforts into identifing specific cell cycle arrest not easily demonstrable by previously described methods, through the use of in vitro kinetics ( pulse and chase ). Finally, in vivo assessment of efficacy and biomarkers modulation after treatment was analyzed. 

Frick, L.W., Adkison, K.L., Wells-Knecht, K.J., Woolard, R, and Higton, D.M., Cassette dosing rapid in vivo assessment of pharmacokinetics, Pharmaceut. Sci. Technol. Today, 1, 12, 1998. 

Digenis, G.A., and Sandefer, E., Gamma scintigraphy and neutron activation techniques in the in vivo assessment of orally administered dosage forms, Crit. Rev. Ther. Drug Carrier Syst., 7 309-345 (1991). 

Increased chance for sphincter preservation Sterilization from surgical seeding In vivo assessment of response to treatment Disadvantages... 

Flow cytometric assessment generates results that reproduce microscopic methods for the in vivo assessment of micronucleus frequency in peripheral blood micronucleated reticulocytes [30] and the method is increasingly applied in in vitro assessments. Litron Laboratories (Rochester, N.Y., USA) recently launched their MicroFlow In Vitro kit for the in vitro micronucleus test, following a six-compound interlaboratory evaluation [31]. This method permits 50 samples to be analyzed over... 

In Vitro and In Vivo Assessment of Drug-Induced Mitochondrial Dysfunction... 

F. Dehdashti, M.A. Mintun, J.S. Lewis, J. Bradley, R. Govindan, R. Laforest, M. J. Welch, B.A. Siegel, In vivo assessment of tumor hypoxia in lung cancer with 60CU-ATSM, Eur. J. Nucl. Med. Mol. Imaging 30(6) (2003) 844-850. 

Bhn J, Baron JC, Dubois B, et al Loss of brain 5-HT2 receptors in Alzheimer s disease in vivo assessment with positron emission tomography and fluorine-18 setoperone. Brain 116 497-510, 1993... 

Mintun, M., Raichle, M., Kilbourn, M., et al. A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography. Ann. Neurol. 15, 217-227, 1984. 

Dujardin, N., et al. 2002. In vivo assessment of skin electroporation using square wave pulses. J Control Release 79 219. 

With proof of concept established that viral vector-delivered GAA can restore biochemical and histological phenotype of affected cells and cross-correct untransduced cells, these studies were quickly followed by in vivo assessment of Ad-mediated GAA delivery in animals. Intracardiac and intramuscular delivery of Ad-human GAA (hGAA) was performed in newborn rats by Pauly et al. (1998) resulting in 10- and 6-fold normal levels of GAA... 

Malik N, Gunn J, Shepherd L, Crossman DC, Cumberland DC, Holt CM, Phosphorylcholine-coated stents in porcine coronary arteries in vivo assessment of biocompatibility. J Invasive Cardiol 2001 13 193-201. 

Haratake, M., M. Fukunaga, M. Ono, and M. Nakayama. 2005. Synthesis of vana-dium(IV,V) hydroxamic acid complexes and in vivo assessment of their insulin-like activity. J. Biol. Inorg. Chem. 10 250-258. 

Partovian C, Jacqz-Aigrain E, Keundjian A, et al. Comparison of chlorguanide and mephenytoin for the in vivo assessment of genetically determined CYP2C19 activity in humans. Clin Pharmacol Ther 1995 58 257-263. 

Parra, J.I.. and Paye, M., EEMCO guidance for the in vivo assessment of skin surface pH, Skin Pharmacol. Appl. Skin Physiol., 16, 188, 2003. 

Leveque, N. et al., In vivo assessment of iron and ascorbic acid in psoriatic dermis, Acta Derm. Venereol., 84, 2, 2004. 

The remainder of this chapter discusses the various methods in the order presented in Figure 9.1. However, this may not necessarily be the order in which the experiments are performed, as in silico and in vitro assays for an initial examination of species relevance may be easier and less costly to perform, and therefore worth completing prior to the more time-consuming and expensive in vivo assessments. 

The evaluations to determine relevant species for toxicity evaluation include various receptor binding assays and tissue cross-reactivity assessments, the later being routinely performed for monoclonal antibody based products (see Chapters 10 and 26). Species specificity can be determined using properly controlled in vitro cell-based response assays, cloning of receptors and ligands to determine compatibility, receptor-based response assays, immunoassays, genomic-based assays, and traditional biochemical-based assays as well as in vivo assessments with validated endpoints and markers for specificity. 

A number of chemicals and drags, such as phenobarbital, strongly induce CYP activity and increase their own metabolism. In vivo assessment of CYP induction is reserved for the later phase of drag development if indicated. It requires multiday treatment, an effort which is not justified for a compound in the early phase. A number of... 

Park CH, Nishimura K, Akamatsu T, Tsukiya T, Matsuda K, Ban T. A new magnetically suspended centrifugal blood pump in vitro and preliminary in vivo assessment. Artif Organs 1996 20(2) 128-131. 

Marzola, P., Degrassei, A., Calderan, L., etal. (2004) In vivo assessment of antiangiogenic activity of SU6668 in an experimental colon carcinoma model. Clinical Cancer Research, 10, 739—750. 

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