Vivo Models

As mentioned above, ascorbic acid acts as a neuroprotective agent in in vitro models of scurvy. Therefore, it is a surprise that no symptoms of brain cell damage have been reported in conditions involving severe systemic ascorbic acid deficiency. This may be explained by the fact that the scorbutic state cannot be produced in the intact animal brain because of the brain s homeostatic mechanisms such as the highly specific ascorbic acid transport system in the choroid plexus (Spector, 1989) and the inability of ascorbic acid to cross the blood-brain barrier, which effectively isolate the ascorbic acid content of the intact brain from the rest of the body s ascorbic acid pool. The active transport of ascorbic acid from blood to cerebrospinal fluid (Spector and Eells, 1984), together with cellular uptake mechanisms, represents the base for homeostasis of brain ascorbic acid concentrations (see also Section 2). This is in agreement with the report about normal ascorbic acid concentrations in brains from patients with Parkinson s disease (Riederer et al., 1989), in which free radical damages are postulated to be involved (see below). 

There is also evidence that normal in vivo concentrations of ascorbic acid are sufficient to protect against lipid peroxidation. With physiological concentrations of iron and tocopherol, a 50% inhibition of lipid peroxidation was obtained with 410 xM ascorbic acid this was reduced to 90 xM when tocopherol content was increased fivefold. Only when endogenous tocopherol was decreased to 20% was the in vivo intracellular ascorbic acid concentration too small for antioxidative protection of lipids (Reiber et al., 1994). Therefore, there is a large antioxidant capacity in brain cells that is additionally supported by a very efficient ascorbic acid homeostasis within the brain. 

Nevertheless, several reports have suggested that the application of large amounts of ascorbic acid can indeed be effective in protecting neurons against insults in vivo. It has been postulated that in ischemia, cell damage is due to lipid peroxidation of biomembranes induced by oxygen free radicals (Flamm et al., 

As the drug is released from a device, it is absorbed into blood and then is distributed into tissues and organs. During these processes, the drug can undergo metaboHsm and/or elimination. The aim of the mathematical model is to consider all the phases involved as a whole (release, absorption, spreading and metabolism/elimination). Hence, the model derivation involves the simultaneous solution of all the equations necessary for the description of each phase. This derivation can be different on the basis of the details used. If more details are considered, the obtained model can be much closer to reality. The more precise and particularized the model is, the more adherent to reality it will be and the more complex its solution will be [196]. 

Pure compartment modeling is based on the schematiza-tion of the body under study by a system of interconnected 

The last approach, named pure mathematical modeling, consists of the correlation between the in vitro results and the plasmatic concentration reached in the in vivo assays. These correlations are commonly called in vitro/ in vivo correlations (IVIVC). The IVIVC can be classified into four levels level A, level B, level C and multiple level C correlations [201]. Only the IVIVC of level A is accepted by regulatory boards (FDA, USP) for scale-up and postapproval changes (SUPAC), which can be justified without the need for additional in vivo studies. This level A IVIVC comprises a point to point relationship between the in vitro release profile and the in vivo plasmatic concentration of the drug. One procedure to achieve this goal consists of the 

Unfortunately, no attempt has been made to model the in vivo release of norgestomet from silicone subcutaneous implants. In contrast, for progesterone release, Turino et al. recently proposed a one-compartment physiologically model based on the Hill equation to predict the plasmatic concentration of progesterone in lactating Holstein cows [210]. The study comprised the analysis of plasmatic progesterone concentration in dairy cattle, which can be predicted with the following equation  

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At the in vivo assay level, the classic ip-ip (iateraperitoneal) in vivo model has been replaced as a selection criteria for advancement of new dmg candidates to clinical trial. More stringent alternative models iaclude subcutaneous or subrenal capsule implantation of tumor followed by iatravenous dmg dosiag (7) and the human tumor xenograft models ia aude mice (8). 

A large number of molecules have provided experimental evidence of neuroprotection in in vitro and in vivo models of Parkinson s disease and many of these putative neuroprotective substances are now the objects of clinical trials. Recently, a team of experts has identified potential neuroprotective agents to be tested in pilot studies [4]. Twelve compounds have been considered for clinical trials caffeine, coenzyme Q 10, creatine, estrogen, GPI1485, GM-1 ganglioside, minocycline, nicotine, pramipexole, ropinirol, rasagiline, and selegiline (for individual discussion see [4]). 

Alkyiresorcinols Protect the DNA from UV-Damage In Vitro and In Vivo Models... 

In this reason the goal of this work is to investigate the complex effects of AR on UV sensitivity of DNA in molecular in intro) and cellular in vivo) models. 

Methods of detection, metabolism, and pathophysiology of the brevetoxins, PbTx-2 and PbTx-3, are summarized. Infrared spectroscopy and innovative chromatographic techniques were examined as methods for detection and structural analysis. Toxicokinetic and metabolic studies for in vivo and in vitro systems demonstrated hepatic metabolism and biliary excretion. An in vivo model of brevetoxin intoxication was developed in conscious tethered rats. Intravenous administration of toxin resulted in a precipitous decrease in body temperature and respiratory rate, as well as signs suggesting central nervous system involvement. A polyclonal antiserum against the brevetoxin polyether backbone was prepared a radioimmunoassay was developed with a sub-nanogram detection limit. This antiserum, when administered prophylactically, protected rats against the toxic effects of brevetoxin. 

In an in vivo model of neuroAIDS, CXCL 12(5-67) therefore recapitulates the acquired properties demoustrated in vitro (Fig. 7.2). Together with its detection in HIV-positive human brains, these data confirm the relevance of the mechanisms described above. 

In this chapter, we review the interactions at the level of protein function, between opioid receptors and chemokine receptors, using both in vitro and in vivo model systems. As a part of this discussion, we also describe our current understanding of the biochemical pathway(s) that are involved in the heterologous desensitization process between these groups of receptors. 

In contrast to previous in vivo models, this in vitro model provides the possibility of dissociating experimentally two important processes of intestinal absorption cellular uptake and secretion. Under conditions mimicking the postprandial state (taurocholate/oleic acid supplementation), differentiated Caco-2 cells were able to (1) take up carotenoids at the apical sides and incorporate them into CMs and (2) secrete them at the basolateral sides associated with CM fractions. Using this approach, the extent of absorption of P-carotene through Caco-2 cell monolayers after 16 hr of incubation was 11.2%, a value falling within the in vivo range (9 to 22%). ° - Of the total amount of P-carotene secreted, 78% was associated with the two CM fractions and 10% with the VLDL fraction. ... 

Skin inflammation induced by reactive oxygen species (ROS) an in vivo model. Br. J. Dermatol. 125, 325-329. 

I would really like to see development of models that are explant or in vivo models, where we can see the animal in a more integrated role and look at the corresponding in vitro events. 

Abbott has also demonstrated in vivo efficacy with two piperazine amides, A-304121 (26) and A-317920 (27). Both (26) and (27) bind to the rat H3 receptor with high affinity (pA) = 9.15 and 8.6, respectively) [92] and are active in several in vivo models, including the acute dipsogenia model and models of cognitive performance and inhibitory avoidance [93]. Unfortunately, these compounds showed markedly reduced affinity for the human H3 receptor, reinforcing the need to screen against the human receptor. 

Novartis AG has filed a patent application on novel naphthalene derivatives as potent cannabinoid agonists, especially at the CBi receptor [208]. One compound was specifically claimed, the naphthalene derivative (319), which exhibited CBi binding with a if value of 15 nM. This compound was also active in an in vivo model of neuropathic pain, reversing hyperalgesia... 

It has been revealed that cannabinoids exhibit neuroprotectant activities in both in vitro and in vivo models [249]. The neuroprotective effects are mainly based on regulation of transmitter release, modulation of calcium homeostasis, anti-oxidant properties and modulation of immune responses. A number of neurological disorders, including brain trauma, cerebral ischaemia, Parkinson s disease and Alzheimer s disease represent possible therapeutic areas for cannabinoids with neuroprotective properties. Cannabinoids are also suggested to have potential against glaucoma due to their neuroprotective nature and lowering of intraocular pressure [250]. 

To provide a complete assessment of all these variables, the final evaluation of safety must be made in the in vivo model using the preparation under the proposed conditions for use, following tissue compatibility with many of the techniques already discussed. Confocal microscopy is a relatively new noninvasive technique that allows a detailed examination of the endothelium in the live animal, and thus may prove useful in following changes in this delicate tissue over time. As in ex vivo models, the... 

Graziano J, Blum CB, Lolacono NJ, et al. 1996. A human in vivo model for determination of lead bioavailability using stable isotope dilution. Environ Health Perspect 104 176-179. 

Ideally, future antineoplastic drug discovery should be based on a more rational, botanical, chemical, and pharmacological approach. A possible way to test the antineoplastic effects of compounds would be to use some semi in vitro-in vivo models. A more rational approach in antineoplastic research, combined with the enormous chemodiversity of flowering plants, will lead to the discovery of several molecules of clinical value. 

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