Animal models administered dose

ACT-078573 (20) is the first oral orexin receptor antagonist that penetrates the blood-brain barrier and is capable of inducing a transient and reversible blockade of the two receptors, 0X1 and 0X2 [61]. In animal models, the administration of 20 resulted in a dose-dependent decrease in alertness and increased non-REM and REM sleep. The compound, administered at oral doses ranging from 10 to 300 mg/kg, dose-dependently decreased alertness in rats and exhibited increased duration of REM and non-REM sleep, indicating no intrusive REM sleep that is characteristic of narcolepsy. In dogs, treatment with 20 (10-100 mg/kg p.o.) resulted in dose-dependent reductions in mobility and also induced signs of clinical somnolence. 

Comparative Toxicokinetics. The metabolism and excretion of orally administered phenol in 18 animal species have been compared to metabolism and excretion in humans (Capel et al. 1972). The rat was the most similar to the human with respect to the fraction of administered dose excreted in urine in 24 hours (95%) and the number and relative abundance of the 4 principal metabolites excreted in urine (sulfate and glucuronide conjugates of phenol and 1,4-dihydroxybenzene). The rat excreted a larger fraction of the orally administered dose than the guinea pig or the rabbit (Capel et al. 1972) and appears to be the least susceptible of the three species to respiratory, cardiovascular, hepatic, renal, and neurological effects of inhaled phenol (Deichmann et al. 1944). More rapid metabolism and excretion of absorbed phenol may account for the lower sensitivity of the rat to systemic effects of phenol. More information on the relative rates of metabolism of phenol in various species is needed to identify the most appropriate animal model for studying potential health effects in humans. 

An acute dose of lobeline impairs attention in one animal model, but not as much as mecamylamine (Turchi et al. 1995). Lobeline improves memory when administered after a passive avoidance paradigm (Decker et al. 1993). Pretreatment with lobeline improves performance in rats with septal lesions on a spatial discrimination water maze. Lobeline is about one-tenth as potent as nicotine in the passive avoidance memory task, but equivalent to nicotine in the water maze. 

First, the procedure now used by the EPA for inhalation data differs from what we have described above, in that the ten-fold factor for interspecies extrapolation (animal-to-human) is dropped in favor of a specific model that describes the well-known physiological differences between animals and humans that affect the relative rates of movement of a given administered dose of a chemical in the respiratory tracts of animals and humans. These physiological models provide fairly accurate predictions of the relative doses of chemicals delivered into the respiratory regions of animals and humans who have received identical administered (inhaled) doses. The estimate of delivered dose offers a well-accepted scientific approach to at least part of the problem of interspecies differences. Details of the delivered dose calculations are beyond the scope of this book (see references in Sources and recommended reading). 

Most materials used to produce liposomes are derived from natural materials, thus are thought to be safe when administered. Generally, however, phospholipids administered in liposomal form are cleared from the lungs more slowly than comparable doses of lung surfactant (Oguchi et al. 1985). Many macromolecules have been incorporated into liposomes in order to improve their pulmonary delivery. Some lipid-entrapped macromolecules have been tested in animal models and human volunteers to determine efficacy (Kellaway and Farr 1990). 

Administration of scopolamine to rats induces amnesia in passive avoidance learning. EGb administered intraperitoneally 30 mm before the initial trial at doses of 150-500 mg/kg significantly attenuated the amnesic effects of scopolamine on step-through latencies in a retention trial 4 hours after training for the passive avoidance test in rats [107]. Hoyer et d. showed that, using an animal model of in tracer ebroventricular streptozotocin treatment, EGb treatment compensated for deterioration in working memory, reference memory and passive... 

The antibodies to IL-4 inhibit allergen-induced airway hyperresponsiveness (AHR), globlet cell metaplasia and pulmonary eosinophilia in animal models. Inhibition of IL-4 by soluble IL-4 receptor (SIL-4R, Nuvance) has proven to be very promising in treating asthma. Clinical trials with recombinant SIL-4R administered by a single weekly dose of 3 mg via nebulization have been effective in controlling the symptoms of moderate persistent asthma. 

Toxicokinetics studies are designed to measure the amount and rate of the absorption, distribution, metabolism, and excretion of a xenobiotic. These data are used to construct predictive mathematical models so that the distribution and excretion of other doses can be simulated. Such studies are carried out using radiolabeled compounds to facilitate measurement and total recovery of the administered dose. This can be done entirely in vivo by measuring levels in blood, expired air, feces, and urine these procedures can be done relatively noninvasively and continuously in the same animal. Tissue levels can be measured by sequential killing and analysis of organ levels. It is important to measure not only the compound administered but also its metabolites, because simple radioactivity counting does not differentiate among them. 

UCL takes into account measurement uncertainty in the study used to estimate the dose-response relationship, such as the statistical uncertainty in the number of tumors at each administered dose, but it does not take into account other uncertainties, such as the relevance of animal data to humans. It is important to emphasize that UCL gives an indication of how well the model fits the data at the high doses where data are available, but it does not indicate how well the model reflects the true response at low doses. The reason for this is that the bounding procedure used is highly conservative. Use of UCL has become a routine practice in dose-response assessments for chemicals that cause stochastic effects even though a best estimate (MLE) also is available (Crump, 1996 Crump et al., 1976). Occasionally, EPA will use MLE of the dose-response relationship obtained from the model if human epidemiologic data, rather than animal data, are used to estimate risks at low doses. MLEs have been used nearly universally in estimating stochastic responses due to radiation exposure. 

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