Dispositional studies, experimental

The literature cites numerous studies on buccal absorption in animals and man. However, in most studies experimental conditions were not well defined, making it difficult to draw appropriate conclusions from the experimental data. In the studies reported here the area of buccal mucosa exposed to the drug was carefully controlled, as was the rate of drug delivery in the case of the buccal disc device. The disposition kinetics of the drug was also defined from intravenous data to allow both the rate and extent of absorption to be determined. 

It is recommended that LD q be determined in mice and rats, and MTD be determined in dogs and monkeys. Drug disposition studies and plasma level determinations should be performed in these species after parenteral administration of the LDio, half the LDiq, and one-tenth the LD o. The area under the serum curve for the various doses should bear a linear relationship to the dose in mg/m or to the dose in mg/kg x If these relationships hold for the different laboratory species, they are likely to hold for man. If reasonably linear relationships do not obtain, it suggests that unique metabolic pathways may exist in some species, or that the enzymatic process may have been overwhelmed by virtue of high tissue levels of the drug [23]. Stated in another way, if one sees great variations in the response of experimental animals that bear no relationship to the size of the animals, then it is unlikely that any prediction can be made for man. On the other hand, where these relationships can be established, it seems possible that an inter-species dose-response phenomena intimately tied to plasma levels can be constructed. 

Animals may not be moved for 14 days after administration of the experimental product, and records on the disposition of trial animals must be retained for 2 years. Bio-security issues will be of particular concern to the environmental impact assessment where trials involve live organisms or genetically modified organisms, either in vaccine challenge studies or as experimental products. 

Histological studies and investigations of disposition processes are being coupled in order to assess the condition of populations of California mussels Mytilus californianus. Whether results of future studies of this sort can be used diagnostically to reveal the presence of chemical stressors in the environment and contribute to evaluation of their impact is a concern which motivates much of our experimental work. 

Pott was a native of Halberstadt, and was sent to Halle by his parents to study for the ministry, but, developing interest in medicine and especially in chemistry, he studied with Hoffmann and Stahl and devoted himself to chemistry. He made his residence in Berlin, and was elected to the Academy. After the death of Neumann (1777), Pott was appointed his successor in the professorship of chemistry in the Medicinisch-Chirurgische-Bildungsanstalt. He was a well-informed chemist, an energetic experimenter, and was very clear and straightforward in his descriptions. He was, on the other hand, of a contentious disposition, and his many disputes with other members of the Academy—as Eller, Marggraf, Brandes—often overstepped the bounds of courtesy. In 1761 his relations with his colleagues in the Academy were such that he severed his connection with it entirely. 

Finally, the effect of chiral groups at the 4-out position in the conrotatory transition structures (114, 115) was studied at the B3LYP/6-31G level. It was found that both transition structures are almost isoenergetic, thus showing that in electrocyclic conrotatory transition structures the 4-outward disposition is much less efficient as a source of chirality, a result already observed by Pannunzio et al. in their experimental studies [32, 33] (Scheme 29). 

This example shows that (1) the mechanistic PK/PD model developed based on literature data of rHu-EPO and predinical information of a new ERA is suitable to provide a better quantification and prediction of the drug disposition and the time course of hemoglobin in adult healthy subjects, and (2) this model can be used to optimize the design of the Phase I studies of new ERAs, with respect to key design features (number of dose levels, selection of dose levels, number of subjects per dose level, PK/PD sampling times). In this way, a quantitative risk-benefit assessment can be obtained by determining the probability of success of a Phase I study with new ERA, conditional on a certain experimental design. 

Gamer RC, Barker J, Flavell C et al. (2000) A validation study comparing accelerator MS and liquid scintillation counting for analysis of 14C-labelled drugs in plasma, urine and faecal extracts. J Pharm Biomed Anal 24 197-209 Hayakawa H, Fukushima Y, Kato H et al. (2003) Metabolism and disposition of novel des-fluoro quinolone garenoxacin in experimental animals and an interspecies scaling of pharmacokinetic parameters. Drug Metab Dispos 31 1409-1418... 

Data on the toxicity and disposition of JP-8 in animals are sparse, and no data are available for humans. No reproductive toxicity studies have been done in experimental animals. One adequate study demonstrated developmental toxicity in rats treated orally at 1,500-2,000 mg/kg/d (Cooper and Mattie 1996). A study in a second species should be supplemented with a multiple-generation reproductive toxicity study in rats or mice, including an evaluation of postnatal endpoints, such as developmental neurotoxicity, immunotoxicity, and hematological, hepatic, and renal effects, that could result from prenatal exposures. 

William Irvine was a native of Glasgow, matriculating at the university at the age of thirteen in 1756. Black soon noticed his interest in chemistry and his disposition to apply mathematics in his studies. Like Black, Irvine s main lines of communication for his work were through his students and the occasional excursion before the local Philosophical Society. Working as Black s assistant, Irvine helped in his professor s determination of the latent heat of steam and contributed values of that quantity for melting tin, zinc and spermaceti and beeswax. He also worked with Black on establishing experimentally the specific heats of various substances. However, Irvine became very much his own man. Andrew Kent puts it colourfully ... 

The fundamental principle of toxicology is the concept that the sixteenth century physician Paracelsus articulated in the 1500s sola dosis facit venenum or the dose makes the poison . The modem version of this observation is the dose-response relationship, which is experimentally and theoretically supported through pharmacokinetic and pharmacodynamic experimentation. Pharmacokinetics is concerned with the study of the time course of the disposition of drugs, specifically absorption, distribution, metabolism and elimination, often referred to as ADME. In non-technical terms it can be thought of as what the body does to the chemical. An understanding of the pharmacokinetic (in the case of dmgs) or toxicokinetic (all chemicals) profile is critical to estimate the... 

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