Experimental Studies in the Rat

Engstroem-Laurent, A. and Hellstroem, S., The role of liver and kidneys in the removal of circulating hyaluronan. An experimental study in the rat, Connect. Tissue Res., 24, 219, 1990. 

Garcia-Ohno, D.C. et al. Effects of long-term treatment of colon adenocarcinoma with crocin, a carotenoid from saffron Crocus sativus L.) an experimental study in the rat, Nutr. Cancer, 35,120,1999. 

Yeung TK, Hopewell JW, Simmonds RH, Seymour LW, Duncan R, Bellini O, Grandi M, Spreafico F, Strohalm J, Ulbrich K. Reduced cardiotoxicity of doxorubicin given in the form of N-(2-hydroxypropyl)methaciylamide conjugates an experimental study in the rat. Cancer Chemotherap Pharmacol 1991 29 105-111. 

Bjorkman R. Central antinociceptive effects of non-steroidal anti-inflammatory drugs and paracetamol. Experimental studies in the rat. Acta Anaesthesiol Scand Suppl 1995 103 1-44. 

Although it has been clearly demonstrated that under normal physiological conditions retinol absorption occurs mainly via the lymphatic route (see above Fidge et al., 1968), the existence of an alternative route for retinol absorption has been suggested both by experimental studies in the rat and by features of the genetic disease abetalipoproteinemia in man. Information available suggests that under abnormal conditions retinol may be able to be absorbed via a nonlymphatic pathway and in a biochemical form other than the chylomicron in amounts sufficient to meet nutritional requirements for vitamin A. 

Olivecrona, T. Kinetics of fatty acid transport. An experimental study in the rat. Thesis University of Lund 1962. 

The ampakines are a group of compounds that facilitate transmission by stimulating the AMPA glutamate receptors (see p. 58). The AMPA receptor is believed to play a major role in long-term potentiation, a physiological process that is important in memory formation. Experimental studies in aged rats have already shown that the ampakines can reverse age-associated memory loss but their activity in Alzheimer s patients has yet to be determined. 

Inoue Y, Goto H, Horinuki R et al. (1990) Experimental atherosclerosis in the rat carotid artery induced by balloon de-endothelialization and hyperlipemia. A histological and biochemical study. J Jpn Atheroscler Soc 18 1147-1154... 

Domoic acid exposure to mammals occurs orally in a matrix of shellfish to human consumers, planktivorous fish and benthic invertebrates to marine mammals, and perhaps zooplankton and chained diatoms to whales. Analysis of the consumed mussels from the 1987 exposure indicated that 1 mg/kg was sufficient to induce gastrointestinal symptoms and 4.5 mg/kg could induce neurological effects in humans (Perl et al. 1990). Experimental studies in monkeys, rats and mice have utilized oral gavage, intraparenteal, and intravenous exposure routes and determined that oral gavage is about ten times less effective that the other routes of exposure (Iverson et al. 1990). Humans appear much more sensitive than either monkeys or rats, which when dosed orally have no observable adverse effect levels (NOAEL) at 5 and 28 mg/kg, respectively. Experimental animals have permitted evaluation of different dose scenarios. A daily NOAEL oral gavage of domoic acid to rats for... 

Gu YD, Ma MK (1991) Nerve transfer for treatment of root avulsion of the brachial plexus Experimental studies in a rat model. J Reconstr Microsurg 7 15-22. 

Marfurt, C., and Rajchert, D. M. (1991). Trigeminal primary afferent projections to "Non-Trigeminal" areas of the rat central nervous system. J. Comp. Neurol. 303, 489-511. McRitchie, D. A. (1992). Cytoarchitecture and chemical neuroanatomy of the nucleus of the solitary tract Comparative and experimental studies in the human and the rat. Unpublished Ph.D. thesis, Univ. of New South Wales. 

Model refinement and validation for both the chltnpyrifos and the diazinon PBPK/PD models wa.s accomplished by conducting a scries of in vivo pharmacokinetic and pharmacodynamic studies in the rat and by evaluating the capability of the model to accurately simulate in vivo data published in the literature. The experimental details are fully described in Timchalk et ai (2002b) and Poet et at. (2004). In brief, these studies involved an acute oral exposure to chlorpyrifos or diazinon and the blood time course of the parent compounds and metabolites was determined, as well as the time course for the cholinesterase inhibition in several tissues. Representative results and model simulations are presented in Fig. 12 and 13 for the pharmacokinetic and pharmacodynamic response in rats following comparable oral doses (50 and 100 mg/kg) of chlorpyrifos and diazinon, respectively, The overall response was fairly comparable for these two insecticides, and the models reasonably simulated both dosimetry and the dose-dependent cholinesterase inhibition. These results arc very consistent with a fairly rapid oral absorption for both insecticides and subsequent metabolism and distribution of the active oxon metabolites. Figure 14 illustrates the capability of the diazinon PBPK/PD model to simulate rodent dosimetry data from the open literature and the capability of the model to accommodate alternative exposure routes (Poet et ai, 2004). In these examples, the time course of diazinon in plasma and cholinesterase inhibition in tissues (i.e.. blood,... 

Genotypic Cellular Markers. All of the cellular markers thus far studied in detail in experimental hepatocarcinogenesis in the rat have been phenotypic markers subject to physiological modulations (e.g./ see 82 for discussion) and are thus... 

A B G Lansdown, B Sampson and P Laiqiattarakasem, Silver aids healing in the sterile wound experimental studies in the laboratory rat , it. J. Dermatol., 1997 137 728-735. 

Hertz studied the effect of vitamin A deficiency on the healing of experimental fractures in the rat. He found a delay in the absorption of the fracture hematoma. There was no effect on the inflammatory reactions on the part of the cambial layer of the periostemn, the endosteum, and the marrow, all of which appeared to pass normally through their various phases. The only direct effect of the deficiency appeared to be a poor development of cartilage in the fracture callus. 

The longitudinal effects of experimental vitamin E deficiency on visual function in the rat have been studied by Goss-Sampson et al. (1992). After 12 months of deficiency, visual function as assessed by electroretinography was absent or grossly abnormal. This was associated with... 

De Olmos J.S., Hardy H. and Heimer L. (1978). The afferent connections in the main and accessory olfactory bulb formations in the rat an experimental HRP study. J Comp Neurol 181, 213-244. 

Stradling GN, Stather JW, Gray SA, et al. 1987. Studies on the metabolic behavior of industrial actinidebearing aerosols after deposition in the rat lung An experimental basis for interpreting chest monitoring data and assessing limits on intake for workers. Hum Toxicol 6 365-375. 

Another site of action for opioids is through the regulatory actions of the central nervous system (CNS) on the immune system. Substantial evidence supports the existence of a complex, bidirectional link between the CNS and the immune system (e.g., [65]). Experimental evidence indicates that morphine s immunomodulatory effects involve central opioid receptors. An initial study by Shavit and colleagues [12] found that systemic administration of morphine, but not N-methylmorphine (a form of morphine which does not readily penetrate the blood-brain barrier), produces a naltrexone-reversible suppression of splenic natural killer cell activity in the rat. That same study showed that intracerebroventricular (icv) administration of morphine dose-dependently suppresses... 

Genetically predisposed animals or induced animal models may also be used to study and predict chemical-induced autoimmunity. In induced models, a susceptible animal strain is immunized with a mixture of an adjuvant and an autoantigen isolated from the target organ. Examples are adjuvant arthritis (AA), experimental allergic encephalomyelitis (EAE) and experimental uveitis in the Lewis strain rat. Examples of spontaneous models... 

There is no experimental evidence available to assess whether the toxicokinetics of -hexane differ between children and adults. Experiments in the rat model comparing kinetic parameters in weanling and mature animals after exposure to -hexane would be useful. These experiments should be designed to determine the concentration-time dependence (area under the curve) for blood levels of the neurotoxic /7-hcxane metabolite 2,5-hexanedione. w-Hcxanc and its metabolites cross the placenta in the rat (Bus et al. 1979) however, no preferential distribution to the fetus was observed. -Hexane has been detected, but not quantified, in human breast milk (Pellizzari et al. 1982), and a milk/blood partition coefficient of 2.10 has been determined experimentally in humans (Fisher et al. 1997). However, no pharmacokinetic experiments are available to confirm that -hexane or its metabolites are actually transferred to breast milk. Based on studies in humans, it appears unlikely that significant amounts of -hexane would be stored in human tissues at likely levels of exposure, so it is unlikely that maternal stores would be released upon pregnancy or lactation. A PBPK model is available for the transfer of M-hcxanc from milk to a nursing infant (Fisher et al. 1997) the model predicted that -hcxane intake by a nursing infant whose mother was exposed to 50 ppm at work would be well below the EPA advisory level for a 10-kg infant. However, this model cannot be validated without data on -hexane content in milk under known exposure conditions. 

Enol esters are distinct from other esters not because of a particular stability or lability toward hydrolases, but due to their hydrolysis releasing a ghost alcohol (an enol), which may immediately tautomerize to the corresponding aldehyde or ketone. A well-studied example is that of vinyl acetate (CH3-C0-0-CH=CH2), a xenobiotic of great industrial importance that, upon hydrolysis, liberates acetic acid (CH3-CO-OH) and acetaldehyde (CH3-CHO), the stable tautomer of vinyl alcohol [25], The results of two studies are compiled in Table 7.1, and demonstrate that vinyl acetate is a very good substrate of carboxylesterase (EC 3.1.1.1) but not of acetylcholinesterase (EC 3.1.1.7) or cholinesterase (EC 3.1.1.8). The presence of carboxylesterase in rat plasma but not in human plasma explains the difference between these two preparations, although the different experimental conditions in the two studies make further interpretation difficult. 

Sancho-Chust, V., Bengochea, M., Fabra-Campos, S., Casabo, V.G., Martinez-Camara, M.J., and Martin-Villodre, A., Experimental studies on the influence of surfactants on intestinal absorption of drugs. Cefadroxil as model drug and sodium lauryl sulfate as model surfactant studies in rat duodenum, Arzneim.-Forsch./Drug Res., 45, 1013, 1995. 

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