Intestinal tissues

The filariform larva found in moist soils may be either ingested or penetrate the skin of its host. It is then carried through the circulatory system to the lungs and migrates up the respiratory tree into the digestive tract. The worms feed on intestinal tissue and blood. Some worms may persist in humans as long as nine years. Infestations cause cutaneous reactions, pulmonary lesions, intestinal ulcerations, and anemia. 

Brayden, D. J. Creed, E. Meehan, E. O Malley, K. E., Passive transepithelial diltiazem absorption across intestinal tissue leading to tight junction openings, J. Control. Rel. 38, 193-203 (1996). 

Precellular solute ionization dictates membrane permeability dependence on mucosal pH. Therefore, lumenal or cellular events that affect mucosal microclimate pH may alter the membrane transport of ionizable solutes. The mucosal microclimate pH is defined by a region in the neighborhood of the mucosal membrane in which pH is lower than in the lumenal fluid. This is the result of proton secretion by the enterocytes, for which outward diffusion is slowed by intestinal mucus. (In fact, mucosal secretion of any ion coupled with mucus-restricted diffusion will provide an ionic microclimate.) Important differences in solute transport between experimental systems may be due to differences in intestinal ions and mucus secretion. It might be anticipated that microclimate pH effects would be less pronounced in epithelial cell culture (devoid of goblet cells) transport studies than in whole intestinal tissue. 

If initial solute uptake rate is determined from intestinal tissue incubated in drug solution, uptake must be normalized for intestinal tissue weight. Alternative capacity normalizations are required for vesicular or cellular uptake of solute (see Section VII). Cellular transport parameters can be defined either in terms of kinetic rate-time constants or in terms of concentration normalized flux [Eq. (5)]. Relationships between kinetic and transport descriptions can be made on the basis of information on solute transport distances. Note that division of Eq. (11) or (12) by transport distance defines a transport resistance of reciprocal permeability (conductance). 

In situ perfusion studies assess absorption as lumenal clearance or membrane permeability and provide for isolation of solute transport at the level of the intestinal tissue. Controlled input of drug concentration, perfusion pH, osmolality, composition, and flow rate combined with intestinal region selection allow for separation of aqueous resistance and water transport effects on solute tissue permeation. This system provides for solute sampling from GI lumenal and plasma (mesenteric and systemic) compartments. A sensitive assay can separate metabolic from transport contributions. 

The use of vesicle cell membranes, isolated cells, and cell monolayers and intestinal tissue studies has provided valuable correlations with in situ and in vivo drug absorption in animals as well as correlations with drug absorption in clinical studies. Most prominent among the literature sources establishing correlations between in vitro tissue and cellular systems with drug absorption in humans are the work of Dowty and Dietsch [73], Lennernas et al. [74], and Stewart et al. [75],... 

In contrast to the protection afforded to suckling rats by Tyv-specific antibodies, passive immunization of weaned rats fails to cause expulsion of T. spiralis (Otubu et al., 1993). Nevertheless, Tyv-specific antibodies do affect the behaviour of larvae in the intestines of weaned rats in the early hours following infection in that larvae are immobile in the intestinal tissue of such rats, though immobility is reversed when the larvae moult. These findings provide further evidence that antibodies specific for Tyv interfere with the LI larva s niche. 

Electron microscopic evaluation of infected Caco-2 monolayers grown on membranes, under conditions that induced cellular polarization, prompted the conclusion that the larvae occupy the cytoplasm of cells they invade (ManWarren et al., 1997). Apical and basal plasma membranes appeared to be preserved in infected cells (Fig. 6.3). These findings reproduced the observations of Wright (1979) in his examination of intestinal tissues from infected mice. In contrast, when Li et al. (1998) performed similar experiments in HT29 monolayers grown on plastic, they concluded... 

In those infections that are associated with enteropathy (exemplified by T. spiralis), no experimental manipulation has, until recently, been able to separate enteropathy and immune expulsion - if one is abrogated, so is the other. This chapter illustrates how the two processes can be separated, and discusses implications of this for understanding immune expulsion of gut nematodes and the prospects for anti-nematode vaccines that cause no ill effects at either the initial induction of immunity or the expression of protective responses. The definition of that which consitututes enteropathy may vary between authors, but we take as our primary definition the most destructive and quantifiable changes in intestinal tissue that are associated with expulsion, villus atrophy and crypt hyperplasia. 

Some transporters such as Na+-dependent dicarboxylate transporter (NADC1), Na+-dependent bicarbonate transporter 2 (SBC2), Na+-dependent bicarbonate transporter HNBC1, several ion transporters, and channels are also expressed in the intestinal tissues [4]. 

Swaan, P. W. and J. J. Tukker. Carrier-mediated transport mechanism of foscamet (trisodium phosphono-formate hexahydrate) in rat intestinal tissue. J. Pharmacol. Exp. Ther. 1995, 272, 242-247. 

In almost all tissues where 5-HT4 receptors are present, 5-HT or any other agonists increase intracellular cAMP synthesis [12], as has been shown for hippocampus, atrium, esophagus, intestinal tissue and adrenal cortex. A number of processes can be triggered by an increase in intracellular cAMP. For instance in the intestine, an increase in intracellular cAMP concentrations following activation of 5-HT4 receptors can trigger a relaxation of the smooth muscle. However, activation of 5-HT4 receptors present on intestinal inter- and motor-neurons leads to a facilitation of acetylcholine release and, thereby, to increased contractions of intestinal smooth muscle [13]. 

With an increase in pH, there is an increased absorption of mercuric chloride [6, 7], whereas accumulation of mercury in the intestinal tissue decreases. Mercury absorption is inversely proportional to its accumulation in the tissue. An increase in water absorption due to hypotonicity or an increase in concentration of sodium ions or urea increases the mercury absorption and accumulation in the epithelial cell, without change in the intracellular distribution pattern [8], Thus, the absorption of mercury is thought to accompany the solvent drag and to be influenced by pH change in the intestinal lumen. 

The permeability of the drug substance can be determined by different approaches such as pharmacokinetic studies in humans (fraction absorbed or mass balance studies) or intestinal permeability studies (in vivo intestinal perfusion studies in humans or suitable animal models or in vitro permeation studies using excised intestinal tissue or epithelial cell culture monolayers like CaCo-2 cell line). In order to avoid misclassification of a drug subject to efflux transporters such as P-glycoprotein, functional expression of such proteins should be investigated. Low- and high-permeability model... 

When pain thresholds are determined by other methods involving, for example, the application of measurable pressure to the calf of the leg, the range of variability is several-fold.17 No one method can be expected to give a complete picture of the pain thresholds, much less the more subtle matter of pain sensitivities. Presumably tests for the pain-inducing effect of heat applied to intestinal tissue of different individuals would yield uniformly negative results, but this, of course, does not mean that individuals are uniform in their pain sensitivity. 

This theory was further explored in an anaesthetised pig model, which facilitated portal vein and bile sampling [86], However, the hepatic extraction ratio and the biliary clearance of fexofenadine were unaffected by verapamil in the pig model. The question as to why verapamil/ketoconazole increase the fraction absorbed (i.e. based on appearance kinetics) and yet the fraction absorbed estimated on the basis of disappearance kinetics (i.e. /err) for the intestinal segment appears unchanged remains to be explored and most likely reflect multiple interplay between absorptive and efflux drug transporters in the intestinal tissue. 

Ungell AL (2002) Transport studies using intestinal tissue ex vivo. In Lehr CM (Ed) Cell Culture Models of Biological Barriers. Taylor and Francis, London, pp 164-188. 

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