Physiological Barriers

Overall, the pattern of perfnsion in human tumours is non-uniform, and hnman tnmours contain well-perfused, rapidly growing regions, as well as poorly-perfnsed, often necrotic, regions. So the first obstacle to effective systemic treatments is the heterogenidty of the distribution of areas of growth within the tnmonr. 

Diffusion, particularly of macromolecules, plays a minor role in transport across this barrier. Convection due to leaky blood vessels, on the other hand, should enhance delivery yet the movement of drugs and macromolecnles into the interstitinm is often surprisingly limited. This is generally attributed to a diminished hydrostatic pressure gradient between the vascular compartment and the interstitium, which is explained by decreased vascnlar pressure or increased interstitial pressure, or both. 

There are several consequences of these anomalies in pressnre gradients for the delivery and distribution of drugs and macromolecules within the tnmonr interstitinm. First, high interstitial pressures mean that the central regions of the tnmonr, already poorly perfused, demonstrate low or non-existent convective flow into the interstitinm. Fnrthermore, interstitial convective flow will tend to radiate outward from the centre, towards the periphery and regions of lower interstitial pressure. Therefore, only small amonnts of drngs or macromolecules will reach cells in the centre of the tumour. At the tumour periphery, where convective transfer across the blood vessel wall might take place, further movement towards the centre of the tumour will be impeded by bulk flow in the opposite direction. 

In summary, in solid tumours the laws of hydrodynamics and transport of solutes mitigate against the successful delivery of drugs and macromolecules to tumour cells. 

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Design of a dmg deflvery device is dictated by the properties of the physiological barrier, the effective plasma levels, and the total dosage. 

The blood-brain barrier (BBB) forms a physiological barrier between the central nervous system and the blood circulation. It consists of glial cells and a special species of endothelial cells, which form tight junctions between each other thereby inhibiting paracellular transport. In addition, the endothelial cells of the BBB express a variety of ABC-transporters to protect the brain tissue against toxic metabolites and xenobiotics. The BBB is permeable to water, glucose, sodium chloride and non-ionised lipid-soluble molecules but large molecules such as peptides as well as many polar substances do not readily permeate the battier. 

Physiological barriers limiting the passage of phama-cological compounds within the body. 

Skin has also been stored for use as a covering of wounds in bum victims. Preserved skin (allograft) serves as a mechanical and physiological barrier decreases loss of water, protein, and heat and provides strata for the regeneration of viable skin by the victim. The storage medium is usually a tissue culture solution and the skin is wrapped up in gauze that is soaked in this solution and kept for about one week. 

Mesobilirubin-XIIIa labelled with 13C in two propionic acid 13COOH groups, 90, has been synthesized75 in 11% overall yield from K13CN in 10 steps shown in equation 34. 90, a model compound not found in nature, is to be used to study the conformation of bilirubin in solution76 or when bound to proteins or in membranes to understand its ability to cross several selective physiological barriers such as placenta and blood-brain barrier... 

A systemic effect is an effect that is normally observed distantly from the site of first contact, i.e., after the substance has passed through a physiological barrier (mucous membrane of the gastrointestinal tract or of the respiratory tract, or the skin) and becomes systemically available. It should be noted, however, that toxic effects on surface epithelia may reflect indirect effects as a consequence of systemic toxicity or secondary to systemic distribution of the substance or its active metabolite(s). 

Poor absorption of small-molecule drugs across such external barriers has been presumed to be due to the drugs physio-chemical properties, which can be systematically modified by medicinal chemists, and the nature of the physiological barrier, which can sometimes be transiently altered. To overcome physiological barriers, scientists have studied a series of synthetic and natural compounds exhibiting absorption enhancement properties. These molecules, included in the dosage formulation to enhance absorption, are... 

Experimental Models of Physiological Barriers to Nasal Drug Absorption.366... 

Relative Contribution of Physiological Barriers to the Absorption of Drugs via the Nasal Cavity... 

FIGURE 19.3 Drugs for administration via the nasal route have specific formulation requirements which, depending on their ability to overcome physiological barriers, may require an absorptionenhancing strategy. 

EXPERIMENTAL MODELS OF PHYSIOLOGICAL BARRIERS TO NASAL DRUG ABSORPTION... 

The challenge for the future is not to let physiological barriers prevent the realization of the unique opportunities offered by nasal drug delivery for safe and effective drug therapy. 

As illustrated in the previous chapter, the human body can be exposed to a variety of toxicants that may be present in various environmental media such as air, soil, water, or food. However, just simply being exposed to these hazardous chemicals does not necessarily translate into a toxicological response. The mammalian body has several inherent defense mechanisms and membrane barriers that tend to prevent the entry or absorption and distribution of these toxicants once an exposure event has occurred. However, if the toxicant is readily absorbed into the body, there are still other anatomical and physiological barriers that may prevent distribution to the target tissue to elicit a toxic response. As the toxicological response is often related to the exposed dose, interactions between the toxicant and the body s barriers and defense mechanisms will have an effect on toxicant movement in the body, and ultimately modulate the rate and extent of toxicant absorption and distribution to the target tissue. 

Several pharmaceutical and physiological barriers must be overcome for the successful pulmonary delivery of peptide and protein drugs [3], For example, many of these macromolecular drugs have relatively low permeability when they are administered without any absorption enhancers [4], Furthermore, the clinical toxicology of peptides/proteins in the lung, especially for chronic disease, should be of some concern [6], Therefore, cost-benefit ratios should be evaluated in the... 

Jain, R. K. (1990). Physiological barriers to delivery of monoclonal antibodies and other macromolecules in tumors. Cancer Res. 50, 814s-819s. 

Kovalevsky (1979, 1987) has used the term barrier-free biosamples for those plants that do not have an exclusion mechanism toward a particular element whereas those plants that have a limiting value of accumulation in the aerial parts are said to have a physiological barrier which operates to exclude elements from the aerial parts. The situation is illustrated in Fig. 8-4. Of these, barrier-free and high-barrier biosamples would be suitable for biogeochemical exploration. All these types are subdivisions of Baker s (1981) accumulators, and what is described as a physical barrier is more likely to be the filling of the available sites. Brooks (1993) has pointed out that Kovalevsky s nomenclature is confusing. 

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