Blood -brain barrier

The movement of substances between the blood and the extracellular fluid surrounding the cells in most tissues of the body occurs very readily. This exchange takes place at the level of the capillaries, the smallest blood vessels in the cardiovascular system whose walls are formed by a single layer of endothelial cells. Lipid-soluble substances are able to move across this layer of endothelial cells at any point because they can move directly through the plasma membrane by passing between the phospholipid molecules of the bilayer. The movement of water-soluble substances is limited to the multiple pores found between the cells however, it also takes place rapidly and efficiently. 

There are several benefits to the presence of this barrier. It protects the neurons of the CNS from fluctuations in plasma components. For example, a change in the potassium ion concentration could alter neuronal function due to its effect on membrane potential. Second, the barrier minimizes the possibility that harmful blood-borne substances reach the CNS. Finally, it prevents any blood-borne substances that could function as neurotransmitters from reaching the brain and causing inappropriate neuronal stimulation. 

Pharmacy application antihistamines and the blood-brain barrier 

The membrane separating the extracellular space of the brain from the intravascular space is somewhat less permeable and is generally considered to be comparable to cellular membranes (with respect to permeability). Thus, many molecules such as pertech-netate ion which are distributed in the extracellular fluid, are unable to penetrate the blood brain barrier. Penetration of cellular membranes is also related to the size of the molecule, however, in this case the pore size is much smaller, being permeable to only simple ions, such as Na , Cl , etc. Due to the small size of the pores in cell membranes, it is unlikely that any Tc-complex will be able to diffuse through the pore. Thus, most of these complexes will be limited to an extracellular 

ACS Symposium Series American Chemical Society Washington, DC, 1980. 

1) Pertechnetate, which is actively transported (as an iodide analog) into the thyroid. 

2) Hepatobiliary agents, such as 33 Tc(HlDA)2 which is actively accumulated by hepatocytes. 

Many attempts have been made to design labeled compounds 

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Concerning the distribution of a drug, models have been published for log BB blood/brain partition coefficient) for CNS-active drugs (CNS, central nervous system) crossing the blood-brain barrier (BBB) [38-45] and binding to human serum albumin (HSA) [46]. 

Specific barriers may serve to limit dmg distribution. The placental barrier is of obvious importance to dmg action in the fetus. Dmg transfers across the placenta primarily by Hpid solubiHty. Hence, this barrier is not particularly restrictive. Similarly, the Hpid solubiHty of a dmg is a primary deterrninant in access to the brain and cerebrospinal fluid. Generally, hydrophilic or charged dmgs can also penetrate to these latter areas, but the result is slow and incomplete. The blood brain barrier is composed of cells having tight junctions which are much less permeable to solutes than are the endotheHal cells of other tissues. 

In other applications of CT, orally administered barium sulfate or a water-soluble iodinated CM is used to opacify the GI tract. Xenon, atomic number 54, exhibits similar x-ray absorption properties to those of iodine. It rapidly diffuses across the blood brain barrier after inhalation to saturate different tissues of brain as a function of its lipid solubility. In preliminary investigations (99), xenon gas inhalation prior to brain CT has provided useful information for evaluations of local cerebral blood flow and cerebral tissue abnormalities. Xenon exhibits an anesthetic effect at high concentrations but otherwise is free of physiological effects because of its nonreactive nature. 

Certain neutral technetium complexes can be used to image cerebral perfusion (Fig. 4). Those in Figure 4a and 4b have been approved for clinical use. Two other complexes (Fig. 4c and 4d) were tested in early clinical trials, but were not developed further. An effective cerebral perfusion agent must first cross the blood brain barrier and then be retained for the period necessary for image acquisition. Tc-bicisate is retained owing to a stereospecific hydrolysis in brain tissue of one of the ester groups to form the anionic complex TcO(ECD) , which does not cross the barrier. This mechanism of retention is termed metaboHc trapping. 

Toxic effects of propranolol are related to its blocking P-adrenoceptor blocking actions. They include cardiac failure, hypotension, hypoglycemia, and bronchospasm. Propranolol is lipophilic and crosses the blood—brain barrier. Complaints of fatigue, lethargy, mental depression, nightmares, hallucinations, and insomnia have been reported. GI side effects include nausea, vomiting, diarrhea, and constipation (1,2). 

Blood-brain barrier permeation of 7, among other drugs, was predicted from its three-dimensional molecular structure by a computational method (0OJMC2204). The combination of molecular topological methods using 137 quinolones, including 7 provided an excellent tool for the design of new... 

A number of quaternary amines are effective at modulating nerve transmissions. They often have the disadvantage of being relatively nonselective and so possess numerous sideeffects. This contrasts with the advantage that they do not cross the blood-brain barrier and so have no central sideeffects. Clo-... 

The sedation side effect commonly observed on administration of classical antihistaminic drugs has been attributed in part to the ease with which many of these compounds cross the blood brain barrier. There have been developed recently a series of agoits, for example, terfenadine (198), which cause reduced sedation by virtue of decreased penetration into the CNS. This is achieved by making them more hydrophilic. Synthesis of a related compound, ebastine (197),... 

Cancer chemothCTapeutic agents as a rule poorly penetrate the blood brain barrier. Brain tumors are thus not readily treatable by chemotherapy. Diaziquone (at one time known as AZQ) is an exception to this generalization. Treatment of chloranil (213) with the anion from urethane gives intermediate 214, probably by an addition elimination scheme. Displacement of the remaining halogen with aziridine yields diaziquone (215) [.55J. 

Demethylation of the tricyclic antihistamine 9, with cyanogen bromide gives the secondary amine 10 acylation of that intermediate with ethyl chloroformate affords the nonsedating H-1 antihistaminic agent loratidine (11) [3], It is of interest that this compound does not contain the zwitterionic funcrion which is thought to prevent passage through the blood-brain barrier, characteristic of this class of compounds. 

Temozolomide crosses the blood brain barrier and can be used for the treatment of brain tumors (e.g., glioblastoma multiforme). The most common side effects are nausea and vomiting. 

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