Brain penetration

Burns and Weaver [6] developed an MLR-based BBB permeability model using two experimental measures of BBB penetrability (brain/plasma ratio and the brain-uptake index) and 14 theoretically derived biophysical predictors based on Stein s hydrogen-bonding number and Randic s topological properties of the molecules. The final model accurately predicted the ability of test molecules to cross the BBB. 

Ingestion of yage in healthy volunteers yields plasma concentrations of 10 to 250 ng/mL for harmine and 1.0 to 25.0 ng/mL of harmaline (Callaway et al. 1996). The dose-concentration relationships are linear in this range. DMT shows linear dose-concentration relationships for plasma concentrations between 5 and 1000 ng/mL. Systemically administered j8-carbolines penetrate brain tissue, with relatively even distribution (Moncrieff 1989). DMT taken alone is not absorbed well orally. It may be taken as a snuff or smoked, or mixed with other plants to improve absorption. 

It has broad range of antifungal activity. It is well absorbed orally (94%). It is primarily excreted unchanged in urine. Fungicidal concentration is achieved in nail, saliva and vagina and also penetrates brain. Adverse effects include nausea, vomiting, headache, abdominal pain, diarrhea and skin rash. 

Henn, U., Surber, C., Schweitzer, A., and Bieli, E. D-Squame adhesive tapes for standardized stratum corneum stripping. In Prediction of percutaneous penetration Brain, K.R., James, V.J., and Walters, K.A. (Eds.). STS Publishing, Cardiff, pp. 477-481 (1993). 

Hahn, G.S. Strontium is a selective and potent inhibitor of sensory irritation (itch, burn and sting) and neurogenic inflammation. In Perspectives in Percutaneous Penetration Brain, K.R., Walters, K.A., Eds. STS Publishing Cardiff, 2000 Vol. 7a, 10. 

Daddona, P.E. Minimally invasive transdermal drug delivery. In Perspectives in Percutaneous Penetration Brain,... 

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. 

Florfenicol has a wide tissue distribution, similar to that reported for chloramphenicol in calves and thiamphenicol in humans (43,44). Chloramphenicol attains concentrations higher than the corresponding plasma concentrations in bile and urine, as does florfenicol (43). Unlike florfenicol, chloramphenicol concentrations in the Hver, kidney, spleen, and lungs are less than corresponding plasma concentrations. However, chloramphenicol penetrates the brain and CSF much better than does florfenicol, reaching values equal to plasma concentrations in the brain. The distribution of thiamphenicol into the kidney, urine, and muscles of humans compared with corresponding plasma concentration is similar to what was observed for florfenicol in calves (44). The penetration of thiamphenicol into the CSF is much smaller than that of florfenicol in calves. 

P-Adrenoceptor Blockers. There is no satisfactory mechanism to explain the antihypertensive activity of P-adrenoceptor blockers (see Table 1) in humans particularly after chronic treatment (228,231—233). Reductions in heart rate correlate well with decreases in blood pressure and this may be an important mechanism. Other proposed mechanisms include reduction in PRA, reduction in cardiac output, and a central action. However, pindolol produces an antihypertensive effect without lowering PRA. In long-term treatment, the cardiac output is restored despite the decrease in arterial blood pressure and total peripheral resistance. Atenolol (Table 1), which does not penetrate into the brain is an efficacious antihypertensive agent. In short-term treatment, the blood flow to most organs (except the brain) is reduced and the total peripheral resistance may increase. 

Methyldopa, through its metaboHte, CX-methyInorepinephrine formed in the brain, acts on the postsynaptic tt2-adrenoceptor in the central nervous system. It reduces the adrenergic outflow to the cardiovascular system, thereby decreasing arterial blood pressure. If the conversion of methyldopa to CX-methyl norepinephrine in the brain is prevented by a dopamine -hydroxylase inhibitor capable of penetrating into the brain, it loses its antihypertensive effects. 

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. 

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