Blood-brain barrier crossing agents

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. 

As the rate-limiting enzyme, tyrosine hydroxylase is regulated in a variety of ways. The most important mechanism involves feedback inhibition by the catecholamines, which compete with the enzyme for the pteridine cofactor. Catecholamines cannot cross the blood-brain barrier hence, in the brain they must be synthesized locally. In certain central nervous system diseases (eg, Parkinson s disease), there is a local deficiency of dopamine synthesis. L-Dopa, the precursor of dopamine, readily crosses the blood-brain barrier and so is an important agent in the treatment of Parkinson s disease. 

CNS prophylaxis is necessary in any treatment regimen for ALL At diagnosis, the incidence of CNS disease is less than 10%, but it increases to 50% to 75% after 1 year in patients without CNS prophylaxisA The justification for CNS prohylaxis is based on two clinical findings. First, many chemotherapeutic agents do not cross the blood-brain barrier easily. Second, the CNS is a frequent sanctuary for leukemia, and undetectable leukemic cells are present in the CNS in many patients at the time of diagnosis.6... 

Some quinolizine derivatives are employed as drugs. One of them is flumequine 280, a member of the quinolone family of antibacterial agents. Cytisine 9 is a ligand of the nicotinic acetylcholine receptor that acts primarily as a cholinomimetic at the ganglionar level, being used as a respiratory stimulant in some countries. Cytisine analogues with improved ability to cross the blood-brain barrier have also been developed <1999FA438>. 

Bufotenine has been found to be behaviorally inactive, or only weakly active, in most animal studies, although at 15 mg/kg, it did produce the head-twitch resonse in mice (43). It was also behaviorally active in experiments in which the blood-brain barrier was bypassed (78). Acylation of the polar hydroxy group of bufotenine increases its lipid solubility (65,74) and apparently enhances its ability to cross the blood-brain barrier (64). For example, O-acetylbufotenine (5-acetoxy-N,N-dimethyltryptamine 54) disrupted conditioned avoidance behavior in rodents (65) and produced tremorigenic activity similar to that elicited by DMT (37) or 5-OMeDMT (59) when administered to mice (64). In this latter study, a comparison of brain levels of bufotenine after administration of O-acetylbufotenine with those of DMT and 5-OMeDMT revealed bufotenine to be the most active of the three agents, based on brain concentration. The pivaloyl ester of bufotenine also appears to possess behavioral activity, since stimulus generalization was observed when this agent was administered to animals trained to discriminate 5-OMeDMT from saline (74). 

The lipophilic complex 99mTc(IV)-L,L-ECD (62) with a deprotonated L,L-ethylcysteine dimer as ligand, is clinically used as a cerebral perfusion imaging agent. It crosses the blood-brain barrier and... 

Flavonoids in the diet have been widely promoted as important antioxidant contributors. Their neuroprotective properties, because of this effect, have been demonstrated by several workers. However, they have also been demonstrated to have MAOI activity and this has been proposed as part of the explanation of the use of the common herb, St Johns Wort, Hypericum perforatum L., as an antidepressant. This dual role has now been proposed for a variety of flavonoids, such as kaempferol (22) from the leaves of Ginkgo biloba L., a widely used herbal product which has been suggested as a preventative agent against neurodegeneration. Quercetin (23), similarly, has also shown to inhibit MAO-B " and reverse the effects of induced catalepsy, which mimics the bradykinesia associated with PD. Tangeretin (24) also inhibits MAO-B and crosses the blood brain barrier in a rat model. 

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 agents, 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),... 

Levodopa, the metabolic precursor of dopamine, is the most effective agent in the treatment of Parkinson s disease but not for drug-induced Parkinsonism. Oral levodopa is absorbed by an active transport system for aromatic amino acids. Levodopa has a short elimination half-life of 1-3 hours. Transport over the blood-brain barrier is also mediated by an active process. In the brain levodopa is converted to dopamine by decarboxylation and both its therapeutic and adverse effects are mediated by dopamine. Either re-uptake of dopamine takes place or it is metabolized, mainly by monoamine oxidases. The isoenzyme monoamine oxidase B (MAO-B) is responsible for the majority of oxidative metabolism of dopamine in the striatum. As considerable peripheral conversion of levodopa to dopamine takes place large doses of the drug are needed if given alone. Such doses are associated with a high rate of side effects, especially nausea and vomiting but also cardiovascular adverse reactions. Peripheral dopa decarboxylase inhibitors like carbidopa or benserazide do not cross the blood-brain barrier and therefore only interfere with levodopa decarboxylation in the periphery. The combined treatment with levodopa with a peripheral decarboxylase inhibitor considerably decreases oral levodopa doses. However it should be realized that neuropsychiatric complications are not prevented by decarboxylase inhibitors as even with lower doses relatively more levodopa becomes available in the brain. 

The aminopyridines (4-aminopyridine 3,4-diaminopyri-dine) accelerate spontaneous exocytosis at central and peripheral synapses. There is also an increase in the number of transmitter quanta released by a nerve action potential. This is probably the result of increased Ca++ inflow at the terminals due to a reduction of K+ conductance and prolongation of the nerve action potential. Muscle strength is increased in patients with the Lambert-Eaton myasthenic syndrome and in others poisoned with botuUnum E toxin (discussed later). Improvement in uncontrolled spasms, muscle tone, and pulmonary function is noted in patients with multiple sclerosis or long-standing spinal cord damage. Side effects that limit clinical utility include convulsions, restlessness, insomnia, and elevated blood pressure. Of the two agents, 3,4-diaminopyridine is the more potent and crosses the blood-brain barrier less readily. 

Mechanism of Action An alkylating agent that inhibits DNAand RNA protein synthesis by cross-linking with DNA and RNA strands, preventing cell growth. Cell cycle-phase nonspedflc. Therapeutic Effect Potent immunosuppressant. Pharmacokinetics Well absorbed from the G1 tract. Protein binding low. Crosses the blood-brain barrier. Metabolized in the liver to active metabolites. Primarily excreted in urine. Removed by hemodialysis. Half-life 3-12 hr. 

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