Precursor therapy

Precursor therapy as a means of increasing dopaminergic transmissions is limited to L-tyrosine and L-dopa. Although under basal conditions the exogenous administration of tyrosine leads to specific enhancement of noradrenergic transmission, it can enhance dopaminergic transmission in conditions of DA deficiency [Kapur and Mann 1992). Only one adequately controlled clinical trial has been reported, in which 65 patients with major depression were randomly selected to treatment for 4 weeks with oral L-tyrosine 100 mg/kg/day, imipramine 2.5 mg/kg/day, or placebo [Gelenberg et al. 1990). Tyrosine increased and imipramine decreased excretion of the main metabolite of NA, but no evidence was found that tyrosine had antidepressant activity in contrast with imipramine. 

The last approach, then, is to increase cholinergic activity by increasing the level of the substrate for choline acetyltransferase. Such precursor therapy aims to augment individual neuronal capacity. There are numerous studies in the literature designed to document the effectiveness of such dietary precursor therapy in patients with dementia. Unfortunately, the results have been generally discouraging. 

Although there is no rehable method as of this writing for induction of Ag-speciftc unresponsiveness, some degree of tolerance has been observed by use of nonspecific immunosuppressive therapy. This conclusion is supported by a decrease in the frequency of precursor T-ceUs reactive with graft HLA Ags in long-term recipients of organ transplants. 

Acetylcholine Precursors. Early efforts to treat dementia using cholinomimetics focused on choline [62-49-7] (12) supplement therapy (Fig. 3). This therapy, analogous to L-dopa [59-92-7] therapy for Parkinson s disease, is based on the hypothesis that increasing the levels of choline in the brain bolsters acetylcholine (ACh) synthesis and thereby reverses deficits in cholinergic function. In addition, because choline is a precursor of phosphatidylcholine as well as ACh, its supplementation may be neuroprotective in conditions of choline deficit (104). 

Various borate esters are chemostetilants for house flies (51). Tributyl borate, available from Eagle-Picher, Miami, Oklahoma, which is isotopically enriched in boron-10, is being used as a chemical precursor in the synthesis of pharmacologically active boron compounds suitable for boron neutron capture therapy. 

Metallacarboranes. These are used in homogeneous catalysis (222), including hydrogenation, hydrosilylation, isomerization, hydrosilanolysis, phase transfer, bum rate modifiers in gun and rocket propellants, neutron capture therapy (254), medical imaging (255), processing of radioactive waste (192), analytical reagents, and as ceramic precursors. 

Amine boranes have been examined by a variety of spectroscopic methods (24—29). The boron-substituted alpha-amino acids have been utilized in animal model studies. These compounds along with their precursors and selected derivatives have been shown to possess antineoplastic, antiarthritic, and hypolipidemic activity (30—32). The boron amino acid analogues are also being evaluated for possible utility in boron neutron capture therapy (BNCT) (33). 

Aromatic biguanides such as proguanil (181) have been found useful as antimalarial agents. Investigation of the metabolism of this class of drugs revealed that the active compound was in fact the triazine produced by oxidative cyclization onto the terminal alkyl group. The very rapid excretion of the active entity means that it cannot be used as such in therapy. Consequently, treatment usually consists in administration of either the metabolic precursor or, alternately, the triazine as some very insoluble salt to provide slow but continual release of drug. 

Nitro ilkenes derived from galdctose or other carbohydrates are converted directly into pyrroles siibsdnited v/ith such carbohydrates at the fi-posidon. They are important precursors for water-soluble porphyrins fEq. 10.29. Such kmds of porphyrins are good candidates for photodynamic therapy of cancer and have been extensively snithed. 

The fungus Streptomyces erythreus is the source of a number of structurally related macrolide antibiotics that are collectively known as the erythromycins. The erythromycins occupy a prominent position in medicine by virtue of their useful antibacterial properties. Their use in therapy over the course of the last three decades has been widespread, and has resulted in the saving of many human lives. In this chapter, we address the landmark total synthesis of erythronolide B (1), the biosynthetic precursor of all the erythromycins, by E.J. Corey and his coworkers which was carried out at Harvard in the 1970s.1... 

Amyloid precursor protein (APP) is the precursor of (3-amyloid, the main component of senile plaques found in the brain of Alzheimer patients. The production of (3-amyloid from APP to the cells from abnormal proteolytic cleavage of the amyloid precursor protein. Enzymes involved in this cleavage may be suitable targets for the therapy of Alzheimer s disease. 

The dopamine precursor l-DOPA (levodopa) is commonly used in TH treatment of the symptoms of PD. l-DOPA can be absorbed in the intestinal tract and transported across the blood-brain barrier by the large neutral amino acid (LNAA) transport system, where it taken up by dopaminergic neurons and converted into dopamine by the activity of TH. In PD treatment, peripheral AADC can be blocked by carbidopa or benserazide to increase the amount of l-DOPA reaching the brain. Selective MAO B inhibitors like deprenyl (selegiline) have also been effectively used with l-DOPA therapy to reduce the metabolism of dopamine. Recently, potent and selective nitrocatechol-type COMT inhibitors such as entacapone and tolcapone have been shown to be clinically effective in improving the bioavailability of l-DOPA and potentiating its effectiveness in the treatment of PD. 

These symptoms are alleviated by administering levodopa (L-dopa), a precursor for dopamine. L-dopa is taken up by the axon terminals of dopaminergic neurons and used to form dopamine. Interestingly, in some patients, a side effect of dopamine replacement therapy is the development of symptoms characteristic of schizophrenia. (Recall that this mental disorder is caused by overactive dopaminergic neurons.) On the other hand, drugs used to treat schizophrenia — dopamine receptor antagonists — may elicit symptoms of Parkinson s disease. 

Precise placement of metal complexing sites within the infrastructure of a cascade molecule is of importance from a variety of perspectives. In the construction of the above noted Micellane family (cf. Sect. 3.1), we reported the construction of dendrimers with four alkyne moieties at sites equidistant from each other in the interior (17, Fig. 8) [60]. These were treated with decaborane (B10H14) to afford 1,2-dicarba-closo-dodecaboranes (o-carboranes) [71]. Rendering boron clusters soluble in water is of interest because of their use in cancer treatment by Boron Neutron Cancer Therapy. First and second generation water-soluble dendrimers containing four and twelve precisely located boron cluster sites, respectively, were synthesized (e.g., 18). These water soluble dendrimers and their precursors were characterized by 13C-, and nB-NMR spectroscopy (Fig. 8). 

The chapters cover the following areas (i) use of coordination complexes in all types of catalysis (Chapters 1-11) (ii) applications related to the optical properties of coordination complexes, which covers fields as diverse as solar cells, nonlinear optics, display devices, pigments and dyes, and optical data storage (Chapters 12-16) (iii) hydrometallurgical extraction (Chapter 17) (iv) medicinal and biomedical applications of coordination complexes, including both imaging and therapy (Chapters 18-22) and (v) use of coordination complexes as precursors to semiconductor films and nanoparticles (Chapter 23). As such, the material in this volume ranges from solid-state physics to biochemistry. 

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